TWI322689B - Method for treating severe heart failure and medicament therefor - Google Patents
Method for treating severe heart failure and medicament therefor Download PDFInfo
- Publication number
- TWI322689B TWI322689B TW093102582A TW93102582A TWI322689B TW I322689 B TWI322689 B TW I322689B TW 093102582 A TW093102582 A TW 093102582A TW 93102582 A TW93102582 A TW 93102582A TW I322689 B TWI322689 B TW I322689B
- Authority
- TW
- Taiwan
- Prior art keywords
- active ingredient
- heart failure
- pharmaceutically acceptable
- acceptable salt
- contained
- Prior art date
Links
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
- C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
- C07D223/16—Benzazepines; Hydrogenated benzazepines
Landscapes
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- General Health & Medical Sciences (AREA)
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- Heart & Thoracic Surgery (AREA)
- Epidemiology (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
1322689 &、發明說明 [發明所屬之技術領域] 本發明係關於一種以苯并氮雜罩化合物為、、 ** ,舌性成分之 樂劑治療嚴重心衰竭之方法’以及所使用之藥 〜眾劑。詳言之’ 本發明係關於一種治療嚴重心衰竭之方法,白 Φ 包括對有此需 要之病患投予治療上有效量之式⑴之笨并氮化▲ 物: °
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[其中R1為氫原子或鹵素原子;R2為羥基或如式:AW 基團(其中R5及R6可相同或不同且各為氫原子或低碳 基);R3為氫原子、i素原子、低碳院基或低碳院氧基; 為虐素原子、低碳烷基或低碳烷氧基],或其醫藥上可接 之鹽。 本發月it #提供-種用於治療嚴重心衰竭之藥劑 其係以上述苯并氮雜萆化合物⑴為活性成分,以及工述」 开氮雜罩化合物⑴在製備用於治療嚴重心衰竭之藥劑」 之用途。 [先前技術] 315467 6 1322689 已知式(1)之苯并氮雜罩化合物具有血管加壓素拮抗 活性且作為管擴張劑、降血壓劑、利尿劑、血小板凝集 抑制劑等(參見WO 91/05549、美國專利案第5,258,5 1〇號、 美國專利案第5,753,677號、JP-A-6-80641)以及此等化合 物亦可作為催產素拮抗劑(WO 94/01113)、白内障治療劑 (WO 94/18975、美國專利案第5,827,862號)、腦水腫治療 劑(JP-A-8-157368)、梅尼爾氏症(Meniere's disease)治療劑 (JP-A-1 0-1 20592)、或抗潰瘍劑(JP-A-7-1 88021)。 儘管過去2 0年美國在預防及治療心血管疾病上有顯 著的進步’此可由例如冠狀動脈疾病(CAD)之特定年齡死 亡率減少 50%反應出(American Heart Association,Heart and Stoke facts:1996 statistical supplement, page 15),心衰 竭的普遍性仍穩定的增加(Massie BM,Shah NB,The heart failure epidemic, Curr. Opin. Cardiol. 1996, 11:221-226)。 這可能係因為美國人口老化及CAD病患壽命延長之結 果。目前,約5百萬人有慢性充血性心衰竭,且預估每年 會診斷出400,000件心衰竭之新病例(Massie BM, Shah NB, The heart failure epidemic, Curr. Opin. Cardiol. 1996, 1 1:221-226)。以及每年約20%的病患需要住院治療以免病 情惡化(“Cardium”,由 Decision Resources 出版(1998))。 已顯示約50%的心衰竭病患在其診斷後5年内死亡 (Konstam M, Dracut K, Baker D, et al., Heart failure: evaluation and care of patients with left ventricular dysfunction, AHCRP Publication No. 94-0612, Rockville 7 315467 1322689 時性地控制呼吸與血壓以及投予強心藥等拯救生命的措施 以調節與穩定臨床症狀,再者從血液動力學的觀點,宜增 加心臟的輸出,降低血管内的循環體積且增加腎臟的血 流。 由於大多數心衰竭無法以因果療法(causal therapy)治 療’ Ik著時間流逝症狀逐漸變得更嚴重。即使藉由暫時性 症狀治療使心臟的功能暫時性地恢復,但是之後心臟功能 變付更差且無法達到永久癌癒。惡化的速度會隨著各種情 形改變’例如疾病的種類、疾病的嚴重程度、治療效果、 以及生活環境。此外’即使病患復原情況良好,有時病患 會無預料地突然死亡。心衰竭病患具有不良的預後生活。 根據美國弗明漢研究(Framingham Study)之統計包括所有 羅患心臟疾病病患之數據,顯示自發病起約4年之存活率 為 50%(Kannel,WB,et al.,1982, Mckee,PA,et al.,1982)。 此外’於紐約心臟協會分類(New York Heart Association Class)中’罹病嚴重程度為i級之病患,其具有良好預後, 但是嚴重程度為IV級之病患顯示在1年内之存活率僅 5 0%,而嚴重程度為II或in級之病患顯示在4年内之存 活率為50%。因此,經診斷患有嚴重心衰竭之病人具有不 良預後。(參見 Integrated Handbook of Internal Medicine
Volume 30, 1990, Nakayma Shoten) [發明内容] 本發明人致力於尋找治療嚴重心衰竭之方法以及新颖 藥劑。結果發現式(1)之苯并氮雜章化合物可有效治療嚴重 9 315467 心哀蝎’因而完成本發明。 因此,本發明包含下列各種具體實施例。 [1]於第一具體實施例中’本發明提供一種治療嚴重 心衰竭之新穎方法,其包括對有此需要之病患投 予治療有效量之式(1)之笨并氮雜罩化合物,或其 醫藥上可接受之鹽
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[其中R1為氫原子或鹵素原子;R2為羥基或如式:_ NR5R6之基團(其中R5及R6可相同或不同且各為氫原 子或低碳烷基);R3為氫原子、鹵素原子、低碳烷基 或低碳烷氧基;R4為鹵素原子、低碳烷基或低碳烷氧 基]。 [2] 於另一具體實施例,本發明提供根據上述[丨]之治 療嚴重心衰蝎之方法,其中該活性化合物(1)係以 每曰小於0·6 mg/kg之劑量投予。 [3] 於另一具體實施例,本發明提供根據上述[丨]之治 療嚴重心衰蝎之方法,其中該活性化合物(1)係以 每曰0.1 mg/kg至小於〇.6 mg/kg之劑量投予。 10 315467 [4] 於另一具體實施例,本發明提供根據上述[i]之治 療嚴重心衰蝎之方法,其中該活性化合物(1)係= 母曰1 5 mg至45 mg/人之劑量投予。 [5] 於另一具體實施例,本發明提供根據上述[1]之治 療嚴重心衰竭之方法,其中該活性化合物(丨)係=_ 二甲胺基甲基苯甲醯基胺基)苯甲醯 基]-2,3,4,5-四氫_11^-苯并氮雜萆。 [6] 於另一具體實施例,本發明提供根據上述[1]之治 療嚴重心衰竭之方法,其中該活性化合物(丨)係5_ 羥基-7-氣-1·[2-甲基-4-(2-甲基苯甲醯基胺基)苯 甲醜基]-2,3,4,5-四氫-1^1-苯并氮雜罩。 [7] 於另一具體實施例,本發明提供根據上述π]之治 療嚴重心衰竭之方法,其中該嚴重心衰竭係急性 心衰竭或急性惡化之慢性心衰竭。 [8] 於另一具體實施例,本發明提供根據上述[1]之治 療嚴重心衰竭之方法,其中該嚴重心衰竭係紐約 心臟協會分類之III及IV級嚴重心衰竭。 [9] 於另一具體實施例,本發明提供一種治療嚴重心 衰竭之藥劑,其包括以式(1)之苯并氮雜萆化合物 或其醫藥上可接受之鹽為活性成分。 [10] 於另一具體實施例,本發明提供根據上述[9]之藥 劑,其中該活性化合物(1)係5_二甲胺基_1[4_(2· 曱基苯甲醯基胺基)苯甲醯基]-^、四氫」^· 笨并氮雜罩。 315467 11 1322689 [1 1]於另一具體實施例,本發明提供根據上述[9]之藥 劑,其中該活性化合物(1)係5-羥基-7·氣-l-[2-曱 基-4-(2-甲基苯甲醯基胺基)苯曱醯基]-2,3,4,5-四 氫-1H-苯并氮雜罩。 [12] 於另一具體實施例,本發明提供一種適用於治療 嚴重心衰竭之醫藥組成物,其包括以式(1)之笨并 氮雜箪化合物或其醫藥上可接受之鹽為活性成分 並與習知醫藥上可接受之載劑或稀釋劑混合。 [13] 於另一具體實施例,本發明提供根據上述[12]之 醫藥組成物,其中該活性化合物(1)係5 _二甲胺基 -l-[4-(2-甲基苯甲醯基胺基)苯甲醯基]_2,3,4,5_ 四氫-1H-苯并氮雜罩。 [14]於另一具體實施例,本發明提供根據上述[12]之 •^藥組成物,其中該活性化合物(1)係5 _經基_ 7 _ 氣-l-[2-甲基_4-(2-甲基苯甲醯基胺基)苯甲醯 基]-^七:四氫-^-苯并氮雜萆。 [15]於另一具體實施例,本發明提供根據上述[丨2]至 [1 4]中任一項之醫藥組成物,其中該活性化合物 (1)之含置為組成物重量之i至7〇重量〇/〇。 於力一具體實施例,本發明提供 氮雜罩化合物或其醫藥上可接受之鹽之用途, 用途係用於製造適用於治療嚴重心'衰竭之藥劑 [17]於另一具體實施例,本發明提供根據上述[16] 式⑴之苯并氮雜罩化合物或其醫藥上可接受 315467 12 鹽之用途’其中該活性化合物(1)係5 -二曱胺基-1-[4-(2-曱基苯甲醯基胺基)苯甲醯基]_2,3,4,5 -四 氫-1H-苯并氮雜罩。 [1 8]於另一具體實施例,本發明提供根據上述[16]之 式(1)之苯并氮雜罩化合物或其醫藥上可接受之 鹽之用途’其中該活性化合物(1)係5_羥基_7_氯_ 1-[2-甲基-4-(2-甲基苯甲醯基胺基)苯甲醯基]_ 2,3,4,5-四氫— in-苯并氮雜萆。 [1 9]於另一具體實施例,本發明提供根據上述[1 6]至 Π8]中任一項之式(1)之苯并氮雜罩化合物或其醫 藥上可接受之鹽之用途,其中該活性化合物(j) 係以在小於0.6 mg/kg之範圍内之每曰單位劑量 含於藥劑中。 [實施方式] 心哀竭之方法的藥劑包括以上 &或其醫藥上可接受之鹽之至 適用於本發明治療嚴重,< 述式(1)之苯并氮雜萆化合物 —者為活性成分。 於說明書及申請專利範圍中, 列基團。 「鹵素原子 上述式(1)之基團係指下 」係指氟原子、氣原子、
戊基或己基。 、邊原子或職原子。 6個碳原子之直鏈或分枝鏈烷 丁基、第三-丁基、 6個碳原子之直鏈或分 低碳烧氧基」係指具有1至6 315467 13 1322689 枝鏈炫氧基,例如甲氧基、乙氧基、丙氧基、異丙氧基、 丁氧基、第三-丁氧基、戊氧基或己氧基。 此外,於說明書及申請專利範圍中之「嚴重心衰竭」 一詞係指急性心衰竭與急性惡化之慢性心衰竭,例如,被 歸類為紐約心臟協會分類:III及IV級之心衰竭。紐約心 臟協會分類:III及IV級之心衰竭(紐約心臟協會標準委員 會.Diseases of the Heart and Blood Vessels, Nomenclature and Criteria of Diagnosis, 6th ed. P.110, Little, Brown & Co..
Boston (1964))的定義如下:第⑴級:患有心臟疾病之病 患其身體活動顯著地受到限制。該病患於休·息時感到舒 適。少於日常身體活動之活動量會造成疲勞、心悸、呼吸 困難或心絞痛。第IV級:患有心臟疾病之病患進行任何 身體活動均感到不適。甚至於休息時亦會出現心功能不全 或心絞痛症候群之症狀。若從事任何身體活動,則會增加 身體不適。 根據本發明之方法,該活性苯并氮雜罩化合物(丨)之有 效劑里遠低於前案(W0 9 1/05549)所請求之劑量。亦即,例 如使用化合物(1)作為抗潰瘍藥,其一般投予劑量範圍在每 天0.6至5〇 mg/kg,例如每天6〇叫至9〇叫/人但是根據 本發明之研究’發現當化合物之投予劑量在每天〇.丨 至小=〇.6mg/kg之範圍、且較佳為每天15叫至杓㈣人 之劑里、更佳為每天約3Qmg/人之劑i,可有效降低體重 以及增加尿量而無令人不適的副作用,例如頻尿等,且可 改善水腫以及死亡率,以及進_步發現於患有低鈉血症 14 315467 1322689 (hyponatremia)之病患中化合物⑴可增加血清中之鈉濃 度。 展 因此,根據本發明之方法,即使患有嚴重心衰蝎且預 後不良之病患,其預後仍可顯著改善,因此,本發明之方 法適用於治療嚴重心衰竭。 式⑴之笨并氮雜萆化合物及其製法係揭示於w〇 91/05549、美國專利5,258,51〇號及美國專利5, 號’以及日本對應案jP_a_8〇641。 式(I)之苯并氮雜萆化合物可輕易地與醫藥上可接受 之酸形成醫藥上可接受之酸加成鹽。醫藥上可接受之酸包 含無機酸,例如硫酸、氫氣酸、磷酸、氫溴酸等,以及有 ^酸,例如乙酉曼 '對-甲苯績酸、甲確酸、$酸、順丁稀二 酸、反丁稀二酸、蘋果酸、酒石酸、檸檬酸、琥珀酸、苯 甲酸等。 式(I)之笨并氮雜罩化合物中,具有酸性基團之化合物 可輕易地與醫藥上可接受之鹼性化合物形成鹽。鹼性化合 物包含金屬氳氧化物例如氫氧化鈉、氫氧化鉀、氫氧化鋰、 氫氧化鈣等;鹼金屬碳酸鹽或碳酸氫鹽,例如碳酸鉀、碳 酸鈉、碳酸氫鈉、碳酸氫鉀等;以及鹼金屬醇鹽例如甲醇 鈉、T醇鉀等。 本發明之活性化合物(1)係以習知醫藥製劑之形式使 用。該製劑係藉由使用習知稀釋劑或載劑例如填充劑、增 稠:二黏結劑、潤濕劑、崩散劑、界面活性劑、潤滑劑等。 X省藥氣劑可視需要之用途從各種劑型選擇,該代表性之 315467 15 1322689 劑型為鍵:劑、丸劑、粉劑、液劑、懸浮劑、乳劑、粒劑 膠囊、栓劑及注射劑(液劑、懸浮劑等)等。 為了形成錠劑,可使用習知之醫藥載劑例如載體(例如 礼糖、白糖、氣化鈉、葡萄糖、尿素、澱粉、木糖醇、甘 露醇、丁四醇、山梨糖醇、碳酸弼、高嶺土、結晶纖維素、 矽酸等)、黏結劑(例如水、乙醇、丙醇、單糖漿、葡萄糖 溶液、澱粉溶液、明膠溶液、羧甲基纖維素、蟲膠、甲基 纖維素、磷酸鉀、聚乙烯吡咯烷酮等)、崩散劑(例如乾二 卷藻酸鈉、填脂粉、褐藻殿粉(laminar叫粉末、碳酸氣 鈉、碳酸舞、聚氧化乙稀山梨醇針脂肪酸醋、硫酸月桂酉匕 =、硬脂酸單甘油醋、殿粉、乳糖等)、崩解抑制劑(例如曰 糖,硬脂酸甘油、可可油脂、氫化油等)、吸收
如四級銨鹽、硫酸月姑西匕細楚、 a v J 瓜酸月桂酉曰鈉專)、潤濕劑(例如甘油、澱粉 、吸附劑(例如澱粉、乳糖、高嶺土、膨潤土、膠體矽 夂鹽等)、潤滑劑(例如經純典 ^ _ 、,化之μ石、硬脂酸鹽、硼酸粉、 =二醇請。再者,鍵劑亦可為習知之加鍵衣鍵: 明膠衣鍵劑、腸衣錠劑、膜衣錠劑、 層或夕層錠劑。製備丸劑時, 載體(例如葡萄糖、乳糖、奸:'知載劑’包含例如, 高嶺土、、骨石… 可可油脂、氫化植物油、 明踢、乙醇等)、例如阿拉㈣粉、西黃蓍膠粉、 拾劍時,可使用習朋例如褐藻激粉、環脂等)等。製備 脂、高二= 藉由習知方法將本❹化半合成甘油脂等。膠囊可 0物/、上述载劑之混合物填充至 315467 16 硬明膠膠囊、齡挪& ^ 囊)予以製備/ 基甲基纖維素膠囊⑽初膠 製備注射劑時,該溶液、乳液以及縣、、^ 、里過減菌且較佳兵制 y年液係 佳為製備成與血液等滲透壓。製備 液、乳液以及縣$/ I備此4溶 醇…子液時,係使用習知之稀釋劑例如水、乙 之4 =、,二醇、乙氧基化之異十八醇、多經基化 該醫举製劑方::乙烯山梨醇酐脂肪酸醋等。此案例中, 使該醫化鈉、葡萄糖、或甘油,俾 、有專滲透壓,以及亦可納入習知之容— J、緩衝劑或麻醉劑。再者, 女疋 可納入基含才丨 右而要该醤樂製劑視需要 劑。 防腐劑、香料、調味劑、甜味劑及其他藥 本發明醫藥組成物中活性化合 限定,其可由廣範圍中選取,作p丄二並無特別 E ^ 下^取,但通常為組成物之重量之τ 至㈣重量,以5至50%重量為較佳。 $合投予本發明藥劑之方法可依各種製劑之形式、病 之年齡、性別以及其他條件、疾病的嚴重程度等而決定。 例如’錠劑、丸劑、玄该 液^、懸浮液劑、乳劑、粒劑以及 膠囊可經口投予。注射劑 町則了早獨經由靜脈投予或與習知之 辅助液一起投予(例如结贫& 甸萄糖、胺基酸溶液),以及若需 可由肌肉内、皮内、虔下.^ 某要 皮下、或腹膜内之途徑單獨投予。栓 劑係經由直腸内途徑投予。 本發明活性化合物之劑量可依據用途、病患之年齡、 ί生別以及其他條件、疾病的嚴重程度等而予以選擇,但通 常為每曰小於〇.6mg/kg之範園,較佳係每曰自0.lmg/kg 315467 17 ^22689 至小於0.6 mg/kg之範圍。適合的劑量為每曰I〗mg至45 mg/人。 (實施例) 本發明經由下列製備例及實驗例予以更詳盡之說明, 但是不應以該等製備例及實驗例限制本發明。 3·二曱基胺基-1-[4-(2-甲基苯甲醯基胺基)苯甲醯基]_150g ^3,4,5·四氫-1H-苯并氮雜萆 ^維素(Avicel,商品名,由 Asahi Chemical Industry,40g C〇.,Ltd.,Japan 製造) 玉米澱粉 3()
硬脂酸鎂 2S 羥丙基甲基纖維素 ^ 聚乙二醇-600 g 笔麻油 Aig 乙醇 4Qg 40g 將本發明活性化合物、艾維素、玉米澱粉以及硬脂酸 鎮混合且捏合,以及使用習知衝壓機(R 1〇mm)將混合物製 成錠劑並加糖衣。將所得之錠劑以膜衣形成劑塗覆而得加 膜衣之錠劑’該膜衣形成係由羥丙基曱基纖維素、聚乙一 醇-6 0 0、蓖麻油以及乙醇所組成。 製備例2 甲 苯 \ly 基 胺 基 醯 g g g g g g 0 5 0 0 0 0 1 3 0 0 5 5 3 7 3 1 1 5 -經基-7-氣-[2-甲基- 4-(2-甲基苯甲 醯基]·2,3,4,5-四氫-1H-笨并氮雜罩 檸檬酸 乳糖 填酸二鈣 普隆尼 F_68 (Pullonic F-68) 硫酸月桂酯鈉 聚乙烯吡咯烷酮 315467 1322689
聚乙二醇(Carbowax 1 500) 4.5S 聚乙二醇(Carbowax 6000) 45.〇羟 玉米澱粉 30g 乾硫酸月桂醋鈉 ;3 > 〇 β 乾硬脂酸鎂 y〇g 乙醇 適量 將本發明活性化合物、檸檬酸、乳糖、嶙酸二的、普 隆尼F-68以及月桂醇硫酸鈉混合。 該混合物以N 〇. 8之過濾器篩選且以含有聚乙稀吼咯 院酮、Carbowax 1500及Carbowax 6000之醇溶液進行造 粒。若需要’將醇加至其中使粉末混合物變成糊狀物質。 於品&物中加入玉米殿粉且持續混合該混合物俾形成單〆 顆粒。將所得之顆粒通過No. 1 0之過濾器然後置入托盤以 loot乾燥至14小時。該乾燥的顆粒以n〇.16之過濾器 筛選’之後加入乾硫酸月桂酯鈉與乾硬脂酸鎂,以及將混 合物打錠成所需之形狀。 將所製得之核錠(core tablet)加工修整並於其上撒滑 石粉,以防潮濕。對該錠劑施加底塗層。為了使錠劑可以 口服,將該核錠加工修整數次。為了獲得圓形且平滑表面 之錠劑,進一步以潤滑劑底塗及塗覆該核錠。將此錠劑進 :步以著色塗覆物質塗覆,直到獲得所欲之著色錠劑。乾 燥後,將經塗覆錠劑磨光,獲得具有均勻光澤之期望錠^ 製備例' 醯基胺基)苯曱 氣·[2'甲基-4·(2_甲基苯甲 5g 0 · 3 g 〇.9g 〇.4g 职7 _213,4,5-四氫_1Η苯并氮雜罩 ^ 士 —醇(分子量:4000) 氯化鈉 聚氧化乙烯山梨醇肝單油酸醋 315467 19 1322689 0. lg O.lBg 〇.〇2g 10.0ml 偏亞硫酸氫 。將所得溶 二醇與聚氧 偏亞硫酸氫鈉 對羥基苯甲酸甲酯(Methyl paraben) 對羥基笨甲酸丙酯(propyl paraben) 注射用蒸餾水 於80°C下’將前述之對羥基苯甲酸酯類、 納及氯化鈉揽拌溶解於約一半體積之蒸館水中 液冷卻至40°C後,將本發明之活性成分及聚乙 化乙烯山梨醇酐單油酸酯溶解於前述溶液。將注射用蒸餾 水加至此溶液中,以調整至所欲之體積,且以合適之濾紙 過濾使溶液無菌化而製得注射製劑。 試驗 (1)方法: 以劑量30、60或90mg/day之5-羥基_7_氯_[2甲 基-4-(2-曱基笨曱醯基胺基)苯甲醯基]_2,3,4,5_四氫_ 1H-苯并氮雜罩對嚴重心衰竭病患(例如,病患為急性 心衰竭或為急性惡化之慢性心衰竭,相當於紐約心臟 協會分類:III及IV級)投予60天期間,該期間從住 院開始,直至出院後(其詳細說明示於表i)。 (2)結果: 結果不於表2至7。 如統計分析所示,於表2之數據以AN〇va方法 分析,表3及4之數據以ANC〇VA法分析,而表5之 數據以Log-Rank測試分析。 當本試驗中劑量轉化為每公斤體重之每日劑量時 在 30mg 治療組為 〇.37l±〇.〇96mg/kg(n=77),在 6〇mg 315467 20 治療組為0.769土0.205mg/kg(n = 83),在9〇mg治療組為 1.149土0.283 mg/kg (n = 76)(所有表示為平均值±標準 差)。 如結果所示,在30mg治療組’總尿量(t〇ui urine output)增加(表2) ’且體重減少(表3)。此外,基礎值 屬低血鈉(hyP〇natremia)之病患(具有低於正常血清鈉 濃度(低於136mEq/L)之病患)顯示血清鈉濃度增加(表 4) 〇 在相同試驗中,若將由醫療開始至死亡發生之天 數列入分析考慮,則由住院期間至門診醫療結束之整 個期間之死亡率(mortality rate),30mg治療組顯然比 對照組低(Log-Rank測試)(表5)。 此外’在用敢低劑量(3Omg)之治療組中,與其他 較商劑量治療組相較,為副作用之頻尿發生率較低(表 )且由於虽丨作用而停樂之比率(discontinued rate)較 低(表7)。從該結果明顯可知本發明化合物之每曰每 公斤體重之劑量控制在低於0.6mg時對嚴重心衰竭具 有優異的治療效果。 21 315467 1322689 表 產品名稱 經基-7-笨甲醯基1 研究計劃 气I2/基-4_(2-甲基笨甲醯基胺基) 氫-ΙΗ-苯并氮雜堇 jRk)進行多中心、雙盲 照,研究,並评估(A)對於惡化 臨床階段 目標 研究設計 患者期效果 充 U7i_ 併用最適之現有 疋)下,給予急性住院病人至多1 0天 。 究用藥物’出院後繼續給藥7週,葬= i估(A)之三劑量或安慰劑之藥效。9匕 •1中心、隨機、雙盲、以安慰齊 各組以相同方式進行。 …、 *此研究係由篩選日、至多1 〇天住院 間及後續7週門診期間所組成。病£ = 門診第1、3、5、及7週回診並進行門診 評估。 •在給予研究用藥物之最後一劑後,以 電話聯絡追蹤7天。 .約8 0個病患,分為四組,每組隨機接 受下列製劑,每日一次,至多接受59日: 1)安慰劑,2)30mg(A),3)6〇mg(A), 4)90mg(A) •所有病患皆持續接受傳統治療,其可 包含利尿劑、異羥基洋地黃毒脊 (digoxin)、ACE抑制劑、肼笨嚷嗪 ——- ____ (hydralazine)、硝’酸醋類、β 阻斷劑 對象族群 ·病患因惡化之心衰竭住院 • ΝΥΗΑ 之 III 及 IV 級 •男性及女性 -~~^ _•足 18 歲者___ 測試產品、劑.(A)30mg、60mg、90mg或安慰劑之口 模式 服錠劑 終點 ^ -- 22 315467 1322689 生院第一期:用藥後24小時體重改變 隹J志第二期:NYHA分類,呼吸困難(dySpnea),直立呼吸 困難(orthopnea),出院時體重,水腫,頸靜脈膨脹(jUgUlar ,nous distention) ’肺囉音(raies),肝臟腫大,排尿量, =1^IΪ質,住院長短,利尿劑使用,病患及醫師評 第—期:心衰竭之惡化以下列任一者定義:1 ·住院.
堂相至急診室、門診室或觀察室之非 二it杉,,t觀察對於心衰竭是否需要增加治療或給予^ g g療,。分析因心衰竭惡化而退出之比率及ΪI 腫rHi:is難水? 重’頸靜脈膨脹,肺 清電解Πϊί5ϊ之ίΚ;困•,排尿量,血 反應’生命徵象,臨床實驗宮消丨对, 原$㈡與活化部分凝血活酶時間試驗 τ° $ , t血漿中(A)及代澧、)及身體k查 315467 23 1322689 茚游t Λ烊S体钋泠荈激扭41烊m= **: ΌΛΟ.01, *Η όλο·05,»^^#1~^^避啉 卡苏南±麴嘀啉 \c σ» Oi to Μ > 1989.17 士 386.14 (6) 1941.67 ± 1349.94 (12) 1896.36 ± 1054.42 (22) 1164.27 ± 1003.99 (4B) 2317.20 ± 1168.09 (61) 2296.46 ± 1134.13 (76) 安慰劑 2908.00 ± 475.59 (5) 2662.81 ± 1507.51 (16) 3146.67 ± 1618.09 (33) 3579.04 ± 1867.86** (52) 3905.61 ± 1942.03** (67) 4056.16 ± 2310.23** (73) U) ο 曰 3753.18 ± 2415.48 (U) 4230.00 3684.56 ω 办 Μ Ο • Μ U) σ\ VD νο • Ν3 σ\ 4175.15 σ\ ο 3 ια ±1691.43* (17) ω η- N) 一 N> -si N> • Ln ± 1902.77** (54) ±2094.02** (74) ±2695.44** (82) 2421.43 ± 1391.12 (7) 3915.12 ± 2101.53 (17) 办 M 00 00 • N> u> 4069.32 U) νο σι Μ • U) 4127.27 ±2275.15** (30) ±2306.07** (50) ±2129.11** (64) ±2050.81** (73) 90 mg 洳2· α(Α)硌海>
24 315467 1322689 抹薄-δ·^烊m>升呤钨澈.伊~烊ΠΒ。i: p<o.or*: PA0.05、躱唞锪驷猫啉 卡茗碎±雜唯啉 最後求診 第7週 第1週 出院 第3天 第2天 第1天 s Λ Λ Λ r!> Λ i 0J ^ Μ 00 Η* .24 ± 5. (59) GO 一 Ο σ\ ω Η- CJt —«► 〇\ ct> H-U) 办 οι Η- ro •45 ± 2· (57) α> 一 -Ο 00 1+ H* 安慰劑 -J Οι u> H* 办 eo CJ1 Νί U> ϋι 1 Νί • ^ Κ> σ\ Η- cn • t>> 1 ro • Η* <·"· Ν3 Ut d> Η- 〇ι • κ» <Λ 1 to • «•J Η* σ\ ϋι Η-• KD U) -4.37 ± 4.69** (76) 1 « 09 Λ Η-\〇 w办 • Μ ♦ * 身 Ca> • U) σί 1+ U) 一 U) • CD 〇 4- -2.14 ± 2.63** (76) 30 mg 1 ω • σ\ CO ro Η-、一 σ\ • ω G9 1 ro • ⑦ 一 cn 办Η· 、一 σν • -2.73 ± 5.45 (59) -4.60 ± 4.67** (82) -3.93 ± 3.33* (47) 1 U) 〇 0J m H-、一 ro 00 -2.10 ± 1.80** (76) <Ti o 3 幻 1 Ν3 « LJ ^ VO -4 σ\ η* ϋι • Μ Ο I Ν> • ro ^ to cn ω Η-ϋι 參 Ι-» VD 1 U) • Ν) 一 U> Ul U η* • σ\ -3.75 ± 4.18 (76) 1 to 争 m —ϋΐ 办 ϋΐ »+ « Μ ro 1 N> • α> 办 σ\ Η- Ι-» 一 Ο) • Μ σ\ 冷 秦 -1.90 ± 2.87** (74) ίο o 3 沐3·5ί(Α)>.&架妗激扭~商»靼:&趣碎*涔卜卡忽淹0=
25 315467 1322689 茚终t β烊邻冷挥澈祙^一烊™· **: ΡΛ0.01, *: ΌΑΟ-OW' 卡苏碎±銥书.t 最後求诊 第7週 第1週 出院 第3天 第2天 第1天 基線 S 133 134 Η1 U> ω 133 Μ OJ Η» Ui Cn Μ OJ 132 • 88 ± (16) σ\ ·*ϋ VD 一 1+ .77 土 (13) tn 00 \〇 —K· • 45 土 (ID .75 ± (16) .81 ± (16) 安慰劑 Cn (J1 u> cn N> Η1 CJ1 CJ1 to Di 1-^ s CO U> 137.00 ± (15) 137.60 ± (10) 138.25 ± (12) 136.13 ± (15) (a) cn • 一 U) 00 —H- 135.09 ± (11) 136.00 士 (15) 132.13 士 (15) OJ ο 9 Ln • ο • <r> Ln 4.22* • a\ M (Ji _ CJ GO cn » o U) * VO σ% U) • 136.18 ± 5.94 (22) 139.36 ± 4.76* (11) 136.88 ± 5.82* (16) 137.18 ± 4.56* (22) 138.62 ± 4.44 (13) 137.29 ± 3.02 (17) 135.77 ± 6.16 (22) 130.86 ± 4.00 (22) 60 mg 136. 138. 136. 137. 136. 137. 137. 133. 60 士 (15) o C\ 一 H· 一 U> α> 一 Η" 13 土 (15) 45 士 (11) 00 土 (15) 13 士 (15) 07 土 (15) VO 0 1 Ln cn u> U) 办 r〇 Μ ω cn s ΟΙ VO s GO tvj cn K> ^4. α(Α)ίο>溆澄鉍綷
26 315467 1322689 表5.— 以(A)治療之病患之死亡率 90mg(77) 飞 2.5% 0.1460— IZ33 ~^g~fT(8Q) l〇mg(2Br~~6~〇mg(8~4) 死亡人數 7 3 8 ^ 8.7% -- 3.8%___9.5% 〇Τ〇326"""" """〇 "78 62 括號中之數目表示各組隨機選取之病患之數目 “至死亡之時間(接受治療者),,之分析係以Log-Rank測試進 行0 表6. f (A)治療之病患中所觀察到之不良反應 (79) T〇^ng(78)60mg784)~~90mg(76「 頻尿 1 1 3 4 % ± ^(%) 1.3%_K3%_3.6%_^30/0 括號中之數目表示各組隨機選取之病患之數目。 表7·以(A)治療之病患中因不良反應而停藥之案例 安慰劑(80)~30mg(78)~~60018(84) 90mpr77) 發生不人數 12 14 ~~25 -Ϊ7- !生色以I_15.0% 17.9% —29.8% 22.1% 括號中之數目表示各組隨機選取之病患之數目。 (產業上可利用性) 本發明之治療嚴重心臟病之方法在治療嚴重心衰竭 (亦即急性心衰竭及急性惡化之慢性心衰竭)上十分有用。 此外,本發明之方法因副作用少,安全性優異。因此,本 發明提供藉由對病患投予苯并氮雜罩化合物(1)或其醫藥 上可接受之鹽而治療嚴重心衰竭之方法,含有該笨/并氮雜 罩化合物(1)或其醫藥上可接受之鹽之醫藥組成物,以及該 活性成分在製造適於治療嚴重心衰竭之藥劑上之用途 315467 27
Claims (1)
- 第93102582號專利申請案 (99年1月29日) **、申請專利範圍: 種治療紐約心臟協會分類中IV級嚴重心衰竭之藥 劍’其包括作為活性成分之5-羥基-7-氣-1-[2-甲基-4-(2~曱基笨甲醯基胺基)苯甲醯基]-2,3,4,5-四氫-1H-苯并 氮雜萆或其醫藥上可接受之鹽。 2 ’如申請專利範圍第1項之藥劑,其中,該活性成分或其 樂上了接受之鹽係以在小於0.6^g/kg之範圍之每曰 單位劑量含於藥劑中。 3 t •如申請專利範圍第丨項之藥劑,其中,該活性成分或其 -樂上了接受之鹽係以在〇. 1 mg/kg到小於0·6mg/kg之 範圍之每日單位劑量含於藥劑中。 4’如申請專利範圍第1項之藥劑,其中,該活性成分或其 邊藥上可接受之鹽係以在15mg/個體至45mg/個體之範 圍之每日單位劑量含於藥劑中。 5 · 種適用於治療紐約心臟協會分類中iv級嚴重心衰蝎 之醫藥組成物,其包括作為活性成分之5_羥基_7_氯-^ [2-甲基-4-(2-甲基笨甲醯基胺基)笨曱醯基]_2,3,4,5_四 氣-1H-苯并氮雜萆或其醫藥上可接受之鹽。 6. 如申請專利範圍第5項之醫藥組成物,其中,該活性成 分或其醫藥上可接受之鹽之含量為該組成物重量之1 至7 0重量%。 7. 如申請專利範圍第5項之醫藥組成物,其中,該活性成 分或其醫藥上可接受之鹽係以在小於0.6mg/kg之範圍 之每曰單位劑量含於組成物中。 28 315467修正本 1322689 第93102582號專利申請案 (99年1月29日) 8. 如申請專利範圍第5項之醫藥組成物,其中,該活性成 分或其醫藥上可接受之鹽係以在〇. 1 mg/kg到小於 0.6mg/kg之範圍之每曰單位劑量含於組成物中。 9. 如申請專利範圍第5項之醫藥組成物,其中,該活性成 分或其醫藥上可接受之鹽係以每曰15至45mg/個體之 範圍之每曰單位劑量含於組成物中。 10. —種作為活性成分之5-羥基-7-氯-l-[2-甲基-4-(2-甲基 苯甲醯基胺基)苯甲醯基]-2,3,4,5-四氫-111-苯并氮雜罩 或其醫藥上可接受之鹽之用途,係用於製造適用於治療 紐約心臟協會分類中IV級嚴重心衰竭之藥劑。 11. 如申請專利範圍第1 〇項之用途,其中,該活性成分或 其醫藥上可接受之鹽係以在小於0.6 mg/kg之範圍内之 每曰劑量單位含於藥劑中。 12. 如申請專利範圍第10項之用途,其中,該活性成分或 其醫藥上可接受之鹽係以在0.1 mg/kg至小於0.6mg/kg 之範圍之每日單位劑量含於藥劑中。 13. 如申請專利範圍第10項之用途,其中,該活性成分或 其醫藥上可接受之鹽係以在15mg/個體至45mg/個體之 範圍之每曰單位劑量含於藥劑中。 29 315467修正本
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