CN107383015B - The application of amino-pyrazol simultaneously [3,4-d] pyrimidine derivatives and anti-non-small cell lung cancer of alkane sulphur end group widow PEG modification - Google Patents
The application of amino-pyrazol simultaneously [3,4-d] pyrimidine derivatives and anti-non-small cell lung cancer of alkane sulphur end group widow PEG modification Download PDFInfo
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- CN107383015B CN107383015B CN201710533525.5A CN201710533525A CN107383015B CN 107383015 B CN107383015 B CN 107383015B CN 201710533525 A CN201710533525 A CN 201710533525A CN 107383015 B CN107383015 B CN 107383015B
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- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/04—Ortho-condensed systems
Abstract
The application of amino-pyrazol simultaneously [3,4-d] pyrimidine derivatives and anti-non-small cell lung cancer of alkane sulphur end group widow PEG modification.The invention discloses pyrazolo [3,4-d] pyrimidine derivatives shown in formula (I).Compound on tumor cell provided by the invention has significant inhibition accretion, can be used for preventing and/or treating tumor-related illness, is with a wide range of applications.
Description
Technical field
The invention belongs to compound medicine fields, and in particular to pyrazolo [3,4-d] pyrimidine derivatives and its application.
Background technique
Malignant growth speed is fast, in infiltrative growth, Yi Fasheng bleeding, necrosis, ulcer etc., and often has and turns at a distance
It moves, causes human body syntexis, inability, anaemia, loss of appetite, fever and serious organ function impaired, it is dead to ultimately cause patient
It dies, has huge threat to population health and life.
Operative treatment radical excision is still current most basic and common cancer treatment method, but usual resection operation
Traumatic larger, the postoperative damage that will cause body tissue and the loss of qi and blood, so being not suitable for the elderly, own bodies quality
It is poor and merge intentionally, lung, the important organs disease patient such as liver select, it is therefore desirable to develop new chemotherapy.In addition,
Chemotherapy is also current treatment one of tumour and the main means of certain autoimmune diseases.Although in the market
There are the drugs of a variety for the treatment of cancers, but all there is various defects, such as bioavilability is not high, specificity is not strong, poison
The problems such as side effect is big.And these defects, brought by the design feature and its action target often caused by compound itself,
It is difficult to overcome in further research and development.
Therefore, those skilled in the art are intended to synthesize the multiple compounds of configurations and explore to new action target
To overcome aforementioned drawback.
Summary of the invention
It is an object of that present invention to provide a kind of pyrazolo of brand new [3,4-d] pyrimidine derivatives.
Formula (I) compound represented or its pharmaceutically acceptable salt or its solvate:
Wherein,
R1Expression-NH2、-NH(C1-C4Alkyl) or-N (C1-C4Alkyl)2；
R2Indicate hydrogen or C1-C6Alkyl；
R3Indicate hydrogen or C1-C6Alkyl；
R4Indicate a substituent group on phenyl ring, wherein substituent group is selected from-(OR5)n-X-R6；
N indicates 0~10 integer；
R5Selected from methylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptamethylene, octamethylene, nonylene
Or decylene；
R6The phenyl replaced selected from 0~2, substituent group therein are selected from halogen, hydroxyl, carboxyl, nitro, amino, methyl, second
Base, propyl or isopropyl
X indicates hetero atom.
Further, R1For-NH2。
Further, R2For hydrogen.
Further, R3For C1-C6Alkyl.
Further, R3For tert-butyl.
Further, R1For-NH2, and R2For hydrogen, and R3For tert-butyl.
Further, 0,1,2,3 or 4 n.
Further, R5For ethylidene.
Further, the hetero atom is O or S,
Preferably, the hetero atom is S.
Further, R6For alkyl-substituted phenyl, alkyl therein is selected from methyl, ethyl, propyl or isopropyl.
Further, R6For tolyl.
Further, above compound structure are as follows:
The invention discloses above compound or its solvate or its pharmaceutically acceptable salt prepare it is antitumor
Purposes in drug.
Further, the tumour is non-small cell lung cancer.
The invention discloses a kind of pharmaceutical compositions, it is characterised in that: it is described in any item with claim 1~13
Compound or its solvate or its pharmaceutically acceptable salt are active constituent, in addition prepared by pharmaceutically acceptable auxiliary material
Made of preparation.
In the present invention, " treatment " also includes recurrent (relapse) prevention or interim (phase) prevention and acute
Or the treatment of chronic sign, symptom and/or malfunction.Treatment can be symptomatic treatment, such as inhibit symptom.It can be short
It realizes, is adjusted in mid-term, or can be described as long-term treatment, such as inside maintenance therapy in phase.
" prevention " includes delay and/or the breaking-out for preventing illness, disease or the patient's condition and/or its concomitant symptom；It prevents
Object catches illness, disease or the patient's condition；Or reduce the method that object catches the risk of illness, disease or the patient's condition.
In the present invention, " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or is formed by
Salt usually in chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually simultaneous with receptor
Hold.
In the present invention, " salt " is the acid by compound or its stereoisomer, with the formation of inorganic and/or organic bronsted lowry acids and bases bronsted lowry
And/or basic salt, also include amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.These salt can be
Compound being finally separating and directly obtaining in purifying.It is also possible to by by compound or its stereoisomer, with a fixed number
The acid or alkali of amount appropriate (such as equivalent) are obtained by mixing.These salt may be formed in the solution precipitating and with filtering side
Method is collected, or recycles obtain after the solvent evaporates, or is freeze-dried and is made after reacting in an aqueous medium.Heretofore described salt
It can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, the acetic acid of compound
Salt, propionate, succinate, oxalates, malate, succinate, fumarate, maleate, tartrate or trifluoro
Acetate.
Test result shows that the compound of the present invention plays the role of lung cancer cell types to inhibit cell Proliferation.
Obviously, above content according to the present invention is not being departed from according to the ordinary technical knowledge and customary means of this field
Under the premise of the above-mentioned basic fundamental thought of the present invention, the modification, replacement or change of other diversified forms can also be made.
Detailed description of the invention
In following attached drawings, number Huaxi03-12 corresponds to the compounds of this invention 4, the corresponding present inventionization of number Huaxi03-11
Close object 6；PP1 is Src inhibitor positive control drug.
Fig. 1: in 48h and 72h, Huaxi03-12, Huaxi03-11 and PP1 be various concentration (12.5um, 25um,
50um, 80um, 100um) when, the survival rate of A549.
Fig. 2: in 48h and 72h, Huaxi03-12, Huaxi03-11 and PP1 to A549 different high concentrations (50um,
80um, 100um) inhibiting rate.
Specific embodiment
The specific embodiment of form by the following examples remakes further specifically above content of the invention
It is bright.But the range that this should not be interpreted as to the above-mentioned theme of the present invention is only limitted to example below.It is all to be based on above content of the present invention
The technology realized all belongs to the scope of the present invention.
In following embodiments, key intermediate product can be obtained by self-control, remaining all reagent for participating in synthesis
It is commercially available from traditional Chinese medicines, Long March company.
The preparation of 1 compound 4 of embodiment
Compound 1 (269mg, 1mmol) is dissolved in Isosorbide-5-Nitrae-dioxane/water (4:1) 150ml solution, and is transferred to
In the round-bottomed flask of 250ml, then (1.38g, 10mol) potassium carbonate is added into reaction solution, is stirred at room temperature after three minutes,
The double diphenyl phosphine ferrocene of catalyst are added and close palladium chloride (73.1mg, 0.1mol), reaction mixture is heated to 100 DEG C, is led to
TLC detection reaction is crossed, after reacting and terminating, firstly, cooling to reaction solution, the distilled water of 50ml is added, is then transferred into point
In liquid funnel, the methylene chloride that 100ml is added is extracted 3 times, merges organic phase, and anhydrous sodium sulfate is added, is spin-dried for organic solvent, with
Methylene chloride/methanol (100:2.5) be eluant, eluent, by silica gel column chromatography separating purification obtain intermediate compound 2 (200mg,
70%).
1H NMR (600MHz, DMSO-6d) δ 9.83 (s, 1H, HOAr), 8.28 (s, 1H, CH), 6.97-7.83 (m, 4H,
Ar), 5.83 (s, 1H), 1.80 (m, 9H, t-Bu)；HR-MS (ESI+): Calc.for [C15H17N5O]:284.1433 [M+H]+；
Found 284.1513[M+H]+。
Compound 2 (283mg, 1mol) is dissolved in the anhydrous acetonitrile of 20ml, is then added to by dropping funel
In the acetonitrile solution of (68mg, 0.5mol) cesium carbonate and two p-methyl benzenesulfonic acid triglycol esters, back flow reaction 3 hours passes through TLC
The progress for monitoring reaction after reaction solution is cooling, is added the distilled water of 50ml, is then transferred into separatory funnel to the end of reacting
In, the methylene chloride that 100ml is added extracts 3 times, merges organic phase, and anhydrous sodium sulfate is added, organic solvent is spin-dried for, with dichloromethane
Alkane/methanol (100:1) is eluant, eluent, obtains intermediate compound 3 (400mg, 76%) by silica gel column chromatography separating purification.
1H NMR(600MHz,DMSO-d6)δ8.22(s,1H),7.79-7.06(m,8H,Ar),4.51–3.50(t,8H),
4.10–4.05(m,6H),2.36(s,3H),1.72(s,9H)；HR-MS (ESI+): Calc.for [C26H31N5O5S]:
526.2046[M+H]+；Found 526.1277[M+H]+.
The synthesis of compound 4: (Huaxi03-12)
Compound 3 (525mg, 1mol) is dissolved in the anhydrous acetonitrile of 20ml, is then added to by dropping funel
In the acetonitrile solution of (68mg, 0.5mol) cesium carbonate and benzenethiol, back flow reaction 3 hours, by TLC monitoring reaction into
Row, to the end of reacting, after reaction solution is cooling, the distilled water of 50ml is added, is then transferred into separatory funnel, 100ml is added
Methylene chloride extract 3 times, merge organic phase, be added anhydrous sodium sulfate, organic solvent is spin-dried for, with methylene chloride/methanol
(100:1) is eluant, eluent, obtains intermediate compound 5 (400mg, 83%) by silica gel column chromatography separating purification.
1H NMR(600MHz,DMSO-d6)δ8.21(s,1H),7.57–7.08(m,8H),4.13–3.09(m,8H),
2.24(s,3H),1.73(s,9H)；HR-MS (ESI+): Calc.for [C20H27N5O3]: 478.2198 [M+H]+； Found
478.2271[M+H]+。
Embodiment 2
The synthesis of compound 2:
Compound 1 (269mg, 1mmol) is dissolved in Isosorbide-5-Nitrae-dioxane/water (4:1) 150ml solution, and is transferred to
In the round-bottomed flask of 250ml, then (1.38g, 10mol) potassium carbonate is added into reaction solution, is stirred at room temperature after three minutes,
The double diphenyl phosphine ferrocene of catalyst are added and close palladium chloride (73.1mg, 0.1mol), reaction mixture is heated to 100 DEG C, is led to
TLC detection reaction is crossed, after reacting and terminating, firstly, cooling to reaction solution, the distilled water of 50ml is added, is then transferred into point
In liquid funnel, the methylene chloride that 100ml is added is extracted 3 times, merges organic phase, and anhydrous sodium sulfate is added, is spin-dried for organic solvent, with
Methylene chloride/methanol (100:2.5) be eluant, eluent, by silica gel column chromatography separating purification obtain intermediate compound 2 (200mg,
70%).
1H NMR (600MHz, DMSO-6d) δ 9.83 (s, 1H, HO Ar), 8.28 (s, 1H, CH), 6.97-7.83 (m,
4H, Ar), 5.83 (s, 1H), 1.80 (m, 9H, t-Bu)；HR-MS (ESI+): Calc.for [C15H17N5O]: 284.1433 [M
+H]+；Found 284.1513[M+H]+.
The synthesis of compound 5:
Compound 2 (283mg, 1mol) is dissolved in the anhydrous acetonitrile of 20ml, is then added to by dropping funel
In (68mg, 0.5mol) cesium carbonate and the acetonitrile solution of tetraethylene glycol bis- (p-methyl benzenesulfonic acid esters), back flow reaction 5 hours, pass through
After reaction solution is cooling, the distilled water of 50ml is added to the end of reacting in the progress of TLC monitoring reaction, is then transferred into liquid separation leakage
In bucket, the methylene chloride that 100ml is added is extracted 3 times, merges organic phase, and anhydrous sodium sulfate is added, organic solvent is spin-dried for, with dichloro
Methane/methanol (100:1) is eluant, eluent, obtains intermediate compound 5 (500mg, 81.6%) by silica gel column chromatography separating purification.
1H NMR(600MHz,DMSO-d6)δ8.22(s,1H),7.79-7.06(m,8H,Ar),4.51–3.50(t,8H),
4.10–4.05(m,6H),2.36(s,3H),1.72(s,9H)；HR-MS (ESI+): Calc.for [C26H31N5O5S]:
526.2046[M+H]+；Found 526.1277[M+H]+.
The synthesis of compound 6:
Compound 5 (613mg, 1mol) is dissolved in the anhydrous acetonitrile of 20ml, is then added to by dropping funel
In the acetonitrile solution of (68mg, 0.5mol) cesium carbonate and benzenethiol, back flow reaction 6 hours, by TLC monitoring reaction into
Row, to the end of reacting, after reaction solution is cooling, the distilled water of 50ml is added, is then transferred into separatory funnel, 100ml is added
Methylene chloride extract 3 times, merge organic phase, be added anhydrous sodium sulfate, organic solvent is spin-dried for, with methylene chloride/methanol
(100:1) is eluant, eluent, obtains intermediate compound 6 (500mg, 88.5%) by silica gel column chromatography separating purification.
1H NMR(600MHz,DMSO-d6)δ8.22(s,1H),7.55–7.07(m,8H),4.14–3.03(m,16H),
2.21(s,3H),1.72(s,9H)；HR-MS (ESI+): Calc.for [C20H27N5O3]: 566.2723 [M+H]+； Found
566.2797[M+H]+。
Illustrate beneficial effects of the present invention below by way of test
Test 1. cyto-inhibitions
It is yellow compound using MTT detection method, is a kind of hydrionic dyestuff of receiving, may act on living cells line
Breathing in plastochondria.
Lung cancer cell line: A549 chain, tetrazolium ring opening under the action of succinate dehydrogenase and cromoci,
The formanzan crystallization of blue is generated, the production quantity of formazan crystallization is only directly proportional to number of viable cells, restores generation
Formanzan crystallization can dissolve in dimethyl sulfoxide (DMSO), measure OD value (OD) value at 490nm using microplate reader,
Living cells quantity can be reflected.
HuaXi03-12 drug is the compounds of this invention 4, and HuaXi03-11 drug is the compounds of this invention 6.
(1) experimental article: lung cancer cell line, cell culture outfit, MTT and compound stock solutions are 10mmol/L,
Positive control drug Src inhibitor PP1.
(2) experimental procedure:
A recovery A549, when in good condition, i.e., cell grows to 80% or so (i.e. logarithmic growth phase) progress after passage is primary
Bed board (96 orifice plate).
B collects cell, concentration of cell suspension is adjusted by tally, with 1000-10000, every hole cell inoculation to 96
Orifice plate, the cell number in specific every hole determine according to the speed of growth and drug treating time of different cells, 549 5000 Hes of paving
1299 pavings 5000, every hole 200ul (the drug dilution liquid of the various concentration gradient of the cell suspension+100ul of 100ul), lateral opening (36
It is a) plus 200ul's is double without culture medium, (edge effect in order to prevent).
After c bed board dosing, handled according to 48h, 72h, then colour generation, the training of every Kong Jiahan 20ulMTT solution (5mg/mL)
Nutrient solution 200ul continues to cultivate 1-4h, terminates culture, and careful inhale abandons culture supernatant in hole, after needing to be centrifuged for suspension cell
The culture supernatant abandoned in hole is inhaled again.Every hole adds 150ulDMSO, and 15~20min is shaken on shaking table, keeps crystal sufficiently molten
Solution.
D colorimetric: measuring in microplate reader, selects 490 or 570nm wavelength, to measure the absorbance value in each hole, records
As a result.
E is calculated
Inhibiting rate=(control-administration)/control × 100%
IC50When (half-inhibitory concentration) calculation can be asked with spass software according to the inhibiting rate of various concentration.
(2) experimental result:
A549 cytosis 48h and 72h, drug dose are divided into 12.5um, 25um, 50um, 80um, 100um, respectively bed board
6000 and 5000 cells are tested, as a result as shown in the following table 1~3 and Fig. 1~2:
Inhibiting effect (48h, 72h) of 1 the compounds of this invention 4 (Huaxi03-12) of table to A549
Inhibiting effect (48h, 72h) of 2 the compounds of this invention 6 (Huaxi03-11) of table to A549
Inhibiting effect (48h, 72h) of the 3 comparison medicine PP1 of table to A549
Fig. 1, Fig. 2 and table 1~3 the result shows that, the compounds of this invention 4 and compound 6 have A549 cell Proliferation bright
Aobvious inhibiting effect.
In conclusion compound on tumor cell provided by the invention, especially non-small cell lung cancer cell, have significant
Inhibit proliferaton effect, can be used for prevent and/or treat tumor-related illness, especially lung cancer, before having a wide range of applications
Scape.
Claims (10)
1. formula (I) compound represented or its pharmaceutically acceptable salt:
Wherein,
R1Expression-NH2、-NH(C1-C4Alkyl) or-N (C1-C4Alkyl)2；
R2Indicate hydrogen or C1-C6Alkyl；
R3Indicate hydrogen or C1-C6Alkyl；
R4A substituent group on phenyl ring is indicated, wherein the substituent group is selected from-(OR5)n-X-R6；
N indicates 1~10 integer；
R5Selected from methylene, ethylidene, propylidene, butylidene, pentylidene, hexylidene, heptamethylene, octamethylene, nonylene or the sub- last of the ten Heavenly stems
Base；
R6The phenyl replaced selected from 0~2, substituent group therein are selected from halogen, hydroxyl, carboxyl, nitro, amino, methyl, ethyl, third
Base or isopropyl；
X indicates hetero atom.
2. compound according to claim 1, it is characterised in that: R1For-NH2；And/or R2For hydrogen；And/or R3For C1-
C6Alkyl.
3. compound according to claim 2, it is characterised in that: R3For tert-butyl.
4. compound according to claim 3, it is characterised in that: R1For-NH2, and R2For hydrogen, and R3For tert-butyl.
5. compound according to claim 4, it is characterised in that: the integer that n is 1~4；And/or R5For ethylidene；With/
Or, the hetero atom is O or S；And/or R6For alkyl-substituted phenyl, alkyl therein is selected from methyl, ethyl, propyl or different
Propyl.
6. compound according to claim 5, it is characterised in that: the hetero atom is S, and/or, R6For tolyl.
7. compound according to claim 6, it is characterised in that: the compound structure are as follows:
8. compound described in claim 1~7 any one or its pharmaceutically acceptable salt are in the preparation of antitumor drugs
Purposes.
9. purposes according to claim 8, it is characterised in that: the tumour is non-small cell lung cancer.
10. a kind of pharmaceutical composition, it is characterised in that: it is with the described in any item compounds of claim 1~7 or its medicine
Acceptable salt is active constituent on, in addition the preparation that pharmaceutically acceptable auxiliary material is prepared.
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| CN201710533525.5A CN107383015B (en) | 2017-07-03 | 2017-07-03 | The application of amino-pyrazol simultaneously [3,4-d] pyrimidine derivatives and anti-non-small cell lung cancer of alkane sulphur end group widow PEG modification |
| PCT/CN2017/118483 WO2019007003A1 (en) | 2017-07-03 | 2017-12-26 | Alkanosulfide-terminated oligomer-peg modified amino-pyrazolo[3,4-d]pyrimidine derivative and application to non-small cell lung cancer resistance |
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| CN107383015B (en) * | 2017-07-03 | 2019-11-08 | 四川大学华西医院 | The application of amino-pyrazol simultaneously [3,4-d] pyrimidine derivatives and anti-non-small cell lung cancer of alkane sulphur end group widow PEG modification |
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| US9376438B2 (en) * | 2011-05-17 | 2016-06-28 | Principia Biopharma, Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
| AU2012283775A1 (en) * | 2011-07-13 | 2014-01-23 | Pharmacyclics Llc | Inhibitors of Bruton's tyrosine kinase |
| CN104844609B (en) * | 2015-05-12 | 2016-07-13 | 杭州和正医药有限公司 | The irreversible bruton's tyrosine kinase inhibitor of dibit point |
| CN106008527B (en) * | 2016-06-29 | 2018-05-15 | 四川大学华西医院 | Pyrazolo [3,4-d] pyrimidine derivatives |
| CN106831790B (en) * | 2017-02-17 | 2019-07-26 | 四川大学华西医院 | 7H- pyrrolo- [2,3-d] pyrimidine derivatives |
| CN107383015B (en) * | 2017-07-03 | 2019-11-08 | 四川大学华西医院 | The application of amino-pyrazol simultaneously [3,4-d] pyrimidine derivatives and anti-non-small cell lung cancer of alkane sulphur end group widow PEG modification |
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