CN104496962B - A kind of Oligopoly thiophene derivative and application thereof - Google Patents
A kind of Oligopoly thiophene derivative and application thereof Download PDFInfo
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- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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Abstract
The invention belongs to organic chemistry filed, be specifically related to a kind of Oligopoly thiophene derivative, shown in the following formula I of its molecular structure, R in formula1It is hydrogen, 3 bromopropyls, 4 brombutyls, 3 aminopropyls, 4 aminobutyls, 3 Azidopropyl, 4 azido butyl, 3 (3 fluorine 5 (trifluoromethyl) benzamido) propyl group and 4 (3 fluorine 5 (trifluoromethyl) benzamido) butyl one of which；R2It is hydrogen, 3 bromopropyls, 4 brombutyls, 3 aminopropyls, 4 aminobutyls, 3 Azidopropyl and 4 azido butyl one of which；N=1,2,3 or 4.Oligopoly thiophene derivative of the present invention has the effect of suppression influenza virus.
Description
Technical field
The invention belongs to sulfur heterocyclic compound, be specifically related to thiophene and derivatives.
Background technology
Influenza infection is firstly the need of entering target cell.As enveloped virus, influenza virus enters the process of target cell needs film
The mediation of glycoprotein.The envelope protein that influenza virus mediation film merges is hemagglutinin (Hemagglutinin, HA).HA is by HA1
With two subunit compositions of HA2.HA1 has 328 amino acid residues, and HA2 has 221 amino acid residues.HA1 and target cell membrane
On sialic acid receptor combine, then virus is entered Cytoplasm by pinocytosis, and is wrapped in endosome (endosome).HA2
It is then cross-film subunit, mediate retroviral film and the fusion of endosome film.Under the low ph conditions within endosome, HA2 occurred conformation
Change, form the Six helix bundle structure of a kind " hair fastener ", so that viromembrane merges with endosome film, formed and merge hole
(fusion pore), the nucleic acid of virus enters in the endochylema of cell from fusion hole, it is achieved the infection of virus.
Influenza virus entry inhibitor is the Tamiflu that a class is novel, and the commitment in virus infection interrupts the link of duplication,
Reduce plasma viral load, there is obvious superiority.
There is presently no influenza virus entry inhibitor in the whole world on a large scale for influenza preventing and treating (Pharm Res.1999,16 (7):
1041～1046).The little molecular flow Influenza Virus entry inhibitor majority of document report is to be become by the HA conformation suppressing low pH induction
Changing and play antivirus action, wherein representative compound is Stachyflin.Experiment in vitro confirms, this compound can stablize HA
Conformation under conditions of neutral ph.But the antiviral activity of Stachyflin is the highest, and action site is the clearest and the most definite.1997, beautiful
BMS drugmaker of state reports the micromolecular compound BMY-27709 of a HA conformation change that low pH can be suppressed to induce
(Bioorg.Med.Chem.Lett.2000,18 (10): 1649-1652.), reports active higher similar compound subsequently
BMS-199945 and BMS-201160, its IC50Respectively reach 0.57 and 1.1 μM, and prove that it is made by the method for photoaffinity labeling
It is HA2 (PNAS.2008,46 (105): 17736-17741) with target spot, around fusogenic peptide, has a hydrophobic pocket, with
Time the structure of these reactive compounds imitated analyzed, the methoxyl group of its precursor structure salicylic acid 2 is most important, separately to activity
External 5 introduce lipophilic group such as-CH3,-Cl ,-F or-CF3The help having had inhibitory activity, if 3 introducings
The group such as-CN ,-NO of polarity2Derivant does not then have activity.Recently Evelien (J Virol.2010,84 (9): 4,277 4288) and
Song etc. (An tiviral Res.2007,76 (2): 178-185.) report some micromolecular compounds can act on virus infection
Starting stage, the virus fusion of suppression HA mediation.With salicylic acid compounds have similar structures compound CL-61917,
CL-385319, CL-62554 have the effect (J Virol.1999,73 (3): 1785-1794) that suppression influenza A virus enters.
2011, Tang Guozhi (J Virol.1998,248 (2): 264 274) etc. reported bigcatkin willow amido entry inhibitor, by inciting somebody to action
Hydroxyl on phenyl ring becomes sulfonamide or chlorine atom, and activity significantly improves, and reaches nM rank, and its mechanism is by little point
Sub-inhibitor is combined with the HA of H1N1 hemagglutinin, stops the conformation of its reproduction process to change, thus reaches suppression disease
The purpose that poison enters.
Changing relative to suppression HA2 conformation under low ph conditions, some compounds can carry out changing before film merges in virus
The pH environment of cytoplasm matter, so that HA2 conformation can not change, reaches to suppress the purpose of cell entry, such as podocarpic acid.
Equally, podocarpic acid series compound is active to H1, H2 type virus, to H3 and the best (ACS of inhibition of Type B virus
Med.Chem.Lett.2011,2,603–607)。
2009, Yingxia Li (J.Med.Chem.2009,52 (23): 7368-7371.) reported first glycosides element series derivatives
Thing can suppress H5N1 virus to enter host cell；2012, its seminar (Eur.J.Med.Chem.2012,53,316-326.)
Report again many glucosides prime system row derivant, best inhibitory activity IC50Between 6.00-9.25 μM, its mechanism is sugar in glycosides element
Chain and aglycone interference hemagglutinin HA are combined with the sialic acid of host cell surface, thus reach to suppress H5N1 virus
Enter the purpose of host cell.2011, we report CL-385319 had inhibitory action (Eur to H5N1 type influenza virus
J Pharmacol.2011,660 (2-3): 460-467.), its IC50Value is 27.03 ± 2.54 μMs；Within 2012, our seminar reports again
CL-385319 Yu HA2 effect is " induced-fit " process (PLOS ONE.2012,7 (8): e41956.)；By right
CL-385319 tentatively changes structure, finds that little molecule 1l is than the piperidines micromolecular higher (Eur.J of inhibitory action to H5N1 virus
Med.Chem.2012,57,211-216.).Oligopoly thiophene, as small molecule compound, there are no document and reports that it suppresses
The effect that influenza enters.
Summary of the invention
The technical problem to be solved in the present invention is to provide a kind of Oligopoly thiophene derivative, and this Oligopoly thiophene has suppression influenza virus
Effect.
The present invention solves the technical scheme of the problems referred to above:
A kind of Oligopoly thiophene derivative, shown in the following formula I of its molecular structure:
In formula, R1It is hydrogen, 3-bromopropyl, 4-brombutyl, 3-aminopropyl, 4-aminobutyl, 3-Azidopropyl, 4-azido fourth
Base, 3-(3-fluoro-5-(trifluoromethyl) benzamido) propyl group or 4-(3-fluoro-5-(trifluoromethyl) benzamido) butyl；R2Be hydrogen,
3-bromopropyl, 4-brombutyl, 3-aminopropyl, 4-aminobutyl, 3-Azidopropyl or 4-azido butyl；N=1,2,3
Or 4；
And, when R1 is 3-(3-fluoro-5-(trifluoromethyl) benzamido) propyl group or 4-(3-fluoro-5-(trifluoromethyl) benzamido)
Butyl, when n is 1 or 2, R2 is hydrogen；When R1 is 3-(3-fluoro-5-(trifluoromethyl) benzamido) propyl group or 4-(the fluoro-5-of 3-(three
Methyl fluoride) benzamido) butyl, when n is 1 or 2, R2 is hydrogen；When R1 is hydrogen, and n is 3 or 4, R2 be 3-bromopropyl,
4-brombutyl, 3-aminopropyl, 4-aminobutyl, 3-Azidopropyl or 4-azido butyl；When R1 is 3-bromopropyl, 4-
Brombutyl, 3-aminopropyl or 4-aminobutyl, when n is 2 or 3, R2 is 3-bromopropyl, 4-brombutyl, 3-aminopropyl
Or 4-aminobutyl.
In above-mentioned Oligopoly thiophene derivative, preferably 3-fluoro-5-(trifluoromethyl)-N-(3-(2-thienyl) propyl group) Benzoylamide, 3-fluorine
-5-(trifluoromethyl)-N-(4-(2-thienyl) butyl) Benzoylamide, 3-fluoro-5-(trifluoromethyl)-N-(3-(5-(2 thienyl) 2 thienyls)
Propyl group) Benzoylamide, 3-fluoro-5-(trifluoromethyl)-N-(4-(5-(2 thienyl) 2 thienyls) butyl) Benzoylamide, 2-(5-(3-bromopropyl) 2
Thienyl)-5-(2 thienyl) thiophene, 2-(4-brombutyl)-5-(5-(2 thienyl) 2 thienyls) thiophene, 3-(5-(5-(2 thienyl) 2 thiophene
Base) 2 thienyls) propylamine, 4-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) butylamine, 2-(5-(3-Azidopropyl) 2 thienyls)-5-(2
Thienyl) thiophene, 2-(4-azido butyl)-5-(5-(2 thienyl) 2 thienyls) thiophene, 2-(3-bromopropyl)-5-(5-(5-(2 thienyl) 2
Thienyl) 2 thienyls) thiophene, 2-(3-Azidopropyl)-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) thiophene, 3-5-(5-(5-(2
Thienyl) 2 thienyls) 2 thienyls) 2 thienyl propylamine, 2,5-bis-(5-(3-bromopropyl) 2 thienyls) thiophene, 4-(5-(5-(4-ammonia
Butyl) 2 thienyls) 2 thienyls) butylamine, 2-(4-brombutyl)-5-(5-(4-brombutyl) 2 thienyls) 2 thienyls) thiophene,
3-(5-(5-(5-(3-aminopropyl) 2 thienyls) 2 thienyls) 2 thienyls) propylamine or 4-5-(5-(5-(4-ammonia butyl) 2 thienyls) 2 thienyls) 2
Thienyl) butylamine.
In above-mentioned Oligopoly thiophene derivative, preferably 3-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) 2 thienyl propylamine,
3-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) propylamine, 2-(4-nitrine butyl)-5-(5-(2 thienyl) 2 thienyls) thiophene,
4-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) butylamine, 2,5-bis-(5-(3-bromopropyl) 2 thienyls) thiophene, 3-(5-(5-(5-(3-
Aminopropyl) 2 thienyls) 2 thienyls) 2 thienyls) propylamine, 2-(4-brombutyl)-5-(5-(4-brombutyl) 2 thienyls) 2 thienyls)
Thiophene or 4-5-(5-(5-(4-ammonia butyl) 2 thienyls) 2 thienyls) 2 thienyls) butylamine.
Oligopoly thiophene derivative of the present invention uses method commonly used in the art synthesis.
Oligopoly thiophene derivative of the present invention can suppress hemagglutinin conformation to change, thus suppresses influenza virus to carry out
Film merges, and plays prevention and the effect for the treatment of influenza, may be used for preparation prevention and the medicine for the treatment of influenza.
The medicine of above-mentioned prevention and treatment influenza can be Oligopoly thiophene derivative of the present invention and pharmaceutically acceptable thereof
Salt.
Detailed description of the invention
Embodiment 1
5mL DMF, 5mLDCM it is sequentially added in round-bottomed flask, 1mmol 2-the third aminothiophene, 1mmol DIC, 1
Mmol HOBT and 1mmol 3-fluoro-5-(Trifluoromethyl)benzoic acid..Stirring reaction 12 hours under room temperature.Then, decompression distillation
Remove solvent, column chromatographic isolation and purification, obtain slightly yellow solid product 3-fluoro-5-(trifluoromethyl)-N-(3-(2-thienyl) third
Base) Benzoylamide (3-fluoro-5-(trifluoromethyl)-N-(3-(thiophen-2-yl) propyl) benzamide compound number
1sd).Above-claimed cpd is characterized as below:1H NMR(CDCl3, 400MHz) and δ: 2,00-2.07 (m, 2H, J=28Hz),
2.94-2.98 (m, 2H, J=14Hz), 3.52-3.57 (m, 2H, J=19.2Hz), 6.27 (s, 1H), 6.92-6.94 (d, 1H, J=
8.0Hz), 7.13-7.14 (d, 1H, J=5.2Hz), 7.42-7.44 (d, 1H, J=7.6Hz), 7.58-7.59 (d, 1H, J=8.4Hz),
7.66(s,1H),13C NMR(CDCl3,125MHz)δ:28.0,31.4,40.3,115.6,115.7,115.8,115.9,118.0,
118.2,119.5,119.5,123.8,124.8,127.3,138.1,138.2,144.3,161.7,163.7,164.9；EI(+)-HRMS
m/z,calcd for C15H13F4NOS(M+23)354.0538,found354.0546.
Embodiment 2
5mL DMF, 5mLDCM it is sequentially added in round-bottomed flask, 1mmol 2-fourth aminothiophene, 1mmol DIC, 1
Mmol HOBT and 1mmol 3-fluoro-5-(Trifluoromethyl)benzoic acid..Stirring reaction 12 hours under room temperature.Then, decompression distillation
Remove solvent, column chromatographic isolation and purification.Obtain slightly yellow solid product 3-fluoro-5-(trifluoromethyl)-N-(4-(2-thienyl) butyl)
Benzoylamide (3-fluoro-5-(trifluoromethyl)-N-(4-(thiophen-2-yl) butyl) benzamide compound number 1se).
Above-claimed cpd is characterized as below: 1.66-1.68 (m, 2H, J=8.4Hz), 1.73-1.82 (m, 2H, J=34Hz), 2.88-2.92 (m,
2H, J=14.0Hz), 3.47-3.52 (m, 2H, J=19.6Hz), 6.10 (s, 1H), 6.79-6.80 (m, 1H, J=3.2Hz),
6.90-6.93 (m, 1H, J=12.0Hz), 7.11-7.13 (d, 1H, J=6.4Hz), 7.44-7.46 (d, 1H, J=8.0Hz),
7.65-7.67 (d, 1H, J=8.4Hz), 7.76 (s, 1H),13C NMR(CDCl3,125MHz)δ:29.0,29.2,29.6,115.7,
115.9,118.0,118.2,119.5,123.3,124.6,127.0,133.0,133.1,133.3,138.2,138.3,144.8,161.7,
163.7,164.9；EI(+)-HRMS m/z,calcd for C16H15F4NOS(M+23)368.0729,found 369.0733.。
Embodiment 3
Round-bottomed flask adds 1mmol 2-(4-nitrine butyl)-5-(5-(4-nitrine butyl) 2 thienyls) thiophene,
10mL oxolane/methanol (1:1) and the activation palladium/carbon of 10%.React 2 days under 50psi hydrogen.Then, will be anti-
Answering product to filter, decompression method removes solvent.Obtain white solid product 4-(5-(5-(4-ammonia butyl) 2 thienyls) 2 thiophene
Base) butylamine (4-(5-(5 (4-aminobutyl) thiophen-2-yl) thiophen-2-yl) butan-1-amine compound number 2sd).
Above-claimed cpd is characterized as below:1H NMR(400MHz,CDCl3):δ:1.48-1.58(m,4H),1.64-1.76(m,4H),2.73
(t,3J (H, H)=7.0Hz, 4H), 2.80 (t,3J (H, H)=7.3Hz, 4H), 6.66 (d,3J (H, H)=3.6Hz, 2H), 6.89 (d,3J (H, H)=3.6Hz, 2H)；13C NMR(75.5MHz,CDCl3):
δ:28.7,29.8,33.1,41.8,122.7,124.9,135.4,143.4；The same document of spectroscopic data (Angew.Chem.Int.Ed.1999,
38, No.10:1396) data of report in.
Embodiment 4
5mL DMF, 5mLDCM, 1mmol 3-(5-(2-thienyl) 2-thienyl) third it is sequentially added in round-bottomed flask
Amine, 1mmol DIC, 1mmol HOBT and 1mmol 3-fluoro-5-(Trifluoromethyl)benzoic acid..Under room temperature, stirring reaction 12 is little
Time.Then, solvent, column chromatographic isolation and purification are removed in decompression distillation.Obtain the fluoro-5-of slightly yellow solid product 3-(trifluoromethyl)
-N-(3-(5-(2 thienyl) 2 thienyls) propyl group) Benzoylamide (3-fluoro-5-
(trifluoromethyl)-N-(3-(5-(thiophene-2-yl) thiophen-2-yl) propyl) benzamide. compound number 2se).On
State characterization of compound as follows:1H NMR(CDCl3, 400MHz) δ: 2.02-2.09 (m, 2H, J=28.4Hz), 2.91-2.95 (m,
2H, J=14.4Hz), 3.55-3.60 (m, 2H, J=19.6Hz), 6.15 (s, 1H), 6.74-6.75 (d, 1H, J=3.2Hz),
6.98-7.00 (m, 2H, J=7.2Hz), 7.07-7.08 (d, 1H, J=3.6Hz), 7.17-7.18 (d, 1H, J=5.6Hz), 7.42-7.44
(d, 1H, J=8Hz), 7.59-7.61 (d, 1H, J=8.4Hz), 7.74 (s, 1H),13C NMR(CDCl3,125MHz)δ:28.1,
31.3,40.2,115.7,115.8,115.9,117.9,118.1,119.6,123.5,123.7,124.3,125.6,127.9,135.8,137.6,
138.0,143.5,161.6,163.6,165.0；EI(+)-HRMS m/z,calcd for C19H15F4NOS2(M+Na)436.0420,
found 436.0423.
Embodiment 5
5mL DMF, 5mLDCM, 1mmol 2sd, 1mmol DIC, 1mmol HOBT it is sequentially added in round-bottomed flask
5-(Trifluoromethyl)benzoic acid. fluoro-with 1mmol 3-.Stirring reaction 12 hours under room temperature.Then, solvent, post are removed in decompression distillation
Chromatography purification.Obtain yellow pin solid product 3-fluoro-5-(trifluoromethyl)-N-(4-(5-(2 thienyl) 2 thienyls)
Butyl) Benzoylamide
(3-fluoro-5-(trifluoromethyl)-N-(4-(5-(thiophene-2-yl) thiophen-2-yl) butyl) benzamide. compound is compiled
Number 2sf).Above-claimed cpd is characterized as below: Mp 87-89 DEG C.1H NMR(CDCl3,400MHz)δ:1.68-1.71(m,2H,
J=14.0Hz), 1.73-1.76 (m, 2H, J=13.6Hz), 2.82-2.86 (m, 2H, J=13.6Hz), 3.46-3.50 (m, 2H, J=
18.8Hz), 6.11 (s, 1H), 6.67-6.68 (d, 1H, J=3.2Hz), 6.96-6.97 (m, 2H, J=8.8Hz), 7.06-7.07 (d,
1H, J=2.4Hz), 7.14-7.15 (d, 1H, J=5.2Hz), 7.42-7.44 (d, 1H, J=8Hz), 7.64-7.66 (d, 1H, J=8.4
Hz),7.75(s,1H),13C NMR(DMSO-D6,125MHz)δ:28.9,29.0,40.2,115.6,115.8,117.9,118.1,
119.4,121.9,123.2,123.6,124.1,125.3,127.8,132.9,133.2,133.3,135.4,137.8,138.1,138.2,
144.1,161.6,163.6,164.9；EI(+)-HRMS m/z,calcd for C20H17F4NOS2(M+Na)450.0579,
found 450.0579。
Embodiment 6
In cyclohexane solution, add 1mmol tri-thiophene tetrahydrofuran solution, under nitrogen protection, at-78 DEG C, instill 4 equivalents
The butyl lithium of 2.6mol/L.Continue stirring 1 hour, then 1,3 dibromopropanes of 4 equivalents are joined in reactant liquor.Reaction
Temperature is raised to room temperature, continues reaction 12 hours.Then go out reaction with 10mL shrend, use ether extraction organic facies.Mix is organic
Wash with saturated aqueous common salt, use MgS04It is dried, concentrates organic facies with pressure reducing mode.Cross post and separate (hexamethylene/dichloromethane
10:1to 5:1).Obtain faint yellow solid product 2-(5-(3-bromopropyl) 2 thienyls)-5-(2 thienyl) thiophene
(2-(5-(3-bromopropyl) thiophen-2-yl)-5-(thiophen-2-yl) thiophen compound number 3sa).Above-claimed cpd
It is characterized as below:1H NMR(CDCl3, 400MHz) and δ: 2.17-2.24 (m, 2H, J=26.8Hz), 2.96-2.99 (m, 2H, J=
14.0Hz), 3.43-3.46 (m, 2H, J=12.8Hz), 6.72-6.74 (d, 1H, J=7.2Hz), 6.95-7.00 (m, 3H, J=20.4
Hz), 7.14-7.15 (d, 1H, J=5.2Hz), 7.19-7.20 (d, 2H, J=8Hz),13C NMR(DMSO-D6,125MHz)δ:
28.5,32.7,34.3,116.8,123.6,123.7,123.8,123.9,124.0,124.5,124.6,126.1,128.1,135.5,136.0,
136.3,136.6,137.4,142.7；EI(+)-HRMS m/z,calcd for C15H13BrS3(M+Na)390.9255,found
390.9254。
Embodiment 7
At 80 DEG C, in round-bottomed flask, add the sodium azide of 3sa, 2mmol of 2mL dry DMF, 1mmol, protect at nitrogen
Protect lower reaction overnight.Then will react cancellation with 10mL water, extract three times with 10mL dichloromethane.Organic facies saturated common salt
Water washs three times, uses MgSO4It is dried.Last column chromatographic isolation and purification.Obtain light yellow crystal 2-(5-(3-nitrine propyl group) 2 thiophene
Base)-5-(2 thienyl) thiophene (compile by 2-(5-(3-azidopropyl) thiophen-2-yl)-5-(thiophen-2-yl) thiophen compound
Number 3sb).Above-claimed cpd is characterized as below:1H NMR(CDCl3, 400MHz) and δ: 1.95-1.99 (m, 2H, J=14.0Hz),
2.89-2.93 (m, 2H, J=14.8Hz), 3.35-3.39 (m, 2H, J=13.2Hz), 6.72-6.73 (d, 1H, J=3.2Hz),
6.97-7.02 (m, 3H, J=20.4Hz), 7.06-7.07 (d, 1H, J=3.6Hz), 7.16-7.17 (d, 1H, J=2.8Hz),
7.21-7.22 (d, 1H, J=4.4Hz),13C NMR(DMSO-D6,125MHz)δ:27.3,30.8,50.5,123.7,123.8,
124.0,124.5,124.6,125.9,128.1,135.4,136.1,136.3,136.6,137.4,143.2；EI(+)-HRMS m/z,
calcd for C15H13N3(M+Na)354.0164,found 354.0157。
Embodiment 8 (S3-3-NH2)
3sb, 10mL oxolane/methanol (1:1) of 1mmol and the activation palladium/carbon of 10% is added in round-bottomed flask.
React 2 days under 50psi hydrogen.Then, product being filtered, decompression method removes solvent.Obtain white solid product
3-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) propylamine (3-(5-(5-(thiophen-2-yl) thiophen
-2-yl) thiophen-2-yl) propan-1-amine compound number 3sc).Above-claimed cpd is characterized as below: 1H-NMR (270MHz)
(CDCl3) δ: 1.78-1.89 (tt, 2H, J=7.3,7.0Hz), 2.76-2.88 (m, 4H), 6.69-7.21 (m, 7H).
The number of report in the same document of spectroscopic data (K.Kawai et al./Bioorg.Med.Chem.Lett.15 (2005) 4,547 4549)
According to.
Embodiment 9
In cyclohexane solution, add 1mmol tri-thiophene tetrahydrofuran solution, under nitrogen protection, at-78 DEG C, instill 4 equivalents
The butyl lithium of 2.6mol/L.Continue stirring 1 hour, then the dibromo alkane of 4 equivalents is joined in reactant liquor.Reaction temperature liter
To room temperature, continue reaction 12 hours.Then go out reaction with 10mL shrend, use ether extraction organic facies.The organic facies of mixing is with full
And brine It, use MgS04It is dried, concentrates organic facies with pressure reducing mode.Cross post and separate (hexamethylene/dichloromethane 10:1to
5:1).Obtain white crystal 2-(4-brombutyl)-5-(5-(2 thienyl) 2 thienyls) thiophene (2-(4-bromobutyl)-5-(5
-(thiophen-2-yl) thiophen-2-yl) thiophene compound number 3sd).Above-claimed cpd is characterized as below:1H NMR
(CDCl3, 400MHz) and δ: 1.83-1.89 (m, 2H, J=22.4Hz), 1.92-1.97 (m, 2H, J=20.4Hz), 2.79-2.86
(m, 2H, J=38.0Hz), 3.42-3.45 (m, 2H, J=12.8Hz), 6.69-6.70 (d, 1H, J=7.8Hz), 6.96-7.02 (d, 4H,
J=22.4Hz), 7.15-7.16 (d, 1H, J=2.8Hz), 7.20-7.21 (d, 1H, J=5.2Hz),13C NMR(CDCl3,125
MHz)δ:29.5,30.2,32.1,33.5,123.7,123.8,123.9,124.5,125.5,128.1,135.1,135.9,136.8,137.5,
144.4；EI(+)-HRMS m/z,calcd for C16H15BrS3(M+1)382.9584,found382.9592。
Embodiment 10
At 80 DEG C, in round-bottomed flask, add the sodium azide of 3sd, 2mmol of 2mL dry DMF, 1mmol, at nitrogen
The lower reaction of protection is overnight.Then will react cancellation with 10mL water, extract three times with 10mL dichloromethane.The saturated food of organic facies
Saline washs three times, uses MgSO4It is dried.Last column chromatographic isolation and purification.Obtain white solid product 2-(4-nitrine butyl)-5-
(5-(2 thienyl) 2 thienyls) thiophene (2-(4-azidobutyl)-5-(5-(thiophen-2-yl) thiophen-2-yl) thiopheneization
Compound numbering 3se).Above-claimed cpd is characterized as below:1H NMR(CDCl3, 400MHz) and δ: 1.66-1.72 (m, 2H, J=
27.2Hz), 1.75-1.82 (m, 2H, J=28.2Hz), 2.83-2.86 (m, 2H, J=14.4Hz), 3.30-3.33 (m, 2H, J=
13.2Hz), 6.69-6.71 (d, 1H, J=3.2Hz), 6.98-7.03 (d, 3H, J=17.6Hz), 7.05-7.07 (d, 1H, J=3.6Hz),
7.16-7.17 (d, 1H, J=3.2Hz), 7.20-7.22 (d, 1H, J=5.2Hz),13C NMR(CDCl3,125MHz)δ:28.4,
28.8,29.9,51.4,123.6,123.8,123.9,124.5,124.6,125.4,128.1,135.1,135.9,136.8,137.4,144.4；
EI(+)-HRMS m/z,calcd for C16H15N3S3(M+1)346.0500,found346.0496。
Embodiment 11
3se, 10mL oxolane/methanol (1:1) of 1mmol and the activation palladium/carbon of 10% is added in round-bottomed flask.
React 2 days under 50psi hydrogen.Then, product being filtered, decompression method removes solvent.Obtain white needles product
4-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) butylamine (4-(5-(5-(thiophen-2-yl) thiophen
-2-yl) thiophene-2-yl) butan-1-amine compound number 3sf).Above-claimed cpd is characterized as below:1H NMR(CDCl3,
400MHz) δ: 1.44-1.48 (m, 2H, J=14.8Hz), 1.64-1.70 (m, 2H, J=23.2Hz), 2.60-2.63 (m, 2H, J
=17.0Hz), 2.80-2.84 (m, 2H, J=14.4Hz), 6.85-6.86 (d, 1H, J=3.6Hz), 7.13-7.15 (m, 1H, J=8.4
Hz), 7.17-7.18 (d, 1H, J=3.6Hz), 7.20-7.21 (d, 1H, J=3.6Hz), 7.27-7.28 (d, 1H, J=3.6Hz),
7.35-7.36 (d, 1H, J=2.8Hz), 7.55-7.56 (d, 1H, J=4.4Hz),13C NMR(CDCl3,125MHz)δ:28.4,
29.2,31.8,40.9,123.9,124.1,125.5,125.7,128.4,133.4,134.7,135.7,136.0,145.0；
EI(+)-HRMS m/z,calcd for C16H17NS3(M+1)320.0584,found320.0595.。
Embodiment 12 (Br-3-S3-3-Br)
In cyclohexane solution, add 1mmol tri-thiophene tetrahydrofuran solution, under nitrogen protection, at-78 DEG C, instill 4 equivalents
The butyl lithium of 2.6mol/L.Continue stirring 1 hour, then 1,3 dibromopropanes of 4 equivalents are joined in reactant liquor.Reaction
Temperature is raised to room temperature, continues reaction 12 hours.Then go out reaction with 10mL shrend, use ether extraction organic facies.Mix is organic
Wash with saturated aqueous common salt, use MgS04It is dried, concentrates organic facies with pressure reducing mode.Cross post and separate (hexamethylene/dichloromethane
10:1to 5:1).Obtain white solid product 2,5-bis-(5-(3-bromopropyl) 2 thienyls) thiophene
(2,5-bis (5-(3-bromopropyl) thiophen-2-yl) thiophen compound number 3sg).Above-claimed cpd is characterized as below:1H
NMR(CDCl3, 400MHz) and δ: 2.17-2.22 (m, 4H, J=20.8Hz), 2.96-2.99 (m, 4H, J=14.4Hz),
3.43-3.47 (m, 4H, J=13.2Hz), 6.71-6.72 (d, 2H, J=3.6Hz), 6.91-6.92 (d, 4H, J=3.6Hz),13C
NMR(DMSO-D6,125MHz)δ:28.5,32.7,34.3,123.6,123.9,126.1,135.6,136.3,142.7；
EI(+)-HRMS m/z,calcd for C18H18Br2S3(M+Na)510.8829,found 510.8834。
Embodiment 13 (NH2-3-S3-3-NH2)
2-(3-nitrine propyl group)-5-(5-(5-(3-nitrine propyl group) 2-thienyl) the 2-thiophene of 1mmol is added in round-bottomed flask
Base) thiophene, 10mL oxolane/methanol (1:1) and the activation palladium/carbon of 10%.React 2 days under 50psi hydrogen.So
After, product is filtered, decompression method removes solvent.Obtain light yellow crystal 3-(5-(5-(5-(3-aminopropyl) 2 thienyls) 2 thiophene
Base) 2 thienyls) propylamine (3-(5-(5-(5-(3
-aminopropyl) thiophen-2yl) thiophen-2-yl) thiophen-2-yl) propan-1-amine compound number 3sh).Above-mentionedization
Compound is characterized as below:1H NMR(DMSO-D6, 400MHz) δ: 1.65-1.71 (m, 4H, J=21.6Hz), 2.57-2.61 (m,
4H, J=13.6Hz), 2.79-2.83 (m, 4H, J=14.8Hz), 6.80-6.81 (d, 2H, J=2.4Hz), 7.10-7.11 (d, 2H, J
=0.8Hz), 7.13 (s, 2H). the same document of spectroscopic data (K.Kawai et al./Bioorg.Med.Chem.Lett.15 (2005)
4547 4549) data of report in.
Embodiment 14
In cyclohexane solution, add 1mmol tri-thiophene tetrahydrofuran solution, under nitrogen protection, at-78 DEG C, instill 4 equivalents
The butyl lithium of 2.6mol/L.Continue stirring 1 hour, then the Isosorbide-5-Nitrae dibromobutane of 4 equivalents is joined in reactant liquor.Reaction
Temperature is raised to room temperature, continues reaction 12 hours.Then go out reaction with 10mL shrend, use ether extraction organic facies.Mix is organic
Wash with saturated aqueous common salt, use MgS04It is dried, concentrates organic facies with pressure reducing mode.Cross post and separate (hexamethylene/dichloromethane
10:1to 5:1).Obtain yellow solid product 2-(4-brombutyl)-5-(5-(4-brombutyl) 2 thienyls) 2 thienyls) thiophene
(2-(4-bromobutyl)-5-(5-(5-(4-bromobutyl) thiophen-2-yl) thiophen-2-yl) thiophene compound number
3sh).Above-claimed cpd is characterized as below:1H NMR(CDCl3, 400MHz) and δ: 1.81-1.86 (m, 4H, J=22.4Hz),
1.92-1.99 (m, 4H, J=27.2Hz), 2.82-2.86 (m, 4H, J=13.6Hz), 3.42-3.45 (m, 4H, J=12.8Hz),
6.69-6.70 (d, 2H, J=3.6Hz), 6.96-6.97 (d, 2H, J=3.6Hz), 6.98 (s, 2H),13C NMR(CDCl3,125
MHz)δ:29.5,30.2,32.1,33.5,123.5,123.9,125.4,135.2,136.3,144.2；EI(+)-HRMS m/z,calcd
for C20H22Br2S3(M+23)538.9169,found538.9142.。
Embodiment 15
2-(4-nitrine butyl)-5-(5-(5-(4-nitrine butyl) 2-thienyl) the 2-thiophene of 1mmol is added in round-bottomed flask
Base) thiophene, 10mL oxolane/methanol (1:1) and the activation palladium/carbon of 10%.React 2 days under 50psi hydrogen.So
After, product is filtered, decompression method removes solvent.Obtain white solid product 5-(5-(4
-aminobutyl) thiophen-2-yl) thiophen-2-yl) thiophene-2-yl) butan-1-amine compound number 3sk).Above-mentionedization
Compound is characterized as below:1H NMR(CDCl3, 400MHz) δ: 1.42-1.47 (m, 4H, J=22.4Hz), 1.64-1.69 (m, 4H,
J=22.8Hz), 2.54-2.60 (m, 4H, J=25.2Hz), 2.79-2.83 (m, 4H, J=14.8Hz), 6.84-6.85 (d, 2H, J=
3.2Hz), 7.14-7.17 (d, 4H, J=10.8Hz),13C NMR(CDCl3,125MHz)δ:28.1,28.9,32.3,40.9,
123.4,123.7,125.1,133.2,135.0,144.8；EI(+)-HRMS m/z,calcd for C20H26N2S3(M+1)
391.1322,found391.1330。
Embodiment 16
In cyclohexane solution, add 1mmol tetra-thiophene tetrahydrofuran solution, under nitrogen protection, at-78 DEG C, instill 4 equivalents
The butyl lithium of 2.6mol/L.Continue stirring 1 hour, then 1,3 dibromopropanes of 4 equivalents are joined in reactant liquor.Reaction
Temperature is raised to room temperature, continues reaction 12 hours.Then go out reaction with 10mL shrend, use ether extraction organic facies.Mix is organic
Wash with saturated aqueous common salt, use MgS04It is dried, concentrates organic facies with pressure reducing mode.Cross post and separate (hexamethylene/dichloromethane
10:1to 5:1).Obtain white solid product 2-(3-bromopropyl)-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) thiophene
(2-(3-bromotubyl)-5-(5-(5-(thiophen-2-yl) thiophen-2-yl) thiophen-2-yl) thiophene compound number
4sa).Above-claimed cpd is characterized as below:1H NMR(CDCl3, 400MHz) and δ: 2.19-2.54 (m, 2H, J=26.8Hz),
2.96-3.01 (m, 2H, J=23.2Hz), 3.45-3.48 (m, 2H, J=12.8Hz), 6.75-6.76 (d, 1H, J=3.6Hz),
6.99-7.03 (m, 2H, J=13.6Hz), 7.03-7.04 (m, 1H, J=1.2Hz), 7.05-7.09 (m, 2H, J=13.6Hz),
7.17-7.18 (d, 1H, J=2.8Hz), 7.22-7.23 (d, 1H, J=4.4Hz),13C NMR(CDCl3,125MHz)δ:28.5,
32.7,34.2,123.8,123.9,124.1,124.4,124.5,124.6,124.7,126.1,128.1,135.5,135.7,136.2,136.5,
136.8,137.3,142.9；EI(+)-HRMS m/z,calcd for C19H15BrS4(M+23)472.9132,found 472.9225.。
Embodiment 17
At 80 DEG C, in round-bottomed flask, add the sodium azide of 4sa, 2mmol of 2mL dry DMF, 1mmol, protect at nitrogen
Protect lower reaction overnight.Then will react cancellation with 10mL water, extract three times with 10mL dichloromethane.Organic facies saturated common salt
Water washs three times, uses MgSO4It is dried.Last column chromatographic isolation and purification.Obtain slightly yellow solid product 2-(3-nitrine third
Base)-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) thiophene (2-(3-azidotubyl)-5
-(5-(5-(thiophen-2-yl) thiophen-2-yl) thiophen-2-yl) thiophene compound number 4sb).Above-claimed cpd characterizes
As follows: 1H NMR (600MHz, CDCl3): d=8.14 (s, 1H), 7.43 7.04 (m, 9H), 5.21 (s, 1H), 3.97 (t, J=
7.1Hz, 2H), 3.67 (m, 1H), 1.84 1.58 (m, 7H), 1.21 1.06 (m, 3H), 0.97 (d, J=7.1Hz, 3H) ppm；
13C NMR (150MHz, CDCl3): d=164.6,164.4,142.7,137.9,137.6,131.3,128.3,128.2,128.0,
124.2,117.3,110.5,61.8,60.0,54.4,30.9,30.6,26.0,25.8,25.2,13.8ppm.ESI-MS:484(M+H+)。
Embodiment 18
4sb, 10mL oxolane/methanol (1:1) of 1mmol and the activation palladium/carbon of 10% is added in round-bottomed flask.
React 2 days under 50psi hydrogen.Then, product being filtered, decompression method removes solvent.Obtain slightly yellow crystalline product
3-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) 2 thienyl propylamine (3-5-(5-(5-(thiophen
-2-yl) thiophen-2-yl) thiophen-2-yl) thiophene-2-yl) propan-1-amine compound number 4sc).Above-claimed cpd
It is characterized as below:1H NMR(DMSO-D6,70℃,400MHz)δ:1.64(s,2H),2.63(s,2H),3.11(s,2H),
6.83 (s, 1H), 7.11-7.18 (m, 3H, J=26.4Hz), 7.27 (s, 3H), 7.34 (s, 1H), 7.53 (s, 1H),13C NMR
(DMSO-D6,70℃,125MHz)δ:26,4,33,7,40.1,123.7,123.8,123.9,124.5,124.6,124.7,125.2,
125.3,127.9,133.1,133.9,134.6,135.3,135.7,135.8,144.8；EI(+)-HRMS m/z,calcd for
C19H17NS4(M+1)388.0310,found 388.0316。
Embodiment 19 (effect experimental)
1, Experimental agents
Numbering 1sd:3-fluoro-5-(trifluoromethyl)-N-(3-(2-thienyl) propyl group) Benzoylamide (3-fluoro-5-(trifluoromethyl)
-N-(3-(thiophen-2-yl)propyl)benzamide)
Numbering 1se:3-fluoro-5-(trifluoromethyl)-N-(4-(2-thienyl) butyl) Benzoylamide
(3-fluoro-5-(trifluoromethyl)-N-(4-(thiophen-2-yl)butyl)benzamide)
Numbering 2sd:4-(5-(5-(4-ammonia butyl) 2 thienyls) 2 thienyls) butylamine (4-(5-(5 (4-aminobutyl) thiophen-2
-yl)thiophen-2-yl)butan-1-amine)
Numbering 2se:3-fluoro-5-(trifluoromethyl)-N-(3-(5-(2 thienyl) 2 thienyls) propyl group) Benzoylamide (3-fluoro-5-
(trifluoromethyl)-N-(3-(5-(thiophene-2-yl)thiophen-2-yl)propyl)benzamide.)
Numbering 2sf3-fluoro-5-(trifluoromethyl)-N-(4-(5-(2 thienyl) 2 thienyls) butyl) Benzoylamide
(3-fluoro-5-(trifluoromethyl)-N-(4-(5-(thiophene-2-yl)thiophen-2-yl)butyl)benzamide)
Numbering 3sa:2-(5-(3-bromopropyl) 2 thienyls)-5-(2 thienyl) thiophene (2-(5-(3-bromopropyl) thiophen-2
-yl)-5-(thiophen-2-yl)thiophen)
Numbering 3sb:2-(5-(3-nitrine propyl group) 2 thienyls)-5-(2 thienyl) thiophene (2-(5-(3-azidopropyl) thiophen
-2-yl)-5-(thiophen-2-yl)thiophen)
Numbering 3sc:3-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) propylamine (3-(5-(5-(thiophen-2-yl) thiophen
-2-yl)thiophen-2-yl)propan-1-amine)
Numbering 3sd:2-(4-brombutyl)-5-(5-(2 thienyl) 2 thienyls) thiophene (2-(4-bromobutyl)-5-(5-(thiophen
-2-yl)thiophen-2-yl)thiophene)
Numbering 3se:2-(4-nitrine butyl)-5-(5-(2 thienyl) 2 thienyls) thiophene (2-(4-azidobutyl)-5-(5-(thiophen
-2-yl)thiophen-2-yl)thiophene)
Numbering 3sf:4-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) butylamine (4-(5-(5-(thiophen-2-yl) thiophen
-2-yl)thiophene-2-yl)butan-1-amine)
Numbering 3sg:2,5-bis-(5-(3-bromopropyl) 2 thienyls) thiophene
(2,5-bis(5-(3-bromopropyl)thiophen-2-yl)thiophen)
Numbering 3sh:3-(5-(5-(5-(3-aminopropyl) 2 thienyls) 2 thienyls) 2 thienyls) propylamine (3-(5-(5-(5-(3
-aminopropyl)thiophen-2yl)thiophen-2-yl)thiophen-2-yl)propan-1-amine)
Numbering 3si:2-(4-brombutyl)-5-(5-(4-brombutyl) 2 thienyls) 2 thienyls) thiophene
(2-(4-bromobutyl)-5-(5-(5-(4-bromobutyl)thiophen-2-yl)thiophen-2-yl)thiophene)
Numbering 3sk:4-5-(5-(5-(4-ammonia butyl) 2 thienyls) 2 thienyls) 2 thienyls) butylamine (4-5-(5-(5-(4
-aminobutyl)thiophen-2-yl)thiophen-2-yl)thiophene-2-yl)butan-1-amine)
Numbering 4sa:2-(3-bromopropyl)-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) thiophene
(2-(3-bromotubyl)-5-(5-(5-(thiophen-2-yl)thiophen-2-yl)thiophen-2-yl)thiophene)
Numbering 4sb:2-(3-nitrine propyl group)-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) thiophene (2-(3-azidotubyl)-5
-(5-(5-(thiophen-2-yl)thiophen-2-yl)thiophen-2-yl)thiophene)
Numbering 4sc:3-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) 2 thienyl propylamine (3-5-(5-(5-(thiophen
-2-yl)thiophen-2-yl)thiophen-2-yl)thiophene-2-yl)propan-1-amine)
2, the activity experiment of In Vitro Anti H5N1 bird flu pseudovirus
Pseudovirus experiment refers to express the HA plasmid of H5N1 influenza virus envelopes albumen, NA plasmid and expressing luciferase
(Luciferase) the pNL4-3.Luc.R-E-plasmid of vpr and the env defect of reporter gene, cotransfection 293T cell, assemble
One-tenth can only replicate H5N1 bird flu pseudovirus once.Owing to bird flu virus enters the process of target cell by envelope protein HA
Being mediated, therefore pseudovirus experiment is the experimental system that extremely sensitive, objective, a safe simulation euvirus enters, available
In the activity evaluating compound suppression influenza virus entrance target cell.
Medicine is hatched with mdck cell, is subsequently adding H5N1 bird flu pseudovirus, after cultivating 48h, cell pyrolysis liquid
Cell lysis, with the Luciferase Assay Reagent box of Promega company, detects chemiluminescence on multi-functional microwell plate analyser
Value, it is judged that the inhibitory activity of compound, calculation of half inhibitory concentration IC50.Positive control medicine is CL-385319.
The results are shown in Table 1.
Table 1
From table 1, it is known that Oligopoly thiophene derivative of the present invention has the effect of suppression H5N1 bird flu virus.
3, the activity experiment of In Vitro Anti H1N1 bird flu live virus
With every hole 2.5 × 104Individual mdck cell kind plate is in 96 orifice plates, and at 37 DEG C of 5%CO2Under the conditions of cultivate 24h.A type
The testing compound of H1N1 influenza virus PR8 and the 2 times of dilutions of 7 Concentraton gradient hatches 1h altogether in 37 DEG C, and initial concentration is
8-200μM.After PBS mdck cell 2 times, infect adherent cell with aforementioned viral-medicinal mixture in 37 DEG C
1h, abandons supernatant, changes the culture medium continuation cultivation 48h processing pancreatin containing respective concentration testing compound and 1 μ g/ml TPCK.
Use the yield of neuraminidase (NA) activity experiment detection culture supernatant generation of neutrons virus.Summary process is as follows, by cultivation
Be transferred to clearly 96 hole blackboards, and with 20 μMs of 2-(4-Methylumbelliferyl-a-D-N-acetylneuraminic acid sodium
Salt (MUNANA, Sigma, cat.No M8639), 33mM 2-[N-morpholino] ethanesulfonic acid (pH 6.5),
4mM CaCl21h is hatched at 37 degree.Then reaction is terminated with 0.14M NaOH (83% ethanol).Use microplate reader (Genios
Pro, Tecan, US) fluorescence intensity, excitation wavelength is 340nm, a length of 535nm of transmitted wave.Use Reed-Muench
Method [Reed, L.J., Muench, H., 1938.A simple method of estimating fifty percent endpoint.Am.J.
Hyg.27,493-497] calculate the IC50 that Drug inhibition is viral, i.e. cause viral yield to reduce by the drug level of 50%.
CL-385319 is as positive control drug.The results are shown in Table 2.
Table 2 part Oligopoly thiophene derivative anti-H1N1 live virus activity
From table 1, it is known that 8 shown in table 1 Oligopoly thiophene derivative has the effect of suppression H1N1 bird flu virus.
The present invention provide Oligopoly thiophene derivative be a class novel influenza entry inhibitor, molecular weight 300-600Da it
Between, in pseudovirus Activity Screening Test, most compounds can suppress the entrance of influenza, has suppression H5N1 activity.As
Products nr is that the activity of 3sf is best, IC50Reach 29nM.It it is the compound that in known compound, activity is best.To part
Compound has carried out the screening of H1N1 influenza virus, finds that 8 compounds have the effect of suppression H1N1 influenza virus, wherein
The activity of 4sc is best.Therefore, this compounds can be as influenza entry inhibitor.It is with a wide range of applications.
The present invention provide Oligopoly thiophene derivative and the most acceptable salt can individually or combine other drug apply,
The medicine of related disorders is had for preparing treatment H5N1, H1N1.
Claims (3)
1. an Oligopoly thiophene derivative, shown in the following formula I of its molecular structure:
Oligopoly thiophene derivative shown in formula I is 2-(5-(3-bromopropyl) 2 thienyls)-5-(2 thienyl) thiophene, 4-(5-(5-(2
Thienyl) 2 thienyls) 2 thienyls) butylamine, 2-(5-(3-Azidopropyl) 2 thienyls)-5-(2 thienyl) thiophene, 2-(4-nitrine
Base butyl)-5-(5-(2 thienyl) 2 thienyls) thiophene, 2-(3-bromopropyl)-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) thiophene,
2-(3-Azidopropyl)-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) thiophene, 3-5-(5-(5-(2 thienyl) 2 thienyls) 2
Thienyl) 2 thienyl propylamine, 2,5-bis-(5-(3-bromopropyl) 2 thienyls) thiophene, 2-(4-brombutyl)-5-(5-(4-brombutyl) 2 thiophene
Base) 2 thienyls) thiophene or 4-5-(5-(5-(4-ammonia butyl) 2 thienyls) 2 thienyls) 2 thienyls) butylamine.
2. the application in preparation treatment H5N1 flu pharmaceutical of the Oligopoly thiophene derivative described in claim 1.
3. the application in preparation treatment H1N1 flu pharmaceutical of the Oligopoly thiophene derivative described in claim 1, wherein said
Oligopoly thiophene derivative is 3-5-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) 2 thienyl propylamine, 2-(4-nitrine butyl)-5-(5-(2
Thienyl) 2 thienyls) thiophene, 4-(5-(5-(2 thienyl) 2 thienyls) 2 thienyls) butylamine, 2,5-bis-(5-(3-bromopropyl) 2 thiophene
Base) thiophene, 2-(4-brombutyl)-5-(5-(4-brombutyl) 2 thienyls) 2 thienyls) thiophene or 4-5-(5-(5-(4-ammonia butyl) 2 thienyls) 2
Thienyl) 2 thienyls) butylamine.
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Non-Patent Citations (2)
| Title |
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| CAS RN;REGISTRY;《STN》;20141017;全文 * |
| 噻吩类衍生物抗H5N1流感的研究;朱志博等;《万方数据库》;20131121;191 * |
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