CN105198866B - Ring the third trifoliate jewelvine hydrazides and its application as neuraminidase inhibitor - Google Patents

Ring the third trifoliate jewelvine hydrazides and its application as neuraminidase inhibitor Download PDF

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CN105198866B
CN105198866B CN201510306297.9A CN201510306297A CN105198866B CN 105198866 B CN105198866 B CN 105198866B CN 201510306297 A CN201510306297 A CN 201510306297A CN 105198866 B CN105198866 B CN 105198866B
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bases
alkyl
ring
halo
hydrazides
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CN105198866A (en
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杨泽慧
邵丹凤
叶姣
胡艾希
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Ningbo University of Technology
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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Abstract

The present invention relates to application of ring the third trifoliate jewelvine hydrazides in influenza virus neuraminidase inhibitor is prepared shown in chemical constitution Formulas I or II：Wherein, R is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight chained alkyl, C3~C4Branched alkyl, C5~C17Straight chained alkyl, C5~C17Branched alkyl, halo C1~C2Alkyl, halo C3~C4Straight chained alkyl, halo C3~C4Branched alkyl, halo C5~C17Straight chained alkyl or halo C5~C17Branched alkyl；R1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkyl.

Description

Ring the third trifoliate jewelvine hydrazides and its application as neuraminidase inhibitor
Technical field
The present invention relates to the novel medical use of a kind of compound, specifically the third trifoliate jewelvine of ring hydrazides are refreshing as influenza virus is prepared Application through propylhomoserin enzyme inhibitor.
Background technology
Rotenone is that early stage people extract separate a kind of from the plant roots such as Derris and have insecticidal activity Compound, it is one of three great tradition botanical pesticide [pesticide plant and botanical pesticide second edition Beijing：Chinese agriculture Publishing house, 2004].Because the insecticidal spectrum of rotenone is wide, residual life is short, be not likely to produce the resistance to the action of a drug, to person poultry safety and is advantageous to The advantages that promoting the ecological balance so that rotenone as environment friendly agricultural with very great development potentiality [the application present situation of rotenone and Problem agricultural chemicals, 2005,44 (8) be present：352-355].
Chinese invention patent [ring the third trifoliate jewelvine hydrazides and preparation method and application, CN201310246431.1, 2013.6.20 apply] with trifoliate jewelvine ketone derivatives (5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- Base) [(R) -4- hydroxyls -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases] ketone is raw material, the carbonyl being conjugated to it Structural modification is carried out, introduces active acylhydrazone group, design has synthesized a series of novel ring the third trifoliate jewelvine hydrazides of structures, and by gained Compound carries out structural characterization and bactericidal activity test, it is expected to obtain noval chemical compound efficiently, less toxic.Preliminary bioactivity research As a result show：Ring the third trifoliate jewelvine hydrazides has preferable bactericidal activity.
Due to the hemagglutinin design feature of avian influenza virus, nonspecific infection birds, when base occurs in a replication process for virus Because matching somebody with somebody again, cause structure to change, obtain the ability of infection people.So far the avian influenza virus subtype of energy direct infection people is found There is H5N1、H7N2、H7N3、H7N7、H9N2、H10N7And H7N9Hypotype, in December, 2013 are found that new bird flu H in China Jiangxi10N9 Hypotype.The Symptoms of these hypotypes are each different, can mainly show as respiratory symptom, conjunctivitis, or even dead.Wherein Highly pathogenic H5N1The new bird flu H that hypotype and in March, 2013 find first on human body7N9Hypotype is particularly noticeable.
H5N1Hypotype was found first in 1997 in Hong Kong can the direct infection mankind.By the end of in March, 2013, the whole world is reported altogether Accuse people and infect highly pathogenic H5N1Bird flu 634, wherein dead 371.Case is distributed in 15 countries, wherein, China It is found that 45, dead 30.Most people infects H5N1Bird flu case is young man and children.In March, 2009 to April, ink Western brother breaks out H1N1A type swine flu epidemic disease tide, the virus is successfully adapted to the mankind, and causes disease stream by person to person's propagation OK.By the end of the H that in December, 2013 World Health Organization (World Health Organization, WHO) announces1N1Swine flu Make a definite diagnosis people more than 1,310,000, dead people more than 14000.In March, 2013, finder infects H first in China7N9Bird flu case, for the whole world The new strain of bird flu hypotype found first.In by the end of March, 2013 to the January in 2014 of evening 12 on the 19th when, the accumulative speaker's sense in the whole nation Contaminate H7N9Confirmed cases are more than 200.
In December, 2013 so far, H7N9More active state is in again, and " onset peak occurs again.”.H at present7N9Epidemic disease Feelings, still in distributed state, but are mainly distributed on China region of Southeast in the human world, such as Zhejiang, Shanghai, Guangdong province.According to new Magnificent society's statistics, 1 to 26 January, the whole nation have made a definite diagnosis people and have infected H7N9Bird flu case 96, the province of Zhejiang and Guangdong Shanghai three make a definite diagnosis 83, Dead 20, wherein dead 12 of Zhejiang, Guangdong 4-case death, Shanghai 4-case death, including 1 medical worker.
New edition《People infects H7N9Bird flu diagnosis and treatment scheme》(referred to as " scheme ") point out, people infects H7N9Bird flu is by H7N9 Acute infections of respiratory tract disease caused by avian influenza virus, wherein severe pneumonia case can often merge acute respiratory distress synthesis Sign, infectious shock, or even MOF.Diagnosis and treatment scheme is to H7N9Bird flu one new " identity identification ".Scheme is brighter True H7N9Gene source, the avian influenza virus subtype that can infect people are H5N1、H9N2、H7N7、H7N2、H7N3Deng, this time be H7N9Fowl is flowed Influenza Virus.The virus is new reassortant virus, encodes HA gene source in H7N3, NA gene source is encoded in H7N9, it 6 Individual internal gene comes from H9N2Avian influenza virus [defends planning commission：H7N9It is not excluded for limited non-continuous human-to-human transmission, Beijing Times .2014 on January 27, in].
Neuraminidase (NA) inhibitor is the First Line medicine of anti-influenza type A virus.Neuraminidase (NA) inhibitor There are the type compounds such as Zanamivir, Oseltamivir and Peramivir, wherein Oseltamivir is widely used.But study It has been found that some Strain generate drug resistance to Oseltamivir.Chinese patent describes thiazide and trifoliate jewelvine ring propionamide Application as influenza virus neuraminidase inhibitor：(1) the 4- tert-butyl groups -6- phenyl -2- amino -6H-1,3- thiazine salt Preparation method and medical usage, Chinese invention patent, ZL 200910043678.7,2010.8.18 are authorized；(2) 4- alkyl -6- Aryl-2-acylamino -1,3- thiazine -5- formic acid esters and preparation method and application, Chinese invention patent, ZL201010225483.7,2012.3.14 are authorized；(3) 4- alkyl-6-aryl-5-acetyl-1,3-thiazines are neural as preparing The application of propylhomoserin enzyme inhibitor, 2011.3.30 applications, ZL201110077574.5,2013.2.27 are authorized；(4) trifoliate jewelvine ring propionyl Amine and preparation method and application, 2011.8.9 applications, ZL201110226848.2,2013.3.20 are authorized.
The content of the invention
It is an object of the invention to provide ring the third trifoliate jewelvine hydrazides shown in chemical constitution Formulas I or II to prepare influenza virus god Through the application in propylhomoserin enzyme inhibitor：
Wherein, R is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight chained alkyl, C3~C4Branched alkyl, C5~C17Straight chain alkane Base, C5~C17Branched alkyl, halo C1~C2Alkyl, halo C3~C4Straight chained alkyl, halo C3~C4Branched alkyl, halo C5~ C17Straight chained alkyl or halo C5~C17Branched alkyl；R1It is selected from：Hydrogen, deuterium, C1~C2Alkyl, C3~C4Straight chained alkyl or branched alkane Base；Halo is selected from：Fluoro, chloro, bromo or iodo；Ring the third trifoliate jewelvine hydrazides shown in Formulas I is (Z)-ring the third trifoliate jewelvine hydrazides；Formula II Shown ring the third trifoliate jewelvine hydrazides is (E)-ring the third trifoliate jewelvine hydrazides.
It is an object of the invention to additionally provide N '-[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] benzo Pyrans -7b- bases] [(R) -4- hydroxyls -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] acethydrazide, N ' - [(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) -4- hydroxyls -2- (propylene -2- Base) -2,3- Dihydrobenzofuranes -5- bases) methylene] propionyl hydrazine, 2- chlorine N '-[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysenes Simultaneously [c] chromene -7b- bases of ring third] [(R) -4- hydroxyls -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene Base] acethydrazide or the chloro- N ' of 2--[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) - 4- hydroxyls -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] propionyl hydrazine prepare influenza virus nerve ammonia Application in sour enzyme inhibitor.
The present invention has the following advantages that compared with prior art：
Present invention application of a kind of the third trifoliate jewelvine of ring hydrazides in influenza virus neuraminidase inhibitor is prepared.
Embodiment
Following examples are intended to illustrate invention rather than limitation of the invention further.
Embodiment 1
The preparation of ring the third trifoliate jewelvine hydrazone
(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases) [(R) -4- hydroxyls -2- (third Alkene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) ketone 2.00g (1.1mmol), the dissolving of 20mL ethanol, 1.5mL contents are 80% hydrazine hydrate, NaOH solids 0.25g (6.25mmol), it is stirred at reflux at 85 DEG C, TLC tracking, is washed after 5h, dry 1.7g White solid, yield 86.4%.177-178.5 DEG C of fusing point.1H NMR(CDCl3, 400MHz) and δ：1.43~1.47 (m, 1H, 1a- H), 1.71 (s, 1H, 1-H), 1.77~1.82 (m, 3H, CH3), 1.96~2.05 (m, 1H, 1-H), 3.01~3.10 (m, 1H, 2-H), 3.34~3.39 (m, 1H, 2-H), 3.64,3.73 (2 × d, J=4.8Hz, 3H, CH30), 3.82 (s, 3H, CH3O), The 4.08 (- H of t, J=10.6Hz, 1H, 3 '), the 4.44 (- H of t, J=10.6Hz, 1H, 3 '), 4.92 (d, J=10.8Hz, 1H ,= CH2), 5.09 (d, J=10.8Hz, 1H ,=CH2), 5.22~the 5.29 (- H of m, 1H, 2 '), 6.26,6.37 (2 × d, 1H, 6-H), 6.50~6.60 (m, 2H, 7 '-H, 5-H), 7.45, the 7.13 (- H of 2 × m, 1H, 6 ').ESI-MS, m/z：422.2(M+, 100%), 423.2(M++ 1,27.8%), 424.2 (M++ 2,13.6%).
Embodiment 2
N '-[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) -4- hydroxyls - 2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] acethydrazide preparation
20mL DMF, ring the third trifoliate jewelvine hydrazone 0.50g (1.2mmol), potassium carbonate 0.3g and appropriate molecular sieve, second is added after dissolving Acid anhydrides 1.5mL, 80 DEG C of reactions, TLC monitorings, salt solution is washed after reacting 3h, and ethyl acetate (3 × 20mL) extraction, decompression precipitation obtains 0.47g white solids, yield 84.8%.m.p.113-116℃.1H NMR(CDCl3, 400MHz) and δ：1.35~1.38 (m, 1H, 1a-H), 1.77~1.82 (m, 3H, CH3), 1.82~2.05 (m, 3H, CH3CO), 2.15,2.32 (2 × s, 1H, 1-H), 2.41 (s, 1H, 1-H), 3.01~3.07 (m, 1H, 2-H), 3.35~3.41 (m, 1H, 2-H), 3.63~3.70 (m, 3H, CH3O), 3.83 (s, 3H, CH3O), 4.08~the 4.19 (- H of m, 1H, 3 '), 4.42~the 4.46 (- H of m, 1H, 3 '), 4.93 (s, 1H ,=CH2), 5.09 (s, 1H ,=CH2), 5.26~the 5.30 (- H of m, 1H, 2 '), 6.27~6.57 (m, 3H, 6-H, 7 '-H, 5-H), 7.23, The 7.60 (- H of 2 × m, 1H, 6 '), 11.65~11.70 (m, 1H, OH).ESI-MS, m/z：463.0(M+- 1,100%), 464.1 (M+, 29.0%), 465.1 (M++ 1,10.0%).
Embodiment 3
N '-[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) -4- hydroxyls - 2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] propionyl hydrazine preparation
Ring the third trifoliate jewelvine hydrazone 0.50g (1.2mmol), it is solvent to add 1mL propionic andydrides, and 25 DEG C of reactions, TLC is monitored, after 15min Raw material has reacted.Filtering, ethyl acetate (3 × 20mL) extraction, column chromatography obtain 0.42g pale solids, yield 74.2%, M.p.75-80 DEG C,1HNMR(CDCl3, 400MHz) and δ：1.19~1.31 (m, 3H, CH3), 1.35 (m, 1H, 1-H), 1.78 (m, 3H, CH3), 1.86,1.92 (2 × t, 1H, 1a-H), 1.99~2.24 (m, 1H, 1-H), 2.30~2.81 (m, 2H, CH2CO), 3.06 (m, 1H, 2-H), 3.38 (m, 1H, 2-H), 3.68 (m, 3H, CH3O), 3.83 (s, 3H, CH3O), the 4.13 (- H of m, 1H, 3 '), The 4.43 (- H of m, 1H, 3 '), 4.92 (m, 1H ,=CH2), 5.08 (m, 1H ,=CH2), the 5.27 (- H of m, 1H, 2 '), 6.30~6.59 (m, 3H, 6-H, 7 '-H, 5-H), 7.20, the 7.56 (- H of m, 1H, 6 '), 11.72 (m, 1H, OH).ESI-MS, m/z：477.2(M+- 1,100%), 478.2 (M++ 1,26.5%), 479.2 (M++ 2,8.2%).
Embodiment 4
The chloro- N ' of 2--[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) -4- Hydroxyl -2- (interior alkene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] acethydrazide preparation
10mL DMF dissolving ring the third trifoliate jewelvine hydrazone 0.50g (1.2mmol), triethylamine 1.2mmol, chloracetyl chloride is added dropwise at 25 DEG C 0.14g (1.21mmol), 1h is reacted, TLC monitorings, washing, ethyl acetate (3 × 20mL) extraction drying, recrystallizes to obtain 0.42g Huangs Color crystal, yield 71.2%, m.p.179-179.5 DEG C.1HNMR(CDCl3, 400MHz) and δ：1.40,1.53 (2 × m, 1H, 1-H), 1.77~1.85 (m, 4H, CH3, 1a-H), 1.98,2.09 (2 × m, 1H, 1-H), 3.02~3.06 (m, 1H, 2-H), 3.36~ 3.41 (m, 1H, 2-H), 3.64~3.73 (m, 3H, CH3O), 3.84 (s, 3H, CH3O), 4.12~4.27 (- the H of m, 3H, 3 ', CH2CO), 4.44~the 4.46 (- H of m, 1H, 3 '), 4.92 (d, 1H ,=CH2), 5.09~5.12 (m, 1H ,=CH2), 5.27~ The 5.31 (- H of m, 1H, 2 '), 6.30~6.53 (m, 3H, 6-H, 7 '-H, 5-H), 7.24, the 7.56 (- H of 2 × m, 1H, 6 '), 10.18, 9.69 (2 × s, 1H, NH), 12.44 (s, 1H, OH).
Embodiment 5
The chloro- N ' of 2--[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) -4- Hydroxyl -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] propionyl hydrazine preparation
α-chlorpromazine chloride of DMF 10mL dilutions is added dropwise in 10mL DMF dissolving ring the third trifoliate jewelvine hydrazone 0.50g (1.2mmol), room temperature 0.15g (1.21mmol), acid binding agent triethylamine 1.2mmol, 40 DEG C of reactions, TLC monitorings, reacts 5h.Washing, extract, dry, post Chromatography (ethyl acetate: petroleum ether=5: 1) 0.15g khaki solids, yield 27.9%, m.p.75-82 DEG C.1H NMR (CDCl3, 400MHz) and δ：1.40~1.63 (m, 1H, 1-H), 1.48~1.56 (m, 1H, 1a-H), 1.98,2.10 (2 × m, 1H, 1-H), 1.68~1.84 (m, 6H, CH3), 3.02~3.06 (m, 1H, 2-H), 3.37~3.43 (m, 1H, 2-H), 3.64~ 3.73 (m, 3H, CH3O), 3.84 (s, 3H, CH3O), 4.14, the 4.28 (- H of 2 × d, J=7.2Hz, 1H, 3 '), 4.46,4.58 (2 × D, J=7.2Hz, 2H, 3 '-H, CHCO), 4.93 (d, J=12.0Hz, 1H ,=CH2), 5.08~5.12 (m, 1H ,=CH2), 5.27~the 5.30 (- H of m, 1H, 2 '), 6.30~6.56 (m, 3H, 6-H, 7 '-H, 5-H), 7.24, the 7.55 (- H of 2 × m, 1H, 6 '), 10.22,9.75 (2 × d, J=15.2Hz, 1H, NH), 12.45 (s, 1H, OH).
Embodiment 6
Ring the third trifoliate jewelvine hydrazides resisiting influenza virus neuraminidase activity
1. experimental principle
Compound MUNANA is neuraminidase
The specific substrate outstanding refreshing NA of virus, caused metabolite swashs in 360nm irradiations under neuraminic acid enzyme effect Give, 450nm fluorescence can be produced, the change of fluorescence intensity can delicately react neuraminidase activity.Enzyme both is from A/ PR/8/34(H1N1) virus stain.
2. experimental method
In enzyme reaction system, finite concentration sample is floated in reaction buffer (pH6.5) with influenza, adds fluorogenic substrate MUNANA starts reaction system, after 37 DEG C are incubated 40 minutes, adds reaction terminating liquid terminating reaction.In excitation wavelength 360nm and hair Under a length of 450nm of ejected wave Parameter Conditions, fluorescence intensity level is determined.The fluorescence intensity of reaction system can reflect the activity of enzyme. Inhibiting rate of the compound to NA activity can be calculated according to the decrement of fluorescence intensity.
3. detect sample：Ring the third trifoliate jewelvine hydrazides
4. Activity Results
Under preferred compound is included in reaction system during 40.0 μ g/mL of detectable concentration to the inhibiting rate of neuraminidase Table：Inhibiting rate of table ring the third trifoliate jewelvine hydrazides to neuraminidase
Active testing result shows that ring the third trifoliate jewelvine hydrazides has good resisiting influenza virus neuraminidase activity, can use In preparing influenza virus neuraminidase inhibitor.

Claims (2)

1. chemical constitution Formulas I or ring the third trifoliate jewelvine hydrazides shown in II in influenza virus neuraminidase inhibitor is prepared should With：
Wherein, R is selected from：C1~C2Alkyl, C3~C4Straight chained alkyl, C3~C4Branched alkyl, halo C1~C2Alkyl or halo C3~ C4Straight chained alkyl or halo C3~C4Branched alkyl；R1It is selected from：Hydrogen, deuterium or C1~C2Alkyl；Halo is selected from：Fluoro, chloro, bromo Or iodo.
2. application as claimed in claim 1, its middle ring the third trifoliate jewelvine hydrazides are selected from：N '-[(5,6- dimethoxys -1,1a, 2,7b- Simultaneously [c] chromene -7b- bases of tetrahydrochysene ring third] [(R) -4- hydroxyls -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) Methylene] acethydrazide, N '-[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) -4- Hydroxyl -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] propionyl hydrazine, the chloro- N ' of 2--[(5,6- dimethoxies Base -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] chromene -7b- bases] [(R) -4- hydroxyls -2- (propylene -2- bases) -2,3- dihydrobenzenes And furans -5- bases) methylene] acethydrazide or the chloro- N ' of 2--[(5,6- dimethoxys -1,1a, 2,7b- tetrahydrochysene rings third simultaneously [c] benzo Pyrans -7b- bases] [(R) -4- hydroxyls -2- (propylene -2- bases) -2,3- Dihydrobenzofuranes -5- bases) methylene] propionyl hydrazine.
CN201510306297.9A 2015-06-01 2015-06-01 Ring the third trifoliate jewelvine hydrazides and its application as neuraminidase inhibitor Expired - Fee Related CN105198866B (en)

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5,6-二甲氧基-N-[(R)-4-甲氧基-2-(丙烯-2-基)-2,3-二氢苯并呋喃-5-基]-1,1a,2,7b-四氢环丙并[c]苯并吡喃-7b-基甲酰胺的合成与表征;陈晓东，等;《有机化学》;20121231;第32卷;第520-525 *
环丙鱼藤双腙的合成与抑菌活性;叶姣，等;《有机化学》;20150228;第35卷(第2期);第396-403页 *

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