JP6514114B2 - 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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- JP6514114B2 JP6514114B2 JP2015553925A JP2015553925A JP6514114B2 JP 6514114 B2 JP6514114 B2 JP 6514114B2 JP 2015553925 A JP2015553925 A JP 2015553925A JP 2015553925 A JP2015553925 A JP 2015553925A JP 6514114 B2 JP6514114 B2 JP 6514114B2
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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))。
なる。
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:
またはその薬学的に許容される塩
(式中、
X、Y、およびZは、それぞれ独立して、N、CH、またはC(NH 2 )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R B 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、
R A は、
であり、
Q a は、C 1 〜C 6 直鎖アルキルであり、
R a は、非置換もしくは置換のC 1 〜C 8 直鎖もしくはC 3 〜C 8 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)
R A が、
である、項目20に記載の方法。
(項目23)
R B 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)
R B が、ハロゲンである、項目23に記載の方法。
(項目25)
R B が、塩素である、項目24に記載の方法。
(項目26)
前記化合物が、
またはその薬学的に許容される塩である、項目20に記載の方法。
(項目27)
前記化合物が、式(II)の化合物:
またはその薬学的に許容される塩
(式中、
R B1 は、非置換もしくは置換のC 1 〜C 8 直鎖もしくはC 3 〜C 8 分岐状のアルキル、C 2 〜C 8 直鎖もしくはC 3 〜C 8 分岐状のアルケニル、C 1 〜C 6 アルコキシ、C 3 〜C 7 シクロアルキル、C 1 〜C 6 アルキル−C 3 〜C 7 シクロアルキル、ヒドロキシル、C 1 〜C 6 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、
R B2 は、H、非置換もしくは置換のC 1 〜C 6 直鎖もしくはC 3 〜C 6 分岐状のアルキル、フェニル、または置換フェニルであり、
R B3 は、H、非置換もしくは置換のC 1 〜C 6 直鎖もしくはC 3 〜C 6 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、
またはその薬学的に許容される塩である、項目1から19のいずれか一項に記載の方法。
(項目31)
前記化合物が、式(IIIa)〜(IIIf)の1つの化合物:
またはその薬学的に許容される塩
(式中、
各R 0 は独立して、ハロゲン、CF 2 H、CF 3 、R b2 、OR b1 、COOR b1 、CON(R b1 ) 2 、N(R b2 ) 2 、NR b1 COR b1 、NR b1 COOR b2 、NR b1 CON(R b1 ) 2 、NR b1 SO 2 R b2 、SO 2 R b2 、SO 2 N(R b1 ) 2 、非置換フェニル、またはF、Cl、CF 2 H、CF 3 、OR b1 、およびR b2 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、
(式中、「 * 」は、前記置換基が前記フェニル環上で結合している炭素原子の位置を表す)から選択される構造を有する5員もしくは6員環を形成し、
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R 0 は、それらが結合している原子と一緒に、
(式中、「 * 」は、前記2個のR 0 が結合している原子の位置を表す)から選択される構造を有する5員もしくは6員環を形成し、あるいは
各R b1 は独立して、H、C 1 〜C 6 直鎖もしくはC 3 〜C 6 分岐状のアルキル、またはC 3 〜C 6 シクロアルキルであり、
各R b2 は独立して、C 1 〜C 6 直鎖もしくはC 3 〜C 6 分岐状のアルキル、またはC 3 〜C 6 シクロアルキルであり、
各R b3 は独立して、H、C 1 〜C 6 直鎖もしくはC 3 〜C 6 分岐状のアルキル、またはハロゲンであり、
各Q b は独立して、H、C 1 〜C 6 直鎖もしくはC 3 〜C 6 分岐状のアルキル、または1〜6個のFで置換されたC 1 〜C 6 直鎖もしくはC 3 〜C 6 分岐状のアルキルであり、
あるいは
両方のQ b は、これらが結合している炭素原子と一緒に、C 3 〜C 6 炭素環または
(式中、「 * 」は、両方のQ b が結合している前記炭素原子の位置を表す)から選択される飽和複素環を形成し、前記炭素環または前記複素環は、1個もしくは複数のR b3 で任意選択で置換されており、
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、
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31に記載の方法。
(項目33)
前記化合物が、
またはその薬学的に許容される塩である、項目32に記載の方法。
(項目34)
前記化合物が、式(IV)の化合物:
またはその薬学的に許容される塩
(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、R C ’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、
であるとき、R C1 は、C(Q C ) 2 OHであり、R C2 は、存在せず、かつR C ’は、存在せず、そして前記ヘテロアリール環が、
であるとき、R C1 は、存在せず、R C2 は、NH 2 であり、かつR C ’は、存在せず、
R C1 は、C(Q C ) 2 OH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、
を形成するとき、R C1 は、存在せず、
R C2 は、NH 2 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、
を形成するとき、R C2 は、存在せず、
各Q C は独立して、C 1 〜C 6 アルキルまたはC 3 〜C 6 シクロアルキルであり、あるいは2個のQ C は、これらが結合している炭素原子と一緒に、C 3 〜C 6 炭素環式環または
(式中、「 * 」は、前記2個のQ C が結合している前記炭素原子の位置を表す)から選択される飽和複素環を形成し、
R C ’は、C 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキルで置換されたC 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキル、アリール、C 1 〜C 6 アルキルで置換されたアリール、またはC 1 〜C 6 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、
を形成するとき、R C ’は、存在せず、
qは、0、1、または2であり、ただし、R C ’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、C 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキルで置換されたC 1 〜C 10 アルキル、C 3 〜C 6 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:
またはその薬学的に許容される塩
(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、R C で置換されており、
R C は、C 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキルで置換されたC 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキル、アリール、C 1 〜C 6 アルキルで置換されたアリール、またはC 1 〜C 6 アルコキシであり、
q 1 は、1または2であり、
各T 1 は独立して、ハロゲン、C 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキルで置換されたC 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキル、またはシアノであり、
各Q C は独立して、C 1 〜C 6 アルキルまたはC 3 〜C 6 シクロアルキルであり、あるいは2個のQ C は、これらが結合している前記炭素原子と一緒に、C 3 〜C 6 炭素環式環または
(式中、「 * 」は、前記2個のQ C が結合している前記炭素原子の位置を表す)から選択される飽和複素環を形成する)である、項目34に記載の方法。
(項目36)
前記化合物が、式(IVb)の化合物:
またはその薬学的に許容される塩
(式中、
R U およびR Z の一方は、C(Q C ) 2 OHであり、他方は、NH 2 であり、
各Q C は独立して、C 1 〜C 6 アルキルまたはC 3 〜C 6 シクロアルキルであり、あるいは2個のQ C は、これらが結合している前記炭素原子と一緒に、C 3 〜C 6 炭素環式環または
(式中、「 * 」は、前記2個のQ C が結合している前記炭素原子の位置を表す)から選択される飽和複素環を形成し、
q 2 は、0、1、または2であり、
各T 2 は独立して、ハロゲン、C 1 〜C 10 アルキル、C 3 〜C 6 シクロアルキルで置換されたC 1 〜C 10 アルキル、C 3 〜C 6 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、
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34に記載の方法。
(項目38)
前記化合物が、
またはその薬学的に許容される塩である、項目37に記載の化合物。
(項目39)
対象に局部的または全身的に、
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を投与することを含む、それ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、または状態を処置し、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、
またはその薬学的に許容される塩である、項目39に記載の方法。
(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。
本発明において有用な化合物
(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)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。
ヒドロキシル、F、Cl、
非置換C1〜C6アルコキシ、ハロゲンまたはフェニルで置換されたC1〜C6アルコキシ、
非置換フェニル、ならびにF、Cl、および非置換C1〜C6アルコキシから独立に選択される1個もしくは複数の置換基で置換されたフェニル、
非置換フェノキシ、ならびにF、Cl、非置換C1〜C6アルキル、FまたはClで置換されたC1〜C6アルキル、非置換C1〜C6アルコキシ、およびニトロから独立に選択される1個もしくは複数の置換基で置換されたフェノキシ
から独立して選択される1個もしくは複数の置換基で置換されたC1〜C8直鎖もしくはC3〜C8分岐状のアルキルである化合物である。
(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
)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、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。
(実施例2)
(実施例3)
(実施例4)
(実施例5)
(実施例6)
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
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]+。
1H NMR (400 MHz, CD3OD) δ: 1.79 (s, 3H), 1.80 (s, 3H), 7.36 (dd, 1H, J = 7.2, 8.8 Hz), 7.61 (dd, 1H, J = 1.6, 9.0 Hz), 8.35 (s, 1H)。13C NMR (100 MHz, CD3OD) δ: 29.8, 29.9, 76.7, 120.4 (d, JC−F = 12 Hz), 120.5 (d, JC−F = 4 Hz), 125.4, 126.1 (d, JC−F = 3 Hz), 126.6 (d, JC−F = 3 Hz), 143.1, 143.2 (d, JC−F = 5 Hz), 148.3, 152.7 (d, JC−F = 248 Hz)。LC−MS:254.9(MH)+、256.9[(M+2)H]+。
(実施例7)
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
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]+。
(実施例8)
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
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]+。
(実施例9)
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
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]+。
(実施例10)
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
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]+。
(実施例11)
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
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]+。
(実施例12)
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
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]+。
当業者は、本明細書に記載の特定の実施形態および方法の多くの均等物を認識するか、または単なる日常の実験を使用して確認することができる。このような均等物は、本発明の範囲に包含されることが意図されている。
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Claims (4)
- 疾患、障害、または状態の処置のための医薬組成物であって、前記医薬組成物は、式(I)の化合物:
またはその薬学的に許容される塩
(式中、
XはCHであり、ZはNであり、YはC(NH2)であり、
pは、0、1、2、または3であり、
各RBは独立して、ハロゲンであり、
RAは、
であり、
Qaは、C1〜C6直鎖アルキルである)を含み、前記疾患、障害、または状態は、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、医薬組成物。 - pが、1である、請求項1に記載の医薬組成物。
- 各Qaがメチルである、請求項1または2に記載の医薬組成物。
- 前記化合物が、
またはその薬学的に許容される塩である、請求項1に記載の医薬組成物。
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