CN110183349B - Oxalyl hydrazone derivative and preparation method and application thereof - Google Patents
Oxalyl hydrazone derivative and preparation method and application thereof Download PDFInfo
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- CN110183349B CN110183349B CN201910499606.7A CN201910499606A CN110183349B CN 110183349 B CN110183349 B CN 110183349B CN 201910499606 A CN201910499606 A CN 201910499606A CN 110183349 B CN110183349 B CN 110183349B
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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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C249/00—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C249/16—Preparation of compounds containing nitrogen atoms doubly-bound to a carbon skeleton of hydrazones
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C251/00—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton
- C07C251/72—Hydrazones
- C07C251/86—Hydrazones having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
Abstract
The invention relates to oxalylhydrazone derivatives shown in a chemical structural formula I, pharmaceutically acceptable salts thereof, a pharmaceutical composition 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 an oxalylhydrazone derivative, a preparation method and application thereof in preparation of an influenza virus neuraminidase inhibitor.
Background
In 2007, Li et al [ Brazilian Journal of Chemical Engineering,2007,24(4):471-475] describe the preparation of adipimidate hydrazone derivatives from adipimidate and aromatic aldehydes by a solvent-free microwave-assisted process.
Disclosure of Invention
The invention aims to provide an oxalylhydrazone 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 oxalylhydrazone derivatives shown as a structural formula I and pharmaceutically acceptable salts thereof:
wherein R is selected from: 2-hydroxy group, 3-hydroxy group, 4-hydroxy group, 2, 4-dihydroxy group, 3, 4-dihydroxy group, 2, 5-dihydroxy group, 3, 5-dihydroxy group, 2, 6-dihydroxy group, 2-hydroxy-3-methoxy group, 2-hydroxy-4-methoxy group, 2-hydroxy-5-methoxy group, 2-hydroxy-6-methoxy group, 3-hydroxy-2-methoxy group, 3-hydroxy-4-methoxy group, 3-hydroxy-5-methoxy group, 3-hydroxy-6-methoxy group, 4-hydroxy-2-methoxy group, 4-hydroxy-3, 5-dimethoxy group, 2-hydroxy-3-ethoxy, 2-hydroxy-4-ethoxy, 2-hydroxy-5-ethoxy, 2-hydroxy-6-ethoxy, 3-hydroxy-2-ethoxy, 3-hydroxy-4-ethoxy, 3-hydroxy-5-ethoxy, 3-hydroxy-6-ethoxy, 4-hydroxy-2-ethoxy, 4-hydroxy-3, 5-diethoxy, 2, 3, 4-trihydroxy, or 4-hydroxy-3, 5-dimethyl.
Further, preferred compounds are selected from: bis (4-hydroxybenzaldehyde) oxalylhydrazone, bis (3-methoxy-4-hydroxybenzaldehyde) oxalylhydrazone, bis (3, 4-dihydroxybenzaldehyde) oxalylhydrazone, or bis (2, 4-dihydroxybenzaldehyde) oxalylhydrazone.
The second aspect of the technical scheme of the invention provides a preparation method of the oxalylhydrazone derivative, which is characterized in that the preparation reaction is as follows:
wherein R is selected from: 2-hydroxy group, 3-hydroxy group, 4-hydroxy group, 2, 4-dihydroxy group, 3, 4-dihydroxy group, 2, 5-dihydroxy group, 3, 5-dihydroxy group, 2, 6-dihydroxy group, 2-hydroxy-3-methoxy group, 2-hydroxy-4-methoxy group, 2-hydroxy-5-methoxy group, 2-hydroxy-6-methoxy group, 3-hydroxy-2-methoxy group, 3-hydroxy-4-methoxy group, 3-hydroxy-5-methoxy group, 3-hydroxy-6-methoxy group, 4-hydroxy-2-methoxy group, 4-hydroxy-3, 5-dimethoxy group, 2-hydroxy-3-ethoxy, 2-hydroxy-4-ethoxy, 2-hydroxy-5-ethoxy, 2-hydroxy-6-ethoxy, 3-hydroxy-2-ethoxy, 3-hydroxy-4-ethoxy, 3-hydroxy-5-ethoxy, 3-hydroxy-6-ethoxy, 4-hydroxy-2-ethoxy, 4-hydroxy-3, 5-diethoxy, 2, 3, 4-trihydroxy, or 4-hydroxy-3, 5-dimethyl.
In a third aspect of the technical scheme of the present invention, a pharmaceutical composition containing the compound of the first aspect and a pharmaceutically acceptable salt thereof is provided, wherein the pharmaceutical composition contains a therapeutically effective amount of the oxalylhydrazone derivative and the pharmaceutically acceptable salt thereof of the present invention, and optionally contains 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 oxalylhydrazone 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 oxalylhydrazone derivatives disclosed by the invention are compounds with influenza virus neuraminidase inhibitory activity.
Detailed Description
The following examples are intended to illustrate the invention without further limiting it.
Example 1
Preparation of bis (4-hydroxybenzaldehyde) oxalylhydrazone (Ia)
(1) Preparation of oxalyl hydrazine
Putting 6.0mmol diethyl oxalate and 24.0mmol 80% hydrazine hydrate into 16mL ethanol, reacting for 3h, cooling the reaction mixture to room temperature, performing suction filtration, washing a filter cake with petroleum ether and ethanol, and drying to obtain oxalyl hydrazine, a white solid, m.p. 240-241 ℃, and the yield is 90.5%.
(2) Preparation of bis (4-hydroxybenzaldehyde) oxalylhydrazone (Ia)
1.0mmol of oxalyl hydrazine, 2.1mmol of 4-hydroxybenzaldehyde and 2 drops of acetic acid were suspended in 16mL of ethanol, refluxed for 4h and monitored by TLC for the reaction. Cooling the reaction liquid to room temperature, performing suction filtration, washing a filter cake by using petroleum ether and ethanol, and drying to obtain di (4-hydroxybenzaldehyde) oxalylhydrazone (Ia), a light yellow solid and m.p.>The yield is 96.9 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)δ：12.07(s，2H，2×NH)，10.00(s，2H，2×OH)，8.49(s，2H，2×CH)，7.54(d，J＝8.0Hz，4H，C6H4)，6.84(d，J＝8.0Hz，4H，C6H4)；13C NMR(100MHz，DMSO-d6)δ：159.86，155.99，151.25，129.26，124.84，115.77。
example 2
Preparation of bis (2, 4-dihydroxybenzaldehyde) oxalylhydrazone (Ib)
Prepared according to the method of (2) in example 1, 1.0mmol oxalyl hydrazine was reacted with 2.1mmol 2, 4-dihydroxybenzaldehyde for 4h to give bis (2, 4-dihydroxybenzaldehyde) oxalyl hydrazone (Ib) as a yellow solid, m.p.>The yield is 94.7 percent at 280 ℃;1HNMR(400MHz，DMSO-d6)δ：12.42(s，2H，2×OH)，11.21(s，2H，2×NH)，10.04(s，2H，2×OH)，8.65(s，2H，CH)，7.30(d，J＝8.5Hz，2H，C6H3)，6.36(d，J＝8.5Hz，2H，C6H3)，6.31(s，2H，C6H3)；13C NMR(100MHz，DMSO-d6)δ：161.26，159.70，155.54，151.92，131.47，110.40，107.97，102.64。
example 3
Preparation of bis (3-methoxy-4-hydroxybenzaldehyde) oxalylhydrazone (ic)
Prepared according to the method of (2) in example 1, 1.0mmol of oxalyl hydrazine was reacted with 2.1mmol of 3-methoxy-4-hydroxybenzaldehyde for 4h to give bis (3-methoxy-4-hydroxybenzaldehyde) oxalyl hydrazone (ic) as a white solid, m.p.>The yield is 95.8 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)δ：12.08(s，2H，2×NH)，9.64(s，2H，2×OH)，8.49(s，2H，2×CH)，7.28(s，2H，C6H3)，7.09(d，J＝8.2Hz，2H，C6H3)，6.85(d，J＝8.2Hz，2H，C6H3)，3.83(s，6H，CH3)；13C NMR(100MHz，DMSO-d6)δ：156.01，151.62，149.51，148.05，125.23，122.61，115.53，109.39，55.62。
example 4
Preparation of bis (3, 4-dihydroxybenzaldehyde) oxalylhydrazone (id)
Prepared according to the method of (2) in example 1, 1.0mmol oxalyl hydrazine was reacted with 2.1mmol 3, 4-dihydroxybenzaldehyde for 4h to give bis (3, 4-dihydroxybenzaldehyde) oxalyl hydrazone (id), a gray solid, m.p.>The yield is 95.7 percent at 280 ℃;1H NMR(400MHz，DMSO-d6)δ：12.03(s，2H，2×NH)，9.47(s，2H，2×OH)，9.30(s，2H，2×OH)，8.40(s，2H，2×CH)，7.23(s，2H，C6H3)，6.92(d，J＝8.1Hz，2H，C6H3)，6.79(d，J＝8.1Hz，2H，C6H3)；13C NMR(100MHz，DMSO-d6)δ：155.98，151.46，148.48，145.76，125.31，121.10，115.64，112.91。
example 5
Anti-influenza virus neuraminidase activity of oxalylhydrazone 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(H1N1) 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 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 1.
TABLE 1 inhibition of neuraminidase H1N1 by oxalylhydrazone derivatives andIC50
| compound (I) | R | Inhibition ratio (%) | IC50(μg/mL) |
| Ⅰa | 4-OH | 89.77±1.64 | 6.79±0.98 |
| Ⅰb | 2,4-(OH)2 | 81.10±1.02 | 13.84±1.43 |
| Ⅰc | 4-OH-3-OCH3 | 88.53±0.90 | 8.46±0.36 |
| Ⅰd | 3,4-(OH)2 | 34.27±0.36 | - |
The oxalylhydrazone derivative has the activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.
Claims (1)
1. An oxalylhydrazone derivative shown in a chemical structural formula I and application of pharmaceutically acceptable salts thereof in preparing influenza virus neuraminidase inhibitors:
the oxalyl hydrazone derivative is selected from the following compounds:
bis (4-hydroxybenzaldehyde) oxalylhydrazone, bis (3-methoxy-4-hydroxybenzaldehyde) oxalylhydrazone, bis (3, 4-dihydroxybenzaldehyde) oxalylhydrazone, or bis (2, 4-dihydroxybenzaldehyde) oxalylhydrazone.
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