TW200526631A - Amide derivatives as ion-channel ligands and pharmaceutical compositions and methods of using the same - Google Patents
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- TW200526631A TW200526631A TW093130317A TW93130317A TW200526631A TW 200526631 A TW200526631 A TW 200526631A TW 093130317 A TW093130317 A TW 093130317A TW 93130317 A TW93130317 A TW 93130317A TW 200526631 A TW200526631 A TW 200526631A
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200526631 九、發明說明: 【發明所屬之技術領域】 本發明係關於新穎化合物及關於含這類化合物的醫藥 組成物。本發明亦關於使用本發明之化合物和醫藥組成物 預防及/或治療哺乳動物中疼痛及發炎相關症狀的方法,例 如預防及/或治療(但不限於):關節炎,帕金森氏症,阿 茲海默氏症,中風,葡萄膜炎,氣喘,心肌梗塞,疼痛綜 合徵(急性與慢性或神經性的)的治療和預防,創傷性腦 才貝傷,急性脊椎神經損傷,神經變性失調,禿頭症(落髮), 發炎性腸道疾病及自身免疫失調。 【先前技術】 身體内化號路徑的研究已顯示離子通道的存在並試圖 解釋匕們的角&。離子通道是具有二種特殊特徵的嵌入膜 之虫白貝·匕們是藉由特異性信號如膜電壓或化學配體的 直接鍵結而調控(打開和關閉),一旦打開之後,它們以 極高速率將離子傳導橫過細胞膜。 有許多類型的離子通道。根據它們對離子的選擇性, 它們可分成㈣子通道、鉀離子通道、鈉離子通道等等。 約離子通道對於約離子比其他類型的離子更具滲透性,鉀 離子選㈣離子優先於其他離子,以此_。離子通道亦 可根據它們的調控機轉予以分類。在電壓調控 (v〇ltage-gated)離子通道中,打開的概率取決於膜電塵, :在配體調控(llgand_gated)離子通道中,打開的概率則 是由小分子(配體)的输紝才 Λ/Γ 丑^扪鍵結來调即。由於配體調控離子通 200526631 道係自配體接收信號,它們可視為配體的”受體π。 配體调控離子通道的例子包括nAChR (於驗乙醯:膽驗 受體)通道、GluR (穀胺酸受體)通道、ATP敏感性鉀離 子通道、G-蛋白活化通道、環:g:酸調控通道等等。 瞬時受體電位(TRP )通道蛋白質構成一個大而多樣的 蛋白質家族,其係於許多組織和細胞類型中表現。此通道 豕族媒介對神經生長因子、信息素、嗅覺、血管緊張度及 代謝壓力等等的應答,且這些通道被發現在各種不同的器 官、組織及細胞類型中,包括非興奮性平滑肌及神經元細 胞。此外,TRP相關的通道蛋白質係牵連於數種疾病中, 例如數種腫瘤和神經變性的失調及諸如此類。見例如Minke, 等人,」PArach 9:0006P (2002)。 傷害受體是特化初級傳入神經元,是在一系列導致疼 痛感覺的神經元中的第一細胞。在這些細胞中的受體可被 不同的有害化學或物理刺激活化。傷害受體的基本功能包 括將有害刺激轉化成引發動作電位的去極化,將來自初級 感覺部位的動作電位傳導至中樞神經系統中的突觸,以及 在突觸前末端將動作電位轉換成神經遞質釋放,這些都與 離子通道有關。 特別感興趣的一種TRP通道是香草精類(vanill〇id) 受體。亦稱為VR1,香草精類受體是一種非選擇性陽離子 通道,其係由一系列不同的刺激,包括辣椒素、熱和酸刺 激,以及脂雙層代謝產物(極樂醯胺(anandamide))和脂氧 化酶代謝產物予以活化或敏化。參見例如Smith等人 200526631 418:186-190 (2002)。VR1並不會在單價陽離子當中 識別,然而,它對於二價陽離子展現出顯著的偏好,^有 Ca2+ > Mg2+ > Na+ = Κ+ = cV的滲透性順序。^2+對術功 能尤其重要,因為細胞外Ca2+係媒介脫敏作用,即一種使 得神經元藉由減小其對特定化學或物理信號之整體應答來 適應特定刺激的過程。VR1在大鼠、小鼠及人類的::感 覺神經元中係高度表現者,且神經支配許多内臟器官,包 括皮膚、骨頭、膀胱、消化道及肺。纟亦在其他神經元盥 非神經元組織中表現,包括CNS、細胞核 '腎臟、胃及丁、_ 細胞。VR1通道是具有6個跨膜結構域之離子通道總族中 的-員TRP家族的離子通道有最高的同質性。… VR1基因剔除小鼠已經被證實對熱與酸刺激有降 感覺敏感性。參見例如Caterina,等人Μ」 (2000)。這支持了 VR1不僅有助於疼痛應答產生,而且還 有助於感覺神經基礎活性飧拄 ^ Γ、、隹持的觀念。VR1激動劑和拮技 劑有作為治療各種不同發峰式 σ Ν〜生或病原疼痛如急性、發炎性盥 神經性疼痛、牙痛及頭痛(例 ^ J女偏頭痛、充血性頭痛和 張性頭痛)之止痛劑的用途 ” ^ 匕們亦可用作抗發炎劑來、么 療關節炎、帕金森氏症、阿茲 如 /π 一 每”,大氏症、中風、葡萄膜炎、 氣喘、心肌梗塞、疼痛徵候群(急性和慢性[神經性])、 創傷性腦損傷、脊髓損傷、神 苟狎經變性失調、禿頭症(落髮 發炎性腸道疾病與自身免瘂 牙尤反失调之治療和預防、腎臟病、 肥胖、飲食失調、癌症、精彳 砰刀裂症、癲癇、睡眠失調、 認知、抑鬱、焦慮、血脂失 曰天凋以及動脈粥樣硬化。 200526631 一些化合物,例如本發明者,其與香草精類受體行交 互作用,因此可在治療或預防或改善這些症狀方面扮演重 要角色。 廣泛不同具有不同結構的香草精類化合物在此技藝中 已為人所知,例如揭示於歐洲專利申請案號Ep 〇 Μ? 〇㈧ 和EP 0 401 903、英國專利申請案號GB 2226313及國際專 利申請案公開案號WO 92/09285中者。特別值得注意的香 草精類化合物或香草精類受體調節劑例子是離析自辣椒植 物的辣椒素(capsaicin)或反式8_甲基_N_香草基_6_壬烯醯 胺、辣椒西泮(capsazepine) ( Tetrahedr〇n,53, 1997, 479ι ) 及奥伐尼(olVanil )或N_(4_羥基_3_曱氧基苄基)油醯胺(j.
Med· Chem·,36,1993, 2595 )。 國際專利申請案公開案號w〇 〇2/〇8221揭示二芳基 呢畊及相關化合物,其係以高選擇性與高親合力與香草精類 受體結合,尤其是與第〗型香草精類受體,又稱為辣椒素或 VR1 *體結合。這些化合物據說可用於治療慢性與急性疼 痛症狀、疥瘡及尿失禁。 國(V、專利申晴案公開案號WQ 〇2/16317、w〇 〇2/16318 和WO 02/163 19提出具有高香草精類受體親合力的化合物 可用來治療胃-十二指腸潰瘍。 美國專利案號US 3,424,760和US 3,424,761二者敘述 系列據况可展現出止痛、中樞神經系統及心理藥理活性 的3-脲基卩比嘻烷。這些專利分別具體地揭示化合物丨_(1_苯 基各烧基)冬苯基脲* !仆苯基_3奇各烧基)小(心甲 200526631 T'專利申鮰案公開案號WO 01/62737和 WO 00/69849揭示一备别祕^ 尔〜艨說可用於治療與Νργ受體亞型 有關之失旧#疾病如肥胖的赃唾衍生物。w〇 g1/62737 ㈣地揭示化合物5-胺基*異傅5-基小[3-(三氟甲基) 本基>ιη普胺。wo嶋9849具體地揭示化合物5_ 甲基NL8·基小[3.(三氟甲基)苯基坐·3·酿胺、 甲基Ν 口圭琳-7_基+ Κ三氟甲基)苯基]比唑小醯 胺、5-甲基善口缚3·基]例三I甲基)苯基]]Η|坐-3- -皿月二N異口圭啉_5备5_甲基小[3_(三氣甲基)苯基]I屬唑 酉-月女5-曱基春啥.5_基+[3《三氟甲基)苯基]-⑶屬 坐1胺、卜(3_氯苯基)-Ν-異喹咐基巧·甲基_1H-吡唑_3_ ^月女N-異口奎咐-5 _基小卜甲氧基苯基)甲基]η鲁坐冬 ^ 1(3·氟苯基異喹啉·5_基·5_曱基-1H-毗唑醯 月女1气2-氣三氟甲基苯基)-N-異喹啉_5·基-5-甲基-1N-毗 j弘騃胺、甲基-N_(3·甲基異喹啉-5-基)-1-[3-(三氟曱基) 苯基]_1N|坐_3_酿胺、5_曱基4(1,2,3,4_四氫異喹啉j 基)1 [3-(二氟曱基)苯基卜1Η_吡唑_3_醯胺。 t國專利申晴案號25〇2588敘述一系列的呢啡衍生 物。此申請案具體地揭示化合物N_[3-[2_(二乙胺基)乙 基]-1,2-二氫_4_曱基側氧_7·喹啉基]·4·苯基_丨_顿畊醯胺。 Ρ我們現在已經發現,某些化合物具有作為VR-1拮抗劑的 ^人/曰力和選擇性。本發明的化合物被認為作為vR-1拮抗 J疋特別有利益的,因為某些化合物展現出改良的水溶性和代謝安定 性。 200526631 【發明内容】 現在已經發現到,一些化合物,如 夠修飾喷乳動物的離子通道,例如VR1陽=:者,能 :見_有治療價值的新穎化合物出子 改善魏動物中==成物及彼等於治療、預防或 不同… 症狀的用途,例如但不限於:各種 性疼動,=原的疼痛’例如急性、慢性、發炎性和神經 痛)。’及頭痛(如偏頭痛、充血性頭痛及緊張性頭 R3·—L- R1 (I) 式中: Α是Ν、CR4、鍵結至l的碳原子,或者不是原子,· 如果A不是原子,則W、Z、B、Y及X之一是鍵結至 的石反原子,W、Z、Β、γ及X之另一者是鍵結至G的碳 原子’而其餘的W、Z、b、Y及X各獨立地為N或CR4 ; L是經取代或未經取代之-(C-C)-、-(CR5 = CR6)_或 G 是 C = 0、 C = s 或 S〇2 ; R1是經取代或未經取代之脂族、烷基、雜烷基、芳基、 雜芳基、芳烷基或雜芳烷基; 200526631 R是氫或經取代或未經取代之烷基; R3是經取代或未經取代之脂族、烷基、雜烷基、芳基、 雜芳基、芳烷基或雜芳烷基;以及 各個R4係獨立地為氫、烷基、經取代或未經取代之烷 基、醯基、醯胺基、烷胺基、烷硫基、烷氧基、烷氧基羰 基、烷基芳胺基、芳基烷氧基、胺基、芳基、芳烷基、亞 楓、楓、硫烷基、胺基磺醯基、芳磺醯基、硫酸、硫酸酯、 二羥基磷醯基、胺基羥基磷醯基、疊氮基、羧基、胺基甲 鼷基、羧基、氰基、環雜烷基、二烷胺基、函基、雜芳氧 基、雜芳基、雜烧基、羥基、硝基或硫代;以及 R和R各獨立地為Η、鹵素,或為經取代或未經取代 之脂族、芳基、雜烷基、芳基、雜芳基、芳烷基或雜芳烷 基; 或其醫藥上可接受之鹽、溶劑合物或前藥; 及其異構物或立體異構物。 在本發明的進一步具體實例中,具有式ΙΑ之化合物能 夠在活體内修飾離子通道·· R3—
(ΙΑ) 在式ΙΑ化合物的特定具體實例中,L是經取代或未經 11 200526631 取代之-(C-C)-、_(CR5 = eR% 及、(C )-’ G 是 c = θ 取代或未經取代之脂族、芳 疋、! 芳烧基或雜芳炫基’ 、雜縣、芳基、雜芳基、 脂族或烷基。 而R疋I取代或未經取代之 在式IA化合物的另一個 特定具體實例中,德令經么4、 IA,化合物者,r3_l表示邱八 後文稱為式 衣不邛分:Cr3r6 = cr5
式中R3係如就式Ϊ化合物 汁疋義者,而R5和R6係獨 地選自於氫、鹵素經取代 % η ^禾經取代之脂族、芳基、 雜燒基、芳基 ' 雜芳基、芳絲及雜芳燒基。 、在某些特定的化合物中’ r3係選自於經取代或未經取 代之C1-6烷基、經取代或未經取代之C1_6環烷基、經取 代或未經取代之芳基及經取代或未經取代之芳烷基;而各 個R和R係獨立地選自於氫、鹵素及經取代和未經取代之 C1-6烷基;以及〇_3個選自於w、ζ、χ和γ的基團表示 在式Ϊ A ’的化合物中,r5和R6舉例來說可獨立地表示 氫、鹵素或經取代或未經取代之C K6烷基。較佳的是,R5 12 200526631 和R6表示氫。 在式1A化合物的另一 『化合物者,… 例中,後文稱為式 R -L表不部分R3C<:。 在式I、IA、1入,及ίΑ,,的化合物 示⑶。或者,G可表示S〇2。 車乂佳的疋,G表 、IA、IA’及1A’’的化合物中,W、z、v 例來說可各表〒Γρ4 ^ ^ Ζ X和γ舉 分表不CR,尤其是CH。或者, W、Z和Y可夂本—X 了表不N,而 了各表不CR4。在化合物的 Y和Z各表示士、甘θ 組例子中,X、 W是N。 R,尤其是CH。在化合物的另-組例子中, H,在式1與1A的化合物中,L較佳LC) 或-C心。因此,在化合物的一組例子中,L表示—( 在化合物的另一組例子中,L表示·c丈… 在式卜,,的化合物中,R1舉例來說可表 示經取代或未經取代之芳基’如經取代之苯基。取代基的 例子包括院基、烧基(OH)、_C0C)H、c(Me)3、CH(Me)2、齒 基、cf3、氰基及甲氧基。或者,它可表示經取代或未經取 代之毗啶基。 在式I、IA、IA’及IA,,的化合物中,R2較佳係表示氫。 在式I、IA、IA’及U,,的化合物中,R3舉例來說可表 不CR6’R7R8,其中R6’表示氫、鹵素或經取代或未經取代之 C1-6烷基;117和R8各獨立地為_基或經取代或未經取代 之CP6烷基;或R與R8—起形成一個經取代或未經取代 之C3-8環烷基環。舉例來說,R7可表示低級烷基(如曱基)。 13 200526631 舉例來說,R 8 π主一 R 了表不低級烷基(如f美) R6,可表示氫,而s ^基)。在特定例子中, 和R可表示甲基。或者 口了表不甲基。或者,r6,、r7和 和 R6,可表干与 7 各可表示氟。或者, J表不虱’而R7與RL起形成 飞書 在守τ ^取個%己基環。 R3舉例:二、-IA,及1A,,化合物的進-步具體實例中, 在:二可表不經取代或未經取代之芳基或雜芳基。 正而其:化合物的第一個替代具體實例中,R3是CF 正丙袭或下式之基團: γ K疋cf3、
R 其巾R2’是氫或烧基;且其中1固R2,可接合
成一個3-8個;f子的if、p其十、γ M H 京子的衣烷基或㈣隹烷基環;但前提是R2,中
至少二個為烷基。 Y ::式以之化合物,R1可為經取代之苯基,或者為經 取代或未經取代之萘基。此外,R,亦可為經取代或未心 代之雜方而在一特定具體實例中’雜芳基可選自於所 組成之群時定基、噻唾基及吡。坐基。更特定言之,雜芳基 可為2|定基、3鲁定基或4普定基。在—特定具體實例 中’雜芳基上的取代度係選自於氫、烷基、三氟甲基、_ 基甲氧基、二敗甲氧基、胺基及羧基所組成之群組。在 更進一步特定具體實例中,雜芳基上的取代度係選自於第 一丁基、氰基、二氟烷基、i!基、硝基、甲氧基、胺基及 敌基所組成之群組。 在本發明衍生自式IA化合物之又更進一步方面,以及 14 200526631 在其第二個替代具體實例中,係揭示其他能夠在活體内修 飾離子通道的化合物,其具有式II ··
R3—L
(Π) 3其中L、W、X、Y、z、Rl係如對於式IA所定義者, 而R係如對於式IA之第一個替代具體實例所定義者。在第 二個替代具體實例的—特定具體實例中,r1可為經取代之 烷基或-(CR22)X-R4’。如果Rl是_(CR22)x_R4,,R2是氮或炫 基,則R疋R且R4係如就式】所敘述者,而η是i _3的 整數。在此同一具體實例中,R4,可選自於第三丁基、芳基、 環烧基、環雜烧基及雜芳基;或者,R4,可選自於經取代或 未經取代之苯基或萘基;又或者,R4,可選自於環丙基、環 戊基或環己基所組成之群組;再者,R4’可為選自於經取代 或未經取代之毗咯烷基、哌啶基或嗎咐基;再進一步者,r4’ 可為選自於經取代或未經取代之毗啶基或嘧啶基;除此之 外,R可為選自於經取代或未經取代之呋喃基、咪唑基、 噻吩基、卩比唑基或噻唑基。R4亦可為選自於經取代或未經取 代之苯并二聘烷基、苯并吡喃基、吲哚基、吲唑基、亞甲基 二氧基苯基、喹啉基、異喹啉基、四氫喹啉基、四氫異喹咐 基、二氫喹啉基或二氫異喹啉基。在一特定具體實例中,R4, 是t-Bu。關於所有在此具體實例内的前述變數,x是i或2。 在根據式2化合物的進一步具體實例中,其中Rl為經 15 200526631 取代之烷基,R1可為t_Bu, 環燒基、環雜烧基或雜芳λ者可為經取代或未經取代之 之環丙基或環戍基。R1亦;::可為經取代或未經取代 基、•基或嗎咐基,或者亦;:取代或未經取代之·炫 基或《基,或進—步而」為經取代或未經取代之_ 基、㈣、噻吩基、_二:經取代或未經取代之呋喃 吡1基或噻唑基。在進一步具體實例 L ?亦可為經取代或未經取代之苯并二嶋、苯㈣ 基、•坐基、亞甲基二氧基苯基、喧咐基、異喧 ::、四氮罐、四氯異喧咐基、二氣哇咐基或二氯異喧 咐基。在更進一步的具體實例中,r1可為經取代或未經取 代之方基,尤其可為經取代或未經取代之苯基、萘基、2- 聯苯基或4-聯苯基。 在本务明衍生自< Π化合物的更進一步方自,係揭示 其他能夠在活體内修飾離子通道的化合物,其具有如下之 式 III :
(III) 其中R1是R4 ;而X係選自於1 _5。在此具體實例中,χ 可為1 ; R1’可選自於曱基、異丙基、第三丁基、氰基、三 氟燒基、il基、硝基、甲氧基、三氟曱氧基、胺基、烷胺 基、二烷胺基、苯基、S02Me、S02CF3、S02NMe2及羧基 所組成之群組;R1取代度可在4-位上。 16 200526631 w、二:明 t . 、^為™且其一或多者可為N。尤其 和可各為N,而並餘為CR4,& ^ “τ 而且四個位置的任咅-伽, 為N,同樣地位置的其餘部 ―個可 每私丨击T R 在此特別敘述的1娜 貝例中,L可為-(CR5 = CR6)·,其中 體 其中之-為甲基,而另-者為氫。此外τ為風’或者 ^ 〇3 1 乳此外,L可為 可為 t-Bu、i-pr 或 CF3。 , 在本發明的進一步且體 體内修飾離子通道,在下、文稱’:他:合物能夠在活 接合至GNRiy的 ·.、、式B化合物,其中B是 二 接合“R3的碳原子;“、 Z係如就式ϊ化合物所定義 尤其是心係如就式!化 ==二, 而^ +和^各如就式^^且^圭為^ 係如就式一 IA,,化合物所=疋義者, 所說2 =的特定具體實例中,本發明的化合物係有 明於表】中'7類化合物的综合列表,稍後於本文說 且以^且右表包含超過物種的化合物,其已經合成 活性,因1在本其活體内修飾離子通道能力方面經證實的 面發揮功能 所述有關於辣椒素與受體的治療應用方 本發明的化 過敏和觸摸痛。 覺過敏和觸摸痛 尿病的神經病變 」勿可用來治療發炎性疼痛及伴隨的痛覺 匕們亦可用來治療神經性疼痛及伴隨的痛 (例如三叉神經的或皰疹性的神經痛、糖 灼痛、父感神經系統由來的疼痛及去傳 17 200526631 入神經機轉徵候群,例如臂神經叢撕裂傷)。本發明的化 亦可用來作為治療關節炎的抗發炎劑,以及作為
來治療帕会在乐+ M 山 ”氏症、阿茲海默氏症、中風、葡萄膜炎、氣 梗基創傷性腦損傷、脊髄損傷、神經變性的失 周儿頭症(洛髮),發炎性腸道疾病與自身免疫失調、
腎臟病、肥脒、从人L 飲艮失調、癌症、精神***症、癲癇、睡 眠失調、認知、抑鬱、焦慮、血脂失調及動脈粥樣硬化。 面本發明提供能夠在活體内修飾離子通道的化 合物。如是修飾之冲主^ μ 、、的化 年之代表性離子通道包括電壓調控通道和配 體調控通道,包枯胳外: 、 一 匕括%離子通道,如香草精類通道。 、,方面本發明提供包含本發明化合物盘醫華葡 劑、賦形劑或稀釋劑白”薙…酉条載 w 、 d的酉樂組成物。在本發明的這-方面, 口亥酉樂組成物可包A 一 3 或夕種本文所說明的化合物。 在本發明的進_牛古Jr- _ /方面,揭示一種治療易患或惱於來 自本文所列症狀當中之 炎、 尸 尤一疋诸如可能與例如關節 、火、乳喘、心肌梗塞、創傷性 椎神經損傷、化症(落髮),發“乂生含 的方…士南礼動物,包括人類以及低等哺乳物種 的方法,该方法包括投予有 藥組成物。 里之或夕種方才說明的醫 在又另一個治療方〉本古;+ . ,、 法方面中,本發明提供一 #、、A瘆 、:::Γ起疼痛反應或與感覺神經基礎:性= 句衡有關之症狀的哺乳動物 H说, 们万/去廷些化合物具有作 為⑺療各種不同發生或 原疼痛之止痛劑的用途,例如治 18 200526631 療急性、發炎性疼痛f你丨上t 關的疼痛);各種不同的、:Λ骨關節炎和風濕性關節炎有 性的神經痛、三又神性疼痛徵候群(例如後鮑療 糖尿病的神經J、::t 射***感神經失養症、 忾文 格林巴里徵候Μ广^ w —e)、纖維肌痛 、 U1 lan Barre 神經病變、請神經病變,肢f /L房切除後疼痛、周邊 神經病變);臟器性;台療誘發和其他醫源性 尿科失調有關者)、=;;!:姨臟炎及各種婦科與泌 痛及緊張性頭痛)。痛及頭痛(例如偏頭痛、充血性頭 在另外的治療方沐士^ 於下列疾病與失調之哺的=明提供治療易患或惱 調,例如帕金森氏症 、:發炎所媒介或產生的疾病與失調,例如創二Γ 營:狂躁,症、焦慮、精神***症、飲=二抑 失凋和涊知失調;痛痛和_㈣ 眠 腸道官能障礙,例如尿失禁、排尿遲緩、直=敏:胱和 排便失禁、攝護腺腫大和發炎性腸道疾病’·呼吸道和^ 的疾病與失調,例如過敏性鼻炎、氣喘 二 及慢性阻塞性肺病;由發炎所媒介或產生的疾病 例如風濕性關節炎盥晋Μx 5 "P人與月關即炎、心肌梗塞、各種 疾病與失調、葡萄膜炎和動脈粥樣硬化 : 牛皮癖;充頭…髮);肥胖;脂質失調,·癌 19 200526631 該方法包括投予有效治療症狀 才說明的醫藥組成物。 壓;脊髓損傷;及腎臟病; 或預防症狀量之一或多種方 本發明提供合成本發明化合物的方法 代表性的合成方案與途徑。 在另外方面 稍後在本文中揭 在考里Ik後的洋細說明並配合下列說明性圖式後,其 他目的和優點對於熟諳此技藝者將變得顯而易見。 【實施方式】 明詳細說曰i 定義 在敘述化合物、含這類化合物的醫藥組成物及使用這 類化合物與組成物的方法時,下列名詞具有下述意義,除 非另外心日月。亦應瞭解的是,以下所定義部分的任一者可 、,'、彳不同取代基取代,而且個別定義係意欲將這類經取 代之部分包括在其範圍内。作為非限制性例子而言,這類 取代基可包括例如··鹵素(如說、氯、漠),-CN,-CF3,-OH, 3 C2 6稀基’ cr6炔基,cr6烧氧基,芳基及二烧胺基。 “醯基’,係指基團-C(0)R,其中R是氫、烷基、環烷基、 壞雜烷基、芳基、芳烷基、雜烷基、雜芳基、I隹芳烷基, 如本文所疋義者。代表性實例包括但不限於:甲醯基、乙 基、環己基羰基、環己基甲基羰基、苯甲醯基、苄基幾 基及诸如此類。 ‘‘酿基胺基,,係指基團-nr,c(o)r,其中R,是氫、烷基、 裒丈元基環雜烧基、芳基、芳烧基、雜烧基、雜芳基、雜 芳少兀基’而R是氫,烷基、烷氧基、環烷基、環雜烷基、 20 200526631 芳基、芳烷基、雜烷基、雜芳基或雜芳烷基,如本文所定 義者。代表性實例包括但不限於··甲醯基胺基、乙醯基胺 基、環己基羰基胺基、環己基甲基-羰基胺基、苯f醯基胺 基、节基幾基胺基及諸如此類。 ‘‘醯氧基’’係指基團-〇C(〇)R,其中R是氫、烷基、芳基 或環烷基。 & ‘‘經取代之烯基,,包括在本文,,經取代,,的定義中所提及 之基團,且特別係指具有丨或多個取代基,如〗至5個取 代基’特別是1至3個取代基的縣,該取代基係選自於 醯基、醯基胺基、醯氧基、烷氧基、經取代之烷氧基、烷 氧基叛基、燒氧基幾基胺基、胺基、經取代之胺基、胺基 羰基、胺基羰基胺基、胺基羰氧基、芳基、芳氧基、疊氮 基、缓基、氰基、環院基、經取代之環院基、^、經基、 酮基石肖基、硫代院氧基、經取代之硫代院氧基、硫代芳 氧^、硫酮基、硫羥基、烷基-s(〇)-、芳基-s(0)-、烷基-s(0)2_ 及芳基-S(O)2·所組成之群組。 “烧氧基”係指基團视,其中R是烧基。舉例來說,特 定的烧氧基包括甲氧基、乙氧基、正丙氧基、㈣基、 正丁氧基、第三丁氧基、第二丁氧基、正戊氧基、正己氧 基、1,2-二甲基丁氧基及諸如此類。 I取代之烷氧基,,包括在本文,,經取代,,的定義中所提 、土團且特別係指具有1或多個取代基,如1至5個 取代基4寺別疋i至3個取代基的燒氧基,該取代基係選 自於酿基、醯基胺基、醯氧基、烧氧基、經取代之烧氧基、 21 200526631 烷氧基羰基、烷氧基羰基胺基、胺基、經取代之胺基、胺 基羰基、胺基羰基胺基、胺基羰氧基、芳基、芳氧基、疊 氣基、誠、氰基、職基、絲代之料基、鹵^、二 芳基、經基、酮基m聽氧基、經取代之硫代烧 乳基、硫代芳氧基、硫酮基、硫經基、炫基_s(〇)·、芳 基-s(0)-、烷基—s(0)2·及芳基·8(〇)2_α組成之群組。 “烷氧基羰基胺基,,係指基團-NRC(〇)〇R,,其中R是 虱、烷基、芳基或環烷基,而R,是烷基或環烷基。 族”係指特徵在於組成碳原子之直鏈、支鏈或環狀排 列且沒有芳族不飽和度的烴基有機化合物或基團。脂族包 括但不限於:烷基、伸烷基、烯基、伸烯基、炔基及伸炔 基。脂族基團通常有1或2個至約丨2個碳原子。 烷基”係指單價飽和脂族烴基,特別是具有至高達約 11個碳原子,更特定地就低級烷基而t,具有i至8個碳 原子,而再更特定言之,為丨至6個碳原子。烴鏈可為直 鏈或支鏈者。此名詞係由曱基、乙基、正丙基、異丙基、 正丁基、異丁基、第三丁基、正己基、正辛基、第三辛基 及諸如此類的基團做例子。“低級烷基,,一詞係指具有丨至6 個厌原子的烧基。‘烧基’’ 一詞亦包括如下文定義的“環烧 基,,。 經取代之烧基”包括在本文”經取代,,的定義中所提及 之基團’且特別係指具有1或多個取代基,如1至5個取 代基,特別是1至3個取代基的烷基,該取代基係選自於 酉监基、醒基胺基、醯氧基、烷氧基、經取代之烷氧基、烷 22 200526631 乳基幾基、燒氧基羰基胺基、胺基、經取代之胺基、胺基 羰基、胺基羰基胺基、胺基羰氧基、芳基、芳氧基、疊氮 基、羧基、氰基、環烷基、經取代之環烷基、鹵素、羥基、 雜芳基、酮基、硝基、硫代烷氧基、經取代之硫代烷氧基、 硫代芳氧基、硫酮基、硫羥基、烷基-s(〇>、芳基一s(〇)_、 烷基—s(0)2·,及芳基-s(o)2-所組成之群組。 “伸烷基”係指二價飽和脂族烴基,特別是具有至高達約 11個奴原子且更特別是丨至6個碳原子者,其可為直鏈或 支鏈者。此名一係由亞甲基(-CH2小伸乙基卜)、 伸丙基異構物(例如-C^CHAH2-和-CH(CH3)CH2-)及諸如 此類的基團做例子。 I取代之伸烷基”包括在本文,,經取代,,的定義中所提 及之基團,且特別係指具有丨或多個取代基,如丨至5個 取代基,特収1至3個取代基的㈣基,該取代基係選 自於酸基、《胺基、醯氧基、烧氧基、經取代之燒氧基、 k氧基^基心氧基羰基胺基、胺基、經取代之胺基、胺 基羰基、胺基羰基胺基、胺基羰氧基、芳基、芳氧基、疊 鼠基、緩基、氰基、^素、經基、酮基、確基、硫代燒氧 基、經取代之硫代烷氧基、硫代芳氧基、硫酮基、硫羥基、 烷基-S(O)- 之群組。 芳基-S(0)-、烷基_s(0)2_及芳基_s(〇)2所組成 烯基”係指單價烯鍵式不飽和烴基,較佳是具有至高達 約11個碳原子’尤其8個碳原子’更特別是^ 6 個碳原子者’其可為直鏈或支鏈者,並有至少1個且特別 23 200526631 是1至2個烯鍵 ('CH=CH2 )、 (-C(CH3)-CH2) 類0 不飽和度的位置。特定的烯基包括乙烯基 正丙烯基(-CH2CH=CH2 )、異丙烯基 、乙烯基與經取代之乙烯基,以及諸如此 中稀基係拓—價烯鍵式不飽和烴基,特別是具有至高 達約11個碳原子且更特別是2至6個碳原子者,其可為直 鏈或支鏈者,並有至少1個且特別是1至2個烯鍵不飽和 度的位置。此名詞係由伸乙烯基(_CH=CH·)、伸丙稀基異
構物(例如-CH-CHCH2-和-c(CH3)=CH-和-CH=C(CH3)-)及 諸如此類的基團做例子。 炔基係指炔鍵式不飽和烴基,特別是具有至高達約 11個碳原子且更特別是2至6個碳原子者,其可為直鍵或 支鏈者,ϋ有至少i個且特別是i至2個炔基不飽和度的 位置炔基的特定非限制性例子包括炔屬、乙炔基 (-CCH)、炔丙基及諸如此類。
經取代之炔基,,包括在本文,,經取代,,的定義中所提及 之基團,且特別係指具有1或多個取代基,如1至5個取 2 土特別疋1至3個取代基的炔基,該取代基係選自於 :基ik基月女基、醯氧基、烷氧基、經取代之烷氧基、烷 氧土羰基纟兀氧基羰基胺基、胺基、經取代之胺基、胺基 緩基:胺基羰基胺基、胺基魏氧基、芳基、芳氧基、疊氮 土-羧基氰基、環烷基、經取代之環烷基、!1素、羥基、 酮基、硝基、硫代烷氧基、經取代之硫代烷氧基、硫代芳 氧基、酮基、硫羥基、烷基_s(〇)_、芳基一s(〇)_、烷基一s(〇)2· 24 200526631 及芳基-S(0)2_所組成之群組。 “烧驢基”或“疏I,,A m _ 土 §用於本文時係指基團R-C(,並 中R疋氫或如以上所定義之烷基。 /、 “芳基”係指經由從芳族母環系統單一碳原子上除去— 個氫原子而得到之留> & #卜# J之早饧方私烴基。典型的芳基包括但不限 方、何生自乙烯合恩、苊、乙烯合菲、憩、奠、苯、蒯、 謹、丙稀合第、第、稠六苯、異稠六苯、並環己二烯 (hexalene )、不對稱_二環戊二烯并苯、對稱-二環戊二烯 并苯一氫茚、節、柰、稠八苯(octacene )、異稠八苯 Uctaphene)、並環辛二浠(〇cta]ene)、箱、戊·2,4_ 二烯、 稠五苯(Pemacene)、並環戊二烯(pentalene)、異稠五 苯(pentaphene)、花、並菲(phenalene)、菲、起、偕烯 (pWadene ) 1、皮憩(pyranthrene )、玉紅省(㈣以以)、 苯并菲(triPhenylene)、聯三萘(trinaphthaiene)及諸如 此類的基團。特定言之,芳基包含6至14個碳原子。 ‘‘經取代之芳基,,包括在本文,,經取代,,的定義中所提及 之基團,且特別係指可視需要被丨或多個取代基,例如i 至5個取代基,特別是丨至3個取代基取代的芳基,該取 代基係選自於醯基、醯基胺基、醯氧基、烯基、經取代之 烯基、烷氧基、經取代之烷氧基、烷氧基羰基、烷基、經 取代之烧基、快基、經取代之炔基、胺基、經取代之胺基、 胺基羰基、胺基羰基胺基、胺基羰氧基、芳基、芳氧基、 疊氮基、羧基、氰基、環烷基、經取代之環烷基、鹵素,羥 基、硝基、硫代烷氧基、經取代之硫代烷氧基、硫代芳氧 25 200526631 基、硫羥基、烷基-s(0)-、芳基—s(0)…烷基_s(〇)2_及芳基 -S(0)2_所組成之群組。 “稠合芳基,,係指環碳中有二個係與第二個芳基環或 脂族環共用的芳基。 烷芳基”係指如以上所定義之芳基,其係經一或多個如 以上所定義之烷基取代。 芳烷基’’或“芳基烷基,,係指如以上所定義之烷基,其係 經一或多個如以上所定義之烷基取代。 方氧基’’係指-0-芳基,其中‘‘芳基,,係如以上所定義者。 “烷胺基”係指基團烷基屮R,R,,,其中R,和R,,各係獨立 地選自於氫和:!:完基。 ‘‘芳胺基”係指基團芳基_ NR,R,,,其中R,和R,,各係獨立 地選自於氫、芳基及雜芳基。 “烷氧基胺基,,係指基團一N(H)〇R,其中R表示如以上所 定義之烧基或環院基。 ‘‘烷氧基羰基,,係指基團<(〇)-烷氧基,其中烷氧基係如 本文中所定義者。 ‘‘烷基芳胺基,,係指基團_NRR,,其中R表示烷基或環 烷基而R’是如本文中所定義之芳基。 、‘烷基磺醯基,,係指基團_S(0)2R,其中R是如本文中所 疋義之纟兀基或環烷基。代表性實例包括但不限於:甲基石生 &基、乙基續酿基、丙基磺醯基、丁基磺醯基及諸如此類。 ‘‘烷基亞磺醯基,,係指基團-S(0)R,其中R是如本文中 所疋義之烷基或環烷基。代表性實例包括但不限於:甲美 26 200526631 亞石黃酿基、乙基亞磺醯基、丙基亞磺醯基、丁基亞磺醯基 及諸如此類。 ‘‘烧硫基”係指基團-SR,其中R是如本文中所定義之烷 基或環烧基’其可如本文中所定義者視需要經取代。代表 性實例包括但不限於:甲硫基、乙硫基、丙硫基、丁硫基 及諸如此類。 “胺基”係指基團-NH2。 經取代之胺基,,包括在本文”經取代,,的定義中所提及 之基團,特別是指基團_N(R)2,其中各個R係獨立地選自於 氫、烷基、經取代之烷基、烯基、經取代之烯基、炔基、 經取代之块基、芳基、環烧基、經取代之環烧基所組成之 竽、、且,且其中_ R基團係接合在一起形成一個伸烧基。當 一 R基團都是氫時,-N(R)2為胺基。 、/‘胺基羰基,,係指基團_C(0)NRR,其中各個汉係獨立地 為虱、烷基、芳基及環烷基,或者其中R基團係接合在一 起形成一個伸统基。 ‘胺基羰基胺基,,係指基團_NRC(0)NRR,其中各個R係 獨立地為氫、烧基、芳基或環烧基,或者二個R基團係接 合在一起形成一個伸烷基。
“胺基幾氧基’’係指基團_0C(0)NRR,其中各個R :地為氫、院基、芳基或環烧基,或者其巾R基團係接合 在一起形成一個伸烷基。 “芳基烧氧基”係指_〇·芳基烧基,其中芳基 文中所定義者。 + 27 200526631 之芳基 芳胺基,,意謂基團-NHR,其中尺表示如本文中所定 義 方乳基碳基,,係指基團_c(〇)_〇_ 文中所定義者。 ,、中方基係如本 ‘‘芳石黃驢基’’位社廿前 ^ ^ , 指基團-S(0)2R,其中尺是如本文中所定 義之方基或雜芳基。 斤疋 “疊氮基,,係指基團氺3。 ^ "C(!)N(R)2 ^ ^ -R ^ ^ 土銥心基或方基,如本文中所定義者, 其可如本文中所定義者視需要經取代。 羧基,係指基團-C(0)〇H。 羧基胺基係指基團-Ν(Η)(:(0)〇Η。 ‘‘環烷基”係指具有3至約10個碳原子且具有單一個環 或多個稠合環(包括稠合與橋接環系統)的環狀烴基,其 視需要可被1 1 3個㈣取代。舉例來說,這類環院基包 括:,環結構’如環丙基、環丁基、環戊基 '環辛基、 甲基環丙基、2 -甲其f + ι m ^ 一 T基%戍基、甲基環辛基及諸如此類,以 及多環結構,如金剛烷基及諸如此類。 、二取代之%烷基”包括在本文,,經取代,,的定義中所提 及之基團’且特別係指具有i或多個取代基,如工至$個 取代基’特別是!至3個取代基的環烧基,該取代基係選 自—於隸、醯基胺基、酿氧基、絲基、經取代之烧氧基、 烷氧基羧1 :)¾氧基羰基胺基、胺基、經取代之胺基、胺 基羰基、胺基羰基胺基、胺基羰氧基、芳基、芳氧基、疊 28 200526631 孔基、叛基、氰基、環烧基、經取代之環烧基、卣素、_ 基、酉同基、硝基、硫代院氧基、經取代之硫代燒、= 代方乳基、硫酮基、硫經基、院基_s(o)·、芳基~s(〇t、产 基—s(0)2_及芳基_s(〇)2-所組成之群組。 兀 ^ % *兀乳基’’係指基團-〇R,其巾R是環烧基。舉例來說, 這類環烷氧基包括環戊氧基、環己氧基及諸如此類。 “環烯基”係指具有3至1〇個碳原子並具有單—個 :個稠口 ί衣(包括稠合與橋接環系統)且具有至少—個: 別疋1至2個烯鍵不飽和度位置的環狀烴基。舉例來銳, 运類丨衣知·基包括显Tffi Λ 1 »t 稀基及諸如結構’如故己稀基、環戍稀基、環丙 、、工取代之環稀基’’包括在本文,,經取代,,的定義 及之基團’且特別係指具有1或多個取代基,如i至 胺 疊 硫 烷 ==㈣是113個取代基的環稀基,該取代基係選 、服土、駄基胺基、醯氧基、烷氧基、經取代之烷 烷乳基碳基、烷氧基羰基胺基、胺基、經取代之胺兀基土 基奴基、胺基幾基胺基、胺基幾氧基、芳基、芳氧基 虱基、羧基、氰基'環烷基、經取代之環烷基、二 基、ϋ同基、硝基、硫代烧氧基、經取代之美 芳氧基、硫《、娜、烧基勢芳i: 土 S(0)2_及芳基_s(〇)r所組成之群組。 或芳:環碳:子中有二個係與第二個脂族 環稀Ar ^ 土 ’且”細鍵不飽和度係位於賦予該 衣~基%方香性的位置。 29 200526631 “氰氧基”係指基團-OCN。 “氰基”係指基團_CN。 “二烷胺基’,意謂基團-NRR,,其中尺和R,係獨立地表一 如本文中所定義之烷基、經取代之烷基、芳基、經取^: 芳基,環烷基、經取代之環烷基、環雜烷基、經取代之環雜 烧基、雜芳基或經取代之雜芳基。 “乙烯基”係指經取代或未經取代之。 伸乙基係指經取代或未經取代之一(c _ c)-。 “乙炔基”係指—(CC)-。 鹵基或鹵素”係指氟、氣、溴及碘,較佳的鹵基為氟 或氯。 “羥基”係指基團-OH。 “硝基”係指基團-N02。 經取代’’係指其中一或多個氫原子各獨立地被相同或 不同取代基置換的基團。典型的取代基包括但不限於: -X、-R14、-〇-、=〇、、_SR14、各、=s、_nr】4r]5、 = NR〗4、_CX3、_CF3、_CN、_〇CN、_SCN、_N0、_N02、=N2、 -n3、_s(o)2cr、_s(〇)2〇h、-s(o)2r14、-〇s(o2)cr、 -0S(0)2R14 、 -P(0)(〇-)2 、 -P(〇)(〇R14)(cr)、-0p(0)(0Ri4)(0Ri5)、c(〇)Rl4、-C⑻Rl4、 -C(0)0RM、-c(0)NR14R15、_c(0)0·、-C(S)ORM、 -NR16C(0)NR14R15 、 .NR16C(S)NR14R15 、 -NR17C(NR16)NR14R]5 及- C(NR16)NR】4R15,其中各個 x 係獨 立地為鹵素;各個R14、R15、R】6和R】7係獨立地為氫、烷 30 200526631 基、經取代之烷基、芳基、經取代之烷基、芳烷基、經取 代之烧基、環烷基、經取代之烷基、環雜烷基、經取代之 環雜烧基、雜烷基、經取代之雜烷基、雜芳基、經取代之 雜芳基、雜芳烷基、經取代之雜芳烷基、-NR18R】9、_c(〇)Rl8 或-s(〇)2r18 ’或者R18與R19連同它們二者連接的原子形成 一個環雜烧基或經取代之環雜烷基環;以及Rl 8和r19係獨 立地為氫、烷基、經取代之烷基、芳基、經取代之烷基、 芳烷基、經取代之烷基、環烷基、經取代之烷基、環雜烷 基、經取代之環雜烷基、雜烷基、經取代之雜烷基、雜芳 基、經取代之雜芳基、雜芳烷基或經取代之雜芳烷基。 經取代之芳基的代表性例子包括下列:
—R6, R7· · 〇 在14些化學式中,R6’和R7’其中之一可為氫且尺6,和R7, 中至少一者係各自獨立地選自於烷基、烯基、炔基、環雜 烷基、烷醯基、烷氧基、芳氧基、雜芳氧基、烷胺基、芳 胺基、雜芳基胺基、NR^COR11、NR10SORn、NR10S〇2Rm、 COO 烧基、coo 芳基、c〇NR10Rn、CONR10〇Rn、NR10R"、 s〇2Nr10r11、s·烷基、S-烷基、SO烷基、S02烷基、s芳基、 SO方基、S〇2芳基;或者R6’和R7,可接合在一起形成一個 5至8個原子的環(飽和或不飽和),視需要含有一或多個 選自於N、Ο或S群組的雜原子。rH)、R】〗和R]2係獨立地 為氫、烷基、烯基、炔基、全氟烷基、環烷基、環雜烷基、 芳基、經取代之芳基、雜芳基、經取代或雜烷基或諸如此 31 200526631 類。 雜在用以敘述一個化合物或存在於化合物上的基團 時,意指在該化合物成其囿+ ^ 飞基園令的—或多個碳原子已經被 氣、乳或硫雜原子置換。雜 谈雜可為用於上述烴基中的任一者, 例如:院基’如雜炫基’環貌基,如環雜炫基,芳基,如 雜芳基,環稀基、環雜稀基及諸如此類,其具有…個, 尤其是1至3個雜原子。 亦隹方基係指經由從雜芳族母環系統中單一個原子上 除去-個氫原子而得到之單價雜芳族基團。典型的雜芳基 包括但不限於··衍生自^、坤雜萌、咔。坐、卜咔咐、 °克稀、•^咐、呋喝、_。坐、α?卜坐、猶麟咐嘲啡、 異:并呋喃、異Β克稀、異_、異吲哚咐、異喧咐、異噻唾、 異聘唾、二氮雜萘(naphthyddine) n、聘唾、哈。定 (perimidine)、菲°定、菲嘻咐、吩啡、酞啡、蝶。定、啤呤、 毗喃、吡畊、毗唆、塔啡、毗咬、㈣、毗洛、毗洛二 唾啉、唾啉n喧喔啉、四唾、噻二唾、坐瞳吩、 三唾、咕吨及諸如此類的基團。較佳而言,雜芳基是在㈣ 芳基特m的雜芳基為街 生自噻吩、毗洛、苯并噻吩、苯并呋喃m定、 咪唑、聘唑及吡畊者。 μ 雜务基的代表性例子包括下列: 32 200526631
環雜烧基的代表性例子包括下列:
其中各個X係選自於CR42、NR4、0及S ;而各個Y 係選自於NR4、Ο及S,且其中R6’是R2。
環雜烯基的代表性例子包括下列 人 /X、 /X、
其中各個X係選自於CR4、NR4、Ο及S ;而各個Y係 選自於羰基、N、NR4、Ο及S。 33 200526631 具有雜原子、含有取代度之芳基的代表性例子包括下
其中各個X係選自於C-R4、CR42、NR4、0及S ;而各 個Y係選自於羰基、NR4、Ο及S。 “雜取代基”係指含_基、〇、S或N原子官能度,其可 在以直接於本發明化合物的A,B,W,X,Y或Z上以取代基 存在的R4C基團中以R4存在,或可以存在於化合物中之“經 取代”芳基及脂族中的取代基存在。 雜取代基的例子包括: -鹵基, -N〇2、-NH2、-NHR、-N(R) 2, -NRCOR、-NRSOR、-NRS02R、OH、CN、C02R, -C〇2H, -R-OH、-O-R、-COOR, -C〇N(R) 2、-CONROR, -S02H、-R_S、-S02N(R)2, -S(0)R、-S(0)2R,其中各個R係獨立地為芳基或脂族, 視需要具有取代度。在含有R基團的雜取代基當中,優先 選擇為具有如本文中所定義之芳基及烷基R基團的物質。 較佳的雜取代基為以上所列舉者。 當用於本文時,“環雜烷基”一詞係指含有一或多個獨立 選自於N、Ο及S之雜原子的穩定雜環狀非芳族環與稠合 200526631 環。稠合雜環系統可包括碳環且只需要包括一個雜環。雜 環的例子包括但不限於:呢啡基、高呢畊基、呢啶基及嗎啉 基,且係示於下列例示性實例中:
視需要經一或多個選自於醯基、醯基胺基、醯氧基、 烷氧基、經取代之烷氧基、烷氧基羰基、烷氧基羰基胺基、 胺基、經取代之胺基、胺基羰基、胺基羰基胺基、胺基羰 氧基、芳基、芳氧基、疊氮基、羧基、氰基、環烷基、經 取代之環烷基、鹵素、羥基、酮基、硝基、硫代烷氧基、 經取代之硫代烷氧基、硫代芳氧基、硫酮基、硫羥基、烷 基-s(o)-、芳基-s(o)-、烷基-s(o)2-及芳基-s(o)2-所組成群 組的基團取代。取代基包括提供例如内醯胺和脲衍生物的 羰基或硫代羰基。在這些例子中,Μ是CR7、NR2、Ο或S ; Q是Ο、NR2或S。R7和R8係獨立地選自於醯基、醯基胺 基、醯氧基、烷氧基、經取代之烷氧基、烷氧基羰基、烷 氧基羰基胺基、胺基、經取代之胺基、胺基羰基、胺基羰 基胺基、胺基羰氧基、芳基、芳氧基、疊氮基、羧基、氰 基、環烷基、經取代之環烷基、鹵素、羥基、酮基、硝基、 硫代烷氧基、經取代之硫代烷氧基、硫代芳氧基、硫酮基、 硫沒基、烧基- S(O)-、方基-S(O)-、烧基-S(0)2-及芳基- S(0)2- 35 200526631 所組成之群組。 “二羥基磷醯基,,係_ ⑸知基團一p〇(〇H)2。
“經取代之二經基pH n S也基”包括在本文”經取,的定義 中所提及之基團,且特别〆 寸⑺係指二羥基磷醯基,其中該羥基 之一或二者係經取代。、金a 週§的取代基係詳細說明於下文。 “胺基經基輕基,,係指基團_p〇(QH_2。 、工取代之月女基起基碟酿基”包括在本文”經取代,,的定 義中所提及之基團,且姓口,^ ^ ^ 且特別係指胺基羥基磷醯基,其中該 胺基係被一或二個取符Α π ^ , 代基取代。適當的取代基係詳細說明 方、下文。在某些具體實例中,羥基亦可經取代。 硫代烷氧基”係指基團_SR,其中R是烷基。 經取代之硫代烷氧基,,包括在本文,,經取代,,的定義中 所提及之基團’且特別係指具有i或多個取代基,如i至5 個取代基,特別是1至3個取代基的硫代烷氧基,該取代 基係選自於醯基、醯基胺基、醯氧基、烷氧基、經取代之 烷氧基、烷氧基羰基、烷氧基羰基胺基、胺基、經取代之 胺基、胺基羰基、胺基羰基胺基、胺基羰氧基、芳基、芳 氧基、豐氮基、羧基、氰基、環烷基、經取代之環烷基、 i素、經基、酮基、硝基、硫代烷氧基、經取代之硫代烷 氧基、硫代芳氧基、硫酮基、硫羥基、烷基-S(〇)_、芳 基-S(O)-、烧基- s(0)2-及芳基-S(0)2-所組成之群組。 ‘‘硫烷基”係指基團HS-。“經取代之硫烷基,,係指RS-之 類的基團,其中R是任何在本文中所說明的取代基。 ‘‘磺醯基”係指二價基團-S(02)-。“經取代之磺醯基,,係指 36 200526631 R-(〇2)S-之類的基團,其中R是任何在本文中所說明的取代 基。“胺基磺醯基,,或“磺醯胺,,係指基團H2N(〇2)s_,而“經取 代之胺基磺醯基,,或“經取代之磺醯胺,,係指基團r2n(02)s- 之類的,其中各個R係獨立地為任何在本文中所說明的取 代基。 “楓”係指基團-S〇2R。在特定具體實例中,化係選自於 Η、低級烷基、烷基、芳基及雜芳基。 “硫代芳氧基,,係指基團_SR,其中R是芳基。 ‘‘硫酮基”係指基團=s。 硫―基”係指基團-SH。 $在有杜:u成技藝中具有通常知識者將瞭解,在穩定、 化學上可行的雜環中,無論它是芳族或非芳制,最大的 雜:子數目係由環的大小、不飽和程度及雜原子的價數來 决疋…般而言’雜環可有—至四個雜原+,只要該 族環是化學上可行且穩定的即可。 ” 醫樂上可接受,,意旨經聯邦規管局或州政府認可, 於美國藥典或其他f遍承認用於動物,更特別是^ 典中。 胡的樂 “醫藥上可接受之鹽,,係指醫藥上可接受且具有所*、 化合物藥理活性之本發明化合物的鹽。這類鹽包括而母 加成鹽,係與無機酸如鹽酸、氫漠酸、硫酸、石肖酸二), ,諸如此類所形成者;或與有機酸如乙酸、丙冑、已:酸 環戊烧丙酸、乙醇酸、丙酉同酸、乳酸、丙二酸、號站:、 頻果酸、馬來酸、宮民祕、、拓τ分 ' 田馬酉夂/酉石酸、檸檬酸、苯甲酸、3 37 200526631 . 經基笨曱醯基)笨曱酸、肉桂酸、扁桃酸、曱烷磺酸、 G少元 績酸、1,2-乙烷二磺酸、2-羥基乙烷磺酸、苯磺酸、 〇 本 磺酸、2-萘磺酸、‘甲苯磺酸、樟腦磺酸、4_曱基二環[2 2 y 辛-2-烯-1-羧酸、葡庚糖酸、3-苯基丙酸、三甲基乙酸、第 三丁基乙酸、月桂基硫酸、葡糖酸酸、穀胺酸酸、羥美荠 曱酸酸、水楊酸、硬脂酸、黏康酸酸及諸如此類所形成 或(2)當存在於母化合物中之酸性質子被金屬離子,如終^ 屬離子、驗土金屬離子或紹離子置換時;或與有機鹼二 :手:、二乙醇胺、三乙醇胺、N-甲基葡糖胺及諸如此類配 立日t所瓜成的鹽。僅作為實例而言,鹽類進—步包括:抽_、 鉀、#5、鎮、錢、 产其 '* 有驗性官能度時,包括 物3 鹽酸鹽、氫漠酸鹽、酒石酸 類,例如 酸鹽、草酸鹽及…"a f w酸鹽、乙酸鹽、馬來 _ w 可接受之陽離子”―^ 指酸性官能基的盔表、 W-于 3係 離子係以納、_、詞=之陽離子抗衡離子。這類陽 此類做例子。 、'、釦、四烷基銨等陽離子及諸如 “醫藥上可接受之媒劑,,得^ 予的稀釋劑、佐劑 /、曰本發明化合物隨之一起投 d賦形劑或载劑。 “預防,,或“預防作用,,係 (亦即使得該疾病臨床徵二低得到疾病或失調的危險 或易罹患該疾病但尚未 少-者不會在可能暴露於 展出來)。 肩不該疾病徵狀的個體中發 ‘‘個體,,包括人類。“人 八頭、“志本” j “ / w者和個體,,等詞係可 38 200526631 互換地用於本文中。 “治療上有效量,,意指化合物 疾病時,足以產生這種對於疾病的、個體以治療 可依據化合物、疾病及其嚴重^、。“治療上有效量” 齡、體重等等而有所改變。 所欲治療個體的年 任何疾病或失調的“治療,,或 例中,#沪拎矣外e t I 作用’在一個具體實 1 Τ 係和改善該疾病或失調f介e 1 JL庐庆η /、Ρ抑制或減輕該疾病或 八^床被狀中至少一種的發展 瘩”十“、Λ汰L 另—個具體實例中,“治 療或治療作用,,係指改善至少一 、〇·、_L 種身體的因素,這可能益 法被個體辨識。在又另一個具 、了此… 粒只例中,“治療,,或“ 'Λ恭七 用係指調節疾病或失調,可為身 η / “ 的穩宏你Λ 旦上的(例如可辨識徵狀 扪t疋作用)、心理上的(例如套驷间主 成一 ^ 1 j如身體因素的穩定作用), 或一者。在又另一個具體實例中, ^ /Ό療或治療作用,,係指 k遲疾病或失調的發作。
月〕藥係扎具有可裂解基團並經由溶劑解或在生理條 件下變成在活體内具有醫藥活性之本發明化合物的化合 物包括本發明化合物的衍生物。這類例子包括但不限於: 吕鹼S曰衍生物與類似物、N-烷基嗎咐酯與類似物。 本發明化合物的其他衍生物在其酸與酸衍生物二形式 ^生但在酸敏感形式通常在嗔乳動物生物中提供溶 解度、組織相容性或延緩釋放的優點(參見Η, Design of prodrugs,pp 7-9,2124,幻⑽^,入⑽㈣⑽ 1985 )。前藥包括此技藝從業者所熟知的酸衍生物,例如: 、、由母®文與適當醇反應所製得的酯類,或經由母酸化合物 39 200526631 與經取代或未經取代之胺反應所製得的酿胺類,或酸酐, =合酸肝。衍生自侧接於本發明化合物上之酸性基團的 間早脂族或芳族酿類、醯胺類及酸酐為較佳的前藥。在某 IS二二’取好是製備雙酯型前藥,例如(醯氧基)烷基酯類 MOo乳基碳基)氧基)烷基醋類。較佳者為本發明化合物的
Ci至C8燒基、c2-C8婦基、苦其、p ρ # 方基C7-CU經取代之芳基及
LyC〗2芳基烧基酯類。 1=解的是,化合物有相同分子式但其原子的鍵結 物,貝:順序或其原子在空間上的排列不同I,稱為“異構 物,,/構物在其原子的空間上排列不同者,稱為“立體異構 立體異構物彼此不為鏡像者稱為“料映異構物”,而彼 為不能重疊的鏡像者則稱為“對映異構物 ::稱中心,比如說,其係鍵結至四個不同的基團::: 二異構物。對映異構物特徵可在於其不對稱* ^ Cahn # prel0§" ^ 子使偏振光旋轉的方式而以右旋或左旋表 個別對Γ別表示為⑴或㈠-異構物)。手性化合物可以 的史八I異構物或以其混合物存在。含等比例對映異構物 此〇物稱為“外消旋混合物,,。 物因2明:匕合物可具有一或多個不對稱中心;這類化合 得。=以 ⑻-或阶立體異構物或以其混合物製 合心否則說明書與申請專利範圍中特定化 月或“係意欲包括個別對映異構物和其混合物 200526631 (外消旋或其他方示者)二者。立 體化子測疋和立體異構 物分離的方法在此技藝中係眾所周知者。 4匕合物 如本文先前所述者,本發明 钐月的化合物可用來預防及/或 治療哺乳動物中廣大範圍的症狀, /、疋關郎炎、帕金森 氏症、阿茲海默氏症、中風、葡 广山 珣膜火、乳%、心肌梗塞, ^療和預防疼痛综合徵(急性與慢性或神經性的)、創傷 性腦損傷、急性脊椎神經損傷、神經變性失調、充頭症(落 髮)、發炎性腸道疾病及自身免疫失調或症狀。 為了可更完全地瞭解太^Γ沉…、 緊解本文所况明的發明,提出下列代 表本發明典型化合物的結構。應瞭解的是,這此實例僅供 說明而不欲解釋成以任何方式限制本發明。 ’、 據此,提供其他特定化合物群。因此,如本文先前所 时論者,能夠在活體内修飾離子通道的適當化合物可選自 於下表 1中所列舉去,& _ ^ 者而且可如所示者或以其醫藥上可接 受之鹽、溶劑合物或前筚 ” 異構物。所有的這類變數都力太“… 飞立體 明範圍内。、類文數都在本文中列入考慮且係在本發 ^在某些方面令,本發明提供根據上式之化合物的前率 ΓΓΓ、前藥為具有可裂解基團並經由溶劑解或在生理 :下文成I活體内具有醫藥活性之本發明化合物的本發 明化合物的衍生物。、丄 ^ 物泛類例子包括但不限於:膽鹼酯衍生 只類似物、N-烷基嗎咐酯類及諸如此類。 本發明化合物的其他衍生物在其酸與酸街生物二形式 41 200526631 都有活性,但在酸敏感形式通常在哺乳動物生物中提供溶 解度、組織相容性或延緩釋放的優點(參見Bundgard,H.,
Design of Pr〇drUgs5 pp. 7-9, 21-24, Elsevier, Amsterdam 1 985 )。則藥包括此技藝從業者所熟知的酸衍生物,例如: 經由母酸與適當醇反應所製得的酷類,或經由母酸化合物 與經取代或未經取代之胺反應所製得的醯胺類,或酸酐, 合酸酐。衍生自側接於本發明化合物上之酸性基團的 簡單脂族或芳族㈣、酿胺類及酸酐為較佳的前藥。在某 些情況中,最好是製備雙酿型前藥,例如(醯氧基)烧基_類 或((烧氧基幾基)氧基)烧基s旨類。較佳者為本發明化合物的
Ci至Cs烷基、c^c:8烯基、芳基、c^Ci2經取代之芳基及 C7-C12芳基烷基酯類。 醫藥組成物 當被當作醫藥時,本發明的醯胺化合物通常係以醫藥 、且成物的形式投予。這類組成物可以醫藥技藝中為人熟知 的方式製備,1包含至少一種活性化合物。 、般而言’本發明化合物係以醫藥上有效量投予。實 際上被投予的化合物量 、 A 、书你由酉師決定,其係根據相關 月L ’匕括所欲、治療的症狀、所選擇的投藥途徑、所投予 的貫際化合物、個別患者的年 的嚴重性,諸如此類。體Μ反應、患者病徵 本發明的醫藥組成物可經由各種不同的途徑投予,作 為非限制性實例者’包括:口服、直腸、經皮、皮下、靜 脈内、肌肉内及鼻内的。依據所意欲投遞的途徑而定,本 42 200526631 發= 匕合物較佳係被調配成可注射的或口服的組成物 配成都是供經皮投藥用的藥膏、藥水或貼片。 < 口服投藥用組成物可採用散 政凌液體浴液或懸洋液或散 衷扣末的形式。然而,更常見 士丄 兄的疋,組成物係以單位劑刑 存在以助於精確的給劑。“單位一 個俨及豆彳▲ + 5司係‘適合作為人類 ?二:他°自乳動物用單-劑量之實質上分離的單位,各 皙,廿#人 蜃效果之預定量的活性物 貝並結合適當的醫藥賦形劑。血刑沾… 組点μ ^ μ典型的早位劑型包括液體 成铷卜主、σJ女瓶或庄射器,或是在固體組 成物十月况中的藥丸劑、 物中,肚土# 胗囊或诸如此類。在這類組成 5 v的成分(從約〇」至約 5()重或較佳係從約i至約 於弗士 & J 4υ重里% ),而其餘為有助 劑:成所欲給劑形式的各種不同媒介物或載劑及加工助 焊介2口服投藥的液體形式可包括適當的水性或非水性 此類;;錢液、懸浮與分散劑m用香料及諸如 化ί物固體形絲财說可包括下列成w似本性之 膠;賦=一者.黏合劑,例如微晶纖維素、黃蓍樹膠或明 7劑,例如澱粉或乳糖’崩解劑,例如藻酸、Prim〇gel :氧=粉;潤滑劑’例如硬脂酸鎮;助滑劑,例如膠態 水楊二t:未劑’例如蔗糖或糖精;或芳香劑例如薄荷、 何^甲酯或橙香料。 緩衝2射組成物通常係以可注射無菌食鹽水或經構酸鹽 食鹽水或其他此技藝中已知的可注射載劑為主。同 43 200526631 前’在這類組成物中的活性化合物通常是較少的成分,通 常是從約0.05至10重量%,其餘則為可注射的載劑及諸如 此類。 矣二皮的組成物通常是調配成局部軟膏或乳膏,其含有 活性成分,一般是在範圍從約〇·〇1至約2〇重量%,較佳從 約0.1至約20重量%,較佳從約〇」至約1〇重量%,且更 佳係從約0.5至約15重量%的量。當調配成軟膏時,活性 成分通常是與石蠟族或水混溶性軟膏基料結合。或者,活 性成分可在乳膏中與例如水包油型乳膏基料調配在一起: 這類經皮的調配物在此技藝中係為人熟知者且一般係包含 額外的成分以增強活性成分或該調配物安定度的皮膚渗透 性。所有這類已知的經皮調配物和成分係包含在本發明的 範圍内。 本發明化合物亦可藉由經皮裝置投予。因此,經皮投 藥可使用貯器或多孔膜型或固體基質種類的貼片來完成。又 以上所述可供口服投藥、注 ^局口 ^又樂組成物用的 成刀僅為代表性者。其他物質以 ^ ^ ΡΠ , 技術及諸如此類係 =聽抓腿胜第8部,第17版,咖年細 方式納入本文中。 /本發明化合物亦可以緩釋形式投藥或由緩釋藥物遞送 系統投予。代表性緩釋物質的 :〜 氏醫藥科 下列調配物實例說明本發 〜衣注w樂組成物。然 44 200526631 而,本發明並不限於下列醫藥組成物。 調配物1、錠劑 式I化合物係以乾粉與乾燥明膠黏合劑以大約1 : 2重 量比摻混。添加少量的硬脂酸鎂作為潤滑劑。將此混合物 在壓錠機中形成240-270毫克錠劑(每錠劑80-90毫克活性 化合物)。 調配物2 -膠囊 式I化合物係以乾粉與澱粉稀釋劑以大約丨:1重量比 掺混。將此混合物填充至250毫克膠囊内(每膠囊125毫 克活性化合物)。 調配物3〜液劑 將式I化合物(125毫克)、蔗糖(丨.75克)與黃原酸 膠(4毫克)摻合,通過1 〇號u· s •網目篩子,然後與事先 製備的被sb纖維素和魏曱基纖維素納(1 1 : $ 9,5 〇毫克) 於水中的浴液混合。將苯甲酸鈉(丨〇毫克)、食用香料及 色料用水稀釋並伴賴拌添加。然後加人充足的水以配製 成5毫升的總體積。 調配物4 -錠劑 式I化合物係以乾粉與乾燥明膠黏合劑澱粉稀釋劑以 大約1 : 2重量比摻混。添加少量的硬脂酸鎂作為潤滑劑。 將此混合物在壓錠機中形成45〇·9〇〇毫克錠劑(每錠 150-300毫克活性化合物)。 、別 調配物5 - >主射劑 將式I化合物溶解或懸浮於緩衝無菌食鹽水注射水性 45 200526631 媒質中至大約5毫克/毫升的濃度。 調配物6〜局部用劑 使硬脂醇(25〇克)與白凡士林( 250克)在約75〇c 熔化,然後添加式I化合物(5〇克)、對羥基苯曱酸曱酯 (〇·25克)、對羥基苯甲酸丙酯(〇15克)、月桂基硫酸 鈉(10克)和丙二醇(120克)溶於水(約37〇克)中的 混合物’並攪拌所得混合物直到其凝結為止。 治療方法 你用忭'口:⑺扎初视征狀的治療劑。因 此’本發明的化合物與醫藥組成物發現作為預防及/或治療 哺乳動物,包括人類中神«性、自 之治療劑的用途。 X人旺屁狀 在治療方法方面中,本發 與關節炎、葡萄臈炎、^ 種治療易患或惱於 自身免疫失調有關症狀之哺乳動 ::疾病及 予有Γ之一或多種方才說明的醫藥組成物投 在又另一個治療方法方面中, 患或惱於會引起疼痛反應或與 =t種治療易 均衡有關之症狀的哺乳動物的方法:::礎活性維持的不 治療各種不同發生或病原痺 、二化合物具有作為 急性、S炎性疼痛(例如與::::劑的用途’例如治療 的疼痛);各種不同的神 p =和凤属性關節炎有關 的神經痛、三叉神經:‘、痛徵候君“例如後皰疹性 …痛、反射***感神經失養症、 46 200526631 糖尿病的神經病變、格林巴里徵候 、危一f 纖維肌痛症、幻肢 兩、礼房切除後疼痛、周邊神經病變、 仆與、Λ成#々 HIV神經病變,以及 予>口療誘發和其他醫源性神經病 ‘作田a 文」,臟杰性疼痛(例 /二道反流疾病、急躁性腸道徵候群、發炎性腸道疾 ^臟炎及各種婦科與泌尿科失調有關者)、牙痛及頭 ^列偏頭痛、充血性頭痛及緊張性頭痛)。 在另外的治療方法方面中,本發 ▲ 於下列疾病與失調之哺乳 —療易心或惱 調,mm ^動物的方法.神經m病與失 Y J如帕孟林氏症、阿益备 M^, 17啟海默氏症和多發性硬化;由神 中 的疾病與失調,例如創傷性腦損傷、 尠, 琛;丨之神經精神疾病與失調,例如抑 头嘴 精神刀W症、飲食失調、睡眠 腸道官能障礙,例如尸^ 腺、膀耽和 排便 水失不、排尿遲緩、直腸過敏反應、 更失不、攝護腺腫大和發炎性腸道疾病;啤吸道和氣管 、;矢病與失調,例如過敏菖、山 八 及俨性阳# 吐 "" 轧而和反應性氣管疾病 例^ 病;由發炎所媒介或產生的疾病與失調, :如風濕性關節炎與骨關節炎、心肌梗塞 疾病與失調、葡萄肢* ^ 裡目豸充反 大和動脈粥樣硬化;疥瘡/搔疼,例如 卞反辦,充頭症(茨髟、. 脊^ 〜,肥胖;脂質失調;癌症;血壓; 防症^ 醎扃,该方法包括投予有效治療症狀或預 I万症狀置之一或容插 α 、 夕種方才說明的醫藥組成物。
注射劑量水平範圍係從約01毫克/公斤/小時到至少W 笔克/公斤/小時,全Α 4 王砟疋就從約1至約120小時,尤其是24 47 200526631 至%小時而言。亦可投予約〇1毫克/公 斤或更多的預填充推吁去 、力1 〇名克/公 40至80公斤人類*者 , 狀心水+。對於 /天。 。者而…大總劑量預計不超過約2克 就長期症狀如神經變性和自身免 痒而古,底AA 6 k ^〜頂丨万及/或治 縻而口 /口療的女排通常延續數月或數车^ 就*去的太而从i ^數年’所以口服給劑 就心者的方面性和耐性而言係較佳 每天一至五次,尤1曰_ 5 彳σ服給劑來說,
兀,、疋一至四次且诵受θ - L 代表性的安排。使用這 疋二_人口服劑量是 約20古古口"^果式,母一劑提供約0.01至 、.”〇€克/公斤的化合物或其衍生物, 劑提供約(Μ至約10毫克/ 的心母一 公斤。 吓尤其疋約1至約5毫克/ 經皮劑通常係選擇來提供與使 或較低的血糖水平。 d所達成者類似 當用以預防神經蠻w、 士 身免疫或杳炎性症狀的發作 量水…師的於告與監督下,以上述的劑 工=家族歷史者或已經由基因試驗或筛檢確認 a易發展出該症狀者。 :發明化合物可作為唯一活性劑投予,或者它們可與 ^樂劑,包括其他活性衍生物合併投予。 一般合成程序 本發明化合物可使用下列一般方法和程序而自易於獲 48 200526631 付之起始物製得。應目參紐沾9 止, ι瞭解的疋,當提供典型或較佳的方法 條件(亦即反應溫度、時間、 汉應物的莫耳比、溶劑、犀 力等等)時’亦可使用苴 /、他方法條件,除非另有敘述。最 佳反應條件可隨著所传用沾4主—c α ,, W便用的特疋反應物或溶劑改變,但這 類條件可由熟諸此技藝者經由例行最佳化程序予以決定。 此外,如對於熟諳此技藝者顯而易見者,可能需要習 知的保護基㈣免某些官能基進行不想要較應。對於特 定官能基的適當保護基的選擇以及保護和去保護的適當條 件在此技藝中係為人所熟知者。舉例來說,有為數眾多的 保護基,以及它們的引進和移除,都敘述於T. w. Greene P. G. M. Wuts, Protecting Groups in Organic Synthesis, 第二版,WUey,New York,1991及其中所引用的參考文獻 中。 標革巴化合物係經由下列方案中所概述的已知反應合 成。產物係經由已知的標準程序離析和純化。這類程序包 括(但不限於)再結晶、管柱層析或Hplc。舉例來說,這 些^革巴化合物可製備如下:使經適當取代之鹵基卩比。定與經 適當官能化之羧基硼酸反應獲得所要的聯芳基羧酸。如是 所得之羧酸中間物可經由活化作用,接著與經適當取代之 胺反應而合宜地被轉化成其對應的醯胺。產物係經由已知 的標準程序離析和純化。這類程序包括(但不限於)再結 晶、管柱層析或HPLC。 經取代苯甲酸的製備 中間物1 49 200526631 4-(〇Ε>3,3;二甲基-丁 烯基)_苯甲酸
/ P(〇C)且充分攪拌之私羧基苯甲醛(2〇克, 13·32毫莫耳)於無水™F⑼毫升)的懸浮液中,在2( /刀知期間添加溶於己燒中之33·3毫莫耳氯化新戊基鎮,並
㈣同溫度下㈣另二小時,然後用飽和氯化錄 合夜:滅將大部分的THF蒸發,水性混合物則用濃 (50毛升)處理並將混合物加熱到回流歷時2小時。然後 將此合物冷部到周圍溫度並用二氣甲烧(h⑽毫升)萃 取,將有機層經硫酸鈉乾燥並濃縮,獲得所要的4_(3,>二 曱基-丁-1-燁基)-苯甲酸。 中間物2 ((^>4-戊-1-烯基)-苯甲酸
Η 在4 -甲基-本甲酸(1·5克,1〇毫莫耳)於_78〇(^ THF 之攪拌過的溶液中,添加溶於己烷中之2·5當量的正丁基 鋰,並將混合物慢慢地溫熱到周圍溫度。在攪拌另2小時 之後,將反應用飽和NH4C1溶液淬滅並用Et〇Ac ( 2 X ! 〇〇 笔升)卒取。將合併的有機萃取液乾燥()並濃縮, 50 200526631 得到粗甲醇,其係在 ^ .. y^ 又下、、、里 30〇/〇 H2S04 處理 30 分 4里。然後將反應混合物用冷 ? ^ V, ,ζ ^ 卞滅,並將所形成的沈澱物 過濾,用水洗旅及真空齡怪 釔知,獲得標題化合物(1.丨克, 57.9%)。 中間物3 6-(3,3-二甲基丁-1炔基)菸酸:
在5耄升反應管瓶中,將6-氯菸酸甲酯(5〇〇毫克;2 93 毫莫耳)懸浮於二聘院(3毫升)中。在該容器内加入 二氣雙(三苯膦)!巴(Π)(70毫克;3莫耳%)、峨化銅(12 毫克)、Ν,Ν-二異丙基乙基胺(〇63毫升;35毫莫耳)及 3,3-二甲基丁小快(〇·44毫升;3 5毫莫耳)。將容器密封 亚讓混合物在80°C下加熱24小時。將溶劑蒸發至乾燥並 加入20毫升四氫呋喃和2〇毫升1〇N Na〇H。讓混合物在室 溫下攪拌30分鐘,然後將溶劑蒸發。將鹼性層用濃Hci酸 化並用EtOAc萃取三次。將有機層用食鹽水洗滌並經
NasSO4乾燥,過濾及蒸發,得到所要的產物,為棕色粉末 (590 毫克;99%)。 MS: MH + = 204 51 200526631 中間物4 4_(3,3_二甲基丁-1-炔基)苯甲酸··
在5耄升反應管瓶中,將心蛾苯甲酸甲酯(5〇〇毫克; 1.9毫莫耳)懸浮於i,4-二腭烷(3毫升)中。在該容器内 加入二氯雙(三苯膦)鈀(π)( 44毫克;3莫耳%)、碘化銅(7.5 愛:克)、Ν,Ν-一異丙基乙基胺(〇·39毫升;3.5毫莫耳)及 3,3-二曱基丁 -1-炔(0.275毫升;3.5毫莫耳)。將容器密 封並讓混合物在80。(:下加熱24小時。將溶劑蒸發至乾燥 並加入20毫升四氫呋喃和20毫升1〇N Na〇H。讓混合物在 室溫下攪拌30分鐘,然後將溶劑蒸發。將鹼性層用濃Hci 酸化並用EtOAc萃取三次。將有機層用食鹽水洗滌並經
NajO4乾燥,過濾及蒸發,得到所要的產物,為棕色粉末 (210 毫克;28%)。 MS: MH + = 203 中間物5 2,2,2 -三氟乙基二苯基氧化膦: 52 200526631
讓二苯基亞膦酸乙g旨(1.98克,5.8愛莫耳)與2,2,2_ 三氟乙基碘(6.1克;29毫莫耳)的混合物於室溫在氮氣下 攪拌24小時。在真空下除女過量的試劑。殘餘物係於石夕凝 膠上使用〇 -1 〇 〇 %己烧-乙酸梯度予以純化而得到標革巴 物,為白色粉末(800毫克;49% )。 MS: MH + = 286 4·(3,3,3-三氟丙稀基)苯甲酸:
TBAF 之THF溶液中, 並於室溫在氮氣下攪拌過夜。在此
將4Α分子篩(7克;活化粉末)懸浮於8·8毫升1〇M 53 200526631 毫升THF與10毫升IN NaOH中並回流3〇分鐘。將混合物 用濃HC1酸化並用EtOAc萃取三次。將有機層用食鹽水洗 滌並經NaeCU乾燥’過濾及蒸發而得到所要的產物,為掠 色粉末(125毫克;60%)。 MS: MH+= 217 除了以上所列的苯甲酸’其他被採用或可被採用以製 備本發明醯胺的苯曱酸,係依照以上就中間物1-6所敘述之 程序和熟諸此技藝者已知的適當試劑、起始物及純化方法 予以合成。 / 叛酸之醯胺化 實施例1 苯甲醯胺的代表性合成
4偶,3,3-二甲基-丁小稀基)_N♦甲氧基-苯基)笨甲 4在已冷卻且充分授拌之4_(3,3·二甲基_ 丁小稀 基)-苯曱酸(1.5克,7.34毫莫耳)於Ftn 毛关吁J於EtOAc與DMF ( ΐ·ι, 25毫升)混合物中的懸浮液裡,慢 住 k k地逐滴添加草醯氣 (0·364克,4·04毫莫耳)並 乳 巧欖拌一小時。然後將 54 200526631 間回香胺(1.36克,11〇1毫莫耳)加入Et〇Ac ( 5毫升) 中亚讓混合物攪拌6〇小時,然後用飽和碳酸鉀溶液淬滅。 將沈澱物過濾’用水洗滌及真空乾燥而獲得標題化合物。 實施例3 使用自動平行合成方法之苯甲醯胺的代表性合成 將適曰的苯甲酸(2毫莫耳)溶解或懸浮於15毫升氯 仿中,亚用20毫莫耳亞硫醯氯處理。讓反應混合物回流十 五刀麵,然後在真空下除去溶劑。將殘餘物溶解於4毫升 無水氯仿中,並將60微升(30微莫耳)此溶液加到96孔 玻璃i的每-個孔中。然後將適當的胺加到對應的孔中( 微莫耳),接著添加%沁二異丙基乙基胺(12〇微莫耳)。 然後讓此盤於6YC加熱15分鐘。使用ητ_12 G^離 心抽真空器除去溶劑,然後將100微升DMSO加到每一個 孔中並將化合物轉移到96孔聚丙稀反應盤。然後使用 盤密封器將這些盤密封並使其接受lc_ms純化。 合成庫自動平行L(>MS純化的一般方法 廷些合成庫係使用與Shimadzu LC泵結合之Perkin Elmer API100質譜儀予以純化。所使用的層析方法是8分 鐘期間乙腈比水之1(M〇〇%梯度,流速為每分鐘6毫升。所 使用的管柱是10X5()mm YMCC18,而化合物係使用㈤_ 204 |留分收集器予以收集。 依照以上就實施例i或2所敘述的程序及熟諸此技藝 55 200526631 。者已知的適當試劑、起始物及純化方法,製備本發明的醯 胺化合物。 下列合成與生物學實施例係供以說明本發明者,而不 應以任何方式解釋為限制本發明的範圍。在以下的實施例 中’所有溫度係以攝氏度數表示(除非另有只是)。已經 根據本發明製備的化合物係以表格形式示於下文。這些代 表性化合物的合成係根據以上詳述的方法進行。 本發明的範例化合物 下列化合物已經根據本發明的方法製得。為表1目的, 各化合物的活性係表示如下: +化δ物展現出對辣椒素刺激所誘發之I弓離子流入的 0-25%抑制。 “ + + ”化合物展現出對辣椒素刺激所誘發之鈣離子流入 的25-5 0%抑制。 + + +化合物展現出對辣椒素刺激所誘發之鈣離子流 入的50-75%抑制。 “ + + + + ”化合物展現出對辣椒素刺激所誘發之鈣離子流 入的7 5 %或更大抑制。 具有以”+ + + + ”所表示之抑制百分比的化合物係特別感
興趣者。 U 56 200526631 表1 :醯胺化合物 ID 結構 MW (計算値) MS (觀測値) HPLC RT (分) HPLC 開始時 間(分) HPLC 結束時 間(分) 抑制% @ 1 uM 1 259.39 260.22 3.99 3.89 4.88 2 309.41 310.41 4.08 3.94 4.48 ++++ 3 337.42 338.29 3.96 3.85 4.39 ++++ 4 285.43 286.25 4.11 3.94 4.44 5 0 yc^ ^ 323.44 324.37 4.01 3.86 4.58 ++ 6 \ OH 247.34 248.19 3.00 2.79 3.36 + 7 333.48 334.38 4.29 4.16 4.58 ++ 8 >C^^j 313.49 314.24 4.36 4.24 4.84 +++ 9 >^0 369.51 370.20 4.36 4.24 4.69 + 10 273.42 274.26 4.11 3.98 4.55 11 341.88 342.21 4.19 3.99 4.65 ++++ 57 200526631 12 341.54 342.29 4.81 4.36 5.14 + 13 293.41 294.23 3.93 3.85 4.41 + 14 245.37 246.25 3.69 3.58 4.05 + 15 309.41 310.39 3.99 3.89 4.29 + 16 287.41 288.07 3.51 3.42 3.96 + 17 337.42 338.29 3.85 3.75 4.24 + 18 0 323.44 324.38 3.92 3.83 4.26 19 F 361.41 362.35 4.29 4.14 4.66 20 386.52 387.24 3.41 3.32 3.69 + 21 、丨 383.49 384.23 3.82 3.75 4.25 22 271.41 272.27 3.92 3.78 4.28 23 Λ^ί 243.35 244.26 3.51 3.42 3.86 24 1 .丨丨:Γ Γ '、' 1 (.1] ί. r 367.49 368.25 3.78 3.61 4.19 + 58 200526631 25 275.39 276.27 3.45 3.35 3.81 26 321.47 322.35 4.19 4.04 4.58 + 27 0 295.38 296.29 3.93 3.79 4.36 28 >cx/k 231.34 232.25 3.51 3.38 4.12 29 299.44 300.24 3.89 3.71 4.17 + 30 304.40 305.35 3.89 3.81 4.29 ++ 31 309.41 310.41 4.32 4.19 4.69 + 32 0 321.47 322.35 4.34 4.21 4.82 + 33 313.83 314.13 4.44 4.21 4.87 + 34 259.39 260.26 3.86 3.78 4.21 35 ^jO^Cq^ 353.47 354.26 3.72 3.62 4.16 + 36 0 311.40 312.21 3.98 3.78 4.38 37 (,、 343.86 344.17 4.22 4.07 4.64 + 59 200526631 38 304.40 305.33 4.08 3.95 4.48 + 39 323.44 324.37 3.75 3.66 4.24 ++++ 40 335.49 336.49 4.61 4.48 5.12 +++ 41 321.47 322.36 4.49 4.38 4.97 ++ 42 .ii iJl r 丨丨:丨 1 335.49 336.50 4.69 4.39 5.05 + 43 361.53 362.46 4.88 4.76 5.21 + 44 377.41 378.30 4.52 4.35 4.81 ++++ 45 307.44 308.40 4.19 3.92 4.64 ++++ 46 273.42 274.27 4.16 4.06 4.64 47 JX〉 ·,Λα^ 323.40 324.33 4.01 3.86 4.39 ++++ 48 308.43 309.36 3.19 3.01 3.75 ++ 49 294.40 295.28 2.73 2.60 3.19 ++++ 50 〇 311.43 312.24 2.75 2.60 3.16 60 200526631 51 0 300.45 301.34 2.76 2.66 3.23 52 、 Y 280.37 281.31 2.98 2.79 3.39 ++++ 53 280.37 281.30 2.88 2.72 3.31 ++++ 54 入4 269.35 270.27 3.22 3.06 3.63 + 55 >0^6 286.40 287.10 3.83 3.72 4.09 + 56 376.55 377.40 3.12 3.00 3.42 + 57 0 316.45 317.25 2.72 2.40 3.08 58 294.40 295.28 2.72 2.48 3.31 59 .,Q 346.48 347.27 3.92 3.74 4.30 60 0 315.46 316.28 2.45 2.19 2.63 + 61 ϊ 322.45 323.24 3.06 2.72 3.46 ++++ 62 丨八r^Sn /、人夕〆、 350.51 351.42 3.18 3.05 3.53 ++++ 63 λ^φ 0 364.49 365.26 3.31 3.19 3.54 61 200526631 64 >^4 294.40 295.30 3.08 2.91 3.48 + 65 Sr」 I 300.45 301.34 2.75 2.68 3.06 + 66 <ΛΧΧ^ 318.42 319.08 3.82 3.73 4.24 ++ 67 281.36 282.29 3.29 3.22 3.65 + 68 >c^y 294.40 295.28 3.00 2.52 3.39 +++ 69 Ur 359.27 359.14 4.39 4.21 4.82 + 70 ¥——l· y 348.37 349.28 4.46 4.19 4.79 + 71 o 382.82 383.15 4.21 4.02 4.48 + 72 308.43 309.39 3.23 2.95 3.55 + 73 314.82 315.02 4.07 3.94 4.34 74 Cl 314.82 315.02 3.99 3.86 4.41 +++ 75 310.40 311.32 3.64 3.56 4.08 ++ 76 314.82 315.06 4.06 3.95 4.42 ++++ 62 200526631 77 人11 309.41 310.43 3.11 2.83 3.36 + 78 330.43 331.27 3.11 2.93 3.74 ++++ 79 ,R0 297.40 298.32 2.76 2.72 2.92 80 294.40 295.27 2.69 2.43 3.03 + 81 336.48 337.47 2.99 2.72 3.36 + 82 335.49 336.49 4.41 4.29 4.74 83 ;J7 X 294.40 295.27 3.00 2.89 3.53 84 231.34 232.17 3.51 3.36 3.96 85 ^ΧΧ+ 245.37 246.20 3.82 3.62 4.22 86 rx^ 271.41 272.26 3.92 3.78 4.31 87 309.41 310.39 3.83 3.63 4.28 + 88 ^v> 269.35 270.27 3.58 3.46 3.99 ++ 89 1 on 233.31 234.16 2.83 2.75 3.22 63 200526631 90 ί 322.45 323.22 2.80 2.63 2.90 91 319.45 320.18 4.12 3.96 4.75 92 '^jO^ 299.46 300.24 4.19 4.04 4.97 93 0 jTtV 280.37 281.29 2.60 2.46 3.05 + 94 297.40 298.30 2.63 2.50 2.75 95 355.48 356.20 4.21 4.01 4.54 ++ 96 丫^〇\ 286.42 287.19 2.65 2.49 3.02 97 259.39 260.17 3.92 3.75 4.52 98 丫今 327.86 328.28 4.04 3.91 4.59 + 99 327.51 328.38 4.64 4.35 4.95 100 0 S〇 279.39 280.19 3.75 3.53 4.09 101 丫 245.37 246.19 3.71 3.59 4.31 102 231.34 232.19 3.49 3.41 3.89 64 200526631 103 265.36 266.09 3.87 3.72 4.34 104 ! 283.35 284.27 3.95 3.76 4.05 105 266.35 267.07 2.82 2.70 3.19 ++ 106 r^6 266.35 267.05 2.76 2.63 2.86 ++ 107 255.32 256.33 3.07 2.95 3.44 108 272.37 273.11 3.65 3.43 4.02 109 273.38 274.17 3.32 3.21 3.81 ++ 110 II Ί I 1 ! Γ !i 1 " i 362.52 363.42 2.95 2.84 3.36 111 323.40 324.31 3.69 3.56 4.08 +++ 112 Λ 302.42 303.14 2.61 2.51 2.72 ++ 113 310.36 311.31 4.34 4.24 4.57 114 0 309.41 310.40 3.78 3.62 4.11 115 F 347.38 348.17 4.04 3.92 4.39 65 200526631 116 372.49 373.17 3.22 3.13 3.58 + 117 為:: 369.46 370.14 3.56 3.48 3.95 + 118 257.38 258.25 3.74 3.62 4.18 119 0 229.32 230.25 3.31 3.22 3.69 120 280.37 281.29 2.62 2.51 2.76 + 121 丨丨丨丨Γ || ! I ! tl I ° .〇 353.47 354.19 3.61 3.49 4.02 +++ 122 γ^Ο ' 各 307.44 308.40 4.01 3.89 4.31 123 „ Q 332.45 333.27 3.75 3.61 4.18 + 124 281.36 282.30 3.73 3.65 4.08 125 Λ 301.44 302.32 2.33 2.28 2.65 ++++ 126 217.31 218.25 3.31 3.18 3.96 ++ 127 285.41 286.12 3.71 3.59 4.19 ++ 128 290.37 291.12 3.73 3.62 4.58 66 200526631 129 308.43 309.34 2.93 2.75 3.03 130 〜Ί 336.48 337.42 3.03 2.92 3.49 +++ 131 cr 299.80 300.15 4.18 3.98 4.55 132 0 295.38 296.26 4.15 3.99 4.45 + 133 307.44 308.39 4.17 3.98 4.77 134 295.38 296.26 3,91 3.71 4.46 135 Λ 0 350.46 351.36 3.16 3.03 3.56 136 299.80 300.15 4,25 4.05 4.66 + 137 280.37 281.30 2.92 2.83 3.26 138 11 323.48 324.41 4.45 4.35 4.84 139 245.37 246.19 3.69 3.49 4.32 + 140 0 广Ν〆 286.42 287.18 2.62 2.45 2.91 141 丫^η 334.25 334.12 4.62 4.45 4.85 67 200526631 142 339.44 340.17 3.55 3.44 3.91 + 143 297.38 298.24 3.82 3.68 4.25 + 144 348.28 348.13 4.19 4.04 4.66 145 329.83 330.12 4.04 3.92 4.45 + 146 333.36 334.22 4.36 4.19 4.78 147 (ι 334.25 334.11 4.54 4.42 4.74 148 為 367.80 368.10 4.47 4.37 4.89 + 149 344.25 345.96 4.26 4.09 4.62 150 290.37 291.12 3.91 3.72 4.21 ++ 151 y^" 309.41 310.39 3.55 3.45 4.12 +++ 152 321.47 322.32 4.44 4.26 4.99 153 307.44 308.38 4.32 4.16 4.79 ++++ 154 丨1’ ίί ! ' Γ ί 丨丨ί 1 321.47 322.32 4.54 4.25 5.05 68 200526631 155 /¾ 363.38 364.29 4.32 4.06 4.55 156 I 293.41 294.16 4.02 3.88 4.76 + 157 /¾ 323.40 324.31 3.81 3.68 4.68 158 /¾ 304.40 305.29 3.66 3.56 4.02 ++ 159 267.33 268.16 3.13 3.05 3.22 160 280.37 281.29 2.88 2.79 2.95 161 jCrW 334.34 335.32 4.29 4.12 4.64 162 368.79 369.07 4.01 3.78 4.35 163 在 294.40 295.28 3.08 2.92 3.35 164 0 ^,j〇Y I 夕 259.39 260.17 3.97 3.84 4.88 + 165 i- !丨i „ :I , i! 300.79 301.19 3.85 3.71 4.42 166 /φ I o 300.79 301.19 3.79 3.64 4.32 + 167 296.37 297.31 3.46 3.38 3.76 69 200526631 168 、〜。'众_ 300.79 301.19 3.86 3.75 4.15 + 169 丫 U 309.37 310.34 3.80 3.68 4.17 +++ 170 /¾ 295.39 296.32 2.98 2.89 3.13 171 316.41 317.19 2.96 2.79 3.43 ++ 172 A 382.51 383.27 4.38 4.15 5.04 ++ 173 283.38 284.27 2.59 2.42 2.92 174 ί^Τ 义NH k〇 280.37 281.29 2.62 2.43 2.98 175 4 353.47 354.18 4.44 4.21 4.74 + 176 Λ 315.42 316.19 4.25 4.06 4.56 177 321.47 322.30 4.24 4.11 4.74 178 294.40 295.26 2.76 2.63 3.25 179 0 231.34 232.17 3.53 3.41 3.92 + 180 245.37 246.20 3.86 3.73 4.64 70 200526631 181 Ο 一 0¾ 271.41 272.27 3.95 3.75 4.41 + 182 ο 〇/ 309.41 310.38 3.86 3.65 4.19 183 0 [Γ^Τ^ΝΙ1 269.35 270.24 3.63 3.55 3.98 + 184 Oil 233.31 234.15 2.88 2.79 3.29 185 322.45 323.21 2.83 2.59 3.11 + 186 329.45 330.19 4.12 3.92 4.51 187 319.45 320.16 4.18 4.08 4.48 188 /¾ 299.46 300.23 4.22 3.95 4.78 189 280.37 281.28 2.66 2.55 3.11 190 ο 297.40 298.27 2.66 2.55 3.12 + 191 355.48 356.19 4.25 4.15 4.81 + 192 0 286.42 287.18 2.68 2.58 3.02 + 193 一 σ1、 259.39 260.17 3.98 3.76 4.68 ++ 71 200526631 194 'Ό 327.86 328.28 3.84 3.51 4.21 + 195 -f 327.51 328.37 4.71 4.42 5.14 196 0 279.39 280.16 3.81 3.61 4.46 + 197 245.37 246.20 3.75 3.63 4.26 + 198 231.34 232.18 3.55 3.43 4.06 ++ 199 0 265.36 266.09 3.96 3.83 4.24 200 295.38 296.20 3.61 3.51 3.89 201 ϊ· 283.35 284.27 4.02 3.79 4.16 202 ο 266.35 267.03 2.88 2.58 3.32 + 203 η 0 266.35 267.04 2.48 2.30 2.99 + 204 〜 255.32 256.34 3.12 2.93 3.51 + 205 272.37 273.10 3.71 3.58 4.34 + 206 ο 273.38 274.16 3.36 3.26 3.91 + 72 200526631 207 362.52 363.38 2.95 2.85 3.25 ++ 208 323.40 324.31 3.78 3.42 4.15 + 209 Λ 302.42 303.13 2.61 2.49 3.15 + 210 ο 309.41 310.39 3.81 3.69 4.16 211 Ι:—|—F 1: 347.38 348.17 3.91 3.72 4.18 + 212 ()Ά 372.49 373.11 3.28 3.16 3.72 213 rVS" η: ^ /° 369.46 370.15 3.61 3.53 4.05 + 214 0 257.38 258.24 3.78 3.64 4.35 + 215 229.32 230.25 3.36 3.25 4.01 216 0 280.37 281.28 2.68 2.46 2.78 + 217 Λ- /° 353.47 354.20 3.69 3.24 4.04 + 218 ο {ΓΥ^ΝΊ, m; 261.37 262.08 3.29 3.22 3.65 + 219 〜 307.44 308.37 4.09 3.76 4.55 + 73 200526631 220 332.45 333.26 3.81 3.68 4.18 221 υΗ 281.36 282.28 3.81 3.59 4.21 222 ,、人Η ,r° S / ς〕 301.44 302.28 2.38 2.29 2.52 223 217.31 218.25 3.33 3.21 3.76 +++ 224 0 285.41 286.10 3.76 3.59 4.15 ++ 225 /V 290.37 291.07 3.81 3.72 4.14 + 226 308.43 309.33 2.68 2.55 3.21 +++ 227 336.48 337.41 2.79 2.64 3.19 + 228 ο 299.80 300.15 4.25 4.12 4.66 +++ 229 295.38 296.23 4.22 4.06 4.72 230 307.44 308.37 4.22 3.66 4.62 + 231 ο Α〜 295.38 296.23 3.68 3.52 3.99 232 350.46 351.37 2.90 2.76 3.16 74 200526631 233 299.80 300.12 4.34 4.08 4.65 + 234 A 280.37 281.28 2.96 2.72 3.49 + 235 II 323.48 324.41 4.51 4.34 5.04 236 0 245.37 246.18 3.72 3.39 4.15 + 237 j。, 286.42 287.18 2.66 2.46 2.76 + 238 ^ο^α: I 339.44 340.16 3.59 3.49 4.04 + 239 0 297.38 298.21 3.86 3.68 4.32 ++ 240 ^jO^XC 348.28 348.13 4.24 3.98 4.81 241 /¾ 329.83 330.11 4.15 3.81 4.44 242 y4 367.80 368.08 4.52 4.41 4.69 ++ 243 344.25 345.95 4.44 4.01 4.68 244 290.37 291.12 3.98 3.85 4.44 ++ 245 ίΓ^Υ^1" 广6〜°" 309.41 310.39 3.61 3.51 3.86 + 75 200526631 246 321.47 322.30 4.48 4.24 4.89 + 247 A 307.44 308.38 4.39 4.26 4.68 + 248 .11 1 1 321.47 322.27 4.58 4.51 4.84 +++ 249 /¾ 363.38 364.29 4.41 4.12 4.82 + 250 293.41 294.14 4.08 3.88 4.78 251 /¾ 323.40 324.30 3.60 3.48 3.90 252 /¾ 304.40 305.27 3.72 3.60 4.18 + 253 /¾ 267.33 268.14 2.86 2.73 3.13 254 280.37 281.28 2.89 2.69 2.99 255 11 368.79 369.06 4.08 3.91 4.68 256 294.40 295.26 3.12 2.92 3.49 + 257 0 259.39 260.17 4.02 3.83 4.84 258 a 300.79 301.16 3.93 3.82 4.32 76 200526631 259 /¾ 300.79 301.17 3.86 3.48 4.24 + 260 /¾ 296.37 297.29 3.21 3.03 3.61 + 261 300.79 301.18 3.92 3.78 4.25 + 262 /¾ 309.37 310.34 3.66 3.46 4.01 263 /¾ 295.39 296.23 2.70 2.60 2.99 264 316.41 317.17 2.80 2.76 3.18 265 /¾ 382.51 383.24 3.82 3.48 3.95 266 283.38 284.26 2.60 2.52 3.11 267 280.37 281.28 2.65 2.46 3.05 + 268 II ! " Ϊ" 丨I Ml I 353.47 354.18 4.45 4.32 4.95 269 Λ 315.42 316.17 4.31 4.05 4.64 270 O 321.47 322.27 4.29 4.09 4.69 271 4 322.45 323.23 3.05 2.82 3.43 77 200526631 272 259.39 260.17 3.79 3.63 4.14 273 273.42 274.18 4.12 4.02 4.62 274 299.46 300.22 4.22 4.02 4.62 275 Ο 337.47 338.29 3.91 3.79 4.31 + 276 ^ν> 297.40 298.26 3.65 3.42 4.04 277 wA 261.37 262.10 3.13 3.05 3.38 278 ύ°\χ I 350.51 351.38 2.73 2.62 3.08 279 347.50 348.24 4.24 4.06 4.69 280 327.51 328.39 4.35 4.14 5.01 281 308.43 309.33 2.56 2.45 2.85 + 282 ο 325.46 326.32 2.89 2.79 3.16 283 383.54 384.22 4.65 4.05 4.75 + 284 Ο 314.47 315.23 2.59 2.43 2.92 78 200526631 285 287.45 288.06 3.99 3.81 4.64 286 355.91 356.17 4.09 3.83 4.44 + 287 355.57 356.29 4.71 4.50 5.17 + 288 307.44 308.35 3.82 3.71 4.42 289 273.42 274.19 3.81 3.68 4.24 290 259.39 260.18 3.55 3.46 4.41 291 if、人ΝΊΙ 293.41 294.13 3.96 3.82 4.31 292 323.44 324.37 3.91 3.72 4.29 293 1* 311.40 312.15 4.01 3.85 4.32 294 >cr°^ 294.40 295.25 2.79 2.64 3.15 295 294.40 295.25 2.71 2.56 3.08 296 >CY<S II 283.38 284.23 3.08 2.93 3.38 297 300.43 301.23 3.72 3.55 3.94 79 200526631 298 301.43 302.28 3.38 3.29 3.76 299 λγ1^) L ^ IP 390.57 391.38 2.89 2.76 3.22 300 λΎ。'Ί。 351.45 352.29 3.75 3.65 4.19 301 0 330.47 331.31 2.53 2.40 2.80 302 xvAy 337.47 338.29 3.81 3.45 4.28 303 1——F 1- 375.44 376.23 4.15 3.89 4.61 304 400.54 401.23 3.25 3.15 3.52 + 305 °\ 1 397.52 398.26 3.65 3.51 3.96 + 306 285.43 286.15 3.83 3.63 4.26 307 257.38 258.26 3.36 3.22 4.06 308 aV^ 308.43 309.33 2.58 2.38 2.96 + 309 丨丨1 'Γ ? 381.52 382.26 3.63 3.43 4.06 310 4 289.42 290.21 3.32 3.24 3.59 80 200526631 311 335.49 336.47 4.14 3.89 4.52 312 „ Q 360.50 361.34 3.79 3.66 4.35 313 309.41 310.37 3.81 3.49 4.11 + 314 g 329.49 330.28 2.19 2.13 2.48 315 245.37 246.22 3.36 3.26 3.72 + 316 313.47 314.10 3.78 3.68 4.12 ++ 317 318.42 319.05 3.78 3.71 4.18 318 /Vy〇^5 I 336.48 337.40 2.92 2.75 3.29 319 364.54 365.28 3.02 2.63 3.32 320 323.44 324.38 4.29 4.06 4.69 321 335.49 336.48 4.25 4.02 4.75 322 0 378.52 379.35 3.16 3.02 3.45 323 327.86 328.28 4.35 4.18 4.67 81 200526631 324 308.43 309.33 2.89 2.72 3.24 + 325 Λύ#, 351.54 352.39 4.61 4.32 5.07 326 273.42 274.17 3.81 3.68 4.15 327 314.47 315.21 2.54 2.39 2.78 328 367.49 368.21 3.59 3.51 3.91 329 325.43 326.28 3.89 3.72 4.28 330 〇\ 357.88 358.17 4.11 3.96 4.55 + 331 λ^Λ ¥— — K K 361.41 362.30 4.41 4.21 4.66 +++ 332 318.42 319.02 4.01 3.86 4.29 +++ 333 337.47 338.29 3.63 3.45 3.99 334 349.52 350.44 4.54 4.38 4.95 +++ 335 335.49 336.48 4.48 4.26 4.91 336 丨: 丨;l Γ ! :! 1 I i 349.52 350.44 4.69 4.54 5.07 ++ 82 200526631 337 1· 391.44 392.21 4.45 4.29 4.78 + 338 I 321.47 322.28 4.11 3.92 4.59 + 339 JCO 351.45 352.28 3.91 3.69 4.44 340 || l ; ..li 332.45 333.28 3.72 3.61 4.02 341 295.39 296.26 3.15 3.05 3.48 + 342 308.43 309.31 2.85 2.66 3.06 343 Mr 373.30 375.06 4.32 3.96 4.74 344 /\V^ 362.40 363.35 4.39 4.18 4.64 + 345 396.84 397.12 4.10 3.94 4.45 + 346 322.45 323.22 3.05 2.86 3.32 347 287.45 288.05 4.12 3.88 4.55 348 328.85 329.25 3.95 3.88 4.25 349 ri 328.85 329.24 3.88 3.69 4.58 83 200526631 350 4 324.43 325.32 3.51 3.23 3.79 351 、丨 328.85 329.24 3.92 3.79 4.25 + 352 "众 337.42 338.29 3.88 3.62 4.26 353 323.44 324.39 2.95 2.86 3.11 354 XO > 344.46 345.09 2.92 2.62 3.28 355 410.56 411.28 4.48 4.21 4.92 356 λγ°\ ,DU 311.43 312.18 2.52 2.39 2.88 + 357 λΎ^ζ) 308.43 309.32 2.55 2.42 2.85 + 358 343.47 344.18 4.36 4.06 4.66 ++++ 359 349.52 350.45 4.36 4.14 4.75 360 入/) 0 0 433.55 437.92 3.49 3.43 3.61 361 "Λ> 321.38 322.26 3.78 3.45 4.22 ++++ 362 :丨:: 317.39 318.16 3.35 3.19 3.61 84 200526631 363 420.56 421.28 3.14 3.09 3.51 +++ 364 307.40 308.37 3.92 3.78 4.16 ++++ 365 π 311.81 309.08 3.76 3.73 3.88 + 366 (>、 341.84 342.18 3,99 3.93 4.38 ++ 367 F 345.37 346.23 4.21 3.92 4.52 ++ 368 1. 01 379.81 380.22 4.41 4.26 4.52 ++++ 369 333.48 334.42 4.36 4.11 4.67 370 319.45 320.28 4.26 4.02 4.48 371 333.48 334.41 4.45 4.39 4.74 372 滅 1. 375.39 376.29 4.25 4.09 4.41 ++++ 373 ,χχ〕 335.41 336.44 3.76 3.55 3.99 ++++ 374 * 345.37 346.22 4.20 4.15 4.41 ++++ 375 >.· 361.37 362.31 4.21 4.05 4.49 85 200526631 376 人 335.45 336.47 4.14 3.95 4.55 +++ 377 ° I ° 355.46 356.25 3.56 3.43 3.82 ++++ 378 328.42 329.30 2.77 2.61 3.05 ++++ 379 328.42 329.29 3.12 2.94 3.51 ++++ 380 348.49 349.37 3.00 2.93 3.43 ++ 381 ^0¾ 0 362.48 363.49 3.12 2.98 3.45 382 Λ-°φ lit 357.25 357.09 4.15 4.01 4.32 ++ 383 346.36 347.14 4.21 4.09 4.34 +++ 384 Ο 312.80 313.12 3.76 3.61 3.99 ++++ 385 η\ 308.38 309.38 3.47 3.34 3.71 ++++ 386 312.80 313.15 3.82 3.62 4.06 387 330.43 331.29 3.83 3.61 4.25 ++++ 388 人1, 434.46 435.36 2.96 2.92 3.11 86 200526631 389 Ο ,..rySr 321.30 322.27 3.46 3.38 3.66 ++++ 390 τ π 325.72 326.25 3.73 3.63 3.85 ++ 391 355.75 356.17 3.59 3.42 3.95 + 392 -ν-°φ I*——1 1: 359.27 360.06 5.14 5.00 5.22 + 393 347.38 348.29 4.24 4.19 4.44 394 333.36 334.28 3.92 3.82 4.22 ++ 395 347.38 348.29 4.14 4.05 4.31 + 396 389.30 390.30 3.96 3.81 4.02 397 ,Χ50 1, 349.31 350.29 3.35 3.26 3.56 +++ 398 359.27 360.14 3.84 3.67 3.97 ++++ 399 ν-^φ 375.27 376.16 3.88 3.79 4.28 ++++ 400 為, 人 349.36 350.33 3.76 3.62 3.96 401 ’’Τ丨丨 369.37 371.10 1.56 1.49 1.70 87 200526631 402 1 342.32 343.09 2.48 2.45 2.55 403 11Λ 342.32 343.10 2.78 2.59 2.85 404 362.40 363.43 2.72 2.50 3.11 405 0 376.38 377.34 2.86 2.82 3.15 406 °x 322.29 323.16 3.04 2.85 3.09 ++ 407 () 326.71 327.08 3.46 3.39 3.58 408 \: 344.34 345.09 3.43 3.18 3.72 409 ja::> 335.29 336.39 3.34 3.25 3.44 410 331.30 332.28 3.06 3.00 3.25 411 為 356.45 357.11 3.05 2.98 3.62 ++++ 412 為 355.46 356.25 4.32 3.74 4.75 ++++ 413 H3C\/N^/\〇A〇 421.54 422.12 2.68 2.62 3.05 + 414 LM3 308.38 309.35 3.32 3.26 3.68 ++++ 88 200526631 415 Cl 312.80 313.11 3.59 3.43 3.91 416 342.83 343.15 3.48 3.39 3.72 ++ 417 F 346.36 347.17 3.76 3.65 4.04 ++++ 418 380.80 381.24 3.96 3.88 4.31 ++++ 419 • H‘C 十 CH, CH 334.47 335.39 3.89 3.82 4.21 ++++ 420 320.44 321.28 3.78 3.32 4.18 +++ 421 、CH·, 334.47 335.41 4.01 3.93 4.31 ++ 422 376.38 377.32 3.82 3.74 4.18 ++++ 423 xo 336.39 337.39 3.21 3.00 3.43 ++++ 424 346.36 347.16 3.75 3.51 4.02 +++ 425 :;Λ^Φ CH. 1 F 。:人 362.35 363.35 3.76 3.66 4.02 + 426 336.44 337.43 3.64 3.46 3.91 427 :νΤ^Φ o=s=o CH, 356.45 357.09 3.03 2.98 3.26 ++ 89 200526631 428 329.41 330.27 2.38 2.23 2.62 ++++ 429 % 329.41 330.26 2.70 2.63 2.99 ++++ 430 ’ φ CH, 349.48 350.44 2.58 2.42 2.98 + 431 〔:〕 363.46 364.39 2.66 2.59 2.95 432 Br 358.24 358.12 3.55 3.48 3.71 + 433 F 347.34 348.22 3.66 3.59 3.91 ++ 434 a 313.79 314.12 3.22 3.12 3.49 + 435 〇、CH, 309.37 310.39 2.92 2.79 3.15 + 436 。入/ 313.79 314.13 3.26 3.16 3.39 437 HC^’N 331.42 332.28 3.29 3.03 3.51 ++++ 438 xo 322.37 323.19 3.22 3.11 3.45 ++++ 439 ηΑΜ· 318.38 319.08 2.89 2.85 3.16 440 3 ch3 Ά 彳、CHj 434.54 435.15 3.03 2.93 3.16 90 200526631 ~ 除了表1中所列的醯胺化合物之外,下列列舉於下文的 化合物,其包含本發明經乙烯基與乙炔基取代之醯胺,其 中R1和R2’係如先前所述者,可使用以上就實施例1或2所述 之程序和對應的苯曱酸、適當的試劑及熟諳此技藝者已知 的純化方法予以製備。
91 200526631
92 200526631
93 200526631
94 200526631
95 200526631
96 200526631
97 200526631
98 200526631
99 200526631 實施例4 約成像檢驗 VR 1蛋白質是一種熱調控陽離子通道,其對每一個鈉 離子交換大約十個鈣離子,而造成神經元膜去極化及升高 的細胞内鈣含量。因此化合物在VR1受體上的功能活性可 藉由測量神經元如背根神經節中細胞内鈣含量的變化來測 定。 使DRG神經元在經PDL塗佈之96孔黑壁盤上,於含 有 5% Penstrep、5°/〇 Glutamax、200 微克/毫升 Hygromycin、 5微克/¾升Blasticide和10%經熱失活之FBS的DMEM培 養基存在下生長。在檢驗之前,於37。c生理食鹽水溶液中 使細胞中裝載5微克/毫升Fura2歷時40分鐘。然後在開始 實驗之前’用生理食鹽水清洗細胞以除去染料。 將經錢敷神經元轉移至Nikon eclipse TE300顯微鏡台 二的j至内,之後在開始實驗之前,先讓神經元到達穩定 的赏光歷時約1 〇分鐘。此檢驗包括二個階段,即預處理階 &,接著處理階段◦首先,將試驗化合物的溶液自多閥灌 注系統添加到細胞歷時丨分鐘(預處理)。之後立刻在試 驗化合物存在下添加辣椒素( 250 nM)(處理)歷時一段 在20至60秒之間的特定時間。 將Fura2在340和380 nM激發以指示相對鈣離子濃 度j在整個實驗過程中進行波長度量的變化。螢光比係經 $將在340 nM所測得之螢光除以在38〇nM所測得者而計 寻J數據係使用InteiHgent工職以叫、siidebook軟體收 100 200526631 集。所有抑制辣椒辛續 認為是陽性的。 &之職人大於75%的化合物都被 表提(、所獲传的數據。圖1表示當化合物1Μ μ 椒素-起投予時所獲得的結果。反映㈣子流入的榮光降 低。圖3和圖4分另丨丨本- η入 1不化5物3和2與辣椒素一起投予 的結果。
--- 表 2 化合物ID 濃度 治療時間 (秒) 辣椒素誘發之妈 流入的抑制% 155 — __300ηΜ 20 _<75 3 ΙμΜ 60 100 2 ΙμΜ 25 1 \J\J 100 實施例5 1 \J\J 用於使用鈣成像檢驗測定活體内功效的VR1拮抗劑高 輸出分析 在使用具有整合流控與溫控的桌上型掃瞄螢光計(Flex
Station,Molecular Devices )的96孔板中使用雙波長比例式 染料Fura2作為鈣離子相對含量的指示劑。 使293神經元在經PDL塗佈之96孔黑壁盤上,於含有 5% Penstrep、5% Glutamax、200 微克 /毫升 Hygr〇mycin、5 微克/毫升Blasticide和10%經熱失活之FBS的DMEM培養 基存在下生長。在檢驗之前,於37。C生理食鹽水溶液中使 細胞中裝載5微克/毫升Fura2歷時40分鐘。然後用生理食 鹽水清洗細胞以除去染料。 此檢驗包括二個階段:預處理階段,接著處理階段。 將5 0微升化合物溶液添加到細胞(預處理)。之後立刻添 101 200526631 加50微升溶於pH 5.1之食鹽水溶液的試驗化合物。將Fmu 在340和3 80 nM激發以指示相對艇雜曲 ’雖子》辰度。在整個實驗 過程中以4秒間隔& 3分鐘期間内進行波長度量的變化。 反應彳/丁、以试驗化合物添加之後的高峰馨 瓦光比减去用試驗化 合物預處理之前的基線營光比予以測量,並使用 SoftMaxPro軟體計算。數據係以使用Excei計算的抑制 分比表示如下: 抑制百分比=〔化合物反x 100 (激動劑反應-對照組反應) 所有抑制百分比數值大於75%之化合物都被認為是陽 性的。各化合物在抑制鈣離子流入方面的相對強度係詳 於表2中。 實施例6 全細胞膜片箝制電生理學 自初生或成年大鼠重新獲取背根神經節(DRG )神經 元並將之鍍敷於經聚-]:)-賴胺酸塗佈之玻璃條狀蓋板上。將 經鍍敷之神經元轉移至小室内並使用電腦控制的電磁閥基 鲁 雇/主系統使藥物溶液得加到細胞上。使用標準DIC光學使 、也成像使用拉細的玻璃電極將細胞補片。使用以 p AMP8 車人月豆放大控制的 Ax〇n instrurnents Multiclamp 進 ' 行電壓箝制電生理學實驗。 將細胞放入全細胞電壓鉗中並保持在-80 mV的電壓 下’同日守以無縫(§aP-free)記錄模式監測膜電流。添加500n]V[ 辣椒素歷時30秒作為對照組。在30秒辣椒素施用之前, 102 200526631 '將各種不同濃度的試驗化合物加到 々刀判細胞上歷時1分鐘。對 照實驗與藥物陽性辣椒素實驗 J的差異係用以測定各试 驗化合物的功效。所有抑制辣椒素誘發之電流大於50%的 化合物都被認為是陽性的。就化合物155所獲得之數據係 詳列於表3中。 _ 志 1 ----—---
化合物ID 一 ---—___50 ㈤2表不化合物! 55在抑制辣椒素誘發之方面 的活性。 &的敘述可知’ #谙此技藝者將會想到本發明組 由物與方法方面的各種不同修改和變化。所有這類在所附 申凊專利範圍内而來的修改係意欲包括在其中。 在本專利說明書中所引用的公開案,包括但不限於專 安與專利申請案,係以引用方式納入本文,猶如個別公開 ^ 糸具體且個別地指示要以在本文引用如同完全詳述之方 式納入。 【圖式簡單說明】 圖1 •例示化合物155在抑制辣椒素誘發之細胞内鈣 〉力匕方面活小生AA Ej ± 注的圖表。鈣離子流量係以螢光表示。 土圖、2 :例示化合物155在抑制辣椒素誘發之細胞内鈣電 US面t性,圖表。在化合物Μ5存在下投予的辣椒素在 、工兀比早獨投予相同神經元的辣椒素產生較少的鈣離 103 200526631 子流入。 圖3 :例示化合物3在抑制辣椒素誘發之細胞内鈣電流 方面活性的圖表。 圖4 :例示化合物2在抑制辣椒素誘發之細胞内鈣電流 方面活性的圖表。 【主要元件符號說明】 (無)
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Claims (1)
- 200526631 十、申請專利範圍·· 1 · 一種能夠在活體内修飾離子通道且具有下式的化合 物或其%藥上可接受之鹽、溶劑合物或前藥, 式中: A疋N、CR4、鍵結至l的碳原子,或者不是原子; 如果A不是原子,則w、ζ、Β、γ及χ之一是鍵結至 L的碳原子,W、ζ、Β、γ及χ之另一者是鍵結至g的碳 原子,而其餘W、Ζ、Β、γ及X各者則獨立地為Ν或CR4 ; L疋經取代或未經取代之-(C-C)-、-(CR5=CR6)-或 -(CC)-; G 是 〇〇、Os 或 s〇2 ; R1是經取代或未經取代之脂族、烷基、雜烷基、芳基、 雜芳基、芳烷基或雜芳烷基; 2 R 是氫或經取代或未經取代之烷基; R3是經取代或未經取代之脂族、烷基、雜烷基、芳基、 雜芳基、芳烷基或雜芳烷基; 各個R4係獨立地為氫、烷基、經取代或未經取代之烷 基、si基、驢胺基、烷胺基、烷硫基、烷氧基、烷氧基羰 基、烧基芳胺基、芳基烷氧基、胺基、芳基、芳烷基、亞 礪、楓、硫烷基、胺基磺醯基、芳磺醯基、硫酸、硫酸酯、 105 200526631 一 基填酸基、胺基經基碟醯基、疊氮基、私f 尸夂丞、胺基曱 醯基、羧基、氰基、環雜烷基、二烷胺基、_基、雜芳氧 基、雜芳基、雜烧基、.基、石肖基或硫代;以及 ,、 R5和R6各獨立地為Η、鹵素,或經取代或未經取代之 脂族、芳基、雜烷基、芳基、雜芳基、芳烷基或雜芳烷基。 2·根據申請專利範圍第i項的化合物,其中該化::具 有下式:3 ·根據申請專利範圍第2項的化合物,其中 L是經取代或未經取代之、·(cr^cv)·或 -(CC).; G 是 C = 〇 ;R1是經取代或未經取代之赌族、烷基、雜烷基、芳基、 雜芳基、芳烷基或雜芳烷基; R2是氫; R3是經取代或未經取代之脂族或烧基。 4.根據申請專利範圍第3項的化合物,其中R3是 基或下式之其囿· 成一個 疋虱或烷基;且其中二個R2’可接合巧 8原子的環烷基或環雜烷基環;但前提是 106 200526631 少二個是垸基。 5·根據申請專利範圍第 下式· 4項的化合物,其中化合物具有R1 〇 6·根據申請專利範圍第 代之烷基。 5項的化合物,其中是經取^ 7· ^據申請專利範圍第ό項的化合物,其中Rl 疋(CR 2)x-r4 ; r2是氫或烷基;r4,是r4 ; r4係如 利範圍第1項中所、+、土 明寻 、〒所述者,而X是從1 - 3的整數。 8·根據申請專利範圍第7項的化合物, 於第二丁 I # 丁八係礎自 ' - 暴、芳基、環烷基、環雜烷基及雜芳基。 、9·根據申請專利範圍第8項的化合物,其中R4,是經取 代或未經取代之苯基或萘基。10.根據申請專利範圍第8項的化合物,其中R4,是經取 代或未經取代之環丙基、環戊基或環己基。 1 1 .根據申請專利範圍第8項的化合物,其中R4’是經取 代或未經取代之毗咯烷基、呢啶基或嗎咐基。 1 2·根據申請專利範圍第8項的化合物,其中R4’是經取 代或未經取代之吡啶基或嘧啶基。 13.根據申請專利範圍第8項的化合物,其中R4’是經取 代或未經取代之呋喃基、咪唑基、噻吩基、毗唑基或噻唑基。 107 200526631 你十土 Λ 一个υw儿兮物,其中R4是經取 :或代之笨并二聘炫基、苯并,南 基:亞甲基二氧基苯基、唾咐基、異唾咐基 四氮異輯基、二氣啥咐基或二氣異轉基。咐基、 15.根據申請專利範圍第8項的化合物,其中r4’是卜‘ 中 艮據申請專利範圍第8七項中任— 是1或2。 其 ::·=請專利範圍第6項的化合物,其中 :·根據申請專利範圍第5項的化合物,其 代或未經取代之環烧基、環雜烧基或雜芳基。 、、取 19:據申請專利範圍第18項的化合物,其“ 取代或未經取代之環丙基或環戊基。 、- 2〇·根據申請專利範圍第18項的化合物,q Ri 1 取代或未經取代之Μ錢基、射基或嗎咐基;、疋』 A根據中請專利範圍第18項的化合物,1中Ri%_ 取代或未經取代之Μ咬基或嘴咬&。 '、 疋、、坐 ’其·中R1是經 毗唑基或噻唾 其中R1是經 22.根據申請專利範圍第18項的化合物 取代或未經取代之呋喃基、㈣基、噻吩基 基。 ::據申請專利範圍第18項的化合物,… =或未經取代之苯并二縣基、苯并w喃基、麵基1 :亞甲基二氧基苯基、備、異啥咐基、四氫唾咐基 四虱”喧咐基、二氫啥咐基或二氫異唾啉基。 " 24.根據申請專利範圍第5項的化合物,其中R】是經苹 108 200526631 代或未經取代之芳美。 25 ·根據申請專利範圍第24項的化合物,其中R1是經 取戈或未、、’二取代之苯基、萘基、2_聯苯基或聯苯基。 26·根據申請專利範圍第25項的化合物,其中化合物具 有下式:式中汉疋R4;而X係選自於1-5。 27·根據申請專利範圍第26項的化合物,其中X是1。 28. 根據申請專利範圍第27項的化合物,其中Rl,係選 自方;曱基、異丙基、第三丁基、氰基、三氟烷基、鹵基、 硝基、甲氧基、三氟甲氧基、胺基、烷胺基、二烷胺基、 本基、S02Me、S〇2CF3、s〇2NMe2及羧基所組成之群組。29. 根據申請專利範圍第28項的化合物,其中r1’取代 度係在4-位上。 3〇·根據申晴專利範圍第5-29項中任一項的化合物,其 中W、X、γ和z各為cr4。 31·根據申請專利範圍第5_29項中任一項的化合物,其 中W為N且X、γ和z各為cr4。 八 32. 根據申請專利範圍第5_29項中任一項的化合物,其 中Y為N且W、X和z各為CR4。 33. 根據申請專利範圍第5_29項中任一項的化合物,其 中W、X、Υ和Z中有二個是N。 八 109 200526631 34·根據申請專利範圍第30-33項中任一項的化合物, 其中 L 是-(cr5:=cr6)-。 3 5.根據申請專利範圍第34項的化合物,其中R5和R6 一者為氣。 36.根據申請專利範圍第34項的化合物,其中R5是甲 基且R6是氫。 3 7.根據申睛專利範圍第3 4項的化合物,其中R5是氫 且R0是甲基。 38.根據申請專利範圍第30-33項中任一項的化合物, 其 t L 是。 39·根據申請專利範圍第34-38項中任一項的化合物, 其中R3是t-Bu或i-Pr。 4〇·根據申請專利範圍第34-38項中任一項的化合物, 其中R3是CF3。 41 ·根據申請專利範圍第1 8項的化合物,其中化合物是 表 1 中者且化合物 ID No.為:5,13,17, 35, 81,87,ill,117, 142, 143, 1 85, 196, 208, 21 1,21 3, 238, 239, 275 或 305,或 以及其立體異構 物,其中化合物是 其醫藥上可接受之鹽、溶劑合物或前藥 1 8項的化合物,其中化合物是42·根據申請專利範圍第18項的 表I中者且 2 1 7,2 8 6 或 以及其立體異構物。 43·根據申請專利範圍第24項的化人 200526631 表 1 中者且化合物 ID No·為:2, 3, 15, 30, 31,32, 33, 37, 39, 4〇, 41,42, 43, 44, 45, 47, 61,62, 66, 78,130, 1 32, 136, 145,148,150,151,153,156,158,169,171,172,225, 226, 227,228,230,233,242,244,245,246,247,248,249,252, 3 1 3, 330, 33 1,332, 334, 336, 337, 338 或 358,或其醫藥上 可接受之鹽、溶劑合物或前藥;以及其立體異構物。 44·根據申請專利範圍第24項的化合物,其中化合物是 表 1 中者且化合物 ID No·為:48, 52, 53, 64, 07, 68, 70, 71, 72,74, 75,76,77,105,106,166,168,202,203,234,256, 259’ 260,261,324,341,344,345 或 351,或其醫藥上可接 受之鹽、溶劑合物或前藥;以及其立體異構物。 45 ·根據申請專利範圍第24項的化合物,其中化合物是 表1中者且化合物ID No.為:54, 55, 204或205,或其醫藥 上可接受之鹽、溶劑合物或前藥;以及其立體異構物。 46·根據申請專利範圍第24項的化合物,其中化合物是 表 1 中者且化合物 ID No.為·· 8,12,56,65,181,207, 214, 23 7或287,或其醫藥上可接受之鹽、溶劑合物或前藥;以 及其立體異構物。 47·根據申請專利範圍第5項的化合物,其中化合物是 表 1 中者且化合物 ID No·為·· 6, 9, 14, 16, 26, 29, 49, 60, 80, 88, 93, 95,1〇9,112,120,123, 125, 126,127, 139,164,179, 183,190,191,192,193,197,198, 206, 209, 216, 218, 219, 223, 224, 236, 267, 281,283, 308, 3 15, 3 16, 356 或 357,或 其醫藥上可接受之鹽、溶劑合物或前藥;以及其立體異構 111 200526631 物。 48.根據申請專利範圍第38項的化合物,其中化合物是 表 1 中者且化合物 ID No·為:360, 361,362, 363, 364, 365, · 366, 367, 368, 369, 370, 371,372, 373, 374, 375, 376, 377, . 378, 379, 380, 38 1,382, 383, 384, 3 85, 386, 387 或 412 或其 士藥上可接受之鹽或前藥。 49·根據申請專利範圍第38項的化合物,其中化合物是 表1中者且化合物ID No·為:411,413-439或440,或其醫 樂上可接受之鹽、溶劑合物或前藥;以及其立體異構物。 _ 5〇·根據申請專利範圍第4〇項的化合物,其中化合物是 表 1 中者且化合物 ID No.為:388, 389, 390, 391,392, 470, 393’ 394,395,396,397,398,399,400,401,402,403, 404 或405 ’或其醫藥上可接受之鹽、溶劑合物或前藥;以及其 立體異構物。 G 51.一:重醫藥組成物’其包含醫藥上可接受之載劑與醫 樂上有效量之如申請專利範圍第1·5〇丨中任一項的化合龜 物。 W 52. 根據巾請專利範圍第^項的醫藥組成物,其中載劑 為非經腸的載劑。 的醫藥組成物,其中載劑 53. 根據申請專利範圍第51項 為口服的載劑。 為局5::::請專利範圍第51項㈣ 理疾病或症狀的方法 55.-種預肖、治療、改善或管 112 200526631 其包括對有需要這種預防、治 預防或 療上有效量的申請專利範圍第卜5 %、者投予 化合物或中請專利範圍第51_54項中任—;項:# 1之 56·根據申請專利範圍第55項的方法項^醫藥組成物。 狀是一種疼痛症狀。 ”中5亥疾病或症 則⑴f專利範圍第^的方i 狀是一種自身免疫疾病。 、°,疾病或症 58·根據申請專利範圍第55㈣方法 狀是一種發炎性疾病或症狀。 ,、中垓疾病或症 59.根據申請專利範圍第55項的方法 狀是一種神經病學或神經變性 /、—疾病或症 V ^病或症狀。 6〇· 一種預防、治療、改善 其包括對有需要這種預防、治 二或症狀的方法’ 預防或治療上可接受量的申請專利範圍。第或^之患者投予 之化合物或申請專利範圍帛51_5 項t任一項 物,其中該疾病或症狀是:疼痛,勺、壬—項之醫藥組成 經性疼痛;慢性H G w性、發炎性和神 頭痛及緊張性頭痛;帕金森氏:肩阿::,痛、充血性 硬化;由神經發炎所媒介或產生的疾病2氏症,多發性 損傷、中風或腦炎,·中心性媒介 ^ 5周、創傷性腦 包括抑、狂躁、躁鬱症、焦慮、精神=神疾病與失調, 睡眠失調和認知失調;癤 衣症、飲食失凋、 胱和腸道官能障礙、尿失禁、排::作失調;***、膀 排便失荦、攝$臉m去 ^ K邊緩、直腸過敏反應、 攝咖大和發炎性腸道疾病;呼吸道和氣管 113 200526631 的疾病與失調,包括過敏性鼻炎、氣喘和反應性氣故 彻生阻塞性肺病;由發炎所媒介或產生的疾病心疾病 匕括關節炎、風濕性關節炎和骨關節炎;心肌梗塞/周’ 土疫疾病與失調;葡萄膜炎和動脈粥樣硬 抵:身 牛成、& •头= "丨席’韻:癢、 厣.谷症(落髮);肥胖;脂質失調;癌症;古血 之,脊髓損傷·,或腎臟病。 円血 61根據巾請專利範圍第⑼項的方法,其 狀是帕金森氏症。 灰病或症 狀θ •根據申清專利範圍第60項的方法,其中該^ 1 狀疋阿茲海默氏症。 、扃或症 63.根據申請專利範圍第6〇項 狀是創傷性_^ 〃中4疾病或症 狀是6中^據中請專利範圍第⑼項的方法,其中該疾病或症 狀是=據中請專利範圍第6〇項的方法,其中該疾病或症 6·根據申請專利範圍第6〇項 狀是神、經性疼痛。 & - m病或症 67·—種製備申請專 的方法m a J粑圍弟】-66項中任-項之化合物 任ι/Γ 以形成根據申請專利範圍第wo項中 的條件τ,使—種式r3·⑽伽、或 且其中Cy二:匕合物與一種式RiR2簡之化合物接觸,· y疋方基或雜芳基。 68·—種治療患有至少一種選自於下列所組成群組之徵 114 200526631 狀的哺乳動物的方法·· i露於辣椒素的徵狀,由於暴露於 熱的燒傷或刺激的徵狀,由於暴露於光的燒傷或刺激的徵 狀,由於暴露於催淚瓦斯的燒傷、支氣管緊縮或刺激的徵 狀’以及由於暴露於酸的燒傷或暴露刺激的徵狀,該方法 包括投予該哺乳動物有效治療疾病或治療症狀量的根據申 請專利範㈣㈣項中任—項的化合物或巾請專利範圍第 51-54項中任一項之醫藥組成物。 69.根據申請專利範圍第⑽項的方法,其中疼痛係與選 自於下列所組成群組之症狀有關:***切除後疼痛徵候 ^殘端痛’幻肢痛,口部神經,时痛,查爾克特氏疼痛 ^ Γ、’δ_),牙痛,毒蛇咬傷,-蛛咬傷,昆蟲整 二乂皰疹性的神經痛,糖尿病的神經病冑,反射***感 神經失養症,三叉袖娘& 炎,纖唯,π广一 骨關節炎’風濕性關節 肌痛症,格林巴里徵候群,感覺異常性股痛,口 ^ =徵候群’兩側周邊神經病變,灼痛,坐骨神經炎, -Γ二’多發性神經炎’體節性崎,宮保特氏神 H(G_bauU,Sneuntls),神經元炎,㈣神經痛 發性神經痛,肋間神二;::Γ"爾 莫頓氏神經痛一 疏痛,έ neuraigia),鼻睫神經痛’枕骨神 緊張性頭翼管動脈神經痛,鼻f頭痛, 根據二=腸漲氣,月經,癌症及創傷。 申明專利乾圍第1·50項令任—項的化合物,其 115 200526631 莫頓氏神經痛(Morton’s neuralgia),鼻睫神經痛,枕骨 神經痛’紅神經痛’斯路德氏神經痛^^^^⑼^), 脾顎神經痛,眼窩神經痛,翼瞢 e * 動脈神經痛,鼻竇頭痛, =頭痛,陣痛,分娩’腸澡氣,月經,癌症及創:。 7〇·根據申請專利範圍第le5〇 乃 其係用作-種藥物。 、中任一項的化合物, 71.根據申請專利範圍第丨_5〇 其係用作治療如巾請專利範圍第55中任—項的化合物, 中所列舉症狀的藥物。 6、68或69項任—項 •種申凊專利範圍第丨_ 係製傷用於治療如申請專利範圍第/之化合物的用途’其 項中所列舉症狀的醫藥組成物。务68或69項任— 十一、圖式: 如次頁116
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-
2004
- 2004-10-07 JP JP2006534356A patent/JP4667384B2/ja not_active Expired - Fee Related
- 2004-10-07 CA CA002541949A patent/CA2541949A1/en not_active Abandoned
- 2004-10-07 AR ARP040103646A patent/AR046276A1/es unknown
- 2004-10-07 TW TW093130317A patent/TW200526631A/zh unknown
- 2004-10-07 EP EP04794499A patent/EP1680109A4/en not_active Withdrawn
- 2004-10-07 BR BRPI0415179-8A patent/BRPI0415179A/pt not_active IP Right Cessation
- 2004-10-07 US US10/961,483 patent/US7432281B2/en not_active Expired - Fee Related
- 2004-10-07 WO PCT/US2004/033163 patent/WO2005046683A1/en active Application Filing
- 2004-10-07 MX MXPA06003951A patent/MXPA06003951A/es not_active Application Discontinuation
-
2008
- 2008-07-18 US US12/218,973 patent/US20080312237A1/en not_active Abandoned
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WO2005046683A1 (en) | 2005-05-26 |
EP1680109A4 (en) | 2009-05-06 |
CA2541949A1 (en) | 2005-05-26 |
US7432281B2 (en) | 2008-10-07 |
AR046276A1 (es) | 2005-11-30 |
JP2007509043A (ja) | 2007-04-12 |
JP4667384B2 (ja) | 2011-04-13 |
US20050222200A1 (en) | 2005-10-06 |
EP1680109A1 (en) | 2006-07-19 |
BRPI0415179A (pt) | 2006-11-28 |
US20080312237A1 (en) | 2008-12-18 |
MXPA06003951A (es) | 2006-06-27 |
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