TW200800169A - Pharmaceutically active tetrahydro-pyrrolizinone compounds - Google Patents
Pharmaceutically active tetrahydro-pyrrolizinone compounds Download PDFInfo
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- TW200800169A TW200800169A TW095137242A TW95137242A TW200800169A TW 200800169 A TW200800169 A TW 200800169A TW 095137242 A TW095137242 A TW 095137242A TW 95137242 A TW95137242 A TW 95137242A TW 200800169 A TW200800169 A TW 200800169A
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- alkyl
- compound
- phenyl
- aryl
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- DYFILXZSBDRFBC-UHFFFAOYSA-N 2,3,5,6-tetrahydropyrrolizin-1-one Chemical class C1CC=C2C(=O)CCN21 DYFILXZSBDRFBC-UHFFFAOYSA-N 0.000 title abstract 2
- 239000003446 ligand Substances 0.000 claims abstract description 20
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 46
- 125000000623 heterocyclic group Chemical group 0.000 claims description 42
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 14
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Landscapes
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200800169 九、發明說明: 【發明所屬之技術領域】 本發明係關於醫藥活性四氫·吡哩酮化合物。 【先前技術】 白血球發炎性補充作用係受控於整合素與内皮細胞免疫 球蛋白總科(immunoglobulin superfamily; IgSF)蛋白(諸如 細胞間黏接分子-l(intercellular adhesion molecule-1 ; ICAM-1)、ICAM-2、ICAM-3)及IgSF成員結合黏接分子 l(junctional adhesion molecule 1 ; JAM-1)之間的動力學相 互作用,該等黏接分子經鑑別均為β(2)整合素淋巴細胞功 能相關抗原l(LFA-l)之配位基。業已發現介導(例如抑制) 與細胞黏接、遷移及活化有關之LFA_ 1與其配位基之相互 作用的化合物係為一種發炎及自體免疫性疾病之治療方 法。 現已令人驚奇地發現介導(例如抑制)與細胞黏接、遷移 及活化有關之LFA-1及其配位基之活性的化合物。 【發明内容】 在一態樣中,本發明提供一種下式之化合物:
其中 環A為下式之基團·· 114891.doc 200800169
Re
R1為
〇 R2 A5 烧基’例如(Ci.u)烧基,諸如(Ci.6)烷基,例如(cN4)烷 基;烯基,例如(c2-18)烯基,諸如(c2_6)烯基;炔基,(C2_18) 炔基’諸如(C2_4)炔基;或 經以下基團取代之烷基、烯基或炔基: -烷氧基,例如(Ci-4)烷氧基; -矽烷基或矽烷氧基,諸如三烷基矽烷基,例如三((^_6)烷 基矽烷基,諸如三曱基矽烷基或三(Cu)烷基矽烷氧基, 諸如(第三丁基)(二曱基)矽烷氧基; -環烷基,例如(c3.18)環烷基; -方基’例如(C6-18)芳基’諸如(C6-12)芳基;或 -雜環基; R2為 環烷基,例如(c3_18)環烷基; 芳基,例如(C3-18)芳基,諸如(C6-12)芳基;或 雜環基; R3為氫或視情況經取代之 114891.doc 200800169 -烷基,例如(c^)烷基;烯基,諸如(c2-8)烯基;炔基,諸 如(C2-8)炔基;例如未經取代之烷基、烯基或炔基,或經 取代之烷基、烯基或炔基,諸如 -經以下基團取代之烷基、烯基或炔基·· -環烷基,例如(c3.18)環烷基; -芳基,例如(C^8)芳基,諸如((:6·12)芳基;或 _ -雜環基; 二烧基砍烧氧基’例如三(c1-6)烧基石夕烧氧基;ν3 ;胺 基;烷基胺基,諸如(Cr·8)烷基胺基;二烷基胺基,諸如 (Ci_8)二烧基胺基;環烧基胺基,諸如(c3_8)環烧基胺基; 醯胺基,例如包括:(C2_u)醯胺基,諸如(Cb8)烷基羰胺 基、(Cw2)芳基羰胺基、(c3-8)環烷基羰胺基及雜環基羰胺 基;或 (醯基)(烷基)-胺基,諸如((C2_18)醯基烷基))-胺 基,例如烷基N-甲基-N-甲基羰基-胺基、N-节基甲基 羰基-胺基、N-乙基-N-甲基羰基·胺基; 磺醯基胺基,諸如(C!·4)烷基磺醯基胺基、(C6-12)芳基磺醯 基胺基、(c3-8)環己基磺醯基胺基;或R4為包含至少一個作 為雜原子之氮原子且經由該氮原子結合至式I化合物之雜 環基;
Rs為氫,未經取代之烷基,例如(CmO烷基,諸如(Cw)烧 基,例如(Cw)烷基;烯基,例如(C2_18)烯基,諸如(c26) 烯基;炔基;(C2-U)炔基,諸如(C2_4)炔基;或經以下基團 114891.doc 200800169 取代之烷基、烯基或炔基: —燒氧基’例如(Ci-4)烷氧基; -矽烷基或矽烷氧基,諸如三烷基矽烷基,例如三(CU)烷 基石夕烧基’諸如三甲基矽烷基或三((:1-6)烷基矽烷氧基, 諸如(第三丁基)(二甲基)矽烷氧基; -環烧基,例如(C3-18)環烷基; -芳基’例如(C6-18)芳基,諸如(c6-12)芳基;或 -雜環基; R6為 〇r7 或 sr7; R7為氫、基團(so)2-R9,其中化9為(Cl-4)烷基或(c6-12)芳 基; 烧基’例如(Cb18)烷基,諸如(Cl-6)烷基,例如(Cl-4)烷 基;烯基’例如(C2-18)烯基,諸如(c2_6)烯基;炔基,(c2-18) 快基’諸如(C2_4)炔基,例如其中烷基、烯基或炔基未經 取代或經以下基團取代: -烷氧基,例如(Ch4)烷氧基; -矽烷基或矽烷氧基,諸如三烷基矽烷基,例如三(c^)烷 基矽烷基,諸如三甲基矽烷基或三(c16)烷基矽烷氧基, 例如(第三丁基)(二甲基)矽烷氧基; -環烷基,例如(C3-18)環烷基; -芳基,例如(Cku)芳基,諸如(C6-12)芳基;或 -雜環基; 或 R7為 COR8 或 CSR8 ; 114891.doc 200800169
Rs為 烷基,例如(Cms)烷基,諸如(C^)烷基,例如((^·4)烷 基;烯基’例如(C2-I8)浠基’諸如(C2_6)烯基;快基,(C2.18) 炔基,諸如(C2-4)炔基,其中烷基、烯基或炔基未經取代 或經以下基團取代: -環烷基,例如(C3-18)環烷基; -方基’例如(C6-18)方基’諸如(C6-12)芳基;或 -雜環基; _ 環烧基’例如(C3-u)環烧基;芳基,例如(c6-18)芳基,諸 如(C6_12)芳基;或雜環基; 例如其中 環烧基、芳基或雜環基未經取代或經取代,例如未經取代 或經一或多個諸如有機化學中習知之基團取代,該等基團 例如包括: 烷基,例如(C^6)烷基;烯基,諸如(c216)烯基;炔基, 籲 諸如(^2-!6)炔基;環烷基,諸如(C3-8)環烷基;芳基,諸如 苯基;芳烧基,諸如苄基;雜環基;鹵代烧基,諸如(C14) 鹵代烷基;烷氧基,諸如(Ci·8)烷氧基;芳氧基,諸如苯 氧基;侧氧基; 1 醯基,諸如(Cm)醯基,例如包括:烷基羰基,例如(Ci_4) 烧基魏基;芳基戴基,例如苯基幾基、雜環基幾基; (Cm)醯氧基,例如包括:烧基羰基氧基,例如(Ci4)烧基 羰基氧基;芳基羰基氧基,例如苯基羰基氧基;雜環基幾 基氧基; 114891.doc 200800169 胺基,諸如未經取代之胺基及經取代之胺基,例如(Cu) 烧基胺基、(Cl.6)二烧基胺基; 醯胺基,諸如(C2-13)醯胺基,包括(Ci.4)烷基胺基羰基、苯 基胺基羰基、苄基胺基羰基、雜環基胺基羰基; 石肖基’氰基,鹵素;烧基績醯基,例如(cle4)烧基績醯 基;芳基磺醯基,諸如甲苯基磺醯基;三(Ci 6)烷基矽烷 基;或三(Ci-6)矽烷氧基; 例如其中雜環基包含:
-脂族及芳族雜環基,較佳為芳族雜環基.; -3至8個環成員,諸如5至6個環成員; -1至4個選自N、〇、s之雜原子; 稠合雜環基,諸如與另一環(系統)稠合之雜環基; -其限制條件為,若I為雜環基,則該雜環基包含至少一 個作為雜原子之氮原子且經由該氮原子結合至式I化合 在化合物中,R4結合至非環A之式k環中的CH2 一:即結合至式〗之吡咯啶基環之CH2基團。 基;14)燒氧以二二心4)说基碳基’諸如甲基: 胺基-基;包含二 =/氧_ 原子之雜淨其 6個核成貝及1至4個選自N、〇、… 為芳族雜=’·例如包括芳族雜環基及脂族雜環基,⑷ 氧基。 三(Cl·6)院基錢基’.或三16)燒基石幻 114891.doc 200800169 R1較佳為: (d烧基,諸如(Cl·4)燒基,例如甲基或乙基,(心)稀 基’諸如丙稀基,例如丙締·3_基;(〇26)炔基諸如 炔基,例如丙炔基,諸如丙炔_3_基,· 其中16)烧基、(C2-6)烯基或(C2 4)快基未經取代或經以下 基團取代: •(CVu)芳基,諸如(c^2)芳基,例如苯基;
矽烷基或矽烷氧基,諸如三烷基矽烷基,例如三(Cl 6)烷 基石夕烧基,諸如三甲基石夕烧基或三(C1屬基石夕烧氧基, 例如(第三丁基)(二甲基)矽烷氧基; 例如其中芳基未經取代或經取代,例如未經取代或經取代 之(CmJ烷基、(Cw)環己基、(Ci_4)烷基羰基,諸如甲基 技基,(C!·4)烷氧基羰基,例如甲氧基羰基;鹵素;氰
基;胺基羰基;包含5至6個環成員及丨至4個選自N、〇、S 之雜原子之雜環基,例如包括芳族雜環基及脂族雜環基, 較佳為芳族雜環基;三(Ci-0)烷基矽烷基或三((:1_6)烷基矽 烷氧基, 例如I為甲基、乙基、丙稀·3-基、卜(三甲基石夕烧基)丙炔_ 3 一基或氰基苯基甲基,諸如‘氰基苯基甲基。 R2較佳為視情況經取代之芳基,例如(C6_18)芳基,諸如苯 基, 例如未經取代之芳基或經以下基團取代之芳基··烷 基’(C3-8)環己基;((:1-4)烷基羰基,諸如甲基羰基;(Ci4) 烷*氧基碳基’例如甲氧基羰基;鹵素;氰基;胺基羰基; H489l.doc 200800169 包含5至6個環成員及〗至4個選自N、〇、8之雜原子之雜環 基,例如包括芳族雜環基及脂族雜環基,較佳為芳族雜= 基;三(Cw)烷基矽烷基;或三(Ci·6)烷基矽烷氧基,·諸如 鹵素, 例如I為二鹵代苯基,諸如3,5•二氯苯基。 h較佳為氫、(c2.6)烯基、(C26)炔基或(C6 i2)芳基(c“4)烷 基, & 例如其中芳基為未經取代之芳基或經以下基團取代·· (c^6)烷基,·(C3·8)環己基;(Ci·4)烷基羰基,諸如甲基羰 基;(C!·4)烷氧基羰基,例如甲氧基羰基;鹵素;氰基; 胺基羰基,包含5至6個環成員及丨至4個選自N、〇、s之雜 原子之雜環基,例如包括芳族雜環基及脂族雜環基,較佳 為方族雜環基;三(Cw)烷基矽烷基或三(Cw)烷基矽烷氧 基; 諸如經鹵素、氰基或芳族雜環基取代之苯基, φ 例如汉3為氫;丙二烯基,例如丙-1,2-二烯基;丙炔基,例 如丙炔3 -基,苄基,氰基苯基甲基,例如氰基苯基甲 基,_代苯基甲基,例如溴苯基曱基,諸如4_溴苯基甲 基;或嘧啶幷苯基甲基。 R4較佳為 三(Cw)烷基矽烷氧基;;胺基;(Ci_4)烷基羰胺基;磺 醯基胺基,諸如(Cw)烷基磺醯基胺基;(Cm)芳基羰胺 基’ N_((C")烧基幾基)_N_((Ci 4)烧基)_胺基;N_((c“2)芳 基(Ci·4)烷基羰基)-^((c^·4)烷基)_胺基;或包含5或6個環 114891.doc -12- 200800169 成員及至夕一個氮原子且經由該氮原子結合至式i化合物 之芳族雜環基, t
例如R4為(第二丁基)(二甲基)石夕烷氧基、仏、胺基、甲基 羰胺基第二丁基羰胺基、苯基羰胺基、N—甲基羰基 甲基-胺基、N_节基甲基羰基-胺基、N-乙基善甲基羰 基-胺基、甲基磺醯基胺基或經由氮雜原子連接至式〗化合 物之未…取代或經取代之三唑基,例如經以下基團取代之 :坐基·異丁基,·異戊基;正三癸基,·環戊基;苯基;甲 氧基羰基;i-甲基-丙基羰基;異丙基羰基;十二烷基羰 基;側氧基;_素,例如碘;三((:14)燒基石夕烷基,諸如 三甲基石夕烧基;或包含5或6個環成員及1至4個(例如⑽)選 自N ' 〇、S之雜原子(例如州之芳族雜環基,諸如吼啶 基0 R5較佳為氫或經苯基取代之中苯基未經取 代或經取代,例如其巾芳為未經取代之芳基,或經以下基 團取代之芳基:(Cl_16m基;(C38)環己基;(Ci4)烧基幾 基,諸如甲基羰基;(Ci·4)烷氧基羰基,例如甲氧基羰 基,_素;氰基;胺基戴基;包含5至6個環成員及山個 、自N 〇 S之雜原子之雜環基,例如包括芳族雜環基及 脂族雜環基;三(Cl.6m基石夕烧基;或三(心)燒基錢氧 基,諸如經齒素、氰基或芳族雜環基取代之苯基, 例如為氰基笨基,諸如4_氰基苯基。 h較佳為OR7。 R7較佳為 114891.doc -13- 200800169 氫、(k8)烧基、(Cl.8)燒氧基(Ci-8)烧基、(C28)稀基、 块基 '經三心狀基钱基取代之(c28)块基、經苯基取 代之(Cw)烧基、基團(s〇)2_R9或c〇R8, 例如其中方基為未經取代之芳基或經以下基團取代:
烷基;(C3-8)環己基;(Ci_4)烷基羰基,諸如甲基羰基; Γ·4)燒氧基㈣,例如甲氧基魏基;Μ ;氰基;胺基 叛基;包含5至6個環成員及1至4個選自N、〇、s之雜原子 之雜裱基,例如包括芳族雜環基及脂族雜環基;三(Ci 6) 烧基石夕燒基,或三(Cl-6)烧基石夕烧氧基;諸如經齒素、氰 基或芳族雜環基取代之苯基, 例如〜為氫、甲基、丙烯基(例如丙烯I基)、三甲基石夕烧 基丙块基(例如I三甲基石夕燒基_丙块冬基卜氛基苯基甲 基(諸如4-氰基苯基甲基)、甲苯基項醯基或甲基幾基。
Rs較佳為(Ci-4)烷基,例如甲基。 R9=佳為(C6.12)芳基,例如苯基,諸如未經取代或經取代 之芳基,例如經(Gw)烷基取代之芳基,諸如甲苯基。 本發明包括-種式ί之化合物’其中所定義之殘基之一 者、多者或所有具有如上所定義之含義,且其他殘基具有 如上所定義之含義。 在弋I化口物中,所定義之各單一取代基可為較佳取代 基,例如,與所定義之其他取代基無關。 在另悲樣中,本發明提供一種式I化合物,其中 環A係如上所定義;
Ri為甲基 乙基、丙烯_3_基、三甲基矽烷基)丙炔基 114891.doc -14- 200800169 或氰基苯基甲基; r2為二鹵代苯基; R3為氫、丙二烯基、丙炔基、苄基、氰基苯基甲基、鹵代 苯基甲基或嘧啶幷苯基曱基; R4為(第三丁基)(二甲基)矽烷氧基、N3、胺基、甲基羰胺 基、第三丁基羰胺基、苯基羰胺基、N·曱基羰基-N-曱基-胺基、N-苄基·Ν-甲基羰基-胺基、N-乙基-N-甲基羰基-胺 基、甲基磺醯基胺基或經由氮雜原子連接至式I化合物之 經取代之三唑基,其中三唑基經以下基團取代:異丁基、 異戊基、正三癸基、環戊基、苯基、甲氧基羰基、卜甲基-丙基羰基、異丙基羰基、十二烷基羰基、側氧基、_素、 二(Ci_4)烧基;5夕燒基或吼咬基; R5為氰基苯基; 尺6為〇R7 ;且 R7為氫、甲基、丙烯基、三甲基矽烷基-丙炔基、氰基苯 基曱基、甲苯基磺醯基或甲基羰基。 在式1化合物中,取代基R4較佳處於下式中所述之位 置:
其中% A為式A1或式A2之基團之式I化合物或其中R6為羥 基、其中環A為式A3或式A5之基團之式I化合物可存在於 114891.doc -15- 200800169 化學平衡中。 在另一悲樣中,本發明提供一種選自由下列各化合物組 成之群之化合物: N-[7a_(4-氰基-节基)-6-(3,5-二氯·苯基)-7_經基_5_侧氧基_ 2,3,5,7a-四氫-1H-吡哩·2·基]-乙醯胺,諸如 N_[(2S,7aS)_7a· (4-氰基-节基)-6-(3,5-二氯-苯基)_7_羥基|侧氧基 2,3,5,7a-四氫_111-°比哩_2_基]乙醯胺; N-[7a-(4-氰基·苄基)-6-(3,5-二氯-苯基)-7_甲氧基_5_側氧 基_2,3,5,7a-四氫-1H-吡哩-2-基]_乙醯胺,諸如N-[(2S,7aS)-7a-(4-氰基·苄基)-6-(3,5-二氣·苯基)·7_ 曱氧基 _5_ 側氧基-2,3,5,7a_四氫-1Η_吡哩-2-基]乙醯胺; N-[7a-(4-氰基-苄基)-6-(3,5-二氣·苯基)-5-甲氧基-7-側氧 基-2,3,7,7a-四氳-1H-吡哩-2-基]-乙醯胺,諸如N_ [(2S,7aS)-7a-(4-氰基-苄基)-6·(3,5-二氯-苯基)_5_ 曱氧基 _7· 側氧基-2,3,7,7a-四氫_ 1Η_^哩-2-基]_乙醯胺; 7a-(4-溴-苄基)-6-(第三丁基·二甲基-矽烷氧基y_2_(3,5-: 氯-苯基)-3-甲氧基-5,6,7,7a-四氫·吼哩-1-酮,諸如 (6R,7aS)-7a-(4-溴-苄基)-6_(第三丁基-二甲基-矽烷氧基)_2· (3,5·二氯-苯基)-3 -甲氧基- 5,6,7,7a-四氫·吼哩-1 ·酮; 7a-(4-溴·苄基)-6_(第三丁基-二甲基-矽烷氧基)_2-(3,5_二 氯·苯基)-3-甲氧基_5,6,7,7a-四氫· °比哩-1-酮,·諸如 (6R,7aS)-7a-(4U基)冬(第三丁基_二甲基_石夕烧氧基)_2_ (3,5-二氯-苯基)_3-甲氧基-5,6,7,7&-四氫-°比哩-1-酮; N-[7a-(4-溴-苄基)-6-(3,5-二氯-苯基)-5-曱氧基-7-側氧基· I14891.doc -16 - 200800169 2,3,7,7a-四氫-1H-吡哩_2_基]·乙醯胺,諸如N-[(2S,7aS)-7a· (4-溴-苄基)-6-(3,5-二氯-苯基)-5·甲氧基-7-側氧基-2,3,7,7a-四氫-1Η-吡哩-2-基]-乙醯胺; 6-疊氮基-2-(3,5-二氯-苯基)-3-甲氧基-7a-(4-嘧啶-5-基-苄 基)-5,6,7,7a-四氫-吡哩-1-酮,諸如(6S,7aS)-6-疊氮基-2-(3,5-二氣-苯基)-3 -甲氧基- 7a-(4-喊咬-5-基-苄基)-5,6,7,7a- 四氫-σ比哩-l-酮;
6-(第三丁基-二曱基·矽烧氧基)-3_甲氧基-2_苯基-5,6,7,7a-四氫-σ比哩-1-酮,諸如(6R,7aS)-6_(第三丁基-二甲基-矽烧 氧基)-3-甲氧基-:2-苯基-5,6,7,7a-四氫-η比哩-1-酮及 (6R,7aR)-6-(第三丁基-二曱基-矽烷氧基)甲氧基_2-苯 基- 5,6,7,7a-四氮-σ比哩-1 -嗣; 7a-(4-溴-苄基)-6-(第三丁基-二甲基_矽烷氧基)_〖·羥基·2_ 苯基-5,6,7,7a-四氫比哩-3-酮’諸如(6R,7aR)_7a_(4| 节 基)-6-(第三丁基-二甲基-石夕燒氧基M_經基·2_苯基-5,6,7,7a-四氫-吡哩_3-酮; 6-(第三丁基-二甲基-矽烷氧基甲氧基苯基_5,6,7,7a_ 四氫-吡哩-3-酮,諸如(6R,7aR)-6_(第三丁基·二甲基-石夕烧 氧基)-1-曱氧基_2_苯基-5,6,7,7a_四氫_吡哩_3_嗣; 6-(第三丁基·二甲基_料氧基)小經基_2•苯基_5,6,7,7a_四 氫-吡哩-3-酮,諸如(6R,7aR)_6_(第三丁基_二甲基-石夕烷氧 基)]-經基-2-苯基-5,6,7,7a-四氫♦里·3_綱;或(6R,7aS)_ 6-(第三丁基-二甲基石夕烧氧基)]·__2苯基Μ,》四 氫-吡哩-3-酮; 114891.doc -17- 200800169 4-[6-(第三丁基-二曱基-矽烷氧基)_3_側氧基_2-苯基· 5,6,7,7a-四氫_3Ii_吡哩-^基氧基甲基]_苯甲腈,諸如4_ [(6R,7aR)-6-(第三丁基-二甲基_矽烷氧基>3_側氧基_2•笨 基-5,6,7,7a"四氫-3H·吡哩-1_基氧基甲基]-苯甲腈; 下式之化合物: 4 [6 (第一丁基_二甲基_矽烷氧基卜^-二側氧基_2_苯基-六
基]_苯甲腈;
氯-笨基Μ-羥基-5,6,7,7a-四氫·吡哩-3-酮,諸如(6R,7aS)-7a-(4-溴-苄基)_6-(第三丁基-二甲基-矽烷氧基兴2_(3,5_二 氯-苯基)-1·經基-5,6,7,7a-四氫-吼哩; 7a-(4-溴-苄基)-6-(第三丁基-二甲基-矽烷氧基)_2_(3,5_二 氯-苯基)-1_甲氧基_5,6,7,7a_四氫-π比哩-3-酮,諸如 (6R,7aS)-7a-(4-溪-苄基)-6-(第三-丁基-二甲基石夕烧氧基) 2-(3,5 - —氣-苯基)-1-甲乳基-5,6,7,7a-四氫比哩-3-酮; 114891.doc -18- 200800169 7a-(4-漠-节基)-6-(第三丁基-二甲基-碎烧乳基)-2-(3,5_ 一 氣-苯基)-1-(4-甲氧基-丁氧基)-5,6,7,7a-四氫-吡哩-3-酮, 諸如(6R,7aS)-7a-(4·溴-苄基)-6-(第三丁基-二甲基-矽烷氧 基)-2-(3,5-二氯-苯基)-卜(4-甲氧基-丁氧基)-5,6,7,7a-四氫-^比哩-3 -酮; 6-(第三丁基-二曱基-矽烷氧基)-1_甲氧基苯基_5,6,7,7a-四氫比哩-3 -嗣,諸如(6R,7aS)-6-(第三丁基-二甲基-石夕燒 氧基)-1-甲氧基-2-苯基-5,6,7,7a-四氫-吡哩-3-酮; 甲苯-4-石黃酸6-(第三丁基-二甲基-梦烧氧基)-3-側氧基-2-笨 基_5,6,7,7a-四氫-3H-吡哩-1-基酯,諸如甲苯-4-磺酸 (6R,7aS)-6-(第三丁基-二甲基·矽烷氧基)-3-側氧基_2_苯基-5,6,7,7a-四氫-3H·吡哩-1-基酯; 4-[6-(第三丁基-二甲基-石夕烧氧基)_3_侧氧基_2·苯基_ 5,6,7,7a-四氫-3H-吡哩-1-基氧基曱基]•苯甲腈,諸如4_ [(6R,7aS)-6-(第二丁基-一曱基_石夕烧氧基)-3-側氧基·2·苯 基-5,6,7,7a-四氫-3H-吡哩-1-基氧基甲基卜苯曱腈; 1-烯丙氧基-6-(第三丁基-二甲基-矽烷氧基苯基-5,6,7,7a-四氫-吡哩_3·輞,諸如丙氧基(第 三丁基-二曱基-矽烷氧基)-2-苯基_5,6,7,7a_四氫-吡哩_3_ 酮; 6-(第三丁基-二甲基-矽烷氧基)_2_苯基·三曱基矽烷 基_丙-2-炔基氧基)'6,7,7,_四氫_〇比〇里_3_酮,土諸: (6R’7aS)_6·(第三丁基-二甲基_石夕燒氧基)_2_苯基 基石夕烷基-丙-2-块基氧基)_5,6,7,71四氯、哩_ .一 114891.doc -19- 200800169 6-疊氮基-7a-(4·溴-苄基)-2-(3,5-二氯苯基)-i- 羥基- 5,6,7,7a_四氫_吡哩_3-酮,諸如(6S,7aS)-6-疊氮基·7a-(4->臭-卞基)-2_(3,5·^ —氣-本基)-1-經基-5,6,7,7a_四氯比哩-3 -酮; 6-胺基-7a-苄基-2-(3,5-二氯-苯基)-1_羥基_5,6,7,7a_四氫_吡 哩-3-酮,諸如(6S,7aS)-6-胺基-7a·苄基-2-(3,5-二氯-苯基)-1-經基-5,6,7,7a-四氫吼哩-3-酮; 乙酸6-乙醯胺基-7a_苄基-2-(3,5-二氣-苯基)-3-側氧基-5,6,7,7a-四氫-3H-吡哩-1-基酯,諸如乙酸(6S,7aS)-6-乙醯 胺基-7a-苄基-2-(3,5-二氯-苯基)-3-側氧基-5,6,7,7a-四氫- 3Η-σ比哩-1 -基醋; 义[7&-(4-溴-苄基)-6-(3,5-二氯-苯基)_7-羥基-5-側氧基-2,3,5,7a-四氫-1Η-吡哩-2-基]-乙醯胺,諸如 N-[(2S,7aS)-7a-(4-溴·苄基)-6(355-二氯·苯基)-7_羥基-5-側氧基-2,3,5,7a- 四鼠_lHσ比哩-2基]-乙酿胺; 1^-[7&-(4-溴-苄基)-6-(3,5-二氣-苯基)-7-曱氧基-5-側氧基-2,3,5,7a-四氫-1H-吼哩-2-基]-乙醯胺,諸如 N-[(2S,7aS)-7a-(4-溴-苄基)·6-(3,5-二氯-苯基)-7-甲氧基-5-側氧基-2,3,5,7a-四氫-1H-吡哩-2·基]-乙醯胺; 6 -疊氮基·2-(3,5_二氯-苯基)-1_曱氧基_7a_(4 -哺唆-5-基-节 基)-5,6,7,7a-四氫-吡哩-3-酮,諸如(6S57aS)-6-疊氮基-2-(3,5-二氣-苯基)-1-甲氧基-7a-(4-嘧啶-5·基-苄基)-5,6,7,7a· 四氫比哩-3-_ ; 6-(第三丁基-二甲基-石夕烧氧基)-2-(3,5-二氯-苯基)-7 a·丙- 114891.doc -20- 200800169 1,2-二烯基_5,6,7,7玨-四鼠-11比哩-3-_,諸如(6反,7&11)-6-(第 三丁基·二曱基-矽烷氧基)_2_(3,5-二氯-苯基)-7a-丙_1,2-二 稀基-5,6,7,7&-四氫_吨哩-3-酮; 6-(第三丁基-二曱基-矽烷氧基)_2_(3,5_二氣-苯基)-l-羥基-7a-丙-2-炔基 _5,6,7,7a_ 四氫-吡哩·3_酮,諸如(6S,7aS)-6-(弟二丁基-一甲基-石夕烧氧基)-2-(3,5-二氣-苯基)-1-經基_ 7a-丙-2-炔基- 5,6,7,7a-四氫·吼哩_3_g同; 下式之化合物:
下式之化合物: 11489l.d〇c -21 - 200800169
EX40
H,C h3c、
CHU 諸如下式之化合物
HX
EX40-S 下式之化合物: CH. H3C火 hue CH.
CH 3 •Si、 ΈΧ41
CH 2 諸如下式之化合物 h3c
下式之化合物:
3 H c 3 I 3 H L H c——si——c EX42
Η c 3 I 3 Η 1 Η c——sic EX42-S ό 諸如下式之化合物 ό 114891.doc -22- 200800169 下式之化合物:
4-[2-@氮基-6-(3,5-二氯-苯基)-7_經基_5_側氧基_2,3_二氮-111,51^比哩七-基曱基]-苯?腈,諸如4七28,7吻_2_疊氮 基冬(3,5-二氯-苯基)_7-經基_5-側氧基'2,3_二氮_ih,5h“比 哩_7a_基曱基]•苯甲腈; 4- [2-胺基-6-(3,5-二氯-苯基)-7-甲氧基_5_侧氧基-2,3-二氫_ 1H,5H-吡哩-7a-基甲基]-苯曱腈,諸如‘[(2S,7aS)_2-胺基_ 6-(3,5·二氯-苯基)_7_甲氧基側氧基_2,3_二氫_1Η,5Η_< 哩-7a-基甲基]-苯甲腈; N-[7a-(4-氛基-节基)·6-(3,5-二氯·笨基)_7•甲氧基士側氧 基-2,3,5,7a-四氯-1Η-吼哩-2-基]•甲烷磺醯胺,諸如斗 [(2S,7aS)-7a-(4-氰基-节基)-6_(3,5-二氣.苯基)·、甲氧基 _5-侧氧基-2,3,5,7a_四氫·1Η-。比哩-2-基]_甲烷磺醯胺; N-[7a-(4-氰基-苄基)-6-(3,5-二氯_苯基)_、曱氧基_5_側氧 基-2,3,5,7a_四氫_1H-呲哩-2-基μ2,2-二甲基_丙醯胺,諸如 N-[(2S,7aS)-7a♦氰基-节基Κ(3,5_二氯_苯基)小甲氧基_ 5- 側氧基-2,3,5,7a-四氫-1Η-吡哩; 114891.doc -23- 200800169 N-[7a-(4-氰基-苄基)-6-(3,5-二氯_苯基)-7_曱氧基-5-側氧 基-2,3,5,7a·四氫-1H_吡哩-2-基]-苯甲醯胺,諸如N- [(2S,7aS)-7a-(4-氰基-苄基)-6-(3,5-二氯-苯基)-7-甲氧基-5- 侧氧基-2,3,5,7a_四氫_1H-吡哩-2-基]-苯甲醯胺; N-[7a-(4-氰基_苄基)-6-(3,5-二氯-苯基)_7_甲氧基_5_側氧 基-2,3,5,7a-四氫_1H-咄哩-2_基]甲基-乙醯胺,諸如N-[(2S,7aS)-7a-(4-氰基·节基)-6-(3,5_二氯-苯基)_7·曱氧基-5-侧氧基-2,3,5,7a-四氫-1H-吡哩基]-N-甲基-乙醯胺; 4- [2-乙醯胺基-6-(3,5-二氣-苯基)_7_甲氧基-5-側氧基-2,3- 二氫-1H,5H-口比哩-7a-基甲基]•苯甲醯胺,諸如4_[(2S,7aS)_ 2-乙醯胺基-6-(3,5-二氯-苯基)-7_曱氧基_5_側氧基_2,3·二 氫_1Η,5Η-吼哩-7a-基甲基]-苯甲醯胺; N-苄基·Ν-[7α-(4-氰基-节基)冬(3,5_二氯-苯基)-7·甲氧基- 5- 侧氧基-2,3,5,7a-四氫-1H-吼哩-2-基]·乙醯胺,諸如N_苄 基仏[(28,7&8)-7&_(4-氰基-节基)_6-(3,5_二氯-苯基)-7-甲氧 基-5-侧氧基-2,3,5,7a·四氫-lH-σ比哩-2-基]-乙醯胺; N-[(7a-(4-氰基-苄基)-6-(3,5-二氯·苯基)-7-甲氧基-5-側氧 基_2,3,5,7&-四氫_111-吼哩_2-基]-:^-乙基-乙醯胺,諸如;^-[(2S,7aS)-7a-(4·氰基-节基)_6-(355-二氣-苯基)-7-曱氧基-5- 侧氧基-2,3,5,7a_四氫·lH-吡哩-2-基]N-乙基-乙醯胺; W7a-(4-氰基苄基)冬(3,5-二氯-苯基)_7_曱氧基-5-側氧 基-2,3,5,7a-四氫-1Η·°比哩-2·基]-1H-[1,2,3]三唾-4-魏酸甲 酯’諸如1-[(28,7&8)-73-(4-氰基-苄基)-6-(3,5-二氯-苯基)-7-甲氧基-5-側氧基-2,3,5,7a-四氳-1H-吼哩基]-1H- 114891.doc -24- 200800169 [1,2,3]三唑-4-羧酸曱酯; 4-[6-(3,5-二氯-苯基)-7-甲氧基-5-側氧基-2-(4-苯基-[1,2,3] 三唑-1-基)-2,3-二氫吡哩-7a-基曱基]-苯曱腈,諸 如4-[(28,7&8)-6-(3,5-二氯-苯基)-7-甲氧基-5-側氧基-2-(4-苯基-[1,2,3]三唑-1-基)-2,3-二氫-1H,5H-吡哩-7a-基甲基]-苯甲腈; 4-{6-(3,5-二氯-苯基)-2-[5-碘-4-(3-甲基-丁基)-[1,2,3]三唑-1-基]-7·甲氧基-5-側氧基-2,3_二氳-1H,5H-吡哩-7a-基甲 • 基}-苯甲腈,諸如 4-{(2S,7aS)-6-(3,5-二氯-苯基)-2-[5-碘- 4 - ( 3 -甲基丁基)-[l,2,3]二ϋ坐-l-基]-7-甲乳基-5-侧乳基_2,3-二氫-lH,5H-吡哩_7a-基曱基}苯甲腈; 4-{(2S,7aS)-6-(3,5-二氯-苯基)-7-甲氧基-2-[4-(3-曱基-丁酿 胺)-[1,2,3]三唑-1-基]-5-側氧基-2,3-二氫-1H,5H-吡哩-7a-基甲基}-苯甲腈,諸如4-{(2S,7aS)-6-(3,5-二氯-苯基)-7-甲 氧基-2-[4-(3 -甲基-丁酿胺)-[1,2,3]二唾-1-基]-5-側氧基_ ^ 2,3-二氫吡哩-7 a·基甲基}-苯甲腈; 4-{(28,7&8)-6-(3,5-二氯-苯基)-7-甲氧基-2-[4-(3-曱基-丁 基)-[1,2,3]三唑-1-基]-5-側氧基-2,3-二氫-1H,5H-吡哩-7a-基甲基}-苯甲腈,諸如4-{(2S,7aS)-6-(3,5-二氯-苯基)-7-甲 氧基-2-[4_(3-甲基·丁基)·[1,2,3]三唑·1_基]-5-側氧基-2,3-二氫-1Η,5Η-。比哩-7a·基甲基}-苯甲腈; 4-{6-(3,5-二氣-本基)-2-[5 -埃-4-(3·甲基-丁酸胺)-[1,2,3]三 唑-1-基]-7-甲氧基-5-側氧基-2,3-二氫-1Η,5Η-吡哩-7a-基甲 基}-苯甲腈,諸如 4-{(2S,7aS)-6-(3,5-二氣-苯基)-2-[5-碘- 114891.doc -25- 200800169 4-(3-甲基-丁醯胺)-^3]三唑d•基]·7_甲氧基_5_側氧基_ 2,3-二氫-1Η,5Η “比哩_7a-基甲基卜苯甲腈; 4-[6-(3,5-二氯-苯基)_2-(5-碘-4·三甲基矽烷基_[i,2,3]三唑-1-基)-7-甲氧基-5-側氧基-2,3·二氫-1Η5:5Η-吡哩_7a•基甲 基]-苯甲腈,諸如4_[(2S57aS)_6<3,5_二氯苯基)-2_(5_碘·心 三甲基矽烷基-[1,2,3]三唑·1-基)-7-甲氧基-5-側氧基-2,3- 二氫-1H,5H-吡哩-7卜基甲基]_苯甲腈; 4- [6-(3,5-二氯-苯基)-2_(5-碘[ny 三唑 基)_7·甲氧基 _ 5- 侧氧基-2,3_二氫_1Η,5Η_吡哩_7a—基曱基苯甲腈·,諸如 4-[(2S,7aS)-6-(3,5_ 二氯·苯基)-2-(5-碘-[1,2,3]三唑-1-基 > 7-甲氧基-5-侧氧基_2,3_二氫_m,5H-吡哩-7a-基甲基]•苯曱 腈; 4-[6-(3,5-二氯-苯基)_7_甲氧基-5_側氧基_2_(4_三甲基矽烷 基_[1,2,3]三唑小基>2,3·二氫-1H,5H_吡哩-7a-基曱基]-笨 曱腈’諸如4-[(2S,7aS)-6-(3,5-二氯-苯基)-7-曱氧基-5_侧氧 基-2-(4-三甲基矽烷基吋12,”三唑小基)·2,3-二氫 °比哩_7a•基甲基l·苯曱腈; 4_[6_(3,5-二氯-苯基)_7_甲氧基_5_側氧基_2气比啶-2_基_ [1,2,3]三唑-1-基)-2,3-二氫_1H,5H-吡哩-7a-基甲基]-苯甲 赌’諸如4-[(2S,7aS)-6-(3,5-二氯-苯基)-7-甲氧基-5-側氧 基-2-(4^比啶 _2_基 _[l52,3]三唑-i基)-2,3·二氫-1H,5H^比 哩_7a_基甲基]-苯甲腈; 4_[6_(3,5_二氯-苯基)_7_甲氧基側氧基-2-(4-σ比啶_3-基· [1,2,3]三唑-卜基)-2,3_二氫·m,5H·吡哩_7a基曱基 > 笨甲 114891.doc -26- 200800169 腈,諸如4-[(2S,7aS)-6-(3,5-二氯-苯基)-7-甲氧基-5-侧氧 基-2-(4-。比啶-3·基-[1,2,3]三唑-1_ 基)_2,3_ 二氫吼 哩-7a-基甲基]-苯甲猜; 4-[6·(3,5-二氣-苯基)-2-(5-碘-4-異丁 醯胺-[1,2,3]三唑-1-基)-7-甲氧基-5-側氧基-2,3-二氫-1H,5H-吡哩_7a-基甲基]-苯甲腈,諸如 4-[(2S,7aS)-6-(3,5-二氯-苯基)-2-(5-碘-4-異 丁醯胺-[1,2,3]三唑-1-基)-7-甲氧基-5-側氧基-2,3-二氫-1H,5H-吡哩-7a-基甲基]-苯曱腈; • 4-[6-(3,5-二氯-苯基)-2-(4-異丁基 _[1,2,3]三唑-1-基)-7-甲 氧基-5-侧氧基-2,3·二氫-1H,5H-吼哩-7a-基曱基]-苯甲腈, 諸如 4-[(2S,7aS)-6-(3,5-二氯-苯基)-2-(4-異丁基-[1,2,3]三 。坐-1 -基)-7 -甲氧基-5 -侧乳基-2,3 -二鼠-1Η,5 Η -π比哩-7 a -基甲 基]-苯甲腈; 4 - [ 6 - ( 3,5 ·二氣-苯基)-2-(4 -異丁 酿胺-[1,2,3]二吐-1-基)-7-甲氧基-5-側氧基-2,3·二氫-1H,5H-吡哩-7a-基甲基]-苯曱 腈,諸如 4-[(2S,7aS)-6-(3,5-二氣-苯基)-2-(4-異丁 醯胺-® [1,2,3]三唑-1-基)-7-甲氧基-5_側氧基-2,3-二氫-111,511-吡 哩-7a-基甲基]-苯甲腈; 4-[2-(4-環戊基 _5_碘-[1,2,3]三唑-1-基)_6_(3,5_二氯-苯基)-7-曱氧基-5-侧氧基-2,3_二氫-1H,5H-吡哩-7a-基曱基]-苯曱 睛’諸如 4 [ ( 2 S,7 a S) - 2 _ ( 4 -環戍基-5 ·埃-[1,2,3 ]三嗤-1 ·基)_ 6-(3,5-二氯-苯基)-7-甲氧基-5-侧氧基-2,3-二氫-111,511-吡 哩-7a-基甲基]-苯甲腈; 4-[2·(4-環戊基-[1,2,3]三唑-1-基)-6-(3,5-二氯-苯基)-7·甲 114891.doc -27 - 200800169 氧基-5-側氧基-2,3-二氫-1H,5 H-°比哩-7 a-基甲基]-苯甲猜, 諸如 4-[(2S57aS)-2_(4-環戊基-[1,2,3]三唑 _丨_基)_6_(3,5_二 氯-苯基)-7_甲氧基-5·側氧基-2,3_二氫-ih,5H-吡哩_7a_基 甲基]-苯甲腈;
4-[6-(3,5_ 二氯-苯基)-2_(5_姨 _4_ 十三燒基 _[i,2,3]三嗤 基)-7-甲氧基-5·側氧基-2,3 -二氫-1115511_°比哩-7旺-基甲美] 苯曱腈,諸如 4-[(2S,7aS)-6_(3,5-二氣-苯基)·2_(5_ 碘 _4_ 十 三烷基-[1,2,3]三唑-1-基)_7_曱氧基-5-侧氧基_2,3_二氫· 1Η,5Η_吡哩-7a-基甲基]-苯甲腈; 4-[6-(3,5 -二氯-苯基)-7-甲氧基_5-側氧基-2-(4-十三燒基_ [1’2,3]二唑-1-基)_2,3·二氫-1Η,5Η-η比哩-7a-基甲基]•苯甲 腈,諸如4-[(2S,7aS)-6-(3,5-二氯-苯基)_7·甲氧基_5_側氧 基-2-(4-十三烷基三唑·丨-基)^,^二氫_ih,5h-吡哩_ 7a-基甲基]-苯甲腈; 4-[6·(3,5·二氯·苯基)-2-(5-碘-4-十三烷醯基my三唑一^ 基)-7_甲氧基-5-側氧基-2,3-二氫吡哩-7a·基甲基]_ 苯甲猜’諸如 4-[(2S,7aS)-6-(3,5_ 二氯·苯基)_2_(5_峨_4_十 三烧酿基-[1,2,3]三唾-i-基)_7_甲氧基_5_侧氧基_2,3·二氯-1H,5H-吡哩_7a-基甲基]-苯甲腈; 及 -5-侧氧基-2,3-二氫_ 4-[璺氮基-6-(3,5-二氯-苯基)_7_甲氧基 ’諸如 4-[(2S,7aS)-2-疊氮 •側氧基 _2,3_ 二氫-1H,5H- 1H,5H_吡哩-7a-基甲基]-苯甲腈 基-6-(3,5- 一氣-苯基)-7-甲氧基 吼哩_7a-基甲基]-苯甲腈; 114891.doc -28- 200800169 諸如 N-[(2S,7aS)-7a-(4-氰基-苄基)-6·(3,5·二氣-苯基甲 氧基-5-侧氧基-2,3,5,7a·四氫_ιη_吼哩-2-基]-乙醯胺,諸如 本文實例部分(除實例3 3、3 4、3 8、3 9、44及4 5外,該等 實例係指在製備式I化合物時可用作中間物之化合物)之表i 及表2中所揭示之化合物。 本發明所提供之式I化合物在下文中稱作"本發明之化合 物丨,。
本發明之化合物包括呈任何形式之化合物,例如游離形 式、鹽形式、溶劑合物形式及鹽及溶劑合物形式。 在另一態樣中,本發明提供一種呈鹽形式之本發明之化 合物。 該等鹽較佳包括醫藥學上可接受之鹽,儘管包括醫藥學 上不可接受之鹽,例如為達製備/分離/純化之目的。 本發明之化合物之鹽包括金屬鹽或酸加成鹽。呈游離形 式之本發明之化合物可轉化成呈鹽形式之相應化合物;反 之亦然。呈游離形式或呈鹽形式且呈溶劑合物形式之轉 =合物可轉化成呈義形式或非溶麻形式之鹽形式: 相應化合物,反之亦然。 本發明之化合物及本發明之中間物可以異構體或… 構=在本Γ光學異構體、非對映異構體:順 含有二 及其混合物之料^ 構體或非對映異構體 ,, y ^ ^ 例如外消旋體。就本發日月Kb人 物之特定位置上的取代^ 不毛月之化合 代基“,本發明之化合物及本發明 11489l.d〇( -29- 200800169 之中間物可以(R)-、(S)-或(R,S)-構型、較佳以(R)_或⑻· 構型存在。舉例而言,式Al、A2、A3、A4或A5之基團中 環A之位置5上的碳原子或式I化合物中非環a之環上、义4所 連接之亞甲基’均為不對稱碳原子,且就本發明之化合物 之該等不對稱碳原子上的各取代基而言,本發明之化合物 可以(R)-、(S)-或(R,S)-構型、較佳以(r)_或⑻·構型存 在’例如就分別連接於以上指定位置之R34R4而言,本發 明之化合物可以(R)·、(S)_4(R,S)_構型、較佳以(幻_或 (S)-構型存在。 適當時,例如根據(例如類似地)習知方法,可分離異構 /心&物以獲得純異構體。本發明包括呈異構形式及呈任何 異構混合物之本發明之化合物。 本發明亦包括本發明之化合物的互變異構體,其中可存 在互變異構體。 在另一·態樣中,本發明提供一種製備式I化合物之方 法: a•製備其中環Α為式A3或Α5之基團之式I化合物,包含以下 步驟: al·使下式化合物:
其中R2、I如上所定義且r,4具有如上所定義之心之 114891.doc 200800169 含義,且R%另外為羥基、側氧基或醯氧基,例如甲 基羰基氧基,與六曱基矽氮烷鉀,(例如)於有機溶 劑中反應; a2·分離式I化合物,其中尺2、&及R,4如上所定義,且其 中Re為來自反應混合物之羥基,且視情況 a3 ·進一步使步驟a2獲得之化合物反應,以獲得式丨彳匕合 物,其中環A為式Al、A2、A3、A4或A5之基團,其 中R5、R6、尺2及尺3如上所定義且尺’4具有如上所定義 之R4之含義。 其中環A為式Al、A2或A4之基團之式I化合物可由步驟 a2所得之化合物藉由進一步與反應性衍生物反應而獲得, 該反應性衍生物例如以下各物之!|化物: 烷基,例如(CmO烧基,諸如(Cl-0)烧基,例如(Ci4)燒 基;烯基,例如(Cm)浠基,諸如(Cw)烯基;炔基;(C2 i8) 炔基,諸如(C2-4)炔基;或 經以下基團取代之烷基、烯基或炔基: -烷氧基,例如(Ci-4)烷氧基; -碎烧基或碎烧氧基,諸如二烧基;烧基,例如三(Cl 6)烧 基梦烧基’堵如二甲基梦烧基或(第三丁基)(二甲基)梦烧 氧基; -環烷基,例如(c3_18)環烷基; -芳基,例如(C6_18)芳基,諸如(C6-12)芳基;或 -雜環基。 其中R6不為羥基之式I化合物可於步驟a3中藉由進一步 114891.doc -31 - 200800169 以燒基化、醯基化、磺醯基化處理步驟a2所得之R6經基獲 得,例如根據(例如類似地)習知方法;在該反應過程中, 亦可獲得其中環A為式Al、A2或A4之式I化合物。 若式II化合物中R’4不為R4,則步驟a3(例如)可如下進 行: 例如,若R’4為醯氧基,諸如甲基羰基氧基,則醯基可(例 如)藉由酯皂化方法分裂,獲得經基; 例如,若R、為側氧基,則可將該側氧基還原為羥基; 例如,若R’4為羥基,則該羥基可進一步反應,例如矽烷基 化或經由胺、Ns或雜環基取代置換,獲得其中汉4如上所定 義之式I化合物。 如此獲得之式I化合物可轉化成另一式I化合物,例如, 或所得之呈游離形式之式〗化合物可轉化成式I化合物之 鹽,反之亦然。 在另一態樣中,本發明提供一種選自由下列各物組成之 群之化合物: 1,6-二羥基-7a·甲基-2-苯基-5,6,7,7a-四氫吡哩_3·酮,諸如 (6R,7aS)_l,6-二羥基-7a-甲基-2-苯基-5,6,7,7a-四氫 _吡哩· 3 ; 7a_(4-溴-苄基)-2-(3,5_二氯·苯基)4,6-二羥基·5,6,7,7α_四 氫-吡哩-3-酮,諸如(6R,7aS)-7a-(4-溴-苄基)-2-(3,5·二氯- 苯基)-1,6-二經基·5,6,7,7α_四氫_吼哩-3-酮; 下式之化合物: 114891.doc -32- 200800169 CN EX38
CN 下式之化合物:
CN EX39
CN
諸如下式之化合物 ΈΧ44
OH
EX44-S 及 乙酸7a-(4-氰基-苄基)-6-(3,5-二氯-苯基)-7-甲氧基-5-側氧 基-2,3,5,7a_四氫-1H-吡哩-2-基酯,諸如乙酸(S)_7a-(4_氰 114891.doc -33- 200800169 基-节基)-6-(3,5_二氯_苯基)_7_曱氧基_5_側氧基·2,3, w 四氫-1H-吡。里基醋; 5 例如可用作製備式1化合物之中間物之化合物,即本文中 亦稱作"本發明之中間物"之化合物。 式Π化合物亦可(例如)藉由使下式之化合物:
其中R3及R’4如上所定義,與活化形式之下式之化合物:
OH
,V R2 , ί 例如相應酸鹵化物,諸如酸氯化物,其中&如上所定義, 於有機溶劑中、在鹼(諸如含水碳酸氫鉀)存在下反應而獲 得。 式II化合物可(例如)藉由使下式之化合物:
其中R3及R’4如上所定義,與肆-(三苯基膦)-鈀於有機溶劑 中反應而獲得。 若式I化合物中R、不為N3或側氧基,則式V化合物可(例 如)藉由使下式之化合物: 114891.doc -34- 200800169
其中r3如上所定義,與鋅粉於冰乙酸中反應,獲得下式之 化合物:
且視情況使所得之胺基進一步反應,獲得式V化合物,其 中R3及R’4如上所定義,除RU為侧氧基外。 其中R3不為氫之式VI化合物可(例如)藉由使下式之化合 物:
ΌΗ. 0,
〇, VNiB 或 0
VIIIA 與強鹼(例如鋰-雙-三甲基矽烷基醯胺,與鋰·雙-三甲基矽 烷基醯胺)於有機溶劑中反應且以下式之化合物處理所得 混合物而獲得:
R3-Hal IX 其中除氫外,R3如上所定義,且Hal為鹵素,諸如Br。 在式 II、III、IV、V、VI 或 VII、VIIIA、VIIIB 及 IX之任 一中間物中,官能基(若存在)視情況可呈經保護形式或呈 114891.doc -35- 200800169 鹽形式(若存在形成鹽之基團)。可於適當階段移除保護基 (視情況存在),例如根據(例如類似地)習知方法。 可例如根據(例如類似地)習知方法(例如或如本文所指 定)適當地製備本文所述之任何化合物,例如本發明之化 合物及式 II、III、IV、V、VI、VII、VIIIA、VIIIB 或 IX之 中間物(起始物質)。 本發明之化合物(例如)藉由介導(諸如抑制)LFA-1與其配 位基之相互作用的活性,例如抑制LFA_1/ICAM]、LFA-l/ICAM-2、LFA-1/ICAM-3 及/或 LFA-1/JAM-1相互作用的 活性,例如LFA-1/ICAM-1相互作用,且因此介導,例如 抑制發炎,例如,如本文活體外及活體内測試系統(TEST SYSTEMS)所示,展示出有價值之藥理學性質。因此說明 本發明之化合物可用於治療。 A.活體外測試系統(無細胞檢定) 該檢定測定可溶性人類IC AM-1與固定化人類LFA-1的結 合。LFA_ 1 藉由類似於Dustin等人,J. Immunol· 148,2654-2663,1992之免疫親和層析法自JY細胞(人類淋巴母細胞b 細胞株)純化。使用 Weitz-Schmidt等人,Anal· Biochem. 23 8,184-190,1996所述之桿狀病毒系統製備ICAM-1小鼠 Ck融合蛋白(ICAM-1)。 將經純化之LFA-11:20倍稀釋於含有2 mM MgCl2、pH值 7.4之磷酸鹽緩衝生理食鹽水(PBS)中,且於37°C下塗覆於 微量滴定盤(Nunc)上,歷時3小時。於37°C下將盤以於PBS 中之1%經熱處理之牛血清白蛋白阻斷,歷時2小時,接著 114891.doc -36- 200800169 為使用?88、2 111]\4]\^(:12、1%胎牛血清、1)11值7.4(檢定緩 衝液)之洗滌步驟。將本發明之化合物(於DMSO中之i〇 mM溶液)稀釋於檢定缓衝液中,且添加至該等盤中。添加 於檢定緩衝液中之生物素標記之重組jCAMae μ§/ηι1)且 使其於37°C下結合1小時。培育後,將孔以檢定缓衝液洗 滌。添加以1:5000倍稀釋於檢定緩衝液中之抗生蛋白鏈菌 素-過氧化酶,且於37°C下培育45分鐘。將盤以檢定緩衝 液洗滌且向各孔中添加2,2,-次偶氮基-雙(3-乙基苯幷噻唑 啉-6-磺酸)二鏔鹽基質溶液。2〇分鐘後將反應終止,且藉 由於微定量盤式計數器中於405 nm量測光密度來測定經結 合之 IC AM-1。 在該檢定中,本發明之化合物展示出活性,例如本發明 之化合物抑制LFA-1與ICAM的黏著。 B·活體内測試系統過敏性接觸性皮炎(ac;d) 以5〇 μΐ嚼嗤嗣(於丙酮中之2%)於經刮腹部將各組8隻雌: 性NMRI小鼠致敏,且7天後於右耳内表面上以1〇 μΐ 〇.2% 噁唑酮攻毒。未攻毒之左耳用作常態對照,且由耳重量之 個體是異來評價皮炎,耳重量在攻毒後24小時作為發炎性 腫脹之量測稱取。以口服測試化合物(攻毒後2小時)處理測 武組,對照組單獨以媒劑類似處理。對於經口投藥而言, 化合物以於Ηβ乳液中之油投藥。於測試組及對照組中評 價皮炎。將動物殺死且將兩耳切除且稱重。以測試化合物 處理之小鼠的右耳與左耳(内部對照)與僅以媒劑處理之動 物相比較的差異來評價測試化合物之抑制活性。藉由 114891.doc -37 - 200800169 ANOVA接著藉由Dunnet T-測試(正態分佈或數據)或分別藉 由Η -測試及U -測試來分析測試組及媒劑處理對照之數據。 本發明之化合物抑制基於耳重量差異之過敏性接觸性皮炎 之引發階段 因此說明本發明之化合物可用於治療或預防病症,包括 由參與細胞黏接、遷移及活化iLFAq及其配位基之相互 作用介導之疾病。本發明之化合物較佳可用於治療或預防 發炎病況、過敏性疾病、自體免疫性疾病、聲植排斥反 _ 應、抗增生性或感染性疾病。 已包括由LFA-1及其參與細胞黏接、遷移及活化之配位 基之相互作用介導之疾病包括例如: -與發炎相關之病症 例如包括(慢性)發炎性病症、例如支氣管炎之與支氣管 發炎有關之病症、例如子宮頸炎之與子宮頸發炎有關之病 症、例如結膜炎之與結膜發炎有關之病症、例如食道炎之 φ 與食道發炎有關之病症、例如心肌炎之與心肌發炎有關之 病症、例如直腸炎之與直腸發炎有關之病症、例如鞏膜炎 之與鞏膜發炎有關之病症、與齒齦發炎有相關之病症、包 括與骨發炎有關之病症、肺部發炎(肺泡炎)、例如哮喘(諸 如支氣管哮喘、急性呼吸窘迫綜合症(ARDS)於氣道發炎 性管之病症、發炎性皮膚病症(諸如接觸性過敏、(過敏性) 接觸性皮炎、異位性皮炎)、纖維化疾病(例如肺部纖維 化)、腦炎、發炎性骨質溶解; -與免疫系統之病況相關之病症 114891.doc -38 - 200800169 免疫疾病,諸如自體免疫性疾病,例如包括格拉夫 (Grave)氏疾病、橋本(Hashimoto)氏疾病(慢性曱狀腺炎)、 多發性硬化症、類風濕性關節炎、關節炎、痛風、骨關節 炎、硬皮病、狼瘡症候群、全身性紅斑狼瘡、休格連 (Sjoegren)氏症候群、牛皮癖;發炎性腸疾病,包括克羅 恩(Crohn)氏疾病、例如潰瘍性結腸炎之結腸炎;敗血症、 敗血性休克、自體免疫性溶血性貧血(AHA)、自體抗體誘 發之蓴麻疹、天疱瘡、腎炎、絲球體腎炎、肺出血腎炎綜 合症、強直性脊椎炎、萊特爾(Reiter)氏綜合症、多發性 肌炎、皮膚肌炎、細胞激素介導之毒性、介白素毒性; 禿頭症,例如斑禿、發生長;葡萄膜炎、扁平苔蘚、大皰 性類天疱瘡、重症肌無力、I型糖尿病;免疫介導之不孕 症,諸如早發性卵巢衰竭;多腺性衰竭、甲狀腺功能低 下、尋常天疮瘡、落葉型天疮瘡(pemphigus 1-oliaceus)、 副腫瘤性天疱瘡;自體免疫性肝炎,包括B型肝炎病毒 (HBV)及C型肝炎病毒(HCV)相關之自體免疫型肝炎;阿狄 森(Addison)氏病;自體免疫性皮膚疾病,諸如牛皮癣、疱 疹樣皮膚炎、大皰性表皮松解症、線狀IgA大皰性皮病、 獲得性大皰性表皮松解症、兒童慢性大皰性皮膚病;惡性 貧血症、溶血性貧血、白斑病、Z型、π型及ΠΙ型自體免疫 性多腺體綜合症、自體免疫性副甲狀腺低能症、自體免疫 性垂體炎、自體免疫性卵巢炎、自體免疫性睾丸炎、妊娠 性類天疱瘡、瘢痕性類天疱瘡、特發性混合性冷球蛋白血 症、免疫性血小板缺乏紫斑症、古德巴斯德氏 114891.doc -39- 200800169 (Goodpasture)症候群、自體免疫性嗜中性白血球過低症、 重症肌無力細合症、僵人綜合症、腦脊髓炎、急性散播性 腦脊髓炎、格林-巴利(Guillain-Barre)綜合症、小腦變性、 視網膜病、原發性膽管硬化、硬化性膽管炎、自體免疫性 肝炎、麩質過敏性腸病、反應性關節炎、多發性肌炎/皮 肌炎、混合性結締組織病、白塞(Bechet)氏綜合症、結節 性多動脈炎、過敏性脈管炎(anguitis)及肉芽腫病(徹奇-斯 全司(Churg_Strauss)疾病)、重疊症候群、(過敏性)脈管 炎、韋袼納(Wegener)氏肉芽腫、顳動脈炎、川崎 (Kawasaki)氏疾病、肉狀瘤病、寒冷病、乳糜瀉; -與細胞激素介導之毒性相關之病症 例如包括介白素-2毒性; -與骨相關之病症 例如包括骨質疏鬆症、骨關節炎; -與大腦及神經相關之病症 神經退化性疾病,例如包括中樞神經系統之病症以及末 梢神經系統之病症,例如CNS病症,包括中樞神經感染、 腦損傷、腦血管病症及其後果、帕金森(Parkins〇n)氏疾 病、皮貝基底核退化症、運動神經元疾病;癡呆,包括 ALS、多發性硬化症;創傷性病症,包括外傷及外傷發炎 性後果、創傷性腦損傷、中風、中風後腦損傷、創傷後腦 損傷, 小血官腦血管疾病、進食障礙;其他癡呆,例如包括阿 兹海默(Alzheimer)氏癡呆、血管型失智症、路易如㈣體 114891.doc 200800169 癡呆、額顳葉型癡呆及染色體17相關之帕金森症;額顳葉 塑癡呆,包括皮克(Pick)氏疾病、惡化性癱瘓、皮質基底 核退化症、亨廷頓(Huntington)氏疾病、丘腦退化症、克 羅伊茨費爾特雅各布(Creutzfeld Jakob)癡呆、HIV癡呆、 神經分裂症及癡呆、柯薩可夫(Korsakoff)氏精神病; 認知相關性病症,諸如輕度認知障礙、年齡相關記憶障 礙、年齡相關性認知下降、血管性認知損害、注意力不足 症、注意力不足過動症及兒童記憶干擾及學習障礙;與下 丘腦-垂體-腎上腺軸相關之病況; 神經元病症’例如包括神經元遷移病症、張力減退(張 力過弱)、肌肉無力、發作、發展遲緩(身體或智力發展障 礙)、智力遲鈍、生長障礙、餵食困難、淋巴水腫、小頭 畸形、影響頭及腦之症狀、運動功能障礙; -與眼相關之病症 例如包括葡萄膜視網膜炎、玻璃體視網膜病變、角膜疾 病、虹膜炎、虹膜睫狀體炎、白内障、葡萄膜炎、糖尿病 性視網膜病變、色素性視網膜炎、結膜炎、角膜炎; -與胃腸道相關之病症 例如包括結腸炎、發炎性腸疾病、結腸炎、克羅恩疾 病、潰癌性結腸炎、消化性潰痛、胃炎、食道炎; -與心臟及血管病況相關之病症 例如包括心血營症 * &届症例如包括心力衰竭、心肌梗塞、 心,肥大;心臟衰竭’例如包括所有形式之心果故障,諸 如间輸出及低輸出、急性及慢性、右侧及左側、心收縮或 114891.doc 200800169 心擴張、與潛在病因無關之心系故障;心肌梗塞⑽)、奶 預防(原發性及繼發性預防)、MI急性治療、併發症之預 臟病纟’增^_性*管病症、全身性a管炎、結節性 多動脈炎、局部缺*之發炎性併發症、局部缺錢心臟疾 病、心肌梗塞、中風、末梢血管疾病、肺動脈高壓; >局部缺血病症,例如包括錢局部缺血,例如穩定性心 纹痛、不穩定性心絞痛、心絞痛、支氣管炎;無症狀心律 不齊’諸如所有形式之心房及心室心律失常、心房心動過 速、心房撲動、心房鐵維性顫動、房室回旋頻脈、預激綜 口症、心室心動過速、心、室撲動、心室纖維性顫動、心搏 緩慢形式之心、律^齊;心、㈣齊、慢㈣雜肺部疾病; 高血壓,諸如心收縮或心擴張高血壓,例如本態性及繼 發性高血壓’例如包括高血m管疾病,諸如原發性以 及所有類型之繼發性動脈、f、内分泌、神經及其他高血 壓; 其_動脈及/或靜脈流因血液供給與組織氧需求之間的 不平衡而降低之末梢血管病症,例如包括動脈粥樣硬化、 慢性周圍動脈硬化閉塞症(PA0D)、急性動脈血栓及栓塞、 發炎性動脈病症、雷諾(Raynaud)現象及靜脈病症;動脈 粥樣硬化,其中動脈壁經重塑之疾病,例如包括細胞平滑 肌細胞及單核細胞/巨嗟細胞、4炎性細胞於動脈壁之内 膜上積累; · 低血壓; -與肝臟及腎臟相關之病症 114891.doc -42- 200800169 例如包括腎臟病症,腎 例如急性腎衰竭、急性腎 病,肝醎病症,例如肝硬化、 叁 肝火、肝哀竭、膽汁淤積、 ί二性肝炎、硬化性膽管炎、原發性膽汁性肝硬化、 急性/慢性間質/絲球體腎炎、肉芽腫性疾病; •與胃或胰腺病況相關之病症 例如包括胃病症,例如胃 胰腺疲勞; 月“、“潰瘍、胰腺病症、 -與呼吸道及肺相關之病症 :如包括肺部病症、慢性腹部疾病、急性(成 μ合f(ARDS)…孝喘、哮喘支氣管炎、支氣管擴張 症、彌散性間質性肺病症、塵 化; T纖維性肺泡炎、肺纖維 _與皮庸及結締組織病況相關之病症 例如包括歸、異位性皮炎、(過敏性)接觸性皮炎 皮癬、痤瘡、皮膚肌炎、Sj0rgen氏症候群、徹奇-斯 症候群、曬傷、皮膚癌、傷口癒合、尊麻診、中 壞死溶解、年齡相關性皮膚病況、脂肪團; -與過敏性病況相關之病症 例如包括遲發性過敏反應、過敏性結膜炎、藥物過敏、 鼻炎、過敏性鼻炎、脈管炎、接觸性皮炎; -與血管生成相關之病症 例如包括補充血液供給能力不^、特徵為良性血管生成 之病症、與血管生成相關之腫瘤; •與癌症及細胞過度增生相關之病症 11489l.doc -43- 200800169 、。例如包括癌前病況、過度增生性病症;原發性或轉移性 π症呂頭及轉移性癌症、源於不受控制之細胞增生的癌 症、實心腫瘤,諸如W002066019所述,包括非小細胞肺 嗝子呂^員癌,腫瘤生長、淋巴瘤、B細胞或T細胞淋巴 瘤良f生腫瘤、良性增生性病症、腎癌、食道癌、胃癌、 月癌、膀胱癌、乳癌、結腸癌、肺癌、黑素瘤、鼻咽癌、 骨癌、印巢癌、子宮癌;前列腺癌、纟膚癌、白血病、腫 ;新生答血笞瘤、脊髓發育不良病症、無感應性至誘 發正常死亡信號(無限增殖化)、高細胞運動性及入侵性、 遺傳不穩定性、無規律基因表達、(神經)内分泌癌症(良性 腫瘤)、血癌、淋巴細胞白血病、神經母細胞瘤;軟組織 癌症、癌轉移預防; -與糖尿病病況相關之病症 例如包括糖尿病(1型糖尿病、„型糖尿病)、糖尿病性視 網膜病、胰島素依賴性糖尿病、糖尿病、妊娠性糖尿病、 胰島素分泌不足、肥胖; -與子宮内膜異位、睾丸功能障礙相關之病症 -與傳染性病症、例如與慢性傳染性病況相關之病症 例如包括細菌性病症、中耳炎、萊姆(Lyme)疾病、甲狀 腺炎、病毒性病症、寄生性病症、真菌性病症;癔疾,例 如癔疾性負血,敗血症、嚴重敗血症;敗血性休克,例如 内毒素誘發之敗血性休克、外毒素誘發之中毒性休克、傳 染性(真敗血性)休克、由格蘭氏(Gram)陰性細菌引起之敗 血性休克;盆腔炎症性疾病、AIDS、腸炎、肺炎、腦膜 I14891.doc -44- 200800169 炎、腦炎; •與重症肌無力相關之病症 -與腎炎相關之病症 例如包括絲球體腎炎、間質性腎炎、韋格納肉芽腫、 維化; ' -與疼痛相關之病症 例如與CNS病症相關之病症,諸如多發性硬化症、脊髓
^丄月神經痛、背部手術後綜合症、創傷性腦損傷、 癲癇症、帕金森氏疾病、中風後及腦及脊髓中之血管損害 (例如梗塞、出血、灰管畸形); 非中樞神經疼痛,例如包括與以下疾病相關之非中樞神 經疼痛:乳房切除後疼痛、幻覺、反射性交感神經營養不 良(RSD)、三叉神經痛、神經線病變、手術後疼痛、 HIV/AIDS相關之疼痛、癌痛、代謝性神經病變(例如糖尿 病性神經病變、結締組織疾病繼發性脈管神經病變)、與 例如肺癌 '或白血病 '或淋巴瘤、或前列腺癌、結腸癌或 胃癌相關之副腫瘤性多發性神經病變、三又神經痛、顧骨 神經痛及疱療後神經痛; 與末梢神經損傷相關之疼痛,中樞性疼痛(亦即歸因於 大腦局部缺血)及各種慢性疚、虑 〖尽痛亦即,腰痛、背痛(低度 背痛)、發炎性及/或風濕性疼痛; 頭痛(例如先兆偏頭痛、 症)、突發性及慢性緊張型 頭痛及慢性突發性偏頭痛; 無先兆偏頭痛及其他偏頭痛病 頭痛、類緊張型頭痛、叢集性 H489l.doc -45- 200800169 内臟疼痛,諸如胰腺、腸道膀胱炎、月經痛、大腸急躁 症、克羅恩疾病、膽絞痛、輸尿管絞痛、心肌梗塞及骨盆 腔疼痛症,例如外陰疼痛、睾丸痛、尿道綜合症15及攝護 腺疼痛(protatodynia;); 急性疼痛,例如手術後疼痛及創傷後疼痛; -與風濕性病症相關之病症 例如包括關節炎、類風濕性關節炎、骨關節炎、牛皮癖 關節火、結晶性關節病變、痛風、假痛風、腳磷酸鈣沈 積疾病、狼瘡症候群、全身性紅斑狼瘡、硬化症、硬皮 病夕發〖生硬化症、動脈粥樣硬化、動脈硬化、脊椎關節 病、全身性硬化症、反應性關節炎、萊特爾(Reiter)氏綜 合症、強直性脊椎炎、多肌炎; -與肉狀瘤病相關之病症 •與移植相關之病症 例如包括移植排斥危症及其他移植後病症,諸如心臟、 肺、心肺組合、肝臟十胰腺、皮膚、角膜移植之受體 治療之器官或組織(異種)移植排斥,諸如骨髓移植後之移 植物抗宿主疾病,缺血性再灌注損傷。 本發明之化合物較佳可用於治療與免疫系統、發炎及抑 制相關之病症,例如包括牛皮癬、類風濕性關節炎、發炎 性腸疾病(克羅恩氏疾病、潰瘍性結腸炎)、(全身性斑 狼瘡、多發性硬化症、休格連氏症料、移植後排斥反應 及移植物抗宿主疾病及發炎性皮膚疾病,例如皮炎,諸如 異位性皮炎,例如過敏性接觸性皮炎。 114891.doc -46· 200800169 在-實施例中,本發明之化合物可用於治療自體免疫疾 病,例如類風濕性關節炎、牛皮癬、發炎性腸疾病、(全 身性)紅斑狼瘡、多發性硬化症或發炎性(皮膚)疾病,例如 皮炎; • 更佳用於治療發炎性腸疾病、類風濕性關節炎或皮炎。 在另一態樣中,本發明提供: -作為藥物使用之本發明之化合物; -本發明之化合物作為藥物之用途; _ Μ如’用於治療由參與細胞黏接、遷移及活化之LFA_ i及 其配位基之相互作用介導之病症。 就藥物使用而言,可使用一或多種本發明之化合物,例 如一種本發明之化合物、或兩種或兩種以上本發明之化合 物組合使用,較佳使用一種本發明之化合物。 本發明之化合物可以醫藥組合物之形式用作藥物。 在另一態樣中,本發明提供一種包含與至少一種醫藥學 φ 上可接受之賦形劑組合之本發明之化合物的醫藥組合物, 該等賦形劑例如適當之載劑及/或稀釋劑,例如包括填充 劑、黏合劑、崩解劑、流動調節劑、潤滑劑、糖或甜味 .劑、芳香劑、防腐劑、穩定劑、濕潤劑及/或乳化劑、增 溶劑、用於調節滲透壓及/或緩衝液之鹽。 在另一態樣中,本發明提供: -本發明之醫藥組合物,其係用於治療由參與細胞黏接、 遷移及活化之L F A -1及其配位基之相互作用介導之疒 症; ^ 114891.doc 200800169 -本發明之醫藥組合物之用途,其係用於治療由參與細胞 黏接、遷移及活化之LFA-1及其配位基之相互作用介導 之病症。 在另一態樣中,本發明提供一種治療由參與細胞黏接、 遷移及活化之LFA-1及其配位基之相互作用介導之病症的 方法’該治療包含投與需要該治療之受檢者治療有效量之 (例如)呈醫藥組合物形式的本發明之化合物。 在另一態樣中,本發明提供: _ 用於製造藥物之本發明之化合物; 或 本發明之化合物用於製造例如醫藥組合物之藥物的用途, 該藥物係用於治療由參與細胞黏接、遷移及活化之LFA_ i 及其配位基之相互作用介導之病症。 本文所用之病症(疾病)治療包括治療及預防。 就该治療而言’適當劑量當然將隨(例如)所用之本發明之 _ 化合物的化學性質及藥物動力學數據、個別宿主、投藥模 式及所治療之病況的性質及嚴重性而變化。然而,就較大 哺乳動物(例如人類)的滿意結果而言,所顯示之日劑量通 常包括以下範圍: -約 0.0001 g至約 1·5 g,諸如 0·001 §至 g ; -約 0.001 mg/kg體重至約 20 mg/kg體重,諸如 〇.〇1 mg/kg 體重至20 mg/kg體重, 例如’以分開劑量每日投藥達四次。 本發明之化合物可藉由類似於習知用於其他參與細胞黏 114891.doc -48- 200800169 接、遷移及活化mi及其配位基 低分子量抑制劑)之投藥模式投與二==如 類)。 孔動物(例如人 本發明之化合物可藉由任何路徑 — 知路辦,在丨Η >、’例如籍由任何習 知路住,例如腸内投藥, 了白 腸、铖口措蕴•也, ^從、、工鼻、經口腔、經直 肌肉内、心臟内、皮下…、:如匕括靜脈内、動脈内、 皮下、骨内灌注、經皮(銥6敫士 ♦ 散)、經黏膜(經黏膜擴散)、 ^正皮膚擴 括上表皮、鼻内、氣管内投筚膜内局部投樂,例如包 入腹腔),·硬媒外投藥(注射或灌注 2 ^主或注射 (庄射或灌注入腦脊髓液); 叔柰 經醫療裝置㈣心 璃體内技樂(經眼投藥),·或 木例如呈經塗覆或未經塗覆支 液、灌注溶液、固體溶液、_浮液^囊、(可注射)溶 …之藥物"…安二 物體分散液 賞、凝膠、糊狀物、& 」樂 呈礼 劑、噴露m “末、泡沫、酊劑、唇膏、滴 贺務或呈栓劑形式之藥物。 曰==至:::包括對眼投藥,結果一每 之活性物質獲得。 部投樂C(諸如M%)濃度 本發明之化合物可以醫藥 / 形式投藥;視情況可以溶劑合受之鹽形式或以游離 溶劑合物形式之本發明之化 ^式投樂。呈鹽及7或 ^ Ό物展示出與呈游離形式之本 ^月之化合物相同之活性等級。 114891.doc -49- 200800169 本發明之化合物可用於任何方法或如本文所述單獨使用 或與-或多種、至少—種其他、第二藥物組合使用。 在另一態樣中,本發明提供: -本發明之化合物與至少一種第二藥物之組合; -包含與至少一種第二藥物組合之本發明之化合物的醫藥 組合; ' -包含與至少-種第二藥物及—或多種醫藥學上可接受之 賦形劑組合之本發明之化合物的醫藥組合物; 例如呈醫藥組合或組合物形式、與至少一種第二藥物組 合之本發明之化合物,其係用於任何本文所定義之方 法,例如 -組合’醫藥組合或醫藥組合物’其包含本發明之化合 物及至少一種用作藥物之藥物; 口 -例如呈醫藥組合或組合物形式、與至少一種藥物組合 之本發明之化合物作為藥物之用途; -本發明之化合物用於製造與第二藥物組合使用之藥物的 用途; 心㈣有需要之受檢者體内之病症的方法,該等病症 係由參與細胞黏接、遷移及活化之LFA,其配位基的 ,互作用介導,該方法包含共投藥、相伴投藥或依序投 藥治療有效量之(例如)呈醫蘂έ人斗 』主百樂組合或組合物形式之本發 明之化合物及至少一種第二藥物; 例如以醫藥組合或組合物形式、與至少一種第二藥物組 合之本發明之化合物用於製備供治療由參與細胞黏接、 114891.doc -50- 200800169 遷移及活化之LFA-1與其配位基相互作用介導之疾病的 藥物。 組合包括··固定組合,其中本發明之化合物與至少一種 第一藥物係處於相同調配物中;套組,其中處於獨立調配 物中之本發明之化合物與至少一種第二藥物係處於例如具 有共技藥說明書之相同包裝中;及自由組合,其中本發明 之化合物與至少一種第二藥物係獨立包裝,但給出相伴投 藥或依序投藥之說明書。 在另一態樣中,本發明提供: -一種醫藥包裝,其包含除組合投藥之說明書外的本發明 之化合物之第一藥物及至少一種第二藥物; • 一種醫藥包裝,其包含除組合投藥之說明書外的與至少 種弟一樂物組合之本發明之化合物; -一種醫藥包裝,其包含除組合投藥之說明書外的至少一 種與本發明之化合物組合之第二藥物。 相較於單獨治療’以本發明之組合治療可提供改良。 在另一態樣中,本發明提供: -一種醫藥組合,其包含一定量本發明之化合物及一定量 弟一藥物’其中該等量適於產生協同治療效應; -一種改良本發明之化合物之治療功效的方法,其包含共 投藥(例如相伴投藥或依序投藥)治療有效量之本發明之 化合物及第二藥物; -一種改良第二藥物之治療功效的方法,其包含共投藥 (例如相伴投藥或依序投藥)治療有效量之本發明之化合 114891.doc 51 200800169 物及第二藥物。 J發明之組合與作為經合相伴物之第二藥物可藉由任一 二。途㈣藥,例如以上關於本發明之化合物所述之途 徑。適當時,可以_定纟丨 i想机― 疋J里杈樂弟二藥劑,例如以類似於
早獨奴樂所用之劑量笳圚於M 〗里乾圍技樂或例如在協同情況下以更低 於白知劑篁範圍投藥。
、本發明之醫藥組合物可根據(例如類似於)習知方法製 =’,例如’错由混纟、粒化、塗覆、溶解或純法。單^ 劑型可含有(例如)約01 mg至約15⑻叫,諸如 1000 mg。 6 適當時,可(例如)根據(例如類似於)習知方法或本文關 於本發明之醫藥組合物所述之方法提供包含本發明之组合 之醫藥組合物及包含本文所述之第二藥劑之醫藥組合物: 術語"第二藥物"意謂化療藥劑,尤其為除本發明之化合 物(諸如式I化合物)外之任何化療藥劑。 舉例而言,本文所用之第二藥物包括例如: -除本發明之化合物外的其他化合物,該等化合物與^冬 1與其配位基之細胞黏接、遷移及活化活性相互作用, 例如包括抗體及低分子量化合物; -抗發炎及/或免疫調節藥; -抗過敏藥; •抗癌藥。 通常與本發明化合物組合使用的抗發炎及/或免疫調節 藥劑包括(例如): 114891.doc -52- 200800169 -mTOR活性介體,例如抑制劑,包括下式之雷帕黴素 (rapamycin) *
及雷帕黴素衍生物,例如包括: 40-0-烷基-雷帕黴素衍生物,諸如40-0-羥基烷基-雷帕黴 素衍生物,諸如40-0-(2-羥基)-乙基-雷帕黴素(依維莫司, everolimus); 32-脫氧-雷帕黴素衍生物及32-羥基-雷帕黴素衍生物,諸 如32-脫氧雷帕黴素; 16-0-經取代之雷帕黴素衍生物,諸如16-戊-2-炔基氧基-32-脫氧雷帕黴素、16-戊-2-炔基氧基-32(S或R)-二氫-雷帕 黴素、16-戊-2-炔基氧基-32(S或R)-二氫-40-0-(2-羥基乙 基)-雷帕黴素; 於位置40之氧基處經醯基化之雷帕黴素衍生物,例如40-[3-羥基-2-(羥基·曱基)-2-甲基丙酸]-雷帕黴素(亦稱作 CCI779); 114891.doc -53- 200800169 於位置40處經雜環基取代之雷帕黴素衍生物,例如40-表-(四唑基)-雷帕黴素(亦稱作ABT578), 所謂雷帕隆(以0&1〇§),例如翟〇98〇2441、\^〇〇114387及 WO 03 643 83中所揭示,諸如AP23 573,及 以 TAFA-93 AP23464、AP23675、AP23841 揭示之化合物及 拜爾莫司(biolimus)(例如拜爾莫司A9);
• -鈣調神經磷酸酶介體,例如抑制劑,例如環孢素A、FK 506 ; 參 -具有免疫抑制性之子囊黴素,例如ABT-281、ASM981 ; -皮質類固醇;環磷醯胺;硫唑嘌呤;來氟米特 (leflunomide);咪唑立賓(miz〇ribine); -黴酚酸或鹽;黴酚酸嗎啉乙酯; -15-去氧斯匹胍素或其免疫抑制性同系物、類似物或衍生 物; -bcr-abl赂胺酸激酶活性介體,例如抑制劑; -c-kit受體路胺酸激酶活性介體,例如抑制劑; -PDGF受體絡胺酸激酶活性介體,例如抑制劑,例如格列 衛(Gleevec)(伊馬替尼,imatinib); • _ p38 MAP激酶活性介體,例如抑制劑; -VEGF受體絡胺酸激酶活性介體,例如抑制劑; -pkc活性介體,例如抑制劑,例如w〇〇238561或w〇 0382859所揭示,例如實例56或70之化合物; -JAK3激酶活性介體,例如抑制劑,例如N_节基_3,4_二羥 基-亞节基-氰基乙醯胺-氰基_(3,4-二羥基)-]仏苄基苯丙 114891.doc -54- 200800169 烯醯胺(Tyrphostin AG 490)、靈菌紅素 25_C (PNU156804)、[4-(4’_羥基苯基)-胺基-6,7-二甲氧基喹唑 啉](WHI-P131)、[4-(3’·溴-4’-羥基苯基)-胺基-6,7-二甲氧 基喹唑啉](WHI-P154)、[4-(3^5^二溴-4’-羥基苯基)-胺 基-6,7-二甲氧基喹唑啉]WHI-P97、KRX-211、3-{(3R,4R)-4-甲基-3-[甲基-(7H-吡咯幷[2,3-d]嘧啶-4-基)-胺基]-哌啶-1-基}-3-側氧基-丙腈,其係呈游離形式或醫 藥學上可接受之鹽形式,例如單檸檬酸酯(亦稱作CP-690,550), 或 WO 2004052359 或 W0 2005066156 所揭示之 化合物; -S1P受體活性介體,例如激動劑或調節劑,例如視情況經 磷酸化之FTY720或其類似物,例如視情況經磷酸化之2-胺基-2-[4-(3 -节基乳基苯硫基)-2 -氯苯基]乙基-1,3·丙二 酉手’或1-{4-[1-(4-環己基-3-二氣甲基-节基氧基亞胺基)_ 乙基1-2-乙基-苄基}-吖丁啶-3-羧酸或其醫藥學上可接受 之鹽; -免疫抑制單株抗體,例如白血球受體之單株抗體,例如 Blys/BAFF 受體、MHC、CD2、CD3、CD4、CD7、 CD8、CD25、CD28、CD40、CD45、CD52、CD58、 CD80、CD86、IL-12受體、IL-17受體、IL-23受體或其配 位基; -其他免疫調節化合物,例如具有CTLA4或其突變體之細 胞外結構域之至少一部分的重組結合分子,例如結合至 非CTLA4蛋白序列之CTLA4或其突變體之至少細胞外部 114891.doc -55- 200800169 分,例如CTLA4Ig(例如稱作ATCC 68629)或其突變體, 例如 LEA29Y ; •黏接分子活性介體,例如抑制劑,例如LFA-1拮抗劑、 ICAM-1或ICAM-3拮抗劑、VCAM-4拮抗劑或VLA-4拮抗 劑; > -CCR9活性介體,例如拮抗劑; ' -MIF活性介體,例如拮抗劑; -5-胺基水揚酸酯(5-ASA)試劑,諸如柳氮磺胺吡啶、 • Azulfidine®、Asacol·®、Dipentum®、Pentasa®、
Rowasa®、Canasa®、Colazal®,例如含有馬沙拉嗓 (mesalamine)之藥劑,例如與肝鱗脂組合之馬沙拉唤; TNF-α活性介體,例如抑制劑,例如包括與TNF-α結合之 抗體,例如英利昔單抗(infliximab)(Remicade®)、沙利度 胺(thalidomide)、來那度胺(lenalidomide); -氧化氮釋放非類固醇抗發炎藥劑(NSAID),例如包括抑 制 COX供 NO 藥劑(CINOD); -磷酸二酯酶,例如PDE4B活性介體,諸如抑制劑; -卡斯蛋白酶活性介體,例如抑制劑; -G蛋白偶合受體GPBAR1之介體,例如激動劑; -神經醯胺激酶活性介體,例如抑制劑; -多功能性抗發炎藥劑(MFAID),例如胞内磷脂酶 A2(cPLA2)抑制劑,諸如與葡糖胺聚聯結之糖膜結合態 填脂酶A2抑制劑; •抗生素,諸如盤尼西林(penicillin)、頭孢菌素 114891.doc -56- 200800169 (cephalosporin)、紅黴素(erythromycin)、四環素;石黃酸 胺,諸如磺胺嘧啶、磺胺異唑;砜類,諸如氨苯颯;截 短側耳素;氟化奎林酮類,例如甲硝噠唑;喹啉酮,諸 如環丙沙星(ciprofloxacin);左氧氟沙星(levofloxacin); 益生菌及共生細菌,例如乳桿菌(Lactobacillus)、羅伊氏 乳桿菌(Lactobacillus reuteri);
-抗病毒藥劑,諸如病毒嗤(ribivirin)、阿糖腺苷、阿昔洛 韋(acyclovir)、更昔洛韋(ganciclovir)、紮那米韋 (zanamivir)、填酸奥斯他韋(oseltamivir phosphate)、泛 昔洛韋(famciclovir)、阿紮那韋(atazanavir)、金剛烧胺、 去經肌苦、依法韋余(efavirenz)、膦甲酸納、茚地那韋 (indinavir)、拉米夫定(lamivudine)、奈非那韋 (nelfinavir)、利托那韋(ritonavir)、沙奎那韋 (saquinavir)、司他夫定(stavudine)、萬乃洛韋 (valacyclovir)、纈更昔洛韋(valganciclovir)、齊多夫定 (zidovudine) 〇 通常與本發明化合物組合使用的抗發炎劑,包括例如非 類固醇抗發炎劑(NSAID),諸如丙酸衍生物(阿明洛芬 (alminoprofen)、苯噁洛芬(benoxaprofen)、布氯酸 (bucloxic acid)、卡洛芬(carprofen)、芬布芬(fenbufen)、 非諾洛芬(fenoprofen)、氟洛芬(fluprofen)、氟比洛芬 (flurbiprofen)、布洛芬(ibuprofen)、。弓丨哚洛芬 (indoprofen)、酮基布洛芬(ketoprofen)、咪洛芬 (miroprofen)、| 普生(naproxen)、奥沙普秦(〇xaprozin)、 114891.doc •57- 200800169
口比洛芬(pirprofen)、普拉洛芬(pranoprofen)、舒洛芬 (suprofen)、嗟洛芬酸(tiaprofenic acid)及硫惡洛芬 (tioxaprofen))、乙酸衍生物(叫丨σ朵美辛(indomethacin)、阿 西美辛(acemetacin)、阿氣芬酸(alclofenac)、環氯茚酸 (clidanac)、雙氯芬酸(diclofenac)、芬氯酸(fenclofenac)、 芬克洛酸(fenclozic acid)、芬替酸(fentiazac)、σ夫羅芬酸 (furofenac)、異 丁芬酸(ibufenac)、伊索克酸(isoxepac)、 oxpinac(歐斯皮尼克)、舒林酸(sulindac)、硫平酸 (tiopinac)、托美、;丁(tolmetin)、齊多美辛(zidometacin)及佐 美酸(zomepirac))、甲酸衍生物(氟滅酸(flufenamic acid)、 曱氯齡那酸(meclofenamic acid)、甲滅酸(mefenamic acid)、說尼酸(niflumic acid)及托滅酸(tolfenamic acid))、 聯苯羧酸衍生物(二氟尼柳(diflunisal)及氟苯柳 (flufenisal))、昔康類(oxicams)(伊索昔康(isoxicam)、炎痛 昔康(piroxicam)、濕痛昔康(sudoxicam)及替諾昔康 (tenoxican))、水揚酸酯(乙醯基水揚酸、柳氮石黃胺。比啶))及 二氫°比。坐酮(阿紮丙宗(apazone)、貝旅瑞隆 (bezpiperylon)、非普拉宗(feprazone)、莫非布宗 (mofebutazone)、氧苯丁嗤(oxyphenbutazone)、保泰松 (phenylbutazone);環加氧酶_2(COX-2)抑制劑,諸如塞内 昔布(celecoxib) ; IV型鱗酸二酯酶抑制劑(PDE-IV);向化 性激動素受體拮抗劑,尤其CCR-1、CCR-2及CCR-3 ;降 膽固醇劑,諸如HMG-CoA還原酶抑制劑(洛伐他汀 (lovastatin)、辛伐他汀(simvastatin)及普伐他汀 114891.doc -58- 200800169 (pravastatin)、氟伐他彡丁(fiuvastatin)、阿托伐他汀 (atorvastatm)及其他士他汀)、錯隔劑(消膽胺及考來替潑 (colestipol)、菸鹼酸、非諾貝酸(fen〇fibric acid)衍生物(吉 非羅齊(gemfibrozil)、安妥明(cl〇fibrat)、非諾貝特 (fenofibrate)及苯紮貝特(benzafibrate))及普羅布可 (bromide);其他化合物,諸如茶鹼、柳氮磺胺吡啶及胺基 水揚酸S旨,例如5_胺基水楊酸及其前藥,抗類風濕藥。
通常與本發明之化合物組合使用的抗過敏藥包括(例如) 抗組織胺(H1-組織胺拮抗劑),例如漠芬尼拉明 (bromopheniramine)、氯芬尼拉明(chl〇rpheniramine)、右 氯务尼拉明 (dexchlorpheniramine)、 曲普利咬 (triprolidine)、氣馬斯汀(clemastine)、苯海拉明 (diphenhydramine)、二苯拉林(diphenylpyraline)、曲 σ比那 明(tripelennamine)、羥嗪、甲吡咯嗪、非那根 (promethazine)、阿利馬嗪(trimeprazine)、阿紮他啶 (azatadine)、塞庚唆(cyproheptadine)、安他嗤琳 (antazoline)、苯丙烯唆(pheniramine) 、 °比拉明 (pyrilamine)、阿司口米嗤(astemizole)、特非那定 (terfenadine)、氣雷他定(loratadine)、西替利唤 (cetirizine)、非索非那定(fexofenadine)、脫碳乙氧基氯雷 他定(descarboethoxyloratadine)及非類固醇止喘藥,諸如 β2-激動劑(特布他林(terbutaline)、異丙喘寧 (metaproterenol)、非諾特羅(fenoterol)、新異丙腎上腺素 (isoetharine)、沙 丁胺醇(albuterol)、比托特羅 114891.doc -59- 200800169 (bitolterol)、 沙美特羅(salmeterol)及吼布特羅 (pirbuterol))、茶驗(theophylline)、色甘酸納(cromolyn sodium)、阿托品(atropine)、異丙托溴胺、白三烯素拮抗 劑(紮魯司特(zafirlukast)、孟魯司特(montelukast)、普侖 司特(pranlukast)、伊拉司特(iralukast)、泊比司特 (pobilukast)、SKB-106,203)、白三烯素生物合成抑制劑 (齊留通(zileuton)、BAY-1005);支氣管擴張劑、止喘藥 (肥大細胞穩定劑)。 本發明化合物與其他藥劑之重量比可隨(例如)所用組合 相伴物之活性、所治療疾病之種類而變化,且可進一步隨 各成分之有效劑量而變化,且可(例如)根據(例如類似於) 習知方法藉由所給之其他藥劑及測試之說明書來確定。 如本文所指出,本發明化合物之化學名稱係沿用自 ISIS,2.5版(AutoNom 2000 Name) 〇 在下列實例中,所有溫度均以攝氏度(°C)為單位表示。 使用下列縮寫:
EtOAc 乙酸乙酯 THF 四氫咬喃 【實施方式】 製備實例1 N-[7a-(4-氰基-苄基)-6-(3,5-二氣-苯基)-7-羥基-5-側氧基-2,3,5,7a-四氫-1H-吡哩-2-基】-乙醯胺(表實例1之化合物) A) (2S,4S)-4·疊氮基·吡咯啶-1,2_二羧酸1-烯丙基酯2-甲: 基酯 114891.doc -60- 200800169 向45 g (2S,4R)-4-羥基-吡咯啶-丨义二羧酸丨_烯丙基酯2_ 甲基酯及65 g三苯基膦於700 ml THF中之冷卻溶液中,添 加46 g偶氮二羧酸二乙酯(DEAD),接著添加53 ml二苯基 磷醯基疊氮化物(DPPA)。將所得混合物溫至室溫且蒸發溶 劑。將所得蒸發殘餘物層析。獲得呈微黃色油之(2S,4S)_ 4-疊氮基-吡咯啶-l?2-二羧酸1-烯丙基酯2_甲基酯。 MS: 277 (MNa+) ; 4-NMR及uC-NMR資料與所提出之結 構一致。 籲 Ba) (2S,4S)-4_叠氮基-2-(4-氣基-节基)_β比咯啶二羧酸 1-烯丙基酯2-甲基酯及
Bb) (2S,4R)-4-叠氮基-2-(4-氟基-节基)-w比洛咬],2-二幾酸 1-烯丙基酯2-甲基酯 將鋰-雙-三甲基矽烷基醯胺於111]?中之11〇 mi丨m溶液 以使溫度不超過-5(TC之方式添加至21·4 g (2S,4S)_4_疊氮 基-咄咯啶-1,2-二羧酸1-烯丙基酯2·甲基酯於2〇〇 ml φ <冷卻(·78Χ)、經㈣溶液中。向所得混合物中添加25·6 g 4-氰基苄基溴化物,又繼.續攪拌且冷卻⑽分鐘。向所得 /吧合物中添加1200 mi Et0Ac及3〇〇 ml j N HC1,將所得相 分離且將所得有機層洗滌、乾燥,將溶劑蒸發且使蒸發殘 餘物經受層析。獲得各呈無色油形式之(2§,48)4_疊氮基_ 2_(4_氛基-节基)_吼嘻淀」,2^叛酸i•烯丙基以曱基酯 (14 g)及(2S,4R)_4-疊氮基_2_(4_氰基-苄基比咯啶-^-二 竣夂稀丙基知2_甲基酯(7g)。兩種化合物之ms:392/761 (MNa /2MNa ) ’ H-NMR及13C-NMR資料與所提出之結構 114891.doc -61 - 200800169 C) (2S,4S)-4-胺基- 2_(4-氣基·节基)-ϊ»比哈唆-1,2-二叛酸1-烯 丙基酯2_甲基酯
於室溫下向3.5 g(2S,4S)-4_疊氮基- 2-(4-氰基-节基各 唆-1,2-二叛酸1-烯丙基酯2-甲基酯於150 ml CH3CN(於30 ml CHyCOOH)中之經攪拌溶液中一次性添加1〇 g鋅粉且將 所得混合物攪拌15分鐘。將所得混合物過濾且向所得濾出 液中添加EtOAc及飽和NaHC〇3水溶液。向經攪拌之所得兩 相混合物中添加固體NaHC〇3直至偵測不到更多c〇2逸出。 分離所得相’將所得有機層洗滌且乾燥,且蒸發溶劑,獲 得呈油形式之(2S,4S)-4-胺基-2-(4-氰基-苄基)_吡咯啶_丨,2-二羧酸1-烯丙基酯2-甲基酯。MS: 344/366/709 (MNH+/ MNa+/2MNa+); ^H-NMR及丨义…崖尺資料與所提出之結構一 致。 D) (2S,4S)_4_乙醯胺基_2_(4_氟基-苄基卜吡咯啶二羧 酸1-烯丙基酯2-甲基酯 於室溫下向(2S,4S)-4-胺基_2_(4_氰基·苄基)_吡咯啶 羧酸1-烯丙基酯2-甲基酯(例如根據步驟c所得)於⑼w THF中之經授拌溶液中添加7 ml_,接著添加4…乙酸 肝。將所得混合物於室溫下檀拌2〇分鐘,且添加㈣⑹ EtOAc、 ml飽和贿叫水溶液及2⑼Μ鹽水。將所得 兩相分離且將所得有機層洗滌、乾燥,且蒸發溶劑。使所 得蒸發殘餘物經歷層析。 醯胺基·2_(4-氰基-苄 獲得呈結晶固體形式之(2S,4S)_4_乙 114891.doc -62 - 200800169 基)-吼洛咬·1,2-二羧酸1-烯丙基酯入曱基酯。 MS: 408/793 (MNa+/2MNa+) ; iH_NMR 及 i3C-NMR資料與所 提出之結構一致。 E) (2S,4S)-4-乙醯胺基_2·(4 -氣基-节基吡咯啶-2-羧酸甲 基酯 於室溫下向2.53 g (2S,4S)-4-乙醯胺基-2-(4-氰基-苄基)_ 吡咯啶-1,2-二羧酸1-烯丙基酯2_曱基酯於15() THF中之 經攪摔溶液中添加3.88 g ι,4-二氮-雙環[2·2.2]辛烷 (DABCO)及782 mg肆-(三笨基膦)_鈀。將所得混合物於室 溫下攪拌35分鐘,添加2〇〇1111扮〇八(:及2〇〇1111飽和]^11(:〇3 水洛液,將所得相分離,將所得有機層洗滌、乾燥,且蒸 發溶劑。 MS:324_aH_NMRA uc_NMR資料與所提出之結構 一致0 )(2S,4S)·4·乙醯胺基氰基·苄基二氣_苯 基)-乙醯基】比咯啶2-羧酸甲基酯 以100 ml CHsCN及40 ml水處理(2S,4S)_4_乙醯胺基·2_ (4-氰基-节基)“比㈣_2•賴甲基醋(❹根據步驟d所 得^^且向所得混合物中一次性添加4 g〖识^仏及2 6层2,5· 一虱本基乙酸。將所得混合物於室溫下攪拌h 3。。一…鹽水及…〇,且將所二 離。將所得有機層洗蘇、乾燥,且蒸發溶劑。使所得蒸發 殘餘物經歷層析。得到呈非Μ彡粉末形式之(28 Λ 醯胺基邻_氰基-节朴叩似二氯.苯基)·乙酿基】“比 114891.doc -63· 200800169 咯啶2-羧酸甲基酯。 之結構 MS: 510 (MNa+) ; i-NMR及 13C-NMR資料與所提出 一致0 G) N-[(2S,7aS)-7a-(4 -氡基苄基)·6·(3,5-二氣-笨基)< 經 基_5_侧氧基_2,3,5,7a -四氫-1Η-σ比哩_2-基]-乙醯胺 將1.75 g六甲基矽氮烷鉀(KHMDS)添加至3.03 g (2S,4S)
4-乙醯胺基-2-(4-氰基-苄基)-1-[2-(3,5 -二氯-苯基)_乙酸 基]比洛唆2-叛酸甲基酯於150 ml無水THF中之經攪拌溶液 中,且將所得混合物攪拌數分鐘。向所得混合物中添加i N HC1及EtOAc。將所得相分離,將有機層洗滌、乾燥, 且蒸發溶劑。獲得N-[(2S,7aS)-7a-(4-氰基-苄基)-6-(3,5-二 氯-苯基)-7-經基_5-側氧基-2,3,5,7a-四氫-ΙΗ-吼哩-2-基]-乙 龜胺。 MS: 478 (MNa+) ; h-NNIR及13C-NMR資料與所提出之結構 一致。 製備實例2及3 N-[7a-(4·氰基-苄基)-6-(3,5-二氣-苯基)_7_甲氧基側氧 基-2,3,5,7a-四氫-1H-吡哩基】-乙醯胺(製備實例2,表實 例2之化合物) 及 N-[7a-(4-氰基-苄基)_6_(3,5-二氣-苯基)_5-甲氧基_7-側氧 基-2,3,7,7a-四氫_1H-吡哩_2·基]-乙醯胺(製備實例3,表實 例3之化合物) 向於 60 ml CH2C12 中之 ι·8 g N-[(2S,7aS)-7a-(4-氰基-苄 114891.doc -64 - 200800169 基)-6-(3,5-二氯-苯基)-7_經基_5_側氧基_2,3,5,7^四氮_他 吡哩-2-基]-乙醯胺中添加CH2N2於乙醚中之溶液,直至未 反應CH2N2之特徵性黃色消失。以氩氣流移除未反應之 CH2N2,且蒸發溶劑。使所得蒸發殘餘物經受層析。 獲得 N-[(2S,7aS)-7a_(4_ 氰基彳基)_6_(3,5•二氯苯基)_7_ 曱氧基-5-側氧基-2,3,5,7a_四氫孤吡哩基]-乙醯峨 例 2)及N-[(2S,7aS)-7a-(4-氰基-节基)·6_(3,5_二氯.苯基)_%
甲氧基-7-側氧基_2,3,7,7a-四氫-1Η-口比哩_2_基]_乙酿胺(實 例3)。 貝 兩種化合物之 MS: 368/713 _a+/2MNa+),1h-Nmr& 13C-NMR資料與所提出之結構一致。 製備實例4 4-[6-(第三丁基-二甲基_矽烷氧基)_3_側氧基1苯基_ 5,6,7,7a-四氫-3H_吼哩小基氧基甲基】_苯甲睛( - 化合物) ^ 下式之化合物:
(表實例15之化合物)及 114891.doc -65 - 200800169 4-【6-(第三丁基-二甲基-矽烷氧基)_153_二侧氧基-2_苯基_六 氫比哩_2_基甲基】·苯甲腈(表實例16之化合物) 將於 50 ml CH2C12 中之 840 mg (6R,7aR)_6-(第三丁 基 _二 曱基-矽烷氧基)-1-羥基-2-苯基-5,6,7,7a-四氫-吡哩-3-酮、
2 ml N-乙基-一異丙基胺(Htinig驗)及1.09 g 4 -氮基-节基漠 化物之混合物於室溫下攪拌15小時,以檸檬酸緩衝液(ρΉ 值3)及EtOAc處理所得混合物,且將相分離。將所得有機 層洗務、乾燥,且蒸發溶劑。使所得蒸發殘餘物經歷層析 (石夕膠;梯度,甲苯:乙腈=10:1至1:1)。 獲得 322 mg式 IEX15_S化合物、55 mg 4-[(6R,7aR)_6_(第三 丁基-二甲基-石夕烷氧基)-3·側氧基-2·苯基-5,6,7,7a-四氫-3H-吼哩-1-基氧基甲基]-苯甲腈及678 mg 4_[(6S,7aS)_6_(第 三丁基-二甲基-石夕烷氧基)4,%二側氧基-2_苯基-六氫·吡 哩-2-基曱基]-苯甲腈 製備實例5 下式之化合物
CN 將255 mg式1”15化合物於7 ml ΤΗρ及2·8以丨河四丁基氟 114891.doc -66 - 200800169 化錄於THF中之溶液於室溫下授摔2〇分鐘。所得混合物以 1M 及EtOACf ’將所得相分離,且將所得有機層洗 務且乾餘。將溶劑自所得混合物蒸發,且將蒸發殘餘物層 析。獲%•呈無色固化合物。MS: 347/369/715 • (MH+/MNa+/2MNa+),士七麗及13c.r資料與所提出之 結構一致。 製備實例6 下式之化合物
使325 mg 1-輕基_1,2_苯幷碘氧雜環戊氧化物 及90 mg式IEX38-S化合物於5 ml EtOAc中之混合物於微波條 件(100 C,65 分鐘,Personal chemistry Emrys optimizer)下 反應。將所得混合物過濾(移除過量試劑)、減壓濃縮且層 析。獲得呈固體形式之式IEX39-S化合物。 MS: 399/755 (MNa++MeOH/2MNa++2MeOH),iH-NMR及 13C-NMR資料與所提出之結構一致。 製備實例7 4·{6·(3,5_二氣苯基)_2-[5·碘 _4-(3_ 甲基丁基)-[1,2,3】三唑- 114891.doc -67- 200800169 1_基]·7_曱氧基-5-侧氧基_2,3-二氫·m,5H_吡哩-7a-基甲 基}_苯曱腈(表實例57之化合物); 4-{6-(3,5-二氣·苯基)_7_甲氧基-2-[4_(3_甲基_ 丁醯胺)· [1,2,3]三唑-1-基】-5-側氧基_2,3_二氫·1Η,5Η_吡哩-7a-基甲 基}_苯曱腈(表實例58之化合物); 4-{6_(3,5_二氣·苯基)_7_ 曱氧基-2-[4_(3-甲基-丁基 三嗤-1-基卜5_側氧基_2,3_二氫_m,5H-吡哩_7a-基甲基}苯 甲腈(表實例5 9之化合物);及 4-{(2S,7aS)-6_(3,5_二氣·苯基)-2-[5·碘-4-(3-甲基-丁醯胺)一 [1,2,3】二唑_1_基】-7-甲氧基-5-侧氧基_2,3_二氫- ΐϋ,5ΙΙ-吡 哩-7a-基曱基}-苯曱腈(表實例6〇之化合物) 向1〇〇 mg 4-[(2S,7aS)-2_疊氮基冬(3,5-二氯苯基)7甲 氧基-5-側氧基-2,3-二氫-1H,5H-吡哩-7a-基甲基]-苯曱腈 (表實例74之化合物)及〇·ΐ4 ml 5 -甲基-1·己炔之經授拌溶 液中添加42.8 mg蛾化銅(I),且將所得混合物於室溫下攪 拌約20小時。為處理之目的,以EtOAc及飽和NaHC03水溶 液處理所得混合物。使蒸發殘餘物經歷管柱層析。 獲得呈固體形式之4-{(2S,7aS)-6-(3,5-二氯-苯基 曱基-丁基)-[1,2,3] 三唑-1-基]-7-甲氧基-5-側氧基-2,3-二氫吡哩-7a-基甲基}•苯曱腈(ms: 698 (MNa+)); 4-{(2S,7aS)-6_(3,5-二氯-苯基)-7·甲氧基-2·[4-(3·甲基-丁醯 胺)-[1,2,3]三嗤-卜基]-5-側氧基-2,3-二氫-1Η,5Η-吼哩- 7a-基甲基卜苯甲腈(MS: 586 (MNa+)); 114891.doc -68- 200800169 4-{(28,7&8)-6-(3,5-二氣-苯基)-7-甲氧基-2-[4-(3_甲基_丁 基)_[1,2,3]三唑-卜基]_5_側氧基-2,3-二氫_1H,5Hu比哩_7a 基甲基}-苯甲腈(MS: 572 (MNa+));及 4-{(28,7&8)-6-(3,5-二氯-苯基)-2-[5-填-4-(3-甲基-丁酿美) [1,2,3]三唑-1-基]·7-甲氧基-5_側氧基-2,3-二氯-哩-7a_基甲基}•苯甲腈(MS: 712 (MNa+))。 以類似於先前實例所述之方法,而使用適當起始物^ (中間物),獲得式I化合物,其為下式之化合物:
IpREF
R 其中環八為式八1、八2、八3、八4或八5且豆中只、〇 /、,八1 、R3、 R4、I及R6如以下表1所定義。分析資料(質譜)亦於表^中 給出。發現以下表!中所述之該等化合物之 NMR資料與所提出之結構一致。 _
實例 33、34、38、 中間物之化合物。 44及45係指可用作製備式工 PREF化合物之 114891.doc 69- 200800169 表i
114891.doc -70- 200800169 資料丨 MS: 668 (MHT) MS: 545/1067 MS: 529/1035 MS: 382/741 I (MNa^MNa^ (ΜΝ^/2ΜΝα) (MNa+GMNa, | 實例9 實例10 實例11 實例12 III 環A 基團A3 基團A5 基團A5 基團A5 Ri - - r2 苯基 苯基 苯基 苯基 r3 /Η ό / /Η /Η R4 H3C3〇y/CH3 H3C3^|/CH3 H3C3〇!^/CH3 H3C3〇^CH3 H3C—Si—CH3 1 H3c—S1-CH3 1 H3C—Si—CH3 1 H3C—Si—CH3 1 。、 0、 0', 〇、 Rs - - - - R6 och3 OH OCH3 OH 資料 MS: 382/741 MS: 536/1049 MS: 382/741 MS: 346/368/713 (MNa+/2MNa+) (MNa^MNa4) (MNa^MNa^ (M^/MNa^MNa^ -- ) 實例13 實例14 實例15 實例16 環A 基團A5 kfflA5 基團A1 基團A4 Ri CN 0 R2 苯基 苯基 苯基 苯基 R3 /H /Η /Η R4 1 H3ciyCH3 Η3σΛ/0Η3 h3c ch H3C^^M3 Η〆一Si—CH3 1 H3C—Si—CH3 H3c—Si~CH3 1 H3C—S1-CH3 1 0', 1 0、 11489Ldoc 71 · 200800169
114891.doc -72- 200800169
R4 h3c Η3(:Ιγ^Η3 h3c-甲卜 ch3 h3c h3c^a/OH3 H3C—Si—CH3 A、 H3C3〇^CH3 H3C—Si_CH3 A', h3c ch H3CA^C 3 H3C—S1-CH3 Rs - 垂 - R6 c CH. Φ 0 1 ( r :N 广ch2 Λ .0 .SL / h3c 1 ch3 ch3 資料 MS: 522/1021 (MNa+/2MNa, MS: 483/943 (MNa^MNa^ MS: 408/793 _a+/2MNa, MS: 478/933 (MNa+/2MNa+) 實例25 實例26 實例27 實例28 環A 基團A5 基團A5 基團A5 基團A5 Ri - - - - r2 3,5-二氯苯基 3,5-二氯苯基 3,5-二氯苯基 3,5-二氯苯基 Ra Br ό 〆 〔 、、'〕 0 Br ό R4 N \、+ N \、 N \ Η2Νχ 0 丫 CH3 HN、 0 丫 ch3 HN、 Rs - - - - R6 OH OH 0 丫 CH3 /〇 OH 資料 MS: 492 (MH+) MS: 389 (MH+) MS: 495 (MNa^) MS: 530 (MiT) 實例29 實例30 實例31 實例32 環A 基團A5 基團A5 基團A5 基團A5 Ri - - - - Ri 3,5-二氯苯基 3,5-二氯苯基 3,5-二氯苯基 3,5-二氯苯基 114891.doc -73- 200800169
Rs ό lj '、〆 ,CH /1 R4 o 丫 ch3 HN、 N_ 、N+、 、N \ h3c H3C^V^ 3 HX—Si-CH3 3 1 3 〇、 h3c … H3C〇y^CH3 H3C—Si—CH3 K Rs - - - - R6 och3 och3 OH OH 資料 MS: 545/1067 (MNa+/ 2MNaf) MS: 529/1035 (MNa+/2MNa+) MS: 474/925 (MNa+/2MNa+) MS: 474/925 (MNa+/2MNa+) 實例33 中間物 I 實例34 中間物 實例35 實例36 I Jll 環A 基團A5 基團A5 基團A1 基團A1 Ri - - h3c’、 H〜 R2 苯基 3,5-二氯苯基 苯基 苯基 Ra 、,H t r 〆 3r /H ,、H R4 HO、 HO、 H3〇iyCH3 H3C-Si-CH3 〇、 H3ciy-CH3 H3C-Si~CH3 〇、 r5 - L:___ - Γ-- R6 OH OH MS: 382/741 (MNa+/2MNa+) 資料 MS: 254/485 (MNa+/2MNa+) MS: 579 (MNa十 + EtOAc) MS: 396/769 (MNa+/2MNa^i EZ 環A 實例37 |實例38中間物 實例 i 丨 - - — | | 實例40 基團A1 II基團A1 基團A1 丨基團A1 —1 114891.doc -74 - 200800169
114891.doc -75- 200800169
環A
Ri R2 r3 R4
Rs R6 實例45中間物 實例46 實例47 實例48 基團A5 基團A5 基團A5 基團A5 3,5-二氯苯基
H3C^^0, och3 資料 MS: 493/963 Ja^MNa^) 實例49 3,5-二氯苯基
CN
N
OH MS : 462 (MNa+) 實例50 3,5-二氯苯基
CN
H2N, OCH3 MS: 428 (MH+)5 450 (MNa+) 實例51 3,5-二氯苯基
HH3〆% OCH3 MS: 528 (MNa+) 實例52
環A 基團A5 基團A5 基團A5 基團A5
Ri R2 R3 3,5-二氯苯基
3,5-二氯苯基
3,5-二氯苯基
3,5-二氯苯基
Re OCH3_ 資料 MS:534(_a+) OCH3 MS: 5554 (MNa+) OCH3_ —MS: 506/989~ (MNa+/2MNa+) OCH3_ MS: 510/997~ (MNa+/2MNa+) 114891.doc -76 - 200800169 以類似於先前實例所述之方法,而使用適當起始物質 (中間物),獲得下式之化合物:
CN CN
'4EX CI
1 4EX CI ,諸如下式之化合物 其中R4EX如以下表2所定義。分析資料(質譜)亦於表2中給 出。發現以下表2中所述之該等化合物之1H-NMR及13C-NMR資料與所提出之結構一致。 表2
實例53 實例54 實例55 實例56 R4 T 〇 0 丫 ch3 h3c^nv och3 Ν ' % N ' Ά 資料 MS: 582/1141 _a+/2MNa+) MS: 582/1141 (MNa+/2MNa+) MS: 560 (MNa, MS: 578 (MNa+) 實例57 實例58 實例59 實例60 R4 CH3^.CH3 Ύ丨 Ν—Ν ' h3c ch3 v〇 A Ν—Ν' ch3 丫 ch3 Λ Ν—N \ h3c ch3 v〇 Ν—N \ 114891.doc •77- 200800169
114891.doc -78 -
Claims (1)
- 200800169 十、申請專利範圍: 1 · 一種下式之化合物:其中環A為下式之基團:r3〇 r2 A5 Ri為(C^8)烷基、(C^8)烯基、(C^)炔基或經以下基團取代 之(Ciu)烧基、(C2-18)烯基、(C2-18)炔基:-(Cm)烷氧基; -矽烷基或矽烷氧基; -(C3.18)環烷基; -(C6-18)芳基;或 -雜環基; R2為(C3-I8)環炫基、(C3-I8)芳基或雜環基; R3為氫或未經取代之(Cu)烷基、(C2-8)烯基、(C2_8)炔基 或經以下基團取代之(Ch8)烷基、(C2·8)烯基、((:2.8)炔 114891.doc 200800169 基· • (^3-18)¾ 烧基; -(C3-18)芳基;或 -雜壞基; R4為 三(Cu)烷基矽烷氧基、N3、胺基、(c1-8)烷基胺基、(C卜8) 一烧基胺基、(C3-8)環烧基胺基、(C2-I8)醯胺基、((C2-18) 醯基)-((Ci-4)烧基))-胺基、(CK4)烧基續醯基胺基、(C6-12) ⑩ 芳基磺醯基胺基、(C3-8)環己基磺醯基胺基,或R4為包含 至少一個作為雜原子之氮原子且經由該氮原子結合至式I 化合物之雜環基; R5為氫、未經取代之(C^s)烷基、(c2-18)烯基、(c2-18)炔 基或經以下基團取代之(c1-18)烷基、(C2-18)烯基、(c2-18) 炔基: -(Ci-4)烷氧基·, _ -三(Cl_6)燒基矽烷基、三(Ci-6)烷基矽烷氧基; -(c3_18)環烷基; -(C6-18)^"基’諸如(C6-12)芳基;或 -雜ί哀基; 鵪 R6為 OR7 或 SR7, r7為氫、基團(so)2-R9,其中R4(Ci-4)烷基或(C612)芳 基、c〇R8、csr8,未經取代之(Ci i8)烷基、(C218)烯基 或(C2-U)炔基,或經以下基團取代之(Cii8)烷基、(C218) 114891.doc 200800169 烯基或(c2_18)炔基: (Cm)烧氧基,二(C1-0)烷基矽烷基,三(Cu)烧基矽烷 氧基,(C3-1S)環烧基,(C6.1S)芳基,或雜環基; I為(Ch8)環烷基、(Cws)芳基、雜環基、未經取代之 (Cbu)烧基、(Cud烯基或(c^8)炔基,或經以下基團取 代之(Cbu)烷基、(c2_18)烯基或(c2-18)炔基: -(C3-18)環烷基,(c6_18)芳基,或雜環基; 其中 環燒基、芳基或雜環基未經取代或經下列一或多個基團 取代: (CW6)烷基、((:2·16)烯基、(C216)炔基、(c3 8)環烷基、 苯基、苄基、雜環基、(Cr-4)鹵代烷基、(Cbs)烷氧基、 苯氧基、側氧基、(C2-13)醯基、(C2-13)醯氧基、胺基、 (Ck6)烷基胺基、(Cw)二烷基胺基、(c2.13)醯胺基、硝 基、氰基、鹵素、(¢:^4)烷基磺醯基、甲苯基磺醯基、三 (Cl·6)烷基矽烷基或三(Cl6)矽烷氧基,且 其中雜環基包含: -脂族及芳族雜環基; -3至8個環成員; -1至4個選自N、0、S之雜原子; -稠合雜環基,諸如與另一環(系統)稠合之雜環基, 其限制條件為:若R4為雜環基,則該雜環基包含至少一 個作為雜原子之氮原子且經由該氮原子結合至式1化合 物。 114891.doc 200800169 2.如請求項1之化合物,其中 環A係如請求項1所定義; Rl為未經取代之(Cr_6)烷基、(C2-6)烯基、(C2-6)炔基,或 經以下基團取代之(Ci-6)烷基、(C2-6)烯基或(C2_4)炔基: -(C6-U)芳基; -三(Cb6)烷基矽烷基、三(Cu)烷基矽烷氧基; R2為視情況經取代之(C6-18)芳基; R3為氫、(c2-6)烯基、(c2-6)炔基或(c6-12)芳基(c^)烷 ® 基、 R4為三(Cu)烷基矽烷氧基、n3、胺基、(Ci-4)烷基羰胺 基、(Α·4)烷基磺醯胺基、(c6_12)芳基羰胺基、N-GCy) 烧基羰基hN-aCw)烷基)-胺基、N-((C6-12)芳基(Cw)烷 基羰基)-N-((Ci_4)烧基)-胺基或包含5或6個環成員及至少 一個氮原子且經該氮原子結合至式I化合物之芳族雜環 基; ^ R5為氫或經(C6_18)芳基取代之(Cw)烷基; R6 為 OR7 ’ R7為氫、(Cu)烧基、(Ci-8)烧氧基(Ci-8)烧基、(C2-8)烯 基、(C2·8)块基、經三(Ci·4)烧基取代之(C2·8)炔基、經苯 基取代之(Ci-4)烷基、(SO)2-R9基團或COR8, 烷基;且 R9為(C6-12)芳基, 其中芳基視情況經(C^6)烷基、(C3-8)環己基、諸如甲基 魏基之(Cl·4)烧基幾基、(Cl·4)烧氧基幾基、鹵素、氰 114891.doc 200800169 基、胺基羰基、包含5至6個環成員及1至4個選自N、0、 s之雜原子之雜環基或三(Ci6)烷基矽烷基取代。 3 ·如請求項1或2中任一項之化合物,其中 環A係如請求項1所定義; Ri為甲基、乙基、丙烯-3-基、1-(三甲基矽烷基)丙炔-3- 基或氰基苯基甲基; R2為二鹵代苯基; I為氫、丙二烯基、丙炔基、苄基、氰基苯基甲基、鹵 代苯基甲基或u密咬幷苯基甲基; R4為(第三丁基)(二甲基)矽烷氧基、Ν3、胺基、甲基羰 胺基、第三丁基羰胺基、苯基羰胺基、Ν_甲基羰基-Ν_ 甲基-胺基、Ν-苄基_Ν-曱基羰基-胺基、Ν-乙基曱基 羰基-胺基、甲基磺醯胺基或經由氮雜原子結合至式I化 合物之經取代三嗤基,其中三嗤基經以下基團取代:異 丁基、異戊基、正三癸基、環戊基、苯基、甲氧基羰 基、1-甲基-丙基羰基、異丙基羰基、十二烷基羰基、側 氧基、鹵素、三(Ci-4)烷基矽烷基或。比啶基; R5為氰基苯基; 尺6為〇R7,且 R7為氫、甲基、丙烯基、三曱基矽烷基_丙炔基、氰基苯 基甲基、曱苯基磺醯基或曱基羰基。 4. 如請求項1至3中任一項之化合物,其係呈鹽形式。 5. 如請求項1至4中任一項之化合物,其係用作藥物。 6· 一種醫藥組合物,其包含併與至少一種醫藥賦形劑結合 114891.doc 200800169 之如請求項1至4中任一項之化合物。 7 種冶療疾病之方法,其中該疾病係藉由與細胞黏接、 遷移及活化活性有關之LFA-1與其配位基之相互作用介 導’該治療包含投予需要該治療之受檢者治療有效量之 如明求項1至4中任一項之化合物。 8 ·如睛求項1至4中任一項之化合物,其係用於製造供治療 由與細胞黏接、遷移及活化活性相關之LFA-丨與其配位 基相互作用介導之疾病的藥物。 9· 一種如請求項1至4中任一項之化合物與至少一種第二藥 物之組合。 10·如請求項1至4中任一項之化合物,其併與至少 種第 藥物組合以用於如請求項5、7或8中任一項 11 一種化合物,其係選自由下列各化合物組成之群: 1,6-二羥基-7a-甲基-2-笨基_5 6 7 7 ,,7,7a·四H里-3-酮(諸 如:二羥基_7a•甲基_2_苯 ’u,/,7a_ 四氫- 吼哩-3 ; 7a-(4-漠-节基叫,二氣·苯基…二羥基-5,6,7,7a-四氫-σ比哩-3-酉同)土 下式之化合物: 114891.doc -6 - 200800169下式之化合物:OHOH及 乙酸7a-(4-氰基-苄基)-6-(3,5-二氯-苯基)-7-曱氧基-5-側 氧基-2,3,5,7&-四氫-11^吡哩-2-基酯(諸如乙酸(8)-7&-(4- 114891.doc 200800169 氰基-节基)-6-(3,5-二氯-苯基)-7_甲氧基-5-侧氧基- 2,3,5,7 a _ 四氣-1Η 11比哩-2 -基 S旨)。114891.doc 200800169 七、 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: 八、 本案若有化學式時,請揭示最能顯示發明特徵的化學式:114891.doc
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