CN102516232A - ErbB2 micro-molecular selective inhibitor and application thereof - Google Patents
ErbB2 micro-molecular selective inhibitor and application thereof Download PDFInfo
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Abstract
The invention discloses an ErbB2 micro-molecular selective inhibitor and an application thereof. The inhibitor is a compound M and a pharmaceutically acceptable salt of the compound M. The application is an application of the inhibitor in the preparation of medicines for treating tyrosine kinase-regulatory diseases. The ErbB2 micro-molecular selective inhibitor which is used as a novel targeting drug has a killing effect on specific cancer cells, and especially has a good treatment efficacy on the breast cancer.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, relate to ERbB2 family's group inhibitor, be specifically related to small molecules selective depressant and the application thereof of a kind of ErbB2.
Background technology
Cancer (being commonly called as tumour) is described as the mankind and is called " evil spirit in century ".It is a kind of disease that produces owing to human tissue cell's neoplasm.Cancer has become the common disease in the global range, frequently-occurring disease.The survey showed that according to 2008 World Health Organization, and the whole world had 6,300,000 people to die from the relevant together complication that causes of cancer in 2006, and this numeral accounts for 12% of annual death toll in 1996.According to estimates.The cancered patient in the whole world will break through 4,000 ten thousand the coming years.According to China hygiene department statistics, China's cancer morbidity is in recent years presenting ascendant trend always, China over nearly 20 years cancer morbidity risen 69%.Mortality ratio has risen 29%, and annual cancer new cases are 2,200,000, because of the cancer mortality number is 1,600,000.Cancer has become one of malignant disease of serious threat human survival.Prevention and treatment to cancer have become human target of making joint efforts.The cancer mortality of the U.S. ranks second after cardiovascular disorder.
The cancer drug treatment comes surgical operation in the past always, after the radiotherapy, occupy auxiliary status.A collection of representational antitumor drug commonly used or the like has appearred in the development along with modern age life science and synthetic chemistry.But existing most anticarcinogens not only have lethal effect to cancer cells, and are that normal human tissue cell is had bigger destruction, produce very big spinoff, and the patient gives birth to quality and obviously descends.In brief, human to novel effectively and the eager increasing demand of the anticarcinogen of safety increases.
Along with developing rapidly of Protocols in Molecular Biology; And from the molecular level of cell receptor and propagation further understanding and understanding to tumor invasion mechanism; It is the research of the treat-ment of target spot that people have begun to key gene, cell receptor and regulatory molecule, is called " targeted therapy ".By contrast, targeted therapy can directly be directed against the target administration, treats cancerous tissue targetedly, reduces the injury to normal human tissue.Because targeting anticarcinogen has high target property, to the hypotoxic advantage of normal people somatic tissue, make the result of treatment of targeting anticarcinogen improve greatly.Targeted therapy is divided into three levels, organ target, cell-targeting and molecular targeted.Molecular targeted is specific highest level in the targeted therapy, and it is the some proteinic molecule to the tumour cell the inside, the fragment of a Nucleotide, and perhaps a gene product is treated.The molecular targeted treatment of tumour is meant on the basis of tumour molecular cytobiology; Utilize specificity (or special relatively) structural molecule that tumor tissues or cell have as target spot, use some can reach one type of therapy of direct treatment or targeted therapy purpose with the antibody of these target molecule specific combination, part etc.Molecular targeted treatment is the breakthrough and revolutionary development in present oncotherapy field, has represented the present the latest development direction of tumor biotherapy.Molecular targeted treatment is to be the treatment of target spot with the sick cell, has more " effecting a permanent cure " effect with respect to operation, chemicotherapy three great tradition treatment meanss.Molecular targeted treatment has molecular selectivity preferably; Can be efficiently and killing tumor cell optionally; Minimizing is to the damage of healthy tissues; And the clinical target that this traditional just chemotherapeutics treatment is difficult to realize, though some novel medicament listings were arranged in the last few years, but still can't satisfy the treatment needs of ever-increasing clinical patient.Therefore, the targeting anti-tumor medicine of development of new has become the most important thing of medicament research and development.
Urogastrone 2 (erbB2/Her-2/neu) is a kind of Urogastrone (EGF) acceptor (EGFR) family, also comprises erbB1 (EGF-R ELISA, member HER-1), (HER-3) of ErbB3 and ERBB4 (HER-4).Such family receptors Tyrosylprotein kinase (RTK), erbB1, especially ERBB2 signal, the existence of conciliation, propagation, differentiation and normal cell are vital.In human malignancies, often be observed amplification and the over-expresses of ERBB2.It is very important related having of carcinogenic conversion and tumour.This phenomenon has caused that extensive efforts removes to seek cocoa preventing/to upset the receptor-mediated growth signals of ERBB2, stops the compound of growth of tumor.Having researched and developed at present some different treat-ment stops ERBB2 to activate; Like a kind of humanized antibody; It can be tied to p185erbB2 and prevent to be also had micromolecular inhibitor by the signal transduction of acceptor adjusting, the acceptor of the erbB2 in the tenuigenin zone of prevention ATP-binding site.
The transfevent mammary cancer Humanized monoclonal antibodies of on market, selling at present that is used for clinical treatment P185ErbB2 high expression level is Herceptin (Trastuzumab); Be that first is directed against the p185erbB2 acceptor and is approved for clinical antibody medication, and can showing and improve one-tenth bioplasm amount and the bulk life time that ERBB2 crosses the patient with breast cancer of expression.But unfortunately, a large amount of patient tumors over-expresses ERBB2 does not respond the monoclonal antibody Trastuzumab, and responds the final resistance treatment that produces most.In addition, many patients' tumour began regeneration in 1 to 2 year, and they can not find the comparison efficacious therapy again and select.The application method of Herceptin needs intravenous injection weekly in addition, and long-term treatment is that very inconvenience also is quite expensive.Therefore, it is a kind of very effective and selective to press for research and development at present, ErbB2RTK suppressor factor that can be for a long time oral.
Cell signaling and incitant (signaltransducersandactivatorsoftranscription; STATs) be one type by cytokine (cytokine), growth factor polypeptide ligand activated transcription factors such as (growthfactor); Physiological functions such as main mediated cell growth, differentiation, migration and apoptosis, its abnormal activation and malignant transformation of cells, tumor proliferation, differentiation and apoptosis obstacle are closely related.EGFR family comprises EGFR (HER1/ERBB1), HER2 (neu/ERBB2), and HER3 (ERBB3) and HER4 (ERBB4), regulation and control are unusual and tumor development is closely related.
Summary of the invention
Goal of the invention: to the deficiency that exists in the prior art, the purpose of this invention is to provide the small molecules selective depressant of a kind of ErbB2, to realize improving the curative effect of cancer.Another object of the present invention provides the preparation method of above-mentioned molecular selectivity suppressor factor.The present invention also has the application that provides above-mentioned molecular selectivity suppressor factor of one side.
Technical scheme: in order to realize the foregoing invention purpose, the technical scheme that the present invention adopts is:
The small molecules selective depressant of a kind of ErbB2, this suppressor factor are the salt of compound M and pharmaceutically receptible compound M; The general structure of compound M is:
In the formula, m is 0,1 or 2; R1 is any in the following group: hydrogen, halogen replaces or unsubstituted C
1-8Alkyl replaces or unsubstituted C
2-8Thiazolinyl replaces or unsubstituted C
2-8Alkynyl replaces or unsubstituted aryl, replaces or unsubstituted heterocyclic C
1-8Alkyloyl, C
1-8Alkoxyl group, C
1-8Alkyl sulphinyl, C
1-8Alkyl sulphonyl, arylsulfonyl, cyanic acid, nitro, hydroxyl, amino, carboxyl, oxo, carbamyl, N, N-two-(C
1-8Alkyl), carbamyl, C
1-8Alkanoyloxy, C
1-8Alkyl amide, C
3-8The alkynyl amide base, N-(C
1-8Alkyl) sulfamyl, N, N-two-(C
1-8Alkyl) sulfamyl;
X is NR
2, CHR
3, O or S; R wherein
2And R
3Be respectively H or C
1-8Alkyl;
X
1Be C or N;
R is any in the following group: replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aryl-C
1-3Alkyl replaces or unsubstituted aryl-C
3-7Naphthenic base;
Preferably: R1 is any in the following group: hydrogen, halogen, C
1-8Alkyl, C
1-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, heterocyclic radical, halo
1-3-C
1-8Alkyl, hydroxyl-C
1-8Alkyl, C
1-4Alkoxy-C
1-8Alkyl, cyanic acid-C
1-8Alkyl, amino-C
1-8Alkyl, aryl-C
1-8Alkyl, heteroaryl-C
1-8Alkyl, heterocyclic radical-C
1-8Alkyl, halo
1-3-C
2-8Thiazolinyl, hydroxyl-C
2-8Thiazolinyl, C
1-4Alkoxy-C
2-8Thiazolinyl, cyanic acid-C
2-8Thiazolinyl, amino-C
2-8Thiazolinyl, aryl-C
2-8Thiazolinyl heteroaryl-C
2-8Thiazolinyl, heterocyclic radical-C
2-8Thiazolinyl, halo
1-3-C
2-8Alkynyl, hydroxyl-C
2-8Alkynyl, C
1-4Alkoxy-C
2-8Alkynyl, cyanic acid-C
2-8Alkynyl, amino-C
2-8Alkynyl, aryl-C
2-8Alkynyl, heteroaryl-C
2-8Alkynyl, heterocyclic radical-C
2-8Alkynyl, C
1-8Alkyloyl, aryl-C
1-8Alkyloyl, heteroaryl-C
1-8Alkyloyl, heterocyclic radical-C
1-8Alkyloyl, C
1-8Carbalkoxy, aryl-C
1-8Carbalkoxy, heteroaryl-C
1-8Carbalkoxy, heterocyclic radical-C
1-8Carbalkoxy, C
1-8Alkyl sulfinyl, C
1-8The alkane alkylsulfonyl, arylsulfonyl, aryl-C
1-8The alkane alkylsulfonyl, heteroaryl-C
1-8The alkane alkylsulfonyl, heterocyclic radical-C
1-8The alkane alkylsulfonyl, aryl, heteroaryl, heterocyclic radical, cyanic acid, nitro, hydroxyl, amino, carboxyl, oxo, carbamyl, C
1-8Alkoxyl group, C
2-8Alkene oxygen base, C
2-8Alkynyloxy group, C
1-8Alkylthio, N-C
1-8Alkyl-carbamyl, N, N-two-C
1-8Alkyl-carbamyl, C
1-8Alkanoyloxy, C
1-8Alkyl amide, C
3-8The alkynyl amide base, N-C
1-8Alkyl-sulfamyl, N, N-two-C
1-8Alkyl-sulfamyl.
Preferably: the amino described in the R1, amino-C
1-8Alkyl, amino-C
2-8Thiazolinyl or amino-C
2-8Alkynyl is freely replaced by any two in the following group: hydrogen, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl.
Preferably: the aryl described in the R1, heteroaryl or heterocyclic radical contain 1-3 following substituting group: halogen, trifluoromethyl, cyanic acid, nitro, hydroxyl, amino, carboxyl, carbamyl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkoxyl group.
Preferably: the amino described in the R or amino-C
1-8Alkyl is freely replaced by any two in the following groups: hydrogen, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl.
Described R is saturated or undersaturated aryl, or, saturated or undersaturated heteroaryl.
The small molecules selective depressant of above-mentioned ErbB2 is used for treating the application of Tyrosylprotein kinase modulability disease medicament in preparation.Described Tyrosylprotein kinase modulability disease comprises the cancer of the brain, lung cancer, scale cell cancer, bladder cancer, cancer of the stomach, mammary cancer, head cancer, neck cancer, esophagus cancer, prostate cancer, colorectal carcinoma, gynaecology and thyroid carcinoma, tumor-blood-vessel growth and their complication.
A kind of medicine that is used to treat Tyrosylprotein kinase modulability disease; Form by effective constituent and pharmaceutically receptible carrier; Wherein effective constituent is the small molecules selective depressant compound M of the described ErbB2 of claim 1, and pharmaceutically receptible carrier is water, gelatin, lactose, starch, Magnesium Stearate, talcum, vegetables oil, natural gum, alcohol, Vaseline and/or their mixture.
Beneficial effect: the small molecules selective depressant of ErbB2 of the present invention, advantage has: the cancer cells to specific has lethal effect, and especially mammary cancer has good therapeutic efficiency.
Embodiment
Explain the present invention below in conjunction with specific embodiment.
The enforcement general rule of compound
The building-up reactions formula of compound M is:
By above-mentioned reaction formula, get 1mmol4-chloro-6-iodine quinazoline, be dissolved in the 10ml volume ratio and be 1: 11, the 2-ethylene dichloride and the trimethyl carbinol add the 1mmol amino benzenes compounds, reflux 2h observes deposition and separates out, and is overanxious, drying, product.Products obtained therefrom is dissolved in THF, adds 4-(6-picoline-3-oxygen base)-3-monomethylaniline quinazoline compound, add 0.02molPd (PhP3) Cl then
2, the indium compounds of adding triatomic ring, tetra-atomic ring, five-ring, six annulus, under nitrogen protection, reflux 24h; Reaction finishes, and is cooled to room temperature, in the impouring enough water, with ethyl acetate extraction 2～3 times; Use the saturated common salt water washing, organic layer is used dried over sodium sulfate then, and removal of solvent under reduced pressure gets resistates, with silicagel column and 3: 1 ethyl acetate purifying; Compound 3 is dissolved in the ethyl acetate then, feed hydrogen chloride gas, have deposition to separate out, then with different acyl chlorides and semi-annular jade pendant acyl chloride reactions; Cross column purification with silicagel column, obtain compound M, yield 65～90% characterizes with nucleus magnetic resonance and mass spectrum product.
Embodiment 1
1-(6-replacement-3-(4-(4-(6-picoline-3-oxygen base)-3-toluidine) quinazoline)-1-azelidinyl) ethyl ketone, structural formula is:
Compound method is used Acetyl Chloride 98Min. and midbody 4 reactions with implementing example in like manner.Product is characterized,
1HNMR (300MHz, DMSO) result: δ 7.82 (s, 1H), 7.67 (dd, 1H), 6.46 (dd, 1H), 6.10 (dd, 1H); 6.09 (m, 1H), 4.01 (m, 2H), 4.0 (m, 1H), 3.51 (m, 1H); 3.24 (s, 3H), 2.75 (s, 3H), 2.35 (s, 3H), 2.02 (s, 3H).
13C?NMR(300MHz，DMSO)：δ172.6，169.3，155.3，152.0，149.5，148.0，140.1，138.9，136.7，135.9，132.3，131.2，128.1，125.4，124.4，123.7，122.0，117.0，116.1，114.3，53.1，53.1，31.9，24.8，20.8，14.4。ESI-MS?m/z?440(M+1)。
Embodiment 2
1-6-(synthesizing of 3-(4-(4-(6-picoline-3-oxygen base-3-monomethylaniline) quinazoline) azetidine)-2-methoxyl group hexanone, structural formula is:
Compound method is used 2-methoxyacetyl chloride and midbody 4 reactions with embodiment 1.Product is characterized,
1HNMR (300MHz, DMSO) result: δ 7.42 (s, 1H), 7.37 (dd, 1H), 6.36 (dd, 1H), 6.10 (dd, 1H); 6.09 (m, 1H), 4.01 (m, 2H), 4.0 (m, 1H), 3.51 (m, 1H); 3.24 (s, 3H), 2.55 (s, 3H), 2.35 (s, 3H), 2.02 (s, 3H).
13C?NMR(75MHz，DMSO)：δ170.2，169.3，155.3，152.0，149.5，148.0，140.1，138.9，136.7，135.9，132.3，131.2，128.1，125.5，124.4，123.7，122.0，117.0，116.1，114.3，69.7，58.3，53.4，53.4，31.9，24.8，14.4。ESI-MS?m/z?470(M+1)。
Embodiment 3
1-6-(3-(4-(4-(6-(trifluoromethyl) pyridine-3-oxygen base) aniline) quinazoline) azetidine) hexanone, structural formula is:
Product is characterized,
1HNMR (300MHz, DMSO) result: δ 7.70 (s, 1H) 7.5 (m, 1H), 7.4 (m, 1H), 6.48 (m, 1H), 6.29 (m, 1H), 4.26 (m, 1H), 4.01 (m, 2H), 4.26 (m, 2H), 4.0 (m, 1H), 3.51 (s, 1H), 3.24 (s, 3H).
13CNMR(300MHz，DMSO)：δ170.2，169.3，155.3，152.0，149.5，148.0，145.2，139.0，136.7，135.9，135.2，131.2，128.1，125.4，125.2，124.4，123.7，122.1，122.1，117.3，117.3，116.1，69.7，58.3，53.4，53.4，31.9。ESI-MS?m/z?510(M+1)。
Embodiment 4
1-(3-(4-(4-(6-(trifluoromethyl) pyridine-3-oxygen base) aniline) quinazoline) azetidine)-2-methoxyl group hexanone, structural formula is:
Product is characterized, 1HNMR (300MHz, DMSO) result: δ 7.70 (d, 1H), 7.5 (dd, 1H), 7.4 (d, 1H), 6.48 (dd, 1H), 6.48 (dd, 1H), 6.29 (d, 1H), 6,4.26; 4.26 (d, 2H), 4.0 (d, 1H), 3.51 (s, 1H), 3.24 (s, 3H).
13NMR(75MHz，DMSO)：δ170.2，169.3，155.3，152.0，149.5，148.0，145.2，139.0，136.7，135.9，135.2，131.2，128.1，125.4，125.2，124.4，123.7，122.1，122.1，117.3，117.3，116.1，69.7，58.3，53.4，53.4，31.9。ESI-MS?m/z?510(M+1)。
Embodiment 5
1-6-(4-(4-(4-(6-(trifluoromethyl) pyridine-3-oxygen base) aniline) quinazoline) piperidines) hexanone, structural formula is:
Use Acetyl Chloride 98Min. and midbody 4 reactions, compound method is with embodiment 1.Product is characterized the result:
1HNMR (300MHz, DMSO): δ 7.5 (dd, 1H), 7.4 (d, 1H), 6.48 (d, 1H), 6.48 (d, 1H), 6.29 (dd, 1H), 6.29 (dd, 1H), 4.0 (d, 1H), 3.29 (m, 2H), 2.78 (dd, 1H), 2.02 (s, 3H), 1.66 (dd, 2H), 1.66 (m, 2H).
13CNMR(75MHz，DMSO)：δ172.6，169.3，152.0，148.0，145.2，139.0，136.7，135.9，135.2，131.2，128.1，125.4，125.2，124.4，123.7，122.1，122.1，117.3，117.3，116.1，172.6，41.9，41.9，41.7，29.6，29.6，21.1。ESI-MS?m/z?508(M+1)。
Embodiment 6
1-6-(3-(4-(4-(6-picoline-3-oxygen base)-3-anisidine) quinazoline) azetidine) hexanone, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): 7.70 (m, 1H), 7.42 (m, 1H), 7.37 (m, 1H), 6.37 (d, 1H), 5.85 (dd, 1H), 5.80 (d, 1H), 4.01 (m, 2H), 4.0 (d, 1H), 3.73 (s, 3H), 3.51 (s, 1H), 2.55 (s, 3H), 2.02 (s, 3H);
13CNMR (300MHz, DMSO) δ 172.6,169.3, and 157.6,155.3,152.0,149.5,148.0,140.0; 136.7,135.9,134.2,131.2,128.1,125.4,124.4,123.7,123.1; 11.5,116.1,109.6,56.2,53.1,53.1,31.9,20.8,24.8; ESI-MSm/z, 456 (M+1).
Embodiment 7
1-6-(3-(4-(4-(6-picoline-3-oxygen base)-3-anisidine) quinazoline) azetidine)-2-methoxyl group hexanone, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO):, 7.70 (dd, 1H), 7.42 (m, 1H), 7.37 (d, 1H), 6.37 (dd, 1H), 5.85 (d, 1H), 5.80 (m, 1H), 4.26 (d, 2H), 4.0 (m, 1H), 3.73 (s, 3H), 3.51 (s, 1H), 3.24 (s, 3H), 2.55 (s, 3H).
13CNMR(300MHz，DMSO)δ170.2，169.3，157.6，155.3，149.5，152.0，148.0，140.0，136.7，135.9，134.2，131.2，128.1，125.4，124.4，123.7，123.1，116.1，109.6，100.5，69.7，58.3，56.2，53.4，53.4，31.9，24.8。ESI-MS?m/z?486(M+1)。
Embodiment 8
1-6-(3-(4-(4-(6-5-flumethiazine-3-oxygen base)-3-anisidine) quinazoline) azetidine)-methyl-n-butyl ketone, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): 7.70 (d, J=7.8Hz, 1H), 7.5 (d, J=7.8Hz, 1H), 7.4 (d, J=8.3Hz; 1H), 6.37 (m, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 4.26 (m, 1H); 4.0 (m, 1H), 3.73 (s, 3H), 3.51 (s, 1H), 2.02 (s, 3H).
13CNMR(300MHz，DMSO)：δ172.6，169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125.4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，56.2，53.1，53.1，31.9，20.8。ESI-MS?m/z?510(M+1)。
Embodiment 9
1-6-(3-(4-(4-(6-5-flumethiazine-3-oxygen base)-3-anisidine) quinazoline) azetidine)-2-methoxyl group hexanone, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): δ 7.70 (d, J=7.8Hz, 1H), 7.5 (m, 1H), 7.4 ((d, J=8.3Hz, 1H), 6.37 (, 1H), 5.85 (, 1H), 5.80 (, 1H), 4.26; 4.01 (, 2H), 4.26; 4.01 (, 2H), 4.26 (, 2H), 4.0 (, 1H), 3.73 (, 3H), 3.51 (, 1H), 3.24 (, 3H).
13CNMR(300MHz，DMSO)：δ170.2，169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125.4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，69.7，58.3，56.2，53.4，53.4，31.9。ESI-MSm/z?540(M+1)。
Embodiment 10
N-(4-(6-(trifluoromethyl) pyridine-3-oxygen base)-3-anisole)-6-(1-(methylsulfonyl) 3-azetidine)-4-quinazoline ammonia, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): δ 8.6 (m, 1H), 8.36 (d, J=7.8Hz, 1H), 7.93 (m, 1H), 7.71 (d, J=8.3Hz, 1H), 7.70 (, 1H), 7.5 (, 1H), 7.4 (, 1H), 6.37 (, 1H), 5.85 (, 1H), 5.80 (, 1H), 4.0; 3.7 (, 2H), 4.0 (, 1H), 3.95; 3.7 (, 2H), 3.73 (, 3H), 3.51 (, 1H), 2.84 (, 3H).
13CNMR(75MHz，DMSO)：δ169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125.4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，56.2，51.1，51.1，39.4，31.0。ESI-MSm/z546(M+1)。
Embodiment 11
N-(4-(6-(trifluoromethyl) pyridine-3-oxygen base)-3-anisole)-6-(1-(ethylsulfonyl) 3-azetidine)-4-quinazoline ammonia, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): 7.70 (d, J=7.8Hz, 1H), 7.5 (d, J=8.3Hz, 1H), 7.4 (dd, 1H), 6.37 (d, 1H), 5.85 (m, 1H), 5.80 (d, 1H), 4.0; 3.7 (d, 2H), 4.0 (m, 1H), 3.55 (m, 2H), 3.73 (s, 3H), 3.51 (s, 1H) 3.45 (s, 2H), 1.28 (s, 3H).
13CNMR(300MHz，DMSO)：δ169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125.4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，56.2，51.1，51.1，44.8，31.0，2.7。ESI-MSm/z?560(M+1)。
Embodiment 12
1-(4-(4-(4-(6-trifluoromethyl) pyridine-3-oxygen base)-3-anisidine) quinazoline ammonia-6-piperidines ethyl ketone, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): 7.78 (d, J=7.8Hz, 1H), 7.5 (d, J=8.3Hz, 1H), 7.4 (d, 1H), 6.37 (d, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 4.0 (d, 1H), 3.73 (s, 3H), 3.39; 3.29 (m, 2H), 2.78 (m, 1H), 2.02 (s, 3H), 1.19; 1.66 (d, J=8.0Hz, 2H), 1.19; 1.66 (d, J=8.0Hz, 2H).
13CNMR(75MHz，DMSO)：δ172.6，169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125，4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，56.2，41.9，41.9，41.7，29.6，29.6，21.1。ESI-MS?m/z?538(M+1)。
Embodiment 13
1-6-(4-(4-(6-(trifluoromethyl) pyridine-3 oxygen base)-3-anisidine) quinazoline)-piperidino)-and 1-acetone, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): 7.70 (d, J=7.8Hz, 1H), 7.5 (dd, 1H), 7.4 (d, 1H), 6.37 (d, 1H), 5.85 (m, 1H), 5.80 (m, 1H), 4.0 (m, 1H), 3.73 (s, 3H), 3.39; 3.29 (m, 2H), 3.39; 3.29 (m, 2H), 2.78 (m, 1H), 2.02 (s, 3H), 1.19; 1.66 (d, J=8.0Hz, 2H), 1.19; 1.66 (d, J=8.0Hz, 2H).
13CNMR(75MHz，DMSO)：δ172.6，169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125，4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，56.2，41.9，41.9，41.7，29.6，29.6，21.1。ESI-MS?m/z?538(M+1)。
Embodiment 14
N-(4-(6-5-flumethiazine 3-oxygen base)-3-p-methoxy-phenyl)-6-(4-piperidyl) quinazoline-4-first semi-annular jade pendant acid amides, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): 7.79 (dd, 1H), 7.5 (d, 1H), 7.4 (m, 1H), 6.37 (dd, 1H), 5.85 (d, 1H), 5.80 (d, 1H), 4.0 (m, 1H), 3.73 (s, 3H), 3.39; 3.29 (m, 2H), 3.39; 3.29 (m, 2H), 2.78 (m, 1H), 2.02 (s, 3H), 1.19; 1.66 (d, J=8.0Hz, 2H), 1.19; 1.66 (d, J=8.0Hz, 2H).
13CNMR(75MHz，DMSO)：δ172.6，169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125，4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，56.2，41.9，41.9，41.7，29.6，29.6，21.1。ESI-MS?m/z?538(M+1)。
Embodiment 15
N-(4-(6-5-flumethiazine 3-oxygen base)-3-p-methoxy-phenyl)-6-(4-piperidyl) quinazoline-4-second semi-annular jade pendant acid amides, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO): δ 8.8 (m, 1H), 8.36 (d, J=7.8Hz, 1H), 7.93 (m, 1H), 7.71 (d, J=8.3Hz; 1H), 7.70 (dd, 1H), 7.5 (d, 1H), 7.4 (m, 1H), 6.37 (d, 1H); 5.85 (d, 1H), 5.80 (dd, 1H), 4.0 (m, 1H), 3.73 (s, 3H), 3.39; 3.29 (m, 2H), 3.39; 3.29 (m, 2H), 2.78 (m, 1H), 2.02 (s, 3H), 1.19; 1.66 (d, J=8.0Hz, 2H), 1.19; 1.66 (d, J=8.0Hz, 2H).
13CNMR(30MHz，DMSO)：δ172.6，169.3，157.6，155.3，152.0，148.0，140.0，136.7，135.9，135.2，134.2，131.2，128.1，125，4，125.2，124.4，123.7，123.1，116.1，109.6，100.5，56.2，41.9，41.9，41.7，29.6，29.6，21.1。ESI-MS?m/z?538(M+1)。
Embodiment 16
N-(4-(6-5-flumethiazine-3-oxygen base)-3-p-methoxy-phenyl)-6-(encircling third semi-annular jade pendant acyl-4-piperidyl) quinazoline-4-amine, structural formula is:
Product is characterized the result:
1HNMR (300MHz, DMSO) δ 8.1 (m, 1H), 7.96 (d, J=7.8Hz, 1H), 7.93 (m, 1H), 7.71 (d, J=8.3Hz; 1H), 7.70 (m, 1H), 7.5 (dd, 1H), 7.4 (d, 1H), 6.37 (dd, 1H); 5.85 (m, 1H), 5.80 (d, 1H), 4.0 (d, 1H), 3.73 (s, 3H), 3.39; 3.29 (m, 2H), 3.39; 3.29 (m, 2H), 2.78 (m, 1H), 2.02 (s, 3H), 1.19; 1.66 (d, J=8.0Hz, 2H), 1.19; 1.66 (d, J=8.0Hz, 2H).
13CNMR(75MHz，DMSO)：δ156.28，144.62，142.73，133.87，132.71，129.58，127.63，126.38，126.13，111.81，110.99，21.24。ESI-MS?m/z?289(M+1)。
Claims (9)
1. the small molecules selective depressant of an ErbB2, it is characterized in that: this suppressor factor is the salt of compound M and pharmaceutically receptible compound M;
The general structure of compound M is:
In the formula, m is 0,1 or 2; R1 is any in the following group: hydrogen, halogen replaces or unsubstituted C
1-8Alkyl replaces or unsubstituted C
2-8Thiazolinyl replaces or unsubstituted C
2-8Alkynyl replaces or unsubstituted aryl, replaces or unsubstituted heterocyclic C
1-8Alkyloyl, C
1-8Alkoxyl group, C
1-8Alkyl sulphinyl, C
1-8Alkyl sulphonyl, arylsulfonyl, cyanic acid, nitro, hydroxyl, amino, carboxyl, oxo, carbamyl, N, N-two-(C
1-8Alkyl), carbamyl, C
1-8Alkanoyloxy, C
1-8Alkyl amide, C
3-8The alkynyl amide base, N-(C
1-8Alkyl) sulfamyl, N, N-two-(C
1-8Alkyl) sulfamyl; X is NR
2, CHR
3, O or S; X
1Be C or N;
R is any in the following group: replace or unsubstituted aryl, replace or unsubstituted heteroaryl, replace or unsubstituted aryl-C
1-3Alkyl replaces or unsubstituted aryl-C
3-7Naphthenic base.
2. the small molecules selective depressant of ErbB2 according to claim 1, it is characterized in that: R1 is any in the following group: hydrogen, halogen, C
1-8Alkyl, C
1-8Thiazolinyl, C
2-8Alkynyl, aryl, heteroaryl, heterocyclic radical, halo
1-3-C
1-8Alkyl, hydroxyl-C
1-8Alkyl, C
1-4Alkoxy-C
1-8Alkyl, cyanic acid-C
1-8Alkyl, amino-C
1-8Alkyl, aryl-C
1-8Alkyl, heteroaryl-C
1-8Alkyl, heterocyclic radical-C
1-8Alkyl, halo
1-3-C
2-8Thiazolinyl, hydroxyl-C
2-8Thiazolinyl, C
1-4Alkoxy-C
2-8Thiazolinyl, cyanic acid-C
2-8Thiazolinyl, amino-C
2-8Thiazolinyl, aryl-C
2-8Thiazolinyl heteroaryl-C
2-8Thiazolinyl, heterocyclic radical-C
2-8Thiazolinyl, halo
1-3-C
2-8Alkynyl, hydroxyl-C
2-8Alkynyl, C
1-4Alkoxy-C
2-8Alkynyl, cyanic acid-C
2-8Alkynyl, amino-C
2-8Alkynyl, aryl-C
2-8Alkynyl, heteroaryl-C
2-8Alkynyl, heterocyclic radical-C
2-8Alkynyl, C
1-8Alkyloyl, aryl-C
1-8Alkyloyl, heteroaryl-C
1-8Alkyloyl, heterocyclic radical-C
1-8Alkyloyl, C
1-8Carbalkoxy, aryl-C
1-8Carbalkoxy, heteroaryl-C
1-8Carbalkoxy, heterocyclic radical-C
1-8Carbalkoxy, C
1-8Alkyl sulfinyl, C
1-8The alkane alkylsulfonyl, arylsulfonyl, aryl-C
1-8The alkane alkylsulfonyl, heteroaryl-C
1-8The alkane alkylsulfonyl, heterocyclic radical-C
1-8The alkane alkylsulfonyl, aryl, heteroaryl, heterocyclic radical, cyanic acid, nitro, hydroxyl, amino, carboxyl, oxo, carbamyl, C
1-8Alkoxyl group, C
2-8Alkene oxygen base, C
2-8Alkynyloxy group, C
1-8Alkylthio, N-C
1-8Alkyl-carbamyl, N, N-two-C
1-8Alkyl-carbamyl, C
1-8Alkanoyloxy, C
1-8Alkyl amide, C
3-8The alkynyl amide base, N-C
1-8Alkyl-sulfamyl, N, N-two-C
1-8Alkyl-sulfamyl.
3. the small molecules selective depressant of ErbB2 according to claim 2 is characterized in that: described amino, amino-C
1-8Alkyl, amino-C
2-8Thiazolinyl or amino-C
2-8Alkynyl is freely replaced by any two in the following group: hydrogen, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl.
4. the small molecules selective depressant of ErbB2 according to claim 2 is characterized in that: described aryl, heteroaryl or heterocyclic radical contain 1-3 following substituting group: halogen, trifluoromethyl, cyanic acid, nitro, hydroxyl, amino, carboxyl, carbamyl, C
1-4Alkyl, C
2-4Thiazolinyl, C
2-4Alkynyl, C
1-4Alkoxyl group.
5. the small molecules selective depressant of ErbB2 according to claim 1 is characterized in that: contain 1-3 substituting group in the following group on aryl in said R or the heteroaryl: halogen, C
1-8Alkyl, C
2-8Thiazolinyl, C
2-8Alkynyl, cyanic acid, nitro, hydroxyl, amino, carboxyl, carbamyl, C
1-8Alkoxyl group, C
2-8Alkene oxygen base, C
2-8Alkynyloxy group, C
1-8Alkylthio, C
1-8Alkyl sulfinyl, C
1-8The alkane alkylsulfonyl, C
1-8Carbalkoxy, N-C
1-8Alkyl-carbamyl, N, N-two-C
1-8Alkyl-carbamyl, halo
1-3-C
1-8Alkyl, halo
1-3-C
1-8Alcoxyl, hydroxyl-C
1-8Alkyl, C
1-4Alkoxy-C
1-8Alkyl, cyanic acid-C
1-8Alkyl, amino-C
1-8Alkyl, aryl, aryl-C
1-8Alkyl, heteroaryl, heteroaryl-C
1-8Alkyl, heterocyclic radical, heterocyclic radical-C
1-8Alkyl, C
2-8Alkyloyl, C
2-8Alkanoyloxy, C
2-8Alkyl amide, C
3-8Alkyl amide, C
3-8The alkynyl amide base, N-C
1-8Alkyl-sulfamyl, N, N-two-C
1-8Alkyl-sulfamyl, C
1-8The alkane alkylsulfonyl, C
1-3Alkylene dioxy base ,-Y-R4; Wherein, Y is O, S, NR5, SO, SO
2, CO, CONR5, NR5CO, SO
2NR5 or NR5SO
2, R5 is hydrogen or C
1-4Alkyl, R4 are halogen-C
1-8Alkyl, hydroxyl-C
1-8Alkyl, C
1-4Alkoxy-C
1-8Alkyl, cyanic acid-C
1-8Alkyl, amino-C
1-8Alkyl, C
1-8Alkylamino-C
1-8Alkyl or two-[C
1-8Alkyl] ammonia-C
1-8Alkyl, aryl, aryl-C
1-8Alkyl, heteroaryl, heteroaryl-C
1-8Alkyl, heterocyclic radical or heterocyclic radical-C
1-8Alkyl.
6. the small molecules selective depressant of ErbB2 according to claim 1, it is characterized in that: described R is saturated or undersaturated aryl, or, saturated or undersaturated heteroaryl.
7. the small molecules selective depressant of the described ErbB2 of claim 1 is used for treating the application of Tyrosylprotein kinase modulability disease medicament in preparation.
8. application according to claim 8 is characterized in that: described Tyrosylprotein kinase modulability disease comprise the cancer of the brain, lung cancer, scale cell cancer, bladder cancer, cancer of the stomach, mammary cancer,, esophagus cancer, prostate cancer, colorectal carcinoma, thyroid carcinoma, tumor-blood-vessel growth and their complication.
9. medicine that is used to treat Tyrosylprotein kinase modulability disease; It is characterized in that: form by effective constituent and pharmaceutically receptible carrier; Wherein effective constituent is the small molecules selective depressant compound M of the described ErbB2 of claim 1, and pharmaceutically receptible carrier is water, gelatin, lactose, starch, Magnesium Stearate, talcum, vegetables oil, natural gum, alcohol, Vaseline and/or their mixture.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018005552A1 (en) | 2016-06-27 | 2018-01-04 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
| US10457578B1 (en) | 2018-06-22 | 2019-10-29 | Gary McInnis | Automated sulfur burner for agricultural irrigation |
| WO2022266458A1 (en) * | 2021-06-17 | 2022-12-22 | Black Diamond Therapeutics, Inc. | 6-heterocycloalkyl-quinazoline derivatives and uses thereof |
| WO2023195773A1 (en) * | 2022-04-05 | 2023-10-12 | 보로노이 주식회사 | Heteroaryl derivative and use thereof |
| US11884647B2 (en) | 2019-10-18 | 2024-01-30 | The Regents Of The University Of California | Compounds and methods for targeting pathogenic blood vessels |
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2011
- 2011-12-14 CN CN2011104168629A patent/CN102516232A/en active Pending
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2018005552A1 (en) | 2016-06-27 | 2018-01-04 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
| EP3939591A1 (en) | 2016-06-27 | 2022-01-19 | Achillion Pharmaceuticals, Inc. | Quinazoline and indole compounds to treat medical disorders |
| US10457578B1 (en) | 2018-06-22 | 2019-10-29 | Gary McInnis | Automated sulfur burner for agricultural irrigation |
| US11884647B2 (en) | 2019-10-18 | 2024-01-30 | The Regents Of The University Of California | Compounds and methods for targeting pathogenic blood vessels |
| WO2022266458A1 (en) * | 2021-06-17 | 2022-12-22 | Black Diamond Therapeutics, Inc. | 6-heterocycloalkyl-quinazoline derivatives and uses thereof |
| WO2023195773A1 (en) * | 2022-04-05 | 2023-10-12 | 보로노이 주식회사 | Heteroaryl derivative and use thereof |
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Application publication date: 20120627 |