TW579375B - 2,2-Diphenylbutanamide derivatives and medicines containing the same - Google Patents

2,2-Diphenylbutanamide derivatives and medicines containing the same Download PDF

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TW579375B
TW579375B TW090125458A TW90125458A TW579375B TW 579375 B TW579375 B TW 579375B TW 090125458 A TW090125458 A TW 090125458A TW 90125458 A TW90125458 A TW 90125458A TW 579375 B TW579375 B TW 579375B
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Taiwan
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group
atom
branched alkyl
compound
straight
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TW090125458A
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Yoshihiko Kanamaru
Tomomi Okada
Kinichi Mogi
Teruo Komoto
Shinichi Morimoto
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Ssp Co Ltd
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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
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    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen 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
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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
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
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    • 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
    • C07D239/28—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 hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C—CHEMISTRY; METALLURGY
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    • 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
    • C07D241/14—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 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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Description

579375 A7
裝 訂
5 五、發明説明（ 土、作為R7、R8、R9、R10及R丨丨之低碳烷基，可舉1〜6 C之 直鏈或支鏈之烷基，具體言之，可舉^基、乙基、正丙基 、異丙基、正丁基、異丁基、第二丁基、第三丁基、正戊 j、正己基等。又，作為環烷基，以3〜8C者為佳，具體 & <，可舉環丙基、環戊基、環己基、環庚基、環辛基。 又，R7以Η原子及乙基，…以H原子及甲基，R9以甲基 為佳。 R10及R11與鄰接原子一起形成之雜環之員數 為佳。作為如此之環，可舉氮呒環、吡咯啶環、哌啶環、 哌啡環、嗎啉環等。 作為視情況取代之苯基，以苯基及鄰位上具取代基之苯 基為佳’取代基以甲基、C1原子、F原予、羥基及甲氧基 為佳。 签 本發明之2,2-二苯丁醯胺衍生物之鹽，只要為藥學上可 接受之鹽，則無特別限制，可舉例如鹽酸、硫酸、氫溴酸 =酸等之加成鹽、甲酸、乙酸、富馬酸、馬來酸、酒石 鉍’《有機酸之加成鹽。又’本發明化合物亦含水合物等 之媒合物。更外，亦包含多元酸鹽。 、（丨-2)或（1-3)表示 本發明化合物可舉例以下式（丨_ j ) 之態樣者。
-10- 579375 A7 B7 五、發明説明（6 ) [式中，R1、R2、n表與前述相同之意義，Ar，表視情況以 下面之基取代之苯基、二環性芳香環、一環性雜環、二環 性雜環或蔡基
(1^表Η原子、鹵原子、苯基、低礙燒基或-Ο-R4基）。於 此，R4表Η原子、低碳烷基或_(CR5R6)m-Y基（於此，R5及R6 表Η原子或低碳烷基，Y表-COOR7基、-OR8基或-OCOR9基 (R7、R8及R9表Η原子、低碳烷基或環烷基），m表1〜6之數）]。
(式中，R1、R2表與前述相同之意義，R3"表Η原子、鹵原 子、低碳烷基、或基或-0-R4基。於此，R4表Η原子、低碳 烷基或-(CR5R6)m-Y基（於此，R5及R6表Η原子或低碳烷基， Υ 表-COOR7 基、-OR8 基、-OCOR9基或-CONFER11 基（R7、R8 及R9表Η原子、低碳烷基或環烷基，R1G及R11表Η原子、低 碳烷基或環烷基，或R1G及R11與鄰接之Ν原子一起形成雜環 亦可），m表1〜6之數）
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 579375 五 、發明説明（7 ) A7 B7
(式中Ri、R2及R3"表與前述同意義） 本發明之2,2-二苯丁醯胺衍生物及其鹽 之（A法卜（L法）製造。 以式（1 - 1 )表示之化合物之製造： (A法） 例如 可依下面 R1 2 ιτ+ R2—
X /—(CH2)n + HN N一/
Ph-
Ph 化合物（3)
化合物（2)
裝
(式中，X表鹵原子，以、尺2、11及Ar表與前述同意義） 亦即，將亞呋喃基銨化合物（2 )與化合物（3 )反應，得本 無明化合物（la)。本反應通常於2〜5當量，較好3當量之 鹼存在下，於40〜140°C，較好80〜1201進行1〜1 8小時。本 反應可於苯、甲苯、二甲苯、四氫呋喃、二甲基甲醯胺等 之無水溶媒中進行。作為鹼可舉Na2C〇3、K2CCh、NaOH、 K〇Η等之無機驗、三乙胺等之有機驗。 於此’化合物（2 )可藉由公知方法[r. a. stokbrokx et al.， J. Med. Chem· 16，782 (1973)]合成。 -12- 本紙張尺度適用中阐國家標準(CNS) A4規格(210X297公釐) 579375 A7 B7 五、發明説明（9 ) (式中，Z表游離基，η及Ar表與前述同意義） 於本反應，溶媒並非一定必要，作為溶媒，具體言之可 舉甲苯、二甲苯、假枯晞等，反應溫度以1004 7〇C為適當 。反應時間4〜2 4小時為佳。 又，下述市售品亦可利用。
4)藉下述文獻中記載之方法可合成。 1) S. L. Buchward et al.5 Angew. Chem. Int. Ed. Engl. 34, 1348 (1995)。 2) J· P. Wolfe et al·，Acc. Chem. Res·，31，805-818 (1998) o /(CH2)n
HN NH
化合物 (式中，n及Ar表與前述同意義） 亦即’作為觸媒使用二氯雙（三-鄰-甲笨膦）鈀（π) [PdCl2(P(o-tolyl)3)2]，游離基使用鹵化合物之溴化物，另外 ’驗使用1〜2當I之第二丁氧基钟為佳，溶媒以甲苯、二 甲苯、假枯烯等為佳，溫度以lOOq 7〇t為適當，上述觸媒 可使用0 · 5〜10莫耳％，較好為5莫耳％。反應時間4〜2 4小 時為佳。 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 579375 A7 B7 五、發明説明（1〇 ) (B法）
Y—(CR5R6)m—z 化合物（4)
CON、 R2 CH2CH2*~N
〇(CR5R6)ra—γ 裝 化合物（1 c) 訂
線 (式中，m表1〜6之數，1^、尺2、11、;^5、1^6、丫表與前述同 意義，Z表鹵原子、甲磺酸酯、甲苯磺酸酯及三富利酸酷 (triflate)) 〇 亦即將化合物（lb)與化合物（4)反應，得本發明化合物 (lc)。反應通常於1〜3當量，較好1〜1.5當量之鹼存在下， 於20〜100°C，較好20〜60°C進行2〜36小時。本反應可於丙 酮、四氫呋喃、二甲基甲醯胺、二〒亞颯等之無水溶媒中 進行。作為鹼，可舉Na2C03、NaOH、NaH等之無機驗、三 乙胺等之有機鹼。又，亦可加鹼並加KI。 於此，化合物（4)可容易地以市售試藥購得，或以公知 之方法合成。 -15- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 579375 A7
本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 579375 A7 B7 五、發明説明（12 ) (式中，RhRin及m表與前述同意義） 又，將於B法合成之化合物（If)(於lc，R5、R6=h、 Y^COOEt之化合物）加水分解，得本發明化合物（lg)。 上述兩反應，通常於1〜3當量，較好1〜1·5當量之鹼存在 下，於2 0〜4 0 °C，較好2 0〜2 5 °C進行1〜5小時。上述兩反 應，可於甲醇、乙醇、二哼烷、四氫呋喃等與水混合之溶 媒中進行。作為鹼可舉NaOH、KOH、Na2C03等之無機鹼。 以式（1 - 2 )表示之化合物之製造： (D法）
化合物（2) 化合物（5) 化合物（l-2a) (式中，X表鹵原子，Ri及R2表與前述同意義，尺3-1表11原子 、F原子、C 1原子、羥基、低碳烷基或低碳烷氧基） 亦即，將亞呋喃基銨化合物（2 )與化合物（5 )反應，得本 务明化合物（l-2a)。本反應通常於2〜5當量，較好3當量 之鹼存在下，於40〜lOOt：，較好50〜60°C進行1〜1 8小時。 本反應可於木、甲苯、二甲苯、四氫吱喃、二甲基甲醯胺 等之無水溶媒中進行。作為鹼可舉Na2C03、K2C〇3、NaOH 、ICOH等之無機鹼及三乙胺等之有機鹼。上述化合物（2) 可以公知之方法[r· A. Stokbrokx et al.，J. Med. Chem.，16, 7 82 ( 1 973)]合成。對上述化合物（5 )，於後面之參考例中記 -17- 本紙張尺度適用中國國家標準(CNs) A4規格（210X297公釐） 579375 A7 B7
述其之合成法。 (E法）
化合物（l-2b) 化合物（l-2c) (式中，尺1、尺2、1^、尺6、11及丫表與前述同意義，：^表鹵原 子、甲磺酸酯、甲苯磺酸酯或三富利酸酯） 亦即，將化合物（l-2b)與化合物（6)反應，得化合物〇_ 2c)。反應通常於1〜3當量，較好1〜1.5當量之鹼存在下， 於20〜丨〇〇°C、較好20〜60°C進行1〜3 6小時。反應於丙鋼、 四氫呋喃、二甲基f醯胺、二甲亞砜等之無水溶媒中進行 。作為鹼可舉NaWO3、NaOH、KaH等之無機鹼及三乙胺等 之有機鹼。又，亦可將κι與鹼一起加入。上述化合物（6) 可容易地自市售試藥購得，又可以公知之方法合成。 (F法）
0(CR5R6)n0C0R9
〇(CRSK\〇H 化合物(l-2d) 4匕合物(l-2e) (式中，R1、R2、R5、R6、R^n表與前述同意義） 將 化合物（l-2d)加水分解，可得本發明化合物（丨_2e) -18- 本紙張尺度適用中國國家標準(CNS) A4規格（210 x 297公釐） 579375 A7 一 ____B7 五、發明説明（14 ) 詳細言之，將化合物（l-2d)於1〜3當量，較好丨〜丨.5當量之 驗存在下，於20〜40°C，較好20〜25°C加水分解1〜5小時，得 本發明化合物（1 - 2 e )。本反應可於甲醇、乙醇、二崎燒、 四氫吱喃等與水混合之溶媒中進行。驗可舉Na〇H、KOH、 Na2C03等之無機驗。 (G法）
化合物（l-2f) 化合物（l-2g) (式中，R1、R2、R5、R6、R7及η表與前述同意義） 亦即，將化合物（l-2f)加水分解，得本發明化合物（i · 2g)。上述反應通常於1〜3當量，較好當量之鹼存在 下，於20〜4(TC，較好20〜25°C進行丨〜5小時。上述反應可於 甲醇、乙醇、二哼烷、四氫呋喃等，與水混合之溶媒中進 行。鹼可舉NaOH、KOH、Na2C03等之無機驗。 以式（1 - 3 )表示之化合物之製造·· -19-
579375 A7 B7 五、發明説明（15 ) (Η法）
化合物（l-3a) (式中，R1及R2表與前述同意義） 與（A )法同樣地’自亞呋喃基銨化合物（2 )與化合物（7 ) 製造化合物（8)，將化合物（8)脫水，得本發明化合物 3a)。脫水反應，藉由於化合物（8)加過量之酸，加熱迴流 數小時而進行。本反應可使用醇、四氫呋喃、二今燒等之 溶媒進行。酸可使用鹽酸、硫酸等。 (I法）
化合物（l-3a) 化合物（1-3b) -20- 木紙張尺度適用中國國家標準(CNS) A4规格(210X 297公釐） 579375
(式中’尺丨、11-、115、116、11及¥表與前述同意義，父表鹵原 子、甲％酸酯、甲苯磺酸酯或三富利酸酯） 上述反應，與（E法）同樣地實施。 U法）
化合物（l-3c) 化合物（l-3d) (式中’ R1、R2、R’、R6、R9及n表與前述同意義） 上述反應，與（F法）同樣地，將化合物（1-3c)加水分解 得本發明化合物（1-3d>。 (K法）
Ι^Ίΐ
conrV 化合物（l-3e) 化合物（l-3f) (式中，R1、R2、R5、R6、R9及n表與前述同意義） 上述反應’與（G法）同樣地，將化合物（le3e)加水分解， 得本發明化合物（1-3f)。 (L法）
R3
(2 R3 (1-2) 21 - 本紙張尺度適用中國国家標準(CNS) A4規格(210 X 297公釐）
二之投予形態’可藉由各業者所公知之慣用之製劑方 1造。 .I備經口用固形製劑之情形，可於本發明之2,2_二苯丁 画盘胺衍生私7式址1、政 、 ’ 一 ^寺又皿，依須要加黏合劑、崩散劑、潤滑 、#、^卜墙味劑、矯臭劑等之後’依習用法製造錠劑 渣布錠劑、顆粒劑、散劑、膠囊劑等。 製m液體製劑之情形，可於本發明之2,2_二苯丁 =衍生物或彼等之鹽中，依須要加墙味劑、缓衝劑、穩 疋训、矯臭劑等’依習用法製造内服液劑等。 ，備，射劑之情形，可於本發明之2,2.二苯丁酿胺衍生 ’彼等〈鹽中，加P Η調節劑 '緩衝劑、穩定劑、等張劑 、、局邵麻醉劑等’依習用法製造皮下、肌肉内及靜脈内用 注射劑。 製備栓劑之情形，於本發明之2,2_二苯丁酿胺衍生物或 彼寺之鹽中加公知之製劑用載劑，例如聚乙二醇、羊毛脂 、可可脂、脂肪酸三甘油酯f ’再依須要加界面活性劑等 之後，可以習用法製造。 製備軟膏劑之情形，於本發明之2,2•二苯丁酿胺衍生物 或彼等之鹽中，依須要摻合通常使用之基劑、穩定劑、濕 潤劑、防腐劑等，依習用法混合、製劑化。 製造貼劑之情形，可依習用法將前；軟膏、霜劑、凝膠 、糊劑等塗佈於通常之撐體而製造。 摻合於上述之各投予單位形態中之本發明之2,2二苯丁 酿胺衍生物或彼等之鹽之量’依可適用此之患者之症狀或 -23-
579375 A7 _ B7 五、發明説明（19 ) 依其劑形等，並不一定，一般每投予單位形態於經口劑為 約0.25〜100毫克，於注射劑為約〇.〇5〜20毫克，於检劑為約 〇·卜50毫克。又，具上述投予形態之藥劑，每天之投予量 依患量之症狀體重、年齡、性別等而異，無法一概決定， 通常成人每曰約0.005〜2毫克/公斤，較好約〇·〇ι〜毫克/ 公斤即可，將此1日1次或分成2〜4次之程度投予為佳。 實施例 其次’舉實施例更詳細說明本發明，無論如何本發明並 不限於此。 參考例1 將4 -溴-2,2-二苯酪酸2 3克（7 2毫莫耳）懸浮於1 5 0毫升氯 仿’於室溫滴下亞硫醯氯2 0毫升（2 7 0毫莫耳）。再加DMF 0.2毫升’加熱迴流4小時。反應後，減壓濃縮溶媒，得4 -溴-2，2-二苯酪醯氯2 3克（產率94.7%)。 將50%二甲胺水溶液8克（90毫莫耳）、Na2C03 18克（170 毫莫耳）懸浮於水1 〇 〇毫升，於0〜5 °C下冷卻。於此滴下溶 於甲苯100毫升之上述4 -溴-2,2-二苯酪醯氣23克（68毫莫 耳）。再攪拌2小時後’取水層，以甲苯洗。接著，以 CHC13抽取水層，水洗、乾燥。減壓濃縮溶媒，所得殘留 物以甲基異丁基酮使結晶，得二甲基（四氫-3,3-二苯基-2-亞呋喃基）銨化溴1 1克（產率46.8%)。 1H-NMR (CDCh) δ (ppm): 2.96 (3H, s), 3.47 (2H, t), 3.83 (3H，s), 4.85 (2H，t)，7.40-7.60 (10H，m) 〇 參考例2 -24- 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 579375 A7 __ B7 五、發明説明（2〇 ) 用"比略淀代替參考例1之5 0 %二甲胺水溶液，得（四氫一 3,3-二苯基-2-亞呋喃基）吡咯錠化溴（產率53·6%)。 •H-NMR (CDC13) δ (ppm): 1.80-2.30 (4H, m), 2.88 (2H? t)? 3.50 (2H，t)，4.37 (2H，t)，4·88 (2H，t)，7.25-7.70 (l〇H，m)。 參考例3 將旅吨6 1 〇毫克（ 7.〇8毫莫耳）、2_溴莕1〇4克（5 〇2毫莫耳） 、第二丁醇鈉6 8 0毫克（7·〇8毫莫耳）及二氯雙（三鄰甲苯膦） 免（II)[PdCl2(P(0-t0ly1)3]2 200 毫克（0.247 毫莫耳）加於假枯婦 (bp 169 C) 20毫升，進行24小時迴流攪拌。接著，反應混 合液中加四氫呋喃稀釋後，用寅式鹽過濾，減壓濃縮濾液 。所得殘留物以矽膠管柱層析，將7% MeOH/CHCl3溶離份 減壓;辰縮，得目的約1-(2-茶基）喊p井之淡黃色固形物、 5 4 6毫克（產率51·5%)。 MS (El) m/z: 212 (M+) [H-NMR (CDC13) δ (ppm): 1.99 (1H, s), 3.05-3.15 (4H, m), 3.21-3.32 (4H，m)，7.13 (1H，d，J=1.9 Hz)，7,20·7.35 (2H，m)， 7.35-7.50 (1H，m)，7.60-7.80 (3H，m)。 參考例4 將哌畊6 10毫克（7.08毫莫耳）、4-氯喳啉82〇毫克（5.01 毫莫耳）加於假枯晞2 0毫升中，迴流8小時。接著將反應混 合液中之溶媒減壓餾除，殘留物中加1當量濃度之Na〇H水 溶液後，以CHCh抽取，以無水MgSCU乾燥。另外，減壓濃 縮後，殘留物以矽膠管柱層析，將AcOEt : MeOH : Et3N=85 :1 5 : 1溶離份減壓濃縮，得目的物1 -(4-ϊτ奎琳基）喊β井之淡 __ -25- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐)
έ Φ 579375 A7 ____B7 五、發明説明（21 ) 黃色固形物738毫克（產率69.0%)。 MS (El) m/z: 213 (M + ) A-NMR (CDCh) δ (ppm): 1.73-1,96 (1H，br)，3.05-3.36 (8H,m), 6.77-6.88 (1H, m), 7.40-7.54 (1H, m), 7.58-7.70 (1H, m)，7.96-8.10 (2H，m)，8.67-8.76 (1H，m)。 參考例5 將1-(3 -甲氧苯基）哌畊3.0克（15.6毫莫耳）加於48%氫溴 酸25毫升中，於140度加熱5小時。冷卻後，加3當量濃度 之NaOH水溶液使成pH 9後，以CHC13抽取，以無水MgS04 乾燥。再於減壓濃縮後於殘留物中加乙醚5 〇毫升，濾取析 出之淡紅色固形物，得目的物1-(3-羥苯基）哌畊2.2克（產率 79.1%) 〇 MS (FAB) m/z: 179 (M+H+) lH-NMR (DMSO) δ (ppm): 2.70-2.85 (4H, m), 2.90-3.00 (4H, m)，6.18 (1H，dd，J=2.0，7·8 Hz)，6.27 (1H，s)，6.33 (1H，d， J = 7.8 Hz)，6.96 (1H，t，J=7.8 Hz)，9·00 (1H，br)。 實施例1 將二甲基（四氫-3，3-二苯基-2 -亞吱喃基）銨化溴350毫克 (1.01毫莫耳）及1-苯基哌畊150毫克（0.899毫莫耳）溶於無 水二甲基甲醯胺20毫升，加Na2C03 200毫克（1.89毫莫耳） ，於1 l〇°C攪拌4小時。接著，自反應液減壓餾除溶媒，所 得殘留物溶於乙酸乙酯，水洗後以無水MgS04乾燥。再將 溶媒減壓濃縮，所得殘留物以矽膠管柱層析法純化，將5〇/〇 MeOH/AcOEt溶離份減壓濃縮，得目的物為淡黃色油狀物 -26- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 裝 訂
579375 A7 ______ B7 五、發明説明（22~) 一 "'-—— ’ M4-苯基喊呼小基）_N，N_二甲基·2,2_二苯丁醯胺（化合 物編號1 ) 373毫克（產率97· 1%)。 —又，上述所得之目的物針對藥理試驗，為提供水溶性， 藉由下述操作，做成鹽酸鹽之無定形粉末。另外，對以下 所得足化合物編號2〜5 1，亦以同樣之操作得鹽酸鹽之無 定形粉末，供藥理試驗。 (鹽酸鹽之製造） 將上述目的物（化合物編號丨）36〇毫克（〇.834毫莫耳）溶於 無水乙醚30毫升，冰冷下加丨當量濃度之鹽酸、乙醚溶液 〇·9毫升。濾取析出之白色沈澱，以乙醚洗淨後，乾燥得上 述目的物（化合物編號1)之鹽酸鹽33〇毫克（產率84.5%)。 實施例2〜4 1、4 6、4 7 與實施例1同樣地進行反應，如下表得化合物編號2〜41 、4 6、4 7 〇 實施例4 2 將4-[4-(2-羥苯基）哌畊-1 -基]_Ν，Ν-二甲基-2,2_二苯丁醯 胺（化合物編號36) 1.1克（2.5毫莫耳）溶於無水二甲基$醯 胺20毫升’加2-溴乙基乙酸酯〇.5克（3〇毫莫耳）及K2C〇3 0.4克（3.0毫莫耳）’於室溫攪拌12小時。反應液中加水以 乙醚抽提’水洗後以無水MgS〇4乾燥。減壓餾除溶媒，所 得殘留物以矽膠管柱層法純化，得乙酸2-[2-[4-[4-(二甲胺 基）-3,3-二苯基-4 -酮丁基]峰呼-U基]苯氧基]乙酯（化合物 編號42) 0.7克（產率51.0%)。 實施例4 4、4 8、5 0 -27- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐) 579375 A7 B7 五、發明説明（23 ) 與實施例4 2同樣地進行反應，如下表得化合物編號4 4 、4 8、5 〇 ° 實施例4 3 將乙酸2-〇[4-[4-(二甲胺基）-3,3-二苯基-4-酮丁基]哌呼-1-基]苯氧基]乙酯（化合物編號42 ) 560毫克（ι·〇毫莫耳）溶 於甲醇5毫升，加1當量濃度之NaOH水溶液5毫升，於50 °C 攪拌1小時。反應液中加水，以CHCh抽提，水洗後以無水 NaJCU乾燥。減壓餾除溶媒，所得殘留物以矽膠層析法純 化，得4-[4-[2-(2-羥乙氧基）苯基]哌啩-1-基]-N，N-二甲基. 2,2 - —冬丁酿胺（化合物編號43) 440毫克（產率85.9%)。 實施例4 5、4 9、5 1 與實施例4 3同樣地進行反應，如下表得化合物編號4 5 、4 9、5 1 〇 實施例52 將4-[4-(2-羥苯基）哌畊-1 -基]_n，N-二甲基-2,2-二苯丁醯 胺1.24克（化合物編號3 6 )(2.80毫莫耳）α-溴異酪酸乙酯6〇〇 克（30.8毫莫耳）、無水k2C〇3 2.〇〇克（14.5毫莫耳）加於無水 二甲基甲酿胺2 0毫升，於外溫5 0 °C攪拌1 6小時。反應終 了後，減壓餾除二甲基甲醯胺，殘留物溶於乙酸乙醋，水 洗後以無水NaJCU乾燥。接著，減壓餾除乙酸乙酯後，用 石夕膠6 0克將殘留之油狀物進行管柱層析，減壓餾除2%
MeOH/CHCh洛離份，得目的物2-[2-[4-(4-二甲胺基）-3 3-二 苯基-4 -酮丁基]哌畊_丨-基]苯氧基p 2 ·甲基丙酸乙酯（化合 物編號5 2 )之淡育色油狀物8 2 0毫克（產率52.6%)。 -28- 本紙張尺度適用中國國家標準(CNS) A4規格(2i〇x 297公釐） 579375 A7 _ B7 五、發明説明（24 ) 實施例5 3 將2-[2-[4-(4-二甲胺基）-3,3 -二苯基-4-酉同丁基]咬π井-1-基 ]苯氧基]-2 -甲基丙酸乙@旨（化合物編號5 2 ) 660毫克（1 · 1 8毫 莫耳）溶於1當量濃度之NaOH水溶液1〇毫升、甲醇1〇毫升 及1,4-二哼烷1 〇毫升之混合溶媒，於室溫攪拌3小時。反 應。反應終了後，反應混合液加水，以稀鹽酸中和（pH 7) ，以CHCh抽提。接著以無水NajO4乾燥後，減壓餘除 CHC13，殘留物以乙醚使結晶，得目的物2吖2-[4气4•二甲胺 基）-3,3-二苯基-4-酮丁基]哌畊-1 -基卜2-甲基丙酸乙醋（化 合物編號5 3 )之無色結晶3 5 6毫克（產率57.1%)。 -29- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 579375 A7 B7 五、發明説明（26 ) 表2 C〇N(CH卞 CH,CH,-N N—Ar 化合物編號 Ar 產率(％) 性狀 融點°C (分解) 16 64.7 淡黃色油狀物 17 C0 66.3 淡黃色油狀物 18 ca 82.5 淡黃色油狀物 19 63.8 淡黃色油狀物 20 yCC〇 69.6 淡黃色油狀物 21 4〕 60,0 淡黃色油狀物 22 a 76.9 淡黃色油狀物 23 71.7 淡黃色油狀物 24 X) 51.7 淡黃色油狀物 25 ca 99.3 淡黃色油狀物 26 ax 50.4 淡黃色油狀物 27 c6 59.3 淡黃色油狀物
-31 - 本紙張尺度適用中國國家標準(CNS) A4規格(21〇x 297公釐） 579375 A7 B7 五、發明説明（27 )
化合物編號 R3 產率(％) 性狀 融點°C (分解） 28 2-CH3 99.8 淡黃色油狀物 29 3-CHs 93.0 淡黃色油狀物 30 4-CH3 95.0 淡黃色油狀物 31 2-F 97.8 淡黃色油狀物 3 2 4-F 97.8 淡黃色油狀物 33 2-C1 96.4 淡黃色油狀物 34 3-C1 96.4 淡黃色油狀物 35 4-Cl 98.6 淡黃色油狀物 36 2-OH 98.9 淡黃色油狀物 37 3-OH 93.6 淡黃色油狀物 38 4-OH 92.5 淡黃色油狀物 39 2-OCHs 97.4 淡黃色油狀物 40 3-OCH3 89.2 淡黃色油狀物 41 4-OCH3 89.9 無色結晶 139-140 42 2-0(CH2)2〇COCH3 50.9 淡黃色油狀物 43 2-0(CH2)2〇H 85.9 淡黃色油狀物 44 2-OCH2COOC2H5 74.3 淡黃色油狀物 45 2-OCH2COOH 51.2 無色結晶 125-126 52 2-OC(CH3)2COOEt 52.6 淡黃色油狀物 53 2-OC(CH3)2COOH 57.1 無色結晶. 173-174 -32- 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 579375 A7 B7 五、發明説明（28 ) 表4
化合物編號 R3 產率(％) 性狀 融點°C (分解) 46 Η 98.5 淡黃色油狀物 47 2-ΟΗ 95.9 淡黃色油狀物 48 2-0(CH2)20C0CH3 60.0 無色結晶 158-159 49 2-0(CH2)2〇H 68.5 淡黃色油狀物 50 2-OCH2COOC2H5 73.1 淡黃色油狀物 5 1 2-OCH2COOH 46.4 無色結晶 150-151 -33- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 579375
AT B7 五、發明説明（29 ) 表5 化合物 編號 質量 (EI:M+) Ή-NMR δ : ppm(CHCl3) 1 427 2.07-2.18 (2H, m), 2.22-2.42 (3H, br)， 2.42-2.58 (6H, m),2.86-3.06 (3H, br), 3.10 (4H, t, /=5.0 Hz), · 6.80 (1H, t, /=7.2 Hz), 6.87 (2H, d, /=8.0 Hz), 7.16-7.32 (4H, m), 7.32-7.47 (8H, m). 2 477 2.12-2.25 (2H, m), 2.25-2.46 (3H, br), 2.46-2.58 (2H, m),2.58-2.78 (4H, br), 2.86-3.20 (7H, m), 7.03 (1H, dd, /=7.4, 1.1 Hz), 7.22-7.56 (14H, m), 7.74-7.84 (1H, ni), 8.08-8.18 (1H, m). 3 477 2.09- 2.22 (2H, m), 2.24-2.44 (3H, br), 2.44-2.70 (6H, m), 2.87-3.14 (3H, br), 3.14-3.34 (4H, br), 7.05 (1H, s), 7.10- 7.55 (13H, m), 7.55-7.76 (3H, m). 4 503 2.07-2.20 (2H, m), 2.20-2.43 (3H, br), 2.43-2.60 (6H, m),2.82-3.10 (3H, br), 3.10-3.22 (4H, m), 6.93 (2H, d, /=8.8 Hz), 7.24-7.58 (17H, m). 5 515 2· 04-2.20 (2H，m), 2.20-2.42 (3H, br)， 2.42-2.62 (6H, in),2.84-3.08 (3H, br), 3.08-3. 24 (4H, br), 3.81 (2H, s), 6.90 (1H, d, /=8.5 Hz), 7.06 (1H, s), 7.13-7.22 (1H, m), 7.22-7.50 (12H, m), 7.56-7.68 (2H, m). 6 434 2.06-2.17 (2H, m), 2.22-2.41 (3H, br), 2.41-2.54 (6H, m), 2.88-3.08 (3H, br), 3.39 (4H, t, /=5.1 Hz), 6.52 (1H, d, /=3.7 Hz), 7.16 (1H, d, /=3.7 Hz), 7.23-7.33 (2H, m), 7.33-7.46 (8H, m). 7 428 2.04-2. 18 (2H, m)， 2.20-2.41 (3H, br), 2.4卜2.56 (6H， m),2.84-3.10 (3H, br), 3.44 (4H, t, /=5.1 Hz), 6.52-6.62 (2H, m), 7.22-7.48 (1 1H, m), 8.11-8.17 (1H, m). 8 428 2.07-2.17 (2H, m), 2.20-2.41 (3H, br), 2.41-2.56 (6H, m), 2.80-3.07 (3H, br), 3.13 (4H, t, /=5.0 Hz), 7.11 (1H, d, /=3.0 Hz), 7.12 (1H, d, /=3.0 Hz), 7.33-7.47 (8H, m), 8.05 (1H, t, /=3.0 Hz), 8.25 (1H, s). 9 428 2.06-2.16 (2H, in), 2.22-2.41 (3H, br), 2.41-2.52 (6H, m), 2.88-3.10 (3H, br), 3.23 (4H, t, /=5.0 Hz), 6.59 (2H, d, /=6.8 Hz), 7.22-7.47 (10H, m), 8.22 (2H, d, /=6.8 Hz). 10 429 2.06-2.17 (2H, m), 2.24-2.43 (3H, br), 2.38 (4H, t, /=5.0 Hz), 2.44-2.53 (2H, m), 2.86-3.10 (3H, br), 3.72 (4H, t, /=5.0 Hz), 6.43 (1H, t, /=4.9 Hz), 7.22-7.32 (2H, m), 7.33-7.46 (8H, m), 8.26 (2H, d, /=4.9 Hz). -34- 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 579375 A7 B7 五、發明説明（30 ) 表6 化*合物 編號 質量 (EI:M〇 11 429 12 429 13 478 14 478 15 478 16 441 17 491 18 491 19 517 Ή-NMR 5 : ppm(CHCl3) 2.08-2.18 (2H, m), 2.22-2.40 (3H, br),~ 2.40-2.60 (6H, m),2.86 -3.12 (3H, br), 3.12-3.24 (4H, m), 7.24- 7.34 (2H, m), 7.34-7.47 (8H, m), 3.30 (2H, d, /=2.9 Hz), 8.65 (1H, d, /=2.9 Hz)._ 2.06- 2.19 (2H, m), 2.22-2.40 (3H, br)， 2.40-2.53 (6H, m),2.86-3.08 (3H, br), 3.50 (4H, t, /=5.0 Hz), 7.24- 7.33 (2H, m), 7.33-7.46 (8H, m), 7.80 (1H, d, /=2.6 Hz), 8.02 (1H, dd, /=2.6, 1.5 Hz), 8.07 (1H, d, /=1.5 Hz). 2.07- 2.19 (2H, m)/ 2. 20-2.43 (3H, br), 2.43-2.57 (6H, m), 2.90-3.12 (3H, br), 3.66 (4H, tr /=5.1 Hz), 6.91 (1H, d, /=9.2 Hz), 7.18 (1H, t, /=7.7 Hz), 7.22-7.32 (2H, m), 7.32-7.46 (8H, in), 7.49 (1H, t, /=7.7 Hz), 7.55 (1H, d, /=7.7 Hz), 7.66 (1H，d, /=7.7 Hz), 7·83 (1H，d，/=9.2 Hz)._ 2.14- 2.26 (2H, m), 2.26-2.46 (3H, br), 2.46-2.56 (2H, m), 2.60-2.72 (4H, br), 2.84-3.10 (3H, br), 3.10- 3.24 (4H, br), 6.77 (1H, d, /=5.0 Hz), 7.24- 7.34 (3H, m), 7.24-7.34 (8H, m), 7.63 (1H, t, /=8.5 Hz), 7.97 (1H, d, J=8.5Hz), 8· 02 (1H，d, /=8.5 Hz), 8.69 (1H，d, /=5.0 Hz)._ 2.14- 2.26 (2H, in), 2.26-2.46 (3H, br), 2.46-2.58 (2H, m), 2.58-2.78 (4H, br), 2.82-3.08 (3H, br), 3.08- 3.22 (4H, br), 7.23-7.34 (2H, m), 7.34-7.50 (8H, m),7.56 (1H, t, /=8.0 Hz), 7.65 (1H, t, /=8.0 Hz), 7.92 (1H, d, /=8.0 Hz), 8.05 (1H, d, /=8.0 Hz), 8.14 (1H, s), 8.93(1H, s). 1.78-1.96 (2H, m), 2.14-2.48 (7H, m), 2.48-2.60 (2H, m), 2.63-2.76 (2H, m), 2.84-3.08 (3H, br), 2.32-3.50 (4H, m), 6.56-6.68 (3H, m), 7.10-7.22 (2H, m), 7.22-7.46 (10H, m). 2.08- 2.46 (5H, m),~2.60-2.80 (4H, m),2.90-3. 10 (3H, br),3.10-3.62 (8H, m), 7.13 (1H, d, /=7.4 Hz), 7.16-7.52 (13H, m), 7.56 (1H, d, /=8.0 Hz), 7.74-7.86 (1H, m), 8.08-8.18 (1H, m)._ 1.94-2.40 (7H, m), 2.48-2.70 (2H, m), 2.80-3.12 (7H, m), 3.30-3.90 (4H, m), 7.00-7.56 (15H, m), 7.56-7.76 (2H, m). 2.10- 2.40 (5H, m), 2.40-2.66 (4H, m), 2.70-3.14 (7H, m)," 3.48 (2H? t, /=6.2 Hz), 3.56-3.84 (2H, m), 6.70 (2H, d, /=8.8 Hz), 7.20-7.43 (13H, m), 7.46 (2H, d, /=8.8 Hz), 7.53 (2H, d, /=8.8 Hz). 本紙張尺度適用中國國家標準(CMS) A4規格（210 x 297公釐） -35- 579375 A7 B7 五、發明説明（31 ) 表7 化合物 編號 質量 (E[:M〇 Ή-NMR δ : ppm(CHCl3) 20 529 1.95-2.17 (2H, br), 2.19-2.60 (7H, m), 2.64-3.10 (7H, m),3.49 (2H, t, /=6.3 Hz), 3.54-3.70 (2H, br), 3.80 (2H, s), 6.65 (1H, dd, /=10.5, 2.2 Hz), 6.82 (1H, d, >2.2 Hz), 7.15 (1H, t, /=8.2 Hz), 7.21-7.49 (12H, m), 7.57 (1H, d, /=8.2 Hz), 7.60 (1H, d, 7=8.2 Hz). 21 448 1.76-1.92 (2H, m), 2.08-2.46 (7H, m), 2.48-2.63 (2H, m), 2.63-2.74 (2H, in), 2.84-3.04 (3H, br), 3.40-3.64 (4H, m),6.41 (1H, d, /=4.1 Hz), 7.13 (1H, d, /=4.1 Hz), 7.23-7.32 (2H, in), 7.32-7.43 (8H, m). 22 442 1.78-1.91 (2H, m), 2.14-2.48 (7H, di), 2.48-2.60 (2H, in), 2.60-2.72 (2H, m), 2.82-3.10 (3H, br), 3.49-3.59 (2H, m), 3.59-3.68 (2H, m), 6.40 (1H, d, /=8.8 Hz), 6.43-6.50 (1H, m), 7.18-7.44 (11H, ni), 8.05-8.12 (1H, m), 23 443 1.72-1.91 (2H, in), 2.16-2.46 (7H, m), 2.48-2.58 (2H, in), 2.60-2.70 (2H, m), 2.84-3.06 (3H, br), 3.62-3.80 (4H, m),6.40 (1H, t, /=4.7 Hz), 7.22-7.30 (2H, m), 7.30-7.44 (8H, m), 8.25 (2H, d, /=4.7 Hz). 24 443 1.80-2.00 (2H, br), 2.14-2.54 (7H, m), 2.54-2.68 (2H, br), 2.70-2.83 (2H, br), 2.88-3.10 (3H, br), 3.34-3.56 (4H, m), 7.20-7.44 (10H, m), 8.10 (2H, d, /=2.4 Hz), 8.51 (1H, d, /=2.4 Hz). 25 492 ί. 82-2.00 (2H, br), 2.15-2.37 (5H, m), 2.37-2.48 (2H, m), 2.48-2.64 (2H, br), 2. 64-2.84 (2H, br), 2.84-3.05 (3H, br), 3.74 (2H, t, /=6.3 Hz), 3.76-3.88 (2H, br), 6.79 (1H, d, /=9.2 Hz), 7.10-7.19 (1H, m), 7.19-7.29 (2H, in), 7.29-7.43 (8H, m)，7.43-7.52 (1H，m)，7.54 (1H，d，/=8· 0 Hz), 7.62 (1H, d, /=8.0 Hz), 7.80 (1H, d, /=9.2 Hz). 26 492 1.86-2.02 (2H, m), 2.10-2.50 (7H, in), 2.50-2. 68 (2H, m), 2.70-3.20 (5H, m), 3.46-3.66 (4H, m), 7.02 (1H, d, /=2.5 Hz), 7.18-7.50 (12H, m), 7.50-7.62 (1H, m), 7.86-7.96 (1H, m), 8.58 (1H, d, /=2.5 Hz). 27 492 1.84-2.01 (2H, ni), 2.20-2.44 (5H, m), 2.44-2.56 (2H, m), 2.72-2.91 (4H, m), 2.91-3.14 (3H, br), 3.35 (4H, t, /=5.9 Hz), 7.20-7.33 (2H, m), 7.33-7.50 (8H, m), 7.52-7.59 (1H, m), 7.60-7.68 (1H, m), 7.91 (1H, d, /=7.5 Hz), 8.08 (1H, d, /=7.5 Hz), 8. 18 (1H, s), 8.88 (1H, s). -36- 本紙張尺度適用中國國家標準(CNS) A4規格（210X 297公I) 579375 A7 B7 五、發明説明（32 ) 表8 化合物 質量 編號 （FAB:(M+fT) 28 442 29 442 30 442 31 446 32 446 33 462 34 462 35 462 36 444 Ή-NMR δ : ppm(CHCl3) 2.10-2.Γ8"(2Η, in), 2.23 (3H, s), 2.26-2.40 (3H, br), 2.43-2.58 (6H, oi), 2.85 (4H, t, /=4.6 Hz), 2.91-3.05 (3H,br), 6.90-5.99 (2H, m), 7.07-7.15 (2H, m), 7.24-7.30 (2H, m), 7.33-7.46 (8H, m)._ 2.07- 2.16 (2H, m), 2. 23-2.40 (3H, br), 2.28(3H, s), 2.42- 2.55 (6H, ni), 2.88 -3.13 (7H, m), 6.60-6.71 (3H, m)y7.1Q(lH, t, /=7.8 Hz), 7.23-7.45 (10H, m)._ 2.08- 2.16 (2H, in), 2.23 (3H, s), 2.26-2.38 (3H, br), 2.43- 2.55 (6H, m), 2.90-3.10 (7H,m), 6.78 (2 H, d, /=8.8 Hz), 7.02 (2H, d, /=8.8 Hz), 7.23-7.29 (2H，m)，7. 32-7.46 (8H，m)._ 2.ί〇-2·ί8 (2H，m), 2.28-2.39 (3H, br), 2.43-2.58 (6H, m), 2.92-3.07 (7H，〇!)， 7.24-7.31 (2H, in), 7.34-7.45 (8H, in). 2.08-2.17 (2H, m), 2.28-2. 39 (3H, br), 2.42-2.57 (6H, m), 2.90-3.10 (7H, in), 6.78-6.85 (2H, m), 6.87-6.96 (2H, m), 7.24-7.31 (2H, m), 7.33-7.46 (8H, m)._ 2.10-2.19 (2H, m), 2.26-2.40 (3H, br), 2.45-2.61 (6H, in), 2.88-3.07 (4H, m), 6.91 (1H, t, /=8.0 Hz), 6.99(1H, d, /=8.0 Hz), 7.17 (1H, t, /=8.0 Hz), 7.23-7.46 (1 1H, m). 2.06-2.16 (2H, m), 2.24-2.39 (3H, br), 2.41-2.52 (6H, m), 2.88- 3.02 (3H, br), 3.05-3.12 (4H, m), 6.70(1H, d, /=8.5 Hz), 6.73 (1H, d, 1=8.5 Hz), 6.79 (1H, s), 7.10 (1H, t, /=8.5 Hz), 7.23-7.30 (2H, m), 7.32-7.46 (8H, m). 2.07-2.16 (2H, m), 2.23-2.40 (3H, br), 2.41-2.54 (6H, m), 2.88- 3.10 (7H, m), 6.76 (4H, d, /=9.0 Hz), 7.13 (4H, d, /=9.0 Hz), 7.22-7.30 (2H, m), 7.31-7.45 (8H, m). 2.09-2.17 (2H, m), 2.27-2.39 (3H, br), 2.43-2. 58 (6H, m), 2.81 (4H, t, /=4.4 Hz), 2.93-3.05 (3H, br), 6.81 (1H, dt, /=7.8, 1.2 Hz), 6.89 (1H, dd, /=7.8, 1.2 Hz), 7.02 (1H, dt, /=7.8, 1.2 Hz), 7.11 (1H, dd, /=7.8, 1.2 Hz), 7.25-7.32 (2H, m), 7. 34-7. 46 (8H, m). 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） -37- 579375 A7 B7 五、發明説明（33 ) 表9 化合物 編號 !質量 (FAB: (M+H)0 Ή-NMR δ : ppm(CHCl3) 37 444 2.09-2.18 (2H, m), 2.27-2.37 (3H, br), 2.43-2.54 (6H, m), 2.91-3.06 (7H, m), 6.17-6.25 (2H, in), 6.34 (1H, d, /=8.0 Hz), 6.97 (1H, t, /=8.0 Hz), 7.21-7.43 (10H，m)· 38 444 2.08-2.17 (2H, m), 2.28-2.36 (3H, br), 2.45-2.56 (6H, m), 2.93-3.02 (7H, br), 6.72 (4H, dd, /=9.3, 4.9 Hz), 7.24-7.30 (2H, m), 7.33-7.42 (8H, in). 39 458 2.10-2.19 (2H, m), 2.27-2.39 (3H, br), 2.44-2.60 (6H, in), 2.90-3.09 (7H, m), 3.80 (3H, s), 6.81 (1H, d, /=8.3 Hz), 6.84-6.90 (2H, in), 6.91-6.98 (1H, m), 7.22-7.30 (2H, m), 7.32-7.45 (8H, m). 40 458 2.08-2.14 (2H, in), 2.28-2.37 (3H, br), 2.43-2.52 (6H, m), 2.93-3. 02 (3H, br), 3.10 (4H, t, /=4.9 Hz), 3.76 (3H, s), 6.37 (1H, dd, /=7.8, 2.0 Hz), 6.40 (1H, t, /=2.0 Hz), 6.47 (1H, dd, /=7.8, 2.0 Hz), 7.12 (1H, t, /=7.8 Hz), 7.24-7.30 (2H, m), 7.33-7.45 (8H, in). 41 458 2.08-2.15 (2H, m), 2.28-2.38 (3H, br), 2.43-2.55 (6H, m), 2.93-3.04 (7H, in), 3.74 (3H, s), 6.80 (2H, d, /=2.4 Hz), 6.84 (2H, d, /=2.4 Hz), 7.24-7.30 (2H, in), 7.33-7.45 (8H, m). 42 530 2.05 (3H, s), 2.10-2.18 (2H, m), 2.27-2.40 (3H, br), 2.43-2.58 (6H, m), 2.88-3.10 (7H, m), 4.17 (2H, t, /=4.8 Hz), 4.40 (3H, t, /=4.8 Hz), 6.78-6.95 (4H, m), 7.24-7.30 (2H, m), 7.33-7.46 (8H, m). 43 488 2.06-2.16 (2H, m), 2.23-2.40 (3H, br), 2.41-2.61 (6H, m), 2.88-3.10 (7H, m), 3.54-3.63 (2H, m), 4.13 (2H, t, /=4.6 Hz), 4.77-4.90 (1H, m), 6.93-7.04 (4H, m), 7.22-7.30 (2H, m), 7.32-7.45 (8H, m). 44 530 1.28 (3H, t, /=7.3 Hz), 2.08-2.18 (2H, m), 2.24-2.40 (3H, br), 2.42-2.60 (6H, m), 2.87-3.13 (7H, m),4.23 (2H, q, /=7.3 Hz), 4.63 (2H, s), 6.75-6.80 (1H, m), 6.87-6.97 (3H,m), 7.23-7.30 (2H, m), 7.32-7.45 (8H, m). 45 502 2.29 (3H, s), 2.52-2.71 (4H, m), 2.90-3.19 (7H, m), 3.21- 3.38 (4H, m), 4.53 (2H, s), 6.80-6.99 (4H, m), 7.22- 7.44 (10H, m). -38- 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） 579375 A7 B7 五、發明説明（34 ) 表1 0 化合物 編號 質量 (FAB: vM+H)f) 46 454 47 470 48 556 49 514 556 51 528 !H-NMR (5 : ppm(CHCl3) 1.52 (2H, dt, /=6.5, 6.5 Hz), 1.66 (2H, dt, /=6.5, 6.5 Hz), 2.14-2.22 (2H, m), 2.42- 2.58 (8H, m), 3.12 (4H, t, /=5.1 Hz), 3.59 (2H, t, /=6.5 Hz), 3.59 (2H, t, /=6.5 Hz), 6.80 (1H, t, /=7.6 Hz), 6.86 (2H, d, /=7.6 Hz), 7.17-7.42 (12H, m)._ 1.53 (2H, dt, /=6.5, 6.5 Hz), 1.67 (2H, dt, /=6.5, 6.5 Hz), 2.15-2.22 (2H, in), 2.42- 2.62 (8H, m), 2.82 (4H, t, /=4.9 Hz), 3.54-3.63 (2H, m), 6.82 (1H, dt, /=7.8, 1.5 Hz), 6.90(1H, dd, /=7.8, 1.5 Hz), 7.03(2H, dt, /=7.8, 1.5 Hz),7.12(lH, dd, /=7.8, 1.5 Hz), 7.24-7.42 (10H, m). 1.52 (2H, dt, /=6.5, 6.5 Hz), 1.67 (2H, dt, /=6.5, 6.5 Hz), 2.05 (3H, s), 2.15-2.24 (2H, m), 2.43-2.61 (8H, m), 2.95-3.11 (4H, m), 3.59 (2H, t, /=6.5 Hz), 4.14-4.21 (2H, m), 4.37-4.44 (2H, m), 6.79-6.83 (1H, m), 6.87-6.96 (3H,m), 7.23- 7.42 (10H, m)._ 1.52 (2H, dt, 7=6.8, 6.8 Hz), 1.67 (2H, dt, /=6.8, 6.8 Hz), 2.13-2.25 (2H, m), 2.40-2.69 (8H, m), 2.93-3.13 (4H, m), 3.54-3.65 (4H, m), 6.92-7. 04 (4H, m,), 7.22-7.42 (10H, m)._ 1.28 (3H, t, /=6.8 Hz), 1.52 (2H, di, /=6.5, 6.5 Hz), 1.67 (2H, dt, /=6.5, 6.5 Hz), 2.16-2.26 (2H, in), 2.43- 2.63 (8H, m), 2.96-3.14 (4H, m), 3.59 (2H, t, /=6.5 Hz), 4.23 (2H, q, /=6.8 Hz), 4.63 (2H, s), 6.76-6.80 (1H, m), 6.87-7.00 (3H,m), 7.23- 7.43 (10H，m)._ 1.53 (2H, dt, /=6.8, 6.8 Hz), 1.68 (2H, dt, /=6.8, 6.8 Hz), 2.40 (2H, t, /=6.8 Hz), 2.53-2.70 (4H, m), 2.84-3.33 (8H, m), 裝
52 558 3.57 (2H, t, /=6.8 Hz), 4.50 (2H, s), 6.73-6.87 (4H, m)y 7.20-7.44 (10H, m)._ 1.23 (3H, tV J=7.0Hz), 1.53 (6H, s), 2.05-2.16 (2H, m), 2.24-2.42 (3H, br), 2.43-2.62 (6H,m), 2.86-3.15 (7H, m), 4.21 (2H, q, J=7.0Hz), 6.77-6.84 (2H,m), 6.86 (1H, dd, J=7.8, 1.5Hz), 6.90-6.96 (1H, m), 7.24-7.32 (2H, m), 53 530 7.32-7.46(8H，m)._ 1.2卜 1.40 (lH，m)，1.48 (3H，m)，1.56-1.73 (1H，m)，1.89 (3H, s), 2.02-2.20 (2H, m), 2.29 (3H, s), 2.38-2.51 (1H, m), 2.51-2.72(2H, m), 2.72-2.90 (1H, in), 2.90-3.22 (2H, m), 2.99 (3H, s), 3.32-3.48 (1H, m), 3.52-3.72 (1H, m), 6.21 (1H, i, J=7.8Hz), 6.32 (1H, t, J = 7.8Hz), 6.57 (1H, t, J = 7.8Hz), 6.93-7. 10 (2H, m), 7. 10-7.70 (9H, m), 7.90-8.70 (1H, br). 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） -39- 579375 A7 _ B7 五、發明説明（35 ) 參考例6 將4 -溴-2,2-二苯基酪酸23克（72毫莫耳）懸浮於CHC13 150¾升’於室溫滴下亞硫醯氯20毫升（270毫莫耳）。再加 一甲基甲醯胺（DMF) 0·2毫升，加熱迴流4小時。反應後， 減壓濃縮溶媒，得4-溴-2,2-二苯基酪醯氯23克（產率 94.7%)。 將5 0 %二甲胺水溶液8克（9 0毫莫耳）、Na2C03 1 8克 (170毫莫耳）懸浮於水1〇〇毫升中，於〇〜5 冷卻。於此滴 下溶於甲苯100毫升之上述4 -溴-2,2-二苯基酪醯氯23克 (6 8毫莫耳）。再攪摔2小時後，取水層以甲苯洗。接著， 以CHCh洗水層，水洗、乾燥。減壓濃縮溶媒，所得殘留 物以甲基異丁基酮使結晶，得二甲基（四氫_3,3·二苯基_2-亞呋喃基）銨化溴1 1克（產率46.8%)。 lH-NMR (CDCb) δ (ppm): 2·96 (3H，s)，3·47 (2H，t，J=6.4 Ηζ)，3·83 (3H，s)，4.85 (2H，t， J=6.4 Hz)，7.40-7.60 (10H，m) 〇 用吡咯啶代替於參考例6之5 0 %二甲胺永溶液，得（四 氫-3,3-二苯基-2-亞呋喃基）吡咯錠化溴（產率53.6%)。 lH-NMR (CDCI3) δ (ppm): 1.96 (2H, quintet, J=6.4 Hz), 2.13 (2H, quintet, J=7.4 Hz), 2.89 (2H, t, J = 6.8 Hz), 3.50 (2H, t, J=6.4 Hz), 4.37 (2H, t, J=7.3 Hz), 4.87 (2H, t, J=6.4 Hz), 7.40-7.55 (10H, m) 參考例7 於無水四氫呋喃2毫升中加Mg粉末240毫克（10毫莫耳） -40- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公發) 579375 A7 B7
五、發明説明（36 ) ，接著將2 -甲氧溴苯丨9克（1〇 7毫莫耳）溶於無水四氫呋喃 ㈧毫升，^此之中加1/5之量。另外，加1，2_二溴乙烷〇」 宅升及少量12，於4 (TC加熱。反應開始，滴下剩下之2 _甲 氧〉臭苯之典水四氫呋喃溶液，再加熱迴流3 0分。
於所得之格利雅試劑之無水四氫呋喃溶液中，室溫下滴 下滴於30¾升無水四氫呋喃之丨89克（1〇毫莫耳）之I·苄基_ 4-哌啶酮。接著加熱迴流3〇分鐘後，滴下飽和氣化銨水^容 液1 0毫升，減壓濃縮溶媒。所得殘留物中加水，以乙趟抽 提、水洗、乾燥。減壓濃縮溶媒，所得殘留物以矽膠層析 法純化，得U爷基-4_(2-甲氧苯基）-4•哌啶醇184克（產率 61.8%)。 裝 !H-NMR (CDCI3) δ (ppm): 1.50- 1.90 (2H，m)，2.52 (2H，dt，JN12.8 Ηζ，4·8 Hz)，2.80-3.25 (3H，m)，3.25·3·50 (2H，m)，3·87 (3H，s)，6.91 (1H，dd，
Hz)，7·03 (1H，s)，7.10-7.40 (1H，m)，7.40-7.60 (1H，m) 參考例8 將1-芊基-4-(2-甲氧苯基）-4-旅咬醇2.08克（7.0毫莫耳）溶 於二噚烷1 0毫升，加6N HC1 2 0毫升，加熱迴流3小時。 反應後，以IN NaOH水溶液使成pH 9後，以乙酸乙酯抽提 、水洗、乾燥。減壓濃縮溶媒，所得殘留物以矽膠層析法 純化’ 1 -苄基-4-(2 -甲氧苯基）-1，2,3，6-四氫吡啶1.5〇克（產率 77.0%) ° •H-NMR (CDCI3) δ (ppm): 2.50- 2.58 (2H, m), 2.67 (2H, t, J=5.9 Hz), 3.15-3.19 (2H, m) -41 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 x 297公釐） 579375 A7 B7 五、發明説明（37 ) 3.65 (2H, s), 3.80 (3H, s), 5.75-5.78 ( 1H, m), 6.85 (1H? d, J = 8.3 Hz), 6.89 (1H, dt, J=8.3 Hz, 1.0 Hz), 7.15-7.42 (7H, m) 參考例9 將1-卞基-4-(2 -甲氧冬基）-1,2,3，6 -四氣p比淀1.5克（5.4毫莫 耳）溶於乙醇3 0毫升，加10% pd/C 0.6克，於室溫1大氣壓 下接觸還原6小時。反應後，濾除觸媒，減壓濃縮濾液， 得4-(2-甲氧苯基）哌啶0.88克（產率855.7%)。 ^-NMR (CDCh) 5 (ppm): 1·95-2·05 (2H，m)，2.10-2.23 (2H，m)，3.04 (2H，t，J=10.2 Hz)， 3.15-3.25 (1H，m)，3·60,3.68 (2H，m)，3.84 (3H，s)，6.87 (1H， d, J = 8.3 Hz), 6.94 (1H, t, J=6.4 Hz), 7.17-7.25 (2H, m) 參考例1 0 將4-(2-甲氧苯基）哌啶530毫克（2.3毫莫耳）加於48% HBr 1 0毫升中，於1 4 0 °C加熱攪拌1 7小時。冷卻後，將3N NaOH水溶液加於反應混合液中，使成pH 9後，以CHCh抽 提、以無水MgS04乾燥。減壓濃縮後，得殘留物為4-(2-羥 苯基）哌啶之粉末2 8 0毫克（68.0%)。 lH-NMR (CDCh) δ (ppm): 1.70-1.93 (4H, m). 2.70-2.90 (2H, m), 2.95-3.10 (1H, m), 3.10-3.32 (2H, m), 4.00-5.20 (2H, br), 6.70 (1H, dd, J=7.7 Hz, 1.4 Hz), 6.84 (1H, dt, J=7.7 Hz, 1.4 Hz), 7.04 (1H, dt, J=7.7 Hz, 1.4 Hz), 7.14 (1H, dd, J=7.7 Hz, 1.4 Hz) 參考例1 1 將二甲基（四氫-3，3-二苯基-2-亞呋喃基）銨化溴3.5克（1 0 -42- 本紙張又度適用中國國家標準(CNS) A4規格（210X 297公釐） 579375 A7 _______B7 五、發明説明（38 ) 耄莫耳）及4-(2-羥苯基）-4-哌啶醇ι·93克（10毫莫耳），於3.2 克NafOa (30毫莫耳）存在下溶於無水二甲基甲醯胺2〇毫 升中，於100 C攪拌3小時。反應液加水，以乙酸乙酯抽提 水’先、乾燥。減壓;農縮落媒，所得殘留物以碎膠層析法 純化，得4-[4-(2-羥苯基）-4-羥基哌啶-1-基]·2,2_二苯基-Ν，Ν-二甲基丁醯胺3.6克（產率78.6%)。 參考例1 2 將（四氫- 3,3-—苯基-2 -亞啥喃基）π比洛錠化溴ι〇·75克（2 9 毫莫耳）及4-(2-#至苯基）-4·喊咬醇6·20克（32毫莫耳），於 Na2C03 8.5克（80¾莫耳）存在下，溶於無水二甲基甲酿胺 2 0 0毫升中’於1 〇 〇 C t覺拌3小時。反應液加水，以乙酸乙 酯抽提，水洗、乾燥。減壓濃縮溶媒，所得殘留物以矽膠 層析法純化，得4-[4-(2-羥苯基）-4-羥基哌啶-1-基]-2,2-二 苯基-1-(1-吡咯啶基）-2-丁酮13.9克（產率99.0%)。 實施例5 4 將二甲基（四氫-3,3-二苯基-2-亞呋喃基）銨化溴5 00毫克 (1·4毫莫耳）及4-(2-甲氧苯基）哌啶300毫克（1.6毫莫耳）溶於 無水二甲基甲醯胺2〇毫升，加NazCO3 500毫克（5毫莫耳）， 於100°C檟:拌3小時。反應液加水，以乙酸乙酯抽提、水洗 、乾燥。減壓濃縮落媒’所彳于殘留物以碎膠層析法純化， 得4-[4-(2-甲氧苯基）哌啶-1-基]-N，N-二甲基-2,2-二苯基丁 醯胺（化合物編號5 4) 440毫克（產率66.9%)。 實施例5 5〜6 4 與實施例1同樣地進行反應，得化合物編號5 5〜6 4。 -43- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 579375 A7 B7
實施例6 5 將4-[4-(2-羥苯基）哌啶-1 -基]-N,N-二甲基·2,2•二苯爲 醯胺（化合物編號5 7 ) 580毫克（1.3毫莫耳）溶於無水二〇爲 甲醯胺12毫升，加K0H (粉末）1〇〇毫克，。噃 土 乙酯180毫克（1.5毫莫耳），於室溫攪拌12小時。反應液加 水，以乙酸乙酯抽提、水洗、乾燥。減壓餾除溶媒，所得 殘留物以矽膠層析法純化。得[2-[1-[；4-(二甲胺基）-3弘―^ 基-4-酮丁基]哌哫-4 -基]苯氧基]乙酸乙酯（化合物編號 6 5 ) 395 毫克（產率 57.0%)。 ' 實施例6 6 將4-[4-(2-經苯基）喊淀-1 -基]_n，N-二甲基-2,2-二苯基丁 醯胺（化合物編號5 7) 1500毫克（3.4毫莫耳）溶於無水二甲 基甲醯胺20毫升，加乙酸2 -溴乙酸600毫克（3.6亳莫耳）' K2C03 600毫克（4.5毫莫耳）、KI少量，於室溫下攪拌1 2小 時。反應液加水，以乙酸乙酯抽提、水洗、乾燥。減壓館 除溶媒’所得殘留物以矽膠層析法純化。得乙酸 [4-(二甲胺基）-3,3-二苯基-4-酮丁基]喊淀-4-基]苯氧基]乙 酯（化合物編號6 6 ) 390毫克（產率21,6%)。 實施例6 7、6 8 與實施例6 6同樣地進行反應，得化合物編號6 7及6 8。 實施例6 9 將乙酸2-[2-[1-[4-(二甲胺基）-3,3-二苯基-4-酮丁基]哌 啶-4-基]苯氧基]乙酯（化合物編號66) 360毫克（0.68毫莫 耳）溶於甲醇5毫升，加IN NaOH水溶液1毫升，於50 °C攪 -44 -本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 579375 A7 ____ B7 五、發明説明（40 ) 拌1小時。反應液加水，以CHC13抽提、水洗、乾燥。減壓 餾除溶媒，所得殘留物以矽膠層析法純化。得心[4-[2兴2-羥乙氧基）苯基]哌啶-1 -基]-N，N-二甲基j，2-二苯丁醯胺（ 化合物6 9 ) 203毫克（產率61.3%)。 實施例7 0、7 1 與實施例6 9同樣地進行反應，得化合物編號7 〇及7 1。 實施例7 2 將2-[1-[4-(二甲胺基）-3,3-二苯基-4-酮丁基]哌啶-4-基] 苯氧基]乙酸乙酯（化合物編號6 5 ) 360毫克（0.7毫莫耳）溶 於甲醇5毫升，加IN NaOH水溶液5毫升，於50°C攪拌1小 時。反應後，反應液加水，以IN HC1使成pH 4-5後，以 CHCh抽提、水洗、乾燥。減壓餾除溶媒，所得殘留物以 矽膠層析法純化，得2-[1-[4-(二甲胺基）-3,3-二苯基-4-酮 丁基]哌啶-4-基]苯氧基]乙酸（化合物編號72) 32〇毫克（產 率 94.0%) 〇 實施例7 3 將4-[4-(2-¾私基）-4-經基喊咬-1-基]-2,2-二苯基-N，N-二 甲基丁醞胺1.40克（3.1毫莫耳）溶於二σ号燒7毫升與6N HC1 14毫升之合）谷媒’加.熱迴流3小時。反應後，以1 ν NaOH水溶液使成pH 1 1，以乙酸乙酯抽提、水洗、乾燥。 減壓濃縮溶媒’所得殘留物以矽膠層析法純化，得4-[4<2-羥苯基）-1,2,3,6-四氫吡啶-1-基]-队>^二甲基_2,2-二苯丁驢 胺（化合物編號7 3 ) 1.24毫克（產率92.3%)。 實施例7 4 -45- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 579375 A7 B7 五、發明説明（41 ) 使用4-(4-(2-羥苯基）-1，2,3,6-四氫吡啶-卜基）-N，N-二甲 基-2,2-二苯丁醯胺（化合物物編號73) ’進行與實施例65同 樣的反應，得[2-[1-[4-(二甲胺基）-3,3-二苯基-4-酮丁基卜 1，2,3,6-四氫吡啶-4-基]苯氧基]乙酸乙酯（化合物編號74)。 實施例7 5 使用化合物編號7 3，進行與實施例6 6同樣的反應’無 須分離繼續與實施例69同樣的反應’得4-[4-[2-(2-技乙氧 基）苯基]-1，2,3,6-四氫吡啶-1 -基]-Ν，Ν-二甲基-2,2-二苯丁 醯胺（化合物編號7 5 )。 實施例7 6 使用[2-[1-[4-(二甲胺基）-3,3-二苯基-4-酮 丁基]-1，2,3,6-四氫吡啶-4-基]苯氧基]乙酸乙酯（化合物編號74) ’與實 施例72同樣地，進行反應，得(二甲胺基）-3,3-二 苯基-4-酮丁基]-1，2,3,6-四氫吡啶-4-基]苯氧基]乙酸（化 合物編號7 6 ) 實施例7 7 將4-[4-(2-經苯基）-4-羥基哌啶-1 ·基>2,2-二苯基-1-(1-吡 咯啶基）-1- 丁酮4.20克（8.7毫莫耳）溶於二哼烷2 〇毫升與6N HC1 4 0毫升之混合溶媒，加熱迴流3小時。反應後’以1N NaOH水溶液使成pH 1 1 ’以乙酸乙醋抽提、水洗、乾燥。 減壓濃縮溶媒，所得殘留物以矽膠層析法純化’得4β[4-(2-經苯基）-1，2,3,6 -四氫比淀--基] )-卜丁酮（化合物編號7 7 ) 3.45克（產率85.3%)。 實施例7 8 -46- 本紙張尺度適用中國國家標準(CNS) A4規格（21〇 x 297公梦） 裝 訂
k 579375 A7 B7 五、發明説明（42 將4-[4-(2-羥苯基）-1，2,3,6-四氫吡啶-1 -基l·2,2-二苯基 (1-吡咯啶基）-1-丁酮（化合物編號7 7 ) 2.50克（5.36毫莫耳） 溶於乙醇8 0毫升，加10% pd/C 0.80克，於室溫1大氣壓H2 大氣接觸下還原1 2小時。反應後濾除觸媒，減壓濃縮液’ 得4-[4-(2-羥苯基）哌啶-1 -基]-2,2-二苯基-1-(1-吡咯淀基 1-丁酮（化合物編號7 8 ) 1.45克（產率60.3%)。 實施例7 9 使用4-[4-(2-羥苯基）哌啶-1 -基]-2,2-二苯基-1-(1-吡咯咬 基）· 1 - 丁酮（化合物編號7 8 )，進行與實施例6 5同樣的反應 ，得[2-[1-(4-(1-吡咯啶基）-3,3-二苯基-4-酮丁基]哌啶- 4-基]苯氧基]乙酸乙酯（化合物79)。 實施例8 0 使用4-[4-(2-羥苯基）哌啶-1-基]-2,2-二苯基-1-(1-吡咯啶 基）-1-丁酮（化合物編號78)，與實施例65同樣進行反應， 得乙酸2-[2-[1-[3,3-二苯基-4-酮基-4-(1-吡咯啶基）丁基]哌 啶-4·基]苯氧基]乙酸乙酯（化合物80)。 實施例8 1 用乙酸2-[2-[1-[3,3-二苯基-4-酮基-4-(1-吡咯啶基）丁基] 哌啶-4 -基]苯氧基]乙酯，與實施例6 9同樣地進行反應， 得4-[4-[2-(2-羥乙氧基）苯基]哌啶-1 -基]-2,2-二苯基 吡咯啶基）-U 丁酮（化合物編號8 1 )。 實施例8 2 用[2-[1-[4-(1-ρ比洛淀基）-3,3 -二苯基-4-綱丁基]喊唉 基]笨氧基]乙酸乙酯（化合物7 9 )，與實施例7 2同樣進行反
裝 訂
k -47-
579375
AT B7 五、發明説明（43 ) 應’得[2-[ 1-[4-( 1-批洛淀基）- 3,3-二苯基_ 4 -酮丁基]喊咬· 4 -基]苯氧基]乙酸（化合物編號82)。 實施例8 3 將4-[4-(2-經苯基）峰啶-1 -基]-N，N-二甲基-2,2-二苯丁醯 胺（化合物編號5 7 ) 400毫克（0.90 5毫莫耳），α_溴異酶酸乙 酯2.00克（10.3毫莫耳）、無水K2C03 700毫克（5.06毫莫耳）加 於無水二甲基甲醯胺1 0毫升中，於外溫5 〇 °c攪拌1 5小時 。反應終了後，以無水NaaSCn乾燥。接著使用矽膠6〇克將 減壓館除乙乙S旨後之殘留油狀物進行層析，減壓館3%
MeOH/CHCl3溶離份，得目的物2-[2-[1-[4-(二甲胺基）-3,3-二苯基-4-酮丁基]哌啶-4-基]苯氧基卜2-甲基丙酸乙酯（化 合物編號8 3 )之淡黃色油狀物1 8 1毫克（產率36.0%)。 實施例8 4 將2·[2-[1-[4-(二甲胺基）-3,3-二苯基-4-酮丁基]喊咬- 4-基]苯氧基]-2-甲基丙酸乙酯（化合物編號8 3 ) 240毫克 (0.432毫莫耳）溶於IN NaOH水溶液5毫升、甲醇5毫升及 1,4-二哼烷5毫升之混合溶媒，於室溫攪拌5小時。反應終 了後，反應混合液加水，以稀鹽酸中和（pH 7)，以CHCI3抽 提。接著以無水NaJO4乾燥，減壓餾除CHC13，以乙醚粉 碎析出之結晶，得目的物2-〇[1-[4-(二甲胺基）-3,3-二苯 基-4-酮丁基]哌啶-4 -基]苯氧基]-2-甲基丙酸（化合物編號 84)之無色結晶1 69毫克（產率74.1%)。 將化合物編號5 4 - 8 4之產率，性狀及融點示於表丨1〜1 4 ，而NMR數據示於表15〜17。 -48- 本紙悵尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 579375 A7 B7 五 、發明説明(
化合物編號 R3 產率(％) 性狀 融點°C(分解) 54 2-OCHs 66.9 淡黃色油狀物 55 3-OCHs 79.1 淡黃色油狀物 56 4-OCH3 58.5 淡燈色油狀物 57 2-OH 74.6 淡黃色油狀物 58 3-OH 57.0 無色結晶 110 59 4-OH 73.6 淡黃色結晶 104 60 2-CH3 56.2 淡黃色油狀物 61 3-CHb 67.2 淡黃色油狀物 62 4-CHs 61.2 淡橙色油狀物 63 3-F 40.0 淡黃色油狀物 64 4-F 46.2 淡燈色油狀物 65 2-OCH2CO2C2H5 57.0 淡黃色油狀物 66 2-0(CH2)2〇COCH3 21.6 淡黃色油狀物 67 3-0(CH2)2〇COCH3 70.3 淡黃色油狀物 68 4-〇(CH2)2〇COCH3 54.4 淡橙色油狀物 69 2-0(CH2)20H 61.3 無色不定型晶 70 3-0(CH2)20H 77.5 淡黃色油狀物 71 4-0(CH2)20H 69.7 淡燈色油狀物 72 2-OCH2CO2H 94.0 無色結晶 202 83 2-OC(CH3)2COOEt 36.0 淡黃色油狀物 84 2-OC(CH3)2COOH 74.1 無色結晶 156-158 -49- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）
579375 A7 B7 五、發明説明（45 ) 表1 2
化合物編號 R3 產率(％) 性狀 融點°C(分解) 73 2-OH 92.3 淡黃色油狀物 74 2-OCH2CO2C2H5 60.0 無色結晶 147 75 2-0(CH2)20H 98.5 淡黃色油狀物 76 2-OCH2CO2H 89.1 無色結晶 135 表1 3
化合物編號 R3 產率(％) 性狀 融點°C(分解) 77 2-OH 85.33 淡黃色油狀物 -50- 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 579375 A7 B7 五、發明説明（46 )
化合物編號 R3 產率(％) 性狀 融點°C (分解) 78 2-OH 60.3 淡黃色油狀物 79 2-OCH2CO2C2H5 54.0 淡黃色油狀物 80 2-0(CH2)2〇COCH3 57.3 淡黃色油狀物 81 2-0(CH2)20H 72.2 淡黃色油狀物 82 2-OCH2CO2H 87.6 無色結晶 239 -51 - 本紙張尺度適用中國國家標準(CNS) A4規格（210X 297公釐） 579375 A7 B7 五、發明説明（47 ) 表1 5 化合物 編號 質量 (FAB: (M+H)1) Ή-NMR δ : ppm (CDC13) 54 457 1.58-i.80(4H, m), i. 94-2.20 (4H, m), 2.24-2.39 (3H, br), 2. 44-2.58 (2H, m), 2.80-3. 06 (6H, m), 3.78(3H, s), 6.78-6.92 (2H, m), 7. 12-7. 19(2H, m), 7. 24-7. 44 (10H, m). 55 457 1.63-1.80 (4H, m), 1.90-2. 05 (3H, br), 2. 08-2. 17 (2H, m), 24-2. 42 (4H, m), 2. 47-2.55 (2H, in), 2. 88-3. 08 (3H, m), 3.76(3H, s), 6.68-6. 74 (2H, m), 6.77(1H, d, J=7.8Hz), 7.i7(iH, t, 1=7.8Hz), 7.25-7. 45 (10H, m). 56 457 1.62-1.77 (4H, m), 1.77-1.93 (2H, m), 1. 93-2. 07 (2H, m), 2.07-2.20 (2H, in), 2. 25-2. 42 (3H, m), 2. 46-2.57(2H, m), 2.90-3.10(4H, m), 3.76(3H, s), 6.8K2H, d, J=8.8Hz), 7.10(2H, d, 1=8. 8Hz), 7.25-7. 30 (2H, m), 7. 34-7.45 (8H, m). 57 443 1.77-i.88(2H, m), 2. 06-2. 22 (2H, m), 2.3K3H, s), 2. 52-2. 79 (6H, in), 2.90-3.04(1H, m), 3.0K3H, s), 3.24-3. 37(2H, in), 6. 72-6· 78(1H, m), 6. 88-6. 97(2H, in), 7. 03-7. 08 (1H, m), 7.26-7. 43 (10H, m). 58 443 1.48-1. 69 (4H, m), 1. 84-1. 97(2H, m), 2. 02-2.16 (2H, m), 2.20-2. 38 (4H, m), 2. 42-2. 53 (2H, m), 2. 80-3. 08 (5H, m), 6. 52-6. 63 (3H, m), 7.05(1H, t, J=7.8Hz), 7.21-7. 40(10H, m). 59 443 1. 62-1. 73 (4H, m), 1.92-2. 07 (2H, m), 2. 08-2. 20 (2H, m), 2.20-2.38 (4Ht m), 2. 47-2.54(2H, in), 2. 87-3. 07(5H, in), 6.7K2H, d, J=8.8Hz), 6.98(2H, d, J=8.8Hz), 7.22-7.29 (2H, m), 7.31-7.43 (8H, m). 60 441 i.62-l.84(4H, m), 1. 97-2. 20(4H, m), 2.26-2. 42 (3H, br), 2.27(3H, s), 2. 46-2. 68 (3H, m), 2. 84-3. 09 (5H, m), 7.02-7.16(3H, in), 7.18-7.22(1H, m), 7.24-7. 46(10H, m). 61 441 1.57-1. 80 (4H, m), 1. 89-2.18(4H, m), 2. 26-2. 57 (5H, in), 2.74-3.08 (6H, m), 6. 81-6. 97(3H, m), 7. 17-7. 44(11H, fli). 62 441 1.50-1. 85 (8H, in), 1. 95-2. 47 (5H, m), 2.29(3H, s), 2. 48-2. 63 (2H, m), 2. 90-3.15 (4H, m), 7.08(4H, s), 7.20-7.30(2H, in), 7.30-7. 45 (8H, m). 63 445 1.63-1. 80 (4H, m), 1. 85-2.20 (4H, m), 2.24-2.58 (6H, m), 2.86-3.10(5H, m), 6.95-7.02 (3H, m), 7.15(1H, t, J=7.3Hz)> 7.24-7.45 O0H, m). 64 445 1·60-1.74(4Η，m)，i.74-1.90 (2H，m), i.90-2.06 (2H，m)， 2· 06-2· 18 (2H，m)，2.22—2.43 (3H，m) , 2.43-2.53 (2H，in)， 2.85-3.10(4H, m), 6.93(2H, t, J=8.8Hz), 7. 1K1H, d, J=8.8Hz), 7.13(1H, d, J=8.8Hz), 7.20-7.30 (2H, m), 7.30-7. 43 (8H, m). 65 529 1.27C3H, t, J=7.3Hz), 1. 64-1. 85 (4H, m), 2. 00-2.23 (4H, m), 2.27-2.42 (3H, br), 2. 46-2.60 (2H, m), 2. 86-3. 09 (6H, m), 4.23(2H, q, J = 7.3Hz), 4.59(2H, s), 6.680H. d, 1=7.8Hz), 6.930H, t, J = 7.3Hz), 7.10(1H, t, J=7.8Hz), 7.20(1H, d, J=7.3Hz). 7.23-7. 46(10H, m). -52- 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公f) 579375 A7 B7 五、發明説明（48 ) 表1 6 66 529 1.55-1. 85 (5H，m)，1.90-2.20(3H, m)，2. 06(3H，s)， 2.25-2.40 (3H, s), 2. 45-2. 60 (2H, m), 2. 80-3. 10(6H, m), 4. 13(2H, t, J=4.9Hz), 4.4K2H, t, J=4.9Hz), 6.79(1H, t, J=7.8Hz), 6.92(1H, t, J=7.3Hz), 7. 13(1H, dt, J=7.8Hz, 1.5Hz), 7. 18(1H, d, J=6.4Hz), T.25-7.30 (2H, m), 7.30-7. 45 (8H, in). 67 529 1.64-1.80 (4H, m), 1. 94-2.17(5H, m), 2.08(3H, br), 2.23-2.55 (6H, m), 2. 84-3. 09 (4H, □), 4.13(2H, t, J=4.8Hz), 4.39(2H, t, J=4.8Hz), 6.69-6. 82 (3H, m), 7. 17(1H, t, J=7.8Hz), 7.23-7. 46 (10H, m). 68 529 1.62-1.77 (4H, m), 1.77-2. 03 (4H, m), 2. 03-2.17(2H, m), 2.08(3H, s), 2.23-2. 42 (3H, m), 2. 43-2.53 (2H, m), 2. 87-3. 07 (4H, m), 4.12(2H, t, J=4. 9Hz), 4.39(2H, t, J=4.9Hz), 6.8K2H, d, J=8.9Hz), 7.09 (2H, d, J=8.9Hz), 7.25-7. 30 (2H, m), 7. 30-7. 40 (8H, m). 69 487 1. 60-1.75 (2H, m), 1.85-2. 00(2H, m), 2. 00-2.10(2H, m), 2.33(3H, br.s), 2. 40-2. 50 (2H, m), 2. 65-2. 75 (1H, m), 2.85-3.15(7H, m), 3.39(1H, br.s), 3.90-4.00(2H, in), 4.02(2H, t, J=4.0Hz), 6.82(1H, d, J=9.0Hz), 6.88(1H, ddd, J= 8.3Hz, 8.3Hz, 1.0Hz), 7.10-7.20(1H, m), 7.20-7.50 (llH, in). 70 487 1.62-1.78 (4H, m), 1. 91-2. 04(2H, m), 2. 08-2.17 (2H, m), 2.24-2. 42 (4H, m), 2. 45-2.55 (2H, m), 2. 86-3. 09 (5H, m), 3.91 (2H, t, J=4.5Hz), 4.03(2H, t, J=4.5Hz), 6. 68-6. 81 (3H, in), 7.16(1H, t, J=7.8Hz), 7.23-7.46 (10H, m). 71 487 1. 60-1.85 (4H, m), 1.90-2. 25 (4H, m), 2.25-2. 45 (3H, m), 2. 47-2. 60(2H, m), 2.90-3.10(6H, m), 3.92(2H, t, J=4.4Hz), 4.04(2H, t, J=4.4Hz), 6.82(2H, d, J=8.3Hz), 7.10 (2H，d, J=8.8Hz)， 7.22-7.30 (2H, m), 7.33-7. 45 (8H, m). 72 501 1.72-2. 03 (4H, m), 2.28(3H, s), 2.35-2.69 (7H, m), 2.95-3.08 (lH, m), 2.97(3H, s), 3.21-3.40(1H, m), 4.40(2H, s), 6. 63-6.95 (4H, m), 7. 24-7. 42 (10H, m). 73 441 2. 15-2.24(2H, m), 2.27-2. 42 (5H, m), 2. 45-2. 54(2H, m), 2.58-2.68 (2H, m), 2. 87-3. 08 (5H, m), 5.7K1H, s), 6.78-6.87 (2H, m), 6.97-7. 02 (1H, m), 7. 05-7.12(1H, in), 7.24-7.44(10H, m). 74 527 1.26(3H, t, J = 7.3Hz), 2. i 3-2. 23 (2H, m), 2. 27-2. 42 (3H, br), 2.47-3. 12(5H, m), 4.22(2H, q, J=7.3Hz), 5.74(2H, s), 6.7K1H, d, J=8.3Hz), 6.92(1H, t, J=7.3Hz), 7. 11-7. 18(2H, m), 7.23-7. 46 (10H, m). 75 485 2.3K3H, s), 2.70-2.84 (4H, m), 2. 89-3. 04(2H, (n), … 3.0K3H, s), 3.07-3.20 (2H, m), 3. 49>3.68(2H, m), 3. 88-4. 03 (4H, m), 5.56(1H, s), 6. 80-6. 92 (2H, m), 7.05(1H, d, J=7.5Hz), 7.22(iH, t, J=7.5Hz), 7.27-7.46 (10H, ni). -53- 本紙張尺度適用中國國家標準(CNS) A4規格（210 X 297公釐） 579375 A7 B7 五、發明説明（49 ) 表1 7 76 499 2.29(3H，s)，2.7卜3.10(7H，m)，2.99(3H，s)， 3. 38-3.55 (2Η, m), 3. 89-4. 04(1H, m), 4.54(2H, m), 5.64(1H, s), 6.76(1H, d, J=7.8Hz), 6.93(1H, t, J=7.8Hz), 7. 10-7. 22 (2H, m), 7.26-7. 46 (10H, m). 77 467 1.47-1.58 (2H, m), 1. 62-1. 72 (2H, m), 2.21-2. 30(2H, m), 2.33-2.57 (4H, m), 2.60-2.68 (2H, m), 3.04(2H, d, J=2.9Hz), 3.60(2H, t, J=T.0Hz), 5.70(1H, s), 6.76-6.85 (2H, in), 6.99(1H, d, J=7.3Hz), 7.08(1H, t, J=7.3Hz), 7.25-7.42 (10H, m). 78 469 1.46-1.5T(2H, m), 1.60-1. 82 (6H, m), 2. 00-2.26 (4H. m), 2. 42-2. 59 (4H, m), 2. 77-3.02 (2H, m), 3.54-3. 65 (2H, m), 6.67(1H, d, J=7.8Hz), 6.76(1H, t, J=7.3Hz), 6.96(1H, t, J=7.8Hz), 7.06(1H, d, J=7.3Hz), 7· 20-7.38(1 OH, m). 79 555 1.26(3H, dt, J=7.3, 2.2Hz), i. 47-i. 58 (2H, m), 1.61-1. 85(6H, in), 2. 03-2. 32 (4H, □), 2.42-2. 63 (4H, m), 2.92-3. iO(3H, m), 3.52-3. 66 (2H, m), 2.4.23(2H, dq, J=7.3, 2.2Hz), 4.60(2H, s), 6.68(1H, d, J=7.8Hz), 6.93(1H, t, J=7.8Hz), 7.10(1H, t, J=7.8Hz), 7.20(iH, d, J=7.8Hz), 7. 23-7.45 (10H，m)· 80 555 i.48-l/58(2H, m), 1.61-i. 85(6H, m), 2.06(3H, s), 2. 08-2. 37 (4H, m), 2. 42-2. 65 (4H, m), 2. 85-3.14 (3H, m), 3. 54-3. 63 (2H, m), 4. 08-4.15 (2H, m), 4. 36-4. 44 (2H, m), 6.79(1H, d, J=7.5Hz), 6.92(1H, t, J=7.5Hz), 7. 09-7.21 (2H, m), 7. 23-7.42 (iOH, ai). 81 513 1.46-1.58 (2H, m), 1. 60-1. 72 (4H, in), 1.80-2.30(6Η» m), 2. 40-2.60 (4H, m), 2.65-2. 78 (1H, m), 2. 89-3. 08 (2H, m), 3. 52-3. 62 (2H, m), 3. 88-4. 05 (4H, m), 6. 77-6. 91(2H, m), 7.07-7. L6(2H, m), 7.22-7.40(10H, m). 82 527 1.47-1.58 (2H, m), 1.61-1. 72(2H, m), 1. 75-2.06 (6H, m), 2. 32-2.53 (4H, m), 2. 57-2. 73 (3H, m), 2. 97-3. 10 (1H, m), 3.26-3. 42 (lH, m), 3.50-3. 60 (2H, m), 4.4K2H, s), 6.63-6. 93 (4H, m), 7.23-7.41 (10H, m). 83 557 1.20(3H, t, J=7.1Hz), 1.56(6H,s), 1.56-1. 94(6H, m), 1.94-2. 25 (2H,m), 2.25-Z. 45 (3H, br), 2. 45-2. 64(2H, br), 2.80-3.20 (6H,m), 4. 20 (2H, q, J=7. 1Hz), 6.61 (1H, dd, J=7. 8,1.0Hz), 6.90(1H, dt, J=7. 8,1. 0Hz), 7.01(lH,dt, J=7.8, 1.0Hz), 7.17(lH,dd, J=7.8,1.0Hz), 7.25-7.32(2H，m)，7.32-7.47(8H，m). 84 529 1.46(6H,s), 1.67-i.96(4H,m), 2. 20-2.36 (3H, br), 2.36-2.5i(2H,m), 2.51-2.63 (2H, m), 2.63-2.76 (2H, m), 2.88-3.06 (5H,m), 3. 28-3. 42 (1H, m), 6.59-6.69 (1H, m), 6.72-6.85 (lH,m), 7. 27-7.35 (2H, m), 7.35-7. 45 (1 OH, m). -54- 本紙張尺度適用中國國家標準(CNS) A4規格（210X297公釐） ^/^/5 A7
試驗例1 (於摘出κ θ (、侗出豚鼠迴腸標本之作用）用體重5 0 0克左六；u 、，.凡反右< Hartley系雄性豚鼠，摘出離迴盲部15〜30公分之迪胳 a、时’作成附有奥厄巴哈氏神經叢之縱向肌標本，以岡菩人士 、, 〒八〈万法（Eur. J. Pharmacol·，77; 137-141，1982),、彳疋文4藥之類鴉牙受體活性。拮抗劑活性之大小，乂相對於選擇性μ -類鴉片拮抗劑之DAMGO ([D-Ala2，N- MePh，Gly5-〇l]-enkephaU幻之效力表示。又，受試藥為類鳥片枪杬浏藉由納洛松（十口丰y > )之拮抗而確認。結果7F於下表。表1 8 化合物編號 _相對力價 3 6 10 3 9 20 4 3 20 45 20 69 10 DAMGO 1.0 嗎啡 0.14 山梗醯胺 4.3 試驗例2 用5週齡之I c R系雄性小白鼠，藉由芬瓦酸酯引發疼痛 ，，評估各藥劑之疼痛之鎮痛作用。亦即，將芬瓦酸酯（Na+ 通活化劑）1微克/部位局部投予小白鼠足摭皮下，測定顯 示藉此引發之疼痛反應（舐足、咬）之時間，以投予後3 〇分 -55- 本紙張尺度通用中國國家標準(CNS) A4規格(210 X 297公登Υ
裝 玎

Claims (1)

  1. 579375 第090125458號專利申請案 g 中文申請專利範圍替換本(92年j j月）認六、申請專利範圍
    η 1· 一種以通式（1)表示之2,孓二苯丁醯胺衍生物或其鹽
    式中’ Α表-(CH2)n-基（η表示1或2 )或次τ基（CH)基， A為-CHy時，B表次甲基或N原子，AB為單鍵，a為· (CH2)2_時，B表N原子，AB為單键，A為次甲基時，B 為四級碳，A B為雙鍵； R1及R2為相同或不同，表Η原子、碳數丨〜6之直鏈或 分枝之烷基’或R1及R2與鄰接原子一起形成吡咯啶 環亦可，Ar係以下面之基所表示之可有取代基之苯基 、莕環、吡啶環、嘧啶環、吡畊環、，塞唑環、喹啉環 、異喹啉環或第基：
    (R3表Η原子、鹵素原子、苯基、碳數1〜6之直鏈或分 枝之烷基或-0-R4基）；於此，R4表Η原子、碳數1〜6之 直鏈或分枝之烷基或-(CR5R6)m-Y基（於此，R5及R6表η 原子或碳數1〜6之直鏈或分枝之烷基，γ表— coor7基、· OR8基或-OCOR9基（R7、R8及R9表Η原子、碳數1〜6之直 鏈或分枝之烷基，），m表1〜6之數）]。 2. —種以通式（1-1)表示之2,2-二苯丁醯胺衍生物或其鹽， 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 579375 A B c D
    1-1) [式中，R1及R2相同或不同，表Η居4 双μ原子、碳數1〜6之 _ 直鏈或分枝之烷基，或R1及R2與鄰接之Ν原子一起形成 ，比咯咬環亦可。η表1或2，Ar’係以下面之基所表=之 可有取代基之苯基、荅環、咐啶環、嘧啶環、说ρ井環、 ρ塞峻環、4淋環、異ρ奎淋環或第基··
    裝 訂 (R3'表氫原子、函素原子、苯基、碳數1〜6之直鏈或分枝 之烷基或-0-R4基）；於此R4表Η原子、碳數丨〜6之直鏈 或分枝之烷基或-(CR5R6)m-Y基（於此，R5及R6表η原子 或碳數1〜6之直鏈或分枝之烷基，Υ表-COOR7基、-OR8 基或-OCOR9基（R7、R8及R9表Η原子、碳數1〜6之直鏈 或分枝之烷基），m表1〜6之數）]。 一種以通式（1-2)表示之2,2-二苯丁醯胺衍生物或其鹽，
    (1-2) [式中，R1及R2相同或不同，表Η原子、碳數1〜6之 -2- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐） 579375 A B c D 六、申請專利範圍 直鏈或分枝之烷基，或Ri及R2與鄰接之N原子一起形成 吡咯啶環亦可。R3"表Η原子、自原子、碳數丨〜6之直 鏈或分枝之烷基、或-0-R4，於此，R4表Η原子、碳數 1〜6之直鏈或分枝之烷基或_(cR5R6)m_Y (於此，R5及R6 表Η原子或碳數1〜6之直鏈或分枝之烷基，¥表-(：〇〇117 基、-0R8基或-0C0RKR7、化8及119表11原子、碳數1〜6 之直鏈或分枝之垸基），m表1〜6之數）]。 4· 一種以通式（1-3)表示之2,2-二苯丁醯胺衍生物或其鹽，
    直鏈或分枝之烷基，或Ri及R2與鄰接原子一起形成 叶匕啥淀環亦可，R3"表Η原子、卣原子、碳數丨〜6之直 鏈或分枝之烷基或-0-R4，於此，R4表Η原子、碳數1〜6 之直鏈或分枝之烷基或基（於此，R5&R6表 Η原子或碳數1〜6之直鏈或分枝之烷基，γ表-C〇〇R7基 、-OR8基或-OCOR9基（R7、R8及r%h原子、碳數丨〜6之 直鏈或分枝之烷基），m表1〜6之數）]。 一種末梢性鎮痛用或神經性疼痛抑制用之醫藥組合物， 其係以申請專利範圍第1〜4項中任一項之2,2•二苯丁醯胺 衍生物或其鹽為其有效成分。 -3- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 579375 8 8 8 8 AB c D 、申請專利範圍 6 . —種末梢性鎮痛用或神經性疼痛抑制用之醫藥組合物， 其係含有申請專利範圍第1〜4項中任一項之2,2-二苯丁醯 胺衍生物或其鹽及藥學上可接受之載劑。 -4 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐)
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US6992090B2 (en) * 2003-06-16 2006-01-31 Adolor Corporation Substituted piperidine compounds and methods of their use
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CN102964279B (zh) * 2012-12-12 2014-05-07 中国药科大学 一类具有外周镇痛作用的κ阿片受体激动剂
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CN107602445B (zh) * 2016-07-12 2020-12-01 中国科学院上海药物研究所 咯哌丁胺衍生物及其在制备治疗混合谱系白血病的药物中的应用
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