TW200407137A - Pyridone of benzothiazole derivatives - Google Patents
Pyridone of benzothiazole derivatives Download PDFInfo
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- TW200407137A TW200407137A TW091133382A TW91133382A TW200407137A TW 200407137 A TW200407137 A TW 200407137A TW 091133382 A TW091133382 A TW 091133382A TW 91133382 A TW91133382 A TW 91133382A TW 200407137 A TW200407137 A TW 200407137A
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- IOJUPLGTWVMSFF-UHFFFAOYSA-N benzothiazole Chemical class C1=CC=C2SC=NC2=C1 IOJUPLGTWVMSFF-UHFFFAOYSA-N 0.000 title 1
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- 150000001875 compounds Chemical class 0.000 claims abstract description 93
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 claims abstract description 4
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- 229940124597 therapeutic agent Drugs 0.000 description 1
- HFRXJVQOXRXOPP-UHFFFAOYSA-N thionyl bromide Chemical compound BrS(Br)=O HFRXJVQOXRXOPP-UHFFFAOYSA-N 0.000 description 1
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 230000009261 transgenic effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 238000001238 wet grinding Methods 0.000 description 1
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Description
200407137 ⑴ 玫、發明說明 (發明說明應敘明··發明所屬之技術領 ^ 71項域、先前技術、内容、實施方式及圖式簡單 本發明係有關具有如下沾々♦ a人μ … r通式之化合物
其中 R為苯基、吡啶-2 -基、-C (0) - 0 -低碳烷基' C ( 0)-低碳垸基、 -C(〇）-嗎啉基、-C(〇）-NR’2、-(CH2)n-NR’2*-(CH2)n-〇· 低碳烷基以及為氫或低碳烷基； 及其醫藥可接受性酸加成鹽。 出乎意外地發現通式I化合物為腺茹受體配位子。特 別，本發明化合物對A2a-受體有良好親和力，對八！及A3受 體有高度選擇性，此外有優異水中溶解度。 腺荅經由與特定細胞表面受體交互作用而調控寬廣多 種生理功能。腺甞受體作為藥劑作用目標之可能首次於 1 9 8 2年檢討。腺甞之結構上及代謝上係有關生物活性核芸 酸腺荅三磷酸（ατρ)、腺：y：二磷酸（ADP)、腺甞一磷酸（AMP) 及環狀腺：y： —磷酸（c A M P);有關生物活性曱基化劑S -腺荅 -L-蛋胺酸（SAM);以及結構上係有關辅酶NAD、FAD及輔 酶A ;以及有關RNA。腺甞及此等相關化合物共同對於細 胞代謝之多方面的調節以及不同中樞神經系統活性之調 控上相當重要。 -7- 200407137 (2)
腺菩受體被歸類為Αι、A2a、A2B及A3受體，屬於G蛋白-= 偶合受體家族。腺茹受體由腺甞引發信號轉導機轉活化。 此等機轉係與g蛋白質相關受體有關。各個腺：y：受體亞型 係以腺嘗酸環化酶效應物系統（其利用c AMP作為第二信使） 作為分類特徵。A !及A3受體偶合Gi蛋白質，抑制腺甞酸環 化酶，結果導致細胞cAMP濃度降低；而A2A及A2B受體偶 合至Gs蛋白質且活化腺甞酸環化酶，結果導致細胞cAMP 濃度的升高。已知A 1受體系統包括磷脂酶C的活化，以及 鉀及鈣離子通道的調控二者。A3亞型除了關聯腺苷環化酶 之外，也刺激鱗脂酶C，因而活化妈離子通道。 A !受體（3 2 6 - 3 2 8胺基酸）係由各種動物（貓、人、大鼠、
犬、雞、牛、天竺鼠）轉殖，於各種哺乳動物間有9 0 - 9 5 % 序列相同性。A2a受體（409-4 1 2胺基酸）係由貓、鼠、人、 天竺鼠及小鼠轉殖。A2B受體（3 3 2胺基酸）係由人及鼠轉 殖’人A2B與人Αι及A2A受體間有45%同源性。A3受體 (317-320胺基酸）係由人、大鼠、犬、兔及羊轉殖。 A i及A2A受體亞型提示於腺甞調節能量供應上扮演互補 角色。腺甞為ATP之代謝產物，腺甞由細胞擴散，局部作 用於活化腺甞受體，而降低氧缺求（A!)、或提高氧供給量 (A2A)，因而回復組織内部能量供應：需求間之平衡。兩種 亞型之作用增加組織可利用之氧量，以及保護細胞不因短 時間氧不平衡造成的傷害。内生性腺甞之主要功能之一係 於外傷期間防止損傷，例如缺氧、缺血、血壓過低及發作 活性。 200407137
(3) 此外，已知腺甞受體促效劑結合至可表現大鼠A3受體之 肥大細胞，結果導致肌糖醇三磷酸濃度及胞内鈣濃度的增 高，如此增強抗原誘生發炎媒介物質之釋放。因此，A3 受體於氣喘發作以及其它過敏反應之媒介上扮演某種角 色。 腺甞為神經調控劑，腺荅可調控腦生理功能之各方面。 内生性腺甞為能量代謝與神經元活性間的關鍵連鎖，内生 性腺甞根據行為狀態及（病理）生理條件改變。於能量需求 增加而能量的利用性降低之情況下（例如缺氧、血糖過低 及/或神經元活性過高），腺甞提供強而有力之保護性回饋 機轉。與腺甞受體交互作用代表多種神經與精神病之治療 性介入上有展望的作用目標，該等神經精神疾病例如癲 癇、睡眠障礙、運動障礙（帕金森氏病或亨丁頓氏病）、阿 茲海默氏病、憂鬱症、精神分裂或成癮。於外傷如缺氧、 缺血及癲癇發作後神經傳遞物質之釋放增加。神經傳遞物 質最終造成神經的退化與神經死亡，造成腦損傷或個體死 亡。腺甞A!拮抗劑之功能模擬腺甞之中樞抑制作用，因此 可作為神經保護劑。曾經提議腺甞作為内生性抗驚厥劑， 抑制由興奮之神經元釋放出麩胺酸，且抑制神經元的觸 發。因此腺甞促效劑可用作為抗癲癇劑。腺甞拮抗劑刺激 中樞神經系統活性，證實可用作為認知提升劑。選擇性A2A 拮抗劑用於治療各型痴呆例如阿茲海默氏病或用於神經 退化病症如中風有治療潛力。腺甞A2a受體拮抗劑調控紋 狀體GAB A激性神經元活性，且調節運動的順利以及協 200407137 (4) 調，如此提供帕金森氏症之潛在治療。腺嘗也涉及多項下 列作用之相關生理過程：鎮定、催眠、精神分裂、焦慮、 疼痛、呼吸、憂營症及藥瘺（安非他命、古柯鹼、鵪片劑、 乙醇、尼古丁、大麻類）。因此作用於腺甞受體之藥劑具 有作為鎮定劑、肌肉鬆弛劑、抗精神病劑、解焦慮劑、止 痛劑、呼吸刺激劑、抗鬱劑、以及治療藥劑濫用之潛力。 此等藥劑也可用於治療ADHD(注意力缺乏過動症）。
腺甞用於心金管系統之重要角色係作為心臟保護劑。内 生性腺苷濃度回應於缺血及缺氧提升，於外生期間及外生 後保護心臟組織（前期調理）。經由作用於A〗受體，腺甞A i 促效劑可保護心臟不受心肌缺血以及再灌流造成的傷 害。A2A受體對腎上腺激性功能調控的影響也影響多種病 症如冠心病及心臟衰竭。A2 a拮抗劑用於需要提高抗腎上 腺激性反應之情況例如於急性心肌缺血期間有治療效 果。A2A受體之選擇性拮抗劑也可提升腺甞結束心室上心 律不整的效果。 腺茹調控腎功能之各方面，包括腎素的釋放、腎絲球體 過濾率及腎血流。可拮抗腺甞之腎臟影響之化合物有可能 作為腎臟保護劑。此外，腺钻A3及/或A2B拮抗劑可用於治 療氣喘及其它過敏反應或/及用於治療糖尿病及肥胖。 無數文件說明目前有關腺甞受體之知識，例如下列公開 文獻： 生物有機及醫藥化學，6，（1998)，619-641， 生物有機及醫藥化學，6，（1998)，707-719, 10- 200407137
(5) 醫藥化學期刊，（1998)，41，2835-2845， 醫藥化學期刊，（1 9 9 8 )，4 1，3 1 8 6 - 3 2 0 1， 醫藥化學期子|J ，（ 1 9 9 8 )，4 1，2 1 2 6 - 2 1 3 3， 醫藥化學期刊，（1999)，42，706-721， 醫藥化學期刊，（1 9 9 6 )，3 9，1 1 6 4 - 1 1 7 1， 藥劑醫藥化學檔案，3 3 2，39-41，（ 1 999)，
美國生理期刊，276， H1113-1116， （1999)或 NaunynSchmied，藥理檔案 362，375-381，（2000)。
本發明之目的為式I化合物本身、式I化合物及其一可接 受性鹽用於製造腺甞A2受體相關疾病之治療用藥之用 途、其製造、基於根據本發明之化合物之藥劑及其生產， 以及式I化合物用於控制或預防基於調控腺甞系統之疾 病，例如阿茲海默氏病、帕金森氏病、亨丁頓氏病、神經 保護、精神分裂、焦慮、疼痛、呼吸缺陷、憂鬱症、藥劑 成瘾（例如安非他命、古柯驗、鵪片劑、乙醇、尼古丁、 大麻類），或對抗氣喘、過敏反應、缺氧、缺血、癲癇發 作及物質濫用。此外，本發明化合物可用作為鎮定劑、肌 肉鬆弛劑、抗精神病劑、抗癲癇劑、抗驚厥劑及心臟保護 劑用於冠狀動脈病及心臟衰竭等病症。根據本發明之最佳 適應症為基於A2 A受體拮抗活性之適應症，以及包括中樞 神經系統病症之適應症，例如用於治療或預防阿茲海默氏 病、某些憂鬱病症、藥劑成癮、神經保護及帕金森氏病以 及 ADHD。 用於此處，”低碳烷基” 一詞表示含1至6個碳原子之直鏈 -11 - 200407137 ⑹ 或分支鏈烧基，例如甲基、乙基、丙基、異丙基、正丁基、 異丁基、2 -丁基、第三丁基等。較佳低碳烷基為含1-4個碳 原子之基團。 π醫藥可接受性酸加成鹽” 一詞涵蓋於無機及有機酸生 成之鹽，該等酸例如鹽酸、硝酸、硫酸、麟酸、檸檬酸、 甲酸、反丁烯二酸、順丁烯二酸、乙酸、丁二酸、酒石酸、 甲烧石黃酸、對-甲苯磺酸等。
較佳本案化合物為其中R為苯基、吡啶-2-基、 -c(o)-o-ch2ch3 、 -c(o)-ch2ch3 、 -c(〇）-嗎口林基或 -c(o)-n(ch3)2之該等化合物如後： 1-芊基-2-酮基-1，2-二氫-吡啶-4-羧酸（4-曱氧基-7-嗎啉- 4-基-苯弁喧。坐-2-基）-酿胺’ [4-(4-曱氧基-7 -嗎淋-4 -基-苯弁遠σ坐-2 -基-胺基甲酿基）-2 _ 嗣基-2 Η -说咬-1 -基]-乙酸乙S旨’
2 -嗣基-1 - (2 -嗣基-丁基）-1，2 -二氮-叶匕°定-4 -竣酸（4 -甲乳基 -7 -嗎淋-4 -基-苯弁癌嗤-2 -基）-酿胺’ 2 -嗣基-1 -叶匕咬-2 -基-曱基-1，2 -二氮-叶匕。定-4 -竣酸（4 -甲氧基 -7 -嗎淋-4 -基-苯并遠嗤-2 -基）-酿胺’ 1 - (2 -嗎口林-4 -基-2 -嗣基-乙基）-2 -嗣基-1，2 -二鼠-ρ比咬-4 -竣 酸（4 -甲乳基-7 -嗎17林-4 -基-苯并ρ墓嗤-2 -基）-酿胺’或 1-二曱基胺基曱醯基曱基-2 -酮基-1,2 -二氫-吡啶-4-羧酸 (4-甲氧基-7-嗎淋-4-基-苯并魂。坐-2-基）-酿胺。 本式I化合物及其醫藥可接受性鹽可經由業界已知方法 製備，例如經由下述方法製備，該方法包含 -12- 200407137 ⑺ a) 一 下式化合物 ?ch3
與一種下 反應成一 式化合物
Br
(7) 下式化合物
其中R為 基， 或 b)—種 基、吡啶基、-c(o)o-低碳烷基 式化合物
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⑻ 與一種下式化合物
P _/R R 「 （7)或 Cl~^ (9) 反應成一種下式化合物
其中R為- C(〇）-嗎啉基、-(CH2)n-0-低碳烷基、-(CH2)nNRf2 或-(CO)NR，2，及 若有所需，將所得化合物轉成醫藥可接受性酸加成鹽。 式I化合物之製備其中R為苯基、吡啶基、-C (0)0-低碳烷 基或C(O)-低碳烷基 一種製備式I化合物（其中R為苯基、吡啶基、-C(0)0-低 碳烷基或C (Ο)_低碳烷基）之方法係始於式（6 ) 2 -甲氧基-異 於驗醯胺中間物，如下反應圖1及2所示。 -14- 200407137 (9)
反應圖1
i. 酸，HATU ii. 胺，鹼
驗
Η 。-ch3 (5)
本反應圖中使用下列縮寫： HATU 0-(7-氮雜苯并三唑-1-基）-N，N,Nf，N’-四曱基六氟 填酸尿錯 -15 - 200407137 (ίο)
反應圖2
其中R為苯基、吡啶基、-C (Ο) Ο -低碳烷基或C (Ο)-低碳烷 式m化合物之製備 起始式（1) 2 -氯異菸鹼酸或2 -溴異菸鹼酸可由市面上獲 得，例如得自梅布利吉（M a y b r i d g e)化學公司，或根據業界 眾所周知之方法製備。 式（1) 2 -鹵異菸鹼酸可轉成對應式（2)醯基鹵衍生物，轉 化方式係經由式（1 )化合物與過量函化劑（如草醯氣或草醯 溴、或亞磺醯氯或亞磺醯溴），使用催化劑如N，N-二甲基 甲醯胺或吡啶，於有機溶劑（較佳為二氯甲烷或二氣乙烷） 於室溫反應約2-16小時，較佳16小時。式（2)產物係藉習知 -16- 200407137
(11) 手段分離，較佳未經進一步純化即用於次一反應。 式（4)化合物之製備 起始式（3) 2-胺基-苯并噻唑化合物可根據EP 00 1 1 3 2 1 9.0 揭示之方法製備。 式（4)化合物之製法，係經由使用微過量式（2)醯基鹵化 合物，於質子惰性有機溶劑（較佳為二氯曱烷與四氫呋喃 混合物），含有鹼（較佳為N -乙基二異丙基胺或三乙基胺） 於室溫，處理式（3 ) 2 -胺基-苯并噻唑化合物2 - 2 4小時，較 佳24小時製備。式（4)化合物可藉習知手段分離，較佳利用 層析術或再結晶純化。 式（4)化合物之另一種製法 式（4)化合物也可由式（1)化合物直接製備。此種方法 中，式（1)化合物使用化學計算當量之肽-偶合劑，且較佳 為〇-(7-氧雜苯并三唑-1-基）-1^川^^、四甲基六氟磷酸 尿鑌（HATU)，於醚系溶劑較佳為四氫呋喃含有鹼，較佳為 N -乙基二異丙基胺，於室溫處理3 0 - 9 0分鐘。然後混合物 使用式（3 ) 2 -胺基-苯并嘧唑化合物於溶劑混合物（較佳為 四氫呋喃、二呤烷與N，N-二曱基曱醯胺混合物），於室溫 處理16-24小時，較佳24小時。式（4)產物係藉習知手段分 離，且較佳利用層析術或再結晶純化。 式（6 )化合物之製備 式（6)化合物之一種製備方法係經由使用過量曱醇連同 金屬-氫化物鹼，較佳為氫化鈉或氫化鉀處理式（4)化合物 而製備。反應係於醚系溶劑（如二嘮烷、四氫呋喃或1,2- -17- 200407137 (12) 二甲氧基乙烷，較佳為二哼烷），視需要地含有助溶劑如 N，N -二甲基曱醯胺，於室溫至溶劑回流溫度之溫度，較佳 約1 0 0 °C進行2 - 7 2小時，較佳1 6小時。式（6 )產物係藉習知 手段分離，且較佳利用層析術或再結晶純化。 式（6)化合物使用過量式（7)烷基溴處理，式（7)烷基溴為 市售，或可藉業界眾所周知之方法根據合成通訊，1 9 9 9， 2 9，4 0 5 1 - 4 0 5 9所述程序製備。反應可於極性有機溶劑如 乙腈或Ν,Ν-二甲基曱醯胺，較佳為N，N-二甲基甲醯胺於升 高溫度，較佳為使用溶劑之回流溫度進行2 - 1 8小時，較佳 為1 6小時。式I產物，此處R為苯基、吡啶基、-C (Ο) Ο -低 碳烷基或C(O)-低碳烷基係藉習知手段分離，且較佳利用 層析術或再結晶純化。
式I化合物之製備，其中R為-C(O)-嗎啉基、、 -(CHrk-O-低碳烷基或 C(0)NRS 一種製備式I化合物之方法，其中R為-C(O)-嗎啉基、 -(CH2)n-NRf2、- (CH2)n-〇-低碳烷基或 C(0)NR’2* 始於式（8) 2 -酮基-1，2 -二氫-吡啶-4 -羧酸醯胺中間物，其製法示於如 下反應圖3。
-18- 200407137 (13)
反應圖3
其中R為- C(O)-嗎啉基、-(CH2)n-NR’2、-(CH2)n-〇-低碳烷 基或- C(0)NRf2以及TMSI為碘三曱基矽烷。 式（8 )化合物之製備 -19- 200407137
(14) 式（6)化合物使用過量碘三甲基矽烷於鹵化有機溶劑，較 佳為氯仿，於室溫或室溫以上之溫度，較佳於溶劑回流溫 度處理2 - 1 6小時，較佳約8小時。然後反應混合物使用醇， 較佳為甲醇，於室溫或室溫以上之溫度，較佳於溶劑混合 物回流溫度處理2 - 1 8小時，較佳為1 6小時。式（8 )產物係藉 習知手段分離，且較佳利用層析術或再結晶純化。 式I化合物之製備，其中R為-C(〇V嗎啉基、 -(CHL)n-〇-低碳烷基或 C(0)NR\ 式（8)化合物使用過量式（7)烷基溴或式（9)烷基氯處理， 式（7)烷基溴或式（9)烷基氯可為市售或藉業界眾所周知之 方法製備。當使用式（9)烷基氯時，反應係於化學計算當量 之溴化鋰存在下進行。反應係於極性有機溶劑（如二吟烷 或N，N-二甲基甲醯胺，較佳為N，N-二甲基甲醯胺與二嘮烷 之混合物），於室溫至使用之溶劑混合物之回流溫度之溫 度進行2 - 1 8小時，較佳1 6小時。式I產物係藉習知手段分 離，且較佳利用層析術或再結晶純化。 化合物之分離與純化 此處所述化合物及中間物之分離與純化若有所需可藉 任一種分離或純化程序進行，例如過濾、萃取、結晶、管 柱層析術、薄層層析術、厚層層析術、製備性低壓或高壓 液相層析術或此等程序的組合。適當分離與單離程序之特 定範例可參照後文製備例及實施例。但當然也可使用其它 相當之分離或單離程序。 式I化合物鹽類 -20- 200407137 (15) 式I化合物可為鹼性，例如當殘餘R含有鹼性基如脂肪族 或芳香族胺部分時為鹼性。此種情況下，式I化合物可轉 成對應酸加成鹽。
轉化係使用至少化學計算量之適當酸達成，酸例如為氫 氣酸、氫溴酸、硫酸、罐酸、填酸等；以及有機酸如乙酸、 丙酸、乙醇酸、丙酮酸、草酸、蘋果酸、丙二酸、丁二酸、 順丁烯二酸、反丁烯二酸、酒石酸、檸檬酸、苯甲酸、桂 皮酸、扁桃酸、曱烧續酸、乙烧石黃酸、對-曱苯石黃酸、水 楊酸等。典型地，自由態鹼溶解於惰性有機溶劑（例如乙 醚、乙酸乙酯、氯仿、乙醇或甲醇等），而酸添加至類似 溶劑。溫度維持於0 °C至5 0 °c。所得鹽自動沉澱，或可使 用極性較低之溶劑由溶液中沉澱出。 式I鹼性化合物之酸加成鹽可經由使用至少化學計算當 量之適當鹼處理而轉成對應之自由態鹼，該等鹼例如為氫 氧化鈉或氫氧化鉀、碳酸鉀、碳酸氫鈉、氨等。
式I化合物及其醫藥有用之加成鹽具有各種藥理性質。 特別證實本發明化合物為腺苷受體配位子，對腺甞A2 A受 體有高度親和力，且對A i受體有良好選擇性。 化合物係根據後述試驗研究。 人類腺棼A,受體 人類腺^Αι受體係使用山利奇森林病毒（semliki forest v i r u s )表現系統於中國倉鼠卵巢（C Η Ο)細胞重組表現。細胞 經收穫，藉離心洗兩次，均化，然後藉離心洗滌。最終洗 滌後之膜丸粒懸浮於Tris (50 mM)緩衝液，其中含有120 -21 - 200407137
(16) 氣化鈉，5 mM氣化鉀，2 mM氣化鈣及1 0 mM氯化鎂（pH 7.4)(緩衝液 A)。[3h]-DPCPX(([丙基- 3H]8-環戊基-1，3 -二丙 基黃原素）；0.6 nM)結合檢定分析係於96孔板，於2.5微克 膜蛋白，0.5毫克Ysi-聚-1-離胺酸SPA珠粒及0.1 U腺甞去胺 酶’於終容積2 0 0微升緩衝液A進行。使用黃原素胺 congener (XAC ; 2 μΜ)定義非特異性結合。化合物係以10 μΜ-0.3 nM之1 0種濃度試驗。全部檢定分析皆係重複進行 且至少重複兩次。檢定分析孔板於室溫培養1小時，隨後 離心’然後使用佩克頂計數（P a c k a r d T 〇 p c 〇 u n t)閃爍計數器 測定結合之配位子。使用非線性曲線匹配程式計算IC5〇 值’使用潛普路索方程式（Cheng-Prussoff equation)計算 Ki值。 人類腺苷A7A受體 人類腺嘗A2 A受體係使用山利奇森林病毒表現系統於中 國倉鼠印巢（C Η Ο)細胞重組表現。細胞經收穫，藉離心洗 兩次，均化，然後藉離心洗滌。最終洗滌後之膜丸粒懸浮 於Tris (5 0 mM)緩衝液，其中含有12〇 mM氯化鈉，5 mM氣 化鉀，2 mM氣化鈣及1〇 mM氯化鎂（pH 7.4)(緩衝液A)。 [3H]-SCH-58261 (Dionisotti等人，1997，英國藥理期刊 121 ’ 353 ’ 1 nM))結合檢定分析係於9 6孔板’於2 5微克膜 蛋白，〇·5毫克Ysi-聚-1-離胺酸SPA珠粒及0.1 11腺芬去胺 酶’於終容積2 0 0微升緩衝液A進行。使用黃原素胺 congener (XAC ; 2 μΜ)定義非特異性結合。化合物係以1〇 μΜ-〇· 3 nM之10種濃度試驗。全部檢定分析皆係重複進行 -22- 200407137
且 離 測 值 有 (17) 至少重複兩次。檢定分析孔板於室溫培養1小時，隨後 心，然後使用佩克頂計數（P a c k a r d T 〇 p c 〇 u n t)閃爍計數器 定結合之配位子。使用非線性曲線匹配程式計算IC 5 〇值 使用潛普路索方程式（Cheng-Prussoff equation)計算Ki 顯然式I化合物對A2 a受體有良好親和力，以及對A i受體 高度選擇性。較佳化合物顯示pKi>7.2，如下表所示：
實施例編號 hAi (pKi) hA2(pKi) 1 5.90 8.67 2 5.18 8.19 3 5.18 8.24 4 5.18 8.10 5 5.18 7.23 6 5.18 7.30 製 包 懸 道 造 或 式I化合物及式I化合物之醫藥可接受性鹽例如可呈醫藥 劑形成用作藥劑。醫藥製劑可經口投予，例如呈錠劑、 衣錠、糖衣錠、硬及軟明膠膠囊劑、溶液劑、乳液劑或 浮液劑。但投藥也可經直腸例如呈栓劑劑型進行、經腸 外例如呈注射溶液劑型實施。 式I化合物可使用醫藥惰性無機或有機載劑加工用於製 醫藥製劑。乳糖、玉米澱粉或其衍生物、滑石、硬脂酸 其鹽等例如可用作為錠劑、包衣錠、糖衣錠及硬明膠膠 -23 - 200407137
(18) 囊劑之載劑。適當軟明膠膠囊之載劑例如為植物油類、蠟 類、脂肪類、半固體及液體多元醇類等。依據活性物質性 質而定，通常於軟明膠膠囊無需載劑。製造溶液劑及糖漿 劑之適當載劑有例如水、多元醇、甘油、植物油等。適當 栓劑載劑有例如天然或硬化油類、蠟類、脂肪類、半液體 或液體多元醇類等。 此外醫藥製劑可含有保藏劑、增溶劑、安定劑、濕潤劑、 乳化劑、甜味劑、著色劑、矯味劑、變更滲透壓之鹽類、 缓衝劑、遮蓋劑或抗氧化劑。也含有其它治療有效物質。 含有式I化合物或其醫藥可接受性鹽及治療惰性載劑之 藥劑也構成本發明之目的，如同其製法亦屬本發明之目 的，其製法包含將一或多種式I化合物及/或其醫藥可接受 性酸加成鹽，以及若有所需之一或多種其它治療有效物質 連同一或多種治療惰性載劑結合成藥劑投藥劑型。 根據本發明，式I化合物及其醫藥可接受性鹽可用於控 制或預防基於腺茹受體拮抗活性之疾病例如阿茲海默氏 病、帕金森氏病、神經保護、精神分裂、焦慮、疼痛、呼 吸缺陷、憂營症、氣喘、過敏反應、缺氧、缺企、癲癇發 作及物質濫用。此外，本發明化合物可用作為鎮定劑、肌 肉鬆弛劑、抗精神病劑、抗癲癇劑、抗驚厥劑及心臟保護 劑，以及用以製造對應藥劑。 根據本發明之最佳適應症為包括中樞神經系統障礙之 病症，例如治療或預防某些憂鬱症、神經保護及帕金森氏 病0 -24 - 200407137
(19) 劑量可於寬廣極限範圍内改變，當然須於個別病理依據' 〆 個別需求調整。以口服投藥為例，成人劑量為每日約0.0 1 _ 毫克至約1000毫克通式I化合物或對應量之其醫藥可接受 性鹽。每曰劑量可呈單劑或平分多劑投藥，此外若發現適 用時劑量也可超過上限。 旋劑調配物（濕造粒） 項目 成分 毫克/鍵 5 25紋 100紋 500 紋 1. 式I化合物 5 25 100 500 2. 乳糖無水DTG 125 105 30 150 3. Sta-Rx 1500 6 6 6 30 4. 微晶纖維素 30 30 30 150 5. 硬脂酸鎂 1 1 1 1 總量 167 167 167 831 製造 程序 1. 混合1、2、 3及4項 且使用純水 造粒。 2. 於5 0 °C乾燥顆粒。 3. 顆粒通過適當研磨設備 0 4. 添加第5項及混合3分鐘 :於適 當壓機打 旋。 膠 •囊調配物 項目 成分 毫克/膠囊 5 統 25紋 100紋 500 紋 1. 式I化合物 5 25 100 500 2. 水合乳糖 159 123 148 …
-25- 200407137 (20) 3. 玉米澱粉 25 35 40 70 4. 滑石 10 15 10 25 5. 硬脂酸鎂 1 2 2 5 總量 200 200 300 600 製造程序 1. 於適當混合器内混合1、2及3項3 0分鐘。 2. 添加4及5項及混合3分鐘。 3. 填裝入適當膠囊。 下列製備例及實施例舉例說明本發明但絕非意圖囿限 其範圍。 實施例1 1 —^基-2-嗣基-1，2 -二鼠-叶匕唆-4 -竣酸（4-甲氧基-7-嗎淋-4- 基-苯并魂σ坐-2-基）-酿胺 於85亳克（0.21毫莫耳）2-甲氧基-Ν-(4 -曱氧基-7-嗎啉-4-基 -苯并噻唑-2-基）-異菸鹼醯胺於2毫升乙腈之經攪拌溶液 内加入73毫克（0.43毫莫耳）碘化鈉及0.05毫升（0·43亳莫耳） 芊基溴。混合物回流加熱1 6小時。然後反應混合物冷卻至 室溫，以乙酸乙酯稀釋，循序以水及飽和鹽水洗滌，然後 有機相以硫酸鈉脫水及真空濃縮。急速層析術（2 /1乙酸乙 酯/曱苯）獲得32毫克（32%)1-芊基-2-酮基-1，2-二氫-吡啶 -4 -竣酸（4-曱氧基-7-嗎ρ林-4-基-苯弁邊。坐-2-基）-酿胺呈黃 色結晶固體。ES-MS m/e (%)·· 499 (M + Na +，14)，477 (Μ + Η +， 100)° 以類似方式獲得： -26- 200407137
(21) 實施例2 [4-(4 -甲氧基-7-嗎4木-4 -基-苯并嘧唑-2-基胺基甲醯基）-2-酮基-2 Η -吡啶-1 -基]-乙酸乙酉旨 始於2-甲氧基-Ν-(4-甲氧基-7-嗎琳-4-基-苯并ρ塞。生-2-基）-異菸鹼醯胺與蛾化鈉及漠乙酸乙酷於D M F。E s -M s m /e (°/〇): 49 5 (M + Na+，25)，47 3 (M + H +，100)。 實施例3 2 -酵J基-1-(2-明基-丁基）-1，2-二氫-ρ比淀-4-叛酸（4 -甲氧基 -7 -嗎4-4-基-苯并0塞嗅基）-醯胺 始於2 -曱氧基-Ν-(4 -甲氧基-7-嗎啉-4-基-苯并噻唑-2-基） -異於驗醯胺與蛾化鈉及1-溴-2-丁酮DMF。ES-MS m/e (%): 479 (M + Na +，32)，45 7 (M + H +，100)。 實施例4 2 -酮基- Ι- p比唆-2-基甲基-1,2 -二氫-t7比咬-4-魏酸（4-曱氧基 -7-嗎啉-4-基-苯并嘍唑-2-基）-醯胺 始於2 -曱氧基-N-(4 -甲氧基-7-嗎啉-4-基-苯并嘧唑-2-基）-異菸鹼醯胺與碘化鈉及2-(溴乙基）吡啶氫溴酸鹽於DMF。 ES-MS m/e (%): 5 00 (M + Na +，30)，47 8 (M + H +，100)。 實施例5 1-(2 -嗎啉-4-基-2-酮基-乙基）-2-酮基-1，2 -二氫“比啶-4-羧 酸（4 -甲氧基-7-嗎啉-4-基-苯并嘍唑-2-基 > 醯胺 於200毫克（0·52毫莫耳）2-酮基-丨，2•二氫-吡啶羧酸（4_ 甲氧基-7-嗎啉-4-基-苯并嘍唑-2-基）·醯胺於1毫升DMF及 4毫升1，2 -二甲氧基乙烷之經攪拌溶液内加入44毫克（丨.〇4 -27- 200407137 (22)
毫莫耳）氫化鈉（6 0 %於礦油分散液）。於室溫攪拌1 5分鐘 後，加入90毫克（1.04毫莫耳）溴化鋰及又持續攪拌15分 鐘。然後加入95毫克（0.58毫莫耳）4-(2-氯乙醯基）嗎啉，混 合物於室溫攪拌1 6小時。然後反應混合物以乙酸乙酯稀 釋，循序以0.5 Μ鹽酸、飽和碳酸氫鈉溶液及飽和鹽水洗 滌。合併有機相經過濾，濾餅以醚洗滌，然後再懸浮於甲 苯及真空濃縮。急速層析術（甲醇/二氯甲烷）接著以乙酸乙 酯濕磨獲得83毫克（31%) 1-(2-嗎啉-4-基-2-酮基-乙基）-2-酉同基-1，2-二鼠-口比°定-4 -竣酸（4-甲氧基-7-嗎。林-4 -基-苯并 噻唑-2-基）-醯胺呈黃色結晶固體。ES-MS m/e (%): 536 (M + Na +，25)，5 14 (M+H +，100)。 以類似方式獲得： 實施例6
1-二曱基胺基甲酿基甲基-2 -S同基-1，2 -二鼠比咬-4 -竣酸 (4 -甲氧基-7-嗎啉-4-基-苯并噻唑-2-基）-醯胺 始於2 -嗣基-1，2 -二鼠-?比淀-4 -竣酸（4 -甲氧基-7 -嗎淋-4 -基_ 苯并嘍唑-2-基）-醯胺與氫化鈉、溴化鋰及2 -氯-N，N-二曱基 乙醯胺於1，2-二甲氧乙烷及DMF。ES-MS m/e (%): 494 (M + Na +，22)，472 (M + H +，100)。 -28 -
Claims (1)
- 200407137 拾、申請專利範圍 1. 一種具有如下通式之化合物 OCH其中 R為苯基、吡啶-2-基、-C(0)-0-低碳烷基、C(O)-低碳 烷基、-C(O)-嗎啉基、-C(0)-NR’2、-(CH2)n-NR’2 或 -(CH2)n-0-低碳烷基以及R’為氫或低碳烷基； 及其醫藥可接受性酸加成鹽。 2. 如申請專利範圍第1項之式I化合物，其中R為苯基。 3. 如申請專利範圍第2項之式I化合物，其中該化合物為1 -芊基-2-酮基-1,2-二氫-吡啶-4-羧酸（4 -甲氧基-7-嗎啉 -4 -基-苯并嘍唑-2-基）-醯胺。 4. 如申請專利範圍第1項之化合物，其中R為-C(0)0-低碳 烧基。 5. 如申請專利範圍第4項之化合物，其中該化合物為[4-(4-甲氧基-7-嗎啉-4-基-苯并噻唑-2-基胺基甲醯基）-2 -酮 基-2 Η -吡啶-1 -基]-乙酸乙酯。 6. 如申請專利範圍第1項之化合物，其中R為-C(O)-低碳烷 2004071377. 如申請專利範圍第6項之化合物，其中該化合物為2 -酮 基-1 - ( 2 - S同基-丁基）-1，2 -二鼠-叶匕°定-4 -藏酸（4 -甲氧基-7 _ 嗎啉-4 -基-苯并噻唑-2 -基）-醯胺。 8. 如申請專利範圍第1項之化合物，其中R為吡啶基。 9. 如申請專利範圍第8項之化合物，其中該化合物為2 -酮 基-1-吡啶-2-基-曱基-1，2-二氫-吡啶-4-羧酸（4 -曱氧基 -7 -嗎淋-4 -基-苯弁邊σ坐· 2 -基）-酿胺。 10. 如申請專利範圍第1項之化合物，其中R為-c(〇）-嗎啉 基。 1 1 .如申請專利範圍第1 〇項之化合物，其中該化合物為 1 - (2 -嗎4木-4 -基-2 -綱基-乙基）-2 - 8¾基-1，2 -二鼠·口比咬-4 _ 緩酸（4 -甲乳基-7-嗎11 林-4-基-苯弁坐-2-基）-酿胺。12.如申請專利範圍第1項之化合物，其中R為- C(0)-NR'2。 1 3 .如申請專利範圍第1 2項之化合物，其中該化合物為1 -二曱基胺基曱醯基甲基-2-酮基-1，2-二氫-吡啶-4-羧酸 (4 -曱氧基-7-嗎啉-4-基-苯并噻唑-2·基）_醯胺。 1 4 · 一種製備如申請專利範圍第1 -1 3項中任一項定義之式I 化合物之方法，該方法包含 a)將一種下式化合物-2 200407137與一種下式化合物 ⑺ 反應成一種下式化合物其中R為苯基、吡啶基、-C(0)0-低碳烷基或-C(O)-低碳 烧基， 或 b)將一種下式化合物與一種下式化合物 R R (7)或 CI-/ (9) 反應成一種下式化合物 200407137其中R為-C(O)-嗎啉基 、-(CH2)n-0-低碳烷基、 -(CH2)nNRf2 或-(CO)NR’2，及 若有所需，將所得化合物轉化成醫藥可接受性酸加成 鹽。 1 5 .如申請專利範圍第1至1 3項中任一項之化合物，其係經 由如申請專利範圍第1 4項之方法或其相當之方法製備。 1 6 · —種藥劑，含有一或多種如申請專利範圍第1至1 3項中 任一項之化合物及醫藥可接受性賦形劑。 1 7 .如申請專利範圍第1 6項之藥劑，其係用於治療腺甞受體 相關疾病。1 8 · —種如申請專利範圍第1至1 3項中任一項之應用，其係 用於治療疾病。 1 9 · 一種如申請專利範圍第1至1 3項中任一項之應用，其係 用於製造對應腺甞A2 a受體相關疾病治療用藥。 200407137 陸、（一）、本案指定代表圖為：第_圖 (二）、本代表圖之元件代表符號簡單說明： 柒、本案若有化學式時，請揭示最能顯示發明特徵的化學 式：
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| SE521512C2 (sv) | 2001-06-25 | 2003-11-11 | Niconovum Ab | Anordning för administrering av en substans till främre delen av en individs munhåla |
| US6727247B2 (en) * | 2001-12-10 | 2004-04-27 | Hoffman-La Roche Inc. | Substituted benzothiazole amide derivatives |
| ES2708552T3 (es) | 2002-12-20 | 2019-04-10 | Niconovum Ab | Método para la preparación de un material particulado que contiene nicotina con una celulosa cristalina (en particular MCC) |
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| WO2005044793A2 (en) | 2003-10-31 | 2005-05-19 | Takeda Pharmaceutical Company Limited | Nitrogen-containing fused heterocyclic compounds |
| BRPI0513510A (pt) * | 2004-07-22 | 2008-05-06 | Hoffmann La Roche | benzotiazóis substituìdos |
| RU2382782C2 (ru) * | 2004-07-22 | 2010-02-27 | Ф. Хоффманн-Ля Рош Аг | Производные бензотиазола |
| ES2273599B1 (es) * | 2005-10-14 | 2008-06-01 | Universidad De Barcelona | Compuestos para el tratamiento de la fibrilacion auricular. |
| JP5694645B2 (ja) | 2006-03-16 | 2015-04-01 | ニコノヴァム エービーＮｉｃｏｎｏｖｕｍ Ａｂ | 改善された嗅ぎたばこ組成物 |
| AU2007322269A1 (en) * | 2006-10-11 | 2008-05-29 | Alpharma Pharmaceuticals, Llc | Pharmaceutical compositions |
| PT2144905E (pt) * | 2007-04-04 | 2013-02-26 | Merck Sharp & Dohme | Agentes terapêuticos |
| US9549909B2 (en) | 2013-05-03 | 2017-01-24 | The Katholieke Universiteit Leuven | Method for the treatment of dravet syndrome |
| EP3393655B1 (en) | 2015-12-22 | 2020-12-09 | Zogenix International Limited | Fenfluramine compositions and methods of preparing the same |
| CA3007673A1 (en) | 2015-12-22 | 2017-06-29 | Zogenix International Limited | Metabolism resistant fenfluramine analogs and methods of using the same |
| EP4201427A1 (en) | 2016-08-24 | 2023-06-28 | Zogenix International Limited | Formulation for inhibiting formation of 5-ht 2b agonists and methods of using same |
| US10682317B2 (en) | 2017-09-26 | 2020-06-16 | Zogenix International Limited | Ketogenic diet compatible fenfluramine formulation |
| JP2021526507A (ja) | 2018-05-11 | 2021-10-07 | ゾゲニクス インターナショナル リミテッド | 発作により誘発される突然死を処置するための組成物および方法 |
| WO2019241005A1 (en) | 2018-06-14 | 2019-12-19 | Zogenix International Limited | Compositions and methods for treating respiratory depression with fenfluramine |
| EP3883555A1 (en) | 2018-11-19 | 2021-09-29 | Zogenix International Limited | Methods of treating rett syndrome using fenfluramine |
| DE102019110904B4 (de) | 2019-04-26 | 2022-01-20 | Helmholtz-Zentrum Dresden - Rossendorf E. V. | N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-acetamid-Derivate und deren Verwendung |
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| RU2295523C2 (ru) | 2007-03-20 |
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| PA8557901A1 (es) | 2003-06-30 |
| MXPA04004683A (es) | 2004-08-12 |
| AR037528A1 (es) | 2004-11-17 |
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| EP1448196B1 (en) | 2005-10-12 |
| RU2004118423A (ru) | 2006-01-10 |
| DE60206652T2 (de) | 2006-06-22 |
| AU2002366194B2 (en) | 2006-10-26 |
| CA2467551A1 (en) | 2003-05-30 |
| GT200200233A (es) | 2003-06-17 |
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| ATE306265T1 (de) | 2005-10-15 |
| CN100346792C (zh) | 2007-11-07 |
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