CN108864061A - It is a kind of for treating the selective PI3K inhibitor of tumour - Google Patents
It is a kind of for treating the selective PI3K inhibitor of tumour Download PDFInfo
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Abstract
The invention discloses one kind such as I compound represented of formula or its pharmaceutically acceptable salt, ester, stereoisomer, solvated compounds,Wherein, R1、R2、R3、R4、R5And R6It is independently selected from H or CN.The experiment of PI3K kinase activity, which is carried out, by ADP-Glo technology show that the compounds of this invention is the selective depressant of PI3K α, it show that the compounds of this invention has external inhibitory activity using the external inhibitory activity experiment that CelltiterGlo assay method carries out BT474, illustrates that the compounds of this invention can be used as cancer treatment drugs and carry out more in-depth study.
Description
Technical field
The present invention relates to a kind of for treating the selective PI3K inhibitor of tumour.
Background technique
Phosphatidyl-inositol 3-kinase (phosphatidylinositol 3-kinase, PI3K) is intracellular important letter
Number transduction molecule participates in adjusting the physiology courses such as proliferation, apoptosis and the differentiation of cell, can specifically make on phosphatidylinositols ring
3- di.As the major downstream effector of receptor tyrosine kinase (RTK) and g protein coupled receptor (GPCR),
PI3K can activate serine threonine protein kinase (Akt) and the phosphatide of other downstream effectors by generating, and will come from various
The signal transduction of growth factor and cell factor is to intracellular courier.Signal path composed by PI3K and downstream molecule Akt
Downstream signaling molecule can be activated, the generation with the tumours such as breast cancer, gastric cancer, colon and rectum carcinoma, oophoroma, prostate cancer
Develop closely related.
PI3K α and PI3K β have expression in various organs, and PI3K δ and PI3K γ are mainly distributed in bone marrow cell.
The physiological function of 4 kinds of hypotypes is also different, and every kind of hypotype regulates and controls different physiological functions, PI3K alpha mediated generation of tissue
Thank to insulin signaling transmitting, PI3K β participates in the integrin signal in regulation blood platelet, and PI3K γ and PI3K δ are then in leucocyte
The different protein signals of middle regulation, especially play a significant role in mast cell, neutrophil leucocyte and eosinophil, PI3K
Signal transduction pathway has not only directly mediated the physiological regulating control of cell, it is also directly related with many diseases.It is swollen in a large amount of entities
It is found in tumor, the gene PIK3CA amplification of coding PI3K α and Activating mutations enhance PI3K α catalytic capability；The formation of thrombus
Closely related with PI3K β activation, PI3K β has been that the important target of curing thrombus is moreover constantly shown on evidence by confirmation
Show PI3K treatment autoimmune disease aspect great potential, while PI3K β also plays one in the occurrence and development of certain tumours
It is set for using；PI3K δ is found in extensive immune and inflammation relevant cell recruitment and activation and plays central role, is
The crucial target spot for treating the Malignancies such as acute myeloid leukaemia；PI3K γ discovery table in inflammation and immunological diseases
Up to exception, there are biggish potentiality in the targeted therapy of inflammation.
PI3K α can the integrator cell outgrowth factor, cell factor and other stimulate effects to cell, be then transmitted to
The a plurality of signal path in downstream is to participate in adjusting the biological functions such as cell survival, growth, proliferation and metabolism.Research shows that PI3K
α participates in the occurrence and development of tumour, and the PIK3CA of coding PI3K α catalytic subunit is the oncogene confirmed.In addition, PI3K α and
The signal path that it is mediated is in the kinds of tumors type such as breast cancer, uterine cancer, head and neck cancer, lung cancer and colorectal cancer with high-frequency
It is abnormal activation.Therefore, PI3K α is the important drugs target for treating tumour.
PI3K has proven to be the drug therapy target having a high potential, and uses selective PI3K inhibitor as anti-
Tumour medicine can increase the selectivity for the treatment of, reduce the generation of adverse reaction and toxicity.The selective PI3K reported at present inhibits
The quantity and compound structure type of agent are also fairly limited, actively develop the research of PI3K and its inhibitor, design and develop
There is the drug of selection specificity for a certain hypotype, there is very big social effect.With continuing deeper into for clinical test, choosing
Validity of the selecting property PI3K inhibitor for oncotherapy will be made known.
Summary of the invention
The invention discloses a kind of compounds of new structure type, specially such as I compound represented of formula or its pharmacy
Upper acceptable salt, ester, stereoisomer, solvated compounds,
Wherein, R1、R2、R3、R4、R5And R6It is independently selected from H or CN.
I compound represented of formula is preferably：
On the other hand, the invention discloses the synthetic method of I compound represented of formula, synthetic route is：
Its specific synthesis step is：
1) in the presence of an inorganic base, 2- hydroxyl benzofuran -3- formaldehyde (compound 1) and the bromo- 4- methoxyl group -2- first of 3-
Base -4- oxo butyl- 1- base (compound 2) in a suitable solvent, with I2It is raw for substitution reaction occurs under conditions of catalyst
At 2- ((3- formyl benzofuran -2- base) oxygroup) -3 Methylbutanoic acid methyl esters (compound 3)；
2) aldol reaction occurs for compound 3 and acetophenone, generates (Z) -2- ((3- (3- oxo -3- propenyl benzene -1-
Base) benzofuran -2- base) oxygroup) -3 Methylbutanoic acid methyl esters (compound 4)；
3) for compound 4 under conditions of Raney nickel is as catalyst, the raw hydro-reduction reaction of elevated pressure, what is obtained is thick
Product generates 2- (3- ((3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3 Methylbutanoic acid first through suitable solvent purifications
Ester (compound 5)；
4) hydrolysis generation 2- (3- ((3- oxo -3- phenylpropyl) benzofuran-occurs under alkaline condition for compound 5
2- yl) oxygroup) -3 Methylbutanoic acid (compound 6)；
5) carboxyl in compound 6 reacts with corresponding amine generates corresponding amide product.
Further, the solvent in the step 1) can be benzene, toluene, dimethylbenzene etc. and its mixture, preferably toluene.
Further, the alkali used in the step 1) can be potassium carbonate, saleratus, sodium carbonate, and calcium carbonate etc. is excellent
Select potassium carbonate.
Further, Hydrogen Vapor Pressure can be 600psi, 400psi, preferably 400psi in the step 3).
Further, the purification of crude product can be methanol, ethyl alcohol, propyl alcohol, preferably methanol in the step 3).
On the other hand, the invention discloses I compound represented of formula or its pharmaceutically acceptable salt, ester, solid are different
The application of structure body, solvated compounds alternatively property PI3K inhibitor.
Claimed Formula I or its pharmaceutically acceptable salt, ester, stereoisomer, solvent chemical combination
Purposes of the object in the drug of preparation treatment and/or prevention proliferative diseases, the proliferative diseases include cancer and non-cancer
Property disease, the cancer be selected from brain tumor, lung cancer, lung cancer in non-cellule type, dermoid cancer, bladder cancer, gastric cancer, ovary
Cancer, peritoneal cancer, cancer of pancreas, breast cancer, people's mammary duct tumor, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer,
Kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, prostate cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, leaching
Bar between tumor, neurofibromatosis, thyroid cancer, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, carcinoma of testis, Small Cell Lung Cancer, gastrointestinal tract
Matter tumor, tumor of prostate, mast cell tumor, Huppert's disease, melanoma, glioma or sarcoma.
On the other hand, I compound represented of formula of the present invention or its pharmaceutically acceptable salt, ester, solid are different
Structure body, solvated compounds further can also form pharmaceutical composition with one or more antitumor agents and immunosuppressor, use
In preparation treatment and/or the drug of prevention proliferative diseases, the antitumor agent and immunosuppressor are (1) antimetabolite,
Selected from capecitabine, gemcitabine, pemetrexed disodium；(2) growth factor receptor inhibitors, selected from pazopanib, Imatinib, angstrom
Sieve replaces Buddhist nun, Lapatinib, Gefitinib, Vande Thani；(3) antibody is selected from Trastuzumab, bevacizumab；(4) mitosis inhibits
Agent is selected from taxol, vinorelbine, docetaxel, Doxorubicin；(5) antitumor steroids, selected from Letrozole, tamoxifen,
Fulvestrant, Flutamide, Triptorelin；(6) alkylating agents are selected from cyclophosphamide, mustargen, melphalan, chlorambucil, Ka Mosi
Spit of fland；(7) metal platinum class is selected from carboplatin, cis-platinum, oxaliplatin；(8) topoisomerase enzyme inhibitor, selected from Topotecan camptothecine,
Topotecan, Irinotecan；(9) immunosuppressant, it is suitable selected from everolimus, sirolimus, special cancer；(10) purine is similar
Object is selected from Ismipur, 6- thioguanine, imuran；(11) antibiotics, selected from rhzomorph D, daunorubicin, adriamycin,
Mitoxantrone, bleomycin, plicamycin；(12) adrenocortical suppressants are selected from aminoglutethimide, dexamethasone；
(13) histon deacetylase (HDAC) inhibitor is selected from Vorinostat.
On the other hand, when being used as drug, the compound of the present invention can be applied in the form of a pharmaceutical preparation.These preparations
It can be prepared in a manner of well known in pharmaceutical technology, and depending on whether needing local treatment or systemic treatment and the area to be treated
Depending on domain, it can apply through a variety of ways.Administration can for part (including percutaneous, epidermis, through eye and be given to mucous membrane, including it is intranasal,
Vagina and rectal delivery), transpulmonary (such as by sucking or be blown into pulvis or aerosol, including use sprayer；Intratracheal or nose
It is interior), oral or parenteral administration.Parenteral administration includes intravenous, intra-arterial, in subcutaneous, peritonaeum or intramuscular injection or defeated
Note；Or encephalic (such as in intrathecal or ventricles of the brain) administration.Parenteral administration can be in single bolus dosage form, or can for example pass through
Continuous pouring pump is reached.Pharmaceutical preparation for local administration may include transdermal patch, ointment, lotion, cream, gel
Agent, drops, suppository, spray, liquid and pulvis.Conventional pharmaceutical carrier, aqueous, powdered or oleaginous base, thickener etc. can
It is required or desirable.The invention also includes containing as the compound of the present invention of active constituent or its can pharmaceutically connect
The pharmaceutical preparation that the salt received is combined with one or more pharmaceutically acceptable carriers (excipient).Preparing preparation of the invention
When, active constituent usually mixes with excipient, by figuration dilution agent or is enclosed in this carrier in such as capsule, anther sac, paper
Or other vessel forms.It can be consolidating for the medium for serving as active constituent, carrier or medium when excipient serves as diluent
Body, semisolid or liquid substance.Therefore, preparation can be tablet, pill, pulvis, mouth containing ingot, anther sac, cachet, elixir, hang
Supernatant liquid, solution, syrup, aerosol (in solid form or in liquid medium), contains such as up to 10 weight % activity at lotion
The ointment of compound, soft and hard gelatine capsule, suppository, sterile injectable solution and sterile packaged powder form.
Specific embodiment
Embodiment 1：2- ((3- (3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3- methyl-N- (quinoline -2-
Base) butyramide synthesis
1, the synthesis of 2- ((3- formyl benzofuran -2- base) oxygroup) -3 Methylbutanoic acid methyl esters
By 2- hydroxyl benzofuran -3- formaldehyde (3.32g, 20.50mmol) (compound 1), K2CO3(5.65g,
40.90mmol), toluene (25mL), p-methyl benzenesulfonic acid (3.62g, 21.0mmol) and iodine (2g, as catalyst) are added to and have
In tetra- neck round-bottom flask of 150mL of mechanical agitator and Dean-Stark condenser, the bromo- 4- methoxyl group -2- first of 3- is then added
Base -4- oxo butyl- 1- base (3.98g, 20.5mmol) (compound 2) flows back reaction 3-4 hours, azeotropic removal of water, simultaneously
Monitor the reaction on TLC.After the reaction was completed, water is added, separates organic layer, water layer is extracted with toluene (2*25mL).By merging
Organic layer is washed with brine and is concentrated under vacuum, and obtains oily mater 2- ((3- formyl benzofuran -2- base) oxygroup) -3-
Methylbutanoic acid methyl esters (compound 3), 5.44g, yield 96%.1H-NMR(400MHz,CDCl3)δ:0.90(d,6H),2.58
(m,1H),3.70(s,3H),5.32(d,1H),7.22(t,1H),7.28(t,1H),7.50(d,1H),7.59(d,1H),9.86
(s,1H).13C-NMR(125MHz,CDCl3)δ:18.70,30.24,52.22,80.21,102.44,112.11,117.77,
123.70,124.68,125.02,149.24,162.92,170.37,198.16.LC-MS(ESI,pos,ion)m/z:277[M+
H]。
2, (Z) -2- ((3- (3- oxo -3- propenyl benzene -1- base) benzofuran -2- base) oxygroup) -3 Methylbutanoic acid methyl esters
Synthesis
By compound 3 (5.44g, 19.69mmol), acetophenone (19.69mmol), piperidines (2mL, 3.52mmol), benzene first
Sour (0.03g, 2.37mmol) and toluene (19.2mL) are added to the 150mL equipped with mechanical agitator and Dean-Stark condenser
In four neck round-bottom flasks, then reaction mixture is flowed back 1-2 hours, while monitoring reaction on TLC.After the reaction was completed, will
Reactant is cooled to 10 DEG C, filters thus obtained solid, is washed and 1-2 hours dry at 80 DEG C, is obtained with toluene (2*25mL)
To (Z) -2- ((3- (3- oxo -3- propenyl benzene -1- base) benzofuran -2- base) oxygroup) -3 Methylbutanoic acid methyl esters (compound
4), 6.48g, yield 87%.1H-NMR(400MHz,CDCl3)δ:0,90(d,6H),2.83(m,1H),3.70(s,3H),5.32
(d,1H),6.70(d,1H),7.22-7.28(m,2H),7.49-7.59(m,6H),7.80(m,2H).13C-NMR(125MHz,
CDCl3)δ:18.7,30.24,52.22,80.21,97.53,112.33,118.1,119.52,123.93,124.67,
124.85,128.76,128.8,133.34,137.81,138.05,150.28,162.7,170.37,191.87.LC-MS
(ESI,pos,ion)m/z:379[M+H]。
3, the synthesis of 2- (3- ((3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3 Methylbutanoic acid methyl esters
It, will after methanol (2*15mL) and the continuous washing Raney nickel of ethyl acetate (2*10mL) with water (2*25mL)
Raney nickel (6mL) and ethyl acetate (60mL) are placed on together in reaction kettle container (2L), then by compound 4 (6.48g,
It 17.12mmol) is packed into container and ethyl acetate (60mL) is added.The mixture is kept to hydrogenate under 400psi Hydrogen Vapor Pressure,
It is kept for 10-15 hours at room temperature, and monitors reaction on HPLC.After the reaction was completed, it is steamed by catalyst filtration and by filtrate decompression
Hair, obtains grease, which is kept under a high vacuum, to obtain solid 2- (the 3- ((3- oxo -3- phenylpropyl alcohol of crude form
Base) benzofuran -2- base) oxygroup) -3 Methylbutanoic acid methyl esters (compound 5), 5.87-5.99g, yield is 94-96%, purity
It is 86-95% (HPLC).Thus obtained crude Compound 5 is dissolved in hot methanol (20mL), and is transferred to and is stirred equipped with machinery
In the 150mL three neck round bottom for mixing device and liquid addition funnel.By additional funnel by demineralized water (40mL) at 30 minutes
It is inside added drop-wise in reaction mixture, and with being vigorously stirred, is settled out white compound during this period.Continue stirring 30 minutes,
And second part water (20mL) is added under stiring, 15 minutes are lasted to ensure that product precipitates completely, are then stirred for 1 hour.
Product is filtered, is washed and is dried under vacuum with water (20mL), obtains pure 2- (3- ((3- oxo -3- phenylpropyl) benzo furan
Mutter -2- base) oxygroup) -3 Methylbutanoic acid methyl esters (compound 5), 5.93g, yield 91%.1H-NMR(400MHz,CDCl3)δ:
0.90(d,6H),2.70(m,3H),3.22(t,2H),3.69(s,3H),5.45(d,1H),7.20-7.26(m,2H),7.47-
7.65(m,5H),7.93(m,2H).13C-NMR(125MHz,CDCl3)δ:200.03,170.37,159.03,148.69,
136.89,133.08,129.00,128.77,125.84,123.84,122.26,120.66,111.90,107.10,80.21,
52.22,41.86,30.24,21.88,18.70.LC-MS(ESI,pos,ion)m/z:381[M+H]。
4, the synthesis of 2- (3- ((3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3 Methylbutanoic acid
The suspension of compound 5 (5.93g, 15.59mmol) and water (54mL) is placed in the round bottom equipped with mechanical agitator
In flask.At 20-25 DEG C, sodium hydroxide solution is slowly added in 5-10 minutes, and (4.0g sodium hydroxide is dissolved in 13.5mL water
In).Continue stirring 1-2 hours at ambient temperature, while being monitored and being reacted by TLC.After the reaction was completed, with dense HCl (temperature liter
To 40-45 DEG C) pH of reaction mixture is adjusted to 2 and reaches room temperature.Mixture is cooled to 10-15 DEG C, filters institute
It obtains solid and is dried in vacuo at 60-70 DEG C, obtain 2- (3- ((3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3-
Methylbutanoic acid (compound 6), 5.43g, yield 95%.1H-NMR(400MHz,CDCl3)δ:0.92(d,6H),2.41(m,1H),
2.71(t,2H),3.27(t,2H),5.48(d,1H),7.22(m,2H),7.49-7.67(m,5H),7.96(m,2H).13C-NMR
(125MHz,CDCl3)δ:18.7,21.88,29.83,41.86,76.93,107.1,111.9,120.66,122.26,
123.84,125.84,128.77,129,133.08,136.89,148.69,159.03,171.87,200.03.LC-MS(ESI,
pos,ion)m/z:367[M+H]。
5,2- ((3- (3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3- methyl-N- (quinoline -2- base) butyryl
The synthesis of amine
By compound 6 (5.43g, 14.81mmol), quinoline -2- amine (14.85mmol) and p-methyl benzenesulfonic acid (~0.20g)
Suspension be placed in equipped with mechanical agitator, in the round-bottomed flask of oil bath and Dean-Stark condenser, by reaction mixture plus
Heat reflux (150-155 DEG C of internal temperature, 170-180 DEG C of oil bath temperature) 12-15 hours, while being monitored and being reacted by TLC.Reaction
After the completion, reactant is cooled to 80 DEG C, methanol (17mL) is slowly added to by dropping funel.Make reaction mixture under stiring
It is down to room temperature, the solid being obtained by filtration simultaneously is washed with methanol (25mL), and 1 hour dry at 100-120 DEG C, and it is solid to obtain white
Body 2- ((3- (3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3- methyl-N- (quinoline -2- base) butyramide,
6.42g, yield 88%.1H-NMR(400MHz,CDCl3)δ:0.89(d,6H),2.72(m,3H),3.25(t,2H),5.81(d,
1H),7.22-7.95(m,13H),8.29(d,2H),9.47(s,1H).13C-NMR(125MHz,CDCl3)δ:18.7,21.88,
28.02,41.86,77.51,107.1,111.9,114.93,120.66,122.26,123.76,123.84,125.84,
126.13,126.47,128.77,128.92,129,131.16,133.08,133.72,136.89,145.37,148.69,
152.76,159.03,170.7,200.03.LC-MS(ESI,pos,ion)m/z:493[M+H]。
Embodiment 2：2- ((3- (3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3- methyl-N- (3- cyano -
Quinoline -2- base) butyramide synthesis
By compound 6 (5.43g, 14.81mmol), 3- cyano-quinoline -2- amine (14.85mmol) and p-methyl benzenesulfonic acid (~
Suspension 0.20g) is placed in equipped with mechanical agitator, in the round-bottomed flask of oil bath and Dean-Stark condenser, reaction is mixed
It closes object and is heated to reflux (150-155 DEG C of internal temperature, 170-180 DEG C of oil bath temperature) 12-15 hours, while being monitored instead by TLC
It answers.After the reaction was completed, reactant is cooled to 80 DEG C, methanol (17mL) is slowly added to by dropping funel.Make reaction mixture
It is down to room temperature under stiring, the solid being obtained by filtration simultaneously is washed with methanol (25mL), and 1 hour dry at 100-120 DEG C, is obtained
To white solid 2- ((3- (3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3- methyl-N- (3- cyano-quinoline -2-
Base) butyramide, 6.44g, yield 84%.LC-MS(ESI,pos,ion)m/z:518[M+H].
Embodiment 3：2- ((3- (3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3- methyl-N- (8- cyano -
Quinoline -2- base) butyramide synthesis
By compound 6 (5.43g, 14.81mmol), 8- cyano-quinoline -2- amine (14.85mmol) and p-methyl benzenesulfonic acid (~
Suspension 0.20g) is placed in equipped with mechanical agitator, in the round-bottomed flask of oil bath and Dean-Stark condenser, reaction is mixed
It closes object and is heated to reflux (150-155 DEG C of internal temperature, 170-180 DEG C of oil bath temperature) 12-15 hours, while being monitored instead by TLC
It answers.After the reaction was completed, reactant is cooled to 80 DEG C, methanol (17mL) is slowly added to by dropping funel.Make reaction mixture
It is down to room temperature under stiring, the solid being obtained by filtration simultaneously is washed with methanol (25mL), and 1 hour dry at 100-120 DEG C, is obtained
To white solid 2- ((3- (3- oxo -3- phenylpropyl) benzofuran -2- base) oxygroup) -3- methyl-N- (8- cyano-quinoline -2-
Base) butyramide, 6.52g, yield 85%.LC-MS(ESI,pos,ion)m/z:518[M+H].
Test example 1：PI3K enzyme assay
PI3K kinase activity biochemical analysis is carried out using the ADP-Glo technology of Promega company.ADP-Glo kinase assay
Kit and PI3K beta kinase are purchased from Promega company, and PI3K α, PI3K δ, PI3K γ kinases are purchased from Millipore company.It is all
Experiment is completed in 384 orifice plates at room temperature.Kinase Mix is diluted with kinase buffer liquid, and kinase buffer liquid includes
50mM HEPES (pH 7.5), 3mM MgCl2, 100mM NaCl, 1mM EGTA, 0.03%CHAPS and 2mM DTT.The bottom ATP/
Object mixture contains 5 μM of PIP2/PS and 25 μM of ATP.Untested compound is dissolved with 100%DMSO, and uses ddH2O is diluted to end
Concentration.2 μ L are diluted into untested compound and 4 μ LATP/ substrate mixtures are added in 384 each holes of hole analysis plates.When reaction starts,
4 μ L Kinase Mix are added in every hole.React final volume be final concentration of 2 μM of 10 μ L, PIP2/PS, PI3K α, PI3K β, PI3K δ and
PI3K γ kinases final concentration is respectively 0.2,0.6,0.25 and 0.4nM, and corresponding ATP final concentration is respectively 40,40,40 and 25 μ
M.Every hole is incubated for 1h after the kinases ADP-Glo reagent of 10 μ L is added, and then 20 μ L kinase assay agent are added in every hole, is incubated for 30min
It is shone and is read with the detection of Envision microplate reader afterwards, calculate compound to the inhibiting rate of kinases, and calculated with XLFIT5 software
IC50(50% inhibition concentration) value.
Suppression result of the untested compound to PI3K kinase activity：
By upper table, it can be concluded that, listed compound is higher than PI3K β, PI3K γ and PI3K δ to the selection activity of PI3K α, is
The selective depressant of PI3K α can be used for preventing and treating the relevant disease of PI3K alpha active, such as proliferative diseases, proliferative
Disease includes cancer and non-cancerous disease, the cancer be selected from brain tumor, lung cancer, lung cancer in non-cellule type, dermoid cancer,
Bladder cancer, gastric cancer, oophoroma, peritoneal cancer, cancer of pancreas, breast cancer, people's mammary duct tumor, head and neck cancer, cervix cancer, endometrium
Cancer, the carcinoma of the rectum, liver cancer, kidney, adenocarcinoma of esophagus, esophageal squamous cell carcinoma, solid tumor, prostate cancer, thyroid cancer, female reproduction
It is road cancer, carcinoma in situ, lymthoma, neurofibromatosis, thyroid cancer, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, carcinoma of testis, small thin
Born of the same parents' lung cancer, gastrointestinal stromal tumor, tumor of prostate, mast cell tumor, Huppert's disease, melanoma, glioma or meat
Tumor.
Experimental example 2：The cell in vitro inhibitory activity of the compounds of this invention
BT474 (people's breast duct tumor cell strain) is carried out to the compounds of this invention using CelltiterGlo assay method
External inhibitory activity research is used as comparison medicine using Buparlisib (BKM120).Test method is summarized as follows：
1) BT474 in logarithmic growth phase is counted, it is 3000 thin into every 100 μ L with culture medium adjustment cell concentration
Born of the same parents, then 100 holes μ L/ are inoculated on 96 orifice plates, 5%CO2It is cultivated for 24 hours in cell incubator.
2) by after untested compound gradient dilution, 50 holes μ L/ are added.It sets up solvent control hole and blank control wells (only adds
Culture medium, not inoculating cell), 5%CO272h is cultivated in cell incubator.
3) every hole removes 80 μ L culture mediums, and culture plate is being placed at room temperature for 30 minutes, and 60 μ L reagents are added in every hole
(Celltiter Glo assay kit), oscillator shake 2min and mix (being protected from light), are incubated at room temperature 10 minutes (being protected from light).
4) multi-function microplate reader reads optical signal value.
5) data processing
Inhibiting rate (%)=(solvent control hole reading-tester hole reading)/(solvent control hole reading-blank control wells
Reading) × 100%；It is mapped using GraphPad Prism5.0, obtains curve and IC50。
| Compd | IC50(μM) |
| HXJG-F001 | 0.63 |
| HXJG-F002 | 0.54 |
| HXJG-F005 | 0.65 |
| HXJG-F007 | 0.55 |
| Buparlisib | 1.1 |
By upper table, it can be concluded that, listed compound has external inhibitory activity to BT474, illustrates that the compounds of this invention can be with
More in-depth study is carried out as breast cancer medicines.
Obviously, above content according to the present invention is not departing from this hair according to the ordinary technical knowledge and means of this field
Under the premise of bright above-mentioned basic fundamental thought, the modification, replacement or change of other diversified forms can also be made.
Claims (5)
1. such as I compound represented of formula or its pharmaceutically acceptable salt, ester, stereoisomer, solvated compounds,
Wherein, R1、R2、R3、R4、R5And R6It is independently selected from H or CN.
2. formula I as described in claim 1, characterized in that be selected from following compound：
3. compound as described in claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, solvated compounds are made
For the application of selective PI3K inhibitor.
4. compound as described in claim 1 or its pharmaceutically acceptable salt, ester, stereoisomer, solvated compounds exist
Purposes in the drug of preparation treatment and/or prevention proliferative diseases.
5. purposes as claimed in claim 4, characterized in that the proliferative diseases include cancer and non-cancerous disease, institute
State cancer be selected from brain tumor, lung cancer, lung cancer in non-cellule type, dermoid cancer, bladder cancer, gastric cancer, oophoroma, peritoneal cancer,
Cancer of pancreas, breast cancer, people's mammary duct tumor, head and neck cancer, cervix cancer, carcinoma of endometrium, the carcinoma of the rectum, liver cancer, kidney, esophageal gland
Cancer, esophageal squamous cell carcinoma, solid tumor, prostate cancer, thyroid cancer, female reproductive tract cancer, carcinoma in situ, lymthoma, nerve are fine
Tie up tumor disease, thyroid cancer, osteocarcinoma, cutaneum carcinoma, the cancer of the brain, colon cancer, carcinoma of testis, Small Cell Lung Cancer, gastrointestinal stromal tumor, prostate
Tumour, mast cell tumor, Huppert's disease, melanoma, glioma or sarcoma.
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|---|---|---|---|
| CN201810636350.5A CN108864061A (en) | 2018-06-20 | 2018-06-20 | It is a kind of for treating the selective PI3K inhibitor of tumour |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810636350.5A CN108864061A (en) | 2018-06-20 | 2018-06-20 | It is a kind of for treating the selective PI3K inhibitor of tumour |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108864061A true CN108864061A (en) | 2018-11-23 |
Family
ID=64340747
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810636350.5A Withdrawn CN108864061A (en) | 2018-06-20 | 2018-06-20 | It is a kind of for treating the selective PI3K inhibitor of tumour |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108864061A (en) |
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2018
- 2018-06-20 CN CN201810636350.5A patent/CN108864061A/en not_active Withdrawn
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