CN107383015A - Alkylthio-terminal-group oligo-PEG-modified amino pyrazolo [3,4-d ] pyrimidine derivative and application thereof in resisting non-small cell lung cancer - Google Patents
Alkylthio-terminal-group oligo-PEG-modified amino pyrazolo [3,4-d ] pyrimidine derivative and application thereof in resisting non-small cell lung cancer Download PDFInfo
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- CN107383015A CN107383015A CN201710533525.5A CN201710533525A CN107383015A CN 107383015 A CN107383015 A CN 107383015A CN 201710533525 A CN201710533525 A CN 201710533525A CN 107383015 A CN107383015 A CN 107383015A
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- 208000002154 non-small cell lung carcinoma Diseases 0.000 title claims abstract description 6
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 title claims abstract description 6
- KFVFSHVEAMTYFQ-UHFFFAOYSA-N 2h-pyrazolo[3,4-d]pyrimidin-3-amine Polymers C1=NC=C2C(N)=NNC2=N1 KFVFSHVEAMTYFQ-UHFFFAOYSA-N 0.000 title abstract description 3
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims description 14
- 150000003839 salts Chemical class 0.000 claims description 14
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims description 9
- 239000001257 hydrogen Substances 0.000 claims description 9
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 6
- 125000005842 heteroatom Chemical group 0.000 claims description 6
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 6
- 239000012453 solvate Substances 0.000 claims description 6
- 125000001424 substituent group Chemical group 0.000 claims description 6
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
- -1 methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene Chemical group 0.000 claims description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 4
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 4
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 4
- AFFLGGQVNFXPEV-UHFFFAOYSA-N 1-decene Chemical group CCCCCCCCC=C AFFLGGQVNFXPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004480 active ingredient Substances 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000000816 ethylene group Chemical group [H]C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 229910052736 halogen Inorganic materials 0.000 claims description 2
- 125000005843 halogen group Chemical group 0.000 claims description 2
- 150000002431 hydrogen Chemical class 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 229910052760 oxygen Inorganic materials 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 229910052717 sulfur Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 7
- 230000002401 inhibitory effect Effects 0.000 abstract description 7
- 201000010099 disease Diseases 0.000 abstract description 6
- 238000011282 treatment Methods 0.000 abstract description 6
- 150000003230 pyrimidines Chemical class 0.000 abstract 1
- 230000004614 tumor growth Effects 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 36
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- 238000006243 chemical reaction Methods 0.000 description 22
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- 210000004027 cell Anatomy 0.000 description 16
- 239000000243 solution Substances 0.000 description 15
- 229940079593 drug Drugs 0.000 description 11
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000005160 1H NMR spectroscopy Methods 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 6
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- 239000012153 distilled water Substances 0.000 description 6
- 239000003480 eluent Substances 0.000 description 6
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- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical compound SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 6
- 238000000746 purification Methods 0.000 description 5
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 4
- 229910000024 caesium carbonate Inorganic materials 0.000 description 4
- 229940125782 compound 2 Drugs 0.000 description 4
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- 201000005202 lung cancer Diseases 0.000 description 4
- 208000020816 lung neoplasm Diseases 0.000 description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 4
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- VMGAPWLDMVPYIA-HIDZBRGKSA-N n'-amino-n-iminomethanimidamide Chemical compound N\N=C\N=N VMGAPWLDMVPYIA-HIDZBRGKSA-N 0.000 description 3
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- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- QUKPALAWEPMWOS-UHFFFAOYSA-N 1h-pyrazolo[3,4-d]pyrimidine Chemical class C1=NC=C2C=NNC2=N1 QUKPALAWEPMWOS-UHFFFAOYSA-N 0.000 description 2
- 229940122924 Src inhibitor Drugs 0.000 description 2
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- 238000012360 testing method Methods 0.000 description 2
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- KCONMNWPRXAWKK-UHFFFAOYSA-N 2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCOCCOCCOS(=O)(=O)C1=CC=C(C)C=C1 KCONMNWPRXAWKK-UHFFFAOYSA-N 0.000 description 1
- SLAONPBUWDUSSO-UHFFFAOYSA-N 2-[2-[2-[2-(4-methylphenyl)sulfonyloxyethoxy]ethoxy]ethoxy]ethyl 4-methylbenzenesulfonate Chemical compound C1=CC(C)=CC=C1S(=O)(=O)OCCOCCOCCOCCOS(=O)(=O)C1=CC=C(C)C=C1 SLAONPBUWDUSSO-UHFFFAOYSA-N 0.000 description 1
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
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- 206010006895 Cachexia Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 102000018832 Cytochromes Human genes 0.000 description 1
- 108010052832 Cytochromes Proteins 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 238000000134 MTT assay Methods 0.000 description 1
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- 206010027476 Metastases Diseases 0.000 description 1
- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 102000019259 Succinate Dehydrogenase Human genes 0.000 description 1
- 108010012901 Succinate Dehydrogenase Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 238000002835 absorbance Methods 0.000 description 1
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- 125000005210 alkyl ammonium group Chemical group 0.000 description 1
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- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 238000004364 calculation method Methods 0.000 description 1
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- 238000002512 chemotherapy Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- LBJNMUFDOHXDFG-UHFFFAOYSA-N copper;hydrate Chemical compound O.[Cu].[Cu] LBJNMUFDOHXDFG-UHFFFAOYSA-N 0.000 description 1
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- 238000011866 long-term treatment Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000007257 malfunction Effects 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
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- 150000007524 organic acids Chemical class 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Alkylthio-terminal-group oligo-PEG-modified amino pyrazolo [3,4-d]Pyrimidine derivatives and their use for the treatment of non-small cell lung cancer. The invention discloses pyrazolo [3,4-d ] s of formula (I)]A pyrimidine derivative. The compound provided by the invention has obvious effect of inhibiting growth of tumor cellsCan be used for preventing and/or treating tumor-related diseases, and has wide application prospect.
Description
Technical Field
The invention belongs to the field of compound medicines, and particularly relates to a pyrazolo [3,4-d ] pyrimidine derivative and application thereof.
Background
Malignant tumor has fast growth speed, infiltrative growth, easy occurrence of hemorrhage, necrosis, ulcer and the like, and often has distant metastasis, which causes emaciation, weakness, anemia, inappetence, fever and serious organ function damage of human body, finally causes death of patients, and has great threat to human health and life.
Surgical treatment radical resection is still the most basic and common cancer treatment method at present, but generally the resection operation has larger trauma, and can cause the damage of body tissues and the loss of qi and blood after the surgery, so the surgery is not suitable for the elderly and the patients with poor physical quality and the diseases of the vital organs such as heart, lung, liver and the like, and therefore, new chemical drug treatment needs to be developed. In addition, chemotherapy is also one of the main approaches for treating tumors and some autoimmune diseases at present. Although various drugs for treating cancer exist in the market, the drugs have various defects, such as low bioavailability, low specificity, high toxic and side effects and the like. These defects are often caused by the structural features of the compound itself and its action target, and are difficult to overcome in further research and development.
Therefore, it is desirable to synthesize various compounds with different structures and to explore new targets for action to overcome the aforementioned drawbacks.
Disclosure of Invention
The invention aims to provide a pyrazolo [3,4-d ] pyrimidine derivative with a novel structure.
A compound of formula (I) or a pharmaceutically acceptable salt, or solvate thereof:
wherein,
R1represents-NH2、-NH(C1-C4Alkyl) or-N (C)1-C4Alkyl radical)2；
R2Represents hydrogen or C1-C6An alkyl group;
R3represents hydrogen or C1-C6An alkyl group;
R4represents a substituent on the benzene ring, wherein the substituent is selected from- (OR)5)n-X-R6；
n represents an integer of 0 to 10;
R5selected from methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, or decylene;
R6is selected from 0-2 substituted phenyl, wherein the substituent is selected from halogen, hydroxyl, carboxyl, nitro, amino, methyl, ethyl, propyl or isopropyl
X represents a hetero atom.
Further, R1is-NH2。
Further, R2Is hydrogen.
Further, R3Is C1-C6An alkyl group.
Further, R3Is a tert-butyl group.
Further, R1is-NH2And R is2Is hydrogen, and R3Is a tert-butyl group.
Further, n is 0, 1, 2, 3 or 4.
Further, R5Is an ethylene group.
Further, the heteroatom is O or S,
preferably, the heteroatom is S.
Further, R6Is phenyl substituted by alkyl, wherein the alkyl is selected from methyl, ethyl, propyl or isopropyl.
Further, R6Is tolyl.
Further, the above compound has the structure:
the invention discloses application of the compound, or a solvate thereof, or a pharmaceutically acceptable salt thereof in preparing an anti-tumor medicament.
Further, the tumor is non-small cell lung cancer.
The invention discloses a pharmaceutical composition, which is characterized in that: the compound, the solvate thereof or the pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable auxiliary materials.
In the present invention, "treatment" also includes recurrent (relapse) or phase (phase) prevention, as well as treatment of acute or chronic signs, symptoms and/or malfunctions. The treatment may be symptomatic treatment, e.g. suppression of symptoms. It can be achieved in the short term, adjusted in the medium term, or it can be said that it is a long term treatment, for example in maintenance therapy.
Such "preventing" includes delaying and/or arresting the onset of the disorder, disease or condition and/or its attendant symptoms; preventing the subject from contracting the disorder, disease, or condition; or reducing the risk of contracting a disorder, disease, or condition in a subject.
As used herein, "pharmaceutically acceptable" means that the carrier, cargo, diluent, excipient, and/or salt formed is generally chemically or physically compatible with the other ingredients comprising a pharmaceutical dosage form and is physiologically compatible with the recipient.
In the present invention, the "salt" is an acid and/or base salt of a compound or a stereoisomer thereof with an inorganic and/or organic acid and a base, and also includes a zwitterionic salt (inner salt), and also includes a quaternary ammonium salt such as an alkylammonium salt. These salts can be obtained directly in the final isolation and purification of the compounds. The compound, or a stereoisomer thereof, may be obtained by appropriately (e.g., equivalentlymixing) a certain amount of an acid or a base. These salts may form precipitates in the solution which are collected by filtration, or they may be recovered after evaporation of the solvent, or they may be prepared by reaction in an aqueous medium followed by lyophilization. The salt in the invention can be hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromide, hydrofluoride, phosphate, acetate, propionate, succinate, oxalate, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate of the compound.
Test results show that the compound has the effect of inhibiting cell proliferation on a lung cancer cell strain A549.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
Drawings
In the following figures, the number Huaxi03-12 corresponds to Compound 4 of the invention, and the number Huaxi03-11 corresponds to Compound 6 of the invention; PP1 is a positive control for Src inhibitor.
FIG. 1: survival of a549 was obtained at different concentrations (12.5um, 25um, 50um, 80um, 100um) of Huaxi03-12, Huaxi03-11, and PP1 at 48h and 72 h.
FIG. 2: inhibition rates of A549 at different high concentrations (50um, 80um, 100um) were determined by Huaxi03-12, Huaxi03-11 and PP1 at 48h and 72 h.
Detailed Description
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
In the following examples, the key intermediate product was obtained by self-production, and all the other reagents involved in the synthesis were purchased from national drug and Yangtze company.
EXAMPLE 1 preparation of Compound 4
Compound 1(269mg,1mmol) was dissolved in 150ml of 1, 4-dioxane/water (4:1) solution and transferred to a 250ml round bottom flask, potassium carbonate (1.38g,10mol) was added to the reaction solution, after stirring at room temperature for three minutes, the catalyst bis-diphenylphosphino ferrocene palladium chloride (73.1mg, 0.1mol) was added, the reaction mixture was heated to 100 ℃ and the reaction was detected by TLC, after the reaction was completed, first, the reaction solution was cooled, 50ml of distilled water was added, then transferred to a separatory funnel, 100ml of dichloromethane was added and extracted 3 times, the organic phases were combined, anhydrous sodium sulfate was added, the organic solvent was spin-dried, and then, using dichloromethane/methanol (100:2.5) as an eluent, the intermediate compound 2(200mg, 70%) was obtained by separation and purification by silica gel column chromatography.
1H NMR(600MHz,DMSO-6d)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) was dissolved in 20ml of anhydrous acetonitrile, and then added to an acetonitrile solution of cesium carbonate (68mg, 0.5mol) and triethylene glycol di-p-toluenesulfonate via a dropping funnel, reflux reaction was carried out for 3 hours, progress of the reaction was monitored by TLC, after the reaction was completed, 50ml of distilled water was added after the reaction liquid was cooled, and then transferred to a separating funnel, extraction was carried out 3 times by adding 100ml of dichloromethane, the organic phases were combined, anhydrous sodium sulfate was added, the organic solvent was spin-dried, and separation and purification by silica gel column chromatography using dichloromethane/methanol (100:1) as an eluent gave intermediate compound 3(400mg, 76%).
1H NMR(600MHz,DMSO-d6)8.22(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]+。
Synthesis of Compound 4: (Huaxi03-12)
Compound 3(525mg, 1mol) was dissolved in 20ml of anhydrous acetonitrile, and then added to an acetonitrile solution of cesium carbonate and benzenethiol (68mg, 0.5mol) through a dropping funnel, the reaction was refluxed for 3 hours, progress of the reaction was monitored by TLC, after the reaction was completed, 50ml of distilled water was added to the reaction solution, which was then transferred to a separatory funnel, extracted 3 times with 100ml of dichloromethane, the organic phases were combined, anhydrous sodium sulfate was added, the organic solvent was spin-dried, and the intermediate compound 5(400mg, 83%) was obtained by separation and purification by silica gel column chromatography using dichloromethane/methanol (100:1) as an eluent.
1H NMR(600MHz,DMSO-d6)8.21(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]+； Found478.2271[M+H]+。
Example 2
Synthesis of Compound 2:
compound 1(269mg,1mmol) was dissolved in 150ml of 1, 4-dioxane/water (4:1) solution and transferred to a 250ml round bottom flask, potassium carbonate (1.38g,10mol) was added to the reaction solution, after stirring at room temperature for three minutes, the catalyst bis-diphenylphosphino ferrocene palladium chloride (73.1mg, 0.1mol) was added, the reaction mixture was heated to 100 ℃ and the reaction was detected by TLC, after the reaction was completed, first, the reaction solution was cooled, 50ml of distilled water was added, then transferred to a separatory funnel, 100ml of dichloromethane was added and extracted 3 times, the organic phases were combined, anhydrous sodium sulfate was added, the organic solvent was spin-dried, and then, using dichloromethane/methanol (100:2.5) as an eluent, the intermediate compound 2(200mg, 70%) was obtained by separation and purification by silica gel column chromatography.
1H NMR(600MHz,DMSO-6d)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]+。
Synthesis of Compound 5:
compound 2(283mg, 1mol) was dissolved in 20ml of anhydrous acetonitrile, and then added to an acetonitrile solution of cesium carbonate (68mg, 0.5mol) and tetraethylene glycol bis (p-toluenesulfonate) via a dropping funnel, and refluxed for 5 hours, progress of the reaction was monitored by TLC, and after the reaction was completed, the reaction solution was cooled, 50ml of distilled water was added, and then transferred to a separating funnel, and extracted 3 times with 100ml of dichloromethane, and the organic phases were combined, added with anhydrous sodium sulfate, dried with an organic solvent, and separated and purified by silica gel column chromatography using dichloromethane/methanol (100:1) as an eluent to give intermediate compound 5(500mg, 81.6%).
1H NMR(600MHz,DMSO-d6)8.22(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]+。
Synthesis of Compound 6:
compound 5(613mg, 1mol) was dissolved in 20ml of anhydrous acetonitrile, and then added to an acetonitrile solution of cesium carbonate and benzenethiol (68mg, 0.5mol) through a dropping funnel, and the reaction was refluxed for 6 hours, and progress of the reaction was monitored by TLC, and after the reaction was completed, 50ml of distilled water was added and then transferred to a separatory funnel, and extracted 3 times with 100ml of dichloromethane, and the organic phases were combined, added with anhydrous sodium sulfate, and spin-dried with an organic solvent, and separated and purified by silica gel column chromatography using dichloromethane/methanol (100:1) as an eluent to give intermediate compound 6(500mg, 88.5%).
1H NMR(600MHz,DMSO-d6)8.22(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]+； Found566.2797[M+H]+。
The following experiments illustrate the advantageous effects of the present invention
Test 1 cytostatic Effect
MTT assay is used, which is a yellow compound, a dye that accepts hydrogen ions, and acts on respiration in the mitochondria of living cells.
Lung cancer cell lines: and (2) cracking a tetrazolium ring under the action of succinate dehydrogenase and cytochrome C to generate blue formazan crystals, wherein the generation amount of the formazan crystals is only in direct proportion to the number of living cells, the formazan crystals generated by reduction can be dissolved in dimethyl sulfoxide (DMSO), and the number of the living cells can be reflected by measuring the Optical Density (OD) value at 490nm by using a microplate reader.
The drug HuaXi03-12 is Compound 4 of the present invention and the drug HuaXi03-11 is Compound 6 of the present invention.
(1) Experimental articles: lung cancer cell strain, tool for cell culture, MTT and compound mother liquor are 10mmol/L, and positive control drug Src inhibitor PP 1.
(2) The experimental steps are as follows:
and a, recovering A549, and when the state is good, namely the cells grow to about 80 percent after one passage (namely a logarithmic growth phase), plating (96-well plates).
b, collecting cells, adjusting the concentration of cell suspension by a counting plate, inoculating 1000-10000 cells per well to a 96-well plate, wherein the number of the cells per well is determined according to the growth speed and the drug action time of different cells, 549 paving 5000 and 1299 paving 5000, 200ul (100ul of cell suspension +100ul of drug dilution with different concentration gradients) per well, and adding 200ul of double-non culture medium into side wells (36 wells) (in order to prevent edge effect).
c, after adding medicine to the plate, treating according to 48h and 72h, then coloring, adding 200ul of culture solution containing 20ul of MTT solution (5mg/mL) into each hole, continuing culturing for 1-4h, stopping culturing, carefully sucking and discarding culture supernatant in the holes, and sucking and discarding culture supernatant in the holes after centrifuging suspension cells. Adding 150ul DMSO per well, and shaking on a shaking table for 15-20 min to fully dissolve the crystals.
d, color comparison: the absorbance of each well was measured on a microplate reader by selecting a wavelength of 490 or 570nm, and the results were recorded.
e calculation
Inhibition ═ control-dosing)/control × 100%
IC50(half inhibitory concentration) the inhibitory rate was calculated by the span software according to the concentration.
(2) The experimental results are as follows:
the A549 cells act for 48h and 72h, the drug dose is divided into 12.5um, 25um, 50um, 80um and 100um, and the cells of 6000 and 5000 cells are respectively plated for experiment, and the results are shown in the following tables 1-3 and figures 1-2:
TABLE 1 inhibitory Effect of Compound 4 of the present invention (Huaxi03-12) on A549 (48h, 72h)
TABLE 2 inhibitory Effect of Compound 6 of the present invention (Huaxi03-11) on A549 (48h, 72h)
TABLE 3 inhibitory Effect of control PP1 on A549 (48h, 72h)
The results of figure 1, figure 2 and tables 1-3 show that the compound 4 and the compound 6 both have obvious inhibition effect on A549 cell proliferation.
In conclusion, the compound provided by the invention has a remarkable proliferation inhibition effect on tumor cells, especially non-small cell lung cancer cells, can be used for preventing and/or treating tumor-related diseases, especially lung cancer, and has a wide application prospect.
Claims (10)
1. A compound of formula (I) or a pharmaceutically acceptable salt, or solvate thereof:
wherein,
R1represents-NH2、-NH(C1-C4Alkyl) or-N (C)1-C4Alkyl radical)2；
R2Represents hydrogen or C1-C6An alkyl group;
R3represents hydrogen or C1-C6An alkyl group;
R4represents a substituent on the benzene ring, wherein the substituent is selected from- (OR)5)n-X-R6；
n represents an integer of 0 to 10;
R5selected from methylene, ethylene, propylene, butylene, pentylene, hexylene, heptylene, octylene, nonylene, or decylene;
R6the compound is selected from 0-2 substituted phenyl, wherein the substituent is selected from halogen, hydroxyl, carboxyl, nitro, amino, methyl, ethyl, propyl or isopropyl;
x represents a hetero atom.
2. The compound of claim 1, wherein: r1is-NH2(ii) a And/or, R2Is hydrogen; and/or, R3Is C1-C6An alkyl group.
3. The compound of claim 1 or 2, wherein: r3Is a tert-butyl group.
4. A compound according to any one of claims 1 to 3, characterized in that: r1is-NH2And R is2Is hydrogen, and R3Is a tert-butyl group.
5. A compound according to any one of claims 1 to 4, characterized in that: n is an integer of 0 to 4; and/or, R5Is an ethylene group; and/or, the heteroatom is O or S; and/or, R6Is phenyl substituted by alkyl, wherein the alkyl is selected from methyl, ethyl, propyl or isopropyl.
6. According to claim 1 or 5The compound is characterized in that: the heteroatom is S, and/or, R6Is tolyl.
7. The compound according to any one of claims 1 to 6, wherein: the structure of the compound is as follows:
8. use of a compound of any one of claims 1 to 7, or a solvate or pharmaceutically acceptable salt thereof, in the preparation of an anti-tumor medicament.
9. Use according to claim 8, characterized in that: the tumor is non-small cell lung cancer.
10. A pharmaceutical composition characterized by: the compound, the solvate thereof or the pharmaceutically acceptable salt thereof as an active ingredient, and pharmaceutically acceptable auxiliary materials.
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| 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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| WO2018209961A1 (en) * | 2017-05-19 | 2018-11-22 | 四川大学华西医院 | Alkoxyl terminal group oligo-peg modified aminopyrimidine derivative and antitumor application |
| WO2019007003A1 (en) * | 2017-07-03 | 2019-01-10 | 四川大学华西医院 | 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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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103857396A (en) * | 2011-07-13 | 2014-06-11 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN104844609A (en) * | 2015-05-12 | 2015-08-19 | 杭州和正医药有限公司 | Double-site irreversible Brutons tyrosine kinase inhibitor |
| CN106008527A (en) * | 2016-06-29 | 2016-10-12 | 四川大学华西医院 | Pyrazolo [3,4-d ] pyrimidine derivatives |
| CN106831790A (en) * | 2017-02-17 | 2017-06-13 | 四川大学华西医院 | 7H-pyrrolo [2,3-d ] pyrimidine derivatives |
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| US9376438B2 (en) * | 2011-05-17 | 2016-06-28 | Principia Biopharma, Inc. | Pyrazolopyrimidine derivatives as tyrosine kinase inhibitors |
| CN107383015B (en) * | 2017-07-03 | 2019-11-08 | 四川大学华西医院 | Alkylthio-terminal-group oligo-PEG-modified amino pyrazolo [3,4-d ] pyrimidine derivative and application thereof in resisting non-small cell lung cancer |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103857396A (en) * | 2011-07-13 | 2014-06-11 | 药品循环公司 | Inhibitors of bruton's tyrosine kinase |
| CN104844609A (en) * | 2015-05-12 | 2015-08-19 | 杭州和正医药有限公司 | Double-site irreversible Brutons tyrosine kinase inhibitor |
| CN106008527A (en) * | 2016-06-29 | 2016-10-12 | 四川大学华西医院 | Pyrazolo [3,4-d ] pyrimidine derivatives |
| CN106831790A (en) * | 2017-02-17 | 2017-06-13 | 四川大学华西医院 | 7H-pyrrolo [2,3-d ] pyrimidine derivatives |
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| WO2018209961A1 (en) * | 2017-05-19 | 2018-11-22 | 四川大学华西医院 | Alkoxyl terminal group oligo-peg modified aminopyrimidine derivative and antitumor application |
| WO2019007003A1 (en) * | 2017-07-03 | 2019-01-10 | 四川大学华西医院 | 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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