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
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- 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
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- lithium
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- 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
- 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
Classifications
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- 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
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.
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| CN201510501161.3A CN105153150B (en) | 2015-08-14 | 2015-08-14 | One class pyridine salt JAK inhibitor, preparation method and its usage |
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| CN201510501161.3A CN105153150B (en) | 2015-08-14 | 2015-08-14 | One class pyridine salt JAK inhibitor, preparation method and its usage |
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| CN105153150B CN105153150B (en) | 2016-09-14 |
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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》 * |
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