JP6662864B2 - ガンマ−ラクタムのエステルプロドラッグ及びそれらの使用 - Google Patents
ガンマ−ラクタムのエステルプロドラッグ及びそれらの使用 Download PDFInfo
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- JP6662864B2 JP6662864B2 JP2017517726A JP2017517726A JP6662864B2 JP 6662864 B2 JP6662864 B2 JP 6662864B2 JP 2017517726 A JP2017517726 A JP 2017517726A JP 2017517726 A JP2017517726 A JP 2017517726A JP 6662864 B2 JP6662864 B2 JP 6662864B2
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- unsubstituted
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- alkyl
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- ISIJQEHRDSCQIU-UHFFFAOYSA-N tert-butyl 2,7-diazaspiro[4.5]decane-7-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)CCCC11CNCC1 ISIJQEHRDSCQIU-UHFFFAOYSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- ILMRJRBKQSSXGY-UHFFFAOYSA-N tert-butyl(dimethyl)silicon Chemical compound C[Si](C)C(C)(C)C ILMRJRBKQSSXGY-UHFFFAOYSA-N 0.000 description 1
- BCNZYOJHNLTNEZ-UHFFFAOYSA-N tert-butyldimethylsilyl chloride Chemical compound CC(C)(C)[Si](C)(C)Cl BCNZYOJHNLTNEZ-UHFFFAOYSA-N 0.000 description 1
- 125000001981 tert-butyldimethylsilyl group Chemical group [H]C([H])([H])[Si]([H])(C([H])([H])[H])[*]C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000004192 tetrahydrofuran-2-yl group Chemical group [H]C1([H])OC([H])(*)C([H])([H])C1([H])[H] 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- RTKIYNMVFMVABJ-UHFFFAOYSA-L thimerosal Chemical compound [Na+].CC[Hg]SC1=CC=CC=C1C([O-])=O RTKIYNMVFMVABJ-UHFFFAOYSA-L 0.000 description 1
- 229940033663 thimerosal Drugs 0.000 description 1
- 125000005309 thioalkoxy group Chemical group 0.000 description 1
- 229930192474 thiophene Natural products 0.000 description 1
- 229960000454 timolol hemihydrate Drugs 0.000 description 1
- 229960005221 timolol maleate Drugs 0.000 description 1
- 229940034744 timoptic Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 229940113006 travatan Drugs 0.000 description 1
- 229960002368 travoprost Drugs 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 229940108420 trusopt Drugs 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
- 229940002639 xalatan Drugs 0.000 description 1
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0048—Eye, e.g. artificial tears
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Description
本出願は、その全体が参照によって本明細書に組み込まれ、かつ優先権の基礎として役立ち、かつ/または本出願の請求に有益である2014年10月2日出願の米国特許仮出願62/058,802号の利益を請求する。
本発明は、ガンマ−ラクタム化合物のエステルプロドラッグ、ならびに特に緑内障及び黄斑変性を含む眼疾患を治療するためにそのような化合物を使用する方法を対象とする。
I.定義
本明細書において使用する略語は、化学及び生物学分野内でのそれらの従来の意味を有する。本明細書において示す化学構造及び化学式は、化学分野において公知の化学的原子価の標準規則に従って構築されている。
(A)−OH、−NH2、−SH、−CN、−CF3、−NO2、オキソ、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、ならびに
(B)下記(i)及び(ii)から選択される少なくとも1個の置換基で置換されているアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、及びヘテロアリール:
(i)オキソ、−OH、−NH2、−SH、−CN、−CF3、−NO2、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、及び
(ii)下記(a)及び(b)から選択される少なくとも1個の置換基で置換されているアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、及びヘテロアリール:
(a)オキソ、−OH、−NH2、−SH、−CN、−CF3、−NO2、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、非置換ヘテロアリール、及び
(b)オキソ、−OH、−NH2、−SH、−CN、−CF3、−NO2、ハロゲン、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、及び非置換ヘテロアリールから選択される少なくとも1個の置換基で置換されているアルキル、ヘテロアルキル、シクロアルキル、ヘテロシクロアルキル、アリール、またはヘテロアリール。
第1の態様では、式(I)の構造を有する化合物:
別の態様では、眼科的薬学的添加剤及び本明細書において提供する化合物(例えば、式(I)、(II)、(III)、(IV)、(V)、(VI)の構造を有する化合物、またはその誘導体、異性体、または鏡像異性体であり、かつ本開示を読めば当業者が特定可能なその実施形態を含む)を含む眼科用医薬組成物を提供する。
本明細書において開示する化合物及び医薬組成物は、液剤、乳剤、ゲル剤、またはフォーム剤を含む様々な形態で調製及び投与することができる。したがって、本明細書において企図する医薬組成物は、薬学的に許容される担体または添加剤、及び1種または複数種の本明細書に記載の化合物を含む。「液剤」は、通例の意味で、化合物(例えば、本明細書に記載の化合物)が少なくとも部分的に溶解していて、好ましくは完全に溶解していて、液体として投与することができる液体医薬組成物を指す。「乳剤」は、通例の意味で、2種以上の不混和性液体の混合物を指し、その際、1種の化合物(例えば、本明細書に記載の化合物またはその溶液)は、他の化合物(例えば、本明細書に記載のとおりの担体)全体に分散している。「ゲル剤」は、通例の意味で、粘稠性な半硬質流体が生じている、連続流体相内の化合物の高度に粘稠性の液剤、乳剤、またはコロイド状懸濁剤を指す。「コロイド剤」は、通例の意味で、重力の影響下でも沈降しない小さい粒子が全体に分散している連続媒体を含む組成物を指す。「フォーム剤」は、通例の意味で、ガス(例えば、空気)が全体に分散している連続媒体(すなわち、液剤、乳剤、ゲル剤など)を含む組成物を指す。
対象または患者において、眼疾患及び障害を治療する方法を、本明細書では提供する。一部の実施形態では、対象または患者は、哺乳類である。好ましい実施形態では、対象または患者は、ヒトである。当該方法は、治療有効量の式(I)〜(VI)のいずれか1つの構造を有する化合物を、それを必要とする対象に投与することを含む。一実施形態では、当該方法は、治療有効量の式(I)〜(III)のいずれか1つの構造を有する化合物を、それを必要とする対象に投与することを含む。一実施形態では、当該方法は、治療有効量の式(I)〜(VI)のいずれか1つの構造を有する化合物、またはその誘導体、異性体、もしくは鏡像異性体を、それを必要とする対象に投与することを含む。
(S)−2,3−ジヒドロキシプロピル5−(3−((S)−1−(4−((S)−1−ヒドロキシヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(3)
化合物3の例示的合成を、次のスキーム1において示す。
スキーム1
(R)−2,3−ジヒドロキシプロピル5−(3−((S)−1−(4−((S)−1−ヒドロキシヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(5)の合成。
((R)−2,2−ジメチル−1,3−ジオキソラン−4−イル)メチル5−(3−((S)−1−(4−((S)−1−ヒドロキシヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(4)。化合物2の調製について上記した手順に従って、カルボン酸1 100mg(0.233mmol)及び(S)−(+)−2,3−O−イソプロピリデングリセロール153.9mg(1.165mmol)を使用して、次の構造を有するアセトニド保護されたエステル4 118.8mg(94%)を得た:
5−(3−((S)−1−(4−((S)−1−((tert−ブチルジメチルシリル)オキシ)ヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボン酸(8)の合成
化合物8の例示的合成を次のスキーム2において示す。
スキーム2
(2R,3R,4S)−2,3,4,5−テトラヒドロキシペンチル5−(3−((S)−1−(4−((S)−1−ヒドロキシヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(11)の合成
化合物11の例示的合成を、次のスキーム3において示す。
スキーム3
(2R,3R,4S,5R)−2,3,4,5,6−ペンタヒドロキシヘキシル5−(3−((S)−1−(4−((S)−1−ヒドロキシヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(14)の合成
(S)−2−ヒドロキシ−2−((4R,4’R,5R)−2,2,2’,2’−テトラメチル−[4,4’−ビ(1,3−ジオキソラン)]−5−イル)エチル5−(3−((S)−1−(4−((S)−1−((tert−ブチルジメチルシリル)オキシ)ヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(12)。化合物9の調製について上記した手順に従って、カルボン酸8 100mg(0.184mmol)及び(S)−1−((4R,4’R,5R)−2,2,2’,2’−テトラメチル−[4,4’−ビ(1,3−ジオキソラン)]−5−イル)エタン−1,2−ジオール57.8mg(0.221mmol)を使用して、次の構造を有するビスアセトニド保護されたエステル12 92.0mg(64%)を得た:
(2S,3S)−2,3,4−トリヒドロキシブチル5−(3−((S)−1−(4−((S)−1−ヒドロキシヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(17)の合成
((4S,5S)−5−(ヒドロキシメチル)−2,2−ジメチル−1,3−ジオキソラン−4−イル)メチル5−(3−((S)−1−(4−((S)−1−((tert−ブチルジメチルシリル)オキシ)ヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(15)。化合物9の調製について上記した手順に従って、カルボン酸8 128mg(0.235mmol)及び(+)−2,3−O−イソプロピリデン−L−スレイトール57.3mg(0.353mmol)を使用して、次の構造を有するアセトニド15 116.7mg(72%)を得た:
(2R,3R)−2,3,4−トリヒドロキシブチル5−(3−((S)−1−(4−((S)−1−ヒドロキシヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(20)の合成
((4R,5R)−5−(ヒドロキシメチル)−2,2−ジメチル−1,3−ジオキソラン−4−イル)メチル5−(3−((S)−1−(4−((S)−1−((tert−ブチルジメチルシリル)オキシ)ヘキシル)フェニル)−5−オキソピロリジン−2−イル)プロピル)チオフェン−2−カルボキシラート(18)。化合物9の調製について上記した手順に従って、カルボン酸8 166mg(0.305mmol)及び(−)−2,3−O−イソプロピリデン−D−スレイトール74.4mg(0.456mmol)を使用して、次の構造を有するアセトニド18 116.1mg(55%)を得た:
例示的な水安定性
式(IIIa)の化合物:
カラム:BioWidePore C18(SUPELCO)、4.6mm×25cm、5μm
移動相A:脱イオン水中の0.1%(V/V)トリフルオロ酢酸(TFA)、0.8ミクロン濾過
移動相B:100%アセトニトリル、0.8ミクロン濾過
カラム温度:周囲温度
注入体積:30μL
UV検出:214nm
流速:1.0mL/分
ランタイム:25分
サンプル希釈剤:脱イオン水中の50%アセトニトリル
勾配条件:表1を参照されたい
表1
下記に示す標準と比較した:
表2
実施形態1。式(I)の構造を有する化合物:
[式中、
R1は、非置換C1〜C10アルキル、R1Aによって置換されているC1〜C10アルキル、非置換2〜10員ヘテロアルキル、またはR1Aによって置換されている2〜10員ヘテロアルキルであり;
R1Aは、ヒドロキシルまたはハロゲンであり;
L1は、結合、C1〜C10アルキレン、2〜10員ヘテロアルキレンであり;
L2は、結合、C1〜C10アルキレン、アリーレン、またはヘテロアリーレンであり;
R2は、置換もしくは非置換アルキル、置換もしくは非置換ヘテロアルキル、置換もしくは非置換シクロアルキル、置換もしくは非置換ヘテロシクロアルキル、置換もしくは非置換アリール、または置換もしくは非置換ヘテロアリールである]。
R2Aが出現する毎に独立に、ハロゲン、ヒドロキシル、非置換アルキル、R2Bによって置換されているアルキル、非置換ヘテロアルキル、R2Bによって置換されているヘテロアルキル、非置換シクロアルキル、R2Bによって置換されているシクロアルキル、非置換ヘテロシクロアルキル、R2Bによって置換されているヘテロシクロアルキル、非置換アリール、R2Bによって置換されているアリール、非置換ヘテロアリール、またはR2Bによって置換されているヘテロアリールであり;
R2Bが出現する毎に独立に、ハロゲン、ヒドロキシル、非置換アルキル、R2Cによって置換されているアルキル、非置換ヘテロアルキル、R2Cによって置換されているヘテロアルキル、非置換シクロアルキル、R2Cによって置換されているシクロアルキル、非置換ヘテロシクロアルキル、R2Cによって置換されているヘテロシクロアルキル、非置換アリール、R2Cによって置換されているアリール、非置換ヘテロアリール、またはR2Cによって置換されているヘテロアリールであり;
R2Cが出現する毎に独立に、ハロゲン、ヒドロキシル、非置換アルキル、非置換ヘテロアルキル、非置換シクロアルキル、非置換ヘテロシクロアルキル、非置換アリール、または非置換ヘテロアリールである、実施形態1から25のいずれか1つに記載の化合物。
nは、1〜10であり;
R2Dは出現する毎に独立に、水素またはヒドロキシルである]。
Claims (15)
- 式(III)、(IV)、(V)又は(VI)の構造を有する化合物:
- 式(IIIa)または(IIIb)の構造を有する、請求項1に記載の化合物:
- 式(IIIa)の構造を有する、請求項1に記載の化合物:
- 式(IVa)、(IVb)、(IVc)、または(IVd)の構造を有する、請求項1
に記載の化合物:
- 式(Va)、(Vb)、(Vc)、(Vd)、(Ve)、(Vf)、(Vg)、または(Vh)の構造を有する、請求項1に記載の化合物:
- 式(VIa)、(VIb)、(VIc)、(VId)、(VIe)、(VIf)、(VIg)、(VIh)、(VIi)、(VIj)、(VIk)、(VIl)、(VIm)、(VIn)、(VIo)、または(VIp)の構造を有する、請求項1に記載の化合物:
- 請求項1から6のいずれか1項に記載の化合物を含み及び眼科的に許容される添加剤を任意に含んでいてもよい、眼科用医薬組成物。
- 対象において眼疾患を治療するための、請求項7に記載の眼科用医薬組成物。
- 局所眼投与のための、請求項8に記載の眼科用医薬組成物。
- 前記疾患が緑内障である、請求項8に記載の眼科用医薬組成物。
- 前記疾患が黄斑変性である、請求項8に記載の眼科用医薬組成物。
- 前記疾患が眼内圧の上昇から生じている、請求項8に記載の眼科用医薬組成物。
- 対象において角膜肥厚化を低減するための、請求項7に記載の眼科用医薬組成物。
- 前記対象が緑内障に罹患している、請求項13に記載の眼科用医薬組成物。
- 前記対象が眼高血圧症に罹患している、請求項13に記載の眼科用医薬組成物。
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PCT/US2015/053865 WO2016054596A1 (en) | 2014-10-02 | 2015-10-02 | Ester prodrugs of gamma-lactams and their use |
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US3149954A (en) * | 1962-02-16 | 1964-09-22 | Du Pont | Method of retarding the growth of vegetation |
US4911920A (en) | 1986-07-30 | 1990-03-27 | Alcon Laboratories, Inc. | Sustained release, comfort formulation for glaucoma therapy |
FR2588189B1 (fr) | 1985-10-03 | 1988-12-02 | Merck Sharp & Dohme | Composition pharmaceutique de type a transition de phase liquide-gel |
JP2594486B2 (ja) | 1991-01-15 | 1997-03-26 | アルコン ラボラトリーズ インコーポレイテッド | 局所的眼薬組成物 |
US5212162A (en) | 1991-03-27 | 1993-05-18 | Alcon Laboratories, Inc. | Use of combinations gelling polysaccharides and finely divided drug carrier substrates in topical ophthalmic compositions |
US6309853B1 (en) | 1994-08-17 | 2001-10-30 | The Rockfeller University | Modulators of body weight, corresponding nucleic acids and proteins, and diagnostic and therapeutic uses thereof |
US6353000B1 (en) | 1996-11-12 | 2002-03-05 | Alcon Laboratories, Inc. | 11-halo prostaglandins for the treatment of glaucoma or ocular hypertension |
DE10322843A1 (de) | 2003-05-19 | 2004-12-16 | Clariant Gmbh | Verfahren zur Herstellung von Anilinboronsäuren und ihren Derivaten |
EP1812017A2 (en) | 2004-10-21 | 2007-08-01 | Duke University | Ophthamological drugs |
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CN105520941B (zh) * | 2005-03-10 | 2020-05-01 | 阿勒根公司 | 作为治疗剂的取代的γ内酰胺 |
WO2007109578A2 (en) * | 2006-03-20 | 2007-09-27 | Allergan, Inc. | Substituted gamma lactams as prostaglandin ep2 agonists |
US20070254920A1 (en) | 2006-04-26 | 2007-11-01 | Aerie Pharmaceuticals, Inc. | Prodrug derivatives of acids using alcohols with homotopic hydroxy groups and methods for their preparation and use |
AU2007272617B2 (en) | 2006-07-11 | 2012-11-01 | Allergan, Inc. | Cyclopentane derivatives as antiglaucoma agents |
US7589213B2 (en) * | 2007-04-27 | 2009-09-15 | Old David W | Therapeutic substituted lactams |
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EP2291367A1 (en) * | 2008-04-24 | 2011-03-09 | Allergan, Inc. | Substituted gamma lactams as therapeutic agents |
AU2009239372B2 (en) * | 2008-04-24 | 2013-09-19 | Allergan, Inc. | Substituted gamma lactams as therapeutic agents |
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CA2882743C (en) | 2012-08-27 | 2021-11-30 | Allergan, Inc. | Reduced central corneal thickening by use of hydrophilic ester prodrugs of beta-chlorocyclopentanes |
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