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CN109467549A - Quinoline-substituted chalcone compound, its preparation method and use - Google Patents

Quinoline-substituted chalcone compound, its preparation method and use Download PDF

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Publication number
CN109467549A
CN109467549A CN201811494253.3A CN201811494253A CN109467549A CN 109467549 A CN109467549 A CN 109467549A CN 201811494253 A CN201811494253 A CN 201811494253A CN 109467549 A CN109467549 A CN 109467549A
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quinoline
pharmaceutically acceptable
substituted chalcone
hydrogen
chalcone compound
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CN109467549B (en
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徐进宜
李文龙
徐盛涛
徐飞杰
帅雯
孙翃昊
朱哲英
姚鸿
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China Pharmaceutical University
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China Pharmaceutical University
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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
    • C07D401/02—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
    • C07D401/06—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 carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/12—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D215/14—Radicals substituted by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/18—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • C07D401/02—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
    • C07D401/04—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 directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/60—Quinoline or hydrogenated quinoline ring systems

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Abstract

本发明公开了一种喹啉取代查尔酮类新化合物、其可药用的盐，及其制备方法；还公开了一种药用组合物，其包含治疗有效量的喹啉取代查尔酮类新化合物和/或其可药用的盐，以及药学上可接收的载体。本发明还公开了一种微管蛋白抑制剂，其包含上述喹啉取代查尔酮类新化合物和/或其可药用的盐。本发明还公开上述喹啉取代查尔酮类新化合物和/或其可药用的盐在制备治疗包括但不限于结肠癌、白血病、肝癌、乳腺癌等疾病的药物中的应用。本申请化合物显示出优异的抗肿瘤活性，其代谢性质更为稳定，具有更好的成药性前景。The invention discloses a new quinoline-substituted chalcone compound, a pharmaceutically acceptable salt thereof, and a preparation method thereof; and also discloses a pharmaceutical composition comprising a therapeutically effective amount of quinoline-substituted chalcone A novel compound and/or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention also discloses a tubulin inhibitor, which comprises the above-mentioned new quinoline-substituted chalcone compounds and/or pharmaceutically acceptable salts thereof. The invention also discloses the application of the above-mentioned quinoline-substituted chalcone compounds and/or their pharmaceutically acceptable salts in preparing medicines for treating diseases including but not limited to colon cancer, leukemia, liver cancer, breast cancer and the like. The compound of the present application shows excellent antitumor activity, its metabolic property is more stable, and it has a better prospect of druggability.

Description

Quinoline replaces chalcone compounds, preparation method and the usage
Technical field
The present invention relates to field of medicinal chemistry, and in particular to a kind of quinoline with anti-tumor activity replaces chalcones Close object.The invention also discloses the Pharmaceutical compositions containing the compound and the compound in preparation treatment tumour and to lead to Cross the application inhibited in drug of the tubulin activity to treat other diseases or illness.
Background technique
Micro-pipe is the chief component of cytoskeleton, durings maintaining cellular morphology, cell division, signal transduction etc. It plays an important role, therefore, tubulin is the target of a very promising new chemotherapeutic drugs.Antitubulin The hyper-proliferative that can prevent tumour cell is a kind of important antineoplaston drug.Currently, the micro-pipe clinically applied inhibits Agent mainly has the inhibition tubulin deaggregated medication by representative of taxol and the inhibition tubulin by representative of vinca Assemble drug.And that there are toxic side effects is big, synthesis difficulty is big, poorly water-soluble, is also easy to produce the disadvantages of drug resistance for these drugs.
Colchicin binding site is to study tubulin a more site at present, acts on the inhibition in the site The usual structure of agent is simpler, such as colchicin, Combretastatin A-4.In addition, acting on the inhibitor in the site also The blood vessel of tumor tissues can be destroyed, therefore, the research for the Antitubulin for acting on colchicin site is had become and is worked as The hot spot of modern antitumor research.
Chalcone compounds are a kind of important Antitubulins.Ducki et al. in 1998 1051-1056 pages of the phase of " Bioorganic&Medicinal Chemistry Letters " the 8th has delivered " Potent Antimitotic and cell growth inhibitory properties of substituted chalcones ", This article has found that a kind of chalcone compound has very high anti-tumour cell proliferative activity, and confirms that it has microtubulin-resisting The effect of aggregation.Xingshu Li et al. people is in 2016 in " Journal of Medicinal Chemistry " the 59th phase 5264-5283 pages has been delivered " Synthesis, Evaluation, and Mechanism Study of Novel Indole- Chalcone Derivatives Exerting Effective Antitumor Activity Through Microtubule Destabilization in Vitro and in Vivo ", this article have found a kind of indoles chalcones Compound, pharmacological evaluation prove that they can effectively inhibit the aggregation of tubulin, and have stronger external and anti-swollen in vivo Tumor activity.
Summary of the invention
Goal of the invention: the present invention is supplied to a kind of quinoline substitution chalcones noval chemical compound, its pharmaceutical salt, and its Preparation method；Additionally provide a kind of Pharmaceutical composition, it includes the quinoline of therapeutically effective amount replace chalcones noval chemical compound and/ Or the carrier of its pharmaceutical salt and pharmaceutical acceptable.The present invention also provides a kind of Antitubulin, it includes Above-mentioned quinoline replaces chalcones noval chemical compound and/or its pharmaceutical salt.Invention additionally discloses above-mentioned quinoline to replace chalcone Class noval chemical compound and/or its pharmaceutical salt are in preparation treatment including but not limited to colon cancer, leukaemia, liver cancer, breast cancer etc. Application in the drug of disease.
Technical solution: quinoline shown in general formula I or II disclosed by the invention replaces that chalcone compounds, its is pharmaceutical Salt:
Wherein:
R1Selected from hydrogen, lower paraffin hydrocarbon, hydroxyl, methoxyl group, halogen, cyano, ester group, amide groups, carboxyl, secondary amino group, tertiary ammonia Base, methylol or aldehyde radical；
R2Selected from hydrogen, lower paraffin hydrocarbon, halogen, methoxyl group, cyano, ester group, amide groups or carboxyl；
R3Selected from methoxyl group, methyl mercapto, cyano, lower paraffin hydrocarbon, halogen, ester group or the different amino replaced；
R4Selected from hydroxyl, amino, fluorine, phosphate-based, disodium hydrogen phosphate, glucosides, boronate, amino acid amide base or (CH2)1- 6OH；
R5Replace formoxyl selected from hydrogen, lower paraffin hydrocarbon, methoxyl group, methylol, fragrance or fat；
In general formula II, the position that alkenyl replaces can be 3 in indoles, 4,5,6 or 7.
Further, R1It is preferred that hydrogen, lower paraffin hydrocarbon, hydroxyl, methoxyl group, halogen, cyano, ester group, amide groups, carboxyl, secondary Amino, tertiary amino, methylol or aldehyde radical.
R2It is preferred that hydrogen or methyl.
R3It is preferred that methoxyl group or methyl mercapto.
R4It is preferred that hydroxyl, amino, fluorine or disodium hydrogen phosphate.
R5Selected from hydrogen or lower paraffin hydrocarbon.
In general formula II, the preferred indoles in position 3,4 or 5 of alkenyl substitution.
Further, the compound of general formula I or II of the invention are preferably the particular compound of following 1-30:
The compound of general formula I or II of the present invention can be prepared with following method:
A. 1 synthesis step of reaction equation solution is as follows:
Using isatin as starting material, reacts to obtain 2- methylquinoline -4- formic acid with condensation of acetone, be prepared into wenreib acyl Intermediate 2- methyl -4- acetylquinoline can be obtained by reacting after amine with methyl-magnesium-bromide；2- methylquinoline -4- formic acid after ester at passing through NaBH4It is reduced into alcohol, then through Dess-Martin reagent oxidation at aldehyde, after then reacting with ethylmagnesium bromide, then through Dess- Martin reagent oxidation can obtain intermediate 2- methyl -4- propiono quinoline.
B. 2 synthesis step of reaction equation solution is as follows:
Using isatin as starting material, 2- oxo -1,2- dihydroquinoline -4- formic acid can be obtained by being condensed in acetic acid with malonic acid, Then 2- chloroquinoline -4- formic acid is obtained through phosphorus oxychloride chloro, finally obtains the chloro- 4- propiono quinoline of 2- according still further to the method for A.
C. 3 synthesis step of reaction equation solution is as follows:
The quinolinone intermediate that the above route obtains can be obtained target product quinoline from different aldehyde generation condensation reactions and take For chalcone compounds I or II.
The utility model has the advantages that a kind of quinoline of the present invention replaces chalcone compounds, the compound can be applied to make The drug of standby treatment tumour can be also used for preparing by inhibiting tubulin activity and treat the medicine of other diseases or illness Object.Also, the application compound shows excellent anti-tumor activity, and activity is better than CA-4 and cis-platinum；Inhibit tubulin Polymerization is considerably better than positive drug CA-4；The activity of tumour growth is inhibited to be higher than CA-4 and cis-platinum, and compared to cis-platinum group, The application toxicity of compound is smaller, and compared to classical CA-4, metabolisming property is more stable, has better druggability Prospect.
Specific embodiment
Form shows specific embodiment by the following examples, carries out further specifically to the content of present invention It is bright, but this should not be interpreted as to the scope of the above subject matter of the present invention is limited to the following embodiments, it is all based in the present invention Stating content achieved technology in the art should belong to the contents of the present invention.
HepG2, KB, HCT-8, MDA-MB-231, K562 Nanjing KaiJi Biology Science Development Co., Ltd；
Cis-platinum, CA-4 Nanjing KaiJi Biology Science Development Co., Ltd.
Embodiment 1
(E) -3- (1H- indoles -5- base) propyl -1- (2- methylquinoline -4- base) -2- alkenyl -1- ketone
(a) after the KOH aqueous solution of indole-2,3-dione (10g, 68mmol) and 85% being mixed in 50 DEG C of stirring 1h, drop Enter 50mL acetone, continue to stir 15h, acetone is removed in rotation, and dilute hydrochloric acid tune pH to 3 is filtered, dry 2- methylquinoline -4- formic acid 11g (white solid, 86.7%)；2- methylquinoline -4- formic acid (500mg, 2.7mml) is dissolved in methylene chloride, is separately added into two First hydroxylamine hydrochloride (310mg, 3.2mmol), triethylamine (440 μ L, 3.2mmol), EDCI (1g, 5.4mmol), catalytic amount DMAP is diluted with water after 2h is stirred at room temperature, and methylene chloride extracts (50mL × 3), merges organic phase, and saturated common salt washing is anhydrous Sodium sulphate is dry, and N- methoxyl group-N, 2- dimethyl quinoline -4- formamide 510mg, yield 83.1% are obtained after concentration；(b) by N- Methoxyl group-N, 2- dimethyl quinoline -4- formamide (500mg, 2.7mmol) is dissolved in anhydrous THF, nitrogen protection, condition of ice bath Under be slowly dropped into the methyl-magnesium-bromide diethyl ether solution (2.2mL, 5.9mmol) of 3M, be diluted with water after reacting at room temperature 2h, methylene chloride It extracts (50mL × 3), merges organic phase, saturated common salt washing, anhydrous sodium sulfate is dry, concentration rear pillar chromatography (PE/EA 2:1) Obtain 2- methyl -4- acetylquinoline 420mg, yield 84%；
(c) 2- methyl -4- acetylquinoline (75mg, 0.4mmol) and indoles -5- formaldehyde (71mg, 0.48mmol) are dissolved in In ethyl alcohol, it is added sodium hydrate particle (80mg, 2mmol), is diluted with water after 1h is stirred at room temperature, methylene chloride extraction (50mL × 3), merging organic phase, saturated common salt washing, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE/EA 2:1) obtains target product 85mg, yield 67.5%；1H NMR(300MHz,CDCl3) δ 8.87 (s, 1H), 8.02 (d, J=8.5Hz, 1H), 7.96 (d, J =8.4Hz, 1H), 7.72 (s, 1H), 7.66- 7.56 (m, 2H), 7.43 (d, J=7.4Hz, 1H), 7.36 (m, 3H), 7.18- 7.08(m,2H),6.48(s,1H), 2.70(s,3H)；13C NMR(75MHz,CDCl3)δ194.83,158.00,150.13, 147.88,145.41, 137.28,129.46,128.48,127.87,126.23,125.55,125.27,124.83, 123.20,122.64, 121.50,119.50,111.41,103.13,76.97,76.54,76.12,24.83；ESI-MS m/ z:312.1calcd for C21H16N2O[M+H]+313.1.
Embodiment 2
(E) -3- (1H- indoles -4- base) propyl -1- (2- methylquinoline -4- base) -2- alkenyl -1- ketone
According to the operation of embodiment 1 (c), yellow solid 63mg, yield 50% are obtained；1H NMR(300MHz, CDCl3)δ 9.11 (s, 1H), 8.11 (dd, J=8.2,4.6Hz, 2H), 7.97 (d, J=16.1Hz, 1H), 7.78- 7.66 (m, 1H), 7.53 (d, J=7.1Hz, 1H), 7.48 (d, J=3.4Hz, 1H), 7.44 (m, 2H), 7.38 (s, 1H), 7.35-7.27 (m, 1H), 7.19 (t, J=7.8Hz, 1H), 6.74 (s, 1H), 2.81 (s, 3H)；13C NMR (75MHz,CDCl3)δ194.85, 158.04,147.94,146.93,145.16,135.97,129.53,128.51, 126.78,126.33,125.77, 125.64,124.84,122.58,121.44,119.69,114.10,100.73, 76.99,76.56,76.14,24.83； ESI-MS m/z:312.1calcd for C21H16N2O[M+H]+313.1.
Embodiment 3
(E) -3- (3- hydroxyl -4- methoxyphenyl) -1- (2- methylquinoline -4- base) propyl -2- alkenyl -1- ketone
According to the operation of embodiment 1 (c), yellow solid 120mg, yield 70.5% are obtained；1H NMR(300 MHz,DMSO)δ 9.26 (s, 1H), 8.03 (d, J=9.0Hz, 2H), 7.76 (t, J=7.6Hz, 1H), 7.65 (s, 1H), 7.57 (t, J= 7.9Hz, 1H), 7.50 (d, J=16.0Hz, 1H), 7.33-7.22 (m, 2H), 7.20 (d, J=6.3Hz, 1H), 6.97 (d, J =8.4Hz, 1H), 3.83 (s, 3H), 2.74 (s, 3H)；13C NMR(75 MHz,DMSO)δ193.80,158.59,150.87, 147.82,147.55,146.77,144.27,129.66, 128.80,126.94,126.61,124.96,123.60, 122.60,122.37,120.42,114.68,111.91, 55.65,40.34,40.06,39.79,39.51,39.23, 38.95,38.68,24.81；ESI-MS m/z:319.1 calcd for C21H17NO3[M+H]+320.1.
Embodiment 4
(E) -1- (3- hydroxyl -4- methoxyphenyl) -3- (2- methylquinoline -4- base) propyl -2- alkenyl -1- ketone
By 2- methylquinoline -4- formaldehyde (50mg, 0.29mmol) and 2- methoxyl group -4- acetyl phenol (48mg, It 0.29mmol) is dissolved in dehydrated alcohol, is added sodium hydrate particle (58mg, 1.45mmol), after being stirred at room temperature one hour, has red Color solid is precipitated, dilute hydrochloric acid tune pH to neutrality, filters, washing, dry product 75mg, yield 75.8%；1H NMR (300MHz, DMSO) δ 8.26 (d, J=15.4Hz, 1H), 8.13 (d, J=8.2 Hz, 1H), 8.01 (d, J=15.4Hz, 1H), 7.92 (s, 1H), 7.88 (d, J=8.3Hz, 1H), 7.67 (dd, J=15.2,7.9Hz, 2H), 7.59-7.44 (m, 2H), 6.97 (d, J=8.4Hz, 1H), 3.79 (s, 3H), 2.62 (s, 3H)；ESI-MS m/z:319.1calcd for C21H17NO3 [M+H]+320.1.
Embodiment 5
(E) -3- (6- methoxyl group -1H- indol-3-yl) -1- (2- methylquinoline -4- base) propyl -2- alkenyl -1- ketone
2- methyl -4- acetylquinoline (100mg, 0.54mmol) and 6- methoxyindole-3-carboxaldehyde (114mg, It 0.65mmol) is dissolved in ethyl alcohol, instills piperidines (87 μ L, 1.08mmol), 90 degree of stirrings are diluted with water afterwards for 24 hours, methylene chloride extraction It taking (50mL × 3), merges organic phase, saturated common salt washing, anhydrous sodium sulfate is dry, concentration rear pillar chromatography (PE/EA 2:1) Target product 124mg, yield 67.4%；1H NMR(300 MHz,DMSO)δ8.04(s,1H),8.01(s,2H),7.81(d,J =15.8Hz, 1H), 7.75 (d, J=7.2 Hz, 1H), 7.63-7.52 (m, 2H), 7.41 (d, J=9.1Hz, 2H), 7.18 (d, J=16.0Hz, 1H), 6.90 (dd, J=8.7,2.1Hz, 1H), 3.83 (s, 3H), 2.75 (s, 3H)；13C NMR(75MHz, DMSO)δ 187.69,159.12,153.34,148.40,147.82,140.03,136.66,130.74,130.01,129.44, 128.48,126.85,124.61,123.63,122.32,119.66,115.45,111.61,56.20,25.27； ESI-MS m/z:342.1calcd for C22H18N2O2[M+H]+343.1.
Embodiment 6
(E)-3- (1H- indoles-5- base)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- ketone
(a) 2- methylquinoline -4- formic acid (20g, 107mml) is dissolved in 100mL methylene chloride, instills the DMF of catalytic amount, It is slowly dropped under condition of ice bath oxalyl chloride (20mL, 214mmol), methanol 20mL is added after reacting at room temperature 2h, continued after stirring 1h Solvent is removed in rotation, is diluted with water rear methylene chloride extraction (50mL × 3), merges organic phase, saturated common salt washing, and anhydrous sodium sulfate is done It is dry, it is concentrated to give 2- methylquinoline -4- methyl formate 18g, yield 85.7%；By 2- methylquinoline -4- methyl formate (20g, It 100mmol) is dissolved in methanol, NaBH is added portionwise in condition of ice bath4(11g, 300mmol), after being stirred at room temperature for 24 hours, by reaction solution It is added dropwise in saturated aqueous ammonium chloride, methylene chloride extraction (50mL × 3) after methanol is gone in rotation, merges organic phase, saturated salt solution It washes, anhydrous sodium sulfate is dry, is concentrated to give 2- methylquinoline -4- methanol 15g, yield 88.2%；By 2- methylquinoline -4- methanol (15g, 86.7mmol) is dissolved in 50mL DMSO, is added IBX (26.7g, 95.4mmol), falls reaction solution after reacting at room temperature 2h Enter in water, ethyl acetate extracts (50mL × 3), merges organic phase, and 10% NaOH aqueous solution is washed three times, saturated common salt washing, nothing Aqueous sodium persulfate is dry, is concentrated to give 2- methylquinoline -4- formaldehyde 12g, yield 80%；By 2- methylquinoline -4- formaldehyde (5g, 29.1mmol) be dissolved in anhydrous THF, be slowly injected under nitrogen protection the ethylmagnesium bromide of 3mol/L diethyl ether solution (12mL, 34.8mmol), it being diluted with water after reacting at room temperature 2h, methylene chloride extracts (50mL × 3), merges organic phase, and saturated common salt is washed, Anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE/EA 2:1) obtains colorless oil 4.3g, yield 74.1%；By previous step product (2g, 9.95mmol) is dissolved in methylene chloride, and addition, which is worn after 2h is stirred at room temperature in this Martin reagent (5.1g, 11.9mmol), adds water Dilution, methylene chloride extract (50mL × 3), merge organic phase, saturated common salt washing, anhydrous sodium sulfate is dry, and rear pillar layer is concentrated It analyses (PE/EA 2:1) and obtains 2- methyl -4- propiono quinoline 1.3g, yield 65.1%.
(b) by 2- methyl -4- propiono quinoline (75mg, 0.38mmol) and indoles -5- formaldehyde (73mg, 0.46mmol) It is dissolved in ethyl alcohol, is added sodium hydrate particle (76mg, 1.9mmol), is diluted with water after 2h is stirred at room temperature, methylene chloride extraction (50mL × 3), merging organic phase, saturated common salt washing, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE/EA 4:1) obtains yellow Color solid 65mg, yield 53.3%；1H NMR(300MHz,CDCl3) δ 8.98 (s, 1H), 8.09 (d, J=8.4Hz, 1H), 7.79 (d, J=8.3Hz, 1H), 7.72 (s, 1H), 7.67 (d, J=7.2Hz, 1H), 7.46 (t, J=7.2Hz, 1H), 7.38- 7.24 (m, 3H), 7.19 (d, J=7.6Hz, 2H), 6.54 (s, 1H), 2.78 (s, 3H), 2.45 (s, 3H)；13C NMR (75MHz,CDCl3)δ198.53,157.80, 148.99,147.57,146.47,135.92,134.36,129.44, 128.41,127.60,126.46,126.03, 125.11,124.89,124.17,123.43,123.37,119.52, 110.76,102.84,24.81,12.51； ESI-MS m/z:326.1calcd for C22H18N2O[M+H]+327.1.
Embodiment 7
(E) -2- methyl -3- (1- Methyl-1H-indole -5- base) -1- (2- methylquinoline -4- base) propyl -2- alkenyl -1- Ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.38 (s, 1H), 8.16 (d, J= 8.4Hz, 1H), 7.98 (d, J=8.3Hz, 1H), 7.71-7.69 (m, 3H), 7.34 (d, J=8.3Hz, 1H), 7.25 (s, 1H), 7.00 (d, J=7.3Hz, 1H), 5.94 (s, 1H), 3.74 (s, 3H), 2.68 (s, 3H), 1.98 (s, 3H)；13C NMR (75MHz,CDCl3)δ190.51,154.20,148.58,145.12,143.92,135.84, 134.20,128.40, 127.41,126.27,126.58,125.09,124.99,124.57,123.33,120.90, 120.48,119.68, 111.13,99.22,36.21,25.82,13.79；ESI-MS m/z:340.1calcd for C23H20N2O3[M+H]+341.1.
Embodiment 8
(E)-3- (1H- indoles-4- base)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.71 (s, 1H), 8.02 (d, J= 8.4Hz, 1H), 7.78 (d, J=8.3Hz, 1H), 7.63 (t, J=7.1Hz, 1H), 7.55 (s, 1H), 7.42 (t, J= 7.4Hz, 1H), 7.29 (d, J=8.0Hz, 1H), 7.26 (s, 1H), 7.22 (d, J=7.3Hz, 1H), 7.14 (dd, J= 13.3,5.6Hz,1H),7.08-7.01(m,1H),5.94(s,1H),2.71(s,3H),2.31(s,3H)；13C NMR(75MHz, CDCl3)δ198.58,157.80,147.58,146.13,144.91,136.89,135.29, 129.49,128.49, 127.27,126.53,126.08,124.90,124.67,123.37,121.20,120.48, 119.68,112.13, 100.22,24.81,12.79；ESI-MS m/z:326.1calcd for C22H18N2O [M+H]+327.1.
Embodiment 9
(E)-3- (6- methoxyl group-1H- indol-3-yl)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl- 1- ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,DMSO)δ8.14(s,1H),8.01(s, 2H),7.75 (d, J=7.2Hz, 1H), 7.63-7.52 (m, 2H), 7.41 (d, J=9.1Hz, 2H), 7.08 (s, 1H), 6.92 (dd, J= 8.7,2.1Hz,1H),3.83(s,3H),2.75(s,3H),2.30(s,3H)；13C NMR (75MHz,DMSO)δ187.69, 159.12,153.34,148.40,147.82,140.03,136.66,130.74, 130.01,129.44,128.48, 126.85,124.61,123.63,122.32,119.66,115.45,111.61,56.20, 25.82,13.59；ESI-MS m/ z:356.1calcd for C23H20N2O2[M+H]+357.1.
Embodiment 10
(E)-3- (3- amino-4-methoxyl phenyl)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- Ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.00 (d, J=8.5Hz, 1H), 7.64 (m, 2H), 7.39 (t, J=7.4Hz, 1H), 7.17 (d, J=9.8Hz, 1H), 6.97 (s, 1H), 6.84-6.56 (m, 3H), 3.79(s,3H),2.70(s,3H),2.28(s,3H)；13C NMR(75MHz, CDCl3)δ198.29,157.71,148.04, 147.56,147.05,146.18,135.72,134.76,129.35, 128.50,127.69,125.95,124.78, 123.32,121.43,119.44,115.79,109.56,76.93,76.50, 76.08,55.05,29.17,24.83；ESI- MS m/z:332.1calcd for C21H20N2O2[M+H]+333.1.
Embodiment 11
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- Ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.08 (d, J=8.5Hz, 1H), 7.76- 7.67 (m 2H), 7.47 (t, J=7.6Hz, 1H), 7.24 (s, 1H), 7.12-6.99 (m, 2H), 6.94-6.78 (m, 2H), 3.89(s,3H),2.77(s,3H),2.35(s,3H)；13C NMR(75MHz, CDCl3)δ198.19,157.71,147.54, 147.44,146.36,146.11,145.21,135.33,129.44, 128.39,128.07,126.03,124.75, 123.30,123.06,119.50,115.76,110.05,76.94,76.52, 76.10,55.45,24.71,12.31；ESI- MS m/z:333.1calcd for C22H18N2O[M+H]+334.1.
Embodiment 12
(E)-3- (the fluoro- 4- methoxyphenyl of 3-)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.08 (d, J=8.4Hz, 1H), 7.76- 7.69 (m, 2H), 7.48 (t, J=7.6Hz, 1H), 7.24 (s, 1H), 7.19 (dd, J=12.3,1.8 Hz, 1H), 7.09- 7.06 (m, 2H), 6.93 (t, J=8.5Hz, 1H), 3.90 (s, 3H), 2.78 (s, 3H), 2.35 (s, 3H)；13C NMR (75MHz,CDCl3)δ198.03,157.72,147.64,145.61,144.67,136.08, 129.43,128.64, 127.72,127.64,126.82,126.05,124.61,123.18,119.43,117.16, 116.91,112.58,55.73, 24.86,12.30；ESI-MS m/z:335.1calcd for C21H18FNO2 [M+H]+336.1.
Embodiment 13
(E)-3- (4- methoxyphenyl)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.01 (d, J=8.4Hz, 1H), 7.71- 7.57 (m, 2H), 7.39 (t, J=7.6Hz, 1H), 7.26 (d, J=8.8Hz, 2H), 7.17 (s, 1H), 7.04 (s, 1H), 6.82 (d, J=8.8Hz, 2H), 3.74 (s, 3H), 2.71 (s, 3H), 2.29 (d, J=1.0 Hz, 3H)；13C NMR(75MHz, CDCl3)δ198.22,160.18,157.72,147.60,146.22, 146.02,134.97,131.65,129.38, 128.56,127.28,125.98,124.74,123.29,119.44, 113.60,54.85,24.85,12.34；ESI-MS m/ z:317.1calcd for C21H19NO2[M+H]+318.1.
Embodiment 14
(E)-3- (3,4- Dimethoxyphenyl)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.01 (d, J=8.4Hz, 1H), 7.74- 7.55 (m, 2H), 7.39 (t, J=7.6Hz, 1H), 7.28-7.26 (m, 2H), 7.14 (d, J=13.8Hz, 1H), 7.04 (s, 1H), 6.82 (d, J=8.8Hz, 2H), 3.74 (s, 3H), 2.71 (s, 3H), 2.29 (d, J=1.0Hz, 3H)；13C NMR (75MHz,CDCl3)δ198.70,158.27,150.32,148.76, 148.10,146.95,146.48,135.67, 129.95,129.04,127.98,126.54,125.25,124.15, 123.77,119.95,113.22,110.90,55.95, 25.42,12.95；ESI-MS m/z:347.1calcd for C22H21NO3[M+H]+348.1.
Embodiment 15
(E)-3- (4- methyl mercapto phenyl)-2- methyl-1-(2- methylquinoline-4- base) propyl-2- alkenyl-1- ketone
The synthetic method of reference embodiment 6,1H NMR(300MHz,CDCl3) δ 8.08 (d, J=8.4Hz, 1H), 7.79- 7.66 (m, 2H), 7.49 (dd, J=11.2,4.0Hz, 1H), 7.30-7.19 (m, 5H), 7.11 (s, 1H), 2.78 (s, 3H), 2.48 (s, 3H), 2.36 (d, J=1.0Hz, 3H)；13C NMR(75MHz,CDCl3) δ198.72,158.25,148.09, 146.29,146.24,141.39,136.77,131.48,130.62,129.97, 129.08,127.61,126.80, 126.57,125.59,125.18,123.72,120.00,25.40,15.06,12.99； ESI-MS m/z:333.1calcd for C21H19NOS[M+H]+334.1.
Embodiment 16
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- chloroquinoline-4- base) propyl-2- alkenyl-1- ketone
A) indoles -2,3- diketone (10g, 68mmol) and malonic acid (10.6g, 102mmol) is dissolved in 80mL glacial acetic acid In, it after back flow reaction 12h, filters, filter cake uses acetone respectively, and ether is washed, dry 10.2 g of product, yield 79.3%；
B) previous step product (10.2g, 53.9mmol) is dissolved in 20mL phosphorus oxychloride, after back flow reaction 1h, rotation goes three Chlorethoxyfos pour into residue in ice water, with saturated sodium bicarbonate aqueous solution tune pH to 4-5, filter, washing, dry 2- chlorine Quinoline -4- formic acid 9.8g, yield 87.5%；
C) 2- chloroquinoline -4- formic acid (9.8g, 47mmol) is dissolved in 50mL methylene chloride, instills the DMF of catalytic amount, ice It is slowly dropped under the conditions of bath oxalyl chloride (7.9mL, 94mmol), methanol 20mL is added after reacting at room temperature 2h, continue to stir 1h back spin Solvent is removed, rear methylene chloride extraction (50mL × 3) is diluted with water, merges organic phase, saturated common salt washing, anhydrous sodium sulfate is done It is dry, it is concentrated to give 2- chloroquinoline -4- methyl formate 8.2g, yield 78.2%；By 2- methylquinoline -4- methyl formate (8.2g, It 37mmol) is dissolved in methanol, NaBH is added portionwise in condition of ice bath4(4.2g, 111mol) after being stirred at room temperature for 24 hours, will react drop Enter into saturated aqueous ammonium chloride, methylene chloride extraction (50mL × 3) after methanol is gone in rotation, merges organic phase, saturated salt solution It washes, anhydrous sodium sulfate is dry, is concentrated to give 2- chloroquinoline -4- methanol 5g, yield 70.4%；By 2- methylquinoline -4- methanol (5g, It 25.8mmol) is dissolved in 30mL DMSO, is added IBX (8g, 28.4mmol), be poured into water reaction solution after reacting at room temperature 2h, second Acetoacetic ester extracts (50mL × 3), merges organic phase, and 10% NaOH aqueous solution is washed three times, saturated common salt washing, anhydrous sodium sulfate It is dry, 2- chloroquinoline -4- formaldehyde 4.2g, yield 84% are obtained after concentration；2- methylquinoline -4- formaldehyde (4.2g, 22mmol) is molten The diethyl ether solution (15mL, 44mmol) of the ethylmagnesium bromide of 3mol/L, room temperature are slowly injected into anhydrous THF, under nitrogen protection It is diluted with water after reaction 2h, methylene chloride extracts (50mL × 3), merges organic phase, saturated common salt washing, and anhydrous sodium sulfate is done Dry, concentration rear pillar chromatography (PE/EA 2:1) obtains colorless oil 3.5g, yield 72.9%；Previous step product (2g, 9mmol) is molten In methylene chloride, addition, which is worn after 2h is stirred at room temperature in this Martin reagent (3g, 10.8mmol), to be diluted with water, methylene chloride extraction (50mL × 3), merging organic phase, saturated common salt washing, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE/EA 2:1) obtains 2- Chloro- 4- propiono quinoline 1.3g, yield 65.0%.
(d) the chloro- 4- propiono quinoline (75mg, 0.34mmol) of 2- is dissolved in 5mL ethyl alcohol, is separately added into MEM protection Isovanillin (99mg, 0.41mmol) and sodium hydrate particle (89mg, 1.7mmol) are diluted with water, dichloro after reacting at room temperature 2h Methane extracts (30mL × 3), merges organic phase, and saturated common salt washing, anhydrous sodium sulfate is dry, and concentration rear pillar chromatographs (PE/EA 5:1) obtain oily 108mg, yield 71.5%；The product is dissolved in 2mL ethyl alcohol, 2 drop concentrated hydrochloric acids are added, are used after return stirring 1h Saturated sodium bicarbonate aqueous solution neutralizes, and methylene chloride extracts (50mL × 3), merges organic phase, saturated common salt washing, anhydrous slufuric acid Sodium is dry, and concentration rear pillar chromatography (PE/EA 2:1) obtains product 55mg, yield 63.9%.1H NMR(300MHz, CDCl3)δ8.01 (d, J=8.4Hz, 1H), 7.78-7.63 (m, 2H), 7.48 (t, J=7.6Hz, 1H), 7.28 (s, 1H), 7.00 (s, 2H), 6.86–6.72(m,2H),5.67(s,1H),3.84(s,3H),2.29(s,3H)；13C NMR(75MHz,CDCl3)δ196.88, 149.93,149.39,148.15,148.00,147.59,145.54, 135.55,131.07,129.01,128.31, 127.74,125.49,124.36,124.01,120.21,116.07, 110.42,56.00,29.70；ESI-MS m/z: 353.1calcd for C22H21NO3[M+H]+354.1.
Embodiment 17
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- (dimethylamino) quinolyl-4) propyl-2- alkene Base -1- ketone
The chloro- 4- propiono quinoline (150mg, 0.68mmol) of 2- is dissolved in 2mL ethyl alcohol, be added 33% dimethylamine it is water-soluble Liquid (930 μ L, 6.8mmol) is diluted with water after 80 degree of tube sealing reaction 4h, and methylene chloride extracts (30mL × 3), merges organic phase, Saturated common salt washing, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE/EA 20:1) obtains 2- dimethylamino -4- propiono quinoline Quinoline 135mg, yield 86.5%.By the operation of embodiment 17 (d), product 84mg, yield 74% are obtained；1H NMR(300MHz, DMSO) δ 9.16 (s, 1H), 7.53 (d, J=8.1Hz, 1H), 7.49-7.36 (m, 1H), 7.32 (d, J=7.9Hz, 1H), 7.07 (d, J=7.3 Hz, 1H), 7.02 (s, 1H), 6.96 (s, 1H), 6.90 (s, 1H), 6.82 (dd, J=16.2,8.1Hz, 2H),3.69 (s,3H),3.08(s,6H),2.17(s,3H)；13C NMR(75MHz,DMSO)δ198.74,156.79, 149.64,148.20,147.51,146.81,146.47,134.80,130.14,128.04,126.84,125.25, 123.62,122.32,119.77,117.40,112.34,107.92,56.01,38.13,13.07；ESI-MS m/z: 362.1calcd for C22H22N2O3[M+H]+363.1.
Embodiment 18
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2 methoxy quinoline-4- base) propyl-2- alkenyl- 1- ketone
The chloro- 4- propiono quinoline (150mg, 0.68mmol) of 2- is dissolved in 2mL methanol, addition sodium methoxide (180mg, 3.4mmol), nitrogen protection, return stirring are diluted with water afterwards after reaction, and methylene chloride extracts (30mL × 3), are associated with Machine phase, saturated common salt washing, anhydrous sodium sulfate is dry, and concentration rear pillar chromatography (PE/EA 20:1) obtains 2- dimethylamino -4- propionyl Base quinoline 130mg, yield 88.4%.By the operation of embodiment 17, yellow solid 47mg is obtained；1H NMR(300MHz,CDCl3)δ 7.90 (d, J=8.4Hz, 1H), 7.68-7.62 (m, 2H), 7.42-7.31 (m, 1H), 7.26 (s, 1H), 7.14 (s, 1H), 7.05 (d, J=1.8Hz, 1H), 6.91-6.77 (m, 3H), 5.62 (s, 1H), 4.11 (s, 3H), 3.91 (s, 3H), 2.34 (s, 3H)；13C NMR(75MHz,CDCl3)δ198.29,161.48,148.95,147.78,146.95,146.86,145.47, 135.64,130.02,128.59,127.64,125.36,124.68,123.77,122.61,116.10,111.42, 110.39,55.95,53.65,12.83；ESI-MS m/z:348.1calcd for C21H19NO4[M+H]+349.1.
Embodiment 19
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- (pyrrolidin-1-yl) quinolyl-4) propyl- 2- alkenyl -1- ketone
According to the operation of embodiment 17, yellow solid is obtained；1H NMR(300MHz,CDCl3) δ 7.76 (d, J=8.5Hz, 1H), 7.61-7.49 (m, 2H), 7.18 (s, 1H), 7.16-7.07 (m, 1H), 7.05 (s, 1H), 6.85 (q, J=8.2Hz, 2H),6.66(s,1H),3.89(s,3H),3.62(s,4H),2.32(s,3H),2.03(s, 4H)；13C NMR(75MHz, CDCl3)δ199.38,154.69,148.62,147.99,147.51,146.68, 145.65,135.59,129.97, 128.67,126.23,125.28,123.65,121.95,119.99,116.25, 110.52,108.61,55.94,47.00, 25.53,12.79；ESI-MS m/z:388.2calcd for C24H24N2O3 [M+H]+389.1.
Embodiment 20
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- morpholine base quinolyl-4) propyl-2- alkene Base -1- ketone
According to the operation of embodiment 17, yellow solid is obtained；1H NMR(300MHz,CDCl3) δ 7.76 (d, J=8.3Hz, 1H), 7.59-7.53 (m, 2H), 7.22 (t, J=7.5Hz, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.90 (s, 1H), 6.89-6.80 (m, 2H), 5.68 (s, 1H), 3.91 (s, 3H), 3.85 (d, J=5.1Hz, 4H), 3.73 (d, J=5.1Hz, 4H),2.34(s,3H)；13C NMR(75MHz,CDCl3)δ199.17,156.49, 148.11,147.97,147.78, 146.78,145.49,135.67,130.12,128.65,127.11,125.14, 123.75,123.29,120.70, 116.08,110.42,107.50,66.82,55.97,45.48,12.83；ESI-MS m/z:404.2calcd for C24H24N2O4[M+H]+405.2.
Embodiment 21
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- hydroxymethyl quinoline-4- base) propyl-2- alkenyl- 1- ketone
2- methyl -4- propiono quinoline (300mg, 1.52mmol) is dissolved in methylene chloride, 75% m-chloro mistake is added Oxybenzoic acid (450mg, 1.98mmol), room temperature reaction, after reaction plus saturation sodium thiosulfate solution, methylene chloride It extracts (30mL × 3), merges organic phase, be saturated NaHCO3Aqueous solution is washed, and saturated common salt washing, anhydrous sodium sulfate is dry, concentration Obtain 2- methyl -4- propiono quinoline N oxide；N oxide is dissolved in aceticanhydride and is stirred in 100 degree, after reaction, spins off vinegar Acid anhydride, residue are dissolved in 10mL methanol, and the methanolic ammonia solution of 2mL is added, and concentration rear pillar chromatography (PE/EA2:1) obtains after reacting 1h 2- methylol -4- propiono quinoline 200mg, three step yields 67.9%.By the synthetic method of embodiment 17, yellow solid is obtained；1H NMR(300MHz,CDCl3) δ 8.07 (d, J=8.5Hz, 1H), 7.69 (dd, J=12.7,8.4Hz, 2H), 7.51-7.42 (m, 1H), 7.20 (d, J=1.5Hz, 1H), 6.97 (s, 2H), 6.75 (d, J=8.7Hz, 2H), 4.88 (s, 2H), 4.69 (s, 1H),3.83(s,3H),2.29(s,3H)；13C NMR(75MHz, CDCl3)δ198.49,158.39,147.89,147.17, 147.08,145.54,135.77,130.31,129.04, 128.46,127.19,125.49,124.95,124.02, 123.80,116.48,116.09,110.42,64.26,55.98, 29.70；ESI-MS m/z:349.1calcd for C21H19NO4[M+H]+350.1.
Embodiment 22
(E) -4- (3- (3- hydroxyl -4- methoxyphenyl) -2- methylacryloyl) quinoline -2- formaldehyde
The product (130mg, 0.52mmol) of embodiment 21 is dissolved in DMSO, is added IBX (100mg, 0.63mmol), 30min is stirred at room temperature, is diluted with water, ethyl acetate extracts (30mL × 3), washes (30 mL × 3), and saturated common salt washing is primary, Dry, concentration rear pillar chromatography (PE/EA 2:1) obtains product 100mg, yield 76.9%；1H NMR(300MHz,CDCl3)δ10.18 (s, 1H), 8.25 (d, J=8.4Hz, 1H), 7.90 (s, 1H), 7.86-7.73 (m, 2H), 7.62 (dd, J=11.2,4.1Hz, 1H),6.95(s,2H),6.77- 6.72(m,2H),5.71(s,1H),3.82(s,3H),2.30(s,3H)；13C NMR (75MHz,CDCl3)δ 197.83,193.27,151.69,148.23,147.93,147.63,147.40,145.51, 135.73,130.92, 130.88,130.06,128.35,127.37,125.71,123.87,116.10,115.47, 110.40,55.97,29.70； ESI-MS m/z:347.1calcd for C21H17NO4[M+H]+348.1.
Embodiment 23
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(quinolyl-4) propyl-2- alkenyl-1- ketone
By 4- propiono quinoline according to the method for embodiment 6, white solid is obtained；1H NMR(300MHz, CDCl3)δ8.88 (d, J=4.3Hz, 1H), 8.11 (d, J=8.5Hz, 1H), 7.73 (d, J=8.0Hz, 1H), 7.66 (dd, J=11.2, 4.1Hz, 1H), 7.47 (dd, J=11.2,4.0Hz, 1H), 7.28 (d, J=4.3Hz, 1H), 7.00-6.90 (m, 2H), 6.82-6.74(m,2H),3.80(s,3H),2.28(s,3H)；13C NMR(75 MHz,CDCl3)δ198.44,149.27, 148.30,148.14,147.22,146.51,145.86,135.69, 130.09,129.57,128.40,127.57, 125.53,123.62,119.20,116.43,110.61,55.94,29.70, 12.87；ESI-MS m/z:319.1calcd for C20H17NO3[M+H]+320.1.
Embodiment 24
(E) -3- (3- hydroxyl -4- methoxyphenyl) -1- (2- ((4- methoxy-benzyl) amino) quinolyl-4) -2- first Base propyl -2- alkenyl -1- ketone
By 1- (2- chloroquinoline -4- base) propane -1- alcohol (100mg, 0.45mmol) in ethyl alcohol, 4-Methoxybenzylamine is added (74mg, 0.54mmol) 150 DEG C of heating in tube sealing for 24 hours, are spin-dried for ethyl alcohol, and column chromatographs (PE/EA 3:1) and obtains 1- (2- ((4- methoxy Base phenyl) amino) quinolyl-4) propane -1- alcohol 150mg；The product (150 mg, 0.46mmol) is dissolved in DMSO, is added IBX (150mg, 0.56mmol), is stirred at room temperature 30min, is diluted with water, and ethyl acetate extracts (30mL × 3), washing (30mL × 3), saturated common salt washing is primary, and anhydrous sodium sulfate is dry, is concentrated to give 2- (4- methoxybenzyl amino) -4- propiono quinoline, directly It throws in next step；By previous step product according to the method for embodiment 17, yellow solid 67mg is obtained；1H NMR(300MHz, CDCl3)δ 7.68 (d, J=8.4Hz, 1H), 7.51-7.40 (m, 2H), 7.23-7.18 (s, 2H), 7.10 (dd, J=11.3,3.8Hz, 1H),7.05(s,1H),6.93(s,1H),6.77-6.74(m,4H),6.49(s,1H),5.14 (s,1H),4.54(s,2H), 3.79(s,3H),3.68(s,3H),2.20(s,3H)；13C NMR(75MHz, CDCl3)δ198.83,158.93,155.68, 148.14,147.94,147.77,146.70,145.57,135.53, 130.93,130.12,129.09,128.61, 126.47,125.32,123.71,122.81,120.96,116.24, 114.09,110.50,109.59,55.94,55.29, 45.40,29.71；ESI-MS m/z:354.1calcd for C28H26N2O4[M+H]+355.2.
Embodiment 25
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- (methylamino) quinolyl-4) propyl-2- alkene Base -1- ketone
According to the synthetic method of embodiment 24,1H NMR(300MHz,CDCl3) δ 7.75 (d, J=8.9Hz, 1H), 7.66- 7.60 (m, 2H), 7.18 (d, J=8.2Hz, 1H), 7.15 (s, 1H), 7.04 (d, J=1.7Hz, 1H), 6.89 (dd, J= 8.4,1.7Hz, 1H), 6.83 (d, J=8.4Hz, 1H), 6.59 (s, 1H), 5.33 (s, 1H), 3.89 (s, 3H), 3.06 (s, 3H),2.31(s,3H)；13C NMR(75MHz,CDCl3)δ198.82,156.54, 148.07,147.67,146.84, 145.67,135.49,130.26,128.58,125.89,125.36,123.68, 122.73,120.67,116.30, 110.55,109.13,55.96,28.78,12.78；ESI-MS m/z:348.1 calcd for C21H20N2O3[M+H]+ 349.1.
Embodiment 26
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- (ethylamino) quinolyl-4) propyl-2- alkene Base -1- ketone
According to the synthetic method of embodiment 24,1H NMR(300MHz,CDCl3) δ 7.72 (d, J=8.5Hz, 1H), 7.64- 7.49 (m, 2H), 7.18-7.14 (m, 2H), 7.04 (d, J=1.8Hz, 1H), 6.90 (dd, J=8.5,1.7Hz, 1H), 6.84 (d, J=8.4Hz, 1H), 6.58 (s, 1H), 4.90 (s, 1H), 3.89 (s, 3H), 3.60-3.48 (m, 2H), 2.31 (s, 3H), 1.27(m,3H)；13C NMR(75MHz,CDCl3)δ198.94, 155.95,148.10,147.90,146.74,145.68, 135.52,130.12,128.61,126.19,125.32, 123.63,122.62,120.77,116.34,110.57, 109.21,55.95,36.67,29.70,14.95；ESI-MS m/z:362.2calcd for C22H22N2O3[M+H]+363.2.
Embodiment 27
(E)-3- (3- hydroxyl-4- methoxyphenyl)-2- methyl-1-(2- (cyclopropylamino) quinolyl-4) propyl-2- alkene Base -1- ketone
According to the synthetic method of embodiment 24,1H NMR(300MHz,CDCl3) δ 7.62 (d, J=8.5Hz, 1H), 7.49- 7.43 (m, 2H), 7.19-7.12 (m, 1H), 7.10 (s, 1H), 6.95 (s, 2H), 6.90-6.83 (m, 1H), 6.79 (d, J= 8.5Hz,1H),5.47(s,1H),3.84(s,3H),2.62-2.49(m,1H),2.28 (s,3H),1.18(s,4H)；13C NMR (75MHz,CDCl3)δ198.98,157.43,148.16,147.79, 146.86,145.75,135.56,130.27, 128.62,125.99,125.40,123.51,122.95,121.10, 116.45,110.60,107.84,55.96,29.70, 24.01,12.82；ESI-MS m/z:374.2calcd for C23H22N2O3[M+H]+375.2.
Embodiment 28
(E) -4- (3- (3- hydroxyl -4- methoxyphenyl) -2- methylacryloyl) quinoline -2- Ethyl formate
The chloro- 4- acetylquinoline (500mg, 2.25mmol) of 2- is dissolved in 10mL anhydrous DMF, nitrogen protection, respectively plus Enter Ph3(PPh3)4(260mg, 0.25mmol), Zn (CN)2(320mg, 2.7mmol) after 120 DEG C of reaction 2h, is diluted with water, second Acetoacetic ester extracts (30mL × 3), washes (30mL × 3), and saturated common salt washing is primary, dry, and concentration rear pillar chromatographs (PE/EA 30:1) obtain 2- cyano -4- propiono quinoline 415mg, yield 87%；By 2- cyano -4- propiono quinoline (75mg, 0.36mmol), the isovanillin (105mg, 0.43mmol) and sodium hydrate particle (72mg, 1.8mmol) of MEM protection, room temperature It is diluted with water after reaction 2h, ethyl acetate extracts (30mL × 3), and saturated common salt washing is primary, dry, concentration rear pillar chromatography (PE/EA 2:1) obtains 50mg oil product and obtains product 46mg, two step yields 33% by the operation of embodiment 17；1H NMR (300MHz,CDCl3) δ 8.26 (d, J=8.5Hz, 1H), 8.04 (s, 1H), 7.75 (d, J=8.3Hz, 1H), 7.73-7.64 (m, 1H), 7.54 (d, J=8.1Hz, 1H), 7.03-6.87 (m, 2H), 6.82-6.66 (m, 2H), 6.27 (s, 1H), 4.44 (q, J=7.1Hz, 2H), 3.75 (s, 3H), 2.27 (s, 3H), 1.36 (t, J=7.1Hz, 3H)；13C NMR(75MHz, CDCl3)δ197.92,164.92,148.18, 147.80,147.63,147.57,147.39,145.63,135.56, 130.99,130.68,129.43,128.30, 126.51,125.29,123.90,119.05,116.29,110.51,62.47, 55.90,29.67,14.29；ESI-MS m/z:391.1calcd for C23H21NO5[M+H]+392.1.
Embodiment 29
(E) -4- (3- (3- hydroxyl -4- methoxyphenyl) -2- methylacryloyl) quinoline-2-one
The chloro- 4- propiono quinoline (100mg, 0.46mmol) of 2- is dissolved in the mixed solution of H2O:AcOH 5:1, is added Methane sulfinic acid sodium (92mg, 0.92mmol), 90 DEG C are stirred overnight, and are adjusted to neutrality, second with saturated sodium bicarbonate after reaction Acetoacetic ester extracts (30mL × 3), and saturated common salt washing is primary, dry, is concentrated to give 2- hydroxyl -4- propiono quinoline crude product 80mg； By the product method of embodiment 17, yellow solid 80mg, three step yields 52.6% are obtained；1H NMR(300MHz,CDCl3)δ 12.71 (s, 1H), 7.44 (s, 2H), 7.39 (d, J=8.2Hz, 1H), 7.23 (s, 1H), 7.12 (s, 1H), 7.02 (s, 1H), 6.84 (d, J=7.8 Hz, 1H), 6.76 (d, J=8.1Hz, 1H), 6.62 (s, 1H), 6.13 (s, 1H), 3.81 (s, 3H), 2.24(s,3H)；13C NMR(75MHz,CDCl3)δ197.04,163.73,151.34,148.13,147.27,145.59, 138.70, 134.95,131.36,128.37,126.12,124.05,123.28,119.17,118.02,116.77, 116.31, 110.52,55.97,29.70；ESI-MS m/z:335.1calcd for C20H17NO4[M+H]+336.1.
Embodiment 30
(E) -2- methoxyl group -5- (2- methyl -3- (2- methylquinoline -4- base) -3- oxopropyl -1- alkenyl -1- base) benzene Base disodium hydrogen phosphate
Embodiment 11 (500mg, 1.5mmol) is dissolved in methylene chloride, be respectively dropped into phosphorus oxychloride (697 μ L, 7.5mmol) and pyridine (605 μ L, 7.5mmol), after 15h is stirred at room temperature, saturated aqueous sodium carbonate is added and continues to stir 2h, instead Liquid is answered to be concentrated, C18 column chromatographs product 250mg, yield 40.5%.1H NMR (300MHz,DMSO-d6) δ 9.08 (d, J= 8.5Hz, 1H), 7.86-7.77 (m 2H), 7.52 (t, J=7.6 Hz, 1H), 7.25 (s, 1H), 7.12-6.99 (m, 2H), 6.84-6.99(m,2H),3.88(s,3H),2.67(s, 3H),2.25(s,3H)；13C NMR(75MHz,CDCl3)δ199.19, 156.72,148.52,147.44, 146.26,145.91,145.01,135.23,139.44,128.39,128.07, 126.03,124.75,123.30, 123.06,119.50,115.76,110.05,76.94,76.52,76.10,55.45, 24.71,12.31；ESI-MS m/z: 457.1calcd for C21H18NO6PNa2[M-Na]-434.1.
31 tablet of embodiment
Above-mentioned formula is taken, is prepared into tablet with conventional method.
Here is the pharmacological results of part of compounds of the present invention:
Antiproliferative experiment
1. experimental method
2. cell dissociation, count, be made concentration be 5 × 104The cell suspension of a/mL, 100 μ l are added in every hole in 96 orifice plates Cell suspension (every hole 5 × 103A cell)；
3.96 orifice plates are placed in 37 DEG C, 5%CO2It is cultivated 24 hours in incubator；
4. diluting drug to required concentration with complete medium, the 100 corresponding pastille culture mediums of μ L are added in every hole；
5.96 orifice plates are placed in 37 DEG C, 5%CO2It is cultivated 72 hours in incubator；
6.MTT method:
1) 96 orifice plates are subjected to MTT dyeing, λ=490nm measures OD value.
2) 20 μ L MTT (5mg/mL) are added in every hole, continue culture 4 hours in incubator；
3) culture medium is discarded, every hole is added 150 μ L DMSO dissolution, mixes gently within shaking table 10 minutes；The nm of λ=490, enzyme mark Instrument reads the OD value in every hole.
6. calculating inhibiting rate.
2. experimental result
IC of 1 the compounds of this invention of table to 5 kinds of human cancer cell's strain antiproliferative activities50It is worth (μM)
Conclusion: it can be found that embodiment 11 all shows optimal anti-tumor activity for five kinds of cell strains from table, Activity is better than positive control CA-4 and cis-platinum embodiment.
Here is the experiment of the external microtubulin-resisting aggregation of part of compounds
1. experimental method
Compound is configured to mother liquor according to corresponding requirements, is diluted to after final concentration according to multiple for follow-up test.Concentration 5 are set as, each concentration biology is repeated 3 times.The amount of 2mg/mL tubulin (cytoskeleton) is resuspended in PEM Buffer [80mM PIPES (pH6.9), 0.5mM EGTA, 2mM MgCl2With 15% glycerol] in, then on ice with compound Or solvent DMSO preincubate 5 minutes.Before detection tubulin polymerization reaction, the PEG containing GTP is added to final concentration of 3mg/mL.By Berthold LB941 micro-pore plate type multi-function microplate reader, absorbance is detected in 340nm after 30 minutes.Pass through Blank control group is set, and the IC of different compounds is calculated in Graphpad50, as a result by μM as unit of.
2. experimental result
The pharmacological results of the ira vitro tube albumen aggregation of the part of compounds of the present invention of table 2:
Embodiment Tubulin is inhibited to assemble IC50
3 2.58
7 2.56
10 1.87
11 1.78
12 2.25
17 2.23
18 2.09
21 2.22
23 2.45
25 1.88
26 2.09
27 2.49
30 2.47
CA-4 2.88
Conclusion: surveyed compound all has preferable inhibition tubulin polymerization effect as can be seen from the table, is better than sun Property medicine CA-4.
Here is the internal anti-tumor experiment of part of compounds
1. experimental method
It is provided by Shanghai Slac Experimental Animal Co., Ltd., week old is 3 weeks, the female Balb/c of weight 12-16g Nude mice 70.The Murine Hepatoma22 cell of culture is collected, is counted, adjustment makes concentration of cell suspension 1.5 × 107A/ml, in naked small The subcutaneous every inoculation 0.1ml of armpit on the right side of mouse.With the diameter of vernier caliper measurement transplanted tumor in nude mice, after inoculated tumour cell 7 days, Tumour is long to 50-75mm3When, nude mice is only randomly divided into 8 groups by every group 10.Derivative is dissolved in DMSO, then instills poloxamer mother Liquid, finally plus physiological saline is to required dosage.Final concentration of 1%, the poloxamer of DMSO final concentration of 2%.Each group nude mice is given Equivalent solvent is injected intraperitoneally in medicine, model group, and injection 1 time, continues 21 days daily；20 mg/kg of positive controls tail vein injection is suitable Platinum, injection 1 time, continues 21 days daily；Experimental group is injected intravenously 20mg/kg embodiment 10,11,18,23,25,30.Note daily It penetrates 1 time, continues 21 days；Administration put to death nude mice after 21 days, strips tumor mass by operation, weighs.Calculate Tumor growth inhibition Rate (%) is analyzed with 17.0 pairs of results of SPSS, carries out statistical analysis processing with t inspection between group, calculation formula is such as Under:
2. experimental result
The internal anti-tumor activity of 3 section Example of table
Conclusion: embodiment 10,11,18,23,25,30 shows preferably to inhibit tumour growth as can be seen from the table Activity, and its inhibiting rate is above positive control cis-platinum group and CA-4 group, and compared to cis-platinum group, body of the embodiment to mouse Ghost image is rung preferably, is illustrated compared to cis-platinum, and the toxicity of compound in embodiment is smaller.

Claims (10)

1.一种通式I所示的喹啉取代查尔酮类化合物、其可药用的盐：1. a quinoline substituted chalcone compound shown in general formula I, its pharmaceutically acceptable salt: 其中，R1选自氢、低级烷烃、羟基、甲氧基、卤素、氰基、酯基、酰胺基、羧基、仲氨基、叔氨基、羟甲基或醛基；Wherein, R 1 is selected from hydrogen, lower alkane, hydroxyl, methoxy, halogen, cyano, ester, amide, carboxyl, secondary amino, tertiary amino, methylol or aldehyde; R2选自氢、低级烷烃、卤素、甲氧基、氰基、酯基、酰胺基或羧基；R 2 is selected from hydrogen, lower alkane, halogen, methoxy, cyano, ester, amide or carboxyl; R3选自甲氧基、甲硫基、氰基、低级烷烃、卤素、酯基或不同取代的氨基；R 3 is selected from methoxy, methylthio, cyano, lower alkane, halogen, ester or differently substituted amino; R4选自羟基、氨基、氟、磷酸酯基、磷酸二钠、糖苷、硼酸基、氨基酸酰胺基或(CH2)1-6OH。R 4 is selected from hydroxyl, amino, fluorine, phosphate, disodium phosphate, glycoside, boronic acid, amino acid amide or (CH 2 ) 1-6 OH. 2.根据权利要求1所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R2为氢或甲基。2 . The quinoline-substituted chalcone compound and its pharmaceutically acceptable salt according to claim 1 , wherein R 2 is hydrogen or methyl. 3 . 3.根据权利要求1所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R3为甲氧基或甲硫基。3 . The quinoline-substituted chalcone compound and its pharmaceutically acceptable salts according to claim 1 , wherein R 3 is methoxy or methylthio. 4 . 4.根据权利要求1所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R4为羟基、氨基、氟或磷酸二钠。4. The quinoline-substituted chalcone compound and its pharmaceutically acceptable salt according to claim 1, wherein R 4 is hydroxyl, amino, fluorine or disodium phosphate. 5.一种通式II所示的喹啉取代查尔酮类化合物、其可药用的盐：5. a quinoline substituted chalcone compound shown in general formula II, its pharmaceutically acceptable salt: 其中，R1选自氢、低级烷烃、羟基、甲氧基、卤素、氰基、酯基、酰胺基、羧基、仲氨基、叔氨基、羟甲基或醛基；Wherein, R 1 is selected from hydrogen, lower alkane, hydroxyl, methoxy, halogen, cyano, ester, amide, carboxyl, secondary amino, tertiary amino, methylol or aldehyde; R2选自氢、低级烷烃、卤素、甲氧基、氰基、酯基、酰胺基或羧基；R 2 is selected from hydrogen, lower alkane, halogen, methoxy, cyano, ester, amide or carboxyl; R5选自氢、低级烷烃、甲氧基、羟甲基、芳香或脂肪取代甲酰基；R 5 is selected from hydrogen, lower alkane, methoxy, hydroxymethyl, aromatic or aliphatic substituted formyl; 烯基取代的位置在吲哚3位、4位、5位、6位或7位。The position of alkenyl substitution is at the 3, 4, 5, 6 or 7 position of the indole. 6.根据权利要求5所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，R2为氢或甲基；R5为氢或低级烷烃。6 . The quinoline-substituted chalcone compound and its pharmaceutically acceptable salt according to claim 5 , wherein R 2 is hydrogen or methyl; R 5 is hydrogen or lower alkane. 7 . 7.根据权利要求5所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，烯基取代的位置优选吲哚3位，4位，5位。7 . The quinoline-substituted chalcone compound and its pharmaceutically acceptable salt according to claim 5 , wherein the positions of the alkenyl substitution are preferably indole 3-position, 4-position and 5-position. 8 . 8.根据权利要求1-7中任一所述的喹啉取代查尔酮类化合物、其可药用的盐，其特征在于，所述喹啉取代查尔酮类化合物选自以下1-30所示的化合物：8. The quinoline-substituted chalcone compound and its pharmaceutically acceptable salt according to any one of claims 1-7, wherein the quinoline-substituted chalcone compound is selected from the following 1-30 Compounds shown: 9.一种药物组合物，其中含有治疗有效量的权利要求1-7中任一所述的喹啉取代查尔酮类化合物和/或其可要用的盐，及药学上可接受的载体。9. a pharmaceutical composition, which contains the quinoline-substituted chalcone compound and/or its available salt of any one of claims 1-7 in a therapeutically effective amount, and a pharmaceutically acceptable carrier . 10.权利要求1-7中任一所述的喹啉取代查尔酮类化合物和/或其可要用的盐在制备治疗肿瘤以及通过抑制微管蛋白活性来治疗其他疾病或病症的药物中的应用。10. The quinoline-substituted chalcone compounds described in any one of claims 1-7 and/or their available salts are used in the preparation of medicines for treating tumors and treating other diseases or conditions by inhibiting tubulin activity Applications.
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CN114031563A (en) * 2021-12-01 2022-02-11 武汉科技大学 Cyclobutylquinoxaline compound and application thereof
CN116253712A (en) * 2023-03-27 2023-06-13 昆山市第一人民医院 5,6, 7-trimethoxy-2, 3-dihydroquinoline compound, pharmaceutical composition and application

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