CN105503860B - The pyridine salt JAK inhibitor of one class itrile group replacement, preparation method and its usage - Google Patents
The pyridine salt JAK inhibitor of one class itrile group replacement, preparation method and its usage Download PDFInfo
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- CN105503860B CN105503860B CN201510658659.0A CN201510658659A CN105503860B CN 105503860 B CN105503860 B CN 105503860B CN 201510658659 A CN201510658659 A CN 201510658659A CN 105503860 B CN105503860 B CN 105503860B
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- 0 *CCCl1CCC1 Chemical compound *CCCl1CCC1 0.000 description 3
- OTGIQOOKEWCZTB-UHFFFAOYSA-N CC1(C=CC(CNc2nccc(C)c2)=CC=C1)C#N Chemical compound CC1(C=CC(CNc2nccc(C)c2)=CC=C1)C#N OTGIQOOKEWCZTB-UHFFFAOYSA-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 present invention relates to the JAK inhibitor of pyridiniujm structure, its preparation method and the application in the disease medicaments such as preparation treatment immunity, inflammatory, autoimmunity or allergic disease, or transplant rejection that a class itrile group replaces.
Description
Technical field
The present invention relates to immunity, inflammatory, autoimmunity or allergic disease, or the medicine of the disease such as transplant rejection
Field.In particular it relates to the pyridiniujm structure that a medicative class nitrile group-containing replaces to above-mentioned disease tool
JAK inhibitor, its preparation method, and the purposes in pharmacy.
Background technology
The phosphorylation of kinase catalytic protein, lipid, sugar, nucleoside and other cell metabolites in eukaryotic cell physiology
All aspects play a crucial role.Especially, protein kinase and lipid kinase participate in signal transduction process, and this process control is to thin
Extracellular instrumentality or irritate the activation of cell that thing (as somatomedin, cytokine or chemotactic factor) responds, growth, differentiation and
Survival.Generally, protein kinase is divided into two classes, the protein kinase of preferential phosphorylation tyrosine residue and preferential phosphorylation serine
And/or the protein kinase of threonine residues.Tyrosine kinase includes transmembrane growth factor receptor such as EGF-R ELISA
And cytosolic non-receptor kinases such as Janus kinases (JAK) (EGFR).Inadequately high protein kinase activity is related to numerous disease, bag
Include cancer, metabolic disease, autoimmunity or inflammatory disease.This effect can be directly or indirectly because the mutation of enzyme, excessively
Expression or inappropriate activation produce control mechanism fault and cause.It is desirable to the selectivity of kinases presses down in all these examples
The beneficial effect of fixture.
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 tyrosine kinase 2 (TYK2).Each egg
White matter all has kinase domain and catalytically inactive pseudokinase domain.JAK protein passes through its amino terminal FERM (band 4.1 albumen
(Band-4.1), ezrin (ezrin), radixin (radixin), moesin (moesin) domain are attached to cell factor receptor
On body.After cytokine and its receptor binding, activation JAKs simultaneously makes receptor phosphorylation, thus producing for signal transduction molecule
The docking site (docking sites) of (the especially member of signal transducer and transcription activator (Stat) family)
(Yamaoka etc., 2004, The Janus kinases (jaks) .Genome Biology, 5 (12), p253).In mammal
In, JAK1, JAK2 and TYK2 generally express.On the contrary, the expression of JAK3 mainly in hematopoietic cell and by cell development with swash
The altitude mixture control (Musso etc., 1995,181 (4), p1425-1431) lived.JAK mono- deficient cells system and gene target mice
Oneself basic, unduplicated function in cytokine signaling conduction for the disclosed JAKs of research.JAK1 knock-out mice shows
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 leads to produce embryonic lethal in embryo the 12.5th day
(Neubauer etc., 1998, Ce1l, 93 (3), 397-409).Enjoyably, JAK3 defect is first with autosomal recessive weight
Identified in the people of degree combined immunodeficiency (SCID) (Macchi etc., 1995, Nature, 377 (6544):65-68).JAK3 strikes
Except mice displays that SCID but do not show non-immunity defect, show that JAK3 inhibitor will have in vivo as immunosuppressant
Limited effect and therefore become for the promising medicine of immunosuppressant (Papageorgiou and Wikman, 2004, Trends
in Pharmacological Sciences,25(11),558-562).In acute megakaryoblastic leukemia (AMKL) patient
In oneself it is observed that to JAK3 activated mutant (Walters etc., 2006, Cancer Cell, 10 (1), 65-75).JAK3 these
Ba/F3 cells switch can be factor independent growth and induce megakaryoblastic leukemia in mouse model by mutant form
Feature.
The disease relevant with JAK3 suppression and disease are further described in such as WO01/42246 and WO2008/060301
In.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 that, effective JAK3 inhibitor (CP-690,550) is in the animal model of organ transplantation
(Changelian etc., 2003, Science, 302 (5646), 875-888) and clinical trial (reference:Pesu etc., 2008,
Immunol.Rev.223,132-142 display effect in).The pyrimidine compound that fluorine replaces is described in WO- as JAK3 inhibitor
In A2010/118986.Heterocyclic radical Pyrazolopyrimidine analogs are described in WO-A2011/048082 as JAK inhibitor.WO-
A2008/129380 relates to treat the sulfamide derivative of abnormal cell growth.WO-A2006/117560 and Journal
Of Molecular Graphics and Modelling (29) 2010,309-320 describe pyrazolyl amino replacement pyrimidine and
Its purposes in treating cancer.EP1054004A1 describes pyrimidine derivatives and its purposes in inflammation.
The invention discloses the JAK inhibitor of pyridiniujm structure that a class nitrile group-containing replaces, these compounds can be used for making
Standby treatment immunity, inflammatory, autoimmunity or allergic disease, or the medicine of the disease such as transplant rejection.
Content of the invention
It is an object of the present invention to provide a kind of JAK inhibitor of the 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 in treatment immunity, inflammatory, autoimmunity
Or allergic disease, or the application of the disease aspect 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 following structural formula：
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 is first processed with highly basic, then reacts with compound III, obtains compound IV；Compound IV first uses highly basic
Process, then react with 1,2- dichloroethanes, obtain compound V；There is Intramolecular substitution reaction in compound V, obtain under heating
Compound I；Wherein, described highly basic is selected from n-BuLi, isobutyl group lithium, tert-butyl lithium, phenyl lithium, lithium diisopropylamine, institute
State X=Cl, Br, I, R is defined as described above.
Compound of Formula I of the present invention has JAK inhibitory action, can be used for preparing immunity, inflammation as effective ingredient
Property, autoimmunity or allergic disease, or the disease therapeuticing medicine such as transplant rejection.Compound of Formula I of the present invention
Activity 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 dosage for example taken daily is about
In the range of 1mg-700mg/ people, it is divided into and being administered once or for several times.The actual dosage taking compound of Formula I of the present invention can be by curing
Take root for determining according to relevant situation.
Specific embodiment
With reference to embodiment, the present invention is further illustrated.It should be noted that following embodiments are only for
Illustrate, and be not intended to limit the present invention.Those skilled in the art all should according to the various change that the teachings of the present invention is made
Within 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, stirring, be cooled in nitrogen atmosphere-
20 DEG C, then with the hexane solution (6.25mL, 10mmol) of the syringe slowly n-BuLi of Deca 1.6M, after completion of dropping,
Reactant mixture continues to stir 1 hour at such a temperature.With syringe more slowly Deca III-1 (1.94g, 10mmol) be dissolved in
The solution that the THF that 3mL is dried makes, after completion of dropping, reactant mixture stirs half an hour at such a temperature, is then warming up to room
Temperature is stirred for overnight.Reactant mixture carefully pours in 200mL frozen water, and stirring, with 50mL × 3CH2Cl2Extraction, merges extraction
Phase, uses salt water washing, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and residue uses
Silica gel column chromatography purification, obtains compound IV-1, white solid, ESI-MS, m/z=224 ([M+H]+).Step B. compound V-
1 synthesis
Compound IV-1 (1.34g, 6mmol) is dissolved in the THF that 10mL is dried, and stirring is cooled to -20 in nitrogen atmosphere
DEG C, then with the hexane solution (3.75mL, 6mmol) of the syringe slowly n-BuLi of Deca 1.6M, after completion of dropping, reaction
Mixture continues to stir 1 hour at such a temperature.With syringe more slowly Deca 1,2- dichloroethanes (0.99g, 10mmol) molten
The solution made in the THF that 3mL is dried, after completion of dropping, reactant mixture stirs half an hour at such a temperature, is then warming up to
Room temperature is stirred for overnight.Reactant mixture carefully pours in 200mL frozen water, and stirring, with 50mL × 3CH2Cl2Extraction, merges extraction
Take phase, use salt water washing, anhydrous sodium sulfate drying.Sucking filtration removes desiccant, and filtrate is evaporated on a rotary evaporator, and residue makes
Purified with silica gel column chromatography, obtain compound V-1, white solid, ESI-MS, m/z=286 ([M+H]+).
The synthesis of step C. compound I-1
Compound V-1 (0.85g, 3mmol) is dissolved in the toluene that 10mL is dried, heated overnight at reflux in nitrogen atmosphere,
TLC display reaction completes.After reactant mixture is cooled to room temperature, add 10mL normal hexane, stir 1 hour, collected by suction solid,
It is vacuum dried under room temperature, obtain compound I-1, white solid, ESI-MS, m/z=250 ([M-Cl-]+).
Embodiment 2-3
With reference to the method for embodiment 1, synthesize compound listed in Table.
The inhibitory action to jak kinase for embodiment 4 Compound ira vitro
The test specified using following article, the ability suppressing JAK1, JAK2 and JAK3 for compound carrys out SCREENED COMPOUND.
Using baculovirus expression system, make one JAKl (aa850-1154), JAK2 (aa826-1132), JAK3
(aa795-1124) and TYK2 (aa871-1187) catalyst structure domain be expressed as N-terminal gst fusion protein and its be purchased from Carna
Biosciences.It is used the peptide of biotin labeling -- poly- (GT)-biotin (CisBio) -- to measure the clean of enzyme as substrate
Property.Peptide concentration in reaction is 60nM, is 20nM, for JAK3 for 140nM and for TYK2 is for JAK2 for JAKl
50nM.By TR-FRET (time-resolved fluorescence energy transfer (TR-FRET) (time-resolved fluorescence energy
Transfer)) method is detecting the degree of phosphorylation.For in 8mM MOPS (pH7.0), 10mM MgC12, 0.05% β-dredge base
Each kinases in the reactant mixture containing enzyme, ATP and peptide in ethanol, 0.45mg/mL BSA measures the IC of compound50.Instead
ATP concentration in answering is 3 μM, is 0.2 μM for JAK2, for JAK3 is 0.6 μM for JAK1 and is 1.8 μM for TYK2.
Enzyme process reaction is carried out 30 minutes at room temperature.Then contain the anti-L-Valine phosphorylation of 0.115 μ g/mL (phosphoTyr) with 20 μ L
(PT66) the floating detection buffer (50mM that goes out of the SA-XL665 (CisBio) of-cryptate (CisBio) and variable concentrations
HEPES, 0.5M KF, EDTA 0.25M, 0.l% (w/v) BSA, pH7.5) non-stopped reaction to be to keep SA-B ratios constant.Incubate
Educate 3 hours, be then set as reading the upper reading of Victor2V spectrofluorimeter (PerkinElmer) of fluorescence resonance energy transmission
Take.
The compound that can be seen that the present invention from upper table result has very strong inhibitory action to JAK, can be used as preparation
The medicine of the diseases such as treatment immunity, inflammatory, autoimmunity or allergic disease, or transplant rejection.
Claims (5)
1. there is the compound of logical formula (I) structure,
2. lead to formula (I) compound defined in claim 1, be selected from：
3. the method synthesizing the arbitrary defined compound belonging to logical formula (I) of claim 1-2：
Compound (II) is first processed with highly basic, then reacts with compound (III), obtains compound (IV)；Compound (IV) is first used
Highly basic is processed, then reacts with 1,2- dichloroethanes, obtains compound (V)；Compound (V) occurs Intramolecular substitution anti-under heating
Should, obtain compound (I)；Wherein, described highly basic is selected from n-BuLi, isobutyl group lithium, tert-butyl lithium, phenyl lithium, diisopropyl
Lithamide., described X=Cl, Br, I.
4. the defined logical purposes in terms of preparing JAK inhibitor medicaments for the formula (I) compound of one of claim 1-2.
5. the purposes described in claim 4, including for preparing autoimmunity, transplant rejection disease medicament.
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