CN105985376B - [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester and preparation method and application - Google Patents
[2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester and preparation method and application Download PDFInfo
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Abstract
The present invention relates to [2 (1H) quinolinone, 3 base] the AminomethylphosphoniAcid Acid esters or its salt shown in chemical structural formula 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 or 1.[2 (1H) quinolinone, the 3 base] application of AminomethylphosphoniAcid Acid ester or its salt in neuraminidase inhibitor is prepared.
Description
Technical field
The present invention relates to the preparation and application of a kind of noval chemical compound；Specifically [2- (1H)-quinolinone -3- bases] aminomethyl phosphine
The preparation of acid esters and the application as influenza virus neuraminidase inhibitor.
Background technology
Avian influenza 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 hypotypes of influenza A virus, H5And H7For highly pathogenic bird flu disease
Poison.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 are each different, mainly may be used
To show as respiratory symptom, conjunctivitis or even death.Wherein highly pathogenic H5N1Hypotype and in March, 2013 on human body for the first time
It was found that new bird flu H7N9Hypotype is particularly noticeable.
1997, find the H of the energy direct infection mankind for the first time in Hong Kong5N1Hypotype.By the end of in July, 2014, the whole world is reported altogether
It has accused people and has infected highly pathogenic H5N1Bird flu 667, wherein 393 dead.Case is distributed in 16 countries, wherein, China
It is found that 45, dead 30.Most people infects H5N1Bird flu case is young man and children.The H of 2009 outbursts1N1Stream
Influenza Virus results in global high speed and propagates, serious threat is constituted to Global Health.By the end of in December, 2014 world
The H that health organization (World Health Organization, WHO) is announced1N1Influenza makes a definite diagnosis people more than 1,310,000, more than dead 14000
People.In March, 2013, finder infects H for the first time in China7N9Bird flu case, the new strain of bird flu found for the first time for the whole world are sub-
Type.End on January 25th, 2015, the H that the World Health Organization announces7N9494 people, dead 221 people are made a definite diagnosis in bird flu.
Anti-influenza virus medicament is broadly divided into two classes：M2 inhibitors of ion channels and NA inhibitor.M2 ion channels inhibit
Agent shows gastrointestinal tract and central nervous system serious side effects, and only effective to A types because being also easy to produce drug resistance, and clinic should
With being extremely restricted.And NA inhibitor is a kind of relatively new anti-A, Type B influenza virus drug, it is by being adhered to new shape
Into the glycoprotein on virion NA surfaces, the virus of host cell release new is prevented, and increases new virus self assemble, is reduced
Its diffusivity and infectivity.Therefore, NA inhibitor becomes the emphasis of current Tamiflu research.Up to the present, as god
The anti-influenza virus medicament listed through propylhomoserin enzyme inhibitor mainly has zanamivir (Zanamivir), oseltamivir
(Oseltamivir) and Peramivir (Peramivir).
2011, the Academia Sinica of TSRL Inc. of the U.S. and TaiWan, China was repaiied on the architecture basics of zanamivir
Decorations, separately design and have synthesized a series of zanamivir L-threonine derivatives of high therapeutic index and zanamivir phosphonic acid ester drug, this two classes drug
With significant NA inhibiting effect, it is possible to the medicine as anti influenza.
Drug research worker studies the neuraminic acid enzyme inhibition activity of a large amount of compounds in recent years.Middle promulgated by the State Council
Bright patent (CN101570521B) describe 4- tertiary butyl -6- phenyl -2- amino -6H-1,3- thiazine salt preparation method and its
Pharmaceutically it is used to prepare influenza virus neuraminidase inhibitor.
Chinese invention patent (CN101891705B；CN102204914B 4- alkyl-6-aryl -2- acyl ammonia) is respectively described
Base -1,3- thiazine -5- formic acid esters and 4- alkyl-6-aryl-5-acetyl-1,3-thiazines, which are used as, prepares neuraminidase inhibitor
Application.
Invention content
The purpose of the present invention is to provide [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid esters shown in chemical structural 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：Hydrochloride, hydrobromate, phosphate, sulfate, nitrate, nitrate,
Mesylate, benzene sulfonate, tosilate, malate, lactate, succinate or butene dioic acid salt.
The purpose of the present invention is to provide [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester be selected from following compounds：
Wherein, R is selected from：C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkyl.
The purpose of the present invention is to provide [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester be selected from：[2- (1H)-quinoline
Quinoline ketone -3- bases] phenylaminomethyl diethyl phosphonate, [2- (1H)-quinolinone -3- bases] benzyl AminomethylphosphoniAcid Acid diethylester, [2- (1H) -
Quinolinone -3- bases] -2- methylbenzene AminomethylphosphoniAcid Acids diethylester, [2- (1H)-quinolinone -3- bases] -2,4- dinitrobenzene aminomethyls
Diethyl phosphonate or the chloro- 4- nitroanilines methylphosphonic acid diethylesters of [2- (1H)-quinolinone -3- bases] -2-.
The object of the present invention is to provide the preparation methods of [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester, special
Sign is 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~C2Alkane
Base；X3、X7It is selected from：Hydrogen, deuterium, C1~C2Alkyl, fluorine, chlorine, bromine, iodine or nitro；X4、X6It is selected from：Hydrogen, deuterium, C1~C2Alkyl；X5Choosing
From：Hydrogen, deuterium, C1~C2Alkyl or nitro；N=0,1；Salt is selected from：Hydrochloride, hydrobromate, phosphate, sulfate, nitrate,
Nitrate, mesylate, benzene sulfonate, tosilate, malate, lactate, succinate or butene dioic acid salt.
The object of the present invention is to provide [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid esters or its salt to prepare god
Through the application in propylhomoserin enzyme inhibitor.
The present invention has the following advantages that compared with prior art：
The present invention is prepared for [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester or its salt for the first time；It is susceptible with anti-current
Malicious neuraminidase activity.
Specific embodiment
Following embodiment is intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of [2- (1H)-quinolinone -3- bases] phenylaminomethyl diethyl phosphonate
(1) preparation of 3- formoxyls -2- (1H)-quinolinone
98ml POCl3It is added dropwise in 7ml n,N-Dimethylformamide, stirs 30min at 0~5 DEG C, add in
50mmol antifebrins are warming up to 90 DEG C, react 16h.Cooling, reaction are also poured into 500ml ice water, are filtered, are washed with water.Gu
The acetum of 200ml 70%, 95 DEG C of reaction 4h are added in body.Reaction solution is cooled down, fluffy solid is precipitated, is filtered, is washed, is done
It is dry to obtain 3- formoxyls -2- (1H)-quinolinone, yield 73.8%, m.p.303~305 DEG C.
(2) preparation of [2- (1H)-quinolinone -3- bases] phenylaminomethyl diethyl phosphonate
2mmol 3- formoxyls -2- (1H)-quinolinone, 2mmol aniline and 15ml toluene, are stirred at room temperature 10min, add in
Solid, filtering, ethyl alcohol is precipitated in 2mmol diethyl phosphites, reflux 4h (TLC monitorings), cooling, reaction solution revolving partial solvent
Washing, dry [2- (1H)-quinolinone -3- bases] 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、
119.99th, 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- bases] benzyl AminomethylphosphoniAcid Acid diethylester
2mmol 3- formoxyls -2- (1H)-quinolinone, 2mmol benzylamines and 15ml toluene, are stirred at room temperature 10min, add in
2mmol diethyl phosphites, reflux 1h (TLC monitorings)；Use VPetroleum ether：VEthyl acetate=1：1 column chromatography, dry [2- (1H)-quinoline
Ketone -3- bases] 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、
119.92nd, 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- bases] -2- methylbenzene AminomethylphosphoniAcid Acid diethylesters
2mmol 3- formoxyls -2- (1H)-quinolinone, 2mmol 2-aminotoluenes and 15ml toluene, are stirred at room temperature
10min adds in 2mmol diethyl phosphites, reflux 3h (TLC monitorings)；Use VPetroleum ether：VEthyl acetate=1：1 column chromatography, dry [2-
(1H)-quinolinone -3- bases] -2- methylbenzene AminomethylphosphoniAcid Acid diethylesters, 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、
111.00th, 63.79,63.53,49.26,47.71,17.66,16.54 and 16.32.
Embodiment 4
The preparation of the chloro- 4- nitroanilines methylphosphonic acid diethylesters of [2- (1H)-quinolinone -3- bases] -2-
The chloro- 4- nitroanilines of 2mmol 3- formoxyls -2- (1H)-quinolinone, 2mmol 2- and 15ml toluene, are stirred at room temperature
10min adds in 2mmol diethyl phosphites, reflux 4h (TLC monitorings)；Use VPetroleum ether：VEthyl acetate=1：1 column chromatography, dry [2-
(1H)-quinolinone -3- bases] the chloro- 4- nitroanilines methylphosphonic acid diethylesters of -2-, 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 with 16.11.
Embodiment 5
The preparation of [2- (1H)-quinolinone -3- bases] -2,4- dinitrobenzene AminomethylphosphoniAcid Acid diethylesters
2mmol 3- formoxyls -2- (1H)-quinolinone, 2mmol 2,4- dinitroanilines and 15ml toluene, are stirred at room temperature
10 min add in 2mmol diethyl phosphites, reflux 4h (TLC monitorings)；Cooling, reaction solution revolving partial solvent, is precipitated solid
Body, filtering, ethyl alcohol washing, dry [2- (1H)-quinolinone -3- bases] -2,4- dinitrobenzene AminomethylphosphoniAcid Acid diethylesters, 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、
115.13rd, 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- bases] AminomethylphosphoniAcid Acid ester
It is measured by patented method [ZL200910043678,2010.8.18 mandates].
1. experimental principle
Compound MUNANA is the specific substrate of neuraminidase, the metabolite generated under neuraminic acid enzyme effect
Under 360nm irradiation excitations, 450nm fluorescence can be generated, the variation of fluorescence intensity can delicately react neuraminic acid enzyme activity
Property.Enzyme both is from A/PR/8/34 (H1N1) virus stain.
2. experimental method
In enzyme reaction system, a certain concentration sample is suspended in reaction buffer (pH6.5) with influenza virus god NA, adds
Enter fluorogenic substrate MUNANA and start reaction system, 37 DEG C are incubated after forty minutes, and reaction terminating liquid is added to terminate reaction.In excitation wavelength
Under 360nm and the Parameter Conditions that launch wavelength is 450nm, fluorescence intensity level is measured.The fluorescence intensity of reaction system can reflect
The activity of enzyme.Inhibiting rate of the compound to NA can be calculated according to the decrement of fluorescence intensity.
3. detect sample：[2- (1H)-quinolinone -3- bases] 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 is in reaction system to the inhibitory activity of neuraminidase during 40.0 μ g/mL of detectable concentration：[2-
(1H)-quinolinone -3- bases] -2,4- dinitrobenzene AminomethylphosphoniAcid Acid diethylesters and [2- (1H)-quinolinone -3- bases] chloro- 4- of -2-
The inhibiting rate of nitroanilines methylphosphonic acid diethylester is respectively 53.09% and 42.02%；[2- (1H)-quinolinone -3- bases] -2,
4- dinitrobenzene AminomethylphosphoniAcid Acid diethylesters and the chloro- 4- nitroanilines methylphosphonic acid diethyls of [2- (1H)-quinolinone -3- bases] -2-
Ester is to the IC of neuraminidase50Respectively 43.2 ± 6.95 μM and 42.57 ± 3.28 μM.
[2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester has preferable inhibitory activity to neuraminidase, can be used for
Prepare influenza virus neuraminidase inhibitor.
Claims (5)
1. [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester or its salt shown in chemical structural formula I：
R is selected from：C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkyl；X1、X2It is selected from：Hydrogen, deuterium, C1~C2Alkyl；X3、X7Choosing
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 or 1；Salt is selected from：Hydrochloride, hydrobromate, phosphate, sulfate, nitrate, mesylate,
Benzene sulfonate, tosilate, malate, lactate, succinate or butene dioic acid salt.
2. [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester described in claim 1 or its salt are selected from following compounds：
Wherein, R is as described in claim 1.
3. [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester described in claim 1 or its salt, are selected from：[2- (1H)-quinoline
Quinoline ketone -3- bases] phenylaminomethyl diethyl phosphonate, [2- (1H)-quinolinone -3- bases] benzyl AminomethylphosphoniAcid Acid diethylester, [2- (1H) -
Quinolinone -3- bases] -2- methylbenzene AminomethylphosphoniAcid Acids diethylester, [2- (1H)-quinolinone -3- bases] -2,4- dinitrobenzene aminomethyls
Diethyl phosphonate or the chloro- 4- nitroanilines methylphosphonic acid diethylesters of [2- (1H)-quinolinone -3- bases] -2-.
4. the preparation method of [2- (1H)-quinolinone -3- bases] AminomethylphosphoniAcid Acid ester described in claim 1, it is characterised in that it
Preparation reaction it is as follows：
Wherein, n, R, X1~X7As described in claim 1.
5. [2- (1H)-quinolinone -3- bases] the AminomethylphosphoniAcid Acid ester or its salt in claims 1 to 3 described in any one are being made
Application in standby neuraminidase inhibitor.
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| WO2004048393A2 (en) * | 2002-11-22 | 2004-06-10 | Methylgene, Inc. | NOVEL INHIBITORS OF β-LACTAMASE |
| 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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| 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 |
| WO2004048393A2 (en) * | 2002-11-22 | 2004-06-10 | Methylgene, Inc. | NOVEL INHIBITORS OF β-LACTAMASE |
| CN1780643A (en) * | 2003-04-25 | 2006-05-31 | 吉里德科学公司 | Antiviral phosphonate analogs |
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