JP2005206515A - Five-membered cyclic compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a compound inhibiting the infiltration of leukocytes including eosinophils and lymphocytes, thus effective as a therapeutic agent for various inflammations. <P>SOLUTION: The five-membered cyclic compound or a pharmaceutically acceptable salt thereof is represented by the formula(I)[ wherein, R<SP>1</SP>is H, an alkyl, aryl or heteroaryl; R<SP>2</SP>is H, an alkyl, aryl, heteroaryl or CON(R<SP>6</SP>)R<SP>7</SP>; Y<SP>1</SP>is a single bond, a (substituted) alkylene group, CO(CH<SB>2</SB>)<SB>n</SB>, SO<SB>2</SB>(CH<SB>2</SB>)<SB>n</SB>, CSNH(CH<SB>2</SB>)<SB>n</SB>or COO(CH<SB>2</SB>)<SB>n</SB>; n is an integer of 0-5; the wavy line means (E)- or (Z)-coodination; R<SP>3</SP>is H, an aryl, heteroaryl or cycloalkyl; Y<SP>2</SP>is an alkylene group, alkenylene group or the like; and R<SP>4</SP>is imidazol-4-yl, benzimidazol-2-yl, 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl group ]. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel 5-membered ring compound or a salt thereof and a pharmaceutical use thereof. More specifically, the present invention binds to a specific binding site of L-threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluorophenyl) propyl] serine pyrrolidine amide in vivo. Furthermore, the present invention relates to a novel 5-membered ring compound or a salt thereof, which inhibits infiltration of leukocytes such as eosinophils and lymphocytes, and thereby is effective in treating various inflammations, and a pharmaceutical use thereof.

  As an experimental model of dyspnea in bronchial asthma, a method is used in which an allergen is inhaled in an atopic asthmatic patient to cause an immediate asthmatic response (IAR). That is, when an allergen is inhaled by an atopic asthmatic patient, an asthmatic reaction (bronchospasm) occurs after about 20 minutes, and the original state is restored after about 2 hours. After that, if we continue to observe the patients who had an immediate asthmatic reaction, it was found that in about half of the cases, bronchospasm occurred again after 6 to 10 hours. Named (for example, Non-Patent Document 1). In late-onset asthma, the bronchospasm reaction lasts long and is accompanied by pulmonary hyperinflation, which is strongly suppressed by steroids. From this, it is recognized that bronchial asthma induced by the allergen attraction is important as a steroid-dependent clinical model of dyspnea of severe bronchial asthma. Immediate type reaction has been recognized as type I allergy resulting from mast cell activation by IgE antibody, and late type reaction has been recognized as T lymphocyte and eosinophilic allergy (eosinophilic inflammation). It was. These immediate and late reactions have been shown to occur in allergic rhinitis and dermatitis. In addition, it has been reported that when a bronchial asthma patient causes a delayed asthmatic reaction with an allergen, eosinophils accumulate in the lung (for example, Non-Patent Document 2). Increased eosinophils in the blood and sputum of many bronchial asthma patients, significant eosinophil infiltration in lung tissue of patients who died asthma, patient bronchial walls and mucous sputum The presence of major basic protein (MBP), a tissue-damaging protein derived from eosinophils, is important for eosinophil-derived products in airway epithelial injury associated with late-onset asthma attacks. It is said that it has a role (for example, nonpatent literature 3).

At present, the concept of onset of bronchial asthma has come to be regarded as a chronic inflammatory disease from simple reversible bronchospasm, and the treatment method is changing accordingly. 1995 US National Heart Lung Blood Institute (NIH / NHLBI) and WHO announced the Global Initiative for Asthma (GINA), an international strategy for managing asthma patients It is a treatment guideline. As described above, until relatively recently, bronchial asthma is a type I allergic disease in which IgE antibody is involved, and the development of therapeutic drugs has been promoted considering the pathogenesis mainly of the role of mast cells. However, as seen in the NIH / NHLBI view, bronchial asthma is now regarded as an inflammatory disease of the respiratory tract, and bronchial asthma is referred to as “chronic epithelial eosinophil infiltrating bronchitis”. / It is regarded as inflammation of the respiratory tract formed by inflammatory cells centering on T lymphocytes. In the above-mentioned GINA, the Western treatment policy so far is mainly adopted, and an inhaled steroid which is an anti-inflammatory agent is used as a first-line drug. In Japan, guidelines that take inhaled steroids as the basis for asthma treatment are set in line with these guidelines.
Steroids are positioned as the only specific medicines for severe bronchial asthma and atopic dermatitis. Have both. Inhaled steroids have been developed for the purpose of alleviating these systemic side effects, but it is difficult to prove that steroids administered by inhalation are not circulating throughout the body. The concerns have not been dispelled. Recently, side effects from inhaled steroids have been reported in the West, and the US FDA has issued warning documents regarding the risk of side effects on inhaled steroids for bronchial asthma and nasal steroids for allergic rhinitis. Guidance is given so that people can go in (for example, Non-Patent Document 4).

As described above, the infiltration of eosinophils into the lesion plays a major role in the onset and exacerbation of delayed reactions of allergic dermatitis and rhinitis, not limited to bronchial asthma. However, there are only steroids to treat allergic diseases such as bronchial asthma by suppressing infiltration and activation of eosinophils, and orally administrable anti-inflammatory agents with few side effects that can replace steroids are medical. It is peeped on the spot. For example, as an attempt to develop a drug that suppresses eosinophilic inflammation, an antibody (in anti-IL-5) that neutralizes interleukin-5 that causes proliferation and differentiation of eosinophil progenitor cells and prolongs survival of mature eosinophils Japanese antibody) (for example, Non-Patent Document 5), a low-molecular inhibitor of very late antigen 4 (VLA-4), an adhesion factor specific for eosinophils (for example, Non-Patent Document 6), and eosinophil migration. A small molecule antagonist (for example, Non-Patent Document 7) against CCR3, which is a receptor for eotaxin, which is a chemokine specific to eosinophils to be induced, has been studied, but has not been replaced with a steroid agent.
On the other hand, L-threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluorophenyl) propyl] serine pyrrolidine amide is known to have an action of suppressing eosinophil migration. (For example, Patent Document 1, Non-Patent Documents 8 and 9). The specific binding site of L-threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluorophenyl) propyl] serine pyrrolidine amide in vivo is a receptor-like membrane protein, It is also called SMBP (for example, Patent Document 1, Non-Patent Document 9).
Therefore, if eosinophil migration is suppressed by binding to SMBP, it is possible to treat allergic diseases such as asthma.

For example, Patent Document 2 and Patent Document 3 are known as those that use iminothiazoline as a mother nucleus and bind to SMBP to suppress infiltration of leukocytes such as eosinophils and lymphocytes. However, each substituent of Y ^{2 at} the 3-position of thiazoline in Patent Document 2 and Non-Patent Document 3 is limited to substituted amino, and does not include those having heteroaryl. Further, Patent Document 4 is known as one having iminothiazoline as a mother nucleus, which is an invention relating to a ligand for somatostatin receptor.
Some of the compounds of the present invention having an imidazole group at the 3-position of iminothiazoline can also be produced by a solid phase synthesis method. The solid-phase synthesis method was devised by Merrifield in 1963 and has been used for the synthesis of high molecular compounds such as peptides and nucleic acids. This synthesis method has an advantage that a large number of compounds can be synthesized at one time without requiring complicated post-treatment and purification operations in each step. Focusing on this advantage, the solid-phase synthesis method has been actively used since 1992 by applying it to general low molecular weight organic compounds and searching for new pharmaceutical compounds. Regarding the solid-phase synthesis reaction method of a compound having an imidazole ring, a solid-phase reaction carrier having a trityl group or a substituted trityl group is bonded to and cleaved from an imidazole part of a histidine side chain or an imidazole part of a histamine derivative. Non-Patent Document 10, Non-Patent Document 11, Non-Patent Document 12, and Non-Patent Document 13 have been reported since 1999 as methods for conducting derivative synthesis. However, a problem with the prior art is that acidic conditions are required to cleave the solid phase reaction carrier having a trityl group. In addition, the trityl group and the substituted trityl group are sterically bulky, and when a substituent is present on the imidazole ring, it is difficult to cause a binding reaction. Furthermore, the electron donating property of the trityl group increases the reactivity of the imidazole ring part and causes various side reactions.
In addition, non-patent document 14 and non-patent document 15 are known regarding indole derivatives as deresin methods using a fluorine ion reagent instead of acidic conditions, but examples of imidazole derivatives are not known.

WO 98/26065 WO 02/02542 WO 03/057693 Booji-Noord, H. et al., J. Allergy Clin. Immunol., 48, 344-354, 1971 De Monchy, J.G., et al., Am. Rev. Respir. Dis., 131, 373-376 (1985) Filley, W.V., et al., Lancet. 2 (8288), 11-6 (1982) Konig, P., Allergol. Int., 49, 1-6 (2000) Garlisi, C.G., Pulm.Pharmacol.Ther., 12,81-85 (1999) Haworth, D., et al., Br. J. Pharmacol., 126, 1751-1760 (1999) Wells, T.N.C., et al., Inflammation Res., 48, 353-62, (1999) 7 Sugasawa, T. and Morooka, S., Recent Advances in Cellular and Molecular Biology, 3, 223-227, Peeters Press, Leuven, Belgium (1992) Sugasawa, T. et al., J. Biol. Chem., 272, 21244-21252 (1997) Sabatito, G; Chelli, M; Mazzucco, S; Ginanneschi, M; Papini, M. Tetrahedron Lett 1999, 40, 809-812. Eleftheriou, S; Gatos, D; Panagopoilos, A; Stathopoulos, S; Barlos, K. Tetrahedron Lett 1999, 40, 2825-2828. Saha, A.K .; Liu, L; Simoneaux, R. L .; Kukla, M. J .; Marichal, P .; Odds, F. Bioorg Med. Chem. Lett., 2000, 10, 2175-2178. Alcaro, M.C .; Orfei, M .; Chelli, M .; Ginanneschi, M .; Papini, A. M. Tetrahedron Lett. 2003, 44, 5217-5219. Zhang, H.-C .; Ye, H .; Moretto, A.F .; Brumfield, K.K .; Maryanoff, B. E. Org. Lett. 2000, 3, 89-92. Zhang, H.-C; Ye, H; White, K.B .; Maryanoff, B. E. Tetrahedron Lett., 2001, 42, 4751-4754.

  The subject of this invention is providing the pharmaceutical which consists of a compound which suppresses infiltration of leukocytes, such as an eosinophil and a lymphocyte, and is effective as a therapeutic agent of various inflammations.

In order to solve the above-mentioned problems, the present inventors have shown that SMBP is also expressed in rat lung membrane. L-threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluoro (Phenyl) propyl] serine pyrrolidine amide and [ ¹²⁵ I] iodocyanopindolol (Sugasawa, T. et al., J. Biol. Chem., 272, 21244-21252 (1997), WO 98/26065 ), A new test method for inhibiting the onset of late-onset reaction was constructed, and various compounds were screened using this method. As a result, certain 5-membered ring compounds bound to SMBP, and eosinophils The inventors have found that the infiltration of leukocytes such as lymphocytes is suppressed and that the pharmacokinetics are excellent, and the present invention has been completed.
In addition, some of the compounds of the present invention can also be produced by a solid phase synthesis method. Specifically, the imidazole nitrogen part of the imidazole derivative represented by the general formula (1) is ligated to a solid phase reaction carrier to iminothiazoline. The present inventors have completed a method for producing an imidazole derivative, which is characterized by chemical synthesis on a solid phase. In addition, after completion of the chemical reaction, a solid-phase synthesis reaction method in which a fluorine ion reagent such as tetrabutylammonium fluoride is used to cut out from the solid-phase reaction support without being subjected to acidic conditions has been completed.

That is, the present invention
[1] Formula (1)

[式中、Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、または置換されていてもよい二環式ヘテロアリールを表す。
Ｒ^２は、水素原子、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、置換されていてもよい二環式ヘテロアリール、または-ＣＯＮ(Ｒ^６)Ｒ^７を表す。
Ｒ^６は、水素原子または置換されていてもよいアルキルを表す。Ｒ^７は、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、または置換されていてもよいアルキルを表す。また、-Ｎ(Ｒ^６)Ｒ^７は環状アミノを表してもよい。
Ｙ^１は、単結合、置換されていてもよいアルキレン、-ＣＯ(ＣＨ_２)_ｎ-、-ＳＯ_２(ＣＨ_２)_ｎ-、-ＣＯＮＨ(ＣＨ_２)_ｎ-、-ＣＳＮＨ(ＣＨ_２)_ｎ-、または-ＣＯＯ(ＣＨ_２)_ｎ-を表す。
ｎは０から５の整数を表す。
波線は、(Ｅ)または(Ｚ)配位を意味する。
Ｒ^３は、水素原子、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、置換されていてもよい二環式ヘテロアリール、または置換されていてもよいシクロアルキルを表す。
Ｙ^２は、置換されていてもよいアルキレン、アルケニレン、または-Ａ-Ｘ-Ｂ-を表す。Ａ、Ｂは同一または異なっていてもよく、それぞれ置換されていてもよいアルキレン、またはアルケニレンを表す。Ｘは、酸素原子または硫黄原子を意味する。
Ｒ^４は、置換されていてもよいイミダゾール-4-イル、置換されていてもよいベンズイミダゾール-2-イル、置換されていてもよい1,2,3-トリアゾール-4-イル、または置換されていてもよい1,2,4-トリアゾール-3-イルを表す。]
で表される５員環化合物もしくはその薬学上許容される塩、またはそれらのプロドラッグ。

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic hetero Represents aryl.
R ² represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or —CON (R ⁶ ) R ⁷ is represented.
R ⁶ represents a hydrogen atom or an optionally substituted alkyl. R ⁷ represents an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted alkyl. Moreover, -N (R ⁶ ) R ⁷ may represent a cyclic amino.
Y ¹ represents a single bond, optionally substituted _{alkylene, -CO (CH 2) n -} , - SO 2 (CH 2) n -, - CONH (CH 2) n -, - CSNH (CH 2) n -, or -COO (CH _{2) n} - represents a.
n represents an integer of 0 to 5.
The wavy line means (E) or (Z) coordination.
R ³ represents a hydrogen atom, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or an optionally substituted cycloalkyl. .
Y ² represents optionally substituted alkylene, alkenylene, or —A—X—B—. A and B may be the same or different and each represents an optionally substituted alkylene or alkenylene. X means an oxygen atom or a sulfur atom.
R ⁴ is optionally substituted imidazol-4-yl, optionally substituted benzimidazol-2-yl, optionally substituted 1,2,3-triazol-4-yl, or substituted 1,2,4-triazol-3-yl optionally represented. ]
Or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[2] The 5-membered ring compound according to the above 1, or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R ¹ is a hydrogen atom, and R ² is optionally substituted phenyl.
[3] The 5-membered ring compound according to 1 or a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein R ¹ is a hydrogen atom and R ² is morpholinophenyl.
[4] The 5-membered ring compound or the pharmaceutically acceptable salt thereof according to ¹ to ³ , wherein R ¹ is a hydrogen atom, R ³ is optionally substituted phenyl, Y ¹ is a single bond, and Y ² is alkylene. , Or their prodrugs.
[5] The 5-membered ring compound or the pharmaceutically acceptable salt thereof according to ¹ to ³ , wherein R ¹ is a hydrogen atom, R ³ is optionally substituted pyridyl, Y ¹ is a single bond, and Y ² is alkylene. , Or their prodrugs.
[6] The 5-membered ring compound according to 1 to 5, wherein R ⁴ is optionally substituted imidazol-4-yl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
[7] The 5-membered ring compound according to 1 to 5 above, wherein R ⁴ is imidazol-4-yl, or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
[8] The 5-membered ring compound or the pharmaceutically acceptable salt thereof according to 1 to 5, wherein R ⁴ is 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, Or their prodrugs.
[9] A medicament comprising the 5-membered ring compound according to any one of 1 to 8 above or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
[10] A leukocyte infiltration inhibitor containing the 5-membered ring compound according to any one of 1 to 8 above or a pharmaceutically acceptable salt thereof, or a prodrug thereof.
[11] A therapeutic agent for an autoimmune disease or allergic disease comprising the 5-membered ring compound or the pharmaceutically acceptable salt thereof according to any one of 1 to 8 above, or a prodrug thereof.
[12] A therapeutic agent for allergic diseases comprising the 5-membered ring compound according to any one of 1 to 8 above or a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[13] Formula (2)

[式中、ＳＳは固相反応担体を表す。Ｙ^２は、置換されていてもよいアルキレン、アルケニレン、または-Ａ-Ｘ-Ｂ-を表す。Ａ、Ｂは同一または異なっていてもよく、それぞれ置換されていてもよいアルキレン、またはアルケニレンを表す。Ｒ^５は、水素原子、アルキル、アルコキシ、ハロゲン原子、または水酸基である。Ｚ^１は、アミノ基の保護基を表し、Ｚ^２は、水素原子を示す。また、Ｚ^１およびＺ^２は結合する窒素原子と一緒になってフタルイミドまたはマレイミドを形成していてもよい。] で表される合成中間体。
[１４] 式（３）

[Wherein SS represents a solid phase reaction carrier. Y ² represents optionally substituted alkylene, alkenylene, or —A—X—B—. A and B may be the same or different and each represents an optionally substituted alkylene or alkenylene. R ⁵ is a hydrogen atom, alkyl, alkoxy, halogen atom, or hydroxyl group. Z ¹ represents an amino-protecting group, and Z ² represents a hydrogen atom. Z ¹ and Z ² may be combined with the nitrogen atom to form phthalimide or maleimide. ] The synthetic intermediate represented by this.
[14] Formula (3)

[式中、Ｙ^２は、置換されていてもよいアルキレン、アルケニレン、または-Ａ-Ｘ-Ｂ-を表す。Ａ、Ｂは同一または異なっていてもよく、それぞれ置換されていてもよいアルキレン、またはアルケニレンを表す。Ｘは、酸素原子または硫黄原子を意味する。Ｒ^５は、水素原子、アルキル、アルコキシ、ハロゲン原子、または水酸基である。Ｚ^１は、アミノ基の保護基を表し、Ｚ^２は、水素原子を示す。また、Ｚ^１およびＺ^２は結合する窒素原子と一緒になってフタルイミドまたはマレイミドを形成していてもよい。]
で表される化合物と式（４）

[Wherein Y ² represents an optionally substituted alkylene, alkenylene, or —A—X—B—. A and B may be the same or different and each represents an optionally substituted alkylene or alkenylene. X means an oxygen atom or a sulfur atom. R ⁵ is a hydrogen atom, alkyl, alkoxy, halogen atom, or hydroxyl group. Z ¹ represents an amino-protecting group, and Z ² represents a hydrogen atom. Z ¹ and Z ² may be combined with the nitrogen atom to form phthalimide or maleimide. ]
And a compound represented by formula (4)

[式中、Ｘは酸素原子または硫黄原子を表す。ＳＳは固相反応担体を表す。]で表される固相反応担体を反応することを特徴とする式（２）

[Wherein, X represents an oxygen atom or a sulfur atom. SS represents a solid phase reaction carrier. Formula (2) characterized by reacting with a solid phase reaction carrier represented by

[式中、Ｙ^２、Ｒ^５、Ｚ^１、Ｚ^２、ＳＳは、前記と同義である。]
で表される化合物の製造方法。

[Wherein, Y ² , R ⁵ , Z ¹ , Z ² , SS are as defined above. ]
The manufacturing method of the compound represented by these.

[15] Compound (6)

[式中、Ｒ^１は、水素原子、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、または置換されていてもよい二環式ヘテロアリールを表す。
Ｒ^２は、水素原子、置換されていてもよいアルキル、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、置換されていてもよい二環式ヘテロアリール、または-ＣＯＮ(Ｒ^６)Ｒ^７を表す。
Ｒ^６は、水素原子または置換されていてもよいアルキルを表す。Ｒ^７は、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、または置換されていてもよいアルキルを表す。また、-Ｎ(Ｒ^６)Ｒ^７は環状アミノを表してもよい。
Ｙ^１は、単結合、置換されていてもよいアルキレン、-ＣＯ(ＣＨ_２)_ｎ-、-ＳＯ_２(ＣＨ_２)_ｎ-、-ＣＯＮＨ(ＣＨ_２)_ｎ-、-ＣＳＮＨ(ＣＨ_２)_ｎ-、または-ＣＯＯ(ＣＨ_２)_ｎ-を表す。
ｎは０から５の整数を表す。
波線は、(Ｅ)または(Ｚ)配位を意味する。
Ｒ^３は、水素原子、置換されていてもよいアリール、置換されていてもよい単環式ヘテロアリール、置換されていてもよい二環式ヘテロアリール、または置換されていてもよいシクロアルキルを表す。
Ｙ^２は、置換されていてもよいアルキレン、アルケニレン、または-Ａ-Ｘ-Ｂ-を表す。 Ｒ^５は、水素原子、アルキル、アルコキシ、ハロゲン原子、または水酸基である。およびＳＳは固相反応担体を表す。]
を、フッ素イオン試薬と反応させることを特徴とする、式（１’）

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic hetero Represents aryl.
R ² represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or —CON (R ⁶ ) R ⁷ is represented.
R ⁶ represents a hydrogen atom or an optionally substituted alkyl. R ⁷ represents an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted alkyl. Moreover, -N (R ⁶ ) R ⁷ may represent a cyclic amino.
Y ¹ represents a single bond, optionally substituted _{alkylene, -CO (CH 2) n -} , - SO 2 (CH 2) n -, - CONH (CH 2) n -, - CSNH (CH 2) n -, or -COO (CH _{2) n} - represents a.
n represents an integer of 0 to 5.
The wavy line means (E) or (Z) coordination.
R ³ represents a hydrogen atom, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or an optionally substituted cycloalkyl. .
Y ² represents optionally substituted alkylene, alkenylene, or —A—X—B—. R ⁵ is a hydrogen atom, alkyl, alkoxy, halogen atom, or hydroxyl group. And SS represent solid phase reaction carriers. ]
Is reacted with a fluorine ion reagent, formula (1 ′)

[式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^５、Ｙ^１、Ｙ^２およびＳＳは前記と同義である。]
で表される５員環化合物の製造方法。

[Wherein, R ¹ , R ² , R ³ , R ⁵ , Y ¹ , Y ² and SS are as defined above. ]
The manufacturing method of the 5-membered ring compound represented by these.

  The 5-membered ring compound of the present invention or a salt thereof, or a prodrug thereof inhibits the infiltration of leukocytes such as eosinophils and lymphocytes, thereby being useful for the treatment of various inflammations.

Throughout this specification, the term of each substituent has the following meaning.
“Alkyl” includes, for example, linear or branched C ₁ -C ₆ alkyl, and specifically includes methyl, ethyl, n-propyl, 2-propyl, n-butyl, 2-butyl, 3-butyl, and the like. Examples thereof include methyl-2-propyl, 1,1-dimethylethyl, n-pentyl, n-hexyl and the like, preferably methyl, ethyl, n-propyl and 2-propyl.
Examples of the substituent in the “optionally substituted alkyl” include a hydroxyl group, a halogen atom, amino, mono- or di (alkyl) amino, carboxy, alkoxycarbonyl, alkoxy, carbamoyl, mono- or di (alkyl) carbamoyl, and cyclic amino. Group, alkoxyalkoxy, hydroxyalkoxy, carboxyalkoxy, alkanoyloxy, aryloxy, aryl, arylcarbonylamino, arylamino, arylalkylamino, alkanoylamino, alkylthio, cycloalkyl, arylalkoxy, arylalkyl (alkyl) amino, arylsulfonyl Alkylsulfonyl, carbamoylalkoxy, mono or di (alkyl) carbamoylalkoxy, arylsulfonylamino, arylcarbamo (The alkyl mentioned here may be substituted with alkoxy, alkoxycarbonyl, carboxy, dialkylamino, hydroxyl group. The aryl mentioned here is alkyl, alkoxy, halogen atom, hydroxyl group. May be substituted). The substituent is selected from one of these, or two or more of the same or different. For example, alkyl substituted with 1 to 3, preferably 1 to 2 of the same or different substituents.
“Alkoxy” includes, for example, linear or branched C ₁ -C ₆ alkoxy, and specifically includes methoxy, ethoxy, n-propoxy, 2-propoxy, n-butoxy, 1,1-dimethylethoxy. , N-pentyloxy, n-hexyloxy and the like, preferably methoxy, ethoxy, n-propoxy and 2-propoxy.
“Alkylamino” includes, for example, amino substituted with linear or branched C ₁ -C ₆ alkyl, specifically, methylamino, ethylamino, n-propylamino, 2-propylamino, Examples include n-butylamino, 2-butylamino, 1-methylpropylamino, 1,1-dimethylethylamino, n-pentylamino, n-hexylamino, and preferably methylamino and ethylamino.
“Dialkylamino” includes, for example, amino substituted with two linear or branched C ₁ -C ₆ alkyl, specifically, dimethylamino, diethylamino, ethylmethylamino, di-n-propyl. Amino, di-n-butylamino, etc. are mentioned, Preferably dimethylamino and diethylamino are mentioned.
Examples of the “halogen atom” include fluorine, chlorine, bromine and iodine, preferably fluorine, chlorine and bromine.
Examples of “cycloalkyl” include C ₃ -C ₈ cycloalkyl, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
Examples of the substituent of “optionally substituted cycloalkyl” include alkyl, alkoxy, hydroxyl group and the like.

“Alkoxycarbonyl” includes, for example, linear or branched C ₁ -C ₆ alkoxycarbonyl, and specifically includes methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, 2-propoxycarbonyl, n-butoxycarbonyl. , 2-butoxycarbonyl, 1-methylpropoxycarbonyl, 1,1-dimethylethoxycarbonyl, n-pentyloxycarbonyl, n-hexyloxycarbonyl and the like.
Examples of “alkanoyl” include linear or branched C ₁ -C ₇ alkanoyl, and specifically include formyl, acetyl, propanoyl, butanoyl, pentanoyl, pivaloyl, hexanoyl, heptanoyl and the like.
“Alkylcarbamoyl” includes, for example, linear or branched C ₁ -C ₆ alkyl-substituted carbamoyl, and specifically includes methylcarbamoyl, ethylcarbamoyl, n-propylcarbamoyl, 2-propylcarbamoyl, n-butyl Examples include rucarbamoyl, 2-butylcarbamoyl, 3-methyl-2-propylcarbamoyl, 1,1-dimethylethylcarbamoyl, n-pentylcarbamoyl, n-hexylcarbamoyl and the like.
“Dialkylcarbamoyl” includes, for example, carbamoyl substituted with two linear or branched C ₁ -C ₆ alkyl, specifically, dimethylcarbamoyl, diethylcarbamoyl, ethylmethylcarbamoyl, di-n- Examples include propylcarbamoyl, di-n-butylcarbamoyl and the like.
“Alkylthio” includes, for example, linear or branched C ₁ -C ₆ alkylthio, and specifically includes methylthio, ethylthio, n-propylthio, 2-propylthio, n-butylthio, 2-butylthio, 1- Examples thereof include methylpropylthio, 1,1-dimethylethylthio, n-pentylthio, n-hexylthio and the like.
Examples of the “alkylsulfonyl” include linear or branched C ₁ -C ₆ alkylsulfonyl, specifically, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, 2-propylsulfonyl, n-butylsulfonyl. , 2-butylsulfonyl, 1-methylpropylsulfonyl, 1,1-dimethylethylsulfonyl, n-pentylsulfonyl, n-hexylsulfonyl and the like.

Examples of the “alkylene” include linear or branched C ₁ -C ₆ alkylene, and specifically include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, methylethylene, 2-methyltrimethylene, 2 , 2-dimethyltrimethylene, hexamethylene and the like. Preferred examples of the “alkylene” in Y ² excluding A and B included in —A—X—B— include linear or branched C ₁ -C ₄ alkylene, and more preferably, linear or branched _C 2 -C ₄ alkylene and the like, particularly preferably ethylene, and trimethylene. Preferable examples of “alkylene” in A and B contained in Y ² include linear or branched C ₁ -C ₄ alkylene, more preferably methylene and ethylene.
Examples of the substituent in the “optionally substituted alkylene” include a hydroxyl group, alkoxy, halogen atom, amino, alkanoylamino and the like, and the substituent may be substituted with 1 to 3 substituents arbitrarily selected from these. Preferably, it can be substituted with 1 to 2 substituents. Specific examples of the substituted alkylene include 2-hydroxytrimethylene.
Examples of “alkenylene” include linear or branched C ₃ -C ₆ alkenylene, and specific examples include propenylene, butenylene, 2-butenylene, pentenylene, 2-pentenylene, 3-pentenylene, and the like. May include propenylene.

“Aryl” includes, for example, C ₆ -C ₁₀ aryl, and specifically includes phenyl, naphthyl and the like, and preferably includes phenyl.
Examples of the substituent in the “optionally substituted aryl” include alkyl, alkoxy, halogen-substituted alkoxy, hydroxyl group, cyclic amino group, monocyclic heteroaryl, halogen atom, carboxy, cyano, amino, mono or di (alkyl ) Amino, nitro, halogen-substituted alkyl or cycloalkyl, cycloalkyl, cycloalkylalkyl, methylenedioxy, ethylenedioxy, alkoxycarbonyl, carbamoyl, mono or di (alkyl) carbamoyl, alkylthio, alkylsulfinyl, alkylsulfonyl Sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl, aryl, aryl substituted with a group selected from alkyl, alkoxy, halogen atom and hydroxyl group, etc. The Preferred substituents include alkyl, alkoxy, halogen-substituted alkoxy, hydroxyl group, cyclic amino group, monocyclic heteroaryl, halogen atom, alkyl substituted with a halogen atom or hydroxyl group, methylenedioxy, and the like. Examples include alkyl, alkoxy, halogen-substituted alkoxy, hydroxyl group, cyclic amino group, halogen atom, methylenedioxy and the like. These substituents are the same or different. For example, 1 to 3 can be substituted with aryl, and preferably 1 to 2 can be substituted. Preferable examples of the substituent for the substituted aryl in R ² include C ₁ -C ₄ alkoxy, trifluoromethoxy, morpholino, halogen atom, methylenedioxy and the like. Particularly preferred is morpholino. Preferable examples of the substituent for substituted aryl in R ³ include C ₁ -C ₄ alkoxy, trifluoromethoxy, morpholino, halogen atom, methylenedioxy and the like.
The “cyclic amino group” includes, for example, a 5-membered or 6-membered cyclic amino group which may further contain an oxygen atom or a nitrogen atom as a ring-forming hetero atom, specifically, pyrrolidino, piperidino, Morpholino and the like can be mentioned. These may be substituted. Examples of the substituent include alkyl, alkoxy, halogen-substituted alkoxy, halogen atom, alkyl substituted with a halogen atom or a hydroxyl group, optionally substituted aryl, and monocyclic heteroaryl. , Bicyclic heteroaryl, preferably alkyl, alkyl substituted with a halogen atom or a hydroxyl group, optionally substituted aryl, and monocyclic heteroaryl. In the cyclic amino group in —N (R ⁶ ) R ⁷ , the benzene ring may be condensed to a 5-membered or 6-membered cyclic amino group which may further contain an oxygen atom or a nitrogen atom as a ring-forming hetero atom. . Examples of such cyclic amino groups include benzopiperidino, benzopyrrolidinyl, benzomorpholino and the like.

The “monocyclic heteroaryl” includes, for example, 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom (however, an oxygen atom and a sulfur atom are not simultaneously contained). Specific examples include heteroaryl such as thienyl, furyl, pyrrolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, and the like. Preferably, pyridyl is mentioned.
Examples of the “bicyclic heteroaryl” include 1 to 3 heteroatoms selected from a nitrogen atom, an oxygen atom, and a sulfur atom (however, oxygen and sulfur atoms are not included at the same time) 5 or 6 A fused heteroaryl in which a membered heteroaryl and a benzene ring are condensed. Specific examples include benzofuryl, benzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl, quinolyl, isoquinolyl, quinazolyl, phthalazinyl, quinoxalinyl and the like.
Examples of the substituent in “optionally substituted monocyclic heteroaryl” and “optionally substituted bicyclic heteroaryl” include alkyl, alkoxy, halogen atom, hydroxyl group and the like. Preferred are alkyl, alkoxy and halogen atoms. The substituents may be the same or different and 1 to 3 may be substituted with monocyclic heteroaryl, and preferably 1 to 2 may be substituted.
"Optionally substituted imidazol-4-yl", "optionally substituted benzimidazole", "optionally substituted 1,2,3-triazol-4-yl" and "substituted Examples of the substituent in “may be 1,2,4-triazol-3-yl” include alkyl, alkoxy, halogen atom, hydroxyl group and the like, and preferably include methyl, ethyl and methoxy.

  “Prodrug” refers to a compound that is hydrolyzed in vivo to regenerate the 5-membered ring compound of the present invention. Prodrugs of the present invention include compounds produced by all prodrugation techniques known to those skilled in the art. For example, when the 5-membered ring compound of the present invention has a carboxyl group or an amino group, a compound derived from such an ester group or amide group that can be easily hydrolyzed in vivo corresponds to a prodrug. . When the 5-membered ring compound has a carboxyl group, the carboxyl group is selected from alkyl such as methyl and ethyl, methyloxymethyl, ethyloxymethyl, 2-methyloxyethyl, 2-methyloxyethyloxymethyl and the like. Alkyloxyalkyl, pivaloyloxymethyl, acetyloxymethyl, cyclohexylacetyloxymethyl, acyloxymethyl such as 1-methylcyclohexylcarbonyloxymethyl, alkoxycarbonylalkyl such as ethyloxycarbonyloxy-1-ethyl, cyclohexyloxycarbonyloxy- And compounds derived from cycloalkyloxycarbonylalkyl such as 1-ethyl. When the 5-membered ring compound has an amino group, a compound in which the amino group is derived to acetamide or the like can be mentioned.

As the “solid phase reaction carrier”, any carrier that does not affect the reaction and that is usually used in a solid phase reaction may be used. Examples thereof include a polymer solid phase and a silica solid phase.
The “protecting group for the amino group in Z1” can be any of various commonly used protecting groups. For example, t-butyl carbamate group, 9-fluorenylmethyl carbamate group, acetyl group, benzoyl group are preferable. , A benzyl group and the like.
Examples of the “fluorine ion reagent” include tetra-lower alkyl ammonium fluoride or tri-lower alkyl aryl-lower alkyl ammonium fluoride, and specific examples include tetraethyl ammonium fluoride or tetrabutyl ammonium fluoride.
The 5-membered ring compound of the formula (1) 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 inorganic acids such as hydrochloride, hydrobromide, and sulfate, organic acids such as citrate, oxalate, malate, tartrate, fumarate, and maleate. Examples of the base addition salt include inorganic base salts such as sodium salt and calcium salt, and organic base salts such as meglumine salt and trishydroxymethylaminomethane salt.
The compounds included in the present invention may have asymmetry or a substituent having an asymmetric carbon, and optical isomers may exist. The present invention includes a mixture or an isolated form of each of these isomers. The present invention also includes solvates such as hydrates of 5-membered ring compounds or pharmaceutically acceptable salts thereof.
The 5-membered ring compound of the formula (1) of the present invention can be produced by the following method and a method analogous thereto.
Manufacturing method 1
Compound (1) can be produced by the following method.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｙ^１およびＹ^２は前記と同義である。Ｘ^１は塩素原子、臭素原子等のハロゲン原子、メタンスルホニルオキシ基、または４−メチルフェニルスルホニルオキシ基等を表す］
化合物（１）は、チオウレア化合物とα−ハロケトン（３）を溶媒中、塩基の存在下または非存在下に反応させる事により製造できる。溶媒としては、例えば、メタノール、エタノール、２−プロパノール等のアルコール溶媒、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，２−ジメトキシエタン等のエーテル溶媒、ジクロロメタン、クロロホルム等のハロゲン化炭化水素溶媒、アセトニトリル、ジメチルホルムアミド、Ｎ−メチルピロリジノン等の非プロトン性極性溶媒、トルエン、ベンゼン等の芳香族炭化水素溶媒、酢酸等の酸性溶媒等が挙げられ、塩基としては、炭酸カリウム、炭酸水素ナトリウム、水酸化ナトリウム等の無機塩基、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の有機塩基が挙げられ、反応温度は０℃から溶媒の沸点の範囲から選択される。

[Wherein, R ¹ , R ² , R ³ , R ⁴ , Y ¹ and Y ² have the same meanings as described above. X ¹ represents a halogen atom such as a chlorine atom or a bromine atom, a methanesulfonyloxy group, or a 4-methylphenylsulfonyloxy group.
Compound (1) can be produced by reacting a thiourea compound and α-haloketone (3) in a solvent in the presence or absence of a base. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as dichloromethane and chloroform, acetonitrile, Examples include aprotic polar solvents such as dimethylformamide and N-methylpyrrolidinone, aromatic hydrocarbon solvents such as toluene and benzene, and acidic solvents such as acetic acid. Examples of the base include potassium carbonate, sodium bicarbonate, sodium hydroxide. Inorganic bases such as triethylamine, pyridine, 4-dimethylaminopyridine and the like, and the reaction temperature is selected from the range of 0 ° C. to the boiling point of the solvent.

Manufacturing method 2
Compound (1) can also be produced by the following method. In this production method, when the substituent of R ⁴ is highly reactive, or for the convenience of taking out the intermediate, the heterocyclic or heterocyclic substituent is protected in advance and reacted with an α-haloketone before deprotection. To do. Examples of the protecting group include general heterocyclic protecting groups such as an alkoxycarbonyl group such as 2-methyl-2-propyloxycarbonyl group and a sulfonyl group such as 4-methylphenylsulfonyl group. Hereinafter, the case where the protecting group is 2-methyl-2-propyloxycarbonyl will be described as an example.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ^１、Ｙ^１およびＹ^２は前記と同義である。Ｂｏｃは、２−メチル−２−プロピルオキシカルボニルを表す。］
化合物（５）は、予め保護したチオウレア化合物（４）とα−ハロケトン等（３）を溶媒中、塩基の存在下または非存在下に反応させる事により製造できる。溶媒としては、例えば、メタノール、エタノール、２−プロパノール等のアルコール溶媒、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，２−ジメトキシエタン等のエーテル溶媒、ジクロロメタン、クロロホルム等のハロゲン化炭化水素溶媒、アセトニトリル、ジメチルホルムアミド、Ｎ−メチルピロリジノン等の非プロトン性極性溶媒、トルエン、ベンゼン等の芳香族炭化水素溶媒が挙げられ、塩基としては、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の有機塩基が挙げられ、反応温度は０℃から溶媒の沸点の範囲から選択される。
次いで化合物（５）を酸もしくは塩基の存在下、溶媒中、或いは無溶媒で脱保護する事によって、化合物（１）が取得出来る。酸としては例えば、塩酸、臭化水素酸等の無機酸、トリフルオロ酢酸、トリフルオロメタンスルホン酸等の有機酸が挙げられ、塩基としては水酸化ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の有機塩基が挙げられる。溶媒としては、例えば、メタノール、エタノール、２−プロパノール等のアルコール溶媒、ジエチルエーテル、テトラヒドロフラン（ＴＨＦ）、１，２−ジメトキシエタン、１，４−ジオキサン等のエーテル溶媒、ジクロロメタン、ジクロロエタン、クロロホルム等のハロゲン化炭化水素溶媒等、アセトニトリル、ジメチルホルムアミド、Ｎ−メチルピロリジノン等の非プロトン性極性溶媒、が挙げられ、反応温度は０℃から溶媒の沸点の範囲から選択される。

[Wherein, R ¹ , R ² , R ³ , R ⁴ , X ¹ , Y ¹ and Y ² have the same meanings as described above. Boc represents 2-methyl-2-propyloxycarbonyl. ]
Compound (5) can be produced by reacting a previously protected thiourea compound (4) with α-haloketone or the like (3) in a solvent in the presence or absence of a base. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,2-dimethoxyethane, halogenated hydrocarbon solvents such as dichloromethane and chloroform, acetonitrile, Examples include aprotic polar solvents such as dimethylformamide and N-methylpyrrolidinone, and aromatic hydrocarbon solvents such as toluene and benzene. Examples of the base include inorganic bases such as potassium carbonate and sodium bicarbonate, triethylamine, pyridine, 4- Examples include organic bases such as dimethylaminopyridine, and the reaction temperature is selected from the range of 0 ° C. to the boiling point of the solvent.
Next, compound (1) can be obtained by deprotecting compound (5) in the presence of an acid or base in a solvent or without a solvent. Examples of the acid include inorganic acids such as hydrochloric acid and hydrobromic acid, and organic acids such as trifluoroacetic acid and trifluoromethanesulfonic acid. Examples of the base include inorganic bases such as sodium hydroxide, potassium carbonate, and sodium bicarbonate. Organic bases such as triethylamine, pyridine, 4-dimethylaminopyridine are exemplified. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,2-dimethoxyethane and 1,4-dioxane, dichloromethane, dichloroethane, chloroform and the like. Examples include halogenated hydrocarbon solvents, and aprotic polar solvents such as acetonitrile, dimethylformamide, N-methylpyrrolidinone, and the reaction temperature is selected from the range of 0 ° C. to the boiling point of the solvent.

Manufacturing method 3
Compound (1) can also be produced by the following method. In this production method, R ⁴ is converted from other precursor functional groups after a 5-membered ring is constructed.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｘ^１、Ｙ^１およびＹ^２は前記と同じ意味を有する。Ｚはニトリル、エステル、アルキン等のヘテロ環前駆官能基を表す。］
上記製造方法１および２において述べた手法により、チオウレア化合物（６）から化合物（７）を取得し、前駆官能基をヘテロアリールに変換する。この変換においては、通常、有機化学において用いられている方法を使用する事が出来る。例えば、ニトリル基をトリアゾール、テトラゾール等へ、エステル基をヒドロキシピラゾール等へ、アミド基をオキサゾール等へ、アルキンをイソキサゾール、ピラゾール等へ変換する事が出来る。この変換方法については、例えば以下に記載されている。
Comprehensive Heterocyclic Chemistry, Vol. 1-8 (Pergamon Press)
Comprehensive Heterocyclic Chemistry II, Vol. 1-8 (Pergamon Press)
1,3-Dipolar Cycloaddition Chemistry, Vol. 1-2 (A Wieley-Interscience Publication)

[Wherein R ¹ , R ² , R ³ , R ⁴ , X ¹ , Y ¹ and Y ² have the same meaning as described above. Z represents a heterocyclic precursor functional group such as nitrile, ester or alkyne. ]
By the method described in the above production methods 1 and 2, compound (7) is obtained from thiourea compound (6), and the precursor functional group is converted to heteroaryl. In this conversion, a method usually used in organic chemistry can be used. For example, a nitrile group can be converted to triazole, tetrazole, etc., an ester group can be converted to hydroxypyrazole, etc., an amide group can be converted to oxazole, etc., and an alkyne can be converted to isoxazole, pyrazole, etc. This conversion method is described below, for example.
Comprehensive Heterocyclic Chemistry, Vol. 1-8 (Pergamon Press)
Comprehensive Heterocyclic Chemistry II, Vol. 1-8 (Pergamon Press)
1,3-Dipolar Cycloaddition Chemistry, Vol. 1-2 (A Wieley-Interscience Publication)

  The raw material compounds used in the production methods 1 to 3 are produced by the following method.

［式中、Ｒ^３、Ｒ^４、Ｙ^１およびＹ^２は前記と同じ意味を有する。Ｒ^１０はアルキルを表す。］
チオウレア化合物（２）は、アミン化合物（８）とイソチオシアネート化合物（９）、またはジチオカルバミド酸エステル（１０）とを溶媒中で反応させることで製造できる。アミン化合物が塩の場合などには必要に応じて塩基を添加する。溶媒としては例えば、メタノール、エタノール、２−プロパノール等のアルコール溶媒、ジエチルエーテル、ＴＨＦ等のエーテル溶媒、ジクロロメタン、ジクロロエタン、クロロホルム等のハロゲン化炭化水素溶媒、アセトニトリル、ジメチルホルムアミド等の非プロトン性溶媒、トルエン等の芳香族溶媒等が挙げられる。塩基としては水酸化ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の有機塩基が挙げられる。反応温度は０℃から溶媒の沸点の範囲から選択される。また、用いるアミン化合物（８）に関しては必要に応じてイソチオシアネート化合物との反応に先立ちＲ^４上、もしくはＲ^４上の置換基上に保護を施したものを用いる事が出来る。さらに得られるチオウレア化合物（２）も同様に必要に応じて反応後に保護を施す事が出来る。上記保護基としては、２−メチル−２−プロピルオキシカルボニル基等のアルコキシカルボニル基、４−メチルフェニルスルホニル基等のスルホニル基等、一般的なヘテロ環の保護基が挙げられる。保護基の導入においては有機化学で通常用いられる手法を用いる事が出来る。

[Wherein R ³ , R ⁴ , Y ¹ and Y ² have the same meaning as described above. R ¹⁰ represents alkyl. ]
The thiourea compound (2) can be produced by reacting the amine compound (8) with the isothiocyanate compound (9) or the dithiocarbamic acid ester (10) in a solvent. When the amine compound is a salt, a base is added as necessary. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as acetonitrile and dimethylformamide, An aromatic solvent such as toluene may be used. Examples of the base include inorganic bases such as sodium hydroxide, potassium carbonate and sodium hydrogen carbonate, and organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine. The reaction temperature is selected from the range of 0 ° C. to the boiling point of the solvent. Further, using the amine compound (8) with respect on R ⁴ prior to the reaction with an isothiocyanate compound, if desired, or it can be used those subjected to protection on a substituent on R ^4. Furthermore, the thiourea compound (2) obtained can be similarly protected after the reaction, if necessary. Examples of the protecting group include general heterocyclic protecting groups such as alkoxycarbonyl groups such as 2-methyl-2-propyloxycarbonyl group and sulfonyl groups such as 4-methylphenylsulfonyl group. In introducing the protecting group, a method usually used in organic chemistry can be used.

［式中、Ｒ^３、Ｒ^４、Ｙ^１およびＹ^２は前記と同じ意味を有する。Ｒ^１１はアルキルを表す。］
チオウレア化合物（２）は、アミン化合物（１１）とイソチオシアネート化合物（１２）またはジチオカルバミド酸エステル（１３）とを溶媒中で反応させることで製造できる。アミン化合物が塩の場合には必要に応じて塩基を添加する。溶媒としては例えば、メタノール、エタノール、２−プロパノール等のアルコール溶媒、ジエチルエーテル、ＴＨＦ等のエーテル溶媒、ジクロロメタン、ジクロロエタン、クロロホルム等のハロゲン化炭化水素溶媒、アセトニトリル、ジメチルホルムアミド等の非プロトン性溶媒、トルエン等の芳香族溶媒等が挙げられる。塩基としては水酸化ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の有機塩基が挙げられる。反応温度は０℃から溶媒の沸点の範囲から選択される。また、用いるイソチオシアネート化合物（１２）に関しては必要に応じてイソチオシアネート化合物との反応に先立ちＲ^４上、もしくはＲ^４上の置換基上に保護を施したものを用いる事が出来る。さらに得られるチオウレア化合物（２）も同様に必要に応じて反応後に保護を施す事が出来る。上記保護基としては保護基としては、２−メチル−２−プロピルオキシカルボニル基等のアルコキシカルボニル基、４−メチルフェニルスルホニル基等のスルホニル基等、一般的なヘテロ環の保護基が挙げられる。保護基の導入においては有機化学で通常用いられる手法を用いる事が出来る。

[Wherein R ³ , R ⁴ , Y ¹ and Y ² have the same meaning as described above. R ¹¹ represents alkyl. ]
The thiourea compound (2) can be produced by reacting the amine compound (11) with the isothiocyanate compound (12) or the dithiocarbamic acid ester (13) in a solvent. When the amine compound is a salt, a base is added as necessary. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as acetonitrile and dimethylformamide, An aromatic solvent such as toluene may be used. Examples of the base include inorganic bases such as sodium hydroxide, potassium carbonate and sodium hydrogen carbonate, and organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine. The reaction temperature is selected from the range of 0 ° C. to the boiling point of the solvent. Furthermore, isothiocyanate compounds (12) as required with respect to on R ⁴ prior to the reaction with an isothiocyanate compound, or it can be used those subjected to protection on a substituent on R ⁴ to be used. Furthermore, the thiourea compound (2) obtained can be similarly protected after the reaction, if necessary. Examples of the protecting group include general heterocyclic protecting groups such as an alkoxycarbonyl group such as 2-methyl-2-propyloxycarbonyl group and a sulfonyl group such as 4-methylphenylsulfonyl group. In introducing the protecting group, a method usually used in organic chemistry can be used.

［式中、Ｒ^３、Ｒ^４、Ｙ^１およびＹ^２は前記と同じ意味を有する。Ｘ^２、およびＸ^３はイミダゾリル基、３−メチルイミダゾリニウム基、メチルチオ基等を表す。］
チオウレア化合物（２）は、アミン化合物（８）とチオカルボニル化試薬（１４）とを溶媒中で反応させて生成する中間体と、アミン化合物（１１）とを溶媒中で反応させることにより製造できる。アミン化合物が塩の場合には必要に応じて塩基を添加する。溶媒としては例えば、メタノール、エタノール、２−プロパノール等のアルコール溶媒、ジエチルエーテル、ＴＨＦ等のエーテル溶媒、ジクロロメタン、ジクロロエタン、クロロホルム等のハロゲン化炭化水素溶媒、アセトニトリル、ジメチルホルムアミド等の非プロトン性溶媒、トルエン等の芳香族溶媒等が挙げられる。塩基としては水酸化ナトリウム、炭酸カリウム、炭酸水素ナトリウム等の無機塩基、トリエチルアミン、ピリジン、４−ジメチルアミノピリジン等の有機塩基が挙げられる。反応温度は０℃から溶媒の沸点の範囲から選択される。また、用いるアミン化合物（８）に関しては必要に応じてイソチオシアネート化合物との反応に先立ちＲ^４上、もしくはＲ^４上の置換基上に保護を施したものを用いる事が出来る。さらに得られるチオウレア化合物（２）も同様に必要に応じて反応後に保護を施す事が出来る。上記保護基としては保護基としては、２−メチル−２−プロピルオキシカルボニル基等のアルコキシカルボニル基、４−メチルフェニルスルホニル基等のスルホニル基等、一般的なヘテロ環の保護基が挙げられる。保護基の導入においては有機化学で通常用いられる手法を用いる事が出来る。

[Wherein R ³ , R ⁴ , Y ¹ and Y ² have the same meaning as described above. X ² and X ³ represent an imidazolyl group, a 3-methylimidazolinium group, a methylthio group, or the like. ]
The thiourea compound (2) can be produced by reacting the amine compound (8) and the thiocarbonylating reagent (14) in a solvent to produce the intermediate produced by the reaction between the amine compound (11) and the amine compound (11). . When the amine compound is a salt, a base is added as necessary. Examples of the solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether and THF, halogenated hydrocarbon solvents such as dichloromethane, dichloroethane and chloroform, aprotic solvents such as acetonitrile and dimethylformamide, An aromatic solvent such as toluene may be used. Examples of the base include inorganic bases such as sodium hydroxide, potassium carbonate and sodium hydrogen carbonate, and organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine. The reaction temperature is selected from the range of 0 ° C. to the boiling point of the solvent. Further, using the amine compound (8) with respect on R ⁴ prior to the reaction with an isothiocyanate compound, if desired, or it can be used those subjected to protection on a substituent on R ^4. Furthermore, the thiourea compound (2) obtained can be similarly protected after the reaction, if necessary. Examples of the protecting group include general heterocyclic protecting groups such as an alkoxycarbonyl group such as 2-methyl-2-propyloxycarbonyl group and a sulfonyl group such as 4-methylphenylsulfonyl group. In introducing the protecting group, a method usually used in organic chemistry can be used.

The isothiocyanate compound is commercially available, or from the corresponding amino form, for example, Synlett. 1997, 773-774, J. Org. Chem., 1997, 62, 4539-4540, or J. It can be synthesized according to the method described in Med. Chem., 1984, 27, 1570-1574. In addition, the corresponding carboxylic acid is synthesized according to a method described in literatures such as Synth. Commun. 1997, 27, 751-756 or Indian, J. Chem., 1998, 1153-1156. be able to.
The dithiocarbamic acid ester compounds (10) and (13) are commercially available, or from the corresponding amino form, for example, J. Chem. Soc. 1956, 1644-1649, or Syn. Commun. 1984, It can be synthesized according to the method described in the literature such as 537-546.
The α-haloketone compound (3) is commercially available, or from the corresponding ketone body, for example, J. Med. Chem. 1987, 1497-1502, Tetrahedoron Lett. 1998, 4987-4990, or Acta Chim It can be synthesized according to the method described in documents such as Scand. 1986, B40, 700-702.

Manufacturing method 6
Compound (1) is produced by the following method.

［式中、Ｒ^３、Ｒ^４、Ｙ^１およびＹ^２は前記と同義である。］
イミン化合物（１５）に、対応するハロゲン化アルキル、エステル、酸クロリド、酸無水物、クロロぎ酸エステル、スルホニルクロリド、スルホン酸エステル、イソシアナートまたはイソチオシアナート等の化合物を、塩基存在下または非存在下、溶媒中反応させることで、あるいはカルボン酸を反応させることで、化合物（１）を得ることができる。
溶媒としては、例えば、エーテル、ＴＨＦ等のエーテル溶媒、メタノール、エタノール、２−プロパノール等のアルコール溶媒、酢酸、水等が挙げられる。反応温度は０℃から溶媒の沸点の範囲から選択される。

[Wherein, R ³ , R ⁴ , Y ¹ and Y ² are as defined above. ]
To the imine compound (15), the corresponding alkyl halide, ester, acid chloride, acid anhydride, chloroformate, sulfonyl chloride, sulfonate, isocyanate, or isothiocyanate is added in the presence or non-existence of a base. Compound (1) can be obtained by reacting in a solvent in the presence or by reacting carboxylic acid.
Examples of the solvent include ether solvents such as ether and THF, alcohol solvents such as methanol, ethanol and 2-propanol, acetic acid and water. The reaction temperature is selected from the range of 0 ° C. to the boiling point of the solvent.

Manufacturing method 7
General formula (5) can also be produced by the following method.

［式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｘ、Ｘ^１、Ｙ^１、Ｙ^２は前記と同義である。Ｒ^５は、アルキル基、アルコキシ基、水酸基、ハロゲン原子、水素原子を表す。Ｚ^１は、アミノ基の保護基として一般的に用いられる置換基、例えばt-ブチルカルバメート基、9-フルオレニルメチルカルバメート基、アセチル基、ベンゾイル基、ベンジル基等を表し、Ｚ^２は水素原子を示す。また、Ｚ^１およびＺ^２は一緒にフタルイミドまたはマレイミドを形成していてもよい。ＳＳは、ポリマー固相、シリカ固相等の固相反応担体を表す。Ｌはトリチル基、置換トリチル基、またはフェニルスルホニル基を表す。］
本製造方法は、一般式（１６）で示されるイミダゾール−４−イル誘導体を、一般式（１７）で示される固相反応担体に反応連結し、得られる化合物（１８）から、公知反応を利用して化合物（２１）を得て、これを酸性試薬または、フッ素イオン試薬との反応で固相反応担体から切り出すことにより、一般式（１'）に示す化合物を得る方法である。

[Wherein, R ¹ , R ² , R ³ , X, X ¹ , Y ¹ , Y ² are as defined above]. R ⁵ represents an alkyl group, an alkoxy group, a hydroxyl group, a halogen atom, or a hydrogen atom. Z ¹ represents a substituent generally used as a protecting group for an amino group, such as t-butyl carbamate group, 9-fluorenylmethyl carbamate group, acetyl group, benzoyl group, benzyl group, etc. Z ² represents hydrogen Indicates an atom. Z ¹ and Z ² may together form phthalimide or maleimide. SS represents a solid phase reaction carrier such as a polymer solid phase or a silica solid phase. L represents a trityl group, a substituted trityl group, or a phenylsulfonyl group. ]
In this production method, an imidazol-4-yl derivative represented by the general formula (16) is ligated to a solid phase reaction carrier represented by the general formula (17), and a known reaction is utilized from the resulting compound (18). Thus, compound (21) is obtained, and this is cleaved from the solid phase reaction carrier by reaction with an acidic reagent or a fluorine ion reagent to obtain the compound represented by general formula (1 ′).

  Compound (18) can be produced by reacting the imidazol-4-yl derivative represented by general formula (16) with a solid phase reaction carrier (17) in a solvent in the presence or absence of a base. Examples of the base include pyridine, triethylamine, and diisopropylethylamine, and examples of the solvent include dichloromethane and dimethylformamide. The reaction temperature is selected from the range from 0 ° C. to the boiling point of the solvent. Next, from (18), the amine compound (19) is obtained by a general deprotection technique. Next, the thiourea compound (20) can be obtained by reacting the amine compound (19) and the isothiocyanate compound (9) in a solvent. When the amine compound (19) forms a salt, a base such as triethylamine is added as necessary. Examples of the solvent include dichloromethane and dimethylformamide. The reaction temperature is selected from the range from 0 ° C. to the boiling point of the solvent. Next, compound (21) can be obtained by reacting thiourea compound (20) with α-haloketone and the like (3) in a solvent in the presence or absence of a base. For example, toluene is used as the solvent. As the base, for example, diisopropylethylamine is used. The reaction temperature is selected from the range from 0 ° C. to the boiling point of the solvent. Next, compound (21) is cleaved with an acidic reagent when L is a trityl group or substituted trityl group in a solvent, and with a fluorine reagent when L is a phenylsulfonyl group, to obtain compound (1). . Examples of the acidic reagent include trifluoroacetic acid and methanesulfonic acid. Examples of the fluorine reagent include tetrabutylammonium fluoride. Examples of the solvent include dichloromethane and tetrahydrofuran. The reaction temperature is selected from the range from 0 ° C. to the boiling point of the solvent.

In carrying out the above reaction, protection and deprotection techniques can be used if necessary. The protection and deprotection techniques are described in detail in, for example, Green et al. (TW Greene and PGM Wuts, “Protecting Groups in Organic Synthesis”, 1991, JOHN WILEY & SONS, INC.).
Moreover, after forming a 5-membered ring, a functional group can also be converted into another functional group. In this conversion, a method usually used in organic chemistry can be used. These methods are described, for example, below.
"Experimental Chemistry" Volume 19-26 (1992, Maruzen)
"Precision Organic Synthesis" (1983, Nanedo)
Compendium of Organic Synthetic Methods, Vol. 1-9 (John Wiley & Sons)
Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon Press)
Comprehensive Organic Transformations (1989, VCH Publishers)
Survey of Organic Syntheses, Vol. 1-2 (1970, 1977, John Wiley & Sons)
Specifically, an ester group, a carboxyl group, an amide group, a hydroxyl group, an ether group and the like can be converted into each other, and a halogen atom can be changed to an amino group and an amino group can be changed to a urea group.

The 5-membered ring compound (1) of the present invention or the intermediate for producing it can be purified by a usual method. Further, when an isomer is present in the 5-membered ring compound (1) of the present invention or an intermediate for producing the compound, it can be purified in the same manner. For example, it can be purified by column chromatography, recrystallization or the like. Examples of the recrystallization solvent include alcohol solvents such as methanol, ethanol and 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, and ketones such as acetone. And solvent solvents, hydrocarbon solvents such as hexane, and mixed solvents thereof.
Examples of a method for obtaining an optical isomer purely include an optical resolution method. As an optical resolution method, when the compound of the present invention or an intermediate thereof has a basic substituent such as an amino group, the compound of the present invention or the intermediate thereof is, for example, in an inert solvent (for example, methanol, ethanol, 2-propanol). Alcohol solvents such as diethyl ether, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, acetonitrile and mixed solvents thereof), optically active acids (for example, mandelic acid) , N-benzyloxyalanine, monocarboxylic acids such as lactic acid, tartaric acid, o-diisopropylidenetartaric acid, dicarboxylic acids such as malic acid, sulfonic acids such as camphorsulfonic acid, bromocamphorsulfonic acid) is there. When the compound of the present invention or an intermediate thereof has an acidic substituent such as a carboxyl group, a salt is formed with an optically active amine (for example, organic amines such as α-phenethylamine, quinine, quinidine, cinchonidine, cinchonine, strychnine). A method can also be adopted. The temperature at which the salt is formed in the optical resolution method is in the range of 0 ° C. 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 collected salt is collected by filtration, it can be cooled as 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 in the range of about 1 equivalent, relative to the substrate. Crystals in an inert solvent as necessary (for example, alcohol solvents such as methanol, ethanol, 2-propanol, ether solvents such as diethyl ether, ester solvents such as ethyl acetate, aromatic hydrocarbon solvents such as toluene, It can be recrystallized with acetonitrile or a mixed solvent thereof to obtain a highly pure optically active salt. If necessary, the obtained salt can be treated with an acid or a base by a conventional method to obtain a free form.

The 5-membered ring compound of the formula (1) or a salt thereof or a prodrug thereof of the present invention is useful as a pharmaceutical, and particularly has an action of suppressing infiltration of leukocytes such as eosinophils and lymphocytes. Thereby, it is useful as a therapeutic agent for autoimmune disease inflammation, allergic inflammation, acute inflammation, and other inflammatory diseases having cell infiltration. Here, examples of the autoimmune disease inflammation include rheumatism, multiple sclerosis, inflammatory bowel disease, type I diabetes and the like. Examples of allergic inflammation include bronchial asthma, inflammatory bowel disease, allergic rhinitis, atopic dermatitis, urticaria, allergic conjunctivitis and the like. Examples of acute inflammation include inflammatory lung disease. Examples of other inflammatory diseases include eosinophilia, eosinophilic vasculitis, eosinophilic granuloma, transplant rejection, tumor metastasis, and the like. When used as an anti-inflammatory agent, it can be used in combination with steroids used as therapeutic agents for inflammatory diseases, enhancing the therapeutic effect and reducing or eliminating steroids with strong side effects. It becomes. When used as a therapeutic agent for allergic diseases, antiallergic agents (such as chemical mediator release inhibitors, antihistamines, antileukotrienes, and antithromboxane agents), and bronchodilators (xanthine preparations such as theophylline) for bronchial asthma, β-stimulants) and anticholinergic agents can be used in combination. When used as a therapeutic agent for autoimmune diseases such as rheumatism, it can be used in combination with non-steroidal anti-inflammatory agents such as cyclooxygenase (COX) inhibitors.
The 5-membered ring compound of the present invention or a salt thereof or a prodrug thereof 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 preparation, nasal preparation and the like. Examples of the oral or rectal administration agent include capsules, tablets, pills, powders, cachets, suppositories, and liquids. Examples of injections include sterile solutions or suspensions. Examples of the topical administration agent include creams, ointments, lotions, transdermal agents (ordinary patches, matrix agents) and the like.
The above dosage form is formulated by a usual method using pharmaceutically acceptable excipients and additives. Examples of pharmaceutically acceptable excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, preservatives, and the like. It is done.
Examples of the pharmaceutically acceptable carrier include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like. It is done.

Capsules can be formulated by placing the compound of the present invention in a capsule together with a pharmaceutically acceptable carrier. The compounds of the present invention can be mixed with pharmaceutically acceptable excipients or placed in capsules without excipients. Cachets can be produced in the same manner.
Powders are formulated with a pharmaceutically acceptable powder base. Examples of the base include talc, lactose, starch and the like. Drops can be formulated with an aqueous or non-aqueous base and one or more pharmaceutically acceptable diffusing agents, suspending agents, solubilizing agents, and the like.
Examples of the liquid for injection include solutions, suspensions, emulsions and the like. Examples thereof include an aqueous solution and a water-propylene glycol solution. The liquid preparation can also be produced in the form of a solution of polyethylene glycol or / and propylene glycol, which may contain water. A solution suitable for oral administration can be produced by adding the compound of the present invention to water and adding a colorant, a fragrance, a stabilizer, a sweetener, a solubilizer, a thickener and the like as necessary. A solution suitable for oral administration can also be produced by adding the compound of the present invention together with a dispersant to water and increasing the viscosity. Examples of the thickener include pharmaceutically acceptable natural or synthetic gum, resin, methylcellulose, sodium carboxymethylcellulose, or a known suspending agent.
Examples of the topical administration agent include the above liquid preparations, creams, aerosols, sprays, powders, lotions, ointments and the like. The above-mentioned topical preparation can be produced by mixing the compound of the present invention with a pharmaceutically acceptable diluent and carrier that are usually used. Ointments and creams are obtained, for example, by adding a thickener and / or a gelling agent to an aqueous or oily base. Examples of the base include water, liquid paraffin, vegetable oil (peanut oil, castor oil, etc.) and the like. Examples of the thickener include soft paraffin, aluminum stearate, cetostearyl alcohol, propylene glycol, polyethylene glycol, lanolin, hydrogenated lanolin, beeswax and the like.
Lotions can add one or more pharmaceutically acceptable stabilizers, suspending agents, emulsifiers, diffusing agents, thickeners, colorants, flavors, etc. to an aqueous or oily base. .
The topical administration agent may contain a preservative such as methyl hydroxybenzoate, propyl hydroxybenzoate, chlorocresol, or benzalkonium chloride, and a bacterial growth inhibitor, if necessary.
The compounds of the present invention can also be administered nasally in liquid sprays, powders or drops.
The dose and frequency of administration 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 divided into several doses. In the case of administration as an injection, the range of about 0.1 to about 300 mg, preferably about 1 to about 100 mg can be administered once or divided into several times.

  EXAMPLES Next, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to these examples.

4-Fluoro-N- [3- [2- (1H-imidazol-4-ylmethoxy) ethyl] -4- (4-morpholin-4-ylphenyl) -1,3-thiazol-2 (3H) -ylidene] Aniline (1) 2- [2-[(4-Fluorophenyl) imino] -4- (4-morpholin-4-ylphenyl) -1,3-thiazol-3 (2H) -yl] ethanol

参考例２５で得られるN-(4-フルオロフェニル)-N'-(2-ヒドロキシエチル)チオウレア（2.14g, 10.0mol）と2-ブロモ-4'-モルホリノアセトフェノン（2.84g, 10.0mmol）のエタノール（40ml）溶液を50℃下1時間攪拌した。溶媒の約半分量を減圧留去後、析出した結晶を濾取、真空乾燥して標題化合物を取得した（4.2g, 88%）。¹H NMR d (DMSO-d⁶) 3.22 (4H, t, J = 4.8 Hz), 3.63 (2H, t, J = 5.3 Hz), 3.76 (4H, t, J = 4.5 Hz), 4.19 (2H, t, J = 5.1 Hz), 6.92 (1H, s), 7.08 (2H, d, J = 8.9 Hz), 7.40-7.48 (4H, m) and 7.54-7.57 (1H, m).

N- (4-fluorophenyl) -N ′-(2-hydroxyethyl) thiourea (2.14 g, 10.0 mol) obtained in Reference Example 25 and 2-bromo-4′-morpholinoacetophenone (2.84 g, 10.0 mmol) The ethanol (40 ml) solution was stirred at 50 ° C. for 1 hour. About half of the solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration and dried under vacuum to obtain the title compound (4.2 g, 88%). ¹ H NMR d (DMSO-d ⁶ ) 3.22 (4H, t, J = 4.8 Hz), 3.63 (2H, t, J = 5.3 Hz), 3.76 (4H, t, J = 4.5 Hz), 4.19 (2H, t, J = 5.1 Hz), 6.92 (1H, s), 7.08 (2H, d, J = 8.9 Hz), 7.40-7.48 (4H, m) and 7.54-7.57 (1H, m).

(2) 4-Fluoro-N- [3- [2- (1H-imidazol-4-ylmethoxy) ethyl] -4- (4-morpholin-4-ylphenyl) -1,3-thiazole-2 (3H) -Iriden] aniline

上記実施例１（１）で取得した2-[2-[(4-フルオロフェニル)イミノ]-4-(4-モルホリン-4-イルフェニル)-1,3-チアゾール-3(2H)-イル]エタノール（960mg, 2.0mmol）のDMF(10.0mL)溶液に0℃下NaH(96mg)を加え30分間攪拌した。その後4-(クロロメチル)-1H-イミダゾール（367mg, 2.4 mmol）を加え0℃下で4時間攪拌した。攪拌終了後、反応溶液しを酢酸エチルと水を加えて分液、さらに有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別し溶媒を減圧留去後、残査を薄層クロマトグラフィー（10%メタノール-クロロホルム）により単離して標題化合物を取得した（10mg,）。¹H NMR d (CDCl₃) 3.09 (4H, t, J = 4.8 Hz), 3.68 (2H, t, J = 7.9 Hz), 3.75-3.81 (6H, m), 3.83 (2H, s), 6.44 (1H, s), 6.63 (1H, s), 6.77-6.94 (5H, m), 7.13-7.19 (4H, m).

2- [2-[(4-Fluorophenyl) imino] -4- (4-morpholin-4-ylphenyl) -1,3-thiazol-3 (2H) -yl obtained in Example 1 (1) above NaH (96 mg) was added to a DMF (10.0 mL) solution of ethanol (960 mg, 2.0 mmol) at 0 ° C., and the mixture was stirred for 30 minutes. 4- (Chloromethyl) -1H-imidazole (367 mg, 2.4 mmol) was then added and the mixture was stirred at 0 ° C. for 4 hours. After completion of stirring, the reaction solution was separated by adding ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Sodium sulfate was filtered off and the solvent was distilled off under reduced pressure. The residue was isolated by thin layer chromatography (10% methanol-chloroform) to obtain the title compound (10 mg). ¹ H NMR d (CDCl ₃ ) 3.09 (4H, t, J = 4.8 Hz), 3.68 (2H, t, J = 7.9 Hz), 3.75-3.81 (6H, m), 3.83 (2H, s), 6.44 ( 1H, s), 6.63 (1H, s), 6.77-6.94 (5H, m), 7.13-7.19 (4H, m).

1- (4-Fluorophenyl) -N- [3- [2- (1H-imidazol-4-yl) ethyl] -4- (4-morpholin-4-ylphenyl) -1,3-thiazole-2 ( 3H) -Ilidene] methanamine

N-4-(フルオロベンジル) -N'-[2-(1H-イミダゾ−ル-4-イル)エチル]チオウレア（1.4g, 3.7 mmol）と2-ブロモ-4'-モルホリノアセトフェノン（1.05g, 3.7 mmol）のエタノール（15 ml）溶液を室温下3時間攪拌した。溶媒留去後、析出した結晶をクロロホルムと飽和炭酸水素ナトリウム水溶液を加えて、分液操作し、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残査に4N-HClジオキサン溶液（5mL）を加えて２４時間静置した。その後溶媒留去し、生じた残査を酢酸エチルと飽和炭酸水素ナトリウム水溶液を加えて分液してフリー化、有機層を無水硫酸ナトリウムで乾燥した。溶媒を減圧留去後、残査をHPLC(22%−アセトニトリル−水溶液)にて単離し、標題化合物を取得した（100mg）。
¹H NMR d (CDCl₃) 2.83 (2H, t, J = 6.7 Hz), 3.15 (4H, t, J = 4.9 Hz), 3.79 (4H, t, J = 4.9 Hz), 3.82 (2H, t, J = 6.8 Hz), 4.23 (2H, s), 5.70 (1H, s), 6.54 (1H, s), 6.85-6.87 (2H, m), 6.96-7.00 (2H, m), 7.09-7.14 (2H, m), and 7.31-7.35 (2H, m).

N-4- (fluorobenzyl) -N '-[2- (1H-imidazol-4-yl) ethyl] thiourea (1.4 g, 3.7 mmol) and 2-bromo-4'-morpholinoacetophenone (1.05 g, A solution of 3.7 mmol) in ethanol (15 ml) was stirred at room temperature for 3 hours. After distilling off the solvent, the precipitated crystals were added with chloroform and a saturated aqueous sodium hydrogen carbonate solution, followed by liquid separation, and the organic layer was dried over anhydrous sodium sulfate. After distilling off the solvent under reduced pressure, 4N-HCl dioxane solution (5 mL) was added to the residue, and the mixture was allowed to stand for 24 hours. Thereafter, the solvent was distilled off, and the resulting residue was separated by adding ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried over anhydrous sodium sulfate. After evaporating the solvent under reduced pressure, the residue was isolated by HPLC (22% -acetonitrile-water solution) to obtain the title compound (100 mg).
¹ H NMR d (CDCl ₃ ) 2.83 (2H, t, J = 6.7 Hz), 3.15 (4H, t, J = 4.9 Hz), 3.79 (4H, t, J = 4.9 Hz), 3.82 (2H, t, J = 6.8 Hz), 4.23 (2H, s), 5.70 (1H, s), 6.54 (1H, s), 6.85-6.87 (2H, m), 6.96-7.00 (2H, m), 7.09-7.14 (2H , m), and 7.31-7.35 (2H, m).

  [2- (4-Fluorophenyl) ethyl] [3- [2- (1H-imidazol-4-yl) ethyl] -4- (4-morpholin-4-ylphenyl) -1,3-thiazole-2 ( 3H) -Ilidene] amine

実施例２と同様の手法で以下の標題化合物を取得した。
1H NMR (CD3OD) d 8.97 (1H, s), 7.60 (1H, s), 6.877.00 (9H, m), 5.82 (1H, s), 6.60 (1H, s), 4.35 (2H, t, J = 6.8 Hz), 3.93 (4H, t, J = 4.9 Hz), 3.83 (2H, t, J = 7.0 Hz), 3.37 (4H, t, J = 4.9 Hz), 3.27 (2H, t, J = 6.8 Hz), 2.83 (2H, t, J = 7.0 Hz).

The following title compound was obtained in the same manner as in Example 2.
1H NMR (CD3OD) d 8.97 (1H, s), 7.60 (1H, s), 6.877.00 (9H, m), 5.82 (1H, s), 6.60 (1H, s), 4.35 (2H, t, J = 6.8 Hz), 3.93 (4H, t, J = 4.9 Hz), 3.83 (2H, t, J = 7.0 Hz), 3.37 (4H, t, J = 4.9 Hz), 3.27 (2H, t, J = 6.8 Hz), 2.83 (2H, t, J = 7.0 Hz).

N- [4- (4-morpholin-4-ylphenyl) -3-[(imidazol-4-yl) methyl] -1,3-thiazol-2 (3H) -ylidene] -4-fluoroaniline

参考例３６で得られるＮ−（４−フルオロフェニル）−Ｎ‘−({１−[(４−メチルフェニル)スルホニル]−イミダゾール−４−イル}メチル)チオウレア(340mg, 0.84mmol) と2-ブロモ-4'-モルホリノアセトフェノン（284mg, 1.0mmol）のエタノール（5ml）溶液を50℃下1時間攪拌した。溶媒を減圧留去後、4N HCl/Dioxane (3ml) と HCl/MeOH (3ml) を加えた。析出した結晶を濾取し、これを水に溶解し、飽和炭酸水素ナトリウム水溶液を加えた。析出した結晶を濾取しメタノールで洗浄、真空乾燥して標題化合物を取得した（192mg）。
MS (ESI-MS): 436[M+1]+., rt = 1.79min.

N- (4-fluorophenyl) -N ′-({1-[(4-methylphenyl) sulfonyl] -imidazol-4-yl} methyl) thiourea (340 mg, 0.84 mmol) obtained in Reference Example 36 and 2- A solution of bromo-4′-morpholinoacetophenone (284 mg, 1.0 mmol) in ethanol (5 ml) was stirred at 50 ° C. for 1 hour. After the solvent was distilled off under reduced pressure, 4N HCl / Dioxane (3 ml) and HCl / MeOH (3 ml) were added. The precipitated crystals were collected by filtration, dissolved in water, and saturated aqueous sodium hydrogen carbonate solution was added. The precipitated crystals were collected by filtration, washed with methanol, and dried under vacuum to obtain the title compound (192 mg).
MS (ESI-MS): 436 [M + 1] +., Rt = 1.79min.

N- [4- (4-morpholin-4-ylphenyl) -3-[(5-methyl-imidazol-4-yl) methyl] -1,3-thiazol-2 (3H) -ylidene] -4-fluoro Aniline

実施例４と同様の手法、即ち、トシル保護されたチオウレア化合物とフェナシルブロミドとの反応で得られる化合物に対して酸を作用させ脱保護を行い生成した塩を中和して通常の精製方法にて精製し標題化合物を取得した。MS (ESI-MS): 450[M+1]+., rt = 1.88min.

The same procedure as in Example 4, that is, a normal purification method by neutralizing the salt produced by deprotecting the compound obtained by the reaction of the tosyl-protected thiourea compound with phenacyl bromide by the action of acid. To obtain the title compound. MS (ESI-MS): 450 [M + 1] +., Rt = 1.88min.

N- [4- (4-morpholin-4-ylphenyl) -3- (imidazol-2-ylmethyl) -1,3-thiazol-2 (3H) -ylidene] -4-fluoroaniline

実施例４と同様の手法、即ち、トシル保護されたチオウレア化合物とフェナシルブロミドとの反応で得られる化合物に対して酸を作用させ脱保護を行い生成した塩を中和して通常の精製方法にて精製し標題化合物を取得した。MS (ESI-MS): 436[M+1]+., rt = 1.79min.

The same procedure as in Example 4, that is, a normal purification method by neutralizing the salt produced by deprotecting the compound obtained by the reaction of the tosyl-protected thiourea compound with phenacyl bromide by the action of acid. To obtain the title compound. MS (ESI-MS): 436 [M + 1] +., Rt = 1.79min.

N- [4- (4-morpholin-4-ylphenyl) -3- [2- (1-methyl-imidazol-4-yl) ethyl] -1,3-thiazol-2 (3H) -ylidene] -4 -Fluoroaniline

実施例６で得られた化合物(113 mg, 0.25mmol)をDMF2mlに溶解し、氷浴下で水素化ナトリウム(12 mg, 0.30 mmol)を加えた。一時間後、ヨウ化メチル(43 mg, 0.3 mmol)を加えて室温までゆっくりと昇温した。1晩放置した後、水10mlを加えて析出したオイル状成分を取り出し、シリカゲルカラムクロマトグラフィーに付し、標題化合物を二種の異性体混合物として取得した。MS (ESI-MS): 464[M+1]+., rt = 1.65min.

The compound (113 mg, 0.25 mmol) obtained in Example 6 was dissolved in 2 ml of DMF, and sodium hydride (12 mg, 0.30 mmol) was added in an ice bath. One hour later, methyl iodide (43 mg, 0.3 mmol) was added, and the temperature was slowly raised to room temperature. After standing overnight, 10 ml of water was added and the precipitated oily component was taken out and subjected to silica gel column chromatography to obtain the title compound as a mixture of two isomers. MS (ESI-MS): 464 [M + 1] +., Rt = 1.65min.

N- [3- [2- (Benzimidazol-2-yl) ethyl] -4- (4-morpholin-4-ylphenyl) -1,3-thiazol-2 (3H) -ylidene] pyridin-3-amine

N- [2- (1H-benzimidazol-2-yl) ethyl] -N′-pyridin-3-ylthiourea (299 mg, 1.0 mmol) and 2-bromo-4′-morpholinoacetophenone obtained in Reference Example 14 After stirring a solution of (340 mg, 1.2 mmol) in ethanol (4 ml) at 60 ° C. for 4 hours, the solvent was distilled off under reduced pressure, and the precipitated crystals were separated by adding ethyl acetate and a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, sodium sulfate was filtered off, the solvent was distilled off under reduced pressure, and the residue was isolated by silica gel column chromatography (2% methanol-chloroform) to obtain the title compound (120 mg, twenty five%). ¹ H NMR d (CDCl ₃ ) 3.25 (4H, t, J = 4.8 Hz), 3.35 (2H, t, J = 6.6 Hz), 3.91 (4H, t, J = 4.8 Hz), 4.35 (2H, t, J = 6.6 Hz), 5.82 (1H, s), 6.92 (2H, d, J = 8.5 Hz), 7.20-7.24 (5H, m), 7.32-7.35 (2H, m), 7.46-7.49 (1H, m ), 8.38-8.39 (1H, m), and 8.5 (1H, d, J = 2.5 Hz).

参考例５３で得られた4-(2-{[(ピリジン-3-イルアミノ)カルボチオイル]アミノ}エチル)-1H-イミダゾール-1-カルボン酸 第三ブチル(63.7 g)のエタノール溶液320 mlにトリエチルアミン28.27 ml、2-ブロモ-4'-モルホリノアセトフェノン(52.10 g)を加え40℃で一時間攪拌した。冷却後、生じた不溶物をろ取、乾燥することにより標題化合物55.71 gを取得した。 Example 9
N- [4- (4-morpholin-4-ylphenyl) -3- [2- (1H-imidazol-4-yl) ethyl] -1,3-thiazol-2 (3H) -ylidene] pyridine-3- Amine (1) 4- {2- [4- (4-morpholin-4-ylphenyl) -2- (pyridin-3-ylimino) -1,3-thiazol-3 (2H) -yl] ethyl} -1H -Imidazole-1-carboxylic acid tert-butyl ester

4- (2-{[(Pyridin-3-ylamino) carbothioyl] amino} ethyl) -1H-imidazole-1-carboxylic acid obtained in Reference Example 53 was added to 320 ml of ethanol solution of tert-butyl (63.7 g). 28.27 ml and 2-bromo-4′-morpholinoacetophenone (52.10 g) were added and stirred at 40 ° C. for 1 hour. After cooling, the resulting insoluble material was collected by filtration and dried to obtain 55.71 g of the title compound.

上記（１）で得られた4-{2-[4-(4-モルホリン-4-イルフェニル)-2-(ピリジン-3-イルイミノ)-1,3-チアゾール-3(2H)-イル]エチル}-1H-イミダゾール-1-カルボン酸 第三ブチル(55.71 g)を水560 ml、メタノール56 mlに懸濁し濃塩酸111 mlを加えた。室温で30分間攪拌した後、酢酸エチル280 mlを加え分層した。得られた水層を水酸化ナトリウム水溶液で中和しクロロホルム1000 mlで抽出した。無水硫酸マグネシウム上で乾燥後、減圧濃縮し酢酸エチル 560 mlで再結晶することにより標題化合物33 g（収率73％）を取得した。 (2) N- [4- (4-morpholin-4-ylphenyl) -3-hydrochloride 3- [2- (1H-imidazol-4-yl) ethyl] -1,3-thiazole-2 (3H) -ylidene ] Pyridin-3-amine

4- {2- [4- (4-morpholin-4-ylphenyl) -2- (pyridin-3-ylimino) -1,3-thiazol-3 (2H) -yl] obtained in (1) above Ethyl} -1H-imidazole-1-carboxylate tert-butyl (55.71 g) was suspended in 560 ml of water and 56 ml of methanol, and 111 ml of concentrated hydrochloric acid was added. After stirring at room temperature for 30 minutes, 280 ml of ethyl acetate was added and the layers were separated. The obtained aqueous layer was neutralized with an aqueous sodium hydroxide solution and extracted with 1000 ml of chloroform. After drying over anhydrous magnesium sulfate, concentration under reduced pressure and recrystallization from 560 ml of ethyl acetate gave 33 g (yield 73%) of the title compound.

上記（２）で得られた三塩酸N-[4-(4-モルホリン-4-イルフェニル)-3-[2-(1H-イミダゾール-4-イル)エチル]-1,3-チアゾール-2(3H)-イリデン]ピリジン-3-アミン(113 g)を6N塩酸400 mlに溶解し活性炭20 g を加えろ過した後、4N水酸化ナトリウム水溶液で中和しクロロホルム1000 mlで抽出した。無水硫酸マグネシウム上で乾燥後、減圧濃縮し酢酸エチル 200 mlで再結晶することにより標題化合物100.4 gを取得した。 ¹H-NMR (400MHz , CDCl₃) :δ3.00 ( 2H , t ( J = 7.1 Hz )) , 3.24 ( 4H , t ( J = 4.8 Hz )) , 3.88 (4H , t ( J = 4.8 Hz )) , 4.09 ( 2H , t ( J = 7.1 Hz )) , 5.75 ( 1H , s ) , 6.73 ( 1H , s ) , 6.94 ( 2H , d ( J = 8.7 Hz )) , 7.20 ( 2H , d ( J = 8.7 Hz )) , 7.28 ( 1H , dd( J = 5.0 Hz , 7.1 Hz )) , 7.42 ( 1H , ddd( J = 1.4 Hz , 2.4 Hz , 7.6 Hz )) , 7.55 ( 1H , s ) , 8.30 ( 1H , dd( J = 1.4 Hz , 5.0 Hz )) , 8.40 ( 1H , dd( J = 0.5 Hz , 2.4 Hz )) (3) N- [4- (4-morpholin-4-ylphenyl) -3- [2- (1H-imidazol-4-yl) ethyl] -1,3-thiazol-2 (3H) -ylidene] pyridine -3-amine

N- [4- (4-morpholin-4-ylphenyl) -3- [2- (1H-imidazol-4-yl) ethyl] -1,3-thiazole-2 trihydrochloride obtained in (2) above (3H) -Ilidene] pyridin-3-amine (113 g) was dissolved in 400 ml of 6N hydrochloric acid, 20 g of activated carbon was added and filtered, and then neutralized with 4N aqueous sodium hydroxide solution and extracted with 1000 ml of chloroform. The extract was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and recrystallized from 200 ml of ethyl acetate to obtain 100.4 g of the title compound. ¹ H-NMR (400 MHz, CDCl ₃ ): δ3.00 (2H, t (J = 7.1 Hz)), 3.24 (4H, t (J = 4.8 Hz)), 3.88 (4H, t (J = 4.8 Hz) ), 4.09 (2H, t (J = 7.1 Hz)), 5.75 (1H, s), 6.73 (1H, s), 6.94 (2H, d (J = 8.7 Hz)), 7.20 (2H, d (J = 8.7 Hz)), 7.28 (1H, dd (J = 5.0 Hz, 7.1 Hz)), 7.42 (1H, ddd (J = 1.4 Hz, 2.4 Hz, 7.6 Hz)), 7.55 (1H, s), 8.30 (1H , dd (J = 1.4 Hz, 5.0 Hz)), 8.40 (1H, dd (J = 0.5 Hz, 2.4 Hz))

Examples 10-30
The compounds shown in Tables 1 and 2 were obtained in the same manner as in Example 9.

Analysis conditions in the above table MS detector Waters micromass ZQ, HPLC waters2790 separations module, Column Impact Cadenza CD-C18 2.0mm X 20mm, Gradient condition; A: H2O, B: CH3CN, C: 2% HCOOH / CH3CN, 0.0-0.1 min A 95% B 2% C 3% 0.1-3.1min Linear gradient from A 95% B 2% C 3% to A 1% B 96% C 3% 3.1-3.5min A 1% B 96% C 3%.
(Example 31)

N- [4- (4-Chlorophenyl) -3- [2- (imidazol-4-yl) ethyl] -1,3-thiazol-2 (3H) -ylidene] -4-methylaniline (1) Resin 7

（上図中Ｘは、ポリスチレン樹脂を示す。）
参考例３９で得た樹脂３をフィルター付きチューブ（ポリプロピレン製：容量5ml）に加え、次にトルエン1.5mlを加えて懸濁させた。さらに2-ブロモ−4'-クロロアセトフェノン(70mg)を加えて溶かし、50℃で6時間加熱した。室温に戻し、反応液をろ過し、チューブ中の樹脂をトルエン(5ml×3), メタノール(5ml×3)、ジクロロメタン(5ml×3)で洗浄。ろ上物を減圧下乾燥させ、表題の樹脂を得た。

(X in the above figure indicates a polystyrene resin.)
Resin 3 obtained in Reference Example 39 was added to a tube with a filter (made of polypropylene: capacity 5 ml), and then 1.5 ml of toluene was added and suspended. Further, 2-bromo-4′-chloroacetophenone (70 mg) was added and dissolved, and the mixture was heated at 50 ° C. for 6 hours. After returning to room temperature, the reaction solution was filtered, and the resin in the tube was washed with toluene (5 ml × 3), methanol (5 ml × 3), and dichloromethane (5 ml × 3). The filtered product was dried under reduced pressure to obtain the title resin.

(2) N- [4- (4-Chlorophenyl) -3- [2- (imidazol-4-yl) ethyl] -1,3-thiazol-2 (3H) -ylidene] -4-methylaniline

上記実施例３１（１）で得た樹脂７にトリフルオロ酢酸−ジクロロメタン−トリエチルシラン（50.47.5:2.5）の混合溶液1.5mlを加え、室温で16時間振とうした。反応液をろ過し、ろ液を減圧下濃縮乾固して、粗生成物を得た。これを高速液体クロマトグラフィーで精製し、標題化合物の精製品を得た。 (rt.1.69min). MS (ESI-MS): 395[M+1]+.

1.5 ml of a mixed solution of trifluoroacetic acid-dichloromethane-triethylsilane (50.47.5: 2.5) was added to the resin 7 obtained in Example 31 (1) and shaken at room temperature for 16 hours. The reaction solution was filtered, and the filtrate was concentrated to dryness under reduced pressure to obtain a crude product. This was purified by high performance liquid chromatography to obtain a purified product of the title compound. (rt.1.69min). MS (ESI-MS): 395 [M + 1] +.

Examples 32-96
The compounds of the present invention shown in Tables 3 to 8 were obtained in the same manner as in Example 31.

Analysis conditions A in the table above: MS detector Waters micromass ZQ, HPLC waters2790 separations module, Column Impact Cadenza CD-C18 2.0mm X 20mm, Gradient condition; A: H2O, B: CH3CN, C: 2% HCOOH / CH3CN, 0.0 -0.1min A 95% B 2% C 3% 0.1-3.1min Linear gradient from A 95% B 2% C 3% to A 1% B 96% C 3% 3.1-3.5min A 1% B 96% C 3 Analysis condition B: MS detector Perkin-Elmer Sciex API 150EX Mass spectrometer, HPLC Shimadzu LC 8A, Column YMC CombiScreen ODS-A -300-CC 4.6mm X 50mm, Gradient condition; A: 0.35% TFA / CH3CN, B: 0.05% TFA / H2O, 0.0-0.5min A 10% B 90% 0.5-4.2min Linear gradient from A 10% B90% to A 99% B 1% 4.2-6.3min A 99% B 1%.
(Example 97)

N- [4- (4-morpholin-4-ylphenyl) -3- [2- (5-chloro-imidazol-4-yl) ethyl] -1,3-thiazol-2 (3H) -ylidene] (4 -Methoxyphenyl) amine (1) Synthesis of Resin 8

（上図中Ｘは、ポリスチレン樹脂を示す。）
参考例４７で得られた樹脂６をフィルター付きチューブ（ポリプロピレン製：容量5ml）に加え、トルエン1.5mlを加える。次に2-ブロモ-4'-モルホリノアセトフェノン(170.5mg)を溶かし、50℃で6時間加熱した。室温に戻し、反応液をろ過、チューブ内の樹脂をトルエン(5ml×3)、メタノール(5ml×3)、ジクロロメタン(5ml×3)で洗浄。減圧下乾燥し、表題の樹脂を得た。
（２）N-[4-(4-モルホリン-4-イルフェニル)-3-[2-(5-クロロ-イミダゾール-4-イル)エチル]-1,3-チアゾール-2(3H)-イリデン](4-メトキシフェニル)アミン

(X in the above figure indicates a polystyrene resin.)
The resin 6 obtained in Reference Example 47 is added to a tube with a filter (made of polypropylene: capacity 5 ml), and 1.5 ml of toluene is added. Next, 2-bromo-4′-morpholinoacetophenone (170.5 mg) was dissolved and heated at 50 ° C. for 6 hours. After returning to room temperature, the reaction solution was filtered, and the resin in the tube was washed with toluene (5 ml × 3), methanol (5 ml × 3), and dichloromethane (5 ml × 3). Drying under reduced pressure gave the title resin.
(2) N- [4- (4-morpholin-4-ylphenyl) -3- [2- (5-chloro-imidazol-4-yl) ethyl] -1,3-thiazole-2 (3H) -ylidene ] (4-Methoxyphenyl) amine

上記実施例９７（１）で得られた樹脂８をパイレックス（登録商標）ガラス製チューブ（容量7ml）に加え、テトラヒドロフラン2.0mlを加える。次にフッ化テトラブチルアンモニウム、１Mテトラヒドロフラン溶液0.2mlを加え、70℃で5時間加熱する。室温に戻し、減圧下濃縮する。次いで、酢酸エチル3mlと水1mlを加え、振とう。酢酸エチル層を抽出し、飽和塩化ナトリウム水溶液1mlを加え振とう。酢酸エチル層を抽出し、減圧下濃縮乾固。さらに高速液体クロマトグラフィーで精製し、標題化合物を取得した。(rt. 3.09) MS (ESI-MS): 496[M+1]+.

Resin 8 obtained in Example 97 (1) above is added to a Pyrex (registered trademark) glass tube (7 ml capacity), and 2.0 ml of tetrahydrofuran is added. Next, 0.2 ml of tetrabutylammonium fluoride and 1M tetrahydrofuran solution are added and heated at 70 ° C. for 5 hours. Return to room temperature and concentrate under reduced pressure. Then add 3 ml of ethyl acetate and 1 ml of water and shake. Extract the ethyl acetate layer, add 1 ml of saturated aqueous sodium chloride solution and shake. The ethyl acetate layer was extracted and concentrated to dryness under reduced pressure. Further purification by high performance liquid chromatography gave the title compound. (rt. 3.09) MS (ESI-MS): 496 [M + 1] +.

Examples 98-132
The compounds of the present invention in Tables 9 to 11 were obtained in the same manner as in Example 97.

  Analysis conditions A in the table above: MS detector Waters micromass ZQ, HPLC waters2790 separations module, Column Impact Cadenza CD-C18 2.0mm X 20mm, Gradient condition; A: H2O, B: CH3CN, C: 2% HCOOH / CH3CN, 0.0 -0.1min A 95% B 2% C 3% 0.1-3.1min Linear gradient from A 95% B 2% C 3% to A 1% B 96% C 3% 3.1-3.5min A 1% B 96% C 3 Analysis condition B: MS detector Perkin-Elmer Sciex API 150EX Mass spectrometer, HPLC Shimadzu LC 8A, Column YMC CombiScreen ODS-A -300-CC 4.6mm X 50mm, Gradient condition; A: 0.35% TFA / CH3CN, B: 0.05% TFA / H2O, 0.0-0.5min A 10% B 90% 0.5-4.2min Linear gradient from A 10% B90% to A 99% B 1% 4.2-6.3min A 99% B 1%.

Reference example 1
{1-[(4-Methylphenyl) sulfonyl] imidazol-4-yl} methanol

４−ヒドロキシメチルイミダゾール塩酸塩（2.69 g, 20 mmol）をジクロロメタン（40 ml）に懸濁し、トリエチルアミン（5.6 ml, 40 mmol）を加え、０℃に冷却後、塩化４−トルエンスルホニルを加えて室温までゆっくりと昇温した。８時間後水（40 ml）を加えて分液、有機層を無水硫酸ナトリウムにて乾燥後、これを濾別し、濾液を濃縮して標題化合物を取得した（4.72 g, 94%）。
¹H NMR d (CDCl3) 2.44 (3H, s), 4.54 (2H, s), 7.22 (1H, d, J = 1.0 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.81 (2H, d, J = 8.1 Hz), and 7.98 (1H, d, J = 1.0 Hz).
参考例２
２−({１−[(４−メチルフェニル)スルホニル]−イミダゾール−４−イル}メチル)−１Ｈ−イソインドール−１，３（２Ｈ）−ジオン

4-Hydroxymethylimidazole hydrochloride (2.69 g, 20 mmol) was suspended in dichloromethane (40 ml), triethylamine (5.6 ml, 40 mmol) was added, and after cooling to 0 ° C., 4-toluenesulfonyl chloride was added to room temperature. The temperature was raised slowly. After 8 hours, water (40 ml) was added to separate the solution, and the organic layer was dried over anhydrous sodium sulfate. This was filtered off and the filtrate was concentrated to obtain the title compound (4.72 g, 94%).
¹ H NMR d (CDCl3) 2.44 (3H, s), 4.54 (2H, s), 7.22 (1H, d, J = 1.0 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.81 (2H, d , J = 8.1 Hz), and 7.98 (1H, d, J = 1.0 Hz).
Reference example 2
2-({1-[(4-Methylphenyl) sulfonyl] -imidazol-4-yl} methyl) -1H-isoindole-1,3 (2H) -dione

参考例１で取得した{１−[(４−メチルフェニル)スルホニル]イミダゾール−４−イル}メタノール（4.72 g, 18.8 mmol）、フタルイミド（3.04 g, 20.7 mmol）、トリフェニルホスフィン（5.42 g, 20.7 mmol）のTHF（70 ml）溶液に、アゾジカルボン酸ジイソプロピル（4.1 ml, 20.7 mmol）のTHF（20 ml）溶液を１０℃において滴下した。滴下終了後、室温まで昇温しながら終夜撹拌した。THFの半分程を濃縮し、ヘキサン（70 ml）を加えて析出した結晶を濾取した。さらにこれを１，４−ジオキサン（25 ml）で洗浄して標題化合物を取得した（5.21 g, 73%）。
¹H NMR d (CDCl3) 2.47(3H, s), 4.67 (2H, s), 7.23 (1H, d, J = 1.0 Hz), 7.64-7.70 (2H, m), 7.76 (2H, d, J = 8.1 Hz), 7.81-7.83 (2H, m), and 8.03 (1H, d, J = 1.0 Hz).

{1-[(4-Methylphenyl) sulfonyl] imidazol-4-yl} methanol (4.72 g, 18.8 mmol), phthalimide (3.04 g, 20.7 mmol), triphenylphosphine (5.42 g, 20.7 mmol) obtained in Reference Example 1 mmol) in THF (70 ml), a solution of diisopropyl azodicarboxylate (4.1 ml, 20.7 mmol) in THF (20 ml) was added dropwise at 10 ° C. After completion of dropping, the mixture was stirred overnight while raising the temperature to room temperature. About half of THF was concentrated, hexane (70 ml) was added, and the precipitated crystals were collected by filtration. This was further washed with 1,4-dioxane (25 ml) to obtain the title compound (5.21 g, 73%).
¹ H NMR d (CDCl3) 2.47 (3H, s), 4.67 (2H, s), 7.23 (1H, d, J = 1.0 Hz), 7.64-7.70 (2H, m), 7.76 (2H, d, J = 8.1 Hz), 7.81-7.83 (2H, m), and 8.03 (1H, d, J = 1.0 Hz).

Reference example 3
({1-[(4-Methylphenyl) sulfonyl] -imidazol-4-yl} methyl) amine

参考例２で取得した２−({１−[(４−メチルフェニル)スルホニル]−イミダゾール−４−イル}メチル)−１Ｈ−イソインドール−１，３（２Ｈ）−ジオン（4.4 g, 11.5 mmol）をエタノール（30 ml）に懸濁し、ヒドラジン１水和物（1.15 g, 23 mmol）を加えて５５℃にて加熱撹拌した。３時間後クロロホルム（30 ml）を加えて析出した固体を濾別後、濾液を濃縮した。残渣にクロロホルムと水を加えて分液、有機層を無水硫酸ナトリウムにて乾燥後、これを濾別し、濾液を濃縮して標題化合物を取得した（2.5 g, 85%）。
¹H NMR d (CDCl3) 2.44 (3H, s), 3.75 (2H, s), 7.13 (1H, d, J = 1.0 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.83 (2H, d, J = 8.1 Hz), and 7.96 (1H, d, J = 1.0 Hz).
参考例４
({１−[(４−メチルフェニル)スルホニル]−イミダゾール−２−イル}メタノール

2-({1-[(4-Methylphenyl) sulfonyl] -imidazol-4-yl} methyl) -1H-isoindole-1,3 (2H) -dione (4.4 g, 11.5 mmol) obtained in Reference Example 2 ) Was suspended in ethanol (30 ml), hydrazine monohydrate (1.15 g, 23 mmol) was added, and the mixture was heated and stirred at 55 ° C. After 3 hours, chloroform (30 ml) was added and the precipitated solid was filtered off, and the filtrate was concentrated. Chloroform and water were added to the residue and the phases were separated. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (2.5 g, 85%).
¹ H NMR d (CDCl3) 2.44 (3H, s), 3.75 (2H, s), 7.13 (1H, d, J = 1.0 Hz), 7.35 (2H, d, J = 8.1 Hz), 7.83 (2H, d , J = 8.1 Hz), and 7.96 (1H, d, J = 1.0 Hz).
Reference example 4
({1-[(4-Methylphenyl) sulfonyl] -imidazol-2-yl} methanol

参考例１の手法で取得した１−（４−トルエンスルホニル）イミダゾール−２−カルボアルデヒド（4.5 g, 18 mmol）をメタノール（172 ml）に溶解し、水素化ホウ素ナトリウム（2.07 g, 54 mmol）をゆっくり加えた。５分後メタノールを留去し、酢酸エチルと水を加えて分液、有機層を無水硫酸ナトリウムにて乾燥後、これを濾別し、濾液を濃縮して標題化合物を取得した（4.6 g, quant.）。
¹H NMR d (CDCl3) 2.45 (3H, s), 4.85 (2H, s), 6.98 (1H, d, J = 1.7 Hz), 7.36 (2H, d, J = 8.1 Hz), 7.39 (1H, d, J = 1.8 Hz), and 7.83 (2H, d, J = 8.1 Hz).

1- (4-Toluenesulfonyl) imidazole-2-carbaldehyde (4.5 g, 18 mmol) obtained by the method of Reference Example 1 was dissolved in methanol (172 ml) and sodium borohydride (2.07 g, 54 mmol). Was added slowly. After 5 minutes, the methanol was distilled off, and ethyl acetate and water were added to separate the layers. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (4.6 g, quant.).
¹ H NMR d (CDCl3) 2.45 (3H, s), 4.85 (2H, s), 6.98 (1H, d, J = 1.7 Hz), 7.36 (2H, d, J = 8.1 Hz), 7.39 (1H, d , J = 1.8 Hz), and 7.83 (2H, d, J = 8.1 Hz).

Reference Example 5
({1-[(4-Methylphenyl) sulfonyl] -imidazol-2-yl} methyl) amine

参考例４で得られたアルコールを、参考例１〜参考例３の手法と同様にして、標題化合物を取得した。
参考例６
Ｎ−（４−フルオロフェニル）−Ｎ‘−({１−[(４−メチルフェニル)スルホニル]−イミダゾール−４−イル}メチル)チオウレア

The title compound was obtained from the alcohol obtained in Reference Example 4 in the same manner as in Reference Examples 1 to 3.
Reference Example 6
N- (4-Fluorophenyl) -N ′-({1-[(4-methylphenyl) sulfonyl] -imidazol-4-yl} methyl) thiourea

参考例３で取得した({１−[(４−メチルフェニル)スルホニル]−イミダゾール−４−イル}メチル)アミン（753 mg, 3.0 mmol）をアセトン（15 ml）に溶解しイソチオシアン酸４−フルオロフェニル（459 mg, 3.0 mmol）を加えて室温にて２時間撹拌した。溶媒を留去し、残渣をシリカゲルカラムクロマトグラフィー（酢酸エチル：ｎ―ヘキサン＝１：１）に付し、標題化合物を取得した（2.5 g, 85%）。
¹H NMR d (CD3OD) 2.31 (3H, s), 4.51 (2H, s), 6.54 (2H, m), 7.17 (2H, m), 7.33 (3H, m), 7.81 (2H, m), and 8.07 (1H, d, J = 1.0 Hz).

({1-[(4-methylphenyl) sulfonyl] -imidazol-4-yl} methyl) amine (753 mg, 3.0 mmol) obtained in Reference Example 3 was dissolved in acetone (15 ml) and 4-fluoroisothiocyanate was dissolved. Phenyl (459 mg, 3.0 mmol) was added and stirred at room temperature for 2 hours. The solvent was distilled off, and the residue was subjected to silica gel column chromatography (ethyl acetate: n-hexane = 1: 1) to obtain the title compound (2.5 g, 85%).
¹ H NMR d (CD3OD) 2.31 (3H, s), 4.51 (2H, s), 6.54 (2H, m), 7.17 (2H, m), 7.33 (3H, m), 7.81 (2H, m), and 8.07 (1H, d, J = 1.0 Hz).

Reference examples 7 and 8
As in Reference Example 6, the thiourea compounds shown in Table 12 were obtained by reacting various isothiocyanates with amine compounds.

Reference Example 9
1-isothiocyanato-2- (methylsulfonyl) benzene

２−メチルスルホニルアニリン塩酸塩、濃塩酸（4.5 ml）と水（18 ml）との混合溶液にチオホスゲン（1.15 g, 10 mmol）を加えて激しく撹拌した。２時間後、析出した結晶を濾取、乾燥して目的物を取得した（2.04 g）。
¹H NMR d (CDCl3) 3.17 (3H, s), 7.36-7.43 (2H, m), 7.57-7.61 (1H, m), and 7.98-8.01 (1H, m).
参考例１０
Ｎ−[２−(イミダゾール−４−イル)エチル]−Ｎ‘−[２−(メチルスルホニル)フェニル]チオウレア

To a mixed solution of 2-methylsulfonylaniline hydrochloride, concentrated hydrochloric acid (4.5 ml) and water (18 ml) was added thiophosgene (1.15 g, 10 mmol) and vigorously stirred. After 2 hours, the precipitated crystals were collected by filtration and dried to obtain the desired product (2.04 g).
¹ H NMR d (CDCl3) 3.17 (3H, s), 7.36-7.43 (2H, m), 7.57-7.61 (1H, m), and 7.98-8.01 (1H, m).
Reference Example 10
N- [2- (imidazol-4-yl) ethyl] -N ′-[2- (methylsulfonyl) phenyl] thiourea

イソチオシアン酸２−メチルスルホニルフェニル（1.07 g, 5.0 mmol）、塩酸ヒスタミン（920 mg, 5.0 mmol）、炭酸カリウム（1.38 g）、アセトン（20 ml）の混合物を終夜撹拌した。溶媒を留去し、水、酢酸エチルを加えて抽出し、有機層を無水硫酸ナトリウムにて乾燥後、これを濾別し、濾液を濃縮して標題化合物を取得した（1.50 g）。
¹H NMR d (DMSO-d6) 2.77 (2H, bm), 3.12 (3H, s), 3.73 (2H, bm), 6.83 (1H, bs), 7.42-7.46 (1H, m), 7.53 (1H, s), 7.62-7.70 (2H, m), 7.84-7.86 (1H, m), 8.60 (1H, bs), 9.03 (1H, bs), and 11.84 (1H, bs).

A mixture of 2-methylsulfonylphenyl isothiocyanate (1.07 g, 5.0 mmol), histamine hydrochloride (920 mg, 5.0 mmol), potassium carbonate (1.38 g), and acetone (20 ml) was stirred overnight. The solvent was distilled off, and extraction was performed by adding water and ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (1.50 g).
¹ H NMR d (DMSO-d6) 2.77 (2H, bm), 3.12 (3H, s), 3.73 (2H, bm), 6.83 (1H, bs), 7.42-7.46 (1H, m), 7.53 (1H, s), 7.62-7.70 (2H, m), 7.84-7.86 (1H, m), 8.60 (1H, bs), 9.03 (1H, bs), and 11.84 (1H, bs).

Reference Examples 11-25
As in Reference Example 10, the thiourea compounds shown in Tables 13 and 14 were obtained by the reaction of various isothiocyanates and amine compound hydrochlorides or amine compound hydrobromides in the presence of a base.

Reference Example 26
N- (6-methylpyridin-3-yl) carbamate tert-butyl ester

６−メチルニコチン酸（6.85 g, 50 mmol）から参考例２９と同様の手法により標題化合物を取得した。
参考例２７
６−メチルピリジン−３−アミン２塩酸塩

The title compound was obtained from 6-methylnicotinic acid (6.85 g, 50 mmol) in the same manner as in Reference Example 29.
Reference Example 27
6-Methylpyridin-3-amine dihydrochloride

上記参考例で取得したＮ−（４−メチル−３−ピリジル）カルバミン酸第３ブチルから参考例３０と同様の手法により標題化合物を取得した。
参考例２８
５−イソチオシアナト−２−メチルピリジン

The title compound was obtained from tert-butyl N- (4-methyl-3-pyridyl) carbamate obtained in the above Reference Example in the same manner as in Reference Example 30.
Reference Example 28
5-isothiocyanato-2-methylpyridine

炭酸水素ナトリウム（5.9 g, 70 mmol）の水溶液（100 ml）にクロロホルム（300 ml）、次いで６−メチルピリジン−３−アミン２塩酸塩（1.83 g, 10 mmol）を加えた後、０℃に冷却してチオホスゲン（1.38 g, 12 mmol）を滴下した。２時間後、クロロホルム層を無水硫酸ナトリウムにて乾燥後、これを濾別し、濾液を濃縮して標題化合物を取得した（1.50 g）。
¹H NMR d (CDCl3) 2.53 (3H, s), 7.12 (1H, d, J = 8.3Hz), 7.38 (1H, dd, J = 2.5 and 8.3 Hz), and 8.37 (1H, d, J = 2.5 Hz).

Chloroform (300 ml) and then 6-methylpyridin-3-amine dihydrochloride (1.83 g, 10 mmol) were added to an aqueous solution (100 ml) of sodium hydrogen carbonate (5.9 g, 70 mmol), and then the mixture was heated to 0 ° C. After cooling, thiophosgene (1.38 g, 12 mmol) was added dropwise. After 2 hours, the chloroform layer was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the title compound (1.50 g).
¹ H NMR d (CDCl3) 2.53 (3H, s), 7.12 (1H, d, J = 8.3 Hz), 7.38 (1H, dd, J = 2.5 and 8.3 Hz), and 8.37 (1H, d, J = 2.5 Hz).

Reference Example 29
N- [2- (imidazol-4-yl) ethyl] -N ′-(6-methylpyridin-3-yl) thiourea

チオカルボニルジイミダゾール（819 mg, 5 mmol）のアセトン（25 ml）溶液に５−アミノ−２−ピコリン２塩酸塩を加えて室温にて撹拌した。３時間後、塩酸ヒスタミン（1.1 g, 6 mmol）を２Ｎ水酸化ナトリウム水溶液に溶解した溶液を加えた。さらに３時間後、アセトンを留去し、残渣に１Ｎ塩酸水を加えて均一溶液とし、これに２Ｎ水酸化ナトリウム水を滴下して析出した結晶を濾取した（521 mg）。
参考例３０〜３４
上記参考例２８と同様に、塩基存在下にて種々のアミン化合物塩酸塩とチオカルボニルジイミダゾールを反応させ、生成する中間体とアリールアミンの反応により表１５に示されるチオウレア化合物を取得した。

5-Amino-2-picoline dihydrochloride was added to a solution of thiocarbonyldiimidazole (819 mg, 5 mmol) in acetone (25 ml) and stirred at room temperature. After 3 hours, a solution of histamine hydrochloride (1.1 g, 6 mmol) dissolved in 2N aqueous sodium hydroxide solution was added. After further 3 hours, acetone was distilled off, 1N aqueous hydrochloric acid was added to the residue to make a homogeneous solution, and 2N aqueous sodium hydroxide was added dropwise thereto, and the precipitated crystals were collected by filtration (521 mg).
Reference Examples 30-34
In the same manner as in Reference Example 28, various amine compound hydrochlorides and thiocarbonyldiimidazole were reacted in the presence of a base, and the thiourea compounds shown in Table 15 were obtained by the reaction of the resulting intermediate and arylamine.

Reference Example 35
4- {2-[({[2- (4-Fluorophenyl) methyl] amino} carbonothioyl) aminoethyl] -1H-imidazole-1-carboxylate tert-butyl

塩酸ヒスタミン（920mg, 5.0mmol）、1-フルオロ-4-(イソチオシアノメチル)ベンゼン（836mg, 5.0 mmol）、トリエチルアミンを（2.1mL, 15.0 mmol）のアセトニトリル（25 ml）溶液を室温で4時間攪拌した後、Boc₂O(1.31g, 6.0mmol)を加えて2時間攪拌した。反応溶液を酢酸エチルと水を加えて分液、さらに有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。硫酸ナトリウムを濾別し溶媒を減圧留去後、残査をシリカゲルカラムクロマトグラフィー（2%メタノール-クロロホルム）により単離生成して標題化合物を取得した（980mg, 78%）。¹H NMR d (CDCl₃) 1.59(9H, s), 2.78 (2H, t, J = 6.1 Hz), 3.78 (2H, bs), 4.63 (2H, bs), 7.00-7.01 (2H, m), 7.14 (1H, s), 7.26-7.31 (3H, m), and 7.83 (1H, bs).
参考例３６
4-{2-[({[2-(4-フルオロフェニルl)エチル]アミノ}カルボノチオイル)アミノエチル]-1H-イミダゾール-1-カルボン酸第三ブチル

A solution of histamine hydrochloride (920 mg, 5.0 mmol), 1-fluoro-4- (isothiocyanomethyl) benzene (836 mg, 5.0 mmol), triethylamine (2.1 mL, 15.0 mmol) in acetonitrile (25 ml) at room temperature for 4 hours After stirring, Boc ₂ O (1.31 g, 6.0 mmol) was added and stirred for 2 hours. The reaction solution was separated by adding ethyl acetate and water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. Sodium sulfate was filtered off and the solvent was distilled off under reduced pressure. The residue was isolated and produced by silica gel column chromatography (2% methanol-chloroform) to obtain the title compound (980 mg, 78%). ¹ H NMR d (CDCl ₃ ) 1.59 (9H, s), 2.78 (2H, t, J = 6.1 Hz), 3.78 (2H, bs), 4.63 (2H, bs), 7.00-7.01 (2H, m), 7.14 (1H, s), 7.26-7.31 (3H, m), and 7.83 (1H, bs).
Reference Example 36
4- {2-[({[2- (4-Fluorophenyl-l) ethyl] amino} carbonothioyl) aminoethyl] -1H-imidazole-1-carboxylate tert-butyl

参考例３５と同様の手法にて標題化合物を取得した。
参考例３７
樹脂１

The title compound was obtained in the same manner as in Reference Example 35.
Reference Example 37
Resin 1

（上図中Ｘは、ポリスチレン樹脂を示す。）
表題の樹脂を文献(Tetrahedron Letters 40 (1999) 2825-2828)記載の方法で取得した。

(X in the above figure indicates a polystyrene resin.)
The title resin was obtained by the method described in the literature (Tetrahedron Letters 40 (1999) 2825-2828).

Reference Example 38
Resin 2

（上図中Ｘは、ポリスチレン樹脂を示す。）
参考例３７で得られた樹脂１(150ｍg)をフィルター付きチューブ（ポリプロピレン製：容量5ml）に加え、次にジメチルホルムアミド(1.2ml)およびピペリジン(0.3ml)を加えて室温で3時間振とうした。反応液をろ過し、チューブ中の樹脂を、ジメチルホルムアミド(5ml×3), メタノール(5ml×3)、ジクロロメタン(5ml×3)で洗浄。ろ上物を減圧下乾燥させて表題の樹脂を得た。
参考例３９
樹脂３

(X in the above figure indicates a polystyrene resin.)
Resin 1 (150 mg) obtained in Reference Example 37 was added to a tube with a filter (made of polypropylene: capacity 5 ml), dimethylformamide (1.2 ml) and piperidine (0.3 ml) were added, and the mixture was shaken at room temperature for 3 hours. . The reaction solution was filtered, and the resin in the tube was washed with dimethylformamide (5 ml × 3), methanol (5 ml × 3), and dichloromethane (5 ml × 3). The filtered product was dried under reduced pressure to give the title resin.
Reference Example 39
Resin 3

（上図中Ｘは、ポリスチレン樹脂を示す）
参考例３８で得た樹脂２をフィルター付きチューブ（ポリプロピレン製：容量5ml）に加え、次にジメチルホルムアミド(2.0ml)を加えて懸濁させた。さらに4-トルイルイソチオシアネート149mgを加えて溶かし、室温で16時間振とうした。反応液をろ過し、チューブ中の樹脂をジメチルホルムアミド(5ml×3), メタノール(5ml×3)、ジクロロメタン(5ml×3)で洗浄。ろ上物を減圧下乾燥させ、表題の樹脂を得た。

(X in the above figure indicates polystyrene resin)
Resin 2 obtained in Reference Example 38 was added to a tube with a filter (made of polypropylene: capacity 5 ml), and then dimethylformamide (2.0 ml) was added and suspended. Further, 149 mg of 4-toluyl isothiocyanate was added and dissolved, and the mixture was shaken at room temperature for 16 hours. The reaction solution was filtered, and the resin in the tube was washed with dimethylformamide (5 ml × 3), methanol (5 ml × 3), and dichloromethane (5 ml × 3). The filtered product was dried under reduced pressure to obtain the title resin.

Reference Example 40-44
The following thiourea resin was synthesized in the same manner as in Reference Example 39 above.

Reference Example 45
Resin 4

（上図中Ｘは、ポリスチレン樹脂を示す。）
スルホニルクロライド樹脂（ポリスチレン−1%ジビニルベンゼン共重合樹脂、官能基量1.5-2.0mmol/g 粒径100-200mesh）13.3gにジクロロメタン(150ml)を加えた。Boc-Cl-Histamine (9.82g)を加えて溶解、次いでピリジン(4.85ml)を加え、室温で16時間振とうした。反応混合物をろ過し、ろ上物をジクロロメタン(200ml×3)、ジメチルホルムアミド(200ml×3)、メタノール(200ml×3)、ジクロロメタン(200ml×3)で洗浄。減圧下乾燥し、表題の樹脂18.6gを得た。(IR) 1699cm^-1, 1706cm^-1
参考例４６
樹脂５

(X in the above figure indicates a polystyrene resin.)
Dichloromethane (150 ml) was added to 13.3 g of a sulfonyl chloride resin (polystyrene-1% divinylbenzene copolymer resin, functional group amount 1.5-2.0 mmol / g particle size 100-200 mesh). Boc-Cl-Histamine (9.82 g) was added to dissolve, and pyridine (4.85 ml) was added, followed by shaking at room temperature for 16 hours. The reaction mixture was filtered, and the filtrate was washed with dichloromethane (200 ml × 3), dimethylformamide (200 ml × 3), methanol (200 ml × 3) and dichloromethane (200 ml × 3). Drying under reduced pressure gave 18.6 g of the title resin. (IR) 1699cm ^-1 , 1706cm ^-1
Reference Example 46
Resin 5

（上図中Ｘは、ポリスチレン樹脂を示す。）
参考例４５で得られた樹脂４(186mg)をフィルター付きチューブ（ポリプロピレン製：容量5ml）に加え、10%トリフルオロ酢酸ジクロロメタン溶液1mlを加えた。室温で１時間振とう後、反応液をろ過、チューブ内の樹脂をジクロロメタン(5ml×3)、ジメチルホルムアミド(5ml×3)、メタノール(5ml×3)、ジクロロメタン(5ml×3)で洗浄、減圧下乾燥し、表題の樹脂を得た。

(X in the above figure indicates a polystyrene resin.)
Resin 4 (186 mg) obtained in Reference Example 45 was added to a tube with a filter (made of polypropylene: volume 5 ml), and 1 ml of a 10% trifluoroacetic acid dichloromethane solution was added. After shaking at room temperature for 1 hour, the reaction solution is filtered, and the resin in the tube is washed with dichloromethane (5 ml × 3), dimethylformamide (5 ml × 3), methanol (5 ml × 3), dichloromethane (5 ml × 3), and decompressed. Under drying, the title resin was obtained.

Reference Example 47
Resin 6

（上図中Ｘは、ポリスチレン樹脂を示す）
参考例４６で得られた樹脂５をフィルター付きチューブ（ポリプロピレン製：容量5ml）に加え、ジクロロメタン(1.5ml)、ジイソプロピルエチルアミン(0.175ml)、4−メトキシフェニルイソチオシアネート(165.2mg)を加え、室温で16時間振とうした。反応液をろ過、チューブ内の樹脂をジクロロメタン(5ml×3)、メタノール(5ml×3)、ジクロロメタン(5ml×3)で洗浄、減圧下乾燥し、表題の樹脂を得た。

(X in the above figure indicates polystyrene resin)
Resin 5 obtained in Reference Example 46 was added to a tube with a filter (made of polypropylene: capacity 5 ml), dichloromethane (1.5 ml), diisopropylethylamine (0.175 ml), 4-methoxyphenyl isothiocyanate (165.2 mg) were added at room temperature. Shake for 16 hours. The reaction solution was filtered, and the resin in the tube was washed with dichloromethane (5 ml × 3), methanol (5 ml × 3), dichloromethane (5 ml × 3) and dried under reduced pressure to obtain the title resin.

Reference Examples 48-52
The following thiourea resin was synthesized in the same manner as in Reference Example 47.

イソチオシアン酸３−ピリジル 36.54 gのアセトニトリル溶液365 mlにヒスタミン二塩酸塩44.45 g、トリエチルアミン75 ml、メタノール365 mlを加え室温で一時間攪拌した。この反応液に二炭酸ジ第三ブチル 64 gを加え室温で二時間攪拌した。反応液を減圧濃縮後、残渣をクロロホルム700 ml、水 350mlに溶解し得られた有機層をさらに水で洗浄した。無水硫酸マグネシウム上で乾燥後、減圧濃縮し残渣に酢酸エチル 182 mlを加え還流した。冷却後生じた結晶をろ取、乾燥することにより標記化合物63 gを得た。
（実施例１３３） Reference Example 53
4- (2-{[(Pyridin-3-ylamino) carbothioyl] amino} ethyl) -1H-imidazole-1-carboxylic acid tert-butyl ester

To 365 ml of acetonitrile solution of 3-pyridyl isothiocyanate 36.54 g, 44.45 g of histamine dihydrochloride, 75 ml of triethylamine and 365 ml of methanol were added and stirred at room temperature for 1 hour. To this reaction solution, 64 g of ditert-butyl dicarbonate was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was dissolved in 700 ml of chloroform and 350 ml of water. The resulting organic layer was further washed with water. After drying over anhydrous magnesium sulfate and concentrating under reduced pressure, 182 ml of ethyl acetate was added to the residue and refluxed. Crystals produced after cooling were collected by filtration and dried to obtain 63 g of the title compound.
(Example 133)

Receptor binding evaluation test of compounds using rat lung membrane The test was performed according to the method described by Sugazawa et al. (Sugasawa, T. et al., J. Biol. Chem., 272, 21244-21252 (1997)).
Preparation of rat lung membrane SD male rats (7 weeks old at the time of the test, Charles River, Japan) Remove trachea and blood vessels from the isolated lung, shred, and ice-cold Tris-saline buffer (10 mM Tris hydrochloride-154 mM chloride) Wash with sodium, pH 7.4). Tris-saline buffer solution containing this buffer for homogenization (1 mM ethylenediaminetetraacetic acid (EDTA), 1 mM 4- (2-aminoethyl) benzenesulfonyl fluoride (AEBSF), 5 μg / ml aprotinin, 5 μg / ml leupeptin) It was homogenized with Hiscotron while cooling with ice (maximum speed: 1 minute). The supernatant after low speed centrifugation (1500 × g, 20 minutes, 4 ° C.) is ultracentrifuged (100,000 × g, 20 minutes, 4 ° C.), and the pellet is suspended in Tris-saline buffer solution at −80 ° C. saved. The protein concentration was measured with a protein assay kit manufactured by Bio-Rad using bovine serum albumin (BSA) as a standard.

1nM to each well of the ligand binding assay protein non-adsorbing round bottom 96 well assay plates (purchased from Iwaki Glass) ^{[125 I]} - iodocyanopindolol (purchased from Amersham), 10 [mu] M serotonin, 20 [mu] m dl-propranolol, 200 μl of Tris-saline buffer solution containing 10 μM phentolamine, 1.1 mM ascorbic acid and 100 μg lung membrane was added, mixed by pipetting, and then incubated at 37 ° C. for 30 minutes. The test compound was dissolved in a 100% dimethyl sulfoxide solution and 2 μl (final DMSO concentration: 1%, compound concentration 30 μM) was added. In addition, in order to determine the amount of non-specific binding, L-threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluorophenyl) propyl] serine having a final concentration of 100 μM was used instead of the test compound. Pyrrolidine amide was added. During this time, 100 μl of 0.3% polyethyleneimine (PEI) / Tris-saline buffer was added to a multiscreen plate (96-well B glass fiber, Millipore Cat. No. MAFB NOB10) and incubated for 30 minutes or longer. The solution was suction filtered and washed (200 μl ice-cold Tris-saline buffer was added and suctioned), and the reaction solution on the 96-well assay plate was suction filtered and washed four times on the multi-screen plate. The B glass fiber filter paper at the bottom of the multi-screen plate was punched out, and the γ dose of [ ¹²⁵ I] -iodocyanopindolol trapped on the filter paper was measured, and this was used as the binding amount. The binding amount in the presence of DMSO (final concentration: 1%) is defined as the total binding amount, and 100 μML-threo-3- (3,4-dihydroxyphenyl) -N- [3- (4-fluorophenyl) propyl] serine pyrrolidinamide The binding amount in the presence was defined as a non-specific binding amount. The value obtained by subtracting the non-specific binding amount from the total binding amount is the specific binding amount. The binding activity of the compound was calculated according to the following formula, and the test compound showed the ratio of inhibiting the specific binding of [ ¹²⁵ I] -iodocyanopindolol to rat lung membrane SMBP.

その結果を以下に示す。

The results are shown below.

（実施例１３４）

(Example 134)

Eosinophil migration inhibition test <br/> Preparation of guinea pig eosinophils
A hartley male guinea pig (SLC, clean) was received at 4 weeks of age, and after quarantine, it was administered intraperitoneally at a dose of 5 mg / ml polymyxin B (Wako Pure Chemical Industries) at a dose of 1 ml / head at least 5 times a week. Approximately 24 hours after the final administration, 50 ml of PBS (−) (GIBCO BRL) was intraperitoneally administered and the abdomen was gently massaged, and then an 18 G injection needle was inserted into the abdomen to recover the intraperitoneal washing solution. The cells in the solution were added with 20 ml of 0.2% NaCl, stirred for 25 seconds, treated with hemolysis to return to isotonicity by adding 20 ml of 1.6% NaCl, treated with 2500 unit / ml DNase (SIGMA) for 10 minutes at room temperature, and then Percoll (Pharmacia) It was layered on a discontinuous density gradient layer (d = 1.070, 1.085, 1.100) and centrifuged (1500 rpm, 40 min, 4 ° C.). A layer of d> 1.085 was collected, washed with 0.5% BSA / mHBSS, and suspended at 1.11 × 10 ⁷ cells / ml. mHBSS was prepared by adding 1 l of distilled water to 9.8 g of Hank's solution powder (Nissui Pharmaceutical), 4.35 g of HEPES (SIGMA), and 0.35 g of NaHCO ₃ , and adjusted to pH 7.3 for use.
Preparation of migration factor
15 uM LTB ₄ (CAYMAN CHEMICAL) was used 150-fold diluted with 0.5% BSA / mHBSS.
Compound preparation
A compound suspended in 10 mM with DMSO was diluted 40-fold (250 uM) with 0.5% BSA / mHBSS and then diluted with 2.5% DMSO / mHBSS to prepare 10 uM.

Migration test
60ul of the compound was added to the lower chamber of 5um pore Transwell (corning) to which 480ul of 0.5% BSA / mHBSS was added, and pre-incubated at 37 ° C for 30 minutes. Meanwhile, 22 ul of the compound was added to 1.5 ml tube to which 198 ul of eosinophil (1.11 × 10 ⁷ cell / ml) was added, and pre-incubated at 37 ° C. for 15 minutes. Thereafter, 100 ul (1 × 10 ⁶ cell) of eosinophils was added to the upper chamber, and 60 ul (10 ⁻⁸ uM) of migration factor LTB ₄ was added to the lower chamber and incubated at 37 ° C. After 90 minutes, the upper chamber was removed, 500 ul of the lower chamber 600 ul was diluted with 9.98 ml of solution, and the concentration of eosinophils migrating to the lower chamber was measured with an automatic blood cell counter (Sysmex).
The concentration of eosinophils migrating to the lower chamber of the control was taken as 100%, and the migration rate when 10 uM compound was added was shown below (n = 2). This experiment was performed twice, and the average value was calculated. In the case of no stimulation, almost no migration of eosinophils was observed.

総細胞数に関して、無刺激群とコントロール群の間で有意な上昇が認められ、このコントロール群に対し、試験化合物投与群は総細胞数を７８．９％抑制した。

With respect to the total cell number, a significant increase was observed between the unstimulated group and the control group. Compared with this control group, the test compound-administered group suppressed the total cell number by 78.9%.

  The 5-membered ring compound of the present invention or a salt thereof, or a prodrug thereof inhibits infiltration of leukocytes such as eosinophils and lymphocytes, thereby being useful for the treatment of various inflammatory diseases or allergic inflammatory diseases. is there.

Claims (15)

Formula (1)

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic hetero Represents aryl.
R ² represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or —CON (R ⁶ ) R ⁷ is represented.
R ⁶ represents a hydrogen atom or an optionally substituted alkyl. R ⁷ represents an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted alkyl. Moreover, -N (R ⁶ ) R ⁷ may represent a cyclic amino.
Y ¹ represents a single bond, optionally substituted _{alkylene, -CO (CH 2) n -} , - SO 2 (CH 2) n -, - CONH (CH 2) n -, - CSNH (CH 2) n -, or -COO (CH _{2) n} - represents a.
n represents an integer of 0 to 5.
The wavy line means (E) or (Z) coordination.
R ³ represents a hydrogen atom, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or an optionally substituted cycloalkyl. .
Y ² represents optionally substituted alkylene, alkenylene, or —A—X—B—. A and B may be the same or different and each represents an optionally substituted alkylene or alkenylene. X means an oxygen atom or a sulfur atom.
R ⁴ is optionally substituted imidazol-4-yl, optionally substituted benzimidazol-2-yl, optionally substituted 1,2,3-triazol-4-yl, or substituted 1,2,4-triazol-3-yl optionally represented. ]
Or a pharmaceutically acceptable salt thereof, or a prodrug thereof. The 5-membered ring compound or a pharmaceutically acceptable salt thereof, or a prodrug thereof according to claim ¹ , wherein R ¹ is a hydrogen atom, and R ² is an optionally substituted phenyl. The 5-membered ring compound or a pharmaceutically acceptable salt thereof, or a prodrug thereof according to claim ¹ , wherein R ¹ is a hydrogen atom, and R ² is morpholinophenyl. The 5-membered ring compound or a pharmaceutically acceptable salt thereof according to claim ¹ , wherein R ¹ is a hydrogen atom, R ³ is optionally substituted phenyl, Y ¹ is a single bond, and Y ² is alkylene. Their prodrugs. The 5-membered ring compound or pharmaceutically acceptable salt thereof according to claim ¹ , wherein R ¹ is a hydrogen atom, R ³ is optionally substituted pyridyl, Y ¹ is a single bond, and Y ² is alkylene. Their prodrugs. R ⁴ is optionally substituted imidazol-4-yl, The 5-membered ring compound or a pharmaceutically acceptable salt thereof, or a prodrug thereof according to claim 1. Salts R ⁴ is acceptable 5-membered ring compound or its pharmaceutically of claims 1 to 5, wherein the imidazol-4-yl, or prodrugs thereof. R ⁴ is 1,2,3-triazol-4-yl or 1,2,4-triazol-3-yl, or a 5-membered ring compound or a pharmaceutically acceptable salt thereof according to claim 1 or Prodrug of. The pharmaceutical containing the 5-membered ring compound in any one of Claims 1-8, its pharmaceutically acceptable salt, or those prodrugs. A leukocyte infiltration inhibitor comprising the 5-membered ring compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. A therapeutic agent for autoimmune diseases or allergic diseases comprising the 5-membered ring compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. A therapeutic agent for allergic diseases comprising the 5-membered ring compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, or a prodrug thereof. Formula (2)

[Wherein SS represents a solid phase reaction carrier. Y ² represents optionally substituted alkylene, alkenylene, or —A—X—B—. A and B may be the same or different and each represents an optionally substituted alkylene or alkenylene. R ⁵ is a hydrogen atom, alkyl, alkoxy, halogen atom, or hydroxyl group. Z ¹ represents an amino-protecting group, and Z ² represents a hydrogen atom. Z ¹ and Z ² may be combined with the nitrogen atom to form phthalimide or maleimide. ] The synthetic intermediate represented by this. Formula (3)

[Wherein Y ² represents an optionally substituted alkylene, alkenylene, or —A—X—B—. A and B may be the same or different and each represents an optionally substituted alkylene or alkenylene. X means an oxygen atom or a sulfur atom. R ⁵ is a hydrogen atom, alkyl, alkoxy, halogen atom, or hydroxyl group. Z ¹ represents an amino-protecting group, and Z ² represents a hydrogen atom. Z ¹ and Z ² may be combined with the nitrogen atom to form phthalimide or maleimide. ]
And a compound represented by formula (4)

[Wherein, X represents an oxygen atom or a sulfur atom. SS represents a solid phase reaction carrier. Formula (2) characterized by reacting a solid-phase reaction carrier represented by

[Wherein, Y ² , R ⁵ , Z ¹ , Z ² , SS are as defined above. ]
The manufacturing method of the compound represented by these. Compound (6)

[Wherein, R ¹ represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted bicyclic hetero Represents aryl.
R ² represents a hydrogen atom, an optionally substituted alkyl, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or —CON (R ⁶ ) R ⁷ is represented.
R ⁶ represents a hydrogen atom or an optionally substituted alkyl. R ⁷ represents an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, or an optionally substituted alkyl. Moreover, -N (R ⁶ ) R ⁷ may represent a cyclic amino.
Y ¹ represents a single bond, optionally substituted _{alkylene, -CO (CH 2) n -} , - SO 2 (CH 2) n -, - CONH (CH 2) n -, - CSNH (CH 2) n -, or -COO (CH _{2) n} - represents a.
n represents an integer of 0 to 5.
The wavy line means (E) or (Z) coordination.
R ³ represents a hydrogen atom, an optionally substituted aryl, an optionally substituted monocyclic heteroaryl, an optionally substituted bicyclic heteroaryl, or an optionally substituted cycloalkyl. .
Y ² represents optionally substituted alkylene, alkenylene, or —A—X—B—. A and B may be the same or different and each represents an optionally substituted alkylene or alkenylene.
R ⁵ is a hydrogen atom, alkyl, alkoxy, halogen atom, or hydroxyl group. And SS represent solid phase reaction carriers. ]
Wherein the compound represented by the formula (1 ′) is reacted with a fluorine ion reagent.

[Wherein, R ¹ , R ² , R ³ , R ⁵ , Y ¹ , Y ² and SS are as defined above. ]
The manufacturing method of the 5-membered ring compound represented by these.