JP2006104195A - Pyrimidine derivative and medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new pyrimidine derivative having excellent c-kit tyrosine kinase-inhibiting activity or its pharmaceutically acceptable salt. <P>SOLUTION: The present invention provides a (5-pyrimidinyl)pyrimidine derivative having a specific structure or its pharmaceutically acceptable salt and a medicinal composition containing the derivative or its pharmaceutically acceptable salt as an active ingredient. The compound is useful as a c-kit tyrosine kinase inhibitor. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a pyrimidine derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing it as an active ingredient.

  c-kit tyrosine kinase is the same type III receptor tyrosine kinase as platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), etc., and SCF (stem cell factor) as a specific ligand thereof. Has been identified (for example, see Non-Patent Document 1). Moreover, c-kit tyrosine kinase is highly expressed in hematopoietic stem cells, hematopoietic progenitor cells, mast cells, melanocytes, germ cells, Cajal intervening cells, etc., and plays an important role in their differentiation, proliferation, and survival ( For example, refer nonpatent literatures 2-4.).

  Mast cells in which c-kit tyrosine kinase is highly expressed are derived from pluripotent hematopoietic stem cells (see, for example, Non-Patent Documents 5 to 6), enter the bloodstream from the bone marrow undifferentiated, and local tissues Then, the cells become mature mast cells by proliferating and differentiating (see, for example, Non-Patent Documents 7 to 8). c-kit tyrosine kinase is an essential factor for this proliferation and differentiation (for example, refer nonpatent literature 9).

  In addition, mast cells induce immediate allergic reactions by releasing histamine and tryptase by degranulation and by releasing and producing leukotrienes and PGD2 by lipid metabolism. In addition, mast cells induce late-phase allergic reactions by producing Th2-type cytokines, chemokines such as MIP-1α and MCP-1 (see, for example, Non-Patent Documents 10 to 11), and inflammation. Leads to the formation of chronic or fibrotic lesions (see, for example, Non-Patent Documents 12 to 14).

  Therefore, by inhibiting c-kit tyrosine kinase, diseases involving mast cells such as asthma, rhinitis, sinusitis, anaphylaxis, urticaria, angioedema, contact dermatitis, atopic dermatitis (eg , Refer to Patent Documents 1 and 2), arthritis such as rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, osteoarthritis, gouty arthritis (for example, refer to Patent Documents 3 to 5), interstitial cystitis ( For example, it is useful for prevention or treatment of various inflammatory diseases represented by autoimmune diseases such as ulcerative colitis and Crohn's disease (for example, see Patent Literature 4).

  On the other hand, c-kit tyrosine kinase is a small cell lung cancer (for example, refer nonpatent literature 15-17). Myeloid leukemia (for example, see non-patent document 18), neurocytoma (for example, see non-patent document 19 and patent document 7), breast cancer (for example, see non-patent document 20), colon cancer (for example, non-patent document) Patent Documents 21 to 22), cervical cancer (for example, see Non-patent Document 23), and ovarian cancer (for example, see Non-Patent Document 23) are highly expressed, and prevention or treatment of these cancers. Also useful.

  In addition, a c-kit positive gastrointestinal stromal tumor (GIST) is a mesenchymal tumor derived from a Cajal intervening cell, and has a c-kit tyrosine kinase function acquisition property (tyrosine kinase). Increased activity) mutation. Therefore, c-kit tyrosine kinase inhibitors are also useful for the prevention or treatment of the disease.

  Mast cytosis is a condition in which abnormal growth of mast cells is observed in the skin and various organs. In part, c-kit tyrosine kinase activation mutations induce constitutive mast cell proliferation. Since c-kit tyrosine kinase plays an important role in the pathogenesis of mast cytosis (see, for example, Patent Document 8), c-kit tyrosine kinase inhibitors are useful for the prevention or treatment of the disease. is there.

  Gleevec (registered trademark) (see, for example, Patent Document 9) is a bcr-abl tyrosine kinase inhibitor containing a drug having the following structure as an active ingredient, and is marketed as a therapeutic agent for chronic myeloid leukemia and the like.

上記医薬は、ｂｃｒ−ａｂｌチロシンキナーゼ阻害作用の他、ｃ−ｋｉｔチロシンキナーゼ阻害作用も有しており、ｃ−ｋｉｔ陽性消化管間質腫瘍の治療にも用いられている。上述の通り、ｃ−ｋｉｔチロシンキナーゼ阻害剤は、ｃ−ｋｉｔ陽性消化管間質腫瘍だけでなく、種々の疾患に対しても有効な治療薬となり得ることから、より強力なｃ−ｋｉｔチロシンキナーゼ阻害作用を有する医薬の創製が切望されている。
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In addition to the bcr-abl tyrosine kinase inhibitory action, the medicament has a c-kit tyrosine kinase inhibitory action and is also used for the treatment of c-kit positive gastrointestinal stromal tumors. As described above, a c-kit tyrosine kinase inhibitor can be an effective therapeutic agent not only for c-kit positive gastrointestinal stromal tumors but also for various diseases. Creation of a medicine having an inhibitory action is eagerly desired.
International Publication No. 03/002106 Pamphlet International Publication No. 02/080925 Pamphlet International Publication No. 03/002108 Pamphlet International Publication No. 03/002109 Pamphlet International Publication No. 03/063844 Pamphlet International Publication No. 03/024386 Pamphlet International Publication No. 03/066059 Pamphlet International Publication No. 03/002114 Pamphlet JP-A-6-87834 International Publication No. 2004/002963 Pamphlet J. et al. Leukoc. Biol. 2000, 67, 135-148 Blood, 1992, 79, 338-346 Blood, 1992, 79, 365-371 J. et al. Exp. Med. 1991, 174, 63-71. Blood, 1999, 94, 2333-2342 Curr. Opin. Immunol. 1993, 5, 937-943. Nature, 1979, 281, 154-155. Nature, 1981, 291 and 159-160. Annu. Rev. Immunol. , 1989, 7, 59-76. Rom. J. et al. Intern. Med. , 1996, 34 (3-4), 159-72. Immunol. Cell Biol. 2001 Apr, 79 (2), 149-53. J. et al. Allergy Clin. Immunol. 1999 Oct, 104, 132-7. Allergy, 1997, 52 (36 Suppl), 7-13. Chem. Immunol. 1995, 62, 84-107. Oncogene, 1991, 6, 2291-2296 Clin. Cancer Res. 2000, 6, 3319-3326 Oncogene, 2000, 19, 3521-3528 Blood, 1992, 80, 1199-1206 Blood, 1994, 84, 3465-3472. Cell Growth Differ. 1995, 6, 769-779. Tumor Biol. , 1993, 14, 295-302. Cancer Res. , 2002, 62, 4879 Cancer Res. 1994, 54, 3049-3053. J. et al. Org. Chem. , 1996, 61, 1133-1135. J. et al. Org. Chem. 2000, 65, 1144-1157 J. et al. Med. Chem. 1975, 18, 1077-1088. J. et al. Org. Chem. , 2002, 67, 5394-5397 J. et al. Amer. Chem. Soc. , 1927, 1368-1373. Bioorg. Med. Chem. Lett. , 2001, 1112235-2239 J. et al. Heterocyclic Chem. 2000, 37, 1457-1462 J. et al. Org. Chem. , 1959, 24, 1261-1267

  An object of the present invention is mainly to provide a novel pyrimidine derivative useful as a pharmaceutical, specifically, a novel pyrimidine derivative having excellent c-kit tyrosine kinase inhibitory activity or a pharmaceutically acceptable salt thereof. is there.

  The present inventors diligently studied various compounds, and found that the following pyrimidine derivatives described below achieve the above object, thereby completing the present invention.

  That is, examples of the present invention include a pyrimidine derivative represented by the following general formula [1] or a pharmaceutically acceptable salt thereof (hereinafter referred to as the present compound).

Ａｒは、次の一般式［２］又は［３］のいずれかの基を表す。

Ar represents any group of the following general formula [2] or [3].

Ｒ^１は、アルキル、シクロアルキル又はアルケニルを表す。

R ¹ represents alkyl, cycloalkyl or alkenyl.

R ² represents alkyl or hydroxyalkyl.

  In addition, as the present invention, a pharmaceutical composition containing the pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient, and more specifically, a c-kit containing the pyrimidine derivative or a pharmaceutically acceptable salt thereof as an active ingredient. Mention may be made of tyrosine kinase inhibitors. Specific indications include, for example, asthma, rhinitis, sinusitis, anaphylaxis, urticaria, angioedema, contact dermatitis, atopic dermatitis, rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, degenerative Arthritis, arthritis such as gouty arthritis, interstitial cystitis, ulcerative colitis, various inflammatory diseases represented by autoimmune diseases such as Crohn's disease, small cell lung cancer, myeloid leukemia, neurocytoma, Examples include breast cancer, colon cancer, cervical cancer, ovarian cancer, gastrointestinal stromal tumor, and cancer represented by mast cytosis.

Among the compounds of the present invention, particularly preferable examples include the following compounds (1) to (15).
(1) 4- (n-propyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (2) 4-ethyl-N- {4-methyl -3- [4- (5-Pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (3) 4-Isopropyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] Phenyl} benzamide (4) 4-methyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (5) 4-cyclopropyl-N- {4-methyl -3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (6) 4- (n-butyl) -N- {4-methyl-3- [4- (5-pi (Midinyl) pyrimidin-2-ylamino] phenyl} benzamide (7) 4-isobutyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (8) 4- ( t-butyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (9) 4- (n-pentyl) -N- {4-methyl-3 -[4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (10) 4-cyclohexyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} Benzamide (11) 4-vinyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzene Zuamide (12) 4-Isopropenyl-N- {4-Methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (13) N- {4-Methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5-methylthiophene-2-carboxamide (14) N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5- (1-hydroxy-1-methylethyl) thiophene-2-carboxamide (15) N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5-isopropyl Thiophene-2-carboxamide The present invention is described in detail below.

  In the present invention, “alkyl” is linear or branched alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert. -Butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl can be mentioned. Among these, C1-C6 alkyl is preferable and C1-C3 alkyl is more preferable.

  In the present invention, examples of the alkyl moiety of “hydroxyalkyl” include the same alkyl as described above.

  In the present invention, “cycloalkyl” includes cyclic cycloalkyl having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Of these, cycloalkyl having 3 to 6 carbon atoms is preferable, and cycloalkyl having 3 to 5 carbon atoms is more preferable.

  In the present invention, “alkenyl” is linear or branched alkenyl having 2 to 8 carbon atoms, such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl and 2-butenyl. , 3-butenyl, 1-pentenyl, 1-hexenyl, 1-heptenyl and 1-octenyl. Among these, alkenyl having 2 to 7 carbon atoms is preferable, and alkenyl having 2 to 6 carbon atoms is more preferable.

  In the present invention, examples of “halogen” include fluorine, chlorine, bromine and iodine.

The compound of the present invention can be produced from a known compound or an easily prepared intermediate according to, for example, the following method. In the production of the compound of the present invention, when the raw material has a substituent that affects the reaction, the reaction is generally carried out after the raw material is protected with a suitable protecting group by a known method in advance. The protecting group can be removed after the reaction by a known method.
Manufacturing method 1

〔式中、Ａｒは、前記と同義である。〕

本反応は、化合物［４］と化合物［５］との縮合反応であって、それ故、縮合反応としてそれ自体公知の方法によって行うことができる。一般式［１］で表される本発明化合物は、化合物［５］で表されるカルボン酸又はその反応性誘導体と、化合物［４］で表されるアミンを反応させることにより製造することができる。化合物［５］の反応性誘導体としては、例えば、酸ハライド（例えば、酸クロリド、酸ブロミド）、混合酸無水物、イミダゾリド、活性アミド等、アミド縮合形成反応に通常用いられるものを挙げることができる。カルボン酸［５］を用いる場合は、縮合剤（例えば、１，１’−オキサリルジイミダゾール、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド、ジシクロヘキシルカルボジイミド、シアノホスホン酸ジエチル、ジフェニルホスホリルアジド、よう化 ２−クロロ−１−メチルピリジニウム、１Ｈ−ベンゾトリアゾール−１−イルオキシトリピロリジノホスホニウム ヘキサフルオロホスフェート、ベンゾトリアゾール−１−イルオキシトリス（ジメチルアミノ）ホスホニウム ヘキサフルオロホスフェート）が使用でき、塩基（例えば、トリエチルアミン、Ｎ，Ｎ−ジイソプロピル−Ｎ−エチルアミン、Ｎ，Ｎ−ジメチルアニリン、ピリジン、４−ジメチルアミノピリジン、１，８−ジアザビシクロ［５．４．０］ウンデセ−７−エンの有機塩基）の存在又は非存在下に、−２０〜１００℃の範囲で反応を行うことができる。使用しうる溶媒は、反応に関与しなければ特に限定されないが、テトラヒドロフラン、ジエチルエーテルなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、アセトニトリル、プロピオニトリルなどのニトリル類、ベンゼン、トルエンなどの炭化水素類、クロロホルム、ジクロロメタンなどのハロゲン化炭化水素類、又はこれらの混合溶媒を挙げることができる。この際、添加剤（１−ヒドロキシベンゾトリアゾール、Ｎ−ヒドロキシコハク酸イミド等）を加えることもできる。反応時間は、原料及び縮合剤の種類、反応温度等によって異なるが、通常、３０分〜２４時間の範囲が適当である。化合物［５］及び縮合剤の使用量は、化合物［４］に対して１〜３倍モル量が好ましい。化合物［５］の反応性誘導体として、例えば酸ハライドを用いる場合は、ピリジン、４−メチルピリジンなどのピリジン系溶媒又は前記と同じ塩基と溶媒を使用し、−２０〜１００℃の範囲で反応を行うことができる。また、添加物として、例えば４−ジメチルアミノピリジンを加えることもできる。反応時間は、使用する酸ハライドの種類、反応温度によって異なるが、通常、３０分〜２４時間の範囲が適当である。

[In the formula, Ar is as defined above. ]

This reaction is a condensation reaction between the compound [4] and the compound [5] and can therefore be carried out by a method known per se as a condensation reaction. The compound of the present invention represented by the general formula [1] can be produced by reacting the carboxylic acid represented by the compound [5] or a reactive derivative thereof with the amine represented by the compound [4]. . Examples of the reactive derivative of the compound [5] include acid halides (for example, acid chloride, acid bromide), mixed acid anhydrides, imidazolides, active amides, and the like that are commonly used in amide condensation formation reactions. . When the carboxylic acid [5] is used, a condensing agent (for example, 1,1′-oxalyldiimidazole, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diethyl cyanophosphonate, diphenylphosphoryl azide 2-chloro-1-methylpyridinium iodide, 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate), A base (for example, triethylamine, N, N-diisopropyl-N-ethylamine, N, N-dimethylaniline, pyridine, 4-dimethylaminopyridine, 1,8-diazabicyclo [5.4.0] undec-7- The reaction can be carried out in the range of -20 to 100 ° C in the presence or absence of the organic base of ene. Solvents that can be used are not particularly limited as long as they do not participate in the reaction, but ethers such as tetrahydrofuran and diethyl ether, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, acetonitrile, propionitrile and the like. Nitriles, hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as chloroform and dichloromethane, or a mixed solvent thereof. At this time, additives (1-hydroxybenzotriazole, N-hydroxysuccinimide, etc.) can also be added. The reaction time varies depending on the types of raw materials and condensing agent, the reaction temperature, etc., but usually a range of 30 minutes to 24 hours is appropriate. The amount of compound [5] and condensing agent used is preferably 1 to 3 times the molar amount relative to compound [4]. For example, when an acid halide is used as the reactive derivative of the compound [5], a pyridine solvent such as pyridine or 4-methylpyridine or the same base and solvent as described above is used, and the reaction is performed within a range of −20 to 100 ° C. It can be carried out. Moreover, 4-dimethylaminopyridine can also be added as an additive, for example. The reaction time varies depending on the type of acid halide used and the reaction temperature, but a range of 30 minutes to 24 hours is usually appropriate.

Compound [4], which is a raw material compound, can be produced, for example, by the same method as described in Patent Document 9.
Manufacturing method 2

〔式中、Ａｒは前記と同義である。Ｘ^１はＣｌ、Ｂｒ、Ｉ、ＳＲ^３を表し、Ｒ^３はアルキルを表す。〕

一般式［１］で表される本発明化合物は、化合物［６］と化合物［７］を反応させることによって製造することができる。本反応は、無溶媒または適当な溶媒中、塩基の存在または非存在下、２０〜２００℃の範囲で行われる。使用しうる塩基としては、例えば、ピリジン、トリエチルアミン、Ｎ，Ｎ−ジイソプロピル−Ｎ−エチルアミン、炭酸カリウム、炭酸水素ナトリウム、水酸化カリウムなどを挙げることができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、テトラヒドロフラン、ジブチルエーテル、１，４−ジオキサンなどのエーテル類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエンなどの炭化水素類、エチレングリコール、２−メトキシエタノールなどのアルコール類、クロロホルム、ジクロロメタンなどのハロゲン化炭化水素類、ジメチルスルホキシド、又はこれらの混合溶媒を挙げることができる。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、１〜２４時間の範囲が適当である。

[Wherein, Ar is as defined above. X ¹ represents Cl, Br, I, SR ³ and R ³ represents alkyl. ]

The compound of the present invention represented by the general formula [1] can be produced by reacting the compound [6] with the compound [7]. This reaction is carried out in the range of 20 to 200 ° C. in the absence of a solvent or in a suitable solvent in the presence or absence of a base. Examples of the base that can be used include pyridine, triethylamine, N, N-diisopropyl-N-ethylamine, potassium carbonate, sodium hydrogen carbonate, potassium hydroxide, and the like. Solvents that can be used are not particularly limited as long as they are not involved in the reaction, but ethers such as tetrahydrofuran, dibutyl ether and 1,4-dioxane, and amides such as N, N-dimethylformamide and N, N-dimethylacetamide. , Hydrocarbons such as benzene and toluene, alcohols such as ethylene glycol and 2-methoxyethanol, halogenated hydrocarbons such as chloroform and dichloromethane, dimethyl sulfoxide, or a mixed solvent thereof. The reaction time varies depending on the type of raw material used and the reaction temperature, but a range of 1 to 24 hours is usually appropriate.

  Moreover, this invention compound represented by General formula [1] can also be manufactured from the compound [6] and the compound [7] using the method (For example, refer nonpatent literature 24-25) using a palladium catalyst. it can.

  Compound [6], which is a raw material compound, is produced, for example, by condensing carboxylic acid represented by 2,4-diaminotoluene and compound [5] or a reactive derivative thereof according to the method of Production Method 1. be able to.

Compound [7], which is a raw material compound, can be produced, for example, by the method of production method 4 described below using 2,4-dichloropyrimidine.
Manufacturing method 3

〔式中、Ａｒは前記と同義である。〕

一般式［１］で表される本発明化合物は、化合物［８］又は該化合物の酸付加塩と、化合物［９］を反応させることにより製造することができる。本反応は適当な溶媒中、２０〜２００℃の範囲で行うことができる。使用しうる溶媒としては、反応に関与しなければ特に限定されないが、例えばメタノール、エタノール、２−プロパノール、２−メトキシエタノールなどのアルコール類を挙げることができる。化合物［９］の使用量は、化合物［８］に対して１〜２倍モル量、好適には、１〜１．２倍モル量の範囲であり、反応時間は、使用する原料の種類、反応温度によって異なるが、通常３０分〜３０時間の範囲が適当である。化合物［８］の酸付加塩を用いる場合は、適当な塩基（例えば炭酸カリウム、炭酸水素ナトリウム、水酸化ナトリウム、水酸化カリウム）を添加し、反応を行うことができる。

[Wherein, Ar is as defined above. ]

The compound of the present invention represented by the general formula [1] can be produced by reacting compound [8] or an acid addition salt of the compound with compound [9]. This reaction can be carried out in a suitable solvent in the range of 20 to 200 ° C. The solvent that can be used is not particularly limited as long as it is not involved in the reaction, and examples thereof include alcohols such as methanol, ethanol, 2-propanol, and 2-methoxyethanol. The amount of the compound [9] used is in the range of 1 to 2 times the molar amount, preferably 1 to 1.2 times the molar amount relative to the compound [8], and the reaction time is the kind of raw material used, Although it varies depending on the reaction temperature, a range of usually 30 minutes to 30 hours is appropriate. When an acid addition salt of compound [8] is used, an appropriate base (for example, potassium carbonate, sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide) can be added to carry out the reaction.

  Compound [8], which is a raw material compound, can be produced in the form of a free or acid addition salt by reacting compound [6] with cyanamide by a method described in the literature (for example, see Non-patent Document 26). .

Compound [9], which is a raw material compound, can be produced, for example, according to the method described in Patent Document 9.
Manufacturing method 4

〔式中、Ａｒは前記と同義である。Ｒ^４及びＲ^５は、同一又は異なって、アルキル又はヒドロキシを表し、Ｒ^６、Ｒ^７及びＲ^８はアルキルを表し、Ｘ^２はハロゲンを表す。〕

本反応は化合物［１０］と、有機ホウ素化合物［１１］又は有機スズ化合物［１２］を用いたクロスカップリング反応であり、公知の方法によって一般式［１］で表される本発明化合物を製造することができる。本反応は、例えばパラジウム触媒存在下、適当な溶媒中、２０〜２００℃の範囲で行う。一般的にパラジウム触媒として、テトラキス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリフェニルホスフィン）パラジウム、ジクロロビス（トリ−ｏ−トリルホスフィン）パラジウムなどが使用され、反応溶媒は、反応に関与しなければ特に限定されないが、テトラヒドロフラン、１，４−ジオキサン、１，２−ジメトキシエタンなどのエーテル類、メタノール、エタノールなどのアルコール類、Ｎ，Ｎ−ジメチルホルムアミド、Ｎ，Ｎ−ジメチルアセトアミドなどのアミド類、ベンゼン、トルエン、キシレンなどの炭化水素類、ピリジン、トリエチルアミンなどの有機アミン類、又はこれらの混合溶媒を挙げることができる。化合物［１１］を用いる場合、塩基（例えば水酸化ナトリウム、炭酸カリウム、りん酸三カリウム）の添加が必須である。反応時間は、使用する原料の種類、反応温度によって異なるが、通常、１〜４８時間の範囲が適当である。また有機ホウ素化合物［１１］は、臭素体から非特許文献２７に記載の方法によって、有機スズ化合物［１２］は非特許文献２８に記載の方法によって製造するとことができる。

[Wherein, Ar is as defined above. R ⁴ and R ⁵ are the same or different and represent alkyl or hydroxy, R ⁶ , R ⁷ and R ⁸ represent alkyl, and X ² represents halogen. ]

This reaction is a cross-coupling reaction using compound [10] and organoboron compound [11] or organotin compound [12]. The compound of the present invention represented by general formula [1] is produced by a known method. can do. This reaction is carried out, for example, in the presence of a palladium catalyst in a suitable solvent in the range of 20 to 200 ° C. In general, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, dichlorobis (tri-o-tolylphosphine) palladium, etc. are used as the palladium catalyst, and the reaction solvent is not particularly limited unless involved in the reaction. Although not, ethers such as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane, alcohols such as methanol and ethanol, amides such as N, N-dimethylformamide and N, N-dimethylacetamide, benzene, Examples thereof include hydrocarbons such as toluene and xylene, organic amines such as pyridine and triethylamine, and mixed solvents thereof. When using the compound [11], the addition of a base (for example, sodium hydroxide, potassium carbonate, tripotassium phosphate) is essential. The reaction time varies depending on the type of raw material used and the reaction temperature, but a range of 1 to 48 hours is usually appropriate. The organoboron compound [11] can be produced from bromine by the method described in Non-Patent Document 27, and the organotin compound [12] can be produced by the method described in Non-Patent Document 28.

  Compound [10], which is a raw material compound, is reacted with, for example, compound [6] and 4-hydroxy-2- (methylthio) pyrimidine and then treated with phosphorus oxychloride (see, for example, Non-Patent Document 29). Alternatively, the compound [6] and 2,4-dichloropyrimidine can be used to produce the compound according to the method described in the literature (for example, see Non-Patent Document 30).

  The compound of the present invention can be used as a medicament as a free base, but can also be used in the form of a pharmaceutically acceptable salt by a known method. Such salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, Mention may be made of salts of organic acids such as methanesulfonic acid.

  For example, the hydrochloride can be obtained by dissolving the free form in an alcohol solution, an ethyl acetate solution or an ether solution of hydrogen chloride.

  Since the compound of the present invention has very high c-kit tyrosine kinase inhibitory activity as compared with the compound specifically disclosed in Patent Document 9 as shown in the test examples described later, It is very useful as a medicine.

  When administering the compound of the present invention as a medicament, a pharmaceutical composition containing, for example, 0.1 to 99.5%, preferably 0.5 to 90%, in a non-toxic and inert carrier that is pharmaceutically acceptable. As a product, it can be administered to mammals including humans.

  As the carrier, one or more solid, semi-solid or liquid diluents, fillers and other formulation aids are used. The pharmaceutical composition is desirably administered in dosage unit form. The pharmaceutical composition according to the present invention can be administered intravenously, orally, intratissue, locally (such as transdermally) or rectally. Of course, it is administered in a dosage form suitable for these administration methods.

  It is desirable that the dose as a c-kit tyrosine kinase inhibitor should be set in consideration of the nature and severity of the disease, the patient's condition such as age and weight, the route of administration, etc. The amount of the active ingredient of the inventive compound is generally in the range of 0.1 to 1000 mg / human, preferably in the range of 1 to 500 mg / human per day.

  In some cases, this may be sufficient, and vice versa. Moreover, it can also be divided and administered to 2 to 3 times a day.

The present invention will be described in more detail with reference examples, examples and test examples below, but the present invention is not limited to these examples.
Reference Example 1 15 ml of an aqueous solution of 2.17 g of sodium 4-cyclopropylbenzoate hydroxide was stirred under ice-water cooling, and 3.50 g of bromine was slowly added dropwise. After stirring for 15 minutes under ice-water cooling, 1.00 g of 1,4-dioxane solution (12 ml) of 4′-cyclopropylacetophenone (for example, see Non-patent Document 31) was added dropwise. After completion of dropping, the mixture was stirred at room temperature for 18 hours. After adding 740 mg of sodium hydrogen sulfite, concentrated hydrochloric acid was added dropwise under cooling with ice water to make it acidic. The mixture was extracted twice with ethyl acetate, the organic layers were combined, washed twice with water, and back-extracted twice with a 10% aqueous sodium hydroxide solution. The back-extracted aqueous layers were combined, neutralized with 10% hydrochloric acid, and the precipitated crystals were collected by filtration to obtain 201 mg of the target compound as white crystals.
Melting point 161 ° C

Reference Example 2 4-Isopropenylbenzoic acid Step 1 A suspension of 2.15 g of methyltriphenylphosphonium bromide in anhydrous tetrahydrofuran (43 ml) was stirred under ice-water cooling in an argon atmosphere of ethyl 4-isopropenylbenzoate. Then, 4.3 ml of t-butyllithium (1.6M n-pentane solution) was added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 25 minutes, and then a solution of 961-mg ethyl 4-acetylbenzoate in anhydrous tetrahydrofuran (10 ml) was added dropwise with stirring under ice-water cooling. After completion of dropping, the mixture was stirred at room temperature for 30 minutes, and then water was added to the reaction solution to separate the aqueous layer. The aqueous layer was extracted twice with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The crude product was purified by silica gel column chromatography to obtain 149 mg of the target compound as a colorless oil.
¹ H-NMR (CDCl ₃ ) δ: 1.40 (3H, t), 2.17 (3H, dd), 4.38 (2H, q), 5.19 (1H, qn), 5.46 ( 1H, dd), 7.48-7.55 (2H, m), 7.97-8.03 (2H, m)
Step 2 4 -Isopropenylbenzoic acid 141 mg of ethyl 4-isopropenylbenzoate obtained in Step 1 was dissolved in 3 ml of methanol, 1.1 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 1 hour. The mixture was allowed to cool, methanol was distilled off under reduced pressure, water was added, and the mixture was washed once with diethyl ether. The aqueous layer was acidified (pH 4) by adding 1.5 ml of 1N hydrochloric acid, and the precipitated crystals were collected by filtration and washed twice with water to obtain 97 mg of the target compound as white crystals.
164-166 ° C

Reference Example 3 5- (1-Hydroxy-1-methylethyl) thiophene-2-carboxylic acid Step 1 5- (1-Hydroxy-1-methylethyl) thiophene-2-carboxylic acid under argon atmosphere, thiophene 2-Carboxylic acid (1.00 g) was dissolved in anhydrous tetrahydrofuran (20 ml), and the mixture was cooled and stirred in a dry ice-acetone bath. 8.58 ml of lithium diisopropylamide (2.0 M heptane / tetrahydrofuran / ethylbenzene solution) was added dropwise over 20 minutes, and the mixture was cooled and stirred for 15 minutes after the addition. After adding 573 μl of anhydrous acetone, the dry ice-acetone bath was removed and the mixture was stirred for 1.5 hours. Ice water was added to the reaction solution, and the aqueous layer was washed twice with ethyl acetate. The aqueous layer was acidified with 2N hydrochloric acid, and extracted twice with ethyl acetate. The organic layer was washed once with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 1.33 g of a crude compound.
Step 2 5- (1-Hydroxy-1-methylethyl) thiophene-2-carboxylic acid methyl ester 2.56 g of 5- (1-hydroxy-1-methylethyl) thiophene-2-carboxylic acid obtained in Step 1 was anhydrous It melt | dissolved in tetrahydrofuran-methanol (62 ml-16 ml), and stirred under ice water cooling. After adding 8.6 ml of trimethylsilyldiazomethane (2.0M hexane solution) and stirring for 20 minutes under ice water cooling, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and the resulting crude crystals were washed with n-hexane to obtain 1.12 g of the objective compound as pale brown crystals.
Melting point 64.5 ° C
Step 3 5- (1-hydroxy- 1-methylethyl) thiophene-2-carboxylic acid 150 mg of methyl 5- (1-hydroxy-1-methylethyl) thiophene-2-carboxylate obtained in Step 2 was added to 3 ml of methanol. After dissolution, 1.13 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was heated to reflux for 30 minutes. Methanol was distilled off under reduced pressure, water was added to the residue, and 1.13 ml of 1N hydrochloric acid was added for neutralization. The operation of distilling off water under reduced pressure and adding methanol to the residue to remove water azeotropically was repeated three times. Anhydrous methanol was added to the residue and the mixture was stirred, insolubles were removed by filtration, and the operation of evaporating the solvent of the filtrate under reduced pressure was repeated twice to obtain 163 mg of the target compound as white crystals.
Melting point: 138-139 ° C

Reference Example 4 5-Isopropylthiophene-2-carboxylic acid Step 1 In a methyl argon atmosphere of 5-isopropylthiophene-2-carboxylate , 342 mg of diphosphorus tetraiodide was dissolved in 20 ml of anhydrous benzene by heating. -(1-Hydroxy-1-methylethyl) thiophene-2-carboxylate (Reference Example 3 (Step 2)) 200 mg of anhydrous benzene in 10 ml was added and heated to reflux for 6 hours. The reaction solution was allowed to cool, 10% aqueous sodium sulfite solution was added and stirred, the aqueous layer was separated, and the aqueous layer was extracted twice with diethyl ether. The organic layers were combined, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography to obtain 106 mg of the target compound as an orange oil.
¹ H-NMR (CDCl ₃ ) δ: 1.34 (6H, d), 3.19 (1H, qn), 3.86 (3H, s), 6.82 (1H, dd), 7.64 ( 1H, d)
Step 2 5 -Isopropylthiophene-2-carboxylic acid 132 mg of methyl 5-isopropylthiophene-2-carboxylate obtained in Step 1 was dissolved in 3 ml of methanol and 1.07 ml of 1N aqueous sodium hydroxide solution was added for 1 hour. Heated to reflux. Methanol was distilled off under reduced pressure, water was added to the residue, and the mixture was washed once with diethyl ether. The mixture was acidified (pH 5) by adding 1.5 ml of 1N hydrochloric acid, extracted twice with ethyl acetate, the organic layers were combined, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 119 mg of the target compound as slightly yellow crystals. Got as.
Melting point 77-78 ° C
Example 1 4- (n-propyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-methyl-3- [4- (5-pyrimidinyl) ) Pyrimidin-2-ylamino] aniline (see, for example, Patent Document 10) 100 mg and 4- (n-propyl) benzoic acid 65 mg are dissolved in 2 ml of anhydrous N, N-dimethylformamide, 125 μl of N, N-diisopropylethylamine, After sequentially adding 191 mg of benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (BOP), the mixture was stirred at room temperature for 24 hours. The reaction solution was diluted by adding ethyl acetate, poured into a mixture of ice water and saturated aqueous sodium hydrogen carbonate solution, the aqueous layer was separated, and the aqueous layer was extracted once with ethyl acetate. The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The resulting crude crystals were washed with ethanol in a slurry slurry while being hot, then collected by filtration, and then washed with diethyl ether to obtain 103 mg of the target compound.
Yellow crystal Melting point 210-212 ° C (decomposition)
Elemental analysis (as _{C 25 H 24 N 6 O ·} 0.2EtOH · 0.2H 2 O)
Calculated value (%) C: 69.76 H: 5.90 N: 19.22
Actual value (%) C: 69.83 H: 6.07 N: 18.85

Example 2 4-ethyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-ethylbenzoic acid was used in the same manner as in Example 1. The target compound was obtained. However, the obtained crude crystals were washed with ethanol in slurry and then washed with ethyl acetate.
Pale yellow crystal Melting point 242-244 ° C (decomposition)
Elemental analysis (as _{C 24 H 22 N 6 O ·} 0.1EtOH · 0.2H 2 O)
Calculated value (%) C: 69.42 H: 5.54 N: 20.07
Actual value (%) C: 69.53 H: 5.60 N: 19.77

Example 3 4-Isopropyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-isopropylbenzoic acid was used in the same manner as in Example 1. The target compound was obtained. However, the obtained crude crystals were washed with ethyl acetate.
Pale yellow crystal Melting point 149 ° C or higher (decomposition)
¹ H-NMR (DMSO-d ₆ ) δ: 1.22 (3H, t), 2.14 (3H, s), 2.23 (3H, s), 2.38 (8H, br), 75 (2H, q), 3.50 (2H, s), 7.21 (1H, d), 7.38 (1H, d), 7.48 (1H, d), 7.51 (1H, d ), 7.61 (1H, d), 7.75 (1H, s), 8.12 (1H, s), 8.57 (1H, d), 9.09 (1H, s), 9.30 (1H, s), 9.46 (2H, s), 10.15 (1H, s)

Example 4 Using 4-methyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-toluic acid in the same manner as in Example 1 A compound was obtained. However, the obtained crude crystals were washed with ethyl acetate.
Yellow crystal Melting point 218 ° C or higher (decomposition)
Elemental analysis (as _{C 23 H 20 N 6 O ·} 0.1H 2 O)
Calculated value (%) C: 69.37 H: 5.11 N: 21.20
Found (%) C: 69.35 H: 5.17 N: 21.18

Example 5 Conducted with 4-cyclopropyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-cyclopropylbenzoic acid (Reference Example 1). The target compound was obtained in the same manner as in Example 1. However, the obtained crude crystals were dissolved in acetonitrile with heating, insolubles were removed by filtration while hot, the filtrate was cooled, and the precipitated crystals were collected by filtration.
Pale yellow crystal Melting point 235-238 ° C (decomposition)
Elemental analysis (as _{C 25 H 22 N 6 O ·} 0.25H 2 O)
Calculated value (%) C: 70.32 H: 5.31 N: 19.68
Actual value (%) C: 70.49 H: 5.36 N: 19.39
Example 6 4- (n-Butyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4- (n-butyl) benzoic acid The target compound was obtained in the same manner as in Example 1.
Yellow crystal Melting point 154-156 ° C (decomposition)
Elemental analysis (as _{C 26 H 26 N 6 O ·} 0.25H 2 O)
Calculated value (%) C: 70.49 H: 6.03 N: 18.97
Actual value (%) C: 70.64 H: 5.97 N: 18.64

Example 7 4-Isobutyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-isobutylbenzoic acid was used in the same manner as in Example 1. The target compound was obtained.
Pale yellow crystal Melting point: 196-198 ° C
Elemental analysis (as _{C 26 H 26 N 6 O ·} 0.2H 2 O)
Calculated value (%) C: 70.63 H: 6.02 N: 19.01
Actual value (%) C: 70.60 H: 6.17 N: 18.84

Example 8 4- (t-Butyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4- (t-butyl) benzoic acid The target compound was obtained in the same manner as in Example 1. However, in the post-treatment, after separating the aqueous layer, the crystals precipitated in the organic layer were collected by filtration and washed with ethanol.
Pale yellow crystal Melting point: 178-183 ° C (decomposition)
Elemental analysis (as _{C 26 H 26 N 6 O ·} 0.37CH 3 COOC 2 H 5 · 0.2H 2 O)
Calculated Value (%) C: 69.53 H: 6.23 N: 17.70
Actual value (%) C: 69.42 H: 6.26 N: 17.38

Example 9 4- (n-pentyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4- (n-pentyl) benzoic acid was used to The target compound was obtained in the same manner as in Example 1. However, the obtained crude crystals were recrystallized with ethyl acetate and then recrystallized with ethanol.
Slightly yellow crystal Melting point 157-159 ° C (decomposition)
Elemental analysis (as _{C 27 H 28 N 6 O ·} 0.2H 2 O)
Calculated value (%) C: 71.09 H: 6.28 N: 18.42
Actual value (%) C: 71.34 H: 6.32 N: 18.13

Example 10 4-Cyclohexyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-cyclohexylbenzoic acid was used in the same manner as in Example 1. The target compound was obtained. However, the obtained crude crystals were washed with ethyl acetate.
Pale yellow crystal Melting point: 183-184 ° C
¹ H-NMR (DMSO-d ₆ ) δ: 1.20-1.58 (6H, m), 1.64-1.84 (4H, m), 2.22 (3H, s), 2.52 -2.65 (1H, m), 7.20 (1H, d), 7.37 (2H, d), 7.47 (1H, d), 7.51 (1H, d), 7.86 ( 2H, d), 8.13 (1H, s), 8.57 (1H, d), 9.08 (1H, s), 9.30 (1H, s), 9.46 (2H, s), 10.13 (1H, s)
Example 11 4-vinyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-vinylbenzoic acid was used in the same manner as in Example 1. The target compound was obtained. However, the crude product was purified by silica gel column chromatography, and the resulting crude crystals were washed with ethyl acetate.
Pale yellow crystal Melting point 218-219 ° C
Elemental analysis (as _{C 24 H 20 N 6 O ·} 0.2CH 3 COOC 2 H 5 · 0.3H 2 O)
Calculated Value (%) C: 69.03 H: 5.19 N: 19.48
Actual value (%) C: 69.02 H: 5.10 N: 19.36

Example 12 Conducted with 4-isopropenyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide 4-isopropenylbenzoic acid (Reference Example 2). The target compound was obtained in the same manner as in Example 1. However, the obtained crude crystals were slurry-washed with ethyl acetate when heated.
Pale yellow crystal Melting point 220-223 ° C
¹ H-NMR (DMSO-d ₆ ) δ: 2.16 (3H, s), 2.23 (3H, s), 5.22 (1H, s), 5.57 (1H, s), 22 (1H, d), 7.48 (1H, dd), 7.51 (1H, d), 7.65 (2H, d), 7.95 (2H, d), 8.14 (1H, d ), 8.58 (1H, d), 9.09 (1H, s), 9.30 (1H, s), 9.46 (2H, s), 10.21 (1H, s)

Example 13 Using N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5-methylthiophene-2-carboxamide 5-methylthiophene-2-carboxylic acid, The target compound was obtained in the same manner as in Example 1. However, the obtained crude crystals were slurry-washed with ethyl acetate when heated.
Pale yellow crystal Melting point: 188-190 ° C (decomposition)
Elemental analysis value (as C ₂₁ H ₁₈ N ₆ OS · 0.35H ₂ O)
Calculated value (%) C: 61.70 H: 4.61 N: 20.56
Actual value (%) C: 62.00 H: 4.80 N: 20.17

Example 14 N- {4-Methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5- (1-hydroxy-1-methylethyl) thiophene-2-carboxamide 5- (1 The target compound was obtained in the same manner as in Example 1 using -hydroxy-1-methylethyl) thiophene-2-carboxylic acid (Reference Example 3, Step 3). However, the obtained amorphous was crystallized with ethyl acetate.
Slight yellow crystal Melting point 190-193 ° C (decomposition)
Elemental analysis (as _{C 23 H 22 N 6 O 2} S · 0.25H 2 O)
Calculated value (%) C: 61.25 H: 5.03 N: 18.63
Actual value (%) C: 61.39 H: 4.97 N: 18.28

Example 15 N- {4-Methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5-isopropylthiophene-2-carboxamide 5-isopropylthiophene-2-carboxylic acid (Reference Example 4) The target compound was obtained in the same manner as in Example 1 using Step 2). However, the obtained crude crystals were slurry-washed with ethyl acetate when heated.
Ocher crystal Melting point 215-220 ° C (decomposition)
¹ H-NMR (DMSO-d ₆ ) δ: 1.30 (6H, d), 2.22 (3H, s), 3.19 (1H, qn), 6.97 (1H, dd), 7. 20 (1H, d), 7.43 (1H, dd), 7.51 (1H, d), 7.84 (1H, d), 8.01 (1H, d), 8.57 (1H, d ), 9.08 (1H, s), 9.30 (1H, s), 9.44 (2H, s), 10.06 (1H, s)
Test Example 1 c-kit tyrosine kinase autophosphorylation inhibitory effect 10% (v / v) fetal calf serum (FCS) (GIBCO BRL) -containing RPMI-1640 medium (GIBCO BRL) NCI-H526 cells in the logarithmic growth phase (American Type Culture Collection) were added to a 6-well flat bottom plate (manufactured by Falcon) at 2 × 10 ⁶ cells / well in RPMI-1640 medium containing 0.1% FCS. After inoculating each ml, it was incubated at 37 ° C. under 5% CO ₂ for 24 hours. 30 μl of each drug prepared in a 10% DMSO (manufactured by nacalai tesque) solution was added per well (final DMSO concentration: 0.1%), pretreated for 90 minutes, and RH-SCF (R & D Systems) Made) Stimulated for 10 minutes with a final concentration of 50 ng / ml. The cells after stimulation were washed twice with PBS (−) (1200 rpm, 3 minutes), the supernatant was removed, and 500 μl of RIPA buffer (50 mM HEPES (pH 7.5), 150 mM NaCl, 10% Glycerol, 1% Triton X-100, 1.5 mM MgCl ₂ , 1 mM EGTA, 2 mM Na ₃ VO ₄ , Protease Inhibitor Cocktail) was added and left on ice for 20 minutes to solubilize the cells, and high-speed centrifugation (15000 rpm, 15 Min) to remove the insoluble fraction. Further, 20 μl of protein G agarose beads (manufactured by oncogene) were added to the obtained total cell extract, and incubated at room temperature for 2 hours to remove nonspecifically adsorbed molecules on the beads. From the total cell extract thus prepared, c-kit molecules were immunoprecipitated using an anti-human CD117 antibody (manufactured by BioSource). The precipitate was electrophoresed on a 6% polyacrylamide gel and then transferred to a PVDF membrane (Millipore). Thereafter, the membrane is reacted with an anti-c-kit antibody (manufactured by Santa Cruz) or an anti-phosphotyrosine antibody (manufactured by BD Biosciences) on the membrane according to a conventional method, and c-kit and tyrosine phosphorylated c- A kit band was detected. The relative concentration of the band corresponding to tyrosine phosphorylated c-kit was measured using Epi-Light UV (F-2000, Aisin Cosmos Laboratories), and the phosphorylation inhibition of the drug-treated group relative to the control group (drug-untreated group) Rates and IC ₅₀ were calculated.

The results of Test Example 1 (phosphorylation inhibition rate and IC ₅₀ when 0.1 μM drug is added) are shown in Table 1.
As the target drug, 4- (4-methylpiperazin-1-ylmethyl) -N- [4-methyl-3- [4- (3-pyridinyl) pyrimidin-2-ylamino] phenyl] benzamide (for example, patent document) 9) was used.

上記表１に示す通り、本発明化合物が優れたｃ−ｋｉｔチロシンキナーゼの阻害作用を有することは明白である。
製剤例１
錠剤（内服錠）
処方１錠８０ｍｇ 中
実施例１の本発明化合物 ５．０ｍｇ
トウモロコシ澱粉 ４６．６ｍｇ
結晶セルロース ２４．０ｍｇ
メチルセルロース ４．０ｍｇ
ステアリン酸マグネシウム ０．４ｍｇ
この割合の混合末を通常の方法により打錠成形し内服錠とする。

製剤例２
錠剤（内服錠）
処方１錠８０ｍｇ 中
実施例２の本発明化合物 ５．０ｍｇ
トウモロコシ澱粉 ４６．６ｍｇ
結晶セルロース ２４．０ｍｇ
メチルセルロース ４．０ｍｇ
ステアリン酸マグネシウム ０．４ｍｇ
この割合の混合末を通常の方法により打錠成形し内服錠とする。

As shown in Table 1 above, it is clear that the compound of the present invention has an excellent c-kit tyrosine kinase inhibitory action.
Formulation Example 1
Tablet (internal tablet)
Prescription 1 tablet 80mg
The compound of the present invention of Example 1 5.0 mg
Corn starch 46.6mg
Crystalline cellulose 24.0mg
Methylcellulose 4.0mg
Magnesium stearate 0.4mg
This proportion of the mixed powder is formed into tablets by a conventional method.

Formulation Example 2
Tablet (internal tablet)
Prescription 1 tablet 80mg
The compound of the present invention of Example 2 5.0 mg
Corn starch 46.6mg
Crystalline cellulose 24.0mg
Methylcellulose 4.0mg
Magnesium stearate 0.4mg
This proportion of the mixed powder is formed into tablets by a conventional method.

  As described above, since the compound of the present invention has an excellent c-kit inhibitory activity, a pharmaceutical composition containing the compound of the present invention as an active ingredient can be used as an asthma, rhinitis, adjunct Rhinitis, anaphylaxis, hives, angioedema, contact dermatitis, atopic dermatitis, rheumatoid arthritis, conjunctivitis, rheumatoid spondylitis, arthritis such as osteoarthritis, gouty arthritis, interstitial cystitis Various inflammatory diseases represented by autoimmune diseases such as ulcerative colitis, Crohn's disease, small cell lung cancer, myeloid leukemia, neurocytoma, breast cancer, colon cancer, cervical cancer, ovarian cancer, gastrointestinal tract It is useful for diseases such as melanoma and cancer represented by mast cytosis.

Claims (8)

A pyrimidine derivative represented by the following general formula [1] or a pharmaceutically acceptable salt thereof.

Ar represents any group of the following general formula [2] or [3].

R ¹ represents alkyl, cycloalkyl or alkenyl.
R ² represents alkyl or hydroxyalkyl. The pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claim 1, which is a compound selected from the group consisting of the following compounds (1) to (15).
(1) 4- (n-propyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (2) 4-ethyl-N- {4-methyl -3- [4- (5-Pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (3) 4-Isopropyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] Phenyl} benzamide (4) 4-methyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (5) 4-cyclopropyl-N- {4-methyl -3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (6) 4- (n-butyl) -N- {4-methyl-3- [4- (5-pi (Midinyl) pyrimidin-2-ylamino] phenyl} benzamide (7) 4-isobutyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (8) 4- ( t-butyl) -N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (9) 4- (n-pentyl) -N- {4-methyl-3 -[4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (10) 4-cyclohexyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} Benzamide (11) 4-vinyl-N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzene Zuamide (12) 4-Isopropenyl-N- {4-Methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} benzamide (13) N- {4-Methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5-methylthiophene-2-carboxamide (14) N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5- (1-hydroxy-1-methylethyl) thiophene-2-carboxamide (15) N- {4-methyl-3- [4- (5-pyrimidinyl) pyrimidin-2-ylamino] phenyl} -5-isopropyl Thiophene-2-carboxamide A pharmaceutical composition comprising the pyrimidine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. A c-kit tyrosine kinase inhibitor comprising the pyrimidine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for inflammatory diseases comprising the pyrimidine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. An anticancer agent containing the pyrimidine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for gastrointestinal stromal tumor comprising the pyrimidine derivative according to any one of claims 1 and 2 or a pharmaceutically acceptable salt thereof as an active ingredient. A therapeutic agent for mast cytosis comprising the pyrimidine derivative according to claim 1 or 2 or a pharmaceutically acceptable salt thereof as an active ingredient.