TWI231298B - Glucopyranosyloxypyrazole derivatives and use thereof in medicines - Google Patents
Glucopyranosyloxypyrazole derivatives and use thereof in medicines Download PDFInfo
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- TWI231298B TWI231298B TW090132750A TW90132750A TWI231298B TW I231298 B TWI231298 B TW I231298B TW 090132750 A TW090132750 A TW 090132750A TW 90132750 A TW90132750 A TW 90132750A TW I231298 B TWI231298 B TW I231298B
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- methyl
- fluorenyl
- inhibitors
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- isopropyl
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- DRTQHJPVMGBUCF-UHFFFAOYSA-N uracil arabinoside Natural products OC1C(O)C(CO)OC1N1C(=O)NC(=O)C=C1 DRTQHJPVMGBUCF-UHFFFAOYSA-N 0.000 description 1
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Classifications
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- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
- C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- C—CHEMISTRY; METALLURGY
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
- C07H17/02—Heterocyclic radicals containing only nitrogen as ring hetero atoms
Description
1231298
本發明為關於可用於做為醫 唑衍生物或其藥理容許鹽、_米扣之咄喃型葡萄糖氧基吡 若更詳古之,目,丨 + i^e及其醫藥上用途。 吁。之,則本發明為關於 病、糖尿病性合併症、肥胖症尊J用於做為起因於糖尿 治療藥等之具有人類SGLT2活性抑血糖症疾病的預防或 庄抑制作用之一般式
(式中之RQ為氫原子或低烷基 Q0及P任一者為
丫 w ΗΟ^'γ^^ΟΗ
OH 所示之基,另一者為低烷基或齒低烷基, 烷基、低烷氧基、低烷硫基、低烷硫基、”、、氧原子、低 子)所示之吡喃型葡萄糖氧基吡唑 & 、、低烷基或i原 一般式 T生物做為活性本體之
⑴
C:\2D-CODE\91-03\90132750.ptd
1231298 五、發明說明(2) [式中之R為氫原子 一者為一般式
、低烷基或構成前體藥物之基,Q及丁任
0H (式中之P為氫原子或構成 者為低烧基或函低烧基, 基、低院硫基、函低烧基 垸基時,P不為氫原子]所 物或其藥理容許鹽、及其 糖尿病為以飲食生活變 習慣病。因此,對於糖尿 但於控制和持續實施困難 雙胍藥、石黃脲類藥和姨島 藥。但是,於雙胍藥中察 類藥中察見低血糖之副作 見浮腫荨副作用,加上擔 出解決此類問題之根據新 近年’於腎臟中阻礙過 泄並令血糖值降低新類型 (J. Clin. Invest., Vol 又’已報導在腎臟之近尿 前體藥物之基)所示之基,另一 R2為氫原子、假、p7 低烷基、低烷氧 或鹵原子’但’ R為氫原子或低 示之吡喃型葡萄糖氧基咄唑衍生 醫藥上用途。 化和運動不足為背景的一種生活 病患者實施食療法和運動療法, 時,併用藥物療法。現在,使用 素感爻性增強劑等做為抗糖尿病 見乳酸酸毒性之副作用,於磺脲 用,於胰島素感受性增強藥中察 心促進肥胖化。因此,期望開發 作用機制的抗糖尿病藥。 剩糖之再吸收下,促進尿糖之排 抗糖尿病藥的研究開發已被推展 .79, ρρ· 1510-1515(1987))。 細管的S1區域中存在SGLT2(鈉依
C:\2D-OODE\91-03\90i32750.ptd 第7頁 1231298 五、發明說明(3) 賴性葡萄糖輪送體2),且此SGLT2 糖的再吸收(J P】. 、 多與絲球體過濾 (1 994 ))〇 0 ,b _1ηώ InVeSt- V〇L 93> ΡΡ· 39 7-404 剩的再吸收並Λ:礙人類SGLT2則可抑制腎臟中之過 化。因此,期望2尿之過剩糖***,使得血糖值正常 根據新的作用機制力的人類和2活性抑制作用,且 體内的蓄積It中將過剩的血糖***,故可減少糖於 果。更且,亦可用於起因於高也糖症,且文 胖症發展而發病之各種關連疾病。 糖尿病和肥 具有吡唑骨架之化合物WAY_ 1 237 83,雖已都 中令尿糖***量增加 。載於正#鼠 發明之搞3 ** V〇1· 395 ΡΡ· 3 92〇-3928 ( 1 9 96 )) 0 本發明者等人為了發現具有人類SGLT2活性 化合物而致力檢討,結果得知前述一般式(1)所八之' :勿J 下述,於生體内變換成活性本體之前述—不„ :匕&物所不之咄喃型葡萄糖氧基咄 ‘:(I) 良的人類SGLT2抑制活性,且達成本發明。立且㉝不出優 本發明為提供經由於生體内發揮人類SGLT2活性抑法丨# 用,抑制糖於腎臟中的再吸收並令過剩的糖***至;制作 則可表現優良的降血糖作用之下述 , 衍生物及其藥理容許鹽及其醫藥上用途。葡甸搪乳基。比唾 即,本發明為關於一般式
C:\2D-CODE\91-03\90l32750.ptd 第8頁 禮1
1231298 五、發明說明(4)
(式中之p 者為低烷 基、低烧 烧基時, 物及其藥 又,本 萄糖氧基 組成物、 的預防或 本發明 型葡萄糖 高血糖症 本發明 吼°坐衍生 為氫原子或構成前體藥物之基)所示之基 μ 基或齒低烷基,R2為氫原子、低烷基、低烷氧 硫基、鹵低烷基或鹵原子,但,R為氫原子或低 ρ不為氫原子]所示之吡喃型葡萄糖氧基毗唑衍生 理容許鹽。 發明為關於含有前述一般式(丨)所示之咄喃型葡 =唾竹生物或其藥理容許鹽做為有效成分之醫藥 =類SGLT2活性抑制藥及起因於高血糖症之疾病 治療藥。 為關於投與有效量之前述一般式(I)所示之吼畴 乳基t坐衍生物或其藥學容許鹽所構成之起因於 之疾病的預防或治療方法。 為關於f述一般式(I)所示之吼喃葡萄糖氧基 物或其樂理容許鹽之使用,係使用於製造起因於
C:\2D-OODE\91-03\90132750.ptd $ 9頁 1231298
南血糖症疾病之預 f且, 預防或治療用之醫藥組成物。 葡萄糖氧基吼唑:工:乂W述-般式(1 )所示之吼喃型 受性增強藥、糖二鹽胰 藥、胰島素f判、p 又肌▲ ^島素刀必促進 酶刺激素、:月糖素受體拮抗劑、胰島素受體激 蛋白路胺酸;mi = ?制藥、二肽基肽酶IV抑制藥、 氣酶、4 市果糖二磷酸酶抑制藥、丙_酸脫 匕,:糖原合成峰激㈣抑制 备劑、醛Γ 劑、糖精、糖精類似物、糖精興 Π 2 原酶抑制藥、終端糖化產物生成抑制藥、蛋 ΫΙ / .(卩制藥、了 —胺基丁酸受體拮抗劑、鈉管i护& ::;::NF-…咖、脂過氧化酶抑制二二 4匕α連接酸—二肽酶抑制藥、類胰島素成長因子—1、 ::板成長因子、來自血小板成長因子類似⑯、上皮增 、神經成長因子、肉鹼衍生物、尿嘧啶核苷、5一羥 19甲8 基乙内醯脲、EGB —761、Bim〇clomo1、Sulodexide
1 U、羥甲基戊二醯輔酶A還原酶抑制藥、F 腎上腺素受體興奮劑、酿基輔*膽固醇: 1轉私酶抑制劑、丙丁酚、甲狀腺激素受體興奮劑、膽固 酵,收抑制藥、脂酶抑制藥、微粒體甘油三酯轉移蛋^抑 制藥、脂氧合酶抑制藥、肉鹼棕櫊醯轉移酶抑制藥、角鯊 烯合成酶抑制藥、低比重脂蛋白受體增強藥、菸鹼酸衍生、
1231298 五、發明說明(6) :逆:藥、納共輕膽酸轉移蛋白抑制寧、,固了 藥抑:ΐ抑:藥,管緊張素變換 胺醆變換酶抑制藥、内;體拮抗藥、内絲 ;藥、血r廣強性降厂$==:荜利拮 老、《2-腎上腺素受體興奮 二梁巾柩性降壓 制藥、尿酸***促進攀 =小板樂、尿酸生成抑 種之藥劑予以組合:::=化藥所組成群令選出至少- 前述-般式⑴所示之°比 素感受性增強藥、糖吸收永=^樂學容許鹽、及(β)胰島 進藥、胰島素製劑、姨高:糖口:藥、胰島素分泌促 激酶刺激素、三肽基肽…:劑、姨島素受體 藥、蛋白酪胺酸磷酸酶_1β梁、—肽基肽酶ιν抑制 藥、葡萄糖-6-磷脂酶抑制带:糖糖:、磷酸化酶抑制 綱酸脫氫•、肝糖新生抑制藥二糖肌-,酸酶抑制藥、、丙 〜3抑制藥、類胰高血糖幸= 1、糖原合成酶激酶 似物、類姨高血糖素:==類=血糖 糖精興奮劑、醛糖還原酶抑 知糖釦類似物、 藥、蛋白激酶C抑制藥 美;:端糖化產物生成抑制 拮抗劑、轉錄因子NF_ Μ抑:;丁 ?體拮抗劑、鈉管道 乙醯化-α -連接酸-:肽崎抑岳;V月曰過氧化酶抑制藥、Ν - 、來自血小板成長因子、來血、類胰島素成長因子-Ι 皮增殖因+、神經成長因+反成長因子類似物、上 因子肉鹼衍生物、尿嘧啶核苷、 第11頁 C:\2D-C0DE\91-03\90132750.ptd 1231298 五、發明說明(7) 5 -美里基—1、田 ^ T暴乙内醯脲、—
Sul〇dexide、Y_m、 Η、Bi_lomol、
Fibrate系化人物、 跃土戊一 輔酶A還原酶抑制藥、
:膽固醇酿基;移酶抑3制;广=體興奮劑、醯基輔酶A 奮劑、膽固醇吸收抑制藥、,二匕、甲狀腺激素受體興 轉移蛋白抑制茲、 ’、月曰酶抑制藥、微粒體甘油三酯 制藥、角當说I λ、I f合_抑制藥、肉鹼棕櫚醯轉移酶抑 於驗酸衍生物、膽酸=、f比重脂蛋白受體增強藥、 藥、膽固醇酽鏟、Γ恭 ”鈉共軛膽酸轉移蛋白抑制 變換酶抑制‘、ί抑制1、食慾抑制藥、血管緊張素 抗藥、内今[1中’内肤峰抑制藥、血管緊張素II受體拮 尿藥、變t峰抑制•、内絲胺酸受體括抗劑、利 中樞性降壓藥α ;上擴生降=交換神經遮斷藥、 尿酸生成永2 -月上腺素受體興奮劑、抗血小板藥、 選出至p |藥、尿酸***促進藥及尿鹼化藥所組成群中 防或治i;;?藥劑所構成之起因於高血糖症之疾病的預 基t : i:: t⑴前述:般式(1)所示之°比喃型葡萄糖氧 Μ 勿或其藥學容許鹽、及(Β)胰島素感受性增強 收抑制藥、雙脈藥、騰島素分泌促進藥、騰島素 :剤且胰南血糖素受體拮抗劑、胰島素受體激酶刺激素、 :=土狀崎1 1抑制藥、二肽基肽酶I V抑制藥、蛋白酪胺酸 6 S义酶j Β抑制藥、糖原磷酸化酶抑制藥、葡萄糖_6 —磷脂 -每卩制某 果糖二構酸酶抑制藥、丙酿I酸脫酸酶、肝糖新 生抑制藥、D-肌醇、糖原合成酶激酶_3抑制藥、類胰高血
C:\2D-C0DE\91-03\90132750.ptd
1231298
1231298
於本發 本體之前 物之化合 可列舉例 基、低烧 通常使用 如低醯基 之前體藥 前述 所明則體藥物為指於生體内,變換成活性 =一般式(11)所示之吡喃型葡萄糖氧基吡唑衍生 。構成岫體藥物之基,於此基為位於羥基時, f低醯基、低烷氧基低醯基、低烷氧羰基低醯 氧羰基、低烷氧基低烷氧羰基等之前體藥物中所 的羥基保護基,此基為位於氮原子時,可列舉例 、低烷氧羰基、低醯氧甲基、低烷氧羰氧曱基等 物中所通常使用之胺基保護基。 列舉例如~般式 身又式(I )所示之p比喃型葡萄糖氧基Π比ϋ坐衍生物可
[式中之R為氯原子、低烧基、低酿基、低烧氧魏基、低 醯氧曱基或低烷氧羰氧甲基,Q1及Τ1任一者為一般式
0Η (式中之Ρ1為氫原子、低醯基、低烧氧基低醯基、低烧氧 幾基低醯基、低烧氧幾基或低烧乳基低燒氧魏基)所示之 基,另一者為低烷基或鹵低烷基,R2為氫原子、低烷基、 低烷氧基、低烷硫基、鹵低烷基或鹵原子,但,R1為氫原
C:\2D-raDE\91-03\90132750.ptd 第 14 頁 1231298 五、發明說明(10) 子或低烧基時,pi不為氫原子]所示之化合物。 於本發明中,所謂的低烷基為指甲基_乙基、丙基、異 丙基、丁基、異丁基、第二丁基、第三丁基、戊基、異戊 基、新戊基、第三戊基、己基等之碳數丨〜6個之直鏈狀或 分支鏈狀,基,所謂低烷氧基為指甲氧基、乙氧基、丙氧 ,、異丙,基、丁氧基、異丁氧基、第二丁氧基、第三丁 氧基、戊氧基 '己氧基等之碳數丨〜6個之直鏈狀或分支鏈 狀烷氧基。所謂低烷硫基為指甲硫基、乙硫基、丙硫基、 異丙硫基、丁硫基、異丁硫基、第二丁硫基、第三丁硫 基、戊硫基、異戊硫基、新戊硫基、第三戊硫基、己硫基 等之碳數1〜6個之直鏈狀或分支鏈狀烷硫基。所謂_原子 為指氟原子、氯原子、溴原子或碘原+。所謂鹵低烷基為 指經異種或同種之i〜3個上述鹵原子所取代之上述低烷 基。所謂低醯基為指乙醯基、丙醯基、丁醯基、異丁醯 基、特戊醯基、己醯基、環己羰基等之碳數2〜7個之直鏈 狀、分,鏈狀或環狀醯基,所謂低烷氧基低醯基為指經上 述低烷氧基所取代之上述醯基。所謂低烷氧羰基為指甲氧 羰基、乙氧羰基、異丙氧羰基、異丁氧羰基、環己氧羰基 等之碳數2〜7個之直鏈狀、分支鏈狀或環狀烷氧羰基,所 謂低烷氧羰基低醯基為指3-(乙氧羰基)丙醯基等之經上述 低烷氧羰基所取代之上述低醯基,所謂低烷氧基低烷氧妒 基為指2-曱氧乙氧羰基等之經上述低烷氧基所取代之上^ 低烷氧羰基。又,所謂低醯氧曱基為指經上述低醯基所 取代之羥甲基,所謂烷氧羰氧甲基為指經上述低烷氧羰基
C:\2D-0QDE\91-03\90132750.ptd 第15頁 1231298 五、發明說明(11) ----- 所0-取代之羥曱基。 於取代基R中,較佳為气π ^ 1 分支鏈狀烷基,更佳為' / /奴數1〜3個之直鏈狀或 人類肝S9餾分之代謝安定性乙^、丙基或異丙基,由 基R2中,較佳為碳數最佳為異丙基。於取代 數卜3個之直鏈狀或分支=鏈=分支鏈狀烧基、碳 .ν ± s叉鏈狀烷虱基或碳數1〜3個直鏈狀 或分支鏈狀烷硫基,更佳為乙基、乙氧基、異丙氧基、甲 氧基或曱硫基。於取代基Q及T中,Q為低烷基或齒低烷基 為佳。其中亦以低烷基為佳,且以碳數!〜3個之直鏈狀或 分支鏈狀烧基為更佳,以甲基為最&。於取代基 ,為低醯基或低烧氧,’更佳為低燒氧艘 數2〜5個之直鏈狀或分支鍵狀燒氧羰基,呈 :火 羰基、乙氧羰基、異丙氧羰基或異丁氧μ 〇 甲乳 J羊1极基為佳。 本發明之化合物以4-[(4-異丙氧笨基 -3-(6-0-甲氧羰基-/3-D-吡喃葡萄糖氧 土 直、丙土 乳基)- 5-曱基口比口坐、 3-(6-0-乙氧羰基_ /S-D-吡喃葡萄糖氧基)_4_[(4_異丙 苯基)曱基]-1-異丙基-5_曱基ϋ比嗤、 ㈣—吼喃葡萄糖氧基)-4_[ (4〜異内氧基苯基”丙基 =基里 1 ί W fr U ^ ^ ~D-〇fcb ^ ^ 、4-[ (4-乙基苯基)甲基卜卜異丙基〜4二基甲5:甲基:。坐 -D-吡喃葡萄糠氧基)-5-曱基η比唑、3、( 氧板土-万 -D-咄喃葡萄糖氧基)-4- [ (4-乙基笨基)甲基]一^ -5-甲基…4-[ (4-乙基苯基)甲基]、3:"_異丙“
C:\2D-C0DE\91-03\90132750.ptd
1231298 五、發明說明(12) 基-/3-D -咄喃葡萄糖氧基)-1_異丙基-5-甲基咄唑、 4 - [(4-乙基苯基)甲基]-3-(6 - 0-異丁氧羰基-石- D-吼喃葡 萄糖氧基)-1-異丙基-5-曱基吼唑、4- [(4_乙氧基苯基)曱 基]-1-異丙基-3-(6 - 0-甲氧魏基-- D-吼喃葡萄糖氧 基)-5-甲基吼17坐、3 -(6-0-乙氧幾基- - D- p比喃葡萄糖氧 基)-4-[(4-乙氧苯基)曱基]- 1-異丙基-5-曱基吼唑、 4-[(4-乙氧基苯基)甲基]-3-(6-0-異丙氧羰基- D-吼喃 葡萄糖氧基)-:!-異丙基-5-甲基吼唑、4-[(4-乙氧基苯基) 甲基]-3-(6-0-異丁氧羰基-沒-D-咄喃葡萄糖氧基)-卜異 丙基-5-曱基口比11坐、1-異丙基-3-(6-0-曱氧幾基- /3 - D-口比 喃葡萄糖氧基)-4-[( 4-曱氧基苯基)曱基]-5-曱基吼唑、 3-(6-0-乙氧美炭基一 /5 - 比喃葡萄糖氧基)-1一異丙基 一4 - [(4-曱氧基苯基)甲基]- 5-曱基咄唑、3-(6-0-異丙氧 罗炭基-/3 - D - σ比喃葡萄糖氧基)- 1-異丙基-4-[(4_曱氧基苯 基)曱基]-5-曱基吼唑、3-(6-0-異丁氧羰基-/5-D-咄喃葡 萄糖氧基)-1-異丙基-4-[(4-曱氧基苯基)曱基]-5 -甲基吼 唑、1-異丙基-3-(6-0-曱氧羰基-/5-D-吼喃葡萄糖氧基) - 5-曱基-4-[(4-曱硫苯基)曱基]吼唑、3-(6-0_乙氧羰基-冷-D-咄喃葡萄糖氧基)-1一異丙基一5-曱基一4一 [ (4一曱硫苯 基)甲基]σ比哇、3-(6 - 0-異丙氧幾基-点-D- 17比σ南葡萄糖氧 基)-1-異丙基-5-曱基-4-[( 4-曱硫苯基)曱基]咄唑、 3-(6-0-異丁氧羰基-D-咄喃葡萄糖氧基)-卜異丙基-5-曱基-4-[(4-曱硫苯基)曱基]吼唑等為佳,且以4- [(4-異 丙氧苯基)甲基]-卜異丙基_3_( 6-0-甲氧羰基-/5 -D-咄喃
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C:\2D-CODE\91-03\90132750.ptd 第18頁 1231298 五、發明說明(14) 步驟4 步驟1 (R0爲Μ歲子時)
(Ih) ,Ν Ν R14 [式中之PG為低醯基、低烷氧基低醯基、低烷氧羰基低醯 基、低烷氧羰基、低烷氧基低烷氧羰基、辛氧羰基等之羥
第19頁 C:\2D-CODE\91-03\90132750.ptd 1231298 五、發明說明(15) 基保護基,P3為低醯基或低烷氧羰基,p4為低醯基,p5為 低烧氧羰基,RW為低醯基或低烷氧羰基,為低醯氧甲基 或低烧氧羰氧曱基,R15為低烷基,低醯基、低烷氧基低醯 基、低燒氧羰基低醯基、低烷氧羰基、低烷氧基低烷氧羰 基、爷氧羰基等之胺基保護基,Q6及T6任一者為一般式
0H 另一者為低烧基或鹵 (式中之PG為與前述同義)所示之基 低烷基,Q7及了7任一者為一般式 0、>0
所示之基,另一者為低烷基或鹵 、氣原子等之離去基,RG、R2、Q0 (式中之P3為與前述同義) 低烧基,X1及X2為溴原子 及TQ為與前述同義] 步驟1 1)將前述一般式(it、 物之氮原子,使用前、+所示之咄喃型葡萄糖氧基咄唑衍生 醋酸等之脂肪酸中,、δ〔 一般式(1 1 1 )所示之脂肪酸酐,於 30分鐘〜1日進行俾、常以〇 °C〜迴流溫度下,通常反應 喃型葡萄糖氧基吡唑’或2)將^前述一般式(11)所示之吡 /T生物之氮原子,使用前述一般式
1231298 五、發明說明(16) (V) 所示之琥珀醯亞胺衍生物,於四氫呋喃等之惰性溶劑 中,通常以室溫〜迴流溫度下,通常反應1小時〜1日進行 保護,則可製造前述一般式(I b )所示之前體藥物。尚,此 些反應時間可根據所使用之原料物質和溶劑,反應溫度等 而適當加減。 斤對前述一般式(I I)示之吼喃型葡萄糖氧基咄唑衍生物之 氮原子,使用曱醛,於各種溶劑中,導入羥甲基則可製造 &述一般式(V )所示之化合物。反應所用之溶劑可列舉例 如水、曱酵、乙醇、四氫吱喃、二氯甲烷、醋酸乙酯、N, N-二曱基曱醯胺、乙腈、其混合溶劑等。反應溫度通常為 〇 °c〜迴流溫度,反應時間雖根據所使用之原料物質和溶 劑、反應溫度等而異,但通常為3 〇分〜工曰。 步驟3 將前述一般 式(VI) °比σ定、 口定、二 所示之 三乙胺 甲基ϋ比 二吖雙環[2. 2 述一般式(I c ) 式(V )所示化合物之羥曱基,使用前述一般 保護化試驗,於惰性溶劑中或無溶劑下,於 、Ν,Ν-二異丙基乙胺、甲基吡啶、二曱基吡 。疋、奎寧環、1,2, 2, 6, 6 -五曱基哌啶、1,4-• 2 ]_辛烷等鹼存在下進行保護,則可製造前 所不之别體藥物、反應所用之惰性溶劑可列 烷、乙腈、醋酸乙酯、二異丙酯、氣仿、四 =曱氧基乙烷、1,4—二g烷、丙酮、第三丁 令劑等。反應溫度通常為_4〇 〇C〜迴流溫 為根據原料物質和溶劑、反應溫度等而異, 舉例如 氮1:7夫ϋ南 醇、或 度,反 二氯甲 、1,2〜 其混合 應時間
第21頁 1231298 五、發明說明(17) 隹通常為3 0分鐘〜2日 將前述一般式(11)辦一 <經甲基、或氮原子及南:氧基°比°坐衍生物 如、n,n-二異丙基乙胺、甲基…二;乙 :咬、奎寧環、五甲基呢咬、u”丫“甲基 2. 2)一辛烧义寻鹼存&下進行保言蔓,料製造前述一般式 d)所不之前體藥物或其類似物。反應所用之惰性溶劑可 |J舉例如二氯曱烷、乙腈、醋酸乙酯、二異丙醚、氯仿、 啤氣咬喃、1,2 -二甲氧基乙院、ι,4-二烧、丙酮、第三 丁醇、或其混合溶劑等。反應溫度通常為-40 t〜迴流溫 度’反應時間為根據所使用之原料物質和溶劑、反應溫度 等而異,但通常為30分鐘〜2日。 將前述一般式(Id)所示之化合物,於曱醇_乙醇等之醇 性溶劑中,碳酸氫鈉、碳酸鈉、碳酸鉀等之弱鹼存在下進 行脫醯化,則可製造前述一般式(I e)所示之前體藥物或其 類似物。反應溫度通常為0 °C〜迴流溫度,反應時間為根 據所使用之原料物質和溶劑、反應溫度等而異,但通常為 1 5分鐘〜1日。 t驟g 將前述一般式(I e)所示化合物之氮原子,(1)使用前述 一般式(I 11 )所示之脂肪酸酐,於醋酸等之脂肪酸中,通
C:\2D-0ODE\91-03\90132750.ptd 第22頁 1231298 五、發明說明(18) 常以0 °C〜迴流溫声,1 r 9、说m , 又 通常反應3 0分鐘〜1日進行保護, (2 )使用前述一般式π ^ , ^ Λ u ν)所示之琥珀醯亞胺衍生物,於四 虱呋喃等之惰性溶劑Φ 也 ^ _, ▼ 士 合剐中,通常以室溫〜迴流溫度,通常及 應1小時〜1日進彳千仅1 ψ久 少仅崎7二進仃保蠖,或(3)使用前述一般式(VI)所示 之保6隻化試樂,於-务 U 卜 、一虱甲烷、乙腈、醋酸乙酯、二異丙 醚、氯仿、四氫呋咗、,η 7 石航 ^ 南Μ,2-二甲氧基乙烷、1,4-二嚿烷、 丙綱、第三丁醇、-k -y. 我,、混合溶劑之惰性溶劑中或無溶劑 下,吼口定、三乙脸、M M 4 ^ L ^ 一 耻 N,二異丙基乙胺、曱基吡啶、二甲
基σ比口疋、三曱基吼咬 X田:Β: W — 1 A 雔 「 1,Z,2,6,6 -五甲基旅口疋、1,4 -二吖 衣、·· 2]辛烧等之鹼存在下,通常以-4〇 i〜迴流溫 ς ’,常反應30分鐘〜2曰進行保冑,則可製造前述一般 I 所不之前體藥物或其類似物。尚,此些反應時間可 二取7所使用之原料物質和溶劑、反應溫度等適當加減。 步驟7 々级!!述一般式(1 e)所示化合物之氮原子,使用甲醛,於 :削中’導入經甲基則可製造前述一般式(V 11 I )所示 之^ a物。反應所用之溶劑可列舉例如水、曱醇、乙醇、 1氮夫,、二氣曱烷、醋酸乙酯、N,N-二曱基甲醯胺、乙 ^ ^其混合溶劑等。反應溫度通常為0 °C〜迴流溫度,反 ,時間雖根據所使用之原料物質和溶劑、反應溫度等而 異’但通常為3 0分鐘〜1曰。 步驟8 &將别述一般式(v 1 Π )所示化合物之羥曱基,使用前述一 般式(VI)所示之保護化試藥,於惰性溶劑中或無溶劑下,
1231298 五、發明說明(19) 咄啶、三乙胺、N,N-二異丙基乙胺、曱基σ比啶、二甲基"比 啶、三甲基吡啶、1, 2,2,6,6 -五甲基哌啶、1,4 -二吖雙環 [2 · 2 · 2 ]辛烧等驗存在下進行保護,則可製造前述一般式 (I g)所示之前體藥物或其類似物。反應所用之惰性溶劑可 列舉例如二氯甲烧、乙腈、醋酸乙酯、二異丙醚、氣仿、 四氫呋喃、1,2 -二曱氧基乙烷、1,4 -二4烷、丙酮、第三 丁醇、或其混合溶劑等。反應溫度通常為-4 0、°C〜迴流溫 度,反應時間為根據所使用之原料物質和溶劑、反應溫度 等而異,但通常為30分鐘〜2日。 步驟9 將前述一般式(I g)所示之化合物,於惰性溶劑中,絶/ 碳等之I巴觸媒存在下予以接觸還原,並且經由脫保幾化 可製造觔述一般式(I h )所示之前體藥物。反應所用 < 情、】 溶劑可列舉例如甲醇、乙醇、四氫呋喃、醋酸乙酯、^故 混合溶劑等。反應溫度通常為〇 t〜迴流溫度,反應日寺其 雖根據所使用之原料物質和溶劑、反應溫度等而異,和' 常為3 0分鐘〜1曰。 、通 於前述製造方法中使用做為起始物質的前述一般式(j 所示之化合物,例如可依據下列方法製造。
C:\2D-CODE\91-03\90132750.ptd 第24頁 1231298
(式中之X3及Y為鹵原子、曱石黃醯氧基、曱苯石黃酿氧義々 離去基,R3為低烷基或鹵低烷基’ R4為甲基或乙義广5等之 低烷基,Q8及T8任一者為2, 3, 4, 6_四_〇_乙醯基_ $_DR5為口 葡萄糖氧基,另一者為低烷基或齒低烷基,πη比南 為與前述同義) K 、QQ&T〇
步驟A 將前述一般式(IX)所示之苄基化合物與前述一般 所示之酮基醋酸酯,於惰性溶劑中,氫化鈉、第^ %) 等鹼之存在下縮合,則可製造前述一般式(χι)所示之== 物。反應所用之惰性溶劑可列舉例如丨,2—二甲氧美乙产σ 四氫呋喃、Ν,Ν-二甲基曱醯胺、其混合溶劑等。译 通常為室溫〜迴流溫度,反應時間雖根據 ^ = 質和溶劑、反應溫度等而異,但通常為“、時二原料物 步驟Β 二刖f二般式(XI)所示之化合物與肼或其一水合物於 性f劑中縮合,則可製造前述一般式(XI I)所示之咄唑啉 酮衍生物。反應所用之惰性溶劑可列舉例如甲笨、四氫咬 :、m其混合溶劑等。反應溫度通常為室溫〜迴流溫 度,反應時間雖根據所使用之原料 k坐琳_衍生物依常法變換成其鹽後,於步
C:\2D-G0DE\91-03\90132750.ptd 第25頁 1231298 五、發明說明(21) 驟C中使用亦可。
步驟C (1) 前述一般式(XII)所示之咣唾 基時,令相對之前述一般式(x丨丨)網何生物中R3為低烷 使用乙醯溴基-a -D-葡萄糖,於不々之咄唑啉酮衍生物 存在下配糖化,視需要使用前述二般m’碳酸銀等鹼 劑,於惰性溶劑中,碳酸鉀等之驗 )所示烧基化 則可製造相對之前述一般式(χΙν) /進仃N〜烷基化, 反應所用之溶劑可列舉例如四氫咬喊、 a物。配糖化 溫〜迴流溫度,反應時間雖根據所用J K U常為室 劑、反應溫度等而[但通常為〗小使時^ 應所使用之溶劑可列舉例如乙腈、N,N—二 況,化反 氫呋喃、纟混合溶劑等,反應溫度通常;甲醯胺、四 久% $马室溫〜迴潘、、田 度,反應時間雖根據所使用之原料物質 等而異,但通常為!小時〜… “ ♦劑、反應溫度 (2) 前述一般式(XII)所示之咄唑啉輞衍生物中R3為函 烷基時,令相對之前述一般式(XII)所示之咄唑啉酮衍生 物使用乙醯溴基-α-D-葡萄糖,於惰性溶劑中,碳酸銀等 驗存在下配糖化’視需要使用前述一般式(χιΙι)所示之烧 基化劑,於惰性溶劑中,碳酸鉀等之鹼存在下進行^烧^ 化’則可製造相對之前述一般式(XIV)所示之化合物。配& 糖化反應所用之溶劑可列舉例如乙腈、四氫呋味,反應溫 度通常為室溫〜迴流溫度,反應時間雖根據所使用之原料 物質和溶劑、反應溫度等而異,但通常為1小時〜1日。N —
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五、發明說明(22) 烷基化反應所使用之溶劑可列舉例如乙腈、NN〜一 酿胺、四氫咬鳴、其混合溶劑等,反應溫度通常:二 迴流溫度,反應時間雖根據所使用之原料物質和溶二咖= 應溫度等而異,但通常為1小時〜1曰。 尚,於起始原料之前述一般式(XII)所示之化合物中, 存在以下所示之三種互變異構物,且根據反應條件之不同 而令狀態變化。
(式中之R2及R3為與前述同義) =,所付之刖述一般式(χ丨v )所示之化合物依常法變換 成其鹽後,於步驟D中使用亦可。
步驟D
义5二ί斗·严式(X 1 V )所示之化合物予以鹼解,則可製3^ =二Γ二二U )所示之°比°南葡萄糖氧基吼u坐衍生物。反 :用列舉例如甲醇、乙醇、四氫咬喃、水、其 :n〇c’〜驗二列舉例如氫氧化納、乙醇納等。反應溫 ’至恤’反應時間雖根據所使用之原料物質矛
1231298
1231298 五、發明說明(24) 生物y依據常法,作成其藥理容許鹽。此類鹽可列舉與鹽 酸、氫溴酸、氫碘酸、硫酸、硝酸、磷酸等無機酸之^二 成鹽、與曱酸、醋酸、甲烷磺酸、苯磺酸、對—曱苯石气 酸、丙酸、檸檬酸、琥珀酸、酒石酸、反丁烯二酸、兴 酸、草酸、丙二酸、順丁烯二酸、乳酸、蘋果^ ^碳=、 麩胺酸、天冬胺酸、己二酸、油酸、硬脂酸等有機^之酸 加成鹽、鈉鹽、鉀鹽、鈣、鎂鹽等無機鹼之鹽。 本發明之前述一般式(I )所示之前體藥物亦含有與水和 乙醇等之醫藥品容許溶劑的溶劑化物。 〜7 σ 气in ί前述一般式⑴所示之化合物中’除去… 萄糖乳基4为具有不對稱碳之化合物,存在κ構型之化合 物與S構型之化合物之二種光學異構物,而本發明中任二 種光學異構物均可使用,且即使為此歧光 物亦無妨。 一尤予異構物之混合 ,衍生物,發揮優良的制二㈣另氧 二方面,WAY-1 23783為人類SGLT2活性抑制 】3 : 法期望做為人類SGLT2活性抑制藥 ,:無 吸收性被改善,含有該前體= 斤示之前體藥物為經。 物做為經口投與製劑亦具有高::有效成分之醫藥組成 體藥物極有用於做為起因於 # 。因此,本發明之前 如,網膜症、神經損害、跃K病、糖尿病性併發症(例 月;正、潰瘍、大血管症)、肥胖 第29頁 C:\2D-CQDE\91-03\90132750.ptd !231298
五、發明說明(25) 胰島素血症、糖代謝異常、高脂血症、古 ^ 二、尚三酸甘油酯血症、脂質代謝異 ::固醇血 高血壓、繫血症、心衰竭、浮腫、高:C硬化 寻两血糖症之疾病的預防或治療藥。 4血症、痛風 少:種=合物亦可與SGLT2活性抑制藥以外之至 裡糸^適當組合使用。可與本發明化人 王 ;列舉例如胰島素感受性增強藥、糖吸收;合之藥劑 :、胰島素分泌促進藥、胰島素製劑::樂、雙胍 抗劑、月夷島素受體激酶刺激素 素受體拮 ί;肽酶1V抑制藥、蛋白赂胺酸她;二、二 •抑制藥、丙嗣酸脫氫酶、肝糖新生:糖二構酸 糖素胜肽1-類似物、:胰;:: = t胜肽〜1、類胰高血 產物生成抑制藥、蛋白激酶c抑:率原酶= 抗劑、納管道括抗劑、轉錄因子^基丁酸受體拮 酶抑制藥、N_乙醯化_α_連 2制樂、脂過氧化 素成長因子]、來自血小板成2 -肽酶抑制藥、類胰島 子(PDGF)類似物(例如,m = f自血小板成長因 -甲基乙内:二
Sulodexide 、 Y-128 、辩甲其氺- imoclomol
Fibrate系化合物、醯輔酶㈣原酶抑制藥、 腎上腺素受體興奮劑、醯基輔酶 « 第30頁 C:\2D-O0DE\9J-03\90J32750.ptd 1231298 -—--- 五、發明說明(2g彡 A:膽固醇酿基轉移酶 奮劑、膽固醇吸收抑 J、丙丁酚、曱狀腺激素受體興 轉移蛋白抑制藥、於」f、脂酶抑制藥、微粒體甘油三酯 制藥、角震烯合成酶曰抑制藥、肉鹼棕櫚醯轉移酶抑 菸鹼酸衍生物、膽酸=f、低比重脂蛋白受體增強藥、 藥、膽固醇醋轉送蛋白如=納共輕膽酸轉移蛋白抑制 變換酶抑制率、中性制樂、食慾抑制藥、血管緊張素 抗藥、内絲胺酸變換醇抑::制::血管緊張素II受體拮 尿藥、两拮抗藥、也管擴強:降:、利 中柩性降壓筚、α —腎h i /&梁父換神經遮斷藥、 尿酸生成抑制藥、us:足r/及: 將本發明之化合物與上述化藥等。 時’、本發明包含單一製劑型式的同時投:以=:j:用 投與路徑間隔投與之任一種又投與別同或相異 與上述藥劑組合而成之醫藥為包含::::之化合物 的投與型態和個別製劑組合的投盥型能’l —製劑型式 明之化合物為經由與-種:戈以:丄上述藥劑適當组 合使用,則可取得上述疾病之預防或治 匕= 的有利效果。又’同樣地’ tb單獨使用時上 量,或者可迴避或減輕併用之SGLT2活姓如⑹# ” 的副作用。 活丨生抑制樂以外藥劑 關於組合使用之藥劑的具體化合物和所處 為如下所例示’但本發明内容並非限定於此,I具:化合 C:\2D-C0DE\91-03\90132750.ptd 第31頁 1231298 五、發明說明(27) 物為包含其游離體、及其他之藥理容許鹽。 胰島素感受性增強藥可列舉了1·0^1 itasone、鹽酸 Piogl i tasone、順丁 烯二酸Roc i g 1 i t asone、Dalglitason 鈉、GI-262570、Isaglitazone、LG- 1 0 0 64 1、NC-2100、 T-174 、 DRF-2189 、CLX-0921 、CS-Oil 、GW-1929 、 Siglitasone、Englitasone 納、NIP-221 等之Peroxysome 增殖藥活化受體7興奮劑、GW-95 7 8、BM-1 70 744等之 Peroxysome增殖藥活化受體α興奮劑、GW-409544、KRP-297 、NN-622 、CLX-0940 、LR-90 、SB-219994 、DRF-4158 、DRF-MDX8等之Peroxysome增殖藥活化受體a / r興奮 劑、ALRT-268 、AGN-4204 、MX-6054 、AGN-194204 、 LG- 1 00754 'Bexarotene等之視黃酸類X受體興奮劑、及
Reglixan 、0N0-5816 、MBX-102 、CRE-1625 、FK-614 、 CLX-0901 、CRE_1633 、NN-2344 、BM-13125 、BM-501050 、 HQL-975 、CLX-0900 、MBX-668 、MBX-675 、S-15261 、 GW-544 、AZ-242 、LY一510929 、AR-H049020 、GW-501516 等 之其他胰島素感受性増強藥。胰島素感受性增強藥特別較 3用::尿病、糖尿病性併發症、肥胖症、高胰島素血 1:二r谢異常、高脂血症、高膽固醇血症、高三酸甘油 改善末梢中之“2:粥性動脈硬化症之處s,又經由 糖被攝人^ ^ t傳遞機構之異f,充進血中葡萄 腌$ + ^ / 糖值降低,故更佳用於糖尿病、高 胰島素血症、糖代謝異f之處卜 151 糖吸收抑制藥可列與 J 舉阿卡波糖(Acarbose)、Boglyb〇se
1231298 五、發明說明(28) 、Myglyt〇l 、CKD-711 、Emiglytate 、MDL〜25 、63
Camigly b〇Se、MDL-73、945 等之 α -葡萄輪 *、37、 ΑΖΜ-127等之α —澱粉酶抑制藥等。糖吸收.甘,抑制藥' 佳用於糖尿病、糖尿病性併發症、肥胖症、—*丨為特別較 症、糖代謝異常之處置,又阻礙食物中所丄,,島素血 於消化道中的酵素消化’延遲或阻礙葡萄:於二::J物 收’故更佳用於糖代謝異常之處置。 ' 雙胍類藥可列舉苯乙雙胍、鹽酸丁二胍、踏 Metoformin等。雙胍劑特別較佳用於糖 發症、高胰島素血症、糖代謝異常之處置’,抑2病性併 中之糖新生抑制作用和組織中之厭氣性解糖=::T 梢中之胰島!抗性改善作用等,令血糖值 末 於糖尿病、高胰島素血症、糖代謝異常之處置。 用 胰島素分泌促進劑可列舉甲苯磺丁脲、^庐二 Trasamide、醋磺環己脲、氯磺丙脲、格列本^丙脲、 Giycraside、卜丁基_3_間胺基苯續醯脲、; Glybornulide、Glypiside ^ ki s 丁脲 氣磺丁嗤、氨磺丁嚷二峻、“二:Glys_de、 績Μ脲、苯續丁脲、甲續:;二二 素分泌促進藥特別較佳用於VV病物糖⑽等。胰島 代謝異常之處置,又經由對胰臟/ &病性併發症、糖 增加則可使得血糖值降低 ::::二二胰島素分泌 常之處置。 又猛用於糖尿病、糖代謝異 C:\2D-C0DE\91-03\90132750.ptd 第33頁 1231298 五、發明說明(29) 騰南血糖素受體拮抗劑可列舉BAY-27-9955、NNC-92- 1 68 7等。胰島素受體激酶刺激藥可列舉丁⑽-丨74U、
L-783 28 1、KRx-613等,且三肽基肽酶II抑制藥可列舉UCL -1397等、二肽基肽酶iv抑制藥可列舉nvp-dPP728A、TSL- 2 2 5、P _ 3 2 / 9 8等,且蛋白酪胺酸磷酸酶—1 β抑制藥可列舉 PTP-112、0C-86839、PNU-1 77496 等,且糖原磷酸化酶抑 制藥可列舉關-420 1、CP-36 82 9 6等,果糖二磷酸酶抑制藥 可列舉R - 1 329 1 7等,丙酮酸脫氫酶抑制藥可列舉azD-7545 荨’肝糖新生抑制藥可列舉F R - 2 2 5 6 5 9等,類胰高血糖素 胜肽-1類似物可列舉£乂611(1111-4、(:了(:-1131等,類胰高血 糖素胜肽-1興奮劑可列舉AZM-134、LY-3 1 5902,糖精、糖 精類似物或糖精興奮劑可列舉醋酸1^1^1111111(:^丨(1等。此些 藥劑、葡萄糖-6 -磷脂酶抑制藥、D -肌醇、糖原合成酶激 酶-3抑制藥及類胰高血糖素胜肽―!特別較佳用於糖尿病、 糖尿病性併發症、高胰島素血症、糖代謝異常之處置,且 更佳用於糖尿病、糖代謝異常之處置。 酸糖還原酶抑制藥可列舉抗壞血酸全順十八碳9,丨2一 三烯酸、特力他(Tolrestat) '依帕司他(Epalrestat)、 ADN-138 、BAL-ARI8 、ZD-5522 、ADN-311 、GP-1447 、 IDD - 598、菲達司他(Phydarestat)、索比尼爾(Sorbinil) 、普那司他(Ponalrestat)、里沙司他(Risarestat)、全 那司他(Zenarestat)、半那司他(Minalrestat)、半他索 尼爾(丛〇1:11〇3〇1'1^1^1)、八1- 1567、衣米司他(1111卜631:31;) 、M-16209 、TAT 、AD-5467 、峻普司他(Zobolrestat)、
11·
第34頁 C:\2D-CODE\91-03\90132750.ptd 1231298 五、發明說明(30) AS-320 1、NZ-314、 (Lindolrestat)。醛糖遣 fTT一811、林多司他 併發症組織中所察見酶抑制藥為經由完進糖尿病性 徑,令過度蓄積之細= 血糖狀態的多元醇代謝路 低,故特別較佳用於糖& ρ =搪酵阻礙醛糖還原酶使其降 終端糖化產物生成併發症的處理。 ALT-946 ^ALT-711 ^^Ρ ^ΠΛ:Ι^'〇ΡΒ-9195' 成抑制藥為經由阻礙糖2 /magAtedl ne寺。終端糖化產物生 終端糖化產物的生態中持續性高血糖所充進之 尿病性併發症的細胞指害’故特別較佳用於糖 J白激酶c抑制藥可列舉LY—3335 31、Mid〇stauiine等。 制糖尿病狀態中持續性高血糖所察 酶C活性的…故特別較佳用於糖尿病性併 ΐβ胺ϋ酸/體枯抗劑可列舉托°比醋(T〇piramate)等 ,鈉通道拮抗劑可列舉鹽酸美西律(Mexiletine)、奥卡西 平(Oxcarbazepine)等,轉錄因子NF_ 抑制藥可列舉地 基普他(Dexhpotam)等,脂過氧化酶抑制藥可列舉甲磺酸 噻拉雜多等,N-乙醯化-α -連接酸二肽酶抑制藥可列舉 GPI-5693等,肉鹼衍生物可列舉肉鹼、鹽醆左旋肉鹼、氯 化左旋肉鹼、左旋肉鹼、ST-261等。此些藥劑、類胰島素 成長因子-I、來自血小板成長因子、來自血小板成長因子 類似物、上皮增殖因子、神經成長因子、尿苷、5_羥基 - 1- 曱基乙内醯脲、EGB - 761、Bimoci〇m〇i、Sul〇dexide 及
__ C:\2D-roDE\91-03\90132750.ptd 第35頁 1231298 五、發明說明(31) Y-128為特別較佳用於糖尿病性併發症之處置。 羥曱基戊二醯輔酶A還原酶抑制藥可列舉絲伐他丁 (Serivastatin)鈉、帕伐他丁(Pravastatin)鈉、洛伐他 丁(Lovastatin)、辛伐他丁(Synvastatin)、氟伐他丁 (Flurastatin)鈉、阿托伐他丁(At〇lvastatin)鈣水合 物、SC-45355 、SQ-33600 、CP-83101 、BB-476 、L-669262 、S-2468 、DMP-565 、U-20685 、 BAY-X-2678 、 BAY- 1 0 - 2 987、皮他伐他丁(Pitavastatin)鈣、洛斯伐他丁( Rosevastatin)、膽固醇酮(Colest〇1〇ne)、達伐他丁 (Dalvastatin)、Acytemate、美伐他丁(Mebavastatin)、 克里伐他丁(Crilvastatin)、BMS- 1 8043 1、BMY-2 1 95 0、 葛蓮伐他丁(Grenvastatin)、卡伐他丁(Calvastatin)、 BMY - 22089、貝伐他丁(Bervastatin)等。羥甲基戊二醯輔 酶A還原酶抑制藥特別較佳用於高脂血症、高膽固醇血 症、高三酸甘油酯血症、脂質代謝異常、粥性動脈硬化症 之處置,因為經由阻礙羥曱基戊二醯輔酶A還原酶令血中 膽固醇降低,故更佳用於高脂血症、高膽固醇血症、粥性 動脈硬化症之處置。
Fibrate系化合物可列舉苯札貝特(Bezafibrate)、苄氣 貝特(Beclobrate)、比尼貝特(Binifibrate)、西普洛貝 特(Ciprofibrate)、克利諾貝特(Crynofibrate)、氣貝特 (Cl of ibrate)、氣貝特鋁、袪脂酸、袪脂羥乙烟酯、非諾 貝特(Fenofibrate)、吉非貝齊(Gemfibrozil)、袪脂烟 酯、袪脂羥曱吡酯(P i r i f i b r a t e)、氣烟貝特
11 III ill II ϋ I C:\2D-〇〇DE\91-03\90132750.ptd 第36頁 1231298
(Ronifibrate)、西姆貝特(Cymfibrate)、經乙苯驗安妥 明(Theofibrate)、AHL-157 等。Fibrate 系化合物特別較 佳用於高胰島素血症、高脂血症、高膽固醇血症、高三酸 甘油S旨血症、脂質代謝異常、粥性動脈硬化症之處置,因 為經由亢進肝臟中脂蛋白脂酶之活化和脂肪酸氧化而令血 中三酸甘油酯降低,故更佳用於高脂血症、高三酸甘油酉旨 血症、粥性動脈硬化症之處置。 /?3-腎上腺素受體興奮劑可列舉81^-284 1 0、51?-58 6 1 1八 、ICI-198157 、ZD-2079 、BMS-194449 、BRL-37344 、CP- 33 1 6 79、CP-1 1 4271、L-750 3 5 5、BMS-1 8741 3、SR-5 90 62A 、BMS-210285 、LY-377604 、SWR-0342SA 、AZ-40140 、SB-226552 、D-7114 、BRL-35135 、FR-149175 、BRL-26830A 、 CL-316243 、AJ-9677 、GW-427353 、N-5984 、GW-2696 等。 -腎上腺素受體興奮劑特別較佳用於肥胖症、高胰島素 血症、高脂血症、高膽固醇血症、高三酸甘油酯血症、脂 質代谢異常之處置,因為經由刺激脂肪中之召厂腎上腺素 X體几進脂肪酸氧化而消耗能量,故更佳用於肥胖症、高 胰島素血症之處置。 酿基輔酶A :膽固醇醯基轉移酶抑制藥可列舉ντε — 1 22、 MCC-147 、PD-13230卜2 、DUP-129 、U-73482 、U-76807 、 RP-70676 、P-06139 、CP-113818 、RP一73163 、fr一129169 、FY-038 、EAB-309 、KY-455 、LS-3115 、FR-145237 、 T-2 5 9 1、J一 1 04 1 27、R —755、FCE-2 8654、YIC-C8-434、阿 伐西米布(avasimibe) 、CI-976 、Rp—64477 、F_1394 、艾 1231298 五、發明說明(33) 達西米布(eldacinibe) 、CS-505 、CL-283546 、YM-17E 、 雷西米布(lecimibide) 、447C88 、ym-750 、E-5324 、KW- 30 3 3、HL-0 04、艾富西米布(eflUCimibe)等。醯基輔酶A: 膽固醇醯基轉移酶抑制藥特別較佳用於高脂血症、高膽固 醇血症、高三酸甘油酯血症、脂質代謝異常之處置,因為 經由阻礙醯基輔酶A :膽固醇醯基轉移酶令血中膽固醇降 低,故更佳用於高脂血症、高膽固醇血症之處置。 甲狀腺激素受體興奮劑可列舉碘甲腺胺酸鈉、甲狀腺素 鈉、KB-2611等,膽固醇吸收抑制藥可列舉Esethymb、 SCH-4846 1 等,脂酶抑制藥可列舉0lulista1:、ATL —962、 AZM-131、RED- 1 03004等,肉鹼棕櫚醯轉移酶抑制藥可列 舉Etomoxyl等,角鯊烯合成酶抑制藥可列舉SDZ-268- 1 98
、BMS-188494 、A-87049 、RPR一101821 、ZD-9720 、RPR - 1 0 73 93、ER-278 5 6等,菸鹼酸衍生物可列舉菸鹼酸、菸 鹼醯胺、菸酸環己醇酯、菸酸戊四醇酯、阿西莫司 、 (Acipimox)、尼可地爾(Nicorandil)等,膽酸吸附藥可列 舉消膽胺(Colestyramine)、Colestyran、鹽酸 Coleseberam、GT- 1 02-279等,鈉共軛膽酸轉移蛋白抑制 藥可列舉264W94、S-8 92 1、SD-5613等,膽固醇酯轉送蛋 白抑制藥可列舉PNU- 1 0 7368E、SC- 795、JTT-70 5、 CP-5 2 94 1 4等。此些藥劑、丙丁酚、微粒體三酸甘油能轉 移蛋白抑制藥、脂氧合酶抑制藥及低比重脂蛋白受體増強 某特別車父佳用於高脂血症、高膽固醇血症、高三酸甘油酽 血症、脂質代謝異常之處置。 ·曰
1231298 五、發明說明(34) 食慾抑制藥可列舉單胺再吸收 〜 抑制藥、5-經色胺釋出刺激華、= 1 色胺再吸收 素釋出刺㈣、二匕腺腎上腺 -胺基丁酸受體拮抗劑、H _組 颌又體拮抗劑、r 蘇驗、勒帕蘇驗類 3 二=二、L-組胺酸、勒帕 ^ ^ ^ ,κ „ : ί ; - ^ ^ 黑素細胞刺激激♦ 上 R〆、田劑)、α
Maphoganin // ^7/Λ' ^ # ^ ^ ^ ^ ^ ^ ^ 肽、Bonbecin、膽囊收縮素 α 土因關連 劑)、促皮質素釋出激素、促皮質Y== f4CK-A興奮 皮質素釋出激素興奮劑、Ur〇c〇rti^釋出//類似物、促 素、生县鉍妾踩4 4 t 6、生長激素釋放抑鈿 ΜίΓ 放制素類似物、生長激素釋放抑制 系列性中性因子、促甲狀腺激素釋=神:成 ==Sovad'神經肽丫拮抗劑、阿片樣肽拮抗。 ;:量夏素拮抗劑、黑素濃縮激素受體拮抗劑、刺鼠: 抑制藥、Olexin受體拮抗劑等。具體而言,單 連 列::力藥可列舉氣苯咪吲哚等,5-羥色胺再吸收抑制藥5 」二右疑酚氟拉明、酚氟拉明、鹽酸西布茶明、順锐了
Ir T戊肟胺、鹽酸舍曲林等,5—羥色胺興奮劑可列舉印: ntriptyline)、( + )消旋酚氟拉明等,腎上 收抑制藥可列舉丁胺苯丙酮、GW-3 2 06 59等,腎上腺素吸 第39頁 1231298
出刺激藥可列舉環戊苯吡酮、瞥卜臆去為 體興奮劑可列嚴絮兩眇本99乂寻,/?2一月上腺素文 本丙fe、右旋***、苯丁胺、窄甲苯丙 甲巧丙胺、苯雙甲嗎啉、,甲嗎啉、二乙基丙酮、 本土丙s予胺、氯卞***等,多巴明興奮劑可列舉心-23〇
Doplexine、甲磺酸溴隱亭(Br〇m〇ci^ptine),***酚酸 類受體拮抗劑可列舉Rlm〇nabant等,T —胺基丁酸受體拮 杬組I列舉托吡酯等,札―組胺拮抗劑可列舉gt_2394等, 勒帕力S鹼、》勒帕茄鹼類似物或勒帕茄鹼受體興奮劑可列舉 LY-355 1 0 1等,右旋曱狀腺素受體興奮劑(特別為ccK —a興 奮劑)可列舉SR-146131、SSR- 1 25 1 80、BP-3.20 0、 A-71623 、FPL-15849 、GI-248573 、GW-7178 、 GI-181771、GW~7854、A-71 378等,神經肽Y拮抗劑可列舉 SR- 1 208 1 9-A、PDM 6 0 1 70、NGD-95-1、ΒΙΒΡ-3226、1 229- ^一91、Cf卜71 683、BIB〇 —33G4、C卜6719G6 —G1、卜 115814 等。食怒抑制藥為特別較佳用於糖尿病、糖尿病性併發 症&肥胖症糖代謝異常、高脂血症、高膽固醇血症、高 f酸甘油酯血症、脂質代謝異常、粥性動脈硬化症、高血 壓L鬱血性心衰竭、浮腫、高尿酸血症、痛風之處置,因 為經由促進或阻礙中樞食慾調節系中之腦内單胺和生理活 性胜肽之作用而抑制食慾,減少所攝取之能量,故更佳用 於肥胖症之處置。 血官緊張素變換目每抑制藥可列舉卡托普利(Capt〇pr丨i ) 、順丁婦二酸依那普利(EnaUpri丨)、阿拉普利 (Alacepril)、鹽酸地拉普利(DelaprU)、雷米普利
C:\2D-00DE\91-03\90132750.ptd
1231298 五、發明說明(36) (R a m i p r i 1 )、賴击普利([丨s丨n 〇 p r丨1 )、鹽酸咪噠普利 (Imidapril)、鹽酸苯駢普利(Benazepril)、西洛普利 (Ceronapril) —水合物、西拉普利(SilazaprU)、福森普 利(Fosinopril)鈉、呢道普利(perin(j〇pru)白蛋白、莫 替普利(Moveltipril)鈣、鹽酸基那普利(Kinapril)、鹽 酸斯哌普利(8?卜3?1^1)、鹽酸鐵莫普利(1^111〇1)1^1)、群 夕普利(T r a n d 〇 p r i 1 )、佐諾普利(z 〇 f e n 〇 p r i 1 )弼、鹽酸默 西普利(Μ o e x i p r i 1)、潤替普利(r e n 丨a p r i 1 )等。血管緊 張素變換酶抑制藥特別較佳用於糖尿病性併發症、高血壓 之處置。 中性内肽酶抑制藥可列舉奥姆帕拉(〇mapatrirate)、 MDL -1 00240、法西多利(Fasid〇tril)、沙姆帕拉 (Sampatrirate)、GW-660511x、米沙普利(Mixanpril)、 SA-7060 、E-4030 、SLV-306 、艾卡多利(Ecadotril)等。 中性内肽酶抑制藥特別較佳用於糖尿病性合併症、高血壓 之處置。 血管緊張素I I受體拮抗藥可列舉堪沙坦雷西 (Candesaltan Cylxetil)、堪沙坦雷西/氫氯ϋ塞畊 (Hydrochlorothiazide)、羅沙魯坦卸(R〇saltan Potassium)、曱磺酸艾普沙坦(Eprosaltan)、巴魯沙坦 (Balsaltan)、鈦魯沙坦(Telmisaltan)、衣魯沙坦 (Ilbesaltan) 、EXP-3174 、L-158809 、EXP-3312 、奥魯沙 坦(Olmesaltan)、他梭沙坦(Tasosaltan)、KT-3-671、GA -0113、RU-64276、EMD-90423、BR-9701 等。血管緊張素
C:\2D-roDE\91-03\90132750.ptd 第41頁 1231298 五、發明說明(37) I I受體枯抗藥特別較佳用於糖尿病性併發症、高血壓之處 置。 内絲胺酸變換酶抑制藥可列舉CGS —31447、CGS_35〇66、 SM-19712等’内絲胺酸受體拮抗劑可列舉L-74 98〇5、TBC一 3214 、BMS-182874 、BQ—610 、TA_〇201 、SB-215355 、 PD- 1 80 98 8、西他先坦(Sitaxsentan)、BMS— 1 93884、達魯 先坦(Darusentan)、TBC-377、玻先坦(Bosentan)、鐵口坐 先坦(Tezosentan)、J-104132、ym-598、S-0139、 SB-234551 、RPR-118031A 、ATZ-1993 、R0-6卜1790 、 ABT-546、艾拉先坦(Elasentan)、BMS-207940 等。此些藥 劑特別較佳用於糖尿病性併發症、高血壓之處置,且更佳 用於高血壓之處置。 利尿藥可列舉氯σ塞酮(Ch 1 or tha 1 i done )、環戊氯σ塞啳 (Cyclopenthiazide)、氫氣°塞啳(Hydrochlorothiazide) 、氫氟σ塞啳(Hydroflumethiazide)、雙環胺氫氯漆啳、戊 氟噻嗉(Penflutizde)、曱氯噻嗉(Methyclothiazide)、 11弓丨滿胺(Indapamide)、曲帕胺(Tripamide)、美夫西特 (Mefruside)、阿佐塞米(Azosemide)、依他尼酸 (Ethacrynic Acid)、特拉塞米(Trasemide)、苯咄磺苯酸 (Piretanide)、氟 11 塞米(Flurosemide)、布美他尼 (Bumetanide)、氨石黃硫色滿(Meticrane)、稀睪丙酸卸、 螺内酯、氨苯蝶啶(Tr i am t e r ene )、氨茶驗、鹽酸環雷坦 尼(Cycletonin)、LLD- a、PNU-80873A、異山梨醇、D-甘 露糖醇、D-山梨糠醇、果糖、甘油、乙醯醋唑胺
C:\2D-CODE\91-03\90132750.ptd 第42頁 1231298 五、發明說明(38) (Acetozolamide)、甲醋唑胺(Metazolamide)、 FR-179544、0PC-31260、力奇巴坦(lixivaptan)、鹽酸可 尼巴坦(Conivaptan)。利尿藥為特別較佳用於糖尿病性併 發症、高血壓、繫血性心衰竭、浮腫之處置,且經由增加 尿***量而降低血壓,改善浮腫,故更佳用於高血壓、鬱 血性心衰竭、浮腫之處置。 鈣拮抗藥可列舉阿拉地平(Alan i dipine)、鹽酸艾弗地 平(Efonidipine)、鹽酸硝苯乙口比咬(Nicardipine)、鹽酸 巴尼地平(Barnidipine)、鹽酸見尼地平(Benidipine)、 鹽酸馬尼地平(Manidipine)、西如地平(silnidipine)、 尼索地平(Nisoldipine)、尼群地平(Nitrendipine)、硝 笨地平(Nifedipine)、尼魯地平(Niiudipine)、費爾地平 (Felodipine)、苯磺酸阿羅地、普拉地平 (Pranidipine)、鹽酸雷卡地平(Relcanidipine)、伊拉地 平(Isradipine)、依高地平(Elg〇dipine)、阿解地平 (Azeldipine)、拉西地平(Lacidipine)、鹽酸巴他地平 (jatanidipine)、雷米地平(Remildipine)、鹽酸地爾硫 f(DiltiaZem)、順丁烯二酸克雷硫尊(clentiazem)、鹽 酸貝拉帕米(Berapamil)、s-貝拉帕米、鹽酸法司狄耳 (Fasdil)、.鹽酸爷普地爾(Bepridil)、鹽酸加羅帕米 (Gal lopami 1 )等,血管擴張性降壓藥可列舉吲滿胺 (Indapamide)、鹽酸乙肼苯噠嗉(T〇dralazine)、鹽酸肼 苯噠嗉(Hydralazine)、卡拉嗉(Cadralazine)、布酞嗉 (Budralazine)等’交換神經遮斷藥可列舉鹽酸氨碘洛爾
1231298 五、發明說明(39) 一' (Am〇SUlal〇1)、鹽酸特拉唑嗉(Terazosin)、鹽酸布那唑 秦(Bunazosin)鹽酸呢。坐嗉(Prazosin)、甲石黃酸多沙17坐 秦(Doxazosin)鹽酸普萘洛爾(Propranolol)、阿貼洛爾 (Atenolol) ’酉石酸美多洛爾(Metoprolol)、卡見洛爾 (Calbedilol)、尼普洛爾(Nipradil〇1)、鹽酸西利普洛爾 (Seriprolol)、尼比補洛爾(Nebib〇1〇1)、鹽酸倍他米松 (Betasolon)、叫丨嗓洛爾(pind〇1〇1)、鹽酸特他洛爾 (Tertatolol)鹽酸見凡洛爾(Bevantolol)、順丁烯二酸 百里紛、鹽酸卡特利多(Cal ter idol )、反丁烯二酸比索洛 爾(Bisoprolol)、丙二酸波吲咯爾(B〇pind〇1〇1)、尼普洛 爾(Nipradilol)、硫酸噴布洛爾(Penbut〇1〇1)、鹽酸醋丁 洛爾(Acebutolol)、鹽酸替索洛爾(TiHs〇1〇1)、納多洛 爾(Nadolol)、哌胺曱尿啶(Urapidil)、吲哚拉明 (Indoramin)等,中樞性降壓藥可列舉利血平(Reserpine) 等’ α2 -腎上腺素受體興奮劑可列舉鹽酸可樂定 (Clonidine)、曱基多巴(Dopa)、CHF_1〇35、醋酸氯壓胍( Guanabenz)、鹽酸氣苯醋胺_(Guanfacine)、嗎氧定 (Moxonidine)、洛非西定(L〇fexidine)、鹽酸塔利培索 (Tal ipexol )等。此些藥劑特別較佳用於高血壓之處置。 抗血小板藥可列舉鹽酸。塞氣匹定(T i c 1 0 p丨d i n e )、雙。密 達莫(Dipyridamole)、西羅達唑(Cirostasole)、二十五 酸乙酯、鹽酸沙波格來(Sarpogrelate)、鹽酸地拉齊普 (Dilazep)、曲匹地爾(Trapidil)、貝拉普羅鈉 (Beraprost Sodium)、阿司匹林等。抗血小板藥特別較佳
1231298 — 五、發明說明(40) 用於粥性動脈硬化症、鬱血性心衰竭之處置。 _ ^生成抑制藥可列舉別㈣(A1 lQpurin 南、丙石買舒(Probenecid)等,尿鹼化藥可 $本夫 摔檬酸钟、檸檬酸納等。此些藥劑二,鈉、 症、痛風之處置。 』罕又佳用於兩尿酸血 糖=之=2活广抑制藥以外之藥劑組合使用時,於 糖尿病之處置中,較佳為與至少一種藥才於 性增強藥、糖吸收抑制藥、雙胍¥ 島素感受 夷土素:d、胰咼血糖素受體拮抗劑、胰島素受體醢 激素、二肽基肽酶丨丨抑制藥、二肽基肽酶r抑制藥/、 酪胺酸磷酸酶-1B抑制藥、糖原磷酸化酶抑制藥、〃 磷脂酶抑制藥、果糖二磷酸酶抑制藥、丙酮酸脫氫 ,、肝糖新生抑制藥、D_肌醇、糖原合成酶激酶_3抑制 糖素胜肽]、類胰高血糖素胜肽卜類似物、 奮劑及食懲抑制藥之組合,且更佳為與至少4華 姨島素感爻性增強藥、糖吸收抑制藥、雙胍藥、胰島素分 刺ϊί素製劑、姨高血糖素受體括抗劑、膜島素 二一 / · /素、二肽基肽酶11抑制藥、二肽基肽酶IV抑 ,樂、蛋白酪胺酸磷酸酶_1Β抑制藥、糖原磷酸化酶抑制 樂、葡萄糖-6-磷脂酶抑制藥、果糖二磷酸酶抑制藥、丙 =酸脫氫冑、肝糖新生抑制藥、D_肌醇、糖原合成酶激酶 _3抑制藥、類姨高血糖素胜肽、類胰高血糖素胜狀卜類 第45頁 C:\2D-O0DE\91-03\90132750.ptd J231298 五、發明說明(41) 糖精興奮::::素::佳m:、糖精、糖精類似物、 樂及胰島素製劑之組合。 果胰島素分泌促進 中,較佳與至少一種藥劑κ胰病性併發症之處置 =制藥、雙胍藥、胰 藥、果糖二磷酸酶抑制冑:匕^、葡萄糖-6-磷脂酶抑制 藥、卜肌醇、糖原:二:::酮酸脫&酶、肝糖新生抑制 肽-1、類胰-血辘:成酶酶―3抑制藥、類胰高血糖素胜 興奮劑、糖:、L ί胜肽卜類似物、類胰高血糖素胜肽-1 制藥、故端:化產^似物 '糖精興奮劑、齡糖還原酶抑 胺基丁酸受體生f”藥、蛋白激酶。抑制藥、r-制藥、η备二、鈉官道拮抗劑、轉錄因子NF_ κ B抑 抑制藥、曰ϊ i島藥、n_乙醯化…連接酸' 二肽酶 長因子類似物、上皮增殖因子、神經成:因 :::】生物R、尿㈣η-經基 張素變換二抑、^1^"101"^、SUl〇deXide、Υ-128、血管緊 體拮抗藥、内丄f酶抑制藥、血管緊張素11受 及利尿藥之組ί 抑制藥、内絲胺酸受體拮抗劑 抑制藥了 ^二二且更佳與至少一種藥劑選自路糖還原酶 〃、官緊張素變換酶抑制藥、中性内肽酶抑制藥及 lmmm 第46頁 C:\2D-roDE\91-03\90132750.ptd^ 1231298 五、發明說明(42) ϊ Ίΐί1」,體ΐ抗藥之組合。又’於肥胖症之處置 吸收抑制華t雙種=自、胰島素感受性增強藥、糖 胰高血糖素二丄胰島素分泌促進藥、胰島素製劑、 肽酶π抑制二太:H素受體激酶刺激素、三肽基 单、耍祕 ^ ^ ^ 丨列永 匍珣糖-6 -鱗脂酶抑制 n,·酸酶抑制藥、丙酮酸脫氫: 肽-1、類胰高血糖素胜狀〗-麵八^制条類胰局血糖素胜 興奮劑、撼掉 ^ 、類胰咼血糖素胜肽-1 ^ ^搪精、糖知類似物、糖精興奮劑、$ -腎上胰音 將太旅3月腺★素x體興奮劑及食慾抑制藥之組合。’、 用法而祛明之醫樂品組成物使用於實際之治療時,可依據 劑、細粒齊i、乾糖漿劑、錠劑例如散劑、顆粒 歛喜為丨认… 修震劑、注射劑、液劑、 权:劑、芒劑、貼附劑等,可經口或非經口 :二斑“】 在些醫藥品組成物可依其劑型 ^ ^ 法,與適當之賦形劑、崩散劑、點子上所使用之手 :;、緩衝劑、等張劑、防腐劑、濕;Ξ 2、安定劑、溶解輔助劑等之醫藥品 =、:二:欠 釋、溶解,並依常法進行調劑則可黎4勿適虽此&或稀 性抑制藥以外之藥劑組合使用時,;;=又、,與SGLT2活 或分別同上述製劑化則可製造。 個活性成分同時 將本發明之醫藥組成物使用於實際之治療時,其有效成 C:\2D-CODE\91-03\90132750.ptd 1231298 五、發明說明(43) 分之前述一般式(j )所 為根據患者年齡、性別化&物或其藥理容許鹽之投與量 當決定,於經口投盥睹i,重、疾病及治療之程度等而適 圍,於非經口投盥時成人每1日約0.1〜1 000毫克之範 圍,可一回或分^ ^為成人每1日約0.01〜30 0毫克之範 藥以外之藥劑叙合使。又,與SGLT2活性抑制 卩制藥以:之= 以下列之參考彳丨、每 之内容,但本發明不試驗例更加詳細說明本發明 知月+破此内容所限定。 參考例1 ’ 气4 [(4異丙氧苯基)甲基]一 5一甲基一 3H-吼ϋ坐一3 - 酮 於4一-異丙氧基节醇(〇. 34克)之四氫呋喃(6毫升)溶液中 加入二乙胺(0.28毫升)及甲烷磺醯氣(〇16毫升),並於室 /皿=拌3 0刀知,濾除不溶物。將所得之甲燒續酸4 _異丙氧 基苄基酯之四氫呋喃溶液加至氫化鈉(6〇% , 81毫 〃 醢醋酸甲醋(0. 20毫升)之2_二甲氧基乙院〇〇毫升) U於8(TC攪拌一晚。將反應混合物注入飽和碳酸‘鈉 水/合液,以二***萃取。有機層以飽和食鹽水予以洗〆 士以無水硫酸鎂乾燥。減壓蒸除溶劑,將殘渣溶於甲^, ,升)’加入無水肼(〇· 1 9毫升),並於80 °c攪拌—晚本(5 壓蒸除溶劑,殘渣以石夕膠柱層析(溶出溶劑:二氣甲 減 醇=1 0/1)精製則取得1,2-二氫-4-[(4-異丙氧苯基甲
1231298 五、發明說明(44) 一5-曱基一 3H-p比哇一3 -酮(95毫克)。 ]H-NMR (DMS 〇- d 6) δ ppm: 1.22 (6H, d, J=6.0Hz), 1.99 (3H, s), 3.45 (2H, s), 4.40-4.60 (1H, m), 6.65-6.80 (2H, m), 6.95-7.10 (2H, m) 參考例2 1,2 -二氮-5*·曱基-4 - [(4-丙基苯基)曱基]- 3H- 口比10坐-3-酮 使用4-丙基苄醇代替4-異丙氧基芊醇,以參考例1同樣 之方法合成標題化合物。 ]H-NMR (DMSO-d6) δ ppm: 0.75-0.95 (3H, m), 1.45-1.65 (2H, m), 1.99 (3H, s), 2.40-2.55 (2H, m), 3.32 (2H, s), 6.95-7.10 (4H, m) 參考例3 1,2 -二氫-4 - [(4 -異丁基苯基)甲基]-5-曱基-3 H-咄唑-3 -酮 使用4-異丁基苄醇代替4-異丙氧基苄醇,以參考例1同 樣之方法合成標題化合物。 -NMR (DMS〇—d6) δ ppm: 0.83 (6H, d, J=6.6Hz), 1.70-1.85 OH, m), 1.99 (3H, s), 2.30-2.45 (2H, m), 3.50 (2H, s), 6.90-7.10 (4H, m) 參考例4 1,2 -二氫-5-曱基-4 - [(4-丙氧基苯基)甲基]- 3H-咄唑-3 -酮 使用4_丙氧基苄醇代替4_異丙氧基苄醇,以參考例1同 樣之方法合成標題化合物。
C:\2D-CODE\91-03\90132750.ptd 第49頁 1231298 五、發明說明(45) lH-NMR (DMSO —dg) δ ppm. 0.95 (3H, t, 1=7.4Hz), 1.60-1.75 (2H, m), 1.98 (3H, s), 3.46 (2H, s), 3 75-3.90 (2H, m), 6.70-6.85 (2H, m), 6.95-7.10 (2H, m) 參考例5 4- [(4-乙氧基苯基)曱基]-1,2 -二氫-5-甲基-3H-吼唑-3 -酮 使用4-乙氧基苄醇代替4-異丙氧基笮醇,以參考例1同 樣之方法合成標題化合物。 ^-NMR (DMS〇-d6) δ ppm: 1.20-1.35 (3H,m),1.98 (3H,s),3.46 (2H,s),3.85-4.05 (2H,m),6.70-6.85 (2H, m), 6.95-7.10 (2H, m) 參考例6 1,2-二氫-5-曱基-4-[(4-三氟甲基苯基)曱基]-311-17比。坐 -3-酮 使用4 -三氟曱基芊醇代替4 -異丙氧基苄醇,以參考例1 同樣之方法合成標題化合物。 JH-NMR (DMS〇-d6) δ ppm: 2.02 (3H, s), 3.64 (2H, s), 7.30-7.45 (2H, m), 7.55-7.70 (2H, m) 參考例7 4-[(4-第三丁基苯基)曱基]-1,2 -二氫-5-甲基-3H - °比°坐 - 3 -酮 使用4 -第三丁基芊醇代替4 -異丙氧基苄醇,以參考例1 同樣之方法合成標題化合物。 — NMR (DM S 〇一 d 6) 6 p pm * 1.24 (9H, s), 2.01 (3H, s), 3.49 (2H, s), 7.00-7.15 (2H, ,), 7.15-7.30 (2H,
C:\2D-CODE\91-03\90132750.ptd 第50頁 1231298 五、發明說明(46) 參考例8 4 - [(4 - 丁氧基苯基)曱基]-1,2 -二氫-5-甲基-3H-咄唑-3-嗣 使用4- 丁氧基苄醇代替4 -異丙氧基苄醇,以參考例1同 樣之方法合成標題化合物。 ^-NMR (DMSO-d 6) δ ppm: 0.91 (3H, t, J=7.4Hz), 1.30-1.50 (2H, m), 1.55-1.75 (2H, m), 1.98 (3H, s), 3.46 (2H, s), 3.80-3.95 (2H,,), 6.70-6.85 (2H, m), 6.95-7.10 (2H,,) 參考例9 1,2 -二氫一5-曱基一4-[(4-甲硫基苯基)曱基]一3H-口比峻一3-酮 使用4-(曱硫基)芊醇代替4-異丙氧基芊醇,以參考例1 同樣之方法合成標題化合物。 】H —NMR (DMSO- de) 6 ppm: 1.99 (3H, s), 2.42 (3H, s), 3.50 (2H, s), 7.05-7.20 (4H, m) 參考例1 0 5-乙基_1,2 -二氫-4 - [(4-甲硫基苯基)曱基]- 3Η-ϋΛ吐-3-酮 使用4-(甲硫基)苄醇代替4-異丙氧基苄醇、使用3 -酮基 戊酸曱酯代替乙醯醋酸曱酯,以參考例1同樣之方法合成 標題化合物。
第51頁 C:\2D-GODE\91-03\90132750.ptd 1231298 五、發明說明(47) 】H — NMR (DMS〇—d6) δ ppm. 1.02 (3H, t, J=7.6Hz), 2.39 (2H, Q, J=7.6Hz), 2.42 (3H, s), 3.51 (2H, s) 7.05-7.20 (4H, m) 參考例11 1,2-二氫-4-[(4-異丙基苯基)甲基]-5-曱基-311-1:1比11坐-3- 酮 於氫化鈉(60%,40毫克)之1,2_二曱氧基乙烷(1毫升)懸 浮液中加入乙醯醋酸甲酯(0 · 11毫升)、4 -異丙基苄基氣( 0 · 1 7克)及觸媒量之碘化鈉,並於8 0 °C攪拌一晚。將反應 混合物注入飽和碳酸氫納水溶液,並以二***萃取。有機 層以飽和食鹽水予以洗淨,且以無水硫酸鎂乾燥。減壓蒸 除溶劑,將殘渣溶於曱苯(1毫升),加入無水肼(0 · 0 9 4毫 升),並於8 0 °C攪拌一晚。減壓蒸除溶劑,殘渣以矽膠柱 層析(溶出溶劑··二氣甲烷/甲醇=10/1)精製,取得1,2-二 氫-4 - [(4 -異丙基苯基)曱基]- 5-曱基-3H - 11比。坐-3 -酮(0· 12 克)。 b — NMR (DMSO-d 6) δ ppm: 1.16 (6H, d, J=6.9Hz), 2.01 (3H, s), 2.70-2.90. (1H, m), 3.49 (2H, s), 6.95-7.20 (4H, m) 參考例1 2 4一 [(4 一乙基苯基)曱基]一1,2-二氫一 5-甲基一3H-口比°坐一 3-酮 使用4-乙基苄基氣代替4-異丙基苄基氣,以參考例11同 樣之方法合成標題化合物。 ]H —NMR (DMS〇-d 6) δ ppm: 1.13 (3H, t, ]=7.6Hz), 2.00 (3H, s), 2.45-2.60 (2H, m), 3.49 (2H, s) 7.00-7.15 (4H, m)
C:\2D-CODE\91-03\90132750.ptd 第52頁 1231298 五、發明說明(48) 參考例1 3 1,2 -二氫-5-甲基-4-[(4-甲基芊基)甲基]-3H_咄唑-3-酮 使用4-曱基苄基溴代替4-異丙基苄基氯,以參考例11同 樣之方法合成標題化合物。 ]H--NMR (DMSO-d 6) δ ppm: 1.98 (3H, s), 2.23 (3H, s), 3.48 (2H, s), 6.95-7.10 (4H, m) 參考例1 4 4-爷基-1,2-二氮-5-三氟甲基-3H- p比唾-3-嗣 使用三氟乙醯醋酸乙酯代替乙醯醋酸曱酯、使用芊基溴 代替4-異丙基芊基溴,以參考例1 1同樣之方法合成標題化 合物。 ^ — NMR (DMSO—dg) ^ ppm· 3.73 (2H, s), 7.05-7.35 (5H, m), 12.50-13.10 (1H, brs) 參考例1 5 1,2-二氫-4 一 [(4 一甲氧基苯基)甲基]一5-甲基-3H—口比唾一 3-酮 使用4-甲氧基苄基溴代替4-異丙基苄基氣,以參考例11 同樣之方法合成標題化合物。 ^-NMR (DMSO~d 6) δ ppm: 1.99 (3H, s), 3.47 (2H, s), 3.69 (3H, s), 6.75-6.85 (2H, m), 7.00-7.10 (2H, in), 8.70-1 1.70 (2H, br)
C:\2D-OODE\91-O3\90132750.ptd 第53頁 1231298 五、發明說明(49) 參考例1 6 4一苄基一 1,2 -二1-5—甲基一3Η— σ比口坐一3-酮 使用芊基溴代替4-異丙基芊基氯,以參考例1 1同樣之方 法合成標題化合物。 ]H-NMR (DMSO-d 6) δ ppm: 2.00 (3H, s), 3.54 (2H, s), 7.05-7.30 (5H, s) 參考例1 7 4 - [(4 -異丙氧基苯基)甲基]-5-甲基-3-(2, 3, 4, 6 -四-0-乙 醢基-yS - D - ϋ比喃葡萄糖氧基)-1 Η - 17比哇 於1,2 -二氫-4- [ (4 -異丙氧基苯基)甲基]-5-甲基-3Η-口比 唑-3-酮(46毫克)、乙醯溴基-α-D-葡萄糖(99毫克)及4Α 分子篩之四氫呋喃(3毫升)懸浮液中加入碳酸銀(6 6毫 克),將反應容器遮光並於6 5 °C攪拌一晚。反應混合物以 胺丙基矽膠柱層析(溶出溶劑:四氫呋喃)精製。再以矽膠 分取用薄相層析(展開溶劑:醋酸乙酯/己烷=2/ 1 )精製,取 得4-[ (4-異丙氧基苯基)甲基]-5-曱基-3-(2, 3, 4, 6-四-0-乙醯基-)S_D-咄喃葡萄糖氧基)-1Η -吡唑(42毫克)。 ]H-NMR (CDC 1 3) δ ppm: 1.25-1.35 (6H, in), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.10 (3H, s), 3.45-3.65 (2H, m), 3.80-3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.4Hz), 4.31 (1H, dd, J=4.0, 12.4Hz), 4.40-4.55 (1H, m), 5.15-5.35 (3H, m), 5.50-5.60 (1H, m), 6.70-6.-80 (2H, m), 6. 95-7.05 (2H, m)
C:\2D-CODE\91-03\90132750.ptd 第54頁 1231298 五、發明說明(50) 參考例1 8 5-甲基-4- [(4-丙基苯基)甲基]-3-(2, 3, 4,6 -四-0-乙醯基 -冷- D -吼喃葡萄糖氧基)- 1 Η -吼峻 使用1,2 -二氫-5-甲基-4 - [(4-丙基苯基)曱基]- 3Η-咄唑 -3 -酮代替1,2 -二氫-4- [(4 -異丙氧基苯基)曱基]-5-曱基 -3Η_吼吐-3-酮,以參考例1 7同樣之方法合成標題化合 物。 ]H —NMR (CDC 1 3) δ ppm: 0.91 (3H, t, J = 7.3Hz), 1.50-1.65 (2H, m), 1.86 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.10 (3H, s), 2.45-2.55 (2H, m), 3.55 (1H, d,J = 15.8Hz), 3.63 (1H, d, J = 15.8Hz), 3.80-3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.4Hz), 4.30 (1H, dd, J=3.9, 12.4Hz), 5.15-5.35 (3H, m), 5.50-5.60 (1H, m), 7.00-7.20 (4H, m) 參考例1 9 4 - [(4-異丁基苯基)甲基]-5-曱基-3-(2, 3, 4,6 -四-0-乙醯 基- /5 - D -吼喃葡萄糖氧基)- 1 Η - p比唾 使用1,2 -二氫-4-[(4 -異丁基苯基)曱基]-5 -甲基-3H-17比 17坐-3 -酮代替1,2 -二氫-4 - [(4 -異丙氧基苯基)曱基]- 5-曱 基-3H-咄唑-3-酮,以參考例17同樣之方法合成標題化合 物。 ]H — NMR (CDC 1 3) δ ppm: 0.87 (6H, d, J=6.6Hz), 1.70-1.85 (1H, m), 1.87 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 2.40 (2H, d, ]=7.2Hz), 3.56 (1H, d, J = 15.8Hz), 3.63 (1H, d, J = 15.8Hz), 3.80-3.90 (1H, m), 4.14 (1H, dd,J=2.3, 12.4Hz), 4.31 (1H, dd, J=4.0, 12.4Hz), 5.15-5.35 (3H, m), 5.50-5.60 (1H, m), 6.95-7.10 (4H, m)
C:\2D-CODE\91-03\90132750.ptd 第55頁 1231298 五、發明說明(51) 參考例2 0 5-曱基-4-[(4-丙氧基苯基)甲基]-3-(2,3,4,6 -四-0-乙醯 基- /5-D-吼喃葡萄糖氧基)-1Η-吼唑 使用1,2_二氫-5-甲基-4- [(4-丙氧基苯基)曱基]-3H_呲 唑-3 -酮代替1,2 -二氫-4-[(4-異丙氧基苯基)甲基]-5-甲 基-3H-咄唑-3-酮,以參考例17同樣之方法合成標題化合 物。 ]H-NMR (CDC 1 3) δ ppm: 1.01 (3H, t, J-7.4Hz), 1.70~1.85 (2H, m), 1.89 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.53 (1H, d, J = 15.7Hz), 3.59 (1H, d, ] = 15.7Hz), 3.80-3.95 (3H, m), 4.14 (1H, dd, J = 2.3, 12.4Hz), 4.31 (1H, dd, 3=4.0, 12.4Hz), 5.15-5.35 (3H, m), 5.50-5.60 (1H, m), 6.70-6.80 (2H, m), 6.95-7.10 (2H, m) 參考例2 1 4 一[(4一乙氧基苯基)曱基]一5-曱基一3-(2, 3,4, 6-四一0-乙醯 基-点-D- 口比喃葡萄糖氧基)-1Η-吼唑 使用4-[(4-乙氧基苯基)甲基]-1,2 -二氫-5-曱基-3 H-咄 唑-3 -酮代替1,2 -二氫-4 - [(4 -異丙氧基苯基)甲基]-5-甲 基- 3 Η -吼ϋ坐-3 -酮,以參考例1 7同樣之方法合成標題化合 物。 ]H — NMR (CDC 1 3) (5 ppm: 1.38 (3H, t, J=7.0Hz), 1.89 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.53 (1H, d, J = 15.8Hz), 3.59 (1H, d, J=15.8Hz), 3.80-3.90
第56頁 C:\2D-CODE\91-03\90132750.ptd 1231298 五、發明說明(52) (1H, m), 3.98 (2H, q, J=7.0Hz), 4.13 (1H, dd, J=2.3, 12.4Hz), 4.31 (1H, dd, J-4,0, 12.4), 5.15-5.30 (3H, m), 5.50-5.60 (1H, m), 6.70-6.80 (2H, m), 6.95-7.10 (2H, m) 參考例2 2 5-曱基-3-(2, 3, 4, 6-四-0-乙醯基-石-D-咄喃葡萄糖氧基) - 4-[(4-三氟甲基苯基)曱基]-1H-吼唑 使用1,2 -二氫-5-曱基-4-[ (4 -三氟甲基苯基)曱基]-3H-°比°坐-3 -嗣代替1,2 -二氮-4 - [(4-異丙氧基苯基)甲基]- 5-甲基-3H-咄唑-3-酮,以參考例17同樣之方法合成標題化 合物。 ]H — NMR (CDC 1 3) δ ppm: 1.85 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.14 (3H, s), 3.65 (1H, d, J = 15.9Hz), 3.71 (1H, d, J = 15.9Hz), 3.80-3.90 (1H, m), 4.14 (1H, dd, J = 2.4, 12.4Hz), 4.31 (1H, dd, J=4.0, 12.4Hz), 5.15-5.40 (3H, m), 5.55-5.65 (1H, m), 7.20-7.30 (2H, m), 7.45-7.55 (2H, m) 參考例2 3 4-[(4-第三丁基苯基)曱基]-5 -曱基-3-(2,3, 4,6 -四-0-乙 醢基-- D -吼喃葡萄糖氧基)-1 Η - °比σ坐 使用4 -[(4-第三丁基苯基)曱基]-1,2-二氫-5-甲基-3Η-°比°坐-3 -酮代替1,2 -二氫-4 - [(4_異丙氧基苯基)曱基]- 5-甲基-3Η-咄唑-3-酮,以參考例17同樣之方法合成標題化 合物。
C:\2D-C0DE\91-03\90132750.ptd 第57頁 1231298 五、發明說明(53) ]H —NMR (CDC 1 3) δ ppm: 1.27 (9H, s), 1.84 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.14 (3H, s), 3.56 (1H, d, 1 = 15.8Hz), 3.64 (1H, d, J = 15.8Hz), 3.80-3.90 (1H, m), 4.13 (1H, dd, J=2.3, 12.4Hz), 4.31 (1H, dd, J=4.0, 12.4Hz), 5.15-5.30 (3H, m), 5.50-5.60 (1H, m), 7.00-7.10 (2H, m), 7.20-7.30 (2H, m) 參考例24 4- [(4 - 丁氧基苯基)曱基]-5-曱基-3-(2,3,4,6_四-0-乙醯 基- /3 -D-吼喃葡萄糖氧基)-1Η-吼唑 使用4-[(4-丁氧基苯基)甲基]-1,2-二氫-5-甲基-3H-咄 唑-3 -酮代替1,2 -二氫-4 - [(4 -異丙氧基苯基)甲基]-5-曱 基-3H-吼嗤-3-酮,以參考例17同樣之方法合成標題化合 物。 ]H-NMR (CDC 1 3) S ppm: 0.96 (3H, t, J=7.4Hz), 1.40-1.55 (2H, m), 1.65-1.80 (2H, m), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.10 (3H, s), 3.52 (1H, d,J = 15.8Hz), 3.59 (1H, d, J = 15.8Hz), 3.80-3.90 (1H, m), 3.91 (2H, t, J = 6.5Hz), 4,13 (1H, dd, J = 2.3, 12.4Hz), 4.31 (1H, dd, J=4.0, 12.4Hz), 5.15-5.30 (3H, m), 5.50-5.60 (1H, m), 6.70-6.80 (2H, m), 6.95-7.10 (2H, m) 參考例2 5 5- 曱基-4-[(4-曱硫基苯基)甲基]- 3 -(2,3,4,6 -四-0_乙醯 基-点-D-吼喃葡萄糖氧基)-1Η-吼唑 使用1,2 -二氫-5-甲基-4-[(4_甲硫基苯基)曱基]-3H-吼 唑-3 -酮代替1,2 -二氫-4 - [(4 -異丙氧基苯基)甲基]-5-甲 基- 3 Η -吼-3 -酮,以參考例1 7同樣之方法合成標題化合 物0
C:\2D-C0DE\91-03\90132750.ptd 第58頁 1231298 五、發明說明(54) ^-NMR (CDC 1 3) δ ppm: 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.07 (3H, s), 2.12 (3H, s), 2.44 (3H, s), 3.50-3.65 (2H, m), 3.80-3.90 (1H, m), 4.13 (1H, dd, J=2.4, 12.4Hz), 4.31 (1H, dd, J=4.1,12.4Hz), 5.15-5.30 (3H, m), 5.55-5.65 (lH,m), 7.00-7.10 (2H, m), 7.10-7.20 (2H, m), 8.65-8.85 (1H, brs) 參考例2 6 5-乙基-4 - [(4-曱硫基苯基)甲基]- 3 -(2,3,4,6 -四-〇-乙醯 基-冷-D-吼喃葡萄糖氧基)-1Η-吼唑 使用5-乙基-1,2 -二氫- 4- [(4-曱硫基苯基)曱基]- 3H-口比 ϋ坐-3-酮代替1,2 -二氫-4- [(4 -異丙氧基苯基)甲基]- 5-曱 基-3Η- 口比唾-3-酮,以參考例17同樣之方法合成標題化合 物。 h — NMR (CDC 1 3) δ ppm: 1 13 (3H, t, ]=7.6Hz), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s) 2.44 (3H, s), 2.45-2.55 (2H, m), 3.50-3.70 (2H, m), 3.80-3.90 (1H, m), 4.05-4.20 (1H, m), 4.31 (1H, dd, ]=4.0, 12.4Hz), 5.15-5.35 (3H, m), 5.55-5.65 (1H, m), 7.00-7.10 (2H, m), 7.10-7.20 (2H, m), 8.80-9.20 (1H, brs) 參考例2 7 4 - [(4 -異丙基苯基)甲基]-5-曱基-3 -(2, 3,4, 6-四-0-乙醯 基-/3 - D -吼喃葡萄糖氧基)-1 Η -吼唾 使用1,2 -二氫-4 - [(4 -異丙基苯基)曱基]-5 -甲基-3Η-吼 ϋ坐-3 -酮代替1,2 -二氫- 4- [(4 -異丙氧基苯基)曱基]- 5-曱 基-3Η-吡唑-3-酮,以參考例17同樣之方法合成標題化合
C:\2D-CODE\91-03\9O13275O.ptd 第59頁 1231298 五、發明說明(55) 物。 ]H —NMR (CDC 1 3) δ ppm: 1.20 (6H, d, J=6. 9Hz), 1.85 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.13 (3H, s), 2.75-2.90 (1H, m), 3.56 (1H, d, J = 15.8Hz), 3.63 (1H, d, J = 15.8Hz), 3.80-3.90 (1H, m), 4.05-4.20 (1H, m), 4.31 (1H, dd, J=4.0, 12.4Hz), 5.15-5.35 (3H, m), 5.50-5.60 (1H, m), 7.00-7.15 (4H, m), 8.70-9.30 (1H, brs) 參考例2 8 4 - [(4-曱硫基苯基)曱基]-3-(2, 3, 4, 6 -四-0-乙醯基-/5 - D-11比σ南葡萄糖氧基)- 5 -三氟甲基-lH-wb11 坐 於1,2 -二氫-4 - [(4-曱硫基苯基)曱基]-5 -三氟甲基-3H -吼唑-3 -酮(2· 0克)之乙腈(100毫升)溶液中加入乙醯溴基-a-D-葡萄糖(3· 1克)及碳酸鉀(1 · 1克),並於室溫攪拌一 晚。於反應混合物中加水,且以醋酸乙酯萃取。有機層以 飽和碳酸氫鈉水溶液及飽和食鹽水依序洗淨,且以無水硫 酸鎂乾燥。減壓蒸除溶劑,殘渣以矽膠柱層析(溶出溶劑: 己烷/醋酸乙酯= 1/1)精製,取得4- [(4-曱硫基苯基)曱 基]-3-(2,3,4,6-四-0-乙醯基-/3-0-吼°南葡萄糖氧基)-5-三氟曱基-1Η-咄唑(2. 0克)。 -NMR (CDC 1 3) (5 ppm: 1.91 (3H, s), 2.03 (3H, s), 2.04 (3H, s), 2.09 (3H, s), 2.45 (3H, s), 3.73 (2H, s), 3.75-3.90 (1H, m), 4.15-4.35 (2H, m), 5.15-5.65 (4H, m), 7.00-7.20 (4H, m) 參考例2 9
C:\2D-G0DE\91-03\90132750.ptd 第60頁 1231298 五、發明說明(56) 4-苄基-3-(2, 3, 4, 6-四-0-乙醯基-/3-D-口比喃葡萄糖氧基) -5-三氟曱基- 使用4-爷基-1,2 -二氫-5-三氟i曱基-3H-吼ϋ坐-3 -嗣代替 1,2 -二氫-4-[ (4-曱硫基苯基)曱基]-5-三氟曱基-3Η-吡唑 -3 -銅,以參考例2 8同樣之方法合成標題化合物。 】H-NMR (CDC 1 3) ό ppm: 1.89 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.08 (3H, s), 3.70-3.90 (3H, m), 4.15-4.30 (2H, m), 5.10-5.50 (4H, m), 7.10-7.30 (5H, m) 參考例3 0 4一 [(4一曱氧基苯基)曱基]一3-(2, 3 ,4, 6-四-0-乙醯基-/5-D -口比喃葡萄糖氧基)-5-三氟曱基-1 Η-吼唑 使用1,2 -二氫-4-[( 4-曱氧基苯基)甲基]-5 -三氟曱基 一3Η-口比ϋ坐一3-酮代替1,2~~二氫一 4一 [(4一曱石荒基苯基)曱基] -5-三氟曱基-3Η-咄唑-3-酮,以參考例28同樣之方法合成 標題化合物。 ]H-NMR (CDC 1 3) δ ppm: 1.93 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.09 (3H, s), 3.65-3.75 (2H, m), 3.77 (3H, s), 3.75-3.90 (1H, m), 4.15-4.35 (2H, m), 5.10-5.45 (4H, m), 6.75-6.85 (2H, m), 7.00-7.15 (2H, m) 參考例3 1 4一 [(4 一甲氧基苯基)甲基]一5-曱基一 3-(2, 3, 4, 6-四一 0-乙醯 基- /5 - D -吼喃葡萄糖氧基)-1 Η -吼唑 使用1,2 -二氮-4-[( 4-甲氧基苯基)曱基]-5-甲基-3Η-口比 σ坐-3 -酮代替1,2 -二氫-4 - [(4 -異丙氧基苯基)甲基]- 5-曱
C:\2D-CODE\91-03\90132750.ptd 第61頁 1231298 五、發明說明(57) 基-3H-。比。坐-3-酮,以參考例17同樣之方法合成標題化合 物。 】H-NMR (CDC 1 3) (5 ppm: 1.89 (3H, s), 2.02 (3H, s), 2.03 (3H, s), 2.05 (3H, s), 2.10 (3H, s), 3.45-3.65 (2H, m), 3.76 (3H, s), 3.80-3.90 (1H, m), 4.11 (1H, dd, J=2.2, 12.4Hz), 4.30 (1H, dd, J=4.0, 12.4Hz), 5.15-5.35 (3H, m), 5.50-5.60 (lH,m), 6.70-6.85 (2H, m), 7.00-7.10 (2H, m) 參考例3 2 4一爷基一 5-曱基一 3-(2,3,4,6-四-〇-乙醯基一 /3 - D- p比喃葡萄 糖氧基)-1 Η -吼唾 使用4-爷基=1,2-二氮-甲基-3Η-吼〇坐-3 -嗣代替1,2-二氫-4-[(4 -異丙氧基苯基)曱基]-5-甲基-3Η-吼唑-3-酮,以參考例1 7同樣之方法合成標題化合物。 】Η-NMR (CDC 1 3) δ ppm: 1.86 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.11 (3H, s), 3.59 (1H, d, J=15.8Hz), 3.66 (1H, d, J = 15.8Hz), 3.80-3.90 (1H, m), 4.11 (1H, dd, J=2.3, 12.4Hz), 4.30 (1H, dd, J=4.0, 12.4Hz), 5.15-5.30 (3H, m), 5.50-5.65 (1H, m), 7.05-7.30 (5H, m), 8.75-9.55 (1H, brs) 參考例3 3 4-[(4-曱氧基苯基)曱基]-1,5-二曱基-3-(2, 3, 4, 6-四-0 -乙醯基-万-D -吼喃葡萄糖氧基)吼峻 將4-[(4-甲氧基苯基)曱基]-5-曱基-3-(2, 3, 4, 6-四-0-乙醯基-/5-D-吼喃葡萄糖氧基)-1Η -吼唑(18毫克)、碳酸 鉀(14毫克)及曱基碘(4·7毫克)之乙腈(2毫升)懸浮液於75
C:\2D-mDE\91-03\90132750.ptd 第62頁 1231298 五、發明說明(58) °C授摔一晚。反應混合物以寅式鹽過濾,並減壓蒸除 之溶劑。殘渣以矽膠分取用薄相層析(展開溶劑:笨/丙-液 =2/1)精製,取得4-[(4-甲乳基本基)甲基]納 一3-(2, 3, 4, 6-四-0_乙醯基_ 口比喃葡萄糖氧基)吡二 毫克)。 h-NMR (CDC 1 3) ό ppm: 1.90 (3H,s),2.01 (3H,s),2.03 (3H,s),2· 06 (3H,s),2 〇7 (3H,s), 3.45-3.60 (2H, m), 3.60 (3H, s), 3.76 (3H, s), 3.80-3.90 (ih, 413 (1Hj dd, J=2· 4,12.4Hz), 4.29 (1H, dd,1=4.1,12.4Hz),5· 15一5.3〇 (3H,爪), 5.50-5.60 (1H, m), 6. 70-6.80 (2H, m), 7.00-7.10 (2H, m) 參考例3 4 1-甲基-4-[(4-甲硫基苯基)甲基]- 3〜(2, 3, 4, 6-四-〇-乙醯 基-召- D -吼喃葡萄糖氧基)- 5 -三氟曱基吼唑 將4-[(4-甲硫基苯基)甲基]-3-(2,3,4,6-四-〇-乙醯基一 /5 - D- 〇比〇南葡萄糖氧基)一5-三亂曱基比嗤(30毫克)、碳 酸鉀(80毫克)及甲基碘(8.2毫克)之四氫呋喃(1毫升)懸浮 液於75 °C攪拌一晚。反應混合物以寅式鹽過濾,並減壓蒸 除濾液之溶劑。殘漁以矽膠分取用薄相層 二、 氣甲烷/醋酸乙酯=5/1)精製, 田| 苯基)甲基]+ (2, 3, 4, 6上。取二:甲基-4一[(4一甲硫基 氧基)-5-三氣甲基咄唑(丨3毫克)乙醯基_石-D-吡喃葡萄糖 ]H-NMR (CDC 1 3) ό ppm: 1.89 (3H, s), 2.02 (3H, s), 2.04 (3H 〇 0 , & s),2·〇7 (3H,s),2.44 (3H, s), 3.65-3.95 (6H, m), 4.14 (1H, dd, J=2 ^ Ί 0 12.4Hz), 5.15-5.35 (3H, m), 5.50-5.65 、 _ UH’m),7.00-7.20(4H,m)
C:\2D-00DE\91-03\90132750.ptd 第63頁 12.4Hz), 4.29 (1H, dd, J=4.3, 1231298 五、發明說明(59) 參考例3 5 卜乙基-4-[(4-曱硫基苯基)甲基]- 3-(2, 3, 4, 6-四-0-乙醯 基--D-吼喃葡萄糖氧基)-5-三氟曱基吼唑 使用乙基碘代替曱基碘,以參考例34同樣之方法合成標 記化合物。 ]H-NMR (CDC 1 3) δ ppm: 1.40 (3H, t, J=7.2Hz), 1.90 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.44 (3H, s), 3.72 (2H, s), 3.80-3.90 (1H, m), 4.05-4.20 (3H, m), 4.27 (1H, dd, J=4.5, 12.4Hz), 5.10-5.35 (3H, m), 5.55-5.65 (1H, m), 7.00-7.10 (2H, m), 7.10-7.20 (2H, m) 參考例3 6 4 - [(4-曱硫基苯基)甲基]-:l -丙基-3 -(2, 3, 4, 6-四-0-乙醯 基- yS - D - nb喃葡萄糖氧基)- 5 -三氟甲基吼唾 使用卜丙基碘代替甲基碘,以參考例34同樣之方法合成 標題化合物。 】H-NMR (CDC 1 3) δ ppm: 0.92 (3H, t, J=7.4Hz), 1.75-1.90 (2H, m), 1.89 (3H, s), 2.02 (3H, s), 2.04 (3H, s), 2.06 (3H, s), 2.44 (3H, s), 3.72 (2H, s), 3.80-3.90 (1H, m), 3.90-4.05 (2H, m), 4.12 (1H, dd, J = 2.3, 12.4Hz), 4.27 (1H, dd, J=4.5, 12.4Hz), 5.10-5.35 (3H, m), 5.55-5.65 (1H, m), 7.00-7.10 (2H, m), 7.10-7.20 (2H, m) 參考例3 7 3-( /3-D-吼喃葡萄糖氧基)- 4-[(4-異丙氧基苯基)曱 基]-5-曱基-1H- nb唑
C:\2D-CODE\91-03\90132750.ptd 第64頁 1231298 五、發明說明(60) 於4- [(4-異丙氧基苯基)曱基]-5 -曱基-3-(2, 3, 4, 6-四 - 0-乙醯基-/J-D-wb17南型葡萄糖氧基)-1Η- ϋ比σ坐(61毫克)之 乙醇(3毫升)溶液中加入1莫耳/升氳氧化納水溶液(0.53毫 克),並於室溫攪拌2小時。減壓蒸除溶劑,殘渣以ODS固 相萃取法(洗淨溶劑:蒸餾水,溶出溶劑:甲醇)精製,取得 3-( ;5-D-吼喃葡萄糖氧基)-4-[(4-異丙氧基苯基)甲基]-5-甲基-1H-吼唑(39毫克)。 】H-NMR (CD3〇D) δ ppm : 1.26 (6H, d, 1 = 5. 9Hz), 2.05 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.75-3.90 (1H, m), 4.45-4.60 (1H, m), 5.00-5.10 〇«, m), 6.70-6.80 (2H, m), 7.00-7. 15 (2H, m) 參考例3 8 3-( /3-D-吼喃葡萄糖氧基)-5_甲基-4-[(4-丙基苯基)曱基 ]-1 Η - σ比唾 使用5-曱基-4- [(4-丙基苯基)曱基]-3-(2, 3, 4, 6 -四-0-乙醯基-召- D _ ϋ比喃葡萄糖氧基)-1 Η -吼唾代替4 - [(4 -異丙 氧基苯基)曱基]_5-曱基-3 -(2, 3, 4, 6-四-0-乙醯基-/3 吼喃葡萄糖氧基)-1 H_吼唑,以參考例37同樣之方法合成 標題化合物。 ]H-NMR (CD3〇D) δ ppm: 0.91 (3H, t, J=7.5Hz), 1.50-1.65 (2H, m), 2.05 (3H, s), 2.45-2.60 (2H, m), 3.25-3.45 (4H, m),3.55-3·75 (3H, m),3.83 (1H, d,J:11.9Hz), 5.00-5.10 (1H, m), 7.00-7.15 (4H, m)
C:\2D-CODE\91-03\90132750.ptd 第65頁 1231298 五、發明說明(61) 參考例3 9 3-(万-D-吼喃葡萄糖氧基)- 4- [(4-異丁基苯基)曱基]-5-甲基- 1 Η - p比嗤 使用4-[(4-異丁基苯基)曱基]-5 -甲基-3-(2, 3, 4, 6-四-0-乙醯基-冷-D-咄喃葡萄糖氧基)- 1 Η-咄唑代替4- [ (4-異 丙氧基苯基)曱基]-5-曱基-3-(2, 3, 4, 6 -四-0-乙醯基-;5 -D-咄喃葡萄糖氧基)-1 Η-咄唑,以參考例3 7同樣之方法合 成標題化合物。 -NMR (CD3〇D) δ ppm: 0.87 (6H, d, J=6.6Hz), 1.70-1.90 (1H, m) 3.25-3.45 (4H, m), 3.55-3.90 (4H, m), m) 2.04 (3H, s), 2.41 (2H, d, J=7.1Hz), 5.00-5.10 OH, m), 6.95-7.15 (4H, 參考例4 0 3-( /3 - D-吼喃葡萄糖氧基)-5-曱基-4-[(4-丙氧基苯基)甲 基]-1 Η _吼σ坐 使用5-甲基-4 - [(4-丙氧基苯基)甲基]-3 -(2, 3, 4, 6-四 -0-乙醯基-/5 -D-吼喃葡萄糖氧基)- 1Η-咄唑代替4_[ (4-異 丙氧基苯基)曱基]- 5-曱基-3 -(2, 3, 4,6 -四-0-乙醯基-泠 - D -吼喃葡萄糖氧基)-1 Η - ϋ比唾,以參考例3 7同樣之方法合 成標題化合物。 ]H-NMR (CD3〇D) δ ppm: 1.02 (3H, t, ]=7.4Hz), 1.65-1.80 (2H, m), 2.05 (3H, s), 3.25-3.45 (4H, m), 3.60-3.75 (3H, m), 3.80-3.90 (3H, m), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.05-7.-15 (2H, m)
C:\2D-raDE\91-03\90132750.ptd 第66頁 1231298 五、發明說明(62) 參考例41 4 - [(4-乙氧基苯基)曱基]-3-( /5-D-吼喃葡萄糖氧基)-5-甲基- 1 Η -吼°坐 使用4-[(4-乙氧基苯基)甲基]-5 -甲基-3-(2, 3, 4, 6-四 - 0-乙酿基- /3 - D-13比喃葡萄糖氧基比σ坐代替4 - [(4-異 丙氧基苯基)曱基]-5-曱基-3 -(2, 3, 4,6 -四-0-乙醯基-;3 -D-咄喃葡萄糖氧基)-1Η-咄唑,以參考例37同樣之方法合 成標題化合物。 ]H — NMR (CD3〇D) δ ppm: 1.34 (3H, t, J=7.0Hz), 2.05 (3H, s), 3.25-3.45 (4H, m), 3.60-3.75 (3H, m), 3.80-3.90 (1H, m), 3.97 (2H, q, J=7.0Hz), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.05-7.15 (2H, m) 參考例42 3-( 喃葡萄糖氧基)-5-曱基-4- [(4-三氟曱基苯基) 曱基]-1 Η -吼哇 使用5-曱基-3-(2, 3, 4,6-四-0-乙醯基-/3-D-咄喃葡萄 糖氧基)- 4-[(4-三氟甲基苯基)曱基]-代替4 - [(4-異丙氧基苯基)曱基]-5-曱基-3-(2,3,4,6 -四-0-乙醯基-冷-D-吼喃葡萄糖氧基)-1Η-咄唑,以參考例37同樣之方法 合成標題化合物。 】H —NMR (CD3〇D) δ ppm: 2.08 (3H, s), 3.20-3.40 (4H, m), 3.67 (1H, dd, J = 5.0, 11.9Hz), 3.75-3.90 (3H, m), 5.00-5.10 (1H, m), 7.30-7.45 (2H, m), 7.45-7.60 (2H, m) 參考例4 3
C:\2D-CODE\91-03\90132750.ptd 第67頁 1231298 五、發明說明(63) 4-[(4 -第三丁基苯基)曱基]- 3- ( /5-D- °比喃葡萄糖氧 基)-5-甲基-1H-U比唾 使用4-[(4-第三丁基苯基)甲基]-5-曱基-3-(2,3,4,6-四-0-乙酿基- /3 - D-11比喃葡萄糖氧基)-1H - 比峻代替4 - [(4 -異丙氧基苯基)甲基]-5-曱基-3 -(2,3,4,6-四-0_乙酿基-冷- D -咄喃葡萄糖氧基)-1 Η - σ比唑,以參考例3 7同樣之方法 合成標題化合物。 ]Η-NMR (CD3〇D) δ ppm: 1.28 (9H, s), 2.06 (3H, s), 3.25-3.45 (4H, m), 3.60-3.90 (4H, m), 5.00-5.10 (1H, m), 7.05-7.15 (2H, m), 7.20-7.30 (2H, m) 參考例44 4-[(4-丁氧基苯基)甲基]-3-( /5-D-吼喃葡萄糖氧基)-5-曱基-1H-吼唑 使用4-[(4 - 丁氧基苯基)曱基]-5-甲基-3-(2, 3, 4, 6-四 -0-乙醯基-万-D咄喃葡萄糖氧基)- 1H-咄唑代替4-[ (4-異 丙氧基苯基)曱基]- 5-曱基-3 -(2,3,4,6-四-0-乙酿基- /3 -D-咄喃葡萄糖氧基)-1Η-咄唑,參考例37同樣之方法合成 標題化合物。 ]H-NMR (CD3〇D) δ ppm: 0.97 (3H, t, J=7.4Hz), 1.40-1.55 (2H, m), 1.65-1.80 (2H, m), 2.05 (3H, s), 3.30-3.45 (4H, m), 3.60-3.75 (3H, m), 3.83 (1H, d, J = 12.0Hz), 3.91 (2H, t, 1 = 6.4Hz), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.05-7.15 (2H, m) 參考例4 5
C:\2D-CODE\91-03\90132750.ptd 第68頁 1231298 五、發明說明(64) 3-( /3 -D-吼喃葡萄糖氧基5-曱基-4-[ (4-曱硫基苯基)曱 基]-1 Η - σ比峻 使用5-曱基-4-[(4-甲硫基苯基)曱基]-3-(2, 3, 4, 6-四 -0-乙醯基-万-D-咄喃葡萄糖氧基)-1Η-咄唑代替4- [ (4 -異 丙氧基苯基)甲基]-5-甲基-3-(2, 3, 4, 6_四-0-乙醯基- /3 - D -吼喃葡萄糖氧基)-1 Η -吼唾,以參考例3 7同樣之方法合 成標題化合物。 ]H-NMR (CD3〇D) δ ppm:
2.06 (3H, s), 2.42 (3H, s), 3.20-3.45 (4H, m), 3.55-3.75 (3H, m), 3.80-3.90 (1H, m), 5.00-5.10 (1H, m), 7.05-7.20 (4H, m) 參考例4 6 5-乙基-3 -( /3-D -吼喃葡萄糖氧基)-4 - [(4-曱硫基苯基)甲 基)-1 Η -吼°坐 使用5-乙基-4- [(4-甲硫基苯基)曱基]-3-(2, 3, 4, 6-四 - 0-乙醯基- /3 - D-11比喃葡萄糖氧基)-1Η-ϋ比ϋ坐代替4 - [(4-異 丙氧基苯基)甲基]-5-甲基-3-(2, 3, 4, 6 -四-0-乙醯基-冷 - D -吼喃葡萄糖氧基)-1 Η -吡唑,以參考例3 7同樣之方法合 成標題化合物。
]H-NMR (CD3OD) δ p pm : 1.06 (3H, t, J = 7.6Hz), 2.42 (3H, s), 2.47 (2H, q, J=7.6Hz), 3.25-3.45 (4H, m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m), 5.00-5.10 (1H, m), 7.10-7.20 (4H, m) 參考例47 3-( /3-D-吼喃葡萄糖氧基)-4-[(4-異丙基苯基)曱基]-5-
C:\2D-raDE\91-03\90132750.ptd 第69頁 1231298 五、發明說明(65) 曱基- 1 Η -吼σ坐 使用4- [(4-異丙基苯基)曱基]-5-甲基-3-(2, 3, 4, 6-四 - 0 -乙醯基-冷-D - 17比喃葡萄糖氧基)- 1 Η -吼σ坐代替4 - [(4 -異 丙氧基苯基)曱基]-5-甲基-3 -(2, 3, 4,6 -四-0-乙醯基-/3-D-咄喃葡萄糖氧基)-1 Η-咄唑,以參考例3 7同樣之方法合 成標題化合物。 ]H-NMR (CD3〇D) δ ppm: 1.20 (6H, d, 1=6. 9Hz), 2.05 (3H, s), 2.75-2.90 (1H, m), 3.25-3.45 (4H, m), 3.55-3.90 (4H, m), 5.00-5.10 (1H, m), 7.00-7.15 (4H, m) 參考例48 3- ( /5-D-吼喃葡萄糖氧基)-4-[(4-甲硫基苯基)曱基]-5-三氣曱基- 1 Η - p比°坐 使用4-[(4-曱硫基苯基)曱基]-3-(2,3,4,6-四-0-乙醯 基- /3-D-吡喃葡萄糖氧基)-5 -三氟曱基-1H-吡唑代替 4- [(4-異丙氧基苯基)曱基]-5-甲基-3-( 2, 3, 4,6 -四-0-乙 酿基-/3 - D - 17比喃葡萄糖氧基)-1 Η -吼°坐,以參考例3 7同樣 之方法合成標題化合物。 ]H —NMR (CD3〇D) δ ppm: 2.42 (3H, s), 3.25-3.50 (4H, m), 3.69 (1H, dd, J=4.9, 12.0Hz), 3.75-3.90 (3H, m), 4.90-5.10 (1H, m), 7.10-7.20 (4H, m) 參考例4 9 4-苄基-3-( /3 -D-咄喃葡萄糖氧基)-5-三氟曱基-1H-咄唑 使用4-辛基-3-(2,3,4,6-四-0-乙酿基-/5 - D- 口比喃葡萄 糖氧基)-5 -三氟曱基-1H-吼唑代替4-[(4 -異丙氧基苯基)
C:\2D-CODE\91-03\90132750.ptd 第70頁 1231298 五、發明說明(66) 曱基]- 5-甲基-3 -(2,3,4,6-四-0-乙醢基-/3 - D - σ比0南葡萄 糖氧基)-1 Η -吼唑,以參考例3 7同樣之方法合成標題化合 物。 ]Η — NMR (CD3〇D) δ ppm. 3.25-3.45 (4H, m), 3.67 (1H, dd, J=5.3, 12.0Hz), 3.80-3.95 (3H, m), 4.97 (1H, d, J=7.4Hz), 7.05-7.25 (5H, m) 參考例5 0 3-( y? - D-吼11南葡萄糖氧基)- 4-[(4-甲氧基苯基)曱基]- 5-三氟*甲基-1 Η -吼17坐 使用4-[(4-甲氧基苯基)甲基]-3 -(2, 3, 4, 6 -四-0-乙醯 基- 南葡萄糖氧基)_5-三氟曱基-1H - 11比唾代替4- [(4-異丙氧基苯基)甲基]-5-曱基-3-(2, 3, 4, 6-四-0-乙醯 基- /5 - D - σ比喃葡萄糖氧基)-1 Η - ϋ比唑,以參考例3 7同樣之 方法合成標題化合物。 ]H-NMR (CD3〇D) 6 ppm: 3.25-3.45 (4H, m), 3.67 (1H, d, J=5.4, 12.1Hz), 3.73 (3H, s), 3. 75-3. 90(3H, m), 4.90-5.00 (1H, m), 6.70-6.85 (2H, m), 7.05-7.15 (2H, m) 參考例5 1 3 -()S-D-吼11南葡萄糖氧基)-4 - [(4-甲氧基苯基)甲基]_5-曱基-1 Η -吼哇 使用4_[(4-甲氧基苯基)甲基]-5 -甲基-3-(2,3,4,6-四 -0-乙醯基-冷-D-吼喃葡萄糖氧基)-1Η-吼唑代替4- [ (4-異 丙氧基苯基)曱基]-5-曱基-3-(2,3,4,6-四-0-乙酿基-)(5 - D - °比喃葡萄糖氧基)-1 Η _呲唑,以參考例3 7同樣之方法合
C:\2D-C0DE\91-03\90132750.ptd 第71頁 1231298 五、發明說明(67) 成標題化合物。 ]H — NMR (CD3〇D) δ ppm: 2.04 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.73 (3H, s), 3.80^3.90 (1H, m), 5.00-5.10 (1H, m), 6.75-6.85 (2H, m), 7.05-7.15 (2H, m) 參考例5 2 4一苄基一3-(冷-D-口比喃葡萄糖氧基)一5-曱基一 1H- 口比唾 使用4一辛基一5-曱基一3 -(2,3,4,6-四一 0-乙酿基一 /3 - D-口比 喃葡萄糖氧基)-1Η-吼唑代替4-[(4-異丙氧基苯基)曱 基]-5-甲基-3-(2,3,4,6-四-0-乙酿基-/5-1)-1?比喃葡萄糖 氧基)-1 H-吡唑,以參考例3 7同樣之方法合成標題化合 物。 ^-NMRCCDgOD) (5ppm: 2.05 (3H, s), 3.25-3.45 (4H, m), 3.60-3.90 (4H, m), 5.00-5.10 (1H, m), 7.05-7.25 (5H, m) 參考例5 3 3-( /3-D-吼喃葡萄糖氧基)-4-[(4-甲氧基苯基)曱 基]- 1,5 -二曱基咄唑 使用4-[(4-甲氧基苯基)曱基]-1,5 -二甲基-3-( 2, 3, 4, 6 -四一 0 -乙醯基一万一 D -吼喃葡萄糖氧基)吼口坐代替4 一 [( 4 一異 丙氧基苯基)曱基]-5-曱基-3 -(2,3,4,6 -四-0-乙酿基- /3 - D - σ比喃葡萄糖氧基)-1 Η - 11比σ坐,以參考例3 7同樣之方法合 成標題化合物。 】Η —NMR (CD3〇D) δ ppm: 2.06 (3H, s), 3.25-3.45 (4H, m), 3.55-3.70 (6H, m), 3.73 (3H, s), 3.75-3.90 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.05-7.15 (2H, m)
C:\2D-C0DE\91-03\90132750.ptd 第72頁 1231298 五、發明說明(68) 參考例54 3- ( /5 -D- nb喃葡萄糖氧基)-1-曱基-4-[(4-曱硫基苯基)曱 基]- 5 -三氣甲基σ比吐 使用卜曱基-4-[(4-甲硫基苯基)甲基]-3-(2, 3, 4, 6 -四-0 -乙醯基-/3 - D -吼喃葡萄糖氧基)- 5 -三氟甲基吼峻代替 4- [(4 -異丙氧基苯基)甲基]-5-曱基-3-(2,3,4,6-四-0-乙 醯基-/3 - D -吼喃葡萄糖氧基)- 1 Η - ϋ比唾,以參考例3 7同樣 之方法合成標題化合物。 ^-NMR (CD3〇D) δ ppm: 2.42 (3H, s), 3.30-3.50 (4H, m), 3.69 (1H, dd, J=4.7, 12.0Hz), 3.75-3.90 (6H, m), 5.25-5.35 (1H, m), 7.05-7.20 (4H, m) 參考例5 5 1-乙基-3 -( - D- σ比喃葡萄糖氧基)-4 - [(4-曱硫基苯 基)- 5 -三說曱基吼。坐 使用1-乙基-4-[(4-甲硫基苯基)曱基]-3-(2, 3, 4, 6 -四-0 -乙醯基-/3 - D - °比喃葡萄糖氧基)-5 -三氟曱基吼嗤代替 4 - [(4-異丙氧基苯基)曱基]_5-曱基-3-(2, 3, 4, 6-四-0-乙 醯基-冷-D -吼喃葡萄糖氧基)-1 Η -吼唾,以參考例同樣之 方法合成標題化合物。 ]H-NMR (CD3OD) δ p pm : 1.38 (3H, t, J=7.1Hz), 2.42 (3H, s), 3.30-3.50 (4H, m), 3.60-3.75 (1H, m), 3.75-3.90 (3H, m), 4.14 (2H, q, J=7.1Hz), 5.25-5.35 (1H, m), 7.05-7.20 (4H, m)
C:\2D-C0DE\91-03\90132750.ptd 第73頁 1231298 五、發明說明(69) 參考例5 6 3- ( /3 -D-吼喃葡萄糖氧基)-4-[(4-甲硫基苯基)甲基]-;1 -丙基-5 -三氟曱基p比唾 使用4-[(4-曱硫基苯基)甲基]-1 -丙基-3-(2, 3, 4, 6-四 -0-乙醯基-石-D-咄喃葡萄糖氧基)-5-三氟曱基咄唑代替 4- [(4 -異丙氧基苯基)曱基)-5-甲基-3-(2,3,4,6_四-0-乙 醯基-/5 -D-咄喃葡萄糖氧基)-1Η-咄唑,以參考例37同樣 之方法合成標題化合物。 】H-NMR (CD3〇D) δ ppm: 0.90 (3H, t, ]=7.4Hz), 1.75-1.90 (2H, m), 2.42 (3H, s), 3.30-3.50 (4H, m), 3.69 (1H, dd, 1=4.9, 12.0Hz), 3.75-3.90 (3H, m), 4.00-4.10 (2H, m), 5.25^5.35 (1H, m), 7.05-7.20 (4H, m) 參考例5 7 3-( /3 -D-吼喃葡萄糖氧基)-5-甲基-4-[(4-曱基苯基)甲 基]-1 Η -吼吐 使用1,2 -二氫-5-曱基-4 - [(4-曱基苯基)甲基]- 3Η_吡唑 -3-酮代替1,2 -二氫-4- [(4-異丙氧基苯基)曱基]-5-曱基 - 3 Η -吼峻-3 -嗣,以參考例1 7同樣之方法合成5 -曱基- 4 -[(4-曱基苯基)甲基]-3-(2, 3, 4, 6-四-0-乙醯基- /3-D-咄 喃葡萄糖氧基)-1Η-吼唑。其次使用5-曱基-4-[ (4-甲基苯 基)曱基]- 3 -(2,3,4,6-四-0-乙酿基-冷- D-0比喃葡萄糖氧 基)-1Η -吼唑代替4-[(4 -異丙氧基苯基)甲基]-5-甲基-3-(2, 3, 4, 6-四-0-乙醯基一 /3 - D-11比喃葡萄糠氧基)-1Η-口比 唑,以參考例3 7同樣之方法合成標題化合物。
C:\2D-00DE\91-03\90132750.ptd 第74頁 1231298 五、發明說明(70) ]H-NMR (CD 3OD) δ ppm: 2.04 (3Η, s), 2.26 (3H, s), 3.25-3.45 (4H, m), 3.55-3.90 (4H, m), 5.00-5.10 (1H, m), 6.95-7.15 (4H, m) 參考例5 8 4-[(4-乙基苯基)甲基]-3 -( /3 - D-吼喃葡萄糖氧基)-5-曱 基-1 Η -吼σ坐 使用4- [(4-乙基苯基)曱基]-1,2 -二氫-5-曱基-3Η比唑 - 3-酮代替1,2-二氫-4 -[(4 -異丙氧基苯基)曱基]- 5-甲基 - 5 Η -吼ϋ坐-3 -酮,以參考例1 7同樣之方法合成4 - [( 4 -乙基 苯基)甲基]一5-曱基一 3 -(2,3,4,6-四一0-乙酿基-冷—D-口比口南 葡萄糖氧基)-1Η-吼唑。其次使用4- [(4-乙基苯基)曱基] -5-曱基-3 -(2,3,4,6-四-0-乙醯基-β - D-吼°南葡萄糖氧 基)-1Η-吼唑代替4-[(4 -異丙氧基苯基)曱基]- 5-甲基 一3-(2,3,4,6-四一 0—乙醢基一召一D-口比口南葡萄糖氧基)一 1Η-口比 唑,以參考例3 7同樣之方法合成標題化合物。 ]H — NMR (CD3〇D) δ ppm: 1.18 C3H, t, J=7. 6Hz), 2.04 (3H, s), 2.57 (2H, q, J=7.6Hz), 3.25-3.45 (4H, m), 3.55-3.90 (4H, m), 5.00-5.10 (1H, m), 6.95-7.20 (4H, m) 參考例5 9 3-( y5-D- 11比鳴葡萄糖氧基)-4 - [(4-甲基苯基)甲基]- 5-三 氟曱基-1 Η-咄唑 使用1,2 -二氫-4-[ (4-甲基苯基)甲基]- 5-三氟甲基-3Η -口比17坐-3 -酮代替1,2 -二氫-4 - [(4-曱硫基苯基)甲基]- 5-三 敗曱基- 3 Η - °比σ坐- 3 - _,以參考例2 8同樣之方法合成
C:\2D-C0DE\91-03\90132750.ptd 第75頁 1231298 五、發明說明(71) 4- [ (4-甲基苯基)曱基]-3-(2, 3, 4, 6 -四-0-乙醯基-)5-D-口比σ南葡萄糖氧基)- 5-三It曱基-1Η_σ比〇坐。其次使用4-[(4 -曱基苯基)曱基]-3-( 2, 3, 4, 6-四-0-乙醯基-冷-D-吼喃葡 萄糖氧基)-5-三氟甲基-1Η-吼唑代替4-[(異丙氧基苯基) 曱基]-5-曱基-3-(2, 3, 4, 6-四-0-乙醯基_ /3 -D-咄喃葡萄 糖氧基)-1 Η - σ比唾,以參考例3 7同樣之方法合成標題化合 物。 3.70-3.90 (3H, m), 】Η一NMR (CD3〇D) δ ppm: 2.25 (3H, s), 3.20^3.45 (4H, m), 3.55-3.70 (1H, m) 4.80-4.95 (1H, m), 6.90-7.15 (4H, m) 參考例6 0 4- [ (4-乙基苯基)曱基]-3-( -D-吼喃葡萄糖氧基)-5_三 氟曱基-1 Η-咄唑 使用4-[(4-乙基苯基)曱基]-1,2 -二氫-5 -二氟曱基-3Η-咄唑-3 -酮代替1,2 -二氫-4- [(4-曱硫基苯基)曱基]-5-三 氟曱基- 3 Η -吼σ坐- 3 -酮,以參考例2 8同樣之方法合成 4 - [(4-乙基苯基)曱基]-3 -(2, 3, 4, 6-四-0-乙醯基-吡喃葡萄糖氧基)-5 -三氟曱基-1H-咄唑。其次使用4[ (4-乙基苯基)甲基]- 3 -(2,3,4,6-四-0-乙酿基- /5 - D-吼11南葡 萄糖氧基)-5 -三氟曱基-1H-吼唑代替4-[(4 -異丙氧基苯 基)甲基]一5-曱基一 3-(2, 3, 4, 6-四一0-乙醯基-冷一D -吼喃葡 萄糖氧基)-1 H-吼唑,以參考例37同樣之方法合成標題化 合物。
C:\2D-CODE\91-03\90132750.ptd 第76頁 1231298 五、發明說明(72) 】H —NMR (CD3〇D) δ ppm: 1.18 (3H, t, I=7.6Hz)? 2.50-2.60 (2H, m), 3.15-3.40 (4H, m), 3.55-3.65 (1H, m), 3.70-3.90 (3H, m), 4.80-4.95 (1H, m), 6.95-7.15 (4H, m) 參考例6 1 3- ( /3-D-吼喃葡萄糖氧基)-4-[ (4-異丙基苯基)曱基]-5-三氟i曱基-1 Η -吼。坐 使用1,2 -二氫-4- [(4-異丙基苯基)曱基]- 5-三氟曱基 - 3Η-咄唑-3 -酮代替1,2 -二氫-4- [(4-甲硫基苯基)曱基 ]- 5 -三I甲基-3 Η -吼°坐-3 - S同,以參例2 8同樣之方法合成 4- [(4-異丙基苯基)甲基]-3 -(2, 3, 4,6 -四-0-乙醯基- /3 -D-咄喃葡萄糖氧基)-5-三氟曱基-1Η-吡唑。其次使用 4- [(4-異丙基苯基)曱基]-3-(2, 3, 4, 6 -四-0-乙醯基-/5 -D -咄喃葡萄糖氧基)-5 -三氟曱基-1Η-咄唑代替4-[ (4-異 丙氧基苯基)甲基]- 5 -甲基-3 -(2,3,4,6 -四-0-乙酿基-/3 - D - 11比喃葡萄糖氧基)-1 Η -吼唾,以參考例3 7同樣之方法合 成標題化合物。 lH-NMR (CD3〇D) δ ppm: 1.20 (6H, d, 1=6. 9Hz), 2.75-2.85 (1H, m), 3.15-3.40 (4H, m), 3.55-3.65 (1H, m), 3.70-3.90 (3H, in), 4.80-4.95 (1H, m), 7.00-7.15 (4H, m) 參考例6 2 4- [ (4-氣苯基)曱基]-3-( /5-D-吼喃葡萄糖氧基)-5-三氟 甲基-1H-咄唑 使用4-[(4-氣苯基)曱基]-1,2 -二氫-5 -三氟曱基-3H-口比 唑-3 -酮代替1,2 -二氫-4- [(4-甲硫基苯基)曱基]-5-三氟
C:\2D-C0DE\91-03\90132750.ptd 第77頁 1231298 五、發明說明(73) 曱基-3 Η -吼ϋ坐-3 -酮,以參考例2 8同樣之方法合成4 - [(4 -氯苯基)曱基]- 3 -(2,3,4,6-四-0-乙酿基-/3 - D-u比喃葡萄 糖氧基)-5-三氟曱基-1H-吼唑。其次使用4-[(4_氣苯基) 甲基]-3-(2, 3, 4, 6 -四-0-乙醯基-/5-D- 口比喃葡萄糖氧 基)-5-三氟甲基-1H-咄唑代替4-[(4-異丙氧基苯基)曱 基]-5-曱基-3-(2, 3, 4, 6 -四-0-乙醯基-/3 -D-咄喃葡萄糖 氧基)-1 Η - p比唾,以參考例3 7同樣之方法合成標題化合 物。 】H —NMR (CD3〇D) δ ppm: 3.20-3.40 (4H, m), 3.55-3.70 (1H, m), 3.75-3.90 (3H, m), 4.80-4.95 (lH,m), 7.10-7.25 (4H, m) 參考例6 3 3-( /5 - D-吼喃葡萄糖氧基)-4-[(4-異丙氧基苯基)甲 基]- 5-甲基-1-丙基吼°坐 於3-( /3 -D-吼喃葡萄糖氧基)-4- [(4 -異丙氧基苯基)曱 基]-5-甲基-1 Η-咄唑(50毫克)及碳酸鉋(0· 20克)之N,N-二 甲基曱醯胺(1毫升)懸浮液中,於50 °C下加入卜丙基碘(0· 036毫升)且攪拌一晚。於反應混合物中加水,並以ODS固 層萃取法(洗淨溶劑:蒸餾水,溶出溶劑:曱醇)精製。所得 之粗精製物以矽膠柱層析(溶出溶劑:二氣曱烷/曱醇= 8/1) 精製,取得3-( f-D-吼喃葡萄糖氧基)-4-[(4-異丙氧基苯 基)甲基]-5-甲基-1-丙基吼唑(28毫克)。
C:\2D-CODE\91-03\90132750.ptd 第78頁 1231298 五、發明說明(74) ]H-NMR (CD3OD) δ ppm: 0.87 (3H, t, J=7.4Hz), 1.26 (6H, d, J=6.0Hz), 1.65-1.80 (2H, m), 2.07 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.75-3.95 (3H, m), 4.40-4.60 (1H, a 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m) 參考例6 4 1-乙基-3 -(々-D_p比喃葡萄糖氧基)-4 - [(異丙氧基苯基)甲 基]- 5 -曱基吼唾 使用乙基碘代替1 -丙基碘,以參考例6 3同樣之方法合成 標題化合物。 ^-NMR (CD3OD) δ ppm : 1.26 (6H, d, J=6.0Hz), 1.29 (3H, t, J=7.2Hz), 2.08 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.75-3.90 (1H, m), 3.96 (2H, q, J=7.2Hz), 4.40-4.60 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m) 參考例6 5 1-乙基-3-( 吼喃葡萄糖氧基)-4- [(4-甲氧基苯基)甲 基]- 5 -曱基吼嗤 使用3-( /3-D-吼喃葡萄糖氧基4-[(4-甲氧基苯基)曱 基]- 5-曱基-1Η-σ比唾代替3-( - D-吼11南葡萄糖氧基)-4-[ (4 -異丙氧基苯基)甲基]_5-甲基-1H_咣唑、使用乙基碘代 替1 -丙基碘,以參考例6 3同樣之方法合成標題化合物。 ]H-NMR (CD3OD) δ ppm: 1.29 (3H, t, J=7.1Hz), 2.07 (3H, s), 3.20-3.45 (4H, m), 3.55-3.75 (6H, m), 3.82 (1H, dd, J=2.0, 12.0Hz), 3.90-4.05 (2H, m), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.05-7.15 (2H, m) 參考例6 6
第79頁 C:\2D-C0DE\91-03\90132750.ptd 1231298 五、發明說明(75) 3- (万- D-吼喃葡萄糖氧基)-4-[(4-曱氧基苯基)曱基]-5-曱基- 1 -丙基吼ϋ坐 使用3-(石-D-吼喃葡萄糖氧基)-4- [ (4-甲氧基苯基> 甲 基]-5-甲基-1 Η-吼唑代替3-(D-吼喃葡萄糖氧 基4-[(4 -異丙氧基苯基)甲基]-5-曱基-1 Η-吼唑,以參 考例6 3同樣之方法合成標題化合物。 ]H-NMR (CD3〇D) δ ppm: 0.87 (3H, t, J=7.5Hz), 1.65-1.80 (2H, m), 2.07 (3H, s), 3.35-3.45 (4H, m),
3.60-3.75 (3H, m), 3.73 (3H, s), 3.75-3.85 (1H, m), 3.85-3.95 (2H, m), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.00-7.15 (2H, m) 參考例6 7 卜乙基-4-[(4-乙氧基苯基)曱基]-3-( /3-D-吼喃葡萄糖氧 基)_ 5 -曱基ϋ比峻 使用4-[(4-乙氧基苯基)曱基]-3冷-D-吼喃葡萄糖氧 基)_5-曱基-1Η - 17比σ坐代替3 -( 南葡萄糖氧基)- 4-
[(4 -異丙氧基苯基)曱基]-5-曱基-1H-吼唑、使用乙基碘 代替1 -丙基碘,以參考例6 3同樣之方法合成標題化合物。 ]H-NMR (CD3OD) δ ppm: 1.28 (3H, t, J=7.4Hz), 1.34 (3H, t, J=7.2Hz), 2.07 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.75-3.85 (1H, m), 3.90-4.00 (4H, m), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.00-7.15 (2H, m) 參考例68 4- [(4-乙氧基苯基)曱基]-3 -(《-D-吼喃葡萄糖氧基)-5-
C:\2D-CODE\91-03\90132750.ptd 第80頁 1231298 五、發明說明(76) 曱基- 1 -丙基吼。坐 使用4- [ (4-乙氧基苯基)甲基]-3-( /3-D-吼喃葡萄糖氧 基)-5-甲基-1H-吼唑代替3-( /3 -D-吼喃葡萄糖氧基)-4-[(4 -異丙氧基苯基)甲基]-5-甲基-1H-吼唑,以參考例63 同樣之方法合成標題化合物。 ]H-NMR (CD3〇D) δ ppm: 0.87 (3H, t, J=7.6Hz), 1.34 (3H, t, J=7.1Hz), 1.65-1.80 (2H, m), 2.07 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.81 (1H, dd, J=2.1, 12.1Hz),
3.85-4.05 (4H, m), 5.00-5.10 (1H, m), 6.70-6.85 (2H, m), 7.00-7.15 (2H, m) 參4例6 9 1-乙基-4 -[(4-乙基苯基)曱基]- 3-( >5 - D-吼喃葡萄糖氧 基)-5 -曱基吼唑 使用4-[ (4-乙基苯基)曱基]-3-( /3 -D-吼喃葡萄糖氧基) -5-曱基-1H-吼唾代替3 -( y3-D-吼喃葡萄糖氧基)-4-[(4 -異丙氧基苯基)曱基]-5-甲基-1 Η-吼唑、使用乙基碘代替 卜丙基碘,以參考例6 3同樣之方法合成標題化合物。 ^-NMR (CD3〇D) δ ppm: 1.17 (3H, t, J=7.6Hz), 1.28 (3H, t, J=7.2Hz), 2.06 (3H, s), 2.56 (2H, Q,
J=7· 6Hz),3.25-3.45 (4H, m),3.55_3·75 (3H, m), 3.75-3·85 (1H,m)’ 3.90-4.00 (2H, m), 5.00-5.10 (1H, m), 7.00-7.15(4H, m) 參考例70 4- [(4-乙基苯基)曱基]-3-( /5 -D-吼喃葡萄糖氧基)-5-甲 基- 1 -丙基ϋ比唾 使用4-[(4-乙基苯基)曱基]-3-( /5 -D-吼喃葡萄糖氧基)
C:\2D-CODE\91-03\90132750.ptd 第81頁 1231298 五、發明說明(77) -5-曱基-1H-P比峻代替3 -(冷- D-1"比喃葡萄糖氧基)- 4-[(4 -異丙氧基苯基)甲基]-5-曱基-1 Η-吼唑,以參考例63 同樣之方法合成標題化合物。 ]H-NMR (CD3〇D) δ ppm: 0.87 (3H, t, J=7.4Hz), 1.17 (3H, t, J=7.6Hz), 1.65-1.80 (2H, m), 2.06 (3H, s), 2.56 (2H, q, J=7.6Hz), 3.25-3.45 (4H, m), 3.60-3.95 (6H, m), 5.00- 5.10 (1H, m), 7.00-7.15 (4H, m) 參考例71 卜丁基-3_( /3-D-吼喃葡萄糖氧基)-4-[(4 -異丙氧基苯基) 甲基]-5 -甲基咄唑 使用1 -溴基丁烷代替1 -丙基碘,以參考例6 3同樣之方法 合成標題化合物。 ]H-NMR (CD3OD) δ p pm : 0.92 (3H, t, J=7.4Hz), 1.20-1.40 (8H, m), 1.60-1.75 (2H, m), 2.07 (3H, s), 3.25-3.45 (4H, m), 3.55-3.75 (3H, m), 3.81 (1H, dd, J=2.1, 12.0Hz), 3.91 (2H, t, J=7. 2Hz), 4.45-4.55 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m) 參考例7 2 3-( /3-D-吼喃葡萄糖氧基)-4-[(4-異丙氧基苯基)甲 基]-1-異丙基-5-甲基σ比峻 使用2-溴基丙烷代替卜丙基碘,以參考例63同樣之方法 合成標題化合物。 ]H-NMR (CD3OD) δ ppm: 1.26 (6H, d, J = 6.0Hz), 1.30-1.40 (6H, m), 2.08 (3H, s), 3.15-3.45 (4H, m),
C:\2D-00DE\91-03\90132750.ptd 第82頁 1231298 五、發明說明(78) —~ 3.55-3.75 (3H, m), 3. 78 (1H, dd, J=2.3, 12.0Hz), 4.35-4.45 (1H, m), 4.45- 4.55 (1H,m),5. 00-5· 10 (1H, m),6.70-6.80 (2H, m), 7. 00-7·1〇 (2H,m) 參考例73 4-[(4-乙硫基笨基)曱基]一12一二氫一5-曱基一3H-d比唑—3 — 酮 於4乙石爪基卞醇(8. 3克)及三乙胺(6·9毫升)之四氫p夫喃 (20$毫升)溶液中,將甲烷磺醯氣(3· 8毫升)於0 °C下加入 士授摔1小斤時,濾除不溶物。將所得之甲烷磺酸私乙硫基 辛S旨之四氫吱喃溶液,加至氫化鈉(6〇%,2· 2克)及乙醯醋 酸甲醋(5· 3毫升)之l 2一二甲氧基乙烷(2〇〇毫升)懸浮液 中,且於80 °C攪拌一晚。於反應混合物中加入飽和碳酸氫 鈉水溶液’並以二***萃取。有機層以飽和食鹽水洗淨, 以無水硫酸鎂乾燥後,減壓下蒸除溶劑。於殘渣之甲苯 (150¾:升)溶液中加入肼-水合物(7.2毫升),且於go °c授 拌1小時。將反應混合物於0 °C中冷卻,再攪拌1小時。遽 取析出物後,以水及己院予以洗淨,取得4 - [( 4 -乙硫基苯 基)曱基]-1,2-二氫-5-曱基-3H-吡唑-3-酮(1· 5克)。 ^-NMR (DMS〇-d6) δ ppm: 1.19 (3H, t, J = 7.3Hz), 2.00 (3H, s), 2.90 (2H, q, J=7.3Hz), 3.51 (2H, s), 7.05-7.15 (2H, m), 7.15-7.25 (2H, m) 參考例7 4 4 - [(4-乙硫基苯基)曱基]- 5-甲基-3 -(2,3,4,6-四-〇-乙醯 基- /3 - D - °比ϋ南葡萄糖氧基)-1 Η -吼0坐 於4-[(4-乙硫基苯基)曱基]-1,2-二氫-5-甲基-3Η - ρ比嗤
C:\2D-C0DE\91-03\90132750.ptd 第 83 頁 1231298 五、發明說明(79) - 3 -酮(1.6克)及乙醯溴基-a-D-葡萄糖(2·9克)之四氫呋 喃(3 0毫升)懸浮液中,加入碳酸銀(2 · 1克),將反應容器 遮光且於6 0 °C攪拌一晚。將反應混合物以胺丙基矽膠柱層 析(溶出溶劑:己烷/醋酸乙酯= 1/3)精製,取得4-[ (4-乙硫 基苯基)曱基]- 5-甲基-3-(2,3,4,6-四-〇-乙酿基_ /3-0-口比 喃葡萄糖氧基)-1 Η - p比唾(1 · 4克)。 b-NMR (CDC 1 3) δ ppm: 1.28 (3H, t, J=7.4Hz), 1.88 (3H, s), 2.01 (3H, s), 2.03 (3H, s), 2.06 (3H, s), 2.11 (3H, s), 2.89 (2H, q, J=7.4Hz), 3.56 (1H, d, J = 15.9Hz), 3.62 (1H, d, J = 15.9Hz), 3.80-3.90 (1H, m), 4.13 (1H, dd, J = 2.3, 12.6Hz), 4.31 (1H} dd, J=3.9, 12.6Hz), 5.15-5.35 (3H, m), 5.55-5.65 (1H, m), 7.00-7.10 (2H, m), 7.15-7.25 (2H, m), 8.79 (1H, brs) 參考例7 5 4-[ (4-乙硫基苯基)曱基]-3-( /5 -D -吼喃葡萄糖氧基)-5-甲基- 1 Η -吼σ坐 於4-[ (4-乙硫基苯基)甲基]-5 -甲基-3-(2, 3, 4, 6-四-0-乙醮基-冷-D -吼喃葡萄糖氧基)- 1 Η -咄。坐(1 · 3克)之曱醇 (10毫升)中加入曱醇鈉(28%甲醇溶液、0.13毫升),並於 室溫攪拌1小時。將反應混合物於減壓下濃縮,殘渣以矽 膠柱層析(溶出溶劑:二氯曱烷/曱醇= 5/1)精製,取得 4 - [(4-乙硫基苯基)曱基]- 3-( y3-D-p比ρ南葡萄糖氧基)-5-甲基-1Η-咄唑(0· 87克)。 4一NMR (CD3〇D) δ ppm: 1.24 (3H, t, J=7.3Hz), 2.06 (3H, s), 2.88 (2H, q, J=7.3Hz), 3.30-3.45 (4H, m), 3.60-3.80 (3H, m), 3.80-3.90 (1H, m), 5.00-5.10 (1H, m), 7.10-7.30 (4H, m)
C:\2D-00DE\91-03\90132750.ptd 第84頁 1231298
參考例7 6 糖氧基)-4-[ (4_異丙氧 1 -(苄氧幾基)- 3-( y3-D-吼喊葡萄 基苯基)曱基]- 5-甲基吼哇 美Γ Λ 氧基)'w(4-異丙氧基苯基)曱 ί τ Λ 坐(1.3克)之四氫咬喃(3〇毫升)溶液中 加入Ν-(卞氧羰氧基)琥抬醯亞胺(1. 6克),並加熱迴流一 晚。將反應混合物於減壓下濃縮,殘渣以矽膠柱層析(溶 出溶劑:一氣甲烧/甲醇=10/1)精製,取得卜(芊氧羰基) -3-( /3-D-吡喃葡萄糖氧基)-4-[ (4一異丙氧基苯基)曱基] -5-甲基咄唑(1· 3克)。 1 H-NMR ( CDC 13 ) (5ppm: 1.27 (6H, d, J=6.3Hz), 2.35 (3H, s), 3.45-3.70 (6H, m), 3.76 OH, dd, J=4.5, 12.0Hz), 3.85 (1H, dd, J=2.8, 12.0Hz), 4.40-4.50 (1H, m), 5.30-5.40 (2H, ,m), 5.48 (1H, d, J=8.0Hz), 6.70-6.80 (2H, m), 6.95-7.05 (2H, m), 7*25-7.50 (5H, m) 參考例7 7 1 -( ¥氧幾基)- 3- (6-0-乙氧艘基-点- D_p比喃葡萄糖氧 基)-4-[(4-異丙氧基苯基)甲基]- 5-甲基11比吐 於1 -(苄氧叛基)-3 -( 鳴葡萄糖氧基)- 4-[(4-異 丙氧基苯基)曱基]-5-曱基咄唑(〇·20克)之2, 4, 6〜三甲基 咄啶(4毫升)溶液中加入氣曱酸乙酯(0.092毫升),並於室 溫攪拌1日。於反應混合物中加入水及檸檬酸—水合物,且 以醋酸乙酯萃取。有機層以水洗淨,以無水硫酸鎂乾燥
C:\2D-00DE\91-03\90132750.ptd 第85頁 1231298 五、發明說明(81) 後,減壓下蒸除溶劑。殘渣以矽膠柱層析(溶出溶劑:二氯 曱烷/曱醇= 10/1)精製,取得卜(苄氧羰基)-3-(6-0-乙氧 羰基-/3-D-吼喃葡萄糖氧基)_4-[(4-異丙氧基苯基)甲基] - 5 -曱基咄唑(0 · 1 7克)。 ]H-NMR (CD3〇D) (5 ppm: 1.19 (3H, t, J=7. 1Hz), 1.26 (6H, d, J=6.0Hz), 2.36 (3H, s), 3.30-3.50 (3H, m), 3,50-3.75 (3H, m), 4.10 (2H, q, J=7.1Hz), 4.25-4.35 (1H, m), 4.35-4.45 (1H, m), 4.45-4.60 (1H, m), 5.35-5.45 (2H, m), 5.45-5.60 (1H, m), 6.70-6.85 (2H, m), 7.00-7.15 (2H, m), 7.30-7.55 (5H, m) 參考例78 1 -(芊氧羰基)-4-[(4-異丙氧基苯基)甲基]-3-(6-0-曱氧 魏基-/3 - D - 17比喃葡萄糖氧基)- 5 -曱基吼唾 使用氣曱酸曱酯代替氯曱酸乙酯,以參考例7 7同樣之方 法合成標題化合物。 ]Η —NMR (CDC 1 3) (5 ppm: 1.30 (6H, d, J=6.4Hz), 2.43 (3H, s), 3.45-3.70 (6H, m), 3.78 (3H, s), 4.39 (1H, dd, J = 2.2, 11.8Hz), 4.40-4.55 (2H, m), 5.38 (2H, s), 5.40-5.50 (1H, m), 6.70-6.85 (2H, m), 7.00-7.10 (2H, m), 7.30-7.50 (5H, m) 實施例1 3-(6-0-乙氧羰基_ Θ-D-吼喃葡萄糖氧基)-4-[(4-異丙氧 基苯基)曱基]- ;1-異丙基-5-甲基吼唑 於3-( /3-D-吼喃葡萄糖氧基)-4- [(4-異丙氧基苯基)甲 基]-卜異丙基-5-曱基咄唑(0. 10克)之2, 4, 6 -二甲基咄啶 (1毫升)溶液中加入氣曱酸乙酯(0 · 0 7 2克),並於室溫攪拌
C:\2D-CODE\91-03\90132750.ptd 第86頁 1231298 五、發明說明(82) 一晚。於反應混合物中加入檸檬酸-水合物(3 · 3克)及水, 並以0 D S固層萃取法(洗淨溶劑:蒸镏水、溶出溶劑:曱醇) 精製。再以矽膠柱層析(溶出溶劑:二氯甲烷/甲醇=1 0/ 1 ) 精製後,進行再結晶(再結晶溶劑:醋酸乙酯/己烧=1 / 3), 取得3-(6-0-乙氧羰基-/3-D-咄喃葡萄糖氧基)-4-[(4-異 丙氧基苯基)曱基]- :1-異丙基-5-甲基吼唑(0.084克)。 ]H-NMR (CD3〇D) δ ppm:
1.23 (3H, t, J=7.0Hz), 1.26 (6H, d, J=5.8Hz), 1.30-1.40 (6H, m), 2.07 (3H, s), 3.25-3.45 (4H, m), 3.60-3.70 (2H, m),4.12 (2H, q, J=7.0Hz), 4.2K1H, dd, J=5.4, 11.6Hz), 4.34 (1H, dd, J = 1.7, 11.6Hz), 4.35-4.45 (1H, m), 4.45-4.55 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m) 實施例2〜1 4 以實施例1同樣之方法由對應之原料化合物合成表1之化 合物。
第87頁 C:\2D-00DE\91-03\90132750.ptd 1231298 五、發明說明(83) [表1] 實施例 R R2 Q 2 曱基 甲氧基 曱基 3 曱基 甲硫基 三氟甲基 4 乙基 甲硫基 三氣甲基 5 丙基 甲硫基 三氣甲基 6 丙基 異丙氧基 甲基 7 乙基 異丙氧基 甲基 8 乙基 丁氧基 甲基 9 丙基 丁氧基 甲基 10 乙基 乙氧基 曱基 11 丙基 乙氧基 曱基 12 乙基 乙基 曱基 13 丙基 乙基 曱基 14 丁基 異丙氧基 曱基 實施例1 5 4 - [(4-異丙氧基苯基)曱基]-1-異丙基-3 -(6-0-曱氧羰基-/3 - D -吼喃葡萄糖氧基)- 5 -曱基吼唑 使用氣曱酸曱酯代替氣甲酸乙酯,以實施例1同樣之方 法合成標題化合物。 】H — NMR (CD3〇D) δ ppm: 1.26 (6H, d, J=6.1Hz), 1.30-1.40 (6H, m), 2.07 (3H, s), 3,25-3.45 (4H, m), 3.60-3.70 (2H, m), 3.71 (3H, s), 4.22 (1H, dd, 1=5.2, 11.7Hz), 4.35 (1H, dd, J = 2.1, 11.7Hz), 4.35-4.45 (1H, m), 4.45-4.60 (1H, m), 5.00-5.10(1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m)
C:\2D-C0DE\91-03\90132750.ptd 第 88 頁 五、發明說明(84) 實施例1 6 3-U-0-異丁氧羰基-万咄。南 丙 氧基苯基)甲基卜卜異丙氧基-5-甲基二基> 使用氯甲酸異丁醋代替氯甲之 方法合成標題化合物。 Λ M ^ ]H-NMR (CD3〇D) (5 Ppm: 0.90 (6H, d, J=6.7Hz), 1.26 (6H Η τ c rm、 1 〇 、⑽,d, J=5.9Hz),】·3〇—h4〇 (6H, m) 8〇一 2.00 (1H, m), 2.07 (3H, s), 3.25-3 ς〇 .,π 、。 3*5〇 (4Η, m), 3.60-3.70 (2Η, m), 3.80-3.90 (2H, m), 4.21 (1H, dd, J=5.2 11 π、 , ^-SHz), 4.36 (1H, dd, j = l.8, 11.5Hz), 4.35-4.45 (1H, m), 4.45-4.55 (1M m\ r UH* m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m) 實施例1 7 4-[(4-異丙氧基苯基)曱基]一卜異丙基一 5—甲基一 3一(6一〇一丙 醯基-/3 -D-咄喃葡萄糖氧基)吡唑 於3 -( /5 - D-吼喃葡萄糠氧基)一4 一 [(4一異丙氧基苯基)甲 基]-卜異丙基-5-甲基咣唑(〇1〇克)之2,4,6一三甲基吡啶 (1毫升)溶液中0 °C下加入丙醯氣(〇 · 〇 7 2克),且攪拌5小 時。於反應混合物中加入檸檬酸-水合物(3. 3克)及水,且 以ODS固層萃取法(洗淨溶劑··蒸餾水、溶出溶劑··甲醇)精 製。再以矽膠柱層析(溶出溶劑:二氣甲烷/甲醇=1〇/1)精 製,取得4 - [(4-異丙氧基苯基)甲基]一1 一異丙基一5—甲基 -3 -(6 - 0-丙醯基-沒-D-咄喃葡萄糖氧基)咄唑(〇.克)。 ]H-NMR (CD3〇D) δ ppm : 1.05 (3H, t, J=7.5Hz), 1.26 (6H, d, J=5.9Hz), 1.30-1.40 (6H, m), 2.07 (3H, s), 2.27 (2H, q, J=7. 5Hz), 3.25-3.45 (4H, m), 3, 60-3.70 (2H, m), 4.18 (1H,
C:\2D-00DE\91-03\90132750.ptd 第89頁 1231298 五、發明說明(85) dd, J=5.6, 11.8Hz), 4.30 (1H, dd, J=2.2, 11.8Hz), 4.35-4.45 (1H, m), 4.45-4.55 (1H, m), 5.00-5.10 (1H, m), 6.70-6.80 (2H, m), 7.00-7.10 (2H, m) 實施例1 8 3-(6-0-乙醯基-/5 -D-吼喃葡萄糖氧基)-4-[ (4 -異丙氧基 苯基)甲基]-1 -異丙基-5-曱基^1比哇 使用乙醯氣代替丙醯氯,以實施例1 7同樣之方法合成標 題化合物。 ^-NMR (CD3〇D) δ ppm:
1.26 (6H, d, J=6.4Hz), 1.30-1.40 (6H, m), 1.98 (3H, s), 2.08 (3H, s), 3.25-3.45 (4H, m), 3.60-3.70 (2H, m), 4.16 (1H, dd, J=5.6, 11.8Hz), 4.29 (1H, dd, J=2.0, 11.8Hz), 4.35-4.55 (2H, m), 5.00-5.10 (1H, m), 6. 70-7. 80 (2H, m), 7.00-7.10 (2H, m) 實施例1 9 3-(6-0- 丁醯基-D-吼喃葡萄糖氧基)-4-[(4 -異丙氧基 苯基)曱基]-1-異丙基-5-曱基ϋ比唾 使用丁醯氯代替丙醯氣,以實施例1 7同樣之方法合成標 題化合物。 ]H — NMR (CD3〇D) δ ppm: 1.30-1.40 (6H, m), 1.50- 0.88 (3H, t, J=7.4Hz), 1.26 (6H, d, J=6.0Hz),
1.65 (2H, ,), 2.07 (3H, s), 2.15-2.30 (2H, m), 3,25-3.50 (4H, m), 3.60-3.70 (2H, m), 4.17 (1H, dd, J=5.7, 11.9Hz), 4.31 (1H, dd, J-2.0, 11.9Hz), 4.30-4.55 (2H, m), 5.00-5.10 OH, ,), 6.70-6.80 (2H, ,), 7.00-7.10 (2H, m) 實施例2 0
第90頁 C:\2D-roDE\91-03\90132750.ptd 1231298 五、發明說明(86) 4-[( 4-異丙氧基苯基)曱基]-1-異丙基-5-曱基-3-(6- 0-特 戊醯基-yS - D -吼喊葡萄糖氧基)ϋ比峻 使用特戊醯氯代替丙醯氣,以實施例1 7同樣之方法合成 樣題化合物。 ]H-NMR (CD3〇D) δ ppm: 1.10 (9H, s), 1.26 (6H, d, J = 6.1Hz), 1.30-1.40 (6H, m), 2.06 (3H, s), 3.30-3.45 (4H, m), 3.60-3.70 (2H, m), 4.16 (1H, dd, 1=5.8, 11.7Hz), 4.30 (1H, dd, J=2.0, 11.7Hz), 4.30-4.55 (2H, m), 5.05-5.15 (lH,;m), 6. 70-6. 80 (2H, m), 7.00-7.10 (2H, m) 實施例2 1 1-乙氧幾基-3-(6-0-乙氧叛基-y?-D- °比喃葡萄糖氧基) -4一 [ (4-乙硫基苯基)甲基]一5-曱基吼唑 於4-[(4-乙硫基苯基)曱基]-3_(石_0-吼喃葡萄糖氧基) -5 -曱基-1H-咄唑(0·03克)之2, 4, 6 -二曱基咄啶(0.5毫升) 溶液中加入氣甲酸乙酯(0 · 0 2 1毫升),並於室溫攪拌一 晚。於反應混合物中加入1 0 %擰檬酸水溶液,且以醋酸乙 酯萃取。有機層以無水硫酸鎂乾燥後,減壓下蒸除溶劑。 殘渣以矽膠分取薄層層析(展開溶劑:二氯甲烷/曱醇= 10/1 )精製,取得1-乙氧羰基-3-(6-0_乙氧羰基-万-D-咄喃葡 萄糖氧基)-4- [(4-乙硫基苯基)甲基]-5-甲基吼唑(0. 023 克)。 -NMR (CD3〇D) δ ppm: 1.15-1.30 (6H, m), 1.39 (3H, t, J=7. 1Hz), 2.37 (3H, s), 2.87 (2H, q, 1=7. 3Hz), 3.35-3.50 (3H, m), 3.60-3.80 (3H, m), 4.12 (2H, q, J=7.1Hz), 4.29 (1H, dd, J=5.3, 11.9Hz), 4.35-4.50 (3H, m), 5.50-5.60 (1H, m), 7.10-7.25 (4H, m)
C:\2D-00DE\91-03\90132750.ptd 第91頁 1231298
C:\2D-OODE\91-03\90132750.ptd
第92頁 1231298 五、發明說明(88) [表2 ] 實施例 R R2 Q 22 乙 氧 羰 基 異 丙 氧 基 甲 基 23 乙 氧 羰 基 丙 基 甲 基 24 乙 氧 羰 基 .異 丁 基 甲 基 25 乙 氧 羰 基 丙 氧 基 甲 基 26 乙 氧 羰 基 乙 氧 基 甲 基 27 乙 氧 羰 基 三 氟 甲 基 曱 基 28 乙 氧 羰 基 第 二 丁 基 曱 基 29 乙 氧 羰 基 丁 氧 基 曱 基 30 乙 氧 羰 基 曱 硫 基 曱 基 31 乙 氧 羰 基 . .. 曱 硫 基 乙 基 32 乙 氧 羰 基 異 丙 基 曱 基 33 乙 氧 羰 基 曱 硫 基 二 氟 甲 基 34 乙 氧 羰 基 氫 原 子 二 氟 甲 基 35 乙 氧 羰 基 曱 氧 基 二 氟 甲 基 36 乙 氧 羰 基 曱 氧 基 甲 基 37 乙 氧 羰 基 氫 原 子 曱 基 38 乙 氧 羰 基 曱 基 甲 基 39 乙 氧 羰 基 乙 基 甲 基 40 乙 氧 羰 基 曱 基 — 氟 曱 基 41 乙 氧 羰 基 乙 基 三 氟 曱 基 42 乙 氧 羰 基 異 丙 基 *—_ 氟 曱 基 43 乙 氧 羰 基 氯 原 子 二 氟 甲 基
C:\2D-CODE\91-03\90132750.ptd 第93頁 1231298 五、發明說明(89) 實施例44 3-(6-0-乙氧緣基-/5-D-吼喃葡萄糖氧基)-1 -(乙氧幾氧曱 基)一4- [ (4-曱硫基苯基)曱基]-5-甲基咄唑 於3 -( /3-D-吼喃葡萄糖氧基)-5-甲基-4-[(4-甲硫基苯 基)甲基]-1H-咄唑(0· 1 1克)之水(0· 5毫升)及乙醇(0· 1毫 升)溶液中,加入甲醛(37%水溶液,0· 0 68毫升),並於40 °C攪拌3日。於反應混合物中加入四氫呋喃及無水硫酸 鎂,濾除不溶物,將濾液之溶劑於減壓下蒸除。將殘渣溶 於2,4,6 -三曱基咄啶(1毫升),加入氯曱酸乙酯(0 · 0 9 9 克),並於室溫下攪拌一晚。於反應混合物中加入擰檬酸-水合物(4克)及水,且以ODS固層萃取法(洗淨溶劑:1 0%檸 檬酸、蒸餾水、溶出溶劑:甲醇)精製。再以矽膠柱層析 (溶出溶劑:二氣甲烷/甲醇= 15/1 )精製,取得3-(6-0-乙氧 罗炭基-/3-D- p比喃葡萄糖氧基)-1-(乙氧幾氧曱基)-4 - [(4-曱硫基苯基)甲基]-5-甲基吼唑(0· 0 58克)。 ]H--NMR (CD3OD) δ ppm: 1.23 (3H, t, J=7.1Hz), 1.26 (3H, t, J=7.1Hz), 2.18 (3H, s), 2.42 (3H, s), 3.30-3.45 (3H, m), 3.50-3.60 (1H, m), 3.63 (1H, d, J = 16.0Hz), 3.70 (1H, d J = 16.0Hz), 4.13 (2H, Q, 4.18 (2H, Q, 3=7.1Hz), 4.28 〇H,dd, ]=4.8, 11.7Hz), 4.39 (1H, dd, 1=2.0, 11.7Hz), 5.25-5.35 (1H, m), 5.80- 5.95 (2H, m), 7.10-7.20 (4H, m) 實施例4 5 1-乙醯基-4- [ (4-乙硫基苯基)曱基]-3-( /3 -D-咄喃葡萄糖 氧基)- 5 -甲基p比唾
C:\2D-CODE\91-03\90132750.ptd 第94頁 1231298 五、發明說明(90) 於4-[(4-乙硫基苯基)甲基]-3-( 吼喃葡萄糖氧基) - 5 -甲基-1Η-°比唾(〇·41克)之四氫吱喃(1〇毫升)溶液中, 加入醋酸(0 · 1 1毫升)及醋酸酐(〇 · 1 8毫升),並於室溫搜掉 一晚。反應液於減壓下濃縮,於殘渣中加入二***。據取 析出之結晶,取得1-乙醯基-4 - [(4 -乙硫基苯基)甲基]—3一 (/3 _ D - ϋ比σ南葡萄糖氧基)一 5 -甲基ρ比17坐(〇 · 3 6克)。 1Η - NM R (C D 3 〇 D) δ ppm: 1.24 (3H, t, J=7.3Hz), 2.43 (3H, s), 2.54 (3H, s), 2.89 (2H, Q, J=7.3Hz), 3.30-3.50 (4H, m), 3.60-3.75 (3H, m), 3.80-3.90 (1H, m), 5.45-5.55 (1H, m), 7.10-7. 30 (4H, m) 實施例4 6 1-乙酿基-3-(6-0-乙氧幾基-/5 - D-ab喃葡萄糖氧基)-4-[(4_乙硫基苯基)曱基]-5-曱基吼唑 於1-乙醯基-4-[(4-乙硫基苯基)甲基]- 3 -(万-D-吼喃葡 萄糖氧基)-5-曱基吼唑(〇· 〇3克)之2, 4, 6-三甲基吼啶(〇· 5 毫升)溶液中加入氣曱酸乙酯(〇. 0 1 2毫升),並於室溫攪拌 一晚。於反應混合物中加入1 〇 %彳寧樣酸水溶液(5毫升),並 於室溫攪拌一晚。收集沈澱物,以1 0 %檸檬酸水溶液及水 予以洗淨’取得1-乙酿基-3-(6 - 0_乙氧幾基~ /5 - D- σ比p南葡 萄糖氧基)-4-[(4-乙硫基苯基)甲基]-5-甲基吼唑(〇. 020 克)。 4-NMR (CD3〇D) δ ppm: 1.20 (3H, t, J=7.2Hz), 1.24 (3H, t, J=7.4Hz), 2.41 (3H, s), 2.55 (3H, s), 2.88 (2H, q, J=7.4Hz), 3.30-3.40 (1H, m), 3.40-3.50 (2H, m), 3.50-3.65 OH,
C:\2D-0QDE\91-03\90132750.ptd 第95頁 1231298 五、發明說明(91) m), 3.65 (1H, d, J-15.8Hz), 3.72 (1H, d, J-15.8Hz), 4.05-4.15 (2H, m), 4.27 (1H, dd, J=6.3, 11.7Hz), 4.42 OH, dd, J=2.0, 11.7Hz), 5.40-5.55 (1H, m), 7.10-7.30 (4H, m) 實施例47 3- (6-0_乙氧羰基-/5-D-吼喃葡萄糖氧基)-4- [(4-異丙氧 基笨基)甲基]-5-曱基-1 Η-咣唑 於1-(苄氧羰基)-3-(6-0-乙氧羰基-/3-D-吼喃葡萄糖氧 基)-4 - [(4-異丙氧基苯基)曱基]-5 -曱基°比嗤(0. 17克)之 四氫呋喃(4毫升)溶液中加入1 0 %鈀/碳粉末,氫氛圍氣 下,於室溫攪拌3小時。濾、除不溶物,濾、液之溶劑於減壓 下蒸除。將殘渣以矽膠柱層析(溶出溶劑:二氯曱烷/甲醇 = 10/1 )精製,取得3-(6-0-乙氧羰基-々-D-吼喃葡萄糖氧 基)-4-[(4-異丙氧基苯基)曱基]-5-曱基-1Η-。比唑(0. 10 克)。 ]H-NMR (CD3〇D) δ ppm: 1.23 (3H, t, J=7. 1Hz), 1.26 (6H, d, J=6.0Hz), 2.04 (3H, s), 3.30-3.55 (4H, m), 3.61 (1H, d, J = 15.9Hz), 3.67 (1H, d, J = 15.9Hz), 4.12 (2H, q, J=7.1Hz), 4.27 (1H, dd, J=4.9, 11.7Hz), 4.38 (1H, dd, J=2. 0, 11.7Hz), 4.45-4.60 (1H, m), 5.10-5.20 (1H, m), 6.70-6.80 (2H, m), 7.00-7.15 (2H, m) 實施例48 4- [(4-異丙氧基苯基)甲基]-3-(6-0-甲氧羰基-比喃 葡萄糖氧基)-5-曱基-1 Η-吼唑 使用1-(笮氧羰基)-4-[(4 -異丙氧基苯基)乙基]-3-(6 - 0 -曱氧羰基-冷-D-吼喃葡萄糖氧基)-5-甲基吼唑代替1-(苄
C:\2D-C0DE\91-03\90132750.ptd 第 96 頁 1231298 五、發明說明(92) 氧羰基)-3:(6-0-乙氧羰基_ p-j)-咄喃葡萄糖氧基)_4_ [(4 -異丙氧基苯基)甲基]_ 5 _甲基咄唑,以實施例4 7同樣 之方法合成標題化合物。 ' -NMR(CD30D)(5Ppm: I. 26 (6H, d, J=5.9Hz), 2.04 (3H, s), 3.30-3.55 (4H, ffl), 3.61 〇Η, d, J=15.9Hz), 3.67 (1H, d, J=l5.9Hz), 3.72 (3H, s), 4.28 (1H, dd, J=5 2, II. 7Hz), 4·39 (1H,dd,J=1.8,η·7Ηζ), 4.45-4.55 OH,m), 5.05-5· 15 (1H, m), 6. 70-6. 80 (2H, m), 7.00-7.15 (2H, m) ’ 試驗例1 人類SGLT2活性抑制作用確認試驗 1 )人類SGLT2表現質體載體之製作 參 BRL: LIFE TECHNOLOGIES),將來自人類腎臟之全 RNA(Origene)以寡dT做為引子予以逆轉錄,製作PCr放大 用cDNA引子。以上述人類腎cDNA引子做為模板,將序列編 號1及2所示之下述寡核苷酸〇702F及071 2R使用於引子,並 且經由PCR反應將編碼人類SGLT2之DNA斷片予以放大。經 放大之DNA斷片於克隆用載體pCR - Blunt(Invitrogen)中依 據此套件之標準法進行連接作用。依常法導入大腸桿菌 HB1 01株後,以含有康納黴素50微克/毫升之LB洋菜培養基 籲 選出轉形株。由其中一個轉形株將質體DNA予以萃取精 製,並以序列編號3及4所示之下述之募核苷酸〇71 4F及 071 5R做為引子且經由PCR反應將編碼人類SGLT2之DNA斷片 予以放大。經放大之DNA斷片以限制酶Xhol及Hind 111予 以切開後,以Wizard Purification System (Promega)進
C:\2D-0QDE\91-03\90132750.ptd 第97頁 1231298 五、發明說明(93) 行精製。將此精製之DNA斷片嵌入融合化蛋白質表現用載 體pcDNA3. 1(-)Myc/His-B(Invitrogen)之對應的限制酶部
位。依常法導入大腸桿菌Η B 1 0 1株後,以含有安比西林1 〇 〇 微克/毫升之LB洋菜培養基選出轉形株。由此轉形株將質 體DNA予以萃取精製,調查於載體pcDNA31( —)Myc/His_B 之多克隆部位所***之DNA斷片的鹼基序列。相對於we 11 s 等人所報告之人類SGLT2 (Am. J. Physiol.,Vol· 263, ρρ·459-465 ( 1 9 92 )),此克隆為具有1個鹼基之取代(編碼 第4 33個之異白胺酸的ATC為更換成GTC)。其結果取得第 4 3 3個殘基之異白胺酸更換成纈胺酸之克隆。將此羧基終 立而側最終殘基之丙胺酸下一個開始表現將序列編號5所示 胜肽融合化之人類SGLT2的質體載體稱為KL29。 序列編號1 ATGGAGGAGCACACAGAGGC 序列編號2 GGCATAGAAGCCCCAGAGGA 序列編號3 AACCTCGAGATGGAGGAGCACACAGAGGC 序列編號4 AACAAGCTTGGCATAGAAGCCCCAGAGGA 序列編號5 KLGPEQKLISEEDLNSAVDHHHHHH 2)人類SGLT2-過性表現細胞之調製 將人類SGLT2表現質體KL29以電穿孔法導入COS-7細胞 (RIKEN CELL BANK RCB0539 )。電穿孔法為使用Gene Pulser II (Bio-Rad Laboratories),於相對於0PTI -MEM I 培養基(Gibco-BRL:LIFE TECHNOLOGIES) 50 0 微升含 有COS-7細胞2 x 106個和KL29 20微克之0· 4公分cuvette 内,以0. 29 0KV,975 # F之條件下進行。導入基因後,以
C:\2D-C0DE\91-03\90132750.ptd 第 98 頁 1231298 五、發明說明(94) 離心回收細胞並且相對於細胞lcuvette份加入1毫升0ΡΠ 一 MEM I培養基令其懸浮。將此細胞懸浮液於96孔穴之每1孔 穴中各分注125微升。於37 t、5% C02之條件下培養一晚 後,於每1孔穴中分別加入125微升含有10%胎牛血清(三光 純藥)、100單位/毫升青黴素G鈉(Gibco-BRL:LIFE TECHNOLOGIES)、1〇〇 微克/ 毫升硫酸鏈黴素(Gibc〇_BRL:
LIFE TECHNOLOGIES)之DMEM 培養基(Gibco-BRL:LIFE TECHNOLOGIES)。培養至隔日且供於測定甲基_ α 一D—咄喃 葡萄糖苔攝入之抑制活性。 3)曱基-a -D-咄喃葡萄糖苷攝入抑制活性之測定 將試驗化合物溶解於二甲基亞砜中,並以攝入用緩衝液 (含有140mM氯化鈉、2mM氯化鉀、lmM氣化鈣、ImM氣化 鎮、5mM曱基-α - D-吡喃葡萄糖苔、i〇mM 2- [4-(2 -羥乙 基)-1-旅喷基]乙烷磺酸、5mM三(羥曱基)胺基曱烷之缓 衝液ρΗ7· 4 )予以稀釋,做為抑制活性測定用之檢體。除去 人類SGLT2-過性表現C0S-7細胞之培養基,且於每1孔穴中 加入前處理用緩衝液(含有14〇mM氣化膽鹼、2mM氯化鉀、 1 mM氣化弼、1 mM氣化鎮、1 〇mM 2 - [ 4 -( 2-經乙基)- 1 -呢口丼 基]乙烧確酸、5mM三(羥曱基)胺基甲烷之緩衝液pH7. 4) 2 0 0微升,並於3 7 °C靜置1 〇分鐘。除去前處理用緩衝液, 再度加入相同緩衝液2 〇 〇微升,並於3 7 靜置丨〇分鐘。於 所製作之檢體525微升中加入7微升之曱基—q:—d-(U - 14C) 17比喃葡萄糖苔(Amersham Pharmacia Biotech )並混合, 做為測定用緩衝液。於對照群中調製不含有試驗化合物之
1231298 五、發明說明(95) 測定用緩衝液。又,同樣調製將含有140mM氣化膽鹼之基 礎攝入測定用緩衝液,代替試驗化合物非存在下及納非存 在下之基礎攝入測定用中的氣化鈉。除去前處理用緩衝 液’並每1孔穴各加入75微升之測定用緩衝液且於37 °C靜 置2小時。除去測定用緩衝液,於每1孔穴分別加入洗淨用 緩衝液(含有140mM氯化膽鹼、2mM氣化鉀、ImM氣化鈣、 lmM氯化鎂、i〇mM甲基一 α—D-吼喃葡萄糖苷、i〇mM 2-[4-(2 -羥乙基)一1一哌畊基]乙烷磺酸、5mM三(羥曱基)胺基甲 烧之緩衝液ρΗ7· 4 ) 200微升並立即除去。此洗淨操作再進 行2回’並於每1孔穴分別加入7 5微升之〇 · 2莫耳/升氫氧化 鈉令細胞可溶化。將可溶化液移至Pickle pute (Packard),加入 150 微升之 Microsinch 40(Packard)且以 微平板閃爍計數器Top Count (Packard)計測放射活性。 將基礎攝入量減去對照群攝入量之值視為丨〇〇%,並由濃度 -抑制曲線以最小二平方法算出抑制5 〇%攝入量之濃度(丨‘ 值)。其結果如下表3。
C:\2D-C0DE\91-03\9013275O.ptd 第100頁 1231298 五、發明說明(96) [表3 ]
試驗化合物 IC5Q 值(nM) 參考例3 7 181 參考例3 8 441 參考例3 9 346 參考例4 0 702 參考例4 1 185 參考例4 5 84 參考例4 6 509 參考例47 441 參考例4 8 679 參考例5 0 415 參考例5 1 383 參考例54 835 參考例5 7 280 參考例5 8 190 參考例6 0 634 參考例7 2 369 WAY-123783 >100000 C:\2D-OODE\91-O3\9013275O.ptd 第101頁 1231298 五、發明說明(97) 試驗例? 1.'1收性碹認詖給 1 )以尾靜脈内投與之藥物濃度測定用檢體的製作 使用絕食一晚之SD系大鼠(日本CLEA、公鼠5週齡、140 〜1 7 〇克)做為實驗動物。對於試驗化合物6 〇毫克,以乙醇 1.8¾升、聚乙二醇4〇〇 7.2毫升及生理食鹽水g毫升之比 例加入並溶解’調製3 · 3毫克/毫升溶液。測定鼠體重,將 試驗化合物溶液以3毫升/公斤之用量(1〇毫克/公斤)於無 麻醉下進行尾靜脈内投與。尾靜脈内投與為使用2 6 〇注射 針及1毫升注射器進行。採血時間為尾靜脈内投與後2、 t ϋ/2 〇、3 〇、6 〇、12 〇分鐘。將血液離心並以血漿做為 血中藥物濃度測定用檢體。 2 )以經口投與之藥物濃度測定用檢體的製作 使用絕食一晚之SD系大鼠(日本CLEA /公鼠5週齡、14〇 〜170克)做為實驗動物。將試驗化合物以 毫克/毫升懸浮或溶解於0.5%W基纖維素納水式1 :二條件下無法均句懸浮時,將試驗化合物以活性本體型 克/毫升溶解於乙酵中’並加入99倍量之〇·5%羧甲 ϋ,准素納水溶液中作成懸浮液。敎鼠體重,將上述試 驗化合物液以10毫克/公斤之用量(活性 ⑽與'經口投與為使用鼠用探針二射 =進仃。採血時間為經口投與後15、30、60、120及240分 υ血液離心並以血漿做為血中藥物濃度測定體。 3)樂物濃度之測定
C:\2D-C0DE\91-03\90132750.ptd
1231298 五、發明說明(98) 方法A ) 於上述1)及2)所得之血漿0.1毫升中,依常法適量添加 行除蛋白< 以移動相 適當的内部標準物質後,加入甲醇丨毫升,進 離心後,於氮氣流下將曱醇層予以蒸發乾燥 30 0微升稀釋’並將其30微升注入HPLC。血中 根據HPLC法以下列條件進行測定。尚’檢量線為經辰:二 白血漿0. 1毫升中’依常法適量係加適當的内部標準工 及相當於各種濃度之活性本體之化合物,並以上之 操作則可作成。 < I j m之 柱:Develosil ODS-UG-5(4·6χ 250 _) 移動相:乙腈/10mM磷酸緩衝液(pH3. 0 ):=22 : 78 (v/ 柱溫:5 0 C 流量:1 · 0毫升/分鐘 測定波長:UV232nm 方法B) 於上述1 )及2 )所得之血漿5 〇微升中,依常法適量六 當的内部標準物質後,加入蒸餾水丨〇 〇微升,並以二、 萃取。離心後,於氮氣流下將二***層予以蒸發乾燥。醚 ^動相20 0微升稀釋,並將其1〇微升注aLC — ms/ms。/血w 藥物濃度為根據C-MS/MS法以下列條件進行測定。尚,檢 量線為經由在空白血漿5〇微升中,依常法適量係加双 内部標準物質及相當於各種濃度之活性本體之化合物=廿 以上述同樣之操作則可作成。 並
LC
C:\2D-C0DE\91-03\90132750.ptd 第103頁 1231298
五、發明說明(99) 柱:Symmetry C8 (2· lx 20mm) 移動相:乙腈/ 0. 1 %醋酸水溶液=6 5 : 3 5 ( v / v ) 柱溫:4 0 °C 流速:0· 2毫升/分鐘
MS/MS 離子化法:E S I ( T u r b ο I ο n S p r a y ),正離子檢測型 離子喷霧電壓:5000V 加熱氣體溫度:4 5 0 °C 踫撞能量:1 7. 5V 倍增器電壓:2300V
滿輪離子噴霧氣體流量:700 0毫升/分鐘 喷霧器氣體:1 1 B I T 遮蔽氣體:1 1 B I 丁 碰撞氣體:4 B I T 尚’生物利用性(% )為由方法A或方法B所得之各時間之 血中藥物》辰度’使用Pharsight Corporation公司製win Monlin Standard ’求出試驗化合物之尾靜脈内投與及經 口投與之血中藥物濃度—時間曲線下面積,並根據下式算 出。其結果為如下表4。
生物利用性(% )=(經口投與之血中藥物濃度-時間曲線下 面積/尾靜脈内投與之血中藥物濃度-時間曲線下面積)X
第104頁 1231298 五、發明說明(100) [表4] 試驗化合物 方法 生物: 實施例1 Β 實施例1 5 Β 實施例1 6 Β 實施例4 7 A 實施例4 8 A 一 ^ 參考例3 7 A 27 0 尿糖***促進作用確認試驗 使用絕食-晚之SD系大鼠(曰本SLC ’公鼠7週齡、2〇2〜 2 2 1克)做為實驗動物。將試驗化合物以2荟古山 叛甲基纖維素納水溶液中懸浮。於此條件下無法白縣乂 時’將試驗化合物以2 0 0毫克/毫升溶解於乙醇中:心’予 99倍量之〇. 5%叛甲基纖維素納水溶液中作成^浮液並$ = 懸浮液之一部分以0.5%缓甲基纖維素鈉水溶液稀釋,調製 〇. 6、0. 2毫克/毫升之各濃度懸浮液。測定鼠體重,將試 驗化合物懸浮液以5毫升/公斤之用量(丨、3、1〇毫克/八 斤)經口投與。對照群為僅將〇. 5%羧甲基纖容A 毫升/公斤之用量經口投與"呈口投與後立即丄;克/ 升fe萄糖水溶液以5毫升/公斤之用量(2克/公斤)經口才八 與。經口投與為使用鼠用探針及2· 5毫升注射器進 又每i 隻鼠。葡萄糖投予終了後開始以代謝籠進行採尿。 抓尿時間為葡萄糖投與後24小時。採尿終了後,記錄尿
C:\2D-OODE\9]-〇3\9〇i32750.ptd 第105頁 1231298 五、發明說明(101) 量,測定尿中所含之葡萄糖濃度。葡萄糖濃度為以臨床檢 測套件:G 1 u c 〇 s e B T e s t W a c 〇 (和光純藥)予以定量。由尿 量、尿中葡萄糖濃度及體重,求出24小時之體重每2 0 0克 的尿糖***量。其結果示於下表5。 [表5 ] 試驗化合物 用量 尿糖***量 (毫克/公斤) (毫克/24小時/20 0克體重) 1 1. 6 實施例1 3 28· 3 10 127.5 1 1. 7 實施例1 5 3 36. 8 10 167· 3 試驗例4 急性毒性試*驗 對4週齡ICR系公鼠(日本SLC,20〜25克,1群5例)絕食4 小時後’將試驗化合物中加入〇· 5%羧甲基纖維素鈉水溶液 所調製之懸浮液(200毫克/毫升)以1〇毫升/公斤(200Q毫克 /公斤)之用量經口投與,並且觀察24小時,其結果示於下 表6 〇
C:\2D-0ODE\91-03\90132750.ptd 第106頁 1231298
本發明之前述一般式(1)所 衍生物或其藥理容許鹽為經口、之吡喃型葡萄糖氧基π比唑 =體内變換成活性本體之前述^收性被改善,經口吸收後 萄糖氧基吡唑衍生物並且表現般式(π)所示之咄喃型葡 制作用,且經由抑制糖於^ =強力的人類SGLT2活性抑 泄至尿中,料發揮•良的降血:之糖排 提供即使做為經口投與製劑亦可。根據本發明則可 病丨生併發纟、肥胖症等高血糖症之疾病的預防或治療藥。
第107頁 1231298圖式簡單說明 ❿ C:\2D-C0DE\91-03\90132750.ptd 第108頁
Claims (1)
1231298 _案號90132750_年月曰 修正_ 六、申請專利範圍 (式中之P2為C2_7酿基或C2_7烧氧幾基)所不之基’ Q2為烧 基,R21為Cu烷基、(V6烷氧基或CV6烷硫基]。 3.如申請專利範圍第2項之呲喃型葡萄糖氧基吼唑衍生 物或其藥理容許鹽,其中一般式
[式中之R12為氫原子或(V3直鏈狀或分支鏈狀之烷基,T4為 一般式
(式中之P2為C2_7醯基或C2_7烷氧羰基)所示之基,Q4為(^_3直 鏈狀或分支鏈狀之烷基,R22為匕_4直鏈狀或分支鏈狀之烷 基、Cu直鏈狀或分支鏈狀之烷氧基或Ci_3直鏈狀或分支鏈 狀之烷硫基]。 4 ·如申請專利範圍第3項之吼喃型葡萄糖氧基吼唑衍生 物或其藥理容許鹽,其為選自4-[(4-異丙氧基苯基)曱 基]-1-異丙基-3-(6-0-曱氧羰基-/3 - D-咣喃葡萄糖氧 基)-5-曱基啦唑、3-(6-0-乙氧羰基-々-D-吼喃葡萄糖氧 基)-4-[ (4-異丙氧基苯基)曱基]-卜異丙基-5-曱基吼唑、
(::\總檔\90\90132750\90132750(替換)-l.ptc 第110頁 1231298 _案號90132750_年月日__ 六、申請專利範圍 3- (6-0-異丙氧基羰基-/5 -D-吡喃葡萄糖氧基)-4-[(4-異 丙氧基苯基)甲基]-1-異丙基-5-甲基吡唑、3-(6 - 0-異丁 氧羰基-/3-D-吼喃葡萄糖氧基)-4-[(4-異丙氧基苯基)曱 基]-卜異丙基-5-曱基吼唑、4- [(4 -乙基苯基)甲基]-卜異 丙基-3-(6-0-甲氧羰基-/5 -D-吼喃葡萄糖氧基)-5-甲基口比 σ坐、3-(6-0_乙氧魏基-/3-D- 口比喃葡萄糖氧基)- 4 - [(4-乙 基苯基)甲基]-卜異丙基-5-甲基吼唑、4-[(4-乙基苯基) 甲基]-3-(6-0-異丙氧羰基-々-D-吡喃葡萄糖氧基)-卜異 丙基-5-甲基吼唑、4-[(4-乙基苯基)甲基]-3 -(6 - 0-異丁 氧羰基-/5-D-咄喃葡萄糖氧基)-:1-異丙基-5-甲基咄唑、 4- [(4-乙氧基苯基)甲基]-:1-異丙基-3-(6-0-曱氧羰基-点 -D-咄喃葡萄糖氧基)-5-曱基吼唑、3-(6-0-乙氧羰基- /3 -D-吼喃葡萄糖氧基)-4-[(4-乙氧基苯基)曱基]-卜異丙基 -5-曱基吼唑、4- [(4-乙氧基苯基)甲基]-3 -(6 -0-異丙氧 罗炭基-/5 - D-n比喃葡萄糖氧基)- 1-異丙基-5-曱基吼〇坐、 4-[(4-乙氧基苯基)甲基]- 3-(6-0異丁氧毅基-/3 - D-11比σ南 葡萄糖氧基)-卜異丙基-5-甲基呲唑、1_異丙基-3-(6-0-曱氧羰基-万-D-吼喃葡萄糖氧基)-4-[(4-曱氧基苯基)曱 基]-5-曱基吼唑、3-(6-0-乙氧羰基-石-D-吡喃葡萄糖氧 基)-1-異丙基-4-[(4-甲氧基苯基)甲基]-5-甲基吼唑、 3 -(6-〇-異丙氧魏基-卢-D-17比喃葡萄糖氧基)-1-異丙基 一4- [(4-曱氧基苯基)曱基]-5-甲基吡唑、3-(6-0 -異丙氧 羰基-沒-D-吼喃葡萄糖氧基)-卜異丙基-4-[(4-甲氧基苯 基)曱基]-5-曱基ρ比ϋ坐、1-異丙基-3-(6_0-曱氧幾基-召
(::\總檔\90\90132750\90132750(替換)-l.ptc 第111頁 1231298 修正 曰 --901327Rn 六、申請專利範圍 一5一甲基「η/人基—喃葡萄糖氧基卜1一異丙基 羰基—万-D-吡喃葡苯基)甲基]吡唑、3-(6一〇-異丙氧 硫苯基)甲W 一異丙基一5一甲基一4一[(4一甲 糖氧基(6 一 〇—異丁氧羰基-/5-D-咄喃葡萄 5·如申請專利=円5哲甲基—4〜[(4—甲硫苯基)甲基]咄唑。 物或其筚理六i :固弟4項之°比喃型葡萄糖氧基咄唑衍生 基]+異丙為選自4-[(4 一異丙氧基苯基)甲 基)一L甲基^唑、3_(6Ί巩羰基-f_D_吡喃葡萄糖氧 基)-4〜[(4〜Β u 一乙氧羰基一石-D-吡喃葡萄糖氧 3-(6-〇、異丙^基苯基)甲基]-卜異丙基-5-甲基咄唑、 氧基笨基)曱H土万-1)- °比喃葡萄糖氧基)-4-[(4-異丙 羰-点~D~ D比益地異^丙基一5~甲基吡唑、3-(6-0-異丁氧 基]-i-h A t \ /基)-4~U4_異丙氧基苯基)甲 兴丙基-5-甲基咄唑。 物或其::ί ::圍J5項之°比喃型葡萄糖氧基°比唑衍生 萄糖氧二广二孤,八為3一(6 —0—乙氧幾基-y5-D—比喃葡 比Ϊ ^4_[(4_異丙氧基笨基)甲基]+異丙基+甲基 含7有士 Ϊ作為人體%1^2活性抑制劑之醫藥組成物,其為 糖ΐ二12 ί利範圍第:至6項中任-項記載之吼喃型葡萄 8·:種作:^ : 5 ΐ ::容許鹽作為有效成分。 組成物,“含有如申請專利;=預防或治療藥= J祀固第1至6項中任一項記載 C:\«\90\90132750\90132750(§^)-l.ptc 第112頁 1231298
Ϊ231298 90132750
、申請專利範圍 胜月;1個毛 原s每抑制二劑、糖精、糖精類似物、糖精興奮劑、醛糖還 藥、 +樂、終端糖化產物生成抑制藥、蛋白激酶C抑制 N F〜/c B彳胺基丁酸爻體拮抗劑、鈉管道拮抗劑、轉錄因子 〜二肢卩制藥、脂過氧化酶抑制藥、N_乙醯化—α —連接酴 因子、來抑制藥、類胰島素成長因子、來自血小板成長 成長因:自血小板成長因子類似物、上皮增殖因子、神經 内二β 、肉鹼衍生物、尿嘧啶核苷、5_羥基-1-曱基乙 甲美 Λ 1EGB〜761、Bimoclomo1、Sul〇dexide、Υ-Π8、_ 软二^二醯輔酶Α還原酶抑制藥、Fibrat^^、化合物、方一工 劑、L素X體興奮劑、醯基輔酶A :膽固醇醯基轉移酶抑制 藥、P I酚、曱狀腺激素受體興奮劑、膽固醇吸收抑制 合心:立體甘油三s旨轉移蛋白抑制藥、脂氧 制藥、H 醯轉移酶抑制藥、κ烯合成酶抑 附荦、m蛋白受體增強藥、菸鹼酸衍生物、膽酸吸 制藥、ίt膽酸轉移蛋白抑制藥、冑固醇賴轉送蛋白抑 皞抑制“怒=、血管緊張素,酶抑制藥、中性内肽 制藥、内呼胺二3:=體拮抗藥、内絲胺酸變換酶抑 強性降壓冑、交換神經遮斷藥、中樞性降壓广血官擴 腺素受體興奮劑、抗血小板藥、&酸生成抑制敏α2-腎上 泄促進藥及尿鹼化藥所組成群中選出至少—’、、尿酸排 組合而成。 種之藥劑予以 1 4 ·如申請專利範圍第丨3項之醫藥組成物, 因於高血糖症疾病之預防或治療。 /、為用於起
C:\ 總檔\90\90132750\90132750(替換)-i.ptc 第114頁 1231298 -麵-90132750^_月 曰_ 六、申請專利範圍
1 5 ·如申睛專利範圍第1 4項之醫藥組成物,其中,如申 凊專利範圍第1至6項中任一項記載之吡喃型葡萄糖氧基吡 。坐衍生,或其藥理容許鹽以外之有效成分為由胰島素感受 性增強藥、糖吸收抑制藥、雙胍藥、胰島素分泌促進藥、 姨島素製劑、胰高血糖素受體拮抗劑、胰島素受體激酶刺 激素、二肽基肽酶丨〗抑制藥、二肽基肽酶〗v抑制藥、蛋白 赂胺酸磷酸酶-1 B抑制藥、糖原磷酸化酶抑制藥、葡萄糖 -6 - %知8每抑制藥、果糖二碗酸酶抑制藥、丙酮酸脫氫 酶、肝糖新生抑制藥、D—肌醇、糖原合成酶激酶—3抑制 藥、,膜高血糖素胜肽-1、類胰高血糖素胜肽卜類似物、 類胰咼血糖素胜肽〜丨興奮劑、糖精、糖精類似物、糖精興 奮劑及食怒抑制藥所組成群中選出至少一種之藥劑,起因 於高血糖症疾病為糖尿病。
1 6·如^申請專利範圍第1 5項之醫藥組成物,其中,如申 請士利範圍第1至6項中任一項記載之咄喃型葡萄糖氧基吡 唑衍生物或其藥理容許鹽以外之有效成分為由胰島素减受 性增強藥、糖吸收抑制藥、雙胍藥、胰島素分泌促進藥、 胰島素$劑、胰高血糖素受體拮抗劑、胰島素受體激酶刺 激素、二肽基肽酶Π抑制藥、二肽基肽酶丨v抑制藥、蛋白 酪胺酸磷酸酶-1 B抑制藥、糖原磷酸化酶抑制藥、葡萄糖 - 6 -磷脂酶抑制藥、果糠二磷酸酶抑制藥、丙酮酸脫氫 酶、肝糖新生抑制藥、^肌醇、糖原合成酶激酶_3抑制 藥、類胰高血糖素胜肽”、類胰高血糖素胜肽卜類似物、 類胰高血糖素胜肽—1興奮劑、糖精、糖精類似物及糖精姐
(::\總檔\90\90132750\90132750(替換)-l.ptc 第115頁
曰 奮劑所組成君篆由、P?L 17 风辟中遥出至少一種之藥劑。
唾衍生物或ί筚』! 項吼葡萄糖氧基吼 增強藥、糖吸鹽以外,有效成分為胰島素感受性 島素製劑所組成群中選出之藥劑。 心促進樂及姨 珠H巾請專利範11 s14項之醫藥組成物,其中,石由 :Γ圍第1至6項中任-項記載之咄喃型葡萄糠《σ其 性增強藥、糖鹽以外之!效成分為由姨島素感受 騰島素製劑ίί::Γ雙脈藥、•島素分泌促進藥、 激素、三肽基肽^ +鱗脂崎抑V華抑L:、r雄酸化酶抑制藥、葡萄糖 酶、肝糖新生抑制率:二 抑制藥、丙酮酸脫氫 類騰高血糖辛胜=·:、類姨高血糖素胜肽卜類似物、 奮劑、醛糖還;劑、糖精、糖精類似物、糖精興 劑、轉錄因4ιΒ:ί:酸受,拮抗劑、鈉管道拮抗 化- α -連接酸一肽樂、月曰過氧化酶抑制藥、Ν-乙醯 自血小板成長因一子肽酶來抑自,小、,:夷島素成長因子-卜來 殖因子、神經成長因子 反長因子類似物、上皮增 肉鹼衍生物、尿嘧啶核I 基f基乙内醯脲、egb〜761、Bi_lomol、“ 5 ^
CA總檔\90\90132750\90132750(替換).】 第116頁 1231298 -^日 V ^f m ^f ^^ ^ ^ ^ t & ^ 抑制藥、U:緊張素11受體拮抗藥、内絲胺酸變換酶 少4之受體則及利尿藥所版成群中選出至 1 9.如申:衰*^»因於咼血糖症疾病為糖尿病性併發症。 請專利第1:乾圍第18項之醫藥組成物,其中,如申 唑衍生物丄』!中任一項記載之吼喃型葡萄糖氧基吼 血管緊張辛二:; 制藥、中性内肽酶抑制藥及 劑。 ’、又體括抗樂所組成群中選出至少一種之藥 ^ # ,Γ/^t 14 JS ^ ^ ^ ^ ^ tt 。坐衍生物或i荜理:::一項k記載…型葡萄糖氧基吼 性增強荜、糖:ΪΓ1 有效成分為由胰島素感受 姨島=劑雙胍藥、騰島素分泌促進藥、 激素、三肽其肽=η女素又體拮抗劑、胰島素受體激酶刺 酥r> _汶&土肽酶抑制藥、二肽基肽酶1 ν抑制華、f & 路胺酸磷酸酶—1B抑制華、嫵丨市』条、蛋白 -6-磷脂酶抑制藥:二:處梅抑制^ ^ 酶、肝糖新生抑制藥抑制樂、、丙酮酸脫氫 藥、類騰高血糖素:月太一】、7、,原合成酶激酶-3抑制 類騰高血糖素胜肽]s备:貝騰局血糖素胜月太1 ~類似物、 奮劑m腺辛受體田姐1;糖精、糖精類似4勿、糖精興 選出至少一種之^ 、奮劑及食慾抑制藥所組成群中 3如申Λ:,起因於高血糖症疾病為肥胖症。 a如申晴專利範圍第20項之醫藥組成物,其中症如申
:\«\90\90132750\90132750(^)-l.ptc 第117頁 I23129R
曰 請專利範圍第1至6項 唑衍生物或其荜理容I任一項記載之吡喃型葡萄糖氧基吼 受體興奮劑及食鹽以外之有效成分為‘腎上腺素 劑。 〜ρ制樂所組成群中選出至少一種之藥 2 2 ·如申請專利範 制藥為由單胺再吸收抑弟m醫藥組成物’其中食您抑 羥色胺釋出刺激藥〜=5羥色胺再吸收抑制藥、5_ 收抑制藥、去曱腎上:J:興奮劑、去曱腎上腺素再吸 酚酸類受體拮抗劑、^ _其、田綃、多巴胺興奮劑、*** 抗劑、L-組胺酸、勒帕* 土 丁酸受體拮抗劑、Ha-組胺拮 受體興奮劑、右旋甲狀^ :::鹼類似物、勒帕茄鹼 激激素、***—安 ’、又/、田劑、α -黑素細胞刺 白、腸道抑制素、降約辛轉錄物、MaPh〇ganin蛋 b—、膽囊收:;;奮m關連胜狀、 質素釋出激素類似物了促 ^皮質素釋出激素、促皮 Ur〇C〇rtine、生長激素釋放抑:素出興奮劑、 類似物、生長激素釋放抑 ,激素釋放抑制素 環化酶活化胜肽、,自腦神經奮劑、下垂體腺普酸 子、促甲狀腺激素釋出激专,、、=長因子、系列性中性因 經肽Y括抗劑、阿片樣肽括、?气降塵肽、Sovadine、神 素濃縮激素受體拮抗劑、刺/ 间良量黃素拮抗劑、黑 體拮抗劑所組成群争選出之^連蛋白抑制藥、〇】exin受
發明專利說明書 啦喃型葡萄魏基㈣彳⑦生物及其醫藥上用途 中文 發明名稱 人 明 發 申請人 英文 名 姓 文 中 名i? 姓s' |籍 國 GLUUUFYKANOSYLUXYFYRAZOLE derivatives and use thereof in medicines 紀彥洋司 秀信俊毅 倉t村林 藤伏西中 1· 2· 3· 4· II· 2· 3· 4· I本 一本 曰曰曰曰j橘 1· 2·13.4· 所 居 4稱文 住 is(t 姓名 夕457-W 原34 TT柏内| 5289字y一 41田大敷 内岡町岡 |島下高松司 宇田穗田公 大岡乘岡限 _本|市市曇市有 本本安本份 松松南松股 一縣縣縣縣業 MM3 U3 Π3 mm3 · I 長長長長品 國國國國藥 一本本本本生 I本 月 望 楝 B 岡 松 > 式会社
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