TWI490220B - 包含ｐｄｅ５抑制劑之用於減少皮膚皺紋之組成物 - Google Patents

包含ｐｄｅ５抑制劑之用於減少皮膚皺紋之組成物 Download PDF

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TWI490220B
TWI490220B TW100126205A TW100126205A TWI490220B TW I490220 B TWI490220 B TW I490220B TW 100126205 A TW100126205 A TW 100126205A TW 100126205 A TW100126205 A TW 100126205A TW I490220 B TWI490220 B TW I490220B
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methyl
propyl
phenyl
ethoxy
dihydro
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TW100126205A
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TW201240994A (en
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Soo Min Lee
Keun-Ho Ryu
Jae-Sun Kim
Bong-Yong Lee
Jung-Hoon Oh
Ye-Ji Jeon
Soo-Hun Lee
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Sk Chemicals Co Ltd
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包含PDE5抑制劑之用於減少皮膚皺紋之組成物
本發明係關於一種有效減少皮膚皺紋之組成物，及一種使用該組成物減少皮膚皺紋的方法。
由於皮膚經常受到各式各樣外部的刺激，皮膚組織相較於人體其他的組織更容易產生皺紋。特別是，臉部皮膚因直接暴露於許多環境因子中，如日光、乾燥空氣及污染物等，相較其他部位的皮膚組織更易於形成皺紋。
最主要的變化是由發生於皮膚基質中皮膚組織的老化所引起，老化過程將降低真皮層中皮膚纖維母細胞產生纖維及基質成分的能力。一般而言，基質成分的減少將導致皮膚厚度減少及皮膚彈性的衰退，進而形成皺紋。即皮膚老化將會造成許多嚴重的問題，如失去彈性、血液循環失調、及皮膚屏障功能缺乏等。
由於紫外光的暴露，在皮膚中或皮膚上將產生自由基、活性氧化物(ROS)、衍生自活性羰基化合物的自由基物種等等。而上述的活性物種被視為造成皮膚細胞受損的主要原因。再者，這些活性物種會引起DNA的受損、攻擊細胞膜結構，並產生老人斑。此外，由於這些活性物種的攻擊，將造成膠原蛋白及纖維的功能喪失並加速皺紋形成，其中膠原蛋白之功能為使皮膚滋潤、柔軟、光滑並富有彈性。藉由施予抗氧化劑以移除自由基可有助於減少皮膚皺紋的形成，然而，並非所有的抗氧化劑皆能達成有效對抗皮膚皺紋生成的效果。以直接觀察的方式可較佳地評估抗氧化劑減少皮膚皺紋的效果。目前許多藥物及化妝品正被積極地研究其減少因外在環境因子及內在機制造成的皮膚皺紋之可能性。
本發明之一目的係在提供一種有效減少皮膚皺紋之組成物，藉以解決先前技術所既有的問題。本發明之另一目的係在提供一種有效減少皮膚皺紋之方法。
為了達成上述目的，本發明提供一種用於減少皮膚皺紋之組成物，其包括磷酸二酯酶第五型(PDE5)抑制劑、或其藥學上可接受之鹽類、溶劑化物、或水合物，用以作為活性成分。
即本發明提供一種磷酸二酯酶第五型(PDE5)抑制劑、或其藥學上可接受之鹽類、溶劑化物、或水合物用於減少皮膚皺紋之新醫學應用。本發明亦提供一種磷酸二酯酶第五型(PDE5)抑制劑或其藥學上可接受之鹽類、溶劑化物、或水合物之用途，係用於製造改善或減少皮膚皺紋之組成物(例如，藥劑、保健食品、或化妝品)。
磷酸二酯酶泛指一類可於活體內切斷磷酸二酯鍵的酵素。PDE家族酶可分類為11個家族，即為PDE1至PDE11，其分類根據各自的胺基酸序列、受質特異性、活體反應中的調節特性、藥理性質及組織分布所定義。目前，已知PDE5抑制劑對於陽萎、女性性行為失調、心絞痛、高血壓、心臟衰竭、及動脈硬化具有令人滿意的效果，尤其PDE5抑制劑已廣泛應用於陽萎的治療。然而，特別是那些具有特定結構之PDE5抑制劑，其用於減少皺紋形成的功效，尚未被揭露。因此，本發明提供一種PDE5抑制劑之新穎用途，其用於作為減少皮膚皺紋之藥物或化妝品。
適用於本發明組成物之PDE5抑制劑，其包括：5-[2-烯丙氧基-5-(4-甲基哌嗪基磺醯基)苯基]-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(-[2-allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-[2-乙氧基-5-(哌嗪基磺醯基)苯基]-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-[2-ethoxy-5-(piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-[2-乙氧基-5-(4-甲基哌嗪基磺醯基)苯基]-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-[2-ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-{2-乙氧基-5-[4-(2-丙基)哌嗪基磺醯基]苯基}-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-{2-ethoxy-5-[4-(2-propyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-{2-乙氧基-5-[4-(2-羥乙基)哌嗪基磺醯基]苯基}-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；1-甲基-5-[5-(哌嗪基磺醯基)-2-n-丙氧基苯基]-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(1-methyl-5-[5-(piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-{5-[4-(2-羥乙基)哌嗪基磺醯基]-2-n-丙氧基苯基}-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；2-[2-乙氧基-5-(4-甲基-哌嗪-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f]-[1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥乙基哌嗪-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f]-[1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxyethylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥基哌啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f]-[1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxypiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥基甲基哌啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxymethylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(3-羥基吡咯啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(3-hydroxypyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；4-乙氧基-N-乙基-N-(2-羥乙基)-3-(5,7-二甲基-4-氧代-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N,N-二乙基-4-乙氧基-3-(5,7-二甲基-4-氧代-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N,N-diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；2-[2-乙氧基-5-(4-(2-嘧啶基)-哌嗪-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑-[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-(2-pyrimidinyl)-piperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(嗎福林-4-磺醯基)-苯基]-5,7-二甲基-3H-咪唑-[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(morpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(1,4-二氧-6-氮雜螺基[4.4]壬烷-6-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(1,4-dioxa-6-azaspiro[4.4]nonane-6-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N,N-雙-(2-甲氧基乙基)-4-乙氧基-3-(5,7-二甲基-4-氧代-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(N,N-bis-(2-methoxyethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；N-(3-異噁唑基)-4-乙氧基-3-(5,7-二甲基-4-氧代-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(N-(3-isoxazolyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；2-[2-乙氧基-5-(2-t-丁氧基羰基胺基甲基嗎福林-4-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(2-t-butoxycarbonylaminomethylmorpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-苯基哌嗪-1-磺醯基)苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-phenylpiperazine-1-sulphonyl)phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(3-羥基-3-甲氧基甲基吡咯啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(3-hydroxy-3-methoxymethylpyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-苯基哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-phenylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-乙基哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-ethylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-甲基-1-胺基-哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-methyl-1-amino-piperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥乙基-1-胺基-哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N,N-雙羥乙基胺基乙基-4-乙氧基-3-(5-甲基(4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N,N-bishydroxyethylaminoethyl-4-ethoxy-3-(5-methyl(4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；2-[2-乙氧基-5-(4-二甲氧基磷氧基甲基-哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-dimethoxyphsphorylmethyl-piperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-二乙氧基磷氧基甲基-哌啶-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-diethoxyphsphorylmethyl-piperidine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥基-哌啶-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxy-piperidine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-羥基-乙基)-哌嗪-1-磺醯基]苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulphonyl]phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(3-羥基-丙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(3-hydroxy-propyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N-烯丙基-4-乙氧基-N-(2-羥基-乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N-allyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N-乙基-4-乙氧基-N-(2-羥基-乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N-ethyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N,N-二乙基-4-乙氧基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N,N-diethyl-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N-(2-甲氧基乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-(2-methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)；N-(2-N,N-二甲基乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-(2-N,N-dimethylethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)；N-[3-(1-嗎啉基)丙基]-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-[3-(1-morpholino)propyl]-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)；N-{3-[1-(4-甲基)哌嗪基]-丙基}-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-{3-[1-(4-methyl)piperazino]-propyl}-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)；2-{2-乙氧基-5-[4-(2-甲氧基-乙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-methoxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-N,N-二甲基-乙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-N,N-dimethyl-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(3-N,N-二甲基-丙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(3-N,N-dimethyl-propyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-二氧五環基-哌啶-1-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-dioxolano-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-(5-甲基-4-氟烷羰基)-哌嗪-1-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-(5-methyl-4-fluroxanecarbonyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-乙醯基-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-acetyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-甲醯基-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-formyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(3-丁基斯德酮亞胺)-1-磺醯基]-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(3-butylsydnoneimine)-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；5-甲基-2-[5-(4-甲基-哌嗪-1-磺醯基)-2-丙氧基-苯基]-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(5-methyl-2-[5-(4-methyl-piperazine-1-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[5-(4-羥基哌啶-1-磺醯基)-2-丙氧基-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[5-(4-羥基甲基哌啶-1-磺醯基)-2-丙氧基-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxymethylpiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{5-[4-(2-羥乙基)-哌嗪-1-磺醯基]-2-丙氧基-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-2-propoxy-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N-(1,1-二氧代四氫基-1λ6-噻吩-3-基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(1,1-dioxotetrahydro-1λ6-thiophen-3-yl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-(2-二甲基胺基乙基)-N-甲基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(2-dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-N-(3-嗎福林-4-基-丙基)-4-丙氧基-苯磺醯胺(3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-propoxy-benzenesulfonamide)；N,N-雙-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N,N-bis-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-(3-羥基苄基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(3-hydroxybenzyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-乙基-N-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-ethyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benz enesulfonamide)；N-(3-乙氧基丙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(3-ethoxypropyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydr o-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfo namide)；2-[5(4-羥基哌啶-1-磺醯基)-2-丙氧基-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5(4-hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propy1-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-N-啶-4-基-苯磺醯胺(3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-N-pyridin-4-yl-benzenesu1fonamide)；N,N-二乙基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N,N-diethy1-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；1-[3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯基]-哌啶-4-羧酸(1-[3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonyl]-piperidine-4-carboxylic acid)；5-甲基-2-[5-(嗎福林-4-磺醯基)-2-丙氧基-苯基]-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(5-methyl-2-[5-(morpholine-4-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N-(2-羥乙基)-N-甲基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(2-hydroxyethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-N-丙基-苯磺醯胺(N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-N-propyl-benzenesulfonamide)；N-[2-(3,4-二甲氧基-苯基)乙基]-N-甲基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-烯丙基-N-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-allyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-烯丙基-N-環戊基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-allyl-N-cyclopentyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-烯丙基-N-乙基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基苯磺醯胺(N-allyl-N-ethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxybenzenesulfonamide)；2-[2-乙氧基-4-甲氧基-5-(4-甲基哌嗪-1-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-4-methoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-羥乙基)-哌嗪-1-磺醯基]-4-甲氧基-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-4-methoxy-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；4-乙氧基-N-乙基-N-(2-羥乙基)-2-甲氧基-5-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；4-乙氧基-N-(4-乙氧基苯基)-2-甲氧基-5-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(4-ethoxy-N-(4-ethoxyphenyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；4-乙氧基-N-乙基-N-(2-羥基-乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(4-ethoxy-N-ethyl-N-(2-hydroxy-ethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N-(2-甲氧基乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基苯磺醯胺(N-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulfonamide)；N,N-雙-(2-甲氧基乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基苯磺醯胺(N,N-bis-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulfonamide)；2-[5-(4-羥基哌啶-1-磺醯基)-2-乙氧基苯基]-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxypiperidine-1-sulphonyl)-2-ethoxyphenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[5-(4-羥基甲基哌啶-1-磺醯基)-2-乙基-苯基]-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxymethylpiperidine-1-sulphonyl)-2-ethyl-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-羥乙基)-哌嗪-1-磺醯基]-苯基}-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-phenyl}-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-甲基哌嗪-1-磺醯基)-苯基]-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；3-(5-乙基-4-氧代-7-丙基-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)-N-(3-嗎福林-4-基-丙基)-4-乙氧基苯磺醯胺(3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-ethoxybenzenesulfonamide)；N-(2-羥乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-N-丙基-苯磺醯胺(N-(2-hydroxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-N-propyl-benzenesulfonamide)；順-2,3,6,7,12,12a-六氫-2-(4-吡啶基甲基)-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；順-2,3,6,7,12,12a-六氫-6-(2,3-二氫苯并[b]呋喃-5-基)-2-甲基-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；順-2,3,6,7,12,12a-六氫-6-(5-溴-2-噻吩基)-2-甲基-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；順-2,3,6,7,12,12a-六氫-2-丁基-6-(4-甲基苯基)-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-異丙基-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-環戊基-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-環丙基甲基-6-(4-甲氧基苯基)-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-6-(3-氯-4-甲氧基苯基)-2-甲基-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-甲基-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-1,4-dione)；(5aR,12R,14aS)-1,2,3,5,6,11,12,14a-八氫-12-(3,4-亞甲基二氧基苯基)-吡咯並[1”,2”:4’,5’]吡嗪並[2’,1’:6,1]吡啶并[3,4-b]吲哚-5-1,4-二酮((5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[1”,2”:4’,5’]pyrazino[2’,1’:6,1]pyrido[3,4-b]indole-5-1,4-dione)；5-[2-乙氧基-5-(異丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(isopropylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(苄基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(benzylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(異丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(isopropylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(異丙基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(isopropylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(propylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(丙基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(propylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(丁基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(butylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(2-丁基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(2-butylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(環丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(cyclopropylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(環丙基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(cyclopropylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(環己基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(cyclohexylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(苄基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(benzylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(苄基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(benzylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(苄基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(benzylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-氟苯基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-fluorophenylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-t-丁基苯基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-t-butylphenylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-t-丁基苯基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-t-butylphenylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-異丙基苯基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-isopropylphenylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-氟苯基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-fluorophenylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(4-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(3-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(4-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(4-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(3-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(3-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(2-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(2-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(2-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(2-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-3-吡咯啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-3-pyrrolidinylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-甲基-3-吡咯啶基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-3-pyrrolidinylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-2-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-甲基-2-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-2-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-3-pyrrolidinylmethylamidosulphonyl)pheny1]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-甲基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-3-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-乙基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-ethyl-3-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-乙基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-ethyl-3-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-2-吡咯啶基乙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-甲基-2-吡咯啶基乙基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-2-pyrrolidinylethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(6,7-二氫-5H-吡咯並[3,4-b]啶-6-基)-4-(3-氰基-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶(2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-甲氧基環己基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-methoxycyclohexyl)carbamoyl]pyrimidine)；2-(6,7-二氫-5H-吡咯並[3,4-b]啶-6-基)-4-(3-氰基-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine)；2-(6,7-二氫-5H-吡咯並[3,4-b]啶-6-基)-4-(3-氰基-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶(2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-morphoiinoethyl)carbamoyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine)；2-[(2S)-2-羥基甲基-1-吡咯啶基]-4-(3-氯-4-甲氧基苄基胺基)-5-[N-[[(2R)-4-甲基-2-嗎福林基]甲基]胺甲醯基]-嘧啶(2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2R)-4-methyl-2-morpholinyl]methyl]carbamoyl]-pyrimidine)；2-[(2S)-2-羥基甲基-1-吡咯啶基]-4-(3-氯-4-甲氧基苄基胺基)-5-[N-[[(2S)-4-甲基-2-嗎福林基]甲基]胺甲醯基]-嘧啶(2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2S)-4-methyl-2-morpholinyl]methyl]carbamoyl]-pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(4-嘧啶基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(4-甲基-3-氧代-1-哌嗪基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(4-methyl-3-oxo-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine)；2-(4-甲醯基-1-哌嗪基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans-4-hydroxycyclohexyl)carbamoyl]pyrimidine)；2-[順-2,5-雙(羥基甲基)-1-吡咯啶基]-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶(2-[cis -2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫-1,7-萘啶-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-乙醯基嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-acetylpyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(4-噠嗪基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyridazinylmethyl)carbamoyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(5-嘧啶基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-吡啶基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine)；(S)-2-[N-(2-嘧啶基甲基)胺甲醯基]-3-(3-氯-4-甲氧基苄基胺基)-5-[2-羥基甲基-1-吡咯啶基]吡嗪((S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[(2-嗎啉基乙基)羰基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrroiidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-[(4-甲基-2-嗎福林基)甲基]胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-[(4-methyl-2-morpholinyl)methyl]carbamoyl]pyrimidine)；(S)-2-[N-(2-嗎啉基乙基)胺甲醯基]-3-(3-氯-4-甲氧基苄基胺基)-5-(2-羥基甲基-1-吡咯啶基)吡嗪((S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine)；2-[N-(2-嘧啶基甲基)胺甲醯基]-3-(3-氯-4-甲氧基苄基胺基)-5-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)吡嗪(2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrazine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[(2-甲氧基乙基)羰基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(1,3,5-三甲基-4-吡唑基)胺甲醯基]嘧啶((S)-2-(2-hydroxy methyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine),及其一藥學上可接受之鹽類、溶劑化物、或水合物。
絲丹奈非(sildenafil)、發丹奈非(vardenafil)、塔大拉非(tadalafil)、烏地那非(udenafil)、阿伐那非(avanafil)，或其藥學上可接受之鹽類、溶劑化物或水合物亦可作為本發明組成物之活性成分，係為最佳之PDE5抑制劑。
上述PDE5抑制劑之製備方法已揭示於，例如：美國專利第5,250,534、6,362,178、5,859,006、6,583,147、及6,656,935號，以上專利所揭示內容均併入本發明以供參考。
本發明之組成物係使用PDE5抑制劑，其作用於皮膚中的PDE5，使肌肉放鬆，並抑制放鬆後的肌肉收縮，進而有效減少皺紋形成，PDE5抑制劑之反應機制類似於BOTOX的反應機制，而BOTOX目前已用於減少皮膚皺紋。然而，本發明並非侷限於此可能機制。
部分PDE5抑制劑(以下簡稱為「化合物」)以藥學上可接受之鹽類形式施用。所謂「藥學上可接受之鹽類」係指利用無毒性或較低毒性的酸或鹼所配製之鹽類。當化合物係為相對酸性時，可藉由將中性形式之化合物於惰性溶劑中與足夠量的鹼接觸，以製得鹼加成鹽類；藥學上可接受之鹼加成鹽類，包括但不侷限於，例如：鋰、鈉、鉀、鈣、銨、鎂、及有機胺鹽類。當化合物係為相對酸性時，可藉由將中性形式之化合物於惰性溶劑中足夠量的酸接觸，以製得酸加成鹽類；藥學上可接受之酸加成鹽類，包括但不侷限於，例如：丙酸(propionic acid)、異丁酸(isobutyric acid)、草酸(oxalic acid)、蘋果酸(malic acid)、丙二酸(malonic acid)、苯甲酸(benzoic acid)、琥珀酸(succinic acid)、栓酸(suberic acid)、丁烯酸(fumaric acid)、杏仁酸(mandelic acid)、酞酸(phthalic acid)、苯磺酸(benzenesulfonic acid)、對-甲苯磺酸(p-tolylsulfonic acid)、檸檬酸(citric acid)、酒石酸(tartaric acid)、甲磺酸(methanesulfonic acid)、氫氯酸(hydrochloric acid)、氫溴酸(hydrobromic acid)、硝酸(nitric acid)、碳酸(carbonic acid)、單氫碳酸(monohydrogencarbonic acid)、磷酸(phosphoric acid)、單氫磷酸(monohydrogenphosphoric acid)、二氫磷酸(dihydrogenphosphoric acid)、硫酸(sulfuric acid)、單氫硫酸(monohydrogensulfuric acid)、氫碘酸(hydroiodic acid)、及亞磷酸(phosphorous acid)。其他例子包括但不侷限於，例如：胺基酸之鹽類(如：精胺酸(arginate))，及有機酸之類似物(analogs of organic acids)(如：葡萄糖醛酸(glucuronic acid)、及半乳糖醛酸(galacturonic acid))。
根據不同化合物的特性，化合物可以非溶劑化形式存在，也可以存在於溶劑化形式存在，其包括水合形式。化合物可以晶相或非晶相形式存在，此類所有物理形式皆涵蓋於本發明之範疇內。
由於化合物具有一或多個不對稱碳原子作為掌性中心，或一個或多個雙鍵，故此化合物可以消旋混合物(racemates)、鏡像異構物(enantiomers)、非對映立體異構物(diastereomers)、幾何異構物(geometric isomers)等之形式存在。此類結構皆涵蓋於本發明之範疇內。部分化合物可以互變異構(tautomeric)形式存在。
本發明之組成物可配製成藥物、保健食品及化妝品。此類藥物、保健食品及化妝品可包括一或多個藥學上可接受之賦形劑或添加劑。本發明之組成物可以單一或合併至少一個藥學上可接受之載體或賦形劑，製備成單一或多劑量形式。
此藥物、保健食品及化妝品可為固體、液體、或半固態製劑。固體製劑之非限定實例，包括如：粉末、粒狀體、錠劑、膠囊、及栓塞劑，固體製劑可包括適當的賦形劑、香料、粘合劑、防腐劑、分解劑、潤滑劑和充填劑等。液體製劑之非限定實例包括：溶液(如：水溶液及丙二醇溶液)、懸浮液、及乳化液，液體製劑可包括適當的著色劑、香料、安定劑及增稠劑。半固體製劑之非限定實例包括：乳霜(creams)、化妝水(lotions)、乳化液(emulsions)及塗敷劑(liniments)，半固體製劑可以包括適當的著色劑、香料、安定劑及增稠劑及介面活性劑。利用本發明之組成物達成減少皮膚皺紋之目的，較佳地為直接地塗敷本發明之組成物於局部皮膚，由於局部的塗敷可以降低身體其他部位產生副作用的可能性。因此，本發明之組成物更佳地配製為半固體製劑。
舉例而言，藉由將化合物與適當的藥學上可接受之賦形劑(如：乳糖、澱粉和微晶型纖維素)簡單混合，可配製得到粉末。藉由將化合物、適當的藥學上可接受之賦形劑、與適當的藥學上可接受之粘合劑(如：聚乙烯氫吡咯酮(polyvinyl pyrrolidone)或羥丙基纖維素)加以混合，接著，利用適當的溶劑(如：水、乙醇、或異丙醇)(濕式造粒)或利用壓縮力(亁式造粒)，可將混合物進行造粒製程，以配製得到粒狀體。藉由將粒狀體與適當的藥學上可接受之潤滑劑(如：硬脂酸美)加以混合，再利用適當的製錠機壓製其混合物，可製得錠劑。
如前所述，較佳地為將本發明之組成物塗敷於局部皮膚，故本發明之組成物可較佳配製成一般皮膚化妝品配方。特別是本發明之組成物可製備成化妝水、精華液、化妝油、乳霜、粉末、填料、粉底霜、化妝基底(make-up bases)及化妝棒(cosmetic sticks)。本發明之組成物可應用於多樣性的狀態，例如，液體、乳霜、糊狀物及固體，其可藉由化妝品領域之通常方法製備。
舉例而言，於純水中將卡波姆(carbomer)攪拌分散，於此分散物中加入丁二醇、甘油及PEG-1500，再將此混合物與含有聚氧乙烯硬化蓖麻油(polyoxyethylene cured castor oil)、三乙醇、防腐劑、及溶於適當溶劑(如：乙醇)的化合物之溶液混合，可製得化妝水。另外，亦可於溫度約70℃下溶解棕櫚醇(cetearyl alcohol)、甘油硬脂酸酯/PEG-100硬脂酸酯(glyceryl stearate/PEG-100 stearate)、聚山梨醇酯60(polysorbate 60)、去水山梨醇倍半油酸酯(sorbitan sesquioleate)、鯨蠟硬脂醇辛酸酯(cetyl octanoate)及鯊烯(squalene)，並於70℃下將此溶液加入由丁二醇、矽酸鎂鋁、黃原膠(xanthan gum)及防腐劑溶於純水之分散液，進行乳化，接著，冷卻乳化液，將乳化液加入一溶於適當的溶劑或成分的化合物之溶液，攪拌其混合物，並冷卻至室溫，可製得化妝水。
本發明之組成物的施用途徑並不受到限制。舉例而言，本發明之組成物可藉由口服、注射(如，肌肉注射(intramuscular injection)、腹膜內注射(intraperitoneal injection)、靜脈注射(intravenous injection)、注入液(infusion)、皮下注射(subcutaneous injection)或植入(implantation))、吸入(inhalation)、經鼻腔(nasally)、經陰道(intravaginally)、經直腸(rectally)、經舌下(sublingually)、經皮膚吸收(transdermally)、及局部的(topically)等方式施用，其係取決於不同類型的疾病及個體的治療條件。本發明之組成物可根據所需之施用途徑，製備成一適當的單位劑量形式，其包括至少一已知無毒性藥學上可接受載體、佐劑或賦形劑(vehicle)。本發明之組成物亦可製備成一保存劑型(depot formulation)，其可於一特定期間內持續性釋放的活性成分，此亦被涵蓋於本發明範疇內。此組成物可直接施用於皮膚，以達到利用本發明之組成物達成減少皮膚皺紋之目的，因此，本發明之組成物更佳地係為用於局部施用於皮膚之製劑。
為了達成本發明之目的，施用PDE5抑制劑之每日劑量範圍為約0.1 mg/kg至200 mg/kg，PDE5抑制劑之每日劑量較佳為約0.5 mg/kg至約100 mg/kg，PDE5抑制劑之劑量可依據病患的條件(例如，年齡、性別及體重及特定病症之嚴重性)有所不同。為了施用之便利性，如有需要，PDE5抑制劑之每日劑量可以單一劑量或分成數個劑量施用。若欲將化合物直接施用於局部皮膚時，每日劑量範圍於皮膚區域中較佳地約為0.05mg/cm2 至50 mg/cm2 ，但不侷限於此劑量範圍。
本發明亦提供一種減少皮膚皺紋之方法，其包括施用或塗敷具有治療上或美妝上之有效量之至少一化合物物於需要接受治療之病患，以減少皮膚皺紋。其中，該至少一化合物係選自絲丹奈非(sildenafil)、發丹奈非(vardenafil)、塔大拉非(tadalafil)、烏地那非(udenafil)、阿伐那非(avanafil)及其藥學上可接受之鹽類、溶劑化物及水合物。
本發明之組成物及方法有效地用於減少皮膚皺紋。
本發明之其他目的及觀點，將參考所附圖示並於以下實施例敘述中明顯指出。
下文將參考隨附圖式，詳細敘述本發明較佳具體實施例。然而，本發明之實施例可以數種其他方式實施，且本發明之範疇不應侷限於以下例子中。對於本發明所屬技術領域中具有通常知識者，本發明之實施例將提供更充分地解釋。
<實施例1> PDE5於皮膚中之表現測定
本實施例中，測定部分皮膚組織中PDE5之表現以檢驗PDE5抑制劑用於減少臉部皮膚皺紋之能力。
切取七週齡之雄性史-道二氏大鼠(Sprague-Dawley,SD rats)的皮膚、腎臟及前列腺組織做實驗，然而，PDE5於腎臟及前列腺組織之表現已為熟知。藉由以下程序確認PDE5於組織中之表現。首先，將各組織切成一重量約100mg之片狀物，接著，將各片狀物進行均質化及RNA萃取，該RNA經定量，以1μg的RNA進行cDNA之建構，以即時PCR(real-time PCR)分析cDNA，確認組織中PDE5之表現。以β-肌動蛋白為一對照組。5’-TTGACGGATCTGGAGACGCT-3’(正向引子)及5’-CACCACGATGGTCCAAATCA-3’(反向引子)作為PDE5的引子。5’-ACCTTCAACACCCCAGCCA-3’(正向引子)及5’-CAGTGGTACGACCAGAGGCA-3’(反向引子)作為β-肌動蛋白的引子。(參照BJU INTERNATIONAL 2006(98) 1259-1263)。表1示為PDE5於不同組織的相對表現程度，且表1所呈現之數據為平均值±標準差(mean ± standard deviation)。
如表1所示之結果，PDE5於皮膚組織中具有高度表現，與腎臟及前列腺組織相似，其中，已知PDE5於腎臟及前列腺組織中之表現程度相當多。結果顯示該化合物可用來抑制皮膚中的PDE5，並對皮膚可具有部分程度之作用。
<實施例2>透過膠原蛋白生成的刺激作用以減少皮膚皺紋之效果評估
本實施例中，為了測定PDE5抑制劑是否能有效減少皮膚皺紋，進而研究主要PDE5抑制劑對於膠原蛋白生成的刺激作用。膠原蛋白在皺紋產生的調節上為一個非常重要的物質，已知膠原蛋白的分解會導致皺紋的產生，因此，膠原蛋白的生成在減少皺紋的過程中扮演一個重要的角色。
將正常人類真皮纖維母細胞(NHDFs)培養於一個完全培養基，於48-孔培養皿的每一孔上放置400μl(1×105 細胞數)之NHDF培養物，並於37℃及5%CO2 之培育箱(MCO-20 AIC,Sanyo,Japan)內培養24小時。培養完成後，去除孔內培養液，將500μl的D-磷酸鹽緩衝液(D-phosphate buffered saline,D-PBS)加至各孔洞中進行清洗。接著，於對應的孔洞中加入800μl之實驗物質及800μl之陽性對照組，並且對應孔洞中加入800μl之含有DMSO之無血清培養基加入作為陰性對照組。將此培養物在37℃及5%CO2 之培育箱內培養48小時，完成培養後，收集各孔洞之培養液，於25C°下以轉速3000rpm離心10分鐘，取上層液進行第一型原膠原蛋白(procollagen type I)之定量。以1 mL的D-PBS加至前述已去除培養液之培養皿的各孔洞中進行清洗，並將30μl之細胞裂解液(cell lysis buffer)(Lot No.: 41,Cell Signaling Technology,U.S.A)加至各孔洞中。將培養皿保存於-70 C°低溫冷凍櫃(DFU-657CL,Operon,Korea)冷凍2小時後，於室溫下解凍，並將此冷凍-解凍之程序重複兩次以溶解細胞。收集各孔洞之細胞裂解產物，並於4℃下以轉速13000rpm離心30分鐘(Micro 17TR,Hanil Science Industrial,Korea)，取上層液進行總蛋白質之定量。
取40μl所得到的上層液添加至96-孔培養皿的每一孔洞中。將BCA蛋白質分析套組之標準溶液(Lot No.: KK140637,Pierce Biotechnology Inc.,USA)逐步稀釋至不同濃度(250、125、50、25、5及0 μg/mL)，並將40μl之已稀釋溶液加至各孔洞中，再將自分析套組之160μl的試劑混合物加至各孔洞中。其後，將所得之混合物放置於60℃的培育箱(NB-201V,n-Biotec,Korea)內，使其反應30分鐘，待完成反應後，利用酵素免疫分析儀(PowerWave XS,BioTek Instruments,Inc.,USA)於波長562 nm下，測定各孔洞的吸光值，藉由將各孔洞所測定之吸光值代入標準曲線方程式內，以測定實驗物質、陽性及陰性對照組各孔洞中的總蛋白質含量。
取100μl所得到的上層液添加至96-孔培養皿的每一孔洞中，其96-孔培養皿來自於第一型原膠原蛋白C-peptide EIA套組(Lot No.: AB01520C,Takara Bio Inc.,Japan)，將此套組之標準溶液逐步稀釋至不同濃度(640、320、160、80、20、10及0 ng/mL)，並將100μl之已稀釋溶液加至各孔洞中，接著，將所得之混合物放置於37℃的培育箱內，使其反應2小時，待完成反應後，除去各孔洞中之反應液，以400 μl的PBS清洗各孔洞且重複3次，接著，取100μl套組中的溶液1添加至每一個孔洞，並於37℃下使其反應1小時。待完成反應後，除去各孔洞中之反應液，再以400 μl的PBS清洗各孔洞且重複4次。取100μl套組中的四甲基聯苯胺(tetramethylbenzidine,TMBZ)基質溶液添加至各個孔洞中，於30℃下使其反應15分鐘。而後，取100 μl的1 N H2 SO4 溶液添加至各孔洞中，以終止反應。利用酵素免疫分析儀於波長450nm下，測定各孔洞的吸光值，藉由將各孔洞所測定之吸光值代入標準曲線方程式內，以測定實驗物質、陽性及陰性對照組各孔洞中的第一型原膠原蛋白(procollagen type I)含量。
實驗物質、陽性及陰性對照組各孔洞中之第一型原膠原蛋白(procollagen type I)含量需藉由含量除以總蛋白質含量加以校正。第一型原膠原蛋白之合成速率則可藉由將經校正後之第一型原膠原蛋白含量代入下列方程式中計算得知。
第一型原膠原蛋白之合成速率(%)=(B-A)/B×100
其中，A為實驗物質或陽性對照組之第一型原膠原蛋白含量，而B為陰性對照組之第一型原膠原蛋白含量。
將上述實驗步驟重複3次，所得到的第一型原膠原蛋白之合成速率以進行統計分析。
利用SAS(version 9.1.3,SAS Institute Inc.,Cary,NC,U.S.A.)完成第一型原膠原蛋白合成速率之統計分析，以巴特雷檢定(Bartlett’s test)進行驗證第一型原膠原蛋白合成速率之等分散性(homoscedasticity)(顯著水平=0.05)。當第一型原膠原蛋白合成速率具有等分散性時，運用單因子變異數分析(one-way ANOVA)處理(顯著水平=0.05)。運用Dunnett’s t-test處理多重比較，以確認每一試驗組相較於陰性對照組之顯著性，其測試結果如圖1所示。
參閱圖1，發丹奈非(vardenafil)濃度為10及100 nM(p<0.01: 10 nM=140.7±7.8%、100 nM=162.7±10.0%)下，其第一型原膠原蛋白合成速率相較於陰性對照組之第一型原膠原蛋白合成速率(100.0±0.0%)，具有統計上顯著地增加。再者，塔大拉非(tadalafil)濃度為10及100 nM(p<0.01: 10 nM=147.2±8.1%、100 nM=174.7±10.2%)下，其第一型原膠原蛋白合成速率相較於陰性對照組之第一型原膠原蛋白合成速率(100.0±0.0%)，具有統計上顯著地增加。然而，10 nM絲丹奈非(sildenafil)(108.6±8.1%)與陰性對照組(100.0±0.0%)間之第一型原膠原蛋白合成速率，並未具有統計上顯著的差異；但100 nM絲丹奈非(sildenafil)(p<0.01、160.7±12.1%)與陰性對照組(100.0±0.0%)間之第一型原膠原蛋白合成速率，可觀察到具有一統計上顯著的差異。陽性對照組濃度為35.2μg/mL(200μM)(p<0.01: 175.7±11.5%)下，其第一型原膠原蛋白合成速率相較於陰性對照組第一型原膠原蛋白合成速率(100.0±0.0%)，具有統計上顯著地增加。由此測試結果可以證實PDE5可有效減少皮膚皺紋。
<實施例3>減少皮膚皺紋效果之評估
此試驗是關於PDE5抑制劑是否可大大地減少動物模型中的皮膚皺紋。七週齡之無毛鼠，以UVB照射(290-320nm，312 nm)引起皺紋產生，對已引起皺紋產生之無毛鼠施用化合物或對照組，以評估化合物針對減少皮膚皺紋之影響。
更具體而言，在小鼠皮膚產生皺紋後的第一週及第二週，以一週照射3天且照射劑量為60 mJ/cm2 (1最小水腫劑量，1 MED)進行照射；於小鼠皮膚產生皺紋後的第三週，以照射3天且照射劑量為120 mJ/cm2 (2 MED)進行照射；於小鼠皮膚產生皺紋後的第四週，以照射3天且照射劑量為180 mJ/cm2 (3 MED)進行照射；於小鼠皮膚產生皺紋後的第五至八週，以一週照射3天且照射劑量為240 mJ/cm2 (4 MED)進行照射；於小鼠皮膚產生皺紋後的第九至十五週，以一週照射5天且照射劑量為240 mJ/cm2 (4 MED)進行照射；於小鼠皮膚產生皺紋後的第十六至十七週，取約0.5mL鯊烯-OOH(squalene-OOH)塗敷一次，進而引起較深的皺紋產生，其中，鯊烯-OOH為鯊烯經UV照射之氧化產物。其後，以化合物或對照組施用於各小鼠上，以每日兩次方式持續施用14天。圖2至圖5係為拍攝皮膚變化之照片。
圖2係為正常組(n=4)的照片，此組並未經過UV照射來引起皺紋產生，隨著小鼠年齡增長，會自然地形成部分淺的皺紋。
圖3係為陰性對照組(n=6)的照片，此組經過UV照射引起皺紋產生，並僅以未含任何活性成分之培養基(20% EtOH，30% DW，50% PEG)給予兩週的治療，由陰性對照組可觀察到許多深的皺紋。
圖4係為一實驗組(n=7)的照片，此組於引起皺紋產生後，以10 mM(約5%)絲丹奈非(sildenafil)給予治療，其中，絲丹奈非(sildenafil)為一具代表性的PDE5抑制劑。在此組中可觀察到皮膚皺紋的減少，且皮膚逐漸呈現白淨。
圖5係為一陽性對照組(n=6)的照片，此組以0.05%視黃酸(retinoic acid)給予治療。可觀察到角質層形成且持續地剝落，藉由改變視黃酸的施用頻率，從每日2次變成每日1次，仍然觀察到角質層持續地形成及剝落，亦可觀察到皮膚皺紋有輕微地減少，但皮膚不再呈現白淨且角質層增厚。
本發明詳細地說明於其上。然而，應了解的是，當為了指出本發明較佳實施例時所提及的詳細敘述與特定的例子，其僅供說明之用，藉由此處的詳細敘述，所屬技術領域中具有通常知識者可明顯知悉本發明的精神與範疇內之各種變化及修飾。
圖1係為PDE5抑制劑刺激膠原蛋白產生之功效測試結果，其膠原蛋白能作用於減少皮膚皺紋。
圖2係為正常組(n=4)的照片，此組並未經過UV照射來引起皺紋產生。
圖3係為陰性對照組(n=6)的照片，此組經過UV照射引起皺紋產生，並以未含任何活性成分之培養基(20% EtOH，30% DW，50% PEG)給予治療。
圖4係為一實驗組(n=7)的照片，此組於引起皺紋產生後，以10mM(約5%)絲丹奈非(sildenafil)給予治療。
圖5係為一陽性對照組(n=6)的照片，此組以0.05%視黃酸(retinoic acid)給予治療。

Claims (3)

  1. 一種磷酸二酯酶第五型(PDE5)抑制劑、或其藥學上可接受之鹽類之用途，係用於製造減少皮膚皺紋之組成物。
  2. 如申請專利範圍第1項所述之用途，其中，該PDE5抑制劑係為至少一選自以下所組成之群組：5-[2-烯丙氧基-5-(4-甲基哌嗪基磺醯基)苯基]-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-[2-allyloxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-[2-乙氧基-5-(哌嗪基磺醯基)苯基]-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-[2-ethoxy-5-(piperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-[2-乙氧基-5-(4-甲基哌嗪基磺醯基)苯基]-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-[2-ethoxy-5-(4-methylpiperazinylsulphonyl)phenyl]-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-{2-乙氧基-5-[4-(2-丙基)哌嗪基磺醯基]苯基}-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-{2-ethoxy-5-[4-(2-propyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)； 5-{2-乙氧基-5-[4-(2-羥乙基)哌嗪基磺醯基]苯基}-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-{2-ethoxy-5-[4-(2-hydroxyethyl)piperazinylsulphonyl]phenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；1-甲基-5-[5-(哌嗪基磺醯基)-2-n-丙氧基苯基]-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(1-methyl-5-[5-(piperazinylsulphonyl)-2-n-propoxyphenyl]-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；5-{5-[4-(2-羥乙基)哌嗪基磺醯基]-2-n-丙氧基苯基}-1-甲基-3-n-丙基-1,6-二氫-7H-吡唑并[4,3-d]嘧啶-7-酮(5-{5-[4-(2-hydroxyethyl)piperazinylsulphonyl]-2-n-propoxyphenyl}-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one)；2-[2-乙氧基-5-(4-甲基-哌嗪-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f]-[1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-methyl-piperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥乙基哌嗪-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f]-[1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxyethylpiperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥基哌啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f]-[1,2,4]三嗪-4-酮 (2-[2-ethoxy-5-(4-hydroxypiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f]-[1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥基甲基哌啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxymethylpiperidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(3-羥基吡咯啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(3-hydroxypyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；4-乙氧基-N-乙基-N-(2-羥乙基)-3-(5,7-二甲基-4-氧代-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N,N-二乙基-4-乙氧基-3-(5,7-二甲基-4-氧代-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N,N-diethyl-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；2-[2-乙氧基-5-(4-(2-嘧啶基)-哌嗪-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑-[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-(2-pyrimidinyl)-piperazine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(嗎福林-4-磺醯基)-苯基]-5,7-二甲基-3H-咪唑-[5,1-f][1,2,4]三嗪-4-酮 (2-[2-ethoxy-5-(morpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo-[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(1,4-二氧-6-氮雜螺基[4.4]壬烷-6-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(1,4-dioxa-6-azaspiro[4.4]nonane-6-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N,N-雙-(2-甲氧基乙基)-4-乙氧基-3-(5,7-二甲基-4-氧代-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(N,N-bis-(2-methoxyethyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；N-(3-異噁唑基)-4-乙氧基-3-(5,7-二甲基-4-氧代-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(N-(3-isoxazolyl)-4-ethoxy-3-(5,7-dimethyl-4-oxo-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；2-[2-乙氧基-5-(2-t-丁氧基羰基胺基甲基嗎福林-4-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(2-t-butoxycarbonylaminomethylmorpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-苯基哌嗪-1-磺醯基)苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(2-t-butoxycarbonylaminomethylmorpholine-4-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)； 2-[2-乙氧基-5-(3-羥基-3-甲氧基甲基吡咯啶-1-磺醯基)-苯基]-5,7-二甲基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(3-hydroxy-3-methoxymethylpyrrolidine-1-sulphonyl)-phenyl]-5,7-dimethyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-苯基哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-phenylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-乙基哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-ethylpiperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-甲基-1-胺基-哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-methyl-1-amino-piperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥乙基-1-胺基-哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxyethyl-1-amino-piperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N,N-雙羥乙基胺基乙基-4-乙氧基-3-(5-甲基(4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺 (N,N-bishydroxyethylaminoethyl-4-ethoxy-3-(5-methyl(4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；2-[2-乙氧基-5-(4-二甲氧基磷氧基甲基-哌嗪-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-dimethoxyphsphorylmethyl-piperazine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-二乙氧基磷氧基甲基-哌啶-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-diethoxyphsphorylmethyl-piperidine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-羥基-哌啶-1-磺醯基)苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-hydroxy-piperidine-1-sulphonyl)phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-羥基-乙基)-哌嗪-1-磺醯基]苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulphonyl]phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(3-羥基-丙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(3-hydroxy-propyl)-piperazine-1-sulphony l]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N-烯丙基-4-乙氧基-N-(2-羥基-乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N-allyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N-乙基-4-乙氧基-N-(2-羥基-乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N-ethyl-4-ethoxy-N-(2-hydroxy-ethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N,N-二乙基-4-乙氧基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(N,N-diethyl-4-ethoxy-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N-(2-甲氧基乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-(2-methoxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)；N-(2-N,N-二甲基乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-(2-N,N-dimethylethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)； N-[3-(1-嗎啉基)丙基]-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-[3-(1-morpholino)propyl]-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)；N-{3-[1-(4-甲基)哌嗪基]-丙基}-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-苯磺醯胺(N-{3-[1-(4-methyl)piperazino]-propyl}-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-benzenesulfonamide)；2-{2-乙氧基-5-[4-(2-甲氧基-乙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-methoxy-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-N,N-二甲基-乙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-N,N-dimethyl-ethyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(3-N,N-二甲基-丙基)-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(3-N,N-dimethyl-propyl)-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)； 2-[2-乙氧基-5-(4-二氧五環基-哌啶-1-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-dioxolano-piperidine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(4-(5-甲基-4-氟烷羰基)-哌嗪-1-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-(5-methyl-4-fluroxanecarbonyl)-piperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-乙醯基-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-acetyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-甲醯基-哌嗪-1-磺醯基]-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-formyl-piperazine-1-sulphonyl]-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[2-乙氧基-5-(3-丁基斯德酮亞胺)-1-磺醯基]-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(3-butylsydnoneimine)-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；5-甲基-2-[5-(4-甲基-哌嗪-1-磺醯基)-2-丙氧基-苯基]-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(5-methyl-2-[5-(4-methyl-piperazine-1-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)； 2-[5-(4-羥基哌啶-1-磺醯基)-2-丙氧基-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[5-(4-羥基甲基哌啶-1-磺醯基)-2-丙氧基-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxymethylpiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{5-[4-(2-羥乙基)-哌嗪-1-磺醯基]-2-丙氧基-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-2-propoxy-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N-(1,1-二氧代四氫基-1λ6-噻吩-3-基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(1,1-dioxotetrahydro-1λ6-thiophen-3-yl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-(2-二甲基胺基乙基)-N-甲基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(2-dimethylaminoethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)； 3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-N-(3-嗎福林-4-基-丙基)-4-丙氧基-苯磺醯胺(3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-propoxy-benzenesulfonamide)；N,N-雙-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N,N-bis-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-(3-羥基苄基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(3-hydroxybenzyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-乙基-N-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-ethyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-(3-乙氧基丙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(3-ethoxypropyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamidel)； 2-[5(4-羥基哌啶-1-磺醯基)-2-丙氧基-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5(4-hydroxypiperidine-1-sulphonyl)-2-propoxy-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-N-吡啶-4-基-苯磺醯胺(3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-N-pyridin-4-yl-benzenesulfonamide)；N,N-二乙基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N,N-diethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；1-[3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯基]-哌啶-4-羧酸(1-[3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulphonyl]-piperidine-4-carboxylic acid)；5-甲基-2-[5-(嗎福林-4-磺醯基)-2-丙氧基-苯基]-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(5-methyl-2-[5-(morpholine-4-sulphonyl)-2-propoxy-phenyl]-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；N-(2-羥乙基)-N-甲基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-(2-hydroxyethyl)-N-methyl-3-(5-methyl-4-oxo-7-propyl-3 ,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-N-丙基-苯磺醯胺(N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-N-propyl-benzenesulfonamide)；N-[2-(3,4-二甲氧基-苯基)乙基]-N-甲基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-烯丙基-N-(2-羥乙基)-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-allyl-N-(2-hydroxyethyl)-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-烯丙基-N-環戊基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基-苯磺醯胺(N-allyl-N-cyclopentyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxy-benzenesulfonamide)；N-烯丙基-N-乙基-3-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-丙氧基苯磺醯胺(N-allyl-N-ethyl-3-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imi dazo[5,1-f][1,2,4]triazin-2-yl)-4-propoxybenzenesulfonamide)；2-[2-乙氧基-4-甲氧基-5-(4-甲基哌嗪-1-磺醯基)-苯基]-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-4-methoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-羥乙基)-哌嗪-1-磺醯基]-4-甲氧基-苯基}-5-甲基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-4-methoxy-phenyl}-5-methyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；4-乙氧基-N-乙基-N-(2-羥乙基)-2-甲氧基-5-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(4-ethoxy-N-ethyl-N-(2-hydroxyethyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；4-乙氧基-N-(4-乙氧基苯基)-2-甲氧基-5-(5-甲基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-苯磺醯胺(4-ethoxy-N-(4-ethoxyphenyl)-2-methoxy-5-(5-methyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-benzenesulfonamide)；4-乙氧基-N-乙基-N-(2-羥基-乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)苯磺醯胺(4-ethoxy-N-ethyl-N-(2-hydroxy-ethyl)-3-(5-ethyl-4-oxo-7-pr opyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)benzenesulfonamide)；N-(2-甲氧基乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基苯磺醯胺(N-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulfonamide)；N,N-雙-(2-甲氧基乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基苯磺醯胺(N,N-bis-(2-methoxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxybenzenesulfonamide)；2-[5-(4-羥基哌啶-1-磺醯基)-2-乙氧基苯基]-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxypiperidine-1-sulphonyl)-2-ethoxyphenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-[5-(4-羥基甲基哌啶-1-磺醯基)-2-乙基-苯基]-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[5-(4-hydroxymethylpiperidine-1-sulphonyl)-2-ethyl-phenyl]-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；2-{2-乙氧基-5-[4-(2-羥乙基)-哌嗪-1-磺醯基]-苯基}-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-{2-ethoxy-5-[4-(2-hydroxyethyl)-piperazine-1-sulphonyl]-phenyl}-5-ethyl-7-propyl-3H-imidazo[5,1-f][1,2,4]triazin-4-one)； 2-[2-乙氧基-5-(4-甲基哌嗪-1-磺醯基)-苯基]-5-乙基-7-丙基-3H-咪唑[5,1-f][1,2,4]三嗪-4-酮(2-[2-ethoxy-5-(4-methylpiperazine-1-sulphonyl)-phenyl]-5-ethyl-7-propy1-3H-imidazo[5,1-f][1,2,4]triazin-4-one)；3-(5-乙基-4-氧代-7-丙基-3,4-二氫咪唑[5,1-f][1,2,4]三嗪-2-基)-N-(3-嗎福林-4-基-丙基)-4-乙氧基苯磺醯胺(3-(5-ethyl-4-oxo-7-propyl-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-N-(3-morpholin-4-yl-propyl)-4-ethoxybenzenesulfonamide)；N-(2-羥乙基)-3-(5-乙基-4-氧代-7-丙基-3,4-二氫-咪唑[5,1-f][1,2,4]三嗪-2-基)-4-乙氧基-N-丙基-苯磺醯胺(N-(2-hydroxyethyl)-3-(5-ethyl-4-oxo-7-propyl-3,4-dihydro-imidazo[5,1-f][1,2,4]triazin-2-yl)-4-ethoxy-N-propyl-benzenesulfonamide)；順-2,3,6,7,12,12a-六氫-2-(4-吡啶基甲基)-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-2-(4-pyridylmethyl)-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；順-2,3,6,7,12,12a-六氫-6-(2,3-二氫苯并[b]呋喃-5-基)-2-甲基-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-6-(2,3-dihydrobenzo[b]furan-5-yl)-2-methyl-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)； 順-2,3,6,7,12,12a-六氫-6-(5-溴-2-噻吩基)-2-甲基-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-6-(5-bromo-2-thienyl)-2-methyl-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；順-2,3,6,7,12,12a-六氫-2-丁基-6-(4-甲基苯基)-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮(cis -2,3,6,7,12,12a-hexahydro-2-butyl-6-(4-methylphenyl)-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-異丙基-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-isopropyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-環戊基-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopentyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-環丙基甲基-6-(4-甲氧基苯基)-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-cyclopropylmethyl-6-(4-methoxyphenyl)-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-6-(3-氯-4-甲氧基苯基)-2-甲基-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮 ((6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3-chloro-4-methoxyphenyl)-2-methyl-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-2-甲基-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-2-methyl-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；(6R,12aR)-2,3,6,7,12,12a-六氫-6-(3,4-亞甲基二氧基苯基)-吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-1,4-二酮((6R,12aR)-2,3,6,7,12,12a-hexahydro-6-(3,4-methylenedioxyphenyl)-pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-1,4-dione)；(5aR,12R,14aS)-1,2,3,5,6,11,12,14a-八氫-12-(3,4-亞甲基二氧基苯基)-吡咯並[1”,2”：4’,5’]吡嗪並[2’,1’：6,1]吡啶并[3,4-b]吲哚-5-1,4-二酮((5aR,12R,14aS)-1,2,3,5,6,11,12,14a-octahydro-12-(3,4-methylenedioxyphenyl)-pyrrolo[1”,2”：4’,5’]pyrazino[2’,1’：6,1]pyrido[3,4-b]indole-5-1,4-dione)；5-[2-乙氧基-5-(異丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(isopropylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(苄基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮 (5-[2-ethoxy-5-(benzylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(異丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(isopropylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(異丙基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(isopropylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(propylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(丙基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(propylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(丁基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(butylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(2-丁基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮 (5-[2-ethoxy-5-(2-butylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(環丙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(cyclopropylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(環丙基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(cyclopropylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(環己基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(cyclohexylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(苄基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(benzylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(苄基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(benzylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(苄基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮 (5-[2-ethoxy-5-(benzylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-氟苯基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-fluorophenylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-t-丁基苯基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-t-butylphenylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-t-丁基苯基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-t-butylphenylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-異丙基苯基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-isopropylphenylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-氟苯基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-fluorophenylamidosulphonyl)phenyl]-1-eth yl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(4-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)5-[2-乙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮 (5-[2-propyloxy-5-(3-pyridylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-乙基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylamidosulphonyl)phenyl]-1-ethyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(4-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(4-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(4-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(4-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(3-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)； 5-[2-乙氧基-5-(3-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(3-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(3-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(3-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(2-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(2-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(2-吡啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(2-pyridylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-3-吡咯啶基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-3-pyrrolidinylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)； 5-[2-乙氧基-5-(1-甲基-3-吡咯啶基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-3-pyrrolidinylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-2-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-甲基-2-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-2-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-3-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-甲基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-3-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)； 5-[2-丙氧基-5-(1-乙基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-ethyl-3-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-乙基-3-吡咯啶基甲基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-ethyl-3-pyrrolidinylmethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-丙氧基-5-(1-甲基-2-吡咯啶基乙基醯胺基磺醯基)苯基]-1-甲基-3-丙基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-propyloxy-5-(1-methyl-2-pyrrolidinylethylamidosulphonyl)phenyl]-1-methyl-3-propyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；5-[2-乙氧基-5-(1-甲基-2-吡咯啶基乙基醯胺基磺醯基)苯基]-1-甲基-3-異丁基-1,6-二氫-7H-吡唑并(4,3-d)嘧啶-7-酮(5-[2-ethoxy-5-(1-methyl-2-pyrrolidinylethylamidosulphonyl)phenyl]-1-methyl-3-isobutyl-1,6-dihydro-7H-pyrazolo(4,3-d)pyrimidin-7-one)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶(S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)； 2-(6,7-二氫-5H-吡咯並[3,4-b]啶-6-基)-4-(3-氰基-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶(2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-甲氧基環己基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans -4-methoxycyclohexyl)carbamoyl]pyrimidine)；2-(6,7-二氫-5H-吡咯並[3,4-b]啶-6-基)-4-(3-氰基-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(trans -4-hydroxycyclohexyl)carbamoyl]pyrimidine)；2-(6,7-二氫-5H-吡咯並[3,4-b]啶-6-基)-4-(3-氰基-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶(2-(6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-6-yl)-4-(3-cyano-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine)； 2-[(2S)-2-羥基甲基-1-吡咯啶基]-4-(3-氯-4-甲氧基苄基胺基)-5-[N-[[(2R)-4-甲基-2-嗎福林基]甲基]胺甲醯基]-嘧啶(2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2R)-4-methyl-2-morpholinyl]methyl]carbamoyl]-pyrimidine)；2-[(2S)-2-羥基甲基-1-吡咯啶基]-4-(3-氯-4-甲氧基苄基胺基)-5-[N-[[(2S)-4-甲基-2-嗎福林基]甲基]胺甲醯基]-嘧啶(2-[(2S)-2-hydroxymethyl-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-[[(2S)-4-methyl-2-morpholinyl]methyl]carbamoyl]-pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(4-嘧啶基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(4-甲基-3-氧代-1-哌嗪基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(4-methyl-3-oxo-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans -4-hydroxycyclohexyl)carbamoyl]pyrimidine)；2-(4-甲醯基-1-哌嗪基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(4-formyl-1-piperazinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans -4-hydroxycyclohexyl)carbamoyl]pyrimidine)； 2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(反-4-羥基環己基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(trans -4-hydroxycyclohexyl)carbamoyl]pyrimidine)；2-[順-2,5-雙(羥基甲基)-1-吡咯啶基]-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶(2-[cis -2,5-bis(hydroxymethyl)-1-pyrrolidinyl]-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嘧啶基甲基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyrimidinylmethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine)；2-(5,6,7,8-四氫-1,7-萘啶-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-嗎啉基乙基)胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydro-1,7-naphthyridin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-morpholinoethyl)carbamoyl]pyrimidine)； (S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-乙醯基嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-acetylpyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(4-噠嗪基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(4-pyridazinylmethyl)carbamoyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(5-嘧啶基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(5-pyrimidinylmethyl)carbamoyl]pyrimidine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(2-吡啶基甲基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(2-pyridylmethyl)carbamoyl]pyrimidine)；(S)-2-[N-(2-嘧啶基甲基)胺甲醯基]-3-(3-氯-4-甲氧基苄基胺基)-5-[2-羥基甲基-1-吡咯啶基]吡嗪((S)-2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-[2-hydroxymethyl-1-pyrrolidinyl]pyrazine)； (S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[(2-嗎啉基乙基)羰基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-morpholinoethyl)carbonyl]pyrimidine)；2-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-[(4-甲基-2-嗎福林基)甲基]胺甲醯基]嘧啶(2-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-[(4-methyl-2-morpholinyl)methyl]carbamoyl]pyrimidine)；(S)-2-[N-(2-嗎啉基乙基)胺甲醯基]-3-(3-氯-4-甲氧基苄基胺基)-5-(2-羥基甲基-1-吡咯啶基)吡嗪((S)-2-[N-(2-morpholinoethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(2-hydroxymethyl-1-pyrrolidinyl)pyrazine)；2-[N-(2-嘧啶基甲基)胺甲醯基]-3-(3-氯-4-甲氧基苄基胺基)-5-(5,6,7,8-四氫咪唑[1,2-a]吡嗪-7-基)吡嗪(2-[N-(2-pyrimidinylmethyl)carbamoyl]-3-(3-chloro-4-methoxybenzylamino)-5-(5,6,7,8-tetrahydroimidazo[1,2-a]pyrazin-7-yl)pyrazine)；(S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[(2-甲氧基乙基)羰基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[(2-methoxyethyl)carbonyl]pyrimidine)； (S)-2-(2-羥基甲基-1-吡咯啶基)-4-(3-氯-4-甲氧基苄基胺基)-5-[N-(1,3,5-三甲基-4-吡唑基)胺甲醯基]嘧啶((S)-2-(2-hydroxymethyl-1-pyrrolidinyl)-4-(3-chloro-4-methoxybenzylamino)-5-[N-(1,3,5-trimethyl-4-pyrazolyl)carbamoyl]pyrimidine)，及其一藥學上可接受之鹽類。
  3. 如申請專利範圍第2項所述之用途，其中，該PDE5抑制劑係為至少一選自以下所組成之群組：絲丹奈非(sildenafil)、發丹奈非(vardenafil)、塔大拉非(tadalafil)、烏地那非(udenafil)、阿伐那非(avanafil)，及其藥學上可接受之鹽類。
TW100126205A 2011-04-04 2011-07-25 包含ｐｄｅ５抑制劑之用於減少皮膚皺紋之組成物 TWI490220B (zh)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1422271A (zh) * 2000-02-17 2003-06-04 Sk化学株式会社 吡咯并嘧啶酮衍生物,其制备方法及用途
US20030216407A1 (en) * 2002-01-31 2003-11-20 Pfizer Inc. Use of PDE5 inhibitors in the treatment of scarring
US20080317679A1 (en) * 2002-10-25 2008-12-25 Foamix Ltd. Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1422271A (zh) * 2000-02-17 2003-06-04 Sk化学株式会社 吡咯并嘧啶酮衍生物,其制备方法及用途
US20030216407A1 (en) * 2002-01-31 2003-11-20 Pfizer Inc. Use of PDE5 inhibitors in the treatment of scarring
US20080317679A1 (en) * 2002-10-25 2008-12-25 Foamix Ltd. Foamable compositions and kits comprising one or more of a channel agent, a cholinergic agent, a nitric oxide donor, and related agents and their uses

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