CN105985376A - [2-(1H)-quinolinone-3-yl]aminomethylphosphonate, and preparation method and application thereof - Google Patents
[2-(1H)-quinolinone-3-yl]aminomethylphosphonate, and preparation method and application thereof Download PDFInfo
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Abstract
The invention relates to [2-(1H)-quinolinone-3-yl]aminomethylphosphonate represented by a chemical structural formula I, or a salt thereof. In the formula, R is selected from C1-C2 alkyl and C3-C4 straight-chain alkyl or branched-chain alkyl; X1 and X2 are selected from hydrogen, deuterium and C1-C2 alkyl; X3 and X7 are selected from hydrogen, deuterium, C1-C2 alkyl, fluoro, chloro, bromo, iodo and nitro; X4 and X6 are selected from hydrogen, deuterium and C1-C2 alkyl; X5 is selected from hydrogen, deuterium, C1-C2 alkyl and nitro; and n=0 or 1. The invention also relates to an application of [2-(1H)-quinolinone-3-yl]aminomethylphosphonate or the salt thereof in preparing neuraminidase inhibitors.
Description
Technical field
The present invention relates to the preparation and application of a class noval chemical compound；The specifically preparation of [2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester and the application as influenza virus neuraminidase inhibitor.
Background technology
Bird flu virus (avian influenza virus, AIV) belongs to influenza A virus, can be divided into 16 H (H1-H16) hypotype and 9 N (N1-N9) hypotype, in the numerous hypotype of influenza A virus, H5And H7For high pathogenic avian influenza virus.So far find that the avian influenza virus subtype of energy direct infection people has H5N1、H7N2、H7N3、H7N7、H9N2、H10N7、H7N9And in December, 2013 is found that new bird flu H in China Jiangxi10N9Hypotype.The Symptoms of these hypotypes is each different, mainly can show as respiratory symptom, conjunctivitis, even dead.The most highly pathogenic H5N1The new bird flu H that hypotype and in March, 2013 find on human body first7N9Hypotype is the most noticeable.
1997, find the H of the energy direct infection mankind first in Hong Kong5N1Hypotype.By the end of in July, 2014, the whole world reports people altogether and infects highly pathogenic H5N1Bird flu 667 example, wherein dead 393 examples.Case is distributed in 16 countries, and wherein, China is found that 45 examples, dead 30 examples.Most people infects H5N1Bird flu case is youngster and child.The H of 2009 outbursts1N1Influenza virus, result in global high speed and propagates, Global Health constitutes serious threat.By the end of in December, 2014 World Health Organization (WHO) (World Health Organization, the WHO) H that announces1N1Influenza makes a definite diagnosis people more than 1,310,000, dead people more than 14000.In March, 2013, China finder first infects H7N9Bird flu case, the new strain of bird flu hypotype found first for the whole world.End on January 25th, 2015, the H that World Health Organization (WHO) announces7N9Bird flu makes a definite diagnosis 494 people, dead 221 people.
Anti-influenza virus medicament is broadly divided into two classes: M2 inhibitors of ion channels and NA inhibitor.M2 inhibitors of ion channels, because being easily generated drug resistance, shows serious side effects to gastrointestinal tract and central nervous system, and only effective to A type, and clinical practice is extremely restricted.And the NA inhibitor anti-A that to be a class the newest, Type B influenza virus medicine, it is by adhering to the glycoprotein being newly formed virion NA surface, stops the virus of host cell release new, and increases new virus self assemble, reduces its diffusibility and infectivity.Therefore, NA inhibitor becomes the emphasis of current Tamiflu research.Up to the present, the anti-influenza virus medicament listed as neuraminidase inhibitor mainly has zanamivir (Zanamivir), GS-4104 (Oseltamivir) and Peramivir (Peramivir).
2011, the Academia Sinica of TSRL Inc. of the U.S. and TaiWan, China modifies on the architecture basics of zanamivir, separately design and synthesized a series of zanamivir L-threonine derivatives of high therapeutic index and zanamivir phosphonic acid ester medicine, this two classes medicine also has significant NA inhibitory action, it is possible to as the medicine of influenza.
The neuraminic acid enzyme inhibition activity of a large amount of compounds is studied by drug research worker in recent years.Chinese invention patent (CN101570521B) describes the 4-tert-butyl group-6-phenyl-2-amino-6H-1, the preparation method of 3-thiazine salt and be pharmaceutically used for preparing influenza virus neuraminidase inhibitor.
Chinese invention patent (CN101891705B；CN102204914B) respectively describing 4-alkyl-6-aryl-2-acylamino--1,3-thiazine-5-formic acid esters and 4-alkyl-6-aryl-5-acetyl-1,3-thiazine are as the application preparing neuraminidase inhibitor.
Summary of the invention
It is an object of the invention to provide [2-(1H)-quinolinone-3-base] the AminomethylphosphoniAcid Acid ester shown in chemical constitution formula I or its salt:
R is selected from: C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；X1、X2It is selected from: hydrogen, deuterium, C1～C2Alkyl；X3、X7It is selected from: hydrogen, deuterium, C1～C2Alkyl, fluorine, chlorine, bromine, iodine or nitro；X4、X6It is selected from: hydrogen, deuterium, C1～C2Alkyl；X5It is selected from: hydrogen, deuterium, C1～C2Alkyl or nitro；N=0,1；Salt is selected from: hydrochlorate, hydrobromate, phosphate, sulfate, nitrate, nitrate, mesylate, benzene sulfonate, tosilate, malate, lactate, succinate or butene dioic acid salt.
[2-(1H)-quinolinone-3-base] the AminomethylphosphoniAcid Acid ester that it is an object of the invention to provide is selected from following compounds:
Wherein, R is selected from: C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl.
[2-(1H)-quinolinone-3-base] the AminomethylphosphoniAcid Acid ester that it is an object of the invention to provide is selected from: [2-(1H)-quinolinone-3-base] phenylaminomethyl diethyl phosphonate, [2-(1H)-quinolinone-3-base] benzyl AminomethylphosphoniAcid Acid diethylester, [2-(1H)-quinolinone-3-base]-2-methylbenzene AminomethylphosphoniAcid Acid diethylester, [2-(1H)-quinolinone-3-base]-2,4-dinitro benzene AminomethylphosphoniAcid Acid diethylester or [2-(1H)-quinolinone-3-base]-2-chloro-4-nitroanilines methylphosphonic acid diethylester.
Object of the present invention is to provide the preparation method of [2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester, it is characterised in that its preparation reaction is as follows:
Wherein, R is selected from: C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；X1、X2It is selected from: hydrogen, deuterium, C1～C2Alkyl；X3、X7It is selected from: hydrogen, deuterium, C1～C2Alkyl, fluorine, chlorine, bromine, iodine or nitro；X4、X6It is selected from: hydrogen, deuterium, C1～C2Alkyl；X5It is selected from: hydrogen, deuterium, C1～C2Alkyl or nitro；N=0,1；Salt is selected from: hydrochlorate, hydrobromate, phosphate, sulfate, nitrate, nitrate, mesylate, benzene sulfonate, tosilate, malate, lactate, succinate or butene dioic acid salt.
Object of the present invention is to provide [2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester or the application in preparing neuraminidase inhibitor of its salt.
The present invention compared with prior art has the advantage that
The present invention is prepared for [2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester or its salt first；It has resisiting influenza virus neuraminidase activity.
Detailed description of the invention
Following example are intended to illustrate rather than limitation of the invention further.
Embodiment 1
The preparation of [2-(1H)-quinolinone-3-base] phenylaminomethyl diethyl phosphonate
(1) preparation of 3-formoxyl-2-(1H)-quinolinone
98ml POCl3It is added dropwise in 7ml DMF, stirs 30min at 0～5 DEG C, add 50mmol acetanilide, be warming up to 90 DEG C, react 16h.Cooling, reaction is also poured in 500ml frozen water, and sucking filtration washes with water.Solid adds the acetum of 200ml 70%, 95 DEG C of reaction 4h.Cooling reactant liquor, separates out fluffy solid, filters, and washing is dried to obtain 3-formoxyl-2-(1H)-quinolinone, yield 73.8%, m.p.303～305 DEG C.
(2) preparation of [2-(1H)-quinolinone-3-base] phenylaminomethyl diethyl phosphonate
2mmol 3-formoxyl-2-(1H)-quinolinone, 2mmol aniline and 15ml toluene; 10min is stirred at room temperature, adds 2mmol diethyl phosphite, backflow 4h (TLC monitoring); cooling; partial solvent is steamed in reactant liquor rotation, separates out solid, filters; washing with alcohol; it is dried [2-(1H)-quinolinone-3-base] phenylaminomethyl diethyl phosphonate, yield 60%, m.p.194～196 DEG C.1H NMR (400MHz, CDCl3) δ: 11.52 (s, 1H, NH), 8.06 (d, J=3.7Hz, 1H), 7.52 (t, J=6.9Hz, 1H), 7.48 (d, J=7.9Hz, 1H), 7.36 (d, J=8.1Hz, 1H), 7.19 (t, J=7.5Hz, 1H), 7.11 (t, J=8Hz, 1H), 6.74～6.68 (m, 3H), 5.58～5.52 (m, 1H, NCHP), 4.32～4.25 (m, 2H, OCH2), 4.11～3.99 (m, 2H, OCH2), 1.34 (t, 3H, J=7.1Hz, CH3), 1.14 (t, 3H, J=7.0Hz, CH3)；13C NMR (100MHz, CDCl3) δ: 163.43,146.26,138.66,138.04,130.53,129.30,128.66,128.17,122.69,119.99,118.47,115.81,113.74,63.89,63.52,48.70,47.16,16.54 and 16.30.
Embodiment 2
The preparation of [2-(1H)-quinolinone-3-base] benzyl AminomethylphosphoniAcid Acid diethylester
2mmol 3-formoxyl-2-(1H)-quinolinone, 2mmol benzylamine and 15ml toluene, be stirred at room temperature 10min, adds 2mmol diethyl phosphite, backflow 1h (TLC monitoring)；Use VPetroleum ether: VEthyl acetate=1:1 column chromatography, is dried to obtain [2-(1H)-quinolinone-3-base] benzyl AminomethylphosphoniAcid Acid diethylester, yield 67.5%, m.p.113～116 DEG C.1H NMR (400MHz, CDCl3) δ: 12.34 (s, 1H, NH), 8.10 (d, J=3.2Hz, 1H), 7.61 (d, J=7.6Hz, 2H), 7.51 (t, J=7.6Hz, 1H), 7.40 (d, 1H, J=8.4Hz, 1H), 7.65 (d, J=7.6Hz, 1H), 7.34～7.26 (m, 4H), 7.24～7.21 (m, 2H), 4.80～4.75 (m, 1H, NCHP), 4.32～4.20 (m, 2H, OCH2), 4.11～4.00 (m, 2H, OCH2), 3.90～3.69 (m, 2H, CH2), 1.32 (t, J=6.8Hz, 3H, CH3), 1.18 (t, J=6.8Hz, 3H, CH3)；13C NMR (100MHz, CDCl3) δ: 163.61,139.44,138.01,130.53,128.40,128.35,127.95,127.12,122.69,119.92,115.96,109.38,63.46,62.88,51.97,51.82,18.35,16.51 and 16.35.
Embodiment 3
The preparation of [2-(1H)-quinolinone-3-base]-2-methylbenzene AminomethylphosphoniAcid Acid diethylester
2mmol 3-formoxyl-2-(1H)-quinolinone, 2mmol 2-aminotoluene and 15ml toluene, be stirred at room temperature 10min, adds 2mmol diethyl phosphite, backflow 3h (TLC monitoring)；Use VPetroleum ether: VEthyl acetate=1:1 column chromatography, is dried to obtain [2-(1H)-quinolinone-3-base]-2-methylbenzene AminomethylphosphoniAcid Acid diethylester, yield 86.3%, m.p.191～193 DEG C.1H NMR (400MHz, CDCl3) δ: 11.59 (s, 1H, NH), 8.01 (d, J=3.6Hz, 1H), 7.54 (d, J=7.9Hz, 1H), 7.49 (t, J=7.6Hz, 1H), 7.20 (t, J=7.4Hz, 1H), 7.05 (d, J=7.2Hz, 1H), 6.97 (t, J=7.7Hz, 1H), 6.65 (t, J=7.3Hz, 1H), 6.58 (d, J=8.0Hz, 1H), 5.56～5.50 (m, 1H, NCHP), 4.86 (s, 1H, NH), 4.31～4.26 (m, 2H, OCH2), 4.14～3.99 (m, 2H, OCH2), 2.30 (s, 3H, CH3), 1.34 (t, 3H, J=7.0Hz, CH3), 1.15 (t, 3H, J=6.9Hz, CH3)；13C NMR (100MHz, CDCl3) δ: 163.37,143.92,138.35,138.02,130.58,130.30,128.49,128.17,127.23,123.02,122.78,119.98,118.31,115.89,111.00,63.79,63.53,49.26,47.71,17.66,16.54 and 16.32.
Embodiment 4
The preparation of [2-(1H)-quinolinone-3-base]-2-chloro-4-nitroanilines methylphosphonic acid diethylester
2mmol 3-formoxyl-2-(1H)-quinolinone, 2mmol 2-chloro-4-nitroaniline and 15ml toluene, 10min is stirred at room temperature, adds 2mmol diethyl phosphite, backflow 4h (TLC monitoring)；Use VPetroleum ether: VEthyl acetate=1:1 column chromatography, is dried to obtain [2-(1H)-quinolinone-3-base]-2-chloro-4-nitroanilines methylphosphonic acid diethylester, yield 70.0%, m.p.137～139 DEG C.1H NMR (400MHz, DMSO-d6) δ: 12.15 (s, 1H), 8.23 (d, J=2.6Hz, 1H), 8.18 (d, J=3.2Hz, 1H), 8.10 (dd, J=9.1,2.8Hz, 1H), 7.71 (d, J=7.7Hz, 1H), 7.54 (t, J=7.7Hz, 1H), 7.36 (d, J=8.2Hz, 1H), 7.22 (t, J=7.3Hz, 1H), 6.96 (d, J=9.3Hz, 1H), 5.63～5.55 (m, 1H, NCHP), 4.15～4.07 (m, 2H, OCH2), 4.02 (m, 2H, OCH2), 1.22 (t, J=7.0Hz, 3H, CH3), 1.12 (t, J=7.0Hz, 3H, CH3)；13C NMR (100MHz, DMSO-d6) δ: 161.29,147.65,138.77,138.12,137.35,130.84,128.07,125.57,125.04,124.75,122.33,117.80,115.15,113.52,110.90,63.08,63.02,50.99,49.46,16.20 and 16.11.
Embodiment 5
The preparation of [2-(1H)-quinolinone-3-base]-2,4-dinitro benzene AminomethylphosphoniAcid Acid diethylester
2mmol 3-formoxyl-2-(1H)-quinolinone, 2mmol 2,4-dinitroaniline and 15ml toluene, be stirred at room temperature 10 min, adds 2mmol diethyl phosphite, backflow 4h (TLC monitoring)；Cooling, reactant liquor rotation is steamed partial solvent, is separated out solid, filter, washing with alcohol, is dried to obtain [2-(1H)-quinolinone-3-base]-2,4-dinitro benzene AminomethylphosphoniAcid Acid diethylester, yield 57.4%, m.p.201～204 DEG C.1H NMR (400MHz, DMSO-d6) δ: 12.20 (s, 1H, NH), 9.70 (s, 1H), 8.89 (d, J=2.8Hz, 1H), 8.34 (dd, J=2.4,2.4Hz, 1H), 8.13 (d, J=7.6Hz, 1H), 7.68 (t, J=8.0Hz, 1H), 7.54 (t, J=8.4Hz, 1H), 7.35 (d, J=8.0Hz, 2H), 7.20 (t, J=7.2Hz, 1H), 7.11 (d, J=9.6Hz, 1H), 5.78～5.70 (m, 1H, NCHP), 4.17～4.03 (m, 4H, 2 × OCH2), 1.25 (t, J=7.2Hz, 3H, CH3), 1.15 (t, J=6.8Hz, 3H, CH3)；13C NMR (100MHz, DMSO-d6) δ: 160.94,146.67,138.44,138.22,136.10,131.11,130.92,130.36,128.16,125.72,123.34,122.29,118.68,115.51,115.13,63.38,63.32,50.54,49.02,16.18 and 16.09.
Embodiment 6
The resisiting influenza virus neuraminidase activity of [2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester
Measure by patented method [ZL200910043678,2010.8.18 mandate].
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, and the metabolite produced under neuraminidase effect, under 360nm irradiates and excites, can produce 450nm fluorescence, and the change of fluorescence intensity can react neuraminidase activity delicately.Enzyme both is from A/PR/8/34 (H1N1) virus stain.
2. experimental technique
In enzyme reaction system, finite concentration sample and influenza virus god NA are suspended in reaction buffer (pH6.5), add fluorogenic substrate MUNANA and start reaction system, after 37 DEG C hatch 40 minutes, add reaction terminating liquid and terminate reaction.Under the Parameter Conditions of a length of 450nm of excitation wavelength 360nm and transmitted wave, measure fluorescence intensity level.The fluorescence intensity of reaction system can reflect the activity of enzyme.Decrement according to fluorescence intensity can be with the computerized compound suppression ratio to NA.
3. detection sample: [2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester (I):
R is selected from: C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；X1、X2It is selected from: hydrogen, deuterium, C1～C2Alkyl；X3、X7It is selected from: hydrogen, deuterium, C1～C2Alkyl, fluorine, chlorine, bromine, iodine or nitro；X4、X6It is selected from: hydrogen, deuterium, C1～C2Alkyl；X5It is selected from: hydrogen, deuterium, C1～C2Alkyl or nitro；N=0,1；
4. Activity Results
Preferred compound inhibitory activity to neuraminidase during detectable concentration 40.0 μ g/mL in response system: the suppression ratio of [2-(1H)-quinolinone-3-base]-2,4-dinitro benzene AminomethylphosphoniAcid Acid diethylester and [2-(1H)-quinolinone-3-base]-2-chloro-4-nitroanilines methylphosphonic acid diethylester is respectively 53.09% and 42.02%；[2-(1H)-quinolinone-3-base]-2,4-dinitro benzene AminomethylphosphoniAcid Acid diethylester and [2-(1H)-quinolinone-3-base]-2-chloro-4-nitroanilines methylphosphonic acid diethylester IC to neuraminidase50It is respectively 43.2 ± 6.95 μMs and 42.57 ± 3.28 μMs.
[2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester has preferable inhibitory activity to neuraminidase, can be used for preparing influenza virus neuraminidase inhibitor.
Claims (5)
1. [2-(1H)-quinolinone-3-base] the AminomethylphosphoniAcid Acid ester shown in chemical constitution formula I or its salt:
R is selected from: C1～C2Alkyl, C3～C4Straight chained alkyl or branched alkyl；X1、X2It is selected from: hydrogen, deuterium, C1～C2Alkane
Base；X3、X7It is selected from: hydrogen, deuterium, C1～C2Alkyl, fluorine, chlorine, bromine, iodine or nitro；X4、X6Be selected from: hydrogen, deuterium,
C1～C2Alkyl；X5It is selected from: hydrogen, deuterium, C1～C2Alkyl or nitro；N=0 or 1；Salt is selected from: hydrochlorate, hydrobromic acid
Salt, phosphate, sulfate, nitrate, nitrate, mesylate, benzene sulfonate, tosilate, malate,
Lactate, succinate or butene dioic acid salt.
2. [2-(1H)-quinolinone-3-base] the AminomethylphosphoniAcid Acid ester described in claim 1 is selected from following compounds:
Wherein, R is as claimed in claim 1.
3. [2-(1H)-quinolinone-3-base] the AminomethylphosphoniAcid Acid ester described in claim 1 is selected from: [2-(1H)-quinolinone-3-base]
Phenylaminomethyl diethyl phosphonate, [2-(1H)-quinolinone-3-base] benzyl AminomethylphosphoniAcid Acid diethylester, [2-(1H)-quinolinone-3-base]-2-
Methylbenzene AminomethylphosphoniAcid Acid diethylester, [2-(1H)-quinolinone-3-base]-2,4-dinitro benzene AminomethylphosphoniAcid Acid diethylester or [2-(1H)-
Quinolinone-3-base]-2-chloro-4-nitroanilines methylphosphonic acid diethylester.
4. the preparation method of [2-(1H)-quinolinone-3-base] the AminomethylphosphoniAcid Acid ester described in claim 1, it is characterised in that it
Preparation reaction is as follows:
Wherein, n, R, X1～X7As claimed in claim 1.
5. in claims 1 to 3 [2-(1H)-quinolinone-3-base] AminomethylphosphoniAcid Acid ester described in any one or its salt in preparation
Application in neuraminidase inhibitor.
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| CN105732711A (en) * | 2016-05-09 | 2016-07-06 | 桂林师范高等专科学校 | 2(1H)-quinolinone phosphate derivative as well as preparation method and application thereof |
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| CN1662505A (en) * | 2002-04-30 | 2005-08-31 | 永进药品工业株式会社 | Quinoline derivatives as caspase-3 inhibitor, preparation for producing the same and pharmaceutical composition comprising the same |
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| CN105732711A (en) * | 2016-05-09 | 2016-07-06 | 桂林师范高等专科学校 | 2(1H)-quinolinone phosphate derivative as well as preparation method and application thereof |
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