JP5042215B2 - 網膜疾患を処置するための組成物および方法 - Google Patents
網膜疾患を処置するための組成物および方法 Download PDFInfo
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- 0 CC(**C1)C1C(*C(*C(O*)=O)=C)O Chemical compound CC(**C1)C1C(*C(*C(O*)=O)=C)O 0.000 description 8
- XLSZMDLNRCVEIJ-UHFFFAOYSA-N Cc1cnc[nH]1 Chemical compound Cc1cnc[nH]1 XLSZMDLNRCVEIJ-UHFFFAOYSA-N 0.000 description 2
- GSOROQLPURPOKH-UHFFFAOYSA-N CC1C=C(C(c2cc(C#N)ccc2)N)C=CC1 Chemical compound CC1C=C(C(c2cc(C#N)ccc2)N)C=CC1 GSOROQLPURPOKH-UHFFFAOYSA-N 0.000 description 1
- VUMICMSAMPEDIU-UHFFFAOYSA-N CCOC(C1=NC(N)=CC(C)C=N1)=O Chemical compound CCOC(C1=NC(N)=CC(C)C=N1)=O VUMICMSAMPEDIU-UHFFFAOYSA-N 0.000 description 1
- FTQNOYWZVZUPCJ-UHFFFAOYSA-N CCOC(c(nc1)ncc1N)=O Chemical compound CCOC(c(nc1)ncc1N)=O FTQNOYWZVZUPCJ-UHFFFAOYSA-N 0.000 description 1
- CPCALRCXLGUQIL-UHFFFAOYSA-N CCOC(c1nc(N)ncc1)=O Chemical compound CCOC(c1nc(N)ncc1)=O CPCALRCXLGUQIL-UHFFFAOYSA-N 0.000 description 1
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Description
便宜上、例示的実施形態を詳細に説明する前に、本明細書、実施例及び添付の特許請求の範囲で使用される特定の用語を以下に纏める。
方法
上で考察した通り、開示した組成物は、黄斑変性並びにA2E及び/又はリポフスチンの蓄積が病因として係わるその他の網膜疾患を処置又は予防するために被験体に投与される場合がある。A2Eの蓄積を特徴とするその他の疾患、障害又は病態も同様に処置される場合がある。
好適な化合物は種々のスクリーニング法によって同定される場合がある。例えば、候補化合物は、黄斑変性、又はA2E及び/又はリポフスチンの蓄積が病因として係わるその他の網膜疾患を有するか、このような疾患を発症する危険性がある被験体に投与される場合があり、A2E等の網膜毒性を有する化合物の蓄積を測定することができる。従って、網膜毒性を有する化合物の蓄積を対照(薬物の不在下)に比べて低下させる薬物は、好適な薬物として同定されると思われる。
本発明の化合物及び関連する誘導体は、当業者に既知の方法で合成することができる。例えば、化合物7を合成する詳細な方法を以下の図式3に示す。
UV/VIS分光器を使用して、RALと本発明の化合物の一級アミンとのシッフ塩基の縮合を監視した。開示した化合物1、2、3、4、5及び6において、RALとのシッフ塩基縮合産物のin vitro解析を実施し、結果を表1に示す。
化合物1、2、3、4、5及び6のログP値を表1に示す。分配係数(ログP)は、pHにおける化合物X(Xは中性でありイオン化されていない)の[X有機]/[X水性]比のログである。ゼロ以上の値は、脂肪親和性が上昇していることを示し、ゼロ以下の値は、親水性が上昇していることを示す。有機溶媒としてはオクタノールが一般的に使用される。以下が例である。
ログP=0: Xは両方に同等に溶ける
ログP=−2: Xは有機溶媒よりも水性溶媒に102倍溶けやすい
通常、ログP値は、Pallas及びACDlabs等のソフトウェアプログラムを使用して、アルゴリズムにより算出される(実験では測定されない)。計算結果はソフトウェア製品により異なり、近似の桁としてみなされる。
暗順応とは、露光後の視覚の感受性の回復を表す。暗順応は、迅速な(ニューロンの)プロセス及び緩徐な(光化学的)プロセスの両方をはじめとする複数の構成要素を有する。視覚色素の再生は、緩徐な光化学的プロセスに関連する。暗順応の速度は幾つかの理由により測定される。夜盲は、暗順応ができないこと(視覚の光感受性の喪失)により生じるものである。暗順応する視覚光感受性に対する薬物の作用を測定することによって、夜盲に対する安全な用量を見出すことができる。
NMR分光器を使用して、RALと本発明の化合物の一級アミンとのシッフ塩基縮合及び環形成を監視した。このRAL反応のNMR解析は、図8及び表2に示す通り、開示化合物6、8及び9において実施した。純粋なクロロホルムにおける縮合速度は、化合物6>8>9の順となった。
本実験は、長期的なRALトラップ化合物の腹腔内注射が、野生型Sprague DawleyラットにおけるA2Eの蓄積速度を低下させるという概念を証明することを目的としている。これらの実験では、RAL−トラップ化合物の治療有効性を、対照化合物及び未処置の結果と比較する。
本試験は、野生型Sprague Dawleyラットで行う。ラットの投与群は、例えば、投与条件毎に雌雄8匹とする。全ての動物は以下の条件の1つに従い処置される。
・対照群:(1)プロトコールの対照となる、視覚サイクルタンパク質のレチノイド結合部位を阻害する13−cisレチノイン酸(このような投与により、放出され、A2Eの形成に利用可能な遊離trans−RALの量が減少するが、夜盲等の副作用が生じる);及び(2)ヒトの網膜機能を調節することが臨床的に知られており、in vitro及びin vivoの動物モデルで遊離RALとシッフ塩基付加物を形成することが実験的に知られている市販の化合物。
・賦形剤
・化合物
・未処置
幾つかの化合物、例えば4つの化合物を試験する。化合物は、1、5、15及び50mg/kg等の容量範囲で試験する。化合物は毎日、腹腔内注射により8週間投与する。
実験は種々の化学的手段を使用する。例えば、これらの実験は、不純物が明らかにされている分析明細シートが添付された市販の化合物を使用する。化合物は合成もされる。化合物は必要な投与量に十分な量を調製する。化合物の配合は、腹腔内注射を行う最初の動物安全性試験で使用するのに好適なものとする。trans−RALと本発明の化合物とのシッフ塩基反応産物では、以下の3つの属性が確認されている。
・種々の反応速度における安定性
・吸収特性、具体的にはuv−vis最大吸光及び吸光係数(例えば、Figure 5 in Rapp and Basinger, Vision Res. 22:1097, 1982を参照)又は反応動態のNMRスペクトル解析
・ログP及びログDの可溶性の(計算)値
生物学及び生化学:
本明細書に記載の実験では、種々の生物学的及び生化学的手段を使用する。本発明の化合物の点眼剤による毎日投与の「無作用量」(NOEL)を、例えば眼刺激プロトコールを使用したウサギ、及び光刺激に対する視覚反応における暗順応をERGで計測するげっ歯類において確立する。投与後及び眼摘出の前に、動物(例えば、ウサギ)を被験体として以下の非侵襲的試験を実施する。
・眼底撮影により明らかにされる、RPE及び視細胞の変性(Karan, et al., 2005, PNAS 102: 4164)
・眼底蛍光撮影により測定される、細胞外ドルーゼン及び細胞内リポフスチン(Karan, et al., 2005)
光反応はERGで確認する(Weng, et al., Cell 98:13, 1999)。RPE細胞抽出物の細胞内A2E濃度を、Karan, et al., 2005; Radu, et al., 2003;及びParish, et al., PNAS 95:14609, 1998に記載のような解析方法を使用して、投与プロトコールの終了時に全ての投与動物で測定する。例えば、投与動物の試料としては、片方の眼で試験を行い、もう片方の眼は組織学的解析(下述)のために保存する。残りの動物では、両方の眼を別々に試験して、A2Eの形成を確認する。
・動物の行動及び食餌習慣を投与期間にわたり毎日観察し記載した所見
・投与期間の終了時にERGにより測定した視機能
・投与期間の終了時における眼の組織学的所見
参考文献の組み入れ
訂正証明書、特許出願書類、科学論文、政府報告書、ウェブサイト及びその他に本明細書で引用した参考文献をはじめとする本特許書類全ての開示内容は、全ての目的において全文が参考として組み入れられている。用語に矛盾が生じた場合には、本明細書が支配する。
以上において本発明を詳細な説明と共に記載してきたが、上記の説明は、添付の特許請求の範囲に規定される本発明の適用範囲を例示することを目的としたものであって、制限することを目的としたものではない。この他の態様、利点及び変更も以下の特許請求の範囲に含まれる。当業者であれば、添付の特許請求の範囲で網羅される本発明の適用範囲から逸脱することなく、形態や詳細に種々の変更を加える場合があることを理解するであろう。
Claims (10)
- 以下の式Iaで表される化合物:
式中、XがCHであり;
ZがNであり;
Yが、Yに結合した−NH2を有するCであり;
pが0、1、2又は3であり;
Bが、ハロゲン原子、ヒドロキシル、カルバモイル、非置換若しくは置換アリール又はアミノであって、ここで、該置換アリールは、ハロゲン、ヒドロキシル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、カルボキシレート、アルキルカルボニル、アルキルアミノカルボニル、アラルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニル、アリールカルボニル、アラルキルカルボニル、アルケニルカルボニル、アルコキシカルボニル、アミノカルボニル、アルキルチオカルボニル、ホスフェート、ホスホナト、ホスフィナト、シアノ、アミノ(アルキルアミノ、ジアルキルアミノ、アリールアミノ、ジアリールアミノ及びアルキルアリールアミノを含む)、アシルアミノ(アルキルカルボニルアミノ、アリールカルボニルアミノ、カルバモイル及びウレイドを含む)、アミジノ、イミノ、スルフヒドリル、アルキルチオ、アリールチオ、チオカルボキシレート、スルフェート、アルキルスルフィニル、スルファモイル、スルホンアミド、ニトロ、トリフルオロメチル、アジド、ヘテロシクリル、アルキルアリール、及び芳香族若しくはヘテロ芳香族成分から選択される1つ以上の置換基を有し;
Aが
Dが非分枝鎖の低級アルキルである、化合物。 - pが1である、請求項1に記載の化合物。
- Bがハロゲンである、請求項1に記載の化合物。
- Bが塩素である、請求項3に記載の化合物。
- DがCH3である、請求項1に記載の化合物。
- 以下の式Iaによって表される化合物又はIaの薬学的に許容される塩、及び薬学的に許容される担体を含む薬学的組成物であって、
ZがNであり;
Yが、Yに結合した−NH2を有するCであり;
pが0、1、2又は3であり;
Bが、ハロゲン原子、ヒドロキシル、カルバモイル、非置換若しくは置換アリール又はアミノであって、ここで、該置換アリールは、ハロゲン、ヒドロキシル、アルコキシ、アルキルカルボニルオキシ、アリールカルボニルオキシ、アルコキシカルボニルオキシ、アリールオキシカルボニルオキシ、カルボキシレート、アルキルカルボニル、アルキルアミノカルボニル、アラルキルアミノカルボニル、アルケニルアミノカルボニル、アルキルカルボニル、アリールカルボニル、アラルキルカルボニル、アルケニルカルボニル、アルコキシカルボニル、アミノカルボニル、アルキルチオカルボニル、ホスフェート、ホスホナト、ホスフィナト、シアノ、アミノ(アルキルアミノ、ジアルキルアミノ、アリールアミノ、ジアリールアミノ及びアルキルアリールアミノを含む)、アシルアミノ(アルキルカルボニルアミノ、アリールカルボニルアミノ、カルバモイル及びウレイドを含む)、アミジノ、イミノ、スルフヒドリル、アルキルチオ、アリールチオ、チオカルボキシレート、スルフェート、アルキルスルフィニル、スルファモイル、スルホンアミド、ニトロ、トリフルオロメチル、アジド、ヘテロシクリル、アルキルアリール、及び芳香族若しくはヘテロ芳香族成分から選択される1つ以上の置換基を有し;
Aが
Dが非分枝鎖の低級アルキルである、薬学的組成物。 - 請求項7に記載の化合物又はその薬学的に許容される塩及び薬学的に許容される担体を含む、薬学的組成物。
- 萎縮型AMD及びシュタルガルト病を処置又は予防するための、請求項7に記載の化合物を含む、組成物。
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