JP3354090B2 - Differentiation-inducing agent - Google Patents

Differentiation-inducing agent

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JP3354090B2
JP3354090B2 JP26027797A JP26027797A JP3354090B2 JP 3354090 B2 JP3354090 B2 JP 3354090B2 JP 26027797 A JP26027797 A JP 26027797A JP 26027797 A JP26027797 A JP 26027797A JP 3354090 B2 JP3354090 B2 JP 3354090B2
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JPH10152462A (en
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理 中西
土屋  克敏
知行 安藤
俊 山下
英司 田中
厳悟 白石
鈴木  常司
明子 齊藤
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シエーリング アクチエンゲゼルシャフト
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    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
    • Y02A50/38Medical treatment of vector-borne diseases characterised by the agent
    • Y02A50/408Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa
    • Y02A50/411Medical treatment of vector-borne diseases characterised by the agent the vector-borne disease being caused by a protozoa of the genus Plasmodium, i.e. Malaria

Description

【発明の詳細な説明】 DETAILED DESCRIPTION OF THE INVENTION

【0001】 [0001]

【産業上の利用分野】本発明は分化誘導剤に関する。 The present invention relates to a differentiation-inducing agent. さらに詳しくは、新規ベンズアミド誘導体または新規アリニド誘導体の分化誘導作用に基づく制癌剤およびその他の医薬品への利用に関するものである。 More specifically, the present invention relates to the use of the anticancer drugs and other pharmaceuticals based on differentiation-inducing effect of the new benzamide derivatives or novel Arinido derivative.

【0002】 [0002]

【従来の技術】現在、癌は死亡原因の中で心疾患、脳血管疾患を抜いて最大の原因となっており、これまで多くの研究が多額の費用と時間をかけて行われてきた。 BACKGROUND OF THE INVENTION Currently, cancer is heart disease in the cause of death, has become the biggest cause by far the cerebrovascular disease, so far a number of studies have been carried out over a large amount of cost and time. しかし、外科的手術、放射線療法、温熱療法など多岐にわたる治療法の研究にも拘らず癌は克服されていない。 However, surgery, radiation therapy, cancer despite treatment studies as diverse as hyperthermia have not been overcome. その中で化学療法は癌治療の大きな柱の一つであるが、今日に至っても十分満足のゆく薬剤は見いだされておらず、 Although chemotherapy among them is one of the major pillars of cancer treatment, the drug has not been found to Yuku sufficiently satisfied even today,
毒性が低く治療効果の高い制癌剤が待ち望まれている。 Toxicity has been long-awaited low high therapeutic effect anticancer agent.
これまでの多くの制癌剤は細胞、主にDNAに作用し細胞毒性を発現することで癌細胞に傷害を与え、制癌効果を発揮している。 Previously many anticancer drugs of the cell, primarily injure the cancer cells to express act cytotoxicity DNA, and exhibits anticancer effect. しかし、癌細胞と正常細胞との選択性が十分でないため、正常細胞において発現する副作用が治療の限界となっている。 However, since selectivity between cancer cells and normal cells is not sufficient, the side effects expressed in normal cells has become the treatment of limitations.

【0003】ところが制癌剤の中でも分化誘導剤は直接の殺細胞ではなく、癌細胞に分化を促し癌細胞の無限増殖を抑えることを目的としている。 [0003] However, differentiation-inducing agents among anticancer drugs is not a direct cell killing, it is an object to suppress the infinite proliferation of cancer cells promote the differentiation in cancer cells. そのため癌の退縮においては直接細胞を殺す種類の制癌剤には及ばないが、 Therefore it falls short of the type of anticancer drugs to kill cells directly in regression of cancer,
低い毒性と異なる選択性が期待できる。 Low toxicity and different selectivity can be expected. 実際、分化誘導剤であるレチノイン酸が治療に用いられ急性前骨髄性白血病で高い効果を示すことはよく知られている[Hua Indeed, retinoic acid has been well known that highly effective in acute promyelocytic leukemia used to treat a differentiation inducer [Hua
ngら;Blood 、72 、567-572(1988)、Castaign ng et al; Blood, 72, 567-572 (1988 ), Castaign
ら;Blood 、76 、1704-1709、(1990)、Warrellら;N Et; Blood, 76, 1704-1709, ( 1990), Warrell et al; N
ew Engl.J.Med. 324 、1385-1393(1991)など]。 ew Engl.J.Med. 324, 1385-1393 (1991 ) , etc.]. また、ビタミンD誘導体が分化誘導作用を示すことから制癌剤への応用も多く研究されている[Olssonら;Cancer Also, application to a cancer drug from the vitamin D derivative shows the differentiation inducing action have been many studies [Olsson et al; Cancer
Res. 43 、5862-5867(1983)他]。 Res. 43, 5862-5867 (1983) other].

【0004】これらの研究を受けて、分化誘導剤であるビタミンD誘導体(特開平6−179622号公報)、 [0004] In response to these studies, vitamin D derivatives (JP-A-6-179622), a differentiation inducing agent,
イソプレン誘導体(特開平6−192073号公報)、 Isoprene derivatives (JP-A-6-192073),
トコフェロール(特開平6−256181号公報)、キノン誘導体(特開平6−305955号公報)、非環状ポリイソプレノイド(特開平6−316520号公報)、安息香酸誘導体(特開平7−206765号公報)、糖脂質(特開平7−258100号公報)等の制癌剤への応用が報告されている。 Tocopherol (JP-A-6-256181), quinone derivatives (JP-A-6-305955), noncyclic polyisoprenoids (JP-A-6-316520 discloses), benzoic acid derivatives (JP-A-7-206765), application of anticancer drugs such as glycolipids (JP-a-7-258100) have been reported. しかしながら、これらの研究によっても癌治療上十分なレベルに達した薬剤はなく、各種の癌に対し有効で安全性の高い薬剤が強く望まれている。 However, no drug has reached a sufficient level on cancer therapy by these studies, effective and highly safe drug has been strongly desired to various cancers.

【0005】 [0005]

【発明が解決しようとする課題】本発明の課題は、分化誘導作用を有し、悪性腫瘍、自己免疫疾患、皮膚病、寄生虫感染症の治療・改善薬などの医薬品として有用な化合物を提供することにある。 Of the present invention 0008] Problems have differentiation inducing action, a compound useful as a malignant tumor, pharmaceuticals such as autoimmune diseases, skin diseases, therapeutic and improving agents for parasitic infections It is to.

【0006】 [0006]

【課題を解決するための手段】本発明者は上記課題を解決すべく鋭意検討した結果、分化誘導作用を有する新規ベンズアミド誘導体および新規アリニド誘導体が抗腫瘍効果を示すことを見いだし、本発明を完成させた。 The present inventors SUMMARY OF THE INVENTION As a result of extensive investigations to solve the above problems, found that novel benzamide derivatives and novel Arinido derivatives show anti-tumor effect with a differentiation inducing action, completed the present invention It was. すなわち本発明は、 [1] 式(1)[化14] Specifically, the present invention provides [1] Equation (1) [formula 14]

【0007】 [0007]

【化14】 [Of 14] [式中、Aは置換されていてもよいフェニル基または複素環(置換基として、ハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、炭素数1〜4のアルキル基、 [In the formula, A as optionally substituted phenyl group or a heterocyclic (substituent, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbon atoms,
炭素数1〜4のアルコキシ基、炭素数1〜4のアミノアルキル基、炭素数1〜4のアルキルアミノ基、炭素数1 Alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, 1 to 4 carbon atoms
〜4のアシル基、炭素数1〜4のアシルアミノ基、炭素数1〜4のアルキルチオ基、炭素数1〜4のパーフルオロアルキル基、炭素数1〜4のパーフルオロアルキルオキシ基、カルボキシル基、炭素数1〜4のアルコキシカルボニル基、フェニル基、複素環からなる群より選ばれた基を1〜4個有する)を表す。 To 4 acyl group, an acylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, a carboxyl group, alkoxycarbonyl group having 1 to 4 carbon atoms, a phenyl group, to 1-4 have a group selected from the group consisting of heterocycle). Xは直接結合または式(2)[化15] X is a direct bond or the formula (2) [Formula 15]

【0008】 [0008]

【化15】 [Of 15] {式中、eは1〜4の整数を表す。 {Wherein, e is an integer of 1-4. gおよびmはそれぞれ独立して0〜4の整数を表す。 g and m represents an integer of independently 0-4. R4は水素原子、置換されていてもよい炭素数1〜4のアルキル基または式(3)[化16] R4 is a hydrogen atom, an alkyl group, or a group of the formula substituted carbon atoms and optionally 1 to 4 (3) [Formula 16]

【0009】 [0009]

【化16】 [Of 16] (式中、R6は置換されていてもよい炭素数1〜4のアルキル基、炭素数1〜4のパーフルオロアルキル基、フェニル基または複素環を表す)で表されるアシル基を表す。 Represents a (wherein, R6 is an optionally substituted alkyl group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, a phenyl group or a heterocycle) acyl group represented by. R5は水素原子または置換されていてもよい炭素数1〜4のアルキル基を表す}で示される構造のいずれかを表す。 R5 represents any one of structures represented by represents a hydrogen atom or substituted 1 to 4 carbon atoms which may have alkyl group}. nは0〜4の整数を表す。 n represents an integer of 0 to 4. 但しXが直接結合の場合は、nは0とはならない。 However, if X is a direct bond, n is 0 and should not be. Qは式(4)[化17] Q has the formula (4) [of 17]

【0010】 [0010]

【化17】 [Of 17] (式中、R7およびR8はそれぞれ独立して、水素原子または置換されていてもよい炭素数1〜4のアルキル基を表す)で示される構造のいずれかを表す。 Represents any one of structures represented by (wherein, R7 and R8 each independently represent a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms).

【0011】R1およびR2はそれぞれ独立して、水素原子、ハロゲン原子、水酸基、アミノ基、炭素数1〜4 [0011] R1 and R2 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, 1 to 4 carbon atoms
のアルキル基、炭素数1〜4のアルコキシ基、炭素数1 Alkyl group, an alkoxy group having 1 to 4 carbon atoms, carbon atoms 1
〜4のアミノアルキル基、炭素数1〜4のアルキルアミノ基、炭素数1〜4のアシル基、炭素数1〜4のアシルアミノ基、炭素数1〜4のアルキルチオ基、炭素数1〜 To 4 aminoalkyl group, an alkylamino group having 1 to 4 carbon atoms, an acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, 1 to carbon atoms
4のパーフルオロアルキル基、炭素数1〜4のパーフルオロアルキルオキシ基、カルボキシル基または炭素数1 4 perfluoroalkyl group, a perfluoroalkyl group having 1 to 4 carbon atoms, carboxyl group or 1 carbon atoms
〜4のアルコキシカルボニル基を表す。 It represents a ~ 4 alkoxycarbonyl group. R3は水酸基またはアミノ基を表す。 R3 represents a hydroxyl group or an amino group. ]で表されるベンズアミド誘導体および薬学的に許容される塩であり、また、 ] In a benzamide derivative and a pharmaceutically acceptable salt thereof, also

【0012】[2] nが1〜4の整数である[1]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0012] [2] n is an integer of 1 to 4 [1] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0013】[3] Qが式(5)[化18] [0013] [3] Q has the formula (5) [of 18]

【0014】 [0014]

【化18】 [Of 18] (式中、R7およびR8は前記と同義。)で示される構造のいずれかである[2]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 (Wherein, R7 and R8 are as defined above.) Is any one of structures represented by [2] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0015】[4] Aが置換されていてもよいヘテロ環である[3]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0015] [4] A is a salt is a benzamide derivative and a pharmaceutically acceptable and which is [3], wherein heterocycle which may be substituted, also,

【0016】[5] Aが置換されていてもよいピリジル基である[4]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0016] [5] A is a benzamide derivative and the pharmaceutically acceptable salts of the a [4], wherein pyridyl group which may be substituted, also,

【0017】[6] Xが直接結合である[4]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0017] [6] X is a benzamide derivative and the pharmaceutically acceptable salts of a direct bond [4], wherein, also,

【0018】[7] R1およびR2が水素原子である[6]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0018] [7] are R1 and R2 benzamide derivatives and pharmaceutically acceptable salts of a is [6], wherein a hydrogen atom, also,

【0019】[8] R3がアミノ基である[7]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0019] [8] R3 is an amino group [7] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0020】[9] Xが式(6)[化19] [0020] [9] X has the formula (6) [of 19]

【0021】 [0021]

【化19】 [Of 19] (式中、eは前記と同義。)で示される構造である[5]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 (Wherein, e is as defined above.) Is a structure represented by [5] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0022】[10] nが1で、R1およびR2が水素原子である[9]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0022] [10] n is 1, it is R1 and R2 are hydrogen atoms [9] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0023】[11] R3がアミノ基である[10] [0023] [11] R3 is an amino group [10]
記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 Benzamide derivatives and pharmaceutically acceptable salt thereof according, also,

【0024】[12] Xが式(7)[化20] [0024] [12] X has the formula (7) [of 20]

【0025】 [0025]

【化20】 [Of 20] (式中、e、gおよびR4は前記と同義。)示される構造のいずれかである[5]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 (Wherein, e, g and R4 as defined above.) Is is either shown as Structure [5] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0026】[13] nが1で、R1およびR2が水素原子である[12]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0026] [13] n is 1, is R1 and R2 are hydrogen atoms [12] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0027】[14] R3がアミノ基である[13] [0027] [14] R3 is an amino group [13]
記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 Benzamide derivatives and pharmaceutically acceptable salt thereof according, also,

【0028】[15] Xが式(8)[化21] [0028] [15] X has the formula (8) [of 21]

【0029】 [0029]

【化21】 [Of 21] (式中、g、mおよびR5は前記と同義。)示される構造のいずれかである[5]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 (Wherein, g, m and R5 are as defined above.) Is is either shown as Structure [5] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0030】[16] nが1で、R1およびR2が水素原子である[15]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0030] In [16] n is 1, benzamide derivatives and pharmaceutically acceptable salts of R1 and R2 is a hydrogen atom [15], wherein, also,

【0031】[17] R3がアミノ基である[16] [0031] [17] R3 is an amino group [16]
記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 Benzamide derivatives and pharmaceutically acceptable salt thereof according, also,

【0032】[18] nが0である[1]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0032] [18] n is 0 in which [1] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0033】[19] Qが式(5)で示される構造のいずれかである[18]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0033] [19] Q is either a is [18] benzamide derivative and a pharmaceutically acceptable salt thereof according to the structure represented by the formula (5), also,

【0034】[20] Aが置換されていてもよいヘテロ環である[19]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0034] [20] A is a salt is a benzamide derivative and a pharmaceutically acceptable in which [19], wherein heterocycle which may be substituted, also,

【0035】[21] Aが置換されていてもよいピリジル基である[20]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0035] [21] A is a benzamide derivative and the pharmaceutically acceptable salts of a is [20], wherein pyridyl group which may be substituted, also,

【0036】[22] R1およびR2が水素原子である[21]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 [0036] [22] a R1 and R2 benzamide derivatives and pharmaceutically acceptable salts of a is [21], wherein a hydrogen atom, also,

【0037】[23] R3がアミノ基である[22] [0037] [23] R3 is an amino group [22]
記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 Benzamide derivatives and pharmaceutically acceptable salt thereof according, also,

【0038】[24] 式(9)[化22] [0038] [24] (9) [of 22]

【0039】 [0039]

【化22】 [Of 22] で示される[1]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 In an indicated by [1] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0040】[25] 式(10)[化23] [0040] [25] (10) [of 23]

【0041】 [0041]

【化23】 [Of 23] で示される[1]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 In an indicated by [1] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0042】[26] 式(11)[化24] [0042] [26] (11) [of 24]

【0043】 [0043]

【化24】 [Of 24] で示される[1]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 In an indicated by [1] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0044】[27] 式(12)[化25] [0044] [27] (12) [of 25]

【0045】 [0045]

【化25】 [Of 25] で示される[1]記載のベンズアミド誘導体および薬学的に許容される塩であり、また、 In an indicated by [1] benzamide derivative and a pharmaceutically acceptable salt thereof according, also,

【0046】[28] 式(13)[化26] [0046] [28] (13) [of 26]

【0047】 [0047]

【化26】 [Of 26] [式中、AおよびBは置換されていてもよいフェニル基または複素環(置換基として、ハロゲン原子、水酸基、 [In the formula, A and B are phenyl optionally substituted group or a heterocyclic (substituent, a halogen atom, a hydroxyl group,
アミノ基、ニトロ基、シアノ基、炭素数1〜4のアルキル基、炭素数1〜4のアルコキシ基、炭素数1〜4のアミノアルキル基、炭素数1〜4のアルキルアミノ基、炭素数1〜4のアシル基、炭素数1〜4のアシルアミノ基、炭素数1〜4のアルキルチオ基、炭素数1〜4のパーフルオロアルキル基、炭素数1〜4のパーフルオロアルキルオキシ基、カルボキシル基、炭素数1〜4のアルコキシカルボニル基、フェニル基、複素環からなる群より選ばれた基を1〜4個有する)を表す。 An amino group, a nitro group, a cyano group, an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, 1 to 4 carbon atoms to 4 acyl group, an acylamino group having 1 to 4 carbon atoms, an alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, a carboxyl group, alkoxycarbonyl group having 1 to 4 carbon atoms, a phenyl group, to 1-4 have a group selected from the group consisting of heterocycle).

【0048】Yは−CO−、−CS−、−SO−および−SO 2 −のいずれかを構造中に有し、AとBを連結する鎖状、環状またはそれらの組み合わされた構造を表す。 [0048] Y is -CO -, - CS -, - SO- and -SO 2 - has one of the structures, the chain connecting the A and B, represent a cyclic or their combined structure . R3は水酸基またはアミノ基を表す。 R3 represents a hydroxyl group or an amino group. ]において、 In],
B環の重心(W1)、A環の重心(W2)、Y中の水素結合受容体となる酸素原子または硫黄原子(W3)のなす距離が、それぞれW1〜W2=6.0〜11.0Å、 B ring of the centroid (W1), the center of gravity of the A-ring (W2), eggplant distance of the hydrogen bond acceptor become oxygen atom or sulfur atom in Y (W3), respectively W1~W2 = 6.0~11.0Å ,
W1〜W3=3.0〜8.0Å、W2〜W3=3.0〜 W1~W3 = 3.0~8.0Å, W2~W3 = 3.0~
8.0Åとなる立体配置をとることが可能なアニリド誘導体および薬学的に許容される塩であり、また、 A salt is anilide derivatives and pharmaceutically acceptable possible to take a three-dimensional configuration as a 8.0 Å, also,

【0049】[29] Aが置換されていてもよい複素環、R3がアミノ基、Yが−CO−を構造中に有するA [0049] [29] A is heterocyclic ring which may be substituted, R3 is an amino group, A having Y is -CO- in the structure
とBを連結する鎖状、環状またはそれらの組み合わされた構造である[28]記載のアニリド誘導体および薬学的に許容される塩であり、また、 A chain connecting the B, and cyclic or combined structure of them [28] anilide derivatives and a pharmaceutically acceptable salt thereof according, also,

【0050】[30] Bが置換されてもよいフェニル基、W1〜W2=7.0〜9.5Å、W1〜W3=3. [0050] [30] B is an optionally substituted phenyl group, W1~W2 = 7.0~9.5Å, W1~W3 = 3.
0〜5.0Å、W2〜W3=5.0〜8.0Åである[29]記載のアニリド誘導体および薬学的に許容される塩であり、また、 0~5.0A, a W2~W3 = a 5.0~8.0Å [29] anilide derivatives and a pharmaceutically acceptable salt thereof according, also,

【0051】[31] [1]〜[30]いずれかに記載の化合物のうち、少なくとも1つを有効成分として含有する制癌剤であり、また、 [0051] [31] [1] - [30] Among the compounds according to any one, a carcinostatic containing at least one as an active ingredient, also,

【0052】[32] [1]〜[30]いずれかに記載の化合物のうち、少なくとも1つを有効成分として含有する医薬品である。 [0052] [32] [1] - [30] Among the compounds according to any are medicaments which comprise at least one as an active ingredient.

【0053】 [0053]

【発明の実施の形態】以下、本発明を詳細に説明する。 BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the present invention will be described in detail.
本発明でいう炭素数1〜4とは、単位置換基あたりの炭素数を表す。 The 1 to 4 carbon atoms in the present invention means the number of carbon per unit substituents. すなわち、例えばジアルキル置換の場合は、炭素数2〜8を意味する。 Thus, for example in the case of dialkyl substitution it means 2 to 8 carbon atoms.

【0054】式(1)および式(13)で示される化合物における複素環とは、窒素原子または酸素原子または硫黄原子を1〜4個を含む5員環または6員環からなる単環式複素環または2環式縮合複素環で、例えば単環式複素環としてはピリジン、ピラジン、ピリミジン、ピリダジン、チオフェン、フラン、ピロール、ピラゾール、 [0054] Equation (1) and the heterocyclic ring in the compound represented by the formula (13), a monocyclic heterocycle comprising a nitrogen atom or an oxygen atom or a sulfur atom from a 5- or 6-membered ring containing 1-4 in ring or bicyclic fused heterocyclic ring, for example pyridine as monocyclic heterocycle, pyrazine, pyrimidine, pyridazine, thiophene, furan, pyrrole, pyrazole,
イソオキサゾール、イソチアゾール、イミダゾール、オキサゾール、チアゾール、ピペリジン、ピペラジン、ピロリジン、キヌクリジン、テトラヒドロフラン、モルホリン、チオモルホリンなどを、2環式縮合複素環としてはキノリン、イソキノリン、ナフチリジン、フロピリジン、チエノピリジン、ピロロピリジン、オキサゾロピリジン、イミダゾロピリジン、チアゾロピリジンなどの縮合ピリジン環、ベンゾフラン、ベンゾチオフェン、ベンズイミダゾールなどを挙げることができる。 Isoxazole, isothiazole, imidazole, oxazole, thiazole, piperidine, piperazine, pyrrolidine, quinuclidine, tetrahydrofuran, morpholine, thiomorpholine, quinoline as bicyclic fused heterocyclic ring, an isoquinoline, naphthyridine, furopyridine, thienopyridine, pyrrolopyridine, oxazolopyridine, imidazolopyridine, fused pyridine ring such as a thiazolopyridine, may be mentioned benzofuran, benzothiophene, and benzimidazole.

【0055】ハロゲン原子とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子を挙げることができる。 [0055] The halogen atom, a fluorine atom, chlorine atom, bromine atom, and an iodine atom. 炭素数1〜4のアルキル基とは、例えばメチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、 The alkyl group having 1 to 4 carbon atoms, such as methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group,
イソブチル基、sec−ブチル基、tert−ブチル基などを挙げることができる。 Isobutyl, sec- butyl group, and the like tert- butyl group.

【0056】炭素数1〜4のアルコキシ基とは、例えばメトキシ基、エトキシ基、n−プロポキシ基、イソプロポキシ基、アリルオキシ基、n−ブトキシ基、イソブトキシ基、sec−ブトキシ基、tert−ブトキシ基などを挙げることができる。 [0056] The alkoxy group having 1 to 4 carbon atoms, such as methoxy, ethoxy, n- propoxy, isopropoxy, allyloxy group, n- butoxy group, isobutoxy group, sec- butoxy group, tert- butoxy group and the like. 炭素数1〜4のアミノアルキル基とは、例えばアミノメチル基、1−アミノエチル基、2−アミノプロピル基などを挙げることができる。 The aminoalkyl group having 1 to 4 carbon atoms, and examples thereof include aminomethyl group, 1-aminoethyl group, and 2-aminopropyl group.

【0057】炭素数1〜4のアルキルアミノ基とは、例えばN−メチルアミノ基、N,N−ジメチルアミノ基、 [0057] The alkylamino group having 1 to 4 carbon atoms, such as N- methylamino group, N, N- dimethylamino group,
N,N−ジエチルアミノ基、N−メチル−N−エチルアミノ基、N,N−ジイソプロピルアミノ基などを挙げることができる。 N, N- diethylamino group, N- methyl -N- ethylamino group, N, and the like N- diisopropylamino group. 炭素数1〜4のアシル基とは、例えばアセチル基、プロパノイル基、ブタノイル基を挙げることができる。 The acyl group having 1 to 4 carbon atoms, and examples thereof include an acetyl group, a propanoyl group, a butanoyl group.

【0058】炭素数1〜4のアシルアミノ基とは、例えばアセチルアミノ基、プロパノイルアミノ基、ブタノイルアミノ基などを挙げることができる。 [0058] The acylamino group having 1 to 4 carbon atoms, and examples thereof include an acetylamino group, propanoylamino group, and the like butanoylamino group. 炭素数1〜4のアルキルチオ基とは、メチルチオ基、エチルチオ基、プロピルチオ基などを挙げることができる。 The alkylthio group having 1 to 4 carbon atoms, methylthio, ethylthio, and the like propylthio group.

【0059】炭素数1〜4のパーフルオロアルキル基とは、例えばトリフルオロメチル基、ペンタフルオロエチル基などを挙げることができる。 [0059] The perfluoroalkyl group having 1 to 4 carbon atoms, and examples thereof include a trifluoromethyl group, pentafluoroethyl group and the like. 炭素数1〜4のパーフルオロアルキルオキシ基とは、例えばトリフルオロメトキシ基、ペンタフルオロエトキシ基などを挙げることができる。 The perfluoroalkyl group having 1 to 4 carbon atoms, and examples thereof include trifluoromethoxy group, pentafluoroethoxy group and the like.

【0060】炭素数1〜4のアルコキシカルボニル基とは、例えばメトキシカルボニル基、エトキシカルボニル基などを挙げることができる。 [0060] The alkoxycarbonyl group having 1 to 4 carbon atoms include a methoxycarbonyl group and an ethoxycarbonyl group. 置換されていてもよい炭素数1〜4のアルキル基とは、例えばメチル基、エチル基、n−プロピル基、イソプロピル基、n−ブチル基、 The substituents on these alkyl groups having 1 to 4 carbon atoms, such as methyl group, ethyl group, n- propyl group, an isopropyl group, n- butyl group,
イソブチル基、sec−ブチル基、tert−ブチル基などやこれに置換基として、ハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、フェニル基、複素環からなる群より選ばれた基を1〜4個有するものを挙げることができる。 Isobutyl, sec- butyl group, as a substituent such as and to tert- butyl group, 1 halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, a phenyl group, a group selected from the group consisting of heterocyclic It may include those having four.

【0061】式(13)で表される化合物において、高い分化誘導活性を示すために重要な要素は,後述するように(a)環A、環Bと水素結合受容体としての酸素原子あるいは硫黄原子の存在,(b)それらの立体的構造配置によって規定される距離である。 [0061] In the compound represented by formula (13), a key element to exhibit high differentiation inducing activity, as described below (a) Ring A, an oxygen atom or sulfur as ring B and hydrogen bond acceptor the presence of atoms, the distance defined by their three-dimensional structural arrangement (b). よって、Yはその構造中に水素結合受容体を持ち、環Aと環Bの立体的配置を必要な位置に規定する構造であれば特に限定されない。 Therefore, Y has a hydrogen bond acceptor in its structure is not particularly limited as long as structure defining the required position a three-dimensional arrangement of the rings A and B. すなわち、Yの−CO−,−CS−,−SO−または−SO 2 −のいずれかを構造中に有し、AおよびBを連結する鎖状または環状あるいはそれらの組み合わされた構造とは、(a) 炭素原子やヘテロ原子などで構成された、直鎖状あるいは分枝した鎖状の構造中に−CO That, Y of -CO -, - CS -, - SO- or -SO 2 - have any of the structure, the chain or cyclic, or a their combined structure linking A and B, (a) it is constituted by a carbon atom or a hetero atom, -CO in the structure of the linear or branched-chain
−,−CS−,−SO−,−SO 2 −を含むAとBを連結する構造、(b)環状構造中に−CO−,−CS−, -, - CS -, - SO -, - SO 2 - structure linking A and B containing, (b) -CO the cyclic structure -, - CS-,
−SO−,−SO 2 −を持つAとBを連結する構造、 -SO -, - SO 2 - linking A and B having the structure,
(c)環状構造と鎖状の構造が組合わさり1つの構造となり、その構造中に−CO−,−CS−,−SO−,− (C) becomes one structure tumbled combined cyclic structure and a chain-like structure, -CO in its structure -, - CS -, - SO -, -
SO 2 −を含むAとBを連結する構造のいずれかを意味する。 SO 2 - refers to any structure that connects the A and B containing.

【0062】環状構造の基本構造として、4から7員環の炭素原子あるいはヘテロ原子を含む環構造、あるいはそれらの縮合環が挙げられる。 [0062] As the basic structure of the ring structure include cyclic structures or their condensed rings containing carbon atoms or heteroatoms from 4 to 7 membered ring. シクロブタン環、シクロペンタン環、シクロヘキサン環、シクロヘプタン環、オキセタン環、オキソラン環、オキサン環、オキセパン環、ピロリジン環、イミダゾリジン環、ピラゾリジン環、ピペリジン環、ピペラジン環、インドリン環、イソインドリン環、チオラン環、チアゾリジン環、オキサゾリジン環などが挙げられ、その構造中に不飽和結合、水素結合受容体や置換基を持つことができる。 Cyclobutane ring, cyclopentane ring, cyclohexane ring, cycloheptane ring, an oxetane ring, oxolane ring, oxane ring, oxepane ring, pyrrolidine ring, imidazolidine ring, pyrazolidine ring, piperidine ring, piperazine ring, indoline ring, isoindoline ring, a thiolane ring, thiazolidine ring, oxazolidine ring, and the like, unsaturated bonds in its structure, it is possible to have a hydrogen bond acceptor or a substituent.

【0063】式(13)で表される化合物のコンフォメーションの自由度を考慮した解析を行うことにより、高い分化誘導活性を示す化合物において、疎水性相互作用や水素結合などの生体−薬物相互作用に関与すると考えられる原子団が特定の空間配置をとることを見いだした。 [0063] By performing the analysis in consideration the degree of freedom of conformation of the compound represented by the formula (13), in the compounds show high differentiation-inducing activity, living body such as hydrophobic interactions and hydrogen bonding - drug interactions atomic group believed to be involved in has been found to take a particular spatial arrangement.

【0064】具体的には、高活性化合物の3次元構造を、分子モデリングソフトウェア(SYBYL6.3)を用いて発生し、すべての回転可能な結合について配座解析を行うことにより最安定構造を求めた。 [0064] Specifically, the three-dimensional structure of highly active compounds were generated using the molecular modeling software (SYBYL6.3), we obtain the most stable structure by performing conformational analysis for all rotatable bonds It was. ここでエネルギーの評価は、Gasteiger-Huckel法により各原子上に電荷を発生させた後、Tripos力場を用いて行った。 Wherein the evaluation of energy, after generating a charge on each atom by Gasteiger-Huckel method was performed using the Tripos force field. ついで最安定構造を出発構造として、コンフォメーションを考慮した重ね合わせをDISCO/SYBYLにより行った結果、ある特定の空間配置が高い分化誘導活性の発現に必要であることを見いだした。 Then the most stable structure as a starting structure, as a result of the superposition considering conformation by DISCO / SYBYL, found that certain spatial arrangement is required for expression of high differentiation inducing activity.

【0065】上記の解析操作において、他の市販の計算パッケージ[CATALYST(MSI社)、 Cerius2/QSAR+(MSI [0065] In the above analysis operations, other commercially available computational package [CATALYST (MSI Inc.), Cerius2 / QSAR + (MSI
社)、SYBYL/DISCO(Tripos社)など]を用いることによっても解析を行うことが可能であり、本発明で得られた距離情報は特定の計算プログラムにより限定されるものではない。 Inc.), SYBYL / DISCO (Tripos Inc.) it is possible to analyze by using the like, the distance information obtained by the present invention is not intended to be limited by the specific calculation program.

【0066】空間配置の定義に用いた環の重心は、環を構成する原子のX、YおよびZ軸の平均として定義することができる。 [0066] center of gravity of the ring with a defined spatial arrangement, X of atoms constituting the ring can be defined as the average of Y and Z-axis. また対象とする環構造が縮合多環系の場合、縮合環全体の重心あるいはその一部の環の重心のいずれかを、空間を定義するための重心として用いることができる。 Also if the ring structure of interest is fused polycyclic, one of the center of gravity of the center of gravity or a part ring of the entire condensed ring, it can be used as the center of gravity for defining space.

【0067】立体配置をとることが可能なとは、空間配置を満たすコンフォーマーがエネルギー的に最安定構造から15kcal/mol以内に存在することを意味するが、より好ましくは8kcal/mol以内に存在することが望ましい。 [0067] The possible to take a three-dimensional configuration, which means that conformers satisfying the spatial arrangement exists from the energetically most stable structure within 15 kcal / mol but more preferably present within 8 kcal / mol it is desirable to. 計算手法の詳細は、Sybylマニュアル:M.ClarkまたはJ.Comput.Chem. 10. 982(1989)に記載の方法に従い行うことができる。 Details of the calculation method, Sybyl Manual:. M.Clark or J.Comput.Chem 10. can be carried out according to the method described in 982 (1989).

【0068】薬学的に許容される化合物の塩とは、この分野で常用される塩酸、臭化水素酸、硫酸、燐酸などの無機酸や、酢酸、乳酸、酒石酸、リンゴ酸、コハク酸、 [0068] The pharmaceutically acceptable salts of the compounds, hydrochloric acid is commonly used in this field, hydrobromic acid, sulfuric acid, and inorganic acids such as phosphoric acid, acetic acid, lactic acid, tartaric acid, malic acid, succinic acid,
フマル酸、マレイン酸、クエン酸、安息香酸、トリフルオロ酢酸、p−トルエンスルホン酸、メタンスルホン酸などの有機酸との塩を挙げることができる。 Fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, p- toluenesulfonic acid, and salts with organic acids such as methanesulfonic acid. 例えば、N For example, N
−(2−アミノフェニル)−4−[N−(ピリジン−3 - (2-aminophenyl) -4- [N- (pyridine -3
−イル)メトキシカルボニルアミノメチル]ベンズアミド塩酸塩、N−(2−アミノフェニル)−4−[N− - yl) methoxycarbonylamino-methyl] benzamide hydrochloride, N-(2-aminophenyl)-4-[N-
(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド臭化水素酸塩、N−(2−アミノフェニル)−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド硫酸塩、 (Pyridin-3-yl) methoxycarbonylamino-methyl] benzamide hydrobromide, N-(2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylamino-methyl] benzamide sulfate,

【0069】N−(2−アミノフェニル)−4−[N− [0069] N-(2-aminophenyl) -4- [N-
(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド燐酸塩、N−(2−アミノフェニル) (Pyridin-3-yl) methoxycarbonylamino-methyl] benzamide phosphate, N-(2-aminophenyl)
−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド酢酸塩、N−(2−アミノフェニル)−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド乳酸塩、N -4-[N-(pyridin-3-yl) methoxycarbonylamino-methyl] benzamide acetate, N-(2-aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide lactate salt, N
−(2−アミノフェニル)−4−[N−(ピリジン−3 - (2-aminophenyl) -4- [N- (pyridine -3
−イル)メトキシカルボニルアミノメチル]ベンズアミド酒石酸、N−(2−アミノフェニル)−4−[N− - yl) methoxycarbonylamino-methyl] benzamide tartrate, N-(2-aminophenyl)-4-[N-
(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミドリンゴ酸塩、N−(2−アミノフェニル)−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミドコハク酸塩、N− (Pyridin-3-yl) methoxycarbonylamino-methyl] benzamide malate, N- (2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylamino-methyl] benzamide succinate, N-
(2−アミノフェニル)−4−[N−(ピリジン−3− (2-aminophenyl) -4- [N- (pyridine-3
イル)メトキシカルボニルアミノメチル]ベンズアミドフマル酸塩、 Yl) methoxycarbonylamino-methyl] benzamide fumarate,

【0070】N−(2−アミノフェニル)−4−[N− [0070] N-(2-aminophenyl) -4- [N-
(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミドマレイン酸塩、N−(2−アミノフェニル)−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミドクエン酸塩、N− (Pyridin-3-yl) methoxycarbonylamino-methyl] benzamide maleate, N- (2-aminophenyl)-4-[N-(pyridin-3-yl) methoxycarbonylamino-methyl] benzamide citrate, N-
(2−アミノフェニル)−4−[N−(ピリジン−3− (2-aminophenyl) -4- [N- (pyridine-3
イル)メトキシカルボニルアミノメチル]ベンズアミドトリフルオロ酢酸、N−(2−アミノフェニル)−4− Yl) methoxycarbonylamino-methyl] benzamide trifluoroacetate, N-(2-aminophenyl) -4-
[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミドp−トルエンスルホン酸塩、N [N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide p- toluenesulfonate, N
−(2−アミノフェニル)−4−[N−(ピリジン−3 - (2-aminophenyl) -4- [N- (pyridine -3
−イル)メトキシカルボニルアミノメチル]ベンズアミドメタンスルホン酸塩などを挙げることができる。 - yl) such as methoxycarbonylaminomethyl] benzamide methanesulfonate and the like.

【0071】医薬品とは制癌剤の他、自己免疫疾患、皮膚病、寄生虫感染症などの治療および/または改善薬を表す。 [0071] Other cancer medicaments and pharmaceuticals, representative of autoimmune diseases, skin diseases, the treatment and / or improving drugs such as parasitic infections.

【0072】式(1)および式(13)で表される化合物において不斉炭素を有する場合は、異なった立体異性形態またはラセミ形態を含む立体異性形態の混合物の形態で存在することができる。 [0072] When having asymmetric carbon in the formula (1) and the compound represented by the formula (13) can be present in the form of a mixture of stereoisomeric forms including different stereoisomeric or racemic forms. すなわち、本発明はこのように規定した種々の形態をも包含するが、これらも同様に有効成分化合物として用いることができる。 That is, the present invention encompasses also a variety of forms as defined in this manner can be used as they likewise active ingredient compound.

【0073】以下、本発明の式(1)および式(13) [0073] Hereinafter, the compounds of formula (1) and formula (13)
で示される代表的化合物を表−1[表1−表24]、表−2[表25−表26]、表−3[表27−表28]および表−4[表29−表30]に具体的に例示する。 In Table 1 Representative compounds shown Table 1 Table 24] Table 2 [Table 25 Table 26] Table 3 [Table 27-Table 28] and Table 4 [Table 29-Table 30] specifically exemplified. なお、本発明はこれらの例に限定されるものではない。 The present invention is not limited to these examples.

【0074】 [0074]

【表1】表−1 [Table 1] Table 1

【0075】 [0075]

【表2】表−1続きの1 [Table 2] Table 1 continuation of the 1

【0076】 [0076]

【表3】表−1続きの2 [Table 3] Table 1 continuation of 2

【0077】 [0077]

【表4】表−1続きの3 [Table 4] Table 1 continuation of the 3

【0078】 [0078]

【表5】表−1続きの4 [Table 5] Table 1 continuation of 4

【0079】 [0079]

【表6】表−1続きの5 5 of Table 6 Table 1 continued

【0080】 [0080]

【表7】表−1続きの6 [Table 7] Table 1 continuation of the 6

【0081】 [0081]

【表8】表−1続きの7 [Table 8] Table 1 continuation of 7

【0082】 [0082]

【表9】表−1続きの8 [Table 9] Table 1 continuation of the 8

【0083】 [0083]

【表10】表−1続きの9 [Table 10] Table 1 continuation of the 9

【0084】 [0084]

【表11】表−1続きの10 [Table 11] Table 1 continuation of the 10

【0085】 [0085]

【表12】表−1続きの11 [Table 12] Table 1 continuation of the 11

【0086】 [0086]

【表13】表−1続きの12 [Table 13] Table 1 continuation of 12

【0087】 [0087]

【表14】表−1続きの13 [Table 14] Table 1 continuation of 13

【0088】 [0088]

【表15】表−1続きの14 [Table 15] Table 1 continuation of the 14

【0089】 [0089]

【表16】表−1続きの15 [Table 16] Table 1 continuation of the 15

【0090】 [0090]

【表17】表−1続きの16 [Table 17] Table 1 continuation of 16

【0091】 [0091]

【表18】表−1続きの17 [Table 18] Table 1 continuation of the 17

【0092】 [0092]

【表19】表−1続きの18 [Table 19] Table 1 continuation of the 18

【0093】 [0093]

【表20】表−1続きの19 [Table 20] Table 1 continuation of the 19

【0094】 [0094]

【表21】表−1続きの20 [Table 21] Table 1 continuation of the 20

【0095】 [0095]

【表22】表−1続きの21 [Table 22] Table 1 continuation of the 21

【0096】 [0096]

【表23】表−1続きの22 [Table 23] Table 1 continuation of the 22

【0097】 [0097]

【表24】表−1続きの23 [Table 24] Table 1 continuation of the 23

【0098】 [0098]

【表25】表−2 [Table 25] Table 2

【0099】 [0099]

【表26】表−2続きの1 [Table 26] Table 2 continuation of the 1

【0100】 [0100]

【表27】表−3 [Table 27] Table 3

【0101】 [0101]

【表28】表−3続きの1 [Table 28] Table 3 continuation of the 1

【0102】 [0102]

【表29】表−4 [Table 29] Table -4

【0103】 [0103]

【表30】表−4続きの1 [Table 30] Table -4 continuation of the 1

【0104】本発明の化合物は、例えば下記のような方法により製造することができる。 The compounds of the present invention can be produced, for example, by the following method. (a) 式(14)[化27] (A) Formula (14) [formula 27]

【0105】 [0105]

【化27】 [Of 27] [式中、AおよびXは前記と同義。 Wherein, A and X are as defined above. R9は−C(=G) R9 is -C (= G)
OH(Gは、酸素原子または硫黄原子を表す)または− OH (G is an oxygen atom or a sulfur atom) or -
NH 2を表す。 Representing the NH 2. ]で示される化合物と式(15)[化2 Compounds represented by 'the formula (15) [Formula 2
8] 8]

【0106】 [0106]

【化28】 [Of 28] [式中、R1、R2およびnは前記と同義。 Wherein, R1, R2 and n are as defined above. R10はR R10 is R
9が−C(=G)OH(Gは前記と同義)のときは−N 9 is -C (= G) -N when the OH (G is as defined above)
2を表し、R9が−NH 2のときは−C(=G)OH It represents H 2, when R9 is -NH 2 -C (= G) OH
(Gは前記と同義)を表す。 (G is as defined above) represents a. R11はtert−ブトキシカルボニル基などの通常のペプチド形成反応に用いられる保護基で保護されたアミノ基またはベンジル基などの通常のペプチド形成反応に用いられる保護基で保護された水酸基を表す。 R11 represents a hydroxyl group protected by a protecting group generally used in peptide formation reactions such as conventional protected amino group or a benzyl group with a protecting group used in the peptide-forming reaction, such as tert- butoxycarbonyl group. ]で示される化合物を縮合反応に付すか、 (b) 式(16)[化29] Compound or subjected to a condensation reaction represented by, (b) formula (16) [formula 29]

【0107】 [0107]

【化29】 [Of 29] (式中、AおよびXは前記と同義。R12は−OHまたは−NH 2を表す。)で示される化合物と式(17) Compound represented by (wherein, A and X are defined as above .R12 represents -OH or -NH 2.) And the formula (17)
[化30] [Of 30]

【0108】 [0108]

【化30】 [Of 30] (式中、R1、R2、R11およびnは前記と同義。R (Wherein, R1, R2, R11 and n are as defined above .R
13は−OHまたは−NH 2を表す。 13 represents -OH or -NH 2. )で示される化合物を、N,N'−カルボニルジイミダゾール、N,N' The compound represented by), N, N'-carbonyl diimidazole, N, N '
−チオカルボニルジイミダゾール、ホスゲンまたはチオホスゲンなどを用いて縮合反応に付して得られる式(1 - thiocarbonyldiimidazole obtained is subjected to a condensation reaction by using a phosgene or thiophosgene formula (1
8)[化31] 8) [of 31]

【0109】 [0109]

【化31】 [Of 31] (式中、A、X、Q、n、R1、R2およびR11は前記と同義。)で示される化合物の保護基を除去することにより本発明の化合物を得ることができる。 It can be obtained (wherein, A, X, Q, n, R1, R2 and R11 are as defined above.) The compound of the present invention by removing the protecting group of the compound represented by. (c) 式(14)で示される化合物と式(19)[化32] (C) a compound represented by the formula (14) and Equation (19) [formula 32]

【0110】 [0110]

【化32】 [Of 32] (式中、R1、R10およびnは前記と同義。R14 (Wherein, R1, R10 and n are as defined above .R14
は、メチル基、エチル基またはtert−ブチル基を表す。 Represents a methyl group, an ethyl group or a tert- butyl group. )で示される化合物を縮合反応に付すか、 (d) 式(16)で示される化合物と式(20)[化33] ) Compound or subjected to a condensation reaction represented by the compound represented by the formula equation (d) (16) (20) [formula 33]

【0111】 [0111]

【化33】 [Of 33] (式中、R1、R13、R14およびnは前記と同義。)で示される化合物を、N,N'−カルボニルジイミダゾール、N,N'−チオカルボニルジイミダゾール、ホスゲンまたはチオホスゲンなどを用いて縮合反応に付して得られる式(21)[化34] (Wherein, R1, R13, R14 and n are as defined above.) The compound represented by using N, N'-carbonyldiimidazole, N, N'-thiocarbonyldiimidazole, etc. phosgene or thiophosgene condensation formula obtained is subjected to a reaction (21) [formula 34]

【0112】 [0112]

【化34】 [Of 34] (式中、A、X、Q、n、R1およびR14は前記と同義。)で示される化合物を加水分解して得られる式(2 (Wherein, A, X, Q, n, R1 and R14 are as defined above.) Compound hydrolysis to be expressions obtained represented (2
2)[化35] 2) [of 35]

【0113】 [0113]

【化35】 [Of 35] (式中、A、X、Q、nおよびR1は前記と同義。)で示される化合物を式(23)[化36] (Wherein, A, X, Q, n and R1 are as defined above.) The compound represented by the formula (23) [formula 36]

【0114】 [0114]

【化36】 [Of 36] (式中、R2およびR11は前記と同義。)で示される化合物と縮合反応に付して得られる式(18)で示される化合物の保護基を除去することによっても本発明の化合物を得ることができる。 (Wherein, R2 and R11 are as defined above.) To obtain a compound of the even present invention by removing the protecting group of the compound represented by the compound represented by the used formula obtained is subjected to a condensation reaction (18) can. (e) 式(22)で示される化合物と式(24)[化37] (E) a compound of formula (22) and Equation (24) [formula 37]

【0115】 [0115]

【化37】 [Of 37] (式中、R2およびR3は前記と同義。)で示される化合物を縮合反応に付すことによっても本発明の化合物を得ることができる。 (Wherein, R2 and R3 as defined above.) To give a compound of the even present invention by subjecting to condensation reaction with the compound represented by the.

【0116】代表的な中間体の合成について述べる。 [0116] describes the synthesis of representative intermediates. 式(15)で示される化合物は、式(25)[化38] Compounds of formula (15), formula (25) [formula 38]

【0117】 [0117]

【化38】 [Of 38] (式中、R1、R10およびnは前記と同義。)で示される安息香酸誘導体に適当な保護基を導入した後、式(23)で示される化合物と縮合反応に付し、さらに脱保護を行うことにより得ることができる。 (Wherein, the R1, R10 and n as defined above.) After introducing a suitable protecting group to a benzoic acid derivative represented by, subjected to compound condensation reaction represented by the formula (23), a further deprotection it can be obtained by carrying out. 式(17)で示される化合物は、式(26)[化39] Compounds of formula (17), formula (26) [formula 39]

【0118】 [0118]

【化39】 [Of 39] (式中、R1、R13およびnは前記と同義。)で示される安息香酸誘導体に適当な保護基を導入した後、式(23)で示される化合物と縮合反応に付し、さらに脱保護を行うことにより得ることができる。 (Wherein, the R1, R13 and n as defined above.) After introducing a suitable protecting group to a benzoic acid derivative represented by, subjected to compound condensation reaction represented by the formula (23), a further deprotection it can be obtained by carrying out. 式(23)で示される化合物は、式(24)で示される化合物に保護基を導入することにより得ることができる。 Compounds of formula (23) can be obtained by introducing a protecting group into compound of formula (24).

【0119】次に反応について述べる。 [0119] will now be described reaction. (a)の縮合反応は、通常のペプチドにおけるアミド結合形成反応、例えば活性エステルまたは混合酸無水物または酸塩化物の方法によって実施することができる。 The condensation reaction of (a) an amide bond formation reaction in conventional peptide, for example, can be carried out by the method of active ester or mixed acid anhydride or acid chloride. 例えば、カルボン酸成分[式(14)においてR9が−C(=G)OH For example, R9 is -C in the carboxylic acid component [formula (14) (= G) OH
(Gは前記と同義。)で示される化合物または式(1 (G is as defined above.) Compound or formula represented by (1
5)においてR10が−C(=G)OH(Gは前記と同義)で示される化合物]と2、4、5−トリクロロフェノール、ペンタクロロフェノールもしくは4−ニトロフェノールなどのフェノール類、またはN−ヒドロキシスクシイミド、N−ヒドキシベンズトリアゾールなどのN R10 is -C in 5) (= G) OH (G is the compound represented by synonymous) and 2,4,5-trichlorophenol, phenols such as pentachlorophenol or 4-nitrophenol, or N- hydroxysuccinimide, N, such as N- hydrin alkoxy benzotriazoles
−ヒドロキシ化合物を、ジシクロヘキシルカルボジイミドの存在下に縮合させ、活性エステル体に変換した後、 - The hydroxy compounds, condensed in the presence of dicyclohexylcarbodiimide, after conversion to an active ester form,
アミン成分[式(14)においてR9が−NH 2で示される化合物または式(15)においてR10が−NH 2 Amine component [formula In the compound R9 is represented by -NH 2 in (14) or formula (15) R10 is -NH 2
で示される化合物]と縮合させることによって行うことができる。 In compound represented by] and can be carried out by condensation.

【0120】また、カルボン酸成分[式(14)においてR9が−C(=G)OH(Gは前記と同義)で示される化合物または式(15)においてR10が−C(= [0120] Further, R9 is -C in the carboxylic acid component [formula (14) (= G) OH (G is as defined above) The compound or R10 is -C in equation (15) indicated by (=
G)OH(Gは前記と同義)で示される化合物]を塩化オキザリル、塩化チオニル、オキシ塩化リンなどと反応させ、酸塩化物に変換した後、アミン成分[式(14) G) OH (G is oxalyl chloride Compound represented by the synonymous), thionyl chloride, is reacted such as phosphorus oxychloride, after converting to the acid chloride, the amine component [formula (14)
においてR9が−NH 2で示される化合物または式(1 R9 is represented by -NH 2 in a compound or the formula (1
5)においてR10が−NH 2で示される化合物]と縮合させることによって行うことができる。 In 5) R10 can be carried out by condensation with the compound represented by the formula] with -NH 2.

【0121】また、カルボン酸成分[式(14)においてR9が−C(=G)OH(Gは前記と同義)で示される化合物または式(15)においてR10が−C(= [0121] Further, R9 is -C in the carboxylic acid component [formula (14) (= G) OH (G is as defined above) The compound or R10 is -C in equation (15) indicated by (=
G)OH(Gは前記と同義)で示される化合物]をクロロ炭酸イソブチルまたはメタンスルホニルクロライドなどと反応させることによって混合酸無水物を得た後、アミン成分[式(14)においてR9が−NH 2で示される化合物または式(15)においてR10が−NH 2で示される化合物]と縮合させることによって行うことができる。 G) OH (G is after obtaining a mixed acid anhydride by reacting such with the same meaning) isobutyl chlorocarbonate or methanesulfonyl chloride Compound a represented by, is R9 in the amine component [formula (14) -NH in a compound or the formula represented by 2 (15) R10 can be carried out by condensation with the compound represented by the formula] with -NH 2.

【0122】さらにまた、当該縮合反応は、ジシクロヘキシルカルボジイミド、N,N'−カルボニルジイミダゾール、ジフェニルリン酸アジド、ジエチルリン酸シアニド、2−クロロ−1,3−ジメチルイミダゾロニウムクロライドなどのペプチド縮合試薬を単独で用いて行うこともできる。 [0122] Furthermore, the condensation reaction is dicyclohexyl carbodiimide, N, N'-carbonyl diimidazole, diphenylphosphoryl azide, cyanide diethyl phosphate, peptide condensation of a 2-chloro-1,3-dimethyl Imidazolopyrimidine chloride reagents can also be carried out using alone.

【0123】反応は、通常−20〜+50℃で0.5〜 [0123] The reaction is, 0.5 in the usual -20~ + 50 ℃
48時間行う。 Perform 48 hours. 用いられる溶媒としては例えば、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、ジエチルエーテルなどのエーテル類、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、N,N−ジメチルホルムアミドの他、メタノール、エタノールなどのアルコール類またはこれらの混合物が挙げられる。 Examples of the solvent to be used, for example, benzene, ethers, such as aromatic hydrocarbons, tetrahydrofuran, dioxane, diethyl ether and toluene, halogenated hydrocarbons such as methylene chloride, chloroform, N, other N- dimethylformamide, alcohols such as methanol, or mixtures thereof, such as ethanol. 必要により有機塩基例えば、トリエチルアミンまたはピリジンなどを加えて反応する。 Organic bases such as necessary, react like is added triethylamine or pyridine.

【0124】(b)の縮合反応は、式(16)または式(17)で示される化合物のどちらか一方をホスゲン、 [0124] The condensation reaction of (b) is phosgene either the compound of formula (16) or formula (17),
チオホスゲン、N,N'−カルボニルジイミダゾールやN,N'−チオカルボニルジイミダゾールなどを用いて活性化した後、もう一方の化合物と反応させることによって行うことができる。 Thiophosgene, N, N'- carbonyldiimidazole or N, was activated with such N'- thiocarbonyldiimidazole, it can be carried out by reaction with other compounds. 反応は、通常−20〜+50℃ The reaction is usually -20~ + 50 ℃
で0.5〜48時間反応行う。 In the reaction is carried out for 0.5 to 48 hours. 用いられる溶媒としては例えば、ベンゼン、トルエンなどの芳香族炭化水素類、 Examples of the solvent to be used, for example, benzene, aromatic hydrocarbons such as toluene,
テトラヒドロフラン、ジオキサン、ジエチルエーテルなどのエーテル類、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、N,N−ジメチルホルムアミド、 Tetrahydrofuran, dioxane, ethers such as diethyl ether, halogenated hydrocarbons such as methylene chloride, chloroform, N, N- dimethylformamide,
またはこれらの混合物が挙げられる。 Or mixtures thereof. 必要により有機塩基例えば、トリエチルアミンまたはピリジンなどを加えて反応を行う。 Organic bases such as required, carry out the reaction such as the addition of triethylamine or pyridine.

【0125】(c)の縮合反応は(a)の縮合反応と同様の方法により行うことができる。 [0125] The condensation reaction of (c) can be carried out by a method similar to the condensation reaction of (a). (d)の縮合反応は(b)の縮合反応と同様の方法により行うことができる。 The condensation reaction of (d) can be carried out by a method similar to the condensation reaction of (b).

【0126】式(17)で示される化合物の保護基の除去は、通常のペプチド形成反応に用いられる条件で行われる。 [0126] The protecting group of the compound represented by formula (17) is removed is carried out under conditions generally used for peptide formation reaction. 例えば、式(18)においてR11が、tert For example, the R11 in the formula (18), tert
−ブトキシカルボニル基で保護されたアミノ基の場合は、塩酸またはトリフルオロ酢酸などの酸で処理することにより脱保護反応を行うことができる。 - For an amino group protected with a butoxycarbonyl group, it can be carried out deprotection reaction by treatment with an acid such as hydrochloric acid or trifluoroacetic acid.

【0127】式(1)および式(13)で示される化合物の塩は、式(1)および式(13)で示される化合物を製造する反応で得ることもできるが、薬学的に許容される酸と容易に塩を形成し得る。 Salts of the compound represented by [0127] formula (1) and formula (13) can also be obtained by reaction for producing the compound represented by the formula (1) and formula (13), a pharmaceutically acceptable easily salts with acids can form. その酸としては、例えば塩酸、臭化水素酸、硫酸、燐酸などの無機酸や、酢酸、酒石酸、フマル酸、マレイン酸、クエン酸、安息香酸、トリフルオロ酢酸、p−トルエンスルホン酸などの有機酸を挙げることができる。 As the acid, for example hydrochloric acid, hydrobromic acid, an organic such as sulfuric acid, and inorganic acids such as phosphoric acid, acetic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzoic acid, trifluoroacetic acid, p- toluenesulfonic acid mention may be made of the acid. これらの塩もまたフリー体の式(1)および式(13)の化合物と同様に本発明の有効成分化合物として用いることができる。 Can be used as active ingredient compounds of these salts are also expression of the free body (1) and similarly the present invention the compound of formula (13).

【0128】式(1)および式(13)で示される化合物は、反応混合物から通常の分離手段、例えば抽出法、 [0128] Equation (1) and the compound represented by the formula (13), conventional separation from the reaction mixture, for example extraction,
再結晶法、カラムクロマトグラフィーなどの方法により単離精製することができる。 Recrystallization, can be isolated and purified by a method such as column chromatography.

【0129】本発明の新規ベンズアミド誘導体および新規アリニド誘導体は分化誘導作用を有しており、悪性腫瘍、自己免疫疾患、皮膚病、寄生虫感染症などの治療および/または改善剤として有用である。 [0129] New benzamide derivatives and novel Arinido derivatives of the present invention has a differentiation inducing action, malignant tumor, autoimmune diseases, skin diseases, is useful as a therapeutic and / or improving agent such as parasitic infections.

【0130】ここで悪性腫瘍とは急性白血病、慢性白血病、悪性リンパ腫、多発性骨髄腫、マクログロブリン血症などの造血器腫瘍の他、大腸癌、脳腫瘍、頭頚部癌、 [0130] Here, acute leukemia and malignant tumors, chronic leukemia, malignant lymphoma, multiple myeloma, other hematopoietic tumors such as macroglobulinemia, colorectal cancer, brain cancer, head and neck cancer,
乳癌、肺癌、食道癌、胃癌、肝癌、胆嚢癌、胆管癌、膵癌、膵島細胞癌、腎細胞癌、副腎皮質癌、膀胱癌、前立腺癌、睾丸腫瘍、卵巣癌、子宮癌、絨毛癌、甲状腺癌、 Breast cancer, lung cancer, esophageal cancer, stomach cancer, liver cancer, gallbladder cancer, cholangiocarcinoma, pancreatic cancer, islet cell carcinoma, renal cell carcinoma, adrenocortical cancer, bladder cancer, prostate cancer, testicular tumor, ovarian cancer, uterine cancer, choriocarcinoma, thyroid cancer,
悪性カルチノイド腫瘍、皮膚癌、悪性黒色腫、骨肉腫、 Malignant carcinoid tumor, skin cancer, malignant melanoma, osteosarcoma,
軟部組織肉腫、神経芽細胞腫、ウィルムス腫瘍、網膜芽細胞腫などの固形腫瘍が挙げられる。 Soft tissue sarcoma, neuroblastoma, Wilm's tumor, include solid tumors such as retinoblastoma.

【0131】自己免疫疾患とはリウマチ、腎炎、糖尿病、全身性エリテマトーデス、ヒト自己免疫生リンパ球増殖性リンパ節症、免疫芽細胞性リンパ節症、クローン病、潰瘍性大腸炎などを示す。 [0131] is an autoimmune disease shows arthritis, nephritis, diabetes, systemic lupus erythematosus, human autoimmune producing lymphocytes proliferative lymphadenopathy, immune blast cell lymphadenopathy, Crohn's disease, and ulcerative colitis. 皮膚病とは、乾せん、アクネ、湿疹、アトピー性皮膚炎などを示す。 The skin diseases, illustrated psoriasis, acne, eczema, and atopic dermatitis. 寄生虫感染症とは、マラリア感染症等の寄生虫の感染によってひきおこされる疾患を示す。 The parasitic infections, indicating a disease caused by infection of parasites such as malaria infections. なお、本発明の対象疾患はこれらに限定されることはない。 Incidentally, target disease of the present invention is the it is not limited thereto.

【0132】本発明の有効成分化合物は、医薬品として有用であり、これらは一般的な医療製剤の形態で用いられる。 [0132] The active ingredient compound of the present invention are useful as pharmaceuticals, which are used in the form of a common medical preparation. 製剤は通常使用される充填剤、増量剤、結合剤、 Fillers formulations normally used, bulking agents, binding agents,
保湿剤、崩壊剤、界面活性剤、滑沢剤等の希釈剤あるいは賦形剤を用いて調製される。 Humectants, disintegrators, surfactants, is prepared by using diluents or excipients such as lubricants. この医薬製剤としては各種の形態が治療目的に応じて選択でき、その代表的なものとして錠剤、丸剤、散剤、液剤、懸濁剤、乳剤、顆粒剤、カプセル剤、注射剤(液剤、懸濁剤等)および坐剤等が挙げられる。 The Pharmaceutical formulations can be selected according to various forms of therapeutic purposes, the tablets as a typical, pills, powders, solutions, suspensions, emulsions, granules, capsules, injections (solutions, suspension Nigozai etc.) and suppositories, and the like.

【0133】錠剤の形態に成形するに際しては、担体としてこの分野で従来よりよく知られている各種のものを広く使用することができる。 [0133] When forming into the form of a tablet can be widely used any of various well known conventionally in this field as a carrier. その例としては、例えば乳糖、ブドウ糖、デンプン、炭酸カルシウム、カオリン、 Examples thereof include lactose, glucose, starch, calcium carbonate, kaolin,
結晶セルロース、ケイ酸等の賦形剤、水、エタノール、 Crystalline cellulose, or silicic acid, water, ethanol,
プロピルアルコール、単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、セラック、メチルセルロース、ポリビニルピロリドン等の結合剤、乾燥デンプン、アルギン酸ナトリウム、カンテン末、カルメロースカルシウム、デンプン、乳糖等の崩壊剤、白糖、 Propyl alcohol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, binders such as polyvinylpyrrolidone, dry starch, sodium alginate, agar powder, carmellose calcium, starch, disintegrating agents such as lactose, white sugar,

【0134】カカオバター、水素添加油等の崩壊抑制剤、第4級アンモニウム塩基、ラウリル硫酸ナトリウム等の吸収促進剤、グリセリン、デンプン等の保湿剤、デンプン、乳糖、カオリン、ベントナイト、コロイド状ケイ酸等の吸着剤、タルク、ステアリン酸塩、ポリエチレングリコール等の滑沢剤等を使用することができる。 [0134] Cocoa butter, disintegrating inhibitors such as hydrogenated oils, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, glycerin, humectants, such as starch, starch, lactose, kaolin, bentonite, colloidal silicic acid adsorbents etc., talc, stearic acid salts, can be used lubricants such as polyethylene glycol. さらに錠剤については、必要に応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶性被包錠、フィルムコーティング錠あるいは二層錠、多層錠とすることができる。 For more tablets, coated tablet conventional capsule shell optionally, such as sugar-coated tablets, gelatin-coated tablets, enteric coated tablets, film-coated tablet or two-layer tablet, and multi-layer tablets.

【0135】丸剤の形態に成形するに際しては、担体として従来この分野で公知のものを広く使用できる。 [0135] When forming into the form of pills, it can be widely used those known conventionally in this field as a carrier. その例としては、例えば結晶セルロース、乳糖、デンプン、 Examples thereof include crystalline cellulose, lactose, starch,
硬化植物油、カオリン、タルク等の賦形剤、アラビアゴム末、トラガント末、ゼラチン等の結合剤、カルメロースカルシウム、カンテン等の崩壊剤等が挙げられる。 Hydrogenated vegetable oil, kaolin and talc, gum arabic powder, tragacanth powder, binding agents such as gelatin, carmellose calcium, disintegrating agents such as agar and the like.

【0136】カプセル剤は、常法に従い通常有効成分化合物を上記で例示した各種の担体と混合して、硬質ゼラチンカプセル、軟質カプセル等に充填して調製される。 [0136] Capsules are normally active ingredient compound in admixture with various carriers exemplified above by a conventional method, hard gelatin capsules are prepared by filling soft capsules, and the like.

【0137】注射剤として調製する場合、液剤、乳剤および懸濁剤は殺菌され、かつ血液と等張であることが好ましく、これらの形態に成形するに際しては、希釈剤としてこの分野において慣用されているもの、例えば水、 [0137] When prepared as injectables, solutions, emulsions and suspensions are sterilized and preferably isotonic with the blood, the case of shaping to these forms, is commonly used in this field as diluents those who are, for example, water,
エタノール、マクロゴール、プロピレングリコール、エトキシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシエチレンソルビタン脂肪酸エステル類等を使用することができる。 Ethanol, macrogol, propylene glycol, can be used ethoxylated isostearyl alcohol, polyoxy isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters. この場合等張性の溶液を調製するのに必要な量の食塩、ブドウ糖あるいはグリセリンを医薬製剤中に含有させてもよく、 Salt in an amount required to prepare the case isotonic solutions, may be glucose or glycerol is contained in the pharmaceutical formulation,
また通常の溶解補助剤、緩衝剤、無痛化剤等を添加してもよい。 The conventional solubilizers, buffering agents, may be added soothing agent or the like.

【0138】坐剤の形態に成形するに際しては、担体として従来公知のものを広く使用することができる。 [0138] When forming into the form of suppositories, it can be widely used those conventionally known as carriers. その例としては、例えば半合成グリセライド、カカオ脂、高級アルコール、高級アルコールのエステル類、ポリエチレングリコール等を挙げることができる。 Examples thereof include, for example semi-synthetic glyceride, cocoa butter, higher alcohols, esters of higher alcohol, and polyethylene glycol.

【0139】さらに必要に応じて着色剤、保存剤、香料、風味剤、甘味剤等や他の医薬品を医薬製剤中に含有させることもできる。 [0139] Furthermore coloring agents, preservatives, perfumes, flavors, sweeteners and other pharmaceuticals may be contained in the pharmaceutical formulation. 本発明のこれらの医薬製剤中に含有されるべき有効成分化合物の量は、特に限定されずに広範囲から適宜選択されるが、通常製剤組成物中に約1 The amount of these pharmaceutical preparations the active ingredient compound to be contained in the present invention may be appropriately selected from a wide range without particular limitation, about the normal formulation composition 1
〜70重量%、好ましくは約5〜50重量%とするのがよい。 70 wt%, it is preferable to preferably about 5-50 wt%.

【0140】本発明のこれら医薬製剤の投与方法は特に制限はなく、各種製剤形態、患者の年齢、性別、疾患の程度およびその他の条件に応じた方法で投与される。 [0140] The method of administration of these pharmaceutical preparations of the present invention is not particularly limited, various preparation forms, patient age, sex, are administered in a manner corresponding to the extent of the disease and other conditions. 例えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤およびカプセル剤の場合には、経口投与され、注射剤の場合は、 For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are orally administered, for injections,
単独でまたはブドウ糖、アミノ酸等の通常の補液と混合して静脈内投与され、さらに必要に応じて単独で筋肉内、皮下もしくは腹腔内投与される。 Alone or glucose, by mixing with conventional replacement fluid such as amino acids are administered intravenously, singly intramuscularly if necessary, be administered subcutaneously or intraperitoneally. 坐剤の場合は直腸内投与される。 For suppositories are administered intrarectally.

【0141】本発明のこれら医薬製剤の投与量は、用法、患者の年齢、性別、疾患の程度およびその他の条件により適宜選択されるが、通常有効成分化合物の量としては、体重1kg当り、一日約0.0001〜100mg程度とするのがよい。 [0141] The dosage of these pharmaceutical preparations of the present invention, usage, patient's age, sex, is suitably selected according to the extent and other conditions of the disease, the amount of the normal active ingredient compound, weight 1kg per one day preferably set to about 0.0001~100mg about. また投与単位形態の製剤中には有効成分化合物が約0.001〜1,000mgの範囲で含有されることが望ましい。 Also it is desirable content range of the active ingredient compound is from about 0.001~1,000mg during formulation of dosage unit form. 本発明の式(1)および式(13)で表される化合物およびその塩は、薬理学的に効果を示す投与量において問題となるような毒性を示さない。 The compounds and their salts represented by the formulas (1) and (13) of the present invention show no toxicity such that a problem in the dosage showing a pharmacologically effective.

【0142】 [0142]

【実施例】以下に本発明を実施例で詳細に説明するが、 EXAMPLES will be described in detail in the examples the present invention below,
本発明はこれらに限定されるものではない。 The present invention is not limited thereto. なお、表題の括弧内の番号は詳細な説明に例示した化合物の番号である。 The numbers in the title in parentheses is the number of the exemplified compounds in the detailed description.

【0143】実施例1 N−(2−アミノフェニル)−4−(N−ベンゾイルアミノメチル)ベンズアミド 塩酸塩(表−1:化合物番号1の塩酸塩)の合成 (1−1) 4−アミノメチル安息香酸21.16g [0143] Example 1 N-(2-aminophenyl)-4-(N-benzoylaminomethyl) benzamide hydrochloride: Synthesis (1-1) 4-aminomethyl (Table 1 hydrochloride salt of Compound No. 1) benzoic acid 21.16g
(140mmol)のジクロロメタン(450ml)懸濁液に、トリエチルアミン42ml(300mmol) In dichloromethane (450 ml) suspension of (140 mmol), triethylamine 42 ml (300 mmol)
を加えた。 It was added. 氷冷下、内温を3〜8℃に保ちながら無水トリフルオロ酢酸60.4g(287mmol)のジクロロメタン(50ml)溶液を滴下した後、3時間攪拌した。 Under ice-cooling, it was added dropwise in dichloromethane (50ml) solution of trifluoroacetic anhydride 60.4g while maintaining the internal temperature at 3 to 8 ° C. (287 mmol), and stirred for 3 hours. 飽和重曹水中に反応液をあけた後、さらに10%塩酸水溶液で酸性にした。 After the reaction mixture was poured into saturated sodium bicarbonate water, and acidified with additional 10% aqueous hydrochloric acid. 析出したゲル状沈澱物を、濾取、乾燥することにより、4−(N−トリフルオロアセチルアミノメチル)安息香酸30.4g(収率87.8 The precipitated gel-like precipitate, collected by filtration and dried, 4-(N-trifluoroacetyl-aminomethyl) 30.4 g benzoic acid (yield 87.8
%)を乳白色固体として得た。 %) Of the title compound as an off-white solid. 1H NMR(270MHz, DMSO-d6)δppm: 4.47(2H,d,J=5.8Hz), 1H NMR (270MHz, DMSO-d6) δppm: 4.47 (2H, d, J = 5.8Hz),
7.39(2H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 10.08(1H, 7.39 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 10.08 (1H,
t,J=5.8Hz), 12.95(1H,br.s). t, J = 5.8Hz), 12.95 (1H, br.s).

【0144】(1−2) o−フェニレンジアミン10 [0144] (1-2) o- phenylenediamine 10
8g(1.0mol)のジオキサン(1000ml)溶液に1規定水酸化ナトリウム水溶液(500ml)を加え、氷冷下ジtert−ブチルジカーボネート218g 8g dioxane (1000 ml) 1 N aqueous sodium hydroxide solution (500 ml) added (1.0 mol), under ice-cooling di-tert- butyl dicarbonate 218g
(1.1mol)のジオキサン(500ml)溶液を加えた。 Dioxane was added (500 ml) solution of (1.1 mol). 室温で6時間攪拌後、一晩放置した。 After stirring at room temperature for 6 hours and left overnight. 溶媒を1/ The solvent 1 /
2容にまで濃縮した後、酢酸エチルで抽出した。 After concentration to a 2 ml, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た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)で精製し、得られた固体をエチルエーテルで洗浄することによりN−tert−ブトキシカルボニル−o− The organic layer was washed with saturated brine, dried, N-tert-butoxy by solvent The residue obtained by distilling off was purified by silica gel column chromatography (chloroform) and washed the resulting solid with ethyl ether carbonyl -o-
フェニレンジアミン68.4g(収率32.8%)を白色固体として得た。 To give phenylenediamine 68.4g of (32.8% yield) as a white solid. 1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 3.75(2H, 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 3.75 (2H,
s), 6.26(1H,s), 6.77(1H,d,J=8.1Hz), 6.79(1H,dd,J= s), 6.26 (1H, s), 6.77 (1H, d, J = 8.1Hz), 6.79 (1H, dd, J =
7.3,8.1Hz), 7.00(1H,dd,J=7.3,8.1Hz), 7.27(1H,d,J= 7.3,8.1Hz), 7.00 (1H, dd, J = 7.3,8.1Hz), 7.27 (1H, d, J =
8.1Hz). 8.1Hz).

【0145】(1−3) 工程(1−1)で得られた化合物30.0g(121mmol)のジクロロメタン(200ml)懸濁液に、氷冷しながら(内温10〜1 [0145] (1-3) in dichloromethane (200ml) suspension of step (1-1) Compound 30.0g obtained in (121 mmol), while cooling with ice (inner temperature 10 to 1
5℃)オキザリルクロライド21g(165mmol) 5 ° C.) of oxalyl chloride 21g (165 mmol)
を徐々に滴下した。 It was gradually dropped. その際にときどき(およそ2ml滴下する毎に0.1ml)DMFを加えた。 It was added DMF (0.1 ml each time of approximately 2ml dropwise) sometimes at that time. 全量滴下後、 After the total amount of the dropping,
発泡が止まるまで攪拌し、その後40℃で1時間攪拌した。 And stirred until bubbling ceased and then stirred for 1 hour at 40 ° C.. 溶媒を留去した後、トルエンで過剰のオキザリルクロライドを共沸し、再度ジクロロメタン(100ml) After distilling off the solvent, and azeotropic excess oxalyl chloride in toluene, again dichloromethane (100ml)
に溶解した。 It was dissolved in. 工程(1−2)で得られた化合物22.8 The compound obtained in step (1-2) 22.8
8g(110mmol)のジクロロメタン(100m Dichloromethane 8g (110mmol) (100m
l)−ピリジン(200ml)溶液に、先に調製した酸クロライド溶液を氷冷下(内温7〜9℃)滴下した。 l) - pyridine (200ml) solution, under ice-cooling The acid chloride solution prepared above (internal temperature 7 to 9 ° C.) was added dropwise.

【0146】滴下終了後、室温まで昇温させた後、一晩放置した。 [0146] After completion of the addition, the temperature was raised to room temperature and left overnight. 反応混合物に飽和重曹水を加えた後、クロロホルムで抽出し、飽和食塩水で洗浄後、乾燥、溶媒を留去した。 After addition of saturated aqueous sodium bicarbonate solution to the reaction mixture, extracted with chloroform, washed with saturated brine, dried and evaporated. 得られた残渣にメタノール−ジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、N−[2−(N−tert−ブトキシカルボニル) The resulting residue in methanol - diisopropyl ether was added, the precipitated solid was collected by filtration and dried, N- [2- (N-tert- butoxycarbonyl)
アミノフェニル]−4−(N−トリフルオロアセチルアミノメチル)ベンズアミド28.1g(収率58%)を淡黄色固体として得た。 Aminophenyl]-4-(N-trifluoroacetyl-aminomethyl) benzamide 28.1g (58% yield) as a pale yellow solid. 1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.48(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.48 (2H,
d,J=5.9Hz), 7.12-7.23(2H,m), 7.44(2H,d,J=8.1Hz), d, J = 5.9Hz), 7.12-7.23 (2H, m), 7.44 (2H, d, J = 8.1Hz),
7.54(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8.68(1H,b 7.54 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.68 (1H, b
rs), 9.83(1H,s), 10.10(1H,br.t,J=5.9Hz). rs), 9.83 (1H, s), 10.10 (1H, br.t, J = 5.9Hz).

【0147】(1−4) 工程(1−3)の化合物1 [0147] compound of formula (1-4) Step (1-3) 1
3.12g(30mmol)のメタノール(120m Methanol of 3.12g (30mmol) (120m
l)−水(180ml)懸濁液に炭酸カリウム4.70 l) - potassium carbonate in water (180 ml) suspension 4.70
g(34.0mmol)を加え、70℃で4時間加熱攪拌した。 g of (34.0 mmol) was added and stirred for 4 hours under heating at 70 ° C.. クロロホルムで抽出し、有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去し、乾燥することにより、4 Was extracted with chloroform, the organic layer was washed with saturated brine, dried, and the solvent was distilled off, dried, 4
−アミノメチル−N−[2−(N−tert−ブトキシカルボニル)アミノフェニル]ベンズアミド10.3g - aminomethyl -N- [2- (N-tert- butoxycarbonyl) aminophenyl] benzamide 10.3g
(定量的)を淡黄色アモルファス状固体として得た。 (Quantitative) as a pale yellow amorphous solid. 1H NMR(270MHz, DMSO-d6)δppm: 3.80(2H,s), 7.13-7.2 1H NMR (270MHz, DMSO-d6) δppm: 3.80 (2H, s), 7.13-7.2
3(2H,m), 7.48-7.58(4H,m), 7.90(2H,d,J=8.1Hz), 8.69 3 (2H, m), 7.48-7.58 (4H, m), 7.90 (2H, d, J = 8.1Hz), 8.69
(1H,br.s), 9.77(1H,br.s). (1H, br.s), 9.77 (1H, br.s).

【0148】(1−5) 工程(1−4)の化合物0. [0148] (1-5) compound of step (1-4) 0.
11g(0.44mmol)のピリジン(5ml)溶液に氷冷下、ベンゾイルクロライド0.08g(0.53 Under ice-cooling in pyridine (5ml) solution of 11g (0.44 mmol), benzoyl chloride 0.08 g (0.53
mmol)を加えた後、室温まで徐々に温度を上げながら8時間攪拌した。 After adding mmol), and stirred for 8 hours while raising the temperature gradually to room temperature. 飽和重曹水を加えた後、酢酸エチルで抽出した。 After addition of saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄し、乾燥、溶媒を留去して得られた残渣をジイソプロピルエーテルで洗浄し、得られた固体を乾燥することにより、N−[2− The organic layer was washed with saturated brine, dried, and the solvent washed residue obtained by removing with diisopropyl ether and drying the obtained solid, N-[2-
(N−tert−ブトキシカルボニル)アミノフェニル]−4−(N−ベンゾイルアミノメチル)ベンズアミド0.14g(収率71.4%)を白色固体として得た。 The (N-tert-butoxycarbonyl) aminophenyl]-4-(N-benzoylaminomethyl) benzamide 0.14 g (71.4% yield) as a white solid. 1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.56(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.56 (2H,
d,J=5.9Hz), 7.11-7.22(2H,m), 7.46-7.56(7H,m), 7.90 d, J = 5.9Hz), 7.11-7.22 (2H, m), 7.46-7.56 (7H, m), 7.90
-7.94(4H,m), 8.67(1H,s), 9.15(1H,t,J= 5.9Hz), 9.81 -7.94 (4H, m), 8.67 (1H, s), 9.15 (1H, t, J = 5.9Hz), 9.81
(1H,s). (1H, s).

【0149】(1−6) 工程(1−5)の化合物0. [0149] (1-6) compound of step (1-5) 0.
10g(0.224mmol)のジオキサン(5ml) Dioxane 10g (0.224mmol) (5ml)
−メタノール(1ml)溶液に4規定塩酸−ジオキサン(5ml)を加え、室温で7時間攪拌した。 - methanol (1 ml) was added 4N hydrochloric acid - dioxane (5ml) was added, followed by stirring at room temperature for 7 hours. 溶媒を留去した残渣にジイソプロピルエーテルを加え、得られた固体を濾取、乾燥することにより、N−(2−アミノフェニル)−4−(N−ベンゾイルアミノメチル)ベンズアミド 塩酸塩0.08g(収率93%)を淡褐色固体として得た。 The solvent of diisopropyl ether was added to the residue which was distilled off, filtered and the resulting solid by drying, N-(2-aminophenyl)-4-(N-benzoylaminomethyl) benzamide hydrochloride 0.08 g ( 93% yield) was obtained as a light brown solid. mp. 206-209℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.57(2H,d,J=5.8Hz), .. Mp 206-209 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.57 (2H, d, J = 5.8Hz),
7.27-7.38(4H,m), 7.47-7.59(5H,m), 7.92(1H,d,J=8.1H 7.27-7.38 (4H, m), 7.47-7.59 (5H, m), 7.92 (1H, d, J = 8.1H
z), 8.05(1H,d,J=8.1Hz), 9.19(1H,t,J=5.8Hz),10.38(1 z), 8.05 (1H, d, J = 8.1Hz), 9.19 (1H, t, J = 5.8Hz), 10.38 (1
H,br.s). IR(KBr)cm-1: 3286,3003(br.),1630,1551,1492,1306,12 . H, br.s) IR (KBr) cm-1:. 3286,3003 (br), 1630,1551,1492,1306,12
50,749,695. 実施例1と同様の方法により、実施例2から実施例44 50,749,695. In the same manner as in Example 1, implemented from Example 2 Example 44
の化合物を合成した。 The compounds were synthesized. 以下に、化合物の融点(mp.)、1 Hereinafter, the melting point of the compound (mp.), 1
H NMR、IRの測定値を示す。 H NMR, showing the measurement of IR.

【0150】実施例2 N−(2−アミノフェニル)−4−[N−(2−クロロベンゾイル)アミノメチル]ベンズアミド(表−1:化合物番号14) mp. 201-204℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.52(2H,t,J=5.9Hz), [0150] Example 2 N-(2-aminophenyl) -4- [N- (2- chlorobenzoyl) aminomethyl] benzamide. (Table 1: Compound No. 14) mp 201-204 ° C. (dec.). 1H NMR (270MHz, DMSO-d6) δppm: 4.52 (2H, t, J = 5.9Hz),
4.89(2H,br.s), 6.60(1H,ddd,J=1.5,7.3,8.1Hz), 6.78 4.89 (2H, br.s), 6.60 (1H, ddd, J = 1.5,7.3,8.1Hz), 6.78
(1H,dd,J=1.5,8.1Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), (1H, dd, J = 1.5,8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz),
7.17(1H,d,J=8.1Hz), 7.38-7.54(6H,m), 7.97(2H,d,J= 7.17 (1H, d, J = 8.1Hz), 7.38-7.54 (6H, m), 7.97 (2H, d, J =
8.1Hz), 9.06(1H,br.t,J=5.9Hz), 9.63(1H,br.s). IR(KBr)cm-1: 3268,1649,1458,1304,748. . 8.1Hz), 9.06 (1H, br.t, J = 5.9Hz), 9.63 (1H, br.s) IR (KBr) cm-1: 3268,1649,1458,1304,748.

【0151】実施例3 N−(2−アミノフェニル)−4−[N−(2−ニトロベンゾイル)アミノメチル]ベンズアミド 塩酸塩(表−1:化合物番号18の塩酸塩) mp. 210-212℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.55(2H,t,J=5.9Hz), [0151] Example 3 N-(2-aminophenyl) -4- [N- (2- nitrobenzoyl) aminomethyl] benzamide hydrochloride. (Table 1: hydrochloride of Compound No. 18) mp 210-212 ° C. (. dec). 1H NMR (270MHz, DMSO-d6) δppm: 4.55 (2H, t, J = 5.9Hz),
7.20-7.40(3H,m), 7.50-7.60(1H,m), 7.53(2H,d,J=8.1H 7.20-7.40 (3H, m), 7.50-7.60 (1H, m), 7.53 (2H, d, J = 8.1H
z), 7.60-7.70(2H,m), 7.83(1H,ddd,J=1.5,8.1,8.1Hz), z), 7.60-7.70 (2H, m), 7.83 (1H, ddd, J = 1.5,8.1,8.1Hz),
8.00-8.10(3H,m), 9.34(1H,t,J=5.9Hz), 10.43(1H,br. 8.00-8.10 (3H, m), 9.34 (1H, t, J = 5.9Hz), 10.43 (1H, br.
s). IR(KBr)cm-1: 3283,2500-3000(br.),1648,1534,1461,13 . S) IR (KBr) cm-1:. 3283,2500-3000 (br), 1648,1534,1461,13
62,1314,754,701. 62,1314,754,701.

【0152】実施例4 N−(2−アミノフェニル)−4−[N−(4−メチルベンゾイル)アミノメチル]ベンズアミド 塩酸塩(表−1:化合物番号28の塩酸塩) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 2.37(3H,s), 4.56(2H, [0152] Example 4 N-(2-aminophenyl) -4- [N- (4- methylbenzoyl) aminomethyl] benzamide hydrochloride. (Table 1: hydrochloride of Compound No. 28) mp (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 2.37 (3H, s), 4.56 (2H,
d,J=5.0Hz), 7.20-7.30(6H,m), 7.47(4H,d,J=8.8Hz), d, J = 5.0Hz), 7.20-7.30 (6H, m), 7.47 (4H, d, J = 8.8Hz),
7.82(2H,d,J=8.8Hz), 8.03(2H,d,J=8.8Hz), 9.09(1H,t, 7.82 (2H, d, J = 8.8Hz), 8.03 (2H, d, J = 8.8Hz), 9.09 (1H, t,
J=5Hz), 10.36(1H,br.s). IR(KBr)cm-1: 3269(br.),2861(br.),1743,1636,1534,15 . J = 5Hz), 10.36 (1H, br.s) IR (KBr) cm-1:.. 3269 (br), 2861 (br), 1743,1636,1534,15
05,1456,1308,1120,753. 05,1456,1308,1120,753.

【0153】実施例5 N−(2−アミノフェニル)−4−[N−(3−メトキシベンゾイル)アミノメチル]ベンズアミド(表−1: [0153] Example 5 N-(2-aminophenyl) -4- [N- (3- methoxybenzoyl) aminomethyl] benzamide (Table 1:
化合物番号30) mp. 182-185℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.81(3H,s), 4.54(2H, .. Compound No. 30) mp 182-185 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.81 (3H, s), 4.54 (2H,
d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,7.3H d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3H
z), 6,78(1H,d,J=7.3Hz), 6.97(1H,dd,J=6.6,7.3Hz), z), 6,78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 6.6,7.3Hz),
7.11(1H,dd,J=1.5,8.1Hz), 7.16(1H,d,J=7.3Hz), 7.35- 7.11 (1H, dd, J = 1.5,8.1Hz), 7.16 (1H, d, J = 7.3Hz), 7.35-
7.51(5H,m), 7.94(2H,d,J=8.1Hz), 9.12(1H,br.t,J=5.9 7.51 (5H, m), 7.94 (2H, d, J = 8.1Hz), 9.12 (1H, br.t, J = 5.9
Hz), 9.63(1H,br.s). IR(KBr)cm-1: 3301,1637,1524,1489,1457,1314,1248,75 . Hz), 9.63 (1H, br.s) IR (KBr) cm-1: 3301,1637,1524,1489,1457,1314,1248,75
2. 2.

【0154】実施例6 N−(2−アミノフェニル)−4−[N−(4−メトキシベンゾイル)アミノメチル]ベンズアミド(表−1: [0154] EXAMPLE 6 N-(2-aminophenyl) -4- [N- (4- methoxybenzoyl) aminomethyl] benzamide (Table 1:
化合物番号31) mp. 149-151℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.82(3H,s), 4.53(2H, .. Compound No. 31) mp 149-151 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.82 (3H, s), 4.53 (2H,
d,J=5.9Hz), 4.88(2H,s), 6.59(1H,dd,J=7.3,7.3Hz), d, J = 5.9Hz), 4.88 (2H, s), 6.59 (1H, dd, J = 7.3,7.3Hz),
6.77(1H,d,J=8.1Hz), 6.94-7.00(1H,m), 7.02(2H,d,J= 6.77 (1H, d, J = 8.1Hz), 6.94-7.00 (1H, m), 7.02 (2H, d, J =
8.8Hz), 7.16(1H,d,J=8.1Hz), 7.43(2H,d,J=8.1Hz), 7. 8.8Hz), 7.16 (1H, d, J = 8.1Hz), 7.43 (2H, d, J = 8.1Hz), 7.
89(2H,d,J=8.8Hz),7.94(2H,d,J=8.1Hz), 8.98(1H,br.t, 89 (2H, d, J = 8.8Hz), 7.94 (2H, d, J = 8.1Hz), 8.98 (1H, br.t,
J= 5.9Hz), 9.61(1H,br.s). IR(KBr)cm-1: 3297,1630,1527,1505,1457,1256,1177,10 . J = 5.9Hz), 9.61 (1H, br.s) IR (KBr) cm-1: 3297,1630,1527,1505,1457,1256,1177,10
24,843,749. 24,843,749.

【0155】実施例7 N−(2−アミノフェニル)−4−[N−(3,4,5 [0155] Example 7 N-(2-aminophenyl) -4- [N- (3,4,5
−トリメトキシベンゾイル)アミノメチル]ベンズアミド(表−1:化合物番号33) mp. 208-210℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.71(3H,s), 3.83(6H, - tri-methoxybenzoyl) aminomethyl] benzamide (Table 1:... Compound No. 33) mp 208-210 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm: 3.71 (3H, s), 3.83 (6H ,
s), 4.55(2H,d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd, s), 4.55 (2H, d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd,
J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6. J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.
6,8.1Hz), 7,16(1H,d,J=8.1Hz), 7.26(2H,s), 7.44(2H, 6,8.1Hz), 7,16 (1H, d, J = 8.1Hz), 7.26 (2H, s), 7.44 (2H,
d,J=8.1Hz), 7.95(2H,d,J=8.8Hz), 9.07(1H,t,J=5.9H d, J = 8.1Hz), 7.95 (2H, d, J = 8.8Hz), 9.07 (1H, t, J = 5.9H
z), 9.62(1H,br.s). IR(KBr)cm-1: 3267,1635,1582,1457,1237,1132,755. . Z), 9.62 (1H, br.s) IR (KBr) cm-1: 3267,1635,1582,1457,1237,1132,755.

【0156】実施例8 N−(2−アミノフェニル)−4−[N−[4−(N, [0156] Example 8 N-(2-aminophenyl) -4- [N- [4- (N,
N−ジメチル)アミノベンゾイル]アミノメチル]ベンズアミド(表−1:化合物番号36) mp. 216-219℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 2.98(6H,s), 4.51(2H, N- dimethyl) aminobenzoyl] aminomethyl] benzamide (Table 1:. Compound No. 36) mp 216-219 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 2.98 (6H, s), 4.51 (2H,
d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=8.1,8.1H d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 8.1,8.1H
z), 6.71(2H,d,J=8.8Hz), 6.97(1H,dd,J=7.3,8.1Hz), z), 6.71 (2H, d, J = 8.8Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16(1H,d,J=7.3Hz), 7.41(2H,d,J=8.1Hz), 7.78(2H,d, 7.16 (1H, d, J = 7.3Hz), 7.41 (2H, d, J = 8.1Hz), 7.78 (2H, d,
J=8.8Hz), 7.93(2H,d,J=8.1Hz), 8.77(1H,t,J=5.9Hz), J = 8.8Hz), 7.93 (2H, d, J = 8.1Hz), 8.77 (1H, t, J = 5.9Hz),
9.63(1H,br.s). IR(KBr)cm-1: 3301,1632,1519,1457,1298,754. 9.63 (1H, br.s) IR (KBr) cm-1:. 3301,1632,1519,1457,1298,754.

【0157】実施例9 N−(2−アミノフェニル)−4−[N−(4−トリフルオロメチルベンゾイル)アミノメチル]ベンズアミド(表−1:化合物番号42) mp. 243-246℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), [0157] Example 9 N-(2-aminophenyl) -4- [N- (4- trifluoromethylbenzoyl) aminomethyl] benzamide.. (Table 1: Compound No. 42) mp 243-246 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz),
4.88(2H,br.s), 6.59(1H,dd,J=6.6,7.3Hz), 6.77(1H,d, 4.88 (2H, br.s), 6.59 (1H, dd, J = 6.6,7.3Hz), 6.77 (1H, d,
J=8.1Hz), 6.94(1H,dd,J=5.9,6.6Hz), 7.16(1H,d,J=8.1 J = 8.1Hz), 6.94 (1H, dd, J = 5.9,6.6Hz), 7.16 (1H, d, J = 8.1
Hz), 7.45(2H,d,J=8.1Hz), 7.88(2H,d,J=8.8Hz), 7.95 Hz), 7.45 (2H, d, J = 8.1Hz), 7.88 (2H, d, J = 8.8Hz), 7.95
(2H,d,J=8.1Hz), 8.11(2H,d,J=8.1Hz), 9.38(1H,t,J=5. (2H, d, J = 8.1Hz), 8.11 (2H, d, J = 8.1Hz), 9.38 (1H, t, J = 5.
9Hz), 9.64(1H,br.s). IR(KBr)cm-1: 3301,1640,1549,1523,1458,1334,1162,11 . 9Hz), 9.64 (1H, br.s) IR (KBr) cm-1: 3301,1640,1549,1523,1458,1334,1162,11
20,1070,856,750. 20,1070,856,750.

【0158】実施例10 N−(2−アミノフェニル)−4−[N−(4−カルボキシベンゾイル)アミノメチル]ベンズアミド 塩酸塩(表−1:化合物番号45の塩酸塩) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), [0158] Example 10 N-(2-aminophenyl) -4- [N- (4--carboxybenzoyl) aminomethyl] benzamide hydrochloride. (Table 1: hydrochloride of Compound No. 45) mp (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d, J = 5.9Hz),
7.29-7.37(3H,m), 7.49(3H,d,J=8.1Hz), 8.02-8.06(6H, 7.29-7.37 (3H, m), 7.49 (3H, d, J = 8.1Hz), 8.02-8.06 (6H,
m), 9.36(1H,t,J=5.9Hz), 10.4(1H,br.s). IR(KBr)cm-1: 3432(br.),1718,1637,1542,1499,1303(b . M), 9.36 (1H, t, J = 5.9Hz), 10.4 (1H, br.s) IR (KBr) cm-1:. 3432 (br), 1718,1637,1542,1499,1303 (b
r.),1116,1018,757. r.), 1116,1018,757.

【0159】実施例11 N−(2−アミノフェニル)−4−[N−(4−メトキシカルボニルベンゾイル)アミノメチル]ベンズアミド(表−1:化合物番号46) mp. 204-209℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.89(3H,s), 4.57(2H, [0159] Example 11 N-(2-aminophenyl) -4- [N- (4- methoxycarbonylbenzoyl) aminomethyl] benzamide. (Table 1: Compound No. 46) mp 204-209 ℃ (dec.) . 1H NMR (270MHz, DMSO-d6) δppm: 3.89 (3H, s), 4.57 (2H,
d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,7.3H d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3H
z), 6.78(2H,d,J=7.3Hz), 6.97(1H,ddd,J=1.5,6.6,7.3H z), 6.78 (2H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,6.6,7.3H
z), 7.16(1H,d,J=7.3Hz), 7.45(2H,d,J=8.1Hz), 7.95(2 z), 7.16 (1H, d, J = 7.3Hz), 7.45 (2H, d, J = 8.1Hz), 7.95 (2
H,d,J=8.1Hz), 8.03(2H,d,J=8.8Hz), 8.07(2H,d,J=8.8H H, d, J = 8.1Hz), 8.03 (2H, d, J = 8.8Hz), 8.07 (2H, d, J = 8.8H
z), 9.35(1H,t,J=5.9Hz), 9.64(1H,br.s). IR(KBr)cm-1: 3287(br.),1721,1634,1281,1113,750,70 . Z), 9.35 (1H, t, J = 5.9Hz), 9.64 (1H, br.s) IR (KBr) cm-1:. 3287 (br), 1721,1634,1281,1113,750,70
3. 3.

【0160】実施例12 N−(2−アミノフェニル)−4−(N−ピコリノイルアミノメチル)ベンズアミド(表−1:化合物番号17 [0160] Example 12 N-(2-aminophenyl)-4-(N-picolinoyl alkanoylamino methyl) benzamide (Table 1: Compound No. 17
3) mp. 173-178℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.57(2H,d,J=6.6Hz), . 3) mp 173-178 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.57 (2H, d, J = 6.6Hz),
4.88(2H,br.s), 6.59(1H,dd,J=7.3,8.1Hz), 6.77(1H,d, 4.88 (2H, br.s), 6.59 (1H, dd, J = 7.3,8.1Hz), 6.77 (1H, d,
J=8.1Hz), 6.96(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=7.3 J = 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 7.3
Hz), 7.44(2H,d,J=8.1Hz), 7.60-7.65(1H,m), 7.93(2H, Hz), 7.44 (2H, d, J = 8.1Hz), 7.60-7.65 (1H, m), 7.93 (2H,
d,J=8.1Hz), 7.98-8.08(2H,m), 8.67(1H,d,J=4.4Hz), d, J = 8.1Hz), 7.98-8.08 (2H, m), 8.67 (1H, d, J = 4.4Hz),
9.45(1H,t,J=6.6Hz), 9.61(1H,br.s). IR(KBr)cm-1: 3330,1656,1634,1523,1456,1294,752. 9.45 (1H, t, J = 6.6Hz), 9.61 (1H, br.s) IR (KBr) cm-1:. 3330,1656,1634,1523,1456,1294,752.

【0161】実施例13 N−(2−アミノフェニル)−4−[N−(6−メチルピコリノイル)アミノメチル]ベンズアミド(表−1: [0161] EXAMPLE 13 N-(2-aminophenyl) -4- [N- (6- methyl-picolyl hexanoyl) aminomethyl] benzamide (Table 1:
化合物番号178) mp. 172-173℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.51(3H,s), 4.57(2H, .. Compound No. 178) mp 172-173 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.51 (3H, s), 4.57 (2H,
d,J=6.6Hz), 5.0(2H,br.s), 6.61(1H,dd,J=7.3,8.1Hz), d, J = 6.6Hz), 5.0 (2H, br.s), 6.61 (1H, dd, J = 7.3,8.1Hz),
6.79(1H,d,J=7.3Hz), 6.98(1H,dd,J=7.3,8.1Hz), 7.17 6.79 (1H, d, J = 7.3Hz), 6.98 (1H, dd, J = 7.3,8.1Hz), 7.17
(1H,d,J=7.3Hz), 7.44(2H,d,J=8.1Hz), 7.43-7.49(1H, (1H, d, J = 7.3Hz), 7.44 (2H, d, J = 8.1Hz), 7.43-7.49 (1H,
m), 7.84-7.90(2H,m), 7.94(2H,d,J=8.1Hz), 9.27(1H, m), 7.84-7.90 (2H, m), 7.94 (2H, d, J = 8.1Hz), 9.27 (1H,
t,J=5.9Hz), 9.64(1H,br.s). IR(KBr)cm-1: 3331,1675,1634,1594,1523,1454,1307,12 . T, J = 5.9Hz), 9.64 (1H, br.s) IR (KBr) cm-1: 3331,1675,1634,1594,1523,1454,1307,12
92,750. 92,750.

【0162】実施例14 N−(2−アミノフェニル)−4−(N−ニコチノイルアミノメチル)ベンズアミド(表−1:化合物番号7 [0162] Example 14 N-(2-aminophenyl)-4-(N-nicotinoyl-aminomethyl) benzamide (Table 1: Compound No. 7
1) mp. 193-196℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d), 4.88(2H, .. 1) mp 193-196 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.58 (2H, d), 4.88 (2H,
br.s), 6.60(1H,t), 6.78(1H,d), 6.97(1H,t), 7.16(1 br.s), 6.60 (1H, t), 6.78 (1H, d), 6.97 (1H, t), 7.16 (1
H,d), 7.46(2H,d), 7.53(1H,dd), 7.95(2H,d), 8.24(1 H, d), 7.46 (2H, d), 7.53 (1H, dd), 7.95 (2H, d), 8.24 (1
H,ddd), 8.73(1H,dd), 9.07(1H,d), 9.32(1H,br.t), 9. H, ddd), 8.73 (1H, dd), 9.07 (1H, d), 9.32 (1H, br.t), 9.
63(1H,br.s) IR(KBr)cm-1: 3301,1639,1522,1457,1314,749,705. 63 (1H, br.s) IR (KBr) cm-1: 3301,1639,1522,1457,1314,749,705.

【0163】実施例15 N−(2−アミノフェニル)−4−[N−(2−メチルニコチノイル)アミノメチル]ベンズアミド(表−1: [0163] Example 15 N-(2-aminophenyl) -4- [N- (2- methyl-nicotinoyl) aminomethyl] benzamide (Table 1:
化合物番号141) mp. 191-194℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 2.53(3H,s), 4.53(2H, . Compound No. 141) mp 191-194 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 2.53 (3H, s), 4.53 (2H,
d,J=5.9Hz), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,8.1H d, J = 5.9Hz), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,8.1H
z), 6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=7.3,8.1Hz), z), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.17(1H,d,J=7.3Hz), 7.29(1H,dd,J=5.1,8.1Hz), 7.47 7.17 (1H, d, J = 7.3Hz), 7.29 (1H, dd, J = 5.1,8.1Hz), 7.47
(2H,d,J=8.1Hz), 7.77(1H,dd,J=1.5,8.1Hz), 7.97(2H, (2H, d, J = 8.1Hz), 7.77 (1H, dd, J = 1.5,8.1Hz), 7.97 (2H,
d,J=8.1Hz), 8.51(1H,dd,J=1.5,5.1Hz), 9.06(1H,t,J= d, J = 8.1Hz), 8.51 (1H, dd, J = 1.5,5.1Hz), 9.06 (1H, t, J =
5.9Hz), 9.64(1H,s). IR(KBr)cm-1: 3261,1642,1523,1310,753. . 5.9Hz), 9.64 (1H, s) IR (KBr) cm-1: 3261,1642,1523,1310,753.

【0164】実施例16 N−(2−アミノフェニル)−4−[N−(6−メチルニコチノイル)アミノメチル]ベンズアミド(表−1: [0164] EXAMPLE 16 N-(2-aminophenyl) -4- [N- (6- methyl-nicotinoyl) aminomethyl] benzamide (Table 1:
化合物番号143) mp. 186-190℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 2.36(3H,s), 4.56(2H, . Compound No. 143) mp 186-190 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 2.36 (3H, s), 4.56 (2H,
d,J=5.9Hz), 4.88(2H,s), 6.60(1H,dd,J=7.4,7.8Hz), d, J = 5.9Hz), 4.88 (2H, s), 6.60 (1H, dd, J = 7.4,7.8Hz),
6.78(1H,d,J=7.8Hz), 6.97(1H,dd,J=6.9,6.9Hz),7.16(1 6.78 (1H, d, J = 7.8Hz), 6.97 (1H, dd, J = 6.9,6.9Hz), 7.16 (1
H,d,J=7.4Hz), 7.37(1H,d,J=8.3Hz), 7.45(2H,d,J=8.3H H, d, J = 7.4Hz), 7.37 (1H, d, J = 8.3Hz), 7.45 (2H, d, J = 8.3H
z), 7.95(2H,d,J=8.3Hz), 8.13(1H,dd,J=2.0,8.3Hz), z), 7.95 (2H, d, J = 8.3Hz), 8.13 (1H, dd, J = 2.0,8.3Hz),
8.96(1H,s), 9.24(1H,t,J=5.9Hz), 9.63(1H,br.s). IR(KBr)cm-1: 3302,1636,1602,1523,1489,1457,1313,75 8.96 (1H, s), 9.24 (1H, t, J = 5.9Hz), 9.63 (1H, br.s) IR (KBr) cm-1:. 3302,1636,1602,1523,1489,1457,1313, 75
1. 1.

【0165】実施例17 N−(2−アミノフェニル)−4−[N−(2−クロロニコチノイル)アミノメチル]ベンズアミド(表−1: [0165] EXAMPLE 17 N-(2-aminophenyl) -4- [N- (2- chloronicotinoyl) aminomethyl] benzamide (Table 1:
化合物番号154) mp. 176-178℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.54(2H,t,J=5.9Hz), . Compound No. 154) mp 176-178 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.54 (2H, t, J = 5.9Hz),
4.90(2H,br.s), 6.60(1H,ddd,J=1.5,7.3,7.3Hz), 6.78 4.90 (2H, br.s), 6.60 (1H, ddd, J = 1.5,7.3,7.3Hz), 6.78
(1H,d,J=8.1Hz), 6.97(1H,ddd,J=1.5,7.3,7.3Hz),7.18 (1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.18
(1H,d,J=8.1Hz), 7.48-7.54(3H,m), 7.94-7.99(3H,m), (1H, d, J = 8.1Hz), 7.48-7.54 (3H, m), 7.94-7.99 (3H, m),
8.49(1H,dd,J=2.1,5.1Hz), 9.23(1H,br.t,J=5.9Hz), 9. 8.49 (1H, dd, J = 2.1,5.1Hz), 9.23 (1H, br.t, J = 5.9Hz), 9.
65(1H,br.s). IR(KBr)cm-1: 3264,1649,1524,1400,1309,751. 65 (1H, br.s) IR (KBr) cm-1:. 3264,1649,1524,1400,1309,751.

【0166】実施例18 N−(2−アミノフェニル)−4−[N−(6−クロロニコチノイル)アミノメチル]ベンズアミド(表−1: [0166] EXAMPLE 18 N-(2-aminophenyl) -4- [N- (6- chloronicotinoyl) aminomethyl] benzamide (Table 1:
化合物番号156) mp. 205-208℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 5.57(2H,d,J=5.9Hz), . Compound No. 156) mp 205-208 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 5.57 (2H, d, J = 5.9Hz),
6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.96 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.96
(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 7.45(2H, (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz), 7.45 (2H,
d,J=8.1Hz), 7.66(1H,d,J=8.8Hz), 7.95(2H,d,J=8.1H d, J = 8.1Hz), 7.66 (1H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.1H
z), 8.27-8.32(1H,m),8.90(1H,d,J=2.1Hz), 9.38(1H,t, z), 8.27-8.32 (1H, m), 8.90 (1H, d, J = 2.1Hz), 9.38 (1H, t,
J=5.9Hz), 9.63(1H,s). IR(KBr)cm-1: 3318(br.),2929,1646,1590,1525,1503,14 . J = 5.9Hz), 9.63 (1H, s) IR (KBr) cm-1:. 3318 (br), 2929,1646,1590,1525,1503,14
54,1108,745. 54,1108,745.

【0167】実施例19 N−(2−アミノフェニル)−4−(N−イソニコチノイルアミノメチル)ベンズアミド(表−1:化合物番号183) mp. 234-237℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.57(2H,t,J=5.9Hz), [0167] Example 19 N-(2-aminophenyl)-4-(N-isonicotinoyl aminomethyl) benzamide.: (. Dec). (Table 1 Compound No. 183) mp 234-237 ℃ 1H NMR ( 270MHz, DMSO-d6) δppm: 4.57 (2H, t, J = 5.9Hz),
4.88(2H,br.s), 6.59(1H,dd,J=6.6,7.3Hz), 6.78(1H,d, 4.88 (2H, br.s), 6.59 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d,
J=8.1Hz), 6.96(1H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=7.3 J = 8.1Hz), 6.96 (1H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3
Hz), 7.45(2H,d,J=8.1Hz), 7.81(2H,d,J=1.5,4.4Hz), Hz), 7.45 (2H, d, J = 8.1Hz), 7.81 (2H, d, J = 1.5,4.4Hz),
7.95(2H,d,J=8.1Hz), 8.75(2H,d,J=6.6Hz), 9.41(1H,t, 7.95 (2H, d, J = 8.1Hz), 8.75 (2H, d, J = 6.6Hz), 9.41 (1H, t,
J=5.9Hz), 9.62(1H,br.s). IR(KBr)cm-1: 3298,1646,1550,1525,1457,1304,843,76 . J = 5.9Hz), 9.62 (1H, br.s) IR (KBr) cm-1: 3298,1646,1550,1525,1457,1304,843,76
0,695. 0,695.

【0168】実施例20 N−(2−アミノフェニル)−4−[N−(ピラジン− [0168] EXAMPLE 20 N-(2-aminophenyl) -4- [N- (pyrazine -
2−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号191) mp. 207℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), 2-yl) carbonylamino-methyl] benzamide (Table 1:. Compound No. 191) mp 207 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.58 (2H, d, J = 5.9Hz),
4.88(2H,br.s), 6.59(1H,dd,J=7.3,7.3Hz), 6.77(1H,d, 4.88 (2H, br.s), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d,
J=8.1Hz), 6.94(1H,ddd,J=1.5,7.3,8.1Hz), 7.15(1H,d, J = 8.1Hz), 6.94 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.15 (1H, d,
J=7.3Hz), 7.45(2H,d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), J = 7.3Hz), 7.45 (2H, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz),
8.77(1H,d,J=1.5Hz), 8.90(1H,d,J=2.1Hz), 9.21(1H, 8.77 (1H, d, J = 1.5Hz), 8.90 (1H, d, J = 2.1Hz), 9.21 (1H,
s), 9.55-9.61(2H,m). IR(KBr)cm-1: 3368(br.),1657,1524,1455,1295,1023,75 . S), 9.55-9.61 (2H, m) IR (KBr) cm-1:. 3368 (br), 1657,1524,1455,1295,1023,75
1. 1.

【0169】実施例21 N−(2−アミノフェニル)−4−[N−(チオフェン−2−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号201) mp. 202-205℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.52(2H,t,J=5.9Hz), [0169] Example 21 N-(2-aminophenyl)-4-[N-(thiophen-2-yl) carbonylamino methyl] benzamide. (Table 1: Compound No. 201) mp 202-205 ° C. (dec. .) 1H NMR (270MHz, DMSO-d6) δppm: 4.52 (2H, t, J = 5.9Hz),
4.88(2H,br.s), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d, 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d,
J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.15-7.18(2H, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.15-7.18 (2H,
m), 7.43(2H,d,J=8.1Hz), 7.78(1H,d,J=4.4), 7.82(1H, m), 7.43 (2H, d, J = 8.1Hz), 7.78 (1H, d, J = 4.4), 7.82 (1H,
d,J=3.7Hz), 7.95(2H,d,J=8.1Hz), 9.12(1H,br.t,J=5.9 d, J = 3.7Hz), 7.95 (2H, d, J = 8.1Hz), 9.12 (1H, br.t, J = 5.9
Hz), 9.62(1H,br.s). IR(KBr)cm-1: 3306,1633,1523,1456,1297,750,716. . Hz), 9.62 (1H, br.s) IR (KBr) cm-1: 3306,1633,1523,1456,1297,750,716.

【0170】実施例22 N−(2−アミノフェニル)−4−[N−(フラン−2 [0170] Example 22 N-(2-aminophenyl) -4- [N- (furan -2
−イル)カルボニルアミノメチル]ベンズアミド(表− - yl) carbonyl aminomethyl] benzamide (Table -
1:化合物番号205) mp. 197℃(dec.). 1:. Compound No. 205) mp 197 ℃ (dec)..

【0171】1H NMR(270MHz, DMSO-d6)δppm: 4.59(2H, [0171] 1H NMR (270MHz, DMSO-d6) δppm: 4.59 (2H,
d,J=6.6Hz), 4.86(2H,br.s), 6.59(1H,dd,J=6.6,6.6H d, J = 6.6Hz), 4.86 (2H, br.s), 6.59 (1H, dd, J = 6.6,6.6H
z), 6.63(1H,dd,J=1.5,3.6Hz), 6.78(1H,d,J=8.1Hz), z), 6.63 (1H, dd, J = 1.5,3.6Hz), 6.78 (1H, d, J = 8.1Hz),
6.96(1H,dd,J=7.3,6.6Hz), 7.10-7.20(2H,m),7.41(2H, 6.96 (1H, dd, J = 7.3,6.6Hz), 7.10-7.20 (2H, m), 7.41 (2H,
d,J=8.1Hz), 7.84(1H,s), 7.94(2H,d,J=8.1Hz), 9.00(1 d, J = 8.1Hz), 7.84 (1H, s), 7.94 (2H, d, J = 8.1Hz), 9.00 (1
H,br.t,J= 5.9Hz), 9.62(1H,s). IR(KBr)cm-1: 3245,1651,1573,1545,1323,1241,745. . H, br.t, J = 5.9Hz), 9.62 (1H, s) IR (KBr) cm-1: 3245,1651,1573,1545,1323,1241,745.

【0172】実施例23 N−(2−アミノフェニル)−4−[N−(ピロール− [0172] Example 23 N-(2-aminophenyl) -4- [N- (pyrrol -
2−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号209) mp. 216-220℃(dec.) 1H NMR(270MHz, DMSO-d6)δppm: 4.50(2H,d,J=5.9Hz), 2-yl) carbonylamino-methyl] benzamide (Table 1:. Compound No. 209) mp 216-220 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:. 4.50 (2H, d, J = 5.9Hz) ,
4.88(2H,br.s), 6.10(1H,dd,J=2.1,5.9Hz), 6.59(1H,d 4.88 (2H, br.s), 6.10 (1H, dd, J = 2.1,5.9Hz), 6.59 (1H, d
d,J=7.3,7.3Hz), 6.77(1H,dd,J=1.5,8.1Hz), 6.84-6.88 d, J = 7.3,7.3Hz), 6.77 (1H, dd, J = 1.5,8.1Hz), 6.84-6.88
(2H,m), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J= (2H, m), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J =
7.3Hz), 7.41(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8. 7.3Hz), 7.41 (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.
62(1H,br.t,J=5.9Hz), 9.62(1H,br.s). IR(KBr)cm-1: 3275,1655,1584,1534,1458,1316,747. 62 (1H, br.t, J = 5.9Hz), 9.62 (1H, br.s) IR (KBr) cm-1:. 3275,1655,1584,1534,1458,1316,747.

【0173】実施例24 N−(2−アミノフェニル)−4−[N−(1−メチル−1H−ピロール−2−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号210) mp. 177ー179℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.84(3H,s), 4.46(2H, [0173] Example 24 N-(2-aminophenyl) -4- [N- (1- methyl--1H- pyrrol-2-yl) carbonylamino methyl] benzamide. (Table 1: Compound No. 210) mp 177 over 179 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 3.84 (3H, s), 4.46 (2H,
d,J=5.9Hz), 4.88(2H,br.s), 6.03(1H,dd,J=2.1,4.4H d, J = 5.9Hz), 4.88 (2H, br.s), 6.03 (1H, dd, J = 2.1,4.4H
z), 6.59(1H,dd,J=8.1,8.1Hz), 6.77(1H,d,J=8.1Hz), z), 6.59 (1H, dd, J = 8.1,8.1Hz), 6.77 (1H, d, J = 8.1Hz),
6.84-6.97(2H,m), 7.16(1H,d,J=7.3Hz), 7.41(2H,d,J= 6.84-6.97 (2H, m), 7.16 (1H, d, J = 7.3Hz), 7.41 (2H, d, J =
8.1Hz), 7.93(2H,d,J=8.1Hz), 8.61(1H,t,J=5.9Hz), 9. 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.61 (1H, t, J = 5.9Hz), 9.
62(1H,br.s). IR(KBr)cm-1: 3325(br.),1630,1551,1520,1507,1324,12 62 (1H, br.s) IR (KBr) cm-1:. (. Br) 3325, 1630,1551,1520,1507,1324,12
65,1154,740. 65,1154,740.

【0174】実施例25 N−(2−アミノフェニル)−4−[N−(イソオキサゾール−5−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号212) mp. 183-185℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.53(2H,d,J=6.6Hz), [0174] Example 25 N-(2-aminophenyl)-4-[N-(isoxazol-5-yl) carbonyl aminomethyl] benzamide. (Table 1: Compound No. 212) mp 183-185 ° C. (dec ..) 1H NMR (270MHz, DMSO-d6) δppm: 4.53 (2H, d, J = 6.6Hz),
4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d, 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d,
J=7.3Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.12(1H,d,J=2.1 J = 7.3Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.12 (1H, d, J = 2.1
Hz), 7.16(1H,d,J=8.1Hz), 7.44(2H,d,J=8.1Hz), 7.95 Hz), 7.16 (1H, d, J = 8.1Hz), 7.44 (2H, d, J = 8.1Hz), 7.95
(2H,d,J=8.1Hz), 8.76(1H,d,J=1.5Hz), 9.61(1H,t,J=5. (2H, d, J = 8.1Hz), 8.76 (1H, d, J = 1.5Hz), 9.61 (1H, t, J = 5.
9Hz), 9.64(1H,br.s). IR(KBr)cm-1: 3278(br.),1636,1576,1522,1458,1220,74 . 9Hz), 9.64 (1H, br.s) IR (KBr) cm-1:. 3278 (br), 1636,1576,1522,1458,1220,74
9. 9.

【0175】実施例26 N−(2−アミノフェニル)−4−[N−(3−メチルイソチアゾール−5−イル)カルボニルアミノメチル] [0175] Example 26 N-(2-aminophenyl) -4- [N- (-5- 3- methylisothiazole-yl) carbonyl aminomethyl]
ベンズアミド(表−1:化合物番号213) mp. 168-169℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.47(3H,s), 4.54(2H, Benzamide.. (Table 1: Compound No. 213) mp 168-169 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.47 (3H, s), 4.54 (2H,
d,J=5.9Hz), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3H d, J = 5.9Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3H
z), 6.78(1H,d,J=7.3Hz), 6.97(1H,ddd,J=1.0,7.3,8.1H z), 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.0,7.3,8.1H
z), 7.17(1H,d,J=7.3Hz), 7.44(2H,d,J=8.1Hz), 7.73(1 z), 7.17 (1H, d, J = 7.3Hz), 7.44 (2H, d, J = 8.1Hz), 7.73 (1
H,s), 7.96(2H,d,J=8.1Hz), 9.44(1H,t,J=5.9Hz), 9.64 H, s), 7.96 (2H, d, J = 8.1Hz), 9.44 (1H, t, J = 5.9Hz), 9.64
(1H,br.s). IR(KBr)cm-1: 3310,1637,1503,1294,751. . (1H, br.s) IR (KBr) cm-1: 3310,1637,1503,1294,751.

【0176】実施例27 N−(2−アミノフェニル)−4−[N−(イミダゾール−4−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号214) mp.(amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.49(2H,d,J=6.4Hz), [0176] Example 27 N-(2-aminophenyl) -4- [N-(imidazol-4-yl) carbonylamino methyl] benzamide.. (Table 1: Compound No. 214) mp (amorphous) 1H NMR ( 270MHz, DMSO-d6) δppm: 4.49 (2H, d, J = 6.4Hz),
4.87(2H,br.s), 6.59(1H,dd,J=6.9,6.9Hz), 6.77(1H,d, 4.87 (2H, br.s), 6.59 (1H, dd, J = 6.9,6.9Hz), 6.77 (1H, d,
J=6.9Hz), 6.96(1H,dd,J=7.4,7.4Hz), 7.16(1H,d,J=6.9 J = 6.9Hz), 6.96 (1H, dd, J = 7.4,7.4Hz), 7.16 (1H, d, J = 6.9
Hz), 7.41(2H,d,J=6.9Hz), 7.64(1H,br.s), 7.73(1H,b Hz), 7.41 (2H, d, J = 6.9Hz), 7.64 (1H, br.s), 7.73 (1H, b
rs), 7.92(2H,d,J=6.9Hz), 8.56(1H,br.t,J=6.4Hz), rs), 7.92 (2H, d, J = 6.9Hz), 8.56 (1H, br.t, J = 6.4Hz),
9.61(1H,s), 12.5(1H,br.s). IR(KBr)cm-1: 3278(br.),1636,1576,1522,1458,1220,74 9.61 (1H, s), 12.5 (1H, br.s) IR (KBr) cm-1:. (. Br) 3278, 1636,1576,1522,1458,1220,74
9. 9.

【0177】実施例28 N−(2−アミノフェニル)−4−[N−(3−アミノフェニル)アセチルアミノメチル]ベンズアミド(表− [0177] Example 28 N-(2-aminophenyl) -4- [N- (3- aminophenyl) acetyl aminomethyl] benzamide (Table -
1:化合物番号23の化合物) mp. 171-176℃ 1H NMR(270MHz, DMSO-d6)δppm: 4.34(2H,d,J=5.9Hz), 1:. Compound Compound Number 23) mp 171-176 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.34 (2H, d, J = 5.9Hz),
5.24(4H,br.s), 6.48-6.63(4H,m), 6.78-6.81(1H,m), 5.24 (4H, br.s), 6.48-6.63 (4H, m), 6.78-6.81 (1H, m),
6.94-7.00(2H,m), 7.18(1H,d,J=8.1Hz), 7.34(2H,d,J= 6.94-7.00 (2H, m), 7.18 (1H, d, J = 8.1Hz), 7.34 (2H, d, J =
8.1Hz), 7.92(2H,d,J=8.1Hz), 8.50(1H,t,J=5.9Hz), 9. 8.1Hz), 7.92 (2H, d, J = 8.1Hz), 8.50 (1H, t, J = 5.9Hz), 9.
61(1H,s). 61 (1H, s).

【0178】実施例29 N−(2−アミノフェニル)−4−[N−(ピリジン− [0178] Example 29 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)アセチルアミノメチル]ベンズアミド(表− 3-yl) acetyl aminomethyl] benzamide (Table -
1:化合物番号74) mp. 127℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.84(2H,s), 4.40(2H, 1:.. Compound No. 74) mp 127 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.84 (2H, s), 4.40 (2H,
d,J=5.8Hz), 7.15-7.29(3H,m), 7.37(1H,d,J=6.6Hz), d, J = 5.8Hz), 7.15-7.29 (3H, m), 7.37 (1H, d, J = 6.6Hz),
7.43(2H,d,J=8.8Hz), 7.96(1H,m), 7.98(2H,d,J=8.8H 7.43 (2H, d, J = 8.8Hz), 7.96 (1H, m), 7.98 (2H, d, J = 8.8H
z), 8.40(1H,d,J=8.8Hz), 8.79-8.87(3H,m), 10.20(1H, z), 8.40 (1H, d, J = 8.8Hz), 8.79-8.87 (3H, m), 10.20 (1H,
s). s).

【0179】実施例30 N−(2−アミノフェニル)−4−[N−[3−(ピリジン−3−イル)プロピオニル]アミノメチル]ベンズアミド(表−1:化合物番号75の化合物) mp. 183-186℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.51(2H,t,J=7.3Hz), [0179] Example 30 N-(2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propionyl] aminomethyl] benzamide. (Table 1: Compound No. 75) mp 183 . -186 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.51 (2H, t, J = 7.3Hz),
2.88(2H,d,J=7.3Hz), 4.31(2H,d,J=5.9Hz), 4.89(2H,b 2.88 (2H, d, J = 7.3Hz), 4.31 (2H, d, J = 5.9Hz), 4.89 (2H, b
rs), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), rs), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz),
6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7.16(1H,d,J=8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1H, d, J = 8.1Hz),
7.23(2H,d,J=8.8Hz), 7.28-7.33(1H,m), 7.63(1H,d,J= 7.23 (2H, d, J = 8.8Hz), 7.28-7.33 (1H, m), 7.63 (1H, d, J =
8.1Hz), 7.89(2H,d,J=8.1Hz), 8.41-8.45(3H,m), 9.62 8.1Hz), 7.89 (2H, d, J = 8.1Hz), 8.41-8.45 (3H, m), 9.62
(1H,br.s). IR(KBr)cm-1: 3407,3313,1640,1552,1522,1456,1309,74 . (1H, br.s) IR (KBr) cm-1: 3407,3313,1640,1552,1522,1456,1309,74
6,717. 6,717.

【0180】実施例31 N−(2−アミノフェニル)−4−[N−[4−(ピリジン−3−イル)−1,4−ジオキソブチル]アミノメチル]ベンズアミド(表−1:化合物番号100) mp. 145-147℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 2.37-2.50(2H,m), 2.6 [0180] Example 31 N-(2-aminophenyl) -4- [N- [4- (pyridin-3-yl) -1,4-dioxobutyl] aminomethyl] benzamide (Table 1: Compound No. 100) . mp 145-147 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 2.37-2.50 (2H, m), 2.6
2-2.68(2H,m), 4.13(2H,s), 4.86(2H,s), 6.56-6.61(1 2-2.68 (2H, m), 4.13 (2H, s), 4.86 (2H, s), 6.56-6.61 (1
H,m), 6.76-6.79(1H,m), 6.94-6.99(1H,m), 7.10-7.39 H, m), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.10-7.39
(4H,m), 7.43-7.46(1H,m), 7.78(2H,d,J=8.1Hz), 8.60- (4H, m), 7.43-7.46 (1H, m), 7.78 (2H, d, J = 8.1Hz), 8.60-
8.64(1H,m), 9.58(1H,s). IR(KBr)cm-1:3348,1691,1655,1534,1508,1458,1395,131 8.64 (1H, m), 9.58 (1H, s) IR (KBr) cm-1:. 3348,1691,1655,1534,1508,1458,1395,131
5,1083,746. 5,1083,746.

【0181】実施例32 N−(2−アミノフェニル)−4−[N−(5−クロロピリジン−3−イル)オキシアセチルアミノメチル]ベンツアミド(表−1:化合物番号158) mp. 199-201℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.43(2H,d,J=6.6Hz), [0181] Example 32 N-(2-aminophenyl) -4- [N- (5- chloropyridin-3-yl) oxy acetylamino methyl] benz amide (Table 1: Compound No. 158) mp 199-. . 201 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.43 (2H, d, J = 6.6Hz),
4.75(2H,s), 4.87(2H,br.s), 6.60(1H,dd,J=7.3,8.1H 4.75 (2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16(1H,d,J=8.1Hz), 7.37(2H,d,J=8.1Hz), 7.59(1H,d, 7.16 (1H, d, J = 8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.59 (1H, d,
J=2.2Hz), 7.93(2H,d,J=8.1Hz), 8.25(1H,d,J=1.5Hz), J = 2.2Hz), 7.93 (2H, d, J = 8.1Hz), 8.25 (1H, d, J = 1.5Hz),
8.81(1H,t,J=6.6Hz), 9.64(1H,s). IR(KBr)cm-1:3288,3058,1675,1633,1523,1457,1314,91 8.81 (1H, t, J = 6.6Hz), 9.64 (1H, s) IR (KBr) cm-1:. 3288,3058,1675,1633,1523,1457,1314,91
2,755. 2,755.

【0182】実施例33 N−(2−アミノ−5−メトキシフェニル)−4−[N [0182] Example 33 N-(2-amino-5-methoxyphenyl)-4-[N
−(ピリジン−3−イル)オキシアセチルアミノメチル]ベンズアミド(表−1:化合物番号175) mp. 141-144℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.66(3H,s), 4.43(2H, - (pyridin-3-yl) oxy acetylaminomethyl] benzamide.. (Table 1: Compound No. 175) mp 141-144 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.66 (3H, s), 4.43 ( 2H,
d,J=5.9Hz), 4.49(2H,br.s), 4.68(2H,s), 6.62(1H,dd, d, J = 5.9Hz), 4.49 (2H, br.s), 4.68 (2H, s), 6.62 (1H, dd,
J=2.9,8.8Hz), 6.75(1H,d,J=8.8Hz), 6.91(1H,d,J=2.2H J = 2.9,8.8Hz), 6.75 (1H, d, J = 8.8Hz), 6.91 (1H, d, J = 2.2H
z), 7.37(4H,m), 7.92(2H,d,J=8.8Hz), 8.21(1H,dd,J= z), 7.37 (4H, m), 7.92 (2H, d, J = 8.8Hz), 8.21 (1H, dd, J =
1.5,4.4Hz), 8.35(1H,d,J=2.7Hz), 8.81(1H,s), 9.65(1 1.5,4.4Hz), 8.35 (1H, d, J = 2.7Hz), 8.81 (1H, s), 9.65 (1
H,s). H, s).

【0183】実施例34 N−(2−アミノフェニル)−4−[N−[3−(ピリジン−3−イル)−1、3−ジオキソプロピル]アミノメチル]ベンズアミド(表−1:化合物番号98) mp. 204-206℃.1H NMR(270MHz, DMS [0183] Example 34 N-(2-aminophenyl) -4- [N- [3- (pyridin-3-yl) -1,3-dioxopropyl] aminomethyl] benzamide (Table 1: Compound No. 98) mp. 204-206 ℃ .1H NMR (270MHz, DMS
O−d6)δppm: 4.08(4/3H,s), 4.39(4/3H,d,J=5.9H O-d6) δppm: 4.08 (4 / 3H, s), 4.39 (4 / 3H, d, J = 5.9H
z), 4.49(2/3H,d,J=5.9Hz), 4.90(2H,br.s), 5.93(1/3 z), 4.49 (2 / 3H, d, J = 5.9Hz), 4.90 (2H, br.s), 5.93 (1/3
H,s), 6.60(1H,t,J=7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97 H, s), 6.60 (1H, t, J = 7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97
(1H,t,J=7.3Hz), 7.16(1H,d,J=7.3Hz), 7.3-7.7(3H,m), (1H, t, J = 7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.3-7.7 (3H, m),
7.8-8.4(3H,m), 8.6-9.2(3H,m), 9.64(1H,s), 14.74(1 7.8-8.4 (3H, m), 8.6-9.2 (3H, m), 9.64 (1H, s), 14.74 (1
/3H,s).(2:1の平衡混合物) IR(KBr)cm-1:3282,1690,1645,1527,1421,1314,1217,102 Equilibrium mixture of /3H,s).(2:1) IR (KBr) cm-1: 3282,1690,1645,1527,1421,1314,1217,102
8,994,911,753,701. 8,994,911,753,701.

【0184】実施例35 N−(2−アミノフェニル)−4−[N−[N−(ピリジン−3−イル)アミノアセチル]アミノメチル]ベンズアミド(表−1:化合物番号96) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.77(2H,d,=6.6Hz), [0184] Example 35 N-(2-aminophenyl) -4- [N- [N- (pyridin-3-yl) aminoacetyl] aminomethyl] benzamide. (Table 1: Compound No. 96) mp (Amorphous .) 1H NMR (270MHz, DMSO-d6) δppm: 3.77 (2H, d, = 6.6Hz),
4.37(2H,d,J=5.9Hz), 4.87(2H,br.s), 6.27(1H,t,J=5.9 4.37 (2H, d, J = 5.9Hz), 4.87 (2H, br.s), 6.27 (1H, t, J = 5.9
Hz), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,7.3Hz), 6. Hz), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, 7.3Hz), 6.
87(1H,d,J=8.1Hz), 6.96(1H,dd,J=7.3,8.1Hz), 7.09(1 87 (1H, d, J = 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.09 (1
H,d,J=4.4Hz), 7.12(1H,d,J=4.4Hz), 7.16(1H,d,J=8.1H H, d, J = 4.4Hz), 7.12 (1H, d, J = 4.4Hz), 7.16 (1H, d, J = 8.1H
z), 7.33(2H,d,J=8.8Hz), 7.81(1H,d,J=4.4Hz), 7.91(2 z), 7.33 (2H, d, J = 8.8Hz), 7.81 (1H, d, J = 4.4Hz), 7.91 (2
H,d,J=7.3Hz), 7.99(1H,d,J=2.9Hz), 8.59(1H,br.t,J= H, d, J = 7.3Hz), 7.99 (1H, d, J = 2.9Hz), 8.59 (1H, br.t, J =
5.1Hz), 9.63(1H,br.s). IR(KBr)cm-1:3350,1658,1525,1502,1314,750. . 5.1Hz), 9.63 (1H, br.s) IR (KBr) cm-1: 3350,1658,1525,1502,1314,750.

【0185】実施例36 N−(2−アミノフェニル)−4−[N−(2−アミノチアゾール−4−イル)アセチルアミノメチル]ベンズアミド(表−1:化合物番号220) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.34(2H,s), 4.35(2H, [0185] Example 36 N-(2-aminophenyl) -4- [N- (-4- 2- aminothiazol-yl) acetylaminomethyl] benzamide. (Table 1: Compound No. 220) mp (Amorphous). 1H NMR (270MHz, DMSO-d6) δppm: 3.34 (2H, s), 4.35 (2H,
d,J=5.9Hz), 4.87(2H,s), 6.25(1H,s), 6.59(1H,dd,J= d, J = 5.9Hz), 4.87 (2H, s), 6.25 (1H, s), 6.59 (1H, dd, J =
7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.87(2H,s), 6.96(1 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.87 (2H, s), 6.96 (1
H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=7.3Hz), 7.37(2H,d,J H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.37 (2H, d, J
=8.1Hz), 7.93(2H,d,J=8.1Hz), 8.44(1H,t,J=5.9Hz), = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.44 (1H, t, J = 5.9Hz),
9.62(1H,s). 9.62 (1H, s).

【0186】実施例37 N−(2−アミノフェニル)−4−[N−(キノリン− [0186] Example 37 N-(2-aminophenyl) -4- [N- (quinolin -
6−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号231) mp. 209-210℃. 1H NMR(270MHz, DMSO-d6)δppm:4.62(2H,d,J=5.9Hz), 6-yl) carbonyl aminomethyl] benzamide (Table 1:.. Compound No. 231) mp 209-210 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.62 (2H, d, J = 5.9Hz),
4.88(2H,s), 6.60(1H,t,J=7.7Hz), 6.78(1H,d,J=7.3H 4.88 (2H, s), 6.60 (1H, t, J = 7.7Hz), 6.78 (1H, d, J = 7.3H
z), 6.95(1H,d,J=7.3Hz), 7.17(1H,d,J=7.3Hz), 7.49(2 z), 6.95 (1H, d, J = 7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.49 (2
H,d,J=8.8Hz), 7.62(1H,dd,J=4.4,8.1Hz), 7.96(2H,d,J H, d, J = 8.8Hz), 7.62 (1H, dd, J = 4.4,8.1Hz), 7.96 (2H, d, J
=8.8Hz), 8.10(1H,d,J=8.8Hz), 8.23(1H,dd,J=2.2,8.8H = 8.8Hz), 8.10 (1H, d, J = 8.8Hz), 8.23 ​​(1H, dd, J = 2.2,8.8H
z), 8.38(1H,m), 8.49(1H,d,J=8.1Hz), 8.58(1H,s), 8. z), 8.38 (1H, m), 8.49 (1H, d, J = 8.1Hz), 8.58 (1H, s), 8.
99(1H,s), 9.64(1H,s). IR(KBr)cm-1:3301,1640,1614,1545,1496,1312,910,853, 99 (1H, s), 9.64 (1H, s) IR (KBr) cm-1:. 3301,1640,1614,1545,1496,1312,910,853,
745. 745.

【0187】実施例38 N−(2−アミノフェニル)−4−[N−(フロ[3, [0187] Example 38 N-(2-aminophenyl) -4- [N- (furo [3,
2−b]ピリジン−2−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号233) mp. 191℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,d,J=5.9Hz), 2-b] pyridin-2-yl) carbonylamino-methyl] benzamide (Table 1:. Compound No. 233) mp 191 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.58 (2H, d, J = 5.9Hz),
4.88(2H,s), 6.57-6.62(1H,m), 6.76-6.79(1H,m), 6.93 4.88 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93
-6.99(1H,m), 7.15-7.25(1H,m), 7.45-7.52(3H,m), 7.7 -6.99 (1H, m), 7.15-7.25 (1H, m), 7.45-7.52 (3H, m), 7.7
4(1H,s), 7.95(2H,d,J=8.1Hz), 8.13(1H,d,J=8.8Hz), 4 (1H, s), 7.95 (2H, d, J = 8.1Hz), 8.13 (1H, d, J = 8.8Hz),
8.63(1H,d,J=3.7Hz), 9.54(1H,t,J=5.9Hz), 9.64(1H, 8.63 (1H, d, J = 3.7Hz), 9.54 (1H, t, J = 5.9Hz), 9.64 (1H,
s). IR(KBr)cm-1:3406,1662,1529,1507.1420,1313,1209,113 . S) IR (KBr) cm-1: 3406,1662,1529,1507.1420,1313,1209,113
9,1170,1139,924,741. 9,1170,1139,924,741.

【0188】実施例39 N−(2−アミノフェニル)−4−[N−(フロ[2, [0188] Example 39 N-(2-aminophenyl) -4- [N- (furo [2,
3−c]ピリジン−2−イル)カルボニルアミノメチル]ベンズアミド(表−1:化合物番号234) mp. 210℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.58(2H,J=6.6Hz), 4. 3-c] pyridin-2-yl) carbonylamino-methyl] benzamide (Table 1:. Compound No. 234) mp 210 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.58 (2H, J = 6.6Hz), 4.
87(2H,s), 6.57-6.62(1H,m), 6.76-6.79(1H,m), 6.93- 87 (2H, s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.93-
6.99(1H,m), 7.14-7.17(1H,m), 7.47(2H,d,J=8.1Hz), 6.99 (1H, m), 7.14-7.17 (1H, m), 7.47 (2H, d, J = 8.1Hz),
7.66(1H,s), 7.82(1H,d,J=4.4Hz), 7.96(2H,d,J=8.1H 7.66 (1H, s), 7.82 (1H, d, J = 4.4Hz), 7.96 (2H, d, J = 8.1H
z), 8.48(1H,d,J=5.1Hz), 9.06(1H,s), 9.60-9.64(2H, z), 8.48 (1H, d, J = 5.1Hz), 9.06 (1H, s), 9.60-9.64 (2H,
m). IR(KBr)cm-1:3320,1653,1632,1598,1457,1424,1308,118 . M) IR (KBr) cm-1: 3320,1653,1632,1598,1457,1424,1308,118
7,1033,853,749. 7,1033,853,749.

【0189】実施例40 N−(2−ヒドロキシフェニル)−4−[N−[3− [0189] Example 40 N-(2-hydroxyphenyl) -4- [N- [3-
(ピリジン−3−イル)プロピオニル]アミノメチル] (Pyridin-3-yl) propionyl] aminomethyl]
ベンズアミド(表−1:化合物番号125) mp. (amorphous). 1H NMR(270MHz, CD3OD)δppm: 2.61(2H,t,J=7.3Hz), 3. Benzamide.. (Table 1: Compound No. 125) mp (amorphous) 1H NMR (270MHz, CD3OD) δppm: 2.61 (2H, t, J = 7.3Hz), 3.
00(2H,t,J=7.3Hz), 4.39(2H,s), 7.04(1H,ddd,J=1.5,8. 00 (2H, t, J = 7.3Hz), 4.39 (2H, s), 7.04 (1H, ddd, J = 1.5,8.
1,8.1Hz), 7.25(2H,d,J=8.1Hz), 7.33(1H,dd,J=5.1,8.1 1,8.1Hz), 7.25 (2H, d, J = 8.1Hz), 7.33 (1H, dd, J = 5.1,8.1
Hz), 7.69(1H,d,J=8.1Hz), 7.85(2H,d,J=8.1Hz), 7.86 Hz), 7.69 (1H, d, J = 8.1Hz), 7.85 (2H, d, J = 8.1Hz), 7.86
(1H,d,J=8.1Hz), 8.41(2H,br.s). IR(neat)cm-1:3276,1645,1614,1536,1509,1435,1415,13 . (1H, d, J = 8.1Hz), 8.41 (2H, br.s) IR (neat) cm-1: 3276,1645,1614,1536,1509,1435,1415,13
85,1333,1280,1247,1091,737. 85,1333,1280,1247,1091,737.

【0190】実施例41 N−(2−ヒドロキシフェニル)−4−[N−(ピリジン−3−イル)オキシアセチルアミノメチル]ベンズアミド(表−1:化合物番号93) mp. (amorphous). 1H-NMR(270MHz,DMSO-d6):4.43(2H,d,J=6.6Hz), 4.69(2 [0190] Example 41 N-(2-hydroxyphenyl)-4-[N-(pyridin-3-yl) oxy acetylamino methyl] benzamide (Table 1: Compound No. 93) mp (amorphous) 1H-.. NMR (270MHz, DMSO-d6): 4.43 (2H, d, J = 6.6Hz), 4.69 (2
H,s), 6.83(1H,t,J=6.6Hz), 6.91(1H,d,J=8.1Hz), 7.68 H, s), 6.83 (1H, t, J = 6.6Hz), 6.91 (1H, d, J = 8.1Hz), 7.68
(1H,d,J=6.6Hz), 7.82(2H,d,J=8.1Hz), 8.21(1H,d,J=4. (1H, d, J = 6.6Hz), 7.82 (2H, d, J = 8.1Hz), 8.21 (1H, d, J = 4.
4Hz), 8.35 (1H,d,J=2.2Hz), 8.81(1H,t,J=6.6Hz), 9.4 4Hz), 8.35 (1H, d, J = 2.2Hz), 8.81 (1H, t, J = 6.6Hz), 9.4
8(1H,s), 9.75(1H,s). IR(KBr)cm-1:3399,1664,1535,1236,1064. . 8 (1H, s), 9.75 (1H, s) IR (KBr) cm-1: 3399,1664,1535,1236,1064.

【0191】実施例42 N−(2−ヒドロキシフェニル)−4−[N−(ピリジン−3−イル)アセチルアミノメチル]ベンズアミド(表−1:化合物番号117) mp. 201-202℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.56(2H,s), 4.37(2H, [0191] Example 42 N-(2-hydroxyphenyl)-4-[N-(pyridin-3-yl) acetylaminomethyl] benzamide.. (Table 1: Compound No. 117) mp 201-202 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.56 (2H, s), 4.37 (2H,
d,J=5.9Hz), 6.83(1H,ddd,J=1.5,8.1,8.1Hz), 6.92(1H, d, J = 5.9Hz), 6.83 (1H, ddd, J = 1.5,8.1,8.1Hz), 6.92 (1H,
br.d,J=8.1Hz), 7.03(1H,ddd,J=1.5,8.1,8.1Hz),7.34(1 br.d, J = 8.1Hz), 7.03 (1H, ddd, J = 1.5,8.1,8.1Hz), 7.34 (1
H,dd,J=3.7,8.1Hz), 7.37(2H,d,J=8.1Hz), 7.70(2H,d,J H, dd, J = 3.7,8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.70 (2H, d, J
=8.1Hz), 7.91(2H,d,J=8.1Hz), 8.45(1H,br.d,J=3.7H = 8.1Hz), 7.91 (2H, d, J = 8.1Hz), 8.45 (1H, br.d, J = 3.7H
z), 8.49(1H,s), 8.73(1H,t,J=5.9Hz), 9.47(1H,s), 9. z), 8.49 (1H, s), 8.73 (1H, t, J = 5.9Hz), 9.47 (1H, s), 9.
73(1H,br.s). IR(KBr)cm-1:3272,3067,1661,1647,1598,1536,1455,133 73 (1H, br.s) IR (KBr) cm-1:. 3272,3067,1661,1647,1598,1536,1455,133
4,1288,1194,1024,742. 4,1288,1194,1024,742.

【0192】実施例43 N−(2−アミノフェニル)−4−[N−(ピリジン− [0192] Example 43 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)オキシアセチル−N−[3−(ピリジン−3 3-yl) oxy-acetyl-N-[3- (pyridin -3
−イル)プロピル]アミノメチル]ベンズアミド(表− - yl) propyl] aminomethyl] benzamide (Table -
1:化合物番号91) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 1.77-1.93(2H,m), 2.5 1:.. Compound No. 91) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 1.77-1.93 (2H, m), 2.5
0-2.63(2H,m), 3.16-3.30(2H,m), 4.63(1.2H,s), 4.71 0-2.63 (2H, m), 3.16-3.30 (2H, m), 4.63 (1.2H, s), 4.71
(0.8H,s), 4.88(1.2H,s), 4.95(0.8H,s), 5.05(2H,s), (0.8H, s), 4.88 (1.2H, s), 4.95 (0.8H, s), 5.05 (2H, s),
6.57-6.63(1H,m), 6.77-6.79(1H,m), 6.94-7.00(1H,m), 6.57-6.63 (1H, m), 6.77-6.79 (1H, m), 6.94-7.00 (1H, m),
7.11-7.42(5H,m),7.58-7.64(1H,m), 7.92-8.02(2H,m), 7.11-7.42 (5H, m), 7.58-7.64 (1H, m), 7.92-8.02 (2H, m),
8.15-8.43(5H,m), 9.65(0.6H,s), 9.69(0.4H,s).(回転異性体の混合物) 8.15-8.43 (5H, m), 9.65 (0.6H, s), 9.69 (0.4H, s). (Mixture of rotamers)

【0193】実施例44 N−(2−アミノフェニル)−4−[N−メチル−N− [0193] Example 44 N-(2-aminophenyl) -4- [N- methyl -N-
(ピリジン−3−イル)オキシアセチル]アミノメチルベンズアミド(表−1:化合物番号92) mp. 117-120℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.84 and 2.99(total (Pyridin-3-yl) oxy acetyl] amino-methylbenzamide.. (Table 1: Compound No. 92) mp 117-120 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.84 and 2.99 (total
3H,s), 4.60 and 4.69(total 2H,s), 4.90(2H,br.s), 3H, s), 4.60 and 4.69 (total 2H, s), 4.90 (2H, br.s),
4.99 and 5.08(total 2H,s), 6.60(1H,dd,J=7.3,8.1H 4.99 and 5.08 (total 2H, s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,7.3Hz), z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,7.3Hz),
7.16(1H,d,J=7.3Hz),7.30-7.43(4H,m), 7.95 and 8.01 7.16 (1H, d, J = 7.3Hz), 7.30-7.43 (4H, m), 7.95 and 8.01
(total 2H,d,J=8.1Hz), 8.17(1H,d,J=4.4Hz),8.31(1H, (Total 2H, d, J = 8.1Hz), 8.17 (1H, d, J = 4.4Hz), 8.31 (1H,
d,J=2.9Hz), 9.65 and 9.68(total 1H,br.s).(回転異性体の混合物) IR(KBr)cm-1:3298,1665,1501,1425,1310,1276,1254,107 d, J = 2.9Hz), 9.65 and 9.68 (total 1H, br.s) (mixture of rotamers) IR (KBr) cm-1:. 3298,1665,1501,1425,1310,1276,1254,107
8,799,746,703. 8,799,746,703.

【0194】実施例45 N−(2−アミノフェニル)−4−[N−(ピリジン− [0194] Example 45 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)オキサモイルアミノメチル]ベンズアミド(表−1:化合物番号95)の合成 (45−1) N−(ピリジン−3−イル)オキサミン酸エチルエステル388mg(2mmol)と実施例1 3-yl) oxamoylamino methyl] benzamide (Table 1: Compound Synthesis (45-1 number 95)) N-(pyridin-3-yl) oxamic acid ethyl ester 388 mg (2 mmol) as in Example 1
の工程(1−4)で得られた化合物638mg(2mm Compound 638 mg (2 mm obtained in the step (1-4)
ol)をエタノールに溶解し、40〜50℃に2.5時間加熱撹拌した。 Was dissolved ol) in ethanol was stirred and heated to 40 to 50 ° C. 2.5 hours. 析出した結晶をろ取し、エタノール2 The precipitated crystals were collected by filtration, ethanol 2
mlとエチルエーテル3mlで洗浄した。 And washed with ml of ethyl ether 3 ml. 得られた結晶を乾燥し、N−[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−[N−(ピリジン−3−イル)オキサモイルアミノメチル]ベンズアミド724m The resulting crystals were dried, N- [2- (N-tert- butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) oxamoylamino methyl] benzamide 724m
g(収率74%)を得た。 It was obtained g (74% yield). 1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.49(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.49 (2H,
d,J=5.9Hz), 7.10-7.30(2H,m), 7.35-7.57(5H,m), 7.93 d, J = 5.9Hz), 7.10-7.30 (2H, m), 7.35-7.57 (5H, m), 7.93
(2H,d,J=8.1Hz), 8.21(1H,br.d,J=5.1Hz), 8.35(1H,dd, (2H, d, J = 8.1Hz), 8.21 (1H, br.d, J = 5.1Hz), 8.35 (1H, dd,
J=1.5,5.1Hz), 8.68(1H,br.s), 9.00(1H,d,J=2.9Hz), J = 1.5,5.1Hz), 8.68 (1H, br.s), 9.00 (1H, d, J = 2.9Hz),
9.70(1H,t,J=5.9Hz), 9.82(1H,s), 10.98(1H,br.s). 9.70 (1H, t, J = 5.9Hz), 9.82 (1H, s), 10.98 (1H, br.s).

【0195】(45−2) 工程(45−1)の化合物720mgをメタノール8mlに懸濁し、4規定塩酸− [0195] (45-2) The compound 720mg step (45-1) was suspended in methanol 8 ml, 4 N hydrochloric acid -
ジオキサン溶液8mlを加えた。 Dioxane was added a solution 8 ml. 3時間撹拌し、希水酸化ナトリウム水溶液へあけアルカリ性とした後、析出した結晶をろ取した。 3 h stirring, was made alkaline opened to dilute aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration. 得られた結晶をTHF/メタノール THF / methanol and the resulting crystals
=1/1で再結晶し、目的物280mgを得た。 = 1 and recrystallized / 1, the desired product was obtained 280 mg. mp. 254-258℃(dec.) 1H NMR(270MHz, DMSO-d6)δppm: 4.67(2H,d,J=5.9Hz), . Mp 254-258 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.): 4.67 (2H, d, J = 5.9Hz),
4.89(2H,br.s), 6.59(1H,dd,J=7.3Hz), 6.77(1H,d,J=8. 4.89 (2H, br.s), 6.59 (1H, dd, J = 7.3Hz), 6.77 (1H, d, J = 8.
1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=8.1Hz), 1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 8.1Hz),
7.38-7.44(1H,m), 7.43(2H,d,J=8.1Hz), 7.95(2H,d,J= 7.38-7.44 (1H, m), 7.43 (2H, d, J = 8.1Hz), 7.95 (2H, d, J =
8.1Hz), 8.18-8.24(1H,m), 8.34(1H,dd,J=1.5,4.4Hz), 8.1Hz), 8.18-8.24 (1H, m), 8.34 (1H, dd, J = 1.5,4.4Hz),
9.00(1H,d,J=2.1Hz), 9.63(1H,s), 9.69(1H,br.t,J=6.6 9.00 (1H, d, J = 2.1Hz), 9.63 (1H, s), 9.69 (1H, br.t, J = 6.6
Hz), 10.97(1H,br.s). IR(KBr,cm-1):3312,3270,1663,1636,1521,1312,1296,10 . Hz), 10.97 (1H, br.s) IR (KBr, cm-1): 3312,3270,1663,1636,1521,1312,1296,10
19 19

【0196】実施例46 N−(2−アミノフェニル)−4−[N−(ピリジン− [0196] Example 46 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)オキシアセチルアミノメチル]ベンズアミド(表−1:化合物番号61)の合成 (46−1) 水素化ナトリウム(60%油状懸濁) 3-yl) oxy acetylamino methyl] benzamide (Table 1: Compound No. 61) Synthesis (46-1) Sodium hydride (60% oil suspension)
0.22g(5.5mmol)のDMF(2ml)懸濁液に、3−ヒドロキシピリジン0.48g(5.0mm In DMF (2 ml) suspension of 0.22g (5.5mmol), 3- hydroxypyridine 0.48 g (5.0 mm
ol)のDMF(2ml)溶液を室温で滴下した後、1 Was added dropwise at room temperature DMF (2 ml) solution of ol), 1
時間攪拌した。 Time and the mixture was stirred. 得られた褐色溶液を氷冷した後、ブロモ酢酸 tert−ブチルエステル0.81ml(5.5 After cooling the resulting brown solution glacial, bromoacetic acid tert- butyl ester 0.81 ml (5.5
mmol)を加え、氷冷下で1時間、室温で2時間攪拌した。 mmol) was added, under ice-cooling for 1 hour, followed by stirring at room temperature for 2 hours. 水を加えた後、酢酸エチルで抽出した。 After addition of water, extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた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:酢酸エチル=5:1)で精製することにより、3− The organic layer was washed with saturated brine, dried, the residue obtained by distilling off the solvent by silica gel column chromatography (chloroform: ethyl acetate = 5: 1) to give 3-
ピリジルオキシ酢酸 tert−ブチルエステル0.3 Pyridyloxyacetate tert- butyl ester 0.3
4g(収率32.5%)を無色油状物として得た。 4g of (32.5% yield) as a colorless oil. 1H NMR(270MHz, CDCl3)δppm: 1.49(9H,s), 4.56(2H, 1H NMR (270MHz, CDCl3) δppm: 1.49 (9H, s), 4.56 (2H,
s), 7.18-7.24(2H,m), 8.26(1H,dd,J=1.5,3.6Hz), 8.32 s), 7.18-7.24 (2H, m), 8.26 (1H, dd, J = 1.5,3.6Hz), 8.32
(1H,d,J=2.9Hz). (1H, d, J = 2.9Hz).

【0197】(46−2) 工程(46−1)の化合物0.14g(0.67mmol)のジクロロメタン(2 [0197] (46-2) in dichloromethane step (46-1) Compound 0.14g of (0.67 mmol) (2
ml)溶液にトリフルオロ酢酸2mlを加えて室温で3 ml) solution was added trifluoroacetic acid 2 ml 3 at room temperature
時間攪拌した。 Time and the mixture was stirred. 溶媒を留去した後、ジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、3−ピリジルオキシ酢酸トリフルオロ酢酸塩0.1 After evaporation of the solvent, diisopropyl ether was added, the precipitated solid was collected by filtration and dried, 3-pyridyloxy acetic acid trifluoroacetate 0.1
5g(収率83.8%)を淡黄色固体として得た。 5g of (83.8% yield) as a pale yellow solid. 1H NMR(270MHz, DMSO-d6)δppm: 4.86(2H,s), 7.57(1H, 1H NMR (270MHz, DMSO-d6) δppm: 4.86 (2H, s), 7.57 (1H,
dd,J=4.4,8.1Hz), 7.67(1H,ddd,J=1.5,1.5,8.8Hz), 8.3 dd, J = 4.4,8.1Hz), 7.67 (1H, ddd, J = 1.5,1.5,8.8Hz), 8.3
1(1H,d,J=5.1Hz), 8.46(1H,d,J=2.1Hz), 13.00(1H,br. 1 (1H, d, J = 5.1Hz), 8.46 (1H, d, J = 2.1Hz), 13.00 (1H, br.
s). s).

【0198】(46−3) 工程(46−2)の化合物100mg(0.37mmol)および実施例1の工程(1−4)で得られた化合物255mg(0.75mm [0198] (46-3) step (46-2) of the compound 100 mg (0.37 mmol) and Example compound obtained in 1 step (1-4) 255 mg (0.75 mm
ol)のジクロロメタン(5ml)懸濁液にトリエチルアミン0.14ml(1.0mmol)を加え、氷冷した。 Triethylamine 0.14ml of (1.0 mmol) in dichloromethane (5ml) suspension of ol), was cooled with ice. 氷冷下2−クロロ−1,3−ジメチルイミダゾリニウムクロライド140mg(0.83mmol)のジクロロメタン(6ml)溶液を加え、室温まで昇温させながら7時間攪拌した後、室温で一晩放置した。 Dichloromethane (6 ml) solution under ice-cooling 2-chloro-1,3-dimethyl imidazolinium chloride 140 mg (0.83 mmol) was added and after stirring for 7 hours while warming to room temperature and left overnight at room temperature. 水および飽和食塩水を加えた後、クロロホルムで抽出した。 After the addition of water and saturated brine, and extracted with chloroform.

【0199】有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた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:メタノール=10:1)で精製することにより、N−[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−[N−(ピリジン−3−イル)オキシアセチルアミノメチル]ベンズアミド0.37g(定量的)を無色油状物として得た。 [0199] The organic layer was washed with saturated brine, dried, the solvent was distilled off and the resultant residue using silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give, N-[2 - a (N-tert-butoxycarbonyl) aminophenyl] -4- [N- (pyridin-3-yl) oxy acetylamino methyl] benzamide 0.37 g (quantitative) was obtained as a colorless oil. mp. 154-155℃ 1H NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 4.62(2H, . Mp 154-155 ℃ 1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 4.62 (2H,
s), 4.63(2H,d,J=7.3Hz),6.76(1H,br.s), 6.90-7.00(1 s), 4.63 (2H, d, J = 7.3Hz), 6.76 (1H, br.s), 6.90-7.00 (1
H,br.s), 7.15-7.35(5H,m), 7.40(2H,d,J=8.1Hz),7.82 H, br.s), 7.15-7.35 (5H, m), 7.40 (2H, d, J = 8.1Hz), 7.82
(1H,d,J=8.1Hz), 7.95(2H,d,J=8.1Hz), 8.32(1H,dd,J= (1H, d, J = 8.1Hz), 7.95 (2H, d, J = 8.1Hz), 8.32 (1H, dd, J =
2.1,4.4Hz), 8.37(1H,d,J=2.8Hz), 9.20(1H,br.s). 2.1,4.4Hz), 8.37 (1H, d, J = 2.8Hz), 9.20 (1H, br.s).

【0200】(46−4) 工程(46−3)の化合物175mg(0.37mmol)のジオキサン(2m [0200] (46-4) in dioxane step (46-3) Compound 175mg of (0.37 mmol) (2m
l)−メタノール(2ml)溶液に、4規定塩酸−ジオキサン(2ml)を加えて室温で2時間攪拌した。 l) - methanol (2 ml) solution, 4N hydrochloric acid - was stirred at room temperature for 2 hours dioxane (2 ml). 飽和重曹水を加えた後、酢酸エチルで抽出した。 After addition of saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣にメタノールおよびジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、N−(2−アミノフェニル)−4−[N−(ピリジン−3−イル)オキシアセチルアミノメチル]ベンズアミド90mg(収率64.6%)を乳白色固体として得た。 The organic layer was washed with saturated brine, dried and the solvent methanol and diisopropyl ether was added to the residue obtained by removing a precipitated solid was filtered off and dried, N-(2-aminophenyl) -4-[N-(pyridin-3-yl) oxy acetylamino methyl] benzamide 90mg of (64.6% yield) as an off-white solid. 1H NMR(270MHz, DMSO-d6)δppm: 4.42(2H,d,J=5.9Hz), 1H NMR (270MHz, DMSO-d6) δppm: 4.42 (2H, d, J = 5.9Hz),
4.69(2H,s), 4.89(2H,br.s), 6.59(1H,dd,J=7.3,8.1H 4.69 (2H, s), 4.89 (2H, br.s), 6.59 (1H, dd, J = 7.3,8.1H
z), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz),
7.16(1H,d,J=7.3Hz), 7.33-7.39(4H,m), 7.92(2H,d,J= 7.16 (1H, d, J = 7.3Hz), 7.33-7.39 (4H, m), 7.92 (2H, d, J =
8.1Hz), 8.21(1H,dd,J=1.5,4.4Hz), 8.35(1H,d,J=2.9H 8.1Hz), 8.21 (1H, dd, J = 1.5,4.4Hz), 8.35 (1H, d, J = 2.9H
z), 8.80(1H,br.t,J=5.9Hz), 9.63(1H,br.s). IR(KBr)cm-1: 3307,1672,1631,1523,1456,1429,1269,12 . Z), 8.80 (1H, br.t, J = 5.9Hz), 9.63 (1H, br.s) IR (KBr) cm-1: 3307,1672,1631,1523,1456,1429,1269,12
31,803,756. 31,803,756.

【0201】実施例47 N−(2−アミノフェニル)−4−[N−[2−(ピリジン−3−イル)オキシ]プロピオニルアミノメチル] [0201] Example 47 N-(2-aminophenyl) -4- [N- [2- (pyridin-3-yl) oxy] propionylaminomethyl]
ベンズアミド(表−4:化合物番号3)の合成 Benzamide (Table 4 compound No. 3) Synthesis

【0202】(47−1) 水素化ナトリウム(60% [0202] (47-1) Sodium hydride (60%
油状懸濁)1.20g(30.0mmol)の乾燥DM Drying DM of oily suspensions) 1.20g (30.0mmol)
F(10ml)懸濁液に、室温で3−ヒドロキシピリジン2.85g(30mmol)の乾燥DMF(10m The F (10 ml) suspension, dried DMF (10 m at room temperature of 3-hydroxypyridine 2.85 g (30 mmol)
l)溶液を40℃以下になるようにしながら滴下した後、室温で90分間攪拌した。 l) After the solution was added dropwise in such a manner that a 40 ° C. or less, followed by stirring at room temperature for 90 minutes. 氷冷下内温を5〜10℃ In the ice-cold temperature 5~10 ℃
に保ちながら2−ブロモプロピオン酸 tert−ブチルエステル6.28g(30mmol)の乾燥DMF Keeping with 2-bromopropionic acid tert- butyl ester 6.28 g (30 mmol) in dry DMF to
(10ml)溶液を徐々に滴下した後、室温まで昇温させながら4時間攪拌した。 (10ml) The solution was slowly added dropwise and stirred for 4 hours while warming to room temperature. 飽和重曹水を加えて中和した後、酢酸エチルで抽出した。 After neutralization by addition of a saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. 有機層を、水、飽和食塩水で洗浄後、乾燥、溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=2:1)で精製することにより2−(ピリジン−3 The organic layer was washed with water and saturated brine, dried and the residue obtained by evaporated the silica gel column chromatography (n- hexane: ethyl acetate = 2: 1) 2- (pyridin purified by -3
−イル)オキシプロピオン酸 tert−ブチルエステル 4.15g(収率62%)を茶色油状物として得た。 - yl) oxy propionic acid tert- butyl ester 4.15g (62% yield) was obtained as a brown oil. 1H-NMR(270MHz, CDCl3)δppm: 1.44(9H,s), 1.61(3H,d, 1H-NMR (270MHz, CDCl3) δppm: 1.44 (9H, s), 1.61 (3H, d,
J=7.3Hz), 4.66(1H,q,J=7.3Hz), 7.13-7.23(2H,m) 8.24 J = 7.3Hz), 4.66 (1H, q, J = 7.3Hz), 7.13-7.23 (2H, m) 8.24
(1H,dd,J=1.5,4.4Hz), 8.29(1H,d,J=2.1Hz). (1H, dd, J = 1.5,4.4Hz), 8.29 (1H, d, J = 2.1Hz).

【0203】(47−2) 工程(47−1)で得た化合物1.65g(7.4mmol)のジクロロメタン(9ml)溶液に30℃以下を保ちながらでトリフルオロ酢酸(9ml)を加えた後、室温で8時間攪拌した。 [0203] (47-2) Step (47-1) obtained in dichloromethane compound 1.65 g (7.4 mmol) (9 ml) was added to trifluoroacetic acid (9 ml) in keeping the 30 ° C. or less to a solution It was stirred at room temperature for 8 hours.
溶媒を留去した後、ジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより2−(ピリジン−3−イル)オキシプロピオン酸 トリフルオロ酢酸塩1.86g(収率43.5%)を淡褐色固体として得た。 After evaporation of the solvent, diisopropyl ether was added, the precipitated solid was collected by filtration and dried 2- (pyridin-3-yl) propionic acid trifluoroacetate 1.86 g (43.5% yield) as a pale brown solid. 1H-NMR(270MHz, DMSO-d6)δppm: 1.53(3H,d,J=6.6Hz), 1H-NMR (270MHz, DMSO-d6) δppm: 1.53 (3H, d, J = 6.6Hz),
5.12(1H,q,J=6.6Hz), 7.60-7.75(2H,m), 8.35(1H,d,J= 5.12 (1H, q, J = 6.6Hz), 7.60-7.75 (2H, m), 8.35 (1H, d, J =
5.1Hz), 8.47(1H,s), 12.9(1H,br.s). 5.1Hz), 8.47 (1H, s), 12.9 (1H, br.s).

【0204】(47−3) 工程(47−2)で得た化合物0.98g(3.5mmol)、実施例1の工程(1−4)で得た化合物1.02g(3.0mmol) [0204] (47-3) Step compound obtained in (47-2) 0.98 g (3.5 mmol), the compound of the obtained in step (1-4) Example 1 1.02 g (3.0 mmol)
をジクロロメタン(20ml)に懸濁させた後、トリエチルアミン1.3ml(9.0mmol)を加え氷冷した。 The was suspended in dichloromethane (20 ml), cooled with ice added triethylamine 1.3 ml (9.0 mmol). 氷冷下、2−クロロ−1,3−ジメチルイミダゾリニウムクロライド0.59g(3.5mmol)のジクロロメタン(5ml)溶液を滴下した後、さらに2時間攪拌した。 Under ice-cooling, it was added dropwise 2-chloro-1,3-dimethyl imidazolinium chloride dichloromethane 0.59g (3.5mmol) (5ml) solution and stirred for an additional 2 hours. 飽和重曹水を加え中和した後、クロロホルムで抽出した。 After neutralized with saturated aqueous sodium bicarbonate solution, and extracted with chloroform. 有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た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:メタノール=10:1)で精製することによりN−[2−(N−tert−ブトキシカルボニルアミノ)フェニル]−4−[N−[2−(ピリジン− The organic layer was washed with saturated brine, dried and the residue obtained by evaporated the silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give N- [2- (N-tert- butoxycarbonylamino) phenyl] -4- [N- [2- (pyridin -
3−イル)オキシプロピオニル]アミノメチル]ベンズアミド1.64gを1,3−ジメチル−2−イミダゾリノンとの混合物として得た。 3-yl) oxy propionylamino] aminomethyl] benzamide 1.64g was obtained as a mixture of 1,3-dimethyl-2-imidazolinone. 1H-NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 1.64(3H,d, 1H-NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 1.64 (3H, d,
J=7.3Hz), 4.54(2H,m),4.78(1H,q,J=6.6Hz), 6.87(2H,b J = 7.3Hz), 4.54 (2H, m), 4.78 (1H, q, J = 6.6Hz), 6.87 (2H, b
rs), 7.13-7.30(6H,m), 7.81(1H,d,J=7.3Hz),7.90(2H, rs), 7.13-7.30 (6H, m), 7.81 (1H, d, J = 7.3Hz), 7.90 (2H,
d,J=8.1Hz), 8.29(1H,dd,J=1.5,4.4Hz), 8.33(1H,d,J= d, J = 8.1Hz), 8.29 (1H, dd, J = 1.5,4.4Hz), 8.33 (1H, d, J =
2.1Hz), 9.22(1H,br.s). 2.1Hz), 9.22 (1H, br.s).

【0205】(47−4) 工程(47−3)で得た化合物1.64gをジオキサン(10ml)−メタノール(4ml)に溶解した。 [0205] (47-4) Step dioxane compound 1.64g obtained in (47-3) (10 ml) - was dissolved in methanol (4 ml). 室温下4規定塩酸−ジオキサン溶液(10ml)を加え、2時間攪拌した。 Under 4 N hydrochloric acid at room temperature - dioxane (10ml) was added and stirred for 2 hours. 飽和重曹水を加え中和した後、酢酸エチルで抽出した。 After neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣にメタノールおよびジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、N−(2−アミノフェニル)−4−[N−[2−(ピリジン−3−イル)オキシ]プロピオニルアミノメチル]ベンズアミド0.7 The organic layer was washed with saturated brine, dried, methanol and diisopropyl ether was added to the residue obtained by distilling off the solvent, the precipitated solid was collected by filtration and dried, N-(2-aminophenyl) -4 - [N- [2- (pyridin-3-yl) oxy] propionylaminomethyl] benzamide 0.7
1g(2stepsで収率60.5%)を白色固体として得た。 1g of (60.5% yield 2 steps) as a white solid.

【0206】mp. 171-173℃(dec.). 1H-NMR(270MHz,DMSO-d6)δppm:1.51(3H,d,J=6.6Hz), 4. . [0206] mp 171-173 ℃ 1H-NMR (270MHz, DMSO-d6) δppm (dec.):. 1.51 (3H, d, J = 6.6Hz), 4.
36(2H,d,J=5.9Hz), 4.89(2H,br.s), 4.90(1H,t,J=6.6H 36 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 4.90 (1H, t, J = 6.6H
z), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d,J=8.1Hz), z), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d, J = 8.1Hz),
6.97(1H,dd,J=6.6,7.3Hz), 7.15(1H,d,J=7.3Hz), 7.27 6.97 (1H, dd, J = 6.6,7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.27
(2H,d,J=8.1Hz), 7.33-7.37(2H,m), 7.89(2H,d,J=8.1H (2H, d, J = 8.1Hz), 7.33-7.37 (2H, m), 7.89 (2H, d, J = 8.1H
z), 8.21(1H,dd,J=2.9,2.9Hz), 8.32(1H,d,J=1.5Hz), z), 8.21 (1H, dd, J = 2.9,2.9Hz), 8.32 (1H, d, J = 1.5Hz),
8.82(1H,t,J=5.9Hz), 9.63(1H,br.s). 8.82 (1H, t, J = 5.9Hz), 9.63 (1H, br.s).

【0207】実施例48 N−(2−アミノフェニル)−4−[N−(ピリジン− [0207] Example 48 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号82)の合成 (48−1) 3−ピリジンメタノール384mg 3-yl) methoxycarbonylamino-methyl] benzamide (Table 1: Synthesis of Compound No. 82) (48-1) 3-pyridinemethanol 384mg
(3.52mmol)を5mlの乾燥THFに溶解し、 The (3.52 mmol) was dissolved in dry THF 5 ml,
N,N'−カルボニルジイミダゾール523mg(3. N, N'-carbonyl diimidazole 523 mg (3.
22mmol)を室温で加えた。 22 mmol) was added at room temperature. 1時間撹拌した後、実施例1の工程(1−4)の化合物1.0g(2.93m After stirring for 1 hour, the compound of step (1-4) of Example 1 1.0 g (2.93M
mol)の乾燥THF溶液6mlを加えた。 It was added dry THF 6ml of mol).

【0208】室温で一夜放置後、クロロホルム100m [0208] After standing overnight at room temperature, chloroform 100m
lを加え、水20mlで3回洗浄した。 l was added, and the mixture was washed three times with water 20ml. ついで飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。 Then washed with saturated brine, and dried over anhydrous magnesium sulfate. 溶媒を減圧留去後、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)で精製し、N− The solvent was evaporated under reduced pressure, silica gel column chromatography (chloroform: methanol = 30 1), N-
[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド1.27gをアモルファス状固体として得た(定量的)。 The [2- (N-tert- butoxycarbonyl) aminophenyl]-4-[N-(pyridin-3-yl) methoxycarbonylamino-methyl] benzamide 1.27g was obtained as an amorphous solid (quantitative). 1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 4.45(2H,d, 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.45 (2H, d,
J=5.9Hz), 5.16(1H,s),7.10-7.50(7H,m), 7.70(1H,d,J= J = 5.9Hz), 5.16 (1H, s), 7.10-7.50 (7H, m), 7.70 (1H, d, J =
8.1Hz), 7.80(1H,d,J=7.3Hz), 7.93(1H,d,J=8.1Hz), 8. 8.1Hz), 7.80 (1H, d, J = 7.3Hz), 7.93 (1H, d, J = 8.1Hz), 8.
57(1H,d,J=4.4Hz), 8.63(1H,s), 9.17(1H,s). 57 (1H, d, J = 4.4Hz), 8.63 (1H, s), 9.17 (1H, s).

【0209】(48−2) 工程(48−1)の化合物1.2g(2.8mmol)をメタノール10mlに溶解した。 [0209] The (48-2) the compound of step (48-1) 1.2 g (2.8 mmol) was dissolved in methanol 10 ml. 4規定塩酸−ジオキサン溶液20mlを加え、 4 N hydrochloric acid - dioxane solution 20ml was added,
室温で1.5時間撹拌した。 It was stirred at room temperature for 1.5 hours. 希水酸化ナトリウム水溶液にあけた後、クロロホルム60mlで3回抽出した。 After opening the dilute sodium hydroxide solution and extracted three times with chloroform 60 ml. 飽和食塩水で2回洗浄後、無水硫酸マグネシウムで乾燥し、濃縮して0.88gの結晶を得た。 After washing twice with saturated brine, dried over anhydrous magnesium sulfate, to give crystals of 0.88g and concentrated. ついでエタノール16mlで再結晶を行い、N−(2−アミノフェニル)−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド668mg(収率7 Then recrystallized in ethanol 16ml, N- (2- aminophenyl) -4- [N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide 668 mg (yield: 7
3%)を得た。 3%) was obtained.

【0210】mp. 159-160℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), .. [0210] mp 159-160 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz),
4.86(2H,s), 5.10(2H,s), 6.60(1H,t,J=7.3Hz), 6.78(1 4.86 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.78 (1
H,d,J=7Hz), 6.97(1H,t,J=7Hz), 7.17(1H,d,J=8Hz), 7. H, d, J = 7Hz), 6.97 (1H, t, J = 7Hz), 7.17 (1H, d, J = 8Hz), 7.
30-7.50(3H,m), 7.78(1H,d,J=8Hz), 7.93(2H,d,J=8Hz), 30-7.50 (3H, m), 7.78 (1H, d, J = 8Hz), 7.93 (2H, d, J = 8Hz),
8.53(1H,d,J=3.7Hz), 8.59(1H,s), 9.61(1H,s). IR(KBr)cm-1: 3295,1648,1541,1508,1457,1309,1183,74 8.53 (1H, d, J = 3.7Hz), 8.59 (1H, s), 9.61 (1H, s) IR (KBr) cm-1:. 3295,1648,1541,1508,1457,1309,1183,74
2. 実施例48と同様の方法により、実施例49から実施例87の化合物を合成した。 2. In the same manner as in Example 48, to synthesize a compound of Example 87 from Example 49. 以下に、化合物の融点(m Below the melting point of the compound (m
p.)、1H NMR、IRの測定値を示す。 p.), shows IH NMR, the measurement of IR.

【0211】実施例49 N−(2−アミノフェニル)−4−[N−(ベンジルオキシカルボニル)アミノメチル]ベンズアミド(表− [0211] Example 49 N-(2-aminophenyl)-4-[N-(benzyloxycarbonyl) aminomethyl] benzamide (Table -
1:化合物番号11) mp. 174-178℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), 1:.. Compound No. 11) mp 174-178 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz),
4.89(2H,br.s), 5.06(2H,s), 6.59(1H,dd,J=7.3,8.1H 4.89 (2H, br.s), 5.06 (2H, s), 6.59 (1H, dd, J = 7.3,8.1H
z), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16(1H,d,J=7.3Hz), 7.30-7.40(6H,m), 7.93(3H,m), 7.16 (1H, d, J = 7.3Hz), 7.30-7.40 (6H, m), 7.93 (3H, m),
9.63(1H,s). IR(KBr)cm-1: 3332,1687,1652,1536,1456,1279,747. . 9.63 (1H, s) IR (KBr) cm-1: 3332,1687,1652,1536,1456,1279,747.

【0212】実施例50 N−(2−アミノフェニル)−4−[N−(4−(イミダゾール−1−イル)ベンジル)オキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号47) mp. 195-198℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.29(2H,d,J=6.6Hz), [0212] Example 50 N-(2-aminophenyl) -4- [N- (4- (imidazol-1-yl) benzyl) oxycarbonyl aminomethyl] benzamide. (Table 1: Compound No. 47) mp 195 . -198 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.29 (2H, d, J = 6.6Hz),
4.88(2H,s), 5.10(2H,s), 6.60-6.63(1H,m), 6.78(1H, 4.88 (2H, s), 5.10 (2H, s), 6.60-6.63 (1H, m), 6.78 (1H,
d,J=8.1Hz), 6.97(1H,t,J=7.3Hz), 7.11(1H,s), 7.16(1 d, J = 8.1Hz), 6.97 (1H, t, J = 7.3Hz), 7.11 (1H, s), 7.16 (1
H,d,J=7.3Hz), 7.37(2H,d,J=8.1Hz), 7.49(2H,d,J=8.8H H, d, J = 7.3Hz), 7.37 (2H, d, J = 8.1Hz), 7.49 (2H, d, J = 8.8H
z), 7.66(2H,d,J=8.1Hz), 7.74(1H,s), 7.92-7.96(3H, z), 7.66 (2H, d, J = 8.1Hz), 7.74 (1H, s), 7.92-7.96 (3H,
m), 8.25(1H,s), 9.62(1H,s). m), 8.25 (1H, s), 9.62 (1H, s).

【0213】実施例51 N−(2−アミノフェニル)−4−[N−(ピリジン− [0213] Example 51 N-(2-aminophenyl) -4- [N- (pyridine -
2−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号171) mp. 166-167℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=5.9Hz), 2-yl) methoxycarbonylamino-methyl] benzamide (Table 1:.. Compound No. 171) mp 166-167 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 5.9Hz),
4.88(2H,br.s), 5.12(2H,s), 6.60(1H,dd,J=7.3,8.1H 4.88 (2H, br.s), 5.12 (2H, s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78(1H,d,J=8.1Hz), 6.97(1H,ddd,J=1.5,7.3,8.1H z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1H
z), 7.16(1H,d,J=7.3Hz), 7.33(1H,dd,J=3.7,7.3Hz), z), 7.16 (1H, d, J = 7.3Hz), 7.33 (1H, dd, J = 3.7,7.3Hz),
7.40(3H,d,J=8.1Hz),7.83(1H,ddd,J=1.5,7.3,8.1Hz), 7.40 (3H, d, J = 8.1Hz), 7.83 (1H, ddd, J = 1.5,7.3,8.1Hz),
7.94(2H,d,J=8.1Hz), 8.03(1H,t,J=5.9Hz), 8.55(1H,d, 7.94 (2H, d, J = 8.1Hz), 8.03 (1H, t, J = 5.9Hz), 8.55 (1H, d,
J=5.1Hz), 9.62(1H,br.s). IR(KBr)cm-1: 3334,1694,1632,1580,1276,755. . J = 5.1Hz), 9.62 (1H, br.s) IR (KBr) cm-1: 3334,1694,1632,1580,1276,755.

【0214】実施例52 N−(2−アミノフェニル)−4−[N−[2−(ピリジン−2−イル)エトキシカルボニル]アミノメチル] [0214] Example 52 N-(2-aminophenyl) -4- [N- [2- (pyridin-2-yl) ethoxycarbonyl] aminomethyl]
ベンズアミド(表−1:化合物番号172) mp. 146-148℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.04(2H,t,J=6.6Hz), Benzamide.. (Table 1: Compound No. 172) mp 146-148 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.04 (2H, t, J = 6.6Hz),
4.23(2H,d,J=5.9Hz), 4.36(2H,t,J=6.6Hz), 4.88(2H,b 4.23 (2H, d, J = 5.9Hz), 4.36 (2H, t, J = 6.6Hz), 4.88 (2H, b
rs), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz), rs), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz),
6.97(1H,dd,J=7.3,8.1Hz), 7.15-7.30(3H,m), 7.34(2 6.97 (1H, dd, J = 7.3,8.1Hz), 7.15-7.30 (3H, m), 7.34 (2
H,d,J=8.1Hz), 7.69-7.77(2H,m), 7.92(2H,d,J=7.3Hz), H, d, J = 8.1Hz), 7.69-7.77 (2H, m), 7.92 (2H, d, J = 7.3Hz),
8.50(1H,d,J=4.4Hz), 9.62(1H,br.s). IR(KBr)cm-1: 3330,1690,1633,1594,1524,1277,760. 8.50 (1H, d, J = 4.4Hz), 9.62 (1H, br.s) IR (KBr) cm-1:. 3330,1690,1633,1594,1524,1277,760.

【0215】実施例53 N−(2−アミノフェニル)−4−[N−(6−メチルピリジン−2−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号179) mp. 138℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.47(3H,s), 4.30(2 [0215] Example 53 N-(2-aminophenyl) -4- [N- (6- methylpyridin-2-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 179) mp 138 ° C.. 1H NMR (270MHz, DMSO-d6) δppm: 2.47 (3H, s), 4.30 (2
H,d,J=5.9Hz), 5.07(4H,s), 6.63(1H,t,J=8.1Hz), 6.80 H, d, J = 5.9Hz), 5.07 (4H, s), 6.63 (1H, t, J = 8.1Hz), 6.80
(1H,d,J=7.34), 6.98(1H,t,J=8.1Hz), 7.18(3H,d,J=7.3 (1H, d, J = 7.34), 6.98 (1H, t, J = 8.1Hz), 7.18 (3H, d, J = 7.3
Hz), 7.40(2H,d,J=8.1Hz), 7.71(1H,t,J=8.1Hz), 7.94 Hz), 7.40 (2H, d, J = 8.1Hz), 7.71 (1H, t, J = 8.1Hz), 7.94
(2H,d,J=8.1Hz), 8.03(1H,t,J=5.9Hz), 9.66(1H,s). IR(KBr)cm-1: 3335,1693,1634,1259. . (2H, d, J = 8.1Hz), 8.03 (1H, t, J = 5.9Hz), 9.66 (1H, s) IR (KBr) cm-1: 3335,1693,1634,1259.

【0216】実施例54 N−(2−アミノフェニル)−4−[N−[2−(ピリジン−3−イル)エトキシカルボニル]アミノメチル] [0216] Example 54 N-(2-aminophenyl) -4- [N- [2- (pyridin-3-yl) ethoxycarbonyl] aminomethyl]
ベンズアミド(表−1:化合物番号83) mp. 120-125℃. 1H NMR(270MHz, DMSO-d6)δppm:2.91(2H,t,J=6.6Hz), Benzamide.. (Table 1: Compound No. 83) mp 120-125 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.91 (2H, t, J = 6.6Hz),
4.22(4H,t,J=6.6Hz), 4.89(2H,s), 6.55-6.63(1H,m), 4.22 (4H, t, J = 6.6Hz), 4.89 (2H, s), 6.55-6.63 (1H, m),
6.78(1H,dd,J=8.1,1.5Hz), 6.97(1H,t,J=6.6Hz),7.17(1 6.78 (1H, dd, J = 8.1,1.5Hz), 6.97 (1H, t, J = 6.6Hz), 7.17 (1
H,d,J=6.6Hz), 7.33(3H,d,J=8.1Hz), 7.69(1H,d,J=8.1H H, d, J = 6.6Hz), 7.33 (3H, d, J = 8.1Hz), 7.69 (1H, d, J = 8.1H
z), 7.79(1H,t,J=6.6Hz), 7.93(2H,d,J=8.0Hz), 8.43- z), 7.79 (1H, t, J = 6.6Hz), 7.93 (2H, d, J = 8.0Hz), 8.43-
8.49(2H,m), 9.62(1H,s). IR(KBr)cm-1: 3234,1705,1655,1260. 8.49 (2H, m), 9.62 (1H, s) IR (KBr) cm-1:. 3234,1705,1655,1260.

【0217】実施例55 N−(2−アミノフェニル)−4−[N−[3−(ピリジン−3−イル)プロピルオキシカルボニル]アミノメチル]ベンズアミド(表−1:化合物番号84) mp. 121-124℃. 1H NMR(270MHz, DMSO-d6)δppm: 1.83-1.94(2H,m), 2.6 [0217] Example 55 N-(2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propyloxy carbonyl] aminomethyl] benzamide. (Table 1: Compound No. 84) mp 121 . -124 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 1.83-1.94 (2H, m), 2.6
7(2H,t,J=7.3Hz), 3.98(2H,t,J=6.6Hz), 4.26(2H,d,J= 7 (2H, t, J = 7.3Hz), 3.98 (2H, t, J = 6.6Hz), 4.26 (2H, d, J =
5.9Hz), 4.89(2H,br.s), 6.60(1H,dd,J=8.1,8.1Hz), 6. 5.9Hz), 4.89 (2H, br.s), 6.60 (1H, dd, J = 8.1,8.1Hz), 6.
78(1H,d,J=7.3Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz), 7. 78 (1H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.
16(1H,d,J=8.1Hz),7.29-7.33(1H,m), 7.37(1H,d,J=8.1H 16 (1H, d, J = 8.1Hz), 7.29-7.33 (1H, m), 7.37 (1H, d, J = 8.1H
z), 7.64(1H,d,J=8.1Hz), 7.81(1H,dd,J=5.9,6.6Hz), z), 7.64 (1H, d, J = 8.1Hz), 7.81 (1H, dd, J = 5.9,6.6Hz),
7.94(2H,d,J=8.1Hz), 8.40-8.44(2H,m), 9.63(1H,br. 7.94 (2H, d, J = 8.1Hz), 8.40-8.44 (2H, m), 9.63 (1H, br.
s). IR(KBr)cm-1: 3348,1696,1635,1523,1458,1302,1272,11 . S) IR (KBr) cm-1: 3348,1696,1635,1523,1458,1302,1272,11
41,1019,754,713. 41,1019,754,713.

【0218】実施例56 N−(2−アミノフェニル)−4−[N−(2−メチルピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号142) mp. 164-165℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.49(3H,s), 4.28(2 [0218] Example 56 N-(2-aminophenyl) -4- [N- (2- methylpyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 142) mp 164-165 ℃ 1H NMR (270MHz, DMSO-d6) δppm:. 2.49 (3H, s), 4.28 (2
H,d,J=6.6Hz), 4.89(2H,s), 5.10(2H,s), 6.60(1H,t,J= H, d, J = 6.6Hz), 4.89 (2H, s), 5.10 (2H, s), 6.60 (1H, t, J =
6.6Hz), 6.78(1H,d,J=8.1Hz), 6.90(1H,t,J=7.3Hz), 7. 6.6Hz), 6.78 (1H, d, J = 8.1Hz), 6.90 (1H, t, J = 7.3Hz), 7.
17(1H,d,J=7.3Hz), 7.21-7.26(1H,m), 7.37(2H,d,J=8.1 17 (1H, d, J = 7.3Hz), 7.21-7.26 (1H, m), 7.37 (2H, d, J = 8.1
Hz), 7.68(1H,d,J=6.6Hz), 7.92-8.00(3H,m), 8.39(1H, Hz), 7.68 (1H, d, J = 6.6Hz), 7.92-8.00 (3H, m), 8.39 (1H,
d,J=4.4Hz), 9.62(1H,s). IR(KBr)cm-1: 3332,1719,1630,1260. . D, J = 4.4Hz), 9.62 (1H, s) IR (KBr) cm-1: 3332,1719,1630,1260.

【0219】実施例57 N−(2−アミノフェニル)−4−[N−(6−メチルピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号144) mp. 164-165℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.46(3H,s), 4.27(2 [0219] Example 57 N-(2-aminophenyl) -4- [N- (6- methylpyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 144) mp 164-165 ℃ 1H NMR (270MHz, DMSO-d6) δppm:. 2.46 (3H, s), 4.27 (2
H,d,J=6.6Hz), 4.88(2H,s), 5.05(2H,s), 6.59(1H,dt,J H, d, J = 6.6Hz), 4.88 (2H, s), 5.05 (2H, s), 6.59 (1H, dt, J
=1.5,8.1Hz), 6.78(1H,dd,J=8.1,1.5Hz), 6.97(1H,dt,J = 1.5,8.1Hz), 6.78 (1H, dd, J = 8.1,1.5Hz), 6.97 (1H, dt, J
=1.5,7.3Hz), 7.17(1H,d,J=7.3Hz), 7.26(1H d,J=8.1H = 1.5,7.3Hz), 7.17 (1H, d, J = 7.3Hz), 7.26 (1H d, J = 8.1H
z), 7.36(2H,d,J=8.1Hz), 7.67(1H,dd,J=8.1,2.2Hz), z), 7.36 (2H, d, J = 8.1Hz), 7.67 (1H, dd, J = 8.1,2.2Hz),
7.93(3H,d,J=8.1Hz), 8.45(1H,d,J=1.5Hz), 9.62(1H, 7.93 (3H, d, J = 8.1Hz), 8.45 (1H, d, J = 1.5Hz), 9.62 (1H,
s). IR(KBr)cm-1: 3293,1701,1632,1260. . S) IR (KBr) cm-1: 3293,1701,1632,1260.

【0220】実施例58 N−(2−アミノフェニル)−4−[N−(2−クロロピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号155) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=5.9Hz), [0220] Example 58 N-(2-aminophenyl) -4- [N- (2- chloropyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 155) mp (Amorphous) . 1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 5.9Hz),
5.00(2H,s), 5.13(2H,s), 6.61(1H,t,J=7.3Hz), 6.79 5.00 (2H, s), 5.13 (2H, s), 6.61 (1H, t, J = 7.3Hz), 6.79
(1H,dd,J=8.1,1.5Hz), 6.98(1H,dt,J=1.5,7.3Hz),7.17 (1H, dd, J = 8.1,1.5Hz), 6.98 (1H, dt, J = 1.5,7.3Hz), 7.17
(1H,d,J=6.6Hz), 7.39(2H,d,J=8.8Hz), 7.47-7.52(1H, (1H, d, J = 6.6Hz), 7.39 (2H, d, J = 8.8Hz), 7.47-7.52 (1H,
m), 7.91-7.96(3H,m), 8.08(1H,t,J=5.9Hz), 8.40(1H,d m), 7.91-7.96 (3H, m), 8.08 (1H, t, J = 5.9Hz), 8.40 (1H, d
d,J=4.4,1.5Hz), 9.64(1H,s). IR(KBr)cm-1: 3340,1702,1632,1273. . D, J = 4.4,1.5Hz), 9.64 (1H, s) IR (KBr) cm-1: 3340,1702,1632,1273.

【0221】実施例59 N−(2−アミノフェニル)−4−[N−(6−クロロピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号157) mp. 180-185℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.24(2H,d,J=5.9Hz), [0221] Example 59 N-(2-aminophenyl) -4- [N- (6- chloropyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 157) mp 180-185 ℃ 1H NMR (270MHz, DMSO-d6) δppm:. 4.24 (2H, d, J = 5.9Hz),
4.89(2H,br.s), 5.10(2H,s), 6.60(1H,t,J=7.3Hz), 6. 4.89 (2H, br.s), 5.10 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.
78(1H,d,J=8.1Hz), 6.97(1H,dt,J=1.5,8.1Hz), 7.16(1 78 (1H, d, J = 8.1Hz), 6.97 (1H, dt, J = 1.5,8.1Hz), 7.16 (1
H,d,J=6.6Hz), 7.37(2H,d,J=8.1Hz), 7.56(1H,d,J=8.1H H, d, J = 6.6Hz), 7.37 (2H, d, J = 8.1Hz), 7.56 (1H, d, J = 8.1H
z), 7.85-8.02(4H,m), 8.44(1H,d,J=2.2Hz), 9.62(1H, z), 7.85-8.02 (4H, m), 8.44 (1H, d, J = 2.2Hz), 9.62 (1H,
s). IR(KBr)cm-1: 3346,3282,1696,1533,1271. . S) IR (KBr) cm-1: 3346,3282,1696,1533,1271.

【0222】実施例60 N−(2−アミノフェニル)−4−[N−(ピリジン− [0222] Example 60 N-(2-aminophenyl) -4- [N- (pyridine -
4−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号181) mp. 180-183℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=6.6Hz), 4-yl) methoxycarbonylamino-methyl] benzamide (Table 1:.. Compound No. 181) mp 180-183 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 6.6Hz),
4.89(2H,s), 5.12(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 4.89 (2H, s), 5.12 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz),
6.78(1H,dd,J=1.5,7.3Hz), 6.97(1H,ddd,J=1.5,7.3,8.1 6.78 (1H, dd, J = 1.5,7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1
Hz), 7.16(1H,d,J=7.3Hz), 7.34(2H,d,J=5.9Hz), 7.39 Hz), 7.16 (1H, d, J = 7.3Hz), 7.34 (2H, d, J = 5.9Hz), 7.39
(2H,d,J=8.1Hz), 7.94(2H,d,J=8.1Hz), 8.09(1H,t,J=5. (2H, d, J = 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.09 (1H, t, J = 5.
9Hz), 8.57(1H,d), 9.64(1H,br.s). IR(KBr)cm-1: 3394,3290,1711,1645,1624,1535,1504,13 . 9Hz), 8.57 (1H, d), 9.64 (1H, br.s) IR (KBr) cm-1: 3394,3290,1711,1645,1624,1535,1504,13
21,1251,1138,1049,763. 21,1251,1138,1049,763.

【0223】実施例61 N−(2−アミノフェニル)−4−[N−[2−(チオフェン−3−イル)エトキシカルボニル]アミノメチル]ベンズアミド(表−1:化合物番号203) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 2.90(2H,t,J=7.3Hz), [0223] Example 61 N-(2-aminophenyl) -4- [N- [2- (thiophen-3-yl) ethoxycarbonyl] aminomethyl] benzamide. (Table 1: Compound No. 203) mp (Amorphous .) 1H NMR (270MHz, DMSO-d6) δppm: 2.90 (2H, t, J = 7.3Hz),
4.17-4.26(4H,m), 4.89(2H,s), 6.60(1H,t,J=8.1Hz), 4.17-4.26 (4H, m), 4.89 (2H, s), 6.60 (1H, t, J = 8.1Hz),
6.78(1H,d,J=6.6Hz), 6.97(1H,t,J=7.3Hz), 7.06(1H,d, 6.78 (1H, d, J = 6.6Hz), 6.97 (1H, t, J = 7.3Hz), 7.06 (1H, d,
J=5.1Hz), 7.17(1H,d,J=7.3Hz), 7.26(1H,s), 7.36(2H, J = 5.1Hz), 7.17 (1H, d, J = 7.3Hz), 7.26 (1H, s), 7.36 (2H,
d,J=8.1Hz), 7.47(1H,t,J=2.2Hz), 7.81(1H,t,J=5.9H d, J = 8.1Hz), 7.47 (1H, t, J = 2.2Hz), 7.81 (1H, t, J = 5.9H
z), 7.93(2H,d,J=8.1Hz), 9.63(1H,s). IR(KBr)cm-1: 3314,1716,1638,1252. . Z), 7.93 (2H, d, J = 8.1Hz), 9.63 (1H, s) IR (KBr) cm-1: 3314,1716,1638,1252.

【0224】実施例62 N−(2−アミノフェニル)−4−[N−(3−フェニルオキサゾール−5−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号211) mp. 192-195℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=5.9Hz), [0224] Example 62 N-(2-aminophenyl) -4- [N- (3- phenyl-5-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 211) mp 192-195 ℃ 1H NMR (270MHz, DMSO-d6) δppm:. 4.30 (2H, d, J = 5.9Hz),
4.89(2H,s), 5.25(2H,s), 6.60(1H,t,J=6.6Hz), 6.68(1 4.89 (2H, s), 5.25 (2H, s), 6.60 (1H, t, J = 6.6Hz), 6.68 (1
H,d,J=8.1Hz), 6.94(1H,t,J=7.3Hz), 7.09(1H,s), 7.16 H, d, J = 8.1Hz), 6.94 (1H, t, J = 7.3Hz), 7.09 (1H, s), 7.16
(1H,d,J=7.3Hz), 7.39(2H,d,J=8.1Hz), 7.51(4H,d,J=2. (1H, d, J = 7.3Hz), 7.39 (2H, d, J = 8.1Hz), 7.51 (4H, d, J = 2.
2Hz), 7.87-7.96(5H,m), 8.12(1H,t,J=5.9Hz), 9.63(1 2Hz), 7.87-7.96 (5H, m), 8.12 (1H, t, J = 5.9Hz), 9.63 (1
H,s). IR(KBr)cm-1: 3292,1718,1630,1262. . H, s) IR (KBr) cm-1: 3292,1718,1630,1262.

【0225】実施例63 N−(2−アミノフェニル)−4−[N−(チアゾール−5−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号216) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), [0225] Example 63 N-(2-aminophenyl)-4-[N-(thiazol-5-yl) methoxycarbonylamino-methyl] benzamide.. (Table 1: Compound No. 216) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz),
4.91(2H,br.s), 5.30(2H,s), 6.60(1H,dd,J=7.3,7.3H 4.91 (2H, br.s), 5.30 (2H, s), 6.60 (1H, dd, J = 7.3,7.3H
z), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16(1H,d,J=7.3Hz), 7.36(2H,d,J=8.1Hz), 7.91-8.00 7.16 (1H, d, J = 7.3Hz), 7.36 (2H, d, J = 8.1Hz), 7.91-8.00
(4H,m), 9.09(1H,s),9.63(1H,s). IR(KBr)cm-1: 3346(br.),1697,1636,1525,1456,1271,87 . (4H, m), 9.09 (1H, s), 9.63 (1H, s) IR (KBr) cm-1: (. Br) 3346, 1697,1636,1525,1456,1271,87
3,753. 3,753.

【0226】実施例64 N−(2−アミノフェニル)−4−[N−[2−(4− [0226] Example 64 N-(2-aminophenyl) -4- [N- [2- (4-
メチルチアゾール−5−イル)エトキシカルボニル]アミノメチル]ベンズアミド(表−1:化合物番号21 Methylthiazole-5-yl) ethoxycarbonyl] aminomethyl] benzamide (Table 1: Compound No. 21
7) mp. 130-133℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.32(3H,s), 3.07(2 .. 7) mp 130-133 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.32 (3H, s), 3.07 (2
H,t,J=5.9Hz), 4.15(2H,t,J=5.9Hz), 4.25(2H,d,J=6.6H H, t, J = 5.9Hz), 4.15 (2H, t, J = 5.9Hz), 4.25 (2H, d, J = 6.6H
z), 4.89(2H,s), 6.60(1H,t,J=5.9Hz), 6.78(1H,dd,J= z), 4.89 (2H, s), 6.60 (1H, t, J = 5.9Hz), 6.78 (1H, dd, J =
7.3,1.5Hz), 6.97(1H,dt,J=1.5,7.3Hz), 7.16(1H,d,J= 7.3,1.5Hz), 6.97 (1H, dt, J = 1.5,7.3Hz), 7.16 (1H, d, J =
8.1Hz), 7.35(2H,d,J=8.1Hz), 7.83(1H,t,J=5.9Hz), 7. 8.1Hz), 7.35 (2H, d, J = 8.1Hz), 7.83 (1H, t, J = 5.9Hz), 7.
94(2H,d,J=8.1Hz), 8.85(1H,s), 9.62(1H,s). IR(KBr)cm-1: 3350,1691,1635,1270. 94 (2H, d, J = 8.1Hz), 8.85 (1H, s), 9.62 (1H, s) IR (KBr) cm-1:. 3350,1691,1635,1270.

【0227】実施例65 N−(2−アミノフェニル)−4−[N−(1−メチルピペリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号225) mp. 130-135℃. 1H NMR(270MHz, DMSO-d6)δppm: 1.49-1.78(3H,m), 1. [0227] Example 65 N-(2-aminophenyl) -4- [N- (1- methylpiperidin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 225) mp 130-135 ℃ 1H NMR (270MHz, DMSO-d6) δppm:. 1.49-1.78 (3H, m), 1.
83-2.01(3H,m), 2.30(3H,s), 2.85(2H,s), 3.74-3.94(2 83-2.01 (3H, m), 2.30 (3H, s), 2.85 (2H, s), 3.74-3.94 (2
H,m), 4.25(2H,d,J=5.8Hz), 6.55-6.62(3H,m), 6.78(1 H, m), 4.25 (2H, d, J = 5.8Hz), 6.55-6.62 (3H, m), 6.78 (1
H,d,J=8.1Hz), 6.97(1H,t,J=7.3Hz), 7.16(1H,d,J=8.1H H, d, J = 8.1Hz), 6.97 (1H, t, J = 7.3Hz), 7.16 (1H, d, J = 8.1H
z), 7.37(2H,d,J=8.1Hz), 7.79(1H,t,J=6.6Hz), 7.93(2 z), 7.37 (2H, d, J = 8.1Hz), 7.79 (1H, t, J = 6.6Hz), 7.93 (2
H,d,J=8.0Hz), 9.66(1H,s). IR(KBr)cm-1: 3323,2722,1702,1648,1263. . H, d, J = 8.0Hz), 9.66 (1H, s) IR (KBr) cm-1: 3323,2722,1702,1648,1263.

【0228】実施例66 N−(2−アミノフェニル)−4−[N−(4−メチルピペラジン−1−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号227) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 1.73(2H,t,J=6.6Hz), [0228] Example 66 N-(2-aminophenyl) -4- [N- (4- methylpiperazin-1-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 227) mp (Amorphous) . 1H NMR (270MHz, DMSO-d6) δppm: 1.73 (2H, t, J = 6.6Hz),
2.36-2.63(13H,m), 4.00(2H,t,J=6.6Hz), 4.30(2H,d,J 2.36-2.63 (13H, m), 4.00 (2H, t, J = 6.6Hz), 4.30 (2H, d, J
=5.8Hz), 6.55-6.63(4H,m), 6.78(1H,d,J=6.6Hz), 6.97 = 5.8Hz), 6.55-6.63 (4H, m), 6.78 (1H, d, J = 6.6Hz), 6.97
(1H,t,J=7.3Hz), 7.16(1H,d,J=7.3Hz), 7.37(2H,d,J=8. (1H, t, J = 7.3Hz), 7.16 (1H, d, J = 7.3Hz), 7.37 (2H, d, J = 8.
7Hz), 7.73(1H,t,J=5.9Hz), 7.94(2H,d,J=8.0Hz), 9.66 7Hz), 7.73 (1H, t, J = 5.9Hz), 7.94 (2H, d, J = 8.0Hz), 9.66
(1H,s). IR(KBr)cm-1: 3341,2706,1701,1262. . (1H, s) IR (KBr) cm-1: 3341,2706,1701,1262.

【0229】実施例67 N−(2−アミノフェニル)−4−[N−(テトラヒドロフラン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号221) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 1.50-1.60(1H,m), 1.8 [0229] Example 67 N-(2-aminophenyl)-4-[N-(tetrahydrofuran-3-yl) methoxycarbonylamino-methyl] benzamide.. (Table 1: Compound No. 221) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 1.50-1.60 (1H, m), 1.8
8-2.00(1H,m), 2.44-2.54(1H,m), 3.41-3.47(1H,m), 3. 8-2.00 (1H, m), 2.44-2.54 (1H, m), 3.41-3.47 (1H, m), 3.
56-3.77(3H,m), 3.85-4.04(2H,m), 4.25(2H,d,J=5.9H 56-3.77 (3H, m), 3.85-4.04 (2H, m), 4.25 (2H, d, J = 5.9H
z), 4.89(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H, z), 4.89 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H,
d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.17(1H,d,J= d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.17 (1H, d, J =
8.1Hz), 7.37(2H,d,J=8.1Hz), 7.81(1H,t,J=5.9Hz), 7. 8.1Hz), 7.37 (2H, d, J = 8.1Hz), 7.81 (1H, t, J = 5.9Hz), 7.
94(2H,d,J=8.1Hz), 9.62(1H,br.s). IR(KBr)cm-1: 3349,1695,1635,1523,1457,1259,754. 94 (2H, d, J = 8.1Hz), 9.62 (1H, br.s) IR (KBr) cm-1:. 3349,1695,1635,1523,1457,1259,754.

【0230】実施例68 N−(2−アミノフェニル)−4−[N−(フェノキシカルボニル)アミノメチル]ベンズアミド(表−1:化合物番号12) mp.174-175℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.36(2H,d,J=5.9Hz), [0230] Example 68 N-(2-aminophenyl)-4-[N-(phenoxycarbonyl) aminomethyl] benzamide. (Table 1: Compound No. 12) mp.174-175 ℃ 1H NMR (270MHz, DMSO -d6) δppm: 4.36 (2H, d, J = 5.9Hz),
4.90(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.77(1H,d 4.90 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d
d,J=7.3,7.3Hz), 6.98(1H,ddd,J=1.5,7.3,7.3Hz),7.05- d, J = 7.3,7.3Hz), 6.98 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.05-
7.24(4H,m), 7.39-7.46(4H,m), 7.97(2H,d,J=8.1Hz), 7.24 (4H, m), 7.39-7.46 (4H, m), 7.97 (2H, d, J = 8.1Hz),
8.41(1H,t,J=5.9Hz), 9.65(1H,br.s). IR(KBr)cm-1: 3443,3362,3313,1732,1706,1636,1527,14 8.41 (1H, t, J = 5.9Hz), 9.65 (1H, br.s) IR (KBr) cm-1:. 3443,3362,3313,1732,1706,1636,1527,14
93,1458,1305,1217,748. 93,1458,1305,1217,748.

【0231】実施例69 N−(2−アミノフェニル)−4−[N−(ピリジン− [0231] Example 69 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)オキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号81) mp. 209℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.38(2H,d,J=6.6Hz), 3-yl) oxycarbonyl aminomethyl] benzamide (Table 1:. Compound No. 81) mp 209 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.38 (2H, d, J = 6.6Hz) ,
4.90(2H,br.s), 6.55-6.63(1H,m), 6.78(1H,d,J=8.1H 4.90 (2H, br.s), 6.55-6.63 (1H, m), 6.78 (1H, d, J = 8.1H
z), 7.00(1H,dd,J=7.3,7.3Hz), 7.17(1H,d,J=8.8Hz), z), 7.00 (1H, dd, J = 7.3,7.3Hz), 7.17 (1H, d, J = 8.8Hz),
7.37-7.47(3H,m), 7.64(1H,d,J=8.8Hz), 7.97(2H,d,J= 7.37-7.47 (3H, m), 7.64 (1H, d, J = 8.8Hz), 7.97 (2H, d, J =
8.1Hz), 8.43(2H,d,J=3.1Hz), 8.59(1H,t,J=5.9Hz), 9. 8.1Hz), 8.43 (2H, d, J = 3.1Hz), 8.59 (1H, t, J = 5.9Hz), 9.
66(1H,br.s). 66 (1H, br.s).

【0232】実施例70 N−(2−アミノ−5−フルオロフェニル)−4−[N [0232] Example 70 N-(2-amino-5-fluorophenyl)-4-[N
−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号110) mp. 160-162℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=6.6Hz), - (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide.. (Table 1: Compound No. 110) mp 160-162 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 6.6 Hz),
4.81(2H,s), 5.10(2H,s), 6.70-6.90(2H,m), 7.10-8.00 4.81 (2H, s), 5.10 (2H, s), 6.70-6.90 (2H, m), 7.10-8.00
(8H,m), 8.53(1H,d,J=3.6Hz), 8.59(1H,s), 9.61(1H, (8H, m), 8.53 (1H, d, J = 3.6Hz), 8.59 (1H, s), 9.61 (1H,
s). IR(KBr)cm-1:3269,1716,1638,1488,1436,1247,1141,104 . S) IR (KBr) cm-1: 3269,1716,1638,1488,1436,1247,1141,104
3,744. 3,744.

【0233】実施例71 N−(2−アミノフェニル)−4−[N−(2−アミノフェニル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号51) mp. 149-151℃(dec.) 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), [0233] Example 71 N-(2-aminophenyl) -4- [N- (2- aminophenyl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 51) mp 149-151 ° C. (dec. ) 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz),
4.88(2H,s), 4.96(2H,s), 5.06(2H,s), 6.53(1H,dd,J= 4.88 (2H, s), 4.96 (2H, s), 5.06 (2H, s), 6.53 (1H, dd, J =
7.3,7.3Hz), 6.56-6.67(2H,m), 6.78(1H,dd,J=1.5,8.1H 7.3,7.3Hz), 6.56-6.67 (2H, m), 6.78 (1H, dd, J = 1.5,8.1H
z), 6.93-7.12(3H,m), 7.16(1H,d,J=6.6Hz), 7.38(2H, z), 6.93-7.12 (3H, m), 7.16 (1H, d, J = 6.6Hz), 7.38 (2H,
d,J=8.1Hz), 7.86(1H,t-like,J=5.9Hz), 7.93(2H,d,J= d, J = 8.1Hz), 7.86 (1H, t-like, J = 5.9Hz), 7.93 (2H, d, J =
8.1Hz), 9.61(1H,s). IR(KBr)cm-1:3336,1685,1632,1527,1276,748. . 8.1Hz), 9.61 (1H, s) IR (KBr) cm-1: 3336,1685,1632,1527,1276,748.

【0234】実施例72 N−(2−アミノフェニル)−4−[N−(キヌクリジン−3−イル)オキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号228) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 1.30-1.90(4H,m), 1.9 [0234] Example 72 N-(2-aminophenyl)-4-[N-(quinuclidin-3-yl) oxycarbonyl aminomethyl] benzamide.. (Table 1: Compound No. 228) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 1.30-1.90 (4H, m), 1.9
0(1H,br.s), 2.45-2.80(6H,m), 3.04-3.13(1H,m), 4.15 0 (1H, br.s), 2.45-2.80 (6H, m), 3.04-3.13 (1H, m), 4.15
(2H,d,J=5.9Hz), 4.55-4.60(1H,m), 4.88(2H,br.s), 6. (2H, d, J = 5.9Hz), 4.55-4.60 (1H, m), 4.88 (2H, br.s), 6.
60(1H,ddd,J=1.5,7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6. 60 (1H, ddd, J = 1.5,7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.
97(1H,ddd,J=1.5,7.3,7.3Hz), 7.17(1H,d,J=6.6Hz), 7. 97 (1H, ddd, J = 1.5,7.3,7.3Hz), 7.17 (1H, d, J = 6.6Hz), 7.
37(2H,d,J=8.1Hz), 7.78(1H,t,J=5.9Hz),7.94(1H,d,J= 37 (2H, d, J = 8.1Hz), 7.78 (1H, t, J = 5.9Hz), 7.94 (1H, d, J =
7.3Hz), 9.62(1H,s). IR(KBr)cm-1:3328,2942,1700,1648,1504,1259,749. . 7.3Hz), 9.62 (1H, s) IR (KBr) cm-1: 3328,2942,1700,1648,1504,1259,749.

【0235】実施例73 N−(2−アミノフェニル)−4−[N−(3−アミノフェニル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号52) mp. 149-153℃(dec.) 1H NMR(270MHz, DMSO-d6)δppm: 4.27(2H,d,J=5.9Hz), [0235] Example 73 N-(2-aminophenyl) -4- [N- (3- aminophenyl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 52) mp 149-153 ° C. (dec. ) 1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 5.9Hz),
4.88 and 4.89(total 4H, each br.s), 5.08(2H,s), 6. 4.88 and 4.89 (total 4H, each br.s), 5.08 (2H, s), 6.
47-6.63(3H,m), 6.78(1H,d,J=8.1Hz), 6.94-7.02(2H, 47-6.63 (3H, m), 6.78 (1H, d, J = 8.1Hz), 6.94-7.02 (2H,
m), 7.15(1H,dd,J=7.3,8.8Hz), 7.37(2H,d,J=8.1Hz), m), 7.15 (1H, dd, J = 7.3,8.8Hz), 7.37 (2H, d, J = 8.1Hz),
7.84(1H,t,J=5.9Hz),7.93(2H,d,J=8.8Hz), 9.61(1H,br. 7.84 (1H, t, J = 5.9Hz), 7.93 (2H, d, J = 8.8Hz), 9.61 (1H, br.
s). IR(KBr)cm-1:3367,1682,1632,1523,1457,1261,754. . S) IR (KBr) cm-1: 3367,1682,1632,1523,1457,1261,754.

【0236】実施例74 N−(2−アミノフェニル)−4−[N−(1−メチルイミダゾール−5−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号218) mp. 162-165℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.62(3H,s), 4.27(2H, [0236] Example 74 N-(2-aminophenyl) -4- [N- (-5- 1- methylimidazole-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 218) mp 162-165 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 3.62 (3H, s), 4.27 (2H,
d,J=5.9Hz), 4.91(2H,br.s), 5.05(2H,s), 6.60(1H,dd, d, J = 5.9Hz), 4.91 (2H, br.s), 5.05 (2H, s), 6.60 (1H, dd,
J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.95-7.00(2H,m), J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.95-7.00 (2H, m),
7.16(1H,d,J=7.3Hz), 7.36(2H,d,J=8.1Hz), 7.63(1H, 7.16 (1H, d, J = 7.3Hz), 7.36 (2H, d, J = 8.1Hz), 7.63 (1H,
s), 7.87-7.95(3H,m), 9.64(1H,br.s). IR(KBr)cm-1:3293,1688,1651,1534,1506,1259,1121,104 . S), 7.87-7.95 (3H, m), 9.64 (1H, br.s) IR (KBr) cm-1: 3293,1688,1651,1534,1506,1259,1121,104
3,748. 3,748.

【0237】実施例75 N−(2−アミノ−4−クロロフェニル)−4−[N− [0237] Example 75 N-(2-amino-4-chlorophenyl) -4- [N-
(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号113) mp. 167-170℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=5.9Hz), (Pyridin-3-yl) methoxycarbonylamino-methyl] benzamide.. (Table 1: Compound No. 113) mp 167-170 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 5.9Hz ),
5.10(2H,s), 5.21(2H,s), 6.72(1H,dd,J=2.2,8.1Hz), 5.10 (2H, s), 5.21 (2H, s), 6.72 (1H, dd, J = 2.2,8.1Hz),
6.81(1H,d,J=2.2Hz), 7.16(1H,d,J=8.1Hz), 7.37(2H,d, 6.81 (1H, d, J = 2.2Hz), 7.16 (1H, d, J = 8.1Hz), 7.37 (2H, d,
J=8.1Hz), 7.78(1H,d,J=8.1Hz), 7.92(2H,d,J=8.1Hz), J = 8.1Hz), 7.78 (1H, d, J = 8.1Hz), 7.92 (2H, d, J = 8.1Hz),
8.53(1H,d,J=4.4Hz), 8.59(1H,s), 9.60(1H,s). IR(KBr)cm-1:3347,3062,2931,1653,1576,1505,1456,142 8.53 (1H, d, J = 4.4Hz), 8.59 (1H, s), 9.60 (1H, s) IR (KBr) cm-1:. 3347,3062,2931,1653,1576,1505,1456,142
8,1301,1232,1114,1070,1019. 8,1301,1232,1114,1070,1019.

【0238】実施例76 N−(2−アミノフェニル)−4−[N−(5−メトキシピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号161) mp. 169-170℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.83(3H,s), 4.29(2H, [0238] Example 76 N-(2-aminophenyl) -4- [N- (5- methoxypyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 161) mp 169-170 ℃ 1H NMR (270MHz, DMSO-d6) δppm:. 3.83 (3H, s), 4.29 (2H,
d,J=6.6Hz), 4.87(2H,s), 5.09(2H,s), 6.57-6.62(1H, d, J = 6.6Hz), 4.87 (2H, s), 5.09 (2H, s), 6.57-6.62 (1H,
m), 6.76-6.79(1H,m), 6.94-6.99(1H,m), 7.14-7.18(1 m), 6.76-6.79 (1H, m), 6.94-6.99 (1H, m), 7.14-7.18 (1
H,m), 7.36-7.39(3H,m), 7.91-7.99(3H,m), 8.19-8.30 H, m), 7.36-7.39 (3H, m), 7.91-7.99 (3H, m), 8.19-8.30
(2H,m), 9.63(1H,s). IR(KBr)cm-1:3330,1694,1633,1524,1457,1298,1269,104 . (2H, m), 9.63 (1H, s) IR (KBr) cm-1: 3330,1694,1633,1524,1457,1298,1269,104
5,760. 5,760.

【0239】実施例77 N−(2−アミノフェニル)−4−[N−(ピラジン− [0239] Example 77 N-(2-aminophenyl) -4- [N- (pyrazine -
2−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号192) mp. 182℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.30(2H,d,J=6.6Hz), 2-yl) methoxycarbonylamino-methyl] benzamide (Table 1:.. Compound No. 192) mp 182 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.30 (2H, d, J = 6.6Hz),
4.88(2H,br.s), 5.20(2H,s), 6.60(1H,dd,J=7.3,8.1H 4.88 (2H, br.s), 5.20 (2H, s), 6.60 (1H, dd, J = 7.3,8.1H
z), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,8.1Hz), z), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,8.1Hz),
7.16(1H,d,J=7.3Hz), 7.39(2H,d,J=8.8Hz), 7.94(2H,d, 7.16 (1H, d, J = 7.3Hz), 7.39 (2H, d, J = 8.8Hz), 7.94 (2H, d,
J=8.8Hz), 8.08(1H,t-like,J=6.6Hz), 8.61(1H,s), 8.6 J = 8.8Hz), 8.08 (1H, t-like, J = 6.6Hz), 8.61 (1H, s), 8.6
5(1H,s), 8.68(1H,s), 9.63(1H,s). IR(KBr)cm-1:3266,1709,1632,1535,1508,1284,1055,102 . 5 (1H, s), 8.68 (1H, s), 9.63 (1H, s) IR (KBr) cm-1: 3266,1709,1632,1535,1508,1284,1055,102
2,744. 2,744.

【0240】実施例78 N−(2−アミノ−5−メトキシフェニル)−4−[N [0240] Example 78 N-(2-amino-5-methoxyphenyl)-4-[N
−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号121) mp.141-143℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.66(3H,s), 4.29(2H, - (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 121) mp.141-143 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.66 (3H, s), 4.29 ( 2H,
d,J=5.9Hz), 4.51(2H,br.s), 5.10(2H,s), 6.63(1H,dd, d, J = 5.9Hz), 4.51 (2H, br.s), 5.10 (2H, s), 6.63 (1H, dd,
J=2.9,8.8Hz), 6.74(1H,d,J=8.8Hz), 6.91(1H,d,J=2.2H J = 2.9,8.8Hz), 6.74 (1H, d, J = 8.8Hz), 6.91 (1H, d, J = 2.2H
z), 7.38(2H,d,J=8.8Hz), 7.41(1H,s), 7.79(1H,d,J=8. z), 7.38 (2H, d, J = 8.8Hz), 7.41 (1H, s), 7.79 (1H, d, J = 8.
1Hz), 7.92(2H,d,J=8.1Hz), 7.98(1H,t,J=5.9Hz), 8.54 1Hz), 7.92 (2H, d, J = 8.1Hz), 7.98 (1H, t, J = 5.9Hz), 8.54
(1H,d,J=3.7Hz), 8.60(1H,s), 9.65(1H,s). (1H, d, J = 3.7Hz), 8.60 (1H, s), 9.65 (1H, s).

【0241】実施例79 N−(2−アミノフェニル)−4−[N−(ピリジン3 [0241] Example 79 N-(2-aminophenyl) -4- [N- (pyridine-3
−イル)メチル−N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号109) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.50(2H,s), 4.56(2H, - yl) methyl -N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide (Table 1:.. Compound No. 109) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.50 (2H, s), 4.56 (2H,
s), 4.87(2H,s), 5.21(2H,s), 6.60(1H,t,J=7.7Hz), 6. s), 4.87 (2H, s), 5.21 (2H, s), 6.60 (1H, t, J = 7.7Hz), 6.
78(1H,d,J=7.3Hz), 6.97(1H,d,J=7.3Hz), 7.17(1H,d,J= 78 (1H, d, J = 7.3Hz), 6.97 (1H, d, J = 7.3Hz), 7.17 (1H, d, J =
7.3Hz), 7.20-7.50(4H,m), 7.60-8.00(4H,m), 8.40-8.6 7.3Hz), 7.20-7.50 (4H, m), 7.60-8.00 (4H, m), 8.40-8.6
0(4H,m), 9.65(1H,s). IR(KBr)cm-1: 3268,1700,1504,1246,1120,940,714. 0 (4H, m), 9.65 (1H, s) IR (KBr) cm-1:. 3268,1700,1504,1246,1120,940,714.

【0242】実施例80 N−(2−アミノフェニル)−4−[N−[3−(ピリジン−3−イル)プロピル]−N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号120) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 1.75-1.90(2H,m), 2.4 [0242] Example 80 N-(2-aminophenyl) -4- [N- [3- (pyridin-3-yl) propyl] -N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide (Table -1:.. compound No. 120) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 1.75-1.90 (2H, m), 2.4
8-2.62(2H,m), 3.20-3.36(2H,m), 4.55(2H,s), 4.89(2 8-2.62 (2H, m), 3.20-3.36 (2H, m), 4.55 (2H, s), 4.89 (2
H,s), 5.16(2H,s), 6.57-6.63(1H,m), 6.76-6.80(1H, H, s), 5.16 (2H, s), 6.57-6.63 (1H, m), 6.76-6.80 (1H,
m), 6.94-6.99(1H,m), 7.14-7.17(1H,m), 7.32-7.74(6 m), 6.94-6.99 (1H, m), 7.14-7.17 (1H, m), 7.32-7.74 (6
H,m), 7.94(2H,d,J=8.1Hz), 8.30-8.65(4H,m), 9.64(1 H, m), 7.94 (2H, d, J = 8.1Hz), 8.30-8.65 (4H, m), 9.64 (1
H,s). H, s).

【0243】実施例81 N−(2−ヒドロキシフェニル)−4−[N−(ピリジン−3−イル)メチル−N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表− [0243] Example 81 N-(2-hydroxyphenyl)-4-[N-(pyridin-3-yl) methyl -N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide (Table -
1:化合物番号115) mp. (amorphous). 1H NMR(270MHz,DMSO-d6): 4.52(2H,s), 4.57(2H,s), 1:.. Compound No. 115) mp (amorphous) 1H NMR (270MHz, DMSO-d6): 4.52 (2H, s), 4.57 (2H, s),
5.20(2H,s), 6.84(1H,t,J=6.6Hz), 6.93(1H,d,J=6.6H 5.20 (2H, s), 6.84 (1H, t, J = 6.6Hz), 6.93 (1H, d, J = 6.6H
z), 7.03(1H,d,J=7.3Hz), 7.37(4H,m), 7.68(2H,dd,J= z), 7.03 (1H, d, J = 7.3Hz), 7.37 (4H, m), 7.68 (2H, dd, J =
1.5,8.1Hz), 7.92(2H,br.s), 8.53(4H,m), 9.49(1H,s), 1.5,8.1Hz), 7.92 (2H, br.s), 8.53 (4H, m), 9.49 (1H, s),
9.77(1H,br.s). IR(KBr)cm-1: 3035,1698,1243,1118,754,640. 9.77 (1H, br.s) IR (KBr) cm-1:. 3035,1698,1243,1118,754,640.

【0244】実施例82 N−(2−ヒドロキシフェニル)−4−[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号111) mp.162-164℃. 1H NMR(270MHz, DMSO-d6): 4.29(1H,d,J=5.9Hz), 5.10 [0244] Example 82 N-(2-hydroxyphenyl)-4-[N-(pyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 111) mp.162-164 ℃ 1H NMR (270MHz, DMSO-d6): 4.29 (1H, d, J = 5.9Hz), 5.10
(2H,s), 6.83(1H,t,J=8.1Hz), 6.92(1H,d,J=6.6Hz), 7. (2H, s), 6.83 (1H, t, J = 8.1Hz), 6.92 (1H, d, J = 6.6Hz), 7.
07(1H,t,J=6.6Hz), 7.39(2H,d,J=8.8Hz), 7.43(1H,d,J= 07 (1H, t, J = 6.6Hz), 7.39 (2H, d, J = 8.8Hz), 7.43 (1H, d, J =
5.1Hz), 7.68(2H,d,J=8.1Hz), 7.80(1H,d,J=8.1Hz), 7. 5.1Hz), 7.68 (2H, d, J = 8.1Hz), 7.80 (1H, d, J = 8.1Hz), 7.
92(2H,d,J=8.1Hz), 7.99(1H,t,J=5.9Hz), 8.54(1H,d,J= 92 (2H, d, J = 8.1Hz), 7.99 (1H, t, J = 5.9Hz), 8.54 (1H, d, J =
4.4Hz), 8.60(1H,s), 9.49(1H,s), 9.76(1H,br.s). IR(KBr)cm-1: 3333,3259,1694,1645,1529,1267,720. . 4.4Hz), 8.60 (1H, s), 9.49 (1H, s), 9.76 (1H, br.s) IR (KBr) cm-1: 3333,3259,1694,1645,1529,1267,720.

【0245】実施例83 N−(2,4−ジヒドロキシフェニル)−4−[N− [0245] Example 83 N-(2,4-dihydroxyphenyl) -4- [N-
(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号116) mp. (amorphous) 1H NMR(270MHz,DMSO-d6): 4.27(2H,d,J=6.6Hz), 5.10 (Pyridin-3-yl) methoxycarbonylamino-methyl] benzamide. (Table 1: Compound No. 116) mp (amorphous) 1H NMR (270MHz, DMSO-d6): 4.27 (2H, d, J = 6.6Hz), 5.10
(2H,s), 6.20(2H,dd,J=2.2,8.1Hz), 6.39(2H,d,J=2.9H (2H, s), 6.20 (2H, dd, J = 2.2,8.1Hz), 6.39 (2H, d, J = 2.9H
z), 6.88(2H,d,J=8.8Hz), 7.33(1H,d,J=8.1Hz), 7.41(1 z), 6.88 (2H, d, J = 8.8Hz), 7.33 (1H, d, J = 8.1Hz), 7.41 (1
H,dd,J=5.1,7.1Hz), 7.89(1H,d,J=8.8Hz), 7.98(1H,t,J H, dd, J = 5.1,7.1Hz), 7.89 (1H, d, J = 8.8Hz), 7.98 (1H, t, J
=6.6Hz), 8.05(2H,s), 8.52(1H,m), 8.59(1H,s), 9.30 = 6.6Hz), 8.05 (2H, s), 8.52 (1H, m), 8.59 (1H, s), 9.30
(2H,br.s). IR(KBr)cm-1: 3387,1702,1612,1311,1169,845. . (2H, br.s) IR (KBr) cm-1: 3387,1702,1612,1311,1169,845.

【0246】実施例84 N−(2−ヒドロキシ−5−メチルフェニル)−4− [0246] Example 84 N-(2-hydroxy-5-methylphenyl) -4-
[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号118) mp. 155-155.5℃. 1H NMR(270MHz,DMSO-d6): 2.22(3H,s), 4.29(2H,d,J= [N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide.. (Table 1: Compound No. 118) mp 155-155.5 ℃ 1H NMR (270MHz, DMSO-d6): 2.22 (3H, s), 4.29 (2H, d, J =
5.8Hz), 5.11(2H,s), 6.82(2H,m), 7.39(2H,d,J=8.8H 5.8Hz), 5.11 (2H, s), 6.82 (2H, m), 7.39 (2H, d, J = 8.8H
z), 7.42(2H,m), 7.51(1H,s), 7.79(1H,d,J=8.1Hz),7.9 z), 7.42 (2H, m), 7.51 (1H, s), 7.79 (1H, d, J = 8.1Hz), 7.9
2(1H,d,J=8.1Hz), 7.98(1H,t,J=5.9Hz), 8.54(1H,d,J= 2 (1H, d, J = 8.1Hz), 7.98 (1H, t, J = 5.9Hz), 8.54 (1H, d, J =
4.4Hz), 8.60(1H,s),9.48(2H,d,J=8.1Hz). IR(KBr)cm-1: 3306,1723,1655,1525,801,639. . 4.4Hz), 8.60 (1H, s), 9.48 (2H, d, J = 8.1Hz) IR (KBr) cm-1: 3306,1723,1655,1525,801,639.

【0247】実施例85 N−(2−ヒドロキシ−5−メトキシフェニル)−4− [0247] Example 85 N-(2-hydroxy-5-methoxyphenyl) -4-
[N−(ピリジン−3−イル)メトキシカルボニルアミノメチル]ベンズアミド(表−1:化合物番号119) mp. 175-176℃. 1H NMR(270MHz,DMSO-d6): 3.69(3H,s), 4.29(2H,d,J= [N- (pyridin-3-yl) methoxycarbonylamino-methyl] benzamide.. (Table 1: Compound No. 119) mp 175-176 ℃ 1H NMR (270MHz, DMSO-d6): 3.69 (3H, s), 4.29 (2H, d, J =
5.9Hz), 5.10(2H,s), 6.63(1H,dd,J=2.9,8.7Hz), 6.84 5.9Hz), 5.10 (2H, s), 6.63 (1H, dd, J = 2.9,8.7Hz), 6.84
(1H,d,J=8.8Hz), 7.41(4H,m), 7.79(1H,d,J=8.1Hz), 7. (1H, d, J = 8.8Hz), 7.41 (4H, m), 7.79 (1H, d, J = 8.1Hz), 7.
91(1H,d,J=8.1Hz), 7.99(1H,t,J=5.9Hz), 8.54(1H,d,J= 91 (1H, d, J = 8.1Hz), 7.99 (1H, t, J = 5.9Hz), 8.54 (1H, d, J =
5.1Hz), 8.60(1H,s), 9.31(1H,s), 9.45(1H,s). IR(KBr)cm-1:3305,1687,1573,1262,1039,868. . 5.1Hz), 8.60 (1H, s), 9.31 (1H, s), 9.45 (1H, s) IR (KBr) cm-1: 3305,1687,1573,1262,1039,868.

【0248】実施例86 N−(2−アミノフェニル)−4−[N−[2−(ピリジン−3−イル)エトキシカルボニル]アミノ]ベンズアミド(表−1:化合物番号124) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.00(2H,t,J=6.6H), [0248] Example 86 N-(2-aminophenyl) -4- [N- [2- (pyridin-3-yl) ethoxycarbonyl] amino] benzamide. (Table 1: Compound No. 124) mp (Amorphous) . 1H NMR (270MHz, DMSO-d6) δppm: 3.00 (2H, t, J = 6.6H),
4.37(2H,t,J=6.6Hz), 4.87(2H,br.s), 6.60(1H,t,J=7.3 4.37 (2H, t, J = 6.6Hz), 4.87 (2H, br.s), 6.60 (1H, t, J = 7.3
Hz), 6.97(1H,t,J=7.3Hz), 7.15(1H,d,J=7.3Hz),7.36(1 Hz), 6.97 (1H, t, J = 7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.36 (1
H,dd,J=4.4,8.1Hz), 7.56(2H,d,J=8.8Hz), 7.92(2H,d,J H, dd, J = 4.4,8.1Hz), 7.56 (2H, d, J = 8.8Hz), 7.92 (2H, d, J
=8.8Hz), 8.46(1H,d,J=4.4Hz), 8.54(1H,d,J=2.2Hz), = 8.8Hz), 8.46 (1H, d, J = 4.4Hz), 8.54 (1H, d, J = 2.2Hz),
9.95(1H,s). IR(KBr)cm-1:3285,1695,1519,1315,1233,1079. . 9.95 (1H, s) IR (KBr) cm-1: 3285,1695,1519,1315,1233,1079.

【0249】実施例87 N−(2−アミノフェニル)−5−[(ピリジン−3− [0249] Example 87 N-(2-aminophenyl) -5 - [(pyridin-3
イル)メトキシカルボニル]アミノベンゾフラン−2− Yl) methoxycarbonyl] amino benzofuran-2-
カルボキシアミド(表−3:化合物番号2) mp.173-174℃. 1H NMR(270MHz, DMSO-d6)δppm: 5.22(2H,s), 6.60(1H, Carboxamide. (Table 3: Compound No. 2) mp.173-174 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 5.22 (2H, s), 6.60 (1H,
dd,J=8.1,8.1Hz), 6.79(1H,dd,J=1.5,8.1Hz),7.00(1H,d dd, J = 8.1,8.1Hz), 6.79 (1H, dd, J = 1.5,8.1Hz), 7.00 (1H, d
d,J=8.1,8.1Hz),7.20(1H,dd,J=1.5,8.1Hz),7.44(1H,m), d, J = 8.1,8.1Hz), 7.20 (1H, dd, J = 1.5,8.1Hz), 7.44 (1H, m),
7.48(1H,dd,J=1.5,8.8Hz), 7.61(1H,d,J=8.8Hz), 7.67 7.48 (1H, dd, J = 1.5,8.8Hz), 7.61 (1H, d, J = 8.8Hz), 7.67
(1H,s), 7.88(1H,dd,J=1.5,8.1Hz), 7.96(1H,d,J=1.5H (1H, s), 7.88 (1H, dd, J = 1.5,8.1Hz), 7.96 (1H, d, J = 1.5H
z), 8.56(1H,dd,J=1.5,4.8Hz), 8.68(1H,d,J=1.5Hz),9. z), 8.56 (1H, dd, J = 1.5,4.8Hz), 8.68 (1H, d, J = 1.5Hz), 9.
83(1H,s), 9.91(1H,s). IR(KBr)cm-1:3308,1707,1667,1584,1536,1452,1316,124 83 (1H, s), 9.91 (1H, s) IR (KBr) cm-1:. 3308,1707,1667,1584,1536,1452,1316,124
8,1157,1128,1070,955,879,795,748,710. 8,1157,1128,1070,955,879,795,748,710.

【0250】実施例88 N−(2−アミノフェニル)−4−[N−(ピリジン− [0250] Example 88 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)メトキシチオカルボニルアミノメチル]ベンズアミド(表−1:化合物番号86)の合成 (88−1) 3−ピリジンメタノール20mg(0. 3-yl) methoxy thiocarbonyl aminomethyl] benzamide (Table 1: Synthesis of Compound No. 86) (88-1) 3-pyridinemethanol 20 mg (0.
18mmol)を5mlの乾燥THFに溶解し、N, Was dissolved 18 mmol) in dry THF 5 ml, N,
N'−チオカルボニルジイミダゾール30mg(0.1 N'- thiocarbonyldiimidazole 30 mg (0.1
6mmol)を室温で加えた。 The 6 mmol) was added at room temperature. 終夜撹拌した後、実施例1の工程(1−4)の化合物50mg(0.14mmo After stirring overnight, compound 50 mg (0.14Mmo process of Example 1 (1-4)
l)を加えた。 l) was added.

【0251】室温で一夜放置後、クロロホルム100m [0251] After standing overnight at room temperature, chloroform 100m
lを加え、水20mlで3回洗浄した。 l was added, and the mixture was washed three times with water 20ml. ついで飽和食塩水で洗浄後、無水硫酸マグネシウムで乾燥した。 Then washed with saturated brine, and dried over anhydrous magnesium sulfate. 溶媒を減圧留去後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)で精製し、N−[2 The solvent was evaporated under reduced pressure and then purified by silica gel column chromatography (chloroform: methanol = 30: 1) to give, N-[2
−(N−tertーブトキシカルボニル)アミノフェニル]−4−[N−(ピリジン−3−イル)メトキシチオカルボニルアミノメチル]ベンズアミド70mg(収率88%)をアモルファスとして得た。 - a (N-tert-butoxycarbonyl4) aminophenyl] -4- [N- (pyridin-3-yl) methoxy thiocarbonyl aminomethyl] benzamide 70 mg (88% yield) as an amorphous solid. 1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 4.73(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.73 (2H,
d,J=5.9Hz), 5.52(2H,s), 6.73-7.33(3H,m), 7.35-7.43 d, J = 5.9Hz), 5.52 (2H, s), 6.73-7.33 (3H, m), 7.35-7.43
(2H,m), 7.58-7.95(5H,m), 8.14-8.65(3H,m), 9.80(1H, (2H, m), 7.58-7.95 (5H, m), 8.14-8.65 (3H, m), 9.80 (1H,
s), 9.91(1H,br.t). s), 9.91 (1H, br.t).

【0252】(88−2) 工程(88−1)の化合物50mg(0.10mmol)をメタノール3mlに溶解した。 [0252] The (88-2) the compound of step (88-1) 50 mg (0.10 mmol) was dissolved in methanol 3 ml. 4規定塩酸−ジオキサン溶液3mlを加え、室温で1.5時間撹拌した。 4 N hydrochloric acid - dioxane solution 3ml was added and stirred for 1.5 hours at room temperature. 希水酸化ナトリウム水溶液にあけ塩酸を中和した後、クロロホルム10mlで3回抽出した。 After neutralization with hydrochloric acid poured into dilute aqueous sodium hydroxide solution and extracted three times with chloroform 10 ml. 飽和食塩水で2回洗浄後、無水硫酸マグネシウムで乾燥し、濃縮して34mg(収率87%)のN− After washing twice with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 34mg (87% yield) N-
(2−アミノフェニル)−4−[N−(ピリジン−3− (2-aminophenyl) -4- [N- (pyridine-3
イル)メトキシチオカルボニルアミノメチル]ベンズアミドを得た。 Yl) methoxy thiocarbonyl aminomethyl] benzamide. mp. 154-156℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.73(2H,d,J=5.9Hz), . Mp 154-156 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 4.73 (2H, d, J = 5.9Hz),
4.88(2H,s), 5.52(2H,s), 6.60(1H,t,J=7.3Hz), 6.77(1 4.88 (2H, s), 5.52 (2H, s), 6.60 (1H, t, J = 7.3Hz), 6.77 (1
H,d,J=8.1Hz), 6.96(1H,t,J=8.1Hz), 7.16(1H,d,J=7.3H H, d, J = 8.1Hz), 6.96 (1H, t, J = 8.1Hz), 7.16 (1H, d, J = 7.3H
z), 7.29-7.41(3H,m), 7.83-7.95(3H,m), 8.50-8.56(1 z), 7.29-7.41 (3H, m), 7.83-7.95 (3H, m), 8.50-8.56 (1
H,m), 8.65(1H,s),9.62(1H,s), 9.93(1H,s). IR(KBr)cm-1:3204,3035,1631,1523,1456,1289,1191,92 . H, m), 8.65 (1H, s), 9.62 (1H, s), 9.93 (1H, s) IR (KBr) cm-1: 3204,3035,1631,1523,1456,1289,1191,92
0,753. 0,753.

【0253】実施例89 N−(2−アミノフェニル)−4−[N'−(ピリジン−3−イルメチル)ウレイドメチル]ベンズアミド(表−1:化合物番号88)の合成 (89−1) 3−ピコリルアミン0.28g(2.6 [0253] Example 89 N-(2-aminophenyl) -4- [N '- (pyridin-3-ylmethyl) ureidomethyl] benzamide: Synthesis of (Table 1 Compound No. 88) (89-1) 3- picolylamine 0.28g (2.6
mmol)のTHF(10ml)溶液に室温でN,N' In THF mmol) (10ml) N at room temperature to a solution, N '
−カルボニルジイミダゾール0.42g(2.4mmo - carbonyldiimidazole 0.42g (2.4mmo
l)を加え、1時間攪拌した。 l) was added, and the mixture was stirred for 1 hour. この溶液に室温で実施例1の工程(1−4)で得られた化合物0.58g(1. Compound obtained in this room temperature of Example 1, step a solution (1-4) 0.58g (1.
8mmol)を加え、3時間攪拌した後、一晩放置した。 8 mmol) and the mixture was stirred for 3 hours and left overnight.

【0254】水を加え希釈した後、酢酸エチルで抽出した。 [0254] After water was added diluted, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た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−メタノール=10:1)で精製して、N− The organic layer was washed with saturated brine, dried and the solvent silica residue obtained by distilling off the gel column chromatography (ethyl acetate - methanol = 10: 1) to give, N-
[2−(N−tert−ブトキシカルボニル)アミノ] [2- (N-tert- butoxycarbonyl) amino]
フェニル−4−[N'−(ピリジン−3−イルメチル) Phenyl -4- [N '- (pyridin-3-ylmethyl)
ウレイドメチル]ベンズアミド0.77g(収率90 Ureidomethyl] benzamide 0.77 g (yield: 90
%)を白色アモルファス状固体として得た。 %) As a white amorphous solid. 1H NMR(270MHz, CDCl3)δppm: 1.46(9H,s), 4.20(2H,d, 1H NMR (270MHz, CDCl3) δppm: 1.46 (9H, s), 4.20 (2H, d,
J=5.1Hz), 4.28(2H,d,J=4.3Hz), 6.10-6.30(2H,m), 7.0 J = 5.1Hz), 4.28 (2H, d, J = 4.3Hz), 6.10-6.30 (2H, m), 7.0
0-7.25(4H,m), 7.33(1H,d,J=7.3Hz), 7.49-7.54(2H,m), 0-7.25 (4H, m), 7.33 (1H, d, J = 7.3Hz), 7.49-7.54 (2H, m),
7.58-7.64(3H,m), 7.75(1H,s), 8.28(1H,br.s), 8.39 7.58-7.64 (3H, m), 7.75 (1H, s), 8.28 (1H, br.s), 8.39
(1H,d,J=5.1Hz), 9.65(1H,br.s). (1H, d, J = 5.1Hz), 9.65 (1H, br.s).

【0255】(89−2) 工程(89−1)で得た化合物0.63g(1.32mmol)のジオキサン(4 [0255] (89-2) in dioxane step (89-1) the compound obtained in 0.63 g (1.32 mmol) (4
ml)−メタノール(2ml)溶液に4規定塩酸−ジオキサン(4ml)を加え、室温2時間で攪拌した。 ml) - methanol (2 ml) was added 4N hydrochloric acid - dioxane (4 ml) was added, followed by stirring at room temperature for 2 hours. 飽和重曹水を加えた後、酢酸エチル−メチルエチルケトンで抽出した。 After addition of saturated aqueous sodium bicarbonate solution, ethyl acetate - it was extracted with methyl ethyl ketone. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た残渣をジイソプロピルエーテルで洗浄することにより、N−(2−アミノフェニル)−4−[N' The organic layer was washed with saturated brine, dried, and the residue obtained by distilling off the solvent and washed with diisopropyl ether, N-(2-aminophenyl) -4- [N '
−(ピリジン−3−イルメチル)ウレイドメチル]ベンズアミド0.37g(収率74.7%)を褐色固体として得た。 - (pyridin-3-ylmethyl) ureidomethyl] benzamide 0.37 g (74.7% yield) as a brown solid.

【0256】mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.27(2H,d,J=5.9Hz), .. [0256] mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 5.9Hz),
4.31(2H,d,J=5.9Hz), 4.89(2H,br.s), 6.57-6.63(3H, 4.31 (2H, d, J = 5.9Hz), 4.89 (2H, br.s), 6.57-6.63 (3H,
m), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), m), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.17(1H,d,J=7.3Hz), 7.32-7.38(3H,m), 7.66(1H,d,J= 7.17 (1H, d, J = 7.3Hz), 7.32-7.38 (3H, m), 7.66 (1H, d, J =
8.1Hz), 7.93(2H,d,J=8.1Hz), 8.44(1H,d,J=5.1Hz), 8. 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.44 (1H, d, J = 5.1Hz), 8.
49(1H,d,J=2.1Hz), 9.63(1H,br.s). IR(KBr)cm-1: 3344,3241,1645,1560,1527,1505,1283,75 49 (1H, d, J = 2.1Hz), 9.63 (1H, br.s) IR (KBr) cm-1:. 3344,3241,1645,1560,1527,1505,1283,75
1,708. 1,708.

【0257】実施例89と同様の方法により、実施例9 [0257] the same manner as in Example 89, Example 9
0から実施例95の化合物を合成した。 0 to synthesize a compound of Example 95 from. 以下に、化合物の融点(mp.)、1H NMR、IRの測定値を示す。 Hereinafter, the melting point of the compound (mp.), 1H NMR, shows the measurements of IR.

【0258】実施例90 N−(2−アミノフェニル)−4−[N'−(3−アミノフェニル)ウレイドメチル]ベンズアミド(表−1: [0258] Example 90 N-(2-aminophenyl) -4- [N '- (3- aminophenyl) ureidomethyl] benzamide (Table 1:
化合物番号24) mp. 206-208℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.35(2H,d,J=5.9Hz), . Compound No. 24) mp 206-208 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.35 (2H, d, J = 5.9Hz),
4.93(4H,br.s), 6.13(1H,d,J=7.3Hz), 6.51-6.62(3H, 4.93 (4H, br.s), 6.13 (1H, d, J = 7.3Hz), 6.51-6.62 (3H,
m), 6.74-6.98(3H,m), 7.12-7.18(1H,m), 7.41(2H,d,J= m), 6.74-6.98 (3H, m), 7.12-7.18 (1H, m), 7.41 (2H, d, J =
8.1Hz), 7.94(2H,d,J=8.1Hz), 8.28(1H,s), 9.61(1H, 8.1Hz), 7.94 (2H, d, J = 8.1Hz), 8.28 (1H, s), 9.61 (1H,
s). IR(KBr)cm-1:3356,3269,1640,1555,1495,1458,1308,123 . S) IR (KBr) cm-1: 3356,3269,1640,1555,1495,1458,1308,123
6,753. 6,753.

【0259】実施例91 N−(2−アミノフェニル)−4−[N'−(ピリジン−3−イル)ウレイドメチル]ベンズアミド(表−1: [0259] Example 91 N-(2-aminophenyl) -4- [N '- (pyridin-3-yl) ureidomethyl] benzamide (Table 1:
化合物番号87) mp. 187-190℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.39(2H,d,J=5.9Hz), .. Compound No. 87) mp 187-190 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.39 (2H, d, J = 5.9Hz),
4.89(2H,br.s), 6.59(1H,d,J=7.3,7.3Hz), 6.77(1H,d,J 4.89 (2H, br.s), 6.59 (1H, d, J = 7.3,7.3Hz), 6.77 (1H, d, J
=6.6Hz), 6.88(1H,t,J=5.9Hz), 6.97(1H,ddd,J=1.5,6. = 6.6Hz), 6.88 (1H, t, J = 5.9Hz), 6.97 (1H, ddd, J = 1.5,6.
6,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.26(1H,dd,J=4.4,8.1 6,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.26 (1H, dd, J = 4.4,8.1
Hz), 7.42(2H,d,J=8.8Hz), 7.95(2H,d,J=8.1Hz), 7.89- Hz), 7.42 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.1Hz), 7.89-
7.96(1H,m), 8.12(1H,dd,J=1.5,4.4Hz), 8.56(1H,d,J= 7.96 (1H, m), 8.12 (1H, dd, J = 1.5,4.4Hz), 8.56 (1H, d, J =
3.0Hz), 8.85(1H,s), 9.62(1H,s). IR(KBr)cm-1: 3248,1663,1541,1423,1280,1054. . 3.0Hz), 8.85 (1H, s), 9.62 (1H, s) IR (KBr) cm-1: 3248,1663,1541,1423,1280,1054.

【0260】実施例92 N−(2−アミノフェニル)−4−[N'−(3−アミノフェニル)チオウレイドメチル]ベンズアミド(表− [0260] Example 92 N-(2-aminophenyl) -4- [N '- (3- aminophenyl) thioureido methyl] benzamide (Table -
1:化合物番号25) mp. 123℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.80(2H,d,J=5.1Hz), 1:. Compound No. 25) mp 123 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.80 (2H, d, J = 5.1Hz),
4.87(2H,s), 5.12(2H,s), 6.36(1H,dd,J=1.5,8.1Hz), 4.87 (2H, s), 5.12 (2H, s), 6.36 (1H, dd, J = 1.5,8.1Hz),
6.48-6.63(3H,m), 6.78(1H,d,J=6.6Hz), 6.94-7.00(2H, 6.48-6.63 (3H, m), 6.78 (1H, d, J = 6.6Hz), 6.94-7.00 (2H,
m), 7.17(1H,d,J=8.1Hz), 7.42(2H,d,J=8.1Hz), 7.92- m), 7.17 (1H, d, J = 8.1Hz), 7.42 (2H, d, J = 8.1Hz), 7.92-
8.01(3H,m), 9.46(1H,s), 9.61(1H,s). IR(KBr)cm-1: 3335,1616,1528,1503,1456,1311,864,75 8.01 (3H, m), 9.46 (1H, s), 9.61 (1H, s) IR (KBr) cm-1:. 3335,1616,1528,1503,1456,1311,864,75
1. 1.

【0261】実施例93 N−(2−アミノフェニル)−4−[N'−(3−ニトロフェニル)チオウレイドメチル]ベンズアミド(表− [0261] Example 93 N-(2-aminophenyl) -4- [N '- (3- nitrophenyl) thioureido methyl] benzamide (Table -
1:化合物番号20) mp. 160℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.87(2H,d,J=5.1Hz), 1:. Compound No. 20) mp 160 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.87 (2H, d, J = 5.1Hz),
7.27-7.33(3H,m), 7.46-7.63(5H,m), 7.89-7.95(2H,m), 7.27-7.33 (3H, m), 7.46-7.63 (5H, m), 7.89-7.95 (2H, m),
8.05(2H,d,J=8.1Hz), 8.70(1H,s), 8.84(1H,t,J=8.9H 8.05 (2H, d, J = 8.1Hz), 8.70 (1H, s), 8.84 (1H, t, J = 8.9H
z), 10.37(1H,s). z), 10.37 (1H, s).

【0262】実施例94 N−(2−アミノ−5−フロロフェニル)−4−[N' [0262] Example 94 N-(2-amino-5-fluorophenyl) -4- [N '
−(ピリジン−3−イル)メチルウレイドメチル]ベンズアミド(表−1:化合物番号112) mp. (amorphous). 1H-NMR(270MHz, DMSO-d6):4.77(4H,d,J=5.1Hz), 4.85 - (pyridin-3-yl) methyl ureido methyl] benzamide.. (Table 1: Compound No. 112) mp (amorphous) 1H-NMR (270MHz, DMSO-d6): 4.77 (4H, d, J = 5.1Hz) , 4.85
(2H,s), 6.81(2H,m), 7.16(1H,dd,J=2.9,10.3Hz), 7.39 (2H, s), 6.81 (2H, m), 7.16 (1H, dd, J = 2.9,10.3Hz), 7.39
(1H,dd,J=5.1,8.1Hz), 7.53(2H,d,J=8.1Hz), 7.81(1H, (1H, dd, J = 5.1,8.1Hz), 7.53 (2H, d, J = 8.1Hz), 7.81 (1H,
d,J=8.1Hz), 7.93(2H,d,J=8.1Hz), 8.51(1H,dd,J=1.5, d, J = 8.1Hz), 7.93 (2H, d, J = 8.1Hz), 8.51 (1H, dd, J = 1.5,
5.1Hz), 8.62(1H,d,J=1.5Hz), 9.66(1H,s). IR(KBr)cm-1: 3399,1730,1638,1508,1444,1411. . 5.1Hz), 8.62 (1H, d, J = 1.5Hz), 9.66 (1H, s) IR (KBr) cm-1: 3399,1730,1638,1508,1444,1411.

【0263】実施例95 N−(2−ヒドロキシフェニル)−4−[N'−(ピリジン−3−イル)メチルウレイドメチル]ベンズアミド(表−1:化合物番号114) mp. (amorphous). 1H-NMR(270MHz, DMSO-d6):4.43(2H,d,J=6.6Hz), 4.69 [0263] Example 95 N-(2-hydroxyphenyl) -4- [N '- (pyridin-3-yl) methyl ureido methyl] benzamide (Table 1: Compound No. 114) mp (amorphous) 1H-.. NMR (270MHz, DMSO-d6): 4.43 (2H, d, J = 6.6Hz), 4.69
(2H,s), 6.83(1H,t,J=6.6Hz), 6.91(1H,d,J=8.1Hz), 7. (2H, s), 6.83 (1H, t, J = 6.6Hz), 6.91 (1H, d, J = 8.1Hz), 7.
68(1H,d,J=6.6Hz), 7.82(2H,d,J=8.1Hz), 8.21(1H,d,J= 68 (1H, d, J = 6.6Hz), 7.82 (2H, d, J = 8.1Hz), 8.21 (1H, d, J =
4.4Hz), 8.35(1H,d,J=2.2Hz), 8.81(1H,t,J=6.6Hz), 9. 4.4Hz), 8.35 (1H, d, J = 2.2Hz), 8.81 (1H, t, J = 6.6Hz), 9.
48(1H,s), 9.75(1H,s). IR(KBr)cm-1: 3399,1664,1535,1236,1064. 48 (1H, s), 9.75 (1H, s) IR (KBr) cm-1:. 3399,1664,1535,1236,1064.

【0264】実施例96 N−(2−アミノフェニル)−4−[2−[N−(ピリジン−3−イル)アセチルアミノ]エチル]ベンズアミド(表−1:化合物番号77)の合成 (96−1) テレフタルアルデヒド酸3.40g(2 Synthesis of (Compound No. 77 Table 1) (96 [0264] Example 96 N-(2-aminophenyl) -4- [2- [N- (pyridin-3-yl) acetylamino] ethyl] benzamide 1) terephthalic aldehyde acid 3.40g (2
2.6mmol)のトルエン(25ml)懸濁液にチオニルクロライド(4ml)を加え、80℃で2時間加熱攪拌した。 2.6 mmol) toluene (25 ml) suspension thionyl chloride (4 ml) were added and heated for 2 hours stirring at 80 ° C.. 放冷後、溶媒を留去し得られた残渣をTHF After cooling, THF solvent was removed by distillation, and the residue
(50ml)に溶解し、酸クロライドを調製した。 It was dissolved in (50 ml), thereby preparing an acid chloride. 実施例1の工程(1−2)の化合物4.16g(20.0m Compound of step of Example 1 (1-2) 4.16g (20.0m
mol)のTHF(10ml)溶液にトリエチルアミン(6ml,42.8mmol)を加え、さらに先に調製した酸クロライドを氷冷下30分かけて滴下した。 Triethylamine (6 ml, 42.8 mmol) was added to THF (10 ml) solution of mol), further acid chloride prepared above was added dropwise over 30 minutes under ice-cooling.

【0265】5時間攪拌後、飽和重曹水を加え、酢酸エチルで抽出した。 [0265] After stirring for 5 hours, saturated aqueous sodium bicarbonate solution was added, and extracted with ethyl acetate. 有機層を飽和食塩水洗浄後、乾燥、溶媒を留去して得られた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→クロロホルム:酢酸エチル=10:1)で精製し、N−[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−ホルミルベンズアミド3.42g(収率50.2%)を淡褐色固体として得た。 After washed with saturated brine and the organic layer was dried, the residue obtained by distilling off the solvent by silica gel column chromatography (chloroform → chloroform: ethyl acetate = 10: 1) to give, N-[2-(N- tert- butoxycarbonyl) aminophenyl] -4-formyl benzamide 3.42g of (50.2% yield) as a light brown solid. 1H NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 6.77(1H,b 1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 6.77 (1H, b
rs), 7.16-7.18(2H,m),7.23-7.26(1H,m), 7.88(1H,d,J rs), 7.16-7.18 (2H, m), 7.23-7.26 (1H, m), 7.88 (1H, d, J
=8.8Hz), 7.98(2H,d,J=8.8Hz), 8.13(2H,d,J=8.8Hz), = 8.8Hz), 7.98 (2H, d, J = 8.8Hz), 8.13 (2H, d, J = 8.8Hz),
9.57(1H,br.s), 10.11(1H,br.s). IR(KBr)cm-1: 3326,3251,1707,1696,1659,1603,1165. 9.57 (1H, br.s), 10.11 (1H, br.s) IR (KBr) cm-1:. 3326,3251,1707,1696,1659,1603,1165.

【0266】(96−2) 工程(96−1)で得られた化合物3.0g(8.82mmol)およびエトキシカルボニルメチルトリフェニルホスフィン4.5g(1 [0266] (96-2) Step (96-1) the compound obtained in 3.0 g (8.82 mmol) and ethoxycarbonylmethyl triphenylphosphine 4.5 g (1
2.9mmol)のトルエン(10ml)懸濁液を窒素気流下80℃で、5.5時間攪拌した。 Toluene (10ml) suspension of 2.9 mmol) at 80 ° C. under a nitrogen stream, and stirred for 5.5 hours. 放冷後、酢酸エチルで希釈した後、飽和重曹水、水、飽和食塩水で洗浄し、乾燥した。 After cooling, diluted with ethyl acetate, saturated aqueous sodium bicarbonate solution, washed with water and saturated brine and dried. 溶媒を留去して得られた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:酢酸エチル=20:1)で精製し、エチル 4−[N−[2− The solvent was evaporated and the resultant residue using silica gel column chromatography (chloroform: ethyl acetate = 20: 1) to give ethyl 4- [N- [2-
(N−tert−ブトキシカルボニル)アミノフェニル]アミノカルボニル]シンナメート3.3g(収率9 (N-tert-butoxycarbonyl) aminophenyl] aminocarbonyl] cinnamate 3.3 g (yield: 9
1.1%)を黄色アモルファス状固体として得た。 1.1%) as a yellow amorphous solid. 1H NMR(270MHz, CDCl3)δppm: 1.35(3H,t,J=7.3Hz), 1. 1H NMR (270MHz, CDCl3) δppm: 1.35 (3H, t, J = 7.3Hz), 1.
52(9H,s), 4.28(2H,q,J=7.3Hz), 6.52(1H,d,J=15.1Hz), 52 (9H, s), 4.28 (2H, q, J = 7.3Hz), 6.52 (1H, d, J = 15.1Hz),
6.80(1H,br.s), 7.16-7.25(3H,m), 7.61(2H,d,J=8.1H 6.80 (1H, br.s), 7.16-7.25 (3H, m), 7.61 (2H, d, J = 8.1H
z), 7.71(1H,d,J=15.1Hz), 7.82(1H,d,7.3Hz), 7.98(2 z), 7.71 (1H, d, J = 15.1Hz), 7.82 (1H, d, 7.3Hz), 7.98 (2
H,d,J=8.1Hz), 9.34(1H,br.s). H, d, J = 8.1Hz), 9.34 (1H, br.s).

【0267】(96−3) 工程(96−2)で得られた化合物2.50g(6.09mmol)のTHF(3 [0267] (96-3) THF step (96-2) the compound obtained in 2.50 g (6.09 mmol) (3
0ml)−メタノール(40ml)溶液に窒素気流下1 0 ml) - under nitrogen flow 1 in methanol (40 ml) solution
0%Pd/C(含水,0.5g)を加えた後、水素気流下30分間攪拌した。 0% Pd / C (hydrous, 0.5 g) was added, followed by stirring hydrogen stream for 30 minutes. 窒素置換した後、触媒を濾過した。 After purged with nitrogen, the catalyst was filtered. 濾液の溶媒を留去して得た残渣にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することによりN−[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−(2−エトキシカルボニルエチル)ベンズアミド2.23g(収率88.8%)を白色固体として得た。 Diisopropyl ether was added to the residue obtained by distilling off the solvent of the filtrate, the precipitated solid was collected by filtration and dried N- [2- (N-tert- butoxycarbonyl) aminophenyl] -4- (2- ethoxycarbonylethyl) benzamide 2.23g of (88.8% yield) as a white solid. 1H NMR(270MHz, CDCl3)δppm: 1.25(3H,t,J=7.3Hz), 1. 1H NMR (270MHz, CDCl3) δppm: 1.25 (3H, t, J = 7.3Hz), 1.
52(9H,s), 2.65(2H,t,J=7.3Hz), 3.02(2H,t,J=7.3Hz), 52 (9H, s), 2.65 (2H, t, J = 7.3Hz), 3.02 (2H, t, J = 7.3Hz),
4.13(2H,q,J=7.3Hz), 6.77(1H,br.s), 7.16-7.33(5H, 4.13 (2H, q, J = 7.3Hz), 6.77 (1H, br.s), 7.16-7.33 (5H,
m), 7.78(1H,d,J=8.1Hz), 7.89(2H,d,J=8.8Hz), 9.06(1 m), 7.78 (1H, d, J = 8.1Hz), 7.89 (2H, d, J = 8.8Hz), 9.06 (1
H,br.s). H, br.s).

【0268】(96−4) 工程(96−3)で得られた化合物2.21g(5.36mmol)のメタノール(10ml)−水(15ml)懸濁液に水酸化リチウム1水和物0.37g(8.82mmol)を加え、40 [0268] (96-4) methanol Step compound obtained in (96-3) 2.21 g (5.36 mmol) (10 ml) - water (15ml) suspension of lithium hydroxide monohydrate zero. 37g (8.82mmol) was added, 40
℃で3時間攪拌した。 3 hours and the mixture was stirred at ℃. 放冷後10%塩酸水溶液を加え、 10% hydrochloric acid solution was added after cooling,
酢酸エチルで抽出した。 And extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、 The organic layer was washed with saturated brine,
乾燥、溶媒を留去して得られた残渣にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、N−[2−(N−tert−ブトキシカルボニル) Dried and the solvent was distilled off and diisopropyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried, N- [2- (N-tert- butoxycarbonyl)
アミノフェニル]−4−(2−カルボキシエチル)ベンズアミド1.87g(収率90.8%)を白色固体として得た。 Aminophenyl] -4- (2-carboxyethyl) benzamide 1.87g of (yield 90.8%) as a white solid. 1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 2.59(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 2.59 (2H,
t,J=7.3Hz), 2.91(2H,t,J=7.3Hz), 7.13-7.20(2H,m), t, J = 7.3Hz), 2.91 (2H, t, J = 7.3Hz), 7.13-7.20 (2H, m),
7.40(2H,d,J=8.1Hz), 7.54(2H,dd,J=7.3,2.1Hz),7.88(2 7.40 (2H, d, J = 8.1Hz), 7.54 (2H, dd, J = 7.3,2.1Hz), 7.88 (2
H,d,J=8.1Hz), 8.66(1H,br.s), 9.79(1H,br.s). H, d, J = 8.1Hz), 8.66 (1H, br.s), 9.79 (1H, br.s).

【0269】(96−5) 工程(96−4)で得られた化合物0.12g(0.3mmol)のベンゼン(5 [0269] (96-5) benzene in step (96-4) the compound obtained in 0.12 g (0.3 mmol) (5
ml)懸濁液にトリエチルアミン0.1ml(0.7m ml) suspension of triethylamine 0.1 ml (0.7 m
mol)およびモレキュラーシーブ4A0.3gを加え、窒素気流下0.5時間攪拌した。 mol) and molecular sieves 4A0.3g and the mixture was stirred under a nitrogen stream for 0.5 hours. この溶液にジフェニルホスホリルアジド0.15ml(0.7mmol) To this solution diphenylphosphoryl azide 0.15 ml (0.7 mmol)
を加え、2時間加熱還流した。 The mixture was heated under reflux for 2 hours. 放冷後、ベンジルアルコール0.4ml(3.8mmol)を加え、さらに2. After cooling, benzyl alcohol 0.4 ml (3.8 mmol) was added, further 2.
5時間加熱還流した。 5 was hours heated to reflux. 酢酸エチルで希釈した後、水、飽和食塩水で洗浄した。 After dilution with ethyl acetate and washed with water and saturated brine.

【0270】有機層を乾燥後、溶媒を留去して得られた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:酢酸エチル=4:1)で精製することにより、N [0270] The organic layer was dried, evaporated and the resultant residue using silica gel column chromatography solvent (chloroform: ethyl acetate = 4: 1) to give, N
−[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−[2−(N−ベンジルオキシカルボニルアミノ)エチル]ベンズアミド129mg(88%) - [2- (N-tert- butoxycarbonyl) aminophenyl] -4- [2- (N- benzyloxycarbonylamino) ethyl] benzamide 129 mg (88%)
を無色油状物として得た。 As a colorless oil. 1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 2.89(2H,t, 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 2.89 (2H, t,
J=7.3Hz), 3.45-3.54(2H,m), 4.80(1H,m), 5.10(2H,s), J = 7.3Hz), 3.45-3.54 (2H, m), 4.80 (1H, m), 5.10 (2H, s),
6.76(1H,br.s), 7.20-7.38(10H,m), 7.79(1H,d,J=8.8H 6.76 (1H, br.s), 7.20-7.38 (10H, m), 7.79 (1H, d, J = 8.8H
z), 7.89(2H,d,J=8.1Hz), 9.10(1H,br.s). z), 7.89 (2H, d, J = 8.1Hz), 9.10 (1H, br.s).

【0271】(96−6) 工程(96−5)で得られた化合物129mg(0.26mmol)のメタノール(10ml)溶液に窒素気流下10%Pd/C(含水, [0271] (96-6) Step (96-5) in the resulting compound 129 mg (0.26 mmol) of methanol (10ml) was added under a nitrogen flow 10% Pd / C (hydrous,
0.05g)を加え、水素気流下2時間攪拌した。 0.05 g) and the mixture was stirred hydrogen stream under 2 hours. 触媒を留去した後、乾燥することにより得られた残渣をジクロロメタン(5ml)に溶解した。 After distilling off the catalyst, the residue obtained by drying was dissolved in dichloromethane (5 ml). この溶液に3−ピリジン酢酸塩酸塩0.18g(1.04mmol)を加え、さらにトリエチルアミン0.28g(2.0mmo To the solution of 3-pyridine acetic acid hydrochloride 0.18 g (1.04 mmol) was added, further triethylamine 0.28g (2.0mmo
l)を加えて氷冷した。 Ice-cold by the addition of l). 氷冷下、2−クロロ−1,3− Under ice-cooling, 2-chloro-1,3
ジメチルイミダゾリニウムクロライド0.17g(1. Dimethyl imidazolinium chloride 0.17 g (1.
0mmol)を加え、2時間攪拌した。 0 mmol) and the mixture was stirred for 2 hours. 飽和重曹水を加えた後、クロロホルムで抽出した。 After addition of saturated aqueous sodium bicarbonate solution and extracted with chloroform. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た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:メタノール= The organic layer was washed with saturated brine, dried, evaporated to give residue was purified by silica gel column chromatography (ethyl acetate: methanol =
10:1)で精製することにより、N−[2−(N−t 10: purified by 1), N- [2- (N-t
ert−ブトキシカルボニル)アミノフェニル]−4− ert- butoxycarbonyl) aminophenyl] -4-
[2−[N−(ピリジン−3−イル)アセチルアミノ] [2- [N- (pyridin-3-yl) acetylamino]
エチル]ベンズアミド50mg(収率40%)を無色油状物として得た。 Ethyl] benzamide 50mg (40% yield) as a colorless oil.

【0272】1H NMR(270MHz, CDCl3)δppm: 1.48(9H, [0272] 1H NMR (270MHz, CDCl3) δppm: 1.48 (9H,
s), 2.80(2H,t,J=6.6Hz), 3.42(2H,m),3.52(2H,s), 6.3 s), 2.80 (2H, t, J = 6.6Hz), 3.42 (2H, m), 3.52 (2H, s), 6.3
3(1H,t-like,J=5.9Hz), 7.09(2H,d,J=8.1Hz), 7.14-7.2 3 (1H, t-like, J = 5.9Hz), 7.09 (2H, d, J = 8.1Hz), 7.14-7.2
0(2H,m), 7.24(1H,dd,J=4.4,7.3Hz), 7.41(1H,dd,J=3. 0 (2H, m), 7.24 (1H, dd, J = 4.4,7.3Hz), 7.41 (1H, dd, J = 3.
7,5.9Hz), 7.50(1H,s), 7.58(1H,dd,J=1.5,5.9Hz), 7.6 7,5.9Hz), 7.50 (1H, s), 7.58 (1H, dd, J = 1.5,5.9Hz), 7.6
9(1H,dd,J=3.7,5.9Hz), 7.75(2H,d,J=8.1Hz), 8.22(1H, 9 (1H, dd, J = 3.7,5.9Hz), 7.75 (2H, d, J = 8.1Hz), 8.22 (1H,
d,J=2.1Hz), 8.44(1H,dd,J=1.5,4.4Hz), 9.49(1H,br. d, J = 2.1Hz), 8.44 (1H, dd, J = 1.5,4.4Hz), 9.49 (1H, br.
s). s).

【0273】(96−7) 工程(96−6)の化合物50mg(0.10mmol)のジオキサン(2ml) [0273] (96-7) Step compound of (96-6) 50 mg dioxane (0.10 mmol) (2 ml)
−メタノール(1ml)溶液に4規定塩酸−ジオキサン(2ml)を加え、室温で2.5時間攪拌した。 - methanol (1 ml) was added 4N hydrochloric acid - dioxane (2 ml) was added, followed by stirring at room temperature for 2.5 hours. 飽和重曹水を加えた後、酢酸エチルで抽出した。 After addition of saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣を乾燥することにより、N−(2−アミノフェニル)−4 The organic layer was washed with saturated brine, dried, and drying the residue obtained by distilling off the solvent, N-(2-aminophenyl) -4
−[2−[N−(ピリジン−3−イル)アセチルアミノ]エチル]ベンズアミド22mg(収率59%)をアモルファス状固体として得た。 - a [2- [N- (pyridin-3-yl) acetylamino] ethyl] benzamide 22 mg (59% yield) as an amorphous solid.

【0274】mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 2.70-2.90(4H,m), 3.4 .. [0274] mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 2.70-2.90 (4H, m), 3.4
2(2H,s), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 2 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz),
6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=7.3,7.3Hz),7.16(1 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.16 (1
H,d,J=7.3Hz), 7.29-7.32(3H,m), 7.59(1H,d,J=8.1Hz), H, d, J = 7.3Hz), 7.29-7.32 (3H, m), 7.59 (1H, d, J = 8.1Hz),
7.89(1H,d,J=8.1Hz), 8.22(1H,t-like), 8.41-8.43(2 7.89 (1H, d, J = 8.1Hz), 8.22 (1H, t-like), 8.41-8.43 (2
H,m), 9.62(1H,br.s). H, m), 9.62 (1H, br.s).

【0275】実施例97 N−(2−アミノフェニル)−4−[2−[N−(3− [0275] Example 97 N-(2-aminophenyl) -4- [2- [N- (3-
ピコリル)アミノカルボニル]エチル]ベンズアミド(表−1:化合物番号80)の合成 (97−1) 実施例96の工程(96−4)で得られた化合物0.58g(1.5mmol)のジクロロメタン(5ml)懸濁液に、3−ピコリルアミン0.22g Picolyl) aminocarbonyl] ethyl] benzamide (Table 1: dichloromethane compound obtained in (97-1) step of Example 96 (96-4) of Compound No. 80) 0.58 g (1.5 mmol) ( to 5ml) suspension of 3- picolylamine 0.22g
(2.0mmol)およびトリエチルアミン0.56m (2.0mmol) and triethylamine 0.56m
l(4.0mmol)を加えた。 It was added to the l (4.0mmol). 氷冷下、2−クロロ− Under ice-cooling, 2-chloro -
1,3−ジメチルイミダゾリニウムクロライド0.39 1,3-dimethyl imidazolinium chloride 0.39
g(2.0mmol)のジクロロメタン(5ml)溶液を加え、1.5時間攪拌した。 Dichloromethane (5ml) solution of g (2.0 mmol) was added and stirred for 1.5 hours. 飽和重曹水を加えた後、 After adding a saturated aqueous solution of sodium bicarbonate,
クロロホルムで抽出した。 And extracted with chloroform.

【0276】有機層を水、飽和食塩水で洗浄後、乾燥、 [0276] The organic layer was washed with water and brine, dried,
溶媒を留去して得られた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:アンモニア水=100:10:1)で精製することにより、N− The solvent was evaporated and the resultant residue using silica gel column chromatography (chloroform: methanol: aqueous ammonia = 100: 10: 1) to give, N-
[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−[2−[N−(3−ピコリル)アミノカルボニル]エチル]ベンズアミド0.71g(収率94 [2- (N-tert- butoxycarbonyl) aminophenyl] -4- [2- [N- (3- picolyl) amino carbonyl] ethyl] benzamide 0.71 g (yield: 94
%)を淡褐色油状物として得た。 %) As a pale brown oil. 1H NMR(270MHz, CDCl3)δppm: 1.45(9H,s), 2.42(2H,t, 1H NMR (270MHz, CDCl3) δppm: 1.45 (9H, s), 2.42 (2H, t,
J=7.3Hz), 2.98(2H,t,J=7.3Hz), 4.32(2H,d,J=6.6Hz), J = 7.3Hz), 2.98 (2H, t, J = 7.3Hz), 4.32 (2H, d, J = 6.6Hz),
6.44(1H,t,J=6.6Hz), 7.14-7.27(5H,m), 7.48-7.57(3H, 6.44 (1H, t, J = 6.6Hz), 7.14-7.27 (5H, m), 7.48-7.57 (3H,
m), 7.63-7.68(3H,m), 7.90(1H,d,J=2.1Hz), 8.43(1H,d m), 7.63-7.68 (3H, m), 7.90 (1H, d, J = 2.1Hz), 8.43 (1H, d
d,J=1.4,4.4Hz),9.86(1H,br.s). d, J = 1.4,4.4Hz), 9.86 (1H, br.s).

【0277】(97−2) 工程(97−1)の化合物0.70g(1.47mmol)のジオキサン(5m [0277] (97-2) in dioxane step (97-1) Compound 0.70g of (1.47 mmol) (5 m
l)溶液に4規定塩酸−ジオキサン(5ml)を加え、 l) was added 4N hydrochloric acid - dioxane (5ml) was added,
さらにメタノール(2ml)を加えて室温で2時間攪拌した。 It was stirred at room temperature for 2 hours and further addition of methanol (2 ml). 飽和重曹水を加えた後、酢酸エチルで抽出した。 After addition of saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate.
有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、N−(2−アミノフェニル)−4−[2−[N−(3−ピコリル)アミノカルボニル]エチル]ベンズアミド0.42g(収率7 The organic layer was washed with saturated brine, dried, evaporated and diisopropyl ether was added to the resulting residue, and the precipitated solid was collected by filtration and dried, N-(2-aminophenyl) -4 - [2- [N- (3- picolyl) amino carbonyl] ethyl] benzamide 0.42 g (yield: 7
6.3%)を乳白色固体として得た。 6.3%) was obtained as an off-white solid.

【0278】mp. 168-170℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.47-2.53(2H,m), 2.9 .. [0278] mp 168-170 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.47-2.53 (2H, m), 2.9
3(2H,t,J=7.3Hz), 4.27(2H,d,J=5.9Hz), 4.90(2H,br. 3 (2H, t, J = 7.3Hz), 4.27 (2H, d, J = 5.9Hz), 4.90 (2H, br.
s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1Hz), s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1Hz),
6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=6.6Hz), 7.28- 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 6.6Hz), 7.28-
7.35(1H,m), 7.33(2H,d,J=8.1Hz), 7.49(1H,dd,J=2.1, 7.35 (1H, m), 7.33 (2H, d, J = 8.1Hz), 7.49 (1H, dd, J = 2.1,
5.9Hz), 7.89(2H,d,J=8.1Hz), 8.39-8.44(3H,m), 9.62 5.9Hz), 7.89 (2H, d, J = 8.1Hz), 8.39-8.44 (3H, m), 9.62
(1H,br.s). IR(KBr)cm-1: 3313,1641,1523,1457,1300,748,713. . (1H, br.s) IR (KBr) cm-1: 3313,1641,1523,1457,1300,748,713.

【0279】実施例98 N−(2−アミノフェニル)−4−[(ピリジン−3− [0279] Example 98 N-(2-aminophenyl) -4 - [(pyridin-3
イル)メチルアミノカルボニルオキシメチル]ベンズアミド(表−1:化合物番号85)の合成 (98−1) メチル 4−ヒドロキシメチルベンゾエート1.99g(12.0mmol)のTHF(20m Yl) methylaminocarbonyl oxymethyl] benzamide (Table -1: THF Synthesis of Compound No. 85) (98-1) Methyl 4-hydroxymethyl benzoate 1.99 g (12.0 mmol) (20 m
l)溶液に室温でN,N'−カルボニルジイミダゾール1.78g(11.0mmol)を加え、1時間攪拌した。 N, N'-carbonyl diimidazole 1.78g of (11.0 mmol) was added at room temperature l) solution and stirred 1 hour. この溶液に室温で3−ピコリルアミン1.08g To the solution at room temperature 3-picolylamine 1.08g
(10.0mmol)を加え、3.5時間攪拌した後、 The (10.0 mmol) was added and after stirring for 3.5 hours,
一晩放置した。 It was allowed to stand overnight. これに水を加え希釈した後、酢酸エチルで抽出した。 After dilution by adding water thereto, and extracted with ethyl acetate.

【0280】有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得た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)で精製して、N−(4−メトキシカルボニル)ベンジルオキシカルボニル−3−ピコリルアミン2.76g(収率91.9%)を白色ワックス状固体として得た。 [0280] The organic layer was washed with saturated brine, dried, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (ethyl acetate), N-(4-methoxycarbonyl) benzyloxycarbonyl - 3-picolylamine 2.76g of (91.9% yield) as a white waxy solid. 1H NMR(270MHz, CDCl3)δppm: 3.91(3H,s), 4.40(2H,d, 1H NMR (270MHz, CDCl3) δppm: 3.91 (3H, s), 4.40 (2H, d,
J=5.9Hz), 5.18(2H,s),5.50(1H,br.s), 7.24-7.28(1H, J = 5.9Hz), 5.18 (2H, s), 5.50 (1H, br.s), 7.24-7.28 (1H,
m), 7.40(2H,d,J=8.1Hz), 7.65(1H,d,J=7.3Hz),8.02(2 m), 7.40 (2H, d, J = 8.1Hz), 7.65 (1H, d, J = 7.3Hz), 8.02 (2
H,d,J=8.8Hz), 8.50-8.53(2H,m). H, d, J = 8.8Hz), 8.50-8.53 (2H, m).

【0281】(98−2) 工程(98−1)の化合物2.40g(8.0mmol)のメタノール(10m [0281] (98-2) methanol of step (98-1) Compound 2.40g of (8.0 mmol) (10 m
l)−水(20ml)懸濁液に、水酸化リチウム1水和物0.42g(10.0mmol)を加え、室温で5時間攪拌した。 l) - water (20ml) suspension of lithium hydroxide monohydrate 0.42g of (10.0 mmol) was added, followed by stirring at room temperature for 5 hours. 10%塩酸水溶液を加え、酸性(pH2〜 10% hydrochloric acid solution was added, acidic (PH2~
4)にした後、析出した固体を濾取、乾燥することにより、N−(4−カルボキシ)ベンジルオキシカルボニル−3−ピコリルアミン1.83g(収率79.9%)を白色固体として得た。 After 4), the precipitated solid was collected by filtration and dried to give N-(4-carboxy) benzyloxycarbonyl-3-picolylamine 1.83g of (yield: 79.9%) as a white solid . 1H NMR(270MHz, DMSO-d6)δppm: 4.24(2H,d,J=5.9Hz), 1H NMR (270MHz, DMSO-d6) δppm: 4.24 (2H, d, J = 5.9Hz),
5.13(2H,s), 7.33-7.38(1H,m), 7.46(2H,d,J=8.1Hz), 5.13 (2H, s), 7.33-7.38 (1H, m), 7.46 (2H, d, J = 8.1Hz),
7.94(2H,d,J=8.1Hz), 7.95-8.01(1H,m), 8.46(1H,d,J= 7.94 (2H, d, J = 8.1Hz), 7.95-8.01 (1H, m), 8.46 (1H, d, J =
5.1Hz), 8.49(1H,d,J=1.5Hz), 13.0(1H,br.s). 5.1Hz), 8.49 (1H, d, J = 1.5Hz), 13.0 (1H, br.s).

【0282】(98−3) 工程(98−2)の化合物1.26g(4.4mmol)のジクロロメタン(20 [0282] (98-3) in dichloromethane compound 1.26g of step (98-2) (4.4 mmol) (20
ml)懸濁液にオキザリルクロライド1.0ml(1 ml) suspension of oxalyl chloride 1.0 ml (1
1.4ml)を徐々に加え、さらにDMFを数滴加えた後室温で10分間、さらに40℃で30分間攪拌した。 1.4 ml) was slowly added, at room temperature for 10 minutes after addition is added several drops of DMF, and stirred for 30 minutes at further 40 ° C..
放冷後、溶媒を留去し、更にトルエンで過剰のオキザリルクロライドを留去した。 After cooling, the solvent was distilled off, followed by distilling off the excess oxalyl chloride further with toluene. この残渣にジクロロメタン(10ml)を加えた後、氷冷し、さらに実施例1の工程(1−2)で得られた化合物0.83g(4.0mm After addition of dichloromethane (10ml) to the residue, ice-cooled, further embodiment of the compound obtained in the first step (1-2) 0.83g (4.0mm
ol)のジクロロメタン(8ml)−ピリジン(8m Dichloromethane ol) (8ml) - pyridine (8m
l)溶液を滴下した後、室温まで昇温させながら7時間攪拌し、一晩放置した。 Was added dropwise l) solution, and stirred for 7 hours while warming to room temperature and left overnight.

【0283】飽和重曹水を加えた後、クロロホルムで抽出した。 [0283] After addition of saturated aqueous sodium bicarbonate solution and extracted with chloroform. 有機層を飽和食塩水で洗浄後、乾燥、溶媒を留去して得られた残渣にトルエンを加え。 The organic layer was washed with saturated brine, dried, toluene to the resulting residue and the solvent was distilled off was added. さらに過剰のピリジンを共沸した。 It was further azeotrope excess of pyridine. 得られた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)で精製することによりN−[2−(N−tert−ブトキシカルボニル)アミノフェニル]−4−[(ピリジン−3−イル)メチルアミノカルボニルオキシメチル]ベンズアミド1.40g The resulting residue was purified by silica gel column chromatography (ethyl acetate) N- [2- (N-tert- butoxycarbonyl) aminophenyl] -4 - [(pyridin-3-yl) methylamino-carbonyl oxymethyl ] benzamide 1.40g
(収率73.4%)を淡褐色固体として得た。 It was obtained (73.4% yield) as a light brown solid. 1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 4.40(2H,d, 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.40 (2H, d,
J=5.9Hz), 5.19(2H,s),5.56(1H,m), 7.07(1H,br.s), 7. J = 5.9Hz), 5.19 (2H, s), 5.56 (1H, m), 7.07 (1H, br.s), 7.
14-7.31(4H,m), 7.43(2H,d,J=8.1Hz), 7.65(1H,d,J=8.1 14-7.31 (4H, m), 7.43 (2H, d, J = 8.1Hz), 7.65 (1H, d, J = 8.1
Hz), 7.76(1H,d,J=7.3Hz), 7.95(2H,d,J=8.1Hz), 8.52 Hz), 7.76 (1H, d, J = 7.3Hz), 7.95 (2H, d, J = 8.1Hz), 8.52
(2H,d,J=4.1Hz),9.32(1H,br.s). (2H, d, J = 4.1Hz), 9.32 (1H, br.s).

【0284】(98−4) 工程(98−3)の化合物1.00g(2.10mmol)のジオキサン(10m [0284] (98-4) in dioxane steps compound of (98-3) 1.00 g (2.10 mmol) (10 m
l)−メタノール(2ml)溶液に室温で4規定塩酸− l) - 4 N hydrochloric acid at room temperature in methanol (2 ml) solution -
ジオキサン(9ml)を加えて2時間攪拌した。 Added dioxane (9 ml) was stirred for 2 hours. 飽和重曹水を加えた後、酢酸エチル−メチルエチルケトン(1:1)で抽出した。 After addition of saturated aqueous sodium bicarbonate solution, ethyl acetate - ethyl ketone (1: 1). 有機層を飽和食塩水で洗浄後、 The organic layer was washed with saturated brine,
乾燥、溶媒を留去し、得られた残渣にメタノール−ジイソプロピルエーテルを加え、生成した固体を濾取、乾燥することにより、N−(2−アミノフェニル)−4− Dried and the solvent was distilled off, the resulting residue in methanol - diisopropyl ether was added, filtered and the resulting solid by drying, N-(2-aminophenyl) -4-
[(ピリジン−3−イル)メチルアミノカルボニルオキシメチル]ベンズアミド0.79g(定量的)を白色固体として得た。 The [(pyridin-3-yl) methylamino-carbonyl oxy methyl] benzamide 0.79 g (quantitative) was obtained as a white solid.

【0285】mp. 139-141℃ 1H NMR(270MHz, DMSO-d6)δppm: 4.25(2H,d,J=5.9Hz), . [0285] mp 139-141 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.25 (2H, d, J = 5.9Hz),
4.90(2H,s), 5.13(2H,s), 6.60(1H,dd,J=6.6,7.3Hz), 4.90 (2H, s), 5.13 (2H, s), 6.60 (1H, dd, J = 6.6,7.3Hz),
6.78(1H,d,J=7.3Hz), 6.97(1H,dd,J=6.6,7.3Hz),7.17(1 6.78 (1H, d, J = 7.3Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.17 (1
H,d,J=7.3Hz), 7.36(1H,dd,J=4.4,8.1Hz), 7.47(2H,d,J H, d, J = 7.3Hz), 7.36 (1H, dd, J = 4.4,8.1Hz), 7.47 (2H, d, J
=8.1Hz), 7.67(1H,d,J=8.1Hz), 7.97(2H,d,J=7.3Hz), = 8.1Hz), 7.67 (1H, d, J = 8.1Hz), 7.97 (2H, d, J = 7.3Hz),
7.90-8.00(1H,m), 8.46(1H,dd,J=1.5,5.1Hz), 8.49(1H, 7.90-8.00 (1H, m), 8.46 (1H, dd, J = 1.5,5.1Hz), 8.49 (1H,
d,J=2.1Hz), 9.65(1H,br.s). IR(KBr)cm-1: 3326(br),1694,1637,1526,1458,1147,75 . D, J = 2.1Hz), 9.65 (1H, br.s) IR (KBr) cm-1: 3326 (br), 1694,1637,1526,1458,1147,75
0,712. 0,712.

【0286】実施例99 N−(2−アミノフェニル)−4−[3−(イミダゾール−1−イル)プロピルアミノカルボニルオキシメチル]ベンズアミド(表−1:化合物番号215) 実施例98と同様の方法により合成した。 [0286] Example 99 N-(2-aminophenyl) -4- [3- (imidazol-1-yl) propyl aminocarbonyl oxymethyl] benzamide same method as (Table 1 Compound No. 215) Example 98 It was synthesized by. mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 1.80-1.89(2H,m), 2.9 .. Mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 1.80-1.89 (2H, m), 2.9
4-3.02(2H,m), 3.98(2H,t,J=7.3Hz), 4.88(2H,s), 5.11 4-3.02 (2H, m), 3.98 (2H, t, J = 7.3Hz), 4.88 (2H, s), 5.11
(2H,s), 6.55-6.63(1H,m), 6.76-6.97(3H,m), 7.10-7.1 (2H, s), 6.55-6.63 (1H, m), 6.76-6.97 (3H, m), 7.10-7.1
8(2H,m), 7.43-7.48(3H,m), 7.61(1H,s), 7.98(2H,d,J= 8 (2H, m), 7.43-7.48 (3H, m), 7.61 (1H, s), 7.98 (2H, d, J =
8.1Hz), 9.66(1H,s). 8.1Hz), 9.66 (1H, s).

【0287】実施例100 N−(2−アミノフェニル)−4−(フェニルアセチルアミノ)ベンズアミド(表−1:化合物番号2)の合成 (100−1) 実施例1の工程(1−2)で得た化合物16.6g(80mmol)のジクロロメタン(12 In: (Compound No. 2 Table 1) Synthesis (100-1) of Example 1, step (1-2) [0287] Example 100 N-(2-aminophenyl) -4- (phenylacetylamino) benzamide the resulting dichloromethane compound 16.6g (80mmol) (12
0ml)溶液にトリエチルアミン16.8ml(120 0 ml) was added triethylamine 16.8 ml (120
mmol)を加え、さらに氷冷下、4−ニトロベンゾイルクロライド16.0g(86.4mmol)のジクロロメタン(40ml)溶液を徐々に加えた後、7時間攪拌した。 mmol) was added, further under ice-cooling, was gradually added dichloromethane (40 ml) solution of 4-nitrobenzoyl chloride 16.0 g (86.4 mmol), and stirred for 7 hours. 飽和重曹水を加えた後、クロロホルムで抽出した。 After addition of saturated aqueous sodium bicarbonate solution and extracted with chloroform.

【0288】有機層を1規定塩酸水溶液、飽和重曹水、 [0288] The organic layer 1 N aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution,
飽和食塩水で洗浄した後、乾燥、溶媒を留去した。 After washing with saturated brine, dried and evaporated. 得られた残渣をジイソプロピルエーテルで洗浄することにより、N−[2−(N−tert−ブトキシカルボニルアミノ)フェニル]−4−ニトロベンズアミド28.0g The obtained residue was was washed with diisopropyl ether, N- [2- (N-tert- butoxycarbonylamino) phenyl] -4-nitrobenzamide 28.0g
(収率98%)を淡黄色固体として得た。 (98% yield) as a pale yellow solid. 1H NMR(270MHz, CDCl3)δppm: 1.53(9H,s), 7.17-7.29 1H NMR (270MHz, CDCl3) δppm: 1.53 (9H, s), 7.17-7.29
(4H,m), 7.85(1H,br.d,J=7.3Hz), 8.17(2H,d,J=8.8Hz), (4H, m), 7.85 (1H, br.d, J = 7.3Hz), 8.17 (2H, d, J = 8.8Hz),
8.32(2H,d,J=8.8Hz), 9.88(1H,br.s). 8.32 (2H, d, J = 8.8Hz), 9.88 (1H, br.s).

【0289】(100−2) 工程(100−1)で得た化合物24.0g(67.2mmol)のTHF(8 [0289] (100-2) THF steps compound obtained in (100-1) 24.0g (67.2mmol) (8
0ml)−メタノール(80ml)混合溶液に窒素気流下10%Pd/C(含水,2.4g)を加え、水素気流下1.5時間攪拌した。 0 ml) - methanol (80 ml) mixed solution under a nitrogen flow 10% Pd / C (hydrous, 2.4 g) was added, followed by stirring hydrogen stream under 1.5 hours. 水素の吸収が停止した後、触媒を濾別、溶媒を留去して得られた残渣にジイソプロピルエーテルおよび酢酸エチルを加え、得られた固体を濾取、乾燥することにより、N−[2−(N−tert− After hydrogen uptake ceased, the catalyst is filtered off, the solvent was distilled off and the residue diisopropyl ether and ethyl acetate, obtained by adding, filtered and the resulting solid by drying, N-[2- (N-tert-
ブトキシカルボニルアミノ)フェニル]−4−アミノベンズアミド18.96g(収率86%)を白色固体として得た。 Butoxycarbonylamino) phenyl] -4-aminobenzamide 18.96g (86% yield) as a white solid. 1H NMR(270MHz, DMSO-d6)δppm: 1.46(9H.s), 5.84(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.46 (9H.s), 5.84 (2H,
s), 6.61(2H,d,J=8.8Hz), 7.10-7.18(2H,m), 7.46-7.55 s), 6.61 (2H, d, J = 8.8Hz), 7.10-7.18 (2H, m), 7.46-7.55
(2H,m), 7.68(2H,d,J=8.8Hz), 8.67(1H,s), 9.49(1H, (2H, m), 7.68 (2H, d, J = 8.8Hz), 8.67 (1H, s), 9.49 (1H,
s). s).

【0290】(100−3) 工程(100−2)で得た化合物1.6g(4.88mmol)の塩化メチレン溶液(15ml)に、ピリジン0.8ml(9.9mm [0290] (100-3) in step a methylene chloride solution (15ml) of the compound obtained in (100-2) 1.6 g (4.88 mmol), pyridine 0.8 ml (9.9 mm
ol)、フェニルアセチルクロライド0.96ml ol), phenylacetyl chloride 0.96ml
(7.26mmol)を加え1日間撹拌した。 (7.26 mmol) and the mixture was stirred for 1 day. 反応終了後、水を加え、析出した結晶を濾取し、N−[2−(N After the reaction, water was added, and the precipitated crystals were collected by filtration, N- [2- (N
−tert−ブトキシカルボニルアミノ)フェニル]− -tert- butoxycarbonylamino-) phenyl] -
4−(フェニルアセチルアミノ)ベンズアミド1.66 4- (phenyl-acetylamino) benzamide 1.66
g(収率76%)を得た。 It was obtained g (76% yield).

【0291】(100−4) 工程(100−3)で得た化合物1g(2.24mmol)のアセトニトリル溶液(25ml)に室温でヨードトリメチルシラン0.8 [0291] (100-4) iodotrimethylsilane at room temperature in acetonitrile solution (25 ml) step the compound obtained in (100-3) 1 g (2.24 mmol) 0.8
8ml(6.18mmol)を加え3時間撹拌した。 8 ml (6.18 mmol) was stirred for 3 hours added. 反応終了後、溶媒を濃縮し得られた残留物をメタノールから再結晶して、N−(2−アミノフェニル)−4−(フェニルアセチルアミノ)ベンズアミド0.29g(収率38%)を白色結晶として得た。 After completion of the reaction, the residue solvent was concentrated and the resulting recrystallized from methanol, N-(2-aminophenyl) -4-white crystals (phenylacetyl) benzamide 0.29 g (38% yield) It was obtained as a.

【0292】mp. 232-237℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.69(2H,s), 4.90(2H, .. [0292] mp 232-237 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.69 (2H, s), 4.90 (2H,
s), 6.60(1H,t,J=7.3Hz), 6.77(1H,d,J=7.3Hz), 6.96(1 s), 6.60 (1H, t, J = 7.3Hz), 6.77 (1H, d, J = 7.3Hz), 6.96 (1
H,t,J=7.3Hz), 7.15(1H,d,J=7.4Hz), 7.22-7.35(5H,m), H, t, J = 7.3Hz), 7.15 (1H, d, J = 7.4Hz), 7.22-7.35 (5H, m),
7.72(2H,d,J=8.8Hz), 7.95(2H,d,J=8.8Hz), 9.57(1H, 7.72 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.8Hz), 9.57 (1H,
s), 10.43(1H,s)IR(KBr)cm-1: 2937,2764,1660,1598,15 s), 10.43 (1H, s) IR (KBr) cm-1: 2937,2764,1660,1598,15
06,1459. 06,1459.

【0293】実施例100と同様の方法により、実施例101から実施例128の化合物を合成した。 [0293] By a method similar to Example 100, to synthesize a compound of Example 128 from Example 101. 以下に、 less than,
化合物の融点(mp.)、1H NMR、IRの測定値を示す。 Melting point of the compound (mp.), Shows IH NMR, the measurement of IR.

【0294】実施例101 N−(2−アミノフェニル)−4−[(4−フェニルブタノイル)アミノ]ベンズアミド(表−1:化合物番号4) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 1.91(2H,hep,J=7.3H .. [0294] Example 101 N-(2-aminophenyl) -4 - [(4-phenyl butanoyl) amino] benzamide (Table 1: Compound No. 4) mp (amorphous) 1H NMR (270MHz, DMSO- d6) δppm: 1.91 (2H, hep, J = 7.3H
z), 2.37(2H,t,J=7.3Hz),2.64(2H,t,J=7.3Hz), 5.0(2H, z), 2.37 (2H, t, J = 7.3Hz), 2.64 (2H, t, J = 7.3Hz), 5.0 (2H,
br.s), 6.61(1H,t,7.0Hz), 6.79(1H,dd,J=1.5,8.1Hz), br.s), 6.61 (1H, t, 7.0Hz), 6.79 (1H, dd, J = 1.5,8.1Hz),
6.97(1H,t,J=7.0Hz), 7.10-7.40(6H,m), 7.71(2H,d,J= 6.97 (1H, t, J = 7.0Hz), 7.10-7.40 (6H, m), 7.71 (2H, d, J =
8.8Hz), 7.94(2H,d,J=8.8Hz), 9.57(1H,s), 10.15(1H, 8.8Hz), 7.94 (2H, d, J = 8.8Hz), 9.57 (1H, s), 10.15 (1H,
s).IR(KBr)cm-1; 3344,1687,1603,1542,1460,1315,103 s) .IR (KBr) cm-1; 3344,1687,1603,1542,1460,1315,103
3,842,737. 3,842,737.

【0295】実施例102 N−(2−アミノフェニル)−4−[(4−クロロフェニルアセチル)アミノ]ベンズアミド(表−1:化合物番号15) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.72(2H,s),7.29-7.43 .. [0295] Example 102 N-(2-aminophenyl) -4 - [(4-chlorophenyl) amino] benzamide (Table 1: Compound No. 15) mp (amorphous) 1H NMR (270MHz, DMSO-d6 ) δppm: 3.72 (2H, s), 7.29-7.43
(8H,m),7.77(2H,d,J=8.8Hz),8.00(2H,d,J=8.8Hz),10.29 (8H, m), 7.77 (2H, d, J = 8.8Hz), 8.00 (2H, d, J = 8.8Hz), 10.29
(1H,s),10.52(1H,s).IR(KBr)cm-1: 3300,2868,1664,163 (1H, s), 10.52 (1H, s) .IR (KBr) cm-1: 3300,2868,1664,163
8,1520. 8,1520.

【0296】実施例103 N−(2−アミノフェニル)−4−[(2−ニトロフェニルアセチル)アミノ]ベンズアミド 塩酸塩(表− [0296] Example 103 N-(2-aminophenyl) -4 - [(2-nitrophenyl) amino] benzamide hydrochloride (Table -
1:化合物番号19の塩酸塩) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.20(2H,s), 7.20-7.3 1:.. Hydrochloride) mp Compound No. 19 (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.20 (2H, s), 7.20-7.3
0(3H,m), 7.40-7.45(1H,m), 7.60(2H,d), 7.71-7.77(3 0 (3H, m), 7.40-7.45 (1H, m), 7.60 (2H, d), 7.71-7.77 (3
H,m), 8.02-8.10(4H,m), 10.27(1H,br.s), 10.64(1H,b H, m), 8.02-8.10 (4H, m), 10.27 (1H, br.s), 10.64 (1H, b
rs). IR(KBr)cm-1: 3263,1676,1647,1518,1184,759. . Rs) IR (KBr) cm-1: 3263,1676,1647,1518,1184,759.

【0297】実施例104 N−(2−アミノフェニル)−4−[(4−ニトロフェニルアセチル)アミノ]ベンズアミド(表−1:化合物番号21) mp. 222-226℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.90(2H,s), 4.96(2H, .. [0297] Example 104 N-(2-aminophenyl) -4 - [(4-nitrophenyl) amino] benzamide (Table 1: Compound No. 21) mp 222-226 ℃ 1H NMR (270MHz, DMSO -d6) δppm: 3.90 (2H, s), 4.96 (2H,
br.s), 6.60(1H,dt,J=1.5,6.6Hz), 6.78(1H,dd,J=1.5, br.s), 6.60 (1H, dt, J = 1.5,6.6Hz), 6.78 (1H, dd, J = 1.5,
6.6Hz), 6.97(1H,dt,J=1.5,6.6Hz), 7.15(1H,dd,J=1.5, 6.6Hz), 6.97 (1H, dt, J = 1.5,6.6Hz), 7.15 (1H, dd, J = 1.5,
6.6Hz), 7.63(2H,d,J=8.8Hz), 7.71(2H,d,J=8.8Hz), 7. 6.6Hz), 7.63 (2H, d, J = 8.8Hz), 7.71 (2H, d, J = 8.8Hz), 7.
95(2H,d,J=8.8Hz),8.22(2H,d,J=8.8Hz), 9.59(1H,s), 1 95 (2H, d, J = 8.8Hz), 8.22 (2H, d, J = 8.8Hz), 9.59 (1H, s), 1
0.54(1H,s). IR(KBr)cm-1: 3395,3334,1671,1630,1519,1346. . 0.54 (1H, s) IR (KBr) cm-1: 3395,3334,1671,1630,1519,1346.

【0298】実施例105 N−(2−アミノフェニル)−4−[(2−アミノフェニルアセチル)アミノ]ベンズアミド(表−1:化合物番号22) mp. 177-182℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.54(2H,s), 4.88(2H, . (. Dec).: - [0298] Example 105 N-(2-Aminophenyl) -4 [(2-aminophenyl) amino] benzamide (Table 1 Compound No. 22) mp 177-182 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.54 (2H, s), 4.88 (2H,
br.s), 5.09(2H,br.s),6.55(1H,dd,J=6.6,7.3Hz), 6.59 br.s), 5.09 (2H, br.s), 6.55 (1H, dd, J = 6.6,7.3Hz), 6.59
(1H,dd,J=7.3,7.3Hz), 6.68(1H,d,J=7.3Hz), 6.78(1H, (1H, dd, J = 7.3,7.3Hz), 6.68 (1H, d, J = 7.3Hz), 6.78 (1H,
d,J=7.3Hz), 6.96(2H,dd,J=7.3,7.3Hz), 7.06(1H,d,J= d, J = 7.3Hz), 6.96 (2H, dd, J = 7.3,7.3Hz), 7.06 (1H, d, J =
6.6Hz), 7.15(1H,d,J=7.3Hz), 7.71(2H,d,J=8.8Hz), 7. 6.6Hz), 7.15 (1H, d, J = 7.3Hz), 7.71 (2H, d, J = 8.8Hz), 7.
95(2H,d,J=8.8Hz), 9.57(1H,br.s), 10.39(1H,br.s). IR(KBr)cm-1: 3374,3256(br.),1683,1597,1503,1317,12 95 (2H, d, J = 8.8Hz), 9.57 (1H, br.s), 10.39 (1H, br.s) IR (KBr) cm-1:. (. Br) 3374,3256, 1683,1597, 1503,1317,12
62,1180,1153,747. 62,1180,1153,747.

【0299】実施例106 N−(2−アミノフェニル)−4−[(4−アミノフェニルアセチル)アミノ]ベンズアミド(表−1:化合物番号26) mp. 219-226℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.46(2H,s), 4.93(4H, . (. Dec).: - [0299] Example 106 N-(2-Aminophenyl) -4 [(4-aminophenyl) amino] benzamide (Table 1 Compound No. 26) mp 219-226 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.46 (2H, s), 4.93 (4H,
br.s), 6.52(2H,d,J=8.1Hz), 6.59(1H,dt,J=1.5,7.3H br.s), 6.52 (2H, d, J = 8.1Hz), 6.59 (1H, dt, J = 1.5,7.3H
z), 6.77(1H,dd,J=1.4,7.3Hz), 6.97(1H,dt,J=1.4,7.3H z), 6.77 (1H, dd, J = 1.4,7.3Hz), 6.97 (1H, dt, J = 1.4,7.3H
z), 6.99(2H,d,J=8.1Hz), 7.15(1H,dd,J=1.5,7.3Hz), z), 6.99 (2H, d, J = 8.1Hz), 7.15 (1H, dd, J = 1.5,7.3Hz),
7.70(2H,d,J=8.8Hz),7.93(2H,d,J=8.8Hz). IR(KBr)cm-1: 3278,3032,1675,1628,1516. 7.70 (2H, d, J = 8.8Hz), 7.93 (2H, d, J = 8.8Hz) IR (KBr) cm-1:. 3278,3032,1675,1628,1516.

【0300】実施例107 N−(2−アミノフェニル)−4−[(4−メトキシフェニルアセチル)アミノ]ベンズアミド(表−1:化合物番号32) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.62(2H,s), 3.74(3 .. [0300] Example 107 N-(2-aminophenyl) -4 - [(4-methoxyphenyl) amino] benzamide (Table 1: Compound No. 32) mp (amorphous) 1H NMR (270MHz, DMSO- d6) δppm: 3.62 (2H, s), 3.74 (3
H,s), 6.90(2H,d,J=8.8Hz), 7.26(2H.dJ=8.8Hz), 7.30 H, s), 6.90 (2H, d, J = 8.8Hz), 7.26 (2H.dJ = 8.8Hz), 7.30
(3H,m), 7.39(1H,m), 7.77(2H,d,J=8.8Hz), 7.99(2H,d, (3H, m), 7.39 (1H, m), 7.77 (2H, d, J = 8.8Hz), 7.99 (2H, d,
J=8.8Hz), 10.26(1H,s), 10.44(1H,s). IR(KBr)cm-1: 3300,2759,1670,1638,1514,1250. . J = 8.8Hz), 10.26 (1H, s), 10.44 (1H, s) IR (KBr) cm-1: 3300,2759,1670,1638,1514,1250.

【0301】実施例108 N−(2−アミノフェニル)−4−[[4−(N,N− [0301] Example 108 N-(2-aminophenyl) -4 - [[4- (N, N-
ジメチルアミノ)フェニルアセチル]アミノ]ベンズアミド(表−1:化合物番号53) mp. 140℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.04(6H,s), 3.67(2H, Dimethylamino) phenylacetyl] amino] benzamide (Table 1:.. Compound No. 53) mp 140 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.04 (6H, s), 3.67 (2H,
s), 7.16(2H,d,J=8.1Hz), 7.29-7.40(6H,m), 7.76(2H, s), 7.16 (2H, d, J = 8.1Hz), 7.29-7.40 (6H, m), 7.76 (2H,
d,J=8.8Hz), 7.99(2H,d,J=8.8Hz), 10.29(1H,s),10.47 d, J = 8.8Hz), 7.99 (2H, d, J = 8.8Hz), 10.29 (1H, s), 10.47
(1H,s). IR(KBr)cm-1: 3244,2951,2639,1647,1599,1507. . (1H, s) IR (KBr) cm-1: 3244,2951,2639,1647,1599,1507.

【0302】実施例109 N−(2−アミノフェニル)−4−[(4−トリフルオロメチルフェニルアセチル)アミノ]ベンズアミド(表−1:化合物番号43) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.84(2H,s), 6.89(1H, .. [0302] Example 109 N-(2-aminophenyl) -4 - [(4-trifluoromethylphenyl) amino] benzamide (Table 1: Compound No. 43) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 3.84 (2H, s), 6.89 (1H,
t,J=7.4Hz), 7.00(1H,d,J=7.4Hz), 7.11(1H,t,J=7.4H t, J = 7.4Hz), 7.00 (1H, d, J = 7.4Hz), 7.11 (1H, t, J = 7.4H
z), 7.25(1H,d,J=7.4Hz), 7.57(2H,d,J=8.8Hz), 7.71(2 z), 7.25 (1H, d, J = 7.4Hz), 7.57 (2H, d, J = 8.8Hz), 7.71 (2
H,d,J=8.8Hz), 7.73(2H,d,J=8.8Hz), 7.97(2H,d,J=8.8H H, d, J = 8.8Hz), 7.73 (2H, d, J = 8.8Hz), 7.97 (2H, d, J = 8.8H
z), 9.87(1H,s), 10.54(1H,s). IR(KBr)cm-1: 3260,1664,1605,1521,1327,1119. . Z), 9.87 (1H, s), 10.54 (1H, s) IR (KBr) cm-1: 3260,1664,1605,1521,1327,1119.

【0303】実施例110 N−(2−アミノフェニル)−4−[(ピリジン−2− [0303] Example 110 N-(2-aminophenyl) -4 - [(pyridin-2
イル)アセチルアミノ]ベンズアミド 2塩酸塩(表− Yl) acetylamino] benzamide dihydrochloride (Table -
1:化合物番号174の塩酸塩) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.60(2H,s), 7.30-7.4 1:.. Hydrochloride) mp Compound No. 174 (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.60 (2H, s), 7.30-7.4
6(3H,m), 7.56(1H,d,J=7.4Hz), 7.79(2H,d,J=8.8Hz), 6 (3H, m), 7.56 (1H, d, J = 7.4Hz), 7.79 (2H, d, J = 8.8Hz),
7.95(1H,t,J=6.6Hz), 8.01(1H,d,J=7.4Hz), 8.11(2H,d, 7.95 (1H, t, J = 6.6Hz), 8.01 (1H, d, J = 7.4Hz), 8.11 (2H, d,
J=8.8Hz), 8.49(1H,t,J=7.4Hz), 8.87(1H,d,J=5.1Hz), J = 8.8Hz), 8.49 (1H, t, J = 7.4Hz), 8.87 (1H, d, J = 5.1Hz),
10.46(1H,s). 10.46 (1H, s).

【0304】実施例111 N−(2−アミノフェニル)−4−[(ピリジン−3− [0304] Example 111 N-(2-aminophenyl) -4 - [(pyridin-3
イル)アセチルアミノ]ベンズアミド 2塩酸塩(表− Yl) acetylamino] benzamide dihydrochloride (Table -
1:化合物番号68の塩酸塩) mp. 182-189℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.12(2H,s), 7.29-7.5 1:. Hydrochloride) mp 182-189 ° C. Compound No. 68 (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.12 (2H, s), 7.29-7.5
9(4H,m), 7.80(2H,d,J=8.8Hz), 8.05(1H,m), 8.11(2H, 9 (4H, m), 7.80 (2H, d, J = 8.8Hz), 8.05 (1H, m), 8.11 (2H,
d,J=8.8Hz), 8.57(1H,d,J=8.1Hz), 8.85(1H,d,J=5.2H d, J = 8.8Hz), 8.57 (1H, d, J = 8.1Hz), 8.85 (1H, d, J = 5.2H
z), 8.95(1H,s), 10.25(1H,s), 10.48(1H,s). z), 8.95 (1H, s), 10.25 (1H, s), 10.48 (1H, s).

【0305】実施例112 N−(2−アミノフェニル)−4−[[3−(ピリジン−3−イル)プロパノイル]アミノ]ベンズアミド(表−1:化合物番号69) mp. 184-186℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.80(2H,t,J=7.3Hz), .. [0305] Example 112 N-(2-aminophenyl) -4 - [[3- (pyridin-3-yl) propanoyl] amino] benzamide (Table 1: Compound No. 69) mp 184-186 ° C. IH NMR (270MHz, DMSO-d6) δppm: 2.80 (2H, t, J = 7.3Hz),
3.08(2H,t,J=7.3Hz), 6.87(1H,t,J=8.0Hz), 6.99(1H,d 3.08 (2H, t, J = 7.3Hz), 6.87 (1H, t, J = 8.0Hz), 6.99 (1H, d
d,J=1.4,8.0Hz), 7.11(1H,dt,J=1.4,8.0Hz), 7.25(1H, d, J = 1.4,8.0Hz), 7.11 (1H, dt, J = 1.4,8.0Hz), 7.25 (1H,
d,J=8.0Hz), 7.70(2H,d,J=8.8Hz), 7.77(1H,dd,J=5.8, d, J = 8.0Hz), 7.70 (2H, d, J = 8.8Hz), 7.77 (1H, dd, J = 5.8,
8.0Hz), 7.96(2H,d,J=8.8Hz), 8.22(1H,d,J=8.0Hz), 8. 8.0Hz), 7.96 (2H, d, J = 8.8Hz), 8.22 (1H, d, J = 8.0Hz), 8.
75(1H,d,J=1.4Hz), 9.83(1H,s), 10.25(1H,s). 75 (1H, d, J = 1.4Hz), 9.83 (1H, s), 10.25 (1H, s).

【0306】実施例113 N−(2−アミノフェニル)−2−クロロ−4−[3− [0306] Example 113 N-(2-aminophenyl) -2-chloro-4- [3-
(ピリジン−3−イル)プロパノイルアミノ]ベンズアミド(表−1:化合物番号123) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 2.70(2H,t,J=8.1Hz), (Pyridin-3-yl) propanoylamino] benzamide.. (Table 1: Compound No. 123) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 2.70 (2H, t, J = 8.1Hz),
2.96(2H,t,J=7.3Hz), 4.74(2H,br.s), 6.60(1H,t,J=6. 2.96 (2H, t, J = 7.3Hz), 4.74 (2H, br.s), 6.60 (1H, t, J = 6.
6Hz), 6.78(1H,d,J=6.6Hz), 6.95(1H,t,J=6.6Hz), 7.19 6Hz), 6.78 (1H, d, J = 6.6Hz), 6.95 (1H, t, J = 6.6Hz), 7.19
(1H,dd,J=1.5,7.3Hz), 7.29(1H,dd,J=5.1,7.3Hz), 7.66 (1H, dd, J = 1.5,7.3Hz), 7.29 (1H, dd, J = 5.1,7.3Hz), 7.66
(2H,d,J=8.8Hz),7.92(2H,d,J=8.8Hz), 8.48(1H,d,J=2.2 (2H, d, J = 8.8Hz), 7.92 (2H, d, J = 8.8Hz), 8.48 (1H, d, J = 2.2
Hz), 9.37(1H,s), 10.00(1H,s). IR(KBr)cm-1: 3273,1675,1519,1315,1181,852,747. . Hz), 9.37 (1H, s), 10.00 (1H, s) IR (KBr) cm-1: 3273,1675,1519,1315,1181,852,747.

【0307】実施例114 N−(2−アミノフェニル)−4−[[N−(ピリジン−3−イル)メチル−N−トリフルオロアセチルアミノ]アセチルアミノ]ベンズアミド(表−1:化合物番号107) mp. 145℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.18 and 4.42(total [0307] Example 114 N-(2-aminophenyl) -4 - [[N- (pyridin-3-yl) methyl -N- trifluoroacetylamino] acetylamino] benzamide (Table 1: Compound No. 107) . mp 145 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 4.18 and 4.42 (total
2H,s), 4.73 and 4.83(total 2H,s), 4.87(2H,br.s), 2H, s), 4.73 and 4.83 (total 2H, s), 4.87 (2H, br.s),
6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=8.1Hz),6.96(1 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 8.1Hz), 6.96 (1
H,dd,J=7.3,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.35-7.45(1 H, dd, J = 7.3,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.35-7.45 (1
H,m), 7.66(2H,d,J=5.9Hz), 7.70-7.80(1H,m), 7.90-8. H, m), 7.66 (2H, d, J = 5.9Hz), 7.70-7.80 (1H, m), 7.90-8.
00(2H,m), 8.51-8.55(1H,m), 8.58(1H,s), 9.60(1H,br. 00 (2H, m), 8.51-8.55 (1H, m), 8.58 (1H, s), 9.60 (1H, br.
s), 10.36 and 10.43(total 1H,br.s). s), 10.36 and 10.43 (total 1H, br.s).

【0308】実施例115 N−(2−アミノフェニル)−4−[[N−(ピリジン−3−イル)メチルアミノ]アセチルアミノ]ベンズアミド(表−1:化合物番号105) mp. 160℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.30(2H,s), 3.79(2H, . [0308] Example 115 N-(2-aminophenyl) -4 - [[N- (pyridin-3-yl) methylamino] acetylamino] benzamide (Table 1: Compound No. 105) mp 160 ° C. (dec ..) 1H NMR (270MHz, DMSO-d6) δppm: 3.30 (2H, s), 3.79 (2H,
s), 4.88(2H,s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H, s), 4.88 (2H, s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H,
d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 7.16(1H,d,J= d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz), 7.16 (1H, d, J =
8.1Hz), 7.74(2H,d,J=8.8Hz), 7.80(1H,d,J=7.3Hz), 7. 8.1Hz), 7.74 (2H, d, J = 8.8Hz), 7.80 (1H, d, J = 7.3Hz), 7.
95(2H,d,J=8.1Hz),8.46(1H,d,J=3.7Hz), 8.57(1H,s), 95 (2H, d, J = 8.1Hz), 8.46 (1H, d, J = 3.7Hz), 8.57 (1H, s),
9.57(1H,s), 10.08(1H,br.s). IR(KBr)cm-1: 3298,1693,1637,1602,1544,1454,1262,84 9.57 (1H, s), 10.08 (1H, br.s) IR (KBr) cm-1:. 3298,1693,1637,1602,1544,1454,1262,84
8,762. 8,762.

【0309】実施例116 N−(2−アミノフェニル)−4−[N−(ピリジン− [0309] Example 116 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)メチルオキサモイルアミノ]ベンズアミド(表−1:化合物番号104) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.43(2H,d,J=6.6Hz), 3-yl) methyl oxamoylamino] benzamide (Table 1:.. Compound No. 104) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.43 (2H, d, J = 6.6Hz),
4.90(2H,br.s), 6.60(1H,dd,J=6.6,7.3Hz), 6.78(1H,d, 4.90 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.3Hz), 6.78 (1H, d,
J=7.3Hz), 6.97(1H,ddd,J=1.5,6.6,7.3Hz), 7.16(1H,d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,6.6,7.3Hz), 7.16 (1H, d,
J=7.3Hz), 7.37(1H,dd,J=4.4,8.1Hz), 7.73(1H,d,J=8.1 J = 7.3Hz), 7.37 (1H, dd, J = 4.4,8.1Hz), 7.73 (1H, d, J = 8.1
Hz), 7.96 and 7.96(4H,AA'BB',J=9.4Hz), 8.47(1H,dd, Hz), 7.96 and 7.96 (4H, AA'BB ', J = 9.4Hz), 8.47 (1H, dd,
J=1.5,5.1Hz), 8.56(1H,d,J=1.5Hz), 9.59(1H,s), 9.67 J = 1.5,5.1Hz), 8.56 (1H, d, J = 1.5Hz), 9.59 (1H, s), 9.67
(1H,t,J=6.6Hz), 10.92(1H,br.s). IR(KBr)cm-1: 3299,1644,1518,1320,1119,748. . (1H, t, J = 6.6Hz), 10.92 (1H, br.s) IR (KBr) cm-1: 3299,1644,1518,1320,1119,748.

【0310】実施例117 N−(2−アミノフェニル)−4−[[N−(ピリジン−3−イル)メチル−N−ニコチノイルアミノ]アセチルアミノ]ベンズアミド(表−1:化合物番号106) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.11(major 2H,s), 4. [0310] Example 117 N-(2-aminophenyl) -4 - [[N- (pyridin-3-yl) methyl -N- nicotinoyl amino] acetylamino] benzamide (Table 1: Compound No. 106) mp .. (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.11 (major 2H, s), 4.
26(minor 2H,s), 4.75(major 2H,s), 4.65(minor 2H, 26 (minor 2H, s), 4.75 (major 2H, s), 4.65 (minor 2H,
s), 4.88(total 2H,br.s), 6.60(total 1H,dd,J=7.3,8. s), 4.88 (total 2H, br.s), 6.60 (total 1H, dd, J = 7.3,8.
1Hz), 6.78(total 1H,d,J=7.3Hz), 6.97(total 1H,dd,J 1Hz), 6.78 (total 1H, d, J = 7.3Hz), 6.97 (total 1H, dd, J
=7.3,8.1Hz), 7.15(total 1H,d,J=8.1Hz), 7.41-7.95(t = 7.3,8.1Hz), 7.15 (total 1H, d, J = 8.1Hz), 7.41-7.95 (t
otal 8H,m), 8.46-8.52(total 1H,m), 8.63-8.70(total otal 8H, m), 8.46-8.52 (total 1H, m), 8.63-8.70 (total
2H,m), 9.59(total 1H,s), 10.22(major 1H,br.s), 1 2H, m), 9.59 (total 1H, s), 10.22 (major 1H, br.s), 1
0.37(minor 1H,br.s). IR(KBr)cm-1:3269,1701,1637,1603,1534,1506,1312,125 0.37 (minor 1H, br.s) IR (KBr) cm-1:. 3269,1701,1637,1603,1534,1506,1312,125
4,752. 4,752.

【0311】実施例118 N−(2−アミノフェニル)−4−[[4−(ピリジン−3−イル)ブタノイル]アミノ]ベンズアミド(表− [0311] Example 118 N-(2-aminophenyl) -4 - [[4- (pyridin-3-yl) butanoyl] amino] benzamide (Table -
1:化合物番号70) mp. 165-167℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 1.88-1.99(2H,m), 2.6 1:. Compound No. 70) mp 165-167 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 1.88-1.99 (2H, m), 2.6
8(2H,t,J=7.3Hz), 2.39(2H,t,J=7.3Hz), 6.78-6.81(1H, 8 (2H, t, J = 7.3Hz), 2.39 (2H, t, J = 7.3Hz), 6.78-6.81 (1H,
m), 6.94-6.99(1H,m), 7.15-7.18(1H,m), 7.34-7.39(1 m), 6.94-6.99 (1H, m), 7.15-7.18 (1H, m), 7.34-7.39 (1
H,m), 7.69-7.72(3H,m), 7.94(2h,d,J=8.8Hz), 8.43-8. H, m), 7.69-7.72 (3H, m), 7.94 (2h, d, J = 8.8Hz), 8.43-8.
48(2H,m). IR(KBr)cm-1: 3291,1660,1626,1308,1261,1182,1027,82 . 48 (2H, m) IR (KBr) cm-1: 3291,1660,1626,1308,1261,1182,1027,82
5,747. 5,747.

【0312】実施例119 N−(2−アミノフェニル)−4−[[N−(ピリジン−3−イル)メチル−N−メチルアミノ]アセチルアミノ]ベンズアミド(表−1:化合物番号108)mp. 15 [0312] Example 119 N-(2-aminophenyl) -4 - [[N- (pyridin-3-yl) methyl -N- methylamino] acetylamino] benzamide (Table 1: Compound No. 108) mp. 15
4-155℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.28(3H,s), 3.27(2H, . 4-155 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.28 (3H, s), 3.27 (2H,
s), 3.71(2H,s), 4.88(2H,br.s), 6.60(1H,dd,J=6.6,7. s), 3.71 (2H, s), 4.88 (2H, br.s), 6.60 (1H, dd, J = 6.6,7.
3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16(1H,d,J=8.1Hz), 7.38(1H,dd,J=2.9,8.1Hz), 7.77 7.16 (1H, d, J = 8.1Hz), 7.38 (1H, dd, J = 2.9,8.1Hz), 7.77
(2H,d,J=8.8Hz),7.75-7.85(1H,m), 7.95(2H,d,J=8.8H (2H, d, J = 8.8Hz), 7.75-7.85 (1H, m), 7.95 (2H, d, J = 8.8H
z), 8.47(1H,d,J=1.5Hz), 8.49(1H,s), 9.56(1H,s), 1 z), 8.47 (1H, d, J = 1.5Hz), 8.49 (1H, s), 9.56 (1H, s), 1
0.02(1H,br.s). 0.02 (1H, br.s).

【0313】実施例120 N−(2−アミノフェニル)−4−[N−(ピリジン− [0313] Example 120 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)オキシアセチルアミノ]ベンズアミド(表− 3-yl) oxy acetylamino] benzamide (Table -
1:化合物番号65) mp. 175-179℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.86(2H,s), 4.90(2H, 1:.. Compound No. 65) mp 175-179 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.86 (2H, s), 4.90 (2H,
br.s), 6.60(1H,d,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), br.s), 6.60 (1H, d, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz),
6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J=8.1Hz), 7.34 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J = 8.1Hz), 7.34
-7.47(2H,m), 7.76(2H,d,J=8.8Hz), 7.98(2H,d,J=8.8H -7.47 (2H, m), 7.76 (2H, d, J = 8.8Hz), 7.98 (2H, d, J = 8.8H
z), 8.22(1H,d,J=3.6Hz), 8.39(1H,d,J=2.9Hz), 9.60(1 z), 8.22 (1H, d, J = 3.6Hz), 8.39 (1H, d, J = 2.9Hz), 9.60 (1
H,br.s), 10.40(1H,br.s). IR(KBr)cm-1: 3321,1655,1530,1276,1231,1068,757. . H, br.s), 10.40 (1H, br.s) IR (KBr) cm-1: 3321,1655,1530,1276,1231,1068,757.

【0314】実施例121 N−(2−アミノフェニル)−4−[4−(ピリジン− [0314] Example 121 N-(2-aminophenyl) -4- [4- (pyridin -
3−イル)−1、4−ジオキソブチルアミノ]ベンズアミド(表−1:化合物番号99) mp. 190-194℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.08(2H,t,J=6.4Hz), 3-yl) -1,4-dioxo-butylamino] benzamide (Table 1:.. Compound No. 99) mp 190-194 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.08 (2H, t, J = 6.4Hz),
3.41(2H,t,J=6.4Hz), 4.86(2H,s), 6.59(1H,t,J=5.6H 3.41 (2H, t, J = 6.4Hz), 4.86 (2H, s), 6.59 (1H, t, J = 5.6H
z), 6.78(1H,d,J=7.9Hz), 6.96(1H,t,J=7.4Hz), 7.15(1 z), 6.78 (1H, d, J = 7.9Hz), 6.96 (1H, t, J = 7.4Hz), 7.15 (1
H,d,J=7Hz), 7.58(1H,dd,J=4.9,7.9Hz), 7.70(2H,d,J= H, d, J = 7Hz), 7.58 (1H, dd, J = 4.9,7.9Hz), 7.70 (2H, d, J =
8.9Hz), 7.94(2H,d,J=8.9Hz), 8.35(1H,d,J=7.9Hz), 8. 8.9Hz), 7.94 (2H, d, J = 8.9Hz), 8.35 (1H, d, J = 7.9Hz), 8.
81(1H,d,J=4Hz), 9.18(1H,s), 9.56(1H,s), 10.32(1H, 81 (1H, d, J = 4Hz), 9.18 (1H, s), 9.56 (1H, s), 10.32 (1H,
s). IR(KBr)cm-1: 3317,1691,1652,1601,1522,1312,982,84 . S) IR (KBr) cm-1: 3317,1691,1652,1601,1522,1312,982,84
7,764,701. 7,764,701.

【0315】実施例122 N−(2−アミノフェニル)−4−[3−[N−(ピリジン−3−イル)アミノ]−1,3−ジオキソプロピルアミノ]ベンズアミド(表−1:化合物番号94) mp. 196℃(dec.) 1H NMR(270MHz, DMSO-d6)δppm: 3.57(2H,s), 4.87(2H, [0315] Example 122 N-(2-aminophenyl) -4- [3- [N- (pyridin-3-yl) amino] -1,3-oxopropyl amino] benzamide (Table 1: Compound No. . 94) mp 196 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:. 3.57 (2H, s), 4.87 (2H,
s), 6.57-6.62(1H,m), 6.76-6.79(1H,m), 6.94-6.99(1 s), 6.57-6.62 (1H, m), 6.76-6.79 (1H, m), 6.94-6.99 (1
H,m), 7.14-7.17(1H,m), 7.33-7.38(1H,m), 7.73(2H,d, H, m), 7.14-7.17 (1H, m), 7.33-7.38 (1H, m), 7.73 (2H, d,
J=8.8Hz), 7.97(2H,d,J=8.8Hz), 8.05-8.08(1H,m), 8.2 J = 8.8Hz), 7.97 (2H, d, J = 8.8Hz), 8.05-8.08 (1H, m), 8.2
7-8.30(1H,m), 8.75-8.76(1H,m), 9.59(1H,s), 10.44(1 7-8.30 (1H, m), 8.75-8.76 (1H, m), 9.59 (1H, s), 10.44 (1
H,s), 10.47(1H,s). IR(KBr)cm-1: 3410,3315,1685,1655,1625,1536,1428,13 . H, s), 10.47 (1H, s) IR (KBr) cm-1: 3410,3315,1685,1655,1625,1536,1428,13
62,1263,1201,744. 62,1263,1201,744.

【0316】実施例123 N−(2−アミノフェニル)−4−[N−(ピリジン− [0316] Example 123 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)メトキシアセチルアミノ]−3−メチルベンズアミド(表−1:化合物番号102) mp. 178-181℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 2.28(3H,s), 4.22(2H, 3-yl) methoxyacetylamino] -3-methylbenzamide (Table 1:. Compound No. 102) mp 178-181 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 2.28 (3H, s) , 4.22 (2H,
s), 4.71(2H,s), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7. s), 4.71 (2H, s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.
3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1Hz), 3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1Hz),
7.16(1H,d,J=7.3Hz), 7.43(1H,dd,J=4.4,8.1Hz), 7.71 7.16 (1H, d, J = 7.3Hz), 7.43 (1H, dd, J = 4.4,8.1Hz), 7.71
(1H,d,J=8.1Hz),7.79-7.89(3H,m), 8.54(1H,dd,J=1.5, (1H, d, J = 8.1Hz), 7.79-7.89 (3H, m), 8.54 (1H, dd, J = 1.5,
4.4Hz), 8.66(1H,d,J=1.5Hz), 9.36(1H,br.s), 9.60(1 4.4Hz), 8.66 (1H, d, J = 1.5Hz), 9.36 (1H, br.s), 9.60 (1
H,br.s). IR(KBr)cm-1:3394,3269,1683,1630,1593,1521,1460,113 . H, br.s) IR (KBr) cm-1: 3394,3269,1683,1630,1593,1521,1460,113
1,750,716. 1,750,716.

【0317】実施例124 N−(2−アミノフェニル)−4−[N−(チオフェン−3−イル)メトキシアセチルアミノ]ベンズアミド(表−1:化合物番号204) mp. 186-189℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.11(2H,s), 4.63(2H, [0317] Example 124 N-(2-aminophenyl)-4-[N-(thiophen-3-yl) methoxyacetylamino] benzamide.. (Table 1: Compound No. 204) mp 186-189 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.11 (2H, s), 4.63 (2H,
s), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1 s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1
H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,7.3Hz), 7.12-7.19(2 H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,7.3Hz), 7.12-7.19 (2
H,m), 7.53-7.57(2H,m), 7.78(2H,d,J=8.8Hz), 7.95(2 H, m), 7.53-7.57 (2H, m), 7.78 (2H, d, J = 8.8Hz), 7.95 (2
H,d,J=8.8Hz), 9.58(1H,br.s), 10.04(1H,br.s). IR(KBr)cm-1: 3341,3248,1694,1631,1611,1506,1314,11 . H, d, J = 8.8Hz), 9.58 (1H, br.s), 10.04 (1H, br.s) IR (KBr) cm-1: 3341,3248,1694,1631,1611,1506,1314, 11
26. 26.

【0318】実施例125 N−(2−アミノフェニル)−4−[N−メチル−N− [0318] Example 125 N-(2-aminophenyl) -4- [N- methyl -N-
(ピリジン−3−イル)メトキシアセチルアミノ]ベンズアミド(表−1:化合物番号103) mp. 180-183℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.24(3H,s), 4.08(2H, (Pyridin-3-yl) methoxyacetylamino] benzamide. (Table 1: Compound No. 103) mp 180-183 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 3.24 (3H, s), 4.08 (2H,
br.s), 4.50(2H,s), 4.94(2H,br.s), 6.60(1H,dd,J=7. br.s), 4.50 (2H, s), 4.94 (2H, br.s), 6.60 (1H, dd, J = 7.
3,7.3Hz), 6.79(1H,d,J=8.1Hz), 6.98(1H,dd,J=7.3,8.1 3,7.3Hz), 6.79 (1H, d, J = 8.1Hz), 6.98 (1H, dd, J = 7.3,8.1
Hz), 8.03(1H,d,J=8.1Hz), 8.48-8.50(2H,m), 9.72(1H, Hz), 8.03 (1H, d, J = 8.1Hz), 8.48-8.50 (2H, m), 9.72 (1H,
br.s). IR(KBr)cm-1: 3395,3283,1683,1639,1604,1506,1459,13 . Br.s) IR (KBr) cm-1: 3395,3283,1683,1639,1604,1506,1459,13
07,1124. 07,1124.

【0319】実施例126 N−(2−アミノフェニル)−4−[N−(ピリジン− [0319] Example 126 N-(2-aminophenyl) -4- [N- (pyridine -
2−イル)メトキシアセチルアミノ]ベンズアミド(表−1:化合物番号176) mp.171-173℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.26(2H,s), 4.74(2H, 2-yl) methoxyacetylamino] benzamide (Table 1:. Compound No. 176) mp.171-173 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.26 (2H, s), 4.74 (2H,
s), 4.89(2H,br.s), 6.60(1H,dd,J=6.6,8.1Hz), 6.78(1 s), 4.89 (2H, br.s), 6.60 (1H, dd, J = 6.6,8.1Hz), 6.78 (1
H,d,J=7.3Hz), 6.97(1H,ddd,J=1.5,7.3,8.1Hz),7.16(1 H, d, J = 7.3Hz), 6.97 (1H, ddd, J = 1.5,7.3,8.1Hz), 7.16 (1
H,d,J=7.3Hz), 7.35(1H,dd,J=5.1,6.6Hz), 7.80(2H,d,J H, d, J = 7.3Hz), 7.35 (1H, dd, J = 5.1,6.6Hz), 7.80 (2H, d, J
=8.1Hz), 7.80-7.89(1H,m), 7.97(2H,d,J=8.1Hz), 8.59 = 8.1Hz), 7.80-7.89 (1H, m), 7.97 (2H, d, J = 8.1Hz), 8.59
(1H,d,J=4.4Hz), 9.59(1H,br.s), 10.30(1H,br.s). IR(KBr)cm-1: 3391,3258,1678,1629,1593,1517,1128,76 . (1H, d, J = 4.4Hz), 9.59 (1H, br.s), 10.30 (1H, br.s) IR (KBr) cm-1: 3391,3258,1678,1629,1593,1517,1128 , 76
7,742. 7,742.

【0320】実施例127 N−(2−アミノフェニル)−4−[N−(N−ニコチノイルアミノ)アセチルアミノ]ベンズアミド(表− [0320] Example 127 N-(2-aminophenyl) -4- [N- (N- nicotinoyl amino) acetylamino] benzamide (Table -
1:化合物番号97) mp. 218-220℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.13(2H,d,J=5.9Hz), 1:. Compound No. 97) mp 218-220 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.13 (2H, d, J = 5.9Hz),
4.89(2H,s), 6.59(1H,dd,J=7.3,7.3Hz), 6.77(1H,d,J= 4.89 (2H, s), 6.59 (1H, dd, J = 7.3,7.3Hz), 6.77 (1H, d, J =
8.1Hz), 6.96(1H,dd,J=7.3,8.1Hz), 7.15(1H,d,J=7.3H 8.1Hz), 6.96 (1H, dd, J = 7.3,8.1Hz), 7.15 (1H, d, J = 7.3H
z), 7.55(1H,dd,J=5.1,8.1Hz), 7.73(2H,d,J=8.8Hz), z), 7.55 (1H, dd, J = 5.1,8.1Hz), 7.73 (2H, d, J = 8.8Hz),
7.96(2H,d,J=8.8Hz),8.25(1H,d,J=8.1Hz), 8.74(1H,d,J 7.96 (2H, d, J = 8.8Hz), 8.25 (1H, d, J = 8.1Hz), 8.74 (1H, d, J
=5.1Hz), 9.07(1H,d,J=1.5Hz), 9.13(1H,t-like,J=5.9H = 5.1Hz), 9.07 (1H, d, J = 1.5Hz), 9.13 (1H, t-like, J = 5.9H
z), 9.58(1H,s), 10.36(1H,s). z), 9.58 (1H, s), 10.36 (1H, s).

【0321】実施例128 N−(2−アミノフェニル)−5−[3−(ピリジン− [0321] Example 128 N-(2-aminophenyl) -5- [3- (pyridin -
3−イル)プロピオンアミド]ベンゾフラン−2−カルボキシアミド(表−3:化合物番号1) mp. 267-272℃. 1H NMR(270MHz, DMSO-d6)δppm: 2.51(2H,t,J=7.3Hz), 3-yl) propionamide] benzofuran-2-carboxamide (Table 3:.. Compound No. 1) mp 267-272 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 2.51 (2H, t, J = 7.3Hz ),
2.97(2H,t,J=7.3Hz), 6.61(1H,dd,J=8.1,8.8Hz), 6.80 2.97 (2H, t, J = 7.3Hz), 6.61 (1H, dd, J = 8.1,8.8Hz), 6.80
(1H,dd,J=1.5,8.1Hz), 6.99(1H,dd,J=8.1,8.8Hz),7.20 (1H, dd, J = 1.5,8.1Hz), 6.99 (1H, dd, J = 8.1,8.8Hz), 7.20
(1H,dd,J=1.5,8.1Hz), 7.32(1H,dd,J=5.2,8.1Hz), 7.49 (1H, dd, J = 1.5,8.1Hz), 7.32 (1H, dd, J = 5.2,8.1Hz), 7.49
(1H,dd,J=1.5,8.8Hz),7.61(1H,d,J=8.8Hz), 7.67(1H, (1H, dd, J = 1.5,8.8Hz), 7.61 (1H, d, J = 8.8Hz), 7.67 (1H,
s), 7.70(1H,m), 8.15(1H,d,J=1.5Hz), 8.40(1H,dd,J= s), 7.70 (1H, m), 8.15 (1H, d, J = 1.5Hz), 8.40 (1H, dd, J =
1.5,5.2Hz), 8.51(1H,d,J=1.5Hz), 9.84(1H,s), 10.1(1 1.5,5.2Hz), 8.51 (1H, d, J = 1.5Hz), 9.84 (1H, s), 10.1 (1
H,s). IR(KBr)cm-1: 3333,3272,1666,1583,1561,1458,1314,12 . H, s) IR (KBr) cm-1: 3333,3272,1666,1583,1561,1458,1314,12
47,1143,807,746,713. 47,1143,807,746,713.

【0322】実施例129 N−(2−アミノフェニル)−4−[N−[2−(ピリジン−3−イル)オキシプロピオニル]アミノ]ベンズアミド(表−4:化合物番号2)の合成 (129−1) 実施例47の工程(47−2)で得た化合物0.34g(1.2mmol)、実施例100の工程(100−2)で得た化合物0.34g(1.0m Synthesis of (Compound No. 2 Table 4) (129- [0322] Example 129 N-(2-aminophenyl) -4- [N- [2- (pyridin-3-yl) oxy propionylamino] amino] benzamide 1) the compound obtained in step (47-2) of example 47 0.34 g (1.2 mmol), the compound obtained in step (100-2) of example 100 0.34 g (1.0 m
mol)をジクロロメタン(10ml)に溶解し、さらにトリエチルアミン0.5ml(3.6mmol)を加えた。 The mol) was dissolved in dichloromethane (10 ml), was added further triethylamine 0.5 ml (3.6 mmol). この溶液を氷冷下、2−クロロ−1,3−ジメチルイミダゾリニウムクロライド0.21g(1.24m Under ice-cooling the solution, 2-chloro-1,3-dimethyl imidazolinium chloride 0.21 g (1.24
mol)のジクロロメタン(5ml)溶液を加え、氷冷下さらに2時間攪拌した。 Dichloromethane (5ml) solution of mol), and stirred under ice cooling for additional 2 hours. 飽和重曹水を加え中和した後、水で希釈してクロロホルムで抽出した。 After neutralized with saturated aqueous sodium bicarbonate solution and extracted with chloroform and diluted with water.

【0323】有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得られた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:メタノール=10:1)で精製することにより、N−[2−(N−tert−ブトキシカルボニルアミノ)フェニル]−4−[N−[2−(ピリジン−3−イル)オキシプロピオニル]アミノ]ベンズアミド0.68gを1,3−ジメチル−2−イミダゾリノンの混合物として得た。 [0323] The organic layer was washed with saturated brine, dried and the residue obtained by evaporated the silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give, N-[2- as (N-tert-butoxycarbonylamino) phenyl] -4- [N- [2- (pyridin-3-yl) oxy propionylamino] amino] benzamide 0.68g mixture of 1,3-dimethyl-2-imidazolinone Obtained. 1H-NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 1.70(3H,d, 1H-NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 1.70 (3H, d,
J=6.6Hz), 4.84(1H,q,J=6.6Hz), 6.89(1H,br.s), 7.12- J = 6.6Hz), 4.84 (1H, q, J = 6.6Hz), 6.89 (1H, br.s), 7.12-
7.31(6H,m), 7.68(2H,d,J=8.8Hz), 7.79(1H,d,J=8.1H 7.31 (6H, m), 7.68 (2H, d, J = 8.8Hz), 7.79 (1H, d, J = 8.1H
z), 7.96(2H,d,J=8.8Hz), 8.34(1H,d,J=2.9,2.9Hz), 8. z), 7.96 (2H, d, J = 8.8Hz), 8.34 (1H, d, J = 2.9,2.9Hz), 8.
43(1H,d,J=1.5Hz),9.25(1H,br.s). 43 (1H, d, J = 1.5Hz), 9.25 (1H, br.s).

【0324】(129−2) 工程(129−1)で得た化合物0.68gのジクロロメタン(5ml)溶液に室温で15%(vol/vol)トリフルオロ酢酸・ジクロロメタン溶液(10ml)を加え室温で4.5時間攪拌した。 [0324] (129-2) Step 15% at room temperature in dichloromethane (5ml) solution of the compound 0.68g obtained in (129-1) and (vol / vol) trifluoroacetic acid-dichloromethane solution (10ml) was added at room temperature 4.5 was stirred for hours. 飽和重曹水を加え中和した後ジクロロメタンを留去した。 Dichloromethane was distilled off was neutralized with saturated aqueous sodium bicarbonate solution. この溶液を酢酸エチルで抽出した。 The solution was extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣にメタノールおよびジイソプロピルエーテルを加え析出した沈澱を濾取、乾燥することにより、N−(2−アミノフェニル)−4−[N−[2−(ピリジン−3−イル) The organic layer was washed with saturated brine, dried, filtered and the precipitate deposited was added methanol and diisopropyl ether to the residue obtained by distilling off the solvent, followed by drying, N-(2-aminophenyl) -4- [N- [2- (pyridin-3-yl)
オキシプロピオニル]アミノ]ベンズアミド0.22g Oxy propionylamino] amino] benzamide 0.22g
(2steps,収率58%)を乳白色固体として得た。 To give (2 steps, 58% yield) as an off-white solid. mp. 193-196℃. 1H-NMR(270MHz, DMSO-d6)δppm: 1.60(3H,d,J=6.6Hz), .. Mp 193-196 ℃ 1H-NMR (270MHz, DMSO-d6) δppm: 1.60 (3H, d, J = 6.6Hz),
4.88(2H,br.s), 5.04(1H,q,J=6.6Hz), 6.60(1H,dd,J=6. 4.88 (2H, br.s), 5.04 (1H, q, J = 6.6Hz), 6.60 (1H, dd, J = 6.
6,7.3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=7.3,8.1 6,7.3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 7.3,8.1
Hz), 7.15(1H,d,J=7.3Hz),7.32-7.39(2H,m), 7.75(2H, Hz), 7.15 (1H, d, J = 7.3Hz), 7.32-7.39 (2H, m), 7.75 (2H,
d,J=8.8Hz), 7.96(2H,d,J=8.1Hz), 8.20(1H,dd,J=1.5, d, J = 8.8Hz), 7.96 (2H, d, J = 8.1Hz), 8.20 (1H, dd, J = 1.5,
3.7Hz), 8.35(1H,d,J=2.1Hz), 9.59(1H,br.s), 10.44(1 3.7Hz), 8.35 (1H, d, J = 2.1Hz), 9.59 (1H, br.s), 10.44 (1
H,br.s). H, br.s).

【0325】実施例130 N−(2−アミノフェニル)−4−[(ピリジン−3− [0325] Example 130 N-(2-aminophenyl) -4 - [(pyridin-3
イル)メトキシアセチルアミノ]ベンズアミド(表− Yl) methoxyacetylamino] benzamide (Table -
1:化合物番号101)の合成 (130−1) 水素化ナトリウム(60%油懸濁状) 1: Synthesis of Compound No. 101) (130-1) of sodium hydride (60% oil suspension concentrate)
4.4g(110mmol)のTHF(300ml)懸濁液に、室温で3−ピリジンメタノール10.91g 4.4g in THF (300 ml) suspension of (110 mmol), at room temperature 3-pyridinemethanol 10.91g
(100mmol)のTHF(20ml)溶液を滴下した後、室温で2時間攪拌した。 It was added dropwise THF (20 ml) solution of (100 mmol), and stirred at room temperature for 2 hours. 得られた白色懸濁液を氷冷し、内温10〜12℃を保ちながらブロモ酢酸ter The resulting white suspension was cooled with ice, bromoacetic acid ter while maintaining the internal temperature 10 to 12 ° C.
t−ブチル19.51g(100mmol)のTHF THF of t- butyl 19.51g (100mmol)
(20ml)溶液を滴下した。 (20ml) was added dropwise. この懸濁液を室温まで昇温させながら3時間攪拌した後、一晩放置した。 After the suspension was stirred for 3 hours while warming to room temperature and left overnight. 水および飽和重曹水を加えた後、酢酸エチルで抽出した。 After the addition of water and a saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥し、溶媒留去して得られた残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=1:1→酢酸エチル)で精製し、 The organic layer was washed with saturated brine, dried and the residue obtained by evaporated was purified by silica gel column chromatography (n- hexane: ethyl acetate = 1 1 → ethyl acetate),
(ピリジン−3−イル)メトキシ酢酸tert−ブチルエステル7.56g(33.8%)を茶色油状物として得た。 (Pyridin-3-yl) methoxyacetic acid tert- butyl ester 7.56 g (33.8%) was obtained as a brown oil.

【0326】1H NMR(270MHz, CDCl3)δppm: 1.49(9H, [0326] 1H NMR (270MHz, CDCl3) δppm: 1.49 (9H,
s), 4.03(2H,s), 4.64(2H,s), 7.30(1H,dd,J=4.9,7.3H s), 4.03 (2H, s), 4.64 (2H, s), 7.30 (1H, dd, J = 4.9,7.3H
z), 7.76(1H,d,J=7.3Hz), 8.56(1H,d,J=4.9Hz), 8.60(1 z), 7.76 (1H, d, J = 7.3Hz), 8.56 (1H, d, J = 4.9Hz), 8.60 (1
H,s). (130−2) 工程(130−1)で得た化合物3. H, s). (130-2) of the compound obtained in step (130-1) 3.
5g(15.7mmol)に氷冷下トリフルオロ酢酸(12ml)を加えた後、室温で6時間攪拌した。 After cooling with ice and trifluoroacetic acid (12 ml) was added to 5 g (15.7 mmol), and stirred at room temperature for 6 hours. その後トリフルオロ酢酸を一部留去し(ピリジン−3−イル)メトキシ酢酸とトリフルオロ酢酸の混合物6.5g Mixture 6.5g subsequent trifluoroacetic acid was distilled off part (pyridin-3-yl) methoxyacetic acid and trifluoroacetic acid
を得た。 It was obtained. これにジクロロメタン(70ml)を加え溶解させた後、ピリジン(25ml)を加えた。 Was dissolved was added dichloromethane (70 ml) to this was added pyridine (25 ml). さらに実施例100の工程(100−2)で得られた化合物4.2 Further example compounds 4.2 obtained in 100 steps (100-2)
6g(13mmol)を加えた。 It was added to 6g (13mmol). 氷冷下、2−クロロ− Under ice-cooling, 2-chloro -
1,3−ジメチルイミダゾリニウムクロライド2.37 1,3-dimethyl imidazolinium chloride 2.37
g(14.0mmol)のジクロロメタン(20ml) Dichloromethane g (14.0mmol) (20ml)
溶液を30分かけて徐々に滴下した。 The solution was gradually added dropwise over a period of 30 minutes.

【0327】氷冷下さらに5時間攪拌した後、飽和重曹水を加え、室温で発泡が止まるまで攪拌した。 [0327] After stirring under ice-cooling for additional 5 hours, saturated aqueous sodium bicarbonate solution was added and stirred until it stops foaming at room temperature. クロロホルムで抽出し、得られた有機層を飽和食塩水で洗浄後、 Was extracted with chloroform, washed the resulting organic layer with saturated brine,
乾燥、溶媒留去して得られた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→酢酸エチル:メタノール=10:1)で精製して、N−[2−(N−tert Drying the residue obtained by evaporated the silica gel column chromatography (ethyl → ethyl acetate acetate: methanol = 10: 1) to give, N- [2- (N-tert
−ブトキシカルボニル)アミノフェニル]−4−[N− - butoxycarbonyl) aminophenyl]-4-[N-
(ピリジン−3−イル)メトキシアセチルアミノ]ベンズアミド4.78g(収率62%)をDMI(1,3− (Pyridin-3-yl) methoxyacetylamino] benzamide 4.78 g (62% yield) DMI (1,3
ジメチル−2−イミダゾリノン)との1:1(mol) Of dimethyl 2-imidazolinone) 1: 1 (mol)
混合物として得た。 It was obtained as a mixture. 1H NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 4.15(2H, 1H NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 4.15 (2H,
s), 4.70(2H,s), 6.92(1H,br.s), 7.15-7.29(3H,m), 7. s), 4.70 (2H, s), 6.92 (1H, br.s), 7.15-7.29 (3H, m), 7.
37(1H,dd,J=7.3,5.1Hz), 7.67(2H,d,J=8.8Hz), 7.71-7. 37 (1H, dd, J = 7.3,5.1Hz), 7.67 (2H, d, J = 8.8Hz), 7.71-7.
79(2H,m), 7.96(2H,d,J=8.8Hz), 8.41(1H,s), 8.62-8.6 79 (2H, m), 7.96 (2H, d, J = 8.8Hz), 8.41 (1H, s), 8.62-8.6
6(2H,m), 9.23(1H,br.s). 6 (2H, m), 9.23 (1H, br.s).

【0328】(130−3) 工程(130−2)で得られた化合物2.39g(4.0mmol)のジクロロメタン(28ml)溶液に15%(vol/vol)トリフルオロ酢酸・ジクロロメタン溶液(55ml)を加え室温で7時間攪拌した。 [0328] (130-3) step (130-2) in dichloromethane compound obtained in 2.39 g (4.0 mmol) (28 ml) was added 15% (vol / vol) trifluoroacetic acid-dichloromethane solution (55 ml) the mixture was stirred at room temperature for 7 hours. 飽和重曹水を加え、中和した後に水を加え室温で攪拌した。 Saturated aqueous sodium bicarbonate solution was added, followed by stirring at room temperature added water after neutralization. 反応混合物を酢酸エチル−メチルエチルケトン(2:1)、酢酸エチル−THF The reaction mixture was diluted with ethyl acetate - ethyl ketone (2: 1), ethyl acetate -THF
(2:1)、酢酸エチルで順に抽出し、全有機層を飽和食塩水で洗浄後、無水硫酸ナトリウムで乾燥した。 (2: 1), ethyl acetate and extracted sequentially, after washing the organic layers with saturated brine and dried over anhydrous sodium sulfate. 乾燥剤を濾別した後、濾液を濃縮し、得られた残渣にメタノールおよびジイソプロピルエーテルを加え析出した固体を濾取、乾燥することにより、N−(2−アミノフェニル)−4−[N−(ピリジン−3−イル)メトキシアセチルアミノ]ベンズアミド1.29g(収率85.6 After filtering off the drying agent, the filtrate was concentrated, filtered and the residue in methanol and diisopropyl ether obtained was added solid precipitated and dried, N-(2-aminophenyl) -4- [N- (pyridin-3-yl) methoxyacetylamino] benzamide 1.29 g (yield: 85.6
%)を茶褐色固体として得た。 %) As a brown solid.

【0329】1H NMR(270MHz, DMSO-d6)δppm: 4.19(2H, [0329] 1H NMR (270MHz, DMSO-d6) δppm: 4.19 (2H,
s), 4.68(2H,s), 4.90(2H,br.s), 6.60(1H,ddd,J=1.5, s), 4.68 (2H, s), 4.90 (2H, br.s), 6.60 (1H, ddd, J = 1.5,
7.3,8.1Hz), 6.78(1H,dd,J=1.5,8.1Hz), 6.97(1H,dd,J= 7.3,8.1Hz), 6.78 (1H, dd, J = 1.5,8.1Hz), 6.97 (1H, dd, J =
7.3,7.3Hz), 7.15(1H,d,J=7.3Hz), 7.42(1H,dd,J=4.4, 7.3,7.3Hz), 7.15 (1H, d, J = 7.3Hz), 7.42 (1H, dd, J = 4.4,
8.1Hz), 7.77(2H,d,J=8.8Hz), 7.85(1H,d,J=7.3Hz), 7. 8.1Hz), 7.77 (2H, d, J = 8.8Hz), 7.85 (1H, d, J = 7.3Hz), 7.
96(2H,d,J=8.8Hz), 8.54(1H,dd,J=1.5,5.1Hz), 8.63(1 96 (2H, d, J = 8.8Hz), 8.54 (1H, dd, J = 1.5,5.1Hz), 8.63 (1
H,s), 9.58(1H,s), 10.09(1H,s). IR(KBr)cm-1: 3403,3341,3250,1694,1630,1610,1506,13 . H, s), 9.58 (1H, s), 10.09 (1H, s) IR (KBr) cm-1: 3403,3341,3250,1694,1630,1610,1506,13
14,1259,1118,764. 14,1259,1118,764.

【0330】実施例131 N−(2−アミノフェニル)−4−[N−[2−(ピリジン−3−イル)メトキシプロピオニル]アミノ]ベンズアミド(表−4:化合物番号1番) (131−1) 水素化ナトリウム(60%油状懸濁) [0330] Example 131 N-(2-aminophenyl) -4- [N- [2- (pyridin-3-yl) methoxy propionylamino] amino] benzamide (Table 4: Compound No. 1) (131-1 ) sodium hydride (60% oil suspension)
1.24g(31mmol)を乾燥THF(90ml) 1.24 g (31 mmol) dry THF (90 ml)
に懸濁させた後、室温で3−ピリジンメタノール3.2 It was suspended in 3-pyridinemethanol 3.2 at room temperature
7g(30mmol)の乾燥THF(10ml)溶液を5分間かけて滴下した。 It was added dropwise dry THF (10 ml) solution of 7 g (30 mmol) over 5 minutes. 得られた白色懸濁液を1時間室温で攪拌したのち、室温で2−ブロモプロピオン酸 t The resulting white suspension was After stirring at room temperature for 1 hour, 2-bromopropionic acid t at room temperature
ert−ブチルエステル6.27g(30mmol)の乾燥THF(10ml)溶液を5分間かけて滴下した。 It was added dropwise ert- dry THF (10 ml) solution of butyl ester 6.27 g (30 mmol) over 5 minutes.
室温で11.5時間攪拌した。 And the mixture was stirred for 11.5 hours at room temperature. 水を加えた後酢酸エチルで抽出した。 And extracted with ethyl acetate after adding water. 有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣をシリカゲルカラムクロマトグラフィー(n−ヘキサン:酢酸エチル=1:1)で精製することにより(ピリジン−3−イル)メトキシ酢酸 ter The organic layer was washed with saturated brine, dried and the residue obtained by evaporated the silica gel column chromatography (n- hexane: ethyl acetate = 1: 1) to give (pyridin-3-yl) methoxy acetic acid ter
t−ブチルエステル4.01g(収率56.3%)を茶褐色油状物として得た。 t- butyl ester 4.01g of (56.3% yield) as a brown oil. 1H-NMR(270MHz, CDCl3)δppm: 1.42(3H,d,J=7.3Hz), 1. 1H-NMR (270MHz, CDCl3) δppm: 1.42 (3H, d, J = 7.3Hz), 1.
50(9H,s), 3.96(1H,q,J=6.6Hz), 4.47, 4.69(2H,ABq,J= 50 (9H, s), 3.96 (1H, q, J = 6.6Hz), 4.47, 4.69 (2H, ABq, J =
11.0Hz), 7.29(1H,dd,J=5.1,8.1Hz), 7.75(1H,d,J=8.1H 11.0Hz), 7.29 (1H, dd, J = 5.1,8.1Hz), 7.75 (1H, d, J = 8.1H
z), 8.50(1H,d,J=4.4Hz), 8.60(1H,s). z), 8.50 (1H, d, J = 4.4Hz), 8.60 (1H, s).

【0331】(131−2) 工程(131−1)で得た化合物1.09g(4.59mmol)のジクロロメタン(5ml)溶液にトリフルオロ酢酸(8ml)を加え室温で9.5時間攪拌した。 [0331] (131-2) was stirred for 9.5 hours in dichloromethane (5ml) was added trifluoroacetic acid (8 ml) of the compound obtained 1.09 g (4.59 mmol) was added at room temperature in step (131-1). 溶媒を留去して得た残渣にジクロロメタン(25ml)を加え、さらにピリジン(3ml)を加えた。 The solvent dichloromethane (25 ml) to the residue obtained by distilling off was added and further added pyridine (3 ml). 氷冷下、2−クロロ−1,3−ジメチルイミダゾリジニウムクロライド0.70g(4. Under ice-cooling, 2-chloro-1,3-dimethylimidazolidinone chloride 0.70 g (4.
1mmol)のジクロロメタン(8ml)溶液を滴下した後、30分間攪拌した。 Was added dropwise in dichloromethane (8 ml) solution of 1mmol), it was stirred for 30 minutes. この溶液に実施例100の工程(100−2)で得た化合物0.98g(3.0mm Compound 0.98 g (3.0 mm obtained in this solution of Example 100 step (100-2)
ol)のジクロロメタン(20ml)−ピリジン(10 Dichloromethane ol) (20ml) - pyridine (10
ml)溶液を氷冷下15分かけて徐々に滴下した後、室温まで昇温させながら8時間攪拌した。 ml) solution was slowly added dropwise over 15 min under ice-cooling, followed by stirring for 8 hours while warming to room temperature. 飽和重曹水を加えた後、水で希釈してクロロホルムで抽出した。 After addition of saturated aqueous sodium bicarbonate solution and extracted with chloroform and diluted with water.

【0332】有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た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−メタノール=8:1)で精製する事により、N−[2−(N−tert−ブトキシカルボニルアミノ)フェニル]−4−[N−[2−(ピリジン−3 [0332] The organic layer was washed with saturated brine, dried and the residue obtained by evaporated the silica gel column chromatography (ethyl acetate - methanol = 8: 1) to give, N-[2-( N-tert-butoxycarbonylamino) phenyl] -4- [N- [2- (pyridin -3
−イル)メトキシプロピオニル]アミノ]ベンズアミド1.19gを1,3−ジメチル−2−イミダゾリノンとの2:3(モル比)混合物として得た。 - yl) methoxy propionylamino] amino] benzamide 1.19g of 1,3-dimethyl-2-imidazolinone 2: 3 (molar ratio) was obtained as a mixture. 1H-NMR(270MHz, CDCl3)δppm: 1.51(9H,s), 1.54(3H,d, 1H-NMR (270MHz, CDCl3) δppm: 1.51 (9H, s), 1.54 (3H, d,
J=6.6Hz), 4.13(1H,q,J=6.6Hz), 4.65, 4.71(2H,ABq,J= J = 6.6Hz), 4.13 (1H, q, J = 6.6Hz), 4.65, 4.71 (2H, ABq, J =
11.7Hz), 7.12-7.18(2H,m), 7.28-7.37(3H,m), 7.65(2 11.7Hz), 7.12-7.18 (2H, m), 7.28-7.37 (3H, m), 7.65 (2
H,d,J=8.1Hz), 7.73(2H,br.d,J=5.9Hz), 7.96(2H,d,J= H, d, J = 8.1Hz), 7.73 (2H, br.d, J = 5.9Hz), 7.96 (2H, d, J =
8.8Hz), 8.59-8.64(3H,m), 9.39(1H,br.s). 8.8Hz), 8.59-8.64 (3H, m), 9.39 (1H, br.s).

【0333】(131−3) 工程(131−2)で得た化合物1.19g(1.8mmol)のジクロロメタン(10ml)溶液に15%(vol/vol)トリフルオロ酢酸・ジクロロメタン溶液(20ml)を加え、 [0333] The (131-3) Step dichloromethane compound obtained in (131-2) 1.19 g (1.8 mmol) (10 ml) was added 15% (vol / vol) trifluoroacetic acid-dichloromethane solution (20ml) In addition,
室温で4.5時間攪拌した。 And the mixture was stirred for 4.5 hours at room temperature. 飽和重曹水中にあけた後、 After opening in saturated sodium bicarbonate water,
ジクロロメタンを濃縮して得られた水層を酢酸エチルで抽出した。 The aqueous layer obtained was concentrated dichloromethane and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得られた残渣にメタノールおよびジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することによりN−(2−アミノフェニル)−4−[N−[2− The organic layer was washed with saturated brine, dried, methanol and diisopropyl ether was added to the residue obtained by distilling off the solvent, the precipitated solid was collected by filtration and dried N-(2-aminophenyl) -4 - [N- [2-
(ピリジン−3−イル)メトキシプロピオニル]アミノ]ベンズアミド585mgを淡褐色固体として得た。 It was obtained as a (pyridin-3-yl) methoxy propionylamino] amino] benzamide 585mg of a pale brown solid.

【0334】mp. 144-148℃. 1H NMR(270MHz, DMSO-d6)δppm: 1.40(3H,d,J=6.6Hz), .. [0334] mp 144-148 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 1.40 (3H, d, J = 6.6Hz),
4.14(1H,q,J=6.6Hz), 4.56 and 4.65(2H,ABq,J=11.8H 4.14 (1H, q, J = 6.6Hz), 4.56 and 4.65 (2H, ABq, J = 11.8H
z), 4.89(2H,br.s), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1 z), 4.89 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1
H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 7.16(1H,d,J H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz), 7.16 (1H, d, J
=7.3Hz), 7.40(1H,dd,J=4.4Hz,7.3Hz), 7.78-7.85(3H, = 7.3Hz), 7.40 (1H, dd, J = 4.4Hz, 7.3Hz), 7.78-7.85 (3H,
m), 7.97(2H,d,J=8.8Hz), 8.52(1H,dd,J=1.5,5.1Hz), m), 7.97 (2H, d, J = 8.8Hz), 8.52 (1H, dd, J = 1.5,5.1Hz),
8.61(1H,d,J=2.1Hz), 9.60(1H,s), 10.15(1H,s). 8.61 (1H, d, J = 2.1Hz), 9.60 (1H, s), 10.15 (1H, s).

【0335】実施例132 N−(2−アミノフェニル)−4−(N−ベンジルアミノ)カルボニルベンズアミド(表−1:化合物番号8 [0335] Example 132 N-(2-aminophenyl)-4-(N-benzylamino) carbonyl benzamide (Table 1: Compound No. 8
番)の合成 (132−1) テレフタル酸モノメチル13.0g Synthesis of turn) (132-1) monomethyl terephthalic acid 13.0g
(72.2mmol)のトルエン(100ml)懸濁液にチオニルクロライド(10ml)を室温で滴下した。 Toluene (100ml) suspension thionyl chloride (72.2mmol) (10ml) was added dropwise at room temperature.
80℃で3時間攪拌した後、溶媒および過剰のチオニルクロライドを留去した。 After stirring for 3 hours at 80 ° C., followed by distilling off the solvent and excess thionyl chloride. 得られた残渣をジオキサン(1 The obtained residue in dioxane (1
00ml)に懸濁させた後、2−ニトロアニリン9.9 Was suspended in 100 ml), 2-nitroaniline 9.9
8g(72.2mmol)を加え、4時間加熱還流した。 8g of (72.2 mmol) and the mixture was heated under reflux for 4 hours.

【0336】冷却後、溶媒を留去し、得られた残渣をメタノールで洗浄することにより、N−(2−ニトロフェニル)−4−メトキシカルボニルベンズアミド20.3 [0336] After cooling, the solvent was distilled off, and the obtained residue is washed with methanol, N-(2-nitrophenyl) -4-methoxycarbonyl benzamide 20.3
g(収率93.7%)を黄色固体として得た。 g (93.7% yield) as a yellow solid. 1H NMR(270MHz, DMSO-d6)δppm: 3.91(3H,s), 7.43-7.4 1H NMR (270MHz, DMSO-d6) δppm: 3.91 (3H, s), 7.43-7.4
9(1H,m), 7.76-7.78(2H,m), 8.03(1H,d,J=8.1Hz), 8.08 9 (1H, m), 7.76-7.78 (2H, m), 8.03 (1H, d, J = 8.1Hz), 8.08
(2H,d,J=8.8Hz), 8.14(2H,d,J=8.8Hz), 10.94(1H,s). (2H, d, J = 8.8Hz), 8.14 (2H, d, J = 8.8Hz), 10.94 (1H, s).

【0337】(132−2) 工程(132−1)で得られた化合物4.24g(14.12mmol)のTH [0337] TH of (132-2) Step compound obtained in (132-1) 4.24g (14.12mmol)
F(50ml)−メタノール(50ml)混合溶液に、 F (50ml) - methanol (50ml) mixture,
窒素気流下10%Pd/C0.4gを加えた後、水素気流下で1.5時間攪拌した。 After addition of nitrogen stream 10% Pd / C0.4g, and stirred for 1.5 hours under a hydrogen stream. 触媒をろ過後、溶媒を留去し、得られた残渣をメタノールで洗浄することによりN N By After filtering the catalyst, the solvent was distilled off, washed the resulting residue with methanol
−(2−アミノフェニル)−4ーメトキシカルボニルベンズアミド3.4g(収率87.5%)を淡黄色固体として得た。 - (2-aminophenyl) -4-methoxycarbonylpyrrolidine benzamide 3.4 g (87.5% yield) as a pale yellow solid. 1H NMR(270MHz, DMSO-d6)δppm: 3.90(3H,s), 4.95(2H, 1H NMR (270MHz, DMSO-d6) δppm: 3.90 (3H, s), 4.95 (2H,
s), 6.60(1H,dd,J=7.3,8.1Hz), 6.78(1H,d,J=7.3Hz), s), 6.60 (1H, dd, J = 7.3,8.1Hz), 6.78 (1H, d, J = 7.3Hz),
6.99(1H,dd,J=7.3,7.3Hz), 7.17(1H,d,J=7.3Hz),8.08(2 6.99 (1H, dd, J = 7.3,7.3Hz), 7.17 (1H, d, J = 7.3Hz), 8.08 (2
H,d,J=8.1Hz), 8.11(2H,d,J=8.1Hz), 9.85(1H,s) H, d, J = 8.1Hz), 8.11 (2H, d, J = 8.1Hz), 9.85 (1H, s)

【0338】(132−3) 工程(132−2)で得られた化合物2.71g(10.0mmol)のジオキサン(100ml)−水(50ml)溶液に5%水酸化ナトリウム水溶液を氷冷下で加えた後、さらにジ−te [0338] (132-3) step (132-2) in dioxane compound obtained in 2.71 g (10.0 mmol) (100 ml) - water (50ml) solution of 5% sodium hydroxide aqueous solution under ice-cooling after the addition, further di -te
rt−ブチルジカ−ボネート2.62g(12.0mm rt- Buchirujika - Boneto 2.62g (12.0mm
ol)のジオキサン(40ml)溶液を滴下した。 ol) dioxane (40 ml) was added dropwise. 室温で4時間攪拌後、一晩放置した。 After stirring at room temperature for 4 hours, allowed to stand overnight. 飽和食塩水及び酢酸エチルを加え二層に分離した後、水層を酢酸エチルで抽出した。 After separation of the two layers added saturated brine and ethyl acetate, the aqueous layer was extracted with ethyl acetate. 有機層を飽和食塩水洗浄した後、乾燥、溶媒を留去して得られた残渣をメタノールで洗浄することにより、N−[2−(N−tert−ブトキシカルボニル) The organic layer was washed with saturated brine, dried, and the solvent was distilled off to give residue was washed with methanol, N- [2- (N-tert- butoxycarbonyl)
アミノフェニル]−4−メトキシカルボニルベンズアミド3.54g(収率95.7%)を淡褐色固体として得た。 Aminophenyl] -4-methoxycarbonyl benzamide 3.54g of (95.7% yield) as a light brown solid. 1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 3.90(3H, 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 3.90 (3H,
s), 7.12-7.24(2H,m), 7.55-7.58(2H,m), 8.09(2H,d,J= s), 7.12-7.24 (2H, m), 7.55-7.58 (2H, m), 8.09 (2H, d, J =
8.8Hz), 8.10(2H,d,J=8.8Hz), 8.72(1H,s), 10.00(1H, 8.8Hz), 8.10 (2H, d, J = 8.8Hz), 8.72 (1H, s), 10.00 (1H,
s). s).

【0339】(132−4) 工程(132−3)で得た化合物3.00g(8.10mmol)のメタノール(50ml)−0.5規定水酸化リチウム水溶液(25 [0339] (132-4) in methanol (50 ml) -0.5 N aqueous lithium hydroxide solution of step the compound obtained in (132-3) 3.00 g (8.10 mmol) (25
ml)懸濁液を40℃で5時間加温攪拌した。 ml) The suspension was stirred for 5 hours by heating to 40 ° C.. メタノールを留去した後、得られた残渣に1規定塩酸水溶液を加え、さらに酢酸エチルで抽出した。 After distilling off the methanol, 1 N hydrochloric acid aqueous solution to the resulting residue and the mixture was further extracted with ethyl acetate. 有機層を少量の水及び飽和食塩水で洗浄した後、乾燥した。 After washing the organic layer with a small amount of water and saturated brine, and dried. 溶媒を留去して得られた残渣をメタノールで洗浄することにより、テレフタル酸 モノ−2−(N−tert−ブトキシカルボニル)アミノアニリド2.24g(収率77.6%)を淡褐色固体として得た。 The residue obtained by distilling off the solvent by washing with methanol, terephthalic acid mono-2-(N-tert-butoxycarbonyl) Aminoanirido 2.24g of (77.6% yield) as a pale brown solid Obtained. 1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 7.12-7.2 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 7.12-7.2
1(2H,m), 7.53-7.58(2H,m), 8.06(2H,d,J=8.8Hz), 8.10 1 (2H, m), 7.53-7.58 (2H, m), 8.06 (2H, d, J = 8.8Hz), 8.10
(2H,d,J=8.8Hz), 8.71(1H,s), 9.97(1H,s). (2H, d, J = 8.8Hz), 8.71 (1H, s), 9.97 (1H, s).

【0340】(132−5) 工程(132−4)で得た化合物0.20g(0.56mmol)のジクロロメタン(4ml)懸濁液にベンジルアミン0.14g [0340] (132-5) benzylamine in dichloromethane (4 ml) suspension of the compound obtained in step (132-4) 0.20 g (0.56 mmol) 0.14 g
(1.3mmol)を加え、さらにトリエチルアミン0.21ml(1.5mmol)を加えた。 (1.3 mmol) was added, further added triethylamine 0.21 ml (1.5 mmol). この溶液に氷冷下2−クロロ−1,3−ジメチルイミダゾリウムクロライド0.25g(1.48mmol)を加え、さらに氷冷下1時間、室温で1時間攪拌した。 To this solution under ice-cooling 2-chloro-1,3-dimethyl-imidazolium chloride 0.25g of (1.48 mmol) was added, further under ice cooling for 1 hour, and stirred at room temperature for 1 hour. クロロホルムで希釈した後、水を加え、水層をクロロホルムで抽出した。 After dilution with chloroform, water was added and the aqueous layer was extracted with chloroform.

【0341】有機層を飽和食塩水洗浄後、乾燥、溶媒を留去して得た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=10:1)で精製し、 [0341] The organic layer washed with saturated brine, dried, the residue obtained by distilling off the solvent was purified by silica gel column chromatography (chloroform: 1: methanol = 10),
得られた固体をエチルエーテルで洗浄することにより、 The resulting solid was washed with ethyl ether,
N−(2−tert−ブトキシカルボニルアミノフェニル)−4−(N−ベンジルアミノ)カルボニルベンズアミド279mg(収率62.6%)を白色固体として得た。 N-(2-tert-butoxycarbonylamino-phenyl)-4-(N-benzylamino) carbonyl benzamide 279mg of (62.6% yield) as a white solid. 1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 4.52(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.52 (2H,
d,J=5.8Hz), 7.13-7.28(4H,m), 7.34-7.35(3H,m), 7.56 d, J = 5.8Hz), 7.13-7.28 (4H, m), 7.34-7.35 (3H, m), 7.56
(2H,d,J=8.1Hz), 8.05(4H,s), 8.71(1H,br.s), 9.23(1 (2H, d, J = 8.1Hz), 8.05 (4H, s), 8.71 (1H, br.s), 9.23 (1
H,t), 9.94(1H,s). H, t), 9.94 (1H, s).

【0342】(132−6) 工程(132−5)で得た化合物151mg(0.339mmol)に4規定塩酸−ジオキサン溶液(5ml)を室温で加え、4時間攪拌した。 [0342] (132-6) 4 N hydrochloric acid in step the compound obtained in (132-5) 151 mg (0.339 mmol) - dioxane (5ml) was added at room temperature and stirred for 4 hours. 溶媒を留去した後、酢酸エチル/飽和重曹水で分離し、析出した沈澱を除いた後に水層をさらに酢酸エチルで抽出した。 After distilling off the solvent, partitioned between ethyl acetate / saturated aqueous sodium bicarbonate solution and extracted with more ethyl acetate aqueous layer after removing the precipitated precipitate. 有機層を飽和食塩水で洗浄後、乾燥、 The organic layer was washed with saturated brine, dried,
溶媒を留去して得た残渣にエチルエーテルを加え、析出した沈澱を濾取、乾燥することによりN−(2−アミノフェニル)−4−(N−ベンジルアミノ)カルボニルベンズアミド78mg(収率67%)を白色固体として得た。 The solvent of ethyl ether was added to the residue obtained by distilling off the, precipitated were collected by filtration precipitated and dried N-(2-aminophenyl)-4-(N-benzylamino) carbonyl benzamide 78 mg (yield: 67 %) as a white solid. mp. 239-241℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.51(2H,s), 4.93(2H, . Mp 239-241 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 4.51 (2H, s), 4.93 (2H,
br.d), 6.60(1H,dd,J=7.3,7.3Hz), 6.78(1H,d,J=8.1H br.d), 6.60 (1H, dd, J = 7.3,7.3Hz), 6.78 (1H, d, J = 8.1H
z), 6.95(1H,dd,J=7.3,8.3Hz), 7.18(1H,d), 7.23-7.35 z), 6.95 (1H, dd, J = 7.3,8.3Hz), 7.18 (1H, d), 7.23-7.35
(5H,m), 8.01(2H,d,J=8.8Hz), 8.07(2H,d,J=8.8Hz), 9. (5H, m), 8.01 (2H, d, J = 8.8Hz), 8.07 (2H, d, J = 8.8Hz), 9.
22(1H,br.t), 9.81(1H,br.s). 22 (1H, br.t), 9.81 (1H, br.s).

【0343】実施例132と同様の方法により、実施例133の化合物を合成した。 [0343] By the same method as in Example 132, to synthesize a compound of Example 133. 以下に、化合物の融点(m Below the melting point of the compound (m
p.)、1H NMR、IRの測定値を示す。 p.), shows IH NMR, the measurement of IR.

【0344】実施例133 N−(2−アミノフェニル)−4−[N−(2−フェニルエチル)アミノ]カルボニルベンズアミド(表−1: [0344] Example 133 N-(2-aminophenyl) -4- [N- (2- phenylethyl) amino] carbonyl benzamide (Table 1:
化合物番号9) mp. 237-240℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 2.87(2H,t,J=7.3Hz), . Compound No. 9) mp 237-240 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 2.87 (2H, t, J = 7.3Hz),
3.51(2H,dt,J=5.9,7.3Hz), 4.94(2H,br.s), 6.60(1H,d 3.51 (2H, dt, J = 5.9,7.3Hz), 4.94 (2H, br.s), 6.60 (1H, d
d,J=7.3,7.3Hz), 6.78(1H,d,J=7.3Hz), 6.98(1H,dd,J= d, J = 7.3,7.3Hz), 6.78 (1H, d, J = 7.3Hz), 6.98 (1H, dd, J =
7.3,7.3Hz), 7.15-7.34(6H,m), 7.93(2H,d,J=8.1Hz), 7.3,7.3Hz), 7.15-7.34 (6H, m), 7.93 (2H, d, J = 8.1Hz),
8.04(2H,d,J=8.1Hz),8.73(1H,t,J=5.1Hz), 9.76(1H,br. 8.04 (2H, d, J = 8.1Hz), 8.73 (1H, t, J = 5.1Hz), 9.76 (1H, br.
s).IR(KBr)cm-1: 3396,3320,1625,1602,1539,1458,131 s) .IR (KBr) cm-1: 3396,3320,1625,1602,1539,1458,131
3,699. 3,699.

【0345】実施例134 N−(2−アミノフェニル)−4−[N−(4−ニトロフェノキシアセチル)アミノ]ベンズアミド(表−1: [0345] Example 134 N-(2-aminophenyl) -4- [N- (4- nitrophenoxy) amino] benzamide (Table 1:
化合物番号54)の合成 (134−1) 実施例100の工程(100−2)で得られた化合物3g(9.2mmol)、4−ニトロフェノキシ酢酸2.16g(11.0mmol)のDMF DMF of Compound No. 54) Synthesis (134-1) Compound obtained in step (100-2) of Example 100 3 g (9.2 mmol), 4-nitrophenoxy acetic acid 2.16 g (11.0 mmol)
溶液(7ml)にジシクロヘキシルカルボジイミド2. Dicyclohexylcarbodiimide 2 in solution (7ml).
82g(13.8mmol)のDMF溶液(5ml)、 DMF solution of 82g (13.8mmol) (5ml),
触媒量のN,N−ジメチルアミノピリジンを加え1日間撹拌した。 A catalytic amount of N, and stirred for 1 day added N- dimethylaminopyridine. 反応終了後、酢酸エチルを加え、不溶物をセライト濾過し、溶媒を留去した。 After completion of the reaction, ethyl acetate was added, then filtered through Celite and the insoluble matter, the solvent was evaporated.

【0346】得られた残留物をクロロホルムから再結晶し、N−[2−(tert−ブトキシカルボニルアミノ)フェニル]−4−[(4−ニトロフェノキシアセチル)アミノ]ベンズアミド2.34g(収率50%)を得た。 [0346] The resulting residue was recrystallized from chloroform, N-[2-(tert-butoxycarbonylamino) phenyl] -4 - [(4-nitrophenoxy) amino] benzamide 2.34 g (yield: 50 %) was obtained. 1H NMR(270MHz, DMSO-d6)δppm: 1.45(9H,s), 4.97(2H, 1H NMR (270MHz, DMSO-d6) δppm: 1.45 (9H, s), 4.97 (2H,
s), 7.12-7.26(3H,m), 7.23(2H,d,J=8.8Hz), 7.53(1H,d s), 7.12-7.26 (3H, m), 7.23 (2H, d, J = 8.8Hz), 7.53 (1H, d
t,J=2.2,7.3Hz), 7.79(2H,d,J=8.8Hz), 7.95(2H,d,J=8. t, J = 2.2,7.3Hz), 7.79 (2H, d, J = 8.8Hz), 7.95 (2H, d, J = 8.
8Hz), 8.25(2H,d,J=8.8Hz), 8.71(1H,s), 9.79(1H,s), 8Hz), 8.25 (2H, d, J = 8.8Hz), 8.71 (1H, s), 9.79 (1H, s),
10.52(1H,s). 10.52 (1H, s).

【0347】(134−2) 工程(134−1)で得られた化合物0.7g(1.38mmol)のアセトニトリル溶液(10ml)に室温でヨードトリメチルシラン1.26ml(8.85mmol)を加え、2時間撹拌した。 [0347] The (134-2) Step iodotrimethylsilane at room temperature in acetonitrile solution (10ml) of the compound obtained in (134-1) 0.7 g (1.38 mmol) 1.26 ml (8.85 mmol) was added, and the mixture was stirred for 2 hours. 反応終了後、溶媒を濃縮し、酢酸エチルを加え20分間撹拌し、析出した結晶を濾取した。 After completion of the reaction, the solvent was concentrated, it was added and stirred for 20 min and ethyl acetate, and the precipitated crystals were collected by filtration. 得られた結晶をメチルエチルケトンに溶解し、飽和チオ硫酸ナトリウム水溶液、飽和食塩水で順次洗浄し、無水硫酸マグネシウムで乾燥し、溶媒を留去した。 The resulting dissolved crystals of methyl ethyl ketone, a saturated aqueous sodium thiosulfate, washed sequentially with saturated brine, dried over anhydrous magnesium sulfate, the solvent was distilled off. 得られた残留物を酢酸エチルで洗浄し、N−(2−アミノフェニル)−4− The resulting residue was washed with ethyl acetate, N-(2-aminophenyl) -4-
[N−(4−ニトロフェノキシアセチル)アミノ]ベンズアミド0.22g(収率39%)を白色結晶として得た。 The [N-(4-nitrophenoxy) amino] benzamide 0.22 g (39% yield) as white crystals.

【0348】mp. 212-215℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.97(2H,s), 6.88(1H, . [0348] mp 212-215 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 4.97 (2H, s), 6.88 (1H,
t,J=7.3Hz), 6.99(1H,d,J=7.3Hz), 7.11(1H,t,J=7.3H t, J = 7.3Hz), 6.99 (1H, d, J = 7.3Hz), 7.11 (1H, t, J = 7.3H
z), 7.23(2H,d,J=8.8Hz), 7.24(1H,m), 7.77(2H,d,J=8. z), 7.23 (2H, d, J = 8.8Hz), 7.24 (1H, m), 7.77 (2H, d, J = 8.
8Hz), 8.00(2H,d,J=8.8Hz), 8.25(2H,d,J=8.8Hz), 9.89 8Hz), 8.00 (2H, d, J = 8.8Hz), 8.25 (2H, d, J = 8.8Hz), 9.89
(1H,s), 10.52(1H,s). IR(KBr)cm-1: 3382,3109,1650,1591,1508,1341. . (1H, s), 10.52 (1H, s) IR (KBr) cm-1: 3382,3109,1650,1591,1508,1341.

【0349】実施例135 N−(2−アミノフェニル)−4−[(4−アミノフェノキシアセチル)アミノ]ベンズアミド(表−1:化合物番号55)の合成 実施例134の工程(134−1)で得られた化合物1.41g(2.78mmol)のメタノール(15m In: (Compound No. 55 Table 1) Step of Example 134 (134-1) - [0349] Example 135 N-(2-Aminophenyl) -4 [(4-aminophenoxy) amino] benzamide the resulting compound 1.41g of (2.78 mmol) in methanol (15 m
l)−THF(25ml)溶液に10%Pd−Cを加え水素雰囲気下室温で1時間撹拌した。 l) -THF (25ml) solution of 10% Pd-C was added and stirred for 1 hour at room temperature under hydrogen atmosphere. 反応終了後、触媒を濾過し溶媒を濃縮後、ジイソプロピルエーテルでスラッジングして、N−[2−(tert−ブトキシカルボニルアミノ)フェニル]−4−[(4−アミノフェノキシアセチル)アミノ]ベンズアミド1.1gを得た。 After the completion of the reaction, the catalyst was filtered solvent concentrated and sludging with diisopropyl ether, N-[2-(tert-butoxycarbonylamino) phenyl] -4 - [(4-aminophenoxy) amino] benzamide 1 It was obtained .1g.

【0350】これをアセトニトリル15mlに溶解し、 [0350] This was dissolved in acetonitrile 15ml,
ヨードトリメチルシラン0.74ml(5.20mmo Iodotrimethylsilane 0.74ml (5.20mmo
l)を加え、室温で3時間撹拌した。 l) and the mixture was stirred for 3 hours at room temperature. 反応終了後、溶媒を濃縮しメチルエチルケトンで洗浄して、N−(2−アミノフェニル)−4−[(4−アミノフェノキシアセチル)アミノ]ベンズアミド0.86g(収率83%)を得た。 After completion of the reaction, it was washed with solvent was concentrated methylethylketone, N-(2-aminophenyl) -4 - was obtained [(4-aminophenoxy) amino] benzamide 0.86 g (83% yield). mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 4.82(2H,s), 7.13(2H, .. Mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 4.82 (2H, s), 7.13 (2H,
d,J=8.8Hz), 7.30-7.48(6H,m), 7.82(2H,d,J=8.8Hz), d, J = 8.8Hz), 7.30-7.48 (6H, m), 7.82 (2H, d, J = 8.8Hz),
8.03(2H,d,J=8.8Hz), 10.34(1H,s), 10.46(1H,s).IR(KB 8.03 (2H, d, J = 8.8Hz), 10.34 (1H, s), 10.46 (1H, s) .IR (KB
r)cm-1: 2873,2590,1680,1602,1505,1243. r) cm-1: 2873,2590,1680,1602,1505,1243.

【0351】実施例136 N−(2−アミノフェニル)−4−(5−フェノキシメチル−1,3−オキサゾリン−2−オン−3−イル)ベンズアミド(表−2:化合物番号1)の合成(136− [0351] Example 136 N-(2-aminophenyl) -4- (5-phenoxymethyl-1,3-oxazolin-2-on-3-yl) benzamide: Synthesis of (Table 2 Compound No. 1) ( 136-
1) 4−(N−ベンジルオキシカルボニルアミノ)安息香酸t−ブチルエステル0.7g(2.14mmo 1) 4-(N-benzyloxycarbonylamino) benzoic acid t- butyl ester 0.7g (2.14mmo
l)のTHF溶液(10ml)に、−78℃でn−ブチルリチウム1.33ml(2.25mmol)を5分間かけて滴下した。 A THF solution (10ml) of l), was added dropwise over at -78 ° C. n-butyl lithium 1.33ml a (2.25 mmol) 5 minutes. 同温でさらに1.5時間撹拌した後、 After stirring for another 1.5 hours at the same temperature,
フェニルグリシドール0.31ml(2.29mmo Phenyl glycidol 0.31ml (2.29mmo
l)を加え同温で更に1時間撹拌した。 l) and the mixture was stirred for a further 1 hour at the same temperature. 室温で1日間放置した後、飽和塩化アンモニウム水溶液を加え、酢酸エチルで2回抽出し、有機層を硫酸マグネシウムで乾燥し、溶媒を留去した。 After standing at room temperature for one day, a saturated aqueous solution of ammonium chloride was added and the mixture was extracted twice with ethyl acetate, the organic layer was dried over magnesium sulfate, the solvent was distilled off. 得られた残査をエーテルから再結晶し、N−[4−(tert−ブトキシカルボニル)フェニル]−5−フェノキシメチル−1,3−オキサゾリジン−2−オン0.31g(収率39%)を得た。 The resulting residue was recrystallized from ether, N- [4- (tert- butoxycarbonyl) phenyl] -5-phenoxymethyl-1,3-oxazolidin-2-one 0.31g of (39% yield) Obtained. 1H NMR(270MHz, DMSO-d6)δppm: 1.53(9H,s), 3.97(1H, 1H NMR (270MHz, DMSO-d6) δppm: 1.53 (9H, s), 3.97 (1H,
dd,J=6.0,8.8Hz), 4.23-4.34(3H,m), 5.11(1H,m), 6.94 dd, J = 6.0,8.8Hz), 4.23-4.34 (3H, m), 5.11 (1H, m), 6.94
-7.00(3H,m), 7.31(2H,m), 7.71(2H,d,J=8.8Hz),7.93(2 -7.00 (3H, m), 7.31 (2H, m), 7.71 (2H, d, J = 8.8Hz), 7.93 (2
H,d,J=8.8Hz). H, d, J = 8.8Hz).

【0352】(136−2) 工程(136−1)の化合物0.26g(0.704mmol)のアセトニトリル溶液(4ml)にトリメチルシリルアイオダイド0. [0352] (136-2) trimethylsilyl iodide 0 in acetonitrile solution (4 ml) in step (136-1) Compound of 0.26 g (0.704 mmol).
15ml(1.05mmol)を加え、室温で2時間撹拌した。 15ml of (1.05 mmol) was added and stirred for 2 hours at room temperature. 反応終了後、溶媒を濃縮し得られた濃縮物を酢酸エチル−メチルエチルケトンでスラッジングし、N− After completion of the reaction, ethyl acetate concentrate the solvent was concentrated and the resulting - was sludged with methyl ethyl ketone, N-
(4−カルボキシフェニル)−5−フェノキシメチル− (4-carboxyphenyl) -5-phenoxymethyl -
1,3−オキサゾリジン−2−オン0.2g(収率91 1,3-oxazolidin-2-one 0.2 g (yield: 91
%)を得た。 %) Was obtained. 1H NMR(270MHz, DMSO-d6)δppm: 3.98(1H,dd,J=6.6,9.6 1H NMR (270MHz, DMSO-d6) δppm: 3.98 (1H, dd, J = 6.6,9.6
Hz), 4.23-4.34(3H,m),5.10(1H,m), 6.94-6.99(3H,m), Hz), 4.23-4.34 (3H, m), 5.10 (1H, m), 6.94-6.99 (3H, m),
7.30(2H,t,J=8.1Hz), 7.72(2H,d,J=8.8Hz), 7.98(2H,d, 7.30 (2H, t, J = 8.1Hz), 7.72 (2H, d, J = 8.8Hz), 7.98 (2H, d,
J=8.8Hz), 12.85(1H,s). J = 8.8Hz), 12.85 (1H, s).

【0353】(136−3) 工程(136−2)の化合物0.15g(0.479mmol)の塩化メチレン溶液(7ml)に触媒量のDMFを加えた後、オキザリルクロライド0.12ml(1.40mmol)を加え室温で2時間撹拌した。 [0353] (136-3) was added a catalytic amount of DMF in step methylene chloride (7 ml) of the compound 0.15 g (0.479 mmol) of (136-2), oxalyl chloride 0.12 ml (1. 40 mmol) and the mixture was stirred for 2 hours at room temperature. 次に溶媒を濃縮し、トルエンで2回共沸した後塩化メチレン(4ml)に溶解し、氷冷下実施例1の工程(1−2)の化合物0.105g The solvent was concentrated, dissolved in methylene chloride (4 ml) was azeotroped twice with toluene, the compound of step under ice-cooling Example 1 (1-2) 0.105 g
(0.504mmol)、ピリジン0.12g(1.5 (0.504mmol), pyridine 0.12g (1.5
2mmol)の塩化メチレン溶液(1ml)を加えた後、室温に昇温し1時間撹拌した。 After addition of 2 mmol) of methylene chloride solution (1 ml), and stirred heated 1 hour at room temperature. 反応終了後、水を加えクロロホルムで2回抽出し、有機層を飽和食塩水で洗浄した。 After the reaction, water was added and extracted twice with chloroform, and the organic layer was washed with saturated brine. 硫酸マグネシウムで乾燥後、溶媒を留去した。 After drying over magnesium sulfate, the solvent was distilled off.
得られた残査をイソプロピルエーテルでスラッジングし、N−[2−(N−tert−ブトキシカルボニルアミノ)フェニル]−4−(5−フェノキシメチル−1, The resulting residue was sludged with isopropyl ether, N- [2- (N-tert- butoxycarbonylamino) phenyl] -4- (5-phenoxymethyl-1,
3−オキサゾリン−2−オン−3−イル)ベンズアミド0.25g(定量的)を得た。 3-oxazolin-2-on-3-yl) benzamide 0.25 g (quantitative). 1H NMR(270MHz, DMSO-d6)δppm: 1.52(9H,s), 4.11(1H, 1H NMR (270MHz, DMSO-d6) δppm: 1.52 (9H, s), 4.11 (1H,
dd,J=5.9,6.6Hz), 4.21-4.27(3H,m), 5.01(1H,m), 6.84 dd, J = 5.9,6.6Hz), 4.21-4.27 (3H, m), 5.01 (1H, m), 6.84
(1H,br.s), 6.91(2H,d,J=8.8Hz), 7.01(1H,t,J=7.4Hz), (1H, br.s), 6.91 (2H, d, J = 8.8Hz), 7.01 (1H, t, J = 7.4Hz),
7.12-7.34(5H,m), 7.68(2H,d,J=8.8Hz). 7.12-7.34 (5H, m), 7.68 (2H, d, J = 8.8Hz).

【0354】(136−4) 工程(136−3)の化合物0.22g(0.437mmol)のアセトニトリル溶液(4ml)に室温でトリメチルシリルアイオダイド0.1ml(0.703mmol)を加え2時間撹拌した。 [0354] (136-4) was added, followed by stirring for 2 hours trimethylsilyl iodide 0.1 ml (0.703Mmol) at room temperature in Step acetonitrile (4 ml) of the compound of (136-3) 0.22 g (0.437 mmol) . 飽和チオ硫酸ナトリウム水溶液を加えた後、酢酸エチルで2回抽出し、有機層を硫酸マグネシウムで乾燥後、溶媒を留去した。 After addition of saturated aqueous sodium thiosulfate solution, and extracted twice with ethyl acetate. The organic layer was dried over magnesium sulfate, the solvent was distilled off. 得られた残留物をメタノールから再結晶し、N−(2−アミノフェニル)−4−(5−フェノキシメチル−1,3−オキサゾリン−2−オン−3 The resulting residue was recrystallized from methanol, N-(2-aminophenyl) -4- (5-phenoxymethyl-1,3-oxazolin-2-one -3
−イル)ベンズアミド0.13g(収率74%)を白色結晶として得た。 - give yl) benzamide 0.13g (74% yield) as white crystals. mp. 165-170℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.01(1H,dd,J=6.6,9.6 . Mp 165-170 ℃ 1H NMR (270MHz, DMSO-d6) δppm (dec.):. 4.01 (1H, dd, J = 6.6,9.6
Hz), 4.28-4.34(3H,m),5.12(1H,m), 5.23(2H,br.s), 6. Hz), 4.28-4.34 (3H, m), 5.12 (1H, m), 5.23 (2H, br.s), 6.
64(1H,t,J=7.4Hz), 6.81(1H,d,J=8.1Hz), 6.95-7.00(3 64 (1H, t, J = 7.4Hz), 6.81 (1H, d, J = 8.1Hz), 6.95-7.00 (3
H,m), 7.18(1H,d,J=6.6Hz), 7.31(2H,t,J=8.1Hz), 7.72 H, m), 7.18 (1H, d, J = 6.6Hz), 7.31 (2H, t, J = 8.1Hz), 7.72
(2H,d,J=8.8Hz),8.05(2H,d,J=8.8Hz), 9.69(1H,s). IR(KBr)cm-1: 3393,1740,1610,1508,1253. . (2H, d, J = 8.8Hz), 8.05 (2H, d, J = 8.8Hz), 9.69 (1H, s) IR (KBr) cm-1: 3393,1740,1610,1508,1253.

【0355】実施例136と同様の方法により、実施例137から143の化合物を合成した。 [0355] By the same method as in Example 136 was synthesized compound from Example 137 143. 以下に、化合物の化合物の融点(mp.)、1H NMR、IRの測定値を示す。 Hereinafter, the melting point (mp.) Of the compound of the compound, IH NMR, shows the measurements of IR.

【0356】実施例137 N−(2−アミノフェニル)−4−[5−(4−ニトロフェノキシ)メチル−1,3−オキサゾリン−2−オン−3−イル]ベンズアミド(表−2:化合物番号2) mp. 162-164℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.97(1H,dd,J=6.6,9.5 [0356] Example 137 N-(2-aminophenyl) -4- [5- (4-nitrophenoxy) methyl-1,3-oxazolin-2-one-3-yl] benzamide (Table 2: Compound No. .. 2) mp 162-164 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.97 (1H, dd, J = 6.6,9.5
Hz), 4.10(1H,dd,J=5.1,11.0Hz), 4.17(1H,dd,J=3.7,1 Hz), 4.10 (1H, dd, J = 5.1,11.0Hz), 4.17 (1H, dd, J = 3.7,1
1.0Hz), 4.27(1H,t,J=8.8Hz), 6.53-6.80(6H,m),6.97(1 1.0Hz), 4.27 (1H, t, J = 8.8Hz), 6.53-6.80 (6H, m), 6.97 (1
H,t,J=8.1Hz), 7.16(1H,d,J=6.6Hz), 7.72(2H,d,J=8.8H H, t, J = 8.1Hz), 7.16 (1H, d, J = 6.6Hz), 7.72 (2H, d, J = 8.8H
z), 8.04(2H,d,J=8.8Hz), 9.65(1H,s). IR(KBr)cm-1: 3356,2365,1741,1609,1510,1247. . Z), 8.04 (2H, d, J = 8.8Hz), 9.65 (1H, s) IR (KBr) cm-1: 3356,2365,1741,1609,1510,1247.

【0357】実施例138 N−(2−アミノフェニル)−4−(5−ベンジルオキシメチル−1,3−オキサゾリン−2−オン−3−イル)ベンズアミド 塩酸塩(表−2:化合物番号3の塩酸塩) mp. 181-183℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.69(1H,dd,J=5.2,11. [0357] Example 138 N-(2-aminophenyl) -4- (5-benzyloxy-1,3-oxazolin-2-on-3-yl) benzamide hydrochloride (Table 2: Compound No. 3 .. hydrochloride) mp 181-183 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.69 (1H, dd, J = 5.2,11.
0Hz), 3.76(1H,dd,J=3.7,11.0Hz), 3.91(1H,dd,J=5.9, 0Hz), 3.76 (1H, dd, J = 3.7,11.0Hz), 3.91 (1H, dd, J = 5.9,
8.8Hz), 4.59(2H,s), 4.93(1H,m), 7.26-7.41(8H,m), 8.8Hz), 4.59 (2H, s), 4.93 (1H, m), 7.26-7.41 (8H, m),
7.51(1H,m), 7.74(2H,d,J=8.8Hz), 8.15(2H,d,J=8.8H 7.51 (1H, m), 7.74 (2H, d, J = 8.8Hz), 8.15 (2H, d, J = 8.8H
z), 10.42(1H,s). z), 10.42 (1H, s).

【0358】実施例139 N−(2−アミノフェニル)−4−[5−(ピリジン− [0358] Example 139 N-(2-aminophenyl) -4- [5- (pyridin -
3−イル)オキシメチル−1,3−オキサゾリン−2− 3-yl) oxy-1,3-oxazolin-2
オン−3−イル]ベンズアミド(表−2:化合物番号4) mp. 199-201℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.01(1H,dd,J=6.6,8.8 One-3-yl] benzamide.. (Table 2: Compound No. 4) mp 199-201 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.01 (1H, dd, J = 6.6,8.8
Hz), 4.28-4.46(3H,m),4.96(2H,br.s), 5.14(1H,m), 6. Hz), 4.28-4.46 (3H, m), 4.96 (2H, br.s), 5.14 (1H, m), 6.
61(1H,t,J=7.4Hz), 6.79(1H,d,J=7.4Hz), 6.98(1H,t,J= 61 (1H, t, J = 7.4Hz), 6.79 (1H, d, J = 7.4Hz), 6.98 (1H, t, J =
7.4Hz), 7.16(1H,d,J=7.4Hz), 7.36(1H,dd,J=4.4,8.1H 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.36 (1H, dd, J = 4.4,8.1H
z), 7.44(1H,dd,J=1.5,8.1Hz). IR(KBr)cm-1: 2815,2631,2365,1752,1610,1520,1225. . Z), 7.44 (1H, dd, J = 1.5,8.1Hz) IR (KBr) cm-1: 2815,2631,2365,1752,1610,1520,1225.

【0359】実施例140 N−(2−アミノフェニル)−4−[5−(ピリジン− [0359] Example 140 N-(2-aminophenyl) -4- [5- (pyridin -
3−イル)メチルオキシメチル−1,3−オキサゾリン−2−オン−3−イル]ベンズアミド(表−2:化合物番号5) mp. 160-164℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 3.73(1H,dd,J=5.2,11. 3-yl) methyloxy-1,3-oxazolin-2-one-3-yl] benzamide (Table 2:... Compound No. 5) mp 160-164 ℃ (dec) 1H NMR (270MHz, DMSO- d6) δppm: 3.73 (1H, dd, J = 5.2,11.
7Hz), 3.79(1H,dd,J=2.9,11.7Hz), 3.91(1H,dd,J=5.9, 7Hz), 3.79 (1H, dd, J = 2.9,11.7Hz), 3.91 (1H, dd, J = 5.9,
8.8Hz), 4.21(1H,t,J=8.8Hz), 4.62(2H,s), 4.91(3H,b 8.8Hz), 4.21 (1H, t, J = 8.8Hz), 4.62 (2H, s), 4.91 (3H, b
rs), 6.60(1H,t,J=7.4Hz), 6.78(1H,d,J=7.4Hz), 6.98 rs), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.4Hz), 6.98
(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.38(1H,dd,J= (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.38 (1H, dd, J =
4.4,7.4Hz), 7.69(2H,d,J=8.8Hz), 7.71(1H,m), 8.03(2 4.4,7.4Hz), 7.69 (2H, d, J = 8.8Hz), 7.71 (1H, m), 8.03 (2
H,d,J=8.8Hz), 8.51(1H,dd,J=1.5,4.4Hz), 8.54(1H,d,J H, d, J = 8.8Hz), 8.51 (1H, dd, J = 1.5,4.4Hz), 8.54 (1H, d, J
=1.5Hz), 9.65(1H,s). IR(KBr)cm-1: 3368,1742,1648,1608,1492,1226. = 1.5Hz), 9.65 (1H, s) IR (KBr) cm-1:. 3368,1742,1648,1608,1492,1226.

【0360】実施例141 N−(2−アミノフェニル)−4−[5−(3−ニトロフェノキシ)メチル−1,3−オキサゾリン−2−オン−3−イル]ベンズアミド(表−2:化合物番号6) mp. 230℃(dec.). 1H NMR(270MHz, DMSO-d6)δppm: 4.04(1H,t,J=8.8Hz), [0360] Example 141 N-(2-aminophenyl) -4- [5- (3-nitrophenoxy) methyl-1,3-oxazolin-2-one-3-yl] benzamide (Table 2: Compound No. . 6) mp 230 ℃ (dec) 1H NMR (270MHz, DMSO-d6) δppm:.. 4.04 (1H, t, J = 8.8Hz),
4.32(1H,t,J=8.8Hz), 4.41-4.53(2H,m), 4.91(2H,s), 4.32 (1H, t, J = 8.8Hz), 4.41-4.53 (2H, m), 4.91 (2H, s),
5.15(1H,m), 6.61(1H,t,J=7.4Hz), 6.79(1H,d,J=7.4H 5.15 (1H, m), 6.61 (1H, t, J = 7.4Hz), 6.79 (1H, d, J = 7.4H
z), 6.98(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.46(1 z), 6.98 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.46 (1
H,dd,J=1.5,8.1Hz),7.61(1H,t,J=8.1Hz), 7.71-7.79(3 H, dd, J = 1.5,8.1Hz), 7.61 (1H, t, J = 8.1Hz), 7.71-7.79 (3
H,m), 7.87(1H,d,J=8.1Hz), 8.06(2H,d,J=8.8Hz), 9.66 H, m), 7.87 (1H, d, J = 8.1Hz), 8.06 (2H, d, J = 8.8Hz), 9.66
(1H,s). IR(KBr)cm-1: 3363,3095,2365,1741,1608,1529. . (1H, s) IR (KBr) cm-1: 3363,3095,2365,1741,1608,1529.

【0361】実施例142 N−(2−アミノフェニル)−4−[5−(ピリジン− [0361] Example 142 N-(2-aminophenyl) -4- [5- (pyridin -
2−イル)メチルオキシメチル−1,3−オキサゾリン−2−オン−3−イル]ベンズアミド(表−2:化合物番号7) mp. 172-174℃. 1H NMR(270MHz, DMSO-d6)δppm: 3.79(1H,dd,J=5.2,11. 2-yl) methyloxy-1,3-oxazolin-2-one-3-yl] benzamide (Table 2:.. Compound No. 7) mp 172-174 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 3.79 (1H, dd, J = 5.2,11.
0Hz), 3.85(1H,dd,J=2.9,11.0Hz), 3.95(1H,dd,J=6.6, 0Hz), 3.85 (1H, dd, J = 2.9,11.0Hz), 3.95 (1H, dd, J = 6.6,
9.6Hz), 4.23(1H,t,J=9.6Hz), 4.67(2H,s), 4.90(2H, 9.6Hz), 4.23 (1H, t, J = 9.6Hz), 4.67 (2H, s), 4.90 (2H,
s), 4.95(1H,m), 6.60(1H,t,J=7.4Hz), 6.78(1H,d,J=7. s), 4.95 (1H, m), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.
4Hz), 6.97(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.29 4Hz), 6.97 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.29
(1H,dd,J=5.2,6.6Hz), 7.40(1H,d,J=6.6Hz),7.70(2H,d, (1H, dd, J = 5.2,6.6Hz), 7.40 (1H, d, J = 6.6Hz), 7.70 (2H, d,
J=8.8Hz), 7.78(1H,dt,J=2.2,7.4Hz), 8.03(2H,d,J=8.8 J = 8.8Hz), 7.78 (1H, dt, J = 2.2,7.4Hz), 8.03 (2H, d, J = 8.8
Hz), 8.51(1H.d,J=4.4Hz), 9.64(1H,s). IR(KBr)cm-1: 3369,1743,1651,1608,1492,1283. . Hz), 8.51 (1H.d, J = 4.4Hz), 9.64 (1H, s) IR (KBr) cm-1: 3369,1743,1651,1608,1492,1283.

【0362】実施例143 N−(2−アミノフェニル)−4−[5−(ピリジン− [0362] Example 143 N-(2-aminophenyl) -4- [5- (pyridin -
2−イル)オキシメチル−1,3−オキサゾリン−2− 2-yl) oxy-1,3-oxazolin-2
オン−3−イル]ベンズアミド(表−2:化合物番号8) mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.96(1H,dd,J=5.9,9.6 One-3-yl] benzamide.. (Table 2: Compound No. 8) mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 3.96 (1H, dd, J = 5.9,9.6
Hz), 4.21-4.40(3H,m),4.90(2H,s), 5.03(1H,m), 6.28 Hz), 4.21-4.40 (3H, m), 4.90 (2H, s), 5.03 (1H, m), 6.28
(1H,t,J=6.6Hz), 6.43(1H,d,J=9.6Hz), 6.60(1H,t,J=6. (1H, t, J = 6.6Hz), 6.43 (1H, d, J = 9.6Hz), 6.60 (1H, t, J = 6.
6Hz), 6.78(1H,d,J=6.6Hz), 6.97(1H,t,J=7.4Hz), 7.15 6Hz), 6.78 (1H, d, J = 6.6Hz), 6.97 (1H, t, J = 7.4Hz), 7.15
(1H,d,J=6.6Hz),7.46(1H,dt,J=7.4,1.5Hz), 7.67(2H,d, (1H, d, J = 6.6Hz), 7.46 (1H, dt, J = 7.4,1.5Hz), 7.67 (2H, d,
J=8.8Hz), 7.69(1H,m), 8.03(2H,d,=8.8Hz), 9.64(1H, J = 8.8Hz), 7.69 (1H, m), 8.03 (2H, d, = 8.8Hz), 9.64 (1H,
s). s).

【0363】実施例144 N−(2−アミノフェニル)−4−[N−[3−[(ピリジン−3−イル)メチルアミノ]シクロブテン−1, [0363] Example 144 N-(2-aminophenyl) -4- [N- [3 - [(pyridin-3-yl) methylamino] cyclobutene-1,
2−ジオン−4−イル]アミノメチル]ベンズアミド(表−2:化合物番号9) (144−1) 3,4−ジ−n−ブトキシ−3−シクロブテン−1,2−ジオン0.073g(0.323m 2-dione-4-yl] aminomethyl] benzamide (Table 2: Compound No. 9) (144-1) 3,4-di -n- butoxy-3-cyclobutene-1,2-dione 0.073 g (0 .323m
mol)のTHF溶液(2ml)に実施例1の工程(1 THF solution (2 ml) in Example 1 steps mol) (1
−4)の化合物0.1g(0.293mmol)を加え4時間撹拌した後、さらに3−アミノメチルピリジン0.033ml(0.327mmol)を加え1日間反応した。 -4) of the compound 0.1 g (0.293 mmol) of After stirring for 4 hours, and the mixture was reacted for 1 day further added 3-aminomethylpyridine 0.033 ml (0.327 mmol). 反応終了後、水を加えメチルエチルケトンで2 After completion of the reaction, 2 methyl ethyl ketone was added water
回抽出した。 And extraction times. 有機層を無水硫酸マグネシウムで乾燥後、 The organic layer was dried over anhydrous magnesium sulfate,
溶媒を留去した。 The solvent was distilled off.

【0364】得られた残留物をメタノールでスラッジングしてN−[2−(N−tert−ブトキシカルボニルアミノ)フェニル]−4−[N−[3−[(ピリジン− [0364] The resulting residue was sludged with methanol N- [2- (N-tert- butoxycarbonylamino) phenyl] -4- [N- [3 - [(pyridin -
3−イル)メチルアミノ]シクロブテン−1,2−ジオン−4−イル]アミノメチル]ベンズアミド0.12g 3-yl) methylamino] cyclobutene-4-yl] aminomethyl] benzamide 0.12g
(収率78%)を得た。 Was obtained (78% yield). 1H NMR(270MHz, DMSO-d6)δppm: 1.44(9H,s), 4.75-4.8 1H NMR (270MHz, DMSO-d6) δppm: 1.44 (9H, s), 4.75-4.8
1(4H,m), 7.15(1H,dt,J=2.2,7.4Hz), 7.20(1H,dt,J=2. 1 (4H, m), 7.15 (1H, dt, J = 2.2,7.4Hz), 7.20 (1H, dt, J = 2.
2,7.4Hz), 7.40(1H,dd,J=2.2,7.4Hz), 7.47(2H,dJ=8.1 2,7.4Hz), 7.40 (1H, dd, J = 2.2,7.4Hz), 7.47 (2H, dJ = 8.1
Hz), 7.54(2H,dd,J=2.2,7.4Hz), 7.73(1H,m), 7.94(2H, Hz), 7.54 (2H, dd, J = 2.2,7.4Hz), 7.73 (1H, m), 7.94 (2H,
d,J=8.1Hz), 8.50(1H,m), 8.55(1H,d,J=1.5Hz), 8.67(1 d, J = 8.1Hz), 8.50 (1H, m), 8.55 (1H, d, J = 1.5Hz), 8.67 (1
H,s), 9.82(1H,s). H, s), 9.82 (1H, s).

【0365】(144−2) 工程(144−1)の化合物0.1g(0.19mmol)のジオキサン(4m [0365] (144-2) in dioxane steps compound of (144-1) 0.1 g (0.19 mmol) (4m
l)−メタノール(1ml)溶液に4規定塩酸−ジオキサン(4ml)を加え2時間反応した。 l) - methanol (1 ml) was added 4N hydrochloric acid - 2 hours added dioxane (4 ml). 反応終了後、溶媒を濃縮し飽和重曹水で中和後、メチルエチルケトンを加え、得られた結晶を濾取してN−(2−アミノフェニル)−4−[N−[3−[(ピリジン−3−イル)メチルアミノ]シクロブテン−1,2−ジオン−4−イル] After completion of the reaction, was neutralized with solvent was concentrated saturated sodium bicarbonate solution, methyl ethyl ketone was added, resulting crystal was collected by filtration to give N-(2-aminophenyl) -4- [N- [3 - [(pyridin - 3-yl) methylamino] cyclobutene-4-yl]
アミノメチル]ベンズアミド0.04g(収率49%) Aminomethyl] benzamide 0.04 g (49% yield)
を得た。 It was obtained. mp. 230℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.76(2H,s), 4.79(2H, .. Mp 230 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.76 (2H, s), 4.79 (2H,
s), 4.90(2H,s), 6.60(1H,t,J=7.4Hz), 6.78(1H,d,J=7. s), 4.90 (2H, s), 6.60 (1H, t, J = 7.4Hz), 6.78 (1H, d, J = 7.
4Hz), 6.97(1H,t,J=7.4Hz), 7.16(1H,d,J=7.4Hz), 7.39 4Hz), 6.97 (1H, t, J = 7.4Hz), 7.16 (1H, d, J = 7.4Hz), 7.39
(1H,m), 7.43(2H,d,J=8.1Hz), 7.73(1H,d,J=8.1Hz), 7. (1H, m), 7.43 (2H, d, J = 8.1Hz), 7.73 (1H, d, J = 8.1Hz), 7.
97(2H,d,J=8.1Hz), 7.99(1H,br.s), 8.51(1H,d,J=8.1H 97 (2H, d, J = 8.1Hz), 7.99 (1H, br.s), 8.51 (1H, d, J = 8.1H
z), 8.55(1H,s), 9.64(1H,s). z), 8.55 (1H, s), 9.64 (1H, s).

【0366】実施例145 N−(2−アミノフェニル)−4−[3−(ピリジン− [0366] Example 145 N-(2-aminophenyl) -4- [3- (pyridin -
3−イル)メチルイミダゾリン−2−オン−1−イル] 3-yl) methyl-2-one-1-yl]
メチルベンズアミド(表−2:化合部番号10番) (145−1) エチレン尿素4.92g(57mmo Methylbenzamide (Table 2: compound unit number 10) (145-1) ethylene urea 4.92 g (57Mmo
l),メチル 4−ブロモメチルベンゾエート5.73 l), methyl 4-bromomethyl benzoate 5.73
g(25mmol)、ヨウ化 テトラノルマルブチルアンモニウム1.85g(5.0mmol)のDMF(3 g (25mmol), DMF iodide tetra-n-butylammonium 1.85g (5.0mmol) (3
0ml)溶液に炭酸カリウム7.88g(57mmo 0 ml) was added potassium carbonate 7.88g (57mmo
l)を加え、80℃で5時間加熱攪拌した。 l) was added and heated under stirring for 5 hours at 80 ° C..

【0367】放冷後、固体分を濾取した後酢酸エチルで固体分を洗浄した。 [0367] After cooling, washing the solids with ethyl acetate after filtration the solids. 濾液を濃縮した後、得られた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:メタノール=10:1)で精製して得られた淡黄色油状物にジイソプロピルエーテルを加え、析出した固体を濾取、乾燥することにより、N−(4−メトキシカルボニルフェニルメチル)イミダゾリン−2−オン3.36g The filtrate was concentrated, the resulting residue was purified by silica gel column chromatography (ethyl acetate: methanol = 10: 1) Diisopropyl ether was added to the pale yellow oil obtained was purified by precipitated solid was filtered off, dried by, N-(4-methoxycarbonylphenyl methyl) imidazolin-2-one 3.36g
(収率57.4%)を淡褐色固体として得た。 It was obtained (57.4% yield) as a light brown solid. 1H-NMR(270MHz,CDCl3)δppm: 3.28-3.35(2H,m), 3.41- 1H-NMR (270MHz, CDCl3) δppm: 3.28-3.35 (2H, m), 3.41-
3.47(2H,m), 3.92(3H,s),4.42(2H,s), 4.61(1H,br.s), 3.47 (2H, m), 3.92 (3H, s), 4.42 (2H, s), 4.61 (1H, br.s),
7.35(2H,d,J=8.1Hz), 8.01(2H,d,J=8.1Hz). 7.35 (2H, d, J = 8.1Hz), 8.01 (2H, d, J = 8.1Hz).

【0368】(145−2) 3−クロロメチルピリジン塩酸塩2.05g(12.5mmol)に飽和重曹水を加えた後、酢酸エチルで抽出した。 [0368] (145-2) was added a saturated aqueous sodium bicarbonate 3-chloromethyl-pyridine hydrochloride 2.05 g (12.5 mmol), and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣にトルエンを加え共沸し、さらに得られた残渣にDMF(5ml)を加えた後、ヨウ化 テトラノルマルブチルアンモニウム0.37g(1.0mmol)を加え、ベンジルハライドのDMF溶液を調製した。 The organic layer was washed with saturated brine, dried, and azeotroped with toluene to the residue obtained by distilling off the solvent, was added DMF (5 ml) to further the obtained residue, iodide tetra-n-butylammonium 0 .37g a (1.0 mmol) was added to prepare a DMF solution of benzyl halide. 水素化ナトリウム(60% Sodium hydride (60%
油状懸濁)0.30g(7.5mmol)のDMF(5 Oily suspension) DMF of 0.30g (7.5mmol) (5
ml)懸濁液に室温で、工程(145−1)で得た化合物1.17g(5.0mmol)のDMF(10ml) At room temperature ml) suspension, DMF of the compound obtained in step (145-1) 1.17g (5.0mmol) (10ml)
溶液を徐々に滴下した後、室温で30分攪拌した。 The solution was slowly added dropwise, and the mixture was stirred at room temperature for 30 minutes. この溶液に先に調製したベンジルハライド溶液を加えた後、 After the addition of benzyl halide solution prepared above to this solution,
80℃で7時間加熱攪拌した。 80 ° C. for 7 hours under heating and stirring.

【0369】一晩室温で放置した。 [0369] was allowed to stand at room temperature overnight. DMFを濃縮した後、酢酸エチル及び水を加え分離した。 After concentration of the DMF, it was separated by adding ethyl acetate and water. さらに水層を酢酸エチル−メチルエチルケトン(2:1)で抽出した。 Additional ethyl acetate and the aqueous layer - methyl ethyl ketone (2: 1).
有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た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:メタノール=10:1)で精製し、N−(4−メトキシカルボニルフェニルメチル)−N'−(ピリジン− The organic layer was washed with saturated brine, dried and the residue obtained by evaporated the silica gel column chromatography (ethyl acetate: methanol = 10: 1) to give, N-(4-methoxycarbonylphenyl methyl) - N '- (pyridine -
3−イル)メチルイミダゾリン−2−オン1.17g 3-yl) methyl-2-one 1.17g
(収率72.3%)を茶色油状物として得た。 The (72.3% yield) as a brown oil. 1H NMR(270MHz, CDCl3)δppm: 3.20(4H,s), 3.92(3H, 1H NMR (270MHz, CDCl3) δppm: 3.20 (4H, s), 3.92 (3H,
s), 4.44(2H,s), 4.46(2H,s), 7.27-7.36(3H,m), 7.64- s), 4.44 (2H, s), 4.46 (2H, s), 7.27-7.36 (3H, m), 7.64-
7.69(1H,m), 8.01(2H,d,J=8.1Hz), 8.53-8.56(2H,m). 7.69 (1H, m), 8.01 (2H, d, J = 8.1Hz), 8.53-8.56 (2H, m).

【0370】(145−3) 工程(145−2)で得た化合物0.55g(1.7mmol)のメタノール(8ml)−水(8ml)溶液に室温で水酸化リチウム1水和物110mg(2.62mmol)を加え50℃ [0370] (145-3) step (145-2) in methanol to give compound 0.55 g (1.7 mmol) in (8 ml) - water (8 ml) was added at room temperature lithium hydroxide monohydrate 110 mg (2 .62Mmol) was added 50 ° C.
で1.5時間加熱攪拌した後、さらに水酸化リチウム1 In After stirring for 1.5 h, further lithium hydroxide
水和物0.05g(1.2mmol)を加え、50℃で1.5時間攪拌した。 Hydrate 0.05g of (1.2 mmol) was added and stirred for 1.5 hours at 50 ° C.. 10%塩酸水溶液を用いて酸性(pH3〜4)にしたのち、飽和食塩水を加え、酢酸エチルで2回、酢酸エチル−メチルエチルケトン(1: After acidification (pH 3-4) with 10% aqueous hydrochloric acid, saturated brine was added, twice with ethyl acetate, ethyl acetate - ethyl ketone (1:
1)で1回抽出した。 Was extracted once with 1). 有機層を無水硫酸ナトリウムで乾燥後、溶媒留去して得た残渣を乾燥することにより4− The organic layer was dried over anhydrous sodium sulfate, and drying the residue obtained by evaporated 4-
[3−(ピリジン−3−イル)メチルイミダゾリン−2 [3- (pyridin-3-yl) methyl imidazoline -2
−オン−1−イル]メチル安息香酸0.32g(収率6 - one-1-yl] benzoate 0.32 g (yield: 6
1%)を茶色油状物として得た。 1%) was obtained as a brown oil. 1H NMR(270MHz, DMSO-d6)δppm: 3.17(2H,s), 3.20(2H, 1H NMR (270MHz, DMSO-d6) δppm: 3.17 (2H, s), 3.20 (2H,
s), 4.36(2H,s), 4.38(2H,s), 7.35-7.42(3H,m), 7.68 s), 4.36 (2H, s), 4.38 (2H, s), 7.35-7.42 (3H, m), 7.68
(1H,dd,J=6.6Hz),7.92(2H,d,J=8.1Hz), 8.51(2H,m). (1H, dd, J = 6.6Hz), 7.92 (2H, d, J = 8.1Hz), 8.51 (2H, m).

【0371】(145−4) 工程(145−3)で得た化合物0.31g(1.0mmol)のジクロロメタン(12ml)溶液に室温でオキザリルクロライド0. [0371] (145-4) Step oxalyl chloride 0 at room temperature in dichloromethane (12 ml) solution of the compound obtained in (145-3) 0.31 g (1.0 mmol).
3ml(3.5mmol)を滴下した後室温で30分、 30 minutes at room temperature was added dropwise 3 ml (3.5 mmol),
40℃で1.5時間攪拌した。 And the mixture was stirred for 1.5 hours at 40 ℃. 溶媒を留去した後トルエンで共沸し、ジクロロメタン10mlに懸濁した。 The solvent was co-evaporated with toluene was distilled off, suspended in dichloromethane 10 ml. この反応懸濁液を氷冷した後、実施例1の工程(1−2)の化合物0.21g(1.0mmol)のジクロロメタン(2ml)−ピリジン(2ml)溶液を滴下した。 After cooling the reaction suspension ice, dichloromethane (2 ml) of the compound of step of Example 1 (1-2) 0.21g (1.0mmol) - pyridine was added dropwise (2 ml) solution. 室温まで昇温させながら攪拌した後、室温で一晩放置した。 After stirring while warming up to room temperature and left overnight at room temperature.
飽和重曹水を加えた後クロロホルムで抽出した。 And extracted with chloroform after addition of a saturated aqueous sodium bicarbonate solution.

【0372】有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た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−メタノール=20:1)で精製することによりN−(2−tert−ブトキシカルボニルアミノフェニル)−4−[3−(ピリジン−3−イルメチル)イミダゾリン−2−オン−1−イル]メチルベンズアミド0.10g(収率20%)を茶色油状物として得た。 [0372] The organic layer was washed with saturated brine, dried and the residue obtained by evaporated the silica gel column chromatography (ethyl acetate - methanol = 20: 1) to give N-(2-tert butoxycarbonylamino) -4- [3- (pyridin-3-ylmethyl) imidazolin-2-one-1-yl] methyl benzamide 0.10g (20% yield) was obtained as a brown oil. 1H NMR(270MHz, CDCl3)δppm: 1.52(9H,s), 3.20(4H, 1H NMR (270MHz, CDCl3) δppm: 1.52 (9H, s), 3.20 (4H,
s), 4.45(2H,s),4.48(2H,s), 6.75(1H,br.s), 7.15-7.4 s), 4.45 (2H, s), 4.48 (2H, s), 6.75 (1H, br.s), 7.15-7.4
0(5H,m),7.65-7.70(2H,m), 7.83(1H,d,J=7.3Hz), 7.94 0 (5H, m), 7.65-7.70 (2H, m), 7.83 (1H, d, J = 7.3Hz), 7.94
(2H,d,J=8.1Hz), 8.50-8.60(3H,br.m). (2H, d, J = 8.1Hz), 8.50-8.60 (3H, br.m).

【0373】(145−5) 工程(145−4)で得た化合物100mg(0.20mmol)をジオキサン(2ml)に溶解した後、4規定塩酸−ジオキサン(2 [0373] (145-5) after the compound obtained in step (145-4) 100 mg of (0.20 mmol) was dissolved in dioxane (2 ml), 4 N hydrochloric acid - dioxane (2
ml)を加えた後、メタノール(0.5ml)を加え溶解させた。 After addition of ml), and added and dissolved in methanol (0.5 ml). 2時間攪拌後、飽和重曹水を加え中和した後、酢酸エチルで抽出した。 After stirring for 2 hours, after neutralized with saturated aqueous sodium bicarbonate solution, and extracted with ethyl acetate. 有機層を飽和食塩水で洗浄後、乾燥、溶媒留去して得た残渣を室温で減圧下乾燥することによりN−(2−アミノフェニル)−4−[3− The organic layer was washed with saturated brine, dried, the residue obtained by evaporated under reduced pressure under dry at room temperature N-(2-aminophenyl) -4- [3-
(ピリジン−3−イル)メチルイミダゾリン−2−オン−1−イル]メチルベンズアミド47mg(収率58 (Pyridin-3-yl) methyl-2-one-1-yl] methyl benzamide 47 mg (yield: 58
%)を褐色油状物として得た。 %) As a brown oil. mp. (amorphous). 1H NMR(270MHz, DMSO-d6)δppm: 3.20(4H,s), 4.37(2H, .. Mp (amorphous) 1H NMR (270MHz, DMSO-d6) δppm: 3.20 (4H, s), 4.37 (2H,
s), 4.39(2H,s), 4.87(2H,br.s), 6.60(1H,dd,J=7.3,7. s), 4.39 (2H, s), 4.87 (2H, br.s), 6.60 (1H, dd, J = 7.3,7.
3Hz), 6.78(1H,d,J=8.1Hz), 6.97(1H,dd,J=6.6,7.3Hz), 3Hz), 6.78 (1H, d, J = 8.1Hz), 6.97 (1H, dd, J = 6.6,7.3Hz),
7.16(1H,d,J=7.3Hz), 7.35-7.41(3H,m), 7.68(1H,d,J= 7.16 (1H, d, J = 7.3Hz), 7.35-7.41 (3H, m), 7.68 (1H, d, J =
8.1Hz), 7.90-8.00(2H,m), 8.50(2H,br.s), 9.63(1H,b 8.1Hz), 7.90-8.00 (2H, m), 8.50 (2H, br.s), 9.63 (1H, b
rs). rs).

【0374】実施例146 N−(2−アミノフェニル)−4−[N−(ピリジン− [0374] Example 146 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)メトキシカルボニルアミノメチル]ベンズアミド 0.5フマル酸塩(表−1:化合物番号82のフマル酸塩)の合成 実施例48で得られた化合物310mgをメタノール1 3-yl) methoxycarbonylamino-methyl] benzamide 0.5 fumarate (Table 1: Compound No. 82 methanol 1 compound 310mg obtained in Synthesis Example 48 of fumarate)
0mlに加え、加熱して溶解させた。 In addition to the 0 ml, it was dissolved by heating. フマル酸96mg Fumaric acid 96mg
をメタノールに溶解した溶液を加えた後、冷却した。 The was added to the solution which was dissolved in methanol and cooled. 析出した結晶をろ取し、メタノール5mlで再結晶し、目的物を200mg得た(収率56%)。 The precipitated crystals were collected by filtration and recrystallized from methanol 5 ml, the desired product was obtained 200 mg (56% yield).

【0375】mp. 166-167℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=6.6Hz), .. [0375] mp 166-167 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 6.6Hz),
5.10(2H,s), 6.60(1H,t,J=8.0Hz), 6.63(1H,s), 6.78(1 5.10 (2H, s), 6.60 (1H, t, J = 8.0Hz), 6.63 (1H, s), 6.78 (1
H,d,J=8.0Hz), 6.90-7.50(5H,m), 7.70-8.00(4H,m), 8. H, d, J = 8.0Hz), 6.90-7.50 (5H, m), 7.70-8.00 (4H, m), 8.
53(1H,d,J=3.6Hz), 8.60(1H,s), 9.63(1H,s). IR(KBr)cm-1: 3332,1715,1665,1505,1283,1136,1044,98 53 (1H, d, J = 3.6Hz), 8.60 (1H, s), 9.63 (1H, s) IR (KBr) cm-1:. 3332,1715,1665,1505,1283,1136,1044,98
3,760,712. 3,760,712.

【0376】実施例146と同様の方法により、実施例147から149の化合物を合成した。 [0376] By the same method as in Example 146 was synthesized compound from Example 147 149. 以下に、化合物の融点(mp.)、1H NMR、IRの測定値を示す。 Hereinafter, the melting point of the compound (mp.), 1H NMR, shows the measurements of IR.

【0377】実施例147 N−(2−アミノフェニル)−4−[N−(ピリジン− [0377] Example 147 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)メトキシカルボニルアミノメチル]ベンズアミド マレイン酸塩(表−1:化合物番号82のマレイン酸塩) mp. 123-124℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.28(2H,d,J=6.6Hz), 3-yl) methoxycarbonylamino-methyl] benzamide maleate (Table 1:.. Maleate) mp Compound No. 82 123-124 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.28 (2H, d, J = 6.6Hz),
5.11(2H,s), 6.24(2H,s), 6.66(1H,t,J=8.0Hz), 6.83(1 5.11 (2H, s), 6.24 (2H, s), 6.66 (1H, t, J = 8.0Hz), 6.83 (1
H,d,J=8.0Hz), 6.90-8.00(9H,m), 8.56(1H,d,J=3.6Hz), H, d, J = 8.0Hz), 6.90-8.00 (9H, m), 8.56 (1H, d, J = 3.6Hz),
8.62(1H,s), 9.69(1H,s). IR(KBr)cm-1: 3298,1719,1546,1365,1313,1250,1194,11 8.62 (1H, s), 9.69 (1H, s) IR (KBr) cm-1:. 3298,1719,1546,1365,1313,1250,1194,11
49,1044,993,862,751. 49,1044,993,862,751.

【0378】実施例148 N−(2−アミノフェニル)−4−[N−(ピリジン− [0378] Example 148 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)メトキシカルボニルアミノメチル]ベンズアミド 塩酸塩(表−1:化合物番号82の塩酸塩) mp. 140(dec.)℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.31(2H,d,J=5.8Hz), 3-yl) methoxycarbonylamino-methyl] benzamide hydrochloride (Table 1:... Compound No. 82 hydrochloride) mp 140 (dec) ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.31 (2H, d, J = 5.8Hz),
5.24(2H,s), 7.10-7.60(6H,m), 7.90-8.50(5H,m), 8.70 5.24 (2H, s), 7.10-7.60 (6H, m), 7.90-8.50 (5H, m), 8.70
-8.90(2H,m), 10.46(1H,s). IR(KBr)cm-1: 2553,1715,1628,1556,1486,1254,1049,77 -8.90 (2H, m), 10.46 (1H, s) IR (KBr) cm-1:. 2553,1715,1628,1556,1486,1254,1049,77
8,687. 8,687.

【0379】実施例149 N−(2−アミノフェニル)−4−[N−(ピリジン− [0379] Example 149 N-(2-aminophenyl) -4- [N- (pyridine -
3−イル)オキシアセチルアミノメチル]ベンズアミド 0.7フマル酸(表−1:化合物番号61のフマル酸塩) 実施例146と同様の方法により、実施例46の化合物より合成した。 3-yl) oxy acetylamino methyl] benzamide 0.7 fumarate (Table 1: in the same manner as fumarate) Example 146 Compound No. 61 was synthesized from the compound of Example 46. mp. 154-155℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.42(2H,d,J=5.9Hz), .. Mp 154-155 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.42 (2H, d, J = 5.9Hz),
4.69(2H,s), 6.60(1H,t,J=8.0Hz), 6.63(0.7H,s), 6.78 4.69 (2H, s), 6.60 (1H, t, J = 8.0Hz), 6.63 (0.7H, s), 6.78
(1H,d,J=8.0Hz), 6.90-7.50(6H,m), 7.93(2H,d,J=8.0H (1H, d, J = 8.0Hz), 6.90-7.50 (6H, m), 7.93 (2H, d, J = 8.0H
z), 8.20-8.40(2H,m), 8.82(1H,br.s), 9.63(1H,s). IR(KBr)cm-1: 3324,1709,1631,1521,1457,1428,1260,10 . Z), 8.20-8.40 (2H, m), 8.82 (1H, br.s), 9.63 (1H, s) IR (KBr) cm-1: 3324,1709,1631,1521,1457,1428,1260, Ten
64,806,698. 64,806,698.

【0380】参考例1 N−(3−アミノフェニル)−4−[N−(ピリジン− [0380] Reference Example 1 N-(3- aminophenyl) -4- [N- (pyridine -
3−イル)メトキシカルボニルアミノメチル]ベンズアミド 実施例48と同様の方法により合成した。 It was synthesized in the same manner as 3-yl) methoxycarbonylamino-methyl] benzamide Example 48. mp. 156℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.27(2H,d,J=6.6Hz), .. Mp 156 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 6.6Hz),
5.06(2H,s), 5.10(2H,s), 6.20-6.40(1H,m), 6.80-7.10 5.06 (2H, s), 5.10 (2H, s), 6.20-6.40 (1H, m), 6.80-7.10
(3H,m), 7.30-7.50(3H,m), 7.70-8.00(4H,m), 8.53(1H, (3H, m), 7.30-7.50 (3H, m), 7.70-8.00 (4H, m), 8.53 (1H,
d,J=3.6Hz), 8.59(1H,s), 9.88(1H,s). IR(KBr)cm-1: 3327,3218,1708,1639,1536,1279,1147,10 . D, J = 3.6Hz), 8.59 (1H, s), 9.88 (1H, s) IR (KBr) cm-1: 3327,3218,1708,1639,1536,1279,1147,10
50,859,788. 50,859,788.

【0381】参考例2 N−(4−アミノフェニル)−4−[N−(ピリジン− [0381] Reference Example 2 N-(4-aminophenyl) -4- [N- (pyridine -
3−イル)メトキシカルボニルアミノメチル]ベンズアミド 実施例48と同様の方法により合成した。 It was synthesized in the same manner as 3-yl) methoxycarbonylamino-methyl] benzamide Example 48. mp. 204-205℃. 1H NMR(270MHz, DMSO-d6)δppm: 4.27(2H,d,J=6.6Hz), .. Mp 204-205 ℃ 1H NMR (270MHz, DMSO-d6) δppm: 4.27 (2H, d, J = 6.6Hz),
4.91(2H,s), 5.10(2H,s), 6.52(2H,d,J=8.8Hz), 7.30- 4.91 (2H, s), 5.10 (2H, s), 6.52 (2H, d, J = 8.8Hz), 7.30-
7.50(5H,m), 7.70-8.00(4H,m), 8.50-8.60(2H,m),9.80 7.50 (5H, m), 7.70-8.00 (4H, m), 8.50-8.60 (2H, m), 9.80
(1H,s). IR(KBr)cm-1: 3336,3224,1706,1638,1530,1279,1145,10 . (1H, s) IR (KBr) cm-1: 3336,3224,1706,1638,1530,1279,1145,10
50,1005,827. 50,1005,827.

【0382】薬理試験例1 A2780細胞に対する分化誘導作用試験 アルカリフォスファターゼ(ALP)活性の上昇は、ヒト大腸癌細胞の分化の指標として知られており、例えば酪酸ナトリウムがALP活性を上昇させることが知られている[Youngら;Cancer Res. [0382] increase in Pharmacological Test Example 1 A2780 differentiation inducing action test alkaline phosphatase to cells (ALP) activity is known as an indicator of differentiation of human colon cancer cells, for example, that the sodium butyrate raises the ALP activity knowledge It is [Young et al; Cancer Res. , 4
、2976(1985)、Moritaら;Canc 5, 2976 (1985), Morita et al; Canc
er Res. er Res. 42 、4540(1982)]。 , 42, 4540 (1982)]. そこでALP活性を指標に分化誘導作用の評価を行った。 So it was evaluated for differentiation-inducing activity of the ALP activity as an index.

【0383】(実験方法) 96穴プレートに15,000ヶ/wellとなるように、A2780細胞を0.1ml [0383] (Experimental method) so that 15,000 month / well in 96-well plates, A2780 cells 0.1ml
ずつまき、翌日培地にて段階希釈した被験薬の溶液を0.1mlずつ添加した。 By Maki, it was added a solution of the test drug was serially diluted by the next day the medium by 0.1ml. 3日間培養後、プレート上の細胞をTBS緩衝液(20mMTris,137mM After 3 days of culture, the cells on the plate TBS buffer (20 mM Tris, 137 mM
NaCl、pH7.6)で2回洗浄した。 NaCl, and washed twice with pH7.6). ついで、0. Then, 0.
6mg/mlの濃度のp−ニトロフェニルフォスフェイト(9.6% ジエタノールアミン、0.5mM Mg 6 mg / ml concentration of p- nitrophenyl phosphate (9.6% diethanolamine, 0.5 mM Mg
Cl 2 (pH9.6))溶液を0.05mlずつ添加し、室温で30分インキュベートした。 Cl 2 (pH9.6)) solution was added portionwise 0.05 ml, and incubated for 30 minutes at room temperature. 3規定水酸化ナトリウム水溶液0.05mlで反応を停止した後、40 After quenching with 3 N aqueous sodium hydroxide 0.05 ml, 40
5nmの吸光度を測定し、ALP活性の上昇を惹起する薬物の最小濃度(ALPmin)を求めた。 Measuring the absorbance of 5 nm, determining the minimum concentration (ALPmin) drugs that cause an increase in ALP activity. (実験結果) 実験結果を、表−5[表31]に示した。 (Experiment Results) The experimental results are shown in Table 5 [Table 31].

【0384】 [0384]

【表31】表−5:A2780細胞に対する分化誘導作用 供試化合物 ALPmin(μM) 実施例1の化合物 1 実施例2の化合物 3 実施例3の化合物 3 実施例4の化合物 1 実施例5の化合物 1 実施例6の化合物 1 実施例7の化合物 1 実施例8の化合物 1 実施例9の化合物 1 Table 31 Table -5: Differentiation-inducing action test compound against A2780 cells ALPmin (μM) of Compound 1 Example 5 Compound 3 Example 4 Compound 3 Example 3 of Compound 1 Example 2 Example 1 1 compound 1 compound 1 example 9 compound 1 example 8 compound 1 example 7 example 6

【0385】 実施例10の化合物 3 実施例11の化合物 1 実施例13の化合物 1 実施例15の化合物 3 実施例16の化合物 3 実施例17の化合物 3 実施例18の化合物 3 実施例23の化合物 1 実施例24の化合物 1 実施例25の化合物 3 [0385] Compounds of Compound 3 Example 23 Compound 3 Example 18 Compound 3 Example 17 Compound 3 Example 16 Compound 1 Example 15 Compound 1 Example 13 Compound 3 Example 11 Example 10 1 compound 3 compound 1 example 25 example 24

【0386】 実施例26の化合物 1 実施例27の化合物 10 実施例28の化合物 10 実施例29の化合物 10 実施例30の化合物 0.1 実施例31の化合物 10 実施例32の化合物 3 実施例33の化合物 0.3 実施例34の化合物 0.1 実施例35の化合物 0.3 [0386] Compounds of Compound 3 Example 33 Compound 10 Example 32 Compound 0.1 Example 31 Compound 10 Example 30 Compound 10 Example 29 Compound 10 Example 28 Compound 1 Example 27 Example 26 0.3 of compound 0.1 eXAMPLE 35 example 34 0.3

【0387】 実施例36の化合物 10 実施例37の化合物 1 実施例38の化合物 3 実施例39の化合物 0.1 実施例40の化合物 10 実施例41の化合物 0.3 実施例42の化合物 10 実施例43の化合物 3 実施例44の化合物 0.01 実施例45の化合物 0.003 [0387] Compounds of Compound 10 Example 43 Compound 0.3 EXAMPLE 42 Compound 10 Example 41 Compound 0.1 EXAMPLE 40 Compound 3 Example 39 Compound 1 Example 38 Compound 10 Example 37 Example 36 3 of compound 0.01 example 45 example 44 0.003

【0388】 実施例46の化合物 0.1 実施例48の化合物 0.1 実施例49の化合物 1 実施例50の化合物 1 実施例51の化合物 1 実施例52の化合物 1 実施例53の化合物 3 実施例54の化合物 1 実施例55の化合物 1 実施例56の化合物 3 [0388] Compounds of Compound 3 Example 54 Compound 1 Example 53 Compound 1 Example 52 Compound 1 Example 51 Compound 1 Example 50 compound 0.1 Example 49 compound 0.1 Example 48 Example 46 1 compound 3 compound 1 example 56 example 55

【0389】 実施例57の化合物 3 実施例58の化合物 3 実施例59の化合物 3 実施例60の化合物 3 実施例63の化合物 3 実施例64の化合物 3 実施例65の化合物 3 実施例66の化合物 3 実施例67の化合物 3 実施例68の化合物 3 [0389] Compounds of Compound 3 Example 66 Compound 3 Example 65 Compound 3 Example 64 Compound 3 Example 63 Compound 3 Example 60 Compound 3 Example 59 Compound 3 Example 58 Example 57 3 compound 3 compound 3 example 68 example 67

【0390】 実施例70の化合物 0.1 実施例71の化合物 10 実施例72の化合物 10 実施例73の化合物 3 実施例74の化合物 10 実施例76の化合物 1 実施例77の化合物 3 実施例79の化合物 0.1 実施例80の化合物 0.1 実施例81の化合物 10 [0390] Compounds of Compound 3 Example 79 Compound 1 Example 77 Compound 10 Example 76 Compound 3 Example 74 Compound 10 Example 73 Compound 10 Example 72 Compound 0.1 EXAMPLE 71 Example 70 0.1 compound 10 compound 0.1 eXAMPLE 81 example 80

【0391】 実施例82の化合物 1 実施例85の化合物 3 実施例86の化合物 0.3 実施例87の化合物 0.1 実施例88の化合物 0.1 実施例89の化合物 0.3 実施例90の化合物 3 実施例91の化合物 0.1 実施例92の化合物 3 実施例93の化合物 3 [0391] Compounds of Compound 3 Example 91 compound 0.3 Example 90 compound 0.1 Example 89 compound 0.1 Example 88 compound 0.3 Example 87 Compound 3 Example 86 Compound 1 Example 85 Example 82 0.1 compound 3 compound 3 example 93 example 92

【0392】 実施例94の化合物 3 実施例95の化合物 3 実施例96の化合物 10 実施例97の化合物 0.1 実施例98の化合物 0.1 実施例99の化合物 3 実施例100の化合物 1 実施例101の化合物 3 実施例102の化合物 3 実施例103の化合物 1 [0392] Compounds of Compound 1 Example 101 Compound 3 Example 100 compound 0.1 Example 99 compound 0.1 Example 98 Compound 10 Example 97 Compound 3 Example 96 Compound 3 Example 95 Example 94 3 compound 1 compound 3 example 103 example 102

【0393】 実施例104の化合物 1 実施例105の化合物 1 実施例106の化合物 1 実施例107の化合物 1 実施例108の化合物 3 実施例109の化合物 1 実施例110の化合物 3 実施例111の化合物 3 実施例112の化合物 0.1 実施例113の化合物 0.3 [0393] Compounds of Compound 3 Example 111 Compound 1 Example 110 Compound 3 Example 109 Compound 1 Example 108 Compound 1 Example 107 Compound 1 Example 106 Compound 1 Example 105 Example 104 3 of compound 0.1 example 113 example 112 0.3

【0394】 実施例114の化合物 3 実施例115の化合物 0.01 実施例116の化合物 0.01 実施例119の化合物 3 実施例120の化合物 0.3 実施例121の化合物 3 実施例122の化合物 0.03 実施例123の化合物 3 実施例124の化合物 3 実施例125の化合物 0.1 [0394] Compounds of the compound 0.03 Example 123 Compound 3 Example 122 Compound 0.3 EXAMPLE 121 Compound 3 Example 120 compound 0.01 Example 119 Compound 0.01 Example 116 Compound 3 Example 115 Example 114 3 of compound 3 example 125 example 124 0.1

【0395】 実施例126の化合物 3 実施例127の化合物 0.3 実施例128の化合物 0.1 実施例129の化合物 1 実施例130の化合物 0.03 実施例131の化合物 0.3 実施例132の化合物 10 実施例133の化合物 3 実施例134の化合物 3 実施例135の化合物 3 [0395] Compounds of Compound 10 Example 133 compound 0.3 Example 132 compound 0.03 Example 131 Compound 1 Example 130 compound 0.1 Example 129 compound 0.3 Example 128 Compound 3 Example 127 Example 126 3 of compound 3 example 135 example 134 3

【0396】 実施例136の化合物 1 実施例137の化合物 1 実施例138の化合物 1 実施例139の化合物 0.3 実施例140の化合物 0.3 実施例141の化合物 1 実施例142の化合物 0.1 実施例143の化合物 3 実施例145の化合物 3 比較例1の化合物 >100 比較例2の化合物 >100 [0396] Compounds of the compound 0.1 Example 143 Compound 1 Example 142 compound 0.3 Example 141 compound 0.3 Example 140 Compound 1 Example 139 Compound 1 Example 138 Compound 1 Example 137 Example 136 3 embodiment compound 3 compound of Comparative example 1 of example 145> 100 compound of Comparative example 2> 100

【0397】薬理試験例2 抗腫瘍試験 (実験方法) マウス骨髄性白血病細胞WEHI−3 [0397] Pharmacological Test Example 2 Antitumor test (Experimental method) Mouse myeloid leukemia cells WEHI-3
(1〜3x10 6 cells)をBalb/cマウス腹腔内に移植し、翌日から薬物の投与を開始した。 Transplanted into (1~3x10 6 cells) to Balb / c intraperitoneally into mice was initiated administration of a drug from the following day. これを1日目とし以後1〜4日および7〜11日に薬剤を1日1回経口投与した。 This drug was administered orally once a day on day 1 and then after 1-4 days and 7-11 days. 移植後の生存日数を観察し、Con To observe the survival days after transplantation, Con
trol群の生存日数に対する薬物投与群の生存日数の比(T/C、%)を算出し、これを延命効果として評価した。 Calculating the ratio of the survival days of the drug administration group relative survival time of trol group (T / C,%), it was evaluated as survival benefit. (実験結果) 実験結果を、表−6[表32]に示した。 (Experiment Results) The experimental results are shown in Table 6. [Table 32].

【0398】 [0398]

【表32】 表−6:WEHI−3細胞に対する抗腫瘍作用 供試化合物 投与量( μmol/kg) T/C(%) 実施例45の化合物 16 138 実施例46の化合物 32 141 実施例48の化合物 130 190 実施例130の化合物 130 189 [Table 32] Table -6: Antitumor activity test compound dose for WEHI-3 cells (μmol / kg) T / C (%) of Compound 32 141 Example 48 Compound 16 138 Example 46 Example 45 of compound 130 190 eXAMPLE 130 130 189

【0399】薬理試験例3 抗腫瘍作用試験 (実験方法) ヌードマウス皮下で継代された腫瘍細胞(HT−29,KB−3−1)をヌードマウスに移植し、体積が20〜100mm3程度になり、生着が確認されたところで薬剤の投与を開始した。 [0399] Pharmacological Test Example 3 Antitumor activity test (Experimental method) nude mice subcutaneously passaged tumor cells (HT-29, KB-3-1) were transplanted into nude mice, volume about 20~100mm3 it was the start of the administration of the drug at engraftment has been confirmed. これを1日目とし以後1〜5日、8〜12日、15〜19日および22 This first day and then after 1-5 days, 8-12 days, 15-19 days and 22
〜26日に薬剤を経口投与した。 The drug was administered orally to 26 days. 腫瘍体積は、(腫瘍体積)=1/2x(長径)x(短径)2 により求めた。 Tumor volume was determined by 2 (tumor volume) = 1 / 2x (major axis) x (minor diameter).

【0400】(実験結果) HT−29に対する実施例48の化合物(投与量66μmol/kg)の実験結果を、[図1]に示した。 [0400] The experimental results for the compound of Example 48 for (experimental results) HT-29 (dose of 66μmol / kg), as shown in FIG. 1.

【0401】KB−3−1に対する実施例48の化合物(投与量66μmol/kg)の実験結果を、[図2] [0401] The compound of Example 48 against KB-3-1 The experimental results of (dose 66μmol / kg), [2]
に示した。 It was shown to.

【0402】計算実施例 (高活性化合物による重ね合わせモデルの構築)高い分化誘導活性を示す化合物である実施例45、実施例46 [0402] Calculation examples Example 45 is a (high build superposition model with the active compounds) Compounds which exhibit high differentiation inducing activity, Example 46
および実施例48の化合物を用い、活性発現に必要な原子団の空間配置に関する情報を抽出するため3次元構造の重ね合わせを行った。 And using the compound of Example 48, it was performed superposition of three-dimensional structure for extracting information on the spatial arrangement of atoms necessary activity expression.

【0403】この目的のためには、市販されている計算パッケージ[CATALYST(MSI社)、Cerius2/QSAR+(MSI [0403] For this purpose, the calculation package, which is commercially available [CATALYST (MSI Inc.), Cerius2 / QSAR + (MSI
社)、SYBYL/DISCO(Tripos社)など]のいずれを用いても同様な解析を行うことが可能であるが、今回の重ね合わせ構造の作成および解析には、SYBYL/DISCO(Tripo Inc.), SYBYL / DISCO (Tripos Inc.), but it is possible to perform a similar analysis using any of such, the creation and analysis of this superimposed structure, SYBYL / DISCO (Tripo
s社)を用いた。 s, Inc.) was used.

【0404】実施例48の化合物について、SYBYLのスケッチ機能を用いて3次元構造を発生し、Gasteiger-Hu [0404] The compound of Example 48, the three-dimensional structure and generated using Sketch of SYBYL, Gasteiger-Hu
ckel法により各原子上に点電荷を付与した後、Tripos力場を用いて構造最適化を行った。 After applying a point charge on each atom by ckel method was subjected to structural optimization with the Tripos force field. 次に、薬物−生体間相互作用に重要と考えられる疎水性相互作用部位(芳香環、脂肪族側鎖)および水素結合部位(カルボニル酸素、ヒドロキシル基、アミノ基など)などの相互作用が想定される部位を特定するためにダミー原子を相互作用が可能な部位に置いた。 Next, Drug - hydrophobic interaction site are considered to be important to biological interactions (aromatic, aliphatic side chains) and hydrogen bonding sites (carbonyl oxygen, hydroxyl group, an amino group) interactions such as are contemplated placing the dummy atoms to the site that can interact to identify that site.

【0405】この時、疎水性相互作用、水素結合および静電相互作用部位などの相互作用の種類を区別するために、相互作用の分類を行い各々異なるダミー原子タイプを設定した。 [0405] At this time, a hydrophobic interaction, in order to distinguish the types of interactions such as hydrogen bonding and electrostatic interaction sites were set respectively different dummy atom types perform classification of interactions. さらに、回転可能結合について回転させたコンフォーマーを発生させ、想定される相互作用部位に配置したダミー原子間の距離が変化するものを、新規なコンフォメーションとして、コンフォメーションファイルに保存した。 Furthermore, to generate a conformer of rotating about the rotatable coupling, those distances between the dummy atoms placed on interaction site is assumed to change, as a new conformation, and stored in the conformation file. 実施例45および実施例46の化合物についても同様に3次元構造の作成およびコンフォメーションの発生を行った。 It was carried out in the same manner as the 3-dimensional structure creation and conformations generated also for the compounds of Examples 45 and Example 46.

【0406】実施例48の化合物を鋳型分子として、そのそれぞれのコンフォメーションに対して実施例45および実施例46の化合物のすべてのコンフォメーションについて同じ種類の相互作用を示すダミー原子が重なるように重ね合わせ構造を作成した。 [0406] The compound of Example 48 as a template molecule, stacked so that the dummy atoms overlap indicating an interaction of the same type for all conformations of the compound of Example 45 and Example 46 that for each of the conformations It was created and the combined structure.

【0407】得られた重ね合わせ構造について、重ね合わせに用いられたダミー原子の個数(共通な相互作用の数)、立体的な重なり具合(重なり体積)および活性値を用いた3次元QSARの解析結果などをもとに、最適な重ね合わせ構造を選択した。 [0407] For the obtained superimposed structure, (the number of common interaction) the number of dummy atoms used for overlay, analysis of three-dimensional QSAR using steric overlap degree (overlap volume) and activity values the results, such as in the original, we select the optimal overlay structure.

【0408】今回得られた重ね合わせ構造では、式(1 [0408] In this resulting overlay structure, formula (1
3)の化合物のB環の重心(W1)、A環の重心(W B ring of the center of gravity of the compound of 3) (W1), A ring of the centroid (W
2)および水素結合受容体(カルボニル酸素など)(W 2) and hydrogen bond acceptor (carbonyl oxygen) (W
3)において、W1〜W2=8.34Å、W1〜W3= In 3), W1~W2 = 8.34Å, W1~W3 =
3.80Å、W2〜W3=5.55Åの配置をとることが示された。 3.80 Å, was shown to take place in W2~W3 = 5.55Å.

【0409】(計算例1:実施例130の化合物) 実施例130の化合物の相互作用想定部位およびベンズアミド構造の構成原子から適当な7個の原子を選択し、上記の重ね合わせに用いた実施例45、実施例46および実施例48の化合物を標的構造として、実施例130の化合物に拘束ポテンシャルを与えて構造最適化を行った。 [0409] (Calculation example 1: exemplary compound of Example 130) and select the appropriate seven atoms from constituent atoms of the interaction assumed sites and benzamide structure of the compound of Example 130, Examples using the superposition of the 45, the compound of example 46 and example 48 as a target structure was subjected to structural optimization giving restraining potential to the compound of example 130. 次に、拘束ポテンシャルを解除して構造最適化を行い、実施例130の化合物の活性コンフォメーションを得た。 Next, the structure optimization and releases the braking potential to give the active conformation of the compound of Example 130. この活性コンフォメーションに対し、ベンズアミドのベンゼン環の重心(W1)およびピリジン環の重心(W2)およびカルボニル酸素(W3)を定義し、空間配置のパラメータの抽出を行った。 For this active conformation, define the centroid of the benzamide benzene ring (W1) and a pyridine ring in the center of gravity (W2) and the carbonyl oxygen (W3), was extracted parameters of the spatial arrangement.

【0410】また、回転可能な結合についてすべてのコンフォメーションを発生し各コンフォメーションでのエネルギーを計算し、最安定構造を求めた。 [0410] Further, to generate all conformational for rotatable coupling to calculate the energy of each conformation, it was determined the most stable structure. 最安定構造でのエネルギーを計算し、活性コンフォメーションとのエネルギー差を求めた。 Calculate the energy at the most stable structure was determined energy difference between the active conformation. その結果、今回得られた構造では、W1〜W2=8.43Å、W1〜W3=3.82 As a result, in this resulting structure, W1~W2 = 8.43Å, W1~W3 = 3.82
Å、W2〜W3=5.88Å(最安定構造とのエネルギー差:2.86kcal/mol)の配置をとることが示された。 Å, W2~W3 = 5.88Å (energy difference between the most stable structure: 2.86kcal / mol) take the place of the indicated.

【0411】また、前記の重ね合わせ構造モデルの構築で得られたダミー原子を標的構造として、解析操作を行うことによっても同一の結果が得られた。 [0411] Further, the dummy atoms obtained in the construction of the overlay structure model as a target structure, the same results were obtained by performing the analysis operation. (計算結果) (Calculation result)
計算結果を表−7[表33]に示した。 The calculation results are shown in Table 7. [Table 33]. 表−7:空間配置のパラメータの計算結果 Table 7: Calculation results of the parameters of spatial arrangement

【0412】 [0412]

【表33】 [Table 33]

【0413】 [0413]

【0414】 [0414]

【0415】 [0415]

【発明の効果】本発明の新規ベンズアミド誘導体および新規アリニド誘導体は分化誘導作用を有し、悪性腫瘍、 New benzamide derivatives and novel Arinido derivatives of the present invention, according to the present invention has a differentiation inducing action, malignant tumor,
自己免疫疾患、皮膚病、寄生虫感染症の治療・改善薬などの医薬品として有用である。 Autoimmune disease, skin disease, is useful as pharmaceuticals, such as therapeutic and improving agents of parasitic infections. 特に制癌剤として効果が高く、造血器腫瘍、固形癌に有効である。 Especially high effect as a carcinostatic, hematopoietic tumors, is effective for solid cancers.

【図面の簡単な説明】 BRIEF DESCRIPTION OF THE DRAWINGS

【図1】 腫瘍細胞(HT−29)に対して実施例48 [1] Example 48 against tumor cells (HT-29)
の化合物投与時の腫瘍体積の変化を示す図である。 It is a graph showing changes in tumor volume at the time of compound administration.

【図2】 腫瘍細胞(KB−3−1)に対して実施例4 [Figure 2] Example 4 against tumor cells (KB-3-1)
8の化合物投与時の腫瘍体積の変化を示す図である。 It is a graph showing changes in tumor volume at the time of compound administration of 8.

───────────────────────────────────────────────────── フロントページの続き (51)Int.Cl. 7識別記号 FI A61K 31/38 A61K 31/38 31/415 31/415 31/42 31/42 31/425 31/425 31/44 31/44 31/445 31/445 31/495 31/495 31/505 31/505 A61P 17/00 A61P 17/00 33/00 33/00 35/00 35/00 35/02 35/02 37/00 37/00 43/00 105 43/00 105 C07C 255/31 C07C 255/31 271/18 271/18 271/40 271/40 275/24 275/24 275/28 275/28 323/52 323/52 323/62 323/62 327/48 327/48 335/16 335/16 C07D 207/34 C07D 207/34 209/42 209/42 211/24 211/24 213/30 213/30 213/40 213/40 213/56 213/56 213/65 213/65 213/70 213/70 213/74 213/74 213/75 213/75 213/81 213/81 213/82 213/82 233/34 233/34 233/42 233/42 233/64 103 233/64 103 239/28 239/28 241/14 241/14 261/08 261/08 261/10 261/10 263/48 263/48 275/02 275/02 277/24 277/24 277/40 277/40 295/08 ────────────────────────────────────────────────── ─── front page continued (51) Int.Cl. 7 identifications FI A61K 31/38 A61K 31/38 31/415 31/415 31/42 31/42 31/425 31/425 31/44 31/44 31/445 31/445 31/495 31/495 31/505 31/505 A61P 17/00 A61P 17/00 33/00 33/00 35/00 35/00 35/02 35/02 37/00 37/00 43/00 105 43/00 105 C07C 255/31 C07C 255/31 271/18 271/18 271/40 271/40 275/24 275/24 275/28 275/28 323/52 323/52 323/62 323 / 62 327/48 327/48 335/16 335/16 C07D 207/34 C07D 207/34 209/42 209/42 211/24 211/24 213/30 213/30 213/40 213/40 213/56 213 / 56 213/65 213/65 213/70 213/70 213/74 213/74 213/75 213/75 213/81 213/81 213/82 213/82 233/34 233/34 233/42 233/42 233/64 103 233/64 103 239/28 239/28 241/14 241/14 261/08 261/08 261/10 261/10 263/48 263/48 275/02 275/02 277/24 277/24 277/40 277/40 295/08 295/08 A 307/12 307/12 307/68 307/68 307/84 307/84 333/16 333/16 333/38 333/38 333/62 333/62 401/06 401/06 401/12 401/12 405/12 405/12 409/12 409/12 413/12 413/12 453/02 453/02 491/048 491/048 495/04 105 495/04 105A 521/00 521/00 (72)発明者 土屋 克敏 千葉県茂原市東郷1144番地 三井東圧化 学株式会社内 (72)発明者 中西 理 千葉県茂原市東郷1900番地1 三井東圧 化学株式会社内 (72)発明者 齊藤 明子 千葉県茂原市東郷1900番地1 三井東圧 化学株式会社内 (72)発明者 山下 俊 千葉県茂原市東郷1900番地1 三井東圧 化学株式会社内 (72)発明者 白石 厳悟 神奈川県横浜市戸塚区平戸3−42−7 東戸塚寮 (72)発明者 田中 英司 千葉県茂原市東郷1144番地 三井東圧化 学株式会社内 (56)参考文献 特表 平9−511764(JP,A) 国際公開97/24328(WO,A1) Chemical Abstract s,Vol. 295/08 A 307/12 307/12 307/68 307/68 307/84 307/84 333/16 333/16 333/38 333/38 333/62 333/62 401/06 401/06 401/12 401 / 12 405/12 405/12 409/12 409/12 413/12 413/12 453/02 453/02 491/048 491/048 495/04 105 495/04 105A 521/00 521/00 (72) invention who Katsutoshi Tsuchiya Mobara City, Chiba Prefecture Togo 1144 address by Mitsui Toatsu chemical Co., Ltd. in the (72) inventor Makoto Nakanishi Mobara City, Chiba Prefecture Togo 1900 address 1 Mitsui Toatsu in the chemical Co., Ltd. (72) inventor Saito, Chiba Prefecture Akiko Mobara City Togo 1900 address 1 Mitsui Toatsu in the chemical Co., Ltd. (72) inventor Shun Yamashita Mobara City, Chiba Prefecture Togo 1900 address 1 Mitsui Toatsu in the chemical Co., Ltd. (72) inventor Shiraishi ImuSatoru Kanagawa Prefecture, Totsuka-ku, Yokohama-shi Hirado 3 -42-7 Higashi-Totsuka dormitory (72) inventor Eiji Tanaka Mobara City, Chiba Prefecture Togo 1144 address by Mitsui Toatsu chemical Co., Ltd. in the (56) references PCT National flat 9-511764 (JP, a) WO 97/24328 ( WO, A1) Chemical Abstract s, Vol. 63(1965),abstra ct No. 63 (1965), abstra ct No. 18311g (58)調査した分野(Int.Cl. 7 ,DB名) CA(STN) CAOLD(STN) REGISTRY(STN) 18311g (58) investigated the field (Int.Cl. 7, DB name) CA (STN) CAOLD (STN ) REGISTRY (STN)

Claims (24)

    (57)【特許請求の範囲】 (57) [the claims]
  1. 【請求項1】 式(1)[化1] 【化1】 [Claim 1] (1) [Formula 1] [Chemical Formula 1] [式中、Aは置換されていてもよいフェニル基または置換されていてもよい複素環(置換基として、ハロゲン原子、水酸基、アミノ基、ニトロ基、シアノ基、炭素数1 [In the formula, A as optionally substituted heterocyclic be also a phenyl group or substituted optionally (substituent, a halogen atom, a hydroxyl group, an amino group, a nitro group, a cyano group, C 1 -C
    〜4のアルキル基、炭素数1〜4のアルコキシ基、炭素数1〜4のアミノアルキル基、炭素数1〜4のアルキルアミノ基、炭素数1〜4のアシル基、炭素数1〜4のアシルアミノ基、炭素数1〜4のアルキルチオ基、炭素数1〜4のパーフルオロアルキル基、炭素数1〜4のパーフルオロアルキルオキシ基、カルボキシル基、炭素数1 To 4 alkyl group, an alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, an acyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms an acylamino group, an alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, a carboxyl group, a carbon number 1
    〜4のアルコキシカルボニル基、フェニル基、複素環からなる群より選ばれた基を1〜4個有する)を表し; Xは直接結合または式(2)[化2] 【化2】 To 4 alkoxycarbonyl group, a phenyl group, a group selected from the group consisting of heterocyclic ring 1-4 Yes) was Table; X is a direct bond or the formula (2) [Formula 2] [Formula 2] {式中、eは1〜4の整数を表し; gおよびmはそれぞれ独立して0〜4の整数を表し; R4は水素原子、置換されていてもよい炭素数1〜4のアルキル基(置換基と {Wherein, e is Represents an integer of 1 to 4; g and m Represents an integer of 0-4 independently; R4 is hydrogen, optionally substituted alkyl of 1 to 4 carbon atoms group (the substituent
    してハロゲン原子、水酸基、アミノ基、ニトロ基、シア A halogen atom, a hydroxyl group, an amino group, a nitro group, shea
    ノ基、フェニル基、複素環からなる群より選ばれた基を Amino group, a phenyl group, a group selected from the group consisting of heterocyclic
    1〜4個有する)または式(3)[化3] 【化3】 1-4 Yes to) or formula (3) [Chemical Formula 3] embedded image (式中、R6は置換されていてもよい炭素数1〜4のアルキル基(置換基としてハロゲン原子、水酸基、アミノ (Wherein, R6 represents a halogen atom as a alkyl group (the substituent of 1 to 4 carbon atoms which may be substituted, a hydroxyl group, an amino
    基、ニトロ基、シアノ基、フェニル基、複素環からなる Group, a nitro group, a cyano group, a phenyl group, consisting of heterocyclic
    群より選ばれた基を1〜4個有する) 、炭素数1〜4のパーフルオロアルキル基、フェニル基または複素環を表す)で表されるアシル基を表し、 R5は水素原子または置換されていてもよい炭素数1〜4のアルキル基(置換 Groups 1-4 have a selected from the group), perfluoroalkyl group having 1 to 4 carbon atoms, and display the acyl group represented by a phenyl group or a heterocyclic), R5 is a hydrogen atom or a substituent which may be an alkyl group having 1 to 4 carbon atoms (substituted
    基としてハロゲン原子、水酸基、アミノ基、ニトロ基、 Halogen atom as a group, a hydroxyl group, an amino group, a nitro group,
    シアノ基、フェニル基、複素環からなる群より選ばれた Cyano group, a phenyl group, selected from the group consisting of heterocyclic
    基を1〜4個有する)を表す}で示される構造のいずれかを表し; nは0〜4の整数を表し、但しXが直接結合の場合は、 To display the any of the structures represented by a group of for 1-4 Yes)}; n is table an integer of 0 to 4, provided that when X is a direct bond,
    nは0とはならず; Qは式(4)[化4] 【化4】 n not is 0; Q is formula (4) [of 4] [of 4] (式中、R7およびR8はそれぞれ独立して、水素原子または置換されていてもよい炭素数1〜4のアルキル基 (Wherein, R7 and R8 each independently represents a hydrogen atom or an optionally substituted alkyl group having 1 to 4 carbon atoms
    (置換基としてハロゲン原子、水酸基、アミノ基、ニト (Halogen atom as a substituent, a hydroxyl group, an amino group, a nitro
    ロ基、シアノ基、フェニル基、複素環からなる群より選 B group, a cyano group, a phenyl group, selected from the group consisting of heterocyclic
    ばれた基を1〜4個有する)を表す)で示される構造のいずれかを表し; R1およびR2はそれぞれ独立して、水素原子、ハロゲン原子、水酸基、アミノ基、炭素数1〜4のアルキル基、炭素数1〜4のアルコキシ基、炭素数1〜4のアミノアルキル基、炭素数1〜4のアルキルアミノ基、炭素数1〜4のアシル基、炭素数1〜4のアシルアミノ基、 Barre groups to display the any of the structures represented by the to 1-4 Yes) represents a); R1 and R2 are each independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group, having 1 to 4 carbon atoms alkyl group, an alkoxy group having 1 to 4 carbon atoms, an aminoalkyl group having 1 to 4 carbon atoms, an alkylamino group having 1 to 4 carbon atoms, an acyl group having 1 to 4 carbon atoms, acylamino group having 1 to 4 carbon atoms,
    炭素数1〜4のアルキルチオ基、炭素数1〜4のパーフルオロアルキル基、炭素数1〜4のパーフルオロアルキルオキシ基、カルボキシル基または炭素数1〜4のアルコキシカルボニル基を表し;そして R3はアミノ基を表す。 Alkylthio group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, perfluoroalkyl group having 1 to 4 carbon atoms, a carboxyl group or an alkoxycarbonyl group having 1 to 4 carbon atoms and Table; and R3 It represents an amino group. ]で表されるベンズアミド誘導体および薬学的に許容される塩。 Benzamide derivatives and pharmaceutically acceptable salts represented by.
  2. 【請求項2】 nが1〜4の整数である請求項1記載のベンズアミド誘導体および薬学的に許容される塩。 2. A benzamide derivative and a pharmaceutically acceptable salt thereof according to claim 1, wherein n is an integer of 1 to 4.
  3. 【請求項3】 Qが式(5)[化5] 【化5】 Wherein Q is Formula (5) [Chemical Formula 5 embedded image (式中、R7およびR8は前記と同義。)で示される構造のいずれかである請求項2記載のベンズアミド誘導体および薬学的に許容される塩。 (Wherein, R7 and R8 as defined above.) Benzamide derivatives and pharmaceutically acceptable salts according to claim 2, wherein any one of structures represented by.
  4. 【請求項4】 Aが置換されていてもよいヘテロ環である請求項3記載のベンズアミド誘導体および薬学的に許容される塩。 4. The benzamide derivatives and pharmaceutically acceptable salts according to claim 3 wherein A is a heterocycle which may be substituted.
  5. 【請求項5】 Aが置換されていてもよいピリジル基である請求項4記載のベンズアミド誘導体および薬学的に許容される塩。 5. The benzamide derivatives and pharmaceutically acceptable salts of claim 4 wherein A is a pyridyl group which may be substituted.
  6. 【請求項6】 Xが直接結合である請求項4記載のベンズアミド誘導体および薬学的に許容される塩。 6. benzamide derivatives and pharmaceutically acceptable salts according to claim 4, wherein X is a direct bond.
  7. 【請求項7】 R1およびR2が水素原子である請求項6記載のベンズアミド誘導体および薬学的に許容される塩。 7. A benzamide derivatives and pharmaceutically acceptable salts of claim 6, wherein R1 and R2 are hydrogen atoms.
  8. 【請求項8】 Xが式(6)[化6] 【化6】 8. X has the formula (6) [Formula 6] [Chemical Formula 6] (式中、eは前記と同義。)で示される構造である請求項5記載のベンズアミド誘導体および薬学的に許容される塩。 (Wherein, e is as defined above.) Acceptable salt structure represented Claim 5 benzamide derivatives and pharmaceutically described is in.
  9. 【請求項9】 nが1で、R1およびR2が水素原子である請求項8記載のベンズアミド誘導体および薬学的に許容される塩。 In 9. n is 1, benzamide derivatives and pharmaceutically acceptable salts according to claim 8 wherein R1 and R2 are hydrogen atoms.
  10. 【請求項10】 Xが式(7)[化7] 【化7】 10. X has the formula (7) [Formula 7] [Chemical Formula 7] (式中、e、gおよびR4は前記と同義。)で示される構造のいずれかである請求項5記載のベンズアミド誘導体および薬学的に許容される塩。 (Wherein, e, g and R4 as defined above.) Benzamide derivatives and pharmaceutically acceptable salts according to claim 5, wherein any one of structures represented by.
  11. 【請求項11】 nが1で、R1およびR2が水素原子である請求項10記載のベンズアミド誘導体および薬学的に許容される塩。 11. n is 1, benzamide derivatives and pharmaceutically acceptable salts according to claim 10, wherein R1 and R2 are hydrogen atoms.
  12. 【請求項12】 Xが式(8)[化8] 【化8】 12. X has the formula (8) [of 8] embedded image (式中、g、mおよびR5は前記と同義。)で示される構造のいずれかである請求項5記載のベンズアミド誘導体および薬学的に許容される塩。 (Wherein, g, m and R5 are as defined above.) Benzamide derivatives and pharmaceutically acceptable salts according to claim 5, wherein any one of structures represented by.
  13. 【請求項13】 nが1で、R1およびR2が水素原子である請求項12記載のベンズアミド誘導体および薬学的に許容される塩。 In 13. n is 1, benzamide derivatives and pharmaceutically acceptable salts according to claim 12, wherein R1 and R2 are hydrogen atoms.
  14. 【請求項14】 nが0である請求項1記載のベンズアミド誘導体および薬学的に許容される塩。 14. benzamide derivatives and pharmaceutically acceptable salts of claim 1, wherein n is 0.
  15. 【請求項15】 Qが式(5)で示される構造のいずれかである請求項14記載のベンズアミド誘導体および薬学的に許容される塩。 15. Q benzamide derivatives and pharmaceutically acceptable salts according to claim 14, wherein any one of structures represented by formula (5).
  16. 【請求項16】 Aが置換されていてもよいヘテロ環である請求項15記載のベンズアミド誘導体および薬学的に許容される塩。 16. benzamide derivatives and pharmaceutically acceptable salts according to claim 15 wherein A is a heterocycle which may be substituted.
  17. 【請求項17】 Aが置換されていてもよいピリジル基である請求項16記載のベンズアミド誘導体および薬学的に許容される塩。 17. benzamide derivatives and pharmaceutically acceptable salts according to claim 16, wherein A is a pyridyl group which may be substituted.
  18. 【請求項18】 R1およびR2が水素原子である請求項17記載のベンズアミド誘導体および薬学的に許容される塩。 18. benzamide derivatives and pharmaceutically acceptable salts of the R1 and R2 claim 17, wherein a hydrogen atom.
  19. 【請求項19】 式(9)[化9] 【化9】 19. Equation (9) [Formula 9] embedded image で示される請求項1記載のベンズアミド誘導体および薬学的に許容される塩。 In benzamide derivatives and pharmaceutically acceptable salts of claim 1, wherein shown.
  20. 【請求項20】 式(10)[化10] 【化10】 20. Equation (10) [formula 10] [Formula 10] で示される請求項1記載のベンズアミド誘導体および薬学的に許容される塩。 In benzamide derivatives and pharmaceutically acceptable salts of claim 1, wherein shown.
  21. 【請求項21】 式(11)[化11] 【化11】 21. Formula (11) [formula 11] [Formula 11] で示される請求項1記載のベンズアミド誘導体および薬学的に許容される塩。 In benzamide derivatives and pharmaceutically acceptable salts of claim 1, wherein shown.
  22. 【請求項22】 式(12)[化12] 【化12】 22. Formula (12) [formula 12] [Formula 12] で示される請求項1記載のベンズアミド誘導体および薬学的に許容される塩。 In benzamide derivatives and pharmaceutically acceptable salts of claim 1, wherein shown.
  23. 【請求項23】 請求項1〜22いずれかに記載の化合物のうち、少なくとも1つを有効成分として含有する制癌剤。 23. Among the compounds according to any one of claims 1 to 22, carcinostatic containing at least one as an active ingredient.
  24. 【請求項24】 請求項1〜22いずれかに記載の化合物のうち、少なくとも1つを有効成分として含有する医薬品。 24. Among the compounds according to any one of claims 1 to 22, medicaments containing at least one as an active ingredient.
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