CN112209922B - Ferulamide derivative, medical application and crystal structure thereof - Google Patents
Ferulamide derivative, medical application and crystal structure thereof Download PDFInfo
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Abstract
The invention relates to a ferulic acid amide derivative shown as a formula I, pharmaceutically acceptable salts thereof, a pharmaceutical composition and a crystal structure thereof, and an application thereof in preparing influenza virus neuraminidase inhibitors:
wherein, R, R1Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl; r2Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl, carboxymethyl, C1-C4 alkoxy carbonyl methyl; r3Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight-chain alkyl or C3-C4 branched-chain alkyl, nitro, alkoxycarbonyl, alkanoyl, 1-imidazolyl, 1,2, 4-triazol-1-yl or 1- (methoxyimino) alkyl.
Description
Technical Field
The invention relates to a novel compound, a crystal structure and application thereof, in particular to a ferulic acid amide derivative, a crystal structure thereof and application thereof in preparing an influenza virus neuraminidase inhibitor.
Background
2012, Li et al [ Bioorganic&Medicinal Chemistry Letters,2012,22(19):6085-6088]Different heterocyclic segments are introduced after the carboxyl terminal of the ferulic acid is esterified, a plurality of series of ferulic acid derivatives are designed and synthesized, and the activity test result shows that the ferulic acid derivatives have general growth inhibition effect on broad-spectrum cancer cell lines such as lung cancer, melanoma, breast cancer and the like. The structure-activity relationship shows that the compound A introduced with the benzenesulfonyl fluoride furan nitrate fragment has better inhibition effect and better growth inhibition effect on the broad-spectrum cancer cell lines, and IC50The value is in the range of 0.40 to 2.88. mu.M.
X＝(CH2)2O，(CH2)2CH(CH3)O，(CH2)4O，(CH2)2O(CH2)2O
2016 [ Medicinal Chemistry Research,2016,25(6):1175-]Various ferulic acid mono-and bisamide derivatives are designed and synthesized, and anti-tumor and anti-oxidation activity tests are carried out. The activity test result shows that after the carboxyl terminal of the ferulic acid forms amide, the antiproliferative activity and the antioxidant activity are improved, and the antiproliferative activity of the heterocyclic amine-containing segment in the ferulic acid amide derivative is generally higher than the activity of the aniline-containing segment. Wherein the compound B1 has best overall antiproliferative activity, and has inhibitory activity IC on breast cancer MDA-MB-231, lung cancer A549 cell, liver cancer HepG2 cell and cervical cancer HeLa cell50The values are 7.29 +/-2.72 mu M, 8.13 +/-3.11 mu M, 9.88 +/-4.67 mu M and 8.75 +/-3.72 mu M respectively; the ferulic acid diamide derivative B2 has the best activity in antioxidant activity, EC50The value was 18.37. + -. 2.74. mu.M.
R＝H,2-OH，2-NO2，4-Cl，4-F，4-Br
Artemisia capillaris et al (computer and applied chemistry, 2004,35(2): 177-)]Screening partial compounds to be tested by a virtual screening method, establishing a high-throughput screening model of NA, further carrying out evaluation on the NA inhibition activity of H3N2 influenza viruses on the compounds, and finding 2 compounds D1 and D2 with ferulic acid fragments to show better NA inhibition activity and IC of the compounds50The values were 0.11. mu.M and 2.4. mu.M, respectively.
In 2012, Liu et al [ Journal Of Medicinal Chemistry,2012,55(19): 8493-]By splicing the cinnamic acid derivative and zanamivir, a novel double-targeting bifunctional anti-influenza medicine E which has anti-inflammatory and anti-influenza effects is discovered. The structure-activity relationship research finds that when the cinnamic acid derivative is combined with a hydroxyl site on the 7-carbon of zanamivir, the obtained target compound still can keep better NA inhibition activity than zanamivir itself. When R is 3,4- (OH)2Compound E, when X ═ O, exhibits superior inhibitory activity against both influenza virus NA and proinflammatory cytokines, with NA inhibitory activity IC50The value is 2.9-7.4 mu M, and the inhibitory activity EC on (H1N1) A/WSN/1933 type influenza virus50A value of 1.4 to 10.0. mu.M, and a low dose administered intranasally to mice: (<1.2 mu mol/kg/day), the anti-inflammatory effect and the anti-influenza virus effect are more obvious than the combined treatment effect of zanamivir and caffeic acid.
R＝3,4-(OH)2，3,4-OCH2O，5-NH2-2-OH；X＝O,NH
2016 [ Scientific Reports,2016,6(1):38692-38701 ] Harionol et al]Through the research on the NA inhibitory activity of the ferulic acid derivative, the result shows that the ferulic acid has a certain NA inhibitory activity IC50A value of 140. mu.M, wherein the compound F1 (IC) is obtained by introducing a nitro group into the 5-position of the benzene ring of ferulic acid50127 μ M) and the ferulic acid derivative F2 (IC) obtained after carboxyl terminal esterification50191 μ M) and F3 (IC)501000 μ M) was significantly reduced.
2016 (year 2016), Shi et al [ Chemical Research in Chinese Universities,2016,32(1):28-34]Takes 2-amino-4-nitrophenol as a starting material, designs and synthesizes benzene acrylamide derivative, and carries out the evaluation of the inhibitory activity of influenza A virus (H5N1), wherein the NA inhibitory activity of a compound G containing ferulic acid fragment is IC50The value was 147. mu.M.
Disclosure of Invention
The invention aims to provide a ferulic acid amide derivative, a preparation method, a crystal structure, a pharmaceutical composition and application thereof.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides a ferulic acid amide derivative shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein R is selected from: hydrogen, C1-C2 alkyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl; r1Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl, or acetyl; r2Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight-chain alkyl or C3-C4 branched-chain alkyl, carboxymethyl, C1-C2 alkoxycarbonylmethyl, C3-C4 straight-chain alkoxycarbonylmethyl or C3-C4 branched-chain alkoxycarbonylmethyl; r3Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight-chain alkyl or C3-C4 branched-chain alkyl, nitro, C1-C2 alkoxycarbonyl, C3-C4 straight-chain alkoxycarbonyl or C3-C4 branched-chain alkoxycarbonyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, 1-imidazolyl, 1,2, 4-triazol-1-yl, 1- (methoxyimino) ethyl, 1- (methoxyimino) propyl, 1- (methoxyimino) butyl or 1- (methoxyimino) pentyl.
The ferulic amide derivative is a 3- (4-hydroxy-3-methoxyphenyl) acrylamide derivative.
The first aspect of the technical scheme of the invention also provides a type of ferulic amide derivative which is selected from the following compounds:
(E) -N- (4-tert-butyl-5-nitrothiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (4-tert-butyl-5- (imidazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -3- (4- Hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (5-acetyl-4-methylthiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -ethyl 2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl ] acetate, (2E) -N- [5- (1- (methoxyimino) ethyl) -4-methylthiazol-2-yl ] -3- (4-hydroxy-3-methoxyphenyl) acrylamide or (E) -2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl ] acrylamide -yl ] acetic acid.
The second aspect of the technical scheme of the invention provides a preparation method of the ferulic amide derivative, which is characterized in that the preparation reaction is as follows:
wherein R is selected from: hydrogen, C1-C2 alkyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl; r1Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight chain alkyl or C3-C4 branched chain alkyl, or acetyl; r2Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight-chain alkyl or C3-C4 branched-chain alkyl, carboxymethyl, C1-C2 alkoxycarbonylmethyl, C3-C4 straight-chain alkoxycarbonylmethyl or C3-C4 branched-chain alkoxycarbonylmethyl; r3Selected from: hydrogen, C1-C2 alkyl, C3-C4 straight-chain alkyl or C3-C4 branched-chain alkyl, nitro, C1-C2 alkoxycarbonyl, C3-C4 straight-chain alkoxycarbonyl or C3-C4 branched-chain alkoxycarbonyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl, 1-imidazolyl, 1,2, 4-triazol-1-yl, 1- (methoxyimino) ethyl, 1- (methoxyimino) propyl, 1- (methoxyimino) butyl or 1- (methoxyimino) pentyl; HOBt 1-hydroxybenzotriazole; EDCI 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DMF is N, N-dimethylformamide.
In a third aspect of the present invention, there is provided a pharmaceutical composition containing the compound of the first aspect and its pharmaceutically acceptable salt, wherein the pharmaceutical composition contains a therapeutically effective amount of the ferulic acid amide derivative and its pharmaceutically acceptable salt of the present invention, and optionally a pharmaceutically acceptable carrier. Wherein the medicinal carrier refers to a medicinal carrier commonly used in the field of pharmacy; the pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention and their pharmaceutically acceptable salts can be formulated into any dosage form suitable for human or animal use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants. The content of the compound of the present invention and the pharmaceutically acceptable salt thereof in the pharmaceutical composition thereof is usually 0.1 to 95% by weight.
The compounds of the present invention and their pharmaceutically acceptable salts or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ocular, pulmonary and respiratory, dermal, vaginal, rectal, and the like.
The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
The compound and the pharmaceutically acceptable salt thereof can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle delivery systems.
For tableting the compounds of the present invention and pharmaceutically acceptable salts thereof, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like.
The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets.
In order to encapsulate the administration unit, the active ingredient of the compound of the present invention and a pharmaceutically acceptable salt thereof may be mixed with a diluent and a glidant, and the mixture may be directly placed in a hard capsule or a soft capsule. Or the effective component of the compound and the pharmaceutically acceptable salt thereof can be prepared into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then the granules or pellets are placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compounds of the present invention and their pharmaceutically acceptable salt tablets may also be used to prepare capsules of the compounds of the present invention and their pharmaceutically acceptable salts.
In order to prepare the compound and the pharmaceutically acceptable salt thereof into injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection.
In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired.
For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
The fourth aspect of the technical scheme of the invention is to provide the ferulamide derivative and the pharmaceutically acceptable salt thereof and the application of the pharmaceutical composition of the third aspect in the preparation of influenza virus neuraminidase inhibitors.
The fifth aspect of the technical scheme of the invention provides (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide crystals shown in a chemical structural formula II.
(E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide crystal structure atom number as follows:
the invention aims to provide a crystal structure of (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide. The unit cell parameters are as follows: monoclinic system, space group P21/c，
α＝90°，β＝90.12(3)°，γ＝90°；Z＝4，
F(000)＝840， Mr＝399.47，Dx＝1.377mg.m-3，μ＝0.20mm-1，T＝273K，MoKαradiation，
S＝0.96。
The carbon-carbon double bond (C8 ═ C9) in the compound II is of E type configuration, and the bond length is long
The dihedral angle of the benzene ring and the thiazole ring in the compound II is 161.9 degrees; the dihedral angle of the thiazole ring and 1,2,3 triazole is 96.1 degrees; the unit cell of compound II has 4 molecules; the compound II has intermolecular hydrogen bonding: n1- -H1A- -N5,length of hydrogen bond
The intermolecular hydrogen bond angle was 164.74 °.
The invention also provides a preparation method of the (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide crystal, which is characterized in that the crystal is obtained by crystallizing (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide in a polar solvent.
The invention also provides a preparation method of the (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide crystal, which is characterized in that the polar solvent is one or more of methanol, ethanol, acetone and water.
Drawings
FIG. 1 shows the molecular structure of (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide crystal.
FIG. 2 is a crystal stacking diagram of crystals of (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide.
FIG. 3 is a graph showing intermolecular hydrogen bonding of (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide crystals
The beneficial technical effects are as follows:
the invention relates to a ferulamide derivative which is a compound with the inhibitory activity of influenza virus neuraminidase.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
(E) Preparation of (E) -N- (4-tert-butyl-5-nitrothiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide
0.23g (1.2mmol) of ferulic acid, 0.16g (1.2mmol) of 1-hydroxybenzotriazole and 0.23g (1.2mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are dissolved in 10mLN, N-dimethylformamide and stirred for 30min, 0.20g (1mmol) of 2-amino-4-tert-butyl-5-nitrothiazole is added, the temperature is raised to 115 ℃ for reaction for 16h (TLC monitoring), the reaction solution is cooled to room temperature and poured into ice water, solid is precipitated and filtered, saturated sodium bicarbonate solution, diluted hydrochloric acid and water are sequentially used for washing, the crude product is recrystallized by ethanol to obtain red powder (E) -N- (4-tert-butyl-5-nitrothiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, the yield is 36.8 percent, and the m.p.262-263 ℃.1H NMR(400MHz，DMSO-d6)δ：1.50(s，9H，3×CH3)，3.88(s，3H， CH3)，6.82(d，J＝15.6Hz，1H，＝CH)，6.91(d，J＝8.0Hz，1H，C6H3)，7.19(d，J＝8.0Hz， 1H，C6H3)，7.26(s，1H，C6H3)，7.79(d，J＝15.6Hz，1H，＝CH)，9.81(s，1H，OH)，13.01(s， 1H，NH)。
Example 2
(E) Preparation of (E) -N- (4-tert-butyl-5- (imidazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide
According to the method of example 1, 0.23g (1.2mmol) of ferulic acid was reacted with 0.20g (1mmol) of 2-amino-4-tert-butyl-5-imidazolothiazole at 115 ℃ for 10h (TLC monitoring), and the crude product was recrystallized from ethanol to give (E) -N- (4-tert-butyl-5- (imidazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide as a pale yellow powder with a yield of 38.2% and m.p.244-246 ℃.1H NMR(400 MHz，DMSO-d6)δ：1.15(s，9H，3×CH3)，3.85(s，3H，OCH3)，6.77(d，J＝15.6Hz，1H，＝CH)，6.88(d，J＝7.6Hz，1H，C6H3) 7.12 to 7.14(m, 2H, imidazole ring-H + C)6H3)，7.21(s，1H， C6H3)7.47(s, 1H, imidazole ring-H), 7.67(d, J ═ 15.6Hz, 1H, ═ CH), 7.94(s, 1H, imidazole ring-H), 9.71(s, 1H, OH), 12.40(s, 1H, NH).
Example 3
(E) Preparation of (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide
According to the method of example 1, 0.23g (1.2mmol) of ferulic acid reacts with 0.22g (1mmol) of 2-amino-4-tert-butyl-5- (1,2, 4-triazole) thiazole at 115 ℃ for 10h (TLC monitoring), the crude product is recrystallized by ethanol to obtain beige powder (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, the yield is 41.5%, and m.p. is 196-198 ℃.1H NMR(400MHz，DMSO-d6)δ：1.14(s，9H，3×CH3)，3.85(s，3H，OCH3)，6.78(d，J＝15.6Hz，1H，＝CH)，6.88(d，J＝8.0Hz，1H，C6H3)，7.14(d，J＝8.0Hz，1H，C6H3)， 7.22(s，1H，C6H3) 7.69(d, J ═ 15.6Hz, 1H, ═ CH), 8.28(s, 1H, triazole ring-H), 8.98(s, 1H, triazole ring-H), 9.74(s, 1H, OH), 12.53(s, 1H, NH).
Example 4
(E) Preparation of (E) -N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide
According to the method of example 1, 0.23g (1.2mmol) of ferulic acid was reacted with 0.19g (1mmol) of ethyl 2-amino-4-methyl-5-carboxylate thiazole at 115 ℃ for 10h (TLC monitoring), and the crude product was recrystallized from ethanol to give (E) -N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide as beige powder in a yield of 40.2% m.p.185-187 ℃.1H NMR(400 MHz，DMSO-d6)δ：1.29(t，J＝7.0Hz，3H，CH3)，2.56(s，3H，CH3)，3.83(s，3H，OCH3)， 4.25(q，J＝13.9，6.9Hz，2H，OCH2)，6.71(d，J＝15.6Hz，1H，＝CH)，6.85(d，J＝8.0Hz， 1H，C6H3)，7.12(d，J＝8.0Hz，1H，C6H3)，7.21(s，1H，C6H3)，7.67(d，J＝15.6Hz，1H，＝CH)，9.70(s，1H，OH)，12.54(s，1H，NH)。
Example 5
(E) Preparation of (E) -N- (5-acetyl-4-methylthiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide
According to the method of example 1, 0.23g (1.2mmol) of ferulic acid is reacted with 0.16g (1mmol) of 2-amino-4-methyl-5-acetylthiazole at 115 ℃ for 12H (monitored by TLC), and the crude product is DMF/H2And recrystallizing O to obtain black solid (E) -N- (5-acetyl-4-methylthiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, wherein the yield is 36.4 percent, and m.p.256-258 ℃.1H NMR(400 MHz，DMSO-d6)δ：2.43(s，3H，CH3)，2.45(s，3H，CH3)，3.77(s，3H，OCH3)，6.66(d，J＝ 16.0Hz，1H，＝CH)，6.80(d，J＝8.0Hz，1H，C6H3)，7.06(d，J＝8.0Hz，1H，C6H3)，7.15(s， 1H，C6H3)，7.61(d，J＝16.0Hz，1H，＝CH)，9.69(s，1H，OH)，12.49(s，1H，NH)。
Example 6
(E) Preparation of ethyl (E) -2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl ] acetate
By the method of example 1, 0.23g (1.2mmol) of ferulic acid was reacted with0.16g (1mmol) 2-amino-4-acetic acid ethyl ester thiazole are reacted at 115 ℃ for 8h (TLC monitoring), and the crude product is recrystallized from ethanol to give (E) -2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl) white solid]Ethyl acetate, yield 32.1%, m.p.181-183 ℃.1H NMR(400MHz，DMSO-d6) δ：1.19(t，J＝7.0Hz，3H，CH3)，3.70(s，2H，CH2)，3.83(s，3H，OCH3)，4.09(q，J＝7.1Hz，2H，OCH2)，6.69(d，J＝15.6Hz，1H，＝CH)，6.85(d，J＝8.0Hz，1H，C6H3) 6.99(s, 1H, thiazole ring-H), 7.09(d, J ═ 8.0Hz, 1H, C6H3)，7.18(s，1H，C6H3)，7.62(d，J＝15.6Hz，1H，＝CH)，9.64(s，1H，OH)，12.24(s，1H，NH)。
Example 7
(2E) Preparation of (E) -N- [5- (1- (methoxyimino) ethyl) -4-methylthiazol-2-yl ] -3- (4-hydroxy-3-methoxyphenyl) acrylamide
0.17g (0.5mmol) of (E) -N- (5-acetyl-4-methylthiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide was dissolved in 5ml DMF; dissolving 0.08g (1mmol) of methoxylamine hydrochloride and 0.08g (1mmol) of sodium acetate in 3mL of water, stirring for 10min, adding the obtained solution into DMF solution, heating to 80 ℃ for reaction for 10h, cooling to room temperature, pouring the reaction solution into water, performing suction filtration, washing a filter cake with saturated sodium bicarbonate solution, washing with water, and drying to obtain white powder (2E) -N- [5- (1- (methoxyimino) ethyl) -4-methylthiazol-2-yl]The yield of the (E) -3- (4-hydroxy-3-methoxyphenyl) acrylamide is 60.6 percent, and the m.p.133-135 ℃.1H NMR(400 MHz，DMSO-d6) δ: 2.23(s, 2H, thiazole-CH)3E-formula), 2.43(s, 1H, thiazole-CH)3Z-type), 2.26(s, 1H, CH)3Z-type), 2.45(s, 2H, CH)3Formula E), 3.85(s, 3H, OCH)3)，3.90(s，3H，NOCH3)， 6.72(d，J＝15.6Hz，1H，＝CH)，6.87(d，J＝8.0Hz，1H，C6H3)，7.13(d，J＝8.0Hz，1H， C6H3)，7.22(s，1H，C6H3)，7.65(d，J＝15.6Hz，1H，＝CH)，9.70(s，1H，OH)，12.24(s，1H， NH)。
Example 8
(E) Preparation of (E) -2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl ] acetic acid
0.10g (0.28mmol) of (E) -2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl]Dissolving ethyl acetate in 10mL of ethanol, dropwise adding 2mL of 0.6N lithium hydroxide solution, reacting at room temperature for 6h (monitoring by TLC), adjusting the pH to 2-3 with dilute hydrochloric acid, precipitating a solid, performing suction filtration, and washing with water to obtain yellow powder (E) -2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl]Acetic acid, yield 65.9%, m.p.210-212 ℃.1H NMR(400MHz，DMSO-d6)δ：3.62(s，2H，CH2)， 3.83(s，3H，OCH3)，6.69(d，J＝15.6Hz，1H，＝CH)，6.85(d，J＝8.0Hz，1H，C6H3) 6.96(s, 1H, thiazole ring-H), 7.10(d, J ═ 8.0Hz, 1H, C6H3)，7.19(s，1H，C6H3)，7.63(d，J＝15.6Hz， 1H，＝CH)，9.63(s，1H，OH)，12.24(s，1H，NH)，12.33(s，1H，COOH)。
Example 9
(E) -crystal structure of (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide (II)
Compound II is dissolved in ethanol/water (V)Ethanol：VWater (W)And (5: 1), filtering the solution through a microporous filter membrane at room temperature, and culturing the solution in a quiet and dark environment for 9 days by a solvent slow volatilization method to obtain yellow transparent crystals. Selecting 0.06 × 0.06 × 0.06mm3The crystal structure is determined by BRUKER SMCRT CPEX 1000 CCD X-ray single crystal diffractometer, and the determination result is analyzed and refined by SHELXS-97, SHELXL-97 and MercuryEditing and displaying the structure and the three-dimensional diagram. Crystal test data and structural parameters are shown in table 1.
TABLE 1 Crystal data and Structure refinement parameters for Compound II
The diffraction result analysis of the X-Ray single crystal shows that the unit cell parameters are as follows: monoclinic system, space group P21/c，a＝10.43(3)，
α＝90°，β＝90.12(3)°，γ＝90°；Z＝4，
F(000)＝840， Mr＝399.47，Dx＝1.377mg.m-3，μ＝0.20mm-1，T＝273K，MoKαradiation，
S is 0.96; the crystal structure of the compound II is shown in figure 1, the molecular stacking is shown in figure 2, the intermolecular hydrogen bond is shown in figure 3, the bond angle and bond length data are shown in tables 2 and 3, and the intermolecular hydrogen bond data are shown in table 4.
TABLE 2 Crystal bond Length of Compound II
TABLE 3 bond angles of crystals of Compound II
| Chemical bond(s) | Key angle (°) | Chemical bond(s) | Key angle (°) |
| C11—S1—C17 | 89.6(2) | C17-C12—N2 | 111.8(3) |
| C2—O1—C7 | 115.9(3) | C17—C12—C13 | 128.4(3) |
| C19—N5—C18 | 103.2(3) | N2—C12—C13 | 119.8(3) |
| C11—N2—C12 | 114.2(3) | C4—C3—C2 | 118.3(3) |
| C3—O2—H2 | 108(3) | C4—C3—O2 | 122.2(4) |
| C19—N3—N4 | 110.1(3) | C2-C3—O2 | 119.5(4) |
| C19—N3—C17 | 127.9(3) | N5—C19—N3 | 109.6(3) |
| N4—N3—C17 | 121.9(3) | N5—C19—H19 | 125.2 |
| C10—N1—C11 | 127.2(3) | N3—C19—H19 | 125.2 |
| C10—N1—H1A | 115(3) | N4—C18—N5 | 115.5(3) |
| C11—N1—H1A | 118(3) | N4—C18—H18 | 122.3 |
| C8—C9—C10 | 123.3(3) | N5—C18—H18 | 122.3 |
| C8—C9—H9 | 118.3 | C6—C5—C4 | 120.6(4) |
| C10—C9—H9 | 118.3 | C6-C5—H5 | 119.7 |
| C18—N4—N3 | 101.6(3) | C4-C5—H5 | 119.7 |
| C3—C4-C5 | 122.1(4) | C13—C15—H15A | 109.5 |
| C3—C4—H4 | 118.9 | C13—C15—H15B | 109.5 |
| C5—C4—H4 | 118.9 | H15A—C15—H15B | 109.5 |
| C5—C6—C1 | 116.6(3) | C13—C15—H15C | 109.5 |
| C5—C6—C8 | 122.2(4) | H15A—C15—H15C | 109.5 |
| C1—C6—C8 | 121.2(3) | H15B—C15—H15C | 109.5 |
| C6—C1—C2 | 122.5(4) | C3—C2—O1 | 111.8(3) |
| C6—C1-H1 | 118.7 | C3-C2-C1 | 119.8(4) |
| C2-C1-H1 | 118.7 | O1-C2-C1 | 128.3(3) |
| O3-C10-N1 | 118.0(4) | C13-C14-H14A | 109.5 |
| O3-C10-C9 | 124.0(4) | C13-C14-H14B | 109.5 |
| N1-C10-C9 | 118.0(3) | H14A-C14-H14B | 109.5 |
| N2-C11-N1 | 122.5(3) | C13-C14-H14C | 109.5 |
| N2-C11—S1 | 113.4(3) | H14A-C14-H14C | 109.5 |
| N1-C11-S1 | 124.0(3) | H14B-C14-H14C | 109.5 |
| C12-C17-N3 | 127.2(3) | O1—C7-H7A | 109.5 |
| C12-C17-S1 | 110.9(3) | O1-C7-H7B | 109.5 |
| N3-C17-S1 | 121.9(3) | H7A-C7-H7B | 109.5 |
| C12—C13—C14 | 105.9(3) | O1—C7—H7C | 109.5 |
| C12—C13—C15 | 108.2(3) | H7A—C7—H7C | 109.5 |
| C14—C13-C15 | 111.0(3) | H7B—C7—H7C | 109.5 |
| C12—C13—C16 | 115.3(3) | C13—C16—H16A | 109.5 |
| C14—C13—C16 | 106.3(3) | C13—C16-H16B | 109.5 |
| C15-C13-C16 | 110.1(3) | H16A-C16-H16B | 109.5 |
| C9-C8-C6 | 130.4(3) | C13-C16-H16C | 109.5 |
| C9-C8-H8 | 114.8 | H16A-C16-H16C | 109.5 |
| C6-C8-H8 | 114.8 | H16B-C16-H16C | 109.5 |
TABLE 4 intermolecular hydrogen bonding of Compound II: (
And degree)
From FIG. 1 it can be seen that the carbon-carbon double bond (C8 ═ C9) in compound II is of the E configuration and the bond length is
This is in conjunction with1The carbon-carbon double bond coupling constant value (J ═ 16.0Hz) in HNMR indicates that the E configuration is consistent; in the compound II, a benzene ring and a thiazole ring are connected through CH ═ CHCONH, and the dihedral angle is 161.9 degrees; the thiazole ring is directly connected with 1,2,3 triazole, and the dihedral angle of the thiazole ring is 96.1 degrees. There are 4 molecules in the unit cell of compound ii. FIG. 3 shows the intermolecular hydrogen bonding of compound II, and the specific parameters are shown in Table 4.
Example 10
Anti-influenza virus neuraminidase activity of ferulamide derivatives
1. Principle of experiment
The compound MUNANA is a specific substrate of neuraminidase, metabolites generated under the action of neuraminidase can generate 450nm fluorescence under the irradiation and excitation of 360nm, and the change of fluorescence intensity can sensitively reflect neuraminidase activity. The enzymes were from the A/PR/8/34(H1N1) and A/Minfang/15/90 (H3N2) virus strains, respectively.
2. Experimental methods
In an enzyme reaction system, a sample with a certain concentration and influenza virus RNA are suspended in a reaction buffer solution (pH6.5), a fluorescent substrate MUNANA is added to start the reaction system, and after incubation for 40 minutes at 37 ℃, a reaction stopping solution is added to stop the reaction. The fluorescence intensity values were determined under the parameters of an excitation wavelength of 360nm and an emission wavelength of 450 nm. The fluorescence intensity of the reaction system may reflect the activity of the enzyme. The inhibition rate of the compound on the NA activity can be calculated according to the reduction of the fluorescence intensity.
3. Detecting a sample: EXAMPLES Compounds
4. Active results
Inhibition rate and IC of compound on neuraminidase when concentration of compound in reaction system is detected to be 40.0 mu g/mL50The values are shown in Table 5.
TABLE 5 inhibitory Activity and IC of Ferulamide derivatives on neuraminidase H1N1/H3N250
The ferulic acid amide derivative has activity of resisting influenza virus neuraminidase, and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (7)
1. A class of ferulamide derivatives represented by the chemical structural formula I:
the ferulic amide derivative is selected from:
(E) -N- (4-tert-butyl-5-nitrothiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (4-tert-butyl-5- (imidazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -3- (4- Hydroxy-3-methoxyphenyl) acrylamide, (E) -N- (5-acetyl-4-methylthiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide, (E) -ethyl 2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl ] acetate, (2E) -N- [5- (1- (methoxyimino) ethyl) -4-methylthiazol-2-yl ] -3- (4-hydroxy-3-methoxyphenyl) acrylamide or (E) -2- [2- (3- (4-hydroxy-3-methoxyphenyl) acrylamido) thiazol-4-yl ] acrylamide -yl ] acetic acid.
2. The process for preparing the ferulic amide derivative of claim 1, which comprises the following steps:
wherein the ferulic amide derivative I is as defined in claim 1; HOBt: 1-hydroxybenzotriazole; EDCI:1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; DMF: n, N dimethylformamide.
3. Use of the ferulic acid amide derivative of claim 1 for the preparation of an influenza virus neuraminidase inhibitor.
4. Crystalline (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide having chemical structure II:
it is characterized in that the unit cell parameters of the crystal structure are as follows: monoclinic system, space group P21/c，
α＝90°，β＝90.12(3)°，γ＝90°；Z＝4，
F(000)＝840，Mr＝399.47，Dx＝1.377mg.m-3，μ＝0.20mm-1，T＝273K，
S＝0.96；
The carbon-carbon double bond (C8 ═ C9) in the compound II is of E type configuration, and the bond length is long
The dihedral angle of the benzene ring and the thiazole ring in the compound II is 161.9 degrees; the dihedral angle of the thiazole ring and 1,2,3 triazole is 96.1 degrees; the unit cell of compound II has 4 molecules; the compound II has intermolecular hydrogen bonding: n1- -H1A- -N5; length of hydrogen bond
The intermolecular hydrogen bond angle was 164.74 °.
5. A process for producing the crystalline (E) -N- (4-tert-butyl-5- (1,2, 4-triazol-1-yl) thiazol-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide according to claim 4; the compound is characterized by being obtained by crystallizing (E) -N- (4-tert-butyl-5- (1,2, 4-triazole-1-yl) thiazole-2-yl) -3- (4-hydroxy-3-methoxyphenyl) acrylamide in a polar solvent.
6. A method for producing the crystal according to claim 5; characterized in that the polar solvent is selected from: one or more of methanol, ethanol, acetone or water.
7. A pharmaceutical composition comprising at least one compound of claim 1 and a pharmaceutically acceptable carrier.
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| WO2012166859A2 (en) * | 2011-06-01 | 2012-12-06 | The Curators Of The University Of Missouri | Modulation of sphingosine 1-phosphate metabolizing enzymes for the treatment of negative-strand rna virus infections |
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