CN105153150A - Pyridinium type JAK (just another kinase) inhibitors as well as preparation method and application thereof - Google Patents
Pyridinium type JAK (just another kinase) inhibitors as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN105153150A CN105153150A CN201510501161.3A CN201510501161A CN105153150A CN 105153150 A CN105153150 A CN 105153150A CN 201510501161 A CN201510501161 A CN 201510501161A CN 105153150 A CN105153150 A CN 105153150A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- jak
- lithium
- inhibitors
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 108091000080 Phosphotransferase Proteins 0.000 title abstract description 10
- 102000020233 phosphotransferase Human genes 0.000 title abstract description 10
- 239000003112 inhibitor Substances 0.000 title abstract 2
- JUJWROOIHBZHMG-UHFFFAOYSA-O pyridinium Chemical compound C1=CC=[NH+]C=C1 JUJWROOIHBZHMG-UHFFFAOYSA-O 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 36
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 229940122245 Janus kinase inhibitor Drugs 0.000 claims abstract description 8
- 206010052779 Transplant rejections Diseases 0.000 claims abstract description 7
- 208000026935 allergic disease Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 230000002757 inflammatory effect Effects 0.000 claims abstract description 7
- 238000000034 method Methods 0.000 claims description 10
- 201000010099 disease Diseases 0.000 claims description 9
- 230000005784 autoimmunity Effects 0.000 claims description 7
- 230000036039 immunity Effects 0.000 claims description 7
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 6
- 230000008569 process Effects 0.000 claims description 6
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 3
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 238000005650 intramolecular substitution reaction Methods 0.000 claims description 2
- CCZVEWRRAVASGL-UHFFFAOYSA-N lithium;2-methanidylpropane Chemical compound [Li+].CC(C)[CH2-] CCZVEWRRAVASGL-UHFFFAOYSA-N 0.000 claims description 2
- UBJFKNSINUCEAL-UHFFFAOYSA-N lithium;2-methylpropane Chemical compound [Li+].C[C-](C)C UBJFKNSINUCEAL-UHFFFAOYSA-N 0.000 claims description 2
- OVEHNNQXLPJPPL-UHFFFAOYSA-N lithium;n-propan-2-ylpropan-2-amine Chemical compound [Li].CC(C)NC(C)C OVEHNNQXLPJPPL-UHFFFAOYSA-N 0.000 claims description 2
- NHKJPPKXDNZFBJ-UHFFFAOYSA-N phenyllithium Chemical compound [Li]C1=CC=CC=C1 NHKJPPKXDNZFBJ-UHFFFAOYSA-N 0.000 claims description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 abstract description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 abstract 1
- 208000023275 Autoimmune disease Diseases 0.000 abstract 1
- 230000001363 autoimmune Effects 0.000 abstract 1
- 229940079593 drug Drugs 0.000 abstract 1
- 208000026278 immune system disease Diseases 0.000 abstract 1
- 208000027866 inflammatory disease Diseases 0.000 abstract 1
- 101000934996 Homo sapiens Tyrosine-protein kinase JAK3 Proteins 0.000 description 11
- 102100025387 Tyrosine-protein kinase JAK3 Human genes 0.000 description 11
- 238000003756 stirring Methods 0.000 description 11
- 108010024121 Janus Kinases Proteins 0.000 description 8
- 102000015617 Janus Kinases Human genes 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 8
- 238000001035 drying Methods 0.000 description 7
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 7
- 101000997832 Homo sapiens Tyrosine-protein kinase JAK2 Proteins 0.000 description 6
- 102100033444 Tyrosine-protein kinase JAK2 Human genes 0.000 description 6
- 230000026731 phosphorylation Effects 0.000 description 6
- 238000006366 phosphorylation reaction Methods 0.000 description 6
- 101000997835 Homo sapiens Tyrosine-protein kinase JAK1 Proteins 0.000 description 5
- 102000001253 Protein Kinase Human genes 0.000 description 5
- 102100033438 Tyrosine-protein kinase JAK1 Human genes 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 5
- 108060006633 protein kinase Proteins 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 4
- 108090000790 Enzymes Proteins 0.000 description 4
- 229940123241 Janus kinase 3 inhibitor Drugs 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 210000004027 cell Anatomy 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- -1 pyrimidine compound Chemical class 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 108090000695 Cytokines Proteins 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 3
- 239000012299 nitrogen atmosphere Substances 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 230000000452 restraining effect Effects 0.000 description 3
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 description 2
- 0 CC(C)Oc1ccc(CN(CC2)c3*2ccc(C)c3)cc1 Chemical compound CC(C)Oc1ccc(CN(CC2)c3*2ccc(C)c3)cc1 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102100020903 Ezrin Human genes 0.000 description 2
- 102000042838 JAK family Human genes 0.000 description 2
- 108091082332 JAK family Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 208000035490 Megakaryoblastic Acute Leukemia Diseases 0.000 description 2
- 102100027869 Moesin Human genes 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 208000013593 acute megakaryoblastic leukemia Diseases 0.000 description 2
- 208000020700 acute megakaryocytic leukemia Diseases 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 108010055671 ezrin Proteins 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 230000014509 gene expression Effects 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 239000003018 immunosuppressive agent Substances 0.000 description 2
- 238000011813 knockout mouse model Methods 0.000 description 2
- 231100000518 lethal Toxicity 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- DLEDOFVPSDKWEF-UHFFFAOYSA-N lithium butane Chemical compound [Li+].CCC[CH2-] DLEDOFVPSDKWEF-UHFFFAOYSA-N 0.000 description 2
- 108010071525 moesin Proteins 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 108020003175 receptors Proteins 0.000 description 2
- 102000005962 receptors Human genes 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000010898 silica gel chromatography Methods 0.000 description 2
- 238000000967 suction filtration Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 238000010792 warming Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- MKXVEGSWSZWPPF-DJFIPANJSA-N CCC/C=C(/CN(CC1)C2=[O]1(C)C=CC(C)=C=C2)\C=C/COC Chemical compound CCC/C=C(/CN(CC1)C2=[O]1(C)C=CC(C)=C=C2)\C=C/COC MKXVEGSWSZWPPF-DJFIPANJSA-N 0.000 description 1
- 102000019034 Chemokines Human genes 0.000 description 1
- 108010012236 Chemokines Proteins 0.000 description 1
- 238000002965 ELISA Methods 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 102000009465 Growth Factor Receptors Human genes 0.000 description 1
- 108010009202 Growth Factor Receptors Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 108090000723 Insulin-Like Growth Factor I Proteins 0.000 description 1
- 101150009057 JAK2 gene Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 101710196266 Protein 4.1 Proteins 0.000 description 1
- 102100031952 Protein 4.1 Human genes 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102100022127 Radixin Human genes 0.000 description 1
- 108091005682 Receptor kinases Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- 102000013275 Somatomedins Human genes 0.000 description 1
- 235000018936 Vitellaria paradoxa Nutrition 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 210000000436 anus Anatomy 0.000 description 1
- 230000005540 biological transmission Effects 0.000 description 1
- 229960002685 biotin Drugs 0.000 description 1
- 239000011616 biotin Substances 0.000 description 1
- 235000020958 biotin Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 230000020411 cell activation Effects 0.000 description 1
- 230000011712 cell development Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000036978 cell physiology Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 102000003675 cytokine receptors Human genes 0.000 description 1
- 108010057085 cytokine receptors Proteins 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 238000013016 damping Methods 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 210000003527 eukaryotic cell Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000007667 floating Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 108020001507 fusion proteins Proteins 0.000 description 1
- 102000037865 fusion proteins Human genes 0.000 description 1
- 210000003958 hematopoietic stem cell Anatomy 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004968 inflammatory condition Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 230000004068 intracellular signaling Effects 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 210000001161 mammalian embryo Anatomy 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003032 molecular docking Methods 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 102000037979 non-receptor tyrosine kinases Human genes 0.000 description 1
- 108091008046 non-receptor tyrosine kinases Proteins 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 230000009984 peri-natal effect Effects 0.000 description 1
- DCWXELXMIBXGTH-UHFFFAOYSA-N phosphotyrosine Chemical compound OC(=O)C(N)CC1=CC=C(OP(O)(O)=O)C=C1 DCWXELXMIBXGTH-UHFFFAOYSA-N 0.000 description 1
- 238000004886 process control Methods 0.000 description 1
- 150000003222 pyridines Chemical class 0.000 description 1
- 229940083082 pyrimidine derivative acting on arteriolar smooth muscle Drugs 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 108010048484 radixin Proteins 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000000341 threoninyl group Chemical group [H]OC([H])(C([H])([H])[H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 238000002877 time resolved fluorescence resonance energy transfer Methods 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 125000001493 tyrosinyl group Chemical group [H]OC1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 1
- 241000701447 unidentified baculovirus Species 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to JAK (just another kinase) inhibitors containing pyridinium structures, a preparation method of the JAK inhibitors and an application of the JAK inhibitors in preparation of drugs for treating immune, inflammatory, autoimmune or allergic diseases, or transplant rejection diseases and the like. The compound has a general formula shown in the specification, wherein R is selected from C1-C3 alkyl.
Description
Technical field
The present invention relates to immunity, inflammatory, autoimmunity or allergic disease, or the pharmaceutical field of the disease such as transplant rejection.Specifically, the present invention relates to JAK inhibitor, its preparation method of the medicative class of above-mentioned disease tool containing pyridinium salt structure, and the purposes in pharmacy.
Background technology
The phosphorylation of kinase catalytic protein, lipid, sugar, nucleosides and other cell metabolites and eukaryotic cell physiology all in play a crucial role.Especially, protein kinase and lipid kinase participate in intracellular signaling process, and this process control is to extracellular instrumentality or irritate the activation of the cell that thing (as somatomedin, cytokine or chemokine) responds, growth, differentiation and survival.Usually, protein kinase is divided into two classes, the protein kinase of preferential phosphorylation tyrosine residues and the protein kinase of preferential phosphorylation Serine and/or threonine residues.Tyrosylprotein kinase comprises transmembrane growth factor receptor if EGF-R ELISA (EGFR) and cytosolic non-receptor kinases are as Janus kinases (JAK).High protein kinase activity relates to numerous disease inadequately, comprises cancer, metabolic trouble, autoimmunity or inflammatory conditions.This effect can cause because of the controlling mechanism fault that produces of the sudden change of enzyme, overexpression or inappropriate activation directly or indirectly.In all these examples, expect that kinase whose Selective depression has useful effect.
Oneself is nonreceptor tyrosine kinase through becoming a class kinases of current drug development focus] anus kinases (JAK) family.In Mammals, this family has four members, JAK1, JAK2, JAK3 and Tyrosylprotein kinase 2 (TYK2).Each protein has kinases territory and catalytically inactive pseudokinase territory.JAK protein (is with 4.1 albumen (Band-4.1), ezrin (ezrin), radicin (radixin) by its N-terminal FERM, moesin (moesin) territory is attached on cytokine receptor.After cytokine and its receptors bind, activate JAKs and make receptor phosphorylation, thus produce docking site (the dockingsites) (Yamaoka etc. being used for signal transduction molecule (especially the member of signal pick-off and transcription activator (Stat) family), 2004, TheJanuskinases (jaks) .GenomeBiology, 5 (12), p253).In Mammals, JAK1, JAK2 and TYK2 generally express.On the contrary, the expression of JAK3 is mainly in hematopoietic cell and by the altitude mixture control (Musso etc., 1995,181 (4), p1425-1431) of cell development and activation.The research of JAK mono-deficient cells system and gene target mouse oneself through disclosing basic in cytokine signaling conduction of JAKs, unduplicated function.JAK1 knock-out mice display lethal phenotype perinatal period, may with the effects on neural system relevant (Rodig etc., 1998, Ce1l, 93 (3): 373-383) stoping its lactation.Due to Dyserythropoiesis, the deletion of JAK2 gene causes producing embryonic lethal (Neubauer etc., 1998, Ce1l, 93 (3), 397-409) when embryo the 12.5th day.Enjoyably, JAK3 defect is identified first in the people suffering from autosomal recessive severe combined immunodeficient (SCID) (Macchi etc., 1995, Nature, 377 (6544): 65-68).JAK3 knock-out mice also shows SCID but does not show non-immunity defect, show that JAK3 inhibitor will have limited effect in vivo as immunosuppressor and therefore become for immunosuppressant promising medicine (Papageorgiou and Wikman, 2004, TrendsinPharmacologicalSciences, 25 (11), 558-562).In acute megakaryoblastic leukemia (AMKL) patient, oneself is through observing the activated mutant (Walters etc., 2006, CancerCell, 10 (1), 65-75) of JAK3.Ba/F3 cells switch can be factor independent growth and in mouse model, induce the feature of megakaryoblastic leukemia by these mutant forms of JAK3.
Relevant disease and illness is suppressed to be further described in such as WO01/42246 and WO2008/060301 with JAK3.In document, oneself some JAK3 inhibitor of report can be used for medical field (O ' Shea etc., 2004, Nat.Rev.DrugDiscov.3 (7): 555-564).It is reported, effective JAK3 inhibitor (CP-690,550) at the animal model (Changelian etc. of organ transplantation, 2003, Science, 302 (5646), 875-888) with clinical trial (reference: Pesu etc., 2008, Immunol.Rev.223,132-142) middle display effect.The pyrimidine compound that fluorine replaces is described in WO-A2010/118986 as JAK3 inhibitor.Heterocyclic radical Pyrazolopyrimidine analogs is described in WO-A2011/048082 as JAK inhibitor.WO-A2008/129380 relates to the sulfone amide derivative being used for the treatment of abnormal cell growth.WO-A2006/117560 and JournalofMolecularGraphicsandModelling (29) 2010,309-320 describes the pyrimidine of pyrazolyl amino replacement and the purposes in Therapeutic cancer thereof.EP1054004A1 describes pyrimidine derivatives and the purposes in inflammation thereof.
The invention discloses a class containing the JAK inhibitor of pyridinium salt structure, these compounds can be used for preparation treatment immunity, inflammatory, autoimmunity or allergic disease, or the medicine of the disease such as transplant rejection.
Summary of the invention
An object of the present invention is to provide a kind of JAK inhibitor with the excellent activity of general formula I.
Another object of the present invention is to provide the method that preparation has the compound of general formula I.
Another object of the present invention is to provide compound containing general formula I at treatment immunity, inflammatory, autoimmunity or allergic disease, or the application of the disease aspect such as transplant rejection.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R is selected from C
1-C
3alkyl.
The compound of preferred formula I has following structure,
Compound of Formula I of the present invention can be synthesized by following route:
Compound II per first uses highly basic process, then reacts with compound III, obtains compound IV; Compound IV first uses highly basic process, then reacts with 1,2-ethylene dichloride, obtains compound V; There is Intramolecular substitution reaction in compound V, obtains Compound I under heating; Wherein, described highly basic is selected from n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, phenyl lithium, lithium diisopropylamine, described X=Cl, Br, I, and the definition of R as previously mentioned.
Compound of Formula I of the present invention has JAK restraining effect, can be used as effective constituent for the preparation of immunity, inflammatory, autoimmunity or allergic disease, or the disease therapeuticing medicine such as transplant rejection.The activity of compound of Formula I of the present invention is verified by the inhibition test of external JAK.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-700mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
the synthesis of embodiment 1 Compound I-1
Steps A. the synthesis of compound IV-1
Compound II per-1 (1.08g, 10mmol) be dissolved in the THF of 10mL drying, stir,-20 DEG C are cooled in nitrogen atmosphere, hexane solution (the 6.25mL of the n-BuLi of 1.6M is then slowly dripped with syringe, 10mmol), after dropwising, reaction mixture continues stirring 1 hour at such a temperature.Slowly drip with syringe the solution that THF that III-1 (2.01g, 10mmol) is dissolved in 3mL drying makes again, after dropwising, reaction mixture stirs half an hour at such a temperature, is then warming up to room temperature and stirs and spend the night.Reaction mixture carefully pours in 200mL frozen water, stirs, with 50mL × 3CH
2cl
2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound IV-1, white solid, ESI-MS, m/z=229 ([M+H]
+).The synthesis of step B. compound V-1
Compound IV-1 (1.37g, 6mmol) be dissolved in the THF of 10mL drying, stir,-20 DEG C are cooled in nitrogen atmosphere, hexane solution (the 3.75mL of the n-BuLi of 1.6M is then slowly dripped with syringe, 6mmol), after dropwising, reaction mixture continues stirring 1 hour at such a temperature.Slowly drip with syringe the solution that THF that 1,2-ethylene dichloride (0.99g, 10mmol) is dissolved in 3mL drying makes again, after dropwising, reaction mixture stirs half an hour at such a temperature, is then warming up to room temperature and stirs and spend the night.Reaction mixture carefully pours in 200mL frozen water, stirs, with 50mL × 3CH
2cl
2extraction, merges extraction phase, uses salt water washing, anhydrous sodium sulfate drying.Suction filtration removing siccative, filtrate is evaporate to dryness on a rotary evaporator, and resistates uses purification by silica gel column chromatography, obtains compound V-1, white solid, ESI-MS, m/z=291 ([M+H]
+).
The synthesis of step C. Compound I-1
Compound V-1 (0.87g, 3mmol) is dissolved in the toluene of 10mL drying, heated overnight at reflux in nitrogen atmosphere, and TLC shows reaction to be completed.After reaction mixture cool to room temperature, add 10mL normal hexane, stir 1 hour, collected by suction solid, ambient temperature in vacuum is dry, obtains Compound I-1, white solid, ESI-MS, m/z=255 ([M-Cl
-]
+).
embodiment 2-8
With reference to the method for embodiment 1, synthesize compound listed in Table.
embodiment 9 Compound ira vitro is to the restraining effect of jak kinase
Using the test as hereafter specified, suppressing the ability of JAK1, JAK2 and JAK3 to carry out SCREENED COMPOUND for compound.
Use baculovirus expression system, makes the catalyst structure domain of people JAKl (aa850-1154), JAK2 (aa826-1132), JAK3 (aa795-1124) and TYK2 (aa871-1187) be expressed as N end gst fusion protein and it is purchased from CarnaBiosciences.Use biotin labeled peptide--poly-(GT)-vitamin H (CisBio)--as substrate to measure the clean property of enzyme.Peptide concentration in reaction is 60nM for JAKl, is 20nM for JAK2, is 140nM and is 50nM for TYK2 for JAK3.The degree of phosphorylation is detected by TR-FRET (time resolved fluorescence energy trasfer (time-resolvedfluorescenceenergytransfer)) method.For at 8mMMOPS (pH7.0), 10mMMgC1
2, 0.05% β-dredge base ethanol, the IC measuring compound containing each kinases in the reaction mixture of enzyme, ATP and peptide in 0.45mg/mLBSA
50.ATP concentration in reaction is 3 μMs for JAK1, is 0.2 μM for JAK2, is 0.6 μM and is 1.8 μMs for TYK2 for JAK3.Enzyme process reaction at room temperature carries out 30 minutes.Then floating the going out containing the SA-XL665 (CisBio) of 0.115 μ g/mL anti-α-amino-isovaleric acid phosphorylation (phosphoTyr) (PT66)-kryptofix 222 (CisBio) and variable concentrations with 20 μ L detects damping fluid (50mMHEPES, 0.5MKF, EDTA0.25M, 0.l% (w/v) BSA, pH7.5) non-stopped reaction to keep SA-B ratios constant.Hatch 3 hours, be then set as the upper reading of Victor2V spectrofluorimeter (PerkinElmer) of reading fluorescence resonance energy transmission.
As can be seen from upper table result, compound of the present invention has very strong restraining effect to JAK, can as preparation treatment immunity, inflammatory, autoimmunity or allergic disease, or the medicine of the disease such as transplant rejection.
Claims (5)
1. there is the compound of general formula I,
Wherein, R is selected from C
1-C
3alkyl.
2. the compound of Formula I that defines of claim 1, is selected from:
3. synthesize arbitrary the defined method belonging to the compound of general formula I of claim 1-2:
Compound II per first uses highly basic process, then reacts with compound III, obtains compound IV; Compound IV first uses highly basic process, then reacts with 1,2-ethylene dichloride, obtains compound V; There is Intramolecular substitution reaction in compound V, obtains Compound I under heating; Wherein, described highly basic is selected from n-Butyl Lithium, isobutyl-lithium, tert-butyl lithium, phenyl lithium, lithium diisopropylamine, described X=Cl, Br, I, and the definition of R is as described in claim 1-2.
4. the compound of Formula I that one of claim 1-2 defines is preparing the purposes in JAK inhibitor medicaments.
5. purposes according to claim 4, comprises for the preparation of disease medicaments such as treatment immunity, inflammatory, autoimmunity, allergic disease, transplant rejections.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510501161.3A CN105153150B (en) | 2015-08-14 | 2015-08-14 | One class pyridine salt JAK inhibitor, preparation method and its usage |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510501161.3A CN105153150B (en) | 2015-08-14 | 2015-08-14 | One class pyridine salt JAK inhibitor, preparation method and its usage |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105153150A true CN105153150A (en) | 2015-12-16 |
| CN105153150B CN105153150B (en) | 2016-09-14 |
Family
ID=54794239
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510501161.3A Active CN105153150B (en) | 2015-08-14 | 2015-08-14 | One class pyridine salt JAK inhibitor, preparation method and its usage |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105153150B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4044015A (en) * | 1975-09-03 | 1977-08-23 | Pfizer Inc. | Imidazopyridinium compounds as hypoglycemic agents |
| WO2008129380A1 (en) * | 2007-04-18 | 2008-10-30 | Pfizer Products Inc. | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
-
2015
- 2015-08-14 CN CN201510501161.3A patent/CN105153150B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4044015A (en) * | 1975-09-03 | 1977-08-23 | Pfizer Inc. | Imidazopyridinium compounds as hypoglycemic agents |
| WO2008129380A1 (en) * | 2007-04-18 | 2008-10-30 | Pfizer Products Inc. | Sulfonyl amide derivatives for the treatment of abnormal cell growth |
Non-Patent Citations (1)
| Title |
|---|
| DACHEN CHENG ET AL.: ""Synthetic Entries to Substituted Bicyclic Pyridones"", 《ORGANIC LETTERS》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105153150B (en) | 2016-09-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2543962T3 (en) | Pyridopyrazine derivatives and their use as modulators of signal transduction pathways | |
| CN101547924B (en) | Compounds for inhibiting mitotic progression | |
| CN105283454B (en) | Quinazoline and azepine quinazoline as RAS/RAF/MEK/ERK and PI3K/AKT/PTEN/MTOR access double inhibitor | |
| EA039357B1 (en) | Novel immunotherapy against several tumors including gastrointestinal and gastric cancer | |
| CN102245610B (en) | Pyrrolotriazine kinase inhibitors | |
| L. Alicea-Velazquez et al. | The use of structural biology in Janus kinase targeted drug discovery | |
| CN103732596A (en) | Novel pyrrolo pyrimidine derivatives | |
| CN105481862B (en) | novel inhibitors of F L T3 kinase and uses thereof | |
| JP6978097B2 (en) | Heterocyclic compounds as JAK inhibitors, salts of the compounds and their therapeutic use | |
| JP2014505091A (en) | 6-Cyclobutyl-1,5-dihydro-pyrazolo [3,4-D] pyrimidin-4-one derivatives and their use as PDE9A inhibitors | |
| Dymock et al. | Selective JAK inhibitors | |
| CN100439365C (en) | Compounds and compositions as protein kinase inhibitors | |
| CN108368494A (en) | Methods, compositions and uses of novel FYN kinase inhibitors | |
| CN107667092A (en) | Formylated N Hete rocyclic derivatives as FGFR4 inhibitor | |
| Quancard et al. | Optimization of the in vivo potency of pyrazolopyrimidine MALT1 protease inhibitors by reducing metabolism and increasing potency in whole blood | |
| WO2015058661A1 (en) | Bcr-abl kinase inhibitor and application thereof | |
| EP3466952A1 (en) | Novel inhibitor for flt3 kinase and uses thereof | |
| CN108368060A (en) | A kind of novel pyridine derivatives kinase inhibitor | |
| CN106831812B (en) | Heterocyclic pyrimidine or pyrazine compound containing biarylamide structure and application thereof | |
| CN107151233B (en) | Hydrazone-containing pyrimidine derivative and application thereof | |
| CN105153150A (en) | Pyridinium type JAK (just another kinase) inhibitors as well as preparation method and application thereof | |
| CN105085519A (en) | Nitro-substituted pyridinium JAK inhibitor, and preparation method and application thereof | |
| CN105503860A (en) | Nitrile-group-substituted pyridine salt JAK inhibitor and preparation method and use thereof | |
| CN105085518A (en) | Amino-substituted pyridinium JAK inhibitor, and preparation method and application thereof | |
| TW201109332A (en) | Derivatives of 6,7-dihydro-5H-imidazo[1,2-a]imidazole-3-carboxylic acid amides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |