JP2014527532A - メタ置換ビフェニル末梢に限局されたfaah阻害剤 - Google Patents
メタ置換ビフェニル末梢に限局されたfaah阻害剤 Download PDFInfo
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- JP2014527532A JP2014527532A JP2014526261A JP2014526261A JP2014527532A JP 2014527532 A JP2014527532 A JP 2014527532A JP 2014526261 A JP2014526261 A JP 2014526261A JP 2014526261 A JP2014526261 A JP 2014526261A JP 2014527532 A JP2014527532 A JP 2014527532A
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Abstract
Description
本出願は、2011年8月19日に出願された米国仮特許出願第61/525,636号の優先権および利益を主張し、その開示の全てが引用により本明細書に組み込まれる。
本発明は、国立衛生研究所より与えられたNIH助成金番号R01 DA0l2413号およびNIDA助成金番号R01 DA0l2447号およびRL1 AA0l7538号のもとで、米国政府支援により創出された。米国政府は本発明に一定の権利を有する。
本発明は、脂肪酸アミド加水分解酵素(FAAH)の末梢に限局された阻害剤を製造および使用する方法を提供する。本発明は、FAAH活性を抑制する化合物を提供し、中枢神経系(CNS)外のアナンダミドレベルを増大させる。脳へのアクセスが比較的できないにもかかわらず、そのような化合物は、炎症の齧歯類モデルにおける持続痛を示す行動反応の軽減に有用である。本発明はまた、FAAHを阻害する方法ならびに、限定されないが、疼痛、炎症、免疫異常、皮膚炎、粘膜炎、末梢感覚ニューロンの過剰反応、神経皮膚炎、および過活動膀胱などの症状を治療するための方法も記載する。したがって、本発明はまた、末梢FAAHの選択的阻害が(CNSのFAAHとは対照的に)有効性をもたらす、症状を治療するための化合物、方法、および医薬組成物も提供する。
本明細書および添付の特許請求の範囲で用いられる場合、単数形「a」、「an」および「the」は、文脈上明白に別段の記載がない限り、複数を包含する。
本出願は、式Iの末梢に限局されたFAAH阻害剤を提供する。これらの阻害剤は、FAAH阻害活性を保持し、末梢に限局され、これは非常に有利であり、なぜなら、これらの阻害剤は哺乳類の対象において代謝される場合に反応性ベンゾキノンを実質的に形成しないからである。
本明細書中で記載される化合物に関するアッセイは、ハイスループットスクリーニングにしたがう。好ましいアッセイは、したがって、FAAHに対する阻害剤の結合またはオレオイルエタノールアミドもしくはアナンダミドなどの基質の加水分解によって生じる反応生成物(たとえば、脂肪酸アミドもしくはエタノールアミン)の放出を検出する。基質を標識して、放出された反応生成物の検出を促進することができる。特定の反応生成物の存在、非存在、または定量化に関するハイスループットアッセイは、当業者に周知である。したがって、たとえば米国特許第5,559,410号は、タンパク質についてのハイスループットスクリーニング法を開示し、米国特許第5,576,220号および同第5,541,061号は、リガンド/抗体結合についてのスクリーニングのハイスループット法を開示する。
末梢カンナビノイド受容体は疼痛開始の強力な阻害制御を発揮するが、この内因性鎮痛機序に通常関与する内因性カンナビノイドシグナルは解明されていない。エンドカンナビノイドアナンダミドの分解の一因となる酵素である脂肪酸アミド加水分解酵素(FAAH)の新しい末梢に限局された阻害剤である、下記実施例で記載される化合物URB937は、FAAH活性を抑制し、中枢神経系(CNS)外のアナンダミドレベルを増加させることが判明している。URB937が脳からの輸送系によって媒介される排出を驚くほど受けやすいことが判明したことは注目に値する。意外にも脳や脊髄に比較的アクセスできないが、URB937は、炎症および末梢神経傷害の齧歯類モデルにおける持続痛を示す行動反応を軽減し、侵害プロセッシング(nociceptive processing)に関与する脊髄領域での侵害刺激によって惹起されるニューロン活性化を抑制する。CB1受容体遮断はこれらの効果を妨げる。この結果は、末梢CB1受容体でのアナンダミド媒介性シグナル伝達が疼痛の情報のCNSへの伝達を制御することを示した。したがって、このゲーティングメカニズムを強化する相対的に脳非透過性のFAAH阻害剤は、疼痛療法に対する新規アプローチを提供する(あらゆる目的に関して、特にFAAH阻害剤をそれらの生物学的および薬剤学的特性、ならびに末梢に限局されたFAAH阻害剤一般の薬理学的特性について分析する方法に関して、その全体が参照によって本明細書中に組み込まれる、2010年7月28日に出願された米国仮特許出願第61/368,500号を参照のこと)。
本明細書中で記載される化合物および組成物は、末梢FAAH阻害が望ましい障害を治療するために有用である。そのような障害としては、疼痛、炎症、自己免疫異常、肥満、摂食障害、および食欲制御、代謝障害、脂肪肝およびぜんそくが挙げられるが、これらに限定されるものではない。本明細書中で記載されるある特定の組成物および化合物は、パラ−ヒドロキシビフェニル部分の肝臓酸化によって毒性ベンゾキノン部分を形成する可能性がある化合物URB937などの末梢に限局されたFAAH阻害剤に勝る顕著な利点を提供する。
本発明はさらに、前述の末梢に限局されたFAAH阻害化合物の医薬組成物も提供する。「組成物」という用語は、医薬組成物における場合、活性成分(複数可)を含む生成物、および担体を構成する不活性成分(複数可)、ならびに任意の2以上の成分の組み合わせ、複合体形成もしくは凝集から、または1以上の成分の解離から、または1以上の成分の他の種類の反応もしくは相互作用から、直接的もしくは間接的に生じる任意の生成物を含むことが意図される。したがって、本発明の医薬組成物は、本発明の化合物と薬剤的に許容される担体とを混合することによって作製される任意の組成物を包含する。「医薬組成物」という用語は、動物またはヒトを包含する対象における製薬学的用途に好適な組成物を意味する。医薬組成物は、一般的に、有効量の活性剤および薬学的に許容可能な担体を含む。
本明細書中で記載する化合物は、医薬組成物として、以下の経路のうちの1つによって投与することができる:経口、全身性(たとえば、経皮的、鼻内もしくは坐薬による)または非経口(たとえば、筋肉内、静脈内もしくは皮下)。組成物は、錠剤、ピル、カプセル、半固体、粉末、持続放出処方、溶液、懸濁液、エリキシル、エアゾル、または任意の他の適切な組成物の形態をとることができ、一般的に、少なくとも1つの薬剤的に許容される賦形剤と組み合わせた本明細書中で記載される化合物から構成される。許容される賦形剤は、非毒性であり、投与を助け、活性成分の治療的有用性に悪影響を及ぼさない。そのような賦形剤は、任意の固体、液体、半固体または、エアゾル組成物の場合は、当業者が一般的に利用可能なガス状賦形剤であり得る。
a.疼痛の制御
いくつかの実施形態において、本明細書中で記載する化合物を投与して、対象における疼痛を緩和または治療することができる。治療は予防的または治療的であり得る。治療をヒト対象に実施することができる。本発明の化合物および組成物は、疼痛の重篤度または頻度または程度を軽減する目的のためだけに投与することができる。治療は別の鎮痛薬または抗炎症薬との併用療法で実施することができる。いくつかの実施形態において、疼痛は、ポスト三叉神経痛(post trigeminal neuralgia)、神経因性腰痛、末梢または多発性神経因性疼痛、複合性局所疼痛症候群(灼熱痛および反射性交感神経性ジストロフィー)、糖尿病性ニューロパシー、中毒性ニューロパシー、および化学療法薬に起因する慢性ニューロパシーからなる群から選択される神経因性疼痛であり得る。他の実施形態において、疼痛は、腎臓および肝臓疝痛または線維筋痛である。いくつかの神経因性疼痛実施形態において、神経系の原発病巣または機能不全は、対象の神経に対する機械的傷害に起因する。さらなる実施形態において、機械的傷害は、対象における神経の圧迫、神経の切断、灼熱痛、脊髄傷害、術後痛、幻肢痛、または瘢痕形成によるものである。
いくつかの実施形態において、式Iの化合物を投与して、対象における炎症を緩和することができる。治療は予防的または治療的であり得る。治療はヒト対象に実施することができる。本発明の化合物および組成物は、炎症の重篤度または頻度または程度を軽減する目的のためだけに投与することができる。治療は別の鎮痛薬または抗炎症薬との併用療法で投与することができる。
a.実施例1
抗侵害受容活性の化合物をスクリーニングする方法:抗侵害受容性作用について、FAAH阻害剤をスクリーニングする方法は、当業者に周知である。例えば、試験化合物は、マウスホットプレート試験およびマウスホルマリン試験において対象動物に投与され得、組織の熱損傷または化学損傷に対する侵害受容反応が測定される。抗侵害受容活性をスクリーニングする方法を教示した米国特許第6,326,156号も参照のこと。Cravatt et al. Proc. Natl. Acad. Sci. U.S.A. 98:9371-9376 (2001)を参照のこと。
末梢に限局されたFAAH阻害剤の薬理学的特性:
機械的痛覚過敏−機械的痛覚過敏は、足を与えられた一定の機械的圧力から背面へと逃避する秒単位の潜時(latency)を測定することにより決定した。機械力を与えるため、円錐先端(直径3mm)を備えた15gの目盛つきガラス円柱棒(直径10mm)を使用した。スタンドに取り付けた2つの環の間に体重を垂直に吊るし、垂直方向に自由に動くようにした。180秒のカットオフタイム(cutoff time)を用いた。逃避閾値を、炎症を起こした同側の足について、経口薬物投与後の異なる時点で測定した。各実験群には、6匹のマウスが含まれた。各マウスでは3種類の評価を行い、結果として合計18測定行った。熱性痛覚過敏を、記載のように(Hargreaves, K., Dubner, R., Brown, F., Flores, C., & Joris, J., A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia. Pain 32 (1), 77-88 (1988))、足底試験装置(Ugo Basile, Italy)を用いて、後足を、足底面に印加した放射熱の集束ビーム(熱強度:赤外線放射3.0)から逃避する潜時を測定し評価した。カットオフタイムは30秒に設定した。逃避潜時を、炎症を起こした同側の足について、経口薬物投与後の異なる時点で測定した。各実験群には、6匹のマウスが含まれた。各マウスでは3種類の評価を行い、結果として合計18測定行った。
[3−(3−カルバモイルフェニル)−5−ヒドロキシ−フェニル]N−シクロヘキシルカルバメート(化合物1)の合成。化合物1を、以下のスキームに記載のように合成した:
末梢でのFAAH阻害能についての、本発明による化合物と他の末梢に限局されたFAAH阻害剤との比較。上述のURB937について記載されたものと同様のFAAH抑制生物アッセイ方法を使用して(Clapper et al. Nature Neuroscience 13:1265-70 (2010)も参照のこと)、(当該FAAH生物アッセイ方法に関する参照により本明細書に組み込まれる)、投与後の化合物の肝臓およびCNSのFAAH阻害活性を、URB937と比較した。具体的には、(1)FAAHアッセイを使用して、IC50値をin vitroで得た。(2)肝臓および(3)脳のin vivo FAAH抑制値の百分率を以下のように測定した。マウスに各化合物の1mg/kg用量を腹腔内経路により投与し,投与2時間後に屠殺した。組織を採取し、FAAH活性を、FAAHアッセイを使用して、組織抽出物(膜画分)でex vivo測定した。データを以下の表1で報告する。
式Iの化合物の、末梢に限局されたFAAH阻害剤としての活性は、一部、p−ヒドロキシフェニル部分の極性に基づいて見出された。この部分は、URB937の末梢隔離(peripheral segregation)への貢献因子(contributor)、モデル末梢に限局されたFAAH阻害剤であることが見いだされた。表3では、R40置換基が弱い極性または無極性の類似化合物、例えば1c、1dおよび1eが、マウスでの全身投与後の脳に侵入していることが見出され、一方で、R40が極性をもつアミノ基からなる類似化合物、例えば化合物1fは、概して排除されていることが見出されたことが、示される。
本発明は、国立衛生研究所より与えられた助成金番号AA0l7538号、DA0l2413号、およびDA0l2447号のもとで、米国政府支援により創出された。米国政府は本発明に一定の権利を有する。
Claims (70)
- 式:
R1は、水素、ヒドロキシおよびその生理的に加水分解可能なエステル、−SH、カルボキシおよびその生理的に加水分解可能なエステル、ヒドロキシル−(C1−C3)アルキルおよびその生理的に加水分解可能なエステル、−NR7R8、および−NHSO2R9からなる群から選択され;R7およびR8は独立して水素または(C1−C3)アルキルから選択され、R9は水素、メチル、エチル、トリフルオロメチルまたはトリフルオロエチルから選択され;
R2およびR3は独立して水素および非置換(C1−C3)アルキルからなる群から選択され;
各R4は独立して水素および非置換(C1−C3)アルキルからなる群から選択され、nは0から4までの整数であり;
各R5は独立して水素、ハロゲン、ヒドロキシおよびその生理的に加水分解可能なエステル、カルボキシおよびその生理的に加水分解可能なエステル、ヒドロキシル−(C1−C3)アルキルおよびその生理的に加水分解可能なエステル、−(C1−C3)アルコキシ、または−NR20R21であり;R20およびR21は独立して水素または(C1−C3)アルキルから選択され;
mは0から3までの整数であり;
R6は非置換もしくは置換シクロヘキシル、シクロペンチル、シクロブチルまたはテトラヒドロピラン−4−イルである)
を有する化合物、またはその薬学的に許容可能な塩。 - R2およびR3がそれぞれHである、請求項1に記載の化合物。
- mおよびnがそれぞれ0である、請求項1または2に記載の化合物。
- R1がヒドロキシ、カルボキシ、またはヒドロキシメチルである、請求項1、2、または3に記載の化合物。
- R6が非置換である、請求項1、2、3、または4に記載の化合物。
- R6がシクロヘキシルである、請求項1、2、3、4、または5に記載の化合物。
- R7およびR8がそれぞれHであるか、またはR9がメチル、エチル、トリフルオロメチルもしくはトリフルオロエチルである、請求項1に記載の化合物。
- mが0であり、nが0または1である、請求項1に記載の化合物。
- mが1であり、nが0または1である、請求項1に記載の化合物。
- R1、R6、R7、およびR8マーカッシュ群の各メンバーが非置換である、請求項1に記載の化合物。
- R1がヒドロキシまたはアルコール基またはヒドロキシルもしくはアルコール基の生理的に加水分解可能なエステルである、請求項1に記載の化合物。
- 前記生理的に加水分解可能なエステルが、式−OC(O)R10、−CH2OC(O)R10または−CH2CH2OC(O)R10であり、式中、R10が置換または非置換ヒドロカルビルである、請求項11に記載の化合物。
- R1が−C(O)OR10であり、R10が水素または置換もしくは非置換ヒドロカルビルである、請求項1に記載の化合物。
- R5がヒドロキシルである、請求項1に記載の化合物。
- mが1である、請求項14に記載の化合物。
- R5がCOOHである、請求項1に記載の化合物。
- mが1である、請求項16に記載の化合物。
- R5がCH2OHである、請求項1に記載の化合物。
- mが1である、請求項18に記載の化合物。
- R5がOCH3である、請求項1に記載の化合物。
- mが1である、請求項20に記載の化合物。
- R5がCH3である、請求項1に記載の化合物。
- mが1である、請求項22に記載の化合物。
- R5がFである、請求項1に記載の化合物。
- mが1である、請求項24に記載の化合物。
- R5がNH2である、請求項1に記載の化合物。
- mが1である、請求項26に記載の化合物。
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の構造:
- 化合物が以下の式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 化合物が式:
- 請求項1〜51のうちいずれか1項に記載の化合物を有する医薬組成物。
- 請求項1〜51のうちいずれか1項に記載の化合物の、FAAHの阻害を必要とする哺乳類でFAAHを阻害するための医薬の製造における使用。
- 前記哺乳類が疼痛、炎症性疾患、または免疫異常の治療を必要とする、請求項53に記載の使用。
- 前記疼痛が侵害受容性疼痛、炎症性疼痛、または神経因性疼痛である、請求項54に記載の使用。
- 前記哺乳類が炎症性疾患または免疫異常を有する、請求項54に記載の使用。
- 末梢脂肪酸アミド加水分解酵素(FAAH)を選択的に阻害する医薬組成物であって、前記組成物が、請求項1〜51のうちいずれか1項に記載の化合物および薬学的に許容可能な添加剤を含む、医薬組成物。
- 疼痛、炎症、および免疫異常から選択される症状を治療する医薬組成物であって、前記組成物が、請求項1〜51のうちいずれか1項に記載の化合物および薬学的に許容可能な添加剤を含む、医薬組成物。
- 疼痛および/または炎症の治療を必要とする哺乳類に、請求項1〜51のうちいずれか1項に記載の化合物の治療有効量を投与することにより、疼痛および/または炎症を治療する方法。
- 前記炎症を治療する、請求項59に記載の方法。
- 前記疼痛を治療する、請求項59に記載の方法。
- 疼痛、炎症、および免疫異常からなる群から選択される症状の治療を必要とする哺乳類に、請求項1〜51のうちいずれか1項に記載の化合物の治療有効量を投与することにより、疼痛、炎症、および免疫異常からなる群から選択される症状を治療する方法。
- 請求項1〜51のうちいずれか1項に記載の化合物を投与することにより、アナンダミド、オレオイルエタノールアミド(OEA)、パルミトイルエタノールアミド(PEA)、またはステアロイルエタノールアミド(SEA)の末梢レベルの増加を必要とする哺乳類でのアナンダミド、オレオイルエタノールアミド(OEA)、パルミトイルエタノールアミド(PEA)、またはステアロイルエタノールアミド(SEA)の末梢レベルを増加させる方法。
- 前記OEA、PEA、SEAまたはアナンダミドは哺乳類に内在性である、請求項63に記載の方法。
- 前記化合物の投与前、投与後、または投与と同時に、前記OEA、PEA、SEAまたはアナンダミドが哺乳類に投与された、請求項63に記載の方法。
- 前記OEA、PEA、SEAまたはアナンダミドの投与が、前記化合物の投与と同時に行われる、請求項63に記載の方法。
- 前記哺乳類が疼痛、炎症、または免疫異常の治療を必要とする、請求項63〜66のうちいずれか1項に記載の方法。
- 皮膚炎、粘膜炎、または末梢感覚ニューロンの過剰反応、神経皮膚炎、過活動膀胱、または咳から選択される症状を治療するための医薬組成物であって、前記組成物が請求項1〜51のうちいずれか1項に記載の化合物および薬学的に許容可能な添加剤を含む、医薬組成物。
- 前記症状が薬剤または放射線誘発性病変である、請求項68に記載の組成物。
- 皮膚炎、粘膜炎、または末梢感覚ニューロンの過剰反応、神経皮膚炎、過活動膀胱もしくは咳の疼痛および/または炎症から選択される症状の治療を必要とする哺乳類に、請求項1〜51のうちいずれか1項に記載の化合物の治療有効量を投与することにより、皮膚炎、粘膜炎、または末梢感覚ニューロンの過剰反応、神経皮膚炎、過活動膀胱もしくは咳の疼痛および/または炎症から選択される症状を治療する方法。
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