CN105541798A - Quinoline multi-target kinase inhibitor with antitumor activity and preparation method thereof - Google Patents
Quinoline multi-target kinase inhibitor with antitumor activity and preparation method thereof Download PDFInfo
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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
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Abstract
The invention relates to a quinoline multi-target kinase inhibitor with antitumor activity and a preparation method thereof. A general structural formula of the compound is shown in a formula (I) described in the specification. In vitro cell experiments verify that the compound provided by the invention has strong in vitro inhibitory activity on five common tumor cell lines, namely human thyroid carcinoma SW579, human hepatic carcinoma HepG2, human lung adenocarcinoma A549, human colorectal adenocarcinoma HCT116 and human gastric carcinoma MKN45, antitumor activities of most of target compounds are better than or equivalent to that of a positive control drug Cabozantinib, and the in vitro cell experiments verify that the compound provided by the invention has strong inhibitory activity on two kinases KDR and MET, so that the compound provided by the invention has a broad application prospect in preparation of a new antitumor drug.
Description
Technical field
The present invention relates to medical art, specifically, relate to the N that a class has anti-tumor activity
1-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N
2-substituted heterocycle-N
3-phenylpropyl alcohol diamide quinoline Mutiple Targets kinase inhibitor and preparation method thereof, and preparing the purposes in antitumor drug.
Background technology
In recent years, along with the raising of people's living standard, and the problem such as human peripheral's environmental pollution, food safety is day by day serious, and cancer has become one of killer of harm humans health, finds a kind of desirable antitumour drug to be with historically new significance.Conventional cell cytotoxic drug is if cis-platinum, endoxan, Fluracil etc. are due to the shortcoming such as its poor selectivity, side effect be large, while disease therapy, also bring misery to patient, therefore developing a kind of efficient, that low toxicity, specificity are high cancer therapy drug becomes study hotspot.
Along with the develop rapidly of Life Sci-Tech and related discipline, people recognize gradually, and the generation of cancer cells is because the signal transduction pathway that somatocyte itself is inherent occurs abnormal, thus result in somatic irregular growth.After this emphasis that oncotherapy is studied also is transferred to come up for the research of abnormal signal path in cancer cells from traditional cell toxicity medicament by people gradually.Through the research and development of decades, in various target therapeutic agent, protein tyrosine kinase (proteintyrosinekinase, PTK) is the more and antitumor drug target spot of successful of at present research.Compared with now conventional clinically cell toxicity medicament, this type of PTK target therapeutic agent for intracellular signal transduction pathway has that specificity is good, efficient, low toxicity and the advantage such as not easily resistance is good, these advantages also make this type of medicine become more and more extensive in clinical application, and treating malignant tumor has welcome the epoch that one has bright prospects.
Patent documentation CN201310313631.4, publication date 2013.11.20, discloses a class and replace 3,4-dihydro-isoquinoline compounds and preparation method thereof, and this compounds is preparing the application in antitumor drug; Patent documentation CN200810039037.X, publication date 2009.12.23, disclose another kind of novel isoquinoline anti-tumor compound and preparation method thereof.But at present about N
1-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N
2-substituted heterocycle-N
3-phenylpropyl alcohol diamide antineoplastic compound have not been reported.
Summary of the invention
The object of this invention is to provide novel quinoline proteinoid tyrosine kinase inhibitor antineoplastic compound of a kind of efficient, low toxicity, wide spectrum and preparation method thereof and application.
In a first aspect of the present invention, provide a kind of quinolines with anti-tumor activity, its general structure is such as formula shown in (I):
Wherein, R
1be selected from hydrogen or halogen, described halogen is selected from F, Cl, Br or I, can be positioned at the neighbour of aromatic ring, a position, can be monosubstituted or polysubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from N, O atom.
As a preference of the present invention,
R
1hydrogen or halogen, described halogen is selected from F or Cl, and can be positioned at the neighbour of aromatic ring, a position, be monosubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from N, O atom.
As another preference of the present invention,
R
1be selected from hydrogen or halogen, described halogen is selected from F, Cl, Br or I, can be positioned at the neighbour of aromatic ring, a position, can be monosubstituted or polysubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from atom N.
As another preference of the present invention,
R
1be selected from hydrogen or halogen, described halogen is selected from F or Cl, can be positioned at the neighbour of aromatic ring, a position, can be monosubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from atom N.
As another preference of the present invention,
R
1be selected from hydrogen;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted;
R
3be selected from H;
X is selected from O atom.
As another preference of the present invention,
R
1be selected from hydrogen;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted;
R
3be selected from H;
X is selected from O atom.
In a second aspect of the present invention, provide the crystal formation of described quinolines, pharmaceutically acceptable inorganic acid salt or organic acid salt, hydrate, solvate or prodrug.
In a third aspect of the present invention, provide described quinolines, or the crystal formation of described quinolines, pharmaceutically acceptable inorganic acid salt or organic acid salt, hydrate, solvate or prodrug are preparing the purposes in antitumor drug.
Described tumour is thyroid carcinoma, liver cancer, adenocarcinoma of lung, intestinal cancer or cancer of the stomach etc.
In a fourth aspect of the present invention, provide the preparation method of the quinolines shown in formula (I).Described preparation method comprises following two reaction scheme ROUTE1 and ROUTE2:
(1) when the quinolines structural formula shown in formula (I) is specifically as shown in compound l or m, ROUTE1 reaction scheme is adopted, as follows:
ROUTE1 synthesis step is as follows:
1) synthesis of compound h
After NaH and anhydrous DMSO fully stirs, add replacement p-aminophenol, react after then adding chloro-6, the 7-dimethoxy-quinolines of 4-under 90-120 degree condition, TLC monitors, and after completion of the reaction, adds water, chloroform extraction evaporate to dryness obtains compound h;
2) synthesis of compound a
4-methyl-formiate piperidines is dissolved in DCM, drips (Boc)
2o, triethylamine, after room temperature reaction, washing DCM layer, evaporate to dryness organic phase obtains compound a;
3) synthesis of compound b
Under nitrogen protection, add THF and compound a in flask, drip LDA, drip methyl-chloroformate after stirring, slowly rise to stirring at room temperature reaction, then add saturated aqueous ammonium chloride cancellation, extraction into ethyl acetate, evaporate to dryness obtains compound b;
4) synthesis of compound c
In compound b and methyl alcohol, slowly drip NaOH solution, stirred overnight, TLC monitors, after completion of the reaction, evaporate most of methyl alcohol, add water, dilute hydrochloric acid adjusts pH, adds methylene chloride, extraction, organic phase evaporate to dryness, to white crystal, adds sherwood oil and filters, dry and obtain compound c;
5) synthesis of compound i
In flask, add compound c, DMAP, EDCI, methylene dichloride, stirring at room temperature is reacted, and adds compound h, back flow reaction, dilute hydrochloric acid solution washing organic phase, and evaporate to dryness purifying obtains compound i;
6) synthesis of compound j
Compound i and methyl alcohol join in flask, slowly drip NaOH solution, stirred overnight, TLC monitors, after completion of the reaction, evaporate most of methyl alcohol, add water, diluted alkaline water adjusts pH, add methylene chloride washing water layer, and water intaking layer adds dilute hydrochloric acid and adjusts pH, dichloromethane extraction, organic phase evaporate to dryness to half oily solid, filtering drying obtains compound j;
7) synthesis of compound k
In flask, add compound j, HATU, DIEA and DMF solution, add substituted aniline, stirred overnight after stirring at room temperature, after raw material reaction, reaction solution is poured in dilute hydrochloric acid solution, and separate out solid, filtering drying, purifying obtains compound k;
8) synthesis of compound l
In flask, add compound k, add methylene chloride after dissolving, add saturated ether solution of hydrogen chloride, stirred overnight, after completion of the reaction, add water, water transfer phase pH, separate out white solid, filtering drying obtains target compound l;
9) synthesis of compound m
In flask, add compound l, solid polyformaldehyde, formic acid, anhydrous methanol, heating reflux reaction, add water water transfer phase pH, and separate out white solid, filtering drying obtains target compound m.
(2) when the quinolines structural formula shown in formula (I) is specifically as shown in compound p, ROUTE2 reaction scheme is adopted, as follows:
ROUTE2 synthesis step is as follows:
1) synthesis of compound h
After NaH and anhydrous DMSO fully stirs, add replacement p-aminophenol, react after then adding chloro-6, the 7-dimethoxy-quinolines of 4-under 90-120 degree condition, TLC monitors, and after completion of the reaction, adds water, chloroform extraction evaporate to dryness obtains compound h;
2) synthesis of compound d
In flask, add dehydrated alcohol and sodium block, ice bath stirs, after sodium block dissolves completely, add dimethyl malonate, drip dibromo ether and reflux after stirring, after completion of the reaction, extraction into ethyl acetate, organic phase evaporate to dryness is to red-brown oily matter, and purifying obtains compound d;
3) synthesis of Verbindung
Compound d and methyl alcohol join in flask, slowly drip NaOH solution, stirred overnight, and TLC monitors, and after completion of the reaction, aftertreatment, to white crystal, is dried and obtained Verbindung;
4) synthesis of compound n
In flask, add Verbindung, DMAP, EDCI and DCM, add compound h after fully stirring, oil bath refluxes, and after completion of the reaction, organic layer dilute hydrochloric acid solution washs, and evaporate to dryness, to brown ceramic powder, is directly used in lower step;
5) synthesis of compound o
The brown ceramic powder that upper step obtains is dissolved in methyl alcohol, drips NaOH solution, stirred overnight, TLC monitors, and after completion of the reaction, add dilute hydrochloric acid and adjust pH, evaporate to dryness reaction solution, solid filters after being dissolved in methylene dichloride and methanol mixed solution, and filtrate evaporate to dryness is to brown ceramic powder;
6) synthesis of compound p
In flask, add compound o, HATU, DIEA and DMF solution, add para-fluoroaniline, stirred overnight after stirring at room temperature, after completion of the reaction, reaction solution adds water, and separate out solid, filtering drying, Purify obtains target compound p.
The invention has the advantages that:
1, to prove to have very strong vitro inhibition to five kinds of common tumor cell line human thyroid carcinomas SW579, people liver cancer HepG2, human lung adenocarcinoma A549, people intestinal cancer HCT116 and people cancer of the stomach MKN45 by In vitro cell experiment active for compound of the present invention, and the antitumor activity of most target compound is better than or is equivalent to positive control drug Cabozantinib.
2, compound of the present invention proves to demonstrate stronger inhibit activities to two kinds of kinases KDR and MET by In vitro cell experiment.
3, preparation method's yield of the compounds of this invention is high.
To sum up, compound of the present invention can be used for preparing new antitumor drug.
Embodiment
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise per-cent and number are weight percent and parts by weight.
In following examples, agents useful for same is commercially available analytical pure.
According to reaction scheme synthesising target compound, for two compounds below.
Embodiment 1: according to ROUTE1 synthetic intermediate quinoline aniline h
(1) synthesis of compound 4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluoroaniline compounds (h)
NaH (3.3g, 82.5mmol) and anhydrous DMSO is added, after fully stirring in the round-bottomed flask of 100ml, add p-aminophenol (6g, 55mmol), stirring at room temperature 10min, then 3h is stirred at 100 degree after adding chloro-6, the 7-dimethoxy-quinolines (12.3g, 55.1mmol) of 4-, TLC monitors, after completion of the reaction, add water, chloroform extraction, extraction liquid evaporate to dryness is obtained gray solid 12.2g, productive rate 74.6%.Spectral data is:
1hNMR (300MHz, CDCl
3) δ 8.50 (d, J=5.5Hz, 1H), 7.64 (d, J=7.0Hz, 1H), 7.48 (s, 1H), 7.09 – 6.97 (m, 2H), 6.86 – 6.76 (m, 2H), 6.48 (d, J=5.3Hz, 1H), 4.09 (s, 6H), 3.7 (s, 2H).
Embodiment 2: according to ROUTE1 synthesising target compound l and m
(1) synthesis of the compound 1-tertiary butyl-4-methyl piperidine-Isosorbide-5-Nitrae-dicarboxylic acid fat (a)
In 1L round-bottomed flask, add 4-methyl-formiate piperidines (30g, 0.21mol), be dissolved in the DCM of 500ml, drip (Boc) with constant pressure funnel
2o (45.72g, 0.21mol), triethylamine (42.3g, 0.42mol), stirring at room temperature, after 8 hours after completion of the reaction, adds isopyknic water washing DCM layer 3 times, the colorless oil 97.5g of evaporate to dryness organic phase, productive rate 95.5%.Spectral data is:
1hNMR (300MHz, CDCl
3) δ 4.05 – 3.83 (m, 2H) 3.68 – 3.56 (m, 3H), 2.76 (t, J=11.6Hz, 2H), 2.45 – 2.30 (m, 1H), 1.80 (dd, J=13.4,2.9Hz, 2H), 1.64 – 1.47 (m, 2H), 1.38 (s, 9H).
(2) the compound 1-tertiary butyl-4,4-lupetidines-Isosorbide-5-Nitrae, the synthesis of 4-tricarboxylic ester (b)
Under nitrogen protection, THF and the compound a (10g of 90ml drying is added in the round-bottomed flask of 250ml, 41mmol), LDA (the 2N of fresh configuration is dripped in-78 degree, 25ml), methyl-chloroformate (4.6g is dripped after stirring 1h, 49mmol), finally slowly rise to room temperature, after stirring 3h, add the saturated aqueous ammonium chloride cancellation of 50ml, add the extraction into ethyl acetate three times of 50ml, organic layer evaporate to dryness is to brown oil, white crystal is separated out after putting into refrigerator freezing, filter after adding a small amount of petroleum ether and stirring, dry to obtain white solid 5.8g, productive rate 46.8%.Spectral data is:
1hNMR (300MHz, CDCl
3) δ 3.77 (s, 6H), 3.50 – 3.40 (m, 4H), 2.16 – 2.02 (m, 4H) .MS (M+H-Boc)
+=202.1.
(3) synthesis of compound 1-(tert-butoxycarbonyl)-4-(methoxycarbonyl) piperidines-4-carboxylic acid (c)
Compound b (20g, 66mmol) and 200ml methyl alcohol join in 500ml round-bottomed flask, slowly drip the NaOH solution (69.8ml of 1mol/L, 69.8mmol), stirred overnight, TLC monitors, after raw material reaction, evaporate most of methyl alcohol, add water, dilute hydrochloric acid adjusts pH=6, adds methylene chloride, extraction, organic phase evaporate to dryness is to white crystal, add sherwood oil to filter, dry to obtain 18.72g, productive rate 98.2%.
(4) synthesis of the compound 1-tertiary butyl-4-methyl-4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) formamyl) piperidines-Isosorbide-5-Nitrae-dicarboxylic ester (i)
Compound c (5.33g, 18.6mmol), DMAP (2.27g, 18.7mmol), EDCI (10.7g is added in the round-bottomed flask of 250ml, 55.8mmol), methylene dichloride 100ml, after stirring at room temperature 20min, add compound h (5g, 16.9mmol), in 45 degree of backflow 7h, dilute hydrochloric acid solution washing organic phase 3 times, organic phase evaporate to dryness is to yellow oil, with silica gel column chromatography, methylene chloride/methanol wash-out, obtains white solid 6g, productive rate 62.9%.
(5) synthesis of compound 1-(tertbutyloxycarbonyl)-4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) formamyl) piperidines-4-carboxylic acid (j)
Compound i (2g, 3.5mmol) join in 100ml round-bottomed flask with 50ml methyl alcohol, NaOH solution (the 3.89ml of slow dropping 1mol/L, 3.89mol), stirred overnight, TLC monitors, after raw material reaction, evaporate most of methyl alcohol, add water, diluted alkaline water adjusts pH=10, add methylene chloride and wash water layer 2 times, water intaking layer adds dilute hydrochloric acid and adjusts pH=2, dichloromethane extraction, organic phase evaporate to dryness to half oily solid, add diethyl ether, separate out solid, filtering drying obtains 1.8g, productive rate 92.3%.
(6) synthesis of compound tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) formamyl)-4-(phenylcarbamoyl) piperidines-1-carboxylicesters (k)
Compound j (0.9mmol), HATU (0.38g is added in the pear-shaped flask of 100ml, 1mmol), DIEA (24mg, 0.18mmol) and the DMF solution of 20ml, various substituted aniline (1mmol) is added after stirring at room temperature 10min, stirred overnight, after raw material reaction, reaction solution is poured in the dilute hydrochloric acid solution of pH=2, separate out solid, filtering drying, solid adds a small amount of methyl alcohol and filters or upper silica gel column chromatography, and PE/EA=1/1 wash-out obtains white solid or gray solid, productive rate 57.3%.
(7) synthesis of compound N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-Phenylpiperidine-4,4-bis-carbamyl (l)
Compound k (0.31mmol) is added in the pear-shaped flask of 50ml, add methylene chloride after dissolving, add the saturated ether solution of hydrogen chloride of 5ml, stirred overnight, after completion of the reaction, add water, dilute hydrochloric acid adjusts pH=2, discards organic phase, water transfer phase pH=12, separate out white solid, filtering drying, productive rate 78.4%.
(8) synthesis of compound N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-1-Methyl-N-phenyl piperidines-4,4-dicarbamoyl base (m)
Compound l (0.09mmol) is added, solid polyformaldehyde (13.3mg, 0.45mmol) in the pear-shaped flask of 50ml, 98% formic acid of 0.1ml, anhydrous methanol 20ml, after reflux 3h, adds water, dilute hydrochloric acid adjusts pH=2, discard organic phase, water transfer phase pH=12, separate out white solid, the solid 50mg of filtering drying, productive rate 85.9%.
In table 1, all the other target compounds use corresponding substrate, and the step repeated in above embodiment 1-2 can be synthesized.The Chinese of each compound is as follows:
Compd A 1: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-((2-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compd A 2: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-((3-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compound A-13: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-((4-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compound A-45: tertiary butyl 4-((3-chloro-phenyl-) carbamyl)-4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl) piperidines-1-carboxylicesters
Compd A 6: tertiary butyl 4-((4-chloro-phenyl-) carbamyl)-4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl) piperidines-1-carboxylicesters
Compd A 10: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-(o-tolyl carbamyl) piperidines-1-carboxylicesters
Compd A 11: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-(m-tolyl carbamyl) piperidines-1-carboxylicesters
Compd A 12: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-(p-tolyl carbamyl) piperidines-1-carboxylicesters
Compd A 13: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-((2-methoxyphenyl) carbamyl) piperidines-1-carboxylicesters
Compd A 14: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-((3-methoxyphenyl) carbamyl) piperidines-1-carboxylicesters
Compd A 15: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-((4-methoxyphenyl) carbamyl) piperidines-1-carboxylicesters
Compd A 28: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) carbamyl)-4-(phenylcarbamoyl) piperidines-1-carboxylicesters
Compound C 1: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-((2-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compound C 2: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-((3-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compound C 3: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-((4-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compound C 5: tertiary butyl 4-((3-chloro-phenyl-) carbamyl)-4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compound C 6: tertiary butyl 4-((4-chloro-phenyl-) carbamyl)-4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl) piperidines-1-carboxylicesters
Compound C 11: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-(m-tolyl carbamyl) piperidines-1-carboxylicesters
Compound C 12: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-(p-tolyl carbamyl) piperidines-1-carboxylicesters
Compound C 14: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-((3-methoxyphenyl) carbamyl) piperidines-1-carboxylicesters
Compound C 15: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-((4-methoxyphenyl) carbamyl) piperidines-1-carboxylicesters
Compound C 28: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-(phenylcarbamoyl) piperidines-1-carboxylicesters
Compound C 32: tertiary butyl 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) carbamyl)-4-((4-hydroxy phenyl) carbamyl) piperidines-1-carboxylicesters
Compd B 3:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(p-fluorophenyl) piperidines-4,4-bis-carboxamide
Compd B 5:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(m-chloro-phenyl-) piperidines-4,4-bis-carboxamide
Compound B-11 0:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(o-tolyl) piperidines-4,4-bis-carboxamide
Compound B-11 1:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(m-tolyl) piperidines-4,4-bis-carboxamide
Compound B-11 2:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(p-tolyl) piperidines-4,4-bis-carboxamide
Compound B-11 3:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(2-methoxyphenyl) piperidines-4,4-bis-carboxamide
Compound B-11 5:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(4-methoxyphenyl) piperidines-4,4-bis-carboxamide
Compd B 28:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-Phenylpiperidine-4,4-bis-carboxamide
Compd B 30:N-(4-bromophenyl)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) piperidines-4,4-bis-carboxamide
Compound D 1:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-N-(2-fluorophenyl) piperidines-4,4-bis-carboxamide
Compound D 2:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-N-(3-fluorophenyl) piperidines-4,4-bis-carboxamide
Compound d3: N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-N-(4-fluorophenyl) piperidines-4,4-bis-carboxamide
Compound D 6:N-(4-chloro-phenyl-)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl) piperidines-4,4-bis-carboxamide
Compound D 11:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-N-(m-tolyl) piperidines-4,4-bis-carboxamide
Compound D 14:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-N-(3-methoxyphenyl) piperidines-4,4-bis-carboxamide
Compound D 28:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-N-Phenylpiperidine-4,4-bis-carboxamide
Compd E 3:N-(4-fluorophenyl)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-1-methyl piperidine-4,4-bis-carboxamide
Compd E 5:N-(3-chloro-phenyl-)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-1-methyl piperidine-4,4-bis-carboxamide
Compd E 11:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-1-methyl-N-(m-tolyl) piperidines-4,4-bis-carboxamide
Compd E 12:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-1-methyl-N-(p-tolyl) piperidines-4,4-bis-carboxamide
Compd E 14:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(3-methoxyphenyl)-1-methyl piperidine-4,4-bis-carboxamide
Compd E 15:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(4-methoxyphenyl)-1-methyl piperidine-4,4-bis-carboxamide
Compd E 28:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(phenyl)-1-methyl piperidine-4,4-bis-carboxamide
Compd E 32:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(4-hydroxy phenyl)-1-methyl piperidine-4,4-bis-carboxamide
Compound F 17-hydroxy-corticosterone 3:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-1-methyl-N-(p-fluorophenyl) piperidines-4,4-bis-carboxamide
Compound F 17-hydroxy-corticosterone 12:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-1-methyl-N-(p-tolyl) piperidines-4,4-bis-carboxamide
Compound F 17-hydroxy-corticosterone 15:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-N-(4-methoxyphenyl)-1-methyl piperidine-4,4-bis-carboxamide
Compound F 17-hydroxy-corticosterone 28:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen)-3-fluorophenyl)-1-Methyl-N-phenyl piperidines-4,4-bis-carboxamide
Embodiment 3: according to ROUTE2 synthesising target compound p
(1) synthesis of compound dimethyl-2H-pyrans-4,4 (3H)-dicarboxylic ester (d)
Dehydrated alcohol 400ml and sodium block (10.8g is added in 1L tri-neck round-bottomed flask, 0.47mol), ice bath stirs, after sodium block dissolves completely, slowly add dimethyl malonate (30g, 0.23mol), after stirring 20min, drip dibromo ether (57.9g, 0.25mol) and reflux 32 hours, TLC monitors, after raw material reaction, water is added after evaporating most of ethanol, with dilute hydrochloric acid solution water transfer phase pH=3, extraction into ethyl acetate, organic phase evaporate to dryness is to red-brown oily matter, 150 degree of oil pump underpressure distillation obtain colorless oil, cross chromatography column by PE/EA=30/1 and obtain colorless oil 21g, productive rate is 46.5%.
(2) synthesis of compound 4-(methoxycarbonyl) tetrahydro--2H-pyrans-4-carboxylic acid (e)
Compound d (21g, 0.104mol) and 200ml methyl alcohol join in 500ml round-bottomed flask, slowly drip the NaOH solution (109.2ml of 1mol/L with constant pressure funnel, 0.109mol), stirred overnight, TLC monitors, after raw material reaction, evaporate most of methyl alcohol, add water, dilute hydrochloric acid adjusts pH=6, add methylene chloride extraction, and organic phase evaporate to dryness, to white crystal, filters after adding petroleum ether and stirring, dry to obtain white crystal 18.03g, productive rate 92.32%.
(3) synthesis of compounds methyl-4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) formamyl) tetrahydro--2H-pyrans-4-carboxylicesters (n)
Verbindung (10.5g is added in 500ml round-bottomed flask, 55.85mmol), DMAP (6.75g, 55.25mmol), EDCI (19.5g, 101.72mmol) and 200mlDCM, compound h (16.35g is added after abundant stirring 10min, 55.25mmol), 50 degree of oil bath backflows, react complete after 9h, organic layer dilute hydrochloric acid solution washs 3 times, organic layer evaporate to dryness, to brown ceramic powder, is directly used in lower step, without the need to repurity.
(4) synthesis of compound 4-((4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) formamyl) tetrahydro--2H-pyrans-4-carboxylic acid (o)
The brown ceramic powder 12g upper step obtained is dissolved in 200ml methyl alcohol, drip 1mol/LNaOH solution 30ml, stirred overnight, TLC monitors, and after completion of the reaction, adds dilute hydrochloric acid and adjusts pH=6, evaporate to dryness reaction solution, solid filters after being dissolved in methylene dichloride and methanol mixed solution, filtrate evaporate to dryness to brown ceramic powder 10.55g, two step productive rates 46.1%.
(5) synthesis of compound N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-phenyl dihydro-2H-pyrans-4,4 (3H)-dicarbamoyl base (p)
Compound o (200mg is added in the pear-shaped flask of 100ml, 0.44mmol), the DMF solution of HATU (0.48mmol), DIEA (0.09mmol) and 10ml, para-fluoroaniline (0.48mmol) is added after stirring at room temperature 10min, stirred overnight, after raw material reaction, reaction solution adds water, separate out solid, filtering drying, solid adds a small amount of methylene dichloride and stirs rear filtration or upper chromatography column chromatography, white solid or gray solid is obtained, productive rate 45.1% with DCM/MeOH=60/1 wash-out.
In table 2, all the other target compounds use corresponding substrate, and the step repeated in above embodiment 3 can be synthesized.The Chinese of each compound is as follows:
Compound G2:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(3-fluorophenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G3:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(4-fluorophenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G5:N-(3-chloro-phenyl-)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G6:N-(4-chloro-phenyl-)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G10:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(o-tolyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G11:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(m-tolyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G12:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(p-tolyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G13:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(2-methoxyphenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G14:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(3-methoxyphenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G15:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(4-methoxyphenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G28:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-phenyl dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G30:N-(4-bromophenyl)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G31:N-(4-aminophenyl)-N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
Compound G32:N-(4-((6,7-dimethoxy-quinoline-4-base) oxygen) phenyl)-N-(4-hydroxy phenyl) dihydro-2H-pyrans-4,4 (3H)-two carboxamide
According to chemical structure, the spectral data of the partial target compound of above embodiment 1-3 synthesis, as shown in Table 1 and Table 2.
Chemical structure, the spectral data of table 1 partial target compound
Chemical structure, the spectral data of table 2 part preferred compound
Embodiment 4: the anti-tumor activity test of the compounds of this invention
The compound of the present invention's synthesis has anti-tumor activity, and its pharmacological evaluation is as follows:
(1) biologic activity testing method
1, cell growth inhibiting activity research
(1) test purpose
Experiment adopts tetrazolium reduction method (mtt assay) to detect 42 the compounds of this invention samples to the action intensity of A549, HCT116, HepG2, MKN45 and SW579 five kinds of cell strains, and positive control drug is Cabozantinib.
(2) material
The long multi-functional microplate reader of all-wave, model: VarioskanFlash, production firm: Thermoscientific; Import 96 well culture plate etc.
(3) test medicine
Title: compound of the present invention.
Sample preparation: after being dissolved into 10mM with DMSO (Merck), adds PBS (-) and is made into the solution of 1000 μMs or uniform suspension, then dilute with the PBS (-) containing DMSO.Sample final concentration 100,10,1,0.1,0.01,0.001 (μM).
(4) cell strain
1. SW579 (human thyroid carcinomas)
2. A549 (human lung adenocarcinoma cell)
3. HCT116 (people's colon-cancer cell)
4. HepG2 (human liver cancer cell)
5. MKN45 (gastric carcinoma cells)
Above cell strain is frozen and go down to posterity by this laboratory.
(5) nutrient solution
DMEM+10%FBS+ is dual anti-.
(6) testing method
1. get and be in one bottle, cell in good condition exponential phase of growth, add 0.25% tryptic digestive juice, digestion makes attached cell come off, and making concentration is 4-5 × 10
4the cell suspension of individual/ml.
2. the 96 every holes of orifice plate add concentration is 4-5 × 10
4the cell suspension 100 μ l of individual/ml, puts 37 DEG C, 5%CO
224h in incubator.
3. sample liquid is added, 10 μ l/ holes, if duplicate hole, 37 DEG C, 5%CO
2effect 72h.
4. every hole adds the MTT solution 20 μ l of 5mg/ml, and add lysate after effect 4h, 100 μ l/ holes, put in incubator, surveys 570nmOD value after dissolving by the long multi-functional microplate reader of all-wave.And calculate the IC of cell
50value.
2, vitro kinase inhibit activities research
(1) experiment purpose
Experiment adopts slide calliper rule transfer method (Mobilityshiftassay) to test 14 the compounds of this invention samples to KDR and MET two kinds of kinase whose inhibiting rates, institute's test compounds concentration is 5 μMs, experiment adopts Staurosporine as the reference compound of test panel, using Cabozantinib as positive control drug.
(2) experiment material
Experiment reagent is to be purchased, on the market in table 3.
Table 3 experiment reagent
(3) testing method
1. with DMSO by sample dissolution, be made into 10mM solution.
2. prepare 1 × Kinasebasebuffer (50mMHEPES, pH7.5; 0.0015%Brij-35; 10mMMgCl
2; 2mMDTT), preparation stops liquid stopbuffer (100mMHEPES, pH7.5; 0.015%Brij-35; 0.2%CoatingReagent#3; 50mMEDTA).
3. with the DMSO solution of DMSO by diluted chemical compound to 250 μM, the compound getting 10 μ l from sample source plate is transferred to 96 new hole intermediate plates, in each hole of intermediate plate, add 90 μ l1 × Kinasebasebuffer, intermediate plate is placed in 10min on shaking table and makes both fully mixing.
4. from each hole of 96 hole intermediate plates, get 5 μ l transfers in 384 hole test panels, and the title in hole, each sample place is constant.
5. prepare the enzyme solution of 2.5 times, prepare the peptide solution of 2.5 times.
6. 10 μ l2.5 enzyme solution is doubly added on the 384 hole test panels adding 5 μ l testing compounds, preheating 10min under room temperature.
7. in 384 hole test plate holes, add the peptide solution 10 μ l of 2.5 times, at 28 DEG C, react for some time.
8. add the termination liquid stopped reaction of 25 μ l, Caliper collects data, is obtained the inhibiting rate of sample by Caliper program computation.
(2) biologic activity test result
1, cell growth inhibiting activity research
Biologic activity test result is in table 4, table 5.Experimental result shows that compound of the present invention has good anti-tumor activity, the vitro inhibition activity of multiple compound to selected tumour cell is better than or close contrast medicine Cabozantinib, and showing visibly different antitumor spectra, prompting the compounds of this invention has broad application prospects preparing in antitumor drug.
Table 4 part piperidines substituted chinoline derivative is to four kinds of cell strain inhibit activities
Table 5 pyran substituted chinoline derivative is to the inhibit activities of MKN45 cell strain
2, vitro kinase inhibit activities research
Part of compounds to KDR and MET two kinds of kinase whose inhibiting rates in table 6.Experimental result shows that compound of the present invention has good KDR and MET inhibit activities, therefore can be used for treating the tumour containing above-mentioned target spot.
Table 6 vitro kinase inhibit activities
" * " represents that compound concentration is 5 μMs.
The above is only the preferred embodiment of the present invention; it should be pointed out that for those skilled in the art, under the prerequisite not departing from the inventive method; can also make some improvement and supplement, these improve and supplement and also should be considered as protection scope of the present invention.
Claims (10)
1. have a quinolines for anti-tumor activity, it is characterized in that, its general structure is such as formula shown in (I):
Wherein, R
1be selected from hydrogen or halogen, described halogen is selected from F, Cl, Br or I, can be positioned at the neighbour of aromatic ring, a position, can be monosubstituted or polysubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from N, O atom.
2. quinolines according to claim 1, is characterized in that,
R
1hydrogen or halogen, described halogen is selected from F or Cl, and can be positioned at the neighbour of aromatic ring, a position, be monosubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, be monosubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from N, O atom.
3. quinolines according to claim 1, is characterized in that,
R
1be selected from hydrogen or halogen, described halogen is selected from F, Cl, Br or I, can be positioned at the neighbour of aromatic ring, a position, can be monosubstituted or polysubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from atom N.
4. quinolines according to claim 1, is characterized in that,
R
1be selected from hydrogen or halogen, described halogen is selected from F or Cl, can be positioned at the neighbour of aromatic ring, a position, can be monosubstituted;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted;
R
3be selected from the alkyl of H or 1-5 carbon atom;
X is selected from atom N.
5. quinolines according to claim 1, is characterized in that,
R
1be selected from hydrogen;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted or polysubstituted;
R
3be selected from H;
X is selected from O atom.
6. quinolines according to claim 1, is characterized in that,
R
1be selected from hydrogen;
R
2be selected from following I-V any one:
I. hydrogen,
II. alkyl: described alkyl is the alkyl of 1-5 carbon atom, alkoxyl group or haloalkyl, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
III. halogen: be selected from F, Cl, Br, I, can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
IV. hydroxyl: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted,
V. amino: can be positioned at the neighbour of aromatic ring, contraposition, can be monosubstituted;
R
3be selected from H;
X is selected from O atom.
7. the crystal formation of quinolines according to claim 1, pharmaceutically acceptable inorganic acid salt or organic acid salt, hydrate, solvate or prodrug.
8. quinolines according to claim 1, or the crystal formation of quinolines according to claim 7, pharmaceutically acceptable inorganic acid salt or organic acid salt, hydrate, solvate or prodrug are preparing the purposes in antitumor drug.
9. purposes according to claim 8, is characterized in that, described tumour is thyroid carcinoma, liver cancer, adenocarcinoma of lung, intestinal cancer or cancer of the stomach.
10. the preparation method of quinolines according to claim 1, is characterized in that, comprises the following steps:
(1) when the quinolines structural formula shown in formula (I) is specifically as shown in compound l or m, step is as follows:
1) synthesis of compound h
After NaH and anhydrous DMSO fully stirs, add replacement p-aminophenol, react after then adding chloro-6, the 7-dimethoxy-quinolines of 4-under 90-120 degree condition, TLC monitors, and after completion of the reaction, adds water, chloroform extraction evaporate to dryness obtains compound h;
2) synthesis of compound a
4-methyl-formiate piperidines is dissolved in DCM, drips (Boc)
2o, triethylamine, after room temperature reaction, washing DCM layer, evaporate to dryness organic phase obtains compound a;
3) synthesis of compound b
Under nitrogen protection, add THF and compound a in flask, drip LDA, drip methyl-chloroformate after stirring, slowly rise to stirring at room temperature reaction, then add saturated aqueous ammonium chloride cancellation, extraction into ethyl acetate, evaporate to dryness obtains compound b;
4) synthesis of compound c
In compound b and methyl alcohol, slowly drip NaOH solution, stirred overnight, TLC monitors, after completion of the reaction, evaporate most of methyl alcohol, add water, dilute hydrochloric acid adjusts pH, adds methylene chloride, extraction, organic phase evaporate to dryness, to white crystal, adds sherwood oil and filters, dry and obtain compound c;
5) synthesis of compound i
In flask, add compound c, DMAP, EDCI, methylene dichloride, stirring at room temperature is reacted, and adds compound h, back flow reaction, dilute hydrochloric acid solution washing organic phase, and evaporate to dryness purifying obtains compound i;
6) synthesis of compound j
Compound i and methyl alcohol join in flask, slowly drip NaOH solution, stirred overnight, TLC monitors, after completion of the reaction, evaporate most of methyl alcohol, add water, diluted alkaline water adjusts pH, add methylene chloride washing water layer, and water intaking layer adds dilute hydrochloric acid and adjusts pH, dichloromethane extraction, organic phase evaporate to dryness to half oily solid, filtering drying obtains compound j;
7) synthesis of compound k
In flask, add compound j, HATU, DIEA and DMF solution, add substituted aniline, stirred overnight after stirring at room temperature, after raw material reaction, reaction solution is poured in dilute hydrochloric acid solution, and separate out solid, filtering drying, purifying obtains compound k;
8) synthesis of compound l
In flask, add compound k, add methylene chloride after dissolving, add saturated ether solution of hydrogen chloride, stirred overnight, after completion of the reaction, add water, water transfer phase pH, separate out white solid, filtering drying obtains target compound l;
9) synthesis of compound m
In flask, add compound l, solid polyformaldehyde, formic acid, anhydrous methanol, heating reflux reaction, add water water transfer phase pH, and separate out white solid, filtering drying obtains target compound m;
(2) when the quinolines structural formula shown in formula (I) is specifically as shown in compound p, ROUTE2 reaction scheme is adopted, as follows:
1) synthesis of compound h
After NaH and anhydrous DMSO fully stirs, add replacement p-aminophenol, react after then adding chloro-6, the 7-dimethoxy-quinolines of 4-under 90-120 degree condition, TLC monitors, and after completion of the reaction, adds water, chloroform extraction evaporate to dryness obtains compound h;
2) synthesis of compound d
In flask, add dehydrated alcohol and sodium block, ice bath stirs, after sodium block dissolves completely, add dimethyl malonate, drip dibromo ether and reflux after stirring, after completion of the reaction, extraction into ethyl acetate, organic phase evaporate to dryness is to red-brown oily matter, and purifying obtains compound d;
3) synthesis of Verbindung
Compound d and methyl alcohol join in flask, slowly drip NaOH solution, stirred overnight, and TLC monitors, and after completion of the reaction, aftertreatment, to white crystal, is dried and obtained Verbindung;
4) synthesis of compound n
In flask, add Verbindung, DMAP, EDCI and DCM, add compound h after fully stirring, oil bath refluxes, and after completion of the reaction, organic layer dilute hydrochloric acid solution washs, and evaporate to dryness, to brown ceramic powder, is directly used in lower step;
5) synthesis of compound o
The brown ceramic powder that upper step obtains is dissolved in methyl alcohol, drips NaOH solution, stirred overnight, TLC monitors, and after completion of the reaction, add dilute hydrochloric acid and adjust pH, evaporate to dryness reaction solution, solid filters after being dissolved in methylene dichloride and methanol mixed solution, and filtrate evaporate to dryness is to brown ceramic powder;
6) synthesis of compound p
In flask, add compound o, HATU, DIEA and DMF solution, add para-fluoroaniline, stirred overnight after stirring at room temperature, after completion of the reaction, reaction solution adds water, and separate out solid, filtering drying, Purify obtains target compound p;
Wherein, compound h structural formula is:
Wherein, compound a structural formula is:
Wherein, compound b structural formula is:
Wherein, compound c structural formula is:
Wherein, compound i structural formula is:
Wherein, compound j structural formula is:
Wherein, compound k structural formula is:
Wherein, compound l structural formula is:
Wherein, compound m structural formula is:
Wherein, compound d structural formula is:
Wherein, Verbindung structural formula is:
Wherein, compound n structural formula is:
Wherein, compound o structural formula is:
Wherein, compound p structural formula is:
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| CN111788207A (en) * | 2017-02-27 | 2020-10-16 | 北京赛特明强医药科技有限公司 | Dioxane quinoline compound and preparation method and application thereof |
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| WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
| WO2009017838A2 (en) * | 2007-08-01 | 2009-02-05 | Exelixis, Inc. | Combinations of jak-2 inhibitors and other agents |
| EP2532657A2 (en) * | 2008-10-14 | 2012-12-12 | Sunshine Lake Pharma Co., Ltd | Compounds and methods of use |
| WO2013032797A2 (en) * | 2011-08-26 | 2013-03-07 | New Hope R & D Bioscience, Inc. | Oxetane 3,3-dicarboxamide compounds and methods of making and using same |
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2016
- 2016-02-03 CN CN201610077368.7A patent/CN105541798B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005030140A2 (en) * | 2003-09-26 | 2005-04-07 | Exelixis, Inc. | C-met modulators and methods of use |
| WO2009017838A2 (en) * | 2007-08-01 | 2009-02-05 | Exelixis, Inc. | Combinations of jak-2 inhibitors and other agents |
| EP2532657A2 (en) * | 2008-10-14 | 2012-12-12 | Sunshine Lake Pharma Co., Ltd | Compounds and methods of use |
| WO2013032797A2 (en) * | 2011-08-26 | 2013-03-07 | New Hope R & D Bioscience, Inc. | Oxetane 3,3-dicarboxamide compounds and methods of making and using same |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111788207A (en) * | 2017-02-27 | 2020-10-16 | 北京赛特明强医药科技有限公司 | Dioxane quinoline compound and preparation method and application thereof |
| CN111788207B (en) * | 2017-02-27 | 2021-03-23 | 北京赛特明强医药科技有限公司 | Dioxane quinoline compound and preparation method and application thereof |
| AU2019218187B2 (en) * | 2017-02-27 | 2021-10-14 | Beijing Scitech-Mq Pharmaceuticals Limited | Dioxinoquinoline compounds, preparation method and uses thereof |
| WO2019154133A1 (en) * | 2018-02-11 | 2019-08-15 | 北京赛特明强医药科技有限公司 | Dioxazoline compound, preparation method therefor, and uses thereof |
| JP2021512930A (en) * | 2018-02-11 | 2021-05-20 | 北京賽特明強医薬科技有限公司 | Dioxynoquinoline compounds, their preparation methods and uses |
| JP7022454B2 (en) | 2018-02-11 | 2022-02-18 | 北京賽特明強医薬科技有限公司 | Dioxynoquinoline compounds, their preparation methods and uses |
| US11407760B2 (en) | 2018-02-11 | 2022-08-09 | Beijing Scitech-Mq Pharmaceuticals Limited | Dioxinoquinoline compounds, preparation method and uses thereof |
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| CN105541798B (en) | 2018-01-23 |
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