JP2012524025A - 黄斑変性を処置するための方法および組成物 - Google Patents
黄斑変性を処置するための方法および組成物 Download PDFInfo
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- JP2012524025A JP2012524025A JP2011544722A JP2011544722A JP2012524025A JP 2012524025 A JP2012524025 A JP 2012524025A JP 2011544722 A JP2011544722 A JP 2011544722A JP 2011544722 A JP2011544722 A JP 2011544722A JP 2012524025 A JP2012524025 A JP 2012524025A
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- compound
- prostaglandin
- macular degeneration
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Abstract
Description
下付1:13,14-不飽和-15-OH
下付2:5,6-および13,14-ジ不飽和-15-OH
下付3:5,6-、13,14-および17,18-トリ不飽和-15-OH。
Aは、-CH3、-CH2OH、-COCH2OH、-COOHまたはそれらの官能性誘導体であり;
Bは、-CH2-CH2-、-CH=CH-または-C≡C-であり;
R1は、非置換、またはハロゲン、低級アルキル、ヒドロキシ、オキソ、アリールまたは複素環基により置換された、二価の飽和または不飽和の低または中級の脂肪族炭化水素基であり、脂肪族炭化水素中の少なくとも1つの炭素原子は所望により酸素、窒素または硫黄により置換されており;そして
Raは、非置換、またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基によって置換された、飽和または不飽和の低または中級の脂肪族炭化水素基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環基;複素環オキシ基である]。
[式中、LおよびMは水素原子、ヒドロキシ、ハロゲン、低級アルキル、ヒドロキシ(低級)アルキル、低級アルカノイルオキシまたはオキソであり、5員環は少なくとも1つの二重結合を有していてもよく;
Aは、-CH3、-CH2OH、-COCH2OH、-COOHまたはそれらの官能性誘導体であり;
Bは、-CH2-CH2-、-CH=CH-または-C≡C-であり;
X1およびX2は、水素、低級アルキル、またはハロゲンであり;
R1は、非置換、またはハロゲン、低級アルキル、ヒドロキシ、オキソ、アリールまたは複素環基により置換された、二価の飽和または不飽和の低または中級の脂肪族炭化水素基であり、脂肪族炭化水素中の少なくとも1つの炭素原子は所望により酸素、窒素または硫黄により置換されており;
R2は、単結合または低級アルキレンであり;そして
R3は、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基である]。
-CH2-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH=CH-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH=CH-、
-CH2-C≡C-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-O-CH2-、
-CH2-CH=CH-CH2-O-CH2-、
-CH2-C≡C-CH2-O-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH=CH-CH2-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH=CH-、
-CH2-C≡C-CH2-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、
-CH2-CH2-CH2-CH2-CH(CH3)-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH=CH-CH2-CH2-CH2-CH2-CH2-、
-CH2-CH2-CH2-CH2-CH2-CH2-CH=CH-、
-CH2-C≡C-CH2-CH2-CH2-CH2-CH2-、および
-CH2-CH2-CH2-CH2-CH2-CH2-CH(CH3)-CH2-。
X1'およびX2'は、水素、低級アルキル、またはハロゲンであり;
Yは
ここで、R4'およびR5'は、水素、ヒドロキシ、ハロゲン、低級アルキル、低級アルコキシまたはヒドロキシ(低級)アルキルであり、R4'およびR5'が同時にヒドロキシおよび低級アルコキシであることはなく、
R1は、非置換、またはハロゲン、アルキル、ヒドロキシ、オキソ、アリールまたは複素環基により置換された、二価の飽和または不飽和の低または中級の脂肪族炭化水素基であり、脂肪族炭化水素中の少なくとも1つの炭素原子は所望により酸素、窒素または硫黄により置換されており;
R2'は、非置換、またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基により置換された、飽和または不飽和の低または中級の脂肪族炭化水素残基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環基;複素環オキシ基であり;
R3'は水素、低級アルキル、シクロ(低級)アルキル、アリールまたは複素環基である]。
方法
ヒト網膜色素上皮細胞[American Type Culture Collection(ATCC)から入手したARPE-19細胞]を試験に使用した。ARPE-19細胞を、10%子ウシ血清を含有するダルベッコ改変イーグル培地中でCorning Transwell 0.4 μm の孔サイズフィルター(Corning Incorporated, NY, USA)上で増殖させた。培養細胞の経上皮電気抵抗(TER)を、EVOM電圧抵抗器を用いて決定した。培養細胞のTERを、培養細胞を用いて測定した耐性値から、フィルターのみを用いて測定した耐性値を控除することにより決定した。
tBHは、TERを急速かつ大きく低下させた。化合物Aは、tBHに起因するTERの低下を防止した(図1)。また、3,000ダルトンの蛍光デキストランの頂端側から側底側の培地への通過により測定したとおり、化合物Aは、tBHに起因するバリア機能の低下を防止した(図2)。これらの結果は、化合物Aが、反応性酸素種に起因する網膜色素上皮細胞の損傷を防止するということを示す。
ピリジニウムビス-レチノイド(A2E)を含有する網膜色素上皮(RPE)細胞における、化合物Aによる光誘導性の細胞死の保護
ヒト網膜色素上皮細胞(ARPE-19細胞)を試験に使用した。ARPE-19細胞を、25 cm2または75 cm2の培養フラスコ中のDMEM/F12培地(10% FBSおよび1% ペニシリン-ストレプトマイシン混合溶液を追加した)中で維持した。実験のために、該細胞を、マルチウェルチャンバースライド上に播種した。該細胞がスライドに付着したことを確認した後に、該培地を、ピリジニウムビス-レチノイド(A2E)を含有する培養培地に交換し、該細胞を5〜14日間培養した。該培地を、リン酸塩緩衝生理食塩水(A2E含有)に交換し、次いで該細胞を、ハロゲン光源から放出された青色光(430 nm)に20分間暴露した。ジメチルスルホキシドに溶解した化合物Aを、光暴露の1時間前に添加した(終濃度は10および50 nMであった)。この光暴露後、該細胞を、DMEM/F12培地中で24時間培養した。その後、該細胞を、10% WST-8(A2Z不含)を含有するDMEM/F12培地中で4時間培養した。450 nmの吸光度を測定した。この吸光度における増加は、細胞生存力を示す。
化合物Aは、A2E/光暴露により誘導される細胞死を防止した(表1)。
滅菌条件下で、以下に示した量(w/v%)の成分を精製水に溶解し、滅菌低密度ポリエチレン(LDPE)容器に充填して、眼用溶液を得た(1滴:およそ35 μL)。
滅菌条件下で、以下に示した量(w/v %)の成分を精製水に溶解し、単位用量型容器に充填して、滅菌単回単位用量の眼用溶液を得た。
滅菌条件下で、以下に示した量(w/v %)の成分を精製水に溶解し、用量単位型容器に充填して、滅菌単回単位用量眼用溶液を得た。
Claims (19)
- 哺乳類対象において黄斑変性を処置するための、有効量の15-ケト-プロスタグランジン化合物を含む医薬組成物。
- 該15-ケト-プロスタグランジン化合物が、以下一般式(I)により示される化合物である、請求項1に記載した組成物。
[式中、L、MおよびNは、水素、ヒドロキシ、ハロゲン、低級アルキル、ヒドロキシ(低級)アルキル、またはオキソであり、ここで該5員環は、少なくとも1つの二重結合を有してもよく;
Aは、-CH3、-CH2OH、-COCH2OH、-COOHまたはそれらの官能性誘導体であり;
Bは、-CH2-CH2-、-CH=CH-または-C≡C-であり;
R1は、非置換、またはハロゲン、低級アルキル、ヒドロキシ、オキソ、アリールまたは複素環基により置換された、二価の飽和または不飽和の低または中級の脂肪族炭化水素基であり、脂肪族炭化水素中の少なくとも1つの炭素原子は所望により酸素、窒素または硫黄により置換されており;そして
Raは、非置換、またはハロゲン、オキソ、ヒドロキシ、低級アルキル、低級アルコキシ、低級アルカノイルオキシ、シクロ(低級)アルキル、シクロ(低級)アルキルオキシ、アリール、アリールオキシ、複素環基または複素環オキシ基によって置換された、飽和または不飽和の低または中級の脂肪族炭化水素基;低級アルコキシ;低級アルカノイルオキシ;シクロ(低級)アルキル;シクロ(低級)アルキルオキシ;アリール;アリールオキシ;複素環基;複素環オキシ基である]。 - 該15-ケト-プロスタグランジン化合物が、13,14-ジヒドロ-15-ケト-プロスタグランジン化合物である、請求項1に記載した組成物。
- 該15-ケト-プロスタグランジン化合物が、15-ケト-20-低級アルキル-プロスタグランジン化合物である、請求項1に記載した組成物。
- 該15-ケト-プロスタグランジン化合物が、13,14-ジヒドロ-15-ケト-20-低級アルキル-プロスタグランジン化合物である、請求項1に記載した組成物。
- 該15-ケト-プロスタグランジン化合物が、15-ケト-20-エチル-プロスタグランジン F 化合物である、請求項1に記載した組成物。
- 該15-ケト-プロスタグランジン化合物が、13,14-ジヒドロ-15-ケト-20-エチル-プロスタグランジンF化合物である、請求項1に記載した組成物。
- 該15-ケト-プロスタグランジン化合物が、13,14-ジヒドロ-15-ケト-20-エチル-プロスタグランジンF2α化合物である、請求項1に記載した組成物。
- 該15-ケト-プロスタグランジン化合物が、13,14-ジヒドロ-15-ケト-20-エチル-プロスタグランジンF2αイソプロピルエステルである、請求項1に記載した組成物。
- 該黄斑変性が、加齢黄斑変性である、請求項1-9のいずれかに記載の組成物。
- 該加齢黄斑変性が、ドライ型加齢黄斑変性である、請求項10に記載した組成物。
- 該組成物が、局所投与のための組成物として製剤される、請求項1-9のいずれかに記載の組成物。
- 該組成物が、眼局所投与のための眼用組成物である、請求項12に記載した組成物。
- 該眼用組成物が、点眼液として製剤される、請求項13に記載した組成物。
- 該点眼液が、保存剤を含まない滅菌単位用量型点眼液として製剤される、請求項14に記載した組成物。
- 該眼用組成物が、塩化ベンザルコニウムを実質的に含まない、請求項13に記載した組成物。
- 哺乳類対象における黄斑変性を処置するための医薬組成物の製造のための、15−ケトプロスタグランジン化合物の使用。
- 哺乳類対象における黄斑変性を処置するための、15-ケト-プロスタグランジン化合物の使用。
- 哺乳類対象における黄斑変性を処置するための方法であって、有効量の15-ケト-プロスタグランジン化合物を、その必要のある対象に投与することを含む、方法。
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TW (1) | TWI501769B (ja) |
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2015125933A1 (ja) * | 2014-02-21 | 2015-08-27 | 国立大学法人 香川大学 | 加齢黄斑変性に伴う地図状萎縮の処置のための医薬組成物 |
JP2015205915A (ja) * | 2009-04-15 | 2015-11-19 | 株式会社アールテック・ウエノ | 黄斑変性を処置するための方法および組成物 |
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KR20140038404A (ko) * | 2011-04-12 | 2014-03-28 | 가부시키가이샤 아루떼꾸 우에노 | 수성 안과용 조성물 |
WO2014159679A1 (en) | 2013-03-12 | 2014-10-02 | The United States Of America, As Represented By The Secretary, Department Of Health & Human Services | Methods for using lubiprostone to absorb fluid from the subretinal space |
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DK0503887T3 (da) * | 1991-03-14 | 1996-09-16 | R Tech Ueno Ltd | Fremme af sårheling med 15-ketoprostaglandinforbindelser |
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JP2015205915A (ja) * | 2009-04-15 | 2015-11-19 | 株式会社アールテック・ウエノ | 黄斑変性を処置するための方法および組成物 |
WO2015125933A1 (ja) * | 2014-02-21 | 2015-08-27 | 国立大学法人 香川大学 | 加齢黄斑変性に伴う地図状萎縮の処置のための医薬組成物 |
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RU2011146128A (ru) | 2013-05-20 |
RU2548762C2 (ru) | 2015-04-20 |
MX338490B (es) | 2016-04-18 |
JP2015205915A (ja) | 2015-11-19 |
BRPI1016081A2 (pt) | 2017-07-18 |
ZA201108151B (en) | 2012-07-25 |
CA2757762A1 (en) | 2010-10-21 |
US20100267832A1 (en) | 2010-10-21 |
NZ596035A (en) | 2013-06-28 |
AU2010237744A1 (en) | 2011-11-17 |
MX2011010899A (es) | 2011-11-01 |
JP6109476B2 (ja) | 2017-04-05 |
CN102458413B (zh) | 2015-05-20 |
TW201039830A (en) | 2010-11-16 |
IL215556A0 (en) | 2011-12-29 |
WO2010119986A1 (en) | 2010-10-21 |
EP2419107A1 (en) | 2012-02-22 |
AR076298A1 (es) | 2011-06-01 |
US8609729B2 (en) | 2013-12-17 |
TWI501769B (zh) | 2015-10-01 |
US20140066506A1 (en) | 2014-03-06 |
CN102458413A (zh) | 2012-05-16 |
AU2010237744B2 (en) | 2015-11-26 |
KR20120018158A (ko) | 2012-02-29 |
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