JPH11335360A - Quinazoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the quinazoline derivative useful as a therapeutic agent for allergic diseases, autoimmune diseases such as systemic lupus erythematous, etc., acquired immunodeficiency syndrome(AIDS), etc., by controlling the production of Th2 type cytokinin such as IL-4, IL-5, etc. SOLUTION: This compound is shown by formula I (ring A is a 3-10C cycloalkane or the like or an oxygen- or sulfur-containing heterocyclic ring; R<1> is a 1-6C alkyl, a 2-6C alkenyl or the like; R<2> to R<5> are each H, an alkoxy or a halogen) such as 1-(2-aminoquinaozlin-4-ylamino)-cyclohexanecarboxylic acid ethyl ester of formula II. The compound of formula I is obtained by reacting a compound of substitute III with phosphorus oxychloride to give a compound of formula IV and reacting the compound with a compound of formula V.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a novel heterocyclic derivative. More specifically, the present invention relates to an immunomodulator that suppresses an immune response on the type 2 helper T cell (hereinafter abbreviated as Th2) side. More specifically, the present invention suppresses the immune response on the Th2 side and provides type 1 helper T cells (hereinafter, T cells).
Abbreviated as h1. The present invention relates to a novel heterocyclic derivative having an immunomodulatory effect by enhancing the immune response on the side and changing the Th1 / Th2 balance in the whole body. Specifically, the present invention relates to therapeutic agents for autoimmune diseases such as allergic diseases, parasitic infections, systemic lupus erythematosus, viral or bacterial infections, malignant tumors, acquired immunodeficiency syndrome (AIDS), and the like. About.

[0002]

BACKGROUND OF THE INVENTION Mosmann et al. For the first time 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. They classified mouse helper T cells (Th) into a subset of Th1 and Th2 according to the type of cytokines produced (J. Immuno.
l. (1986) 136: 2348-2357). Examples of Th1 type cytokines include interleukin 2 (IL-2), interferon gamma (IFN-γ), and the like. Th2
Interleukin 4 (I
L-4), interleukin 5 (IL-5), interleukin 10 (IL-10), interleukin 13
(IL-13) and the like. Today, this Th1
The classification of Th2 and Th2 goes beyond simply classifying a subset of helper T cells, and is used to identify various immune responses in a living body.
It has been classified as a one-sided immune response or a Th2-sided immune response. Further, it is known that Th1-type cytokine is involved in cell-mediated immunity and Th2-type cytokine is involved in humoral immunity.

[0003] As a main mechanism of the immune response on the Th1 side, T1 such as interleukin 2 (IL-2) and interferon γ (IFN-γ) produced upon activation of Th1 are used.
There is activation of macrophages, natural killer cells, etc. by h1 type cytokines. Or conversely, there is enhancement of Th1 activation by the action of IL-12 or the like produced from activated macrophages. Specifically, it is known that an immune response on the Th1 side is involved in protection against infection with viruses, bacteria, and the like.

[0004] On the other hand, the immune response on the Th2 side includes Th2 such as IL-4, IL-5 and IL-10 produced from Th2.
Induction of antibody production from B cells (including IgE class) by two types of cytokines is included. Furthermore, the reason why the concept of Th1 / Th2 has received particular attention in recent years is that, in some diseases, the onset mechanism is Th
It has been clarified that abnormalities in the balance of 1 / Th2 are involved. As a result, Th1 in the patient
Normalizing or approaching abnormalities in the balance of / Th2 balance has been recognized as a new direction in the treatment of these diseases.

[0005] Since Th2 produces many cytokines involved in allergic reactions, it is regarded as important as a regulatory cell for allergic reactions. For example, the Th2 type cytokine IL-4 induces IgE antibody production on B cells, and VCAM-1 is an important molecule that functions when eosinophils adhere to vascular endothelial cells and invade tissues.
Also induces gene expression. Recently, IL-4 is Th2
It is also attracting attention as its own differentiation factor. Also, Th2
The type cytokine IL-5 is used for eosinophil differentiation, proliferation,
It induces migration and activation and is considered a trigger of allergic inflammatory response. Therefore, Th2 is Ig
It can be said that it is a central cell that controls two allergic reactions, an immediate reaction involving E antibodies and mast cells, and a late reaction involving eosinophils. That is, it can be said that the allergic disease is a state in which Th2 is pathologically activated (hyperfunction). Actually, as the production of Th2 type cytokines such as IL-4 and IL-5 or the presence of Th2 is confirmed in the respiratory tract and skin, which are allergic disease lesions, in order to treat allergic diseases,
Recognition that it is important to control Th2 activation,
Widely accepted (Clinician (1994) 20: 4
0-46). Similar hyperactivity of Th2 has also been confirmed in the pathology of parasitic infections (Clinical Immunity (1995) 27:
652-656).

[0006] In autoimmune diseases in which antibody production or humoral immunity such as systemic lupus erythematosus is abnormally enhanced, it is also presumed that Th2 is pathologically enhanced in function (Medical Immunology (1988) 15). : 401).
In a recent study, an abnormal state of balance in which Th2 is superior to Th1 in the late stage of the onset of AIDS has been confirmed, and passing this abnormal state leads to a final transition to an immunodeficiency state. Suggests that this may be an important step. If this abnormal state of balance, in which Th2 is superior to Th1, can be improved, AI
It has been pointed out that the onset of DS can be delayed and stopped (Immunology Today (1993) 14: 107-)
111).

[0007] Conversely, by enhancing the Th1 side immune response, macrophages and natural killers are mainly produced through the production of Th1 type cytokines such as interleukin 2 (IL-2) and interferon γ (IFN-γ). By activating cells, cell-mediated immunity is enhanced, and protection against infection with viruses or bacteria such as intracellular parasites or enhancement of cancer immunity is expected (Int. Arc).
h. Allergy Immunol. (1992) 98: 279-285).

[0008] Among allergic diseases, particularly in severe asthma and atopic dermatitis, late-onset allergic reactions are considered to play an important role. However, currently used antiallergic drugs mainly suppress only immediate allergic reactions, and their clinical effects are not sufficient, and ultimately, against severe asthma and atopic dermatitis. State that steroids are effective only at present, as they are effective. However, it is problematic that the steroid causes various side effects (steroid dermatosis, induced infection, adrenocortical dysfunction, etc.) due to long-term administration. There is a need for the development of drugs that suppress the Th2 side immune response, such as treating or preventing allergic diseases in which both types of allergic reactions are involved.

[0009] Further, in consideration of the development of therapeutic or prophylactic drugs with fewer side effects, if a drug that suppresses the Th2 side immune response as described above enhances the Th1 side immune response, a drug may be used. Seems to be more convenient as. That is, as described above, Th1 is mainly I
Since FN-γ plays an important role in living organisms to protect against viruses, bacteria, and the like by producing FN-γ, the drug developed for suppressing the Th2 side immune response enhances the action of Th1. If it does, it is highly desirable in terms of side effects. For example, immunosuppressants such as cyclosporine and FK50
6 is known to strongly suppress Th2 activation. However, these cyclosporins and FK506 do not
Since it has a nonspecific immunosuppressive effect of suppressing Th1 activation similarly to or even stronger than suppressing h2 activation, such nonspecific immunosuppression is Opportunistic infections caused by its effects are a serious side effect.

[0010] Certain quinazoline derivatives are known as insecticides and fungicides (Japanese Patent Application Laid-Open No. 53484/1983, No. 17068/1991, Japanese Patent Publication No. 502462/1993).
No., Japanese Patent Publication No. 505741 and U.S. Pat.
No. 4518, WO9418980). However, a quinazoline derivative that enhances the Th1 side immune response and suppresses the Th2 side immune response is not known.

[0011]

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 agents.

[0012]

Means for Solving the Problems The present inventors have made intensive studies in order to solve the above-mentioned problems, and as a result, the heterocyclic derivative of the present invention and a salt thereof enhance the immune response on the Th1 side,
By suppressing the immune response on the Th2 side,
As a whole, they found that the Th1 / Th2 balance was changed to regulate the immune response, and the present invention was completed.

[0013] The present invention provides: Equation (1)

Embedded image (Wherein ring A is a cycloalkane having 3 to 10 carbon atoms,
Represents a cycloalkene having 5 to 10 carbon atoms, a substituted cycloalkane, a bicycloalkane having 7 to 10 carbon atoms, a substituted bicycloalkane, or a heterocyclic ring containing oxygen or a sulfur atom as a hetero atom; May be bonded to an oxygen atom to form sulfinyl or sulfonyl. R ¹ is a lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, A cycloalkylalkyl group or OR ⁶ (R ⁶ is a lower alkyl group having 1 to 6 carbon atoms,
A lower alkenyl group having 3 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a cycloalkylalkyl group having 4 to 10 carbon atoms. R ² represents a hydrogen atom, an alkoxy group or a halogen atom; R ³ represents a hydrogen atom, an alkoxy group or a halogen atom; R ⁴ represents a hydrogen atom, an alkoxy group or a halogen atom;
⁵ represents a hydrogen atom, an alkoxy group or a halogen atom. And a salt thereof.

An agent for suppressing an immune response on the type 2 helper T cell side comprising the quinazoline derivative or a salt thereof described in 2.1 as an active ingredient, and a type 2 helper T cell containing the quinazoline derivative or a salt thereof as described in 3.1 as an active ingredient Suppresses the side immune response,
An immunomodulator that enhances the immune response of the type 1 helper T cell side. 4.1. Autoimmune diseases such as allergic diseases, parasitic infections, systemic lupus erythematosus, viruses, and the like, which contain the quinazoline derivative or a salt thereof according to 4.1 as an active ingredient. Treatment or prevention of bacterial infection, malignant tumor or acquired immunodeficiency syndrome (AIDS), etc. 5.1 Caused by pathological activation of Th2 containing quinazoline derivative or its salt as described in 5.1 as an active ingredient Autoimmune diseases such as allergic diseases, parasitic infections, systemic lupus erythematosus, or acquired immunodeficiency syndrome (AI)
DS) and the like.

[0015]

BEST MODE FOR CARRYING OUT THE INVENTION Examples of specific compounds included in the formula (1) include the following.

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image

Embedded image Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are represented by the formula (1)
And n represents an integer of 0, 1 or 2.

[0016] The substituents in the present invention are specifically described below. Examples of the cycloalkane having 3 to 10 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

As the cycloalkene having 5 to 10 carbon atoms,
For example, cyclopentenyl, cyclohexenyl and the like can be mentioned.

The bicycloalkane having 7 to 10 carbon atoms includes bicyclo [2.2.1] heptane and bicyclo [2.
2.1] hept-5-ene, bicyclo [2.2.2] octane, bicyclo [2.2.2] oct-5-ene and the like.

Examples of the heterocycle containing an oxygen or sulfur atom as a hetero atom include oxetane, thiethane (trimethylene sulfide), thietane-1-oxide (trimethylene sulfoxide), and thietane-1,1-dioxide (trimethylene). Sulfone), tetrahydrofuran, tetrahydrothiophene, tetrahydrothiophene-1-
Oxide, tetrahydrothiophen-1,1-dioxide, tetrahydro-4H-pyran, thiane (pentamethylene sulfide), thiane-1,1-dioxide (pentamethylene sulfone), thiane-1-oxide (pentamethylene sulfoxide), oxepane ( Hexamethylene oxide), thiepane (hexamethylene sulfide),
Thiepane-1-oxide (hexamethylene sulfoxide), Thiepane-1,1-dioxide (hexamethylene sulfone), 7-oxabicyclo [2.2.1] heptane, 7-oxabicyclo [2.2.1] hepta 5-ene and the like.

Examples of the substituent of the substituted cycloalkane and the substituted bicycloalkane include an alkyl group having 1 to 3 carbon atoms, a carbonyl group, a hydroxy group, an alkoxycarbonyl group, a hydroxycarbonyl group, and a carbamoyl group. And the substituents on the carbon atoms may be combined to form a tetramethylene group, or the carbon atoms on the ring may be substituted with a carbonyl group. The substituent is one, or the same or different. Examples of the alkyl group having 1 to 3 carbon atoms include methyl, ethyl, propyl, and 2-propyl.

Examples of the alkyl group having 1 to 6 carbon atoms include straight-chain or branched lower alkyl groups having 6 or less carbon atoms, and specifically, for example, methyl, ethyl, propyl, 2-propyl, butyl , 2-butyl, 3-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl and the like.

[0022] Examples of the alkenyl group having 2 to 6 carbon atoms include vinyl, allyl, butenyl, pentenyl, hexenyl and the like.

The alkynyl group having 3 to 6 carbon atoms includes, for example, propargyl, butynyl, pentynyl and the like.

Examples of the cycloalkyl group having 4 to 7 carbon atoms include cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.

Examples of the cycloalkylalkyl group having 4 to 10 carbon atoms include cyclopropylmethyl, cyclobutylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylpropyl and the like.

Examples of the alkenyl group having 3 to 6 carbon atoms include allyl, butenyl, pentenyl, hexenyl and the like.

Examples of the alkoxy group include a linear or branched lower alkoxy group having 1 to 6 carbon atoms. Specific examples include methoxy, ethoxy, propoxy and 2-alkoxy.
And propoxy, butoxy, 1,1-dimethylethoxy, pentoxy, hexoxy and the like.

As the halogen atom, for example, fluorine, chlorine,
Bromine, iodine and the like can be mentioned.

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

Embedded image In the formula, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and the ring A have the same meaning as in the formula (1), and the compound (22) is produced by reacting the 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 ranges from about room temperature to around the reflux temperature of the solvent.

The compound (22) is reacted with the compound (23) to obtain the 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 selected from, for example, 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.

Production method 3 Compound (26) is reacted with bromocyanide in a solvent,
Compound (27) can be obtained. If necessary, an organic base such as triethylamine, an inorganic base such as sodium carbonate or 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;
Examples include ether solvents such as HF, and inert solvents such as DMF, acetonitrile, methanol, and ethanol. The reaction temperature is selected, for example, from a room temperature to a temperature around the boiling point of the solvent.

The compound (27) is reacted with R ¹ ONa in R ¹ OH to obtain the compound (1) of the present invention. 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). Compound (2
7) is protected with a t-butoxycarbonyl group, and R ¹ Mg in an ether inert solvent such as THF, diethyl ether or the like.
The compound (1) included in the present invention can be obtained by reacting with a Grignard reagent represented by Br. 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 (In the formula, ring A and R ¹ have the same meaning as in formula (1).) Compound (28) can be reacted with a corresponding alcohol in the presence of an acid catalyst to give 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 and the ring A are represented by formula (1)
Has the same meaning as )

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, by heating compound (29) in thionyl chloride or the like, for example, to about 40 to about 60 ° C.
The compound (31) can also be obtained by converting the carboxylic acid residue of the compound (29) to the corresponding acid chloride and reacting the compound (30) with a suitable organic solvent in the presence of an organic base such as triethylamine. it can. 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 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.

Compound (30) and compound (33) are reacted in an organic solvent to give 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) which 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.

Method for producing compound (23)

Embedded image Compound (36) can be synthesized by a known method. For example, by reacting compound (35) with an alkali metal cyanide compound such as KCN and NaCN in a concentrated ammonia aqueous solution in the presence of a weak acid such as acetic acid at around room temperature,
Compound (36) can be obtained. Compound (23) can be obtained by hydrolyzing compound (36) with alkaline water, aqueous ammonia, hydrogen peroxide or the like in a co-solvent if necessary. 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. As the co-solvent, for example, TH
Examples thereof include ether solvents such as F 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.

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 also 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.

In 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 in the range of about 0.5 to about 2.0 equivalents, preferably about 1 equivalent, relative to the substrate.
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; Recrystallized with acetonitrile and the like and a mixed solvent thereof)
Highly pure optically active salts can also be obtained. If necessary, the obtained salt can be treated with an acid or a base by a usual method to obtain a free form.

[0051] 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. Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter and the like. Can be 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. The solution may include water,
It can also be produced in the form of a solution of polyethylene glycol or / and propylene glycol. Liquid preparations suitable for oral administration are obtained by adding the compound of the present invention to water, adding a colorant, flavor,
Stabilizers, sweeteners, solubilizers, thickeners and the like can be added as required to produce the composition. 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. Examples of the thickener include pharmaceutically acceptable natural or synthetic gums, resins,
Examples include methylcellulose, sodium carboxymethylcellulose, and known suspending agents. Examples of the topical preparation 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 may be added to an aqueous or oily base with one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, coloring agents, perfumes and the like. . 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. A liquid spray, powder or drop formulation containing the compound of the present invention as an active ingredient can be administered nasally. The dosage and 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, in the range of about 0.1 to about 300 mg;
Preferably, the range of about 1 to about 100 mg can be administered once or in divided doses.

[0052] 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.

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 (1-5 x 10 ⁶ cells / ml)
Add KLH (1-100 μg / ml) and drug, and add
Culture for 4 days in the presence of% CO ₂ (Corning 25850, 0.15 ml / we
ll) After that, the cytokine produced in the supernatant was
Quantify by ISA 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 1-aminocyclohexanecarboxamide 1-1) Synthesis of 1-aminocyclohexanecarbonitrile

Embedded image Acetic acid (6.0 ml) was slowly added dropwise to a solution of an aqueous solution (14 ml) of sodium cyanide (5.68 g, 116 mmol) and 29% aqueous ammonia (60 ml) under a nitrogen stream. Cyclohexanone (10.0 ml, 96.5 mmol) was added dropwise to the reaction solution, and the mixture was 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. The magnesium sulfate was filtered off, and the solvent of the filtrate was distilled off to obtain the title compound (9.67 g, 81%). ¹ H NMR (CDCl ₃ ) δ; 1.96 to 2.02 (m, 2H), 1.41 to 1.82
(m, 9H), 1.18 to 1.27 (m, 1H)

1-2) Synthesis of 1-aminocyclohexanecarboxamide

Embedded image Under a nitrogen stream, 1-aminocyclohexanecarbonitrile (9.10 g, 73.3 mmo) was added to 12N ammonia water (56 ml).
l) and 30% aqueous hydrogen peroxide (16.3 ml, 161 mmol) were simultaneously added dropwise and stirred for 7 hours. 10% palladium-carbon (2.0
g) was added, excess hydrogen peroxide was crushed, the mixture was filtered through celite, and the solvent in the filtrate was distilled off to obtain the title compound (8.75 g, 84%). _{^{1 H NMR (CDCl 3) δ}} ; 7.57 (br, 1H), 5.12 (br, 1H),
2.51 (t, 1H, J = 6.3 Hz), 2.20 (t, 1H, J = 6.1 H
z), 1.93 ~ 2.03 (m, 2H), 1.28 ~ 1.68 (m, 8H)

Reference Example 2 1-Amino-1-cyclohexanecarboxylic acid methyl ester hydrochloride

Embedded image 1-amino-1-cyclohexanecarboxylic acid (14.32 g,
100 mmol) into a methanol (250 ml) solution at room temperature with stirring.
Thionyl chloride (36 ml, 500 mmol) was added dropwise, followed by stirring at room temperature for 19 hours. The reaction solution was distilled off and azeotroped with methanol three times to obtain the title compound (8.75 g, 84%). ¹ H NMR (DMSO-d ₆ ) δ; 8.80 (3H, brs), 3.76 (3H, s),
1.41-2.01 (10H, m)

Reference Example 3 1-Amino-1-cyclohexanecarboxylic acid ethyl ester hydrochloride

Embedded image 1-amino-1-cyclohexanecarboxylic acid hydrochloride (8.
Thionyl chloride (18 ml, 250 mmol) was added dropwise to a solution of 98 g (50 mmol) in ethanol (100 ml) with stirring at room temperature. Thereafter, the reaction solution was refluxed for 7 hours. The reaction solution was concentrated under reduced pressure, ethanol was added to the concentrated residue, and the mixture was concentrated under reduced pressure.
This operation was repeated three times. Toluene was added to the residue and recrystallized to obtain 9.74 g (94%) of the title compound. _{^{1 H NMR (DMSO-d 6}} ) δ; 8.98 (3h, br), 4.27 (2H, q, J =
7.1 Hz), 2.00-2.10 (4H, m), 1.83-1.94 (2H, m), 1.62
-1.73 (3H, m), 1.39-1.47 (1H, m), 1.33 (3H, t, J = 7.
1 Hz)

Reference Example 4 5-amino-2-spirocyclohexane-imidazo [1,2
Synthesis of -c] quinazolin-3 (2H) -one 3-1) Synthesis of 1- (2-nitrobenzamido) cyclohexanecarboxamide

Embedded image 1-aminocyclohexanecarboxamide under a nitrogen stream
(1.03 g, 7.24 mmol) and triethylamine (1.80 ml, 12.
To a solution of 9 mmol) in tetrahydrofuran (25 ml) was added 2-nitrobenzoyl chloride (1.04 ml, 7.96 mmol).
Stir at room temperature for 9 hours. 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. Magnesium sulfate was filtered off, the solvent of the filtrate was distilled off, and the precipitated crystals were suspended in a mixed solution of ethyl acetate and ether and collected by filtration.
The solvent in the filtrate was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate), and combined with the crystals collected by filtration to give the title compound (916 mg, 43%). ¹ H NMR (DMSO-d ₆ ) δ; 8.46 (s, 1H), 8.06 (d, 1H, J
= 8.3 Hz), 7.65 to 7.84 (m, 3H), 6.98 (brs, 1H), 6.83
(brs, 1H), 2.08-2.12 (m, 2H), 1.54-1.76 (m, 7
H), 1.20 (m, 1H)

3-2) Synthesis of 1- (2-aminobenzamide) cyclohexanecarboxamide

Embedded image 1- (2-Nitrobenzamide) cyclohexanecarboxamide (871 mg, 2.99 mmol), 10% palladium-carbon (630 mg) were suspended in methanol (50 ml), and hydrogenated for 2.5 hours. The reaction solution was filtered through celite, and the solvent of the filtrate was distilled off to obtain the title compound (739 mg, 95%). ¹ H NMR (CDCl ₃ ) δ; 7.37 (dd, 1H, J = 1.3, 8.6 Hz),
7.24 (ddd, 1H, J = 1.3, 8.6, 8.6 Hz), 6.86 (br, 1
H), 6.65 to 6.71 (m, 2H), 6.10 (brs, 1H), 5.47 (br, 2
H), 5.40 (br, 1H), 2.24 to 2.29 (m, 2H), 1.90 to 2.06
(m, 2H), 1.33 to 1.76 (m, 6H)

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

Embedded image Under a nitrogen stream, 1- (2-aminobenzamide) cyclohexanecarboxamide (673 mg, 2.58 mmol) was suspended in tetrahydrofuran (15 ml), and a 5.15 N aqueous potassium hydroxide solution (1.0 ml, 5.15 mmol) was added. The mixture was refluxed for 7 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 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) to give the title compound (305
mg, 49%). ¹ H NMR (CDCl ₃ ) δ; 9.83 (brs, 1H), 7.38 (dd, 1H, J
= 1.5, 7.9 Hz), 7.24 (ddd, 1H, J = 1.5, 7.9, 7.9 H
z), 6.72-6.78 (m, 2H), 6.43 (brs, 2H), 1.80-1.86
(m, 6H), 1.43 to 1.62 (m, 4H)

3-4) 5-Amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2H)-
On synthesis

Embedded image Under a nitrogen stream, 2- (2-aminophenyl) -5-oxo-2-imidazoline-4-spirocyclohexane (102 m
g, 4.17 × 10 ^-1 mmol) in ethanol (3.0 ml),
95% bromocyanine (55.0 mg, 4.93 × 10 ^-1 mmol) was added, and triethylamine (60 μm) was added at room temperature for 3.5 hours.
1, 4.32 × 10 ^-1 mmol) and stirred at 50 ° C. for 7 hours.
The mixture was cooled to room temperature, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, and dried over magnesium sulfate. The solvent was distilled off and the residue was subjected to silica gel column chromatography (hexane / ethyl acetate =
2/1) to give the title compound (20.7 mg, 19
%). ¹ H NMR (DMSO-d ₆ ) δ; 7.93 (dd, 1H, J = 1.5, 7.9 H
z), 7.50 (ddd, 1H, J = 1.5, 7.9, 7.9 Hz), 7.50 (br,
2H), 7.11 (dd, 1H, J = 1.5, 7.9 Hz), 7.10 (ddd, 1
H, J = 1.5, 7.9, 7.9 Hz), 1.40 to 1.71 (m, 10H)

Example 1 Synthesis of 1- (2-aminoquinazolin-4-ylamino) -cyclohexanecarboxylic acid ethyl ester 1-1) 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)

1-2) 1- (2-aminoquinazoline-4-)
Synthesis of ylamino) -cyclohexanecarboxylic acid ethyl ester

Embedded image 2-amino-4-chloroquinazoline (43.5 mg, 0.242 mm
ol), 1-amino-1-cyclohexanecarboxylic acid ethyl ester hydrochloride (60.3 mg, 0.29 mmol), triethylamine (50 mg, 0.484 mmol) and butanol (5 ml) were refluxed for 6.5 hours. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The chloroform layer was washed with water and then with saturated saline, dried over sodium sulfate and concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography (1% MeOH / CHCl ₃ → 10% MeOH / CHCl ₃ ).
The title compound (30.7 mg, 40.5%) was obtained. _{^{1 H NMR (CDCl 3) δ}} ; 7.59 (1H, d, J = 7.9Hz), 7.58 (1H,
dd, J = 7.9, 7.9Hz), 7.44 (1H, d, J = 7.9Hz), 7.16 (1H,
dd, J = 7.9, 7.9Hz), 5.71 (1H, brs), 4.81 (2H, brs),
4.12 (2H, q, J = 7.0Hz), 2.27-2.32 (2H, m), 1.93-2.04
(2H, m), 1.36-1.71 (6H, m), 1.11 (3H, t, J = 7.0Hz)

Example 2 Synthesis of 1- (2-aminoquinazolin-4-ylamino) -cyclohexanecarboxylic acid methyl ester 2-1) Synthesis of 1- (2-chloroquinazolin-4-ylamino) -cyclohexanecarboxylic acid methyl ester

Embedded image 2,4-dichloroquinazoline (1.99 g, 10 mmol), potassium carbonate (2.07 g, 30 mmol), 1-amino-1-cyclohexanecarboxylic acid methyl ester hydrochloride (2.91 g, 15 m
mol) and THF (20 ml) was refluxed for 30 minutes. Potassium carbonate (2.07 g, 30 mmol) was added to the mixture, which was further refluxed for 30 minutes. Ethyl acetate and aqueous sodium bicarbonate were added to the reaction solution for extraction. The organic layer was washed with saturated saline, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate 5: 1 → hexane: ethyl acetate 1: 1) to obtain the title compound (1.13 g, 35%). ¹ H NMR (CDCl ₃ ) δ; 7.72-7.80 (3H, m), 7.45-7.52 (1H,
m), 6.02 (1H, brs), 3.73 (3H, s), 2.30 (2H, brd), 2.
05 (2H, dt-like), 1.39-1.80 (6H, m)

2-2) 1- (2-aminoquinazoline-4-)
Synthesis of ylamino) -cyclohexanecarboxylic acid methyl ester

Embedded image 1- (2-chloroquinazolin-4-ylamino) -cyclohexanecarboxylic acid methyl ester (319 mg, 1 mmo
l), sodium azide (98 mg, 1.5 mmol) and DMF
(1.5 ml) of the mixture was heated and stirred at 100 ° C. for 11 hours. The reaction solution was poured into water, and the precipitated crystals were collected by filtration. The obtained crystals were dried, triphenylphosphine (262 mg, 1 mmol) and THF (4 ml) were added, and the mixture was refluxed for 6 hours. The reaction solution is concentrated, and the residue is subjected to silica gel column chromatography (10% M
eOH / CHCl ₃ ) to give the title compound (34 mg, 2
3%). ¹ H NMR (CDCl ₃ ) δ; 7.55-7.60 (2H, m), 7.44 (1H, d, J
= 7.6Hz), 7.16 (1H, dd, J = 7.6, 7.6Hz), 5.70 (1H, brs),
4.81 (2H, brs), 3.63 (3H, s), 2.26-2.31 (2H, m), 1.41
-1.99 (8H, m)

Example 3 Synthesis of ethyl 1- (2-aminoquinazolin-4-ylamino) -cyclohexanecarboxylate

Embedded image Under a nitrogen stream, 5-amino-2-spirocyclohexane-
Imidazo [1,2-c] quinazolin-3 (2H) -one
(15.7 mg, 5.85 × 10 ^-2 mmol) was dissolved in ethanol (1.0 ml), and sodium ethoxide (5.9 mg, 8.66 × 10 ^-2 mmo) was dissolved.
l) was added and the mixture was stirred at room temperature for 0.5 hour. A 5% aqueous potassium carbonate solution was added, 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 give the title compound (12.2).
mg, 66%). ¹ H NMR (CDCl ₃ ) δ; 7.59 (d, 1H, J = 7.9 Hz), 7.58
(dd, 1H, J = 7.9, 7.9Hz), 7.44 (d, 1H, J = 7.9H
z), 7.16 (dd, 1H, J = 7.9, 7.9 Hz), 5.71 (brs, 1
H), 4.81 (brs, 2H), 4.12 (q, 2H, J = 7.0 Hz), 2.27
~ 2.32 (m, 2H), 1.93 ~ 2.04 (m, 2H), 1.36 ~ 1.71 (m,
6H), 1.11 (t, 3H, J = 7.0 Hz)

Example 4 1- [1- (2-aminoquinazolin-4-ylamino)
Synthesis of -cyclohexyl] butan-1-one 4-1) 1- [1- (2-t-butoxycarbonylamino-quinazolin-4-ylamino) -cyclohexyl]
Synthesis of butan-1-one

Embedded image Under a nitrogen stream, 5-amino-2-spirocyclohexane-
Imidazo [1,2-c] quinazolin-3 (2H) -one
(5 g, 0.021 mol) was dissolved in THF (50 ml), and a mixture of triethylamine (6.2 g, 0.062 mol) and di-tert-butyl dicarbonate (13.5 g, 0.062 mol) was stirred for 3 hours. N, N'-dimethylaminopyridine (50
mg) and stirred at room temperature for 1 hour. The reaction solvent was distilled off, and the residue was added with 200 ml of ethyl acetate, washed twice with 50 ml of water, and washed with 50 ml of saturated aqueous sodium hydrogen carbonate. The organic layer was dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane / ethyl acetate = 4 /
Purification in 1) gave 7.2 g of a protected Boc (Boc is an abbreviation for t-butoxycarbonyl). Boc protected body under nitrogen stream
(1 g) was dissolved in tetrahydrofuran (10 ml), 2M propylmagnesium chloride (3.6 ml, 7.2 mmol) was added under ice-cooling, and the mixture was stirred at room temperature for 1 hour. 50 ml of 10% aqueous ammonia chloride was added to the reaction solution, and the mixture was extracted with 130 ml of chloroform. The aqueous layer was re-extracted with 50 ml of chloroform, 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 subjected to silica gel column chromatography (hexane / ethyl acetate = 5/5).
1 → 2/1) to give the title compound (980 mg). _{^{1 H NMR (CDCl 3) δ}} ; 7.85 (dd, 1H, J = 1.2, 7.4 Hz),
7.65 to 7.70 (m, 2H), 7.34 (ddd, 1H, J = 1.2, 7.4,
7.4 Hz), 6.99 (brs, 1H), 5.93 (brs, 1H), 2.48 (q,
2H, J = 7.2 Hz), 2.17 to 2.23 (m, 2H), 1.23 to 1.90
(m, 8H), 1.53 (s, 9H), 0.83 (t, 3H, J = 7.2 Hz)

4-2) 1- [1- (2-aminoquinazoline-
Synthesis of 4-ylamino) -cyclohexyl] butan-1-one

Embedded image To a 1- [1- (2-t-butoxycarbonylaminoquinazolin-4-ylamino) -cyclohexyl] butan-1-one (960 mg) was added 4N hydrochloric acid in dioxane (10 ml) under a nitrogen stream, and the mixture was stirred at room temperature. For 4.5 hours. The crystals were collected by filtration. Ethyl acetate 80 ml and saturated aqueous sodium bicarbonate 30
ml was added for liquid separation. The extracted organic layer was washed with 30 ml of saturated saline, dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on 50 g of silica gel with chloroform to give the title compound (260 mg). ¹ H NMR (CDCl ₃ ) δ; 7.57-7.63 (m, 2H), 7.46 (dd, 1
H, J = 1.3, 8.9 Hz), 7.19 (t, 1H, J = 8.3 Hz), 5.
85 (brs, 1H), 4.77 (brs, 2H), 2.50 (q, 2H, J = 7.3 H
z), 2.17 to 2.21 (m, 2H), 1.16 to 1.89 (m, 8H), 0.84
(t, 3H, J = 7.3 Hz)

Example 5 1- (2-aminoquinazoline-4-
Synthesis of ylamino) -cyclohexanecarboxylic acid propyl ester

Embedded image According to the method of Example 3, synthesis was performed using 1-propyl alcohol instead of ethanol and sodium propoxide instead of sodium ethoxide to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ; 7.54-7.60 (2H, m), 7.43 (1H, dd,
J = 7.9,1.3Hz), 7.16 (1H, ddd, J = 1.3, 7.8, 7.8Hz), 5.7
2 (1H, brs), 4.82 (1H, brs), 4.02 (2H, t, J = 6.6Hz),
2.28-2.33 (2H, m), 1.94-2.03 (2H, m), 1.48-1.71 (6H, m
m), 0.72 (3H, t, J = 7.3Hz)

Example 6 1- (2-aminoquinazoline-4-
Synthesis of butyl (ylamino) -cyclohexanecarboxylate

Embedded image According to the method of Example 3, synthesis was performed using 1-butanol instead of ethanol and sodium-1-butoxide instead of sodium ethoxide to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ; 7.54-7.60 (2H, m), 7.44 (1H, dd,
J = 1.3, 7.8Hz), 7.16 (1H, ddd, J = 1.3, 7.8, 7.8Hz),
5.74 (1H, brs), 4.98 (2H, brs), 4.06 (2H, t, J = 6.6H
z), 1.42-2.33 (12H, m), 1.15 (2H, qt, J = 7.4, 7.4Hz),
0.78 (3H, t, J = 7.4Hz)

Example 7 1- (2-amino-quinazoline-4)
Synthesis of -ylamino) -cyclohexanecarboxylic acid allyl ester

Embedded image According to the method of Example 3, synthesis was performed using allyl alcohol instead of ethanol and sodium allyl alkoxide instead of sodium ethoxide to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ; 7.53-7.61 (2H, m), 7.43 (1H, d,
J = 8.2 Hz), 7.14 (1H, dd, J = 8.2, 8.2 Hz), 5.73-5.8
6 (2H, m), 5.19 (1H, d, J = 17.1Hz), 5.14 (1H, d, J = 1
0.6 Hz), 4.92 (1H, brs), 4.57 (2H, d, J = 5.7Hz), 2.
29-2.34 (2H, m), 1.96-2.10 (2H.m), 1.26-1.76 (6h,
m)

Example 8 1- (2-aminoquinazoline-4-
Synthesis of ylamino) -cyclohexanecarboxylic acid 2-propyl ester

Embedded image According to the method of Example 3, synthesis was performed using isopropyl alcohol instead of ethanol and sodium isopropoxide instead of sodium ethoxide to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ; 7.56-7.61 (1H, m), 7.46 (1H, d, J
= 8.0Hz), 7.18 (1H, ddd, J = 1.0, 8.9, 8.9), 5.74 (1H, b
rs), 4.96 (2H, brs), 4.85-5.07 (3H, m), 2.20-2.40 (3
H, m), 1.92-2.05 (2H, m), 1.25-1.80 (5H, m), 1.10 (6
(H, d, J = 6.3Hz)

Example 9 1- (2-aminoquinazoline-4-
Synthesis of ylamino) -cyclohexanecarboxylic acid-2-methyl-1-propyl ester

Embedded image According to the method of Example 3, synthesis was performed using 2-methyl-1-propyl alcohol instead of ethanol and sodium 2-methyl-1-propoxide instead of sodium ethoxide to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ; 7.55-7.61 (2H, m), 7.44 (1H, d, J
= 8.0Hz), 7.17 (1H, dd, J = 8.0, 8.0Hz), 5.72 (1H, brs),
4.82 (2H, brs), 3.83 (2H, d, J = 6.6Hz), 2.29-2.34 (2
H, m), 1.95-2.03 (2H, m), 1.41-1.83 (7H, m), 0.72 (6
H, d, J = 6.8Hz),

Example 10 1- (2-aminoquinazoline-4
Synthesis of -ylamino) -cyclohexanecarboxylic acid cyclopropyl methyl ester

Embedded image According to the method of Example 3, synthesis was performed using cyclopropanemethanol instead of ethanol, and using sodium cyclopropanemethoxide instead of sodium ethoxide to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ; 7.56-7.62 (2H, m), 7.45 (1H, d, J
= 7.7Hz), 7.17 (1H, ddd, J = 7.7, 7.0, 1.3Hz), 5.76 (1H,
brs), 4.89 (2H, brs), 3.98 (2H, d, J = 7.1Hz), 2.20-2.
40 (2H, m), 2.08-2.19 (2H, m), 1.30-1.70 (6H, m), 0.9
1-1.05 (1H, m), 0.35-0.43 (2H, m), 0.07-0.13 (2H, m)

Example 11 1- (2-Aminoquinazoline-4)
Synthesis of 2-ylamino) -cyclohexanecarboxylic acid 2-methyl-2-propene ester

Embedded imageAccording to the method of Example 3, 2-methylmeth was used instead of ethanol.
Sodium 2-ethene-1-ol
Sodium 2-methyl-2-propene in place of oxide
The title compound was obtained by synthesis using -1-oxide. ¹ H NMR (CDCl_Three) δ; 7.55-7.60 (2H, m), 7.44 (1H, dd,
J = 8.7, 1.3Hz), 7.17 (1H, ddd, J = 7.0, 1.3Hz), 5.72
(1H, brs), 4.90 (1H, brs), 4.83 (1H, brs), 4.80 (2H,
brs), 2.31-2.36 (2H, m), 1.97-2.05 (2H, m), 1.41-1.7
2 (6H, m), 1.53 (3H, s)

Example 12 1- [1- (2-Aminoquinazolin-4-ylamino) -cyclohexyl] ethane-1-
On synthesis

Embedded image According to the method of Example 4, synthesis was performed using methyl magnesium chloride instead of 2M propyl magnesium chloride to obtain the title compound. _{^{1 H NMR (CDCl 3) δ}} ; 7.59-7.64 (2H, m), 7.49 (1H, dd,
J = 8.9, 1.3), 7.21 (1H, ddd, J = 8.3, 1.3Hz), 5.96 (1H,
brs), 5.05 (1H, brs), 2.14-2.22 (2H, m), 2.14 (3H,
s), 1.67-1.88 (6H, m), 1.26-1.55 (2H, m)

Example 13 1- [1- (2-Aminoquinazolin-4-ylamino) -cyclohexyl] propane-1
-On synthesis

Embedded image According to the method of Example 4, synthesis was performed using ethyl magnesium chloride instead of 2M propyl magnesium chloride to obtain the title compound. _{^{1 H NMR (DMSO-d 6}} ) δ; 8.79 (1H, s), 8.53 (1H, d, J = 7.
5Hz), 8.0 (2H, br), 7.83 (1H, dd, J = 7.5, 7.5Hz), 7.4
3-7.49 (2H, m), 2.59 (2H, d, J = 7.1Hz), 2.32-2.37 (2
H, m), 1.19-1.77 (8H, m), 0.91 (3H, t, J = 7.1Hz)

Example 14 1- [1- (2-Amino-quinazolin-4-ylamino) -cyclohexyl] pentane-
Synthesis of 1-one

Embedded image According to the method of Example 4, synthesis was performed using butyl magnesium chloride instead of 2M propyl magnesium chloride to obtain the title compound. _{^{1 H NMR (CDCl 3) δ}} ; 7.71 (1H, d, J = 8.1Hz), 7.61 (1H,
dd, J = 8.1, 8.2), 7.46 (1H, d, J = 8.2Hz), 7.21 (1H, d
d, J = 8.2, 8.2Hz), 6.18 (1H, brs), 5.32 (2H, brs), 2.
49 (2H, t, J = 7.3Hz), 2.08-2.18 (2H, m), 1.73-1.88 (6
H, m), 1.16-1.56 (8H, m), 0.83 (3H, t, J = 7.3Hz)

Example 15 1- (2-aminoquinazoline-4
-Ylamino) -cyclopentanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
5-amino-2-spirocyclopentane-imidazo [1,2-c] quinazoline-3 (2
The title compound was obtained by synthesis using H) -one. ¹ H NMR (CDCl ₃ ) δ; 7.56-7.64 (2H, m), 7.46 (1H, d, J
= 8.6Hz), 7.14-7.19 (1H, m), 6.19 (1H, brs), 5.14 (2H,
brs), 4.15 (2H, q, J = 7.1Hz), 2.39-2.49 (2H, m), 2.08
-2.17 (2H, m), 1.84-1.89 (4H, m), 1.44 (3H, t, J = 7.1
Hz)

Example 16 1- (2-aminoquinazoline-4
-Ylamino) -cycloheptanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
5-amino-2-spirocycloheptane-imidazo [1,2-c] quinazoline-3 (2
The title compound was obtained by synthesis using H) -one. ¹ H NMR (CDCl ₃ ) δ; 7.54-7.59 (2H, m), 7.43 (1H, dd,
J = 6.8, 1.3Hz), 7.16 (1H, ddd, J = 6.8, 6.8, 1.3Hz),
5.69 (1H, brs), 4.75 (2H, brs), 4.11 (2H, q, J = 7.1H
z), 2.18-2.38 (4H, m), 1.62-1.76 (8H, m), 1.10 (3H,
(t, J = 7.1Hz)

Example 17 1- (2-aminoquinazoline-4
-Ylamino) -cyclooctanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
5-amino-2-spirocyclooctane-imidazo [1,2-c] quinazoline-3 (2
The title compound was obtained by synthesis using H) -one. ¹ H NMR (CDCl ₃ ) δ; 7.54-7.59 (2H, m), 7.43 (1H, dd,
J = 8.6, 1.0Hz), 7.15 (1H, ddd, J = 8.6, 8.6, 1.0Hz),
5.57 (1H, brs), 4.75 (2H, brs), 4.12 (2H, q, J = 7.1H
z), 2.37-2.43 (2H, m), 2.16-2.24 (2H, m), 1.60-1.70
(10H, m), 1.12 (3H, t, J = 6.9Hz)

Example 18 1- (2-aminoquinazoline-4)
-Ylamino) -tetrahydropyran-4-carboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
5-amino-2- (spiro-4-) instead of H) -one
Synthesis was performed using (tetrahydropyran) -imidazo [1,2-c] quinazolin-3 (2H) -one to obtain the title compound. _{^{1 H NMR (CDCl 3) δ}} ; 7.58-7.63 (2H, m), 7.46 (1H, d, J
= 7.5Hz), 7.19 (1H, dd, J = 7.5, 7.5Hz), 5.75 (1H, brs),
4.92 (2H, brs), 4.15 (2H, q, J = 6.9Hz), 3.89-3.96 (2
H, m), 3.74-3.82 (2H, m), 2.35-2.45 (2H, m), 2.15-2.
25 (2H, m), 1.13 (3H, t, J = 6.9Hz)

Example 19 1- (2-Amino-7-methoxyquinazolin-4-ylamino) -cyclohexanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
H) Instead of 5-one, 5-amino-7-methoxy-2-
Synthesis was performed using spirocyclohexane-imidazo [1,2-c] quinazolin-3 (2H) -one to obtain the title compound. _{^{1 H NMR (CDCl 3) δ}} ; 7.50 (1H, d, J = 9.0Hz), 6.85 (1H,
d, J = 2.4Hz), 6.80 (1H, dd, J = 9.0, 2.4Hz), 5.71 (1H, b
rs), 5.34 (1H, br), 4.12 (2H, q, J = 7.1Hz), 3.88 (3H,
s), 2.28 (2H, br), 1.99 (2H, dt-like), 1.71 (3H, m),
1.25-1.58 (3H, m), 1,12 (3H, t, J = 7.1Hz)

Example 20 1- (2-Amino-7-chloroquinazolin-4-ylamino) -cyclohexanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
The title compound was obtained by synthesis using 5-amino-7-chloro-2-spirocyclohexane-imidazo [1,2-c] quinazolin-3 (2H) -one instead of H) -one. _{^{1 H NMR (CDCl 3) δ}} ; 7.50 (1H, d, J = 8.8Hz), 7.42 (1H,
d, J = 2.0Hz), 7.09 (1H, dd, J = 8.8Hz), 5.63 (1H, brs),
5.93 (1H, s), 4.87 (1H, brs), 4.12 (2H, q, J = 7.1Hz),
2.28 (2H, brs), 1.99 (2H, t-like), 1.75 (3H, m), 1.25
-1.55 (3H, m), 1.11 (3H, t, J = 7.1Hz)

Example 21 1- (2-Amino-6-methoxyquinazolin-4-ylamino) -cyclohexanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
H) Instead of 5-one, 5-amino-6-methoxy-2-
Synthesis was performed using spirocyclohexane-imidazo [1,2-c] quinazolin-3 (2H) -one to obtain the title compound. _{^{1 H NMR (CDCl 3) δ}} ; 7.48 (1H, d, J = 9.2Hz), 7.28 (1H,
dd, J = 9.2, 2.7Hz), 6.97 (1H, d, J = 2.6Hz), 5.91 (1H,
brs), 5.85 (1H, br), 4.94 (1H, br), 4.13 (2H, q, J = 7.
1Hz), 3.89 (3H, s), 2.29 (2H, brs), 2.06 (2H, br), 1.
74 (3H, m), 1.35-1.60 (3H, m), 1.14 (3H, t, J = 7.1Hz)

Example 22 1- (2-Amino-6-fluoroquinazolin-4-ylamino) -cyclohexanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
5-amino-6-fluoro-2- instead of H) -one
Synthesis was performed using spirocyclohexane-imidazo [1,2-c] quinazolin-3 (2H) -one to obtain the title compound. _{^{1 H NMR (CDCl 3) δ}} ; 7.44 (1H, dd, J = 9.2, 5.3Hz), 7.3
5 (1H, dt, J = 8.3, 2.6Hz), 7.22 (1H, dd, J = 9.0, 2.6H
z), 5.52 (1H, br), 4.93 (2H, br), 4.12 (2H, q, J = 7.1H
z), 2.31 (2H, brm), 1.95 (4H, brm), 1.77 (2H, brm),
1.55 (2H, brm), 1.12 (3H, t, J = 7.1Hz)

Example 23 1- (2-Amino-6-chloroquinazolin-4-ylamino) -cyclohexanecarboxylic acid ethyl ester

Embedded image According to the method of Example 3, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
The title compound was obtained by synthesis using 5-amino-6-chloro-2-spirocyclohexane-imidazo [1,2-c] quinazolin-3 (2H) -one instead of H) -one. _{^{1 H NMR (CDCl 3) δ}} ; 7.52 (2H, m), 7.38 (1H, d, J = 9.0H
z), 5.59 (1H, br), 4.90 (2H, br), 4.11 (2H, q, J = 7.1H
z), 2.29 (2H, brm), 1.99 (2H, dt-like), 1.69 (4H, br
m), 1.26-1.60 (2H, brm), 1.11 (3H, t, J = 7.1Hz)

Example 24 1- (1- (2-Aminoquinazolin-4-ylamino) -4-tetrahydropyranyl) butan-1-one

Embedded image According to the method of Example 4, 5-amino-2-spirocyclohexane-imidazo [1,2-c] quinazoline-3 (2
5-amino-2- (spiro-4-) instead of H) -one
Synthesis was performed using (tetrahydropyran) -imidazo [1,2-c] quinazolin-3 (2H) -one to obtain the title compound. ¹ H NMR (CDCl ₃ ) δ; 7.61 (d, 1H, J = 8.3 Hz), 7.52
(dd, 1H, J = 8.3, 8.3Hz), 7.38 (d, 1H, J = 8.3H
z), 7.11 (dd, 1H, J = 8.3, 8.3 Hz), 6.00 (brs, 1
H), 4.99 (brs, 2H), 3.90-3.80 (m, 2H), 3.70-3.60
(m, 2H), 2.40 (t, 2H, J = 7.5 Hz), 2.25-2.13 (m, 2
H), 2.05-1.95 (m, 2H), 1.51 (tt, 2H, J = 7.5, 7.5 H
z), 0.74 (t, 3H, J = 7.5 Hz)

Example 25 Effect of Compound of Example 1 on Cytokine Production from Mouse Lymph Node Cells Experimental Method 1. Animals BALB / c mice were purchased from Charles River Japan (Yokohama), and 8-week-old females were used. . 2. Medium RPMI1640 medium "Daigo" (Nippon Pharmaceutical, Tokyo) at 56 ℃
Inactivated fetal bovine serum (Fetal Bovine Serum,
Characterized, Code No.A-1115-L, HyClone Lab., Log
an, Utah) to 10%, 2-mercaptoethanol (Sigma,
St Louis, MO, Code No. M-6250) was added and used at 50 μM. 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 the drug, and added at 37 ° C in the presence of 5% CO _2.
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 carried out 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 a 96-well plate (Falcon 3912, Becton Dickinson and company, F
ranklin Lakes, NJ) and coated overnight at 4 ° C. Thereafter, the plate was washed with PBS (-) containing 3% BSA (Phosphate- without calcium chloride and magnesium chloride).
buffered saline) (200μl / wel
l). PBS containing 0.05% polyoxyethylene sorbitan monolaurate (Tween 20® Nacalai Tesque (Kyoto) Code No. 281-51)
(−) Wash three times with (PBST), and culture
1 / well, and incubated at room temperature for 4 hours.
Recombinant mouse IL-4 (Pharmi
ngen, Code No. 19231W). PBST plate
After washing three times with a biotin-labeled rat anti-mouse IL-4 antibody (Pharmingen, Code No. 18042D, 0.
(5 mg / ml) diluted 500-fold with PBS (-) containing 0.1% BSA was added (100 μl / well) and incubated at room temperature for 1 hour. The bound secondary antibody was a streptavidin alkaline phosphatase (Kirkegaard & Perry Lab., Ga.
ithersburg, MD, Code No.15-30-00) (0.25μg / ml, 10
0 μl / well). After incubating at 37 ° C for 1 hour, the plate was washed three times with PBST,
Substrate (d-sodium p-nitrophenylphosphate, Nacalai Tesque) (1 mg / ml, 100 μl / well) was added to develop color. For measurement, use a microplate reader (MTP-120 Micr
oplatereader, Corona Electric) (wavelength 415n)
m). For the quantification of IFN-γ, a rat anti-mouse IFN-γ antibody (Pharmingen, San Diego, CA, Code No. 18) was used as the primary antibody.
181D, 0.5 mg / ml) and a biotin-labeled rat anti-mouse IFN-γ antibody (Pharmingen, Code No. 18112D, 0.
5 mg / ml) in the same manner. Recombinant mouse IFN-γ (Pharmingen, Code N
o.19301U) was used. For the quantification of IL-5, a rat anti-mouse IL-5 antibody (Pharmingen, SanDiego, C
A, Code No. 18051D, 0.5 mg / ml), biotin-labeled rat anti-mouse IL-5 antibody (Pharmingen, Code N)
o.18062D, 0.5 mg / ml) in the same manner. Recombinant mouse IL-5 (Pharming
en, CodeNo.19241W). Experiment triplicate
And the average was determined.

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.

[Table 1]

Example 26 Effect of Example Compounds on Cytokine Production from Mouse Lymph Node Cells Experimental Method 1. Drugs As in Example 25, various analogous compounds were dimethyl sulfoxide (Nacalai Tesque (Kyoto) Code No. 11J). )), It was dissolved to 100 mM, and diluted with the medium to the final concentration. 2. Preparation of antigen-sensitized lymph node cells, cytokine production by antigen stimulation and cytokine quantification are described in Example 25.
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 The results are shown in Table 2.

[0093]

[Table 2]

Example 27 Effect of Compound of Example 1 on IgE Production in Mice In Vivo Experimental Method 1) Animals BALB / c was purchased from an 8-week-old female mouse from Japan Mouse Charles River (Yokohama), and was used for 9 days. It was used after preliminary breeding. 2) Ovalbumin sensitization Ovalbumin (Sigma Chemical Co., St. Louis, M
O) physiological saline solution (4μg / ml) and aluminum hydroxide
Adjuvant (Alu-Gel-S; Serva Feinbiochemica GmbH
& Co., Code No. 12261) were mixed in equal amounts and 0.5 ml was administered intraperitoneally to mice. 3) Drug administration method The test compound (the compound of Example 1) was suspended in methylcellulose, 1 hour before sensitization with ovalbumin and 1 hour after sensitization.
Oral administration was carried out once a day from day to day 12. The control group received only methylcellulose. 4) Blood collection and preparation of plasma On the 13th day after sensitization, blood was collected from the eye or venous plexus using a heparin-treated capillary under anesthesia, and centrifuged to prepare plasma. 5) Measurement of blood IgE level The blood IgE level was measured using an ELISA method. Using a rat anti-mouse IgE monoclonal antibody (code No. 7627, Yamasa Shoyu Co., Chiba) as the primary antibody and a biotin-labeled rat anti-mouse IgE monoclonal antibody (code No. 7617, Yamasa Shoyu Co., Chiba) as the secondary antibody The measurement was performed in the same manner as in Example 25. 500 plasma
The concentration of IgE in the blood was measured by diluting the mouse IgE (part number 76).
26 Yamasa soy sauce, Chiba). 6) Statistical processing method The results were statistically processed by Dunnett's-test.

Results As shown in Table 3, the compound of Example 1 significantly inhibited the increase in blood IgE induced by intraperitoneal sensitization of ovalbumin / aluminum hydroxide adjuvant. The rise in blood IgE in this experimental system is
It has already been confirmed that it depends on L-4 production.
This result indicates that the compound of Example 1 suppressed the increase in blood IgE by suppressing the production of IL-4 in the living body of a mouse.

[Table 3]

Example 28 Effect of compound of Example 1 on TNCB-induced contact dermatitis Experimental method 1) Animals BALB / c was purchased from Charles River Japan, an 8-week-old female mouse, and spared for 14 days. 2) Sensitization Kitagaki et al.'S method (Kitagaki et al., J. Invest. Dermatol. 105 , 74)
9-755 (1995)). 1% on both sides of mouse right ear
The solution was sensitized by applying 10 μl of an acetone solution of 2,4,6-trinitrochlorobenzene (TNCB). From day 6 after the initial sensitization, application sensitization was repeated three times a week. 3) Method of measuring pinna thickening Hapten was applied to induce skin thickening, and 4, 24 and 48
The skin thickening after time was measured. Auricular thickening was expressed as (thickness of right ear applied)-(thickness of left ear without application). 4) Drug administration method 0.4 mg of the compound of Example 1 was dissolved in 20 μl of acetone, and applied to the right ear of the mouse on days 20, 21, 22, 23 and 24 after the initial sensitization. 5) Statistical processing method Dunnett's-test was performed using a SAS program.

Results [0097] The administration of the compound of Example 1 showed a tendency to suppress skin thickening 4, 24 and 48 hours after hapten application 20 days after the first sensitization, as compared with the control group. Hapten application on days 22, 24 and 4 after first sensitization
Skin thickening 8 hours later was suppressed with a significant difference (p <0.05). Chronic contact dermatitis induced by repeated application of TNCB is accompanied by an increase in IgE antibody titer and Th2 allergic inflammation on the skin from around 8 days after the first sensitization.
It has been reported that a type of immune response is induced and shows skin symptoms similar to chronic atopic dermatitis (Kitagaki et al.,
J. Invest. Dermatol. 105 , 749-755 (1995)). This result indicates that the compound of Example 1 acts transdermally and Th
This shows that type 2 immune response was suppressed and allergic inflammation was suppressed.

Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI A61K 31/505 ADU A61K 31/505 ADU ADY ADY ADZ ADZ AEA AEA AED AED C07D 405/12 239 C07D 405/12 239 (72) Inventor Kiyotaka Iwai 3-1-98 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Tanaka 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Ryu Nagata 3-98, Kasuganaka, Konohana-ku, Osaka-shi Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Ochi 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Takamasa Watanabe 3-1-198, Kasuganaka, Konohana-ku, Osaka-shi Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Kazuji Fujita 3-1-198, Kasuganaka, Konohana-ku, Osaka-Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hajime Kawakami 3-1-198 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. Within the company

Claims (2)

[Claims] (1) Formula (1) (Wherein ring A is a cycloalkane having 3 to 10 carbon atoms,
Represents a cycloalkene having 5 to 10 carbon atoms, a substituted cycloalkane, a bicycloalkane having 7 to 10 carbon atoms, a substituted bicycloalkane, or a heterocyclic ring containing oxygen or a sulfur atom as a hetero atom; May be bonded to an oxygen atom to form sulfinyl or sulfonyl. R ¹ is a lower alkyl group having 1 to 6 carbon atoms, a lower alkenyl group having 2 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, A cycloalkylalkyl group or OR ⁶ (R ⁶ is a lower alkyl group having 1 to 6 carbon atoms,
A lower alkenyl group having 3 to 6 carbon atoms, a lower alkynyl group having 3 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a cycloalkylalkyl group having 4 to 10 carbon atoms. R ² represents a hydrogen atom, an alkoxy group or a halogen atom; R ³ represents a hydrogen atom, an alkoxy group or a halogen atom; R ⁴ represents a hydrogen atom, an alkoxy group or a halogen atom;
⁵ represents a hydrogen atom, an alkoxy group or a halogen atom. And a salt thereof. 2. An immunomodulator comprising the quinazoline derivative according to claim 1 or a salt thereof as an active ingredient, which suppresses an immune response on a type 2 helper T cell side and enhances an immune response on a type 1 helper T cell side.