JP2000281660A - Quinazoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new quinazoline derivative which has an IgE production- inhibiting action or IgE secretion-inhibiting action, and a proteoglycan production-promoting action in chondrocytes and is useful as an allergic disease treating medicine and a chondrocyte disease treating medicine. SOLUTION: A compound of formula I [G is methane or N; R1, R2 re each H, a (substituted) alkyl, a (substituted) alkenyl, a halogen, nitro or the like; R3, R4 are each H, a (substituted) alkyl, a (substituted) aryl or the like, or R3 and R4 form together with N to form a (substituted) cyclic amine; R5 is a (substituted) alkyl, a (substituted) alkenyl, (substituted) carbomoyl or the like], for example a compound of formula II. The compound of formula I can be produced, for example, by a method comprising reacting (A) a compound of formula III with (B) a compound of formula IV in an amount of 1 to 2 equivalents, more preferably 1 to 1.5 equivalents, based on the component A in the presence of (C) a base (for example, K2CO3) in (D) a solvent (for example, butanol) in the range from 0 deg.C to the boiling point of the component D.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a quinazoline derivative useful as a therapeutic agent for allergic diseases, a therapeutic agent for cartilage disorders and the like.

[0002]

2. Description of the Related Art Allergic diseases such as atopic asthma, conjunctivitis, allergic rhinitis, atopic dermatitis, food allergy, hypersensitivity to IgE, irritability, and anaphylaxis are caused by specific IgE binding to antigens and mast cell surface. Is caused by release of various chemical mediators (histamine, prostaglandin, leukotriene, thromboxane, platelet activating factor, etc.) from mast cells. Antihistamines, bronchodilators,
Although steroids and the like have been used as therapeutics for allergic diseases, they cannot be said to always treat patients sufficiently because they are not sufficiently effective or have side effects. Although immunosuppressive agents have been tried as therapeutic agents for autoimmune diseases and hypersensitivity, side effects are problematic in suppressing other necessary immune reactions, and the range of application is limited. As a causative therapeutic agent, a therapeutic agent that suppresses the release step of a chemical mediator (sodium cromoglycate, tranilast, ketotifen, azelastine, etc.) and a therapeutic agent that inhibits IgE production before the release step of the chemical mediator (IPD, etc.) Are used, but their strength is not sufficient.

[0003] Cartilage is a connective tissue composed of chondrocytes and a matrix surrounding the chondrocytes, joints, intervertebral discs of the spine, costal cartilage, auricles,
Present in the ear canal, pubic symphysis, and epiglottis. Cartilage consists of chondrocytes and cartilage matrix produced by chondrocytes, and depending on the mixing ratio of cartilage matrix components, hyaline cartilage (articular cartilage, costal cartilage, throat cartilage, etc.), fibrocartilage (disc cartilage, pubic cartilage, meniscus) ) And elastic cartilage (such as auricular cartilage). The main components of the cartilage matrix are collagen (type II, type IX, etc.) in addition to proteoglycan. It is known that proteoglycans are involved in the swelling characteristic of cartilage tissue (that is, strength against compressive force), and collagen fibers are involved in the rigidity of cartilage against tension and shear force. Aggrecan is 9 of the proteoglycans in the cartilage matrix.
Glucosaminoglycan chains such as chondroitin sulfate and keratan sulfate chains bind to core protein cartilage having a molecular weight of about 220,000 to form macromolecules (molecular weight reaches several million). Many water molecules are hydrated between the glucosaminoglycan chains (in the case of aggrecan, 1
This is thought to contribute to the swellability described above (The Bone 8, 4 , 1994). As described above, cartilage has an important function in maintaining the function of a living body, and various diseases caused by cartilage disorders have been known from the past. For example, chondrogenesis including osteoarthritis has been known. Examples include abnormal diseases, osteoarthritic intervertebral disc disease, and incomplete repair / healing of fractures. Various treatments have been tried in the past to treat cartilage disorders, but they are not aimed at directly eliminating the cause, for example, by administering an anti-inflammatory agent and the like. It is only a symptomatic treatment, such as a method of suppressing a disorder such as pain due to a disease, or a method of injecting a hyaluronic acid preparation or the like into a joint to lubricate the movement of the joint.

[0004]

An object of the present invention is to provide a remedy for allergic diseases having few side effects and a remedy for cartilage disorders which can cure joint disorders radically.

[0005]

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 promotes the inhibitory action of IgE production or IgE secretion and the production of proteoglycan in chondrocytes. It has been found that it has an action and is effective as a therapeutic agent for allergic diseases and a therapeutic agent for cartilage disorders, and completed the present invention.

[0006] That is, the present invention is as follows. [1] Equation 1:

[Formula 2] [In the formula, G represents a methine or nitrogen atom. R ¹ and R ² independently represent a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxy, a halogen atom or nitro. R ³ and R ⁴ independently represent a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl or an optionally substituted heteroaryl. Or R ³ and R ^{4 taken} together with the nitrogen atom represent an optionally substituted cyclic amine. R
⁵ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, a substituted Represents an optionally substituted alkanoyl, an optionally substituted arylcarbonyl, an optionally substituted alkoxycarbonyl or an optionally substituted carbamoyl. Or a pharmaceutically acceptable salt thereof.

[2] The quinazoline derivative according to [1], wherein G is a nitrogen atom, or a pharmaceutically acceptable salt thereof. [3] The quinazoline derivative or the pharmaceutically acceptable salt thereof according to [1] or [2], wherein R ¹ and R ² are independently a hydrogen atom or alkoxy. [4] R ³ and R ⁴ are both hydrogen atoms, and R ⁵ is-
The quinazoline derivative or the pharmaceutically acceptable salt thereof according to any one of [1] to [3], which is CH ₂ -R ⁶ . (R ⁶ represents substituted phenyl.) [5] [1] wherein R ³ is a hydrogen atom, R ⁴ is phenethyl which may be substituted, and R ⁵ is-(CH ₂ ) _n -R ^7. ] The quinazoline derivative according to any one of [3] or a pharmaceutically acceptable salt thereof. (N represents 1, 2 or 3. R ⁷ represents phenyl which may be substituted.) [6] An IgE production inhibitor containing the compound according to any one of [1] to [5], or I
gE secretion inhibitor. [7] An allergic disease therapeutic agent comprising the compound according to any one of [1] to [5]. [8] A proteoglycan production promoter containing the compound according to any one of [1] to [5]. [9] A therapeutic agent for cartilage disorders containing the compound according to any one of [1] to [5]. [10] A therapeutic agent for osteoarthritis comprising the compound according to any one of [1] to [5].

[0008] Examples of "alkyl" include straight-chain or branched alkyl having 1 to 6 carbon atoms, and specifically, for example, methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl, 2-methylpropyl, 1,
1-dimethylethyl, pentyl, hexyl and the like. Examples of “alkenyl” include straight-chain or branched alkenyl having 2 to 6 carbon atoms, specifically, vinyl, allyl, 2-butenyl, 3-butenyl, 3-pentenyl, 5-hexenyl and the like. Can be “Alkynyl” includes, for example, straight-chain or branched C 2-6
And specific examples include ethynyl, propargyl, 2-butynyl, 4-pentynyl, 3-hexynyl and the like. “Alkoxy” includes, for example, straight-chain or branched alkoxy having 1 to 6 carbon atoms. Specifically, methoxy, ethoxy, propoxy, 1-
Methylethyl, butoxy, 1,1-dimethylethoxy,
Pentoxy, hexoxy and the like. Examples of the “alkoxycarbonyl” include straight-chain or branched alkoxycarbonyl having 1 to 6 carbon atoms, and specific examples include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, hexyloxycarbonyl and the like. As "alkanoyl",
For example, straight-chain or branched alkanoyl having 1 to 6 carbon atoms may be mentioned, and specific examples include formyl, acetyl, propanoyl and pivaloyl.

[0009] The "substituent" in the substituted alkyl, substituted alkenyl, substituted alkynyl, substituted alkoxy, substituted alkoxycarbonyl and substituted alkanoyl includes, for example, alkoxy, halogen atom, cyano, nitro, hydroxyl group,
Alkanoyl, alkoxycarbonyl, carboxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl, alkylthio,
Alkylsulfinyl, alkylsulfonyl, optionally substituted cycloalkyl, optionally substituted cycloalkyloxy, optionally substituted cycloalkylcarbonyl, optionally substituted aryl, optionally substituted arylcarbonyl, substituted Aryloxy, optionally substituted arylthio, optionally substituted arylamino, optionally substituted heterocyclic group and the like. One or more of these can be independently substituted.

[0010] "Cycloalkyl" includes, for example, carbon atoms of 3
To 7, and specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. "Heterocyclic groups" include heteroaryl and aliphatic heterocyclic groups. Examples of the aliphatic heterocyclic group include an aliphatic heterocyclic group containing 1 or 2 hetero atoms selected from 6 or less carbon atoms and nitrogen atoms, an oxygen atom and a sulfur atom, and 10 or less carbon atoms and nitrogen An aliphatic heterocyclic group containing 1 to 2 hetero atoms selected from an atom, an oxygen atom and a sulfur atom and having a benzene ring fused thereto, specifically, piperidyl, piperazinyl, morpholinyl, tetrahydropyranyl, tetrahydrofuranyl , Pyrrolidinyl, dithianyl, indolyl, isoindolyl, tetrahydro-1
-Quinolinyl and the like. Further, the heterocyclic group includes
Mono- or bicyclic cyclic imides such as phthalimide and tetrahydrophthalimide are also included as suitable groups.

[0011] The "substituent" in the substituted cycloalkyl and the substituted heterocyclic group includes, for example, alkyl, alkenyl, alkynyl, alkoxy, halogen atom, cyano,
Nitro, hydroxyl, alkanoyl, alkoxycarbonyl, carboxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkyl, cycloalkyloxy, aryl, aryl Oxy, heterocyclic group, arylalkyl and the like can be mentioned, and a benzene ring can also be condensed. One or more of these can be independently substituted.

As the “cyclic amine”, for example, azetidine,
Examples thereof include a 3- to 7-membered cyclic amine such as pyrrolidine and piperidine, and a 5- to 7-membered cyclic amine containing another hetero atom such as an oxygen atom or a nitrogen atom such as piperazine and morpholine. "Substituent" in substituted cyclic amines
Are, for example, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, halogen atom, cyano, nitro, hydroxyl group, optionally substituted alkanoyl, substituted Optionally substituted alkoxycarbonyl, carboxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cycloalkyl, cycloalkyloxy, aryl, aryloxy, hetero And a benzene ring can be condensed. One or more of these can be independently substituted.

The "aryl" includes, for example, aryl having 10 or less carbon atoms, and specifically includes phenyl, 1-naphthyl, 2-naphthyl and the like. "Heteroaryl" includes, for example, 5-6 containing up to 4 nitrogen atoms.
Membered heteroaryls, containing up to 2 nitrogen atoms and up to 1 oxygen atom, and / or up to 1 sulfur atom
And a 6- or 6-membered heteroaryl, a benzene-ring-condensed 5- or 6-membered heteroaryl containing up to 3 nitrogen atoms and up to 1 oxygen atom, and / or up to 1 sulfur atom. Is pyridyl, thienyl, oxadiazolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, tetrazolyl, furyl,
Examples include pyrrolyl and benzotriazole.

The “substituent” in the substituted aryl and the substituted heteroaryl includes, for example, alkyl, alkenyl,
Alkynyl, alkoxy, halogen atom, cyano, nitro, hydroxyl group, alkanoyl, alkoxycarbonyl, carboxy, optionally substituted amino, optionally substituted carbamoyl, optionally substituted sulfamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl, cyclo Examples include alkyl, cycloalkyloxy, aryl, aryloxy, heterocyclic groups, arylalkyl and the like. One or more of these can be independently substituted.

The "substituent" of the substituted carbamoyl and the substituted sulfamoyl includes, for example, alkyl, aryl, arylalkyl and the like, and one or two of them can be independently substituted. As the “substituent” of the substituted amine, for example, alkyl, aryl, arylalkyl, alkanoyl and the like can be mentioned, and one or two can be independently substituted. As the halogen atom, for example, a fluorine atom,
Examples thereof include a chlorine atom, a bromine atom and an iodine atom, and preferably include a chlorine atom and a bromine atom.

The pharmaceutically acceptable salts of the present quinazoline derivatives include, for example, salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid, and acetic acid, oxalic acid, citric acid, lactic acid, tartaric acid, malonate Acid, fumaric acid, maleic acid, salts with organic acids such as methanesulfonic acid, lithium salt, sodium salt,
Inorganic metal salts such as potassium salts, magnesium salts, aluminum salts and barium salts, and organic base salts such as ammonium salts, triethylammonium salts, tetrabutylammonium salts, pyridinium salts, pyrrolidinium salts, piperidinium salts and the like. The present invention also includes solvates such as hydrates of the quinazoline derivative or a pharmaceutically acceptable salt thereof.

[0017] The IgE production inhibitor or secretion inhibitor of the present invention can be administered orally or parenterally. I.e. commonly used dosage forms, such as tablets, capsules,
It can be administered orally in the form of a syrup, suspension or the like. Alternatively, solutions in the form of solutions, emulsions, suspensions and the like can be parenterally administered as injections.
It can also be administered rectally parenterally in the form of suppositories. Such a dosage form can be produced according to a general method by blending the active ingredient with a usual carrier, excipient, binder, stabilizer and the like. When used in the form of an injection, a buffer, a solubilizing agent, an isotonic agent and the like can be added.

The quinazoline derivative of the formula 1 can be produced, for example, by the following method. Manufacturing method 1

Embedded image [Wherein, G, R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined above. X represents a chlorine atom, a bromine atom or an iodine atom. The quinazoline derivative of the formula 1 can be produced by reacting the compound (2) with the compound (3) in the presence of a base. The amount of compound (3) to be used is, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (2). As the base, for example, K ₂ CO ₃ , Na ₂ CO _{3
For example,} alkali carbonates such as ₃ ; alkali hydroxides such as NaOH; and amines such as triethylamine can be used. The amount of the base to be used is, for example, 1 to 5 equivalents relative to compound (2). Examples of the reaction solvent include alcohol solvents such as butanol, 2-propanol, ethanol, and methanol, and DMF. The reaction temperature is, for example, in the range of 0 ° C to the boiling point of the solvent. In the case of compound (3) wherein X is a chlorine atom or a bromine atom,
It is also preferable to add an alkali iodide such as NaI.

Manufacturing method 2

[Formula 4] [Wherein, G, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X are as defined above. The quinazoline derivative of the formula 1 can be produced by reacting the compound (4) with the compound (5) in the presence of a base in the same manner as in Production Method 1.

[0020] Manufacturing method 3

[Formula 5] [Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ and X have the same meanings as described above. A quinazoline derivative of the formula 1 wherein G is a nitrogen atom (1a)
Are compound (6) and compound (7) in the same manner as in Production Method 1.
Can be produced by reacting in the presence of a base.

Manufacturing method 4

[Formula 6] [Wherein, R ¹ , R ² , R ³ and R ⁴ are as defined above. R ⁸ represents an optionally substituted alkyl, an optionally substituted cycloalkyl, an optionally substituted aryl or an optionally substituted heterocyclic group. The quinazoline derivative (1b: a quinazoline derivative of the formula 1 wherein R ⁵ is optionally substituted alkyl) is a compound (6)
And compound (8) to a reductive alkylation reaction. Examples of the reducing agent include those usually used in a reductive alkylation reaction, for example, NaBH ₃ CN, hydrogen / catalyst and the like. In this reaction,
The reaction is preferably performed in the presence of an acid such as acetic acid and a dehydrating agent such as Molecular Sieves (registered trademark). The amount of compound (8) to be used is, for example, 1 to 2 equivalents, preferably 1 to 1.5 equivalents, relative to compound (6). Examples of the reaction solvent include alcohols such as butanol, 2-propanol, ethanol, and methanol. The reaction temperature is, for example, in the range of 0 ° C to the boiling point of the solvent.

Production method 5

Embedded image [Wherein, R ¹ , R ² , R ³ , R ⁴ and R ⁸ are as defined above. The quinazoline derivative (10: a quinazoline derivative of the formula 1 wherein R ⁵ is an optionally substituted alkanoyl or an optionally substituted arylcarbonyl) is produced by condensing compound (6) with compound (9). Can be. In the present condensation reaction, conditions used in a general amidation reaction can be used. For example, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSC
HCl), dicyclohexylcarbodiimide (DC
A method using a condensing agent such as C) and a method using an acid halide to react. In a reaction using a condensing agent, it is preferable to add 1-hydroxy-benzotriazole monohydrate (HOBt) or the like as a reaction assistant. Also, a base such as triethylamine can be added. The amount of the condensing agent to be used is, for example, in the range of 1 to 2 equivalents to the compound (6) derivative.
The quinazoline derivative (1b) is a quinazoline derivative (1b).
0) can be produced by reduction. Examples of the reducing agent include LiAlH ₄ and LiAlH (OCH ₃ ) ₃ .
The amount of the reducing agent used is, for example, a quinazoline derivative (1
The range of 1 to 6 equivalents to 0) is exemplified. Examples of the reaction solvent include ethers such as diethyl ether and THF. The reaction temperature is, for example, in the range of 0 ° C to the boiling point of the solvent.

In the above reaction, the functional group can be protected and deprotected as required (“Protective Groups”).
in Organic Syntheses ”TW Greene and PGMW
uts, 1990). After the above reaction, the functional group can be converted if necessary. Each compound can be purified by a usual method, for example, column chromatography, recrystallization and the like.

[0024] The compound of the present invention, a therapeutic agent and an enhancer are
It has an E production inhibitory action or an IgE secretion inhibitory action. Accordingly, the compounds, therapeutics and inhibitors of the present invention may comprise IgE
It is effective for the treatment and prevention of various allergic diseases caused by production or IgE secretion, and these include, for example, the following diseases. Atopic asthma conjunctivitis allergic rhinitis atopic dermatitis food allergy IgE excess syndrome hypersensitivity anaphylaxis

The compounds, therapeutic agents and promoters of the present invention have the effect of promoting the production of proteoglycans in chondrocytes.
Therefore, the compounds, therapeutic agents and promoters of the present invention are effective for treating and preventing various diseases caused by cartilage disorders, and include, for example, the following diseases. Osteoarthritis Rheumatoid arthritis Osteoarthritis Intervertebral disc herniation Chondrodysplasia Healing and repair of fractures Repair of articular cartilage and articular disc by trauma Acute suppurative arthritis Tuberculous arthritis Syphilitic arthritis Rheumatic fever, Systemic lupus erythematosus Bone transplant Repair by

The compounds, therapeutic agents and promoters of the present invention can be used in mammals (eg, cows, horses, pigs, sheep,
It is applied to the treatment and prevention of various diseases caused by cartilage disorders in dogs, cats and the like.

The compound of the present invention, the therapeutic agent and the accelerator can be in various preparation forms (for example, liquid preparation, solid preparation, capsule preparation, etc.). Oral preparations, injections, inhalants, or suppositories together with carriers. Oral drugs include, for example, tablets, granules, fine granules, powders, soft or hard capsules, solutions, emulsions,
They are formulated into dosage forms such as suspensions and syrups, and these formulations can be prepared according to the usual methods of formulation. Injectables can be prepared by a conventional method. For example, after dissolving the present compound in an appropriate solvent (eg, sterilized water, buffer, physiological saline, etc.), the solution is sterilized by filtration through a filter or the like. And then filling into sterile containers. Suppositories can be prepared by a conventional method using a conventional base (for example, cacao butter, laurin butter, glycerogelatin, macrogol, witepsol, etc.). Inhalants can be prepared according to conventional methods for preparation. The content of the present compound in the preparation can be appropriately adjusted depending on the dosage form, applicable disease and the like.

At the time of formulation, a stabilizer is preferably added. Examples of the stabilizer include albumin, globulin, gelatin, glycine, mannitol, glucose, and the like.
Dextran, sorbitol, ethylene glycol and the like can be mentioned. Further, the preparation of the present invention may contain additives necessary for preparation, for example, excipients, solubilizing agents, antioxidants, soothing agents, isotonic agents and the like. In the case of a liquid preparation, it is desirable to preserve by freezing or freeze-drying to remove water. The lyophilized preparation is used after reconstitution by adding distilled water for injection or the like at the time of use.

[0029] The compound of the present invention, therapeutic agent and promoter can be administered by an appropriate administration route depending on the form of the preparation.
For example, it can be administered in the form of an injection to vein, artery, subcutaneous, intramuscular, and the like. The dose of the present compound is appropriately adjusted depending on the condition, age, body weight, etc. of the patient, but is usually 0.05 mg to 500 mg, preferably 1 mg to 100 mg, which is administered once or several times a day. Is appropriate.

[0030]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Embodiment 1

[Formula 8] 2-chloro-4-amino-6,7-dimethoxyquinazoline 2.4 g (0.01 mol), 1- (3,4- difluorophenyl) piperazine 2.1 g (0.011 mol) and K ₂ CO ₃ 1.5g (0.011
mol) was added to 24 mL of butanol, heated under reflux for 35 hours, further added with 1.5 g (0.011 mol) of K ₂ CO ₃ , and heated under reflux for 12 hours. Water was added to the reaction solution, extracted with ethyl acetate, dried over MgSO ₄ , concentrated, and diethyl ether was added to crystallize. The obtained crystals were dissolved in 50 mL of methanol, and 3.2M HCl /
5.8 mL of 2-propanol was added, and 3.1 g of the target compound was obtained as crystals from diethyl ether. ¹ H NMR (DMSO-d ₆ , free base) δ 7.53 (1H, s), 7.01-7.4
3 (4H, m), 6.76-6.80 (2H, m), 3.80-3.87 (10H, m),
3.16 (4H, m)

Embodiment 2

[Formula 9] 1.0 g (2.95 mM) of 4-chloro-2- (4-benzylpiperazinyl) -quinazoline and 358 mg of β-phenethylamine
Was added to 10 mL of butanol, and the mixture was heated under reflux for 1 hour. By adding 10 mL of 2-propanol to the reaction solution and cooling,
1.11 g of the desired compound were obtained as crystals. ¹ H NMR (CDCl ₃ , free base) δ 7.21-7.52 (13H, m), 6.9
8-7.04 (1H, m), 5.52 (1H, brs), 3.95 (4H, t-like),
3.82 (2H, q, J = 6.9 Hz), 3.56 (2H, s), 2.98 (2H, t,
J = 6.9 Hz), 2.54 (4H, t-like)

Embodiment 3

[Formula 10] 4-amino-2-piperazinyl-quinazoline 2.9 g (0.0
1 mol), 2-picolyl chloride hydrochloride 2.O g (0.012 m
ol) and K ₂ C0 ₃ 3.4 g of (0.01 mol) was added to DMF Loo mL, about 10
Stirred at 0 ° C. for 6 hours. Water was added to the reaction solution, extracted with ethyl acetate and dichloromethane, washed with saturated saline, and
The extract was dried over SO ₄ , concentrated, and purified by silica gel column chromatography (dichloromethane: methanol: 29% aqueous ammonia = 500: 25: 2). The obtained compound was dissolved in 100 mL of 2-propanol, added with 16 mL of 1.31 M HCl / 2-propanol, and crystallized from diethyl ether to obtain 2.4 g of the desired compound. ¹ H NMR (CDCl ₃ , free base) δ 8.58 (1H, d, J = 5Hz), 7.
68 (1H, t, J = 8Hz), 7.46 (1H, d, J = 8 Hz), 7.19 (1H,
t, J = 5Hz), 6.91 (1H, s), 6.78 (1H, s), 5.15 (2H, b
rs), 3.96 (3H, s), 3.91 (3H, s), 3.88 (4H, t, J = 5H
z), 3.71 (2H, s), 2.59 (4H, t, J = 5Hz) Melting point: 246 ° C (decomposition)

Embodiment 4

[Formula 11] 2.9 g (0.01 mol) of 4-amino-2-piperazinyl-6,7-dimethoxyquinazoline and 2.2 g of betraraldehyde
(0.013 mol) in 100 mL of methanol and 1.1 g of acetic acid
(0.02 mol) and 4 g of Molecular Sieves 3A (registered trademark) were added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was added with NaBH ₃ CN l.3 g (0.02 mol) under ice cooling, and the mixture was stirred for 5 hours.
Stirred at room temperature for 10 hours. The reaction mixture was concentrated, saturated aqueous sodium hydrogen carbonate was added, extracted with ethyl acetate, washed with water, dried over MgSO ₄ , concentrated, and silica gel column chromatography (CHCl ₃ → CHCl ₃ : methanol: 29% aqueous ammonia = Ten
0: 5: 0.4). The obtained compound was dissolved in methanol, and 19 mL of 2.1 M HCl / 2-propanol was added.
From diethyl ether, 3.1 g of the desired compound was obtained as crystals. ¹ H NMR (CDCl ₃ , free base) δ 6.84-6.98 (5H, m), 5.70
(2H, brs), 3.82-3.96 (16H, m), 3.51 (2H, s), 2.53-
2.55 (4H, m) Melting point: 271 ℃ (decomposition)

Embodiment 5

Embedded image 2.9 g (0.01 mol) of 4-amino-2-piperazinyl-6,7-dimethoxyquinazoline, 2.1 g (0.012 M) of 3,4-difluorophenylacetic acid, 2.6 g (0.015 mol) of WSCHCl and HOB
t l.8 g (0.012 mol) was added to DMF (29 mL), and the mixture was stirred at room temperature for 9 hours. Brine was added to the reaction solution, extracted with ethyl acetate, washed with brine, dried over MgSO ₄ and concentrated to give 4.39 g of the free form. Dissolve 1.0 g of the free form in 200 mL of methanol and add 3.2 M HCl / 2-propanol 2.1
Add 0.93 g of the desired compound from diethyl ether.
Was obtained as crystals. ¹ H NMR (CDCl ₃ , free base) δ 7.06-7.16 (2H, m), 6.97
-6.99 (1H, m), 6.90 (1H, s), 6.79 (1H, s), 5.18 (2
H, brs), 3.97 (3H, s), 3.93 (3H, s), 3.80-3.88 (2
H, m), 3.66-3.80 (6H, m), 3.47-3.58 (2H, m) Melting point: 245 ° C (decomposition)

Embodiment 6

Embedded image LiAlH ₄ O.4 g (0.0106 mol) was added to THF 20 mL, a THF solution (50 mL) of the compound of Example 5 (2.2 g, 0.0053 mol) was added dropwise at room temperature, and the mixture was heated under reflux for 10 hours. After cooling to room temperature, water 2.4
mL and a 25% K0H aqueous solution (0.4 mL) were added, stirred for 1 hour, filtered using Celite (registered trademark), the filtrate was concentrated, and silica gel column chromatography (CHCl ₃ : methanol: 29% aqueous ammonia = 100: Purification by 5: 0.4) gave 1.0 g of the desired compound. ¹ H NMR (CDCl ₃ , free base) δ 7.00-7.08 (2H, m), 6.92
(2H, m), 6.78 (1H, m), 5.12 (2H, brs), 3.97 (3H,
s), 3.93 (3H, s), 3.88 (4H, t, J = 5 Hz), 2.80-2.84
(2H, m), 2.56-2.64 (6H, m)

The following compounds were produced in the same manner as in Examples 1 to 6.

Embodiment 7

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Embodiment 8

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Embodiment 9

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Embodiment 10

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Embodiment 11

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Embodiment 12

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Embodiment 13

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Embodiment 14

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Embodiment 15

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Embodiment 16

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Test Example 1Primary response IgE production suppression test  Remove spleen cells from BALB / c mice (female, 6 weeks old)
B cells were obtained by anti-Thy 1.2 antibody and complement treatment. 10% calf
Polysaccharide (4 mg / ml) was added to RPMI-1640 medium supplemented with baby serum.
mL) and add (2.5 x 10^Five cells / mL), 37 ° C, 5% CO_TwoI
The cells were cultured in an incubator. On the first day after starting the culture, IL-4
(500 U / ml), followed by culturing for 7 days. End of culture
Thereafter, IgE in the culture supernatant was measured by ELISA. That is,
Hirano et al. (Int. Archs. Allergy Appl. Immun., Vol. 85,
Page 47, 1988).
Sandwich with noclonal antibodies 6HD5 and HMK12
The amount of IgE antibody produced was quantified by the method.

[0049]

[Table 1] Compound inhibitory rate (%) (drug concentration: 10 μM) Example 3 46 Example 4 68 Example 7 (11) 67 Example 8 (13) 81 Example 8 (15) 89

Test Example 2Secondary response IgE production suppression test  BALB / c mice (female, 8 weeks old) were reared for 1 week
Later, sensitization was performed. For sensitization, mice received 10 mg of DNP-KLH
Intraperitoneal administration with lum 3 mg, Bordetella pertussis t
It was sensitized by intradermally administering 0.1 mg of oxin. Three weeks later, DNP-KL
The rats were sensitized again by intraperitoneal administration of 2 mg of H and 2 mg of alum.
Four weeks after the final sensitization, the spleen was excised and cells were prepared. 6
 x 10⁶ Adjust the cells adjusted to cells / mL to a concentration of 10 ng / mL in DNP.
-Cultured in a 24-well plate in the presence of KLH (1 mL / wel
l). DNP-KLH is a solvent BBS (borate buffered saline)
After dilution, the medium was used (final concentration of BBS 1.67%). Culture 2
One day later, the cells were collected, washed, and resuspended in RPMI-FCS. 96
Dwell in well plate and add 4 days in the absence of DNP-KLH
Cultured. DMSO and compounds are antigen-free on day 2 of culture
Added below. Compound, n = 4, DMSO and no DMSO added
Wells were n = 8 or 12. After the culture is completed, use the ELISA method.
The amount of antigen-specific IgE and the number of viable cells by the MTT method.
Was.

[0051]

[Table 2] Compound inhibitory rate (%) (drug concentration: 10 μM) Example 2 86 Example 9 (7) 91 Example 14 ( 14) 81 Example 14 (20) 80

Test Example 3Proteoglycan production promotion test  Materials and methodsCells and cell culture  Chondrocytes are described in the literature (Calcif.Tissue Res.19, 1975)
The method described above was changed slightly, and the ribs of a 3-week-old Japanese white rabbit were
Growth plate chondrocytes were isolated from cartilage. In this way,
The released chondrocytes were 10% FBS, penicillin 50 U / m
L, DMEM / F-1 containing 50 μg / mL streptomycin
37 ° C, 5% CO2 in a bi-equivalent mixed medium (hereinafter referred to as medium A)_Two/
Maintained under 95% air.

[0053]Measurement of proteoglycan synthesis  For chondrocytes, use 6mm wells (collagen-coated 96-well plate)
G) 2 × 10^FourSeeded at a density of 0.15 ml and maintained in 0.15 mL of medium A.
I carried it. The next day, in 0.15 mL of Medium A containing 0.3% BSA
Replaced and pre-incubated for 24 hours. afterwards,
0.3% BSA and the above compound (concentration in culture solution is 1, 3, 1
0, 30 μM) for 24 hours in 0.1 mL of Medium A
I did. 5 μl of 100 μCi / mL [³⁵S] -sulfuric acid
20 hours before the end of the reaction. End of incubation
After that, 10 μL per well of a 96-well plate where cell culture was performed
Aqueous solution (0.2mg / mL chondroitin sulfate, 25mM MgSO_Four 
And 15 μL of 33% aqueous sodium acetate solution
And stirred. 8 per well from a 96-well plate after stirring
Transfer 0 μL to another assay plate and add 140 μL of 99.5%
Add ethanol, stir and leave at -20 ° C for 30 minutes.
Was. Transfer the suspension in the assay plate to the microcell harvester.
Glass fiber filter (WAL) with Star (SKATRON)
LAC) and trap it for liquid scintillation.
After infiltration into the cowl using a 1205 beta plate (WALLAC)
(Biochimica et Biophysica Acta,96
9, 1988). ED₅₀Is the TGF-β of each plate
(1ng / mL) count is 100%, count of no additive group is 0%
The dose of the sample corresponding to 50% (molarity: μ
M).

[0054]

[Table 3] Compound ED₅₀  ――――――――――――― Example 7 (16) 2.69 Example 8 (6) 15.2 Example 9 (20) 9.24 Example 12 (9) 6.4

[0055]

Industrial Applicability According to the present invention, a quinazoline derivative useful as a therapeutic agent for allergic diseases, a therapeutic agent for cartilage disorders and the like can be provided.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61K 31/517 A61K 31/505 605 C07D 401/04 C07D 401/04 (72) Inventor Ayumu Kurimoto Konohana, Osaka City 3-1-98, Kasuganaka-ku, Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Hiroshi Tanaka 3-1-198, Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Yutaka Okumura Osaka Sumitomo Pharmaceutical Co., Ltd. 2-2-2 Doshu-cho, Chuo-ku, Tokyo (72) Inventor Naoko Omi 4-2-1 Takashi Takarazuka-shi, Hyogo Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Ikuko Harada Osaka-shi Chuo Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Kanji Hashimoto 3-2-1 Kasuganaka, Konohana-ku, Osaka Sumitomo Pharmaceutical Co., Ltd. (72) Inventor Kawakami Hajime 3F 1-98, Kasuganaka, Konohana-ku, Osaka-shi F-term (reference) in Sumitomo Pharmaceutical Co., Ltd. 4C063 AA01 AA03 BB02 BB09 CC31 CC82 DD10 DD12 DD31 EE01 4C086 AA01 AA02 AA03 BC46 BC50 GA02 GA07 GA08 GA12 MA01 MA04 NA14 ZA33 ZA34 ZA59 ZA66 ZA96 ZB13 ZB15 ZC02 ZC41

Claims (10)

[Claims] [Claim 1] Formula: [In the formula, G represents a methine or nitrogen atom. R ¹ and R ² independently represent a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted alkoxy, a halogen atom or nitro. R ³ and R ⁴ independently represent a hydrogen atom, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted aryl or an optionally substituted heteroaryl. Or R ³ and R ^{4 taken} together with the nitrogen atom represent an optionally substituted cyclic amine. R
⁵ is an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heterocyclic group, a substituted Represents an optionally substituted alkanoyl, an optionally substituted arylcarbonyl, an optionally substituted alkoxycarbonyl or an optionally substituted carbamoyl. Or a pharmaceutically acceptable salt thereof. 2. The quinazoline derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein G is a nitrogen atom. 3. The quinazoline derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ and R ² are independently a hydrogen atom or alkoxy. 4. R ³ and R ⁴ are both hydrogen atoms;
⁵ is either quinazoline derivative or a pharmaceutically acceptable salt thereof according to claim 1 which is _-CH 2 -R ^6.
(R ⁶ represents substituted phenyl.) 5. R ³ is a hydrogen atom, R ⁴ is phenethyl which may be substituted, and R ⁵ is — (CH ₂ ) _n —R ⁷
The quinazoline derivative according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof. (N represents 1, 2 or 3. R ⁷ represents phenyl which may be substituted.) 6. An IgE production inhibitor or an IgE secretion inhibitor comprising the compound according to any one of claims 1 to 5. A therapeutic agent for an allergic disease, comprising the compound according to any one of claims 1 to 5. A proteoglycan production promoter containing the compound according to any one of claims 1 to 5. A therapeutic agent for cartilage disorders comprising the compound according to any one of claims 1 to 5. A therapeutic agent for osteoarthritis, comprising the compound according to any one of claims 1 to 5.