CN108863972B - Oxazole amide derivative and preparation method and application thereof - Google Patents
Oxazole amide derivative and preparation method and application thereof Download PDFInfo
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Abstract
The present invention relates to 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamido oxazole and pharmaceutically acceptable salts thereof, pharmaceutical compositions and use thereof in the preparation of influenza virus neuraminidase inhibitors.
Wherein R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy; r2Selected from: hydrogen, C1～C4A linear alkyl group.
Description
Technical Field
The invention relates to a novel oxazole amide derivative, a preparation method and application thereof, in particular to 4-alkyl-5- (3-phenyl acryloyl) -2-alkyl amido oxazole, a preparation method thereof and application thereof in preparing influenza virus neuraminidase inhibitors.
Background
Azizi et al [ Deep aqueous-assisted one-pot synthesis of 2-aminotriazole and 2-aminotriazole derivatives. computers Rends-Chimie, 2015,18(6):626 629] describe a synthesis method for obtaining 4-methyl-5-acetyl-2-aminooxazole by microwave catalytic ring closure using 3-bromo-2, 4-pentanedione as the starting material and urea, with a yield of 27%; quattropani et al [ Thiazol derivatives and usetherof: US9150561.2015.10.06] describe the acetylation of 4-methyl-5-acetyl-2-aminooxazole to give 4-methyl-5-acetyl-2-acetylaminooxazole in 43% yield.
Aly et al [ antibacterial, antioxidant and cytoxicity activities of new wysiwyes and third metal complexes, European journal of medical Chemistry 2014,76:517-530] describe the Aldol condensation of N- (3-acetylphenyl) acetamide with p-hydroxybenzaldehyde to give 3- [3- (4-hydroxyphenyl) acryloyl ] acetaminophenyl C in 21% yield.
Disclosure of Invention
The invention aims to provide a 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamido oxazole, a preparation method thereof, 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 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamido oxazole shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy; r2Selected from: hydrogen, C1～C4A linear alkyl group.
The first aspect of the technical scheme of the invention also provides a 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamido oxazole compound selected from the following compounds: 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-formylaminooxazole, 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-acetaminooxazole, 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-propionylaminooxazole, 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-butyrylaminooxazole, 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] -2-formylaminooxazole, 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] - -2-acetamidooxazole, 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] -2-propionylaminooxazole or 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] -2-butyrylaminooxazole.
The second aspect of the technical scheme of the invention provides a preparation method of 4-alkyl-5- (3-phenyl acryloyl) -2-alkyl acylamino oxazole, which is characterized in that the preparation reaction is as follows:
wherein R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy; r2Selected from: hydrogen, C1～C4A linear alkyl group.
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, the pharmaceutical composition comprising a therapeutically effective amount of a 4-alkyl-5- (3-phenylpropenoyl) -2-alkanoylaminooxazole and a pharmaceutically acceptable salt thereof 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 thereof 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 are added, wherein the solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl- β -cyclodextrin and the like, the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide and the like, the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate and the like, and mannitol, glucose and the like can be added as a propping agent for preparing freeze-dried powder 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 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamido oxazole and pharmaceutically acceptable salts 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 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamidooxazole of the present invention is a compound having an inhibitory activity against influenza virus neuraminidase.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-acetaminooxazole (D)
(1) Preparation of 4-methyl-5-acetyl-2-aminooxazole
1.200g (20mmol) of urea are dissolved in 30m L ethanol solution and catalysis is addedAmount of Et3And N, 3.580g (20mmol) of 3-bromopentane-2, 4-dione is added dropwise, and the mixture reacts at room temperature for 30min and then is refluxed for 8 h. Standing and cooling, pouring the reaction solution into water, adjusting the pH value of the reaction solution to 10 with ammonia water, extracting with ethyl acetate, and extracting with anhydrous Na2SO4Drying, and recrystallizing the crude product with ethanol to obtain a tan solid 4-methyl-5-acetyl-2-aminooxazole with the yield of 48.8 percent and the m.p.186-188 ℃.
(2) Preparation of 4-methyl-5-acetyl-2-acetamido-oxazole
Dissolving 0.360g (6.0mmol) of glacial acetic acid in 10m L DMF solution, adding 0.972g (6mmol) of N, N' -Carbonyldiimidazole (CDI) in batches, stirring at room temperature for 30min, adding 0.560g (4mmol) of 2-amino-4-methyl-5-acetyl oxazole, reacting at 85 ℃ for 8h, cooling to room temperature, pouring the reaction liquid into 30m L ice water, separating out a large amount of solid, performing suction filtration, washing with a proper amount of saturated sodium bicarbonate solution and ice water in sequence, and purifying by column chromatography (V)Ethyl acetate：VPetroleum ether1:1) to obtain brown solid 4-methyl-5-acetyl-2-acetamido oxazole, yield 51.7%, m.p.214-216 ℃.
(3) Preparation of 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-acetaminooxazole (D)
0.182g (1mmol) of 4-methyl-5-acetyl-2-acetamido oxazole and 0.122g (1mmol) of p-hydroxybenzaldehyde solution are put into 6m L ethanol solution, dried HCl gas is introduced to the solution until the solution is saturated, the reaction is carried out for 6h at room temperature, solid is separated out from the reaction solution, the filtration and the ethanol recrystallization are carried out, and dark yellow solid 4-methyl-5- [3- (4-hydroxyphenyl acryloyl) is obtained after the drying]The yield of the (E) -2-acetamido oxazole D is 63.8 percent, and the temperature is m.p.209-211 ℃.1H NMR(400MHz，DMSO-d6)：2.39(s，3H，CH3CO)，2.53(s，3H，CH3)，6.86(d，J＝8.4Hz，2H，C6H4)，7.11(d，J＝15.7Hz，1H，CH)，7.54～7.60(m，3H，C6H4+CH)，7.70(s，1H，OH)，10.07(s，1H，NH)。13C NMR(101MHz，DMSO-d6)：14.72，24.20，116.40，119.64，126.16，130.71，131.09，140.70，142.06，149.74，160.30，162.33，175.40。
Example 2
Preparation of 3- [3- (4-hydroxyphenyl) acryloyl ] acetamidobenzene (C)
(1) Preparation of 3-acetamidoacetophenone
Dissolving 0.180g (3.0mmol) of glacial acetic acid in 6m L DMF solution, adding 0.486g (3mmol) of N, N' -Carbonyl Diimidazole (CDI) in batches, stirring at room temperature for 30min, adding 0.270g (2mmol) of m-aminoacetophenone, reacting at 85 ℃ for 8h, cooling to room temperature, pouring the reaction liquid into 30m L ice water, separating out a large amount of solid, and recrystallizing the crude product by ethyl acetate to obtain white solid 3-acetamidoacetophenone, wherein the yield is 89.1 percent and m.p.130-132 ℃.
(2) Preparation of 3- [3- (4-hydroxyphenyl) acryloyl ] acetamidobenzene
Adding 0.177g (1mmol) of 3-acetamidoacetophenone and 0.122g (1mmol) of p-hydroxybenzaldehyde solution into 6m L ethanol solution, introducing dry HCl gas to saturation, reacting at room temperature for 6h, separating out solids in the reaction solution, performing suction filtration, recrystallizing with ethanol, and drying to obtain yellow solid 3- [3- (4-hydroxyphenyl) acryloyl ] acetamidobenzene C with the yield of 43.5% and m.p.229-231 ℃.
Example 3
Anti-influenza virus neuraminidase activity with 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamidooxazoles
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 are all from A/PR/8/34 (H)1N1) A viral 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 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/m L50The (. mu.g/m L) values are shown in Table 1.
TABLE 1 inhibitory Activity of Compound C and Compound D on neuraminidase H1N1 and IC50
| Compound (I) | 40.0. mu.g/m L, inhibition/%) | IC50(μg/mL) | IC50(μM) |
| C | 72.53±1.60 | 19.1±1.4 | 67.9±5.0 |
| D | 69.79±2.64 | 21.0±1.4 | 73.3±4.9 |
The 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamido oxazole has the activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (5)
1. A class of 4-alkyl-5- (3-phenylpropenoyl) -2-alkylamidooxazoles of formula I:
wherein R is selected from: methyl, ethyl; r1Selected from: hydrogen, 3-hydroxy, 4-hydroxy, 3, 4-dihydroxy, 3, 5-dihydroxy, 2-hydroxy-3-methoxy, 3-hydroxy-4-methoxy, 4-hydroxy-3-methoxy; r2Selected from: hydrogen, C1～C4A linear alkyl group.
2. A4-alkyl-5- (3-phenylpropenoyl) -2-alkylamidooxazole and pharmaceutically acceptable salts thereof are selected from the following compounds: 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-formylaminooxazole, 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-acetaminooxazole, 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-propionylaminooxazole, 4-methyl-5- [3- (4-hydroxyphenylacryloyl) ] -2-butyrylaminooxazole, 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] -2-formylaminooxazole, 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] - -2-acetamidooxazole, 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] -2-propionylaminooxazole or 4-methyl-5- [3- (4-hydroxy-3-methoxyphenylacryloyl) ] -2-butyrylaminooxazole.
3. A process for the preparation of 4-alkyl-5- (3-phenylpropenoyl) -2-alkanoylaminooxazole as claimed in claim 1 which is prepared by the following reaction:
wherein, R, R1And R2Is as defined in claim 1.
4. Use of a 4-alkyl-5- (3-phenylpropenoyl) -2-alkanoylaminooxazole as claimed in claim 1 or claim 2 and pharmaceutically acceptable salts thereof in the preparation of influenza virus neuraminidase inhibitors.
5. A pharmaceutical composition comprising at least one compound of claim 1 or 2 and a pharmaceutically acceptable carrier.
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