TWI249519B - Immunoregulatory compounds and derivatives and methods of treating diseases therewith - Google Patents
Immunoregulatory compounds and derivatives and methods of treating diseases therewith Download PDFInfo
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- TWI249519B TWI249519B TW090121181A TW90121181A TWI249519B TW I249519 B TWI249519 B TW I249519B TW 090121181 A TW090121181 A TW 090121181A TW 90121181 A TW90121181 A TW 90121181A TW I249519 B TWI249519 B TW I249519B
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Description
1249519 A7
扭關Φ 本專利案申請在2000年8月29曰申請之美國臨時專利案 號60/228,683的優點，該申請案經本篇完整引述為參考^ 件0 登明筋.轉 本發明係關於免疫調節化合物及用其治療疾病的方法。 發_明背景 許多人罹患發炎性腸症（IBD)。IBD是用來泛指兩種發炎 性疾病的通稱，潰瘍性結腸炎及克隆氏（Cr〇hn，s)症。潰廣 性結腸炎是一種未知病源的慢性發炎症，其影響大部份的 胃腸（GI)道，特別是下GI道，尤其是結腸及/或直腸。克隆 氏（Crohn s)症疋一種嚴重的GI道發炎症。主要發生在小腸 (迴腸）及大腸（結腸）。已有多種醫藥使用在治療發炎性腸 症。 已知使用美沙爾胺（mesalamine)、5-胺基水揚酸（5-ASA) ~療潰癌性結腸炎。雖然美沙爾胺（mesalamine)在治療潰 瘍性結腸炎具有活性，但在通過GI道時可能會被吸收。該 吸收對達到下GI道，尤其是結腸及直腸的美沙爾胺 (mesalamine)數量有負面的影響。 已有多種美沙爾胺（mesalamine)調合物在使用時嘗試保 護美沙爾-胺（mesalamine)通過腸道及上GI道。其中一種調 合物是採用延遲釋放調合物，其依賴包圍美沙爾胺 (mesalamine)的pH-感應塗層。該塗層使得美沙爾胺 (mesalamine)通過腸道及上GI道而不被吸收，因此美沙爾 -4 - 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1249519 A7 B7 五、發明説明（2 ) 胺（me sal amine)可完整的到達目標物（即，下GI道，特別是 結腸及/或直腸）。其他調合物將美沙爾胺（mesalamine)微 粒包圍美沙爾胺（mesalamine)核心。該調合物在GI道中釋 放美沙爾胺（mesalamine)，而不是專一性標乾在結腸。當 投藥給廣泛的個體時，將很困難預測多種美沙爾胺 (mesalamine)調合物的生物可利用性。因此也難以訂定個 別個體的適當劑量。 已知使用具有如下式之石黃胺匹林（sulfasalazine)治療潰 瘍性結腸炎。
(mesalamine)(5-胺基水揚酸（5-ASA))及續醯比唆。已觀察 到數種使用石黃胺匹林（sulfasalazine)的副作用包括僅舉出 數種如，噁心、嘔吐、腹部不適及頭痛。該副作用的產生 通常是因為磺醯比啶在GI道的活性，以及經吸收至系統中。
Chan所申請的美國專利第4,412,992號中提出美沙爾胺 (mesalamine)的衍生物。不像石黃胺匹林（sulfasalazine)，該 化合物在腸道中分解將不產生不欲的代謝物。事實上，非 美沙爾胺（mesalamine)代謝物可為無害的。 同時已知使用具有如下式之歐沙爾畊（olsalazine)治療潰 瘍性結腸炎。 ____ -5- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1249519 A7 B7 五、發明説明（3
HOOC, ,COOH
除了製造起來相當昂貴外，之歐沙爾_ (olsalazine)也具有 包括腹瀉的副作用。 同時已知使用硫嗤σ票呤（azathioprine)(6-( 1 -甲基-4-硝基 -咪唑-5-基硫基）嘌呤）治療發炎性腸症。硫唑嘌呤 (azathioprine)具有如下的化學結構：
Η 同時已知使用硫唑嘌呤（azathioprine)代謝物之6-硫基嘌 吟治療發炎性腸症。6 -硫基σ票吟具有如下的化學結構：
SH
甲胺喋昤（methotrexate)(L-4-胺基-Ν10-甲基嗓醯基-楚胺 本紙張尺度適用中國國家標準(CNS) Α4規格(210X297公釐) 1249519 A7 B7 五 發明説明（4 酸）也被使用在治療發炎性腸症 具有如下的化學結構： h2n
HOOC一·H^C H2C-—CH 一—COOU 傳統上被用來投藥予器官移植患者以避免產生排斥的多 胜肽環孢黴素也被用來治療發炎性腸症。不過，以環孢徽 素治療IBD的用途將因伴隨該藥物所產生的多種副作用受 到限制。該副作用包括高血壓、腎臟受損、發抖、頭痛、 猝务、毛髮生長過度、牙齦生長過度、迷惑、昏迷及痛風。 發明捅要 根據本發明的具體實例
其提供具有如下式的化合物: R1 --COOR3 Q r 其中R1，R。及R4分別是氫或（^至C4烷基，且R2是
其中R5是選自由氫及（^至(：4烷基，或
本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1249519 A7 B7 五、發明説明（5 1至C4烧基）所組成的基團
(其中R6，R7及R8分別是氫或C ，以及該化合物的酯或其於醫藥上可接受的鹽。同時也提 供包括根據本發明具體實例的化合物之醫藥組合物，以及 利用該化合物治療發炎症狀的方法。
根據本發明的其他具體實例，治療需要該治療受者之GI 道發炎症狀的方法包括投藥予該受者有效劑量的包括如下 式II化合物的活性醫藥組成份：
其中R9，R10及R11分別選自由氫或（^至（^烷基所組成的基 團，且R12是選自由氫及-C(〇）R13所組成的基團，其中Ri3 是（^至匕烷基或芳基基團，或該化合物的酯或其於醫藥上 可接受的鹽，與固體或液體醫藥稀釋劑或載體的混合物。 該活性醫藥組成份可進一步的包括如下式ΠΙ的化合物：
簡明圖解 圖1說明本發明化合物的合成途徑。 圖2說明本發明化合物的合成途徑。 圖3說明相較於利用本發明的具體實例（4-APaa/DNBS 及混合物/DNBS)及利用以前的技藝（5-ASA/DNBS)及控制 組所達到的結腸：體重[% BW]的平均降低結果。 本紙張尺度適％中國國家標準(CNS) A4規格(2ι〇χ297公爱) 1249519 A7 B7 五、發明説明（6 圖4說明相較於利用本發明的具體實例（4_ApAA/DNBS 及混合物/DNBS)及利用以前的技藝（5-ASa/DNBS)及控制 組（載體/DNBS及載體/S虛擬物）所達到的DNBS結腸炎黏連 性計分。 較隹具艚膏例詳埽 本發明將分別以本處所描述的較佳具體實例來說明。吾 人應瞭解該具體實例僅為說明本發明的目的，而不是為了 限制本發明在申請專利範圍所定義的範缚。 如本處使用，名詞“發炎性腸症，，包括潰瘍性結腸炎及克 隆氏症。 根據本發明的具體實例，所提供的化合物如下式：
R1，R3及R4分別是氫或CdC4烷基。較佳的，Ri , R3及 R4分別選自由H、CH3、CH2CH3及CH(CH3)2m組成的基團 。更佳的，R1，R3及R4是Η或CH3。 H0
R2是： r5ooc 或
R6 r7ooc-- i8 -9 -
1249519 A7 __________B7 五、發明説明（7 ) R5是選自由氫及（^至（：4烷基所組成的基團。較佳的，R5 是選自由Η、CH3、CH2CH3及CH(CH3)2所組成的基團。更 佳的，R5是Η或CH3，且R5是η為最佳。 R6，R7及R8分別是氫或（^至c4烷基。較佳的，R6 , R7及 R8分別選自由Η、CH3、CH2CH3及CH(CH3)2所組成的基團 。更佳的，R6，R7及R8是Η或CH3。 本發明化合物可利用已知的起始物及試劑來製造。例如 ’合成途徑的具體實例如圖1及圖2所說明。 本發明化合物可用來預防或治療多種疾病，尤其是GJ道 的發炎症狀包括，但不限於口的發炎症狀如黏膜炎、感染 性疾病（例’病毒性、細菌性及真菌性疾病），以及克隆氏 症（Crohn’s disease);食道的發炎性症狀如食道炎、因化 學傷害引起的症狀（例，食入驗液）、胃液逆流症、膽汁逆 流症、巴瑞特氏食道（Barrett’s esophogas)、克隆氏症 (Crohn’s disease)及食道狹窄；胃的發炎性症狀如胃炎（例 ，幽門螺旋桿菌、酸性消化症及萎縮性胃炎）、消化性潰 瘍、胃的癌化前病變、非潰瘍性逍化不良及克隆氏症 (Crohn’s disease);小腸的發炎症狀如腹部病、克隆氏症 (Crohn’s disease)、細菌過度生長、消化性潰癌及小腸裂 傷，結腸的發炎症狀如克隆氏症（C r 〇 h II ’ s d i s e a s e)、消化 性潰瘍、感染性結腸炎（例，假膜結腸炎如芽胞桿菌感毕 、沙門桿菌腸炎、志贺氏菌感染 '小腸結腸炎耶爾森氏菌 感染（yersinosis)、隱孢子蟲症及微孢子蟲感染及病毒感 染）、經輻射誘發的結腸炎、免疫功能不足或缺損患者 -10- 1249519 A7 B7 五、發明説明（8 ) (Immunocompromised host)的結腸炎（例，盲腸炎）、結腸 的癌化前症狀（例，發育不良、腸道的發炎症狀及結腸息 肉）、直腸炎、痹瘡相關的發炎、移動性直腸痛及直腸裂 傷；肝膽囊及/或膽道症狀如膽道炎、硬化性膽道炎、初 期膽硬化及膽囊炎；以及小腸膿腫。本發明化合物可用來 在生物系統或樣本中進行組成份、症狀或疾病狀態的診斷 ’以及在非生理系統中做為診斷的目的。甚至本發明化合 物可應用在預防或治療植物系統中的症狀或疾病狀態。藉 由實例，本發明化合物可具有使用在多種植物系統的殺昆 蟲、除草、殺真菌及/或殺害蟲效用。 根據有些具體實例，本發明的化合物可在腸道中裂解以 生成式IV的代謝產物：
其中R , R及R4如前述參考式〗所描述，以及式V的代謝產
式iv的代謝產物擁有抗發炎活性及/或免疫調節活性。式v 的代謝產物擁有抗發炎活性，而且更可抑制前列腺素合成 酶I及II。 在有些具體貫例中，本發明的化合物可在腸道中裂解以 ί紙張尺度適用中國國家標準(CNS) A4規格(21()χ 297/^ί------------- 1249519 A7
1249519 A7 B7 五、發明説明（1〇 ) 本發明也包含可使用在獸醫及人類醫藥用途的醫藥調合 物’其中包括做為活性試劑的一種或數種本發明化合物。 在該醫藥及藥物調合物中，較佳的將活性試劑與一種或多 種醫藥上可接受的載體共用且視情況與任何其他治療組成 伤/、用。泫載體必須是醫藥上可接受的與調合物中的其他 組成份相容且較佳的對其受者不具破壞性。所提供的活 °式劑劑i可有效的達到如前述所欲的藥理效用，並且以 當的量達到所欲的每日劑量。 該調合物包括適用於非經腸道使用及經腸道使用方式 以及特殊的投服形態包括口服、直腸、頰、表面、鼻内 眼、皮下、肌肉内、靜脈内、皮膚内、椎管内、關節内 動脈内、蜘蛛膜下、支氣管、淋巴、陰道及子宮内投藥 以適用於口服及非經腸道使用的調合物為佳，以適用於 服投藥的調合物為最佳。 田本發明化合物是以包含液體溶液的調合物使用時， 調合物較佳的以口服或非經腸道方式投服。當本發明化合 物是採用液體懸浮液調合物或以溶於生物相容載體的粉: 調^物，較佳的該調合物以口服、直腸或支氣f方式投藥。 當本發明化合物直接以粉末固體方式使用，該化合物 口服方式投藥為佳。另外，可利用支氣管方式投藥 將粉末以載體氣體噴霧以生成粉末的氣體噴霧，其利用曰 括合適的噴霧裝置經由患者的呼吸道吸入。 八 包括本發明化合物的調合物可便利的以單位劑型方 現而且可利用任何醫藥上已知的方法製備。該方法 性 適
D 該 合 以 著 包 呈 包 t m^^(CNS) Α4^(21〇χ^^ 1249519 五 、發明説明（11 A7 B7 括將本發明化合物鱼A _ 相結合的步驟一般而一：二：:辅組成份組成的載體 份與液體載體、經細：：固=物：製備是將活性組成 以結合，而且視需要：：：=或兩者經規則化的加 祝*要將該產物塑形為所欲的調合物劑型。 適用於口服的本發明調合物可利用 謂囊、小膠囊、鍵劑或菱形鍵，每_單位中包括事見先訂 疋的活性組成份劑量’可為粉末或顆粒；或在水性液或非 水性液體中的懸浮液，如糖n乳化液或口服液。 錠劑的製備可利用壓製或塑模，視情況與-種或多種輔 助的組成份㈣。經壓製㈣的製備可在合適的機器中壓 製’該活性化合物為自由流動形態如為粉末或顆粒，其視 情況與結合劑、分散劑、潤滑劑、惰性稀釋劑、界面活性 劑或染色劑相混合。經塑模的錠劑包括粉末的活性化合物 與適當載體的混合物在合適的機器中經塑模製備。 糖聚的製備係添加活性化合物至經濃縮的糖水溶液中， 例如庶糖，其中可再加入任何輔助的組成份。該輔助的組 成份可包括，例如加味劑、^當的保存劑、延緩糖結晶的 試劑以及提高任何其他組成份溶解度的試劑如聚羥基醇， 例如甘油或山梨醇。 適合以非經腸道方式使用的調合物一般包括活性化合物 的無菌水性製備液，較佳的其與接受者的血液為等張溶液 (例，生理食鹽水溶液）。該調合物可包括懸浮試劑及增厚 劑或其他經設計將化合物標的於血液組成份或一個或^個 器官的微顆粒系統。該調合物可利用單位劑型或多重劑型 -14- 1249519 A7
的方式呈現。 冗内嘴霧；合物包括活性化合物的經純化水性溶液與保 子j及等m較佳的，將該調合物調整至與鼻内黏膜 相容的pH值及等張狀態。 、 以直腸投藥的調合物的呈現可利用栓劑結合適當的載體 可可油經氫化脂肪，或經氫化脂肪竣酸。 眼用凋合物利用與製備鼻内噴霧相似的方法製備，除了 其pH值及等張因子應調整以配合眼睛為佳。 表面塗佈的調合物包括將活性化合物溶於或使懸浮在一 種或多種介質如礦物油、石油、聚羥基醇，或其他使 用在表面塗佈醫藥調合物的鹼。 除了 $述的組成份，本發明的調合物更可包括一種或多 種輔助組成份選自稀釋劑、緩衝液、加味劑、分散劑、界 面活性劑、增厚劑、潤滑劑、保存劑（包括抗氧化劑），及 其相似者。 因此’根據本發明的化合物可經利用來預防或治療多種 疾病’特別是GI道的疾病包括，但不限於發炎性腸道症。 在本發明的其他實例中，在治療或預防需要該治療或預 防受者之發炎性腸道症的方法包括給予該受者有效劑量的 包括式II化合物之活性醫藥組成份：
其中R9，R1G及R11分別選自由氫或(^至c4烧基所組成的基 ____ -15- 本紙張尺度適用中國國家標準(CNS) Α4規格(210 X 297公釐) 1249519 A7 B7 五、發明説明（13 ) 團；且R12是選自由氫及-C(0)R13所組成的基團，其中R13 是（^至<：6烷基或芳基基團，或該化合物的酯或其於醫藥上 可接受的鹽，與固體或液體醫藥稀釋劑或載體的混合物。 該活性醫藥組成份可進一步包含一種或多種醫藥物包括 ，但不限於抗發炎試劑如美沙爾胺（mesalamine)、續胺匹 林（sulfasalazine)、巴沙疊氮（balsalazide)及歐沙爾口井 (olsalzine);免疫調節劑如硫唾σ票吟（azathiopurine)、6-氫 硫基嘌吟、環孢黴素及甲胺嗓玲（methotrexate);固醇化合 物如類固醇；以及抗生素如曱石肖璉唾（metronidazole)及環 丙沙星（ciporfloxacin)。該活性醫藥組成份以包括如下式 III化合物美沙爾胺（me sal amine)為佳：
當活性醫藥組成份包括式II及式III化合物，較佳的，式Η 化合物是由活性醫藥組成份的約1 〇至9〇重量百分比且更佳 是由活性醫藥組成份的約40至60重量百分比。當活性醫藥 組成份包括式II及式ΠΙ化合物，較佳的，式I化合物對式Π 化合物的莫耳比是介於1:10及10:1，且以介於1:2及2:1為 更佳。 利用根據本發明具體實例方法來治療的受者包括人類及 非人類的動物（例，鳥、狗、貓、牛、馬）受者，而且以哺 乳類受者為佳，且以人類受者為最佳。 根據要克服的特定症狀或疾病狀態，可利用任何適當的
1249519 A7 B7 發明説明 治療有效及安全劑量將本發明化合物投藥予動物受者，其 可容易的以該技藝訂定且不需進行過度的實驗。例如，本 务明化合物的投服劑量可介於約0 · 1及200毫克/公斤重之間 ，以約1至90毫克/公斤重之間為佳，且更佳為介於丨〇至 8〇毫克/公斤重之間。 本發明將以下述實例為參考來說明。吾人應瞭解下述實 例是為說明本發明各方面之目的，同時不限制申請專利範 圍中所提出的範疇。 膏例 實例1至4 合成本發明化合物 以貫驗設備Mel-Temp II毛細管熔點裝置測量熔點並且 未再修正。以Varian Unity 300 MHz取得1HNMR光譜，同 時化學位移（5 )是以相對於内標準四甲基矽烷以百萬分之 一（ppm)來報告。以Nicolet Impact 410取得紅外線光譜。 以Beckman DU 640i分光光譜儀取得紫外光及可見光光譜 。由Μ-Scan lnc·獲得快速原子撞擊（FAB)質量光譜數據。 所有使用的試劑是來自Aldrich化學公司。 f例1及2 佥成5-Γ4-ΓΚ游乙某V茉某偶氮1-2-_某-芰甲醅 f例1 2-(4-胺基-苯基）-丙酸 加入（R，S) 2-(4-硝基苯基）丙酸（5.00克，25.6毫莫耳）、 絕對乙醇（200毫升）及鈀（1〇 wt. %在活性碳上，0.27克， -17- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1249519 A7 B7 五、發明説明（15 2·56亳莫耳）至5〇〇毫升經烘箱乾燥的，配有攪拌子的3頸 燒瓶中。倒入氫氣至燒瓶中並使混合物在室溫下攪拌6小 時。使粗製反應混合物經赛力特矽藻土過濾並於減壓下除 去乙醇。在真空下使粗製產物乾燥過夜可得淺黃色固體 (70%產率，2.98克）：mp 125-129°C，4 NMR (DMSO-d6) • 5 1·24 (3H，s)，1.26 (3H，s)，3.41 (1H，s)，3.43 (2H，s) ’ 6.46 (2H，d，J=7.6 Hz)，6.91 (2H，d，J=7.6 Hz) ; IR (KBr) 2596 ， 2189 ， 1630 ， 1581 ， 1441 ， 1375 ， 1277 ， 1192，1052 , 876 cm-1 ; FAB-MS (NBA) m/z 165 (M+H)+。 實例2 5-[4·(1·羧基-乙基）-苯基偶氮]羥基-苯曱酸 將得自實例1步驟中的2-(4-胺基-苯基）·丙酸（3 ·9〇克， 23.6¾莫耳）HC1水溶液（75毫升，36.5 -38.0% HC1在8毫升 KUO中）中，並加入200毫升的燒杯中且使於冰浴中冷卻至 〇°C。當溶液在〇°C下穩定後，滴加溶於水（2毫升）的亞石肖 酸鈉（1.79克，26.0毫莫耳）。使溫度維持在〇 - 5°c並將所得 的二偶氮鹽攪拌1 5分鐘。 當一偶氣鹽溶液在擾拌中，將配有擾拌子、溫度計及 pH偵測器（〇ri〇n 420A型帶有Orion半微pH偵測器）的800毫 升燒杯加入水楊酸，溶於氫氧化鈉（4.25克，106毫莫耳）及 H2〇 (1〇〇毫升）中的鈉鹽（η·3克，20.8毫莫耳）。利用冰浴 將水％酸 >谷液冷卻至1 7 C並緩慢的滴加1 0毫升二偶氮鹽溶 液。在添加過程中，利用添加氫氧化鈉水溶液維持pH在 1 3.2 - 1 3.3並以添加冰將溫度保持在1 7 - 1 8°C。待添加完畢 1249519 A7 B7 五、發明説明（16 ) ----- 後*將所侍的暗紅色溶液回溫至室溫並持續攪拌9〇分鐘。 以JCl (〜20毫升，36·5 _ 38%)將溶液酸化至3 5，將 產生暗紅色固體沉澱並以真空過濾收集。 將粗製產物（8.49克，27.0毫莫耳）在112〇(3〇〇毫升）中使 懸矛並加熱至70°C達30分鐘以除去多餘的水揚酸。使該懸 浮/夜冷卻至50 C並以抽氣過濾收集固體。所收集的固體經 快速色譜純化（Si〇2 :乙酸乙酯/己烷，1:1)。載入溶於 DMF (〜4.5亳升）的粗製產物（2·5〇克，7·95毫莫耳）並收集 黃色的分液，待收齊後在減壓下使濃縮。在真空下乾燥後 ’所獲得的經純化產物是產率為55%的橘色固體（1.38克） :mp 147 C，4 NMR (DMSO_d6) : δ 1·38 (3Η，s)，1.39 (3Η，s) ’ 3·76 (1Η，s)，3·78 (1Η，s)，7.11 (1Η，d，J=8.4 Hz) ，7.46 (2H，d，J = 7.8 Hz)，7.80 (2H，d，J = 8.4 Hz)，8.03 (1H，d，J = 9.0 Hz)，8.30 (1H，s) ; IR (KBr) 2973，1921 , 1708，1652，1577，1477，1339，1289，1226，1164， 1101，1013，857，663 cm.1 ; UV-Vis (MeOH) Xmax=355 nm ，ε =23,700 mol’1 cm-1 L ; FAB-MS (NBA) m/z 3 13 (M)、 實例3 合成5-(4-羧基甲基-苯基偶氮基）-2-羥基-苯曱酸[ΑΡΑΖΑ] 將4-胺基苯基乙酸（10.0克，66.2毫莫耳）溶於HC1水性液 (20毫升，36·5 -38.0% HC1溶於200毫升的Η2Ο中）並置於 500毫升的燒杯且在冰浴中冷卻至〇°C。當該溶液在〇°C中 穩定後，滴加溶於水中（50毫升）的亞硝酸鈉（5.02克， 72.8毫莫耳）。使溫度維持在〇 -5°C並將所得的二偶氮鹽溶 ___- 19- 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公¥) 1249519 A7
液攪拌1 5分鐘。 當二偶氮鹽溶液在攪拌中，將配有攪拌子、溫度叶及 PH積測器（0rion 420A型帶有〇ri〇n半微pH偵測器）的=升 燒杯加入水揚酸，溶於氫氧化鈉（11·9克，23〇亳莫耳）及水 (2〇〇毫升）中的鈉鹽（31.8克，198毫莫耳）。利用冰浴將水 楊酸溶液冷卻至丨7。(：並緩慢的滴加25毫升的二偶氮鹽溶液 。在添加過程中，利用添加氫氧化鈉水溶液維持阳在 13.2 -13.3並以添加冰將溫度保持在17_18〇c。待添加完畢 後，將所得的暗紅色溶液回溫至室溫並持續攪拌3〇分鐘。 以濃HC1 (〜50毫升，36.5 _38。/〇)將溶液酸化至pH 3，將產 生褐色固體沉殿並以抽氣過濾收集。 將粗製產物經快速色譜純化（Si〇2 ··乙酸乙酯/己烧， U)°在充填有70 - 230孔目，60 A矽膠，其BE丁表面積是 〜500平方公尺/克且孔徑體積是〇 75立方公分/克的管柱中 載入溶於DMF (〜12毫升）的粗製產物（η·5克，38·2毫莫耳） 。收集分液並以顏色分類集合，第一個色帶的顏色是黃色 且包含多餘的水揚酸及少量所欲的產物。第二個色帶是橘 色並包含所欲的產物且第三個色帶是紅色，其中包括了未 知的不純物。收集所有的分液並在減壓下濃縮及在真空下 乾燥。 所獲得的經純化產物是產率為28%的橘色固體（2.75克） :mP 2〇代，咕 NMR (DMSO-d6) : δ 3·67 (2Η，s)，7.11 (1Η，d，J = 9.0 Hz)，7.44 (2Η，d，J = 8.4 Hz)，7.79 (2Η，d， J==8.4 Hz)，8.02 (1H，d of d，J = 2.4 Hz，9.0 Hz)，8.29 ---------------- -zu - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1249519 A7 B7 五、發明説明（18 ) (1H, s) ; IR (KB〇 3098，1696，1614，1458，1345，1195 ，83 8 cm·1 ; UV-Vis (MeOH) Xmax = 350 nm，ε =25,700 mol.1 cnT1 L ;帶正電FAB-MS (NBA) m/z 301 (M+H)+，帶 負電 FAB-MS (NBA) m/z 299 (M)-。 實例4 合成4-(4 -竣基曱基-苯基偶氮基）-苯基乙酸 將4-胺基苯基乙酸（3.75克，24.8毫莫耳）溶於水（75毫升） 及濃鹽酸（8毫升）中。使溶液在冰浴中冷卻至〇°c並加以快 速攪拌。滴加溶於水中（20毫升）的亞硝酸鈉（1 ·80克， 26.1毫莫耳）至4-胺基苯基乙酸溶液並加以快速攪拌。小心 使溫度一直維持在〇 - 5 °C，尤其是在添加NaN02時。使反 應再攪拌20分鐘。同時將苯基乙酸（i〇.i克，74.4亳莫耳） 溶於NaOH水溶液（4.50克，113毫莫耳的NaOH在100毫升 H2〇中）。使溶液在17。〇及pH 13.3下劇烈攪拌。滴加二偶 氮鹽溶液至苯基乙酸溶液中。最重要的是一直維持苯基乙 酸溶液的溫度在17 - 18°C間並使pH維持在13.2 -13.3，尤其 是在添加二偶氮鹽溶液時。利用添加冰調節溫度並以添加 8 M NaOH調節pH值。待添加完畢後，使該溶液回溫至室 /JDL並持續擾拌3 〇分鐘。以抽氣過滤除去反應混合物中任何 未溶解的顆粒或不要的副產物。以HC1水溶液（1 〇毫升濃 HCh容在20毫升HzO中）酸化濾液將產生暗紅色沉澱。以抽 氣過濾收集沉澱物並以冷H2〇淋洗數次至濾液變成澄清。 將所收集的固體於空氣中乾燥過夜可獲得所欲的化合物為 產率 37%的紅色固體·· IR (KBr) 3030 (b〇，1696，1658， 21 - 本紙張尺錢用巾s _準(CNS)織格_ χ撕公爱) 1249519 A7 B7 五、發明説明（19 1452，1414，1201，850，675 cnT1 FABMS m/z 299 (M+H)+，320 (M+Na) ; 4 NMR (DMSO-d6) : δ 3.47 (s，4H) ，7.33 (4H，d，J=8.1 Hz)，7.84 (4H，d，J = 8.4 Hz)。 實例5 ΑΡΑΖΑ在經口服傳遞後的代謝 測定本發明化合物Apaza (5-(4-羧基甲基-苯基偶氮基）-2-經基-苯甲酸）及確胺匹林（sulfasalazine)(做為控制組； 不是本發明的一部份）以口服投藥劑量給予大鼠後的裂解 及所產生的代謝物以確定Apaza及讀胺匹林（sulfasalazine) 經細菌性偶氮還原並產生其代謝物，磺胺匹林 (sulfasalazine)是5-胺基水揚酸（5-ASA)及石黃醯比啶，而 八卩32&是5-胺基水楊酸（5-八8八）及4-胺基苯基乙酸（4-八？八八）。 執行本貫驗以確定偶氮化合物，Apaza在活體代謝中經 過細菌性還原過程並產生其代謝物。同時測定其代謝物的 量。利用不是本發明一部份的磺胺匹林（3111“3&1以丨1^)做 為控制組，因為細菌也會切開相似的偶氮鍵，而產生5 _胺 基水揚酸及磺醯比啶做為其代謝物。Apaza及續胺匹林 (sulfasalazine)均經裂解並產生預期中的代謝物。 在尿液試驗方面，僅測定第1天收集尿液中之原化合物 及其代謝物。其餘所收集的並未測出任何的化合物。在翼 便試驗方面，則測定2天内收集中之化合物。 給予Apaza的大鼠（大鼠1、2及3)在尿液中出現Apaza、 4-APAA、乙醯基胺基苯基乙酸及乙醯化5-ASA。給予石备 胺匹林（sulfasalazine)劑量的大鼠（大鼠4、5及6)在尿液中 -22- 1249519 A7 _____B7 五、發明説明（20 ) 出現磺胺匹林（sulfasalazine)、磺醯比啶及乙醯化5-ASA。 不論給予那一種化合物，在糞便中均僅測到乙醯化5- ASA 。5-ASA會快速的轉變為乙醯化5-ASA。 令人值得注意的是雖然給予磺胺匹林（sulfasalazine)的 大鼠所產生的代謝物，5-ASA (在本實例是乙醯化5-ASA) 及磺醯比啶是1:1，但是給予Apaza的大鼠所產生的 4-APAA是乙醯化5-ASA的7至10倍。 吾人咸信所攝入的續胺匹林（sulfasalazine)將由小腸到 達結腸並經過細菌性偶氮還原以產生磺醯比啶及5-ASA分 子。本實驗所獲得的結杲確認前述的說法並顯示Apaza也 經過相似的細菌性偶氮還原。 總共使用了 8隻大鼠在實驗中並以甲基纖維素做為載體 。劑量是每隻大鼠為1 00毫克/公斤重。將3隻大鼠投以 Apaza並以續胺匹林（sulfasalazine)投予另3隻大鼠。將2隻 鼠做為控制組並投予曱基纖維素。收集4天内的尿液及糞 便並以HPLC分析。 每天收集尿液並將每一個樣品的300微升分裝液經 5000 g離心10分鐘。將80微升的上清液注射分析。收集每 天的糞便並以1:1的水及乙腈混合物使均質化。使該混合 物在5000 g下離心20分鐘。將80微升的上清液注射分析。 使用Waters 2690 HPLC進行如下的樣品分析： 移動相程式： 梯度
移動相： A=水+0.1% TFA
B=乙腈+0.1% TFA _-23- ___ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐） 1249519 A7 B7 五、發明説明（21 ) 流速： 1毫升/分鐘 管柱： Phenomenex Max RP，80A，4.6毫米 χ250毫米 PDA設定： 收集光譜範圍：210 - 400 nm 經萃取色譜：280及/或其他 分析時間/樣品：約50分鐘 時間 流速(毫升/分鐘） 移動相％ A相 移動相％ B相 - 1 100 0 40 1 50 50 43 1 5 95 44 1 95 5 50 1 95 5 5-八3八將快速轉變為乙醯化5-八3八。在尿液中，八？&2&及 磺胺匹林（sulfasalazine)產生相同量的乙酿化5-ASA。在給 予石黃胺匹林（sulfasalazine)的大鼠的尿液中所產生的5-ASA 及磺醯比啶是1:1。但是給予Apaza的大鼠的尿液中所產生 的4-APAA是乙醯化5-ASA的約7至10倍。不論給予那一至 種化合物，在糞便中僅能測到乙醯化5-ASA。在糞便中較 尿液中測得更多的乙醯化5-ASA。 -24- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐) 1249519 A7 B7 五、發明説明（22 ) 第1天 尿液 給予Apaza 總劑量 (毫克） Apaza (毫克） 4APAA (毫克） 乙醯基胺基苯基乙酸 (毫克） 乙醯化5 ASA (毫克） 大鼠1 22.0 0.48 3.456 0.0717 0.299 大鼠2 23.5 0.3546 3.177 0.422 大鼠3 22.5 0.4707 4.674 0.298 給予續胺匹林(sulfasalazine) 總劑量 (毫克） 石黃胺匹林(sulfasalazine) (毫克） 石黃醯比唆 (毫克） 乙醯化5 ASA (毫克） 大鼠4 21 0.00882 0.337 0.288 大鼠5 22.5 0.01279 0.305 0.328 大鼠6 21 0.01092 0.41 0.39 糞便 給予Apaza 總劑量(毫克） 乙醯化5ASA (毫克） 大鼠1 22 1.9254 大鼠2 23.5 1.9519 大鼠3 22.5 1.2437 給予績胺匹林(sulfasalazine) 總劑量(毫克） 乙醯化5 ASA (毫克） 大鼠4 21 1.2158 大鼠5 22.5 1.3708 大鼠6 21 0.9033 第2天 糞便 給1 ;Apaza 總劑量(毫克） 乙醯化5ASA (毫克） 大鼠1 22 0.2562 大鼠2 23.5 0.7755 大鼠3 22.5 0.1827 給予磺胺匹; 木(sulfasalazine) 總劑量(毫克） 乙醯化5ASA (毫克） 大鼠4 21 0.2 大鼠5 22.5 0.2584 大鼠6 21 0.1458 -25- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1249519 A7 B7 五、發明説明（23 ) 實例6 本發明化合物的生物效應 本試驗的目的是在組織上評估及比較三種不同的活性醫 藥組成份以直腸内投藥予公Lewis鼠後（每天2次，共4天） ，接著以直腸内投藥二硝基苯磺酸（DNBS)的效應。根據 已知的實驗模型（Richard et al.，2000; Bertran et al·，1996; Blau et al·，2000; Kimura et al·，1998; Hogaboam et al·， 1996)，DNBS在大鼠中將誘發結腸炎。分別以模擬物 (SHAM)及DNBS群組做為陰性及陽性控制組。表1為每一 組動物的分佈： 表1 群組 動物數 SHAM 6 DNBS 5 5-ASA 6 4-APAA 6 5-ASA及4-APAA的混合物 4 材料及方法 測定取自27隻公鼠的結腸切片樣品，包括顯微切片及蘇 木素和伊紅染色。以顯微鏡觀察所得的27個玻片（每個玻 片1個橫切面）。除了取自模擬物（SHAM)群組的1隻大鼠及 取自DNBS群組的1隻大鼠，所有的玻片都經過標示以加速 盲讀。將損傷分為1-5分（1 =最低；2 =輕微；3=中度；4=中 度-嚴重；5 =嚴重）。 結果 在所有以DNBS處理（不論有任何額外的治療）的大鼠的 _-26-_ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1249519 A7
結腸切片上觀察到的組織外觀改變，主要是部份至完全的 增厚、兀整長度的凝固性壞死。在以生理食鹽水/甲基纖 維素處，的大鼠（模擬物（SHAM)群組）未觀察到壞死二在 所有的實例中，壞死區域的特性是劇烈的損失細胞内容及 染色的親和性；在該區域僅以“魏殼，，表示仍維持結腸的架 構。偶而也觀察到明顯的區段喪失或“丢失，，小腸組織層。 壞死的組織受到多種細菌的嚴重侵害。在未完全壞死^區 域，壞死的形態傾向分層，一般是影響到黏膜及下黏膜而 保存了部份的外肌層及/或動脈外膜（漿膜及鄰近的腸系膜） 。在這些區域中，很厚的一層核崩解中性球經壞死的内層 與較少損傷的外層分開。在所有經DNB S處理的大鼠中均 觀察到下黏膜血管發生類纖維蛋白壞死的脈管炎。在壞死 及；又壞死的區域都觀察到脈管炎，通常伴隨栓塞（纖維蛋 白的、纖維素細胞的，及/或細菌的血栓），以及由最低至 中度下黏膜出血（有或沒有纖維蛋白聚積）。有些出血處包 含充滿色素的巨喔細菌（鐵噬細胞-未分開診斷）。在所有經 DNBS處理大鼠的切片，漿膜及鄰近的腸系膜因輕微至中 度至嚴重的纖維脈管增生（早期顆粒化組織）而擴大。來自 兩隻老鼠的切片（#4及#11，5-ASA及4-APAA群組的混合 物）’每一個都包含單一、短、清楚劃分的非壞死、非潰 瘍黏膜的區域。在這些比較不受影響黏膜區域的變化僅限 於最低至輕微腺窩上皮增生、最低的腺窩擴張及最低的中 性球渗入。 結腸壞死的嚴重性計分是基於組織的參與程度；不過5 ___-27- _ 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公董） 1249519 A7 B7 五、發明説明（25 ) 分（嚴重）是代表壞死所引起嚴重組織喪失的損傷。因為壞 死的形態通常在每一個區域都不同，因此分別對個別的小 腸層計分。一般而言，壞死的平均嚴重性計分在經DNB S 處理大鼠的四個群組中是可比較的（表2)。在5-ASA及 4-APAA混合物群組的黏膜壞死平均計分較經DNBS處理大 鼠的其他群組的計分為低，這是因為在5-ASA及4-APAA 混合物群組中的兩隻老鼠有保留黏膜區域。 表2 :平均組鐵壞死計分 群組 模擬物 (SHAM) DNBS 5-ASA 4-APAA 5-ASA 及 4-APAA 混合物 動物數 (6) (5) (6) (6) (4) 黏膜 0.00 4.20 4.50 4.33 3.50 下黏膜 0.00 4.20 4.17 4.00 4.25 肌層 0.00 3.60 3.5 3.17 3.00 動脈外膜 0.00 1.40 1.67 1.67 1.50 摘要 在所有以DNBS處理（不論有任何額外的治療）的大鼠的 結腸切片上觀察到的組織外觀改變，主要是部份至完全的 增厚、完整長度的凝固性壞死。相關的改變包括在壞死組 織有大量的細菌入侵、伴隨血栓及出血的纖維蛋白壞死脈 管炎，以及嚴重的中性球滲入。在經生理食鹽水/甲基纖 維素處理的大鼠（模擬物（SHAM)群組）未觀察到壞死。四 個經DNBS處理大鼠群組（DNBS、5-ASA、4-APAA及 5-ASA和4-APAA混合物）的壞死嚴重性（程度）是可比較的 ，除了在5-ASA及4-APAA混合物群組中的2/4大鼠比較性 的保留了單一區段的黏膜。 _-28-_ 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐） 1249519 A7
實例7 藥物混合物的抗發炎活性 —在4組，每組6隻Lewis鼠中誘發（不經乙醚麻醉）二硝基 苯磺酸（DNBS)結腸炎。將一組DNBS群組給予載體 甲基纖維素）以及另一組6隻動物的模擬物（SHAM)群組， 其給予生理食鹽水灌腸劑取代DNBS。以直腸内投藥方式 對意識清楚的動物每日施行2次，共4天。藥物處理如下： 5-胺基水揚酸（5-ASA): 50毫克/公斤重 4-胺基苯基乙酸（4-APAA) : 49.5毫克/公斤重（與5_asa 等莫耳） 混合物· 5-ASA + 4-APAA : 50毫克/公斤重+ 49.5亳克/ 公斤重 使藥物溶於前述的載體並使處理者不知藥物群組的内容 。記錄每日的體重及腹瀉計分。在第5天將刺激後的老鼠 殺死’剖腹並記錄腸道的黏連及裂傷；切除結腸並記錄結 腸的重量，將結腸由縱向剖開並將發炎/潰瘍的程度計分。 圖3及圖4說明的結果指出5-ASA、4-APAA及混合物產 生相似的抗發炎活性（結腸：體重[% B W]降低〜3 1 %)。發 炎的嚴重性趨近於最大。該嚴重性可能因DNB S劑量的減 低而趨緩，並且進行一個小型試驗來驗證該假設。若以較 輕微的發作，則可更明顯的分開處理的效果。 在6隻Lewis鼠上誘發DNBS結腸炎（3隻以30，另3隻以 1 5毫克/鼠的DNBS)，並使發病5天而不做處理以測定發炎 的嚴重性。在1-4天發現有腹瀉症狀並在第5天殺死老鼠， _-29- 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐） 1249519 A7 B7 五、發明説明（27 ) 計分並訂定結腸：體重的結果。該結果顯示相較於30毫克 ，15毫克/鼠的DNBS產生較輕微但較不一致的發炎症狀。 30毫克/公斤重DNBS的結果是較為一致如前所示。 前述僅用來說明本發明，並不是做任何的限制。本發明 經下述申請專利範圍及申請專利範圍所包含的相等物所定 義。 ’ _-30- 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐)
Claims (1)
1181號專利申請案 A8 專利範圍替換本(94年| 六、申請專利範圍 f’·.一、一一 一一、' 9|9·殳， 公 Η • I 種如下式I的化合物， R1
COOR3 (D 其中R1、R3及R4分別是 H0- 氫或(^至0：4烷基，且R2是
r3ooc〆 其中r5是選自由氫及<^至（:4烷基，或 R6 R?OOC-
i 裝 訂 其中R6，R7及R8分別是氫或（^至^烷基，其條件為當6 個取代基R1，R3, r4, r6, r>r8中有5個為氫時，剩 下的取代基為(：】至C4烷基，而且進一步的條件為當Rl， R3, R6和R7每一個均為氫時，R4和R8不同時為匕^基； 或其於醫藥上可接受的鹽。 2·根據申請專利範圍第1項之化合物，其具有如下結 R1 、、°
的 其中R1是選自由Η、CH3、CH2CH3及CH(CH3)2m組成 本紙張尺度適用中國國家標準(CNS) A4規格(21〇Χ297公釐）~一 一 --- _ 1249519 a、申請專利範圍
群組； 且R2是：
其中R3是選自由Η、CH3、CH2CH3及CH(CH3)；^/t組成的 群組，其條件為當R1是Η時，R3選自由CH3，CH2CH3和 CH(CH3)2所組成之群組，且當r3是η時，Ri選自由ch3 ’ CHzCH3和CH(CH：3)2所組成之群組，而且進一步的條 件為R1是CH2CH3時，R3選自由Η，CH3和CH(CH3)2所組 成之群組，而當R3是CH2CH3時，R〗選自由Η，ch3和 ch(ch3)2所組成之群組； 或其於藥理上可接受的鹽。 3·根據申请專利犯圍第2項的化合物，其中及r3分別選 自由Η及CH3所組成的群組。 4.根據申請專利範圍第2項的化合物，其為5-(4•紱基甲基_ 本基偶氛基）-2-經基-苯甲酸。 5·根據申請專利範圍第2項的化合物，其為％[4•(卜叛基乙 基）-苯基偶氮基]-2-羥基-苯甲酸。 73519.940902 替換.doc - 2 ~
1249519 A8 B8
0.— 有效劑===症狀_組合物 具包括 R1 •C00X3 (I) R4 其中V、R3及R4分別是氫或CjC4烧基
且R2是： 其中R5是選自由氩及CjC4烷基，或
r7ooc 其中R6，R7及R8分別是氫或CiSC4烷基所組成的群組， 或其於醫藥上可接受的鹽；與醫藥上可接受的稀釋劑 載體混合。 / 7·根據申請專利範圍第6項之醫藥組合物，其包括治療發 炎性腸道症有效劑量的如下式之化合物： R】
其中R1是選自由Η、CH3、CH2CH3及CH(CH3)2m組成的 群組； 73519-940902 替換.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公爱） 1249519 六、申請專利範園 A8 B8 C8 D8 且R2是：
R3
群組； 或其於藥理上可接受的鹽，與固體或液體醫藥稀釋劑或 載體混合。
裝 訂 8·根據申請專利範圍第7項的醫藥組合物，其中r丨及分 別選自由Η及CH3所組成的群組。
9.根據申請專利範圍第1項的化合物，其中，…及R4分 別是選自由Η、CH3、C&CH3及CH(CH3)2K組成的群組 〇 10·根據申請專利範圍第1項的化合物，其中R6，化7及R8分 別是選自由Η、CH3、CHWH3及CH(CH3)2所組成的群組 11·根據申清專利範圍第1項的化合物，其中r5是選自由Η 、CH3、CH2CH3及CH(CH3)2所組成的群組。 12·根據申清專利範圍第6項的醫藥組合物，其中r1，r3及 73519-940902 替換.doc - 4 - 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公釐）. 1249519 A8 B8 C8 D8 六、申請專利範圍 R4是分別選自由Η、CH3、CH2CH3及CH(CH3)2所組成的 群組。 13·根據申請專利範圍第6項的醫藥組合物，其中r6，r7及 R是分別選自由Η、CH3、CH2CH3及CH(CH3)2所組成的 群組，。 14·根據申請專利範圍第6項的醫藥組合物，其中R5是選自 由Η、CH3、CH2CH3及CH(CH3)2所組成的群組。 15. 根據申請專利範圍第6項的醫藥組合物，其中的化合物 是4-(4-羧基甲基-苯基偶氮基）_苯基乙酸。 16. 根據申請專利範圍第6項的醫藥組合物，其中GI道的發 炎性症狀是潰瘍性結腸炎。 17·根據申请專利範圍第6項的醫藥組合物，其中gi道的發 k性症狀疋克隆氏症（Crohn’s disease)。 18·根據申請專利範圍第6項的醫藥組合物，其中有效劑量 的式I化合物是經口服投藥給需要該項治療的患者。 19·根據申請專利範圍第6項的醫藥組合物，其中有效劑量 的式I化合物是經直腸投藥給需要該項治療的患者。 20·根據申請專利範圍第1項之化合物，其中r2為：
R6 R7OOC一一 R3 其中R6、R7和R8分別為氫或（^至匕烷基。 21·根據申請專利範圍第20項之化合物，其中R7為氮 73S19-940902.doc · 5 ^ 本紙張尺度適用中國國家標準(CNS) A4規格(210X297公爱) 1249519 A8 B8 C8 _____ D8 六、申請專利範園 22·根據申請專利範圍第2〇項之化合物，其中R6為氫，且R8 選自由Η，CH3，CH2CH3和CH(CH3)2所組成之群組。 23.根據申請專利範圍第2〇項之化合物，其中R6為氫，且rS 選自由Η和CH3所組成之群組。 24·根據申請專利範圍第2〇項之化合物，其中ri和r6為氫， 且R4和R8分別選自由Η，CH3，CH2CH3和CH(CH3)2所組 成之群組。 25. 根據申請專利範圍第2〇項之化合物，其中Ri和R6為氫， 且R4和R8分別選自由Η和CH3所組成之群組。 26. 根據申請專利範圍第2〇項之化合物，其中Ri、“和R6為 氫，且R4和R8分別選自由Η和CH3所組成之群組。 27. 根據申請專利範圍第20項之化合物，其中Ri，R3，R6和 R為氫，且R4和R8分別選自由Η，CH3，CH2CH3和 CH(CH3)2所組成之群組。 28·根據申請專利範圍第20項之化合物，其中ri，r3，R6和 R7為氫，且R4和R8分別選自由H*CH3所組成之群組。 29·根據申凊專利範圍第1項之化合物，其具有如下結構
其中R1，R3、R4和R5分別為氫或C^C4烷基；或其於 醫藥上可接受之鹽類。 73519·Μ0902 替換.doc - β . 本紙張尺度適用中國國家標準(CNS) Α4規箱^210X 297公笼------ 1249519 A8 B8 C8 --------— '____D8 六、申請專利範園 3〇_根據申請專利範圍第29項之化合物，其中R5為氫。 31·根據申請專利範圍第29項之化合物，其中Ri為氫，且R4 選自由Η，CH3，CH2CH3和CH(CH3)2所組成之群組。 32·根據申請專利範圍第29項之化合物，其中R4為氫，且Ri 選自由Η和CH3所組成之群組。 33·根據申請專利範圍第29項之化合物，其中R3為氫。 34·根據申請專利範圍第29項之化合物，其中Ri，R3#Rs為 氣，且R4選自由Η，CH3，CH2CH3和CH(CH3)2所組成之 群組。 35·根據申請專利範圍第2項之化合物，其具有如下結構
其中R1為（^至匕烷基；或其於醫藥上可接受之鹽類。 36·根據申請專利範圍第35項之化合物，其中…為^^^烷 基。 37·根據申請專利範圍第35項之化合物，其為5_(4_羧基甲 基-苯基偶氮基）-2-羥基-苯甲酸，或其藥理上可接受之 鹽類。 & 38·根據申請專利範圍第35項之化合物，其為5·[(4·(卜羧基 乙基·笨基偶氮基]-2-羥基-苯甲酸，或其藥理上可接受 之鹽類。 73519·940902 替換.doc 本紙張尺度適财@ ®家標準(CNS) A4規格(21GX297公董) ------- A BCD 1249519 六、申請專利範園 39·根據申請專利範圍第6項之醫藥組合物，其包含治療gi 道發炎性症狀有效劑量的如下結構之化合物：
其中R1，R3、R4和R5分別為氫或(^至。烷基；或其於 醫藥上可接受的鹽，與醫藥稀釋劑或載體混合。 40.根據申請專利範圍第39項之醫藥組合物，其中r5為氫。 41·根據申請專利範圍第39項之醫藥組合物，其中Ri為氫， 且R4選自由Η，CH3，CH2CH3和CH(CH3)2所組成之群組 〇 42·根據申請專利範圍第39項之醫藥組合物，其中R4為氫， 且R選自由Η和C Η 3所組成之群組。 43.根據申請專利範圍第39項之醫藥組合物，其中r3為氫。 44·根據申請專利範圍第39項之醫藥組合物，其中Rl，R3和 R5為氫，且R4選自由Η，CH3，CH2CH3和CH(CH3)2所組 成之群組。 45·根據申請專利範圍第7項之醫藥組合物，其包含治療〇ι 道發炎性症狀有效劑量的如下結構之化合物： 73519-940902 替換,doc - Q - 本紙張尺度適用中國國家標準(CNS) A4規格(210X 297公釐) 1249519 A8 B8
其中R1為（^至^烷基；或其於醫藥上可接 醫藥稀釋劑或載體混合。 i，與 46·根據申請專利範圍第45項之醫藥組合物，其中… C2烷基。 馬6或 47·根據申請專利範圍第7項之醫藥組合物，其包括治療⑴ 道發炎性症狀有效劑量5-(4-羧基甲基-苯基偶氮基）_2_ 經基-苯甲酸或其醫藥上可接受之鹽類，與醫藥上可接 受之稀釋劑或載體混合。 48·根據申請專利範圍第7項之醫藥組合物，其包括治珍GI 道發炎性症狀有效劑量5-[4-(1-羧基乙基）-苯基偶氮基]-2-羥基-苯甲酸或其醫藥上可接受之鹽類，與醫藥上可 接受之稀釋劑或載體混合。 -9-
裝 訂
73519-940902 替換.doc 本紙張尺度適用中國國家標準(CNS) A4規格(210 X 297公釐）
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2006
- 2006-09-07 US US11/470,655 patent/US7425578B2/en not_active Expired - Lifetime
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2010
- 2010-01-04 CY CY20101100001T patent/CY1110593T1/el unknown
- 2010-04-28 IL IL205420A patent/IL205420A/en not_active IP Right Cessation
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