TWI280132B - Pharmaceutical composition for treating premature ejaculation - Google Patents
Pharmaceutical composition for treating premature ejaculation Download PDFInfo
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- TWI280132B TWI280132B TW090128482A TW90128482A TWI280132B TW I280132 B TWI280132 B TW I280132B TW 090128482 A TW090128482 A TW 090128482A TW 90128482 A TW90128482 A TW 90128482A TW I280132 B TWI280132 B TW I280132B
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Landscapes
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Soy Sauces And Products Related Thereto (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Orthopedics, Nursing, And Contraception (AREA)
Description
1280132 A7 B7 五、發明説明(1) 本發明係關於使用3 /,5 > -環鳥苷酸磷酸二酯酶 第五型抑制劑(下文稱之爲P D E 5抑制劑)以治療早泄 (P E )上之用途,特別之p D E 5抑制劑爲西得那非( sildenafil),I C — 3 5 1,凡得那非(vardenafil),5 —〔2 —乙氧基—5— (4 —乙基哌嗪一1 一基磺醯)d比 D定—3 —基〕一3 —乙基—2-〔2 —甲氧基乙基〕—2 ,6 -二氫基—7H — d比π坐並〔4,3 - d〕嘧π定—7-酮及5 — (5 —乙醯—2 -丁氧基-3-吡啶基)—3 — 乙基一 2 —(1—乙基一 3 —吖丁啶基)—2,6 —二氫 基一 7H —吡唑並〔4,3 — d〕嘧啶一 7 —酮。 根據國際專利申請案W〇 9 4 / 2 8 9 0 2之專利 說明書,吾人發現作爲c G Μ P P D Ε 5酵素抑制劑之 化合物爲強有力且有效以供治療男性勃起功能障礙( Μ E D,陽萎)及供女性性官能病症用之化合物,此發現 導致西得那非(5 —〔2—乙氧基—5— (4 —甲基一 1 一哌嗪基磺醯)苯基〕一 1 一甲基一 .3 —正丙基一 1,6 _二氫基—7 Η —吡唑並〔4,3 - d〕嘧啶一 7 —酮( VIAGRATM )之發展,彼經證實可顯著成功地作爲男性勃起 功能障礙之首要口服有效治療法。 早泄爲男性較常見之性功能障礙,其已有數種不同之 方式定義,但最廣爲接受者爲Diagnostic and Statistical Manual ofMental Disorders IV,其陳述:a 早泄爲因爲進 入之前,之即或之後不久且病患想要之前之最小性刺激而 致之終身持久性或再發性射精,臨床醫生必需考慮影響興 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) Ί--^--^---裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -4- 1280132 A7 _ B7 _ 五、發明説明(2) 奮相之持續時間之因素,諸如年齡,性伴侶或刺激之新鮮 度,及性慾活動之頻率,此障礙將導致顯著苦惱或人際困 難"。 在疾病1 0之國際分類(The International Classification of Diseases 10)定義陳述 ''此乃一種無能力 延緩足以歡享做愛之射精之病症,其顯現如下:(1 )在 性交之前或之後不久很快地發生射精(如果需要時間限制 :則在性交之前或在性交之1 5秒內);(2 )在缺乏能 先成性交之充分勃起之狀況下發生射精。此問題並非禁慾 時間延長之結果"。 其它已使用之定義包括依下列標準之分類: •與伴侶之性高潮有關 •進入與射精間之間隔時間 •插入次數及自意控制之能力 生理學因素可能涉及早泄,舉凡親密關係問題,焦慮 ,抑鬱,先前之性失敗均佔有一席之地。 經估計之早泄普及率約爲男性人口之2 2 - 3 8 % ; % 不似男性勃起功能障礙,其與年齡並無明確關如採用 3 0 %之平均普及率,則美國經估算有二千四Υ受害者( 1995年18—65歲男性有八千萬),普及率在嚴重 性方面之資料並不多,經估計,早泄之操作定義可應用至 5 — 1 0 %之男性,然而小於0 . 2 %接受治療,口服有 效療法之可利用性極似乎可改變此狀況。 現今以泌尿科醫師爲構成治療早泄之醫篩之主體( 本紙張尺度適用中國國家標準(CNS ) Α4規格(210Χ297公釐) Ί--^--^---裝-- (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -5- 1280132 A7 B7 五、發明説明(3) 5 9 % );普通開業醫師則佔治療此病況之醫師之3 3 % 。性治療師,行爲治療師及輔導者亦可治療早泄病患,專 家估測有5 0 %接受治療者願意治療係因爲病況衝撃到與 伴侶之親密關係所致。壓力,親密關係困難及/或對生活 品質之影響爲受害者尋求早泄治療之主要誘因。 射精需依賴交感及副交感神經系統,傳出神經衝動經 由交感神經系統至輸精管及副睪而產生平滑肌收縮,使精 液移至後尿道。精囊攝護腺及尿道球腺之類似收縮則可增 加精液之體積及流體容量,精液之排出係藉由源自脊髓中 Onuf核之傳出神經衝動所促成,其經過副交感神經系統並 導致球海綿體肌,坐骨海綿體肌及骨盆底肌之節律收縮。 人類有關射精之皮質控制仍有爭論。鼠體中,下視丘之內 側視葉前區及副室核似乎涉及射精。 目前並無經認可可用以治療早泄之藥物,最常見之去 標籤化處方藥爲抗憂鬱劑(例如氯丙咪嗉)及選擇性血淸 素再吸收抑制劑(例如巴龍克亭(paroxetine)及絲特啉( sertraline))。這些藥物因被視爲抗憂鬱劑,故通常不爲 病患所充分接受。彼等爲舊有之、、去標籤化〃藥物,且雖 然當依所需(亦即~ p r η >)使用時,由於具有長藥物 動力T m a X (時間對口服藥物後血漿中之最大藥物濃度) 而有效,但彼等似乎開始作用之時間緩慢。此類藥物當長 期使用時,常可見副作用,行爲療法爲另一種處理方法, 但並非極有效且又具有高度半途而廢,及再發率,故需要 新穎且更有效之療法。 本紙張尺度通用中國國家標準(CNS ) A4規格(210X29*7公釐) ;—--Mr--备---裝-- (請先閱讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 -6 - 1280132 A 7 B7 ___ 五、發明説明(4) 根據第一觀點,本發明係提供使用p D E 5抑制劑以 製造供治療正常勃起功能病患之早泄之藥劑上之用途。 (請先閲讀背面之注意事項再填寫本頁) P D E 5抑制劑乃意指c G Μ P P D Ε 5同功酶之 有效及選擇性抑制劑。 根據本發明,正常勃起功能病患爲彼些可達成足以穿 入陰道之勃起(不需任何藥劑或醫學儀器諸如真空泵)且 可保持勃起直至射精爲止之病患,這些病患之早泄通常爲 原發性早泄。 根據本發明,受早泄所苦但具有正常勃起功能之病患 會因穿後不久及身體想要之前之最小性刺激而經歷持久性 或再發性射精。此外,這些病患之早泄並非情境性或由已 知之器質性原因所續發,這些病患之早泄通常從其第一次 .性經驗開始即存在。 本發明之理想具體實施例中,具有正常勃起功能之病 患爲彼些在勃起功能領域問卷(Erectile Function Domain Questionnaire (參見下文)中獲得2 2分以上(最好大於 25分)之分數者。 經濟部智慧財產局員工消費合作社印製 下文所謂P D E 5抑制劑〃乃意指供本發明使用之 P D E 5抑制劑,此稱謂包括供本發明使用之P D E 5抑 制劑之製藥學上可接受性鹽,溶劑化物及多晶型物。 P D E 5抑制劑之適當性可藉使用文獻方法估測其效 力及選擇性,繼而根據標準製藥學操作估測其毒性,吸收 作用,.藥效動力等而輕易測知。 P D E 5抑制劑所具有之對抗P D E 5酵素之I C 5 〇 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) 1280132 A7 B7 五、發明説明(5) 値最好小於1 0 0毫微米,尤其小於5 〇毫微米。 P D E 5抑制劑之I C 5 〇値可使用下列測試方法文節 中之P D E 5分析法予以測定。 (請先閱讀背面之注意事項再填寫本頁) P D E 5抑制劑最好對P D E 5酵素具有選擇性,彼 等對P D E 5之選擇性最好超過對P D E 3者之1 0 0倍 ,尤其大於3 0 0倍,P D E 5抑制劑對P D E 5之選擇 性尤其超過對PDE 3及PDE4二者之1 0 0倍,更尤 其大於3 0 0倍。 選擇牲之比可由熟知技藝者藉由相關特定酵素之相關 I C 5。値之比而測知,對P D E 3及P D E 4酵素之 I C 5。値可使用已確立之文獻方法測知,參見S A Ballard et al,Journal of Urology, 1 998,vol. 159, pages 2164- 2171 o P D E 5抑制劑所具有之對抗P D E 5之I C 5 Q値乃 小於1 0 0 η M且比對P D E 3之選擇性超過1 0 〇倍。 供本發明使用之P D E 5抑制劑之實例爲: EP— A - 0 4 6 3 7 5 6中所揭示之吡唑並〔4, 經濟部智慧財產局員工消費合作社印製 3 — d〕嘧啶—7 —酮類;EP— A— 0526004 所 揭示之吡唑並〔4,3 - d〕嘧啶一 7 -酮類;已公告之 國際專利申請案W 0 9 3 / 0 6 1 0 4中所揭示之吡唑 並〔4,3 — d〕嘧啶—7 -酮類;已公告之國際專利申 請案W〇 9 3 / 0 7 1 4 9中所揭示之異構性吡唑並〔 3,4 一 d〕嘧啶—4 一酮類;已公告之國際專利申請案 W〇 9 3/1 2 0 9 5中所揭示之喹唑啉—4 —酮類; 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公嫠) " -8- 1280132 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(6) 已公告之國際專利申請案W〇9 4 / 0 5 6 6 1中所揭 示之吡唑並〔3 , 2 - d〕嘧啶—4 —酮類;已公告之國 際專利申請案W0 9 4/0 〇 4 5 3中所揭示之嘌呤一 6 -酮類;已公告之國際專利申請案 W.〇 98 / 49166中所揭示之吡唑並〔4, 3 — d 〕嘧啶- 7 -酮類;已公告之國際專利申請案 WO 99/543 3 3中所揭不之d比d坐並〔4, 3 — d 〕嘧啶—7 —酮類;E P — A. — 〇 9 9 5 7 5 1中所揭示 之吡唑並〔4,3 — d〕嘧啶一 4 一酮類;已公告之國際 專利申請案W〇 〇 〇 / 2 4 7 4 5中所揭示之吡唑並〔 4,3 — d〕嘧啶—7 —酮類; EP— A — 0995750中所揭示之吡哇並〔4,3 — d〕嘧啶一 4 一酮類;已公告之國際專利申請案 WO 9 5/ 1 9 9 7 8中所揭示之化合物;已公告之國 際專利申請案W〇 9 9/244 3 3中所揭示之化合物 及已公告之國際專利申請案WO 9 3/0 7 1 2 4中所 揭示之化合物。 於已公告之國際專利申請案WO 01/27112 中所揭示之吡唑並〔4,3 - d〕嘧啶—7 —酮類;已公 告之國際專利申請案WO 0 1/2 7 1 1 3中所揭示之 吡唑並〔4,3 — d〕嘧啶一 7 —酮類; EP - A — 1 〇 9 2 7 1 8中所揭示之化合物及 E P - A — 1 〇 9 2 7 1 9中所揭示之化合物。 供本發明使用之理想P D E 5抑制劑: 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ;- I -T !裝------訂------0 (請先閱讀背面之注意事項再填寫本頁) -9- Ϊ280132
五、 發明説明(7) 醯) 7 Η ,亦 口定〜 (參 基一 5 —〔2 -乙氧基—5 —(4 —甲基一1 一哌嗪基磺 苯基〕一 1 一甲基—3 —正丙基—1,6 -二氫基一 〜吡唑並〔4 ’ 3 — d〕嘧啶—7 —酮(西得那非) 已知爲1—〔〔3 -(6,7 —二氫基一 1 一甲基— 合氧基一 3 —丙基一 1H —吡唑並〔4,3 — d〕嘧 5 —基)一 4 一乙氧基苯基〕磺醯〕一 4 一甲基哌嗪 見 EP- A- 0463756); 5 - (2 —乙氧基—5 —嗎啉代乙醯苯基)—1—甲 3 —正丙基—1,6 -二氫基一 7H —吡唑並〔4, d〕嘧啶—7 —酮(參見 EP — A — 05 26 004 3 —乙基一5 —〔 5 —( 4 —乙基喊嗦一1 —基礦釀 )一2 —正丙氧基苯基〕一 2 -(D比π定一 2 -基)甲基一 2,6 —二氫基—7H—吡唑並〔4, 3 — d〕嘧啶一 7 一酮(參見 W 〇 98/49166); 3 —乙基一 5 —〔5 -(4 —乙基哌嗪—1 一基礦釀 )一 2 —(2 —甲氧基乙氧基)d比啶一3 —基〕一 2 -( 吡啶一 2 —基)甲基一 2,6 —二氫基—7 Η -吡唑並〔 4,3 - d〕π密u定—7 —嗣(參見 W0 9 9/ 54333); (+ ) - 3 —乙基—5 —〔5— (4 —乙基哌嗪—1 —基擴釀)—2 — (2 —甲氧基—1 (R)—甲基乙氧基 )吡啶—3 -基〕—2 —甲基一 2, 6 —二氫基一7H — 口比口坐並〔4,3 — d〕喃卩定—7 —嗣,亦已知爲3 —乙基 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) Ί--Ί------------IT------ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 -10- 1280132 A7 B7 五、發明説明(8) 一 5 —丨5 —〔4 —乙基哌嗪一 1—基磺醯〕一 2 —(〔 (1R) — 2 —甲氧基一 1—甲基乙基〕氧基)d比啶—3 —基丨一 2 —甲基—2,6—二氫基一 7H —吡唑並〔4 ,3 — d〕嘧啶一 7 —酮(參見w〇 99/54333 ); 5 —〔2 -乙氧基—5 —(4 —乙基哌嗪一 1 一基磺 醯)吡啶一 3 —基〕—3 —乙基—2 —〔2 —甲氧基乙基 〕-2,6 —二氫基—7H — π比 ti坐並〔4,3 - d〕嘧 d定 —7 —酮,亦已知爲1—丨6 —乙氧基一 5 —〔3 —乙基 —6,7 -二氫基一 2 — (2 —甲氧基乙基)—7 —合氧 基—2H -吡唑並〔4,3 — d〕嘧啶—5 —基〕一 3 — 吡啶基磺醯丨- 4 -乙基哌嗪(參見 W 0 01/27113,實例 8); 5 -〔2 -異丁氧基一 5 —(4 一乙基哌嗓一 1—基 磺醯)11比陡—3 —基〕一 3 —乙基—2 — (1 —甲哌d定一 4 —基)一 2,6 -二氫基一 7H—D比哩並〔4,3 — d 〕嘧啶一 7 —酮(參見W〇 01/271 13,實例 15); 5 —〔2 -乙氧基—5— (4 —乙基哌嗪一 1—基磺 醯)π比啶一 3 —基〕一3 —乙基一 2 —苯基一 2, 6 —二 氫基一 7 Η —吡唑並〔4,3 — d〕嘧啶—7 —酮(參見 W 0 01/27113,實例 66) ; 5. —(5 —乙醯一 2 —丙氧基一3 —吡啶基)一 3 — 乙基一 2 -( 1 —異丙基—3 —吖丁啶基)—2,6 -二 ^紙張尺度適用中國國家標準(CNS)A4胁(21GX297公酱) "" -11 - m- am-— laa§ mu ϋϋ^ ml —^ϋ ϋϋ -ϋ (請先閲讀背面之注意事項再填寫本頁) 訂 經濟部智慧財產局員工消費合作社印製 1280132 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(9) 氫基一 7H —吡唑並〔4,3-d〕嘧啶—7 一酮(參見 W 0 0 1/ 2 7112,實例 I24); 5 — (5 —乙醯—2 — 丁氧基一 3 —吡啶基)—3 — 乙基—2 — (1—乙基—3 —吖丁啶基)—2,6 —二氫 基—7H —吡唑並〔4,3 — d〕嘧啶一 7 一酮(參見 W 0 01/27112,實例 132); (6 R , 1 2 a R ) - 2 , 3,6,7,12, 12a —六氫基—2 —甲基—6 一(3,4 —甲二氧基苯 基)—吡嗪並〔2 ' 1^:6,1〕吡啶並〔3,4 — b〕吲哚—1,4 —二酮(I C 一 3 5 1 ),亦即已公告 之國際專利申請案WO 9 5/1 9 9 78之實例78及 9 5化合物,以及實例1,3,7及8化合物; 2 —〔2 —乙氧基_5 —(4 一乙基一哌嗪一 1—基 —1 一礦醯)一苯基〕—5 -甲基一 7 —丙基一 3 Η -咪 唑並〔5,1 — f〕〔 1,2,4〕三嗪—4 —酮(瓦得 那非)亦已知爲1 —〔〔 3 —( 3,4 —二氫基一 5 —甲 基—4 一合氧基—7 —丙基咪哇並〔5,1 — f〕— aS 一二嗦—2~基)一 4 —乙氧基苯基〕礦釀〕一 4 一乙基 哌嗪,亦即已公告之國際專利申請案 W 0 99/2443 3 之實例 20, 19, 337 及 3 3 Θ化合物;及 已公告之國際專利申請案WO 93/071 24之 實例1. 1化合物(E I S A I );及 得自11〇^611&0?,1.%6(1.(:1^111.,2000,43,1 25 7之化合 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ------裝------訂-----# (請先閱讀背面之注意事項再填寫本頁) -12- 1280132 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(1c) 物3及1 4。 其它供本發明使用之P D E 5抑制劑包括:4 -溴基 一 5 —(吡啶基甲胺基)—6 -〔3 -(4 —氯苯基)— 丙氧基〕—3 (2H)噠嗪酮;1 一〔4 一〔(1,3 — 苯並二噚茂一 5 -基甲基)胺基〕一 6 —氯基一 2 -喹唑 啉基〕〜4 一哌啶一羧酸,單鈉鹽;(+ )—順式一 5, 6 a,7,9,9 a -六氮基一 2 -〔4—(二氣甲基) —苯甲基—5 —甲基—環戊—4,5〕咪唑並〔2,1-b〕嘌呤一 4 ( 3 Η )酮;夫洛西林(furazlocillin);順 式—2 —己基—5 —曱基—3,4, 5, 6a, 7,8, 9,9a -八氫基環戊〔4,5〕一咪唑並〔2, 1 - b 〕嘌呤一 4 —酮;3 —乙醯—1 一(2 —氯苄基)—2 — 丙基吲哚一 6 —羧酸鹽;3 -乙醢一 1一(2 -氯苄基) 一 2 —丙基吲哚一 6 -羧酸鹽;4 —溴基—5 -(3 -吡 啶基甲胺2) - 6— (3— (4 -氯苯基)丙氧基)—3 一(2H) -噠嗪酮;1 一甲基一 5 -(5 —嗎啉代乙醯 -2—正丙氧基苯基)—3—正丙基—1, 6—二氫基- 7 Η —吡唑並(4,3 - d )嘧啶—7 —酮;1 一〔 4 — 〔(1,3 -苯並二噚茂—5 —基甲基)一胺基〕一 6 - 氯基—2 -喹唑啉基〕一 4 一哌啶羧酸,單鈉鹽; Pharmaprojects No. 4 5 16 (Glaxo Wellcome); Pharmaproj ect s No. 5 0 5 1 (Bayer); Pharmaprojects No. 5064 (Kyowa Hakko; 參見 WO 96/26940); Pharmaprojects No. 5069 (Schering Plough); GF-196960 (Glaxo Wellcome); E-8010及 E-4010 本紙張尺度逍用中國國家標準(CNS ) Α4規格(210Χ297公釐) :—--Ί--_---裝------訂------ (請先閱讀背面之注意事項再填寫本頁) -13- 1280132 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明説明(11) (Eisai); Bay-3 8-3045 & 3 8-9456 (Bayer)及 Sch-5 1 866。 已公告之專利申請案及期刊文章之內容,尤其是申請 專利範圍中有效醫療化合物之通式及於本文中之例示化合 物均整體倂入本文中以供參考。 供本發明使用之更理想P D E 5抑制劑係由下列中所 擇定= 5 —〔2 —乙氧基—5 -(4 —甲基一 1 一哌嗪基磺 醯)苯基〕—1—甲基—3—正丙基—1,6 —二氫基— 7 Η -吡锉並〔4,3 - d〕嘧啶—7 —酮(西得那非) j (6 R , 1 2 a R ) - 2 , 3,6,7,12, 1 2 a —六氫基—2 —甲基—6 —(3,4 —甲—^氧基苯 基)一吡嗪並〔2 ' 1 / ·· 6,1〕吡啶並〔3,4 — b〕吲哚—1,4 —二酮(I C 一 3 5 1 ); 2 —〔2 —乙氧基—5 — (4 —乙基—哌嗪一1一基 —1—磺醯)—苯基〕一 5 —甲基—7 —丙基一 3H —咪 唑並〔5,1 — f〕〔 1,2,4〕三嗪—4 —酮(瓦得 那非); 5 -〔2 —乙氧基—5 — (4 —乙基哌嗪—1〜基磺 醯)¾啶一3 —基〕一3 —乙基一 2 —〔2 —甲氧基乙基 〕—2,6 -二氫基—7H —吡唑並〔4,3 — d〕嘧啶 —7 —酮;及 5 — (5 —乙酸—2 — 丁氧基—3 attfeE基)—3 — 乙基一 2 — (1—乙基一 3 —吖丁啶基)—2,6 —二氫 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁} -裝 、可 -14 - 1280132 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(θ 基—7 Η —吡唑並〔4,3 — d〕嘧啶一 7 -酮及其製藥 學上可接受性鹽類。 特別理想之P D E 5抑制劑爲5 -〔 2 -乙氧基一 5 一(4 —甲基一 1 一哌嗪基磺醯)苯基〕一 1 一甲基一 3 —正丙基-1,6 -二氫基—7H —吡唑並〔4,3 — d 〕嘧啶一 7 -酮(西得那非)亦已知爲1 一〔〔3 -(6 ,7 -二氫基—1 一甲基一 7 —合氧基—3 —丙基—1H 一吡唑並〔4,3 - d〕嘧啶—5 —基)一 4 一乙氧基苯 基〕磺醯〕- 4 -甲基哌嗪)及其製藥學上可接受性鹽類 。西得那非檸檬酸鹽爲理想之鹽。 口服生物可利用性乃意指可達成系統循環之口服藥物 之比例,決定藥物之口服生物可利用性之因素爲溶解度, 膜滲透性及代謝安定性,通常乃使用首先試管內而後活體 內技術之串連篩檢來決定口服生物可利用性。 溶解度,藥物藉由胃腸道之水性內容物所致之溶解作 用,可由在模擬胃腸道之適當pH下進行之試管內溶解度 實驗而預測。P D E 5抑制劑最好具有5 0微克/毫升之 最小溶解度。溶解度可藉技藝中已知諸如Adv. Drug Deliv. Rev. 23,3-25,1997中所述之標準步驟測知。 膜滲透性意指化合物穿過胃腸道之通行作用。親脂性 爲預測膜滲透性之主要工具且係藉使用有機溶劑及緩衝劑 進行試管內L 〇 g D 7 · 4測量法而定義,P D E 5抑制 劑最好具有-2至+4,尤其一 1至+3之Log D 7 . 4。1 〇 g D可藉技藝中已知諸如J. Pharm. 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) Ί--Ί------^-裝------訂------ (請先閲讀背面之注意事項再填寫本頁) -15- 1280132 A7 B7 五、發明説明(
Pharmacol. 1990, 42: 144中所述之標準步驟測知。 (請先閲讀背面之注意事項再填寫本頁) 細胞單層分析法諸如C a C 〇 2可於射流運輸劑諸如p -糖蛋白之存在下實質增加對理想膜滲透性之預測,即所 謂c a c 〇 — 2流量。P D E 5抑制劑最好具有大於2 X 10— 6cms—丄,尤其大於 5x 1 0 一ecms-1 之 c a c 〇-2流量。c a c 〇-2流量値可藉技藝中已知 諸如J. Pharm. Sci,1990, 79, 5 95- 600中所述之標準步驟測 定。 代謝安定性可顯示胃腸道或肝在吸收過程期間將化合 物代謝之能力:第一通行效應。分析系統諸如微粒體,肝 細胞等可預測代謝之狀況。P D E 5抑制劑於分析系統中 所顯示之代謝安定性最好與小於0 . 5之肝萃取作用相稱 ,分析系統之實例及資料之處理乃述於Curt*. Opin. Drug Disc. Devel',201,4,36-44,Drug Met. Disp·,2000,28, 1 5 1 8- 1 523 中 ° 經濟部智慧財產局員工消費合作社印製 因爲上述各種方法之交互作用而更進一步支持藥物於 人類中之口服生物可利用性可藉由動物之活體內實驗獲得 ,絕對生物可利用性於這些硏究中係藉將化合物個別地或 混合地藉由口服路徑投服而測定。供絕對測定方面(吸收 % ),亦可使用靜脈內路徑,動物之口服生物可利用性之 估測實例可於 Drug Met. Disp.,2001,29,82-87; J. Med Chem,1 997,40,827- 829, Drug Met. Disp., 1999,27, 221-226中尋見。 P D E 5抑制劑可單獨投服,但通常與依所欲投服路 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) " -16- 1280132 A7 B7 五、發明説明( 徑及標準製藥學操作所擇定之適當製藥學賦形劑,稀釋劑 或載體混合投服。 (請先閲讀背面之注意事項再填寫本頁) 例如,P D E 5抑制劑可以片劑,膠囊,多微粒,凝 膠,薄膜,卵劑,酏劑,溶液或懸浮液之形式經口,頰部 或舌下投服,彼等可含有增香或著色劑並供立即一,延緩 一,改良一,持續一,脈動一或控制一釋出之應用, P D E 5抑制劑亦可以快速分散或快速溶解之劑型或以高 能量分散液形式或以包衣微粒之形式投服,適當之配方可 依所期望而爲包衣或未包衣之形式。 此固態製藥學組成物,例如,片劑,可含有賦形劑諸 如微晶纖維素,乳糖,檸檬酸鈉,碳酸鈣,二鹼價磷酸鈣 ,甘胺酸及澱粉(最好爲玉米,馬鈴薯或樹薯澱粉),崩 解劑諸如羥基乙酸澱粉鈉,交聯羧甲基纖維素鈉及一些錯 合矽酸鹽,及粒化結合劑諸如聚乙烯基吡咯酮,羥丙基曱 基纖維素(HPMC),羥丙基纖維素(HPC),蔗糖 ,明膠及金合歡膠,此外,潤滑劑諸如硬脂酸鎂,硬脂酸 ,二十二酸甘油酯及滑石亦可涵蓋。 經濟部智慧財產局員工消費合作社印製 下列配方僅供說明而不欲限制本發明之範圍,有效成 分意指P D E 5抑制劑。 配方1 : 片劑係使用下列成分製備: 將有效成分(5 0毫克)與纖維素(微晶),二氧化 矽,硬脂酸(發煙)混合,再將混合物壓縮以形成片劑。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X29*7公釐) -17- 1280132 A7 B7 五、發明説明( 配方2 : (請先閲讀背面之注意事項再填寫本頁) 靜脈內配方可藉將有效成分(1 〇 〇毫克)與等張鹽 水(1 0 0 0毫升)結合而製得。 .片劑係藉標準方法,例如,直接壓縮法或濕或乾粒化 法製得,片劑核可包上適當之外衣。 類同型式之固態組成物亦可用以作爲明膠或Η P M C 膠囊中之塡料。與此有關之理想賦形劑包括乳糖,澱粉, 纖維素,牛奶糖或高分子量聚乙二醇,供水性懸浮液及/ 或酏劑方面,P D Ε 5抑制劑可與各種不同之甜化或增香 劑,著色物質或染料,與乳化劑及/或懸浮劑及與稀釋劑 諸如水,乙醇,丙二醇及甘油,及其結合物結合。 經濟部智慧財產局員工消費合作社印製 改良釋出及脈動釋出性劑型可含有賦形劑諸如詳述以 供立即釋出性劑型使用者以及可充作釋出速率改良劑之其 它賦形劑,彼等乃包在裝置之上及/或涵蓋在裝置體內, 釋出速率改良劑包括(但不限定於)羥丙基甲基纖維素, 甲基纖維素,羧甲基纖維素鈉,乙基纖維素,乙酸纖維素 ,聚氧化乙烯,黃原膠,羧甲基纖維素,甲基丙烯酸銨共 聚物,氫化箆麻油,巴西棕櫚蠘,石鱲,乙酸酞酸纖維素 ,酞酸羥丙基甲基纖維素,甲基丙烯酸共聚物及其混合物 ,改良釋出及脈動釋出性劑型可含有一種或結合之釋出速 率改良賦形劑釋出速率改良賦形劑可存在於劑型之內,亦 即基質之內,及/或存在於劑型之上,亦即表面或包衣之 上。 本紙張尺度適用中國國家標準(CNsYa4規格(210X297公釐) -18· 1280132 A7 B7 五、發明説明(1硿 (請先閲讀背面之注意事項再填寫本頁) 快速分散或溶解性劑量配方(F D D F s )可含有下 列之成分:阿斯巴甜,合成糖精,檸檬酸,交聯竣甲基纖 維素鈉,交聯聚乙烯基吡咯啶酮,二抗壞血酸,丙烯酸乙 酯,乙基纖維素,明膠,羥丙基甲基纖維素,硬脂酸鎂, 甘露糖醇,甲基丙烯酸甲酯,薄荷香料,聚乙二醇,發煙 矽石,二氧化矽,羥基乙酸澱粉鈉,硬脂醯富馬酸鈉,山 梨糖醇,木糖醇,本文所用之說明FDDFs之分散或溶 解性係依所使用之藥物之溶解度而定,亦即,當藥物不可 溶時,則可製得快速分散性劑型,而當藥物可溶時,則可 製得快速溶解性劑型。 經濟部智慧財產局員工消費合作社印製 PDE5抑制劑亦可非經腸部,例如海綿體內,靜脈 內,動脈內,腹膜內,鞘內,室內,尿道內,胸骨內,顱 .內,肌內或皮下投服,或者彼等可藉輸注或無針注射技術 予以投服,供此非經腸部投服方面,以使用無菌水性溶液 最佳,其可含有其它物質,例如,足量之鹽或葡萄糖以使 溶液與血液成等張狀態,如有需要,水性溶液必需予以適 度緩衝化(最好達3至9之p Η ),適當非經腸部配方於 無菌狀況下之製備可藉由熟知技藝者詳知之標準製藥學技 術輕易達成。 下列劑量値及本文之其它劑量値係供體重範圍約6 5 至7 0公斤之平均人類病患所用,熟練者可輕易決定體重 超出此範圍之外之病患諸如兒童及老人所需之劑量値。 Ρ. D Ε 5抑制劑於此些配方中之劑量乃依其效力而定 ,但預期可在1至5 0 0毫克之範圍內且供每日最高投服 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X297公釐) -19- 1280132 A7 B7 五、發明説明(17) Ξ次,如爲西得那非,則理想劑量爲1 〇至1 〇 〇毫克之 SI內(例如10,25, 5〇及100毫克),其可一 (請先閲讀背面之注意事項再填寫本頁) 曰投服一,二或三次(最好一次)。然而,精確劑量係由 _力醫師決定且係依病患之年齡及體重及症狀之嚴重性而 定。 供經口及非經腸部投服予人類病患方面,P D Ε 5抑 制劑之每日劑量値通常爲5至5 0 0毫克/公斤(單一或 分劑量)。 經濟部智慧財產局員工消費合作社印製 故P D Ε 5抑制劑之片劑或膠囊可含有5毫克至 2 5 0毫克(最好1 〇至1 〇 〇毫克)有效化合物以適度 地供單一或每次二或更多粒地投服,無論如何,醫師可決 定最適合任何個別病患之實際劑量且係依特定病患之年, 齡’體重及反應而變,上述劑量爲平均案例之範例,當然 可依個別狀況而採用更高或更低之劑量且此乃在本發明之 範圍內。熟練者已知,p D Ε 5抑制劑可依所需或期望( 亦即p r η )而採用單一劑量之形式,本文中用以治療之 所有參考資料已知包括急性治療(依所需攝取)及慢性治 療(較長期之連續治療)。
P D Ε 5抑制劑亦可由鼻內或藉吸入法投服且最好以 乾燥粉末吸入劑或氣溶膠噴霧形式由加壓容器,泵,噴霧 器,霧化器或噴灑器中,使用或無需使用適當推進劑,例 如二氯基二氟基甲烷,三氯基氟基甲烷,二氯基四氟基乙 烷,氫氟烷諸如1, 1,1,2 -四氟基乙烷(HFA 13 4 Α〔商標名〕)或 1, 1,1,2,3,3,3 — 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -20- 1280132 A7 _ B7 五、發明説明(1分 (請先閱讀背面之注意事項再填寫本頁) 七氟基丙烷(HFA 2 2 7EA〔商標名〕),二氧化 碳或其它適當氣體而遞送,如爲加壓式氣溶膠,則劑量單 位可藉由提供一個用以遞送計量之量之閥而決定。加壓之 容器,泵,噴霧器,霧化器或噴灑器可含有有效化合物之 溶液或懸浮液,例如使用乙醇及推進劑之混合液以作爲溶 劑,彼可另含有潤滑劑,例如山梨糖醇酐三油酸酯。供用 於吸入器或吹藥器中之膠囊及彈射劑(例如由明膠中製得 )可予調配以含有P D E 5抑制劑與適當粉末藥基諸如乳 糖或澱粉等之泡沬混合物。 氣溶膠或乾燥粉末配方最好加以安排以使每一計量之 劑量或^泡芙〃含有1微克至5 0毫克之P D E 5抑制劑 以供遞送予病患,氣溶膠之整體每日劑量在1微克至50 毫克之範圍內,其可以單一劑量投服,但更常在整日之中 以分劑量形式投服。 經濟部智慧財產局員工消費合作社印製 此外,P D E 5抑制劑可以坐藥或栓劑之形式投服, 或者彼等可以凝膠,水凝膠,洗劑,溶液,乳油,軟膏或 撒佈粉之形式局部塗敷。P D E 5抑制劑亦可由皮膚或經 皮投服,例如藉使用皮膚貼布投服。 供局部塗敷至皮膚方面,PDE5抑制劑可調配成適 當之軟膏形式,其含有有效成分且有效成分乃懸浮或溶於 ,例如,一或更多下列之混合物中:礦油,液態礦脂,白 色凡士林,丙二醇,聚氧化乙烯聚氧化丙烯化合物,乳化 蠛及水,另外,彼等可調配成適當之洗劑或乳油,且係懸 浮或溶於,例如,一或更多下列之混合物中:礦油,山梨 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ~ -21 - 1280132 Α7 Β7 五、發明説明(id (請先閲讀背面之注意事項再填寫本頁) 糖醇酐單硬脂酸酯,聚乙二醇,液態石蠟,縮聚山梨醇油 酸酯6 0,鯨蠘酯鱲,鯨鱲硬脂醇,2 -辛基十二烷醇, 苄醇及水。 P D E 5抑制劑亦可與環糊精結合使用,環糊精已知 可與藥物分子形成包容及非包容錯合物。藥物一環糊精錯 合物之形成可改善藥物分子之溶解度,溶解速率,生物可 利用性及/或安定性質。藥物-環糊精錯合物通常有用以 供大多數劑型及投服路徑所用.,環糊精與藥物直接錯合之 另一作用爲作爲輔助之添加劑,例如作爲載劑,稀釋劑解 劑。α -,/3 -及r 一環糊精最常使用,且適當之實例乃 述於W〇一A — 9 1/1 11 72, W〇一A — 94/02518 及 W〇一A — 98/55 148 中。 對人類而言,經口投服P D E 5抑制劑爲理想之路徑 ,且最爲便利。而在接受者受吞嚥病症或受口服後藥物吸 收減弱所苦之狀況下,藥物可由非經腸部,舌下或頰部投 月δ 〇 經濟部智慧財產局員工消費合作社印製 其它理想路徑爲經由皮膚局部投服,最好局部投服至 男性生殖器。 ’ 本發明之具體實施例中,PDE5抑制劑亦可與一或 更多種供治療具正常勃起功能病患之早泄用之其它有效製 劑結合,有效製劑係由下列列表中所擇定: 1.) 一或更多種天然存在或合成之前列腺素或其酯; 供本文使用之適當前列腺素包括化合物諸如阿波斯塔迪( 石氏張尺度適用中國國家標準( CNS ) Α4規格(210X297公釐) -22- 1280132 A7 B7 五、發明説明(2c) (請先閱讀背面之注意事項再填寫本頁) alprostadil),前列腺素Ει,前列腺素E〇,13,14 一二氫基前列腺素E i,前列腺素E 2,埃皮斯迪諾( eprostinol),天然合成及半合成前列腺素及其衍生物包括 W〇一000338 25及/或2 0 00年3月14曰發 布之US 6, 037, 346中所述者,PGE。, PGEi,PGA!,PGBi,PGFia,19 —羥基 PGAi,19 —羥基—PGBi,PGE2,PGB2, 1 9 —經基—PGA2,1 9 —經基—PGB2, P G E 3 α,卡巴普斯特托米沙林迪諾普斯特(carboprost tromethaminedinoprost),2 - 胺基—2 —經甲基—1, 3 —丙二醇(tromethamine),迪諾普斯同(dinoprostone ),里卜普斯特(lipoprost),幾米普斯特(gemeprost) ,米提諾普斯特(metenoprost),沙普斯登(sulprostune ),提阿普斯特(tiaprost)及馬克西雷特(moxisylate) 等; 經濟部智慧財產局員工消費合作社印製 2 ) —或更多之α -腎上腺素激導性受體拮抗劑(亦 已知爲α-腎上腺素受體阻斷劑,α-受體阻斷劑或α-阻斷劑);適當之α : -腎上腺素激導性受體拮抗劑包括: 酚胺唑啉,哌唑嗪,酚胺唑啉甲磺酸鹽,茶若同( trazodone),阿氟若辛(alfuzosin),吲哚臘明,內夫妥 皮迪(naftopidil),坦素洛辛(tamsulosin),苯氧苄胺, 蘿芙木生物鹼,Recordati 15/2739, SNAP 1 069, SNAP 5089,RS 1 7053, S L 8 9 · 0 5 9 1,達克若辛(doxazosin),特拉若 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇X;297公釐) -23- 1280132 A7 B7 五、發明説明(21) 辛(terazosin)及阿巴諾奎(abanoquil);適當之α 2〜腎 上腺素激導性受體拮抗劑包括地苯那寧(dibenarnine), 托拉佐林(tolazoline ),三甲哌哗嗪,伊法洛克森( efaroxan),育亨賓(yohimbine),伊達若克森(idaz〇xan ),可樂亭(clonidine)及地苯那寧(dibenarnine);適 當 非 選 擇 性 a — 腎 上 腺 素 激 導性 受體 拮抗 劑 包括地皮 普 ( dapiprazole ) 9 其它 a — 腎上 腺素: 激 導 性 受體 拮抗 劑 述 於 1 9 9 8 年 6 月 1 4 曰 公告 之P C T 專 利申 請案 W 〇 9 9 / 3 0 6 9 7 及 美國 專利 : 4 ’ 1 8 8 , 3 9 0 二 4 0 2 6, 8 9 4 3 y 5 1 1 y 8 3 6 4 , 3 1 5, 0 0 7 3 y 5 2 7 , 7 6 1 3 9 9 7, 6 6 6 2 y 5 0 3 0 5 9 9 4 > 7 0 3, 0 6 3 3 y 3 8 1 , 0 0 9 ; 4 2 5 2, 7 2 1 及 2 5 9 9 0 0 0 中 y 每 一者 均倂入本文 中以 供參 考 3 ) * 或 更 多 之血 管 擴 張劑 :供本文用 之適 當血 管 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 張劑包括尼莫狄平(nimodepine),皮那西迪(pinacidil) ,環迪雷特(cyclandelate ),苯氧丙酣胺,氯普馬林( chloroprumazine),氟哌 丁苯,R e C 1 5 / 2 7 3 9 及茶若東(trazodone )。 4)一或更多之麥角生物鹼;適當之麥角生物鹼乃述 於2 0 0 0年3月1 4日發布之美國專利 6,0 3 7,3 4 6中且包括阿西格明(acetergamine ), 布拉果林(brazergoline),布馬格來(bromerguride), 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -24- 1280132 A7 B7 _ 五、發明説明(23 (請先閲讀背面之注意事項再填寫本頁) 西拿果林(cianergoline ),狄洛果查(delorgotrile ),狄 沙拉金(disulergine),順丁烯二酸麥角新鹼,酒石酸麥角 胺,伊替沙拉金(etisulergine),樂果查(lergotrile), 二乙麥角醯胺,米沙拉金(mesulergine),米它果林( metergoline),米它果它明(metergotamine),麥角溴煙 酯,普果來得(pergolide),普西蓋得(propisergide), 普特谷來得(proterguride),特谷來得(terguride); 5 ) —或更多之血管緊張素受體拮抗劑諸如洛沙登( losartan) ; 6 ) —或更多之鈣管道阻斷劑諸如安洛狄平( amlodipine ) ; 7)—或更多之內皮素受體拮抗劑及內皮素轉換酶抑 制劑; 8 ) —或更多之降膽固醇劑諸如斯達丁類(statins )( 例如阿妥凡斯達丁(atorvastatin) /Lipitor —商標)及法 伯瑞特(fibrates ); 經濟部智慧財產局員工消費合作社印製 9 ) 一或更多之乙醯膽鹼酯酶抑制劑諸如多內曰皮( donezipil ); 1 0 ) —或更多之雌激素受體調節劑及/或雌激素激 動劑及/或雌激素拮抗劑,最好爲雷拉克西芬(raloxifene )或拉索法克西芬(lasofoxifene),(—)—順式—6 -苯基—5 -〔4 — (2 -吡咯啶—1—基—乙氧基)一苯 基〕一 5,6,7,8 —四氫萘_2 -醇及其製藥學上可 接受性鹽類,其製法乃詳述於W〇 9 6 / 2 1 6 5 6中 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -25- 1280132 A7 B7 五、發明説明(2^> , 11)一或更多之其它PDE抑制劑,尤其是 P D E 2,7或8抑制劑,最好爲p D E 2抑制劑,上述 抑制劑對抗個別酵素之1 c 5 0値最好小於1 〇 〇 η Μ ; 1 2 ) —或更多之Ν Ρ Υ (神經肽γ )抑制劑,尤其 是N P Y 1或N P Y 5抑制劑,最好爲N ρ γ 1抑制劑, 上述N P Y抑制劑(包括N P Y Y 1及N P Y Y 5 ) 最好具有小於1 〇 〇 n Μ之I C 5 〇値,以小於5 〇 η Μ更 佳;Ν Ρ Υ抑制劑之鑑定分析法乃示於 W ◦- Α — 98/52890 (參見 96 頁,2 至 28 行 )中; 1 3 ) —或更多之血管活性腸蛋白質(ν I ρ ), V I Ρ模擬劑,V I Ρ類似物,尤其是由一或更多之 VIP 受體亞型 VPACL,VPAC 或 PACAP (腦 下垂體腺苷酸環化酶活化肽),一或更多種V I Ρ受體激 動劑或V I Ρ類似物(例如R。一 1 2 5 - 1 5 5 3 )或 V I Ρ片段,一或更多之α -腎上腺素受體拮抗劑與 V I Ρ之結合(例如引文卡布(invicorp ),阿維塔迪( aviptadil ); 1 4 ) 一或更多之黑皮質素受體激動劑或調節劑或黑 皮質素增強劑,諸如黑素登(melanotan II ),Ρ T - 1 4 ,PT— 141 或於w〇一0996400 2, W〇一〇〇〇 74679 , W〇一099 5 5679, WO - 00105401, WO-00058361^ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閲讀背面之注意事項再填寫本頁) 裝· 訂 經濟部智慧財產局員工消費合作社印製 -26- 1280132 Α7 Β7 五、發明説明(2』 WO-00 1 1 4879, WO-00 113112, W〇一 〇 9 9 5 4 3 5 8中所申請專利之化合物; (請先閱讀背面之注意事項再填寫本頁) 1 5 ) —或更多之5 - HT3拮抗劑(最好爲貝塔普來 得(batanopride),格雷尼沙頓(granisetron),歐登沙頓 (ondansetron ),茶皮斯頓(tropistron )或 MDL-73147EF); 1 6 ) —或更多之5 - Η T 4激動劑(最好爲西沙普來 得(cisapride )及D —麥角酸二乙醯胺); 1 7 ) —或更多之睪酮,睪酮替代劑(包括脫氫雄固 烯二酮),睪酮(Tostrelle),二氫睾酮或睪酮植入物; 1 8 ) —或更多之雌二醇,雌激素,雌激素與6 α -甲—1 7 —羥孕酮或6α —甲一 1 7 -羥孕酮乙酸酯( 經濟部智慧財產局員工消費合作社印製 Μ P A )(亦即結合物之形式),或雌激素與甲基睪酮雌 激素替代療法劑(例如H R T尤其是Premarin,Cenestin, Oestrofeminal,Equin,Estrace,Estrofem,Elleste Solo, Estring, Eastraderm TTS, Eastraderm Matrix, Dermestril, Premphase, Preempro,Prempak,Premique, Estratest, Estratest HS, Tibolone); 1 9 ) 一或更多之供正腎上腺素,多巴胺及/或血淸 素用之運送劑之調節劑,諸如丁氨苯丙酮及 G W - 3 2 0 6 5 9 ; 2 0 ) —或更多之嘌呤激導性受體激動劑及/或調節 劑; 一或更多之神經激肽(N K )受體拮抗劑,包括 本紙張尺度適用中國國家標準(CNS ) A4規格(210Χ297公釐) -27- 1280132 A7 B7 五、發明説明( w〇一099 6 4008中所述者; 2 2 ) —或更多之類鵪片受體激動劑,拮抗劑或調節 (請先閱讀背面之注意事項再填寫本頁) 劑; 2 3 ) —或更多之類大麻受體調節劑; 2 4 )伽馬戊烯(gabapentene); 2 5 ) —或更多之血管緊張素轉換酶(AC E )抑制 劑,例如奎那普里(quinapril);及 2 6 ) —或更多之抗抑鬱劑;例如選擇性血淸素再吸 收抑制劑(絲特啉(sertraline),氟克西丁(fluoxetine) ,氟克沙胺(fluvoxamine),巴龍克西丁(paroxetine), 西特洛普南(citalopram),凡拉法克辛(venlafaxine), 經濟部智慧財產局員工消費合作社印製 米它拉平(mirtazapine),尼法若同(nefazodone),茶若 同(trazodone ));三環抗抑鬱劑(T C A,與心血管副 作用有關)克洛米普胺(clomipramine),去醫敏( desipramine),丙咪嗪,阿米替林(amitriptynne),多慮 平(doxepin),阿莫沙平(amoxapine), 馬普替林( maprotiline),諾曲替林(nortriptyline),普曲替林( protriptyline),三甲丙咪嗪,丁胺苯丙酮);及單胺氧化 酶抑制劑苯乙肼,反苯環丙胺。 供與P D E 5抑制劑(最好爲西得那非,凡得那非, I C — 3 5 1,5 —〔 2 —乙氧基—5— (4 —乙基哌嗪 一 1—基磺醯)吡啶—3 —基〕—3 —乙基一 2 —〔2 -甲氧基乙基〕—2,6 — 一氨基—7H — π比n坐並〔4,3 一 d〕嘧啶一 7 —酮及5 —( 5 —乙醯—2 —丁氧基—3 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公羡) '~ -28 - 1280132 A7 B7 五、發明説明(26) (請先閲讀背面之注意事項再填寫本頁) 一吡啶基)—3 —乙基一 2 — ( 1 —乙基—3 —吖丁啶基 )—2,6 -二氫基一 7H —吡唑並〔4,3 - d〕嘧啶 - 7 -酮)結合以供本發明使用之其它環想有效製劑係由 下列列表中所擇定: a ) —或更多之α -腎上腺素激導性拮抗劑(最好爲 哌唑嗪,阿氟若辛(alfuzosin),吲哚臘明,坦素洛辛( tamsulosin),苯氧苄胺,育亨賓(yohimbine),達克若 辛(doxazosin),特拉若辛(terazosin),可樂亭( clonidine) , Recordati 1 5/273 9, SNAP 1069, SNAP 5089 及 RS 17053); b ) —或更多之5 - HT3拮抗劑(最好爲貝塔普來得 (batanopride),格雷尼沙頓(granisetron),歐登沙頓( ondansetron),茶皮斯頓(tropistron)或 MDL — 7 3 147EF); c)一或更多之供正腎上腺素,多巴胺及/或血淸素 用之運送劑之調節劑,諸如丁氨苯丙酮及 GW- 320659;及 經濟部智慧財產局員工消費合作社印製 d )抗抑鬱劑(最好爲絲特啉(semaline),氟克西 丁(fluoxetine),氟克沙胺(fluvoxamine),巴龍克西丁 (paroxetine),西特洛普南(citalopram),凡拉法克辛 (venlafaxine ),克洛米普胺(clomipramine ) ) 〇 供與西得那非結合以供本發明使用之特別理想之其它 有效製劑係由下列列表中所擇定:絲特琳(sertraline ), 氟克西丁(fluoxetine),巴龍克西丁(paroxetine),克洛 本紙張尺度適用中國國家標準(CNS ) A4規格(21〇X29*7公釐) "~ -29- 1280132 A7 B7 五、發明説明(27) 米普胺(clomipramine),歐登沙頓(ondansetron),苯氧 爷胺,阿氟若辛(alfuzosin)及特拉若辛(terazosin) (請先閱讀背面之注意事項再填寫本頁) 供與5 —〔2 —乙氧基一 5 -(4 —乙基哌嗪—1 一 基礦釀)吼卩定一 3 -基〕—3 —乙碁一 2 —〔2 —甲氧基 乙基〕一 2,6 -二氫基—7H -吡唑並〔4,3 - d〕 嘧啶- 7 -酮結合以供本發明使用之特別理想之其它有效 製劑係由下列列表中所擇定:絲特啉(sertraline ),氟克 西丁( fluoxetine ),巴龍克西丁( paroxetine ),克洛米普 胺(clomipramine ),歐登沙頓(ondansetron),苯氧苄胺 ,阿氟若辛(alfuzosin)及特拉若辛(terazsin)。 供與5 -(5 -乙醯一 2 — 丁氧基一 3 -吼B定基)一 3 —乙基一 2 — (1 - 乙基—3 — 11 丫丁 π定基)一2,6 — 二氫基—7 Η —吡唑並〔4,3 — d〕嘧啶—7 —酮結合 以供本發明使用之特別理想之其它有效製劑係由下列列表 中所擇定:絲特啉(sertraline),氟克西丁(fluoxetine) 經濟部智慧財產局員工消費合作社印製 ,巴龍克西丁( paroxetine ),克洛米普胺(clomipramine ),歐登沙頓(ondansetron ),苯氧苄胺,阿氟若辛( alfuzo sin )及特拉若辛(terazsin ) 〇 本文中所提及之所有治療已知乃包括治療性,緩解性 及預防.性治療。 如果投服結合之有效製劑,則彼等可同時地,個別地 或接續投服。 本發明已知可提供下列更進一步觀點之準則,而上文 供第一觀點用所明確指定之具體實施例已知可延伸至這些 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) ―" 30- 1280132 A7 ___ B7 _ 五、發明説明(2硿 觀點中: (請先閲讀背面之注意事項再填寫本頁) i)一種供治療具正常勃起功能病患之早泄之 P D E 5抑制劑; ϋ ) 一種供治療具正常勃起功能病患之早泄之製藥學 組成物,其包含P D Ε 5抑制劑及上文所定義之其它有效 製劑; 迅)使用製藥學組成物以製造供治療具正常勃起功能 病患之早泄之藥劑上之用途,此製藥學組成物包含 P D Ε 5抑制劑及上文所定義之其它有效製劑; iv ) —種供治療具正常勃起功能病患之早泄之套組, 此套組包含:(a )含P D E 5抑制劑之第一種製藥學組 成物;;b)含有上文所定義之其它有效製劑之第二種組 成物;及c )供第一及第二種組成物用之容器; 經濟部智慧財產局員工消費合作社印製 v )使用套組以製造供治療具正常勃起功能病患之早 泄之藥劑上之用途,此套組包含:(a )含P D E 5抑制 劑之第一種製藥學組成物;b )含上文所定義之其它有效 製劑之第二種組成物;及c )供第一及第二種組成物用之 容器; vi ) —種治療具正常勃起功能但受早泄所苦之病患之 方法,其包含使用有效量之P D E 5抑制劑以治療上述病 患; vii ) —種治療具正常勃起功能但受早泄所苦之病患之 方法,.其包括使用含P D E 5抑制劑及上文所定義之其它 有效製劑之製藥學組成物以治療上述病患。 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -31 - 1280132 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明説明(y 下列所進行之硏究係硏究P D E 5抑制劑在治療具正 常勃起功能之病患之早泄上之用途。 硏究係使用西得那非(威而剛,Viagra® )進行,然而 已知硏究亦可以其它P D E 5抑制劑,例如一或更多之上 文所列之理想P D E 5抑制劑來進行。 硏究包含第二相,經安慰劑對照之硏究以估測有早泄 現象但具正常勃起功能之病患(亦即在勃起功能領域問卷 (參見下文)中大於2 2分之病患)在性交之一小時前之 口服西得那非(威而剛,ViagraTM)之效力。 下列之效力變數(終點)乃予使用以估測此硏究。 i )陰道內之射精潛伏時間(I E L T )-此構成主 要之效力變數,將威而剛群之I E L T由基線中之變化與 安慰劑群者相比較。I E L T係使用碼錶測定並由病患經 由曰誌記錄。病患乃記錄每一次性事時之I E L T,並要 求病患收集每一次單一性事期間第一次陰道內穿入之 I E L T資料。此外,日誌亦記錄投藥及相關性交嘗試方 面之資訊,並於當病患攝取硏究之藥物及/或從事性交時 完成。 η )早泄指數(I Ρ Ε ) -此指數記錄病患在其性生 活方面之性問題之結果,此構成硏究之次要效力終點。 iii )性生活品質(男性)問卷(SQoL — Μ) -此 問卷係評估治療前及治療後之性生活品質,此構成硏究之 次要效力終點。 iv )總體效力問題-此問題乃記錄性交期間整體滿意 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) Ί — ^ !.!♦裝------訂·-----# (請先閲讀背面之注意事項再填寫本頁) -32- 1280132 A7 B7 五、發明説明(3d> 程度因治療而改善之程度。此構成硏究之次要效力終讓占。 V )使用陰莖振動刺激而產牛射精之時間--^些病患 經要求記錄使用陰莖振動刺激產生射精之時間,此技術爲 供測量射精潛伏期之可靠方法,陰莖振動器爲市售,例如 ’’FERTICARE®,’ personal” (參見 www. multicept. com/ ferticare. html,multicept A/S,Lyngs 0 Alle 3, 2970 H 応 rsholm,Denmark ) o 勃起功能領域問卷之內容 (請先閲讀背面之注意事項再填寫本頁) -裝· 訂 經濟部智慧財產局員工消費合作社印製 準 標 家 國 -國 -中 用 適 度 尺 張 -紙 本 I釐 公 7 9 2 -33- 1280132 A7 B7 五、發明説明(31) 經濟部智慧財產局員工消費合作社印製 問題 反應之選擇 問題1 :過去4星期內,在 0 =無性活動 性活動期間,能達到勃起之 1 =幾乎沒有/從來沒有 頻率爲何? 2 =很少次(比一半次數少得 多) 問題2 :過去4星期內,當 3 =偶爾(約爲一半次數) 因性刺激而有勃起時,你的 4=大部分(比一半次數多得 勃起硬到足以穿入之頻率爲. 多 何? 5 =幾乎總是/總是 問題3:過去4星期內,當 0 =未試圖性交 你試圖性交時,你能穿入( 1 =幾乎沒有/從未 進入)你伴侶體內之頻率爲 2 =很少次(比一半次數少得 何? 多) 3 =偶爾(約爲一半次數) 問題4 :過去4星期內,在 4=大部分(比一半次數多得 性交期間,當你穿入(進入 多) )你伴侶體內後,能保持勃 5 =幾乎總是/總是 起之頻率爲何? 問題5:過去4星期內,在 0 =未試圖性交 性交期間,你要維持勃起以 1 =極端困難 完成性交之困難度爲何? 2 =非常困難 3 =困難 4 =略爲困難 5 =不困難 問題1 5 :過去4星期內, 1 =極低 你在達到並保持勃起方面, 2 =低 如何評斷你的自信力? 3 =中等 4 =局 5 =極高 (請先閲讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS ) A4規格(210 X 297公釐) _ 34 - 1280132 A7 ___B7 _ 五、發明説明(33 分析 本文所提及之P D E效力價値乃藉由下列分析法測定 (請先閲讀背面之注意事項再填寫本頁) 〇 適於供根據本發明使用之理想P D E化合物爲有效且 具選擇性之P D E 5抑制劑。P D E於試管內抑制環鳥苷 3' -單磷酸鹽(cGMP)及環腺苷3>, -單磷酸鹽(c A Μ P )磷酸二酯酶之效力可藉測量其 I C 5。値(供抑制5 0 %酵素活性所需之化合物濃度)而 得知。 經濟部智慧財產局員工消費合作社印製 所需之PDE酵素可由各種不同之來源,包括人類之 海綿體,人類及兔之血小板,人類之心室,人類之骨骼肌 及牛之視網膜中,實質藉由W.J. Thompson及1]^· Appleman (Biochem·,1971,1〇_, 311)之方法離析出,尤其, cGMP —專一性 PDE (PDE5)及 cGMP —抑制 性c A Μ P P D Ε ( P D Ε 3 )可由人類海綿體組織, 人類血小板或兔血小板中獲得;c G Μ P -刺激性P D E (P D Ε 2 )由人類海線體中獲得;鈣/調鈣素(C a / C A Μ )—依賴性P D E ( P D Ε 1 )由人類心室中獲得 ;cAMP —專一性PDE (PDE4)由人類骨骼肌中 獲得;而光受體P D E ( P D E 6 )則由牛視網膜中獲得 ,磷酸二酯酶7 - 1 1可由已轉染至S F 9細胞中之全長 重組株中產生。 分析可使用 W. J. ThompsonHGDI Ο (Biochem.,1979, !!_,5228 )之、、分批"法之改良法或使用以Amersham pic以 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) - 35- 1280132 A7 B7 —--—--------------- 五、發明説明(3:^ 產物代碼T R K Q 7 0 9 0 / 7 1 0 0所述擬案之改良法 供直接測定A Μ P / G Μ P之閃爍接近分析法來進行,略 言之,P D Ε抑制劑之效應係藉於各種不同抑制劑濃度及 低基質之存在下分析固定量之酵素而硏究出c GMP或 c. A Μ P之未標記對〔3 Η〕—標記之比爲3 : 1,於約 1 / 3 K m下)(如此而使I C 5 Q E K i ),最終分析量則 以分析緩衝液〔2 0 m Μ T r i s - H C 1 ρΗ7·4, 5mM氯化鎂,1毫克/毫升牛血淸白蛋白 〕使成1 0 0微升,反應係以酵素開始進行,於3 0 °C下 保溫30-60分以得<30%基質轉換率,再以50微 升矽酸釔SPA珠粒(含3mM供PDE s 9及1 1用之 個別未標記環核苷酸)令反應終止,而後將盤再密封並搖 動2 0分鐘,其後令珠粒於暗室中安置3 0分鐘,繼而於 TopCount盤判讀器(Packard,Meriden,CT )上計數。將放 射活性單位轉換成估未經抑制之對照組(1 〇 〇 % )之百 分比,對抑制劑濃度繪圖,再使用vvFit Curve〃微軟試算 表而得抑制劑之I C 5 〇値。 (請先閲讀背面之注意事項再填寫本頁) -裝· 訂 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) -36-
Claims (1)
1280132 A8 B8 C8 D8 ….7Π 專, 六、申請專利範圍1 附件2A : 第90 128482號專利申請案 ψ 中文申請專利範圍替換本: 民國95年12月2S曰f-j正 1 · 一種用於治療具正常勃起功能之病患之早泄的藥學組 成物,其包括5-[2-乙氧基-5-(4-甲基-1-哌嗪基磺醯基)苯 基]-1·甲基_3_正丙基- I,6-二氫_7H-吡唑並[4,3-d]嘧啶-7-酮 (西得那非(sildenafil))或其藥學上可接受鹽及藥學上 可接受之賦形劑、稀釋劑或載劑。 2.如申請專利範圍第1項之藥學組成物,其中西得那非 或其藥學上可接受鹽之存在量爲5至500 mg。 3 .如申請專利範圍第2項之藥學組成物,其中西得那非 或其藥學上可接受鹽之存在量爲10至100 mg。 4·如申請專利範圍第1項之藥學組成物,其中該組成物 爲口服組成物。 5 .如申請專利範圍第1至4項中任一項之藥學組成物, 其包括西得那非檸檬酸鹽。 (請先閲讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公嫠)
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GBGB0028245.9A GB0028245D0 (en) | 2000-11-20 | 2000-11-20 | New therapeutic use |
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EP (1) | EP1335730B1 (zh) |
JP (1) | JP2004520279A (zh) |
KR (1) | KR100595807B1 (zh) |
CN (1) | CN1474692A (zh) |
AT (1) | ATE296631T1 (zh) |
AU (2) | AU2002215149B2 (zh) |
BR (1) | BR0115413A (zh) |
CA (1) | CA2429114C (zh) |
DE (1) | DE60111254T2 (zh) |
ES (1) | ES2240537T3 (zh) |
GB (1) | GB0028245D0 (zh) |
HU (1) | HUP0301915A3 (zh) |
IL (1) | IL155521A0 (zh) |
MX (1) | MXPA03003586A (zh) |
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NZ (1) | NZ525167A (zh) |
PL (1) | PL362058A1 (zh) |
PT (1) | PT1335730E (zh) |
TW (1) | TWI280132B (zh) |
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US6403597B1 (en) * | 1997-10-28 | 2002-06-11 | Vivus, Inc. | Administration of phosphodiesterase inhibitors for the treatment of premature ejaculation |
AU2003903597A0 (en) * | 2003-07-11 | 2003-07-24 | Jakov Vaisman | Treatment of premature ejaculation |
AT512084A1 (de) | 2011-10-20 | 2013-05-15 | Univ Wien Tech | Diazabicyclo- und diazaspiro-alkanderivate als phosphodiesterase-5 inhibitoren |
EP3646871A1 (en) * | 2018-10-30 | 2020-05-06 | SEROJAC PME Handels GmbH | Treatment and prevention of premature ejaculation (pe) |
CN111297869A (zh) * | 2020-04-23 | 2020-06-19 | 白文智 | 一种用于治疗早泄和勃起功能障碍的复方制剂 |
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AU1514902A (en) | 2002-05-27 |
NZ525167A (en) | 2005-02-25 |
MY131573A (en) | 2007-08-30 |
IL155521A0 (en) | 2003-11-23 |
JP2004520279A (ja) | 2004-07-08 |
HUP0301915A2 (hu) | 2003-09-29 |
ATE296631T1 (de) | 2005-06-15 |
HUP0301915A3 (en) | 2007-03-28 |
KR100595807B1 (ko) | 2006-07-03 |
BR0115413A (pt) | 2003-10-07 |
GB0028245D0 (en) | 2001-01-03 |
DE60111254D1 (de) | 2005-07-07 |
CN1474692A (zh) | 2004-02-11 |
WO2002040027A1 (en) | 2002-05-23 |
PL362058A1 (en) | 2004-10-18 |
EP1335730B1 (en) | 2005-06-01 |
DE60111254T2 (de) | 2006-05-04 |
ZA200302947B (en) | 2004-04-28 |
CA2429114C (en) | 2007-09-11 |
AU2002215149B2 (en) | 2006-04-06 |
EP1335730A1 (en) | 2003-08-20 |
ES2240537T3 (es) | 2005-10-16 |
KR20030048476A (ko) | 2003-06-19 |
CA2429114A1 (en) | 2002-05-23 |
MXPA03003586A (es) | 2003-07-14 |
PT1335730E (pt) | 2005-09-30 |
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