CN105566306B - A kind of application of chromocor derivative prepared and its neuraminidase is inhibited - Google Patents
A kind of application of chromocor derivative prepared and its neuraminidase is inhibited Download PDFInfo
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- CN105566306B CN105566306B CN201410540175.1A CN201410540175A CN105566306B CN 105566306 B CN105566306 B CN 105566306B CN 201410540175 A CN201410540175 A CN 201410540175A CN 105566306 B CN105566306 B CN 105566306B
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Abstract
The present invention relates to a kind of heteroaromatic carboxylate chromocor derivatives and preparation method thereof, purposes；The heteroaromatic carboxylate chromocor derivative structural formula such as formula () shown in；Wherein R1、R4Respectively hydrogen, vinegar acyl group or heteroaromatic acyl group；R2、R3Respectively hydroxyl or acetate groups；R5Respectively hydrogen, hydroxyl or acetate groups, the derivative are 7- heteroaromatic carboxylate chromocor derivative, 4 '-heteroaromatic carboxylate chromocor derivatives or 7,4 '-heteroaromatic carboxylate chromocor derivatives.The invention further relates to preparation method, the purposes of aforementioned heteroaromatic carboxylate chromocor derivative.Heteroaromatic carboxylate chromocor derivative of the invention can inhibit the activity of neuraminidase, the inhibitory activity original of part of compounds to be higher than natural flavone, can be used for preparing prevention and treat the drug of virus flu.
Description
Technical field: the present invention relates to the novel chromocor derivatives for carrying heteroaromatic ester, and the chromocor derivative is to mind
The application and preparation method thereof inhibited through propylhomoserin enzyme；Belong to drug field.
Background technique: influenza abbreviation influenza is a kind of acute viral upper respiratory tract as caused by influenza virus
Infectious disease has the characteristics that infectiousness is strong, propagates that fast, incubation period is short, disease incidence is high, very big to human health risk, at
For the highest viral infection disease of lethality.Rapidly due to influenza virus variation, novel influenza virus is emerged one after another, such as close
The bird flu broken out in the world over year, just once allowed whole world medical worker helpless, seriously threatened the strong of the mankind
Health and life security, cause huge economic losses.Therefore, the novel anti-influenza virus medicament for different target spots is constantly looked for,
It is effectively to control new virus strain for fast-spreading unique channel.
Currently, the major measure of prevention and treatment influenza has in the world: vaccine inoculation, adamantane amine drug, influenza disease
Malicious receptor blocker and antisense nucleoside acids Tamiflu, neuraminidase inhibitor.In contrast neuraminidase inhibits
Agent (NA) is the current breakthrough explored and obtained in the research of anti influenza chemotherapeutic agent, it can effectively block influenza
The reproduction process of virus.Compared with other types of anti-influenza virus medicament, NA inhibitor is with higher curative effect and preferably
Safety and tolerance, and it is effective to all influenza virus sub-strains, also seldom there is the drug resistance of virus, it has also become the world
The hot spot that major pharmaceuticals is competitively studied.There are two types of the NA inhibitor listed at present: the Zanamivir of Ge Lansu company
The Oseltamivir(054104 of (GG167, trade name Relenza) and Roche Holding Ag, trade name Tamiflu).The former is sucking
Administration, the country there is no production and import；The latter is that the current country is generally believed to the effective drug of Influenza A H1N1, but from
There is drug resistance since 2007.
Many natural products, which are also reported, in recent years has certain resisiting influenza virus NA activity, and wherein most is flavonoids
Close object, including flavanones, flavones, chalcone and diaryl class compound.Its structure activity study finds electrical factor and space
Factor is the key that influence flavonoids NA inhibitor activity, 4-OH, 7-OH, C4=O and C2=C3It is necessary to be to maintain NA inhibitory activity
Pharmacophore, and such NA inhibitor be noncompetitive NA inhibitor, may by conjunction with the region outside the activated centre NA come
Inhibitory enzyme activity is expected to solve the problems, such as NA drug resistance.But the more poorly water-solubles of flavone compound, it is difficult to absorb, greatly reduce
Its bioavilability has no the successful exploitation of efficient flavonoids neuraminidase inhibitor so far.Therefore how to enhance flavonoids
Ingredient improves its bioavilability to the inhibitory activity of neuraminidase, is the research emphasis for developing such inhibitor.At present
Flavones ingredient is concentrated mainly on the screening of natural origin flavones to the research of neuraminic acid enzyme inhibition activity, and in terms of derivative
Only glucosides replaces, alicyclic heterocyclic replaces and the activity research of the substitution product of the simple group such as methoxyl group, hydroxyl, does not send out therefrom
Existing highly efficient depressor, therefore still have larger research space in this regard.We carry out chemistry to flavone compound luteolin and spread out
Raw, introduce heteroaromatic in the molecule, find to the activity research of its derivative: gained derivative has neuraminidase more preferable
Inhibiting effect.
Summary of the invention: an object of the present invention is to find one kind to inhibit the novel flavonoids of neuraminidase activity
Derivative.
The second purpose of the invention is to provide a kind of methods for preparing chromocor derivative.
The third object of the present invention is to provide purposes of the chromocor derivative on medicine or treatment.
Technical solution provided by the present invention is:
Novel chromocor derivative with following general formula:
Its
Middle R1And R4The heteroaryl CO for being respectively selected from for example preferred Ac of H, C1-6 alkyl CO, optionally replacing, wherein the heteroaryl CO optionally replaced
Are as follows:
,
Substitution on heteroaryl preferably wherein
It can be monosubstituted or polysubstituted；R is the C1-6 alkyl optionally replaced, halogen, hydroxyl, sulfydryl, amino etc., wherein taking
Dai Jiwei halogen, hydroxyl, sulfydryl, amino or carboxyl etc.；X is NH, S, O or CH2；X1 is N or CH；
R2And R3It is respectively selected from OH, OAc, SH, NH2Or H；
R5For H, OH, C1-6 alkyl acyl (preferably acetyl group), halogen (preferably chlorine, bromine or fluorine).
The present invention also provides the preparation method of above-mentioned novel chromocor derivative, route is following (sheme 1-3):
The preparation of 1 7- heterocyclic ester luteolin derivative of Scheme
The preparation of Scheme 24 '-heterocyclic ester luteolin derivative
The preparation of Scheme 3 7,4 '-bis- heterocyclic esters luteolin derivative
It is currently preferred the preparation method is as follows:
The preparation of 1.7-heterocyclic ester luteolin derivatives
Luteolin is dissolved in benzyl oxide, with excessive dichloro-diphenyl methane (Ph2CCl2) reaction, it obtains
3 ', 4 '-OH selective protection products.The product and heterocyclic carboxylic acid stoichiometric number in THF under DCC, DMAP catalysis
Hour, it obtains 7- heterocyclic ester and replaces luteolin derivative.Chosen property deprotection, acetylating hydroxyl groups obtain final product 7- heterocycle again
Ester substitution-full acetylated luteolin derivative.
By taking niacin as an example, below reaction route (Scheme 4) is clearer represents the reaction process.
The preparation of 4 7- nicotinate luteolin derivative of Scheme
2. the preparation of 4 '-heterocyclic ester luteolin derivative
Luteolin is dissolved in, luteolin is dissolved in benzyl oxide, with excessive dichloro-diphenyl methane
(Ph2CCl2) reaction, obtain 3 ', 4 '-OH selective protection products.The product is dissolved in THF, K2CO3Catalysis it is lower with
Chloromethyl methyl ether (MOMCl) reaction obtains 7-OMOM protection product.Again after 3 ', 4 '-OH deprotection, exist with heterocyclic carboxylic acid
A few hours are reacted in THF under DCC, DMAP catalysis, are obtained 4 '-heterocyclic esters and are replaced luteolin derivative.The derivative is in acidity
Under the conditions of removing MOM protection, the full acetylated 4 '-heterocyclic esters that obtain replace-full acetylated luteolin derivative.
By taking niacin as an example, below reaction route (Scheme 5) is clearer represents the reaction process.
The preparation of Scheme 54 '-nicotinate luteolin derivative
3.7-heterocyclic ester luteolin derivatives, 4 '-heterocyclic ester luteolin derivatives and 7,4 '-bis- heterocyclic ester wood
Luteolin is dissolved in THF by the preparation of the plain derivative of rhinoceros grass, is descended and enough heterocycle carboxylics in DCC, DMAP catalysis
After acid reaction a few hours, products therefrom is that DMAP catalysis is lower and reacts with aceticanhydride, obtains 7- heterocyclic ester substitution-full acetylated sweet-scented osmanthus
Careless element derivative and 4 '-heterocyclic esters substitution-full acetylated luteolin derivative.
By taking niacin as an example, below reaction route (Scheme 6) is clearer represents the reaction process.
The preparation of Scheme 6 7,4 '-bis- nicotinates luteolin derivative
When synthesizing compound 2b, 3c, 1a and 1b in above-mentioned reaction, compound 2a, 3b and 1 with mole score of heterocyclic carboxylic acid
Not are as follows: 1:1.1 ~ 3,1:1.1 ~ 3,1:2 ~ 5.
When synthesizing compound 2,3, the molar ratio of compound 2c, 3d, 1a and 1b and aceticanhydride is all are as follows: 1:4 ~ 20 guarantee excessive.
The present invention has carried out neuraminidase to the noval chemical compound of synthesis using neuraminidase inhibitor screening reagent box
The screening of inhibitory activity finds that synthesized compound all has certain neuraminic acid enzyme inhibition activity, wherein there is 4 kinds of compounds
Neuraminic acid enzyme inhibition activity be substantially better than reference substance luteolin, can do to prepare neuraminidase inhibitor, for resisting
Virus drugs.
Specific embodiment:
Technical solution of the present invention and application are described further below in conjunction with specific embodiment:
Embodiment 1:7- nicotinate -5,3 ', the synthesis of 4 '-triacetate base luteolin derivatives
Luteolin 1 (500 mg, 1.74 mmol) is placed in 50 ml round-bottomed flasks, is dissolved with 15 ml benzyl oxides
Afterwards, dichloro-diphenyl methane (1.23 g, 5.19mmol) are added, in 175 DEG C of reaction 30min, evaporated under reduced pressure solvent is depressurized back
Add 10%HCl after receiving solvent, is acidified to pH ≈ 6, methylene chloride (10 ml × 3) extraction, combining extraction liquid, anhydrous Na2SO4It is dry
It is dry, solvent is recovered under reduced pressure, obtains residue 2a.After residue 2a is dissolved in 20 ml THF, add DMAP (488 mg, 4 mmol), in
DCC(537 mg, 2.61 mmol are added dropwise after 40 DEG C of 30 min of stirring), be stirred for after 30min plus niacin (250 mg, 2.1
Mmol) the reaction was continued at 40 DEG C 6 h.NH is added410 ml of Cl saturated solution terminates reaction, after getting THF layers, continues to use
CH2Cl2(10 ml × 2) aqueous layer extracted merges THF layers and CH2Cl2Extract liquor, anhydrous Na2SO4It is dry, solvent is recovered under reduced pressure, obtains
Residue 2b.Residue 2b is dissolved in 20 ml THF-MeOH(1:1) in, it is hydrogenated, is reacted at room temperature under 10%Pd/C catalysis
48h, filtering, recycling design obtain residue 1a.Residue 1a is dissolved in 20 ml methylene chloride, with DMAP (425 mg, 3.48
Mmol under) being catalyzed, 7h is reacted at room temperature with 3 ml aceticanhydrides (about 32 mmol), adds NH after methylene chloride is recovered under reduced pressure4Cl saturated solution
Dissolution, AcOEt (10 ml × 3) extraction, combining extraction liquid, anhydrous Na2SO4It is dry, solvent is recovered under reduced pressure, obtains residue 2.Residual
Object 2 obtains the faint yellow amorphous powder of compound 2(through silica gel (10 g) column chromatography for separation, chloroform-methanol (220:1) elution
End, 270 mg, yield 54%).1H NMR (400MHZ, DMSO): 2.32,2.33,2.34, (each 3H, s, 3 ×
OAc); 6.68(1H, d, J = 2Hz, H-6); 7.11 (1H, d, J = 2Hz, H-8); 7.17(1H, s, H-
3); 7.52(1H, d, J = 9.2Hz, H-5’); 7.73(1H, dd, J 1= 8 Hz, J 2= 4.8Hz, H-5’’);
8.25(1H, hidden, H-6’’); 8.27(2H, hidden, H-6’,H-2’); 8.65(1H, dd, J 1= 4.8
Hz, J 2= 1.2Hz, H-4’’); 9.15(1H, s, H-2’’); 12.78 (1H, s, 5’-OH); 13C NMR
(400MHZ, DMSO): 182.7 (C-4), 168.6 (OAc), 168.4 (OAc), 162.7 (C=O), 162.5 (C-2),
160.9(C-5), 156.4(C-7), 156.1(C-9), 152.9(C-4’’), 151.7(C-2’’), 145.3(C-4’),
142.7(C-3’), 138.8(C-6’’), 129.2(C-1’), 125.4(C-1’’), 125.1(C-6’), 124.8(C-
5’’), 124.8(C-5’), 122.4(C-2’), 108.4(C-10), 106.4(C-6), 106.3(C-3), 102.0(C-
8), 21.1(OAc), 20.5(OAc) , 20.5(OAc); ESIMS m/z 556 [M +K]+。
The synthesis of embodiment 2:4 '-nicotinate -5,7,3 '-triacetate base luteolin derivative
Luteolin 1 (500 mg, 1.74 mmol) is placed in 50 ml round-bottomed flasks, is dissolved with 15 ml benzyl oxides
Afterwards, dichloro-diphenyl methane (1.23 g, 5.19mmol) are added, in 175 DEG C of reaction 30min, evaporated under reduced pressure solvent is depressurized back
Add 10%HCl after receiving solvent, is acidified to pH ≈ 6, methylene chloride (10 ml × 3) extraction, combining extraction liquid, anhydrous Na2SO4It is dry
It is dry, solvent is recovered under reduced pressure, obtains residue 2a.Residue 2a is dissolved in 20 ml EtOH, and K is added2CO3(80 mg, 0.58
Mmol) after 50 DEG C of 15 min of stirring, chloromethyl methyl ether (MOMCl, 160 mg, 2 mmol) the reaction was continued 5h is added dropwise, pressurizes back
After receiving ethyl alcohol, add saturation NH4Cl solution 10 ml, CHCl3(10 ml × 3) extraction, combining extraction liquid, anhydrous Na2SO4It is dry, subtract
Recycling design is pressed, residue 3a is obtained.Residue 3a is dissolved in 20 ml THF-MeOH(1:1) in, lower progress hydrogen is catalyzed in 10%Pd/C
Change, react at room temperature 48h, filtering, recycling design obtains residue 3b.After residue 3b is dissolved in 20 ml THF, add DMAP (488
Mg, 4 mmol), DCC(537 mg, 2.61 mmol are added dropwise after 40 DEG C of 30 min of stirring), add niacin after being stirred for 30min
(250 mg, 2.1 mmol) the reaction was continued at 40 DEG C 6 h.It is dissolved in 10 mlEtOH after THF is recovered under reduced pressure, adds 10%HCl sour
Change to pH ≈ 3,3 h are stirred at room temperature, is evaporated under reduced pressure to no alcohol taste, uses CH2Cl2(10 ml × 3) extraction, combining extraction liquid are anhydrous
Na2SO4It is dry, solvent is recovered under reduced pressure, obtains residue 1b.Residue 3d is dissolved in 20 ml methylene chloride, with DMAP (425 mg,
3.48 mmol) under catalysis, 7h is reacted at room temperature with 3 ml aceticanhydrides (about 32 mmol), it is recovered under reduced pressure after methylene chloride plus 10%HCl,
It is acidified to pH ≈ 6, AcOEt (10 ml × 3) extraction, combining extraction liquid, anhydrous Na2SO4It is dry, solvent is recovered under reduced pressure, obtains remaining
Object 3.Residue 3 obtains compound 3(yellow without fixed through silica gel (10 g) column chromatography for separation, chloroform-methanol (220:1) elution
Shape powder, 180 mg, yield 36%).1H NMR (400MHZ, DMSO): 2.21,2.22,2.33 (each 3H, s, 3 ×
OAc); 6.68(1H, d, J = 2Hz, H-3); 7.09 (1H, d, J = 2Hz, H-2’); 7.20(1H, s, H-
8); 7.60(1H, d, J = 8.8Hz, H-5’); 7.70(1H, dd, J 1= 8 Hz, J 2= 4.8Hz, H-5’’);
8.16(1H, dd, J 1= 8.4 Hz, J 2= 2Hz, H-6’); 8.32(1H, d, J = 2Hz, H-6); 8.48(1H,
d, J 1= 8 Hz, J 2= 2Hz, H-6’’); 8.95(1H, dd, J 1= 4.8 Hz, J 2= 1.2Hz, H-4’’); 9.27
(1H, s, H-2’’); 12.83 (1H, s, 5’-OH); 13C NMR (400MHZ, DMSO): 182.7 (C-4), 168.6
(OAc), 168.1(OAc), 162.7(C=O), 162.5(C-2), 160.9(C-5), 156.4(C-7), 156.1(C-
9), 154.9(C-4’’), 150.7(C-2’’), 145.2(C-4’), 142.4(C-3’), 137.8(C-6’’), 129.3
(C-1’), 125.8(C-1’’), 124.9(C-6’), 124.5(C-5’’), 124.4(C-5’), 122.5(C-2’),
108.4(C-6), 106.4(C-10), 102.0(C-3), 101.9(C-8), 20.6(OAc), 20.5(OAc), 20.5
(OAc); ESIMS m/z 518[M + H]+。
Embodiment 3:7- nicotinate luteolin derivative, 4 '-nicotinate luteolin derivatives and 7,4 '-bis- nicotinates
The synthesis of luteolin derivative
Luteolin 1 (500 mg, 1.74 mmol) is placed in 50 ml round-bottomed flasks, after being dissolved in 20 ml THF,
Add DMAP (488 mg, 4 mmol), DCC(537 mg, 2.61 mmol be added dropwise after 40 DEG C of 30 min of stirring), it is stirred for
After 30min plus niacin (550 mg, 4.5 mmol) the reaction was continued at 40 DEG C 24 h.NH is added410 ml of Cl saturated solution is terminated
Reaction, after getting THF layers, continues to use CH2Cl2(10 ml × 2) aqueous layer extracted merges THF layers and CH2Cl2Extract liquor, it is anhydrous
Na2SO4It is dry, solvent is recovered under reduced pressure, obtains residue.The residue is through silica gel (10 g) column chromatography for separation, chloroform-methanol
(220:1) elution, obtain compound 1a(Yellow amorphous powder, 50 mg, yield 10%), 1b(Yellow amorphous powder, 55
Mg, yield 11%), 1c(Yellow amorphous powder, 30 mg, yield 6%).Compound 1a:1H NMR (400MHZ, CDCl3+
CD3OD): 6.43 (1H, d,J = 1.2Hz, H-2’); 6.71(1H, s, H-3); 6.76 (1H, s, H-6);
6.91 (1H, d, J = 5.6 Hz, H-5’); 7.43(1H, s, H-8); 7.45(1H, d, J = 5.6Hz, H-
6’); 7.66(1H, dd, J 1= 5.2 Hz, J 2= 3.2Hz, H-5’’); 8.58(1H, d, J = 5.2 Hz, H-
6’’); 8.84(1H, d, J = 3.2 Hz, H-4’’); 9.31(1H, s, H-2’’); ESIMS m/z 391 [M]+,
390[M-H]+。
Compound 1b:1H NMR (400MHZ, CDCl3+CD3OD): 6.20 (1H, d,J = 1.2Hz, H-2’);
6.53(1H, s, H-6); 6.89 (1H, d, J = 5.6Hz, H-5’); 7.11 (1H, s, H-3); 7.37(1H,
s, H-8); 7.37(1H, d, J = 5.2Hz, H-6’); 7.56(1H, dd, J 1= 5.2 Hz, J 2= 3.2Hz, H-
5’’), 8.39(1H, d, J =5.2 Hz, H-6’’); 8.73(1H, d, J = 4.4 Hz, H-4’’); 9.11(1H,
s, H-2’’); ESIMS m/z 391。
Compound 1c: 1H NMR (400MHZ, DMSO+CD3OD): 6.18 (1H, d,J = 1.2Hz, H-2’);
6.48 (1H, d, J = 1.2Hz, H-6); 6.90(1H, s, H-3); 7.46(2H,m, H-8, H-5’), 7.69
(1H, d, J = 6.0Hz, H-6’); 8.08(1H, d, J 1= 5.6 Hz, J 2= 1.6Hz, H-5’’’), 8.20(1H,
d, J = 1.2 Hz, H-5’’), 8.29(1H, dt, J 1 =4.0 Hz, J 2 =1.2 Hz, H-6’’’); 8.32(1H,
dt, J 1 =5.2 Hz, J 2 =1.2 Hz,H-6’’); 8.73(1H, dd, J 1= 3.2 Hz, J 2= 0.8Hz,, H-
4’’’);8.74(1H, dd, J 1= 3.6 Hz, J 2= 1.2Hz,, H-4’’); 9.06 (1H, d, J = 0.8Hz, H-
2’’’); 9.09 (1H, d, J = 0.8Hz, H-2’’); ESIMS m/z 496 [M]+, 495[M-H]+。
The synthesis of embodiment 4:7- iso-nicotinate luteolin derivative, 4 '-iso-nicotinate luteolin derivatives
Luteolin 1 (500 mg, 1.74 mmol) is placed in 50 ml round-bottomed flasks, after being dissolved in 20 ml THF,
Add DMAP (488 mg, 4 mmol), DCC(537 mg, 2.61 mmol be added dropwise after 40 DEG C of 30 min of stirring), it is stirred for
After 30min plus isonicotinic acid (550 mg, 4.5 mmol) the reaction was continued at 40 DEG C 24 h.NH is added410 ml of Cl saturated solution is whole
It only reacts, after getting THF layers, continues to use CH2Cl2(10 ml × 2) aqueous layer extracted merges THF layers and CH2Cl2Extract liquor, it is anhydrous
Na2SO4It is dry, solvent is recovered under reduced pressure, obtains residue.The residue is through silica gel (10 g) column chromatography for separation, chloroform-methanol
(220:1) elution, obtain compound 4a(Yellow amorphous powder, 70 mg, yield 14%), 4b(Yellow amorphous powder, 60
Mg, yield 12%).Compound 4a:1H NMR (400MHZ, DMSO+CD3OD): 6.97 (1H, s, H-6); 7.21 (1H,
d, J = 8.4Hz, H-2’); 7.36(1H, s, H-3); 7.47(1H, s, H-8); 7.65(1H, d, J =
5.6Hz, H-5’); 7.79(1H, d, J = 5.6Hz, H-6’); 7.92(1H, d, J = 5.2 Hz, H-6’’);
8.23(2H, m, H-2’’, H-5’’); 9.42(1H, d, J = 2.8Hz, H-3’’); ESIMS m/z 414 [M+
Na]+。
Compound 4b:1H NMR (400MHZ, DMSO+CD3OD): 6.95 (1H, s, H-6); 7.24(1H, s, H-
2’); 7.35(1H, s, H-3); 7.47(1H, s, H-8); 7.79(1H, d, J = 5.6 Hz, H-5’); 8.14
(1H, d, J = 6.4 Hz, H-6’); 8.45(2H, hidden, H-5’’, H-6’’); 8.50(1H, d, J =
6.0Hz, H-2’’); 9.14(1H, d, J = 2.8Hz, H-3’’); ESIMS m/z 430[M+K]+。
Embodiment 5:7- furancarboxylic acid ester luteolin derivative, 7,4 '-Coumarin formic acid esters luteolin derivatives
Synthesis
Luteolin 1 (500 mg, 1.74 mmol) is placed in 50 ml round-bottomed flasks, after being dissolved in 20 ml THF,
Add DMAP (488 mg, 4 mmol), DCC(537 mg, 2.61 mmol be added dropwise after 40 DEG C of 30 min of stirring), it is stirred for
After 30min plus furans -2- formic acid (430 mg, 4.5 mmol) the reaction was continued at 40 DEG C 24 h.NH is added4Cl saturated solution 10
Ml terminates reaction, after getting THF layers, continues to use CH2Cl2(10 ml × 2) aqueous layer extracted merges THF layers and CH2Cl2Extract liquor,
Anhydrous Na2SO4It is dry, solvent is recovered under reduced pressure, obtains residue.The residue is through silica gel (10 g) column chromatography for separation, chloroform-methanol
(220:1) elution, obtains compound 5a(Yellow amorphous powder, 80 mg, yield 16%) and 5b(Yellow amorphous powder, 35
Mg, yield 7%).Compound 5a:1H NMR (400MHZ, DMSO+CD3OD): 6.67 (1H, d, J = 1.2Hz, H-4’),
6.73 (1H,s, H-3); 6.86 (1H, d, J = 5.6Hz, H-5’); 7.38(1H, d, J = 1.2Hz, H-6);
7.50(1H, d, J = 2.4Hz, H-2’); 7.60(1H, d, J = 5.6Hz, H-6’); 7.77(1H, s, H-8);
7.94(1H, s, H-5’’); 8.11(1H, d, J = 1.2Hz, H-3’’); ESIMS m/z 380 [M]+, 379 [M-
H] +.Compound 5b:1H NMR (400MHZ, DMSO+CD3OD): 6.48 (1H, d,J = 1.2Hz, H-6); 6.56
(1H, dd, J 1= 2.8Hz, J 2= 1.2Hz, H-4’’’); 6.61(1H, dt, J 1= 4.8Hz, J 2= 1.2Hz, H-
5’) , 6.70(1H, d, J 1= 2.0Hz, J 2= 0.8Hz, H-4’’), 6.87(1H, s, H-3); 7.06 (1H, d,J = 1.2Hz, H-2’); 7.18 (1H, d, J = 2.0Hz, H-8); 7.32 (1H, d, J = 2.4Hz, H-
5’’’); 7.36(1H, d, J = 2.4Hz, H-5’’); 7.40 (1H, dd, J 1 = 5.6Hz, J 2 = 1.6Hz, H-
3’’’); 7.86(1H, d, J = 4.4Hz, H-6’);8.02 (1H, dd, J 1 = 5.6Hz, J 2 = 1.6Hz, H-
3’’); ESIMS m/z 474[M]+, 473[M-H]+。
The synthesis of embodiment 6:7,4 '-bis- ester thiohenic acids luteolin derivative
Luteolin 1 (500 mg, 1.74 mmol) is placed in 50 ml round-bottomed flasks, after being dissolved in 20 ml THF,
Add DMAP (488 mg, 4 mmol), DCC(537 mg, 2.61 mmol be added dropwise after 40 DEG C of 30 min of stirring), it is stirred for
After 30min plus thiophene -2-carboxylic acid (500 mg, 4.5 mmol) the reaction was continued at 40 DEG C 24 h.NH is added4Cl saturated solution 10
Ml terminates reaction, after getting THF layers, continues to use CH2Cl2(10 ml × 2) aqueous layer extracted merges THF layers and CH2Cl2Extract liquor,
Anhydrous Na2SO4It is dry, solvent is recovered under reduced pressure, obtains residue.The residue is through silica gel (10 g) column chromatography for separation, chloroform-methanol
(220:1) elution, obtains compound 6(Yellow amorphous powder, 110 mg, yield 22%).1H NMR (400MHZ, DMSO+
CD3OD): 6.90 (1H, s, H-3); 7.11(2H, m, H-4'',H-4'''); 7.23 (1H, d,J = 2.4Hz,
H-6); 7.68 (2H,s, H-8, H-2’); 7.72(2H, m, H-5’,H-6’); 7.86(1H, dd, J 1 =
5.6Hz, J 2 = 1.2Hz, H-5’’’); 7.92(1H, d, J = 4.4Hz, H-5’’); 7.98(2H, m, H-3’’,
H-3’’’); ESIMS m/z 505[M]+, 506[M-H]+。
The synthesis of embodiment 7:7,4 '-bis- pyrrole carboxylic acids ester luteolin derivative
Luteolin 1 (500 mg, 1.74 mmol) is placed in 50 ml round-bottomed flasks, after being dissolved in 20 ml THF,
Add DMAP (488 mg, 4 mmol), DCC(537 mg, 2.61 mmol be added dropwise after 40 DEG C of 30 min of stirring), it is stirred for
After 30min plus pyrroles -2- formic acid (430 mg, 4.5 mmol) the reaction was continued at 40 DEG C 24 h.NH is added4Cl saturated solution 10
Ml terminates reaction, after getting THF layers, continues to use CH2Cl2(10 ml × 2) aqueous layer extracted merges THF layers and CH2Cl2Extract liquor,
Anhydrous Na2SO4It is dry, solvent is recovered under reduced pressure, obtains residue.The residue is through silica gel (10 g) column chromatography for separation, chloroform-methanol
(220:1) elution, obtains compound 7(Yellow amorphous powder, 70 mg, yield 14%).1H NMR (400MHZ, DMSO+
CD3OD): 7.04 (2H, dd,J 1 = 5.6Hz, J 2 = 1.2Hz, H-4’’,H-4’’’); 7.46(1H, d, J =
1.2Hz, H-6); 7.68 (1H, s, H-3); 7.82 (2H,m, H-5’,H-6’); 7.87(3H, m, hidden,
H-5’’’, H-8, H-2’); 8.36(1H,m, H-5’’); 8.65(2H, m, H-3’’, H-3’’’); ESIMS m/z
472[M]+, 471[M-H]+。
Embodiment 8:
The experiment of neuraminic acid enzyme inhibition activity:
Activity experiment is carried out using each compound prepared in embodiment 1-7.
Using influenza virus neuraminidase inhibitor screening reagent box, primary dcreening operation is carried out to all compounds of preparation.
The screening of 8.1 neuraminidase inhibitor screening reagent boxes
1) experimental principle
Sheme 7 presses down proenzyme reason
MUNANA (2 ' -4-methylumbelliferyl-a-N-acetylneuraminate, 2 ' -4-methyl umbelliferones -
A-N- n acetylneuraminic acid n) be influenza neuraminidase specific substrate, it is generated under the action of neuraminidase
Metabolite under 355 nm irradiation excitation, can produce the fluorescence of 460nm, can spirit by the variation of fluorescence intensity
Reflect the activity of neuraminidase quickly, to reflect the inhibitory activity of compounds on nerve propylhomoserin enzyme indirectly.
2) instrument and reagent
Micro sample adding appliance (50 μ L, 200 μ L, 1000 μ L)；Thermo seientific Multiskan Spectrum is micro-
Plate optical detecting instrument；96 orifice plate of fluoremetry (SPL company, South Korea, Cosmo company, the U.S.)；Constant incubator；Neuraminidase
Inhibitor screening kit P0309 (the green skies biotechnology research institute in Jiangsu)；
3) activity determination method
(1) preparation of testing compound solution
Accurate weighing test compound sample, be made into concentration be 1mg/ml (i.e. 1000 μ g/ml) DMSO solution (when necessary
Ultrasonic dissolution assisting can be used), it then dilutes in proportion, is configured to 200 μ g/ml, 40 μ g/ml, the DMSO solution of 8 μ g/ml respectively
(being denoted as A, B, C, D respectively) is spare.
(3) preparation of sample detection:
According to shown in table 1, being separately added into 70 μ L neuraminic acid enzyme buffers in each hole of sample sets set by 96 fluorescence ELISA Plates
Solution, 10 μ L neuraminidases, 10 μ L neuraminidase inhibitor samples add Mili-Q water and supply 90 μ L, and vibration mixes
L min, 37 DEG C of 2 min of incubation act on inhibitor and neuraminidase sufficiently.Every hole adds 10 μ L neuraminidase fluorescence
Substrate, vibration mix 1min.37 DEG C of incubation 20min carry out fluoremetry.Excitation wavelength is 360 nm, launch wavelength 440
nm。
Inhibiting rate is calculated according to following formula:
Inhibiting rate=(fluorescent degree-blank)/(enzyme values fluorescence-blank)
According to the concentration of compound and corresponding inhibiting rate, it is fitted beneficial effect curve using 7.5 software of origin, is calculated
Each compound IC50。
The sample-adding amount in each hole when 1 active testing of table
The selection result is as follows:
2 synthetic sample NA inhibitory activity primary dcreening operation result of table
| Sample number into spectrum | IC50(mg/mL) | Sample number into spectrum | IC 50 (mg/mL) |
| 1 | 0.496 | 4a | 0.633 |
| 1a | 0.092 | 4b | 0.737 |
| 1b | 0.076 | 5a | 0.685 |
| 1c | 1.164 | 5b | 1.129 |
| 2 | 0.023 | 6 | 1.922 |
| 3 | 0.046 | 7 | 0.548 |
The result shows that the luteolin derivative being prepared using present invention process all has good neuraminic acid
Enzyme inhibition activity, especially nitrogen containing derivative effect is best, and monosubstituted effect is preferable, and effect can enhance after acetylation, wherein
Nicotinic acid derivates --- compound 1a, compound 1b, compound 2, compound 3 just have good neuraminic acid enzyme inhibition activity,
Inhibitory activity is respectively raw material --- and 5.4 times, 6.5 times, 21.6 times and 10.8 times of luteolin produce unexpected skill
Art effect is expected to the preparation applied to neuraminidase inhibitor.
Claims (4)
1. a kind of heteroaromatic carboxylate chromocor derivative, which is characterized in that the structural formula of the heteroaromatic carboxylate chromocor derivative is such as
1a, 1b, 2, shown in 3:
。
2. the active medicine that a kind of heteroaromatic carboxylate chromocor derivative as described in claim 1 inhibits neuraminidase in preparation
In purposes.
3. a kind of heteroaromatic carboxylate chromocor derivative described in claim 1 is in preparing the drug that preventing viral flu occurs
Purposes.
4. a kind of heteroaromatic carboxylate chromocor derivative described in claim 1 is in the drug that preparation treatment virus flu occurs
Purposes.
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| CN101712705A (en) * | 2008-10-07 | 2010-05-26 | 上海医药工业研究院 | Intermediate of flavonoid compound and preparation method and application thereof |
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