TW201033216A - Pyrrolidine compounds - Google Patents
Pyrrolidine compounds Download PDFInfo
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- TW201033216A TW201033216A TW099106891A TW99106891A TW201033216A TW 201033216 A TW201033216 A TW 201033216A TW 099106891 A TW099106891 A TW 099106891A TW 99106891 A TW99106891 A TW 99106891A TW 201033216 A TW201033216 A TW 201033216A
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- compound
- aryl
- alkyl
- heteroaryl
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- 210000002437 synoviocyte Anatomy 0.000 description 1
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- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
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- A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
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Description
201033216 六、發明說明: 【發明所屬之技術領域】 本發明係關於一種β比洛咬化合物。 【先前技術】 雙肽基胜肽酶(Dipeptidyl peptidases),其為催化多肽 水解而釋放出雙胜肽之酵素,在生理及病理過程中扮演重 要的角色。雙肽基胜肽酶族群中,雙肽基胜肽酶IV (DPP-IV) 及纖維母細胞活化蛋白(fibroblast activation protein,FAP) 為兩個廣為人知的成員。 為因應營養攝取,由腸内分泌L-細胞(intestinal endocrine L-cells)所產生之類_升糖激素胜肽-1 (glucagon-like peptide-1)荷爾蒙及葡萄糖依賴性促胰島素 多肽(glucose-dependent insulinotropic polypeptide)荷爾 蒙,會受到DPP-IV降解,因而抑制DPP-IV可以提高胰島素 分泌、降低血糖含量以及改善胰臟β-細胞功能(Deacon C. et al., Expert Opin. Investig. Drugs 2007 16: 533-545 以及 Deacon C. Cwr". 0/7/«· /«vesiz.g. 2008,9: 402-413)。對 於DPP-IV的抑制作用,人類具有良好的耐受性,且此作用 不會造成血糖過低或體重增加(Deacon C. Cwrr. C>pfw. /«vejiig. Drwgi1 2008, 9: 402-413 以及 Rosenstock J. et al., 2008,10: 376-386) ’ 因此DPP-IV抑制 劑具有成為第二型糖尿病藥物的潛力(例如參考Peders〇n R. et al., Diabetes 1998, 47: 1253-1258 I Ahren B. et al., 201033216
Diabetes Care 2002, 25: 869-875 Deacon C. et al., Expert /«veshg. Drwgj 2004,13:1091-1102 ;以及 pei z. Cmat. DrwgDiicov. Deve/. 2008,1 1: 512-532)。 FAP專門表現在胎兒細胞、受傷組織及惡性上皮組織 腫瘤之基質纖維母細胞(stromal Hbroblasts)(參考Scanlan M. et al., Proc. Natl. Acad. Sci. U.S.A 1994, 91: 5657-5661 i Rettig W. et al., Proc. Natl. Acad. Sci. U.S.A 1988, 85: ©3110-3114 ;以及Huber M. et al.,/· iVivesi. 200, 120: 182-188),研究顯示持續表現FAP的異體移植小鼠,發 展出腫瘤的可能性為模擬轉植小鼠的2至4倍,且顯示出對 照組小鼠的10至40倍腫瘤生長率(參考Cheng J. et al., 2002,62: 4767-4772),當以抗FAP抗血清治 療異種移植小鼠時,可減緩腫瘤生長。人類臨床試驗顯示, 結腸腫瘤中具高含量基質性FAP的病人,更有可能發展成具 侵襲性的疾病,並且會有轉移或復發的可能性(見Henry L. et al.,C7irt. 2007, 13: 1736-1741),因此可使用 © 抗FAP藥劑治療癌症。 此外,在類風濕性關節炎(rheumatoid arthritis,RA)及 骨關節炎(osteroarthritis,OA)病人中,類纖維母細胞的滑 膜細胞(ibroblast-like synoviocytes)也會大量表現 FAP (Bauer S. et al·,772er· 2006,8: R171),故建議 將FAP當作治療標來治療RA或OA。 【發明内容】 5 201033216 本發明基於意外發現雙環二醯胺化合物群組可以抑制 雙肽基胜肽酶的活性。本發明之一態樣關於下式之雙環二 酿胺化合物:
其中,R!、R2、R3、R4、R5、R6、尺7及 R8各別為 Η、i 素、烷基、氱基、硝基、胺基、硼酸基、硼酸酯基、環烷 基、雜環烷基、芳基或雜芳基·,T為C(RaRb)、NRC、Ο或S ; 其中Ra及Rb各別為Η、院基 '鹵素、氰基、硝基、胺基、院 氧基、羥基、環烷基、雜環烷基、芳基或雜芳基;以及Rc 為Η、院基、環烷基、雜環烷基、芳基或雜芳基;X為c(RdRe)、 NRf、Ο、S或刪除X ;其中R(^Re各別為H、烷基、鹵素、 氮基、硝基、烷氧基、羥基、環烷基、雜環烷基、芳基或 雜芳基;以及心為Η、烷基、環烷基、雜環烷基、芳基或雜 芳基,以及R為烷基、環烷基、雜環烷基 '芳基、雜芳基、 -C(0)0Rg或-C(〇)NRhRi ;其中Rg為烷基、環烷基、雜環烷 基、芳基、雜芳基;以及以及Ri各別為H、烷基、環烷基、 雜環烷基、芳基 '雜芳基、芳基烷基或羥基’或1及心與 其兩者連接之N原子一起形成5或6員環,選擇性經烷基、芳 基、鹵素、羥基、烷氧基(akyl〇xy〇、硝基、胺基、烷氧羰 基或羧基所取代;以及選擇性與含〇、丨、2或3個雜原子之 3-8員芳香族環或非芳香族環稠合。 201033216 對於上式,前述化合物中—子群組的特徵在於τ為cH2 或S,X為CH2或刪除x,R為々〇师成;R^R與其兩者 連接之N原子一起形成5或6員環,選擇性經烷基芳基幽 素、羥基、烷氧基、硝基、胺基、烷氧羰基或羧基所取代; 以及選擇性與含0、1、2或3個雜原子之3·8員芳香族環或非 芳香族環稠合。化合物中另一子群組的特徵在於尺為 -C^C^NRhRi ;心及&各別為η、烧基、環烧基、雜環烧基、 方基、雜芳基、芳基院基或經基。 以下所示為本發明示例性的化合物:
9
8 7 7 201033216
以及 「烧基」一詞係指直鏈或支鏈之單價碳氫基團,其包 含1 -10個碳原子,烷基舉例包括但不限於:曱基、乙基、 正丙基、異丙基、正丁基、異丁基及第三丁基。「烷氧基 一 係指單價基團_〇_烷基。「烷氧烷基」一 调係指烷基有經過一個以上的烷氧基取代。「函烷基」一 8 201033216 詞係指烷基有經過一個以上的鹵素取代。「羥烷基」_詞 係指统基有經過一個以上的經基取代。 「芳基」一詞係指單價C6單環狀、c1()雙環狀、c14三 環狀芳香環系統,其中各環可具有丨至4個取代基,芳基舉 例包括但不限於:苯基、萘基及蒽基。「芳氧基」一詞係 指單價基團-Ο-芳基。「芳烷基」一詞係指烷基有經過—個 芳基取代。 「環烧基」一詞係指飽和或部分飽和之碳氫環結構, 其具有3至12個碳原子。環烧基舉例包括但不限於:環丙 基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環 庚基及環辛基。 「雜芳基」一詞係指具有一個以上的雜原子(例如〇、 N或S)之芳香性5-8員單環、8-12員雙環或11-14員三環結 構。雜芳基舉例包括但不限於:吡啶基(pyHdy) '呋喃基 (furyl)米嗤基(imidazolyl)、苯並味 β坐基(benzimidazolyl)、 鳴咬基(pyrimidinyl)、嘆吩基(如⑶丫丨)、啥琳基(quinoUnyi)、 吲哚基(indolyl)及噻唑基(thiaz〇ly〇。「雜芳烷基」一詞係 指院基有經過一個雜芳基取代。 「雜環烧基」一詞係指一個以上的雜原子(例如〇、N 或S)之非芳香性5-8員單環結構、8_12員雙環結構或n_14M 二%結構。雜環烷基舉例包括但不限於:哌嗪基 (piperazinyl)、《»比略院基(pyrr〇iidinyi)、二。惡烧基 (dioxanyl)、嗎琳基(m〇rph〇iiny丨)及四氫咬喃基 (tetrahydrofuranyl)。 201033216 「硼酸基」一詞係指-B(OH)2。「硼酸酯基」一詞係 指-B(OH)(OR)或-B(OR)(OR’),R及R’各別為烷基、芳基、 雜芳基、環烷基或雜環;或R與R’ 一起為亞烷基。硼酸酯基 —i」 P 乂 〇-\ \ —B、 / —g \ —B、 舉例包括 〇~Λ、 以及 '〇」<。
本文所述之烷基、環烷基、雜環烷基、芳基、雜芳基、 芳烷基、雜芳烷基、烷氧基及芳氧基,包括經取代及未經 取代等兩種基團。取代基舉例包括但不限於:鹵素、羥基、 胺基、氣基、琐基、魏基(mercapto)、炫氧幾基 (alkoxycarbonyl)、酿胺基(amido)、叛基(carboxy)、烧績醯 基(alkanesulfonyl)、院艘基(alkylcarbonyl)、脲基 (carbamido)、胺曱酿基(carbamyl)、缓酸基(carboxyl)、硫脲 基(thioureido)、硫氰酸基(thiocyanato)、績醯胺基 (sulfonamido)、烧基、烯基、炔基、烧氧基、芳基、雜芳基、 環烧基、雜環烧基,其中烧基、稀基、炔基、烧氧基、芳 基、雜芳基、環烷基及雜環烷基更可被取代。 如果可以實施的話,上述二醯胺化合物包括化合物在 醫藥上可接受的鹽類、其溶劑化物、以及其前驅藥,而二 醯胺化合物上帶有正電之離子基團(例如銨基)與帶有負電 之相對離子(例如三氟醋酸根)之間,便可形成這類的鹽類; 同理,二醯胺化合物上帶有負電之離子基團(例如羧酸根) 與帶有正電之相對離子(例如鈉、鉀、鈣或鎂)之間,亦可形 成鹽類。二醯胺化合物可含有非芳香族性雙件與一個以上 的不對稱中心,因此其能以消旋混合物(racemic 10 201033216 mixtures)、單一鏡像異構物、個別非鏡像異構物、非鏡像 體混合物、或順式或反式異構物的形式存在,而所有異構 物皆考慮在内。 本發明其他態樣關於一種使用前述二醯胺化合物來 抑制雙肽基胜肽酶(例如DPP-IV或FAP)活性或治療癌症或 發炎情況之方法。 含上述一種以上前述二酿胺化合物機醫藥可接受載體 φ 之醫藥組成物’以及使用該組成物製造治療癌症或發炎藥 劑的用途’同樣在本發明的範疇中。 本發明於後文將提出一個以上的詳細實施例,由此描 述及申請專利範圍將更為了解本發明的其他特徵、目的、 以及優點。 【實施方式】 本發明之二酿胺化合物可使用本領域已知合成方法來 製備,示例性的合成途徑如下流程1所示。 流程1
P i為胺基保護機團 P2為酸基保護機團 201033216
vi
起始化合物吡咯啶-2-酮化合物⑴之胺基及4-曱羧基受 A 到保護,其可由本領域以之方法製備,例如參考心办⑽
Lett. 1988, 39, 2199-2202 ; J. Chem. Soc. Perkin Trans. /, 2002, 613-621 I J. Chem. Soc. Perkin Trans. /, 2001, 2361-2371 ;以及J. Orf CTzew. 1994, 59, 4327-4331。化合 物⑴與市面上可購得的L-脯氨酿胺(L-prolinamide)(ii)反 應,得到5-氧代吡咯啶-2-羰基-吡咯啶-2-曱醯胺(5-oxopyrrolidine-2-carbonylpyrrolidine-2-carboxamide)(iii), 其進行脫水作用以將2-甲醯胺基轉換成氰基,以生成化合 物(iv)。化合物(iv)而後去保護以移去胺基及酸基保護基 ® 團,以生成化合物(v),其與胺基偶合後可獲得化合物(vi), 即本發明之化合物。 如此所合成之二醯胺化合物可經管柱層析法、高效液 相層析法或結晶來純化。 前述流程說明本發明某特定二醯胺化合物的合成方 法,本領域通常知識者可修飾前述方法已獲得本發明其他 12 201033216 二醯胺化合物。或者,他或她可以使用其他本領域已知的 方法來合成本發明的二醯胺化合物。 用於合成可用化合物之合成化學轉變法及保護基方法 論(保護及去保護)為本領域已知方法,例如包括R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T.W. Greene及P.G.M. Wuts,jProieciz.ve Organic Synthesis, 3rd Ed., John Wiley and Sons (1999) · L. Fieser及 M. Fieser,·Fieier awt/Fz.eMr’i
John Wiley and Sons (1994);以及L. Paquette, ed”
Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995)及其後續版本中所述。 本發明二醯胺化合物對於雙肽基胜肽酶(如DDP-IV及 FAP),有效地表現出抑制作用,因此本發明關於一種抑制 雙肽基胜肽酶的方法,其係藉由將酵素與一種以上有效劑 量之二醯胺化合物接觸。本發明也包括一種治療癌症或發 炎情況的方法,其係藉由將一種以上有效劑量的前述二醯 〇 胺化合物投予需要治療的主體。「治療」一詞係指將二醯 胺化合物,應用於或投予具有癌症或發炎、癌症或發炎之 症狀或朝癌症或發炎發展之傾向的主體,以期達到治療、 治癒、減輕、緩和、改變、補救、改良、改善或影響疾病、 症狀或發展傾向。「有效劑量」一詞係指對於治療主體產 生預期療效所需的二醯胺化合物劑量,對於有效劑量’本 領域具有通常知識者可了解到其會根據投藥路徑、使用賦 形劑、以及與其它藥劑共同使用的可能性而改變。 13 201033216 癌症為一類疾病,其中細胞群具有自發性的生長能 力,即不正常狀態或細胞具快速增生特色的情況及某些時 候會有腫瘤轉移。癌症舉例包含但不限於:癌(carcinoma) 及肉瘤(sarcoma),例如白血病(leukemia)、肉瘤(sarcomas)、 月肉瘤(osteosarcoma)、淋巴瘤(lymphomas)、黑色素瘤 (melanoma)、印巢癌、皮膚癌、睾丸癌、胃癌、騰腺癌、 腎癌(renal cancer)、乳腺癌、前列腺結腸直腸癌(pr〇state colorectal cancer)、頭頸部癌、腦癌、食道癌、膀胱癌、腎 上腺皮質癌、肺癌、支氣管癌、子宮内膜癌、鼻咽癌、子 ® 呂頸癌或肝癌、結腸癌、腎臟癌(kidney cancer)、曱狀腺癌、 造血癌症(haematopoietic cancer)、原發部位不明的癌症。 發炎情形包含但不限於:氣喘、成人型呼吸窘迫綜合 症、糖尿病(如第II型糖尿病)、嬰兒型呼吸窘迫综合症骨 關節炎、類風濕性關節炎、發炎性腸道疾病、牛皮癣和皮 膚炎。 為了治療癌症或發炎,可將具有一種以上前述二醯胺 化合物的組成物,經由非口服、口服、鼻、直腸、局部、 ◎ 或舌下的方式,投遞給需要此種治療的主體。於此使用之 「非口服」(parenteral)—詞係指皮下注射、皮内注射、靜 脈内注射、肌肉内注射、關節腔内注射、動脈内注射、關 節液内注射、胸腔内注射、脊髓内注射、疾病部位内注射、 顱内注射或注入技術,以及任何合適的灌注技術。 無菌可注射溶液可為無毒非口服注射稀釋液或溶劑 (例如1,3-丁二醇的溶液)之溶液或懸浮液,可被使用之可接 14
201033216 受載體及溶劑為甘露醇(mannit〇1)及水。除此之 採用非揮發油作為溶劑或是懸浮介質(例如 :雙甘油醋)。脂肪酸如油酸一⑷與其::::: 可用於製備注射劑;天然醫藥可接受之心 視油或萬麻油,特別是其多氧乙基化之型態,同樣可用於 製=這些油醋溶液或懸浮液,可包含長鍵醇類 =:幾甲基纖維素或類似之分散劑。其他常用之界: ''*Tween4Spans或其他類似乳化劑或一般醫藥f 造業所使用於醫藥可接受之固態、液態或其他可用於= 開發目的之劑量型式之生物可利用增強劑。 用於口服投藥之組成物可為任何一種口服可接受之 ,型’包括膝囊、錠片、乳化液與水懸浮液、分散液與溶 鍵片為例’一般所使用之載體包括乳糖或是玉米澱 粉’调滑劑(如硬脂酸鎮)亦常被添入其中。以口服膠囊投 藥型式而言’可用的稀釋劑包括乳糖與乾燥玉米殿粉。合 以水懸浮液或乳化液經口投藥時’活性成分可懸浮或是溶 解於混有乳化劑或懸浮劑之油狀界面中。如果需要,可添 加適度的甜味劑、風味劑或是色素。 鼻用氣化嘴霧劑或吸入劑組成物,可根據醫藥劑型領 域中已知技術進行製備。例如,此組成物可製備為鹽溶液, 應用苯甲醇(be— aicoho〇或其他適合的防腐劑、增強生 物可利用性之促吸收劑、碳氟化合物、及/或該領域中其他 技藝中已知之溶解劑或分散劑。具有二酿胺化合物之組成 物,亦可以栓劑方式進行直腸投藥。 15 201033216 醫藥組成物之載體必須為「可接受性」,即其必須與 組成物之活性主成份相容(較佳係能穩定活性主成份),並 且不能對被治療之試體造成傷害。例如’一種以上的溶解 劑,也可作為傳遞活十生二醜胺化合物之醫藥載趙。其他載 趙舉例包括膠質氧化石夕、硬脂酸鎮、纖維素、月桂硫酸鈉 與D&C黃色10號。 對於本發明二醯胺化合物是否具有一種以上所希冀 的活性(例如抑制DPP-IV或FAp的活性),可使用適合的體 外(以分析初步進行篩選,若在初步篩選中展現出高 0 活性的化合物,則進一步以或體内(b Wv〇)分析篩該些2 合物的效力。舉例而言,在罹癌或具有發炎情況的動物(如 老鼠模式)中投遞待測化合物,然後評估其療效。基於這些 結果,可同時決定適合的劑量範圍以及投藥途徑。 上述已經足以實施本發明,而無需更多的闞述,因此 下列特定具體實施例僅解釋為說明性,無論以任何方式皆 不限制本發明其餘揭示範圍,並將本文所引述之所有發表 文獻及專利申請案全部併入本文以供參考。 0 實施例 1 : (25)-1-(((25,45)-4-12-(1,3-二氩-2丑-異"弓丨哚 _2_ 基)-2-氧代乙基】-5-氧代吡咯啶_2-基丨羰基)吡咯啶_2•甲腈 ((25)-l-({(25,45,)-4-[2-(l,3-dihydro-2Jy-isoindol-2-yI)-2- oxoethyl]-5-oxopyrrolidin-2-yl}carbonyl)pyrrolidine-2- carbonitri丨e)的製備(化合物〇 16 201033216
A Λ~
Λ-
反應試劑:(a) EDC, HOBt, 1,4-二噁烷/CH2CI2, L-脯氨醯胺;⑼咪攻,p〇CI3,吡啶; ⑹ CF3C00H, CH3CN;⑼ EDC, HOBt, 1,4-二噁炫/CH2Ci2,丨異,引<•朵淋 根據 Le". 1988, 39, 2 199-2202所述方法製 備(2S,45)-1-(第三丁氧基羰基)-4-(2-第三丁氧基-2-氧代乙 基 )-5-氧代 °比咯啶 -2-羧酸
butoxycarbonyl)-4-(2-ier/-butoxy-2-oxoethyl)-5-oxopyrrolid ine-2-carboxylic acid),並將 1-乙基-3-(3-二甲基胺基丙基) 碳_ 二醢亞胺(l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC),211 mg, 1.1 mmol)之CH2C12 (5 mL)溶液,加入含此 化合物(343 mg, 1.0 mmol)及N-經基笨並三唾 (hydroxybenzotrizole(HOBt),168 mg,1.1 mmol)之 1,4-二0惡 烧(1,4-dioxane,5 mL)溶液,在室溫將此混合液擾拌10分鐘 後,隨著攪拌將(S)- °比咯啶-2-曱醯胺 ((S)-pyrrolidine-2-carboxamide,125 mg, 1.1 mmol)之CH2C12 (4 mL)溶液加入其中,待16個小時後’以飽和NaHC03水溶 液(10mL)、1 N棒樣酸水溶液(10 mL)及鹽水(1〇 mL)清洗反 應混合液,合併有機層並以MgS〇4乾燥,過濾後濃縮。所 得殘餘物以矽膠使用CH/h/MeOH (95 : 5)作為流洗液進行 17 201033216 純化,可得到化合物A (347 mg,0.79 mmol, 79%)。 將氣化填醯(phosphoryl chloride, 484 mg, 3.16 mmol) 在-30°C於5分鐘内滴入(35,55)-5-{[(25>2-胺曱醯吡咯啶-1-基]羰基}-3-(2-第三丁氧基-2-氡代乙基)-2-氧代η比咯啶-1-羧 酸第 三丁酯(kri-butyl (3S,5S)-5-{[(2S)-2-carbamoylpyrrolidin- 1-yl] carbonyl}-3-(2-,e"-butoxy-2-oxoethyl)-2-oxopyrrolidine-l-carboxylate, 347 mg, 0.79 mmol)、味吐(imidazole, 80 mg, 1.18 mmol)及0比咬(pyridine, 7 ml)之混合液中,所得的白雲狀反應混合物在-30°C下攪拌 1小時後轉變成微帶淡黃色不透明懸浮液,在真空下濃縮, 再以CH2C12稀釋,然後用1 N檸檬酸水溶液(5 mL)處理,以 MgS04乾燥有機層,過濾後濃縮。所得殘餘物以矽膠使用 Hexane/EtOAc (1 : 2)作為流洗液進行純化,可得到預期的 化合物 B (286 mg,0.68 mmol, 86%) 〇 將 TFA 5ml在 0°C於 5分鐘内滴入(3·5,55)-5-{[(25)-2-氰 基。比咯啶-1-基]羰基}-3-(2-第三丁氧基-2-氧代乙基)-2-氧代 吼咯啶-1-羧酸第三丁酯〇小1)1^丫1(35,5>5)-5-{[(25)-2-cyanopyrrolidin-1 -yl]carbonyl}-3-(2-ieri-butoxy-2-oxoethyl) -2-oxopyrrolidine-1 -carboxylate, 286 mg, 0.68 mmol)之 CH3CN (5 ml)溶液,在室溫下將反應混合液攪拌1小時後, 真空濃縮反應混合液,並以EA/乙醚結晶而可得到化合物C。 將 EDC (105 mg,0.55 mmol)之 CH2C12 (3 mL)溶液加入 [(35·,55)-5-{[(25)-2-氰基吡咯啶-1-基]羰基}-2-氧代吡咯啶 -3-基]醋酸([(SS’SSO-S-UG^-Z-cyanopyrrolidin-l-yl] carbonyl }-2-oxopyrrolidin-3-yl] acetic acid, 265 mg, 0.50 201033216 mmol)及HOBt (42 mg, 0.55 mmol)之 1,4-二噁烷(3 mL)攪拌 溶液中,在室溫下將混合液攪拌10分鐘後,於攪拌下加入 異吲哚啉(65 mg,0.5 5 mmol)之 CH2C12 (2 mL)溶液,待 16 小 時後,以飽和NaHC03水溶液(10 mL)、1 N檸檬酸水溶液(10 mL)及鹽水(10 mL)清洗反應混合液,有機層以MgS〇4乾 燥,過濾後濃縮。所得殘餘物以矽膠使用CH2Cl2/MeOH (98 : 2)作為流洗液進行純化,可得到化合物1 (128 mg, 0.35 赢 mmol, 70 %)。4 NMR (300 MHz, CDC13) : (6/1 之反/順醯胺 旋轉異構體混合物)(5 7.30-7.26 (m,4H),6.56 (s,0.86H), 6.06(3,0.141"1),4_82-4.77 (111,4.8611,在4.82,4.77部分重疊 的雙單峰),4.60 (d,*/= 6.6 Hz, 0.14H),4.55 (d,9.0 Hz, 0.14H), 4.40 (dd, J= 3.0, 9.0 Hz, 0.86H), 3.61-3.04 (m, 2H), 3.02-2.88 (m, 2H),2.68-2.36 (m, 3H), 2.29-2.12 (m, 4H)。 MS (ES+) m/z 以 C2〇H22N403 計算值:366.17 ;實驗值:367.1 (M+H)。 實施例 2 : (24S,41S)-l-({(2ίS,4S)-4-[2-(l,3-二氫_2i/-異吲哚-2-^^ 基)-2 -氧代乙基】-5-氣代0it略咬-2-基}幾基)-4 -氣"tfc洛咬- 2- 甲腈((25,45)-1-(((25,45)-4-[2-(l,3-dihydro-2^-isoindoU 2-y l)-2-oxoethyl】-5-oxo pyrrolidi n-2-yi} car bony l)-4-fluoro pyrrolidine-2-carbonitrile)的製備(化合物 2) 所述之化合物以類似於實施例1所述方法製備。 hNMRpOO MHz, CDC13) : (7/1之反/順醯胺旋轉異構 體混合物)(5 7.28-7.25 (m, 4H), 7.23 (s, 0.88H), 6.28 (s, 0.12H), 5.54 (brs, 0.44H), 5.46 (brs, 0.06H), 5.36 (brs, 0.44H), 5.30 (brs, 0.06H), 5.09 (d, J = 8.4 Hz, 0.88H), 4.84 19 201033216 (d, J= 8.4 Hz, 0.12H), 4.80 (s, 2H), 4.75 (s, 2H), 4.57 (d, J = 8.4 Hz, 0.12H), 4.38 (d, J = 8.4 Hz, 0.88H), 3.39-3.76 (m, 2H), 3.02-2.78 (m, 2H), 2.67-2.25 (m,5H)。MS (ES+) m/z 以 C20H2丨FN403計算值:384.16;實驗值:385.0 (M+H)。 實施例 3 : (25)-1-(((25,45)-4-【2-(l,3-二氩-2i/-異吲哚-2-基)-2-氧代乙基】-5-氧代吼咯啶-2-基}羰基)-4,4-二氟nt咯啶 -2- 甲 腈 ((25)-1-(((25,45^-4-12-(1,3-^1^31^0-2^-isoindol-2-yl)-2-oxoethyl]-5-oxopyrrolidin-2-yl}carbonyl)-4,4-difluoropyrrolidine-2-carbonitrile)的製備(化合物 3) 所述之化合物以類似於實施例1所述方法製備。 4 NMR (300 MHz,DMSO-A) : (6/1 之反/順醯胺旋轉 異構體混合物)(5 8.03 (s,0.86H),7.97 (s,0.14H), 7.36-7.25 (m, 4H), 5.37 (d, 7= 8.4 Hz, 0.14H), 5.09 (dd, J = 4.2, 8.4 Hz, 0.86H), 4.82 (s, 2H),4.62 (s, 2H), 4.32 (d, J = 8.7 Hz, 1H), 4.25-4.04 (m, 2H), 2.93-2.66 (m, 4H), 2.49-2.05 (m, 3H)。MS (ES+) m/z 以 C20H20F2N4O3計算值:402.15 ;實驗 值:403.1 (M+H)。 實施例 4 : (2S)-l-({(2S,4S)-4·[2-(l,3-二氩-2_f^異吲哚-2_ 基)-2-氧代乙基l-5-氧代吡咯咬-2-基}羰基)nb咯咬_2-蝴酸 ((25)-l-({(25,45)-4-[2-(l,3-dihydro-2/T-isoindoI-2-yl)-2-oxoethy 1】-5-oxo pyrr olid in-2-yl} car bony l)pyrr〇lid in e-2- boronic acid)的製備(化合物4) 所述之化合物以類似於實施例1所述方法製備。 *H NMR (400 MHz, D20) : (4/1之反/順醯胺旋轉異構體
混合物)(5 7.19-7.17 (m,4H), 4.69-4.61 (m,2H),4.43 (d,J 201033216 =6.4 Hz, 0.8H), 4.24 (d, J = 6.4 Hz, 0.2H), 3.65-3.55 (m, 1H), 3.39-3.31 (m, 1H), 3.19 (s, 2H), 3.06-3.02 (m, 1H), 2.91-2.72 (m, 2H), 2.53-2.49 (m, 1H), 2.37-2.21 (m, 2H), 2.01-1.86 (m,3H), 1.62-1.56 (m,1H)。 實施例 5 : (25)-1-(((25,45)-4-12-(5-氯-1,3-二氫-2/f·異吲哚 -2-基)-2-氧代乙基卜5-氧代吡咯啶-2-基}羰基)吡咯啶-2-甲 isoindol-2-yl)-2-oxoethyl]-5-oxopyrrolidin-2-yl} carbonyl) e pyrrolidine-2-carbonitriIe)的製備(化合物 5) 所述之化合物以類似於實施例1所述方法製備。 hNMRQOO MHz, CDC13) : (7/1之反/順醯胺旋轉異構 體混合物)6 7.37-7.18 (m, 3.88H), 6.56 (s, 0.12H), 5.31-4.69 (m, 5H), 4.53 (d, J= 9.3 Hz, 0.12H), 4.42 (dd, J = 2.1, 9.3 Hz, 0.88H), 3.61-3.57 (m, 2H), 3.01-2.87 (m, 2H), 2.57-2.18 (m,7H)。MS (ES+)m/z 以 C20H21ClN4O3計算值: 400.13 ;實驗值400.9 (M+H),402.9 (M+2)。 ^ 實施例 6 : (25)-1-(((25,45)-4-12-(1,3-二氩-2丑·異喹啉-2-基)-2-氧代乙基】-5-氧代吡咯啶-2-基}羰基)吡咯啶-2-甲腈 ((25)-l-({(25,45)-4-[2-(l,3-dihydro-2^-isoquinoI-2-yl)-2-oxoethyI]-5-oxopyrroIidin-2-yl}carbonyI)pyrrolidine-2-car bo nitrile)的製備(化合物6) 所述之化合物以類似於實施例1所述方法製備。 ’H NMR (300 MHz, CDC13) : (7/1之反/順醯胺旋轉異構 體混合物)<5 7.28-7.12 (m, 4.88H), 6.54 (s,0.12H), 4.84 (t like, 7 = 5.1 Hz, 1H), 4.63 (s, 1H), 4.62 (s, 1H), 4.49 (d, J = 9.3 Hz, 0.12H), 4.38 (d, J= 9.3 Hz, 0.88H), 3.81-3.66 (m, 21 201033216 2H), 3.57-3.53 (m, 2H), 3.00-2.82 (m, 4H), 2.57-2.15 (m5 7H)。MS (ES+) m/z 以C2〇H24N403計算值:380.18 ;實驗值: 381.0 (M+H)。 實施例 7 : (25)-1-(((25,4^-4-12-14-(4-氟-苯基)-哌嗪·1-基】-2-氧代6基卜5-氧代吡咯啶-2-基}羰基)吡咯啶-2-甲腈 ((25)-1-(((25,45)-4-[2-[4-(4-Fluoro-p he nyl)-piperazin-l-yi] -2-oxoethyI]-5-oxopyrrolidin-2-yl}carbonyl)pyrrolidine-2- carbonitrile)的製備(化合物7) 所述之化合物以類似於實施例1所述方法製備。 WNMRPOO MHz, CDC13) : (7/1之反/順醯胺旋轉異構 體混合物)5 7.27-6.85 (m, 4.88H), 6.27 (s, 0.12H), 4.83-4.82 (m, 0.88H), 4.60 (d, J = 6.6 Hz, 0.12H), 4.48 (d, J =8.4 Hz, 0.12H), 4.36 (d, 8.4 Hz, 0.88H), 3.80-3.55 (m, 6H), 3.10-2.91 (m, 6H), 2.56-2.47 (m, 2H), 2.38-2.17 (m, 7H)。MS (ES+) m/z 以C22H26FN503計算值:427.20;實驗 值:428,0 (M+H)。 實施例 8: (25)-1-(((25,45)-4-12-(6,7-二氩噻吩并【3,2-c]吡咬 -5(4好)-基)-2 -氧代乙基丨-5-氧代0tfc略咬-2-基}叛基)吼洛咬 -2-甲腈((2幻-1-(((2145)-4-(2-(6,7-dihydr〇thieno[3,2-C] pyridin-5(4/i)-yl)-2-oxoethyl]-5-oxopyrrolidiii-2-yl}carbo nyl)pyrrolidine-2-carbonitrile)的製備(化合物 8) 所述之化合物以類似於實施例1所述方法製備。 !H NMR (3 00 MHz, CDC13) : (8/1之反/順醯胺旋轉異構 體混合物)(5 7,14 (t, «/ = 5.4 Hz, 1H),6.88 (d, */ = 5.4 Hz, 0.89H), 6.79 (dd, J = 3.3, 5.4 Hz, 1H), 6.43 (d, J = 5.4 Hz, 201033216 0.11H),4.82-4.80 (m,0.89H),4.72-4.44 (m,2.22H,在 4.64, 4.56部份重疊的雙單峰),4.36(〇1,</=9.6沿,0.8州), 3.96-3.48 (m, 4H),3.04-2-83 (m, 4H), 2.62-2.11 (m,5H)» MS (ES+) m/z 以 C19H22N403S計算值:386.14;實驗值:386.9 (M+H) 〇 實施例9:(25)-1-({(25,45)-4-[2-[4_(4-氣苯基)-3,6-二氫吼啶 基】-2-氧代乙基】-5-氡代吡咯啶_2-基}羰基)吡咯啶 -2-甲 腈((2^5)-1-(((215,45)-4-12-(4-(4-011101^00116115^1)-3,6-dihydropyridin-l(2/T)-yl]-2-oxoethyIJ-5-oxopyrrolidin -2-yl}carbonyl)pyrrolidine-2_carbonitrile)的製備(化合物 9) 所述之化合物以類似於實施例1所述方法製備。 ^HNMRPOO MHz, CDC13) : (9/1之反/順醢胺旋轉異構 體混合物)(5 7.30 (s,4H),6.80 (d,J = 3.9 Hz,0.9H),6.19 (s, 0.1H), 6.06 (brs, 0.5H), 5.99 (brs, 0.5H), 4.83-4.81 (m, 0.9H), 4.60 (d, J = 6.9 Hz, 0.1H), 4.58 (d, J = 9.3 Hz, 0.1H), 4.36 (dd, 2.4, 9.3 Hz, 0.9H), 4.20 (brs, 1H), 4.13 (d, y = 2.4 Hz, 1H), 3.82-3.52 (m, 4H), 3.02-2.87 (m, 2H), 2.59-2.46 (m, 4H), 2.39-2.14 (m,5H)。MS (ES+) m/z 以 C23H25C1N403計算值: 440.16 ;實驗值:440.9 (M+H),442.0 (M+2)。 實施例10: 2-[(3又5S)-5-{[(25>2-氰基吡咯啶-1_基]羰基}-2-氧代咐•咯啶-3-基】苯基乙醯胺(2-[(345,515)-5-{【(2*5)-2-cyanopyrroIidin-l-yI]carbonyl}-2-oxopyrrolidin-3-yl]-7V- phenylacetamide)的製備(化合物 1〇) 所述之化合物以類似於實施例1所述方法製備。 23 201033216 hNMRGOO MHz,CDC13) : (8/1之反/順醢胺旋轉異構 體混合物8.96 (s,1H),7.54 (d, ·/ = 7.6 Hz, 2H), 7.32-7.15 (m, 2.89H), 7.06 (t, J = 7.6 Hz, 1H), 6.47 (s, 0.11H), 4.75-4.73 (m, 0.89H), 4.61 (d, 7= 7.6 Hz, 0.11 H), 4.49 (d, 8.8 Hz, 0.11H), 4.33 (dd, J= 2.8, 8.8 Hz, 0.89H), 3.50-3.47 (m, 2H), 3.03-2.95 (m, 1H), 2.76 (dd, J= 6.4, 15.2 Hz, 1H), 2.52 (dd, «/= 6.4, 15.2 Hz, 1H), 2.40-2.04 (m,6H)。 MS (ES+) m/z 以 C丨8H20N4〇3計算值:340.15 ;實驗值:341.0 (M+H)。 實施例 11 : (2S)-l-({(2S,4S)-4-[2-丨 4-(吡啶 e-4-基)-哌嗪-1-基】-2-氧代乙基】-5-氣代吼洛咬-2-基}獄基)*Λ洛唆-2-甲膀 ((2S)-l-({(2S,4S)-4-[2-[4-(pyridine-4-yl)-piperazin-l-yl]-2 -oxoethyl]-5-oxopyrrolidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile)的製備(化合物11) 所述之化合物以類似於實施例1所述方法製備。 hNMRGOO MHz, CDC13) : (9/1之反/順醯胺旋轉異構 體混合物)<5 8.29 (d, J = 5.2 Hz, 2H),6.95 (s. 0.9H),6.65 (d, J = 5.2 Hz, 2H), 6.39 (s, 0.1H), 4.82-4.80 (m, 0.9H), 4.60 (d, J= 8.0 Hz, 0.1H), 4.49 (d, J= 8.0 Hz, 0.1H), 4.36 (d, J = 8.0 Hz, 0.9H), 3.85-3.48 (m, 6H), 3.45-3.31 (m, 4H), 3.07-2.87 (m,2H),2.55-2.16 (m, 7H)。MS (ES+) m/z 以 C2iH26N603計算值:410.21 ;實驗值:411.3 (M+H),433.3 (M+23)。 實施例12 : (2^-1-(((25,45)-5-氧代-4-【2-氧代-【2-(三氟甲 基)_5,6·二氩咪唑并[1,2-α】吡嗪-7(8i/)-基I乙基】吡咯啶_2· 201033216 基}幾>基)咕洛咬-2-甲腈((25>)-1-({(2*5,451)-5_〇\〇-4-【2-〇\〇-【2_(trifluoromethy〇-5,6-dihydi*oimidazo[l,2-fl】pyrazin-7 (8/T)-yI] ethyl] pyrrolidin-2-yI}carbonyl)pyrrolidine-2- carbonitrile)的製備(化合物12) 所述之化合物以類似於實施例1所述方法製備。 hNMR (400 MHz, CDC13) : (6/1之反/順醯胺旋轉異構 體混合物7.22 ((!,·/= 10.0 Hz,0.86H),7.08 (s,1H),6.58 (d, J = 10.0 Hz, 0.14H), 4.94-4.57(m, 3H), 4.47-4.46 (m, ® 0.14H), 4.32 (d, J = 9.6 Hz, 0.86H), 4.11-3.92 (m, 4H, overlapped singlet at 4.01), 3.61-3.52 (m, 2H), 2.92-2.88 (m, 2H),2.63-2.54 (m,1H), 2.42-2.14 (m, 6H)。MS (ES+) m/z 以 C19H21F3N603計算值:438.16 ;實驗值:439.1 (M+H)。 實施例 13 : (25)-1-(((25,45)-5-氧代-4-[2-氧代-2-(吡咯啶-1-基)乙基]吡咯啶-2-基}羰基)吼咯啶-2-甲腈((215)-1-({(25^45)-5-(^0-4-[2-oxo-2-(pyrrolidin-l-yl)e thy I] pyrrolidin-2-yl}carbonyl)pyrroIidine-2-carbonitrile)的製 ^ 備(化合物13) 所述之化合物以類似於實施例1所述方法製備。 4 NMR (300 MHz, CDC13) : (13/1 之反/順醯胺旋轉異 構體混合物)<5 7.41 (s,0.93H),6.74 (s,0.07H),4.83-4.80 (m, 0.93H), 4.67 (d, J = 4.5 Hz, 0.07H), 4.51 (d, J= 7.8 Hz, 0.07H), 4.42 (d, 7 = 7.8 Hz, 0.93H), 4.03 (brs, 1H), 3.60-3.56 (m, 2H), 3.45-3.39 (q like, J= 6.3 Hz, 4H), 2.95-2.76 (m, 2H),2.48-2.15 (m, 6H), 1.99-1.80 (m, 4H)。MS (ES + ) m/z 以 C16H22N403計算值:318.17 ;實驗值:319.1 (M+H),341.1 25 201033216 (M+23) ° 實施例 14 : (25)-1-(((25,45)-5-氧代-4-[2-氧代-2-[3-(三氟甲 基)-5,6-二氩丨1,2,4】三唑【4,3-λτ] «Λ嗪-7(8f〇-基]乙基1吼咯啶 -2-基}叛基)咐> 洛咬-2-甲猜((25>)-1-({(25>,4|5)-5-〇\〇-4-【2· oxo-2-[3-(trifluoromethyl)-5,6-dihydro[l,2,4]triazolo[4,3-<j】pyrazin-7(8/〇-yl】ethyl] pyrrolid in-2-yl} carbonyl) pyrrolidine-2-carbonitrile)的製備(化合物 14) 所述之化合物以類似於實施例1所述方法製備。 'H NMR (300 MHz, CD3OD) : δ 5.04-4.98 (m, 2H), 4.78 (t, J = 5.4 Hz, 1H), 4.49 (dd, J = 3.0, 8.7 Hz, 1H), 4.35-4.20 (m, 2H), 4.08-4.04 (m, 2H), 3.71-3.57 (m, 2H), 3.04-2.94 (m,2H),2.77-2.65 (m,1H),2.44-2.05 (m, 6H)。 MS (ES+) m/z 以 C18H2〇F3N703 計算值:439.16 ;實驗值: 440.0 (M+H) ° 實施例15 : (3S,5S)-3-[2-(l,3-二氩·2丑-異吲哚-2-基)-2-氧代 乙基】嘆吐咬-3-基羰基)吼洛咬-2-明 ((35,51^)-3-(2-(1,3-dihyd ro-2/f-isoi n dol-2-yl)-2-oxoethyl]-5 •(l,3-thiazolidin-3-ykarbonyl)pyrr〇Hdin-2-one)的製備(化 合物15) 所述之化合物以類似於實施例1所述方法製備。 Ή NMR (300 MHz, CDCl3): δ 7.30-7.26 (m, 4H), 6.96 (d, 10.2 Hz, 1H), 4.82 (s, 2H), 4.77 (s, 2H), 4.66-4.40 (m, 3H), 3.94-3.67 (m, 2H), 3.11 (t, J= 6.3 Hz, 1H), 3.03-2.93 (m, 2H), 2.60-2.46 (m, 2H), 2.40-2.30 (m, 2H)° MS (ES+) m/z 以 C18H2iN303S計算值:359 13 ;實驗值:36〇」(M+H)。 201033216 實施例16:(25)-1-({(2<5,4/?)-4-【2-(1,3-二氫-2好-異吲哚-2-基)-2-氧代乙基】-5-氧代吡咯啶-2-基}羰基)吡咯啶-2-甲腈 ((25)-l-({(2S,,4/?)-4-[2-(l,3-dihydro-2/ir-isoindoI-2-yI)-2-oxoethyl]-5-oxopyrroIidin-2-yl}carbonyl)pyrrolidine-2-carbonitrile)的製備(化合物16) 所述之化合物以類似於實施例1所述方法製備。 ΑΝΜΪΙΜΟΟΜΗζ,Οϋί^) : (6/1之反/順醯胺旋轉異構 體混合物)(5 7.29-7.26 (m,4Η), 6.51 (s,0.86Η), 6.24 (s, 0.14H), 4.83-4.74 (m, 5H), 4.59-4.55 (m, 0.14H), 4.40-4.35 (m, 0.86H), 3.69-3.52 (m, 2H), 3.15-3.03 (m, 2H), 2.50-2.38 (m, 1H), 2.31-2.04 (m, 3H), 1.87-1.75 (m, 3H)〇 MS (ES+) m/z 以 C2〇H22N4〇3計算值:366.17 ;實驗值:367.1 (M+H)。 實施例 17: (25)-1-(((25,45)-4-12-(5-氟-1,3-二氩-2好-異吲哚 -2-基)-2-氧代乙基卜5-氧代吡咯啶-2-基}羰基)吡咯啶-2-甲 iso i n dol-2-yl)-2-oxoethyl]-5-oxopyrrolidin-2-yl} carbonyl) pyrrolidine-2-car bo nitrile)的製備(化合物 17) 所述之化合物以類似於實施例1所述方法製備。 4 NMR (400 MHz, CDC13) : (7/1之反/順醯胺旋轉異構 體混合物)ά 7.24-7.19 (m,1H),7.02-6,95 (m, 2H), 6.70 (d, J=4.0 Hz, 0.88H), 6.18 (d, J= 4.0 Hz, 0.12H), 4.83-4.72 (m, 4.88H), 4.61 (d, J = 7.2 Hz, 0.12H), 4.51 (d, J = 8.8 Hz, 0.12H), 4.39 (dd, J= 2.8, 8.8 Hz, 0.88H), 3.69-3.52 (m, 2H), 2.98-2.87 (m,2H),2.61-2.39 (m, 3H), 2.30-2.17 (m,4H)。 MS (ES ) m/z 以 C2〇H2iFN4〇3 計算值:384.16;實驗值:385.3 27 201033216 (Μ+Η) 〇 實施例 18: (25)-1-({(25·,4·5)_4-[2-(5-三氟甲基-1,3-二氩-2丑-異吲哚-2-基)-2-氧代乙基】-5-氧代吡咯啶-2-基丨羰基)吡咯 咬-2-甲腈((251)_1-({(251,451)-4-【2-(5-會|^11|1〇1*〇1116作>^-1,3-d ihydro-2fT-isoi n doI-2-yl)-2-oxoe thy I]-5-0X0 pyrrol id in-2-丫1}〇31"1>〇11丫1)卩丫1>1*〇11<11116-2-〇31>1)〇11^1^1€)的製備(化合物18) 所述之化合物以類似於實施例1所述方法製備。 4 NMR (300 MHz, CDC13) : (7/1之反/順醯胺旋轉異構 體混合物)<5 7.60-7.55 (m,2H),7.42 (t, «/= 7.5 Hz,1H), 7.19 (d, J = 4.2Hz, 0.88H), 6.55 (d, J = 4.2 Hz, 0.12H), 4.90-4.83 (m,在4.90, 4.83部分重疊的雙單峰,4.88H),4.69 (d,J= 7.8 Hz, 0.12H), 4.56 (d, J= 8.4 Hz, 0.12H), 4.65 (d, J =7.8 Hz, 0.88H), 3.64-3.60 (m, 2H), 3.09-2.91 (m, 2H), 2.63-2.20 (m,7H)。MS (ES+) m/z 以 C21H21F3N403計算值: 434.16 ;實驗值:435.0 (M+H)。 實施例19 :生物分析 DPP-IV之表現舆純化 由健康的亞洲人類精液中,根據Chien C. et al. 乂 βί·ο/. CTiem·,2004, 279 : 523 3 8-52345所述之方法純化DPP-IV,蛋 白質的純度以SDS-PAGE評估’並以考馬斯藍(Commassie blue)染色法顯現,並利用已完善建立的方法(8以(1[(^£1,1^.\1· (1976) 72, 248-254),使用牛 jk清蛋白(BSA) 作為標準品,估算DPP-IV的濃度。 或者,自Hi5昆蟲細胞中表現及純化重組蛋白DPP-IV (^-^Chien C. et al. J. Biol. Chem., 2004, 279 · 52338-52345 201033216 and Chien C. et al·,B/ocAemuirj; 2006, 45 : 7006-7012)。簡 而言之’將編譯人類DPP-IV蛋白之cDNA片段,與CD5訊號 序列於其中融合’將所得的CD5/DPP-IV建構體插入表現載 體pBac-PAC-His2 (Clontech)中,以產生重組桿狀病毒。於 1.0 TCID50單位/細胞(TCID50 : 50%組織培養感染劑量)的感 染數量(multiplicity of infection,MOI)下,使用此重組病毒 感染長在不含血清的培養基(Express V)之Hi5昆蟲細胞,持 續培養72小時後,收取所分泌的DPP-IV蛋白。 DPP-VIII之表現及純化 自Sf9昆蟲細胞中表現及純化DPP-VIII (參考(:1^11丫· 6【31.,尸"〇^/«£:\:/^/>«,,7'.2004,35:142-146與1^6 1'1.6131·, «/· 5ί·σ/. CTzem. 2006, 25/ : 38653-38662)。簡而言之,將全 長之人類DPP-VIII cDNA,以RT-PCR由人類肝臟cDNA庫中 放大出來,然後複製於桿狀病毒表現載體pBac-PAC-His2 (Clontech)中,並將MT-eGFP盒區插入於£coRV位置來修飾 此載體,以期加速鑑定表現eGFP蛋白的重組桿狀病毒,並 利用螢光的eGFP表現、酵素活性及西方點墨法(Western blot)確定重組病毒有被分離出來,以不同的MOIs檢測蛋白 質表現量,對於DPP-VIII的表現量,則以蛋白酶活性(其與 所表現的蛋白質量相對應)決定。於0.5 TCIDsq單位/細胞的 感染數量下感染Sf9細胞,於72小時後收集以供後續蛋白質 純化步驟。 DPP-II的純化與表現 以類似前述表現及純化DPP-IV所用的方法,自Hi5昆蟲 29 201033216 細胞中表現及純化重組DPP-ΙΙ蛋白,以c〇nA-壤脂糖凝膠 (ConA-sepharose)及 Q-瓊脂糖凝膠(Q-sephar〇se) HP層析法 純化DPP-II。收集培養基後將其pH值調整到7.4,之後裝載 入0:〇11八-瓊脂糖凝膠管柱,以卩117.4之2〇1111^11^、50〇1111^ NaC卜1 mM CaCl2及1 mM MgCl2清洗,再以250 mM曱基丙 噻(methyl-mannopyranoside)之 pH 7.4 20 mM tris及 500 mM NaCl溶液溶離,並利用Amicon YM-30膜(Millipore)讓溶離 液的緩衝液換成含pH 7.4 20 mM tris之緩衝液,再與Q-瓊脂 糖凝膠HP管柱結合,以0至200 mM NaCl梯度溶離DPP-II, 使用Amicon YM-30膜濃縮酵素溶離液。酵素的純度以 SDS-PAGE及考馬斯藍(Commassie blue)染色法測定,前述 布萊德福法(Bradford method),使用牛金清蛋白(BSA)作為 標準品計算其濃度。 DPP-IX之表現及純化 以類似前述表現及純化DPP-VIII所用的方法,自Sf9昆 蟲細胞中表現及純化重組DPP-IX。以含DPP-IX的桿狀病毒 感染之Sf9細胞形成團狀後,再重新懸濁在含1 50 mM NaCl、100 mM tris-HCl、1 mM EDTA之pH 8.0結合緩衝液 中,震盪後將細胞溶解物裝入Strep’Tactin®管柱(EMD Chemicals Inc.,Darmstadt, Germany),以結合緩衝液接著再 以含 150 mM NaC卜 100 mM tris-Ηα、1 mM EDTA及 2.5 mM 去硫生物素(desthiobiotin)之緩衝液(pH 8.0)溶離。使用l〇 kDa 隔離膜(Millipore, Billerica, MA,USA)之 Amicon 濃縮溶 離液,於-80°C 10%甘油中存放純化的DPP-IX。 201033216 FAP之表現及純化 以類似前述表現及純化DPP-IV所用的方法,自Hi5昆蟲 細胞中表現及純化重組FAP蛋白。 IC50之測定 於此分析中測試化合物1-18,其中對於各個待測化合 物,所使用之一系列100 pL-含0.003-100μΜ待測化合物之 溶液與1% DMSO,以及酵素、基質與緩衝液系統列於下表 中0 基質 緩衝液系統 DPP-IV 500 μΜ Gly-Pro-pNA* 2 mM tris-HCl, pH 8.0 DPP-II 1.5 mM Gly-Pro-pNA PBS緩衝液,pH 5.5 DPP-VIII 2.5 mM Gly-Pro-pNA PBS緩衝液,pH 8.0 DPP-IX 1.5 mM Gly-Pro-pNA PBS緩衝液,pH 8.0 FAP 1.5 mM Ala-Pro-pNA* PBS緩衝液,pH 8.0 *酵素基質Gly-Pro-pNA及Ala-Pro-pNA購自 Bachem。 根據 Jiaang W. et al·,5,’〇〇,容 Med C/zew 2005,/*5 : 687-691 J Lu L. et al., Bioorg Med Chem Lett 2005, 15 · 3271-3275 i Tsai T. et al., Bioorg Med Chem Lett 2006, 16 · 〇 3268-3272 \ Tsu H. et al., J Med Chem 2006, 49 : 373-380 ; 以及 Coumar M. et al.,Bioorg Med CTze/w Le" 2007,17 : 1274-1279所述方法,使用ELISA分析儀,在37°C持續30分 鐘分析酵素活性(每分鐘裂解1 μηιοί基質所需的酵素量)之 405 ηΜ放射° 以市面上可得的曲線擬合程式(SigmaPlot)計算各個酵 素之IC5〇值,結果顯示待測化合物中幾乎所有都可以有效抑 制FAP,其中化合物1-9、11-14、16-18及20之1(:5〇值低於20 201033216 卩1^’而化合物1_9、12、13、1£, 1(5-18及20之之IC50值低於1 μΜ〇 此外,一些化合物可以有效抑制Dpp iν、μ卜以 或 DPP-Π。 其他具«實施例 本說明書中所揭示之全部特徵可以任何方式組合。本 說明書中所揭示之特徵可被相同、相當或類似目的之另一 種特徵所取代。因此,除非另有指明,否則所揭示之各特 徵僅為一般性之相當或類似特徵之實例。
藉由上述說明,本發明可輕易的由熟習本項技藝者瞭 解本發明必要之特徵,且在不悖離本發明之範疇下,能夠 對本發明有種種改變及修飾,以適用於種種用途與情況。 舉例而言’可以製造結構上類似於本發明化合物之化合 物’並且使用其實施本發明’因此其他具體實施例亦在本 申請專利範圍内。 【圖式簡單說明】 &. 〇 4«*、
【主要元件符號說明】 無0 32
Claims (1)
- 201033216 七、申請專利範圍: h ~種下式之化合物,其中:❹ 基、氰基、硝基、胺基、硼酸基、硼酸酯基、環烷基、雜 環烧基'芳基或雜芳基; T^C(RaRb)、NRC、〇或S;其中R^Rb各別為H、烷基、 鹵素、氰基、硝基、胺基、烷氧基、羥基、環烷基、雜環 烧基、芳基或雜芳基;以及心為Η '烷基、環烷基、雜環烷 基、芳基或雜芳基; X為C(RdRe)、NRf、〇、S或刪除X ;其中Rd&Re各別為 Η、烷基、鹵素、氰基、硝基、烷氧基、羥基、環烷基、雜 環烷基、芳基或雜芳基;以及心為Η、烷基、環烷基、雜環 院基、芳基或雜芳基;以及 R為烷基、環烷基、雜環烷基、芳基、雜芳基、_c(〇K)Rg 或-C^CONRhRi ;其中Rg為烷基、環烷基、雜環烷基、芳基、 雜芳基;以及Rh及Ri各別為Η、烷基、環烷基、雜環烷基、 芳基、雜芳基、芳基烷基或羥基,或1及Ri與其兩者連接 之N原子一起形成5或6員環,選擇性經烷基、芳基、鹵素、 經基、燒氧基(akyloxyl)、硝基、胺基、烷氧羰基或羧基所 33 201033216 取代;以及選擇性與含〇、丨、2或3個雜原子之3-8員芳香族 環或非芳香族環稍合。 2. 如申請專利範圍第1項所述之化合物,其中,尺為 -C(〇)〇Rg或-(:(0)ΝΚ^Κ ;其中Rg為烷基、環烷基、雜環烷 基、芳基、雜芳基;以及1及Ri各別為H、烷基、環烷基' 雜環烷基、芳基、雜芳基、芳基烷基或羥基,或&及心與 其兩者連接之N原子一起形成5或6員環,選擇性經烷基、芳 基、鹵素、羥基、烷氧基、硝基、胺基、烷氧羰基或羧基 所取代;以及選擇性與含0、丨、2或3個雜原子之3 8員芳香 © 族環或非芳香族環稠合。 3. 如申請專利範圍第2項所述之化合物,其中,χ為 CH2。 4. 如申請專利範圍第3項所述之化合物,其中,丁為 CH2。 5. 如申請專利範圍第4項所述之化合物,其中,尺為 -C(0)NRhRi,心及心與其兩者連接原子一起形成5或6員 環選擇性經烧基、芳基、齒素 '羥基、院氧基、硝基、 @ 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇、丨、2或 3個雜原子之3-8員芳香族環或非芳香族環稠合。 6·如申請專利範圍第5項所述之化合物,其中,心為 CN。 7.如申請專利範圍第丨項所述之化合物,其中,χ為不 存在》 34 201033216 8. 如申請專利範圍第7項所述之化合物,其中,丁為^出 及心為口^。 9. 如申請專利範圍第8項所述之化合物,其中,尺為 -C^CONRhRi ; 1及&與其兩者連接之N原子一起形成5或6員 環,選择性經烷基、芳基、函素、羥基、烷氧基、硝基、 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇、丨、2或 3個雜原子之3-8員芳香族環或非芳香族環稠合。 e ίο.如申請專利範圍第丨項所述之化合物,其中,R為 -C(0)NRhRi ;化及心與其兩者連接原子一起形成5或6員 % ’選擇性經炫基、芳基、函素、經基、烷氧基、硝基、 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇、1、2或 3個雜原子之3-8員芳香族環或非芳香族環稠合。 11. 如申請專利範圍第丨項所述之化合物,其中,r為 -C(0)NRhRi ;心及心各別為H、烷基、環烷基雜環烷基、 芳基、雜芳基、芳基烷基或羥基。 12. 如申請專利範圍第i項所述之化合物其中,τ ’ CH2。 ' 13. 如申請專利範圍第12項所述之化合物,其中,R| 為 CN。 ’、 14. 如申請專利範圍第13項所述之化合物其中,r 為-C(0)NRhRi ;心及心與其兩者連接之N原子—起形成$或6 員環,選擇性經烷基、芳基、齒素、羥基、烷氧基、硝基、 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇、1、2或 3個雜原子之3-8員芳香族環或非芳香族環稠合。 35 201033216 15. 如申請專利範圍第1項所述之化合物,其中,τ為s。 16. 如申請專利範圍第14項所述之化合物,其中,心 為CN。 17. 如申請專利範圍第16項所述之化合物,其中,R 為-C(0)NRhRi ;心及&與其兩者連接原子一起形成5或6 員環,選擇性經烷基、芳基、鹵素、羥基、烷氧基、硝基、 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇、丨、2或 3個雜原子之3-8員芳香族環或非芳香族環稠合。 19·如申請專利範圍第1項所述之化合物,其中,Ri 為 CN。 、 ’其中,該化20.如申請專利範圍第1項所述之化合物36 201033216 21.如申請專利範圍第1項所述之化合物,其中,該化 合物選自由37 201033216所組群組。22. -種抑制雙肽基錄_性之方法,包括:將纖 維母細胞活化蛋白與-有效劑量之中請專利範圍第i項所 述之化合物接觸。 23. 如申請專利範圍第i項所述之方法,其巾,該雙狀 基胜肽酶為FAP或DPP-IV。 又 24. -種治療癌症之方法’包括:將—有效劑量 請專利範圍第1項所述之化合物投遞給一所需主體。25. -種治療發炎情況之方法,包括:將一有效劑量 之申請專利範圍第i項所述之化合物投遞給—所需主體。 26. 種/。療第二型糖尿病之方法,包括將一有效 劑量之申請專利範圍第丨項所述之化合物投遞給一所需主 體0 38 201033216 四、 指定代表圖: (一) 本案指定代表圖為:無。 (二) 本代表圖之元件符號簡單說明:無。 五、 本案若有化學式時,請揭示最能顯示發明特徵的化學式:其中定義如說明書所述。 201033216 第99106891號,99年S月修正頁 4 七、申請專利範圍: 1,一種下式之化合物,其中Ri、r2、r3、r4、r5、r6、m8各別為η、鹵素、烷 φ 基、氰基、硝基、胺基、硼酸基、硼酸酯基、環烷基、雜 環烷基、芳基或雜芳基; • TgC(RaRb)、NRC、0或S ;其中Ra及Rb各別為Η、烷基、 - 齒素、氰基、硝基、胺基、烷氧基、羥基、環烷基、雜環 烷基、芳基或雜芳基;以及Rc為Η、烷基、環烷基、雜環烷 基、芳基或雜芳基; X為C(RdRe)、NRf、Ο、S或刪除X ;其中RaRe各別為 Η、烷基、鹵素、氰基、硝基、烷氧基、羥基、環烷基、雜 環炫•基、芳基或雜芳基;以及Rf為Η、烧基、環烷基、雜環 院基、芳基或雜芳基;以及 R為烧基、環烧基、雜環烧基、芳基、雜芳基、_C(〇)〇Rg 或-C(0)NRhRi ;其中Rg為烷基、環烷基、雜環烷基' 芳基、 雜芳基:以及Rh及Ri各別為Η、院基、環烧基、雜環烧基、 芳基、雜芳基、芳基烷基或羥基,或{^及&與其兩者連接 之Ν原子一起形成5或6員環,選擇性經烷基、芳基、鹵素、 羥基、烷氧基(alkyloxyl)、硝基、胺基、烷氧羰基或羧基所 33 201033216 取代,以及選擇性與含〇、丨' 2或3個雜原子之38員芳香族 環或非芳香族環稠合。 2. 如申請專利範圍第1項所述之化合物,其中,民為 -C(0)ORr^-C(0)NRhRi;其中Rg為烷基、環烷基、雜環烷 基、芳基、雜芳基:以及心及&各別為Η、烷基、環烷基、 雜環烷基、芳基、雜芳基、芳基烷基或羥基,或以及心與 其兩者連接之Ν原子一起形成5或6員環,選擇性經烷基 '芳 基、函素、羥基、烷氧基、硝基、胺基、烷氧羰基或羧基 所取代;以及選擇性與含〇、i、2或3個雜原子之38員芳香 族環或非芳香族環稠合。 3. 如申請專利範圍第2項所述之化合物,其中,χ CH2。 ”" CH: 4.如申請專利範圍第3項所述之化合物,其中,τ為 或 5. 如申請專利範圍第4項所述之化合物,其中,r -qCONRhRi ;心及比與其兩者連接之N原子一起形成$或6 : 環,選擇性經坑基、芳基、函素、經基、貌氣基^其' 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇、1 3個雜原子之3-8員芳香族環或非芳香族環稠合。 CN 6. 如申請專利範圍第5項所述之化合物其中’ &為 存在 7·如申請專利範圍第丨項所述之化合物,其中, X為不 201033216 8.如申請專利範圍第7項所述之化合物,其中,τ為〔η2 及Ri為CN。 9. 如申請專利範圍第8項所述之化合物,其中,尺為 -C(0)NRhRj,Rh及Ri與其兩者連接之n原子一起形成$或6員 環,選擇性經烷基、芳基、南素、羥基、烷氧基、硝基、 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇 '丨、2或 3個雜原子之3-8員芳香族環或非芳香族環稠合。10. 如申請專利範圍第i項所述之化合物其中,r為 -C(0)NRhRi ; Rh及&與其兩者連接之N原子一起形成5或6員 環,選擇性經烧基、芳基、齒素、經基、烧氧基硝基、 胺基、烧氧幾基或缓基所取代;以及選擇性與含〇、^ ' 2或 3個雜原子之3-8員芳香族環或非芳香族環稠合。 之化合物’其中,R為 '環烷基、雜環烷基、 11.如申請專利範圍第1項所述 -CXC^NRhRi,Rh及&各別為η、炫基 芳基、雜芳基、芳基烷基或羥基。12.如申請專利範圍第i項所述之化合物, CH2 » ’、 T為 如甲清專利範圍 牙> 為CN 12項所述之化合物,其中 如中請專利範圍第13項所述之化合物, 為-C⑴輝hRi %及R,與其兩者連接之崎子—料、令, 員環,選擇性經烷基、芳基、鹵素 、^ ^成从6 胺基、烷氧羰基或羧基所取代;以:土、烷氧基、硝基、 及違擇性斑含Q、丨^ ,, 3個雜原子之3·8員J香族環或非芳香族環稠;。 或 201033216 如甲請專利範圍第1項所述之化合物 16.如申請專利範圍第15項所述之化合物,其中,心 為CN 17. 如申請專利範圍第16項所述之化合物,其中,r 為-C^CONRhRi ;1及&與其兩者連接原子一起形成5或6 員環,選擇性經絲、芳基、_素、㈣、院氧基、硝基、 胺基、烷氧羰基或羧基所取代;以及選擇性與含〇、丨、2或 3個雜原子之3-8員芳香族環或非芳香族㈣合。 一 為CN 18. 如申請專利範圍第!項所述之化合物,立中,r丨© 合物為36 201033216 κ 20.如申請專利範圍第1項所述之化合物,其中,該化 合物選自由37 20103321620 所組群組。 21. —種抑制雙肽基胜肽酶活性之方法,I枯:將纖 維母細胞活化蛋白與一有效劑量之申請專利範圍第1項 述之化合物接觸。 # 22. 如申請專利範圍第21項所述之方法,其中,該雙 肽基胜肽酶為FAP或DPP-IV。 23. 一種治療癌症之醫藥組成物,包括:一有效劑量 之申請專利範圍第丨項所述之化合物及一醫燊可接受載體。24. 種治療發炎情況之醫藥組成物,包括:一有效 劑量之申请專利範圍第1項所述之化合物及一醫藥可接受 載體。 ' 25· 一種治療第二型糖尿病之醫藥組成物,包括··一 有效劑量之申請專利範圍第1項所述之化合物及一醫藥可 接受載體。 38
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