CN107602591A - A kind of JAK3 inhibitor - Google Patents
A kind of JAK3 inhibitor Download PDFInfo
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- CN107602591A CN107602591A CN201711049509.5A CN201711049509A CN107602591A CN 107602591 A CN107602591 A CN 107602591A CN 201711049509 A CN201711049509 A CN 201711049509A CN 107602591 A CN107602591 A CN 107602591A
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Abstract
The invention provides the compound or its pharmaceutically acceptable salt that one kind has following formula (I) expression；
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of JAK3 inhibitor.
Background technology
Janus kinases is cytoplasm junket ammonia kinase man of the transducer cell factor signal from membrane receptor to STAT transcription factors
Race, inflammation, autoimmune disease, proliferative disease, graft rejection are participated in, be related to the impaired disease of cartilage renewal, congenital soft
Bone malformation and/or the disease related to IL6 hypersecretions.Janus kinases is a kind of non-receptor type tyrosine protein kinase, there is 4
Individual family member, it is JAK1, JAK2, TYK2 and JAK3 respectively.Preceding 3 are widely present in various tissues and cell, and JAK3
Exist only in marrow and lymphatic system.
JAK3 (JAK3) is the member in protein kinase family.JAK3 inhibitor is successfully used for clinic
Treatment, is initially organ transplant, and present immunity disease also has extensive use, mainly including rheumatoid arthritis (RA), silver
Bits disease and clone's disease etc..Now, the anti-inflammatory drug research using JAK3 as target spot is one of focus of new drug development.
The content of the invention
It is an object of the invention to disclose a kind of JAK3 inhibitor, to inflammation, allergic reaction and immune
Disease realizes more outstanding therapeutic effect.
To achieve the above object, the invention provides one kind the compound or its is pharmaceutically acceptable that following formula (I) represents
Salt；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S
(=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkanes
Base, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6Member
Cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl,
Substituted C3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6It is miscellaneous
Alkyl, unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
Further, the compound or other pharmaceutically acceptable salts of above-mentioned formula I, for preventative or therapeutic suppression
Immune response processed.
Further, the compound or other pharmaceutically acceptable salts of above-mentioned formula I, for suppressing the immune of mammal
Reaction.
Meanwhile the invention also provides a kind of pharmaceutical composition, comprising the compound described in above-mentioned formula (I) or its pharmaceutically
Acceptable salt.
Compared with prior art, the beneficial effects of the invention are as follows：A kind of disclosed JAK3 inhibitor,
Inflammation, allergic reaction and immunological diseases can be realized with more outstanding therapeutic effect.
Embodiment
With reference to each embodiment, the present invention is described in detail, but it should explanation, these embodiments are simultaneously
Non- limitation of the present invention, those of ordinary skill in the art are according in these embodiment institute work energy, method or structures
Equivalent transformation or replacement, belong within protection scope of the present invention.
Unless otherwise specified, the term " room temperature " in each embodiment of this specification is specially 23 DEG C；When term " h " is specially
Between measurement unit：Hour；Term " min " is specially time measurement unit：Minute；Term " ml " is specially volume unit：Milliliter；
Term " L " is specially volume unit：Rise；Term " mol/L " is specially concentration unit.Term " mmol " is specially the amount of material
Unit, i.e., mM；Term " mg " is unit of weight, i.e. milligram.
One kind has the compound or its pharmaceutically acceptable salt of following formula (I) expression；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S
(=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkanes
Base, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6Member
Cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl,
Substituted C3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6It is miscellaneous
Alkyl, unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
The compound or other pharmaceutically acceptable salts of above-mentioned formula I, it is immune anti-for preventative or therapeutic suppression
Should.The compound or other pharmaceutically acceptable salts of above-mentioned formula I, for suppressing the immune response of mammal.The present invention is also
A kind of pharmaceutical composition is proposed, includes the compound or its pharmaceutically acceptable salt described in above-mentioned formula (I).The drug regimen
Thing can be the pharmaceutical dosage forms of the other forms such as intravenous injection injection, oral tablet.The pharmaceutical composition can be used for preventative
The either therapeutic disease or the patient's condition relevant with pathology JAK activation.
For example, compound or its pharmaceutically acceptable salt that disclosed formula (I) represents can be used for organ
Rejection caused by transplanting, rheumatic arthritis, rheumatoid arthritis, myotenositis, myocarditis, leucoderma, psoriasis,
The treatment and prevention of the diseases such as vaginitis, enteritis, asthma, tumour.
Meanwhile this specification also discloses a kind of compound of formula (I) expression or the synthesis of its pharmaceutically acceptable salt
Method.The synthetic method is that 9 steps react (i.e. step a~step i), the following institute of reaction equation involved by its synthetic route
Show：
Step a
Added into 50ml reaction bulbs dichloromethane 10ml, 2- amino -4- nitro -5- picolines (225mg,
1.4mmol) starting material 1 and bromo- 2 oxo-propionates (280ml, 1.4mmol) of 3-, room temperature magnetic agitation are reacted 1~2h, subtracted
Pressure concentration removes solvent, residue 10ml ethanol, and specially after absolute ethyl alcohol dissolving, is heated to reflux 3h, and TLC detections have been reacted
Entirely.Reaction solution, which naturally cools to after room temperature to be concentrated under reduced pressure, removes ethanol.Residue is washed with saturated sodium bicarbonate solution, and water layer is used
Dichloromethane extracts, and organic layer solution is stayed overnight using anhydrous sodium sulfate drying, filters and concentrate, the separation of residue silica gel column chromatography,
It is intermediate 2 to obtain yellow solid.MS calculated values 235, measured value 250 [M+1].
Step b
Under normal temperature condition, 150mg intermediates 2 are dissolved in 20ml ethanol (being specially absolute ethyl alcohol), gradually add 2ml concentration
Hydrochloric acid and 15mg platinum dioxides for 1mol/L, nitrogen protection, it is passed through hydrogen (50psi) and reacts 16h in 50 DEG C of magnetic agitations,
TLC detection reactions are complete, reaction solution concentrated half, filter, obtain white solid 120mg i.e. intermediate 3.MS:224[M+H]+。
Step c
100mg intermediates 3 and 4- chloro- 7- (p-toluenesulfonyl) pyrrolo- [2,3-d] pyrimidine 137mg are dissolved in 5ml
N-butanol, 158mgDIEA (i.e. DIPEA) is continuously added, magnetic agitation, is heated to back flow reaction 16h, TLC inspection
It is complete to survey reaction, reaction solution pressurization concentration, residue is diluted with 10ml water, and aqueous phase ethyl acetate extracts 3 times, each 20ml, merges
Organic layer is simultaneously stayed overnight to organic layer solution using anhydrous sodium sulfate drying, is filtered, is concentrated under reduced pressure, and residue uses silica gel column chromatography point
From (PE:EA=1:2) light yellow solid 68mg, i.e. intermediate 4, yield 32.4%, are obtained.Wherein, PE is petroleum ether, and EA is acetic acid
Ethyl ester.The mixing for being selected from petroleum ether and ethyl acetate in step c to the eluent used in the separation of residue silica gel column chromatography is molten
Liquid, and the mol ratio of eluent petrochina ether and ethyl acetate is 1:2.
Step d
Condition of ice bath, nitrogen protection, it (is specially anhydrous tetrahydrochysene that 3.1g intermediates 4 and THF are added into 250ml there-necked flasks
Furans) 120ml, magnetic agitation, NaH about 500mg, insulation reaction 1h is added portionwise, iodomethane about 7.5g, drop is then gradually added dropwise
Add complete, warm naturally to room temperature, react 1h, TLC detection reactions are complete, add 10ml saturated ammonium chlorides extraction and go out reaction, then
Frozen water 50ml is added, extracts 3 times, each 50ml, is associated with using by the mixed solution of dichloromethane (DCM) and methanol (MeOH)
Machine layer, anhydrous sodium sulfate drying is overnight, filters, and intermediate 5 is obtained after filtrate concentration and is directly used in reaction in next step.Wherein, walk
It is 3 for the dichloromethane (DCM) in the mixed solution that is extracted and the mol ratio of methanol (MeOH) in rapid d:1.
Step e
Under room temperature condition, intermediate 5 obtained by step d is dissolved in 20ml ethanol solutions, adds caustic alcohol 1.0g, insulation is stirred
16~20h is mixed, TLC detection reactions are complete, and reaction solution concentration, residue is diluted with 50ml water, layering, water layer dichloromethane 30ml
Extraction 3 times, merge organic layer solution, and organic layer solution is stayed overnight using anhydrous sodium sulfate drying, filter, filtrate concentration is residual
Excess obtains intermediate 6 about using silica gel column chromatography separation (DCM/MeOH=1/1~10/1, mol ratio in eluent)
589mg, yield 58.2%.MS:355[M+H]+。
Step f
Condition of ice bath, 500mg intermediates 6 are dissolved in 10mlTHF (anhydrous tetrahydro furan), 111mg tetrahydrochysene lithiums are added portionwise
Aluminium, warm naturally to react at room temperature 2h after adding, TLC detection reactions are complete, are cooled to 0 DEG C, add frozen water 10ml extractions and go out, mistake
Filter, water layer DCM/MeOH (10:1) extract 3 times, each 20ml, merge organic layer solution, and organic layer solution is used anhydrous
Sodium sulphate is dried overnight, and is filtered, filtrate decompression concentration, obtains the crude product of intermediate 7, and not purified be directly used in is reacted in next step.MS:
313[M+H]+。
Step g
Under normal temperature condition, 150mg intermediates 7 are dissolved in 10ml anhydrous methylene chlorides, add thionyl chloride 300mg, 70 DEG C
Magnetic agitation reacts 1h, and TLC detection reactions are complete, and reaction solution is concentrated under reduced pressure, and obtains intermediate 8, it is straight that the crude product of intermediate 8 is not required to purifying
Connect for reacting in next step.MS:331[M+H]+。
Step h
150mg intermediates 8 are dissolved in 10mlDMSO (dimethyl sulfoxide (DMSO)), 41mg Cymags is added, is warming up to 40 DEG C of reactions
10h, TLC detect reaction completely, are naturally cooling to room temperature, add 10ml frozen water extraction and go out, solution dichloromethane extraction 2 times, often
Secondary 20ml, merge organic layer solution, and organic layer solution is washed 2 times using saturated brine, each 10ml, then using nothing
Aqueous sodium persulfate is dried overnight, and is filtered, and filtrate concentration, residue is separated using silica gel column chromatography, obtains white solid 60mg, i.e. intermediate
9。MS:322[M+H]+。
Step i
500mg racemate intermediates 9 are split by hand-type post, then respectively with isopropanol 35 DEG C recrystallize white solid
Body, produce target product 10, target product 11, target product 12 and target product 13.Optical purity is above 99.5%.
Jak1, Jak2, Jak3 kinases external activity are tested
Experiment material
Recombination human source Jak1, Jak2, Jak3 protease is purchased from life technology.LANCE Ultra
ULightTM- Jak1 (Tyr1023) peptide and LANCE Eu-w1024 Anti-phosphotyrosine (PT66) are purchased from
PerkinElmer。
Use multi-joint ELIASA Envision (PerkinElmer).
Experimental method
Test compound is subjected to 3 times of concentration gradient dilutions, final concentration of 10 μM are arrived 0.17nM totally 11 concentration, Mei Genong
Spend two multiple holes；Contents of the DMSO in detection is reacted is 1%.
Jak1 enzyme reactions
0.02nM Jak1 protein kinases, 50nM LANCE Ultra ULightTM-Jak1(Tyr1023)peptide,38
Μ m ATP, 50mM HEPES (PH 7.5), 10nM MgCl2,1mM EGTA, 2mM DTT, 0.01%BRIG-35.Detection plate is
White Proxiplate 384-Plus plate (PerkinElmer), 90min is reacted at room temperature, reaction system is 10 μ l.
Jak2 enzyme reactions
0.02nM Jak2 protein kinases, 50nM LANCE Ultra ULightTM-Jak1(Tyr1023)peptide,38
Μ m ATP, 50mM HEPES (PH 7.5), 10nM MgCl2,1mM EGTA, 2mM DTT, 0.01%BRIG-35.Detection plate is
White Proxiplate 384-Plus plate (PerkinElmer), 90min is reacted at room temperature, reaction system is 10 μ l.
Jak3 enzyme reactions
0.02nM Jak3 protein kinases, 50nM LANCE Ultra ULightTM-Jak1(Tyr1023)peptide,38
Μ m ATP, 50mM HEPES (PH 7.5), 10nM MgCl2,1mM EGTA, 2mM DTT, 0.01%BRIG-35.Detection plate is
White Proxiplate 384-Plus plate (PerkinElmer), 90min is reacted at room temperature, reaction system is 10 μ l.
Reaction detection
Add 10 μ l detection reagents into reaction plate, wherein LANCE Eu-w1024 Anti-phosphotyrosine
(PT66) the final concentration of 10mM of final concentration of 2nM, EDTA, 60min, Envision instrument read plates are incubated at room temperature.
Data analysis
Reading is converted into by inhibiting rate (%)=(Min-Ratio)/(Max-Min) × 100% by following equation.Four ginsengs
Curve fit (the inXLFIT5 iDBS of Model 205) measures IC50 data, specifically see the table below.
| Compound | JAK1 | JAK2 | JAK3 |
| WXFQ-001 | C | D | B |
| WXFQ-002 | C | C | B |
| WXFQ-003 | D | C | B |
| WXFQ-004 | D | C | C |
| WXFQ-005 | C | C | B |
| WXFQ-006 | D | B | B |
| WXFQ-007 | D | D | A |
| WXFQ-008 | D | D | C |
| WXFQ-009 | D | C | A |
| WXFQ-0010 | D | B | B |
| WXFQ-0011 | D | C | B |
| WXFQ-0012 | C | C | C |
| WXFQ-0013 | D | C | C |
| WXFQ-0014 | C | C | D |
| WXFQ-0015 | C | C | C |
| WXFQ-0016 | B | C | C |
A≤10nM, 10nM≤B≤100nM, 100nM≤C≤100nM, D ＞ 1000nM
Those listed above is a series of to be described in detail only for feasibility embodiment of the invention specifically
Bright, they simultaneously are not used to limit the scope of the invention, all equivalent implementations made without departing from skill spirit of the present invention
Or change should be included in the scope of the protection.
It is obvious to a person skilled in the art that the invention is not restricted to the details of above-mentioned one exemplary embodiment, Er Qie
In the case of without departing substantially from spirit or essential attributes of the invention, the present invention can be realized in other specific forms.Therefore, no matter
From the point of view of which point, embodiment all should be regarded as exemplary, and be nonrestrictive, the scope of the present invention is by appended power
Profit requires rather than described above limits, it is intended that all in the implication and scope of the equivalency of claim by falling
Change is included in the present invention.
Moreover, it will be appreciated that although the present specification is described in terms of embodiments, not each embodiment is only wrapped
Containing an independent technical scheme, this narrating mode of specification is only that those skilled in the art should for clarity
Using specification as an entirety, the technical solutions in the various embodiments may also be suitably combined, forms those skilled in the art
It is appreciated that other embodiment.
Claims (4)
1. one kind has the compound or its pharmaceutically acceptable salt of following formula (I) expression；
Wherein, in formula (I)：
A be selected from singly-bound-C (=O)-,-C (=O) O- ,-S (=O)2- ,-C (=O) NH- ,-NH- ,-S (=O) NH- ,-S (=O)2NH-；
B is selected from C and N；
R is selected from H, CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6First cycloalkyl, quilt
Substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6First cycloalkanes
Base or unsubstituted C3-C6Circle heterocycles alkyl；
R2And R3Simultaneously or it is respectively selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, taken
The C in generation3-C6First cycloalkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl,
Unsubstituted C3-C6First cycloalkyl or unsubstituted C3-C6Circle heterocycles alkyl.
2. the compound or other pharmaceutically acceptable salts of the formula I that claim 1 describes, it is characterised in that for preventative
Or therapeutic suppression immune response.
3. the compound or other pharmaceutically acceptable salts of the formula I that claim 1 describes, it is characterised in that for suppressing to feed
The immune response of newborn animal.
4. a kind of pharmaceutical composition, it is characterised in that comprising compound as claimed in claim 1 or its is pharmaceutically acceptable
Salt.
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Cited By (8)
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|---|---|---|---|---|
| CN107573364A (en) * | 2017-10-31 | 2018-01-12 | 无锡福祈制药有限公司 | A kind of jak kinase inhibitors |
| CN107602590A (en) * | 2017-10-31 | 2018-01-19 | 无锡福祈制药有限公司 | Endocyclic compound with Janus kinase inhibiting activities |
| CN107652308A (en) * | 2017-10-31 | 2018-02-02 | 无锡福祈制药有限公司 | A kind of JAK3 inhibitor |
| CN107721988A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | The ketone compounds of iso-indoles 1 with anti-inflammatory activity |
| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
| CN107778321A (en) * | 2017-10-31 | 2018-03-09 | 无锡福祈制药有限公司 | A kind of tropsch imatinib analog |
| CN107805259A (en) * | 2017-10-31 | 2018-03-16 | 无锡福祈制药有限公司 | A kind of azolopyrimidines |
| CN111039963A (en) * | 2019-12-31 | 2020-04-21 | 卓和药业集团有限公司 | WXFL10203614 water-soluble analogue and synthetic method thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107573364A (en) * | 2017-10-31 | 2018-01-12 | 无锡福祈制药有限公司 | A kind of jak kinase inhibitors |
| CN107602590A (en) * | 2017-10-31 | 2018-01-19 | 无锡福祈制药有限公司 | Endocyclic compound with Janus kinase inhibiting activities |
| CN107652308A (en) * | 2017-10-31 | 2018-02-02 | 无锡福祈制药有限公司 | A kind of JAK3 inhibitor |
| CN107721988A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | The ketone compounds of iso-indoles 1 with anti-inflammatory activity |
| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
| CN107778321A (en) * | 2017-10-31 | 2018-03-09 | 无锡福祈制药有限公司 | A kind of tropsch imatinib analog |
| CN107805259A (en) * | 2017-10-31 | 2018-03-16 | 无锡福祈制药有限公司 | A kind of azolopyrimidines |
| CN111039963A (en) * | 2019-12-31 | 2020-04-21 | 卓和药业集团有限公司 | WXFL10203614 water-soluble analogue and synthetic method thereof |
| CN111039963B (en) * | 2019-12-31 | 2021-03-19 | 卓和药业集团有限公司 | WXFL10203614 water-soluble analogue and synthetic method thereof |
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