JP2000053654A - New quinazoline derivatives - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an autoimmune disease such as allergic disease, systemic lupus erythematosus, or acquired immunodeficiency syndrome (AIDS) by suppressing the production of Th2 type cytokines such as IL-4 and IL-5. )). SOLUTION: Formula (1) (Wherein, R ¹ represents a linear or branched lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms, and R ² represents a hydrogen atom, a 1 to 6 carbon atoms. It represents a linear or branched lower alkyl group, a carbamoyl group or a hydroxymethyl group,, R ³ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, R ^4, R ⁵ , R ⁶ and R ⁷ are a hydrogen atom,
Represents a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a halogen atom. Or a pharmaceutically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to quinazoline derivatives. More specifically, the present invention suppresses the immune response on the type 2 helper T cell (hereinafter abbreviated as Th2) side, enhances the immune response on the type 1 helper T cell (hereinafter abbreviated as Th1) side, The present invention relates to an immunomodulator comprising, as an active ingredient, a quinazoline derivative or a pharmaceutically acceptable salt thereof that changes the balance of Th1 / Th2. Specifically, the present invention relates to a therapeutic agent for an allergic disease in which the immune response on the Th2 side is abnormally enhanced. More specifically, the present invention provides a T
Diseases caused by abnormally enhanced Th2 side immune response by suppressing the immune response on the h2 side and enhancing the immune response on the Th1 side, ie, allergic diseases such as asthma, allergic dermatitis or allergic rhinitis, Alternatively, the present invention relates to an immunomodulator containing a quinazoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient, which is effective for treating or preventing an autoimmune disease such as systemic lupus erythematosus, and acquired immunodeficiency syndrome (AIDS). Furthermore, the quinazoline derivative or the pharmaceutically acceptable salt thereof for treating or preventing a virus or a bacterial infection, a malignant tumor, or the like resulting from the action of enhancing the Th1 side immune response of the present invention, or an immunity containing the pharmaceutically acceptable salt thereof as an active ingredient. It relates to a regulator. Th
By a selective immunomodulatory action that enhances the one-sided immune response,
Immunomodulation using a quinazoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient for treating or preventing various diseases, for example, bacterial infections, malignant tumors, etc., that enhance or enhance the Th1 side immune response leads to treatment or prevention. Agent.

[0002]

BACKGROUND OF THE INVENTION Mosmann et al. First proposed that lymphocytes called helper T cells (hereinafter abbreviated as Th), which play a central role in the immune response, are classified into two different subsets. is there. They classified mouse helper T cells (Th) into a subset of Th1 and Th2 according to the type of cytokines produced (J.I.
mmunol. (1986) 136: 2348-2357). Th1 type cytokines include interleukin 2 (IL-2),
Interferon γ (IFN-γ) and the like. T
h2 type cytokines include interleukin 4
(IL-4), interleukin 5 (IL-5), interleukin 10 (IL-10), interleukin 1
3 (IL-13) and the like.

[0003] Today, the concept of Th1 / Th2 classification goes beyond simply classifying subsets of helper T cells, and which subset of helper T cells is mainly involved in various immune responses in a living body. From the viewpoint, “Th1 side immune response” and “Th2 side
Side's immune response ". The main components of the Th1 side immune response are cytokines such as interferon γ (IFN-γ) and interleukin 2 (IL-2) that are produced with the activation of Th1. These Th1-type cytokines induce activation of macrophages, natural killer cells, and the like, and enhance Th1 activation by IL-12 and the like produced from the activated macrophages. It is known to be involved in cell-mediated immunity such as protection against infection. On the other hand, the main components of the immune response on the Th2 side include IL-4 and IL-4 produced upon activation of Th2.
-5 and other cytokines. These Th2-type cytokines are known to be involved in humoral immunity such as antibody production from B cells (including the IgE class).

[0004] Th2 is regarded as an important regulatory cell for allergic reactions because it produces cytokines involved in allergic reactions such as IL-4 and IL-5 as described below. For example, IL which is a representative of Th2-type cytokine
-4 induces IgE antibody production against B cells. It also induces gene expression of VCAM-1, an important molecule that functions when eosinophils adhere to vascular endothelial cells and infiltrate tissue (Pharmacia (1993) 29 : 1123-1128). Recently, IL-
4 is also attracting attention as a differentiation and growth factor of Th2 itself. In addition, IL-2 is a Th2-type cytokine like IL-4.
Induces eosinophil differentiation, migration, or activation. Allergic inflammation is characterized by eosinophil infiltration, activation and degranulation, as typified by chronic airway inflammation in asthma, for example. From this, IL
-5 is thought to be a trigger for allergic inflammatory response.

[0005] From the above characteristics of Th2-type cytokines, Th2 has two allergies: an "immediate-type reaction" of allergy involving IgE antibodies and mast cells, and a "late-onset reaction" of eosinophils. Control any of the reactions,
It is recognized as a central cell in the allergic inflammatory response. Therefore, an allergic disease is considered to be a disease caused by abnormally enhanced Th2 immune response. This idea is supported by the production of Th2-type cytokines such as IL-4 and IL-5 or the presence of Th2 in the respiratory tract and skin, which are lesions of allergic diseases. .

[0006] From the above, both immediate and delayed allergic reactions are suppressed, or marked eosinophil infiltration,
In order to suppress the allergic inflammatory reaction characterized by activation at the stage of its underlying cause, and to treat and prevent allergic diseases in general, it is important to suppress the Th2 side immune response. Conceivable. In other words, if a drug capable of suppressing the immune response on the Th2 side is developed,
It is considered to be an effective therapeutic or preventive drug for allergic diseases.

[0007] Among allergic diseases, late-onset allergic reactions are considered to play an important role, especially in severe chronic asthma and atopic dermatitis. However, currently used antiallergic drugs mainly suppress only an immediate allergic reaction mainly due to antihistamine action and the like, and their clinical effects are not sufficient. From such a viewpoint, it is desired to develop a drug that suppresses both the late-type and immediate-type allergic reactions as described above and treats or prevents allergic diseases in general, and suppresses the Th2 side immune response. -ing

Further, bronchodilators such as xanthine derivatives or β-stimulants which have been used for many years in the treatment of asthma are known to have an action of suppressing the contraction of bronchial smooth muscle due to various stimuli. I have. However, it is ineffective against chronic airway inflammation, the underlying etiology of asthma. In addition, both xanthine derivatives and β-stimulants pose a problem of circulatory side effects. In the treatment of asthma today, as clearly indicated in the WHO guidelines, asthma should be regarded as chronic inflammation of the respiratory tract, and the elimination of this chronic airway inflammation should be the primary goal of treatment. Became. Chronic airway inflammation in asthma is triggered by infiltration, activation, and degranulation of eosinophils, and is characterized by a pathological image that leads to thickening and fibrosis of airway epithelium with chronic inflammation. The guidelines now state that inhaled steroids, the only agents effective for this chronic airway inflammation, are ranked first-line for moderate to moderate asthma.

[0009] After all, only steroids are effective for these severe asthma and atopic dermatitis, and the steroids are currently frequently used. However, there is a problem that the long-term administration of the steroid causes various side effects (steroid dermatosis, induced infection, adrenocortical dysfunction, etc.). From these perspectives,
Allergic inflammatory response characterized by marked suppression of both immediate and delayed allergic reactions or marked eosinophil infiltration and activation by selectively suppressing Th2 side immune responses At its root cause stage,
There is a demand for the development of a drug capable of treating and preventing allergic diseases in general.

[0010] Further, in consideration of the development of a therapeutic or prophylactic drug with less side effects, if the drug that suppresses the Th2 side immune response as described above enhances the Th1 side immune response, It appears to be more convenient as a medicament. That is, as described above, Th1 is mainly
The drug developed for the purpose of suppressing the Th2 side immune response enhances the action of Th1 because it plays an important role for the living body to protect against viruses, bacteria, etc. by producing IFN-γ. If it does, it is highly desirable in terms of side effects. For example, immunosuppressants cyclosporin and FK506
Is known to strongly suppress Th2 activation. However, these cyclosporins and FK506 are Th2
Has a non-specific immunosuppressive action that suppresses Th1 activation as well as, or even stronger than, the suppression of Th1 activation. Serious side effects such as opportunistic infections or increased carcinogenesis rates are a problem.
Similar problems can be considered for other non-specific immunosuppressants.

From the above, T represented by the production of IFN-γ
If a drug that enhances the immune response on the h1 side and suppresses the immune response on the Th2 side typified by the production of IL-4 and IL-5 is developed, the treatment for allergic diseases as described above is effective and has few side effects. It is thought to be a drug or prophylactic. Autoimmune diseases such as systemic lupus erythematosus, in which antibody production or humoral immunity is abnormally enhanced, are also presumed to be in a state in which the Th2 side immune response is abnormally enhanced (Medical Immunology (1988) 15: 401).
Therefore, the immune response on the Th1 side is enhanced as described above,
The drug that suppresses the side immune response is expected to be a therapeutic drug for autoimmune diseases.

[0012] WO 93/07124 discloses quinazoline derivatives that exhibit activity as phosphodiesterase inhibitors. It also discloses its potential as an antiallergic agent based on its activity as a phosphodiesterase inhibitor. However, in the case of theophylline, which is representative of existing anti-allergic agents based on its activity as a phosphodiesterase inhibitor, its main anti-allergic effect is bronchodilator effect in asthma. As described above, bronchodilators represented by xanthine derivatives or β-stimulants are known to have the effect of suppressing the contraction of bronchial smooth muscle due to various stimuli, but they only suppress the symptoms, It is ineffective against chronic airway inflammation, the underlying etiology of asthma. Furthermore, considering the phosphodiesterase isoenzyme, the isoenzyme mainly involved in allergic inflammation is cAMP phosphodiesterase (PDE-III or IV), and cA
By inhibiting MP phosphodiesterase,
It is considered that the intracellular cAMP concentration increases, and an anti-inflammatory effect appears. On the other hand, the inhibitors disclosed in WO 93/07124 are cGMP phosphodiesterases as isoenzymes
(PDE-V) and calmodulin-dependent phosphodiesterase (PDE-I) .When these cGMP phosphodiesterases are inhibited, the intracellular cGMP concentration increases, and vasodilation and bronchodilation are caused. Although expressed, it does not have an inhibitory effect on inflammatory cells, and therefore cannot be expected to have an anti-inflammatory effect. Rather, many researchers today are investigating PDE-IV specific inhibitors to reduce side effects and enhance antiallergic effects. WO 93/07124 does not specifically disclose the quinazoline derivative of the present invention that enhances the Th1 side immune response and suppresses the Th2 side immune response. Further, the quinazoline derivative of the present invention does not show a phosphodiesterase inhibitory activity.

[0013]

The problem to be solved by the present invention is that Th
It is an object of the present invention to provide a compound that enhances the immune response on one side and suppresses the immune response on the Th2 side, thereby changing the Th1 / Th2 balance as a whole and modulating the immune response. Specifically, interferon γ (IFN-
γ) and other compounds that enhance the production of Th1 type cytokines and, conversely, suppress the production of Th2 type cytokines such as interleukin 4 (IL-4) and interleukin 5 (IL-5). More specifically, for example,
Allergic diseases, parasitic infections, autoimmune diseases such as systemic lupus erythematosus, viral or bacterial infections, malignant tumors or acquired immunodeficiency syndrome (AID)
S) and other therapeutic or prophylactic agents.

[0014]

Means for Solving the Problems The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, the quinazoline derivative and its salt have enhanced the Th1 side immune response,
The inventors have found that the immune response on the two sides is suppressed, and furthermore, they have found that the balance of Th1 / Th2 is changed as a whole to regulate the immune response, and the present invention has been completed.

[0015] The present invention provides: Equation (1)

Embedded image (Wherein, R ¹ represents a linear or branched lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms, and R ² represents a hydrogen atom, a 1 to 6 carbon atoms. A straight-chain or branched lower alkyl group, an aryl group having 6 to 10 carbon atoms, a halogen atom, an alkoxy group having 1 to 4 carbon atoms or an alkyl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 4 carbon atoms; Represents an aryl group, a carbamoyl group or a hydroxymethyl group, R ³ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, and R ⁴ represents a hydrogen atom, a hydroxyl group, a carbon number R ⁵ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a halogen atom, and R ⁶ represents a hydrogen atom, a hydroxyl group, a 1 to 6 carbon atom having 1 to 6 carbon atoms. A It represents Kokishi group or a halogen atom, R
⁷ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a halogen atom. 1.) a quinazoline derivative or a pharmaceutically acceptable salt thereof; R ¹ is a linear or branched lower alkyl group having 1 to 4 carbon atoms. 2. the quinazoline derivative or a pharmaceutically acceptable salt thereof described above; R ¹ is a lower alkoxy group having 1 to 3 carbon atoms. 4.1. The quinazoline derivative or a pharmaceutically acceptable salt thereof according to the above. 2. Or 3. Type 2 comprising the quinazoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient
5.1. An immunomodulator that suppresses an immune response on the side of helper T cells and enhances an immune response on the side of type 1 helper T cells; 2. Or 3. Type 2 comprising the quinazoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient
5. A therapeutic or preventive agent for a disease in which the immune response on the helper T cell side is abnormally enhanced; 4. A disease in which the immune response on the type 2 helper T cell side is abnormally enhanced is an allergic disease. 6. The therapeutic or prophylactic agent as described above; 5. The allergic disease in which the immune response on the type 2 helper T cell side is abnormally enhanced is asthma, allergic rhinitis or atopic dermatitis. A therapeutic or prophylactic agent as described above;
Or 8.1. 2. Or 3. A therapeutic or preventive agent for a virus or bacterial infection, malignant tumor or acquired immunodeficiency syndrome (AIDS), comprising the quinazoline derivative or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016]

DETAILED DESCRIPTION OF THE INVENTION

[0017] The substituents in the present invention are specifically described below. Examples of the linear or branched lower alkyl group having 1 to 6 carbon atoms for R ¹ include methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, pentyl group, -Methylbutyl, 2-methylbutyl, 3-methylbutyl, 1-ethylpropyl, 2-ethylpropyl, hexyl and the like. A preferred range of the straight-chain or branched lower alkyl group having 1 to 6 carbon atoms for R ^{1 includes} a straight-chain or branched lower alkyl group having 1 to 4 carbon atoms. Methyl, ethyl, propyl,
1-methylethyl, butyl and the like.

Examples of the alkoxy group having 1 to 6 carbon atoms for R ¹ include methoxy, ethoxy, propyloxy,
2-propyloxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like.

Examples of the linear or branched alkyl group having 1 to 6 carbon atoms for R ² and R ³ include methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl,
-Methylpropyl, 1,1-dimethylethyl, pentyl, hexyl and the like.

[0020] As the aryl group having a carbon number of 6 in R ² 10, for example phenyl, naphthyl and the like. R
The halogen atom in the substituted aryl group having a carbon number of 6 to 10 in ^2, for example, fluorine, chlorine, bromine, and iodine. Examples of the alkoxy group having 1 to 4 carbon atoms in the substituted aryl group having 6 to 10 carbon atoms in R ² include methoxy, ethoxy, propyloxy, 2-propyloxy, butoxy and the like.

The alkoxy group having 1 to 6 carbon atoms for R ⁴ , R ⁵ , R ⁶ and R ⁷ includes, for example, methoxy, ethoxy, propyloxy, 2-propyloxy, butoxy,
Examples include 1,1-dimethylethoxy, pentoxy, hexoxy and the like.

[0022] Examples of the halogen atom in R ⁴ , R ⁵ , R ⁶ and R ⁷ include fluorine, chlorine, bromine and iodine.

The heterocyclic compound as an active ingredient of the medicament of the present invention can be converted into a pharmaceutically acceptable salt. Pharmaceutically acceptable salts include acid addition salts and base addition salts. Examples of acid addition salts include hydrochloride, hydrobromide,
Inorganic acid salts such as sulfates, citrates, oxalates, malates, tartrate salts, fumarate salts, organic acid salts such as maleate salts, as base addition salts, sodium salts,
Examples include inorganic base salts such as calcium salts, and organic base salts such as meglumine salts and trishydroxymethylaminomethane salts. The present invention also includes solvates such as hydrates of the heterocyclic compound or a pharmaceutically acceptable salt thereof.

The compound of the present invention represented by the formula (1) can be produced by the following method or a method analogous thereto.

Embedded image Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷
Has the same meaning as in formula (1). Production Method 1 Compound (22) can be obtained by reacting compound (21) with phosphorus oxychloride (JP-A-2-50)
2462, JP-A-3-17068, Journal of
Chemical Society (J. Chem. Soc. 775, (194
7)), Journal of Chemical Society (J.
Chem. Soc. 1766, (1948))). In the reaction, a solvent may be added as necessary. Examples of the solvent include aromatic hydrocarbon solvents such as toluene and xylene. In the reaction, a reaction aid such as N, N-dimethylaminopyridine may be optionally used. The reaction temperature is selected from, for example, a temperature range from room temperature to around the boiling point of the solvent.

Compound (22) is reacted with compound (23) to give compound (1) of the present invention. Examples of the reaction solvent include aromatic hydrocarbon solvents such as toluene and xylene, tetrahydrofuran (hereinafter abbreviated as THF), ether solvents such as dioxane, ethanol, and isopropyl alcohol (hereinafter abbreviated as IPA).
Examples include alcohol solvents such as butanol, dimethylformamide (hereinafter abbreviated as DMF), and inert solvents such as acetonitrile. In the reaction, an organic base such as triethylamine and an inorganic base such as sodium carbonate and potassium carbonate may be added as necessary. The reaction temperature is
For example, it is selected from a temperature range from room temperature to around the boiling point of the solvent.

Production method 2 Compound (25) can be obtained by reacting compound (24) with compound (23). As the reaction solvent, for example, aromatic hydrocarbon solvents such as toluene and xylene,
Ether solvents such as THF and dioxane, alcohol solvents such as ethanol, IPA and butanol, DM
And inert solvents such as F and acetonitrile. In the reaction, an organic base such as triethylamine and an inorganic base such as sodium carbonate and potassium carbonate may be added as necessary. The reaction temperature is selected from, for example, a temperature range from room temperature to around the boiling point of the solvent.

The compound (25) can be reacted with ammonia in an organic solvent to obtain the compound (1) of the present invention. Examples of the organic solvent include alcohol solvents such as methanol and ethanol, and ether solvents such as dioxane and ethylene glycol dimethyl ether. The reaction is carried out in an autoclave from about room temperature to about 200 ° C.
Perform in the temperature range up to. Compound (25) can be reacted with sodium azide and then reduced with triphenylphosphine to obtain compound (1) of the present invention. The reaction with sodium azide is performed in an inert solvent such as DMF. The reaction temperature is selected from the range of about room temperature to around the boiling point of the solvent. The reduction with triphenylphosphine is performed in an ether solvent such as THF. The reaction temperature is selected from a temperature range from about room temperature to around the boiling point of the solvent.

Compound (26) is reacted with bromocyanide in a solvent to give compound (27). If necessary, an organic base such as triethylamine, sodium carbonate,
An inorganic base such as potassium carbonate or sodium hydride may be added. Examples of the solvent include aromatic hydrocarbon solvents such as toluene, halogenated hydrocarbon solvents such as methylene chloride and chloroform, ester solvents such as ethyl acetate, ether solvents such as THF, DMF, acetonitrile, methanol, and ethanol. And the like. The reaction temperature is selected, for example, from a room temperature to a temperature around the boiling point of the solvent.

When R ¹ is a lower alkoxy group having 1 to 6 carbon atoms, it can be produced by the following production method. Compound (27) is represented by R ¹
The compound of the present invention (1) can be obtained by reacting with R ¹ ONa in OH. The reaction temperature is selected, for example, from the range of room temperature to the boiling point of the solvent. R ¹ has the same meaning as in formula (1). When R ¹ is a linear or branched lower alkyl group having 1 to 6 carbon atoms, it can be produced by the following production method.
Compound (27) is protected with a t-butoxycarbonyl group,
The compound (1) included in the present invention can be obtained by reacting with a Grignard reagent represented by R ¹ MgBr in an ether-based inert solvent such as THF and diethyl ether. The reaction temperature is selected, for example, from the range of room temperature to the boiling point of the solvent.

Next, a method for synthesizing the raw materials used in the above reaction will be described. The raw materials were synthesized according to a known reaction or a known reaction. Production of compound (23)

Embedded image (Wherein, R ² and R ³ represent the same meaning as in formula (1). R
¹ represents a lower alkoxy group having 1 to 6 carbon atoms. The compound (28) can be reacted with the corresponding alcohol in the presence of an acid catalyst to give the compound (23). Examples of the acid catalyst include organic acids such as paratoluenesulfonic acid and inorganic acids such as hydrochloric acid and sulfuric acid. The reaction temperature is selected from a temperature range from about room temperature to around the boiling point of the solvent.

Method for producing compound (26)

Embedded image (Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ and R ⁷ are
Represents the same meaning as in equation (1). )

Compound (29) is reacted with compound (30) in an organic solvent in the presence of a dehydrating condensing agent to give compound (31). Examples of the organic solvent include halogenated hydrocarbon solvents such as methylene chloride and chloroform, ester solvents such as ethyl acetate, ether solvents such as THF, and inert solvents such as DMF. The reaction temperature is selected, for example, from the range of about -10C to about 60C.
Examples of the dehydrating condensing agent include condensing agents such as dicyclohexylcarbodiimide and 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, and are used together with a reaction aid. Examples of the reaction assistant include N, N
-Dimethyl-4-aminopyridine and the like. As another dehydration condensing agent, for example, N, N-bis (2-oxo-3-oxazolidinyl) phosphinic chloride or the like can be used in combination with an organic base such as triethylamine.

Alternatively, the carboxylic acid residue of compound (29) is converted to the corresponding acid chloride by heating compound (29) in thionyl chloride or the like, for example, at about 40 to about 60 ° C. ) In a suitable organic solvent in the presence of an organic base such as triethylamine to give compound (31). As an organic solvent,
For example, halogenated hydrocarbon solvents such as methylene chloride and chloroform, ester solvents such as ethyl acetate, THF
And an inert solvent such as dimethylformamide. The reaction temperature is selected, for example, from the range of about -10C to about 60C.

The compound (32) can be obtained by heating the compound (31) in a suitable inert solvent, for example, from about 60 ° C. to a temperature near the boiling point of the solvent. If necessary, a base or acid may be added as a catalyst. Examples of the base include an aqueous solution of an alkali metal hydroxide such as potassium hydroxide and sodium hydroxide. Examples of the acid include a protic acid such as paratoluenesulfonic acid and trichloroacetic acid, and a Lewis acid such as phosphorus oxychloride and boron trifluoride. Examples of the inert solvent include water, aromatic hydrocarbon solvents such as toluene, halogenated hydrocarbon solvents such as methylene chloride and chloroform, alcohol solvents such as methanol and ethanol, ether solvents such as THF, and DMF. Inert solvent.

The compound (30) and the compound (33) are reacted in an organic solvent to obtain a compound (34). During the reaction, an organic base such as dimethylaminopyridine may be added as necessary. As the organic solvent, for example, aromatic hydrocarbon solvents such as toluene, halogenated hydrocarbon solvents such as methylene chloride and chloroform, ether solvents such as THF,
And inert solvents such as DMF. The reaction temperature is selected, for example, from a temperature range from about room temperature to around the boiling point of the solvent.

The compound (26) can be obtained by heating the compound (34) in a suitable inert solvent, for example, from about 60 ° C. to a temperature near the boiling point of the solvent. If necessary, a base or acid may be added as a catalyst. Examples of the base include an aqueous solution of an alkali metal hydroxide such as potassium hydroxide and sodium hydroxide. Examples of the acid include a protic acid such as paratoluenesulfonic acid and trichloroacetic acid, and a Lewis acid such as phosphorus oxychloride and boron trifluoride. As the inert solvent, for example,
Water, aromatic hydrocarbon solvents such as toluene, halogenated hydrocarbon solvents such as methylene chloride and chloroform, alcohol solvents such as methanol and ethanol, ether solvents such as THF, and inert solvents such as DMF. .

The nitro group of compound (31) and compound (32) can be reduced to obtain compound (34) and compound (26) that have become amino groups. Here, as the reducing agent, such as sodium borohydride -NiCl ₂ - methanol, hydrochloric acid - iron, hydrochloric acid - tin, alkaline water - iron, titanium trichloride aqueous solution, hydrogen -Pd / C and the like. The reaction temperature ranges from room temperature to about 80 ° C.

Preparation of compound (30)

Embedded image In the formula, R ² and R ³ have the same meaning as in formula (1). Compound (36) can be synthesized by a known method. For example, the compound (36) can be obtained by reacting the compound (35) with an alkali metal cyanide compound such as KCN or NaCN in a concentrated aqueous ammonia solution in the presence of a weak acid such as acetic acid at around room temperature. Compound (3
If necessary, the compound (30) can be hydrolyzed with an alkaline solvent, aqueous ammonia, hydrogen peroxide or the like in a co-solvent to obtain the compound (30). Examples of the alkaline water include an aqueous solution of an alkali metal hydroxide such as an aqueous solution of sodium hydroxide and an aqueous solution of potassium hydroxide. Examples of the co-solvent include ether solvents such as THF and dioxane, and alcohol solvents such as methanol. The reaction temperature is selected, for example, from the range of about 0 ° C. to about room temperature.

The compound represented by the formula (1) and contained in the present invention or an intermediate for producing the compound can be purified by a conventional method. For example, it can be purified by column chromatography, recrystallization and the like. As the recrystallization solvent,
For example, alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, ketone solvents such as acetone, and hexane. Examples thereof include hydrocarbon solvents and the like and mixed solvents thereof.

The raw materials were synthesized according to a known reaction or a known reaction. The compound represented by the formula (1) included in the present invention or an intermediate for producing the compound can be purified by a usual method. For example, it can be purified by column chromatography, recrystallization and the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene; and ketones such as acetone. Solvent, a hydrocarbon solvent such as hexane, etc., or a mixed solvent thereof.

In carrying out the above reaction, if necessary, techniques for protection and deprotection can be used. For protection and deprotection technologies, see (TW Greene and PGM Wut
s, "Protecting Groups in Organic Synthesis", 1991,
JOHN WILEY & SONS, INC.).

The quinazoline derivative of the present invention or a pharmaceutically acceptable salt thereof may form a solvate such as a hydrate, and the present invention includes these.

The compounds included in the present invention may have asymmetry or may have a substituent having an asymmetric carbon, and such compounds have optical isomers. The compounds of the present invention include mixtures of these isomers and isolated ones. As a method for obtaining such an optical isomer purely, for example, optical resolution can be mentioned.

As the optical resolution method, the compound of the present invention or an intermediate thereof is dissolved in an inert solvent (for example, an alcohol solvent such as methanol, ethanol or 2-propanol, an ether solvent such as diethyl ether, or an ester solvent such as ethyl acetate). Solvents, aromatic hydrocarbon solvents such as toluene, acetonitrile and the like and mixed solvents thereof), optically active acids (for example, monocarboxylic acids such as mandelic acid, N-benzyloxyalanine, lactic acid, tartaric acid, o-diisopropylate) And dicarboxylic acids such as tartaric acid and malic acid, and sulfonic acids such as camphorsulfonic acid and bromocamphorsulfonic acid). When the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, an optically active amine (for example, α-
Phenethylamine, quinine, quinidine, cinchonidine,
Salts with organic amines such as cinchonine and strychnine) can also be formed.

The temperature at which the salt is formed may be in the range from room temperature to the boiling point of the solvent. In order to improve the optical purity, it is desirable to raise the temperature once to near the boiling point of the solvent. Before the precipitated salt is collected by filtration, the salt can be cooled, if necessary, to improve the yield. The amount of the optically active acid or amine used is about 0.5 to about 2.0 with respect to the substrate.
A range of equivalents, preferably a range of about 1 equivalent is appropriate. If necessary, the crystals are placed in an inert solvent (for example, alcohol solvents such as methanol, ethanol, and 2-propanol; ether solvents such as diethyl ether; ester solvents such as ethyl acetate; aromatic hydrocarbon solvents such as toluene; Recrystallization with acetonitrile or the like and a mixed solvent thereof) to obtain a high-purity optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a usual method to obtain a free form.

The quinazoline derivative of the present invention can be administered orally or parenterally. When administered orally,
It can be administered in a commonly used dosage form. Parenterally, it can be administered in the form of topical administration, injection, transdermal, nasal, and the like. Examples of the oral preparation or rectal administration preparation include capsules, tablets, pills, powders, cachets, suppositories, and liquid preparations. Examples of the injection include a sterile solution or suspension. Examples of the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.
The above dosage forms are formulated in a conventional manner together with pharmaceutically acceptable excipients and additives. Pharmaceutically acceptable excipients, additives include carriers, binders, flavors, buffers,
Thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents,
Preservatives and the like.

[0047] Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc,
Sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. Capsules can be formulated by incorporating a compound of the present invention together with a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in a capsule without excipients. Cachets can be prepared in a similar manner. Solutions for injection include solutions, suspensions, emulsions and the like. For example, an aqueous solution, a water-propylene glycol solution and the like can be mentioned. Solutions can also be prepared in the form of a solution of polyethylene glycol or / and propylene glycol, which may contain water. Liquid preparations suitable for oral administration can be prepared by adding the compound of the present invention to water and adding a colorant, flavor, stabilizer, sweetener, solubilizer, thickener and the like as necessary. Also, liquid preparations suitable for oral administration can be produced by adding the compound of the present invention to water together with a dispersant to make it viscous. As the thickener, for example, pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose,
Examples include sodium carboxymethyl cellulose or a known suspending agent.

[0048] Examples of the agents for topical administration include the above-mentioned liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like. The above-mentioned preparation for topical administration can be prepared by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier usually used. Ointments and creams are obtained, for example, by formulating an aqueous or oily base with a thickener and / or a gelling agent. Examples of the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.). Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, beeswax, and the like.

Lotions are obtained by adding one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, fragrances and the like to an aqueous or oily base. be able to. The powder is formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like. Drops may be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like. The topical preparation may contain a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, benzalkonium chloride, and a bacterial growth inhibitor, if necessary.

[0050] A liquid spray, powder or drop preparation containing the compound of the present invention as an active ingredient can be administered nasally. The dose and the number of administrations vary depending on symptoms, age, body weight, dosage form, etc., but when administered orally, it is usually in the range of about 1 to about 500 mg, preferably about 5 to about 100 mg per day for an adult. The range can be administered once or in several divided doses. When administered as an injection, it can be administered in the range of about 0.1 to about 300 mg, preferably in the range of about 1 to about 100 mg, in one or several divided doses.

[0051] The quinazoline derivative of the present invention suppresses IL-4 production and IL-5 production from mouse lymph node cells due to antigen-specific stimulation, and conversely enhances IFN-γ production. The cytokine production regulating activity test used for this evaluation is performed by the following method.

[0052] Cytokine production regulating activity test Keyhole Lympet Hemocyanin (hereinafter referred to as KLH) 0.2
mg of aluminum hydroxide adjuvant (Alu-Gel-S; Se
rva Feinbiochemica GmbH & Co., Code No. 12261) or Freund's complete adjuvant (Difco Lab., Detroi
t, Michigan, Code No. 3113-60-5) and injected subcutaneously into the mouse footpad (0.1 ml). Eight to ten days later, popliteal lymph nodes are removed, and a cell suspension is prepared using an animal cell culture medium. Lymph node cell suspension (1 to 5 x 10 ⁶ cells / m
l) Add KLH (1 to 100 μg / ml) and drug to 37)
C. for 4 days in the presence of 5% CO ₂ (Corning 25850, 0.1
After 5 ml / well), the cytokine produced in the supernatant is quantified by a specific ELISA method. Interleukin 4 (IL-4) and interleukin 5 (IL-5) are quantified as typical Th2 type cytokines, and interferon γ (IFN-γ) is quantified as typical Th1 type cytokines.

【Example】

Reference Example 1 Synthesis of 2-amino-4-chloroquinazoline

Embedded image 2-amino-4-hydroxyquinazoline hydrochloride (16 g)
And a mixture of phosphorus oxychloride (100 ml) was refluxed for 4.5 hours. After completion of the reaction, excess phosphorus oxychloride was distilled off, toluene was added to the residue, and the residue was distilled again. Ice water and sodium hydroxide were added to the residue, and the mixture was stirred overnight, and the solid substance was collected by filtration to obtain the title compound (9.04 g, 38.6%). _{^{1 H NMR (CDCl 3) δ}} ; 8.05 (1H, d, J = 7.8 Hz), 7.75 (1H,
t, J = 8.1 Hz), 7.59 (1H, d, J = 8.1 Hz), 7.35 (1H, t,
J = 7.8 Hz), 5.32 (2H, brs)

[0054]

EXAMPLES Reference Example 2 Synthesis of 2-amino-2,3-dimethylbutyramide

Embedded image 2-1) Synthesis of 2-amino-2,3-dimethylbutyronitrile

Embedded image Acetic acid (14 ml) was slowly added dropwise to a solution of sodium cyanide (13.7 g, 280 mmol) in an aqueous solution (32 ml) and 29% aqueous ammonia (140 ml) under a nitrogen stream. Thereafter, isopropyl methyl ketone (25 ml, 234 mmol) was added dropwise, and the mixture was heated at 40 ° C. for 4 hours. The reaction solution was returned to room temperature, extracted with toluene, and the organic layer was washed twice with aqueous ammonia and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the solvent of the filtrate was distilled off to obtain the title compound (16.5 g, 63%). ¹ H NMR (CDCl ₃ ) δ; 1.74 to 1.73 (m, 3H), 1.43 (s, 3
H), 1.08 (d, 3H, J = 6.9 Hz), 1.07 (d, 3H, J = 6.9
Hz)

2-2) Synthesis of 2-amino-2,3-dimethylbutyramide

Embedded image Under a nitrogen stream, 2-amino-2,3-dimethylbutyronitrile (16.5 g, 147 mmo) was added to 12N aqueous ammonia (117 ml).
l) and 30% aqueous hydrogen peroxide (33 ml, 326 mmol) were simultaneously added dropwise, and the reaction solution was stirred for 5 hours. 10% palladium hydroxide (2.6 g) was added to the reaction solution, and excess hydrogen peroxide was crushed.
The mixture was filtered through celite, the solvent of the filtrate was distilled off, and the title compound (16.
7 g, 87%). ¹ H NMR (CDCl ₃ ) δ; 7.44 (br, 1H), 5.63 (br, 1H),
2.21 (sep, 1H, J = 6.9Hz), 1.34 (br, 2H), 1.28 (s,
3H), 0.90 (d, 3H, J = 6.9 Hz), 0.86 (d, 3H, J = 6.
9 Hz)

Reference Example 3 Synthesis of 2-amino-2-ethylbutyramide

Embedded image 3-1) Synthesis of 2-amino-2-ethylbutyronitrile

Embedded image Under a nitrogen stream, acetic acid (6.0 ml) was slowly added dropwise to a solution of an aqueous solution (14 ml) of sodium cyanide (5.84 g, 119 mmol) and 29% aqueous ammonia (60 ml). Diethyl ketone (10.0 ml, 99.0 mmol) was added dropwise to the reaction solution, and the mixture was heated at 40 ° C. for 3 hours.
And heated. The reaction solution was returned to room temperature, extracted with toluene,
The organic layer was washed twice with aqueous ammonia and dried over magnesium sulfate. The magnesium sulfate was filtered off, and the solvent of the filtrate was distilled off to obtain the title compound (7.03 g, 63%). ¹ H NMR (CDCl ₃ ) δ; 1.55-1.82 (m, 6H), 1.09 (t, 6H,
(J = 7.4 Hz)

3-2) Synthesis of 2-amino-2-ethylbutyramide

Embedded image Under a nitrogen stream, 2-amino-2-ethylbutyronitrile (6.58 g, 58.7 mmol) and 30% aqueous hydrogen peroxide (13.1 ml, 129 mmol) were simultaneously added dropwise to 12N aqueous ammonia (47 ml), Stirred for hours. 10% palladium on carbon
(2.0 g) was added to crush excess hydrogen peroxide, filtered through celite, and the solvent in the filtrate was distilled off to give the title compound (4.63 g, 61%)
I got ¹ H NMR (CDCl ₃ ) δ; 7.37 (br, 1H), 5.64 (br, 1H), 1.
86 (dq, 2H, J = 14.5,7.3 Hz), 1.46 (dq, 2H, J = 1
4.5, 7.3 Hz), 1.40 (br, 2H), 0.91 (t, 6H, J = 7.3 H
z)

Example 1 Synthesis of ethyl 2-[(2-aminoquinazolin-4-yl) amino] -2,3-dimethylbutanoate

Embedded image 1-1) Synthesis of 2- (nitrobenzamide) -2,3-dimethylbutylamide

Embedded image Under a nitrogen stream, 2-amino-2,3-dimethylbutyramide (16.7 g, 1284 mmol) and triethylamine (32 ml, 231
2-nitrobenzoyl chloride (20 ml, 153 mmol) was added to a tetrahydrofuran solution (160 ml) of the resulting mixture under ice-cooling, and the mixture was stirred at room temperature for 1 hour. The reaction solution was added to a 5% aqueous potassium hydrogen sulfate solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over magnesium sulfate. The magnesium sulfate was filtered off, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (11.0 g, 31%). _{^{1 H NMR (CDCl 3) δ}} ; 8.08 (dd, 1H, J = 1.2, 7.6 Hz),
7.70 (ddd, 1H, J = 1.2, 7.6, 7.6 Hz), 7.60 (ddd, 1
H, J = 1.7, 7.6, 7.6 Hz), 7.52 (dd, 1H, J = 1.7, 7.
6 Hz), 6.53 (br, 1H), 6.37 (brs, 1H), 5.55 (br, 1
H), 2.57 (sep, 1H, J = 6.9 Hz), 1.70 (s, 3H), 1.06
(d, 3H, J = 6.9 Hz), 1.03 (d, 3H, J = 6.9 Hz)

1-2) 2- (aminobenzamide) -2,3
-Synthesis of dimethylbutyramide

Embedded image 2- (Nitrobenzamide) -2,3-dimethylbutyramide (11.0 g, 39.7 mmol) was dissolved in methanol (150 ml), 10% palladium hydroxide (2.11 g) was added, and the mixture was hydrogenated for 2.5 hours. . The reaction solution was filtered through celite, and the solvent in the filtrate was distilled off to obtain the title compound (9.43 g, 95%). ¹ H NMR (CDCl ₃ ) δ; 7.33 (dd, 1H, J = 1.5, 8.0 Hz),
7.22 (ddd, 1H, J = 1.5, 8.0, 8.0 Hz), 6.63 to 6.69
(m, 3H), 6.45 (s, 1H), 5.45 (br, 3H), 2.60 (sep, 1
H, J = 6.9 Hz), 1.57 (s, 3H), 1.05 (d, 3H, J = 6.9
Hz), 1.01 (d, 3H, J = 6.9 Hz)

1-3) Synthesis of 2- (2-aminophenyl) -4-isopropyl-4-methyl-5-oxo-2-imidazoline

Embedded image Under a nitrogen stream, 2- (aminobenzamide) -2,3-dimethylbutyramide (9.43 g, 37.8 mmol) was added to tetrahydrofuran (50 ml) and a 5.02 N aqueous potassium hydroxide solution.
(15 ml, 75.3 mmol) was added and the mixture was refluxed for 7 hours. The reaction solution was returned to room temperature, extracted with ethyl acetate, and dried over magnesium sulfate. The magnesium sulfate was filtered, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain the title compound (7.44 g, 85%). ¹ H NMR (CDCl ₃ ) δ; 10.48 (s, 1H), 7.46 (dd, 1H, J =
1.3, 8.0 Hz), 7.23 (ddd, 1H, J = 1.3, 8.0, 8.0 H
z), 6.72 to 6.77 (m, 2H), 6.40 (brs, 2H), 2.11 (sep,
1H, J = 6.8 Hz), 1.42 (s, 3H), 1.08 (d, 3H, J = 6.
8 Hz), 0.87 (d, 3H, J = 6.8 Hz)

1-4) 5-Amino-2-isopropyl-2-
Synthesis of methyl-imidazo [1,2-c] quinazolin-3 (2H) -one

Embedded image Under a nitrogen stream, 2- (2-aminophenyl) -4-isopropyl-4-methyl-5-oxo-2-imidazoline
(7.44 g, 32.2 mmol) was dissolved in ethanol (40 ml).
Add 5% bromocyan (4.82 g, 43.2 mmol) and add 7% at room temperature.
Stirred for hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. The magnesium sulfate was filtered off, the solvent of the filtrate was distilled off, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 3.
/ 1 → 2/1 → 1/1 → 0/1) to give the title compound
(5.12 g, 62%). Collect the fraction behind,
The solvent was distilled off, and the residue was purified once more by silica gel column chromatography (acetonitrile → ethyl acetate) to give ethyl 2-[(2-aminoquinazoline-4).
-Yl) amino] -2,3-dimethylbutanoate (220
mg, 2.3%). _{^{1 H NMR (CDCl 3) δ}} ; 8.11 (dd, 1H, J = 1.6, 7.6 Hz),
7.52 (ddd, 1H, J = 1.6, 7.6, 7.6 Hz), 7.13 to 7.19
(m, 2H), 7.03 (br, 2H), 2.14 (sep, 1H, J = 6.9 Hz),
1.45 (s, 3H), 1.08 (d, 3H, J = 6.9 Hz), 0.90 (d,
(3H, J = 6.9 Hz)

1-5) Synthesis of ethyl 2-[(2-aminoquinazolin-4-yl) amino] -2,3-dimethylbutanoate

Embedded image Under a nitrogen stream, 5-amino-2-isopropyl-2-methyl-imidazo [1,2-c] quinazolin-3 (2H) -one (5.
12 g, 20 mmol) was dissolved in ethanol (150 ml), sodium ethoxide (2.45 g, 36 mmol) was added, and the mixture was stirred at room temperature for 1 hour. A 5% aqueous potassium carbonate solution was added to the reaction solution,
Extracted with ethyl acetate and dried over magnesium sulfate. The magnesium sulfate was filtered off, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1 → 0/1) to give the title compound (3.36).
g, 56%). _{^{1 H NMR (CDCl 3) δ}} ; 7.56 (ddd, 1H, J = 1.3, 7.8, 7.8
Hz), 7.55 (dd, 1H, J = 1.3, 7.8 Hz), 7.43 (dd, 1H,
J = 1.3, 7.8 Hz), 7.15 (ddd, 1H, J = 1.3,7.8, 7.8
Hz), 6.09 (brs, 1H), 4.81 (brs, 2H), 4.12 to 4.24
(m, 2H), 2.46 (sep, 1H, J = 6.9 Hz), 1.69 (s, 3H),
1.20 (t, 3H, J = 7.1 Hz), 1.13 (d, 3H, J = 6.9 H
z), 0.99 (d, 3H, J = 6.9 Hz)

Example 2 Synthesis of ethyl 2-[(2-aminoquinazolin-4-yl) amino] -2-ethylbutanoate

Embedded image 2-1) Synthesis of 2- (2-nitrobenzamide) -2-ethylbutyramide

Embedded image Under a nitrogen stream, 2-amino-2-ethylbutyramide (75
3 mg, 5.78 mmol), triethylamine (1.40 ml, 10.0
2-nitrobenzoyl chloride (830 μl, 6.35 mmol) was added to a tetrahydrofuran solution (20 ml) of the above (3 mmol), and the mixture was stirred at room temperature for 0.5 hr. The reaction solution was added to a 5% aqueous potassium hydrogen sulfate solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline and dried over magnesium sulfate. The magnesium sulfate was filtered off, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/2 → 0/1) to obtain (1.18 g, 73%). . ¹ H NMR (DMSO-d ₆ ) δ; 8.01 (dd, 1H, J = 1.3, 7.4 H
z), 7.86 (s, 1H), 7.79 (ddd, 1H, J = 1.3, 7.4, 7.4
Hz), 7.65 to 7.72 (m, 2H), 7.47 (brs, 1H), 7.37 (br
s, 1H), 2.27 (dq, 2H, J = 14.5, 7.2 Hz), 1.82 (dq,
2H, J = 14.5, 7.2 Hz), 0.81 (t, 6H, J = 7.2 Hz)

2-2) 2- (2-aminobenzamide) -2
-Synthesis of ethyl butyramide

Embedded image 2- (2-nitrobenzamide) -2-ethylbutyramide (930 mg, 3.33 mmol), 10% palladium-carbon
(549 mg) was suspended in methanol (80 ml) for 3 hours.
Hydrogenated. The reaction solution was filtered through celite, and the solvent of the filtrate was distilled off to obtain the title compound (840 mg, quant.). _{^{1 H NMR (CDCl 3) δ}} ; 7.46 (dd, 1H, J = 1.5, 7.6 Hz),
7.36 (brs, 1H), 7.21 (ddd, 1H, J = 1.5, 7.6, 7.6 H
z), 6.65-6.70 (m, 2H), 5.48-5.82 (br, 4H), 2.73
(dq, 2H, J = 14.6, 7.3 Hz), 1.65 (dq, 2H, J = 14.
6, 7.3 Hz), 0.88 (t, 6H, J = 7.3 Hz)

2-3) 2- (2-aminophenyl) -4,4
Of -Diethyl-5-oxo-2-imidazoline

Embedded image Under a nitrogen stream, 2- (2-aminobenzamide) -2-ethylbutyramide (750 mg, 3.01 mmol) was dissolved in tetrahydrofuran (20 ml), and a 5.06 N aqueous potassium hydroxide solution (1.7 ml, 8.60 mmol) was used. Was added and the mixture was refluxed for 13 hours. The reaction solution was returned to room temperature, a 5% aqueous potassium carbonate solution was added, extracted with ethyl acetate, and dried over magnesium sulfate. The magnesium sulfate is filtered off, the solvent of the filtrate is distilled off,
The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 2/1) to give the title compound (343 mg,
49%). ¹ H NMR (CDCl ₃ ) δ; 9.95 (brs, 1H), 7.38 (dd, 1H, J
= 1.3, 7.6 Hz), 7.24 (ddd, 1H, J = 1.3, 7.6, 7.6
Hz), 6.72 to 6.78 (m, 2H), 6.37 (brs, 2H), 1.87 (q,
4H, J = 7.4 Hz), 0.82 (t, 6H, J = 7.4 Hz)

2-4) Synthesis of 5-amino-2,2-diethyl-imidazo [1,2-c] quinazolin-3 (2H) -one

Embedded image Under a nitrogen stream, 2- (2-aminophenyl) -4,4-diethyl-5-oxo-2-imidazoline (207 mg, 8.94
× 10 ^-1 mmol) was dissolved in ethanol (4.5 ml), 95% bromocyanine (105 mg, 9.42 × 10 ^-1 mmol) was added, the mixture was stirred at room temperature for 3.5 hours, and triethylamine (130 μl, 9.37 ×) was added.
10 ^-1 mmol) and further stirred at 50 ° C. for 7 hours. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. The magnesium sulfate was separated by filtration, the solvent of the filtrate was distilled off, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2/2).
By performing 1), a crude product of the title compound (46.5 mg)
I got

2-5) Synthesis of ethyl 2-[(2-aminoquinazolin-4-yl) amino] -2-ethylbutanoate

Embedded image Under a nitrogen stream, a crude product of 4-amino-2,2-diethyl-imidazo [1,2-c] quinazolin-3 (2H) -one (40.0 mg) was dissolved in ethanol (2.0 ml), and sodium ethoxy was dissolved. (15.4 mg, 2.26 × 10 ^-1 mmol) was added, and the mixture was stirred at room temperature for 0.5 hour. A 5% aqueous potassium carbonate solution was added to the reaction solution, extracted with ethyl acetate, and dried over magnesium sulfate. The magnesium sulfate was filtered off, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate) to obtain the title compound (27.8 mg, 12%). ¹ H NMR (CDCl ₃ ) δ; 7.67 (dd, 1H, J = 1.3, 8.2 Hz),
7.57 (ddd, 1H, J = 1.3, 8.2, 8.2 Hz), 7.43 (dd, 1
H, J = 1.3, 8.2 Hz), 7.17 (ddd, 1H, J = 1.3, 8.2,
8.2 Hz), 6.73 (brs, 1H), 4.77 (brs, 2H), 4.31 (q,
2H, J = 7.1 Hz), 2.86 (dq, 2H, J = 15.2, 7.6 Hz),
1.91 (dq, 2H, J = 15.2, 7.6 Hz), 1.33 (t, 3H, J =
7.1 Hz), 0.74 (t, 6H, J = 7.6 Hz)

Example 3 Synthesis of ethyl 2-[(2-aminoquinazolin-4-yl) amino] -2-phenylpropanoate

Embedded image 3-1) Synthesis of 2-amino-2-phenylpropanamide

Embedded image Acetic acid was added to an aqueous solution (14 ml) of sodium cyanide (6.03 g, 123 mmol) and 29% aqueous ammonia (62 ml) under a nitrogen stream.
(6.1 ml) was slowly added dropwise. Acetophenone in the reaction solution
(12.0 ml, 103 mmol) was added dropwise and heated at 40 ° C. for 6 hours. The reaction solution was returned to room temperature, extracted with toluene, and the organic layer was washed twice with aqueous ammonia and dried over magnesium sulfate. Magnesium sulfate was filtered off, and the solvent of the filtrate was distilled off to obtain 14.3 g of a mixture of an aminonitrile compound and acetophenone (raw material). Under a nitrogen stream, a mixture of an aminonitrile compound and acetophenone (14.0 g) in 12 N aqueous ammonia (70 ml) and a 30% aqueous hydrogen peroxide solution (21 ml, 207 mmo) were used.
l) was simultaneously added dropwise and stirred for 7 hours. 10% palladium-carbon (2.1 g) was added, excess hydrogen peroxide was crushed, and the mixture was filtered through celite. The filtrate was extracted with toluene, and the solvent of the extract was distilled off to obtain the title compound (4.34 g, 26%). ¹ H NMR (CDCl ₃ ) δ; 7.51 to 7.54 (m, 2H), 7.27 to 7.38
(m, 3H), 7.15 (br, 1H), 5.99 (br, 1H), 1.94 (br, 2
H), 1.77 (s, 3H)

3-2) 2- (2-nitrobenzamide) -2
-Synthesis of phenylpropanamide

Embedded image 2-amino-2-phenylpropanamide under a nitrogen stream
(1.65 g, 10.0 mmol), triethylamine (2.50 ml, 17.
To a solution of 9 mmol) in tetrahydrofuran (35 ml) was added 2-nitrobenzoyl chloride (1.45 ml, 11.1 mmol) under ice-cooling, and the mixture was stirred at room temperature for 2.5 hours. A 5% aqueous potassium hydrogen sulfate solution was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over magnesium sulfate. The magnesium sulfate was filtered off, the solvent of the filtrate was distilled off, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate = 1/1 → 1/2) to give the title compound (2.16).
g, 69%). _{^{1 H NMR (CDCl 3) δ}} ; 8.03 (d, 1H, J = 7.9 Hz), 7.31
Up to 7.68 (m, 9H), 5.56 (br, 2H), 2.16 (s, 3H)

3-3) 2- (2-aminobenzamide) -2
-Synthesis of phenylpropanamide

Embedded image 2- (2-Nitrobenzamide) -2-phenylpropanamide (1.87 g, 5.97 mmol) was dissolved in methanol (25 ml), 10% palladium-carbon (810 mg) was added, and the mixture was hydrogenated for 1 hour. The reaction solution was filtered through celite, and the solvent in the filtrate was distilled off to obtain the title compound (1.51 g, 89%). _{^{1 H NMR (CDCl 3) δ}} ; 7.91 (brs, 1H), 7.49~7.55 (m,
3H), 7.28 to 7.42 (m, 3H), 7.20 (ddd, 1H, J = 1.5, 7.
6, 7.6 Hz), 6.68 (ddd, 1H, J = 1.0, 7.6,7.6 Hz),
6.62 (dd, 1H, J = 1.0, 8.2 Hz), 5.56 (br, 4H), 2.1
0 (s, 3H)

3-4) Synthesis of 2- (2-aminophenyl) -4-methyl-5-oxo-4-phenyl-2-imidazoline

Embedded image Under a nitrogen stream, 2- (2-aminobenzamide) -2-phenylpropanamide (1.16 g, 4.10 mmol) was dissolved in tetrahydrofuran (15 ml), and a 5.02 N aqueous potassium hydroxide solution (1.7 ml, 8.53 mmol) was dissolved. Was added and heated under reflux for 3 hours. The reaction solution was returned to room temperature, water was added, extracted with ethyl acetate, and dried over magnesium sulfate. The magnesium sulfate was separated by filtration, the solvent of the filtrate was distilled off, and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 2/2).
Purification in 1) gave the title compound (886 mg, 81%). ¹ H NMR (CDCl ₃ ) δ; 9.71 (brs, 1H), 7.64 to 7.68 (m,
2H), 7.24 to 7.38 (m, 5H), 6.73 to 6.79 (m, 2H), 6.48
(brs, 2H), 1.82 (s, 3H)

3-5) Synthesis of ethyl 2-[(2-aminoquinazolin-4-yl) amino] -2-phenylpropanoate

Embedded image Under a nitrogen stream, 2- (2-aminophenyl) -4-methyl-5-oxo-4-phenyl-2-imidazoline (306 m
g, 1.15 mmol) was dissolved in ethanol (7 ml), and 95% bromocyanide (223 mg, 2.00 mmol) and triethylamine (16
0 μl, 1.15 mmol) and at room temperature for 2 hours at 50 ° C.
Stir for 6 hours. The reaction solution was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. The magnesium sulfate is filtered off, the solvent of the filtrate is distilled off,
The residue was purified by silica gel column chromatography (ethyl acetate) and (acetonitrile → ethyl acetate) to obtain the title compound (38.1 mg, 9.9%). ¹ H NMR (DMSO-d ₆ ) δ; 8.16 (d, 1H, J = 7.6 Hz), 7.9
8 (s, 1H), 7.60 to 7.63 (m, 2H), 7.53 (dd, 1H, J =
6.9, 6.9 Hz), 7.31 to 7.40 (m, 3H), 7.23 (d, 1H, J =
7.6 Hz), 7.04 (dd, 1H, J = 6.9, 6.9 Hz), 5.81 (br
s, 2H), 4.03 (q, 2H, J = 7.1 Hz), 1.99 (s, 3H), 1.
04 (t, 3H, J = 7.1 Hz)

Example 4 Synthesis was carried out according to the method of Example 1, and ethyl 2-[(2
-Aminoquinazolin-4-yl) amino] -2-methylpropanoate was obtained.

Embedded image ¹ H NMR (300 MHz, CDCl ₃ ) δ; 7.63 (d, 1H, J = 8.3 H
z), 7.49 (ddd, 1H, J = 8.3, 8.3, 1.1 Hz), 7.36 (d,
1H, J = 8.3 Hz), 7.02 (ddd, 1H, J = 8.3, 8.3, 1.1
Hz), 6.61 (d, 1H, J = 7.1 Hz), 5.09 (brs, 2H), 4.9
9 (dt, 1H, J = 7.1, 7.1 Hz), 4.32-4.17 (m, 2H), 1.8
9-1.75 (t, 3H, J = 7.1 Hz), 0.98-0.96 (m, 6H) 13 C NMR (75.45 MHz, CDCl 3) δ;. 174.9, 159.2, 158.
7, 150.3, 132.9, 124.6, 121.9, 121.1, 110.8, 61.3,
57.2, 24.9, 14.1.IR (KBr) 3380, 3128, 1722, 1631, 1573, 1527, 1476,
1434, 1402, 1285, 1223, 1150, 1016, 758 cm ^-1

Example 5 Synthesis of ethyl 2-[(2-aminoquinazolin-4-yl) amino] acetate

Embedded image 2-amino-4-chloroquinazoline (509 mg, 2.83 mmo
l), triethylamine (1.43 g, 14.2 mmol) and dimethylformamide (5 ml) were added to glycine ethyl ester hydrochloride (475 mg, 3.40 mmol) at room temperature. The reaction solution was kept at an internal temperature of 80 ° C. for 1 hour, and after cooling, water was added to the reaction solution. The mixture was extracted with chloroform, and the organic layer was washed with saturated saline. The organic layer was dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (3% MeO
H / CHCl ₃ ) to give the title compound (126 mg, 16.4%). ¹ H-NMR (CDCl ₃ ) δ; 1.29 (3H, t, J = 7.3 Hz), 4.25 (2
(H, q, J = 7.3Hz), 4.33 (2H, s), 5.28 (2H, bs), 7.06
(1H, t, J = 8.1Hz), 7.21 (1H, bs), 7.40 (1H, d, J =
8.1Hz), 7.50 (1H, t, J = 8.1Hz), 7.71 (1H, d, J = 8.1H
z).

Example 6 The reaction was carried out according to the method of Example 5 to obtain methyl [(2-aminoquinazolin-4-yl) amino] -3-hydroxy-2-propanoate.

Embedded image ¹ H-NMR (CDCl ₃ ) δ; 3.31 (1H, bs), 3.86 (3H, s), 4.
08 (1H, dd, J = 11.3, 4.6Hz), 4.23 (1H, dd, J = 11.3,
3.0Hz), 4.90 (2H, bs), 5.02 (1H, m), 6.67 (1H, b
s), 7.14 (1H, t, J = 8.1Hz), 7.42 (1H, d, J = 8.1Hz),
7.57 (2H, m).

Example 7 Methyl 2-[(2-aminoquinazolin-4-yl) amino] hexanoate

Embedded image ¹ H NMR (CDCl ₃ ) δ; 7.67 (dd, 1H, J = 8.0, 1.0 Hz),
7.55 (ddd, 1H, J = 7.3, 7.3, 1.0 Hz), 7.43 (d, 1
H, J = 7.9 Hz), 7.13 (dd, 1H, J = 8.0, 8.0 Hz), 6.
49 (d, 1H, J = 6.8 Hz), 5.22 (brs, 2H), 4.97 (dt,
1H, J = 6.8, 5.6 Hz), 3.79 (s, 3H), 2.10-1.95 (m, 1
H), 1.95-1.80 (m, 1H), 1.45-1.25 (m, 4H), 0.89 (t,
. 3H, J = 7.1 Hz) 13 C NMR (CDCl 3) δ; 173.8, 160.1, 159.3, 133.1, 12
4.7, 121.9, 121.1, 110.7, 53.4, 52.4, 31.8, 27.4,
22.3, 13.8.

Example 8 Ethyl 2-[(2-aminoquinazolin-4-yl) amino] propanoate

Embedded image ¹ H NMR (CDCl ₃ ) δ; 7.59 (d, 1H, J = 8.0 Hz), 7.53
(ddd, 1H J = 8.0, 8.0, 1.3 Hz), 7.40 (d, 1H, J = 8.
0 Hz), 7.11 (ddd, 1H, J = 8.0, 8.0, 1.3 Hz), 6.31
(brd, 1H, J = 6.9 Hz), 4.94-4.86 (m, 3H), 4.24 (q,
2H, J = 7.1 Hz), 1.55 (d, 2H, J = 7.0 Hz), 1.28
(t, 3H, J = 7.1 Hz). ¹³ C NMR (CDCl ₃ ) δ; 13.9, 159.71, 159.66, 151.7, 1
32.9, 125.4, 121.7, 121.0, 110.9, 61.5, 49.3, 18.
3, 14.2.IR (KBr); 3388, 1731, 1620, 1574, 1532, 1161 cm ^-1

Example 9 Ethyl 2-[(2-aminoquinazolin-4-yl) amino] -4-methylpentanoate

Embedded image _{^{1 H NMR (CDCl 3) δ}} ; 7.63 (d, 1H, J = 8.3 Hz), 7.49
(ddd, 1H, J = 8.3, 8.3, 1.1 Hz), 7.36 (d, 1H, J =
8.3 Hz), 7.02 (ddd, 1H, J = 8.3, 8.3, 1.1 Hz), 6.6
1 (d, 1H, J = 7.1 Hz), 5.09 (brs, 2H), 4.99 (dt, 1
(H, J = 7.1, 7.1Hz), 4.32-4.17 (m, 2H), 1.89-1.75
(t, 3H, J = 7.1 Hz), 0.98-0.96 (m, 6H). ¹³ C NMR (CDCl ₃ ) δ; 174.2, 160.3, 151.4, 132.7, 13
2.7, 125.0, 121.4, 121.1, 110.8, 61.2, 52.2, 41.3,
24.9, 22.8, 22.0, 14.2.IR (KBr); 375, 2959, 1728, 1618, 1575, 1532, 1472,
1434, 1400, 1270, 1202, 1155, 760 cm ^-1

Example 10 1-[(2-aminoquinazolin-4-yl) amino] pentan-2-one

Embedded image Under a nitrogen gas stream, 1-[(2-aminoquinazoline-4-
Il) amino] pentan-2-ol (33.7 mg, 0.13
7 mmol) was dissolved in dichloromethane (30 ml), and stirred at room temperature with pyridinium chlorochromate (PCC) (88.0 m
g, 0.408 mmol) and stirred at room temperature for 2 hours. PCC
(44.0 mg, 0.204 mmol) was added, the mixture was stirred for 30 minutes, and the reaction solution was concentrated under reduced pressure. The residue was prepared by preparative TLC (PT
LC) (10% MeOH / CHCl ₃ ) to give the title compound (30.8 m
g, 92.0%). ¹ H-NMR (CDCl ₃ ) δ; 0.98 (3H, t, J = 7.6 Hz), 1.72 (2H,
m), 2.55 (2H, t, J = 7.0Hz), 4.43 (2H, s), 5.59 (2
H, bs), 7.17 (1H, bs), 7.20 (1H, m), 7.48 (1H,
m), 7.56 (1H, m), 7.76 (1H, m).

Example 11 Example Effect of the Compound of Example 3 on Cytokine Production from Mouse Lymph Node Cells <Experimental Method> 1. Animal BALB / c mice were purchased from Charles River Japan (Yokohama) and were 8 weeks old. Females were used. 2. Medium Fetal bovine serum (Fetal Bovine Serum, Characterized, Cod) inactivated in D-MEM (High Glucose) medium (Niken Institute of Biomedical Research, Kyoto, Code No. CM4402) at 56 ° C for 30 minutes.
e No.A-1115-L, HyClone Lab., Logan, Utah)
2-mercaptoethanol (Sigma, St Louis, MO, Code
No.M-6250) at 50 μM and penicillin at 100 units / m
l, streptomycin at 100 μg / ml (Penicilin-Strept
omycin; Gibco-BRL, Code No. 15140-122). 3. Drug Compound is dissolved in dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No. 11J) to 100 mM,
Diluted to final concentration with medium. 4. Sensitization and lymph node cell preparation KLH 0.2 mg was added to Freund's complete adjuvant (Difco La
b., Detroit, Michigan, Code No. 3113-60-5) and injected subcutaneously (0.1 ml) in the mouse footpad. Eight days later, popliteal lymph nodes were removed and cell suspensions were prepared. 5. Cytokine production by antigen stimulation KLH (0.1m) was added to lymph node cell suspension (2.5 x 10 ⁶ cells / ml).
g / ml) and drugs were _{added, 37 ℃, 5% CO 2} 4 in the presence
After culturing for one day (Corning 25850, 0.15 ml / well), cytokines produced in the supernatant were quantified by a specific ELISA method. Representative Th2 type cytokines are interleukin 4 (IL-4) and interleukin 5 (IL-5)
Was quantified for interferon gamma (IFN-γ) as a representative Th1-type cytokine. 6. ELISA method The quantification of IL-4 was performed by the following ELISA method. As a primary antibody, a rat anti-mouse IL-4 antibody (Pharmingen, San
Diego, CA, Code No. 18031D, 0.5 mg / ml) was diluted 250-fold with a carbonate buffer, and was added to a 96-well plate (Falcon 3912, Becton Dickinson and company, F., 50 μ / well).
ranklin Lakes, NJ) and coated overnight at 4 ° C. Thereafter, the plate was blocked with PBS (−) containing 3% BSA (200 μl / well). Plate 0.05
% Polyoxyethylene sorbitan monolaurate (Tween 20® Nacalai Tesque, Kyoto) Code
No. 281-51) was washed three times with PBS (-) (PBST), and the culture supernatant was spread at 50 μl / well at room temperature.
Incubated for hours. For preparing a calibration curve, recombinant mouse IL-4 (Pharmingen, Code No. 19231W) was used. The plate was washed three times with PBST, and a biotin-labeled rat anti-mouse IL-4 antibody (Pharmi
ngen, Code No.18042D, 0.5mg / ml) with 0.1% BSA
Add 500-fold dilution with S (-) (100μl / wel
l), incubated for 1 hour at room temperature. The bound secondary antibody was streptavidin alkaline phosphatase (Kirkegaard & Perry Lab., Gaithersburg, MD, Code N
o.15-30-00) (0.25 μg / ml, 100 μl / well). After incubating at 37 ° C. for 1 hour, the plate was washed three times with PBST, and the PNPP substrate (p-nitrophenyl phosphate disodium, Nacalai Tesque) (1 mg / ml, 100 mg / ml) was added.
μl / well) was added for color development. For measurement, use a microplate reader (MTP-120 Microplatereader, Corona Ele
ctric) (wavelength 415 nm). For the determination of IFN-γ, 1
Rat anti-mouse IFN-γ antibody (Pharmingen, S
an Diego, CA, Code No. 18181D, 0.5 mg / ml), and a biotin-labeled rat anti-mouse IFN-γ antibody (Pharmi
ngen, Code No. 18112D, 0.5 mg / ml) in the same manner. Recombinant mouse IF to create a calibration curve
N-γ (Pharmingen, Code No. 19301U) was used. IL-5
For the quantification of rat anti-mouse IL-5 antibody (Pharmingen, SanDiego, CA, Code No. 18051D, 0.5 mg /
ml), biotin-labeled rat anti-mouse IL-5 as secondary antibody
The same procedure was performed using an antibody (Pharmingen, Code No. 18062D, 0.5 mg / ml). For preparing a calibration curve, recombinant mouse IL-5 (Pharmingen, Code No. 19241W) was used. The experiment was performed by triplicate, and the average value was obtained. <Results> The compound of Example 1 suppressed the production of IL-4 and IL-5. On the other hand, it markedly enhanced IFN-γ production.

Example 12 Effect of Analogue Compounds on Cytokine Production from Mouse Lymph Node Cells <Experimental Method> 1. Drugs As in Example 11, various analogous compounds were prepared using dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No.) 11J), it was dissolved to 10-100 mM, and diluted to the final concentration with the medium. 2. Preparation of antigen-sensitized lymph node cells, cytokine production by antigen stimulation, and cytokine quantification are described in Example 13.
Was performed in the same manner as described above. IL-4 was quantified as a representative Th2-type cytokine. For each analog compound, the inhibitory rate of IL-4 production at various concentrations was calculated, and the 50% inhibitory concentration (IC ₅₀ ) value of each analog compound was determined from a graph of the compound concentration and the inhibitory rate. <Results> Table 1 shows the results of typical compounds.

[Table 1]

Example 13 Effect of Example Compounds on IgE Production in Mice <Experimental Method> 1) Animal BALB / c was purchased from Charles River Japan (Yokohama), and
Week-old females were used. 2) Ovalbumin sensitization Ovalbumin (Sigma Chemical Co., St. Louis, M
O) A solution obtained by dissolving 4.5 mg / ml sodium chloride (Nacalai Tesque, Kyoto) in a physiological saline solution (4 μg / ml) and aluminum hydroxide adjuvant (Alu-Gel-S; Serva Feinbioche)
mica GmbH & Co., Code No. 12261), and 0.5 ml / head was administered intraperitoneally to mice. 3) Drug administration method The test compound was suspended in methylcellulose and orally administered continuously for 13 days from the day of sensitization to ovalbumin (8 per group).
One). The control group (10 per group) received only methylcellulose. 4) Blood collection and preparation of plasma On the 12th day after sensitization, blood was collected from the orbital plexus under anesthesia to prepare plasma. 5) Measurement of total IgE level in blood The total IgE level in blood was measured by ELISA. Using a rat anti-mouse IgE monoclonal antibody (code No. 7627, Yamasa Shoyu Co., Ltd., Chiba) as the primary antibody and a biotin-labeled rat anti-mouse IgE monoclonal antibody (code No. 7617, Yamasa Shoyu Co., Ltd., Chiba) as the secondary antibody The measurement was performed in the same manner as in Example 13. 400 plasma
The total IgE level in the blood was measured using mouse IgE
(No. 7626 Yamasa soy sauce, Chiba) was calculated from the standard curve. 6) Statistical processing method Comparison was performed by Dunnett's multiple comparison test. 5% risk rate
And the presence or absence of a significant difference was determined.

<Results> As shown in Table 2, the compounds of the Examples significantly inhibited the increase in total IgE in blood induced by intraperitoneal sensitization of ovalbumin / aluminum hydroxide adjuvant. It has already been confirmed that the increase in blood total IgE in this experimental system is dependent on IL-4 production in vivo. This result indicates that the example compound suppresses IL-4 production in the living body of mice, and
Indicates that the increase in E was suppressed.

[Table 2]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/505 ABM A61K 31/505 ABM ACD ACD ADA ADA ADU ADU ADY ADY ADY ADZ ADZ (72) Inventor Fujio Ando 3-1-98 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Kiyotaka Iwai 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Tanaka 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Ryu Nagata 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Ochi 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Takamasa Watanabe Konohana-ku, Osaka-shi 3-1-98 Hijinaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Kazuji Fujita 3-1-198 Kasuganaka, Konohana-ku, Osaka City Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hajime Kawakami Osaka 3-1-98 Kasuganaka, Konohana-ku, Sumitomo Pharmaceutical Co., Ltd. F-term (reference) 4C086 AA01 AA02 AA03 BC46 MA01 MA04 NA14 ZA34 ZA59 ZA89 ZB05 ZB07 ZB08 ZB09 ZB13 ZB26 ZB33 ZB35 ZB39 ZC55

Claims (7)

[Claims] (1) Formula (1) (Wherein, R ¹ represents a linear or branched lower alkyl group having 1 to 6 carbon atoms or a lower alkoxy group having 1 to 6 carbon atoms, and R ² represents a hydrogen atom, a 1 to 6 carbon atoms. A linear or branched lower alkyl group, an aryl group having 6 to 10 carbon atoms, a halogen atom, an alkoxy group having 1 to 4 carbon atoms, or an alkyl group having 6 to 10 carbon atoms substituted with an alkyl group having 1 to 4 carbon atoms; Represents an aryl group, a carbamoyl group or a hydroxymethyl group, R ³ represents a hydrogen atom or a linear or branched lower alkyl group having 1 to 6 carbon atoms, and R ⁴ represents a hydrogen atom, a hydroxyl group, a carbon number R ⁵ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms or a halogen atom, and R ⁶ represents a hydrogen atom, a hydroxyl group, a 1 to 6 carbon atom. A It represents Kokishi group or a halogen atom, R
⁷ represents a hydrogen atom, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or a halogen atom. Or a pharmaceutically acceptable salt thereof. 2. The quinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a straight or branched lower alkyl group having 1 to 4 carbon atoms. 3. The quinazoline derivative according to claim 1, wherein R ¹ is a lower alkoxy group having 1 to 3 carbon atoms, or a pharmaceutically acceptable salt thereof. 4. A type 1 helper comprising the quinazoline derivative according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof as an active ingredient, which suppresses an immune response on a type 2 helper T cell side. An immunomodulator that enhances an immune response on the T cell side. 5. A method for treating a disease in which the immune response of a type 2 helper T cell side is abnormally enhanced, comprising the quinazoline derivative according to claim 1, 2 or 3 or a pharmaceutically acceptable salt thereof as an active ingredient. Or prophylactic agent. 6. The therapeutic or prophylactic agent according to claim 5, wherein the disease in which the immune response on the type 2 helper T cell side is abnormally enhanced is an allergic disease. 7. The therapeutic or preventive agent according to claim 6, wherein the allergic disease in which the immune response on the type 2 helper T cell side is abnormally enhanced is asthma, allergic rhinitis or atopic dermatitis.