JP2020079305A - 毒性アルデヒド関連疾患および処置 - Google Patents
毒性アルデヒド関連疾患および処置 Download PDFInfo
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- 229940117972 triolein Drugs 0.000 description 1
- JBWKIWSBJXDJDT-UHFFFAOYSA-N triphenylmethyl chloride Chemical compound C=1C=CC=CC=1C(C=1C=CC=CC=1)(Cl)C1=CC=CC=C1 JBWKIWSBJXDJDT-UHFFFAOYSA-N 0.000 description 1
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Abstract
Description
本出願は、2013年1月23日に出願された米国仮特許出願第61/755,613号および2013年11月8日に出願された米国仮特許出願第61/901,796号の優先権および利益を主張し、この米国仮特許出願の全内容が、本明細書において参考として援用される。
細胞における代謝過程および炎症過程は、毒性アルデヒド、例えば、マロンジアルデヒド(MDA)、4−ヒドロキシル−2−ノネナール(4HNE)、および8−ヒドロキシ−2−デオキシグアノシン(8−OHdg)を生じさせる。これらのアルデヒドは、タンパク質、炭水化物、脂質およびDNAに対して高度に反応性であり、化学修飾された生物学的分子、炎症メディエーター、例えば、NF−カッパBの活性化、および多種多様な器官の損傷をもたらす。例えば、レチンアルデヒドは、ホスファチジルエタノールアミン(PE)と反応して、加齢黄斑変性症(AMD)の発達および進行に関与していると考えられるリポフスチンの成分であるA2Eと呼ばれる高度に毒性の化合物を形成することができる。多くの身体防御機構は、毒性アルデヒドを除去またはそのレベルを低下させるように機能する。新規な小分子治療を使用して、網膜における「逃れた」レチンアルデヒドをスカベンジし、したがってA2Eの形成を低減させ、AMDのリスクを低下させることができる(Jordanら(2006年))。
一実施形態において、例えば、以下の項目が提供される。
(項目1)
アルデヒド毒性が結びつけられている疾患、障害、状態、または美容上の徴候の処置、予防、またはそのリスクの低減を必要とする対象において、アルデヒド毒性が結びつけられている疾患、障害、状態、または美容上の徴候を処置し、予防し、またはそのリスクを低減する方法であって、前記方法は、対象に局部的または全身的に第一級アミンを含む化合物を投与することを含み、ただし、前記疾患、障害、または状態は、黄斑変性症でもシュタルガルト病でもない、方法。
(項目2)
前記疾患、障害、または状態が、眼の障害であり、ただし、前記眼の障害が、黄斑変性症でもシュタルガルト病でもない、項目1に記載の方法。
(項目3)
前記眼の障害が、ドライアイ症候群、白内障、円錐角膜、水疱性角膜症および他の角膜症、フックス内皮ジストロフィー、アレルギー性結膜炎、眼性瘢痕性類天疱瘡、PRKの治癒および他の角膜の治癒と関連する状態、涙液脂質の分解または涙腺機能障害と関連する状態、ブドウ膜炎、強膜炎、眼のスティーブンスジョンソン症候群、ならびに眼性酒さからなる群から選択される、項目2に記載の方法。
(項目4)
前記眼の障害が、ドライアイ症候群である、項目3に記載の方法。
(項目5)
前記眼の障害が、PRKの治癒および他の角膜の治癒と関連する状態である、項目3に記載の方法。
(項目6)
前記眼の障害が、ブドウ膜炎、強膜炎、眼のスティーブンスジョンソン症候群、および眼性酒さからなる群から選択される、項目3に記載の方法。
(項目7)
前記眼の障害が、眼性酒さまたはブドウ膜炎である、項目6に記載の方法。
(項目8)
前記眼の障害が、円錐角膜、白内障、水疱性角膜症および他の角膜症、フックス内皮ジストロフィー、眼性瘢痕性類天疱瘡、ならびにアレルギー性結膜炎からなる群から選択される、項目3に記載の方法。
(項目9)
前記疾患、障害、または状態が、乾癬、局部(円板状)狼瘡、接触性皮膚炎、アトピー性皮膚炎、アレルギー性皮膚炎、放射線皮膚炎、尋常性座瘡、シェーグレン−ラルソン症候群および他の魚鱗癬からなる群から選択される皮膚の疾患、障害、または状態であり、前記美容上の徴候が、日光弾力線維症/しわ、肌の張りと弾力、腫脹、湿疹、喫煙または刺激物質誘発性皮膚変化、皮膚切開、および火傷または創傷が関連する皮膚状態からなる群から選択される、項目1に記載の方法。
(項目10)
前記皮膚の疾患、障害、または状態が、乾癬、強皮症、局部(円板状)狼瘡、接触性皮膚炎、アトピー性皮膚炎、アレルギー性皮膚炎、放射線皮膚炎、尋常性座瘡、ならびにシェーグレン−ラルソン症候群および他の魚鱗癬からなる群から選択される、項目9に記載の方法。
(項目11)
前記皮膚の疾患、障害、または状態が、接触性皮膚炎、アトピー性皮膚炎、アレルギー性皮膚炎、または放射線皮膚炎である、項目10に記載の方法。
(項目12)
前記皮膚の疾患、障害、または状態が、シェーグレン−ラルソン症候群である、項目10に記載の方法。
(項目13)
前記美容上の徴候が、日光弾力線維症/しわ、肌の張りと弾力、腫脹、湿疹、喫煙または刺激物質誘発性皮膚変化、皮膚切開、および火傷または創傷が関連する皮膚状態からなる群から選択される、項目9に記載の方法。
(項目14)
前記疾患、障害、または状態が、びらん剤の毒性作用またはアルカリ剤からの火傷と関連する状態である、項目1に記載の方法。
(項目15)
前記びらん剤が、サルファマスタード、ナイトロジェンマスタード、またはホスゲンオキシムである、項目14に記載の方法。
(項目16)
前記アルカリ剤が、石灰、灰汁、アンモニア、または排水管洗浄剤である、項目14に記載の方法。
(項目17)
前記疾患、障害、または状態が、自己免疫性、免疫媒介性、炎症性、心血管性、もしくは神経系の疾患、または糖尿病、メタボリックシンドローム、もしくは線維性疾患である、項目1に記載の方法。
(項目18)
前記疾患、障害、または状態が、狼瘡、強皮症、喘息、慢性閉塞性肺疾患(COPD)、関節リウマチ、炎症性腸疾患、敗血症、アテローム性動脈硬化症、虚血再灌流傷害、パーキンソン病、アルツハイマー病、多発性硬化症、および筋萎縮性側索硬化症からなる群から選択される、項目17に記載の方法。
(項目19)
前記線維性疾患が、腎臓、肝臓、肺、または心臓の線維症である、項目17に記載の方法。
(項目20)
前記化合物が、式(I)の化合物:
(式中、
X、Y、およびZは、それぞれ独立して、N、CH、またはC(NH2)であり、ただし、X、Y、およびZのうちの1つは、Nであり、
pは、0、1、2、または3であり、
各RBは独立して、ハロゲン、ヒドロキシル、カルバモイル、アミノ、または非置換もしくは置換アリールであり、
RAは、
Qaは、C1〜C6直鎖アルキルであり、
Raは、非置換もしくは置換のC1〜C8直鎖もしくはC3〜C8分岐状のアルキルである)である、項目1から19のいずれか一項に記載の方法。
(項目21)
pが、1である、項目20に記載の方法。
(項目22)
RAが、
(項目23)
RBが、ハロゲン、ヒドロキシル、カルバモイル、アミノ、またはアリールである、項目20に記載の方法。
(項目24)
RBが、ハロゲンである、項目23に記載の方法。
(項目25)
RBが、塩素である、項目24に記載の方法。
(項目26)
前記化合物が、
(項目27)
前記化合物が、式(II)の化合物:
(式中、
RB1は、非置換もしくは置換のC1〜C8直鎖もしくはC3〜C8分岐状のアルキル、C2〜C8直鎖もしくはC3〜C8分岐状のアルケニル、C1〜C6アルコキシ、C3〜C7シクロアルキル、C1〜C6アルキル−C3〜C7シクロアルキル、ヒドロキシル、C1〜C6アルキルフェノキシ、フェニル、または置換フェニルであり、
RB2は、H、非置換もしくは置換のC1〜C6直鎖もしくはC3〜C6分岐状のアルキル、フェニル、または置換フェニルであり、
RB3は、H、非置換もしくは置換のC1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはカルボキシルである)である、項目1から19のいずれか一項に記載の方法。
(項目28)
前記化合物が、
3−アミノメチル−5−メチルヘキサン酸、3−アミノメチル−5−メチルヘプタン酸、3−アミノメチル−5−メチル−オクタン酸、3−アミノメチル−5−メチル−ノナン酸、3−アミノメチル−5−メチル−デカン酸、3−アミノメチル−5−メチル−ウンデカン酸、3−アミノメチル−5−メチル−ドデカン酸、3−アミノメチル−5−メチル−トリデカン酸、3−アミノメチル−5−シクロプロピル−ヘキサン酸、3−アミノメチル−5−シクロブチル−ヘキサン酸、3−アミノメチル−5−シクロペンチル−ヘキサン酸、3−アミノメチル−5−シクロヘキシル−ヘキサン酸、3−アミノメチル−5−トリフルオロメチル−ヘキサン酸、3−アミノメチル−5−フェニル−ヘキサン酸、3−アミノメチル−5−(2−クロロフェニル)−ヘキサン酸、3−アミノメチル−5−(3−クロロフェニル)−ヘキサン酸、3−アミノメチル−5−(4−クロロフェニル)−ヘキサン酸、3−アミノメチル−5−(2−メトキシフェニル)−ヘキサン酸、3−アミノメチル−5−(3−メトキシフェニル)−ヘキサン酸、3−アミノメチル−5−(4−メトキシフェニル)−ヘキサン酸、3−アミノメチル−5−ベンジル−ヘキサン酸、(S)−3−アミノメチル−5−メチルヘキサン酸、(R)−3−アミノメチル−5−メチルヘキサン酸、(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸、3−アミノメチル−4,5−ジメチル−ヘキサン酸、(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;(3S,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸、(3R,4R)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;3−アミノメチル−4−イソプロピル−ヘキサン酸、3−アミノメチル−4−イソプロピル−ヘプタン酸、3−アミノメチル−4−イソプロピル−オクタン酸、3−アミノメチル−4−イソプロピル−ノナン酸、3−アミノメチル−4−イソプロピル−デカン酸、3−アミノメチル−4−フェニル−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−エトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−プロポキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−イソプロポキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−tert−ブトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−フルオロメトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−フルオロ−エトキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−フェノキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−クロロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−クロロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−クロロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−フルオロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−フルオロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−フルオロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−メトキシ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−メトキシ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−メトキシ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−6−ヒドロキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−メトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−エトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル−6−プロポキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−6−イソプロポキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−tert−ブトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−フルオロメトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−フルオロ−エトキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル−6−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル−6−フェノキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−クロロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−クロロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−クロロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(4−トリフルオロメチル−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(3−トリフルオロメチル−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(2−トリフルオロメチル−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(4−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(3−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(2−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−6−ベンジルオキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−7−ヒドロキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−メトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−エトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−プロポキシ−ヘプタン酸、(3S,5S)−3−アミノメチル−7−イソプロポキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−tert−ブトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−フルオロメトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−フルオロ−エトキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(3,3,3−トリフルオロ−プロポキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−7−ベンジルオキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−フェノキシ−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(4−クロロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(3−クロロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−クロロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(4−フルオロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(3−フルオロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−フルオロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(4−メトキシ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(3−メトキシ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−メトキシ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(4−トリフルオロメチル−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(3−トリフルオロメチル−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(2−トリフルオロメチル−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(4−ニトロ−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(3−ニトロ−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(2−ニトロ−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−クロロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−クロロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−クロロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェニル)−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(4−クロロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(3−クロロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(2−クロロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(4−メトキシ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(3−メトキシ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(2−メトキシ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(4−フルオロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(3−フルオロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(2−フルオロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−5−メチル−オクタ−7−エン酸、(3S,5R)−3−アミノメチル−5−メチル−ノナ−8−エン酸、(E)−(3S,5S)−3−アミノメチル−5−メチル−オクタ−6−エン酸、(Z)−(3S,5S)−3−アミノメチル−5−メチル−オクタ−6−エン酸、(Z)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸、(E)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸、(E)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸、(Z)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸、(Z)−(3S,5R)−3−アミノメチル−5−メチル−デカ−7−エン酸、(E)−(3S,5R
)−3−アミノメチル−5−メチル−ウンデカ−7−エン酸、(3S,5S)−3−アミノメチル−5,6,6−トリメチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5,6−ジメチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−シクロプロピル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−シクロブチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−シクロペンチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−シクロヘキシル−ヘキサン酸、(3S,5R)−3−アミノメチル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−5−メチル−ノナン酸、(3S,5R)−3−アミノメチル−5−メチル−デカン酸、(3S,5R)−3−アミノメチル−5−メチル−ウンデカン酸、(3S,5R)−3−アミノメチル−5−メチル−ドデカン酸、(3S,5R)−3−アミノメチル−5,9−ジメチル−デカン酸、(3S,5R)−3−アミノメチル−5,7−ジメチル−オクタン酸、(3S,5R)−3−アミノメチル−5,8−ジメチル−ノナン酸、(3S,5R)−3−アミノメチル−6−シクロプロピル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−6−シクロブチル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−6−シクロペンチル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−6−シクロヘキシル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−7−シクロプロピル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−シクロブチル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−シクロペンチル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−シクロヘキシル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−8−シクロプロピル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−8−シクロブチル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−8−シクロペンチル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−8−シクロヘキシル−5−メチル−オクタン酸、(3S,5S)−3−アミノメチル−6−フルオロ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−7−フルオロ−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−8−フルオロ−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−9−フルオロ−5−メチル−ノナン酸、(3S,5S)−3−アミノメチル−7,7,7−トリフルオロ−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−8,8,8−トリフルオロ−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−5−メチル−8−フェニル−オクタン酸、(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸、および(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸
からなる群から選択される化合物またはその薬学的に許容される塩である、項目27に記載の方法。
(項目29)
前記化合物が、(S)−3−(アミノメチル)−5−メチルヘキサン酸もしくは(R)−3−(アミノメチル)−5−メチルヘキサン酸、またはその薬学的に許容される塩もしくはラセミ混合物である、項目28に記載の方法。
(項目30)
前記化合物が、
(項目31)
前記化合物が、式(IIIa)〜(IIIf)の1つの化合物:
(式中、
各R0は独立して、ハロゲン、CF2H、CF3、Rb2、ORb1、COORb1、CON(Rb1)2、N(Rb2)2、NRb1CORb1、NRb1COORb2、NRb1CON(Rb1)2、NRb1SO2Rb2、SO2Rb2、SO2N(Rb1)2、非置換フェニル、またはF、Cl、CF2H、CF3、ORb1、およびRb2から独立して選択される1〜3個の置換基で置換されたフェニルであり、あるいは2個のこのような置換基は、これらが結合しているフェニル環の炭素原子と一緒に、
あるいは、隣接する原子に結合しているとき、任意の2個のR0は、それらが結合している原子と一緒に、
各Rb1は独立して、H、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはC3〜C6シクロアルキルであり、
各Rb2は独立して、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはC3〜C6シクロアルキルであり、
各Rb3は独立して、H、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはハロゲンであり、
各Qbは独立して、H、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、または1〜6個のFで置換されたC1〜C6直鎖もしくはC3〜C6分岐状のアルキルであり、あるいは
両方のQbは、これらが結合している炭素原子と一緒に、C3〜C6炭素環または
nは、0、1、2、または3である)である、項目1から19のいずれか一項に記載の方法。
(項目32)
前記化合物が、
(項目33)
前記化合物が、
(項目34)
前記化合物が、式(IV)の化合物:
(式中、
A’およびR’は、これらが結合している2個の隣接する炭素原子と一緒に、1個の窒素原子および1個の酸素原子を含有する5員ヘテロアリール環を形成し、前記ヘテロアリール環は、RC’で置換されており、「1」、「2」、「3」、「4」、「5」、および「6」は、前記フェニル環への前記ヘテロアリール環の結合点を表し、ただし、前記ヘテロアリール環が、
RC1は、C(QC)2OHであり、または、A’およびR’が、これらが結合している前記2個の隣接する炭素原子と一緒に、
RC2は、NH2であり、または、A’およびR’が、これらが結合している前記2個の隣接する炭素原子と一緒に、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している炭素原子と一緒に、C3〜C6炭素環式環または
RC’は、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、アリール、C1〜C6アルキルで置換されたアリール、またはC1〜C6アルコキシであり、あるいはA’およびR’が、これらが結合している前記2個の隣接する炭素原子と一緒に、
qは、0、1、または2であり、ただし、RC’がフェニルであるとき、qは、0ではなく、
各Tは独立して、ハロゲン、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノである)である、項目1から19のいずれか一項に記載の方法。
(項目35)
前記化合物が、式(IVa)の化合物:
(式中、
AおよびRは、これらが結合している2個の隣接する炭素原子と一緒に、1個の窒素原子および1個の酸素原子を含有する5員ヘテロアリール環を形成し、前記ヘテロアリール環は、RCで置換されており、
RCは、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、アリール、C1〜C6アルキルで置換されたアリール、またはC1〜C6アルコキシであり、
q1は、1または2であり、
各T1は独立して、ハロゲン、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノであり、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している前記炭素原子と一緒に、C3〜C6炭素環式環または
(項目36)
前記化合物が、式(IVb)の化合物:
(式中、
RUおよびRZの一方は、C(QC)2OHであり、他方は、NH2であり、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している前記炭素原子と一緒に、C3〜C6炭素環式環または
q2は、0、1、または2であり、
各T2は独立して、ハロゲン、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノである)である、項目34に記載の方法。
(項目37)
前記化合物が、
(項目38)
前記化合物が、
(項目39)
対象に局部的または全身的に、
前記疾患、障害、または状態は、
ドライアイ症候群、白内障、円錐角膜、水疱性角膜症および他の角膜症、フックス内皮ジストロフィー、アレルギー性結膜炎、眼性瘢痕性類天疱瘡、PRKの治癒および他の角膜の治癒と関連する状態、涙液脂質の分解または涙腺機能障害と関連する状態、ブドウ膜炎、強膜炎、眼のスティーブンスジョンソン症候群、ならびに眼性酒さからなる群から選択される眼の障害、
乾癬、局部(円板状)狼瘡、接触性皮膚炎、アトピー性皮膚炎、アレルギー性皮膚炎、放射線皮膚炎、尋常性座瘡、シェーグレン−ラルソン症候群および他の魚鱗癬からなる群から選択される皮膚の疾患、障害、または状態、ならびに日光弾力線維症/しわ、肌の張りと弾力、腫脹、湿疹、喫煙または刺激物質誘発性皮膚変化、皮膚切開、および火傷または創傷が関連する皮膚状態からなる群から選択される美容上の徴候、
びらん剤の毒性作用またはアルカリ剤からの火傷と関連する状態、ならびに
自己免疫性、免疫媒介性、炎症性、心血管性、または神経系の疾患、糖尿病、メタボリックシンドローム、および線維性疾患
からなる群から選択される、方法。
(項目40)
前記化合物が、
(項目41)
対象におけるアルデヒド毒性が結びつけられている疾患、障害、状態、または美容上の徴候の処置、予防、またはそのリスクの低減のための医薬の製造における、第一級アミンを含む化合物の使用であって、ただし、前記疾患、障害または状態は、黄斑変性症でもシュタルガルト病(Stargradt disease)でもない、使用。
(項目42)
対象においてアルデヒド毒性が結びつけられている疾患、障害、状態、または美容上の徴候を処置し、予防し、またはそのリスクを低減することにおける、第一級アミンを含む化合物の使用であって、ただし、前記疾患、障害または状態は、黄斑変性症でもシュタルガルト病でもない、使用。
本発明は、アルデヒド毒性が病態形成に結びつけられている疾患、障害、または状態の処置、予防、および/またはそのリスクの低減のための化合物(例えば、第一級アミン化合物)に関する。
本発明において使用することができる化合物は、1個もしくは複数の第一級アミン基を含有し、かつ、アルデヒド(例えば、MDAおよびHNE)と反応し(例えば、シッフ塩基縮合機構によって)、錯体を形成する化合物である。好ましくは、このように形成されたアルデヒド錯体は、閉環構造を有し、それによってアルデヒドが錯体から放出され細胞環境中に戻ることを予防し、ここでアルデヒドは、様々な細胞の標的、例えば、タンパク質、脂質、炭水化物、およびDNAと反応し、多数の正常な生理学的過程を妨げ、したがって、疾患、障害、および他の望ましくない状態をもたらしうる。したがって、本発明において使用することができる化合物は、アルデヒド(例えば、MDAおよびHNE)と反応し、それによって、これを減少させ、または排除する化合物である。例えば、化合物の非存在下でのアルデヒドの量または濃度と比較したとき、化合物はアルデヒドの量または濃度を、少なくとも10%、20%、30%、40%、50%、60%、70%、80%、または90%減少させる。
(式中、
X、Y、およびZは、それぞれ独立して、N、CH、またはC(NH2)であり、ただし、X、Y、およびZのうちの1つは、Nであり、
pは、0、1、2、または3であり、
各RBは独立して、ハロゲン、ヒドロキシル、カルバモイル、アミノ、または非置換もしくは置換アリールであり、
RAは、
Qaは、C1〜C6直鎖アルキルであり、
Raは、非置換もしくは置換のC1〜C8直鎖もしくはC3〜C8分岐状のアルキルである)を含む。
(式中、
RB1は、非置換もしくは置換のC1〜C8直鎖もしくはC3〜C8分岐状のアルキル、C2〜C8直鎖もしくはC3〜C8分岐状のアルケニル、C1〜C6アルコキシ、C3〜C7シクロアルキル、C1〜C6アルキル−C3〜C7シクロアルキル、ヒドロキシル、C1〜C6アルキルフェノキシ、フェニル、または置換フェニルであり、
RB2は、H、非置換もしくは置換のC1〜C6直鎖もしくはC3〜C6分岐状のアルキル、フェニル、または置換フェニルであり、
RB3は、H、非置換もしくは置換のC1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはカルボキシルである)を含む。
(式中、
各R0は独立して、ハロゲン、CF2H、CF3、Rb2、ORb1、COORb1、CON(Rb1)2、N(Rb2)2、NRb1CORb1、NRb1COORb2、NRb1CON(Rb1)2、NRb1SO2Rb2、SO2Rb2、SO2N(Rb1)2、非置換フェニル、またはF、Cl、CF2H、CF3、ORb1、およびRb2から独立して選択される1〜3個の置換基で置換されたフェニルであり、あるいは2個のこのような置換基は、これらが結合しているフェニル環の炭素原子と一緒に、
あるいは、隣接する原子に結合しているとき、任意の2個のR0は、それらが結合している原子と一緒に、
各Rb1は独立して、H、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはC3〜C6シクロアルキルであり、
各Rb2は独立して、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはC3〜C6シクロアルキルであり、
各Rb3は独立して、H、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、またはハロゲンであり、
各Qbは独立して、H、C1〜C6直鎖もしくはC3〜C6分岐状のアルキル、または1〜6個のFで置換されたC1〜C6直鎖もしくはC3〜C6分岐状のアルキルであり、あるいは
両方のQbは、これらが結合している炭素原子と一緒に、C3〜C6炭素環または
nは、0、1、2、または3である)を含む。
この態様の1つのクラスは、式(IIIa)の化合物:
(式中、
A’およびR’は、これらが結合している2個の隣接する炭素原子と一緒に、1個の窒素原子および1個の酸素原子を含有する5員ヘテロアリール環を形成し、ヘテロアリール環は、RC’で置換されており、「1」、「2」、「3」、「4」、「5」、および「6」は、フェニル環へのヘテロアリール環の結合点を表し、ただし、ヘテロアリール環が、
RC1は、C(QC)2OHであり、または、A’およびR’が、これらが結合している2個の隣接する炭素原子と一緒に、
RC2は、NH2であり、または、A’およびR’が、これらが結合している2個の隣接する炭素原子と一緒に、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している炭素原子と一緒に、C3〜C6炭素環式環または
RC’は、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、アリール、C1〜C6アルキルで置換されたアリール、またはC1〜C6アルコキシであり、あるいはA’およびR’が、これらが結合している2個の隣接する炭素原子と一緒に、
qは、0、1、または2であり、ただし、RC’がフェニルであるとき、qは、0ではなく、
各Tは独立して、ハロゲン、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノである)を含む。
(式中、
AおよびRは、これらが結合している2個の隣接する炭素原子と一緒に、1個の窒素原子および1個の酸素原子を含有する5員ヘテロアリール環を形成し、ヘテロアリール環は、RCで置換されており、
RCは、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、アリール、C1〜C6アルキルで置換されたアリール、またはC1〜C6アルコキシであり、
q1は、1または2であり、
各T1は独立して、ハロゲン、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノであり、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している炭素原子と一緒に、C3〜C6炭素環式環または
(式中、
RCは、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、アリール、C2〜C6アルキルで置換されたアリール、またはC1〜C6アルコキシであり、
T1は、F、Cl、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノであり、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している炭素原子と一緒に、C3〜C6炭素環式環または
RCが、C3〜C6シクロアルキル、アリール、またはC1〜C6アルキルで置換されたアリールであり、
T1が、F、Cl、メチル、シクロプロピル、シクロブチル、またはシアノであり、
各QCが独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルである化合物、またはその薬学的に許容される塩である。
QCがメチルである化合物、またはその薬学的に許容される塩である。
(式中、
RCは、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、アリール、C1〜C6アルキルで置換されたアリール、またはC1〜C6アルコキシであり、
q1は、1または2であり、
各T1は独立して、F、Cl、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノであり、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している炭素原子と一緒に、C3〜C6炭素環式環または
RCがC3〜C6シクロアルキル、アリール、またはC1〜C6アルキルで置換されたアリールであり、
q1が1であり、
T1がF、Cl、メチル、シクロプロピル、シクロブチル、またはシアノであり、
各QCが独立してC1〜C6アルキルまたはC1〜C6シクロアルキルである化合物、
またはその薬学的に許容される塩である。
(式中、RC、T1、およびQCは、式(IVa2)もしくは(IVa3)において上記で定義されている)である。
RCが、C3〜C6シクロアルキル、アリール、またはC1〜C6アルキルで置換されたアリールであり、
T1が、F、Cl、メチル、シクロブチル、シクロプロピル、またはシアノであり、
各QCが独立して、C1〜C6アルキルまたはC1〜C6シクロアルキルである化合物:またはその薬学的に許容される塩である。
(式中、
RCは、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、アリール、C1〜C6アルキルで置換されたアリール、またはC1〜C6アルコキシであり、
q1は、1または2であり、
各T1は独立して、F、Cl、C1〜C10アルキル、C3〜C6シクロアルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、またはシアノであり、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している炭素原子と一緒に、C3〜C6炭素環式環または
RCがC3〜C6シクロアルキル、アリール、またはC1〜C6アルキルで置換されたアリールであり、
q1が1であり、
T1がF、Cl、メチル、シクロプロピル、シクロブチル、またはシアノであり、
各QCが独立してC1〜C6アルキルまたはC1〜C6シクロアルキルである化合物、
またはその薬学的に許容される塩である。
(式中、
RUおよびRZの1つは、C(QC)2OHであり、他方は、NH2であり、
各QCは独立して、C1〜C6アルキルまたはC3〜C6シクロアルキルであり、あるいは2個のQCは、これらが結合している炭素原子と一緒に、C3〜C6炭素環式環または
q2は、0、1、または2であり、
各T2は独立して、ハロゲン、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノである)である。
(式中、
q2は、0、1、または2であり、
各T2は独立して、F、Cl、C1〜C10アルキル、C3〜C6シクロアルキルで置換されたC1〜C10アルキル、C3〜C6シクロアルキル、またはシアノである)である。
3−アミノメチル−5−メチルヘキサン酸、3−アミノメチル−5−メチルヘプタン酸、3−アミノメチル−5−メチル−オクタン酸、3−アミノメチル−5−メチル−ノナン酸、3−アミノメチル−5−メチル−デカン酸、3−アミノメチル−5−メチル−ウンデカン酸、3−アミノメチル−5−メチル−ドデカン酸、3−アミノメチル−5−メチル−トリデカン酸、3−アミノメチル−5−シクロプロピル−ヘキサン酸、3−アミノメチル−5−シクロブチル−ヘキサン酸、3−アミノメチル−5−シクロペンチル−ヘキサン酸、3−アミノメチル−5−シクロヘキシル−ヘキサン酸、3−アミノメチル−5−トリフルオロメチル−ヘキサン酸、3−アミノメチル−5−フェニル−ヘキサン酸、3−アミノメチル−5−(2−クロロフェニル)−ヘキサン酸、3−アミノメチル−5−(3−クロロフェニル)−ヘキサン酸、3−アミノメチル−5−(4−クロロフェニル)−ヘキサン酸、3−アミノメチル−5−(2−メトキシフェニル)−ヘキサン酸、3−アミノメチル−5−(3−メトキシフェニル)−ヘキサン酸、3−アミノメチル−5−(4−メトキシフェニル)−ヘキサン酸、3−アミノメチル−5−ベンジル−ヘキサン酸、(S)−3−アミノメチル−5−メチルヘキサン酸、(R)−3−アミノメチル−5−メチルヘキサン酸、(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸、3−アミノメチル−4,5−ジメチル−ヘキサン酸、(3R,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;(3S,4S)−3−アミノメチル−4,5−ジメチル−ヘキサン酸、(3R,4R)−3−アミノメチル−4,5−ジメチル−ヘキサン酸MP;3−アミノメチル−4−イソプロピル−ヘキサン酸、3−アミノメチル−4−イソプロピル−ヘプタン酸、3−アミノメチル−4−イソプロピル−オクタン酸、3−アミノメチル−4−イソプロピル−ノナン酸、3−アミノメチル−4−イソプロピル−デカン酸、3−アミノメチル−4−フェニル−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−エトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−プロポキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−イソプロポキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−tert−ブトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−フルオロメトキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−フルオロ−エトキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−フェノキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−クロロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−クロロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−クロロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−フルオロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−フルオロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−フルオロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−メトキシ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−メトキシ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−メトキシ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(4−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(3−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−(2−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−6−ヒドロキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−メトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−エトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル−6−プロポキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−6−イソプロポキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−tert−ブトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−フルオロメトキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−フルオロ−エトキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル−6−(3,3,3−トリフルオロ−プロポキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル−6−フェノキシ−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−クロロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−クロロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−クロロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェノキシ)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(4−トリフルオロメチル−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(3−トリフルオロメチル−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(2−トリフルオロメチル−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(4−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(3−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−5−メチル6−(2−ニトロ−フェノキシ)−ヘキサン酸、(3S,5S)−3−アミノメチル−6−ベンジルオキシ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−7−ヒドロキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−メトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−エトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−プロポキシ−ヘプタン酸、(3S,5S)−3−アミノメチル−7−イソプロポキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−tert−ブトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−フルオロメトキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−フルオロ−エトキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(3,3,3−トリフルオロ−プロポキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−7−ベンジルオキシ−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−フェノキシ−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(4−クロロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(3−クロロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−クロロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(4−フルオロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(3−フルオロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−フルオロ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(4−メトキシ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(3−メトキシ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−7−(2−メトキシ−フェノキシ)−5−メチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(4−トリフルオロメチル−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(3−トリフルオロメチル−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(2−トリフルオロメチル−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(4−ニトロ−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(3−ニトロ−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−7−(2−ニトロ−フェノキシ)−ヘプタン酸、(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−クロロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−クロロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−クロロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−メトキシ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−メトキシ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−メトキシ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(4−フルオロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(3−フルオロ−フェニル)−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−6−(2−フルオロ−フェニル)−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(4−クロロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(3−クロロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(2−クロロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(4−メトキシ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(3−メトキシ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(2−メトキシ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(4−フルオロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(3−フルオロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−(2−フルオロ−フェニル)−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−5−メチル−オクタ−7−エン酸、(3S,5R)−3−アミノメチル−5−メチル−ノナ−8−エン酸、(E)−(3S,5S)−3−アミノメチル−5−メチル−オクタ−6−エン酸、(Z)−(3S,5S)−3−アミノメチル−5−メチル−オクタ−6−エン酸、(Z)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸、(E)−(3S,5S)−3−アミノメチル−5−メチル−ノナ−6−エン酸、(E)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸、(Z)−(3S,5R)−3−アミノメチル−5−メチル−ノナ−7−エン酸、(Z)−(3S,5R)−3−アミノメチル−5−メチル−デカ−7−エン酸、(E)−(3S,5R
)−3−アミノメチル−5−メチル−ウンデカ−7−エン酸、(3S,5S)−3−アミノメチル−5,6,6−トリメチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5,6−ジメチル−ヘプタン酸、(3S,5S)−3−アミノメチル−5−シクロプロピル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−シクロブチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−シクロペンチル−ヘキサン酸、(3S,5S)−3−アミノメチル−5−シクロヘキシル−ヘキサン酸、(3S,5R)−3−アミノメチル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−5−メチル−ノナン酸、(3S,5R)−3−アミノメチル−5−メチル−デカン酸、(3S,5R)−3−アミノメチル−5−メチル−ウンデカン酸、(3S,5R)−3−アミノメチル−5−メチル−ドデカン酸、(3S,5R)−3−アミノメチル−5,9−ジメチル−デカン酸、(3S,5R)−3−アミノメチル−5,7−ジメチル−オクタン酸、(3S,5R)−3−アミノメチル−5,8−ジメチル−ノナン酸、(3S,5R)−3−アミノメチル−6−シクロプロピル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−6−シクロブチル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−6−シクロペンチル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−6−シクロヘキシル−5−メチル−ヘキサン酸、(3S,5R)−3−アミノメチル−7−シクロプロピル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−シクロブチル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−シクロペンチル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−7−シクロヘキシル−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−8−シクロプロピル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−8−シクロブチル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−8−シクロペンチル−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−8−シクロヘキシル−5−メチル−オクタン酸、(3S,5S)−3−アミノメチル−6−フルオロ−5−メチル−ヘキサン酸、(3S,5S)−3−アミノメチル−7−フルオロ−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−8−フルオロ−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−9−フルオロ−5−メチル−ノナン酸、(3S,5S)−3−アミノメチル−7,7,7−トリフルオロ−5−メチル−ヘプタン酸、(3S,5R)−3−アミノメチル−8,8,8−トリフルオロ−5−メチル−オクタン酸、(3S,5R)−3−アミノメチル−5−メチル−8−フェニル−オクタン酸、(3S,5S)−3−アミノメチル−5−メチル−6−フェニル−ヘキサン酸、(3S,5R)−3−アミノメチル−5−メチル−7−フェニル−ヘプタン酸。
ラット皮質初代培養物を、インキュベーター中に24時間または48時間入れ、様々な濃度の化合物9で処置した。次いで、20μLの培養培地を、Bergmeyerら、Methods of Enzymatic Analysis、第3版(1983年)に記載された通りのLDHアッセイのために取り出した。図2に示すように、化合物9は、ニューロンにおいてアルデヒド媒介性の細胞死を予防した。
雄性C57BI/6マウスに、LPS(20mg/kg)に曝露させる30分前に化合物9を投与した。LPS曝露の2時間後、血液をマウスから収集し、ELISAを行って、循環サイトカインの量を判定した。図3および図4に示すように、化合物9による処置は、炎症促進性サイトカイン、例えば、IL−5およびIL−1β、IL−17、およびTNFの低減をもたらした。また、図4は、化合物9による処置が、抗炎症性サイトカイン、例えば、IL−10の上昇をもたらしたことを示す。さらに、様々な他のケモカイン、例えば、エオタキシン、IL−12、IP−10、LIF、MCP−1、MIG、MIP、およびRANTESはまた、化合物9による処置によって減少した。
接触性皮膚炎の処置における化合物9の有効性を判定するために、酢酸ミリスチン酸ホルボール(「PMA」)を、マウス(群毎にN=10)の右の耳介の前側部分および後側部分の両方に局部的に適用した(20μL中2.5μg)。対照として、左の耳介の前側部分および後側部分の両方に、20μLのエタノール(PMA賦形剤)を投与した。PMA適用の6時間後、右および左の耳介の両方の厚さを判定した。測定は、毛または折り畳まれた耳介を含まないように注意しながら両方の耳の同じ領域から少なくとも2回判定した。結果を図5Aに示す。
アレルギー性皮膚炎の処置における化合物9の有効性を測定するために、オキサゾロン(「OXL」)を、マウスの剪毛した腹部に適用した(アセトン中1.5%、100μL)。7日後、OXL処置マウスの耳介の厚さを判定した。次いで、化合物9(100mg/kg)またはビヒクル(すなわち、Captisol)を、マウスの腹腔内に投与し、それに続いて右の耳介の前側部分および後側部分の両方に30分後にOXL(1%、20μL)を局部適用した。対照として、左の耳介の前側部分および後側部分の両方に、20μLのアセトン(OXL賦形剤)を投与した。両方の耳の耳介の厚さを、24時間後に再び測定した。群毎にN=10。結果を図5Bに示す。
5つの別々の反応バイアルに、それぞれ、化合物1、2、12、14、および16(0.064mmol)、MDA塩(22.7%MDA、0.064mmol)、ならびにトリオレイン酸グリセリル(600mg)を添加した。混合物に、PBS水溶液(約2.5ml)中の20重量%Capitsol、それに続いてリノール酸(600mg)を添加した。反応混合物を周囲温度にて激しく撹拌し、LC/MSによってモニターした。化合物は、MDAと急速に反応し、MDA付加体を形成する。化合物1、12、14、および16について、付加体の大部分は、ビス−オキサミナールであった。他のMDA付加体がまた、反応の異なる時点において形成された。
2−(3−アミノ−6−クロロ−5−フルオロキノリン−4−イル)プロパン−2−オール(化合物(1))の合成
(E)−および(Z)−3−クロロ−2−フルオロ−6−(2−ニトロビニルアミノ)安息香酸(1−1)。粗製の湿ったメタゾン酸(G.B. Bachmanら、J. Am. Chem. Soc.69巻、365〜371頁(1947年)の方法によって調製した)37.19gを、6−アミノ−3−クロロ−2−フルオロ安息香酸(Butt Park Ltd.、Camelford、Cornwall、UK)50gおよびアセトン750mLと混合し、透明溶液が形成されるまで振盪した。この溶液に、水200mLおよび12N HCl 200mLを順次添加し、溶液を室温で3日間維持した。混合物を水2Lで希釈し、濾過した。濾液を蒸発させてアセトンを除去し、濾過した。合わせた固体を水(4×200mL)で洗浄し、高真空下で60℃にて乾燥させ、1−1をE−およびZ−異性体の4.5:1混合物として得た。
1H NMR (400 MHz, DMSO−d6) δ: E−異性体 6.79 (d, 1H, J = 6.4 Hz), 7.58 (d, 1H, J = 8.4 Hz), 7.83 (t, 1H, J = 8.4 Hz), 7.99 (dd, 1H, J = 6.4, 13.2 Hz), 12.34 (d, 1H, NH, J = 13.2 Hz), 14.52 (br, 1H, OH)。Z−異性体 7.39 (d, 1H, J = 11.2 Hz), 7.42 (d, 1H, J = 9.6 Hz), 7.71 (t, 1H, J = 8.4 Hz), 8.49 (t, 1H, J = 11.6 Hz), 10.24 (d, 1H, NH, J = 12.4 Hz), 14.52 (br, 1H, OH)。LC−MS:259[(M−H)−]。
1H NMR (400 MHz, DMSO−d6) δ: 7.52 (dd, 1H, J = 0.8, 8.8 Hz), 7.91 (dd, 1H, J = 7.2, 8.8 Hz), 9.15 (s, 1H), 13.0 (br, 1H, OH)。LC−MS:242.9(MH)+、264.9(MNa)+。
1H NMR (400 MHz, CDCl3) δ: 4.70 (br, 2H, NH2), 7.42 (dd, 1H, J = 6.0, 9.0 Hz), 7.73 (dd, 1H, J = 1.8, 8.8 Hz)。LC−MS:274.8(MH)+、276.8[(M+2)H]+、278.8[(M+4)H]+。
1H NMR (400 MHz, CDCl3) δ: 4.70 (br, 2H, NH2), 7.42 (dd, 1H, J = 6.0, 9.0 Hz), 7.73 (dd, 1H, J = 1.8, 8.8 Hz)。LC−MS:274.8(MH)+、276.8[(M+2)H]+、278.8[(M+4)H]+。
2−(3−アミノ−6−クロロキノリン−4−イル)プロパン−2−オール(化合物(2))の合成
6−クロロ−3−ニトロキノリン−4−オール(2−1)。乾燥DMF 1L中のcis−およびtrans−5−クロロ−2−(2−ニトロビニルアミノ)安息香酸(68.4 g, Susら, Liebigs Ann. Chem. 583: 150 (1953年))、EDC 73g、およびHOSu 35.7gの混合物を、室温で1時間撹拌した。DMAP 45.8gを添加した後、混合物を室温で2時間撹拌した。撹拌した混合物に、10% HOAc 1Lをゆっくりと添加し、得られた懸濁液を10% HOAc 2L中に注いだ。固体を濾別し、10% HOAc(4×400mL)で洗浄し、高真空下で80℃にて乾燥させ、(2−1)を黄褐色粉末として得た。
1H NMR (400 MHz, CDCl3) δ: 4.47 (br, 2H, NH2), 7.41 (dd, 1H, J = 2.4, 8.8 Hz), 7.89 (d, 1H, J = 9.2 Hz), 7.96 (d, 1H, J = 2.4 Hz), 8.45 (s, 1H)。LC−MS:256.7(MH)+、258.7[(M+2)H]+、260.7[(M+4)H]+。
1H NMR (400 MHz, CDCl3) δ: 1.93 (s, 6H), 3.21 (br, 1H, OH), 5.39 (br, 2H, NH2), 7.29 (dd, 1H, J = 2.0, 8.8 Hz), 7.83 (d, 1H, J = 8.8 Hz), 7.90 (d, 1H, J = 2.0 Hz), 8.21 (s, 1H)。13C NMR (100 MHz, CDCl3) δ: 31.5, 76.5, 123.2, 124.6, 125.7, 127.5, 131.5, 131.9, 138.8, 141.5, 146.5。LC−MS:236.9(MH)+、238.9[(M+2)H]+。
2−(5−アミノ−7−クロロ−2−p−トリルベンゾオキサゾール−6−イル)プロパン−2−オール(化合物(12))の合成
3−メトキシ−4−(トリフルオロアセチルアミノ)安息香酸(12−1)。4−アミノ−3−メトキシ安息香酸5.0gのEtOAc 200mL懸濁液に、撹拌しながらEtOAc 50mL中の(CF3CO)2O 5.0mLの溶液を添加した。完全に添加した後、反応混合物を室温にて2時間さらに撹拌した。溶液を濾過し、濾液を蒸発乾固した。残留物をEtOAc中に溶解して蒸発させることを2回行った。最終残留物を高真空下にて乾燥させ、純粋な(12−1)を白色固体として得た。
1H NMR (400 MHz, CDCl3) δ: 1.89 (s, 6H), 2.41 (s, 3H), 4.45 (br, 3H, NH2およびOH), 6.81 (s, 1H), 7.27 (d, 1H, J = 8.8 Hz), 8.07 (d, 1H, J = 8.4 Hz). 13C NMR (100 MHz, CDCl3) δ: 21.7, 31.0, 76.9, 106.2, 113.5, 124.0, 126.8, 127.6, 129.6, 140.9, 142.2, 142.9, 145.3, 164.1.LC−MS:317.0(MH)+、319.0[(M+2)H]+。
2−(5−アミノ−7−クロロ−2−フェニルベンゾオキサゾール−6−イル)プロパン−2−オール(化合物(13))の合成
4−ベンゾイルアミノ−5−ヒドロキシ−2−ニトロ安息香酸エチルエステル(13−1)。1,4−ジオキサン25mL中の粗製4−アミノ−5−ヒドロキシ−2−ニトロ安息香酸エチルエステル(12−4)2.26gおよび塩化ベンゾイル1.91gの混合物を、95℃で1時間撹拌した。溶媒を除去し、残留物をEtOHで2回蒸発させた。残留物をさらにEtOAcで2回蒸発させ、次いで、高真空下にて60℃で乾燥させ、粗製(13−1)を黄褐色固体として得た。
1H NMR (400 MHz, CDCl3) δ: 1.92 (s, 6H), 4.69 (br, 3H, NH2およびOH), 6.87 (s, 1H), 7.48−7.54 (3H), 8.21 (m, 2H). 13C NMR (100 MHz, CDCl3) δ: 31.0, 77.0, 106.3, 113.6, 126.8, 126.9, 127.7, 128.9, 131.6, 140.9, 143.0, 145.4, 163.9. LC−MS:303.1(MH)+、305.0[(M+2)H]+。
2−(6−アミノ−4−クロロ−3−シクロプロピルベンゾイソオキサゾール−5−イル)プロパン−2−オール(化合物(14))の合成
(2−クロロ−4,6−ジメトキシフェニル)シクロプロピルメタノン(14−1)。1−クロロ−3,5−ジメトキシベンゼン28.28gおよびシクロプロパンカルボニルクロリド17.8mLの乾燥1,2−ジクロロエタン(DCE)300mL溶液をアルゴンで保護し、ドライアイス/アセトン浴中で−30〜−40℃まで冷却した。これに、AlCl3粉末32.4gを活発に撹拌しながら少しずつ添加した。完全に添加した後、溶液を−30〜−40℃で30分間撹拌し、次いで、室温まで加温した。室温にて20分間さらに撹拌した後、混合物を1kgの氷上に撹拌しながら添加した。混合物をエーテル(3×300mL)で抽出した。合わせた有機層をMgSO4で乾燥させ、蒸発させた。残留物を溶離液としてヘキサン/EtOAcを用いたカラムクロマトグラフィーによって分離し、純粋な(14−1)を白色固体として得た。
1H NMR (400 MHz, CDCl3) δ: 1.10 (m, 2H), 1.20 (m, 2H), 1.91 (s, 6H), 2.18 (m, 1H), 4.28 (br, 2H, NH2), 6.57 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 8.68, 9.35, 30.0, 77.4, 97.4, 121.2, 125.1, 133.1, 145.7, 149.3, 166.4. LC−MS:266.9(MH)+、269.0[(M+2)H]+。
2−(5−アミノ−7−クロロ−3−シクロプロピルベンゾイソオキサゾール−6−イル)プロパン−2−オール(化合物(15))の合成
シクロプロパンカルボン酸メトキシメチルアミド(15−1)。DCM 200mL中のN,O−ジメチルヒドロキシルアミン塩酸塩9.75gおよびピリジン9.7mLの懸濁液を、室温にて10分間撹拌し、次いで、撹拌しながら氷浴中で冷却した。この懸濁液に、DCM 40mL中のシクロプロパンカルボニルクロリド9.03mLの溶液を活発に撹拌しながら滴下した。完全に添加した後、混合物を0℃で30分間、次いで、室温にて1時間撹拌した。溶液をDCM 100mLで希釈し、ブライン(3×200mL)で洗浄し、MgSO4で乾燥させた。溶媒を蒸発させ、残留物を真空蒸留した。画分を43〜45℃/1mmHgで収集し、(15−1)を無色液体として得た。
1H NMR (400 MHz, CDCl3) δ: 1.10 (m, 2H), 1.15 (m, 2H), 1.91 (s, 6H), 2.09 (m, 1H), 4.33 (br, 3H, NH2およびOH), 6.70 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 7.11, 7.25, 30.7, 77.1, 105.6, 113.7, 120.4, 132.5, 144.4, 155.4, 160.5. LC−MS:267.1(MH)+、269.1[(M+2)H]+。
2−(6−アミノ−4−クロロ−3−シクロプロピルベンゾイソオキサゾール−7−イル)プロパン−2−オール(化合物(16))の合成
1−(6−アミノ−4−クロロ−3−シクロプロピル−ベンゾイソオキサゾール−7−イル)エタノン(16−3)。撹拌し、氷浴によって冷却しながら、(16−2)636mgおよびCuI 43mgの混合物に、3MのMeMgCl/THF 8.16mLをゆっくりと添加した。懸濁液をアルゴン下で保護し、油浴中で70℃で15分間加熱した。混合物を氷浴中で0℃に冷却した。これに、MeOH 136mL、それに続いて固体NH4Cl 2.17gおよび水13.6mLを添加した。混合物を撹拌しながら室温に加温し、透明な溶液を得て、これをシリカゲル上に吸着させ、空気乾燥させ、溶離液としてヘキサン−EtOAcを用いたシリカゲルカラムクロマトグラフィーによって分離し、(16−3)を黄色固体として得た。
1H NMR (400 MHz, CDCl3) δ: 1.12 (m, 2H), 1.18 (m, 2H), 1.78 (s, 6H), 2.17 (m, 1H), 4.86 (br, 2H, NH2), 6.60 (s, 1H). 13C NMR (100 MHz, CDCl3) δ: 8.81, 9.26, 30.1, 74.1, 112.7, 114.4, 121.8, 131.3, 143.8, 148.6, 166.1. LC−MS:267.0(MH)+、268.9[(M+2)H]+。
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JP2008542291A (ja) * | 2005-05-26 | 2008-11-27 | ニューロン システムズ | 網膜疾患を処置するための組成物および方法 |
WO2011071995A2 (en) * | 2009-12-08 | 2011-06-16 | Case Western Reserve University | Compounds and methods of treating ocular disorders |
WO2011078204A1 (ja) * | 2009-12-24 | 2011-06-30 | 浜理薬品工業株式会社 | 高脂血症の予防または治療剤、および抗疲労剤 |
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