CN110229081B

CN110229081B - 2, 4-dinitrophenylhydrazone derivative and preparation method and application thereof

Info

Publication number: CN110229081B
Application number: CN201910585002.4A
Authority: CN
Inventors: 陈平; 陈爱羽; 胡艾希
Original assignee: Changsha University of Science and Technology
Current assignee: Changsha University of Science and Technology
Priority date: 2019-07-01
Filing date: 2019-07-01
Publication date: 2022-02-08
Anticipated expiration: 2039-07-01
Also published as: CN110229081A

Abstract

The invention relates to a2, 4-dinitrophenylhydrazone derivative shown in a chemical structural formula I, a pharmaceutically acceptable salt thereof, a pharmaceutical composition and an application thereof in preparing an influenza virus neuraminidase inhibitor, wherein the pharmaceutical composition comprises the following components:

Description

2, 4-dinitrophenylhydrazone derivative and preparation method and application thereof

Technical Field

The invention relates to a novel compound, a preparation method and application thereof, in particular to a2, 4-dinitrophenylhydrazone derivative, a preparation method and application thereof in preparation of an influenza virus neuraminidase inhibitor.

Background

Hydrazone compounds are Schiff base compounds obtained by dehydrating condensation of aldehyde or ketone compounds and hydrazine compounds, and contain imino and nitrilo groups [ Asian Journal of Pharmacy and Pharmacy, 2018,4(2):116-122 ]. The aromatic hydrazone compound has wide bioactivity, such as antiviral, antidepressant, antitumor, antibacterial, antiinflammatory, antimalarial, analgesic, platelet aggregation inhibiting and vasodilating activities.

In 2003, Jarikote et al [ Ultrasonics Sonochhemistry, 2003,10(1):45-48] synthesized arylhydrazone compounds by reacting phenylhydrazine with a carbonyl compound under ultrasonic irradiation without adding a catalyst:

in 2010, Ajani et al [ Bioorganic & Medicinal Chemistry,2010,18(1):214-221] described 3-hydrazinoquinoxalin-2 (1H) -one and 2-substituted cyclohexanone, 2-quinoxalin-3-hydrazone derivatives were synthesized by microwave irradiation technique and evaluated for their antibacterial activity:

in 2014, Oliveira et al [ RSC Advances,2014,4(100):56736-56742] described organic hydrazine and benzaldehyde derivatives, and synthesized a series of hydrazone compounds by a catalyst-free and solvent-free mechanochemical pathway:

2015, Parveen et al [ New Journal of Chemistry,2015,39(1):469-481]Describes hydrazine hydrate and substituted aromatic aldehydes in ionic liquids [ Et₃NH][HSO₄]The aromatic dihydrazone derivative is synthesized under the catalysis of a catalyst:

disclosure of Invention

The invention aims to provide 2, 4-dinitrophenylhydrazone derivatives, 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 2, 4-dinitrophenylhydrazone derivatives shown as a structural formula I and pharmaceutically acceptable salts thereof:

wherein Y 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: 4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone, 3-methoxy-4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone, 3, 4-dihydroxybenzaldehyde-2, 4-dinitrophenylhydrazone or 2, 4-dihydroxybenzaldehyde-2, 4-dinitrophenylhydrazone.

The second aspect of the technical scheme of the invention provides a preparation method of the 2, 4-dinitrophenylhydrazone derivative, which is characterized in that the preparation reaction is as follows:

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 2, 4-dinitrophenylhydrazone derivatives and pharmaceutically acceptable salts thereof according to 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 2, 4-dinitrophenylhydrazone derivatives and the 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 2, 4-dinitrophenylhydrazone derivatives 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 4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A1)

1.0mmol of 2, 4-dinitrophenylhydrazine and 1.05mmol of 4-hydroxybenzaldehyde are dissolved in 10mL of ethanol, stirred at room temperature for 6h and the reaction is monitored by TLC. Filtering the reaction mixture, washing a filter cake by using a mixed solution (1:1) of petroleum ether and ethyl acetate, and drying to obtain 4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A1), wherein the red solid is m.p.263-264 ℃, and the yield is 89.7%;¹H NMR(400MHz，DMSO-d₆)δ：11.82(s，1H，NH)，9.94(s，1H，OH)，8.98(d，J＝2.5 Hz，1H，C₆H₃)，8.34(dd，J＝9.3，2.5 Hz，1H，C₆H₃)，8.12(s，1H，CH)，7.57(d，J＝8.4 Hz，2H，C₆H₄)，7.26(d，J＝9.3 Hz，1H，C₆H₃)，6.83(d，J＝8.4 Hz，2H，C₆H₄)；¹³C NMR(100 MHz，DMSO-d₆)δ：160.04，150.08，144.61，136.89，130.06，129.71，125.12，123.78，123.40，116.90，116.11。

example 2

Preparation of 3-methoxy-4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A2)

Prepared according to the method of the embodiment 1, 1.0mmol of 2, 4-dinitrophenylhydrazine reacts with 1.05mmol of 3-methoxy-4-hydroxybenzaldehyde for 6h to obtain 3-methoxy-4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A2) which is red solid, m.p.266-267 ℃ and has the yield of 96.1 percent;¹H NMR(400 MHz，DMSO-d₆)δ：11.55(s，1H，NH)，9.69(s，1H，OH)，8.83(s，1H，CH)，8.54(d，J＝4.2 Hz，1H，C₆H₃)，8.32(d，J＝9.6 Hz，1H，C₆H₃)，8.06(dd，J＝9.6，4.2 Hz，1H，C₆H₃)，7.36(s，1H，C₆H₃)，7.15(d，J＝8.1 Hz，1H，C₆H₃)，6.86(d，J＝8.1 Hz，1H，C₆H₃)，3.86(s，3H，CH₃O)；¹³C NMR(100 MHz，DMSO-d₆)δ：150.16，149.65，148.11，144.40，136.53，129.66，128.93，125.10，123.08，122.61，116.71，115.59，109.56，55.65。

example 3

Preparation of 3, 4-dihydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A3)

Prepared according to the method of the embodiment 1, 1.0mmol of 2, 4-dinitrophenylhydrazine reacts with 1.05mmol of 3, 4-dihydroxybenzaldehyde for 6h to obtain 3, 4-dihydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A3) and red solid, wherein m.p.272-273 ℃ has the yield of 91.2%;¹H NMR(400 MHz，DMSO-d₆)δ：11.52(s，1H，NH)，9.58(s，1H，OH)，9.28(s，1H，OH)，8.85(s，1H，CH)，8.51(d，J＝3.0 Hz，1H，C₆H₃)，8.36(d，J＝9.6 Hz，1H，C₆H₃)，7.98(dd，J＝9.6，3.0 Hz，1H，C₆H₃)，7.24(s，1H，C₆H₃)，7.03(d，J＝8.1 Hz，1H，C₆H₃)，6.82(d，J＝8.1 Hz，1H，C₆H₃)；¹³C NMR(100 MHz，DMSO-d₆)δ：150.43，148.64，145.79，144.41，136.48，129.74，128.87，125.12，123.15，120.94，116.41，115.74，113.31。

example 4

Preparation of 2, 4-dihydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A4)

Prepared according to the method of example 1, 1.0mmol of 2, 4-dinitrophenylhydrazine was reacted with 1.05mmol of 2, 4-dihydroxybenzaldehyde for 6h to give 2, 4-dihydroxybenzaldehyde-2, 4-dinitrophenylhydrazone (A4) as a red solid, m.p.>The yield is 91.2 percent at 280 ℃;¹H NMR(400 MHz，DMSO-d₆)δ：11.57(s，1H，NH)，10.11(s，1H，OH)，9.94(s，1H，OH)，8.84(s，1H，C₆H₃)，8.79(s，1H，CH)，8.31(d，J＝9.6 Hz，1H，C₆H₃)，7.93(d，J＝9.6 Hz，1H，C₆H₃)，7.63(d，J＝9.2 Hz，1H，C₆H₃)，6.35(s，1H，C₆H₃)，6.34(d，J＝9.2Hz，1H，C₆H₃)；¹³C NMR(100 MHz，DMSO-d₆)δ：161.33，158.69，147.69，144.16，136.24，129.65，128.71，128.26，123.14，116.38，111.51，108.19，102.39。

example 5

Anti-influenza virus neuraminidase activity of 2, 4-dinitrophenylhydrazone 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 (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 1.

TABLE 12 inhibitory Activity and IC of 4-dinitrophenylhydrazone derivatives on neuraminidase H1N1₅₀

Compound (I)	Y	Inhibition ratio (%)	IC₅₀(μg/mL)
				A1	4-OH	73.08±8.21	18.39±2.91
A2	4-OH-3-OCH₃	76.88±4.60	17.40±1.49
				A3	3,4-(OH)₂	41.53±2.60	-
A4	2,4-(OH)₂	80.48±2.22	13.81±0.80

The 2, 4-dinitrophenylhydrazone derivative has the activity of resisting influenza virus neuraminidase and can be used for preparing influenza virus neuraminidase inhibitors.

Claims

1. The application of 2, 4-dinitrophenylhydrazone derivatives shown in a chemical structural formula I and pharmaceutically acceptable salts thereof in preparing influenza virus neuraminidase inhibitors is as follows:

wherein, the 2, 4-dinitrophenylhydrazone derivative is selected from: 4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone, 3-methoxy-4-hydroxybenzaldehyde-2, 4-dinitrophenylhydrazone or 2, 4-dihydroxybenzaldehyde-2, 4-dinitrophenylhydrazone.