TW200300681A - Carboxylic acid derivative compound and medicament containing same as active ingredient - Google Patents
Carboxylic acid derivative compound and medicament containing same as active ingredient Download PDFInfo
- Publication number
- TW200300681A TW200300681A TW091132640A TW91132640A TW200300681A TW 200300681 A TW200300681 A TW 200300681A TW 091132640 A TW091132640 A TW 091132640A TW 91132640 A TW91132640 A TW 91132640A TW 200300681 A TW200300681 A TW 200300681A
- Authority
- TW
- Taiwan
- Prior art keywords
- amino
- ethoxy
- allyl
- acetic acid
- benzyl
- Prior art date
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- 239000003814 drug Substances 0.000 title claims abstract description 25
- 239000004480 active ingredient Substances 0.000 title claims abstract description 9
- -1 Carboxylic acid derivative compound Chemical class 0.000 title claims description 99
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- 239000003795 chemical substances by application Substances 0.000 claims abstract description 39
- 150000003839 salts Chemical class 0.000 claims abstract description 37
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- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 208
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 125
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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Description
200300681 經濟部智慧財產局員工消費合作社印製 Α7 五、發明說明(1 ) [發明所屬之技術領域] 本智明係有關魏酸衍生物化合物 詳言之,本發明係有關 (1)通式(I)
(式中,所有符號與後述者同意義)所示之羧酸衍生物化合 物或該等之非毒性鹽、 (2) 該等化合物之製造方法及 (3) 含有該等化合物作為有效成分之藥劑。 [先前技術] 最近,在研究與脂肪細胞分化標識基因之表現誘導相 關之轉錄因子時,核内受體之過氧化微粒增殖藥活性化受 體(Peroxisome Proliferator Activated Receptor ;以下簡稱 為PPAR受體)廣受注目。PPAR受體從各式各樣動物種類 cDAN選殖’發現複數之同型(isoform)基因,已知於哺乳 類有 CC、5、T 3 種類(參照 J · S t e r 〇 i d B i 〇 c h e m. Μ ο 1 e c B i ο 1 11,1 57(1994) ; Gene Expression,生,281(1995) ; Biochem
Biophys. Res. Commum.,224· 43 1 (1996) ; Mol. Endocrinology,4, 1 63 4( 1992))。r 型主要表現於脂肪組 織、免疫細胞、腎上腺、脾臟、小腸,α型主要表現於脂 肪組織、肝臟、視網膜,(5型未見組織特異性,而係普遍 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 314159 ---------------------訂---------線 (請先閱讀背面之注音?事項再填寫本頁) 200300681 A7 五、發明說明(2 地表現(參照 Endocrinology,jj_?9 354(1996)) 已知以下所示之噻嗤烧衍生物為騰島素非依賴型糖尿 病(NIDDM(Non-Insuline Dependent Diabetes Mellitus))之 治療藥’為用以改正糖尿病病患高血糖所制之降血糖 劑。其顯示改正或改善高胰島素血症、改善耐糖能或降低 血清脂質之效果,為極有希望作為胰島素抵抗性改善藥之 化合物。
匹歐利他松(Piogl i tazone)
ο
G 系利他松(sigli tazone)
I I--------^--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 該等噻唑烷衍生物之細胞内標的蛋白質之一為ppA々 受體,判定可增大PPARy之轉錄活性(參照End〇crin〇1〇gy,112, 4189(1996); Cell,Βχ 803(1995); Cell,狂 8 13(1 995); J· Biol· Chem·,2^,12953(1995))。使 pPARy 轉錄活性增 大之ΡΡΑΙΙγ活化劑(激動劑(ag0nisth咸認可作為降血糖劑 及/或降脂質劑。由已知ΡΡΑΙΙγ激動劑可亢進ρρΑΚγ蛋白 本身之表現(Genes & Development,!〇_,974(1996)),而認為 不僅可使ΡΡΑΙΙγ活化,在臨床上亦可作為使ppARy蛋白 本身表現增加之藥劑使用。 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 2 314159 200300681 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(3 ) 已知核内受體ΡΡΑΙΙγ與脂肪細胞分化有關(參照J.
Biol· Chem·,211,5637(1997)及 Cell,ϋ,803(1995)),已知 可使ΡΡΑΙΙγ活化之噻唑烷衍生物可促進脂肪細胞分化。最 近有於人類,噻唑烷衍生物可使體脂肪增生、體重增加、 引起肥胖之報告(參照Lancet,952(1997))。因此認為 抑制ΡΡΑΙΙγ活性之拮抗劑(antagonist)或可減少ρρΑΚγ蛋 白本身表現之藥劑亦可用於臨床上。於Science,274, 2100 (1996)介紹可經由將?1>八^^磷酸化而抑制1>1>八1^活性之化 合物,由此認為雖不與ΡΡΑΚγ蛋白結合但抑制其活性之藥 劑亦可用於臨床上。 由此可知,ΡΡΑΙΙγ受體之活化劑(激動劑)或可增加蛋 白本身表現之ΡΡΑΙΙγ蛋白表現控制劑期待可作為降血糖 劑、降脂質劑、糖尿病、肥胖、χ徵候群、高膽固醇血症、 同月曰蛋白血症等代謝異常疾病、高脂血症、動脈硬化症、 问血壓、循環器系疾病、過食症等之預防及/或治療劑使 用。 另一方面’可抑制PPARy受體轉錄活性之拮抗劑或可 抑制蛋白本身表現之ρρΑΚγ蛋白表現控制劑期待可作為 降血糖劑、糖尿病、肥胖、X徵候群等代謝異常疾病、高 月曰血症、動脈硬化症、高血壓、過食症之預防及/或治療劑 使用。 以下所不之貝特(fibrate)系化合物,例如已知氯貝特 (clofibrate) --------------------訂---------線 (請先閱讀背面之注音心事項再填寫本頁)
314159 200300681 A7 B7 經濟部智慧財產局員工消費合作社印製 4 五、發明說明(4
0> 為降脂質劑,判定貝特系化合物之細胞内標的蛋白質之一 為 PPARa 受體(參照 Nature,347: 645(1990) ; J. Steroid
Biochem· Molec. Biol·,11,157(1994) ; Biochemistry,11, 5 5 98(1993))。由此可知貝特系化合物為可活化ppAR α受 體之控制劑,咸認具有降低脂質之作用,期待可作為高脂 血症等之預防及/或治療劑使用。 除此之外’與PPAR α相關之生物活性最近於w〇 9736579號說明書有具有抗肥胖作用之報告。於厂 1^5.,1£,17(1998)之報告指出有經由1^八1^受體之活 化,可使高密度脂蛋白(HDL)膽固醇上昇,具有降低低密 度脂蛋白(LDL)膽固醇或超低密度脂蛋白(vldl,固醇, 尤其是三酸甘油酯之作用。於Diabetes,处,348(ι 997)之報 告確㈣特系化合物之—之苯扎貝特有改善血中m组 成或高血壓,改善胰島素抵抗性之作用。活化PPARa接 受體之激動劑或使PPAR 蛋白太 α史白本身之表現亢進之PPAR α 控制劑不僅可作為降脂質劑、古 午如貝4 同月曰血症治療藥使用,還具 有提昇高密度膽固醇作用、減少低密度膽固醇及/或超低密 度膽固知之作用,因此期待有抑制動脈硬化進展、治㈣ 脈硬化或抑制肥胖之效果, 士 _ 亦^付作為降血糖劑可治療或 頂防糖尿病、改善高岛厭 _血壓、減輕χ徵候群之危險因子或預 尺度適用中關家標、 314159 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 200300681
五、發明說明(5 ) 防虛血性心疾病發症。 另-方面,很少有關使P P A R δ受體有意義地活化之配 位體或與ΡΡΑΪΙδ受體所參予生物活性之報告。 ΡΡΑΙΙδ有日可亦稱為PPARp或人類時亦稱為nuci。至 今PPARS之生物活性於w〇96〇143〇號說明書揭示 (與人類NUC1有1個胺基酸不同之ppAR亞型)可抑制人 類PPARct或甲狀腺荷爾蒙受體之轉錄活性。最近於w〇 9728149號說明書指出發現對於ppARS蛋白質具有高親和 性,使ΡΡΑΙΙδ有意義活化之化合物(激動劑),該等化合物 具有提昇高密度(高密度脂蛋白)膽固醇之作用。因而,可 使ΡΡΑΪΙδ活化之激動劑具有提昇高密度膽固醇之作用,期 待可應用於抑制動脈硬化進展、治療動脈硬化、降脂質劑 或降血糖劑’認為亦可用於治療高脂血症、降血糖劑、> 療糖尿病、減輕X徵候群之危險因子或預防虛血性心疾病 發症。 — 於WO01 2 1602號揭示有通式(Α)
,2bA -------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 (2aA V R p3A气^丫彳χΧη2)2,‘υ
〇2cA AA"\R1A (A) (式中,χΑ為1、2、3或4,mA為1或2,n為1或2, 為碳原子或氮原子,Aa為氧原子或硫原子、ZA為氧原」 或單鍵,R1A為氫原子或烷基,Xa為ch或氮原子,R2a 氫原子或烷基等,RM、rM及為氫原子、烷基、 本紙張尺㈣財關家標準(CNS)A4 g⑵G x 297 ^ 5 314159 200300681 A7 B7 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 五、發明說明(6 ) 氧基、鹵素原子、胺基或經取代之胺基(經取代之胺基為經 1至2個相同或不同之烷基、芳基、芳烷基、雜芳基、雜 芳烷基、環雜烷基、環雜烷基烷基、環烷基、環烷基烷基、 鹵化烷基、羥基烷基、烷氧基烷基、硫烷基等基取代之胺 基,或胺基之取代基與所結合之氮原子一同形成1 ·吡咯烧 基、· 1 -六氫吡啶基、1 -吖庚因基、4-嗎啉基、4-硫代嗎啉基、 六氫吡畊基、4-烷基-1-六氫吡哄基、4-芳烷基-1-六氫吼 >哄基、4-二芳基烷基-1-六氫吡哄基、1-吡咯烷基、丨·六氫 吡啶基、1-吖庚因基(此等基可經烷基、烷氧基、烷硫基、 鹵素原子、三氟甲基、羥基取代),r3a為氫原子、烧基、 芳烷基等,丫為C〇2R4A(R4A為氫原子、烷基)等)所示之氧 雜或噻唾衍生物及該等之藥學所容許之鹽可作為抗糖尿病 及抗肥胖劑使用(式中之基係摘錄必要之部分加以說明)。 [發明内容] 本發明人等為了發現具有控制ppAR受體作用之化合 I物,經過不斷地深入研究之結果發現通式⑴所 口 化合物可達到目的,因而完成本發明。 本發明係有關 (1)通式(I)所示之羧酸衍生物化合物及該等之非毒性鹽: 令-z R4 R2 /R3 X—N一C 一 CO〇r1
-------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 示之本發明 (0 314159 6 200300681 A7 B7 五、發明說明(7 ) Z為-0-基或-s-基、 R1、R2、R3及R4各自獨立為氫原子或C R5為C2_8鏈烯基、 A為-基或-S-基、 D 為 、D2、Ο3、D4 或 D5、 D]為Cw :):完基、(R^)m d2 為、 烷基 環1為含有1個氮原子及另可含有1個選自氧原子、 子或氮原子之雜原子之3至7員單環之飽和雜芳基、 硫原
(1) 一部分或全部經飽和之C3·】。單環或二環式碳产_ (2) 含有1至4個選自氧原子、氮原子或硫 人衣方基」 亲隹~7 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製
0-0-' D5 為《R、-、 D6為(1)氫原子、(2)Cb8:J:完基、(3)CKS燒氧基、 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐)
3]4]59 200300681 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(8 ) (5)OCF3基、(6)鹵素原子、(7)硝基或(8)NR7R8基、 R7及R8為氫原子或C^8烷基或 R7及R8亦可與所結合之氮原子一同形成含有1個氮原 或更可含有1個選自氧原子、硫原子或氮原子之雜原子+ 3至7員單環之飽和雜芳基、該飽和雜芳基亦可細 之 基取代、 、^“烷 E為CH或氮原子、 γπ為1至3之整數)、 (2) 該等之製造方法及 (3) 含有該等化合物作為有效成分之藥劑。 本說明書中,Cy烷基為甲基、乙基、丙基、丁基、 戊基、己基、庚基、辛基及該等之異構體。 本說明書中,C2·8鏈烯基為乙烯基、丙烯基、丁烯基、 戊烯基、己烯基、庚烯基、辛烯基及該 ,說明書中,U氧基為曱氧基、乙氧基冓:氧基、 丁乳基、戊氧基、己氧基、庚氧基、辛氧基及該等之異構 體。 本說明書中’伸院基為伸甲基、伸乙基、伸丙基、 伸丁基及該等之異構體。 本說明書中’函素原子為氯原子、漠原子、氣原子、 碘原子。 本說明書中,環1所示之含有1 ^ 令Μ固虱原子,更可含有 ^固選自氧原子、硫原子或氮原子之雜原子之3至7員單 上餘和雜芳基可列舉氮雜」f丙烧、氮雜環丁按、…早
本紙張尺度刺巾關家鮮(CNS)A4祕⑵Q 314159 ^--------^---------^ ftt先閱讀背面之注意事項再填寫本頁) 200300681 A7 五、發明說明(9 ) 味唾义兀、吼唾琳烧、六氯吼σ定、六㈣啡、全氯喷口定、全 氫達畊、全氫吖庚因、全氫二吖庚因、四氫噁唑(噁唑烷)、 :氫異噁唑(異噁唑烷)、四氫噻唑(噻唑烷)、四氫異噻唑(異 噻哇烧)、四氫嗔曉、全氫討庚因、四氫噻嗦、全氯㈣ 庚因、嗎啉、硫代嗎啉等。 土 f 本,兒月書中,R及R7與所結合之氮原子一同形成含 有1個氮原子,更可含有1個選自氧原子、硫原子或氮原 子之雜原子之3至6員單環之飽和雜芳基可列舉氮雜環丙 烷:氮雜竦丁烷、吡咯烷、咪唑烷、吡唑啉烷、六氫吡啶、 六鼠D比哄、全氣口密σ定、全新σ逢晚 疋王式選〇井、四氫噁唑(噁唑烷)、四 經濟部智慧財產局員工消費合作社印製 氮異嗔唾(異嗔。坐燒)、四氫噻唾(噻嗤院)、四氯異嚷 嘻嗤烧)、四氮。惡嗦、四氫噻嗪、嗎啉、硫代嗎啉等。” 本說明書中,環2所示可一部分或全部為飽和之c 單環或二環式碳環其可列舉環丙燒 '環丁烧、環戊院、= 己烧、環庚炫、環辛烧、環壬垸、環癸燒、環丙稀、環衣 稀、環戊稀、環己稀、環庚稀、環辛稀、環戍二稀、^ 二稀、環庚二=、環辛二稀、笨、戍搭稀、f、全氮算' 全氫戊搭稀、印、全氫印、萌滿、蔡、四氣蔡、全氣萃等。 噻吩 本說明書中,環2所示含有1至4個選自氧原子、氮 原子或硫原子之雜原子,可-部分或全部為飽和之3至;〇 員單環或二環式雜芳基中’含有丨至4個選自氧原子、^ 原子或硫原子之雜原子之3至10員單環或二環式雜芳基二 列舉吡咯、咪唑、三唑、四唑、吡唑、吡啶、吡嗪、嘧二、 噠哄、吖庚因、二吖庚因、呋喃、吡喃、噁庚因、山疋、 本紙張尺度適用中國國家摞率(CNS)A4規格(210 X 297公釐) 314159 200300681 經濟部智慧財產局員工消費合作社印製 Α7 Β7 五、發明說明(1G ) 硫因、噻嗯、噁唑、異噁唑、噻唑、異噻唑、咲咱、噁二 唑、噁嗪、噁二嗓、噁庚因、噁二庚因、噻二唑、噻嗪、 噻二嗪、噻吖庚因、噻二吖庚因、吲哚、異吲哚、吲哚嗦、 苯并呋喃、異笨并呋喃、苯并噻吩、異苯并噻吩、二硫萘、 吲唑、喹啉、異喹啉、喹畊、嘌呤、酞嗪、蝶啶、萘錠、 喹喔啉、喹ϋ坐啉、。曾啉、苯并鳴、。坐、苯并噻嗤、苯并Π米。坐、 色烯、苯并呋咱、苯并噻二唑、苯并三唑等。 > 又,含有1至4個選自氧原子、氮原子或硫原子之雜 原子,一部分或全部為飽和之3至1 0員單環或二環式雜芳 基可列舉氮雜環丙烷、氮雜環丁烷、吡咯啉、吡咯烷、咪 口坐啉、咪。坐烧、三。坐啉、三。坐:):完、四嗤啉、四峻:):完、D比峻 啉、D比。坐烧、二氫D比tr定、四氫D比。定、六氫D比唆、二氫D比嗪、 四氫1:1比嘻、六氫D比哄、二氫密17定、四氫,σ定、全氫ϋ密σ定、 二氫噠哄、四氫噠畊、全氫噠畊、二氫吖庚因、四氫吖庚 因、全氫吖庚因、二氫二吖庚因、四氫二吖庚因、全氫二 I吖庚因、環氧乙烷、氧雜環丁烷、二氫呋喃、四氫呋喃、 二氫D比喃、四氫D比喃、二氫噁庚因、四氫噁庚因、全氫噁 庚因、硫化乙烯、硫雜環丁烷、二氫噻吩、四氫噻吩、二 氫硫因(二氫噻喃)、四氫硫因(四氫噻喃)、二氫噻嗯、四氫 噻嗯、全氫噻嗯、二氫噁唑、四氫噁唑(噁唑烷)、二氫異 噁唑、四氫異噁唑(異噁唑烷)、二氫噻唑、四氫噻唑(噻吐 烷)、二氫異噻唑、四氫異噻唑(異噻唑烷)、二氫呋咱、四 氫咲咱、二氫嗔二嗤、四氫噁二。坐(噁二唑:):完)、二氫嗔嗪、 四氫噁嗪、二氫噁二嗪、四氫噁二嗪、二氫噁吖庚.因、四 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 10 314159 200300681 經濟部智慧財產局員工消費合作社印製 A7 _B7 五、發明說明(1 2 ) 氫噁吖庚因、全氫噁吖庚因、二氫噁二吖庚因、四氫噁二 吖庚因、全氫噁二吖庚因、二氫噻二唑、四氫噻二唑(噻二 唑烷)、二氫噻嗦、四氫噻嗪、二氫噻二嗪、四氫噻二嗪、 二氫噻吖庚因、四氫噻吖庚因、全氫噻吖庚因、二氫噻二 吖庚因、四氫噻二吖庚因、全氫噻吖庚因、嗎啉、硫代嗎 啉、噁噻烷、吲哚滿、異吲哚滿、二氫苯并呋喃、全氫苯 并咲喃、二氫異苯并咲喃、全氫異苯并咲喃、二氫苯并噻 吩、全氫苯并噻吩、二氫異苯并噻吩、全氫異苯并噻吩、 二氫吲唑、全氫吲唑、二氫喹啉、四氫喹啉、全氫喹啉、 二氫異喹啉、四氫異喹啉、全氫異喹啉、二氫酞嗦、四氫 酞嗪、全氫酞嗪、二氫萘錠、四氫萘錠、全氫萘錠、二氫 嗤喔啉、四氫喹喔啉、全氫喹喔啉、二氫喹唾啉、四氫_ 嗤啉、全氫喹唑琳、二氫噌啉、四氫噌啉、全氫噌啉、苯 并噁噻烷、二氫苯并噁嗪、二氫苯并噻嗪、吡嗦嗎啉、二 氫苯并噁唑、全氫笨并噁唑、二氫苯并噻唑、全氫苯并噻 唑、二氫苯并咪唑、全氫笨并咪唑、二氧雜環戊烧、二氧 雜環己烷、二硫雜環戊烷、二噻烷、二噁茚滿、苯并二口惡 烷、色滿、苯并二硫雜環戊烷、苯并二噻烷等。 本發明中未特別指示時包含所有之異構體。例如烷 基、烷氧基及伸烷基係包含直鏈及支鏈基。此外,雙鍵、 環、稠環之異構體(E、Z、順式、反式體)因不對稱碳存在 產生之異構體(R、S體、α、/3體、對映異構體、非對映 異構體)、具有旋光性之光學活性體(D、L、d、1體)、經由 |層析法分離之極性體(高極性體、低極性體)、平衡化合物、 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 1 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 2 314159 200300681 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(12 ) 旋轉異構體、該等任意比例之混合物、消旋混合物均包含 於本發明中。 本發明中為了使業者容易明白,若未特別指明則符號 .··、、、''為結合於紙的對面(亦即α -構型),/為結合於紙的跟前 (亦即/3 -構型),〆為α -、/3 -或該等之混合物,/為α -構型與/3 -構型之混合物。 本發明化合物可以公知之方法轉換為非毒性鹽。 > 非毒性鹽以藥學所容許,為水溶性者較理想。 本發明化合物之非毒性鹽可列舉鹼金屬(鉀、鈉、鋰等) 鹽、鹼土金屬(鈣、鎂等)鹽、銨鹽(四曱銨鹽、四丁銨鹽等)、 有機胺(三乙胺、曱胺、二曱胺、環戊胺、Τ胺、苯乙胺、 六氫吡啶、單乙醇胺、二乙醇胺、三(羥曱基)曱胺、賴胺 酸、精胺酸、Ν-甲基-D-谷胺酸等)鹽、酸加成鹽(無機酸鹽 (鹽酸鹽、氫溴酸鹽、氫碘酸鹽、硫酸鹽、磷酸鹽、硝酸鹽 等)、有機酸鹽(乙酸鹽、三氟乙酸鹽、乳酸鹽、酒石酸鹽、 草酸鹽、富馬酸鹽、馬來酸鹽、苯曱酸鹽、檸檬酸鹽、甲 石黃酸鹽、乙項酸鹽、苯績酸鹽、甲苯確酸鹽、經乙績酸鹽、 葡糖醛酸鹽、葡糖酸鹽等))。 本發明化合物之非毒性鹽包含溶劑化物或上述本發明 化合物之鹼(土)金屬鹽、銨鹽、有機胺鹽、酸加成鹽之溶 劑化物。 溶劑化物以非毒性且為水溶性者較理想。適當之溶劑 化物可列舉水、醇系溶劑(乙醇等)等之溶劑化物。 本發明中,PPAR受體控制劑包含PPAR受體α型、r -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 12 314159 200300681 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明(13 ) 型、U、《型+ 7型、《型+ (5型、^型+ 5型及 型+ 5型控制劑。本發明之理想控制樣式為ppAR受體0型 控制劑、PPAR受體r型控制劑、PPAR受體δ型控制劑、 PPAR文體α型+ r型控制劑、PPAR受體α型+ δ型控制 劑,又以PPAR受體α型+ r型控制劑較理想。 本發明之PPAR受體控制劑亦包含ppAR受體激動劑 及PPAR受體拮抗劑’較好為ppAR受體激動劑,更好為 PPAR受體α型激動劑、PPAR受體y型激動劑、ppAR受 體占型激動劑、PPAR受體,型+ 7型激動齊j、ppAR受於 α型以型激動劑,最好為PPAR受體_ + “激動劑。 本說明書中R5較好為丙烯基,更好為烯丙基。 本說明書中X較好為Cl.2伸燒基(伸甲基、伸乙 更好為伸甲基。 本說明書中Y較好為U燒基(伸甲基、伸乙基), 更好為伸乙基。 本說明書中Z較好為-〇·基或I基,更好為_〇•基。 本說明書中A較好為-〇_基或I基,更好為_〇_基。 ^說明書〇較好為D,、D2、DW,更好為〇3及 D4,最好為D4。 通式⑴所示之化合物中,理想之化合物可列舉通式 (I-A) ' r2r3 N—C-COOR1 (I-A) 本紙張尺度剌中國格⑵G χ 297公^ 314159 ---------------------訂---------線 i^w. ί靖先閱讀背面之注音?事項再填寫本頁) 200300681 A7 B7 五、發明說明(14 ) (式中,所有符號與上 B) 述者同意義)所 示之化合物、通式(I.
R2 /R3 C^COOR1 (I-B) ut ’所有符號與上述者同意義)所 C) 示之化合物、通式(I-
R2戶 •ΝΑ/- COOR1 (I-C) =中,所有符號與上述者同意義)所示之化合物、通式(I.
經濟部智慧財產局員工消費合作社印製
(I-D) (式中,所有符號與上述者同意義)所示之化合物及 E)
R2 R3 X 〜N—C^COOR1 (Ι·Ε) 314159 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 200300681 A7 B7 五、發明說明() (式中,所有符號與上述者同意義)所示 化合4^7 本發明之具體化合物可列舉表1至夺 物、實施例之化合物及該等之非毒性鹽。所不之化合
各表中Me為甲基、Et為乙基、p A Γ為丙基、i-Pr*為昱 丙基、t-Bu為第三_丁基’其他符號與上述者同意義。、 D1 A Z 11 Me .s- ·〇_ 12 E* 各·〇· 13 Pr _s· 〇. 14 i-Pr -s- 〇. 15 t^u .S· 〇· 16 Me 各各 17 Et .S_ 各 18 Pr .s· .S- 19 i-Pr 各各 20 ^Bu _s· --------^---------^ .^w— (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 適 一度 I尺一張 紙一本 格 規 4 A s) N (c 準 標 97
No· D1 A z 1 Me ·〇· ·〇. 2 Et -0- 〇· 3 Pr -O- 4 i-Pr 0- 5 t43u «〇· -0- 6 Me ·〇· -S· 7 Et ·〇· •s· 8 Pr -0- -S- 9 i-Pr -0- -S- 10 t-Bu -Ο- -S- 15 314159 200300681 A7 B7 五、發明說明( 16 表2
ο. R6
A 0· R6
ZA p 1 2 3 4 5 6 7 8 910 ό6ό96ό669 I -- _- 99-09999999 -0--0--0--0--0--S.-S.-S-各各 1 2 3 4 5 6 7 89 s 1 1 1 1111 1 1 2 06s6i6> 〕 -S--S--S--s--s·^·^·-s-^--s.
-099 9-0.S-S-S-S.S --------------裝--- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 16 314159 200300681 A7 B7 五、發明說明( 17 表
-----------------丨—訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 17 314159 200300681 A7 B7 經濟部智慧財產局員工消費合作社印製
五、發明說明(1 〇
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 18 314159 200300681 A7 B7 五、發明說明( 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 °Λ4γ-ζ·〇 表
[實施方式] [本發明化合物之製造方法] (1)通式(I)所示之本發明化合物中R]為CN8烷基之化合 物,亦即,通式(IA) R2严3 X—N-V-COOR1 R5 (ΙΑ) (式令,R1·1為c]-s烷基,其他符號與上述者同意義)戶 本紙張尺玉適用標準(CNS)A4規&⑵〇 x 297公髮)一— ----、斤示 3M】59 ------------Aw%.-------"丨訂---------線 (請先閱讀背面之注意事項再填寫本頁) 19 200300681 A7 B7 五、發明說明(2G ) 之化合物之製造,係使通式(π) 〇6Λΐ Y^R9 (II) (式中’ Μ為脫離基(函素原子、甲伽氧基、甲苯續酿氧 基等)D6與D同意義,但是d6所 不基所含之胺基若需保護 經濟部智慧財產局員工消費合作社印製 時為經保護者。其他符號與上述者 每Μ思義)所示之化合物與 通式(ΙΠ) R(/R3R1°O r5 《叫 (式中’ R】0為OHU SH基,其他符號與上述者同意義) 所示之化合物進行反應,必要時進行保護基之脫保護反應 即可製造。 该反應為公知,例如於有機溶劑(四氫呋喃(ΤΗ]ρ , TdM bydrogenFuran)、乙醚、二氯甲烷、氯仿、四氯化碳、戊 烧、己烧、苯、甲苯、二曱基甲醯胺(dmf,Dimethyl Formamide)、二甲基亞碉(DMS〇,Dimethyl Sulf〇xid)、六 甲基磷醯胺(HMPA,Hexamethylphosphorylamide)等)中, 在鹼(氫化鈉、碳酸鉀、三乙胺、吡啶、碘化鈉、碳酸鉋等) 存在下,於〇至8 〇 進行。 保護基之脫保護反應可根據以下之方法進行。 胺基保護基之脫保護反應為熟知,可列舉 (I)在酸性條件下之脫保護反應、 本紙張尺度適用中國國家標準―4規格⑵〇x 297公餐) 20 314159 --------^---------^ (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 21 200300681 五、發明說明(21 (2)經由加氲公& L刀角午之脫保護反應。 將該等方法加、 石刀π Μ具體說明: (1)在酸性條件π + 、 脫保護反應為例如在有機溶劑(-氯曱烷、氯仿、二。亞^ 7 〜烷、乙酸乙酯、茴香醚、甲醇、乙醇、 異丙醇等)中,或右總、— 一 ^谷劑不存在下或於其水溶液中、有機 文(Λ 氣乙酸、甲石黃酸等)、無機酸m酸、硫酸等) 、― 、、匕虱/乙酸等)中,於0至loot:之溫声 進行。 又 f⑺經由加氫分解之脫保護反應為例如在溶劑(鍵 氫口夫喃、二口惡燒、-田与 _ 一曱虱基乙烷、乙醚等)、醇系(甲醇、 乙醇專)、苯系(笨、曱策耸 y 本寺)、酮糸(丙酮、曱基乙基曱酮等)、 腈系(乙腈等)、驗胺李(- 、 妝乐(一甲基曱醯胺等)、水、乙酸乙酯、 乙酸或該等2種以卜夕、、曰人、— 之此β〉谷劑寺)中,在催化劑(鈀-碳、 鈀黑、氫氧化鈀、氧化鉑、贫 β " 1兀;鎳寺)存在下,於常壓或加 下之風1大氣下或甲酿 酉欠叙存在下’於0至200T:之溫度進 行。 胺基之保護基可列舉例如〒氧基㈣、第三_丁氧基幾 基、二氟乙醯基、9-芴基曱氧基羰基等。 胺基之保護基除了上述者之外,只要能容易且可選擇 性地脫離之基即可,並無特別之限制。例如可使用T. W.
Greene,Protective Groups in Orow. c t garlic Synthesis 第 3 版, iley,New Y〇rk(1 999)所揭示之基。 由於業者可容易瞭解,妹ώ + 由Μ應㈣等之脫保護反 應’即可容易地製造本發明之化合物。 本紙張尺度_中關家鮮(CNS)A4祕⑵。χ 297^^- 314159 --------------------訂------—線 (請先閱讀背面之注音?事項再填寫本頁) A7 B7 五、發明說明(22 ) — (2)通式(I)所示之本發明化合物中…
基之化合物,亦即,通式(IB) C 烷基、Z為-〇·
D R3 八、?rc:c〇〇R1·1 ν(Υ-〇"0 (ΙΒ) (式中,所有符號與上述者同意義)所 式(IV) 示之化合物,係使通 〇βΛΐγ· (IV) (式中’所有符號與上述者 (ΙΙΜ) 同心義)所示之化合物與通式
Wr,·1 (HM) --------^--------- (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印制衣 所有符號與上述者同音義)-^ 」心義)所不之化合物進行 Π 玄 W:, /T-*
(式T 應,必要時付與保護基之脫保護反應即可製造。 該反應為公知,例如於有機溶劑(二氣;:、二乙醇 四氫咲喃、乙腈、笨、甲穿笪、占 t甲本寺)中,在偶氮化合物(偶氮 竣酸二乙酯、偶氮二叛酸-昱 义—兴丙®日、i,i,-(偶氮二羰基) 六氫吼咬、一1 J、偶氮雙(N,N-二甲基曱酿胺)等)及膦化合 (二苯科一丁膦、二曱膦等)存在下與適當之醇化合物方 314159 200300681 A7 五、發明說明(23 ) 至6 0 °C進行反應。 保護基之脫保護反應可依照與上述相同之方 (3)通式⑴所示之本發明化合物中R1 :進行。 物,亦即,通式(1C) 匕δ D\lrz-0
R2 R3 N^HC-COOH (1C) 經濟部智慧財產局員工消費合作社印製 (式中,所有符號與上述者同意義)所示之化合物, 述通式(IA)或(IB)所示之化合物付予水解反應而製造之〜 上述之水解反應為公知,可列舉 (1) 於可與水混合之有機溶劑(四氫呋喃、二噁烷、乙醇、 曱醇等)或該等之混合溶劑中,使用鹼(氫氧化鉀、氫氧化 鈉、氫氧化鋰、碳酸鉀、碳酸鈉等)之水溶液或是 (2) 於烷醇(甲醇、乙醇等)中使用上述之鹼,在無水條件下 進行。該等反應通常在0至1 00它之溫度進行。 通式(Π)及(IV)所示之化合物為公知之化合物或是可 以公知之方法或以實施例所揭示之方法為基準製造。 例如通式(IV)所示之化合物中,2_(5_甲基_2-苯基噁唑 -4-基)乙醇可根據 j· Med· Chem·,王1,1 853 至 1 864(1992) 所揭示之方法製造。 例如通式(IV)所示之化合物中,2-(5-甲基-2-(嗎啉-4-基)噁唑-4-基)乙醇可根據j· Med· Chem·,4JL,503 7至5054 (1 9 9 8)所揭示之方法製造。 本—尺度適用中國國家標準T^^F(2]0 x 297公f ; 可使上 --------^---------^ (請先閱讀背面之注音?事項再填寫本頁) 314159 200300681 A7 B7 % 五、發明說明(24 ) 例如通式(III)所示之化合物可根據反應方程式1所示 之方法製造。 反應方程式1中R11為羥基之保護基,X1為Cp3伸烷 基,其他符號與上述者同意義。 反應方程式1 Φ -d (V) ,CHO羥基 保護化 OCHO 反應 A/Π
HO
(VII) X e〇2H保護化 R110
(VI) X1—C〇2H (VIII) R’1。 還原反應
X-OH η〇·〇 釤 R3 X-N-C-COOR1 脫保護 反應 (ΗΜ) R11〇-〇 k8 (IX) 1) 導入脫離基 R2 R3 2) r6-nXco2r- H (X) R2 R3 X-N-V-COOR1-1 (XI) 硫羰基氯 2)加熱反應 3〉水解反應 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製 R2尸 .X-H-C-COORUi 反應方程式1中作為起始原料使用之通式(V)及(VII) 所示之化合物為公知之化合物或是根據公知之方法可容易 製造。 於本說明書中之各反應,反應生成物可經由通常之精 製方法,例如在常壓下或減壓下蒸餾、使用矽膠或矽酸鎮 之高效液體層析法、薄層層析法、管柱層析法或洗淨、再 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 24 314159 200300681 A7 五、發明說明(25 ) 結晶等方法精製。精製可於 應完成後進行。 ㈣反應‘了,亦可於數個反 [藥理活性] (請先閱讀背面之注意事項再填寫本頁) 由以下之實驗證明通式⑴所示之本發 控制PPAR受體之活性。 物,、再 PPARa激動劑活性及ppARr激動劑活性之測定: () 巧PPAR α或7文體之蟲螢光素酶化驗材料之調 製 ⑽:體之操作以基本之基因工學手法為基礎或活用在酵 母單此種(One_hybnd)、二混種(τ·_㈣別)系統為常法之 手法。 在胸腺定激酶(thymidinekinase,TK)啟動子支配下之 蟲螢光素酶基因表現載體(vect〇r)為從picaGene Basic 經濟部智慧財產局員工消費合作社印柴
VeCt〇r2(商品名,東洋印墨公司產品目錄編號309-04821) 切出蟲螢光素酶構造基因,作為具有τκ起動子之ρΤκβ(克 隆技術(cl〇netech)公司、產品目錄編號6179-1)最小必要之 起動子活性,作成在TK起動子(_1〇5/ + 51)支配下之蟲螢光 素酶基因表現載體-pTK-Luc·。於ΤΚ起動子上流插入酵母 之基本轉錄因子G a 1 4蛋白之對應序列,插入將u A S (上游 致活序歹U,upstream activation sequence)反覆 4 次之力口強 子序列,構築4xUAS-TK-Luc,作為通訊基因。以下為所 使用之加強子序列(序列編號1) 序列編號1 ··反覆Gal4蛋白對應序列之加強子序列 5,-T(CGACGGAGTACTGTCCTCCG)x4 AGCT-3, 本紙張尺度適用中國國家標準(CNS)a4規格(210 x 297公釐) 25 314159 200300681 % 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明(26 ) 以如下所述之方法於酵母_蛋白之崎結合領域 之竣基末端融合核内受體人類ppARa或^受體配位體結 合領域,作成表現嵌合體受體蛋白之載體。亦即,作為基 本表現載體之Piea Gene Basie Vee⑹2(商品名東洋印墨 公司產品目錄編號309-04821),於故私工 ,^ ;於起動子·加強子領域以 原狀將構造基因與嵌合體接受蛋白交換。 在Gal4蛋白之DNA結合領域,於編碼第i至第Μ? 號胺基酸序列之DNA下流,將編碼人類ppAR ^或τ受體 之配位體結合領域之DNA框架符合地融合,插入picaGene Basic VeCt〇r2之起動子·加強子領域下流。此時,所表現 之嵌合體蛋白均局限在核内,於人類ppAR α或7受體之 配位體基結合領域之胺基末端配置源自SV40T-抗原 (antigen)之核移行信號、AlaProLysLysLysArgLysValGiy(序 列編號2),另一方面,於羧基末端依序配置作為表現蛋白 夤檢驗用抗原決疋基標識序列(epit〇p tagsequence)、流行 >性感冒(influenza)之血球凝集素(hemagglutinin)抗原決定 基、TyrProTyrAspValProAspTyrAla(序列編號 3)與翻譯密 碼子作成DNA序列。 人類PPAR 或τ受體之配位體結合領域所使用之構 造基因部分與R· Mukherjee等人(參照J. Steroid Biocheni· Molec· Biol.,11,1 5 7(1994))、Μ· Ε· Green 等人(參照 Gene Expression,生,281(199 5))、A· Elbrecht 等人(參照 Biochem. Biopliys· Res· Commum·,2,.24., 43 1 (1 996))或 A· Schmidt 等人 (參照 Mol· Endocrinology,4,163 4(1 992))所揭示之人類 -------------^ I------^---------^ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210x 297公釐) 26 314159 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 314159 200300681 A7 -____________B7___ 五、發明說明(27 ) PPAR受體構造相比較,係 使用編碼人類PPARa配位體結合領域:Ser167-Tyr468 人類PPARt配位體結合領域:Ser176-Tyr478 (人類PPAR τ 1受體、人類ppar τ 2受體對應於Ser204-Tyr5G6為幾乎相同之鹼序列)之DNA。又,一併調製具有可 監測影響基本轉錄,缺乏PPAR配位體結合領域之Ga 14 蛋白之DNA結合領域、只編碼第1個至第1 47個胺基酸 序列之DNA表現載體。 (2)使用人類ppar α或r受體之蟲螢光素酶之化驗 將作為宿主細胞使用之CV-1細胞依照常法培養。亦 即’於 Dulbecco’s Modified Eagle’s Medium(DMEM)中加 入牛胎兒血清(吉必克gibcobrl公司製造,產品目錄編 號26 140-061)使最終濃度為10%,於加有最終濃度為50U/ 毫升之青黴素G與5 0微克/毫升之硫酸鏈黴素之培養基 中,在5%碳酸氣體中,於37。(:培養。 將通訊基因、Gal4-PPAR表現載體之兩DNA導入宿 主細胞内進行轉染時,於1 〇公分培養皿中預先將細胞播種 2 X 1 0 6個細胞,以不含血清之培養基實施一次洗淨操作後 加入同一培養基1〇毫升。將通訊基因微克、Gal4-ppAR 表現載體0.5微克與Lipofection AMINE(商品名,吉必克 公司製造,產品目錄編號1 8324-012)50微升充分混合,添 加至上述培養皿中。37°C連續培養5至6小時,加入1〇 I升之含有2 0 %透析牛胎兒血清(吉必克公司製造,產品目 錄編號26300-061)之培養基。於37。(:培養一晚後將細胞經 巧張尺度適財關家鮮(CNS)A4規格⑵Gx 297公爱) 27 % > * · , --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 200300681 A7 B7 % 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 五、發明說明(28 ) 由胰蛋白酶處理使分散,以8〇〇〇個細胞/1〇〇毫升 1 0%透析血清/洞之細胞密度再播種於96洞盤,培養數小 時,於細胞付著時添加含有檢定濃度2倍濃度之本發明化 合物之DMEM-10%透析血清溶液1〇〇微升。於3:rc培養 42小時將細胞溶解,依照常法測定蟲螢光素酶之活性。 於本實驗,以添加對PPAR ^可有意義的將蟲螢光素 酶基因之轉錄活性化之陽性對照化合物卡巴環素 > (carbacycline)(參照 Eur· j. Bi〇chem,瓜,242(1996); & Development,过,974( 1996))1 〇Mm,之蟲螢光素酶活性 作為1 ·〇,添加本發明化合物丨0μΜ時之相對活性如表6 所示。 以添加對PPAR r可有意義的將蟲螢光素酶基因之轉 錄活性化,作為降血糖劑上市之陽性對照化合物托利他松(參照 CeU,虹,863(1995)、End〇crin〇1〇gy,m,4189(1996) 及J· Med. Chem·,选665(1996))1〇μΜ時之蟲螢光素酶活 性作為1 ·0,添加本發明化合物i 〇μΜ時之相對活性如表7 所示。 此外,對有希望之化合物進行3次試驗,以檢視其再 顯性’同時亦碟認有無用量依存性。表6
0.9 ---I--I--II--· I------訂--------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公餐一 28 314159 200300681
五、發明說明(29 ) 表7 化合物編號 —------- 實施例2 ___________— 以陽性對照化合物(托利他松) 作為1時之相對活性 "" ---- (請先閱讀背面之注意事項再填寫本頁) 11.5 本么明化合物之降低血糖及血中脂質之作用可經由以 下之方法測定。 降低血糖及血中脂質之作用G: 購入8週齡之雄性KKAy/Ta Jcl老鼠(1群5隻),個別 於籠内進行約-星期之預備飼養。於預備飼養期間自由攝 取固體飼料及從給水瓿自由攝取自來水。接著替換為粉末 飼料,進行酬化飼養3日後開始實驗。實驗開始當天(〇日) 測定體重,用微毛細管從尾靜脈採血後測定血糖值。以血 糖值作指標,分別隨機進行分群,每群5隻。於隔日早上 測定體重,以後6日間給予含有本發明化合物〇〇3% 經濟部智慧財產局員工消費合作社印製 (W/W)、0.01%(W/W)、〇.〇〇3%(w/w)之飼料或粉末飼料飼 養之。於開始投藥第4天及第7天上午測定體重及攝餌量, 從平均攝餌量換算投予量。開始投予後第6天進行尾靜脈 採血,測定血糖值、血漿中三酸甘油酯(TG)值(飯後血糖及 三酸甘油酯值)。測定開始投予第7天之體重後在乙醚麻醉 下從腹部大靜脈採血,用市售之組套測定血中胰島素、遊 離脂肪酸(NEFA)、GOT(谷胺酸草醯乙酸轉胺酶,Glutamic oxalo-acetictransaminase)及GPT(谷胺酸丙胺酸轉胺酶, glutamic pyruvic transaminase)。取出肝臟,測定濕重量。 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 29 314159 200300681 A7 五、發明說明(30 ) 從外側左f之一部分抽出、總RNA,根據北方印潰(Ν〇Γ·η 跑)法測定二種酵素之基因表現水平。又,控制攝飼量群 (只投予粉末飼料)與本發明化合物群(投予含有化合物 0.03%、0·0”/。或〇·_之粉末飼料)兩者並無有意義差, 從平均攝餌量換算之投予量為含有〇〇3%飼料投予群約4〇 毫克/公斤/曰。 對KKAy/Ta老鼠降低飯後血糖、血中胰島素、遊離脂 肪酸值或血聚中三酸甘油醋值之作用,顯示可作為糖尿 病、高脂血症、動脈硬化症等之預防及/或治療劑。該作用 係源自PPAR r於生體中之活化。另―方面,顯示肝重量 增加或肝之二種酵素表現量增大反映PPARa於生體中活 化。 降低血糖及血中脂質之作用(2): 購入8週齡雄性Zucker fa/fa老鼠(系統名:c小[zuc]_ fa/fa)及正常對照動物痩〇ean)老鼠(系統名· crj-[zuc]· 消 1叫’於個別籠㈣行約二星期之預備飼養。於予員備飼養 期間自由攝取固體飼料及從自動給水裝置自由攝取自來 水。從開始投予5天前經口用胃管進行模擬投藥,開始實 馬双。方;忒期間貫施一般狀態觀察,將確認無異常之1 〇週齡 動物供給實驗。於開始實驗日之上午測定體重,用微毛細 & k尾靜脈採血後測定血糖、遊離脂肪酸(nefa)、三酸甘 /由月曰及HbA成人血紅蛋白(a(juithaem〇gi〇bin)ic濃度。其 中,將HbAl c值及體重作為指標,各別隨機進行分群,每 _群5隻。在不使其他參數之平均值產生偏差下任意更換。 30 訂 線 本紙張尺度適財關家標準(CNS)A^^^ X挪公餐) 314159 200300681 消 A7 五、發明說明(31
=二曰起於上午測定體重後以該體重 、、工口將本發明化合物連續13日強制瘦 用月S 及正常對照群(瘦老鼠)係投予作為介質二 於開始投予第丨、4、7、10及13日 Mc。 算出平均攝名耳量。於開始投予第 量, r後測定血糖、遊離脂肪酸、三酸甘油脈 又又,於開始投予第μ日實施經口糖負冇敗 〇raigiuc〇set〇1—- 糖負何試驗為於採血前曰(開始 、二 後…)實施採血後以; 广口投予40%葡萄糖液。糖負荷後於6〇分鐘及⑽ /刀鐘後用微毛細管從尾靜脈採血,測定血糖值。 几經口糖負荷試驗完成後再給辑,於開始投予第日亦 投予本發明化合物。於開始投予第16日上午敎體重,用 乙㈣老鼠麻醉,從腹部大靜脈採血,用市售組套測定血 糖、血中胰島素、遊離脂肪酸、三酸甘油脂、g〇t及GpT。 取出肝臟,測定濕重量。 對Zucker fa/fa老鼠之降低飯後血糖、血中胰島素、 遊離脂肪酸、HbAlc值或血漿中三酸甘油酯值之作用”,顯 :可作為糖尿病、高脂血症或動脈硬化症等之預防及/治療 割。於經口糖負荷試驗時降低空腹時血糖值或改善耐糖能 之作用顯示可作為糖尿病之預防及/或治療劑。該等作用源 自PPAR 9’於生體中之活化。另一方面,亦顯示肝重量增 反映PPARa於生體中活化。 P氏張—中國國家標準(CNS)A4規石^ χ 297公/ W 》 31 314159 --, . --------t--------- (請先閱讀背面之注意事項再填寫本頁) 200300681 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(32 ) 降低血糖及血中脂質之作用(3) ·· ::年齡3至4歲,平均體重約3公斤之雄性食蟹猴, 、已貫施法定檢疫之所有動物在試驗實施設施再進行約1 個月以上之檢疫及㉚丨化。動物個別收容於猴籠内,每日 次給予市販固體飼料約1〇〇公克。酬化進展 日幾乎在1小時以内即將飼料吃完。又,從自動給水Π 自由攝取自來水。接著進们4曰之預備飼育,於;
,前2週及前丨週測定體 / ^ ^ ^ ^ ^ ^ 又汗D 〜版夏傻,伙後肢fe職靜脈採血,垂 血液學檢查(紅血球數、血球容積、血色素量、血小板數及 二血定)及血液化學檢查(g〇t、gpt、驗性她 _ (a_Ph〇Sphatase)、總蛋白質、尿中氮、肌酸、肌酸激 酶(atine kinase)、總膽紅素、血糖、總膽固醇、助l、 及三酸甘油酷之測定)。同時觀察-般狀態,選擇於酬 化及預備飼育期間發育正常之個體使用。又,每曰測定包 含預備飼育期間所有動物之攝食量。 1卩各動物酬化期完成最後一天之體重為基準,各別隨 機進行分群,每群3隻。於開始投予第卜3、7、1()、14 日上午測定體重,以最新體重為基礎投予本發明化合物。 用營養導管或注射筒1日1次投予含有稀釋液或本發明化 口物3至100笔克/公斤/日之藥液,反覆經鼻胃内投予共 :4曰。開:投藥第1、7、14曰於投予本發明化合物前進 灯抓血’貫施上述之血液學檢查及血液化學檢查,確認本 毛明化口物不會影響隨時血糖值。又,於投藥開始前3週 及杈市俊第1 4曰之投藥後第〗、2、4小時及給餌(攝取時 Μ氏張尺 / 32 314159 -------------· I------^---------線 (請先閱讀背面之注意事項再填寫本頁) 200300681 A7 五、發明說明(33 ^4 )後’於1、2、3小時從後肢隱藏靜脈或前腕皮靜 脈知血,測定血糖、三酸甘油酯值。 才$ &蟹狼降低空腹時血漿三酸甘油酉旨值之作用, 鮮員不可作為高脂血症或動脈硬化症等之預防及/或治療 劑。该作用推論是反映PPAR α於生體中活化。同樣地確 6忍亦抑制食餌負荷後三酸甘油酯之上昇。從其他血液生化 本ί數可一併評估有無毒性變化。 [毒性] 通式(I)所不本發明化合物之毒性非常低,作為醫藥使 用十分安全。 [產業上利用之可能性] [醫藥品之使用] L式(I)所示之本發明化合物及該等之非毒性鹽具有 &制PPAR X體之作用,期待可應用作為降血糖劑、降脂 質劑、糖尿病、肥胖、χ徵候群、高膽固醇血症、高脂蛋 白血症等代謝異常疾病、高脂血症、動脈硬化症、高血壓、 經濟部智慧財產局員工消費合作社印製 (請先閱讀背面之注咅?事項再填寫本頁) =環器系疾病、過食症、虛血性心疾病之預防及/或治療 H、hdl膽固醇上昇劑、LDL膽固醇及/或膽固醇 / 徵候群之危險ϋ子減輕劑。
通式⑴所示之本發明化合物及該等之非毒性鹽由 不、具有PPAR α激動齊ij竹闲芬/七PD ” Μ用及/或PPART激動劑作用’期待 L =用於降血糖劑、降脂質劑、糖尿病、肥胖、χ徵候群、 :膽固醇血症、高脂蛋白血症等代謝異常疾病、高脂血症、 ----循為糸疾病、過食症之預防及/ 本紙張ϋ國國家標準 314159 200300681 200300681 B7 五、發明說明(34 或治療劑,HDL膽固醇上昇
膽固醇減少作用,£ # 、£膽固醇及/或VLDL 肥胖之效果,作制動脈硬化進展、治療或抑制 善高血壓,減輕又徵 °療或預防糖尿病’改 症預防劑。 "險因子或虛血性心疾病之發 υ補充通^)所示之化合物或該等之非毒性鹽為 2::或增強該化合物之預防及/或治療效果、 及):或。该化合物之動態.吸收,減低投予量、 3)為了減輕該化合物之 併用劑投予。 乍用,亦可與其他藥劑組合作為 訂 製劑中^己人兩11化°物與其他藥劑之併用劑可以於1個 二分之配合劑形態投予,亦可為個別作成製 線 於個別作成製劑投予時包括同時投予及根 像才間i技予。又。根據時間差投予可 之化合物再投予其他藥劑’亦可先 二:式⑴所不 式⑴所示之化合物,各 :、樂制再投予通 杈予方法可相同亦可不同。 特別;併用劑顯示預防及/或治療效果之疾病並無 ’则、要能補充及/或增強通式⑴ 及/或治療效果之疾病即可。 口物之預防 可併=充及/或增強通式⑴所示化合物之作用,咸認為 李降血^ mu療效R其他藥劑例如石黃酿脲 :分心:雙胍系製劑、α _配糖酶抑制劑、逮效型胰島 …促進劑、胰島素製劑、PPAR激動劑、不且摩, 314159 34 消 200300681 A7 五、發明說明(35 ; 動劑作用之騰島素感受性增強劑、沒3腎上腺素受體動作 藥、酸糖還原酶抑制劑、二肽肽酶IV抑制劑等。 石戸、脲劑可列舉乙續己胺(acet〇hexamide)、格列本脲 (glibenclamide)、曱磺吡脲(gliclazide)、糖吡脲 (glyclopyr amide)、氯苯石黃丙脲(chl〇rpr〇pam ide)、妥拉脲 (tolazamide)、甲本石黃酸丁脲(t〇ibutamide)、格列滅得 (glymepiride)等。 雙胍系製劑可列舉布佛命(bllf〇rmin)鹽酸、美佛命 (metformin)鹽酸等。 α -配糖酵素抑制劑可列舉阿卡玻糖(acarbose)、凡格 玻糖(vaglibose)等。 速效可胰島素分泌促進劑可列舉納特格得 (nateglinide)、雷迫袼得(repagHnide)等。 PPAR激動劑可列舉匹歐利他松、托利他松、羅系利 他松、JTT-501等。 不.、PPAR ,放動劑作用之胰島素感受性增強劑可列舉 ONO-5816、YM-440 等。 /5 3月上腺素受體動作藥可列舉AJ9677 ' 、 CP331648 等 。 醛糖還原酶抑制劑可列舉埃帕雷斯特(e_estat)、非 達雷斯特(fidarestat)、日那雷斯特(zenarestat)等。 通式⑴所示之化合物與其他藥劑之質量比並無特別 限制。 其他藥劑亦可任意2種以上組合、投予。
本纸張尺度適用中國國家標準(CNS)A4規格(2J0 X 35 314159 --------------------^---------— — (請先閱讀背面之注意事項再填寫本頁) 200300681 經濟部智慧財產局員工消費合作社印製 A7 五、發明說明(36 ) ▲又’補充及/或增強通式⑴所示化合物之預防及/或治 療效果之其他藥劑以上述之作用機序為基礎者,不僅包含 至今所發現者,亦包含以後所發現者。 3 通式⑴所示之本發明化合物或通式 ^ 、八(1)所不之化合物 …H叙併用㈣於上述之目的,通f以全身或局 部、經口或非經口之形態投予。 投予量依年齡、體重、症狀、治療效果、投予方法、 處理時間等而異,通常,成人每人每 A m 1 人在1ng至100毫克 粑圍,日從!次至數次經口投予或 O.lng至10毫克之範圍,i曰從^欠 :人母-人在 β ^ . 数次非經口投予或 疋1曰在1小時至24小時之範圍靜脈内持續投予。/ 當然,如上所述,投予量依種種條件而變動,有時於 予比上述投予量少之量即足夠, 又 圍之量。 兀有日可而投予超過上述範 通式(I)所示之本發明化合物或通 與其他藥劑之併用劑用於上述之目的:():示之化合物 部'經口或非經口之形態投予,以選 :要 投予路徑較理想。 ,、上取具效果之 投予量依年齡、體重、症狀、治療 處理時間等而異’通常,成人每人 、投卞方法、 之範圍,!日從!次至數次經口投予或3在^至⑽毫克 〇.1%至10毫克之範圍,i曰從i次至二人每人每次在 是1日在i小時至24小時=經口投予或 當然,如上所述,投予量依種種條件^投予。 ^iiitiiii^cNS)A4 ^ (21^~ 、而變動,有時: 314159 --------^---------線 (請先閱讀背面之注意事項再填寫本頁) 36 200300681 A7 五、發明說明(37 ) 予比上述投予量少之量即足夠,亦有時需投予超過上述範 圍之量。 (請先閱讀背面之注意事項再填寫本頁) 才又予通式(I)所示之本發明化合物或通式⑴所示之化 合物與其他藥劑之併用劑時,可使用經口投予之内服用固 體劑、内服用液劑及非經口投予之注射劑、外用劑、栓劑 等。. Θ 經口投予之内服用固體劑包括錠劑、丸劑、膠囊劑、 散劑、顆粒劑等。膠囊劑包括硬膠囊及軟膠囊。 於該等内服用固體劑,係一種或一種以上之活性物質 以原狀或與賦形劑(乳糖、甘露糖醇、葡萄糖、微結晶纖維 素、澱粉等)、黏合劑(羥丙基纖維素 '聚乙烯吡咯烷酮、 矽酸鋁酸鎂等)、崩解劑(纖維素乙醇酸鈣等)、潤滑劑(硬脂 ^女疋劑、〉谷解輔助齊彳(谷胺酸、天冬胺酸等)等混 。1根據吊法製劑化使用。又,必要時可用塗覆劑(白糖、 明膠、羥丙基纖維素、羥丙基曱基纖維素酞酸酯等)包覆, ,、 復層以上。又,亦包括如明膠之可被吸收物質之 膠囊。 、 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 經口投予之内服用液劑包括藥劑上所容許之水劑、懸 濁劑·乳劑、糖漿劑、聽劑等。於該等液劑中,一種或一 種:上之活性物質係溶解、懸濁或乳化於一般所使用之稀 釋^ (知衣水、乙醇或該等之混合液)。該液劑亦可含有濕 潤t fe濁劑、乳化劑、甜味劑、風味劑、芳香劑、保存 劑、緩衝劑等。 #1=予之注射劑包含溶液、懸濁液、乳濁液及使 F本紙張尺度適用中1規格⑵。X 297公髮)------- 37 314159 200300681 B7 五、發明說明(% 用時溶解或懸濁於 個或-個以,,便用之固-左射劑。注射劑為將一 溶物#溶解、_或乳化於溶劑使用, :=用>主射用蒸館水、生理食鹽水、植物油、丙二醇、 二二乙%寺醇類及該等之組合。該注射劑更可含有 女疋蜊、溶解輔助劑(谷胺酸、天夂胺酸、取山利t 冊商炉彳望、„ . 八、妝敲、聚山梨酸酯8〇(註 劑等。該等係於最德牛驟d ^緩衝劑、保存 可擊…二: 由無菌操作法製造。亦 ……囷之固组劑,例如凍結乾燥品,於使用前益菌化 或溶解於無菌注射用蒸餾水或其他溶劑後使用。 訂 經口投予之外用劑劑型包含軟膏劑、凝膠劑、乳春 创、敷布劑、貼布劑、塗抹劑、喷霧劑、吸人劑、噴霧劑: 點眼劑及點鼻劑。該等含有一種或一種以上之活性物質, 經由公知之方法或通常所使用之處方製造。 線 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 軟貧劑可以公知或通常所使用之處方製造。例如將一 種或一種以上之活性物質研和或熔融於基劑中調製。軟春 •基劑為選自公知或通常所使用之基劑。例如選自高級脂: 酸或高級脂肪酸酯(己二酸、肉豆蔻酸、棕櫚酸、硬脂酸、, 油&L、己二酸酯、肉豆蔻酸酯、棕櫚酸酯、硬脂酸酯、、由 酸酯等)、蠟類(蜜蠟、鯨蠟、微晶蠟等)、界面活性劑(聚環 氧乙烷烷基醚磷酸酯等)、高級醇(鯨蠟醇、硬脂醇、乙醉 硬酯醇等)、矽油(二甲基聚矽氧烷等)、烴類(親水凡士林、 白色凡士林、精製羊毛脂、液體石蠟等)、乙二醇類(乙二 醇、二乙二醇、丙二醇、聚乙二醇、巨乙二醇(macr〇glyc⑴) 等)、植物油(蓖麻油、撖欖油、芝麻油、松節油等)、動物 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 200300681 A7 _B7 五、發明說明(39 ) 油(I口油Α κ ’由、角鯊烷、角鯊烯等)、水、吸收促進,、 斑療防止劑者,可單獨使用或2種以上混合使用。亦;含 有保/”、、d 4呆存劑、安定化劑、抗氧化劑、芳香劑等。 ,是膠;^可以公知或通常所使用之處方製造。例如將一 ♦或種乂上之,舌性物質熔融於基劑中調製。凝膠基 選自公知或通常所你田甘 ' 厅使用之基劑。例如選自低級醇(乙醇、異 丙醇等)、凝膠化劑淡甲基纖維素、經乙基纖維素、經丙 基i准素、乙基纖維素等)、中和劑(三乙醇胺、二显丙醇 胺等)、界面活性劑(單硬脂酸聚乙二醇等)、樹膠類、、水、 吸收促進劑、斑療防止劑者,可單獨使用或2種以上混八 使用。亦可含有保存劑、抗氧化劑、芳香劑等。 。 、乳霄劑可以公知或通常所使用之處方製造。例如將一 種或-種以上之活性物質溶融或乳化於基劑 線 :::為::公知或通常所使用之基劑。例如選 _曰、低級醇、烴類、多元醇(丙二醇M,3-丁二r耸、、 尚級醇(2-己基癸醇、鯨蠟醇等)、 子, _員、脂肪酸酷類等)、水、吸收促進劑 ==乙糧 單獨使用或2種以…㈣斑療防止劑,可 禋以上耽*合使用。亦可含有保存南丨、γ @ | 劑、芳香劑等。 卄Μ、抗乳化 …敷布劑可以公知或通常所使用之處方製造。例如將一 禮或一種以上之活性物質熔融於基 涂姑於發雕L 作為研磨物,展延 合 作 社 印 製 」“載月豆上而製造者。敷布基劑為選自公 用之基劑。例如選自增黏劑(聚丙烯酸、聚乙3 I吊 阿拉伯樹膠、激粉、明膠、甲基纖 $咯^酮 «_____—寻j、濕潤劑(尿素、 本紙張尺中國國li^.NS)A4規格 (210 x 297 公釐) 314159 39 200300681 經濟部智慧財產局員工消費合作社印製 40 A7 五、發明說明(4^ ) 麵 " " 甘油、丙二醇等)、填充劑(高嶺土、氧化鋅、滑石粉、 鎭等)、}、、々& 、 1 、、 &、洛解補助劑、黏著賦予劑、斑疹防止劑,可單 獨使用或2種以上混合使用。亦可含有保存劑、抗氧化 芳香劑等。 θ 、貼布劑可以公知或通常所使用之處方製造。例如將— 種I:種以上之活性物質熔融於基劑中,^塗抹於載體 f製造之。貼布劑用基劑為選自公知或通常所使用之基 ^例如砥自向分子基劑、油脂、高級脂肪酸、黏著賦予 f、斑疹防止劑,可單獨使用或2種以上混合使用。亦可 έ有保存劑、抗氧化劑、芳香劑等。 、塗抹劑可以公知或通常所使用之處方製造。例如將一 種或種以上之活性物質溶解、懸濁或乳化於單獨i種或 :種以上選:水、醇(乙醇、聚乙二醇等)、高級脂肪酸、甘 二/巴皂、乳化劑、懸濁化劑中而調製。亦可含有保存劑、 4几氧化劑、芳香劑等。 豨釋:霧劑、吸入劑、噴霧劑及點鼻劑除了-般所使用之 月之外亦可含有如亞硫酸氫鈉之安定劑及賦予等張性 :緩衝劑、如氯化鈉、檸檬酸鈉或檸檬酸之等 = Γ詳細揭示於美國專利第2娜9"虎… 專利弟3,〇95,355號。又,亦可作為煙霧劑。 之:鼻劑時—般係將含有藥劑之溶液及粉末以專用 H益或㈣器’於鼻腔内定量噴霧投予。 非I 口投予之點眼劑包含點眼 濁型點眼液、用時、…蜀型點眼液、乳 欣用日守冷解型點眼液及眼软膏。 314159 ^ ^---------^ (請先閱讀背面之注意事項再填寫本頁) 200300681 A7 B7 五、發明說明(Μ ) 該等點眼劑以公知之方法為基準製造之。例如將一種 或一種以上之活性物質溶解、懸濁或乳化於溶劑中使用。 點眼劑之溶劑使用滅菌精製水、生理食鹽水、其他水性溶 劑或注射用非水性用劑(例如植物油等)等及該等之組合。 點眼劑必要時可適當選擇含有等張化劑(氣化鈉、濃甘油 等).、緩衝劑(磷酸鈉、乙酸鈉等)、界面活性劑(聚山梨酸酯 80(商品名)、聚環氧乙烷硬脂酸酯4〇、聚環氧乙烷硬化蓖 麻油等)、安定劑(檸檬酸鈉、依底酸鈉等)、防腐劑(潔而滅、 仲斑等)。該等可在最終步驟滅菌或經由無菌操作法製造、 調製。又,亦可使用無菌之固體劑,例如製造凍結乾燥品, 於使用前無菌化或溶解於無菌之滅菌精製水或其他溶劑中 使用。 非經口投予之吸入劑包含煙霧劑、吸入用粉末劑或吸 入用液劑,吸入用液劑亦可為使用時溶解或懸濁於水或其 他適當溶劑使用之形態。 該等吸入劑以公知之方法為基準製造之。 例如’吸入用液劑於必要時可適當選擇防腐劑(潔而 滅、仲斑等)、著色劑、緩衝劑(磷酸鈉、乙酸鈉等)、等張 化劍(氣化納、濃甘油等)、增黏劑(羧基乙烯聚合物等)、吸 收促進劑等而調製。 於吸入用粉末劑,必要時可適當選擇潤滑劑(硬脂酸及 其鹽等)、黏合劑(澱粉、糊精等)、賦形劑(乳糖、纖維素等)、 者色劑、防腐劍(潔而滅、仲斑等)、吸收促進劑等調製。 投予吸入用液劑時通常使用噴霧器(霧化器 ϋ氏張尺度i用中國國家規格·(ϋ 297公以--- 41 (請先閱讀背面之注音心事項再填寫本頁) 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製
· I ϋ n I»=-OJI n n n ϋ I ^ ϋ n n n I n ϋ ·ϋ I ϋ n ϋ n ϋ n n ϋ If I n I 314159 200300681 A7
五、發明說明(42(at_zer)、噴霧器(nebulizer)),投予吸人用粉末劑時通常 使用粉末樂劑用吸入投予器。非I 口投予之其他組成物為含有一種或一種以上之活性物g ’根據常法處方之直腸内投予之栓劑及陰道内投予 用之子宮壓定器等。[本發明之最佳實施方式] 以下,根據參考例及實施例對本發明加以詳細敘述, >但是本發明並不只限於該等例。層析法分離處及TLC所示括弧中之溶劑為所使用之 溶出溶劑或展開溶劑’比率為體積比。NMR處所示括弧中 之溶劑為測定時所使用之溶劑。MOMO為甲氧美甲5其 參考例1 : 土 手土。3-甲氧基甲氧基苯甲醛MOMO、/CHO 裝 (請先閱讀背面之注意事項再填寫本頁) .
經濟部智慧財產局員工消費合作社印製 1 在or於3-羥基苯甲醛(1.0公克)之 ;四虱呋喃(25毫升) 溶液中加入氫化鈉(3 74毫克),在〇°c攪採0 ^卞分鐘。於反 應混合物中加入曱氧基氯曱烷(0.92毫升+ 元可),在室溫攪拌30 分鐘。將反應混合物倒入冷水中,用乙酸^ , 己酯抽出。有機 層用飽和食鹽水洗淨,用無水硫酸鎂乾燥後填縮 碎膠管柱層析法(己少元· G酸乙S旨=8 : 1 . 具有以下物性值之標題化合物(1 ·36公克) TLC : Rf 〇·69(己少元·乙酸乙 S| = 2 . 1); 殘渣用 :Ό精製,獲得 ί線· 本紙張尺度_ 家標規格⑵〇 X 297公釐) 42 314159 200300681 A7 B7
五、發明說明(43 ) NMR(CDC13): δ 9.98 (s, 1H), 7.62-7.40 (m, 3H), 7.30 5.24 (s, 2H), 3.50 (s, 3H)0參考例2 :3_曱氧基甲氧基笨曱醇MOMO
經濟部智慧財產局員工消費合作社印製 在0 °C於氫化紹經(1 7 8毫克)之四氫咲喃(1 5 0毫升)懸 濁液中滴下參考例1所製造化合物(1 · 3 0公克)之四氫呋喃 (24毫升)溶液,在同溫度攪拌20分鐘。於反應混合物中滴 下飽和硫酸鈉水溶液,再加入乙醚。反應混合物用無水硫 酸鎂乾燥後濃縮,獲得具有以下物性值之粗製標題化合物 (1·39公克)。所獲得之標題化合物不進行以上之精製,即 用於下一個反應。 TLC : Rf 0·25(己烷:乙酸乙酯=2 : 1); NMR(CDC13): δ 7.28 (dd, J = 7.8, 7.8 Hz, 1H), 7.10-6.92 (m, 3H), 5.19 (s, 2H), 4.67 (brd, J = 3.01¾ 2H), 3.48 (s,3H)。參考例3 : 2-(N-烯丙基-N-(3-甲氧基曱氧基苄基)胺基)乙酸•乙酷 i / -泰 * * ---------------------^---------^ (請先閱讀背面之注意事項再填寫本頁)
MOMO χτςτ° 在0 °C於參考例2所製造化合物之四氫D夫喃(丨6毫升) 溶液中加入三乙胺(2.0毫升)及甲苯磺醯氯(〇·72毫升),名 〇°C攪拌40分鐘。於反應混合物中加入乙醇(〇 ?3毫升), 私紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 43 314159 200300681 A7 B7 五、發明說明(44 ) 在〇°C攪拌20分鐘。於反應混合物中加入乙腈(5.0毫升)、 碳酸鉀(2.16公克)及N-烯丙基甘胺酸·乙酯(1·68公克)之 乙腈(18毫升)溶液,在75 °C攪拌40分鐘。將反應混合物 冷卻至室溫,倒入冷水中,用乙酸乙酯抽出。有機層用飽 和食鹽水洗淨,用無水硫酸鎂乾燥後濃縮。殘渣用矽膠管 柱層析法(己烷:乙酸乙酯=8 : 1— 6 : 1)精製,獲得具有以 下物性值之標題化合物(1 ·84公克)。 • TLC : Rf 0.40(己烷:乙酸乙酯=5 : 1); NMR(CDC13): δ 7.23 (dd, J = 7.8, 7.8 Hz, 1H), 7.08-6.90 (m, 3H), 5.88 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 5.28-5.10 (m, 2H), 5.17 (s, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.77 (s, 2H), 3.48 (s, 3H), 3.32 (s, 2H), 3.28 (d, J = 6.6 Hz, 2H), 1.27 (t, J = 7.2 Hz,
3H)C 參考例4 : 2-(N-稀丙基-N-(3-經基卞基)胺基)乙酸·乙西旨
υ V 於參考例3所製造化合物(1.80公克)之乙醇(6·1毫升) 溶液中加入4Ν氯化氫-二噁烷溶液(3 · 1毫升),於室溫授掉 整夜。將反應混合物倒入冷飽和碳酸氫鈉水溶液,用乙酸 乙酯抽出。有機層用飽和食鹽水洗淨,用無水硫酸鎭乾燥 後濃縮’獲得具有以下物性值之標題化合物(1 · 6 1公克)。 TLC : Rf 0.3 9(己烷:乙酸乙酯=2 : 1); -------------裝—— (請先閱讀背面之注咅?事項再填寫本頁)
=D 線 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210x 297公釐) 44 314159 200300681 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製 45 A7 B7 五、發明說明(45 ) NMR(CDC13): δ 7.17 (dd, J = 7.8, 7.8 Hz, 1H), 6.94-6.84 (m, 2H), 6J3 (m, 1H), 5.87 (ddt, J = 16.8, 10.2, 6.6 Hz, 1H), 5.28-5.10 (m, 2H), 4.15 (q, J = 6.9 Hz, 2H), 3.73 (s, 2H), 3.31 (s, 2H), 3.26 (d, J = 6.6 Hz, 2H), 1.26 (t, J = 6.9 Hz, 3H)〇 茶考例5 : 6_(全氫吖庚因-1-基)煙酸
於氬大氣下將6-氯煙酸(5.0公克)及全氫吖庚因(7.16 毫升)之二曱苯(20毫升)懸濁液在i4〇°C攪拌30分鐘。將 反應混合物冷卻至室溫後用己烷稀釋,將稀釋液過濾。不 溶物溶解於乙酸乙酯。有機層依次用水及飽和食鹽水洗 淨’用無水硫酸鎂乾燥後濃縮,獲得具有以下物性值之標 題化合物(3.19公克)。 TLC : Rf 0.21(氯仿:甲醇=9 : 1)。 參考例6 : 3 -甲氧基羰基- 2-(6-(全氫吖庚因-1_基)口比啶-3-基羰基胺基) 丙酸•节酉旨
於參考例5所製造之化合物(3· 19公克)及3 _胺基苄 氧基羰基丙酸·曱酯·鹽酸鹽(4·38公克)之無水二曱基曱 醯胺(4()毫升)溶液中加入丨_乙基-3-(3-二曱胺基丙基)碳化 本紙 1尺度適用中國國家標準(CNS)A4規格(210 X 297公餐) 314159 w· /, - i * wr ------------Aw--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) A7
200300681 五、發明說明(46 ) 二亞胺(3.34公克)及三乙胺(4 45毫升),在室溫攪拌Η小 時。反應混合物用水稀釋,用乙酸乙酯抽出。有機層依次 用水及飽和食鹽水洗淨,用無水硫酸鎂乾燥後濃縮。殘渣 用矽膠管柱層析法(己烷:乙酸乙酯=3 : !精製,獲得具有 以下物性值之標題化合物(2 · 9 4公克)。 TLC· Rf0.77(氯仿:甲醇=9: 1)。 參考例7 : · I I (請先閱讀背面之注意事項再填寫本頁) 3 -曱氧基羰基-2-(6-(全氫吖庚因4 —基)吼啶基羰基胺基) 丙酸
訂 於10%鈀碳(300毫克、50%wet)之乙醇(10亳升)懸濁 液中加入參考例6所製造之化合物(2·94公克)之乙醇(15 毫升)溶液,在氫大氣下在室溫攪拌2小時。將反應混合物 過濾,將滤液濃縮,獲得具有以下物性值之標題化合物。 TLC : Rf 0.10(氯仿:曱醇=9 ·· 1)。 參考例8 : 3-乙醯基-3-(6-(全氫吖庚因-1-基)D比啶-3-基羰基胺基)丙 酸·甲西旨 線 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 46 314159 200300681 A7 B7 五、發明說明(47
克)之無水吡啶(10毫升)溶液加入乙酸酐(126毫升),在8〇 °C攪拌1 5小時。將反應混合物冷卻至室溫後濃縮,獲得具 有以下物性值之標題化合物。 TLC : Rf 〇·20(己烧:乙酸乙 |旨=1 : 1)。 春者例9 : 2-(2-(6-(全氫吖庚因_丨_基)吼啶基)5_甲基噁唑_4_基)乙 酸•甲酯
(請先閱讀背面之注音心事項再填寫本頁) 0 訂--- 經濟部智慧財產局員工消費合作社印製 於夢考例8所製造化合物之乙酸酐(2〇毫升)溶液中加 入濃硫酸(2毫升),在90t:攪拌2小時。將反應混合物冷 卻至室溫後用飽和碳酸|甲水溶液中和,用乙酸乙酯抽出。 有機層依次用水及飽和食鹽水洗淨,用無水硫酸鎂乾燥後 濃縮。殘渣用矽膠管柱層析法(己烷··乙酸乙酯=2: 1}精製, 後得具有以下物性值之標題化合物(1 · 4 4公克)。 TLC ·· Rf 0.44(己烷··乙酸乙酯=i : 1)。 本紙張尺度過用Τ ϋΐ國豕標準(CNS)A4規格(21〇 X 297公爱) 47 314159 •線丨-- 200300681 經濟部智慧財產局員工消費合作社印製 A7 _____B7__ 五、發明說明(48 ) NMR(CDC13): δ 8.71 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 9.0, 2.4 Hz, 1H), 6.50 (d, J = 9.0 Hz, 1H), 3.72 (s, 3H), 3.67 (dd, J - 6.0, 5.7 Hz, 4H), 3.54 (s, 2H), 2.33 (s, 3H), L83-1.77 (m, 4H), 1.60-1.52 (m, 4H)〇 參考例 10: 2-(2-(6-(全氫吖庚因-1-基)p比啶-3-基)5-甲基噁唑-4-基)乙 醇
在〇 C、氬氣體氣流下於氫化鋁鋰(166毫克)之無水四 氫呋喃(1 〇毫升)懸濁液中滴下參考例9所製造之化合物 (1.44公克)之無水四氫呋喃(1 ·〇毫升)溶液,在室溫攪拌2 小時。將反應混合物冷卻至0 °C後滴下甲醇(1 0毫升),攪 拌1 5分鐘。反應混合物用二異丙醚稀釋。於稀釋液中加入 飽和碳酸鈉水溶液(1 0毫升),在室溫攪拌1小時。將反應 混合物用已塗抹硫酸納之過濾、器過濾。不溶物用二異丙_ 洗淨。將合併之有機層濃縮,獲得具有以下物性值之標題 化合物(1.20公克)。 TLC : Rf 0.45(乙酸乙酯); NMR(CDC13): δ 8.72 (d, J = 2.4 Hz, 1H), 7.94 (dd, J = 9.0,2.4 Hz, 1H), 6.51 (d, J = 9.0 Hz, 1HX 3.94-3.87 (m, 2H), 3.68 (dd, J = 6.3, 5.7 Hz, 4H), 3.47-3.40 (m, 1H), 2.69 (t, J = 6.0 Hz, 2H), 2.30 (s, 3H)5 1.83-1.77 (m, 4H), 1.62-1.52 (m, 4H)〇 實施例1 : 2-(N-烯丙基-N-(3-(2-(2-(6-(全氫吖庚因-i-基)吼啶-3·基) ^--------^---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公餐) 48 314159 經濟部智慧財產局員工消費合作社印製 200300681 A7 __ B7 五、發明說明(49 ) 5 -曱基°惡°坐-4-基)乙氧基)▼基)胺基)乙酸·乙酉旨
在室溫、氬氣體大氣下於參考例1 〇所製造之化合物 (5 00毫克)及參考例4所製造之化合物(623毫克)之無水二 氣曱烷(30毫升)溶液中加入三笨膦(656毫克)及M,气偶氮 一鑛基)二-六氫D比咬(6 3 1毫克),攪拌1 8小時。將反應混 合物濃縮,殘渣用二乙基醚稀釋後過濾。濾液依次用2N 氫氧化鈉水溶液、水及飽和食鹽水洗淨,用無水硫酸鎂乾 燥後濃縮。殘渣用矽膠管柱層析法(己烷:乙酸乙酯=4 ·· 1 ) 精製,獲得具有以下物性值之本發明化合物(7 7 7毫克)。 T L C · R f 0 · 4 7 (己;):完··乙酸乙 = 1 : 1); NMR(CDC13): δ 8.71 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 9.0, 2.4 Hz, 1H), 7.20 (dd, J = 7.8, 7.5 Hz, 1H), 6.92-6.88 (m, 2H), 6.82-6.77 (m, 1H), 6.50 (d, J= 9.0 Hz, 1H), 5.94-5.80 (m, 1H), 5.23-5.12 (m, 2H), 4.22 (t, J - 6.9 Hz, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.76 (s, 2H), 3.68 (dd, J = 6.3, 5.7 Hz, 4H), 3.30 (s, 2H), 3.27 (d, J = 6.6 Hz, 2H), 2.95 (t, J = 6.9 Hz, 2H), 2.34 (s, 3H)? 1.83-1.77 (m, 4H), 1.58-1.52 (m, 4H), 1.24 (t, J = 6.9Hz>3H)〇 實施例1(1)至實施例:ΙΠ 7): 使用適當之醇衍生物取代參考例丨丨所製造之化合物 及以適當之酚衍生物取代參考例5所製造之化合物,經由 與實施例1相同之操作,獲得以下所示之本發明化合物。 實施例1 (Π : ---------------------訂---------線 4^ (請先閱讀背面之注音?事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公复) 49 314159 200300681 A7 _____B7 五、發明說明(50 ) 2-(N-烯丙基-N-(3-(2-(2-異丙基-5-曱基。惡哇基)乙氧基) T基)胺基)乙酸•乙酯
TLC : Rf 〇·3 5(己烧:乙酸乙酯=4 : 1)。 f施例1(2): _2-(N-烯丙基-N-(3-(2-(2-(4-曱基六氫口比π井]_基)_5_曱基噻 唑_4-基)乙氧基)苄基)胺基)乙酸•乙酯 --------------裝— (請先閱讀背面之注咅心事項再填寫本頁) h3c-n
訂 TLC : Rf 0.43(氯仿:曱醇=l〇 : 1); NMR(CDC13): δ 7.19 (dd, J = 8.0, 8.0 Hz, 1H), 6.93-6.86 (m, 2H), 6.78 (m, 1H), 5.87 (ddt, J = 16.5, 10.0, 6.4 Hz, 1H), 5.21 (m, 1H), 5.15 (m, 1H), 4.19 (t, J = 7.0 Hz, ^ 2H), 4J5 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.46-3.37 (m, 4H), 3.30 (s, 2H), 3.27 (d, J =6.5 Hz, 2H), 2.95 (t, J = 7.0 Hz, 2H), 2.56-2.48 (m, 4H), 2.33 (s, 3H), 2.25 (s, 3H), 1.26(t, J = 7.0Hz,3H)o 實施例1(3): 2-(N-烯丙基-N-(3-(2-(2-(4-(1,2,3-噻二唑-4-基)苯基)-5-曱 基噁唑-4-基)乙氧基)节基)胺基)乙酸•乙酯 線 經濟部智慧財產局員工消費合作社印製
本紙張尺度適用中國國家標準(CNS)A4規格(2〗〇χ 297公釐) 50 314159 200300681
A7 B7 五、發明說明(51 ) TLC : Rf 0.66(己烷:乙酸乙酯=1 : 1); NMR(CDC13): 6 8.71 (s, 1H), 8.13 (s, 4H), 7.21 (dd, J = 7.9, 7.9 Hz, 1H), 6.98- 6.75 (m, 3H), 5.87 (m, 1H), 5.30-5.08 (m, 2H), 4.26 (t, J = 6.6 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.75 (s, 2H), 3,38-3.20 (m, 4H), 3.00 (t, J = 6.6 Hz, 2H), 2.41 (s, 3H), 1.25(t, J = 7.2Hz,3H)〇 實施例1(4): 2-(N-烯丙基-N-(3-(2-(2-(4-環己基苯基)-5 -曱基噁唑-4-基) 乙氧基)苄基)胺基)乙酸•乙酯 TLC : Rf 0.65(己烧:乙酸乙酯=2 : 1); NMR(CDC13): δ 7.94-7.84 (m, 2H), 7.32-7.23 (m, 2H), 7.19 (dd, J = 7.8, 7.8 Hz, 1H), 6.96-6.86 (m, 2H)? 6.79 (m, 1H), 5.87 (ddt, J = 17.1, 10.2, 6.6 Hz, 1H), 5.28-5.10 (m, 2H), 4.23 (t, J = 6.6 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.74 (s, 2H), 3.29 (s, 2H), 3.26 (d, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.53 (m, 1H), 2.36 (s, 3H), 1.96-1.28 (巩 10H), 1.25 (t J = 7.2 取 3H)。 實施例1(5): 2-(N-烯丙基-N-(3-(2-(2-(4-(四氫吡喃-4-基)苯基)-5-甲基 °惡°坐-4 -基)乙氧基)节基)胺基)乙酸•乙酯 Ν^γ。, TLC: Rf0.20(己:):完:乙酸乙酉旨=2: 1); --------------------訂---------線 (請先閱讀背面之注咅心事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製
本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 51 314159 200300681 經濟部智慧財產局員工消費合作社印製
A7 B7 五、發明說明(52 ) NMR(CDC13): δ 7.96-7.88(m,2H), 7J4-7.24(m,2H), 7.20(dd,J = 8.1,8.1Hz, 1H), 6.96-6.86 (m, 2H), 6.79 (m, 1H), 5.87 (ddt, J = 17.1, 10.2, 6.6 Hz, 1H), 5.28-5.10 (m, 2H), 4.23 (t, J = 6.6 Hz, 2H), 4.20-4.04 (m, 4H), 3.74 (s, 2H), 3.60-3.48 (m, 2H), 3.30 (s, 2H), 3.26 (d, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.79 (m, 1H), 2.37 (s, 3H), 1.94-1.70 (m, 4H), L25 (t, J = 7.2 Hz, 3H)〇 實施例U6): 2-(N·細丙基-Ν-(3-(2·(5·曱基-2-六氮D比。定基嚷唾-4-基)乙 I氧基)苄基)胺基)乙酸•乙酯 …ch3 NMR(CDC13): δ 7.19(^ J = 8.1 Hz, 1Η), 6.92-6.87 (m,2H), 6.69 (m, 1Η), 5.87 (m, 1H), 5.26 - 5.12 (m, 2H), 4.19 (t, J = 7.2 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.75 (s, 2H), 3.40 - 3.32 (m, 4H), 3.30 (s, 2H), 3.27 (d, J = 6.3 Hz, 2H), 2.94 (t, J = 7.2 Hz, 2H), 1.71 - 1.54 (i^ 6H), 1.26 仏卜 7.2 取 3H)0 I實施例1(7): 2-(N-細丙基-N-(3-(2-(2 -苯基-5-甲基°惡σ坐-4-基)乙氧基)节 基)胺基)乙酸•乙酯 〇x^ch3 -------------•裝--------訂·-------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 52 314159 200300681 經濟部智慧財產局員工消費合作社印製 A7 B7 五、發明說明(53 ) NMR(CDC13): δ 8.03-7.93 (m, 2H), 7.49-7.36 (m, 3H), 7.20 (dd, J = 7.8, 7.8 Hz, 1H), 6.96-6.87 (m, 2H), 6.80 (m, 1H), 5.87 (m, 1H), 5.28-5.10 (m, 2H), 4.24 (t, J = 6.8 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.30 (s, 2H), 3.28 (m, 2H), 2.98 (t, J = 6.8 Hz, 2H), 2.38 (s, 3H), 1.25 (t, J = 7.0 Hz, 3H)〇 實施例1(8): 2-(N-烯丙基-N_(3-(2-(2-(6-二甲胺基吡啶-3-基)-5-甲基噁 唑-4-基)乙氧基)苄基)胺基)乙酸•乙酯
NMR(CDC13): δ 8.74 (m, 1H), 7.99 (dd, J = 9.0, 2.4 Hz, 1H), 7.20 (dd, J = 8.0, 8.0 Hz, 1H), 6.94^.86 (m, 2H), 6.79 (m, 1H), 6.53 (m, 1H), 5.87 (ddt, J - 16.8, 10.0, 6.5 Hz, 1H), 5.21 (m, 1H), 5.14 (m, 1H), 4.22 (t, J = 70 Hz, 2H), 4.14 (q, J = 7.0 Hz, 2H), 3.75 (s, 2H), 3.30 (s, 2H), 3.27 (d, J = 6.5 Hz, 2H), 3.14 (s, 6H), 2.95 (t, J = 7.0 1¾ 2H),2.34 (s,3H),1.25 (t, J = 7.01¾ 3H)。 實施例1(9): 2-(N-烯丙基-N-(3-(2-(2-(4-二甲胺基苯基)-5 -曱基噁唑-4· 基)乙氧基)卞基)胺基)乙酸•乙酯
TLC : Rf 0.26(己烷:乙酸乙酯=4 : 1)。 實施例1Π0): 1 / - # · _ --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 53 314159 200300681 A7 B7 五、發明說明(54 ) 2-(N-烯丙基-N-(3-(2-(5-甲基-2-苯基噁唑-4-基)乙氧基)苄 基)胺基)-2 -甲基丙酸·甲酉旨
TLC : Rf 0.48(己烷:乙酸乙酯=4 : 1); NMR(CDC13): δ 8.02-7.94 (m, 2H), 7.48-7.37 (m, 3H), 7.17 (dd, J = 8.0, 8.0 Hz, 1H), 6.98-6.88 (m, 2H), 6.73 (m, 1H), 5.78 (ddt, J= 16.5, 10.0, 6.5 Hz, 1H), 5.00 (m, 1H), 4.90 (m, 1H), 4.24 (t, J = 6.5 Hz, 2H), 3.77 (s, 2H), 3.69 (s, 3H), 3.28 (d, J = 6.5 1¾ 2H),2·98 汰 J = 6.51¾ 2H),2.38 (s,3H),1.38 (s, 6H)。 實施例1 (1 u : 2-(N-稀丙基-N-(3-(2-(2-(6-嗎啉代D比咬-3-基)-5 -甲基ϋ惡。坐 基)乙氧基)苄基)胺基)乙酸•乙酯 -------------裝--------訂· (請先閱讀背面之注意事項再填寫本頁)
經濟部智慧財產局員工消費合作社印製 TLC : Rf 0.44(氯仿:甲醇=10 : 1) NMR(CDC13): δ 8.76 (d, J = 2.4 Hz, 1H), 8.04 (dd, J = 9.0, 2.4 Hz, 1H), 7.19 (t, J = 9.2 Hz, 1H), 6.96-6.85 (m, 2H), 6.83-6.74 (m, 1H), 6.64 (d, J = 9.0 Hz, 1H), 5.98-5.74 (m, 1H), 5.27-5.04 (m, 2H), 4.28-4.06 (m, 4H)5 3.87-3.78 (m, 4H), 3.74 (s, 2H), 3.65-3.55 (m, 4H), 3.32-3.22 (m, 4H), 2.95 (t, J = 7.0 Hz, 2H), 2.35 (s, 3H), 1.25 (m, 3K)〇 實施例1(12): 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 54 314159 200300681 Α7 _____________ Β7 五、發明說明(55 ) 2-(N-烯丙基-N-(3-(2-(2-(6-六氫吡啶基吡啶-3-基)-5-甲基 噁唑基)乙氧基)苄基)胺基)乙酸•乙酯
NMR(CDC13): δ 8.72 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 9.0, 2.4 Hz, 1H), 7.19 (t, J = 8.0 Hz, 1H), 6.96-6.85 (m, 2H), 6.79 (m, 1H), 6.64 (d, J = 9.0 Hz, 1H), 5.98-5.73 (m, 1H), 5.27-5.04 (m, 2H), 4.28-4.03 (m, 4H), 3.74 (s, 2H), 3.61 (brs, 4H), 3.32-3.22 (巩 4H), 2.94 汰 J = 6.61¾ 2H), 2.34 (s,3H),1·65 (brs,6H),1.25 (巩 3H)。 實施例1 Π 3): 2-(N-烯丙基-N-(3-(2-(2-(6-二乙胺基D比咬-3-基)-5-甲基°惡 唑-4 -基)乙氧基)▼基)胺基)乙酸•乙酯 (請先閱讀背面之注意事項再填寫本頁)
〇v^ch3 TLC : Rf 0·48(氯仿:甲醇=10 : 1); 經濟部智慧財產局員工消費合作社印製 NMR(CDC13): δ 8.71 (d, J - 2.6 Hz, 1H), 7.95 (dd, J = 9.2, 2.6 Hz, !H), 7.19 (t, J - 6.8 Hz, 1H), 6.95-6.75 (m, 3H), 6.47 (d, J = 9.2 Hz, 1H), 5.85 (m, 1H), 5.21 (d, J =17.2 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.22 (t, J = 6.8 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.74 (s, 2H), 3.55 (q, J = 7.0 Hz, 4H), 3.29 (s, 2H), 3.27 (d J - 6.4 Hz, 2H), 2.91 仏 J = 6·81¾ 2H), 2.34 (s, 3H),1.35-1.15 (叫 9H)。 實施例1(14) ·· 2-(N-稀丙基-Ν-(3-(2-(2-(6-〇ϋ p各烧基Π比。定-3-基)-5 -曱基。惡 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 55 314159 200300681 A7 ___B7__ 五、發明說明(56 ) 唑-4-基)乙氧基)苄基)胺基)乙酸•乙酯
TLC : Rf 0.80(氣仿:甲醇=10 : 1); NMR(CDC13): 8 8.73 (d, J = 2.4 Hz, 1H), 7.98 (dd, J = 8.8, 2.4 Hz, 1H), 7.19 (t, J = 7.2 Hz, 1H), 6.93-675 (m, 2H), 6.91 (s, 1H), 6.37 (d, J = 8.8 Hz, 1H), 5.98-5.74 Φ (m, 1H), 5.29-5.09 (m, 2H), 4.22 (t, J = 6.6 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 3.74 (s, 2H), 3.50 (m, 4H), 3.29 (s, 2H), 3.26 (d, J = 6.6 Hz, 2H), 2.94 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H), 2.02 (m, 4H), 1.24 (t, J - 7.2 Hz, 3H)〇 實施例1Π5): 2-(N-烯丙基-N-(3-(2-(2-(4-嗎啉代苯基)-5-甲基噁唑-4-基) 乙氧基)卞基)胺基)乙酸·乙酉旨 -------------裝--------訂. (請先閱讀背面之注意事項再填寫本頁)
經濟部智慧財產局員工消費合作社印制π NMR(CDC13): δ 7.87 (d, J = 9.0 Hz, 2H), 7.20 (t, J = 8.1 Hz, 1H), 6.95 - 6.87 (m, 4H), 6.79 (m, 1H), 5.86 (m, 1H), 5.25 - 5.11 (m, 2H), 4.23 (t, J = 6.6 Hz, 2H), 4.14 (q, J = 6.9 Hz, 2H), 3.87 (t, J = 4.5 Hz, 4H), 3.74 (s, 2H), 3.32 - 3.20 (m, 8H), 2.96 (t, J = 6.6 Hz, 2H), 2.35 (S> 3H), 1.25 (t, J = 6.9 Hz, 3H)〇 · 實施例1(16): 2-(N-烯丙基-N-(3-(2-(2-嗎啉代-5-曱基噻唑·ζμ基)乙氧基) 卞基)胺基)乙酸·第三丁 g旨 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 56 314159 經濟部智慧財產局員工消費合作社印制衣 200300681 A7 B7 五、發明說明(57 )
TLC : Rf 0.85(氯仿··甲醇=9 : 1); >iMR(CDCI3): δ 7.19 (t, J = 8.4 Hz, 1H), 6.94 - 6.87 (m, 2H), 6.77 (m, 1H), 5.86 (m, 1H), 5.26 - 5.10 (m, 2H), 4.19 (t, J = 6.9 hz, 2H), 3.79 (t, J = 4.5 Hz, 4H), 3.75 (s? 2H), 3.37 (t, J = 4.5 Hz, 4H), 3.26 (d, J = 6.6 Hz, 2H), 3.21 (s, 2H), 2.95 (t, J = 6.9 Hz, 2H),2.05(s,3H),1.46(s,9H)。 實施例1(17): 2-(N-細丙基-N-(4_(2-(5 -曱基-2-苯基°惡。坐-4-基)乙氧基)节 基)胺基)乙酸•乙酯
NMR(CDC13) : δ 8.00-7.95 (m, 2H), 7.44^7.39 (m, 3H), 7.23 (d, J = 8.7 Hz, 2H), 6.85 (d, J - 8.7 Hz, 2H), 5.94-5.80 (m, 1H), 5.23-5.11 (m, 2H), 4.23 (t, J = 6.6 Hz, 2H), 4.14 (q, J = 7.2 Hz, 2H), 3.70 (s, 2H), 3.27 (s, 2H), 3.24 (d, J = 6.6 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.37 (s, 3H), 1.25 (t, J = 7.2 Hz, 3H)〇 實施例2 : 2-(N-烯丙基-N-(3-(2-(2-(6-(全氫吖庚因-l-基)口比啶-3-基) 5-甲基噁唑-4-基)乙氧基)苄基)胺基)乙酸 ----------------------------- (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 57 314159 200300681 A7 -_ B7 五、發明說明(58 )
在室温,於實施例1所製造之化合物(777毫克)之乙醇 及四氫呋喃(20毫升、1 : 1)溶液中加入2N氫氧化鈉水溶 液(3 ·0耄升),攪拌1 5小時。反應混合物用2N鹽酸將pH 值调整為約5 ’用乙酸乙酯抽出。抽出液依次用水及飽和 •食鹽水洗淨,用無水硫酸鎂乾燥後濃縮,獲得具有以下物 性值之本發明化合物(5 46毫克)。 TLC : Rf 〇.18(氯仿:甲醇=9 : 1); NMR(CDC13): δ 8.71 (d, J = 2.4 Hz, 1H), 7.96 (dd, J = 9.0,2.4 Hz, 1H), 7.24 (dd, J = 7.8, 7.5 Hz, 1H), 6.93-6.82 (m, 3H), 6.51 (d, J = 9.0 Hz, 1H), 5.96-5.80 (m, 1H), 5.35-5.26 (m, 2H), 4.23 (t, J = 6.9 Hz, 2H), 3.81 (s, 2H), 3.67 (dd, J = 6.0, 6.0 Hz, 4H), 3.34 (d, J = 6.9 Hz, 2H), 3.29 (s, 2H), 3.00-2.70 (br, 1H), 2.94 (t, J = 6.9 Hz, 2H), 2.34 (s, 3H), 1.84-1.72 (m, 4H), 1.59-1.50 (m, 4H)〇 1_施例2Π)至膏施例2(17): 使用實施例1(1)至實施例1(17)所製造之化合物取代 實施例1所製造之化合物,經由與實施例2相同之操作, 必要時可根據公知之方法轉換為適當之鹽,獲得以下所示 之本發明化合物。 實施例2 Π、: 2-(N-烯丙基-N-(3-(2-(2-異丙基-5-曱基噁唑-4-基)乙氧基) 下基)胺基)乙酸 -------------裝 i. (請先閱讀背面之注意事項再填寫本頁) 訂 線 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(21〇x 297公釐) 58 314159 經濟部智慧財產局員工消費合作社印製 200300681 A7 B7 五、發明說明(59 )
TLC: Rf0.32(氯仿:甲醇:乙酸= 100: 1〇: 1); NMR(CDC13): δ 7.20 (dd, J = 8.0, 8.0 Hz, 1H), 6.94-6.78 (m, 3H), 5.92 (m, 1H), 5.30 (d, J = 11.4 Hz, 1H), 5.29 (d, J = 15.0 Hz, 1H), 4.15 (t, J = 7.0 Hz, 2H), 3.88 (s, 2H), 3.38 (d, J = 7.0 Hz, 2H), 3.31 (s, 2H), 2.99 (sept, J = 7.0 Hz, 1H), 2.86 (t, J = 7.0 Hz, 2H), 2.24 (s, 3H), 1.30 (d, J = 7,0 Hz, 6H)0 實施例2(2): 2-(N-烯丙基-N-(3-(2-(2-(4-甲基六氫吡哄-l-基)-5-曱基噻 σ坐-4-基)乙氧基)卞基)胺基)乙酸
TLC : Rf 0.69(氯仿:甲醇:水=50 : 20 : 1); NMR(CDC13) : δ 7.20 (dd, J = 8.0, 8.0 Hz, 1H), 6.95^.87 (m, 2H), 6.81 (dd, J = 8.0, 2.0 Hz, 1H), 5.93 (m, 1H), 5.28 (d, J = 16.8 Hz, 1H), 5.27 (d, J = 10.5 Hz, 1H), 4J9 (t, J = 7.0 Hz, 2H), 3.88 (s, 2H), 3.45 ( dd, J = 5.0, 5.0 Hz, 4H), 3.38 (d, J = 6.5 Hz, 2H), 3.31 (s, 2H), 2.92 (t, J = 7.0 Hz, 2H), 2.59 (dd, J = 5.0, 5.0 Hz, 4H), 2.37 (s, 3H),2.24 (s,3H)。 實施例2(3): 2-(N-烯丙基-N-(3-(2-(2-(4-( 1,2,3-噻二唑-4-基)苯基)-5-曱 基噁唑-4-基)乙氧基)苄基)胺基)乙酸•鈉鹽 · I----.— ^---------^ AW. (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210x 297公釐) 59 314159 200300681 Α7 Β7 經濟部智慧財產局員工消費合作社印製 五、發明說明( 60
TLC : Rf 0.36(氯仿:曱醇=8 ·· 1); NMR(DMSO-d6) : 5 9.74 (s, 1H), 8.28 (d, J = 8.6 Hz, 2H), 8.07 (d, J = 8.6 Hz, 2H), 7.16 (dd, J = 7.8, 7.8 Hz, 1H), 6.95-6.70 (m, 3H), 5.80 (m, 1H), 5.19-4.96 (m, 2H), 4.20 (t, J = 6.5 Hz, 2H), 3.67 (s, 2H), 3.19 ( 4 J = 6.0 Hz, 2H), 2.94 (t, J = 6.5 取 2H), Z77 (s, 2H), 2.38 (s,3H)。 實施例2(4) ·· 2-(N-烯丙基-N-(3-(2-(2-(4-環己基苯基)-5 -曱基噁唑-4-基) 乙氧基)苄基)胺基)乙酸
TLC : Rf 0.32(氯仿:甲醇=8 : 1) NMR(CDC13) : δ 7.86 (d, J = 8.4 Hz, 2H), 7.30-7.18 (m, 3H), 7.12-7.00 (m, 2H), 6.88 (m, 1H), 6.03 (m, 1H), 5.56 (brs, 1H), 5.48-5.30 (m, 2H), 4.36-4.04 (m, 4H), 3.68 (d, J = 6.3 Hz, 2H), 3.52 (s, 2H), 2.93 (t, J = 6.6 Hz, 2H), 2.51 (m, 1H), 2.34 (s, 3H),1.96-1.68 (% 5H), 1.52-1.14 (取 5H)。 實施例2(5): 2-(N-稀丙基-N-(3-(2-(2-(4-(四氫D比喃-4-基)苯基)-5 -曱基 噁唑-4-基)乙氧基)T基)胺基)乙酸 -------------裝--------訂· (請先閱讀背面之注意事項再填寫本頁) 線 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 60 314159 經濟部智慧財產局員工消費合作社印製 200300681 A7 B7 五、發明說明(61 )
TLC : Rf 0.39(氣仿:甲醇=4 : 1); NMR(CDC13) : δ 7.91 (d, J= 8.1 Hz, 2H), 7.36-7.24 (m, 3H), 7.16 (m, 1H), 7.05 (m, 1H), 6.92 (m, IH), 6.14 (m, 1H), 5.54-5.38 (m, 2H), 5.08 (brs, 1H), 4.34-4.02 (m, 6H), 3.76 (d, J = 6.3 Hz, 2H), 3.62-3.54 (m, 4H ), 2.94 (t, J = 6.6 Hz, 2H), 2.80 (m, 1H),2.38 (s,3H),1·92-1·70 (巩 4H)。 實施例2(6): 2-(Ν-烯丙基-N-(3-(2-(5-甲基-2-六氫吡啶基噻唑-4-基)乙 氧基)Τ基)胺基)乙酸· 1/2鈣鹽
NMR(CDC13): δ 7.13 (t, J = 8.1 Hz, 1H), 6.89 - 6.80 (m, 2H), 6.72 (m, 1H), 5.80 (m, 1H), 5.16 - 4.98 (m, 2H), 4.09 (t, J = 6.9 Hz, 2H), 3.67 (s, 2H), 3.36 - 3.12 (m, 6H), 2.92 (s, 2H), 2.80 (t, J = 6.9 Hz, 2H), 2.16 (s, 3H), 1.58 - 1.48 (m, 6H)〇 實施例2(7): 2-(N-稀丙基-N-(3-(2-(5 -甲基-2-苯基嗔°坐-4-基)乙氧基)节 基)胺基)乙酸 --------^---------^ (請先閱讀背面之注意事項再填寫本頁)
本紙張尺度適用中國國家標準(CNS)A4規格ΟΠΟ X 297公釐) 61 314159 200300681
V 經濟部智慧財產局員工消費合作社印製
A7 __B7___ 五、發明說明(62 ) 自由體 TLC : Rf 0·21(氯仿:甲醇=8 ·· 1); NMR(CDC13): δ 8.02-7.90 (m, 2H), 7.48-7.35 (m, 3H), 7.23 (m, 1H), 7.05-6.83 (m, 3H), 5.96 (m, 1H), 5.44-5.28 (m, 2H), 4.22 (t, J = 6.6 Hz, 2H), 4.12 (s, 2H), 3.60 (m, 2H), 3.47 (s, 2H), 2.94 (t, J = 6.6 Hz, 2H), 2.35 (s, 3H)〇 納鹽 丁1^:1^0.61(氣仿:曱醇=4:1); ’ NMR (DMSOO : δ 7.95-7.90 (m, 2H), 7.55-7.45 (m, 3H), 7.15 (dd, J = 8, 8 Hz, 1H), 6.95-6.70 (m, 3H), 5.80 (m, 1H), 5.20-5.00 (m, 2H), 4.20 (t, J = 6.5 Hz, 2H), 3.70 (s, 2H), 3.20 (d, J = 7 Hz, 2H ), 2.95 (t, J = 6.5 Hz, 2H), 2.80 (s, 2H), 2.35 (s, 3H)〇 實施例2(8): 2-(N-烯丙基-N-(3-(2-(2-(6-二曱胺基吡啶-3·基)-5-甲基噁 唑-4-基)乙氧基)苄基)胺基)乙酸
TLC : Rf 0.2 6(氯仿:甲醇:乙酸= 100 : 10 : 1); NMR(CDC13): δ 8.73 (d, J - 2.4 Hz, 1H), 7.99 (dd, J - 2.4, 9.0, 1.5 Hz, 1H), 7.24 (dd, J - 8.0, 8.0 Hz, 1H), 6.94^.81 (m, 3H), 6.52 (d, J = 9.0 Hz, 1H), 5.90 (m, 1H), 5.31 (d, J = 11.2 Hz, 1H), 5.30 (d, J = 15 .8 Hz, 1H), 4.22 (t, J = 7.0 Hz, 2H), 3.85 (s, 2H)? 3.36 (d, J = 7.0 Hz, 2H), 3.31 (s, 2H), 3.14 (s, 6H), 2.93 (t, J = 7.0 Hz, 2H), 2.34 (s, 3H)〇 實施例2(9): 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 62 314159 II 丨 ---— II----. I-----I 訂· —------- (請先閱讀背面之注意事項再填寫本頁) 200300681 A7 B7 五、發明說明(63 ) 2-(N-烯丙基-N-(3-(2-(2-(4-二甲胺基苯基)-5 -甲基噁唑-4-基)乙氧基)苄基)胺基)乙酸
TLC : Rf 0.31(氣仿:甲醇:乙酸= 100 : 10 : 1); NMR(CDC15): δ 7.83 (m, 2H), 7.22 (dd, J = 8.0, 8.0 Hz, 1H), 6.94-6.80 (m, 3H), 6.70 (m, 2H), 5.89 (m, 1H), 5.29 (d, J = 11.8 Hz, 1H), 5.28 (d, J = 15.2 Hz, 1H), 4.22 (t, J = 7.0 Hz, 2H), 3.84 (s, 2H), 3.35 (d, J = 7.0 Hz, 2H), 3.29 (s, 2H), 3.00 (s, 6H), 2.93 汰 J = 7.01¾ 2H),2·32 (s, 3H)。 實施例2(10): 2-(N-烯丙基-N-(3-(2-(2-笨基-5-曱基噁唑-4-基)乙氧基)节 基)胺基)-2-甲基丙酸 (請先閱讀背面之注意事項再填寫本頁)
經濟部智慧財產局員工消費合作社印製 自由體 TLC : Rf 0·3 2(氯仿:甲醇=10 : 1); NMR(CDC13) : δ 8.02-7.95 (m, 2H), 7.47-7.39 (m, 3H), 7.25 (m, 1H), 6.96-6.89 (m, 2H), 6.85 (m, 1H), 5.85 (ddt, J = 16.8,10.2, 6.6 Hz, 1H), 5.21 (m, 1H), 5.18 (m, 1H), 4.25 (t, J - 7.0 Hz, 2H), 3.74 (s, 2H), 3.32 (d, J = 6.6 Hz, 2H), 2.98 (t, J = 7.0 Hz, 2H), 2.38 (s, 3H), 1.45 (s, 6K)〇 鈉鹽 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 63 314159 200300681 A7 ___B7__ 五、發明說明(64 ) TLC : Rf 0.42(氯仿:曱醇=10 : 1); NMR (DMSO-cQ : δ 7.96-7.86 (m, 2H), 7.56-7.43 (m, 3H), 7.12 (dd, J - 8.0, 8.0 : Hz, 1H), 6.99 (brs, 1H), 6.89 (d, J = 8.0 Hz, 1H), 6.69 (dd, J - 8.0,2.0 Hz, 1H), 5.75 、 (ddt, J = 17.0, 10.5, 6.0 Hz, 1H), 4.92 (m, 1H), 4.76 (m, 1H), 4.18 (t, J = 7.0 Hz, 2H),
3.76 (s, 2H), 3.29 (d, J = 6.0 Hz, 2H), 2.92 (t, J = 7.0 Hz, 2H), 2.36 (s, 3H), 1.17 (s, 6H)P 實施例2(1 Π : 2-(N-烯丙基-N-(3-(2-(2-(6-嗎啉代吡啶-3-基)-5-曱基噁唑-4-基)乙氧基)卞基)胺基)乙酸 -------------裝— (請先閱讀背面之注意事項再填寫本頁) 訂 TLC : Rf 0.22(氯仿:曱醇=10 : 1); NMR(CDC13): δ 8.76 (d, J = 2.2 Hz, 1H), 8.04 (dd, J = 9.0, 2.2 Hz, 1H), 7.24 (t, J = 8.0 Hz, 1H), 6.96-6.82 (m, 3H), 6.64 (d, J = 9.0 Hz, 1H), 6.01-5.78 (m, 1H), 5.32 ^ (d, J = 10.8 Hz, 1H), 5.31 (d, J = 15.4 Hz, 1H), 4.22 (t, J = 6.8 Hz, 2H), 3.84 (s, 2H), 3.82 (t, J = 5.0 Hz, 4H), 3.59 (t, J = 5.0 Hz, 4H), 3.37 (d, J = 6.8 Hz, 2H), 3.31 (s, 2H), 2·94 汰 J = 6.81¾ 2H), 2·35 (s, 3H)。 實施例2(12): 2-(N-烯丙基-N-(3-(2-(2-(6-六氫吡啶基吡啶-3-基)-5-曱基 噁唑-4-基)乙氧基)苄基)胺基)乙酸 線 經 濟 部 智 慧 財 產 局 員 工 消 費 合 作 社 印 製
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 64 314159 經濟部智慧財產局員工消費合作社印製 200300681 A7 B7 五、發明說明(65 ) TLC ·· Rf 0.2 8(氯仿··甲醇=10 : 1); NMR(CDC13): δ 8.72 (d, J = Z2 Hz, 1H), 7.97 (dd, J = 9.0,2.2 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 6.97-6.79 (m, 3H), 6.64 (d, J = 9.0 Hz, 1H), 6.02-5.77 (m, 1H), 5.31 (d, J = 9.8 Hz, 1H), 5.29 (d, J = 16.0 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 3.85 (s, 2H), 3.60 (br s, 4H), 3.36 (d, J = 7.0 Hz, 2H), 3.30 (s, 2H), 2.92 (t, J = 6.8 Hz, 2H), 2.33 (s, 3H), 1.65(brs,6H)0 實施例2(13): 2-(N-細丙基-N-(3-(2-(2-(6-二乙胺基〇比σ定-3-基)-5-曱基°惡 唑-4-基)乙氧基)苄基)胺基)乙酸
NMR(CDC13): δ 8.71 (d, J = 2.4 Hz, 1H), 7.95 (dd, J = 9.0,2.4 Hz, 1H), 7.23 (t, J = 7.8 Hz, 1H), 6.97-6.81 (m, 3H), 6.47 (d, J = 9.0 Hz, 1H), 6.00-5.78 (m, 1H), 5.31 (d, J - 10.8 Hz, 1H), 530 (d, J = 15.8 Hz, 1H), 4.22 (t, J = 7.0 Hz, 2H), 3.84 (s, 2H), 3.55 (q, J = 7.2 Hz, 4H), 3.36 (d, J = 7.4 Hz, 2H), 3.30 (s, 2H), 2.93 (t, J = 7.0 Hz, 2H), 2.33 (s, 3H), 1.99 (t, J = 7.2 Hz, 6H)〇 實施例2(14): 2-(N-稀丙基-N-(3-(2-(2-(6-吼洛统基D比咬-3-基)-5 -曱基°惡 唑-4-基)乙氧基)苄基)胺基)乙酸 CKKOO^丫 --------------------訂---------線\^ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 65 314159 200300681
A7 ______ _B7_ 五、發明說明(66 ) TLC : Rf 0.49(氣仿··甲醇=6 ·· 1); NMR(CDC13): δ 8.73 (d, J = 2.2 Hz, 1H), 7.98 (dd, J = 8.8,2.2 Hz, 1H), 7.23 (t5 J = 8.0 Hz, 1H), 6.97-6.81 (m, 3H), 6.38 (d, J = 8.8 Hz, 1H), 6.04-5.77 (m, 1H), 5.30 (d, J = 10.4 Hz, 1H), 5.29 (d, J = 15.6 Hz, 1H), 4.22 (t, J = 7.0 Hz, 2H), 3.80 (s, 2H), 3.50 (m, 4H), 3.33 (d, J = 6.6 Hz, 2H), 3.28 (s, 2H), 2.93 (t, J = 7.0Hz, 2H), 2.34 (s, 3H), Z02 ㈣ 4H)0 f 實施例2(15): >2-(N-烯丙基-N-(3-(2-(2-(4-嗎啉代苯基)-5_曱基噁唑-4-基) 乙氧基)卞基)胺基)乙酸·鹽酸鹽
TLC : Rf 0.25(氯仿:甲醇=9 : 1); NMR (DMSO-屯):δ 7.74 (d,J = 9.0 取 2Η),7·20 (t J = 8·11¾ 1Η),7·01 (d, J =9.0 Hz, 2Η), 6.91 - 6.77 (m, 3H), 5.81 (m, 1H), 5.22 - 5.09 (m, 2H), 4.17 (t, J = 6.3 Φ Hz, 2H), 3.73 (t, J = 4.2 Hz, 4H), 3.68 (s, 2H), 3.52 - 3.08 (m, 9H), 2.87 (t, J = 6.3 Hz, 2H), 2.3 l(s, 3H)〇 實施例2(16): 2-(N-烯丙基-N-(3-(2-(5-曱基-2-嗎啉代噻唑-4-基)乙氧基) 苄基)胺基)乙酸· 2鹽酸鹽 ------— II----裝-------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 經濟部智慧財產局員工消費合作社印製
本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 66 314159 經濟部智慧財產局員工消費合作社印製 200300681 A7 __ B7 五、發明說明(67 ) TLC : Rf 0.28(氯仿:曱醇=9 : 1); NMR(DMSOd,): δ 10.96 (br, 1H), 7.34 (t, J = 8.1 Hz, 1H), 7.24 (m, 1H), 7.09 (d, J = 8.1 Hz, 1H), 6.99 (dd, J = 8J, 2.1 Hz, 1H), 6.03 (m, 1H), 5.56 - 5.47 (m, 2H), 4.35 (s, 2H), 4.24 (t, J = 6.3 Hz, 2H), 3.89 (s, 2H), 3.82 (d, J = 6.9 Hz, 2H), 3.76 -3.54 (m, 8H), 3.07 (t, J = 6.3 Hz, 2H), 2.34 (s, 3H)〇 實施例2Π7): 2-(N-烯丙基-Ν-(4-(2·(5-甲基-2-苯基噁唑-4-基)乙氧基)▼ 基)胺基)乙酸
TLC : Rf 0·14(氯仿:甲醇=9 : 1); NMR(CDC13): δ 8.00-7.95 (m, 2H), 7.43-7.39 (m, 3H), 7.23 (d, J = 8.4 Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 5.95- 5.80 (m, 1H), 5.37-5.28 (m, 2H), 4.24 (t, J = 6.6 Hz, 2H), 3.84 (s, 2H), 3.35 (d, J = 7.2 Hz, 2H), 3.29 (S> 2H), 2.98 (t, J = 6.6 Hz, 2H), 2.60-2.20 (brs, 1H), 2.38 (s, 3H)〇 製劑例1 : 將下述之各成分依照常法混合後打錠,獲得一錠中含 有5 0毫克活性成分之錠劑1 0 0錠。 • 2-(N-烯丙基-N-(3-(2-(2-(6-(全氫吖庚因-1-基)吼啶-3-基) -5 -甲基噁唑-4-基)乙氧基)苄基)胺基)乙酸.........5.0公克 •羧曱基纖維素鈣(崩解劑) .........〇·2公克 •硬脂酸鎂(潤滑劑) .........〇· 1公克 •微結晶纖維素 .........4 · 7公克 --------------------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(2】〇x 297公釐) 67 314159 A7 B7
200300681 五、發明說明(68 ) 製劑例2 : “將下述之各成刀依照常法混合後將溶液根據常法滅 囷,於各安親中充填5毫升,根據常法康結乾燥,獲得每 安瓿中含有20毫克活性成分之安瓿1〇〇支。 2-(N-烯丙基-N-(3-(2-(2-(6-(全氫π丫庚因-1-基)π比咬-3-基) -5-甲基嗔峻-4-基)乙氧基)苄基)胺基)乙酸..........2〇公克 •甘露糖醇 ........20公克 ’ · ?备館水 .... 1000毫升 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) ^1 I !! -- I -1. - - --1 1- / 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(2】0 X 297公釐) 68 314159 經濟部智慧財產局員工消費合作社印製 200300681 A7 B7 五、發明說明(69 ) 序列表 <110〉小野藥品工業股份有限公司 <120〉羧酸衍生物及含有該衍生物 作為有效成份之藥劑
<130〉 ONF-4357PCT <15Q> JP2001-346583 <151〉 2001-1卜12 <160〉 3 <170> Patentln Ver. 2. 1 <210〉 1 <211> 85 <212> DNA <213〉人工序列 <220〉 <223〉加強子序列包括熏覆4次之Gal 4蛋白質反應序列 <400> 1 tcgacggagt actgtcctcc gcgacggagt actgtcctcc gcgacggagt actgtcctcc 60 gcgacggagt actgtcctcc gagct 85 <210〉 2 〈211〉 9 <212〉 PRT <213〉未知 <220〉 <223〉源自SV-40 T-抗原之核定域化信號 <400> 2
Ala Pro Lys Lys Lys Arg Lys Val Gly 1 5 -------------------訂---------線^^^ (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 69 314159 200300681 A7 B7
五、發明說明(7G
<210〉 3 <211〉 9 <212> PRT <213〉 Influenza virus <220〉 <223> hemagglutinin epitope <400> 3
Tyr Pro Tyr Asp Val Pro Asp Tyr Ala 1 5 0- ; 經濟部智慧財產局員工消費合作社印製 -------------裝--------訂---------線 (請先閱讀背面之注意事項再填寫本頁) 本紙張尺度適用中國國家標準(CNS)A4規格(210 x 297公釐) 70 314159
Claims (1)
- 200300681 A8 B8 CS D8 六、申請專利範圍 1 · 一種式(I)所示之羧酸衍生物化合物或其非毒性鹽 。々: -Ο R2 R3 X—N—C-COOR1 (式中,X及Y各自獨立為c1-4伸烷基, Z為-0-基或-S-基、 R】、R2、R3及R4各自獨立為氫原子或C R5為C2_8鏈烤基、 A為·0-基或-S-基、 ϋ 為 Di、D2、D3、D4 或 D5、 D1為(V8烷基、 烷基 ------ (請先閱讀背面之注意事項再填寫本頁)環1為含有1個氮原子或可另含有1個選自氧原子、碎 原子或氮原子之雜原子之3至7員單環之飽和雜芳基、 訂--------- 線· 經濟部智慧財產局員工消費合作社印製(1 ) σ卩分或全部為飽和之C 3 · 1 〇單壤或二環式碳产— 九衣方基或 (2)含有1至4個選自氧原子、氮原子或硫原 子,部分或全部為飽和之3至10員單環或_冉 ^ 4 一裱式雜芳 表紙張尺用T關家鮮(CNS)A4 公釐3 m I 3】4】59 200300681 A8 B8 C8 D8 六、申請專利範圍 基 (RS)m D4為 D5為 t 經 濟 部 智 慧 財 產 局 消 費 合 作 社 印 製 D6為⑴氫原子、(2)C]-8烷基、(3)Cl-8烷氧基、(4)CF3 基、(5)〇CF3基、(6)_素原子、(7)硝基或(8)nr7r8基、 R7及R8為氫原子或烷基或 R7及R8亦可與所結合之氮原子一同形成含有i個氮原 子或可另含有1個選自氧原子、硫原子或氮原子之雜原 子之3至7員單環之飽和雜芳基、該飽和雜芳基亦可經 C ! _ 8烧基取代、 E為CH或氮原子、 m為1至3之整數)。 如申請專利範圍第i項之羧酸衍生物化合物或其非毒 性鹽,其中,Z為-S-基者。 3 ·如申請專利範圍第1項之羧酸衍生物化合物或其非毒性鹽,其中,Z為-〇-基,〇為、D2、D3或D4者。 4 ·如申請專利範圍第1項之羧酸衍生物化合物或其非毒性鹽,其中,D係為D】者。 5 ·如申请專利範圍第1項之竣酸衍生物化合物或其非毒 性鹽,其中,D為D2者。 6 ·如申凊專利範圍第1項之竣酸衍生物化合物或其非毒 2 本紙張尺度適用中國國家標準(CNS)A4規袼(210 X 297公釐) 72 314159 --------------^--------訂---------^ (請先閱讀背面之注意事項再填寫本頁} 200300681六、申請專利範圍性鹽,其中,D為D3者。 經濟部智慧財產局員工消費合作社印制衣 7·如申請專利範圍第1項之羧酸衍生物化合物或其非毒 性鹽,其中,D為D4者。 8·如申請專利範圍第1項之羧酸衍生物化合物或其非毒 性鹽,其中,D為D5者。 9.如申請專利範圍第4項之化合物或其非毒性鹽,其中, 該化合物為 (1) 2-(Ν·烯丙基-N-(3-(2-(2-異丙基-5-曱基噁唑_4_基)乙 氧基)苄基)胺基)乙酸·乙酯或 (2) 2-(Ν·烯丙基·Ν-(3-(2-(2-異丙基-5-曱基噁唑基)乙 氧基)苄基)胺基)乙酸者。 1 0 ·如申明專利範圍笫5項之化合物或其非毒性鹽,其中, 該化合物為 (1) 2-(Ν-烯丙基-Ν·(3_(2-(2气4_甲基六氫吡哄^•基>5· 曱基噻唾-4-基)乙氧基)苄基)胺基)乙酸·乙酯、 (2) 2-(Ν·烯丙基·ν-(3-(2-(5 -甲基-2-六氫吡啶基噻唑 基)乙氧基)苄基)胺基)乙酸·乙酯、 (3) 2-(Ν-烯丙基-Ν-(3-(2-(2-嗎啉代-5-曱基噻唑-4-基)乙 氧基)卞基)胺基)乙酸•第三丁醋、 (4) 2-(Ν-烯丙基-N-(3-(2-(2-(4-甲基六氫吡畊-1-基 甲基噻唑-4·基)乙氧基)〒基)胺基)乙酸、 (5) 2-(Ν-烯丙基·Ν-(3-(2-(5-甲基-2-六氫吡啶基噻唑 基)乙氣基)卞基)胺基)乙酸或 (6) 2-(Ν-烯丙基-Ν-(3-(2-(5 -甲基-2-嗎啉代噻唑-I基)乙 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 73 314159 ------------裝---- (請先閱讀背面之注意事項再填寫本頁) 訂--------- # 200300681 Λ € 蟢 經 濟 部 智 慧 財 產 局 員 工 消 f 合 作 社 印 製 B8 C8 D8 六、申請專利範圍 氧基)苄基)胺基)乙酸者。 11.如申請專利範圍第6項之化合物或其非毒性鹽,其中, 該化合物為 (1) 2-(N-烯丙基 _N-(3_(2-(2_(Mi,2,3_噻二唑-4·基)苯 基)-5-曱基噁唑-4-基)乙氧基)苄基)胺基)乙酸·乙酯、 (2) 2-(Ν-烯丙基-Ν-(3_(2_(2_(4_環己基苯基)甲基噁唑 -4-基)乙氧基)〒基)胺基)乙酸·乙酯、 (3) 2-(^烯丙基-仏(3-(2-(2-(4-(四氫吡喃_4-基)笨基)_5一 甲基°惡唾-4-基)乙氧基)苄基)胺基)乙酸·乙酯、 (4) 2-(Ν-稀丙基 _Ν-(3-(2-(2-(4-(1,2,3-噻二嗤-4-基)苯 基)-5-甲基噁唑-4-基)乙氧基)苄基)胺基)乙酸、 (5) 2-(Ν-烯丙基-N-(3-(2-(2-(4-環己基苯基卜5_甲基噁唑 _4-基)乙氧基)苄基)胺基)乙酸或 (6) 2-(Ν-烯丙基-Ν-(3-(2-(2-(4-(四氫吡喃 基)苯基)_5-甲基σ惡唾-4-基)乙氧基)苄基)胺基)乙酸者。 12·如申請專利範圍第7項之化合物或其非毒性鹽,其中, 该化合物為 (1) 2-(Ν-烯丙基-N-(3-(2-(2-(6-(全氫吖庚因q-基)吼啶-3-基)5-甲基噁唑-4-基)乙氧基)苄基)胺基)乙酸·乙酯或 (2) 2-(Ν-烯丙基-N_(3-(2-(2-(6-(全氫吖庚因q •基)吼啶_ 3-基)5-曱基噁唑-4-基)乙氧基)苄基)胺基)乙酸者。 13·如申請專利範圍第8項之化合物或其非毒性鹽,其中, 該化合物為 (1)2-(N-烯丙基·ν_(3-(2-(2-苯基·5·曱基噁唑-4•基)乙氧 本紙張尺度適用中國國石票準(CNS)A4規格(2Κ) X 297公愛) ---—--------- 74 314159 -------------- --------訂--------- (請先閱讀背面之注意事項再填寫本頁} ΙΓΓ0300681 A8 B8 CS D8 六、申請專利範圍 基)苄基)胺基)乙酸•乙酯 (2) 2-(N-烯丙基-N-(3-(2-(2-(6-二甲胺基吡啶-3-基)-5- 甲基噁嗤-4-基)乙氧基)苄基)胺基)乙酸•乙酯 (3) 2-(N-烯丙基(3-(2-(2-(4-二甲胺基苯基)-5 -甲基噁 唑-4-基)乙氧基)苄基)胺基)乙酸•乙酯 (4) 2-(N-烯丙基-N-(3_(2-(5_甲基苯基噁唑_4_基)乙氧 基)▼基)胺基)-2-曱基丙酸•曱酯 (5) 2-(N-烯丙基-N-(3-(2-(2-(6-嗎啉代吡啶-3·基)-5-甲 基噁嗤-4-基)乙氧基)苄基)胺基)乙酸•乙酯 (6) 2-(N-烯丙基-N-(3-(2-(2-(6-六氫吡啶基吡啶-3-基卜 5-甲基噁峻-4-基)乙氧基)苄基)胺基)乙酸•乙酯 (7) 2-(N-烯丙基-N-(3-(2-(2-(6-二乙胺基吡啶-3-基)-5- 曱基噁唑-4-基)乙氧基)苄基)胺基)乙酸•乙酯 (8) 2-(N-烯丙基-N-(3-(2-(2-(6-吼咯烷基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)苄基)胺基)乙酸•乙酯 (9) 2-(N-烯丙基-N-(3-(2-(2-(4-嗎啉代苯基)-5 -曱基噁唑 _4_基)乙氧基)节基)胺基)乙酸·乙酯 經濟部智慧財產局員工消費合作社印製 (10) 2-(N-烯丙基-N-(4-(2-(5-曱基-2-苯基噁唑-4-基)乙 氧基)T基)胺基)乙酸•乙酯 (11) 2-(N-烯丙基-Ν·(3-(2-(5-曱基-2-苯基噁唑基)乙 氧基)苄基)胺基)乙酸 (12) 2-(Ν-烯丙基·Ν-(3-(2-(2-(6-二曱胺基吡啶-3-基)-5-甲基噁唑-4-基)乙氧基)〒基)胺基)乙酸 (13) 2·(Ν-烯丙基-Ν-(3-(2-(2-(4-二曱胺基苯基)-5-曱基 本紙張尺度適用中國國家標準(CNS)A4規格(21〇 χ 297公髮) 75 314159 200300681 A8 B8 C8 D8 六、申請專利範圍 噁唑-4-基)乙氧基)苄基)胺基)乙酸 (14)2-(N-稀丙基- N-(3-(2-(2 -苯基-5-甲基鳴。坐-4-基)乙 ---------------裝--- (請先閱讀背面之注意事項再填寫本頁) 氧基)卞基)胺基)-2-甲基丙酸 (1 5)2-(N-烯丙基-N-(3-(2-(2-(6-嗎啉代 π比唆-3-基)-5 -甲 基噁唑-4-基)乙氧基)苄基)胺基)乙酸 (16) 2-(N-烯丙基-N-(3-(2-(2-(6-六氫D比啶基D比啶-3-基)_ 丨甲基噁唑基)乙氧基)苄基)胺基)乙酸 (17) 2-(N-烯丙基-N-(3-(2-(2-(6-二乙胺基吡啶-3·基)_5-甲基噁唑-4-基)乙氧基)节基)胺基)乙酸 (1 8)2·(Ν-烯丙基-N-(3-(2-(2-(6-D比咯烷基吡啶-3-基)-5- 甲基噁唑-4-基)乙氧基)苄基)胺基)乙酸 (19) 2-(N-烯丙基-N-(3-(2-(2-(4_嗎啉代笨基卜5 -甲基噁 °坐基)乙氧基)节基)胺基)乙酸或 •線 (20) 2-(N-烯丙基(心(2_(5_甲基苯基噁唑_4_基)乙 氧基)苄基)胺基)乙酸。 經濟部智慧財產局員工消費合作社印製 14·一種過氧化微粒(per〇xis〇me)增殖藥活性化受體控制 劑’係含有申請專利範圍第1項之通式⑴所示之化合物 或其非毒性鹽作為有效成分。 15.種糖尿病、肥胖、X徵候群、高膽固醇血症、高脂蛋 白血症專代謝兴常疾病、高脂血症、動脈硬化症、高土 I 循環态乐疾病、過食症、虛血性心疾病之預防及/ 或治療劑,係含有申請專利範圍第1項之通式(I)所示之 化合物或其非毒性鹽作為有效成分。 16·—種HDL膽固醇上昇劑、LD]L膽固醇及/或V]LDl膽區 本紙張尺度適财x 297公董) 314159 76 200300681 A8 B8 C8 D8 六、申請專利範圍 醇減少劑、糖尿病及/或X徵候群之危險因子減輕劑’ 係含有申請專利範圍第1項之通式(I)所示之化合物或 分 成 效 有 為 作 鹽 性 毒 br 其 ------------裝— (請先閱讀背面之注意事項再填寫本頁) f 訂—------· 經濟部智慧財產局員工消費合作社印製 本紙張尺度適用中國國家標準(CNS)A4規格(210 X 297公釐) 77 314159
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WO2007056496A1 (en) * | 2005-11-07 | 2007-05-18 | Irm Llc | Oxazole and thiazole ppar modulator |
AR077428A1 (es) * | 2009-07-29 | 2011-08-24 | Sanofi Aventis | (aza) indolizinacarboxamidas ciclicas su preparacion y su uso como agentes farmaceuticos |
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RU2004117874A (ru) | 2006-01-10 |
MXPA04004442A (es) | 2004-08-12 |
NO20041878D0 (no) | 2004-05-07 |
PL370405A1 (en) | 2005-05-30 |
NZ532812A (en) | 2005-02-25 |
RU2296760C2 (ru) | 2007-04-10 |
ZA200403594B (en) | 2004-12-02 |
US7323456B2 (en) | 2008-01-29 |
JPWO2003042194A1 (ja) | 2005-03-10 |
US20040254370A1 (en) | 2004-12-16 |
HUP0402072A3 (en) | 2008-08-28 |
KR20050044853A (ko) | 2005-05-13 |
NO20041878L (no) | 2004-08-12 |
IL161768A0 (en) | 2005-11-20 |
WO2003042194A1 (fr) | 2003-05-22 |
EP1445256A1 (en) | 2004-08-11 |
CA2465861A1 (en) | 2003-05-22 |
HUP0402072A2 (hu) | 2005-02-28 |
EP1445256A4 (en) | 2006-01-04 |
CN1608056A (zh) | 2005-04-20 |
AU2002363776B2 (en) | 2008-04-17 |
BR0214049A (pt) | 2004-10-13 |
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