JPH0987282A - Thiazole derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new thiazole derivative useful as an antiinflammatroy agent, antiallergic agent, cancer metastasis inhibitor, immunosuppressive agent, etc., having inhibitory activity against cell adhesion. SOLUTION: This thiazole derivative is shown by formula II R<1> is H, a lower alkyl, OH, etc.; R<2> and R<3> are each H or a lower alkyl; A is a group of formula II [R<4> to R<6> are each H, a (substituted) lower alkyl, etc.; Y is O, S, etc.]; B is C(O)N(R<7> ) (R<7> is H or a lower alkyl), etc.; D is a (substituted) aryl, a (substituted) aromatic heterocyclic ring, etc.; (m) is 0 or 1} such as (E)- N- 4-[2-(3-indolyl)ethylamino)carbonyl]-2-thiazolyl}-3-(4-biphenyl)-2-pro penamide. The derivative B, C(O)N(R<7> ) is obtained by condensing a compound of the formula, A-CO2 H with a compound of formula III (R<8> is a lower alkyl) to give a compound of formula IV, hydrolyzing the compound and reacting the resultant substance with a compound of formula V.

Description

【発明の詳細な説明】Detailed Description of the Invention

【０００１】[0001]

【発明の属する技術分野】本発明は、細胞接着阻害活性
を有し、抗炎症剤、抗アレルギー剤、ガン転移抑制剤、
免疫抑制剤などとして有用なチアゾール誘導体に関す
る。TECHNICAL FIELD The present invention relates to an anti-inflammatory agent, an anti-allergic agent, a cancer metastasis inhibitor, which has an activity of inhibiting cell adhesion,
The present invention relates to a thiazole derivative useful as an immunosuppressant and the like.

【０００２】[0002]

【従来の技術】近年、炎症の惹起に関係する段階、即ち
血管内を流れている炎症性細胞が血管外へ浸潤し炎症部
位に遊走する過程において、炎症性細胞上および血管内
皮細胞上に発現した接着分子と総称される生体内分子が
相互に接着することが不可欠であることが明らかにされ
ている。また、この細胞接着は、免疫反応やガンの転移
などにも強く関与していることが示唆されている。従っ
て、ザ・ハンドブック・オブ・イムノファーマコロジー
・アドヒージョン・モルキュールズ（ＴＨＥ ＨＡＮＤ
ＢＯＯＫ ＯＦ ＩＭＭＵＮＯＰＨＡＲＭＡＣＯＬＯＧ
Ｙ，ＡＤＨＥＳＩＯＮ ＭＯＬＥＣＵＬＥＳ），アカデ
ミックプレス：ロンドン（１９９４年）、臨床医のため
の実験医学シリーズ，第１８巻，細胞接着分子と疾患，
羊土社（１９９４年）などに開示されているように、細
胞接着を阻害する化合物は、炎症、アレルギー、自己免
疫疾患、ガンなどに対する治療剤として、あるいは臓器
移植時の拒絶反応の抑制剤として有用であることが期待
される。上記文献を含む種々の公知文献では、各接着分
子のモノクローナル抗体が、種々の炎症、アレルギー、
臓器移植などのモデルにおいて有効であることが明らか
にされている。しかしながら、抗体は、その抗原性や経
口吸収性の低さなどから薬剤として必ずしも満足できる
ものではない。一方、その欠点を克服すべく種々の低分
子接着阻害剤が報告されている。例えば、アニュアル・
レポーツ・イン・メディシナル・ケミストリー（Ａｎ
ｎ．Ｒｅｐ．Ｍｅｄ．Ｃｈｅｍ．），第２９巻，２１５
〜２２４頁（１９９４年）、エキスパート・オピニョン
・オン・インベスティゲイショナル・ドラッグス（Ｅｘ
ｐ．Ｏｐｉｎ．Ｉｎｖｅｓｔ．Ｄｒｕｇｓ），第３巻，
７０９〜７２４頁（１９９４年）にはセレクチン／糖鎖
の接着を阻害する糖類が記載されている。また、エキス
パート・オピニョン・オン・インベスティゲイショナル
・ドラッグス（Ｅｘｐ．Ｏｐｉｎ．Ｉｎｖｅｓｔ．Ｄｒ
ｕｇｓ），第３巻，８６１〜８６９頁（１９９４年）、
エキスパート・オピニョン・オン・セラピューティック
・パテンツ（Ｅｘｐ．Ｏｐｉｎ．Ｔｈｅｒ．Ｐａｔｅｎ
ｔｓ），第５巻，３５〜４０頁（１９９５年）には種々
の細胞接着阻害作用を示す低分子化合物が記載されてい
る。2. Description of the Related Art In recent years, it is expressed on inflammatory cells and vascular endothelial cells in the stage related to the initiation of inflammation, that is, in the process in which inflammatory cells flowing in the blood vessel infiltrate outside the blood vessel and migrate to the inflammatory site. It has been clarified that it is indispensable that the in-vivo molecules, which are collectively referred to as “adhesion molecules”, adhere to each other. Further, it has been suggested that this cell adhesion is strongly involved in immune reaction and cancer metastasis. Therefore, the Handbook of Immunopharmacology Adhesion Molcules (THE HAND
BOOK OF IMMUNOPHARMACOLOG
Y, ADHESION MOLECULES), Academic Press: London (1994), Experimental Medicine Series for Clinicians, Volume 18, Cell Adhesion Molecules and Diseases,
As disclosed in Yodosha (1994) and the like, a compound that inhibits cell adhesion is used as a therapeutic agent for inflammation, allergy, autoimmune disease, cancer, etc., or as an inhibitor of rejection during organ transplantation. Expected to be useful. In various known literatures including the above literature, monoclonal antibodies of each adhesion molecule, various inflammation, allergy,
It has been shown to be effective in models such as organ transplantation. However, antibodies are not always satisfactory as drugs because of their antigenicity and low oral absorbability. On the other hand, various low molecular adhesion inhibitors have been reported to overcome the drawbacks. For example, the annual
Reports in Medicinal Chemistry (An
n. Rep. Med. Chem. ), Vol. 29, 215
~ 224 (1994), Expert Opinion on Investigative Drugs (Ex
p. Opin. Invest. Drugs), Volume 3,
709 to 724 (1994) describe sugars that inhibit the adhesion of selectin / sugar chains. In addition, Expert Opinion on Investigative Drugs (Exp. Opin. Invest. Dr.
Augs), Vol. 3, pp. 861-869 (1994),
Expert Opinion on Therapeutic Patents (Exp. Opin. Ther. Paten
ts), Vol. 5, pp. 35-40 (1995), low-molecular compounds having various cell adhesion inhibitory effects are described.

【０００３】細胞接着阻害作用を有するチアゾール誘導
体として、ＲＷＪ５０２７１がジャーナル・オブ・メデ
ィシナル・ケミストリー（Ｊ．Ｍｅｄ．Ｃｈｅｍ．），
第３８巻，１０５７〜１０５９頁（１９９５年）に開示
されている。As a thiazole derivative having an inhibitory effect on cell adhesion, RWJ50271 is described in Journal of Medicinal Chemistry (J. Med. Chem.),
38, 1057-1059 (1995).

【０００４】[0004]

【化４】 Embedded image

【０００５】[0005]

【発明が解決しようとする課題】本発明の目的は、強力
な細胞接着阻害作用を有し、優れた抗炎症作用、抗アレ
ルギー作用、臓器移植時の拒絶反応の抑制作用、ガン転
移抑制作用などを有する新規化合物を提供することにあ
る。SUMMARY OF THE INVENTION An object of the present invention is to have a strong cell adhesion inhibitory effect, an excellent anti-inflammatory effect, an anti-allergic effect, an inhibitory effect on rejection during organ transplantation, an inhibitory effect on cancer metastasis and the like. To provide a novel compound having the following formula:

【０００６】[0006]

【課題を解決するための手段】本発明者らは、細胞接着
阻害剤、特に血管内皮細胞と好中球の接着を抑制する化
合物の創製を目的に研究を行った結果、ヒト臍帯静脈内
皮細胞 (ｈｕｍａｎｕｍｂｉｌｉｃａｌ ｖｅｉｎ ｄ
ｅｒｉｖｅｄ ｅｎｄｏｔｈｅｌｉａｌ ｃｅｌｌｓ，
ＨＵＶＥＣ) と白血病細胞（ＨＬ６０）の接着を強力に
阻害する化合物を見い出し、本発明を完成させるに至っ
た。[Means for Solving the Problems] The inventors of the present invention have conducted research for the purpose of creating a cell adhesion inhibitor, particularly a compound that suppresses adhesion between vascular endothelial cells and neutrophils. (humanumbilical vein d
erected endotherial cells,
We have found a compound that strongly inhibits the adhesion between HUVEC) and leukemia cells (HL60) and completed the present invention.

【０００７】本発明、は式（Ｉ）The present invention has the formula (I)

【０００８】[0008]

【化５】 Embedded image

【０００９】［式中、Ｒ¹ は、水素、低級アルキル、ヒ
ドロキシ、低級アルコキシ、カルボキシ、低級アルコキ
シカルボニルまたは置換もしくは非置換のアリールを表
し、Ｒ ² およびＲ³ は、同一または異なって水素または
低級アルキルを表し、Ａは、[Wherein R¹Is hydrogen, lower alkyl,
Droxy, lower alkoxy, carboxy, lower alkoxy
Represents carbonyl or substituted or unsubstituted aryl
Then R ²And R^ThreeAre the same or different and are hydrogen or
Represents lower alkyl, A is

【００１０】[0010]

【化６】 [Chemical 6]

【００１１】（式中、Ｒ⁴ 、Ｒ⁵ およびＲ⁶ は、同一ま
たは異なって水素、置換もしくは非置換の低級アルキ
ル、低級シクロアルキル、低級シクロアルキルアルキ
ル、ヒドロキシ、低級アルコキシ、カルボキシ、低級ア
ルコキシカルボニル、低級アルカノイル、ハロゲン、ニ
トロ、アミノ、モノあるいはジ低級アルキルアミノ、置
換もしくは非置換のアラルキル、置換もしくは非置換の
アリール、置換もしくは非置換の芳香族複素環基または
置換もしくは非置換の脂環式複素環基を表し、Ｙは、
Ｏ、Ｓ、ＮＨまたは−Ｃ＝Ｃ−を表す）または(Wherein R ⁴ , R ⁵ and R ⁶ are the same or different and are hydrogen, substituted or unsubstituted lower alkyl, lower cycloalkyl, lower cycloalkylalkyl, hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl. , Lower alkanoyl, halogen, nitro, amino, mono- or di-lower alkylamino, substituted or unsubstituted aralkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group or substituted or unsubstituted alicyclic Represents a heterocyclic group, Y is
O, S, NH or -C = C-) or

【００１２】[0012]

【化７】 [Chemical 7]

【００１３】（式中、Ｚ¹ およびＺ² は、共に水素を表
すかＺ¹ とＺ² が一緒になって単結合を表し、ｎおよび
ｐは、同一または異なって０または１を表し、Ｒ⁴ およ
びＲ⁵は前記と同義である）を表し、Ｂは、−Ｃ（Ｏ）
Ｎ（Ｒ⁷ ）−（式中、Ｒ⁷ は、水素または低級アルキル
を表す）または−ＣＨ₂ ＮＨ−を表し、ｍは、０または
１を表し、Ｄは、置換もしくは非置換のアリール、置換
もしくは非置換の芳香族複素環基または置換もしくは非
置換の脂環式複素環基を表す］で表されるチアゾール誘
導体［以下、化合物（Ｉ）という。他の式番号の化合物
についても同様である］またはその薬理学的に許容され
る塩に関する。(Wherein Z ¹ and Z ² both represent hydrogen or Z ¹ and Z ² together represent a single bond, n and p are the same or different and represent 0 or 1, and R ⁴ and R ⁵ are as defined above, and B is —C (O).
N (R ⁷⁾ - (wherein, R ⁷ represents hydrogen or lower alkyl) or represents -CH ₂ NH-, m is 0 or 1, D is a substituted or unsubstituted aryl, substituted Alternatively, a thiazole derivative represented by an unsubstituted aromatic heterocyclic group or a substituted or unsubstituted alicyclic heterocyclic group [hereinafter, referred to as compound (I). The same applies to compounds of other formula numbers] or a pharmaceutically acceptable salt thereof.

【００１４】式（Ｉ）の各基の定義において、低級アル
キルおよび低級アルコキシ、低級アルコキシカルボニ
ル、低級アルカノイル、低級シクロアルキルアルキル、
モノあるいはジ低級アルキルアミノの低級アルキル部分
としては、直鎖または分枝状の炭素数１〜６の、例えば
メチル、エチル、プロピル、イソプロピル、ブチル、イ
ソブチル、ｓｅｃ−ブチル、ｔｅｒｔ−ブチル、ペンチ
ル、イソペンチル、ヘキシルなどがあげられ、低級シク
ロアルキルおよび低級シクロアルキルアルキルの低級シ
クロアルキル部分としては、炭素数３〜８の、例えばシ
クロプロピル、シクロブチル、シクロペンチル、シクロ
ヘキシル、シクロヘプチル、シクロオクチルなどがあげ
られる。アリールとしては、フェニル、ナフチルなどが
あげられ、アラルキルとしては、炭素数７〜１５の、例
えばベンジル、ナフチルメチル、フェネチル、ベンズヒ
ドリルなどがあげられる。芳香族複素環基としては、ピ
リジル、ピラジニル、ピリミジニル、ピリダジニル、キ
ノリル、イソキノリル、フタラジニル、ナフチリジニ
ル、キノキサリニル、チエニル、フリル、ピロリル、イ
ミダゾリル、ピラゾリル、トリアゾリル、テトラゾリ
ル、チアゾリル、オキサゾリル、インドリル、インダゾ
リル、ベンゾイミダゾリル、プリニルなどがあげられ、
脂環式複素環基としては、ピロリジニル、イミダゾリジ
ニル、ピラゾリジニル、ピペリジノ、ホモピペリジノ、
ピペラジニル、ホモピペラジニル、モルホリノ、チオモ
ルホリノ、ピラニル、ピペリジル、テトラヒドロフラニ
ルなどがあげられる。ハロゲンは、フッ素、塩素、臭
素、ヨウ素の各原子を意味する。In the definition of each group of formula (I), lower alkyl and lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, lower cycloalkylalkyl,
The lower alkyl moiety of mono- or di-lower alkylamino is a linear or branched C 1-6 carbon atom, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, Isopentyl, hexyl and the like can be mentioned. As the lower cycloalkyl and the lower cycloalkyl moiety of the lower cycloalkylalkyl, there can be mentioned, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like having 3 to 8 carbon atoms. . Examples of aryl include phenyl and naphthyl, and examples of aralkyl include those having 7 to 15 carbon atoms, such as benzyl, naphthylmethyl, phenethyl, and benzhydryl. Examples of the aromatic heterocyclic group include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolyl, isoquinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl. Such as purinil,
Examples of the alicyclic heterocyclic group include pyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidino, homopiperidino,
Examples thereof include piperazinyl, homopiperazinyl, morpholino, thiomorpholino, pyranyl, piperidyl, and tetrahydrofuranyl. Halogen means each atom of fluorine, chlorine, bromine and iodine.

【００１５】置換アルキルの置換基としては、例えばヒ
ドロキシ、低級アルコキシ、カルボキシ、低級アルコキ
シカルボニル、低級アルカノイル、カルバモイル、アミ
ノ、モノあるいはジ低級アルキルアミノなどがあげられ
る。置換基の定義において、低級アルコキシ、低級アル
コキシカルボニル、低級アルカノイルおよびモノあるい
はジ低級アルキルアミノは、それぞれ前記と同義であ
る。置換アリール、置換アラルキル、置換芳香族複素環
基および置換脂環式複素環基の置換基としては、同一ま
たは異なって置換数１〜３の、例えば置換もしくは非置
換の低級アルキル、アラルキル、ヒドロキシ、置換もし
くは非置換の低級アルコキシ、低級アルケニルオキシ、
低級アルキニルオキシ、カルボキシ、低級アルコキシカ
ルボニル、低級アルカノイル、ハロゲン、ニトロ、アミ
ノ、モノあるいはジ低級アルキルアミノ、メルカプト、
低級アルキルチオ、トリフルオロメチルなどがあげられ
る。置換基の定義において、低級アルケニルオキシにお
ける低級アルケニル部分としては、直鎖または分枝状の
炭素数２〜６の、例えばビニル、プロペニル、１−ブテ
ニル、２−ブテニル、ペンテニル、２−メチル−２−ブ
テニル、ヘキセニルなどがあげられ、低級アルキニルオ
キシにおける低級アルキニル部分としては、炭素数３〜
６の、例えばプロパルギル、１−ブチニル、ペンチニ
ル、ヘキシニル、ヘプチニルなどがあげられる。低級ア
ルキルチオの低級アルキル部分は、前記低級アルキルと
同義であり、低級アルキル、アラルキル、低級アルコキ
シ、低級アルコキシカルボニル、低級アルカノイル、ハ
ロゲンおよびモノあるいはジ低級アルキルアミノは、そ
れぞれ前記と同義である。置換低級アルキルおよび置換
低級アルコキシの置換基としては、ヒドロキシ、低級ア
ルコキシ、カルボキシ、低級アルコキシカルボニル、低
級アルカノイル、カルバモイル、アミノ、モノあるいは
ジ低級アルキルアミノなどがあげられ、低級アルコキ
シ、低級アルコキシカルボニル、低級アルカノイルおよ
びモノあるいはジ低級アルキルアミノは、それぞれ前記
と同義である。Examples of the substituent of the substituted alkyl include hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, amino, mono- or di-lower alkylamino and the like. In the definition of substituents, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl and mono- or di-lower alkylamino have the same meanings as defined above. The substituted aryl, the substituted aralkyl, the substituted aromatic heterocyclic group and the substituted alicyclic heterocyclic group have the same or different substituents 1 to 3, for example, substituted or unsubstituted lower alkyl, aralkyl, hydroxy, Substituted or unsubstituted lower alkoxy, lower alkenyloxy,
Lower alkynyloxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, halogen, nitro, amino, mono- or di-lower alkylamino, mercapto,
Examples include lower alkylthio and trifluoromethyl. In the definition of the substituent, the lower alkenyl moiety in the lower alkenyloxy is, for example, a straight chain or branched chain having 2 to 6 carbon atoms, for example, vinyl, propenyl, 1-butenyl, 2-butenyl, pentenyl, 2-methyl-2. -Butenyl, hexenyl and the like can be mentioned, and the lower alkynyl moiety in the lower alkynyloxy has 3 to 3 carbon atoms.
Examples of 6 include propargyl, 1-butynyl, pentynyl, hexynyl, heptynyl and the like. The lower alkyl part of lower alkylthio has the same meaning as the above lower alkyl, and lower alkyl, aralkyl, lower alkoxy, lower alkoxycarbonyl, lower alkanoyl, halogen and mono- or di-lower alkylamino have the same meanings as described above. Examples of the substituent of the substituted lower alkyl and the substituted lower alkoxy include hydroxy, lower alkoxy, carboxy, lower alkoxycarbonyl, lower alkanoyl, carbamoyl, amino, mono- or di-lower alkylamino, lower alkoxy, lower alkoxycarbonyl, lower Alkanoyl and mono- or di-lower alkylamino are as defined above.

【００１６】化合物（Ｉ）の薬理学的に許容される塩と
しては、例えば塩酸塩、硫酸塩、硝酸塩、リン酸塩など
の無機酸塩、酢酸塩、フマル酸塩、マレイン酸塩、酒石
酸塩、クエン酸塩、乳酸塩、シュウ酸塩、メタンスルホ
ン酸塩、ベンゼンスルホン酸塩、パラトルエンスルホン
酸塩などの有機酸塩、ナトリウム塩、カリウム塩などの
アルカリ金属塩、マグネシウム塩、カルシウム塩などの
アルカリ土類金属塩、アンモニウム、テトラメチルアン
モニウムなどのアンモニウム塩、モルホリン付加塩、ピ
ペリジン付加塩などの有機アミン付加塩などがあげられ
る。Examples of the pharmacologically acceptable salt of compound (I) include inorganic acid salts such as hydrochlorides, sulfates, nitrates and phosphates, acetates, fumarates, maleates and tartrates. , Citrate, lactate, oxalate, methanesulfonate, benzenesulfonate, paratoluenesulfonate and other organic acid salts, sodium salts, potassium salts and other alkali metal salts, magnesium salts, calcium salts, etc. Examples thereof include alkaline earth metal salts, ammonium salts such as ammonium and tetramethylammonium, organic amine addition salts such as morpholine addition salts and piperidine addition salts.

【００１７】次に、化合物（Ｉ）の製造法について説明
する。方法１ 化合物（Ｉ）においてＢが−Ｃ（Ｏ）Ｎ（Ｒ⁷ ）−であ
る化合物（Ｉａ）は、次の反応工程に従い製造すること
ができる。Next, the method for producing the compound (I) will be described. Method 1 Compound (Ia) in which B is —C (O) N (R ⁷ ) — in Compound (I) can be produced according to the following reaction steps.

【００１８】[0018]

【化８】 Embedded image

【００１９】（式中、Ｒ⁸ は低級アルキルを表し、
Ｒ¹ 、Ｒ² 、Ｒ³ 、Ｒ⁷ 、Ａ、Ｄおよびｍはそれぞれ前
記と同義である） Ｒ⁸ の定義における低級アルキルは前記と同義である。
化合物（ＩＶ）は、公知の方法［ジャーナル・オブ・オ
ーガニック・ケミストリー（Ｊ．Ｏｒｇ．Ｃｈｅ
ｍ．），第３８巻，４０８６頁（１９７３年）、ジャー
ナル・オブ・ケミカル・ソサエティー（Ｊ．Ｃｈｅｍ．
Ｓｏｃ．）（Ｃ），８５頁（１９７０年）、ケミカル・
ファーマシューティカル・ブリテン（Ｃｈｅｍ．Ｐｈａ
ｒｍ．Ｂｕｌｌ．），第２５巻，３１１０頁（１９７７
年）、特開昭６１−１９１６８３号公報、ジャーナル・
オブ・アメリカン・ケミカル・ソサエティー（Ｊ．Ａ
ｍ．Ｃｈｅｍ．Ｓｏｃ．），第８０巻，４６２１頁（１
９５８年）、テトラヘドロン・レターズ（Ｔｅｔｒａｈ
ｅｄｒｏｎ Ｌｅｔｔ．），第３５巻，１８４７頁（１
９９４年）、ジャーナル・オブ・メディシナル・ケミス
トリー（Ｊ．Ｍｅｄ．Ｃｈｅｍ．），第３５巻，９５８
頁（１９９２年）、テトラヘドロン（Ｔｅｔｒａｈｅｄ
ｒｏｎ），第４７巻，４６４５頁（１９９１年）］もし
くはそれに準じて得られる化合物（ＩＩ）と公知の方法
［ジャーナル・オブ・ヘテロサイクリック・ケミストリ
ー（Ｊ．Ｈｅｔｅｒｏｃｙｃｌｉｃ Ｃｈｅｍ．），第
２６巻，１６４３頁（１９８９年）、特開昭５０−１２
１２７０号公報］もしくはそれに準じて得られる化合物
（ＩＩＩ）とを縮合させることにより得ることができ
る。縮合の方法としては、一般に行われる方法、例えば
化合物（ＩＩ）を酸ハロゲン化物、酸無水物、混合酸無
水物、ｐ−ニトロフェニルエステル、ｐ−ニトロチオフ
ェニルエステル、ペンタフルオロフェニルエステルなど
のカルボン酸の反応性誘導体に変換した後化合物（ＩＩ
Ｉ）と縮合する方法、あるいは縮合剤として１，３−ジ
シクロヘキシルカルボジイミド、１−（３−ジメチルア
ミノプロピル）−３−エチルカルボジイミド・塩酸塩、
ヨウ化２−クロロ−１−メチルピリジニウムなどを用い
て化合物（ＩＩ）と化合物（ＩＩＩ）とを縮合する方法
などがあげられる。(In the formula, R ⁸ represents lower alkyl,
R ¹ , R ² , R ³ , R ⁷ , A, D and m have the same meanings as described above.) The lower alkyl in the definition of R ^{8 has} the same meanings as described above.
Compound (IV) can be produced by a known method [J. Org. Che.
m. ), 38, 4086 (1973), Journal of Chemical Society (J. Chem.
Soc. ) (C), p. 85 (1970), Chemical.
Pharmaceutical Bulletin (Chem.Pha
rm. Bull. ), 25, p. 3110 (1977).
Year), Japanese Patent Laid-Open No. 61-191683, Journal
Of the American Chemical Society (JA
m. Chem. Soc. ), 80, 4621 (1
958), Tetrahedron Letters (Tetrah)
edron Lett. ), 35, 1847 (1
994), Journal of Medicinal Chemistry (J. Med. Chem.), Volume 35, 958.
Page (1992) Tetrahedron
ron), Vol. 47, page 4645 (1991)] or a compound (II) obtained according thereto or a known method [J. Heterocyclic Chem.], Vol. 26, 1643 (1989), JP-A-50-12
No. 1270] or a compound (III) obtained according to the above method is condensed. The condensation may be carried out by a generally-used method, for example, by using the compound (II) as an acid halide, an acid anhydride, a mixed acid anhydride, a p-nitrophenyl ester, a p-nitrothiophenyl ester, a pentafluorophenyl ester or the like. After conversion to the reactive derivative of the acid, the compound (II
I) condensation method, or 1,3-dicyclohexylcarbodiimide, 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride as a condensing agent,
Examples thereof include a method of condensing the compound (II) with the compound (III) using 2-chloro-1-methylpyridinium iodide and the like.

【００２０】例えば、化合物（ＩＩ）を、１〜１０当量
のヨウ化２−クロロ−１−メチルピリジニウムなどの存
在下、塩化メチレンなどのハロゲン化炭化水素類、テト
ラヒドロフラン、ジオキサンなどのエーテル類などの不
活性溶媒中、−７８℃〜用いた溶媒の沸点の間の温度で
１〜２４時間処理することにより化合物（ＩＩ）の酸無
水物を得る。次いで、化合物（ＩＶ）は、該酸無水物と
１〜１０当量の化合物（ＩＩＩ）とを、必要により当量
〜大過剰のトリエチルアミン、ジシクロヘキシルエチル
アミンなどの塩基の存在下、さらに必要ならば触媒量〜
２当量のジメチルアミノピリジンなどの反応活性化剤の
存在下、ピリジンなどの塩基性芳香族炭化水素類などの
不活性溶媒中、５０℃〜用いた溶媒の沸点の間の温度で
１〜２４時間反応させることにより得ることができる。For example, compound (II) is treated with halogenated hydrocarbons such as methylene chloride and ethers such as tetrahydrofuran and dioxane in the presence of 1 to 10 equivalents of 2-chloro-1-methylpyridinium iodide and the like. The acid anhydride of compound (II) is obtained by treating in an inert solvent at a temperature between −78 ° C. and the boiling point of the solvent used for 1 to 24 hours. Then, the compound (IV) is obtained by adding the acid anhydride and 1 to 10 equivalents of the compound (III), if necessary, in an equivalent amount to a large excess of a base such as triethylamine or dicyclohexylethylamine, and if necessary, in a catalytic amount.
In the presence of 2 equivalents of a reaction activator such as dimethylaminopyridine, in an inert solvent such as basic aromatic hydrocarbons such as pyridine, at a temperature between 50 ° C. and the boiling point of the solvent used for 1 to 24 hours. It can be obtained by reacting.

【００２１】また、化合物（ＩＶ）は、以下の方法によ
って得ることもできる。化合物（ＩＩ）とｐ−ニトロフ
ェノール、ｐ−ニトロチオフェノール、ペンタフルオロ
フェノールなどのフェノール類とを、１〜１０当量のヨ
ウ化２−クロロ−１−メチルピリジニウムなどの存在
下、塩化メチレンなどのハロゲン化炭化水素類、テトラ
ヒドロフラン、ジオキサンなどのエーテル類などの不活
性溶媒中、室温〜用いた溶媒の沸点の間の温度で１〜２
４時間反応させることにより化合物（ＩＩ）のｐ−ニト
ロフェニルエステル、ｐ−ニトロチオフェニルエステ
ル、ペンタフルオロフェニルエステルなどを得る。次い
で、化合物（ＩＶ）は、該エステルと１〜１０当量の化
合物（ＩＩＩ）とを、必要により当量〜大過剰のトリエ
チルアミン、ジシクロヘキシルエチルアミンなどの塩基
の存在下、さらに必要ならば触媒量〜２当量のジメチル
アミノピリジンなどの反応活性化剤の存在下、１，２−
ジクロロエタンなどのハロゲン化炭化水素類、ジメチル
ホルムアミドなどのアミド類、テトラヒドロフラン、ジ
オキサンなどのエーテル類、ピリジンなどの塩基性芳香
族炭化水素類などの不活性溶媒中、室温〜用いた溶媒の
沸点の間の温度で１〜２４時間反応させることにより得
ることができる。Compound (IV) can also be obtained by the following method. Compound (II) and phenols such as p-nitrophenol, p-nitrothiophenol, pentafluorophenol and the like in the presence of 1 to 10 equivalents of 2-chloro-1-methylpyridinium iodide and the like, such as methylene chloride and the like. 1-2 in an inert solvent such as halogenated hydrocarbons, ethers such as tetrahydrofuran and dioxane at a temperature between room temperature and the boiling point of the solvent used.
By reacting for 4 hours, p-nitrophenyl ester, p-nitrothiophenyl ester, pentafluorophenyl ester, etc. of compound (II) are obtained. Then, the compound (IV) is obtained by adding the ester and 1 to 10 equivalents of the compound (III), if necessary, in the presence of an equivalent amount to a large excess of a base such as triethylamine or dicyclohexylethylamine, and if necessary, a catalytic amount to 2 equivalents. In the presence of a reaction activator such as dimethylaminopyridine, 1,2-
Between halogenated hydrocarbons such as dichloroethane, amides such as dimethylformamide, ethers such as tetrahydrofuran and dioxane, and basic aromatic hydrocarbons such as pyridine, between room temperature and the boiling point of the solvent used. It can be obtained by reacting at the temperature of 1 to 24 hours.

【００２２】また、化合物（ＩＶ）は、以下の方法によ
って得ることもできる。化合物（ＩＩ）を、１〜２０当
量の塩化チオニル、塩化オキザリル、五塩化リン、オキ
シ塩化リン、三臭化リンなどのハロゲン化剤の存在下、
塩化メチレンなどのハロゲン化炭化水素類などの不活性
溶媒中、−７８℃〜用いた溶媒の沸点の間の温度で１〜
２４時間処理することにより酸ハライドを得、次いで、
化合物（ＩＶ）は、該酸ハライドと１〜１０当量の化合
物（ＩＩＩ）とを、必要により当量〜大過剰のトリエチ
ルアミン、ジシクロヘキシルエチルアミンなどの塩基の
存在下、さらに必要ならば触媒量〜２当量のジメチルア
ミノピリジンなどの反応活性化剤の存在下、塩化メチレ
ンなどのハロゲン化炭化水素類、ジメチルホルムアミド
などのアミド類、テトラヒドロフラン、ジオキサンなど
のエーテル類、ピリジンなどの塩基性芳香族炭化水素類
などの不活性溶媒中、−７８℃〜用いた溶媒の沸点の間
の温度で１〜２４時間反応させることにより得ることが
できる。The compound (IV) can also be obtained by the following method. Compound (II) in the presence of 1 to 20 equivalents of a halogenating agent such as thionyl chloride, oxalyl chloride, phosphorus pentachloride, phosphorus oxychloride, phosphorus tribromide,
In an inert solvent such as halogenated hydrocarbons such as methylene chloride, at a temperature between −78 ° C. and the boiling point of the solvent used, 1 to
The acid halide is obtained by treating for 24 hours, and then
Compound (IV) is obtained by reacting the acid halide with 1 to 10 equivalents of compound (III) in the presence of an equivalent to a large excess of a base such as triethylamine or dicyclohexylethylamine, if necessary, and a catalytic amount to 2 equivalents if necessary. In the presence of a reaction activator such as dimethylaminopyridine, halogenated hydrocarbons such as methylene chloride, amides such as dimethylformamide, ethers such as tetrahydrofuran and dioxane, basic aromatic hydrocarbons such as pyridine, etc. It can be obtained by reacting in an inert solvent at a temperature between −78 ° C. and the boiling point of the solvent used for 1 to 24 hours.

【００２３】化合物（Ｖ）は、化合物（ＩＶ）を、１〜
１０当量の水酸化ナトリウム、水酸化カリウム、水酸化
リチウムなどの適当な塩基の存在下、メタノール、エタ
ノールなどのアルコール類、テトラヒドロフラン、ジオ
キサンなどと水との混合溶媒などの不活性溶媒中、室温
〜用いた溶媒の沸点の間の温度で処理することにより得
ることができる。The compound (V) is obtained by converting the compound (IV) into 1 to
In the presence of a suitable base such as 10 equivalents of sodium hydroxide, potassium hydroxide, lithium hydroxide or the like, in an inert solvent such as an alcohol such as methanol or ethanol, a mixed solvent of tetrahydrofuran, dioxane or the like and water, at room temperature to It can be obtained by treating at a temperature between the boiling points of the solvents used.

【００２４】化合物（Ｉａ）は、化合物（Ｖ）と公知の
方法［シンセシス（Ｓｙｎｔｈｅｓｉｓ），６５１頁
（１９８７年）、ジャーナル・オブ・ザ・ケミカル・ソ
サエティー（Ｊ．Ｃｈｅｍ．Ｓｏｃ．），２６４１頁
（１９５４年）］もしくはそれに準じて得られる化合物
（ＶＩ）とを、化合物（ＩＩ）と化合物（ＩＩＩ）から
化合物（ＩＶ）を得る方法に準じて反応させることによ
り得ることができる。例えば、化合物（Ｖ）と化合物
（ＶＩ）とを、１〜３当量の１−（３−ジメチルアミノ
プロピル）−３−エチルカルボジイミド・塩酸塩、１，
３−ジシクロヘキシルカルボジイミドなどの縮合剤の存
在下、必要により当量〜大過剰のトリエチルアミン、ピ
リジンなどの塩基の存在下、さらに必要ならば２〜４当
量の１−ヒドロキシベンゾトリアゾールなどの反応活性
化剤の存在下、ジメチルホルムアミドなどのアミド類、
テトラヒドロフラン、ジオキサンなどのエーテル類など
の不活性溶媒中、−５０℃〜室温の間の温度で０．５〜
４８時間反応させることにより得ることができる。Compound (Ia) can be prepared by the known method from compound (V) [Synthesis, page 651 (1987), Journal of the Chemical Society (J. Chem. Soc.), Page 2641]. (1954)] or a compound (VI) obtained in accordance therewith, can be obtained by reacting the compound (II) with the compound (III) according to the method of obtaining the compound (IV). For example, the compound (V) and the compound (VI) are mixed with 1 to 3 equivalents of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 1,
In the presence of a condensing agent such as 3-dicyclohexylcarbodiimide, if necessary in the presence of an equivalent to a large excess of a base such as triethylamine or pyridine, and if necessary, in an amount of 2 to 4 equivalents of a reaction activator such as 1-hydroxybenzotriazole. In the presence of amides such as dimethylformamide,
In an inert solvent such as tetrahydrofuran or ether such as dioxane, at a temperature between -50 ° C and room temperature, 0.5 to
It can be obtained by reacting for 48 hours.

【００２５】方法２ 化合物（Ｉａ）は、次の反応工程に従い製造することも
できる。 Method 2 Compound (Ia) can also be produced according to the following reaction steps.

【００２６】[0026]

【化９】 Embedded image

【００２７】（式中、Ｒ⁹ は低級アルキルまたは置換も
しくは非置換のアラルキルを表し、Ｒ ¹ 、Ｒ² 、Ｒ³ 、
Ｒ⁷ 、Ｒ⁸ 、Ａ、Ｄおよびｍはそれぞれ前記と同義であ
る） Ｒ⁹ の定義における低級アルキルおよび置換もしくは非
置換のアラルキルはそれぞれ前記と同義である。化合物
（ＶＩＩＩ）は、化合物（ＩＩＩ）と１〜２当量の化合
物（ＶＩＩ）とを、触媒量〜５当量のジメチルアミノピ
リジンなどの適当な塩基の存在下、塩化メチレン、アセ
トニトリルなどの不活性溶媒中、−２０℃〜室温の間の
温度で反応させることにより得ることができる。Where R⁹Is also lower alkyl or substituted
Or unsubstituted aralkyl, R ¹, R², R^Three,
R⁷, R⁸, A, D and m are as defined above.
R)⁹In the definition of lower alkyl and substituted or non-substituted
The substituted aralkyl has the same meaning as above. Compound
(VIII) is a compound (III) and a compound of 1 to 2 equivalents.
(VII) with a catalytic amount to 5 equivalents of dimethylaminopyrrole.
In the presence of a suitable base such as lysine, methylene chloride, acetone
In an inert solvent such as trinitrile, between -20 ° C and room temperature
It can be obtained by reacting at temperature.

【００２８】化合物（ＩＸ）は、化合物（ＶＩＩＩ）を
用い、方法１に記載した化合物（ＩＶ）から化合物
（Ｖ）を得る方法に準じて得ることができる。化合物
（Ｘ）は、化合物（ＩＸ）と化合物（ＶＩ）とを、方法
１に記載した化合物（Ｖ）と化合物（ＶＩ）から化合物
（Ｉａ）を得る方法に準じて反応させることにより得る
ことができる。Compound (IX) can be obtained according to the method of obtaining compound (V) from compound (IV) described in Method 1, using compound (VIII). Compound (X) can be obtained by reacting compound (IX) with compound (VI) according to the method described in Method 1 for obtaining compound (Ia) from compound (V) and compound (VI). it can.

【００２９】化合物（ＸＩ）は、化合物（Ｘ）を通常の
方法で脱保護することにより得ることができる。例え
ば、Ｒ⁹ がｔｅｒｔ−ブチルなどの場合、化合物（Ｘ
Ｉ）は、化合物（Ｘ）を、触媒量〜大過剰の塩酸、トリ
フルオロ酢酸などの強酸の存在下、塩化メチレン、クロ
ロホルムなどのハロゲン化炭化水素類、酢酸エチルなど
のエステル類などの不活性溶媒中、−２０℃〜室温の間
の温度で１〜２４時間処理することにより得ることがで
きる。また、Ｒ⁹ がベンジルなどの場合、化合物（Ｘ
Ｉ）は、適当な還元方法、例えばパラジウム−炭素、二
酸化白金、ラネーニッケルなどの触媒の存在下、必要に
より触媒量〜大過剰の塩酸、酢酸などの酸の存在下、メ
タノール、エタノールなどのアルコール類、酢酸エチル
などのエステル類などの不活性溶媒中、常圧〜中圧の水
素雰囲気下、室温〜６０℃の間の温度で化合物（Ｘ）を
処理することにより得ることができる。Compound (XI) can be obtained by deprotecting compound (X) by a conventional method. For example, when R ⁹ is tert-butyl or the like, the compound (X
I) is a compound (X) in the presence of a catalytic amount to a large excess of hydrochloric acid, strong acid such as trifluoroacetic acid, and halogenated hydrocarbons such as methylene chloride and chloroform; and esters such as ethyl acetate. It can be obtained by treating in a solvent at a temperature between −20 ° C. and room temperature for 1 to 24 hours. When R ⁹ is benzyl or the like, the compound (X
I) is a suitable reduction method, for example, in the presence of a catalyst such as palladium-carbon, platinum dioxide or Raney nickel, optionally in the presence of a catalytic amount to a large excess of an acid such as hydrochloric acid or acetic acid, and an alcohol such as methanol or ethanol. Can be obtained by treating compound (X) in an inert solvent such as esters such as ethyl acetate under a hydrogen atmosphere at normal pressure to medium pressure at a temperature between room temperature and 60 ° C.

【００３０】化合物（Ｉａ）は、化合物（ＸＩ）と化合
物（ＩＩ）とを、方法１に記載した化合物（ＩＩ）と化
合物（ＩＩＩ）から化合物（ＩＶ）を得る方法に準じて
反応させることにより得ることができる。Compound (Ia) is obtained by reacting compound (XI) with compound (II) according to the method described in Method 1 for obtaining compound (IV) from compound (II) and compound (III). Obtainable.

【００３１】方法３ 化合物（Ｉ）においてＢが−ＣＨ₂ ＮＨ−である化合物
（Ｉｂ）は、次の反応工程に従い製造することができ
る。 Method 3 In compound (I), compound (Ib) in which B is —CH ₂ NH— can be produced according to the following reaction steps.

【００３２】[0032]

【化１０】 Embedded image

【００３３】（式中、Ｒ¹⁰およびＲ¹¹は同一または異な
って低級アルキルを表し、Ｒ¹ 、Ｒ²、Ｒ³ 、Ｒ⁷ 、Ｒ
⁸ 、Ｒ⁹ 、Ａ、Ｄおよびｍはそれぞれ前記と同義であ
る） Ｒ¹⁰およびＲ¹¹の定義における低級アルキルは前記と同
義である。化合物（ＸＩＩ）は、化合物（ＩＩ）を通常
の方法でエステル化することにより得ることができる。
例えば、化合物（ＸＩＩ）は、化合物（ＩＩ）を、触媒
量の塩酸、硫酸、過塩素酸などの酸の存在下、メタノー
ル、エタノールなどの低級アルコール類中、室温〜溶媒
の沸点の間の温度で１〜２４時間処理することにより、
また、化合物（ＩＩ）と１当量〜大過剰のヨウ化メチ
ル、ヨウ化エチルなどのハロゲン化アルキルとを、１〜
１０当量の炭酸カリウム、炭酸水素ナトリウム、水素化
ナトリウムなどの適当な塩基の存在下、ジメチルホルム
アミドなどのアミド類などの不活性溶媒中、室温〜６０
℃の間の温度で１〜２４時間反応させることにより得る
ことができる。(In the formula, R ¹⁰ and R ¹¹ are the same or different and represent lower alkyl, and R ¹ , R ² , R ³ , R ⁷ and R
⁸ , R ⁹ , A, D and m have the same meanings as described above.) The lower alkyl in the definition of R ¹⁰ and R ¹¹ has the same meaning as above. Compound (XII) can be obtained by esterifying compound (II) by a conventional method.
For example, the compound (XII) is obtained by converting the compound (II) into a lower alcohol such as methanol or ethanol in the presence of a catalytic amount of an acid such as hydrochloric acid, sulfuric acid or perchloric acid at a temperature between room temperature and the boiling point of the solvent. By treating for 1 to 24 hours,
Further, the compound (II) and 1 equivalent to a large excess of alkyl iodide such as methyl iodide and ethyl iodide are combined with 1 to
Room temperature to 60 in an inert solvent such as amides such as dimethylformamide in the presence of a suitable base such as 10 equivalents of potassium carbonate, sodium hydrogen carbonate, sodium hydride and the like.
It can be obtained by reacting at a temperature between ° C and 1 to 24 hours.

【００３４】化合物（ＸＩＩＩ）は、化合物（ＩＩ）も
しくは化合物（ＸＩＩ）を通常の方法で還元することに
より得ることができる。例えば、化合物（ＸＩＩＩ）
は、化合物（ＩＩ）もしくは化合物（ＸＩＩ）を、０．
５〜１０当量の水素化リチウムアルミニウム、水素化ジ
イソブチルアルミニウムなどの還元剤の存在下、ジエチ
ルエーテル、テトラヒドロフランなどのエーテル類など
の不活性溶媒中、−７０℃〜溶媒の沸点の間の温度で
０．５〜２４時間処理することにより得ることができ
る。Compound (XIII) can be obtained by reducing compound (II) or compound (XII) by a conventional method. For example, compound (XIII)
Is the compound (II) or the compound (XII).
In the presence of a reducing agent such as 5 to 10 equivalents of lithium aluminum hydride or diisobutylaluminum hydride, in an inert solvent such as ethers such as diethyl ether or tetrahydrofuran, at a temperature between −70 ° C. and the boiling point of the solvent, 0 It can be obtained by treating for 0.5 to 24 hours.

【００３５】化合物（ＸＶ）は、化合物（ＸＩＩＩ）と
化合物（ＶＩＩＩａ）とを、１〜２当量のトリフェニル
ホスフィンおよびアゾジカルボン酸ジエステル（ＸＩ
Ｖ）の存在下、ベンゼン、トルエンなどの芳香族炭化水
素類、テトラヒドロフラン、ジオキサンなどのエーテル
類などの不活性溶媒中、０℃〜室温の間の温度で１〜２
４時間反応させることにより得ることができる。The compound (XV) is obtained by converting the compound (XIII) and the compound (VIIIa) into 1 to 2 equivalents of triphenylphosphine and azodicarboxylic acid diester (XI).
1-2) at a temperature between 0 ° C. and room temperature in the presence of V) in an inert solvent such as aromatic hydrocarbons such as benzene and toluene, ethers such as tetrahydrofuran and dioxane.
It can be obtained by reacting for 4 hours.

【００３６】化合物（ＸＶＩ）は、化合物（ＸＶ）を用
い、方法１に記載した化合物（ＩＶ）から化合物（Ｖ）
を得る方法に準じて加水分解を行い、次いで得られたカ
ルボン酸と化合物（ＶＩ）とを、方法１に記載した化合
物（Ｖ）と化合物（ＶＩ）から化合物（Ｉａ）を得る方
法に準じて反応させることにより得ることができる。化
合物（Ｉｂ）は、化合物（ＸＶＩ）を用い、方法２に記
載した化合物（Ｘ）から化合物（ＸＩ）を得る方法に準
じて得ることができる。As the compound (XVI), the compound (XV) is used to prepare the compound (IV) to the compound (V).
According to the method for obtaining the compound (Ia) from the compound (V) and the compound (VI) described in Method 1, followed by hydrolysis according to the method for obtaining the compound (VI). It can be obtained by reacting. Compound (Ib) can be obtained according to the method of obtaining compound (XI) from compound (X) described in method 2 using compound (XVI).

【００３７】上述した製造法で得られる化合物（Ｉ）の
中には、これを中間体としてさらに新規な誘導体（Ｉ）
へ導くことができる場合もある。例えば、置換基として
カルボキシル基を有する化合物（Ｉ）は、置換基として
低級アルコキシカルボニル基を有する化合物（Ｉ）を用
い、方法１に記載した加水分解法もしくはそれに準じて
得ることができる。Among the compounds (I) obtained by the above-mentioned production method, the compound (I) is used as an intermediate to obtain a novel derivative (I).
Sometimes you can lead to. For example, the compound (I) having a carboxyl group as a substituent can be obtained by using the compound (I) having a lower alkoxycarbonyl group as a substituent, the hydrolysis method described in Method 1 or a modification thereof.

【００３８】置換基としてモノあるいはジ低級アルキル
アミノ基を有する化合物（Ｉ）は、置換基としてニトロ
基を有する化合物（Ｉ）を用い、方法２または３に記載
した還元法もしくはそれに準じて還元を行った後、生成
したアミンと１〜１０当量の適当なカルボニル化合物と
を、例えば、０．５〜４当量の水素化ホウ素ナトリウ
ム、水素化シアノホウ素ナトリウムなどの還元剤の存在
下、メタノール、エタノールなどのアルコール類などの
不活性溶媒中反応させて還元的アルキル化を行うことに
より得ることができる。カルボニル化合物としては、例
えばホルムアルデヒド、アセトアルデヒドなどがあげら
れ、それぞれ（ジ）メチルアミノ基、（ジ）エチルアミ
ノ基を有する化合物に導くことができる。また、上記ニ
トロ基の還元により生成するアミノ基は、ジアゾニウム
塩に変換することができ、さらにこのジアゾニウム塩を
水素原子、ハロゲンなどに置換することも可能である。
例えば、アミノ基を有する化合物（Ｉ）を、１〜３当量
の亜硝酸ナトリウムの存在下、次亜リン酸中、０℃〜室
温の間の温度で０．５〜５時間処理することにより、ア
ミノ基が水素原子に置換された化合物（Ｉ）を得ること
ができる。As the compound (I) having a mono- or di-lower alkylamino group as a substituent, the compound (I) having a nitro group as a substituent can be used to carry out the reduction method described in Method 2 or 3 or reduction according to the reduction method. After that, the produced amine and 1 to 10 equivalents of a suitable carbonyl compound are treated with methanol, ethanol in the presence of a reducing agent such as 0.5 to 4 equivalents of sodium borohydride or sodium cyanoborohydride. It can be obtained by performing reductive alkylation by reacting in an inert solvent such as alcohols. Examples of the carbonyl compound include formaldehyde and acetaldehyde, which can be led to compounds having a (di) methylamino group and a (di) ethylamino group, respectively. Further, the amino group produced by the reduction of the nitro group can be converted into a diazonium salt, and the diazonium salt can be further substituted with a hydrogen atom, a halogen or the like.
For example, by treating the compound (I) having an amino group in the presence of 1 to 3 equivalents of sodium nitrite in hypophosphorous acid at a temperature between 0 ° C. and room temperature for 0.5 to 5 hours, A compound (I) having an amino group substituted with a hydrogen atom can be obtained.

【００３９】Ｒ⁶ がＮ原子上のＨである化合物（Ｉ）
は、Ｒ⁶ がＮ原子上の置換もしくは非置換の低級アルキ
ル、低級シクロアルキル、低級シクロアルキルアルキ
ル、低級アルコキシカルボニル、低級アルカノイルまた
は置換もしくは非置換のアラルキルである化合物（Ｉ）
の置換基Ｒ⁶ を除去することにより得ることができる。
例えば、Ｒ⁶ がベンジルである場合、適当な還元方法、
例えば、パラジウム−炭素、二酸化白金、ラネーニッケ
ルなどの触媒の存在下、必要により触媒量〜大過剰の塩
酸、酢酸などの酸の存在下、メタノール、エタノールな
どのアルコール類、酢酸エチルなどのエステル類などの
不活性溶媒中、常圧〜中圧の水素雰囲気下、室温〜溶媒
の沸点の間の温度で１〜２４時間処理することにより、
また、Ｒ⁶ が４−メトキシベンジルである場合、１〜１
０当量の２，３−ジクロロ−５，６−ジシアノ−１，４
−ベンゾキノン（ＤＤＱ）などの適当な酸化剤の存在
下、含水の塩化メチレン、１，２−ジクロロエタンなど
の不活性溶媒中、−１０℃〜溶媒の沸点の間の温度で１
〜１０時間処理することにより、あるいはジャーナル・
オブ・ケミカル・ソサエティー，ケミカル・コミュニケ
ーションズ（Ｊ．Ｃｈｅｍ．Ｓｏｃ．，Ｃｈｅｍ．Ｃｏ
ｍｍｕｎ．），４７２頁（１９７６年）に開示されてい
る方法（トリフルオロ酢酸／硫酸／アニソール）もしく
はそれに準じて、Ｒ ⁶ がＮ原子上のＨである化合物
（Ｉ）を得ることができる。R⁶Wherein I is H on the N atom (I)
Is R⁶Is a substituted or unsubstituted lower alkyl on the N atom
R, lower cycloalkyl, lower cycloalkyl alk
Ru, lower alkoxycarbonyl, lower alkanoyl
Is a substituted or unsubstituted aralkyl (I)
Substituent R⁶Can be obtained by removing.
For example, R⁶Is benzyl, a suitable reduction method,
For example, palladium-carbon, platinum dioxide, Raney-Nicke
In the presence of a catalyst such as
In the presence of acid, such as acetic acid, methanol, ethanol, etc.
Such as alcohols, esters such as ethyl acetate
In an inert solvent, under normal to medium pressure hydrogen atmosphere, room temperature to solvent
By treating at a temperature between the boiling points of 1 to 24 hours,
Also, R⁶Is 4-methoxybenzyl, 1-1
0 equivalents of 2,3-dichloro-5,6-dicyano-1,4
The presence of a suitable oxidant such as benzoquinone (DDQ)
Below, water-containing methylene chloride, 1,2-dichloroethane, etc.
In an inert solvent of 1 at a temperature between -10 ° C and the boiling point of the solvent.
By processing for ~ 10 hours, or by journal
Of Chemical Society, Chemical Communiqué
Solutions (J. Chem. Soc., Chem. Co.
mmun. ), Page 472 (1976).
Method (trifluoroacetic acid / sulfuric acid / anisole)
Is the same as R ⁶Is a compound in which H is H on the N atom
(I) can be obtained.

【００４０】上記製造法における中間体および目的化合
物は、有機合成化学で常用される精製法、例えば濾過、
抽出、洗浄、乾燥、濃縮、再結晶、各種クロマトグラフ
ィーなどに付して精製単離することができる。また、中
間体においては、特に精製することなく次の反応に供す
ることも可能である。化合物（Ｉ）の塩を取得したいと
き、化合物（Ｉ）が塩の形で得られる場合には、そのま
ま精製すればよく、また、遊離の形で得られる場合に
は、化合物（Ｉ）を適当な溶媒に溶解または懸濁させ
て、適当な酸または塩基を加えることにより塩を形成さ
せ単離すればよい。The intermediate and the target compound in the above-mentioned production method are purified by a conventional purification method in synthetic organic chemistry such as filtration,
It can be purified and isolated by subjecting it to extraction, washing, drying, concentration, recrystallization, various chromatography and the like. In addition, the intermediate can be subjected to the next reaction without further purification. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is. When it is obtained in a free form, compound (I) is suitable. It may be dissolved or suspended in a suitable solvent to form a salt by adding an appropriate acid or base, and then isolated.

【００４１】また、化合物（Ｉ）およびその薬理学的に
許容される塩は、水あるいは各種溶媒との付加物の形で
存在することもあるが、これら付加物も本発明に包含さ
れる。上記製造法によって得られる化合物（Ｉ）の具体
例を第１表に示す。The compound (I) and its pharmaceutically acceptable salt may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Specific examples of compound (I) obtained by the above production method are shown in Table 1.

【００４２】[0042]

【表１】 [Table 1]

【００４３】[0043]

【表２】 [Table 2]

【００４４】[0044]

【表３】 [Table 3]

【００４５】[0045]

【表４】 [Table 4]

【００４６】[0046]

【表５】 [Table 5]

【００４７】[0047]

【表６】 [Table 6]

【００４８】[0048]

【表７】 [Table 7]

【００４９】[0049]

【表８】 [Table 8]

【００５０】[0050]

【表９】 [Table 9]

【００５１】次に、化合物（Ｉ）の薬理作用について試
験例により説明する。 試験例 細胞接着阻害作用試験 ヒト臍帯静脈内皮細胞（ＨＵＶＥＣ）は、Ｆ１２Ｋ培地
（大日本製薬）に１０％ウシ胎児血清［ＦＢＳ; ライフ
テックオリエンタル（株）］、内皮細胞成長因子［Ｅｎ
ｄｏｔｈｅｒｉａｌ ｃｅｌｌ ｇｒｏｗｔｈ ｓｕｐ
ｐｌｅｍｅｎｔ，ＥＣＧＳ; コスモ・バイオ（株）］
（３０μｇ／ｍｌ）、ヘパリン（和光純薬）（１００μ
ｇ／ｍｌ）、ペニシリン（１００Ｕ／ｍｌ）およびスト
レプトマイシン（１００μｇ／ｍｌ）を添加した培地を
用いて培養した。ヒト白血病細胞（ＨＬ６０）は、１０
％ＦＢＳ、ペニシリン（１００Ｕ／ｍｌ）およびストレ
プトマイシン（１００μｇ／ｍｌ）を添加したＲＰＭＩ
−１６４０培地を用いて培養した。ＨＬ６０細胞に３−
（４，５−ジメチルチアゾール−２−イル）−２，５−
ジフェニルテトラゾリウムブロマイド（ＭＴＴ; シグマ
社）（１ｍｇ／ｍｌ）を添加して３０分間反応させて標
識した。ＨＵＶＥＣをコラーゲンコートした９６穴マイ
クロプレートで上記の条件下培養し、コンフルエントの
状態になった時点で腫瘍壊死因子（ＴＮＦ）α（１０Ｕ
／ｍｌ）で刺激した。刺激時に種々の濃度の薬物を添加
した。４時間後、ＭＴＴ標識したＨＬ６０細胞を２×１
０⁵ 細胞添加し、さらに３０分間インキュベートして細
胞を接着させた。非接着細胞を洗浄後、ジメチルスルホ
キシドを添加してＭＴＴ色素を溶解し、５４０ｎｍの吸
収をマイクロプレートリーダーで測定した。阻害率は、
ＴＮＦαで刺激したＨＵＶＥＣに対するＨＬ６０細胞の
接着量および非刺激下のＨＵＶＥＣに対するＨＬ６０細
胞の接着量をそれぞれ最大接着量および最小接着量とし
て、薬剤存在下でのＨＬ６０細胞の接着量から次式に従
い算出した。Next, the pharmacological action of compound (I) will be described with reference to test examples. Test Example Cell Adhesion Inhibitory Action Test Human umbilical vein endothelial cells (HUVEC) were prepared by using F12K medium (Dainippon Pharmaceutical Co., Ltd.) with 10% fetal bovine serum [FBS; Lifetech Oriental Co., Ltd.], endothelial cell growth factor [En
general cell grow sup
plant, ECGS; Cosmo Bio Co., Ltd.]
(30 μg / ml), heparin (Wako Pure Chemical) (100 μ
(g / ml), penicillin (100 U / ml) and streptomycin (100 μg / ml) were added to the culture medium. 10 human leukemia cells (HL60)
RPMI supplemented with% FBS, penicillin (100 U / ml) and streptomycin (100 μg / ml)
It culture | cultivated using -1640 culture medium. 3-in HL60 cells
(4,5-dimethylthiazol-2-yl) -2,5-
Diphenyltetrazolium bromide (MTT; Sigma) (1 mg / ml) was added and reacted for 30 minutes for labeling. HUVECs were cultured in collagen-coated 96-well microplates under the above conditions, and when they became confluent, tumor necrosis factor (TNF) α (10 U
/ Ml). Various concentrations of drug were added during stimulation. After 4 hours, MTT-labeled HL60 cells were treated with 2 × 1.
0 ⁵ cells was added and incubated for another 30 minutes to adhere the cells. After washing the non-adherent cells, dimethyl sulfoxide was added to dissolve the MTT dye, and the absorption at 540 nm was measured with a microplate reader. The inhibition rate is
The amount of adhesion of HL60 cells to HUVEC stimulated with TNFα and the amount of adhesion of HL60 cells to non-stimulated HUVEC were calculated as the maximum adhesion amount and the minimum adhesion amount, respectively, from the adhesion amount of HL60 cells in the presence of a drug according to the following formula. .

【００５２】阻害率（％）＝［１−（Ｐ₂ −Ｐ₀ ）／
（Ｐ₁ −Ｐ₀ ）］×１００ Ｐ₀ ：非刺激下のＨＵＶＥＣに対するＨＬ６０細胞の接
着量 Ｐ₁ ：ＴＮＦαで刺激したＨＵＶＥＣに対するＨＬ６０
細胞の接着量 Ｐ₂ ：薬剤存在下でのＨＬ６０細胞の接着量 ５０％阻害濃度（ＩＣ₅₀値）は、最小二乗法で近似した
曲線から求めた。Inhibition rate (%) = [1- (P ₂ -P ₀ ) /
(P ₁ −P ₀ )] × 100 P ₀ : adhesion amount of HL60 cells to HUVEC under non-stimulation P ₁ : HL60 to HUVEC stimulated with TNFα
Cell adhesion amount P ₂ : Adhesion amount of HL60 cells in the presence of a drug 50% inhibitory concentration (IC ₅₀ value) was determined from a curve approximated by the method of least squares.

【００５３】結果を第２表に示す。The results are shown in Table 2.

【００５４】[0054]

【表１０】 [Table 10]

【００５５】[0055]

【表１１】 [Table 11]

【００５６】第２表から明らかなように、本発明により
得られる化合物（Ｉ）またはその薬理学的に許容される
塩は、優れた細胞接着阻害作用を有している。化合物
（Ｉ）またはその薬理学的に許容される塩は、そのまま
単独で投与することも可能であるが、通常各種の医薬製
剤として提供するのが好ましい。また、それら医薬製剤
は、動物および人に使用されるものである。As is clear from Table 2, compound (I) or a pharmaceutically acceptable salt thereof obtained by the present invention has an excellent cell adhesion inhibitory action. Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually preferable to provide it as various pharmaceutical preparations. These pharmaceutical preparations are used for animals and humans.

【００５７】本発明に係わる医薬製剤は、活性成分とし
て化合物（Ｉ）またはその薬理学的に許容される塩を単
独で、あるいは任意の他の治療のための有効成分との混
合物として含有することができる。また、それら医薬製
剤は、活性成分を薬理学的に許容される一種もしくはそ
れ以上の担体と一緒に混合し、製剤学の技術分野におい
てよく知られている任意の方法により製造される。The pharmaceutical preparation according to the present invention contains Compound (I) or a pharmaceutically acceptable salt thereof as an active ingredient, alone or as a mixture with any other active ingredient for treatment. You can In addition, these pharmaceutical preparations are prepared by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.

【００５８】投与経路は、治療に際し最も効果的なもの
を使用するのが好ましく、経口または例えば、直腸内、
口腔内、皮下、筋肉内および静脈内などの非経口をあげ
ることができる。投与形態としては、カプセル剤、錠
剤、顆粒剤、散剤、シロップ剤、乳剤、座剤、注射剤、
軟膏、テープ剤などがある。The route of administration is preferably the one which is most effective for the treatment, and is orally or, for example, intrarectally,
Parenteral, such as buccal, subcutaneous, intramuscular and intravenous, can be mentioned. Dosage forms include capsules, tablets, granules, powders, syrups, emulsions, suppositories, injections,
There are ointments and tapes.

【００５９】経口投与に適当な、例えば乳剤およびシロ
ップ剤のような液体調製物は、水、ショ糖、ソルビッ
ト、果糖などの糖類、ポリエチレングリコール、プロピ
レングリコールなどのグリコール類、ゴマ油、オリーブ
油、大豆油などの油類、ｐ−ヒドロキシ安息香酸エステ
ル類などの防腐剤、ストロベリーフレーバー、ペパーミ
ントなどのフレーバー類などを使用して製造できる。ま
た、カプセル剤、錠剤、散剤および顆粒剤などは、乳
糖、ブドウ糖、ショ糖、マンニットなどの賦形剤、澱
粉、アルギン酸ソーダなどの崩壊剤、ステアリン酸マグ
ネシウム、タルクなどの滑沢剤、ポリビニルアルコー
ル、ヒドロキシプロピルセルロース、ゼラチンなどの結
合剤、脂肪酸エステルなどの界面活性剤、グリセリンな
どの可塑剤などを用いて製造できる。Liquid preparations suitable for oral administration, such as emulsions and syrups, include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil. And oils such as, preservatives such as p-hydroxybenzoic acid esters, flavors such as strawberry flavor and peppermint, and the like. In addition, capsules, tablets, powders, granules and the like include excipients such as lactose, glucose, sucrose and mannitol, disintegrating agents such as starch and sodium alginate, lubricants such as magnesium stearate and talc, polyvinyls. It can be produced using a binder such as alcohol, hydroxypropyl cellulose, gelatin, a surfactant such as fatty acid ester, a plasticizer such as glycerin, and the like.

【００６０】非経口投与に適当な製剤は、好ましくは受
容者の血液と等張である活性化合物を含む滅菌水性製剤
からなる。例えば、注射剤は、塩溶液、ブドウ糖溶液ま
たは塩水とブドウ糖溶液の混合物からなる担体などを用
いて注射用の溶液を調製する。腸内投与のための製剤
は、通常の担体、例えばカカオ脂、水素化脂肪または水
素化カルボン酸などの担体を用いて調製され、座剤とし
て提供される。Formulations suitable for parenteral administration preferably consist of sterile aqueous preparations containing the active compound which is isotonic with the blood of the recipient. For example, as an injection, a solution for injection is prepared by using a carrier such as a salt solution, a glucose solution or a mixture of salt water and a glucose solution. Formulations for enteral administration are prepared using a conventional carrier such as cocoa butter, hydrogenated fat or hydrogenated carboxylic acid and provided as a suppository.

【００６１】局所製剤は、活性化合物を１種もしくはそ
れ以上の媒質、例えば鉱油、石油、多価アルコールまた
は局所医薬製剤に使用される他の基剤中に溶解または懸
濁して調製される。また、これら非経口剤においても、
経口剤で例示した希釈剤、香料、防腐剤（抗酸化剤を含
む）、賦形剤、崩壊剤、滑沢剤、結合剤、界面活性剤、
可塑剤などから選択される１種もしくはそれ以上の補助
成分を添加することもできる。Topical formulations are prepared by dissolving or suspending the active compound in one or more vehicles, such as mineral oil, petroleum, polyhydric alcohols or other bases used in topical pharmaceutical formulations. Also, in these parenteral preparations,
Diluents, fragrances, preservatives (including antioxidants), excipients, disintegrants, lubricants, binders, surfactants exemplified for the oral preparation,
One or more auxiliary components selected from plasticizers and the like can be added.

【００６２】化合物（Ｉ）もしくはその薬理学的に許容
される塩の有効容量および投与回数は、投与形態、患者
の年令、体重、治療すべき症状の性質もしくは重篤度に
より異なるが、通常投与量は、１日当たり、０．１〜１
００００ｍｇ／人、好ましくは１〜１０００ｍｇであ
り、投与回数は１日１回または分割して投与するのが好
ましい。The effective dose of the compound (I) or a pharmacologically acceptable salt thereof and the number of administrations will vary depending on the administration form, the age of the patient, the body weight, the nature or severity of symptoms to be treated. Dosage is 0.1-1 per day
The dose is 0000 mg / person, preferably 1 to 1000 mg, and the administration frequency is preferably once a day or divided.

【００６３】以下に、実施例および参考例を示す。Examples and reference examples will be shown below.

【００６４】[0064]

【実施例】 実施例１ （Ｅ）−Ｎ−｛４−［［２−（３−インドリル）エチル
アミノ］カルボニル］−２−チアゾリル｝−３−（４−
ビフェニル）−２−プロペンアミド（化合物１） （１）４−フェニル桂皮酸3.73 g (16.63 mmol) を塩化
メチレン70 mL に懸濁し、ピリジン2.7 mL (33.38 mmo
l) を加え、これに、氷冷下、塩化オキザリル2.9mL (3
3.24 mmol) を滴下し、室温で4 時間攪拌した。溶媒を
減圧下留去し、残渣をピリジン100 mLに溶解した。４−
ジメチルアミノピリジン (DMAP) 100 mgを加え、これ
に、氷冷下、２−アミノチアゾール−４−カルボン酸エ
チル3.44 g (19.98 mmol) のピリジン30 mL 溶液を滴下
し、室温で24時間攪拌した。溶媒を減圧下留去後、残渣
に塩化メチレンを加え、1 N 塩酸、飽和重曹水、飽和食
塩水で順に洗浄し、無水硫酸マグネシウムで乾燥した。
溶媒を減圧下留去後、得られた粗結晶をエタノールから
再結晶することにより、（Ｅ）−Ｎ−（４−エトキシカ
ルボニル−２−チアゾリル）−３−（４−ビフェニル）
−２−プロペンアミド1.66g (26.4%)を白色結晶物とし
て得た。¹ H NMR (CDCl₃) δ 10.92 (1H, bs), 7.95 (1H, s),
7.88 (1H, d, J = 15.8),7.60 (6H, m), 7.46 (3H, m),
6.65 (1H, d, J = 15.8), 4.34 (2H, q, J = 6.9), 1.
34 (3H, t, J = 6.9).Example 1 (E) -N- {4-[[2- (3-indolyl) ethylamino] carbonyl] -2-thiazolyl} -3- (4-
Biphenyl) -2-propenamide (Compound 1) (1) 4-phenylcinnamic acid 3.73 g (16.63 mmol) was suspended in methylene chloride 70 mL, and pyridine 2.7 mL (33.38 mmo).
l) was added, and 2.9 mL of oxalyl chloride (3 mL
3.24 mmol) was added dropwise, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in 100 mL of pyridine. 4-
Dimethylaminopyridine (DMAP) 100 mg was added, and a solution of ethyl 2-aminothiazole-4-carboxylate (3.44 g, 19.98 mmol) in pyridine (30 mL) was added dropwise thereto under ice cooling, and the mixture was stirred at room temperature for 24 hours. After evaporating the solvent under reduced pressure, methylene chloride was added to the residue, washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
After the solvent was distilled off under reduced pressure, the obtained crude crystals were recrystallized from ethanol to give (E) -N- (4-ethoxycarbonyl-2-thiazolyl) -3- (4-biphenyl).
2-Propentamide, 1.66 g (26.4%), was obtained as white crystals. ¹ H NMR (CDCl ₃ ) δ 10.92 (1H, bs), 7.95 (1H, s),
7.88 (1H, d, J = 15.8), 7.60 (6H, m), 7.46 (3H, m),
6.65 (1H, d, J = 15.8), 4.34 (2H, q, J = 6.9), 1.
34 (3H, t, J = 6.9).

【００６５】（２）（１）で得られた化合物1.5 g (3.9
6 mmol) をメタノール150 mLに懸濁し、水酸化ナトリウ
ム0.79 g (19.75 mmol) の水15 mL 溶液を加え、60℃で
6.5 時間加熱した。反応液を濃縮後、残渣を氷水に溶解
し、これに4 N 塩酸を加え、pHを2.6 とした。析出した
結晶を濾取し、水洗、乾燥することにより、（Ｅ）−２
−｛［３−（４−ビフェニル）−２−プロペノイル］ア
ミノ｝チアゾール−４−カルボン酸1.39 g (定量的) を
淡黄色結晶物として得た。¹ H NMR (DMSO-d₆) δ 12.65 (1H, bs), 7.99 (1H, s),
7.74 (7H, m), 7.49 (2H, m), 7.39 (1H, m), 6.93 (1
H, d, J = 15.8).(2) 1.5 g (3.9%) of the compound obtained in (1)
6 mmol) in 150 mL of methanol, 0.79 g (19.75 mmol) of sodium hydroxide in 15 mL of water was added, and the mixture was stirred at 60 ° C.
Heated for 6.5 hours. After concentrating the reaction solution, the residue was dissolved in ice water, and 4 N hydrochloric acid was added to adjust the pH to 2.6. The precipitated crystals are collected by filtration, washed with water and dried to give (E) -2.
1.39 g (quantitative) of-{[3- (4-biphenyl) -2-propenoyl] amino} thiazole-4-carboxylic acid was obtained as pale yellow crystals. ¹ H NMR (DMSO-d ₆ ) δ 12.65 (1H, bs), 7.99 (1H, s),
7.74 (7H, m), 7.49 (2H, m), 7.39 (1H, m), 6.93 (1
H, d, J = 15.8).

【００６６】（３）（２）で得られた化合物1.0 g (2.8
5 mmol) のジメチルホルムアミド (DMF) 20 mL溶液にト
リエチルアミン1.6 mL (11.51 mmol) を加え、これに、
氷冷下、クロロギ酸エチル0.27 mL (2.85 mmol) を滴下
し、2 時間攪拌した。次いで、トリプタミン500 mg (3.
06 mmol)を加え、さらに3 時間攪拌した。反応液を減圧
下濃縮後、残渣に塩化メチレンを加え、1 N 塩酸、飽和
重曹水、飽和食塩水で順に洗浄し、無水硫酸マグネシウ
ムで乾燥した。溶媒を減圧下留去後、得られた粗結晶を
エタノールでトリチュレーションすることにより、化合
物１, 0.6 g (42.6%) を白色結晶物として得た。(3) The compound obtained in (2) 1.0 g (2.8
(5 mmol) in 20 mL of dimethylformamide (DMF) was added with 1.6 mL (11.51 mmol) of triethylamine.
Ethyl chloroformate (0.27 mL, 2.85 mmol) was added dropwise under ice cooling, and the mixture was stirred for 2 hours. Then tryptamine 500 mg (3.
06 mmol) was added, and the mixture was further stirred for 3 hours. The reaction solution was concentrated under reduced pressure, methylene chloride was added to the residue, washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude crystals were triturated with ethanol to give Compound 1, 0.6 g (42.6%) as a white crystalline substance.

【００６７】融点: 243-247 ℃ (エタノール) 元素分析: 0.2 水和物として C₂₉H₂₄N₄O₂S ・0.2H₂O 計算値 (%): C 70.20, H 4.96, N 11.29 実測値 (%): C 70.08, H 4.78, N 11.17 FABMS (m/z): 493 (M ⁺ +1)¹ H NMR (DMSO-d₆: 40 ℃で測定) δ 12.37 (1H, bs), 1
0.76 (1H, bs), 7.7-7.8(9H, m), 7.60 (1H, d, J = 7.
9), 7.49 (2H, t, J = 7.4), 7.37 (2H, m), 7.18 (1H,
d, J = 2.0), 7.08 (1H, m), 6.99 (1H, m), 6.97 (1
H, d, J = 15.8),3.63 (2H, ABq, J = 13.4, 6.9), 2.9
8 (2H, t, J = 6.9). 以下の実施例２〜５、７、８、１９〜２３、２５および
３８では、４−フェニル桂皮酸に代えて対応するカルボ
ン酸を用い、実施例１とほぼ同様の方法により目的化合
物を得た。Melting point: 243-247 ° C. (Ethanol) Elemental analysis: 0.2 hydrate C ₂₉ H ₂₄ N ₄ O ₂ S ・ 0.2H ₂ O Calculated value (%): C 70.20, H 4.96, N 11.29 Measured value (%): C 70.08, H 4.78, N 11.17 FABMS (m / z): 493 (M ⁺ +1) ¹ H NMR (DMSO-d ₆ : measured at 40 ° C) δ 12.37 (1H, bs), 1
0.76 (1H, bs), 7.7-7.8 (9H, m), 7.60 (1H, d, J = 7.
9), 7.49 (2H, t, J = 7.4), 7.37 (2H, m), 7.18 (1H,
d, J = 2.0), 7.08 (1H, m), 6.99 (1H, m), 6.97 (1
H, d, J = 15.8), 3.63 (2H, ABq, J = 13.4, 6.9), 2.9
8 (2H, t, J = 6.9). In Examples 2-5, 7, 8, 19-23, 25 and 38 below, the corresponding carboxylic acid was used in place of 4-phenylcinnamic acid, and Example 1 was used. The target compound was obtained by substantially the same method as described above.

【００６８】実施例２ （Ｅ）−Ｎ−｛４−［［２−（３−インドリル）エチル
アミノ］カルボニル］−２−チアゾリル｝−３−フェニ
ル−２−プロペンアミド（化合物２） 融点: 227-228 ℃ (エタノール) 元素分析: C₂₃H₂₀N₄O₂S 計算値 (%): C 66.33, H 4.84, N 13.45 実測値 (%): C 66.38, H 4.80, N 13.48 FABMS (m/z): 417 (M ⁺ +1)¹ H NMR (DMSO-d₆) δ 12.44 (1H, bs), 10.81 (1H, b
s), 7.89 (1H, bt, J = 5.6), 7.81 (1H, s), 7.75 (1
H, d, J = 16.2), 7.63 (3H, m), 7.46 (3H, m), 7.35
(1H, d, J = 7.9), 7.19 (1H, s), 7.08 (1H, t, J =
6.9), 6.97 (1H, m),6.93 (1H, d, J = 15.8), 3.61 (2
H, m), 2.96 (2H, t, J = 6.9).Example 2 (E) -N- {4-[[2- (3-indolyl) ethylamino] carbonyl] -2-thiazolyl} -3-phenyl-2-propenamide (Compound 2) Melting point: 227 -228 ℃ (Ethanol) Elemental analysis: C ₂₃ H ₂₀ N ₄ O ₂ S Calculated value (%): C 66.33, H 4.84, N 13.45 Measured value (%): C 66.38, H 4.80, N 13.48 FABMS (m / z): 417 (M ⁺ +1) ¹ H NMR (DMSO-d ₆ ) δ 12.44 (1H, bs), 10.81 (1H, b
s), 7.89 (1H, bt, J = 5.6), 7.81 (1H, s), 7.75 (1
H, d, J = 16.2), 7.63 (3H, m), 7.46 (3H, m), 7.35
(1H, d, J = 7.9), 7.19 (1H, s), 7.08 (1H, t, J =
6.9), 6.97 (1H, m), 6.93 (1H, d, J = 15.8), 3.61 (2
H, m), 2.96 (2H, t, J = 6.9).

【００６９】実施例３ （Ｅ）−Ｎ−｛４−［［２−（３−インドリル）エチル
アミノ］カルボニル］−２−チアゾリル｝−３−（３，
４−ジメトキシフェニル）−２−プロペンアミド（化合
物３） 融点: 121-125 ℃ (エタノール) 元素分析: C₂₅H₂₄N₄O₄S 計算値 (%): C 63.01, H 5.08, N 11.76 実測値 (%): C 63.22, H 4.98, N 11.75 FABMS (m/z): 477 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.66 (1H, s), 8.12 (1H, s), 7.7
7 (1H, s), 7.76 (1H, d, J = 15.3), 7.58 (1H, d, J
= 7.4), 7.30 (1H, d, J = 7.9), 7.17 (2H, t,J = 6.
9), 7.08 (2H, m), 6.97 (2H, m), 6.84 (1H, d, J =
8.4), 6.38 (1H, d, J = 15.3), 3.90 (3H, s), 3.87
(3H, s), 3.72 (2H, m), 2.98 (2H, t, J =6.9).Example 3 (E) -N- {4-[[2- (3-indolyl) ethylamino] carbonyl] -2-thiazolyl} -3- (3
4-Dimethoxyphenyl) -2-propenamide (Compound 3) Melting point: 121-125 ° C (Ethanol) Elemental analysis: C ₂₅ H ₂₄ N ₄ O ₄ S Calculated value (%): C 63.01, H 5.08, N 11.76 Actual measurement Value (%): C 63.22, H 4.98, N 11.75 FABMS (m / z): 477 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.66 (1H, s), 8.12 (1H, s), 7.7
7 (1H, s), 7.76 (1H, d, J = 15.3), 7.58 (1H, d, J
= 7.4), 7.30 (1H, d, J = 7.9), 7.17 (2H, t, J = 6.
9), 7.08 (2H, m), 6.97 (2H, m), 6.84 (1H, d, J =
8.4), 6.38 (1H, d, J = 15.3), 3.90 (3H, s), 3.87
(3H, s), 3.72 (2H, m), 2.98 (2H, t, J = 6.9).

【００７０】実施例４ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−３−フェニルベンゾ
［ｂ］フラン−２−カルボキサミド（化合物４） 融点: 234-237 ℃ (メタノール) 元素分析: C₂₉H₂₂N₄O₃S 計算値 (%): C 68.76, H 4.38, N 11.06 実測値 (%): C 68.37, H 4.28, N 10.95 FABMS (m/z): 507 (M ⁺ +1)¹ H NMR (DMSO-d₆) δ 12.74 (1H, bs), 10.84 (1H, b
s), 7.95 (1H, bt, J = 5.9), 7.87 (1H, s), 7.75 (1
H, d, J = 8.3), 7.66 (3H, m), 7.60 (2H, d, J =7.
3), 7.53 (2H, m), 7.43 (1H, m), 7.36 (1H, d, J =
7.9), 7.20 (1H, d, J= 2.3), 7.09 (1H, m), 6.70 (1
H, m), 3.63 (2H, ABq, J = 6.9, 13.2), 2.97(2H, t,
J = 7.3).Example 4 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -3-phenylbenzo [b] furan-2-carboxamide (Compound 4) Melting point: 234-237 ° C (methanol) Elemental analysis: C ₂₉ H ₂₂ N ₄ O ₃ S Calculated value (%) : C 68.76, H 4.38, N 11.06 Found (%): C 68.37, H 4.28, N 10.95 FABMS (m / z): 507 (M ⁺ +1) ¹ H NMR (DMSO-d ₆ ) δ 12.74 (1H , bs), 10.84 (1H, b
s), 7.95 (1H, bt, J = 5.9), 7.87 (1H, s), 7.75 (1
H, d, J = 8.3), 7.66 (3H, m), 7.60 (2H, d, J = 7.
3), 7.53 (2H, m), 7.43 (1H, m), 7.36 (1H, d, J =
7.9), 7.20 (1H, d, J = 2.3), 7.09 (1H, m), 6.70 (1
H, m), 3.63 (2H, ABq, J = 6.9, 13.2), 2.97 (2H, t,
J = 7.3).

【００７１】実施例５ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−３−フェニルベンゾ
［ｂ］チオフェン−２−カルボキサミド（化合物５） 融点: 121-123 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: 0.5 水和物として C₂₉H₂₂N₄O₂S₂・0.5H₂O 計算値 (%): C 65.52, H 4.36, N 10.54_. 実測値 (%): C 65.46, H 3.98, N 10.49 FABMS (m/z): 523 (M ⁺ +1)¹ H NMR (DMSO-d₆) δ 12.33 (1H, bs), 10.81 (1H, b
s), 8.15 (1H, d, J = 7.9), 7.87 (1H, bs), 7.82 (1
H, s), 7.4-7.7 (9H, m), 7.33 (1H, d, J = 7.9),7.15
(1H, d, J = 2.0), 7.06 (1H, m), 6.96 (1H, m), 3.5
5 (2H, ABq, J = 6.9, 13.2), 2.91 (2H, t, J = 7.3).Example 5 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -3-phenylbenzo [b] thiophene-2-carboxamide (Compound 5) Melting point: 121-123 ° C (ethyl acetate / diisopropyl ether) Elemental analysis: 0.5 As a hydrate C ₂₉ H ₂₂ N _{4 O 2 S 2 · 0.5H 2} O calculated _{(%):. C 65.52,} H 4.36, N 10.54 Found (%): C 65.46, H 3.98, N 10.49 FABMS (m / z): 523 (M + +1) ¹ H NMR (DMSO-d ₆ ) δ 12.33 (1H, bs), 10.81 (1H, b
s), 8.15 (1H, d, J = 7.9), 7.87 (1H, bs), 7.82 (1
H, s), 7.4-7.7 (9H, m), 7.33 (1H, d, J = 7.9), 7.15
(1H, d, J = 2.0), 7.06 (1H, m), 6.96 (1H, m), 3.5
5 (2H, ABq, J = 6.9, 13.2), 2.91 (2H, t, J = 7.3).

【００７２】実施例６ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−フェニルインド
ール−２−カルボキサミド（化合物６） （１）１−フェニルインドール−２−カルボン酸3.0 g
(12.64 mmol)を塩化メチレン75 mL に溶解し、トリエチ
ルアミン7 mL (50.22 mmol) およびヨウ化２−クロロ−
１−メチルピリジニウム 6.46 g (25.28 mmol)を加え、
室温で1 時間攪拌した。反応混合物を2 N 塩酸、飽和重
曹水、飽和食塩水で順に洗浄し、無水硫酸マグネシウム
で乾燥した。溶媒を減圧下留去後、残渣をシリカゲルカ
ラムクロマトグラフィー（ヘキサン：酢酸エチル＝３：
１）で精製することにより、１−フェニルインドール−
２−カルボン酸無水物2.66 g (93%)を黄色泡状物として
得た。¹ H NMR (CDCl₃) δ 7.75 (2H, d, J = 7.9), 7.48 (8
H, m), 7.35 (6H, m), 7.22 (2H, m), 7.13 (1H, dd, J
= 1.0, 8.4).Example 6 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1-phenylindole-2-carboxamide (Compound 6) (1) 1-phenylindole-2-carboxylic acid 3.0 g
(12.64 mmol) was dissolved in 75 mL of methylene chloride, 7 mL (50.22 mmol) of triethylamine and 2-chloro-iodide were added.
6.46 g (25.28 mmol) of 1-methylpyridinium was added,
The mixture was stirred at room temperature for 1 hour. The reaction mixture was washed successively with 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
By purifying in 1), 1-phenylindole-
Obtained 2.66 g (93%) of 2-carboxylic acid anhydride as a yellow foam. ¹ H NMR (CDCl ₃ ) δ 7.75 (2H, d, J = 7.9), 7.48 (8
H, m), 7.35 (6H, m), 7.22 (2H, m), 7.13 (1H, dd, J
= 1.0, 8.4).

【００７３】（２）（１）で得られた化合物2.66 g (5.
84 mmol)をピリジン50 mL に溶解し、２−アミノチアゾ
ール−４−カルボン酸エチル2.01 g (11.67 mmol) を加
え、3.5 時間加熱還流した。溶媒を減圧下留去後、残渣
に塩化メチレンを加え、2 N 塩酸、飽和重曹水、飽和食
塩水で順に洗浄し、無水硫酸マグネシウムで乾燥した。
溶媒を減圧下留去後、残渣をシリカゲルカラムクロマト
グラフィー（クロロホルム：メタノール＝５０：１）で
精製し、得られた粗結晶をイソプロピルエーテルでトリ
チュレーションすることにより、Ｎ−（４−エトキシカ
ルボニル−２−チアゾリル）−１−フェニルインドール
−２−カルボキサミド1.8 g (78.9%) を淡褐色結晶物と
して得た。¹ H NMR (CDCl₃) δ 10.70 (1H, bs), 7.76 (1H, s),
7.69 (1H, m), 7.51 (3H,m), 7.43 (2H, m), 7.27 (2H,
m), 7.19 (2H, m), 4.11 (2H, q, J = 6.8), 1.21 (3
H, t, J = 6.8).(2) 2.66 g of the compound obtained in (1) (5.
84 mmol) was dissolved in 50 mL of pyridine, 2.01 g (11.67 mmol) of ethyl 2-aminothiazole-4-carboxylate was added, and the mixture was heated under reflux for 3.5 hours. After evaporating the solvent under reduced pressure, methylene chloride was added to the residue, and the mixture was washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1), and the obtained crude crystals were triturated with isopropyl ether to give N- (4-ethoxycarbonyl). 1.8 g (78.9%) of 2-thiazolyl) -1-phenylindole-2-carboxamide was obtained as light brown crystals. ¹ H NMR (CDCl ₃ ) δ 10.70 (1H, bs), 7.76 (1H, s),
7.69 (1H, m), 7.51 (3H, m), 7.43 (2H, m), 7.27 (2H,
m), 7.19 (2H, m), 4.11 (2H, q, J = 6.8), 1.21 (3
H, t, J = 6.8).

【００７４】（３）（２）で得られた化合物1.71 g (4.
34 mmol)をメタノール50 mL に懸濁し、水酸化ナトリウ
ム0.86 g (21.5 mmol)の水10 mL 溶液を加え、60℃で45
分間加熱した。反応液を濃縮後、残渣を氷水に溶解し、
これに4 N 塩酸を加え、pHを3.0 とした。析出した結晶
を濾取し、水洗、乾燥することにより、２−［Ｎ−（１
−フェニルインドール−２−イルカルボニル）アミノ］
チアゾール−４−カルボン酸1.56 g (98.7%)を淡褐色結
晶物として得た。¹ H NMR (CDCl₃) δ 12.89 (1H, bs), 7.95 (1H, s),
7.83 (1H, s), 7.80 (1H,d, J = 7.4), 7.55 (3H, m),
7.40 (2H, m), 7.31 (1H, m), 7.21 (1H, t, J =6.9),
7.09 (1H, d, J = 8.4).(3) 1.71 g of the compound obtained in (2) (4.
34 mmol) in 50 mL of methanol, add 0.86 g (21.5 mmol) of sodium hydroxide in 10 mL of water, and add 45 mL at 60 ° C.
Heated for minutes. After concentrating the reaction solution, dissolve the residue in ice water,
4N hydrochloric acid was added thereto to adjust the pH to 3.0. The precipitated crystals are collected by filtration, washed with water and dried to give 2- [N- (1
-Phenylindol-2-ylcarbonyl) amino]
1.56 g (98.7%) of thiazole-4-carboxylic acid was obtained as pale brown crystals. ¹ H NMR (CDCl ₃ ) δ 12.89 (1H, bs), 7.95 (1H, s),
7.83 (1H, s), 7.80 (1H, d, J = 7.4), 7.55 (3H, m),
7.40 (2H, m), 7.31 (1H, m), 7.21 (1H, t, J = 6.9),
7.09 (1H, d, J = 8.4).

【００７５】（４）（３）で得られた化合物1.44 g (3.
96 mmol)のテトラヒドロフラン (THF)40 mL溶液にトリ
エチルアミン2.2 mL (15.78 mmol) を加え、これに、氷
冷下、クロロギ酸エチル0.38 mL (3.98 mmol) を滴下
し、1 時間攪拌した。次いで、トリプタミン700 mg (4.
37 mmol)のTHF 40 mL 溶液を滴下し、さらに2 時間攪拌
した。反応液を減圧下濃縮後、残渣に塩化メチレンを加
え、2 N 塩酸、飽和重曹水、飽和食塩水で順に洗浄し、
無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去
後、残渣をシリカゲルカラムクロマトグラフィー（ヘキ
サン：酢酸エチル＝２：１〜酢酸エチル）で精製し、得
られた粗結晶をイソプロパノールでトリチュレーション
することにより、化合物６, 1.30 g (65.2%)を白色結晶
物として得た。(4) 1.44 g of the compound obtained in (3) (3.
To a solution of 96 mmol) in 40 mL of tetrahydrofuran (THF) was added 2.2 mL (15.78 mmol) of triethylamine, and to this was added 0.38 mL (3.98 mmol) of ethyl chloroformate under ice cooling, and the mixture was stirred for 1 hour. Then tryptamine 700 mg (4.
A 40 mL solution of THF (37 mmol) in THF was added dropwise, and the mixture was further stirred for 2 hours. The reaction mixture was concentrated under reduced pressure, methylene chloride was added to the residue, and the mixture was washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine,
It was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1-ethyl acetate), and the obtained crude crystals were triturated with isopropanol to give compound 6, 1.30. g (65.2%) was obtained as white crystals.

【００７６】融点: 234-235 ℃ (イソプロパノール) 元素分析: C₂₉H₂₃N₅O₂S 計算値 (%): C 68.89, H 4.59, N 13.85 実測値 (%): C 68.91, H 4.70, N 13.53 FABMS (m/z): 506 (M ⁺ +1)¹ H NMR (DMSO-d₆) δ 12.83 (1H, s), 10.82 (1H, b
s), 7.85 (1H, bt, J = 5.9), 7.80 (1H, s), 7.76 (2
H, m), 7.53 (4H, m), 7.36 (3H, m), 7.28 (1H, dd, J
= 1.3, 6.9), 7.21 (1H, m), 7.18 (1H, d, J = 1.0),
7.08 (2H, m), 6.99(1H, m), 3.64 (2H, ABq, J = 6.
9, 13.2), 2.97 (2H, t, J = 6.9).Melting point: 234-235 ° C. (isopropanol) Elemental analysis: C ₂₉ H ₂₃ N ₅ O ₂ S Calculated value (%): C 68.89, H 4.59, N 13.85 Found value (%): C 68.91, H 4.70, N 13.53 FABMS (m / z): 506 (M ⁺ +1) ¹ H NMR (DMSO-d ₆ ) δ 12.83 (1H, s), 10.82 (1H, b
s), 7.85 (1H, bt, J = 5.9), 7.80 (1H, s), 7.76 (2
H, m), 7.53 (4H, m), 7.36 (3H, m), 7.28 (1H, dd, J
= 1.3, 6.9), 7.21 (1H, m), 7.18 (1H, d, J = 1.0),
7.08 (2H, m), 6.99 (1H, m), 3.64 (2H, ABq, J = 6.
9, 13.2), 2.97 (2H, t, J = 6.9).

【００７７】実施例７ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−５−メトキシ−３−
（１−メチルエトキシ）ベンゾ［ｂ］チオフェン−２−
カルボキサミド（化合物７） 融点: 203-205 ℃ (ジイソプロピルエーテル) 元素分析: C₂₇H₂₆N₄O₄S₂ 計算値 (%): C 60.66, H 4.90, N 10.48 実測値 (%): C 60.68, H 5.01, N 10.31 FABMS (m/z): 535 (M ⁺ +1)¹ H NMR (CDCl₃) δ 10.73 (1H, bs), 8.08 (1H, bs),
7.80 (1H, s), 7.69 (2H, m), 7.39 (1H, d, J = 7.9),
7.32 (1H, bt, J = 5.9), 7.18 (5H, m), 4.92(1H,
m), 3.91 (3H, s), 3.82 (2H, ABq, J = 6.6, 13.2),
3.12 (2H, t, J = 6.9), 1.49 (6H, d, J = 6.3).Example 7 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -5-methoxy-3-
(1-Methylethoxy) benzo [b] thiophen-2-
Carboxamide (Compound 7) Melting point: 203-205 ° C (diisopropyl ether) Elemental analysis: C ₂₇ H ₂₆ N ₄ O ₄ S ₂ Calculated value (%): C 60.66, H 4.90, N 10.48 Measured value (%): C 60.68 , H 5.01, N 10.31 FABMS (m / z): 535 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 10.73 (1H, bs), 8.08 (1H, bs),
7.80 (1H, s), 7.69 (2H, m), 7.39 (1H, d, J = 7.9),
7.32 (1H, bt, J = 5.9), 7.18 (5H, m), 4.92 (1H,
m), 3.91 (3H, s), 3.82 (2H, ABq, J = 6.6, 13.2),
3.12 (2H, t, J = 6.9), 1.49 (6H, d, J = 6.3).

【００７８】実施例８ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝インドール−２−カル
ボキサミド（化合物８） 融点: 115-118 ℃ (ジイソプロピルエーテル) 元素分析: 0.9 ジイソプロピルエーテル付加物として
C₂₅H₂₃N₅O₄S ・0.9[(CH₃) ₂CH]₂O 計算値 (%): C 62.79, H 6.17, N 12.04 実測値 (%): C 62.69, H 5.93, N 11.98 FABMS (m/z): 430 (M ⁺ +1)¹ H NMR (CDCl₃) δ 11.87 (1H, bs), 10.78 (1H, bs),
8.20 (1H, s), 7.8 (2H, m), 7.6-7.7 (3H, m), 7.50
(1H, d, J = 8.2), 7.38 (1H, d, J = 7.9), 7.2-7.3
(1H, m), 7.0-7.2 (6H, m), 6.82 (1H, m), 3.6-3.7 (2
H, m), 3.00 (2H,m).Example 8 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} indole-2-cal
Voxamide (Compound 8) Melting point: 115-118 ° C (diisopropyl ether) Elemental analysis: 0.9 As diisopropyl ether adduct
C_{twenty five}H_{twenty three}N_FiveO_FourS ・ 0.9 [(CH_Three) ₂CH]₂O Calculated value (%): C 62.79, H 6.17, N 12.04 Measured value (%): C 62.69, H 5.93, N 11.98 FABMS (m / z): 430 (M⁺+1)¹ H NMR (CDCl_Three) δ 11.87 (1H, bs), 10.78 (1H, bs),
 8.20 (1H, s), 7.8 (2H, m), 7.6-7.7 (3H, m), 7.50
(1H, d, J = 8.2), 7.38 (1H, d, J = 7.9), 7.2-7.3
(1H, m), 7.0-7.2 (6H, m), 6.82 (1H, m), 3.6-3.7 (2
H, m), 3.00 (2H, m).

【００７９】実施例９ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−ベンジルインド
ール−２−カルボキサミド（化合物１２） （１）参考例１で得られる１−ベンジルインドール−２
−カルボン酸4.97 g (19.8 mmol)を塩化メチレン100 mL
に溶解し、トリブチルアミン11.3 mL (47.43 mL)および
ヨウ化２−クロロ−１−メチルピリジニウム6.06 g (2
3.7 mmol)を加え、4 時間加熱還流した。反応液に1 N
塩酸を加え、クロロホルムで抽出した。有機層を飽和食
塩水で洗浄し、硫酸マグネシウムで乾燥後、溶媒を減圧
下留去することにより、１−ベンジルインドール−2 −
カルボン酸無水物3.74 g (37%)を黄色結晶物として得
た。¹ H NMR (CDCl₃) δ 7.74 (2H, d, J = 8.3), 7.57 (2
H, s), 7.4-7.5 (4H, m),7.2-7.3 (8H, m), 7.12 (4H,
m), 5.86 (4H, s).Example 9 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1-benzylindole-2-carboxamide (Compound 12) (1) 1-benzylindole-2 obtained in Reference Example 1
-Carboxylic acid 4.97 g (19.8 mmol) in methylene chloride 100 mL
And tributylamine 11.3 mL (47.43 mL) and 2-chloro-1-methylpyridinium iodide 6.06 g (2
(3.7 mmol) was added and the mixture was heated under reflux for 4 hours. 1 N for reaction
Hydrochloric acid was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine and dried over magnesium sulfate, and the solvent was evaporated under reduced pressure to give 1-benzylindole-2-
3.74 g (37%) of carboxylic acid anhydride was obtained as yellow crystals. ¹ H NMR (CDCl ₃ ) δ 7.74 (2H, d, J = 8.3), 7.57 (2
H, s), 7.4-7.5 (4H, m), 7.2-7.3 (8H, m), 7.12 (4H,
m), 5.86 (4H, s).

【００８０】（２）（１）で得られた化合物3.74 g (7.
72 mmol)および２−アミノチアゾール−４−カルボン酸
エチル1.33 g (7.72 mmol)をピリジン70 mL に溶解し、
6 時間加熱還流した。反応液を減圧下留去後、残渣に1
N 塩酸を加え、酢酸エチルで抽出した。有機層を1 N 水
酸化ナトリウム水溶液、飽和食塩水で順に洗浄し、無水
硫酸マグネシウムで乾燥した。溶媒を減圧下留去後、得
られた粗結晶を酢酸エチル／ヘキサンから再結晶するこ
とにより、Ｎ−（４−エトキシカルボニル−２−チアゾ
リル）−１−ベンジルインドール−２−カルボキサミド
2.49 g (80%)を白色結晶物として得た。¹ H NMR (CDCl₃) δ 7.83 (1H, s), 7.74 (1H, d, J =
7.9), 7.1-7.4 (8H, m),7.10 (2H, m), 5.90 (2H, s),
4.3-4.4 (2H, m), 1.35 (3H, t, J = 6.8).(2) 3.74 g of the compound obtained in (1) (7.
72 mmol) and 1.32 g of ethyl 2-aminothiazole-4-carboxylate (7.72 mmol) were dissolved in 70 mL of pyridine,
The mixture was heated under reflux for 6 hours. After distilling the reaction solution under reduced pressure, 1 was added to the residue.
N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with a 1 N aqueous sodium hydroxide solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate / hexane to give N- (4-ethoxycarbonyl-2-thiazolyl) -1-benzylindole-2-carboxamide.
2.49 g (80%) was obtained as a white crystalline substance. ¹ H NMR (CDCl ₃ ) δ 7.83 (1H, s), 7.74 (1H, d, J =
7.9), 7.1-7.4 (8H, m), 7.10 (2H, m), 5.90 (2H, s),
4.3-4.4 (2H, m), 1.35 (3H, t, J = 6.8).

【００８１】（３）（２）で得られた化合物3.9 g (9.6
2 mmol) をエタノール80 mL に溶解し、10 N水酸化ナト
リウム水溶液2.9 mLを加え、60℃で1.5 時間攪拌した。
反応液を減圧下濃縮後、残渣に水を加え、pHを3 とし
た。析出した結晶を濾取することにより、２−［Ｎ−
（１−ベンジルインドール−２−イルカルボニル）アミ
ノ］チアゾール−４−カルボン酸3.63 g (定量的) を白
色結晶物として得た。¹ H NMR (DMSO-d₆) δ 13.00 (1H, bs), 8.02 (1H, s),
7.80 (1H, s), 7.73 (1H, d, J = 7.6), 7.55 (1H, d,
J = 8.2), 7.1-7.3 (6H, m), 7.05 (2H, d, J =7.3),
5.92 (2H, s).(3) 3.9 g (9.6%) of the compound obtained in (2)
2 mmol) was dissolved in 80 mL of ethanol, 2.9 mL of 10 N sodium hydroxide aqueous solution was added, and the mixture was stirred at 60 ° C. for 1.5 hours.
The reaction solution was concentrated under reduced pressure and water was added to the residue to adjust the pH to 3. 2- [N-
3.63 g (quantitative) of (1-benzylindol-2-ylcarbonyl) amino] thiazole-4-carboxylic acid was obtained as white crystals. ¹ H NMR (DMSO-d ₆ ) δ 13.00 (1H, bs), 8.02 (1H, s),
7.80 (1H, s), 7.73 (1H, d, J = 7.6), 7.55 (1H, d,
J = 8.2), 7.1-7.3 (6H, m), 7.05 (2H, d, J = 7.3),
5.92 (2H, s).

【００８２】（４）（３）で得られた化合物1.5 g (3.9
7 mmol) をTHF 30 mL に溶解し、これに、氷冷下、トリ
エチルアミン 1.66 ml (12.05 mmol) およびクロロギ酸
エチル0.38 ml (3.97 mmol) を加え、30分間攪拌した。
次いで、トリプタミン0.64 g (3.99 mmol)を加え、さら
に室温で2 時間攪拌した。反応混合物を減圧下濃縮後、
残渣をシリカゲルカラムクロマトグラフィー（ヘキサ
ン：酢酸エチル：酢酸＝１６：８：１）で精製すること
により、化合物１２, 1.1 g (53%) を淡黄色結晶物とし
て得た。(4) 1.5 g (3.9%) of the compound obtained in (3)
7 mmol) was dissolved in 30 mL of THF, and 1.66 ml (12.05 mmol) of triethylamine and 0.38 ml (3.97 mmol) of ethyl chloroformate were added to this under ice cooling, and the mixture was stirred for 30 minutes.
Next, tryptamine 0.64 g (3.99 mmol) was added, and the mixture was further stirred at room temperature for 2 hours. After concentrating the reaction mixture under reduced pressure,
The residue was purified by silica gel column chromatography (hexane: ethyl acetate: acetic acid = 16: 8: 1) to obtain Compound 12, 1.1 g (53%) as pale yellow crystals.

【００８３】融点: 105-107 ℃ (イソプロパノール／ジ
イソプロピルエーテル) 元素分析: 0.5 水和物・0.5イソプロパノール付加物とし
て C₃₀H₂₅N₅O₂S ・0.5H₂O ・0.5(CH₃)₂CHOH 計算値 (%): C 67.72, H 5.41, N 12.54 実測値 (%): C 67.79, H 5.10, N 12.53 FABMS (m/z): 520 (M ⁺ +1)¹ H NMR (CDCl₃) δ 8.09 (1H, s), 7.73 (1H, s), 7.7
2-7.63 (2H, m), 7.40-7.30 (3H, m), 7.26-7.06 (12H,
m), 5.89 (2H, s), 3.82-3.75 (2H, m), 3.07 (2H, t,
J = 6.6). 以下の実施例１０〜１４、１８、２６〜２９、３１、３
２、３４〜３７、５４および８０では、１−ベンジルイ
ンドール−２−カルボン酸に代えて対応するカルボン酸
を用い、実施例９とほぼ同様の方法により目的化合物を
得た。Melting point: 105-107 ° C. (isopropanol / diisopropyl ether) Elemental analysis: 0.5 hydrate / 0.5 As isopropanol adduct C ₃₀ H ₂₅ N ₅ O ₂ S / 0.5H ₂ O / 0.5 (CH ₃ ) ₂ CHOH Calculated value (%): C 67.72, H 5.41, N 12.54 Measured value (%): C 67.79, H 5.10, N 12.53 FABMS (m / z): 520 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 8.09 (1H, s), 7.73 (1H, s), 7.7
2-7.63 (2H, m), 7.40-7.30 (3H, m), 7.26-7.06 (12H,
m), 5.89 (2H, s), 3.82-3.75 (2H, m), 3.07 (2H, t,
J = 6.6). Examples 10-14, 18, 26-29, 31, 3 below.
In 2, 34 to 37, 54 and 80, the corresponding carboxylic acid was used in place of 1-benzylindole-2-carboxylic acid, and the target compound was obtained by substantially the same method as in Example 9.

【００８４】実施例１０ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−メチルインドー
ル−２−カルボキサミド（化合物９） 融点: 113-115 ℃ (酢酸エチル／ヘキサン) 元素分析: 2 酢酸付加物として C₂₄H₂₁N₅O₂S ・2CH₃COO
H 計算値 (%): C 59.67, H 5.19, N 12.43 実測値 (%): C 59.78, H 5.12, N 12.44 FABMS (m/z): 444 (M ⁺ +1)¹ H NMR (CDCl₃) δ 8.07 (1H, s), 7.77 (1H, s), 7.7
2-7.65 (2H, m), 7.43-7.37 (3H, m), 7.24-7.09 (7H,
m), 4.14 (3H, s), 3.85-3.78 (2H, m), 3.10 (2H, t,
J = 6.6).Example 10 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1-methylindole-2-carboxamide (compound 9) Melting point: 113-115 ° C. (ethyl acetate / hexane) Elemental analysis: 2 As acetic acid adduct C ₂₄ H ₂₁ N ₅ O ₂ S 2CH ₃ COO
H calculated value (%): C 59.67, H 5.19, N 12.43 Measured value (%): C 59.78, H 5.12, N 12.44 FABMS (m / z): 444 (M ⁺ +1) ¹ H NMR (CDCl ₃ ). δ 8.07 (1H, s), 7.77 (1H, s), 7.7
2-7.65 (2H, m), 7.43-7.37 (3H, m), 7.24-7.09 (7H,
m), 4.14 (3H, s), 3.85-3.78 (2H, m), 3.10 (2H, t,
J = 6.6).

【００８５】実施例１１ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−イソプロピルイ
ンドール−２−カルボキサミド（化合物１０） 融点: 113-115 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: 0.3 水和物・0.6イソプロパノール付加物とし
て C₂₆H₂₅N₅O₂S ・0.3H₂O ・0.6(CH₃)₂CHOH 計算値 (%): C 59.67, H 5.19, N 12.43 実測値 (%): C 59.78, H 5.12, N 12.44 FABMS (m/z): 472 (M ⁺ +1)¹ H NMR (CDCl₃) δ 8.07 (1H, s), 7.77 (1H, s), 7.7
2-7.65 (2H, m), 7.43-7.37 (3H, m), 7.24-7.09 (7H,
m), 4.14 (3H, s), 3.85-3.78 (2H, m), 3.10 (2H, t,
J = 6.6).Example 11 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1-isopropylindole-2-carboxamide (Compound 10) Melting point: 113-115 ° C. (isopropanol / diisopropyl ether) Elemental analysis: 0.3 hydrate / 0.6 As isopropanol adduct C ₂₆ H ₂₅ N ₅ O ₂ S ・ 0.3H ₂ O ・ 0.6 (CH ₃ ) ₂ CHOH Calculated value (%): C 59.67, H 5.19, N 12.43 Measured value (%): C 59.78, H 5.12, N 12.44 FABMS (m / z ): 472 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 8.07 (1H, s), 7.77 (1H, s), 7.7
2-7.65 (2H, m), 7.43-7.37 (3H, m), 7.24-7.09 (7H,
m), 4.14 (3H, s), 3.85-3.78 (2H, m), 3.10 (2H, t,
J = 6.6).

【００８６】実施例１２ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−シクロヘキシル
メチルインドール−２−カルボキサミド（化合物１１） 融点: 113-117 ℃ (ジイソプロピルエーテル) 元素分析: 1.3 酢酸付加物として C₃₀H₃₁N₅O₂S ・1.3CH
₃COOH 計算値 (%): C 64.86, H 6.04, N 11.60 実測値 (%): C 64.89, H 6.05, N 11.64 FABMS (m/z): 526 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.60 (1H, bs), 8.06 (1H, bs),
7.78 (1H, s), 7.71-7.66(2H, m), 7.46-7.37 (3H, m),
7.26-7.15 (6H, m), 4.51 (2H, d, J = 7.3), 3.83-3.
78 (2H, m), 3.11 (2H, t, J = 6.8), 1.87 (1H, bs),
1.51-1.65 (4H, m), 1.08-1.14 (6H, m).Example 12 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1-cyclohexylmethylindole-2-carboxamide (Compound 11) Melting point: 113-117 ° C (diisopropyl ether) Elemental analysis: 1.3 As acetic acid adduct C ₃₀ H ₃₁ N ₅ O ₂ S ・ 1.3 CH
₃ COOH Calculated value (%): C 64.86, H 6.04, N 11.60 Measured value (%): C 64.89, H 6.05, N 11.64 FABMS (m / z): 526 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.60 (1H, bs), 8.06 (1H, bs),
7.78 (1H, s), 7.71-7.66 (2H, m), 7.46-7.37 (3H, m),
7.26-7.15 (6H, m), 4.51 (2H, d, J = 7.3), 3.83-3.
78 (2H, m), 3.11 (2H, t, J = 6.8), 1.87 (1H, bs),
1.51-1.65 (4H, m), 1.08-1.14 (6H, m).

【００８７】実施例１３ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−（３−メトキシ
ベンジル）インドール−２−カルボキサミド（化合物１
３） 融点: 110-114 ℃ (ジイソプロピルエーテル) 元素分析: 0.5 水和物・0.5イソプロパノール付加物とし
て C₃₁H₂₇N₅O₃S ・0.5H₂O ・0.5(CH₃)₂CHOH 計算値 (%): C 64.34, H 5.65, N 11.54 実測値 (%): C 64.37, H 5.05, N 11.31 FABMS (m/z): 550 (M ⁺ +1)¹ H NMR (CDCl₃) δ 8.07 (1H, bs), 7.74 (1H, s), 7.
71 (1H, d, J = 7.9), 7.65 (1H, d, J = 7.9), 7.40-
7.33 (3H, m), 7.30-7.08 (7H, m), 7.06 (1H, d,J =
1.0), 6.75-6.63 (3H, m), 5.87 (2H, s), 3.82-3.75
(2H, m), 3.70 (3H,s), 3.08 (2H, t, J = 6.8).Example 13 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1- (3-methoxybenzyl) indole-2-carboxamide (Compound 1
3) Melting point: 110-114 ℃ (diisopropyl ether) Elemental analysis: 0.5 hydrate ・ 0.5 As isopropanol adduct C ₃₁ H ₂₇ N ₅ O ₃ S ・ 0.5H ₂ O ・ 0.5 (CH ₃ ) ₂ CHOH Calculated value ( %): C 64.34, H 5.65, N 11.54 Actual value (%): C 64.37, H 5.05, N 11.31 FABMS (m / z): 550 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 8.07 (1H , bs), 7.74 (1H, s), 7.
71 (1H, d, J = 7.9), 7.65 (1H, d, J = 7.9), 7.40-
7.33 (3H, m), 7.30-7.08 (7H, m), 7.06 (1H, d, J =
1.0), 6.75-6.63 (3H, m), 5.87 (2H, s), 3.82-3.75
(2H, m), 3.70 (3H, s), 3.08 (2H, t, J = 6.8).

【００８８】実施例１４ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−（４−メトキシ
ベンジル）インドール−２−カルボキサミド（化合物１
４） 融点: 122-125 ℃ (ジイソプロピルエーテル) 元素分析: 1.3 酢酸付加物として C₃₁H₂₇N₅O₃S ・1.3CH
₃COOH 計算値 (%): C 64.34, H 5.65, N 11.54 実測値 (%): C 64.37, H 5.05, N 11.64 FABMS (m/z): 550 (M ⁺ +1)¹ H NMR (CDCl₃) δ 8.05 (1H, bs), 7.75 (1H, s), 7.
71 (1H, d, J = 7.9), 7.66 (1H, d, J = 7.9), 7.44-
7.32 (3H, m), 7.25-7.12 (7H, m), 7.06 (2H, d,J =
8.6), 6.77 (2H, d, J = 8.9), 5.83 (3H, s), 3.84-3.
77 (2H, m), 3.73(3H, s), 3.09 (2H, t, J = 6.8). 以下の実施例１５〜１７、２４、４０〜５３、５５、７
４および７５では、１−フェニルインドール−２−カル
ボン酸に代えて対応するカルボン酸を用い、実施例６と
ほぼ同様の方法により目的化合物を得た。Example 14 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1- (4-methoxybenzyl) indole-2-carboxamide (Compound 1
4) Melting point: 122-125 ℃ (diisopropyl ether) Elemental analysis: 1.3 As an acetic acid adduct C ₃₁ H ₂₇ N ₅ O ₃ S ・ 1.3CH
₃ COOH Calculated value (%): C 64.34, H 5.65, N 11.54 Measured value (%): C 64.37, H 5.05, N 11.64 FABMS (m / z): 550 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 8.05 (1H, bs), 7.75 (1H, s), 7.
71 (1H, d, J = 7.9), 7.66 (1H, d, J = 7.9), 7.44-
7.32 (3H, m), 7.25-7.12 (7H, m), 7.06 (2H, d, J =
8.6), 6.77 (2H, d, J = 8.9), 5.83 (3H, s), 3.84-3.
77 (2H, m), 3.73 (3H, s), 3.09 (2H, t, J = 6.8). Examples 15-17, 24, 40-53, 55, 7 below
In 4 and 75, the corresponding carboxylic acid was used in place of 1-phenylindole-2-carboxylic acid, and the target compound was obtained in the same manner as in Example 6.

【００８９】実施例１５ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−（４−メチルフ
ェニル）インドール−２−カルボキサミド（化合物１
５） 融点: 141-149 ℃ (ジイソプロピルエーテル) 元素分析: 0.5 水和物・0.5イソプロパノール付加物とし
て C₃₀H₂₅N₅O₂S ・0.5H₂O ・0.5(CH₃)₂CHOH 計算値 (%): C 68.70, H 5.69, N 11.96 実測値 (%): C 68.82, H 5.93, N 11.68 FABMS (m/z): 520 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.08 (1H, bs), 8.06 (1H, bs),
7.74 (1H, d, J = 7.9),7.71 (1H, s), 7.67 (1H, d, J
= 7.6), 7.41 (1H, d, J = 7.9), 7.35-7.13 (11H,
m), 7.07 (1H, d, J = 2.0), 3.79-3.74 (2H, m), 3.08
(2H, t, J = 6.8),2.44 (3H, s).Example 15 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1- (4-methylphenyl) indole-2-carboxamide (Compound 1
5) Melting point: 141-149 ° C (diisopropyl ether) Elemental analysis: 0.5 hydrate / 0.5 As isopropanol adduct C ₃₀ H ₂₅ N ₅ O ₂ S / 0.5H ₂ O / 0.5 (CH ₃ ) ₂ CHOH Calculated value ( %): C 68.70, H 5.69, N 11.96 Found (%): C 68.82, H 5.93, N 11.68 FABMS (m / z): 520 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.08 (1H , bs), 8.06 (1H, bs),
7.74 (1H, d, J = 7.9), 7.71 (1H, s), 7.67 (1H, d, J
= 7.6), 7.41 (1H, d, J = 7.9), 7.35-7.13 (11H,
m), 7.07 (1H, d, J = 2.0), 3.79-3.74 (2H, m), 3.08
(2H, t, J = 6.8), 2.44 (3H, s).

【００９０】実施例１６ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−（４−クロロフ
ェニル）インドール−２−カルボキサミド（化合物１
６） 融点: 150-155 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: 0.5 水和物・0.5イソプロパノール付加物とし
て C₂₉H₂₂ClN₅O₂S ・0.5H₂O ・0.5(CH₃)₂CHOH 計算値 (%): C 63.26, H 4.70, N 12.09 実測値 (%): C 63.02, H 4.32, N 11.72 FABMS (m/z): 540 (M ⁺ +1)¹ H NMR (CDCl₃) δ 8.09 (1H, bs), 7.74 (1H, d, J =
7.6), 7.71 (1H, s), 7.66 (1H, d, J = 7.6), 7.51-
7.48 (2H, m), 7.41-7.25 (9H, m), 7.17-7.06 (3H,
m), 3.82-3.75 (2H, m), 3.08 (2H, t, J = 6.8).Example 16 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1- (4-chlorophenyl) indole-2-carboxamide (Compound 1
6) Melting point: 150-155 ℃ (isopropanol / diisopropyl ether) Elemental analysis: 0.5 hydrate / 0.5 As isopropanol adduct C ₂₉ H ₂₂ ClN ₅ O ₂ S / 0.5H ₂ O / 0.5 (CH ₃ ) ₂ CHOH calculation Value (%): C 63.26, H 4.70, N 12.09 Actual value (%): C 63.02, H 4.32, N 11.72 FABMS (m / z): 540 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 8.09 (1H, bs), 7.74 (1H, d, J =
7.6), 7.71 (1H, s), 7.66 (1H, d, J = 7.6), 7.51-
7.48 (2H, m), 7.41-7.25 (9H, m), 7.17-7.06 (3H,
m), 3.82-3.75 (2H, m), 3.08 (2H, t, J = 6.8).

【００９１】実施例１７ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−５−メトキシ−１−
フェニルインドール−２−カルボキサミド（化合物１
７） 融点: 135-140 ℃ (ジイソプロピルエーテル) 元素分析: 0.6 酢酸付加物・0.6ジイソプロピルエーテル
付加物として C₃₀H₂₅N₅O₃S ・0.6CH₃COOH ・0.6[(CH₃)₂C
H]₂O 計算値 (%): C 66.04, H 5.70, N 11.06 実測値 (%): C 66.15, H 5.76, N 10.94 FABMS (m/z): 536 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.25 (1H, bs), 8.10 (1H, bs),
7.87-7.64 (2H, m), 7.52-7.45 (3H, m), 7.41-7.34 (2
H, m), 7.24-6.96 (9H, m), 3.87 (3H, s), 3.80-3.73
(2H, m), 3.07 (2H, t, J = 6.8).Example 17 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -5-methoxy-1-
Phenylindole-2-carboxamide (Compound 1
7) Melting point: 135-140 ℃ (diisopropyl ether) Elemental analysis: 0.6 As acetic acid adduct / 0.6 Diisopropyl ether adduct as C ₃₀ H ₂₅ N ₅ O ₃ S / 0.6CH ₃ COOH / 0.6 [(CH ₃ ) ₂ C
H] ₂ O calculated (%): C 66.04, H 5.70, N 11.06 Found (%): C 66.15, H 5.76, N 10.94 FABMS (m / z): 536 (M ⁺ +1) ¹ H NMR ( CDCl ₃ ) δ 9.25 (1H, bs), 8.10 (1H, bs),
7.87-7.64 (2H, m), 7.52-7.45 (3H, m), 7.41-7.34 (2
H, m), 7.24-6.96 (9H, m), 3.87 (3H, s), 3.80-3.73
(2H, m), 3.07 (2H, t, J = 6.8).

【００９２】実施例１８ Ｎ−｛４−［［２−（３−インドリル）エチルアミノ］
カルボニル］−２−チアゾリル｝−１−ベンジルインド
ール−３−カルボキサミド（化合物１８） 融点: 134-139 ℃ (ジイソプロピルエーテル) 元素分析: 1 酢酸付加物として C₃₀H₂₅N₅O₂S ・ CH₃COO
H 計算値 (%): C 66.31, H 5.04, N 12.08 実測値 (%): C 66.15, H 4.92, N 11.96 FABMS (m/z): 520 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.66 (1H, bs), 8.47 (1H, dd, J
= 1.5, 6.1), 8.02 (1H,bs), 7.91 (1H, s), 7.72 (1H,
s), 7.66 (1H, d, J = 7.9), 7.41-7.31 (7H,m), 7.23
-7.09 (6H, m), 5.37 (2H, s), 3.83-3.76 (2H, m), 3.
09 (2H, t, J =6.8).Example 18 N- {4-[[2- (3-indolyl) ethylamino]]
Carbonyl] -2-thiazolyl} -1-benzylindole-3-carboxamide (Compound 18) Melting point: 134-139 ° C. (diisopropyl ether) Elemental analysis: 1 As acetic acid adduct C ₃₀ H ₂₅ N ₅ O ₂ S.CH ₃ COO
H calculated value (%): C 66.31, H 5.04, N 12.08 Measured value (%): C 66.15, H 4.92, N 11.96 FABMS (m / z): 520 (M ⁺ +1) ¹ H NMR (CDCl ₃ ). δ 9.66 (1H, bs), 8.47 (1H, dd, J
= 1.5, 6.1), 8.02 (1H, bs), 7.91 (1H, s), 7.72 (1H,
s), 7.66 (1H, d, J = 7.9), 7.41-7.31 (7H, m), 7.23
-7.09 (6H, m), 5.37 (2H, s), 3.83-3.76 (2H, m), 3.
09 (2H, t, J = 6.8).

【００９３】実施例１９ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝ベンズア
ミド（化合物１９） 融点: 155.5-156 ℃ (酢酸エチル／ジイソプロピルエー
テル) 元素分析: C₂₁H₂₁N₃O₄S 計算値 (%): C 61.30, H 5.14, N 10.21 実測値 (%): C 61.30, H 5.00, N 10.09 FABMS (m/z): 412 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.91 (1H, s), 8.01 (2H, d, J =
7.3), 7.77 (1H, s), 7.63 (1H, m), 7.53 (2H, m), 7.
06 (1H, bt, J = 5.9), 6.76 (3H, m), 3.83 (3H, s),
3.80 (3H, s), 3.65 (2H, ABq, J = 6.6, 13.2), 2.82
(2H, t, J = 6.9).Example 19 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} benzamide (Compound 19) Melting point: 155.5-156 ° C. (ethyl acetate / diisopropyl ether) ) Elemental analysis: C ₂₁ H ₂₁ N ₃ O ₄ S Calculated value (%): C 61.30, H 5.14, N 10.21 Measured value (%): C 61.30, H 5.00, N 10.09 FABMS (m / z): 412 ( M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.91 (1H, s), 8.01 (2H, d, J =
7.3), 7.77 (1H, s), 7.63 (1H, m), 7.53 (2H, m), 7.
06 (1H, bt, J = 5.9), 6.76 (3H, m), 3.83 (3H, s),
3.80 (3H, s), 3.65 (2H, ABq, J = 6.6, 13.2), 2.82
(2H, t, J = 6.9).

【００９４】実施例２０ （Ｅ）−Ｎ−｛４−［［２−（３，４−ジメトキシフェ
ニル）エチルアミノ］カルボニル］−２−チアゾリル｝
−３−（３，４−ジメトキシフェニル）プロペンアミド
（化合物２０） 融点: 147-149 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: C₂₅H₂₇N₃O₆S 計算値 (%): C 60.35, H 5.47, N 8.45 実測値 (%): C 60.10, H 5.53, N 8.31 FABMS (m/z): 498 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.49 (1H, s), 7.81 (1H, d, J =
15.3), 7.80 (1H, s), 7.13 (2H, m), 7.05 (1H, d, J
= 2.0), 6.87 (1H, d, J = 8.4), 6.75 (3H, m),6.50
(1H, d, J = 15.3), 3.92 (3H, s), 3.91 (3H, s), 3.8
4 (3H, s), 3.82(3H, s), 3.65 (2H, ABq, J = 6.4, 1
3.4), 2.82 (2H, t, J = 6.4).Example 20 (E) -N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl}
-3- (3,4-Dimethoxyphenyl) propenamide (Compound 20) Melting point: 147-149 ° C (ethyl acetate / diisopropyl ether) Elemental analysis: C ₂₅ H ₂₇ N ₃ O ₆ S Calculated value (%): C 60.35 , H 5.47, N 8.45 Found (%): C 60.10, H 5.53, N 8.31 FABMS (m / z): 498 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.49 (1H, s), 7.81 (1H, d, J =
15.3), 7.80 (1H, s), 7.13 (2H, m), 7.05 (1H, d, J
= 2.0), 6.87 (1H, d, J = 8.4), 6.75 (3H, m), 6.50
(1H, d, J = 15.3), 3.92 (3H, s), 3.91 (3H, s), 3.8
4 (3H, s), 3.82 (3H, s), 3.65 (2H, ABq, J = 6.4, 1
3.4), 2.82 (2H, t, J = 6.4).

【００９５】実施例２１ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝ナフタレ
ン−２−カルボキサミド（化合物２１） 融点: 175-176 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: C₂₅H₂₃N₃O₄S 計算値 (%): C 65.06, H 5.02, N 9.10 実測値 (%): C 65.03, H 5.22, N 8.77 FABMS (m/z): 462 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.86 (1H, s), 8.54 (1H, s), 8.0
1 (2H, m), 7.94 (2H, m), 7.80 (1H, s), 7.63 (2H,
m), 7.11 (1H, bt, J = 5.9), 6.78 (3H, m), 3.84 (3
H, s), 3.82 (3H, s), 3.67 (2H, ABq, J = 6.9, 13.
4), 2.85 (2H, t, J =6.9).Example 21 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} naphthalene-2-carboxamide (Compound 21) Melting point: 175-176 ° C. (isopropanol / Diisopropyl ether) Elemental analysis: C ₂₅ H ₂₃ N ₃ O ₄ S Calculated value (%): C 65.06, H 5.02, N 9.10 Measured value (%): C 65.03, H 5.22, N 8.77 FABMS (m / z) : 462 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.86 (1H, s), 8.54 (1H, s), 8.0
1 (2H, m), 7.94 (2H, m), 7.80 (1H, s), 7.63 (2H,
m), 7.11 (1H, bt, J = 5.9), 6.78 (3H, m), 3.84 (3
H, s), 3.82 (3H, s), 3.67 (2H, ABq, J = 6.9, 13.
4), 2.85 (2H, t, J = 6.9).

【００９６】実施例２２ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝ナフタレ
ン−１−カルボキサミド（化合物２２） 融点: 174-175 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: C₂₅H₂₃N₃O₄S 計算値 (%): C 65.06, H 5.02, N 9.10 実測値 (%): C 65.03, H 5.22, N 8.77 FABMS (m/z): 462 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.64 (1H, s), 8.42 (1H, m), 8.0
2 (1H, d, J = 8.4), 7.92 (1H, m), 7.80 (1H, s), 7.
59 (2H, m), 7.50 (2H, m), 7.09 (1H, bt, J =5.9),
6.74 (2H, m), 6.70 (1H, s), 3.80 (3H, s), 3.79 (3
H, s), 3.60 (2H,ABq, J = 6.9, 13.4), 2.79 (2H, t,
J = 6.9).Example 22 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} naphthalene-1-carboxamide (Compound 22) Melting point: 174-175 ° C. (isopropanol / Diisopropyl ether) Elemental analysis: C ₂₅ H ₂₃ N ₃ O ₄ S Calculated value (%): C 65.06, H 5.02, N 9.10 Measured value (%): C 65.03, H 5.22, N 8.77 FABMS (m / z) : 462 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.64 (1H, s), 8.42 (1H, m), 8.0
2 (1H, d, J = 8.4), 7.92 (1H, m), 7.80 (1H, s), 7.
59 (2H, m), 7.50 (2H, m), 7.09 (1H, bt, J = 5.9),
6.74 (2H, m), 6.70 (1H, s), 3.80 (3H, s), 3.79 (3
H, s), 3.60 (2H, ABq, J = 6.9, 13.4), 2.79 (2H, t,
J = 6.9).

【００９７】実施例２３ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−３−フ
ェニルベンゾ［ｂ］フラン−２−カルボキサミド（化合
物２３） 融点: 99-100℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: 0.5 水和物として C₂₉H₂₅N₃O₅S ・0.5H₂O 計算値 (%): C 64.91, H 4.88, N 7.83 実測値 (%): C 64.88, H 5.04, N 7.78 FABMS (m/z): 528 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.70 (1H, bs), 7.79 (1H, s), 7.
69 (3H, m), 7.55 (5H,m), 7.37 (1H, m), 7.22 (1H, b
t, J = 6.3), 6.80 (3H, m), 3.89 (3H, s), 3.87 (3H,
s), 3.69 (2H, ABq, J = 6.9, 13.2), 2.88 (2H, t, J
= 6.9).Example 23 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -3-phenylbenzo [b] furan-2-carboxamide (Compound 23) Melting point: 99-100 ° C (Ethyl acetate / diisopropyl ether) Elemental analysis: As C.H. ₂₅ hydrate C ₂₉ H ₂₅ N ₃ O ₅ S ・ 0.5H ₂ O Calculated value (%): C 64.91, H 4.88, N 7.83 Actual measurement Value (%): C 64.88, H 5.04, N 7.78 FABMS (m / z): 528 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.70 (1H, bs), 7.79 (1H, s), 7 .
69 (3H, m), 7.55 (5H, m), 7.37 (1H, m), 7.22 (1H, b
t, J = 6.3), 6.80 (3H, m), 3.89 (3H, s), 3.87 (3H,
s), 3.69 (2H, ABq, J = 6.9, 13.2), 2.88 (2H, t, J
= 6.9).

【００９８】実施例２４ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−フ
ェニルインドール−２−カルボキサミド（化合物２４） 融点: 210-210.5 ℃ (エタノール) 元素分析: C₂₉H₂₆N₄O₄S 計算値 (%): C 66.14, H 4.98, N 10.64 , 実測値 (%): C 65.85, H 5.24, N 10.31 FABMS (m/z): 527 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.47 (1H, bs), 7.75 (1H, d, J =
7.6), 7.71 (1H, s), 7.55 (3H, m), 7.43 (1H, s),
7.39 (2H, m), 7.30 (1H, m), 7.24 (1H, m), 7.17 (1
H, m), 7.07 (1H, bt, J = 5.9), 6.78 (3H, m), 3.86
(3H, s), 3.84 (3H,s), 3.65 (2H, ABq, J = 6.9, 13.
5), 2.84 (2H, t, J = 6.9).Example 24 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-phenylindole-2-carboxamide (Compound 24) Melting point: 210- 210.5 ℃ (Ethanol) Elemental analysis: C ₂₉ H ₂₆ N ₄ O ₄ S Calculated value (%): C 66.14, H 4.98, N 10.64, Found value (%): C 65.85, H 5.24, N 10.31 FABMS (m / z): 527 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.47 (1H, bs), 7.75 (1H, d, J =
7.6), 7.71 (1H, s), 7.55 (3H, m), 7.43 (1H, s),
7.39 (2H, m), 7.30 (1H, m), 7.24 (1H, m), 7.17 (1
H, m), 7.07 (1H, bt, J = 5.9), 6.78 (3H, m), 3.86
(3H, s), 3.84 (3H, s), 3.65 (2H, ABq, J = 6.9, 13.
5), 2.84 (2H, t, J = 6.9).

【００９９】実施例２５ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝インドー
ル−２−カルボキサミド（化合物２５） 融点: 118-121 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: 0.1 ジイソプロピルエーテル付加物として
C₂₃H₂₂N₄O₄S ・0.1[(CH₃) ₂CH]₂O 計算値 (%): C 61.52, H 5.12, N 12.16 実測値 (%): C 61.41, H 4.96, N 11.97 FABMS (m/z): 415 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.41 (1H, bs), 7.80 (1H, s), 7.
73 (1H, d, J = 7.9), 7.48 (1H, d, J = 7.6), 7.41-
7.35 (2H, m), 7.28-7.18 (2H, m), 7.15-7.06 (1H,
m), 6.79 (2H, s), 6.75 (1H, s), 3.73-3.66 (2H, m),
2.86 (2H, t, J = 6.8).Example 25 N- {4-[[2- (3,4-dimethoxyphenyl) ethyl]
Cylamino] carbonyl] -2-thiazolyl} indole
Le-2-carboxamide (Compound 25) Melting point: 118-121 ° C (isopropanol / diisopropyl
Ether) Elemental analysis: 0.1 as diisopropyl ether adduct
C_{twenty three}H_{twenty two}N_FourO_FourS ・ 0.1 [(CH_Three) ₂CH]₂O Calculated value (%): C 61.52, H 5.12, N 12.16 Measured value (%): C 61.41, H 4.96, N 11.97 FABMS (m / z): 415 (M⁺+1)¹ H NMR (CDCl_Three) δ 9.41 (1H, bs), 7.80 (1H, s), 7.
73 (1H, d, J = 7.9), 7.48 (1H, d, J = 7.6), 7.41-
7.35 (2H, m), 7.28-7.18 (2H, m), 7.15-7.06 (1H,
m), 6.79 (2H, s), 6.75 (1H, s), 3.73-3.66 (2H, m),
 2.86 (2H, t, J = 6.8).

【０１００】実施例２６ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−メ
チルインドール−２−カルボキサミド（化合物２６） 融点: 203-207 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: C₂₄H₂₄N₄O₄S 計算値 (%): C 62.05, H 5.21, N 12.06 実測値 (%): C 61.79, H 5.20, N 11.94 FABMS (m/z): 465 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.36 (1H, s), 7.81 (1H, s), 7.7
1 (1H, d, J = 8.3), 7.43-7.41 (2H, d, J = 9.5), 7.
24-7.16 (4H, m), 6.82-6.77 (3H, m), 4.15 (3H, s),
3.88 (3H, s), 3.86 (3H, s), 3.66-3.73 (2H, m), 2.8
8 (2H, t, J = 6.9).Example 26 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-methylindole-2-carboxamide (Compound 26) Melting point: 203- 207 ℃ (isopropanol / diisopropyl ether) Elemental analysis: C ₂₄ H ₂₄ N ₄ O ₄ S Calculated value (%): C 62.05, H 5.21, N 12.06 Measured value (%): C 61.79, H 5.20, N 11.94 FABMS ( m / z): 465 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.36 (1H, s), 7.81 (1H, s), 7.7
1 (1H, d, J = 8.3), 7.43-7.41 (2H, d, J = 9.5), 7.
24-7.16 (4H, m), 6.82-6.77 (3H, m), 4.15 (3H, s),
3.88 (3H, s), 3.86 (3H, s), 3.66-3.73 (2H, m), 2.8
8 (2H, t, J = 6.9).

【０１０１】実施例２７ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−エ
チルインドール−２−カルボキサミド（化合物２７） 融点: 160-162 ℃ (ジイソプロピルエーテル) 元素分析: C₂₅H₂₆N₄O₄S 計算値 (%): C 62.74, H 5.48, N 11.71 実測値 (%): C 62.70, H 5.44, N 11.65 FABMS (m/z): 478 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.46 (1H, s), 7.79 (1H, s), 7.7
2 (1H, d, J = 8.0), 7.47 (1H, d, J = 8.4), 7.41 (1
H, ddd, J = 1.3, 7.0, 8.0), 7.21 (1H, ddd, J= 1.3,
7.0, 8.0), 6.85 (1H, d, J = 7.8), 6.80 (1H, d, J
= 7.8), 6.78 (br, 1H), 4.68 (2H, q, J = 6.9), 3.89
(3H, s), 3.88 (3H, s), 3.70 (2H, dt,J = 6.3, 6.
3), 2.88 (2H, t, J = 6.8), 1.47 (3H, t, J = 7.2).Example 27 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-ethylindole-2-carboxamide (Compound 27) Melting point: 160- 162 ℃ (Diisopropyl ether) Elemental analysis: C ₂₅ H ₂₆ N ₄ O ₄ S Calculated value (%): C 62.74, H 5.48, N 11.71 Measured value (%): C 62.70, H 5.44, N 11.65 FABMS (m / z): 478 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.46 (1H, s), 7.79 (1H, s), 7.7
2 (1H, d, J = 8.0), 7.47 (1H, d, J = 8.4), 7.41 (1
H, ddd, J = 1.3, 7.0, 8.0), 7.21 (1H, ddd, J = 1.3,
7.0, 8.0), 6.85 (1H, d, J = 7.8), 6.80 (1H, d, J
= 7.8), 6.78 (br, 1H), 4.68 (2H, q, J = 6.9), 3.89
(3H, s), 3.88 (3H, s), 3.70 (2H, dt, J = 6.3, 6.
3), 2.88 (2H, t, J = 6.8), 1.47 (3H, t, J = 7.2).

【０１０２】実施例２８ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−イ
ソプロピルインドール−２−カルボキサミド（化合物２
８） 融点: 74-76 ℃ (イソプロパノール／ジイソプロピルエ
ーテル) 元素分析: 0.5 イソプロパノール付加物・1酢酸付加物と
して C₂₆H₂₈N₄O₄S ・0.5(CH₃)₂CHOH・ CH₃COOH 計算値 (%): C 60.81, H 6.23, N 9.62 実測値 (%): C 60.95, H 5.95, N 9.32 FABMS (m/z): 491 (M ⁺ +1)¹ H NMR (CDCl₃) δ 10.89 (1H, br), 7.72 (1H, d, J
= 7.9), 7.65 (1H, d, J= 8.6), 7.44 (1H, s), 7.35-
7.26 (3H, m), 7.19-7.14 (1H, m), 6.80-6.79 (3H,
m), 5.81-5.66 (1H, m), 4.03-3.98 (2H, m), 3.88 (3
H, s), 3.86 (3H, s), 2.95 (2H, t, J = 7.8), 1.71
(3H, s), 1.68 (3H, s).Example 28 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-isopropylindole-2-carboxamide (Compound 2
8) Melting point: 74-76 ℃ (isopropanol / diisopropyl ether) Elemental analysis: 0.5 as isopropanol adduct / 1 acetic acid adduct C ₂₆ H ₂₈ N ₄ O ₄ S ・ 0.5 (CH ₃ ) ₂ CHOH ・ CH ₃ COOH Calculated value (%): C 60.81, H 6.23, N 9.62 Actual value (%): C 60.95, H 5.95, N 9.32 FABMS (m / z): 491 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 10.89 ( 1H, br), 7.72 (1H, d, J
= 7.9), 7.65 (1H, d, J = 8.6), 7.44 (1H, s), 7.35-
7.26 (3H, m), 7.19-7.14 (1H, m), 6.80-6.79 (3H,
m), 5.81-5.66 (1H, m), 4.03-3.98 (2H, m), 3.88 (3
H, s), 3.86 (3H, s), 2.95 (2H, t, J = 7.8), 1.71
(3H, s), 1.68 (3H, s).

【０１０３】実施例２９ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−ブ
チルインドール−２−カルボキサミド（化合物２９） 融点: 150-152 ℃ (酢酸エチル／ヘキサン) 元素分析: C₂₇H₃₀N₄O₄S 計算値 (%): C 64.01, H 5.97, N 11.06 実測値 (%): C 63.82, H 6.04, N 11.01 FABMS (m/z): 507 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.30 (1H, s), 7.80 (1H, s), 7.7
2 (1H, d, J = 8.0), 7.47 (1H, d, J = 8.8), 7.40 (1
H, ddd, J = 1.1, 6.7, 8.8), 7.21 (1H, ddd, J= 1.1,
6.7, 8.0), 7.19 (1H, s), 7.16 (1H, t, J = 5.9),
6.80 (1H, d, J =7.5), 6.79 (1H, s), 4.63 (2H, t, J
= 7.4), 3.88 (3H, s), 3.87 (3H, s),3.70 (3H, dt,
J = 5.9, 6.9), 2.88 (2H, t, J = 6.9), 1.90-1.74 (2
H, m), 1.47-1.29 (2H, m), 0.94 (3H, t, J = 7.3).Example 29 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-butylindole-2-carboxamide (Compound 29) Melting point: 150- 152 ℃ (Ethyl acetate / hexane) Elemental analysis: C ₂₇ H ₃₀ N ₄ O ₄ S Calculated value (%): C 64.01, H 5.97, N 11.06 Measured value (%): C 63.82, H 6.04, N 11.01 FABMS ( m / z): 507 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.30 (1H, s), 7.80 (1H, s), 7.7
2 (1H, d, J = 8.0), 7.47 (1H, d, J = 8.8), 7.40 (1
H, ddd, J = 1.1, 6.7, 8.8), 7.21 (1H, ddd, J = 1.1,
6.7, 8.0), 7.19 (1H, s), 7.16 (1H, t, J = 5.9),
6.80 (1H, d, J = 7.5), 6.79 (1H, s), 4.63 (2H, t, J
= 7.4), 3.88 (3H, s), 3.87 (3H, s), 3.70 (3H, dt,
J = 5.9, 6.9), 2.88 (2H, t, J = 6.9), 1.90-1.74 (2
H, m), 1.47-1.29 (2H, m), 0.94 (3H, t, J = 7.3).

【０１０４】実施例３０ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−シ
クロペンチルインドール−２−カルボキサミド（化合物
３０） ４−フェニル桂皮酸に代えて参考例２で得られる１−シ
クロペンチルインドール−２−カルボン酸を用い、実施
例１に記載した方法に準じて、化合物３０を得た。 融点: 166-168 ℃ (ジイソプロピルエーテル) 元素分析: C₂₈H₃₀N₄O₄S 計算値 (%): C 64.84, H 5.83, N 10.80 実測値 (%): C 64.55, H 5.89, N 10.52 FABMS (m/z): 519 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.34 (1H, bs), 7.79 (1H, s), 7.
71 (1H, d, J = 7.9), 7.55 (1H, dd, J = 0.7, 7.9),
7.33 (1H, ddd, J = 1.3, 6.9, 8.6), 7.24-7.15(2H,
m), 7.13 (1H, s), 6.85-6.80 (2H, m), 6.77 (1H, s),
5.84 (2H, dt, J= 9.2, 9.2), 3.87 (3H, s), 3.86 (3
H, s), 3.73-3.66 (2H, m), 2.87 (2H, t, J = 6.9),
2.31-2.17 (4H, m), 2.08-2.03 (2H, m), 1.84-1.80 (2
H, m).Example 30 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-cyclopentylindole-2-carboxamide (Compound 30) 4-phenylcinnamate Compound 1 was obtained according to the method described in Example 1 using 1-cyclopentylindole-2-carboxylic acid obtained in Reference Example 2 instead of the acid. Melting point: 166-168 ° C (diisopropyl ether) Elemental analysis: C ₂₈ H ₃₀ N ₄ O ₄ S Calculated value (%): C 64.84, H 5.83, N 10.80 Found value (%): C 64.55, H 5.89, N 10.52 FABMS (m / z): 519 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.34 (1H, bs), 7.79 (1H, s), 7.
71 (1H, d, J = 7.9), 7.55 (1H, dd, J = 0.7, 7.9),
7.33 (1H, ddd, J = 1.3, 6.9, 8.6), 7.24-7.15 (2H,
m), 7.13 (1H, s), 6.85-6.80 (2H, m), 6.77 (1H, s),
5.84 (2H, dt, J = 9.2, 9.2), 3.87 (3H, s), 3.86 (3
H, s), 3.73-3.66 (2H, m), 2.87 (2H, t, J = 6.9),
2.31-2.17 (4H, m), 2.08-2.03 (2H, m), 1.84-1.80 (2
H, m).

【０１０５】実施例３１ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−シ
クロヘキシルメチルインドール−２−カルボキサミド
（化合物３１） 融点: 159-162 ℃ (ジイソプロピルエーテル) 元素分析: C₃₀H₃₄N₄O₄S 計算値 (%): C 65.91, H 6.27, N 10.25 実測値 (%): C 65.91, H 6.39, N 10.15 FABMS (m/z): 547 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.35 (1H, bs), 7.79 (1H, s), 7.
70 (1H, d, J = 7.9), 7.40-7.34 (1H, m), 7.25-7.13
(2H, m), 6.85-6.77 (3H, m), 4.51 (2H, d, J =7.6),
3.88 (3H, s), 3.86 (3H, s), 3.73-3.66 (2H, m), 2.8
8 (2H, t, J = 6.9), 1.87 (1H, br), 1.66-1.52 (6H,
m), 1.14-1.23 (4H, m).Example 31 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-cyclohexylmethylindole-2-carboxamide (Compound 31) Melting point: 159 -162 ℃ (Diisopropyl ether) Elemental analysis: C ₃₀ H ₃₄ N ₄ O ₄ S Calculated value (%): C 65.91, H 6.27, N 10.25 Found value (%): C 65.91, H 6.39, N 10.15 FABMS (m / z): 547 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.35 (1H, bs), 7.79 (1H, s), 7.
70 (1H, d, J = 7.9), 7.40-7.34 (1H, m), 7.25-7.13
(2H, m), 6.85-6.77 (3H, m), 4.51 (2H, d, J = 7.6),
3.88 (3H, s), 3.86 (3H, s), 3.73-3.66 (2H, m), 2.8
8 (2H, t, J = 6.9), 1.87 (1H, br), 1.66-1.52 (6H,
m), 1.14-1.23 (4H, m).

【０１０６】実施例３２ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（ｔｅｒｔ−ブトキシカルボニルメチル）インドール−
２−カルボキサミド（化合物３２） 融点: 182-185 ℃ (ジイソプロピルエーテル) 元素分析: C₂₉H₃₂N₄O₆S 計算値 (%): C 61.69, H 5.71, N 9.92 実測値 (%): C 61.75, H 5.81, N 9.91 EIMS (m/z): 564 (M⁺ )¹ H NMR (CDCl₃) δ 9.68 (1H, s), 7.75 (1H, s), 7.6
8 (1H, d, J = 9.8), 7.36 (1H, dd, J = 6.9, 6.9),
7.30 (1H, d, J = 6.9), 7.30 (1H, s), 7.17 (1H, dd,
J = 6.9, 6.9), 7.10 (1H, t, J = 5.8), 6.72-6.82
(2H, m), 6.78 (1H,s), 5.29 (2H, s), 3.88 (3H, s),
3.87 (3H, s), 3.69 (2H, dt, J = 5.8, 6.7), 2.88 (2
H, t, J = 6.7), 1.47 (9H, s).Example 32 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(Tert-Butoxycarbonylmethyl) indole-
2-Carboxamide (Compound 32) Melting point: 182-185 ° C (diisopropyl ether) Elemental analysis: C ₂₉ H ₃₂ N ₄ O ₆ S Calculated value (%): C 61.69, H 5.71, N 9.92 Measured value (%): C 61.75, H 5.81, N 9.91 EIMS (m / z): 564 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ 9.68 (1H, s), 7.75 (1H, s), 7.6
8 (1H, d, J = 9.8), 7.36 (1H, dd, J = 6.9, 6.9),
7.30 (1H, d, J = 6.9), 7.30 (1H, s), 7.17 (1H, dd,
J = 6.9, 6.9), 7.10 (1H, t, J = 5.8), 6.72-6.82
(2H, m), 6.78 (1H, s), 5.29 (2H, s), 3.88 (3H, s),
3.87 (3H, s), 3.69 (2H, dt, J = 5.8, 6.7), 2.88 (2
H, t, J = 6.7), 1.47 (9H, s).

【０１０７】実施例３３ ２−｛４−［２−（３，４−ジメトキシフェニル）エチ
ルカルバモイル］−２−チアゾリルカルバモイル｝−１
−インドール酢酸（化合物３３） 実施例３２で得られた化合物３２, 2.46 g (4.36 mmol)
をメタノール15 mL に溶解し、水酸化ナトリウム0.87 g
(21.8 mmol)の水15 mL 溶液を加え、1 時間加熱還流し
た。反応液を減圧下濃縮後、残渣を水に溶解し、pHを2
に調整した。析出した結晶を濾取、水洗することによ
り、化合物３３, 1.89 g (85%)を白色結晶物として得
た。Example 33 2- {4- [2- (3,4-dimethoxyphenyl) ethylcarbamoyl] -2-thiazolylcarbamoyl} -1
-Indole acetic acid (Compound 33) Compound 32 obtained in Example 32, 2.46 g (4.36 mmol)
Dissolved in 15 mL of methanol, 0.87 g of sodium hydroxide
A solution of (21.8 mmol) in 15 mL of water was added, and the mixture was heated under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water, and the pH was adjusted to 2
Adjusted to. The precipitated crystals were collected by filtration and washed with water to obtain Compound 33, 1.89 g (85%) as a white crystalline substance.

【０１０８】EIMS (m/z): 508 (M⁺ )¹ H NMR (CDCl₃) δ 12.71-12.87 (2H, m), 7.79-7.87
(2H, m), 7.77 (1H, s),7.74 (1H, bd, J = 7.3), 7.64
(1H, bd, J = 7.3), 7.36 (1H, bdd, J = 7.3,7.3),
7.18 (1H, bdd, J = 7.3, 7.3), 6.89 (1H, d, J = 7.
8), 6.85 (1H, bs), 6.77 (1H, bd, J = 7.8), 5.36 (2
H, s), 3.74 (3H, s), 3.74 (3H, s), 3.55 (2H, t, J
= 7.1), 2.79 (2H, t, J = 7.1).EIMS (m / z): 508 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ 12.71-12.87 (2H, m), 7.79-7.87
(2H, m), 7.77 (1H, s), 7.74 (1H, bd, J = 7.3), 7.64
(1H, bd, J = 7.3), 7.36 (1H, bdd, J = 7.3,7.3),
7.18 (1H, bdd, J = 7.3, 7.3), 6.89 (1H, d, J = 7.
8), 6.85 (1H, bs), 6.77 (1H, bd, J = 7.8), 5.36 (2
H, s), 3.74 (3H, s), 3.74 (3H, s), 3.55 (2H, t, J
= 7.1), 2.79 (2H, t, J = 7.1).

【０１０９】実施例３４ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−ジメチルアミノプロピル）インドール−２−カル
ボキサミド・塩酸塩（化合物３４） 塩酸塩の調製（以下の実施例においても同様） 化合物３４の遊離塩基0.88 g (1.64 mmol)を酢酸エチル
に溶解し、1.4 M 塩酸／酢酸エチル溶液3.5 mLを加え
た。析出した白色結晶を濾取し、酢酸エチルで洗浄する
ことにより、化合物３４の塩酸塩0.98 g (94%)を得た。 融点: 125-130 ℃ (塩酸塩: 酢酸エチル) 元素分析: 1 塩酸塩・3.6水和物として C₂₈H₃₃N₅O₄S ・
HCl ・3.6H₂O 計算値 (%): C 52.80, H 6.52, N 10.99 実測値 (%): C 52.95, H 6.35, N 10.49 EIMS (m/z): 535 (M⁺ )¹ H NMR (遊離塩基: CDCl₃) δ 10.33 (1H, s), 7.78
(1H, s), 7.68 (1H, d, J= 8.0), 7.42 (1H, d, J = 7.
0), 7.33 (1H, ddd, J = 0.9, 6.7, 8.0), 7.32(1H,
s), 7.17 (1H, ddd, J = 0.9, 6.7, 7.0), 7.04 (1H,
t, J = 6.2), 6.79(1H, d, J = 7.6), 6.74 (1H, d, J
= 7.6), 6.73 (1H, s), 4.51 (2H, t, J =5.8), 3.85
(3H, s), 3.83 (3H, s), 3.72 (2H, dt, J = 6.2, 6.
8), 2.85 (2H,t, J = 6.8), 2.13-2.34 (4H, m), 2.16
(6H, s).Example 34 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(3-Dimethylaminopropyl) indole-2-carboxamide hydrochloride (compound 34) Preparation of hydrochloride salt (same in the following examples) 0.88 g (1.64 mmol) of the free base of compound 34 was dissolved in ethyl acetate, 3.5 mL of 1.4 M hydrochloric acid / ethyl acetate solution was added. The precipitated white crystals were collected by filtration and washed with ethyl acetate to give the hydrochloride salt of Compound 34 (0.98 g, 94%). Melting point: 125-130 ° C (Hydrochloride: Ethyl acetate) Elemental analysis: 1 Hydrochloride ・ 3.6 As hydrate C ₂₈ H ₃₃ N ₅ O ₄ S ・
HCl ・ 3.6H ₂ O Calculated value (%): C 52.80, H 6.52, N 10.99 Measured value (%): C 52.95, H 6.35, N 10.49 EIMS (m / z): 535 (M ⁺ ) ¹ H NMR ( Free base: CDCl ₃ ) δ 10.33 (1H, s), 7.78
(1H, s), 7.68 (1H, d, J = 8.0), 7.42 (1H, d, J = 7.
0), 7.33 (1H, ddd, J = 0.9, 6.7, 8.0), 7.32 (1H,
s), 7.17 (1H, ddd, J = 0.9, 6.7, 7.0), 7.04 (1H,
t, J = 6.2), 6.79 (1H, d, J = 7.6), 6.74 (1H, d, J
= 7.6), 6.73 (1H, s), 4.51 (2H, t, J = 5.8), 3.85
(3H, s), 3.83 (3H, s), 3.72 (2H, dt, J = 6.2, 6.
8), 2.85 (2H, t, J = 6.8), 2.13-2.34 (4H, m), 2.16
(6H, s).

【０１１０】実施例３５ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−ベ
ンジルインドール−２−カルボキサミド（化合物３５） 融点: 172-175 ℃ (酢酸エチル／ヘキサン) 元素分析: C₃₀H₂₈N₄O₄S 計算値 (%): C 66.65, H 5.22, N 10.36 実測値 (%): C 66.93, H 5.23, N 10.07 FABMS (m/z): 540 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.39 (1H, bs), 7.77 (1H, s), 7.
72 (1H, d, J = 7.9), 7.38-7.35 (2H, m), 7.25-7.20
(6H, m), 7.14-7.08 (2H, m), 6.83-6.77 (3H, m), 5.9
1 (2H, s), 3.88 (3H, s), 3.86 (3H, s), 3.73-3.66
(2H, m), 2.87 (2H, t, J = 6.9).Example 35 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-benzylindole-2-carboxamide (Compound 35) Melting point: 172- 175 ℃ (Ethyl acetate / hexane) Elemental analysis: C ₃₀ H ₂₈ N ₄ O ₄ S Calculated value (%): C 66.65, H 5.22, N 10.36 Measured value (%): C 66.93, H 5.23, N 10.07 FABMS ( m / z): 540 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.39 (1H, bs), 7.77 (1H, s), 7.
72 (1H, d, J = 7.9), 7.38-7.35 (2H, m), 7.25-7.20
(6H, m), 7.14-7.08 (2H, m), 6.83-6.77 (3H, m), 5.9
1 (2H, s), 3.88 (3H, s), 3.86 (3H, s), 3.73-3.66
(2H, m), 2.87 (2H, t, J = 6.9).

【０１１１】実施例３６ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−メトキシベンジル）インドール−２−カルボキサ
ミド（化合物３６） 融点: 183-187 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: 0.5 イソプロパノール付加物として C₃₁H₃₀
N₄O₅S ・0.5(CH₃)₂CHOH 計算値 (%): C 64.98, H 5.70, N 9.33 実測値 (%): C 65.15, H 5.39, N 9.28 FABMS (m/z): 571 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.48 (1H, br), 7.76 (1H, s), 7.
72 (1H, d, J = 7.9), 7.47-7.23 (4H, m), 7.20-7.09
(2H, m), 6.84-6.65 (6H, m), 5.88 (2H, s), 3.87 (3
H, s), 3.85 (3H, s), 3.74-3.60 (5H, m), 2.86 (2H,
t, J = 6.9).Example 36 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(3-Methoxybenzyl) indole-2-carboxamide (Compound 36) Melting point: 183-187 ° C (isopropanol / diisopropyl ether) Elemental analysis: 0.5 C ₃₁ H ₃₀ as an isopropanol adduct
N ₄ O ₅ S ・ 0.5 (CH ₃ ) ₂ CHOH Calculated value (%): C 64.98, H 5.70, N 9.33 Measured value (%): C 65.15, H 5.39, N 9.28 FABMS (m / z): 571 ( M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.48 (1H, br), 7.76 (1H, s), 7.
72 (1H, d, J = 7.9), 7.47-7.23 (4H, m), 7.20-7.09
(2H, m), 6.84-6.65 (6H, m), 5.88 (2H, s), 3.87 (3
H, s), 3.85 (3H, s), 3.74-3.60 (5H, m), 2.86 (2H,
t, J = 6.9).

【０１１２】実施例３７ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−メトキシベンジル）インドール−２−カルボキサ
ミド（化合物３７） 融点: 175-178 ℃ (ジイソプロピルエーテル) 元素分析: 0.1 水和物として C₃₁H₃₀N₄O₅S ・0.1H₂O 計算値 (%): C 65.04, H 5.32, N 9.79 実測値 (%): C 65.00, H 5.28, N 9.44 FABMS (m/z): 571 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.34 (1H, bs), 7.77 (1H, s), 7.
72 (1H, d, J = 7.9), 7.44 (1H, d, J = 8.3), 7.39-
7.36 (1H, m), 7.25-7.11 (4H, m), 7.07 (2H, d,J =
8.6), 6.87-6.76 (4H, m), 5.83 (2H, s), 3.88 (3H,
s), 3.86 (3H, s),3.73-3.65 (5H, m), 2.87 (2H, t, J
= 6.9).Example 37 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Methoxybenzyl) indole-2-carboxamide (Compound 37) Melting point: 175-178 ° C (diisopropyl ether) Elemental analysis: C ₃₁ H ₃₀ N ₄ O ₅ S ・ 0.1H ₂ O calculated as 0.1 hydrate (Calculated value ( %): C 65.04, H 5.32, N 9.79 Found (%): C 65.00, H 5.28, N 9.44 FABMS (m / z): 571 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.34 (1H) , bs), 7.77 (1H, s), 7.
72 (1H, d, J = 7.9), 7.44 (1H, d, J = 8.3), 7.39-
7.36 (1H, m), 7.25-7.11 (4H, m), 7.07 (2H, d, J =
8.6), 6.87-6.76 (4H, m), 5.83 (2H, s), 3.88 (3H,
s), 3.86 (3H, s), 3.73-3.65 (5H, m), 2.87 (2H, t, J
= 6.9).

【０１１３】実施例３８ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（チオフェン−２−イル）インドール−２−カルボキサ
ミド（化合物３８） 融点: 132-135 ℃ (ジイソプロピルエーテル) 元素分析: 0.1 ジイソプロピルエーテル付加物として
C₂₇H₂₄N₄O₄S₂・0.1[(CH₃) ₂CH]₂O 計算値 (%): C 61.07, H 4.72, N 10.32 実測値 (%): C 61.06, H 4.63, N 10.14 FABMS (m/z): 533 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.13 (1H, bs), 7.75 (1H, d, J =
7.6), 7.74 (1H, s), 7.46 (1H, s), 7.44 (1H, dd, J
= 1.7, 5.6), 7.42-7.36 (1H, m), 7.30-7.20 (3H,
m), 7.14 (1H, dd, J = 3.6, 5.6), 7.07 (1H, t, J =
6.2), 6.87-6.77 (3H, m), 3.89 (3H, s), 3.86 (3H,
s), 3.83-3.60 (2H, m), 2.86 (2H, t, J = 6.9).Example 38 N- {4-[[2- (3,4-dimethoxyphenyl) e]
Cylamino] carbonyl] -2-thiazolyl} -1-
(Thiophen-2-yl) indole-2-carboxa
Mido (Compound 38) Melting point: 132-135 ° C (diisopropyl ether) Elemental analysis: 0.1 As a diisopropyl ether adduct
C₂₇H_{twenty four}N_FourO_FourS₂・ 0.1 [(CH_Three) ₂CH]₂O Calculated value (%): C 61.07, H 4.72, N 10.32 Measured value (%): C 61.06, H 4.63, N 10.14 FABMS (m / z): 533 (M⁺+1)¹ H NMR (CDCl_Three) δ 9.13 (1H, bs), 7.75 (1H, d, J =
 7.6), 7.74 (1H, s), 7.46 (1H, s), 7.44 (1H, dd, J
 = 1.7, 5.6), 7.42-7.36 (1H, m), 7.30-7.20 (3H,
m), 7.14 (1H, dd, J = 3.6, 5.6), 7.07 (1H, t, J =
6.2), 6.87-6.77 (3H, m), 3.89 (3H, s), 3.86 (3H,
s), 3.83-3.60 (2H, m), 2.86 (2H, t, J = 6.9).

【０１１４】実施例３９ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−ピリジル）インドール−２−カルボキサミド・塩
酸塩（化合物３９） ４−フェニル桂皮酸に代えて参考例３で得られる１−
（２−ピリジル）インドール−２−カルボン酸を用い、
実施例１に記載した方法に準じて、化合物３９を得た。 融点: 152-156 ℃ (塩酸塩: エタノール) 元素分析: 1 塩酸塩・0.5水和物として C₂₈H₂₅N₅O₄S ・
HCl ・0.5H₂O 計算値 (%): C 58.69, H 4.75, N 12.22 実測値 (%): C 58.77, H 4.69, N 12.18 FABMS (m/z): 528 (M ⁺ +1)¹ H NMR (遊離塩基: CDCl₃) δ 12.00 (1H, bs), 8.75
(1H, m), 8.00 (1H, dt,J = 2.0, 7.9), 7.62 (1H, s),
7.58 (2H, d, J = 7.9), 7.25 (4H, m), 7.12(1H, bt,
J = 5.9), 7.08 (1H, s), 7.01 (1H, dt, J = 1.5, 7.
9), 6.88 (1H,d, J = 8.9), 6.80 (2H, m), 6.75 (1H,
d, J = 8.4), 3.88 (3H, s), 3.87 (3H, s), 3.71 (1H,
d, J = 6.9), 3.67 (1H, d, J = 6.9), 2.88 (2H, t,
J = 6.9).Example 39 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Pyridyl) indole-2-carboxamide hydrochloride (Compound 39) 1-obtained in Reference Example 3 in place of 4-phenylcinnamic acid
With (2-pyridyl) indole-2-carboxylic acid,
Compound 39 was obtained according to the method described in Example 1. Melting point: 152-156 ℃ (Hydrochloride: ethanol) Elemental analysis: 1 Hydrochloride as hemihydrate C ₂₈ H ₂₅ N ₅ O ₄ S ・
HCl ・ 0.5H ₂ O Calculated value (%): C 58.69, H 4.75, N 12.22 Measured value (%): C 58.77, H 4.69, N 12.18 FABMS (m / z): 528 (M ⁺ +1) ¹ H NMR (free base: CDCl ₃ ) δ 12.00 (1H, bs), 8.75
(1H, m), 8.00 (1H, dt, J = 2.0, 7.9), 7.62 (1H, s),
7.58 (2H, d, J = 7.9), 7.25 (4H, m), 7.12 (1H, bt,
J = 5.9), 7.08 (1H, s), 7.01 (1H, dt, J = 1.5, 7.
9), 6.88 (1H, d, J = 8.9), 6.80 (2H, m), 6.75 (1H,
d, J = 8.4), 3.88 (3H, s), 3.87 (3H, s), 3.71 (1H,
d, J = 6.9), 3.67 (1H, d, J = 6.9), 2.88 (2H, t,
J = 6.9).

【０１１５】実施例４０ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−メチルフェニル）インドール−２−カルボキサミ
ド（化合物４０） 融点: 174-175 ℃ (ジイソプロピルエーテル) 元素分析: 0.9 水和物として C₃₀H₂₈N₄O₄S ・0.9H₂O 計算値 (%): C 64.23, H 5.36, N 9.42 実測値 (%): C 63.99, H 5.00, N 9.82 FABMS (m/z): 541 (M ⁺ +1)¹ H NMR (CDCl₃) δ 8.92 (1H, bs), 7.65 (1H, d, J =
7.3), 7.58(1H, s), 7.33-7.11 (7H, m), 6.95 (1H,
t, J = 5.8), 6.80-6.64 (4H, m), 3.77 (3H, s),3.74
(3H, s), 3.58-3.51 (2H, m), 2.73 (2H, t, J = 6.9),
1.83(3H, s).Example 40 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Methylphenyl) indole-2-carboxamide (Compound 40) Melting point: 174-175 ° C (diisopropyl ether) Elemental analysis: 0.9 As a hydrate C ₃₀ H ₂₈ N ₄ O ₄ S ・ 0.9H ₂ O Calculated value ( %): C 64.23, H 5.36, N 9.42 Found (%): C 63.99, H 5.00, N 9.82 FABMS (m / z): 541 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 8.92 (1H) , bs), 7.65 (1H, d, J =
7.3), 7.58 (1H, s), 7.33-7.11 (7H, m), 6.95 (1H,
t, J = 5.8), 6.80-6.64 (4H, m), 3.77 (3H, s), 3.74
(3H, s), 3.58-3.51 (2H, m), 2.73 (2H, t, J = 6.9),
1.83 (3H, s).

【０１１６】実施例４１ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−メチルフェニル）インドール−２−カルボキサミ
ド（化合物４１） 融点: 165-168 ℃ (ジイソプロピルエーテル) 元素分析: C₃₀H₂₈N₄O₄S 計算値 (%): C 66.65, H 5.22, N 10.36 実測値 (%): C 66.38, H 5.37, N 10.06 FABMS (m/z): 541 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.15 (1H, bs), 7.75 (1H, d, J =
7.9), 7.72 (1H, s), 7.47-7.15 (8H, m), 7.09 (1H,
t, J = 5.9), 6.86-6.77 (3H, m), 3.89 (3H, s), 3.86
(3H, s), 3.71-3.62 (2H, m), 2.86 (2H, t, J = 6.
9), 2.43 (3H, s).Example 41 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(3-Methylphenyl) indole-2-carboxamide (Compound 41) Melting point: 165-168 ° C (diisopropyl ether) Elemental analysis: C ₃₀ H ₂₈ N ₄ O ₄ S Calculated value (%): C 66.65, H 5.22, N 10.36 Found (%): C 66.38, H 5.37, N 10.06 FABMS (m / z): 541 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.15 (1H, bs), 7.75 (1H, d, J =
7.9), 7.72 (1H, s), 7.47-7.15 (8H, m), 7.09 (1H,
t, J = 5.9), 6.86-6.77 (3H, m), 3.89 (3H, s), 3.86
(3H, s), 3.71-3.62 (2H, m), 2.86 (2H, t, J = 6.
9), 2.43 (3H, s).

【０１１７】実施例４２ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−メチルフェニル）インドール−２−カルボキサミ
ド（化合物４２） 融点: 192-194 ℃ (ジイソプロピルエーテル) 元素分析: C₃₀H₂₈N₄O₄S 計算値 (%): C 66.65, H 5.22, N 10.36 実測値 (%): C 66.49, H 5.21, N 10.20 FABMS (m/z): 541 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.09 (1H, bs), 7.75 (1H, dd, J
= 1.0, 7.9), 7.72 (1H,s), 7.38-7.21 (7H, m), 7.15
(1H, d, J = 8.3), 7.10 (3H, t, J = 6.3), 6.86-6.77
(3H, m), 3.89 (3H, s), 3.86 (3H, s), 3.71-3.64 (2
H, m), 2.86 (2H, t, J = 6.9), 2.46(3H, s).Example 42 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Methylphenyl) indole-2-carboxamide (Compound 42) Melting point: 192-194 ° C (diisopropyl ether) Elemental analysis: C ₃₀ H ₂₈ N ₄ O ₄ S Calculated value (%): C 66.65, H 5.22, N 10.36 Found (%): C 66.49, H 5.21, N 10.20 FABMS (m / z): 541 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.09 (1H, bs), 7.75 (1H, dd, J
= 1.0, 7.9), 7.72 (1H, s), 7.38-7.21 (7H, m), 7.15
(1H, d, J = 8.3), 7.10 (3H, t, J = 6.3), 6.86-6.77
(3H, m), 3.89 (3H, s), 3.86 (3H, s), 3.71-3.64 (2
H, m), 2.86 (2H, t, J = 6.9), 2.46 (3H, s).

【０１１８】実施例４３ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−ニトロフェニル）インドール−２−カルボキサミ
ド（化合物４３） 融点: 208-212 ℃ (ジイソプロピルエーテル) 元素分析: 0.2 水和物・0.2ジイソプロピルエーテル付加
物として C₂₉H₂₅N₅O₆S・0.2H₂O ・0.2[(CH₃)₂CH]₂O 計算値 (%): C 60.90, H 4.77, N 11.76 実測値 (%): C 60.91, H 4.79, N 11.63 FABMS (m/z): 572 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.65 (1H, bs), 8.22 (1H, d, J =
7.9), 7.82-7.73 (2H,m), 7.69 (1H, s), 7.57 (1H,
d, J = 7.9), 7.48 (1H, s), 7.32-7.26 (2H, m), 7.10
-7.00 (1H, m), 6.95 (1H, d, J = 8.4), 6.80-6.76 (4
H, m), 3.87 (3H,s), 3.84 (3H, s), 3.66-3.62 (2H,
m), 2.85 (2H, t, J = 6.9).Example 43 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Nitrophenyl) indole-2-carboxamide (Compound 43) Melting point: 208-212 ° C (diisopropyl ether) Elemental analysis: 0.2 hydrate / 0.2 C ₂₉ H ₂₅ N ₅ O ₆ S / 0.2 as diisopropyl ether adduct H ₂ O ・ 0.2 [(CH ₃ ) ₂ CH] ₂ O Calculated value (%): C 60.90, H 4.77, N 11.76 Measured value (%): C 60.91, H 4.79, N 11.63 FABMS (m / z): 572 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.65 (1H, bs), 8.22 (1H, d, J =
7.9), 7.82-7.73 (2H, m), 7.69 (1H, s), 7.57 (1H,
d, J = 7.9), 7.48 (1H, s), 7.32-7.26 (2H, m), 7.10
-7.00 (1H, m), 6.95 (1H, d, J = 8.4), 6.80-6.76 (4
H, m), 3.87 (3H, s), 3.84 (3H, s), 3.66-3.62 (2H,
m), 2.85 (2H, t, J = 6.9).

【０１１９】実施例４４ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−ニトロフェニル）インドール−２−カルボキサミ
ド（化合物４４） 融点: 235-238 ℃ (ジイソプロピルエーテル) 元素分析: 0.5 酢酸付加物として C₂₉H₂₅N₅O₆S ・0.5CH
₃COOH 計算値 (%): C 59.89, H 4.52, N 11.64 実測値 (%): C 59.80, H 4.53, N 11.70 FABMS (m/z): 572 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.50 (1H, bs), 8.40-8.36 (1H,
m), 8.27-8.26 (1H, m),7.81-7.73 (4H, m), 7.45 (1H,
s), 7.41-7.24 (2H, m), 7.13 (1H, d, J = 8.3), 7.0
9 (1H, t, J = 5.6), 6.87-6.78 (3H, m), 3.89 (3H,
s), 3.87 (3H, s),3.73-3.66 (2H, m), 2.87 (2H, t, J
= 6.8).Example 44 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(3-Nitrophenyl) indole-2-carboxamide (Compound 44) Melting point: 235-238 ° C (diisopropyl ether) Elemental analysis: 0.5 As an acetic acid adduct C ₂₉ H ₂₅ N ₅ O ₆ S ・ 0.5CH
₃ COOH Calculated value (%): C 59.89, H 4.52, N 11.64 Measured value (%): C 59.80, H 4.53, N 11.70 FABMS (m / z): 572 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.50 (1H, bs), 8.40-8.36 (1H,
m), 8.27-8.26 (1H, m), 7.81-7.73 (4H, m), 7.45 (1H,
s), 7.41-7.24 (2H, m), 7.13 (1H, d, J = 8.3), 7.0
9 (1H, t, J = 5.6), 6.87-6.78 (3H, m), 3.89 (3H,
s), 3.87 (3H, s), 3.73-3.66 (2H, m), 2.87 (2H, t, J
= 6.8).

【０１２０】実施例４５ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−ニトロフェニル）インドール−２−カルボキサミ
ド（化合物４５） 融点: 183-190 ℃ (ジイソプロピルエーテル) 元素分析: 1.5 酢酸付加物として C₂₉H₂₅N₅O₆S ・1.5CH
₃COOH 計算値 (%): C 58.09, H 4.72, N 10.58 実測値 (%): C 58.01, H 4.69, N 10.54 FABMS (m/z): 572 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.42 (1H, bs), 7.92 (2H, d, J =
8.9), 7.80 (1H, d, J= 7.9), 7.74 (1H, s), 7.57 (2
H, d, J = 8.9), 7.46-7.31 (3H, m), 7.19 (1H, d, J
= 8.6), 7.10-7.05 (1H, m), 6.87-6.81 (2H, m), 6.78
(1H, s), 3.89(3H, s), 3.87 (3H, s), 3.73-3.62 (2
H, m), 2.88 (2H, t, J = 6.9).Example 45 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Nitrophenyl) indole-2-carboxamide (Compound 45) Melting point: 183-190 ° C (diisopropyl ether) Elemental analysis: 1.5 As an acetic acid adduct C ₂₉ H ₂₅ N ₅ O ₆ S ・ 1.5CH
₃ COOH Calculated value (%): C 58.09, H 4.72, N 10.58 Measured value (%): C 58.01, H 4.69, N 10.54 FABMS (m / z): 572 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.42 (1H, bs), 7.92 (2H, d, J =
8.9), 7.80 (1H, d, J = 7.9), 7.74 (1H, s), 7.57 (2
H, d, J = 8.9), 7.46-7.31 (3H, m), 7.19 (1H, d, J
= 8.6), 7.10-7.05 (1H, m), 6.87-6.81 (2H, m), 6.78
(1H, s), 3.89 (3H, s), 3.87 (3H, s), 3.73-3.62 (2
H, m), 2.88 (2H, t, J = 6.9).

【０１２１】実施例４６ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−メトキシフェニル）インドール−２−カルボキサ
ミド（化合物４６） 融点: 197-200 ℃ (ジイソプロピルエーテル) 元素分析: 0.6 酢酸付加物として C₃₀H₂₈N₄O₅S ・0.6CH
₃COOH 計算値 (%): C 63.23, H 5.17, N 9.45 実測値 (%): C 63.35, H 5.22, N 9.32 FABMS (m/z): 557 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.24 (1H, bs), 7.76 (1H, d, J =
7.6), 7.72 (1H, s), 7.41-7.50 (2H, m), 7.35 (1H,
s), 7.20-7.34 (2H, m), 7.06-7.18 (4H, m), 6.78-6.8
7 (3H, m), 3.90 (3H, s), 3.87 (3H, s), 3.63-3.73
(4H, m), 2.87 (2H, t, J = 6.9).Example 46 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-methoxyphenyl) indole-2-carboxamide (Compound 46) mp: 197-200 ° C. (diisopropyl ether) Elemental _{analysis: 0.6 C 30 H 28 N 4} O 5 S · 0.6CH as acetate adduct
₃ COOH Calculated value (%): C 63.23, H 5.17, N 9.45 Measured value (%): C 63.35, H 5.22, N 9.32 FABMS (m / z): 557 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.24 (1H, bs), 7.76 (1H, d, J =
7.6), 7.72 (1H, s), 7.41-7.50 (2H, m), 7.35 (1H,
s), 7.20-7.34 (2H, m), 7.06-7.18 (4H, m), 6.78-6.8
7 (3H, m), 3.90 (3H, s), 3.87 (3H, s), 3.63-3.73
(4H, m), 2.87 (2H, t, J = 6.9).

【０１２２】実施例４７ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−メトキシフェニル）インドール−２−カルボキサ
ミド（化合物４７） 融点: 145-148 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: 0.2 ジイソプロピルエーテル付加物として
C₃₀H₂₈N₄O₅S ・0.2[(CH₃) ₂CH]₂O 計算値 (%): C 64.94, H 5.38, N 9.71 実測値 (%): C 64.66, H 5.39, N 9.59 FABMS (m/z): 557 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.30 (1H, bs), 7.75 (1H, t, J =
7.9), 7.72 (1H, s), 7.45 (1H, t, J = 8.0), 7.41
(1H, s), 7.36-7.30 (1H, m), 7.24-7.19 (2H, m), 7,2
8-6.96 (3H, m), 6.93 (1H, t, J = 2.1), 6.85-6.76
(3H, m), 3.87 (3H,s), 3.85 (3H, s), 3.83 (3H, s),
3.69-3.63 (2H, m), 2.85 (2H, t, J = 6.9).Example 47 N- {4-[[2- (3,4-dimethoxyphenyl) ethyl]
Cylamino] carbonyl] -2-thiazolyl} -1-
(3-Methoxyphenyl) indole-2-carboxa
Mide (Compound 47) Melting point: 145-148 ℃ (Ethyl acetate / diisopropyl ether
Le) Elemental analysis: 0.2 as diisopropyl ether adduct
C₃₀H₂₈N_FourO_FiveS ・ 0.2 [(CH_Three) ₂CH]₂O Calculated value (%): C 64.94, H 5.38, N 9.71 Actual value (%): C 64.66, H 5.39, N 9.59 FABMS (m / z): 557 (M⁺+1)¹ H NMR (CDCl_Three) δ 9.30 (1H, bs), 7.75 (1H, t, J =
 7.9), 7.72 (1H, s), 7.45 (1H, t, J = 8.0), 7.41
(1H, s), 7.36-7.30 (1H, m), 7.24-7.19 (2H, m), 7,2
8-6.96 (3H, m), 6.93 (1H, t, J = 2.1), 6.85-6.76
(3H, m), 3.87 (3H, s), 3.85 (3H, s), 3.83 (3H, s),
3.69-3.63 (2H, m), 2.85 (2H, t, J = 6.9).

【０１２３】実施例４８ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−メトキシフェニル）インドール−２−カルボキサ
ミド（化合物４８） 融点: 183-185 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: 0.2 ジイソプロピルエーテル付加物として
C₃₀H₂₈N₄O₅S ・0.2[(CH₃) ₂CH]₂O 計算値 (%): C 64.94, H 5.38, N 9.71 実測値 (%): C 64.81, H 5.26, N 9.57 FABMS (m/z): 557 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.17 (1H, bs), 7.75 (1H, d, J =
7.9), 7.72 (1H, s), 7.38 (1H, d, J = 0.7), 7.35-
7.21 (4H, m), 7.14-7.03 (4H, m), 6.86-6.76 (3H,
m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.71
-3.62 (2H, m), 2.86(2H, t, J = 6.9).Example 48 N- {4-[[2- (3,4-dimethoxyphenyl) ethyl]
Cylamino] carbonyl] -2-thiazolyl} -1-
(4-Methoxyphenyl) indole-2-carboxa
Mide (Compound 48) Melting point: 183-185 ° C (isopropanol / diisopropyl
Ether) Elemental analysis: 0.2 as diisopropyl ether adduct
C₃₀H₂₈N_FourO_FiveS ・ 0.2 [(CH_Three) ₂CH]₂O Calculated value (%): C 64.94, H 5.38, N 9.71 Actual value (%): C 64.81, H 5.26, N 9.57 FABMS (m / z): 557 (M⁺+1)¹ H NMR (CDCl_Three) δ 9.17 (1H, bs), 7.75 (1H, d, J =
 7.9), 7.72 (1H, s), 7.38 (1H, d, J = 0.7), 7.35-
7.21 (4H, m), 7.14-7.03 (4H, m), 6.86-6.76 (3H,
m), 3.89 (3H, s), 3.88 (3H, s), 3.86 (3H, s), 3.71
-3.62 (2H, m), 2.86 (2H, t, J = 6.9).

【０１２４】実施例４９ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−クロロフェニル）インドール−２−カルボキサミ
ド（化合物４９） 化合物４９は、実施例６３（１）で得られるＮ−｛４−
［［２−（３，４−ジメトキシフェニル）エチルアミ
ノ］カルボニル］−２−チアゾリル｝−１−（４−アミ
ノ−２−クロロフェニル）インドール−２−カルボキサ
ミドから、以下の方法によって得ることもできる。Example 49 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Chlorophenyl) indole-2-carboxamide (Compound 49) Compound 49 is N- {4- obtained in Example 63 (1).
It can also be obtained from [[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (4-amino-2-chlorophenyl) indole-2-carboxamide by the following method.

【０１２５】Ｎ−｛４−［［２−（３，４−ジメトキシ
フェニル）エチルアミノ］カルボニル］−２−チアゾリ
ル｝−１−（４−アミノ−２−クロロフェニル）インド
ール−２−カルボキサミド2.62 g (4.55 mmol)を50% 次
亜リン酸60 g-THF 40 mL中に溶解し、これに、氷冷下、
亜硝酸ナトリウム380 mg (5.51 mmol)の水5 mL溶液を滴
下し、室温で15時間攪拌した。反応液を減圧下濃縮後、
残渣を塩化メチレン／水で分配し、有機層を飽和重曹
水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムで
乾燥した。溶媒を減圧下留去後、残渣をシリカゲルカラ
ムクロマトグラフィー（ヘキサン：酢酸エチル＝１：
１）で精製し、得られた粗結晶をエタノール／イソプロ
ピルエーテルでトリチュレーションすることにより、化
合物４９, 1.83 g (72%)を白色結晶物として得た。N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (4-amino-2-chlorophenyl) indole-2-carboxamide 2.62 g ( 4.55 mmol) was dissolved in 50% hypophosphorous acid 60 g-THF 40 mL, and this was cooled under ice-cooling.
A solution of 380 mg (5.51 mmol) of sodium nitrite in 5 mL of water was added dropwise, and the mixture was stirred at room temperature for 15 hours. After concentrating the reaction solution under reduced pressure,
The residue was partitioned with methylene chloride / water, the organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Purification in 1) and trituration of the resulting crude crystals with ethanol / isopropyl ether gave compound 49, 1.83 g (72%) as white crystals.

【０１２６】融点: 166-168 ℃ (ジイソプロピルエーテ
ル) 元素分析: 0.4 ジイソプロピルエーテル付加物として
C₂₉H₂₅ClN₄O₄S ・0.4[(CH ₃)₂CH]₂O 計算値 (%): C 62.66, H 5.12, N 9.31 実測値 (%): C 62.38, H 5.05, N 9.19 FABMS (m/z): 561 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.28 (1H, bs), 7.79 (1H, d, J =
7.3), 7.72 (1H, s), 7.64-7.50 (1H, m), 7.49-7.41
(3H, m), 7.39 (1H, s), 7.35-7.30 (1H, m), 7.29-7.2
4 (1H, m), 7.18-7.09 (1H, m), 7.00 (1H, d, J = 7.
9), 6.84-6.72 (3H, m), 3.89 (3H, s), 3.87 (3H, s),
3.72-3.60 (2H, m), 2.87 (2H, t, J = 6.9).Melting point: 166-168 ° C. (diisopropyl ether
Le) Elemental analysis: 0.4 as diisopropyl ether adduct
C₂₉H_{twenty five}ClN_FourO_FourS ・ 0.4 [(CH _Three)₂CH]₂O Calculated value (%): C 62.66, H 5.12, N 9.31 Measured value (%): C 62.38, H 5.05, N 9.19 FABMS (m / z): 561 (M⁺+1)¹ H NMR (CDCl_Three) δ 9.28 (1H, bs), 7.79 (1H, d, J =
 7.3), 7.72 (1H, s), 7.64-7.50 (1H, m), 7.49-7.41
(3H, m), 7.39 (1H, s), 7.35-7.30 (1H, m), 7.29-7.2
4 (1H, m), 7.18-7.09 (1H, m), 7.00 (1H, d, J = 7.
9), 6.84-6.72 (3H, m), 3.89 (3H, s), 3.87 (3H, s),
 3.72-3.60 (2H, m), 2.87 (2H, t, J = 6.9).

【０１２７】実施例５０ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−クロロフェニル）インドール−２−カルボキサミ
ド（化合物５０） 融点: 145-148 ℃ (ジイソプロピルエーテル) 元素分析: 0.6 水和物として C₂₉H₂₅ClN₄O₄S ・0.6H₂O 計算値 (%): C 60.91, H 4.62, N 9.80 実測値 (%): C 60.75, H 4.35, N 9.54 FABMS (m/z): 561 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.30 (1H, bs), 7.76 (1H, d, J =
7.6), 7.73 (1H, s), 7.50-7.48 (2H, m), 7.31-7.24
(5H, m), 7.17 (1H, d, J = 8.3), 7.10 (1H, t,J = 5.
8), 6.86-6.77 (3H, m), 3.88 (3H, s), 3.86 (3H, s),
3.72-3.65 (2H,m), 2.87 (2H, t, J = 6.9).Example 50 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(3-Chlorophenyl) indole-2-carboxamide (Compound 50) Melting point: 145-148 ° C (diisopropyl ether) Elemental analysis: 0.6 As a hydrate C ₂₉ H ₂₅ ClN ₄ O ₄ S ・ 0.6H ₂ O Calculated value (% ): C 60.91, H 4.62, N 9.80 Found (%): C 60.75, H 4.35, N 9.54 FABMS (m / z): 561 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.30 (1H, bs), 7.76 (1H, d, J =
7.6), 7.73 (1H, s), 7.50-7.48 (2H, m), 7.31-7.24
(5H, m), 7.17 (1H, d, J = 8.3), 7.10 (1H, t, J = 5.
8), 6.86-6.77 (3H, m), 3.88 (3H, s), 3.86 (3H, s),
3.72-3.65 (2H, m), 2.87 (2H, t, J = 6.9).

【０１２８】実施例５１ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−クロロフェニル）インドール−２−カルボキサミ
ド（化合物５１） 融点: 175-178 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: 1 酢酸付加物として C₂₉H₂₅ClN₄O₄S ・ CH₃C
OOH 計算値 (%): C 59.95, H 4.71, N 9.02 実測値 (%): C 60.27, H 4.46, N 8.67 FABMS (m/z): 561 (M ⁺ +1)¹ H NMR (CDCl₃) δ 11.29 (1H, bs), 7.78 (1H, d, J
= 7.9), 7.57 (1H, s),7.52-7.49 (2H, m), 7.34-7.21
(6H, m), 7.12 (1H, d, J = 7.9), 6.97-6.77 (3H, m),
4.00-3.94 (2H, m), 3.87 (3H, s), 3.85 (3H, s), 2.
92 (2H, t, J =7.6).Example 51 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Chlorophenyl) indole-2-carboxamide (Compound 51) Melting point: 175-178 ° C (isopropanol / diisopropyl ether) Elemental analysis: 1 As an acetic acid adduct C ₂₉ H ₂₅ ClN ₄ O ₄ S.CH ₃ C
Calculated OOH value (%): C 59.95, H 4.71, N 9.02 Measured value (%): C 60.27, H 4.46, N 8.67 FABMS (m / z): 561 (M ⁺ +1) ¹ H NMR (CDCl ₃ ). δ 11.29 (1H, bs), 7.78 (1H, d, J
= 7.9), 7.57 (1H, s), 7.52-7.49 (2H, m), 7.34-7.21
(6H, m), 7.12 (1H, d, J = 7.9), 6.97-6.77 (3H, m),
4.00-3.94 (2H, m), 3.87 (3H, s), 3.85 (3H, s), 2.
92 (2H, t, J = 7.6).

【０１２９】実施例５２ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−５−メ
トキシ−１−フェニルインドール−２−カルボキサミド
（化合物５２） 融点: 109-114 ℃ (ジイソプロピルエーテル) 元素分析: 1 酢酸付加物として C₃₀H₂₈N₄O₅S ・ CH₃COO
H 計算値 (%): C 62.33, H 5.23, N 9.09 実測値 (%): C 62.41, H 5.43, N 8.80 FABMS (m/z): 557 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.29 (1H, bs), 7.71 (1H, s), 7.
64-7.49 (3H, m), 7.40-7.36 (2H, m), 7.33 (3H, s),
7.14-7.13 (2H, m), 7.08-6.96 (3H, m), 6.84-6.77 (3
H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s),
3.72-3.64 (2H,m), 2.87 (2H, t, J = 6.9).Example 52 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -5-methoxy-1-phenylindole-2-carboxamide (Compound 52) Melting point: 109-114 ° C (diisopropyl ether) Elemental analysis: 1 As acetic acid adduct C ₃₀ H ₂₈ N ₄ O ₅ S CH ₃ COO
H calculated value (%): C 62.33, H 5.23, N 9.09 Found value (%): C 62.41, H 5.43, N 8.80 FABMS (m / z): 557 (M ⁺ +1) ¹ H NMR (CDCl ₃ ). δ 9.29 (1H, bs), 7.71 (1H, s), 7.
64-7.49 (3H, m), 7.40-7.36 (2H, m), 7.33 (3H, s),
7.14-7.13 (2H, m), 7.08-6.96 (3H, m), 6.84-6.77 (3
H, m), 3.90 (3H, s), 3.89 (3H, s), 3.87 (3H, s),
3.72-3.64 (2H, m), 2.87 (2H, t, J = 6.9).

【０１３０】実施例５３ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−５−ク
ロロ−１−フェニルインドール−２−カルボキサミド
（化合物５３） 融点: 113-116 ℃ (ジイソプロピルエーテル) 元素分析: 1 水和物として C₂₉H₂₅ClN₄O₄S ・ H₂O 計算値 (%): C 60.15, H 4.70, N 9.68 実測値 (%): C 60.04, H 4.73, N 9.52 FABMS (m/z): 561 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.46 (1H, bs), 7.72-7.71 (2H,
m), 7.56-7.51 (3H, m),7.35 (3H, m), 7.26 (1H, dd,
J = 2.0, 8.9), 7.08 (2H, d, J = 8.9), 6.84-6.75 (3
H, m), 3.88 (3H, s), 3.84 (3H, s), 3.70-3.63 (2H,
m), 2.85 (2H, t,J = 6.9).Example 53 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -5-chloro-1-phenylindole-2-carboxamide (Compound 53) Melting point: 113-116 ° C (diisopropyl ether) Elemental analysis: As monohydrate C ₂₉ H ₂₅ ClN ₄ O ₄ S H ₂ O Calculated value (%): C 60.15, H 4.70, N 9.68 Measured value (%) : C 60.04, H 4.73, N 9.52 FABMS (m / z): 561 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.46 (1H, bs), 7.72-7.71 (2H,
m), 7.56-7.51 (3H, m), 7.35 (3H, m), 7.26 (1H, dd,
J = 2.0, 8.9), 7.08 (2H, d, J = 8.9), 6.84-6.75 (3
H, m), 3.88 (3H, s), 3.84 (3H, s), 3.70-3.63 (2H,
m), 2.85 (2H, t, J = 6.9).

【０１３１】実施例５４ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−ベ
ンジルインドール−３−カルボキサミド（化合物５４） 融点: 110-113 ℃ (ジイソプロピルエーテル) 元素分析: 1 酢酸付加物として C₃₀H₂₈N₄O₄S ・ CH₃COO
H 計算値 (%): C 63.99, H 5.37, N 9.33 実測値 (%): C 63.82, H 5.51, N 9.14 FABMS (m/z): 541 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.71 (1H, bs), 8.24 (1H, d, J =
6.6), 7.97 (1H, s), 7.73 (1H, s), 7.42-7.31 (6H,
m), 7.22-7.18 (2H, m), 7.00 (1H, br), 6.81-6.76 (3
H, m), 5.39 (2H, s), 3.86 (3H, s), 3.85 (3H, s),
3.72-3.64 (2H, m), 2.87 (2H, t, J = 6.9).Example 54 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-benzylindole-3-carboxamide (Compound 54) Melting point: 110- 113 ° C (diisopropyl ether) Elemental analysis: 1 As acetic acid adduct C ₃₀ H ₂₈ N ₄ O ₄ S ・ CH ₃ COO
H calculated value (%): C 63.99, H 5.37, N 9.33 Measured value (%): C 63.82, H 5.51, N 9.14 FABMS (m / z): 541 (M ⁺ +1) ¹ H NMR (CDCl ₃ ). δ 9.71 (1H, bs), 8.24 (1H, d, J =
6.6), 7.97 (1H, s), 7.73 (1H, s), 7.42-7.31 (6H,
m), 7.22-7.18 (2H, m), 7.00 (1H, br), 6.81-6.76 (3
H, m), 5.39 (2H, s), 3.86 (3H, s), 3.85 (3H, s),
3.72-3.64 (2H, m), 2.87 (2H, t, J = 6.9).

【０１３２】実施例５５ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−フ
ェニルインドール−３−カルボキサミド（化合物５５） 融点: 172-177 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: 0.4 水和物・0.3ジイソプロピルエーテル付加
物として C₂₉H₂₆N₄O₄S・0.4H₂O ・0.3[(CH₃)₂CH]₂O 計算値 (%): C 65.54, H 5.54, N 9.93 実測値 (%): C 65.58, H 5.25, N 9.76 FABMS (m/z): 526 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.51 (1H, bs), 8.30 (1H, dd, J
= 1.3, 6.9), 8.16 (1H,s), 7.74 (1H, s), 7.61-7.32
(8H, m), 7.12 (1H, t, J = 5.8), 6.78-6.74 (3H, m),
3.82 (3H, s), 3.81 (3H, s), 3.69-3.62 (2H, m), 2.
84 (2H, t, J =6.8).Example 55 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-phenylindole-3-carboxamide (Compound 55) Melting point: 172- 177 ℃ (Ethyl acetate / diisopropyl ether) Elemental analysis: 0.4 hydrate ・ 0.3 Diisopropyl ether adduct as C ₂₉ H ₂₆ N ₄ O ₄ S ・ 0.4H ₂ O ・ 0.3 [(CH ₃ ) ₂ CH] ₂ O Calculation Value (%): C 65.54, H 5.54, N 9.93 Actual value (%): C 65.58, H 5.25, N 9.76 FABMS (m / z): 526 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.51 (1H, bs), 8.30 (1H, dd, J
= 1.3, 6.9), 8.16 (1H, s), 7.74 (1H, s), 7.61-7.32
(8H, m), 7.12 (1H, t, J = 5.8), 6.78-6.74 (3H, m),
3.82 (3H, s), 3.81 (3H, s), 3.69-3.62 (2H, m), 2.
84 (2H, t, J = 6.8).

【０１３３】実施例５６ Ｎ−｛４−［［２−（３，４−ジエトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−メチルフェニル）インドール−２−カルボキサミ
ド（化合物５６） ２−［Ｎ−［１−（３−メチルフェニル）インドール−
２−イルカルボニル］アミノ］チアゾール−４−カルボ
ン酸0.8 g (2.12 mmol) をDMF 20 mL に溶解し、３，４
−ジエトキシフェネチルアミン0.44 g (2.10 mmol)、１
−ヒドロキシベンズトリアゾール・１水和物 (HOBt・ H₂
O) 0.64 g (4.18 mmol) 、次いで１−（３−ジメチルア
ミノプロピル）−３−エチルカルボジイミド・塩酸塩
(WSC ・ HCl) 0.49 g (2.56 mmol) を加え、室温で50分
間攪拌した。反応液を濃縮後、残渣に塩化メチレンを加
え、2 N 塩酸、飽和重曹水、飽和食塩水で順に洗浄し、
無水硫酸マグネシウムで乾燥した。溶媒を減圧下留去
後、得られた粗結晶を酢酸エチル／イソプロピルエーテ
ル／エタノールの混合溶媒でトリチュレーションするこ
とにより、化合物５６, 0.87 g (72%)を白色結晶物とし
て得た。Example 56 N- {4-[[2- (3,4-diethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(3-Methylphenyl) indole-2-carboxamide (Compound 56) 2- [N- [1- (3-methylphenyl) indole-
2-ylcarbonyl] amino] thiazol-4-carboxylic acid 0.8 g (2.12 mmol) was dissolved in DMF 20 mL, and 3,4
-Diethoxyphenethylamine 0.44 g (2.10 mmol), 1
-Hydroxybenztriazole monohydrate (HOBt-H ₂
O) 0.64 g (4.18 mmol), then 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride
(WSC.HCl) 0.49 g (2.56 mmol) was added, and the mixture was stirred at room temperature for 50 minutes. After concentrating the reaction solution, methylene chloride was added to the residue, and the mixture was washed successively with 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine,
It was dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained crude crystals were triturated with a mixed solvent of ethyl acetate / isopropyl ether / ethanol to give Compound 56, 0.87 g (72%) as a white crystalline substance.

【０１３４】融点: 152-154 ℃ (酢酸エチル) 元素分析: C₃₂H₃₂N₄O₄S 計算値 (%): C 67.58, H 5.67, N 9.85 実測値 (%): C 67.63, H 5.63, N 9.84 FABMS (m/z): 569 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.44 (1H, bs), 7.92 (1H, d, J =
7.9), 7.70 (1H, s), 7.45 (1H, s), 7.42 (1H, d, J
= 8.4), 7.32 (1H, m), 7.25 (2H, m), 7.19 (3H, m),
7.04 (1H, bt, J = 5.9), 6.83 (1H, d, J = 8.9), 6.7
5 (2H, m), 4.08(2H, q, J = 6.9), 4.05 (2H, q, J =
6.9), 3.67 (1H, d, J = 6.9), 3.64 (1H, d, J = 6.
9), 2.83 (2H, t, J = 6.7), 2.43 (3H, s), 1.44 (3H,
t, J = 6.9), 1.40 (3H, t, J = 6.9). 以下の実施例５７〜６１では、２−［Ｎ−［１−（３−
メチルフェニル）インドール−２−イルカルボニル］ア
ミノ］チアゾール−４−カルボン酸に代えて対応するカ
ルボン酸を用い、実施例５６とほぼ同様の方法により目
的化合物を得た。Melting point: 152-154 ° C. (ethyl acetate) Elemental analysis: C ₃₂ H ₃₂ N ₄ O ₄ S Calculated value (%): C 67.58, H 5.67, N 9.85 Found value (%): C 67.63, H 5.63 , N 9.84 FABMS (m / z): 569 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.44 (1H, bs), 7.92 (1H, d, J =
7.9), 7.70 (1H, s), 7.45 (1H, s), 7.42 (1H, d, J
= 8.4), 7.32 (1H, m), 7.25 (2H, m), 7.19 (3H, m),
7.04 (1H, bt, J = 5.9), 6.83 (1H, d, J = 8.9), 6.7
5 (2H, m), 4.08 (2H, q, J = 6.9), 4.05 (2H, q, J =
6.9), 3.67 (1H, d, J = 6.9), 3.64 (1H, d, J = 6.
9), 2.83 (2H, t, J = 6.7), 2.43 (3H, s), 1.44 (3H,
t, J = 6.9), 1.40 (3H, t, J = 6.9). In Examples 57 to 61 below, 2- [N- [1- (3-
The target compound was obtained in substantially the same manner as in Example 56 by using the corresponding carboxylic acid instead of methylphenyl) indol-2-ylcarbonyl] amino] thiazol-4-carboxylic acid.

【０１３５】実施例５７ Ｎ−｛４−［［２−（４−エトキシ−３−メトキシフェ
ニル）エチルアミノ］カルボニル］−２−チアゾリル｝
−１−（３−メチルフェニル）インドール−２−カルボ
キサミド（化合物５７） 融点: 154-155 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: C₃₁H₃₀N₄O₄S 計算値 (%): C 67.13, H 5.45, N 10.10 実測値 (%): C 67.16, H 5.62, N 9.97 FABMS (m/z): 555 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.60 (1H, bs), 7.74 (1H, d, J =
7.9), 7.70 (1H, s), 7.46 (1H, s), 7.41 (1H, m),
7.31 (1H, m), 7.26 (2H, m), 7.18 (3H, m), 7.04 (1
H, bt, J = 5.9), 6.75 (3H, m), 4.06 (2H, q, J = 6.
9), 3.82 (3H, s),3.66 (1H, d, J = 6.9), 3.62 (1H,
d, J = 6.9), 2.82 (2H, t, J = 6.9), 2.42 (3H, s),
1.44 (3H, t, J = 6.9).Example 57 N- {4-[[2- (4-ethoxy-3-methoxyphenyl) ethylamino] carbonyl] -2-thiazolyl}
-1- (3-Methylphenyl) indole-2-carboxamide (Compound 57) Melting point: 154-155 ° C (ethyl acetate / diisopropyl ether) Elemental analysis: C ₃₁ H ₃₀ N ₄ O ₄ S Calculated value (%): C 67.13, H 5.45, N 10.10 Found (%): C 67.16, H 5.62, N 9.97 FABMS (m / z): 555 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.60 (1H, bs), 7.74 (1H, d, J =
7.9), 7.70 (1H, s), 7.46 (1H, s), 7.41 (1H, m),
7.31 (1H, m), 7.26 (2H, m), 7.18 (3H, m), 7.04 (1
H, bt, J = 5.9), 6.75 (3H, m), 4.06 (2H, q, J = 6.
9), 3.82 (3H, s), 3.66 (1H, d, J = 6.9), 3.62 (1H,
d, J = 6.9), 2.82 (2H, t, J = 6.9), 2.42 (3H, s),
1.44 (3H, t, J = 6.9).

【０１３６】実施例５８ Ｎ−｛４−［［２−（４−エトキシ−３，５−ジメトキ
シフェニル）エチルアミノ］カルボニル］−２−チアゾ
リル｝−１−（３−メチルフェニル）インドール−２−
カルボキサミド（化合物５８） 融点: 149-150 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: C₃₂H₃₂N₄O₄S 計算値 (%): C 65.74, H 5.52, N 9.58 実測値 (%): C 65.75, H 5.63, N 9.55 FABMS (m/z): 585 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.27 (1H, bs), 7.75 (1H, d, J =
7.9), 7.72 (1H, s), 7.46 (1H, d, J = 7.4), 7.41
(1H, s), 7.31 (2H, d, J = 8.4), 7.20 (4H, m),6.45
(2H, s), 4.06 (2H, q, J = 6.9), 3.82 (6H, s), 3.69
(1H, d, J = 6.9), 3.63 (1H, d, J = 6.9), 2.85 (2
H, t, J = 6.9), 2.43 (3H, s), 1.37 (3H,t, J = 6.
9).Example 58 N- {4-[[2- (4-ethoxy-3,5-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (3-methylphenyl) indole-2-
Carboxamide (Compound 58) Melting point: 149-150 ° C (ethyl acetate / diisopropyl ether) Elemental analysis: C ₃₂ H ₃₂ N ₄ O ₄ S Calculated value (%): C 65.74, H 5.52, N 9.58 Measured value (%): C 65.75, H 5.63, N 9.55 FABMS (m / z): 585 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.27 (1H, bs), 7.75 (1H, d, J =
7.9), 7.72 (1H, s), 7.46 (1H, d, J = 7.4), 7.41
(1H, s), 7.31 (2H, d, J = 8.4), 7.20 (4H, m), 6.45
(2H, s), 4.06 (2H, q, J = 6.9), 3.82 (6H, s), 3.69
(1H, d, J = 6.9), 3.63 (1H, d, J = 6.9), 2.85 (2
H, t, J = 6.9), 2.43 (3H, s), 1.37 (3H, t, J = 6.
9).

【０１３７】実施例５９ Ｎ−｛４−［［２−（３，４−ジエトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（３−クロロフェニル）インドール−２−カルボキサミ
ド（化合物５９） 融点: 199-201 ℃ (酢酸エチル) 元素分析: C₃₁H₂₉ClN₄O₄S 計算値 (%): C 63.20, H 4.96, N 9.51 実測値 (%): C 63.04, H 5.05, N 9.08 FABMS (m/z): 589 (M ⁺ +1), 591 (M ⁺ +3)¹ H NMR (DMSO-d₆) δ 12.88 (1H, bs), 7.83 (1H, s),
7.77 (3H, m), 7.56 (3H, m), 7.36 (2H, m), 7.23 (1
H, t, J = 7.3), 7.12 (1H, d, J = 8.3), 6.84(2H,
m), 6.73 (1H, d, J = 8.3), 3.98 (4H, q, J = 6.9),
3.55 (1H, d, J =6.3), 3.51 (1H, d, J = 6.3), 2.77
(2H, t, J = 6.6), 1.32 (3H, t, J = 6.9), 1.31 (3H,
t, J = 6.9).Example 59 N- {4-[[2- (3,4-diethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(3-Chlorophenyl) indole-2-carboxamide (Compound 59) Melting point: 199-201 ℃ (Ethyl acetate) Elemental analysis: C ₃₁ H ₂₉ ClN ₄ O ₄ S Calculated value (%): C 63.20, H 4.96, N 9.51 Found (%): C 63.04, H 5.05, N 9.08 FABMS (m / z): 589 (M ⁺ +1), 591 (M ⁺ +3) ¹ H NMR (DMSO-d ₆ ) δ 12.88 (1H, bs), 7.83 (1H, s),
7.77 (3H, m), 7.56 (3H, m), 7.36 (2H, m), 7.23 (1
H, t, J = 7.3), 7.12 (1H, d, J = 8.3), 6.84 (2H,
m), 6.73 (1H, d, J = 8.3), 3.98 (4H, q, J = 6.9),
3.55 (1H, d, J = 6.3), 3.51 (1H, d, J = 6.3), 2.77
(2H, t, J = 6.6), 1.32 (3H, t, J = 6.9), 1.31 (3H,
t, J = 6.9).

【０１３８】実施例６０ Ｎ−｛４−［［２−（４−エトキシ−３−メトキシフェ
ニル）エチルアミノ］カルボニル］−２−チアゾリル｝
−１−（３−クロロフェニル）インドール−２−カルボ
キサミド（化合物６０） 融点: 181-183 ℃ (エタノール) 元素分析: C₃₀H₂₇ClN₄O₄S 計算値 (%): C 62.66, H 4.73, N 9.74 実測値 (%): C 62.76, H 4.81, N 9.68 FABMS (m/z): 575 (M ⁺ +1), 577 (M ⁺ +3)¹ H NMR (CDCl₃ + DMSO-d₆) δ 11.82 (1H, bs), 7.76
(1H, d, J = 7.9), 7.70(1H, s), 7.68 (1H, s), 7.45
(2H, m), 7.2-7.4 (5H, m), 7.14 (1H, d, J =8.4), 6.
84 (1H, d, J = 8.4), 6.76 (2H, m), 4.08 (2H, q, J
= 6.9), 3.84 (3H, s), 3.70 (1H, d, J = 6.9), 3.66
(1H, d, J = 6.9), 2.86 (2H, t, J = 6.9), 1.45 (3H,
t, J = 6.9).Example 60 N- {4-[[2- (4-ethoxy-3-methoxyphenyl) ethylamino] carbonyl] -2-thiazolyl}
-1- (3-chlorophenyl) indole-2-carboxamide (Compound 60) mp: 181-183 ° C. (ethanol) Elemental _{analysis: C 30 H 27 ClN 4 O} 4 S Calculated (%): C 62.66, H 4.73, N 9.74 Found (%): C 62.76, H 4.81, N 9.68 FABMS (m / z): 575 (M ⁺ +1), 577 (M ⁺ +3) ¹ H NMR (CDCl ₃ + DMSO-d ₆ ). δ 11.82 (1H, bs), 7.76
(1H, d, J = 7.9), 7.70 (1H, s), 7.68 (1H, s), 7.45
(2H, m), 7.2-7.4 (5H, m), 7.14 (1H, d, J = 8.4), 6.
84 (1H, d, J = 8.4), 6.76 (2H, m), 4.08 (2H, q, J
= 6.9), 3.84 (3H, s), 3.70 (1H, d, J = 6.9), 3.66
(1H, d, J = 6.9), 2.86 (2H, t, J = 6.9), 1.45 (3H,
t, J = 6.9).

【０１３９】実施例６１ Ｎ−｛４−［［２−（４−エトキシ−３，５−ジメトキ
シフェニル）エチルアミノ］カルボニル］−２−チアゾ
リル｝−１−（３−クロロフェニル）インドール−２−
カルボキサミド（化合物６１） 融点: 150-151 ℃ (酢酸エチル／ジイソプロピルエーテ
ル／エタノール) 元素分析: 0.5 水和物として C₃₁H₂₉ClN₄O₅S ・0.5H₂O 計算値 (%): C 60.63, H 4.92, N 9.12 実測値 (%): C 60.70, H 4.83, N 9.02 FABMS (m/z): 605 (M ⁺ +1), 607 (M ⁺ +3)¹ H NMR (CDCl₃)δ 9.73 (1H, bs), 7.74 (1H, d, J =
7.3), 7.73 (1H, s), 7.46 (3H, m), 7.38 (1H, m), 7.
35 (1H, m), 7.25 (2H, m), 7.16 (1H, d, J = 8.3),
7.13 (1H, bt, J = 5.9), 6.43 (2H, s), 4.05 (2H, q,
J = 6.9), 3.81 (6H, s), 3.68 (1H, d, J = 6.9), 3.
64 (1H, d, J = 6.9), 2.83 (2H, t, J = 6.9), 2.43
(3H, s), 1.36 (3H, t, J = 6.9).Example 61 N- {4-[[2- (4-ethoxy-3,5-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (3-chlorophenyl) indole-2-
Carboxamide (Compound 61) Melting point: 150-151 ° C (Ethyl acetate / diisopropyl ether / Ethanol) Elemental analysis: C ₃₁ H ₂₉ ClN ₄ O ₅ S ・ 0.5H ₂ O calculated as hemihydrate (%): C 60.63 , H 4.92, N 9.12 Found (%): C 60.70, H 4.83, N 9.02 FABMS (m / z): 605 (M ⁺ +1), 607 (M ⁺ +3) ¹ H NMR (CDCl ₃ ) δ 9.73 (1H, bs), 7.74 (1H, d, J =
7.3), 7.73 (1H, s), 7.46 (3H, m), 7.38 (1H, m), 7.
35 (1H, m), 7.25 (2H, m), 7.16 (1H, d, J = 8.3),
7.13 (1H, bt, J = 5.9), 6.43 (2H, s), 4.05 (2H, q,
J = 6.9), 3.81 (6H, s), 3.68 (1H, d, J = 6.9), 3.
64 (1H, d, J = 6.9), 2.83 (2H, t, J = 6.9), 2.43
(3H, s), 1.36 (3H, t, J = 6.9).

【０１４０】実施例６２ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−クロロ−４−ニトロフェニル）インドール−２−
カルボキサミド（化合物６４） （１）参考例４で得られる１−（２−クロロ−４−ニト
ロフェニル）インドール−２−カルボン酸3.0 g (9.47
mmol) を塩化メチレン75 mL に溶解し、トリエチルアミ
ン3.17 mL (22.75 mmol)、ヨウ化２−クロロ−１−メチ
ルピリジニウム2.9 g (11.35 mmol)、次いでペンタフル
オロフェノール1.9 g (10.32 mmol)を加え、室温で2 時
間攪拌した。反応混合物を2 N 塩酸、飽和重曹水、飽和
食塩水で順に洗浄し、溶媒を留去した。残渣をピリジン
150 mLに溶解し、２−アミノチアゾール−４−カルボン
酸エチル2.22 g (12.89 mmol) を加え、14時間加熱還流
した。反応液を濃縮後、残渣に塩化メチレンを加え、2
N 塩酸、飽和重曹水、飽和食塩水で順に洗浄した。溶媒
を留去後、残渣をシリカゲルカラムクロマトグラフィー
（ヘキサン：酢酸エチル＝２：１）で精製し、得られた
粗結晶をイソプロピルエーテルでトリチュレーションす
ることにより、Ｎ−（４−エトキシカルボニル−２−チ
アゾリル）−１−（２−クロロ−４−ニトロフェニル）
インドール−２−カルボキサミド3.26 g (75%)を淡黄色
結晶物として得た。¹ H-NMR (CDCl₃) δ 10.57 (1H, bs), 8.49 (1H, d, J
= 2.5), 8.33 (1H, dd,J = 2.5, 8.4), 7.81 (1H, s),
7.75 (1H, d, J = 7.4), 7.70 (1H, d, J = 8.4), 7.2-
7.4 (3H, m), 6.92 (1H, d, J = 8.9), 4.22 (2H, m),
1.28 (3H, t, J= 6.9).Example 62 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-chloro-4-nitrophenyl) indole-2-
Carboxamide (Compound 64) (1) 3.0 g (9.47) of 1- (2-chloro-4-nitrophenyl) indole-2-carboxylic acid obtained in Reference Example 4
(3 mmol) in 75 mL of methylene chloride, 3.17 mL (22.75 mmol) of triethylamine, 2.9 g (11.35 mmol) of 2-chloro-1-methylpyridinium iodide, and then 1.9 g (10.32 mmol) of pentafluorophenol were added at room temperature. And stirred for 2 hours. The reaction mixture was washed successively with 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and the solvent was evaporated. Pyridine residue
It was dissolved in 150 mL, ethyl 2-aminothiazole-4-carboxylate (2.22 g, 12.89 mmol) was added, and the mixture was heated under reflux for 14 hours. After concentrating the reaction mixture, add methylene chloride to the residue and
The mixture was washed successively with N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1), and the obtained crude crystals were triturated with isopropyl ether to give N- (4-ethoxycarbonyl-). 2-thiazolyl) -1- (2-chloro-4-nitrophenyl)
3.26 g (75%) of indole-2-carboxamide was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ 10.57 (1H, bs), 8.49 (1H, d, J
= 2.5), 8.33 (1H, dd, J = 2.5, 8.4), 7.81 (1H, s),
7.75 (1H, d, J = 7.4), 7.70 (1H, d, J = 8.4), 7.2-
7.4 (3H, m), 6.92 (1H, d, J = 8.9), 4.22 (2H, m),
1.28 (3H, t, J = 6.9).

【０１４１】（２）（１）で得られた化合物3.0 g (6.3
7 mmol) をメタノール90 mL に懸濁し、水酸化ナトリウ
ム1.27 g (31.75 mmol) の水15 mL 溶液を加え、80℃で
1 時間攪拌した。反応液を濃縮後、残渣を氷水に溶解
し、これに4 N 塩酸を加え、pHを2 とした。析出した結
晶を濾取し、水洗、乾燥することにより、２−｛Ｎ−
［１−（２−クロロ−４−ニトロフェニル）インドール
−２−イルカルボニル］アミノ｝チアゾール−４−カル
ボン酸2.98 g (定量的) を淡黄色結晶物として得た。(2) 3.0 g (6.3%) of the compound obtained in (1)
(7 mmol) in 90 mL of methanol, add a solution of 1.27 g (31.75 mmol) of sodium hydroxide in 15 mL of water, and add at 80 ° C.
Stir for 1 hour. After the reaction solution was concentrated, the residue was dissolved in ice water, and 4N hydrochloric acid was added to adjust the pH to 2. The precipitated crystals are collected by filtration, washed with water and dried to give 2- {N-
2.98 g (quantitative) of [1- (2-chloro-4-nitrophenyl) indol-2-ylcarbonyl] amino} thiazol-4-carboxylic acid was obtained as pale yellow crystals.

【０１４２】（３）（２）で得られた化合物2.5 g (5.6
5 mmol) をDMF 50 mL に溶解し、３，４−ジメトキシフ
ェネチルアミン0.95 mL (5.63 mmol) 、 HOBt ・ H₂O 1.
73 g (11.30 mmol) 、次いでWSC ・ HCl 1.08 g (5.63 m
mol)を加え、室温で3.5 時間攪拌した。反応液を濃縮
後、残渣に塩化メチレンを加え、2 N 塩酸、飽和重曹
水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムで
乾燥した。溶媒を減圧下留去後、残渣をシリカゲルカラ
ムクロマトグラフィー（ヘキサン：酢酸エチル＝３：
２）で精製し、得られた粗結晶をイソプロパノールでト
リチュレーションすることにより、化合物６４, 2.48 g
(73%)を淡黄色結晶物として得た。(3) 2.5 g (5.6%) of the compound obtained in (2)
The 5 mmol) were dissolved in DMF 50 mL, 3,4-dimethoxy-phenethylamine 0.95 mL (5.63 mmol), HOBt · H 2 O 1.
73 g (11.30 mmol), then WSC HCl 1.08 g (5.63 m
mol) was added, and the mixture was stirred at room temperature for 3.5 hours. After the reaction solution was concentrated, methylene chloride was added to the residue, washed with 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 3:
The crude crystal obtained in 2) was triturated with isopropanol to give compound 64, 2.48 g.
(73%) was obtained as pale yellow crystals.

【０１４３】融点: 189-190 ℃ (イソプロパノール) 元素分析: C₂₉H₂₄ClN₅O₆S 計算値 (%): C 57.47, H 3.99, N 11.56 実測値 (%): C 57.34, H 4.00, N 11.56 FABMS (m/z): 606 (M ⁺ +1), 608 (M ⁺ +3)¹ H NMR (CDCl₃) δ 12.99 (1H, bs), 8.57 (1H, d, J
= 2.5), 8.38 (1H, dd,J = 2.5, 8.4), 8.00 (1H, s),
7.88 (2H, m), 7.80 (1H, bt, J = 5.4), 7.77(1H, s),
7.31 (2H, m), 6.98 (1H, d, J = 8.4), 6.86 (2H,
m), 6.75 (1H, d,J = 8.4), 3.73 (6H, s), 3.56 (1H,
d, J = 6.9), 3.54 (1H, d, J = 6.9), 2.78 (2H, t, J
= 6.9).Melting point: 189-190 ° C. (isopropanol) Elemental analysis: C ₂₉ H ₂₄ ClN ₅ O ₆ S Calculated value (%): C 57.47, H 3.99, N 11.56 Found value (%): C 57.34, H 4.00, N 11.56 FABMS (m / z): 606 (M ⁺ +1), 608 (M ⁺ +3) ¹ H NMR (CDCl ₃ ) δ 12.99 (1H, bs), 8.57 (1H, d, J
= 2.5), 8.38 (1H, dd, J = 2.5, 8.4), 8.00 (1H, s),
7.88 (2H, m), 7.80 (1H, bt, J = 5.4), 7.77 (1H, s),
7.31 (2H, m), 6.98 (1H, d, J = 8.4), 6.86 (2H,
m), 6.75 (1H, d, J = 8.4), 3.73 (6H, s), 3.56 (1H,
d, J = 6.9), 3.54 (1H, d, J = 6.9), 2.78 (2H, t, J
= 6.9).

【０１４４】実施例６３ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−クロロ−４−ジメチルアミノフェニル）インドー
ル−２−カルボキサミド・塩酸塩（化合物６５） （１）実施例６２で得られた化合物６４, 1.74 g (2.87
mmol)をメタノール180mLおよび水18 mL の混合溶媒に
懸濁し、還元鉄1.6 g (28.65 mmol)および塩化第二鉄50
mg (0.31 mmol) を加え、6 時間加熱還流した。還元鉄
0.8 g (14.32 mmol)および塩化第二鉄50 mg (0.31 mmo
l) を追加し、さらに2 時間加熱還流した。不溶物をセ
ライトを通して濾去し、濾液を減圧下濃縮後、残渣に水
を加え、10 N水酸化ナトリウムでpHを12とした。塩化メ
チレンで抽出後、有機層を飽和食塩水で洗浄し、無水硫
酸マグネシウムで乾燥した。溶媒を減圧下留去後、残渣
をシリカゲルカラムクロマトグラフィー（ヘキサン：酢
酸エチル＝１：２）で精製することにより、Ｎ−｛４−
［［２−（３，４−ジメトキシフェニル）エチルアミ
ノ］カルボニル］−２−チアゾリル｝−１−（４−アミ
ノ−２−クロロフェニル）インドール−２−カルボキサ
ミド1.44 g (87%)を淡褐色油状物として得た。¹ H NMR (CDCl₃) δ 10.21 (1H, bs), 7.70 (2H, m),
7.49 (1H, s), 7.30 (1H,m), 7.17 (2H, m), 7.10 (1H,
bt, J = 5.9), 7.01 (1H, d, J = 7.9), 6.78 (1H, d,
J = 2.6), 6.72 (3H, m), 6.63 (1H, dd, J = 2.6, 8.
6), 3.80 (3H, s), 3.77 (3H, s), 3.61 (1H, d, J =
6.6), 3.59 (1H, d, J = 6.6), 2.77 (2H,t, J = 6.9).Example 63 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-chloro-4-dimethylaminophenyl) indole-2-carboxamide hydrochloride (Compound 65) (1) Compound 64 obtained in Example 62, 1.74 g (2.87)
suspension) in a mixed solvent of 180 mL of methanol and 18 mL of water, and 1.6 g (28.65 mmol) of reduced iron and 50 parts of ferric chloride.
mg (0.31 mmol) was added, and the mixture was heated under reflux for 6 hours. Reduced iron
0.8 g (14.32 mmol) and ferric chloride 50 mg (0.31 mmo
l) was added, and the mixture was heated under reflux for 2 hours. The insoluble material was filtered off through Celite, the filtrate was concentrated under reduced pressure, water was added to the residue, and the pH was adjusted to 12 with 10 N sodium hydroxide. After extraction with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 2) to give N- {4-.
[[2- (3,4-Dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (4-amino-2-chlorophenyl) indole-2-carboxamide 1.44 g (87%) as a light brown oil. Got as. ¹ H NMR (CDCl ₃ ) δ 10.21 (1H, bs), 7.70 (2H, m),
7.49 (1H, s), 7.30 (1H, m), 7.17 (2H, m), 7.10 (1H,
bt, J = 5.9), 7.01 (1H, d, J = 7.9), 6.78 (1H, d,
J = 2.6), 6.72 (3H, m), 6.63 (1H, dd, J = 2.6, 8.
6), 3.80 (3H, s), 3.77 (3H, s), 3.61 (1H, d, J =
6.6), 3.59 (1H, d, J = 6.6), 2.77 (2H, t, J = 6.9).

【０１４５】（２）（１）で得られた化合物1.2 g (2.0
8 mmol) をメタノール60 mL に懸濁し、水素化シアノホ
ウ素ナトリウム790 mg (12.57 mmol) および触媒量のブ
ロモクレゾールグリーンを加えた。反応液の色が黄色に
なるまで7.34 M塩酸／エタノールを加え、これに、氷冷
下、37% ホルマリン1.5 mL (15.91 mmolのホルムアルデ
ヒド含有) を滴下した。7.34 M塩酸／エタノールを適宜
添加することにより反応液の色を黄色に保ちながら、室
温で13時間攪拌した。溶媒を減圧下留去後、飽和重曹水
／塩化メチレンで分配し、有機層を飽和食塩水で洗浄
し、無水硫酸マグネシウムで乾燥した。溶媒を留去後、
残渣を酢酸エチルに溶解し、2.25 M塩酸／酢酸エチル1
mLを加えた。析出した白色結晶を濾取することにより、
化合物６５,0.62 g (46%)を塩酸塩・0.5 水和物として
得た。(2) 1.2 g (2.0%) of the compound obtained in (1)
8 mmol) was suspended in 60 mL of methanol, and 790 mg (12.57 mmol) of sodium cyanoborohydride and a catalytic amount of bromocresol green were added. 7.34 M hydrochloric acid / ethanol was added until the color of the reaction solution became yellow, and thereto, 1.5 mL of 37% formalin (containing 15.91 mmol of formaldehyde) was added dropwise under ice cooling. The mixture was stirred at room temperature for 13 hours while keeping the color of the reaction solution yellow by appropriately adding 7.34 M hydrochloric acid / ethanol. After evaporating the solvent under reduced pressure, the mixture was partitioned with saturated aqueous sodium hydrogen carbonate / methylene chloride, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent,
Dissolve the residue in ethyl acetate and add 2.25 M hydrochloric acid / ethyl acetate 1
mL was added. By collecting the precipitated white crystals by filtration,
The compound 65, 0.62 g (46%) was obtained as a hydrochloride-hemihydrate.

【０１４６】融点: 128-131 ℃ (酢酸エチル) 元素分析: 1 塩酸塩・0.5水和物として C₃₁H₃₀ClN₅O₄S
・ HCl ・0.5H₂O 計算値 (%): C 57.32, H 4.97, N 10.78 実測値 (%): C 57.00, H 4.98, N 10.51 FABMS (m/z): 604 (M ⁺ +1), 606 (M ⁺ +3)¹ H NMR (CDCl₃) δ 7.77 (2H, m), 7.59 (1H, s), 7.4
8 (1H, bs), 7.45 (2H,m), 7.31 (1H, m), 7.25 (2H,
m), 6.96 (1H, d, J = 7.9), 6.78 (3H, m), 3.85 (3H,
s), 3.83 (3H, s), 3.68 (1H, d, J = 6.6), 3.64 (1
H, d, J = 6.6), 3.18 (6H, s), 2.86 (2H, t, J = 6.
9). 以下の実施例６４、６６および６９では、１−（２−ク
ロロ−４−ニトロフェニル）インドール−２−カルボン
酸に代えて対応するカルボン酸を用い、実施例６２とほ
ぼ同様の方法により目的化合物を得た。Melting point: 128-131 ° C. (Ethyl acetate) Elemental analysis: C ₃₁ H ₃₀ ClN ₅ O ₄ S as monohydrochloride hemihydrate
・ HCl ・ 0.5H ₂ O Calculated value (%): C 57.32, H 4.97, N 10.78 Measured value (%): C 57.00, H 4.98, N 10.51 FABMS (m / z): 604 (M ⁺ +1), 606 (M ⁺ +3) ¹ H NMR (CDCl ₃ ) δ 7.77 (2H, m), 7.59 (1H, s), 7.4
8 (1H, bs), 7.45 (2H, m), 7.31 (1H, m), 7.25 (2H,
m), 6.96 (1H, d, J = 7.9), 6.78 (3H, m), 3.85 (3H,
s), 3.83 (3H, s), 3.68 (1H, d, J = 6.6), 3.64 (1
H, d, J = 6.6), 3.18 (6H, s), 2.86 (2H, t, J = 6.
9). In Examples 64, 66 and 69 below, a method similar to that in Example 62 was used, except that 1- (2-chloro-4-nitrophenyl) indole-2-carboxylic acid was replaced with the corresponding carboxylic acid. The target compound was obtained by.

【０１４７】実施例６４ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−メチル−４−ニトロフェニル）インドール−２−
カルボキサミド（化合物６２） 融点: 225-228 ℃ (エタノール) 元素分析: C₃₀H₂₇N₅O₆S 計算値 (%): C 61.53, H 4.65, N 11.96 実測値 (%): C 61.57, H 4.48, N 11.89 FABMS (m/z): 586 (M ⁺ +1)¹ H NMR (DMSO-d₆) δ 12.95 (1H, bs), 8.38 (1H, d,
J = 2.3), 8.22 (1H, dd, J = 2.3, 8.6), 7.96 (1H,
s), 7.83 (2H, m), 7.76 (1H, s), 7.57 (1H, d,J = 8.
9), 7.30 (2H, m), 6.86 (3H, m), 6.75 (1H, dd, J =
2.0, 8.2), 3.74(3H, s), 3.73 (3H, s), 3.56 (1H, d,
J = 2.0), 3.52 (1H, d, J = 2.0), 2.78 (2H, t, J =
6.9), 1.99 (3H, s). 以下の実施例６５、６８および７１では、化合物６４に
代えて対応するニトロ体を用い、実施例６３とほぼ同様
の方法により目的化合物を得た。Example 64 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Methyl-4-nitrophenyl) indole-2-
Carboxamide (Compound 62) Melting point: 225-228 ℃ (Ethanol) Elemental analysis: C ₃₀ H ₂₇ N ₅ O ₆ S Calculated value (%): C 61.53, H 4.65, N 11.96 Measured value (%): C 61.57, H 4.48, N 11.89 FABMS (m / z): 586 (M ⁺ +1) ¹ H NMR (DMSO-d ₆ ) δ 12.95 (1H, bs), 8.38 (1H, d,
J = 2.3), 8.22 (1H, dd, J = 2.3, 8.6), 7.96 (1H,
s), 7.83 (2H, m), 7.76 (1H, s), 7.57 (1H, d, J = 8.
9), 7.30 (2H, m), 6.86 (3H, m), 6.75 (1H, dd, J =
2.0, 8.2), 3.74 (3H, s), 3.73 (3H, s), 3.56 (1H, d,
J = 2.0), 3.52 (1H, d, J = 2.0), 2.78 (2H, t, J =
6.9), 1.99 (3H, s). In Examples 65, 68 and 71 below, the corresponding nitro compound was used in place of compound 64 to obtain the target compound by a method similar to that in Example 63.

【０１４８】実施例６５ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−ジメチルアミノ−２−メチルフェニル）インドー
ル−２−カルボキサミド・塩酸塩（化合物６３） 融点: 124-128 ℃ (塩酸塩: 酢酸エチル) 元素分析: 1 塩酸塩・1水和物として C₃₂H₃₃N₅O₄S ・ HC
l ・ H₂O 計算値 (%): C 60.23, H 5.69, N 10.97 実測値 (%): C 59.94, H 5.95, N 10.92 FABMS (m/z): 584 (M ⁺ +1)¹ H NMR (遊離塩基: CDCl₃) δ 9.10 (1H, bs), 7.75
(1H, d, J = 7.6), 7.70(1H, s), 7.49 (1H, d, J = 0.
7), 7.24 (3H, m), 7.09 (1H, bt, J = 5.9), 6.97 (1
H, d, J = 7.9), 6.83 (1H, d, J = 8.6), 6.75 (2H,
m), 6.69 (2H, m),3.87 (3H, s), 3.84 (3H, s), 3.66
(1H, dd, J = 2.0, 6.9), 3.61 (1H, dd, J= 2.0, 6.
9), 3.02 (6H, s), 2.84 (2H, t, J = 6.9), 1.90 (3H,
s).Example 65 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Dimethylamino-2-methylphenyl) indole-2-carboxamide / hydrochloride (Compound 63) Melting point: 124-128 ° C (hydrochloric acid: ethyl acetate) Elemental analysis: 1 Hydrochloride / monohydrate C ₃₂ H ₃₃ N ₅ O ₄ S ・ HC
lH ₂ O calculated (%): C 60.23, H 5.69, N 10.97 Found (%): C 59.94, H 5.95, N 10.92 FABMS (m / z): 584 (M ⁺ +1) ¹ H NMR (Free base: CDCl ₃ ) δ 9.10 (1H, bs), 7.75
(1H, d, J = 7.6), 7.70 (1H, s), 7.49 (1H, d, J = 0.
7), 7.24 (3H, m), 7.09 (1H, bt, J = 5.9), 6.97 (1
H, d, J = 7.9), 6.83 (1H, d, J = 8.6), 6.75 (2H,
m), 6.69 (2H, m), 3.87 (3H, s), 3.84 (3H, s), 3.66
(1H, dd, J = 2.0, 6.9), 3.61 (1H, dd, J = 2.0, 6.
9), 3.02 (6H, s), 2.84 (2H, t, J = 6.9), 1.90 (3H,
s).

【０１４９】実施例６６ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−ニトロ−２−トリフルオロメチルフェニル）イン
ドール−２−カルボキサミド（化合物６７） 融点: 202-204 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: C₃₀H₂₄F₃N₅O₆S 計算値 (%): C 56.34, H 3.78, N 10.95 実測値 (%): C 56.23, H 3.66, N 10.81 FABMS (m/z): 640 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.85 (1H, bs), 8.75 (1H, d, J =
2.3), 8.61 (1H, dd, J= 2.6, 8.6), 7.80 (1H, d, J
= 7.3), 7.70 (1H, s), 7.67 (1H, m), 7.58 (1H, s),
7.34 (2H, m), 7.02 (1H, bt, J = 5.9), 6.85 (1H, d,
J = 8.3), 6.80(2H, bs), 6.75 (1H, bs), 3.87 (3H,
s), 3.83 (3H, s), 3.68 (2H, m), 2.86(2H, t, J = 6.
9). 以下の実施例６７および７０では、Ｎ−｛４−［［２−
（３，４−ジメトキシフェニル）エチルアミノ］カルボ
ニル］−２−チアゾリル｝−１−（４−アミノ−２−ク
ロロフェニル）インドール−２−カルボキサミドに代え
て対応するアミノ体を用い、実施例４９に記載した別法
とほぼ同様の方法により目的化合物を得た。Example 66 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Nitro-2-trifluoromethylphenyl) indole-2-carboxamide (Compound 67) Melting point: 202-204 ° C (ethyl acetate / diisopropyl ether) Elemental analysis: C ₃₀ H ₂₄ F ₃ N ₅ O ₆ S Calculated value (%): C 56.34, H 3.78, N 10.95 Found (%): C 56.23, H 3.66, N 10.81 FABMS (m / z): 640 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.85 ( 1H, bs), 8.75 (1H, d, J =
2.3), 8.61 (1H, dd, J = 2.6, 8.6), 7.80 (1H, d, J
= 7.3), 7.70 (1H, s), 7.67 (1H, m), 7.58 (1H, s),
7.34 (2H, m), 7.02 (1H, bt, J = 5.9), 6.85 (1H, d,
J = 8.3), 6.80 (2H, bs), 6.75 (1H, bs), 3.87 (3H,
s), 3.83 (3H, s), 3.68 (2H, m), 2.86 (2H, t, J = 6.
9). In Examples 67 and 70 below, N- {4-[[2-
(3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (4-amino-2-chlorophenyl) indole-2-carboxamide was used in place of the corresponding amino form, and described in Example 49. The target compound was obtained by a method substantially similar to the above-mentioned alternative method.

【０１５０】実施例６７ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−トリフルオロメチルフェニル）インドール−２−
カルボキサミド（化合物６６） 融点: 205-207 ℃ (ジイソプロピルエーテル) 元素分析: C₃₀H₂₅F₃N₄O₄S 計算値 (%): C 60.60, H 4.24, N 9.42 実測値 (%): C 60.60, H 4.20, N 9.34 FABMS (m/z): 595 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.75 (1H, bs), 7.86 (1H, m), 7.
75 (2H, m), 7.68 (1H,s), 7.67 (1H, m), 7.47 (2H,
m), 7.27 (2H, m), 7.06 (1H, bt, J = 5.9), 6.88 (1
H, d, J = 7.9), 6.78 (3H, m), 3.86 (3H, s), 3.83
(3H, s), 3.66 (2H,m), 2.84 (2H, t, J = 6.9).Example 67 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Trifluoromethylphenyl) indole-2-
Carboxamide (Compound 66) Melting point: 205-207 ° C (diisopropyl ether) Elemental analysis: C ₃₀ H ₂₅ F ₃ N ₄ O ₄ S Calculated value (%): C 60.60, H 4.24, N 9.42 Measured value (%): C 60.60, H 4.20, N 9.34 FABMS (m / z): 595 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.75 (1H, bs), 7.86 (1H, m), 7.
75 (2H, m), 7.68 (1H, s), 7.67 (1H, m), 7.47 (2H,
m), 7.27 (2H, m), 7.06 (1H, bt, J = 5.9), 6.88 (1
H, d, J = 7.9), 6.78 (3H, m), 3.86 (3H, s), 3.83
(3H, s), 3.66 (2H, m), 2.84 (2H, t, J = 6.9).

【０１５１】実施例６８ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−ジメチルアミノ−２−トリフルオロメチルフェニ
ル）インドール−２−カルボキサミド・塩酸塩（化合物
６８） 融点: 133-135 ℃ (塩酸塩: 酢酸エチル) 元素分析: 1 塩酸塩・0.5水和物として C₃₂H₃₀F₃N₅O₄S
・ HCl ・0.5H₂O 計算値 (%): C 56.26, H 4.72, N 10.25 実測値 (%): C 56.16, H 4.69, N 9.91 FABMS (m/z): 638 (M ⁺ +1)¹ H NMR (遊離塩基: CDCl₃)δ 9.53 (1H, bs), 7.73 (1
H, m), 7.69 (1H, s), 7.67 (1H, m), 7.37 (1H, d, J
= 0.7), 7.24 (3H, m), 7.10 (1H, bt, J = 5.9),7.03
(1H, d, J = 3.0), 6.93 (2H, m), 6.79 (3H, m), 3.87
(3H, s), 3.85 (3H, s), 3.64 (2H, m), 3.09 (6H,
s), 2.85 (2H, t, J = 6.9).Example 68 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Dimethylamino-2-trifluoromethylphenyl) indole-2-carboxamide / hydrochloride (Compound 68) Melting point: 133-135 ° C (hydrochloride: ethyl acetate) Elemental analysis: 1 Hydrochloride / 0.5 hydrate C ₃₂ H ₃₀ F ₃ N ₅ O ₄ S
・ HCl ・ 0.5H ₂ O Calculated value (%): C 56.26, H 4.72, N 10.25 Measured value (%): C 56.16, H 4.69, N 9.91 FABMS (m / z): 638 (M ⁺ +1) ¹ H NMR (free base: CDCl ₃ ) δ 9.53 (1H, bs), 7.73 (1
H, m), 7.69 (1H, s), 7.67 (1H, m), 7.37 (1H, d, J
= 0.7), 7.24 (3H, m), 7.10 (1H, bt, J = 5.9), 7.03
(1H, d, J = 3.0), 6.93 (2H, m), 6.79 (3H, m), 3.87
(3H, s), 3.85 (3H, s), 3.64 (2H, m), 3.09 (6H,
s), 2.85 (2H, t, J = 6.9).

【０１５２】実施例６９ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−フルオロ−４−ニトロフェニル）インドール−２
−カルボキサミド（化合物７０） 融点: 209-211 ℃ (酢酸エチル／ジイソプロピルエーテ
ル) 元素分析: C₂₉H₂₄FN₅O₆S 計算値 (%): C 59.08, H 4.10, N 11.88 実測値 (%): C 59.23, H 4.05, N 11.86 FABMS (m/z): 590 (M ⁺ +1)¹ H NMR (CDCl₃) δ 10.04 (1H, bs), 8.26 (1H, ddd,
J = 1.0, 1.3, 8.6), 8.15 (1H, dd, J = 2.6, 9.6),
7.80 (1H, d, J = 7.6), 7.73 (1H, s), 7.72 (1H, m),
7.60 (1H, d, J = 0.7), 7.36 (2H, m), 7.15 (1H, d,
J = 8.3), 7.03 (1H, bt, J = 5.9), 6.76 (3H, m),
3.86 (3H, s), 3.82 (3H, s), 3.68 (2H, m), 2.86 (2
H, t, J = 6.9).Example 69 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Fluoro-4-nitrophenyl) indole-2
-Carboxamide (Compound 70) Melting point: 209-211 ° C (ethyl acetate / diisopropyl ether) Elemental analysis: C ₂₉ H ₂₄ FN ₅ O ₆ S Calculated value (%): C 59.08, H 4.10, N 11.88 Measured value (%) : C 59.23, H 4.05, N 11.86 FABMS (m / z): 590 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 10.04 (1H, bs), 8.26 (1H, ddd,
J = 1.0, 1.3, 8.6), 8.15 (1H, dd, J = 2.6, 9.6),
7.80 (1H, d, J = 7.6), 7.73 (1H, s), 7.72 (1H, m),
7.60 (1H, d, J = 0.7), 7.36 (2H, m), 7.15 (1H, d,
J = 8.3), 7.03 (1H, bt, J = 5.9), 6.76 (3H, m),
3.86 (3H, s), 3.82 (3H, s), 3.68 (2H, m), 2.86 (2
H, t, J = 6.9).

【０１５３】実施例７０ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（２−フルオロフェニル）インドール−２−カルボキサ
ミド（化合物６９） 融点: 173-175 ℃ (イソプロパノール／ジイソプロピル
エーテル) 元素分析: C₂₉H₂₅FN₄O₄S 計算値 (%): C 63.96, H 4.63, N 10.29 実測値 (%): C 63.82, H 4.59, N 10.18 FABMS (m/z): 545 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.72 (1H, bs), 7.76 (1H, d, J =
7.6), 7.70 (1H, s), 7.51 (1H, d, J = 7.6), 7.46
(1H, s), 7.45 (1H, m), 7.34 (2H, m), 7.28 (2H, m),
7.14 (1H, d, J = 8.6), 7.07 (1H, bt, J = 5.9), 6.
78 (3H, m), 3.86(3H, s), 3.83 (3H, s), 3.66 (2H,
m), 2.84 (2H, t, J = 6.9).Example 70 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(2-Fluorophenyl) indole-2-carboxamide (Compound 69) Melting point: 173-175 ° C (isopropanol / diisopropyl ether) Elemental analysis: C ₂₉ H ₂₅ FN ₄ O ₄ S Calculated value (%): C 63.96, H 4.63 , N 10.29 Found (%): C 63.82, H 4.59, N 10.18 FABMS (m / z): 545 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.72 (1H, bs), 7.76 (1H, d, J =
7.6), 7.70 (1H, s), 7.51 (1H, d, J = 7.6), 7.46
(1H, s), 7.45 (1H, m), 7.34 (2H, m), 7.28 (2H, m),
7.14 (1H, d, J = 8.6), 7.07 (1H, bt, J = 5.9), 6.
78 (3H, m), 3.86 (3H, s), 3.83 (3H, s), 3.66 (2H,
m), 2.84 (2H, t, J = 6.9).

【０１５４】実施例７１ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（４−ジメチルアミノ−２−フルオロフェニル）インド
ール−２−カルボキサミド・塩酸塩（化合物７１） 融点: 138-142 ℃ (塩酸塩: エタノール) 元素分析: 1 塩酸塩・3.5水和物として C₃₁H₃₀FN₅O₄S・
HCl ・3.5H₂O 計算値 (%): C 54.18, H 5.57, N 10.19 実測値 (%): C 54.10, H 5.46, N 10.06 FABMS (m/z): 588 (M ⁺ +1)¹ H NMR (遊離塩基: CDCl₃) δ 9.46 (1H, bs), 7.74
(1H, d, J = 7.9), 7.71(1H, s), 7.38 (1H, s), 7.27
(3H, m), 7.15 (1H, d, J = 8.3), 7.11 (1H, bt, J =
5.9), 6.81 (3H, m), 6.55 (2H, m), 3.87 (3H, s), 3.
84 (3H, s), 3.69(1H, d, J = 6.6), 3.63 (1H, d, J =
6.6), 3.03 (6H, s), 2.84 (2H, t, J =6.6).Example 71 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(4-Dimethylamino-2-fluorophenyl) indole-2-carboxamide / hydrochloride (Compound 71) Melting point: 138-142 ° C (hydrochloride: ethanol) Elemental analysis: 1 Hydrochloride / 3.5 hydrate as C ₃₁ H ₃₀ FN ₅ O ₄ S
HCl ・ 3.5H ₂ O Calculated value (%): C 54.18, H 5.57, N 10.19 Measured value (%): C 54.10, H 5.46, N 10.06 FABMS (m / z): 588 (M ⁺ +1) ¹ H NMR (free base: CDCl ₃ ) δ 9.46 (1H, bs), 7.74
(1H, d, J = 7.9), 7.71 (1H, s), 7.38 (1H, s), 7.27
(3H, m), 7.15 (1H, d, J = 8.3), 7.11 (1H, bt, J =
5.9), 6.81 (3H, m), 6.55 (2H, m), 3.87 (3H, s), 3.
84 (3H, s), 3.69 (1H, d, J = 6.6), 3.63 (1H, d, J =
6.6), 3.03 (6H, s), 2.84 (2H, t, J = 6.6).

【０１５５】実施例７２ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チル（メチル）アミノ］カルボニル］−２−チアゾリ
ル｝−１−（２−メチルフェニル）インドール−２−カ
ルボキサミド（化合物７２） ２−｛Ｎ−［１−（２−メチルフェニル）インドール−
２−イルカルボニル］アミノ｝チアゾール−４−カルボ
ン酸0.76 g (2.01 mmol)をDMF 15 mL に溶解し、トリエ
チルアミン0.84 mL (6.03 mmol) 、３，４−ジメトキシ
フェネチル（メチル）アミン0.51 g (2.20 mmol)、 HOB
t ・ H₂O 0.62 g (4.05 mmol)、次いでWSC ・ HCl 0.50 g
(2.61 mmol)を加え、室温で12時間攪拌した。反応液を
濃縮後、残渣に酢酸エチルを加え、2 N 塩酸、飽和重曹
水、飽和食塩水で順に洗浄し、無水硫酸マグネシウムで
乾燥した。溶媒を減圧下留去後、残渣をシリカゲルカラ
ムクロマトグラフィー（ヘキサン：酢酸エチル＝１：
２）で精製することにより、化合物７２, 0.86 g (86%)
を淡黄色泡状物として得た。Example 72 N- {4-[[2- (3,4-dimethoxyphenyl) ethyl (methyl) amino] carbonyl] -2-thiazolyl} -1- (2-methylphenyl) indole-2-carboxamide (Compound 72) 2- {N- [1- (2-methylphenyl) indole-
2-ylcarbonyl] amino} thiazol-4-carboxylic acid 0.76 g (2.01 mmol) was dissolved in DMF 15 mL, triethylamine 0.84 mL (6.03 mmol) and 3,4-dimethoxyphenethyl (methyl) amine 0.51 g (2.20 mmol). ), HOB
t ・ H ₂ O 0.62 g (4.05 mmol), then WSC ・ HCl 0.50 g
(2.61 mmol) was added, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, ethyl acetate was added to the residue, washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate = 1: 1).
Compound 72, 0.86 g (86%) after purification in 2)
Was obtained as a pale yellow foam.

【０１５６】FABMS (m/z): 555 (M ⁺ +1)¹ H NMR (CDCl₃) δ 9.42 (1H, bs), 7.79 (1H, d, J =
8.6), 7.47 (1H, s), 7.42 (3H, m), 7.28 (4H, m),
6.91 (1H, d, J = 8.6), 6.79 (2H, m), 6.62 (1H, m),
3.85 (3H, s), 3.72 (2H, m), 3.08 (3H, s), 2.85 (2
H, m), 1.96 (3H,s).FABMS (m / z): 555 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 9.42 (1H, bs), 7.79 (1H, d, J =
8.6), 7.47 (1H, s), 7.42 (3H, m), 7.28 (4H, m),
6.91 (1H, d, J = 8.6), 6.79 (2H, m), 6.62 (1H, m),
3.85 (3H, s), 3.72 (2H, m), 3.08 (3H, s), 2.85 (2
H, m), 1.96 (3H, s).

【０１５７】実施例７３ Ｎ−｛４−［［２−（３，４−ジメチルフェニル）エチ
ルアミノ］カルボニル］−２−チアゾリル｝−Ｎ−メチ
ル−１−（２−メチルフェニル）インドール−２−カル
ボキサミド（化合物７３） （１）２−メチルアミノチアゾール−４−カルボン酸エ
チル5.65 g (30.34 mmol) およびDMAP 0.37 g (3.03 mm
ol) を塩化メチレン100 mLに溶解し、これに、氷冷下に
ジ（ｔｅｒｔ−ブチル）ジカーボネート10.6 g (48.57
mmol) を加え、室温で6 時間攪拌した。反応混合物を1
M 硫酸水素カリウム水溶液、飽和重曹水、飽和食塩水で
順に洗浄し、無水硫酸マグネシウムで乾燥した。溶媒を
減圧下留去後、得られた粗結晶をヘキサンでトリチュレ
ーションすることにより、２−［Ｎ−（ｔｅｒｔ−ブト
キシカルボニル）−Ｎ−メチルアミノ］チアゾール−４
−カルボン酸エチル5.32 g (61%)を白色結晶物として得
た。¹ H NMR (CDCl₃) δ 7.79 (1H, s), 4.38 (2H, q, J =
6.9), 3.62 (3H, s), 1.59 (9H, s), 1.39 (3H, t, J =
6.9).Example 73 N- {4-[[2- (3,4-dimethylphenyl) ethylamino] carbonyl] -2-thiazolyl} -N-methyl-1- (2-methylphenyl) indole-2- Carboxamide (Compound 73) (1) Ethyl 2-methylaminothiazole-4-carboxylate 5.65 g (30.34 mmol) and DMAP 0.37 g (3.03 mm)
ol) was dissolved in 100 mL of methylene chloride, and 10.6 g (48.57) of di (tert-butyl) dicarbonate was added to the solution under ice cooling.
mmol) was added and the mixture was stirred at room temperature for 6 hours. 1 reaction mixture
M potassium bisulfate aqueous solution, saturated aqueous sodium hydrogen carbonate and saturated brine were sequentially washed, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained crude crystals were triturated with hexane to give 2- [N- (tert-butoxycarbonyl) -N-methylamino] thiazole-4.
-5.32 g (61%) of ethyl carboxylate was obtained as a white crystalline substance. ¹ H NMR (CDCl ₃ ) δ 7.79 (1H, s), 4.38 (2H, q, J =
6.9), 3.62 (3H, s), 1.59 (9H, s), 1.39 (3H, t, J =
6.9).

【０１５８】（２）（１）で得られた化合物5.32 g (1
8.58 mmol) をメタノール100 mLに溶解し、水酸化ナト
リウム3.7 g (92.5 mmol) の水30 mL 溶液を加え、室温
で2 時間攪拌した。反応液を濃縮後、残渣を氷水に溶解
し、これに4 N 塩酸を加え、pHを2 とした。析出した結
晶を濾取し、水洗、乾燥することにより、２−［Ｎ−
（ｔｅｒｔ−ブトキシカルボニル）−Ｎ−メチルアミ
ノ］チアゾール−４−カルボン酸4.44 g (93%)を白色結
晶物として得た。¹ H NMR (CDCl₃) δ 9.43 (1H, bs), 7.93 (1H, s), 3.
60 (3H, s), 1.59 (9H,s).(2) 5.32 g (1 of the compound obtained in (1)
8.58 mmol) was dissolved in 100 mL of methanol, a solution of 3.7 g (92.5 mmol) of sodium hydroxide in 30 mL of water was added, and the mixture was stirred at room temperature for 2 hours. After the reaction solution was concentrated, the residue was dissolved in ice water, and 4N hydrochloric acid was added to adjust the pH to 2. The precipitated crystals are collected by filtration, washed with water and dried to give 2- [N-
4.44 g (93%) of (tert-butoxycarbonyl) -N-methylamino] thiazole-4-carboxylic acid was obtained as a white crystalline substance. ¹ H NMR (CDCl ₃ ) δ 9.43 (1H, bs), 7.93 (1H, s), 3.
60 (3H, s), 1.59 (9H, s).

【０１５９】（３）（２）で得られた化合物4.3 g (16.
65 mmol)をDMF 50 mL に溶解し、３，４−ジメトキシフ
ェネチルアミン3.37 mL (19.97 mmol)、 HOBt ・ H₂O 5.
1 g (33.3 mmol) 、次いでWSC ・ HCl 3.2 g (16.7 mmo
l) を加え、室温で0.5 時間攪拌した。反応液を濃縮
後、残渣に酢酸エチルを加え、1 M 硫酸水素カリウム水
溶液、飽和重曹水、飽和食塩水で順に洗浄し、無水硫酸
マグネシウムで乾燥した。溶媒を減圧下留去することに
より、Ｎ−［２−（３，４−ジメトキシフェニル）エチ
ル］−２−［Ｎ−（ｔｅｒｔ−ブトキシカルボニル）−
Ｎ−メチルアミノ］チアゾール−４−カルボキサミド7.
11 gを淡黄色泡状物として得た。¹ H NMR (CDCl₃) δ 7.71 (1H, s), 7.29 (1H, bt, J =
5.9), 6.81 (3H, m), 3.87 (3H, s), 3.85 (3H, s),
3.65 (2H, m), 3.48 (3H, s), 2.87 (2H, t, J =6.9),
1.59 (9H, s).(3) 4.3 g of the compound obtained in (2) (16.
The 65 mmol) were dissolved in DMF 50 mL, 3,4-dimethoxy-phenethylamine 3.37 mL (19.97 mmol), HOBt · H 2 O 5.
1 g (33.3 mmol), then WSC HCl 3.2 g (16.7 mmo
l) was added and the mixture was stirred at room temperature for 0.5 hour. The reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed successively with 1 M aqueous potassium hydrogen sulfate solution, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give N- [2- (3,4-dimethoxyphenyl) ethyl] -2- [N- (tert-butoxycarbonyl)-.
N-methylamino] thiazole-4-carboxamide 7.
11 g was obtained as a pale yellow foam. ¹ H NMR (CDCl ₃ ) δ 7.71 (1H, s), 7.29 (1H, bt, J =
5.9), 6.81 (3H, m), 3.87 (3H, s), 3.85 (3H, s),
3.65 (2H, m), 3.48 (3H, s), 2.87 (2H, t, J = 6.9),
1.59 (9H, s).

【０１６０】（４）（３）で得られた化合物7.11 g (<1
6.65 mmol)を塩化メチレン80 mL に溶解し、これに、氷
冷下、トリフルオロ酢酸 (TFA) 80 mLを加え、室温で12
時間攪拌した。反応混合物を減圧下濃縮後、残渣を氷水
に溶解し、10 N水酸化ナトリウム水溶液でpHを13に調整
した。析出した淡黄色油状物を塩化メチレンで抽出後、
有機層を飽和食塩水で洗浄し、無水硫酸マグネシウムで
乾燥した。溶媒を減圧下留去することにより、Ｎ−［２
−（３，４−ジメトキシフェニル）エチル］−２−メチ
ルアミノチアゾール−４−カルボキサミド7.11 g (92%
：２工程) を淡黄色油状物として得た。¹ H NMR (CDCl₃) δ 7.38 (1H, bt, J = 5.9), 7.29 (1
H, s), 6.77 (3H, m), 5.92 (1H, bq, J = 5.0), 3.84
(3H, s), 3.83 (3H, s), 3.61 (2H, q, J = 6.9), 2.93
(3H, d, J = 5.0), 2.83 (2H, t, J = 7.3).(4) 7.11 g (<1 of the compound obtained in (3)
6.65 mmol) was dissolved in 80 mL of methylene chloride, to which 80 mL of trifluoroacetic acid (TFA) was added under ice cooling, and the mixture was stirred at room temperature for 12 hours.
Stir for hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ice water, and the pH was adjusted to 13 with a 10 N aqueous sodium hydroxide solution. After extracting the precipitated pale yellow oily matter with methylene chloride,
The organic layer was washed with brine and dried over anhydrous magnesium sulfate. By distilling off the solvent under reduced pressure, N- [2
-(3,4-Dimethoxyphenyl) ethyl] -2-methylaminothiazole-4-carboxamide 7.11 g (92%
: 2 steps) was obtained as a pale yellow oil. ¹ H NMR (CDCl ₃ ) δ 7.38 (1H, bt, J = 5.9), 7.29 (1
H, s), 6.77 (3H, m), 5.92 (1H, bq, J = 5.0), 3.84
(3H, s), 3.83 (3H, s), 3.61 (2H, q, J = 6.9), 2.93
(3H, d, J = 5.0), 2.83 (2H, t, J = 7.3).

【０１６１】（５）１−（２−メチルフェニル）インド
ール−２−カルボン酸1.0 g (3.98 mmol) を塩化メチレ
ン50 mL に溶解し、トリエチルアミン1.33 mL (9.54 mm
ol) 、ヨウ化２−クロロ−１−メチルピリジニウム1.22
g (4.78 mmol)、次いでペンタフルオロフェノール0.58
mL (4.35 mmol) を加え、室温で1 時間攪拌した。反応
混合物を2 N 塩酸、飽和重曹水、飽和食塩水で順に洗浄
し、溶媒を留去した。残渣をピリジン50 mL に溶解し、
（４）で得られた化合物1.28 g (4.0 mmol) を加え、2
時間加熱還流した。反応液を濃縮後、残渣に塩化メチレ
ンを加え、2 N 塩酸、飽和重曹水、飽和食塩水で順に洗
浄した。溶媒を留去後、残渣をシリカゲルカラムクロマ
トグラフィー（ヘキサン：酢酸エチル＝１：１）で精製
し、得られた粗結晶をイソプロピルエーテル／イソプロ
パノールでトリチュレーションすることにより、化合物
７３, 1.03 g (47%)を白色結晶物として得た。(5) 1.0 g (3.98 mmol) of 1- (2-methylphenyl) indole-2-carboxylic acid was dissolved in 50 mL of methylene chloride and 1.33 mL (9.54 mm) of triethylamine was dissolved.
ol), 2-chloro-1-methylpyridinium iodide 1.22
g (4.78 mmol), then pentafluorophenol 0.58
mL (4.35 mmol) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was washed successively with 2 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and the solvent was evaporated. Dissolve the residue in 50 mL of pyridine,
1.28 g (4.0 mmol) of the compound obtained in (4) was added, and 2
Heated to reflux for an hour. The reaction mixture was concentrated, methylene chloride was added to the residue, and the mixture was washed successively with 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1), and the obtained crude crystals were triturated with isopropyl ether / isopropanol to give compound 73, 1.03 g ( 47%) was obtained as a white crystalline substance.

【０１６２】融点: 141-142 ℃ (イソプロパノール／ジ
イソプロピルエーテル) 元素分析: C₃₁H₃₀N₄O₄S 計算値 (%): C 67.13, H 5.45, N 10.10 実測値 (%): C 67.20, H 5.48, N 10.11 FABMS (m/z): 555 (M ⁺ +1)¹ H NMR (CDCl₃) δ 7.78 (1H, bs), 7.76 (1H, s), 7.
73 (2H, m), 7.28 (5H,m), 7.04 (1H, s), 6.97 (1H,
d, J = 7.9), 6.79 (3H, m), 3.87 (3H, s), 3.86 (3H,
s), 3.85 (3H, s), 3.70 (1H, d, J = 6.9), 3.65 (1
H, d, J = 6.9), 2.88 (2H, t, J = 6.9), 2.05 (3H,
s).Melting point: 141-142 ° C. (isopropanol / diisopropyl ether) Elemental analysis: C ₃₁ H ₃₀ N ₄ O ₄ S Calculated value (%): C 67.13, H 5.45, N 10.10 Found value (%): C 67.20, H 5.48, N 10.11 FABMS (m / z): 555 (M ⁺ +1) ¹ H NMR (CDCl ₃ ) δ 7.78 (1H, bs), 7.76 (1H, s), 7.
73 (2H, m), 7.28 (5H, m), 7.04 (1H, s), 6.97 (1H,
d, J = 7.9), 6.79 (3H, m), 3.87 (3H, s), 3.86 (3H,
s), 3.85 (3H, s), 3.70 (1H, d, J = 6.9), 3.65 (1
H, d, J = 6.9), 2.88 (2H, t, J = 6.9), 2.05 (3H,
s).

【０１６３】実施例７４ Ｎ−｛４−［［２−（４−ジメチルアミノ−３−メトキ
シフェニル）エチルアミノ］カルボニル］−２−チアゾ
リル｝−１−（２−メチルフェニル）インドール−２−
カルボキサミド（化合物７４） EIMS (m/z): 553 (M⁺ )¹ H NMR (CDCl₃) δ 9.37 (1H, s), 7.79 (1H, bd, J =
7.8), 7.71 (1H, s), 7.21-7.50 (8H, m), 7.11 (1H,
d, J = 6.0), 6.93 (1H, d, J = 8.0), 6.80 (1H, dd,
J = 1.7, 8.0), 6.75 (1H, d, J = 1.7), 3.86 (3H,
s), 3.67 (2H, dt,J = 6.0, 7.1), 2.86 (2H, t, J =
7.1), 2.80 (6H, s), 1.96 (3H, s).Example 74 N- {4-[[2- (4-dimethylamino-3-methoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (2-methylphenyl) indole-2-
Carboxamide (Compound 74) EIMS (m / z): 553 (M ⁺ ) ¹ H NMR (CDCl ₃ ) δ 9.37 (1H, s), 7.79 (1H, bd, J =
7.8), 7.71 (1H, s), 7.21-7.50 (8H, m), 7.11 (1H,
d, J = 6.0), 6.93 (1H, d, J = 8.0), 6.80 (1H, dd,
J = 1.7, 8.0), 6.75 (1H, d, J = 1.7), 3.86 (3H,
s), 3.67 (2H, dt, J = 6.0, 7.1), 2.86 (2H, t, J =
7.1), 2.80 (6H, s), 1.96 (3H, s).

【０１６４】実施例７５ Ｎ−｛４−［［２−［３，４−ビス（ジメチルアミノ）
フェニル］エチルアミノ］カルボニル］−２−チアゾリ
ル｝−１−（２−メチルフェニル）インドール−２−カ
ルボキサミド・２塩酸塩（化合物７５） 融点: 145-153 ℃ (2 塩酸塩: 酢酸エチル) 元素分析: 2 塩酸塩として C₃₂H₃₄N₆O₂S ・2HCl 計算値 (%): C 60.09, H 5.67, N 13.14 実測値 (%): C 60.26, H 6.29, N 12.95 EIMS (m/z): 566 (M+)¹ H NMR (遊離塩基: CDCl₃) δ 9.30 (1H, s), 7.78 (1
H, d, J = 7.6), 7.70 (1H, s), 7.21-7.50 (7H, m),
7.17 (1H, t, J = 6.0), 6.93 (1H, d, J = 8.1),6.86
(1H, d, J = 8.0), 6.78 (1H, dd, J = 1.5, 8.0), 6.7
6 (1H, bs), 3.65(2H, dt, J = 6.0, 7.3), 2.79 (2H,
t, J = 7.3), 2.79 (6H, s), 2.78 (6H,s), 1.96 (3H,
s).Example 75 N- {4-[[2- [3,4-bis (dimethylamino)]
[Phenyl] ethylamino] carbonyl] -2-thiazolyl} -1- (2-methylphenyl) indole-2-carboxamide dihydrochloride (Compound 75) Melting point: 145-153 ° C (2 hydrochloride: ethyl acetate) Elemental analysis : As dihydrochloride C ₃₂ H ₃₄ N ₆ O ₂ S ・ 2HCl Calculated value (%): C 60.09, H 5.67, N 13.14 Measured value (%): C 60.26, H 6.29, N 12.95 EIMS (m / z) : 566 (M +) ¹ H NMR (free base: CDCl ₃ ) δ 9.30 (1H, s), 7.78 (1
H, d, J = 7.6), 7.70 (1H, s), 7.21-7.50 (7H, m),
7.17 (1H, t, J = 6.0), 6.93 (1H, d, J = 8.1), 6.86
(1H, d, J = 8.0), 6.78 (1H, dd, J = 1.5, 8.0), 6.7
6 (1H, bs), 3.65 (2H, dt, J = 6.0, 7.3), 2.79 (2H,
t, J = 7.3), 2.79 (6H, s), 2.78 (6H, s), 1.96 (3H,
s).

【０１６５】実施例７６ Ｎ−｛４−［［２−（４−ジメチルアミノ−３−メトキ
シフェニル）エチルアミノ］カルボニル］−２−チアゾ
リル｝−１−（２−ピリジル）インドール−２−カルボ
キサミド・２塩酸塩（化合物７６） ４−フェニル桂皮酸に代えて参考例３で得られる１−
（２−ピリジル）インドール−２−カルボン酸を用い、
実施例１に記載した方法に準じて、化合物７６を得た。Example 76 N- {4-[[2- (4-dimethylamino-3-methoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1- (2-pyridyl) indole-2-carboxamide. Dihydrochloride (Compound 76) 1-obtained in Reference Example 3 in place of 4-phenylcinnamic acid
With (2-pyridyl) indole-2-carboxylic acid,
Compound 76 was obtained according to the method described in Example 1.

【０１６６】融点: 145-155 ℃ (2 塩酸塩: 酢酸エチ
ル) 元素分析: 2 塩酸塩・0.1水和物として C₂₉H₂₈N₆O₃S ・2
HCl ・0.1H₂O 計算値 (%): C 56.60, H 4.95, N 13.66 実測値 (%): C 56.68, H 5.52, N 13.37 EIMS (m/z): 540 (M ⁺)¹ H NMR (遊離塩基: CDCl₃) δ 12.17 (1H, s), 8.82
(1H, dd, J = 1.4, 5.1),8.00 (1H, ddd, J = 1.7, 8.
0, 8.0), 7.59 (1H, bd, J = 8.0), 7.58 (1H, s), 7.1
7-7.32 (3H, m), 7.13 (1H, d, J = 5.9), 7.12 (1H,
d, J = 8.3), 7.01(1H, s), 6.97 (1H, d, J = 8.1),
6.96 (1H, ddd, J = 1.6, 6.2, 6.2), 6.83(1H, dd, J
= 1.8, 8.1), 6.78 (1H, d, J = 1.8), 3.88 (3H, s),
3.68 (2H, dt, J = 5.9, 6.9), 2.89 (2H, t, J = 6.
9), 2.79 (6H, s).Melting point: 145-155 ° C. (dihydrochloride: ethyl acetate) Elemental analysis: Dihydrochloride. As a monohydrate C ₂₉ H ₂₈ N ₆ O ₃ S. 2
HCl ・ 0.1H ₂ O Calculated value (%): C 56.60, H 4.95, N 13.66 Measured value (%): C 56.68, H 5.52, N 13.37 EIMS (m / z): 540 (M ⁺ ) ¹ H NMR ( Free base: CDCl ₃ ) δ 12.17 (1H, s), 8.82
(1H, dd, J = 1.4, 5.1), 8.00 (1H, ddd, J = 1.7, 8.
0, 8.0), 7.59 (1H, bd, J = 8.0), 7.58 (1H, s), 7.1
7-7.32 (3H, m), 7.13 (1H, d, J = 5.9), 7.12 (1H,
d, J = 8.3), 7.01 (1H, s), 6.97 (1H, d, J = 8.1),
6.96 (1H, ddd, J = 1.6, 6.2, 6.2), 6.83 (1H, dd, J
= 1.8, 8.1), 6.78 (1H, d, J = 1.8), 3.88 (3H, s),
3.68 (2H, dt, J = 5.9, 6.9), 2.89 (2H, t, J = 6.
9), 2.79 (6H, s).

【０１６７】実施例７７ Ｎ−｛４−［［２−［３，４−ビス（ジメチルアミノ）
フェニル］エチルアミノ］カルボニル］−２−チアゾリ
ル｝−１−（２−ピリジル）インドール−２−カルボキ
サミド・３塩酸塩（化合物７７） ４−フェニル桂皮酸に代えて参考例３で得られる１−
（２−ピリジル）インドール−２−カルボン酸を用い、
実施例１に記載した方法に準じて、化合物７７を得た。Example 77 N- {4-[[2- [3,4-bis (dimethylamino)]
Phenyl] ethylamino] carbonyl] -2-thiazolyl} -1- (2-pyridyl) indole-2-carboxamide-3-hydrochloride (compound 77) 1-obtained in Reference Example 3 in place of 4-phenylcinnamic acid
With (2-pyridyl) indole-2-carboxylic acid,
Compound 77 was obtained according to the method described in Example 1.

【０１６８】融点: 165-173 ℃ (3 塩酸塩: 酢酸エチ
ル) 元素分析: 3 塩酸塩・3.4水和物として C₃₀H₃₁N₇O₂S ・3
HCl ・3.4H₂O 計算値 (%): C 49.75, H 5.68, N 13.54 実測値 (%): C 49.84, H 5.67, N 13.40 EIMS (m/z): 553 (M ⁺)¹ H NMR (遊離塩基: CDCl₃) δ 12.19 (1H, s), 8.86
(1H, bd, J = 4.6), 7.99(1H, ddd, J = 2.0, 7.8, 7.
8), 7.58 (1H, d, J = 8.2), 7.56 (1H, s), 7.18-7.33
(3H, m), 7.13 (1H, t, J = 5.8), 7.08 (1H, bd, J =
8.5), 6.96 (1H,s), 6.83 (1H, bd, J = 8.5), 6.79
(1H, s), 6.72-7.02 (2H, m), 3.66 (2H, dt, J = 5.8,
7.1), 2.83 (1H, t, J = 7.1), 2.80 (6H, s), 2.78
(6H, s).Melting point: 165-173 ° C. (3 hydrochloride: ethyl acetate) Elemental analysis: 3 hydrochloride · 3.4 hydrate as C ₃₀ H ₃₁ N ₇ O ₂ S · 3
HCl ・ 3.4H ₂ O Calculated value (%): C 49.75, H 5.68, N 13.54 Measured value (%): C 49.84, H 5.67, N 13.40 EIMS (m / z): 553 (M ⁺ ) ¹ H NMR ( Free base: CDCl ₃ ) δ 12.19 (1H, s), 8.86
(1H, bd, J = 4.6), 7.99 (1H, ddd, J = 2.0, 7.8, 7.
8), 7.58 (1H, d, J = 8.2), 7.56 (1H, s), 7.18-7.33
(3H, m), 7.13 (1H, t, J = 5.8), 7.08 (1H, bd, J =
8.5), 6.96 (1H, s), 6.83 (1H, bd, J = 8.5), 6.79
(1H, s), 6.72-7.02 (2H, m), 3.66 (2H, dt, J = 5.8,
7.1), 2.83 (1H, t, J = 7.1), 2.80 (6H, s), 2.78
(6H, s).

【０１６９】実施例７８ Ｎ−［２−（３，４−ジメトキシフェニル）エチル］−
２−｛Ｎ−［１−（２−メチルフェニル）−２−インド
リルメチル］アミノ｝チアゾール−４−カルボキサミド
・塩酸塩（化合物７８） （１）１−（２−メチルフェニル）インドール−２−カ
ルボン酸2.6 g (10.4 mmol) をTHF 100 mLに溶解し、こ
れに、氷冷下、水素化リチウムアルミニウム0.79g (20.
8 mmol)を加え、4 時間攪拌した。水1.6 mL、10 N水酸
化ナトリウム、次いで水4 mLを加え、反応液を濾過し
た。濾液を減圧下濃縮後、残渣を酢酸エチル／飽和食塩
水で分配し、有機層を無水硫酸マグネシウムで乾燥し
た。溶媒を留去後、残渣をシリカゲルカラムクロマトグ
ラフィー（ヘキサン：酢酸エチル４：１）で精製するこ
とにより、１−（２−メチルフェニル）インドール−２
−イルメタノール2.31 g (94%)を淡黄色油状物として得
た。¹ H-NMR (CDCl₃) δ 7.64 (1H, m), 7.37 (2H, m), 7.2
7 (2H, m), 7.12 (2H, m), 6.84 (1H, m), 6.63 (1H,
s), 4.55 (1H, d, J = 13.4), 4.46 (1H, d, J =13.4),
1.90 (3H, s).Example 78 N- [2- (3,4-dimethoxyphenyl) ethyl]-
2- {N- [1- (2-methylphenyl) -2-indolylmethyl] amino} thiazole-4-carboxamide hydrochloride (Compound 78) (1) 1- (2-methylphenyl) indole-2- 2.6 g (10.4 mmol) of carboxylic acid was dissolved in 100 mL of THF, and 0.79 g (20.
(8 mmol) was added and stirred for 4 hours. 1.6 mL of water, 10 N sodium hydroxide, and then 4 mL of water were added, and the reaction solution was filtered. The filtrate was concentrated under reduced pressure, the residue was partitioned with ethyl acetate / saturated saline, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate 4: 1) to give 1- (2-methylphenyl) indole-2.
2.31 g (94%) of -ylmethanol was obtained as a pale yellow oil. ¹ H-NMR (CDCl ₃ ) δ 7.64 (1H, m), 7.37 (2H, m), 7.2
7 (2H, m), 7.12 (2H, m), 6.84 (1H, m), 6.63 (1H,
s), 4.55 (1H, d, J = 13.4), 4.46 (1H, d, J = 13.4),
1.90 (3H, s).

【０１７０】（２）（１）で得られた化合物2.26 g (9.
52 mmol)、参考例５で得られる２−（ｔｅｒｔ−ブトキ
シカルボニルアミノ）チアゾール−４−カルボン酸エチ
ル2.59g (9.51 mmol)およびトリフェニルホスフィン3.7
5 g (14.3 mmol)のTHF 50 mL溶液に、氷冷下、アゾジカ
ルボン酸ジエチル (DEAD) 1.8 mL (11.4 mmol)をゆっく
りと滴下し、室温で一晩攪拌した。反応液を減圧下濃縮
後、残渣にエーテルを加え、1 N 塩酸、飽和重曹水、飽
和食塩水で順に洗浄し、無水硫酸マグネシウムで乾燥し
た。溶媒を減圧下留去後、残渣をシリカゲルカラムクロ
マトグラフィー（ヘキサン：酢酸エチル＝５：１）で精
製することにより、２−｛Ｎ−（ｔｅｒｔ−ブトキシカ
ルボニル）−Ｎ−［１−（２−メチルフェニル）−２−
インドリルメチル］アミノ｝チアゾール−４−カルボン
酸エチル2.73 g (58%)を淡黄色泡状物として得た。¹ H NMR (CDCl₃) δ 7.70 (1H, s), 7.57 (1H, m), 7.2
8 (4H, m), 7.09 (2H, m), 6.80 (1H, m), 6.38 (1H,
s), 5.29 (2H, s), 4.32 (2H, q, J = 6.9), 1.98(3H,
s), 1.51 (9H, s), 1.37 (3H, t, J = 6.9).(2) 2.26 g of the compound obtained in (1) (9.
52 mmol), 2.59 g (9.51 mmol) of ethyl 2- (tert-butoxycarbonylamino) thiazole-4-carboxylate obtained in Reference Example 5 and 3.7 of triphenylphosphine.
To a solution of 5 g (14.3 mmol) in 50 mL of THF, 1.8 mL (11.4 mmol) of diethyl azodicarboxylate (DEAD) was slowly added dropwise under ice cooling, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the mixture was washed successively with 1 N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 2- {N- (tert-butoxycarbonyl) -N- [1- (2- Methylphenyl) -2-
2.73 g (58%) of ethyl indolylmethyl] amino} thiazole-4-carboxylate was obtained as a pale yellow foam. ¹ H NMR (CDCl ₃ ) δ 7.70 (1H, s), 7.57 (1H, m), 7.2
8 (4H, m), 7.09 (2H, m), 6.80 (1H, m), 6.38 (1H,
s), 5.29 (2H, s), 4.32 (2H, q, J = 6.9), 1.98 (3H,
s), 1.51 (9H, s), 1.37 (3H, t, J = 6.9).

【０１７１】（３）（２）で得られた化合物2.73 g (5.
55 mmol)をメタノール30 mL に懸濁し、10% 水酸化ナト
リウム水溶液10 mL 溶液を加え、80℃で3 時間攪拌し
た。反応液を濃縮後、残渣を氷水に溶解し、これに4 N
塩酸を加え、pHを2 に調整した。析出した結晶を濾取
し、水洗、乾燥することにより、２−｛Ｎ−（ｔｅｒｔ
−ブトキシカルボニル）−Ｎ−［１−（２−メチルフェ
ニル）−２−インドリルメチル］アミノ｝チアゾール−
４−カルボン酸2.5 g (95%) を黄色結晶物として得た。
該カルボン酸1.30 g (2.75 mmol)をDMF 15 mL に溶解
し、３，４−ジメトキシフェネチルアミン0.65 mL (3.8
5 mmol) 、 HOBt ・ H₂O 0.84 g (5.49 mmol)、次いでWS
C ・ HCl 0.52 g (2.71 mmol)を加え、室温で40分間攪拌
した。反応液を濃縮後、残渣に塩化メチレンを加え、2
N 塩酸、飽和重曹水、飽和食塩水で順に洗浄し、無水硫
酸マグネシウムで乾燥した。溶媒を減圧下留去後、残渣
をシリカゲルカラムクロマトグラフィー（ヘキサン：酢
酸エチル＝１：１）で精製することにより、Ｎ−［２−
（３，４−ジメトキシフェニル）エチル］−２−｛Ｎ−
（ｔｅｒｔ−ブトキシカルボニル）−Ｎ−［１−（２−
メチルフェニル）−２−インドリルメチル］アミノ｝チ
アゾール−４−カルボキサミド1.31 g (77% ：２工程)
を白色泡状物として得た。¹ H NMR (CDCl₃) δ 7.62 (1H, s), 7.59 (1H, m), 7.0
-7.3 (6H, m), 6.90 (1H, bt, J = 5.9), 6.74 (4H,
m), 6.43 (1H, s), 5.25 (1H, d, J = 16.5), 5.16(1H,
d, J = 15.8), 3.81 (3H, s), 3.75 (3H, s), 3.60 (2
H, m), 2.82 (2H,t, J = 6.9), 1.83 (3H, s), 1.49 (9
H, s).(3) 2.73 g of the compound obtained in (2) (5.
(55 mmol) was suspended in 30 mL of methanol, 10 mL of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 80 ° C. for 3 hours. After concentrating the reaction mixture, dissolve the residue in ice water and add 4 N to it.
Hydrochloric acid was added to adjust the pH to 2. The precipitated crystals are collected by filtration, washed with water and dried to give 2- {N- (tert.
-Butoxycarbonyl) -N- [1- (2-methylphenyl) -2-indolylmethyl] amino} thiazole-
2.5 g (95%) of 4-carboxylic acid was obtained as yellow crystals.
The carboxylic acid 1.30 g (2.75 mmol) was dissolved in DMF 15 mL, and 3,4-dimethoxyphenethylamine 0.65 mL (3.8
_{5 mmol), HOBt · H 2} O 0.84 g (5.49 mmol), followed by WS
0.52 g (2.71 mmol) of C · HCl was added, and the mixture was stirred at room temperature for 40 minutes. After concentrating the reaction mixture, add methylene chloride to the residue and
The extract was washed with N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give N- [2-
(3,4-Dimethoxyphenyl) ethyl] -2- {N-
(Tert-Butoxycarbonyl) -N- [1- (2-
Methylphenyl) -2-indolylmethyl] amino} thiazole-4-carboxamide 1.31 g (77%: 2 steps)
Was obtained as a white foam. ¹ H NMR (CDCl ₃ ) δ 7.62 (1H, s), 7.59 (1H, m), 7.0
-7.3 (6H, m), 6.90 (1H, bt, J = 5.9), 6.74 (4H,
m), 6.43 (1H, s), 5.25 (1H, d, J = 16.5), 5.16 (1H,
d, J = 15.8), 3.81 (3H, s), 3.75 (3H, s), 3.60 (2
H, m), 2.82 (2H, t, J = 6.9), 1.83 (3H, s), 1.49 (9
H, s).

【０１７２】（４）（３）で得られた化合物1.3 g (2.0
7 mmol) を塩化メチレン20 mL に溶解し、これに、氷冷
下、TFA 20 mL を加え、1 時間攪拌した。反応混合物を
減圧下濃縮後、残渣を氷水に溶解し、10 N水酸化ナトリ
ウム水溶液でpHを13に調整した。析出した淡黄色油状物
を塩化メチレンで抽出後、有機層を飽和食塩水で洗浄
し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留
去後、残渣をシリカゲルカラムクロマトグラフィー（ヘ
キサン：酢酸エチル＝２：１）で精製することにより、
化合物７８・塩酸塩0.77 g (71%)を淡黄色泡状物として
得た。(4) 1.3 g (2.0%) of the compound obtained in (3)
(7 mmol) was dissolved in 20 mL of methylene chloride, TFA (20 mL) was added thereto under ice cooling, and the mixture was stirred for 1 hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ice water, and the pH was adjusted to 13 with a 10 N aqueous sodium hydroxide solution. The precipitated pale yellow oily matter was extracted with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give
Compound 78.hydrochloride 0.77 g (71%) was obtained as a pale yellow foam.

【０１７３】融点: 142-147 ℃ (塩酸塩: 酢酸エチル) 元素分析: 1 塩酸塩として C₃₀H₃₀N₄O₃S ・ HCl 計算値 (%): C 63.99, H 5.55, N 9.95 実測値 (%): C 64.21, H 5.64, N 9.97 FABMS (m/z): 527 (M ⁺ +1)¹ H NMR (遊離塩基: CDCl₃) δ 7.63 (1H, m), 7.35 (2
H, m), 7.24 (3H, m), 7.12 (3H, m), 6.79 (3H, m),
6.75 (1H, s), 6.65 (1H, s), 5.05 (1H, bt, J =5.9),
4.45 (1H, dd, J = 5.9, 15.3), 4.35 (1H, dd, J =
5.9, 15.3), 3.84(6H, s), 3.62 (1H, d, J = 6.9), 3.
58 (1H, d, J = 6.9), 2.83 (2H, t, J =6.9), 1.88 (3
H, s).Melting point: 142-147 ° C. (hydrochloride: ethyl acetate) Elemental analysis: 1 As hydrochloride: C ₃₀ H ₃₀ N ₄ O ₃ S.HCl Calculated value (%): C 63.99, H 5.55, N 9.95 Measured value (%): C 64.21, H 5.64, N 9.97 FABMS (m / z): 527 (M ⁺ +1) ¹ H NMR (free base: CDCl ₃ ) δ 7.63 (1H, m), 7.35 (2
H, m), 7.24 (3H, m), 7.12 (3H, m), 6.79 (3H, m),
6.75 (1H, s), 6.65 (1H, s), 5.05 (1H, bt, J = 5.9),
4.45 (1H, dd, J = 5.9, 15.3), 4.35 (1H, dd, J =
5.9, 15.3), 3.84 (6H, s), 3.62 (1H, d, J = 6.9), 3.
58 (1H, d, J = 6.9), 2.83 (2H, t, J = 6.9), 1.88 (3
H, s).

【０１７４】実施例７９ Ｎ−［２−（３，４−ジメトキシフェニル）エチル］−
２−｛Ｎ−［［１−（４−ジメチルアミノ−２−メチル
フェニル）−２−インドリル］メチル］アミノ｝チアゾ
ール−４−カルボキサミド・２塩酸塩（化合物７９） （１）参考例６で得られる１−（２−メチル−４−ニト
ロフェニル）インドール−２−イルメタノール3.5 g (1
2.4 mmol) 、参考例５で得られる２−（ｔｅｒｔ−ブト
キシカルボニルアミノ）チアゾール−４−カルボン酸エ
チル3.38 g (12.4mmol)およびトリフェニルホスフィン
4.88 g (18.6 mmol)のTHF 80 mL 溶液にDEAD 2.34 mL
(14.9 mmol)をゆっくりと滴下し、室温で2 時間攪拌し
た。反応液を減圧下濃縮後、残渣にエーテルを加え、1
N 塩酸、飽和重曹水、飽和食塩水で順に洗浄し、無水硫
酸マグネシウムで乾燥した。溶媒を減圧下留去後、残渣
をシリカゲルカラムクロマトグラフィー（ヘキサン：酢
酸エチル＝５：１）で精製することにより、２−｛Ｎ−
（ｔｅｒｔ−ブトキシカルボニル）−Ｎ−［［１−（２
−メチル−４−ニトロフェニル）−２−インドール］メ
チル］アミノ｝チアゾール−４−カルボン酸エチル4.79
g (72%)を黄色泡状物質として得た。¹ H NMR (CDCl₃) δ 8.10 (1H, d, J = 2.6), 8.07 (1
H, s), 7.63 (1H, s), 7.61 (1H, dd, J = 2.6, 7.3),
7.54 (1H, d, J = 7.3), 7.14 (2H, m), 6.72 (1H, m),
6.58 (1H, s), 5.36 (1H, d, J = 16.2), 5.32 (1H,
d, J = 16.2), 4.33(2H, q, J = 6.9), 2.05 (3H, s),
1.53 (9H, s), 1.38 (3H, t, J = 6.9).Example 79 N- [2- (3,4-dimethoxyphenyl) ethyl]-
2- {N-[[1- (4-dimethylamino-2-methylphenyl) -2-indolyl] methyl] amino} thiazole-4-carboxamide dihydrochloride (Compound 79) (1) Obtained in Reference Example 6. 1- (2-methyl-4-nitrophenyl) indol-2-ylmethanol 3.5 g (1
2.4 mmol), ethyl 2- (tert-butoxycarbonylamino) thiazole-4-carboxylate obtained in Reference Example 3.38 g (12.4 mmol) and triphenylphosphine.
2.34 mL of DEAD in 80 mL of THF solution of 4.88 g (18.6 mmol)
(14.9 mmol) was slowly added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and 1
The extract was washed with N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to give 2- {N-
(Tert-Butoxycarbonyl) -N-[[1- (2
-Methyl-4-nitrophenyl) -2-indole] methyl] amino} thiazole-4-carboxylate ethyl 4.79
g (72%) was obtained as a yellow foam. ¹ H NMR (CDCl ₃ ) δ 8.10 (1H, d, J = 2.6), 8.07 (1
H, s), 7.63 (1H, s), 7.61 (1H, dd, J = 2.6, 7.3),
7.54 (1H, d, J = 7.3), 7.14 (2H, m), 6.72 (1H, m),
6.58 (1H, s), 5.36 (1H, d, J = 16.2), 5.32 (1H,
d, J = 16.2), 4.33 (2H, q, J = 6.9), 2.05 (3H, s),
1.53 (9H, s), 1.38 (3H, t, J = 6.9).

【０１７５】（２）（１）で得られた化合物4.79 g (8.
93 mmol)をメタノール50 mL に懸濁し、10% 水酸化ナト
リウム水溶液18 mL 溶液を加え、70℃で3 時間攪拌し
た。反応液を濃縮後、残渣を氷水に溶解し、これに4 N
塩酸を加え、pHを3 とした。析出した結晶を濾取し、水
洗、乾燥することにより、２−｛Ｎ−（ｔｅｒｔ−ブト
キシカルボニル）−Ｎ−［［１−（２−メチル−４−ニ
トロフェニル）−２−インドリル］メチル］アミノ｝チ
アゾール−４−カルボン酸3.95 g (87%)を黄色結晶物と
して得た。該カルボン酸3.85 g (7.57 mmol)をDMF 40 m
L に溶解し、３，４−ジメトキシフェネチルアミン1.53
mL (9.07 mmol) 、 HOBt ・ H₂O 2.31 g (15.1 mmol)、
次いでWSC ・ HCl 1.45 g (7.56 mmol)を加え、室温で5
時間攪拌した。反応液を濃縮後、残渣に塩化メチレンを
加え、1 N 塩酸、飽和重曹水、飽和食塩水で順に洗浄
し、無水硫酸マグネシウムで乾燥した。溶媒を減圧下留
去後、残渣を塩化メチレン50 mL に溶解し、氷冷下にTF
A 50 mL を加え、室温で一晩攪拌した。反応混合物を減
圧下濃縮後、残渣を氷水に溶解し、10 N水酸化ナトリウ
ム水溶液でpHを13に調整した。析出した黄色油状物を塩
化メチレンで抽出し、飽和食塩水で洗浄し、無水硫酸マ
グネシウムで乾燥した。溶媒を減圧下留去後、残渣をシ
リカゲルカラムクロマトグラフィー（ヘキサン：酢酸エ
チル＝１：１）で精製することにより、Ｎ−［２−
（３，４−ジメトキシフェニル）エチル］−２−｛Ｎ−
［［１−（２−メチル−４−ニトロフェニル）−２−イ
ンドリル］メチル］アミノ｝チアゾール−４−カルボキ
サミド4.05 g (57% : ３工程) を黄色泡状物として得
た。¹ H NMR (CDCl₃) δ 8.20 (1H, d, J = 2.3), 8.10 (1
H, dd, J = 2.3, 8.6), 7.65 (1H, m), 7.39 (1H, d, J
= 8.6), 7.23 (1H, s), 7.18 (2H, m), 6.98 (1H, bt,
J = 5.9), 6.79 (4H, m), 6.71 (1H, s), 5.13 (1H, b
t, J = 5.6), 4.48(1H, dd, J = 5.6, 15.5), 4.37 (1
H, dd, J = 5.6, 15.5), 3.84 (1H, s), 3.83 (3H, s),
3.60 (2H, m), 2.82 (2H, t, J = 6.9), 1.99 (3H,
s).(2) 4.79 g of the compound obtained in (1) (8.
93 mmol) was suspended in 50 mL of methanol, 18 mL of 10% aqueous sodium hydroxide solution was added, and the mixture was stirred at 70 ° C. for 3 hours. After concentrating the reaction mixture, dissolve the residue in ice water and add 4 N to it.
Hydrochloric acid was added to adjust the pH to 3. The precipitated crystals were collected by filtration, washed with water, and dried to give 2- {N- (tert-butoxycarbonyl) -N-[[1- (2-methyl-4-nitrophenyl) -2-indolyl] methyl]. Amino} thiazole-4-carboxylic acid 3.95 g (87%) was obtained as yellow crystals. The carboxylic acid 3.85 g (7.57 mmol) was added to DMF 40 m.
Dissolve in L, 3,4-dimethoxyphenethylamine 1.53
mL (9.07 mmol), HOBt · H 2 O 2.31 g (15.1 mmol),
Next, 1.45 g (7.56 mmol) of WSC / HCl was added, and the mixture was mixed at room temperature for 5
Stir for hours. After the reaction solution was concentrated, methylene chloride was added to the residue, which was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine in that order, and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was dissolved in methylene chloride (50 mL) and TF was added under ice cooling.
A 50 mL was added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ice water, and the pH was adjusted to 13 with a 10 N aqueous sodium hydroxide solution. The precipitated yellow oily matter was extracted with methylene chloride, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give N- [2-
(3,4-Dimethoxyphenyl) ethyl] -2- {N-
[[1- (2-Methyl-4-nitrophenyl) -2-indolyl] methyl] amino} thiazole-4-carboxamide 4.05 g (57%: 3 steps) was obtained as a yellow foam. ¹ H NMR (CDCl ₃ ) δ 8.20 (1H, d, J = 2.3), 8.10 (1
H, dd, J = 2.3, 8.6), 7.65 (1H, m), 7.39 (1H, d, J
= 8.6), 7.23 (1H, s), 7.18 (2H, m), 6.98 (1H, bt,
J = 5.9), 6.79 (4H, m), 6.71 (1H, s), 5.13 (1H, b
t, J = 5.6), 4.48 (1H, dd, J = 5.6, 15.5), 4.37 (1
H, dd, J = 5.6, 15.5), 3.84 (1H, s), 3.83 (3H, s),
3.60 (2H, m), 2.82 (2H, t, J = 6.9), 1.99 (3H,
s).

【０１７６】（３）（２）で得られた化合物1.5 g (2.6
2 mmol) をエタノール40 mL および濃塩酸40 mL の混合
溶媒に溶解し、塩化スズ・２水和物2.96 g (13.1 mmol)
のエタノール20 mL 溶液を滴下し、室温で一晩攪拌し
た。反応液を減圧下濃縮後、残渣を氷水に溶解し、10 N
水酸化ナトリウムでpHを13とした。塩化メチレンで抽出
後、有機層を飽和食塩水で洗浄し、無水硫酸マグネシウ
ムで乾燥した。溶媒を減圧下留去後、残渣をシリカゲル
カラムクロマトグラフィー（クロロホルム：メタノール
＝３０：１）で精製することにより、Ｎ−［２−（３，
４−ジメトキシフェニル）エチル］−２−｛Ｎ−［［１
−（２−メチル−４−アミノフェニル）−２−インドリ
ル］メチル］アミノ｝チアゾール−４−カルボキサミド
1.07 g (75%)を淡黄色泡状物として得た。¹ H NMR (CDCl₃) δ 7.59 (1H, m), 7.22 (1H, s), 7.1
6 (1H, bt, J = 5.9), 7.11 (2H, m), 6.96 (1H, d, J
= 7.9), 6.86 (1H, m), 6.77 (3H, m), 6.58 (2H, m),
6.51 (1H, dd, J = 2.5, 7.9), 5.28 (1H, bt, J = 5.
9), 4.42 (1H, dd,J = 5.9, 15.8), 4.32 (1H, dd, J =
5.9, 15.8), 3.83 (6H, s), 3.63 (1H, d, J = 6.9),
3.57 (1H, d, J = 6.9), 2.82 (2H, t, J = 6.9), 1.74
(3H, s).(3) The compound obtained in (2) 1.5 g (2.6
2 mmol) was dissolved in a mixed solvent of 40 mL of ethanol and 40 mL of concentrated hydrochloric acid, and tin chloride dihydrate 2.96 g (13.1 mmol)
20 mL of ethanol solution was added dropwise and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ice water,
The pH was adjusted to 13 with sodium hydroxide. After extraction with methylene chloride, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give N- [2- (3,3.
4-dimethoxyphenyl) ethyl] -2- {N-[[1
-(2-Methyl-4-aminophenyl) -2-indolyl] methyl] amino} thiazole-4-carboxamide
1.07 g (75%) was obtained as a pale yellow foam. ¹ H NMR (CDCl ₃ ) δ 7.59 (1H, m), 7.22 (1H, s), 7.1
6 (1H, bt, J = 5.9), 7.11 (2H, m), 6.96 (1H, d, J
= 7.9), 6.86 (1H, m), 6.77 (3H, m), 6.58 (2H, m),
6.51 (1H, dd, J = 2.5, 7.9), 5.28 (1H, bt, J = 5.
9), 4.42 (1H, dd, J = 5.9, 15.8), 4.32 (1H, dd, J =
5.9, 15.8), 3.83 (6H, s), 3.63 (1H, d, J = 6.9),
3.57 (1H, d, J = 6.9), 2.82 (2H, t, J = 6.9), 1.74
(3H, s).

【０１７７】（４）（３）で得られた化合物1.34 g (2.
47 mmol)をメタノール40 mL に懸濁し、水素化シアノホ
ウ素ナトリウム940 mg (15.0 mmol)および触媒量のブロ
モクレゾールグリーンを加えた。反応液の色が黄色にな
るまで7.34 M塩酸／エタノールを加え、これに、氷冷
下、37% ホルマリン1.2 g (14.8 mmolのホルムアルデヒ
ド含有) を滴下した。7.34 M塩酸／エタノールを適宜添
加することにより反応液の色を黄色に保ちながら、室温
で一晩攪拌した。溶媒を減圧下留去後、飽和重曹水／塩
化メチレンで分配し、有機層を飽和食塩水で洗浄し、無
水硫酸マグネシウムで乾燥した。溶媒を留去後、得られ
た粗結晶をTHF に溶解し、7.34 M塩酸／エタノール 1 m
L を加えた。さらにアセトンを加え、析出した白色結晶
を濾取することにより、化合物７９・２塩酸塩0.97 g
(61%)を得た。(4) 1.34 g of the compound obtained in (3) (2.
47 mmol) was suspended in 40 mL of methanol, and 940 mg (15.0 mmol) of sodium cyanoborohydride and a catalytic amount of bromocresol green were added. 7.34 M hydrochloric acid / ethanol was added until the color of the reaction solution became yellow, and 1.2 g (containing 14.8 mmol of formaldehyde) of 37% formalin was added dropwise thereto under ice cooling. The mixture was stirred overnight at room temperature while keeping the color of the reaction solution yellow by appropriately adding 7.34 M hydrochloric acid / ethanol. After evaporating the solvent under reduced pressure, the mixture was partitioned with saturated aqueous sodium hydrogen carbonate / methylene chloride, the organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After distilling off the solvent, the obtained crude crystals were dissolved in THF, and 7.34 M hydrochloric acid / ethanol 1 m was added.
L was added. Acetone was further added, and the precipitated white crystals were collected by filtration to give compound 79.2-hydrochloride 0.97 g
(61%) was obtained.

【０１７８】融点: 130-134 ℃ (遊離塩基: アセトン／
テトラヒドロフラン) 元素分析: 2 塩酸塩・0.5水和物として C₃₂H₃₅N₅O₃S ・2
HCl ・0.5H₂O 計算値 (%): C 58.98, H 5.88, N 10.75 実測値 (%): C 59.09, H 5.91, N 10.80 FABMS (m/z): 570 (M ⁺ +1)¹ H NMR (遊離塩基: CDCl₃) δ 7.61 (1H, m), 7.25 (1
H, d, J = 4.0), 7.11 (4H, m), 6.87 (1H, m), 6.77
(3H, m), 6.60 (3H, m), 5.08 (1H, bt, J = 5.9), 4.4
2 (1H, dd, J = 5.9, 15.8), 4.35 (1H, dd, J = 5.9,
15.3), 3.84 (3H,s), 3.83 (3H, s), 3.69 (1H, d, J =
6.9), 3.65 (1H, d, J = 6.9), 3.01 (6H, s), 2.83
(2H, t, J = 6.9), 1.83 (3H, s).Melting point: 130-134 ° C. (free base: acetone /
Tetrahydrofuran) Elemental analysis: C ₃₂ H ₃₅ N ₅ O ₃ S
HCl ・ 0.5H ₂ O Calculated value (%): C 58.98, H 5.88, N 10.75 Measured value (%): C 59.09, H 5.91, N 10.80 FABMS (m / z): 570 (M ⁺ +1) ¹ H NMR (free base: CDCl ₃ ) δ 7.61 (1H, m), 7.25 (1
H, d, J = 4.0), 7.11 (4H, m), 6.87 (1H, m), 6.77
(3H, m), 6.60 (3H, m), 5.08 (1H, bt, J = 5.9), 4.4
2 (1H, dd, J = 5.9, 15.8), 4.35 (1H, dd, J = 5.9,
15.3), 3.84 (3H, s), 3.83 (3H, s), 3.69 (1H, d, J =
6.9), 3.65 (1H, d, J = 6.9), 3.01 (6H, s), 2.83
(2H, t, J = 6.9), 1.83 (3H, s).

【０１７９】実施例８０ Ｎ−｛４−［［２−（３，４−ジメトキシフェニル）エ
チルアミノ］カルボニル］−２−チアゾリル｝−１−
（１−メチル−４−ピペリジニル）インドール−２−カ
ルボキサミド・０．５フマル酸塩（化合物８０） 融点: 214-217 ℃ (0.5 フマル酸塩: エタノール) 元素分析: 0.5 フマル酸塩として C₂₉H₃₃N₅O₄S ・0.5C₄
H₄O₄ 計算値 (%): C 61.47, H 5.82, N 11.56 実測値 (%): C 61.16, H 5.92, N 11.36 FABMS (m/z): 548 (M ⁺ +1)¹ H NMR (遊離塩基: CDCl₃) δ 9.48 (1H, bs), 7.86
(1H, d, J = 8.6), 7.79(1H, s), 7.69 (1H, d, J = 7.
9), 7.33 (1H, t, J = 7.9), 7.16 (3H, m), 6.83 (1H,
d, J = 7.9), 6.81 (1H, m), 6.77 (1H, bs), 5.34 (1
H, m), 3.87 (3H,s), 3.86 (3H, s), 3.71 (1H, d, J =
6.9), 3.67 (1H, d, J = 6.9), 3.09 (2H, bd, J = 1
1.2), 2.87 (2H, t, J = 6.9), 2.79 (2H, m), 2.42 (3
H, s), 2.30 (2H, m), 1.95 (2H, m).Example 80 N- {4-[[2- (3,4-dimethoxyphenyl) ethylamino] carbonyl] -2-thiazolyl} -1-
(1-Methyl-4-piperidinyl) indole-2-carboxamide.0.5 fumarate (Compound 80) Melting point: 214-217 ° C. (0.5 fumarate: ethanol) Elemental analysis: 0.5 C ₂₉ H as fumarate ₃₃ N ₅ O ₄ S ・ 0.5C ₄
H ₄ O ₄ Calculated value (%): C 61.47, H 5.82, N 11.56 Measured value (%): C 61.16, H 5.92, N 11.36 FABMS (m / z): 548 (M ⁺ +1) ¹ H NMR ( Free base: CDCl ₃ ) δ 9.48 (1H, bs), 7.86
(1H, d, J = 8.6), 7.79 (1H, s), 7.69 (1H, d, J = 7.
9), 7.33 (1H, t, J = 7.9), 7.16 (3H, m), 6.83 (1H,
d, J = 7.9), 6.81 (1H, m), 6.77 (1H, bs), 5.34 (1
H, m), 3.87 (3H, s), 3.86 (3H, s), 3.71 (1H, d, J =
6.9), 3.67 (1H, d, J = 6.9), 3.09 (2H, bd, J = 1
1.2), 2.87 (2H, t, J = 6.9), 2.79 (2H, m), 2.42 (3
H, s), 2.30 (2H, m), 1.95 (2H, m).

【０１８０】参考例１ １−ベンジルインドール−2 −カルボン酸 （１）インドール−２−カルボン酸エチル3.0 g (15.9
mmol) をDMF 50 mL に溶解し、これに、氷冷下、カリウ
ムｔｅｒｔ−ブチラート2.14g (19.1 mmol) を加え、30
分間攪拌した。次いで、臭化ベンジル2.26 mL (19.0 mm
ol) を加え、室温で5 時間攪拌した。反応液に氷水を加
え、酢酸エチルで抽出した。有機層を飽和食塩水で洗浄
し、無水硫酸マグネシウムで乾燥し、減圧濃縮すること
により、１−ベンジルインドール−２−カルボン酸エチ
ル5.23 g (定量的) を白色結晶として得た。¹ H NMR (CDCl₃) δ 7.70 (1H, d, J = 8.3), 7.1-7.4
(7H, m), 7.0-7.1 (2H,m), 5.84 (2H, s), 4.3-4.4 (2
H, m), 1.35 (3H, t, J = 6.9).Reference Example 1 1-Benzylindole-2-carboxylic acid (1) Ethyl indole-2-carboxylate 3.0 g (15.9)
(mmol) was dissolved in 50 mL of DMF, and 2.14 g (19.1 mmol) of potassium tert-butyrate was added thereto under ice cooling,
Stir for minutes. Then benzyl bromide 2.26 mL (19.0 mm
ol) was added and the mixture was stirred at room temperature for 5 hours. Ice water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give ethyl 1-benzylindole-2-carboxylate (5.23 g (quantitative)) as white crystals. ¹ H NMR (CDCl ₃ ) δ 7.70 (1H, d, J = 8.3), 7.1-7.4
(7H, m), 7.0-7.1 (2H, m), 5.84 (2H, s), 4.3-4.4 (2
H, m), 1.35 (3H, t, J = 6.9).

【０１８１】（２）（１）で得られた化合物6.7 g (24.
0 mmol) をエタノール100 mlに溶解し、これに、氷冷
下、10N 水酸化ナトリウム水溶液7.0ml (70 mmol) を加
え、60℃で1 時間攪拌した。反応液を減圧濃縮後、残渣
に水を加え、pHを4 とした。析出した結晶を濾取するこ
とにより、１−ベンジルインドール−２−カルボン酸4.
97g (82%) を白色結晶として得た。¹ H NMR (DMSO-d₆) δ 12.7 (1H, bs), 7.68 (1H, d, J
= 7.9), 7.45 (1H, d,J = 8.6), 7.30(1H, s), 7.0-7.
3 (7H, m), 5.88 (2H, s).(2) 6.7 g (24.) of the compound obtained in (1)
(0 mmol) was dissolved in 100 ml of ethanol, 7.0 ml (70 mmol) of 10N sodium hydroxide aqueous solution was added thereto under ice cooling, and the mixture was stirred at 60 ° C. for 1 hour. The reaction solution was concentrated under reduced pressure, and water was added to the residue to adjust the pH to 4. The precipitated crystals were collected by filtration to give 1-benzylindole-2-carboxylic acid 4.
97 g (82%) was obtained as white crystals. ¹ H NMR (DMSO-d ₆ ) δ 12.7 (1H, bs), 7.68 (1H, d, J
= 7.9), 7.45 (1H, d, J = 8.6), 7.30 (1H, s), 7.0-7.
3 (7H, m), 5.88 (2H, s).

【０１８２】参考例２ １−シクロペンチルインドール−２−カルボン酸 （１）インドール−２−カルボン酸8.0 g (49.6 mmol)
をDMF 200 mLに溶解し、塩化ベンジルトリエチルアンモ
ニウム11.3 g (49.6 mmol)、炭酸カリウム180g (1.3 mo
l)および臭化ｔｅｒｔ−ブチル275 mL (2.39 mol) を加
え、55℃で10時間撹拌した。不溶物を濾去し、濾液に1
N 塩酸を加え、酢酸エチルで抽出した。有機層を飽和重
曹水、飽和食塩水で順に洗浄後、無水硫酸マグネシウム
で乾燥し、溶媒を減圧下留去することにより、インドー
ル−２−カルボン酸ｔｅｒｔ−ブチル2.29 g (21%)を白
色結晶として得た。¹ H NMR (CDCl₃) δ 8.29 (1H, bs), 7.68 (1H, dd, J
= 1.0, 7.9), 7.41 (1H,dd, J = 1.0, 8.3), 7.34 (1H,
m), 7.15 (2H, m), 1.62 (9H, s).Reference Example 2 1-Cyclopentylindole-2-carboxylic acid (1) Indole-2-carboxylic acid 8.0 g (49.6 mmol)
Was dissolved in 200 mL of DMF, and 11.3 g (49.6 mmol) of benzyltriethylammonium chloride and 180 g (1.3 mo of potassium carbonate) were added.
l) and tert-butyl bromide 275 mL (2.39 mol) were added, and the mixture was stirred at 55 ° C for 10 hr. Insoluble matter was filtered off, and 1 was added to the filtrate.
N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give tert-butyl indole-2-carboxylate 2.29 g (21%) as white crystals. Got as. ¹ H NMR (CDCl ₃ ) δ 8.29 (1H, bs), 7.68 (1H, dd, J
= 1.0, 7.9), 7.41 (1H, dd, J = 1.0, 8.3), 7.34 (1H,
m), 7.15 (2H, m), 1.62 (9H, s).

【０１８３】（２）（１）で得られた化合物2.36 g (1
0.9 mmol)をDMSO 20 mLに溶解し、ｐ−トルエンスルホ
ニルオキシシクロペンタン7.8 g (32.5 mmol) のDMSO 3
0 mL溶液を2 時間かけて滴下し、室温で14時間撹拌し
た。反応液に水を加え、酢酸エチルで抽出した。有機層
を飽和食塩水で洗浄し、無水硫酸マグネシウムで乾燥
し、溶媒を減圧下留去することにより、１−シクロペン
チルインドール−２−カルボン酸ｔｅｒｔ−ブチル2.24
g (72%)を無色油状物として得た。¹ H NMR (CDCl₃) δ 7.83 (1H, d, J = 7.9), 7.56 (1
H, d, J = 8.6), 7.1-7.3(3H, m), 6.05 (1H, m), 2.34
(2H, m), 2.15 (4H, m), 1.82 (2H, m), 1.68 (9H,
s).(2) 2.36 g (1) of the compound obtained in (1)
0.9 mmol) was dissolved in 20 mL of DMSO, and 7.8 g (32.5 mmol) of p-toluenesulfonyloxycyclopentane DMSO 3 was dissolved.
The 0 mL solution was added dropwise over 2 hours, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give tert-butyl 1-cyclopentylindole-2-carboxylate 2.24.
g (72%) was obtained as a colorless oil. ¹ H NMR (CDCl ₃ ) δ 7.83 (1H, d, J = 7.9), 7.56 (1
H, d, J = 8.6), 7.1-7.3 (3H, m), 6.05 (1H, m), 2.34
(2H, m), 2.15 (4H, m), 1.82 (2H, m), 1.68 (9H,
s).

【０１８４】（３）（２）で得られた化合物2.24 g (7.
85 mmol)を塩化メチレン20 mL に溶解し、これに、氷冷
下、TFA 20 mL を加え、2 時間攪拌した。反応混合物を
氷水に注ぎ、pHを12に調整した。水層を分離後、酢酸エ
チルで洗浄し、4 N 塩酸でpHを3 に調整した。析出した
結晶を濾取することにより、１−シクロペンチルインド
ール−２−カルボン酸0.93 g (52%)を白色結晶として得
た。¹ H NMR (DMSO-d₆) δ 12.86 (1H, bs), 1.72 (2H, m),
7.67 (1H, d, J = 7.9), 7.56 (1H, d, J = 8.6), 7.2
8 (1H, m), 7.20 (1H, s), 7.11 (1H, m), 5.9-6.0 (1
H, m), 2.1-2.2 (2H, m), 2.00 (4H, m).(3) 2.24 g of the compound obtained in (2) (7.
(85 mmol) was dissolved in 20 mL of methylene chloride, 20 mL of TFA was added thereto under ice cooling, and the mixture was stirred for 2 hours. The reaction mixture was poured into ice water and the pH was adjusted to 12. The aqueous layer was separated, washed with ethyl acetate, and the pH was adjusted to 3 with 4 N hydrochloric acid. The precipitated crystals were collected by filtration to give 0.93 g (52%) of 1-cyclopentylindole-2-carboxylic acid as white crystals. ¹ H NMR (DMSO-d ₆ ) δ 12.86 (1H, bs), 1.72 (2H, m),
7.67 (1H, d, J = 7.9), 7.56 (1H, d, J = 8.6), 7.2
8 (1H, m), 7.20 (1H, s), 7.11 (1H, m), 5.9-6.0 (1
H, m), 2.1-2.2 (2H, m), 2.00 (4H, m).

【０１８５】参考例３ １−（２−ピリジル）インドール−２−カルボン酸 （１）インドール10.0 g (85.4 mmol)をDMF 200 mLに溶
解し、これに、氷冷下、60% 水素化ナトリウム4.13 g
(103.3 mmol) をあらかじめペンタンで洗浄したものを
加え、室温で30分間攪拌した。次いで、２−フルオロピ
リジン12.5 mL (145.2 mmol)を加え、100 ℃で30分間加
熱した。反応液を氷冷後、4 N 塩酸を加え、溶媒を減圧
下留去した。残渣に氷水を加え、10 N水酸化ナトリウム
でpHを11に調整した。エーテルで抽出後、有機層を飽和
食塩水で洗浄し、無水硫酸マグネシウムで乾燥した。溶
媒を留去後、残渣をシリカゲルカラムクロマトグラフィ
ー（ヘキサン：酢酸エチル＝５：１）で精製することに
より、１−（２−ピリジル）インドール6.83 g (75%)を
オレンジ色油状物として得た。¹ H-NMR (CDCl₃) δ 8.57 (1H, m), 8.20 (1H, dd, J =
1.0, 8.3), 7.82 (1H,m), 7.73 (1H, d, J = 3.3), 7.
67 (1H, m), 7.50 (1H, m), 7.25 (3H, m), 6.71 (1H,
dd, J = 0.7, 3.3).Reference Example 3 1- (2-pyridyl) indole-2-carboxylic acid (1) 10.0 g (85.4 mmol) of indole was dissolved in 200 mL of DMF, and 60% sodium hydride 4.13 was added thereto under ice cooling. g
(103.3 mmol) previously washed with pentane was added, and the mixture was stirred at room temperature for 30 minutes. Then, 12.5 mL (145.2 mmol) of 2-fluoropyridine was added, and the mixture was heated at 100 ° C for 30 minutes. The reaction solution was ice-cooled, 4 N hydrochloric acid was added, and the solvent was evaporated under reduced pressure. Ice water was added to the residue, and the pH was adjusted to 11 with 10 N sodium hydroxide. After extraction with ether, the organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1) to obtain 1- (2-pyridyl) indole (6.83 g, 75%) as an orange oily substance. . ¹ H-NMR (CDCl ₃ ) δ 8.57 (1H, m), 8.20 (1H, dd, J =
1.0, 8.3), 7.82 (1H, m), 7.73 (1H, d, J = 3.3), 7.
67 (1H, m), 7.50 (1H, m), 7.25 (3H, m), 6.71 (1H,
dd, J = 0.7, 3.3).

【０１８６】（２）（１）で得られた化合物15.4 g (7
9.3 mmol)をTHF 300 mLに溶解し、アルゴン気流下、内
温が-68 ℃になるまで冷却した。1.66 M ｎ−ブチルリ
チウム (ヘキサン溶液) 96 mL (159.4 mmol 含有) を45
分間かけて滴下し、-68 ℃で1.5時間攪拌した。反応混
合物を、ドライアイスをエーテル500 mLに懸濁させた懸
濁液に注ぎ、一晩放置した。溶媒を減圧下留去後、残渣
を氷水に溶解し、エーテルで洗浄した。水層を氷冷し、
4 N 塩酸でpHを1.8 とし、析出した粘稠固体を酢酸エチ
ルで抽出し、有機層を無水硫酸マグネシウムで乾燥し
た。溶媒を減圧下留去後、得られた粗結晶をイソプロピ
ルエーテルでトリチュレーションすることにより、１−
（２−ピリジル）インドール−２−カルボン酸15.8 g
(84%)を淡黄色結晶物として得た。¹ H-NMR (CDCl₃) δ 8.64 (1H, m), 7.90 (1H, m), 7.7
3 (1H, d, J = 7.9), 7.54 (1H, s), 7.43 (1H, d, J =
8.3), 7.37 (1H, m), 7.34 (2H, m), 7.23 (1H,m), 6.
39 (1H, bs).(2) 15.4 g (7) of the compound obtained in (1)
9.3 mmol) was dissolved in THF (300 mL), and the solution was cooled under an argon stream until the internal temperature reached -68 ° C. 1.66 M n-butyllithium (hexane solution) 96 mL (containing 159.4 mmol) 45
The mixture was added dropwise over 1 minute, and the mixture was stirred at -68 ° C for 1.5 hours. The reaction mixture was poured into a suspension of dry ice in 500 mL of ether and left overnight. After evaporating the solvent under reduced pressure, the residue was dissolved in ice water and washed with ether. Cool the water layer with ice,
The pH was adjusted to 1.8 with 4 N hydrochloric acid, the precipitated viscous solid was extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained crude crystals were triturated with isopropyl ether to give 1-
(2-pyridyl) indole-2-carboxylic acid 15.8 g
(84%) was obtained as pale yellow crystals. ¹ H-NMR (CDCl ₃ ) δ 8.64 (1H, m), 7.90 (1H, m), 7.7
3 (1H, d, J = 7.9), 7.54 (1H, s), 7.43 (1H, d, J =
8.3), 7.37 (1H, m), 7.34 (2H, m), 7.23 (1H, m), 6.
39 (1H, bs).

【０１８７】参考例４ １−（２−クロロ−４−ニトロフェニル）インドール−
２−カルボン酸 （１）インドール−２−カルボン酸エチル5.0 g (26.43
mmol)をDMF 100 mLに溶解し、これに、氷冷下、60% 水
素化ナトリウム1.59 g (39.75 mmol) をあらかじめペン
タンで洗浄したものを加え、室温で30分間攪拌した。次
いで、３−クロロ−４−フルオロニトロベンゼン6.96 g
(39.64 mmol) を加え、110 ℃で40分間加熱した。反応
液を氷冷後、1 N 塩酸を加え、溶媒を減圧下留去した。
残渣にエーテルを加え、飽和重曹水、飽和食塩水で順に
洗浄した。溶媒を留去後、残渣をシリカゲルカラムクロ
マトグラフィー（ヘキサン：酢酸エチル＝５：１）で精
製し、得られた粗結晶をイソプロピルエーテルでトリチ
ュレーションすることにより、１−（２−メチル−４−
ニトロフェニル）インドール−２−カルボン酸エチル6.
83 g (75%)を黄色結晶物として得た。¹ H-NMR (CDCl₃) δ 8.46 (1H, d, J = 2.5), 8.30 (1
H, dd, J = 2.5, 8.4), 7.77 (1H, d, J = 7.4), 7.60
(1H, d, J = 8.4), 7.53 (1H, d, J = 1.0), 7.30(2H,
m), 6.92 (1H, d, J = 7.9), 4.25 (2H, q, J = 6.9),
1.28 (3H, t, J =6.9).Reference Example 4 1- (2-chloro-4-nitrophenyl) indole-
2-Carboxylic Acid (1) Ethyl Indole-2-carboxylate 5.0 g (26.43
mmol) was dissolved in 100 mL of DMF, and 60% sodium hydride 1.59 g (39.75 mmol) washed with pentane in advance under ice cooling was added thereto, and the mixture was stirred at room temperature for 30 minutes. Then, 3-chloro-4-fluoronitrobenzene 6.96 g
(39.64 mmol) was added and the mixture was heated at 110 ° C. for 40 minutes. The reaction solution was ice-cooled, 1 N hydrochloric acid was added, and the solvent was evaporated under reduced pressure.
Ether was added to the residue, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine. After evaporating the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 5: 1), and the obtained crude crystals were triturated with isopropyl ether to give 1- (2-methyl-4). −
Nitrophenyl) indole-2-carboxylate ethyl 6.
83 g (75%) was obtained as yellow crystals. ¹ H-NMR (CDCl ₃ ) δ 8.46 (1H, d, J = 2.5), 8.30 (1
H, dd, J = 2.5, 8.4), 7.77 (1H, d, J = 7.4), 7.60
(1H, d, J = 8.4), 7.53 (1H, d, J = 1.0), 7.30 (2H,
m), 6.92 (1H, d, J = 7.9), 4.25 (2H, q, J = 6.9),
1.28 (3H, t, J = 6.9).

【０１８８】（２）（１）で得られた化合物6.5 g (18.
85 mmol)をメタノール150 mLに懸濁し、水酸化ナトリウ
ム3.9 g (97.5 mmol) の水30 mL 溶液を加え、70℃で2
時間攪拌した。反応液を濃縮後、残渣を氷水に溶解し、
これに4 N 塩酸を加え、pHを2.0 とした。析出した結晶
を濾取し、水洗、乾燥することにより、１−（２−クロ
ロ−４−ニトロフェニル）インドール−２−カルボン酸
5.83 g (98%)を白色結晶物として得た。 EIMS (m/z): 316 (M⁺ )(2) 6.5 g (18.) of the compound obtained in (1)
85 mmol) in 150 mL of methanol, add a solution of 3.9 g (97.5 mmol) of sodium hydroxide in 30 mL of water, and add 2 at 70 ° C.
Stir for hours. After concentrating the reaction solution, dissolve the residue in ice water,
4N hydrochloric acid was added thereto to adjust the pH to 2.0. The precipitated crystals were collected by filtration, washed with water and dried to give 1- (2-chloro-4-nitrophenyl) indole-2-carboxylic acid.
5.83 g (98%) was obtained as white crystals. EIMS (m / z): 316 (M ⁺ )

【０１８９】参考例５ ２−（ｔｅｒｔ−ブトキシカルボニルアミノ）チアゾー
ル−４−カルボン酸エチル ２−アミノチアゾール−４−カルボン酸エチル5.0 g (2
9.04 mmol)を塩化メチレン80 mL に懸濁し、DMAP 355 m
g (2.91 mmol) を加え、これに、氷冷下、ジ（ｔｅｒｔ
−ブチル）ジカーボネート6.3 mL (29.44 mmol) の塩化
メチレン10 mL溶液を滴下し、室温で一晩攪拌した。反
応液を減圧下濃縮後、残渣にエーテルを加え、1 M 硫酸
水素カリウム、飽和重曹水、飽和食塩水で順に洗浄し、
無水硫酸マグネシウムで乾燥した。溶媒を留去後、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：
ヘキサン＝１：４）で精製し、得られた粗結晶をヘキサ
ンでトリチュレーションすることにより、２−（ｔｅｒ
ｔ−ブトキシカルボニルアミノ）チアゾール−４−カル
ボン酸エチル5.86 g (74.1%)を白色結晶として得た。¹ H NMR (CDCl₃) δ 8.74 (1H, bs), 7.79 (1H, s), 4.
38 (2H, q, J = 6.8), 1.53 (9H, s), 1.38 (3H, t, J
= 6.8).Reference Example 5 Ethyl 2- (tert-butoxycarbonylamino) thiazole-4-carboxylate Ethyl 2-aminothiazole-4-carboxylate 5.0 g (2
9.04 mmol) in 80 mL of methylene chloride, and DMAP 355 m
g (2.91 mmol) was added, and to this was added di (tert) under ice cooling.
A solution of 6.3 mL (29.44 mmol) of -butyl) dicarbonate in 10 mL of methylene chloride was added dropwise, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, ether was added to the residue, and the mixture was washed successively with 1 M potassium hydrogen sulfate, saturated aqueous sodium hydrogen carbonate and saturated brine,
It was dried over anhydrous magnesium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (ethyl acetate:
2- (ter) by purifying with hexane = 1: 4) and triturating the obtained crude crystals with hexane.
Ethyl t-butoxycarbonylamino) thiazole-4-carboxylate (5.86 g, 74.1%) was obtained as white crystals. ¹ H NMR (CDCl ₃ ) δ 8.74 (1H, bs), 7.79 (1H, s), 4.
38 (2H, q, J = 6.8), 1.53 (9H, s), 1.38 (3H, t, J
= 6.8).

【０１９０】参考例６ １−（２−メチル−４−ニトロフェニル）インドール−
２−イルメタノール （１）インドール−２−カルボン酸エチル6.0 g (31.7
mmol) をTHF 100 mLに溶解し、これに、氷冷下、水素化
リチウムアルミニウム 1.32 g (34.8 mmol) を加え、20
分間攪拌した後、氷、次いで4 N 塩酸を徐々に加えた。
溶媒を減圧下留去後、残渣を酢酸エチル／飽和重曹水で
分配した。有機層を飽和食塩水で洗浄し、無水硫酸マグ
ネシウムで乾燥した。溶媒を留去後、残渣をシリカゲル
カラムクロマトグラフィー（ヘキサン：酢酸エチル＝
３：１）で精製し、得られた油状物をTHF 40 mL に溶解
した。イミダゾール2.64 g (38.8 mmol)およびｔｅｒｔ
−ブチルジメチルクロロシラン5.84 g (38.8 mmol)を加
え、室温で1 時間攪拌した。溶媒を留去後、残渣に酢酸
エチルを加え、飽和食塩水で洗浄し、無水硫酸マグネシ
ウムで乾燥した。溶媒を減圧下留去後、残渣をシリカゲ
ルカラムクロマトグラフィー（ヘキサン：酢酸エチル＝
７：１）で精製することにより、２−［（ｔｅｒｔ−ブ
チルジメチルシリルオキシ）メチル］インドール7.02 g
(85% ：２工程)を淡黄色油状物として得た。Reference Example 6 1- (2-Methyl-4-nitrophenyl) indole-
2-ylmethanol (1) Ethyl indole-2-carboxylate 6.0 g (31.7
mmol) in 100 mL of THF, and under cooling with ice, 1.32 g (34.8 mmol) of lithium aluminum hydride was added to the solution.
After stirring for 1 minute, ice and then 4 N hydrochloric acid were gradually added.
The solvent was evaporated under reduced pressure, and the residue was partitioned with ethyl acetate / saturated aqueous sodium hydrogen carbonate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
The resulting oily substance was dissolved in 40 mL of THF. Imidazole 2.64 g (38.8 mmol) and tert
-Butyldimethylchlorosilane (5.84 g, 38.8 mmol) was added, and the mixture was stirred at room temperature for 1 hr. After the solvent was distilled off, ethyl acetate was added to the residue, washed with saturated saline and dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (hexane: ethyl acetate =
7: 1) to give 2-[(tert-butyldimethylsilyloxy) methyl] indole 7.02 g
(85%: 2 steps) was obtained as a pale yellow oil.

【０１９１】（２）（１）で得られた化合物6.8 g (26.
0 mmol) をDMF 100 mLに溶解し、これに、氷冷下、60%
水素化ナトリウム 1.25 g (31.3 mmol) をあらかじめペ
ンタンで洗浄したものを加え、室温で30分間攪拌した。
次いで、２−フルオロ−５−ニトロトルエン4.44 g (2
8.62 mmol) を加え、室温で4 時間攪拌した。反応液を
減圧下濃縮後、残渣を酢酸エチル／飽和食塩水で分配
し、有機層を無水硫酸マグネシウムで乾燥した。溶媒を
留去後、残渣をシリカゲルカラムクロマトグラフィー
（ヘキサン：酢酸エチル＝７：１）で精製し、得られた
粗結晶をヘキサン／イソプロピルエーテルでトリチュレ
ーションすることにより、２−［（ｔｅｒｔ−ブチルジ
メチルシリルオキシ）メチル］−１−（２−メチル−４
−ニトロフェニル）インドール5.70 g (55%)を黄色結晶
物として得た。¹ H NMR (CDCl₃) δ 8.34 (1H, d, J = 2.6), 8.26 (1
H, dd, J = 2.6, 8.6), 7.73 (1H, m), 7.54 (1H, d, J
= 8.6), 7.23 (2H, m), 6.83 (1H, m), 6.72 (1H, s),
4.67 (1H, d, J = 12.9), 4.63 (1H, d, J = 12.9),
2.12 (3H, s), 0.86(9H, s), -0.03 (6H, s).(2) 6.8 g (26.) of the compound obtained in (1)
(0 mmol) was dissolved in 100 mL of DMF, and 60% of this was dissolved under ice cooling.
Sodium hydride (1.25 g, 31.3 mmol) previously washed with pentane was added, and the mixture was stirred at room temperature for 30 minutes.
Then, 2-fluoro-5-nitrotoluene 4.44 g (2
(8.62 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was partitioned with ethyl acetate / saturated brine, and the organic layer was dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (hexane: ethyl acetate = 7: 1), and the obtained crude crystals were triturated with hexane / isopropyl ether to give 2-[(tert- Butyldimethylsilyloxy) methyl] -1- (2-methyl-4)
-Nitrophenyl) indole 5.70 g (55%) was obtained as yellow crystals. ¹ H NMR (CDCl ₃ ) δ 8.34 (1H, d, J = 2.6), 8.26 (1
H, dd, J = 2.6, 8.6), 7.73 (1H, m), 7.54 (1H, d, J
= 8.6), 7.23 (2H, m), 6.83 (1H, m), 6.72 (1H, s),
4.67 (1H, d, J = 12.9), 4.63 (1H, d, J = 12.9),
2.12 (3H, s), 0.86 (9H, s), -0.03 (6H, s).

【０１９２】（３）（２）で得られた化合物5.47 g (1
3.8 mmol)をTHF 100 mLに溶解し、4 N塩酸40 mL を加
え、室温で2 時間攪拌した。重曹を徐々に加えてpHを7
とし、反応混合物を減圧下濃縮した。残渣に酢酸エチル
を加え、飽和重曹水、飽和食塩水で順に洗浄し、無水硫
酸マグネシウムで乾燥した。溶媒を減圧下留去後、得ら
れた粗結晶をヘキサン／イソプロピルエーテルでトリチ
ュレーションすることにより、１−（２−メチル−４−
ニトロフェニル）インドール−２−イルメタノール3.67
g (94%)を黄色結晶物として得た。¹ H NMR (CDCl₃) δ 8.29 (1H, d, J = 2.6), 8.21 (1
H, dd, J = 2.6, 8.6), 7.68 (1H, m), 7.50 (1H, d, J
= 8.6), 7.18 (2H, m), 6.79 (1H, m), 6.71 (1H, s),
4.59 (1H, d, J = 13.2), 4.52 (1H, d, J = 13.2),
2.06 (3H, s), 1.62(1H, bs).(3) The compound obtained in (2) 5.47 g (1
3.8 mmol) was dissolved in 100 mL of THF, 40 mL of 4 N hydrochloric acid was added, and the mixture was stirred at room temperature for 2 hours. Slowly add baking soda to bring the pH to 7
And the reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the obtained crude crystals were triturated with hexane / isopropyl ether to give 1- (2-methyl-4-).
Nitrophenyl) indol-2-ylmethanol 3.67
g (94%) was obtained as yellow crystals. ¹ H NMR (CDCl ₃ ) δ 8.29 (1H, d, J = 2.6), 8.21 (1
H, dd, J = 2.6, 8.6), 7.68 (1H, m), 7.50 (1H, d, J
= 8.6), 7.18 (2H, m), 6.79 (1H, m), 6.71 (1H, s),
4.59 (1H, d, J = 13.2), 4.52 (1H, d, J = 13.2),
2.06 (3H, s), 1.62 (1H, bs).

【０１９３】参考例７ 錠剤 常法により次の組成からなる錠剤を作成する。 化合物４０ １００ｍｇ 乳 糖 ６０ｍｇ 馬鈴薯でんぷん ３０ｍｇ ポリビニルアルコール ２ｍｇ ステアリン酸マグネシウム １ｍｇ タール色素 微量Reference Example 7 Tablet A tablet having the following composition is prepared by a conventional method. Compound 40 100 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Trace amount

【０１９４】参考例８ 散剤 常法により次の組成からなる散剤を作成する。 化合物５３ １５０ｍｇ 乳 糖 ２８０ｍｇReference Example 8 Powder A powder having the following composition is prepared by a conventional method. Compound 53 150 mg Lactose 280 mg

【０１９５】参考例９ 常法により次の組成からなるシロップ剤を作成する。 化合物４０ １００ｍｇ 精製白糖 ４０ ｇ ｐ−ヒドロキシ安息香酸エチル ４０ｍｇ ｐ−ヒドロキシ安息香酸プロピル １０ｍｇ ストロベリーフレーバー ０．１ｃｃ これに水を加えて全量１００ｃｃとする。Reference Example 9 A syrup having the following composition is prepared by a conventional method. Compound 40 100 mg Purified sucrose 40 g Ethyl p-hydroxybenzoate 40 mg Propyl p-hydroxybenzoate 10 mg Strawberry flavor 0.1 cc To this, water is added to bring the total amount to 100 cc.

【０１９６】[0196]

【発明の効果】本発明により、強力な細胞接着阻害活性
を有し、抗炎症剤、抗アレルギー剤、臓器移植時の拒絶
反応の抑制剤、ガン転移抑制剤などとして有用なチアゾ
ール誘導体およびその薬理学的に許容される塩を提供す
ることができる。INDUSTRIAL APPLICABILITY According to the present invention, a thiazole derivative having a strong cell adhesion-inhibiting activity and useful as an anti-inflammatory agent, an anti-allergic agent, a rejection inhibitor for organ transplantation, a cancer metastasis inhibitor, etc. A physically acceptable salt can be provided.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl.⁶ 識別記号 庁内整理番号 ＦＩ 技術表示箇所 Ａ６１Ｋ 31/44 ＡＤＵ Ａ６１Ｋ 31/44 ＡＤＵ 31/445 ＡＥＤ 31/445 ＡＥＤ Ｃ０７Ｄ 277/56 Ｃ０７Ｄ 277/56 417/14 ２０９ 417/14 ２０９ ３３３ ３３３ (72)発明者 熊沢 利昭 静岡県駿東郡長泉町下土狩1194−83 (72)発明者 関根 進 神奈川県横浜市都筑区荏田東３−１−10− 105─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/44 ADU A61K 31/44 ADU 31/445 AED 31/445 AED C07D 277/56 C07D 277 / 56 417/14 209 417/14 209 333 333 (72) Inventor Toshiaki Kumazawa 1194-83 Shimochikari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture Inventor Susumu Sekine 3-10-10 Edahigashi, Tsuzuki-ku, Yokohama-shi, Kanagawa Prefecture

Claims (1)

【特許請求の範囲】[Claims] 【請求項１】 式（Ｉ） 【化１】 ［式中、Ｒ¹ は、水素、低級アルキル、ヒドロキシ、低
級アルコキシ、カルボキシ、低級アルコキシカルボニル
または置換もしくは非置換のアリールを表し、Ｒ ² およ
びＲ³ は、同一または異なって水素または低級アルキル
を表し、Ａは、 【化２】 （式中、Ｒ⁴ 、Ｒ⁵ およびＲ⁶ は、同一または異なって
水素、置換もしくは非置換の低級アルキル、低級シクロ
アルキル、低級シクロアルキルアルキル、ヒドロキシ、
低級アルコキシ、カルボキシ、低級アルコキシカルボニ
ル、低級アルカノイル、ハロゲン、ニトロ、アミノ、モ
ノあるいはジ低級アルキルアミノ、置換もしくは非置換
のアラルキル、置換もしくは非置換のアリール、置換も
しくは非置換の芳香族複素環基または置換もしくは非置
換の脂環式複素環基を表し、Ｙは、Ｏ、Ｓ、ＮＨまたは
−Ｃ＝Ｃ−を表す）または 【化３】 （式中、Ｚ¹ およびＺ² は、共に水素を表すかＺ¹ とＺ
² が一緒になって単結合を表し、ｎおよびｐは、同一ま
たは異なって０または１を表し、Ｒ⁴ およびＲ⁵は前記
と同義である）を表し、Ｂは、−Ｃ（Ｏ）Ｎ（Ｒ⁷ ）−
（式中、Ｒ⁷ は、水素または低級アルキルを表す）また
は−ＣＨ₂ ＮＨ−を表し、ｍは、０または１を表し、Ｄ
は、置換もしくは非置換のアリール、置換もしくは非置
換の芳香族複素環基または置換もしくは非置換の脂環式
複素環基を表す］で表されるチアゾール誘導体またはそ
の薬理学的に許容される塩。1. A compound of the formula (I)[Wherein, R¹Is hydrogen, lower alkyl, hydroxy, low
Grade alkoxy, carboxy, lower alkoxycarbonyl
Or a substituted or unsubstituted aryl, R ²And
And R^ThreeAre the same or different and are hydrogen or lower alkyl
And A is(In the formula, R^Four, R^FiveAnd R⁶Are the same or different
Hydrogen, substituted or unsubstituted lower alkyl, lower cyclo
Alkyl, lower cycloalkylalkyl, hydroxy,
Lower alkoxy, carboxy, lower alkoxy carbonyl
Le, lower alkanoyl, halogen, nitro, amino, mo
No or di-lower alkylamino, substituted or unsubstituted
Aralkyl, substituted or unsubstituted aryl, also substituted
Or unsubstituted aromatic heterocyclic group or substituted or non-substituted
Represents a substituted alicyclic heterocyclic group, Y is O, S, NH or
-C = C-) or(In the formula, Z¹And Z²Both represent hydrogen or Z¹And Z
²Together represent a single bond, and n and p are identical.
Or differently represents 0 or 1, and R^FourAnd R^FiveIs the above
Is synonymous with, and B is -C (O) N (R⁷)-
(In the formula, R⁷Represents hydrogen or lower alkyl)
Is -CH₂Represents NH-, m represents 0 or 1, and D
Is a substituted or unsubstituted aryl, substituted or unsubstituted
Aromatic heterocyclic group or substituted or unsubstituted alicyclic group
Represents a heterocyclic group] or a thiazole derivative represented by
A pharmacologically acceptable salt of.