JPWO2002055525A1 - Retinoid active substance - Google Patents

Abstract

Formula (I) having an action of enhancing the physiological action of retinoic acid or a retinoid [R1 represents a hydrogen atom or a C1-6 alkyl group; R2 and R3 represent a hydrogen atom or a C1-6 alkyl group; R4, R5 , And R6 represent a hydrogen atom, a halogen atom, a C1-6 alkyl group or the like; Y represents a phenylene group or a pyridinediyl group; X represents -S- or -N (R7)-(R7 represents a hydrogen atom or C1- 6 represents an alkyl group); Z represents C—R 8 (R 8 represents a hydrogen atom or a halogen atom) or N], for example, (1) Z is N, or (2) R 1 is hydrogen R2 and R3 together with the carbon atom on the benzene ring to which they are attached form a 6-membered ring having one or more C1-4 alkyl groups on the ring. , R4 R5, and R6 are hydrogen atoms, Y is pyridinediyl group, X is -S-, the compound or a salt thereof, Z is is CH.

Description

〔式中、Ｒ^１は水素原子又はＣ_１−６アルキル基を示し；Ｒ^２及びＲ^３はそれぞれ独立に水素原子又はＣ_１−６アルキル基を示すか、あるいはＲ^２及びＲ^３は一緒になってそれらが結合するベンゼン環上の炭素原子とともに５又は６員環を形成してもよく（上記の環は環上に１又は２以上のＣ_１−４アルキル基を有していてもよい）；Ｒ^４、Ｒ^５、及びＲ^６はそれぞれ独立に水素原子、ハロゲン原子、Ｃ_１−６アルキル基、又はハロゲン化Ｃ_１−６アルキル基を示し；Ｙはフェニレン基又はピリジンジイル基を示し；Ｘは−Ｓ−又は−Ｎ（Ｒ^７）−（Ｒ^７は水素原子又はＣ_１−６アルキル基を示す）を示し；ＺはＣ−Ｒ^８（Ｒ^８は水素原子、ハロゲン原子、Ｃ_１−６アルキル基、又はハロゲン化Ｃ_１−６アルキル基を示す）、又はＮを示す〕において、
（１）ＺがＮである化合物又はその塩；
（２）Ｒ^１が水素原子又はＣ_１−６アルキル基であり、Ｒ^２及びＲ^３が一緒になってそれらが結合するベンゼン環上の炭素原子とともに環上に１又は２以上のＣ_１−４アルキル基を有する６員環を形成し、Ｒ^４、Ｒ^５、及びＲ^６が水素原子であり、Ｙがピリジンジイル基であり、Ｘが−Ｓ−であり、ＺがＣＨである化合物又はその塩；
（３）Ｒ^１が水素原子又はＣ_１−６アルキル基であり、Ｒ^２及びＲ^３が一緒になってそれらが結合するベンゼン環上の炭素原子とともに環上に１又は２以上のＣ_１−４アルキル基を有する６員環を形成し、Ｒ^４及びＲ^６が水素原子であり、Ｒ^５がハロゲン原子であり、Ｙがフェニレン基であり、ＺがＣＨである化合物又はその塩；
（４）Ｒ^４、Ｒ^５、Ｒ^６、及びＲ^８のうち少なくとも２以上の基が水素原子以外の基である化合物又はその塩；あるいは
（５）Ｒ^４、Ｒ^５、Ｒ^６、及びＲ^８のうち少なくとも１つの基がハロゲン化Ｃ_１−６アルキル基である化合物又はその塩；
を提供するものである。
別の観点からは、本発明により、上記の化合物又は生理学的に許容されるその塩を有効成分として含む医薬、上記の化合物又は生理学的に許容されるその塩を有効成分として含むレチノイド作用増強剤；及び上記の化合物又は生理学的に許容されるその塩を有効成分として含む核内レセプターリガンド作用増強剤が提供される。
さらに別の観点からは、本発明により、上記の医薬の製造のための上記の化合物又は生理学的に許容されるその塩の使用；ヒトを含む哺乳類動物の体内においてレチノイドの作用を増強する方法であって、上記の化合物又は生理学的に許容されるその塩の有効量をヒトを含む哺乳類動物に投与する工程を含む方法；ヒトを含む哺乳類動物の体内において核内レセプターリガンドの作用を増強する方法であって、上記の化合物又は生理学的に許容されるその塩の有効量をヒトを含む哺乳類動物に投与する工程を含む方法が提供される。
発明を実施するための最良の形態
Ｒ^１は水素原子又はＣ_１−６（炭素数１ないし６の）アルキル基を示す。本明細書において、アルキル基は直鎖状、分枝鎖状、環状、又はそれらの組み合わせのいずれでもよく、アルキル部分を有する置換基（例えばハロゲン化アルキル基など）のアルキル部分についても同様である。アルキル基としては、例えば、メチル基、エチル基、ｎ−プロピル基、イソプロピル基、ｎ−ブチル基、ｓｅｃ−ブチル基、ｔｅｒｔ−ブチル基などを挙げることができ、好ましくはメチル基を用いることができる。
Ｒ^２及びＲ^３は、それぞれ独立に水素原子又はＣ_１−６アルキル基を示す。アルキル基としては、例えば上記に例示したものを用いることができるが、好ましくは、エチル基、イソプロピル基、ｔｅｒｔ−ブチル基などを用いることができる。Ｒ^２及びＲ^３の置換位置は特に限定されず、それぞれ独立に任意の位置に置換することができる。例えば、Ｒ^２及びＲ^３がＸに対してそれぞれパラ位及びメタ位であるか、Ｒ^２及びＲ^３がＸに対してそれぞれメタ位及びオルト位であってもよく、あるいはＲ^２及びＲ^３がＸに対してそれぞれパラ位及びメタ位であってもよい。
また、Ｒ^２及びＲ^３が一緒になって、Ｒ^２及びＲ^３がそれぞれ結合するベンゼン環上の２個の炭素原子とともに、５又は６員環を形成することができる。形成される環は１個または２個以上のＣ_１−４アルキル基を有していてもよく、例えば、２〜４個のメチル基、好ましくは４個のメチル基を有していてもよい。例えば、Ｒ^２及びＲ^３が置換するベンゼン環とＲ^２及びＲ^３とにより、５，６，７，８−テトラヒドロナフタレン環や５，５，８，８−テトラメチル−５，６，７，８−テトラヒドロナフタレン環などが形成されることが好ましい。
Ｒ^４、Ｒ^５、及びＲ^６は、それぞれ独立に水素原子、ハロゲン原子、Ｃ_１−６アルキル基、又はハロゲン化Ｃ_１−６アルキル基を示す。ハロゲン原子としては、フッ素原子、塩素原子、臭素原子、又はヨウ素原子のいずれを用いてもよいが、フッ素原子であることが好ましい。Ｃ_１−６アルキル基としては、例えば上記に例示したものを用いることができるが、好ましくはメチル基、エチル基などである。ハロゲン化アルキル基を構成するハロゲン原子としてはフッ素原子、塩素原子、臭素原子、又はヨウ素原子のいずれでもよいが、フッ素原子又は塩素原子が好ましく、フッ素原子がより好ましい。ハロゲン化アルキル基としては、モノフルオロメチル基、ジフルオロメチル基、トリフルオロメチル基、トリクロロメチル基、ジクロロフルオロメチル基、テトラフルオロエチル基などを挙げることができる。
ＸはＲ^７で置換された窒素原子（−ＮＲ^７−）又は硫黄原子（−Ｓ−）を示す。Ｒ^７は水素原子、Ｃ_１−６アルキル基を示す。Ｃ_１−６アルキル基としては上記に例示したものを用いることができ、例えば、メチル基が好ましい。窒素原子又は硫黄原子はそれぞれＮ−オキシド又はスルホキシドであってもよい。
Ｙはフェニレン基またはピリジンジイル基を示す。例えば、ｐ−フェニレン基、ｍ−フェニレン基、ｏ−フェニレン基、ピリジン−２，４−ジイル基、ピリジン−２，５−ジイル基、ピリジン−３，５−ジイル基など、任意のフェニレン基またはピリジンジイル基を用いることができる。好ましくは、ｐ−フェニレン基またはピリジン−２，５−ジイル基を用いることができる。ピリジン−２，５−ジイル基を用いる場合、ピリジンの２−位または５−位のいずれの位置に−ＣＯＯＲ^１で示される基が置換していてもよい。
本発明の化合物は、上記の式（Ｉ）において、
（１）ＺがＮである化合物；
（２）Ｒ^１が水素原子又はＣ_１−６アルキル基であり、Ｒ^２及びＲ^３が一緒になってそれらが結合するベンゼン環上の炭素原子とともに環上に１又は２以上のＣ_１−４アルキル基を有する６員環を形成し、Ｒ^４、Ｒ^５、及びＲ^６が水素原子であり、Ｙがピリジンジイル基であり、Ｘが−Ｓ−であり、ＺがＣＨである化合物；
（３）Ｒ^１が水素原子又はＣ_１−６アルキル基であり、Ｒ^２及びＲ^３が一緒になってそれらが結合するベンゼン環上の炭素原子とともに環上に１又は２以上のＣ_１−４アルキル基を有する６員環を形成し、Ｒ^４及びＲ^６が水素原子であり、Ｒ^５がハロゲン原子であり、Ｙがフェニレン基であり、ＺがＣＨである化合物；
（４）Ｒ^４、Ｒ^５、Ｒ^６、及びＲ^８のうち少なくとも２以上の基が水素原子以外の基である化合物；あるいは
（５）Ｒ^４、Ｒ^５、Ｒ^６、及びＲ^８のうち少なくとも１つの基がハロゲン化Ｃ_１−６アルキル基である化合物；
のいずれかである。
上記の（１）〜（５）の化合物において、Ｒ^２及びＲ^３は一緒になってそれらが結合するベンゼン環上の炭素原子とともに６員環を形成することが好ましく、上記の環は環上に２〜４個のＣ_１−４アルキル基を有することが好ましい。環上に存在するアルキル基としてはメチル基が好ましい。最も好ましいのは環上に４個のメチル基が存在する場合である。
上記（１）の化合物において、Ｒ^４、Ｒ^５、及びＲ^６は水素原子であることが好ましく、Ｙはフェニレン基であることが好ましく、Ｘは−Ｓ−であることが好ましい。
上記（２）の化合物においてＹが２，５−ピリジンジイル基であることが好ましい。
上記（３）の化合物において、Ｒ^５がフッ素原子であり、Ｙがｐ−フェニレン基であり、Ｘが−Ｎ（Ｒ^７）−（Ｒ^７は水素原子又はメチル基である）又は−Ｓ−であることが好ましい。
上記（４）の化合物において、Ｒ^５及びＲ^８が水素原子以外の基であることが好ましく、さらに好ましいのはＲ^４及びＲ^６がともに水素原子又はハロゲン原子であり、かつＲ^５及びＲ^８が水素原子以外の基である場合である。Ｒ^５及びＲ^８がともにハロゲン原子であることがさらに好ましく、Ｒ^５及びＲ^８がともにフッ素原子である場合が最も好ましい。Ｒ^５、Ｒ^６、Ｒ^７、及びＲ^８がすべてフッ素原子である場合も好ましい。
上記（５）の化合物において、Ｙがフェニレン基であり、Ｘが−Ｓ−であることが好ましい。Ｒ^４、Ｒ^５、Ｒ^６、及びＲ^８のうち少なくとも１つの基がトリフルオロメチル基であることが好ましい。Ｒ^５がトリフルオロメチル基である場合がさらに好ましく、さらに好ましいのはＲ^５がトリフルオロメチル基であり、かつＲ^４、Ｒ^６、及びＲ^８が水素原子の場合である。
本発明の化合物は、酸付加塩または塩基付加塩として存在する場合があり、塩の形態の物質も本発明の範囲に包含される。酸付加塩としては、塩酸塩若しくは臭化水素酸塩などの鉱酸塩、又はｐ−トルエンスルホン酸塩、メタンスルホン酸塩、シュウ酸塩、若しくは酒石酸塩などの有機酸塩を挙げることができる。塩基付加塩はＲ^１が水素原子を示す場合に形成され、ナトリウム塩、カリウム塩、マグネシウム塩、若しくはカルシウム塩などの金属塩、アンモニウム塩、又はトリエチルアミン塩若しくはエタノールアミン塩などの有機アミン塩などを挙げることができる。
本発明の化合物は、置換基の種類に応じて１個または２個以上の不斉炭素を有する場合があるが、このような不斉炭素に基づく純粋な形態の光学異性体やジアステレオ異性体などの立体異性体のほか、立体異性体の任意の混合物、ラセミ体などはいずれも本発明の範囲に包含される。また、遊離化合物又は塩の形態の化合物の任意の水和物又は溶媒和物も本発明の範囲に包含されることはいうまでもない。
本発明の化合物の製造方法は特に限定されないが、例えば特開平１０−５９９５１号公報に記載された製造方法に準じて製造することができる。本明細書の実施例には、本発明の化合物の製造方法が具体的かつ詳細に説明されているので、上記の刊行物及び本明細書の実施例を参照しつつ、これらの方法において用いられた出発原料、試薬、及び反応条件などを適宜変更し、必要に応じてこれらの方法に適宜の修飾ないし改変を加えることにより、本発明の範囲に包含される化合物をいずれも製造可能である。
本発明の化合物は、それ自体はレチノイド様の作用を実質的に有していないか、あるいは微弱又は中程度のレチノイド様作用を有する化合物であるが、本発明の化合物をレチノイン酸などのレチノイドと共存させた場合には、レチノイドの生理活性（代表的なものとして細胞分化作用、細胞増殖促進作用、及び生命維持作用など）が顕著に増強される。いかなる特定の理論に拘泥するわけではないが、本発明の化合物はレチノイドレセプター（本明細書において用いられる「レチノイドレセプター」という用語は、レチノイン酸レセプターＲＡＲ及びＲＸＲを包含しており、レチノイン酸などのレチノイドが相互作用可能なレセプターの１種又は２種以上を意味している。）に対して相互作用することができ、それ自体がアゴニストとしてレチノイド様の生理活性を発揮するか、あるいはレチノイドの生理活性を増強する作用を有している。また、いかなる特定の理論に拘泥するわけではないが、本発明の化合物自体がレチノイド作用を有する場合には、その作用は相乗的作用である。
従って、本発明の化合物は、レチノイン酸やレチノイン酸様の生物活性を有する上記化合物（例えば、４−［（５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチル−２−ナフタレニル）カルバモイル］安息香酸：Ａｍ８０など）と同様にビタミンＡ欠乏症、上皮組織の角化症、乾癬、アレルギー疾患、リウマチなどの免疫性疾患、骨疾患、白血病、糖尿病、又は癌などの疾患の予防・治療のための医薬として投与することができ、あるいはレチノイドを上記の疾患の予防・治療のために投与するに際して本発明の化合物を該レチノイドの作用増強剤として用いることができる。
また、本発明の化合物は、レチノイドを上記疾患の治療・予防のために投与しない場合においても、生体内に既に存在するレチノイン酸の作用を増強するので、上記疾患の治療・予防の目的で本発明の化合物自体を投与することも可能である。さらに、本発明の化合物は、レチノイドに対しての作用増強効果のみならず、細胞の核内に存在する核内レセプター・スーパーファミリー（Ｅｖａｎｓ，Ｒ．Ｍ．，Ｓｃｉｅｎｃｅ，２４０，ｐ．８８９，１９８８）に属するレセプターに結合して生理作用を発揮するステロイド化合物、ビタミンＤ_３などのビタミンＤ化合物、又はチロキシンなどの生理活性物質の作用増強に用いることもできる。
本発明の化合物又は生理学的に許容されるその塩からなる医薬は、それ自体を投与してもよいが、好ましくは、当業者に周知の方法によって製造可能な経口用あるいは非経口用の医薬組成物として投与することが好ましい。また、レチノイン酸などのレチノイドを有効成分として含む医薬に配合して、いわゆる合剤の形態の医薬組成物として用いることもできる。経口投与に適する医薬用組成物としては、例えば、錠剤、カプセル剤、散剤、細粒剤、顆粒剤、液剤、及びシロップ剤等を挙げることができ、非経口投与に適する医薬組成物としては、例えば、注射剤、坐剤、吸入剤、点眼剤、点鼻剤、軟膏剤、クリーム剤、経皮吸収剤、経粘膜吸収剤、及び貼付剤等を挙げることができる。本発明の医薬の有効成分としては、遊離形態の化合物又は生理学的に許容されるその塩のほか、その水和物や溶媒和物を用いてもよい。
上記の医薬組成物は、薬理学的、製剤学的に許容しうる添加物を加えて製造することができる。薬理学的、製剤学的に許容しうる添加物の例としては、例えば、賦形剤、崩壊剤ないし崩壊補助剤、結合剤、滑沢剤、コーティング剤、色素、希釈剤、基剤、溶解剤ないし溶解補助剤、等張化剤、ｐＨ調節剤、安定化剤、噴射剤、及び粘着剤等を挙げることができる。本発明の医薬の有効成分としては、遊離形態の化合物及び生理学的に許容されるその塩、並びにそれらの水和物及びそれらの溶媒和物からなる群から選ばれる１または２種以上の物質を用いることができる。
本発明の医薬の投与量は特に限定されず、レチノイン酸などのレチノイドを有効成分として含む医薬と本発明の医薬とを併用してレチノイドの作用を増強する場合、あるいは、レチノイドを含む医薬を併用せずに、生体内に既に存在するレチノイン酸の作用増強のために本発明の医薬を投与する場合など、あらゆる投与方法において適宜の投与量が容易に選択できる。例えば、経口投与の場合には成人一日あたり０．０１〜１，０００ｍｇ程度の範囲で用いることができる。レチノイドを有効成分として含む医薬と本発明の医薬とを併用する場合には、レチノイドの投与期間中、あるいはその前後のいずれの期間においても本発明の医薬を投与することが可能である。
実施例
以下、本発明を実施例によりさらに具体的に説明するが、本発明の範囲は下記の実施例の範囲に限定されることはない。なお、実施例中の化合物番号は、下記のスキーム中の化合物番号に対応している。
例１：ＨＸ９００の合成

ＮａＨ（３５１ｍｇ，８．７８ｍｍｏｌ）の乾燥ジメチルホルムアミド（ＤＭＦ，２５ｍＬ）懸濁液に、塩−氷浴冷却下０−５℃で５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチルナフタレン−２−チオール（化合物１−１：Ｊ．Ｍｅｄ．Ｃｈｅｍ．，３８，ｐｐ．３１６３−３１７３，１９９５，１．９３５ｇ，８．７８ｍｍｏｌ）の乾燥ＤＭＦ（５ｍＬ）溶液を滴下した。室温まで徐々に昇温し１時間攪拌後、塩−氷浴冷却下０−５℃で２−クロロ−３−ニトロピリジン（１．３２５ｇ，８．３６ｍｍｏｌ）の乾燥ＤＭＦ（５ｍＬ）溶液を滴下した。室温まで徐々に昇温し２時間攪拌した後、反応液を水にあけ酢酸エチルで抽出した。有機相を水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４０／１）で精製し化合物１−２（２．７５５ｇ，９６．２％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ８．５２（ｄｄ，１Ｈ，Ｊ＝１．８，４．８Ｈｚ），８．４８（ｄｄ，１Ｈ，Ｊ＝１．８，８．４Ｈｚ），７．４６（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ），７．３７（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），７．２９（ｄｄ，１Ｈ，Ｊ＝１．８，８．４Ｈｚ），７．１７（ｄｄ，１Ｈ，Ｊ＝４．５，８．１Ｈｚ），１．７１（ｓ，４Ｈ），１．３２（ｓ，６Ｈ），１．２８（ｓ，６Ｈ）．
化合物１−２（２．６８７ｇ，７．８５ｍｍｏｌ）をエタノール（２．６ｍＬ）および水（２．６１ｍＬ）に懸濁し、濃塩酸（６．５ｍＬ）を加えた。この混合物に鉄粉（２．１９２ｇ，３９．２５ｍｍｏｌ）を加えて１時間加熱還流した。室温まで冷却後、反応液をＮａＯＨ（１０．０ｇ，２５０ｍｍｏｌ）、ジクロルメタン（１２５ｍＬ）および水（２５０ｍＬ）の混合液にあけ、セライト１５ｇを加えて攪拌した後セライト濾過した。濾液の水相をジクロルメタンで抽出し、合わせた有機相を水および飽和食塩水で洗浄しＮａ_２ＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝３／１）で精製し化合物１−３（１．０５６ｇ，４３．０％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ８．２０（ｄｄ，１Ｈ，Ｊ＝１．５，４．５Ｈｚ），７．２７（ｄ，１Ｈ，Ｊ＝２．４Ｈｚ），７．１９（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），７．０６（ｄｄ，１Ｈ，Ｊ＝４．５，７．８Ｈｚ），７．００（ｄｄ，２Ｈ，Ｊ＝１．８，８．１Ｈｚ），４．２０（ｂｒｓ，２Ｈ），１．６４（ｓ，４Ｈ），１．２３（ｓ，６Ｈ），１．２１（ｓ，６Ｈ）．
化合物１−３（１８３ｍｇ，０．５８６ｍｍｏｌ）およびトリエチルアミン（６５．２ｍｇ，０．６４５ｍｍｏｌ）を乾燥ジクロルメタン（５ｍＬ）に溶解し、塩−氷浴冷却下０−５℃でテレフタル酸モノメチルクロライド（１２８ｍｇ，０．６４５ｍｍｏｌ）の乾燥ジクロルメタン（２ｍＬ）溶液を滴下した。室温まで徐々に昇温し１５時間攪拌した。反応液をジクロルメタンで希釈し、水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５／１）で精製し化合物１−４（２１６ｍｇ，７７．７％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ８．８４（ｂｒｓ　ａｎｄ　ｄｄ，１Ｈ＋１Ｈ，Ｊ＝１．５，８．４Ｈｚ），８．３８（ｄｄ，１Ｈ，Ｊ＝１．５，４．５Ｈｚ），８．１２（ｄ，２Ｈ，Ｊ＝８．４Ｈｚ），７．７４（ｄ，２Ｈ，Ｊ＝８．７Ｈｚ），７．３５（ｄｄ，１Ｈ，Ｊ＝４．５，８．１Ｈｚ），７．２６（ｄ，１Ｈ，Ｊ＝１．５Ｈｚ），７．２３（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），７．０４（ｄｄ，１Ｈ，Ｊ＝１．８，８．４Ｈｚ），３．９６（ｓ，３Ｈ），１．６３（ｓ，４Ｈ），１．２１（ｓ，６Ｈ），１．１５（ｓ，６Ｈ）．
化合物１−４（１９２ｍｇ，０．４０５ｍｍｏｌ）をジクロルメタン（１ｍＬ）に溶解しポリリン酸（ＰＰＡ，４．５０ｇ）を加え１２０℃で１時間加熱攪拌した。反応液に水を加えジクロルメタンで抽出した。有機相を水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４／１）で精製し化合物１−５（９３．４ｍｇ，５０．５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ８．３２（ｄｄ，１Ｈ，Ｊ＝１．８，４．５Ｈｚ），８．１１（ｄ，２Ｈ，Ｊ＝８．７Ｈｚ），７．９０（ｄ，２Ｈ，Ｊ＝８．７Ｈｚ），７．６６（ｄｄ，１Ｈ，Ｊ＝１．８，８．１Ｈｚ），７．５７（ｓ，１Ｈ），７．２９（ｄｄ，１Ｈ，Ｊ＝４．５，８．４Ｈｚ），７．０８（ｓ，１Ｈ），３．９６（ｓ，３Ｈ），１．６６（ｓ，４Ｈ），１．３１（ｓ，３Ｈ），１．２８（ｓ，３Ｈ），１．１５（ｓ，３Ｈ），１．０９（ｓ，３Ｈ）．
化合物１−５（８０．８ｍｇ，０．１７５ｍｍｏｌ）をテトラヒドロフラン（ＴＨＦ，３ｍＬ）およびＭｅＯＨ（１ｍＬ）に溶解し２Ｎ　ＮａＯＨ（０．８８ｍＬ，１．７６ｍＬ）を加え室温で２時間加熱攪拌した。反応液を減圧下濃縮し残渣に２Ｎ　ＨＣｌ（１ｍＬ）を加えた後水で希釈し酢酸エチルで抽出した。有機相を水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去しＨＸ９００（７１．０ｍｇ，９１．７％）を得た。トルエンから再結晶して精製体を得た。ｍ．ｐ．＞３００℃。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ８．３１（ｄｄ，１Ｈ，Ｊ＝１．５，４．５Ｈｚ），８．０６（ｄ，２Ｈ，Ｊ＝８．４Ｈｚ），７．８４（ｄ，２Ｈ，Ｊ＝８．４Ｈｚ），７．７７（ｄｄ，１Ｈ，Ｊ＝１．５，８．１Ｈｚ），７．５９（ｓ，１Ｈ），７．４７（ｄｄ，１Ｈ，Ｊ＝４．５，８．１Ｈｚ），７．１９（ｓ，１Ｈ），１．６３（ｓ，４Ｈ），１．２８（ｓ，６Ｈ），１．１４（ｓ，３Ｈ），１．０７（ｓ，３Ｈ）．
例２：ＨＸ９０１の合成

２−［（５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチル−２−ナフチル）チオ］アニリン（化合物２−１：Ｊ．Ｍｅｄ．Ｃｈｅｍ．，４０，ｐｐ．４２２２−４２４３，１９９７，２１８ｍｇ，０．７０ｍｍｏｌ）および５−エチル−２，５−ピリジンジカルボキシレート（Ｎｉｐｐｏｎ　Ｋａｇａｋｕ　Ｚａｓｓｈｉ，８８，ｐｐ．５５３−５５６，１９６７，２７３ｍｇ，１．４０ｍｍｏｌ）の乾燥ジクロルメタン（３．５ｍＬ）懸濁液に塩酸１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（２６９ｍｇ，１．４０ｍｍｏｌ）を加え室温で４時間攪拌した。反応液をジクロルメタンで希釈し、水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝５／１）で精製し化合物２−２（３０６ｍｇ，８９．５％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ１１．１４（ｂｒｓ，１Ｈ），９．２０（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ），８．６６（ｄｄ，１Ｈ，Ｊ＝１．２，８．１Ｈｚ），８．４６（ｄｄ，１Ｈ，Ｊ＝１．８，８．１Ｈｚ），８．３１（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），７．６５（ｄｄ，１Ｈ，Ｊ＝１．８，７．５Ｈｚ），７．４３−７．４９（ｍ，１Ｈ），７．２６−７．２７（ｍ，１Ｈ），７．１３−７．１８（ｍ，１Ｈ），７．１２（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），６．９５（ｄｄ，１Ｈ，Ｊ＝１．８，８．１Ｈｚ），４．４５（ｑ，２Ｈ，Ｊ＝７．２Ｈｚ），１．５９（ｓ，４Ｈ），１．４４（ｔ，３Ｈ，Ｊ＝７．２Ｈｚ），１．１６（ｓ，６Ｈ），１．１２（ｓ，６Ｈ）．
化合物２−２（２８０ｍｇ，０．５７２ｍｍｏｌ）をジクロルメタン（１ｍＬ）に溶解し、ＰＰＡ（５．２８ｇ）を加え１２０℃で４時間加熱攪拌した。反応液に水を加え酢酸エチルで抽出した。有機相を水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ジクロルメタン／メタノール／酢酸＝３８０／２０／１）で精製しＨＸ９０１（１５３ｍｇ，６０．４％）を得た。トルエンから再結晶して精製体を得た。ｍ．ｐ．２８３℃。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）δ９．０３（ｄｄ，１Ｈ，Ｊ＝１．２，２．１Ｈｚ），８．５１（ｄｄ，１Ｈ，Ｊ＝１．２，８．１Ｈｚ），８．４７（ｄｄ，１Ｈ，Ｊ＝２．１，８．４Ｈｚ），７．５２（ｄｄ，１Ｈ，Ｊ＝０．９，７．８Ｈｚ），７．４６（ｓ，１Ｈ），７．３７−７．４４（ｍ，２Ｈ），７．２０−７．２６（ｍ，１Ｈ），７．１５（ｓ，４Ｈ），１．６１（ｓ，４Ｈ），１．２６（ｓ，６Ｈ），１．１３（ｓ，３Ｈ），１．０４（ｓ，３Ｈ）．
例３：ＨＸ９０２の合成

２−［（５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチル−２−ナフチル）チオ］アニリン（化合物２−１，２０２ｍｇ，０．６５ｍｍｏｌ）および２−エチル−２，５−ピリジンジカルボキシレート（Ｎｉｐｐｏｎ　Ｋａｇａｋｕ　Ｚａｓｓｈｉ，８８，ｐｐ．５５３−５５６，１９６７，２５３ｍｇ，１．３０ｍｍｏｌ）の乾燥ジクロルメタン（３．５ｍＬ）懸濁液に塩酸１−（３−ジメチルアミノプロピル）−３−エチルカルボジイミド（２４９ｍｇ，１．３０ｍｍｏｌ）を加え室温で１５時間攪拌した。反応液をジクロルメタンで希釈、水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣をシリカゲルカラムクロマトグラフィー（ヘキサン／酢酸エチル＝４／１）で精製し化合物３−２（３００ｍｇ，９４．４％）を得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ９．１０（ｂｒｓ，１Ｈ），９．０３（ｄ，１Ｈ，Ｊ＝２．４Ｈｚ），８．６２（ｄ，１Ｈ，Ｊ＝８．４Ｈｚ），８．１５（ｄ，１Ｈ，Ｊ＝７．８Ｈｚ），７．９９（ｄｄ，１Ｈ，Ｊ＝２．４，８．１Ｈｚ），７．６７（ｄｄ，１Ｈ，Ｊ＝１．５，７．８Ｈｚ），７．４９−７．５５（ｍ，１Ｈ），７．２２（ｄｄ，１Ｈ，Ｊ＝１．５，７．８Ｈｚ），７．１８（ｄ，１Ｈ，Ｊ＝８．１Ｈｚ），７．０７（ｄ，１Ｈ，Ｊ＝１．８Ｈｚ），６．８１（ｄｄ，１Ｈ，Ｊ＝２．１，８．４Ｈｚ），４．５０（ｑ，２Ｈ，Ｊ＝７．２Ｈｚ），１．６１（ｓ，４Ｈ），１．４６（ｔ，３Ｈ，Ｊ＝７．２Ｈｚ），１．１９（ｓ，６Ｈ），１．１３（ｓ，６Ｈ）．
化合物３−２（２５８ｍｇ，０．５２７ｍｍｏｌ）をジクロルメタン（１ｍＬ）に溶解し、ＰＰＡ（６．０５ｇ）を加え１２０℃で４時間加熱攪拌した。反応液に水を加え酢酸エチルで抽出した。有機相を水および飽和食塩水で洗浄しＭｇＳＯ_４で乾燥後溶媒を減圧留去した。得られた残渣（１４０ｍｇ）をヘキサン−酢酸エチルから再結晶してＨＸ９０２（１１０ｍｇ，４７．２％）を得た。ｍ．ｐ．１５４−１５５℃。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）δ９．０７（ｄｄ，１Ｈ，Ｊ＝０．９，２．１Ｈｚ），８．３７（ｄｄ，１Ｈ，Ｊ＝２．１，８．１Ｈｚ），８．２８（ｄｄ，１Ｈ，Ｊ＝０．９，７．８Ｈｚ），７．４８−７．５３（ｍ，１Ｈ），７．４７（ｓ，１Ｈ），７．３７−７．３８（ｍ，２Ｈ），７．１４−７．２０（ｍ，１Ｈ），７．０１（ｓ，１Ｈ），１．６６（ｓ，４Ｈ），１．３１（ｓ，３Ｈ），１．２９（ｓ，３Ｈ），１．１６（ｓ，３Ｈ），１．０８（ｓ，３Ｈ）．
例４：ＨＸ９０３の合成

６−ブロモ−１，２，３，４−テトラヒドロ−１，１，４，４−テトラメチルナフタレン１．００ｇ（３．７４ｍｍｏｌ）、４−フルオロ−２−ニトロアニリン（化合物４−１ａ）０．５８ｇ（３．７１ｍｍｏｌ）、Ｋ_２ＣＯ_３　０．５７ｇ（４．１２ｍｍｏｌ）、ＣｕＩ　０．０４ｇ（０．２１ｍｍｏｌ）にｏ−キシレン２０ｍＬを加え、９時間加熱還流した。減圧下にキシレンを留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：１５）で精製し、化合物４−２ａを得た（１．０４ｇ，８１％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）９．３５（ｓ，１Ｈ），７．９０（ｄｄ，Ｊ＝９．２，２．４Ｈｚ，１Ｈ），７．３３（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．１４−７．２１（ｍ，３Ｈ），７．０１（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），１．７１（ｓ，４Ｈ），１．３０（ｓ，６Ｈ），１．２８（ｓ，６Ｈ）
ＮａＨ（６０％　ｉｎ　ｏｉｌ）０．１８ｇ（４．５ｍｍｏｌ）をｎ−ヘキサンで洗い、ＤＭＦ　３ｍＬに懸濁し、氷浴で冷却した後、化合物４−２ａ　１．０４ｇ（３．０３ｍｍｏｌ）を３０ｍＬのＤＭＦに溶解して加え、室温で３０分間撹拌した。この混合物にＣＨ_３Ｉ　０．４ｍＬ（６．４２ｍｍｏｌ）を加えて５時間撹拌した。反応混合物を氷水にあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、化合物４−３ａを得た（１．０５ｇ，９８％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．５７（ｄｄ，Ｊ＝７．６，２．８Ｈｚ，１Ｈ），７．３５（ｄｄ，Ｊ＝９．２，４．８Ｈｚ，１Ｈ），７．２９（ｍ，１Ｈ），７．１２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．５８（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），６．５１（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），３．２５（ｓ，３Ｈ），１．６３（ｓ，４Ｈ），１．２２（ｓ，６Ｈ），１．１８（ｓ，６Ｈ）
化合物４−３ａ　１．０５ｇ（２．９８ｍｍｏｌ）を酢酸エチル３０ｍＬに溶解し、１０％　Ｐｄ／Ｃ　０．１ｇを加え、水素雰囲気下１時間激しく撹拌した。反応混合物をセライトを通して濾過し、溶媒を減圧留去した。得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：１０）で精製し、化合物４−４ａを得た（０．６１ｇ，６３％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．１１（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），６．９７（ｄｄ，Ｊ＝８．４，６．０Ｈｚ，１Ｈ），６．５８（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），６．５０（ｄｄ，Ｊ＝１０．４，２．８Ｈｚ，１Ｈ），６．４３（ｄｄ，Ｊ＝８．８，２．４Ｈｚ，１Ｈ），６．４１（ｄｄ，Ｊ＝６．０，２．８Ｈｚ，１Ｈ），３．９５（ｂｒｓ，２Ｈ），３．１４（ｓ，３Ｈ），１．６５（ｓ，４Ｈ），１．２３（ｓ，６Ｈ），１．２２（ｓ，６Ｈ）
化合物４−４ａ　０．６１ｇ（１．８７ｍｍｏｌ）を乾燥ベンゼン１５ｍＬに溶解し、ピリジン１．５ｍＬを加えた。氷浴で冷却後、テレフタル酸モノメチルエステルクロリド０．４１ｇ（２．０６ｍｍｏｌ）を加え、室温で１６時間撹拌した。反応混合物を２Ｎ　ＨＣｌにあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：４）で精製し、化合物４−５ａを得た（０．９１ｇ，ｑｕａｎｔ）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．５８（ｂｒｓ，１Ｈ），８．４４（ｄｄ，Ｊ＝１０．８，２．８Ｈｚ，１Ｈ），８．００（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．４８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．２１（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），７．１８（ｄｄ，Ｊ＝８．８，５．６Ｈｚ，１Ｈ），６．８７（ｄｔ，Ｊ＝８．０，３．２Ｈｚ，１Ｈ），６．６５（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），６．５７（ｄｄ，Ｊ＝８．８，２．８Ｈｚ，１Ｈ），３．９３（ｓ，３Ｈ），３．２７（ｓ，３Ｈ），１．６５（ｓ，４Ｈ），１．２５（ｓ，６Ｈ），１．１７（ｓ，６Ｈ）
化合物４−５ａ　０．９１ｇ（１．８６ｍｍｏｌ）を少量の乾燥ジクロロメタンに溶解し、ＰＰＡ　１０ｇを加えて１１０℃で１時間撹拌した。冷却後、反応混合物に氷水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：４）で精製し、化合物４−６ａを得た（０．７１ｇ，８１％）
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．０８（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．８６（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．０１（ｄｄ，Ｊ＝９．６，２．８Ｈｚ，１Ｈ），６．９２（ｓ，１Ｈ），６．８８（ｓ，１Ｈ），６．８１−６．６９（ｍ，２Ｈ），３．９５（ｓ，３Ｈ），３．２３（ｓ，３Ｈ），１．６３−１．６８（ｍ，４Ｈ），１．３２（ｓ，３Ｈ），１．２７（ｓ，３Ｈ），１．１３（ｓ，３Ｈ），１．０５（ｓ，３Ｈ）
化合物４−６ａ　０．７１ｇ（１．５０ｍｍｏｌ）をエタノール１０ｍＬ及び２０％　ＮａＯＨ　２ｍＬに懸濁し、室温で５時間撹拌した。反応混合物を酸性にした後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をエタノールから再結晶することによりＨＸ９０３を得た（０．６２ｇ，９０％）。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）１３．１（ｂｒｓ，１Ｈ），８．０２（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．７８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），６．９８−７．０９（ｍ，４Ｈ），６．８６（ｓ，１Ｈ），３．１９（ｓ，３Ｈ），１．５９−１．６１（ｍ，４Ｈ），１．２９（ｓ，３Ｈ），１．２５（ｓ，３Ｈ），１．１０（ｓ，３Ｈ），１．０１（ｓ，３Ｈ）
Ａｎａｌ．Ｃａｌｃｄ　ｆｏｒ　Ｃ_２９Ｈ_２９ＦＮ_２Ｏ_２，Ｃ：７６．２９％，Ｈ：６．４０％，Ｎ：６．１４％；Ｆｏｕｎｄ　Ｃ：７６．００％，Ｈ：６．３９％，Ｎ：６．０２％
例５：ＨＸ９０４の合成
６−ブロモ−１，２，３，４−テトラヒドロ−１，１，４，４−テトラメチルナフタレン１．５３ｇ（７．５２ｍｍｏｌ）、２，４−ジフルオロ−６−ニトロアニリン（化合物４−１ｂ）１．００ｇ（５．７４ｍｍｏｌ）、Ｋ_２ＣＯ_３　０．９０ｇ（６．５１ｍｍｏｌ）、ＣｕＩ　０．０５５ｇ（０．２９ｍｍｏｌ）にｏ−キシレン２０ｍＬ　を加え、２４時間加熱還流した。減圧下にキシレンを留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：５０→１：１０）で精製し、化合物４−２ｂを得た（１．８２ｇ，８８％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．５４（ｂｒｓ，１Ｈ），７．７５（ｄｄｄ，Ｊ＝８．４，３．２，２．０Ｈｚ，１Ｈ），７．２２（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．１４（ｄｄｄ，Ｊ＝１１．２，７．６，３．２Ｈｚ，１Ｈ），６．８８（ｄｄ，Ｊ＝２．８，２．４Ｈｚ，１Ｈ），６．７４（ｄｄｄ，Ｊ＝８．４，２．８，２．４Ｈｚ，１Ｈ），１．６８（ｓ，４Ｈ），１．２７（ｓ，６Ｈ），１．２５（ｓ，６Ｈ）
ＮａＨ（６０％　ｉｎ　ｏｉｌ）０．３３ｇ（８．３ｍｍｏｌ）をｎ−ヘキサンで洗い、ＤＭＦ　５ｍＬに懸濁し、化合物４−２ｂ　１．９７ｇ（５．４７ｍｍｏｌ）を４０ｍＬのＤＭＦに溶解して加え、室温で、３０分間撹拌した。この混合物にＣＨ_３Ｉ　０．７ｍＬ（１１．２ｍｍｏｌ）を加えて室温で１時間撹拌した。反応混合物を氷水にあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：７）で精製し、化合物４−３ｂを得た（２．０４ｇ，ｑｕａｎｔ）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．３９（ｄｄｄ，Ｊ＝７．６，３．２，２．０Ｈｚ，１Ｈ），７．１８（ｄｄｄ，Ｊ＝９．６，８．０，２．８Ｈｚ，１Ｈ），７．１１（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），６．４７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），６．４１（ｄｄ，Ｊ＝８．８，２．８Ｈｚ，１Ｈ），３．２４（ｓ，３Ｈ），１．６３（ｓ，４Ｈ），１．２２（ｓ，６Ｈ），１．１８（ｓ，６Ｈ）
化合物４−３ｂ　２．０４ｇ（５．４４ｍｍｏｌ）を酢酸エチル３０ｍＬに溶解し、１０％　Ｐｄ／Ｃ　０．８ｇを加え、水素雰囲気下１３時間激しく撹拌した。反応混合物をセライトを通して濾過し、溶媒を減圧留去し、化合物４−４ｂを得た（１．１９ｇ，６３％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．１２（ｄ，Ｊ＝８．８Ｈｚ，１Ｈ），６．５６（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），６．４１（ｄｄ，Ｊ＝８．８，２．８Ｈｚ，１Ｈ），６．２８（ｄｄｄ，Ｊ＝１０．０，２．８，１．６Ｈｚ，１Ｈ），６．２３（ｄｄｄ，Ｊ＝１０．４，９．２，２．８Ｈｚ，１Ｈ），４．１０（ｂｒｓ，２Ｈ），３．１８（ｓ，３Ｈ），１．６５（ｓ，４Ｈ），１．２３（ｓ，１２Ｈ）
化合物４−４ｂ　１．１９ｇ（３．４５ｍｍｏｌ）を乾燥ベンゼン１５ｍＬに溶解し、ピリジン１．５ｍＬを加えた。氷浴で冷却後、テレフタル酸モノメチルエステルクロリド０．７５ｇ（３．７７ｍｍｏｌ）を加え、室温で１４時間撹拌した。反応混合物を２Ｎ　ＨＣｌにあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：７→１：４）で精製し、化合物４−５ｂを得た（１．６６ｇ，９５％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．５８（ｂｒｓ，１Ｈ），８．３０（ｄｄｄ，Ｊ＝１０．８，２．４，２．０Ｈｚ，１Ｈ），８．００（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．４６（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．２１（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．７０（ｄｄｄ，Ｊ＝１０．８，８．８，２．８Ｈｚ，１Ｈ），６．６２（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），６．５３（ｄｄ，Ｊ＝８．４，２．８Ｈｚ，１Ｈ），３．９３（ｓ，３Ｈ），３．２９（ｓ，３Ｈ），１．６５（ｓ，４Ｈ），１．２５（ｓ，６Ｈ），１．１８（ｓ，６Ｈ）
化合物４−５ｂ　１．６６ｇ（３．２７ｍｍｏｌ）を少量の乾燥ジクロロメタンに溶解し、ＰＰＡ　１５ｇを加えて１１０℃で２時間撹拌した。冷却後、反応混合物に氷水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：７）で精製し、化合物４−６ｂを得た（１．１５ｇ，７２％）
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．０８（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．８１（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．１１（ｓ，１Ｈ），６．８７（ｓ，１Ｈ），６．８２（ｄｄｄ，Ｊ＝９．２，２．８，１．６Ｈｚ，１Ｈ），６．６４（ｄｄｄ，Ｊ＝１１．６，８．０，２．８Ｈｚ，１Ｈ），３．９５（ｓ，３Ｈ），３．３７（ｄ，Ｊ＝４．８Ｈｚ，３Ｈ），１．６４−１．７２（ｍ，４Ｈ），１．３３（ｓ，３Ｈ），１．３０（ｓ，３Ｈ），１．１３（ｓ，３Ｈ），１．０６（ｓ，３Ｈ）
化合物４−６ｂ　０．８８ｇ（１．８０ｍｍｏｌ）をエタノール１５ｍＬ及び２０％　ＮａＯＨ　３ｍＬに懸濁し、室温で５時間撹拌した。反応混合物を酸性にした後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をエタノールから再結晶することによりＨＸ９０４を得た（０．８１ｇ，９５％）。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）１３．１（ｂｒｓ，１Ｈ），８．０２（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．７５（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．２３（ｓ，１Ｈ），７．０８（ｄｄｄ，Ｊ＝１１．６，８．８，３．２Ｈｚ，１Ｈ），６．９２（ｄｄ，Ｊ＝９．６，１．６Ｈｚ，１Ｈ），６．８９（ｓ，１Ｈ），３．３３（ｄ，Ｊ＝５．２Ｈｚ，３Ｈ），１．６０−１．６２（ｍ，４Ｈ），１．３０（ｓ，３Ｈ），１．２７（ｓ，３Ｈ），１．１１（ｓ，３Ｈ），１．０１（ｓ，３Ｈ）
Ａｎａｌ．Ｃａｌｃｄ　ｆｏｒ　Ｃ_２９Ｈ_２８Ｆ_２Ｎ_２Ｏ_２，Ｃ：７３．４０％，Ｈ：５．９５％，Ｎ：５．９０％；Ｆｏｕｎｄ　Ｃ：７３．２７％，Ｈ：６．１１％，Ｎ：５．８７％
例６：ＨＸ９０５の合成

５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチルナフタレン−２−チオール０．５０ｇ（２．２７ｍｍｏｌ）を１０ｍｌの乾燥ベンゼンに溶解し、氷浴で冷却し、ｔｅｒｔ−ブトキシカリウム０．２７ｇ（２．４１ｍｍｏｌ）を加え、室温で１０分間撹拌した。この混合物を氷浴で冷却し、４−クロロ−３−ニトロベンゾトリフルオリド（化合物５−１ａ）０．５１ｇ（２．２６ｍｍｏｌ）を加え、室温で２時間撹拌した。反応混合物を氷水にあけ、中和後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：５０→１：３０）で精製し、化合物５−２ａを得た（０．９０ｇ，９７％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．５１（ｄ，Ｊ＝０．８Ｈｚ，１Ｈ），７．５６（ｄｄ，Ｊ−＝８．８，２．０Ｈｚ，１Ｈ），７．５１（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），７．４４（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．２８（ｄｄ，Ｊ＝８．０，２．０Ｈｚ，１Ｈ），７．００（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），１．７３（ｓ，４Ｈ），１．３３（ｓ，６Ｈ），１．２８（ｓ，６Ｈ）
化合物５−２ａ　０．９０ｇ（２．１９ｍｍｏｌ）を水３ｍＬ及びエタノール１５ｍＬに懸濁し、濃塩酸０．８ｍＬを加えた。この混合物に鉄粉０．９ｇを加えて１時間加熱還流した。冷却後反応混合物をセライトを通して濾過し、濾液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：１０）で精製し、化合物５−３ａを得た（０．５４ｇ，６５％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．４６（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．１７（ｄ，Ｊ＝２．８Ｈｚ，１Ｈ），６．９６（ｍ，１Ｈ），６．９３（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．８２（ｄｄ，Ｊ＝８．４，２．０Ｈｚ，１Ｈ），４．４２（ｂｒｓ，２Ｈ），１．６５（ｓ，４Ｈ），１．２３（ｓ，６Ｈ），１．２２（ｓ，６Ｈ）
化合物５−３ａ　０．５４ｇ（１．４２ｍｍｏｌ）を乾燥ベンゼン１０ｍＬに溶解し、ピリジン１．０ｍＬを加えた。これにテレフタル酸モノメチルエステルクロリド０．３１ｇ（１．５６ｍｍｏｌ）を加え、室温で１４時間撹拌した。反応混合物を２Ｎ　ＨＣｌにあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：７）で精製し、化合物５−４ａを得た（０．６４ｇ，８４％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．９７（ｂｒｓ，１Ｈ），８．９５（ｓ，１Ｈ），８．０８（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．６９（ｄ，Ｊ＝７．６Ｈｚ，１Ｈ），７．６７（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．３９（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．２３（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．１８（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），６．８８（ｄｄ，Ｊ＝８．０，２．０Ｈｚ，１Ｈ），３．９５（ｓ，３Ｈ），１．６３（ｓ，４Ｈ），１．２２（ｓ，６Ｈ），１．１６（ｓ，６Ｈ）
化合物５−４ａ　０．６４ｇ（１．１８ｍｍｏｌ）を少量の乾燥ジクロロメタンに溶解し、ＰＰＡ　１０ｇを加えて１１０℃で８時間撹拌した。冷却後、反応混合物に氷水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：１０）で精製し、化合物５−５ａを得た（０．２２ｇ，３６％）
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．１１（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．９０（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．６０（ｄ，Ｊ＝１．２Ｈｚ，１Ｈ），７．５７（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．４４（ｓ，１Ｈ），７．３３（ｄｄ，Ｊ＝８．０，２．０Ｈｚ，１Ｈ），７．０５（ｓ，１Ｈ），３．９６（ｓ，３Ｈ），１．６４−１．６５（ｍ，４Ｈ），１．３１（ｓ，３Ｈ），１．２９（ｓ，３Ｈ），１．１５（ｓ，３Ｈ），１．０８（ｓ，３Ｈ）
化合物５−５ａ　０．２２ｇ（０．４２ｍｍｏｌ）をエタノール１０ｍＬ及び２Ｎ　ＮａＯＨ　２ｍＬに懸濁し、室温で１６時間撹拌した。反応混合物を酸性にした後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をメタノールから再結晶することによりＨＸ９０５を得た（０．１０ｇ，４７％）。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）１３．２（ｂｒｓ，１Ｈ），８．０５（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．８６（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．７１（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．６６（ｓ，１Ｈ），７．５４（ｓ，１Ｈ），７．５１（ｄ，Ｊ＝８．０Ｈｚ，１Ｈ），７．１４（ｓ，１Ｈ），１．６１（ｂｒｓ，４Ｈ），１．２７（ｓ，３Ｈ），１．２５（ｓ，３Ｈ），１．１３（ｓ，３Ｈ），１．０４（ｓ，３Ｈ）
Ａｎａｌ．Ｃａｌｃｄ　ｆｏｒ　Ｃ_２９Ｈ_２６Ｆ_３ＮＯ_２Ｓ，Ｃ：６８．３５％，Ｈ：５．１４％，Ｎ：２．７５％；Ｆｏｕｎｄ　Ｃ：６８．５４％，Ｈ：５．０９％，Ｎ：２．７７％
例７：ＨＸ９０６の合成
ＮａＨ（６０％　ｉｎ　ｏｉｌ）０．１２ｇ（３．０ｍｍｏｌ）をｎ−ヘキサンで洗い、乾燥ベンゼン５ｍＬに懸濁し、氷浴で冷却した後、５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチルナフタレン−２−チオール０．５２ｇ（２．３６ｍｍｏｌ）を５ｍＬの乾燥ベンゼンに溶解して加え、室温で１５分間撹拌した。この混合物にペンタフルオロニトロベンゼン（化合物５−１ｂ）０．５０ｇ（２．３５ｍｍｏｌ）を３ｍＬの乾燥ベンゼンに溶解して加え、室温で１時間撹拌した。反応混合物を氷水にあけ、中和後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー（ｎ−ヘキサン）で精製し、化合物５−２ｂを得た（０．５３ｇ，５５％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．４６（ｄ，Ｊ＝１．６Ｈｚ，１Ｈ），７．２３（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．１７（ｄｄ，Ｊ＝８．４，２．０Ｈｚ，１Ｈ），１．６６（ｓ，４Ｈ），１．２６（ｓ，６Ｈ），１．２４（ｓ，６Ｈ）
化合物５−２ｂ　０．８１ｇ（１．９６ｍｍｏｌ）をエタノール１５ｍＬに懸濁し、２Ｎ塩酸３ｍＬを加えた。この混合物に鉄粉０．９ｇを加えて１時間加熱還流した。冷却後、反応混合物をセライトを通して濾過し、濾液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：７）で精製し、化合物５−３ｂを得た（０．６９ｇ，９２％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．１９（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），７．１７（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），６．９３（ｄｄ，Ｊ＝８．４，２．０Ｈｚ，１Ｈ），４．５２（ｂｒｓ，２Ｈ），１．６４（ｓ，４Ｈ），１．２２（ｓ，１２Ｈ）
化合物５−３ｂ　０．６９ｇ（１．８０ｍｍｏｌ）を乾燥ベンゼン１５ｍＬに溶解し、ピリジン１．５ｍＬを加えた。これにテレフタル酸モノメチルエステルクロリド０．３９ｇ（１．９６ｍｍｏｌ）を加え、室温で１４時間撹拌した後、２時間加熱還流した。反応混合物を２Ｎ　ＨＣｌにあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：４）で精製し、化合物５−４ｂを粗生成物として得た。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．０９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．７９（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．７８（ｓ，１Ｈ），７．１４（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．１４（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），６．８３（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），３．９６（ｓ，３Ｈ），１．６１（ｓ，４Ｈ），１．２０（ｓ，６Ｈ），１．１０（ｓ，６Ｈ）
粗生成物５−４ｂを少量の乾燥ジクロロメタンに溶解し、ＰＰＡ　１０ｇを加えて１１０℃で１４時間撹拌した。冷却後、反応混合物に氷水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をメタノールで結晶化し、化合物５−５ｂを得た（０．６１ｇ，６５％［２ｓｔｅｐｓ］）
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）８．０９（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．８６（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．５８（ｓ，１Ｈ），７．２１（ｓ，１Ｈ），３．８９（ｓ，３Ｈ），１．６２（ｓ，４Ｈ），１．２８（ｓ，３Ｈ），１．２６（ｓ，３Ｈ），１．１３（ｓ，３Ｈ），１．０６（ｓ，３Ｈ）
化合物５−５ｂ　０．６１ｇ（１．１５ｍｍｏｌ）をエタノール２０ｍＬ及び２Ｎ　ＮａＯＨ　５ｍＬに懸濁し、室温で１６時間撹拌した。反応混合物を酸性にした後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をメタノールから再結晶することによりＨＸ９０６を得た（０．５０ｇ，８３％）。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）１３．２（ｂｒｓ，１Ｈ），８．０６（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．８３（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５８（ｓ，１Ｈ），７．２１（ｓ，１Ｈ），１．６２（ｓ，４Ｈ），１．２８（ｓ，３Ｈ），１．２６（ｓ，３Ｈ），１．１４（ｓ，３Ｈ），１．０７（ｓ，３Ｈ）
Ａｎａｌ．Ｃａｌｃｄ　ｆｏｒ　Ｃ_２８Ｈ_２３Ｆ_４ＮＯ_２Ｓ，Ｃ：６５．４９％，Ｈ：４．５１％，Ｎ：２．７３％；Ｆｏｕｎｄ　Ｃ：６５．２４％，Ｈ：４．６３％，Ｎ：２．６２％
例８：ＨＸ９０７の合成
５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチルナフタレン−２−チオール０．５０ｇ（２．２７ｍｍｏｌ）を乾燥ベンゼン２０ｍＬに溶解し、氷浴で冷却し、ｔｅｒｔ−ブトキシカリウム０．２８ｇ（２．５０ｍｍｏｌ）を加え、室温で１５分間撹拌した。この混合物を氷浴で冷却し、５−フルオロ−２−ヨードニトロベンゼン（化合物５−１ｃ）０．６０ｇ（２．２５ｍｍｏｌ）を加え、室温で５時間撹拌した。反応混合物を氷水にあけ、中和後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：２０）で精製し、化合物５−２ｃを得た（０．５７ｇ，７０％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．９５（ｄｄ，Ｊ＝８．４，２．８Ｈｚ，１Ｈ），７．４９（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），７．３９（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．２７（ｄｄ，Ｊ＝８．０，２．０Ｈｚ，１Ｈ），７．１２（ｄｄｄ，Ｊ＝９．２，７．２，２．８Ｈｚ，１Ｈ），６．８８（ｄｄ，Ｊ＝９．２，５．６Ｈｚ，１Ｈ），１．７２（ｓ，４Ｈ），１．３２（ｓ，６Ｈ），１．２７（ｓ，６Ｈ）
化合物５−２ｃ　０．５６ｇ（１．５７ｍｍｏｌ）をエタノール１０ｍＬに溶解し、２Ｎ塩酸３ｍＬ、鉄粉０．５ｇを加えて２時間加熱還流した。冷却後反応混合物をセライトを通して濾過し、濾液を酢酸エチルで抽出した。有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：２０）で精製し、化合物５−３ｃを得た（０．３７ｇ，７２％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）７．４１（ｄｄ，Ｊ＝８．４，６．４Ｈｚ，１Ｈ），７．１４（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．０５（ｄ，Ｊ＝２．０Ｈｚ，１Ｈ），６．７４（ｄｄ，Ｊ＝８．４，２．０Ｈｚ，１Ｈ），６．４８（ｄｄ，Ｊ＝１０．８，２．８Ｈｚ，１Ｈ），６．４５（ｔｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），４．４０（ｂｒｓ，２Ｈ），１．６４（ｓ，４Ｈ），１．２２（ｓ，６Ｈ），１．２０（ｓ，６Ｈ）
化合物５−３ｃ　０．３７ｇ（１．１３ｍｍｏｌ）を乾燥ベンゼン１０ｍＬに溶解し、ピリジン１ｍＬを加えた。これにテレフタル酸モノメチルエステルクロリド０．２５ｇ（１．２６ｍｍｏｌ）を加え、室温で２時間撹拌した。反応混合物を２Ｎ塩酸にあけ、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：５）で精製し、化合物５−４ｃを得た（０．４９ｇ，８８％）。
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）９．１２（ｂｒｓ，１Ｈ），８．５２（ｄｄ，Ｊ＝１０．８，２．８Ｈｚ，１Ｈ），８．０５（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．６５（ｄｄ，Ｊ＝８．８，６．４Ｈｚ，１Ｈ），７．６３（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．１９（ｄ，Ｊ＝８．４Ｈｚ，１Ｈ），７．０７（ｄ，Ｊ＝２．４Ｈｚ，１Ｈ），６．９０（ｔｄ，Ｊ＝８．０，２．８Ｈｚ，１Ｈ），６．８０（ｄｄ，Ｊ＝８．４，２．４Ｈｚ，１Ｈ），３．９５（ｓ，３Ｈ），１．６２（ｓ，４Ｈ），１．２０（ｓ，６Ｈ），１．１４（ｓ，６Ｈ）
化合物５−４ｃ　０．４９ｇ（０．９９ｍｍｏｌ）を乾燥ジクロロメタン２ｍＬに溶解し、ＰＰＡ　１０ｇを加えて１１０℃で８時間撹拌した。冷却後、反応混合物に氷水を加え、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣をシリカゲルクロマトグラフィー（酢酸エチル：ｎ−ヘキサン＝１：５）で精製し、化合物５−５ｃを得た（０．３４ｇ，７２％）
^１Ｈ−ＮＭＲ（ＣＤＣｌ_３）８．０７（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．８６（ｄ，Ｊ＝８．８Ｈｚ，２Ｈ），７．４１（ｓ，１Ｈ），７．４０（ｄｄ，Ｊ＝８．８，５．６Ｈｚ，１Ｈ），７．０４（ｄｄ，Ｊ＝１０．０，２．８Ｈｚ，１Ｈ），７．０１（ｓ，１Ｈ），６．８１（ｔｄ，Ｊ＝８．０，２．８Ｈｚ，１Ｈ），３．９４（ｓ，３Ｈ），１．６３−１．６７（ｍ，４Ｈ），１．２９（ｓ，３Ｈ），１．２７（ｓ，３Ｈ），１．１３（ｓ，３Ｈ），１．０６（ｓ，３Ｈ）
化合物５−５ｃ　０．３４ｇ（０．７２ｍｍｏｌ）をエタノール１０ｍＬ及び２Ｎ　ＮａＯＨ　１．５ｍＬに懸濁し、室温で１６時間撹拌した。反応混合物を酸性にした後、酢酸エチルで抽出し、有機層を水、飽和食塩水で洗い、無水Ｎａ_２ＳＯ_４で乾燥した。溶媒を減圧留去し、得られた残渣を酢酸エチル／ｎ−ヘキサンから再結晶することにより化合物ＨＸ９０７を得た（０．２３ｇ，７１％）。
^１Ｈ−ＮＭＲ（ＤＭＳＯ−ｄ_６）１３．１（ｂｒｓ，１Ｈ），８．０４（ｄ，Ｊ＝８．０Ｈｚ，２Ｈ），７．８２（ｄ，Ｊ＝８．４Ｈｚ，２Ｈ），７．５２（ｄｄ，Ｊ＝８．４，６．４Ｈｚ，１Ｈ），７．５１（ｓ，１Ｈ），７．１９（ｄｄ，Ｊ＝１０．０，２．８Ｈｚ，１Ｈ），７．１２（ｓ，１Ｈ），７．０４（ｔｄ，Ｊ＝８．４，２．８Ｈｚ，１Ｈ），１．６１−１．６２（ｍ，４Ｈ），１．２７（ｓ，３Ｈ），１．２５（ｓ，３Ｈ），１．２３（ｓ，３Ｈ），１．０５（ｓ，３Ｈ）
Ａｎａｌ．Ｃａｌｃｄ　ｆｏｒ　Ｃ_２８Ｈ_２６ＦＮＯ_２Ｓ，Ｃ：７３．１８％，Ｈ：５．７０％，Ｎ：３．０５％；Ｆｏｕｎｄ　Ｃ：７２．９２％，Ｈ：５．９９％，Ｎ：２．９５％
試験例１：ＨＬ−６０細胞における細胞分化誘導検定
実施例で製造した各化合物を用いて、単独での細胞分化誘導作用および共存するレチノイドの細胞分化誘導作用に対する効果を検討した。比較および共存させるレチノイドとしてＡｍ８０［４−［（５，６，７，８−テトラヒドロ−５，５，８，８−テトラメチル−２−ナフタレニル）カルバモイル］安息香酸を用いた。特開昭６１−７６４４０号公報に記載された方法に準じて、前骨髄球性白血病細胞株ＨＬ−６０を用いて、顆粒球系への分化を形態変化およびニトロブルーテトラゾリウム（ＮＢＴ）の還元能測定により判定した。以下の表に示した分化した細胞の割合（％）はＮＢＴ還元能から算出したものである。結果を表１〜３に示す。試験に供した化合物の構造は下記のとおりである。

産業上の利用可能性
本発明の化合物はレチノイド作用を有する化合物、及びレチノイドの作用を顕著に増強することができる化合物として医薬の有効成分として有用である。Technical field
The present invention relates to a novel compound, and more particularly to a novel compound that enhances the physiological action of a nuclear receptor ligand represented by retinoic acid or a compound having a retinoic acid-like physiological activity (retinoid).
Background art
Retinoic acid (Vitamin A acid) is an active metabolite of Vitamin A. It has the effect of differentiating developing immature cells into mature cells with unique functions, promoting cell growth and maintaining life. It has a very important physiological effect. Various vitamin A derivatives synthesized so far, for example, benzoic acid derivatives described in JP-A-61-22047 and JP-A-61-76440, and Journal of Medicinal Chemistry , 1988, Vol. 31, No. 11, p. 2182) have been shown to have similar physiological effects. The above compounds having retinoic acid and retinoic acid-like biological activity are collectively referred to as "retinoids".
For example, all-trans retinoic acid is a retinoic acid receptor (Evans, RM, Science, 240, p. 889, 1988) belonging to the nuclear receptor superfamily (Evans, RM, Science, 240, p. 889, 1988). (RAR) as a ligand to control proliferation, differentiation, cell death, etc. of animal cells (Petkovich, M., et al., Nature, 330, pp. 444-450, 1987). ). The above compound having retinoic acid-like biological activity (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid: Am80 and the like) Has also been suggested to bind to RAR and exert a physiological activity similarly to retinoic acid (Hashimoto, Y., Cellstruct. Funct., 16, pp. 113-123, 1991; Hashimoto, Y., et. Al.). al., Biochem.Biophys.Res.Commun., 166, pp. 1300-1307, 1990). These compounds have been found clinically to be useful in the treatment and prevention of vitamin A deficiency, keratosis of epithelial tissue, rheumatism, delayed allergy, bone disease, and leukemia and certain cancers. ing.
Compounds that act antagonistically on such retinoids and attenuate the typical effects of the retinoids are known (Eyrolles, L., et al., Journal of Medicinal Chemistry, 37 (10), pp. .1508-1517, 1994). However, almost no substance is known that enhances the action of retinoids, such as retinoic acid, even though it has no retinoid action itself or its retinoid action is weak. For example, EP 694,301 A1 suggests that a specific ligand compound for the RXR receptor has an action of enhancing the action of Am80 which is a specific ligand compound for the RAR-α receptor. In addition, JP-A-10-59951 discloses a compound that enhances the action of a retinoid.
Disclosure of the invention
An object of the present invention is to provide a compound having the same action as a retinoid such as retinoic acid, and a compound that enhances the action of a retinoid. More specifically, it is an object of the present invention to provide a compound which itself has a retinoid action and a compound which can remarkably enhance the action of a retinoid.
The present inventors have made intensive efforts to solve the above problems, and as a result, have found that a compound represented by the following general formula is useful as a retinoid and has a property of enhancing the action of a retinoid, and completed the present invention. I came to.
That is, according to the present invention, the following formula (I):

[Wherein, R ¹ Is a hydrogen atom or C _1-6 R represents an alkyl group; ² And R ³ Is independently a hydrogen atom or C _1-6 Represents an alkyl group, or R ² And R ³ May together form a 5- or 6-membered ring with the carbon atom on the benzene ring to which they are attached (the ring being one or more C _1-4 May have an alkyl group); R ⁴ , R ⁵ , And R ⁶ Is independently a hydrogen atom, a halogen atom, C _1-6 Alkyl group or halogenated C _1-6 X represents an alkyl group; Y represents a phenylene group or a pyridinediyl group; X represents -S- or -N (R ⁷ )-(R ⁷ Is a hydrogen atom or C _1-6 Z represents C—R. ⁸ (R ⁸ Is a hydrogen atom, a halogen atom, C _1-6 Alkyl group or halogenated C _1-6 Represents an alkyl group) or represents N)
(1) a compound wherein Z is N or a salt thereof;
(2) R ¹ Is a hydrogen atom or C _1-6 An alkyl group; ² And R ³ Together with one or more C atoms on the ring with the carbon atom on the benzene ring to which they are attached _1-4 Forming a 6-membered ring having an alkyl group, ⁴ , R ⁵ , And R ⁶ Is a hydrogen atom, Y is a pyridinediyl group, X is -S-, and Z is CH, or a salt thereof;
(3) R ¹ Is a hydrogen atom or C _1-6 An alkyl group; ² And R ³ Together with one or more C atoms on the ring with the carbon atom on the benzene ring to which they are attached _1-4 Forming a 6-membered ring having an alkyl group, ⁴ And R ⁶ Is a hydrogen atom, and R ⁵ Is a halogen atom, Y is a phenylene group, and Z is CH, or a salt thereof;
(4) R ⁴ , R ⁵ , R ⁶ , And R ⁸ Wherein at least two or more of the groups are groups other than hydrogen atoms, or salts thereof; or
(5) R ⁴ , R ⁵ , R ⁶ , And R ⁸ At least one group is a halogenated C _1-6 A compound which is an alkyl group or a salt thereof;
Is provided.
From another viewpoint, according to the present invention, a medicament containing the above compound or a physiologically acceptable salt thereof as an active ingredient, a retinoid action enhancer containing the above compound or a physiologically acceptable salt thereof as an active ingredient And a nuclear receptor ligand action enhancer comprising the above compound or a physiologically acceptable salt thereof as an active ingredient.
In still another aspect, the present invention provides for the use of the above-mentioned compound or a physiologically acceptable salt thereof for the manufacture of the above-mentioned medicament; a method of enhancing the action of a retinoid in a mammal, including a human. A method comprising administering an effective amount of the compound or a physiologically acceptable salt thereof to a mammal including a human; a method for enhancing the action of a nuclear receptor ligand in the body of a mammal including a human Wherein the method comprises administering to a mammal, including a human, an effective amount of the compound or a physiologically acceptable salt thereof.
BEST MODE FOR CARRYING OUT THE INVENTION
R ¹ Is a hydrogen atom or C _1-6 Represents an alkyl group having 1 to 6 carbon atoms. In the present specification, the alkyl group may be linear, branched, cyclic, or a combination thereof, and the same applies to the alkyl moiety of a substituent having an alkyl moiety (for example, a halogenated alkyl group). . Examples of the alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group, and a tert-butyl group. Preferably, a methyl group is used. it can.
R ² And R ³ Is independently a hydrogen atom or C _1-6 Shows an alkyl group. As the alkyl group, for example, those exemplified above can be used, but preferably, an ethyl group, an isopropyl group, a tert-butyl group and the like can be used. R ² And R ³ Is not particularly limited, and can be independently substituted at any position. For example, R ² And R ³ Is para and meta to X, respectively. ² And R ³ May be meta and ortho to X, respectively, or R ² And R ³ May be para and meta positions with respect to X, respectively.
Also, R ² And R ³ Together, R ² And R ³ Can form a 5- or 6-membered ring with the two carbon atoms on the benzene ring to which each is attached. The ring formed is one or more C _1-4 It may have an alkyl group, for example, may have 2 to 4 methyl groups, preferably 4 methyl groups. For example, R ² And R ³ Is substituted with a benzene ring and R ² And R ³ Thus, it is preferable that a 5,6,7,8-tetrahydronaphthalene ring, a 5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalene ring or the like be formed.
R ⁴ , R ⁵ , And R ⁶ Is independently a hydrogen atom, a halogen atom, C _1-6 Alkyl group or halogenated C _1-6 Shows an alkyl group. As the halogen atom, any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom may be used, but a fluorine atom is preferable. C _1-6 As the alkyl group, for example, those exemplified above can be used, and a methyl group, an ethyl group, and the like are preferable. The halogen atom constituting the halogenated alkyl group may be any of a fluorine atom, a chlorine atom, a bromine atom and an iodine atom, but is preferably a fluorine atom or a chlorine atom, and more preferably a fluorine atom. Examples of the halogenated alkyl group include a monofluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trichloromethyl group, a dichlorofluoromethyl group, and a tetrafluoroethyl group.
X is R ⁷ With a nitrogen atom (-NR ⁷ -) Or a sulfur atom (-S-). R ⁷ Is a hydrogen atom, C _1-6 Shows an alkyl group. C _1-6 As the alkyl group, those exemplified above can be used. For example, a methyl group is preferable. The nitrogen or sulfur atom may be N-oxide or sulfoxide, respectively.
Y represents a phenylene group or a pyridinediyl group. For example, any phenylene group such as p-phenylene group, m-phenylene group, o-phenylene group, pyridine-2,4-diyl group, pyridine-2,5-diyl group, pyridine-3,5-diyl group, or A pyridinediyl group can be used. Preferably, a p-phenylene group or a pyridine-2,5-diyl group can be used. When a pyridine-2,5-diyl group is used, -COOR is added to either the 2- or 5-position of the pyridine. ¹ The group represented by may be substituted.
The compound of the present invention has the formula (I)
(1) a compound wherein Z is N;
(2) R ¹ Is a hydrogen atom or C _1-6 An alkyl group; ² And R ³ Together with one or more C atoms on the ring with the carbon atom on the benzene ring to which they are attached _1-4 Forming a 6-membered ring having an alkyl group, ⁴ , R ⁵ , And R ⁶ Is a hydrogen atom, Y is a pyridinediyl group, X is -S-, and Z is CH;
(3) R ¹ Is a hydrogen atom or C _1-6 An alkyl group; ² And R ³ Together with one or more C atoms on the ring with the carbon atom on the benzene ring to which they are attached _1-4 Forming a 6-membered ring having an alkyl group, ⁴ And R ⁶ Is a hydrogen atom, and R ⁵ Is a halogen atom, Y is a phenylene group, and Z is CH;
(4) R ⁴ , R ⁵ , R ⁶ , And R ⁸ Wherein at least two or more of the groups are groups other than hydrogen atoms; or
(5) R ⁴ , R ⁵ , R ⁶ , And R ⁸ At least one group is a halogenated C _1-6 Compounds that are alkyl groups;
Is one of
In the compounds of the above (1) to (5), R ² And R ³ Preferably together form a 6-membered ring with the carbon atom on the benzene ring to which they are attached, said ring having 2 to 4 carbon atoms on the ring. _1-4 It preferably has an alkyl group. As the alkyl group present on the ring, a methyl group is preferred. Most preferred is when there are four methyl groups on the ring.
In the compound of the above (1), R ⁴ , R ⁵ , And R ⁶ Is preferably a hydrogen atom, Y is preferably a phenylene group, and X is preferably -S-.
In the compound of the above (2), Y is preferably a 2,5-pyridinediyl group.
In the compound of the above (3), R ⁵ Is a fluorine atom, Y is a p-phenylene group, and X is -N (R ⁷ )-(R ⁷ Is a hydrogen atom or a methyl group) or -S-.
In the compound of the above (4), R ⁵ And R ⁸ Is preferably a group other than a hydrogen atom, and more preferably R ⁴ And R ⁶ Are both a hydrogen atom or a halogen atom, and R ⁵ And R ⁸ Is a group other than a hydrogen atom. R ⁵ And R ⁸ Are more preferably both halogen atoms, and R ⁵ And R ⁸ Are most preferably fluorine atoms. R ⁵ , R ⁶ , R ⁷ , And R ⁸ Are also preferably fluorine atoms.
In the compound of the above (5), Y is preferably a phenylene group, and X is preferably -S-. R ⁴ , R ⁵ , R ⁶ , And R ⁸ Is preferably a trifluoromethyl group. R ⁵ Is more preferably a trifluoromethyl group, even more preferably R ⁵ Is a trifluoromethyl group, and R ⁴ , R ⁶ , And R ⁸ Is a hydrogen atom.
The compounds of the present invention may exist as acid addition salts or base addition salts, and the substances in salt form are also included in the scope of the present invention. Acid addition salts include mineral acid salts such as hydrochloride or hydrobromide, or organic acid salts such as p-toluenesulfonate, methanesulfonate, oxalate, or tartrate. . The base addition salt is R ¹ Represents a hydrogen atom, and examples thereof include metal salts such as sodium salt, potassium salt, magnesium salt, or calcium salt, ammonium salts, and organic amine salts such as triethylamine salt or ethanolamine salt.
The compound of the present invention may have one or more asymmetric carbons depending on the type of the substituent, and the optical isomers and diastereoisomers in pure form based on such asymmetric carbons may be provided. In addition to such stereoisomers, any mixtures of the stereoisomers, racemates and the like are all included in the scope of the present invention. It goes without saying that any hydrate or solvate of the compound in the form of a free compound or salt is also included in the scope of the present invention.
The production method of the compound of the present invention is not particularly limited, but it can be produced, for example, according to the production method described in JP-A-10-59951. In the examples of the present specification, since the method for producing the compound of the present invention is specifically and in detail described, the method used in these methods may be referred to the above-mentioned publications and the examples of the present specification. Any of the compounds included in the scope of the present invention can be produced by appropriately changing the starting materials, reagents, reaction conditions, and the like, and by appropriately modifying these methods as necessary.
The compound of the present invention itself has substantially no retinoid-like action, or is a compound having a weak or moderate retinoid-like action.However, the compound of the present invention can be combined with a retinoid such as retinoic acid. When coexisting, the retinoid's physiological activity (typically, cell differentiation action, cell growth promoting action, life sustaining action, etc.) is significantly enhanced. Without wishing to be bound by any particular theory, it is understood that the compounds of the present invention may be referred to as retinoid receptors (the term "retinoid receptor" as used herein includes the retinoic acid receptors RAR and RXR and includes retinoic acid, such as retinoic acid. Retinoid means one or more of the interactable receptors.), Which itself exerts a retinoid-like physiological activity as an agonist, or Has the effect of enhancing activity. Also, without wishing to be bound by any particular theory, if the compound of the present invention itself has a retinoid action, the action is synergistic.
Therefore, the compound of the present invention is a compound having the same retinoic acid or retinoic acid-like biological activity (for example, 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2). -Naphthalenyl) carbamoyl] benzoic acid: similar to Am80), for the treatment of diseases such as vitamin A deficiency, keratosis of epithelial tissue, psoriasis, allergic diseases, immunological diseases such as rheumatism, bone diseases, leukemia, diabetes, and cancer. The compound of the present invention can be used as a medicament for prevention or treatment, or the compound of the present invention can be used as an agent for enhancing the action of the retinoid when the retinoid is administered for prevention or treatment of the above-mentioned diseases.
In addition, the compound of the present invention enhances the action of retinoic acid already present in a living body even when retinoid is not administered for the treatment or prevention of the above-mentioned diseases. It is also possible to administer the compounds of the invention themselves. Furthermore, the compounds of the present invention have not only an effect of enhancing action on retinoids, but also a nuclear receptor superfamily existing in the nucleus of cells (Evans, RM, Science, 240, p. 889, 1988). Vitamin D, a steroid compound that exerts a physiological action by binding to a receptor belonging to ₃ For enhancing the action of a physiologically active substance such as a vitamin D compound such as thyroxine.
The medicament comprising the compound of the present invention or a physiologically acceptable salt thereof may be administered as such, but preferably, an oral or parenteral pharmaceutical composition which can be produced by a method well known to those skilled in the art. It is preferable to administer as a substance. In addition, it can be used as a so-called pharmaceutical composition in the form of a mixture by blending it with a medicine containing a retinoid such as retinoic acid as an active ingredient. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, fine granules, granules, liquids, and syrups.Pharmaceutical compositions suitable for parenteral administration include: Examples include injections, suppositories, inhalants, eye drops, nasal drops, ointments, creams, transdermal absorbents, transmucosal absorbents, patches, and the like. The active ingredient of the medicament of the present invention may be a free form compound or a physiologically acceptable salt thereof, or a hydrate or solvate thereof.
The above pharmaceutical composition can be produced by adding pharmacologically and pharmaceutically acceptable additives. Examples of pharmacologically and pharmaceutically acceptable additives include, for example, excipients, disintegrants or disintegration aids, binders, lubricants, coatings, dyes, diluents, bases, Agents, solubilizing agents, tonicity agents, pH regulators, stabilizers, propellants, adhesives and the like. As the active ingredient of the medicament of the present invention, one or two or more substances selected from the group consisting of a compound in a free form and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof are used. Can be used.
The dose of the medicament of the present invention is not particularly limited, when the action of the retinoid is enhanced by using a medicament of the present invention in combination with a medicament containing a retinoid such as retinoic acid as an active ingredient, or a medicament containing a retinoid is used in combination. Instead, an appropriate dose can be easily selected in any administration method, for example, when administering the medicament of the present invention for enhancing the action of retinoic acid already present in the living body. For example, in the case of oral administration, it can be used in the range of about 0.01 to 1,000 mg per adult day. When a medicament containing a retinoid as an active ingredient and the medicament of the present invention are used in combination, the medicament of the present invention can be administered during the retinoid administration period, or before or after the administration period.
Example
Hereinafter, the present invention will be described more specifically with reference to Examples, but the scope of the present invention is not limited to the following Examples. The compound numbers in the examples correspond to the compound numbers in the following scheme.
Example 1: Synthesis of HX900

To a suspension of NaH (351 mg, 8.78 mmol) in dry dimethylformamide (DMF, 25 mL) was added 5,6,7,8-tetrahydro-5,5,8,8 at 0-5 ° C under a salt-ice bath cooling. A solution of tetramethylnaphthalene-2-thiol (compound 1-1: J. Med. Chem., 38, pp. 3163-3173, 1995, 1.935 g, 8.78 mmol) in dry DMF (5 mL) was added dropwise. After the temperature was gradually raised to room temperature and stirred for 1 hour, a solution of 2-chloro-3-nitropyridine (1.325 g, 8.36 mmol) in dry DMF (5 mL) was added dropwise at 0-5 ° C. while cooling in a salt-ice bath. . After gradually warming to room temperature and stirring for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with water and saturated saline, ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 40/1) to obtain Compound 1-2 (2.755 g, 96.2%).
¹ H-NMR (CDCl ₃ ) Δ 8.52 (dd, 1H, J = 1.8, 4.8 Hz), 8.48 (dd, 1H, J = 1.8, 8.4 Hz), 7.46 (d, 1H, J = 1) .8 Hz), 7.37 (d, 1H, J = 8.1 Hz), 7.29 (dd, 1H, J = 1.8, 8.4 Hz), 7.17 (dd, 1H, J = 4. 5, 8.1 Hz), 1.71 (s, 4H), 1.32 (s, 6H), 1.28 (s, 6H).
Compound 1-2 (2.687 g, 7.85 mmol) was suspended in ethanol (2.6 mL) and water (2.61 mL), and concentrated hydrochloric acid (6.5 mL) was added. Iron powder (2.192 g, 39.25 mmol) was added to this mixture, and the mixture was heated under reflux for 1 hour. After cooling to room temperature, the reaction solution was poured into a mixture of NaOH (10.0 g, 250 mmol), dichloromethane (125 mL) and water (250 mL), 15 g of celite was added, and the mixture was stirred and filtered through celite. The aqueous phase of the filtrate was extracted with dichloromethane, and the combined organic phases were washed with water and brine, washed with Na ₂ SO ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 3/1) to obtain compound 1-3 (1.056 g, 43.0%).
¹ H-NMR (CDCl ₃ ) Δ 8.20 (dd, 1H, J = 1.5, 4.5 Hz), 7.27 (d, 1H, J = 2.4 Hz), 7.19 (d, 1H, J = 8.1 Hz), 7.06 (dd, 1H, J = 4.5, 7.8 Hz), 7.00 (dd, 2H, J = 1.8, 8.1 Hz), 4.20 (brs, 2H), 1.64 (S, 4H), 1.23 (s, 6H), 1.21 (s, 6H).
Compound 1-3 (183 mg, 0.586 mmol) and triethylamine (65.2 mg, 0.645 mmol) were dissolved in dry dichloromethane (5 mL), and terephthalic acid monomethyl chloride (128 mg, (0.645 mmol) in dry dichloromethane (2 mL) was added dropwise. The temperature was gradually raised to room temperature and stirred for 15 hours. The reaction solution was diluted with dichloromethane, washed with water and saturated saline, and washed with MgSO. ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain compound 1-4 (216 mg, 77.7%).
¹ H-NMR (CDCl ₃ ) Δ 8.84 (brs and dd, 1H + 1H, J = 1.5, 8.4 Hz), 8.38 (dd, 1H, J = 1.5, 4.5 Hz), 8.12 (d, 2H, J = 8.4 Hz), 7.74 (d, 2H, J = 8.7 Hz), 7.35 (dd, 1H, J = 4.5, 8.1 Hz), 7.26 (d, 1H, J = 1.5 Hz), 7.23 (d, 1H, J = 8.1 Hz), 7.04 (dd, 1H, J = 1.8, 8.4 Hz), 3.96 (s, 3H), 1. 63 (s, 4H), 1.21 (s, 6H), 1.15 (s, 6H).
Compound 1-4 (192 mg, 0.405 mmol) was dissolved in dichloromethane (1 mL), polyphosphoric acid (PPA, 4.50 g) was added, and the mixture was heated with stirring at 120 ° C. for 1 hour. Water was added to the reaction solution, which was extracted with dichloromethane. The organic phase was washed with water and saturated saline, ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain compound 1-5 (93.4 mg, 50.5%).
¹ H-NMR (CDCl ₃ ) Δ 8.32 (dd, 1H, J = 1.8, 4.5 Hz), 8.11 (d, 2H, J = 8.7 Hz), 7.90 (d, 2H, J = 8.7 Hz), 7.66 (dd, 1H, J = 1.8, 8.1 Hz), 7.57 (s, 1H), 7.29 (dd, 1H, J = 4.5, 8.4 Hz), 7.08 (S, 1H), 3.96 (s, 3H), 1.66 (s, 4H), 1.31 (s, 3H), 1.28 (s, 3H), 1.15 (s, 3H) , 1.09 (s, 3H).
Compound 1-5 (80.8 mg, 0.175 mmol) was dissolved in tetrahydrofuran (THF, 3 mL) and MeOH (1 mL), 2N NaOH (0.88 mL, 1.76 mL) was added, and the mixture was heated with stirring at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 2N HCl (1 mL) was added to the residue, diluted with water, and extracted with ethyl acetate. The organic phase was washed with water and saturated saline, ₄ After drying with, the solvent was distilled off under reduced pressure to obtain HX900 (71.0 mg, 91.7%). Recrystallization from toluene gave a purified product. m. p. > 300 ° C.
¹ H-NMR (DMSO-d ₆ ) Δ 8.31 (dd, 1H, J = 1.5, 4.5 Hz), 8.06 (d, 2H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.4 Hz), 7.77 (dd, 1H, J = 1.5, 8.1 Hz), 7.59 (s, 1H), 7.47 (dd, 1H, J = 4.5, 8.1 Hz), 7.19 (S, 1H), 1.63 (s, 4H), 1.28 (s, 6H), 1.14 (s, 3H), 1.07 (s, 3H).
Example 2: Synthesis of HX901

2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) thio] aniline (Compound 2-1: J. Med. Chem., 40, pp. 4222) -4243, 1997, 218 mg, 0.70 mmol) and 5-ethyl-2,5-pyridinedicarboxylate (Nippon Kagaku Zasshi, 88, pp. 553-556, 1967, 273 mg, 1.40 mmol) in dry dichloromethane (3 To the suspension was added 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (269 mg, 1.40 mmol), and the mixture was stirred at room temperature for 4 hours. The reaction solution was diluted with dichloromethane, washed with water and saturated saline, and washed with MgSO. ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 5/1) to obtain compound 2-2 (306 mg, 89.5%).
¹ H-NMR (CDCl ₃ ) Δ 11.14 (brs, 1H), 9.20 (d, 1H, J = 1.8 Hz), 8.66 (dd, 1H, J = 1.2, 8.1 Hz), 8.46 (dd, 1H, J = 1.8, 8.1 Hz), 8.31 (d, 1H, J = 8.1 Hz), 7.65 (dd, 1H, J = 1.8, 7.5 Hz), 7.43 −7.49 (m, 1H), 7.26 to 7.27 (m, 1H), 7.13 to 7.18 (m, 1H), 7.12 (d, 1H, J = 8.4 Hz) , 6.95 (dd, 1H, J = 1.8, 8.1 Hz), 4.45 (q, 2H, J = 7.2 Hz), 1.59 (s, 4H), 1.44 (t, 3H, J = 7.2 Hz), 1.16 (s, 6H), 1.12 (s, 6H).
Compound 2-2 (280 mg, 0.572 mmol) was dissolved in dichloromethane (1 mL), PPA (5.28 g) was added, and the mixture was heated with stirring at 120 ° C. for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (dichloromethane / methanol / acetic acid = 380/20/1) to obtain HX901 (153 mg, 60.4%). Recrystallization from toluene gave a purified product. m. p. 283 ° C.
¹ H-NMR (DMSO-d ₆ ) Δ 9.03 (dd, 1H, J = 1.2, 2.1 Hz), 8.51 (dd, 1H, J = 1.2, 8.1 Hz), 8.47 (dd, 1H, J = 2) .1, 8.4 Hz), 7.52 (dd, 1H, J = 0.9, 7.8 Hz), 7.46 (s, 1H), 7.37-7.44 (m, 2H), 7 .20-7.26 (m, 1H), 7.15 (s, 4H), 1.61 (s, 4H), 1.26 (s, 6H), 1.13 (s, 3H), 1. 04 (s, 3H).
Example 3: Synthesis of HX902

2-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl) thio] aniline (compound 2-1,202 mg, 0.65 mmol) and 2-ethyl-2 1- (3-Dimethylaminopropyl) hydrochloride in a suspension of 5,5-pyridinedicarboxylate (Nippon Kagaku Zasshi, 88, pp. 553-556, 1967, 253 mg, 1.30 mmol) in dry dichloromethane (3.5 mL) -3-Ethylcarbodiimide (249 mg, 1.30 mmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction solution was diluted with dichloromethane, washed with water and a saturated saline solution, and washed with MgSO 4. ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane / ethyl acetate = 4/1) to obtain compound 3-2 (300 mg, 94.4%).
¹ H-NMR (CDCl ₃ ) Δ 9.10 (brs, 1H), 9.03 (d, 1H, J = 2.4 Hz), 8.62 (d, 1H, J = 8.4 Hz), 8.15 (d, 1H, J = 7.8 Hz), 7.99 (dd, 1H, J = 2.4, 8.1 Hz), 7.67 (dd, 1H, J = 1.5, 7.8 Hz), 7.49-7.55 (M, 1H), 7.22 (dd, 1H, J = 1.5, 7.8 Hz), 7.18 (d, 1H, J = 8.1 Hz), 7.07 (d, 1H, J = 1.8 Hz), 6.81 (dd, 1H, J = 2.1, 8.4 Hz), 4.50 (q, 2H, J = 7.2 Hz), 1.61 (s, 4H), 1. 46 (t, 3H, J = 7.2 Hz), 1.19 (s, 6H), 1.13 (s, 6H).
Compound 3-2 (258 mg, 0.527 mmol) was dissolved in dichloromethane (1 mL), PPA (6.05 g) was added, and the mixture was heated with stirring at 120 ° C. for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic phase was washed with water and saturated saline, ₄ After drying with, the solvent was distilled off under reduced pressure. The obtained residue (140 mg) was recrystallized from hexane-ethyl acetate to obtain HX902 (110 mg, 47.2%). m. p. 154-155 ° C.
¹ H-NMR (CDCl ₃ ) Δ 9.07 (dd, 1H, J = 0.9, 2.1 Hz), 8.37 (dd, 1H, J = 2.1, 8.1 Hz), 8.28 (dd, 1H, J = 0) 7.9, 7.8 Hz), 7.48-7.53 (m, 1H), 7.47 (s, 1H), 7.37-7.38 (m, 2H), 7.14-7.20 (M, 1H), 7.01 (s, 1H), 1.66 (s, 4H), 1.31 (s, 3H), 1.29 (s, 3H), 1.16 (s, 3H) , 1.08 (s, 3H).
Example 4: Synthesis of HX903

1.00 g (3.74 mmol) of 6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene, 4-fluoro-2-nitroaniline (compound 4-1a). 58 g (3.71 mmol), K ₂ CO ₃ 20 mL of o-xylene was added to 0.57 g (4.12 mmol) and 0.04 g (0.21 mmol) of CuI, and the mixture was refluxed for 9 hours. Xylene was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 15) to obtain compound 4-2a (1.04 g, 81%).
¹ H-NMR (CDCl ₃ ) 9.35 (s, 1H), 7.90 (dd, J = 9.2, 2.4 Hz, 1H), 7.33 (d, J = 8.4 Hz, 1H), 7.14-7. 21 (m, 3H), 7.01 (dd, J = 8.4, 2.4 Hz, 1H), 1.71 (s, 4H), 1.30 (s, 6H), 1.28 (s, 6H)
0.18 g (4.5 mmol) of NaH (60% in oil) was washed with n-hexane, suspended in 3 mL of DMF, cooled in an ice bath, and then 1.04 g (3.03 mmol) of compound 4-2a was added to 30 mL of Dissolved in DMF, added, and stirred at room temperature for 30 minutes. This mixture contains CH ₃ 0.4 mL (6.42 mmol) of I was added and stirred for 5 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, the organic layer was washed with water and saturated saline, and anhydrous Na was added. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure to obtain compound 4-3a (1.05 g, 98%).
¹ H-NMR (CDCl ₃ 7.) 7.57 (dd, J = 7.6, 2.8 Hz, 1H), 7.35 (dd, J = 9.2, 4.8 Hz, 1H), 7.29 (m, 1H), 7. 12 (d, J = 8.4 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.51 (dd, J = 8.4, 2.4 Hz, 1H), 3.25 (S, 3H), 1.63 (s, 4H), 1.22 (s, 6H), 1.18 (s, 6H)
1.05 g (2.98 mmol) of compound 4-3a was dissolved in 30 mL of ethyl acetate, 0.1 g of 10% Pd / C was added, and the mixture was vigorously stirred for 1 hour under a hydrogen atmosphere. The reaction mixture was filtered through celite and the solvent was removed under reduced pressure. The obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 10) to obtain compound 4-4a (0.61 g, 63%).
¹ H-NMR (CDCl ₃ ) 7.11 (d, J = 8.8 Hz, 1H), 6.97 (dd, J = 8.4, 6.0 Hz, 1H), 6.58 (d, J = 2.4 Hz, 1H), 6.50 (dd, J = 10.4, 2.8 Hz, 1H), 6.43 (dd, J = 8.8, 2.4 Hz, 1H), 6.41 (dd, J = 6.0, 2.8 Hz, 1H), 3.95 (brs, 2H), 3.14 (s, 3H), 1.65 (s, 4H), 1.23 (s, 6H), 1.22 (s, 6H) )
0.61 g (1.87 mmol) of compound 4-4a was dissolved in 15 mL of dry benzene, and 1.5 mL of pyridine was added. After cooling in an ice bath, 0.41 g (2.06 mmol) of terephthalic acid monomethyl ester chloride was added, and the mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into 2N HCl, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 4) to obtain compound 4-5a (0.91 g, quant).
¹ H-NMR (CDCl ₃ ) 8.58 (brs, 1H), 8.44 (dd, J = 10.8, 2.8 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.8 Hz, 1H), 7.18 (dd, J = 8.8, 5.6 Hz, 1H), 6.87 (dt, J = 8.0, 3.2 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 6.57 (dd, J = 8.8, 2.8 Hz, 1H), 3.93 ( s, 3H), 3.27 (s, 3H), 1.65 (s, 4H), 1.25 (s, 6H), 1.17 (s, 6H)
0.91 g (1.86 mmol) of compound 4-5a was dissolved in a small amount of dry dichloromethane, 10 g of PPA was added, and the mixture was stirred at 110 ° C for 1 hour. After cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 4) to obtain compound 4-6a (0.71 g, 81%).
¹ H-NMR (CDCl ₃ ) 8.08 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.01 (dd, J = 9.6, 2.8 Hz, 1H), 6.92 (s, 1H), 6.88 (s, 1H), 6.81-6.69 (m, 2H), 3.95 (s, 3H), 3.23 (s, 3H), 1 0.63-1.68 (m, 4H), 1.32 (s, 3H), 1.27 (s, 3H), 1.13 (s, 3H), 1.05 (s, 3H)
0.71 g (1.50 mmol) of compound 4-6a was suspended in 10 mL of ethanol and 2 mL of 20% NaOH and stirred at room temperature for 5 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to obtain HX903 (0.62 g, 90%).
¹ H-NMR (DMSO-d ₆ ) 13.1 (brs, 1H), 8.02 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.4 Hz, 2H), 6.98-7.09 (m, 4H), 6.86 (s, 1H), 3.19 (s, 3H), 1.59-1.61 (m, 4H), 1.29 (s, 3H), 1.25 (s, 3H) ), 1.10 (s, 3H), 1.01 (s, 3H)
Anal. Calcd for C ₂₉ H ₂₉ FN ₂ O ₂ , C: 76.29%, H: 6.40%, N: 6.14%; Found C: 76.00%, H: 6.39%, N: 6.02%
Example 5: Synthesis of HX904
6-bromo-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene 1.53 g (7.52 mmol), 2,4-difluoro-6-nitroaniline (compound 4-1b) 1.00 g (5.74 mmol), K ₂ CO ₃ 20 mL of o-xylene was added to 0.90 g (6.51 mmol) and 0.055 g (0.29 mmol) of CuI, and the mixture was heated under reflux for 24 hours. Xylene was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 50 → 1: 10) to obtain compound 4-2b (1.82 g, 88%).
¹ H-NMR (CDCl ₃ ) 8.54 (brs, 1H), 7.75 (ddd, J = 8.4, 3.2, 2.0 Hz, 1H), 7.22 (d, J = 8.4 Hz, 1H), 7. 14 (ddd, J = 11.2, 7.6, 3.2 Hz, 1H), 6.88 (dd, J = 2.8, 2.4 Hz, 1H), 6.74 (ddd, J = 8. 4, 2.8, 2.4 Hz, 1H), 1.68 (s, 4H), 1.27 (s, 6H), 1.25 (s, 6H)
0.33 g (8.3 mmol) of NaH (60% in oil) was washed with n-hexane, suspended in 5 mL of DMF, and 1.97 g (5.47 mmol) of compound 4-2b was dissolved in 40 mL of DMF and added. Stirred at room temperature for 30 minutes. This mixture contains CH ₃ 0.7 mL (11.2 mmol) of I was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, extracted with ethyl acetate, the organic layer was washed with water and saturated saline, and anhydrous Na was added. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 4-3b (2.04 g, quant).
¹ H-NMR (CDCl ₃ ) 7.39 (ddd, J = 7.6, 3.2, 2.0 Hz, 1H), 7.18 (ddd, J = 9.6, 8.0, 2.8 Hz, 1H), 7.11 (D, J = 8.8 Hz, 1H), 6.47 (d, J = 2.4 Hz, 1H), 6.41 (dd, J = 8.8, 2.8 Hz, 1H), 3.24 ( s, 3H), 1.63 (s, 4H), 1.22 (s, 6H), 1.18 (s, 6H)
2.04 g (5.44 mmol) of compound 4-3b was dissolved in 30 mL of ethyl acetate, 0.8 g of 10% Pd / C was added, and the mixture was vigorously stirred under a hydrogen atmosphere for 13 hours. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure to obtain compound 4-4b (1.19 g, 63%).
¹ H-NMR (CDCl ₃ ) 7.12 (d, J = 8.8 Hz, 1H), 6.56 (d, J = 2.8 Hz, 1H), 6.41 (dd, J = 8.8, 2.8 Hz, 1H), 6.28 (ddd, J = 10.0, 2.8, 1.6 Hz, 1H), 6.23 (ddd, J = 10.4, 9.2, 2.8 Hz, 1H), 4.10 ( brs, 2H), 3.18 (s, 3H), 1.65 (s, 4H), 1.23 (s, 12H)
1.19 g (3.45 mmol) of compound 4-4b was dissolved in 15 mL of dry benzene, and 1.5 mL of pyridine was added. After cooling in an ice bath, 0.75 g (3.77 mmol) of terephthalic acid monomethyl ester chloride was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into 2N HCl, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7 → 1: 4) to obtain compound 4-5b (1.66 g, 95%). .
¹ H-NMR (CDCl ₃ ) 8.58 (brs, 1H), 8.30 (ddd, J = 10.8, 2.4, 2.0 Hz, 1H), 8.00 (d, J = 8.4 Hz, 2H), 7. 46 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.4 Hz, 1H), 6.70 (ddd, J = 10.8, 8.8, 2.8 Hz, 1H) , 6.62 (d, J = 2.8 Hz, 1H), 6.53 (dd, J = 8.4, 2.8 Hz, 1H), 3.93 (s, 3H), 3.29 (s, 3H), 1.65 (s, 4H), 1.25 (s, 6H), 1.18 (s, 6H)
1.66 g (3.27 mmol) of compound 4-5b was dissolved in a small amount of dry dichloromethane, 15 g of PPA was added, and the mixture was stirred at 110 ° C for 2 hours. After cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 4-6b (1.15 g, 72%).
¹ H-NMR (CDCl ₃ ) 8.08 (d, J = 8.4 Hz, 2H), 7.81 (d, J = 8.4 Hz, 2H), 7.11 (s, 1H), 6.87 (s, 1H), 6 .82 (ddd, J = 9.2, 2.8, 1.6 Hz, 1H), 6.64 (ddd, J = 11.6, 8.0, 2.8 Hz, 1H), 3.95 (s , 3H), 3.37 (d, J = 4.8 Hz, 3H), 1.64-1.72 (m, 4H), 1.33 (s, 3H), 1.30 (s, 3H), 1.13 (s, 3H), 1.06 (s, 3H)
0.88 g (1.80 mmol) of compound 4-6b was suspended in 15 mL of ethanol and 3 mL of 20% NaOH, and the mixture was stirred at room temperature for 5 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethanol to obtain HX904 (0.81 g, 95%).
¹ H-NMR (DMSO-d ₆ ) 13.1 (brs, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.75 (d, J = 8.0 Hz, 2H), 7.23 (s, 1H), 7 .08 (ddd, J = 11.6, 8.8, 3.2 Hz, 1H), 6.92 (dd, J = 9.6, 1.6 Hz, 1H), 6.89 (s, 1H), 3.33 (d, J = 5.2 Hz, 3H), 1.60-1.62 (m, 4H), 1.30 (s, 3H), 1.27 (s, 3H), 1.11 ( s, 3H), 1.01 (s, 3H)
Anal. Calcd for C ₂₉ H ₂₈ F ₂ N ₂ O ₂ , C: 73.40%, H: 5.95%, N: 5.90%; Found C: 73.27%, H: 6.11%, N: 5.87%
Example 6: Synthesis of HX905

0.50 g (2.27 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-thiol is dissolved in 10 ml of dry benzene, cooled in an ice bath and tert- 0.27 g (2.41 mmol) of potassium butoxide was added, and the mixture was stirred at room temperature for 10 minutes. The mixture was cooled in an ice bath, 0.51 g (2.26 mmol) of 4-chloro-3-nitrobenzotrifluoride (compound 5-1a) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into ice water, neutralized and extracted with ethyl acetate.The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 50 → 1: 30) to obtain compound 5-2a (0.90 g, 97%).
¹ H-NMR (CDCl ₃ ) 8.51 (d, J = 0.8 Hz, 1H), 7.56 (dd, J− = 8.8, 2.0 Hz, 1H), 7.51 (d, J = 2.0 Hz, 1H) , 7.44 (d, J = 8.0 Hz, 1H), 7.28 (dd, J = 8.0, 2.0 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 1.73 (s, 4H), 1.33 (s, 6H), 1.28 (s, 6H)
0.90 g (2.19 mmol) of compound 5-2a was suspended in 3 mL of water and 15 mL of ethanol, and 0.8 mL of concentrated hydrochloric acid was added. 0.9 g of iron powder was added to this mixture, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 10) to obtain compound 5-3a (0.54 g, 65%).
¹ H-NMR (CDCl ₃ 7.46 (d, J = 7.6 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 2.8 Hz, 1H), 6.96 ( m, 1H), 6.93 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 8.4, 2.0 Hz, 1H), 4.42 (brs, 2H), 1. 65 (s, 4H), 1.23 (s, 6H), 1.22 (s, 6H)
0.54 g (1.42 mmol) of compound 5-3a was dissolved in 10 mL of dry benzene, and 1.0 mL of pyridine was added. 0.31 g (1.56 mmol) of terephthalic acid monomethyl ester chloride was added thereto, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into 2N HCl, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 5-4a (0.64 g, 84%).
¹ H-NMR (CDCl ₃ ) 8.97 (brs, 1H), 8.95 (s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 7.6 Hz, 1H), 7 .67 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 7.18 (d, J = 2.0 Hz, 1H), 6.88 (dd, J = 8.0, 2.0 Hz, 1H), 3.95 (s, 3H), 1.63 (s, 4H), 1.22 ( s, 6H), 1.16 (s, 6H)
0.64 g (1.18 mmol) of compound 5-4a was dissolved in a small amount of dry dichloromethane, 10 g of PPA was added, and the mixture was stirred at 110 ° C for 8 hours. After cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 10) to obtain compound 5-5a (0.22 g, 36%).
¹ H-NMR (CDCl ₃ ) 8.11 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 1.2 Hz, 1H), 7.57 ( d, J = 8.0 Hz, 1H), 7.44 (s, 1H), 7.33 (dd, J = 8.0, 2.0 Hz, 1H), 7.05 (s, 1H), 3.0. 96 (s, 3H), 1.64-1.65 (m, 4H), 1.31 (s, 3H), 1.29 (s, 3H), 1.15 (s, 3H), 1.08 (S, 3H)
0.22 g (0.42 mmol) of compound 5-5a was suspended in 10 mL of ethanol and 2 mL of 2N NaOH, and the mixture was stirred at room temperature for 16 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from methanol to obtain HX905 (0.10 g, 47%).
¹ H-NMR (DMSO-d ₆ ) 13.2 (brs, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 8. 0 Hz, 1H), 7.66 (s, 1H), 7.54 (s, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.14 (s, 1H), 1.61 (Brs, 4H), 1.27 (s, 3H), 1.25 (s, 3H), 1.13 (s, 3H), 1.04 (s, 3H)
Anal. Calcd for C ₂₉ H ₂₆ F ₃ NO ₂ S, C: 68.35%, H: 5.14%, N: 2.75%; Found C: 68.54%, H: 5.09%, N: 2.77%
Example 7: Synthesis of HX906
0.12 g (3.0 mmol) of NaH (60% in oil) was washed with n-hexane, suspended in 5 mL of dry benzene, cooled in an ice bath, and then cooled with 5,6,7,8-tetrahydro-5,5. 0.58 g (2.36 mmol) of 8,8-tetramethylnaphthalene-2-thiol was dissolved in 5 mL of dry benzene, and the mixture was stirred at room temperature for 15 minutes. To this mixture, 0.50 g (2.35 mmol) of pentafluoronitrobenzene (compound 5-1b) dissolved in 3 mL of dry benzene was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water, neutralized and extracted with ethyl acetate.The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (n-hexane) to obtain compound 5-2b (0.53 g, 55%).
¹ H-NMR (CDCl ₃ ) 7.46 (d, J = 1.6 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 7.17 (dd, J = 8.4, 2.0 Hz, 1H), 1.66 (s, 4H), 1.26 (s, 6H), 1.24 (s, 6H)
0.81 g (1.96 mmol) of compound 5-2b was suspended in 15 mL of ethanol, and 3 mL of 2N hydrochloric acid was added. 0.9 g of iron powder was added to this mixture, and the mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was filtered through celite and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 7) to obtain compound 5-3b (0.69 g, 92%).
¹ H-NMR (CDCl ₃ ) 7.19 (d, J = 2.0 Hz, 1H), 7.17 (d, J = 8.4 Hz, 1H), 6.93 (dd, J = 8.4, 2.0 Hz, 1H), 4.52 (brs, 2H), 1.64 (s, 4H), 1.22 (s, 12H)
0.69 g (1.80 mmol) of compound 5-3b was dissolved in 15 mL of dry benzene, and 1.5 mL of pyridine was added. 0.39 g (1.96 mmol) of terephthalic acid monomethyl ester chloride was added thereto, and the mixture was stirred at room temperature for 14 hours, and then heated and refluxed for 2 hours. The reaction mixture was poured into 2N HCl, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 4) to obtain compound 5-4b as a crude product.
¹ H-NMR (CDCl ₃ ) 8.09 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.78 (s, 1H), 7.14 (d, J = 8. 4 Hz, 1 H), 7.14 (d, J = 2.4 Hz, 1 H), 6.83 (dd, J = 8.4, 2.4 Hz, 1 H), 3.96 (s, 3 H), 61 (s, 4H), 1.20 (s, 6H), 1.10 (s, 6H)
The crude product 5-4b was dissolved in a small amount of dry dichloromethane, 10 g of PPA was added, and the mixture was stirred at 110 ° C for 14 hours. After cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was crystallized from methanol to obtain compound 5-5b (0.61 g, 65% [2 steps]).
¹ H-NMR (DMSO-d ₆ ) 8.09 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.58 (s, 1H), 7.21 (s, 1H), 3 .89 (s, 3H), 1.62 (s, 4H), 1.28 (s, 3H), 1.26 (s, 3H), 1.13 (s, 3H), 1.06 (s, 3H) 3H)
0.61 g (1.15 mmol) of compound 5-5b was suspended in 20 mL of ethanol and 5 mL of 2N NaOH, and stirred at room temperature for 16 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from methanol to obtain HX906 (0.50 g, 83%).
¹ H-NMR (DMSO-d ₆ ) 13.2 (brs, 1H), 8.06 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 7.58 (s, 1H), 7 .21 (s, 1H), 1.62 (s, 4H), 1.28 (s, 3H), 1.26 (s, 3H), 1.14 (s, 3H), 1.07 (s, 3H)
Anal. Calcd for C ₂₈ H ₂₃ F ₄ NO ₂ S, C: 65.49%, H: 4.51%, N: 2.73%; Found C: 65.24%, H: 4.63%, N: 2.62%
Example 8: Synthesis of HX907
0.50 g (2.27 mmol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethylnaphthalene-2-thiol was dissolved in 20 mL of dry benzene, cooled in an ice bath, and tert-butoxy. 0.28 g (2.50 mmol) of potassium was added, and the mixture was stirred at room temperature for 15 minutes. The mixture was cooled in an ice bath, 0.60 g (2.25 mmol) of 5-fluoro-2-iodonitrobenzene (compound 5-1c) was added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was poured into ice water, neutralized and extracted with ethyl acetate.The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 20) to obtain compound 5-2c (0.57 g, 70%).
¹ H-NMR (CDCl ₃ ) 7.95 (dd, J = 8.4, 2.8 Hz, 1H), 7.49 (d, J = 2.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.27 (dd, J = 8.0, 2.0 Hz, 1H), 7.12 (ddd, J = 9.2, 7.2, 2.8 Hz, 1H), 6.88 (dd, J = 9.2, 5.6 Hz, 1H), 1.72 (s, 4H), 1.32 (s, 6H), 1.27 (s, 6H)
0.56 g (1.57 mmol) of compound 5-2c was dissolved in 10 mL of ethanol, 3 mL of 2N hydrochloric acid and 0.5 g of iron powder were added, and the mixture was heated under reflux for 2 hours. After cooling, the reaction mixture was filtered through celite, and the filtrate was extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 20) to obtain compound 5-3c (0.37 g, 72%).
¹ H-NMR (CDCl ₃ ) 7.41 (dd, J = 8.4, 6.4 Hz, 1H), 7.14 (d, J = 8.4 Hz, 1H), 7.05 (d, J = 2.0 Hz, 1H), 6.74 (dd, J = 8.4, 2.0 Hz, 1H), 6.48 (dd, J = 10.8, 2.8 Hz, 1H), 6.45 (td, J = 8.4, 2.4 Hz, 1 H), 4.40 (brs, 2 H), 1.64 (s, 4 H), 1.22 (s, 6 H), 1.20 (s, 6 H)
0.37 g (1.13 mmol) of compound 5-3c was dissolved in 10 mL of dry benzene, and 1 mL of pyridine was added. To this was added 0.25 g (1.26 mmol) of terephthalic acid monomethyl ester chloride, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 2N hydrochloric acid, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 5) to obtain compound 5-4c (0.49 g, 88%).
¹ H-NMR (CDCl ₃ ) 9.12 (brs, 1H), 8.52 (dd, J = 10.8, 2.8 Hz, 1H), 8.05 (d, J = 8.4 Hz, 2H), 7.65 (dd, J = 8.8, 6.4 Hz, 1H), 7.63 (d, J = 8.8 Hz, 2H), 7.19 (d, J = 8.4 Hz, 1H), 7.07 (d, J = 2.4 Hz, 1H), 6.90 (td, J = 8.0, 2.8 Hz, 1H), 6.80 (dd, J = 8.4, 2.4 Hz, 1H), 3.95 ( s, 3H), 1.62 (s, 4H), 1.20 (s, 6H), 1.14 (s, 6H)
0.49 g (0.99 mmol) of compound 5-4c was dissolved in 2 mL of dry dichloromethane, 10 g of PPA was added, and the mixture was stirred at 110 ° C for 8 hours. After cooling, ice water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 5) to obtain compound 5-5c (0.34 g, 72%).
¹ H-NMR (CDCl ₃ ) 8.07 (d, J = 8.8 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H), 7.41 (s, 1H), 7.40 (dd, J = 8. 8, 5.6 Hz, 1H), 7.04 (dd, J = 10.0, 2.8 Hz, 1H), 7.01 (s, 1H), 6.81 (td, J = 8.0, 2 .8 Hz, 1H), 3.94 (s, 3H), 1.63-1.67 (m, 4H), 1.29 (s, 3H), 1.27 (s, 3H), 1.13 ( s, 3H), 1.06 (s, 3H)
0.34 g (0.72 mmol) of compound 5-5c was suspended in 10 mL of ethanol and 1.5 mL of 2N NaOH, and the mixture was stirred at room temperature for 16 hours. After acidifying the reaction mixture, the mixture was extracted with ethyl acetate, and the organic layer was washed with water and saturated saline, and dried over anhydrous Na. ₂ SO ₄ And dried. The solvent was distilled off under reduced pressure, and the obtained residue was recrystallized from ethyl acetate / n-hexane to obtain compound HX907 (0.23 g, 71%).
¹ H-NMR (DMSO-d ₆ ) 13.1 (brs, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.82 (d, J = 8.4 Hz, 2H), 7.52 (dd, J = 8. 4,6.4 Hz, 1H), 7.51 (s, 1H), 7.19 (dd, J = 10.0, 2.8 Hz, 1H), 7.12 (s, 1H), 7.04 ( td, J = 8.4, 2.8 Hz, 1H), 1.61-1.62 (m, 4H), 1.27 (s, 3H), 1.25 (s, 3H), 1.23 ( s, 3H), 1.05 (s, 3H)
Anal. Calcd for C ₂₈ H ₂₆ FNO ₂ S, C: 73.18%, H: 5.70%, N: 3.05%; Found C: 72.92%, H: 5.99%, N: 2.95%
Test Example 1: Cell differentiation induction assay in HL-60 cells
Using each of the compounds produced in the examples, the cell differentiation-inducing action alone and the effect of coexisting retinoids on the cell differentiation-inducing action were examined. Am80 [4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl) carbamoyl] benzoic acid was used as a retinoid for comparison and coexistence. According to the method described in JP-A-61-76440, the differentiation into granulocytic cells was performed using a promyelocytic leukemia cell line HL-60, and the ability to reduce nitroblue tetrazolium (NBT) was changed. It was determined by measurement. The percentage (%) of the differentiated cells shown in the following table was calculated from the NBT reducing ability. The results are shown in Tables 1 to 3. The structures of the compounds subjected to the test are as follows.

Industrial applicability
The compound of the present invention is useful as an active ingredient of a medicament as a compound having a retinoid action and a compound capable of significantly enhancing the action of a retinoid.

Claims (4)

Formula (I) below:

[Wherein, R ¹ represents a hydrogen atom or a C _1-6 alkyl group; R ² and R ³ each independently represent a hydrogen atom or a C _1-6 alkyl group, or R ² and R ³ together To form a 5- or 6-membered ring together with the carbon atom on the benzene ring to which they are attached (the ring may have one or more C _1-4 alkyl groups on the ring) R ⁴ , R ⁵ , and R ⁶ each independently represent a hydrogen atom, a halogen atom, a C _1-6 alkyl group, or a halogenated C _1-6 alkyl group; Y represents a phenylene group or a pyridinediyl group. X represents —S— or —N (R ⁷ ) — (R ⁷ represents a hydrogen atom or a C _1-6 alkyl group); Z represents C—R ⁸ (R ⁸ represents a hydrogen atom, a halogen atom, C _1-6 alkyl group, or a halogenated _{C 1-6} alkyl group) In or an N],
(1) a compound wherein Z is N or a salt thereof;
(2) R ¹ is a hydrogen atom or a C _1-6 alkyl group, and R ² and R ³ together form a carbon atom on a benzene ring to which they are attached with one or more C _{1- A} compound wherein a 6-membered ring having a _4- alkyl group is formed, R ⁴ , R ⁵ , and R ⁶ are hydrogen atoms, Y is a pyridinediyl group, X is —S—, and Z is CH, or Its salt;
(3) R ¹ is a hydrogen atom or a C _1-6 alkyl group, and R ² and R ³ together form one or two or more C ₁ -C ₁ -carbon atoms together with the carbon atom on the benzene ring to which they are bonded. _A compound or a salt thereof, which forms a 6-membered ring having a _4- alkyl group, wherein R ⁴ and R ⁶ are hydrogen atoms, R ⁵ is a halogen atom, Y is a phenylene group, and Z is CH;
(4) a compound or a salt thereof in which at least two or more of R ⁴ , R ⁵ , R ⁶ , and R ⁸ are groups other than a hydrogen atom; or (5) R ⁴ , R ⁵ , R ⁶ , and R ^A compound or a salt thereof, wherein at least one group out of ⁸ is a halogenated C _1-6 alkyl group. A medicament comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient. A retinoid action enhancer comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient. A nuclear receptor ligand action enhancer comprising the compound according to claim 1 or a physiologically acceptable salt thereof as an active ingredient.