CN106831725A - The quinazoline compounds and its application of quinoline containing indoline and similar structures - Google Patents
The quinazoline compounds and its application of quinoline containing indoline and similar structures Download PDFInfo
- Publication number
- CN106831725A CN106831725A CN201710033671.1A CN201710033671A CN106831725A CN 106831725 A CN106831725 A CN 106831725A CN 201710033671 A CN201710033671 A CN 201710033671A CN 106831725 A CN106831725 A CN 106831725A
- Authority
- CN
- China
- Prior art keywords
- bases
- dihydro
- indole
- quinoline
- acetamide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- DULZVFFGUXLRSB-UHFFFAOYSA-N CCC1(C)NC1 Chemical compound CCC1(C)NC1 DULZVFFGUXLRSB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Abstract
The invention discloses a kind of quinoline containing indoline and the quinazoline compounds of similar structures, as shown in formula I：
Description
Technical field
The present invention relates to quinazoline compounds, in particular to a kind of quinoline containing indoline and the quinazoline ditosylate salt of similar structures
Compound and its application.
Background technology
Cancer, also referred to as malignant tumour, are often as cell proliferation machinery not normal caused.Global cancer newly-increased every year
Disease case load will be up to 19,300,000, it is seen that cancer is always to threaten one big " killer " of human health.
EGF-R ELISA (epidermal growth factor receptor, EGFR) is ErbB family members
One of, it is a kind of important transmembrane receptor with tyrosine kinase activity.EGFR is started intracellular signal after ligand activation and is passed
Lead, by the cascade reaction of adaptin, enzyme in cytoplasm, adjust the transcription of transcription factor activation gene, instruct cell migration,
Stick, breed, breaking up, apoptosis, and formation with tumour and deteriorate closely related.The research and development of EGFR inhibitor are controlled molecular targeted
Treating human cancer direction has turned into focus.Substantial amounts of EGFR micromolecular inhibitors (shown in following structural formula) are had reported at present,
In these micromolecular inhibitors, document (Suda.K, Murakami.I, Katayama.T, et
Al.Clin.Cancer.Res.16 (2010) 5489-5498.) Afatinib is reported biological cell is active and antitumor enzyme
There is efficient effect, in addition, also many EGFR micromolecular inhibitors have excellent antitumor activity, such as in activity
Gefitinib (Fukuoka.M, Yano.S, Giaccone G, et al.J.Clin.Oncol.21 (2003) 2237-2246.),
Up to grammeter for your (Gonzales.A.J, Hook.K.E, Althaus.I.W, Mol, et al.Cancer.Ther.7 (2008)
1880-1889.), LP-7 (Lai.Y.S, Pang.J.X, Luo.M.H, C.N.Patent 201510184302,2015) and sheet
Seminar's latter design, quinazoline derivative 10k (Yuanbiao T, Yiqiang O.Y, the Shan X, et of synthesis
Al.Bioorg.Med.Chem.24 (2016) 1495-1503) etc..Document (Wang, X.F., et al. " Optimization of
4-(N-cycloamino)phenylquinazolines as a novel class of tubulin-polymerization
inhibitors targeting the colchicine site."Journal of Medicinal Chemistry 57.4
(2014):1390-1402.) report a series of novel contains the quinazoline derivant of 2,3- indoline structures, wherein changing
Compound A shows very excellent antitumor activity.
On the basis of bibliography, design has synthesized a series of quinoline azoles of quinolines containing indoline and similar structures to the present invention
Quinoline class compound, this series compound introduces acylhydrazone active group while remaining the agent structure of Afatinib, design
And synthesized various quinazoline compounds containing acylhydrazone structure.And it is different substituted containing dihydro that the present invention is investigated emphatically
The antitumor activity of the quinazoline compounds of indoline and similar structures, it is more preferably anti-swollen with selectivity to filter out activity
Tumor medicine.
The content of the invention
It is an object of the invention to provide a kind of quinoline containing indoline and the quinazoline compounds and its system of similar structures
Preparation Method and application.
The present invention provides quinazoline compounds, its geometry of the quinoline containing indoline and similar structures as shown in formula I
Isomers and its pharmaceutically acceptable salt, hydrate, solvate or prodrug, structure is as shown in following formula I：
Wherein：
A rings are selected from and contain 1~3 identical or different R1Substituted aromatic ring or hetero-aromatic ring；
B rings be it is thick with A rings and saturation nitrogenous five yuan or hexa-member heterocycle；
R1Selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, (C1~
C4) alkyl, (C3~C6) cycloalkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alkoxy, azido, (C1~C4) alkane
Epoxide methyl, (C1~C4) alkyl acyl or (C1~C4) alkylthio group；
R2Selected from trifluoromethyl, (C1~C4) alkyl, (C3~C6) cycloalkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1
~C4) alkoxy methyl,
R3Selected from (C1~C4) alkyl, (C3~C6) cycloalkyl, S- tetrahydrofuran -3- bases, N- methyl piperidine -4- methyl or
R4、R5It is identical or different, separately selected from (C1~C6) alkyl or (C3~C6) cycloalkyl, and R4And R5Contain 1
~2 hydrogen, hydroxyl, amino, halogen, sulfydryl or carboxyl substitutions；Or R4And R5Formed together with the nitrogen-atoms being connected with them
5~10 yuan of saturated heterocyclyls, the saturated heterocyclyl except with R4And R5Outside the nitrogen-atoms of connection, optionally it is selected from containing 1~3
The hetero atom of O, N and S；
N is 0~3.
Present invention is preferably related to such as above-mentioned compounds of formula I, its geometric isomer and its pharmaceutically acceptable salt,
Hydrate, solvate or prodrug, wherein：
The heterocycle of the thick sum of A, B is selected from：
R1Selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, methyl,
Ethyl, propyl group, butyl, cyclopropane, ethene, propylene, acetylene, propine, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, fourth oxygen
Base or azido；
R2Selected from trifluoromethyl, methyl, ethyl, propyl group, butyl, ethene, isobutene, cyclopropane, cyclobutane, pentamethylene,
Hexamethylene, ethene, propylene, butylene, acetylene, propine, butine, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy,
R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl, S- tetrahydrofuran -3- bases, N-
Methyl piperidine -4- methyl or
It is selected from：
N is 0~3.
In the present invention, the quinoline containing indoline of the formula I and the quinazoline compounds of similar structures are selected from following
One kind in compound, but these compounds are not meant to any limitation of the invention：
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- isopropoxy quinazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases)-acetamide,
N- (7- butoxy -4- (2,3- Dihydro-indole -1- bases)-quinazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-propionamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-Methacrylamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-Methacrylamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acrylamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- dimethylaminos-acetamide,
2- lignocaines-N- (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- pyrrolidin-1-yls-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases) -2- piperidines -
1- bases-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- morpholines -4- bases-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases) -2- (4- first
Base piperazine -1- bases)-acetamide,
The amyl- 3- olefin(e) acids of 5- dimethylaminos (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acid amides
Synthesis,
The amyl- 3- olefin(e) acids of 5- dimethylaminos (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-acid amides,
5- pyrrolidin-1-yls-amyl- 3- olefin(e) acids (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) oxygen
Base)-quinazoline -6- bases)-acid amides,
5- piperidin-1-yls-amyl- 3- olefin(e) acids (7- butoxy -4- (2,3- Dihydro-indole -1- bases)-quinazoline -6- bases)-acyl
Amine,
5- morpholine -4- bases-amyl- 3- olefin(e) acids (4- (2,3- Dihydro-indole -1- bases) -7- isopropoxy quinazoline -6- bases) -
Acid amides,
5- (4- thyl-piperazin -1- bases)-amyl- 3- olefin(e) acids (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochlorides -
6- yls)-acid amides,
N- (4- (the bromo- 2,3,4- dihydros of 6--(1,8) naphthyridines -1- bases) -7- (piperidin-4-yl methoxyl group)-quinoline -6- bases) -
2- (4- methanesulphonyl-piperazine -1- bases)-acetamide,
Cyclopentane-carboxylic acid (4- (2- methyl -5,6,7- dihydro-pyridos simultaneously (2,3-d) pyrimidine -8- bases) -7- trifluoromethyls-quinoline
Quinoline -6- bases)-acid amides,
N- (4- (5- ethyoxyl -2,3,4- dihydros-(1,7) naphthyridines -1- bases) -7- propoxy-alphauinazoline -6- bases) -2,2,
2- trifluoroacetamides,
The acid of 4- dimethylaminos-but-2-ene (4- (the bromo- 2,3- dihydro-pyrroles of 5- simultaneously (2,3-b) pyridine -1- bases) -7-
((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases)-acid amides.
Following synthetic route describes the preparation of the quinazoline compounds of formula I of the present invention, and all of raw material is all
It is being prepared by way of described in synthetic route, by organic chemistry filed method well-known to the ordinarily skilled artisan or can business
Purchase.The final quinazoline compounds of whole of the invention are all by the method described in synthetic route or by similar with its
Method prepare, these methods are organic chemistry fileds well-known to the ordinarily skilled artisan.That is applied in synthetic route all may be used
Become the definition of factor following article or such as the definition in claim.
By taking N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acetamide as an example, synthetic method
As follows, it is pure that all raw materials are commercially available analysis.
It is with N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- morpholines -4- bases-acetamide
Example, synthetic method is as follows, and it is pure that all raw materials are commercially available analysis.
With the acid of 4- dimethylaminos-but-2-ene (4- (the bromo- 2,3- dihydro-pyrroles of 5- simultaneously (2,3-b) pyridine -1- bases) -7-
((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases) as a example by-acid amides, synthetic method is as follows, and all raw materials are commercially available point
Analysis is pure.
Present invention synthetic intermediate VII first, then obtained through from different substituted small molecule acyl chlorides docking or other modes
Target compound.
According to some usual methods of the art, the quinazoline compounds of above-mentioned formula I can in the present invention
Pharmaceutically acceptable salt is generated with acid.Pharmaceutically acceptable addition salts include inorganic acid and organic acid addition salt, with following sour addition
Salt be particularly preferred：Hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethyl sulfonic acid, p-methyl benzenesulfonic acid, benzene sulfonic acid, the sulphur of naphthalene two
Acid, acetic acid, propionic acid, lactic acid, trifluoroacetic acid, maleic acid, citric acid, fumaric acid, oxalic acid, tartaric acid, benzoic acid etc..
Additionally, present invention additionally comprises the prodrug of derivative of the present invention.The prodrug of derivative of the present invention is spreading out for above-mentioned formula I
Biology, their own may have weaker activity even without activity, but upon administration, (for example lead in physiological conditions
Cross metabolism, solvolysis or other mode) it is converted to corresponding biologically active form.
The present invention can contain above-mentioned formula I quinazoline compounds, and its pharmaceutically acceptable salt, hydrate or
Solvate is prepared by mixing into composition as active ingredient with pharmaceutically acceptable carrier or excipients, and is prepared into and faces
Acceptable formulation on bed, above-mentioned pharmaceutically acceptable excipients refer to any diluent that can be used for pharmaceutical field, auxiliary
Agent and/or carrier.Derivative of the invention can be applied in combination with other active ingredients, as long as they do not produce other unfavorable
Effect, such as allergic reaction.
The clinical dosage that the quinazoline compounds of the above-mentioned formula I of the present invention are used for patient can basis：Active component exists
Internal therapeutic efficiency and bioavilability, the age of their metabolism and discharge rate and patient, sex, disease phase are carried out
Appropriate adjustment, but the daily dosage of adult typically should be 10~500mg, preferably 50~300mg.Therefore, the present invention is worked as
Pharmaceutical composition when being made into unit dosage forms, it is contemplated that above-mentioned effective dose, per unit preparation should be containing on 10~500mg
State the quinazoline compounds of formula I, preferably 50~300mg.According to the guidance of doctor or pharmacist, these preparations can be with one
Fixed interval point is administered (preferably one to six time) several times.
Pharmaceutical composition of the invention can be configured to several formulation, wherein containing some conventional figurations in drug field
Agent.Several formulation as described above can be using injection, tablet, capsule, aerosol, suppository, film, pill, outer
With drug forms such as liniment, ointments.
Carrier for pharmaceutical composition of the present invention is available common type in drug field, including：Adhesive, profit
Lubrication prescription, disintegrant, cosolvent, diluent, stabilizer, suspending agent, non-pigment, flavouring, preservative, solubilizer and matrix etc..
Pharmaceutical preparation can by oral administration or parenteral (such as intravenous, subcutaneous, intraperitoneal or local) administration, if some drugses
It is unstable under the conditions of stomach, enteric coated tablets can be configured to.
It has also been found that the quinazoline compounds of above-mentioned quinoline containing indoline and similar structures prepare treatment and/or
Application in prevention proliferative disease medicine.Reactive compound of the invention or its officinal salt and its solvate can be used as only
One anti-proliferate medicine is used alone, or can with the anti-proliferate Drug combination for having listed, for treat and/
Or prevent proliferative disease, such as psoriasis, benign prostatauxe, atherosclerosis and ISR.
It has also been found that the quinazoline compounds of above-mentioned quinoline containing indoline and similar structures prepare treatment and/or
Application in the medicine of pre- anti-cancer.The compounds of this invention has suppression tumor cell growth activity in vitro, therefore, it can be used
Make the medicine of preparation treatment and/or pre- anti-cancer, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, son
Palace, pancreas, marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma
Deng.
It has also been found that the quinazoline compounds of above-mentioned quinoline containing indoline and similar structures prepare treatment and/or
Application in prevention prostate cancer, lung cancer and cervical carcinoma, the medicine of breast cancer.
Suppress lung cell A549, Human Prostate Cancer Cells PC-3, human breast cancer cell line Bcap-37 and cervical carcinoma by external
Cell Hela activity tests, the compounds of this invention is to lung carcinoma cell, prostate gland cancer cell, breast cancer cell and cervical cancer cell
With significantly inhibiting effect, it is especially useful in prepare the medicine for the treatment of and/or prevention prostate cancer, lung cancer and cervical carcinoma.
Found by testing EGFR and VEGFR2/KDR kinase activities, the compounds of this invention has significant suppression EGFR
With VEGFR2/KDR kinase activities, lung carcinoma cell, Human Prostate Cancer Cells, breast cancer cell and uterine neck to EGFR expression high
Cancer cell etc. has stronger inhibitory action, it is especially useful in prepare the medicine for the treatment of and/or prevention lung cancer.
Reactive compound of the invention or its officinal salt and its solvate can be independent as unique antineoplastic
Use, or can be with antineoplastic (such as platinum medicine cis-platinum, camptothecine Irinotecan, the Changchun for having listed
Flower bases medicine NVB, deoxidation born of the same parents' former times class medicine gemcitabine, etoposide, taxol etc.) it is used in combination.Therapeutic alliance is led to
Cross each therapeutic component simultaneously, order or separate administration and realize.
As a result the present invention shows tool through carrying out antitumor activity screening to various EGFR inhibitor overexpression cell lines in vitro
There is stronger antitumor activity and selectivity, the activity in vivo that many compounds have also carried out EGFR and VEGFR2/KDR kinases is surveyed
Examination.Experiment shows that some compounds have efficient antitumor activity.
Specific embodiment
In order to preferably explain the present invention, below in conjunction with specific embodiment, the present invention is described in further detail, but
They do not constitute to the present invention and limit.
Embodiment is intended to illustrate rather than limitation the scope of the present invention.The proton nmr spectra Bruker of derivative
ARX-400 is determined, and mass spectrum is determined with the LC/MSD of Agilent 1100；It is pure or chemical pure that agents useful for same is analysis.
The quinoline containing indoline of formula I and the quinazoline compounds of similar structures：
The structural formula of the embodiment of the present invention 1~25 is as shown in table 1 below.
The structural formula of the embodiment 1~25 of table 1
The synthesis of step A 7- Fluquinconazoles quinoline -4- ketone (II)
Successively to the fluoro- 2- aminobenzoic acids of 4- and 67.0g that 50.0g is added in the three-necked bottle equipped with 300mL absolute ethyl alcohols
Formamidine acetate, mixture heating reflux reaction 24h.Reaction is finished, evaporated under reduced pressure major part solvent, and reaction solution is poured into 1000mL
30min is stirred in sodium-chloride water solution, suction filtration, filter cake is washed with 60% ethanol water, dried, obtain 51.0g white solids,
That is 7- Fluquinconazoles quinoline -4- ketone (II), yield：96.4%.
Mp 260.1-261.0,1H NMR (400MHz, CDCl3) δ 12.35 (s, 1H), 8.17 (d, J=6.8Hz, 1H),
(t, J=8.8Hz, the 1H) of 8.14 (d, J=7.2Hz, 1H), 7.43 (d, J=9.8Hz, 1H), 7.37
The synthesis of the fluoro- 6- nitro-quinazolines -4- ketone (III) of step B 7-
The 7- Fluquinconazole quinoline -4- ketone of 50.0g is slowly added into the 103mL concentrated sulfuric acids and 105mL fuming nitric aicds under ice bath
In the nitration mixture being made into, 110 DEG C of reaction 3h are heated to after 1h is stirred at room temperature.Reaction is finished, and is cooled to room temperature, and reaction solution is poured into
Strong agitation in 1000mL mixture of ice and water, suction filtration, the filter cake water washing of 500mL, the dried filter cake ethanol of 300mL
30min is heated to reflux, while hot suction filtration, dried, obtain the fluoro- 6- nitro-quinazolines -4- ketone (III) of faint yellow solid 48.5g, i.e. 7-,
Yield：76.1%.
Mp 277.3-278.5, ESI-MS [M-H] m/z:208,1H NMR(400MHz,DMSO)δ12.77(s,1H),
(dd, J=12.2,2.8Hz, the 1H) of 8.68 (dd, J=8.2,2.7Hz, 1H), 8.28 (s, 1H), 7.73
The synthesis of the fluoro- 6- nitros -4- chloro-quinazolines (IV) of step C 7-
The fluoro- 6- nitro-quinazolines -4- ketone of the 7- of 48.0g is added to 407.0mL thionyl chlorides and 75.0mL POCl3s
In mixed liquor, the DMF (DMF) of 2.4mL is added dropwise to mixed liquor, 80 DEG C are heated to reflux 3h, and reaction solution becomes yellow
After clarification again 110 DEG C be heated to reflux 6h.Reaction is finished, evaporated under reduced pressure excess of solvent, and a small amount of solvent, solid powder are taken away with toluene
1h is stirred in end in being poured slowly into the sodium bicarbonate aqueous solution of ice, and suction filtration, washing is dried, and obtains the fluoro- 6- of 50.7g yellow solids, i.e. 7-
Nitro -4- chloro-quinazolines, yield：97.0%.
Mp 118.2-119.3 DEG C, ESI-MS [M+H] m/z:228.5,1H NMR (400MHz, DMSO) δ 8.66 (dd, J=
8.2,1.2Hz, 1H), 8.41 (s, 1H), 7.75 (d, J=12.2Hz, 1H)
The synthesis of step D 4- (2,3- Dihydro-indole -1- bases) fluoro- 6- nitro-quinazolins (V) of -7-
Successively to the 2,3- bis- of the fluoro- 6- nitros -4- chloro-quinazolines of 7- of addition 50.0g, 38.4g in the isopropanol of 400mL
Hydrogen indoles, to dropwise addition 32.6mL triethylamines, stirring at normal temperature 1.5h in reaction solution.Reaction is finished, suction filtration, filter cake isopropyl alcohol and water
Washing, is dried, and the stirring of filtrate increasing amount water separates out solid, and suction filtration, washing is dried, merged, and obtains 60.0g dark yellow solids, i.e. 4-
(2,3- Dihydro-indole -1- bases) fluoro- 6- nitro-quinazolins (V) of -7-, yield：88.6%.
Mp 261.4-262.5, ESI-MS [M+H] m/z:313.0,1H NMR(400MHz,CDCl3) δ 9.02 (d, J=
8.1Hz, 1H), 8.74 (s, 1H), 7.90 (d, J=8.1Hz, 1H), 7.85 (d, J=12.5Hz, 1H), 7.36 (d, J=
7.3Hz, 1H), 7.20 (t, J=7.8Hz, 1H), 7.08 (t, J=7.4Hz, 1H), 4.59 (t, J=7.8Hz, 2H), 3.21 (t,
J=7.7Hz, 2H)
Step E 4- (2,3- Dihydro-indole -1- bases) -7- methoxyl group -6- nitro-quinazolins (VI1) synthesis
By 4- (2,3- Dihydro-indole -1- bases) fluoro- 6- nitro-quinazolins of -7- of 11.37g be added to 227mL methyl alcohol and
In 50% sodium hydrate aqueous solution of 15mL, 1.5h is heated to reflux, room temperature is cooled to after completion of the reaction, poured into 200mL frozen water
Strong agitation 30min, suction filtration, washing is dried, and obtains 11.2g yellow solids, i.e. 4- (2,3- Dihydro-indole -1- bases) -7- methoxies
Base -6- nitro-quinazolins, yield：94.9%.
m.p.292.3-293.0℃.ESI-MS m/z:[M+H] 323.0,1H NMR(400MHz,CDCl3)δ8.50(s,
1H), 7.27 (d, J=7.1Hz, 1H), 7.17 (s, 1H), 7.03 (d, J=7.4Hz, 1H), 7.00 (s, 1H), 6.87 (s, 2H),
(d, J=8.1Hz, the 2H) of 4.23 (t, J=7.6Hz, 2H), 3.98 (s, 3H), 3.15
Step F 4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- base amine (VII1) synthesis
4- (2,3- Dihydro-indole -1- bases) -7- methoxyl group -6- nitro-quinazolins of 21.4g are added to 700mL ethanol
In, it is heated to adding 15.0g activated carbons, 4.2g ferric trichlorides at 60 DEG C, 80% water of 24.5mL is slowly added dropwise when rising to 80 DEG C
Hydrazine is closed, continues to be heated to reflux 1.5h.Reaction is finished, while hot suction filtration, filter residue ethyl acetate rinse, and vacuum rotary steam filtrate is threaded to
Add 500mL water, strong agitation, suction filtration to dry during 10% solvent, obtain 17.3g pale solids, i.e. 4- (2,3- dihydro-Yin
Diindyl -1- bases) -7- methoxyquinazoline hydrochloride -6- base amine, yield：87.3%.
Mp 139.3-140.1, [M+H] m/z:293.0,1H NMR(400MHz,DMSO)δ9.41(s,1H),8.38(s,
1H), 8.17 (t, J=12.6Hz, 1H), 7.88-7.73 (m, 1H), 7.38 (dd, J=17.2,8.2Hz, 2H), 7.05 (s,
1H), 5.41 (s, 2H), 5.20 (s, 1H), 4.00-3.87 (m, 3H), 3.77 (dd, J=12.6,7.8Hz, 1H), 2.29 (td, J
=14.2,7.2Hz, 1H), 2.19-2.06 (m, 1H)
The synthesis of step G N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acetamide
4- (2,3- Dihydro-indole -1- the bases) -7- methoxyquinazoline hydrochlorides -6- bases amine of 0.1g and 6 drop N, N- diisopropyl second
Amine is added in the Isosorbide-5-Nitrae-dioxane of 8.0mL, adds 6 drop chloroacetic chlorides, is stirred at room temperature 1 hour, after the completion of reaction, suction filtration,
Dry, obtain white solid 0.081g, i.e. N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acetyl
Amine, yield：70.8%.
Embodiment 1
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acetamide
First according to step A~C synthesis fluoro- 6- nitros -4- chloro-quinazolines (IV) of 7-, then closed by step D by intermediate compound IV Into4- (2,3- Dihydro-indole -1- bases) fluoro- 6- nitro-quinazolins (V) of -7-, then 4- (2,3- dihydro-Yin are synthesized by step E Diindyl -1- bases) -7- methoxyl group -6- nitro-quinazolins (VI1)；
4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- base amine (VII is synthesized by step F1), finally
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acetamide is obtained by step G.
Mp 229.8-231.0, [M+H] m/z:335.3,1H NMR(400MHz,DMSO)δ11.21(s,1H),9.86(s,
1H), 9.13 (s, 1H), 9.00 (s, 1H), 8.51 (s, 1H), 8.09 (d, J=6.3Hz, 1H), 8.03 (s, 1H), 7.85-7.75
(m, 3H), 7.42 (s, 1H), 7.33 (s, 1H), 7.28 (t, J=8.5Hz, 2H), 5.45 (s, 1H), 4.04 (s, 2H), 3.95
(s, 1H), 3.87 (d, J=4.9Hz, 1H), 2.42 (dd, J=13.8,6.6Hz, 1H), 2.19-2.10 (m, 1H)
According to the method for embodiment 1, respectively with the intermediate VII of different substituents2、VII3、VII4And VII5With chloroacetic chloride
Reaction is obtained the compound of embodiment 2~5.
The N- of embodiment 2 (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-acetamide
Mp 239.8-241.0, [M+H] m/z:349.11H NMR(400MHz,CDCl3)δ9.61(s,1H),9.18(s,
1H), 8.85 (s, 1H), 8.06 (d, J=7.7Hz, 1H), 7.42 (d, J=7.2Hz, 2H), 7.29 (t, J=7.6Hz, 1H),
7.20 (t, J=7.4Hz, 1H), 4.67 (t, J=7.3Hz, 2H), 4.40-4.32 (m, 2H), 3.27 (s, 2H), 2.20 (s,
3H), 1.51 (t, J=6.7Hz, 3H)
The N- of embodiment 3 (4- (2,3- Dihydro-indole -1- bases) -7- isopropoxy quinazoline -6- bases)-acetamide
Mp 235.8-237.0, [M+H] m/z:363.41H NMR(400MHz,CDCl3)δ9.48(s,1H),9.18(s,
1H), 8.85 (s, 1H), 8.08 (d, J=8.2Hz, 1H), 7.57 (s, 1H), 7.42 (d, J=7.1Hz, 1H), 7.30 (t, J=
7.4Hz, 1H), 7.20 (t, J=7.4Hz, 1H), 4.92-4.84 (m, 1H), 4.67 (t, J=7.0Hz, 2H), 3.59 (s, 2H),
3.27(s,2H),2.21(s,3H),1.47(s,3H),1.46(s,3H).
The N- of embodiment 4 (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases) -
Acetamide
Mp 299.8-301.0, [M+H] m/z:391.01H NMR(400MHz,DMSO)δ9.25(s,1H),8.89(s,
1H), 8.60 (s, 1H), 7.38 (d, J=7.8Hz, 1H), 7.33-7.26 (m, 2H), 7.10 (s, 1H), 6.96 (d, J=
7.5Hz, 1H), 5.32 (s, 1H), 4.37 (s, 2H), 4.04 (s, 2H), 3.95 (d, J=7.5Hz, 1H), 3.80 (s, 1H),
(s, the 3H) of 3.19 (d, J=7.0Hz, 2H), 2.35 (s, 1H), 2.21 (s, 1H), 2.16
The N- of embodiment 5 (7- butoxy -4- (2,3- Dihydro-indole -1- bases)-quinazoline -6- bases)-acetamide
Mp 260-262.0, [M+H] m/z:377.5,1H NMR(400MHz,DMSO)δ9.56(s,1H),9.13(s,
1H), 8.85 (s, 1H), 8.05 (d, J=7.9Hz, 1H), 7.43 (s, 1H), 7.41 (s, 1H), 7.29 (t, J=7.7Hz, 1H),
7.20 (t, J=7.3Hz, 1H), 4.67 (t, J=7.4Hz, 2H), 4.29 (t, J=6.5Hz, 2H), 3.26 (d, J=7.0Hz,
2H), (t, J=7.4Hz, the 3H) of 2.19 (s, 3H), 1.92-1.85 (m, 2H), 1.52 (dd, J=15.0,7.6Hz, 2H), 0.98
The N- of embodiment 6 (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-propionamide
By 4- (2,3- Dihydro-indole -1- the bases) -7- methoxyquinazoline hydrochloride -6- base amine (VII of 0.1g1) and 6 drop N, N- bis-
Wopropyl ethyl amine is added in the Isosorbide-5-Nitrae-dioxane of 8.0mL, adds 6 drop propionyl chlorides, is stirred at room temperature 1 hour, and reaction is completed
Afterwards, suction filtration, dries, and obtains white solid 0.081g, i.e. N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochlorides -6-
Base)-propionamide, yield：70.8%.
Mp 179.8-181.0, [M+H] m/z:349.4,
The N- of embodiment 7 (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-Methacrylamide
By 4- (2,3- Dihydro-indole -1- the bases) -7- methoxyquinazoline hydrochloride -6- base amine (VII of 0.1g1) and 6 drop N, N- bis-
Wopropyl ethyl amine is added in the Isosorbide-5-Nitrae-dioxane of 8.0mL, adds 6 drop methacrylic chlorides, is stirred at room temperature 1 hour, instead
After the completion of answering, suction filtration is dried, and obtains white solid 0.085g, i.e. N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyl group quinolines
Oxazoline -6- bases)-Methacrylamide, yield：68.9%.
Mp 200.1-204.0, [M+H] m/z:361.1,1H NMR(400MHz,DMSO)δ9.27(s,1H),8.81(s,
1H), 8.66 (s, 1H), 7.49 (d, J=7.9Hz, 1H), 7.37 (s, 1H), 7.32 (d, J=6.9Hz, 1H), 7.13 (t, J=
7.7Hz, 1H), 6.99 (t, J=7.4Hz, 1H), 4.42 (t, J=7.8Hz, 2H), 3.21 (s, 2H), 2.21-2.13 (m, 1H),
(s, the 3H) of 1.96 (d, J=19.7Hz, 1H), 1.63 (s, 3H), 1.61
The N- of embodiment 8 (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-Methacrylamide
According to the method for embodiment 7, with intermediate VII2The compound of embodiment 8 is obtained with methacrylic chloride reaction.
Mp 305.4-307.0, [M+H] m/z:417.5,1H NMR(400MHz,DMSO)δ9.32(s,1H),8.85(s,
1H), 8.70 (s, 1H), 7.61 (d, J=7.6Hz, 1H), 7.36 (s, 1H), 7.33 (s, 1H), 7.17 (t, J=7.5Hz, 1H),
7.04 (t, J=7.3Hz, 1H), 4.48 (t, J=8.0Hz, 2H), 4.37-4.31 (m, 2H), 3.23 (s, 2H), 2.18 (dd, J
=17.9,13.0Hz, 1H), 1.98 (dd, J=18.2,11.9Hz, 1H), 1.64 (s, 3H), 1.61 (s, 3H)
The N- of embodiment 9 (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acrylamide
By 4- (2,3- Dihydro-indole -1- the bases) -7- methoxyquinazoline hydrochloride -6- base amine (VII of 0.1g1) and 6 drop N, N- bis-
Wopropyl ethyl amine is added in the Isosorbide-5-Nitrae-dioxane of 8.0mL, adds 6 drop acryloyl chlorides, is stirred at room temperature 1 hour, has been reacted
Cheng Hou, suction filtration is dried, and obtains white solid 0.083g, i.e. N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyl group quinoline azoles
Quinoline -6- bases)-acrylamide synthesis, yield：70.0%.
Mp 237.0-238.0, [M+H] m/z:347.1,
The N- of embodiment 10 (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- dimethylaminos -
Acetamide
By 4- (2,3- Dihydro-indole -1- the bases) -7- methoxyquinazoline hydrochloride -6- base amine (VII of 0.1g1) and 0.2 gram of carbonic acid
Hydrogen sodium is added in the Isosorbide-5-Nitrae-dioxane of 8.0mL, adds 6 drop chloracetyl chlorides, is stirred at room temperature 1 hour, after the completion of reaction, is taken out
Filter, dries, and obtains white solid 0.09g.After product drying, it is added in the Isosorbide-5-Nitrae-dioxane of 8.0mL, 10 drops two is being added dropwise
Methylamine water solution, reacts 2 hours at 80 DEG C, after the completion of reaction, is added in 30mL water.There is solid to separate out, suction filtration is dried, and is obtained
To white solid 0.081g, i.e. N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- dimethylaminos
Base-acetamide, yield：56.4%.
Mp 283.8-285.0, [M+H] m/z:478.5
According to the method for embodiment 10, intermediate VII is first used1、VII2And VII5Reacted with chloracetyl chloride, then respectively at not
Same small molecule amine reaction is obtained the compound of embodiment 11~15.
2- lignocaines-the N- of embodiment 11 (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-second
Acid amides
Mp 305.5-307.0, [M+H] m/z:406.5,1H NMR(400MHz,DMSO)δ10.27(s,1H),9.07(s,
1H), 8.60 (s, 1H), 7.39-7.32 (m, 2H), 7.30 (d, J=7.5Hz, 1H), 7.10 (t, J=7.7Hz, 1H), 6.94
(t, J=7.3Hz, 1H), 4.36 (dt, J=13.6,7.3Hz, 4H), 3.19 (d, J=12.1Hz, 4H), 2.60 (dd, J=
13.9,6.7Hz, 4H), 1.48 (t, J=6.7Hz, 3H), 1.06 (t, J=6.9Hz, 6H)
The N- of embodiment 12 (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- pyrrolidines -1-
Base-acetamide
Mp 323.5-325.0, [M+H] m/z:404.5
The N- of embodiment 13 (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6-
Base) -2- piperidin-1-yls-acetamide
Mp 301.8-303.0, [M+H] m/z:474.3
The N- of embodiment 14 (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- morpholine -4- bases -
Acetamide
Mp 319.3-321.0, [M+H] m/z:476.4,1H NMR(400MHz,DMSO)δ10.04(s,1H),9.02(s,
1H), 8.63 (s, 1H), 7.37 (d, J=8.3Hz, 2H), 7.31 (d, J=6.7Hz, 1H), 7.10 (s, 1H), 6.95 (s, 1H),
4.39(s,2H),4.11(s,3H),3.69(s,4H),3.19(s,4H),2.57(s,4H).
The N- of embodiment 15 (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6-
Base) -2- (4- methylpiperazine-1-yls)-acetamide
Mp 339.6-341.0, [M+H] m/z:489.5
The 4- dimethylaminos of embodiment 16-but-2-ene acid (4- (2,3- Dihydro-indole-1- bases)-7- methoxyl groups-quinoline azoles
Quinoline -6- bases)-acid amides synthesis
By 4- (2,3- Dihydro-indole -1- the bases) -7- methoxyquinazoline hydrochloride -6- base amine (VII of 0.1g1) and 0.15 gram
Diethyl phosphorus acetic acid is condensed, and obtains white solid 0.09g.(dimethylamino) diethylacetal condensation with 0.2 gram, obtains again
White solid 0.081g, i.e. 4- dimethylamino-but-2-ene acid (4- (2,3- Dihydro-indole -1- bases) -7- methoxyl groups-quinoline azoles
Quinoline -6- bases)-acid amides, yield：58.7%.
Mp 310.0-312.0, [M+H] m/z:404.5,1H NMR(400MHz,CDCl3)δ9.29(s,1H),8.67(s,
1H), 8.13 (s, 1H), 7.65 (d, J=8.0Hz, 1H), 7.29 (s, 1H), 7.19 (t, J=7.5Hz, 1H), 7.00 (d, J=
7.0Hz, 1H), 6.98-6.93 (m, 1H), 6.30 (d, J=15.3Hz, 1H), 4.55 (t, J=8.0Hz, 2H), 4.07 (s,
3H), (s, the 1H) of 3.28 (d, J=5.8Hz, 2H), 3.23 (t, J=7.9Hz, 2H), 2.41 (s, 6H), 1.25
According to the method for embodiment 16, respectively with the intermediate VII of different substituents2、VII3、VII4、VII5And VII1With
Diethyl phosphorus acetic acid is condensed, then the compound of embodiment 17~21 is obtained from different (amino) diethylacetal condensation reactions.
The 4- dimethylaminos of embodiment 17-but-2-ene acid (4- (2,3- Dihydro-indole-1- bases)-7- ethoxies yl-quinoline-
6- yls)-acid amides
Mp 342.9-345.0, [M+H] m/z:446.1
The 4- pyrrolidin-1-yls of embodiment 18-but-2-ene acid (4- (2,3- Dihydro-indole-1- bases)-7- ((tetrahydrofuran-
3- yls) epoxide)-quinazoline -6- bases)-acid amides
Mp 329.8-331.0, [M+H] m/z:483.5
The 4- piperidin-1-yls of embodiment 19-but-2-ene acid (7- butoxy-4- (2,3- Dihydro-indole-1- bases)-quinoline azoles
Quinoline -6- bases)-acid amides
Mp 292.1-294.0, [M+H] m/z:486.4
4- morpholines-4- the bases of embodiment 20-but-2-ene acid (4- (2,3- Dihydro-indole-1- base-7- isopropoxy quinoline azoles
Quinoline -6- bases)-acid amides
Mp 282.6-284.0, [M+H] m/z:474.5
The 4- of embodiment 21 (4- methylpiperazine-1-yls)-but-2-ene acid (4- (2,3- Dihydro-indole -1- bases) -7- methoxies
Yl-quinoline -6- bases)-acid amides
Mp 296.9-299.0, [M+H] m/z:459.9
The N- of embodiment 22 (4- (the bromo- 2,3,4- dihydros of 6--(1,8) naphthyridines -1- bases) -7- (piperidin-4-yl methoxyl group)-quinolines
Quinoline -6- bases) -2- (4- methanesulphonyl-piperazine -1- bases)-acetamide
Intermediate compound IV obtains V with the bromo- 2,3,4- dihydros of 6--(1,8) benzodiazine reactiona, then with piperidin-4-yl-methyl alcohol
Reaction, obtains dark yellow solid VIa.By intermediate VIaWith activated carbon, ferric trichloride and hydrazine hydrate reduction obtain pale solid
Ⅶa.Again by VIIaWith chloracetyl chloride condensation, compound VIII is obtaineda, it is condensed with 1- methanesulfonyl-piperazins, obtain target chemical combination
Thing.Yield：48.6%.
Mp 375.0-377.0, [M+H] m/z:673.7.
The cyclopentane-carboxylic acid of embodiment 23 (4- (2- methyl -5,6,7- dihydro-pyridos simultaneously (2,3-d) pyrimidine -8- bases) -7- three
Methyl fluoride-quinoline -6- bases)-acid amides
Simultaneously the reaction of (2,3-d) pyrimidine obtains V to intermediate compound IV with 2- methyl -5,6,7- dihydro-pyridosb, then with trifluoro methyl alcohol
Reaction, obtains dark yellow solid VIb.By intermediate VIbWith activated carbon, ferric trichloride and hydrazine hydrate reduction obtain pale solid
Ⅶb.Again by VIIbWith Cyclopentanecarbonyl chloride condensation, target compound is obtained.Yield：48.7%.
Mp 303.0-305.0, [M+H] m/z:473.5.
The N- of embodiment 24 (4- (5- ethyoxyl -2,3,4- dihydros-(1,7) naphthyridines -1- bases) -7- propoxy-alphauinazolines -6-
Base) -2,2,2- trifluoroacetamides
Intermediate compound IV obtains V with 5- methoxyl group -2,3,4- dihydros-(1,7) benzodiazine reactionc, then it is anti-with normal propyl alcohol
Should, obtain dark yellow solid VIc.By intermediate VIcWith activated carbon, ferric trichloride and hydrazine hydrate reduction obtain pale solid VIIc。
Again by VIIcTarget compound is condensed to yield with trifluoro-acetyl chloride.Yield：51.7%.
Mp 280.0-282.3, [M+H] m/z:476.5.
4- dimethylaminos of embodiment 25-but-2-ene acid (4- (the bromo- 2,3- dihydro-pyrroles of 5- simultaneously (2,3-b) pyridine-1-
Base) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases)-acid amides
Intermediate compound IV obtains V with bromo- 2,3- dihydros -1H- pyrrolo-es (2,3-b) the pyridine reactions of 5-d, then with (S) -3- hydroxyls
Base tetrahydrofuran reacts, and obtains dark yellow solid VId.By intermediate VIdWith activated carbon, ferric trichloride and hydrazine hydrate reduction obtain grey
White solid VIId.Again by VIIdWith the condensation of diethyl phosphorus acetic acid, compound VIII is obtainedd, with (dimethylamino) diethylacetal
Condensation, obtains target compound.Yield：48.7%.
Mp 309.0-311.0, [M+H] m/z:539.4.
The pharmacological research of product of the present invention
In vitro cytotoxic effect
The quinazoline compounds of quinoline containing indoline and similar structures to formula I of the present invention have carried out external suppression lung
Cancer cell A549, prostate cancer PC-3, breast cancer cell MCF-7, cervical cancer cell Hela screening active ingredients, reference substance Afatinib
Prepared according to patent document (WO2007085638A1) methods described.
1) after 2~3 stabilizations of cell recovery and passage, it is made to disappear from blake bottle bottom with trypsin solution (0.25%)
Change is got off.After cell dissociation buffer is poured into centrifuge tube, nutrient solution is added to terminate digestion afterwards.By centrifuge tube in 800r/min
Lower centrifugation 10min, adds 5mL nutrient solutions after abandoning supernatant, piping and druming mixes cell, draws 10 μ L cell suspensions and adds cell
Counted in tally, adjustment cell concentration is 104Individual/hole.Except A1 holes for blank well is not added with extracellular in 96 orifice plates, remaining all adds
Enter 100 μ L cell suspensions.96 orifice plates are put into incubator and cultivate 24h.
2) with 50 μ L dmso solution given the test agent, appropriate nutrient solution is subsequently adding, sample is dissolved into 2mg/mL
Liquid, then in 24 orifice plates by Sample Dilution be 20,4,0.8,0.16,0.032 μ g/mL.
Each concentration add 3 holes, wherein around the row cell growing way of two row two it is affected by environment larger, only and be blanc cell
Hole uses.96 orifice plates are put into incubator and cultivate 72h.
3) band medicine nutrient solution in 96 orifice plates is discarded, is rinsed cell twice with phosphate buffer solution (PBS), in every hole
Add MTT (tetrazole) (0.5mg/mL) 100 μ L to be put into incubator after 4h, discard MTT solution, add the μ of dimethyl sulfoxide (DMSO) 100
L.Vibration makes survivaling cell fully be dissolved with MTT product formazans on magnetic force oscillator, is put into measurement result in ELIASA.
Medicine IC can be obtained by Bliss methods50Value.
The breast cancer cell MCF-7 of compound, lung cell A549, prostate cancer PC-3 Activity Results are shown in Table 2.
EGFR, VEGFR enzymatic activity are tested
With Afatinib as positive control, using HTRF technologies, the new synthesis compound of test is to EGFR or VEGFR kinases
Inhibitory action, and part of detecting compound is to the IC of EGFR or VEGFR kinase inhibitory activities50Value.
Specific method：ATP, TK Substrate-biotin (TK- substrates biotin), the Kinase of concentration needed for preparing
The working solution of buffer (kinase buffer liquid), ATP, TK Substrate-biotin, Kinase buffer example 2 by volume:
2:2 take liquid mixing；Medicine is diluted with Kinase buffer be formulated as required concentration；Prepare EGFR, VEGFR enzyme working solution.White
In the orifice plate of color 384, add 6 μ L mixing liquids, 2 μ L medicines, 2 μ L kinases to mix per hole, 30min is reacted at being placed in 37 DEG C.Then plus
The XL-665 and 5 μ L for entering 5 μ L streptokinases element mark combine the cryptate antibody of Eu3+, mix.After room temperature places 30min
Excited in ELIASA 314nm, the fluorescence at detection 665,620nm wavelength calculates kinase inhibition rate.
Inhibiting rate (%)=(Ratio665/620 control wells-Ratio665/620 dosing holes)/Ratio665/620 controls
Hole × 100%
Experimental result is as shown in table 2.IC in table 250>=80%, represented with " +++ ", 80%>IC50>=60%, with " ++ "
Represent, 60%>IC50>=40%, represented with "+", IC50<=40%, represented with "-", " NA " represents inactive, and " ND " is represented
Do not test.
The target compound enzymatic activity of table 2 and anti tumor activity in vitro
From above-mentioned result of the test it can be clearly seen that the quinoline containing indoline and class of claimed formula I of the invention
Like the quinazoline compounds of structure, with good anti tumor activity in vitro.
The quinoline containing indoline of formula of I of the present invention and the quinazoline compounds of similar structures can be administered alone, but logical
Often to be given with pharmaceutical carrier mixture, the selection of the pharmaceutical carrier will according to required route of administration and standard pharmaceutical practice,
Separately below with the various pharmaceutical dosage forms of such compound, such as tablet, capsule, injection, aerosol, suppository, film, drop
The preparation method of pill, externally-applied liniment and ointment, illustrates its new opplication in pharmaceutical field.
Application examples 1：Tablet
With the compound 5g of embodiment 2, after adding auxiliary material 10g to mix according to the general pressed disc method of pharmacy, 100 are pressed into, often
Piece weight 150mg.
Application examples 2：Capsule
With the compound 10g of embodiment 8, after auxiliary material 20g is mixed according to the requirement of pharmacy capsule, load hollow glue
Capsule, each capsule weight 150mg.
Application examples 3：Injection
With the compound 10g of embodiment 9, according to pharmacy conventional method, charcoal absorption is carried out, through 0.65 μm of miillpore filter
After filtering, insert nitrogen pot and be made hydro-acupuncture preparation, every dress 2mL, altogether filling 100 bottles.
Application examples 4：Aerosol
With the compound 10g of embodiment 12, after being dissolved with appropriate propane diols, after adding distilled water and other spoke material, it is made
The settled solution of 500mL is obtained final product.
Application examples 5：Suppository
With the compound 10g of embodiment 15, by finely ground addition glycerine it is appropriate, the glycerin gelatine for having melted is added after grinding well,
Grinding is uniform, is poured into the model for having applied lubricant, and suppository 50 is obtained
Application examples 6：Film
With the compound 5g of embodiment 17, by heating for dissolving, 80 mesh sieves after the stirring expansion such as polyvinyl alcohol, medicinal glycerin, water
Net filtration, then the compound of embodiment 12 is added to stirring and dissolving, film applicator masking 50 in filtrate.
Application examples 7：Pill
With the compound 15g of embodiment 18, after being mixed with the matrix 50g heating fusings such as gelatin, in instilling cryogenic liquid paraffin,
The ball of dripping pill 1000 is obtained altogether.
Application examples 8：Externally-applied liniment
With the compound 10g of embodiment 20, according to auxiliary material 2.5g mixed grindings such as conventional dose method and emulsifying agents, then add
Distilled water is prepared to 200mL.
Application examples 9：Ointment
With the compound 5g of embodiment 24, it is finely ground after ground well with the oleaginous base 250g such as vaseline it is prepared.
Although describing the present invention by particular, modification and equivalent variations are for being proficient in this field
Be will be apparent from for technical staff, and they are included within the scope of the invention.
Claims (6)
1. a kind of quinazoline compounds of quinoline containing indoline and similar structures, it is characterised in that for example following formula I institutes of structure
Show：
Wherein：
A rings are selected from and contain 1~3 identical or different R1Substituted aromatic ring or hetero-aromatic ring；
B rings be it is thick with A rings and saturation nitrogenous five yuan or hexa-member heterocycle；
R1Selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, (C1~C4) alkane
Base, (C3~C6) cycloalkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alkoxy, azido, (C1~C4) alkoxy
Methyl, (C1~C4) alkyl acyl or (C1~C4) alkylthio group；
R2Selected from trifluoromethyl, (C1~C4) alkyl, (C3~C6) cycloalkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4)
Alkoxy methyl,
R3Selected from (C1~C4) alkyl, (C3~C6) cycloalkyl, S- tetrahydrofuran -3- bases, N- methyl piperidine -4- methyl or
R4、R5It is identical or different, separately selected from (C1~C6) alkyl or (C3~C6) cycloalkyl, and R4And R5Contain 1~2
The substitution of individual hydrogen, hydroxyl, amino, halogen, sulfydryl or carboxyl；Or R4And R5Form 5 together with the nitrogen-atoms being connected with them~
10 yuan of saturated heterocyclyls, the saturated heterocyclyl except with R4And R5Outside the nitrogen-atoms of connection, optionally O, N are selected from containing 1~3
With the hetero atom of S；
N is 0~3.
2. quinazoline compounds of quinoline containing indoline according to claim 1 and similar structures, it is characterised in that：
The heterocycle of the thick sum of A, B is selected from：
R1Selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, methyl, ethyl,
Propyl group, butyl, cyclopropane, ethene, propylene, acetylene, propine, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy or folded
Nitrogen base；
R2Selected from trifluoromethyl, methyl, ethyl, propyl group, butyl, ethene, isobutene, cyclopropane, cyclobutane, pentamethylene, hexamethylene
Alkane, ethene, propylene, butylene, acetylene, propine, butine, methoxyl group, ethyoxyl, propoxyl group, isopropoxy, butoxy,
R3Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl, S- tetrahydrofuran -3- bases, N- methyl
Piperidines -4- methyl or
It is selected from：
N is 0~3.
3. quinazoline compounds of quinoline containing indoline according to claim 1 and similar structures,
It is characterized in that：The compounds of formula I is selected from the one kind in following compounds：
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- isopropoxy quinazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases)-acetamide,
N- (7- butoxy -4- (2,3- Dihydro-indole -1- bases)-quinazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-propionamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-Methacrylamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-Methacrylamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acrylamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- dimethylaminos-acetamide,
2- lignocaines-N- (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- pyrrolidin-1-yls-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases) -2- piperidin-1-yls -
Acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases) -2- morpholines -4- bases-acetamide,
N- (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline -6- bases) -2- (4- methyl piperazines
Piperazine -1- bases)-acetamide,
The conjunction of the amyl- 3- olefin(e) acids of 5- dimethylaminos (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochloride -6- bases)-acid amides
Into,
The amyl- 3- olefin(e) acids of 5- dimethylaminos (4- (2,3- Dihydro-indole -1- bases) -7- ethoxyquin oxazoline -6- bases)-acid amides,
5- pyrrolidin-1-yls-amyl- 3- olefin(e) acids (4- (2,3- Dihydro-indole -1- bases) -7- ((tetrahydrofuran -3- bases) epoxide)-quinoline
Oxazoline -6- bases)-acid amides,
5- piperidin-1-yls-amyl- 3- olefin(e) acids (7- butoxy -4- (2,3- Dihydro-indole -1- bases)-quinazoline -6- bases)-acid amides,
5- morpholine -4- bases-amyl- 3- olefin(e) acids (4- (2,3- Dihydro-indole -1- bases) -7- isopropoxy quinazoline -6- bases)-acid amides,
5- (4- thyl-piperazin -1- bases)-amyl- 3- olefin(e) acids (4- (2,3- Dihydro-indole -1- bases) -7- methoxyquinazoline hydrochlorides -6-
Base)-acid amides,
N- (4- (the bromo- 2,3,4- dihydros of 6--(1,8) naphthyridines -1- bases) -7- (piperidin-4-yl methoxyl group)-quinoline -6- bases) -2-
(4- methanesulphonyl-piperazine -1- bases)-acetamide,
Cyclopentane-carboxylic acid (4- (2- methyl -5,6,7- dihydro-pyridos simultaneously (2,3-d) pyrimidine -8- bases) -7- trifluoromethyl-quinolines -
6- yls)-acid amides,
N- (4- (5- ethyoxyl -2,3,4- dihydros-(1,7) naphthyridines -1- bases) -7- propoxy-alphauinazoline -6- bases) -2,2,2- three
Fluorakil 100,
The acid of 4- dimethylaminos-but-2-ene (4- (the bromo- 2,3- dihydro-pyrroles of 5- simultaneously (2,3-b) pyridine -1- bases) -7- ((tetrahydrochysenes
Furans -3- bases) epoxide)-quinoline -6- bases)-acid amides.
4. the quinazoline compounds of a kind of quinoline containing indoline as claimed in claim 1 and similar structures, treat preparing
And/or the application in prevention proliferative disease medicine.
5. the quinazoline compounds of a kind of quinoline containing indoline as claimed in claim 1 and similar structures, treat preparing
And/or the application in the medicine of pre- anti-cancer.
6. the quinazoline compounds of a kind of quinoline containing indoline as claimed in claim 1 and similar structures, treat preparing
And/or the application in the medicine of prevention prostate cancer, lung cancer and cervical carcinoma.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2016106455160 | 2016-08-09 | ||
| CN201610645516 | 2016-08-09 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106831725A true CN106831725A (en) | 2017-06-13 |
| CN106831725B CN106831725B (en) | 2019-08-20 |
Family
ID=59123605
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710033671.1A Expired - Fee Related CN106831725B (en) | 2016-08-09 | 2017-01-17 | The quinazoline compounds and its application of quinoline containing indoline and similar structures |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106831725B (en) |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017621A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Morpholinyl acetylamino dimethoxy benzo [d] azepine * bases quinazoline compounds and preparation and application |
| CN108164510A (en) * | 2018-01-24 | 2018-06-15 | 浙江工业大学 | Chloro acetylamino benzo [d] azepine * base quinazoline compounds and its preparation method and application |
| CN108329300A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Nitro benzo [d] azepine * base quinazoline compounds and its preparation method and application |
| CN108456165A (en) * | 2018-05-30 | 2018-08-28 | 江西科技师范大学 | Sulfonyl urea compound and its preparation method and application |
| CN108456214A (en) * | 2018-05-30 | 2018-08-28 | 江西科技师范大学 | The quinazoline compounds and its application of Han oxazoles or glyoxaline structure |
| CN110872291A (en) * | 2019-11-26 | 2020-03-10 | 五邑大学 | Tetrahydropyridopyrimidine compound and preparation method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999006396A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible bicyclic inhibitors of tyrosine kinases |
| CN103980287A (en) * | 2014-05-21 | 2014-08-13 | 江西科技师范大学 | Preparation method and application of thienopyrimidine compound containing chromone hydrazone structure |
| CN105153026A (en) * | 2015-08-21 | 2015-12-16 | 江西科技师范大学 | Biaryl amide structure containing sorafenib derivative as well as preparation method and applications thereof |
-
2017
- 2017-01-17 CN CN201710033671.1A patent/CN106831725B/en not_active Expired - Fee Related
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1999006396A1 (en) * | 1997-07-29 | 1999-02-11 | Warner-Lambert Company | Irreversible bicyclic inhibitors of tyrosine kinases |
| CN103980287A (en) * | 2014-05-21 | 2014-08-13 | 江西科技师范大学 | Preparation method and application of thienopyrimidine compound containing chromone hydrazone structure |
| CN105153026A (en) * | 2015-08-21 | 2015-12-16 | 江西科技师范大学 | Biaryl amide structure containing sorafenib derivative as well as preparation method and applications thereof |
Cited By (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108017621A (en) * | 2018-01-24 | 2018-05-11 | 浙江工业大学 | Morpholinyl acetylamino dimethoxy benzo [d] azepine * bases quinazoline compounds and preparation and application |
| CN108164510A (en) * | 2018-01-24 | 2018-06-15 | 浙江工业大学 | Chloro acetylamino benzo [d] azepine * base quinazoline compounds and its preparation method and application |
| CN108329300A (en) * | 2018-01-24 | 2018-07-27 | 浙江工业大学 | Nitro benzo [d] azepine * base quinazoline compounds and its preparation method and application |
| CN108164510B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Chloroacetamidobenzo [ d ] aza-based quinazoline compound and preparation method and application thereof |
| CN108017621B (en) * | 2018-01-24 | 2020-08-21 | 浙江工业大学 | Morpholinyl acetamido dimethoxy benzo [ d ] aza-based quinazoline compound and preparation and application thereof |
| CN108329300B (en) * | 2018-01-24 | 2020-10-09 | 浙江工业大学 | Nitrobenzo [ d ] aza-quinazoline compound and preparation method and application thereof |
| CN108456165A (en) * | 2018-05-30 | 2018-08-28 | 江西科技师范大学 | Sulfonyl urea compound and its preparation method and application |
| CN108456214A (en) * | 2018-05-30 | 2018-08-28 | 江西科技师范大学 | The quinazoline compounds and its application of Han oxazoles or glyoxaline structure |
| CN108456214B (en) * | 2018-05-30 | 2020-08-11 | 江西科技师范大学 | Quinazoline compound containing oxazole or imidazole structure and application thereof |
| CN108456165B (en) * | 2018-05-30 | 2021-05-25 | 江西科技师范大学 | Sulfonylurea compound and preparation method and application thereof |
| CN110872291A (en) * | 2019-11-26 | 2020-03-10 | 五邑大学 | Tetrahydropyridopyrimidine compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106831725B (en) | 2019-08-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106831725B (en) | The quinazoline compounds and its application of quinoline containing indoline and similar structures | |
| CN103965120B (en) | Quinoline and quinazoline derivant, preparation method, intermediate, compositions and application | |
| JP5719770B2 (en) | Icotinib hydrochloride, compound, crystallographic form, concomitant drug and its use | |
| CN109422752A (en) | One kind has inhibition and the active compound of bruton's tyrosine protein kinase B tk of degrading | |
| CN109422733A (en) | One kind inhibits and the compound for the tyrosine protein kinase ALK that degrades | |
| CN105732616B (en) | Pyrrolopyridines of the amide structure containing biaryl and its preparation method and application | |
| CN102977014A (en) | New quinoline compounds and uses thereof | |
| JP7323896B2 (en) | Casein kinase 1ε inhibitor, pharmaceutical composition and use thereof | |
| CN106831824A (en) | Pyrrolopyridines and its application containing naphthyridones structure | |
| CN105705493A (en) | Quinazoline derivative, preparation method therefor, and pharmaceutical composition and application thereof | |
| CN104230952B (en) | Compound containing pyrimidine skeleton, and preparation method and use of compound | |
| CN105153026B (en) | Sorafenib derivative of the amide structure containing biaryl and its preparation method and application | |
| CN107383016A (en) | The preparation and application of the Pyrrolopyrimidine compounds of the structure containing heteroaryl amide | |
| CN106831812B (en) | Simultaneously pyrimidine or pyrazine compounds and its application of the heterocycle of the amide structure containing biaryl | |
| CN107573340A (en) | The preparation and application of the miscellaneous pyridine compounds and their of the virtue of 2 carbamyl 4 | |
| CN102108078B (en) | 1,4-substituted phthalazine compound and preparation method and applications thereof | |
| CN105153190B (en) | Heterocycle miazines compound of the amide structure containing biaryl and its preparation method and application | |
| CN109280048A (en) | A kind of pyrimidines of the structure of acrylamide containing substituted-phenyl and its application | |
| CN104086562B (en) | The preparation of the heterocycle miazines compound containing virtue hydrazone structure and application | |
| CN107151233A (en) | Pyridine derivatives containing hydrazone and application thereof | |
| CN110467616B (en) | Preparation and application of triazolopyrazine compound containing heteroaryl substituted pyridazinone structure | |
| CN104496896B (en) | The preparation and application of the Sorafenib derivative of the urea structure containing sulphonyl | |
| CN106866642A (en) | The quinazoline compounds of the structure of acylhydrazone containing aryl and its application | |
| CN106892907A (en) | Quinazoline compounds and its application containing acylhydrazone structure | |
| CN108456214A (en) | The quinazoline compounds and its application of Han oxazoles or glyoxaline structure |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20190820 Termination date: 20200117 |