TWI299663B - Methods of treatment - Google Patents
Methods of treatment Download PDFInfo
- Publication number
- TWI299663B TWI299663B TW092112854A TW92112854A TWI299663B TW I299663 B TWI299663 B TW I299663B TW 092112854 A TW092112854 A TW 092112854A TW 92112854 A TW92112854 A TW 92112854A TW I299663 B TWI299663 B TW I299663B
- Authority
- TW
- Taiwan
- Prior art keywords
- platelet aggregation
- metabolite
- valsartan
- methyl
- acid
- Prior art date
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- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000012439 solid excipient Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000010959 steel Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000004575 stone Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960000651 tasosartan Drugs 0.000 description 1
- ADXGNEYLLLSOAR-UHFFFAOYSA-N tasosartan Chemical compound C12=NC(C)=NC(C)=C2CCC(=O)N1CC(C=C1)=CC=C1C1=CC=CC=C1C=1N=NNN=1 ADXGNEYLLLSOAR-UHFFFAOYSA-N 0.000 description 1
- 150000004101 tasosartan derivatives Chemical class 0.000 description 1
- 229960005187 telmisartan Drugs 0.000 description 1
- 150000004100 telmisartan derivatives Chemical class 0.000 description 1
- 150000003505 terpenes Chemical class 0.000 description 1
- 235000007586 terpenes Nutrition 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- WMIMTKPCWTYEPD-UHFFFAOYSA-N tetrabutylphosphanium;azide Chemical compound [N-]=[N+]=[N-].CCCC[P+](CCCC)(CCCC)CCCC WMIMTKPCWTYEPD-UHFFFAOYSA-N 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000004299 tetrazol-5-yl group Chemical group [H]N1N=NC(*)=N1 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- PHWBOXQYWZNQIN-UHFFFAOYSA-N ticlopidine Chemical compound ClC1=CC=CC=C1CN1CC(C=CS2)=C2CC1 PHWBOXQYWZNQIN-UHFFFAOYSA-N 0.000 description 1
- 229960005001 ticlopidine Drugs 0.000 description 1
- COKMIXFXJJXBQG-NRFANRHFSA-N tirofiban Chemical compound C1=CC(C[C@H](NS(=O)(=O)CCCC)C(O)=O)=CC=C1OCCCCC1CCNCC1 COKMIXFXJJXBQG-NRFANRHFSA-N 0.000 description 1
- 229960003425 tirofiban Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- JSPLKZUTYZBBKA-UHFFFAOYSA-N trioxidane Chemical compound OOO JSPLKZUTYZBBKA-UHFFFAOYSA-N 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 229960005356 urokinase Drugs 0.000 description 1
- 229940070710 valerate Drugs 0.000 description 1
- 208000019553 vascular disease Diseases 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000007998 vessel formation Effects 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 1
- 229960005080 warfarin Drugs 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
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Description
l299663 玖、發明說明: 【發明所屬之技術領域】 本^明係關於一種抑制血小板凝集之方法,其包括投予於 治療上有效量之ARB或其代謝物,尤其是瓦沙坦(vaisan 或其代謝物戊醯基4-羥基瓦沙坦。 【先前技術】 瓦沙坦(Valsartan)可選擇性阻斷血管緊張素π結合至引起 血管擴張之Ατι受體,且使醛留酮分泌變少。最近之臨床研究 證明瓦沙坦對一群曾患急性血管症狀之病患具額外效益。考 量血小板活化在冠狀動脈及腦血管阻塞之發病上扮演重要角 色且AT1雙體存在於血小板表面,因此評估瓦沙坦及其主要肝 臟代4ί物戊自监基4-¾基瓦沙坦對具有血管疾病之多重危險因 子之個體之活體外效果。 【發明内容】 本發明一目的係有關抑制血小板凝集之方法,包括對需要 之病患投予治療有效量血管緊張素Π受體阻斷劑(”ARB,,),較 好為瓦沙坦(valsartan)或其醫藥接受性鹽,視情況存在有醫藥 接受性載劑。 本發明另一具體例係有關一種抑制血小板凝集之方法,包 括對於需要之病患投予治療有效量之ARB代謝物,尤其是瓦 沙坦之代謝物(戊醯基4-羥基瓦沙坦),視情況存在有醫藥接 受性載劑。 、本發明另-目的係提供-種治療與血小板凝集有關之病況 之方法’包括對需要之病患投予ARB或ARB之代謝物。與血 84878 1299663 小板凝集有關之病況包含急性心肌梗塞、缺血性中風、心絞 痛、急性冠狀動脈徵候群、TIA (暫時性缺血侵襲、或急性腦 血管徵候群)、心臟衰竭、缺血造成之胸腔疼痛、徵候群X、 血栓性栓塞症、肺高血壓、糖尿病、末梢血管疾病、深度血 管之血栓形成、任何血管之動脈性血栓形成、導管血小板阻 塞或再阻塞。 本發明另一目的係有關一種醫藥組合物,該組合物包括 ARB或ARB之代謝物及醫藥接受性載劑。 【實施方式】 AT1-受體拮抗劑(亦稱為血管緊張素η受體拮抗劑)據了 為可結合至血管緊張素π受體之Ατι-受體亞型但不會造成我 體活化之活性成分。由於Ατι受體抑制結果,該等拮抗劑可又 用於例如避免血小板凝集及治療與其相關之病況。 使
An文體拮抗劑之種類包括具有不同結構特性之化合物, 本上較好為非吠者。本發明範園中之ARBs包含瓦沙^复基 式(Ik AT1文體拮抗劑⑻叛基_2_甲基-丙基為 酉皿基也[2;(1H-四唆-5-基)聯苯|基_甲基]胺: 戊
84878 1299663 且揭示於EP 0443983 A及美國專利第5,399,578號中,該揭示 併於本文供參考。其他ARB化合物包含(但不限於)羅莎坦 (losartan)、肯代沙坦(candesartan)、愛普沙坦(eprosartan)、 愛貝沙坦(irbesartan)、沙派沙坦(saprisartan)、塔索沙坦 (tasosartan)、泰米沙坦(telmisartan)、歐美沙坦(olmesartan) 、唑藍沙坦(zolarsartan)(l-[[3-溴-2-[2-(1Η·四唑-5-基)苯基 ]-5-冬并咬喃基]甲基]-2-丁基-4 -氯-1Η-味咬-5-叛酸,及3_(3-溴-2-[2-(1Η·四吐-5-基)-苯基]-苯并吱喃-5-基甲基)-2-丁基 -5-氯-3H-咪吐-4-叛酸、methyl 2-[[4-丁基-2-甲基-6-氧代 -5-[[2’-(1Η-四唑·5·基)[1,1’_聯苯]-4·基]甲基]-1(6H)·嘧啶基] 甲基]-3·塞吩羧酸甲酯亦稱為LR-B/081及methyl 2-[[4-丁基 -2-甲基-6·氧代-5-[[2’_(1Η-四唑-5-基)[1,1’_聯苯]-4-基]甲基 ]-1-(6Η)-嘧啶基]甲基]-3-塞吩羧酸甲酯亦稱為3k,LR-B/081 ,其在3-位置導入(羧基雜芳基)甲基基團(Lusofarmaco)、揭 示於 Biol Pharm Bull 2000年 2 月;23(2):174-81 中之 2,7-二乙基 -5_[[2f-(lH-四唑-5-基)聯苯-4-基]甲基]-5H-吡唑并 [l,5-b][l,2,4]-三唑钾鹽(亦稱為 YM 358 (Yamanouchi))、揭示 於丁111*〇11^1^8 2002 3 15;105(6):531-6之1^15 8,809,揭示於心 臟血管藥理期刊1995 1; 25(1):22-9之KT3 671、揭示於心臟血 管藥理期刊 1998 4 ;31(4):568-75之 TA 606、揭示於 Fundam Clin Pharmacol 1997; 1 1 (5): 3 95-401 之 ΤΗ 142177、揭示於Br J Pharmacol 1997 2; 120(3):488-94之 UP269-6,下式之稱為 E-1477之化合物: ^99663
下式稱為SC-52458之化合物:
及下式稱為化合物ZD-8731之化合物:
或在各例中之其醫藥接受性鹽。 已意外地發現ARBs之代謝物亦可明顯降低血小板凝集。 ARB之代謝物包含羅莎坦之代謝物,其為2_正丁基_心氯 小[(2’-(1Η,唑-5-基)聯苯_4_基)甲基]咪唑巧_羧酸鹽酸鹽( 84878 1299663 亦稱為 EXP_3 174,揭示於 J Pharmacol Exp Ther 1990 1〇· 255 (1):211_7) ’ 及代謝物 EXP_3 174 (11)(揭示於 j chromatogr 1992 1? 17;573(2):295-301); 愛貝沙坦之代謝物,其為(1)愛貝沙坦之四-葡糖醛酸 咁共軛物、(2)由丁基側鏈之ω -1氧化產生之單羥基化代謝物 、(3,4)因螺環戊燒之環被氧化產生之二種不同單經基化代謝 物,(5)因丁基側鏈之ω _ 1氧化及螺環戊垸之環被氧化產生乏 二元醇,(6)因ω -1單幾基代謝物進一步氧化產生之酮基代謝 物,(7)因二元醇之ω-l羥基進一步氧化產生之酮基-醇,及 (8)Drug Metab Dispos 1998 5; 26(5):408-17 中揭示之因丁基 側鏈之終端甲基氧化產生之羧酸代謝物; 肯代沙坦塞樂替(cilexetil)之代謝物(其為肯代沙坦(2_乙氧基 1-[[2’-(1Η-四唑-5-基)聯苯-4-基]甲基]-1H-苯并咪唑_7_羧酸( 亦稱為 CV 11974 及CV-15959,揭示於Clin Pharmacokinet 2002;41(1):7-17? J Chromatogr B Biomed Sci Appl 1999 8 20;731(2):411-7,及 J Hum Hypertens 1997 9; 11 增補版 2:S19-25 中); 泰米沙坦之代謝物,其為1-鄰-醯基葡糖醛咁,揭示於Drug Metab Dispos 1999 10; 27(10):1143-9 ; 歐美沙坦鎂代索米(medoxomil)之代謝物,其為歐美沙坦或cS866 ,揭示於J Hypertens Suppl 2001 Jun; 19增補版 1:S21-32 ; 愛普沙坦之代謝物’其為匍糖酸咐’揭不於Pharmacotherapy 1999 4; 19(4 Pt 2):73S-78S ; 塔索沙坦之代謝物,其係因諾塔索沙坦(enohasosartan),揭 84878.doc -10 - 1299663 示於 J. Pharmacol Exp Ther 2000 11; 295(2):649-54,及五種其 他代謝物,揭示於醫藥化學期刊1998,10. 22, 41(22),4251-60 ; 唑藍沙坦之代謝物,其為葡糖醛酸共軛物,及五種相關之生 物轉換產物、在脂族系側鏈上經輕基化之三種,進一步氧化 成酮之一種及在苯環上經經基化之一種揭示於j Pharm
Biomed Anal 1994 9; 12(9): 1181-7及J Pharm Biomed Anal 1994 9; 12(9):1181-7 ; ZD-873 1之代謝物; (5-[(3,5-二丁基·1Η_1,2,4·三唑-1-基)甲基]-2-[2-(lH-四唑-5-基苯基)]吡啶之代謝物(亦稱為SC-52458之代謝物),揭示於心 臟血管藥理期刊1993 10; 22(4):617-25 ; 及下列 ARB之代謝物:ZD-873 1 (Zeneca)、methyl 2·[[4_丁基 _2_甲基·6·氧代_5-[[2’_(1Η-四唑·5_基)[1,Γ-聯苯]-4-基]甲基 ]-1(6Η)-嘧啶基]甲基]-3-塞吩羧酸甲酯(亦稱為LR-B/081),及 methyl 2-[[4-丁 基 _2_ 甲基 _6_氧代 _5-[[2’-(1Η-四唑-5-基)[1,1,-聯苯]-4-基]甲基]-1 - (6Η)〃密淀基]甲基]-3-塞吩羧酸甲酯(亦 稱為3k,LR-B/081),其在3-位置導入(羧基雜芳基)甲基基團 (Lusofarmaco),2,7-二乙基 _5-[[2,-(1Η-四唑 _5_基)聯苯-4-基] 甲基]-511-吡唑并[1,5_13][1,2,4]_三唑钾鹽(亦稱為丫皿358 (Yamanouchi),揭示於Biol Pharm Bull 2000 2; 23(2):174-81) ,L-158,809(揭示於 Thromb Res 2002 3 15; 105(6):53 1-6),KT3 671(揭示於心臟血管藥理期刊丨995 1; 25(1 ):22_9),ΤΑ 606( 揭示於心臟血管藥理期刊1998 4; 31(4):568-75),ΤΗ 142177( 84878 -11 - 1299663 揭示於 Fundam Clin Pharmacol 1997;1 1(5):395-401)及 UP 269-6(揭示於 Br J Pharmacol 1997 2; 120(3):488-94)。 較佳為瓦沙坦之代謝物,其為具有下式之戊醯基4-羥基瓦 沙坦:
揭示於 Waldmeier F.,等人,Xenobiotica,1997,卷 27,第 1期, 59-71頁,其均併於本文供參考。 ARB及其代謝物在本文中可稱為π本發明化合物π 〇本發明化 合物依其取代基之性質可具有一或多個非對稱中心。所得非 立體異構物、對映體及幾何異構物均包含於本發明。 依據選用之起始物質及方法,化合物可為異構物之一或其 混合物之形式,例如,實質上純的幾何(順式或反式)異構物 、光學異構物(對映體)、消旋體或其混合物。前述可能之異 構物或其混合物均包含於本發明範圍中。 異構物之任何最終混合物均可依其結構之物理化學差異, 以例如層析及/或分段結晶分離成純的幾何或光學異構物、非 立體異構物、消旋體。 84878 -12- 1299663 終產物或中間物之任何所得消旋體均可以已知方法解析成 先學對映ff,例如分離其非立體異構物鹽,以光學活性之酸 或驗U並釋出光學活性之酸性或驗性化合物。羧酸中間物 因此可藉由例如使下列分段結晶’解析成其光學對映體:d_ 或=(α_甲基爷基胺、辛尼可丁、辛可寧、喹寧、喹尼丁、 麻,、素去氫松香胺 '馬錢子驗或番目酿驗鹽。消旋產物 亦可藉由對掌性層析,例如使用對掌性吸附劑之高壓液相声 析。 曰 最後,本發明化合物亦可為游離形式,或若含有鹽形成基 則為其鹽。 本發明之酸性化合物可藉其醫藥接受性鹼轉化成鹽,例如 驗金屬氫氧化物水溶液’且較好在醚或醇溶劑如低碳燒醇存 在下轉化。由後者之溶液,鹽可以醚(例如乙醚)沉澱。所得 义鹽可藉由以酸處理轉化成游離化合物。此等或其他鹽亦可 用於純化所得化合物。 具有鹼性基之本發明化合物可轉化成酸加成鹽,尤其是醫 木接文性鹽。其係與例如無機酸如礦酸例如硫酸及磷酸或气 鹵酸,或與有機羧酸如(C1-C4)-烷羧酸(其為例如未經取代或 經_素取代)例如乙酸,如飽和或不飽和二羧酸例如草酸、丁 一酸、順丁烯二酸或反丁晞二酸,如羥基_羧酸例如乙醇酸、 乳酸、蘋果酸、酒石酸或檸檬酸,如胺基酸例如天門冬胺酸 或议胺級或與有機續酸如(C1-CU)-燒基-續酸(例如甲燒碍酸 )或芳基—酸(其為未經取代或經取代(例如經自素取代))所形 成者。較佳為與鹽酸、甲燒績酸及順丁缔二酸形成之_。 84878 -13- 1299663 鑒·於游離化合物與其鹽形式之化人弘 、 八 口物間〈緊密關聯,本說 明書中有關本化合物,亦包含豆相對處、 匕口 /、祁對應 < 鹽,其條件為其在 環境下可能或適當者。 化合物(包含其鹽)亦可以其水合物形式存在,或包含用以 結晶之其他溶劑。 本發明另-目的包含醫藥組合物,其包括治療有效量之本 發明化合物及醫藥可接受性載劑。本發明之醫藥組合物可依 本身已知方式製備,且適於經腸道如口服或直腸及非經腸道 對哺乳動物(溫血動物包含人類)投藥,該醫藥組合物包括醫 藥有效量之醫藥活性化合物(單獨或與一種或多種醫藥可接 文性載劑併用),尤其適用於經腸道或非經腸道之應用。一般 之口服調配物包含錠劑、膠囊、糖漿、甘草劑及懸浮劑。一 般之可注射調配物包含溶液及懸浮液。該醫藥組合物可用於 治療受血小板凝集調節之病況,尤其是急性心肌梗塞、缺血 性中風、心绞痛、急性冠狀徵候群、TIA (短暫缺血侵襲或急 性腦血管徵候群)、心臟衰竭、局部缺血造成之胸腔疼痛、^ 候群X、血栓性栓塞症、肺高血壓、糖尿病、末梢血管疾病 、深度血管之血栓形成、任何血管之動脈性血栓形成、導管 血小板阻塞或再阻塞。 上述調配物中所用之一般醫藥可接受載劑列舉者為:醫藥 調配物常用之糖類如乳糖、蔗糖、甘露糖醇及山梨糖醇;殿 粉如玉米澱粉、樹薯粉及馬鈴薯澱粉;纖維素及衍生物如幾 基甲基纖維素鈉、乙基纖維素及甲基纖維素;磷酸舞如鱗酸 二鈣及磷酸三鈣;硫酸鈉、硫酸鈣;聚乙烯基吡咯咬網;聚 84878 -14- 1299663 乙晞基醇;硬脂酸;鹼土金屬硬脂酸鹽如硬脂酸鎂及硬脂酸 转,硬脂酸;植物油如花生油、棉子油、芝麻油、橄揽油及 玉米油;非離子、陽離子及陰離子界面活性劑;乙二醇聚合 物;石環糊精;脂肪醇;及氫化榖類固體以及其他無毒性可 相容填料、結合劑、崩解劑、緩衝劑、防腐劑、抗氧化劑、 潤滑劑、矯味劑等。 此等醫藥製劑係供經腸道用如口服亦可經直腸或非經腸道 對溫血動物投藥,且該製劑包括醫藥活性化合物,其為單獨 使用或與慣用之醫藥佐藥物質併用。例如,該醫藥製劑係由 約0.1 %至90%,較好約1%至約80%之活性化合物組成。經腸 道或非經腸道投藥之醫藥製劑為例如單位劑型如包衣鍵、錠 ^ 膠嚴、或栓劑以及安親。其亦依本身已知方式製備,例 如使用慣用之混合、造粒、包衣、溶解或凍乾製程。因此, 口服使用之醫藥製劑可藉由混合活性化合物與固體賦型劑, 右而要,使所得之混合物造粒,及若需要則使混合物或顆粒 在添加適當佐藥物質後,加工成錠劑或包衣錠蕊。 ARBS (尤其是瓦沙坦)及ARBs之代謝物(尤其是戊醯基仁羥 基瓦沙坦)均可與其他藥劑併用,例如本技藝提出之有效治療 劑。該治療劑包含肝素、苄丙酮香豆素、t_pA、尿激酶、溶 栓激酶、阿斯匹靈、替羅吡啶(ticlopidine)、羅比多葛 (cl〇pid〇grel)、愛希色脈(abciximab)、愛替非呔㈣tifibatide) 曰、、隹非班(tirofiban)、柷高血壓劑及抗糖尿病劑。 活性化合物之劑量可依各種因素而定,如投藥模式、溫血 動物種類、年齡及/或個體病況。 84878 -15- 1299663 本發明活性成分之較佳劑量 沙坦之劑量。 為治療有效劑量 尤其市售瓦 、通常,本發明化合物經口投藥之例中,對於體重約 尤涡患,預估每日劑量約0.1毫克至約360毫克。 瓦沙坦係以適當劑型投藥,例如膠囊或錠劑,且包括治療 有效量例如約20至約320毫克之可對病患投藥之瓦沙相。活性 成分之使用可達每日三次,例如以日㈣戰克或仙毫克之 瓦沙坦開始’增加至每日80毫克,且進一步增至每日16〇毫克 至320毫克。較好’瓦沙坦係以每日—或二次對病患投藥,且 每次之劑量分別為80毫克或16G毫克。對應之劑量可在例如早 晨、中午或晚上服用。 在戊醯基4-羥基瓦沙坦之例中,較佳劑型為例如錠劑或膠 囊,其對約50至75公斤之哺乳類而言,包括約丨毫克至約1〇〇〇 *克,較好約5毫克至約5〇〇毫克,更好約2〇毫克至約32〇毫克 ,每曰一次投藥。 上述劑量包含治療有效量之本發明活性成分。 意外地發現ARBs (尤其是瓦沙坦)及ARBs之代謝物(尤其 是戊醯基4-羥基瓦沙坦)均展現明顯之體外人類血小板抑制 作用。 本發明化合物可抑制血小板凝集,且因此可用於治療受血 小板凝集调卽之病況’尤其是急性心肌梗塞、缺血性中風、 心絞痛、急性冠狀徵候群、ΤΙ A (短暫缺血性侵襲或急性腦血 管徵候群)、心臟衰竭、局部缺血造成之胸腔疼痛、徵候群X 、血检性检基症、肺南血壓、糖尿病、末梢血管疾病、深度 84878 -16- 1299663 血管之血栓形成、任何血管之動脈性血栓形成、導管血小板 阻塞或再阻塞。 本發明亦有關本發明化合物在預防、延遲進展、治療受血 小板凝集調節之疾病或病況之用途,尤其是急性心肌梗塞、 缺血性中風、心絞痛、急性冠狀徵候群、TIA(短暫缺血性侵 襲或急性腦血管徵候群)、心臟衰竭、局部缺血造成之胸腔疼 痛、徵候群X、血栓性栓塞症、肺高血壓、糖尿病、末梢血 管疾病、深度血管之血栓形成、任何血管之動脈性血栓形成 、導管血小板阻塞或再阻塞。 本發明亦關於本發明化合物在製造預防、延遲進展、治療 文血小板凝集調節之疾病或病況之醫藥之用途,尤其是急性 心肌梗塞、缺血性中風、心絞痛、急性冠狀徵候群、tia ( 短暫缺血性侵襲或急性腦血管徵候群)、心臟衰竭、局部缺血 造成之胸腔疼痛、徵候群X、血栓性栓塞症、肺高血壓、糖 尿病、末梢血管疾病、深度血管之血栓形成、任何血管之動 脈性血栓形成、導管血小板阻塞或再阻塞。 上述性質已由下列方法證明:由20位已知具有血管危險因 子之自願者獲得血小板凝集之血液樣品,流動之巨噬細胞研 死、及匣式血小板分析之分析劑。研究之參予者若具有出血 性體質、中風病歷、在過去六個月内經歷外科手術或明顯腫 瘤,及高血壓超過200/11〇 mm,則被排除在外。沒有任一位 服用阿斯匹靈或任何其他抗血小板劑。所有個體均在休息至 少30分鐘及斷食2或數小時後經血液取樣。早上8及1〇點之間 抽取血液,以避免任何白天之影響,並使用含3 8%檸檬酸鈉 84878 -17- 1299663 (19把知)之21-規格蝴蝶針頭自肘前抽血,前15亳升之自由 机動血硬予以丟棄。u個真空容器管(4·5毫升)自各研究參與 者收集合计49*升之全血_檸檬酸鹽混合物。一管維持作為内 對照組且與緩衝溶液培育。5管與瓦沙坦在37。(:培育60分鐘以 達到化合物終濃度1〇ηΜ、1〇〇ηΜ、^Μ、 剩餘5官類似地與增加量之戊醯基‘羥基瓦沙坦培育以達到 '辰度1〇11]\4、1〇〇福、1//]^、1〇//1^及100//]^。瓦沙坦及戊 醯基4_禮基瓦沙坦濃度範圍自低於治療量至經歷瓦沙坦療法 、4 %中所觀祭之顯著超治療血漿量。瓦沙坦高辛血漿濃度 在丨6〇耄克攝取後高達7·5/ζ Μ,而戊醯基4_羥基瓦沙坦之血漿 濃度僅瓦沙坦量之10%。在進行血小板研究之同一天早上即 席製備瓦沙坦及戊醯基4_羥基瓦沙坦新鮮溶液。為了避免可 旎:觀察偏差,血液樣品編碼並遮住。取樣程序及血小板研 先藉未察覺策略之個體進行。 血小板凝集 Α.冨含血小板之血漿 知裱酸鹽與全血之混合物在丨2〇〇g離心5分鐘以獲得富含血 】板〈血漿(PRP) ’其保持在室溫於i小時内使用。以C—如 計數器ZM (C()ulter公司,Hialeah,FL)測定各pRp樣品中血 小8板數。以均質之缺乏血小板血聚調整血小板數量為35〇χ 1〇8/毫升。藉5#MADP及5#厘腎上腺素謗發血小板凝集(1)八) 。所有激動劑均得自Chronolog公司(Havert〇Wn , pA)。使用4 2道之chronolog照光-凝集計(型號560_Ca)進行凝及研究。凝 集作用表示為記錄時間結束時光穿透對基準線之變化最大百 84878 -18- 1299663 分比(%max),係使用缺乏血小板之血漿作為參考。記錄凝集 曲線6分鐘並依據國際建立之標準分析。Ruggeri ZM,Semin Hemat 1994; 3 1:229-239 ° B.全血 此方法詳細描述於Abbate R等人之Amer J Clin Pathol 1986; 86: 91-96。簡言之,全血檸檬酸鹽混合物以0.5毫升TBS 稀釋1··1接著溫和渦動。具有攪拌棒之小杯置入培育洞中並使 溫至37°C歷時5分鐘。接著樣品移至分析洞中。將電極置入樣 品小杯中’以1微克/毫升膠原刺激血小板凝集。使用 Aggrolink'1軟體使用Chrono-Log全血凝集計進行血小板凝及 研究。血小板凝集性以電阻變化表示並以歐姆表示。 全血流動細胞計 血小板受體表現係使用下列單株抗體測定:CD3 1 (血小板 表皮細胞黏著分子(PECAM-1))、CD41 (糖蛋白[GP]IIb/IIIa) 、(IIb(3)、CD42b(GP lb)、CD51/CD61 ((v(3、或透明質蛋白 受體)、CD62p (P-選擇素)、CD107a (溶酶體相關之膜蛋白質 -1 ; LAMP-1)、CD 107b (LAMP-2)、CD151 (血小板/内皮四 指距抗原-3 ; PETA-3)、及對血纖維蛋白原使用PAC-1 (PharMingen,聖地牙哥,CA)。血小板-白血球相互作用分析 ,對泛-血小板標記基因(CD 151)係使用雙重抗體與CD14(單 細胞/巨噬菌標記基因)一起。該血液-檸檬酸鹽混合物(50微升 )以450微升Tris緩衝之食鹽水(TBS)(10毫莫耳/L Tris,0.15莫 耳/升氯化鋼)稀釋並藉溫和倒轉Eppendorf管2次予以混合。接 著於各溶液中添加5微升對應之抗體且樣品培育30分鐘。培育 84878 -19- 1299663 後,添加400微升2%緩衝之仲甲酸予以固定。樣品藉Becton Dickinson FACS掃描流動細胞計分析,設定而測量螢光散射 ,如 Gurbel PA等人,J Am Coll Cardiol. 1998; 31:1466-1473 所述。以列示模式檔案收集數據並分析。P選擇素表示為正細 胞之百分比,如Gurbel PA等人,Am Heart J 2000; 139:320-328 所述。其他抗員表示為平均螢光強度之對數。 匣-為主之血小板分析器 血小板功能分析器(PFA-100’,Dade Behring,Deerfield,IL) 為模擬在小血管損傷後血流狀態下之主要止血變化之裝置。 Kundu SK,等人,Semin Thromb Hemost 1995;21 (增補版 2) ••106-112。獲得傷口凝聚所需之時間以剪力-謗發之血小板凝 集作用指標數位化地記錄。重複2次進行閉合時間測定。 使用具有凍乾之人類纖維蛋白原-塗佈之微顆粒之聚乙晞 珠粒塗佈之匣進行快速血小板功能分析匣測試(RPFA_ASA, Ultegra(r) Accumetrics公司,聖地牙哥,CA,USA)。全血擰 檬酸鹽混合物添加至該匣中,並記錄血小板與塗佈珠粒間之 聚集作用。該數據反應濁度測定血小板凝集作用並反應血小 板前列腺素阻斷程度。Smith JW等人,Circulation 1999; 99:620-625。Ultegra(r)分析重複進行2次。在各儀器上使用任 何個體樣品之前每隔天進行電子品質控制測試。 統計學分析 藉Student’s t-測試計算所有比較以鑑定血小板凝集作用、 Ultegra(r),Dade-PFA 100 (tm)及基準線與瓦沙坦/戊醯基4-輕 基瓦沙坦培育後之間之受體表現之特定差異。使用 84878 -20- 1299663
Mann-Whitney U測試分析非參數數據。正常分佈數據表示為 平均土SE,及歪斜數據為平均(範圍)。ρ<〇·〇5之或然率值表 示為統計學有意義。所有研究參與者藉使用SPSS ν9.0程式 (SPSS公司,芝加哥,伊利諾州)應用線性回歸分析至該正常 分佈之數據。 富含血小板之血漿之血小板凝集 以增量劑量瓦沙坦前培育僅在100 // Μ之濃度可導致ADP-誘發之血小板凝集作用受到抑制,其超過治療值,且不影響 腎上腺素誘發之血小板凝集。相反地,以戊醯基4-羥基瓦沙 坦培育在1 // Μ及10 /ζ Μ濃度可抑制腎上腺素謗發之凝集作 用,且對ADP-誘發之凝集作用無任何影響。5 // M ADP及5 # Μ腎上腺素-刺激之凝集作用之代表性數據示於表1。 表1. PRP血小板凝集作用 變數 瓦沙坦(V) 戊酉盛基4-經基瓦沙坦 藥物濃度 P-值對基準線 P-值對基準線 P-值對戊醯基4-羥 基瓦沙坦 藉5 μ M ADP(%)謗發之富含血小板之血漿凝集作用 基準線 75±8 75 土 8 10 nM 74 土 6 NS 75+6 NS NS 100 nM 75±8 NS 76±8 NS NS 1 μΜ 76 土 7 NS 77 土 9 NS NS 10 μΜ 75±8 NS 76±8 NS NS 100 μΜ 55±12 0.0002 77+9 NS 0.001 84878 -21 - 1299663 藉5 // Μ腎上腺素謗發之富含血小板之血漿凝集作用(%) 基準線 78土10 78±10 10 nM 77土 11 NS 77 土 10 NS NS 100 nM 76±10 NS 76+9 NS NS 1 μΜ 78 土 6 NS 54±11 0.0001 0.0001 10 μΜ 75±9 NS 56±13 0.001 0.003 100 μΜ 76土7 NS 52±9 0.0001 0.0001 全血中血小板凝集作用 瓦沙坦及戊醯基4-羥基瓦沙坦在治療活性範圍内於全血中 可抑制藉1 // Μ膠原謗發之人類血小板凝集作用。對化合物兩 者均觀察到劑量依存效果,但以戊醯基4-輕基瓦沙坦預培育 產生血小板凝集性之明顯降低作用。膠原-誘發之血小板凝集 作用之結果由表2證明。 表2 ·全血血小板凝集作用 變數 瓦沙坦(V) 戊醯基4-羥基瓦沙坦 藥物濃度 p-值對基準線 P-值對基準線 P-值對戊醯基4-羥 基瓦沙坦 藉1毫克/毫升膠原誘發之全血阻礙血小板凝集作用(ohms)
基準線 29土7 29+7 10 nM 30±8 NS 32±8 NS NS 100 nM 30±7 NS 31±9 NS NS 1 μΜ 27 土 7 NS 14±6 0.0001 0.0001 10 μΜ 29±6 NS 16±8 0.004 0.001 100 μΜ 20±8 0.02 17土 8 0.01 NS 匣為主之血小板功能分析器(PFA-100TM&Ultegra®) 觀察到因血小板凝集作用單元降低(Ultegra)之閉合時間之 持績劑f依存延遲(P F A)’顯不在南與力條件下之血小板抑制 84878 -22- 1299663 作用。類似於全血凝集作用及腎上腺素-誘發之凝集作用,戊 醯基4-羥基瓦沙坦比瓦沙坦具有更強之抗血小板性質。表3 證明以匣為主分析器之代表性實驗。 表3.匣-為主之分析器 變數 瓦沙坦(V) 戊醯基4-羥基瓦沙坦 藥物濃度 P-值對基準線 p-值對基準線 P-值對戊酸基4-經 基瓦沙坦 以腎上腺素/膠原匣之PFA-100TM閉合時間(秒)*
基準線 201±22 201+22 10 nM 187±30 NS 179±28 NS NS 100 nM 209+21 NS 190±24 NS NS 1 μΜ 268±19 0.02 259±20 0.03 NS 10 μΜ 278±20 0.02 257±25 0.04 NS 100 μΜ 200±27 NS 232±31 NS NS
Ultegra®(血小板活性單元)分析器
基準線 159±27 159±27 10 ηΜ 164土16 NS 177+23 NS NS 100 ηΜ 160土29 NS 181±31 NS NS 1 μΜ 129±26 NS 134土29 NS NS 10 μΜ 130土31 NS 119±38 NS NS 100 μΜ 152±19 NS 168±35 NS NS 全血流動細胞計 以瓦沙坦及戊醯基4-羥基瓦沙坦培育略降低GP Ilb/IIIa (CD41)之表現及纖維蛋白原結合(PAC-1),且戊醯基4-羥基瓦 沙坦在治療濃度可達到此效果,而瓦沙坦僅在高劑量可降低 CD41表現。兩藥劑均明顯減少血小板表面上之P-選擇素濃度 ,且適度地降低透明質蛋白受體之表現,甚至此效果不具有 統計學功率以顯示瓦沙坦及戊醯基4-羥基瓦沙坦間之差異。 84878 -23- 1299663 以瓦沙坦及戊醯基4-輕基瓦沙坦培育與對pec AM-1 (CD3 1) ;GP lb (CD42)及 LAMP-2 (CD107b)、PETA-3 (CD151)及血 小板-白血球微顆粒(CD 15 1 + 14)之影響無關。流動細胞計結果 列於表4。 表4.瓦沙坦及戊醯基4-幾基瓦沙坦培育對主要血小板受體 表現之影響 變數 瓦沙坦(V) 戊醯基4-羥基瓦沙坦 藥物濃度 P-值對基準線 p-值對基準線 P-值對戊醯基4-罗曼 基瓦沙坦 & 血小板/内皮細胞黏著分子-UPECAM-l、CD31、對數MFI)之表現 基準線 69_2 士 10·3 69.2±10.3 10 nM 71_8 土 11.9 NS 74.2±13.4 NS NS 100 nM 70·6 士 12.6 NS 69.7±15.1 NS NS 1 μΜ 74.5土16.2 NS 70.3±16.4 NS NS 10 μΜ 68.2 土 16.2 NS 73·1±9·3 NS NS 100 μΜ 70·6±15_8 NS 71.2±15.5 NS NS 血小板糖蛋白Ilb/IIIa抗原(GPIIb、CD41、 J 對數MFI)之表現 基準線 521.8+98.2 521.8 土 98.2 10 nM 531.2+102.5 NS 505·6 土 77·8 NS NS 100 nM 502.9±112.7 NS 432.7±116.8 0.03 0.04 1 μΜ 498.2土 94.5 NS 427.2土 114.1 0.02 NS 10 μΜ 506·7±100·1 NS 515.9±156.2 NS NS 100 μΜ 455.2+99.6 0.03 529.3±121.8 NS 0.04 84878 -24- 1299663 糖蛋白lb (GPIb、CD42b、對數MFI)之表現
基準線 246.4±26.7 246.4±26.7 10 nM 256.4±31.4 NS 236.4土 18.7 NS NS 100 ηΜ 248.7±20.9 NS 267.9±39.4 NS NS 1 μΜ 264.8土 18.2 NS 255.5±24.8 NS NS 10 μΜ 244.3±46.9 NS 249.7±41.8 NS NS 100 μΜ 255·9±19·7 NS 248.1±19.5 NS NS 血小板透明質蛋白受體(CD51/CD61 、對數MFI)之表現 基準線 11.2 土 4.6 11.2 土 4.6 10 ηΜ 11·9±6·0 NS 12.1±4.2 NS NS 100 ηΜ 12.1±5.1 NS 8.5±3.1 0.02 0.01 1 μΜ 7·8±3·6 0.01 8·1±3·8 0.02 NS 10 μΜ 7_6±2.3 0.01 7·2±5·6 0.01 NS 100 μΜ 7.3+4.8 0.006 7·6±3·3 0.01 NS P-選擇素(CD62p、細胞積極性%)之表現
基準線 9.1±3.8 9.1 土 3.8 10 nM 9.8 土 2.7 NS 9.3±4.3 NS NS 100 nM 10·3±4·1 NS 10.2±5.4 NS NS 1 μΜ 7.2±3.2 0.03 7·3±3·7 0.03 NS 10 μΜ 7.2 士 3.6 0.03 6.9±4.2 0.03 NS 100 μΜ 7·8±4·2 NS 8·9±3·8 NS NS 溶酶體相關之膜蛋白質-1(LAMP-1、CD107a、 ‘對數MFI)之表現 基準線 8.7±3.2 8.7±3·2 10 nM 9.1±3.8 NS 10.2 土 3.6 NS NS 100 nM 8.9±2.7 NS 9.0±4.0 NS NS 1 μΜ 9·4 土 3.9 NS 6·6±2·9 0.04 0.02 10 μΜ 6·5±3·2 0.04 5_8±3_2 0.03 NS 100 μΜ 10.1±4.5 NS 8_0±3·4 NS NS 84878 -25- 1299663 溶酶體相關之膜蛋白質-2(LAMP-2、CD107b、對數MFI)之表現
基準線 10 nM 100 nM 1 μΜ 10 μΜ 100 μΜ 6.6±2.1 7.6±3.2 NS 7·0±2·7 NS 6.8±3.5 NS 7.1±3.3 NS 7·2±3·8 NS 6.6±2.1 7·7±3·8 NS 7·0±3·0 NS 6_6±3·4 NS 7·2±3·9 NS 7.1±2.9 NS NS NS NS NS NS 血小板/内皮四指距抗原·3(ΡΕΤΑ_3、CD151、 對數MFI)之表現 基準線 88.7+24.2 88.7 土 24.2 10 nM 84.1±19.7 NS 89·4±18·2 NS NS 100 nM 91.5±23.4 NS 92.7±22.2 NS NS 1 μΜ 81.6±20.1 NS 90·5±15·7 NS NS 10 μΜ 87·9±18·3 NS 84.2131.1 NS NS 100 μΜ 91.7+22.1 NS 83.4+27.4 NS NS 血小板-白血球微顆粒(CD151+CD14,對數MFI)之形成
基準線 92.2±19.3 92.2±19.3 10 nM 91.2±20.5 NS 99.4±29.7 NS NS 100 nM 88.4+21.9 NS 94.3±18.7 NS NS 1 μΜ 93.5±23.8 NS 90.7±20.5 NS NS 10 μΜ 96·5±18.7 NS 89·2±18·7 NS NS 100 μΜ 90.5±19.2 NS 95·6 土 19.9 NS NS 糖蛋白Ilb/IIIa活性(纖維蛋白原結合,PAC-1、對數MFI)
基準線 10·3±2·8 10·3±2·8 10 nM 9·3±2_87 NS 11.0±4.5 NS NS 100 nM 11.2±3.4 NS 9.0+3.3 NS NS 1 μΜ 7.0+2.9 0.03 6.7±2.7 0.02 NS 10 μΜ 6.9±2.7 0.02 7.5 土 3·1 0.04 NS 100 μΜ 9.9±3.1 NS 9_9±3·0 NS NS 下列實例說明上述之本發明;但不用以限制本發明。 84878 -26- 1299663 實例1 瓦沙坦代謝物之合成 (8)-2-{(4-經基-戊酸基)-[2’-(111_四。坐-5_基)-聯苯_4_其甲芙] 胺基}-3-甲基-丁酸
6.7克(S)_3-甲基_2-{(4-氧代-戊醯基)-[2’-(ιΗ_四唑_5_基)- 聯苯-4-基甲基]胺基卜丁酸溶於6〇毫升甲醇中並冷卻至〇。〇。 以小部份添加2.25克硼氫化鈉以使攪拌之反應混合物保持低 於27°C (強烈發泡)。混合物在室溫攪拌1小時,真空濃縮,溶 於二氯甲烷並以2N鹽酸水溶液萃取2次。有機相乾燥,真空 濃縮且產物藉層析純化(快速管柱,240克矽膠60, KG40-62微 米’使用一鼠甲燒、甲醇、濃氨水(3 0:10·· 1 v/v)之混合物溶離 )。含產物之溶離份予以濃縮,溶於二氯甲烷並以2N鹽酸水溶 液萃取並以硫酸鈉乾燥。濃縮後,殘留物真空乾燥(60°c )3天 ’獲得白色泡沫之(S)-2-{(4-羥基-戊醯基)-[2’_(1Η-四唑-5-基 )-聯苯-4-基甲基]胺基卜3-甲基-丁酸([a ]D20=-58。(cM,甲醇 ))。TLC-Rf: 〇·18(甲苯/乙酸乙酯/二氯甲烷/甲酸16:40:40:4)。 起始物(8)_3_曱基-2_{(4-氧代-戊醯基)-[2,-(111-四唑-5-基)-聯苯基甲基]胺基卜丁酸製備如下·· (3)-2-{(2’-氰基-聯苯-4-基甲基)-[3-(2-甲基-[1,3]二氧環戊_2-84878 -27- 1299663
基)-丙酿基]胺基}-3 -甲基-丁酸节酉I
13.8克(S)-2-[(2’_氰基-聯苯-4·基甲基)-amino]-3 -甲基-丁酸 苄酯鹽酸鹽(述於EP 443983)溶於50毫升二氯甲烷,冷卻至〇 °C並以23.8毫升乙基二異丙基胺(HCinig驗)處理。於此混合物 中在0C添加3-(2 -甲基-[1,3] 一^氧壤戊-2 -基)-丙驗氯(自8.9克 3_(2_甲基-[1,3]二氧環戊-2-基)丙酸(四面體37,307,1981)及 10.31毫升(1-氯-2-甲基-丙烯基)-二曱基胺(四面體54,9207, 1998)於40毫升二氯甲烷中製備)溶液。反應混合物在室溫揽 拌3-4天,視轉化過程而定。較好,3-(2-甲基-[1,3]二氧環戊 -2-基)-丙醒氯以2天分3-4次添加。反應混合物真空濃縮,溶 於乙酸乙酯,以水、1N鹽酸水溶液、水洗滌,以硫酸鈉乾燥 並真空濃縮。快速層析(240克矽膠60,40-63微米,石油 乙酸乙酯2:1至1:1),產物在50 0°C乾燥後,獲得金色黏稠殘 留物之純的(S)-2-{(2’_氰基-聯苯-4-基甲基)-[3-(2-甲基-[ι,3] 二氧環戊_2_基)-丙酸基]-胺基}-3-甲基-丁酸芊酯。TLC-Rf· 0_23(石油醚/乙酸乙酯2:1)。 (S)_2_[(2’_氰基-聯苯_4_基甲基H4·氧代-戊醯基)-胺基]_3•甲 基-丁酸芊酯 84878 -28- 1299663
9.8克(S)-2-{(2’_氰基-聯苯_4_基甲基)_[3_(2_曱基-[13]二氧 環戊_2-基)-丙酿基]-胺基}_3_甲基_丁酸苄酿溶於1〇〇毫升四 氫呋喃並以50毫升1N鹽酸水溶液處理。混合物在室溫攪拌65 ^日寺’真空濃縮並以二氣甲料取。有機相以水洗務,以硫 酸鈉乾燥,真空濃縮,蒸發並在5〇 01真空乾燥丨小時。獲得 橘色黏油之(S)-2-[(2,-氰基·聯苯·4_基甲基)_(4_氧代_戊醯基)_ 胺基]-3-甲基-丁酸苄酯。TLC_Rf: 〇18(石油醚/乙酸乙酯2:〇。 (S) 3 -曱基-2-{(4-氧代-戊醯基)_[2'_(ih-四唑_5_基)_聯苯_4_ 基甲基]-胺基} -丁酸苄酯
8·64克(s)-2-[(2’_氰基-聯苯-4-基甲基)-(4-氧代-戊酸基)-胺 基]甲基-丁酸苄酯及12.71克四丁基鍚疊氮化物(Aldrich) 84878 -29- 1299663 於20毫升二甲苯中回流28小時。混合物以〇·5Ν氫氧化納處理 ,水相以乙醚洗條及乙醚相以水萃取一次。合併乏士 4 〜不相以濃 鹽酸水溶液酸化,以二氯甲烷萃取,以水洗滌,懸浮活性# ,過濾,以硫酸鈉乾燥,濃縮及真空乾燥。獲得棕色泡、末之 產物(S)-3-甲基-2_{(4-氧代-戊醯基)_[2’-(1Η-四唑^ w 王基)-聯苯 -4-基甲基]-胺基}-丁酸芊酯。TLC-Rf: 0.36(甲基/二* ~^氧Ψ燒/ 甲醇 /甲酸 40:40:40:4)。 (S)-3 -甲基-2-{(4-氧代-戊醒基)-[2’_(1Η-四峻-5-基)_聯苯4 基甲基]-胺基卜丁酸
7.9克(S)_3-甲基-2-{(4·氧代-戊醯基H2,_(1h四唑巧_基> 聯苯_4_基甲基]胺基卜丁时酿之⑽毫升四氫咳喃在常土壓 下在1.5克鈀/碳(10%)存在下於室溫氫化直至達成飽和。混合 物過滤並真空濃縮,獲得幾乎白色泡沫之(S)-3-甲基_2·{(1 氧代-戊臨基Η2’-(1Η-四吐_5·基)_聯苯_4_基甲基]胺基}_丁酸 ° TLC-Rf: 〇·1(甲苯/二氯甲烷/曱醇/曱酸4〇:4㈣㈣)。 、雖然本發明以參考某些較佳變體相當詳細地描述,但在不 脫離本發明較佳變體之精神及範圍内可做其他變化。 本文所述之所有公報&專利均併於本 文供參考。 84878 -30-
Claims (1)
- 拾、申請專利範圍: ^1^2854號專利申請案 睛專利範圍替換本(97年4月) (更)正本 一種代謝物戊醯基4-羥基瓦沙坦(valeryl 4_hydrQxy valsartan)或其醫藥可接受性鹽、視情況在醫藥可接受性 载劑之存在下、用於製造供抑制血小板凝集作用之藥物 之用途。 種代身物戊酸基4-經基瓦沙坦或其醫藥可接受性鹽用 於製造供預防、延遲發展或治療受血小板凝集作用調節 之症狀之藥物之用途。 種代谢物戊醯基4-羥基瓦沙坦或其醫藥可接受性鹽用 於製造供預防、延遲發展或治療受血小板凝集作用調節 之疾病及障礙之藥物之用途,該等疾病及障礙尤其是急 性心肌梗塞、缺血性中風、心絞痛、急性冠狀徵候群、 TIA (短暫缺血侵襲或急性腦血管徵候群)、心臟衰竭、 局邛缺血造成之胸腔疼痛、徵候群χ、血栓性栓塞症、肺 回血壓、糖尿病、末梢血管疾病、深度血管之血栓形成 、任何血管之動脈性血栓形成、導管血小板阻塞或再阻 塞。 4·:種代謝物戊醯基4_羥基瓦沙坦或其醫藥可接受性鹽,其 係作為抑制血小板凝集作用之藥物。 84878-970425.doc
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RU2004136583A (ru) | 2005-09-10 |
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IL164774A (en) | 2010-04-29 |
ES2268403T3 (es) | 2007-03-16 |
ATE334677T1 (de) | 2006-08-15 |
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JP4467427B2 (ja) | 2010-05-26 |
DE60307265D1 (de) | 2006-09-14 |
EP1505965A1 (en) | 2005-02-16 |
NZ536295A (en) | 2006-12-22 |
MXPA04011282A (es) | 2005-01-25 |
AU2003267447A1 (en) | 2003-11-11 |
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CN100408035C (zh) | 2008-08-06 |
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HK1074395A1 (en) | 2005-11-11 |
KR101005367B1 (ko) | 2010-12-30 |
WO2003094915A1 (en) | 2003-11-20 |
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AU2003267447B2 (en) | 2006-11-02 |
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