TWI285550B - s for combating menopausal hot flushes Use of CGRP antagonists and CGRP release inhibitor - Google Patents
s for combating menopausal hot flushes Use of CGRP antagonists and CGRP release inhibitor Download PDFInfo
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- TWI285550B TWI285550B TW089115923A TW89115923A TWI285550B TW I285550 B TWI285550 B TW I285550B TW 089115923 A TW089115923 A TW 089115923A TW 89115923 A TW89115923 A TW 89115923A TW I285550 B TWI285550 B TW I285550B
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- dihydro
- dibromo
- carbonyl
- amino
- hexahydro
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Classifications
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- A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
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Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Reproductive Health (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
- Plural Heterocyclic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
Description
1285550 A7 — ___Β7 五、發明說明(1 ) 熱潮紅爲絕經時期/絕經後徵候簇之一種常見病徵,其 生理學仍然不完全明瞭。激素替補療法爲一種複雜干涉, 且由於其副作用,故經常不能夠長期使用,除了該療法之 外’直到目前爲止,對於此種通常不易處理之症狀,仍然 沒有大致上無副作用之簡易療法。 熱潮紅係因血管擴張及增加之血液流量所造成。許多刊 物已指出CGRP (降血鈣素基因有關聯之肽)在絕經熱潮紅發 生上,扮演一項角色之可能性,其係在雌激素缺乏之婦女 中’由於此神經肽之血管擴張性質所致([i] : j End〇crin〇1 (1995), 146 (3), 431-437 ; [2] : Acta Physiol. Scand. (1998), 162 (4), 517- 522 ; [3] : M· J· 〇bstet· Gynecol: (1996),175 (3, Pt. 1),638-642)。 CGRP拮抗劑對於治療絕經期徵候誤之治療用途,在先前未 曾於文獻上提出。 目前已發現,藉由會拮抗CGRP作用之物質(CGRP拮抗劑) ’或抑制或減少CGRP自感覺神經末梢釋出之物質(CGRp釋 出抑制劑)’則絕經熱潮紅之病徵,可有效地被防止,或 其痛苦作用實質上被減輕,此治療途徑係優於激素替補療 法’特別是由於其缺乏副作用。 本發明因此係關於CGRP拮抗劑及/或CGRP釋出抑制劑 對抗絕經熱潮紅之用途,包括防止與急性治療。根據本發 明 < 用途,較佳係包括使用單一物質之單一療法,但亦包 括合併療法,使用得自特定活性物質族群之多種物質。再 者’根據本發明之治療可另外以習用激素替補療法進行。 本發明亦關於CGRP拮抗劑及/或CGRP釋出抑制劑於製 (請先閱讀背面之注意事項再填寫本頁) ^------------_---β— 經濟部智慧財產局員工消費合作社印製
本紙張尺度翻規格⑵〇 χ撕公髮) 1285550
經濟部智慧財產局員工消費合作社印製 五、發明說明(2 ) 備醫藥組合物以治療絕經熱潮紅之用途,以及含有一或多 種CGRP括抗劑及/或CGRP釋出抑制劑作爲活性物質之相 應醫樂組合物。 會枯抗已知CGRP作用或抑制CGRP自感覺神經末梢釋出 之任何藥學上可接受之活性物質,均可供本發明之目的使 用。 CGRP拮抗劑之實例,包括描述於W0 98/11128或DE 19911039中之胺基酸衍生物,以及描述於w〇 98/56779、 WO 98/09630及WO 97/09046中之非肽活性物質。 CGRP釋出抑制劑之實例,包括5-羥色胺5-HTid_催動劑, 譬如阿維催坦(avitriptan)、也理催坦(detriptan)、那拉催坦 (naratriptan)、利雜催坦(rizatriptan)、沙馬催坦(sumatriptan)或坐 米催坦(zolmitriptan),以及5-ΗΊ^ F •催動劑或NPY-催動劑。 描述於WO 98/11128中之CGRP拮抗劑,其中例如下列化合 物,可用於治療絕經熱潮紅,用於製備相應醫藥組合物, 及作爲相應醫藥組合物之成份: (A) l-[N2-[3,5-二溴-Ν-[[4·(3,4-二氫-2(1H>酮基喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-酪胺醯基]-L-離胺醯基]-4-(4-吡啶基)-六 氫吡畊, (B) 1-[4_胺基·3,5_二溴-仏[[4_(2,3,4,5_四氫-2(1印-酮基-1,3-苯幷 二氮七圜-3-基)-1-六氫吡啶基]羰基]-D-苯基-丙胺醯基]-4-(1-六 氫叶b咬基)-六氫ρ比淀, - (C) 1-[Ν2-[4·胺基-3,5-二溴-Ν-[[4-(3Λ二氫-2(1H)-酮基喹唑啉· 3-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-L-離胺醯基]-4-(4-吡 紙&尺度適用中國國家標準(CNS)A4規格(210 X 297公H " ^----^-------裝---------訂----I---- (請先閱讀背面之注意事項再填寫本頁) !285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(3) 啶基六氫吡畊, (D) 1-[Ν2-[4-胺基-3,5-二溴-Ν·[[4-(3,4-二氫-2(1H)-酮基喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]心離胺醯基]-4_(4-吡 啶基六氫吡啶, (E) 1-[Ν2-[3,5-二溴·Ν-[[4·(1,3_ 二氫-4_苯基 _2(2H)_酮基咪唑小 基)·1-六氫吡啶基]羰基]-D-酪胺醯基]-L-離胺醯基]-4-(4-吡啶基) -六氫p比喷, (F) 1-[Ν2-[4-胺基-3,5_二溴-N_[[4-(l,3-二氫-4-苯基-2(2H)_酮基 咪唑-1-基)-1-六氫吡啶基]羰基]-D-苯基-丙胺醯基]-L-離胺醯基] -4-(4-吡啶基)-六氫吡畊, (G) 1·[3,5_二溴-N-[[4-(3,4-二氫-2(1H)·酮基嘧吩幷[3,4-d]_嘧啶-3-基)_1-六氫说淀基]談基]-D-絡胺酿基]-4-(1-六氫叶I:淀基)-六氫 外匕淀, (Η) H4-胺基-3,5-二溴-N-[[4_(2,4-二氫-5-苯基-3(3H)_酮基-1,2,4- 三唑-2-基)-1-六氫吡啶基]羰基]苯基-丙胺醯基]-4-(1-甲基-4- 六氫峨淀基)-六氫1^比淀’ (I) 1-[4-胺基-3,5-二溴 _N_[[4-(2,4-二氫·5_苯基-3(3H)_酮基·1,2,4-三唑-2_基>1-六氫吡啶基]羰基]-D-苯基-丙胺醯基]-4-(1-六氫吡 啶基)_六氫吡啶, (J) 1-[4-胺基-3,5-二溴-N_[[4-(2,4-二氳 苯基·3(3Η)_酮基-1,2,4_ 三唑-2-基)_1_六氫吡啶基]羰基]-D-苯基-丙胺醯基]·4-(1-甲基-4-六氫p比症基)-六氫说ρ井, - (Κ) 1-[4-胺基-3,5-二溴 _Ν_[[4-(3,4-二氫-2(m>酮基·嘧吩 p,2-d] 嘧淀-3-基)-1-六氫吡啶基]羰基]_D-苯基-丙胺醯基]-4-(1-六氫吡 觸6 _ ^紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ϊ ---------------^——---- (請先閱讀背面之注意事項再填寫本頁) 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(4) 淀基)·"Κ鼠p比淀’ (L) 1-[4-胺基-3,5-二溴-Ν·[[4-[1,3_二氫-4·[3-(三氟甲基)苯基]- 2(2Η)-酮基咪唑-1·基]-1-六氫吡啶基]羰基]_D-苯丙胺醯基]-4-(1-乙基-4-TT風p比1基)-穴鼠口比’ (Μ) 1-[4-胺基-3,5-二溴-Ν-[[4·[3,4-二氫-2(1H)-酮基喹唑啉·3-基] -1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-己基-4-六氫吡啶基)-六氛说淀, (N) 1-[4·胺基-3,5-二溪-N-[[4_[3,4-二氮-2(1H)-嗣基峻峻琳-3-基] 小六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-環丙基甲基-4-六氫 吡啶基)-六氫吡啶, (Ο) 1-[Ν-[[4-[3,4_二氫-2(1H)-酮基喹唑啉-3-基]-1-六氫吡啶基] 羰基]-3-乙晞基-D,L-苯丙胺醯基]-4·(六氫-1H-1-—氮七圜烯基)-六氫p比淀, (P) (1^)-1-[4-[4-(3,4-二氫-2(111)-酮基峻唑啉_3-基)小六氫吡啶 基]-2-[(4-羥基-3,5-二甲基苯基)甲基]-1,4-二酮基丁基]-4-(1-六氫 p比淀基)-六氫峨淀, (Q) 1-[4-胺基-3,5-二溴-N-[[4-[N-(胺基羰基)-N-苯基-胺基]小 六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-六氫吡啶基)-六氫吡啶, (R) 1-[4-胺基-3,5-二溴-Ν·[[4-(3,4-二氫-2(1H)-酮基喹唑啉-3-基) -1-7T風?比淀基]談基]-D-苯丙胺疏基]-4-(5-甲氧基-4·喃淀基)-穴 氫ρ比畊, (S) 1-[4·胺基-3,5_二溴 _Ν-[[4-(1,1:·二氧化 _3(4Η)_酮基-1,2,4-苯幷 口塞-呼-2-基鼠ρ比症基]談基]-D-本丙胺酿基]鼠口比 淀基)-六氫p比淀, -7· 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) : ---k-------裝--------訂---------. (請先閱讀背面之注意事項再填寫本頁) 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(5) (T) 1-[4-胺基-3,5-二溴-Ν-[[4·[2(1Η)-酮基喹啉·3_基]-1-六氫吡 啶基]羰基]-D-苯丙胺醯基]冬(1-六氫吡啶基)-六氫吡啶, (U) 1-[4-胺基-3,5-二溴-Ν·[[4-[3,4·二氫-2(1H)-酮基喳唑啉·3_基] -1-六氫吡啶基]羰基]-D·苯丙胺醯基]-4-[3·(二甲胺基)丙基]-六 氫吡畊, (V) 1-[4_胺基 _3,5_二溴-Ν-[[4-[3,4_二氫·2(1Η)_酮基喹唑啉-3_基] 1·六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(4-甲基-1-六氫吡畊基)-六氫p比淀, (W) 1-[4-胺基 _3,5_二溴 _N-[[4-[3,4-二氫-2(1H)-酮基音唑啉-3-基] -1-六氫吡啶基]羰基]-D·苯丙胺醯基]-4-[(l-甲基-4-六氫吡啶基) 羰基]-六氫吨p井, (X) 1-[4·胺基-3,5·二溴-N-[[4-[3,4-二氫-2(1H>酮基喹唑啉·3-基] -1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[(1-甲基-4-六氫吡畊基) 談基]-六氫1"比ρ井, (Υ) 1-[4_胺基·3,5-二溴-Ν-[[4_(3,4_ 二氫·2(1Η)-酮基·喹唑啉 _3- 基>1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[4-[4-(二甲胺基)丁基] 苯基]-六氫说p井,
(Z) 1-[4_胺基-3,5-二溴-N-[[4-(3,4-二氫-2(1Η>酮基-喹唑啉 I 基)-1-ττ氮卩比咬基]談基]苯丙胺酿基]-4·[4·(二甲胺基氣 叶匕咬基]-六氫吨淀, (ΑΑ) 1-[Ν2-[[4-(1,3-二氫-4-苯基-2(2Η)-酮基咪唑-1-基)_1_六氫 ρ比 啶基]羰基]-Ν1-甲基-D-色醯基]-4_(4-甲基-1-六氫吡畊基)_六氫 0比淀, (ΑΒ) 1·[Ν2-[[4_(1,3_二氫·4_苯基·2(2Η)_酮基咪唑小基)-1-六氫吡 -8- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ~ I --------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1285550 A7 B7 五、發明說明(6 ) (請先閱讀背面之注意事項再填寫本頁) 淀基]羧基]二甲基乙氧碳基)-D-色醯基]-4-(1-甲基·4_六 氫ρ比淀基)-六氫p比淀, (八(3)取8)-1-[4-[4-(3,4-二氫-2(111)_酮基4峻琳_3-基)_1-六氫11比淀 基]-2-[(3,5-二溴基-4_甲基苯基)甲基]-1,4-二酮基丁基]冬(4_甲基 -1-六氫吡畊基)-六氫峨淀, (AD) (R,S)_l-[4_[4-(3,4·二氫-2(1Η)-_ 基 4 也琳-3-基)-1-六氫 ρ比淀 基]-2·[(3,5-二溴基-4-甲氧苯基)甲基]-1,4-二酮基丁基;|_4·(1·甲基- 4-TT風卩比基)-六鼠卩比’ (处)(氏8)_1-[4-[4-(3,4-二氫-2(111)-_基4峻淋-3-基)-1-六氫咐;淀 基]-2-[(3,4·二溴苯基)曱基]-1,4_二61¾基丁基]·4·(4_甲基·1_六氫峨 ρ井基)-六氫ρ比淀, (AF) 1-[Ν2·[Ν-[[4_(1,3-二氫·2(2Η)-_ 基苯幷咪吐-1-基)-1-六氫 吡啶基]羰基]-3,5-二溴-D-酪胺醯基]-L-離胺醯基]-4-(4-吡啶基)-六氫说p井, (AG) 1-[4-胺基-3,5-二溴-N_[[4_(l,3_二氫-6-羥基 _2(2H)_酮基苯幷 咪唑-1-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-六氫吡啶 基)-六氫吡啶, 經濟部智慧財產局員工消費合作社印製 (AH) 1-[Ν2-[4-胺基-3,5-二溴-N-[[4-(l,3-二氫·2(2Η>酮基-苯幷咪 唑-1-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-Ν6,Ν6-二甲基心 離胺醯基]-4-(4-吡啶基)-六氫吡畊, (AI) 1-[1^2-[4-胺基_3,5-二溴-^4[4-(3,4-二氫-2(111>酮基-喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-苯两胺醯基]-N6,N6-二甲基-L-離 胺醯基]-4-(4-吡啶基)-六氫吡啡, (AJ) (R,S)-l_[2-(4_胺基-3,5-二溴基苯甲醯基)-4-[4-(3,4_ 二氫_ -9- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(7 ) 2(1H)_酮基喹唑啉-3-基)小六氫吡啶基]-4-酮基丁基]-4-(1-六氫 p比淀基)-六氫吨淀, (ΑΚ) 1·[4-胺基-3,5_ 二溴-Ν_[[4·(3,4-二氫-2,2-二氧化-2,1,3-苯幷 嘍二畊-3-基)-1-六氫吡啶基]羰基]-D-苯基-丙胺醯基]-4-(1_六氫 p比淀基)-六氫p比淀, (AL) 1_[4_胺基-3,5_二溴-N_[[4-[l,3-二氫-2(2H)·酮基咪唑幷[4,5_c] 喹啉基-3-基]-1-六氫吡啶基]羰基]-D·苯基-丙胺醯基]-4-(1-六氫 叶匕淀基)羰基]-六氫ρ比淀, (AM) 1-[4-胺基·3,5-二溴-Ν-[[4-(3,4-二氫·2(1Η)_酮基喹唑啉-3-基) _1·六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-六氫吡啶基)-六氫吡 淀, (AN) 1-[Ν2-[3,5-二溴-Ν·[[4-(3,4·二氫-2(1H)-酮基喹唑啉-3-基)-1-六氫吡啶基]羰基]-D_酪胺醯基]-N6,N6_二甲基-L-離胺醯基]-4-(4·^比淀基)-六氫说p井, (AO) 1-[4-胺基-N-[[4-[4-(3-溴苯基)-1,3-二氫-2(2H>酮基咪唑小 基]-1-六氫吡啶基]羰基]-3,5-二溴-D-苯丙胺醯基>4-(1-甲基-4-六 氫叶1:淀基)-六氫p比淀, (ΑΡ) 1·[4_胺基-3,5-二溴 _Ν-[[4-[1,3-二氫-4·苯基-2(2H)-酮基咪唑 -1-基]·1-六氫吡啶基]羰基]-D·苯丙胺醯基]-4_(4-甲基-1-六氫吡 畊基)-六氫吡啶, (AQ) 1_[4·胺基 _3,5-二溴-N-[[4-[l,3_二氫 _4_[3_(三氟甲基)苯基]-2(2H)-酮基咪唑小基]·1·六氳吡啶基]羰基]-D_苯丙胺醯基]-4-(1-六氫p比淀基)-六氫p比淀, (AR) 1_[4·胺基·3,5_二溪《Ν_[[4·[1,3-二鼠-4-[3-(二氣曱基)苯基]- -10- 張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) " " -1丨丨k-------·裝------ C請先閱讀背面之注意事項再填寫本頁) · 禮— 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(8 ) 2(2H)-酮基咪唑-1-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(外 向-8-甲基-8-氮雙環幷[3,2,1]辛-3-基)-六氫吡畊, (AS) 1_[3,5_二溴-N_[[4-(l,3-二氫-4·苯基 _2(2H)_酮基咪唑 _1_基)-1_ 六氫说淀基]談基]酿胺醯基]-4-(1-六氫p比淀基)-六氫p比違, (AT) 1-[4-胺基-3,5-二溴-Ν·[[4-[1,3_二氫-4-[3-(三氟甲基)苯基]-2(2Η)-酮基咪峻-1-基]-1-六氫p比淀基]黢基]-D-苯丙胺醯基]-4-(1-乙基氮p比淀基)-穴鼠口比卩井’ (AU) 1-[4-胺基-3,5-二溴-Ν-[[4·[1,3-二氫-4-苯基-2(2H)_酮基咪唑 -1-基]-Ι-t?氮ρ比咬基]談基]-D-表丙胺酿基]氮-4·甲基-1H-1,4-—氮七園_1_基)穴風p比淀’ (AV) 1-[3,5-二溴-N-[[4-(3,4-二氫-2(1H)_酮基喹唑啉-3·基)-1·六 氮p比淀基]談基]-D-絡胺S&基]-4-[1-(甲基續酿基)-4-六氮p比淀基] -六氫p比淀, (AW) 1_[4_胺基-3,5-二溪-N_[[4-(l,3_二氣-4_苯基·2(2Η)_嗣基味峻 -1-基)-1-穴氮竹b淀基]談基]-D-苯丙胺酿基]_4_(1_甲基-4-六氮口比 淀基)-六氫p比淀, (ΑΧ) l-p,5-二溴-N-[[4_[1,3-二氫-4·[3-(三氟甲基)_苯基]_2(2H)-酮 基味峻-1-基]-1-7T氯p比淀基]談基]-D·路胺酿基]-4-(六氮-1H-1-— 氮七圜晞基)-六氫ρ比淀, (AY) 1-[3,5-二溴-N-[[4_(3,4-二氫 _2(1H)·酮基喳唑啉-3-基)_1_ 六 風p比淀基]談基]-D-路胺酿基]-4-(1-甲基-4-六氯ρ比淀基)-六氯p比 淀, - (AZ) 1_[4_胺基-3,5-二漠-N-[[4-(3,4-二氫·2(1Η)_酮基-p奎峻琳-3-基)-1-六氫峨淀基]談基]-D·苯丙胺酿基]-4-(外向-8-甲基_8_氮雙 -11 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ---I I 1 I I I I I I --------訂----I I I I I (請先閱讀背面之注意事項再填寫本頁) 1285550 A7 B7 五、發明說明(9 ) 環幷[3,2,1]辛·3-基)-六氫吡畊, (請先閱讀背面之注意事項再填寫本頁) (ΒΑ) 1-[4_胺基-3,5-二溴-N-[[4-(l,3-二氫冬苯基-2(2Η)-酮基咪唑 -1-基)小穴風峨淀基]談基]·0-苯丙胺酿基]-4-(1-甲基-4-六氮叶匕 啶基)-六氫吡啩, (ΒΒ) 1·[3,5-二溴-Ν·[[4-[1,3·二氫-4-[3-(三氟甲基)-苯基]-2(2H)-酮 基咪唑-1-基]-1-六氫吡啶基]羰基]-D-酪胺醯基]-4-(1_六氫吡啶 基)-六氫p比咬, (BC) 1-[N6-乙醯基-N2-[3,5-二溴-Ν·[[4-(3,4-二氫-2(1Η>酮基喹唑 淋-3-基風p比淀基]談基]-D-路胺酿基]-L-離胺酿基]-4-(4-外匕 啶基)-六氫吡畊, (BD) 1-[3,5-二溴-N-[[4-(l,3-二氫-4-苯基-2(2H)-酮基咪唑-1-基)小 六氫吡啶基]羰基]-D-酪胺醯基]-4-(六氫-1H-1-—氮七圜烯基)-六氫说淀, (BE) 1-[4-胺基-3,5-二溪·Ν-[[4·(1,3-二氮-4_(3-p塞吩基)-2(2H)·嗣基 咪唑小基)-1_六氫吡啶基]羰基]-D_苯基丙胺醯基]-4-(1·甲基-4- 六氫p比淀基)-六氫p比淀, 經濟部智慧財產局員工消費合作社印製 (BF) 1-[4_胺基·3,5-二溴-Ν-[[4·[1,3-二氫-4-P-(三氟甲基)苯基]-2(2Η)-酮基咪唑-1-基]小六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-甲基-4-六氫p比淀基)-六见p比淀, (BG) 1-[3,5-二溴-N-[[4-(3,4-二氫 _2(1Η>酮基喹唑啉 _3·基)小六 氫吡啶基]羰基]-D-酪胺醯基]-4-[1-(羥羰基-甲基)-4-六氫吡啶 基]-六氫p比淀, -· (BH) 1-[4-胺基-3,5-二溴-N-[[4-[3,4·二氫 _2(1H)_酮基-喹唑啉 _3· 基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-甲基磺醯基-4-六 -12- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(1Q) 氫外b淀基)-六氫p比淀, (BI) 1-[3,5·二溴·Ν-[[4_(3,4-二氫-2(1H)-酮基喹唑啉-3-基)小六 氫吡啶基]羰基]-D-酪胺醯基]-4·(4_六氫吡啶基)-六氫吡啶, (BJ) 1-[4_胺基 _3,5-二溴 _Ν-[[4·(1,3·二氫 4-苯基-2(2Η)-酮基咪唑 -1-基)-1-ά氮卩比淀基]談基]_D-豕丙胺酿基]·4_(1·乙基-4-ΤΤ氣叶匕 淀基)_ 7?風卩比淀, (ΒΚ) 1_[4_胺基 _3,5_二溴 _Ν-[[4·(1,3-二氫·4_(3_羥基苯基)·2(2Η)_ 酮基咪唑-1-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-甲基-4-六氫p比淀基)-六氫批症, (BL) 1-[3,5-二溴·Ν-[[4·(3,4-二氫-2(1H)-酮基喹唑啉-3-基)_1-六 氫吡啶基]羰基]-D-酪胺醯基]-4-(六氫·1Η·1-—氮七圜締基)·六 氫被淀, (ΒΜ) Η4-胺基_3,5_二溴-N_[[4-(l,3_二氫斗苯基_2(2Η)_酮基咪唑 -1-基)-1-ττ氮ρ比淀基]談基]-D-豕丙胺赌基]-4·(1-7Τ風叶b淀基)-ττ 氫峨淀, (BN) 1-[4-胺基·3,5-二溴-Ν-[[4-[4-(3-溴苯基)-1,3_二氫-2(2Η)-酮基 咪唑-1-基]-1-六氫吡啶基]羰基]-D-苯基-丙胺醯基]-4-(外向-8-甲 基-8-氮雙環幷[3,2,1]辛-3_基}-六氫吡畊, (BO) 1-[4_胺基 _3,5-二溴-N-[[4-(3,4-二氫-2(1H)·酮基-喹唑啉-3· 基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-乙基-4-六氫吡啶 基)-六氫吹淀, (BP) 1-[4-胺基-3,5-二溴-Ν-[[4-(3,4»二氫-2(1H)-酮基-喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-乙基_4_六氫吡啶 基)-六氫峨p井, -13- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) " 丨丨k-------•裝--------訂_ (請先閱讀背面之注意事項再填寫本頁) 1285550 Α7 Β7 五、發明說明(11 ) (請先閱讀背面之注咅?事項再填寫本頁) (BQ) 1-[4-胺基-3,5-二溴-N-[[4-[l,3-二氫冰(3-甲氧基-苯基)-2(2H)-酮基咪唑-1-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(外 向-8-甲基-8_氮雙環幷[3,2,1]辛_3_基)-六氫吡畊, (BR) 1-[3,5-二溴-N-[[4-(3,4-二氫-2(1H)-酮基 4 唑啉 基 H-六 氫吡啶基]羰基]酪胺醯基]-4-[1-(環丙基-甲基>4-六氫吡啶 基]-六氫p比淀, (BS) 1-[4_胺基-3,5_二溴-Ν-[[4·(3,4-二氫-2(1H)-酮基喹唑啉 基) -1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(六氫-1Η·1-—氮七圜烯 基)-六氫ρ比淀, (ΒΤ) 1-[4·胺基-3,5-二溴-Ν·[[4-(3,4-二氫-2(1Η)-酮基-喹唑啉·3-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(4-六氫吡啶基)-六 氫吡啶, (BU) 1-[3,5-二溴 _Ν-[[4-(1,3-二氫-4·苯基-2(2Η)_酮基-咪唑-1-基)_ 1-六氫吡啶基]羰基]酪胺醯基]-4-(4-吡啶基)-六氫吡啶, (BV) 1-[3,5-二溴 _N-[[4_[1,3-二氫-4-[3-(三氟甲基)-苯基]-2(2H>酮 基咪唑-1-基]-1-六氫吡啶基]羰基]-D-酪胺醯基]-4-(1-甲基-4-六 氫p比淀基)-六氫p井, 經濟部智慧財產局員工消費合作社印製 (BW) 1-[Ν2-[3,5-二溴-N-[[4-[l,3_ 二氫-4-[3-(三氟甲基)苯基]-2(2H)-酮基咪唑-1-基]-1_六氫吡啶基]羰基]-D-酪胺醯基]-L-離胺 醯基]-4-(4-p比淀基)-六氫峨p井, (BX) 1_[3,5_二溴-N-[[4_(l,3-二氫-4-(3-嘧吩基)-2(2H)_酮基咪唑-1-基)-1-六氮卩比淀基]談基]路胺酿基]氮卩比淀基氣 ρ比症, (BY) 1-[4_胺基-Ν_[[4-[4_(3-氣苯基)-1,3-二氫-2(2Η)_酮基咪唑-1- -14- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(12) 基]-1·六氫吡啶基]羰基]·3,5-二溴-D-苯丙胺醯基]-4-(1-甲基·4·六 氫吡啶基)-六氫吡啶, (ΒΖ) 1_[4_胺基-3,5-二溴-N-[[4-[l,3_二氫-4-[Μ三氟甲基)苯基]-2(2Η>酮基咪唑-1·基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(六 氫_1Η·1_—氮七圜晞基)-六氫p比淀, (CA) 1-[4_胺基-3,5-二溴-Ν·[[4-[1,3-二氫-4-[3-(三氟甲基)苯基] 2(2Η)-酮基咪唑-1-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-甲基_4_六氫π比淀基)-六氫a比ρ井, (CB) 1-[4-胺基-Ν-[[4-[4-(3·氣苯基)-1,3-二氫 _2(2Η)·酮基咪唑 _1_ 基]-1_ττ氮卩比淀基]談基]·3,5-二溪-D-苯丙胺酿基]-4-(ττ氯-1Η-1-一氮七圜#基)-六氫峨淀, (CC) 1-[4胺基-3,5-二溴-Ν-[[4-(1,3·二氫-4-苯基-2(2Η)-酮基咪唑 -1-基)-1·六氫吡啶基]羰基]苯丙胺醯基]-4-(4-吡啶基)-六氫吡 畊, (CD) 1-[3,5_二 >臭·Ν·[[4-(1,3-二氮-4-本基·2(2Η)·酬基味唆-1-基)-1-六氫吡啶基]羰基]-D-酪胺醯基]-4-(1-甲基-4-六氫吡啶基)-六氫 叶匕症, (CE) 1-[4_胺基-3,5_二溴-Ν_[[4·[1,3·二氫 _4-苯基-2(2Η)-酮基咪唑 -1-基]小六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[4-(1-酮基乙基)苯 基]-六氫峨叫1, (CF) 1-[3,5_二溴 _Ν-[[4-[3,4-二氫-2(1Η)_酮基喹唑啉-3-基]·1_ 六 鼠ρ比淀基]談基]-D-赂胺酿基]-4_(1-·甲基-4-ΤΤ氮卩比咬基)_穴氮口比 畊, (CG) 1_[4_胺基-3,5_二溴·Ν-[[4-[1,3_二氫-4-(3-硝基苯基)-2(2Η)·酮 -15- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) ------.-------裝------ (請先閱讀背面之注意事項再填寫本頁) · 線_ 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(13) 基味咬-1-基]-1-7?氫p比咬基]談基]-D-苯丙胺酿基]-4-(1-甲基《4-六氫p比淀基)-六氫峨淀, (CH) 1-[4_胺基·3,5_ 二溴-N-[[4-[3,4-二氫-2(1H)-酮基-喹唑啉-3· 基]-1-7T氮卩比咬基]談基]苯丙胺酿基]-4-(1-四氮p比洛基)-六 氫吡啶, (CI) 1_[4·胺基-3,5·二溴-Ν·[[4-(1,3_二氫 _4·苯基-2(2H)-酮基咪唑 1-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(六氫-1H-1-—氮七 圜晞基)-六氫p比淀,及 (CJ) 1_[4·胺基-3,5-二溴-N-[[4-(l,3-二氫-4-(3-嘧吩基)-2(2H)_酮基 味峻-1·基)-1-ττ鼠p比淀基]碳基]-D·苯基-丙胺酿基]-4-(1•甲基_4- 六氫p比淀基)-六嚴p比哨1, 其互變異構物,非對映異耩物,對掌異構物,其混合物, 及其生理學上可接受之鹽,而以下化合物 (Α) 1·[Ν2-[3,5-二溴-N-[[4-(3,4-二氫-2(1H)-酮基喹唑啉-3-基)-μ 六氫吡啶基]羰基]-D-酪胺醯基]-L·離胺醯基]-4-(4-吡啶基)-六 氫p比畊, (B) H4-胺基·3,5-二溴-化[[4-(2,3,4,5-四氫-2(111)-酮基_1,3-苯并 二氮七圜-3-基)-1-六氫吡啶基]羰基]-D·苯基-丙胺醯基]-4-(1-六 氫吡啶基)-六氫吡啶, (I) 1·[4·胺基-3,5-二溴-Ν·[[4-(2,4-二氫-5_苯基 _3(3H)_酮基-1,2,4- 三吐-2-基)-1-六氮p比淀基]默基]-D·苯基-丙胺酿基]-4-(1-六氯ρ比 症基)-六氫p比淀’ ** (J) 1-[4-胺基-3,5-二漠-N-[[4-(2,4-二氫-5_苯基-3(3H)_嗣基-1,2,4_ 三峻-2·基)-1·六氫?比淀基]碳基]_D_苯基丙胺酿基]-4-(1-甲基-4- -16- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1----%-------^^裂------ (請先閱讀背面之注意事項再填寫本頁} Ηδτ_ 1285550 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(14) 六氫P比淀基)-六氫P比17井, (AC) (R,S)-l-[4-[4_(3,4-二氫 _2(1H)-嗣基,奎峻琳-3-基)-1-六氫 p比咬 基]-2-[(3,5-二溴基-4·甲基苯基)甲基]-1,4-二酮基_丁基]-4-(4-甲基 -1-六氫p比喷基)-六氫ρ比淀, (AF) 1·[Ν2_[Ν_[[4·(1,3·二氫 _2(2H)_酮基苯幷咪唑小基)-1-六氫 吡啶基]羰基]-3,5-二溴-D-酪胺醯基]_L-離胺醯基]-4-(4-吡啶基)_ 六氫1^比p井,及 (AM) 1-[4_胺基 _3,5_二溴·Ν_[[4_(3,4·二氫-2(1H)-酮基喹唑啉 _3_基) -1-7T鼠p比淀基]談基]-D-苯丙胺酿基]-4-(1-六氫p比淀基)-六氯p比 咬, 其互變異構物,非對映異構物,對掌異構物,其混合物, 及其生理學上可接受之鹽,且尤其是以下化合物 (A) 1_[Ν2-[3,5-二溴 _N-[[4-(3,4-二氫·2(1Η)-酮基喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-酪胺醯基]-L-離胺醯基]-4-(4-吡啶基)-六 氫峨畊,與 (B) 1-[4_胺基·3,5-二溴-Ν-[[4-(2,3,4,5·四氫-2(m)-酮基-1,3_苯幷 二氮七圜-3-基)-1-六氫吡啶基懷基苯基丙胺醯基]_4_(1_六 氫p比淀基)-六氫p比淀, 其互變異構物’非對映異構物,對掌異構物,其混合物, 及其生理學上可接受之鹽,係爲特佳的。 爲產生所要作用所需要之劑量,對靜脈内或皮下投藥而 S ’係適當地爲0.0001至3毫克/·.公斤體重,較佳爲〇 〇1至1 毫克/公斤體重,而對藉由口服或鼻途徑或藉吸入投藥而 言,爲0.01至10毫克/公斤體重,較佳爲〇丨至1〇毫克/公 -17-
In---^-------裝·----I--訂-------- (請先閱讀背面之注意事項再填寫本頁) ¾ 公 / y K υ 1 Μ V C / r X ) \ •~ 1285550 A7 B7 經濟部智慧財產局員工消費合作社印製 五、發明說明(15) 斤體重,於各情況中,一天i至3次。 若以CGRP枯抗劑及/或CGRp釋出抑制劑之治療,係作 爲對於習用激素替補療法之補充,則最好降低上文所予之 劑量,且在此情況中,其劑量範園可從上文所指定下限之 1/5至南達上文所指定上限之Μ。 對此項目的而言,可將^^拮抗劑及/或CGRp釋出抑 制劑與一或多種習用惰性載劑及/或稀釋劑一起調配,例 如使用玉米澱粉、乳糖、葡萄糖、微晶性纖維素、硬脂酸 鎂、聚乙烯基四氫吡咯酮、檸檬酸、酒石酸、水、水/乙 醇、水/甘油、水/花楸醇、水/聚乙二醇、丙二醇、鮮 蠟基硬脂基醇、羧甲基纖維素或脂肪物質,譬如硬質脂肪 ,或其適當混合物,在習用蓋倫製劑中,譬如素片劑或塗 層片劑、膠囊、粉末、懸浮液、溶液、計量氣溶膠或栓劑。 特別適於治療絕經熱潮紅之製劑,係爲含有以下活性物 質之一 (A) 1-[Ν2-[3,5_二溴-N-[[4_(3,4-二氫-2(1H)-酮基喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-酪胺醯基]心離胺醯基]-4-(4-吡啶基)-六 氫吡畊, (B) 1_[4_胺基-3,5·二溴-N-[[4-(2,3,4,5-四氫-2(1H)·酮基-1,3-苯幷 二氮七圜·3·基)-1-六氫峨淀基]談基]-D-苯基-丙胺酿基]-4-(1-六 氫p比淀基)-六氫p比淀, (I) 1-[4-胺基-3,5_二溴-Ν·[[4-(2,4-二氫 _5_苯基-3(3H)-嗣基-1,2,4- 三峻-2-基)-1-穴風p比淀基]凝基]-D·苯基-丙胺感基]-4-(1-六氮口比 啶基)-六氫p比淀, -18- (請先閱讀背面之注意事項再填寫本頁) .•敦 訂---- 華_ 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) A7 1285550 __B7__ 五、發明說明(16 ) (J) 1·[4-胺基-3,5-二溪-Ν·[[4·(2,4-二氯-5-苯基·3(3Η)-嗣基-1,2,4- 三唑-2·基)-1-六氫吡啶基]羰基]-D-苯基·丙胺醯基]-4-(1-曱基-4- 六氫p比淀基)_六氫说P井, (AC) (R,S)-l_[4-[4-(3,4-二氫 _2(1H)_酮基 p奎峻 p林 _3_基)-1_六氫 ρ比淀 基]-2-[(3,5-二溴基-4-甲基苯基)甲基]-1,4·二酮基-丁基]-4-(4-甲基 -1-六氫p比畊基)-六氫吨淀, (AF) 1-[Ν2-[Ν_[[4·(1,3-二氫-2(2H)_酮基苯幷咪唑·ι·基)-1-六氫 吡啶基]羰基]-3,5-二溴-D_絡胺醯基]-L-離胺醯基]-4-(4-吨啶基)-六氫说p井,或 (AM) 1-[4·胺基 _3,5_二漠 _N-[[4-(3,4-二氫-2(1H)·酮基 P奎吃淋-3-基) -1-7T鼠p比淀基]羰基]-D-苯丙胺醯基]-4-(1-六氳p比淀基)_六氫p比 淀, 在下述醫藥配方之一中: 供粉末吸入用之膠囊,含有1毫克活性物質,較佳爲活 性物質(A)或(B), 供霧化器用之可吸入溶液,含有1亳克活性物質,較佳 爲活性物質(A)或(B), 推進劑氣體操作之計量氣溶膠,含有1毫克活性物質, 較佳爲活性物質(A)或(B), 鼻噴霧劑,含有1毫克活性物質,較佳爲活性物質(A)或 (B), 片劑,含有20毫克活性物質,教佳爲活性物質(B), 膠囊,含有20毫克活性物質,較佳爲活性物質, 供鼻施用之水溶液,含有10毫克活性物質’較佳爲活性 — *19- 本紙張尺度中關家標準(CN《)A4規格⑽X 2Θ7公爱) l·----------裝--------訂--------- (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 1285550
五、發明說明(17 ) 經濟部智慧財產局員工消費合作社印製 物質(A)或(B), 供鼻施用之水溶液,含有5亳克活性物質,較佳爲活性 物質(A)或(B),或 供鼻施用之懸浮液,含有20毫克活性物質,較佳爲活性 物質(A)或(B)。 CGRP係藉由感覺神經釋出,例如三叉神經,其係神經支 配邵份臉郅皮膚,已証實在人類中三叉神經節之刺激會導 致增加CGRP血漿含量,及造成臉部紅腫([4]: p JG〇adsby等 人,神經學年鑑,第23卷,第2期,1988, 193-196)。 爲註實熱潮紅可成功地使用CGRP拮抗劑與CGRP釋出抑 制劑治療,故在狨中,藉由刺激三叉神經節,導致增加流 經皮膚血管之血液流量,引致内源CGRP之增加釋出。下列 試驗物質之功效,係藉由測定靜脈内投予之劑量,作特徵 鑒定,其會使流經臉部皮膚而已因内源CGRP導致之所增加 之血液流量降低50% : (A) = 1_[Ν2·[3,5-二溴-N_[[4-(3,4-二氫 _2(1Η)_酮基喹唑啉-3-基)_1-六 氫吡啶基]羰基]酪胺醯基]-L-離胺醯基]-4-(4-吡啶基)_六氣 吡畊, (B) = 1-[4-胺基-3,5-二溴-1^[[4-(2,3,4,5-四氫-2(1印-酮基-1,3_苯幷二 氮七圜-3-基)-1-六氫吡啶基]羰基]苯基-丙胺醯基]-4-(1-六氫 p比淀基)-六氫说淀, (八(3) = (1^)-1-[4-[4-(3,4-二氫-2(111)-齡基喹唑啉-3-基)-1-六氫吡啶 基]-2-[(3,5_二溴基斗甲基苯基)甲基]-1,4-二酮基-丁基]-4_(4-甲基 小六氫吡畊基)-六氫吡啶, -20- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 11 裝--------訂---- (請先閱讀背面之注意事項再填寫本頁) ^#1. 1285550 A7 B7 五、發明說明(18) <請先閱讀背面之注意事項再填寫本頁) (AM) = 1·[4-胺基 _3,5_二溴-N-[[4-(3,4-二氫 _2(1H)_酮基喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1•六氫吡啶基)-六氫吡 淀, (DA)=沙馬催坦(sumatriptan)及 (E)B)=坐米催坦(zolmitriptan)。 方法之説明: 將兩種性別之狨(300-400克)以戊巴比妥麻醉(首先使用30 毫克/公斤腹膜腔内,接著爲肌肉内灌注6毫克/公斤/ 小時)。使用加熱板,使體溫保持在37°C下。投予盤可明 (Pancurmium)作爲肌肉鬆弛劑(首先爲1毫克/公斤,其後每 一小時爲0.5毫克)。使動物之頭部固定在立體定向裝置中 。在頭皮已使用縱向切開術打開後,在頭顱中鑽出小孔, 並使雙極電極(Rhodes SNES 100)降低至三叉神經節中。探出 神經節之位置,係較簡易地利用X-射線施行,其會顯現出 頭顱之骨骼結構。岩骨係充作用以放置電極(CCX-數字X-射線裝置)之導溝。電極在神經節中之位置,係在每次實 驗結束時監測。刺激參數爲: 10 Hz,2 mA,2毫秒,歷經30秒。 經濟部智慧財產局員工消費合作社印製 臉部皮膚微血管中之血液流量,係藉由雷射Doppler流量 度量法,使用PeriFlux雷射Doppler系統測定。 於各情況中,每隔30分鐘,使動物曝露至2至3次刺激週 期。第一次刺激係充作其他刺激之參考値。試驗物質係在 第2次及第3次刺激週期之前5分鐘,以靜脈内投藥。 表1 : "50%劑量"=會使因爲内源CGRP所造成流經臉部皮 -21 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1285550 A7 活性物質(A)或(B) 乳糖 硬明膠膠囊 五、發明說明(19 )
物質 f 〜/G 内劑 50% ^»Γ|Γ A B 0 042笔克/公斤 AC AM DA ^280^X7^~~ DB · · a w Ί尺斤j I醫藥製劑,其本 CGRP拮抗劑或CGRP釋出抑制劑作爲活性物質,其較: 在刪謝128或DE 199 11 039中卢斤述之胺基酸衍生物之_ 例如上述活性物質(A)或(B)之一:
實例I 質㈧或⑻ 組成: 1個供粉末吸入之膠囊含有: 1.0毫克 20.0毫克 5〇.〇毫克 71·〇亳克 製備方法: 將活性物質研磨成供吸入所需要之粒子大小。將已哥 之活性物質均勻地與乳糖混合。將混合物裝填至硬明塌 囊中。 里入漆^,具有物質(A)或0 -k-----------裝--------訂---------^9— (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 -22- 1285550 A7 五、發明說明(2〇 ) 組成: 1份噴霧劑含有: 活性物質(A)或(B) 氣化苄烷氧銨 乙底酸二鈉 純水至 製備方法: 1.0毫克 〇·〇02亳克 〇·0〇75亳克 15.0微升 使活性物質與氣化芊烷氧銨溶於, Respimate®藥筒中。 ,並將其裝填在 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 實例m 供霧化器用t可吸入溶液,展差1 組成: 1個小玻瓶含有·· 活性物質(A)或(Β) 〇·1克 氣化鈉 0.18克 氣化芊烷氧銨 0.002克 純水至 2〇.〇毫升 製備方法i 使活性物質、氣化鈉及氯化爷烷氧銨溶於水中。 實例IV 查差作之計量氣遂屋」毫物1.(Δλ或 (Β) - 組成: 1份噴霧劑含有·· — l· --------^------ (請先閱讀背面之注意事項再填寫本頁) 華 -23 本紙張尺度適用中國國家標準(CNS)A4規格(21() χ 297公爱) 1285550 A7 B7 五、發明說明(21 ) 活性物質(A)或(B) 1.0毫克 (請先閱讀背面之注意事項再填寫本頁) 卵鱗脂 (X1 % 推進劑氣體至 50.0微升 製備方法:
使微粉化活性物質均勻地懸浮於卵磷脂與推進劑氣體之 混合物中。將此懸浮液轉移至具有計量閥之加壓容器中。 實例V 鼻噴霧劑,具有1毫克活性物質(A)或(B) 組成: 1份噴霧劑含有 活性物質(A)或(B) 1.0毫克 甘露醇 5.0毫克 乙底酸二鈉 0.05毫克 抗壞血酸 1.0毫克 純水至 0.1毫升 製備方法: 使活性物質與賦形劑溶於水中’並轉移至適當容器。
實例VI 經濟部智慧財產局員工消費合作社印製 每5毫升具有5毫克活性物質(A) iUB) 組成: 呈鹼式之活性物質(A)或(B) 5毫克 酸/鹽形成劑,形成中性鹽所必.須之量 足量 葡萄糖 250毫克 人類血清白蛋白 10毫克 1285550 250毫克 5毫升 A7 B7 五、發明說明(22 ) 糖呋喃醛 注射用水至 製備: 使糖吱喃趁與葡萄糖溶於注射用水(Wfl)中;添加人類血 清白蛋白;添加鹽形成劑;以加熱使活性物質溶解;以 Wfl補足至所指定之體積;於氮氣下轉移至安瓿瓶。 實例νπ 您皮下投藥溶液,每1毫升含有5臺#.活性物質⑷ 或(B) 組成: 活性物質(A)或(B) 5毫克 葡萄糖 50毫克 聚花揪酸酯80 = Tween 80 2毫克 注射用水至 1毫升 製備: 使葡萄糖與聚花楸酸酯溶於注射用水中;以加熱或使用 超音波,使活性物質溶解;以Wfl補足至所指定之體積; 於惰性氣體下,轉移至安瓿瓶。 實例vm 5注赶屋液二每ίο毫升含有100毫患質⑷或(B) 組成·· 活性物質(A)或(B) -· 100毫克 磷酸二氫單鉀=ΚΗ2Ρ04 12毫克 嶙酸氫二鈉=Na2HP04 · 2Η2 Ο 2毫克 -25 l·----------裝 *-------訂--------- (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 -一一 } i ί » r
A 3 ▲ * A 1285550 A7
發明說明(23) 氣化鈉 180毫克 人類血清白蛋白 50毫克 聚花楸酸酯80 20毫克 注射用水至 10毫升 製備: 使聚花揪酸酯80、氣化鈉、磷酸二氫單鉀及磷酸氫二鈉 溶於注射用水(Wfl)中;添加人類血清白蛋白;以加熱使活 性物質溶解;以Wfl補足至所指定之體積;轉移至安瓿瓶。 實例IX j東乾物,含有10毫克活性物皙(7^)或 組成: 呈鹼式之活性物質(A)或(B) 10毫克 酸/鹽形成劑,形成中性鹽所必須之量 足量 甘露醇 300毫克 注射用水至 2毫升 製備: (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 使甘露醇溶於注射用水(Wfl)中;添加鹽形成劑;以加熱 使活性物質溶解,·以Wfl補足至所指定之體積;轉移至小 玻瓶;凍乾。 凍乾物用之容剗: 聚花揪酸S旨80 = Tween 80 甘露醇 注射用水至 製備: 20毫克 206毫克 10毫升 -26- 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 1285550
五、發明說明(24 ) 經濟部智慧財產局員工消費合作社印製 使聚花楸酸酯80與甘露醇溶於注射用水_中;轉移至 安訊瓶。
實例X 兔乾物’含有5毫克活性物質(八)或(b、 組成: 呈鹼式之活性物質(A)或(B) 5古 極性或非極性溶劑(其可藉冷凍乾燥移除 — 製備: 笔升 使活性物質溶於適當溶劑中;轉移至小玻瓶;涑乾。 凍乾物用之溶劑: 聚花楸酸醋80 = Tween 80 5毫克 甘露醇 1〇〇毫克 注射用水至 2毫升 製備: 使聚花楸酸酯80與甘露醇溶於注射用水中;轉 安說瓶。 f
實例XI 片劑,含有20毫克活性物質 組成: 活性物質(A)或(B) 乳糖 玉米澱粉 硬脂酸鎂 波威酮(povidone) K 25 20毫克 120毫克 40·毫克 2毫克 18毫克 • -------------------訂---- (請先閱讀背面之注意事項再填寫本頁> S! -27- 1285550 A7 五、發明說明(25 ) 製備: 將活性物質、乳糖及玉米凝粉均勾地混合;以波威酬之 水溶液造粒;與硬脂酸錢混合;在壓片機中壓製;片劑重 量200毫克。 實例ΧΠ 膠囊,含有20毫克活性物皙 組成: 活性物質(A)或(B) 玉米澱粉 高度分散之矽石 硬脂酸鎂 製備: 2〇毫克 80毫克 5毫克 2·5毫克 i----------•裝------ (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 將活性物質、玉米殿粉及夕石均勻地混合;與硬脂酸鎂 混合;在膠囊充填機中,將混合物轉移至3號硬明膠膠囊 中。 實例xm 栓劑,含有50毫克活性物質(A)或ΠΒ) 組成: 活性物質(A)或(B) 50毫克 硬質脂肪(動物脂固體)足量至 1700毫克 製備: 使硬質脂肪在約38X:下熔解;··使已磨碎之活性物質均勻 地分散於熔融態硬質脂肪中;於冷卻至約35。(:後,傾倒至 急冷模具中。 -28- ‘紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 訂·III-----ΜΨ, 1285550 A7 五、發明說明(26 ) 實例 供鼻投藥之水溶液,含有古士 —--~~活性物質(A)或(B1 組成: 活性物質(A)或(B) 鹽酸,形成中性鹽所必須之量 對羥基苯甲酸(PHB)甲酯 對羥基苯甲酸(PHB)丙酯 純水至 製備: 使活性物質溶於純水中;夭*略A 士 ,、 添加鹽直到溶液透明爲 添加PHB甲酯與丙酯;以純. 、 ^ 、、七水將此落股補足至所指定 積;將此溶液殺菌過濾,並轉移至適當容器中。 實例XV 色盖投藥之水溶液,含活性物質⑷_ 組成: 10.0毫克 0.01毫克 0.005毫克 1.0毫升 止 經濟部智慧財產局員工消費合作社印製 活性物質(A)或(B) 1,2·丙二醇 羥乙基纖維素 花楸酸 純水至 製備: 5亳克 3〇〇毫克 5毫克 1毫克 1毫升 使活性物質溶於1,2-丙二醇中Γ在純水中製備本有4 之羥乙基纖維素溶液,並將其添加至活性物質 *化概酸 、 只义〉各液;脱 此》谷液殺囷過滤’並轉移至適當容器中。 、 29 ^紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公爱 --------^--------- (請先閱讀背面之注意事項再填寫本頁} I285550 A7 B7 五、發明說明(27 tj^ncvi 内投藥之水溶潘,人亡< ^ ^^7 "~克活性物質(A)或(B) 活性物質(A)或(B) ^ _ 5 ί:克 1,2-丙二醇 3〇〇毫克 甘露醇 、 50毫克 >王射用水(wfi)至 i古 製備: 〇
I 使活性物質溶於1,2_丙二醢 θ π # +、^ π ~轉中;以Wfl將此溶液補足至大 約所指定之體積;添加甘靈 人 a、μ政 耳露轉,並以Wfl補足至大約所指 疋之體積;將此溶液殺菌過滹,.^ y ^ 行熱壓處理。 固、遽,轉移至個別容器中’並進 f 例 ΧΥΠ 7·5亳克 ιοο·ο毫克 50·0亳克 50.0毫克 1·0亳升 脈内注射之脂皙體 組成: k 活性物質(A)或(B) 蛋卵嶙脂,例如Lipoid E 80 膽固醇 甘油 注射用水至 製備: 使活性物質溶於卵磷脂與膽固-醇之混合物中;將此々 添加至甘油與·之混合物中’並藉高,均化作用或;; 流體化床技術進行均化;於無菌狀態下,將所獲 -30 - 本紙張尺度適ffl巾园家標準(CNS)A4規格(210 X 297公爱 1285550 經濟部智慧財產局員工消費合作社印製 10.0毫克 7.0 4.0毫克 0.5毫升 A7 B7 五、發明說明(28 ) 體配方轉移至適當容器中。 實例xvm 供鼻投藥之懸淳浚,含有20毫克活性物質(A)或(¾ 組成: 活性物質(A)或(B) 20.0毫克 羧甲基纖維素(CMC) 20.0毫克 磷酸單氫鈉/磷酸二氫鈉緩衝劑,pH 6.8 適量 氣化鈉 8.0毫克 對羥基苯甲酸甲酯 0.01毫克 對羥基苯甲酸丙酯 0.003毫克 純水至 1.0毫升 製備: 使活性物質懸浮於CMC水溶液中;將其他成份連續添加 至此懸浮液中,並於此懸浮液頂部添加純水,至所指定之 體積。
實例XIX 供皮下投藥之水溶液,具有10毫克活性物質(a) < (p) 組成: 活性物質(A)或(B) 磷酸單氫鈉/磷酸二氫鈉緩衝劑,足量至pH 氣化鈉 注射用水至 ·· 數備: 使活性物質溶於磷酸鹽緩衝溶液中,於添加食鹽後,以 -31 - 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) l·----------裝 *-------訂--------- (請先閱讀背面之注意事項再填寫本頁) 1285550 A7 B7 五、發明說明(29 ) 水將此溶液補足至所指定之體積。將此溶液殺菌過濾,轉 移至適當容器中,並進行熱壓處理。
實例XX 供皮:L毯藥之含水浮液5毫克活Ί兔^A)或(B) 組成·· 活性物質(A)或(B) 5.0毫克 聚花楸酸醋80 0.5毫克 注射用水 0.5毫克 製備: 使活性物質懸浮於聚花楸酸酯80溶液中,並使用適各八 散技術(例如濕磨、高壓均化、微流體化等),粉碎=約1 微米之粒子大小。於無菌狀態下,將此懸浮液輕 —_丄 得牙夕至相應 容器中。 l·----------•裝--------訂---------^9— (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 -32- 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 X 297公釐)
Claims (1)
- 27 27 公告本 A8 rQcr C8 pS. 9 D8 · 1285觉P9115923號專利申請案 中文申請專利範圍替換本(95年9月) 六、申誚^專利範園 " 一種CGRP拮抗劑之用途,其係用以製備用於治療絕經 熱潮紅之醫藥組合物,其特徵在於該CGRp拮抗劑係選 自以下物質之中: (A) 1_[Ν2-[3,5·二溴·Ν-[[4-(3,4-二氫-2(1H)_ 酮基喹唑啉-3-基)-1_六氳吡啶基]羰基]路胺醯基]-L-離胺醯基]冬(44啶 基)_穴氣卩比卩井,(B) 1-[4-胺基-3,5-二溴-Ν_[[4-(2,3,4,5·四氫-2(1H)-酮基-1,3-苯 并二氮七圜-3-基)-1-六氫吡啶基]羰基]苯基-丙胺醯基]-4-(1-六氫p比淀基)-六氫P比淀, (C) 1-[N2 -[4-胺基-3,5_二溴-N-[[4-(3,4-二氫-2(1H)-酮基喹唑 啉-3·基)·1-六氫吡啶基]羰基]-D-苯丙胺醯基]心離胺醯基]·4_ (4-ρ比淀基)-六氫ρ比呼, (D) 1,[Ν2 -[4-胺基-3,5-二溴-Ν-[[4-(3,4-二氫·2(1Η)_酮基喹唑 啉-3-基)小六氫吡啶基]羰基]-D-苯丙胺醯基]心離胺醯基]-4-(4-p比淀基)-六氫0比淀,(Ε) 1-[Ν2 -[3,5-二溴-N-[[4-(l,3-二氫-4_苯基-2(2Η)·酮基咪唑-1-基)-1•六鼠ρ比淀基]窥基]-D-略胺酿基]離胺酸基]-4-(4-ρ比 啶基)·六氫吡畊, (F) 1-[Ν2 -[4·胺基-3,5-二溴·Ν-[[4-(1,3_二氫-4-苯基-2(2Η)-酮 基味唆-1-基)-1_ττ風?比咬基]談基]-D-冬基-丙胺酿基]-L-離 胺醯基]-4-(4-吡啶基)-六氫峨畊, (G) 1-[3,5-二溴-N-[[4-(3,4-二氫-2(1H)-酮基噻吩并[3,4-d]-嘧 淀基)小六氫?比淀基]談基]-D-赂胺酸基]-4-(1-六氫ρ比淀 基)-六氳p比淀, 65022-950927.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公嫠) 1285550 έ88 C8 D8 六、申請專利範園 (Η) 1·[4-胺基-3,5-二溴·Ν-[[4_(2,4-二氫-5-苯基 _3(3H)-酮基-1,2,4-三唑-2-基)-1-六氫吡啶基]羰基]_D-苯基丙胺醯基]-4-(1-甲基-4-六氫吡啶基)-六氫吡啶, (I) 1-[4-胺基-3,5-二溴-N-[[4-(2,4-二氫-5-苯基-3(3H)-酮基-1,2,4-三咬-2-基)-1-穴鐵*17比症基]窥基]-D·苯基丙胺酿基]_4-(1_ 六氫p比淀基)-六氫17比淀, (J) H4-胺基-3,5-二溴-N-[[4-(2,4-二氫·5·苯基-3(3H)-酮基-1,2,4-三唑-2-基)小六氫吡啶基]羰基]-D-苯基-丙胺醯基]-4-(1-甲基-4-六氩p比淀基)-六氫峨p井, (K) H4-胺基-3,5-二溴 _Ν·[[4-(3,4-二氫-2(1H)·酮基嘧吩[3,2-d]口密咬-3-基)-1-六氯?比淀基]談基]-D-秦基-丙胺酸基]·4-(1-ττ 氫ρ比淀基)-六氫峨淀, (L) 1-[4-胺基-3,5-二溴 _Ν-[[4-[1,3-二氫-4-[3-(三氟甲基)苯 基]-2(2Η)-酬基味峻-1_基]鼠11比1基]幾·基冬丙胺酿 基]-4-(1-乙基-4-TT農p比淀基)-六風p比’ (Μ) 1-[4-胺基·3,5-二溴-N_[[4-[3,4-二氫-2(1H)-酮基喹唑啉-3-基]_1_六氫吡啶基]羰基]-D-萃丙胺醯基]-4-(1-己基-4-六氫 外匕淀基)-六氫p比淀, (N) 1-[4-胺基-3,5·二溴-N_[[4_[3,4-二氫 _2(1H)_酮基喹唑啉- 3- 基]-1·六氫p比咬基]羰基]-D-苯丙胺醯基]-4-(1-環丙基甲基- 4- 六氫峨淀基)-六氫峨淀, (Ο) 1-[Ν-[[4-[3,4-二氫_2(1H)_酮基喹唑啉-3-基]小六氫吡啶 基]裝基]-3-乙婦基-D,L-苯丙胺醯基]-4_(六氫-1H-1·—氮七圜 婦基)-六氫p比淀, 65022-950927.DOC - 2 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1285550 έ88 C8 ____D8 六、申請專利範圍 (P) (R,S)-l_[4-[4-(3,4-二氫-2(1H)-酮基 p奎峻淋-3-基)-1-六氫 外匕淀基]-2-[(4-經基-3,5-二甲基苯基)甲基]_ι,4_二酮基丁基]-4-(1-六氫p比淀基)-六氫批淀, (Q) 1-[4·胺基_3,5_二溴·Ν·[[4-[Ν-(胺基羰基)-N-苯基-胺基]- 1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1·六氫吡啶基)_六氫 p比淀, (R) 1-[4-胺基-3,5-二溴 _N-[[4_(3,4-二氫-2(1H)-酮基 p奎峻琳- 3-基)小六氫吡啶基]羰基]苯丙胺醯基]-4-(5-甲氧基-4-嘧 啶基)-六氫吡畊, (S) 1-[4-胺基-3,5·二溴 _Ν-[[4-(1,1-二氧化-3(4H)-酮基-1,2,4-苯并嘍二畊-2-基)小六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-六氫峨淀基)-六氫p比淀, (T) 1-[4-胺基-3,5-二溴-Ν-[[4-[2(1Η)-酮基峻淋-3-基]-1-六氫 p比淀基]談基]-D-苯丙胺酿基]-4-(1-六氫峨淀基)-六氫p比症, (U) H4-胺基-3,5-二溴·Ν-[[4_[3,4-二氫·2(1Η)-酮基喹唑啉-3-基]·1·六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[3-(二甲胺基)丙 基]-六氫?比0井, (V) 1-[4-胺基-3,5-二溴-Ν·[[4-[3,4-二氫·2(1Η)_酮基喹唑啉-3-基]-1-六氫吡啶基]羰基]_D-苯丙胺韹基]·4-(4ν甲基-1-六氫 叶匕ρ井基)-六氫ρ比淀, (W) 1-[4-胺基 _3,5·二溴-Ν_[[4_[3,4-二氫-2(1Η)-酮基喳唑啉-3-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[(1-甲基-4-六氫 ρ比喊基)羰基]-六氫说ρ井, (X) 1·[4-胺基-3,5-二溴 _Ν-[[4_[3,4-二氫-2(1Η)-酮基喳唑啉- 65022-950927.DOC - 3 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1285550 έ88 C8 __ _D8 _ 六、申請專利範圍 3-基]-1-六氫吡啶基]羰基]苯丙胺醯基PK(1-甲基斗六氫 吡呼基)羰基]-六氫吡畊, (γ) 1-[4-胺基-3,5-二溴-Ν·[[4-(3,4-二氫-2(1Η)-酮基-喹唑啉 3-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[4-[4-(二甲胺基) 丁基]苯基]-六氫吡畊, (Z) 1-[4-胺基-3,5-二溴-N_[[4-(3,4-二氫·2(1Η)_酮基-喹唑啉- 3- 基)小六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[4-(二甲胺基)-1-六氫17比淀基]-六氫峨淀, (AA) 1_[N2_[[4-(1,3-二氫-4-苯基-2(2H)-酮基咪唑小基)-1-六 氫吡啶基]羰基]-Μ-甲基-D-色醯基]-4-(4-甲基小六氫吡畊 基)-穴氮卩比咬’ (AB) 1-[Ν2-[[4-(1,3-二氫 _4_ 苯基-2(2H)-酮基咪唑-1-基)·1-六 氫吡啶基]羰基]·ΝΗ1,1-二甲基乙氧羰基)-D·色醯基]-4-(1-甲 基-4-六氫p比淀基)-六氳ρ比咬, (AC) (R,S)-l-[4_[4-(3,4-二氳-2(1H)-酮基喹唑啉-3-基)小六氫 p比淀基]-2-[(3,5-二漠基-4-甲基苯基)T基]-1,4-二嗣基-丁基]_ 4- (4-甲基-1-六氫吡畊基)·六氫吡啶, (AD) (R,S)-l-[4-[4-(3,4-二氫·2(1Η)·酮基喹唑啉-3·基)小六氫 吡啶基]-2-[(3,5-二溴基-4-甲氧苯基)甲基]-1,4-二酮基丁基]-4_ (1-甲基-4-六氫ρ比淀基)-六氳π比淀, (AE) (R,S)-l_[4-[4-(3,4_二氳-2(1H)-酮基喹唑啉-3-基)小六氫 吡啶基]-2-[(3,4-二溴苯基)甲基]-1,4-二酮基丁基]冰(4-甲基小 六氫吡畊基)-六氫吡啶, (AF) 1-[Ν2·[Ν-[[4-(1,3-二氫-2(2H)-酮基苯并咪唑-1-基)小六 -4- 65022-950927.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1285550 έβ8 C8 __ D8 ___________ 六、申請專利範園 風ρ比淀基]幾基]·3,5-二溪-D-路胺酿基]-L-離胺酸基]比 淀基)-六氫p比呼, (AG) 1·[4-胺基 _3,5_二溴-N-[[4-(l,3-二氫 _6_羥基-2(2H)-酮基 苯并咪唑-1-基)-1-六氫吡啶基]羰基]苯丙胺醯基PK1-六 氫p比淀基)-六氫p比淀, (AH) 1-[N2_[4-胺基 _3,5_二溴-N-[[4-(l,3-二氫-2(2H)-酮基-苯 并咪唑-1-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]·Ν6,Ν6-二 甲基-L-離胺醯基]-4-(4-吡啶基)-六氫吡畊, (ΑΙ) 1-[Ν2-[4·胺基·3,5_二溴·Ν-[[4-(3,4-二氫-2(1H)-酮基喹 唑啉-3-基)小六氫吡啶基]羰基]-D-苯丙胺醯基]-N6,N6 -二甲 基-L-離胺醯基]-4-(4-吡啶基)-六氫吡呼, (AJ) (R,S)-l-[2_(4-胺基-3,5-二》臭基苯甲酿基)-4-[4-(3,4-^一 風-2(1H)-酉同基口奎唾淋·3-基)-1-ττ風口比淀基]_4_嗣基丁基]-4-(1-ττ 氫叶b淀基)-六氬ρ比淀, (AK) 1-[4_胺基·3,5·二溴-N_[[4-(3,4-二氫-2,2-二氧化-2,1,3-苯 并噻二畊-3-基)-1-六氫吡啶基]羰基]_D-苯基·丙胺醯基]-4·(1-六氫ρ比淀基)-六氫ρ比淀, (AL) 1-[4_胺基-3,5_二溴-N-[[4_[l,3-二氫-2(2Η)-酮基咪唑并 [4,5-c]喹啉基-3-基]-1-六氫吡啶基]羰基]-D-苯基丙胺醯基]-4-(1-ττ鼠卩比咬基)談基]氮卩比淀, (ΑΜ)1-[4-胺基-3,5-二溴-Ν·[[4-(3,4-二氫-2(1H)-酮基 p奎峻淋-3-基)-1-穴氫p比淀基]羰基]-D-苯丙胺醯基]_4-(1-六氫ρ比淀基)-六氫p比症, (八!^)1耶2-[3,5-二溴-1^[[4-(3,4-二氫-2(111)-酮基喹唑啉-3- -5- 65022-950927.DOC 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1285550 έ88 C8 D8 六、申請專利範圍 基)-1-六氫吡啶基]羰基]-D-赂胺醯基]-N6,N6 -二甲基-L-離胺 酿基]-4-(4-p比淀基)-六氫?比p井, (ΑΟ)1-[4-胺基-N-[[4-[4-(3-溴苯基)·1,3-二氫 _2(2H)_酮基咪 峻-1-基]-1-穴氯p比淀基]談基]-3,5-二溪-D_私丙胺酿基]-4-(1-甲基-4-六氫p比淀基)-六氫ϊ7比淀, (AP) 1-[4-胺基-3,5·二溴-Ν·[[4-[1,3-二氫-4-苯基-2(2H)-酮基 味峻_1_基]氮p比淀基]談基]-D-苯丙胺酿基]-4-(4-甲基-1-六氫说哨1基)-六氫p比淀, (AQ) 1-[4-胺基-3,5·二溴·Ν-[[4-[1,3-二氫-4-[3-(三氟甲基)苯 基]-2(2Η)-嗣基味吐-1-基]-1-7Τ氮ρ比淀基]談基]-D-苯丙胺酿 基]-4-(1-六氫ρ比淀基)-六氫ρ比淀, (AR) 1-[4-胺基-3,5-二溴-N-[[4-[l,3-二氫-4-[3-(三氟甲基)苯 基]-2(2H)-酮基咪唑-1-基]-1-六氫吡啶基]羰基]_D-苯丙胺醯 基]-4-(外向-8-甲基各氮雙環并[3,2,1]辛-3-基)-六氫吡畊, (AS) 1-[3,5-二溴-N-[[4-(l,3-二氫-4-苯基-2(2H)-嗣基味唾 _1_ 基)-1-穴氮p比淀基]談基]-D-酶胺酿基]-4-(1-六氫p比淀基)-六 氫对t淀, (AT) 1-[4-胺基-3,5-二溴·Ν·[[4-[1,3-二氫-4-[3·(三氟甲基)苯 基]_2(2Η)_酮基咪嗅-1_基]-1-六氫ρ比淀基]羰基]-D-苯丙胺醯 基]-4-(1-乙基-4-ΤΤ鼠卩比淀基)-ττ風峨ρ井, (AU) 1-[4-胺基-3,5·二溴-N-[[4-[l,3-二氫 _4-苯基-2(2Η)·酮基 咪唑-1-基]-1_六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(六氫-4-甲 基-1H-1,4-二氮七圜小基)六氫吡啶, (AV) 1-[3,5·二溴-Ν-[[4·(3,4_二氫-2(1H)_酮基 π奎唾琳-3-基)-1_ 65022-950927.DOC - 6 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 1285550 έΐ C8 _D8_ 六、申請專利範園 六氫吡啶基]羰基]-D-酪胺醯基]-4-[1-(甲基磺醯基)-4·六氫吡 淀基]-六氫p比咬, (AW) 1_[4_胺基-3,5-二溴-Ν-[[4-(1,3·二氫-4-苯基-2(2H)-酮 基咪唑-1-基)·1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-甲基- 4-六氫p比淀基)-六氫p比淀, (ΑΧ)1-[3,5-二溴·Ν-[[4-[1,3-二氫 _4-[3_(三氟甲基)-苯基]-2(2Η)_酮基咪唑-1-基]-1-六氫吡啶基]羰基]-D_酪胺醯基]-4-(六氫·1Η-1-—氮七圜烯基)-六氫吡啶, (AY) 1-[3,5-二溴·Ν-[[4_(3,4·二氫-2(1Η)-酮基喹唑啉-3-基)小 六氫吡啶基]羰基]-D-酪胺醯基]-4<1-甲基4-六氫吡啶基)-六 氫外b淀, (AZ) 1-[4·胺基-3,5-二溴-N-[[4_(3,4-二氫 _2(1H)-酮基-喹唑啉-3-基)-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(外向-8-甲基-8-氮雙環并[3,2,1]辛-3-基)-六氫吡畊, (BA) 1-[4-胺基-3,5-二溴-Ν·[[4_(1,3·二氫-4-苯基-2(2H)_ 酮基 咪唑-1-基)-1-六氫吡啶基]羰基]苯丙胺醯基]-4-(1甲基-4-六氫p比淀基)-六氫咕p井, (BB) 1-[3,5-二溴-N-[[4_[l,3-二氫-4-[3-(三氟甲基)-苯基]-2(2H)-酮基咪吐-1-基]-1_六氫吡啶基]羰基]-D-赂胺醯基]冰(1-六氫p比淀基)-六氫p比咬, (BC) 1-[N6-乙醯基-N2-[3,5-二溴·Ν·[[4-(3,4-二氫-2(1H)-酮基 喳唑啉-3-基)·1-六氫吡啶基]羰基]-D-酪胺醯基]-L-離胺醯 基]-4-(4-0比淀基)-六氫?比ρ井, (BD) 1-[3,5-二溴-N-[[4-(l,3-二氳-4-苯基-2(2Η)-酮基咪唑-1- 65022-950927.DOC - 7 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1285550 έ88 C8 D8 六、申請專利範園 基)-1-六氫吡啶基]羰基]-D-酪胺醯基]-4-(六氫·1Η-1-—氮七 圜婦基)-六氫ρ比淀, (BE) 1-[4-胺基·3,5-二溴-Ν-[[4·(1,3-二氫-4-(3-噻吩基)·2(2Η)· 網基味嗅-1-基風ρ比淀基]窥基]冬基-丙胺酿基]-4-(1· 甲基-4-六氫ρ比淀基)-六氫ρ比淀, (BF) 1-[4-胺基 _3,5_二溴-N-[[4-[l,3-二氫·4-[3-(三氟甲基)苯 基]-2(2Η)-酮基咪唑小基]小六氫吡啶基]羰基]-D-苯丙胺醯 基]-4-(1-甲基-4-六氫吡啶基)-六氫吡啶, (BG) 1_[3,5_ 二溴-N_[[4-(3,4-二氫-2(1H)-酮基喹唑啉-3-基)小 穴鼠卩比淀基]談基]-D-S§胺酸基]-4-[1-(技窥基-甲基)-4-ττ風 叶匕淀基]-六氫p比淀, (BH) 1-[4-胺基-3,5-二溴-N-[[4-[3,4-二氫-2(1H)-酮基-喹唑啉- 3- 基]-1·六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-甲基磺醯基_ 4- 六氫峨淀基)-六氫ρ比淀, (BI) 1-[3,5-二溴-Ν·[[4-(3,4-二氫·2(1Η)-酮基喹唑啉-3-基)小 六氫吡啶基]羰基]-D-酪胺醯基]-4-(4-六氫吡啶基)-六氫吡 淀, (BJ) 1·[4-胺基-3,5-二溴-Ν_[[4·(1,3-二氫斗苯基-2(2H)-酮基 咪唑-1·基)小六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-乙基-4- 六氫p比淀基)-六氫p比淀, (BK) 1-[4-胺基-3,5-二溴-N-[[4-(l,3-二氫-4·(3-羥基-苯基)_ 2(2Η)-酮基咪唑-1-基)小六氫吡啶基]羰基]-D-苯丙胺醯基 (1-甲基-4_六氫外b淀基)-六氫?比咬, (BL) 1-[3,5-二溴-Ν-[[4-(3,4·二氫-2(1H)·酮基喳唑啉-3-基)小 65022-950927.DOC - 8 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1285550 έ88 C8 _________ D8_________ 六、申請專利範圍 六氫吡啶基]羰基]-D_酪胺醯基]-4-(六氫—氮七圜婦 基)-六氫p比淀, (ΒΜ)1-[4_胺基·3,5-二溴-Ν-[[4·(1,3-二氫冬苯基-2(2H)-酮基 咪唑-1-基)-1-六氳吡啶基]羰基]苯丙胺醯基]4-(1-六氫吡 淀基)-六氫p比淀, (ΒΝ) 1·[4-胺基 _3,5_二溴 _N-[[4-[4-(3-溴苯基)-1,3-二氫-2(2H)-酮基咪唑-1-基]小六氫吡啶基]羰基]-D-苯基-丙胺醯基]-4-(外向-8-甲基-8-氮雙環并[3,2,1]辛-3-基}-六氫吡畊, (BO) 1-[4_胺基·3,5-二溴 _N-[[4-(3,4-二氫-2(1H)-酮基-喹唑啉-3-基)小氣卩比淀基]窥基]-D-苯丙胺酿基]-4-(1-乙基-4-7T氯 p比淀基)-六氫p比淀, (BP) 1-[4-胺基-3,5-二溴-N-[[4-(3,4-二氫-2(1H)-酮基-喹唑啉-3-基氮p比淀基]魏基]-D-苯丙胺酿基]-4-(1-乙基-4-氯 叶匕淀基)-六氫峨p井, (BQ) 1·[4-胺基-3,5·二溴-N-[[4-[l,3-二氫-4-(3-甲氧基-苯基) 2(2H)-酮基咪唑-1-基]-1_六氫吡啶基]羰基]苯丙胺醯基]-4-(外向各甲基-8-氮雙環并[3,2,1]辛-3-基)-六氫吡畊, (BR) 1-[3,5-二溴-N-[[4-(3,4-二氫-2(1H)_酮基喹唑啉 _3_基)-1· 六氫吡啶基]羰基]-D-酪胺醯基]-4-[1-(環丙基-甲基)-4-六氫 峨淀基]-六氫p比淀, (BS) 1-[4-胺基-3,5-二溴 _N-[[4-(3,4-二氫·2(1Η)-酮基喹唑啉· 3-基)·1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(六氫-1Η-1-—氮 七園婦基)-六氫ρ比淀, (BT) 1-[4_胺基-3,5-二溴-N-[[4-(3,4-二氫·2(1Η)-酮基-喹唑啉- 65022-950927.DOC - 9 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1285550 A8 B8 C8 D8 六、申請專利範園 " 3-基風p比淀基]談基]-D-苯丙胺醯基]-4-(4-六氫p比淀基)-六氫吡啶, (BU) 1-[3,5-二溴-N-[[4-(l,3-二氫-4_苯基-2(2H)-酮基-咪唑小 基氫p比淀基]談基]-D-酶胺醯基]-4·(4-ρ比淀基)-六氫p比 淀, (BV) 1_[3,5-二溴-N-[[4-[l,3_ 二氫-4-[3-(三氟甲基)-苯基] 2(2Η)·酮基咪唑-1-基]-1-六氫吡啶基]羰基]-D-路胺醯基]-4·(1-甲基-4-六氫ρ比淀基)-六氫被ρ井, (BW) l-[N2-[3,5-二溴·Ν·[[4-[1,3-二氫-4-[3-(三氟甲基)苯基]-2(2Η>酮基咪唑-1-基]-1-六氫吡啶基]羰基]酪胺醯基]心離 胺醯基]-4·(4-吡啶基)-六氫吡畊, (ΒΧ) 1·[3,5·二溴-N-[[4-(l,3-二氫·4-(3-ρ塞吩基)-2(2Η)-嗣基味 唆-1-基)-1-ττ氯ρ比淀基]窥基]-D-酷胺酿基]-4-(1-六氯ρ比咬 基)-六氫p比淀, (BY) 1-[4-胺基-N-[[4-[4-(3-氯苯基 >1,3·二氫-2(2H)-酮基咪 咬·1-基]-1-穴氮p比淀基]談基]-3,5-二 >臭-D-苯丙胺酿基]-4·(1· 甲基-4-六氫外1:淀基)-六氫外t;淀, (BZ) 1-[4-胺基-3,5-二溴-Ν-[[4-[1,3·二氫·4_[3-(三氟甲基)苯 基]-2(2Η)-酮基咪唑-1-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯 基]-4-(六氫_1Η·1-—氮七圜烯基 >六氳吡啶, (CA) 1-[4-胺基-3,5-二溴-N-[[4-[l,3-二氫-4-[3-(三氟甲基)苯 基]-2(2Η)-酮基咪唑-1-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯 基]-4·(1-甲基-4-六氫吡啶基)-六氫吡畊, (CB) 1-[4-胺基-Ν-[[4-[4-(3-氯苯基)-1,3-二氫·2(2Η)-酮基咪 65022-950927.DOC - 10 - 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1285550 έΐ C8 _;__D8 穴、申請專利範圍 唑-1-基]-1-六氫吡啶基]羰基]-3,5-二溴-D-苯丙胺醯基]-4-(六 氫-1H-1-—氮七圜浠基)-六氫p比淀, (CC) 1-[4·胺基-3,5-二溴-N-[[4_(l,3-二氫-4-苯基-2(2H)-酮基 咪唑-1-基)小六氫吡啶基]羰基]_D-苯丙胺醯基]-4-(4-吡啶 基)-六氫?比p井, (CD) 1-[3,5-二溴-N-[[4-(l,3-二氫-4-苯基·2(2Η)_酮基咪唑-1-基)-1-六氫吡啶基]羰基]-D-酪胺醯基]-4-(1-甲基-4-六氫吡啶 基)-六氫p比淀, (CE) 1-[4-胺基-3,5-二溴·Ν-[[4-[1,3_ 二氫-4-苯基·2(2Η)·酮基 咪唑-1-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-[4·(1·酮基 乙基)苯基]-六氫吡畊, (CF) 1-[3,5-二溴 _Ν-[[4-[3,4-二氫-2(1Η)_酮基喹唑啉-3-基]小 六氫吡啶基]羰基]-D-酪胺醯基]-4-(1-甲基-4-六氫吡啶基)-六 氫外b _, (CG) 1_[4-胺基-3,5-二溴 _Ν-[[4-[1,3-二氫-4-(3-硝基苯基)-2(2H)-嗣基味嗤-1-基]-1-7T氮p比淀基]談基]-D-苯丙胺酿基]-4· (1-曱基-4-六氫峨淀基)-六氫p比淀, (CH) 1-[4-胺基-3,5-二溴-Ν·[[4-[3,4_二氫-2(1H)-酮基-喹唑啉· 3-基]-1-六氫吡啶基]羰基]-D-苯丙胺醯基]-4-(1-四氫吡咯基)-六氫p比淀, (Cl) 1-[4-胺基-3,5-二溴 _Ν-[[4-(1,3-二氫-4_ 苯基-2(2H)-酮基 咪唑-1-基)·1-六氫吡啶基]羰基]-D_苯丙胺醯基]-4-(六氫-1H-1-一氮七圜埽基)-六氫外b淀,及 (CJ) 1_[4_胺基-3,5-二溴-Ν-[[4·(1,3-二氫-4-(3-噻吩基)-2(2H)· 65022-950927.DOC - 11 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1285550 as Β8 C8 __ ____ D8 六、申請專利範園 嗣基咪m Μ-六氫吡啶基]羰基]-D-苯基-丙胺醯基]-4-(1-甲基-4-:ΓΓ氫P比淀基)_六氫p比TT井, 及其生理學上可接受之鹽。 2.根據申請專利範圍第1項之用途,其特徵在於其係作為 激素替補療法之補充而達成。 3·根據申請專利範圍第1項之用途,其特徵在於該醫藥組 合物只含有一個活性物質。 4· 一種用於治療絕經熱潮紅之醫藥組合物,其含有選自根 據申請專利範圍第1項族群之CGRP拮抗劑作為活性物 質’視情況伴隨著一或多種惰性載劑及/或稀釋劑。 -12- 65022-950927.DOC本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐)
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DE19952147A1 (de) | 1999-10-29 | 2001-05-03 | Boehringer Ingelheim Pharma | Neue Cyclopropane, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
DE10139410A1 (de) * | 2001-08-17 | 2003-02-27 | Boehringer Ingelheim Pharma | Verwendung von BIBN4096 in Kombination mit anderen Arzneistoffen gegen Migräne für die Behandlung von Migräne |
US7115609B2 (en) | 2001-12-12 | 2006-10-03 | Eli Lilly And Company | Alanyl-piperidine heterocyclic derivatives useful against cardiovascular diseases |
DE10206770A1 (de) * | 2002-02-19 | 2003-08-28 | Boehringer Ingelheim Pharma | Verfahren zur Herstellung eines Pulverinhalativums enthaltend ein Salz des CGRP-Antagonisten BIBN4096 |
US6900317B2 (en) | 2002-02-19 | 2005-05-31 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Salts of the CGRP antagonist BIBN4096 and inhalable powdered medicaments containing them |
DE10207026A1 (de) * | 2002-02-20 | 2003-08-28 | Boehringer Ingelheim Kg | Pulverinhalativum, enthaltend den CGRP-Antagonisten BIBN4096 und Verfahren zu dessen Herstellung |
DE10227294A1 (de) * | 2002-06-19 | 2004-01-08 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Zubereitungen zur intranasalen Applikation ausgewählter, von Aminosäuren abgeleiteter CGRP-Antagonisten sowie Verfahren zu deren Herstellung |
US7595312B2 (en) | 2002-10-25 | 2009-09-29 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Selected CGRP antagonists, processes for preparing them and their use as pharmaceutical compositions |
DE10250080A1 (de) * | 2002-10-25 | 2004-05-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
DE10300973A1 (de) * | 2003-01-14 | 2004-07-22 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Neue Carbonsäuren und deren Ester, diese Verbindungen enthaltende Arzneimittel und Verfahren zu ihrer Herstellung |
EP1648466A1 (en) * | 2003-07-07 | 2006-04-26 | Boehringer Ingelheim International GmbH | Use of cgrp antagonists in treatment and prevention of hot flushes in prostate cancer patients |
AU2004259675A1 (en) * | 2003-07-15 | 2005-02-03 | Merck & Co., Inc. | Hydroxypyridine CGRP receptor antagonists |
DE10338399A1 (de) * | 2003-08-18 | 2005-03-17 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Mikropartikel, enthaltend den CGRP-Antagonisten 1-[N2-[3,5-Dibrom-N-[[4-(3,4-dihydro-2(1H)-oxochinazolin-3-yl)-1-piperidinyl]carbonyl]-D-tyrosyl]-L-Iysyl]-4-(4-pyridinyl)-piperazin, Verfahren zu deren Herstellung sowie deren Verwendung als Inhalaltionspulver |
DE102004015723A1 (de) | 2004-03-29 | 2005-10-20 | Boehringer Ingelheim Pharma | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
DE102004019492A1 (de) * | 2004-04-22 | 2005-11-10 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Ausgewählte CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
US7696195B2 (en) | 2004-04-22 | 2010-04-13 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
DE102004063755A1 (de) * | 2004-12-29 | 2006-07-20 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung von CGRP-Antagonisten zur Behandlung und Vorbeugung von Hitzewallungen bei Patienten mit Prostatakrebs |
DE102004063752A1 (de) * | 2004-12-29 | 2006-07-13 | Boehringer Ingelheim Pharma Gmbh & Co. Kg | Verwendung ausgewählter CGRP-Antagonisten zur Bekämpfung menopausaler Hitzewallungen |
US7491717B2 (en) | 2005-03-23 | 2009-02-17 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
EP1770091A1 (de) | 2005-09-29 | 2007-04-04 | Boehringer Ingelheim Pharma GmbH & Co. KG | CGRP-Antagonisten, Verfahren zu deren Herstellung sowie deren Verwendung als Arzneimittel |
US7439237B2 (en) | 2005-04-15 | 2008-10-21 | Boehringer Ingelheim International Gmbh | Selected CGRP-antagonists, process for preparing them and their use as pharmaceutical compositions |
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US5910482A (en) * | 1996-03-19 | 1999-06-08 | Board Of Regents, The University Of Texas System | Treatment or prevention of preeclampsia, eclampsia with calcitonin gene related peptide, CGRP analog, progestational agent, nitric oxide source, and cyclooxygenase inhibitor |
US5710024A (en) * | 1996-07-23 | 1998-01-20 | Smithkline Beecham Corporation | Polynucleotides that encode the calcitonin gene-related peptide receptor coponent factor (HOUNDC44) |
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1999
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2000
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