CN106892907A - Quinazoline compounds and its application containing acylhydrazone structure - Google Patents
Quinazoline compounds and its application containing acylhydrazone structure Download PDFInfo
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- CN106892907A CN106892907A CN201710041058.4A CN201710041058A CN106892907A CN 106892907 A CN106892907 A CN 106892907A CN 201710041058 A CN201710041058 A CN 201710041058A CN 106892907 A CN106892907 A CN 106892907A
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- 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
- C07D405/02—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 two hetero rings
- C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
- C07D239/72—Quinazolines; Hydrogenated quinazolines
- C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
- C07D239/94—Nitrogen atoms
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- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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- 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
- C07D403/12—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 linked by a chain containing hetero atoms as chain links
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- 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
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
The invention discloses a kind of quinazoline compounds containing acylhydrazone structure, as shown in formula I:
Description
Technical field
The present invention relates to quinazoline compounds, in particular to a kind of quinazoline compounds containing acylhydrazone structure and its should
With.
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 (Zijian Liu, Shasha Wu, Yu Wang, et
Al.Eur.J.Med.Chem.87 (2014) 782-793) report the thieno [3,2- containing acylhydrazone structure of a series of novel
D] pyrimidine derivatives, wherein compound (Z) -36 shows very excellent antitumor activity.
On the basis of bibliography, design has synthesized series of quinazoline class compound, this series compound to the present invention
Acylhydrazone active group is introduced while the agent structure for remaining Afatinib, has been designed and synthesized and various has been contained acylhydrazone structure
Quinazoline compounds.Because the compound dissolubility of the part structure of acylhydrazone containing aryl of this seminar early stage design is not very
It is good, it is contemplated that to be probably the too big reason of structure, so what secondary invention focused on to investigate is quinazoline ditosylate salt chemical combination that non-aryl replaces
The antitumor activity of thing, to filter out activity with selectivity more preferably antineoplastic.
The content of the invention
It is an object of the invention to provide a kind of quinazoline compounds containing acylhydrazone structure and its preparation method and application.
The present invention provides the quinazoline compounds containing acylhydrazone structure, its geometric isomer and its pharmacy as shown in formula I
Upper acceptable salt, hydrate, solvate or prodrug, structure is as shown in following formula I:
Wherein:
R is selected from H, CF3、COOH、(C1~C8) alkyl, (C3~C6) cycloalkyl, contain 1~3 miscellaneous original selected from O, N and S
5~10 yuan of saturated heterocyclyls of son formation,
R1Selected from (C1~C4) alkyl, (C3~C6) cycloalkyl, S- tetrahydrofuran -3- bases,
R2Selected 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, (C1~C4) alkylthio group or
R3Selected from H or CH3;
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;
R6Selected from hydrogen, (C1~C4) alkyl, (C3~C6) cycloalkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alkane
Epoxide, azido, (C1~C4) alkoxy methyl, (C1~C4) alkyl acyl, (C1~C4) alkylthio group;
N is 0~3.
Present invention is preferably related to compounds of such as above-mentioned formula I containing acylhydrazone structure, its geometric isomer and its pharmaceutically may be used
The salt of receiving, hydrate, solvate or prodrug, wherein:
R is selected from H, CF3, COOH, methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl,
R1Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl, S- tetrahydrofuran -3- bases,
R2Selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, methyl,
Ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl, cyclopenta, acrylic, acetenyl, methoxyl group, ethyoxyl, ring
Propoxyl group, tert-butoxy, methoxy, ethoxyl methyl, i-propoxymethyl, formoxyl, acetyl group, propiono, ring third
Acyl group, methyl mercapto, ethylmercapto group, pi-allyl, (2- methyl) pi-allyl or
R3Selected from H or CH3;
It is selected from:
R6Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl or pi-allyl;
N=0~3.
In the present invention, the quinazoline compounds of the formula I are but these chemical combination selected from the one kind in following compounds
Thing is not meant to any limitation of the invention:
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- (2- (dimethylamino) ethyl) Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Methyl Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Ethyl Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Propyl group Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Isopropyl Hydrazinecarboxamidederivatives,
(E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- (2- (dimethylamino) second
Base) Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- methyl Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyl group quinoline azoles -6- bases) -2- ethyls Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- propyl group Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- isopropyls Hydrazinecarboxamidederivatives,
2- (2- ((4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) carbamoyl) diazanyl) second
Acid,
(S, E)-tertbutyloxycarbonyl -4- ((2- ((4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) oxygen
Base) quinazoline -6- bases) carbamoyl) diazanyl) methyl) piperidines -1- carboxylic acid tert-butyl esters,
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- ((1- (3- chloropropyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- ((1- (3- morphoinopropyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (4- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -7- (cyclo propyl methoxy) quinazoline -6- bases) -
2- ((1- (3- morphoinopropyls) pyrrolidin-3-yl) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (4- ((4- allyl phenyls) amino) -7- (3- (piperidin-1-yl) propoxyl group) quinazoline -6- bases) -2-
((4- ((dimethylamino) methyl) morpholine -3- bases) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (7- ((1- methyl piperidine -4- bases) methoxyl group) -4- ((3- (methyl mercapto) phenyl) amino) quinoline -6-
Base) -2- ((1- (2- morpholinoethyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(S, E) -2- ((1- (2- morpholinoethyls) piperidin-4-yl) methylene)-N- (4- ((3- morphlinophenyls) ammonia
Base) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) Hydrazinecarboxamidederivatives,
(S, E)-N- (4- ((4- propionylphenyls) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- ((1- (2- (pyrrolidin-1-yl) ethyl) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (4- ((4- cyano-phenyls) amino) -7- ethoxyquin oxazoline -6- bases) -2- ((1- (2- (pyrrolidines -1-
Base) ethyl) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(E) -2- ((1- (3- (4- methylpiperazine-1-yls) propyl group) piperidin-4-yl) methylene)-N- (7- (2- (piperidines -1-
Base) ethyoxyl) -4- ((4- (trifluoromethoxy) phenyl) amino) quinoline -6- bases) Hydrazinecarboxamidederivatives,
(E) -2- ((1- (3- (diethylamino) propyl group) piperidin-4-yl) methylene)-N- (4- ((4- isopropyl phenyls)
Amino) -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -6- bases) Hydrazinecarboxamidederivatives.
Following synthetic route describes the preparation of quinazoline compounds of the formula I of the present invention containing acylhydrazone structure, owns
Raw material be all to be prepared by way of described in synthetic route, by organic chemistry filed method well-known to the ordinarily skilled artisan
Or it is commercially available.The final quinazoline compounds of whole of the invention are all by the method described in synthetic route or logical
Cross prepared by similar method, these methods are organic chemistry fileds well-known to the ordinarily skilled artisan.Should in synthetic route
Definition in the definition of whole variable factor following articles or such as claim.
The synthetic route of the target compound I of route 1
The synthetic intermediate IX first of pass course of the present invention 1, then obtain targeted through from the docking of different small molecule aldehydes or ketones
Compound I.
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 that above-mentioned formula I contains acyl
The quinazoline compounds of hydrazone structure, their own may have weaker activity even without activity, but upon administration,
Under physiological condition corresponding biologically active form is converted to (such as by metabolism, solvolysis or other mode).
The present invention can contain quinazoline compounds of the above-mentioned formula I containing acylhydrazone structure, and its pharmaceutically acceptable
Salt, hydrate or solvate are prepared by mixing into composition as active ingredient with pharmaceutically acceptable carrier or excipients,
And it is prepared into clinically acceptable formulation, above-mentioned pharmaceutically acceptable excipients refer to that any can be used for the dilute of pharmaceutical field
Release agent, adjuvant and/or carrier.Derivative of the invention can be applied in combination with other active ingredients, as long as they are not produced
Other unfavorable effects, such as allergic reaction.
The clinical dosage that present invention quinazoline compounds of the above-mentioned formula I containing acylhydrazone structure are used for patient can basis:
Active component therapeutic efficiency in vivo and bioavilability, the age of their metabolism and discharge rate and patient, sex, disease
Stadium is suitably adjusted, but the daily dosage of adult typically should be 10~500mg, preferably 50~300mg.Cause
This, when pharmaceutical composition of the invention is made into unit dosage forms, it is contemplated that above-mentioned effective dose, per unit preparation should contain
Quinazoline compounds of the above-mentioned formula I of 10~500mg containing acylhydrazone structure, preferably 50~300mg.According to doctor or pharmacist
Instruct, these preparations can at certain intervals divide administration (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 above-mentioned quinazoline compounds containing acylhydrazone structure are preparing treatment and/or are preventing Hypertrophic disease
Application in medicine.Reactive compound of the invention or its officinal salt and its solvate can be used as unique anti-proliferate
Medicine be used alone, or can with the anti-proliferate Drug combination for having listed, for treating and/or preventing Hypertrophic
Disease, such as psoriasis, benign prostatauxe, atherosclerosis and ISR.
It has also been found that the above-mentioned quinazoline compounds containing acylhydrazone structure are preparing the medicine for the treatment of and/or pre- anti-cancer
Application in thing.The compounds of this invention has suppression tumor cell growth activity in vitro, therefore, it can serve as preparing treatment
And/or the medicine of pre- anti-cancer, such as mammary gland, lung, liver, kidney, colon, rectum, stomach, prostate, bladder, uterus, pancreas, bone
Marrow, testis, ovary, lymph, soft tissue, neck, thyroid gland, the cancer of esophagus and leukaemia, neuroblastoma etc..
It has also been found that the above-mentioned quinazoline compounds containing acylhydrazone structure are preparing treatment and/or prevention prostate
Application in the medicine of cancer, lung cancer, cervical carcinoma and 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 Agilent 1100LC/MSD;It is pure or chemical pure that agents useful for same is analysis.
Quinazoline compounds of the formula I containing acylhydrazone structure:
The structural formula of the embodiment of the present invention 1~22 is as shown in table 1 below.
The structural formula of the embodiment 1~22 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,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- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitros -7- Fluquinconazoles quinoline (V)
Successively to the fluoro- 3- of 4- of the fluoro- 6- nitros -4- chloro-quinazolines of 7- of addition 50.0g, 32.3g in the isopropanol of 400mL
Chloroaniline, to dropwise addition 34.0mL 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 65.0g dark yellow solids, i.e. 4-
[(the chloro- 4- fluorophenyls of 3-) amino] -6- nitro -7- Fluquinconazole quinolines, yield:87.8%.
Mp 261.4-262.5, ESI-MS [M+H] m/z:337.1,1H NMR(400MHz,DMSO)δ10.43(s,1H),
9.51 (d, J=7.8Hz, 1H), 8.68 (s, 1H), 8.08 (d, J=6.4Hz, 1H), 7.79 (d, J=5.2Hz, 1H), 7.76
(s, 1H), 7.45 (t, J=9.0Hz, 1H)
Step E 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitros -7- [(S)-(tetrahydrofuran -3- bases)-epoxide]-quinoline
The synthesis of oxazoline (VIa)
60% sodium hydride 4.7g is added in 400mL tetrahydrofurans (THF) and is stirred, be slowly added dropwise (S) -3- of 12.0mL
Hydroxyl tetrahydrofuran, ice bath stirring 45min.20.0g intermediates V (being dissolved in the THF of 200mL) are slowly dropped into, normal-temperature reaction 5h.
Reaction is finished, evaporated under reduced pressure solvent, plus 500mL sodium bicarbonate aqueous solutions stirring 30min, suction filtration, filter cake with 40% ethanol water
Solution is washed, and is dried, and obtains 23.9g dark yellow solids, i.e. 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitros -7- [(S)-(tetrahydrochysenes
Furans -3- bases)-epoxide]-quinazoline (VIa), yield:99.5%.
Mp 210.1-211.0, [M+H] m/z:405.1,1H NMR (400MHz, DMSO) δ 10.10 (d, J=11.8Hz,
1H), 9.16 (d, J=13.2Hz, 1H), 8.62 (d, J=13.4Hz, 1H), 8.13 (d, J=6.8Hz, 1H), 7.75 (s, 1H),
7.45-7.35 (m, 2H), 5.40 (s, 1H), 3.99-3.79 (m, 4H), 2.34 (dd, J=13.8,6.2Hz, 1H), 2.04 (d, J
=5.6Hz, 1H)
Step F 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitro -7- methoxyl groups]-quinazoline (VIb) synthesis
11.37g intermediates V is added in 50% sodium hydrate aqueous solution of 227mL methyl alcohol and 15mL, is heated to reflux
1.5h, is cooled to room temperature after completion of the reaction, pours into strong agitation 30min in 200mL frozen water, and suction filtration, washing is dried, and obtains 11.2g
Yellow solid, i.e. 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitro -7- methoxyl groups]-quinazoline (VIb), yield:94.9%.
m.p.292.3-293.0℃.ESI-MS m/z:[M+H] 349.1,1H NMR(400MHz,DMSO)δ10.13(s,
1H),9.20(s,1H),8.66(s,1H),8.20–8.10(m,1H),7.84–7.73(m,1H),7.51–7.41(m,2H),
4.05(s,3H).
Step G 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- amino -7- [(S)-(tetrahydrofuran -3- bases)-epoxide]-quinoline
The synthesis of oxazoline (VIIa)
21.4g intermediates VIa is added in 700mL ethanol, is heated to adding 15.0g activated carbons, 4.2g tri- at 60 DEG C
Iron chloride, is slowly added dropwise 80% hydrazine hydrate of 24.5mL when rising to 80 DEG C, continue to be heated to reflux 1.5h.Reaction is finished, and is taken out while hot
Filter, filter residue ethyl acetate rinse, vacuum rotary steam filtrate adds 500mL water, strong agitation, suction filtration to do when being threaded to 10% solvent
It is dry, obtain 17.3g pale solids, i.e. 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- amino -7- [(S)-(tetrahydrofuran -3- bases) -
Epoxide]-quinazoline (VIIa), yield:87.3%.
Mp 139.3-140.1, [M+H] m/z:375.2,1H 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)
Can synthesize VIIb according to step G.
Step H (S)-phenyl-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinoline azoles
Quinoline -6- bases) carbamic acid (VIIIa) synthesis
The DIPEA (DIPEA) of 5.5mL is added in the Isosorbide-5-Nitrae-dioxane of 102.0mL, 4.2mL chlorine
Phenyl formate is added in mixed liquor, and 5.07g intermediates VIIa is added in the Isosorbide-5-Nitrae-dioxane of 30.0mL, is delayed under ice bath
It is slow to instill mixed liquor, add the water quenching of 200.0mL to go out reaction after completion of the reaction, suction filtration, filter cake washing is dry, obtains 5.36g
Yellow solid, i.e. (S)-phenyl-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -
6- yls) carbamic acid (VIIIa), yield:80%.
[M+H]m/z:494.2。
Can synthesize VIIIb according to step H.
Step I (S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6-
Base) Hydrazinecarboxamidederivatives (IXa) synthesis
2.0g intermediates VIIIa is added to the 1,4- dioxane of 10.0mL and the 80% hydrazine hydrate mixed liquor of 2.0mL
In 80 DEG C of heating response 30min, reaction finishes, while hot suction filtration, dries, and obtains 1.49g white solids, i.e. (((3- is chloro- for 4- for (S)-N-
4- fluorophenyls) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) Hydrazinecarboxamidederivatives (IXa), yield:85%.
[M+H]m/z:433.2,1H NMR(400MHz,DMSO)δ9.78(s,1H),9.28(s,1H),8.92(s,1H),
8.43 (d, J=12.7Hz, 1H), 8.07 (d, J=6.6Hz, 1H), 7.92 (s, 1H), 7.76 (d, J=8.6Hz, 1H), 7.40
(t, J=9.1Hz, 1H), 7.24 (s, 1H), 5.36 (s, 1H), 4.68 (s, 2H), 4.01 (dd, J=10.2,4.0Hz, 1H),
3.98-3.86 (m, 2H), 3.82 (dd, J=12.4,7.9Hz, 1H), 2.37 (td, J=14.2,7.5Hz, 1H), 2.15-1.84
(m,1H).
Can synthesize IXb according to step I.
Step J (S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -
6- yls) -2- (2- (dimethylamino) ethyl) Hydrazinecarboxamidederivatives synthesis
2- (dimethylamino) acetaldehyde of 0.1g intermediate compound Is Xa and 0.04g are added in 8.0mL ethanol, add 2 to drip ice
Acetic acid, is heated to reflux 1.5 hours, after the completion of reaction, and vacuum distillation major part solvent, suction filtration is dried, and obtains white solid
0.11g, obtains final product (S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6-
Base) -2- (2- (dimethylamino) ethyl) Hydrazinecarboxamidederivatives, yield:80.1%.
Embodiment 1
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- (2- (dimethylamino) ethyl) Hydrazinecarboxamidederivatives
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
Into 4- [(the chloro- 4- fluorophenyls of 3-) amino] -6- nitros -7- Fluquinconazoles quinoline (V), 4- [(the chloro- 4- fluorobenzene of 3- is synthesized by step E
Base) amino] -6- nitros -7- [(S)-(tetrahydrofuran -3- bases)-epoxide]-quinazoline (VIa);4- [(3- are synthesized by step G
Chloro- 4- fluorophenyls) amino] -6- amino -7- [(S)-(tetrahydrofuran -3- bases)-epoxide]-quinazoline (VIIa), by step H
Obtain (S)-phenyl-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) ammonia
Base formic acid (VIIIa), (S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) are obtained by step I
Epoxide) quinazoline -6- bases) Hydrazinecarboxamidederivatives (IXa), obtain (S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) ammonia finally by step J
Base) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2- (2- (dimethylamino) ethyl) Hydrazinecarboxamidederivatives.
Mp 227.9-230.0, ESI-MS m/z:[M+H] 502.2,1H NMR(400MHz,DMSO)δ10.86(s,1H),
9.84 (s, 1H), 8.95 (d, J=14.7Hz, 2H), 8.49 (s, 1H), 8.08 (d, J=6.6Hz, 1H), 7.76 (s, 1H),
7.41 (t, J=9.0Hz, 1H), 7.29 (s, 2H), 5.40 (s, 1H), 4.05-3.98 (m, 1H), 3.91 (d, J=10.3Hz,
2H), 3.86 (d, J=4.4Hz, 1H), 3.04 (d, J=5.3Hz, 2H), 2.37 (dd, J=13.7,6.1Hz, 1H), 2.19 (s,
6H),2.12(s,1H).
According to the method for embodiment 1, respectively replacing aldehydes or ketones that the compound of embodiment 2~22 is obtained accordingly.
Embodiment 2
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Methyl Hydrazinecarboxamidederivatives
Mp 260.0-261.5, ESI-MS m/z:[M+H] 445.1,1H NMR(400MHz,DMSO)δ10.99(s,1H),
9.83 (s, 1H), 8.93 (s, 1H), 8.80 (s, 1H), 8.50 (s, 1H), 8.08 (d, J=6.5Hz, 1H), 7.77 (d, J=
8.8Hz, 1H), 7.41 (t, J=9.1Hz, 1H), 7.29 (s, 1H), 6.96 (d, J=11.6Hz, 1H), 6.43 (d, J=
11.7Hz, 1H), 5.35 (d, J=12.7Hz, 1H), 4.00 (dd, J=10.4,4.3Hz, 1H), 3.91 (dd, J=12.3,
8.4Hz, 2H), 3.82 (dd, J=12.8,8.2Hz, 1H), 2.36 (dt, J=14.0,6.9Hz, 1H), 2.13-2.03 (m,
1H).
Embodiment 3
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Ethyl Hydrazinecarboxamidederivatives
Mp 258.5-260.0, ESI-MS m/z:[M+H] 459.1,1H NMR(400MHz,DMSO)δ10.72(s,1H),
9.83 (s, 1H), 8.95 (d, J=12.7Hz, 2H), 8.49 (s, 1H), 8.08 (d, J=5.9Hz, 1H), 7.76 (s, 1H),
7.41 (t, J=8.9Hz, 1H), 7.34 (d, J=4.9Hz, 1H), 7.29 (s, 1H), 5.40 (s, 1H), 4.01 (d, J=
5.7Hz, 1H), 3.91 (dd, J=16.1,9.1Hz, 2H), 3.88 (s, 1H), 2.40-2.31 (m, 1H), 2.11 (s, 1H),
1.92 (d, J=5.2Hz, 3H)
Embodiment 4
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Propyl group Hydrazinecarboxamidederivatives
Mp 266.4-268.8, ESI-MS m/z:[M+H] 473.1,1H NMR(400MHz,DMSO)δ10.72(s,1H),
9.83 (s, 1H), 8.97 (s, 2H), 8.49 (s, 1H), 8.07 (d, J=5.9Hz, 1H), 7.76 (d, J=8.6Hz, 1H), 7.41
(s, 2H), 7.28 (s, 1H), 5.39 (s, 1H), 4.01 (dd, J=10.4,4.3Hz, 1H), 3.97-3.86 (m, 2H), 3.87-
(t, J=7.3Hz, the 3H) of 3.78 (m, 1H), 2.44-2.33 (m, 1H), 2.33 (s, 2H), 2.14-2.04 (m, 1H), 1.09
Embodiment 5
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
Isopropyl Hydrazinecarboxamidederivatives
Mp 275.3-276.8, ESI-MS m/z:[M+H] 612.2,1H NMR (400MHz, DMSO) δ 9.83 (d, J=
12.6Hz, 2H), 9.25 (s, 1H), 8.94 (s, 1H), 8.49 (s, 1H), 8.07 (d, J=6.8Hz, 1H), 7.75 (s, 1H),
7.41 (t, J=9.0Hz, 1H), 7.29 (s, 1H), 5.40 (s, 1H), 4.01 (dd, J=10.3,3.8Hz, 1H), 3.98-3.87
(m,2H),3.87(s,1H),2.43–2.31(m,1H),2.16–2.05(m,1H),1.98(s,3H),1.92(s,3H).
Embodiment 6
(E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- (2- (dimethylamino) second
Base) Hydrazinecarboxamidederivatives
Mp 226.3.4-227.4, ESI-MS m/z:[M+H] 447.1,1H NMR(400MHz,DMSO)δ10.82(s,
1H), 9.82 (s, 1H), 8.91 (s, 1H), 8.77 (s, 1H), 8.49 (s, 1H), 8.08 (d, J=6.1Hz, 1H), 7.76 (s,
1H), 7.40 (t, J=9.0Hz, 1H), 7.32 (t, J=5.3Hz, 1H), 7.29 (s, 1H), 4.04 (s, 3H), 3.07 (d, J=
5.1Hz,2H),2.21(s,6H).
Embodiment 7
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- methyl Hydrazinecarboxamidederivatives
Mp 260.0-261.2, ESI-MS m/z:[M+H] 389.1,1H NMR(400MHz,DMSO)δ10.99(s,1H),
9.84 (s, 1H), 8.93 (s, 1H), 8.75 (s, 1H), 8.51 (s, 1H), 8.08 (d, J=6.5Hz, 1H), 7.77 (s, 1H),
7.41 (t, J=9.0Hz, 1H), 7.30 (s, 1H), 6.97 (d, J=12.1Hz, 1H), 6.45 (d, J=11.5Hz, 1H), 4.05
(s,3H).
Embodiment 8
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyl group quinoline azoles -6- bases) -2- ethyl Hydrazinecarboxamidederivatives
Mp 289.4-291.2, ESI-MS m/z:[M+H] 404.1,1H NMR(400MHz,DMSO)δ10.67(s,1H),
9.80 (s, 1H), 8.92 (d, J=8.4Hz, 2H), 8.77 (s, 1H), 8.50 (s, 1H), 8.44 (s, 1H), 8.08 (d, J=
7.1Hz,1H),7.78(s,1H),7.01(s,1H),4.05(s,3H),3.99(s,3H).
Embodiment 9
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- propyl group Hydrazinecarboxamidederivatives
Mp307.9-308.6, ESI-MS m/z:[M+H]417.1.
Embodiment 10
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- isopropyl Hydrazinecarboxamidederivatives
Mp 283.1-285.2, ESI-MS m/z:[M+H] 418.1,1H NMR(400MHz,DMSO)δ9.82(s,1H),
9.75 (d, J=8.7Hz, 1H), 9.02 (s, 1H), 8.92 (s, 2H), 8.50 (s, 1H), 8.08 (d, J=7.0Hz, 1H), 7.76
(s, 1H), 7.41 (t, J=9.0Hz, 1H), 7.29 (s, 1H), 4.05 (s, 3H), 1.99 (s, 3H), 1.91 (s, 3H)
Embodiment 11
2- (2- ((4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) carbamoyl) diazanyl) acetic acid
ESI-MS m/z:[M+H]433.1。
Embodiment 12
(S, E)-tertbutyloxycarbonyl -4- ((2- ((4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) oxygen
Base) quinazoline -6- bases) carbamoyl) diazanyl) methyl) piperidines -1- carboxylic acid tert-butyl esters,
ESI-MS m/z:[M+H]629.2。
Embodiment 13
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- ((1- (3- chloropropyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]605.2。
Embodiment 14
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- ((1- (3- morphoinopropyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]656.3。
Embodiment 15
(E)-N- (4- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -7- (cyclo propyl methoxy) quinazoline -6- bases) -
2- ((1- (3- morphoinopropyls) pyrrolidin-3-yl) methylene) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]676.3。
Embodiment 16
(E)-N- (4- ((4- allyl phenyls) amino) -7- (3- (piperidin-1-yl) propoxyl group) quinazoline -6- bases) -2-
((4- ((dimethylamino) methyl) morpholine -3- bases) methylene) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]631.2。
Embodiment 17
(E)-N- (7- ((1- methyl piperidine -4- bases) methoxyl group) -4- ((3- (methyl mercapto) phenyl) amino) quinoline -6-
Base) -2- ((1- (2- morpholinoethyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]677.4。
Embodiment 18
(S, E) -2- ((1- (2- morpholinoethyls) piperidin-4-yl) methylene)-N- (4- ((3- morphlinophenyls) ammonia
Base) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]675.4。
Embodiment 19
(S, E)-N- (4- ((4- propionylphenyls) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -
2- ((1- (2- (pyrrolidin-1-yl) ethyl) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]630.4。
Embodiment 20
(E)-N- (4- ((4- cyano-phenyls) amino) -7- ethoxyquin oxazoline -6- bases) -2- ((1- (2- (pyrrolidines -1-
Base) ethyl) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]557.3。
Embodiment 21
(E) -2- ((1- (3- (4- methylpiperazine-1-yls) propyl group) piperidin-4-yl) methylene)-N- (7- (2- (piperidines -1-
Base) ethyoxyl) -4- ((4- (trifluoromethoxy) phenyl) amino) quinoline -6- bases) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]742.4。
Embodiment 22
(E) -2- ((1- (3- (diethylamino) propyl group) piperidin-4-yl) methylene)-N- (4- ((4- isopropyl phenyls)
Amino) -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -6- bases) Hydrazinecarboxamidederivatives
ESI-MS m/z:[M+H]673.5。
The pharmacological research of product of the present invention
In vitro cytotoxic effect
To having carried out external suppression lung carcinoma cell according to quinazoline compounds of the formula I of the present invention containing acylhydrazone structure
A549, prostate cancer PC-3, breast cancer cell MCF-7, cervical cancer cell Hela screening active ingredients, reference substance Afatinib is according to special
Sharp document (WO2007085638A1) methods described is prepared.
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, VEGFR2 enzymatic activity are tested
With Afatinib as positive control, using HTRF technologies, the new synthesis compound of test is to EGFR or VEGFR2 kinases
Inhibitory action, and part of detecting compound is to the IC of EGFR or VEGFR2 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: 2 by volume
: 2 take liquid mixing;Medicine is diluted with Kinase buffer be formulated as required concentration;Prepare EGFR, VEGFR2 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.Inhibiting rate in table 1>=80%, represented with " +++ ", 80%>Inhibiting rate>=60%,
Represented with " ++ ", 60%>Inhibiting rate>=40%, represented with "+", inhibiting rate<=40%, represented with "-", " NA " is indicated without work
Property, " ND " is represented and not tested.
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 quinazolines of the claimed formula I of the invention containing acylhydrazone structure
Class compound, with good anti tumor activity in vitro.
Quinazoline compounds of the formula of I of the present invention containing acylhydrazone structure can be administered alone, but be typically and pharmaceutical carrier
Mixture gives, and the selection of the pharmaceutical carrier will separately below use such according to required route of administration and standard pharmaceutical practice
The various pharmaceutical dosage forms of compound, such as tablet, capsule, injection, aerosol, suppository, film, pill, externally-applied liniment
With the preparation method of ointment, its new opplication in pharmaceutical field is illustrated.
Application examples 1:Tablet
With the compound 5g of embodiment 1, after adding auxiliary material 10g to mix according to the general pressed disc method of pharmacy, 50, every are pressed into
Weight 150mg.
Application examples 2:Capsule
With the compound 5g of embodiment 1, after auxiliary material 10g is mixed according to the requirement of pharmacy capsule, load Capsules,
Each capsule weight 150mg.
Application examples 3:Injection
With the compound 5g of embodiment 6, 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 50 bottles.
Application examples 4:Aerosol
With the compound 5g of embodiment 3, after being dissolved with appropriate propane diols, after adding distilled water and other spoke material, 250mL is made
Settled solution obtain final product.
Application examples 5:Suppository
With the compound 5g of embodiment 4, by finely ground addition glycerine it is appropriate, the glycerin gelatine for having melted is added after grinding well, grind
Mill is uniform, is poured into the model for having applied lubricant, and suppository 25 is obtained.
Application examples 6:Film
With the compound 5g of embodiment 7, by heating for dissolving, 80 eye mesh screens after the stirring expansion such as polyvinyl alcohol, medicinal glycerin, water
Filtering, then the compound of embodiment 7 is added to stirring and dissolving, film applicator masking 50 in filtrate.
Application examples 7:Pill
With the compound 15g of embodiment 8, 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 1, 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 1, 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 containing acylhydrazone structure, it is characterised in that structure is as shown in following formula I:
Wherein:
R is selected from H, CF3、COOH、(C1~C8) alkyl, (C3~C6) cycloalkyl, containing 1~3 selected from O, N and S hetero atom formed 5~
10 yuan of saturated heterocyclyls,
R1Selected from (C1~C4) alkyl, (C3~C6) cycloalkyl, S- tetrahydrofuran -3- bases,
R2Selected 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, (C1~C4) alkylthio group or
R3Selected from H or CH3;
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;
R6Selected from hydrogen, (C1~C4) alkyl, (C3~C6) cycloalkyl, (C2~C4) alkenyl, (C2~C4) alkynyl, (C1~C4) alcoxyl
Base, azido, (C1~C4) alkoxy methyl, (C1~C4) alkyl acyl, (C1~C4) alkylthio group;
N is 0~3.
2. the quinazoline compounds of acylhydrazone structure are contained according to claim 1, it is characterised in that:
Wherein:
R is selected from H, CF3, COOH, methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl,
R1Selected from methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl, S- tetrahydrofuran -3- bases,
R2Selected from hydrogen, halogen, trifluoromethyl, cyano group, nitro, hydroxyl, amino, sulfydryl, carboxyl, trifluoromethoxy, methyl, ethyl,
N-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl, cyclopenta, acrylic, acetenyl, methoxyl group, ethyoxyl, the oxygen of ring third
Base, tert-butoxy, methoxy, ethoxyl methyl, i-propoxymethyl, formoxyl, acetyl group, propiono, ring propiono,
Methyl mercapto, ethylmercapto group, pi-allyl, (2- methyl) pi-allyl or
R3Selected from H or CH3;
It is selected from:
R6Selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, normal-butyl, the tert-butyl group, cyclopropyl or pi-allyl;
N=0~3.
3. the quinazoline compounds of acylhydrazone structure are contained according to claim 1, it is characterised in that:The chemical combination of the formula I
Thing is selected from the one kind in following compounds:
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
(2- (dimethylamino) ethyl) Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2- methyl
Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2- ethyls
Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2- propyl group
Hydrazinecarboxamidederivatives,
(S)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2- isopropyls
Base Hydrazinecarboxamidederivatives,
(E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- (2- (dimethylamino) ethyl)
Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- methyl Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxyl group quinoline azoles -6- bases) -2- ethyls Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- propyl group Hydrazinecarboxamidederivatives,
N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) -2- isopropyls Hydrazinecarboxamidederivatives,
2- (2- ((4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- methoxy quinoline -6- bases) carbamoyl) diazanyl) acetic acid,
(S, E)-tertbutyloxycarbonyl -4- ((2- ((4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide)
Quinazoline -6- bases) carbamoyl) diazanyl) methyl) piperidines -1- carboxylic acid tert-butyl esters,
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
((1- (3- chloropropyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(S, E)-N- (4- ((the chloro- 4- fluorophenyls of 3-) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
((1- (3- morphoinopropyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (4- ((4- chloro- 3- (trifluoromethyl) phenyl) amino) -7- (cyclo propyl methoxy) quinazoline -6- bases) -2-
((1- (3- morphoinopropyls) pyrrolidin-3-yl) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (4- ((4- allyl phenyls) amino) -7- (3- (piperidin-1-yl) propoxyl group) quinazoline -6- bases) -2- ((4-
((dimethylamino) methyl) morpholine -3- bases) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (7- ((1- methyl piperidine -4- bases) methoxyl group) -4- ((3- (methyl mercapto) phenyl) amino) quinoline -6- bases) -2-
((1- (2- morpholinoethyls) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(S, E) -2- ((1- (2- morpholinoethyls) piperidin-4-yl) methylene)-N- (4- ((3- morphlinophenyls) amino) -7-
((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) Hydrazinecarboxamidederivatives,
(S, E)-N- (4- ((4- propionylphenyls) amino) -7- ((tetrahydrofuran -3- bases) epoxide) quinazoline -6- bases) -2-
((1- (2- (pyrrolidin-1-yl) ethyl) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(E)-N- (4- ((4- cyano-phenyls) amino) -7- ethoxyquin oxazoline -6- bases) -2- ((1- (2- (pyrrolidin-1-yl) second
Base) piperidin-4-yl) methylene) Hydrazinecarboxamidederivatives,
(E) -2- ((1- (3- (4- methylpiperazine-1-yls) propyl group) piperidin-4-yl) methylene)-N- (7- (2- (piperidin-1-yl)
Ethyoxyl) -4- ((4- (trifluoromethoxy) phenyl) amino) quinoline -6- bases) Hydrazinecarboxamidederivatives,
(E) -2- ((1- (3- (diethylamino) propyl group) piperidin-4-yl) methylene)-N- (4- ((4- isopropyl phenyls) ammonia
Base) -7- (2- (piperidin-1-yl) ethyoxyl) quinazoline -6- bases) Hydrazinecarboxamidederivatives.
4. a kind of quinazoline compounds containing acylhydrazone structure as claimed in claim 1, are preparing treatment and/or are preventing Hypertrophic
Application in disease medicament.
5. a kind of quinazoline compounds containing acylhydrazone structure as claimed in claim 1, are preparing treatment and/or pre- anti-cancer
Application in medicine.
6. a kind of quinazoline compounds containing acylhydrazone structure as claimed in claim 1, are preparing treatment and/or prevention prostate
Application in the medicine of cancer, lung cancer and cervical carcinoma.
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
JP7449028B2 (en) | 2020-08-10 | 2024-03-13 | 上海和誉生物医薬科技有限公司 | EGFR inhibitor and its manufacturing method and application |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020128553A1 (en) * | 2001-03-12 | 2002-09-12 | Hadasit Medical Research Services And Development Ltd. | Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy |
CN103717590A (en) * | 2011-05-17 | 2014-04-09 | 江苏康缘药业股份有限公司 | Quinazoline-7-ether compounds and methods of use |
CN104230845A (en) * | 2014-08-22 | 2014-12-24 | 沈阳药科大学 | Semicarbazone derivatives and application thereof |
-
2017
- 2017-01-17 CN CN201710041058.4A patent/CN106892907B/en active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20020128553A1 (en) * | 2001-03-12 | 2002-09-12 | Hadasit Medical Research Services And Development Ltd. | Radiolabeled irreversible inhibitors of epidermal growth factor receptor tyrosine kinase and their use in radioimaging and radiotherapy |
CN103717590A (en) * | 2011-05-17 | 2014-04-09 | 江苏康缘药业股份有限公司 | Quinazoline-7-ether compounds and methods of use |
CN104230845A (en) * | 2014-08-22 | 2014-12-24 | 沈阳药科大学 | Semicarbazone derivatives and application thereof |
Non-Patent Citations (2)
Title |
---|
RANIA S.M. ISMAIL, ET AL.: "Recent advances in 4-aminoquinazoline based scaffold derivatives targeting EGFR kinases as anticancer agents", 《FUTURE JOURNAL OF PHARMACEUTICAL SCIENCES》 * |
XIN ZHAI, ET AL.: "Design, synthesis and biological evaluation of novel 4-phenoxy-6,7-disubstituted quinolines possessing (thio)semicarbazones as c-Met kinase inhibitors", 《BIOORGANIC & MEDICINAL CHEMISTRY》 * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
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 |
CN108456165B (en) * | 2018-05-30 | 2021-05-25 | 江西科技师范大学 | Sulfonylurea compound and preparation method and application thereof |
JP7449028B2 (en) | 2020-08-10 | 2024-03-13 | 上海和誉生物医薬科技有限公司 | EGFR inhibitor and its manufacturing method and application |
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