TW544448B - Pyridine derivatives - Google Patents
Pyridine derivatives Download PDFInfo
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- TW544448B TW544448B TW087110887A TW87110887A TW544448B TW 544448 B TW544448 B TW 544448B TW 087110887 A TW087110887 A TW 087110887A TW 87110887 A TW87110887 A TW 87110887A TW 544448 B TW544448 B TW 544448B
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- methyl
- phenyl
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- alkyl
- hydrogen
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Description
544448 A7 B7 五、發明説明(1 ) 一 本發明係關於2 -芳基鏈知基-、2 -雜芳基鍵晞基-、2 -芳 基鏈炔基·、2-雜芳基鏈炔基-、2_芳基偶氮-和2-雜芳基偶 氮·吨淀於緩和TT1GluR類活性及於治療mGluR5媒介疾病方 面 < 使用’係關於用於這些治療的藥用組合物上之使用, 及係關於新頭的2 -芳基鏈晞基、2 -雜芳基鏈婦基、2 _芳基 鏈炔基、2 -雜芳基鏈炔基、2 -芳基偶氮_和2 -雜芳基偶氮_ p比咬。 已經發現到2 -芳基鏈~基、2 -雖芳基缝晞基、2 -芳基鍵 块基、2 -雜芳基鏈炔基、2 -芳基偶氮-和2 -雜芳基偶氮-吡 啶(包括藥用可接受的鹽類)(下文稱爲本發明之物劑)可作 爲mGluR的緩和劑。tnGluR的緩和作用由幾種方式得到證 實,尤其是在結合分析及官能性分析(如:第二個信使分析 或測定細胞間妈濃度變化)°舉例言之,表達mGluR5 a之測 定重組細胞鏈中的肌醇反轉顯示本發明之選定物劑的I C 5 () 約1 η Μ /升至約5 0 " Μ /升。 經滴部中央標準局員工消費合作社印繁 特別地,本發明之物劑具有價値的藥用性質。例如,它 們在人體代謝谷胺酸鹽受體(mGluR)具有顯著及選定的緩 和(特別是拮抗)作用。此可由活體外測定,如:於重組的 人體代謝谷胺酸鹽受體(特別是丼與P L C _偶合的次類, 如:mGluR5 )的例子中,使用不同程序(如:根據L.P. Dagget 等人,Neuropharm.,34., 871-886 (1995), P.J. Flor 等人,J. Neurochem.,67, 58-63 (1996))測定拮抗誘發細 胞間C a2濃度提高之抑制作用,或者由丁. Knoepfel等人, J. Pharmacol.,288, 389-392 (1994),L.P. Daggett 等人, -4 - 本纸張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 Α7 Β7 五、發明説明(2 ) 請 閱 讀 背 面 之 注-意 事 項 4 'Α 舄 % 頁
Neuropharm·,5 8-73 ( 1996 )及所列的文獻所述測定拮抗 誘導的肌醇磷酸鹽反轉受到抑制的程度。人體mGluR次類 的隔離和表示述於US Patent No. 5,52 1,297 °本發明選定 的物劑在重組細胞中之抑制奎思奎特(qUisqUalate )誘發的 肌醇磷酸鹽反轉的[C5G値顯示hmGluR5a約Ί nM /升至約 50" M/升。 據此,本發明係關於本發明之物劑於治療與谷胺酸訊息 傳遞不規則有關的失調方面之使用及於與完全或部分由 mGluR5媒介的神經系統失調方面之使用。 與谷胺酸-訊息傳遞不規則有關的疾病如:癲癇、大腦局 邵貧血(特別是急性貧血)、眼部貧血疾病、肌肉抽筋(如: 局部或全部抽筋),及特別是驚風或疼痛。 元全或邶分由mGluR5媒介的神經系統失調如:神經系統 的急性外傷和慢性退化、精神病和疼痛。 4 本發明亦係關於本發明的物劑於治療與谷胺酸訊息傳遞 不規則有關的失調方面之使用,及治療完全或部分由第丨類 mGluR媒介的神經系統失調方面之使用。 經濟部中央標準局員工消費合作社印繁 此外,本發明係關於本發明之物劑於製造用以治療與谷 胺酸訊息傳遞不規則有關的失調及治療完全或部分由第;^類 mGluR媒介的經系統失調之藥用組合物方面之使用。 本發明的另一特點係關於及治療完全或部分由第工類 mGluR(以mGluR5爲佳)媒介的神經系統失調的方法,此方 法包含在需要此治療的溫血生物上施用療效量的本發明之 物劑。 ______ - 5 -___ 本紙張尺度適用中國國家標準(CNS ) A4規格21 〇χ 297公釐)~ " ----. ---- 544448 A7 B7 _ __-_ -__ ~——一 ______—— 五、發明説明(3 ) 另一特點中,本發明係關於新穎的2 ·芳基鏈烯基-、2 -雜 芳基鏈締基-、2 -芳基鏈決基-、2 -雜芳基鏈炔基·、2 -芳基 偶氮-和2-雜芳基偶氮-吡啶及它們的鹽類及其製法。 此外,本發明係關於一種藥用組合物,包含藥用活性成 物及慣用的藥用賦形劑、新穎的2 -芳基鏈烯基-、2 -雜芳 基鏈晞基-、2-芳基鏈決基-、2-雜芳基鏈炔基-、2-芳基偶 氮-和2 -雜芳基偶氮-吡啶或其於藥用上可被接受的鹽類。 本發明的物劑如式I化合物 凡 (請先閱讀背面之注意事項存填寫本頁)
其中, 經濟部中央標準局員工消費合作社印紫 R 1代表氫、低碳烷基、經基-低碳燒基、低瘦燒基-胺 基、旅νί定基、幾基、醋化的叛基、廳:胺化的幾基、不 飽和或經低%。fe基"、低Ί氣基-、卣基-和//或三氣 曱基-取代的N -低碳烷基-N -苯基胺基甲醯基、低碳烷 氧基、鹵基-低碳坑基或1¾基-低緩fe氧基, R 2代表氫、低碳烷基、羧基、酯化的羧基、醯胺化的羧 基、經基-低壤紀基、經基、低碳號氧基或低碳燒醯:氧 基、4-(4 -氣-卞S’S基)-旅咬-i -基複基、4 -第三丁氧基 幾基-泰唤-丨-基·致基、4 - ( 4 - ®氮基-2 -幾基爷gg基)_ -6 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(210x 297公釐) 544448 A7 B7 經滴部中央標率局員Η消費合作社印繁 五、發明説明(4 ) 哌嗉_ 1 -基-羧基或4 - ( 4 -疊氮基-2 -羥基-3 -碘·芊醯 基)-旅17秦-〗_基複基’ R 3代表氫、低碳烷基、羧基、低碳烷氧基-羰基、低碳烷 基-胺甲醯基、羥基-低竣烷基、二-低碳烷基-胺基甲 基、嗎淋代藏基或4 ·( 4 -氟-节醯基)-喊淀 1 -基幾基, R 4代表氫、低碳烷基、羥基、羥基-低碳烷基、胺基-低 碳烷基、低碳烷基胺基-低碳烷基、二-低碳烷胺基-低 碳燒基、不飽和或經經基取代的低碳伸燒基胺基·低破 烷基、低碳烷氧基、低碳烷醯氧基、胺基-低碳烷氧 基、低碳燒基胺基-低碳燒氧基、二-低瑗烷胺基-低碳 坑氧基、自大Si亞胺-低碳燒氧基、不飽和或經幾基或經 2 -氧-咪唑烷-1 ·基取代的低碳伸烷胺基-低碳烷氧基、 羧基、酯化的或醯胺化的羧基、羧基-低碳烷氧基或酯 化的羧基-低碳烷氧基, X 代表視情況經鹵基取代的低碳伸烯基或伸炔基,其經 由附近的不飽和碳原子或偶氮N = N -)基鍵結,而 R 3代表芳族或雜芳族,其爲未經取代或被一或多個取代 基所取代’其取代基選自低旋燒基、齒基、鹵基-低緩 烷基、鹵基-低碳烷氧基、低碳鏈烯基、低碳鏈炔基、 未經取代或經低碳烷基_、低碳烷氧基-、卣基-和/或 一氣甲基-取代的笨基、未經取代或經低碳烷基·、低 蛟烷氧基·、齒基-和/或三氟甲基-取代的笨基-低碳 块基 ♦基、.¾基-低碳烷基、低碳燒驗氧基_低碳燒 低%L '丨7〇氧基、低唆、丨布氧基、低碳伸燒二氧基、低 本紙張尺度剌胁(2107^7 (讀先閱讀背面之注意事項再填寫本頁) •裝- 、1Τ 4 544448 A7 B7 發明説明(5 ) 唆燒醯氧基、胺基-、低碳烷胺基-、低碳烷醯胺基-或 N -低緩烷基-n -低碳烷基-N -低碳烷醯胺基-低碳烷氧 基、未經取代或經低後坑基-、低碳烷氧基-、鹵基-和 /或三氟甲基-取代的苯氧基、未經取代或經低碳烷基 -、低後烷氧基-、卣基-和/或三氟甲基-取代的苯基_ 低碳燒氧基、醯基、羧基、酯化的羧基、醯胺化的複 基、氰基、羧基-低碳烷基胺基、酯化的羧基-低碳烷 胺基、醯胺化的羧基-低碳烷胺基、亞磷酸基-低碳虎 胺基、酯化的亞磷酸基-低碳烷胺基、硝基、胺基、低 碳烷胺基、二-低碳烷胺基、醯胺基、N -醯基_ N ·低峻 坑胺基、苯胺基、苯基-低碳烷胺基、環烷基-低碳燒 胺基或雜環芳基-低碳烷胺基,其中的每一者未經取代 或經低碳燒基-低碳烷氧基-、卣基-和/或三氟甲基_ 取代, 慣用的親光性配位子和慣用的射線活性標記物(含括它們的 N -氧化物)及它們於藥用上可被接受的鹽類。 經濟部中央標率局員工消費合作社印繁 (請先閱讀背面之注意事項再填寫本頁) 式I化合物有鹼性基圑能夠形成酸加成鹽,式丨化合物有 酸性基圑能夠形成鹼加成鹽。式I化合物有鹼係基圑及至少 一個酸性基圑,可形成内鹽。 亦含括全鹽或部分鹽,即,式I的每莫耳酸有1,2或 3 (以2爲佳)當量鹼之鹽類,或式I的每莫耳鹼有1 , 2或 3(以1爲佳)當量酸之鹽類。 就分離或純化的目的’也能夠使用樂用上無法接受的鹽 類。僅藥用上可接受、無毒鹽類可用於治療,因此以它們 -B - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 A7 B7 經满部中央標準局員工消費合作社印繁 五、發明説明(6 ) 爲佳。 此描述中的鹵素是指氟、氯、溴或碘。 X代表鏈晞基時,以順式構形爲佳。 較佳的式I化合物中, X 代表經由附近的不飽和碳原子鍵接視情況被鹵基取 代的(C 2 _ 4 )伸鏈垸基, R 1是氫,(C〗-4)烷基、(C丨_ 4)燒氧基、#圼基(C丨· 4 )烷 基、氰基、乙炔基、羧基、(C 1 _ 4 )烷氧基羰基、二 (c ] _4 )燒基胺基、(c】_ 6 )烷基胺基羰基、三氟甲基苯 基胺基羰基, R 2是氫,輕基、(C丨_ 4 )燒基、經基(C丨_ 4 )垸基、(C丨_ 4 ) 坑氧基、致基、(C 2 _ 5 )燒醯氧基、(C丨_ 4 )燒氧基馥 基、二(C ] -4 )梡基胺基(C 1 ·4)烷醯基、二(C ! ·4 )烷基 胺基甲基、4 - ( 4 -氟苄Sfe基)·喊啶-1 ·基-幾基、4 -第三 丁氧基談基喊嗉-基-幾基、· 4 - ( 4 -疊氮基-2 -幾基节 基)-喊唤-1-基-敌基或4-(4 -疊氮基-2-幾基-3-破-苄醯基)-哌嗉-1 -基羧基, R3是氫、烷基、羧基、(C〗_4)烷氧基羰基、(Cm) 烷基胺甲醯基、羥基(C】_4 )烷基、二(C i _4)烷基胺基 甲基、嗎啉代羰基或4 - ( 4 ·氟苄醯)-哌啶-1 -基羧基, R4是氫、羥基、(C】_4)烷氧基、(C2_5)烷醯氧基、(Ci_4) 士元氧基觀基、胺基(C丨_ 4 ) fe氣基、二(C 1 · 4 )燒基胺基 (C】_4)烷氧基、二(CVO烷基胺基(CV4)烷基、羧基 (C,_4)烷基羰基、(C! _4)烷氧基羰基(Ci-4)烷氧基、 —_____ - 9-_____ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) (請先閱讀背面之注意事項再填寫本頁) 裝·
、1T 4 544448 A7 — ___B7 五、發明説明(7 ) 羥基(C】·4)烷基、二(Cl_4)烷基胺基((:14)烷氧基、 間-羥基-對-疊氮基苯基羰基胺基(c i _ 4)烷氧基,而 R 5是下列基團
Η 其中, 經满部中决標率局員工消費合作社印繁 (讀先閲讀背面之注意事項再填寫本頁) R a和R b分別是氫、羥基、齒素、硝基、氰基、羧基、(C } _ 4 ) 基、(C 1 _ 4 )烷氧基、羥基(C i _ 4 )烷基、(C丨· 4 )燒 氧基羰基·、( C 2 · 7 )烷醯基、(C 2 _ 5 )烷醯氧基、(C 2 _ 5 ) 坑酿氧基(C ] _4) fe基、三氟甲基、三氟甲氧基、三曱 基甲碎坑基乙炔基、(c 2 _ 5 )鏈炔基、胺基、疊氮基、 胺基(C丨_ 4 )烷氧基、(C 2 _ 5)烷醯基胺基(c丨· 4)烷氧 基、(Ci·4)烷基胺基(c】-4)烷氧基、二烷基胺 基(C丨· 4 )烷氧基、(C丨_ 4 )烷基胺基、二(C 1 _ 4 )烷基胺 基、一鹵节基胺基、嘍嗯基甲基胺基、嘧嗯基羰基胺 基、二氟甲基苯基胺基羰基、四吐基、(C 2 _ 5 )丨完醯基 胺基、芊基羰基胺基、(C 1 _ 4)烷基胺基羰基胺基、 (C 1 _ 4 )坑氧基談基-胺基幾基胺基或(C i _ 4 )、院基績酿 基, ^__-10- _ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) M4448 A7 B7 五 、發明説明(8
R R ^ C是氫、氟、氯、溴、超基、/广 一 I (Ch4)烷基 氧基、(C〗_4)烷氧基或氰其 公’而
Rd是氫、鹵素或(Cm)烷基。 更佳的式I化合物是X如前兩批^ D V义義,但R基團如下者. R】是氫,(Ch)烷基、(Cl计 有. 烷虱基、氰基、乙块 二(C丨_4)烷基胺基, 基或 是氫,羥基、羧基、(C〗、^ 】-4)烷虱基羰基、二(c 基胺基甲基、4·(4·氟-;_ A _4)" ^ % -哌哫-1 -基-羧基、4 第三丁氧基羰基哌嗪-1- 卷K基、4-(4-疊氮基-2_羥 基芊醯基)-喊嗪-1 -基-幾其七 α ^ 工 夂%或4 - ( 4 - ®亂基-2 -幾基-3 _ 碘-苄醯基)-哌嗉-1 _基幾基, 如前面所定義者, 疋氫、嫂基、竣基、(C2·5)烷醯氧基、(Ci 4)烷氧基 恢基、fe:基(CW4) 氧基、二(Ci _4)烷基胺基(Ci4) 烷氧基、二((:丨_4)烷基胺基(C1_4)烷基或羥基(C1_4) 燒基,而 R 5是下列基圑 (請先閲讀背面之注意事項再填寫本頁) .裝. -訂· 經滴部中央標準局員工消費合作社印繁 R, 或 R, 其中 R a和R b分別是氫、卣素、硝基、氰基、(C丨_ 4)嫁基、(〔 -11 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 A7 B7 五、發明説明(9 工氟甲基、三氟甲氧基或(C2_5)鏈炔基, 經濟部中央標牟局員工消費合作社印繁 4 )貌氧基 而 R c和R d如前面所定義者。 本發明之物劑包括,如:下文中的例子所述的化合物。 本發明之物劑於治療前述失調上之用途可有下列標準試 驗件到證賞: 以腹膜内或P . 〇 ·方式施用約1 〇至10〇毫克/公斤藥量而 預先處理1 5分鐘至8小時,本發明之物劑在電擊誘發的抽 筋模式中顯現抗抽筋活性[請參考E A. Swinyar(j, j. Pham· Assoc. Scient. Ed·,丛,201 (1949 )和 J. Pharmacol. Exptl. Thei.ap·逝,3 1 9 (1952 )]。 以Ρ·〇.方式施闬約4至40毫克/公斤劑量,本發明之物 劑在Freund完全輔助劑(F C a )誘發的痛覺過敏中顯現逆轉 十同況[請參考 j· Donnerei·等人,Neuroscience 41, 693-698 ( 1992 )和 C.J· Woolf, Neuroscience 62_, 327-33 1 (1994 )。 就所有的前述指示,適當劑量當然視,如:所用的化合 物、施用對象、施用方式、及欲治療疾病的木質和嚴重程 度而改文°但是,通常,每日施用量約〇 5至約1 〇〇毫克 /公斤動物體重,可以得到令人滿意的結果。用於大型哺 乳:物(如:人類)時·容易每日分高至四次施用的化:物 或是持續釋出的化合物之每日劑量約5至15 至約1〇〇0毫克爲佳。 毛兄、、勺 前述指示的較佳的化合物包括(3 ·丨2 _ [ 2 _順_㈠5 _二氯苯 基)乙晞基]-6-甲基-吡啶_2_基氧基卜丙基)_二甲基胺 -12- 本紙張尺度適用中國國家標準(CNS ) A4規格(2H)>< 297公釐 I !-1 ...... - - - - - - I- - ---- ---- 0 1讀先閱讀背面之注意事項#填寫本貢) 訂 Φ 544448 經濟部中央標率局員工消費合作社印製 A7 B7 五、發明説明(10 ) (A)、2 -甲基-6 -笨乙烯基吡咬(β)、2七_氣-苯基乙块 基)-6·甲基“比咬(C)和2-(仁乙氧基-三氟甲基-苯基乙決 基)-6-甲基“比咬(D)。例如,已經在前述電擊誘發的抽筋 模^中得知化合物八和8有抗抽筋活性,心。分別是3〇和 3 5耄克/公斤腹膜内施用(前處理時間分別是4小時和1 5分 鐘),前述FC A誘發的痛覺過敏模式中,化合物〔和〇顯示 痛覺過敏逆轉情況,ED”分別是4 2和19毫克/公斤p 〇 施用(後處理時間:3小時)。 如前述者,本發明之物劑包括新穎的芳基鏈烯基_、2_ 雜方基鏈%基_、2 -芳基鏈炔基·、2 _雜芳基鏈炔基·、2 _芳 基偶氮_和2-雜芳基偶氮_吡啶及其鹽類,下文中稱爲”本發 明之化合物”。 本發明I化合物包拾前面所定義的式丨化合物,及它們的 鹽類,其中,X和L至R5如前面之定義,但當R3是氫時, a)在其R 1、R 2和R4是氫的式I化合物中,當X代表乙烯 基時,R5不是笨基、一鹵代笨基、2,4-和3,仁二氯苯 基、3 -和4-三氟曱基苯基、甲基苯基、3,4_和2,5_二 甲基苯基、4·異丙基苯基、3,5_二·第三丁基苯基、甲 氧基苯基、3,4-二甲氧基苯基、2,4,5-和3,4,5-三甲 氧基笨基、羥基笨基、3,5 -二羥基笨基、4 -羥基-3,5-—甲基私基、3-¾基-4 -曱氧基·和4-經基》3 -甲氧基-苯基、4_羥基_(3_甲基_5_第三丁基,2_和4•乙醯基胺 基笨基、3. 5-二異丙基·和3,5-二-第三丁基)苯基、4_ 罗艾基和4 -乙氧基|基苯基、4 -氰基笨基、3 -甲氧基藏 __ 一 - 13- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297 ^¾ ) '~' ' (讀先閱讀背面之注意事項再填寫本頁) 裝·
、1T 544448 A7 B7 五、發明説明(11 經濟部中央標準局員工消費合作社印製 基苯基、j -幾基_ 5 -甲氧基_笨基、2 - p比咬基、5 _氯_ 2 _ 吡啶基和6-甲基_2_吡啶基:或者,當X代表接在r5的 2-位置上的ι,2_伸丙基時,Rs不是苯基、4_甲基苯 基、4 -甲氧基苯基、4 -溴苯基和2 -及4 -氯苯基:或 者,當X代表接在I的b位置上的1,2_伸丙基時, 不疋苯基、2 -和4 -氯笨基和3-甲氧基笨基;或者,當 x代表接在R 5的2 -位置上的2,3 _伸丁 _ 2 -基或1,2 _伸丁 1基時,R 5不是4 -甲氧基苯基:或者當χ代表接在 尺5的3_位置上的2,3-伸戊基時,R5不是4 -甲氧基 本基和4_異丙基苯基··或者,當X代表3,4-伸己-3-基 時’ I不是笨基、4-甲基苯基、甲氧基苯基和4-羥基 笨基: b )其R 1是甲基而R2和I是氫的式1化合物,當χ是伸乙 基時’ L不是苯基、3 -曱基苯基、2-甲氧基苯基、2- 氯苯基、4-氰基笨基、2 _吡啶和卜甲基_2_吡啶基: c )其R 1和R 2是氫而R4是複基的式I化合物,當X是伸乙 基時,R 5不是苯基、3 _甲基苯基、2 _甲氧基苯基和4 _ 溴苯基: d)其Rl和是氫而R4是甲基的式I化合物,當X是伸乙 基時,R 5不是苯基、3 -甲氧基-、4 -甲氧基-和3,4 -二 曱氧基笨基、2 -氯-和2,4 -二氯苯基及6 -甲基-吡啶- 2-基’或者:當X是接在R 5的2 ·位置上的〗,2 -伸丙-1 _基 時,R 5不是苯基: e )其R 1和汉2是氫而R4是2 _二甲基胺基乙氧基羰基或3 -二 -14- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐 —ΊΤ (讀先閱讀背面之注意事項再填寫本頁) -裝· 、1" 經满部中央標準局員工消費合作社印聚 544448 kl ____ B7 五、發明説明(12 ) 甲基胺基丙氧基羰基的式I化合物,當X是伸乙基時, R5不是4-甲氧基笨基: f) 其R 1和R 2是氫而R 4是2 ·二甲氧基乙氧基的式I化合 物,當X是伸乙基時,R 5不是苯基、4 -曱基笨基和4 · 甲氧基羰基苯基: g) 其Ri和是氫且R4是輕基或乙氧基鍰基,或者,其 Ri和R2是氫且1^是輕基,或者,Ri是甲基且以2是氫 且R4是甲氧基,或者,Ri是丁-1-烯基且R2是氫且r4 是氫,或者,R!是氫且R4是2 -二曱基乙氧基且前述的 每個X都是伸乙基時,R 5不是苯基: 但當R 3是氫,X是乙块基時: a ’)當R丨、R 2和R4是氫時,r 5不是苯基、2 -和4 -硝基苯 基、4 -胺基苯基、4 -氣苯基、4 -甲基笨基、4 -甲氧基 笨基、4 -乙氧基羰基笨基、5 -曱醯基—2 -甲氧基-苯 基、5 -竣基-2 -甲基-苯基和U比咬基: b ’)R 2和R 4是氫的式1化合物中,R】是甲基時,R $不是苯 基、3 -甲基苯基、6 -甲基吡啶-2-基和2 -甲氧基苯基: R !是溴時,R 5不是6 -溴吡啶-2 -基:R 1是己氧基時, R5不是6 -己氧基p比η定-2-基: c ’)其R !和R 4是氫的式I化合物中,r 2是甲基時,r 5不是 苯基、4 -胺基苯基和4 -丙基苯基:R2是乙基時,尺5不 是苯基、4 -氰基笨基和4 -戊基苯基:1^2是丁基時,r5 不是3 -氰基-4 -乙氧基-苯基和3 -溴-4 -甲氧基-苯基; R2是戊基時’ R5不是4 -甲氧基苯基和4 -丁氧基苯基: t____-15- __ 本紙張尺度適用中國國家標率(CNS ) A4規格(210X297公釐) —ΊΤ (讀先閱讀背面之注意事項再填寫本頁) -裝· 544448 A7 五、發明説明(13 ) R2是羧基時,R5不是4 -第三丁基苯基、3_第三丁基-4 -爽基木基、4 -第三丁基- 3-¾基-笨基和4 -己氧基苯 基:R2是曱氧基羰基或甲基胺基曱醯基時,r5不是苯 基:R2是乙氧基羰基時,R4不是3 -第三丁基苯基、3 _ 第三丁基-4-羥基苯基和4-(4-甲基戊基)苯基:r2是 2 -甲基丁氧基羰基時,R 5不是4 -戊氧基苯基: d ’)其R !和R 2是氫的式I化合物中,當r 4是超基、甲基、 乙基、羧基、甲氧基羰基或胺基甲醯基時,R 5不是苯 基、 本發明之較佳的化合是前述的本發明之物劑。 本發明之化合物可藉與合成已知的式1化合物之方法類似 的方式製得。 因此,本發明之式I化合物之製法包含 a)使式II化合物 (請先閱讀背面之注意事項再填寫本買) 裝- 、1'
經滴部中央標準局員工消費合作社印繁
與式Y2化合物一Km)反應,其中,Υι和γ2之一代表低 碳烷醯基,另一者代表低碳烷基或三芳基 phosphoranylidene甲基,或者,YdpY2之一代表具反應性 的酯化羥基,另一者代表基團γ 3 - X -,其中,丫3是氣或金 屬基圑,R】、R 2、R 3、R 4和R 5如前面所定義者,R -16 - 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公釐)^-- 544448 A7 B7 五、 發明説明(14 尺2、R3、R4官能基及R」官能取代基可以暫時受到保護 或者 b )由式IV化合物消去Η - Y 4 、'广 (IV), 經滴部中央標率局員工消費合作社印繁 其中’ Υ4代表離電子基,Rl、R2、R3、R4、乂和^如前 面之定義,官能基L、r2、h和^及化5官能取代基可以 暫時受到保護,移除任何的暫時保護基,及,必要時,將 由前面所定義的方法可得到的式丨化合物轉化成不同的式J 化合物,將可能得到的異構物混合物解析成單獨的異構物 和/或將前述定義方法中可得到之有至少一個成鹽基團的 式I化合物轉化成鹽,或者,將可由前述定義法得到的鹽轉 化成相關的自由化合物或轉化成不同鹽。 低碳烷醯基Y2或更佳的Υι基團時,如:Ci-C3烷醯基 (如:甲醯基、乙醯基或丙醯基,特別是甲醯基)。低碳烷 基丫!或更佳的Y2是,如:Ci-(:3烷基(如:甲基、乙基或 丙基,特别疋甲基)。三芳基ph〇sph〇ranyHdene γ 2或更佳 的 Yl 疋,如·二苯基 ph〇Sph〇ranylidene 甲基。 Y 1和Y 2 I 一是具反應性的酯化羥基且另一者是式γ 3 _ X 基團(其中,Υ3代表氫)時,縮合反應以根據Heck偶合法實 犯馬佳,例如:實施時,有銅或銅觸媒存在,或有貴金屬 -17 本紙張尺度適用中國國家標準(CNS ) A4規格(21 Ο χ 297公釐) (諳先閱讀背面之注意事項再填寫本頁) -裝· 、1Τ 8 44 44 五、 發明説明( B7 15 t 7 =(-如/三級啤的鈀或pd(n)鹽,如:醋酸1已)存 ’ 一有—广基膦存在’或有雙-三苯基膦-二氯化鈀存在 \二m基胺(如:三曱胺)存在爲佳),有利的情況 疋Cu⑴1存在於極性有機溶劑(如:N,N_二(低碳烷基) 反基酸驢胺(如:二甲替甲醯胺)、二(低碳虎基)亞職(如· t甲亞颯)或〕惡垸)中於約15τ至約12(rc(以於海點爲佳) 實施爲佳。 γ 1和Y 2之一代表具反應性的酯化輕基,另一者代表式 Y 3 - X基圑(其中’ γ3代表金屬基團,如:圏帶鎂基))時, 此反應以根據Gngnard法實施爲佳,其中,金屬中間體以 於原處形成爲佳。 Y 1和Y 2 (—代表低碳烷醯基,另一者代表低碳烷基時, 式Π和III化合物的分子内縮合反應以根據Shaw和 Wangstaff法或其許多修飾法之一進行爲佳。 Y!和Y2之一代表低碳烷醯基,另一者代表三芳基 phosphoranylidene甲基時,此縮合反應以根據習知的 Wittig烯烴構築法實施爲佳,以由相關的三芳基膦鹵化物 於當場形成phosphoranylidene構份爲佳(如:使後者與金屬 鹼(如:驗金屬氫化物,如:氫化鈉)反應,或者使後者與 金屬有機臉(如:低碳燒基金屬化合物,如:丁基鍾)反 應,或者使後者與鹼金屬烷醇鹽(如:三級丁氧化鉀)反 應),此反應以於惰性有機溶劑(如:苯或甲苯)中於約-1 0 °C至約3 9 X:(以先於〇 °C至1 0 °C ),之後於常溫爲佳)進行爲 佳。 -18 本紙張^適用中國國家CNS ) A4規格(210X 297公釐) (讀先閱讀背面之注意事項再填寫本頁) •裝·
、1T 經滴部中央標率局員工消費合作社印絮 544448 ΚΊ 經濟部中央標率局員工消費合作社印繁 五、發明説明(16 ) 離電子基Y4是,如:酯化的禮基(如:被有機酸g旨化的 羥基(如:低碳烷醯氧基)或被無機酸酯化的羥基(如:_基 或三級胺基(如:三低碳烷基胺基(如:三甲胺基))、低碳 氮雜伸坑基胺基、低碳氧伸烷基胺基或低碳三伸燒基胺基 (如:吡咯基、吡啶基、嗎啉代或硫代嗎啉代))或相關的四 級銨基。 官能基以這樣的保護基保護,保護基本身及它們的移除 反應述於,如:標準著作中。 由式IV化合物除去Η- Y4可藉慣用的方式進行。因此, 水或低碳烷基酸可藉共沸蒸餾法(如:在甲苯中,以於溫和 酸性條件下爲佳)去除。鹵化氫可於鹼性條件下去除,如: 與鹼金屬烷醇鹽反應(以於相關低碳烷醇作爲溶劑或輔助溶 劑時爲佳)或者藉由在三級胺(如:三-低碳烷基胺)存在時 加熱。 前述反應的起始物已爲習知,根據製備已知起始物類似 的方法可製得新的起始物。 根據此方法可得的式丨化合物可以慣用的方法轉化成不同 的式I化合物,慣用的方法如:將自由的羧基加以酯化或醯 胺化’可以將酯化或醯胺化的羧基轉化成自由的幾基,可 將酷化的羧基轉化成未經取代或經取代的胺基甲醯基,可 將自由的胺基加以醯化或烷基化,可將自由的羥基加以_ 化。 -敌 同樣地,可藉慣用的方法(如:與有機過氧酸反應)將式I 化合物加以氧化’得到相關之ρ比淀-Ν _氧化物衍生物。 __— _ 19- 本紙張尺度適用中家標隼(CNS ) Μ規格(21〇χ—Μ7公襲) ' ' --- ijm. (請先閱讀背面之注意事項再填寫本頁) •裝- 、-口 Φ 544448 A7 B7 五、 發明説明( 17 經滴部中央標準局員工消費合作社印f 可以目前已知的方式將式Ϊ化合物的鹽類轉化成自由化合 物,如:以驗或酸處理。 所得鹽可藉目前已知的方法轉化成不同鹽類。 式I化合物(包括其鹽類)可以水合物形式得到,或者可包 括結晶用的溶劑。 因爲自由形式的新穎化合物與其鹽類形式的新穎化合物 <間的關係,下文及前文中所提到的自由化合物及其鹽類 係包括自由化合物及其相關鹽類。 式I化合物中,各個對掌中心的構形可選擇性地反轉。例 如,帶有親核取代基(如:胺基或羥基)之不對稱碳原子的 構形可因爲第二順位親核取代作用而反轉,視情況地在鍵 結的親核取代基轉化成適當的離核離去基並與引入原取代 基的物劑反應之後而反轉,或者,有羥基的碳原子構形可 以因爲氧化反應或還原反應而反轉,此類似於Europe⑽ Patent Application ΕΡ-Α-0 236 734。 本發明亦係關於包含式丨化合物的藥用組合物。 本發明之藥用上可接受的化合物可用於,如:製備包本 藥效量活性成物之藥用組合物亦包含大量無機或有機、^ 態或液態藥用上可接受的載劑之藥用組合物。 根據本發明之藥用組合物可是經腸(如:鼻用、直腸用戈 口服)或非經腸(如:肌肉内或靜脈内)組合物,施用於溫: 動物(人類和動物),包含有效量藥用活性成份或另包= 量藥用可接受載體。活性成份的劑量視溫血動物種類二 重、年齡和個別狀況、單獨的藥物動力數據、治療的疾= 20- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X297公釐) (請先閱讀背面之注意事項再填寫本頁) -裝-
、1T Φ 544448 A7 B7 五、發明説明(18) 及施用模式而定。 此藥用組合物包含約1 %至約95 %(以約20%至约90%爲 佳)的活性成份。根據本發明的藥用組合物可以是,如,以 單包裝形式,如:安瓶、小瓶、栓劑、糖衣藥丸、錠劑或 膠囊形式。 本發明之藥用組合物以目前已知的方式製備,如:利用 慣用的溶解、凍乾、混合、造粒或裹糖衣法。 藥劑施用在溫血動物(如:體重約7 0公斤的人類),治療 與谷胺酸訊息傳遞不規則有關的失調之特別有效的劑量是 約3毫克至約3克,以約1 0毫克至約1克爲佳,如:約2 0亳 克至500毫克/人/天,分1至4次施用,每次可施用相同 量。通常,孩童劑量約成人半量。每個個體所須施藥量可 由測定血清中的活性成份濃度來測定並調整至最適量。 下列不具限制性的實例用以説明本發明:實施例的溫度 單位是°C,壓力單位是毫巴。 實例1 3 - [ 2二(6 -甲基吡啶-2 -基)-乙烯基1苯甲腈 經漓部中央標準局員工消費合作社印^ (請先閱讀背面之注意事項再填寫本頁} 2,6 -二甲基吡啶(4.2毫升,36.28毫莫耳)、3 -氰基苯甲 醛(4.59克,37.74毫莫耳)在醋酸酐(6.85毫升)中之溶液迴 餾加熱1 6小時。然後,此醋酸酐在眞空中蒸發,殘渣以管 柱層析術(矽膠400克)純化。管柱先以甲苯(400毫升)沖 提,然後以甲笨/乙酸乙酯9 5 : 5沖提。合併含有所欲化 合物的鶴份’在眞空中蒸發。固態渣質由二氯甲烷/己燒 再結晶,分離出3.1 8克白色固體(熔點:9 1 - 9 2 °C )。 _______ _-21 -_ 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 A7 B7 五、發明説明( 19 -—-------- 經漓部中央標率局員工消費合作社印製 實例2 比啶-2 ·基)-·乙瘦甲腈 2,6-二甲&比啶(5.8毫升,50毫莫耳)、2_氰基苯甲酸 (6.81克,52¾莫耳)在醋酸酐(95毫升)中之溶液迴餾加熱 16小時。然後,此醋酸酐在眞空中蒸發,殘渣以管柱層析 術(矽膠400克)純化。管柱先以甲苯(4〇〇毫升)沖提,然後 以甲苯/乙酸乙酯95 : 5沖提。合併含有所欲化合物的餾 份,在眞空中蒸發。固態渣質由二氯甲烷/二異丙醚再結 晶’分離出白色晶體(溶點:1 i 3 - 1 i )。 實例3 6 - [ 2 -吡淀-4 -基)-乙烯某1毗诠 2,6 - —甲基ρ比淀(5 · 8毫升,5 0毫莫耳)、ρ比淀-4 -甲酸 (4.9毫升’ 5 2愛莫耳)在醋酸纤(9 · 5毫升)中之溶液迴|留加 熱1 6小時。然後,此醋酸酐在眞空中蒸發,殘渣以管柱層 析術(珍膠900克)純化。> 管柱先以甲苯/丙酮4 : 1 ( 5升)沖 提,然後以甲苯/丙酮3 : 1 ( 5升)沖提,最後以甲苯/丙 酮3 : 1 ( 5升)沖提。合併含有所欲化合物的餾份,在眞空 中蒸發。固態渣質由二氯甲烷/二異丙醚再結晶,分離出 0.965克白色固體(熔點:7 2 - 7 3 X:)。 實例4 2 -甲基-6 - f 2 -吡啶-3 -基)-乙烯基1吡啶 2,6 -二甲基π比啶(5.8毫升,5 0毫莫耳)、吡啶-3 -曱駿 (4.9毫升,5 2毫莫耳)在醋酸酐(9.5毫升)中之溶液迴餾力口 熱1 0小時。然後,此醋酸奸在眞空中蒸發,殘;查以管柱層 -22 - 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) ----- (讀先閱讀背面之注意事項再填寫本頁) ;裝· 544448 經满部中央標準局員工消費合作社印$ί A7 B7 五、發明说明(2Q ) 析術(矽膠900克)純化。管柱先以甲苯/两酮9 : 1 ( 7升)沖 提,然後以甲苯/丙酮4 : 1 ( 5升)沖提,最後以甲苯/丙 酮2 : 1 ( 5升)沖提。合併含有所欲化合物的餾份,在眞空 中蒸發。固態渣質由二氯甲烷/二異丙醚再結晶,得到 4 · 2 8克無色油,其於6 - 8 °C靜置而固化。 Am 2 _ [ 溴苯暴)卜ό _甲基_p比淀 1.2克(2.8毫莫耳)2-[1,2-二溴-2(3-溴苯基)-乙基]-6- 甲基-吡啶溶解於1 0毫升乙醇中。添加〇9克(16 j毫莫耳) 氫氧化鉀(粉末)’所得懸洋液迴餘加熱4小時。然後將懸浮 液冷卻至室溫,倒入1 〇〇毫升鹽水中,以第三丁基甲基醚 萃取兩次(每次3 0毫升)。合併的有機相以3 〇毫升鹽水清洗 兩次,以硫酸鈉乾燥,過滤並在眞空中蒸發。得到〇 720克 標題化合物,其爲無色油,靜置之後結晶:熔點:60-61 °C。 起始物得自: a) 2 -『2 - ( 3 -溴苯基)-乙烯基1 - 6 -甲 24毫升(200毫莫耳)2,6-二甲基吡啶和25.6毫升(2〇7毫 莫耳)3-溴苯甲酸於38毫升醋酸奸中之溶液迴餾加熱7.5小 時,醋酸酐在眞空中蒸發,殘渣溶解於5〇〇毫升4 N鹽酸 中,以己烷萃取兩次(每次200毫升)。然後,水相以第三丁 基甲基醚萃取四次(每次300毫升)。合併的有機相以 NaHC03飽和水溶液清洗兩次(每次3〇〇亳升),然後以3〇〇 毫升鹽水清洗一次,以歸:酸鈉乾燥,過遽並於眞空中乾 -23- 本紙張尺度適用中國國家標準(CNS ) Α4規格(210X 297公釐) ------ij· 装-- (讀先閱讀背面之注意事項再填寫本頁)
、1T -Φ 544448 經滴部中央標準局員工消費合作社印$1 A7 B7 五、發明説明(21) 燥’仔到4.2兄標題化合物’其爲溶點5 8 _ 5 9的無色晶 體。 b) 2-「1,_^_1_^溴-2-(3-溴笨基卜乙基1_6-甲基-吡啶 1克(3.6毫莫耳)2 - ( 3 -溴-苯基乙炔基)_ 6 -甲基-峨淀溶解 於5毫升四氣化碳中,溶液加熱至5 5 -6 0 °C。逐滴添加0.23 毫升(4 · 4毫莫耳)溴的〗毫升四氯化碳溶液。此反應混合物 維持於5 5 - 6 (TC達3 0分鐘,之後冷卻至室溫。以過濾法收 集所得沉澱物並於眞空中乾燥。分離出1.3克標題化合物, 其爲黃色晶體,熔點丨64 - 1 66 °C。 實例6 3 - [ 2 - ((3 ·甲基吡啶-2 -基)乙炔基]苯曱腈 1克(8.54耄莫耳)2 -乙炔基-6 _曱基-吡啶(以類似於d.e.
Ames 等人,Synthesis,364-5 (1981 )製得)、2.3 克(12.8 毫莫 耳)3 -溴-苯甲腈、0.47克(0.7毫莫耳)雙_(三苯基膦)·氯化 飽(II )、8 0毫克(0.41毫莫耳)碘化銅和丨.53毫升(丨5毫莫耳) 三乙胺於1 0毫升二甲替甲醯胺中之混合物於9 〇 攪掉3小 時。將此反應混合物冷卻至室溫’倒入水中,以二氯甲嫁 萃取。有機層以硫酸鈉乾燥,過濾,蒸發,渣質以層析法 在發膠上純化,以己燒/乙酸乙酯(4 : 1}作爲沖提液。所 得產物由己烷結晶,得到0.53克(28.4%)標題化合物,其 爲棕色晶體,熔點1 20 - 3 °C。 實例7 以類似於實例1(其中的X是伸烷基)或實例5(其中的乂是 伸晞基)的方式,製得下列式I化合物: _______-24-_ 本紙張尺用中國國家標率(CNS ) A4規格(210X 297公釐) — .一 -—- ~IT (讀先閱讀背面之注意事項再填寫本頁) 544448 A7 B7 五、發明説明() 經滴部中央標準局員工消費合作社印絮 式I化合物 熔點(°C) 2-苯乙烯基^比啶-3-醇 249-252 2-甲基-6-[2-(3-硝基-苯基)-乙烯基]•吡啶 100-101 2-[2-(2-氯-苯基)-乙烯基]-吡啶 無色油 2-甲基-6-苯乙烯基-口比啶 40-42 醋酸6-[2-(2-氯-苯基)乙晞基]-吡啶-3_基酯 75-77 6-[2-(2-氯-苯基)乙烯基]-吡啶-3-醇 168-171 醋酸2_[2-(2-氯-苯基)乙烯基]-吡啶-3-基酯 99-102 2-[2-(2-氯-苯基)乙烯基]-吡啶-3-基 232-234 6-甲基-2-苯乙烯基4比啶-3-醇 261分解 醋酸2-[2-(2-氯-苯基)乙晞基]-6-甲基-吡啶-3-基酯 92-94 2-[2-(2-氯-苯基)-乙晞基]-6-甲基-口比啶-3-基 232-234 (Ζ)·6-甲基-2-笨乙烯基-外1:啶-3-醇 145-148 2-[2-(2·氯-苯基)-乙烯基]-6-曱基-口比啶 51-52 2-[2-(2-氣-麥基)-乙缔基]-叶匕口足 69-70 2-[2-(2_硝基-冬基)-乙細基]-’比呢 97-99 醋酸2-[2-(4-氯-苯基)-乙烯基]-6-甲基-吡啶-3-基酯 102-103 醋酸6-[2-(4-氯·苯基)-乙烯基]-2-曱基-吡啶-3-基酯 130-131 2-[2-(4-氣-冬基)-乙細基]-6-甲基-ρ比咬3-酉竽 275-278 分解 6·[2-(4·氣-木基)-乙缔基]-2-甲基-p比咬-3-Sf· 265-270 分解 醋酸6-甲基-2-[2-(2-硝基-苯基)-乙烯基]-吡啶-3-基酯 139-140 6-曱基-2-[2-(2-硝基-笨基)-乙烯基]-吡啶-3-醇 190_195 分解 醋酸2-甲基-6-[2-(2-硝基-苯基)-乙晞基]-吡啶-3-基酯 99-100 2-曱基-6-[2·(2-硝基-苯基)-乙烯基]吡啶-3-醇 230-233 分解 醋酸2-[2-(3-氯-苯基)-乙烯基]-6-甲基-吡啶-3-基酯 97-99 --------裝-- (讀先閱讀背面之注意事項再填寫本頁) -25- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 A7 B7 五、發明説明(25) 經滴部中央標準局貝Η消費合作社 {2-[2-(2-氯-苯基)-乙烯基]-6-甲基氧基卜醋酸乙酯 無色膠 3-[2-(6-甲基-吡啶-2-基)-乙蚪V、卜Ν-(3-三氟甲基-苯基)苯甲 醯胺:HC1鹽 249-25! 4-[2-(6-曱基-吡啶-2- V、)-乙綿基]-Ν-(3-三氟甲基-苯基)苯甲 醯胺 160-161 2-[2-(3-硝基H )-乙烯基]-吡啶 127-128 6-苯乙婦V、比咬-2-叛酸(3-氟甲基-苯基)-醯胺 128-129 2-(6- :V、乙岣基-口比啶-2-基)-丙-2-醇:HC1鹽 171-174 2」丨/ 4各(2-嘧吩-2-基-乙晞基)-吡啶;/HC1鹽 208-211 2^2-(3-氯-苯基f乙烯基]吡啶 / 51-53 2-[2-(3-氰基-苯基)-乙烯基]-吡啶 85-86 2-[2-(3-溴-苯基)-乙烯基]-6-甲基-吡啶 58-59 2-[2-(2>二甲氧基-苯基)-乙烯基]-6-甲基-吡啶 無色油 2-[2-(2,3-二氯-苯基)-乙晞基]-6-甲基-吡啶 67 - 68 2-[2-(3-氯·苯基)-1 -甲基-乙烯基]-吡啶 無色油 {2_[2-(2-氯-苯基)·乙烯基]-6-甲基-吡啶-3-基卜甲醇 87-90 2-甲基-6-[2-(3·三甲基矽烷基乙炔基-苯基)-乙烯基〗-吡啶 黃色油 2-[2-(3,4-二氟-苯基)-乙烯基]-6-甲基4匕啶 61^62 2-[2-(3-乙炔基-苯基)-乙烯基]各甲基-吡啶 黃色油 2-[2-(3,5-二氟苯基)-乙烯基]-6-甲基-吡啶 黃色油 2-[2-(3-氟-苯基)-乙烯基]-6-甲基-吡啶 黃色油 2-[2-(3-甲氧基-笨基)-乙缔基]-6-甲基-吡啶 黃色油 2-甲基-6-[2-(3-苯氧基-笨基)-乙烯基匕啶 黃色油 2-[2-(3-爷氧基-苯基)-乙晞基]-6-甲基匕淀 68-69 2-[2-(2,5-二氟-苯基)-乙晞基]-6-甲基-吡啶 44-45 {2-[2-(2-氯-苯基)-乙烯基]-6.·甲基-吡啶-3-基氧基)-醋酸 230^33 -28- (請先閱讀背面之注意事項再填寫本頁)
衣纸張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 A7 B7 五 發明説明(26) 經滴部中央標準局負工消費合作社印製 (3-丨2-[2-(3-氯·苯基)-乙烯基]-6-甲基-吡啶-3-基氧基}·丙基)-二甲胺 203-205 {6-丨2-(2-氯-苯基)-乙烯基]冬甲基-吡啶各基卜甲醇 131-133 2-(3-溴-苯基乙決基)-6-甲基-吡啶 61-63 2-甲基-6-丨2-[3-(3-三氟甲基-表氧基)-苯基]-乙缔基}-外匕淀 黃色油 2_[2-(3,5-二甲氧基-苯基)-乙烯基]各甲基-吡啶 43 - 45 2-[2-(3·氯-苯基)-乙烯基]:曱氧基各甲基-吡啶 52-53 醋酸4-澳-2-[2-(6_甲基-对1^定-2-基)-乙締基]-苯基酉旨 黃色油 醋酸3-[2-(6-甲基-吡啶-2-基)-乙晞基]苯基酯 黃色油 2-[2-(3,4-二氯-苯基)-乙烯基]-6-甲基-吡啶 73-75 4-溴-2-[2-(6-甲基4匕啶-2-基)-乙晞基]-酚 246-248 醋酸2-[2-(3,5-二氯-苯基)-乙烯基]-6-甲基-吡啶-3-基酯 156-158 醋酸6-[2-(3,5-二氣-苯基)-乙烯基]-2-甲基-吡啶-3-基酯 159-161 醋酸2·[2-(3,5·二氣-苯基)-乙烯基]-吡啶-3-基酯 154-156 2-甲基-6-(2-茬-1-基·乙晞基)-吡啶 黃色油 2-[2-(2,3-二氫-苯並[M]二喔星(dioxin)-6-基)·乙缔基]-6-甲基 -p比淀 99-101 2-甲基-6_(2-荅-2·基-乙烯基)-吡啶 97-99 2-甲基-6_(2-間-甲苯基-乙烯基)-吡啶 黃色油 2-{2-[3-(3,5·二氯-苯氧基)-苯基]-乙烯基卜6·甲基-吡啶 黃色膠 2-[2-(3-氯-笨基)-丙烯基]-6-甲基_吡啶 黃色油 2-[2-(2,3-二氯-苯並咬喃-5-基)-乙%基]-6-甲基-p比口定 88-90 2-[2-(4-氟-苯基)-乙晞基>6-甲基-吡啶 50-51 2-曱基-6-(2-鄰-甲苯基-乙烯基)-吡啶 黃色油 2-甲基各(2-對·甲苯基-乙烯基)-吡啶 85-86 2-甲基-6-(2-對-曱苯基-丙烯基)-吡啶 黃色油 (讀先閲讀背面之注意事項再填寫本頁) ΦΤ d- -29- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 A7
7 B 五、發明説明(27 ) 經濟部中央標準局員工消費合作社印掣 3-[2-(6-甲基-吡啶-2-基)-乙烯基]笨胺 126-129 (2,3-二甲氧基-7-硝基-喹噁啉-5-基甲基)-丨3-[2-(6-甲基比啶-2-基)-乙烯基]-苯基卜胺 淡橘色泡沫 N- {3-[2_(6-甲基^比啶-2-基)-乙烯基]-苯基卜乙醯胺 147 N-丨3-[2-(6-甲基-说啶-2-基)-乙烯基]-苯基卜2-苯基-乙醯胺 156 2,2-二甲基-义{3-[2-(6-甲基-吡啶-2-基)-乙烯基]-苯基}- 丙61胺 166-168 嘧吩-2-羧酸{3-[2-(6-甲基-吡啶-2-基)-乙晞基]_苯基卜醯胺 197分解 環己羧酸丨3-[2-(6-甲基-吡啶-2-基)-乙烯基]_苯基卜醯胺 215 1_(4_溴-苯基)-3_{3-[2-(6-甲基^比啶-2-基)-乙烯基]-苯基} •尿素 197 2一甲基-6-[2·(4-硝基-苯基)-乙烯基]-吡啶 134-135 4-[2-(6-甲基-口比啶-2-基)-乙烯基]苯胺 147-148 2-[2-(3,5-二氯-苯基)-乙烯基]-6-甲基-吡啶-3-醇 218-220 6-[2-(3,5-二氯-苯基)-乙烯基]-2-甲基-吡啶-3-醇 286分解 2-[2_(3,5-二氯-苯基)-乙烯基]-吡啶-3-醇 240-242 2-[2_(6·氯苯並[1,3 ]二oxol-5-基)-乙烯基]各甲基-吡啶 131-132 2-[2-(2,3-二氟-苯基)-乙晞基]-6-甲基-吡啶 55-56 2-[2-(3,4-二氯-苯基)-丙烯基]-6-甲基-吡啶 黃色油 2_[2-(3,5-雙-三氟甲基-苯基)-乙烯基]-6-甲基-吡啶 85-86 醋酉父2-甲氧基-6-[2-(6-甲基比η足·,2-基)-乙 >希基]-冬基酉旨 黃色油 2-甲氧基-6-[2-(6-甲基·吡啶-2-基)-乙烯基]-酚 118-120 2-甲基-6-[2_(2,3,6-三氟-苯基)-乙烯基]-吡啶 59-62 2_[2-(4-氟-3-三氟曱基-苯基)-乙烯基]-6-甲基-吡啶 黃色油 2-甲基-6-(2,3,6-三氟-苯基乙炔基)-吡啶 93-94 醋酸4-氯-2-[2-(6_甲基-吡啶-2·基)-乙晞基]-苯基酯 醋酸2,6-二-第三丁基-4-[2-(6-甲基4比啶-2-基)-乙烯基]· 127-128 (請先閱讀背面之注意事項再填寫本頁 -30- 本紙張尺度適用中國國家標準(CNS ) A4規格(210X 297公釐) 544448 A7 B7 Λ 五 發明説明(28 經滴部中央榡準局員工消費合作社印製 苯基酯 3-ί 6-甲基-外1:。定-2-基-乙块基)苯甲胺 187-189 醋酸4-溴-2-甲氣基甲基比咬冬基)-乙烯基]苯基酯 151-153 2-(6-氣-笨並[1,3]二氧基-5·基乙炔基)-6_甲基-外匕啶 105-106 淡ί冢色晶體 2-f2-(3,5-二氢-笨基)-乙晞基]各甲氧基-6-甲基^比啶 127-129 2·『2-ί3 二氣-策基V乙烯基]·3·甲氧基-吡啶 111-113 5·疊氮基2-[2-(6-甲基比啶_2_基)_乙烯基l·酉分 143分解 2-[2-(吡啶-3-基)乙炔基]-6-甲基^比啶 淡黃色晶體 60-61 Ν-{3-[2-(6-甲基比症-2-基)-乙細基]-苯基卜丁二酸 212-213 1-第三丁基-3·ί3-丨2-(6-甲基-吡啶-2-基)-乙烯基]-苯基}-尿素 191-192 5-({3-[2-(6-甲基-竹匕咬-2-基)-乙細基]-苯基月$基}-甲基)-7-硝 基-1,4-二氮^奎u惡淋-2,3-二酉同 250分解 四氫唉喃-2-獲酸丨3-[2-(6-曱基-p比淀-2-基)-乙、^市基]-苯基} -S&胺 160-161 (M3-[2-(6-甲基-吡啶-2-基)-乙烯基]-苯基胺基甲醯[2-苯基-乙基)_胺基甲酸第三丁酯 ({3-[2-(6_甲基-被啶-2-基)-乙烯基]-苯基胺基甲醯卜甲基)-胺 基曱酸第三丁酯 一乙基-{3·[2-(6-甲基4比呢-2-基)-乙細基]-苯基丨-胺 217分解 乙基-{3 - [2-(6-甲基-口比啶-2-基)·乙晞基]-苯基卜胺 225分解 乙基]3-[2·(6-甲基-吡啶-2-基)-乙烯基]-苯基卜胺 183分解 2_(2·乙氧基-3,6_二氟苯基乙炔基)-6-甲基吡啶 黃色油 -二氟-苯基乙炔基)-6-甲基-,比啶 黃色油 1(3-氟-苯基乙块基)-6-甲基-吡啶 26-28 二甲基-苯基)-乙烯基]-6·甲基^比啶 56-57 _Η^(3,4-二甲氧基-笨基)-乙烯基1-6-曱基·吡啶 55-56 -31 (請先閲讀背面之注意事項再填寫本頁) 一裝· ‘度適用中國國家標準 (CNS ) A4規格(210X 297公釐) 544448 A7 B7 五、發明説明() 經满部中央標準局員工消費合作社印顰 2-胺基-N-丨3-[2-(6-甲基·欢啶-2_基)-乙烯基]-苯基卜乙醯胺 105 2-胺基-N-丨4-[2-(6-甲基-吡啶-2-基)-乙烯基]-苯基卜乙醯胺 217-219 分解 1 -[ 1 -({2-[2-(2-氣-苯基)-乙烯基]-6-甲基-吡啶-3-基氧基卜乙醯 基户派淀-4-基]-咪。坐燒-2-酮 非晶狀泡沫 1 - {4-[2-(6•甲基^比啶-2-基)-乙烯基]-苯基胺基卜乙基)-膦酸二 甲酯 2-[2-(2-曱氧基-苯基)-乙烯基]-6-甲基^比啶 129-130 2-(3-乙氧基-4-氟-苯基乙炔基)-6-甲基-吡啶 82-83 2-(3-氣-苯基乙块基)-6-甲基-口比呢 57-59 1-(3 比淀-2-基乙決基-秦基)-乙細明 48-51 4-氯-2-[2-(6-甲基-吡啶-2-基)-乙烯基]-酚 256-260 4-溴-2-甲氧基-6-[2-(6-甲基^比啶-2-基)-乙烯基]-酚 121-123 2-甲基-6-間-甲苯基乙炔基-吡啶 57-58 2-(2,5·二氟-苯基乙炔基)-6-甲基^比啶 49-50 2-(3,5-二曱基-苯基乙块基)-6-甲基-吡啶 黃色油 2_[2_(3,5-二溴-苯基乙烯基)-0-甲基-吡啶 68-70 2-甲基-6-[2-( 口密症-5-基)-乙炔:基]-¾匕症 110-112 (2-{2-[2-(3-氯-苯基)-乙烯基]-6-甲基-吡啶-3_基氧基卜乙基)-二甲胺 165-167 醋酸1 - {4-丨2-(6-甲基-吡啶-2-基)-乙烯基]-笨基}乙酯 3-[2-(6-曱基-吡啶-2-基)-乙烯基]-酚 250-251 3 -(6-甲基-吡啶-2-基乙炔基)-苯基胺 129-130 N-[3-(6-甲基-吡啶-2-基乙炔基)-艽基]-2-苯基乙醯胺 133-135 分解 噹吩_2_羧酸[3-(6-曱基-吡啶-2-基乙炔基)-苯基]-醯胺 156-157 分解 2-甲基-6+塞吩-2-基乙炔基]-吡啶 34-36 3-(6-甲基-吡啶-2-基乙炔基)-笨甲酸乙酯 56-58 -------------1T-----Φ (請先閲讀背面之注意事項再填寫本頁) -33- 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X 297公釐) 544448 經滴部中央標準局員工消費合作社印絮 A7 B7 發明説明(31 ) 2-(3,5-二溴-苯基乙块基)-6甲基匕咬 100-101 {2-[2-(2-氯-苯基)-乙烯基]各甲基^比啶-3-基甲基卜二甲基胺 227-229 分解 3- {6-[2-(3-氯-笨基)-乙細基]-2-甲基·说呢·。-基氧》基丨-丙基)_ 二甲基胺 184-186 5_疊氮-4·破-2-[2-(6-甲基4比途-2-基)-乙晞基]酉分 紅色玻璃 2,6-二-第三丁基_4-『2-(6-甲基-吡啶-2-基)乙烯基]-酚 126-127 1-{4-[2-(6-甲基-吡啶-2-基)-乙晞基]苯基卜乙醇 97-99 2-甲基-6-『2-(嘧口定-2-基)-乙烯基]·吡啶 144-145 [3-(6-甲基-吡啶_2_基乙炔基)-苯基]-苯基-甲烯酮 90-100 6-(6-甲基比啶-2-基乙炔基)-3,4-二氫-1H-喹啉-2-酮 189-191 2-(3·{2-[2-(3-氤·苯基)-乙晞基]-6-曱基-吡啶-3-基氧基卜丙 基)-異Μ卜果-1,3-二酬 101-103 3-甲氧基-6-甲基-2-間-甲苯基乙炔基-吡啶 棕色油 醋酸2-[2-(6-甲基4比啶-2-基)-乙綿基]_4_硝基苯基酯 129-131 6-(6-甲基-吡啶-2·基乙炔基)-茚滿-1 -酮 160-165 2-曱基_6-[2-(口瓜口秦-2-基)-乙決基]_u比口足 95-96 N-甲基-Ν·(3-丨4-[2·(6-甲基-吡啶"2-基)-乙晞基]•苯氧基卜丙 基)-乙酿胺 62-70 2-[2-(3,5-雙三氟曱基-苯基)小乙氧基-乙晞基]-6-甲基-吡啶 黃色油 醋酸2-苯基乙、决基^比啶-3-基酯 棕色油 醋酸6-甲基-2-間-甲苯基乙烯基4比啶-3-基酯 综色油 醋酸4-[2_(6-甲基^比啶-2-基)-乙烯基]-2-硝基·苯基酯 91-93 2-[2-(6·甲基-吡啶-2-基)-乙烯基]-4-硝基. 275分解 二甲基-[3-(2·苯基乙炔基-吡啶-3-基氧基)-丙基]-胺 黃色油 二甲基-(3-丨4-[2-(6-甲基-17比淀-2-基)乙缔基]-苯氧基卜 丙基)胺 240-243 1-{4-[2-(6-甲基-吡啶-2-基)-乙晞基]-苯基卜乙烯酮 56-58 --------裝-- (讀先閱讀背面之注意事項再填寫本頁)
、1T _-34- (CNS)A4規格( 210X297公釐) 544448 A7
7 B 五、發明説明(32 ) 經漓部中央標率局員工消費合作社印製 2-(3-氟苯基乙炔基)-喹啉 81-83 醋酸2-甲基-6-笨乙烯基-吡啶-3-基酯 93-96 4-[2·(6·曱基-外匕口定基)-乙晞基1_2-硝基_酉分 141-143 3_乙氧基-4-[2_(6-甲基比啶_2_基)-乙烯基]·2-硝基-酚 175-178 分解 4·(6_甲基比口定_2_基)_乙块基1-2-硝基-紛 184-187 分解 醋酸2-[2-(6_甲基-ρ比口定_2_基)-乙綿基]_6-硝基—苯基酉旨 105-110 分解 二甲基-[3·(6_甲基苯基乙炔基·吡啶·3-基氧基)-丙基]•胺 黃色膠 2_疊氮-4_|>(6-甲基-吡啶基)-乙晞基]-g分 155_157 分解 二甲基-[3-(6·甲基·2·間-甲笨基乙炔基吡啶-3·基氧基)-丙 基]-胺 黃色油 2_(3_甲續BS基-苯基乙块基)-6-甲基-ρ比淀 108-110 分解 3 - {2-[2-(3 -氯·笨基)-乙晞基]-6-甲基-ρ比淀-3 -基氧基卜丙胺 186-189 4_疊氮-Ν·(3-{2-[2_(3-氯-苯基)-乙綿基]-6-甲基比淀-3-基氧 基}-丙基)-2-羥基-苯甲醯胺 99-102分解 3-[3·(3-二甲基月安基-丙氧基)-6-甲基-ρ比咬-2-基乙块基]- 苯甲腈 黃色膠 5-(6·甲基-吡啶-2-基)-乙炔基1-印滿-1-酮 133-134 2-曱基-6-(2,3,5-三氣-苯基乙块基卜口比咬 112-114 2-[2_(6-甲基-北啶-3-基)-乙烯基]各甲基-吡啶 118-119 二甲基-{3-[6-甲基-2-(3-三氟甲基-苯基乙块基)-P比咬-3-基氧 基]-丙基卜胺 黃色膠 2-[2·(6·甲基-吡啶-3-基)-乙炔基]_.3_甲氧基-6·甲基-峨啶氯化 氫鹽 198-199 2-甲基-6-(5,6,7,8-四氫-茶-2-基乙炔基)-吡啶 50-51 3-[2-(3-氯-苯基乙炔基)_6·甲基-吡啶:基氧基]-丙基胺 151-153 (3_丨4_溴_2·甲氡基-6·[2-(6·甲基-吡啶_2·基)-乙烯基]-苯氧基} 丙基)-二甲基-月安 211-215 [6-(3-氟-苯基乙炔基)-ρ比症-2-基]-·二甲基·胺 棕色油 (讀先閱讀背面之注意事項再填寫本頁) -35- 本紙張尺度適用中國國家標擎-(CNS ) A4規格(210X297公釐) 544448 五、 經濟部中央標準局員工消費合作社印繁 A7 __B7 發明説明(35 ) 3-{2-[2-(3-氟-笨基)-乙烯基]-6-甲基-竹1:啶-3-基氧基卜丙-1-醇 86-88 [6-(3-氟-苯基乙炔基)-2·甲基-吡啶-3-基甲基]-二甲基-胺 220-222 2,2-二曱基-丙酸3-[2-(3-氟-苯基乙決基)-6-甲基-吡啶-3-基]- 丙酉旨 黃色油 二-營乱基-冬石典^-^-甲基-吹呢-二-基乙块基彡-酉分 140分解 6_疊氮基-2,4·二碘-3-(6-甲基^比啶-2-基乙炔基)·酚 162分解 4-疊氮基-2-羥基-5-碘-N-[3-(6-甲基-吡啶-2-基乙炔基)-苯基]· 苯甲醯胺 185分解 醋酸3-乙醯氧基甲基-5-(6-甲基-吡啶-2-基乙炔基)-芊基酯 棕色油 (苄基-{[2-(3-氣-苯基乙炔基)-6-甲基-吡啶-3-基氧基]-乙醯 基卜胺基)-乙酸乙酯 棕色油 2-[2-(3-氟苯基)-乙晞基-6-甲基-異菸鹼酸乙酯 76-77 〕-[2_(3-氣苯基乙块基)·6-甲基-峨淀-3_基氧基]-丙-1-酉手 72-74 [3-羥基曱基-5-(6-甲基4啶-2_基乙炔基)-苯基]-甲醇 115-117 (3-{2-[2-(3>二甲基-苯基)-乙烯基]-6甲基-吡啶-3-基氧基}-丙基-二甲基-胺 黃色膠 [4-(4-氣-苯甲廳1基)-喊淀-1-基]-丨6-[2-(3-氟-苯基)-乙締基]-2- 甲基-峨啶-3-基}-甲烯酮 156-158 2_[2·(3·氟-苯基)-乙烯基1-6_曱基-昊菸鹼酸 245-248 {6-[2-(2氯-苯基)-乙烯基]-2-甲基-吡啶_3_基卜4-(4_氟·苯甲醯 基)-喊淀-1-基]-甲烯酮 109-112 2-(3_乙炔基-笨基乙炔基)-6·甲基4匕啶 48-49 (3-{2-[2-(2,6-二氯-苯基)-乙晞基]-6*"甲基基氧基}丙 基)-二甲基胺1化氫鹽 207-210 (3-{2-[2-(2,3·二氯-苯基)-乙烯基]-6-甲基^比啶各基氧基卜丙 基)-二甲基-胺氯化氫鹽 161-169 4-[6-(3-氟苯基乙炔基)-2-甲基^比啶-3-羰基]-哌嗪-1-羧酸第 三丁酯 97-99 [6-(3-氟苯基乙炔基)·2-甲基-外t啶-3-基]-味嗪-1-甲烯酮 250-252 分解 (請先閱讀背面之注意事項再填寫本頁) "Λ I張 紙 一本 -38- (CNS ) A4規格(210 X 297公釐) 544448 經濟部中央標率局貝工消費合作社印製 A7 B7 五、發明説明(36 ) [4-(4-疊氮基-2-羥基-苯甲醯基)-哌嗪-1 -基]各(3 -氟-苯基乙烯 基)-2-甲基· 口比啶-3-基]-甲烯酮 186-188 分解 (3-丨2-[2-(2,4-二氯-苯基)-乙烯基]-6-甲基4匕啶-3-基氧基卜丙 基)-二甲基胺氯化氫鹽 170-176 2-(3-鼠-冬基乙決基)-6-甲基-兴於齡乙酉旨 89-91 2-(3-氟-苯基乙炔基)-6-甲基-異菸鹼酸異丁酯 94-96 2-(3-氟·苯基乙炔基)-6_甲基-異菸鹼酸 231分解 [2-(3-氟-苯基乙炔基)-6-甲基-吡淀-4-基]-甲醇 143-146 [4-(4-氣-苯甲廳基)-味咬>1-基]-[2-(3-氣-苯基乙決基)-6·甲基_ 外匕口定-4_基-甲烯酮 156-158 3-烯丙氧基-2-[2-(3,5-二氯-苯基)-乙烯基]-6-甲基吡啶 105-106 [2-(3-氟-苯基乙块基)-6-甲基比咬-4-基]-嗎4-4-基-甲晞酮 114-116 醋酸3-(6-甲基-吡啶-2-基乙炔基)-苯甲酯 棕色油 [2-(3-氟·苯基乙炔基)-6·甲基-吡啶-4-基甲基]-二甲基_胺 209-212 (3-丨2-[2-(3,5-二氯-苯基)-丙烯基]-6-甲基-吡啶-3-基氧基}-丙 基)-二甲基-胺氯化氫鹽 182-184 2-(3-氟·苯基乙決基)-3-甲氧基-6·甲基-¾匕口定 黃色油 (3-丨2-[2-(3,5-二氣-苯基)-乙烯基]-吡啶-3-基氧基卜丙基)-二 甲基-胺氯化氫鹽 171-174 4-疊氮基-2_羥基-5 _碘-笨基-丨4-[6··( 3 _氟-苯基乙烯基)-2·甲基-吡啶-3-羰基]-哌嗪-1 -基丨甲烯酮 195-200 分解 4-®氣基-Ν-丨3-[2-(3-氣-苯基乙块基)-6-甲基-Ρ比淀-3-基氧 基]-丙基卜2-經基-5-碘-苯甲醯胺 142-150 分解 4-(2·吡啶-2-基-乙烯基)-苯甲酸乙酯 100-102 (3·{2-[2-(4-氯-苯基)-乙晞基]-6-甲基-说啶-3-基氧基卜丙基)- 二甲基-胺氯化氫鹽 159-171 [3-(6_甲基-外(:淀-2-基乙块基)-苯基]-曱醇 43-45 6-(3_氟-苯基乙块基)-於驗酸第三丁酉旨 96-98 (3-{2-[2-(3,4_二氯-苯基)-乙晞基]-6-甲基-吡啶-3-基氧基}-丙 174-177 (讀先閱讀背面之注意事項再填寫本頁) _____ -39- 本纸張尺度適用中國國家標準(CNS ) A4規格(21〇X297公釐) 544448 五、發明説明(37 A7 B7 基)-二甲基-胺氯化氫鹽 昊-2-苯基-乙晞基)-4-甲基-17密淀 黃色油 6-(3-氟-笨基乙块^基)-於驗酸 223分解 [4_(4_氟-苄醯基)-喊啶小基]-[6-(3-氟-苯基乙块基)-吡啶-3-基]-甲烯酿] 136.0-139.0 2-(2-第三丁氧基-3,6-二氟-苯基乙炔基)-6-甲基-吡啶 72.0-74.0 2-甲基-6-丨2-(2,4,5-三氟-苯基)-乙烯基]-吡啶 74-76 2-甲基-6_[2-(2,3,4-三氟-苯基)-乙晞基]叶匕口定 79-82 3-(6-甲基·吡啶-2-基乙炔基)-酚 142-144 2-曱基-6-[2-(3,4,5-^氣-苯基)-乙蹄基]-叶匕17足 74-76 2_(3-曱氧基-苯基乙块基)-6-甲基-外匕咬 55-57 2-甲基-6-(2,3,4-三氟-苯基乙炔基)-吡啶 104-106 (讀先閱讀背面之注意事項再填寫本頁) 經漓部中央標率局員工消費合作社印繁 ___ - 40 - 本紙張尺度適用中國國家標隼(CNS ) A4規格(210X297公釐)
Claims (1)
- 544448第術丨I·7號專利申請案 中文申請專利範圍修正本(91年7月) 、申請幸痛HI------------! 丨公告本j 丨 j ,一 ~ ' 一 1. 一種式I化合物 I補充 本"\丨年七巧(I), 其中, X 代表伸乙块基, Ri是(C^4)烷基、(Cu)烷氧基、氰基、乙炔基或 (C丨·4)烷基胺基, R2是氫,經基、複基、(C 1 ·4)垸氧基馥基、二(C 1 ·4) 虎基胺基甲基、4-(4 -氟-爷8¾基)-來症-1-基·幾 基、4 -第三丁氧基羰基哌嗪-1-基-羧基、4-(4 -疊 氮基-2 -羥基芊醯基)-哌嗪-1 -基-羧基或4 - ( 4 -疊氮 基-2 -護基-3 -碘-苄醯基)-哌嗪-1 -基-羧基’ R3是氫、(Cl -4)烷基、羧基、(Ci _4)烷氧基羰基、 (Ci·4)烷基胺甲醯基、羥基(Ci·4)烷基、二(C〖.4) 烷基胺基甲基、嗎啉代羰基或4 - (4 -氟芊S&基)-哌 啶-1 -基-羧基, R4是氫、羥基、羧基、(C2-5)烷醯氧基、(Ci“)境氧 基羰基、胺基(C丨_4)烷氧基、二(C丨-4)虎基胺基 (Ci·4)烷氧基、二(Ci·4)燒基胺基(Cm)淀基或羥 基(C卜4)烷基,且 R 5是下式基團 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公董) 544448 A8 B8 C8六、申請專利範圍其中, L和Rb分別是氫、自素、硝基、氰基、(Ci 4)烷基、 (Cl·4)烷氧基、三氟甲基、三氟甲氧基或(C25)炔 基, I是氫、氟、氯、溴、羥基、(cU4)烷基、(c2-5)烷 酿氧基、(Ci-4)烷氧基或氰基,且 Rd是氫、鹵素或(c14)烷基, 其限制條件為,於其中R2、R3及R4為氫之化合物中, 當Ri為甲基時,Rs係不同於苯基、甲基苯基、6•甲 基吡啶-2-基及3-甲氧基苯基,其為自由形式或醫藥上 可接受的鹽之形式。 2·根據申請專利範圍第i項之化合物,其中R5係不同於視 情況經取代之苯基,其為自由形式或醫藥上可接受的鹽 之形式。 3·根據申請專利範圍第2項之化合物,其中r5係視情況經 取代之叶b違-3 -基’其為自由形式或醫藥上可接受的鹽 之形式。 4.根據申請專利範圍第1項之化合物,其為2 - [ 2 - ( p比咬· 3 · 基)乙決基]-6 -甲基-吡啶,其為自由形式或醫藥上可接 本紙張足度適用中國國家標準(CNS) A4規格(210 X 297公釐) 8 8 8 8 A B c D 544448 六、申請專利範圍 受的鹽之形式。 5. 一種用於治療與谷胺酸訊息傳遞不規則有關的病症及於 與完全或部分由mGluR5所媒介的神經系統病症之醫藥 組成物,其包含作為醫藥活性成份之根據申請專利範圍 第1至4項中任一項之呈自由形式或醫藥上可接受的鹽之 形式之化合物,及慣用的醫藥賦形劑。 -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
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BR9811685A (pt) | 2000-09-19 |
CN1262676A (zh) | 2000-08-09 |
DE69839398D1 (de) | 2008-06-05 |
PT998459E (pt) | 2008-07-31 |
TR200000059T2 (tr) | 2000-06-21 |
JP3481208B2 (ja) | 2003-12-22 |
CA2295678A1 (en) | 1999-01-21 |
KR20010021712A (ko) | 2001-03-15 |
CN1203060C (zh) | 2005-05-25 |
ES2308811T3 (es) | 2008-12-01 |
IL133904A0 (en) | 2001-04-30 |
NO20000124L (no) | 2000-03-02 |
PE97799A1 (es) | 1999-11-08 |
DE69839398T2 (de) | 2009-05-28 |
JP2001509504A (ja) | 2001-07-24 |
WO1999002497A2 (en) | 1999-01-21 |
CA2295678C (en) | 2010-04-13 |
HUP0004225A2 (hu) | 2001-05-28 |
WO1999002497A3 (en) | 1999-04-01 |
HUP0004225A3 (en) | 2001-06-28 |
SK232000A3 (en) | 2000-06-12 |
EP0998459B1 (en) | 2008-04-23 |
ATE393145T1 (de) | 2008-05-15 |
US6656957B1 (en) | 2003-12-02 |
NO20000124D0 (no) | 2000-01-10 |
EP0998459A2 (en) | 2000-05-10 |
AR016314A1 (es) | 2001-07-04 |
RU2203889C2 (ru) | 2003-05-10 |
PL343865A1 (en) | 2001-09-10 |
NZ502210A (en) | 2002-07-26 |
AU8974398A (en) | 1999-02-08 |
ID23889A (id) | 2000-05-25 |
MY119800A (en) | 2005-07-29 |
AU738973B2 (en) | 2001-10-04 |
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