TW201249858A - Substituted indole derivatives - Google Patents
Substituted indole derivatives Download PDFInfo
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- TW201249858A TW201249858A TW101117465A TW101117465A TW201249858A TW 201249858 A TW201249858 A TW 201249858A TW 101117465 A TW101117465 A TW 101117465A TW 101117465 A TW101117465 A TW 101117465A TW 201249858 A TW201249858 A TW 201249858A
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- Prior art keywords
- compound
- disease
- formula
- alkyl
- pharmaceutically acceptable
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- 150000002475 indoles Chemical class 0.000 title abstract 2
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- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 201000005112 urinary bladder cancer Diseases 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229960000241 vandetanib Drugs 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- KDQAABAKXDWYSZ-PNYVAJAMSA-N vinblastine sulfate Chemical compound OS(O)(=O)=O.C([C@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 KDQAABAKXDWYSZ-PNYVAJAMSA-N 0.000 description 1
- 229960004982 vinblastine sulfate Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- AQTQHPDCURKLKT-JKDPCDLQSA-N vincristine sulfate Chemical compound OS(O)(=O)=O.C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C=O)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 AQTQHPDCURKLKT-JKDPCDLQSA-N 0.000 description 1
- 229960002110 vincristine sulfate Drugs 0.000 description 1
- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
- 229960002066 vinorelbine Drugs 0.000 description 1
- 229940087652 vioxx Drugs 0.000 description 1
- 201000001862 viral hepatitis Diseases 0.000 description 1
- 229910052725 zinc Inorganic materials 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
- XRASPMIURGNCCH-UHFFFAOYSA-N zoledronic acid Chemical compound OP(=O)(O)C(P(O)(O)=O)(O)CN1C=CN=C1 XRASPMIURGNCCH-UHFFFAOYSA-N 0.000 description 1
- 229960004276 zoledronic acid Drugs 0.000 description 1
- CGTADGCBEXYWNE-JUKNQOCSSA-N zotarolimus Chemical compound N1([C@H]2CC[C@@H](C[C@@H](C)[C@H]3OC(=O)[C@@H]4CCCCN4C(=O)C(=O)[C@@]4(O)[C@H](C)CC[C@H](O4)C[C@@H](/C(C)=C/C=C/C=C/[C@@H](C)C[C@@H](C)C(=O)[C@H](OC)[C@H](O)/C(C)=C/[C@@H](C)C(=O)C3)OC)C[C@H]2OC)C=NN=N1 CGTADGCBEXYWNE-JUKNQOCSSA-N 0.000 description 1
- 229950009819 zotarolimus Drugs 0.000 description 1
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Description
201249858 六、發明說明: 【發明所屬之技術領域】 本發明係關於經取代之吲喵 5丨木何生物、其製備方法、其竹 為藥劑之用途及包含其之醫藥μ合物。 、 【先前技術】 藥品之生物利用率不良诵沓办κ + 通吊係邊樂有效成份之限制因 素。在。引〇朵衍生物之特定領祕士 戈中’此問題現藉由將相應原 藥轉化為其衍生物而解決,彳汗4 4 竹生物相較於其母體化合物似 乎具有始料未及的良好效果。 【發明内容】 具體而s,本發明係Μ於一種式⑴化合物或其醫藥學上 可接受之鹽或水合物,
/OR
其中 X為CH或N ; R為 Η或 Ρ03Η2 ; R1為Η或CN4烷基; R2為Η或C!_4烷基; R3為 Η、Cw 烷基、CN、Hal 或 OH ;及 163746.doc 201249858 R4及R5為相互獨立的H*^·4烷基;或R4及R5與其所附 接的碳原子一起形成3至6員環恍基。 在另一實施例中,本發明係關於一種式(I)化合物或其醫 藥學上可接受之鹽或水合物, 其中 X 為 CH ; R為 Ρ03Η2 ; R1為 Η ; R2為Η或Ci.4烧基; R3為Η或Ci.4烧基;及 R4及R5為相互獨立的Η ;或R4及R5與其所附接的碳原子 一起形成3至6員環烷基。 在另一實施例中,本發明係關於一種式(I)化合物或其醫 藥學上可接受之鹽或水合物, 其中 X 為 CH ; R為Η ; R1為 Η ; R2為HiCw院基; R3為Η ;或Ci.4烷基;及 R4及R5為相互獨立的Η ;或R4及R5與其所附接的碳原子 一起形成3至6員環烷基。 在另一實施例中’本發明係關於一種式(I)化合物或其醫 藥學上可接受之鹽或水合物, 163746.doc -4- 201249858 其中 X為N ; R為 Ρ03Η2 ; R1為 Η ; R2為HSCm烷基; R3為Η ;及 R4及R5為相互獨立的Η ;或R4及R5與其所附接的碳原子 一起形成3至6員環烷基。 在另一實施例中,本發明係關於一種式(I)化合物或其醫 藥學上可接受之鹽或水合物, 其中 X為Ν ; R為 Ρ03Η2 ; R1為 Η ; R2為Η或Cw烷基; R3為Η ;及 R4及R5為相互獨立的烷基。 在另一實施例中,本發明係關於一種式(11)化合物
163746.doc 201249858 或其醫藥學上可接受之鹽。 在另一實施例中,本發明係關於一種式(ΠΙ)化合物 Ρ I ,0 ΌΗ
Η (HI) 或其醫藥學上可接受之鹽或水合物。 在另一實施例中’本發明係關於一種式(jV)化合物 PC I ,ο OH Ν
(IV) 或其醫藥學上可接受之鹽。 【實施方式】 先前技術 N. Fotouhi等人(ΕΡ 1,224,181)描述經取代之吡咯衍生 物’其中該吡咯環上之化學修飾由大量變量組成且亦可含 有一個亞曱基羥基或一個亞曱基磷酸基。 163746.doc 201249858 定義 如本文所用,術語「鹵素」(或鹵基)指氟、溴、氯或 碘’尤其係氟、氯。 如本文所用’術語「烷基」指一種含有多達4個碳原子 之完全飽和分支或無分支烴基部分。烷基的代表性實例包 括(但不限於)甲基、乙基、正-丙基、異-丙基、正-丁基、 第二丁基、異-丁基、第三丁基等等。 如本文所用,術語「烷氧基」指烷基_〇_,其中烷基如 上文疋義。烧氧基的代表性實例包括(但不限於)甲氧基、 乙氧基、丙氧基、2·丙氧基'丁氧基、第三_ 丁氧基、戊氧 基、己氧基、環丙基氧基-、環己基氧基等等。一般而 言’烷氧基具有1至4個碳原子。 如本文所用’術語「環烷基」指3至6個碳原子的飽和或 不飽和單環烴基,特定言之,3至5個碳原子,尤其係3至4 或3個碳原子。 如本文所用,術語「鹽(salt)」或「鹽(salts)」指本發明 化合物之酸加成鹽或鹼加成鹽。「鹽(salts)」尤其包括「醫 藥學上可接受之鹽」。術語「醫藥學上可接受之鹽」指保 留本發明化合物之生物有效性及特性之鹽,一般而言它 們在生物學上或在其他方面不是非所要的。在諸多情況 中’本發明之化合物可憑藉存在胺基及/或缓基或與其相 似之基團而形成酸及/或鹼鹽。 可與無機酸及有機酸形成醫藥學上可接受之酸加成鹽, 如醋酸鹽、天冬胺酸鹽、苯甲酸鹽、苯磺酸鹽、溴化物/ I63746.doc 201249858 氫溴酸鹽、碳酸氫鹽/碳酸鹽、硫酸氫鹽/硫酸鹽、樟腦磺 酸鹽、氯化物/氫氯酸鹽、氣茶鹼普鲁米近鹽、檸檬酸 鹽、乙二續酸鹽、富馬酸鹽、葡庚糖酸鹽、葡萄糖酸鹽、 葡萄糖酿酸鹽、馬尿酸鹽、虱硬酸鹽/峨化物、經乙石黃酸 鹽、乳酸鹽、乳糖酸鹽、月桂基硫酸鹽、蘋果酸鹽、馬來 酸鹽、丙二酸鹽、杏仁酸鹽、甲磺酸鹽(mesylate)、曱磺 酸鹽(methylsulphate)、萘酸鹽、萘磺酸鹽、菸鹼酸鹽、确 酸鹽、十八酸鹽、油酸鹽、草酸鹽、棕櫚酸鹽、雙經蔡酸 鹽、磷酸鹽/磷酸氫鹽/磷酸二氫鹽、聚半乳糖醛酸鹽、丙 酸鹽、硬脂酸鹽、琥珀酸鹽、磺基水楊酸鹽、酒石酸鹽、 曱苯磺酸鹽及三氟醋酸鹽。 可自其衍生鹽之無機酸包括,諸如氫氣酸、氫漠酸、硫 酸、硝酸、磷酸等等。 可自其竹生鹽之有機酸包括,諸如醋酸、丙酸、乙醇 酸、草酸、馬來酸、丙二酸、琥珀酸、富馬酸、酒石酸、 檸檬酸、苯甲酸、杏仁酸、曱磺酸、乙磺酸、曱苯績酸、 續基水楊酸等等。醫藥學上可接受之驗加成鹽可使用無機 鹼及有機鹼形成。 可竹生成鹽之無機驗包括’諸如敍鹽及自週期表第I至 XII列之金屬。在某些實施例中,該鹽可衍生自鈉、鉀、 銨、鈣、鎂、鐵、銀、鋅及銅’尤其合適之鹽包括銨鹽、 钟鹽、鈉鹽、鹤鹽及鎮鹽。 可竹生成鹽之有機驗包括’諸如一級胺、二級胺及三級 胺,包括天然經取代的胺之經取代的胺、環胺、鹼性離子 163746.doc 201249858 交換樹脂等等《某些有機胺包括異丙胺、苄乙二胺、膽 驗、二乙醇胺、二乙胺、離胺酸、葡f胺、哌嗪及緩血酸 胺0 本發明之醫藥學上可接受之鹽可藉由傳統化學方法自一 種母體化合物、一種驗或酸性部分合成。通常,此等鹽可 藉由使此等化合物之游離酸形式與化學計量之合適驗(諸 如Na、Ca、Mg、或κ之氫氧化物、敌酸鹽或碳酸氫鹽等 等)反應’或藉由使此等化合物之游離驗形式與化學計量 之合適酸反應而製備。通常在水中或在一種有機溶劑中或 二者之混合物中進行此等反應。通常,若可行,需使用諸 如醚、乙酸乙酯、乙醇、異丙醇或乙腈之非水性介質。可 在如「Remington’s Pharmaceutical Sciences」,第 2〇 版,
Mack Publishing Company,Easton,Pa.,(1985);及 Stahl and Wermuth 的「Handb〇〇k 〇f 心職
Weinheim,
Properties, Selection, and Use j (Wiley-VCH
Germany,2002)中找到其他合適鹽之列表。 本文所給定的任何化學式亦欲代表化合物之未經標記形 式及丄同位素‘ a£> 式。經同位素標記之化合物具有依據 本文所、、.。疋化學式而描繪之結構,除非其中一個或多個原 子被一個具有經選擇的原子量或質 量數之原子所替代。可 併入本發明化合物之同 磷、氟及氣之同位素, 14c、15N、18F、31p、3 義’本發明包括多種經 位素之實例包括氫、碳、氮、氡、 分別爲諸如2H、3H、nc、13c、 P、 s、36ci、125I。如本文所定 门位素k δ己之化合物,諸如彼等存 163746.doc 201249858 在放射性同位素(諸如3H及"C)者或彼等存在非放射性同位 素(諸如A及Μ者。此等經同位素標記之化合物適用於代 謝研究(使用14〇、反應動力學研究(使用諸如4或如、檢 測或成像技術(諸如正子發射斷層攝影術(_或單光子放 射電腦斷層攝影術(SPECT),包括藥物或基本組織分佈分 析)或病人之放射治療。特定言之,在叩丁或”“丁研究 中,18F或經標記之化合物係尤其所要的。通常,本發明 之經同位素標記之化合物及其前藥可藉由下面所述流程中 或實例與製備中所揭示之步驟(藉由易得到之經同位素標 S己之試藥取代未經同位素標記之試藥)製備。 另外,用較重同位素(尤其係氘’即治或〇)取代會由於 較南代謝穩定性而提供-定治療優勢,諸如提高體内半衰 期或減少劑量需求或改善治療指標。應瞭解,在上下文中 將氘視為本發明之取代基。此種較重同位素(具體而言氘) 之濃度可藉由同位素濃化因素定義。如本文所用,術語 「同位素濃化因素」意為同位素豐度與特定同位素之天然 豐度之比例β若本發明化合物之一種取代基指氘,則此種 化合物具有各指定氘原子為至少35〇〇(各指定氘原子併入 52.5%氘)、至少4000(併入60%氘)、至少4500(併入67.5% 氘)、至少5000(併入75%氘)、至少5500(併入82_5❶/〇氘)、至 少6000(併入90%氘)、至少6333.3(併入95%氘)、至少 6466.7(併入97%氘)、至少6600(併入99%氘)、至少 6633.3(併入99.5%氘)之同位素濃化因素。 本發明之經同位素標記之化合物通常可藉由為熟習此項 163746.doc ιΛ 201249858 技術者已知之傳統技術,或蕤 飞精由類似於彼等描述於隨附實 例及製備之方法利用一箱人、吞 口適經同位素標記之試藥代替先 前採用未經標記之試藥製備。 按照本發明,醫藥學上可垃A ^ τ接梵之溶劑化物包括結晶溶劑 可經同位素取代,如D 〇、 2 d6-丙酮、d6-DMSO的溶劑化 物。 本發明之化合物’如包含可作為氫鍵供體及/或受體之 基團的式(I)化合物可盘人,吞u τ與σ適共結晶體形成劑形成共結晶 體。此等共結晶體可藉由眾所周知之共結晶體形成步驟自 式⑴化合物製備。此等步驟包括研磨、加熱、共昇華、共 熔或在結晶條件下於溶液中使式⑴化合物與共結晶體形成 知接觸並刀離由此形成的共結晶體。合適共結晶體形成劑 包括彼等描述於WO 2〇_78163者。因此,本發明進—步 提供包含式(I)化合物之共結晶體。 ,如本文所用’術語「醫藥學上可接受之載劑」包括如熟 S此項技術者所知之任何及所有溶劑、分散介質、塗料' 表面活性劑、抗氧化劑、保存劑(如抗菌劑、抗真菌劑)、 等滲劑、延遲吸收劑、鹽、防腐劑、藥品、藥品穩定劑、 黏合劑、賦形劑、崩解劑、潤滑劑、甜味劑、調味劑、染 料寺專及其組合(參見如Remington's Pharmaceutical
Sciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329)。除非任何傳統載劑與活性成份不相容,否則將其 用於治療或醫藥組合物值得期待。 本發明化合物之術語「治療有效量」指本發明化合物引 163746.doc 201249858 起個體生物或醫學反應(諸如酶或蛋白質活性之降低或抑 制或改善病癥、減輕病狀、減緩或延遲疾病進展或預防疾 病等)之量。在一非限定性實施例中,術語「治療有效 量J指投與個體時’本發明化合物有效(1)至少部份減輕、 抑制、預防及/或缓解⑴受蛋白激酶C介導、或(u)與蛋白 激酶C活性相關’或(iii)特徵為蛋白激酶c活性(正常咬異 * )的病狀或病症或疾病;或(2)降低或抑制蛋白激酶c活 性;或(3)降低或抑制蛋白激酶c表現之量。在另一非限定 性實施例中,術語「治療有效量」指投與細胞或組織或非 細胞生物材料或培養基時,本發明化合物有效至少部份降 低或抑制蛋白激酶C活性;或至少部份降低或抑制蛋白激 酶c表現之量。 如本文所用,術語「個體」指動物。通常該動物為哺乳 動物。個體亦指諸如靈長類(如人類,男性或女性)、牛、 綿羊、山羊、馬 '狗、猶、兔、A鼠、小鼠'魚、鳥等 4在某些貫施例中,個體為靈長類。在其它實施例中, 個體為人類。 如本文所用’術語「抑制(inhibit)」、「抑制(inhibition)」 或「抑制(inhibiting)」指降低或抑制既定病狀、病癥或病 症或疾病,或顯著降低生物活性或過程之基線活性。 如本文所用’術語任何疾病或病症之「治療(treat)」、 /口療(treating)」或「治療(treatment)」指在一實施例中 改。疾病或病症(即減緩或阻止或降低疾病之發展或其至 少一種臨床病癥)。在另一實施例中,「治療々eat)」、「治 163746.doc -12· 201249858 療(treating)」或「治療(treatment)」指減輕或改善至少一 種包括彼等不可由患者辨別之身體參數。在另一實施例 中,「治療(treat)」、「治療(treating)」或「治療…⑽则加)」 才曰在身體上(如穩定明顯病癥)、生理上(穩定身體參數)或 一者兼有調節疾病或病症。在另一實施例中,「治療 (treat)」、「治療(treating)」或「治療(treatment)」指預防 或延遲疾病或病症之發生、發展或進展。 如本文所用,「需要」治療之個體,此個體將會在生物 學上、醫學上或生活品質上受益於此治療。 如本文所用’在本發明上下文内所用之術語「一(a)」、 「一(an)」、「該(the)」及類似術語視為涵蓋單數及複數, 除非本文另有說明或與上下文明顯矛盾。 所有本文所描述之方法可以任何適當順序進行,除非本 文另有說明絲非與±下文明财;|。本文使用的任何及 所有貫例或舉例性語言(如「諸如」(such as))僅為更適當 地闡明本發明而不對本發明之範圍構成限制除非另有說 明。 。 製備方法 本發明化合物可藉由以下提供的方法製備,例如在存在 或不存在溶劑或鹼(諸如碳酸鉀)下(例如)用甲醛將式(V勾之 馬來醯亞胺轉化為式(Vb)之醇,並(例如)式(Va)化合物(其 中為式⑴提供之可變量X、R、R1、R2、R3、R4&R5具有 =義)中存在游離及反應性胺基基團時,視情況在此反應 則引進保護基(例如按照當前技術反應之第三丁氧基獄 I63746.doc 13 201249858 基)。
1磷酸二-第三丁基酯 2.水解
可視隋况(例如)用三氣甲基乙腈及合適驗(例如將 弋()之醇轉化為反應性酯,及然後可在存在或不存在合 C谷劑(例如種非質子溶劑,如乙腈)下與合適鱗酸化劑 (例如磷酸二·第三丁基酯)反應,及然後可用(例如)三氟乙 I於(例如氣甲烧或匕2•二氣乙烧中水解以提供最終産 物Vc。 另外,式(Vb)之醇可與一種磷酸酯(例如磷酸二_第三丁 基6日)(例如)在光延(Mitsun〇bu)反應條件下直接反應,以提 供磷酸醋,然後用(例如)三氟乙酸於(例如)二氯甲烷中水 解以提供最終產物。 163746.doc
• 14· 201249858 實驗部份: ’但化合物為 法或如此後所 限制。 此’雖然並未具體描述起始材料之製備 眾所周知或可用類似於此項技術中已知之方 闡述之方法製備。 以下為本發明之示範性實例,而不受任何 略語: bs 寬單態 d 雙重態 DMSO 一甲亞硬 d.n. 劑量標準化 EtOAc 乙酸乙酯 Et20 二乙醚 FCC 快速管柱層析法 MeOH 甲醇 MS 質譜分析 M 多重態 NMR 核磁共振 p.o. 經口 r.t. 室溫 s 單態 t 三重態 TFA 三氟乙酸 TLC 薄層層析法 UPLC 超南壓液相層析法 163746.doc 201249858 所有化合物之化學命名法係藉由使用AutoNom®產生。 在室溫下將NMR光譜記錄在Bruker Avance DPX 400光言普 儀上β 使用的LCMS方法: LC方法l(Rt(1)):應用一組梯度(溶劑A :水+0.1%曱酸, 溶劑B :乙腈;t=0分鐘:99% A,1% B ; t=l分鐘98% A, 2% B ; t=2.25分鐘 1% A,99°/。B ; t=4.5分鐘 0°/。A,100。/〇 B),利用 Waters BEH C18 1.7 μηι 2.1x50 mm管柱(流速= 0.7 ml/分鐘;檢波 240-350 nm ; DAD)在連接至 Waters ZQ 2000質譜分析器的Waters Acquity UPLC系統上得到滞留時 間(Rt) » LC方法2(Rt(2)):在1.7分鐘内應用一組梯度(H20+0.05°/〇 曱酸+3.75 mM醋酸銨)/(CH3CN+0.04% 曱酸)90/10至 5/95並 以1.2 mL/分鐘作為溶劑流動,然後在0.7分鐘内應用5/95 並以1.4 mL/分鐘作為溶劑流動且烘箱溫度為40°C,在具有 Ascentis® Express管柱之Agilent HPLC系統上得到滯留時 間(Rt)。檢測方法為 UV 214-350 nm-MS。 純化方法:
製備型逆相Gi丨son HPLC WATERS之 SunFire prep C18 OBD 5 μιη,30x100 mm管 柱,含H20+0.1% TFA及乙腈+0.1% TFA作為移動相。檢測 方法為 UV 220-400 nm。 實例1:磷酸單-[3-[3-(4,7-二氮雜-螺丨2.5]辛-7-基)-異喹啉-1-基】-4-(7-甲基-1H-吲哚-3-基)-2,5-二側氧基-2,S-二氫-吡 163746.doc •16· 201249858 鳴·_ι_基甲基]醋 0γ: r° /η。立 在 〇°C 氬氣下將 TFA (8.27 g,72·5 mmol)加入 7-{l-[l-(二-第三-丁氧基_磷醯基氧基甲基)-4-(7-甲基-lH-吲哚-3-基)-2,5-二側氧基-2,5-二氫-lH-吡咯-3-基]-異喹啉-3-基}-4,7_二氮雜-螺[2.5]辛烷-4-羧酸第三丁基酯(1.90 g, 2_42 mmol)於l,2-二氣乙烷(50 mL)之溶液中》在0。(:氬氣下 將反應混合物攪拌3.5小時直至UPLC-MS顯示起始材料發 生完全轉化。用1,2-二氯乙烷(50 mL)稀釋反應混合物並在 減壓下濃縮以得到紅色固體之粗產物。將反應粗產物溶解 於MeOH中並在減壓下緩慢濃縮直至開始結晶。加入戊烧 並過渡固體並用EtaO清洗。藉由將粗產物懸浮於dms〇中 達到進一步純化,然後超音波震動30分鐘。過濾固體,用 玢2〇清洗並在高度真空(<1 mm Hg)下乾燥以得到暗紅色固 體之標題化合物。iH-NMR (400 MHz, DMSO-d6): 12.10 (s,1H),8.08 (d,1H),7.65-7.61 (m,2H),7.44 (t,1H),7.20 (s, 1H), 7.06 (t, 1H), 6.74 (d, 1H), 6.43 (t, 1H), 6.00 (dj 1H), 5.29 (d, 2H), 3.87-3.01 (m5 6H), 2.37 (s5 3H), 〇.97. 163746.doc 201249858 0.62 (m,4H)。31P-NMR (162 MHz,DMSO-d6): -6.0 〇 LCMS: [Μ+1]+=574·0, Rt(1)=1.77分鐘,Rt(2)=〇.71 分鐘。 製備曱基-lH-n引鳴冬基二側氧基-2,5-二 氫-1H-吡咯-3-基]-異喹啉-3-基}-4,7-二氮雜-螺[2.5]辛烷-4-羧酸第三丁基醋
在室溫 1 氣下將 DBU(0.374 g,0.37 1 mL,2.46 mmol)於 三氣乙腈(17.8 g,12.3 mL,123 mmol)之溶液一滴一滴地 加入7-{ 1-[1-經甲基-4-(7-甲基-1Η-β弓丨哚-3-基)-2,5-二側氧 基-2,5-二氫-1Η-。比嘻-3-基]-異喹你-3-基}-4,7-二氮雜-螺 [2.5]辛烷-4-羧酸第三丁基酯(7.30 g,12.3〇 mm〇1)於乙腈 (60 mL)之溶液中。在室溫下攪拌反應混合物5小時直至 TLC (Si〇2,EtOAc/環己烷6:4)顯示完全轉化。將反應混合 物在減壓下蒸發至乾燥並將殘留物懸浮於乙腈(6〇 mL) 中。加入填酸二-第三丁基酯(3.36 g,15.99 mmol)並在室 溫氬氣下攪拌反應混合物約3.5小時直至TLC (Si02, EtOAc/環己烧6:4)顯示反應完全。在減壓下濃縮反應混合 163746.doc -18· 201249858 物並將殘留物在EtOAc及水之間分配。分離該等層並用水 清洗有機相(5次)》在NaJO4上乾燥有機相並在減壓下濃 縮以得到紅色固體。藉由FCC(Biotage SP4TM系統,Si〇2, 環己烷/EtOAc 20:80)純化粗產物以產生紅色固體之標題化 合物。’H-NMR (400 MHz,DMSCM6): 12.03 (s,1H),8.08 (d,lH),7.70-7.65 (m,2H),7.47(t,lH),7.11(s,lH),7.11-7.07 (m,1H),6.77(d,1H),6.44 (t,1H),5.97 (d,1H),5.39 (d, 1H), 3.49-3.08 (m, 6H), 2.39 (s, 3H), 1.45 (s, 18H), 1.41 (s,9H),0.87-0.56 (m, 4H)。31P-NMR (162 MHz,DMSO-d6): -12.1。LCMS: [M+l]+=786_4,Rt(l)=2.53 分鐘,Rt(2)= 1.62分鐘。 製備7-{1-[1-羥甲基-4-(7-甲基-111-吲哚-3-基)-2,5-二侧氧 基-2,5-二氫-1H-吡咯-3-基]-異喹啉-3-基}-4,7-二氮雜-螺 [2.5]辛烷-4-羧酸第三丁基醋
在室溫氬氣下將曱醛之37%水性溶液(9.5 g,8.72 mL, 117 mmol)加入 7-{ 1-[4-(7-甲基-1H-0弓卜朵-3-基)-2,5-二側氧 基-2,5-二氫-1H-吡咯-3-基]-異喹啉-3-基}·4,7-二氮雜-螺 163746.doc •19· 201249858 [2.5]辛烷-4-羧酸第三 丁基酷(3.00 g,5.32 mmol)於 MeOH (25 mL)之溶液中。將反應混合物加熱至85°C並攪拌4小 時。將反應混合物於連續攪拌下冷卻至室溫並過濾。用冰 水清洗固體並在高度真空下mm Hg)乾燥以得到暗紅色 結晶體之標題化合物。1H-NMR (400 MHz,DMSO-d6): 11.96 (s, 1H), 8.05 (s, 1H), 7.69-7.64 (m, 2H), 7.47 (t, 1H), 7.12-7.06 (m,2H),6.76 (d,1H),6.42 (t,1H),6.01 (d,1H), 5.00 (d, 2H), 3.49-3.10 (m, 6H), 2.39 (s, 3H), 1.41 (s, 9H), 0.89-0.57 (m,4H)。LCMS: [M]+=593.7, Rt(l)=2.34分鐘。 製備Ί-{1·ί4-(Ί-甲基-1H-吲哚-I基二側氡基-2>5-二 氫-1H-吡咯-3-基]-異喹啉-3-基}-4,7-二氮雜-螺[2.5]辛烷· 4-羧酸第三丁基醋
在室溫氬氣下將二-第三丁基碳酸酯(2.77 g,10.8 mmol) 及三乙基胺(2.18 g,21,6 mmol)加入3-[3-(4,7-二氮雜-螺 [2.5]辛-7 -基)-異嗅琳-1-基]-4-(7-曱基-1H-0弓丨°朵-3 -基)-ίι比 0各_2,5_ 二剩(5.0 g,10.8 mmol)於 THF(50 mL)之溶液中。 攪拌反應混合物16小時並在減壓下濃縮。將殘留物在飽和 NH/l水性溶液及之間分配。分配層並用CH2C12萃 163746.doc •20- 201249858 取水性層。用飽和NaHCCb水性溶液及鹽水清洗合併有機 層,在無水NazSO4上乾燥,並在減壓下濃縮以得到橙色固 體之標題化合物。1H-NMR (400 MHz,DMS0-d6): U.88 (s, 1H),11.15 (s,1H),8.00 (d,1H),7.68-7.65 (m,2H),7.46 (t, 1H),7.09 (t,1H),7.06 (s,1H),6,73 (d,1H),6,41 (t,1H), 6.01 (d, 1H), 3.48-3.16 (m, 6H), 2.38 (s, 3H), 1.40 (s, 9H), 0.87-0.54 (m,4H)。LCMS: [M+l]+=563.9,Rt(1)=3.5l 分 鐘,Rt(l)=2.36分鐘,Rt(2)=1.37分鐘。 實例2 : 3-[3-(4,7-二氮雜-螺[2.5】辛-7-基)-異喹啉·1_基】-1 羥甲基-4-(7-甲基-1H-吲哚-3-基)-吡咯_2,5_二酮
在〇°C 氬氣下將TFA(1.44 g ’ 0.973 mL,12.7 mmol)加入 7-{l-[l -羥甲基-4-(7-曱基-1H-吲哚_3·基)_2,5-二側氧 基-2,5-二氫-1H-«比咯-3-基]-異喹啉_3-基}·4,7-二氮雜-螺 [2_5]辛院-4-羧基第三丁基酯於1,2-二氯乙烷(5 mL)之溶液 中。在〇°C氬氣下將反應混合物攪拌1小時後,額外添加 ΤΡΑ(0·768 g ’ 0.52 mL,6·74 mmol) 〇 在 〇°c 下連續攪拌 1.5 小時。在減壓下將反應混合物蒸發至乾燥並自Me〇H結晶 粗產物以得到紅色固體(TFA鹽)、暗紅色固體之標題化合 163746.doc 201249858 物。1H-NMR (400 MHz,DMSO-d6): 12.01 (d, 1H), 9.06 (bs, 2H), 8.11 (d, 1H), 7.71-7.66 (m, 2H), 7.51 (t, 1H), 7.27 (s, 1H), 7.14 (t, 1H), 6.77 (d, 1H), 6.45-6.39 (m, 2H), 5.92 (d, 1H), 5.00 (d, 2H), 3.84-3.54 (m, 6H), 2.39 (s, 3H), 0.96-0.67 (m,4H)。LCMS: [M+l]+=493.7, Rt(1)=1.84分鐘。 實例3 : 3-[3-(4,7-二氮雜-螺[2.5】辛-7-基)-異喹啉-1-基卜4-(7-甲基-1H-吲哚-3-基)-吡咯-2,5-二酮
標題化合物之合成已作為實例69描述於WO03082859 中。 實例4 :磷酸單-{3-(1Η-吲哚-3-基)-4-[2-(4-甲基·哌嗪-1- 基)-啥嗤淋-4 -基]-2,5 -二側氧基-2,5 -二氮·β比洛· 1 -基甲基} 6旨
OH
〜OH
在氬氣下,將磷酸二-第三丁基氣曱基酯(1.24 g,4.81 I63746.doc -22- 201249858 mmol)及 Cs2C03 (3.14 g,9.63 mmol)加入 3-(lH-0弓卜朵-3- 基)-4-[2-(4-甲基-派°秦-1-基)-啥<»坐琳-4-基]· e比略·2,5_二嗣 (2.0 g ’ 4.01 mmol)於丙酮(40 mL)之溶液中。在5〇°C氬氣 下將反應混合物攪拌16小時,然後在減壓下濃縮。將殘留 物在EtOAc及飽和NEUC1水性溶液之間分配,分離層並在 無水NazSCU上乾燥有機層。在減壓下濃縮得到紅色發泡體 之粗產物。藉由如上所述之逆相Gilson HPLC純化粗產 物。在真空中濃縮所需溶離份後得到紅色固體^ UPLC-MS 顯示第二-丁基醋基團發生部份分解。將所得混合物(28〇 mg)溶解於1,2-二氯乙烷(4 mL)及乙腈(2.0 mL)之混合物 中。加入TFA (145 mg,98 μί,1.27 mmol)並在〇。〇氬氣下將 所得溶液攪拌3小時至UPLC-MS顯示起始材料已完全轉 化。用1,2-二氣乙烷(4.0 mL)稀釋反應混合物並在減壓下 濃縮以得到紅色固體之粗產物。將粗反應產物溶解於 MeOH (3 mL)中並在減壓下緩慢濃縮直至開始發生結晶。 過遽、結晶體並用Et;2〇及戊院清洗以得到撥色固體之標題化 合物。'H-NMR (400 MHz, DMSO-d6): 12.27 (s,1H),8 21 (s,1H),7.72-7.66 (m,2H),7.58 (d,1H),7.40 (d,1H),7.14 (t,1H),7.02 (t,1H),6.65 (t,1H),6.24 (d,1H),5.34 (d, 2H),4.14-3.72 (bs,4H),3.00-2.73 (bs,4H),2.60 (s,3H) 〇 31P-NMR (162 MHz,DMSO-d6): -2.7。LCMS: [M]+=548.6
Rt⑴=1.72分鐘,Rt(2)=0.73分鐘。 製備實例1化合物之結晶物質: 將2克磷酸單-[3-[3-(4,7-二氮雜-螺[2.5]辛-7-基)·異嗤 163746.doc •23· 201249858 啉-1-基]-4-(7-甲基-1H-吲哚-3-基)-2,5-二側氧基-2,5-二 氫-吡咯-1-基甲基]酯(實例No. 1)分散於800 ml乙醇及200 ml水之混合物中。在室溫下攪拌此懸浮液3天。此後,經 由燒結玻璃濾器過濾該懸浮液並將由此所得之結晶體在常 壓氣流中乾燥。將4 ml 80%乙醇/20%水(vol./vol.)溶液加 入至1克此等結晶體中並將所得混合物在大氣壓下蒸發至 乾燥以得到實例No· 1之單水合物。 圓1 以上結晶單水合物之X-射線繞射圖顯示於圖1中,相對 2Θ角之峰值記錄於表1中。 表1.實例No. 1結晶單水合物之X-射線繞射圖之主岭 2Θ角 d值埃 強度計數 計數% 強度 強度% 8.506 10.38645 8.506 10.38645 5215 26.0 9.525 9.27790 9.525 9.27790 7052 35.2 13.793 6.41501 13.793 6.41501 4245 21.2 14.926 5.93044 14.926 5.93044 3513 17.5 15.172 5.83502 15.172 5.83502 3360 16.8 15.413 5.74440 15.413 5.74440 3384 16.9 16.356 5.41519 16.356 5.41519 6738 33.6 17.091 5.18400 17.091 5.18400 20046 100 18.005 4.92268 18.005 4.92268 10587 52.8 19.224 4.61338 19.224 4.61338 6442 32.1 20.859 4.25526 20.859 4.25526 9742 48.6 22.433 3.96009 22.433 3.96009 5332 26.6 23.316 3.81209 23.316 3.81209 5751 28.7 25.792 3.45140 25.792 3.45140 8574 42.8 27.402 3.25222 27.402 3.25222 3930 19.6 27.712 3.21657 27.712 3.21657 3575 17.8 28.091 3.17398 28.091 3.17398 4187 20.9 30.521 2.92662 30.521 2.92662 2899 14.5 31.502 2.83768 31.502 2.83768 3756 18.7 163746.doc 24· 201249858 因此,本發明在另一實施例中提供磷酸單-[3-[3·(4,7-二 氮雜-螺[2.5]辛-7-基)-異喹啉基]_4_(7_甲基-瓜吲喝小 基)-2,5_二側氧基_2,5_二氫_ „比洛_卜基f基]酿之結晶形 式,尤其係單水合物,其x_射線粉末繞射圖較佳在以下Μ 折射角(各偏差土0.2,尤係描述於圖!中者)處出現至少一 個,較佳兩個’更佳三個,甚至更佳四個,尤佳五個最 佳所有以下波峰值:9.525、16,356、17.091、18.005、 20.859 〇 表2 ·實例No _ 1之非晶體及結晶之化學穩定性 化合物 固體狀態 初始 純度 (%) 溫度 [°C] 曝露 時間 純度 [%] 實例No. 1 非晶體 98.5 50 1週 95.8 實例No. 1 ^非晶體 98.5 80 1週 89.7 實例No. 1 結晶單水合物 100 50 1週 100 實例No. 1 結晶單水合物 100 80 1週 100 表概述DSC(差示掃描熱量儀)及tga(熱重分析)上所見 之熱事件。 溫度範圍[°c] 事件 30-125 失水 225-265 分解 圖2 實例No. 1單水合物結晶之水吸收譜顯示於圖2中。施用 以下濕度曝露:在50% RH下平衡6小時,然後以1〇% rh 梯級進行兩個自50% RH至90% RH至〇% 1^至9〇% rH至 0% RH至50% RH之RH循環。(RH=相對濕度) 163746.doc -25- 201249858 生物醫藥部份 本發明之化合物,例如一種呈游離形式或呈醫藥學上可 接受之鹽或水合物形式之式(I)、(II)、(III)或(IV)之化合物 等等在如以下測試(例如在活體外或活體内測試)中所描述 頗具價值之醫藥特性,並因此用於治療。 A.活體外 1.蛋白激酶C(X及Θ測試 根據以下方法測試本發明化合物對於不同PKC同型物之 活性。所有測試在384孔微量滴定板中進行。每個測試平 板含有40個測試化合物之8點連續稀釋及星形孢菌素之2組 16點連續稀釋液作為參照化合物,加上16個高及16個低控 制組。在配備有Innovadyne Nanodrop Express之自動化工 作站上完成液體處理及培養步驟。 藉由加入每孔50 nL於90% DMSO中之化合物溶液來製備 測試平板。逐步加入4.5 μΐ 2x肽/ATP-溶液/孔及4.5 μΐ 2x 酶溶液/孔開始激酶反應。試藥在激酶反應期間之最終濃度 為:50 mM HEPES、pH 7.5、1 mM DTT、0.02% Tween20 ' 0.02°/。BSA、0.6% DMSO、10 mM β-甘油礙酸酯及 10 μΜ 原釩酸鈉。PKC-α及PKC-Θ測試所用之肽受質為Dy495-X5-ME-Mpr-RFARKGSLRQKNV-COOH。兩種酶皆為昆蟲細胞 中所表現之人類全長重組蛋白(Invitrogen AG,Basel, Switzerland)。其它組份特地為各次激酶測試而調整: PKC-ct:12 pM酶、17 μΜ ATP、1 μΜ肽受質、7 mM MgCl2、 0.2 mM CaCl2,ΡΚΟΘ:29 pM酶、70 μΜ ATP、1 μΜ肽受 163746.doc -26- 201249858 質、7 mM MgCl2 ' 0.2 mM CaCl2。 在30°C下培育激酶反應60分鐘並隨後藉由加入每孔16 μΐ 停止溶液(100 mM HEPES pH 7.5、5% DMSO、0.1% Caliper 塗佈試藥、i〇mMEDTA 及 0.015%Brij35)而終止。 將經終止激酶反應之平板轉移至Caliper LC3000工作站 讀數。利用Caliper微流體遷移改變技術(Caliper microfluidic mobility shift technology)分離經破酸化及未 經磷酸化之肽並自所形成磷酸肽之量計算激酶活性。 測試 實例1 實例3 PKCa (IC5〇 以 nM 計) 1677 0.4 PKC0 (IC50 以 nM 計) 462 0.2 上文及下文所顯示之測試結果可支持本發明化合物之前 藥概念。 2.骨髓細胞增殖(B Μ)測試 在 100 pL含 10% FCS、100 U/mL青黴素、1〇〇 pg/mL鏈 黴素(Gibco BRL,Basel Switzerland)、50 μΜ 2-疏基乙醇 (Fluka,Buchs,Switzerland)、WEHI-3 條件培養基(7.5% v/v)及L929條件培養基(3% v/v)作為生長因素源及經連續 稀釋化合物之RPMI培養基中培育自CBA小鼠之骨髓細胞 (平底組織培養微量滴定板中2.5 X 1 〇4細胞/孔)》每種測試 化合物重複進行七次三倍稀釋步驟。培育四天後加入1 μ(:ί 3H-胸苷。在另外五小時培育時間後收穫細胞,並根據 標準步驟測定併入的3H-胸苷。如下製備條件培養基。各 自在RPMI培養進中培養WEHI-3細胞(ATCC TIB68)及L929 I63746.doc •27· 201249858 細胞(ATCC CCL 1)4天及一週直至匯合。收穫細胞,再次 懸浮於相同培養瓶之含1°/。FCS的培養基C (Schreier and Tess 1981)中(用於WEHI-3細胞)及RPMI培養基(用於L929 細胞),並培育2天(WEHI-3)或一週(L929)。收集上清液, 經由0.2 μιη過濾並以等分試樣貯存在-80°C下。將不含測試 化合物及不含WEHI-3及L929上清液之培養物用作低控制 值。所有數值皆減去低控制值。不含任何樣品之高控制組 視為1 00%增殖。計算受樣品抑制之百分比並測定50%抑制 (IC5〇值)所需之濃度。 實例1 實例3 IC50 以 πΜ 言·* 6741 土 1117 1672士256 B.活體内 投與實例No.l化合物 將單次劑量之實例No.l化合物(3.0 mg/kg)經口投與至3 條雄性小獵犬。化合物1係作為結晶單水合物形式於曱基 纖維素(0.5%) : Tween 80(1%)(90:10)中之水性懸浮液投 與。藉由靜脈穿刺以均勻間隔取血,分析樣品多達24小時 之時段。隨時間定量測定實例1、2及3化合物,並將結果 製成以下表格: 時間⑻ 化合物1 〇ιΜ) 化合物2 (ηΜ) 化合物3 (ηΜ) 0 - - 0.083 10.0 15.0 0.25 3.1 39.6 166.7 0.5 1.1 31.3 757.4 0.75 - 19.1 1198.0 1 6.3 1308.3 163746.doc -28 - 201249858 2 - 7.7 1118.6 3 - 1.0 958.9 4 - - 762.0 7 - - 403.1 24 - - 67.9 在口服實例No.l後,1、2及3之重要藥物動力學參數(平 均值土標準偏差(n=3))。 參數 化合物1 化合物2 化合物3 Cmax d.n. (πΜ) - 15 士8 441±165 Tmax (h) - 0·4±0.1 0.9±0.1 AUC d.n. (nM»h) - 低 3350±1402 投與實例No.3化合物 將實例No.3化合物作為單乙酸鹽以硬明膠膠囊口服投與 至6條禁食雄性小獵犬。提供1 00 mg/犬之名義劑量,得到 8.9-11.3 mg/kg之劑量(犬重為8.9至11.3 kg)。藉由靜脈穿 刺取血,取樣多達32小時。對3進行生物分析測定並製成 以下表格。 時間(h) 化合物3 (nM) 0 0.25 177 0.5 936 1 2155 2 2548 3 2000 4 1898 6 1486 8 1238 24 276 32 116 163746.doc •29- 201249858 如上所述口服投與後化合物No·3之重要藥物動力學參數 (平均值或範圍)。 參數 化合物3 Cmax d,n. (πΜ) 323 Tmax (h) 0.5-2 AUC d.n. (nM.h) 2790 物理化學部份 溶解度測試 室溫下實例No. 1化合物在模擬胃液及模擬腸液中之溶解度 介質 溶解度[mg/mL] 最終pH 模擬胃液(SGF) pH 2 0.04 2.22 禁食狀態之模擬腸液 (FaSSIF) pH 6.5 0.1 6.59 飽食狀態之模擬腸液 (FeSSIF) pH 5.8 0.13 6.05 實例Νο·3化合物(游離形式/乙酸鹽形式)在模擬胃液中之 溶解度: 游離形式 乙酸鹽 介質 溶解度 [mg/ml] 最終pH 溶解度 [mg/ml] 最終pH 模擬胃液(SGF) pH 2 0.12 0.15 5.45 禁食狀態之模擬腸液 (FaSSIF) pH 6.5 0.03 - 0.05 3.97 飽食狀態之模擬腸液 (FeSSIF) pH 5.8 0.28 0.55 6.5 穩定性測試 實例No.l cpd在37°C下於模擬胃液及腸液中之穩定性: 163746.doc •30· 201249858 介質 時間(小時) 實例No.l化合物之面積 %之量 模擬胃液(SGF)pH2 0 95.9 1 95.5 2.5 95.3 4.2 95.6 7 95.6 禁食狀態之模擬腸液 0 95.1 (FaSSIF) pH 6.5 1 93.8 2.5 92.3 4.2 90.5 7 87.7 飽食狀態之模擬腸液 0 95.0 (FeSSIF) pH 5.8 1 94.9 2.5 94.8 4.2 94.8 7 94.8 實例No.3化合物(游離形式/乙酸鹽形式)在37°C下於模擬 胃液及腸液中之穩定性: 介質 時間(小時) 游離形式 實例No.3化合物 之面積%之量 乙酸鹽 實例No.3化合物 之面積%之量 模擬胃液(SGF) 0 98.8 100 pH 2 1 98.6 96.4 2.5 98.1 93.2 4 97.9 92.4 7 97.9 90.0 禁食狀態之模擬 0 100 100 腸液(FaSSIF) pH 1 100 98.6 6.5 2.5 100 98.7 4 90.7 95.1 7 82.5 88.5 飽食狀態之模擬 0 100 100 腸液(FeSSIF) pH 1 100 99.1 5.8 2.5 100 98.9 4 99.2 98 7 98.7 97.5 163746.doc -31 - 201249858 實用性部份 本發明化合物通常適用於預防或治療受PKc或其它激酶 之介體影響的病症或疾病,例如由T淋巴細胞、B淋巴細 胞、肥大細胞、嗜伊紅細胞或心肌細胞介導之疾病或病 症,因此其適應症為器官或組織同種移植或異種移植之急 性或慢性排斥、移植物抗宿主疾病、宿主抗移植物疾病 動脈粥狀硬化、腦梗塞、由於血管損傷(諸如血管成形術) 之也管阻塞、再狹窄症、纖維化(尤其係肺纖維化及其它 類型之纖維化,諸如腎纖維化)、血管新生、高血壓、、心 臟衰竭、慢性阻塞性肺部疾病、CNS疾病(諸如阿茲海默症 或肌萎縮性脊髓側衾硬化症)、癌症、傳染性疾病(諸如 AIDS、敗血性休克或成人呼吸窘迫症候群)、局部缺血/再 灌注損傷(例如心肌梗塞、中風、腸缺血、腎衰竭或出血 性休克)或創傷性休克。 本發明化合物亦適用於治療及/或預防急性或慢性發炎 性疾病或病症或自體免疫疾病,例如類肉瘤病、肺纖維變 性、特發性間質性肺炎、障礙性氣管疾病(包括諸如氣 喘、内因性哮喘、外因性哮喘、塵埃性哮喘、尤其係慢性 或頑固哮喘(例如晚期哮喘及氣道高反應性)、支氣管炎(包 括支氣官性哮喘、小兒哮喘)之病狀)、類風濕性關節炎、 骨關節炎、全身性紅斑狼瘡、狼瘡性腎病综合症、橋本氏 曱狀腺炎 '多發性硬化、重症肌無力症、第I型糖尿病及 與此相關之併發症、第„型成年人發病型糖尿病、葡萄膜 炎、腎病症候群、類固醇依賴性及類固醇抗性腎病、掌跛 163746.doc
(S -32- 201249858 膿皰病、過敏性腦脊髓炎、腎小球腎炎、牛皮癬、牛皮癣 關節炎、異位性濕疹(異位性皮炎)、過敏性接觸性皮炎、 刺激性接觸性皮炎及進一步濕疹性皮炎、脂溢性皮炎、扁 平台癖、天皰瘡、大皰性類天皰瘡'大疱性表皮鬆懈、蓴 麻疹、血官性水腫、血管炎、紅斑、皮膚壞死性嗜伊紅血 球增多、痤瘡、斑禿、嗜伊紅細胞筋膜炎、動脈粥狀硬 化、結膜炎、角膜結膜炎、角膜炎、春季結膜炎、與貝切 特氏病相關之葡萄膜炎、皰疹性角膜炎、圓錐形角膜、修 格連氏症候群、角膜上皮營養不良、角膜白斑、眼天疱 瘡、莫倫氏潰瘍、鞏膜炎、葛瑞夫茲氏眼病、嚴重眼内發 炎 '黏膜或血管發炎(諸如白三烯B4介導之疾病、胃潰 瘍、缺血性疾病及血栓形成所導致之血管損傷)、心臟肥 大、缺血性腸疾、發炎性腸病(例如克羅恩氏病或潰瘍性 結腸炎)、壞死性小腸結腸炎、腎疾病(包括間質性腎炎、 古德巴斯德症候群、溶血性尿毒综合症及糖尿病性腎 病)、神經疾病(選自多發性肌炎、格-巴二氏症候群、美尼 爾氏病及神經根病變)、膠原病(包括硬皮病、韋格納肉芽 腫及修格連氏症候群)、慢性自體免疫肝病(包括自體免疫 !生肝炎、原發性膽汁性肝硬化及硬化型膽管炎)、部份肝 切除、急性肝壞死(例如毒素、病毒性肝炎、休克或缺氧 症所導致壞死)、肝硬化、猛爆型肝炎、膿皰型牛皮癬、 貝切特氏病、慢性活動型肝炎、伊文氏綜合症、花粉症、 特發f·生田甲狀腺機能減退、艾迪生㉟、自體免疫萎縮性胃 九、狼瘡樣肝炎、腎小管間質性腎炎、膜性腎炎或風濕 163746.doc -33· 201249858 執。 本發明化合物亦可適用於治療腫瘤,例如乳癌、泌尿生 殖腫瘤、肺癌、胃腸癌、類上皮癌、黑色素瘤、卵巢癌、 胰腺癌、神經胚細胞瘤、頭及/或頸癌或膀胱癌,或廣而 言之腎癌、腦癌或胃癌,特定言之(i)乳癌;表皮瘤(諸如 頭表皮及/或頸表皮瘤或口腔腫瘤);肺癌(例如小細胞或非 小細胞肺癌”胃腸腫瘤(例如結腸直腸癌);或泌尿生殖腫 瘤(例如前列腺腫瘤(尤其係激素難治療性前列腺腫瘤)); 或(11)難用其它化學治療劑治療之增生性疾病;或㈣由於 夕重抗藥性而難用其它化學治療劑治療之腫瘤。 化合物亦可有效治療血液及淋巴系統的腫瘤(例如何傑 金氏病、非何傑金氏淋巴瘤、伯基特氏淋 關淋巴瘤、惡性免疫增生疾病、多發性骨_、惡性::: 胞腫瘤、淋巴細胞性白血病、急性或慢性骨髓性白血病、 急性或慢性淋巴細胞性白血病、單核細胞性白血病、其它 特定細胞類型之白血病、非特^細胞類型之白血病、其它 及非特定淋巴、造血及相關組織之惡性腫瘤(例如彌散性 大細胞淋巴瘤、丁細胞淋巴瘤或皮膚了細胞淋巴瘤》。骨髓 性癌包括(例如)急性或慢性骨髓性白血病。 另外或此外’若提及腫瘤、 含原始器官或組織及/或任何 瘤及/或轉移之位置。 腫瘤疾病、癌或癌症,亦隱 其它部位中之轉移,無論腫 較佳地,本發明化合物尤其適 _,,ππ獠由丁淋 胞”導之疾病或病纟,諸如器官或組織同種移植或異 163746.doc -34· 201249858 之〜、/·生或it性排斥、移植物抗宿主疾病、宿主抗移植 j病夕發性硬化、牛皮癖或類風濕性關節炎。 藥品之生物利用率不良係極其常見之醫藥有效成份之限 制因素。而且生物利用率可能與物種有關。例如’ 一種被 机大鼠或狗等等體内吸收良好之藥品可能不能轉化為 人類之適當生物利用率。本發明藉由提供式⑴化合物之前 f,為其母體化合物產生良好生物利用率而解決這個問 題’尤其係在人類體内。々,丨a , ^ 内例如,如貫驗部份所顯示的,實 例1化合物被轉化為實例3化合物,在投藥不久後,其可於 企液中作為主要組份被檢測到(例如約—小時後),因此證 明轉化為母體化合物之有效性及及有利性。 對於以上用途,所需劑量自然將隨投與方式、待治療之 特定病狀及所需效果而不同…般而言,mo_25 mg/kg體重之曰劑量全身投藥時可得到滿意結果。較大型 哺乳動物(例如人類)所需之日劑量通常宜投與約0.2 mg至 約“的範圍内,例如’以—天多達四次分次或以延遲形 式給樂。口服投與之合適單位劑型通常可包含約(U至500 mg活性成份。 本發明化合物可依任何傳統途役投與,特定言之,非經 腸式’例如以注射溶液或懸浮液之形式;經腸式,例如口 服’例如以鍵劑或膠囊之形式;局部式,例如以洗劑、凝 膠、軟膏或乳霜之形式;或以鼻劑或栓劑之形式。例如可 局部投與至皮膚。另-局部投與形式可以投與眼部。包含 163746.doc •35· 201249858 本發明化合物與至少 結合之醫藥組合物可依傳統 接受之載劑或稀釋劑混合 、 劑 方法,藉由與一種醫藥學上可 :醫藥學上可接受之載劑或稀釋 而製備 本發明化合物可呈游離 呈水合物形式投與,例如f或呈醫藥學上可接受之鹽或 可依傳統方法製備,且通常二上所示者。此等鹽或水合物 之活性。 ”可顯示與游離化合物相同等級 依照刖文,本發明亦提供: ⑴-種本發明化合物或其醫藥學上 物,供用作醫藥; a或水合 ⑺-種本發明化合物或其醫藥學上可接受 物,供用作PKC抑制劑,例如 ‘或水。 定適應症; -用於上文k出的任何特 (3)一種醫藥組合物,例 —%庙e 例如.供用於上文提出的任何特 疋適應症’該醫藥組合物包 餘士政n 學上可接受之物或其醫藥 h /、一種或多種其醫藥學上可接 又之稀釋劑或載劑; 種治療或預防受PKC活化作用影響或相關之疾病或 驻’》例如.供治療需要之個體之上文提出的任何 甘^適應症,其包括向個體投與有效量之本發明化合物或 ,、醫藥學上可接受之鹽或水合物; ()種本發明化合物或其醫藥學上可接受之鹽或水合 用途供製備用以治療或預防PCK活化起作用或相關 163746.doc •36· 201249858 之疾病或病狀之藥物;例如如上所指出的。 組合物 本發明化合物可作為唯一活性成份或與(例如作為佐劑 的)其它藥品(例如免疫抑制或免疫調節療法或其它抗炎劑) 起投與,例如:供治療或預防同種移植或異種移植之急 性或慢性排斥或發炎性或自體免疫病狀,化學治療劑或抗 傳染劑(例如抗病毒劑,諸如(例如)抗逆轉錄病毒劑或抗生 素)。 例如,本發明化合物可與下列組合使用:鈣調神經磷酸 酶抑制劑(例如環孢菌素A、ISA2474 FK5〇6) ; 制 劑(例如雷帕黴素、40-0-(2-羥乙基)_雷帕黴素、ccn79、 • ABT578、TAFA-93、AP23573、AP23464、AP23841、 bi〇Iimus-7或biolimus-9);具有免疫抑制特性之子囊黴素 (例如ABT-281、ASM981等);皮質類固醇;環磷醯胺;硫 °坐°示吟’甲知嗓吟,來I米特;味。坐立賓;黴紛酸或鹽; 黴酚酸酯;15-去氧斯匹胍素(15_de〇xysperguaHne)或免疫 抑制相似物’類似物或其衍生物;PKC抑制劑(例如w〇 02/38561或W0 03/82859所揭示的,例如實例56或7〇之化 合物);S1P受體激動劑或調節劑(例如FTY720,視情況經 磷酸化或其類似物,例如2-胺基_2-[4·(3-苄氧基苯硫基)_2_ 氣苯基]乙基-1,3-丙二醇,視情況經鱗酸化或1_{4-[ 1-(4-環 己基-3-三氟甲基-苄氧基亞胺基)-乙基]_2-乙基-苄基卜氮雜 環丁烷-3 -羧酸或其醫藥學上可接受之鹽);免疫抑制性單 163746.doc -37· 201249858 株抗體(例如針對白血球受體之單株抗體,例如MHC、 CD2、CD3、CD4、CD7、CD8、CD25、CD28、CD40、 CD45、CD52、CD5 8、CD80、CD86或其配體);其它免疫 調節性化合物,例如具有至少一部份CTLA4之細胞外結構 域或其突變型之重組結合分子,例如連接至非-CTLA4蛋 白序列之至少CTLA4之細胞外部份或其突變型,例如 CTLA4Ig(例如指定ATCC 68629)或其突變型(例如 LEA29Y);黏附分子抑制劑(例如LFA-1拮抗劑、ICAM-1 或-3拮抗劑,VCAM-4拮抗劑或VLA-4拮抗劑,(例如那他 珠單抗(ANTEGREN®)));或抗趨化激素抗體或抗趨化激 素受體抗體或低分子量趨化激素受體拮抗劑(例如抗MCP-1 抗體)。 本發明化合物亦可與其它抗增殖劑組合使用》此類抗增 殖劑包括(但不限於): (i) 芳香酶抑制劑,例如類固醇、尤其係依西美坦及福美 斯坦及,特定言之非類固醇,尤其係安魯米特、伏氯唑、 法屈。坐、阿那曲。坐及特別係來曲β坐; (ii) 抗雌激素,例如它莫西芬、氟維司群、雷洛昔芬及 雷洛昔芬鹽酸鹽; (iii) 拓撲異構酶I抑制劑,例如拓撲替康、伊立替康、9-硝基喜樹鹼及喜樹鹼巨分子共軛物PNU-166148 (WO99/17804之化合物 A1); (iv) 拓撲異構酶II抑制劑,例如蒽環類阿黴素(包括微脂 163746.doc -38 - 201249858 體調配物,例如CAELYX™)、表柔比星、伊達比星及奈莫 柔比星、蒽醌米托蒽醌及洛索蒽醌,及鬼臼素依託泊苷及 替尼泊苷; (v) 微管活性劑’例如紫杉烷太平洋紫杉醇及多烯紫杉 醇、長春花生物鹼,例如長春花鹼,尤其係長春花鹼硫酸 鹽’長春新驗’尤其係長春新鹼硫酸鹽,及長春瑞濱、盤 皮海綿内酯(discodermolide)及埃坡黴素,諸如埃坡黴素3 及D ; (vi) 烧化劑’例如環磷醢胺、異環磷醯胺及美法侖; (Vii)組蛋白脫乙醯基酶抑制劑; (viii)法呢基轉移酶抑制劑; (lx) COX-2抑制劑,例如塞來考昔(CeUbrex@)、羅非考 昔(Vioxx®)及羅美考昔(CC)X189); (X) MMP抑制劑; (xi) mTOR抑制劑; (XII) 抗头生性抗代謝物,例如5-氟尿嘧啶、替加氟、卡 培他凑、克拉屈濱、阿糖胞發、氟達拉賓鱗酸鹽、乳尿喷 °定核普:吉西他濱、卜疏基嗓吟、經基腺、m令、依達曲 々及此等化5物之鹽,及此外(ral^TREXedTM)、 LY23 1514 (ALIMTatmx MTA M)、LY264618 (LOMOTREXOLtm)及 OGT719 ; (XIII) 鉑化σ物,例如卡鉑、順紐及奥沙利鉑; (V)降低蛋白激酶活性之化合物及進—步抗血管生成化 163746.doc -39· 201249858
合物’例如(i)降低血管内皮生長因子(VEGF)、(b)上皮細 胞生長因子(EGF)、c-Src、蛋白激酶C、血小板衍生的生 長因子(PDGF)、Bcr-Abl酪胺酸激酶、c-kit、Flt-3及類胰 島素生長因子I受體(IGF-IR)及細胞週期素依賴激酶(cdKs) 活性之化合物;(ii)伊馬替尼、米哚妥林、IressaTM (ZD1839) ' CGP 75 166、凡他拉尼、ZD6474、GW2016、 CHIR-200131、CEP-7055/CEP-5214、CP-547632 及 KRN-633 ; (iii)沙利竇邁(THALOMID)、塞來考昔(Celebrex)、 SU5416及 ZD6126 ; (xv) 性腺釋素促效劑,例如阿巴瑞克、戈舍瑞林及戈舍 瑞林乙酸鹽; (xvi) 抗雄性激素,例如比卡魯胺(CASODEX™); (xvii) 班醯胺(bengamides); (xviii) 雙膦酸酯,例如伊替膦酸、氯曲膦酸、替魯羅 酸、帕米膦酸、阿侖膦酸、伊班膦酸、利塞膦酸及唑來膦 酸; (xix) 抗增殖抗體,例如曲妥珠單抗(Herceptin™)、曲妥 珠單抗-DM 1、厄洛替尼(Tarceva™)、貝伐單抗(Avastin™) ' 利妥昔單抗(Rituxan®)、PR064553(抗-CD40)及 2C4 抗體; (XX)替莫唑胺(TEMODAL®); (xxi)斯他;丁。 藉由代號、通用名或商標名識別之活性劑結構可取自現 163746.doc •40- 201249858 版標準綱要「默克索引(The Merck Index)」或取自資料 庫’例如專利國際(Patents International)(例如 IMS World Publication)。 依照前文’本發明進一步提供: (6) —種如上定義之方法,其包括共同投與(例如同時地 或依次地)治療有效量之a)式I化合物或其醫藥學上可接受 之鹽或水合物,及b)第二原料藥,該第二原料藥(例如)適 用於以上提出之任何特定適應症; (7) —種組合物(例如套組),其包含治療有效量之式“匕 合物或其醫藥學上可接受之鹽或水合物,及第二原料藥, 該第一原料藥(例如)如上所述。 當本發明化合物與其它免疫抑制劑/免疫調節劑、抗發 炎劑或抗癌藥物(例如如上所述)共同投與時,共同投與藥 品或藥劑之劑量自然將隨所採用之共同藥品或共同藥劑、 或所使用之特定藥品或藥劑,或所治療之病狀等等之類型 而不同。 在另一實施例中提供一種製備式⑴化合物之方法,
41 163746.doc 201249858 為 1€或(:1-4烷基;R3 為 Η、Ci.4烷基、CN、Hal或 OH ;及 R4 及R5為相互獨立的H4C1-4烷基;或R4及R5與其所附接的 碳原子一起形成3至6員環烧基,該方法包括: (a) 視情況地’對於其中R1及/或R2為氫之化合物,(例 如)利用二碳酸二-第三丁基酯在存在或不存在諸如THF或 二氣曱烧之溶劑及/或諸如三乙基胺之驗下處理式(Va)之馬 來醯亞胺’從而得到若適當時在^及/或R2上改包含第三 丁氧基羰基替代氫之式(Va)之馬來醯亞胺; (b) (例如)利用曱醛在存在或不存在溶劑及/或鹼(諸如碳 酸鉀)下處理式(Va)之視情況受保護之馬來醯亞胺,從而得 到式(Vb)之醇,其中; (c) 視情況(例如)利用三氣乙腈通常在鹼(例如DBu或三 甲胺)存在下處理式(Vb)之醇以形成反應性酯,然後利用 磷酸化劑(例如利用磷酸酯,例如利用磷酸二-第三丁基酯) 通常在鹼(例如卿或三曱胺)存在下處理,因此利用合適 酸(例如氫氯酸或TFA)在不存在或存在溶劑(諸如碰、二 氯甲烧、二氣乙烧等等)下處理所得中間物酉旨以得到按照 通式(I)之終產物’或作為替代步驟⑷ 式(vb)之醇可直接與碟酸酿(例如填酸二-第三丁基 酿)(例如)在光延反應條件下反應以得到她旨,然後其; 利用(mu乙㈣(例如)二氣甲炫中水解以得到式⑴ 163746.doc •42· 201249858
Va 2.甲醛 1.視情況進行之保護步驟
(Vc)或⑴ 【圖式簡單說明】 圖1顯示磷酸單-[3-[3-(4,7-二氮-螺[2,5]辛-7-基)-異喹啉_ 1-基]-4-(7-曱基-1H-吲哚-3-基)-2,5-二側氧基-2,5-二氫-吡 咯-1-基甲基]酯單水合物結晶之X射線繞射圖(實例No.l之 單水合物)。 圖2顯示實例No.l單水合物結晶之水吸收譜[在50% RH 下平衡6小時,然後在10% RH步驟中進行兩個自50% RH 至 90% RH至 〇% RH至 90% RH至 0% RH至 50% RH之RH循 環]。RH=相對濕度。 163746.doc -43-
Claims (1)
- 201249858 七、申請專利範圍: 1. 一種式(I)化合物或其醫藥學上可接受之鹽或水合物其中 X為CH或N ; R為 Η或 Ρ03Η2 ; R1為烷基; R2為11或(:1.4烷基; R3為 Η、Cu 烷基、CN、Hal 或 OH ;及 R4及R5為相互獨立的Η或C,.4烷基;或R4及R5與其所 附接的碳原子一起形成3至6員環烧基。 2·如請求項1之式⑴化合物或其醫藥學上可接受之略或火 合物, 其中X為CH ; R為Η ; R1為 Η ; R2為HSCm烷基; R3為11或(:1.4烷基;及 163746.doc 201249858 R4及R5為相互獨立的Η ;或R4及R5與其所附接的破原 子一起形成3至6員環烧基。 3. 如請求項1之式(I)化合物或其醫藥學上可接受之鹽或水 合物, 其中X為Ν ; R為 Ρ〇3Η2 ; R1為 Η ; R2為H或C1.4烷基; R3為Η ;及 R4及R5為相互獨立的Η;或R4及R5與其所附接的碳原 子一起形成3至6員環烷基。 4. 如請求項1之化合物,其為式(ΠΙ)化合物或其醫藥學上可接受之鹽或水合物。 5. 如請求項1或4之化合物,其為磷酸單-[3-[3-(4,7-二氮 雜-螺[2.5]辛-7-基)-異喹啉-丨_基]-4-(7-曱基-lHm3· 基)2’5 - 一側氧基-2,5-二氫比(7各基甲基]g旨單水合物。 6. 如請求項1或2之化合物’其為3·[3-(4,7-二氮雜_螺[2 5] 163746.doc 201249858 辛-7-基)-異喹啉q •基]羥甲基·4_(7-甲基-1H-吲哚·3-基)·°比D各-2,5-二酮或其醫藥學上可接受之鹽。 7. 如請求項1或3之化合物,其為磷酸單-{3-(1Η-吲哚_3_ 基)4-[2-(4-甲基-π底嗓-1 _基)_啥σ坐琳-4-基]-2,5-二側氧 基-2’5,二氫-吡咯-1-基曱基}酯或其醫藥學上可接受之 0 8. 如晴求項1至4中任一項之化合物或其醫藥學上可接受之 鹽或水合物’其係用作藥劑,特定言之用於治療受Ρκχ 或其它激酶之介體影響之病症或疾病。 9. 一種如請求項1至7中任一項之化合物或其醫藥學上可接 受之鹽或水合物之用途,其係用於製備藥物,特定言之 為有需要之個體治療或預防受PKC活化作用影響或與之 相關之疾病或病狀。 1 〇.如請求項8使用之化合物’其中該治療或預防可由τ淋巴 細胞、Β淋巴細胞、肥大細胞、嗜伊紅細胞或心肌細胞 介導’因此其適應症為器官或組織同種移植或異種移植 之急性或慢性排斥、移植物抗宿主疾病、宿主抗移植物 疾病、動脈粥狀硬化、腦梗塞、由於血管損傷(諸如血管 成形術)之血管阻塞、再狹窄症、纖維化(尤其係肺纖維 化及其它類型之纖維化’諸如腎纖維化)、血管新生、高 血壓、心臟衰竭、慢性阻塞性肺部疾病、CNS疾病(諸如 阿茲海默症或肌萎縮性脊髓側索硬化症)、癌症、傳染性 疾病(諸如AIDS、敗血性休克或成人呼吸窘迫症候群)、 163746.doc 201249858 局部缺血/再灌注損傷(例如心肌梗塞、中風、腸缺血、 腎衰竭或出血性休克)或創傷性休克。 11. 12. 13. 14. 如請求項9之用途,其中該治療或預防可由τ淋巴細胞、 Β淋巴細胞、肥大細胞 '嗜伊紅細胞或心肌細胞介導, 因此其適應症為器官或組織同種移植或異種移植之急性 或慢性排斥、移植物抗宿主疾病、宿主抗移植物疾病、 動脈粥狀硬化、腦梗塞、由於血管損傷(諸如血管成形 術)之血管阻塞、再狹窄症、纖維化(尤其係肺纖維化及 其它類型之纖維化,諸如腎纖維化)、血管新生、高血 壓、心臟衰竭、慢性阻塞性肺部疾病、CNS疾病(諸如阿 茲海默症或肌萎縮性脊髓側索硬化症)、癌症、傳染性疾 病(諸如AIDS、敗血性休克或成人呼吸窘迫症候群)、局 部缺血/再灌注損傷(例如心肌梗塞、中風、腸缺血 '腎 衰竭或出血性休克)或創傷性休克。 如請求項8使用之化合物’其中該治療或預防係指器官 或組織同種移植或異種移植之急性或慢性排斥、移植物 抗宿主疾病、宿主抗移植物疾病、多發性硬化、牛皮癖 或類風濕性關節炎。 如請求項9之用途,其中該治療或預防係指器官或組織 同種移植或異種移植之急性或慢性排斥、移植物抗宿主 疾病、宿主抗移植物疾病、多發性硬化、牛皮癬或類風 濕性關節炎。 一種組合物(例如套組),其&含治療有效量之請求項!至 163746.doc 201249858 7中任一項之化合物或其醫藥學上可接受之鹽或水合 物,及第二原料藥。 15. —種磷酸單-[3-[3-(4,7-二氮雜-螺[2.5]辛_7_基)_異啥 琳-1-基]-4-(7-甲基-1H·0弓丨》朵-3-基)-2,5-二側氧基_2 $ _ 氩-吡咯-1·基曱基]酯之結晶形式,尤其係單水合物,其 X-射線粉末繞射圖較佳在以下2Θ折射角(各±0.2,尤其描f 述於圖1及/或表1中者)中出現至少一個,較佳兩個,更 佳三個’甚至更佳四個,尤佳五個’最佳所有波峰. 9.525、16.356、17.091、18.005、20.859。 16· —種製備如請求項1所定義之式⑴化合物之方法,其中X為CH或N ; R為 Η或 Ρ03Η2 ; R1為H$C1.4烷基; R2為1^或(:|-4烷基.; R3為 Η、Cm 烷基、CN、Hal或 OH ;及 R4及R5為相互獨立的hSCm烷基;或R4及R5與其所 附接的碳原子一起形成3至6員環烷基, 該方法包括: I63746.doc 201249858 ()視It况地,對於其中幻及/或尺2為氫之化合物, TH利用一碳酸二_第三丁基酯在存在或不存在諸如 THF或二氣甲烧之溶劑及/或諸如三乙基胺之驗下,處 式(Va)之馬來酿亞胺,從而得到若適當時在R1及/或 上改包含第二丁氧基羰基替代氫之式(Va)之馬來酿 亞胺; (b) 例如利用甲醛在存在或不存在溶劑及/或鹼(諸如 下處理式(va)之視情況受保護之馬來醯亞胺, 從而得到式(Vb)之醇,其中r=h ; (c) 視情況(例如)利用三氣乙腈,通常在鹼(例如DBU 或二甲胺)存在下處理式(Vb)之醇,以形成反應性酯, 然後利用磷酸化劑(例如利用磷酸酯,例如利用磷酸 二-第三丁基酯),通常在鹼(例如DBU或三甲胺)存在 下處理’因此利用合適酸(例如氫氣酸或TFA)在不存 在或存在溶劑(諸如THF '二氣曱烷、二氣乙烷等等 下處理所得中間物酯,以得到通式⑴終產物,或作為 替代步驟(c) 式(Vb)之醇可直接與磷酸酯(例如磷酸二-第三丁基 酯)(例如)在光延反應(Mitsunobu reaction)條件下反應,以 得到稱酸酯,然後可利用(例如)三氟乙酸於(例如)二 氯曱烷中水解,得到式(I)終產物。 163746.doc 2012498581. 磷酸二·第三丁基酯 2. 水解 opo3h2R2 (Vc)或(I) I63746.doc
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