TW557295B - Amide derivatives or salts thereof - Google Patents

Amide derivatives or salts thereof Download PDF

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TW557295B
TW557295B TW087117145A TW87117145A TW557295B TW 557295 B TW557295 B TW 557295B TW 087117145 A TW087117145 A TW 087117145A TW 87117145 A TW87117145 A TW 87117145A TW 557295 B TW557295 B TW 557295B
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Taiwan
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salt
ethyl
patent application
amino
group
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TW087117145A
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Tatsuya Maruyama
Takayuki Suzuki
Kenichi Onda
Masahiko Hayakawa
Hiroyuki Moritomo
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Yamanouchi Pharma Co Ltd
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    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
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    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
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    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • C07D235/16—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/10—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D241/12—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D513/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04—Ortho-condensed systems

Description

經滴部中央標率局员Η消费合竹社印裝 557295 Α7 ____ Η 7 五、發明説明彳) 技術領域 本發明係關於藥物且特別是關於新穎的醯胺衍生物或 其鹽及用於糖尿病之治療劑。 發明背景 糖尿病是伴隨著高血糖狀態的疾病及因多種環境因子 及基因因子的作用所導致。血糖的主要控制因子是胰島素 ，且已知高血糖症是胰島素不足或抑制其作用的因子過多 (如基因引起、缺乏運動、肥胖症及壓力）所導致。 糖尿病被分爲兩大類型。一類爲自體免疫病減少胰腺 的胰島素分泌作用所引起的胰島素依賴型糖尿病（ I D D Μ )，另一類爲伴隨連續高胰島素分泌作用的有關 胰腺的疲勞而減少胰腺的胰島素分泌作用所引起的非胰島 素依賴型糖尿病（1^100“）。在日本9 5%或更多的 備冰俩俩忠定i u JJ Μ，丑四α吊土衍！恶匕乂婴 起的病患的增加已逐漸成爲一問題。 至於糖尿病的治療，飮食控制、治療性運動及肥胖症 的療法適於中等程度的案例，當疾病發展惡化時，口服抗 糖尿病的藥物（例如，胰島素分泌促進劑如磺醯脲，及胰 島素敏感性增效劑以強化胰島素敏感性）被給予。在嚴重 案例中，胰島素製劑被給予。無論如何，對於血糖有較佳 控制的藥物的創造存在著一強烈的需要，具有新機制及高 有用性的抗糖尿病藥物發展已被需要。 11.3.?4，396，627及4，478，84 (¾先閱讀.背而之注*事項再硝朽本否 • 1— Mu J— ίί .
、1T 本紙張尺度適用中國國家掠準（CNS ) 格（210Χ2^'>^ 4 557295 A7 經满部中央標卑局Μ,χ消費合竹社印奴 五、發明説明$ ) 9描述苯基-乙醇胺衍生物及揭露那些化合物被作爲肥胖 症及高血糖症的藥物。那些化合物的作用被報導是由於對 β 3 -接受器的刺激作用。附帶地，已知β -腎上腺素接受器 分局β 1，β 2及β 3亞型，β 1 -接受器的刺激作用會增加心跳 速率，β 2 -接受器的刺激作用會刺激肌肉中糖原質的分解 作用，因此糖原質的合成被抑制而引起一作用如肌肉的震 顫，及β 3 -接受器的刺激作用顯示抗肥胖症及抗高血糖症 的作用（如減低甘油三酯、減低膽固醇及增加H D L -膽 固醇）。 不幸地，那些β 3 —激動劑亦具有一些係由β 1 -及β 2 — 接受器的刺激作用所引起的作用如增加心跳速率及肌肉的 震顚，及它們有一些負效果的問題。 最近，被確定β -接受器有不同的種類’及已報導被確 定的在嚅齒動物如老鼠中有β 3 -接受器選擇性的化合物顯 不一作用1系由在人類的β i -及β 2 -接受器的刺激作用。鑑 於上述，對於在人類的β 3 -接受器具有選擇性刺激作用的 化合物最近使用人類細胞或細胞在試驗，顯示人類接受器 被運送。例如，W〇9 5 / 2 9 1 5 9揭示經取代的磺胺 衍生物如下式所示： 0Η
r〇2(CHA—R7 其中符號可參考此專利案的說明書，及揭示由於其對 人類的β 3 -接受器的選擇性刺激作用，被用於抵抗肥胖症 本紙張尺度適用中國國家標準（CNsYa4«L梢(210X297^>«.) -5- («尤閲讀背而之注&萝項^:項寫本负 Ί -I 1 J— · 557295 A7 1Π 五、發明説明 、高血糖症，等等。然而，此專利案並未揭示那些化合物 的胰島素分泌促進作用及胰島素敏感性增強作用。 對於高臨床效果的新糖尿病治療劑的創造仍有需要。 發明內容 本發明者已集中硏究具有胰島素分泌促進作用及胰島 素敏感性增強作用的化合物且發現新穎醯胺衍生物顯示良 好的胰島素分泌促進作用及良好的胰島素敏感性增強作用 ，此外亦顯示對β 3 -接受器的選擇性刺激作用，而導致本 發明的完成。 因此，本發明係關於如下式（I )所示之醯胺衍生物
Η (I) 經滴部中央標導局Μ_τ消费合竹社印紫 其中環Β爲雜芳基；X爲一鍵或低伸烷基；R爲氫原 子、鹵原子、低院基、胺基、芳基低院基或鹵基芳基低院 基，或其鹽，其具有胰島素分泌促進作用及胰島素敏感性 增強作用且因對β 3 -接受器有選擇刺激作用而進一步具有 減肥及抗高脂血症作用。本發明亦關於糖尿病治療劑’其 包括醯胺衍生物或其鹽作爲有效成分° 式（I )化合物的進一步說明如下。 本紙張尺度適用中國國家標準（CMS ) A4AL格（21〇x2W:Mi ) -6- 經滴部中央標率局貝工消费合作社印製 557295 A7 Η 7 五、發明説明4 ) 說明書中化學式所用的定義，“低”表示1至6個碳原 子的直鏈或支鏈的烴鏈，除非另有說明。 低級烷基爲甲基、乙基及直鏈或支鏈的丙基、丁基、 戊基或己基，較佳爲具有1至4個碳原子的烷基，且特別 是甲基、乙基、丙基或異丙基。 低級伸烷基爲上述低級烷基移除一個氫原子所得到的 雙價基團，較佳爲具有1至4個碳原子的伸烷基，且特別 是伸甲基、伸乙基、伸丙基或伸丁基。 雜芳基爲單環雜芳基，如呋喃基、噻吩基、吡咯基、 咪唑基、噻唑基、吡唑基、異噻唑基、異噁唑基、吡啶基 、嘧啶基、嗒哄基、吡畊基、噻二唑基、三唑基及四唑基 ，及雙Ϊ哀雜方基’如蔡D定基、吼D定並嚼D定基。 鹵素原子爲氟原子、氯原子、溴原子或碘原子，及鹵 基低級院基爲在上述方基低級院基的芳基上的氫原子或原 子被鹵素原子或原子所取代的基團。 此案例中當X爲鍵時意謂著一 C 〇 一基團是直接鍵結 至B環。 本發明式（I )化合物至少有一不對稱碳原子，因此 有光學異構物如（R ) 一化合物及（S ) 一化合物、消旋 化合物、對映異構物，等等。本發明包括所有及每一單離 的異構物及其混合物。本發明亦包括水合物、溶劑化物（ 如那些與乙醇）及式（丨）化合物的多晶型物質。 本發明式（I )化合物可與酸形成鹽。鹽爲與無機酸 之酸加成鹽。該無機酸爲氫氯酸、氫溴酸、氫碘酸、硫酸 本紙張尺度適用中國國家掠準（CNS ) Λ4規枱（21 Ox 297公私) --- (許1閱讀介而之注t事項再硪涔本s ) s_ -- .if— !MI- 、-u 557295 A7 ------_____H7 _________ __________ 五、發明説明_ ) 一· 、硝酸及憐酸；及那些與有機酸之酸加成鹽。該有機酸爲 甲酸、乙酸、丙酸、草酸、丙二酸、丁二酸、富馬酸、馬 來酸、乳酸、蘋果酸、檸檬酸、酒石酸、碳酸、苦味酸、 甲磺酸、乙磺酸及谷氨酸。 (製造方法） 本發明的化合物或其鹽可藉由使用取代基的基本骨架 或種類的特徵的不同合成方法的應用給予製造。代表性的 製造方法說明於下文。 第一種製浩方法 (^先閱讀背而之注&事項再^寫本貝) ϋ - 、-口 經滴部中央標導局員Η消費合作社印聚 OH Ra
(在式中，B，R及X已有相同的意義；Ra爲氨基保 護機；Y 1爲離去基’及特別爲羥基、低烷氧基或鹵原子。 ) 在此方法中，式（I I )化合物及式（I I I )化合 物被醯胺化，然後移除保護基以合成本發明之式（I )化 本紙張尺度適用中國國家標隼(CNS ) ( 210X297*^，) """ '' 經漓部中央標噑局貝工消t合作社印 557295 A7 H7 五、發明説明6 ) 合物。 在此製造方法的醯胺化作用可藉由習知方法給予進行 0 溶劑可視式（I I I )化合物的Y 1而不同，大部分惰 性溶劑或醇溶劑（如異丙醇）可被應用。 當Y 1爲羥基時，反應係在上述溶劑中及縮合劑存在下 進行。該縮合劑爲N，Ν’一二環己基羰二亞胺（DCC) 、1—乙基—3 —（3 —二甲基胺基丙基）羰二亞胺（Ε DCI) 、1，1，—羰基—二咪唑（CDI)、二苯基磷 醯基疊氮化物（DPPA)及二乙基磷醯基氰化物（ D E P C )。 當Υ 1爲低烷氧基時，反應係自身或在上述溶劑下加熱 或回流中進行。 當Υ 1爲鹵原子時，反應係在上述惰性溶劑中及鹼存在 下進行。 惰性溶劑爲二甲基甲醯胺（D M F )、二甲基乙醯胺 、四氯乙烷、二氯甲烷、二氯乙烷、氯仿、四氯甲烷、四 氫呋喃、二噁烷、二甲氧基乙烷、乙酸乙酯、苯、甲苯、 二甲苯、乙腈、二甲亞砚及其混合溶劑，及其適宜視反應 條件而被選擇。鹼爲如氫氧化鈉、氫氧化鉀、碳酸鈉及碳 酸鉀之無機鹼；及如Ν -甲基嗎啉、三乙基胺、二異丙基 乙基胺及吼D定之有機驗。 氨基保護基藉由尺9是保護基爲代表，Ra通常被作爲 氨基，及其代表例爲醯基如甲醯基、乙醯基、丙醯基、甲 本紙張尺度適用中國國家榡準（CNS ) /\4叱福（210X297 ☆於）~
(¾先閲讀背而之注意事項再硝、1>:?本PC 訂 - 1 i 1: -1 - 經滴部中央標率局貝工消費合作社印紫 557295 A7 _ H7 五、發明説明（） 氧基乙醯基、甲氧基丙醯基、苄醯基、噻吩基乙醯基、噻 唑基乙醯基、四唑基乙醯基、噻唑基乙醛醯基及噻吩基乙 醛醯基；低烷氧羰基如甲氧羰基、乙氧羰基、及特丁氧羰 基；芳烷氧基羰基如苄氧羰基及對-硝基苄氧羰基；低烷 磺醯基如甲磺醯基及乙磺醯基；芳烷基如苄基、對-硝基 苄基、二苯甲基及三苯甲基；及三一（低烷基）甲矽烷基 如三甲基甲矽烷基。 在此製造方法中，保護基的移除可藉由習知方法給予 進行。例如藉由R a代表的氨基保護基易於被移除，如i ) 在保護基爲二苯甲基、鄰-甲氧基苯基、三苯甲基、特丁 氧羰基、甲醯基等等的案例中，可藉由酸處理，該酸爲甲 酸、三氟乙酸、三氟乙酸及苯甲醚的混合物、氫溴酸及乙 酸的混合物、氫氯酸及二噁烷的混合物等等；i i )在保 護基爲苄基、對一硝基苄基、二苯甲基、三苯甲基等等的 案例中’可藉由使用鈀-碳或氫氧化鈀-碳的催化還原反 應進fT，及i i i )在保護基爲二一（低院基）甲砂院基 或其它類似的基的案例中，可藉由水、氟離子（氟化四一 正丁基銨、氟化鈉、氟化鉀或氫氟酸）處理。 第二種製造方法 本紙張尺度適用中國國奪、標準（CNS ) /\4化格（210x 2W公黏） (計尤閱讀背而之注意事項再蛾巧本Ή )
經滴部中央標枣局只工消费合作社印製 557295 A7 H7 五、發明説明$ )
Η (在式中，Β，R及X已有相同的意義。） 在此方法中，式（I V )化合物與式（V )化合物反 應以得到本發明之式（I )化合物。 式（I V )胺化合物與式（V )化合物反應係自身或 在惰性溶劑下加熱或回流1至2 4小時以得到本發明之式 (I )化合物。 惰性溶爲乙腈、四氫呋喃、2 -丁酮、二甲亞硕及Ν -甲基吡咯烷酮。在反應中，如碳酸鈉、碳酸鉀及二異丙 基乙基胺的鹼被加至反應混合物中。 附帶地，在上述製造方法中，可能藉由再結晶、粉碎 作用、製備性薄膜層析法、矽凝膠火燄層析法（如〜.（：· Still，et al. ; J.〇rg. Chem.，43，2923 ( 1 978 )所述 )、中壓液相層析法及Η P L C移除不想要的副產物以純 化產物。藉由Η P L C得到的化合物可以相對應的鹽被單 離。 用於上述製造方法的起始物，易於被熟知此項技藝者 本紙張尺度適用中國國家標準（cns ) Λ4ϋ( 2ΐ〇χϋ> η') 7777^ ϋ^— 1— _· ·1 - m - - - n ϋ.— (計先閲讀背而之注意事項再項价？本50 、-口 557295 A7 ______ B7 五、發明説明〇 ) — · 所知之方法製備。一代表性的方法如下文所示。 (起始化合物（I I )的製造方法）
RbNH
.-In衣. (在式中，Ra已有相同的定義·，Rb爲氫原子或氨基 的芳烷基種類的保護基；R。爲環氧基、2 —鹵乙醯基或1 一殘基甲一 1 一醇。） 經滴部中央標準局貝工消費合竹社印製 此製造方法係由步驟（a )至步驟（C )組成的’其 中步驟（a )是式（V I )化合物與式（V I I )化合物 反應，接著視R ^種類實施還原反應以得到式（V I I 1 a )化合物；步驟（b )是當式（V I I I a )化合物的R ^ 爲氫原子時，此步驟施與保護作用；及步驟（c )是硝® 被還原爲氨基以得到式（I I )化合物。 用於上述製造方法的氨基的芳烷基種類的保護棊爲$ 基、鄰一硝基苄基、二苯甲基等等。 步驟（a ): 下面三種情形被說明。 -12- 本紙張尺度適用中國國家標準（CNS Γλ4^#, ( 210X297：^^ ) 經漓部中央標率局貝X,消費合作社印裝 557295 Μ ____ Η 7 五、發明説明彳Ο ) 1 )當R。爲環氧基時，式（V I )化合物可以相同於 上述第二種製造方法的方式與式（V I I )化合物反應。 反應條件如反應溫度、溶劑等等亦相同。 2 )當R。爲2 —鹵乙醯基時，式（V I )化合物在鹼 的存在下與式（V I I )化合物反應，接著被實施還原反 應以製備式（VI I la)化合物。鹼與第一種製造方法 中提到的鹼相同。還原反應可在上述提到的惰性溶劑或是 在與還原劑存在下一起攪拌的醇型溶劑下進行。還原劑爲 硼氫化鈉、氰硼氫化鈉、氫化鋁鋰及甲硼烷。 3)當R。爲1 一羧基甲—1—醇時，式（V I )化合 物在縮合劑的存在下與式（V I I )化合物反應，接著被 施與同2)方式的還原反應以製備式（VI I la)化合 物。縮合劑與第一種製造方法中提到的縮合劑相同。 步驟（b ): 當式（V I I I a )化合物的R b爲氫原子時，氨基藉 由習知方法（如二-特丁機二碳酸酯或其它類似基團）保 護，以製備式（V I I I a )化合物。 步驟（c ): 硝基還原至氨基的方法，可藉由習知方法（如使用鐵 、鋅等等的金屬還原作用及使用觸媒如鈀-碳、氫氧化鈀 - 碳、阮來鎳等等的觸媒還原作用）給予進行。R a視還 原條件變爲氫原子，但其可藉由習知方法給予再次保護。 本紙張尺度適用中國國家標準（CNS )/\4规梠（210x?97〉># ) . . (^先閱讀背而之注&萝項洱硪寫本頁)
、1T 經满部中央標率局貝工消費合作社印裂 557295 A7 H7 五、發明説明纟1 ) 關於其它化合物，如式（I I I )化合物、式（I V )化合物、式（V )化合物、式（V I )化合物及式（ V I I )化合物，易於購買或可藉由使用市售化合物以習 知方法（如醯胺化作用、還原作用、N -烷基化作用、環 化作用及水解作用）製備之。 本發明之式（I )化合物被製備、單離及純化爲自由 態化合物、其鹽可藉由習知方法被製成鹽的形態、用不同 的溶劑如乙醇製成水合物、溶劑化物或多形態晶體。單離 及純化可使用常用化學操作方法如萃取、濃縮、蒸發、結 晶、過濾、再結晶及不同的層析方法給予進行。 不同的異構物可利用異構物間物化性差異以藉由習知 方法給予單離。例如，消旋物可藉由消旋解析作用（如消 旋物用習知光學活性酸〔如酒石酸〕被變爲非對映異構物 ，接著被實施光學解析作用）被轉化爲立體化學純異構物 。附帶地，非對映異構物的混合物，可藉由習知方法如部 分結晶作用或層析法，給予分離。在光學活性化合物的案 例中，其可從適合的光學活性物質起始製備。 產業利用性 本發明之式（I )苯乙醇衍生物及其鹽，具有胰島素 分泌促進作用及胰島素敏感性增強作用且亦具有選擇性的 β 3 -接受器刺激作用，以致於作爲糖尿病治療劑。 藉由如後面所述，在胰島素-抵抗模型的動物D -葡 萄糖耐受性試驗及低血糖試驗，以證明本發明之化合物具 本紙張尺度適用中國國家掠準（CNS ) ( 210X297； .777 (邡先閱讀背而之注意事項洱硝寫本Ή ) 、11 __ 557295 經消部中央標攀局負工消费合作社印t A7 Η 7 五、發明説明松） 有胰島素分泌促進作用及胰島素敏感性增強作用，以致於 被期望用於治療糖尿病。雖然β 3 -接受器刺激作用可能具 有參與胰島素分泌促進作用及胰島素敏感性增強作用的表 現的可能性，其它機制亦可能參與其中，且其詳細內容尙 未知曉。本發明化合物的β 3 -接受器刺激作用是選擇對人 類的β 3 -接受器。已知道β 3 -接受器的刺激作用刺激脂肪 的分解（脂肪組織甘油三酯分解爲甘油或自由脂肪酸）， 藉此促進脂肪塊的消失。因此，本發明化合物具有抗肥胖 症作用及抗高脂血症作用（如甘油三酯的減低作用、膽固 醇的減低作用及H D L膽固醇的增加作用）及作爲肥胖症 及高脂血症（如高甘油三酯血症、高膽固醇血症及血脂蛋 白過少症）的預防及治療劑。已知道那些疾病是糖尿病的 活潑因子，及那些疾病的改善亦可用於糖尿病的預防及治 療。 本發明化合物亦可作爲其它疾病的預防及治療劑，其 係藉由肥胖症及高脂血症如局部缺血的心臟血管疾病（例 如動脈硬化、心肌梗塞形成及心絞痛）、腦動脈硬化症（ 例如大腦梗塞）或動脈瘤的徵狀的減低而達到其它疾病徵 狀的改善。 再者，本發明化合物的β 3 -接受器刺激作用可用於許 多疾病的預防及治療，其已被報導係藉由改善β 3 —接受器 的刺激作用。那些疾病如下所述。 已提到β 3 -接受器媒介非括約平滑肌收縮作用的能動 性，及因爲相信選擇性的β 3 -接受器刺激作用幫助未伴隨 本紙張尺度適用中國國家彳準（CNS ) Λ4規g ( 210X2W〉> ) -15- (部先閱讀背而之注&事項洱填寫本否)
、1T 經漓部中央標率局K工消費合作社印製 557295 A7 五、發明説明衫） 心血管作用的腸能動性的藥理控制，本發明化合物有可能 用於治療因異常的腸能動性引起的疾病，如不同的胃腸疾 _包括應激性大腸徵候群。其亦可能用於治療消化性潰瘍 '食管炎、胃炎及十二指腸炎（包括幽門螺旋菌引起的） '腸潰瘍（如腸炎疾病、潰瘍結腸炎、無性繁殖系的疾病 及直腸炎）。 進一步顯示β 3 -接受器會影響肺部一些感覺纖維的神 經肽的釋放的抑制作用。感覺神經在呼吸道的神經源發炎 包括咳嗽，扮演著重要角色，及因此本發明的特定β 3 一催 動肌用於治療神經源發炎及具有齟肺系統的一點點作用。 此外’ β 3 -腎上腺素接受器有能力導致選擇性的抗抑 制作用，係由於在大腦中β 3 -接受器的刺激作用，及據此 ，本發明化合物具有作爲抗抑制劑的可能性。 本發明化合物的作用已確定對β 3 -接受器具有選擇性 ，係爲使用人類細胞的實驗結果，且藉由其它β 3 —接受器 刺激作用引起的負作用是少的或無。 本發明化合物的效果已藉由下面試驗被證明。
1 ·在k k鼠（胰島素-抵抗模式；肥胖症及高脂血 症）的低血糖試驗Z 雄性的k k鼠（血糖値：不低於2 0 0 m g / d 1 ) 在餵食情況下被測量血糖値，且然後隨機分爲兩群。每天 強迫口服或皮下投藥，持續四天’從最後投藥1 5 — 1 8 小時後的血糖値與投藥前相比（n = 6 )。使用玻璃毛細 管從鼠的尾巴靜脈收集血液（先用肝素處理），從血液中 本紙張尺度適用中國國家彳车(CNS ) ( 210X2^7：^^ ) . 16 - (^先閱讀背而之注&事項办^巧本刃 衣·
、1T 557295 經滴部中央標準局貝工消t合作社印製 Α7 \\Ί 五、發明説明彳4 ) 移除蛋白質，上淸液的D -葡萄糖含量（mg/d 1 )係 藉由D -葡萄糖氧化酶方法使用比色測定法給予測量。 本發明化合物明顯降低血糖値，當其與在口服及皮下 投藥兩案例中，比較藥物被投藥前相比。例如，實例6化 合物顯示以1 〇mg/k g 口服投藥，平均降低血糖速率 4 8 %。從此結果，顯示本發明化合物具有良好的胰島素 敏感性增強作用。 2 ·正常老鼠的D -葡萄糖耐受性試驗·· 七週大雄性老鼠的S D菌株被快速生長一天一夜，然 後隨機分爲兩群且實施口服D -葡萄糖耐受性試驗（ OGTT) (n = 4)。被測試的化合物在投于D —葡萄 糖（以口服投藥2 g/kg) 3 0分鐘前以口服或皮下方 式被投藥。使用已處理的肝素玻璃注射器，從用戊巴比妥 麻醉的老鼠的腹主動脈收集血液，從血液中移除蛋白質， 上淸液的D -葡萄糖含量（mg/d 1 )係藉由D -葡萄 糖氧化酶方法使用比色測定法給予測量。血液中胰島素値 ，是藉由放設免疫分析法（R I A )測量血漿（n g / m 1 )中胰島素含量，而給予測定。 在本發明化合物係以口服或皮下方式被投藥的群體中 ，可觀察到其血液中胰島素値較未給藥的群體的胰島素値 明顯增加。在投于D -葡萄糖後血糖値的增加明顯地被抑 制。從那些結果，明顯顯示在本發明化合物具有良好的胰 島素分泌促進作用及良好的高脂血症抑制作用。 3 ·人類β 3 —、β 2 -及β i -接受器的刺激試驗： 本紙張尺度適用中國國家標丰（CNS )八4驟—(210x757：.> II') Γ17. · (^先閱讀背而之注*事項-»續^?本刃) .-m泰· 557295 經滴部中央標擎局負Η消费合作社印裝 Α7 Η 7 五、發明説明（15 ) 人類β 3 -刺激作用係使用S K — N - M C細胞系統（ 細胞可購得，且其中的每一人類β 3 -接受器及人類β 1 -接 受器被恆久地表現）給予硏究，然而，人類β 2 -及β 1 -刺 激作用係使用C Η〇細胞系統（細胞可購得，且其中的每 一人類β 2 -及β i -接受器及人類β i —接受器必定表現）給 予硏究。化合物（1 〇 - 1 ◦至1 〇 _ 4 Μ )的刺激作用藉由 溫育在2 4 -井板每一細胞的1 0 5細胞/井及使用環狀 A Μ P ( c A Μ Ρ )兩天後產生的活性作爲指標後，檢查 半滿狀態，而給予硏究。附帶地，人類β 3 -刺激作用係在 β!—接受器阻斷器（CGP20712A，10— 5Μ)存 在下’給予硏究。在每一*細胞（ΡΠΊΟ 1/ΐΉ 1 )產生 CAMP的量藉由使用125 I — cAMP的R I Α方法給 予測量。每一化合物的作用強度藉由從劑量-反應曲線結 果計算p D 2値及最大活性（I · A ·( % ) 1 〇 - 8 M iso pro ter enol的最大反應被定義爲1 0 0 % )，而給予比較。 已確定本發明化合物對於人類β 3 -接受器具有選擇性 刺激作用。 藥學組成物包括一或多種的本發明化合物或其鹽作爲 有效成分，其利用通常藥學上可接受的賦形劑給予製備。 根據本發明藥學組成物的投藥可藉由口服投藥或經g g 藥，例如，注射、栓劑、皮下劑、吸入劑或耳內浸齊(j。 劑量視每一特殊案例，如考慮患者的徵兆、年g、个生 別等等，而給予適當的決定，對於成人口服劑量通常每天 約 0 · 0 1mg/kg 至 l〇〇mg/kg，其一天一次 本紙張尺度適用中國國家標準（( 210X297»^ ) '---- (邡先閱讀竹而之注&事項:功寫本Ή )
、1T 557295 Α7 Η7 五、發明説明（I6 ) 或分爲一天2至4次地被投藥。當視徵狀而進行靜脈注射 ’其成人劑量通常每天約0 · 0 0 lmg/k g至1 0 mg/kg，其一天一次或分爲一天2至4次地被投藥。 關於製備用的賦形劑，藥學上無毒的固體或液體物質 可被使用。 根據本發明經由口服投藥的固體組成物爲錠劑、九劑 、膠囊、稀釋的粉末及顆粒。在此固體組成物中，一或多 種的活性物質藉由習知方法與至少一種惰性賦形劑相混合 ，該賦形劑爲乳糖、甘露醇、D -葡萄糖、羥基丙基木纖 維質、微晶形木纖維質、澱粉、聚乙烯吡咯烷酮、瓊脂、 果膠、矽酸鎂及鋁酸鎂。除了惰性賦形劑，組成物亦可包 括其它添加劑，如潤滑劑（例如，硬酯酸鎂）、崩解劑（ 例如，木纖維乙醇酸鈣）、穩定劑（例如，乳糖）及輔助 溶解劑（例如，谷氨酸或門冬氨酸）。錠劑及九劑，若需 要，可用糖衣或胃的或腸的塗覆物質的膜塗覆，該糖衣爲 蔗糖、明膠、羥基丙基木纖維質及羥基丙基甲基木纖維質 酞酸鹽。 經濟部中央標率局貝工消費合作社印製 (¾先閱讀背而之注4事項坪蛾寫本Ή 口服投藥的液體組成物包括藥學上可接受的乳液、溶 液、懸浮液、糖漿及配劑，及包括通常利用的惰性賦形劑 如純化的水或乙醇。除了惰性賦形劑外，組成物可進一步 包括輔助劑，如潤濕劑或懸浮劑、甜味劑、味覺劑、芳香 劑及防腐劑。 靜脈投藥的注射液包括防腐水溶液或非水溶液的溶液 、懸浮液及乳液。非水溶液的溶液及懸浮液包括，例如， 本紙張尺度適用中國國家標準（CNS )八4規格（210X 297 經滴部中央標率局貝X消費合作社印製 557295 A7 _________ Η 7 五、發明説明（17 ) 注射用蒸餾水及生理食鹽水。對於非水溶液的溶液及懸浮 液的溶劑爲丙二醇、乙二醇、植物油（如可可油、橄欖油 及芝麻油）、醇類（如乙醇）、阿拉伯膠及PolysolvaU 8 0 (市售名字）。此組成物可進一步包括輔劑，如等張 劑、防腐劑、潤濕劑、乳化劑、分散劑、穩定劑（如乳糖 )及輔助溶解劑（例如，谷氨酸或門冬氨酸）。這些可被 滅菌’例如，藉由通過細菌過濾器的過濾作用或用殺菌放 設線作用。這些亦可被製備爲無菌的固體組成物，接著在 注射前溶解於無菌的水或無菌的溶劑中。 進行本發明的最好模式 本發明藉由下面實例給予進一步說明。下面實例並非 用於限制本發明化合物，但涵蓋所有上述式（I )化合物 、其鹽、其水合物、其幾何異構物及光學異構物，及其多 晶形型態。附帶地，被用於本發明的物質是新的，其藉由 參考實例給予說明。 參考實例] 2 -吡啶碳醯氯（1 46毫克）被加至448毫克特 丁基（R) — N -〔2 -（4 一胺基苯基）—N— (2 — 羥基一 2 -苯基乙基）乙基〕氨基甲酸酯及3 3 0毫克三 乙基胺在4毫升氯仿中的溶液中。反應溶液在室溫下攪拌 2小時，然後在真空下蒸發溶劑。殘留物用氯仿稀釋’有 機層用碳酸氫鈉飽和溶液洗及用無水硫酸鎂乾燥。在真空 本紙張尺度適用中國國家榡準（CNS ) A4AL你（210/297公々_ i . 20 - (1¾先閲讀背而之注意事π ¢¾寫本R ) 衣· 、11 557295 A7 H7 五、發明説明（18 ) 下蒸發溶劑，殘留物藉由矽凝膠管柱層析法（沖提液：己 院/乙酸乙酯=1 / 3 )給予純化，得到3 2 1毫克特丁 基（R) — N —（2 —羥基—2 —苯基乙基）—N -〔2 一〔4 一〔 （2 —吡啶羰基）胺基〕苯基）乙基〕氨基甲 酸酯。 實例1 4N氫氯酸一乙酸乙酯溶液（1 〇毫升）被加至1 〇 笔升的4 5 8克特丁基（R) - N— (2 —經基一 2 —苯 基乙基）—N —〔2 —〔4 —〔 （2_吡啶羰基）胺基〕 苯基）乙基〕氨基甲酸酯乙醇溶液。反應溶液在室溫下攪 拌3小時，然後在真空下蒸發溶劑。從甲醇一乙醇-乙酸 乙酯中再結晶得到粗晶體的2 8 9克（R ) — 4 ’ 一〔 2 — 〔（2 -羥基_2 —苯基乙基）胺基〕乙基〕—2 —吡啶 羰基醯基苯胺鹽酸鹽。 經滴部中央標準局負工消费合作社印裝 (^先閱讀背而之注&事項再项寫本貝) 以相同於實例1的方法製備實例2至4的化合物。 實例2 (R) —2 —〔 1— (4 一氯爷基）一 1H — 味哇— 2 -基〕—4’—〔2 —〔 （2 -羥基一 2 -苯基乙基）胺 基〕乙基〕-乙醯基苯胺鹽酸鹽 實例3 (R) — 2 —〔 1— (3，4 —二氯节基）一1H — 本紙張尺度適用中國國家樣準(CNS)/\4^ ( 210x7^/； ) : 21 : 557295 A7 --- H7 經滴部中央標率局員工消費合作社印製 五、發明説明彳9 ) 四口坐一5 —基〕一4，一〔2_〔 （2 —羥基一2 —苯基乙 胺基〕乙基〕一乙醯基苯胺鹽酸鹽 (R) - 2 — (2 —胺基吡啶—6 —基）—4，—〔2 一〔（2 —羥基一 2 —苯基乙基）胺基〕乙基〕一乙醯基 苯胺鹽酸鹽 1 5毫升4 N氫氯酸一乙酸乙酯溶液被加至在甲醇（ 30 毫升）的 690 克特丁基（R) - N -〔2 -〔4一 〔2 -（2 -胺基噻唑一 4 一基）乙醯胺基〕苯基〕乙基 〕—N —（2 —羥基一 2 —苯基）乙基〕〕氨基甲酸酯溶 液。混合物在室溫下攪拌2小時。在真空下蒸發溶劑，然 後殘留物藉由逆相管柱層析法（沖提液：水/甲醇二2 / 1 )給予純化，得到3 1 0毫克（R ) - 2 -（ 2 -胺基 噻唑—4 —基）一 4，—〔2 —〔 （2 —羥基一 2 —苯基乙 基）胺基〕乙基〕-乙醯基苯胺鹽酸鹽。 實例6 10%鈀一碳（5 · 96克）被加至400毫升的 20 · 1 克 4’一〔2 —〔N -苯基—N — (2 -羥基—2 一苯基乙基）胺基〕乙基〕—2 —（2 —吼卩定）乙酿基苯 胺甲醇溶液。反應溶液在氫大氣壓及室溫下攪拌6小時。 本紙張尺度適用中國國家榡準(CNS )八4况& ( 210X2W〉U4.; -22- (^先閱讀.背而之注;&:事項弄^寫本石0
、1T . 557295 A7 —____ Η 7 五、發明説明扣） 使用塞里塑料（C e 1 i t e )過濾不溶物質且濾液在真 空下濃縮。殘留物的甲醇溶液被加至1 〇 · 8毫升4 N氫 氯酸-乙酸乙酯溶液，然後在真空下蒸發溶劑。從甲醇一 乙醇中再結晶得到粗晶體的（R ) — 4，一〔 2 —〔 （ 2 — 羥基一 2 —苯基乙基）胺基〕乙基〕一 2 —吡啶乙醯基苯 胺鹽酸鹽。 實例化合物的結構如表1 ;參考實例1化合物的物化 性性質如表2 ;及實例化合物的物化性性質如表3。 表中所使用的符號具有下述意義。因此，R e X :參 考實例；E X :實例；D A T A :物化性性質；N M R : 核磁共振光譜（T M S內標物；溶劑爲D M S〇一 d除非 另有說明）；mp:熔點；dec:分解；MS(m/z )質譜分析數據（m / z )。 ——U-------0^丨丨 (¾先閱讀ff而之注&事項洱^寫本刃) 、11 . 經漓部中央標率局員Η消費合作社印聚 本紙張尺度適用中國國家椋準（CNS ) ΛΜί格(210X 297：^^ ) . 23 - 557295 Λ7 H7 五、發明説明（>> ) 表2丨 參考例 數據‘ , 1 NMR (CDCI3) δ: 1.47(9H,s), 2.62-2.93(2H,m), 3.14-3.58(4H,m), 4.35(1 H,brs ),4.90(1 H,br), 7.06-7.40(7H,m), 7.45-7.50(1 H,m), 7.67-7.72(2H,m), 7.90(1 H, dt,J=2.0, 8.0Hz), 8.25-8.31 8.58-8.63(1 H,m), 9.98(1 H,brs) 經满部中央標準局貝,χ消費合竹社印製 表3 實例 數據. : 1 mp : 223-225°C NMR δ: 2.95-3.28(6H,m), 4.98-5.07(1 H,m), 7.23-7.44(6H,m), 7.65-7.75(1 H, m), 7.88(2H,d,J=8.4Hz), 8.05-8.22(2Hfm), 8.75(1 H,d,J=4.4Hz), 8.97(1 H,brs), 9.43(1 H,brs), 10.65(1 H,brs) 2 mp : 203-209t： , NMR δ: 2.90-3.10(3H,m), 3.10-3.20(3H,m), 4.41-4.48(2H,m), 4.95-5.05(1 H, m), 5.46(2H,s), 6.21 (1 H,brs)f 7.20(2H,d,J=8.6Hz)f 7.30-7.42(6H,m), 7.50-7.5 4(2H,m), 7.70(2H,s), 8.92(1 H,brs), 9.39(1 H,brs), 10.88-10.95(1 H,m) 3 mp : 240-242T： NMR δ: 2.90-3.10(3H,m), 3.10-3.25(3H,m)f 4.32(2H,s), 4.98(1 Hfdt,J=10.3, 3 •4Hz), 5.72(2H,s), 6.20(1 H，d,J=3.9Hz), 7.20(2H,d，J=8.3Hz), 7·30·7·40(6Η,πί) ,7.51(2H,d,J=8.8Hz), 7.62(1 H,d,J=8.3Hz), 7.67(1 H,d,J=2.0Hz), 8.86(1 H,brs), 9.17(1 H.brs), 10.67(1 H,s) 4 mp : 151-1591 NMR δ: 2.90-3.10(3H,m), 3.10-3.20(3Hfm), 3.76(2H,s), 5.02(1 H,dd,J=10.2, 2.7Hz), 6.70(1 H,s), 7.20(2H,d,J=8.8Hz)f 7.25-7.40(5H,m), 7.59(2H,d,J=8.8Hz ),8.96(1 H,brs), 9.21 (1 H,brs), 9.43(1 H,brs), 10.58(1 H,s) 5 mp : 150-152t： NMR δ: 2.88-3.07(3Hfm), 3.08(3H,m), 3.95(2H,s), 5.00(1 H,dd,J=2.8, 10.0Hz ),6.21 (1H,s), 6.82(1 H,d,J=7.6Hz), 6.91(1H,d,J=8.0Hz), 7.17-7.23(2H,m), 7.2 8-7.43(5H,m), 7.55-7.62(2H,m), 7.82-8.04(3H,m), 8.90(1 H.brs), 9.31(1H,brs), 10.67(1 H,brs), 14.07(1 H,brs) 6 mp : 223-224^C NMR δ: 2.86-3.22(6H,m), 3.49(2Hfs), 4.93-5.03(1 H,m), 6.20(1 Hfd,J=4.0Hz), 7.15-7.43(9H,m), 7.55-7.62(2H,m), 7.75(1 H,dt,J=1.6, 8.0Hz), 8.45-8.53(1 H,m I), 8.06-9.50(2H,br), 10.35(1H,brs) ----i---1______ 鄣先閱讀背而之注意事項洱硝寫本s )
、1T 本紙張尺度適用中國國家標準（CNS ) Λ4现枋（210X2W公却）-广-

Claims (1)

  1. 557295 ：4s8 C8 D8 告本 、申請專利範圍 修正i補充 本卩年a 第871 1 7145號專利申請案 < 中文申請專利範圍修正本 民國92年8月 5 日修正 如下式之醯胺衍生物
    Η R (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 其中環B爲選自咪唑基、噻唑基、吡啶基及四唑基之雜 方基；X爲一鍵或Ci.6伸焼基；R爲氣原子、胺基或經鹵素 取代的苄基，及其鹽。 2 .如申請專利範圍第1項之醯胺衍生物或其鹽，其係 選自下列任一者：（R)— 4’一〔2 —〔（2 —羥基一 2 -苯基乙基）胺基〕乙基〕—2 -吡啶羰基醯基苯胺； (R) — 2 -〔1— (4 一 氯苄基）—1H —咪唑—2 一基〕—4’—〔2 —〔 （2 -羥基—2 —苯基乙基）胺基 〕乙基〕一乙醯基苯胺； (R) — 2 —〔1— (3，4 —二氯苄基）一1H —四 唑—5 —基〕—4’—〔2 —〔（2 —羥基—2 -苯基乙基 )胺基〕乙基〕-乙醯基苯胺； (R) — 2 — (2 —胺基噻唑—4 —基）—4’—〔2 —〔（2 -羥基—2 -苯基乙基）胺基〕乙基〕一乙醯基苯 胺； 本纸張尺度適用中國國家標準（CNS)A4規格（2i〇x297公釐） 557295 A8 B8 C8 D8 六、申請專利範圍 (R) — 2，（2 -胺基 D比陡—6 —基）—4’—〔2 —〔（2 -羥基一 2 -苯基乙基）胺基〕乙基〕一乙醯基苯 胺；或 (R) — 4’—〔2 -〔 （2 —羥基一 2 —苯基乙基） 胺基〕乙基〕—2 — (2 -吡啶）乙醯基苯胺；或其鹽。 3 . —種具有抗肥胖及抗高脂血作用之醫藥組成物，包 括如申請專利範圍第1項之醯胺衍生物或其鹽。 4 . 一種具有抗肥胖及抗高脂血作用之醫藥組成物，包 括如申請專利範圍第2項之醯胺衍生物或其鹽。 5 . —種用於治療糖尿病之醫藥組成物，包括如申請專 利範圍第1項之醯胺衍生物或其鹽作爲有效成分。 6 . —種用於治療糖尿病之醫藥組成物，包括如申請專 利範圍第2項之醯胺衍生物或其鹽作爲有效成分。 (請先聞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 -2- 本紙張尺度適用中國國家標準（CNS ) A4規格（210X297公釐）
TW087117145A 1997-10-17 1998-10-15 Amide derivatives or salts thereof TW557295B (en)

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Families Citing this family (78)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2356197A (en) * 1999-10-12 2001-05-16 Merck & Co Inc Amide derivatives as beta 3 agonists
US6451814B1 (en) 2000-07-17 2002-09-17 Wyeth Heterocyclic β-3 adrenergic receptor agonists
US6537994B2 (en) 2000-07-17 2003-03-25 Wyeth Heterocyclic β3 adrenergic receptor agonists
US6410734B1 (en) * 2000-07-17 2002-06-25 Wyeth 2-substituted thiazolidinones as beta-3 adrenergic receptor agonists
US6498170B2 (en) 2000-07-17 2002-12-24 Wyeth Cyclamine sulfonamides as β-3 adrenergic receptor agonists
US6525202B2 (en) * 2000-07-17 2003-02-25 Wyeth Cyclic amine phenyl beta-3 adrenergic receptor agonists
US6465501B2 (en) 2000-07-17 2002-10-15 Wyeth Azolidines as β3 adrenergic receptor agonists
UA82048C2 (uk) * 2000-11-10 2008-03-11 Эли Лилли Энд Компани Агоністи альфа-рецепторів, активованих проліфератором пероксисом
US7342117B2 (en) * 2001-10-30 2008-03-11 Astellas Pharma Inc. α-form or β-form crystal of acetanilide derivative
TWI249515B (en) * 2001-11-13 2006-02-21 Theravance Inc Aryl aniline beta2 adrenergic receptor agonists
WO2003042160A1 (en) 2001-11-13 2003-05-22 Theravance, Inc. Aryl aniline beta-2 adrenergic receptor agonists
EP1458381B1 (en) * 2001-12-20 2005-11-30 Applied Research Systems ARS Holding N.V. Triazoles as oxytocin antagonists
ES2360353T3 (es) 2002-11-07 2011-06-03 Astellas Pharma Inc. Acción correctora para hiperactividad de vejiga urinaria que comprende un derivado de anilida de ácido acético como principio activo.
EP1424079A1 (en) * 2002-11-27 2004-06-02 Boehringer Ingelheim International GmbH Combination of a beta-3-receptor agonist and of a reuptake inhibitor of serotonin and/or norepinephrine
DE102004001413A1 (de) * 2004-01-09 2005-08-18 Boehringer Ingelheim Pharma Gmbh & Co. Kg 3-Hydroxymethyl-4-Hydroxy-Phenyl-Derivate zur Behandlung von chronisch obstruktiver Lungenerkrankung
WO2006014704A1 (en) * 2004-07-21 2006-02-09 Theravance, Inc. DIARYL ETHER β2 ADRENERGIC RECEPTOR AGONISTS
KR101479048B1 (ko) 2007-01-31 2015-01-05 도레이 카부시키가이샤 벤질아민 유도체 또는 그 약학적으로 허용되는 산부가염, 및 그 의약 용도
SI2216021T1 (sl) 2007-11-02 2013-01-31 Astellas Pharma Inc. Farmacevtski sestavek za zdravljenje prekomerno aktivnega sečnega mehurja
EP2223690A4 (en) 2007-12-21 2011-02-23 Astellas Pharma Inc PHARMACEUTICAL COMPOSITION USED TO MITIGATE SYMPTOMS OF THE INFINITE URINARY TRACT
DE102008014523A1 (de) * 2008-03-15 2009-09-17 Robert Bosch Gmbh Heizgerät
US8598355B2 (en) 2008-05-14 2013-12-03 Astellas Pharma Inc. Amide compound
TWI478712B (zh) * 2008-09-30 2015-04-01 Astellas Pharma Inc 釋控性醫藥組成物
US8586760B2 (en) * 2009-06-15 2013-11-19 Auspex Pharmaceuticals, Inc. Aminothiazole modulators of beta-3-adrenoreceptor
JP5849946B2 (ja) 2010-03-29 2016-02-03 アステラス製薬株式会社 放出制御医薬組成物
EP2554168B1 (en) * 2010-03-29 2018-01-24 Astellas Pharma Inc. Controlled release pharmaceutical composition
EP2709993A4 (en) 2011-05-18 2015-02-25 Reddys Lab Ltd Dr AMORPHIC MIRABEGRON AND METHOD FOR CRYSTALLINE FORMS OF MIRABEGRON
US9655885B2 (en) 2011-05-18 2017-05-23 Dr. Reddy's Laboratories Ltd. Amorphous mirabegron and processes for crystal forms of mirabegron
US20150031734A1 (en) 2012-03-30 2015-01-29 Astellas Pharma Inc. Pharmaceutical composition containing mirabegron
CN103387500A (zh) * 2012-05-11 2013-11-13 上海医药工业研究院 一种米拉贝隆及其中间体的制备方法
TW201424772A (zh) 2012-08-31 2014-07-01 Astellas Pharma Inc 經口投與用醫藥組成物
US9784726B2 (en) 2013-01-08 2017-10-10 Atrogi Ab Screening method, a kit, a method of treatment and a compound for use in a method of treatment
CN103193730A (zh) * 2013-04-17 2013-07-10 苏州永健生物医药有限公司 一种米拉贝隆的合成方法
CN103232368B (zh) * 2013-04-18 2015-08-12 苏州永健生物医药有限公司 一种(r)-4-硝基苯乙基-(2-羟基-2-苯乙基)-氨基甲酸叔丁酯的合成方法
WO2015040605A1 (en) 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Crystalline form of mirabegron
WO2015040573A1 (en) 2013-09-23 2015-03-26 Ranbaxy Laboratories Limited Mirabegron dimethyl sulphoxide solvate and its use for the treatment of overactive bladder
WO2015044965A1 (en) 2013-09-30 2015-04-02 Megafine Pharma (P) Ltd. A process for preparation of mirabegron and alpha crystalline form thereof
ITMI20131653A1 (it) * 2013-10-07 2015-04-08 Dipharma Francis Srl Forme cristalline di un agonista adrenergico
CN104876889B (zh) * 2014-02-27 2017-02-22 人福医药集团股份公司 化合物的合成方法
WO2015162536A1 (en) * 2014-04-22 2015-10-29 Calyx Chemicals And Pharmaceuticals Ltd. Novel process for preparation of mirabegron and it's intermediate
CN103896872A (zh) * 2014-04-29 2014-07-02 黑龙江大学 米拉贝隆的合成方法
WO2016020440A1 (en) 2014-08-06 2016-02-11 Interquim, S.A. Method for the synthesis of mirabegron and its derivatives
WO2016024284A2 (en) 2014-08-07 2016-02-18 Wanbury Ltd. A process for the preparation of mirabegron and its intermediates
CN105481705A (zh) * 2014-08-23 2016-04-13 南京海纳医药科技有限公司 (r)-2-[[2-(4-氨基苯基)乙基]氨基]-1-苯乙醇的制备及应用
US20170291882A1 (en) * 2014-10-01 2017-10-12 Apotex Inc. Solid Forms of Mirabegron
CN104496841B (zh) * 2014-11-26 2017-01-25 南京工业大学 一种米拉贝隆中间体的合成方法
JP2018508497A (ja) 2015-02-02 2018-03-29 ルピン・リミテッド ミラベグロンの多形型の調製方法
JP2018090490A (ja) 2015-03-31 2018-06-14 アステラス製薬株式会社 ミラベグロン含有医薬組成物
CN105111165B (zh) * 2015-09-14 2017-10-31 保定博洋生物科技有限公司 一种米拉贝隆的制备方法
US10696642B2 (en) 2015-09-23 2020-06-30 The General Hospital Corporation TEAD transcription factor autopalmitoylation inhibitors
FR3043555B1 (fr) * 2015-11-17 2019-10-25 Centre National De La Recherche Scientifique (Cnrs) Mirabegron pour le traitement de maladies retiniennes
EP3184516A1 (en) 2015-12-23 2017-06-28 Enantia, S.L. Crystalline inclusion complexes of mirabegron with beta-cyclodextrin
HU231124B1 (hu) * 2016-02-10 2020-12-28 Egis Gyógyszergyár Zrt. Eljárás morfológiailag egységes mirabegron és mirabegron monohidroklorid előállítására
WO2017186593A1 (en) 2016-04-25 2017-11-02 Synthon B.V. Tablets comprising mirabegron and solifenacin
WO2017186598A1 (en) 2016-04-25 2017-11-02 Synthon B.V. Modified release tablet composition comprising mirabegron
GB201612165D0 (en) * 2016-07-13 2016-08-24 Atrogi Ab Combinations for the treatment of type 2 diabetes
US9988402B2 (en) 2016-08-19 2018-06-05 Purdue Research Foundation Amine-boranes bearing borane-intolerant functionalities
EP3335700A1 (de) 2016-12-13 2018-06-20 Stada Arzneimittel Ag Feste pharmazeutische orale darreichungsform mit verlängerter wirkstofffreisetzung umfassend mirabegron
EP3489224A1 (en) 2017-02-14 2019-05-29 Alfred E. Tiefenbacher (GmbH & Co. KG) Mirabegron prodrugs
KR101868438B1 (ko) 2017-04-13 2018-06-20 (주) 성운파마코피아 아미드 유도체의 제조방법
KR102398639B1 (ko) 2017-06-20 2022-05-17 (주) 성운파마코피아 아미드 유도체의 염 및 그 제조방법
WO2019013583A2 (ko) 2017-07-14 2019-01-17 주식회사 대웅제약 약제학적 제제 및 그 제조방법
KR101937713B1 (ko) 2017-07-14 2019-01-14 주식회사 대웅제약 약제학적 제제 및 그 제조방법
GB201714736D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714740D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714734D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
GB201714745D0 (en) 2017-09-13 2017-10-25 Atrogi Ab New compounds and uses
WO2019072404A1 (en) 2017-10-12 2019-04-18 Synthon B.V. MODIFIED RELEASE COMPRESSED COMPOSITION COMPRISING MIRABEGRON
EP3292864A1 (en) 2017-10-12 2018-03-14 Synthon B.V. Modified release tablet composition comprising mirabegron
US10478399B2 (en) 2017-10-12 2019-11-19 Synthon B.V. Modified release tablet composition comprising mirabegron
KR101928987B1 (ko) * 2018-08-28 2018-12-13 (주) 성운파마코피아 신규한 고순도 미라베그론의 결정질 일수화물, 이의 제조방법 또는 용도
CN109776373B (zh) * 2019-01-29 2020-04-21 广东东阳光药业有限公司 酰胺取代的吡咯烷酰胺衍生物及其用途
CN109734712B (zh) * 2019-01-30 2020-10-20 广东东阳光药业有限公司 芳基或杂芳基取代的吡咯烷酰胺衍生物及其用途
KR20200117091A (ko) 2019-04-02 2020-10-14 제이투에이치바이오텍 (주) 미라베그론 전구체 약물 화합물 및 이의 과민성 방광 질환의 치료 또는 개선을 위한 의약 용도
KR20210012082A (ko) 2019-07-23 2021-02-03 콜마파마(주) 미라베그론 및 탐스로신을 포함하는 약학 조성물
CN110590699B (zh) * 2019-09-29 2022-11-15 广东先强药业有限公司 一种米拉贝隆的精制方法
EP3722285B1 (en) 2020-04-08 2022-03-30 Alfred E. Tiefenbacher (GmbH & Co. KG) Process for preparing mirabegron enacarbil
KR102333167B1 (ko) 2021-05-26 2021-12-01 유니셀랩 주식회사 효율적이고 대량생산이 가능한 미라베그론 무정형 제조방법
GB202205895D0 (en) 2022-04-22 2022-06-08 Atrogi Ab New medical uses

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2965655D1 (en) * 1978-06-28 1983-07-21 Beecham Group Plc Secondary amines, their preparation, pharmaceutical compositions containing them and their use
DE3743265A1 (de) * 1987-12-19 1989-06-29 Boehringer Ingelheim Kg Neue ammoniumverbindungen, ihre herstellung und verwendung
US5223614A (en) * 1987-12-19 1993-06-29 Boehringer Ingelheim Gmbh New quaternary ammonium compounds, their preparation and use
WO1993019861A1 (en) 1992-03-27 1993-10-14 Kawasaki Steel Corporation Method of detecting roll clearance setting error for universal rolling machines and method of rolling h-beam having favorable flange size by utilizing said method
US5451677A (en) * 1993-02-09 1995-09-19 Merck & Co., Inc. Substituted phenyl sulfonamides as selective β 3 agonists for the treatment of diabetes and obesity
US5614544A (en) 1993-09-14 1997-03-25 Takeda Chemical Industries, Ltd. Oxazolidinedione derivatives and their use
JP3722855B2 (ja) * 1993-09-14 2005-11-30 武田薬品工業株式会社 ２，４−オキサゾリジンジオン誘導体およびそれを含んでなる医薬
IL113410A (en) * 1994-04-26 1999-11-30 Merck & Co Inc Substituted sulfonamides having an asymmetric center and pharmaceutical compositions containing them
US5541197A (en) * 1994-04-26 1996-07-30 Merck & Co., Inc. Substituted sulfonamides as selective β3 agonists for the treatment of diabetes and obesity
ES2191922T3 (es) 1997-01-23 2003-09-16 Yamanouchi Pharma Co Ltd Nuevos derivados de amida y sus composiciones medicinales.
JPH10218861A (ja) * 1997-02-04 1998-08-18 Yamanouchi Pharmaceut Co Ltd 新規なフェネタノール誘導体又はその塩

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