JP6248199B2 - ハーダー腺分泌物に見出される化合物で眼疾患を治療する方法 - Google Patents
ハーダー腺分泌物に見出される化合物で眼疾患を治療する方法 Download PDFInfo
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Description
1.自己免疫疾患、先天性無涙症、麻痺性分泌不全または排泄管閉塞などの涙腺障害に由来する、最も高頻度にドライアイの状態の原因となる涙液不足;
2.トラコーマ、熱傷及び化学熱傷、ビタミンA欠乏症に関連した状態に観察されるムチン欠乏症;
3.脂質異常;
4.瞼機能の低下;
に、細分化される(参照:US6107289)。
R1は、無置換アルキルまたはアルケニルであり;
R2は、無置換のアルキルであり;
L1は、−L2−C(O)−L3−、または、−CH(−L4−R3)−L3−であり;
L2は、単結合であり、または無置換のアルキレンであり;
L3及びL4は、独立して、無置換のアルキレンであり;
R3は、ヒドロキシル、または、−O−C(O)−R4であり;及び
R4は、無置換のアルキルである。
いくつかの実施形態において、化合物は、式:
いくつかの実施形態において、化合物は、式:
いくつかの実施形態において、化合物は:
いくつかの実施形態において、化合物は、式:
いくつかの実施形態において、化合物は、式:
いくつかの実施形態において、R1は、無置換のC6−C30アルキルまたはアルケニルであり;R2は、無置換のC5−C31アルキルであり;及び、R4は、無置換のC5−C31アルキルである。いくつかの実施形態において、R1は、無置換のC14−C22アルキルまたはアルケニルであり;R2は、無置換のC13−C17アルキルであり;及び、R4は、無置換のC13−C19アルキルである。いくつかの実施形態において、R2は、無置換のC15アルキルである。いくつかの実施形態において、化合物は、式:
いくつかの実施形態において、本発明は、治療剤と組み合わせてハーダー腺の分泌物から得られたハーダー腺脂質化合物の有効量を含み、それを必要とするヒトのドライアイを治療するための医薬組成物を提供する。いくつかの実施形態において、治療成分から成るグループから選択される治療薬は、NMDA拮抗薬、抗菌薬、抗ヒスタミン薬、充血緩和剤、抗炎症剤、駆虫薬、縮瞳薬、交感神経作動薬(syrnpathomimetics)、抗コリン薬、アドレナリン作動薬、抗ウイルス剤、局所麻酔剤、抗真菌剤、殺アメーバ薬(amoebicidal)、殺トリコモナス薬、鎮痛剤、散瞳薬、抗緑内障薬、炭酸脱水酵素阻害剤、眼科診断薬、手術で助剤として使用される眼科薬、キレート化剤、抗腫瘍薬、抗高血圧薬、筋弛緩薬、診断薬、アドレナリン作動性麻酔薬、β−遮断薬、α−2−アゴニスト、毛様麻痺薬、プロスタグランジン、その誘導体、及びその混合物からなるグループから選択される物質を含む。
(a)ウサギのハーダー腺分泌物サンプルから検出された構成成分イオンを示す質量スペクトル(横軸−質量対電荷比m/z:縦軸−相対強度)(図1A);
(b)図2A、B、C、Dで示す通り、m/z=593、791、819、847におけるハーダー腺分泌化合物のHPLCの液体クロマトグラフィーカラム分離物から得られた質量クロマトグラム(横軸−時間(分):縦軸−選択イオンモニタリングシグナル強度);
(c)図3で示す通り、ハーダー腺分泌物サンプルのHPLC/MS/MSで得られたm/z=593、791、819、847での第二のMS分析器からのTICシグナルを示すグラフ(横軸−時間(分);縦軸−シグナル強度);
(d)図4で示す、HPLC/MS/MSの質量スペクトル、ここで、親イオン、及び複数のフラグメントイオンは、m/z=593、377、338、319、238;m/z=791、551、535、317;m/z=819、579、563、535、479、317;及び、m/z=847、591、563、507、317、297を含むグループから選択されるフラグメントイオンを組み合わせた親イオンの断片化をもたらす;
(e)質量スペクトル及び質量ユニットの機能に現れる特定m/zを有する親イオンは、図5で示す通り、C39H77O3、C51H99O5、C53H103O5、及びC55H107O5を含むグループに対応する分子式に対応する強シグナルを示すことになる;
(f)図5で示す少なくとも1つの構造に対応する化学構造;
の特性を有する脂質化合物からその本質的に純粋な形態を提供する。
R1は、無置換のアルキル、または、アルケニルであり;
R2は、無置換のアルキルであり;
L1は、−L2−C(O)−L3−、または、−CH(−L4−R3)−L3−であり;
L2は、単結合、または、無置換のアルキレンであり;
L3及びL4は、独立して、無置換のアルキレンであり;
R3は、ヒドロキシル、または、−O−C(O)−R4であり;及び
R4は、無置換のアルキルである。
いくつかの実施形態において、脂質化合物は、式:
いくつかの実施形態において、脂質化合物は、式:
いくつかの実施形態において、R1は、無置換のC6−C30アルキルまたはアルケニルであり;R2は、無置換のC5−C31アルキルであり;及び、R4は、無置換のC5−C31アルキルである。いくつかの実施形態において、R1は、無置換のC14−C22アルキルまたはアルケニルであり;R2は、無置換のC13−C17アルキルであり;及び、R4は、無置換のC13−C19アルキルである。
いくつかの実施形態において、R2は、無置換のC15アルキルである。いくつかの実施形態において、脂質化合物は、式:
いくつかの実施形態において、ハーダー腺脂質化合物は、式:
いくつかの実施形態において、R1は、無置換のC6−C30アルキルまたはアルケニルであり;R2は、無置換のC5−C31アルキルであり;及び、R4は、無置換のC5−C31アルキルである。いくつかの実施形態において、R1は、無置換のC14−C22アルキルまたはアルケニルであり;R2は、無置換のC13−C17アルキルであり;及び、R4は、無置換のC13−C19アルキルである。いくつかの実施形態において、R2は、無置換のC15アルキルである。いくつかの実施形態において、化合物は、更に:
を含み、式中、x、y及びzは、独立して、5、7、9、11、13、15、17、19、21、23、25、27または29であり;及び、wは、8、10、12、14、16、18、20、22、24、26、28、または、30である。いくつかの実施形態において、xは、11、13、または15であり;y及びzは、独立して、11、13、15、または17であり;及び、wは、16、18、または20である。
いくつかの実施形態において、化合物は、式:
「アルキル」は、一価の直鎖、分枝鎖または環状の、飽和脂肪族炭化水素基を指す。好ましくは、アルキル基は、1〜40個の炭素原子を有する直鎖基である。より好ましくは、5〜31個の炭素原子を有するアルキル基であり、最も好ましくは、13〜17個の炭素原子を有するアルキル基である。一般的なアルキル基は、ペンチル、ヘキシル、トリデカニル、テトラデカニル、ノナデカニル、ドコサニル、トリアコンタニル、ヘントリアコンタニルなどを含む。好ましくは、この用語は、式CnH2n+1で表される非環状の炭素または飽和非環状炭素鎖を意味し、ここに、nは、1〜31の整数である。
ハーダー腺脂質化合物は:
R1は、無置換のアルキルまたはアルケニルであり;
R2は、無置換のアルキルであり;
L1は、−L2−C(O)−L3−、または、−CH(−L4−R3)−L3−であり;
L2は、単結合、または、無置換のアルキレンであり;
L3及びL4 は、独立して、無置換のアルキレンであり;
R3は、ヒドロキシル、または、−O−C(O)−R4であり;及び
R4は、無置換のアルキルである。
式IVの好ましい化合物は:
x、y及びzは、独立して、5、7、9、11、13、15、17、19、21、23、25、27または29であり;及び、wは、8、10、12、14、16、18、20、22、24、26、28または30であり;
或いは、xは、11、13または15であり;y及びzは、独立して、11、13、15または17であり、;及び、wは、16、18または20である。
ハーダー腺脂質涙分泌物は、生きたウサギから回収され、抽出物は、ウサギのハーダー腺から作られる。コントロールである涙分泌物は、正常なヒト被験者から収集し、ドライアイを患っているヒト被検者の対照とした。これらのサンプルは、ESI−CI/MS/MSにより分析し、図1Aでハーダー腺サンプルとして、及び、図1Bでヒト涙サンプルとして表される。図1A及び図1Bの質量スペクトルを比較すると、m/z=593のハーダー腺化合物、及び複数の関連化合物は、ヒトスペクトルサンプルでは見出されなかった。
MW[M+H]+=791;
分子式=C51H99O5;
保持時間:22.2分;
MW[M+H]+=891;
分子式=C53H103O5;
HPLCMS保持時間=23.8分;
MW[M+H]+=847;
分子式=C55H107O5;
HPLCMS保持時間=25.4分;
MW[M+H]+=593;
分子式=C39H77O3;
HPLC保持時間=6.9、16.7、22.2、23.8分;
分子式=C39H79O4;
加水分解生成物のMW=593;
に同定された。
上記の脂質化合物の質量スペクトルは、また、不飽和官能基の、加水分解、脱加水分解、及び/または、転位で現れることがあり得る。例えば、R1がC20アルキル基であり、R2がC13アルキル基である、例えば、m/z=611の不安定なハーダー腺化合物は、化学的にイオン化されたものとして代用的に示されるか、または、MW=593などのその脱水形態であってもよい。また、m/z=593の化合物は、4つのHPLC保持時間を有し、及び、ハーダー腺化合物と共溶出するような代替官能基を有するいくつかの化学構造的に関連した形態を有していた。
HPLC/MS/MSで同定した、m/z=593の化合物を含むウサギからのハーダー腺分泌物、または涙は、ヒトの「ドライアイ」を治療するのに有効な量で眼科的に投与された。定量化したm/z=593の化合物量は、図1Bで表されるヒト涙サンプル中の脂質を定量した量と比較可能である。化合物の有効量は、通常の方法で指定され、そして、緩衝溶液、例えば、リン酸塩緩衝生理食塩水、または不活性な担体化合物、グリセロール、鉱物油、または目の眼球表面の類似物質を含む薬学的に許容可能な物質と組み合わせて目の眼球表面に投与された。m/z=593の化合物を含むウサギのハーダー腺分泌物の投与量は、処方に応じて最適化され、そして、送達の方法及び投与形態は、従来の手順により決定され、そして、効果的にヒトの「ドライアイ」症状を治療した。
ハーダー腺の分泌物に関連する新規組成物は、理論構造に基づき合成され、そして、標準構造の断片化パターンは、それが基礎となる単離された脂質m/z=593の理論構造を確認した。
本発明は、更に、1つ若しくはそれ以上の該ハーダー腺脂質化合物を含む眼科用ビヒクルを含有する。ビヒクルは、ハーダー腺分泌物、または、合成されたもののいずれかから、m/z=593を含む化合物、m/z=791、819、847に関連する化合物(図1A)の定量化された量を含み、そして、ヒトの「ドライアイ」症状を治療するために、図1Bで表されるヒト涙サンプル中の脂質の定量化された量と比較可能である。
Claims (10)
- R1が、無置換のC6−C30アルキル、またはアルケニルであり;
R2が、無置換のC5−C31アルキルであり;及び
R4が、無置換のC5−C31アルキルである;
請求項1に記載の眼科用ビヒクル。 - R1が、無置換のC14−C22アルキル、またはアルケニルであり;
R2が、無置換のC13−C17アルキルであり;及び
R4が、無置換のC13−C19アルキルである;
請求項1に記載の眼科用ビヒクル。 - R2が無置換のC15アルキルである、請求項1に記載の眼科用ビヒクル。
- xが、11、13、または15であり;
y及びzが、独立して、11、13、15、または17であり;及び
wが、16、18、または、20である;
請求項7に記載の眼科用ビヒクル。 - NMDA拮抗薬、抗菌薬、抗ヒスタミン薬、充血除去剤、抗炎症剤、抗寄生虫薬、縮瞳薬、交感神経作動薬、抗コリン薬、アドレナリン作動薬、抗ウイルス薬、局所麻酔剤、抗真菌剤、殺アメーバ薬、殺トリコモナス薬、鎮痛薬、散瞳薬、抗緑内障薬、炭酸脱水酵素阻害剤、眼科用診断薬、手術において助剤として使用される眼科用薬剤、キレート化剤、抗腫瘍薬、抗高血圧薬、筋弛緩剤、診断薬、アドレナリン作動性麻酔薬、β−遮断薬、α−2−アゴニスト、毛様麻痺薬、プロスタグランジンから成るグループから選択される治療薬を、更に、含む請求項1に記載の眼科用ビヒクル。
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