TWI250873B - Ophthalmic compositions for treating ocular hypertension - Google Patents
Ophthalmic compositions for treating ocular hypertension Download PDFInfo
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- TWI250873B TWI250873B TW092130678A TW92130678A TWI250873B TW I250873 B TWI250873 B TW I250873B TW 092130678 A TW092130678 A TW 092130678A TW 92130678 A TW92130678 A TW 92130678A TW I250873 B TWI250873 B TW I250873B
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- alkyl
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- acid
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- 239000000203 mixture Substances 0.000 title claims abstract description 27
- 206010030043 Ocular hypertension Diseases 0.000 title description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6503—Five-membered rings
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Description
1250873 玖、發明說明: 【發明所屬之技術領域】 本發明係關於式I之有效卸通道阻斷劑化合物或其調配 物、,以用於治療青光眼及在病人眼睛中導致提高的眼内壓 力之其他病症。本發明亦關於該等化合物之使用,以為哺 礼動物物種(特別係人類)之眼睛提供神經保護效應。 【先前技術】 —青光眼係一種眼睛退化疾病,其中眼内壓力太高而無法 具現正苇的眼睛功此。因此,視神經頭部可受到損害,並 導致視覺功能之不可逆的損失。若未治療,則青光i可最 終導致失明。高眼壓(亦艮p,不具有視神經頭部損害或特徵 性青光眼視場缺陷的眼内壓力提高的病症)現在被多數眼科 學家相信可僅代表青光眼發病之最早階段。 雖然存在右干用於治療青光眼及提高的眼内壓力之療法 ,但是該等藥劑之功效及副作用特性(side effectpr〇file)不理想 。最近發現,鉀通道阻斷劑可減少眼睛中之眼内壓力,且 因此提供又一方法來治瘵高眼壓及與其相關之退化眼部病 症。鉀通道之阻斷可減少流體分泌,且在某些情況下,可 增加平滑肌收縮,且將被期望來降低I〇p並具有眼睛中之神 經保護效應。(參看美國第5,573,758及5,925,342號專利;乂〇咖
等人,Invest. Ophthalmol· Vis. Sci 38,1997 ; WO 89/10757、WO 94/28900及 WO 96/33719)。 【發明内容】 本發明係關於有效鉀通道阻斷劑或其調配物在青光眼及 88762 1250873 -(CH2)nC3_1G雜環基,該雜環基與烷基視情況經1至3個選自Ra 之個基團所取代時,可實現本發明之又一實施例。當η為0 時,可實現本發明之一子實施例。 本發明又另一具體例中,當Ra選自F、a、Br、I、CF3、N(R)2 > N02 > CN > -O- ^ -CONHRg > -CON(R8)2 ^ -0(CH2)nC00R > -NH(CH2)n0R 、-C〇〇R、-0CF3、-NHCOR、-S〇2R、-S〇2NR2、-SR、(CrC6烷基)〇-、-(CH2)n〇(CH2)m〇R、-(012)ηα6烷氧基、(芳基)〇·、-〇H、(CVC6 烷基)S(〇)„r、H2N-C(NH)-、(CrC6 烷基)C(〇)-、(CrC6 烷基)0C(〇)NH-、-(CrC6 烷基)NRw(CH2)nC3_10 雜環基-Rw、-(CHA-ZLCPZ2):^!^、 _(C2_6烯基)NRw(CH2)nC3_1G雜環基-Rw、-(C2_6晞基 VZ^CPZ2)—!^、 -(CH2)nS〇2R、-(CH2)nS〇3H、-(CH2)nP〇(〇R)2、C2_6烯基、及(^-€10烷 基,該烷基及烯基視情況經1至3個選自CrC6烷基及COOR之 基團所取代。 本發明中可用之化合物實例見於表1 : 表1
〇
R1 R2 K 88762 -10- 1250873 K K K K xV K '〇 ^rr^< '〇 »/ντυ 0 p^r (〇)汾 η η=0-3 OH '〇 -1-(CH2)n〇H n=0-3 v-T< '〇 或醫藥上可接受之鹽、對映體、非對映體或其混合物。 此處利用以下定義之術語(除非另外規定),来詳細描述 本發明。 本發明之化合物可具有不對稱中心、對掌軸及對掌平面 ,且可以消旋物、外消旋混合物,及具有被包括在本發明 中之所有可能的同分異構體(包括光學異構體)的各個非對 88762 -11 - 1250873 映體的形態存在。(參看E丄.Eliel與S.H· Wilen之“Stereochemistry of Carbon Compounds”(John Wiley與 Sons,紐約 1994)中的特定 頁:1119-1190) 〇 當任何變數(例如芳基、雜環、R1、R6等)在任何組份中 出現超過一次時,其每次出現的定義在每次其他出現時是 獨立的。僅當取代基/或變數之組合可產生穩定的化合物時 ,才允許該等組合。 當Ra係且键結於碳原子時,其被稱為羰基;當其鍵結 於氮(例如吡啶基上之氮原子)時或硫原子時,其分別被稱 為N-氧化物及硫氧化物基團。 除非另外定義,術語“烷基”係指單價烷烴(碳氫化合物) 所衍生之包含1至10個碳原子的基團。該基團可係直線的、 分支的或環狀的。較佳烷基包括甲基、乙基、丙基、異丙 基、丁基、t-丁基、環丙基、環戊基及環己基。當該烷基 被稱為經烷基所取代時,則其與“分支烷基,,可互換使用。 除非另外定義,環烷基係包含3至15個碳原子,且在碳原 子之間不具有交替或共振雙鍵之烷基。其可包含丨至4個稠 合的環。該等環烷基單元之實例包含(但不限於)環丙基、 環丁基、環戊基、環己基及環庚基。 烯基為c2-c6烯基。 燒氧基係指具有ϋ由氧橋而鍵結於其上之所示S目的碳 原子之燒基’減基可按此處所描述的方式視情況經取代 。該等基®為具有指定長度且以直鏈或分支組態存在的基 團,且若該長度上具有兩個或兩個以上碳原子,則該等基 -12 - 88762 l25〇873 團可包括雙键或三鍵。該等'燒氧基之實例為甲氧基、乙s 基、丙氧基、異丙氧基、丁氧基、異丁氧基、第:丁氧: 、戊氧基、異戊氧基、己氧基、異己氧基、晞丙氧基、二 丙氧基,及其類似物。 鹵素(鹵基)係指氯、氟、礎或溴。 芳基係指芳香環(例如苯基、經取孜 取代足奉基及其類似物) ,以及稠合的環(例如審基、菲基及其類似 包含具有至少6個碳原子之至少一個 U此万基 一 ^ 個% 可存在鬲達5個該 寺環,其中包含高達22個原子,且在相鄰唉原子或合適的 雜原子=具有交替(共振)雙鍵。芳基之實例為苯基、萘 基、四氮奈基、印滿基 辦貧 # * — ,^ 丞·冬基、非基、1基或厄基及菲 基’較佳為木基、審基式菲I ^ ,、戈非基。方基可同樣按所定義的方 式經取代。較佳經取代之芳基包括苯基與萘基。 此處所使用之術語·“雜戸+{,,4*、“、, 町〜雖%基或“雜環,,代表飽和或不 的穩定3-至7-員單環,十拉—。 或%疋8-至11-員雙環雜環,且並由 碳原子及選自N、C^s 、 /、、,且成足群的1至4個雜原子組成,且 括其中上述雜環稠人^ 、 口土冬%《任何雙環基團。該種雜環 可鍵結至任何雜原子戋 入二卜^ 原子上,產生一種穩定結構。稠 口雄裱系統可包括碳環,+ π 且而要僅包括一個雜環。術語‘‘雜 裱基”或“雜環”包拓%〜甘、、 " 命方基邵分。該等雜環單元之實例包括 (但不限於)吖庚因其 # ;, ,μ # #、, 土、+并咪唑基、苯并異噁唑基、苯并 % ^㈣基 '苯并Ρ塞喃基、苯并吱喃基、苯并噻 一二:“基、笨并噁唑基、色滿基、幸啉基、二氫 …喃基、二氣苯并,塞吩基、二氣苯并。塞喃基、二氯苯 88762 1250873 咳喃基、咪峻口定
p林基、4諾琳基、四氫吱喃基、 、四氫異喳淋基、四氫p奎啉 并噻喃砜、二氫吡咯基、丨,3_二氧戊環基、 基、咪唑啉基、咪唑基、啕哚啉基、啕嗓 兴17弓卜木口林基、兴峻P林基、異口塞口垒餘其、 基、噻嗎啉基、噻嗎啉亞颯、噻唑基、噻唑啉基、魂吩并 呋喃基、噻吩并噻吩基及噻吩基。雜環較佳選自:I吖庚 因醯基(azepinonyl)、苯并咪唑基、2_二吖庚因醯基、二氫咪 唑基、二氫吡咯基、咪唑基、2_咪唑啶醯基(imidaz^di⑽邮) 六氫吡啶基、六氫吡畊基 、吲嗓基、異p奎淋基、嗎淋基、 比走基峨P各淀基、氫P比淀g盔基(piperidin〇nyl)、2_喃 啶醯基(pyrimidinonyl)、2-吡咯啶醯基(pyr〇mdin〇nyl)、喹啉基 、四氫呋喃基、四氫異喹啉基及噻吩基。 術語“雜原子,,意即在一獨立基礎上所選擇的〇、S或N。 術吾雜芳基”係指具有5或6個環原子的單環芳香烴,或 具有8至1〇個原子的二環芳香基團,其包含至少一個雜原子 ◦、S或N,其中碳原子或氮原子是鍵結點,·且‘其中一個或 兩個額外之碳原子視情況被選自〇或s的雜原子取代,且其 中1至3個額外之碳原子視情況被氮雜原子取代,該雜芳基 視情況被按此處所描述的方式取代。該等雜環單元之實例 包括(但不限於)苯并咪唑基、苯并異噁唑基、苯并呋咕基 88762 -14 - 1250873
、苯并吡喃基、苯并嘍喃基、苯并呋喃基、苯并噻唑基、 苯并噻吩基、苯并噁唑基、色滿基、幸啉基、二氫苯並并 咬喃基、二氯苯并p塞吩基、二氯本并p塞喃基、二A私并17塞 喃颯、吱喃基、咪吐基、4卜朵淋基、吲嗓、異色滿基、異 啕哚啉基、異喳啉基、異嘧唑基' 莕啶基、噁二唑基、吡 淀基、说啡基、说α坐基、塔17井基、喊淀基、说p各基、峻σ坐 口林基、?奎ρ林基、ρ奎諾琳基、四氫異峻ρ林基、四氫峻ρ林基、 噻唑基、噻吩并咬喃基、嘧吩并噻吩基、噻吩基及***基 。額外之氮原子可該第一個氮與氧或硫共同存在,生成(例 如)Ρ塞二吐。
本發明亦關於治療高眼壓或青光眼之組合物及方法,其 係藉由對需要治療之病人投予式I之化合物之一種與以下各 物之組合·· β-腎上腺素阻斷劑,例如4嗎心安(timolol)、倍 他索洛爾(betaxolol)、左旋倍他索洛爾、山羊豆甞(carteolol)、 左旋布諾洛爾;擬副交感劑,例如腎上腺素、艾比定(i〇Pidine) 、溴莫尼定(brimonidine) '可樂定(clonidine)、對-胺基可樂定 ;碳酸if酶抑制劑,例如漆素得(dorzolamide)、醋峻績胺 (acetazolamide)、間峻續胺(metazolamide)或布吲唑橫胺(brinzolamide) ;EP4促效劑(例如在 WO 02/24647、W〇 02/42268、EP 1114816、 W〇01/46140及WO 01/72268中揭示之該等促效劑)‘;***素 ,例如樂通舒特(latanoprost)、青服平(travaprost)、烏諾前列酮 (unoprostone)、利視即樂(rescula) ; S1033(在美國第 5,889,052、 5,296,504、5,422,368及5,151,444號專利中陳述之化合物);低血 壓脂質,例如露明甘(lumigan)及在美國第5,352,708號專利中陳 88762 -15 - 1250873
述之化合物;在美國第4,690,931號專利中揭示之神經保護劑 ,特別係在WO 94/13275中陳述之依利羅地(eliprodil)及R-依利 羅地(eliprodil),包括美金剛胺(memantine);或在 PCT/US00/31247 陳述之5-HT2受體的促效劑’特別係1 - (2 -胺基丙基)-3 -甲基-1H-咪唑-6-醇富馬酸鹽及2-(3-氣-6-甲氧基-吲唑小基)小甲 基-乙胺。低血壓脂質(在具有驗性***素結構之α-鏈環上 的羧酸基團被電化學中性取代基所取代)之一實例在於:在 該實例中,該羧酸基團被Cm烷氧基例如〇CH3 (PGF2a 1-〇CH3) 或羥基(PGF2al-〇H)所取代。 較佳的鉀通道阻斷劑為鈣活化之鉀通道阻斷劑。更佳的 鉀通道阻斷劑為高傳導、鈣活化之鉀(Maxi-K)通道阻斷劑。 Maxi-K通道為離子通道之族,該等離子通道普遍存在於神 經元、平滑肌及上皮組織中,且被細胞膜電位及細胞内的 Ca2+所門控。
本發明基於該發現,即Maxi-K通道若被阻斷則可藉由抑 制淨溶質及H2〇流出,來抑制含水體液產生,且因此降低 I0P。該發現提示了,Maxi-K通道阻斷劑可用於治療其他眼 科疾病(例如斑狀水腫及斑狀退化)。已知降低I0P將促進血 液流向視網膜及視神經。因此,本發明之化合物可用於治 療斑狀水腫及/或斑狀退化。 據信,降低I0P之Maxi-K通道阻斷劑可用於提供神經保護 效應。該等Maxi-K通道阻斷劑亦被認為可藉由降低IOP來有 效地增加視網膜及視神經頭部的血液速度,並增加視網膜 及視神經氧含量,當將這些搞合在一起時可有利於視神經 88762 -16- 1250873 健康。因此,本發明還關於一種方法,其用於增加視網膜 及視神經頭部血液速度,增加視網膜及視神經氧張力,以 及提供神經保護效應或其組合。 許多市售藥物可充當鉀通道拮抗劑之功能。該等藥物中 最重要的藥物包括化合物Glyburide、Glipizide及Tolbutamide。該 等鉀通道拮抗劑可用作抗糖尿病試劑。本發明之化合物可 組合一種或多種該等化合物以治療糖尿病。
钾通道拮抗劑亦可被用作第3類抗心律失常試劑,其可被 用來治療人類中的急性梗塞。已知許多自然出現之毒素可 阻斷4甲通道,該等毒素包括蜂毒明肽(Apamin)、伊貝瑞毒素 (Iberiotoxin)、卡律蟹毒素(Charybdotoxin)、諾辛毒素(Noxiustoxin) 、卡裏毒素(Kaliotoxin)、(多種)樹木毒素、肥大細胞脫粒 (MCD)肽,及β-銀環蛇毒素(β-ΒΤΧ)。本發明之化合物可組 合一種或多種該等化合物以治療心律失常。
抑鬱症係關於神經傳遞質釋放的降低。抑鬱症之當前治 療方法包括神經傳遞質攝取之阻斷劑,及涉及神經傳遞質 退化之酶的抑制劑,該等抑制劑可延長神經傳遞質的壽命。 阿茲海默氏疾病(Alzheimer’s disease)之特徵亦在於減少的神 經傳遞質釋放。3種等級的藥物係被研究以用於治療阿茲海 默氏疾病:膽驗能增效劑,例如:抗膽驗酯酶藥物(例如毒 爲豆驗(eserine)及塔克林(四氫胺基 p丫淀(tetrahydroaminocridine))) ;影響神經元新陳代謝(在別處幾乎無影響)之抗痴呆藥 (nootropic)(例如p比乙驢胺、奥拉驢胺);及影響腦脈管系統 之該等藥物(例如甲績酸雙氫麥角毒與包括印棟素酸 88762 17 1250873 (Nimodipine)之鈣通道阻斷藥物的混合物)。據報導,司立士 林(SdegHine),為-種增加腦多巴胺及降腎上腺素之 化酶B抑制劑,已使某歧阿兹沲點氏咗 一 木一丨』炫母默氏屄涡病人的病情適度 改善1蟄合劑已引起相信阿兹海默氏疾病㈣因於銘= 性的人的注意。已採用影響行為之藥物(包括神經安定^ 及抗焦慮藥。抗焦慮藥(其為溫和鎮定劑)不比神經安定藥 有效。本發明係關於可充當鉀通道拮抗劑使用之新穎化合 物。 在本發明範圍中的化合物展示鉀通道拮抗劑活性,且因 此可用糸與鉀通道功能失調相關聯之失調症治療中。許多 認:失調症(例如阿茲海默氏疾病、記憶力喪失或抑鬱症) 可受益於提高的神經傳遞質釋放,該等神經傳遞質例如 為·五蛵色胺、多巴胺或乙醯膽鹼及其類似物。%狀丨《通 C之阻斷保持了細胞去極化,且因此提高該等活神經傳遞 質的分泌。 ~ 本發明之化合物在老年癡呆症治療中可與以下各物組合 瓦膽驗ϋ日每藥物’例如毒爲豆驗及塔克林(四氫胺其 口丫 \ · "哫),抗痴呆藥,例如吡乙醯胺、奥拉醯胺、甲磺醯雙氫 麥角母’可選擇的鈣通道阻斷劑,例如印楝素酸;或單胺 氧化酶Β抑制劑,例如司立吉林。本發明之化合物在治療 〜率不整中可與以下各物組合使用:蜂毒明肽、伊貝瑞毒 素、卡律蟹毒素、諾辛毒素、卡裏毒素、(多種)樹木毒素 肥大細胞脫粒(MCD)肽、β-銀環蛇毒素(β-ΒΤΧ)或其組合 。本發明 > 几 〈化合物可與以下各物組合使用以治療糖尿病: 88762 -18- 1250873 優降糖、格列甲嗪、甲苯磺丁脲或其組合。 處”例為例示性,並不限制所申請之本發明。本發明 之化口物中的每一種均為鉀通道拮抗劑,因此可用於所描 逑足神銓學失碉症,在該種失調症中,需要將細胞保持在 去極化狀怨,以獲得最大的神經傳遞質釋放。本發明所生 2 ^化合物容易與合適且已知的醫藥上可接受之賦形劑組 合來生產組合物,可將該等組合物施用至哺乳動物(包括人 類)以獲得有效的鉀通道阻斷。 就,藥用途而言,式ϊ化合物的鹽將係醫藥上可接受之鹽 疋/、他鹽可用於製備根據本發明之化合物或其醫藥 矣义之I ^本發明之化合物是酸性時,合適的“醫藥 上可接文< 鹽”係指由包括無機鹼及有機鹼的醫藥上可接受 〈無毒驗製備而來的鹽。由無機驗衍生而來的鹽包括銘鹽 、銨鹽、鈣鹽、銅鹽、鐵鹽、亞鐵鹽、鋰鹽、鎂鹽、錳鹽 亞孟最钾鹽、納鹽、鋅鹽及其類似物。特別較佳的係 銨=、鈣鹽、鎂鹽、鉀鹽及鈉鹽。由醫藥上可接受之有機 無毒鹼衍生而來的鹽包括··一級胺鹽、二級胺鹽及三級胺 鹽,i取代胺,其包括天然經取代胺、環胺及鹼離子交換 樹脂,例如精胺酸、甜菜鹼、咖啡因、膽鹼、n,nL:苄基 伸乙基一版、二乙胺、二乙胺基乙醇、2-二甲胺基乙醇 、乙醇胺、乙二胺、N-乙基嗎啉、队乙基六氫吡啶、葡萄 糖胺、胺基葡萄糖、組胺酸、海卓胺(hydrabamine)、異丙胺 、賴胺酸、甲基葡萄糖胺、嗎啉、六氫吡畊、六氫吡啶、 聚胺樹脂、普魯卡因、嗓呤、可可驗、三乙胺、三甲胺、 88762 -19- 1250873 二丙胺、三竣甲基胺甲貌及其類似物。 當本發明之化合物是鹼性時,鹽可由包括無機酸及有機 酸的醫藥上可接受之無毒酸製備而來。該等酸包括乙酸、 苯磺酸、苯甲酸、樟腦磺酸、檸檬酸、乙磺酸、富馬酸、 葡萄糖酸、穀胺酸、氫溴酸、鹽酸、2羥乙基磺酸、乳酸、 馬來酸、羥基丁二酸、扁桃酸、甲磺酸、半乳糖二酸、硝 酸、雙羥萘甲酸(pamoic acid)、泛酸、磷酸、丁二酸、硫酸 、酒石酸、對甲苯磺酸及其類似物。特別較佳的酸為檸檬 酸、氫溴酸、鹽酸、馬來酸、磷酸、硫酸及酒石酸。 在 Berg等人之 r“Pha麵cemical Salts,,,;此續 ⑼:h9」 中更芫整地描述上述醫藥上可接受之鹽與其他典型醫藥上 可接受之鹽的製備。 如此處所使用,術語“組合物,,意欲包含具有特定劑量之 特足成份的產物,以及由特定劑量之特定成份的組合(直接 或間接)產生的任何產物。 當根據本發明之化合物對人類個體投藥時,日劑量通常 由處方醫師確定,該劑量通常根據個別病人之年齡、體重 f生別及反應’以及病人症狀的嚴重性而變化。 所使用之Ma破通道阻斷劑可以一治療有效劑f,經靜 脈内、皮下、局部、經皮、腸道夕卜或藉由熟習此項技術 者熟知的任何其他方法來施用。 眼用醫樂組合物較佳適合於以溶液、懸浮液、軟膏、軟 劑形式或固體插人物之形態局部施用於眼晴。該化合物之 眼用調配物可包含⑽i,至1%之藥劑,尤其係㈣至1% 88762 -20- 1250873 彻。可採用較高劑量(例如約1〇%)或更低之劑 是該劑量可有效地減少眼内壓力、治療青光眼、増加:: 流動速度或氧張力。對單劑量而言,嶋5_啤,較2 0.1至500 ng,尤其為丨至丨⑻吨之化合物可施加至人類眼部。 /便!含該化合物之醫藥製劑與無毒醫藥有機裁 戶|或典母酉樂典機載劑混合。典型的醫藥上可接受之 劑係’(例如)水、水及水溶性溶劑(例如低錢㈣或芳: 醇)的混合物、植物油、聚燒二醇、石油基之膠質、乙基: 維素、油酸乙酉旨、幾甲基纖維素、聚乙缔㈣燒酉同、十四 燒酸異丙酿及其他習知可採用的可接受之載劑。醫藥製劑 吓可包含·無毒輔助物質,例如乳化劑、防腐劑、潤濕劑 、基礎劑(bodymg agent)及其類似物,例如聚乙二醇2〇〇、3如Y 400 及 600,碳蠟(carb_x)1,〇〇〇、15〇〇、4,_、6 〇〇〇 及 ; 抗菌組份,例如四級銨化合物、已知具有冷滅菌屬性且使 用時無害的苯汞基鹽、硫柳汞、對_羥基苯甲酸甲酯及丙酯 、苯甲醇、苯乙醇;緩衝成份,例如硼酸鈉、乙酸鈉、葡 萄糖鹽緩衝劑,及其他習知成份,例如脫水山梨糖醇單 月桂酸酯、三乙醇胺、油酸鹽、聚氧乙晞脫水山梨糖醇單 标櫚酸酯、丁二酸二辛基磺酸鈉、單硫代甘油、硫代山梨 糖醇伸乙二胺四乙酸’及其類似物。另外,’合適的眼用 載體(vehicle)可充當載劑媒體而被用於本發明之目的,該等 眼用載體包括習知的磷酸鹽緩衝劑載體系統、等滲硼酸載 體、等滲氣化鈉載體、等滲硼酸鈉及其類似物。該醫藥製 劑亦可以微粒調配物之形式存在。該醫藥製劑也可以固體 88762 -21 - 1250873
***物的形式存在。舉例而言,吾人可使用一種水可溶之 固體聚合物以充當該藥劑之載劑。用來形成該***物之聚 合物可為任何水溶性無毒聚合物,例如:纖維素衍生物, 例如甲基纖維素、竣甲基纖維素鈉、(經低竣烷基纖維素) 、羥乙基纖維素、羥丙基纖維素、羥丙基甲基纖維素;丙 稀酸鹽’例如聚丙烯酸鹽、乙基丙烯酸鹽、聚丙缔醯胺; 天然產物,例如凝膠、藻朊酸鹽、果膠、黃蓍膠、刺梧桐 、用又菜屬、瓊脂、***膠;澱粉衍生物,例如澱粉酷 酸@曰每甲基藏粉醚、輕丙基澱粉;以及其他合成衍生物 ,例如聚乙烯醇、聚乙烯吡咯烷酮、聚乙烯甲醚、聚氧化 乙烯、中和的卡波(carbopol)及黃原膠、結蘭膠职⑷、 及該聚合物之混合物。 用於被施用本發明之調配物的合適的個體包括靈長類動 物、人類及其他動物,特別係人類及馴化的動物(例如貓與 狗)。 ”
居酱藥製劑可包含:無毒輔助物質,例如使用時係無害的 抗菌組份,例如硫柳汞、苯曱氯烷銨、對-羥基苯甲酸甲酯 丙酉曰 +基十二统溴按(benzyldodecinium bromide)、苯甲醇 或苯乙醇;緩衝成份,例如氯化鈉、硼酸鈉、乙酸鈉、檸 檬酸鈉、或葡萄糖酸鹽緩衝劑;及其他習知成‘份,例如脫 水山梨糖醇單月桂酸酯、三乙醇胺、聚氧乙晞脫水山梨糖 醇單棕櫚酸酯、乙二胺四乙酸,及其類似物。 可按需要經常施用眼用溶液或懸浮液,以在眼睛中保持 可接文之IOP值。可設想每日約一次或兩次對哺乳動物眼晴 88762 -22- 1250873 進行施藥。 局邵眼部施藥而言,本發明之新穎調配物可呈溶潘 r 、懸浮液或固體***物之形態、,其係調配使 早仫训里包含孩活性組份之治療有效劑量或复 倍(在組合治療的情況下)。 ,、右干 藉由示例方式提供的下列實例對本發明加以說明。 孩等實例所使用之術語的定義如下: SM —起始材料, DMS〇 一二甲亞砜, TLC -薄層層析法, SGC-矽膠層析法, PhMgBr —溴化苯鎂, 小時, THF —四氫吱喃, DMF—二甲基甲醯胺, min —分鐘, LC/MS —液體層析法/質譜分析法, HPLC -高效能液體層析法,
PyBOP —六氟瑪酸苯并三。坐小基氧代參、(二甲胺基)鱗, Equiv=eq=當量, NBS —N-溴琥珀醯胺,及 AIBN — 2,2’-偶氮二異 丁腈。 根據圖1製成(可適當地加以修改)本發明之化合物。亦根 據圖1製造實例1-3。 88762 •23 - 1250873
在圖1中,利用NBS、AIBN及過氧化苯酸來溴化硝基茴香 醚。以氫化鉀處理溴硝基茴香醚產生該氰基硝基茴香醚。 以氫化作用使硝基轉化成胺基。接著以亞硝酸鈉及HC1處理 該胺基,以產生州唑環。在該反應中,一旦苯胺部分之亞 硝化作用產生重氮基,該重氮基就被該酸性苯氰化物捕獲 在分子内。所得衍生物之互變作用生成了 4丨。坐核。以格利 亞(Gringard)處理該腈,接著水解所得的亞胺鎂錯合物,生 成所要的燒基/芳基i同。 製備實例1
COOEt 在 500 mL燒瓶中,注入 336 mmole(13.44g;60o/())之NaH。在氬 氣氛下,添加150 mL之DMS0,接著在5°C逐滴添加32 mL之氰 乙酸乙醋(2.2 equiv; 352 mmole)。當所有添加完成後,該反應 經1小時溫至室溫。添加30 g粉末態之起始物硝基苯衍生物 (160 mmole)。該反應混合物在一封閉系統中於9(TC下加熱8 88762 -24 - 1250873 小時。酸化及標準操作獲得粗製油狀殘餘物,其經矽膠管 柱純化獲得39 g所需結晶產物,該結晶產物如下經予以去羧 基獲得芊腈。以上所獲得的38克SM溶於400 mL之1N碳酸鈉 中。該均質溶液在室溫下攪拌2天。TLC分析指示反應完成 。反應混合物酸化,且以乙酸乙酯(100 mL X 4)萃取。所組 合之有機相經硫酸鈉乾燥並濃縮,且殘留物進行SGC獲得 所需產物。 !H NMR CDC13: 7.72 (1H? d? J = 3 Hz); 7.61 (1H, d? J - 8.5 Hz); 7.25 (1H, dd5 J = 3 及 8.5 Hz); 4.17 (2H,s); 3·94 (3H,s)· LCMS [M+H] = 193。
製備實例2
10 g芊腈衍生物溶於20 mL THF中,接著以50 mL甲醇稀釋 。將該反應混合物放在一壓力管中,添加Pd-C (10% wt/10 mole %),且該反應混合物在40 psi下氫化。當用於N〇2基還原 所需量的氳被消耗後,停止該反應。TLC分析顯示為點對 點轉換。該反應混合物經矽藻土墊過濾,且濾液濃縮成固 體且在下一步驟中直接使用。粗製苯胺衍生物(52 mmole)溶 解/懸浮在2NHCl(150mL)中,且被卻至5°C,接著添加5.4g亞 硝酸鋼之10 mL水溶液。該反應混合物攪拌1小時,並逐漸 溫至室溫。TLC分析指示SM完全消耗並形成一新的點。以 乙酸乙脂(100 mL X 4)萃取該反應混合物;收集、乾燥並濃 縮有機相。殘餘物藉SCG純化獲得所需產物。LCMS [M+H]= 174。 88762 -25- 1250873 製備實例3
稱出4.15 g叫丨唑且將水與2次甲苯(100 ml)洗液共沸,藉由 旋轉蒸發器移除甲苯共沸混合物。在高真空下充分乾燥並 執行氬氣清洗。在氬氣下,溶於40 ml乾燥THF與92 ml乾燥 ***中。在冰水槽中冷卻至。饋入3 eq之氯化異丙鎂(在 THF中6 ml 2 Μ溶液),且在室溫下攪拌0.5小時。小心饋入1N HC1 (240 ml)並攪拌1小時。利用TLC追蹤反應。以EtOAc萃取 ,旋轉蒸發,並生產所需產物。LCMS [M+H] = 219。 製備實例4
Etoy^〇Et ΜθΟ**-ίχ^νγ^ Νν Χλ<ν CH〇
步驟A :在室溫下使聯氨(0.624 mol,20 g)與400 mL乙二醇中 之100 g 2-氟-4-甲氧基-苯乙酮攪拌4小時,接著該反應混合 物加熱至150°C歷時48小時。TLC分析指示完全反應。將該 反應混合物分成二氯甲烷與鹽水。有機相經硫酸鈉乾燥, 且蒸發成固體。自己烷/二氯甲烷再結晶獲得6-甲氧基-3-甲 基-1H-丨口坐。 ^NMIICCDCI^): 7.5 (1¾ d,7.5 Hz); 6.8 (2¾ m); 3.8 (3¾ s); 2.55 (3¾ s)。 LCMS [M+H] = 163。
78g6 -甲氧基-3-甲基-1Η-Θ卜坐溶於包含1.1 equiv三乙胺之1L 88762 -26- 1250873
MeCN中,0.2 equiv之DMAP冷卻至-5°C ;接著緩慢添加含Boc20 (1.1 equiv)之200 mL MeCN。在室溫下攪拌該反應2小時後,該 反應混合物蒸發成油狀,其分配於Et〇Ac與鹽水間、經硫酸 鈉乾燥並蒸發。殘餘物施加至一短SGC,且以15% EtOAc之 己烷溶離。蒸發獲得Boc保護之產物。 NMR (CDCL3): 7.6 (1H, bs); 7.42 (1H? d? J = 7.5 Hz); 6.85 (1¾ dd); 3.8 (3H,s);2.5(3H,s); 1.7(9H,s)。 LCMS [M+H] = 263。 100 g BOC-保護之吲唑溶於600 mL CC14中,接著添加1.1 equiv之NBS及0·2 equiv之Bz2〇。反應混合用氬氣真空清洗, 且在日光燈下在光線存在下回流加熱5小時。反應混合物經 一 SG墊過濾並濃縮。殘餘之油經一短SGC純化。獲得單溴 化物,及二溴化衍生物之混合溶離份。 單溴化物:W NMR (CDCL3)·· 7·7 (1H,d,7.5 Ηζ); 7·6 (1H,bs); 6·95 (1H, dd); 4.7 (2¾ s); 3.9 (3H5 s); 1.7 (9H, s); 二溴化物:NMR (CDCL3): 8.05 (1H,d,J = 7.5 Hz); 7·6 (1H,bs); 7.0 (1H,dd); 6.85 (1H,s); 3·9 (3H,s); 1.7 (9H,s); 乙酸鈉(22.5 g)添加至二溴化物(23.2 g)之乙酸溶液中。該 混合物放置在油槽中,且回流加熱若干小時直至反應完全 。混合物冷卻至室溫,且接著倒入冰/水中獲得‘米色固體之 所需化合物。該固體藉由過濾分離,且在氮氣氛内乾燥。 lH NMR (CDC13): δ 10.23 (1H? s); 8.19 (1Η? d); 7.02 (1Η, dd); 6.96 (1H? d); 3.90 (3H,s)。 步驟B : 88762 -27- 1250873 原甲酸二乙酯(40 ml)添加至由步驟A所得的中間物中,且 於130°C加熱若干小時。所得混合物濃縮乾燥,獲得褐色固 體的標題化合物。 ^ NMR (DMSO): δ 10.08 (1¾ s); 7.98 (1H5 d); 7.25 (1H? d); 7.02 (1¾ dd); 6·81 (lH,s); 3.82 (3H,s);3.52(4H,q); l.ll (6H,t)。 製備實例5 在0 C下,環戊基溴化鎂(6.32 mL,12.65 mmol)添加至溶解於 THF (15 mL)之由製備實例2 (1·〇〇 g,a5 mmd)所得的中間物溶 液中。使反應溫至周圍溫度,且反應完成後,以飽和 淬冷。利用EtOAc萃取所得的反應混合物,且合併之有機層 以鹽水洗滌、經MgS〇4乾燥並在真空中濃縮。經由Si〇2凝膠 層析法純化該產物,獲得580 mg之所需產物。lHNMR(CDcy δ : 1·702 (2 H,m),1.803 (2 H,m),2.005 (4 H,m), 3.904 (3 H,s),4.070 (1 H, m),6.915 (1 H,s),7.010 (1 H,d),8·272 (1 H,d)。 製備實例6 1。
經由與製備實例5所描述之程序相似的程序製備所需化合 物’但以環己基溴化鎂替代環戊基溴化錢。1H NMR δ : 1.327 (1 H,m),1.479 (2 H,m),1.604 (2 H,m),1.781 (1 H,m),1.861 (2 88762 -28- 1250873 H? m)5 2.000 (2 H5 m)? 3.641 (l H? m)5 3.902 (3 H? s)? 6.923 (1 H, s)? 7.008 (1 H,d),8.259 (1 H,d)。 實例1
料办万;DMF (3 mL)中,接著添加氫化鈉(〇·88麵㈣。在室溫 下攪拌該反應15分鐘,接著添加溴乙酸第三丁酯(0.669 mmole)。在至溫下攪拌該反應3〇分鐘。分析顯 示起始材料完全消耗同時形成新的產物點。藉由添加水淬 冷該反應混合物。^行標準含水操作,接著藉由SGC純化 該粗製產物,後得白色固體之所需產物。 1H 證於 CDCL 中·· 8·22 (1H,d,卜 9 邮 6 97 (1H,dd,卜 2 及 9 Hz); 6.5 (1H, d J = 2 Hz); 5.4 (2¾ s); 3.94 ( 3H5 s); 2.8 (1¾ m); 1.38 (9H? s); 1.27 (6H,d,J = 6.5 Hz)。 LCMS = [M+H] = 317 〇 實例2
88762 •29- 1250873 l-(3-{[6-(2-羥基乙基)吡啶_3_基]羰基卜6_曱氧基_1H_吲唑小 基)-3,3-二甲基丁 酮 步驟A :
在氮氣氛下,三丁基烯丙基錫(3.4ml)與二氯雙(三苯膦) 鈀(〇.7g)添加至含2,5_二溴吡啶(24g)之甲苯溶液中。混合物 回流加熱若干小時並減壓濃縮。殘餘物再溶於“濕***,,中 並緩慢添加DBU (3 ml)獲得渾濁液體。該混合物經矽膠墊過 滤並濃縮。殘餘物溶於二氣甲烷/甲醇=1/1溶液中,並冷卻 至-78 C °於溶液中通入臭氧直至反應混合物變成藍色。反 應加熱至0 C,且分批添加氫硼化鈉(〇·5 g)。在〇它攪拌丨小時 後,混合物倒入水中,且以乙酸乙酯萃取。有機層以1N Na〇 、鹽水洗滌,乾燥(MgS〇4),且在減壓力下濃縮,獲得粗製 醇類。該醇類經矽膠(二氯甲烷/乙酸乙酯=丨/丨)純化獲得所 需醇類。在0°C下,咪唑(0.4 g)與TBS-C1 (0.8 g)添加至該醇於 二氣甲燒之溶液中。該混合物攪拌1小時。反應倒入〇1 N HClaq中並以二氣甲燒萃取。該有機層以鹽水洗務,以MgS04 乾燥且蒸發。殘餘物藉矽膠(100%二氯甲烷)純化獲得所需 化合物。 !H NMR (CDC13): δ 8.61 (1H? d); 7.73 (1H, dd); 7.14 (1H, d); 3.97 (2H, t); 2·96 (2H,t); 0.86 (9H,s); -0.02 (6H,s)。 步驟B : 88762 -30- 1250873
藉由與實例5、步驟5、6、7與8所描述之程序相似的程序 製備所需化合物。該化合物經矽膠(己烷/乙酸乙酯=1/3)純 化。 lU NMR (CHC13): δ 9.53 (1H5 d); 8.54 (1¾ dd); 8.35 (1H? d); 7.37 (1¾ d); 7.07 (1H,dd); 6.56 (1H,d); 5.45 (2H,s); 4.11 (2H,t); 3.90 (3H,s); 3.18 (2H, t); 1.38(9H,s)。 LC-MS (Μ+Η)=396·2。 藉由如實例1所描述之吲唑的烷化反應(對製備實例6之所 需化合物進行某些修改)製造以下所示之實例3_5。另外, 可藉由使用製備實例4之吲唑或由此處所描述之程序製備的 其他坐’採用類似程序製備實例1與4之類似物。 實例3
DMF(lOmL)與中間物 3 (597 m 以己纟元洗務之60%油分散液)中 (597 mg,2.44 mmol)添加至 195 mg NaH 液)中。反應在在室溫下被攪拌30 38762 -31 - 1250873 min後,添加1-氯頻哪酮(3.81 mL,2.92 mmol)。20分鐘後,該反 應物以吐〇淬冷且用EtOAc稀釋。水層以EtOAc萃取,且組合 之有機層以H2〇、鹽水洗滌,以MgS〇4乾燥,並在真空中濃 縮。該粗製材料經由矽膠層析法純化。 4 NMR (CDC13) δ : 1.361 (9 H,s),1_683 (2 H,m),1.788 (2 H,m),1·974 (4 H,m),3·872 (3 H,s),4.029 (1 H,m),5.372 (2 H,s),6.514 (1 H,s),6.986 (1 Η,d),8.267 (1 Η,d)。 實例4
使用製備實例8,以實例3所描述之程序製備該化合物。 該標題化合物經由Si02製備性板層析法純化。1HNMR (CDC13) δ : 1.285-1.575 (15 H,m),1.833 (2 H,d),1·994 (2 H,d),3.615 (1 H, m), 3.860 (3 Η,s),5.372 (2 Η,s),6.490 (1 Η,s),6.981 (1 Η,d),8.254 (1 Η,d)。 實例5
U162 -32- 1250873 二-弟二-丁基4-{[l-(3,3-二甲基-2-氧代丁基)-6 -甲氧基-1-H-㈤唑-3-基]羰基}羥基乙基芊基 步驟1
在室溫下,聯氨(0.624 mol,20 g)與在400 mL乙二醇中之100 g氟乙醯苯一起攪拌4小時,其後,該反應混合物加熱至150 °C歷時48小時。TLC分析顯示完全反應。將該反應混合物分 配於二氣甲燒與鹽水間。經硫酸鋼來乾燥有機相並蒸發成 為固體。自己烷/二氣甲烷再結晶獲得4唑。 iHNMR^CDOU): 7.5 (1H,d,7.5 Hz); 6.8 (2H,m); 3.8 (3H,s); 2·55 (3H,s)。 LCMS [Μ+Η] = 163。 步驟2
6-甲氧基-3-甲基小Η_啕唑 6-甲氧基-3-甲基小啕唑 甲酸-第三丁酯 78 丨峻溶於含1.1 equiv三-乙基胺的1L MeCN中,0.2 equiv之 DMAP冷卻至-5°C ;接著缓慢添加含Boc2〇(1.1 equiv)之200 mL MeCN。在室溫下攪拌該反應物2小時後,該反應混合物蒸 發成油狀,其分配於EtOAc與鹽水間、經硫酸鈉乾燥,蒸發 。殘餘物施加至一短SGC上,且以15% EtOAc之己:):完溶離。 蒸發獲得產物。 lH NMR (CDCL3): 7.6 (1H, bs); 7.42 (1H? d, J = 7.5 Hz); 6.85 (1H? dd); 3.8 Λ勹 -JJ -
88762 1250873 (3H,s);2.5(3H,s); L7(9H,s)。 LCMS [M+H] = 263。 步驟3
100 g 4卜坐溶於600 mL之CC14中,接著添加1 · 1 equiv之NBS與 0·2 equiv之Bz2〇。反應混合物以氬氣真空清洗,且在日光燈 光線下回流加熱5小時。反應混合物經一 SG墊過濾並濃縮 。殘餘油經一短SGC純化。獲得85 g純溴化物。混合之溶離 份產生二-溴化物衍生物。 單溴化物:W NMR (CDCL3)·· 7.7 (1H,d,7.5 Hz); 7.6 (1H,bs); 6.95 (1H, dd); 4·7 (2H,s); 3·9 (3H,s); 1·7 (9H,s)。 二溴化物:4 NMR (CDCL3): 8.05 (1H,d,J = 7.5 Hz); 7.6 (1H, bs); 7·0 (1H,dd); 6.85 (1H,s); 3·9 (3H,s); 1·7 (9H,s)。 步驟4
3-(溴甲基)-6•甲氧基小Η- 3-甲醯基各甲氧基小Η- 吲唑 啕唑-甲酸第三丁酯
5 g溴化物溶於10 mL之DMSO中,冷卻至0°C,接著添加2.5 equiv之TMANO(三甲基胺N-氧化物)。反應攪拌0.5小時,接 著進行標準操作且經SG墊過漉定量地獲得所需產物。LCMS 88762 -34 - 1250873 [M+H] = 277。 lU NMR (CDCL3): 10.2 (1H? s); 8.1 (1H? d, J - 7.5 Hz); 7.6 (1H, bs); 7.0 (lH,dd);3.9(3H,s); 1.7(9H,s)。 步驟5
Boc
玻璃儀器在高真空下以火焰乾燥。 在燒瓶中,異丙基MgCl (5 mL,2 Μ溶液)緩慢添加至純碘-芊基醇衍生物(3.6 g,10 mmol)中。在室溫下攪拌2小時後,添 加含4卜坐衍生物(1.1 g,4 mmol)之15 mL THF。反應混合物在室 溫下攪拌2小時。LC-MS顯示該反應完成。將該反應混合物 注入30 mL飽和NH4C1中,接著添加40 mL***。分離有機層 ,水層以***(40 mL)萃取。組合之有機層以飽和K2C〇3 (2x30 mL)、水(40 mL)及鹽水(20 mL)洗條。移除溶劑,殘餘物用於 下一步驟反應,且不進一步純化。LCMS [M+H] = 499。 步騾6與7
88762 -35 1250873 5 g石夕藻土與4·3 g之PCC (MW 215.56,約2 eq)添加至含4卜坐 (由步驟5所得的粗製產物)之20 mL二氯甲烷溶液中。反應混 合物在室溫攪拌2小時。LC-MS顯示反應完成,[CMS [M+H]= 497。反應混合物經過濾。移除溶劑,殘餘物溶解在1〇 mL MeOH中,且添加20 mL之2N HC1。在室溫下攪拌丨小時後, LCMS與TLC分析顯示完全反應。該反應混合物以Et〇Ac (2x30 mL)萃取。移除溶劑,殘餘物用於下一步驟反應,且 不進一步純化。LCMS [M+H] = 283。 步驟8
1.5 g 之 K2CO3 與 1.5 mL 溴頻哪酮(Bromopinacolone)(Mw 179.06, dl.326, 2.0 g,11 mmol)添加至含丨峻(由步驟7所得的342 mg粗製 產物,約10 mmol)之15 mL丙_中。混合物在一密封管中在80°C 攪拌2小時。濾除鹽後,移除溶劑,殘餘物以HPFC純化獲 得白色固體產物。 lH NMR (CDCL3) = 8.3 (3H, m); 7.5 (1H? d5 J = 7.5 Hz); 7.05 (1H, dd); 7.6 (1H,bs); 5·4 (2H,s); 4.8 (2H,bs); 3.9 (3H,s); 1·38 (9H,s)。 LCMS [M+H] = 38卜 功能分析 A. Maxi-K 通道 88762 -36- 1250873
Maxi-K通道抑制劑之識別可利用Aurora生物科學技術進行 ,且基於所表現之Maxi-K通道在TsA-201細胞中之通道之α與 β次單位兩者的過渡型轉染(transient transfection)後設定細胞休 止電位之能力。在無抑制劑的情況下,細胞展示内部為負 、接近Ek (-80 mV)的超極化之薄膜電位,該Ek係由Maxi-K通 道之活性所導致。Maxi-K通道之阻斷將導致細胞去極化。 薄膜電位之變化可由電壓感應熒光共振能量轉移(FRET)染 色對(dye pair)確定,該等染色對使用兩種組份、施體香豆素 (CC2DMPE)與接受體歐辛諾(〇xanol)(DiSBAC2(3))。該歐辛諾係 一種親油性陽離子,且根據薄膜電位在該薄膜上分佈。在 通常條件下,當該細胞内部相對於外部為負時,歐辛諾被 積聚在該薄膜之外葉,且香豆素之激活將導致FRET出現。 導致薄膜去極化之條件將導致該歐辛諾重新分佈於細胞内 部,因此,導致FRET降低。因此,在薄膜去極化後,比率 變化(施體/受體)增加。
可藉由將FUGENE6TM充當轉染劑,按先前方式(Hanner等人 之(1998) J· Biol· Chem. 273,16289-16296)執行 TsA-201細胞中之 Maxi-K通道的過渡型轉染。在轉染後24小時,細胞收集於 不含Ca2'Mg2+的Dulbecco磷酸鹽-緩衝鹽水(D-PBS)中,離心分 離,以60,000細胞/孔之密度舖在96孔聚-d-離胺酸所塗覆之 平板上,並隔夜培養。該等細胞接著以D-PBS洗滌1次,且 以 D-PBS 中之 100 μΐ之 4 μΜ CC2DMPE-0.02% pluronic-127裝載(load) 。在室溫下,細胞在暗處培養30分鐘。然後,細胞以D-PBS 洗滌2次,且以含下列各物(mM)之100 μΐ之6 μΜ DiSBAC2(3)裝 88762 -37- 1250873 載:140 NaQ、0·1 κα、2 CaCl2、1 MgCl2、20 Hepes-Na〇H、pH 7.4 、10葡萄糖。試驗化合物稀釋於此溶液中,且同時添加。 在室溫下,細胞在暗處培養3 0分鐘。
平板被裝入電壓/離子探針讀數(VIPR)儀器中,且記錄 CC2DMPE與DiSBAC2(3)兩者之螢光發射記錄10秒。此處,添 加100 μΐ之含下列之高鉀溶液(mM): 140 κα、2 CaCl2、1 MgCl2、 2〇 Hepes-KOH、pH 7·4、10葡萄糖,且兩種染料之榮光發射又 記錄10秒。在添加高鉀溶液前,該比率CC2DMPE/DiSBAC2(3) 等於1。在不存在任何抑制劑的情況下,在添加高鉀溶液之 後,該比率在1.65-2.0之間變化。當該等Maxi-K通道被已知的 標準或試驗化合物中的任一種完全抑制時,該比率仍為1。 因此,可藉由監控螢光比率之濃度相依變化,來滴定Maxi-K 通道抑制劑的活性。
吾人發現,本發明之化合物在IC5G於約1 nM至約20 μΜ範 圍内之螢光比率有濃度相依抑制作用,更佳在約10 ηΜ至約 500 nM範圍内。 B. 化合物對高傳導鈣活化之钾通道的影響的電生理分析 人類無色纖毛上皮細胞 利用電生理分析方法來確定人類無色纖毛上皮細胞中之 高傳導4弓活化之钟(Maxi-K)通道的活性。通過Maxi-K通道的 電流記錄在貼片挾制(patch clamp)技術的内外組態中,在該 組態中,該吸管溶液朝向通道外側,該槽液朝向細胞内邊 。被切除之貼片包含1至約50個Maxi-K通道。藉由Maxi-K通 道之較大單通道電導(250-300 pS)、並藉由通道對於細胞電 88762 -38 - 1250873 位之門控的敏感性及細胞内鈣濃度,可識別Maxi_K通道。 利用標準電生理技術記錄薄膜電流。玻璃吸管(Gamer 7〇52) 以Kopf拉出券(型號750)拉於兩個階段中,且當裝滿鹽水時 電極電阻係1 -3兆歐姆。薄膜電流以EpC9 (heka儀器)或 Axopatch ID (Axon儀器)放大器記錄,且以ITC>16介面(Instmtech 公司)完成數位轉換。吸官裝滿下列成分(mM) : 15〇 KC1、10
Hepes、1 MgCl2、0·01 CaCl2、3·65 KOH、PH 7.20。該槽(細胞内)溶
液相同’除了在某些狀況下’移除鈣、添加1 mM之EGTA、 用20 mM KF代替20 mM KC1以消除鈣來試驗通道門控之鈣敏 感性。利用槽灌注將藥物施加至該通道之細胞内邊。 人類無色纖毛上皮細胞以所描述的方式(Martin-Vasallo、P·,
Ghosh,S.、及 Coca-Prados,Μ.,1989, J. Cell. Physiol. ML 243-252)在組
織培養中生長,且在使用前被鍍至玻璃蓋玻片上。於該吸 管與細胞表面之間形成高電阻封組阻(> 1 Gohm),且切除内 外貼片。在該貼片中之Maxi-K通道由於其門控屬性而被識 別;增加通道開啟機率以響應細胞去極化,並提高細胞内 之鈣。在用來藥理分析之貼片中,「移除細胞内之鈣」可消 除電壓門控電流。在導致通道開啟的去極化電壓階躍或斜 線上升後,量測Maxi-K電流。 以合適的濃度(0.001至100 μΜ)將本發明之化合‘物施加至該 通道之細胞内邊。該等化合物減少通道開啟機率,且一旦 化合物被自該實驗腔室清除,該效應就被逆轉。在本發明 之化合物的該等條件下,用於阻斷Maxi-K通道之IC5G在約0.5 nM至約10 μΜ範圍内。 88762 -39-
Claims (1)
- 130678號專利申請案 t請專利範圍替換本(94年12月) 拾、申請專利範圍 月曰修(更)正本 H __ 1· 一種具有式I結構之化合物,、、〇 R3 式I 或醫藥上可接受之鹽、對映體、非對映體或其混合物: 隹 其中, Ry代表Η或Cm烷基; R2 代表氫、Q.U)烷基、OH、C2·6 埽基、_(CH2)n〇(CH2)m〇R、或 _ (CHJnCw燒氧基,該燒基視情況經個選自Ra之基所取 代; ' R3代表氫、Q-K)烷基、-(CH2)nC00R、硝基、氰基或_素, · 該烷基視情況經1-3個選自Ra之基所取代; R4與R5獨立地代表氫、C】-6烷氧基、〇H、Ck烷基、COOR、 φ SOqCw烷基、COCw烷基、S03H、-〇(CH2)nN(R)2、-〇(CH2)nC02R …0P0(0H)2、CF3、OCFrN(R)2、硝基、氰基、C1>>6 燒胺基, 或鹵素;且 R6 代表氫、Ci-io 坑基、-(CH2)nC6-i〇 芳基、雜環基 、-(CH2)nC3_8環烷基,該烷基、雜環基或芳基視情況經L3 個選自Ra之基所取代,其中該(等)Ra可键結於任何碳原子 或選自N與S之雜原子上; 88762 1250873 Ra代表 F、α、Br、I、CF3、N(R)2、N02、CN、办、.COR8、 -CONHR8、-CON(R8)2、-0(CH2)nC00R、-NH(CH2)nOR、_CO〇R、 -OCF3、CF2CH2OR、-NHCOR、-S02R、-S02NR2、-SR、(CrC6 烷 基)0-、-(CH2)nO(CH2)mOR、-(CHACw 烷氧基、(芳基)〇-、 -(CH2)nOH、(CrC6 烷基)S(0)m-、H2N-C(NH)-、(CrC6 烷基)C(O)-、 (Crc6 烷基)0C(0)NH-、-(CrC6烷基)NRw(CH2)nC3_10雜環基-Rw、 -(C1-C6 燒基)〇(CH2)nC3_i〇 雜環基-Rw、-(C〗-C6 坑基)S(CH2)nC3]〇 雜 環基 _RW、-(Q-C6烷基)-C3_H)雜環基-Rw、 、-(C2-6 締基)NRw(CH2)nC3.i〇 雜 ί募基-Rw、_(C2-6 歸基)〇(CH2)nC3.i〇 雜琢基-Rw、KC2-6 晞基)S(CH2)nC3.n^^·每基-Rw、-(C2-6 晞基)-C3.10 雜環基-Rw、-(C2-6 晞基 、-(CH2)nS〇2R、-(CH2)nS03H 、-(CH2)nPO(OR)2、C3-1()環烷基、C㈣芳基、C3.1()雜環基、C2.6 烯基及CrC1G烷基,該烷基、晞基、烷氧基、雜環基及芳 基視情況經1-3個選自CrC6烷基、鹵素、(CH2)nOH、CN、 N02、CON(R)2及COOR之基所取代; Z1與Z2獨立地代表NRW、Ο、CH2或S ; R代表氫或(^6烷基; Rw代表 Η、Ck燒基、-C(0)Ci_6:fe 基、燒基、- S〇2N(R)2 、-SC^Cm烷基、-S02C6-1G 芳基、N02、CN 或-C(0)N(R)2 ; R8代表-(CH2)nC3_8環烷基、-(CH2)nC3_1G雜環基、匕6烷氧基或 -(CH2)nC5-lG雜芳基、-(CH2)nC6_1()芳基’該雜環基、芳基或雜 芳基視情況經1-3個選自Ra之基所取代; m係 0-3 ; η係0-3 ;且 1250873 q係 0-2 〇 2. 如申請專利範圍第1項之化合物,其中R6係Q-u)烷基或 -(CH2)nC3_8環烷基,且心係(^_6烷基,該烷基視情況經1-3個 選自Ra之基所取代。 3. 如申請專利範圍第1項之化合物,其中R2係Cwo烷基,且 R3係Qw烷基,該烷基視情況經1-3個選自Ra之基所取代 〇 4. 一種化合物,其為·· 表1R1 R2 K -K K •K 88762 -3- !25〇873或醫藥上可接受之鹽、對映體、非對映體或其混合物。 如申叫專利範圍第1項之化合物,其用於治療高眼壓或 光眼。 如申請專利項之化合物,其用於治療斑狀水腫、 斑狀退化、增加視網膜與視神經頭部血液速度、增加視 網膜與視神經氧張力、及/或神經保護效應。 如申請專利範圍第1項之化合物,其用於防止包含鉀通道 之哺乳動物細胞的複極化或超極化,或對需要之病人治 療阿茲海默氏疾病、抑鬱症、認知障礙,及/或心律不整 失調症。 88762 -4 - 1250873 8·種用於治療高眼壓或青光眼之醫藥組合物,直包本如 申請專利範圍第i項之式丨化合物與醫藥上可接受之;劑 9·如申請專利範圍第8項之醫藥組合物,其中式地合物係 以相調配物施用’該種局部調配物以溶液或懸浮液態 施:,且视情況包含黃原膠或結冷膠。 10·如申請專利範圍第8項之醫藥組合物,其中視情況添加屬 、由X下各物組成之群之活性成分··卜腎上腺素阻斷劑 、$副交感劑、擬交感劑、碳酸肝酶抑制劑、Ep4促效劑 則列腺素或其衍生物、降壓脂質、神經保護劑,及/或 5-HT2受體促效劑。 11·如申請專利範圍第1〇項之醫藥組合物,其中該卜腎上腺 素阻斷劑係嘧嗎心安(timolol)、倍他索洛爾(betax〇1〇1)、左 万疋倍他索洛爾、山羊豆苷(carte〇1〇1)、或左旋布諾洛爾,·該 挺一文感劑係毛果芸香驗;該擬交感劑係腎上腺素、艾 比定(lopidme)、溴莫尼定(brim〇nidine)、可樂定(咖咖此)或 對-胺基可樂定;該碳酸酐酶抑制劑係漆素得(d〇rz〇lamide) 、醋唑磺胺(acetaz〇iamide)、間唑磺胺(metaz〇lamide)或布峋 峻續胺(brinzolamide);該***素係樂通舒特(latan〇pr〇st)、 月服平(travaprost)、烏諾前列J同(unoprostone)、利視即樂 (rescula)或S1033 ;該降壓脂質係露明甘(lumigan);該神經 保護劑係依利羅地(eliprocm)、R-依利羅地或美金剛胺 (memantine);且該5-HT2受體促效劑係1-(2-胺基丙基)-3-甲 基-1H-咪唑-6·醇富馬酸或2-(3-氯-6-甲氧基唑小基)小 88762 -5- 1250873 甲基-乙胺。88762 -6 -
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EA005293B1 (ru) | 1999-12-22 | 2004-12-30 | Пфайзер Продактс Инк. | Производные пирролидин-2-она и их применение при лечении остеопороза |
DE60135972D1 (de) | 2000-01-18 | 2008-11-13 | Merck & Co Inc | Orhthalmologische zusammenstellungen zur behandlung von ocularer hypertension |
CN1450995A (zh) | 2000-03-17 | 2003-10-22 | 爱尔康公司 | 用于治疗青光眼的5-羟基吲唑衍生物 |
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EP1186287A1 (en) | 2000-03-31 | 2002-03-13 | Toray Industries, Inc. | Hair growth or hair formation controlling agents |
WO2002024647A1 (fr) | 2000-09-21 | 2002-03-28 | Ono Pharmaceutical Co., Ltd. | Agonistes du recepteur de l'ep4 comprenant comme principe actif des derives de la 8-azaprostaglandine |
CZ20031257A3 (cs) | 2000-11-27 | 2004-04-14 | Pfizer Products Inc. | Selektivní agonisty receptoru EP4 při léčení osteoporosy |
FR2827861B1 (fr) | 2001-07-27 | 2004-04-02 | Aventis Pharma Sa | Derives des indazoles ou des indoles, leur utilisation en medecine humaine et plus particulierement en cancerologie |
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