CN109293644B - Application of 6-methyl nicotinate in preparation of NA inhibitor - Google Patents
Application of 6-methyl nicotinate in preparation of NA inhibitor Download PDFInfo
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- CN109293644B CN109293644B CN201710608398.0A CN201710608398A CN109293644B CN 109293644 B CN109293644 B CN 109293644B CN 201710608398 A CN201710608398 A CN 201710608398A CN 109293644 B CN109293644 B CN 109293644B
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Abstract
The invention discloses a method for preparing 3- (6-methylpyridine-3-yl) -4- [ (thiophene-2-yl) methylene amino by using 6-methyl nicotinic acid methyl ester as a raw material through the following synthetic route]-1H-1,2, 4-triazole-5 (4H) -thione. 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino represented by formula I]-1H-1,2, 4-triazole-5 (4H) -thione and pharmaceutically acceptable salts thereof, preparation methods and pharmaceutical compositions thereof, and application thereof in preparing influenza virus neuraminidase inhibitors.
Description
Technical Field
The invention relates to a novel compound, a preparation method and application thereof, in particular to 3- (6-methylpyridin-3-yl) -4- [ (thiophene-2-yl) methylene amino ] -1H-1,2, 4-triazole-5 (4H) -thioketone, a preparation method thereof and application thereof in preparing influenza virus neuraminidase inhibitors.
Background
The 6-methyl nicotinate is reduced and oxidized to prepare a key intermediate 6-methylpyridine-3-formaldehyde for treating (rheumatoid) rheumatoid arthritis [ China journal of pharmaceutical industry, 2005,36 (5): 266 to 268; chinese invention patent, 201210020938.0, 2012.7.4 publication ]:
vora et al [ J.Chil.chem.Soc.,2011,56(3):771-773] describe the preparation of 3- (6-methylpyridin-3-yl) -4- [ (4-methoxyphenyl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione from 6-methylnicotinate. 3- (6-methylpyridin-3-yl) -4- [ (4-methoxyphenyl) methylene amino ] -1H-1,2, 4-triazole-5 (4H) -thione has better antibacterial effect.
Disclosure of Invention
The invention solves the technical problem of providing the application of 6-methyl nicotinate in preparing a compound with the activity of resisting influenza virus neuraminidase.
In order to solve the technical problem, the invention provides the following technical scheme:
in a first aspect of the present invention, there is provided 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione having the structural formula i:
the second aspect of the present invention provides a method for preparing 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione according to the first aspect, wherein 6-methylnicotinic acid methyl ester is used as a raw material, and 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione is prepared by the following synthetic route:
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, said pharmaceutical composition comprising a therapeutically effective amount of 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione and a pharmaceutically acceptable salt thereof, 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 and liniment; 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 provides 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione and pharmaceutically acceptable salts thereof in the first aspect of the invention and application of the pharmaceutical composition in the third aspect in preparing influenza virus neuraminidase inhibitors.
The beneficial technical effects are as follows:
the 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione of the 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 6-methylnicotinhydrazide
And dropwise adding the mixed solution of 100.0mmol of 6-methylnicotinic acid methyl ester and 5mL of ethanol into 300.0mmol of 80% hydrazine hydrate, stirring at room temperature for 2h, recovering the solvent by rotary evaporation, adding 5mL of diethyl ether, carrying out suction filtration and drying to obtain 13.52g of white solid 6-methylnicotinhydrazide, wherein the yield is 90%, and m.p.138-140 ℃.
Example 2
Preparation of 4-amino-3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione
Dissolving 40.0mmol of 6-methylnicotinhydrazide and 60.0mmol of potassium hydroxide in 50mL of methanol under ice bath, dropwise adding a mixed solution of 60.0mmol of carbon disulfide and 2mL of ethanol, stirring at room temperature for 5 hours after dropwise adding is finished, separating out a solid, performing suction filtration, and drying; dissolving the solid in 7.50g of 80% hydrazine hydrate, refluxing, reacting completely, neutralizing with dilute hydrochloric acid, separating out the solid, performing suction filtration and drying, immersing the crude product in 20mL of carbon disulfide, stirring for 30min, performing suction filtration and drying to obtain 5.73g of white solid 4-amino-3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione, wherein the yield is 71%, and m.p.264-266 ℃;1H NMR(400MHz，DMSO+D2o) δ 9.02(d, J ═ 2.0Hz, 1H, pyridine ring 2-H), 8.26(dd, J ═ 8.0Hz, 2.0Hz, 1H, pyridine ring 4-H), 7.44(d, J ═ 8.0Hz, 1H, pyridine ring 5-H), 2.55(s, 3H, CH, pyridine ring 5-H)3)。
Example 3
Preparation of 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione
5.0mmol of 4-amino-3- (6-methylpyridin-3-yl) -1H-1,2, 4-triazole-5 (4H) -thione, 5.1mmol of 2-thiophenecarboxaldehyde and 10mL of acetic acid are refluxed for 5.0H, cooled, a solid is separated out, filtered by suction and dried to obtain a yellow solid, namely 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino]-1H-1,2, 4-triazole-5 (4H) -thione in 73% yield, m.p.241 to 243 ℃;1H NMR(400MHz，CDCl3+D2o) δ 10.48(s, 1H, N ═ CH), 9.12(d, J ═ 2.0Hz, 1H, pyridine ring 2-H), 8.19(dd, J ═ 8.0Hz, 2.0Hz, 1H, pyridine ring 4-H), 7.60(d, J ═ 4.0Hz, 2H, thiophene ring 3, 5-H), 7.30(d, J ═ 8.0Hz, 2H, pyridine ring 5-H), 7.18 to 7.08(m, 1H, thiophene ring 4-H), 2.65(s, 3H, CH), 9.12(d, J ═ 2.0Hz, 1H, pyridine ring 4-H), 7.18 (m, 1H, thiophene ring 4-H), 2.65(s, 3H, CH, g ═ c, and so-c), and so-c3)。
Example 4
Anti-influenza virus neuraminidase activity of 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione
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 neuraminidase NA 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 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 inhibition rate of the compound on the NA activity can be calculated according to the reduction of the fluorescence intensity.
3. Detecting a sample: 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione
4. Active results
At a concentration of 40.0. mu.g/mL in the reaction system, 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione inhibited neuraminidase by 42.19%.
3- (6-methylpyridine-3-yl) -4- [ (thiophene-2-yl) methylene amino ] -1H-1,2, 4-triazole-5 (4H) -thioketone prepared by taking 6-methyl nicotinic acid methyl ester as a raw material has good activity of resisting influenza virus neuraminidase, and can be used for preparing an influenza virus neuraminidase inhibitor.
Claims (4)
1. 3- (6-methylpyridine-3-yl) -4- [ (thiophene-2-yl) methylene amino ] -1H-1,2, 4-triazole-5 (4H) -thioketone shown as chemical structural formula I and pharmaceutically acceptable salt thereof
2. The process for preparing 3- (6-methylpyridin-3-yl) -4- [ (thien-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione according to claim 1, wherein 3- (6-methylpyridin-3-yl) -4- [ (thien-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione is prepared by the following synthetic route using methyl 6-methylnicotinate as a starting material
3. Use of 3- (6-methylpyridin-3-yl) -4- [ (thiophen-2-yl) methyleneamino ] -1H-1,2, 4-triazole-5 (4H) -thione according to claim 1 in the preparation of influenza virus neuraminidase inhibitors.
4. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
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