JP2016147807A - Hydroxamic acid derivative and salt thereof - Google Patents

Hydroxamic acid derivative and salt thereof Download PDF

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JP2016147807A
JP2016147807A JP2013118110A JP2013118110A JP2016147807A JP 2016147807 A JP2016147807 A JP 2016147807A JP 2013118110 A JP2013118110 A JP 2013118110A JP 2013118110 A JP2013118110 A JP 2013118110A JP 2016147807 A JP2016147807 A JP 2016147807A
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俊彦 田島
Toshihiko Tajima
俊彦 田島
英彦 児玉
Hidehiko Kodama
英彦 児玉
宏朗 村田
Hiroo Murata
宏朗 村田
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NIPPON RIKAGAKU KOGYO KK
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    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

PROBLEM TO BE SOLVED: To provide a hydroxamic acid derivative useful as a histone deacetylation enzyme inhibitor or a salt thereof, further a pharmaceutical composition containing the hydroxamic acid derivative or the salt thereof, the histone deacetylation enzyme inhibitor and an antitumor agent.SOLUTION: There is provided a hydroxamic acid derivative represented by a general formula (A) or a salt thereof.SELECTED DRAWING: None

Description

本発明は、ヒストン脱アセチル化酵素阻害剤として有用なヒドロキサム酸誘導体またはその塩に関する。   The present invention relates to hydroxamic acid derivatives or salts thereof useful as histone deacetylase inhibitors.

従来、遺伝形質の発現は、ＤＮＡ複製、ＲＮＡ転写、タンパク質への翻訳、形質発現というセントラルドグマで提唱された経路により、ＤＮＡに記録されている遺伝情報が表現型として実現した結果とされてきた。セントラルドグマにおいて、遺伝子発現の変化とは、ＤＮＡの一次配列の変化であって、遺伝子発現の変化の大半はＤＮＡ配列の変化に起因することが実証されている。   Conventionally, the expression of genetic traits has been realized as a result of realizing the genetic information recorded in DNA as a phenotype through the pathway proposed by Central Dogma of DNA replication, RNA transcription, translation into protein, and expression of traits. . In the central dogma, changes in gene expression are changes in the primary sequence of DNA, and it has been demonstrated that most changes in gene expression result from changes in the DNA sequence.

これに対して、ＤＮＡ配列の変化を伴うことなく、ＤＮＡへの後天的な作用により遺伝子発現の変化が生じる機構も見出されている。例えば、ヒストンの化学修飾による遺伝子発現の変化（ヒストンのメチル化、アセチル化、リン酸化など）などの機序に基づく変化は、ＤＮＡ配列の変化とは独立している。   On the other hand, a mechanism has also been found in which gene expression changes due to an acquired action on DNA without accompanying changes in the DNA sequence. For example, changes based on mechanisms such as changes in gene expression due to chemical modification of histones (histone methylation, acetylation, phosphorylation, etc.) are independent of DNA sequence changes.

例えば、ヒストンのアセチル化は、ヒストンアセチル化酵素とヒストン脱アセチル化酵素とのバランスによって制御されていることが知られている。近年、ヒストンアセチル化酵素及びヒストン脱アセチル化酵素が同定され、転写調節におけるその重要性が明らかになってきている。ヒストン脱アセチル化酵素（以下、「ＨＤＡＣ」ということがある）としては、現在までにＨＤＡＣ１〜１１の１１種類が同定されており（例えば非特許文献１を参照）、これらのＨＤＡＣが遺伝子の発現を抑制していると考えられている。そこで、ＨＤＡＣを阻害することによって、特定の遺伝子の発現を活性化する試みがなされている。   For example, it is known that histone acetylation is controlled by the balance between histone acetylase and histone deacetylase. In recent years, histone acetylases and histone deacetylases have been identified and their importance in transcriptional regulation has become clear. As histone deacetylases (hereinafter sometimes referred to as “HDACs”), 11 types of HDACs 1 to 11 have been identified so far (see, for example, Non-Patent Document 1), and these HDACs express genes. It is thought that it is suppressing. Thus, attempts have been made to activate the expression of specific genes by inhibiting HDAC.

ＨＤＡＣ阻害剤は、転写機構において機能するＨＤＡＣを阻害し、ヒストン過アセチル化を誘発することによって、細胞周期停止、形質転換細胞の形態正常化、分化誘導、アポトーシス誘導作用などを示すため、例えば、抗腫瘍剤などとしての利用が期待されている。例えば、特許文献１には、ＨＤＡＣ阻害剤としてスベロイルアニリドヒドロキサム酸（ＳＡＨＡ）を含む薬学的組成物の投与によって、最終分化、細胞増殖停止、新生物細胞のアポトーシスを選択的に誘導し、ヒストン脱アセチル化酵素を阻害する方法が提案されている。   HDAC inhibitors inhibit HDAC functioning in the transcription mechanism and induce histone hyperacetylation, thereby exhibiting cell cycle arrest, normalization of transformed cells, induction of differentiation, apoptosis-inducing action, etc. It is expected to be used as an antitumor agent. For example, Patent Document 1 discloses that administration of a pharmaceutical composition containing suberoylanilide hydroxamic acid (SAHA) as an HDAC inhibitor selectively induces terminal differentiation, cell growth arrest, and apoptosis of neoplastic cells. Methods for inhibiting deacetylase have been proposed.

このような状況下、ヒストン脱アセチル化酵素阻害剤として有用な化合物の開発が望まれている。   Under such circumstances, development of compounds useful as histone deacetylase inhibitors is desired.

特開２０１０−１３０２号公報JP 2010-1302 A

Ｃａｎｃｅｒ Ｌｅｔｔｅｒｓ ２７７（２００９）８−２１Cancer Letters 277 (2009) 8-21

本発明は、ヒストン脱アセチル化酵素阻害剤として有用なヒドロキサム酸誘導体またはその塩を提供することを主な目的とする。さらに、本発明は、ヒドロキサム酸誘導体またはその塩を有効成分として含む医薬組成物、ヒストン脱アセチル化酵素阻害剤、及び抗腫瘍剤を提供することも目的とする。   The main object of the present invention is to provide a hydroxamic acid derivative or a salt thereof useful as a histone deacetylase inhibitor. Another object of the present invention is to provide a pharmaceutical composition comprising a hydroxamic acid derivative or a salt thereof as an active ingredient, a histone deacetylase inhibitor, and an antitumor agent.

本発明者は、上記課題を解決すべく鋭意検討を行ったところ、上記一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩が、ヒストン脱アセチル化酵素阻害剤として有用であることを見出した。本発明は、かかる知見に基づいて更に検討を重ねることにより完成したものである。   As a result of intensive studies to solve the above problems, the present inventors have found that the hydroxamic acid derivative represented by the general formula (A) or a salt thereof is useful as a histone deacetylase inhibitor. It was. The present invention has been completed by further studies based on such knowledge.

即ち、本発明は、下記態様の発明を提供する。
項１． 下記一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩。
［一般式（Ａ）中、基Ａは、酸素原子、窒素原子、または−ＮＲ6−である。
基Ａが酸素原子または−ＮＲ6−であるときは、複素環の１位の基Ａと２位の炭素原子との結合は単結合であり、基Ａが窒素原子であるときは、前記複素環の１位の炭素原子と２位の炭素原子との結合は二重結合である。基Ｒ6は、置換基を有していてもよい低級アルキル基、または水素原子である。
基Ｂは、酸素原子または置換基を有していてもよい低級アルコキシ基であり、基Ｂが酸素原子であるときは、基Ｂと前記複素環の２位の炭素原子との結合は二重結合であり、基Ｂが置換基を有していてもよい低級アルコキシ基であるときは、基Ｂと前記複素環の２位の炭素原子との結合は単結合である。
基Ｒ1及び基Ｒ3は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であるか、基Ｒ1及び基Ｒ3のいずれか一方は基Ｘと置換している。
基Ｒ2及び基Ｒ4は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であるか、互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。
基Ｒn 5は、前記複素環が縮合しているベンゼン環上の水素原子と置換したｎ＝０〜３個の置換基であり、それぞれ独立に、ハロゲン原子または置換基を有していてもよい低級アルキル基である。
基Ｘは、前記ベンゼン環上の水素原子、前記複素環上の水素原子、または基Ｒ1及び基Ｒ3のいずれか一方と置換しており、基Ｘは、単結合、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−である。
基Ｙは、単結合、飽和もしくは不飽和の炭素数１〜１０のアルキレン基、または基−Ｙ1−Ｙ2−Ｙ3−である。基Ｙ1は、飽和もしくは不飽和の炭素数１〜６のアルキレン基、または単結合である。基Ｙ2は、置換基を有していてもよいフェニレン基、置換基を有していてもよいシクロヘキシレン基である。基Ｙ3は、飽和もしくは不飽和の炭素数１〜６のアルキレン基である。］
項２． 一般式（Ａ）において、基Ｒ1及び基Ｒ3は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であり、基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、単結合、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−である、項１に記載のヒドロキサム酸誘導体またはその塩。
項３． 下記一般式（Ａ１）で表されるヒドロキサム酸誘導体またはその塩であって、
一般式（Ａ１）において、基Ｒ6は、メチル基または水素原子であり、
基Ｒ1は、水素原子またはメチル基であり、基Ｒ3は、水素原子であり、基Ｒ2は、水素原子またはメチル基であるか、基Ｒ4と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、基Ｒ4は、水素原子であるか、基Ｒ2と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、
基Ｒ5は、水素原子またはフッ素原子であり、
基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−であり、
基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基、または基−Ｙ1−Ｙ2−Ｙ3−であり、基Ｙ1は、飽和もしくは不飽和の炭素数２のアルキレン基（−ＣＨ＝ＣＨ−であり、基Ｙ2は、フェニレン基またはシクロヘキシレン基であり、基Ｙ3は、メチレン基である、項２に記載のヒドロキサム酸誘導体またはその塩。
項４． 下記一般式（Ａ２）で表されるヒドロキサム酸誘導体またはその塩であって、
一般式（Ａ２）において、基Ｒ1は、水素原子またはメチル基であり、基Ｒ3は、水素原子であり、基Ｒ2は、水素原子またはメチル基であるか、基Ｒ4と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、基Ｒ4は、水素原子であるか、基Ｒ2と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、
基Ｒ7は、メチル基またはエチル基であり、
基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、酸素原子、−ＣＯＮＨ−、または−ＮＨＣＯ−であり、
基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基である、項２に記載のヒドロキサム酸誘導体またはその塩。
項５． 下記一般式（Ａ３）で表されるヒドロキサム酸誘導体またはその塩であって、
一般式（Ａ３）において、基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、酸素原子、−ＣＯＮＨ−、または−ＮＨＣＯ−であり、
基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基である、項２に記載のヒドロキサム酸誘導体またはその塩。
項６． 項１〜５のいずれかに記載のヒドロキサム酸誘導体またはその塩を有効成分とする医薬組成物。
項７． 項１〜５のいずれかに記載のヒドロキサム酸誘導体またはその塩を有効成分とするヒストン脱アセチル化酵素阻害剤。
項８．項１〜５のいずれかに記載のヒドロキサム酸誘導体またはその塩を有効成分とする抗腫瘍剤。
項９． 下記一般式（Ａａ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａａ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム１で表される、下記化合物Ｄ１と下記化合物Ｄ２とのカップリング反応により、下記化合物Ｄ３を合成する工程１と、
［スキーム１中、Ｍは、アルキル基またはベンジル基であり、Ｘ1は、ハロゲン原子であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム２で表される、化合物Ｄ３のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム２中、基Ｍは、スキーム１と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａａ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。
項１０． 下記一般式（Ａｂ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｂ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム３で表される、下記化合物Ｄ４と下記化合物Ｄ５とのカップリング反応により、化合物Ｄ６を合成する工程１と、
［スキーム３中、Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム４で表される、化合物Ｄ６のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム４中、基Ｍは、スキーム３と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｂ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。
項１１． 下記一般式（Ａｃ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｃ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム５で表される、下記化合物Ｄ７と下記化合物Ｄ８とのカップリング反応により、化合物Ｄ９を合成する工程１と、
［スキーム５中、Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム６で表される、下記化合物Ｄ９のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム６中、基Ｍは、スキーム５と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｃ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。
項１２． 下記一般式（Ａｄ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｄ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム７で表される、下記化合物Ｄ１０と下記化合物Ｄ１１とのカップリング反応により、化合物Ｄ１２を合成する工程１と、
［スキーム７中、基Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム８で表される、下記化合物Ｄ１２のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム８中、基Ｍは、スキーム７と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｄ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。
項１３． 下記一般式（Ａｅ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｅ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム９で表される、下記化合物Ｄ１３と下記化合物Ｄ１４とのカップリング反応により、化合物Ｄ１５を合成する工程１と、
［スキーム９中、基Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム１０で表される、下記化合物Ｄ１５のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム１０中、基Ｍは、スキーム９と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｅ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。 That is, this invention provides invention of the following aspect.
Item 1. A hydroxamic acid derivative represented by the following general formula (A) or a salt thereof.
[In the general formula (A), the group A is an oxygen atom, a nitrogen atom, or —NR 6 —.
When the group A is an oxygen atom or —NR 6 —, the bond between the first-position group A and the second-position carbon atom of the heterocyclic ring is a single bond, and when the group A is a nitrogen atom, The bond between the carbon atom at the 1st position and the carbon atom at the 2nd position of the ring is a double bond. The group R 6 is a lower alkyl group which may have a substituent, or a hydrogen atom.
The group B is an oxygen atom or an optionally substituted lower alkoxy group. When the group B is an oxygen atom, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is double. When it is a bond and the group B is an optionally substituted lower alkoxy group, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is a single bond.
The group R 1 and the group R 3 are each independently a hydrogen atom or an optionally substituted lower alkyl group, or either the group R 1 or the group R 3 is substituted with the group X. Yes.
The group R 2 and the group R 4 are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or bonded to each other to form a 3-position carbon atom and a 4-position carbon. It forms a double bond with the atom.
The group R n 5 is n = 0 to 3 substituents substituted with hydrogen atoms on the benzene ring to which the heterocycle is condensed, and each independently has a halogen atom or a substituent. A good lower alkyl group.
The group X is substituted with a hydrogen atom on the benzene ring, a hydrogen atom on the heterocyclic ring, or one of the group R 1 and the group R 3 , and the group X is a single bond, an oxygen atom, —CONH -, - NHCO -, - SO 2 NH-, or -NHSO 2 - a.
The group Y is a single bond, a saturated or unsaturated alkylene group having 1 to 10 carbon atoms, or a group —Y 1 —Y 2 —Y 3 —. The group Y 1 is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, or a single bond. The group Y 2 is an optionally substituted phenylene group or an optionally substituted cyclohexylene group. The group Y 3 is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms. ]
Item 2. In the general formula (A), the group R 1 and the group R 3 are each independently a hydrogen atom or a lower alkyl group which may have a substituent, and the group X is a hydrogen atom on the benzene ring. substituted and the group X is a single bond, an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO 2 - and is, hydroxamic acid derivative or salt thereof according to claim 1.
Item 3. A hydroxamic acid derivative represented by the following general formula (A1) or a salt thereof,
In the general formula (A1), the group R 6 is a methyl group or a hydrogen atom,
The group R 1 is a hydrogen atom or a methyl group, the group R 3 is a hydrogen atom, the group R 2 is a hydrogen atom or a methyl group, or is bonded to the group R 4 to form a 3 A carbon atom at the position and a carbon atom at the 4th position, and the group R 4 is a hydrogen atom or bonded to the group R 2 to form a carbon atom at the 3rd position of the heterocyclic ring. Forming a double bond with the 4-position carbon atom,
The group R 5 is a hydrogen atom or a fluorine atom;
Group X is substituted with a hydrogen atom on the benzene ring, the group X represents an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO 2 - and is,
The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, or a group —Y 1 —Y 2 —Y 3 —, and the group Y 1 is a saturated or unsaturated alkylene group having 2 carbon atoms ( a -CH = CH-, group Y 2 is a phenylene group or a cyclohexylene group, group Y 3 is a methylene group, a hydroxamic acid derivative or salt thereof according to claim 2.
Item 4. A hydroxamic acid derivative represented by the following general formula (A2) or a salt thereof,
In the general formula (A2), the group R 1 is a hydrogen atom or a methyl group, the group R 3 is a hydrogen atom, and the group R 2 is a hydrogen atom or a methyl group, or is bonded to the group R 4. A double bond is formed between the carbon atom at the 3rd position and the carbon atom at the 4th position of the heterocyclic ring, and the group R 4 is a hydrogen atom or bonded to the group R 2 to form the heterocyclic ring. Forming a double bond between the 3-position carbon atom and 4-position carbon atom of
The group R 7 is a methyl group or an ethyl group,
The group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-;
Item 3. The hydroxamic acid derivative or a salt thereof according to Item 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms.
Item 5. A hydroxamic acid derivative represented by the following general formula (A3) or a salt thereof,
In the general formula (A3), the group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-,
Item 3. The hydroxamic acid derivative or a salt thereof according to Item 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms.
Item 6. Item 6. A pharmaceutical composition comprising the hydroxamic acid derivative or a salt thereof according to any one of Items 1 to 5 as an active ingredient.
Item 7. The histone deacetylase inhibitor which uses the hydroxamic acid derivative or its salt in any one of claim | item 1 -5 as an active ingredient.
Item 8. Item 6. An antitumor agent comprising the hydroxamic acid derivative or a salt thereof according to any one of Items 1 to 5 as an active ingredient.
Item 9. A method for producing a hydroxamic acid derivative represented by the following general formula (Aa) or a salt thereof,
[In General Formula (Aa), group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing the following compound D3 by a coupling reaction of the following compound D1 and the following compound D2 represented by the following scheme 1:
[In Scheme 1, M is an alkyl group or a benzyl group, X 1 is a halogen atom, the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are represented by the general formula Same as (A). ]
Step 2 of converting the ester group of the compound D3 represented by the following Scheme 2 to a hydroxamic acid group by reacting with NH 2 OH;
[In the scheme 2, the group M is the same as that in the scheme 1, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Aa) or a salt thereof.
Item 10. A method for producing a hydroxamic acid derivative represented by the following general formula (Ab) or a salt thereof,
[In the general formula (Ab), the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 1 for synthesizing Compound D6 by a coupling reaction of Compound D4 and Compound D5 shown below in Scheme 3;
[In scheme 3, M is an alkyl group or a benzyl group, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as those in formula (A). ]
Step 2 of converting the ester group of compound D6 represented by the following Scheme 4 to a hydroxamic acid group by reacting with NH 2 OH;
[In the scheme 4, the group M is the same as that in the scheme 3, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ab) or a salt thereof.
Item 11. A method for producing a hydroxamic acid derivative represented by the following general formula (Ac) or a salt thereof,
[In General Formula (Ac), group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
Step 1 for synthesizing Compound D9 represented by the following Scheme 5 by a coupling reaction between Compound D7 and Compound D8,
[In scheme 5, M is an alkyl group or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D9 represented by the following Scheme 6 into a hydroxamic acid group by reacting with NH 2 OH;
[In scheme 6, group M is the same as scheme 5, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ac) or a salt thereof, comprising:
Item 12. A method for producing a hydroxamic acid derivative represented by the following general formula (Ad) or a salt thereof,
[In General Formula (Ad), group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing Compound D12 represented by the following Scheme 7 by a coupling reaction of Compound D10 and Compound D11 below;
[In Scheme 7, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D12 represented by the following Scheme 8 into a hydroxamic acid group by reacting with NH 2 OH;
[In scheme 8, the group M is the same as in scheme 7, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ad) or a salt thereof, comprising:
Item 13. A method for producing a hydroxamic acid derivative represented by the following general formula (Ae) or a salt thereof,
[In the general formula (Ae), the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 1 of synthesizing Compound D15 represented by the following Scheme 9 by a coupling reaction of Compound D13 and Compound D14 below;
[In the scheme 9, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Represented by the following Scheme 10, is reacted with NH 2 OH to an ester group of the following compounds D15, and step 2 of converting a hydroxamic acid group,
[In scheme 10, group M is the same as in scheme 9, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
The manufacturing method of the hydroxamic acid derivative represented by general formula (Ae) or its salt containing these.

本発明によれば、ヒストン脱アセチル化酵素阻害剤として有用なヒドロキサム酸誘導体またはその塩を提供することができる。また、本発明によれば、当該ヒドロキサム酸誘導体またはその塩を有効成分とする医薬組成物、ヒストン脱アセチル化酵素阻害剤、及び抗腫瘍剤を提供することができる。   According to the present invention, a hydroxamic acid derivative or a salt thereof useful as a histone deacetylase inhibitor can be provided. Moreover, according to this invention, the pharmaceutical composition which uses the said hydroxamic acid derivative or its salt as an active ingredient, a histone deacetylase inhibitor, and an antitumor agent can be provided.

１．一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩
本発明のヒドロキサム酸誘導体またはその塩は、下記一般式（Ａ）で表される。
 1. Hydroxamic acid derivative or salt thereof represented by general formula (A) The hydroxamic acid derivative or salt thereof of the present invention is represented by the following general formula (A).

一般式（Ａ）において、基Ａは、酸素原子、窒素原子、または−ＮＲ6−である。基Ａが酸素原子または−ＮＲ6−であるときは、複素環の１位の基Ａと２位の炭素原子との結合は単結合である。このとき、基Ｒ6は、置換基を有していてもよい低級アルキル基、または水素原子である。低級アルキル基としては、例えば、メチル基、エチル基、プロピル基などの炭素数１〜３のアルキル基が挙げられる。また、低級アルキル基が有し得る置換基としては、例えばハロゲン原子、好ましくはフッ素原子が挙げられる。基Ｒ6としては、好ましくはメチル基または水素原子が挙げられる。基Ａが窒素原子であるときは、前記複素環の１位の炭素原子と２位の炭素原子との結合は二重結合である。 In the general formula (A), the group A is an oxygen atom, a nitrogen atom, or —NR 6 —. When the group A is an oxygen atom or —NR 6 —, the bond between the 1-position group A and the 2-position carbon atom of the heterocyclic ring is a single bond. At this time, the group R 6 is a lower alkyl group which may have a substituent, or a hydrogen atom. As a lower alkyl group, C1-C3 alkyl groups, such as a methyl group, an ethyl group, a propyl group, are mentioned, for example. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The group R 6 is preferably a methyl group or a hydrogen atom. When group A is a nitrogen atom, the bond between the 1st carbon atom and the 2nd carbon atom of the heterocyclic ring is a double bond.

一般式（Ａ）において、基Ｂは、酸素原子または置換基を有していてもよい低級アルコキシ基である。低級アルコキシ基としては、例えば、メトキシ基、エトキシ基、プロポキシ基などの炭素数１〜３のアルコキシ基が挙げられる。低級アルコキシ基が有し得る置換基としては、例えば、例えばハロゲン原子、好ましくはフッ素原子が挙げられる。基Ｂとしては、好ましくは酸素原子またはメトキシ基が挙げられる。また、基Ｂが酸素原子であるときは、基Ｂと前記複素環の２位の炭素原子との結合は二重結合である。基Ｂが置換基を有していてもよい低級アルコキシ基であるときは、基Ｂと前記複素環の２位の炭素原子との結合は単結合である。   In the general formula (A), the group B is an oxygen atom or a lower alkoxy group which may have a substituent. As a lower alkoxy group, C1-C3 alkoxy groups, such as a methoxy group, an ethoxy group, a propoxy group, are mentioned, for example. Examples of the substituent that the lower alkoxy group may have include, for example, a halogen atom, preferably a fluorine atom. The group B is preferably an oxygen atom or a methoxy group. When group B is an oxygen atom, the bond between group B and the carbon atom at the 2-position of the heterocyclic ring is a double bond. When the group B is a lower alkoxy group which may have a substituent, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is a single bond.

一般式（Ａ）において、基Ｒ1及び基Ｒ3は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であるか、基Ｒ1及び基Ｒ3のいずれか一方は基Ｘと置換している。基Ｒ1及び基Ｒ3は、好ましくは、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基である。基Ｒ1及び基Ｒ3において、低級アルキル基としては、例えば、メチル基、エチル基、プロピル基などの炭素数１〜３のアルキル基が挙げられる。低級アルキル基が有し得る置換基としては、例えばハロゲン原子、好ましくはフッ素原子が挙げられる。基Ｒ1としては、好ましくは水素原子またはメチル基が挙げられる。また、基Ｒ3としては、好ましくは水素原子が挙げられる。基Ｒ2及び基Ｒ4は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であるか、互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。基Ｒ2及び基Ｒ4において、低級アルキル基としては、例えば、メチル基、エチル基、プロピル基などの炭素数１〜３のアルキル基が挙げられる。低級アルキル基が有し得る置換基としては、例えばハロゲン原子、好ましくはフッ素原子が挙げられる。基Ｒ2は、好ましくは、水素原子またはメチル基であるか、基Ｒ4と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。また、基Ｒ4は、好ましくは、水素原子であるか、基Ｒ2と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。 In the general formula (A), the group R 1 and the group R 3 are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or one of the group R 1 and the group R 3. Substitutes the group X. The group R 1 and the group R 3 are preferably each independently a hydrogen atom or a lower alkyl group which may have a substituent. In the group R 1 and the group R 3 , examples of the lower alkyl group include alkyl groups having 1 to 3 carbon atoms such as a methyl group, an ethyl group, and a propyl group. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The group R 1 is preferably a hydrogen atom or a methyl group. The group R 3 is preferably a hydrogen atom. The group R 2 and the group R 4 are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or bonded to each other to form a 3-position carbon atom and a 4-position carbon. It forms a double bond with the atom. In the group R 2 and the group R 4 , examples of the lower alkyl group include alkyl groups having 1 to 3 carbon atoms such as a methyl group, an ethyl group, and a propyl group. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The group R 2 is preferably a hydrogen atom or a methyl group, or is bonded to the group R 4 to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. . The group R 4 is preferably a hydrogen atom or bonded to the group R 2 to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring.

一般式（Ａ）において、基Ｒn 5は、前記複素環が縮合しているベンゼン環上の水素原子と置換したｎ＝０〜３個の置換基である。ｎ個の基Ｒn 5は、それぞれ独立に、ハロゲン原子または置換基を有していてもよい低級アルキル基である。低級アルキル基としては、例えば、メチル基、エチル基、プロピル基などの炭素数１〜３のアルキル基が挙げられる。低級アルキル基が有し得る置換基としては、例えばハロゲン原子、好ましくはフッ素原子が挙げられる。基Ｒn 5の数（ｎ）は、好ましくは０または１である。また、基Ｒn 5のハロゲン原子としては、好ましくはフッ素原子が挙げられる。 In the general formula (A), the group R n 5 is n = 0 to 3 substituents substituted with hydrogen atoms on the benzene ring to which the heterocycle is condensed. Each of the n groups R n 5 is independently a halogen atom or a lower alkyl group which may have a substituent. As a lower alkyl group, C1-C3 alkyl groups, such as a methyl group, an ethyl group, a propyl group, are mentioned, for example. Examples of the substituent that the lower alkyl group may have include a halogen atom, preferably a fluorine atom. The number (n) of the radicals R n 5 is preferably 0 or 1. The halogen atom of the group R n 5 is preferably a fluorine atom.

一般式（Ａ）において、基Ｘは、前記ベンゼン環上の水素原子、前記複素環上の水素原子、または基Ｒ1及び基Ｒ3のいずれか一方と置換しており、好ましくは前記ベンゼン環上の水素原子、前記複素環上の水素原子と置換している。また、基Ｘは、単結合、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−であり、好ましくは酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−であり、特に高いヒストン脱アセチル化酵素阻害活性をを有する観点からは、より好ましくは−ＣＯＮＨ−または−ＮＨＣＯ−である。 In the general formula (A), the group X is substituted with a hydrogen atom on the benzene ring, a hydrogen atom on the heterocyclic ring, or one of the groups R 1 and R 3 , preferably the benzene ring It replaces the hydrogen atom on the top and the hydrogen atom on the heterocycle. The group X is a single bond, an oxygen atom, —CONH—, —NHCO—, —SO 2 NH—, or —NHSO 2 —, preferably an oxygen atom, —CONH—, —NHCO—, —SO 2. NH-, or -NHSO 2 -; and particularly from the viewpoint of having a high histone deacetylase inhibitory activity, more preferably -CONH- or -NHCO-.

一般式（Ａ）において、基Ｙは、単結合、飽和もしくは不飽和の炭素数１〜１０のアルキレン基、または基−Ｙ1−Ｙ2−Ｙ3−であり、好ましくは飽和もしくは不飽和の炭素数３〜７のアルキレン基または基−Ｙ1−Ｙ2−Ｙ3−であり、より好ましくは飽和の炭素数３〜７のアルキレン基または基−Ｙ1−Ｙ2−Ｙ3−である。基Ｙ1は、ヒドロキサム酸基のカルボニル炭素と結合している。基Ｙ1は、飽和もしくは不飽和の炭素数１〜６のアルキレン基、または単結合であり、好ましくは飽和もしくは不飽和の炭素数２〜４のアルキレン基であり、より好ましくは不飽和の炭素数２のアルキレン基（−ＣＨ＝ＣＨ−）である。また、基Ｙ2は、置換基を有していてもよいフェニレン基または置換基を有していてもよいシクロヘキシレン基である。フェニレン基またはシクロへキシレン基が有し得る置換基としては、例えばハロゲン原子、好ましくはフッ素原子が挙げられる。基Ｙ2は、好ましくはフェニレン基またはシクロヘキシレン基である。基Ｙ3は、基Ｘと結合しており、飽和もしくは不飽和の炭素数１〜６のアルキレン基であり、好ましくは飽和もしくは不飽和の炭素数１〜３のアルキレン基であり、より好ましくはメチレン基である。基Ｙ2がフェニレン基である場合、基Ｙ1と基Ｙ3は、ベンゼン環上において、オルト、メタ、パラのいずれの位置関係で基Ｙ2と結合していてもよい。また、基Ｙ2がシクロヘキシレン基である場合、基Ｙ1と基Ｙ3は、シクロヘキサン環の１位と１位、１位と２位、１位と３位、１位と４位のいずれの位置関係で基Ｙ2と結合していてもよく、また、シス及びトランスのいずれの立体構造で基Ｙ2と結合していてもよい。 In the general formula (A), the group Y is a single bond, a saturated or unsaturated alkylene group having 1 to 10 carbon atoms, or a group —Y 1 —Y 2 —Y 3 —, preferably saturated or unsaturated. is more preferably an alkylene group or a group -Y 1 -Y 2 -Y 3 to 7 carbon atoms, saturated 3 - - number 3-7 alkylene group or a group -Y 1 -Y 2 -Y 3 carbon is . The group Y 1 is bonded to the carbonyl carbon of the hydroxamic acid group. The group Y 1 is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, or a single bond, preferably a saturated or unsaturated alkylene group having 2 to 4 carbon atoms, more preferably an unsaturated carbon. It is an alkylene group of formula 2 (—CH═CH—). The group Y 2 is a phenylene group which may have a substituent or a cyclohexylene group which may have a substituent. Examples of the substituent that the phenylene group or cyclohexylene group may have include a halogen atom, preferably a fluorine atom. The group Y 2 is preferably a phenylene group or a cyclohexylene group. The group Y 3 is bonded to the group X and is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, preferably a saturated or unsaturated alkylene group having 1 to 3 carbon atoms, more preferably A methylene group. When the group Y 2 is a phenylene group, the group Y 1 and the group Y 3 may be bonded to the group Y 2 in any positional relationship of ortho, meta, and para on the benzene ring. Further, when the group Y 2 is a cyclohexylene group, the group Y 1 and the group Y 3 are any of the 1-position, 1-position, 1-position and 2-position, 1-position and 3-position, 1-position and 4-position of the cyclohexane ring. it may be bonded in a positional relationship between the group Y 2, or may be bonded to the group Y 2 in any stereostructure of cis and trans.

本発明において、一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩の中でも、下記一般式（Ａ１）で表されるヒドロキサム酸誘導体またはその塩が好ましい例として挙げられる。
In the present invention, among hydroxamic acid derivatives represented by the general formula (A) or salts thereof, preferred are hydroxamic acid derivatives represented by the following general formula (A1) or salts thereof.

一般式（Ａ１）において、基Ｒ6は、メチル基または水素原子である。また、基Ｒ1は、水素原子またはメチル基である。基Ｒ3は、水素原子である。基Ｒ2は、水素原子またはメチル基であるか、基Ｒ4と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。基Ｒ4は、水素原子であるか、基Ｒ2と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。基Ｒ5は、水素原子またはフッ素原子である。 In the general formula (A1), the group R 6 is a methyl group or a hydrogen atom. The group R 1 is a hydrogen atom or a methyl group. The group R 3 is a hydrogen atom. The group R 2 is a hydrogen atom or a methyl group, or is bonded to the group R 4 to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. The group R 4 is a hydrogen atom or is bonded to the group R 2 to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. The group R 5 is a hydrogen atom or a fluorine atom.

また、一般式（Ａ１）において、基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−である。基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基、または基−Ｙ1−Ｙ2−Ｙ3−であり、好ましくは飽和の炭素数３〜７のアルキレン基、または基−Ｙ1−Ｙ2−Ｙ3−である。基Ｙ1は、飽和もしくは不飽和の炭素数２のアルキレン基である。基Ｙ2は、フェニレン基またはシクロヘキシレン基である。基Ｙ3は、メチレン基である。基Ｙ2がフェニレン基である場合、基Ｙ1と基Ｙ3は、ベンゼン環上において、オルト、メタ、パラのいずれの位置関係で基Ｙ2と結合していてもよい。また、基Ｙ2がシクロヘキシレン基である場合、基Ｙ1と基Ｙ3は、シクロヘキサン環の１位と１位、１位と２位、１位と３位、１位と４位のいずれの位置関係で基Ｙ2と結合していてもよく、また、シス及びトランスのいずれの立体構造で基Ｙ2と結合していてもよい。 In the general formula (A1), the group X is substituted with a hydrogen atom on the benzene ring, and the group X is an oxygen atom, —CONH—, —NHCO—, —SO 2 NH—, or —NHSO. 2 −. The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, or a group —Y 1 —Y 2 —Y 3 —, preferably a saturated alkylene group having 3 to 7 carbon atoms, or the group —Y. 1 -Y 2 -Y 3- . The group Y 1 is a saturated or unsaturated alkylene group having 2 carbon atoms. The group Y 2 is a phenylene group or a cyclohexylene group. The group Y 3 is a methylene group. When the group Y 2 is a phenylene group, the group Y 1 and the group Y 3 may be bonded to the group Y 2 in any positional relationship of ortho, meta, and para on the benzene ring. Further, when the group Y 2 is a cyclohexylene group, the group Y 1 and the group Y 3 are any of the 1-position, 1-position, 1-position and 2-position, 1-position and 3-position, 1-position and 4-position of the cyclohexane ring. it may be bonded in a positional relationship between the group Y 2, or may be bonded to the group Y 2 in any stereostructure of cis and trans.

一般式（Ａ１）で表されるヒドロキサム酸誘導体またはその塩の中でも、より好ましくは、下記一般式（Ａ１１）〜（Ａ１３）で表されるヒドロキサム酸誘導体またはその塩が挙げられる。
Among the hydroxamic acid derivatives represented by the general formula (A1) or salts thereof, more preferred are hydroxamic acid derivatives represented by the following general formulas (A11) to (A13) or salts thereof.

一般式（Ａ１１）〜（Ａ１３）において、基Ｒ5、基Ｒ6、基Ｘ、及び基Ｙは、一般式（Ａ１）と同じである。 In the general formulas (A11) to (A13), the group R 5 , the group R 6 , the group X, and the group Y are the same as those in the general formula (A1).

また、本発明において、一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩の中でも、下記一般式（Ａ２）で表されるヒドロキサム酸誘導体またはその塩も、上記一般式（Ａ１）で表されるヒドロキサム酸誘導体またはその塩と共に、好ましい例として挙げられる。
In the present invention, among hydroxamic acid derivatives represented by the general formula (A) or salts thereof, hydroxamic acid derivatives represented by the following general formula (A2) or salts thereof are also represented by the general formula (A1). A preferred example is a hydroxamic acid derivative or a salt thereof.

一般式（Ａ２）において、基Ｒ1は、水素原子またはメチル基である。基Ｒ3は、水素原子である。基Ｒ2は、水素原子またはメチル基であるか、基Ｒ4と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。また、基Ｒ4は、水素原子であるか、基Ｒ2と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。基Ｒ7は、メチル基またはエチル基である。 In the general formula (A2), the group R 1 is a hydrogen atom or a methyl group. The group R 3 is a hydrogen atom. The group R 2 is a hydrogen atom or a methyl group, or is bonded to the group R 4 to form a double bond between the 3-position carbon atom and the 4-position carbon atom of the heterocyclic ring. The group R 4 is a hydrogen atom or is bonded to the group R 2 to form a double bond between the third and fourth carbon atoms of the heterocyclic ring. The group R 7 is a methyl group or an ethyl group.

また、一般式（Ａ２）において、基Ｘは、前記ベンゼン環上の水素原子と置換している。基Ｘは、酸素原子、−ＣＯＮＨ−、または−ＮＨＣＯ−である。基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基であり、好ましくは飽和の炭素数３〜７のアルキレン基である。   In general formula (A2), group X is substituted with a hydrogen atom on the benzene ring. The group X is an oxygen atom, —CONH—, or —NHCO—. The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, preferably a saturated alkylene group having 3 to 7 carbon atoms.

一般式（Ａ２）で表されるヒドロキサム酸誘導体またはその塩の中でも、より好ましくは、下記一般式（Ａ２１）及び（Ａ２２）で表されるヒドロキサム酸誘導体またはその塩が挙げられる。
Among the hydroxamic acid derivatives represented by the general formula (A2) or salts thereof, more preferred are hydroxamic acid derivatives represented by the following general formulas (A21) and (A22) or salts thereof.

一般式（Ａ２１）及び（Ａ２２）において、基Ｒ7、基Ｘ、及び基Ｙは、一般式（Ａ２）と同じである。 In the general formulas (A21) and (A22), the group R 7 , the group X, and the group Y are the same as those in the general formula (A2).

さらに、本発明において、一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩の中でも、下記一般式（Ａ３）で表されるヒドロキサム酸誘導体またはその塩も、上記一般式（Ａ１）及び（Ａ２）で表されるヒドロキサム酸誘導体またはその塩と共に、好ましい例として挙げられる。
Furthermore, in the present invention, among the hydroxamic acid derivatives represented by the general formula (A) or salts thereof, the hydroxamic acid derivatives represented by the following general formula (A3) or salts thereof are also represented by the above general formulas (A1) and ( A preferred example is a hydroxamic acid derivative represented by A2) or a salt thereof.

一般式（Ａ３）において、基Ｘは、前記ベンゼン環上の水素原子と置換している。基Ｘは、酸素原子、−ＣＯＮＨ−、または−ＮＨＣＯ−である。また、基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基であり、好ましくは飽和の炭素数３〜７のアルキレン基である。   In the general formula (A3), the group X is substituted with a hydrogen atom on the benzene ring. The group X is an oxygen atom, —CONH—, or —NHCO—. The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, preferably a saturated alkylene group having 3 to 7 carbon atoms.

本発明のヒドロキサム酸誘導体またはその塩としては、薬理学的に許容し得る塩であれば特に制限されず、例えば、ナトリウム、カリウム、リチウム、カルシウムなどの無機塩基との塩；トリエチルアミンなどの第三級アミンやテトラメチルアンモニウムなどの第四級アミンなどの有機アミン塩などが挙げられる。   The hydroxamic acid derivative of the present invention or a salt thereof is not particularly limited as long as it is a pharmacologically acceptable salt. For example, a salt with an inorganic base such as sodium, potassium, lithium or calcium; a third such as triethylamine And organic amine salts such as quaternary amines such as quaternary amines and tetramethylammonium.

本発明のヒドロキサム酸誘導体またはその塩は、ヒストン脱アセチル化酵素に対する阻害活性を備えており、ヒストン脱アセチル化酵素阻害剤として使用することができる。また、ヒストン脱アセチル化酵素は、腫瘍（Ｔ細胞性リンパ腫などのがんなど）、記憶障害（アルツハイマーなど）、炎症、ＨＩＶ潜伏感染、神経変性疾患、うつ、自己免疫疾患、ハンチントン病等の発症や症状の悪化に関与していることが知られており、本発明の化合物は、これらの疾患の予防又は治療剤として使用することができる。ヒストン脱アセチル化酵素の中でも、ＨＤＡＣ１、ＨＤＡＣ２、及びＨＤＡＣ８は、がんの発症などに関与していることが知られている。特に、本発明の一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩において、基Ｘが−ＣＯＮＨ−及び−ＮＨＣＯ−で表される構造を有する場合、ＨＤＡＣ１、ＨＤＡＣ２、及びＨＤＡＣ８に高い活性を有するため、がんの治療剤として有用である。本発明のヒドロキサム酸誘導体またはその塩を前記用途に使用する場合、医薬組成物として提供すればよい。   The hydroxamic acid derivative of the present invention or a salt thereof has inhibitory activity against histone deacetylase and can be used as a histone deacetylase inhibitor. In addition, histone deacetylase is used to develop tumors (such as cancers such as T cell lymphoma), memory disorders (such as Alzheimer), inflammation, HIV latent infection, neurodegenerative diseases, depression, autoimmune diseases, Huntington's disease, etc. And the compounds of the present invention can be used as preventive or therapeutic agents for these diseases. Among histone deacetylases, HDAC1, HDAC2, and HDAC8 are known to be involved in the development of cancer. In particular, in the hydroxamic acid derivative represented by the general formula (A) of the present invention or a salt thereof, when the group X has a structure represented by -CONH- and -NHCO-, high activity in HDAC1, HDAC2, and HDAC8 Therefore, it is useful as a therapeutic agent for cancer. What is necessary is just to provide the hydroxamic acid derivative or its salt of this invention as a pharmaceutical composition, when using it for the said use.

本発明のヒドロキサム酸誘導体またはその塩は、生体内において代謝されることにより、本発明における一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩に変換される化合物（すなわち、いわゆるプロドラッグ）として提供してもよい。   The hydroxamic acid derivative of the present invention or a salt thereof is converted in vivo into a hydroxamic acid derivative represented by the general formula (A) or a salt thereof (that is, a so-called prodrug) in the present invention. May be provided as

また、本発明のヒドロキサム酸誘導体またはその塩（プロドラッグを含む）は、大気中に放置しておいたり、再結晶することにより、水分や他の溶媒を吸収し、吸着水や溶媒が付いたり、水和物や溶媒和物となることがあり得る。そのような水和物または溶媒和物を形成する場合、本発明のヒドロキサム酸誘導体またはその塩の水和物または溶媒和物も本発明のヒドロキサム酸誘導体またはその塩に含まれる。   The hydroxamic acid derivatives or salts thereof (including prodrugs) of the present invention can be left in the atmosphere or recrystallized to absorb moisture and other solvents, and adsorbed water and solvents can be attached. May be hydrated or solvated. When such a hydrate or solvate is formed, a hydrate or solvate of the hydroxamic acid derivative or salt thereof of the present invention is also included in the hydroxamic acid derivative or salt thereof of the present invention.

本発明のヒドロキサム酸誘導体またはその塩を前記用途に使用する場合、一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩は、１種類単独で使用してもよいし、２種類以上を組み合わせて使用してもよい。また、本発明のヒドロキサム酸誘導体またはその塩を含む医薬組成物は、賦形剤、希釈剤、溶解補助剤等の薬学的に許容される添加剤と共に製剤化して、粉剤、顆粒剤、錠剤、カブレット剤、カプセル剤、注射剤、座剤、軟膏剤等の剤型に調製される。当該医薬組成物の投与形態については、特に制限されず、経口投与であっても、また全身投与、局所投与等の非経口投与であってもよい。医薬組成物の中の本発明のヒドロキサム酸誘導体またはその塩の含量は、剤型等により種々異なるが、例えば０．１〜１００質量％程度が挙げられる。当該医薬組成物の投与量は、投与経路、患者の年齢、予防・治療すべき実際の症状、剤型等により異なるが、例えば成人に経口投与する場合、本発明のヒドロキサム酸誘導体またはその塩の量に換算して１日０．０１ｍｇ〜２０００ｍｇ程度、好ましくは０．１ｍｇ〜１０００ｍｇ程度とすることができ、１日１〜数回に分けて投与できる。   When the hydroxamic acid derivative of the present invention or a salt thereof is used for the above application, the hydroxamic acid derivative represented by the general formula (A) or a salt thereof may be used alone or in combination of two or more. May be used. Further, the pharmaceutical composition containing the hydroxamic acid derivative of the present invention or a salt thereof is formulated with a pharmaceutically acceptable additive such as an excipient, a diluent, a solubilizing agent, etc. It is prepared into dosage forms such as a capsule, capsule, injection, suppository and ointment. The administration form of the pharmaceutical composition is not particularly limited, and may be oral administration or parenteral administration such as systemic administration and local administration. The content of the hydroxamic acid derivative of the present invention or a salt thereof in the pharmaceutical composition varies depending on the dosage form and the like, and is, for example, about 0.1 to 100% by mass. The dosage of the pharmaceutical composition varies depending on the administration route, the age of the patient, the actual symptoms to be prevented or treated, the dosage form, etc. For example, when administered orally to an adult, the hydroxamic acid derivative of the present invention or a salt thereof In terms of amount, it can be about 0.01 mg to 2000 mg per day, preferably about 0.1 mg to 1000 mg per day, and can be divided into 1 to several times per day.

２．一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩の製造方法
本発明の一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩は、公知の方法により製造することができ、例えば、Ｊ． Ｍｅｄ． Ｃｈｅｍ． ２０１０，５３，２９５２−２９６３、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００６，４９，４８０９−４８１２、実験化学講座第５版、１４、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２０１０，５３，１９３７−１９５０、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２０１０，５３，３０３８−３０４７、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００９，５２，２７７６−２７８５、Ｊ．Ｏｒｇ．Ｃｈｅｍ．２００９，７４，３５４０−３５４３、Ｊ．Ｍｅｄ．Ｃｈｅｍ．２００７，５０，４４０５−４４１８などの文献や、実施例に例示した方法により製造することができる。 2. Process for producing hydroxamic acid derivative represented by general formula (A) or a salt thereof The hydroxamic acid derivative represented by general formula (A) of the present invention or a salt thereof can be produced by a known method, for example, J. et al. Med. Chem. 2010, 53, 2952-2963, J. MoI. Med. Chem. 2006, 49, 4809-4812, Experimental Chemistry Course 5th edition, 14, J. MoI. Med. Chem. 2010, 53, 1937-1950, J. MoI. Med. Chem. 2010, 53, 3038-3047, J. MoI. Med. Chem. 2009, 52, 2776-2785, J. MoI. Org. Chem. 2009, 74, 3540-3543, J. MoI. Med. Chem. It can be produced by the literatures such as 2007, 50, 4405-4418 and the methods exemplified in the examples.

（１）一般式（Ａ）において、基Ｘが酸素原子である場合
例えば、本発明の一般式（Ａ）で表される化合物は、基Ｘが酸素原子である場合には、例えば、下記スキーム１のように、化合物Ｄ１と化合物Ｄ２とのカップリング反応により、化合物Ｄ３を合成する工程１と、
［スキーム１中、Ｍは、メチル基、エチル基、プロピル基などのアルキル基またはベンジル基であり、Ｘ1は、Ｃｌ、Ｂｒ、Ｉなどのハロゲン原子であり、基Ａ、基Ｂ、基Ｒn 5、基Ｒ1〜Ｒ4、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム２のように、化合物Ｄ３のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム２中、基Ｍは、スキーム１と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む方法により製造することができる。 (1) In the general formula (A), when the group X is an oxygen atom, for example, the compound represented by the general formula (A) of the present invention has, for example, the following scheme when the group X is an oxygen atom: Step 1 of synthesizing compound D3 by a coupling reaction between compound D1 and compound D2 as shown in FIG.
[In Scheme 1, M is an alkyl group such as a methyl group, an ethyl group, or a propyl group, or a benzyl group; X 1 is a halogen atom such as Cl, Br, or I; n 5 , groups R 1 to R 4 , and group Y are the same as those in formula (A). ]
As shown in the following scheme 2, the ester group of compound D3 is reacted with NH 2 OH to convert it into a hydroxamic acid group,
[In the scheme 2, the group M is the same as that in the scheme 1, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
It can manufacture by the method containing.

スキーム１において、化合物Ｄ１と化合物Ｄ２とのカップリング反応は、化合物Ｄ１のハロゲンＸ1と化合物Ｄ２の水酸基とを反応させることができれば、特に制限されず、例えば、ＮａＨなどの塩基を用いることによって行うことができる。また、カップリング反応には、溶媒を使用してもよく、溶媒としては、特に制限されず、例えばＤＭＦなどを用いることができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−７８℃〜１５０℃程度の温度で、０．５〜２４時間程度反応させることができる。 In Scheme 1, coupling reaction of the compound D2 with the compound D1 is, if the reaction of hydroxyl groups of halogen X 1 and compound D2 compound D1, is not particularly limited, for example, by using a base such as NaH It can be carried out. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, DMF can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-150 degreeC.

スキーム２において、化合物Ｄ３のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換し、一般式（Ａａ）で表されるヒドロキサム酸誘導体またはその塩を得る方法は、特に制限されず、例えばＮａＯＣＨ3などの塩基の存在下に行うことができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−１０〜１００℃程度の温度で、０．５〜２４時間程度反応させることができる。 In Scheme 2, the method of obtaining the hydroxamic acid derivative represented by the general formula (Aa) or a salt thereof by reacting the ester group of compound D3 with NH 2 OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH 3 . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10-100 degreeC.

（２）一般式（Ａ）において、基Ｘが−ＮＨＣＯ−である場合
例えば、本発明の一般式（Ａ）で表される化合物は、基Ｘが−ＮＨＣＯ−である場合には、例えば、下記スキーム３のように、化合物Ｄ４と化合物Ｄ５とのカップリング反応により、化合物Ｄ６を合成する工程１と、
［スキーム３中、Ｍは、メチル基、エチル基、プロピル基などのアルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム４のように、化合物Ｄ６のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム４中、基Ｍは、スキーム３と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む方法により製造することができる。 (2) In the general formula (A), when the group X is —NHCO—, for example, when the group X is —NHCO—, the compound represented by the general formula (A) of the present invention is, for example, Step 1 for synthesizing Compound D6 by a coupling reaction of Compound D4 and Compound D5 as shown in Scheme 3 below,
[In scheme 3, M is an alkyl group such as a methyl group, an ethyl group, a propyl group, or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are It is the same as formula (A). ]
As shown in the following scheme 4, the ester group of compound D6 is reacted with NH 2 OH to convert it into a hydroxamic acid group,
[In the scheme 4, the group M is the same as that in the scheme 3, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
It can manufacture by the method containing.

スキーム３において、化合物Ｄ４と化合物Ｄ５とのカップリング反応は、化合物Ｄ４の基ＮＨ2と化合物Ｄ５の基ＣＯＯＨとを反応させることができれば、特に制限されず、例えば、ジフェニルリン酸アジド（ＤＰＰＡ）、１−エチル−３−（３−ジメチルアミノプロピル）カルボジイミド（ＥＤＣＩ）などの縮合剤や、トリエチルアミンなどのアミンを用いて行うことができる。また、カップリング反応には、溶媒を使用してもよく、溶媒としては、特に制限されず、例えばＤＭＦなどを用いることができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−７８℃〜１５０℃程度の温度で、０．５〜２４時間程度反応させることができる。 In scheme 3, the coupling reaction between compound D4 and compound D5 is not particularly limited as long as the group NH 2 of compound D4 and the group COOH of compound D5 can be reacted. For example, diphenyl phosphate azide (DPPA) , 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDCI) and the like, and amine such as triethylamine can be used. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, DMF can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-150 degreeC.

スキーム４において、化合物Ｄ６のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換し、一般式（Ａｂ）で表されるヒドロキサム酸誘導体またはその塩を得る方法は、特に制限されず、例えばＮａＯＣＨ3などの塩基の存在下に行うことができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−１０〜１００℃程度の温度で、０．５〜２４時間程度反応させることができる。 In Scheme 4, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ab) or a salt thereof by reacting the ester group of compound D6 with NH 2 OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH 3 . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10-100 degreeC.

（３）一般式（Ａ）において、基Ｘが−ＣＯＮＨ−である場合
例えば、本発明の一般式（Ａ）で表される化合物は、基Ｘが−ＣＯＮＨ−である場合には、例えば、下記スキーム５のように、化合物Ｄ７と化合物Ｄ８とのカップリング反応により、化合物Ｄ９を合成する工程１と、
［スキーム５中、基Ｍは、メチル基、エチル基、プロピル基などのアルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム６のように、化合物Ｄ９のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム６中、基Ｍは、スキーム５と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む方法により製造することができる。 (3) In the general formula (A), when the group X is —CONH—, for example, the compound represented by the general formula (A) of the present invention is, for example, when the group X is —CONH—, Step 1 of synthesizing compound D9 by a coupling reaction between compound D7 and compound D8 as shown in Scheme 5 below,
[In Scheme 5, the group M is an alkyl group such as a methyl group, an ethyl group, a propyl group, or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are It is the same as general formula (A). ]
As shown in the following scheme 6, the ester group of compound D9 is reacted with NH 2 OH to convert it into a hydroxamic acid group,
[In scheme 6, group M is the same as scheme 5, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
It can manufacture by the method containing.

スキーム５において、化合物Ｄ７と化合物Ｄ８とのカップリング反応は、化合物Ｄ７の基ＣＯＯＨと化合物Ｄ８の基ＮＨ2とを反応させることができれば、特に制限されず、例えば、トリエチルアミンなどのアミンの存在下に行うことができる。また、カップリング反応には、溶媒を使用してもよく、溶媒としては、特に制限されず、例えばＤＭＦなどを用いることができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−７８℃〜１５０℃程度の温度で、０．５〜２４時間程度反応させることができる。 In scheme 5, the coupling reaction between compound D7 and compound D8 is not particularly limited as long as the group COOH of compound D7 and the group NH 2 of compound D8 can be reacted. For example, in the presence of an amine such as triethylamine. Can be done. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, DMF can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-150 degreeC.

スキーム６において、化合物Ｄ９のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換し、一般式（Ａｃ）で表されるヒドロキサム酸誘導体またはその塩を得る方法は、特に制限されず、例えばＮａＯＣＨ3などの塩基の存在下に行うことができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−１０〜１００℃程度の温度で、０．５〜２４時間程度反応させることができる。 In Scheme 6, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ac) or a salt thereof by reacting the ester group of compound D9 with NH 2 OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH 3 . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10-100 degreeC.

（４）一般式（Ａ）において、基Ｘが−ＮＨＳＯ 2 −である場合
例えば、本発明の一般式（Ａ）で表される化合物は、基Ｘが−ＮＨＳＯ2−である場合には、例えば、下記スキーム７のように、化合物Ｄ１０と化合物Ｄ１１とのカップリング反応により、化合物１２を合成する工程１と、
［スキーム７中、基Ｍは、メチル基、エチル基、プロピル基などのアルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム８のように、化合物Ｄ１２のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム８中、基Ｍは、スキーム７と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む方法により製造することができる。 (4) In formula (A), the group X is -NHSO 2 - For example, when a compound represented by the general formula (A) of the present invention, group X is -NHSO 2 - if it is, the For example, as shown in Scheme 7 below, Step 1 for synthesizing Compound 12 by a coupling reaction between Compound D10 and Compound D11;
[In Scheme 7, the group M is an alkyl group such as a methyl group, an ethyl group, a propyl group, or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are It is the same as general formula (A). ]
As shown in the following scheme 8, the ester group of compound D12 is reacted with NH 2 OH to convert it into a hydroxamic acid group,
[In scheme 8, the group M is the same as in scheme 7, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
It can manufacture by the method containing.

スキーム７において、化合物Ｄ１０と化合物Ｄ１１とのカップリング反応は、化合物Ｄ１０の基ＮＨ2と化合物Ｄ１１の基ＳＯ2Ｃｌとを反応させることができれば、特に制限されず、例えば、トリエチルアミンなどのアミンの存在下に行うことができる。また、カップリング反応には、溶媒を使用してもよく、溶媒としては、特に制限されず、例えばジクロロメタンなどを用いることができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−７８℃〜８０℃程度の温度で、０．５〜２４時間程度反応させることができる。 In Scheme 7, the coupling reaction between the compound D10 and the compound D11 is not particularly limited as long as the group NH 2 of the compound D10 and the group SO 2 Cl of the compound D11 can be reacted. For example, an amine such as triethylamine Can be done in the presence. In the coupling reaction, a solvent may be used, and the solvent is not particularly limited, and for example, dichloromethane can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -78 degreeC-80 degreeC.

スキーム８において、化合物Ｄ１２のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換し、一般式（Ａｄ）で表されるヒドロキサム酸誘導体またはその塩を得る方法は、特に制限されず、例えばＮａＯＣＨ3などの塩基の存在下に行うことができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−１０℃〜１００℃程度の温度で、０．５〜２４時間程度反応させることができる。 In Scheme 8, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ad) or a salt thereof by reacting the ester group of compound D12 with NH 2 OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH 3 . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10 degreeC-100 degreeC.

（５）一般式（Ａ）において、基Ｘが−ＳＯ 2 ＮＨ−である場合
例えば、本発明の一般式（Ａ）で表される化合物は、基Ｘが−ＳＯ2ＮＨ−である場合には、例えば、下記スキーム９のように、化合物Ｄ１３と化合物Ｄ１４とのカップリング反応により、化合物１５を合成する工程１と、
［スキーム９中、基Ｍは、メチル基、エチル基、プロピル基などのアルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム１０のように、化合物Ｄ１５のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム１０中、基Ｍは、スキーム９と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む方法により製造することができる。 (5) In the general formula (A), when the group X is —SO 2 NH— For example, the compound represented by the general formula (A) of the present invention may be used when the group X is —SO 2 NH—. For example, as shown in Scheme 9 below, Step 1 for synthesizing Compound 15 by a coupling reaction of Compound D13 and Compound D14;
[In scheme 9, the group M is an alkyl group such as a methyl group, an ethyl group, a propyl group or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are It is the same as general formula (A). ]
As shown in Scheme 10 below, the ester group of compound D15 is reacted with NH 2 OH to convert it into a hydroxamic acid group,
[In scheme 10, group M is the same as in scheme 9, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
It can manufacture by the method containing.

スキーム９において、化合物Ｄ１３と化合物Ｄ１４とのカップリング反応は、化合物Ｄ１３の基ＳＯ3Ｈと化合物Ｄ１４の基ＮＨ2とを反応させることができれば、特に制限されず、例えば、トリエチルアミンなどのアミンとトリクロロトリアジンなどの縮合剤を用いて行うことができる。また、カップリング反応には、溶媒を使用してもよく、溶媒としては、特に制限されず、例えばアセトンなどを用いることができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−０℃〜１００℃程度の温度で、０．２５〜２４時間程度反応させることができる。 In Scheme 9, the coupling reaction between the compound D13 and the compound D14 is not particularly limited as long as the group SO 3 H of the compound D13 and the group NH 2 of the compound D14 can be reacted. For example, an amine such as triethylamine It can be carried out using a condensing agent such as trichlorotriazine. In addition, a solvent may be used for the coupling reaction, and the solvent is not particularly limited, and for example, acetone or the like can be used. What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.25 to 24 hours at the temperature of about -0 degreeC-100 degreeC.

スキーム１０において、化合物Ｄ１５のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換し、一般式（Ａｅ）で表されるヒドロキサム酸誘導体またはその塩を得る方法は、特に制限されず、例えばＮａＯＣＨ3などの塩基の存在下に行うことができる。反応時間、反応温度などは、適宜設定すればよく、例えば、−１０℃〜１００℃程度の温度で、０．５〜２４時間程度反応させることができる。 In Scheme 10, the method of obtaining the hydroxamic acid derivative represented by the general formula (Ae) or a salt thereof by reacting the ester group of compound D15 with NH 2 OH to convert it into a hydroxamic acid group is not particularly limited. For example, it can be carried out in the presence of a base such as NaOCH 3 . What is necessary is just to set reaction time, reaction temperature, etc. suitably, for example, it can be made to react for about 0.5 to 24 hours at the temperature of about -10 degreeC-100 degreeC.

以下に実施例を示して本発明を詳細に説明する。ただし、本発明は、実施例に限定されるものではない。   Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples.

１．各種ヒドロキサム酸誘導体の製造
実施例１（6-(3,4-dihydrocarbostyril-6-yloxy)hexanoic acid hydroxyamideの合成）
まず、下記のスキームに従い、6-(3,4-dihydrocarbostyril-6-yloxy)hexanoic acid ethyl esterを合成した。
100 mlナスフラスコに、NaH (60% in mineral oil) 0.59 g (14.709 mmol, 1.2 eq.)を取り、DMF 5 mlを加えて白色懸濁液とした。塩化カルシウム管と滴下漏斗を付け、氷浴上、攪拌下、6-hydroxy-3,4-dihydrocarbostyril 2.00 g (12.257 mmol)をDMF 9 mlに溶かしたものと洗い込みのDMF 1 mlを14分間かけて滴下した。そのまま、氷浴上にて20分間攪拌して、6-bromohexanoic acid ethyl ester 3.06 g (13.483 mmol, 1.1 eq.)をDMF 6 mlと洗い込みのDMF 1 mlを7分間かけて滴下した。氷が融けるにまかせて一晩攪拌した。オイルバス110℃上にて3時間攪拌して放冷した。水100 mlを加えてAcOEt 100 ml×3で抽出し、水100 ml×1、brine 100 ml×1で順次洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、淡橙色粗結晶4.13 gを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 1 : 2）にて精製し、白色粗結晶2.56 g (8.376 mmol, y.68%)を得た。 1. Production of various hydroxamic acid derivatives
Example 1 (Synthesis of 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid hydroxyamide)
First, 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid ethyl ester was synthesized according to the following scheme.
In a 100 ml eggplant flask, 0.59 g (14.709 mmol, 1.2 eq.) Of NaH (60% in mineral oil) was taken, and 5 ml of DMF was added to form a white suspension. Attach a calcium chloride tube and a dropping funnel, stir in an ice bath and stir, dissolve 2.00 g (12.257 mmol) of 6-hydroxy-3,4-dihydrocarbostyril in 9 ml of DMF and 1 ml of washed DMF for 14 minutes. And dripped. The mixture was stirred for 20 minutes on an ice bath, and 6 ml of 6-bromohexanoic acid ethyl ester (13.483 mmol, 1.1 eq.) And 1 ml of washed DMF were added dropwise over 7 minutes. Allow the ice to melt and stir overnight. The mixture was stirred for 3 hours on an oil bath at 110 ° C. and allowed to cool. 100 ml of water was added, extraction was performed with AcOEt 100 ml × 3, washed sequentially with water 100 ml × 1, brine 100 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 4.13 g of pale orange crude crystals. Purification was performed with an open silica gel column (n-hexane: AcOEt = 1: 2) to obtain 2.56 g (8.376 mmol, y.68%) of white crude crystals.

次に、下記のスキームに従い、表１に記載の6-(3,4-dihydrocarbostyril-6-yloxy) hexanoic acid hydroxyamide（化合物１）を合成した。
20 mlナスフラスコに、6-(3,4-dihydrocarbostyril-6-yloxy)hexanoic acid ethyl ester 200 mg (0.655 mmol)を取り、MeOH 1.2 ml (6.549 mmol, 10 eq.)を加えて溶かした。氷浴上、攪拌下、析出してきたが、NH2OH in water 50% 0.40 mlをシリンジで滴下し、活栓をした。そのまま、氷浴上にて4分間攪拌してNaOMe in MeOH 25% 0.75 ml (3.275 mmol, 5 eq.)をシリンジで滴下した。白色懸濁液が徐々に溶けていった。そのまま、氷浴上にて1時間15分攪拌し、sat.NH4Cl 10 mlを加えた。析出物を桐山漏斗で濾取し、水、n-hexaneで順次洗浄して風乾した。ナスフラスコに移して真空ポンプで乾燥し、白色粗結晶173 mg (0.591 mmol, y,90%)を得た。colorless powder (AcOEt). mp.178-179℃. 1H-NMR (300 MHz / DMSO / TMS) δ1.31-1.41 (2H, m, CH2), 1.49-1.59 (2H, m, CH2), 1.62-1.71 (2H, m, CH2), 1.96 (2H, t, J = 7.2 Hz, CH2), 2.39 (2H, t, J = 7.5 Hz, CH2), 2.82 (2H, t, J = 7.7 Hz, CH2), 3.87 (2H, t, J = 6.5 Hz, CH2), 6.69 (1H, dd, J = 8.6 Hz, 2.6 Hz, ArH), 6.75 (1H,d, J = 8.1 Hz, ArH), 6.76 (1H, s, ArH), 8.66 (1H, s, NH), 9.88 (1H, bs, NOH). LRMS (EI) m/z 292 (M+). LRMS (ESI+) m/z 293 ([M+H]+). LRMS (ESI-) m/z 291 ([M-H]-). Next, 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid hydroxyamide (Compound 1) described in Table 1 was synthesized according to the following scheme.
To a 20 ml eggplant flask, 200 mg (0.655 mmol) of 6- (3,4-dihydrocarbostyril-6-yloxy) hexanoic acid ethyl ester was taken and dissolved by adding 1.2 ml (6.549 mmol, 10 eq.) Of MeOH. On an ice bath, under stirring, it has been deposited, the NH 2 OH in water 50% 0.40 ml was added dropwise via syringe and the stopcock. The solution was stirred for 4 minutes on an ice bath, and NaOMe in MeOH 25% 0.75 ml (3.275 mmol, 5 eq.) Was added dropwise with a syringe. The white suspension gradually dissolved. The mixture was stirred on the ice bath for 1 hour and 15 minutes, and sat.NH 4 Cl (10 ml) was added. The precipitate was collected by filtration with a Kiriyama funnel, washed successively with water and n-hexane and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 173 mg (0.591 mmol, y, 90%) of white crude crystals were obtained. colorless powder (AcOEt) .mp.178-179 ° C. 1 H-NMR (300 MHz / DMSO / TMS) δ1.31-1.41 (2H, m, CH 2 ), 1.49-1.59 (2H, m, CH 2 ) , 1.62-1.71 (2H, m, CH 2 ), 1.96 (2H, t, J = 7.2 Hz, CH 2 ), 2.39 (2H, t, J = 7.5 Hz, CH 2 ), 2.82 (2H, t, J = 7.7 Hz, CH 2 ), 3.87 (2H, t, J = 6.5 Hz, CH 2 ), 6.69 (1H, dd, J = 8.6 Hz, 2.6 Hz, ArH), 6.75 (1H, d, J = 8.1 Hz , ArH), 6.76 (1H, s, ArH), 8.66 (1H, s, NH), 9.88 (1H, bs, NOH). LRMS (EI) m / z 292 (M + ). LRMS (ESI +) m / z 293 ([M + H] + ). LRMS (ESI-) m / z 291 ([MH]-).

実施例２〜１１
原料を変更したこと以外は、実施例１と同様にして、表１に記載のヒドロキサム酸誘導体（化合物２〜１１）を合成した。
 Examples 2-11
The hydroxamic acid derivatives (compounds 2 to 11) shown in Table 1 were synthesized in the same manner as in Example 1 except that the raw materials were changed.

実施例１２（7-[(3,4-dihydrocarbostyril-6-carbony)amino]heptanoic acid hydroxyamideの合成）
まず、下記のスキームに従い、7-aminoheptanoic acid benzyl esterを合成した。
50 mlナスフラスコに、DPPA 1.25 g (4.540 mmol, 1.2 eq.)、suberic acid monobenzyl ester 1.00 g (3.793 mmol)、Et3N 0.77 g (7.567 mmol, 2.0 eq.)、t-BuOH 10 mlを加えてオイルバス100℃上にて2時間反応を止めて放冷した。エバポレートし、淡黄色オイルを残渣として得た。AcOEt 8.3 ml、conc.HCl 0.5 mlを加えてオイルバス100℃上にて1時間30分攪拌して放冷した。sat.NaHCO3 30 mlを加えて、更に、NaHCO3を加えてpH 8とした。水20 mlを加えてAcOEt 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で順次洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、黄色オイル1.01 gを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 2 : 1）にて精製し、透明オイル0.47 g (1.979 mmol, y.52%)を得た。 Example 12 (Synthesis of 7-[(3,4-dihydrocarbostyril-6-carbony) amino] heptanoic acid hydroxyamide)
First, 7-aminoheptanoic acid benzyl ester was synthesized according to the following scheme.
Add DPPA 1.25 g (4.540 mmol, 1.2 eq.), Suberic acid monobenzyl ester 1.00 g (3.793 mmol), Et 3 N 0.77 g (7.567 mmol, 2.0 eq.), And t-BuOH 10 ml to a 50 ml eggplant flask. The reaction was stopped for 2 hours on an oil bath at 100 ° C. and allowed to cool. Evaporation gave a pale yellow oil as a residue. AcOEt (8.3 ml) and conc. HCl (0.5 ml) were added, and the mixture was stirred for 1 hour and 30 minutes on an oil bath at 100 ° C. It added sat.NaHCO 3 30 ml, further, was pH 8 by adding NaHCO 3. Water (20 ml) was added and the mixture was extracted with AcOEt (30 ml × 3), washed successively with water (30 ml × 1, brine 30 ml × 1) and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 1.01 g of yellow oil. Purification with an open silica gel column (n-hexane: AcOEt = 2: 1) gave a clear oil 0.47 g (1.979 mmol, y.52%).

次に、下記のスキームに従い、7-[(3,4-dihydrocarbostyril-6-carbony)amino]heptanoic acid benzyl esterを合成した。
20 mlナスフラスコに、7-aminoheptanoic acid benzyl ester 304 mg (1.291 mmol, 1.0 eq.)、3,4-dihydrocarbostyril-6-carboxylic acid 247 mg (1.291 mmol)、HOBt 175 mg (1.291 mmol, 1.0 eq.)、Et3N 131 mg (1.291 mmol, 1.0 eq.)を取り、DMF 6 mlを加え、EDCI・HCl 248 mg (1.291 mmol, 1.0 eq.)を加えて活栓をし、室温にて一晩攪拌した。sat.NaHCO3 50 mlを加えてAcOEt 50 ml×3で抽出し、水50 ml×1、1NHCl 50 ml×1、brine 50 ml×1で順次洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、ベージュ色オイル586 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 1 : 4）にて精製し、白色粗結晶95 mg (0.232 mmol, y.18%)を得た。 Next, 7-[(3,4-dihydrocarbostyril-6-carbony) amino] heptanoic acid benzyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, 7-aminoheptanoic acid benzyl ester 304 mg (1.291 mmol, 1.0 eq.), 3,4-dihydrocarbostyril-6-carboxylic acid 247 mg (1.291 mmol), HOBt 175 mg (1.291 mmol, 1.0 eq. ), Et 3 N 131 mg (1.291 mmol, 1.0 eq.), Add DMF 6 ml, add EDCI · HCl 248 mg (1.291 mmol, 1.0 eq.), Turn off the stopper, and stir at room temperature overnight. did. Sat. NaHCO 3 50 ml was added, extracted with AcOEt 50 ml × 3, washed successively with water 50 ml × 1, 1N HCl 50 ml × 1, brine 50 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 586 mg of beige oil. Purification by an open silica gel column (n-hexane: AcOEt = 1: 4) gave 95 mg (0.232 mmol, y.18%) of white crude crystals.

次に、実施例１と同様にして、下記のスキームに従い、表２に記載の7-[(3,4-dihydrocarbostyril-6-carbony)amino]heptanoic acid hydroxyamide（化合物１２）を合成した。
colorless powder (AcOEt). mp.189-190℃. 1H-NMR (300 MHz / DMSO / TMS) δ1.27-1.28 (4H, m, CH2×2), 1.46-1.51 (4H, m, CH2×2), 1.94 (2H, t, J = 7.4 Hz, CH2), 2.47 (2H, m, CH2), 2.91 (2H, t, J = 7.4 Hz, CH2), 3.18-3.24 (2H, m, CH2), 6.86 (1H, d, J = 8.1 Hz, ArH), 7.63 (1H, d, J = 8.4 Hz, ArH), 7.67 (1H, s, ArH), 8.25 (1H, t, J = 5.4 Hz, NH), 8.64 (1H, s, NH), 10.26 (1H, s, NH), 10.32 (1H, s, NOH). LRMS (ESI+) m/z 334 ([M+H]+). LRMS (ESI-) m/z 332 [M-H]-). Next, in the same manner as in Example 1, 7-[(3,4-dihydrocarbostyril-6-carbony) amino] heptanoic acid hydroxyamide (Compound 12) shown in Table 2 was synthesized according to the following scheme.
colorless powder (AcOEt) .mp.189-190 ℃. 1 H-NMR (300 MHz / DMSO / TMS) δ1.27-1.28 (4H, m, CH 2 × 2), 1.46-1.51 (4H, m, CH 2 × 2), 1.94 (2H, t, J = 7.4 Hz, CH 2 ), 2.47 (2H, m, CH 2 ), 2.91 (2H, t, J = 7.4 Hz, CH 2 ), 3.18-3.24 (2H , m, CH 2 ), 6.86 (1H, d, J = 8.1 Hz, ArH), 7.63 (1H, d, J = 8.4 Hz, ArH), 7.67 (1H, s, ArH), 8.25 (1H, t, J = 5.4 Hz, NH), 8.64 (1H, s, NH), 10.26 (1H, s, NH), 10.32 (1H, s, NOH). LRMS (ESI +) m / z 334 ([M + H] + LRMS (ESI-) m / z 332 [MH] - ).

実施例１３〜２２
原料を変更したこと以外は、実施例１２と同様にして、表２に記載のヒドロキサム酸誘導体（化合物１３〜２２）を合成した。
 Examples 13-22
Hydroxamic acid derivatives (compounds 13 to 22) listed in Table 2 were synthesized in the same manner as in Example 12 except that the raw materials were changed.

実施例２３（7-(3,4-dihydrocarbostyril-6-ylcarbamoyl)heptanoic acid hydroxyamideの合成）
まず、下記のスキームに従い、suberic acid monobenzyl esterを合成した。
20 mlナスフラスコに、BnOH 62 mg (0.574 mmol, 1.0 eq.)を取り、CH2Cl2 2 mlを加えて溶かし、suberic acid 100 mg (0.574 mmol)、DMAP 130 mg (1.148 mmol, 2.0 eq.)、DCC 130 mg (0.631 mmol, 1.1 eq.)を加えて白色懸濁液とし、活栓をして室温にて一晩攪拌した。エバポレートし、2NHCl 20 mlを加えた。AcOEt 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で順次洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、白色粗結晶220 mgを得た。n-hexane : AcOEt = 4 : 1の混合液5 mlを加えて固液抽出し、不溶物を桐山漏斗で濾過し、n-hexaneで洗い込んだ。エバポレートして透明オイル128 mg (0.484 mmol, y.84%)を得た。 Example 23 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid hydroxyamide)
First, suberic acid monobenzyl ester was synthesized according to the following scheme.
In 20 ml eggplant-shaped flask, BnOH 62 mg (0.574 mmol, 1.0 eq.) Takes dissolved by adding CH 2 Cl 2 2 ml, suberic acid 100 mg (0.574 mmol), DMAP 130 mg (1.148 mmol, 2.0 eq. ) And DCC 130 mg (0.631 mmol, 1.1 eq.) Were added to form a white suspension, which was stoppered and stirred overnight at room temperature. Evaporate and add 20 ml of 2N HCl. The mixture was extracted with AcOEt 30 ml × 3, washed successively with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 220 mg of white crude crystals. 5 ml of a mixed solution of n-hexane: AcOEt = 4: 1 was added for solid-liquid extraction, insoluble matter was filtered through a Kiriyama funnel, and washed with n-hexane. Evaporation gave 128 mg (0.484 mmol, y.84%) of a clear oil.

次に、下記のスキームに従い、7-(3,4-dihydrocarbostyril-6-ylcarbamoyl)heptanoic acid benzyl esterを合成した。
20 mlナスフラスコに、suberic acid monobenzyl ester 128 mg (0.484 mmol, 1.0 eq.)、6-amino-3,4-dihydrocarbostyril 78 mg (0.484 mmol)、HOBt 65 mg (0.484 mmol, 1.0 eq.)、Et3N 49 mg (0.484 mmol, 1.0 eq.)、DMF 2 ml、EDCI・HCl 93 mg (0.484 mmol, 1.0 eq.)を取り、活栓をして室温にて一晩攪拌した。sat.NaHCO3 30 mlを加えてAcOEt 30 ml×3で抽出し、2NHCl 30 ml×1、brine 30 ml×1で順次洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、橙色粗結晶209 mgを得た。オープンシリカゲルカラム（AcOEt only）にて精製し、淡橙色粗結晶101 mg (0.247 mmol, y.51%)を得た。 Next, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid benzyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, suberic acid monobenzyl ester 128 mg (0.484 mmol, 1.0 eq.), 6-amino-3,4-dihydrocarbostyril 78 mg (0.484 mmol), HOBt 65 mg (0.484 mmol, 1.0 eq.), Et 3 N 49 mg (0.484 mmol, 1.0 eq.), DMF 2 ml, EDCI · HCl 93 mg (0.484 mmol, 1.0 eq.) Were taken, stoppered and stirred at room temperature overnight. 30 ml of sat. NaHCO 3 was added and extracted with 30 ml × 3 of AcOEt, washed successively with 30 ml × 1 of 2NHCl and 30 ml × 1 of brine, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 209 mg of orange crude crystals. Purification by an open silica gel column (AcOEt only) gave 101 mg (0.247 mmol, y.51%) of pale orange crude crystals.

次に、実施例１と同様にして、下記のスキームに従い、表３に記載の7-(3,4-dihydrocarbostyril-6-ylcarbamoyl)heptanoic acid hydroxyamide（化合物２３）を合成した。
colorless powder (AcOEt). mp.196-197℃ .1H-NMR (300 MHz / DMSO / TMS) でδ1.26-1.28 (4H, m, CH2×2), 1.46-1.56 (4H, m, CH2×2), 1.94 (2H, t, J = 7.4 Hz, CH2), 2.25 (2H, t, J = 7.2 Hz, CH2), 2.41 (2H, t, J = 7.5 Hz, CH2), 2.82 (2H, t, J = 8.6 Hz, 2.3 Hz, ArH), 6.76 (1H, d, J = 8.4 Hz, ArH), 7.29 (1H, dd, J = 8.6 Hz, 2.3 Hz, ArH), 7.43 (1H, d, J = 1.5 Hz, ArH), 8.65 (1H, s, ArH), 9.73 (1H, s, NH), 9.98 (1H, s, NH), 10.33 (1H, s, NOH). LRMS (ESI+) m/z 334([M+H]+). LRMS (ESI-) m/z 332 ([M-H]-). Next, in the same manner as in Example 1, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid hydroxyamide (Compound 23) shown in Table 3 was synthesized according to the following scheme.
colorless powder (AcOEt) .mp.196-197 ° C. 1 H-NMR (300 MHz / DMSO / TMS) at δ1.26-1.28 (4H, m, CH 2 × 2), 1.46-1.56 (4H, m, CH 2 × 2), 1.94 (2H, t, J = 7.4 Hz, CH 2 ), 2.25 (2H, t, J = 7.2 Hz, CH 2 ), 2.41 (2H, t, J = 7.5 Hz, CH 2 ) , 2.82 (2H, t, J = 8.6 Hz, 2.3 Hz, ArH), 6.76 (1H, d, J = 8.4 Hz, ArH), 7.29 (1H, dd, J = 8.6 Hz, 2.3 Hz, ArH), 7.43 (1H, d, J = 1.5 Hz, ArH), 8.65 (1H, s, ArH), 9.73 (1H, s, NH), 9.98 (1H, s, NH), 10.33 (1H, s, NOH). LRMS (ESI +) m / z 334 ([M + H] + ). LRMS (ESI-) m / z 332 ([MH]-).

実施例２４〜３２
原料を変更したこと以外は、実施例２３と同様にして、表３に記載のヒドロキサム酸誘導体（化合物２４〜３２）を合成した。
 Examples 24-32
Hydroxamic acid derivatives (compounds 24-32) listed in Table 3 were synthesized in the same manner as in Example 23 except that the raw materials were changed.

実施例３３（4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 3-(2-hydroxycarbamoylvinyl) benzylamideの合成）
まず、下記のスキームに従い、2-(3-bromobenzyl)isoindole-1,3-dioneを合成した。
50 mlナスフラスコに、m-bromobenzyl bromide 1.00 g (4.001 mmol)、phthalimide potassium salt 0.82 g (4.401 mmol, 1.1 eq.)を取り、DMF 10 mlを加えた。塩化カルシウム管を付け、オイルバス100℃上にて8時間30分攪拌して放冷した。水50 mlを加えてAcOEt 50 ml×3で抽出し、水50 ml×1、brine 50 ml×1で洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、白色粗結晶1.27 g (4.018 mmol, y.100%)を得た。 Example 33 (Synthesis of 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 3- (2-hydroxycarbamoylvinyl) benzylamide)
First, 2- (3-bromobenzyl) isoindole-1,3-dione was synthesized according to the following scheme.
To a 50 ml eggplant flask, 1.00 g (4.001 mmol) of m-bromobenzyl bromide and 0.82 g (4.401 mmol, 1.1 eq.) Of phthalimide potassium salt were added, and 10 ml of DMF was added. A calcium chloride tube was attached, and the mixture was stirred for 8 hours and 30 minutes on an oil bath at 100 ° C. and allowed to cool. 50 ml of water was added and extracted with 50 ml × 3 AcOEt, washed with 50 ml × 1, 50 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 1.27 g (4.018 mmol, y.100%) of white crude crystals.

次に、下記のスキームに従い、3-bromobenzylamineを合成した。
50 mlナスフラスコに、H2NNH2・H2O (100%) 317 mg (6.326 mmol, 2.0 eq.)を取り、MeOH 10ml、2-(3-bromobenzyl)isoindole-1,3-dione 1.00 g (3.163 mmol)を加えてオイルバス90℃上にて1時間30分攪拌して放冷した。エバポレートしてMeOHを留去し、conc.HCl 4 mlを加えた。オイルバス120℃上にて1時間30分攪拌して放冷した。桐山漏斗で不溶物を濾過して2NHCl、水で順次洗浄した。濾液に2NNaOH 40 mlを加えてpH 11とした。AcOEt 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、淡黄色液体557 mg (2.996 mmol, y.95%)を得た。 Next, 3-bromobenzylamine was synthesized according to the following scheme.
In a 50 ml eggplant flask, take 317 mg (6.326 mmol, 2.0 eq.) Of H 2 NNH 2 and H 2 O (100%), 10 ml of MeOH, 1.00 g of 2- (3-bromobenzyl) isoindole-1,3-dione (3.163 mmol) was added and the mixture was stirred on an oil bath at 90 ° C. for 1 hour and 30 minutes and allowed to cool. After evaporation, MeOH was distilled off and 4 ml of conc. HCl was added. The mixture was stirred for 1 hour and 30 minutes on an oil bath at 120 ° C. and allowed to cool. The insoluble material was filtered through a Kiriyama funnel and washed successively with 2N HCl and water. The filtrate was adjusted to pH 11 by adding 40 ml of 2N NaOH. Extracted with AcOEt 30 ml × 3, washed with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 557 mg (2.996 mmol, y.95%) of a pale yellow liquid.

次に、下記のスキームに従い、(3-bromobenzyl)carbamic acid t-butyl esterを合成した。
20 mlナスフラスコに、3-bromobenzylamine 500 mg (2.687 mmol)を取り、CH2Cl2 5 ml、Et3N 299 mg (2.956 mmol, 1.1 eq.)を加えて溶かした。氷浴上、攪拌下、Boc2O 645 mg (2.656 mmol, 1.1 eq.)をCH2Cl2 4 mlに溶かしたものと洗い込みのCH2Cl2 2 mlを3分間かけて滴下した。氷浴を外して室温にて一晩攪拌した。水30 mlを加えて有機層を分取し、水層をCHCl3 30 ml×3で抽出して有機層を合わせた。有機層を水30 ml×1、brine 30 ml×1で順次洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、淡黄色オイル862 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 4 : 1）にて精製し、白色粗結晶734 mg (2.566 mmol, y.95%)を得た。 Next, (3-bromobenzyl) carbamic acid t-butyl ester was synthesized according to the following scheme.
To a 20 ml eggplant flask, 500 mg (2.687 mmol) of 3-bromobenzylamine was taken, and CH 2 Cl 2 5 ml and Et 3 N 299 mg (2.956 mmol, 1.1 eq.) Were added and dissolved. Under stirring in an ice bath, Boc 2 O (645 mg, 2.656 mmol, 1.1 eq.) Dissolved in CH 2 Cl 2 ( 4 ml) and washed CH 2 Cl 2 ( 2 ml) were added dropwise over 3 minutes. The ice bath was removed and the mixture was stirred overnight at room temperature. 30 ml of water was added, the organic layer was separated, the aqueous layer was extracted with 3 ml of CHCl 3 30 ml, and the organic layers were combined. The organic layer was washed successively with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 862 mg of a pale yellow oil. Purification was performed using an open silica gel column (n-hexane: AcOEt = 4: 1) to obtain 734 mg (2.566 mmol, y.95%) of white crude crystals.

次に、下記のスキームに従い、3-[3-(tert-butoxycarbonylaminomethyl)phenyl]acrylic acid ethyl esterを合成した。
20 mlナスフラスコに、(3-bromobenzyl)carbamic acid t-butyl ester 100 mg (0.349 mmol)、ethyl acrylate 38 mg (0.384 mmol, 1.1 eq.)、P(o-tolyl)3 21 mg (0.070 mmol, 0.2 eq.)、EtCN 1.5 ml、DMF 0.4 ml、DIEA 0.13 ml (0.748 mmol, 2.1 eq.)を取り、室温にて攪拌下、Pd(OAc)2 8 mg (0.035 mmol, 0.1 eq.)を加えた。窒素風船と三方コックとジムロートを付け、簡易的に窒素置換した。そのまま、室温にて10分間攪拌し、オイルバス90℃上にて7時間30分攪拌して放冷した。水30 mlを加えてAcOEt 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で順次洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、褐色オイル152 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 2 : 1）にて精製し、黄色オイル103 mg (0.337 mmol, y.96%)を得た。 Next, 3- [3- (tert-butoxycarbonylaminomethyl) phenyl] acrylic acid ethyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, (3-bromobenzyl) carbamic acid t-butyl ester 100 mg (0.349 mmol), ethyl acrylate 38 mg (0.384 mmol, 1.1 eq.), P (o-tolyl) 3 21 mg (0.070 mmol, 0.2 eq.), EtCN 1.5 ml , DMF 0.4 ml, DIEA 0.13 ml (0.748 mmol, take 2.1 eq.), at room temperature under stirring, Pd (OAc) 2 8 mg (0.035 mmol, a 0.1 eq.) was added It was. A nitrogen balloon, a three-way cock and a Jimroth were attached, and the nitrogen was simply replaced. The mixture was stirred at room temperature for 10 minutes as it was, then stirred on an oil bath at 90 ° C. for 7 hours and 30 minutes and allowed to cool. 30 ml of water was added, extraction was performed with AcOEt 30 ml × 3, washed successively with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 152 mg of a brown oil. Purification by an open silica gel column (n-hexane: AcOEt = 2: 1) gave 103 mg (0.337 mmol, y.96%) of a yellow oil.

次に、下記のスキームに従い、3-(3-aminomethylphenyl)acrylic acid ethyl esterを合成した。
20 mlナスフラスコに、3-[3-(tert-butoxycarbonylaminomethyl)phenyl]acrylic acid ethyl ester 61 mg (0.200 mmol)を取り、CH2Cl2 1 ml、TFA 1 mlを加えて室温にて1時間攪拌した。エバポレートしてCH2Cl2とTFAを留去し、sat.NaHCO3 30 mlを加えた。AcOEt 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして黄色オイル44 mg (quant. y.)を得た。 Next, 3- (3-aminomethylphenyl) acrylic acid ethyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 61 mg (0.200 mmol) of 3- [3- (tert-butoxycarbonylaminomethyl) phenyl] acrylic acid ethyl ester, add 1 ml of CH 2 Cl 2 and 1 ml of TFA, and stir at room temperature for 1 hour. did. Evaporate to remove CH 2 Cl 2 and TFA, and add sat. NaHCO 3 30 ml. Extracted with AcOEt 30 ml × 3, washed with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 44 mg (quant. Y.) Of yellow oil.

次に、下記のスキームに従い、3-[3-[[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline -6-carbonyl)amino]methyl]phenyl]acrylic acid ethyl esterを合成した。
20 mlナスフラスコに、3-(3-aminomethylphenyl)acrylic acid ethyl ester 100 mg (0.487 mmol)、4,4-dimethyl-3,4-dihydrocarbostyril 107 mg (0.487 mmol, 1.0 eq.)、HOBt 66 mg (0.4870mmol, 1.0 eq.)、DMF 2 ml、Et3N 5 mg (0.487 mmol, 1.0 eq.)を取り、EDCI・HCl 93 mg (0.487 mmol, 1.0 eq.)を加えて活栓をし、室温にて一晩攪拌した。水30 mlを加えてAcOEt 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして淡黄色粗結晶296 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 1 : 4、続いてAcOEt only、続いてAcOEt : MeOH = 10 : 1）にて精製し、白色粗結晶139 mg (0.342 mmol, y.70%)を得た。 Next, according to the following scheme, 3- [3-[[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl) amino] methyl] phenyl] acrylic acid Ethyl ester was synthesized.
In a 20 ml eggplant flask, 3- (3-aminomethylphenyl) acrylic acid ethyl ester 100 mg (0.487 mmol), 4,4-dimethyl-3,4-dihydrocarbostyril 107 mg (0.487 mmol, 1.0 eq.), HOBt 66 mg ( 0.4870 mmol, 1.0 eq.), DMF 2 ml, Et 3 N 5 mg (0.487 mmol, 1.0 eq.), Add EDCI-HCl 93 mg (0.487 mmol, 1.0 eq.) And stirred overnight. 30 ml of water was added and extracted with 30 ml × 3 AcOEt, washed with 30 ml × 1, 30 ml × 1 water and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 296 mg of pale yellow crude crystals. Purification with an open silica gel column (n-hexane: AcOEt = 1: 4, then AcOEt only, then AcOEt: MeOH = 10: 1) gave 139 mg (0.342 mmol, y.70%) of white crude crystals. It was.

次に、下記のスキームに従い、表４に記載の4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 3-(2-hydroxycarbamoylvinyl) benzylamide（化合物３３）を合成した。
3-[3-[[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl)amino]methyl]phenyl]acrylic acid ethyl ester 123 mg (0.304 mmol)を20 mlナスフラスコに取り、MeOH 3 mlを加えて白色懸濁液とし、氷浴上にて攪拌下、NH2OH in water 50% 0.19 ml (3.036 mmol, 10 eq.)をシリンジで1分間かけて滴下した。活栓をして氷浴上にて10分間攪拌し、活栓を外してNaOMe in MeOH 25% 0.35 ml (1.518 mmol, 5 eq.) をシリンジで4分間かけて滴下した。活栓をして氷浴上にて1時間30分攪拌し、MeOH 2 mlを加えた。更に、氷浴上にて1時間30分攪拌し、氷浴を外し、MeOH 4 mlを加えて、室温にて一晩攪拌した。エバポレートしてMeOHを留去し、sat.NH4Cl 20 mlを加えた。不溶物を桐山漏斗で濾取し、sat.NH4Cl、水、n-hexane : AcOEt = 1 : 1の混合液、n-hexaneで順次洗浄し、風乾した。ナスフラスコに移して真空ポンプで乾燥し、ベージュ色粗結晶89 mg (0.227 mmol, y.75%)を得た。colorless powder (AcOEt / MeOH). mp.159-163℃. 1H-NMR (300 MHz / DMSO / TMS) δ1.26 (6H, s, CH3×2), 2.39 (2H, s, CH2), 4.49 (2H, d, J = 5.1 Hz, CH2), 6.46 (1H, d, J = 15.9 Hz, CH=), 6.92 (1H, d, J = 9.0 Hz, ArH), 7.33-7.60 (5H, m, ArH and CH=), 7.74 (1H, d, J = 9.0 Hz, ArH), 7.86 (1H, s, ArH), 9.01 (1H, s, NH), 10.39 (1H, s, NH). LRMS (ESI+) m/z 394 ([M+H]+). LRMS (ESI-) m/z 392 ([M-H]-). Next, according to the following scheme, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 3- (2-hydroxycarbamoylvinyl) benzylamide (Compound 33) described in Table 4 was synthesized.
3- [3-[[(4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-quinoline-6-carbonyl) amino] methyl] phenyl] acrylic acid ethyl ester 123 mg (0.304 mmol) taken up in 20 ml eggplant flask, a white suspension was added to MeOH 3 ml, stirring the solution at an ice-bath, NH 2 OH in water 50% 0.19 ml (3.036 mmol, 10 eq.) for 1 minute with a syringe It was dripped over. The stopcock was put on, stirred for 10 minutes on an ice bath, the stopcock was removed, and NaOMe in MeOH 25% 0.35 ml (1.518 mmol, 5 eq.) Was added dropwise with a syringe over 4 minutes. The stopcock was put on, and the mixture was stirred for 1 hour and 30 minutes on an ice bath, and 2 ml of MeOH was added. Further, the mixture was stirred for 1 hour and 30 minutes on an ice bath, the ice bath was removed, 4 ml of MeOH was added, and the mixture was stirred overnight at room temperature. Evaporate to remove MeOH and add sat.NH 4 Cl 20 ml. The insoluble material was collected by filtration with a Kiriyama funnel, washed successively with sat.NH 4 Cl, water, a mixed solution of n-hexane: AcOEt = 1: 1, n-hexane, and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 89 mg (0.227 mmol, y.75%) of beige crude crystals were obtained. colorless powder (AcOEt / MeOH) .mp.159-163 ° C. 1 H-NMR (300 MHz / DMSO / TMS) δ1.26 (6H, s, CH 3 × 2), 2.39 (2H, s, CH 2 ) , 4.49 (2H, d, J = 5.1 Hz, CH 2 ), 6.46 (1H, d, J = 15.9 Hz, CH =), 6.92 (1H, d, J = 9.0 Hz, ArH), 7.33-7.60 (5H , m, ArH and CH =), 7.74 (1H, d, J = 9.0 Hz, ArH), 7.86 (1H, s, ArH), 9.01 (1H, s, NH), 10.39 (1H, s, NH). LRMS (ESI +) m / z 394 ([M + H] + ). LRMS (ESI-) m / z 392 ([MH] - ).

実施例３４〜３５
原料を変更したこと以外は、実施例３３と同様にして、表４に記載のヒドロキサム酸誘導体（化合物３４〜３５）を合成した。
 Examples 34-35
Hydroxamic acid derivatives (compounds 34 to 35) listed in Table 4 were synthesized in the same manner as in Example 33 except that the raw materials were changed.

実施例３６（4,4-dimethyl-3,4-dihydrocarbostyril -6-carboxylic acid [trans-4-(2-hydroxycarbamoylvinyl)-cyclohexyl -methyl]amideの合成）
まず、下記のスキームに従い、 (trans-4-benzyloxymethyloxycyclohexyl)methanolを合成した。
20 mlナスフラスコに、NaH (60% in mineral oil) 42 mg (1.040 mmol, 0.5 eq.)を取り、DMF 1 mlを加えて白色懸濁液とし、塩化カルシウム管と滴下漏斗を付けた。氷浴上、攪拌下、trans-1,4-cyclohexanedimethanol 300 mg (2.080 mmol)をDMF 1.5 mlに溶かしたものと洗い込みのDMF 0.5 mlを3分間かけて滴下した。そのまま、氷浴上にて30分間攪拌した後、BnBr 178 mg (1.040 mmol, 1.5 eq.)をDMF 1.5 mlに溶かしたものと洗い込みのDMF 0.5 mlを1分間かけて滴下した。氷浴上にて1時間30分攪拌し、氷浴を外して室温にて一晩攪拌した。更に、オイルバス60℃上にて2時間攪拌して放冷した。水30 mlを加えてAcOEt 50 ml×3で抽出し、水30 ml×1、brine 30 ml×1で順次洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、透明オイル340 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 2 : 1）にて精製し、透明オイル177 mg (0.753 mmol, y.36%)を得た。 Example 36 (Synthesis of 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4- (2-hydroxycarbamoylvinyl) -cyclohexyl-methyl] amide)
First, (trans-4-benzyloxymethyloxycyclohexyl) methanol was synthesized according to the following scheme.
To a 20 ml eggplant flask, 42 mg (1.040 mmol, 0.5 eq.) Of NaH (60% in mineral oil) was taken, and 1 ml of DMF was added to form a white suspension, and a calcium chloride tube and a dropping funnel were attached. In an ice bath, with stirring, trans-1,4-cyclohexanedimethanol 300 mg (2.080 mmol) dissolved in DMF 1.5 ml and washed DMF 0.5 ml were added dropwise over 3 minutes. After stirring for 30 minutes on an ice bath, BnBr 178 mg (1.040 mmol, 1.5 eq.) Dissolved in DMF 1.5 ml and washed DMF 0.5 ml were added dropwise over 1 minute. The mixture was stirred for 1 hour and 30 minutes on the ice bath, removed from the ice bath and stirred overnight at room temperature. Further, the mixture was stirred for 2 hours on an oil bath at 60 ° C. and allowed to cool. 30 ml of water was added, extraction was performed with AcOEt 50 ml × 3, washed sequentially with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 340 mg of a clear oil. Purification with an open silica gel column (n-hexane: AcOEt = 2: 1) gave a clear oil of 177 mg (0.753 mmol, y.36%).

次に、下記のスキームに従い、trans-methanesulfonic acid trans-4-benzyloxymethyl cyclohexylmethyl esterを合成した。
20 mlナスフラスコに、(trans-4-benzyloxymethyloxycyclohexyl)methanol 177 mg (0.753 mmol)を取り、CH2Cl2 1.8 ml、Et3N 229 mg (2.260 mmol, 3.0 eq.)を加えて溶かし、塩化カルシウム管と滴下漏斗を付けた。氷浴上、攪拌下、MsCl 104 mg (0.904 mmol, 1.2 eq.)をCH2Cl2 1 mlに溶かしたものと洗い込みのCH2Cl2 1 mlを1分間かけて滴下した。氷浴を外して室温にて一晩攪拌した。水30 mlを加えてCHCl3 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で順次洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、黄色オイル250 mgを得た。オープンシリカゲルカラム（φ＝2 cm, SiO2 = 20 g, fr. = 10 ml, n-hexane : AcOEt = 4 : 1）にて精製し、透明オイル199 mg (0.637 mmol, y.85%)を得た。 Next, trans-methanesulfonic acid trans-4-benzyloxymethylcyclohexylmethyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 177 mg (0.753 mmol) of (trans-4-benzyloxymethyloxycyclohexyl) methanol, add CH 2 Cl 2 1.8 ml, Et 3 N 229 mg (2.260 mmol, 3.0 eq.), Dissolve, and add calcium chloride. A tube and dropping funnel were attached. On ice bath, with stirring, MsCl 104 mg (0.904 mmol, 1.2 eq.) Dissolved in CH 2 Cl 2 1 ml and washed CH 2 Cl 2 1 ml were added dropwise over 1 minute. The ice bath was removed and the mixture was stirred overnight at room temperature. 30 ml of water was added, and the mixture was extracted with 30 ml × 3 of CHCl 3 , washed successively with 30 ml of water and 30 ml × 1 of brine, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 250 mg of a yellow oil. Purification using an open silica gel column (φ = 2 cm, SiO 2 = 20 g, fr. = 10 ml, n-hexane: AcOEt = 4: 1), and 199 mg (0.637 mmol, y.85%) of clear oil Obtained.

次に、下記のスキームに従い、2-(trans-4-benzyloxymethylcyclohexylmethyl) isoindole-1,3-dioneを合成した。
20 mlナスフラスコに、methanesulfonic acid trans-4-benzyloxymethyl cyclohexylmethyl ester 182 mg (0.582 mmol)、phthalimide potassium salt 108 mg (0.582 mmol, 1.0 eq.)を取り、DMF 4 mlを加えて塩化カルシウム管を付け、室温にて一晩攪拌した。更に、オイルバス80℃上にて1時間攪拌して放冷した。水30 mlを加えてAcOEt 50 ml×3で抽出し、水30 ml×1、brine 30 ml×1で順次洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、白色粗結晶325 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 4 : 1）にて精製し、白色粗結晶184 mg (0.507 mmol, y.87%)を得た。 Next, 2- (trans-4-benzyloxymethylcyclohexylmethyl) isoindole-1,3-dione was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 182 mg (0.582 mmol) of methanesulfonic acid trans-4-benzyloxymethyl cyclohexylmethyl ester and 108 mg (0.582 mmol, 1.0 eq.) Of phthalimide potassium salt, add 4 ml of DMF, and attach a calcium chloride tube. Stir overnight at room temperature. Further, the mixture was stirred for 1 hour in an oil bath at 80 ° C. and allowed to cool. 30 ml of water was added, extraction was performed with AcOEt 50 ml × 3, washed sequentially with water 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 325 mg of white crude crystals. Purification was performed with an open silica gel column (n-hexane: AcOEt = 4: 1) to obtain 184 mg (0.507 mmol, y.87%) of white crude crystals.

次に、下記のスキームに従い、(trans-4-azidomethylcyclohexylmethyl)benzeneを合成した。
20 mlナスフラスコに、methanesulfonic acid trans-4-benzyloxymethyl cyclohexylmethyl ester 200 mg (0.640 mmol)を取り、DMF 2 ml、NaN3 42 mg (0.640 mmol, 1.0 eq.)を加えて活栓をして室温にて一晩攪拌した。更に、オイルバス80℃上にて1時間30分攪拌して放冷した。水30 mlを加えてAcOEt 30 ml×3で抽出し、水30 ml×1、brine 30 ml×1で順次洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、透明オイル231 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 5 : 1）にて精製し、透明オイル184 mg (quant.y.)を得た。 Next, (trans-4-azidomethylcyclohexylmethyl) benzene was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 200 mg (0.640 mmol) of methanesulfonic acid trans-4-benzyloxymethyl cyclohexylmethyl ester, add 2 ml of DMF and 42 mg of NaN 3 (0.640 mmol, 1.0 eq.) Stir overnight. Further, the mixture was stirred for 1 hour and 30 minutes on an oil bath at 80 ° C. and allowed to cool. 30 ml of water was added and the mixture was extracted with 30 ml × 3 AcOEt, washed successively with 30 ml × 1, 30 ml × 1 brine, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 231 mg of a clear oil. Purification was performed with an open silica gel column (n-hexane: AcOEt = 5: 1) to obtain 184 mg (quant.y.) Of a clear oil.

次に、下記のスキームに従い、C-(trans-4-benzyloxymethylcyclohexyl)methylamineを合成した。
100 mlガラスオートクレーブに、 (trans-4-azidomethylcyclohexylmethyl)benzene 1.57 g (6065 mmol)を取り、10%Pd-C 0.16 g、EtOH 15 mlを加えて黒色懸濁液とした。水素置換して室温にて0.18MPaで7時間接触水素還元をした。リークして桐山漏斗で濾過してMeOHで洗い込み、エバポレートして白色粗結晶1.36 g (5.807 mmol, y.96%)を得た。 Next, C- (trans-4-benzyloxymethylcyclohexyl) methylamine was synthesized according to the following scheme.
To a 100 ml glass autoclave, 1.57 g (6065 mmol) of (trans-4-azidomethylcyclohexylmethyl) benzene was taken, and 0.16 g of 10% Pd—C and 15 ml of EtOH were added to form a black suspension. After hydrogen substitution, catalytic hydrogen reduction was performed at room temperature at 0.18 MPa for 7 hours. The solution was leaked, filtered through a Kiriyama funnel, washed with MeOH, and then evaporated to obtain 1.36 g (5.807 mmol, y.96%) of white crude crystals.

次に、下記のスキームに従い、4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-benzyloxymethylcyclohexyl-methyl)amideを合成した。
20 mlナスフラスコに、 (trans-4-benzyloxymethylcyclohexyl)methylamine 106 mg (0.456 mmol)、4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 100 mg (0.456 mmol, 1.0 eq.)、HOBt 62 mg (0.456 mmol, 1.0 eq.)、DMF 2 ml、Et3N 46 mg (0.456 mmol, 1.0 eq.)、EDCI・HCl 87 mg (0.456 mmol, 1.0 eq.)を取り、活栓をして室温にて一晩攪拌した。sat.NaHCO3 30 mlを加えてAcOEt 30 ml×3で抽出し、1NHCl 30 ml×1、brine 30 ml×1で順次洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、橙色オイル233 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 1 : 4）にて精製し、白色粗結晶94 mg (0.215 mmol, y.47%)を得た。 Next, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-benzyloxymethylcyclohexyl-methyl) amide was synthesized according to the following scheme.
In a 20 ml eggplant flask, (trans-4-benzyloxymethylcyclohexyl) methylamine 106 mg (0.456 mmol), 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid 100 mg (0.456 mmol, 1.0 eq.), HOBt 62 mg (0.456 mmol, 1.0 eq.), DMF 2 ml, Et 3 N 46 mg (0.456 mmol, 1.0 eq.), EDCI / HCl 87 mg (0.456 mmol, 1.0 eq.) And stirred overnight. 30 ml of sat. NaHCO 3 was added and extracted with 30 ml × 3 AcOEt, washed successively with 30 ml × 1N HCl and 30 ml × brine, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 233 mg of an orange oil. Purification by an open silica gel column (n-hexane: AcOEt = 1: 4) gave 94 mg (0.215 mmol, y.47%) of white crude crystals.

次に、下記のスキームに従い、4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-hydroxymethylcyclohexyl-methyl)amideを合成した。
100 mlガラスオートクレーブに、4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-benzyloxymethylcyclohexylmethyl)amide 81 mg (0.185 mmol)を取り、10%Pd-C 8 mg、EtOH 3 mlを加えて黒色懸濁液とした。水素置換して室温にて0.30MPaで7時間接触水素還元をした。リークして桐山漏斗で濾過してMeOHで洗い込み、エバポレートして透明オイル51 mg (0.149 mmol, y.80%)を得た。 Next, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-hydroxymethylcyclohexyl-methyl) amide was synthesized according to the following scheme.
In a 100 ml glass autoclave, take 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-benzyloxymethylcyclohexylmethyl) amide 81 mg (0.185 mmol), 10% Pd-C 8 mg, EtOH 3 ml To give a black suspension. After hydrogen substitution, catalytic hydrogen reduction was performed at 0.30 MPa at room temperature for 7 hours. Leaked and filtered through Kiriyama funnel, washed with MeOH and evaporated to give 51 mg (0.149 mmol, y.80%) clear oil.

次に、下記のスキームに従い、4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-formylcyclohexylmethyl)amideを合成した。
20 mlナスフラスコに、4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-hydroxymethylcyclohexylmethyl)amide 50 mg (0.145 mmol)を取り、CH2Cl2 1 mlを加えて溶かし、塩化カルシウム管と滴下漏斗を付けた。室温にて攪拌下、Dess-Martin periodinane 68 mg (0.160 mmol, 1.1 eq.)をCH2Cl2 2 mlに懸濁させたものと洗い込みのCH2Cl2 1 mlを3分間かけて滴下した。室温にて一晩攪拌し、sat.NaHCO3 30 mlにNa2S2O3を少量加えたものを反応液に加えた。CHCl3 30 ml×3で抽出し、brine 30 ml×1で洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、透明オイル41 mg (0.120 mmol, y.83%)を得た。 Next, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-formylcyclohexylmethyl) amide was synthesized according to the following scheme.
In a 20 ml eggplant flask, take 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-hydroxymethylcyclohexylmethyl) amide 50 mg (0.145 mmol), add 1 ml of CH 2 Cl 2 and dissolve. A calcium chloride tube and a dropping funnel were attached. While stirring at room temperature, 68 mg (0.160 mmol, 1.1 eq.) Of Dess-Martin periodinane suspended in 2 ml of CH 2 Cl 2 and 1 ml of washed CH 2 Cl 2 were added dropwise over 3 minutes. . The mixture was stirred overnight at room temperature, and a small amount of Na 2 S 2 O 3 added to 30 ml of sat. NaHCO 3 was added to the reaction solution. Extracted with CHCl 3 30 ml × 3, washed with brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 41 mg (0.120 mmol, y.83%) of a clear oil.

次に、下記のスキームに従い、3-[trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril -6-carbonyl) amino]methyl]cyclohexyl]acrylic acid ethyl esterを合成した。
100 ml三頸に、NaH (60% ni mineral oil) 5 mg (0.132 mmol, 1.1 eq.)を取り、活栓とセプタムと三方コックとジムロートを付け、真空ポンプを使って窒素置換し、シリンジでTHF 5 mlを加えて白色懸濁液とした。氷浴上、攪拌下、triethyl phosphonoacetate 30 mg (0.132 mmol, 1.1 eq.)をTHF 1 mlに溶かしたものと洗い込みのTHF 1 mlを2分間かけて滴下した。そのまま、氷浴上にて15分間攪拌し、4,4-dimethyl- 3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-formylcyclohexylmethyl)amide 41 mg (0.120 mmol) をTHF 1 mlに溶かしたものと洗い込みのTHF 1 mlを氷浴上、攪拌下、4分間かけて滴下した。そのまま、氷浴上にて6時間攪拌し、エバポレートしてTHFを留去した。水30 mlを加えてAcOEt 30 ml×3で抽出し、brine 30 ml×1で洗浄し、無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、白色オイル49 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 1 : 4）にて精製し、白色オイル33 mg (0.080 mmol, y.66%)を得た。 Next, 3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] acrylic acid ethyl ester was synthesized according to the following scheme.
Take NaH (60% ni mineral oil) 5 mg (0.132 mmol, 1.1 eq.) In three 100 ml necks, attach a stopcock, septum, three-way cock, and Dimroth, and replace with nitrogen using a vacuum pump. 5 ml was added to give a white suspension. In an ice bath, with stirring, triethyl phosphonoacetate 30 mg (0.132 mmol, 1.1 eq.) Dissolved in THF 1 ml and washed THF 1 ml were added dropwise over 2 minutes. Stir for 15 minutes in an ice bath, and dissolve 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid (trans-4-formylcyclohexylmethyl) amide 41 mg (0.120 mmol) in 1 ml of THF. Then, 1 ml of washed THF was added dropwise over 4 minutes with stirring on an ice bath. The mixture was stirred for 6 hours on an ice bath and evaporated to remove THF. 30 ml of water was added and extracted with AcOEt 30 ml × 3, washed with brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 49 mg of a white oil. Purification was performed with an open silica gel column (n-hexane: AcOEt = 1: 4) to obtain 33 mg (0.080 mmol, y.66%) of a white oil.

次に、実施例１と同様にして、下記のスキームに従い、表５に記載の4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4-(2-hydroxycarbamoylvinyl) -cyclohexyl-methyl]amide（化合物３６）を合成した。
colorless cotton (n-hexane / AcOEt / MeOH). mp.184-187℃. 1H-NMR (300 MHz / DMSO / TMS) δ1.01-1.06 (4H, m, CH2×2), 1.26 (6H, s, CH3×2), 1.52 (2H, bs, CH×2), 1.73-1.80 (4H, m, CH2×2), 2.38 (2H, s, CH2), 3.11 (2H, t, J = 5.9 Hz, CH2), 5.70 (1H, d, J = 15.6 Hz, CH=), 6.59 (1H, dd, J = 15.5 Hz, 6.8 Hz, CH=), 6.89 (1H, d, J = 8.4 ArH), 7.67 (1H, d, J = 8.1 Hz, ArH), 7.79 (1H, s, ArH), 8.35 (1H, t, J = 5.6 Hz, NH), 10.34 (1H, s, OH). LRMS (ESI+) m/z 400 ([M+H]+). LRMS (ESI-) m/z 398 ([M-H]-). Next, in the same manner as in Example 1, according to the following scheme, 4,4-dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid described in Table 5 [trans-4- (2-hydroxycarbamoylvinyl) -cyclohexyl- methyl] amide (Compound 36) was synthesized.
colorless cotton (n-hexane / AcOEt / MeOH) .mp.184-187 ° C. 1 H-NMR (300 MHz / DMSO / TMS) δ1.01-1.06 (4H, m, CH 2 × 2), 1.26 (6H , s, CH 3 × 2), 1.52 (2H, bs, CH × 2), 1.73-1.80 (4H, m, CH 2 × 2), 2.38 (2H, s, CH 2 ), 3.11 (2H, t, J = 5.9 Hz, CH 2 ), 5.70 (1H, d, J = 15.6 Hz, CH =), 6.59 (1H, dd, J = 15.5 Hz, 6.8 Hz, CH =), 6.89 (1H, d, J = 8.4 ArH), 7.67 (1H, d, J = 8.1 Hz, ArH), 7.79 (1H, s, ArH), 8.35 (1H, t, J = 5.6 Hz, NH), 10.34 (1H, s, OH). LRMS (ESI +) m / z 400 ([M + H] + ). LRMS (ESI-) m / z 398 ([MH] - ).

実施例３７
原料を変更したこと以外は、実施例３６と同様にして、表５に記載のヒドロキサム酸誘導体（化合物３７）を合成した。
 Example 37
Hydroxamic acid derivatives (Compound 37) shown in Table 5 were synthesized in the same manner as in Example 36 except that the raw materials were changed.

実施例３８（4,4-Dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4- (2-hydroxycarbamoylethyl)-cyclohexylmethyl]amideの合成）
まず、下記のスキームに従い、3-[trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril -6-carbonyl)amino]methyl]cyclohexyl]propionic acid ethyl esterを合成した。
3-[trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl)amino]methyl]cyclohexyl]acrylic acid ethyl ester 107 mg (0.260 mmol) 、10%Pd-C 11 mgを100 mlガラスオートクレーブに取り、MeOH 4 mgを加えて黒色懸濁液とし、水素置換して室温にて0.16 MPaで3日間攪拌した。桐山漏斗で濾過してMeOHで洗い込み、エバポレートして透明オイル100 mgを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 1 : 4）にて精製し、白色オイル78 mg (0.188 mmol, y.72%)を得た。 Example 38 (Synthesis of 4,4-Dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4- (2-hydroxycarbamoylethyl) -cyclohexylmethyl] amide)
First, 3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] propionic acid ethyl ester was synthesized according to the following scheme.
3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] acrylic acid ethyl ester 107 mg (0.260 mmol), 10% Pd-C 11 mg Was taken up in a 100 ml glass autoclave and 4 mg of MeOH was added to make a black suspension, which was purged with hydrogen and stirred at room temperature at 0.16 MPa for 3 days. Filtration through a Kiriyama funnel, washing with MeOH, and evaporation gave 100 mg of a clear oil. Purification was performed with an open silica gel column (n-hexane: AcOEt = 1: 4) to obtain 78 mg (0.188 mmol, y.72%) of a white oil.

次に、下記のスキームに従い、表６に記載の4,4-Dimethyl-3,4-dihydrocarbostyril -6-carboxylic acid [trans-4-(2-hydroxycarbamoylethyl) cyclohexylmethyl]amide（化合物３８）を合成した。
3-[trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl)amino]methyl]cyclohexyl]propionic acid ethyl ester 105 mg (0.254 mmol)を20 mlナスフラスコに取り、MeOH 2 mlを加えて溶かした。氷浴上、攪拌下、NH2OH in water 50% 0.16 ml (2.538 mmol, 10 eq.) をシリンジで滴下して活栓をして氷浴上にて10分間攪拌した。NaOMe in MeOH 25% 0.29 ml (1.269 mmol, 5 eq.)をシリンジで滴下した。活栓をして氷浴上にて2時間攪拌し、sat.NH4Cl 30 mlを加えた。析出物を桐山漏斗で濾取し、水、n-hexaneで順次洗浄して風乾した。ナスフラスコに移して真空ポンプで乾燥し、白色粗結晶91 mgを得た。他方、濾液をAcOEt 30 ml×2で抽出し、brine 30 ml×1で洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、白色粗結晶20 mgを得た。両者を合わせて、オープンシリカゲルカラム（AcOEt : MeOH = 5 : 1）にて精製し、白色粗結晶81 mg (0.202 mmol, y.80%)を得た。colorless powder (AcOEt / MeOH). mp.195-197℃. 1H-NMR (300 MHz / DMSO / TMS)δ0.81-0.88 (4H, m, CH2×2), 1.26 (6H, s, CH3×2), 1.37-1.42 (2H, m, CH2), 1.47 (2H, bs, CH×2), 1.71-1.73 (4H, m, CH2×2), 1.95 (2H, t, J = 7.7 Hz, CH2), 2.38 (2H, s, CH2), 3.08 (2H, t, J = 6.3 Hz, NCH2), 6.88 (1H, d, J = 5.7 Hz, ArH), 7.66 (1H, dd, J = 8.4 Hz, 1.8 Hz, ArH), 7.68 (1H, d, J = 1.8 Hz, ArH), 8.32 (1H, t, J = 5.7 Hz, ArH), 8.65 (1H, s, NH), 10.34 (2H, s, OH and NH). LRMS (ESI+) m/z 402 ([M+H]+). LRMS (ESI-) m/z 400 ([M-H]-). Next, 4,4-Dimethyl-3,4-dihydrocarbostyril-6-carboxylic acid [trans-4- (2-hydroxycarbamoylethyl) cyclohexylmethyl] amide (Compound 38) shown in Table 6 was synthesized according to the following scheme.
Take 3- [trans-4-[[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] methyl] cyclohexyl] propionic acid ethyl ester 105 mg (0.254 mmol) in a 20 ml eggplant flask, 2 ml of MeOH was added to dissolve. Under stirring in an ice bath, NH 2 OH in water 50% 0.16 ml (2.538 mmol, 10 eq.) Was added dropwise with a syringe, the stopper was put on, and the mixture was stirred on an ice bath for 10 minutes. NaOMe in MeOH 25% 0.29 ml (1.269 mmol, 5 eq.) Was added dropwise with a syringe. The stopcock was put on, and the mixture was stirred on an ice bath for 2 hours, and 30 ml of sat.NH 4 Cl was added. The precipitate was collected by filtration with a Kiriyama funnel, washed successively with water and n-hexane and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 91 mg of white crude crystals were obtained. On the other hand, the filtrate was extracted with AcOEt 30 ml × 2, washed with brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 20 mg of white crude crystals. Both were combined and purified with an open silica gel column (AcOEt: MeOH = 5: 1) to obtain 81 mg (0.202 mmol, y.80%) of white crude crystals. colorless powder (AcOEt / MeOH) .mp.195-197 ° C. 1 H-NMR (300 MHz / DMSO / TMS) δ0.81-0.88 (4H, m, CH 2 × 2), 1.26 (6H, s, CH 3 × 2), 1.37-1.42 (2H, m, CH 2 ), 1.47 (2H, bs, CH × 2), 1.71-1.73 (4H, m, CH 2 × 2), 1.95 (2H, t, J = 7.7 Hz, CH 2 ), 2.38 (2H, s, CH 2 ), 3.08 (2H, t, J = 6.3 Hz, NCH 2 ), 6.88 (1H, d, J = 5.7 Hz, ArH), 7.66 (1H, dd, J = 8.4 Hz, 1.8 Hz, ArH), 7.68 (1H, d, J = 1.8 Hz, ArH), 8.32 (1H, t, J = 5.7 Hz, ArH), 8.65 (1H, s, NH), 10.34 (2H, s, OH and NH). LRMS (ESI +) m / z 402 ([M + H] + ). LRMS (ESI-) m / z 400 ([MH] - ).

実施例３９
原料を変更したこと以外は、実施例３８と同様にして、表６に記載のヒドロキサム酸誘導体（化合物３９）を合成した。
 Example 39
A hydroxamic acid derivative (Compound 39) shown in Table 6 was synthesized in the same manner as in Example 38 except that the raw materials were changed.

実施例４０（7-(6-aminosulfonylcarbostyril) heptanohydroxamicaciの合成）
まず、下記のスキームに従い、7-aminoheptanoic acid methyl ester hydrochlorideを合成した。
50mlナスフラスコに、7-aminoheptanoic acid1.4g (9.4 mmol)を取り、窒素雰囲気下、MeOH 8.8ml加えて懸濁液とした。室温にて攪拌下、trimethylchlorosilane1.2ml (9.3 mmol, 1.0 eq.)を加え、そのまま、室温にて16時間撹拌した。反応液を減圧留去して白色粗結晶1.9 g（9.0 mmol, y. 96%）を得た。 Example 40 (Synthesis of 7- (6-aminosulfonylcarbostyril) heptanohydroxamicaci)
First, 7-aminoheptanoic acid methyl ester hydrochloride was synthesized according to the following scheme.
In a 50 ml eggplant flask, 1.4 g (9.4 mmol) of 7-aminoheptanoic acid was taken, and 8.8 ml of MeOH was added to form a suspension in a nitrogen atmosphere. While stirring at room temperature, 1.2 ml (9.3 mmol, 1.0 eq.) Of trimethylchlorosilane was added, and the mixture was stirred as it was at room temperature for 16 hours. The reaction solution was distilled off under reduced pressure to obtain 1.9 g (9.0 mmol, y. 96%) of white crude crystals.

次に、下記のスキームに従い、2-oxo-1,2-dihydroquinoline-6-sulfonyl chlorideを合成した。
30mlナスフラスコに、2-quinolinol 1.0 g (6.8 mmol)、chlorosulfonic acid 3.0 ml (45 mmol, 6.6 eq.)を取り、窒素風船を備え付けた三方コックを付け、オイルバス65℃上にて3時間攪拌した。放冷後、反応液を氷水にあけ、析出物を桐山漏斗で濾取して水で洗い込み、風乾した。ナスフラスコに移して真空ポンプで乾燥し、白色粗結晶1.1 g（4.6 mmol, y. 68%）を得た。 Next, 2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride was synthesized according to the following scheme.
To a 30 ml eggplant flask, take 1.0 g (6.8 mmol) of 2-quinolinol and 3.0 ml (45 mmol, 6.6 eq.) Of chlorosulfonic acid, attach a three-way cock equipped with a nitrogen balloon, and stir for 3 hours on an oil bath at 65 ° C. did. After allowing to cool, the reaction solution was poured into ice water, and the precipitate was filtered with a Kiriyama funnel, washed with water, and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 1.1 g (4.6 mmol, y. 68%) of white crude crystals were obtained.

次に、下記のスキームに従い、7-(6-aminosulfonylcarbostyril) heptanoicacid methyl esterを合成した。
30 mlナスフラスコに、7-aminoheptanoic acid methyl ester hydrochloride 142 mg (0.73 mmol, 1.3 eq.)を取り、CH2Cl2 2.0 mlを加えて溶かし、2-oxo-1,2-dihydroquinoline-6-sulfonyl chloride 138mg (0.57 mmol)を加えて懸濁液とし、次いでEt3N 114 mg (3.24 mmol, 5.7 eq.)をCH2Cl2 0.5 mlに溶かしたものと洗い込みのCH2Cl2 0.5 mlをシリンジで滴下した。滴下の過程で白煙が発生し、反応液は桃色懸濁液へと変化した。この懸濁液を室温にて16時間撹拌し、反応液に水10 ml、AcOEt 10ml、n-hexane 2mlを順次加え、析出物を桐山漏斗で濾取し、水で洗い込んで風乾した。ナスフラスコに移して真空ポンプで乾燥し、桃色粗結晶127 mg（0.35 mmol, y. 61%）を得た。 Next, 7- (6-aminosulfonylcarbostyril) heptanoicacid methyl ester was synthesized according to the following scheme.
In a 30 ml eggplant flask, take 142 mg (0.73 mmol, 1.3 eq.) Of 7-aminoheptanoic acid methyl ester hydrochloride, add 2.0 ml of CH 2 Cl 2 and dissolve, and dissolve in 2-oxo-1,2-dihydroquinoline-6-sulfonyl. a suspension by adding chloride 138 mg of (0.57 mmol), followed by Et 3 N 114 mg (3.24 mmol , 5.7 eq.) and the CH 2 Cl 2 CH 2 Cl 2 0.5 ml inclusive washing as dissolved in 0.5 ml It was dripped with a syringe. White smoke was generated during the dropping process, and the reaction liquid changed to a pink suspension. This suspension was stirred at room temperature for 16 hours, 10 ml of water, 10 ml of AcOEt, and 2 ml of n-hexane were sequentially added to the reaction solution, and the precipitate was collected by filtration with a Kiriyama funnel, washed with water and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and 127 mg (0.35 mmol, y. 61%) of pink coarse crystals were obtained.

次に、下記のスキームに従い、表７に記載の7-(6-aminosulfonylcarbostyril) heptanohydroxamicacid（化合物４０）を合成した。
50 mlナスフラスコに、7-(aminosulfonylcarbostyril) heptanoicacid methyl ester 44 mg (0.12 mmol)を取り、MeOH 1.5 mlを加えて溶かした。氷浴上、攪拌下、NH2OH（50% in water）0.10 mL (1.7 mmol, 14.2 eq.)をシリンジで滴下し、活栓をした。氷浴上にて5分間攪拌した後にNaOMe（25% in MeOH,）0.20 ml (0.82 mmol, 6.8 eq.)をシリンジで滴下し、引き続き氷浴上にて2時間攪拌した。sat.NH4Cl 15 mlを加え、氷冷下15分間撹拌した後に白色析出物を桐山漏斗で濾取し、sat.NH4Cl 10 ml、水10mlで順次洗浄し50℃にて減圧乾燥して白色粗結晶36 mgを得た。この粗結晶にMeOH 2.0mlを加えて懸濁液とし、室温にて1時間撹拌して桐山漏斗で濾取した。、MeOH、CHCl3で順次洗浄し、風乾した。ナスフラスコに移して真空ポンプで乾燥し、白色粗結晶9.3 mg (0.025 mmol, y. 21%)を得た。colorless powder (MeOH). mp. 不明（242℃で炭化）. 1H-NMR (300 MHz / DMSO / TMS) δ1.08-1.24 (4H, m, CH2CH2), 1.32-1.47 (4H, m, CH2CH2), 1.89 (2H, t, J = 7.4 Hz, C(O)CH2), 2.72-2.74 (2H, m, NCH2), 6.61 (1H, d, J = 9.6 Hz, CH=CH), 7.43 (1H, d, J = 8.7 Hz ArH), 7.52 (1H, br, NH), 7.84 (1H, dd, J = 8.7, 1.8 Hz ArH), 8.07 (1H, d, J = 9.6 Hz, CH=CH), 8.62 (1H, d, J = 1.8 Hz, ArH), 8.96 (1H, br, OH), 10.31 (1H, br, NH). Next, 7- (6-aminosulfonylcarbostyril) heptanohydroxamicacid (compound 40) shown in Table 7 was synthesized according to the following scheme.
In a 50 ml eggplant flask, 44 mg (0.12 mmol) of 7- (aminosulfonylcarbostyril) heptanoicacid methyl ester was taken and dissolved by adding 1.5 ml of MeOH. Under stirring in an ice bath, 0.10 mL (1.7 mmol, 14.2 eq.) Of NH 2 OH (50% in water) was added dropwise with a syringe, and the stopcock was put on. After stirring for 5 minutes on an ice bath, 0.20 ml (0.82 mmol, 6.8 eq.) Of NaOMe (25% in MeOH,) was added dropwise with a syringe, followed by stirring for 2 hours on an ice bath. After adding 15 ml of sat.NH 4 Cl and stirring for 15 minutes under ice cooling, the white precipitate was collected by filtration with a Kiriyama funnel, washed successively with 10 ml of sat.NH 4 Cl and 10 ml of water, and dried under reduced pressure at 50 ° C. As a result, 36 mg of white crude crystals were obtained. To this crude crystal, 2.0 ml of MeOH was added to make a suspension, stirred at room temperature for 1 hour, and filtered through a Kiriyama funnel. , Washed sequentially with MeOH, CHCl 3 and air dried. It moved to the eggplant flask and dried with the vacuum pump, and white crude crystal 9.3 mg (0.025 mmol, y. 21%) was obtained. colorless powder (MeOH). mp. Unknown (carbonized at 242 ° C). 1 H-NMR (300 MHz / DMSO / TMS) δ1.08-1.24 (4H, m, CH 2 CH 2 ), 1.32-1.47 (4H, m, CH 2 CH 2 ), 1.89 (2H, t, J = 7.4 Hz, C (O) CH 2 ), 2.72-2.74 (2H, m, NCH 2 ), 6.61 (1H, d, J = 9.6 Hz, CH = CH), 7.43 (1H, d, J = 8.7 Hz ArH), 7.52 (1H, br, NH), 7.84 (1H, dd, J = 8.7, 1.8 Hz ArH), 8.07 (1H, d, J = 9.6 Hz, CH = CH), 8.62 (1H, d, J = 1.8 Hz, ArH), 8.96 (1H, br, OH), 10.31 (1H, br, NH).

実施例４１〜４２
原料を変更したこと以外は、実施例４０と同様にして、表７に記載のヒドロキサム酸誘導体（化合物４１〜４２）を合成した。
 Examples 41-42
Hydroxamic acid derivatives (compounds 41 to 42) shown in Table 7 were synthesized in the same manner as in Example 40 except that the raw materials were changed.

実施例４３（7-(6-sulfonylamino-3,4-dihydrocarbostyril) heptanohydroxamicacidの合成）
まず、下記のスキームに従い、7-(chlorosulfonyl)heptanoic acid methyl esterを合成した。
20 mlナスフラスコに、7-bromoheptanoic acid methyl ester 800 mg (3.6 mmol)、Na2SO3 580 mg (4.6 mmol, 1.3 eq.)、水3.6 mlを取り、オイルバス上にて17時間加熱還流した。放冷して桐山漏斗で濾取し、Et2O 10 ml×3で洗浄して風乾した。ナスフラスコに移して真空ポンプで乾燥し、白色粗結晶1.4 gを得た。得られた粗結晶は1H-NMRにより基質転嫁率が>99%に達していることを確認した後に、精製せず次の反応へと用いた。 Example 43 (Synthesis of 7- (6-sulfonylamino-3,4-dihydrocarbostyril) heptanohydroxamicacid)
First, 7- (chlorosulfonyl) heptanoic acid methyl ester was synthesized according to the following scheme.
In a 20 ml eggplant flask, 800 mg (3.6 mmol) of 7-bromoheptanoic acid methyl ester, 580 mg of Na 2 SO 3 (4.6 mmol, 1.3 eq.) And 3.6 ml of water were taken and heated to reflux on an oil bath for 17 hours. . The mixture was allowed to cool, filtered through a Kiriyama funnel, washed with Et 2 O 10 ml × 3, and air-dried. It transferred to the eggplant flask and dried with a vacuum pump to obtain 1.4 g of white crude crystals. The obtained crude crystals were used for the next reaction without purification after confirming that the substrate pass-through rate reached> 99% by 1 H-NMR.

次に、下記のスキームに従い、7-(6-sulfonylamino-3,4-dihydrocarbostyril) heptanoicacid methyl esterを合成した。
10-20mL MW反応用バイヤルに、7-(chlorosulfonyl)heptanoic acid methyl ester 1.0 g (4.6mmol)を取り、acetone 8.0 mlを加えて懸濁液とし、trichlorotriazine 926 mg (5.0 mmol, 1.1 eq.)を加えた。次いでEt3N 530 mg (5.2 mmol, 1.1 eq.)をacetone 1.0 mlに溶解させたものと洗い込みのacetone 1.0 mlをシリンジで5分間かけて滴下した。反応液は薄黄色懸濁液となった。この懸濁液をマイクロウェーブ合成装置（InitiatorTM Eight, Biotage）を用いて80℃にて20分間加熱した後に空冷し、内容物をセライト濾過し、濾液に2N NaOH 3.0 ml、THF 2.5 ml、6-amino-3,4-dihydrocarbostyril 800 mg (4.9 mmol, 1.1 eq.)を加え、マイクロウェーブ合成装置を用いて80℃にて20分間加熱した。空冷後内容物のセライト濾過を行い、濾液に水15 mlおよびAcOEt 15 mlを加え、有機層を分取した。水層をAcOEt 10 ml×3で抽出し、有機層を合わせた。有機層をbrine 15ml×2で洗浄した。無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして得た残渣を、シリカゲルカラムクロマトグラフィー（AcOEt : MeOH = 7 : 1）にて精製し、薄桃色粗結晶223 mg（0.62mmol, y. 13%）を得た。 Next, 7- (6-sulfonylamino-3,4-dihydrocarbostyril) heptanoicacid methyl ester was synthesized according to the following scheme.
Add 10 g (4.6 mmol) of 7- (chlorosulfonyl) heptanoic acid methyl ester to a vial for 10-20 mL MW reaction, add 8.0 ml of acetone to make a suspension, and add 926 mg (5.0 mmol, 1.1 eq.) Of trichlorotriazine. added. Next, Et 3 N 530 mg (5.2 mmol, 1.1 eq.) Dissolved in acetone 1.0 ml and washed acetone 1.0 ml were added dropwise over 5 minutes with a syringe. The reaction solution became a pale yellow suspension. This suspension was heated at 80 ° C. for 20 minutes using a microwave synthesizer (InitiatorTM Eight, Biotage) and then air-cooled. The contents were filtered through Celite, and the filtrate was filtered with 2N NaOH 3.0 ml, THF 2.5 ml, 6- Amino-3,4-dihydrocarbostyril 800 mg (4.9 mmol, 1.1 eq.) was added, and the mixture was heated at 80 ° C. for 20 minutes using a microwave synthesizer. After air cooling, the contents were filtered through Celite, 15 ml of water and 15 ml of AcOEt were added to the filtrate, and the organic layer was separated. The aqueous layer was extracted with AcOEt 10 ml × 3, and the organic layers were combined. The organic layer was washed with brine 15 ml × 2. Dried over anhydrous Na 2 SO 4 . The residue obtained by filtration through a Kiriyama funnel and evaporation was purified by silica gel column chromatography (AcOEt: MeOH = 7: 1) to obtain 223 mg (0.62 mmol, y. 13%) of pale pink crude crystals.

次に、下記のスキームに従い、表８に記載の7-(6-sulfonylamino-3,4 -dihydrocarbostyril) heptanohydroxamicacid（化合物４３）を合成した。
30 mlナスフラスコに、7-(6-sulfonylamino-3,4-dihydrocarbostyril) heptanoicacid methyl ester 136 mg (0.37 mmol)を取り、MeOH 3.3 mlを加えて溶かし、氷浴上、攪拌下、NH2OH（50% in water）0.23 ml (3.5 mmol, 9.5 eq.)をシリンジで滴下し、活栓をした。氷浴上で5分間攪拌した後にNaOMe（25% in MeOH）0.41 mL (1.8 mmol, 4.9 eq.)をシリンジで滴下し、引き続き氷浴上にて2時間攪拌し続けた。その後、sat.NH4Cl 20mLを加え氷冷下15分撹拌した後に反応液を桐山漏斗で濾過し、sat.NH4Cl 10ml、水10 ml、CHCl310 mlで順次洗い込み、濾液の水層を分取して、AcOEt 10mlで洗い、1N HCl 2.0mLを加えた。、白色析出物を桐山漏斗で濾取し、水10 ml、1N HCl 2.0 mlで順次洗浄し50℃に加熱しながら減圧乾燥して白色粗結晶60 mg (0.16 mmol, y. 44%)を得た。colorless powder (H2O). mp. 133-135℃. 1H-NMR (300 MHz / DMSO / TMS) δ1.16-1.36 (4H, m, CH2CH2), 1.39-1.49 (2H, m, CH2), 1.58-1.68 (2H, m, CH2), 1.91 (2H, t, J = 7.4 Hz, CH2), 2.39-2.44 (2H, m, CH2), 2.83 (2H, t, J = 7.5 Hz, C(O)CH2), 2.95-3.00 (2H, m, NCH2), 6.80 (1H, d, J = 8.4 Hz, ArH), 6.96-7.00 (2H, m, ArH), 7.24 (1H, br, NH), 8.67 (1H, br, NH), 10.04 (1H, br, OH), 10.35 (1H, br, NH).
Next, 7- (6-sulfonylamino-3,4-dihydrocarbostyril) heptanohydroxamicacid (compound 43) described in Table 8 was synthesized according to the following scheme.
In 30 ml recovery flask, 7- take (6-sulfonylamino-3,4-dihydrocarbostyril ) heptanoicacid methyl ester 136 mg (0.37 mmol), dissolved by addition of MeOH 3.3 ml, on an ice bath, under stirring, NH 2 OH ( 503 in water) 0.23 ml (3.5 mmol, 9.5 eq.) Was added dropwise with a syringe, and the stopcock was put on. After stirring for 5 minutes on the ice bath, 0.41 mL (1.8 mmol, 4.9 eq.) Of NaOMe (25% in MeOH) was added dropwise with a syringe, and the stirring was continued for 2 hours on the ice bath. Then, 20 mL of sat.NH 4 Cl was added, and the mixture was stirred for 15 minutes under ice-cooling. The reaction solution was filtered through a Kiriyama funnel, washed successively with 10 ml of sat.NH 4 Cl, 10 ml of water, and 10 ml of CHCl 3. The layers were separated and washed with 10 ml AcOEt and 2.0 mL 1N HCl was added. The white precipitate was collected by filtration with a Kiriyama funnel, washed sequentially with 10 ml of water and 2.0 ml of 1N HCl, and dried under reduced pressure while heating to 50 ° C. to obtain 60 mg (0.16 mmol, y. 44%) of white crude crystals. It was. colorless powder (H 2 O) .mp. 133-135 ° C. 1 H-NMR (300 MHz / DMSO / TMS) δ1.16-1.36 (4H, m, CH 2 CH 2 ), 1.39-1.49 (2H, m , CH 2 ), 1.58-1.68 (2H, m, CH 2 ), 1.91 (2H, t, J = 7.4 Hz, CH 2 ), 2.39-2.44 (2H, m, CH 2 ), 2.83 (2H, t, J = 7.5 Hz, C (O) CH 2 ), 2.95-3.00 (2H, m, NCH 2 ), 6.80 (1H, d, J = 8.4 Hz, ArH), 6.96-7.00 (2H, m, ArH), 7.24 (1H, br, NH), 8.67 (1H, br, NH), 10.04 (1H, br, OH), 10.35 (1H, br, NH).

参考例１（7-(3,4-dihydrocarbostyril-6-ylcarbamoyl)heptanoic acid N-hydroxy-N-methylamideの合成）
下記のスキームに従い、表９に記載の7-(3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide（化合物４４）を合成した。
 Reference Example 1 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide)
According to the following scheme, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide (Compound 44) shown in Table 9 was synthesized.

参考例２（7-(3,4-dihydrocarbostyril-6-ylcarbamoyl)heptanoic acid N-hydroxy-N-methylamideの合成）
下記のスキームに従い、表１０に記載の7-(3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide（化合物４５）を合成した。
 Reference Example 2 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide)
According to the following scheme, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide (Compound 45) shown in Table 10 was synthesized.

参考例３（7-(3,4-dihydrocarbostyril-6-ylcarbamoyl)heptanoic acid N-hydroxy-N-methylamideの合成）
下記のスキームに従い、表１１に記載の7-(3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide（化合物４６）を合成した。
 Reference Example 3 (Synthesis of 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide)
According to the following scheme, 7- (3,4-dihydrocarbostyril-6-ylcarbamoyl) heptanoic acid N-hydroxy-N-methylamide (Compound 46) shown in Table 11 was synthesized.

参考例４（7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl)amino]heptanoic acid N-hydroxyl-N-ethylamideの合成）
下記のスキームに従い、表１２に記載の7-[(4,4-dimethyl-3,4-dihydrocarbostyril -6-carbonyl) amino]heptanoic acid N-hydroxyl-N-ethylamide（化合物４７）を合成した。
 Reference Example 4 (Synthesis of 7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-ethylamide)
According to the following scheme, 7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-ethylamide (Compound 47) shown in Table 12 was synthesized.

参考例５（7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl)amino]heptanoic acid N-hydroxyl-N-isopropylamideの合成）
下記のスキームに従い、表１３に記載の7-[(4,4-dimethyl-3,4-dihydrocarbostyril -6-carbonyl)amino]heptanoic acid N-hydroxyl-N-isopropylamide（化合物４８）を合成した。
 Reference Example 5 (Synthesis of 7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-isopropylamide)
7-[(4,4-dimethyl-3,4-dihydrocarbostyril-6-carbonyl) amino] heptanoic acid N-hydroxyl-N-isopropylamide (Compound 48) described in Table 13 was synthesized according to the following scheme.

参考例６（スベロイルアニリドヒドロキサム酸（ＳＡＨＡ）の合成）
まず、下記のスキームに従い、7-phenylcarbamoylheptanoic acid benzyl esterを合成した。
50 mlナスフラスコに、suberic acid monobenzyl ester 851 mg (3.221 mmol, 1.0 eq.)、aniline 300 mg (3.221 mmol)、EDCI・HCl 618 mg (3.221 mmol, 1.0 eq.)、HOBt 435 mg (3.221 mmol, 1.0 eq.)、Et3N 326 mg (3.221 mmol, 1.0 eq.)、DMF 13 mlを取り、活栓をして室温にて一晩攪拌した。sat.NaHCO3 30 mlを加えてAcOEt 30 ml×3で抽出し、水30 ml×1、2NHCl 30 ml×1、brine 30 ml×1で順次洗浄して無水Na2SO4で乾燥した。桐山漏斗で濾過しエバポレートして、白色粗結晶1.058 gを得た。オープンシリカゲルカラム（n-hexane : AcOEt = 2 : 1）にて精製し、白色粗結晶942 mg (2.775 mmol, y.86%)を得た。 Reference Example 6 (Synthesis of suberoylanilide hydroxamic acid (SAHA))
First, 7-phenylcarbamoylheptanoic acid benzyl ester was synthesized according to the following scheme.
In a 50 ml eggplant flask, suberic acid monobenzyl ester 851 mg (3.221 mmol, 1.0 eq.), Aniline 300 mg (3.221 mmol), EDCI ・ HCl 618 mg (3.221 mmol, 1.0 eq.), HOBt 435 mg (3.221 mmol, 1.0 eq.), Et 3 N 326 mg (3.221 mmol, 1.0 eq.), And DMF 13 ml were taken, stoppered and stirred at room temperature overnight. 30 ml of sat. NaHCO 3 was added, extracted with AcOEt 30 ml × 3, washed successively with water 30 ml × 1, 2NHCl 30 ml × 1, brine 30 ml × 1, and dried over anhydrous Na 2 SO 4 . Filtration through a Kiriyama funnel and evaporation gave 1.058 g of white crude crystals. Purification by an open silica gel column (n-hexane: AcOEt = 2: 1) gave 942 mg (2.775 mmol, y.86%) of white crude crystals.

次に、下記のスキームに従い、表１４に記載のスベロイルアニリドヒドロキサム酸（化合物４９）を合成した。
20 mlナスフラスコに、7-phenylcarbamoylheptanoic acid benzyl ester 300 mg (0.884 mmol)を取り、MeOH 2 mlを加えて溶かした。氷浴上にて攪拌下、NH2OH in water 50% 0.54 ml (8.838 mmol, 10 eq.)をシリンジで1分間かけて滴下した。途中析出したので、MeOH 1 mlを加えて活栓をし、氷浴上にて5分間攪拌してNaOMe in MeOH 25% 1.01 ml (4.419 mmol, 5 eq.)をシリンジで1分間かけて滴下した。溶液になっていった。活栓をして氷浴上にて2時間攪拌し、sat.NH4Cl 20 mlを加えた。白濁した。水10 mlを加えて希釈し、桐山漏斗で濾取して、水、n-hexaneで順次洗浄し、風乾した。ナスフラスコに移して真空ポンプで乾燥し、白色粗結晶179 mg (0.675 mmol, y.76%)を得た。colorless powder (n-hexane / AcOEt / MeOH). mp.158-159℃. 1H-NMR (300 MHz / DMSO / TMS) δ1.26-1.29 (4H, m, CH2×2), 1.44-1.51 (2H, m, CH2), 1.55-1.60 (2H, m, CH2), 1.94 (2H, t, J = 7.4 Hz, CH2), 2.29 (2H, t, J = 7.4 Hz, CH2), 7.01 (1H, t, J = 7.4 Hz, ArH), 7.27 (2H, t, J = 7.8 Hz, ArH), 7.59 (2H, d, J = 7.5 Hz, ArH), 8.66 (1H, s, NH), 9.88 (1H, s, NH), 10.35 (1H, s, NOH). LRMS (ESI+) m/z 265 ([M+H]+). LRMS (ESI-) m/z 263 ([M-H]-).
Next, according to the following scheme, suberoylanilide hydroxamic acid (compound 49) described in Table 14 was synthesized.
In a 20 ml eggplant flask, 300 mg (0.884 mmol) of 7-phenylcarbamoylheptanoic acid benzyl ester was taken and dissolved by adding 2 ml of MeOH. Stirring the solution at an ice-bath, NH 2 OH in water 50% 0.54 ml (8.838 mmol, 10 eq.) Was added dropwise over 1 min via syringe. Since it precipitated in the middle, 1 ml of MeOH was added to stop the cock, and the mixture was stirred on an ice bath for 5 minutes, and NaOMe in MeOH 25% 1.01 ml (4.419 mmol, 5 eq.) Was added dropwise over 1 minute with a syringe. It became a solution. The stopper was put on, and the mixture was stirred for 2 hours on an ice bath, and 20 ml of sat.NH 4 Cl was added. It became cloudy. The mixture was diluted with 10 ml of water, filtered through a Kiriyama funnel, washed successively with water and n-hexane, and air-dried. It moved to the eggplant flask and dried with the vacuum pump, and white crude crystal 179 mg (0.675 mmol, y.76%) was obtained. colorless powder (n-hexane / AcOEt / MeOH) .mp.158-159 ° C. 1 H-NMR (300 MHz / DMSO / TMS) δ1.26-1.29 (4H, m, CH 2 × 2), 1.44-1.51 (2H, m, CH 2 ), 1.55-1.60 (2H, m, CH 2 ), 1.94 (2H, t, J = 7.4 Hz, CH 2 ), 2.29 (2H, t, J = 7.4 Hz, CH 2 ) , 7.01 (1H, t, J = 7.4 Hz, ArH), 7.27 (2H, t, J = 7.8 Hz, ArH), 7.59 (2H, d, J = 7.5 Hz, ArH), 8.66 (1H, s, NH ), 9.88 (1H, s, NH), 10.35 (1H, s, NOH). LRMS (ESI +) m / z 265 ([M + H] + ). LRMS (ESI-) m / z 263 ([MH] - ).

試験例１（ヒストン脱アセチル化酵素阻害活性の測定）
実施例１〜４３及び参考例１〜６で得られた化合物１〜４９それぞれについて、Ｙｏｓｈｉｄａ Ｍ ｅｔ ａｌ． Ｃａｎｃｅｒ Ｃｈｅｍｏｔｈｅｒ Ｐｈａｒｍａｃｏｌ．４８（Ｓｕｐｐｌ１）：Ｓ２０，２００１に記載の方法に従い、以下の条件において、化合物濃度がそれぞれ０．１μＭ及び１０μＭでのヒストン脱アセチル化酵素阻害活性（％）を測定した（ｎ＝２）。なお、本試験では、ヒストン脱アセチル化酵素として、ＨＤＡＣ１〜１１（ｒａｔ ｌｉｖｅｒ ＨＤＡＣｓ Ｍｅｒｃｋ社製）の混合物を使用しているため、ヒストン脱アセチル化酵素のサブタイプに非特異的に阻害する化合物はヒストン脱アセチル化酵素阻害活性（％）が高い値になり、またヒストン脱アセチル化酵素のサブタイプに特異的に阻害する化合物はヒストン脱アセチル化酵素阻害活性（％）が低い値になる。 Test Example 1 (Measurement of histone deacetylase inhibitory activity)
About each of the compounds 1-49 obtained in Examples 1-43 and Reference Examples 1-6, Yoshida M et al. Cancer Chemother Pharmacol. 48 (Suppl1): According to the method described in S20, 2001, histone deacetylase inhibitory activity (%) was measured at the compound concentrations of 0.1 μM and 10 μM, respectively, under the following conditions (n = 2). In this test, since a mixture of HDAC1 to 11 (manufactured by rat river HDACs Merck) is used as the histone deacetylase, compounds that inhibit nonspecifically the histone deacetylase subtype are A histone deacetylase inhibitory activity (%) has a high value, and a compound that specifically inhibits a histone deacetylase subtype has a low histone deacetylase inhibitory activity (%).

インキュベーションバッファー:25mM Tris-HCL, 137mM NaCl, 2.7mM KCl, 1mM MgCl2, pH8.0
アッセイ：
化合物（１％ＤＭＳＯ*） １μｌ
ヒストン脱アセチル化酵素（３２μｇ／ｍｌ*） ５０μｌ
Ｂｏｃ−Ｌｙｓ（Ａｃ）−ＡＭＣ（２５０μＭ*） ５０μｌ
＊最終濃度
手順：
１．化合物とヒストン脱アセチル化酵素とを混合する。
２．すぐに蛍光光度計の値をバックグランドとして読み取る。
３．３７℃で１５分間プレインキュベートする。
４．反応を開始するために、加温したＢｏｃ−Ｌｙｓ（Ａｃ）−ＡＭＣを加える。
５．シールし、３７℃で３０分間インキュベートする。
６．反応をクエンチするために、１０μｌのdiluted Developer Concentrateを加える。
７．３７℃で１時間置く。
８．蛍光光度計の値を読み取る（励起光：３６０ｎｍ、発光：４６５ｎｍ）。 Incubation buffer: 25 mM Tris-HCL, 137 mM NaCl, 2.7 mM KCl, 1 mM MgCl 2 , pH 8.0
Assay:
Compound (1% DMSO * ) 1 μl
Histone deacetylase (32 μg / ml * ) 50 μl
Boc-Lys (Ac) -AMC (250 μM * ) 50 μl
* Final concentration Procedure:
1. Mix compound with histone deacetylase.
2. Immediately read the fluorometer value as background.
3. Pre-incubate for 15 minutes at 37 ° C.
4). To start the reaction, warm Boc-Lys (Ac) -AMC is added.
5. Seal and incubate at 37 ° C. for 30 minutes.
6). Add 10 μl diluted Developer Concentrate to quench the reaction.
7. Place at 37 ° C. for 1 hour.
8). The value of the fluorometer is read (excitation light: 360 nm, emission: 465 nm).

得られた結果を表１５に示す。試験例１の結果から、実施例の化合物は、全てヒストン脱アセチル化酵素阻害活性を示し、とりわけ、基Ｘが−ＣＯＮＨ−または−ＮＨＣＯ−である実施例１２〜３９の化合物では、活性が極めて高く、公知のヒストン脱アセチル化酵素阻害である参考例６の化合物と同等以上の活性を有していた。
The results obtained are shown in Table 15. From the results of Test Example 1, all of the compounds of Examples exhibit histone deacetylase inhibitory activity, and in particular, the compounds of Examples 12 to 39 in which the group X is —CONH— or —NHCO— have extremely high activity. It was high and had an activity equal to or higher than that of the compound of Reference Example 6 which is a known histone deacetylase inhibitor.

試験例２（ヒストン脱アセチル化酵素阻害活性の評価）
現在までにヒストン脱アセチル化酵素として同定されているＨＤＡＣ１〜１１（Ｃａｎｃｅｒ Ｌｅｔｔｅｒｓ ２７７（２００９）８−２１を参照）をそれぞれ単独で用いて、実施例１２、１３、２３、２４、３６及び参考例６で得られた化合物１２、１３、２３、２４、３６及び４９について、それぞれのＨＤＡＣ１〜１１に対するこれらの化合物の５０％阻害濃度（ＩＣ50値）を測定した。５０％阻害濃度（ＩＣ５０値）は、測定キットとしてＰｒｏｍｅｇａ社製のＨＤＡＣ−ＧｌｏTM Ｉ／ＩＩ Ａｓｓａｙ ａｎｄ Ｓｃｒｅｅｎｉｎｇ Ｓｙｓｔｅｍ Ｇ６４２０を用い、ヒトＨＤＡＣ１〜１１（Ｓｉｎｇａｌ Ｃｈｅｍ社製）の最終濃度がそれぞれ２．０８３３ｎｇ／５０ｍｌμｌとなるようにして、ヒストン脱アセチル化酵素阻害活性に基づき算出した（ｎ＝３以上）。 Test Example 2 (Evaluation of histone deacetylase inhibitory activity)
Examples 12, 13, 23, 24, 36 and Reference Examples using HDAC1-11 (see Cancer Letters 277 (2009) 8-21), which have been identified as histone deacetylases, to date alone With respect to the compounds 12, 13, 23, 24, 36 and 49 obtained in 6, the 50% inhibitory concentrations (IC 50 values) of these compounds against the respective HDACs 1 to 11 were measured. The 50% inhibitory concentration (IC50 value) was determined by using HDAC-Glo ™ I / II Assay and Screening System G6420 manufactured by Promega as a measurement kit. / 50 ml μl was calculated based on histone deacetylase inhibitory activity (n = 3 or more).

得られた結果を表１６に示す。試験例２の結果から、基Ｘが−ＣＯＮＨ−及び−ＮＨＣＯ−で表される構造を有する場合、ＨＤＡＣ１、ＨＤＡＣ２、及びＨＤＡＣ８に高い活性を有することが分かる。
The obtained results are shown in Table 16. From the results of Test Example 2, it can be seen that when the group X has a structure represented by -CONH- and -NHCO-, HDAC1, HDAC2, and HDAC8 have high activity.

Claims (13)

下記一般式（Ａ）で表されるヒドロキサム酸誘導体またはその塩。
［一般式（Ａ）中、基Ａは、酸素原子、窒素原子、または−ＮＲ6−である。
基Ａが酸素原子または−ＮＲ6−であるときは、複素環の１位の基Ａと２位の炭素原子との結合は単結合であり、基Ａが窒素原子であるときは、前記複素環の１位の炭素原子と２位の炭素原子との結合は二重結合である。基Ｒ6は、置換基を有していてもよい低級アルキル基、または水素原子である。
基Ｂは、酸素原子または置換基を有していてもよい低級アルコキシ基であり、基Ｂが酸素原子であるときは、基Ｂと前記複素環の２位の炭素原子との結合は二重結合であり、基Ｂが置換基を有していてもよい低級アルコキシ基であるときは、基Ｂと前記複素環の２位の炭素原子との結合は単結合である。
基Ｒ1及び基Ｒ3は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であるか、基Ｒ1及び基Ｒ3のいずれか一方は基Ｘと置換している。
基Ｒ2及び基Ｒ4は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であるか、互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成している。
基Ｒn 5は、前記複素環が縮合しているベンゼン環上の水素原子と置換したｎ＝０〜３個の置換基であり、それぞれ独立に、ハロゲン原子または置換基を有していてもよい低級アルキル基である。
基Ｘは、前記ベンゼン環上の水素原子、前記複素環上の水素原子、または基Ｒ1及び基Ｒ3のいずれか一方と置換しており、基Ｘは、単結合、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−である。
基Ｙは、単結合、飽和もしくは不飽和の炭素数１〜１０のアルキレン基、または基−Ｙ1−Ｙ2−Ｙ3−である。基Ｙ1は、飽和もしくは不飽和の炭素数１〜６のアルキレン基、または単結合である。基Ｙ2は、置換基を有していてもよいフェニレン基、置換基を有していてもよいシクロヘキシレン基である。基Ｙ3は、飽和もしくは不飽和の炭素数１〜６のアルキレン基である。］ A hydroxamic acid derivative represented by the following general formula (A) or a salt thereof.
[In the general formula (A), the group A is an oxygen atom, a nitrogen atom, or —NR 6 —.
When the group A is an oxygen atom or —NR 6 —, the bond between the first-position group A and the second-position carbon atom of the heterocyclic ring is a single bond, and when the group A is a nitrogen atom, The bond between the carbon atom at the 1st position and the carbon atom at the 2nd position of the ring is a double bond. The group R 6 is a lower alkyl group which may have a substituent, or a hydrogen atom.
The group B is an oxygen atom or an optionally substituted lower alkoxy group. When the group B is an oxygen atom, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is double. When it is a bond and the group B is an optionally substituted lower alkoxy group, the bond between the group B and the carbon atom at the 2-position of the heterocyclic ring is a single bond.
The group R 1 and the group R 3 are each independently a hydrogen atom or an optionally substituted lower alkyl group, or either the group R 1 or the group R 3 is substituted with the group X. Yes.
The group R 2 and the group R 4 are each independently a hydrogen atom or a lower alkyl group which may have a substituent, or bonded to each other to form a 3-position carbon atom and a 4-position carbon. It forms a double bond with the atom.
The group R n 5 is n = 0 to 3 substituents substituted with hydrogen atoms on the benzene ring to which the heterocycle is condensed, and each independently has a halogen atom or a substituent. A good lower alkyl group.
The group X is substituted with a hydrogen atom on the benzene ring, a hydrogen atom on the heterocyclic ring, or one of the group R 1 and the group R 3 , and the group X is a single bond, an oxygen atom, —CONH -, - NHCO -, - SO 2 NH-, or -NHSO 2 - a.
The group Y is a single bond, a saturated or unsaturated alkylene group having 1 to 10 carbon atoms, or a group —Y 1 —Y 2 —Y 3 —. The group Y 1 is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms, or a single bond. The group Y 2 is an optionally substituted phenylene group or an optionally substituted cyclohexylene group. The group Y 3 is a saturated or unsaturated alkylene group having 1 to 6 carbon atoms. ] 一般式（Ａ）において、基Ｒ1及び基Ｒ3は、それぞれ独立に、水素原子または置換基を有していてもよい低級アルキル基であり、基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、単結合、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−である、請求項１に記載のヒドロキサム酸誘導体またはその塩。 In the general formula (A), the group R 1 and the group R 3 are each independently a hydrogen atom or a lower alkyl group which may have a substituent, and the group X is a hydrogen atom on the benzene ring. substituted and the group X is a single bond, an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO 2 - and is, hydroxamic acid derivative or salt thereof according to claim 1. 下記一般式（Ａ１）で表されるヒドロキサム酸誘導体またはその塩であって、
一般式（Ａ１）において、基Ｒ6は、メチル基または水素原子であり、
基Ｒ1は、水素原子またはメチル基であり、基Ｒ3は、水素原子であり、基Ｒ2は、水素原子またはメチル基であるか、基Ｒ4と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、基Ｒ4は、水素原子であるか、基Ｒ2と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、
基Ｒ5は、水素原子またはフッ素原子であり、
基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、酸素原子、−ＣＯＮＨ−、−ＮＨＣＯ−、−ＳＯ2ＮＨ−、または−ＮＨＳＯ2−であり、
基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基、または基−Ｙ1−Ｙ2−Ｙ3−であり、基Ｙ1は、飽和もしくは不飽和の炭素数２のアルキレン基（−ＣＨ＝ＣＨ−であり、基Ｙ2は、フェニレン基またはシクロヘキシレン基であり、基Ｙ3は、メチレン基である、請求項２に記載のヒドロキサム酸誘導体またはその塩。 A hydroxamic acid derivative represented by the following general formula (A1) or a salt thereof,
In the general formula (A1), the group R 6 is a methyl group or a hydrogen atom,
The group R 1 is a hydrogen atom or a methyl group, the group R 3 is a hydrogen atom, the group R 2 is a hydrogen atom or a methyl group, or is bonded to the group R 4 to form a 3 A carbon atom at the position and a carbon atom at the 4th position, and the group R 4 is a hydrogen atom or bonded to the group R 2 to form a carbon atom at the 3rd position of the heterocyclic ring. Forming a double bond with the 4-position carbon atom,
The group R 5 is a hydrogen atom or a fluorine atom;
Group X is substituted with a hydrogen atom on the benzene ring, the group X represents an oxygen atom, -CONH -, - NHCO -, - SO 2 NH-, or -NHSO 2 - and is,
The group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms, or a group —Y 1 —Y 2 —Y 3 —, and the group Y 1 is a saturated or unsaturated alkylene group having 2 carbon atoms ( a -CH = CH-, group Y 2 is a phenylene group or a cyclohexylene group, group Y 3 is a methylene group, a hydroxamic acid derivative or salt thereof according to claim 2. 下記一般式（Ａ２）で表されるヒドロキサム酸誘導体またはその塩であって、
一般式（Ａ２）において、基Ｒ1は、水素原子またはメチル基であり、基Ｒ3は、水素原子であり、基Ｒ2は、水素原子またはメチル基であるか、基Ｒ4と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、基Ｒ4は、水素原子であるか、基Ｒ2と互いに結合して前記複素環の３位の炭素原子と４位の炭素原子との二重結合を形成しており、
基Ｒ7は、メチル基またはエチル基であり、
基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、酸素原子、−ＣＯＮＨ−、または−ＮＨＣＯ−であり、
基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基である、請求項２に記載のヒドロキサム酸誘導体またはその塩。 A hydroxamic acid derivative represented by the following general formula (A2) or a salt thereof,
In the general formula (A2), the group R 1 is a hydrogen atom or a methyl group, the group R 3 is a hydrogen atom, and the group R 2 is a hydrogen atom or a methyl group, or is bonded to the group R 4. A double bond is formed between the carbon atom at the 3rd position and the carbon atom at the 4th position of the heterocyclic ring, and the group R 4 is a hydrogen atom or bonded to the group R 2 to form the heterocyclic ring. Forming a double bond between the 3-position carbon atom and 4-position carbon atom of
The group R 7 is a methyl group or an ethyl group,
The group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-;
The hydroxamic acid derivative or a salt thereof according to claim 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms. 下記一般式（Ａ３）で表されるヒドロキサム酸誘導体またはその塩であって、
一般式（Ａ３）において、基Ｘは、前記ベンゼン環上の水素原子と置換しており、基Ｘは、酸素原子、−ＣＯＮＨ−、または−ＮＨＣＯ−であり、
基Ｙは、飽和もしくは不飽和の炭素数３〜７のアルキレン基である、請求項２に記載のヒドロキサム酸誘導体またはその塩。 A hydroxamic acid derivative represented by the following general formula (A3) or a salt thereof,
In the general formula (A3), the group X is substituted with a hydrogen atom on the benzene ring, the group X is an oxygen atom, -CONH-, or -NHCO-,
The hydroxamic acid derivative or a salt thereof according to claim 2, wherein the group Y is a saturated or unsaturated alkylene group having 3 to 7 carbon atoms. 請求項１〜５のいずれかに記載のヒドロキサム酸誘導体またはその塩を含有する医薬組成物。   The pharmaceutical composition containing the hydroxamic acid derivative or its salt in any one of Claims 1-5. 請求項１〜５のいずれかに記載のヒドロキサム酸誘導体またはその塩を有効成分とするヒストン脱アセチル化酵素阻害剤。   The histone deacetylase inhibitor which uses the hydroxamic acid derivative in any one of Claims 1-5, or its salt as an active ingredient. 請求項１〜５のいずれかに記載のヒドロキサム酸誘導体またはその塩を有効成分とする抗腫瘍剤。 The antitumor agent which uses the hydroxamic acid derivative in any one of Claims 1-5, or its salt as an active ingredient. 下記一般式（Ａａ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａａ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム１で表される、下記化合物Ｄ１と下記化合物Ｄ２とのカップリング反応により、下記化合物Ｄ３を合成する工程１と、
［スキーム１中、Ｍは、アルキル基またはベンジル基であり、Ｘ1は、ハロゲン原子であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム２で表される、化合物Ｄ３のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム２中、基Ｍは、スキーム１と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａａ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。 A method for producing a hydroxamic acid derivative represented by the following general formula (Aa) or a salt thereof,
[In General Formula (Aa), group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing the following compound D3 by a coupling reaction of the following compound D1 and the following compound D2 represented by the following scheme 1:
[In Scheme 1, M is an alkyl group or a benzyl group, X 1 is a halogen atom, the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are represented by the general formula Same as (A). ]
Step 2 of converting the ester group of the compound D3 represented by the following Scheme 2 to a hydroxamic acid group by reacting with NH 2 OH;
[In the scheme 2, the group M is the same as that in the scheme 1, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Aa) or a salt thereof. 下記一般式（Ａｂ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｂ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム３で表される、下記化合物Ｄ４と下記化合物Ｄ５とのカップリング反応により、化合物Ｄ６を合成する工程１と、
［スキーム３中、Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム４で表される、化合物Ｄ６のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム４中、基Ｍは、スキーム３と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｂ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。 A method for producing a hydroxamic acid derivative represented by the following general formula (Ab) or a salt thereof,
[In the general formula (Ab), the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 1 for synthesizing Compound D6 by a coupling reaction of Compound D4 and Compound D5 shown below in Scheme 3;
[In scheme 3, M is an alkyl group or a benzyl group, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as those in formula (A). ]
Step 2 of converting the ester group of compound D6 represented by the following Scheme 4 to a hydroxamic acid group by reacting with NH 2 OH;
[In the scheme 4, the group M is the same as that in the scheme 3, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ab) or a salt thereof. 下記一般式（Ａｃ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｃ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム５で表される、下記化合物Ｄ７と下記化合物Ｄ８とのカップリング反応により、化合物Ｄ９を合成する工程１と、
［スキーム５中、Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム６で表される、下記化合物Ｄ９のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム６中、基Ｍは、スキーム５と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｃ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。 A method for producing a hydroxamic acid derivative represented by the following general formula (Ac) or a salt thereof,
[In General Formula (Ac), group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
Step 1 for synthesizing Compound D9 represented by the following Scheme 5 by a coupling reaction between Compound D7 and Compound D8,
[In scheme 5, M is an alkyl group or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D9 represented by the following Scheme 6 into a hydroxamic acid group by reacting with NH 2 OH;
[In scheme 6, group M is the same as scheme 5, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ac) or a salt thereof, comprising: 下記一般式（Ａｄ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｄ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム７で表される、下記化合物Ｄ１０と下記化合物Ｄ１１とのカップリング反応により、化合物Ｄ１２を合成する工程１と、
［スキーム７中、基Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム８で表される、下記化合物Ｄ１２のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム８中、基Ｍは、スキーム７と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｄ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。 A method for producing a hydroxamic acid derivative represented by the following general formula (Ad) or a salt thereof,
[In General Formula (Ad), group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
Step 1 of synthesizing Compound D12 represented by the following Scheme 7 by a coupling reaction of Compound D10 and Compound D11 below;
[In Scheme 7, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 2 of converting the ester group of the following compound D12 represented by the following Scheme 8 into a hydroxamic acid group by reacting with NH 2 OH;
[In scheme 8, the group M is the same as in scheme 7, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
A process for producing a hydroxamic acid derivative represented by the general formula (Ad) or a salt thereof, comprising: 下記一般式（Ａｅ）で表されるヒドロキサム酸誘導体またはその塩の製造方法であって、
［一般式（Ａｅ）中、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム９で表される、下記化合物Ｄ１３と下記化合物Ｄ１４とのカップリング反応により、化合物Ｄ１５を合成する工程１と、
［スキーム９中、基Ｍは、アルキル基またはベンジル基であり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
下記スキーム１０で表される、下記化合物Ｄ１５のエステル基をＮＨ2ＯＨと反応させて、ヒドロキサム酸基に変換する工程２と、
［スキーム１０中、基Ｍは、スキーム９と同じであり、基Ａ、基Ｂ、基Ｒ1〜Ｒ4、基Ｒn 5、及び基Ｙは、一般式（Ａ）と同じである。］
を含む、一般式（Ａｅ）で表されるヒドロキサム酸誘導体またはその塩の製造方法。 A method for producing a hydroxamic acid derivative represented by the following general formula (Ae) or a salt thereof,
[In the general formula (Ae), the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Step 1 of synthesizing Compound D15 represented by the following Scheme 9 by a coupling reaction of Compound D13 and Compound D14 below;
[In the scheme 9, the group M is an alkyl group or a benzyl group, and the group A, the group B, the groups R 1 to R 4 , the group R n 5 , and the group Y are the same as those in the general formula (A). ]
Represented by the following Scheme 10, is reacted with NH 2 OH to an ester group of the following compounds D15, and step 2 of converting a hydroxamic acid group,
[In scheme 10, group M is the same as in scheme 9, and group A, group B, groups R 1 to R 4 , group R n 5 , and group Y are the same as in general formula (A). ]
The manufacturing method of the hydroxamic acid derivative represented by general formula (Ae) or its salt containing these.
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