CN111138377B - Vanilamide derivative and preparation method and application thereof - Google Patents
Vanilamide derivative and preparation method and application thereof Download PDFInfo
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- CN111138377B CN111138377B CN201911403856.2A CN201911403856A CN111138377B CN 111138377 B CN111138377 B CN 111138377B CN 201911403856 A CN201911403856 A CN 201911403856A CN 111138377 B CN111138377 B CN 111138377B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/44—Acylated amino or imino radicals
- C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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- C07—ORGANIC CHEMISTRY
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- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a vanillic amide derivative shown as a formula I, a pharmaceutically acceptable salt thereof, a pharmaceutical composition thereof and an application thereof in preparing influenza virus neuraminidase inhibitors:
wherein R is 2 ＝Me，t‑Bu；R 3 ＝CO 2 Et，COCH 3 Imidazolyl, 1,2, 4-triazolyl, C (= NOCH) 3 )CH 3 。
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to a vanillylamide derivative, a preparation method thereof and application thereof in preparing influenza virus neuraminidase inhibitors.
Background
In 2017, ryu et al [ WO 2017039395A1, 2017]The compound A with the structure of benzamide and benzoate is found to have the effect of inhibiting platelet aggregation; when R is 1 When the compound A is an vanillic acid derivative, the inhibition rate of the compound A for inhibiting the shear stress induced platelet aggregation is about 30 percent under the concentration of 25 mu M, wherein the inhibition rates of A1 and A2 are both more than 30 percent; the compound A1 has low cytotoxicity, and the survival rate of Ea.hy926 cell strain is 99.6 percent and 99.5 percent respectively under the test concentration of 25 mu M and 100 mu M; meanwhile, the medicine has the effects of preventing and treating thrombotic diseases due to small side effects such as bleeding.
R 1 = OH or alkoxy; x = O or N;
R 2 = H or heterocycle; r 3 = H or heterocycle
2018, meira et al [ Bioorganic&Medicinal Chemistry,2018,26(8):1971-1985]4- (nitrophenyl) hydrazone derivatives of N-acylhydrazones B are described and screened for inhibitory activity on lymphocyte proliferation in macrophages. When the substituent R is 4-OH,4-Cl,4-NO 2 Or 4-OH-3-OMe, compound B has good activity of resisting lymphocyte proliferation; therein, change intoIC of antiproliferative activity of Compound B1 (R = 4-OH-3-OMe) 50 The value was 5.1. + -. 0.9. Mu.M; and is also less cytotoxic, and is found by the Alamarblue test to be cytotoxic to mouse macrophage line J774 CC 50 The value is greater than 100. Mu.M.
R＝2-OH，2-NH 2 ，2-Cl，2-I，4-OH，4-OMe，4-CF 3 ，
4-Bu-t，4-Cl，4-NH 2 ，4-NO 2 ，4-OH-3-OMe
Disclosure of Invention
The invention aims to provide a vanillic amide derivative, a preparation method, 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 vanillic amide derivative shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein R is 2 ＝Me，t-Bu，R 3 ＝CO 2 Et，COCH 3 Imidazolyl, 1,2, 4-triazolyl, C (= NOCH) 3 )CH 3 。
Further said vanillyl amide derivative is selected from the following compounds:
n- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide,
N- (5-imidazolyl-4-tert-butylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide,
N- (5- (1, 2, 4-triazol-1-yl-4-tert-butylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide,
N- (5-acetyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide or
N- [5- [1- (methoxyimino) ethyl ] -4-methylthiazol-2-yl ] -4-hydroxy-3-methoxybenzamide.
The second aspect of the technical scheme of the invention provides a preparation method of the vanillin amide derivative, which is characterized in that the preparation reaction is as follows:
Ⅰa：R 2 ＝Me，R 3 ＝CO 2 Et；Ⅰb：R 2 ＝Me，R 3 ＝COCH 3 ；Ⅰc：R 2 ＝t-Bu，R 3 = imidazolyl; and id: r is 2 ＝t-Bu，R 3 1,2,4-triazolyl; HOBt 1-hydroxybenzotriazole; 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 comprising a compound of the first aspect and a pharmaceutically acceptable salt thereof, wherein the pharmaceutical composition comprises a therapeutically effective amount of the vanillin amide derivative and the pharmaceutically acceptable salt thereof of the 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 compounds of the present invention and their pharmaceutically acceptable salts are generally present in the pharmaceutical compositions in an amount of 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, solid or 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 can 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, etc.
The tablets may be further formulated as coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layered and multi-layered tablets.
For the encapsulation of the administration units, the active ingredients of the compounds according to the invention and their pharmaceutically acceptable salts can be mixed with diluents, glidants and the mixture can be placed directly into hard or soft capsules. Or preparing the effective component of the compound and the pharmaceutically acceptable salt thereof into granules or pellets with a diluent, an adhesive and a disintegrating agent, and then placing the granules or pellets 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, in the preparation of lyophilized powder for injection, mannitol and glucose can also be added as proppant.
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 vanillyl amide derivative and the pharmaceutically acceptable salt thereof, and the application of the pharmaceutical composition in the third aspect in the preparation of influenza virus neuraminidase inhibitors.
The beneficial technical effects are as follows:
the vanillic amide derivative is a compound with the activity of inhibiting influenza virus neuraminidase.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Synthesis of N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -4-acetoxy-3-methoxybenzamide (if)
Dissolving 1.68g (10 mmol) of vanillic acid in 10mL of 4.0mol/L potassium hydroxide solution, dropwise adding 3.06g (30 mmol) of acetic anhydride under ice bath, reacting for 1h, performing suction filtration and water washing, dissolving a filter cake into 50mL of ethyl acetate, sufficiently washing a saturated sodium carbonate solution, adjusting the pH of a water layer to 2-3 by using dilute hydrochloric acid, separating out a large amount of solid, performing suction filtration, water washing, and drying to obtain white powder 4-acetoxyl-3-methoxybenzoic acid, wherein the yield is 76.1%, and m.p.135-136 ℃.
0.25g (1.2 mmol) of 4-acetoxy-3-methoxybenzoic acid, 0.16g (1.2 mmol) of 1-hydroxybenzotriazole, 0.23g (1.2 mmol) of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride are dissolved in 10mL of N, N-dimethylformamide and stirred for 30min, 0.19g (1 mmol) of 2-amino-4-methylthiazole-5-carboxylic acid ethyl ester is added, the reaction is carried out at the temperature of 115 ℃ for 10h (TLC monitoring), the reaction liquid is cooled to room temperature and poured into ice water to precipitate a solid, the solid is filtered by suction, saturated sodium bicarbonate solution, diluted hydrochloric acid and water are sequentially used for washing, and the off-white powder N- (5-ethoxycarbonyl-4-methylthiazole-2-yl) -4-acetoxy-3-methoxybenzamide is obtained by drying, the yield is 74.0%, and m.p.195-197 ℃.
Example 2
Synthesis of N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide (Ia)
0.15g (0.40 mmol) of N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -4-acetoxyl-3-methoxybenzamide is dissolved in 5mL of tetrahydrofuran, 2mL of 0.6mol/L lithium hydroxide solution is dripped in, the mixture reacts for 5 hours at room temperature (TLC monitoring), dilute hydrochloric acid is used for adjusting the pH value to 2-3, solid is separated out, the solid is filtered, washed by water and dried to obtain whiteThe color powder N- (5-ethoxycarbonyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide Ia, the yield is 95.0 percent, and m.p.238-241 ℃; 1 H NMR(400MHz，DMSO-d 6 )δ：1.32(t，J＝7.2Hz，3H，CH 3 )，2.61(s，3H，CH 3 )，3.89(s，3H，OCH 3 )，4.28(q，J＝7.1Hz，2H，CH 2 )，6.93(d，J＝8.4Hz，1H，C 6 H 3 )，7.67(d，J＝8.4，2.0Hz，1H，C 6 H 3 )，7.77(s，1H，C 6 H 3 )，10.07(s，1H，OH)，12.79(s，1H，NH)。 13 C NMR(100MHz，DMSO-d 6 )δ：14.68，17.43，56.22，60.93，112.28，114.51，115.72，122.43，123.12，147.81，151.81，156.51，161.11，162.70，165.44。
example 3
Synthesis of N- (5-acetyl-4-methylthiazol-2-yl) -4-acetoxy-3-methoxybenzamide (Ig)
Prepared according to the method of example 1, 0.25g (1.2 mmol) of 4-acetoxy-3-methoxybenzoic acid and 0.16g (1 mmol) of 2-amino-4-methyl-5-acetylthiazole are condensed to give N- (5-acetyl-4-methylthiazol-2-yl) -4-acetoxy-3-methoxybenzamide as a coffee-colored powder, yield 81.5%, m.p.254-256 ℃.
Example 4
Synthesis of N- (5-acetyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide (Ib)
Prepared according to the method of example 2, 0.15g (0.36 mmol) N- (5-acetyl-4-methylthiazol-2-yl) -4-acetoxy-3-methoxybenzamide is hydrolyzed in 0.6mol/L lithium hydroxide to give N- (5-acetyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide Ib as a tan powder, yield 84.6%, m.p.230-232 ℃; 1 H NMR(400MHz，DMSO-d 6 )δ：2.47(s，3H，CH 3 )，2.59(s，3H，CH 3 )，3.86(s，3H，OCH 3 )，6.89(d，J＝8.4Hz，1H，C 6 H 3 )，7.64(d，J＝8.4Hz，1H，C 6 H 3 )，7.75(s，1H，C 6 H 3 )； 13 C NMR(100MHz，DMSO-d 6 )δ：18.58，30.55，56.17，112.33，115.62，123.02，123.57，125.03，151.51，154.97，162.45，166.21，190.90。
example 5
Synthesis of N- (4-tert-butyl-5- (1H-imidazol-1-yl) thiazol-2-yl) -4-hydroxy-3-methoxybenzamide (ih)
Prepared according to the method of example 1, 0.25g (1.2 mmol) 4-acetoxy-3-methoxybenzoic acid and 0.22g (1 mmol) 4-tert-butyl-5- (1H-imidazol-1-yl) thiazol-2-amine are condensed to give N- (4-tert-butyl-5- (1H-imidazol-1-yl) thiazol-2-yl) -4-acetoxy-3-methoxybenzamide as a white powder in 66.3% yield m.p.171-173 ℃.
Example 6
Synthesis of N- (4-tert-butyl-5- (1H-imidazol-1-yl) thiazol-2-yl) -4-hydroxy-3-methoxybenzamide (ic)
Prepared according to the method of example 2, 0.15g (0.36 mmol) N- (4-tert-butyl-5- (1H-imidazol-1-yl) thiazol-2-yl) -4-acetoxy-3-methoxybenzamide was hydrolyzed in 0.6mol/L lithium hydroxide to give white powder IC, yield 88.9%, m.p.165-167 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ：1.18(s，9H，3×CH 3 )，3.90(s，3H，OCH 3 )，6.93(d，J＝8.2Hz，1H，C 6 H 3 ) 7.09 (s, 1H, imidazole ring-H), 7.47 (s, 1H, imidazole ring-H), 7.67 (dd, J =8.2,1.8Hz,1H, C 6 H 3 )，7.78(d，J＝1.8Hz，1H，C 6 H 3 ) 7.94 (s, 1H, imidazole ring-H), 10.10 (s, 1H, OH), 12.53 (s, 1H, NH). 13 C NMR(100MHz，DMSO-d 6 )δ：29.87，35.79，56.27，112.33，115.63，119.64，122.55，123.07，124.69，129.23，141.34，147.76，151.68，153.75，154.53，165.38。
Example 7
Synthesis of N- (4-tert-butyl-5- (1H-1, 2, 4-triazolyl-1-yl) thiazol-2-yl) -4-acetoxy-3-methoxybenzamide (II)
Prepared by the method of example 1, 0.25g (1.2 mmol) of 4-acetoxy-3-methoxybenzoic acid and 0.22g (1 mmol) of 4-tert-butyl-5- (1H-triazol-1-yl) thiazol-2-amine were condensed to give N- (4-tert-butyl-5- (1H-1, 2, 4-triazol-1-yl) thiazol-2-yl) -4-acetoxy-3-methoxybenzamide as a white powder in 68.2% yield, m.p.163-165 ℃.
Example 8
Synthesis of N- (4-tert-butyl-5- (1H-1, 2, 4-triazolyl-1-yl) thiazol-2-yl) -4-hydroxy-3-methoxybenzamide (Id)
Prepared according to the method of example 2, 0.15g (0.36 mmol) N- (4-tert-butyl-5- (1H-1, 2, 4-triazolyl-1-yl) thiazol-2-yl) -4-acetoxy-3-methoxybenzamide is hydrolyzed in 0.6mol/L lithium hydroxide to give N- (4-tert-butyl-5- (1H-1, 2, 4-triazolyl-1-yl) thiazol-2-yl) -4-hydroxy-3-methoxybenzamide id, yield 79.6%, m.p.140-142 ℃; 1 H NMR(400MHz，DMSO-d 6 )δ：1.14(s，9H，3×CH 3 )，3.89(s，3H，OCH 3 )，6.90(d，J＝8.4Hz，1H，C 6 H 3 )，7.66(dd，J＝8.4，1.8Hz，1H，C 6 H 3 )，7.78(d，J＝1.8Hz，1H，C 6 H 3 ) 8.25 (s, 1H, triazole ring-H), 8.95 (s, 1H, triazole ring-H), 9.97 (s, 1H, OH), 12.62 (s, 1H, NH).
Example 9
Synthesis of N- [5- [1- (methoxyimino) ethyl ] -4-methylthiazol-2-yl ] -4-hydroxy-3-methoxybenzamide (ie)
0.21g (0.63 mmol) of N- (5-acetyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide is dissolved in 5mL of DMF; 0.10g (1.2 mmol) of methoxylamine hydrochloride, 0.08g (1 mmol) of sodium acetate and 3mL of water are stirred for 10min, added into DMF solution, heated to 80 ℃ for reaction for 10h, cooled to room temperature, poured into water, filtered, washed by saturated sodium bicarbonate solution and water in sequence, and dried to obtain a reddish brown solid N- [5- [1- (methoxyimino) ethyl ] ethyl]-4-methylthiazol-2-yl]-4-hydroxy-3-methoxybenzamide ie, yield 90.0%, m.p. 133-135 ℃. 1 H NMR(400MHz，DMSO-d 6 )δ：2.22～2.46，2.62(m，6H，2×CH 3 )，3.87～3.89(m，6H，2×OCH 3 )，6.89～6.92(m，1H，C 6 H 3 )，7.62～7.67(m，1H，C 6 H 3 )，7.75～7.76(m，1H，C 6 H 3 )，9.96(s，1H，OH)，12.46(s，1H，NH)。
Example 10
Anti-influenza virus neuraminidase activity of vanilloid amide 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 all from the A/PR/8/34 (H1N 1) virus strain.
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 (pH 6.5), a fluorescent substrate MUNANA is added to start the reaction system, and after incubation for 40 minutes at 37 ℃, a reaction termination solution is added to terminate the reaction. The fluorescence intensity values were measured 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 from the decrease in the fluorescence intensity.
3. Detecting a sample: compounds of the examples
4. Activity results
Inhibition rate and IC of compound on neuraminidase when concentration of compound in reaction system is detected to be 40.0 mu g/mL 50 The values are shown in Table 1.
TABLE 1 inhibitory Activity and IC of vanilloid amide derivatives on neuraminidase H1N1 50
The vanillic amide derivative has the activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (4)
1. A vanilloid amide derivative of the formula ie:
2. a process for the preparation of a vanillin amide derivative of formula ie, characterized in that it is prepared by the following reaction:
the specific operation process comprises the following steps: 0.21g of N- (5-acetyl-4-methylthiazol-2-yl) -4-hydroxy-3-methoxybenzamide (Ib) is dissolved in 5mL of DMF; 0.10g of methoxylamine hydrochloride, 0.08g of sodium acetate and 3mL of water are stirred for 10min, added into a DMF solution and heated to 80 ℃ for reaction for 10h, cooled to room temperature, the reaction solution is poured into water and filtered, a filter cake is washed by saturated sodium bicarbonate solution, washed by water and dried to obtain a reddish brown solid N- [5- [1- (methoxyimino) ethyl ] -4-methylthiazol-2-yl ] -4-hydroxy-3-methoxybenzamide ie with the yield of 90.0 percent and m.p.133-135 ℃.
3. The use of the vanillin amide derivative of claim 1 and pharmaceutically acceptable salts thereof in the preparation of an influenza virus neuraminidase inhibitor.
4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
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| "Bioassay of ferulic acid derivatives as influenza neuraminidase inhibitors";Cui Man-Ying;《Archiv der Pharmazie (Weinheim, Germany)》;20191028;第353卷(第1期);第83-93页 * |
| "RN号 1302959-75-6等";ACS on STN;《REGISTRY》;20110530 * |
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