CN107778321A - A kind of tropsch imatinib analog - Google Patents
A kind of tropsch imatinib analog Download PDFInfo
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- CN107778321A CN107778321A CN201711049479.8A CN201711049479A CN107778321A CN 107778321 A CN107778321 A CN 107778321A CN 201711049479 A CN201711049479 A CN 201711049479A CN 107778321 A CN107778321 A CN 107778321A
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- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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Abstract
The invention provides a kind of tropsch imatinib analog, and it contains the compound or its pharmaceutically acceptable salt of formula (I) expression；
Description
Technical field
The present invention relates to pharmaceutical technology field, more particularly to a kind of tropsch imatinib analog.
Background technology
Rheumatoid arthritis (RA) is a kind of chronic progressive, with arthrosynovitis and symmetry, destructive arthropathy
For the autoimmune disease of principal character.The research of RA pathogenesis and remedy measures is constantly in continuous development, many
Research attempts to find treatment opportunity from different approaches such as intracellular signal transduction path, cell factors, and obtains certain progress.Example
If methotrexate (MTX) (MTX) is since clinical practice in 1980, very good effect has been achieved in RA treatments；It is first with tumor necrosis factor
Sub (TNF) is that the biological agent of target (tnf inhibitor, mainly disturbs immunocyte acceptor and the inflammatory cells such as T cell, B cell
The factor produces) be used for RA treatments in 2000, then it is new milestone.Because more and more RA patients are insensitive to MTX treatments,
MTX joint biological agent schemes provide new approaches for clinical treatment.Biological agent currently used for RA treatments is with tnf inhibitor
Based on, these medicines have obtained the effect of good when combining MTX applications or being used alone.But still there are some patientss to this kind of
Medicine is unresponsive, or can not be applied because occurring adverse reaction.
Janus kinases signal transduction and activating transcription factor (Janus-activated kinase Singal
Transducers and activators of transcriprion, JAK-STAT) be in recent years newfound one with it is thin
The closely related Cellular Signaling Transduction Mediated path of intracellular cytokine, participates in many such as propagation, differentiation, apoptosis and the immunological regulation of cell
Important biological process.Janus kinases is a kind of non-receptor type tyrosine protein kinase.There are 4 family members, be respectively
JAK1, JAK2, TYK2 and JAK3.Preceding 3 are widely present in various tissues and cell, and JAK3 exists only in marrow and lymph
System.
Research shows, JAK3 is expressed lymphocyte is high, main mediation participate in interleukins (IL) -2, IL-4,
The synthesis of the cell factors such as IL-7, IL-9, IL-15, IL-21, therefore JAK3 missings or dysfunction will cause lymph thin
Born of the same parents can not work orderly, and ultimately result in immunodeficiency etc., and in these IL of lymphocytic emiocytosis it is proinflammatory because
Son, damage and reparation of the anti-inflammatory factors to cartilaginous tissue play a significant role.It can be seen that JAK3 is played extremely in RA pathogenic processes
Important effect.
In recent years many researchs are directed to finding new high selectivity immunosuppressive drug, and Janus kinases (JAK)/signal turns
Lead and activating transcription factor (STAT) signal transduction pathway is as the focus that treatment RA new target drone is drug development.Tropsch imatinib
A kind of small molecule JAK3 inhibitor of (tofacitinib, CP-690550) as new oral, obtained in RA treatments good
Good effect, but clinical practice still suffers from many deficiencies；Before finding new tropsch imatinib analog there is good clinical practice
Scape.
The content of the invention
It is an object of the invention to disclose a kind of tropsch imatinib analog, to improve the treatment effect to rheumatoid arthritis
Fruit.
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 CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6Yuan of rings
Alkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6
First 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 may be used
The salt of receiving.
Compared with prior art, the beneficial effects of the invention are as follows：A kind of tropsch imatinib analog disclosed in this invention, it is right
Rheumatoid arthritis has significant 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 CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected from H, OH, halogen, substituted C1-C6Alkyl, substituted C1-C6Miscellaneous alkyl, substituted C3-C6Yuan of rings
Alkyl, substituted C3-C6Circle heterocycles alkyl, unsubstituted C1-C6Alkyl, unsubstituted C1-C6Miscellaneous alkyl, unsubstituted C3-C6
First 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 oxobutyric acid ethyl esters (300mg, 1.4mmol) of 4-, room temperature magnetic agitation are reacted 1~2h, subtracted
Pressure concentration removes solvent, and residue is heated to reflux 3h after being dissolved with 10ml ethanol, TLC detection reactions are complete.Reaction solution natural cooling
It is concentrated under reduced pressure after to room temperature and removes ethanol.Residue is washed with saturated sodium bicarbonate solution, and water layer is extracted with dichloromethane, organic
Layer solvent is stayed overnight using anhydrous sodium sulfate drying, is filtered and is concentrated, residue column chromatography, obtains yellow solid, i.e. intermediate 2.MS is counted
Calculation value 235, measured value 254 [M+1].
Step b
Under normal temperature condition, 150mg intermediates 2 are dissolved in 20ml ethanol, gradually add 2ml hydrochloric acid and 15mg platinum dioxides,
Nitrogen is protected, and is passed through hydrogen (50psi) and is reacted 16h in 50 DEG C of magnetic agitations, and TLC detection reactions are complete, reaction solution concentrated half,
Filter, obtain white solid 120mg, i.e. intermediate 3.MS:238[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 using anhydrous sodium sulfate drying, is filtered, is concentrated under reduced pressure, residue column chromatography (PE:EA=1：2), obtain light yellow
Solid 68mg, i.e. intermediate 4.Yield 32.4%.
Step d
Condition of ice bath, nitrogen protection, adds 3.1g intermediates 4 into 250ml there-necked flasks and THF120ml is (specially anhydrous
Tetrahydrofuran), 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, is stayed overnight using anhydrous sodium sulfate drying, is filtered, and after filtrate concentration, is obtained intermediate 5 and is directly used in reaction in next step.Its
In, in step d, the mol ratio for the dichloromethane (DCM) in the mixed solution that is extracted and methanol (MeOH) is 3:1.
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, and organic layer solution is stayed overnight using anhydrous sodium sulfate drying, filter, filtrate concentration, residue
(DCM/MeOH=1/1~10/1, mol ratio in eluent) is separated using silica gel column chromatography, obtains the about 589mg of intermediate 6, is produced
Rate 58.2%.MS:369[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, and anhydrous slufuric acid is used to organic layer solution
Sodium 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:327[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 the crude product of intermediate 8, and the crude product of intermediate 8 is not required to pure
Change is directly used in reacts in next step.
MS:345[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 and wash 2 times, each 10ml with saturated brine, then anhydrous sodium sulfate drying is stayed overnight, and is filtered, and is filtered
Liquid is concentrated, and residue is separated using silica gel column chromatography, obtains white solid 60mg, i.e. intermediate 9.MS:336[M+H]+。
Step i
500mg racemate intermediates 9 are split by hand-type post, then 35 DEG C of isopropanol recrystallizes to obtain white solid
170mg, target product 10, target product 11, target product 12 and target product 13 are produced, optical purity is above 99.72%.
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-w1024Anti-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-w1024Anti-phosphotyrosine (PT66)
The final concentration of 10mM of final concentration of 2nM, EDTA, it is incubated at room temperature 60min, Envision instrument read plates.
Data analysis
Reading is converted into by inhibiting rate (%)=(Min-Ratio)/(Max-Min) × 100% by following equation.Four ginsengs
Curve fit (Model 205inXLFIT5iDBS) measures IC50 data, specifically see the table below.
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 CN, OH, NH2、Me、Et、CF3、CH2CF3、NHCH3、N(CH3)2Or halogen；
R1Selected 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-C6Miscellaneous alkyl, unsubstituted C3-C6Yuan of rings
Alkyl 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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| Application Number | Priority Date | Filing Date | Title |
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| CN201711049479.8A CN107778321A (en) | 2017-10-31 | 2017-10-31 | A kind of tropsch imatinib analog |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711049479.8A CN107778321A (en) | 2017-10-31 | 2017-10-31 | A kind of tropsch imatinib analog |
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Cited By (7)
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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 |
| CN107602591A (en) * | 2017-10-31 | 2018-01-19 | 无锡福祈制药有限公司 | A kind of JAK3 inhibitor |
| 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 |
| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
| 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 |
| CN107805259A (en) * | 2017-10-31 | 2018-03-16 | 无锡福祈制药有限公司 | A kind of azolopyrimidines |
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Cited By (7)
| 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 |
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| 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 |
| CN107722006A (en) * | 2017-10-31 | 2018-02-23 | 无锡福祈制药有限公司 | A kind of thalidomide analogs |
| 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 |
| CN107805259A (en) * | 2017-10-31 | 2018-03-16 | 无锡福祈制药有限公司 | A kind of azolopyrimidines |
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