CN105061423B - Pyridine salt JAK inhibitor containing halogeno-benzene structure, preparation method and its usage - Google Patents
Pyridine salt JAK inhibitor containing halogeno-benzene structure, preparation method and its usage Download PDFInfo
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- CN105061423B CN105061423B CN201510500817.XA CN201510500817A CN105061423B CN 105061423 B CN105061423 B CN 105061423B CN 201510500817 A CN201510500817 A CN 201510500817A CN 105061423 B CN105061423 B CN 105061423B
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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
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Abstract
The present invention relates to a class containing the JAK inhibitor of pyridiniujm structure of halogeno-benzene structure, its preparation method and the application in the disease medicaments such as preparation treatment immunity, inflammatory, autoimmunity or allergic disease, or transplant rejection.
Description
Technical field
The present invention relates to the diseases such as immunity, inflammatory, autoimmunity or allergic disease, or transplant rejection
Drug world.Tie in particular it relates to above-mentioned disease is had a medicative class containing halogeno-benzene
The JAK inhibitor of the pyridiniujm structure of structure, its preparation method, and the purposes in pharmacy.
Background technology
The phosphorylation of kinase catalytic protein, lipid, sugar, nucleoside and other cell metabolites at eukaryotic cell
All aspects of physiology play a crucial role.Especially, protein kinase and lipid kinase participate in signal conductive process,
This process control is to extracellular instrumentality or irritates thing (such as somatomedin, cytokine or chemotactic factor) and responds
The activation of cell, grow, break up and survive.Generally, protein kinase is divided into two classes, preferential phosphorylation tyrosine
The protein kinase of residue and preferential phosphorylation serine and/or the protein kinase of threonine residues.Tyrosine kinase
Including transmembrane growth factor receptor such as EGF-R ELISA (EGFR) and cytosolic non-receptor kinases such as Janus
Kinases (JAK).High protein kinase activity relates to numerous disease inadequately, including cancer, metabolic disease, from
Body immunity or inflammatory disease.This effect can be directly or indirectly because of the sudden change of enzyme, overexpression or discomfort
Cause when the control mechanism fault activating generation.In all these examples, it is desirable to kinase whose Selective depression
There is useful effect.
Oneself is nonreceptor tyrosine kinase through becoming a class kinases of current drug development focus] anus kinases
(JAK) family.In mammal, this family has four members, JAK1, JAK2, JAK3 and cheese ammonia
Acid kinase 2 (TYK2).Each protein has kinases territory and catalytically inactive pseudokinase territory.JAK albumen
Matter by its amino terminal FERM (carry 4.1 albumen (Band-4.1), ezrin (ezrin), radixin (radixin),
Moesin (moesin) territory is attached on cytokine receptor.After cytokine is combined with its receptor, activate
JAKs also makes receptor phosphorylation, thus produce for signal transduction molecule (especially the member of signal transducer and
Transcription activator (Stat) family) docking site (docking sites) (Yamaoka etc., 2004, The Janus
kinases(jaks).Genome Biology,5(12),p253).In mammal, JAK1, JAK2 and TYK2
Generally express.On the contrary, the main height in hematopoietic cell and by cell development Yu activation of the expression of JAK3
Regulation (Musso etc., 1995,181 (4), p1425-1431).JAK mono-deficient cells system and gene target mice
Basic in cytokine signaling conducts of oneself disclosed JAKs of research, unduplicated function.JAK1
Knock-out mice display perinatal stage lethal phenotype, may with stop its suckling effects on neural system relevant (Rodig etc.,
1998,Ce1l,93(3):373-383).Due to Dyserythropoiesis, the deletion of JAK2 gene causes at embryo
Embryonic lethal (Neubauer etc., 1998, Ce1l, 93 (3), 397-409) is produced during tire the 12.5th day.Enjoyably,
JAK3 defect is identified in the people suffering from autosomal recessive severe combined immunodeficient (SCID) first
(Macchi etc., 1995, Nature, 377 (6544): 65-68).JAK3 knock-out mice displays that SCID but does not shows
Non-immunity defect, shows that JAK3 inhibitor will have limited effect therefore in vivo as immunosuppressant
Become for the promising medicine of immunosuppressant (Papageorgiou and Wikman, 2004, Trends in
Pharmacological Sciences,25(11),558-562).Suffer from acute megakaryoblastic leukemia (AMKL)
In person, oneself it be observed that the activated mutant (Walters etc., 2006, Cancer Cell, 10 (1), 65-75) of JAK3.
Ba/F3 cells switch can be factor independent growth and lure in mouse model by these mutant forms of JAK3
Lead the feature of megakaryoblastic leukemia.
The disease relevant with JAK3 suppression and disease be further described in such as WO01/42246 and
In WO2008/060301.In document oneself report some JAK3 inhibitor can be used for medical domain (O ' Shea etc.,
2004,Nat.Rev.Drug Discov.3(7):555-564).It is reported, effective JAK3 inhibitor
(CP-690,550) organ transplantation animal model (Changelian etc., 2003, Science, 302 (5646),
875-888) with display effect in clinical trial (reference: Pesu etc., 2008, Immunol.Rev.223,132-142).
The substituted pyrimidine compound of fluorine is described in WO-A2010/118986 as JAK3 inhibitor.Heterocyclic radical pyrazoles
Miazines is described in WO-A2011/048082 as JAK inhibitor like thing.WO-A2008/129380
Relate to treat the sulfamide derivative of abnormal cell growth.WO-A2006/117560 and Journal of
Molecular Graphics and Modelling (29) 2010,309-320 describes the substituted pyrimidine of pyrazolyl amino
And the purposes in treatment cancer.EP1054004A1 describes pyrimidine derivatives and the purposes in inflammation thereof.
The invention discloses the JAK inhibitor of the class pyridiniujm structure containing halogeno-benzene structure, these compounds can
For preparing the diseases such as treatment immunity, inflammatory, autoimmunity or allergic disease, or transplant rejection
Medicine.
Summary of the invention
It is an object of the present invention to provide the JAK inhibitor of a kind of excellent activity with formula I.
It is a further object to provide the method that preparation has compounds of formula I.
It is also another object of the present invention to provide containing compounds of formula I treatment immunity, inflammatory, self
Application in terms of immunity or allergic disease, or the disease such as transplant rejection.
In conjunction with the purpose of the present invention, present invention is specifically described.
The present invention has compounds of formula I and has a following structural formula:
Wherein, R is selected from halogenic substituent.
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 first processes with highly basic, then reacts with compound III, obtains compound IV；Compound IV
First process with highly basic, then with 1,2-dichloroethanes reacts, and obtains compound V；Compound V occurs under heating
Intramolecular substitution reaction, obtains compound I；Wherein, described highly basic is selected from n-BuLi, isobutyl group lithium, uncle
Butyl lithium, phenyl lithium, lithium diisopropylamine, described X=Cl, Br, I, R's is defined as described above.
Compound of Formula I of the present invention has JAK inhibitory action, can exempt from for preparation as effective ingredient
Epidemic disease, inflammatory, autoimmunity or allergic disease, or the disease therapeuticing medicine such as transplant rejection.The present invention
The activity of described compound of Formula I is to be verified by the inhibition test of external JAK.
The compound of Formula I of the present invention is effective in comparatively wide dosage range.The agent that such as every day takes
Amount, about in the range of 1mg-700mg/ people, is divided into once or is administered for several times.Actual take formula Iization of the present invention
The dosage of compound can be determined according to relevant situation by doctor.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that following embodiment is only
For illustrating, and it is not intended to limit the present invention.Those skilled in the art are made according to the teachings of the present invention
Various changes all should be within the protection domain required by the application claim.
The synthesis of embodiment 1 compound I-1
The synthesis of step A. compound IV-1
Compound II-1 (1.08g, 10mmol) is dissolved in the THF that 10mL is dried, and stirring, at nitrogen atmosphere
In be cooled to-20 DEG C, then slowly drip with syringe the n-BuLi of 1.6M hexane solution (6.25mL,
10mmol), after dropping, reactant mixture continues to stir 1 hour at such a temperature.The slowest with syringe
Slowly drip III-1 (1.89g, 10mmol) and be dissolved in the solution that the THF that 3mL is dried makes, after dropping,
Reactant mixture stirs half an hour at such a temperature, is then warming up to room temperature and is stirred for overnight.Reactant mixture is little
The heart pours in 200mL frozen water, and stirring, with 50mL × 3CH2Cl2Extraction, merges extraction phase, uses salt
Water washs, and anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, residue
Use silica gel column chromatography purification, obtain compound IV-1, white solid, ESI-MS, m/z=217 ([M+H]+)。
The synthesis of step B. compound V-1
Compound IV-1 (1.30g, 6mmol) is dissolved in the THF that 10mL is dried, and stirring, at nitrogen atmosphere
In be cooled to-20 DEG C, then slowly drip with syringe the n-BuLi of 1.6M hexane solution (3.75mL,
6mmol), after dropping, reactant mixture continues to stir 1 hour at such a temperature.The slowest with syringe
Slow dropping 1,2-dichloroethanes (0.99g, 10mmol) is dissolved in the solution that the THF that 3mL is dried makes, dropping
After, reactant mixture stirs half an hour at such a temperature, is then warming up to room temperature and is stirred for overnight.Reaction
Mixture carefully pours in 200mL frozen water, and stirring, with 50mL × 3CH2Cl2Extraction, merges extraction
Phase, washs with saline, and anhydrous sodium sulfate is dried.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator,
Residue uses silica gel column chromatography purification, obtains compound V-1, white solid, ESI-MS, m/z=279
([M+H]+)。
The synthesis of step C. compound I-1
Compound V-1 (0.83g, 3mmol) is dissolved in the toluene that 10mL is dried, and heats back in nitrogen atmosphere
Flowing through night, TLC display reaction completes.After reactant mixture is cooled to room temperature, add 10mL normal hexane,
Stirring 1 hour, collected by suction solid, ambient temperature in vacuum is dried, and obtains compound I-1, white solid, ESI-MS,
M/z=243 ([M-Cl-]+)。
Embodiment 2-8
With reference to the method for embodiment 1, synthesize compound listed in Table.
Embodiment 10 Compound ira vitro inhibitory action to jak kinase
Using the test as hereafter specified, the ability for compound suppression JAK1, JAK2 and JAK3 is screened
Compound.
Use baculovirus expression system, make people JAKl (aa850-1154), JAK2 (aa826-1132), JAK3
(aa795-1124) and the catalyst structure domain of TYK2 (aa871-1187) be expressed as N end gst fusion protein and its
Purchased from Carna Biosciences.Use biotin labeled peptide--poly-(GT)-biotin (CisBio)--as substrate
Measure the clean property of enzyme.Peptide concentration in reaction for JAKl be 60nM, for JAK2 be 20nM, for
JAK3 is 140nM and is 50nM for TYK2.By TR-FRET, (time-resolved fluorescence energy shifts
(time-resolved fluorescence energy transfer)) method detects the degree of phosphorylation.For at 8mM
MOPS(pH7.0)、10mM MgC12, 0.05% β-dredge in base ethanol, 0.45mg/mL BSA containing enzyme,
Each kinases in the reactant mixture of ATP and peptide measures the IC of compound50.ATP concentration in reaction for
JAK1 is 3 μMs, be 0.2 μM for JAK2, for JAK3 be 0.6 μM and be 1.8 μMs for TYK2.
Enzyme process reaction is at room temperature carried out 30 minutes.Then 0.115 μ g/mL anti-valine phosphorylation is contained with 20 μ L
(phosphoTyr) SA-XL665's (CisBio) of (PT66)-cryptate (CisBio) and variable concentrations is floating
Go out and detect buffer (50mM HEPES, 0.5M KF, EDTA 0.25M, 0.l% (w/v) BSA, pH7.5)
Non-stopped reaction is to keep SA-B ratios constant.Hatch 3 hours, be then set as reading fluorescence resonance energy
The Victor2V spectrofluorimeter (PerkinElmer) of amount transmission is upper to be read.
From upper table result it can be seen that the compound of the present invention has the strongest inhibitory action to JAK, permissible
As diseases such as preparation treatment immunity, inflammatory, autoimmunity or allergic disease, or transplant rejections
Medicine.
Claims (5)
1. there is the compound of general formula I,
Wherein, R is selected from halogenic substituent.
2. compound of Formula I defined in claim 1, is selected from:
3. synthesis claim 1-2 arbitrary defined in belong to the method for compounds of formula I:
Compound II first processes with highly basic, then reacts with compound III, obtains compound IV；Compound IV
First process with highly basic, then with 1,2-dichloroethanes reacts, and obtains compound V；Compound V occurs under heating
Intramolecular substitution reaction, obtains compound I；Wherein, described highly basic is selected from n-BuLi, isobutyl group lithium, uncle
Butyl lithium, phenyl lithium, lithium diisopropylamine, described X=Cl, Br, I, the definition of R such as claim
Described in 1-2.
4. the defined compound of Formula I purposes in terms of preparing JAK inhibitor medicaments of one of claim 1-2.
5. the purposes described in claim 4, including for preparing treatment immunity, inflammatory, autoimmunity, change
Answering property disease, transplant rejection disease medicament.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN201510500817.XA CN105061423B (en) | 2015-08-14 | 2015-08-14 | Pyridine salt JAK inhibitor containing halogeno-benzene structure, preparation method and its usage |
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| CN201510500817.XA CN105061423B (en) | 2015-08-14 | 2015-08-14 | Pyridine salt JAK inhibitor containing halogeno-benzene structure, preparation method and its usage |
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| Publication Number | Publication Date |
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| CN105061423A CN105061423A (en) | 2015-11-18 |
| CN105061423B true CN105061423B (en) | 2016-09-14 |
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Non-Patent Citations (1)
| Title |
|---|
| In vitro production of drug metabolites by human cell lines;Holland, Herbert L.;《Chimica Oggi 》;19970831;第15卷(第8期);第70-74页 * |
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