KR101978541B1 - Pharmaceutical composition for treating influenza virus containing the quinazoline derivatives - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating influenza viruses containing a quinazoline derivative, wherein the quinazoline derivative of the formula (1) according to the present invention is not only toxic to normal cells but also has excellent antiviral activity against influenza virus It can be usefully used as a pharmaceutical composition for the prevention or treatment of influenza virus.

Description

[0001] The present invention relates to a pharmaceutical composition for treating influenza virus containing quinazoline derivatives,

The present invention relates to a pharmaceutical composition for treating influenza virus containing a quinazoline derivative.

Influenza (influenza) is an infectious disease caused by the influenza virus (virus) of Osomixovirus. Influenza viruses cause pandemic influenza throughout the world, where thousands to tens of thousands of people die each season. In the 20th century, there was a global epidemic of influenza caused by a new virus, and tens of millions of people were killed. This variant virus occurs frequently when an infection occurs from another animal to a human, when the host, the host, receives the gene from a host that uses another host as the host. The emergence of H5N1, which appeared in Asia in 1990, attracted great interest in the global influenza epidemic, but the species at this time were not mutated to be specific to human-to-human infections. In April 2009, variants of H1N1 emerged in Mexico and emerged in several countries. The International Health Organization (WHO) on July 11, 2009 defined the epidemic as a "global epidemic."

Influenza viruses are divided into three types, A, B, and C, depending on the type of antigen. Virus A can be a host of several animals, while virus B and C are predominantly human hosts. Most influenza epidemics are caused by types A and B, and infection with the virus type C is uncommon and usually follows a light course. On the virus particle surface, there are protuberances with antigenicity. The A and B protrusions contain a unique hemagglutinin (HA) and neuraminidase (NA), and no C-type neuraminidase. Hemagglutinin aggregates are involved in adhering to host cells. Neuraminidase inhibits the neuraminic acid in the airway mucin (mucin inhibits the attachment of the virus to the cells due to its inhibitory effect on the hemagglutinin) It is known to work. Type A is again subclassified according to the hematopoietic aggregation and the anti-circularity of neuraminidase. There are 16 types of hemagglutinin of influenza A virus causing human infection. H1, H2, and H3 have 16 kinds. Agglutination of N1 and N2 is included in neuraminidase. H3N2, H1N1, H2N2 etc. do. The name of the influenza virus is written in the order of type / separation site / separation number / separation year (subtype). For example, A / Hong Kong / 8/68 (H3N2).

The presence or absence of specific antibodies to the influenza virus antigens determines immunity. There are two antiviral variants in influenza virus: the shift of antigen in HA or NA due to gene rearrangement such as the change from H1 to H2, the accumulation of point mutations in the same subtype, A slight change in sex is called the antigen's urine (drift). The pandemic influenza A virus is caused by the feces of the antigen every 10 to 40 years, and in the middle of the pandemic, it is carried out every 2 to 3 years. The great outbreak of type B usually occurs every four to seven years. In the pandemic of type A, the infection rates of children between 5 and 14 years old are the highest at 50%, and infection rates of the same age are known to be about 15% at the time of ownership. In Korea, influenza A was observed every year, and influenza B was observed every two years according to the recent 4 respiratory viral epidemics.

Two classes of antiviral drugs are used to treat influenza. Neuraminidase inhibitors and M2 protein inhibitors (adamantane derivatives) are used as antiviral drugs. A neuraminidase inhibitor is currently preferred for the treatment of influenza virus infections because it is highly toxic and highly effective. The US Centers for Disease Control recommends prescribing a neuraminidase inhibitor for influenza season 2005-2006 rather than an M2 inhibitor because of high levels of drug resistance. Since pregnant women are likely to be more affected by the 2009 H1N1 virus than the general population, it is recommended that an immediate anti-influenza drug be prescribed. Neuraminidase Inhibitors Neuraminidase inhibitors such as oseltamivir (commercial name Tamiflu) and zanamivir (commercial name Lilenga) are drugs designed to prevent the spread of the virus in the body. These drugs are effective against both influenza viruses A and B. Different influenza virus strains show different degrees of resistance to these antiviral drugs. M2 inhibitors The antiviral drugs amantadine and rimantadine inhibit the viral ion channel (M2 protein) and prevent the virus from infecting cells. These drugs are sometimes effective against influenza virus A if they are prescribed early in the infection. However, it is not effective against influenza virus B. This is because the M2 protein of influenza B virus is structurally different from the M2 protein of the type A virus and does not bind amantadine. The measured tolerance of amantadine and rimantadine of H3N2 in the United States increased by 91% in 2005. The high level of tolerance may be due to the fact that Amantadine is the easiest to use among prescription cold medicines sold in China and Russia. And it may be because Amantadine is easily used by poultry to prevent influenza on the farm.

Therefore, there is a continuing need to develop new therapeutic agents that can overcome resistance by existing antiviral drugs.

Accordingly, the inventors of the present invention have conducted studies on a compound having an activity against influenza virus, confirming that the quinazoline derivative is selectively toxic to influenza virus while having low toxicity to normal cells, and completed the present invention.

US Patent Publication No. US2011 / 0281860

It is an object of the present invention to provide a pharmaceutical composition for preventing or treating influenza virus containing as an active ingredient a quinazoline derivative or a pharmaceutically acceptable salt thereof.

In order to achieve the above object,

The present invention provides a pharmaceutical composition for the prevention or treatment of influenza virus comprising as an active ingredient a quinazoline derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are independently hydrogen, halogen, C _1-6 straight or branched chain alkoxy, or amine,

Wherein R ^1b and R ^1c together with the carbon atoms to which they are attached may form a 5-8 membered heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S;

R ² and R ³ are independently hydrogen or - (CH ₂ ) _n C (═O) OR ⁸ , R ⁸ is C _1-6 straight or branched chain alkyl, n is an integer of 1-5,

Wherein R ² and R ³ together with the nitrogen atom to which they are attached may form a 5-8 membered heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S, May be substituted with C _1-6 straight-chain or branched alkyl;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, or C _1-6 straight or branched alkoxy.

The quinazoline derivative of formula (I) according to the present invention is not only low in toxicity to normal cells but also has an excellent antiviral activity against influenza virus, and thus can be effectively used as a pharmaceutical composition for the prevention or treatment of influenza virus .

Fig. 1 shows the results of (a), weight change (b) and survival rate (c) measured when the compound according to the present invention was administered to mice for 5 days each day.

Hereinafter, the present invention will be described in detail.

Pharmaceutical composition for the prevention or treatment of influenza virus

The present invention provides a pharmaceutical composition for the prevention or treatment of influenza virus comprising as an active ingredient a quinazoline derivative represented by the following formula (1), or a pharmaceutically acceptable salt thereof.

In Formula 1,

R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are independently hydrogen, halogen, C _1-6 straight or branched chain alkoxy, or amine,

Wherein R ^1b and R ^1c together with the carbon atoms to which they are attached may form a 5-8 membered heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S;

R ² and R ³ are independently hydrogen or - (CH ₂ ) _n C (═O) OR ⁸ , R ⁸ is C _1-6 straight or branched chain alkyl, n is an integer of 1-5,

Wherein R ² and R ³ together with the nitrogen atom to which they are attached may form a 5-8 membered heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S, May be substituted with C _1-6 straight-chain or branched alkyl;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, or C _1-6 straight or branched alkoxy.

Preferably,

R ^1a , R ^1b , R ^1c , R ^1d and R ^1e are independently hydrogen, halogen, C _1-3 linear or branched alkoxy, or amine,

Wherein R ^1b and R ^1c together with the carbon atoms to which they are attached may form a 5-6 membered heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S;

R ² and R ³ are independently hydrogen or - (CH ₂ ) _n C (═O) OR ⁸ , R ⁸ is C _1-3 linear or branched alkyl, n is an integer of 1-3,

Wherein R ² and R ³ together with the nitrogen atom to which they are attached may form a 5-6 membered heterocycle comprising at least one heteroatom selected from the group consisting of N, O and S, May be substituted with C _1-3 linear or branched alkyl;

R ⁴ , R ⁵ , R ⁶ and R ⁷ are independently hydrogen, halogen, or C _1-3 straight or branched alkoxy.

More preferably,

R ^1a is hydrogen, F, Cl, Br, amine, or methoxy;

R ^1b is hydrogen, Cl, or methoxy;

R ^1c is hydrogen, Cl, methoxy, or ethoxy;

R ^1d and R ^1e are hydrogen;

And R < ^1b > and R < ^1c > together with the carbon atoms to which they are attached may form a five membered heterocycle comprising two O atoms;

R ² is hydrogen;

R ³ is hydrogen, or - (CH ₂ ) ₂ C (═O) OEt;

Wherein R ² and R ³ together with the nitrogen atom to which they are attached may form 4-methylpiperazin-1-yl, or morpholinyl;

R < ⁴ > and R < ⁷ > are hydrogen;

R < ⁵ > is hydrogen or methoxy;

R < ⁶ > is hydrogen, Cl, or methoxy.

Preferred examples of the quinazoline derivatives represented by the formula (1) according to the present invention include the following compounds.

1) 2-phenylquinazoline-4-amine;

2) 2- (2-aminophenyl) quinazolin-4-amine;

3) 2- (2-methoxyphenyl) quinazolin-4-amine;

4) 2- (2-Chlorophenyl) quinazolin-4-amine;

5) 2- (3-methoxyphenyl) quinazolin-4-amine;

6) 2- (3-chlorophenyl) quinazolin-4-amine;

7) 2- (4-methoxyphenyl) quinazolin-4-amine;

8) 2- (4-ethoxyphenyl) quinazolin-4-amine;

9) 2- (4-chlorophenyl) quinazolin-4-amine;

10) 2- (3,4-dimethoxyphenyl) quinazolin-4-amine;

12) 2- (benzo [d] [1,3] dioxol-5-yl) quinazolin-4-amine;

13) 7-Chloro-2-phenylquinazolin-4-amine;

14) 2- (2-Amino-4-chlorophenyl) -7-chloroquinazolin-4-amine;

16) 6,7-Dimethoxy-2-phenylquinazolin-4-amine;

18) 2- (3-Chlorophenyl) -6,7-dimethoxyquinazolin-4-amine;

19) 6,7-Dimethoxy-2- (4-methoxyphenyl) quinazolin-4-amine;

31) 2- (2-fluorophenyl) quinazolin-4-amine;

35) 6,7-Dimethoxy-2- (3-methoxyphenyl) quinazolin-4-amine;

43) 2- (3,4-Dimethoxyphenyl) -4- (4-methylpiperazin-1-yl) quinazoline;

44) 4- (2-Phenylquinazolin-4-yl) morpholine; And

45) Ethyl 3- (2-phenylquinazolin-4-ylamino) propanoate.

The chemical structures of the compounds 1-10, 12-14, 16, 18-19, 31, 33, 35 and 43-45 are shown in Table 1 below.

compound Chemical structural formula compound Chemical structural formula One

13

2

14

3

16

4

18

5

19

6

31

7

35

8

43

9

44

10

45

12

- -

In the pharmaceutical composition according to the present invention, the influenza virus may be influenza virus A type, influenza virus B type, influenza virus C type, and preferably influenza virus A type and / or influenza virus B type.

The influenza virus type A strain is not limited to strains of H1N1 and H3N2 including A / Puerto Rico / 8/34 (H1N1, PR8) and A / Hong Kong / 8/68 (H3N2, HK), H3N8, H5N1, H5N8 , H7N9, H9N2, and the like.

The influenza virus B type may be viruses of various Yamagata lineage and Victoria lineage including B / Lee / 40 (Lee).

The derivatives of formula (1) of the present invention can be used in the form of pharmaceutically acceptable salts, and acid addition salts formed by pharmaceutically acceptable free acids are useful as salts. The term pharmaceutically acceptable salt means a concentration that is relatively non-toxic to a patient and has a beneficial effect that is harmless to the patient, such that the side effects caused by the salt are any organic or inorganic salt of the base compound of Formula 1 that does not impair the beneficial effects of the base compound of Formula An inorganic addition salt. Examples of the inorganic acid include hydrochloric acid, bromic acid, nitric acid, sulfuric acid, perchloric acid and phosphoric acid. Examples of the organic acid include citric acid, acetic acid, lactic acid, maleic acid, (D) or (L) malic acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, maleic acid, tartaric acid, succinic acid, malonic acid, succinic acid, malonic acid, glutamic acid, aspartic acid, oxalic acid, P-toluenesulfonic acid, salicylic acid, citric acid, benzoic acid or malonic acid. These salts also include alkali metal salts (sodium salts, potassium salts, etc.) and alkaline earth metal salts (calcium salts, magnesium salts, etc.). For example, the acid addition salt may be selected from the group consisting of acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camylate, citrate, eddylate, Hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, malate, glucoside, gluconate, gluconate, glucuronate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / Hydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydrogen phosphate, dihydroxyacetate, Lactate, stearate, succinate, tartrate, tosylate, trifluoroacetate Diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, zinc salts, and the like. Preferred is hydrochloride or trifluoroacetate.

The acid addition salt according to the present invention can be obtained by a conventional method, for example, by dissolving a derivative represented by the formula (1) in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and the like, Followed by filtration and drying. Alternatively, the solvent and excess acid may be distilled off under reduced pressure, followed by drying or crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. The corresponding silver salt is also obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (for example, silver nitrate).

Furthermore, the present invention encompasses derivatives of Formula 1 and pharmaceutically acceptable salts thereof, as well as possible solvates, hydrates, isomers, optical isomers and the like, which can be prepared therefrom.

The compound of the present invention may be administered orally or parenterally in various dosage forms during clinical administration. In the case of formulation, the diluent or excipient such as a filler, an extender, a binder, a wetting agent, a disintegrant, .

Solid form preparations for oral administration include tablets, patients, powders, granules, capsules, troches and the like, which may contain one or more excipients such as starch, calcium carbonate, It is prepared by mixing sucrose, lactose or gelatin. In addition to simple excipients, lubricants such as magnesium stearate talc are also used. Liquid preparations for oral administration include suspensions, solutions, emulsions or syrups. Various excipients such as wetting agents, sweeteners, fragrances, preservatives and the like are included in addition to commonly used simple diluents such as water and liquid paraffin. .

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, suppositories, and the like. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The effective dose of the compound of the present invention on the human body may vary depending on the age, weight, sex, dosage form, health condition and disease severity of the patient, and is generally about 0.001-100 mg / kg / 0.0 > mg / kg / day. ≪ / RTI > It is generally from 0.07 to 7000 mg / day, preferably from 0.7 to 2500 mg / day, based on an adult patient weighing 70 kg, and may be administered once a day It may be divided into several doses.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the present invention is not limited by the following examples.

Preparation of experiments

(American Type Culture Collection (ATCC, Rockville, Md.)), Influenza virus A / Puerto Rico / 8/34 (H1N1, PR8), A / Hong Kong / 8/68 (H3N2, HK) and B / Lee / . Influenza virus type B (Lee) was infected with MDCK (Madin-Darby canine kidney) cells in a serum-free condition. And amplified. The virus was partially purified by centrifugation (3,000 rpm) for 5 minutes in the collected egg supernatant or cell culture supernatant.

Virus titers were measured by hemagglutinin assay or plaque assay and stored at -70 ° C prior to use. MDCK cells were maintained in MEM (Minimum Essential Medium) supplemented with 10% fetal bovine serum (Invitrogen) at 37 ° C and 5% CO ₂ .

Amantadine hydrochloride (AMT), ribavirin (RBV) and oseltamivir phosphate (OSV-P) were used as positive control antiviral agents. US Biological, Swampscott, MA. Test compounds were dissolved in DMSO at a concentration of 40 mg / mL and stored at -20 ° C.

< Experimental Example  1> Cytotoxic effect Cytopathic  effect, CPE ) Inhibition evaluation ( in vitro )

The cytotoxic and antiviral activities of the quinazoline derivatives according to the present invention were tested as follows. The results are shown in Table 2 below.

Specifically, MDCK cells were plated in 96-well plates and cultured until 100% fused. Next, the cells were washed with phosphate-buffered saline (PBS), and the cells were infected with influenza virus at a multiplicity of infection of 0.001 for 1 hour at 35 ° C in a serum-free condition. -infected) or infected. Unabsorbed virus was removed by washing with PBS and a three-fold serial dilution of the compound of Example dissolved in MEM and 2 mg / mL TPCK-trypsin was added to each well. Three days after infection, cell viability was measured using MTT (3- (4,5-dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide; Sigma-Aldrich). After reading the absorbance at a wavelength of 540/690 nm, the 50% cytotoxic concentration (CC ₅₀ ) and the 50% effective concentration (EC ₅₀ ) were calculated using GraphPad Prism 6 (GraphPad Software, La Jolla, Calif.). In the following Table 2, " selectivity index " means the ratio of CC ₅₀ to EC ₅₀ .

Compd No. Toxicity (CC ₅₀ , μM) Antiviral activity
(EC ₅₀ , uM) Selectivity index PR8 HK Lee PR8 HK Lee One
(HCl salt) > 100.0 8.5 4.6 4.7 > 11.8 > 21.7 > 21.3 2
(HCl salt) > 100.0 > 100.0 100 41.1 ND > 1.0 > 2.4 3
(HCl salt) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 4
(HCl salt) > 100.0 > 100.0 35.4 26.8 ND > 2.8 > 3.7 5
(HCl salt) > 100.0 15.5 20.2 11.8 > 6.5 > 5.0 > 8.5 6
(HCl salt) > 100.0 20.4 7.2 11.3 > 4.9 > 13.9 > 8.9 7
(HCl salt) > 100.0 > 100.0 > 100.0 26.4 ND ND > 3.8 8
(HCl salt) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 9
(HCl salt) > 100.0 > 100.0 12.4 14.8 ND > 8.1 > 6.8 10
(HCl salt) > 100.0 > 100.0 73.1 > 100.0 ND > 1.4 ND 12
(HCl salt) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 13
(HCl salt) 62.6 > 62.6 9.3 18.2 ND 6.7 3.4 14
(HCl salt) > 100.0 65.4 18.6 23.5 > 1.5 > 5.4 > 4.3 16
(HCl salt) > 100.0 > 100.0 26.2 > 100.0 ND > 3.8 ND 18
(HCl salt) 61.8 > 61.8 > 61.8 > 61.8 ND ND ND 19
(HCl salt) 21 > 21.0 > 21.0 > 21.0 ND ND ND 31
(HCl salt) > 100.0 18.1 15.1 16.3 > 5.5 > 6.6 > 6.1 35
(HCl salt) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 43
(HCl salt) > 100.0 82.9 24.9 > 100.0 > 1.2 > 4.0 ND 44
(HCl salt) > 100.0 > 100.0 > 100.0 > 100.0 ND ND ND 45
(HCl salt) > 100.0 > 100.0 > 100.0 97.4 ND ND > 1.1

As shown in Table 2, the compounds of Examples 5, 6 and 31 according to the present invention have low cytotoxicity and excellent antiviral activity.

&Lt; Experimental Example 2 > Evaluation of antiviral efficacy ( in vivo )

In order to examine the antiviral efficacy of Compound 5 according to the present invention and Compound 5 (HCl salt), half-life lethal dose was evaluated and the results are shown in FIG.

Specifically, half the mouse lethal dose (MLD ₅₀ ) was measured as a ten-fold serial dilution of the maPR8 virus nasal infection based on the Reed-Muench method. Groups of 5, 6 or 7-week-old female mice were anesthetized with isoflurane and inoculated into the nasal passages by mixing with maPR8 virus alone (5 MLD ₅₀ ) or with PBS (20 mg / kg) in which the compound of Example was dissolved. After 6 hours of infection with maPR8-infected mice, OSV-P (oseltamivir phosphate, Tamiflu) was orally administered at a dose of 20 mg / kg as a positive control. On the first day of infection, the compounds of the examples were administered nasally or orally at a dose of 20 mg / kg / d for 5 days each day. Weight change and 11-day survival rate of mice were observed every day. When the weight of the mouse was reduced by 30%, it was euthanized.

Fig. 1 shows the results of (a), weight change (b) and survival rate (c) measured when the compound according to the present invention was administered to mice for 5 days each day.

As shown in FIG. 1, the 8-day survival rate of the mouse was 0% when the salt-removed compound was administered, but 100% in the HCl salt-administered group of the compound 5, as in the case of no treatment after infection with the influenza virus, , Indicating that the compounds according to the present invention are effective for the treatment of influenza virus.

&Lt; Formulation Example 1 > Preparation of pharmaceutical preparation

<1-1> Preparation of powder

2 g &lt; RTI ID = 0.0 &gt;

Lactose 1 g

After mixing the above components, the mixture was packed in an airtight container to prepare a powder.

<1-2> Preparation of tablets

100 mg of the compound of formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, tablets were prepared by tableting according to a conventional method for producing tablets.

&Lt; 1-3 > Preparation of capsules

100 mg of the compound of formula (1)

Corn starch 100 mg

100 mg of milk

2 mg of magnesium stearate

After mixing the above components, the capsules were filled in gelatin capsules according to the conventional preparation method of capsules.

<1-4> Preparation of Injection Solution

10 [mu] g / ml of the compound of formula (1)

Until dilute hydrochloric acid BP pH 3.5

Sodium chloride BP injected up to 1 ml

The compound of formula 1 according to the invention is dissolved in a suitable volume of sodium chloride BP and the pH of the resulting solution is adjusted to pH 3.5 with diluted hydrochloric acid BP and the volume is adjusted using injectable sodium chloride BP . The solution was filled in a 5 ml type I ampoule made of transparent glass, sealed in an upper lattice of air by dissolving the glass, sterilized by autoclaving at 120 DEG C for 15 minutes or longer, and an injection solution was prepared.

<1-5> Preparation of Nasal Spray

1.0 g of the compound of formula (1)

Sodium acetate 0.3 g

0.1 g of methylparaben

Propyl paraben 0.02 g

Sodium Chloride Amount

HCl or NaOH pH adjustment qs

Purified water quantity

According to a conventional method for producing a cost absorbent, 3 mg of the compound of the formula (1) is contained per 1 mL of saline (0.9% NaCl, w / v, and the solvent is purified water), filled in an opaque spray container and sterilized Absorbent.

<1-6> Liquid  Produce

100 mg of the compound of formula (1)

10 g per isomer

5 g mannitol

Purified water quantity

Each component was added to purified water to dissolve and add lemon fragrance, then the above components were mixed, and purified water was added to adjust the total volume to 100 mL. The solution was filled in a brown bottle and sterilized to prepare a liquid preparation Respectively.

Claims (7)

A pharmaceutical composition for the prevention or treatment of influenza virus selected from the group consisting of influenza virus A type and influenza virus type B comprising a pharmaceutically acceptable salt of a quinazoline derivative represented by the following formula 1 as an active ingredient:
[Chemical Formula 1]

(In the formula 1,
R ^1a is hydrogen, F, Cl, or an amine;
R ^1b is hydrogen, Cl, or methoxy;
R ^1c is hydrogen, Cl, or methoxy;
R ^1d and R ^1e are hydrogen;
R ² is hydrogen;
R ³ is hydrogen;
Said R ² and R ³ together with the nitrogen atom to which they are attached may form 4-methylpiperazin-1-yl;
R &lt; ⁴ &gt; and R &lt; ⁷ &gt; are hydrogen;
R &lt; ⁵ &gt; is hydrogen or methoxy;
R &lt; ⁶ &gt; is hydrogen, Cl, or methoxy,
However, the compound of formula (1) excludes one of the following compounds:
35) 6,7-Dimethoxy-2- (3-methoxyphenyl) quinazolin-4-amine).
delete delete The method according to claim 1,
Wherein the quinazoline derivative represented by the formula (1) is any one selected from the group consisting of the following compounds:
1) 2-phenylquinazoline-4-amine;
2) 2- (2-aminophenyl) quinazolin-4-amine;
4) 2- (2-Chlorophenyl) quinazolin-4-amine;
5) 2- (3-methoxyphenyl) quinazolin-4-amine;
6) 2- (3-chlorophenyl) quinazolin-4-amine;
7) 2- (4-methoxyphenyl) quinazolin-4-amine;
9) 2- (4-chlorophenyl) quinazolin-4-amine;
10) 2- (3,4-dimethoxyphenyl) quinazolin-4-amine;
13) 7-Chloro-2-phenylquinazolin-4-amine;
14) 2- (2-Amino-4-chlorophenyl) -7-chloroquinazolin-4-amine;
16) 6,7-Dimethoxy-2-phenylquinazolin-4-amine;
18) 2- (3-Chlorophenyl) -6,7-dimethoxyquinazolin-4-amine;
19) 6,7-Dimethoxy-2- (4-methoxyphenyl) quinazolin-4-amine;
31) 2- (2-fluorophenyl) quinazolin-4-amine; And
43) 2- (3,4-Dimethoxyphenyl) -4- (4-methylpiperazin-1-yl) quinazoline.
delete The method according to claim 1,
Wherein said influenza A virus type is at least one selected from the group consisting of H1N1, H3N2, H3N8, H5N1, H5N8, H7N9 and H9N2.
The method according to claim 1,
Wherein said influenza virus B type is at least one selected from the group consisting of Yamagata lineage and Victoria lineage.

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