TW200831081A - Glucokinase activator - Google Patents

Glucokinase activator Download PDF

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Publication number
TW200831081A
TW200831081A TW096147470A TW96147470A TW200831081A TW 200831081 A TW200831081 A TW 200831081A TW 096147470 A TW096147470 A TW 096147470A TW 96147470 A TW96147470 A TW 96147470A TW 200831081 A TW200831081 A TW 200831081A
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TW
Taiwan
Prior art keywords
group
pharmaceutically acceptable
acceptable salt
atom
methylsulfonyl
Prior art date
Application number
TW096147470A
Other languages
English (en)
Inventor
Yasumichi Fukuda
Yoshikazu Asahina
Ayako Nakamura
Kenji Fujita
Tomohiro Ide
Fumiyoshi Kobayashi
Shinji Kobayashi
Kanji Komatsu
Original Assignee
Kyorin Seiyaku Kk
Teijin Pharma Ltd
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Publication date
Application filed by Kyorin Seiyaku Kk, Teijin Pharma Ltd filed Critical Kyorin Seiyaku Kk
Publication of TW200831081A publication Critical patent/TW200831081A/zh

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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D241/14—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • Plural Heterocyclic Compounds (AREA)

Description

200831081 β 九、發明說明 【發明所屬之技術領域】 本發明關於葡糖激酶（可於以下簡稱爲GK )活化劑 。本發明亦關於含有GK活化劑作爲適合於治療或預防糖 尿病、肥胖症及其他病症之活性成分的醫藥組成物。 【先前技術】 在2002年，由日本的厚生勞動省（the Ministry of Health，Labor，and Welfare)所進行的病患調查顯露出患 有糖尿病的總病患人數在日本是2,280,000人。在同年所 進行的糖尿病硏究評估強力懷疑患有糖尿病的病患人數及 具有不可能否認糖尿病可能性的病患人數總計達到 16,200,0 00 人 〇 就國內市場而言，日本人具有低胰島素分泌的遺傳因 子，而因此有缺陷的胰島素分泌佔大部份。然而，增加的 病患人數正遭受胰島素抗性所苦，其係由於轉變成西方飲 食之故。因此，對有效對抗有缺陷的胰島素分泌及胰島素 抗性二者的藥物有需求。 葡糖激酶（GK)爲催化葡萄糖磷酸化的酵素。因應 高蔔萄糖値，該酵素藉由促進胰島素分泌及肝中葡萄糖利 用率而充當在體內的葡萄糖感應器。因爲糖尿病患無法維 持全身的葡萄糖體內恆定’所以在這些病患中的GK活化 作用可藉由促進在胰臟中的葡萄糖依賴之胰島素分泌及促 進在肝中的葡萄糖利用率或抑制葡萄糖從肝釋放（雙重作 -5- 200831081 用）而減低血液葡萄糖値（非專利文件1至3 )。有效對 抗有缺陷的胰島素分泌（胰臟的作用）及胰島素抗性（肝 臟的作用）二者的GK活化劑被認爲理想的糖尿病治療。 已知的GK活化劑爲各種醯胺化合物（專利文件11 至19)，包括芳基環烷基丙醯胺（專利文件1) ，2,3-二 取代之反式烯烴N-雜芳香族環-或脲基-丙醯胺（專利文件 2)，炔苯基雜芳香族醯胺（專利文件3 )，乙內醯脲（專 利文件4 )，經取代之苯基乙醯胺（專利文件5 )，對·烷 基-、芳基、環雜烷基-或雜芳基-(羰基或磺醯基）胺取代 之苯醯胺（專利文件6 )，α -醯基及α -雜原子取代之苯 乙醯胺（專利文件7 )，四唑基苯基乙醯胺（專利文件8 )，稠合之雜芳香族環（專利文件9)及具有單一碳原子 被取代之環烷烴或具有雜環狀環的苯基乙醯胺（專利文件 10)。然而，沒有任何報導敘述其中兩個氟原子與環戊基 不同的碳原子連接的GK活化劑。 專利文件1 : W02000/058293小冊 專利文件2 : WO2001/04421 6小冊 專利文件3: W02001/083465小冊 專利文件4: W02001/083478小冊 專利文件5 : W02001/085706小冊 專利文件6 ： W0200 1/085707小冊 專利文件7 ： W02002/008209小冊 專利文件8 : W02 002/0143 12小冊 專利文件9: W02002/046173小冊 200831081
專利文件10: W02003/095438小冊 專利文件11: W02004/052869小冊 專利文件12: W02004/072031小冊 專利文件13 ·· W02004/0 72 066小冊 專利文件14: W02005/1 03021小冊 專利文件15: W02006/01 61 74小冊 專利文件16: W02006/01 61 78小冊 專利文件17: W02006/01 61 94小冊 專利文件18: W02006/059 1 63小冊 專利文件1 9 : U S 6 9 1 1 5 4 5 非專利文件 1 : Diabetes 45，223-241 ( 1 996 ) 非專利文件 2 : Diabetes 4 1，792-806 ( 1 992 ) 非專利文件 3 : FASEB J· 10，1213-1218 ( 1996) 【發明內容】 由本發明所解決的問題 因此，本發明的目的係提供充當有效的GK活化劑或 降血糖劑且有用於治療或預防糖尿病、肥胖症及其它病症 的化合物。 解決問題的方法 在本發明者找出達成上述目的之方式的硏究過程中， 本發明者發現在位置3上具有3,4-二氟基環戊基的丙醯胺 化合物之中，具有特殊的立體結構的那些化合物爲有效的 200831081 GK活化劑或降血糖劑。這是最終引導至本發明的發現。 特定言之，本發明關於下列者： η —種以下列通式（1)代表的化合物，或其醫藥上 可接受之鹽： (化學式1)
(其中以*表示之碳原子具有R組態；R1及R2各自獨立爲 氫原子、鹵素原子、胺基、羥基、羥胺基、硝基、氰基、 胺磺醯基、烷基、Κ6烷氧基、（^-0：6烷硫基、Cl-C6丨兀基亞齒釀基或Ci-Cs燒基礦釀基，及A爲經取代或未 經取代之雜芳基）。 2) 根據1)之化合物，或其醫藥上可接受之鹽，其中 Rl爲氫原子及R2爲烷基磺醯基。 3) 根據1)之化合物，或其醫藥上可接受之鹽，其中 R爲氫原子及R2爲甲基磺醯基。 4 )根據1 )至3 )中任一者之化合物，其係以下列通 式（la)代表，或其醫藥上可接受之鹽： 200831081 (化學式2)
‘ （其中以*、R1、R2及A如上述所定義）。 • 5)根據1)至3)中任一者之化合物，其係以下列通 式（lb)代表，或其醫藥上可接受之鹽： (化學式3)
(其中以及Α如上述所定義）。 6) 根據1)至5)中任一者之化合物，或其醫藥上可 接受之鹽，其中A爲未經取代或經鹵素原子、Cl_c6烷基 、c!-c6烷氧基、硝基、氰基或_(CH2) mc(0) OR3 (其 中R3爲氫原子或，及m爲〇至2之整數）單 取代之雜芳基。 7) 根據1)至5)中任一者之化合物，或其醫藥上可 接受之鹽’其中A爲未經取代或經鹵素原子或c 1 - C 6院基 單取代之雜芳基。 8) 根據ό)或7)之化合物，或其醫藥上可接受之鹽 -9- 200831081 ’其中A爲未經取代或經單取代之雜芳基，其爲含有1至 3個選自硫原子、氧原子及氮原子之雜原子的5_或6_員芳 香族雜環狀環，雜原子之一爲與環鍵聯原子鄰接之氮原子 〇 9)根據6)或7)之化合物，或其醫藥上可接受之鹽 ’其中A爲未經取代或經單取代之雜芳基，其爲稠合之雜 環狀環，該環包括含有丨至3個選自硫原子、氧原子及氮 原子之雜原子的5_或6_員芳香族雜環狀環，雜原子之一爲 與環鍵聯原子鄰接之氮原子。 10 )根據 6 )或 7、/，a Λ 7 )之化合物，或其醫藥上可接受之 鹽，其中A爲未經取代成 或，經取代之雜芳基，其係選自下列 者： -10- 200831081
(化學式4)
11) ( R) -3- ( ( lr，3R，4S ) -3,4-二氟基環戊基 (4-(甲基磺醯基）苯基）-N-(噻唑-2-基）丙醯胺 )-3-((11*，311，43)- 3 5 4 -二氟基環戊基）-2-(4-(甲 醯基）苯基）-N- ( 5-氟基噻唑-2-基）丙醯胺，（R ((lr，3R，4S ) -3,4-二氟基環戊基）-2- ( 4-(甲基磧 )苯基）( 1-甲基吡唑-3-基）丙醯胺，（R) -3 li*，3R，4S ) -3,4-二氟基環戊基）-2- ( 4-(甲基磺醯基 基）-N-(吡啶並[3,2-d]噻唑-2-基）丙醯胺或（R) )-2 - ，(R |基磺 )-3- i醯基 -(( "苯 -3-( -11 - 200831081 (lr，3R，4S ) -3,4-二氟基環戊基）-2- ( 4-(甲基磺醯基） 苯基）-N- (3-甲基噻二唑-5-基）丙醯胺，或其醫藥上可 接受之鹽。 12 ) —種以下列通式（2 )代表的（-)-3-[ ( 1 α，3 α ，4α ) -3,4·二氟基環戊基]_2-(4-(甲基磺醯基）苯基）-Ν-(噻唑-2-基）丙醯胺： (化學式5)
(2) 或其醫藥上可接受之鹽。 13 ) — 種（-)-3-[ ( 1 α，3 α，4 α ) -3,4-二氟基環戊 基）-2-(4-(甲基磺醯基）苯基）-Ν-( 5-氟基噻唑-2-基 )丙醯胺，或其醫藥上可接受之鹽。 14 )——種（-)-3-[ ( 1 α，3 α，4 α ) -3,4-二氟基環戊 基）-2- ( 4-(甲基磺醯基）苯基）-Ν- ( 1-甲基吡唑-3-基 )丙醯胺，或其醫藥上可接受之鹽。 15)—種（-)-3-[(16^5361：，41)- 3 54 -二氟基環戊 基）-2- ( 4-(甲基磺醯基）苯基）-Ν-(吡啶並[3,2-d]噻 唑-2-基）丙醯胺，或其醫藥上可接受之鹽。 16 ) —種（-)-3-[ ( 1 α，3 αα ) -3,4-二氟基環戊 基）-2- ( 4-(甲基磺醯基）苯基）( 3-甲基噻二唑- 5- 基）丙醯胺，或其醫藥上可接受之鹽。 -12- 200831081 1 7 ) —種根據申請專利範圍第1 )至1 6 )項中任一項 之化合物或其醫藥上可接受之鹽在製造供治療人類疾病之 醫藥劑中的用途。 1 8 ) —種根據申請專利範圍第1 )至1 6 )項中任一項 之化合物或其醫藥上可接受之鹽在製造供治療或預防糖尿 病之醫藥劑中的用途。 1 9 ) 一種包含根據1 )至1 6 )中任一者之化合物及醫 藥上可接受之載體的醫藥組成物。 2〇 ) —種以下列通式（3 )代表的化合物： (化學式6)
(其中以*表示之碳原子具有R組態；R1及R2各自獨立爲 氫原子、鹵素原子、胺基、羥基、羥胺基、硝基、氰基、 胺磺醯基、CrCs烷基、CrC6烷氧基、Ci-G烷硫基、Cp C6烷基亞磺醯基或（：1-(：6烷基磺醯基）。 21 )根據20)之化合物，其中R1爲氫原子及R2爲甲 基磺醯基。 【實施方式】 本發明的效應 根據本發明，其係提供一種充當有效的GK活化劑或 -13- 200831081 降血糖劑且引起較少副作用（如QT間隔的延長及低血糖 症）之化合物，與有用於治療或預防糖尿病、肥胖症及其 他病症的醫藥組成物。 進行本發明的最好模式 如本文所使用的、、鹵素原子〃術語係指氟原子、氯原 子、溴原子或碘原子。 如本文所使用的、"C 1 - C 6院基〃術語係指具有1至6 個碳原子之直鏈或支鏈烷基，或具有3至6個碳原子之環 烷基，如甲基、乙基、丙基、異丙基、丁基、異丁基、第 二丁基、第三丁基、環丙基及環丁基。 如本文所使用的烷氧基〃術語係指具有1至 6個碳原子之直鏈或支鏈烷氧基，或具有3至6個碳原子 之環烷氧基，如甲氧基、乙氧基、丙氧基、異丙氧基、丁 氧基、異丁氧基、第二丁氧基、第三丁氧基、環丙氧基及 環丁氧基。 如本文所使用的> Κ6烷硫基〃術語係指具有1至 6個碳原子之直鏈或支鏈烷硫基，如甲硫基、乙硫基、丙 硫基、異丙硫基、丁硫基、異丁硫基、第二丁硫基及第三 丁硫基。 如本文所使用的Α 烷基亞磺醯基〃術語係指具 有1至6個碳原子之直鏈或支鏈烷基亞磺醯基，如甲基亞 磺醯基、乙基亞磺醯基、丙基亞磺醯基、異丙基亞磺醯基 、丁基亞磺醯基、異丁基亞磺醯基、第二丁基亞磺醯基及 -14 - 200831081 第三丁基亞磺醯基。 如本文所使用的、CpC6烷基磺醯基〃術語係指具有 1至6個碳原子之直鏈或支鏈垸基磺醯基，如甲基磺醯基 、乙基磺醯基、丙基磺醯基、異丙基磺醯基'丁基磺醯基 、異丁基磺醯基、第二丁基磺醯基及第三丁基磺醯基。 如本文所使用的、、雜芳基〃術語係指5-或6-員芳香族 雜環狀環’其包括1至3個選自硫原子、氧原子及氮原子 之雜芳基，且可與苯環或5-或6-員芳香族雜環狀還形成稠 合環。較佳的雜芳基爲包括1至3個選自硫原子、氧原子 及氮原子之雜原子的雜芳基，雜原子之一爲與環鍵聯原子 鄰接之氮原子。如本文所使用的、、環鍵聯原子〃術語係指 與醯胺基的氮原子結合的雜環狀環的成員之一。環鍵聯原 子係以碳原子較佳。 較佳的雜芳基實例包括噻唑基、噻二唑基、吡唑基、 吡啶基、吡哄基、’嘧啶基、嗒哄基、噁唑基、咪唑基、三 哄基、苯並噻唑基、苯並噁唑基、苯並咪唑基、吡啶並噻 唑基及喹啉基。在該等之中，以噻唑基、吡唑基、噻二唑 基及吡啶並噻唑基特別佳。 以A表示的經取代或未經取代之雜芳基較佳地爲未經 取代或經單取代之雜芳基。取代基可爲鹵素原子、CrQ 烷基、烷氧基、硝基、氰基及以- (CH2) mC(0) OR3代表的基團（其中R3爲氫原子或CKC6烷基，及m 爲〇至2之整數）。 具有上述結構的本發明化合物充當有效的G K活化劑 -15- 200831081 。當A爲未經取代或經鹵素原子或Ci-Ce烷基單取代之雜 芳基時，則化合物顯示有利的藥物動力學及有效地轉移至 血液中，充當有效的降血糖劑。如下文所述，於環戊基及 與其結合之氟原子的立體結構及/或以*表示之碳原子的組 構不同於本發明化合物的化合物（例如（+ ) ( 1 α，3 α，4α ) -3,4-二氟基環戊基;1-2- (4-甲基磺醯基）苯基）-Ν-(噻唑_2_基）丙醯胺（S-組態）、（-)-3-[ ( 1冷，3 α ，4α ) -3,4-二氟基環戊基]-2- (4 -甲基磺醯基）苯基）-Ν-(噻唑-2-基）丙醯胺及（+)-3-[(1/3,3“，4〇:)-3,4-二 氟基環戊基]-2- ( 4 -甲基磺醯基）苯基）(噻唑-2-基） 丙醯胺）不展現高的降血糖活性。 除非有其他另外的說明，所謂的 ''光學旋轉" 用語代表使用氯仿作爲溶劑以鈉D線所測定之化合物的光 學旋轉是負値（-)。 應注意（-)( H3 α，4 α ) ·3,4-二氟基環戊基]· 2- ( 4-(甲基磺醯基）苯基）-N-(噻唑-2-基）丙醯胺亦 被稱爲（R) -3-[(1α，3α，4α ) -3,4-二氟基環戊基]_2_( 4-(甲基磺醯基）苯基）-N-(噻哩_2_基）丙醯胺或（R )-3- ( ( lr，3R，4S) -3,4-二氟基環戊基）-2- ( 4-(甲基磺 醯基）苯基）-N-(噻唑_2-基）丙醯胺。（-)_3-[(1α，3 α，4α) -3,4-二氟基環戊基]·2·(4·(甲基磺醯基）苯基 )-Ν- ( 5-氟基噻唑-2-基）丙醯胺亦被稱爲（r ) _3_[ ( 1 α，3α，4α ) -3,4-二氟基環戊基]-2- ( 4-(甲基磺醯基） 苯基）-Ν- ( 5-氟基噻唑·2_基）丙醯胺或（R ) -3-(( -16- 200831081 11：，3尺，43)-3,4-二氟基環戊基）-2-(4-(甲基磺醯基）苯 基）-N- ( 5-氟基噻唑-2-基）丙醯胺。（_ ) -3_[ ( 1 α，3 α ，4^)-3,4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基）· Ν· ( 1_甲基吡唑-3-基）丙醯胺亦被稱爲（R)…3-[ ( j α，3 〇：，4以）-3,4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基 )-Ν- ( 1-甲基吡唑·3-基）丙醯胺或（r) -3- ( ( lr，3R，4S )-3，4-二氟基環戊基）-2-(4-(甲基磺醯基）苯基）·Ν_ (1-甲基吡唑-3-基）丙醯胺。（·）-3-[(ΐα，3α，4α)· 3,4-二氟基環戊基]-2- ( 4-(甲基磺醯基）苯基）-Ν-(吡 啶並[3,2-d]噻唑-2-基）丙醯胺亦被稱爲（R) -3-[ ( 1 α，3 α，4α ) -3，4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基 )-N-(吡啶並[3,2-d]噻唑-2·基）丙醯胺或（R) -3-(( lr，3R，4S) -3,4-二氟基環戊基）-2- ( 4-(甲基磺醯基）苯 基）-N-(吡啶並[3,2-d]噻唑-2-基）丙醯胺。（-)-3-[ ( 1 α，3α，4α) -3,4-二氟基環戊基]-2-(4-(甲基磺醯基） 苯基）-N- ( 3_甲基噻二唑-5-基）丙醯胺亦被稱爲（11)-3-[(1α，3α，4α ) -3,4-二氟基環戊基]-2-(4-(甲基磺醯 基）苯基）-N-(3-甲基噻二唑-5-基）丙醯胺或（&)-3-((1^，311，48)-3,4-二氟基環戊基）-2-(4-(甲基磺醯基 )苯基）-N- ( 3-甲基噻二唑-5-基）丙醯胺。 醫藥上可接受之鹽可爲以無機或有機酸，如氫氯酸、 氫溴酸、硝酸、硫酸、磷酸、檸檬酸、甲酸、順丁烯二酸 、乙酸、琥珀酸及酒石酸所形成的任何鹽。 以通式（1 )代表的化合物可藉由例如使用通式（3 ) -17- 200831081 化合物作爲中間物的下列生產步驟來生產。 (化學式7)
(其中以*、R1、R2及A如上所述）。 在該步驟中，將通式（3)化合物與雜芳胺在適合的 試劑存在下反應，以形成通式（1 )化合物。 反應可使用常見的縮合劑或使用任何下列技術來進行 =活性酯技術、混合的酸酐技術、鹵化酸技術及碳化二醯 亞胺技術。用於這些反應的試劑包括亞硫醯氯、草醯氯、 N，N’-二環己基碳化二醯亞胺、N，N’-二異丙基碳化二醯亞 胺、碘化；1_甲基-2-溴基吡錠、N.N’-羰基二咪唑、氯化二 苯基磷酸、二苯基磷醯疊氮化物、碳酸N，N-二琥珀醯亞胺 酯、草酸N，N’-二琥珀醯亞胺酯、1-乙基-3- (3-二甲胺基 丙基）碳化二醯亞胺鹽酸鹽、氯基甲酸乙酯、氯基甲酸異 丁酯、六氟磷酸苯並三唑-1-氧基-參（二甲胺基）鱗及N-溴基琥珀醯亞胺/三苯膦。在該步驟中，鹼或縮合輔劑（ 縮合添加劑）可與該等試劑一起使用。鹼可爲任何不涉入 反應中的任何鹼。例如，反應可在鹼金屬烷醇化物，如甲 醇鈉及乙醇鈉；鹼金屬氫化物，如氫化鈉及氫化鉀；鹼金 屬有機鹼，如正丁基鋰、雙（三甲基矽烷基）醯胺鋰、雙 -18- 200831081 (三甲基矽烷基）醯胺鈉及雙（三甲基矽烷基）醯胺鉀； 三級有機鹼，如三乙胺、二異丙基乙胺、吡啶、N-甲基嗎 啉、咪唑、N-甲基吡咯啶、N-甲基六氫吡啶、1，5-二氮雜 雙環[4.3.0]壬-5-烯及1，8-二氮雜雙環[5.4.0]十一 -7-烯； 或無機鹼，如碳酸鉀及碳酸氫鈉的存在下進行。縮合輔劑 可爲N-羥基苯並三唑水合物、N-羥基琥珀醯亞胺、N-羥 基-5-降莰烯-2,3-二羧酸醯亞胺、3-羥基-3,4-二氫-4-酮基-1，2,3-苯並三唑或五氟酚。反應溶劑可爲不涉入反應中的 任何溶劑。較佳的實例包括烴溶劑，如戊烷、己烷、環己 烷、苯、甲苯及二甲苯；鹵化烴溶劑，如二氯甲烷、1，2-二氯乙烷、氯仿及四氯化碳；醚溶劑，如二乙醚、四氫呋 喃及1，4-二噁烷；及非質子極性溶劑，如乙腈、丙腈、硝 基甲烷、硝基乙烷、N，N-二甲基甲醯胺、N-甲基六氫吡啶 酮、亞颯及二甲基亞颯。反應通常在-78 °C至200 °C下平穩 地進行。 在一個觀點中，本發明關於包含以通式（1)代表的 任何化合物或醫藥上可接受之鹽作爲活性成分的醫藥劑。 本發明的醫藥劑爲有效的GK活化劑或降血糖劑，並因此 有用於治療或預防I型糖尿病、II型糖尿病、高脂血症（ 高- LDL膽固醇血症、高三酸甘油酯血症及高HDL膽固醇 血症）、肥胖症、胰島素抗性、葡萄糖耐性異常、代謝症 候群及其他病症。 本發明的醫藥組成物可經口服投予，或可經由直腸內 、皮下、靜脈內、肌肉內或經皮途徑的非經腸投予。 -19 - 200831081 本發明的化合物或醫藥上可接受之鹽可以固體組成物 型式'液體組成物型式或任何適合用作醫藥劑的其他型式 提供。本發明的醫藥劑可與醫藥上可接受之載體調配。特 定言之，加入常使用的賦形劑、塡充劑、結合劑、崩散劑 、包衣劑、糖衣劑、pH調整劑、溶解劑或水性或非水性 溶劑，並且藥片、藥九、膠囊、顆粒、藥粉、粉末狀藥物 、溶液、乳液、懸浮液或注射劑可藉由常使用的藥物製備 技術來調配。 雖然本發明的化合物或其醫藥上可接受之鹽的劑量可 依據受藥者的病症類型、徵候、體重、年齡及性別與投予 途徑而改變，但是經口服投予成人的劑量較佳地在約〇.〇 1 至約1000毫克/公斤/天之範圍內，而更佳地在約0.5至約 200毫克/公斤/天之範圍內。該量係以單次或多次劑量投 予。 當必要時，本發明的化合物或其醫藥上可接受之鹽可 與除了 GK活化劑之外的一或多種化合物組合使用。例如 ，彼等可與含有磺醯尿素類、雙胍類、升糖素拮抗劑類、 α -葡萄糖酶抑制劑類、胰島素分泌增強劑類或胰島素敏 感劑類的一或多種抗糖尿病劑、抗高血糖劑或抗肥胖劑組 合使用。 磺醯尿素的實例包括格列苯脲（glyburide )、格列美 脲（glimepiride )、格列卩比特（glipyride )、格列卩比嗪（ g 1 i p i z i d e )、氯基丙醯胺、格列齊特（g 1 i c 1 a z i d e )、格列 派特（glisoxepide)、醋擴己脲（acetohexamide)、格列 -20 - 200831081
波脲（glibornuride )、甲苯磺丁脲（tolbutamide )、妥 拉磺脲（tolazamide )、磺胺丁脲（carbutamide )、格列 喹酮（gliquidone )、格列己脲（glyhexamide )、苯磺丁 脲（phenbutamide)及1-環己基-3-對-甲苯磺醯尿素（ tolcyclamide )。雙胍的實例包括甲福明（metformin )、 苯乙福明（phenformin )及丁雙胍（buformin )。升糖素 拮抗劑的實例包括肽或非肽升糖素拮抗劑。α -蔔萄糖酶 抑制劑的實例包括阿卡波糖（acarbose )、伏格列波糖（ voglibose )及米格列醇（miglitol )。胰島素敏感劑的實 例包括曲格列酮 （troglitazone )、羅格列酮 （ rosiglitazone)、卩比格列酮（pioglitazone)及環格列酮（ ciglitazo ne )。抗肥胖劑的實例包括諾美婷（sibutr amine )及羅氏纖（orlistat )。本發明的化合物或其醫藥上可接 受之鹽及其他的抗糖尿病劑、抗高血糖劑或抗肥胖劑可同 時、連續或分開投予。 實例1 (±)-3-[(lα536K，4α)-3,4-二氟基環戊基]-2-(4- (甲基磺醯基）苯基）丙酸 (化學式8) φ
|f^V^c〇2H
Me〇2S 200831081 將在四氫呋喃（7毫升）中的4-甲基磺醯基苯基乙酸 (1.04公克）之溶液在-78°C下逐滴加入含有N，N-二甲基 丙烯尿素（3.92毫升）之二異丙基醯胺鋰（10.2毫莫耳） 的四氫呋喃溶液（20毫升）中。將混合物在-45至-30 °C下 攪拌2小時。接著，在-7 8°C下逐滴加入（1 α，3α，4α )-3,4 -一氟基環戊基甲基碘（1.20公克），並允許混合物在 攪拌下逐漸溫熱至室溫。接著加入水（1 5毫升）及將四氫 呋喃在減壓下蒸發。將6莫耳/公升之氫氯酸加入所得殘 餘物中，使pH成爲2。接著將混合物以乙酸乙酯萃取， 並將有機層經無水硫酸鈉乾燥，過濾及濃縮。藉由矽膠管 柱層析法純化所得殘餘物，以供應（± ) - 3 - [ ( 1 α，3 α，4 α ) -3,4-二氟基環戊基]-2- (4-(甲基磺醯基）苯基）丙 酸（956毫克）。 MS ( CI+ ) m/z ：3 3 3 ( MH+ ) C15H19F204S ( MH+)之 HRMS ( CI+) ··計算値 333.0972，實測値 333.0997。 實例2 (41〇-4-苯甲基-3-[3-[(1〇:，3“，40)-3,4-二氟基 環戊基]-2- ( 4-(甲基磺醯基）苯基）丙醯基]噁唑啶-2-酮 -22- 200831081 (化學式9)
將三乙胺（ 975毫升）加入在四氫呋喃（12毫升）中 的（土）-3-[(lα，3α54α)-3,4-二氟基環戊基]-2-(4-( 甲基磺醯基）苯基）丙酸（93 1毫克）之溶液中。將混> 物在鹽-冰浴中冷卻的同時，逐滴加入三甲基乙醯氯（3 62 毫升）及將混合物攪拌1小時。接著，加入（R) -4-苯甲 基噁唑啶酮（4 9 4毫克）及氯化鋰（13 0毫克），並將混 合物在室溫下再攪拌4小時。以過濾移除不溶物質及濃縮 過濾物。將所得殘餘物溶解在乙酸乙酯中。將溶液連續以 碳酸氫鈉飽和水溶液及氯化鈉飽和溶液清洗’經無水硫酸 鈉乾燥，過濾及濃縮。藉由矽膠管柱層析法（Kanto Chemical之Si60NS，溶離劑··甲苯：乙酸乙酯=3 : 1 )純 化所得殘餘物，以供應（4R) -4-苯甲基- 3-[3-[ ( 1 α，3 α ，4以）-3,4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基） 丙醯基]卩惡嗤卩定-2-酮的較筒極性異構物A (521毫克）及 較低極性異構物B ( 43 3毫克），異構物A及B分別溶離 在後段流份及前段流份中。 異構物A : MS ( El ) m/z : 49 1 ( M+ ) -23- 200831081 C25H27F2N05S ( M+ )之 HRMS ( EI ):計算値 491.1578，實測値 491.1557。 異構物B : MS ( EI ) m/z : 491 ( M+ ) C25H27F2N05S ( M+)之 HRMS ( EI):計算値 4 9 1.1 5 7 8，實測値 4 9 1 · 1 5 7 8。
實例3 (-)-3-[(1α，3α，4α ) -3,4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基）丙酸 (化學式10)
將含有30%過氧化氫溶液（206微升）的氫氧化鋰（ 24 · 0毫克）之水溶液（1 · 3毫升）在以冰冷卻下加入（4R )-4 -苯甲基-3 - [ 3 - [ ( 1 α，3 α，4 α ) - 3，4 -二氟基環戊基]-2 -(4-(甲基磺醯基）苯基）丙醯基]噁唑啶_2-酮之異構物 A ( 2 5 0毫克）的四氫呋喃溶液（5毫升）中。將混合物攪 拌1小時。接著，加入1莫耳/公升之亞硫酸鈉溶液及碳 酸氫鈉飽和水溶液’並將混合物以乙酸乙醋清洗。將1旲 耳/公升之氫氯酸加入水層中’使ph成爲2 ’並將水層以 -24- 200831081 乙酸乙酯萃取。將有機層以氯化鈉飽和溶液清洗，經無水 硫酸鈉乾燥，過濾及濃縮。將所得殘餘物以二乙醚清洗， 以供應（-)-3·[ ( 1 α，3 α，4 α ) -3,4-二氟基環戊基]-2-( 4-(甲基磺醯基）苯基）丙酸（159毫克）。 lR NMR ( CDCls ) (5 1.62-2.33 ( m，7H )， 3.06 ( s51H )，3.71 (t，J = 7.9Hz，1H)，4.71-4.93 (m，2H)，7·53 ( d? J = 8.6Hz?2H ) ? 7.93 ( d 5 J = 8.6 H z, 2 H )。
MS ( CI+ ) m/z : 3 3 3 ( MH+ ) C15H19F204S ( MH+ )之 HRMS ( CI+ ):計算値 3 3 3.0972，實測値 3 3 3.0974 ° 實例4 (-)-3·[(1α，3α，4α: ) -3,4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基）-N-(噻唑-2-基）丙醯胺（化合物 第1號）
將N -溴基琥珀醯亞胺（8 1.9毫克）加入在以冰冷卻 下的二氯甲烷（1.4毫升）中的三苯膦（120毫克）中及 將混合物攪拌30分鐘。接著，加入（-)-3-[ ( 1 α，3α，4 α ) -3，4-二氟基環戊基]-2- ( 4-(甲基磺醯基）苯基）丙 -25- 200831081 酸（90.6毫克）及將混合物在室溫下攪拌40分鐘。接著 加入2-胺基噻唑（67.8毫克）及在室溫下再攪拌1.5小時 。接著將反應混合物以乙酸乙酯稀釋，並連續以水、1莫 耳/公升之氫氯酸、5 %碳酸氫鈉水溶液及氯化鈉飽和溶液 清洗。接著將有機層經無水硫酸鎂乾燥，過濾及濃縮。藉 由矽膠管柱層析法純化所得殘餘物，以供應（-)-3_[ ( 1 α ,3α ?4α ) -3,4 - 一氯基環戊基]_2-( 4-(甲基礦酿基） 苯基）-N-(噻唑-2-基）丙醯胺（106毫克）。 lU NMR ( CDCls) (5 1.65-2.49 ( m,7H ) , 3.04 ( s53H )，3·74 ( t，J = 7.3Hz，1H)，4·73-4·90 ( m，2H)，7.08 ( d，K7Hz)，7.48-7.51 ( m，3H)，7.88 ( d，J = 8.6Hz，2H)， 10.65 ( brs?lH )。 MS ( El ) m/z ·· 414 ( M+ ) C25H27F2N05S ( M+)之 HRMS ( El):計算値 4 1 4 · 0 8 8 3，實測値 4 1 4 · 0 8 9 0。 實例5 化合物第2號至第89號係如實例4所製備。在下表 中所示之每一化合物的旋光性係使用氯仿作爲溶劑所測定 ，除了以DMSO用於化合物第7、15號及以DMF用於化 合物第 17、32、44、45、47、48、49、50、54、55、56、 57 、 58 、 72 、 73 、 74 、 75 、 78 號。 -26- 200831081 (化學式12)
(以*表示之碳原子具有R組態）
-27- 200831081 表1
化合物編號 結構(A) IHNMR(400MHz) MS (m/z) 旋光性 2 冬 (CDC13) d i.67-t.85(m,3HX 2.01-2.18 (m, 3H). 2.37-2.44 (mt 1HX 3.06 (s. 3H). 3.S5 (t, J = 7.7 Hr. 1H), 4J3-4.92 (m, 2H). 7.02 (i J =2.4 Hr, 1HX 7.51 (dt J = 8.6 Hz, 2H), 7.92 (A J = 8.0 Hz. 2H), 9.42 (brt IH). CESI+) 433.1 (MH+) (一） 3 ^Me (d6DMSO) δ 1.49-1.81 (m, 4H)# 2.04-^17 (rnt 3HX 3.17 (s, 3H)f a.69 (s, 3H), 3.88-3.92 (m» 1H)· 4.81-4.97 (m, 2W· β.3& (d, J = 1.8 Hz, 1H). 7.50 (d. J = 1.8 Ηζ» 1H), 7.62 (d. J = 8.0 Hz, 2H). 7.87 (d. J = Θ.6 Hz, 2H)t 10.7 {s, 1HX (ESW 412.2 (MH+) ㈠ 4 (CDCI3) <5 U3-1.89 (m. 3H)t 2.04-2^0 (m. 3H), 2.42-2.49 Cm, TH), 3.08 (s. 3H). 3.75 (t, J = 7.7 Hz. 1H). 4.75-4.91 (m, 2H). 7.39 (dd. J = 8.6. 4.9 Hz, 1H)r 7.53 (d, J = 8.6 Hz. 2H), 7J4-7J7 (m. 3H>, 8.51-8.52 (mt 1H). (ESH-) 468.1 (MH+) (一） 5 (CDCI3) <5 1.63-1.84 (m. 3H), 2.05-2.17 (m, 3H), Z40-2.51 (m. 1H), 2.51 (s. 3H)t 3.09 (s. 3H), ZJB (t J = 7J Hz. IH), 4.74-4.91 (m, 2H). 7.52 (4 J = 8,6 Hz, 2Ηλ 7.95 Cd. J = 8.6 Hz. 2H). 9.47 (bn tH). (ESI+) 430.1 (MH+) (-) 6 /-CO^Et (CDCI3) δ t.28 (t J = 7.0 Hz. 3H)f t.71-1.83 (m. 3HX 2.03-2.17 (m, 3H). 2.39-2.45 (m, tH). 3.07 (s, 3H). 3.64-3.68 (mf 3H). 4.16 Cq. J = 7.1 Hz« 2H). 4.74-4.90 (m. 2H). 6.80 (s. 1H), 7.52 (d. J = 8.6 Hz. 2H). 7.94 (d J = 8.0 Hz. 2H). (ESI+) 501.2 (MH+) (-) 7 (d6DMSO) δ ί.49-1.73 (m, 3H), 1.82-1.89 (m, 1Ηλ 2.04-2^5 (m. 3H). 3.18 (sf 3H). 3.56 (s. 2H). 3.99 (t, J = 7.4 Hz, 1H)t 4.81-4.97 (m. 2H), 0.94 (s. 1H)t 7.63 (dt J = 8.6 Hz. 2H)t 7.89 (d, J = 8.6 Hz. 2H), 12.4 Cbr, !H), 12.5 (br. tH). (ESI+) 473.1 (MH+) (-) β e〇2日 (CDCI3) 5 t.38 (t vl = 7.0 Hz, 3H), 1,65-1.80 (nv 3H), 2.01-2.17 (m, 3H). 2.39-2.46 (m. tH). 3.00 (s. 3H). 3.75 (t J = 7.3 Hz. 1Ή). 4.38 (q. J = 7J Hj. 2H), 4.72-4.88 (m. 2H), 7.42 (d. J = 6.7 Hz. 2H). 7.84 (s. tH). 7.90 (d, J = 6.7 Hz, 2H). 9.47(bn 1H). (IESI+) 487.2 (MH+> (一） -28- 200831081 表2
化合物編號 結構(A) 1HNMR(400MHz) MS (m/z) 旋光性 9 co2h CCDCI3) 6 1.73-t.99 (mf 3H), 2.12-2.24 (m, 3H), 2.42-^49 (m, 1H). 3.04 (st 3H), 3J3 (t J = 7.7 Hr. 1H). 4.76-4.93 (m, 2H). 7.67 (4 J =Β.β 2Ηλ 7.94 W, J = S S 2Ηλ 8.02 (s. 1H). 12 β (br. 1Ηλ 15.5 (br· 1H). (ESH 459.1 CMH+> (+) 10 (CDC13) <5 1.37 (t J = 7.3 Hzr 3H)f 1.69-1.87 (m, 3H>, 2.04-2.18 (m. 3H). 2.3&-2.46 (m. 1H)· 3.07 (s· 3W. 3.74 (t* J = λ3 Hi 1H), 4.36 (q. J = 7.1 Hz, 2H), 4.74-4.92 (rof 2HX 7.52 (d. J = 8.6 Hz, 2H), 7.92 (d, J = 8.6 2H). 8.07 (8.1HX 9.87 (br. 1H). (ESI+) 487.2 (MH+) (-) 11 -^S^C°2H (d8DMS0) S 151-1.71 (m. 3H), 1.88-1.95 (m. 1H), 2.04-2.24 (in, 3H). 3.18 Cs, 3H). 4.06 (1 J = 7.7 Hzf 1H). 4.79-4.98 (m. 2H), 7.S4 (d, J = 8.6 Hz. 2HX 7.90 (<l. J = δ.β Hz. 2H). 8.03 (s. 1H). 12.8 (br. 1H). 13.1 (br, 1H). (ESW 459.1 (MH+) (-) 12 (CDCI3) δ t.39 (t, J = 7.0 Hz. 3H), 1.66-1.88 (mf 3H), 2.01-2.21 (m, 3H). 2.37-2.45 (m. 1H)( 3.08 (s. 3H). 3.63 (t J = 7.7 Hz. 1HX 4.39 (q, J = 7J 2H). 4·71-4·92 (m. 2Ηλ 7.58 Cd. J = 7.9 Hz, 2H), 7.95 (d. J = 8.6 Hz. 2H). 8.06 (br, 1H). 8.24 Cd. J = 8.6 Hz, 1HX 8.30 (dd J = 8.et 2.2 Hzf IH), 8.8$ (d, J = 2.5 Hz. 1H). (ESI+) 481.2 (MH+) (一） 13 (CDC13) <5 1.65-1.88 (m. 3H). 2.01-Z18 (m, 3H), 2：39-2.46 (m. tH), 3.08 (s, 3H), 3.67 (t J = 7.6 Hz. 1H), 4.01 (s, 3H). 4.73-4.91 (mt 2H). 6.B3 (d, J = β.6 Hz, 1H>. 7.43 (d. J = 7.3 Hr, 2H). 7.84 (d J = 8.6 Hz, 1H). 7.91 (d. J = 8.6Hz, 2H>. 9.11 (br, 1H). (ESW 496.2 (MH+) (-) 14 (d6DMSO) i t.49-1.80 (m, 4H). 2.04-2.20 (m. 3H). 3.t7 (s. 3H), 3.65 (dd, J = If, 5.5 Hz. 2H). 3.88-3.92 (m. tH). 3.98 (t J = 5.5 Hz, 2H). 4.79-5.00 (m. 2H), 4.80 (t J = 5.2 Hz. ΙΗλ 8.40 (dr J = 1.8 Hz, 1H), 7.52 Cd, J = 2.4 Hz, 1H). 7.62 (d, J = 8.6 Hz. 2H). 7.87 (d. J = 8.8 Hz. 2H). 10.8 (s, 1H). (ESI+) 442.2 (MH+) (-) -29- 200831081 表3
No. 結構(A) lHNMR(400MHz) MS (m/z) 旋光性 15 冬N ：CDC!3) δ 1.45-1.72 (m. 3H), 1.90-1.98 (m, 1H), 2.02-2.24 (m. 3HX 3.19 (s. 3Ηλ 4Ό7 (t, J = 7.9 Hz, 1H), 4.77-5.00 (m, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.91 (d, J = 8.6 Hz, 2H), 8.12 (s, 0.3H), 8.37 (s. 0.7H), 13.3 (sr 1H). ：CI) 440 (MH+) (-) (DMSO) 16 Me (CDCi3) <S 1.56-1.87 (m, 4H), 1.98-2.20 (mr 3H), 2.32 (s, 1HX 2.38-2.45 (m, 1H)t 3.07 t(m. 3H). 3.63 (t J = 7.6 Hz, 1H), 4.71-4.92 (mt 2H), 6.56 (S> 1H), 7.45 (i J = 8.6 Hz, 2HX 7.90 (4 J =8.6 Hz, 2Ηλ 9.18 {br, 1H). (ESI+) 429.2 (-) 17 (d6DMSO) δ 1.30 (t J = 7.3 Hz. 3H), 1.45-1.65 (m, 2H), t .66-1.80 (mt 2HX 2.20-2.04 (mt 3H)f 3.17 (s, 3H), 3.90 [dd, J = 8.6, 6.1 Hz. tH), 3.98 (q, J = 7.1 Hz, 2H), 4.79-5.00 (m, 2H), δ,39 (d, J = 2.4 Hz, 1H), 7.55 (df J = 2.4 Hz, 1HX 7.62 (d, J =8.6 Hz, 2H), 7.87 (d, J = 8.6Hz, 2H), 10.8 (s, 1H). (ESI+) 426.2 CMH+) (+) (DMF) 18 Ph id6DMSO) δ 1.45-1.78 (mt 2H)t 1.71 (dt, J = 7.3, 7.9 Hz, 1H), 1.89 Cddd, J = 6.1, 6.9, 14.1 Hz, 1H), 2.02-2.28 (m, 2H)t 2.23 (dt, J = 7.3, 7.9 Hz, 1H), 3.31, (s, 3H), 4.07 (t, J =7.3 Hz, 1H), 4.77-5.02 (m, 2H), 7.30 (t, J = 7.6 Hz, 1H), 7.4t (tr J = 7.6 Hzt 2H)t 7.62 (s, 1H)f 7.66 (d. J = 7.6 Hz, 2H), 7.86 (dr J = 8.6 Hz. 2H), 7.90 (dr J = 8.6 Hz, 2H), 12.6 (s, 1H). CESI+) 491.2 CMH+) (+) 19 ^ζΟ·Μβ (CDCI3) δ 1.56-1.86 (m, 3H)t 1.98-2.18 (mt 3H), 2.37-2.44 (mf 1H), 2.49 (s, 3H), 2.69-2.82 (m, 4H)r 3.07 (s, 3H). 3.58 (sf 2H)f 3.63 (t, J = 7.4 Hz, 1H)t 4.70-4.92 (m, 2H)t 7.47 (d, J = 8.6 Hz, 2H)t 7.90 (d. J = 8.6 Hzr 2H) 9.16 (s, 1HX [ESI+) 4842 (MH+) ㈠ -30- 200831081 表4
No· 結構(A) 1HNMR(400MHz) MS (m/z) 旋光性 20 N-n CDCI3) δ t.54-1.88 (m, 3H). 2.00-2.20 (mt 3H), 2.40-2.47 (m, 4H), 3.03 (s. 3H), 3.71 (t J = 7.6 Hz. 1H), 1.93-4.72 (mf 2H), 6?3i (d, J = 2.4 Hz, 1H), 7.12 (d, J = 1.2 Hz, 1H)f 7.48 (df J = 8.6 Hzt 2H)f 7.87 (d, J = 8.6 Hz, ZH), 10.89 (sf 1HX :ESI+) 429.2 rMH+) (-) 21 ：CHC13) 5 1.63-1.82 (m, 3H). 1.96-2.17 (m, 3H), 2.34-2.41 (m. 1H), 3.06 (s, 3H). 3.61 (t, J =7.6 Hz, 2H), 3.89 (s, 3H), 4.71-4.91 (mf 2H), 7.08 (dd, J = 2.4. 9.2 Hz, 1H), 7 23 (d, J = 8.6Hz, 1H), 7.32 (d, J = 2.4 Hz, 1H), 7.65 [dt J = 9.2 Hz, 1Ηλ 7.81 (d, J = 8.6 Hz, 2HX 9.84 (st 1H). ：ESI+) 495.2 ：MH+) (一） 22 (d6DMSO) δ 1.45-1.82 (mt 3HX 1.87-1.94 (m. tH), 2.01-2.28 (mf 3H), 3.18 (sr 3H). 4.08 (t J = 7.6 Hz, tH)f 4.78-5.01 (m. 2H), 7.67 (dr J = 8.6 Hz, 2H). 7.80 (dd, J = 1.8, 4.9 Hz, 2H)t 7.91 (d, J = 8.6 Hz( 2H)P 7.99 (s, 1H), 8.60 (ddt J = 1.8r 4.9 Hzf 2H)f 12.7 (s, 1H). [ES1+) 492.2 CMH+) (+) 23 (CHCI3) δ 1.61-1.85 Cmf 3H), 2.01-2.18 (m, 3H), 2.38-2.45 (m, 1H), 3 07 (sr 3H), 3.66-3.73 (m. 1H), 4.75-4.89 (m, 2H). 7.16-7.22 (m, 1H), 7.41 (d, J = 8.6 Hz, 2H), 7.51-7.54 (m, 1 H)f 7.68 (qt J = 4.5 Hz, 1H). 7.87-7.91 (m, 2H), 9.47 (s, tH). (ESI+) 483.2 (MH+) (一） 24 N-O CCDCI3) δ t .66-1.86 (m, 3H), 2.02-2.22 (m, 3H), 2.33-2.40 (m, 1H), 2.46 (sr 3H), 3.03 (sf 3H)t 3.79 (t, J = 7.6 Hzt 1H), 4.71-4.92 (m, 2H), 6.77 (s, 1H), 7.61 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hzt 2HX 9.96 (s. 1H). 〔ESI+) 413.2 CMH+) (一） 25 CdSDMSO) δ t.47-1.76 Cm. 3H). t.88-1.98 (m. 1H), 2.03-2.28 (m, 3H). 3.18 (s, 3H), 4.09 (t, J =7.6 Hzr 1H) 4.79-5.00 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H), 7.42 (t J = 7.6 Hz, 1H), 7.67 (d, J = 8.6 Hz, 2H), 7.72 (d. J = 7.9 Hz. IH) 7.92 (d, J = 8.6 Hzr 2H), 7.96 (dt J = 7.9 Hz, tH). 12.7 (s 1H). CESI+) 465.2 (MH+) ㈠ 26 j〇 (CDCI3) δ 1.75-1.89 (m. 3H)f 1.05-2.03 (mf IH) 2.06-2.21 (m, 2HX 2.33-2.42 Cm, 1H), 3.08 (sf 3H), 3.68 (t J = 7.6 Hz, 1HX 4.74-4.90 (mt 2H)? 7.25-7.29 (m, 1H) 7.57 (dr J = 8.6 Hz, 2H\ 7.88 (d, J = 8.6 Hzr 2H) 8,15-8.20 (m, 1H)r 8.30-8.37 (m. 2H), 8.52 (d, J = 1.8 Hz 1HX (ESI+) 409.2 _+) f ㈠ -31 - 200831081 表5
No. 結構(A) lHNMR(400MHz) MS (m/z) 旋光性 27 CDCI3) δ 1,66-1.90 (mt 3H), t.99-2.06 (m, 1H)f( 2.09-2.22 (m. 2H), 2.38-2.45 (m, tHX 3.05 (s, 3H), 3.61 (t,! i = 7.3 Hz, 1H), 4.72-4.93 (m, 2H), 7.06 (dd, J = 6.7, 4.9 Hz, 1H). 7.57 (d, J = 7.9 Hz, 2HX 7.71 (td, J = 7.9, 1.8 Hz, IH\ 7.93 (d, J = 7.9 Hz, 2H), 8.02 (s, 1H), 8.17 (d, J = 8.6 Hz, 1HX 8.24 (ddt J = 1.2, 4.9 Hzt 1H). ESI+) 409.2 MH+) ㈠ 28 [CDCI3) δ t .70-1.91 (m, 3H)t 1.96-2.03 (m, tH), 2.07-2.21 (m, 2H), 2.33-2.42 (mr 1HX 3.07 (s. 3H), 3.64 (t, J = 7.6 Hz, 1H), 4.72-4.93 (m, 2H), 7.47-7.48 (mr 2H), 7.55 (d, J = 8.6 Hz, 2H), 7.89 (d, J = 8.6 Hz, 2H)t 8.07 (s, 1H), 8.45-8.47 (m, 2H). ：ES1+) 409.2 ：MH+) (-) 29 N-O (CDC13) δ t.68-1.86 (m, 3H), 2.02-2.24 (mf 3H), 2.35-2.43 (m, 1H), 3.04 (s, 3H), 3.78 Ct J = 7.3 Hz, 1H), 4.72-4.92 (m, 2H), 7.13 (df J = 1.8 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), 7.91 (dt J = 8.6 HzT 2H)r 8.36 (d, J = 1.8 Hz, 2H), 9.73 (s, 1H). (ESI+) 399.2 (MH+) (-) 30 (CDC13) δ 1.64-1.78 (m, 3H)· 1.98-2.05 (m, 1H), 2.08-2.22 (m, 2H), 2.28 (s, 3H), 2.37-2.44 (m, 1H)r 3.05 (s, 3HX 3.59 (t J = 7.6 Hz, 1H), 4.71-4.92 (mr 2H), 7.52 (dd, J = 8.6, 2.4 Hz, 1H), 7.56 (d, J = 8.6 Hzt 2H)r 7.92 (d, J = 8.6 Hz, 2H), 8.02-8.07 (m, 3H). (ESI+) 423.2 (MH+) (-) 31 Cd6DMSO) δ 1,47-1.73 (mr 3H)( 1.87-1.94 (m, 1H), 2.02-2.22 (m, 3H)f 2.04-2.26 (m. 9H). 2.45-2.50 (m, 2H) 3.02 (s, 3H). 3.18 (s, 3H), 3.64 (t J = 6.7 Hz, 2H). 4.05 (t J = 7.6 Hz, 1H)r 4.79-5.00 (m, 2H), 6.77 (s, tH), 6.72 (dr J =9·2 Hz, 2H), 7.66 (d, J = 8·6 Ηζ· 2H), 7 80 (d, J = 9.2 Hz, 2H), 7 91 (d, J = 8.6 Hz. 2H). 12.4 (s, 1H). (ESI+) 566.2 〔MH.) • (一） 32 CCDC13) δ 1.67-1,92 (m, 3HX t.96-2.05 (m, 1H) 2.06-2.23 (m, 2H), 2.39-2.48 (m, 1H)f 3.04 (s, 3H) 4.71-4.80 (m, ΙΗλ 4.84-4.93 (m? ΙΗλ 7Ό5 (t J = 4.9 Hz 1H), 7.62 (d, J = 8,6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H) 8.35 (bn 1H), 8.61 (d, J = 4.9 Hz, 2H). ,[ES1+) 410.2 ,(MH+) (-) (DMF) -32- 200831081 表6
No. 結構(A) lHNMR(400MHz) MS (m/z) 旋光性 33 ,Ν d6DMSO) δ 1.44-1.79 (m, 3H), 1.79-193 (m, 1H)f 1.98-2.25 (m, 3H)t 3.20 (s, 3H), 4.12 (t J = 7.3 Hz. 1H)f 175-5.02 (m. 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.91 (d, J = B.6 Hz, 2HX 8.35 (dt J = 2.4 Hzr 1H)r 8.38 (dd, J = 1.2, 2.4 Hz, 1HX 9.3 (d, J = 1.2 Hz, 1H). 11.2 (st 1H). ESI+) 410.2 ：MH+) ㈠ 34 iT ：d6DMSO) δ 1.45-1.79 (mf 3H), 1.80-1.91 (mr 1H), 2.00-2.24 (m, 3Ή), 3.18 (s. 3H)r 4.13 (t J = 7.3 Hz, 1H), 4.78-5.01 (m, 2H)r 7.66 (dt J = 8.6 Hz, 2H), 7.89 (df J = 8.6 Hz, 2H)f 8.18 (d, J = 8.6 Hzt 1H). 8.23 (dd, J = 1.8, 8.6 Ηζ· 1H), 8.77 (t, J = 1.2 Hz, 1H), 11.4 (s，1H). [ESI+) 434.2 〔MH+) (-) 35 i?c, (d6DMSO) δ 1.45-1.77 (mf 3H), t.77-1.89 (mt tH), t .99-2.25 (mr 3H), 3.18 (s, 3H), 4.09 (t J = 7.9 Hz, 1H). 4.78-5.01 (m, 2H), 7.65 (d, J = 8.6 Hz, 2H)f 7.87 (dd, J = 2Λ 9-2 Hz, 1H), 7.89 (d, J = 8.6 Hz, 2H). 8.08 (d, J = 9.2 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H)· 11.0 (s，1H). (ESI 十）443.2 CMH.) ㈠ 36 Cd6DMSO) δ 1.42-1.77 (m, 3H)r Ί.77-1.8Β (m, 1H), 2.00-2.24 (m, 3H)t 3.18 (s, 3H), 4.08 (t J = 7.9 Hz, 1H)( 4.78-5.04 (m. 2H). 7.68 (d, J = 8,6 Hz, 2H)( 7J1 (dt J = 3.1, 9.2 Hzf 1H), 7.88 (dt J = 8.6 Hz, 2H). 8.09 (dd, J = 3.1, 9.2 Hz, tH), 8.3t (d, J = 3.t Hz, 1H)t 11.0 (s( 1H). (ESI+) 427.2 〔MH+) (-) 37 xo (d6DMSO) 6 1.43-1.92 (m, 4H), 2.02-2.29 im, 3HX 3.17 (st 3H)f 4.08 (t, J = 7.3 Hz, 1H)r 4.74-5.02 (mf 2H), 7.52 Cdt J = t.2. 7.3 Hz. 1H), 7.69 (dt J = 1.2r 7.3 Hz, 1H) 7.70 (d, J = 8.6 Hz，2H), 7.86 (d，J = 7.9 Hz，1H)，7.89 (d J = 8.6 Hzf 1HX 8.03 (d, J = 7.9 Hz, 1HX 8.45 (s, 1H) 9.13 (s, 1HX 11.0 (sf 1HX (ESI+) 459.2 (MH+) (-) 38 Me (d6DMSO) δ 1.44-1.86 (m, 4H), 2.00-2.22 (m, 3H), 2.21 (s, 3H). 3.17 (s, 3H), 4.09 (t, J = 7.3 Hz, 1H), 4.74-5.02 (m, 2H). 6.93 (d, J = 4.9 Hz. 1Ηλ 7.66 (d, J = 8.6 Hz, 2H) 7.88 (d, J = 8.6 Hz, 2H), 7.89 (df J = 4.9 Hz, 1H). 8.14 (d J = 5.5 Hz, 1H), 10.8 (s, 1H). ^(ESH 423.2 (一） -33- 200831081 表7
No. 結構(A) lHNMR(400MHz) MS (m/z) 旋光性 39 Μ ；d6DMSO) δ 1.45-1.87 (mt 3H), 1.88-195 (m, 1H), 2.06-2.29 (mr 3H)f 3.19 (s. 3H), 4.17 (t J = 7.3 Hz, 1H), 4.76-5.02 (m, 2H), 7.71 (d, J = 7.9 Hz? 2H), 7.72 (dd, J = 1.8, 8.6 Hz, 1H), 7.80 (ddd, J = 1.2, 1.8, 7.3 Hz, 1HX 7.87 ：dd, J = t.2, 7.3 Hz, IH), 7.9t (df J = 7.9 Hzt 2H)f 8.03 (dd, J = 1.2, 7.3 Hz, 1H), 9.61 (s, 1H), 11.5 (s, 1H). ；ESI+) 460.2 [MH+) (+ ) 40 [d6DMSO> δ 1.46-1.92 (m, AH), 2.01-2.26 (m, 3HX 3.18 Cs, 3H), 4.17 Ctf J = 7.3 Hz, IH), 4.75-5.03 (m, 2H)t 7.48 Cm, 1H), 7.70 (m, 1H), 7.71 (d, J = 8.6 Hz, 2H), 7.79 (dr J =1.8, 8.6 Hz, 1H), 7.80 (df J = 8.6 Hz, 1H)f 7.89 (m, 1H), 7.90 (df J = 8.6 Hzt 2H), S.26 (dt J = 9.2 Hz, 1H)t 8.33 Cd, J = 9.2 Hz, tH), 11.2 (s, 1H). CESI+) 459.2 CMH+) (+ ) 41 从 (d6DMSO) δ 1.43-1.77 (m. 3H)t 1.79-1.91 (m, 1H), I. 99-2.25 (m, 3H), 3.18 (sf 3H), 4.15 (t J = 7.3 Hzf 1H), 4.75-5.03 (m, 2H)t 7.58 (d, J = 7.3 Hz, 1H), 7.66 (d, J = 8.6 Ηζ» 2H), 7.89 (d，J = 8.6 Ηζ· 2H)，7.79 (d, J = 1.8, 8.6 Hzf 1H), 8.05 (t J = 7.9 Hz, 1H), 8.34 (d, J = 8.6 Hz, 1H), II. 3 (sr 1H). (ESI+) 477.2 iMH+) ㈠ 42 Cd6DMSO) δ 1.50-1.68 (m, 2H), 1.72-1.86 (mf 2H), 2.07-2.21 (m, 3H), 3.20 (s, 3H). 3.95 (t, J = 7.3 Hz, 1H), 4.80-5.02 (m, 2H)t 7.64 (d, J = 8.6 Hz, 2H), 7.90 (d, J = 8.6 Hz, 2H), 7.99 (ddd, J = 9.8, 8.6, 2.4 Hz, 1H), 8.3t (d, J = 2.4Hz, 1H), 10.6 (s, 1H). (ESI+) 445.2 (MH+) (-) 43 (CDCI3) δ 1.15-1.43 (m, 4H). 1.55-1.76 (mt 4H) 1.83-1.91 (m, 3H)t 1.95-2.20 (m, 5H)f 2.38-2.45 (m, 1H) 3.05 (st 3H), 3.54 (t, J = 7.7 Hz. 1H)( 3.89 (tt, J = 1.6, 3.8 Hz, 1H), 4.71-4.91 (m, 2H)f 6.62 (d, J = 2.4 Hz, 1H), 7.29 (1H, d, J = 2.4 Hz, 1H)f 7.56 (ddr J = 8.6 Hz, 2H), 7.86 (s 7.91 (d, J = 8.6 Hz, 2H). [ESW 480.2 (MH+) (-) 44 (CDCI3) δ 1.66-2.02 (m, 10HX 2.05-2.22 (m, 4H) 2.37-245 (m, 1H)r 3.05 (sf 3H), 3.53 (t, J = 7.6 Hz 1H), .4.43-4.50 (m. 1H), 4.70-4.92 (m, 2H), 6.62 (dr J = 2.4 Hz, 1H), 7.3Q (dt J = 2.4 Hzt tH)f 7.56 (dd, J = 8.6 Hz 2HX 7.76 (s, 1HX 7.92 (d, J = 8.6 Hz, 2H). (ESI+) 466.2 細十） (+ ) (DMF) -34- 200831081 表8
No. 結構(A) 1H NMR(400MHz) MS (m/z) 旋光性 45 ；d6DMSO) <S 1.44-1.82 (m, 4H), 2.03-2,21 (mt 3H), 3.17 ：s, 3H), 3.28-3.32 (m, 1H), 3.88-3.94 Cmr 1H), 4.28 (dt, J = 27.7f 4.7 Hz, 2H), 4.68 (dt, J = 47.3, 4.7 Hz, 2H), 4.78-5.00 (m. 2H), 6.45 (d. J = 2.4 Hz, 1H), 7.60 (d, J = 1A Hz. tH), 7.63 (d, J = 8.6 Hz, 2H), 7.87 (d. J = 8.6 Hz? 2H),t0.8 (s, 1H). ：ESI+) 444.2 ：MH+) (+ ) (DMF) 46 W6DMSO) δ 1.43-1.91 (m, 4H)t 2.00-2.24 (mf 3H), 2.42 [s, 3H), 3.18 (sr 3HX 4.09 (t, J = 7.3 Hz, 1H), 4.77-5.01 (m, 2H), 7.67 (df J = 8.6 Hz, 1HX 7.89 (dt J = 8.6 Hzr 1H), 8.27 (d, J = 1.2 Hz, 1H)t 9.16 (d, J = 1.2 Hzt 1HX 11.0 (s, tHX ：ESI+) 4232 [MH+) ㈠ 47 (CDCI3) <5 1.12 (t. J = 7.0 Hz, 3H). 1.21 (t J = 7.0 Hz, 3H), 1.63-1.90 (m, 3H). 1.94-2.01 (m, 1H). 2.07-2.20 (m, 2H), 2.37-2.44 (m. 1H)f 3.05 (s, 3H), 3.30-3.41 (mt 4H), 3.54 (t. J = 7·6 Hz, 1H), 4.71 -4.77 (m，2H)· 6,72 (d· J = 2.4 Hz，f Η), 7·37 (d· J = 2.4 Hz, 1H)· 7.54 (d, J = 8.6 Hz, 2H). 7.75(sf 1H), 7.91 (d, J = 8.6 Hz, 2H). CESI+) 511.2 (MHt) (+) (DMF) 48 (CDCI3) δ 1.43 (d, J = 6.7 Hz, 6H), 1.66-1.89 (m, 3H), 1.95-2.02 (m, 1H), 2.08-2.20 (m· 2H), 2.38-2.45 (m. 1H), 3.05 (s, 3H), 3.54 (t, J = 7.6 Hz, 1H), 4.27-4.34 (mt 1H), 4.71-4.92 (m, 2H)r 6t62 (d, J = 2.4 Hz, 1HX 7.30 (d. J = 2.4 Hzf 1H)f 7.56 (dr J = 8.6 Hz, 2H)f 7.79 (s, tH), 7.92 (d, J = 8.6 Hz，2H)· (ESI+) 440.2 (MH+) (+) (DMF) 49 (CDCI3) δ 1.50 (s, 9H), 1.66-1.90 (m, 3H), 1.95^2.02 (m, 1H). 2.09-2.21 (m, 1H). 3.05 (s, 3H). 3.54 (t J = 7.6 Hz, 1Ηλ 4.71-4.92 (m, 2H)t 6,62 (dt J = 2.4 Hzf 1H), 7.39 (d, J =2.4 Hz, ΊΗλ 7.57 (d, J = 8.6 Hz, 2H)t 7.79 (sr tH), 7.92 〔d，J = 8,6 Hz，2H). (ESI+) 454.2 〔MH+) (+) (DMF) 50 (CDCI3) δ 0.91 {% J = 7.3 Hzt 3H). 1.28 (q, J - 7.3 Hz, 2H), 1.66-1.87 (mr 2H), 1.96-2.20 (mf 3H), 2.38-2.45 (m 1HX 3.05 (s, 3HX 3.54 (t, J = 7.6 Hz, 1H)t 3.95 (t, J = 7.C Hzr 2H). 4.71-4.91 (m, 2HX 6f62 (d, J = 2.4 Hzt 1H)t 7.25 [d, J = 2.4 Hz. 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.70 (s, 1H) 7.92 (d, J = 8.6 Hz, 2H). CESI+) 454.2 (MH+) (+) (DMF) -35- 200831081 表9
No. 結構(A) lHNMR(400MHz) MS (m/z) 旋光性 51 iT Id6DMSO) δ 1.43-1.77 (mr 3H), 1.78-1.89 (m, 1H), 1.99-2.26 (m, 3H), 3.18 (st 3H)f 4.14 (t, J = 7.3 Hz, 1H), 4.76-5.02 (m. 2H), 7.66 (dr J = 8.6 Hz, 2H), 7.90 (df J = 8.6 Hz, 2H), 8.16 (dd, J = 2.4r 8.4 Hz, 1H). 8.24 (d, J = 8.4 Hz, 1H), 8.70 (dt J = 2.4 Hz, 1HX 11.3 (sf 1H). :ESI+) 477.1 ；MH+) (一） 52 [d6DMSO> δ 1.42-1.88 (m, 4H)t 2.00-2.26 (mt 3H), 2.4t (s, 3H), 3.18 (s? 3H), 4.11 (t, J = 7.3 Hz, 1H), 4.76-5 02 (mr 2H), 7.66 (d, J = 8.6 Hz, 2H). 7.89 (d, J = 8.6 Hz, 2H), 8.25 (s, 1H)f 9.11 (sf 1H), 11.1 (s, 1H). :ESI+) 424.1 [MH+) (一） 53 (CDCI3) δ t.74-1.88 (m, 3H), 2.01-2.08 (m, 1H), 2.10-2.23 (m, 2Ηλ 2.42 (dt J = 15.3r 7.9 Hz, 1H), 3.06 (s, 3H), 3.64 (t. J = 7.6 Hz. 1H). 4.72-4.94 (m, 2H)t 7.28 (s, tH), 7.59 (dt J = 8.6, 1.8 Hz, 2HX 7.96 (dt, J = S.6, t.8 Hz, 2H)r 8.07 (s, 1H), 8.40 (df J = 4.9 Hz, 1HX 8.48 (s( 1H). (ESI+) 477 (MH+) (一） 54 CCDC13) δ 1.65-1.89 (m, 3H), 1.97-2.05 (m, 1H)t 2.09-2.20 (m, 2H), 2.36-2.44 (m. 1H), 3.06 (sf 3H)f 3.56 (t, J = 7.6 Hz, tH), 4.53 (q, J = 8.4 Hz. 2H), 4.71-4.91 (m, 2H), 6,81 (d, J = 2.4 Hz, 1H), 7.38 (d, J = 2.4 Hz, 1H), 7.56 (d, J = 8.6 Hz, 2H), 7.80 (s, tH)? 7.93 (d, J = 8.6 Hz, 2H)· [ESW 4801 (MH+) (+) (DMF) 55 F (CDCI3) δ 1.66-1.89 (m，3H), 1.98-2.20 (m, 3H)· 2.37-2.44 (mr 1H), 3.06 (s, 3H)f 3.59 (t, J = 7.6 Hz, 1H), 4.72-4.92 (m, 2H). 6.94 (dt J = 3.1 Hzt 1H)( 6.97 (t J = 61.1 Hz, tHX 7.56 (dr J = 8.6 Hzf 1HX 7.69 (dr J = 3.1 Hz, 1H), 7.79 (s, IH), 7.94 (d. J = 8.6 Hzt 2H). (ESI+) 448.1 〔MH+) (+ ) (DMF) 56 〔CDCI3) <5 1.71-1.91 (m, 3H), 2.03-2.25 (m, 3H), 2.34-2.41 (m, tH), 3.01 (sf 3H), 4.67-4.91 (mr 3H), 7.6C (dd, J = 9.2r 4.9 Hz. 1H)( 7.71 (d, J = 8.6 Hz, 2Hl 7.86 (d J = 8.6 Hz, tH), 8,69 (,ddt J =9.2. t.8 Hz, 1H), 9.01 (dd( J = 4.g, 1.8 Hzt tHX 11.4(s, 1H). 〔ESI.) 410.1 (MH+) (-) (DMF) -36- 200831081 表10
No. 結構(A) 1H NMR(400MHz) MS (m/z) 旋光性 57 ：d6DMSO) δ 149-1.79 (m, 3H), 1.84-1.91 (m, 1H),( 2.05-2-27 (m, 3H), 3.18 (s, 3H), 4.22-4.15(m, 1H),( Φ.79-5.01 (m, 2H)f 7.70-7.74 Cm. 3H)t 7.91 (d, J = 8.6 Hz, 2H), 8.18 (df J = 8.6 Hzt !H), 8.39 (d, J = 9.2 Hz, 1H)f B.49 (d, J = 9.2 Hz, 1H)r 8.86 (q. J = 2.0 Hz, 1H), 11.3 (sf 2H). ：ESI+) 460.2 ：MH+) (+) (DMF) 58 ΐΟ W6DMSO) S 1.48-1.80 (mf 3H)r 1.84-1.91 (m, 1H)f 2.05-2.27 (mf 3H)f 3.18 (s, 3H)f 4.21-4.15(mf 1H)f 4.79-5.01 (m, 2H), 7.51 (ddr J = 8.6, 4.3 Hz, 1H), 7.71 (d, J = 7.9 Hzf 2H), 7.91 (d, J = 8.6 Hz, 2H)f 8.37 (dd, J = 7.9, 1.8 Hzr 2HX 8.43 (d, J = 9.2 Hz, 1H), 8.98 (q, J = 4.3, 1.8 1HX 11.5 (st IHX ：ESI+) 460.2 ：MH+) (+) (DMF) 59、 (CDCI3) δ 1.26 (s, 9H), 1.65-t.9t (m, 3H)f 1.97-2.22 (m, 3H), 2.38-2.48 (mr 1H), 3.06 (s, 3H), 3.64 (tf J = 7.3 Hzf m), 4.70-4J3 (m, 2H), 6.55 (s, 1H). 7.55 (d, J = 8.6 Hz, 2HX 7.94 (d, J = 8.6 Hz, 2H), 8.80 (brt 1H). CESK) 471.2 CMH+) (一） 60 [CDCI3) δ 1.65-1.88 (m, 3Ηλ 2,01-2.17 (m, 3H), 2.38-2.47 (m, tH). 3.08 (s, 3H). 3.46 (s. 3HX 3.68 (t, J = 7.6 Hz, 1HX 3.77-3.80 (m, 2H), 4.53-4.56 (m, 2H), 4.71-4.93 (m, 2HX 6.87 (dt J = 9.2 Hz, 1H), 7.46 (d, J = 8.6 Hz, 2H), 7.83 (d, J = 9.2 Hz, 1H)( 7.91 (d, J = 8.6 Hz, 2H). 9.20 (sr 1H). CES1+) 540.1 〔MH+) ㈠ 61 Λ7 (CDCI3) <5 1.72-1.87 (m. 3H). 1.98-2.07 (mr 1H). 2.07-2.21 (m. 2H). 2.36-2.45 (mt 1H)t 2.47 (s, 3H). 3.05 (s, 3H)t 3.59 (t J = 7.3 Hzt 1H), 4.71-4.93 (m, 2H), 7.57 (dt, J = 8.6, 1.8 Hz, 2H), 7.63 (dd, J = 8.6, 2.4 Hzf 1H), 7.89 (s, 1H). 7.94 (dt, J = 8.6, 1.8 Hz, 2H), 8.12 (dt J = 8.6 Hz, 1H), 8.16 (d, J = 2.4 Hz, 1H). (ESI+) 455.1 (MH+) (-) 62 CCDCI3) δ 1.68-1.86 (m, 2H)f t.87-2.04 (m, 2H), 2.11-2.25 (mf 2H), 2.44-2.52 (m, 1H)f 3.04 (sr 3H), 3：94 (s, 3H). 4.02 (s, 1H)f 4.71-4.93 (m, 2H). 708 (ddf J = 7.9. 4.S Hzr 1H). 7.66 (dt, J = 8,9, 1.8 Hz, 2H), 7.91 (dt J = 8.6 1.8 Hzr 2H)r 8.30 (dd, J = 7.6, 1.8 Hz, 1H), 8.61 (dd, J = 4.9.1.8 Hz, 1H), 11.1 (s, 1H). (ESI+) 467.1 〔MH+) (+) -37- 200831081 表11
No. 結構(A) 1H NMR(400MHz) MS (m/z) 旋光性 63 Me ：CDCI3) δ 1.66-1,δ5 (m, 3H), 1.§8-2.06 (m, 1H)f 2.Q8-2.18 (m, 2H), 2.26 (s, 3H), 2.33-2.42 (mf 1H)r 3.08 (sf 3H). 3.69 (t, J = 7.6 Hz, IH), 4.71-494 (in, 2H)f 6.23 (s, 1H), 7.54 (df J = 8.6 Hzt 2H), 7.92 (d, J = 8.6 Hz, 2H), B.67 (sf tH). ：ESI+) 413.1 ：MH+) (-) 64 CCDCI3) δ 1.26 (ddt J = 7.3. 1.8 Hz, 6H), 1.65-1.88 (mf 3HX 1.98-2.20 (m, 3H), 2.38 (dt, J = 13.4, 7.3 Hzt 1H), 2.95-3.05 (mf 1H)f 3.08 (st 3H), 3.68 (t, J = 7.3 Hzt TH), 4.72-4.94 (m, 2H), 6.27 (s, tH), 7.54 (dt. J = 8.6, 1.8 Hz, 2H). 7.92 (dt, J = 8.6, 1.8 Hz, 2H), 8.51 (s, 1H). ：ESI+) 441.2 [MH+) ㈠ 65 -^〇^C02Et (CDCI3) δ 1.37 (t J = 7.3 Hz, 3H). Ι.65Ί.89 (mf 3H)f 1,96-2.05 (m, 1H)r 2.06-2.21 (m； 2H), 2.34-2.43 (m, 1Ή), 3.08 (s, 3H)t 4.37 (q, J = 7.3 Hz, 2HX 4.71-4.93 (m. 2H), 7.57 (d, J = 7.9 Hz, 2H). 7.62 (s, 1H), 7.91 (dt, J = 8.6, t.8 Hz, 2H), 8.85 (s, 1H). (ESI+) 471.1 (MH+) (-) 66 ^^^S02Me i7 (CDCI3) δ 1.67-1.89 (m, 3H), 2.02-2.21 (m. 3H), 2.36-2.45 (m, 1H), 3.07 (s, 3H), 3.08 (s, 3H), 3.68 (t, J = 7.3 Hzf 1H)f 4.72-4.93 (m, 2H), 7 58 (dt, J = 7.9, 1.8 Hz, 2Hr). 7.96 (dt, J = 7.9, 1.8 Hz, 2H), 8.18-8 22 (m, 2H)r 8.39 (4 J = 9.2 Hzr 1H)r 8.77 (d, J = 2.4 Hz, 1H). (ESI+) 487.1 (MH+) (-) 67 Me (CDCI3) δ 1.64-1.78 (mt 2HX 1.80-1.92 (m, 1H), 1,94-2.02 (mt 1H)r 2.07-2.21 (m, 2HX 2.35 (s, 3H), 2.36-2.45 (m, IH), 3.09 (s, 3H)f 3.75 (dd, J = 7.9, 6.7 Hz, 1H), 4.71-4.93 (m, 2H), 6.60 (sf 1H), 7.52 (dt, J = 8.6. 1.8 Hz, 2H). 7.85 (dt J = 8.6, 1.8 Hz, 2H). 9.32 (s. 1H). (ES1+) 429.1 CMH+) (-) 68 冬 (CDCI3) δ 1.64-188 (m. 3H). 2.00-2.21 (m, 3H) 2.37-2.46 (mf 1H)f 3.07 (s, 3H)# 3.70 (t J = 7.3 Hz, tH) 4.71-4.93 (m. 2H), 7.25 (s. tH), 7.49-7.55 (m, 2H) 7.91-7.96 (m, 2H), 9.28 (sr 1H). (ESI+) 449.C 〔MH十） (一） -38- 200831081 表12
No. 結構(A) IH NMR(400MHz) MS (m/z) 旋光性 69 ：CDC13) δ 1.66-1.99 (m, 3N), 2.02-2.28 (m, 3H), 2.49-2.59 (mf 1H), 3.02 (s, 3H),4.03 (t J = 7.3 Hz, 1H)^ 4.69-4.95 (mt 2H)f 7.32 (s, 1H), 7.47-7 53 (mf 1H), 7.60 (d, J = 8.6 Hz, 乂 7.89 (d J = 8.6 Hz, 2H), 8.10-8.17 (m, IH), 8.64-8.69 (m, 1H)t 9.79 (s, 1H), 12.8 (br, 1H). ：ESI+) 492.1 ：MH+) (+) 70 ^^C02Et [CDCI3) δ 1.37 (t, J = 7.3 Hz, 3Ηλ 163-1.87 (m, 3H), 1.98-2.22 (m, 3H), 2.36-2.47 (m, 1H). 3」1 (s, 3H), 3.77 (t J = 7.3 Hz，1H)· 4.38 (q, J : 7.3 Ηζ· 2H). 4,70-4.94 (m, 2H>, 7·50 (d· J = 8.6 Hz· 2H)f 7.93 (d· J = 8·6 Hz，2H), 9.59 (brJH). [ESI+) 555.1 (MH+) (一） 71 Me -^s^C02Me (CDCI3) δ t .63-1.89 (m, 3H), 199-2.22 (m, 3H). 2.37-2.48 (m, 1H). 2.59 (s, 3H)r 3.08 (s, 3H), 3.68 (t J = 7.6 Hz, 1HX 3.85 (s, 3H)f 4.70-4.93 (m, 2HX 7.42-7.54 (m, 2H), 7.9t-7.97 (mr 2H), 8.89 (s, 1H). (ESI+) 487.1 _+) ㈠ 72 Me 方 (CDCI3) cS 1.67-1.88 (m, 3H). 1.99-2.21 (m, 3H)f 2.31 (d, J = 1.2 Hz. 1H), 2.37-2.44 (m. 1H), 3.05 (s. 3H), 3,58 (t J =7·6 Hz. 1H)，4.72-4.92 (mt 2H). 7.57 (d, J = 8.6 Hz，2H)， 7.81 (s, 1H), 7.94 (dr J = 8.6 Hz, 2H), 7.97 (sr 1H), 8.08 (d ： J =5.5 Hz, 1H). (ESI+) 441.2 (MH+) ㈠ (DMF) 73 ^^^S〇2NMe2 Λ/ (CDCI3) <S 1.67-1.90 (mt 3H)t 2.01-2.23 (m, 3H), 2.37-2.45 (m, tH), 2.72 (sf 6H)T 3.07 (s, 3H), 3,67 (t, J = 7.3 Hzt 1H), 4.73-4.94 (m； 2H), 7.59 (d, J = 8,6 Hz, 2H), 7.95 (df J = 8.6 Hz, 2HX 8.05 (dd. J = B2r 2.4 Hz, IH), 8.19 (s. 1H). 8.36 (d, J = 8.6 Hz, 1H), 8.62 (d, J 二 2.4 Hz_ IH). (ESI+) 516.1 〔MH+) (-) (DMF) 74 ΛΧ CCDCI3) δ t.68-1.88 (m, 3H), 2.03-2.22 (m. 3H), 2.37-2.44 (m. 1H), 3.06 (s, 3H), 3,66 (t, J = 7.6 Hz. 1H) 4.73-4.93 (m. 2H), 7.58 (d. J = 8.6 Hz, 2H), 7.80 (s. IH) 7.96 (d, J = 8.6 Hzf 2H), 8.3t (d, J = t.8 Hz, 1H). 9.30 (d J = 1.2 Hz, Ί Η). (ESI+) 488.0 (MH+) ㈠ (DMF) -39- 200831081 表13
No. 結構(A) lHNMR(400MHz) MS (m/z) 旋光性 75 XT [CDCI3) δ 1.68-1.93 Cmt 3H), 2.04-2.23 (m, 3H), 2.41-2.48 (m. 1H), 3.07 (sf 3H), 3,69 (t, J = 7.6 Hz, 1H), 4.74-4.93 (mr 2H), 7.42-7.58 (m, 2H), 7.61 (dP J = 8.6 Hz, 2H), 7.86 (sr 1HX 7.95-7.98 (m, 4H)f 8.64 (d, J = 1.8 Hz, 1H), 9.54 (s, tH). £SI+) 486.2 〔_+) (-) (DMF) 76 €02Et (d6DMSO) δ 1.33 Ct, J = 7.3 Hz, 3H), 1.50Ί.83 (m, 3H), t .86-1.95 (m. IH)f 2.10-2.29 (m. 3H), 3.26 (s, 3HX 3.96 (br, 1H)r 4.31 (q, J = 6.7 Hz, 2H)( 4.85-5.07 (m, 2H), 7-69 Cdt J = 7.9 Hz, 2H). 7.97 (d, J = 7.9 Hz, 2H), 8.60 (s. IH), 11.9 (s, 1H). (ESI+) 471.1 (MH+) ㈠ 77 (d6DMSO) 5 1.5S-1.83 (mf 3H), 2.07-2.31 (mr 3H), 2.37-2.46 (m. tH), 3.28 (s, 3H), 4J7 (t, J = 7.9 Hz, 1H), 4.85-5.08 (m, 2H)f 6.44 (tr J = 6.1 Hzr 1H)f 7.71 (dd, J = 6.1 r 2.4 Hz, 1H)r 7.79 (dt J = 8.6, 1.8 Hz. 2H), 8.0t Wt J =8.6, 1.8 Hz, 2HX 8.27 (dd, J = 7.3, 2.4 Hz, 1H), 12.3 (s, 1H). ：ESI+) 450.1 (MH+) (-) 78 寻/ W6DMSO) S 1.47-1.69 (m, 2H), 1.69-1,78 (mt tH), 1.80-1.88 (m, 1H), 2.05-2.24 (m, 3H), 3.18 (sf 3H), 4.06 (br. 1H)f 4.80-5.01 (m, 2H)f 721 (dd, J = 6.7, 4.3 Hz, tH), 7.66 (d, J = 8.6 Hz, 2H)r 7 90 (d, J = 8.6 Hz, 2H)f 8.75 (dd, J = 4.3f 1.8 Hzr 1H), 9.26 (dd, J = 6.7, 1.8 Hz, 1H), 11.4 (s, 1H). CESI+) 450.2 (MH+) (-) (DMF) 79 -rOH (d6DMSO) δ 1.43-1.76 (m, 3H), 1.78-1.93 (mr 1H), t.99-2.27 (mr 3H), 2.70 (t J = 7.3 Hz, 2H)f 3.32 (s, 3H), 3.63 (dd, J = 11.0, 7.3 Hz, 2H), 3.99 (t, J = 7.9 Hz, 1H), 4.59 (t J = 4.8 Hz, 1H), 4.76-5.02 (mt 2H)t 6.78 (s, 1H), 7.63 (d, J = 7.9 Hz, 2H)，7.89 (d. J = 8.6 Hz, 2H)，124 (br, 1H). (ESI+) 459.1 (MH+) (一） 80 濟，* (CDCI3) d 1.80-1.90 (m, 2H), 2.02-2.21 (m, 4H), 2.37 (s, 3H), 2.39-2.49 (m, 1H)r 2.77 (t J = 5.5 Hz, 2H), 3.07 (s, 3H). 3.73 (t. J = 7.6 Hz, 1H), 4.49 (t, J = 5.5 Hz, 2H) 4.71-4.93 (m, 2H), 6.78 (dr J = 8.6 Hzt 1H), 7.52 (d, J = 8.6 Hz, 2H), 7.76 (dr J = 8.6 Hz, 1H), 7.93 (d, J = 8.6 Hz, 2H). 〔ESI+) 553.2 〔MH+) (-) -40- 200831081 表14
No· 結構(A) 1HNMR(400MHz) MS (m/z) 旋光性 81 ：CDCI3) δ 1.44 (% J = 7.3 Hzf 3H), 1.66-1.90 (mt 3H), 2.03-2.24 (m, 3H), 2.37-2.46 (m. 1H), 3.07 (s. 3H), 3,72 (t, J = 7.3 Hz. 1H)t 4.49 (q, J = 7.3 Hzr 2H), 4.72-4.94 (m, 2H), 7.59 (d, J = 8.6 Hz, 2H), 7.97 (d, J = 8.6 Hzf 2H), B.11 (s· 1H), 8.94 (d· J = 1.2 Hz, 1H). 9.61 (d, J = 1.2 Hz, 1H). ；ESI+) 482.2 ：MH+) ㈠ 82 .N^COaMe Λ；ϊ CCDC13) δ t.65-1.91 (mr 3H)t 2.04-2.23 (mt 3H), 2.38-2.46 (m, 1H)，3.07 (s, 3H). 3.71 (t, J = 7.3 Hz· 4.02 (s, 3H). 4.73-4.94 (mf 2H), 7.59 (dt, J = 8.6, 1.8 Hz, 2H)t 7.97 (dt, J = 8.6, 1.8 Hz. 2H)t 8.08 (s, 1H), 8,95 (d, J =t.8 Hz, 1H). 9.60 (d, J = 1.2 Hz, 1H). CESI+) 468.2 (MH+) (-) 83 CCDCI3) δ 0.60-0.70 (m? 2H), 0.94-1.03 {m, 2H), 1.64-1.90 (m, 4H), t.95-2.23 (mf 3H), 2.34-2.45 (mr 1H), 3.05 (sr 3HX 3.57 (t, J = 7.3 Hz, 1H) 4.68-4.93 (mt 2H), 7.33 (dd· J = 8.6, 1.8 Ηζ· 1H), 7.54 (d，J = 7,9 Ηζ· 2H), 7.91 (d, J = 8,6 Hz, 2H), 7.98 (br, 1H), 8.02-8.07 (m, 2H). (ESI+) 449.2 〔MH 十〉 (一） 84 (CDCi3) <5 1.02 (d, J = 7.9 Hz, 4H), t.63-1.90 (m, 3H), 1.95-2.25 (mf 4H)f 2.35-2.47 (mf 1H)r 3.06 (sr 3H), 3.63 (t, J = 7.6 Hz, 1H), 4.70-4.94 (m. 2H)f 7.57 (d, J = 8.6 Hz, 2HX 7.70 (sr 1H)( 7.94 (dr J = 8.6 Hz, 2H)r 8.09 (d, J = 1.8 Hz, 1HX9.29 (s, 1H). CESI+) 450.2 (MH+) (一） 85 Me ^f{e (CDCI3) δ 1.64-1.89 (m, 3H)( 2,02-2.24 (m, 3H)f 2.41 (m tH), 2.50 (s, 3H)t 2.60 (s, 3H)f 3Ό8 (s, 3H), 3.73 (t, J = 7.6 Hz, 1H), 4.70-4.95 (m, 2HX 7.49-7.55 (m, 2H) 7.92-7.97 (m, 2H), 9.12 (s, 1H). (ESI+) 47t.t 〔MH+) (-) 86 jP^： CCDCI3) δ t.25 (t, J = 7.6 Hz, tH), t.41 (d, J = 6.1 Hz 6H), t.64-1.89 (mt 3H), 1.97-2.20 (mt 3H)t 2.36-2.48 (m 1H). 3.08 (s. 3H)f 3.70 (t, J = 7.3 Hz, 1H), 4.69-4.95 (m 2H)f 5.30 (seq. J = 6.1 Hz, tH). 7.37 (dt J = 8.6 Hz, 2H) 7.75 (d, J = 8.6 Hz. 1H), 7.88 (dt J = 8.6 Hz, 2H), 8.14 (dd J = 8.6,1.2 Hzf 1H), 8.55 (d, J = 1.2 Hz, 1HX 9.75 (s, 1H). (ESI+) 551.2 〔MH+) (-) -41 - 200831081 表15
No· 結構(A) lHNMR(400MHz) MS (m/z) 旋光性 87 iT (CDCI3) δ 1.26 (t, J = 7.3 Hzf 3H)f 1.64-1.91 (m, 3H), t J5-2.25 (mt 3HX 2.34-2.46 (m, Ί Η), 2.87 (q, J = 7.3 Hz, 2H), 3.05 (s, 3H)r 3.60 (t, J = 7.3 Hz, 1H) 4.70-4.94 (m, 2H), 7.56 (ddr J = 7.9, 1.8 Hz, 2H), 7.71 (dd, J = 8.6, 2.4 Hz, 1H), 7.93 (dd, J = 7.9, 1.8 Hz, 2H)f 7.98 (br. 1H), 8.12 (d, J = 9.2 Hz, 1H)f 8.22 (d, J = 1.8 Hz, 1H). (ESI+) 469.2 (MH+) (-) 88 (d6DMSO) S t.46-1.76 (m, 3H)f 1.77-1.87 (mr 1H), 2.02-2.23 (m, 3HX 3.17 (s, 3HX 4.08 (t J = 7.6 Hz, 1H), 4.44 (d, J = 5.5 Hz, 2H), 4.78-5.00 (mf 2H), 5.21 (t, J = 5.5 Hz( 1H)( 7.64-7.70 (mf 3H), 7.89 (d. J = 8.6 Hz, 2H), 8.00 (d, J = 8.6 Hz, 1HX 8.23 (d, J = U Hz, 1H). [ESW 439.2 [MH+) (一） 89 及丫 (CDC13) d 1.32 (d, J = 6.1 Hz. 6H), t.63-1.91 (m, 3H)f t.96-2.06 (m, 1H), 2.07-2.23 (m, 2H)f 2.35-2.45 (m, 1H)f 3.05 (s, 3H), 3.56 (t, J = 7.6 Hz, IH). 4.69-4.94 (m. 2H), 7.23 (dd. J = 8.7, 2.4 Hz. 1H)· 7.57 (d, J = 8.6 Hz, 2H), 7.79 (sr IHX 7.89 (d, J = 2.4 Hz. 1HX 7.92 (d, J = 8.6 Hz, 2HX8.0S (d, J = 8.7 Hz, IH). (ESI+) 467.2 (MH+) ㈠
-42- 200831081 參考實例1 (+ ) -3-[ ( Ια，3α，4α) -3,4 - 一基環戊基]-2-( 4 · (甲基磺醯基）苯基）丙酸 如在實例3中，使用（4R) -4-苯甲基- 3-[3-[ ( 1 α，3 α ,4α ) -3,4 - _*氣基環戊基]-2- (4-(甲基擴釀基）苯基 )丙醯基]噁唑啶-2-酮的異構物B ( 202毫克），以供應（ + ) -3-[(1α，3α，4α ) -3,4-二氟基環戊基]-2-(4-(甲基 磺醯基）苯基）丙酸（118毫克）。 MS ( CI+ ) m/z ：3 3 3 ( MH+ ) C15H19F204S ( MH+ )之 HRMS ( CI+ ):計算値 333.0972，實測値 333.0983 ° 參考實例2 (+ ) -3-[ ( Ια，3α，4α ) -3,4 - 一^鐘(基環戊基]-2- ( 4-(甲基磺醯基）苯基）-N-(噻唑-2_基）丙醯胺 如在實例 4 中，使用（+ ) -3-[ ( 1 α ,3 α，4 α ) -3,4· 二氟基環戊基]_2-(4-(甲基磺醯基）苯基）丙酸（90·8 毫克）及2-胺基噻唑（67.8毫克），以供應（+ ) -3-[ ( 1 α ,3α ?4α ) -3,4 - 一赢基ί哀戊基]-2· ( 4-(甲基礦釀基） 苯基）-N-(噻唑-2-基）丙醯胺（104毫克）。 MS ( El ) m/z ： 414 ( M+ ) C25H27F2N05S ( M+ )之 HUMS ( El ):計算値 4 1 4.0 8 8 3，實測値 4 1 4 · 0 8 8 5。 -43- 200831081 參考實例3 (±) -3-[(1/3,3α，4α ) -3,4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基）丙酸 如在實例1中，使用4-甲基磺醯基苯基乙酸（1.04公 克）及（1/5, 3a，4 a ) -3,4 - _氣基環戊基甲基确（1.20 公克），以供應（±)-3-[(1/3,3〇:，40)-3,4-二氟基環 ^ 戊基]-2- ( 4-(甲基磺醯基）苯基）丙酸（1.24公克）。 • MS ( CI+ ) m/z ：3 3 3 ( MH+ ) C15H19F204S ( MH+ )之 HRMS ( CI+ ):計算値 333.0972，實測値 333.0986。 參考實例4 (41〇-4-苯甲基-3-[3-[(1/3,3 61：，4“）-3,4-二氟基 環戊基]-2-(4-(甲基磺醯基）苯基）丙醯基]噁唑啶-2-酮 如在實例 2 中，使用（±) -3-[(10，3α，4α ) -3,4-® 二氟基環戊基]-2-(4-(甲基磺醯基）苯基）丙酸（1·15 ' 公克）及（R) -4-苯甲氧基噁唑啶酮（613毫克），以供 • 應（4R) -4-苯甲基 _3-[3-[(1 沒，3α，4α ) -3,4-二氟基環 戊基]-2- ( 4-(甲基磺醯基）苯基）丙醯基]噁唑啶-2-酮的 較低極性異構物Α’（ 139毫克）及較高極性異構物Β’（ 207毫克）。 異構物Α’ ： MS ( El ) m/z ： 491 ( M+ ) C25H27F2N05S ( M+ )之 HRMS ( El ):計算値 -44- 200831081 49 1.1 57 8，實測値 49 1.1 562。 異構物: MS ( El ) m/z ： 49 1 ( M+ ) C25H27F2N05S ( M+ )之 HRMS ( El ) ••計算値 4 9 1.1 5 7 8，實測値 4 9 1 · 1 5 6 0 ° U 參考實例5 φ () -3-[(1 冷，3α，4α ) -3,4-二氟基環戊基]-2-(4- (甲基磺醯基）苯基）丙酸 如在實例3中，使用（4R) -4-苯甲基- 3-[3-[ ( 1 /3，3 α，4a )-3,4-二氟基環戊基]-2-(4-(甲基磺醯基）苯基 )丙醯基]嚼哩啶-2-酮的異構物A’（150毫克），以供應 (· ) -3-[ ( 1 沒，3 α，4 α ) -3,4-二氟基環戊基]-2- ( 4-(甲 基磺醯基）苯基）丙酸（85·9毫克）。 MS ( CI+ ) m/z : 3 3 3 ( MH+ ) • C15H19F204S ( MH+ ) 2HRMS(CI+):計算値 3 3 3.0972，實測値 3 3 3.0934 ° 馨 參考實例6 (+ ) -3-[ ( 1/3，3α，4α ) -3,4 - 一 氧基環戊基]-2- ( 4- (甲基磺醯基）苯基）丙酸 如在實例3中，使用（4R) -4-苯甲基- 3-[3-[ ( 1 /3，3 a ,4α ) -3,4 - 一*氣基環戊基]-2- ( 4-(甲基礦釀基）苯基 )丙醯基]噁唑啶-2-酮的異構物Β’（ 110毫克），以供應 -45- 200831081 (+ ) -3-[ ( 1 ^，3 α，4 α ) -3,4·二氟基環戊基]-2- ( 4-(甲 基磺醯基）苯基）丙酸（67.3毫克）。 MS ( CI+ ) m/z ：3 3 3 ( MH+ ) C15H19F204S ( MH+ )之 HRMS ( CI+ ):計算値 3 3 3.0972，實測値 3 3 3、0 9 5 2 ° ‘ 參考實例7 • ( - ) -3-[ ( 1 沒，3 α，4 α ) -3,4-二氟基環戊基]-2- ( 4- (甲基磺醯基）苯基）-N-(噻唑-2-基）丙醯胺 如在實例4中，使用（-)-3-[ ( 1冷，3 α，4 a ) -3,4-二氟基環戊基]-2_ ( 4-(甲基磺醯基）苯基）丙酸（66.6 毫克）及2-胺基噻唑（49.0毫克），以供應（-)-3-[ ( 1 冷，3α ,4α ) -3，4_二氟基環戊基]-2- ( 4-(甲基磺醯基） 苯基）-Ν-(噻唑-2-基）丙醯胺（60.3毫克）。 MS ( El ) m/z ： 414 ( M+ ) _ C25H27F2N05S ( M+ )之 HRMS ( El ):計算値 ^ 4 1 4.0 8 8 3，實測値 4 1 4.0 8 9 1。 參考實例8 (+ ) -3-[ ( 1/3，3α，4a ) -3,4 - _^ 截基環戊基]-2-( 4-(甲基磺醯基）苯基）-N-(噻唑-2-基）丙醯胺 如在實例 4 中，使用（+ ) -3-[ ( 1 /3，3 α，4 α ) ·3,4-二氟基環戊基]-2- ( 4_ (甲基磺醯基）苯基）丙酸（45.3 毫克）及2-胺基噻唑（33.9毫克），以供應（+ ) -3-[ ( 1 -46- 200831081 /5，3 α，4 α ) -3,4-二氟基環戊基]-2- ( 4-(甲基磺醯基） 苯基）-N-(噻唑-2-基）丙醯胺（40.6毫克）。 MS(EI) m/z： 414 (M+) C25H27F2N05S ( M+ )之 HRMS ( El ):計算値 414.0883，實測値 414.0844。 - 參考實例9 • ( Ια，3α，4α ) -3,4-二氟基環戊基甲基碘
步驟I 苯甲酸[(la，3y3，4沒）-3,4 -二羥基環戊基]甲酯 (化學式13)
HO
Ο 將N-甲基嗎啉N-氧化物（50%之水溶液，22.0毫升 )及四氧化餓（2.5 %之第三丁醇溶液，1 · 9 〇毫升）溶解 在丙酮（190毫升）中。在將溶液攪拌的同時，經105分 鐘的時間期限逐滴加入在丙酮（125毫升）中的苯甲酸（ 3-環戊烯-1-基）甲酯（PCT申請案第7-5068 1 6號的發表 之日本翻譯）（20.2公克），並將混合物在室溫下再攪拌 1 5小時。接著，加入氯仿（3 10毫升）及水（1 90毫升） ，並將有機層分開。將分開的有機層連續以1莫耳/公升 -47- 200831081 之氫氯酸（2 x 90毫升）、水（90毫升）及碳酸氫鈉飽和 水溶液（60毫升）清洗，接著經無水硫酸鈉乾燥及在減壓 下濃縮。將甲苯（120毫升）加入所得殘餘物中，並以過 濾收集所得晶體，得到苯甲酸[(1 a，3/S，4yS ) -3,4-二羥 基環戊基]甲酯（16·9公克）。 lR NMR ( CDC13) 5 1.71-1.78 ( m52H) , 1.95-2.02 ( m，2H)，2.27 ( br，2H)，2.75-2.87 ( m，lH)，4.19-4.23 ( m，4H)，7.43 -7.47 (m，2H)，7.5 5 -7.59 (m，lH)，8.01-8 · 0 4 ( m，2 H )。 將過濾物在減壓下濃縮，得到苯甲酸[(1 a，3 0，4 /3 )-3,4-二羥基環戊基]甲酯與苯甲酸[(1々，3 /3，4 /3 ) -3,4-二羥基環戊基]甲酯之混合物（4.23公克，由1H NMR之 積分比測定出爲1 : 2之混合物）。 lU NMR ( CDCI3) (5 1.58-1.65 ( m?1.3H) , 1.71-1.78 (m，0.7H) 5 1·96·2·17 ( m，2H) ，2.75 -2.8 5 ( m，lH)， 4.09-4.32 (m，4H)，7.42-7.46 ( m?2H) 5 7.54-7.5 9 ( m?lH )，8.0 1 - 8.0 6 ( m，2 H )。-
步驟II 苯甲酸（3aa，5a，6aa )-(四氫-4H-環戊-1，3,2-二 噁噻唑-5-基）甲酯S，S-二氧化物 -48- 200831081 (化學式14)
將苯甲酸[(1^，3/3,40)-3,4-二羥基環戊基]甲酯（ 5.00公克）懸浮在四氯化碳（75毫升）中。將亞硫醯氯 (1.90毫升）力卩入該懸浮液中及將混合物在攪拌下回流 1 · 5小時。接著，加入額外的亞硫醯氯（0.5 0毫升）及將 混合物在攪拌下再回流1小時。接著將反應混合物在減壓 下濃縮。將甲苯（25毫升）加入所得殘餘物中及將混合物 在減壓下濃縮。將濃縮物在減壓下乾燥，得到苯甲酸（3 a α，5α，6aa )-(四氫-4H-環戊-1，3,2-二噁噻唑-5-基）甲 酯S-氧化物（6.09公克）。將所得苯甲酸（3aa，5a，6a α)-(四氫-4H-環戊-1，3,2-二噁噻唑-5-基）甲酯 S-氧化 物（4.27公克）、乙腈（30毫升）與四氯化碳（30毫升 )混合在一起。將過碘酸鈉（6.46公克）、氯化釕水合物 (3 1 · 3毫克）及水（3 0毫升）加入該混合物中，並將混 合物在室溫下攪拌30分鐘。接著，加入二氯甲烷（50毫 升）及以過濾移除不溶物質。將過濾物的有機層分開及將 水層以二氯甲烷（50毫升）萃取。將有機層與二氯甲烷萃 取物合倂，並連續以1莫耳/公升之硫代硫酸鈉水溶液（2 X 40毫升）及水（2 X 40毫升）清洗。將清洗的有機層經 無水硫酸鈉乾燥及在減壓下濃縮。將殘餘物在減壓下乾燥 -49- 200831081 ，得到苯甲酸（3aα，5α，6aα)-(四氫-4H-環戊-l,3,2-二噁噻唑-5-基）甲酯S，S-二氧化物（4.35公克）。 MS ( CI+ ) m/z ： 299 ( MH+ )
Ci3H15〇6S ( MH+)之 HRMS ( CI+):計算値 299.0589，實測値 299.0593 〇
‘ 步驟III • 苯甲酸[(1 a，3 a，4/3 ) -3-氟基-4-羥基環戊基]甲酯 (化學式15)
將氟化四丁基銨水合物（571毫克）溶解在脫水乙腈 (5毫升）中及將溶液在減壓下濃縮。將其重複兩次以上 ，並將殘餘物在減壓下於40 °C下乾燥45分鐘。將所得殘 餘物溶解在脫水乙腈（5毫升）中，並加入苯甲酸（3 a a ，5 a，6a a )-(四氫-4H·環戊-1，3,2-二噁噻唑-5-基）甲酯 S，S-二氧化物（500毫克）。將該反應混合物在攪拌下回 流45分鐘及接著在減壓下濃縮。將殘餘物溶解在乙醇（5 毫升）中及加入硫酸（0.15毫升）。將混合物在攪拌下再 回流1 〇分鐘及在減壓下濃縮。將殘餘物溶解在乙酸乙酯 (4 0毫升）中，並將溶液連續以碳酸氫鈉飽和水溶液（5 毫升）及氯化鈉飽和溶液（5毫升）清洗’經無水硫酸鈉 -50- 200831081 乾燥及在減壓下濃縮。將所得殘餘物以矽膠管柱（溶離劑 :己烷/乙酸乙酯=1 : 1 )純化，得到苯甲酸[(1 α，3 α，4 /3 ) -3-氟基-4-羥基環戊基]甲酯（342毫克）。 MS ( El ) m/z ： 23 8 ( M+ ) C13H15F03 ( M+)之 HRMS ( El)：計算値 23 8.1 005 ，實測値 23 8.1 046。
步驟IV 苯甲酸[(1以，3以，4 6〇-3,4-二氟基環戊基]甲酯 (化學式16)
Ο ξ 將苯甲酸[(1 α，3 α，4 θ ) -3-氟基-4-羥基環戊基]甲 酯（326毫克）溶解在脫水四氫呋喃（5毫升）中。將在 脫水四氫呋喃（2毫升）中的雙（2 -甲氧基乙基）胺基三 氟化硫（4 5 5毫克）加入該溶液中，並將混合物在攪拌下 回流1 · 5小時。接著，將反應混合物倒入碳酸氫鈉飽和溶 液（1 〇毫升）中及將混合物以乙酸乙酯（2 X 3 0毫升）萃 取。將乙酸乙酯萃取物合倂，以氯化鈉飽和溶液（2 X 10 毫升）清洗，經無水硫酸鈉乾燥及在減壓下濃縮。將所得 殘餘物以矽膠管柱（溶離劑··己烷/乙酸乙酯=4 : 1 )純化 ，得到苯甲酸[(1α，3α，4α ) -3,4 -二氟基環戊基]甲酯（ 233毫克）。 -51 - 200831081 MS ( CI+ ) m/z : 241 ( MH+ ) C13H15F2O2 ( MH+)之 HRMS (CI+):計算値 241.1040，實測値 241.1 043 °
步驟V
[(Ια，3α，4α ) -3,4 -二氟基環戊基]甲醇 ^ (化學式17)
參 G 將苯甲酸[(1α，3α，4α ) -3,4-二氟基環戊基]甲酯（ 221毫克）溶解在乙醇（3毫升）中。將碳酸鉀（ip〗毫克 )的水溶液（1笔升）加入該丨谷液中及將混合物在擾泮下 回流4小時。接著，將反應混合物在減壓下濃縮，並將所 得殘餘物以矽膠管柱（溶離劑：己烷/乙酸乙酯=1 ·· 2 )純 • 化，得到[(1 α，3 α，4 α ) -3,4-二氟基環戊基]甲醇（123 毫克）。 ' MS ( CI+ ) m/z ： 137 ( MH+ )
CeHnFe ( MH+ )之 HRMS ( CI+ ):計算値 1 3 7.0778 ，實測値 1 3 7 · 0 8 0 1。
步驟VI (1 α，3 α，4 α ) ·3,4-二氟基環戊基甲基碘 -52- 200831081 (化學式18) ζ ρ”Ον» 將碘（120毫克）加入在以冰冷卻下的二氯甲烷（2.0 毫升）中的咪唑（64.5毫克）及三苯膦（124毫克）之溶 液中。將混合物在室溫下攪拌3 〇分鐘。接著，加入在二 氯甲烷（〇·5毫升）中的[(1α，3α，4α) -3,4-二氟基環戊 基]甲醇（43.0毫克）及將混合物在室溫下再攪拌4小時 。以過濾移除不溶物質及將過濾物濃縮。藉由矽膠管柱層 析法純化所得殘餘物，以供應（Ια，3α，4α ) -3,4-二氟基 環戊基甲基碘（28.0毫克）。 MS ( El ) m/z ： 246 ( M+ ) C6H9F2I ( M+)之 HRMS ( El):計算値 245.97 1 7， 實測値245.974 1。 參考實例1 〇 (，3α，4a ) -3，4-二氟基環戊基甲基碘
步驟I 苯甲酸（3a α，5 沒，6a α )-(四氫-4Η-環戊-1，3,2-二 噁噻唑-5-基）甲酯S，S-二氧化物 將在參考實例9的步驟I中所獲得的苯甲酸[(1 α，3 冷，4冷）-3，4-二羥基環戊基]甲酯與[(1/5,3/3，4/3 ) -3，4- -53- 200831081 二羥基環戊基]甲酯之混合物（4 · 2 3公克）與四氯化碳（ 75毫升）混合。將亞硫醯氯（2.00毫升）加入該混合物 中及·將混合物在攪拌下回流3 〇分鐘。接著，將反應混合 物在減壓下濃縮。將甲苯（75毫升）加入殘餘物中及將混 合物在減壓下再濃縮。將殘餘物在減壓下乾燥。將乾燥的 殘餘物與乙腈（3 5毫升）及四氯化碳（3 5毫升）混合。 接著加入過碘酸鈉（7.6 6公克）、氯化釕水合物（3 7 · 1毫 克）及水（3 5毫升）及在室溫下攪拌3 〇分鐘。接著，加 入二氯甲烷（60毫升）及以過濾移除不溶物質。將過濾物 的有機層分開及將水層以二氯甲烷（60毫升）萃取。將有 機層與二氯甲烷萃取物合倂。將合倂的有機層連續以1莫 耳/公升之硫代硫酸鈉水溶液（2 X 5 0毫升）及水（2 X 5 0 毫升）清洗，經無水硫酸鈉乾燥及在減壓下濃縮。將所得 殘餘物以矽膠管柱（溶離劑：己烷/乙酸乙酯=1: 1)純化 ，得到苯甲酸（3a a，5 /3，6a α )-(四氫-4H-環戊-1，3,2-二噁噻唑-5-基）甲酯S,S-二氧化物（2.43公克）及苯甲 酸（3aa，5a，6aa )-(四氫-4H-環戊-1，3,2-二噁噻唑- 5-基）甲酯S，S_:氧化物（1.33公克）。 MS ( El ) m/z ： 298 ( M+ ) C13H1406S ( M+)之 HRMS ( El)：計算値 298.05 1 1 ，實測値 2 9 8.0 4 9 3 °
步驟II 苯甲酸[(1 θ，3 α，4Θ ) -3-氟基-4-羥基環戊基]甲酯 -54- 200831081 如在參考實例9之步驟III中，該反應係使用（3 a α ，5冷，6aa )-(四氫-4Η-環戊-1，3,2-二噁噻唑-5-基）甲酯 S，S-二氧化物（1.00公克）來進行，以供應苯甲酸[(1冷 ，3α，4/3 ) -3-氟基-4-羥基環戊基]甲酯（660毫克）。 MS ( CI+ ) m/z ： 23 9 ( MH+ ) # C13Hi6F03 ( MH+)之 HRMS ( CI+):計算値 u 2 3 9.1 083，實測値 23 9.1 040 °
步驟III 苯甲酸[(1/3,3α，4α) -3,4-二氟基環戊基]甲酯 如在參考實例9之步驟IV中，該反應係使用苯甲酸[ (1 /3，3 α，4 /3 ) -3-氟基-4·羥基環戊基]甲酯（644毫克） 來進行，以供應苯甲酸[(1/3, 3α，4α ) -3，4-二氟基環戊 基]甲酯（3 65毫克）。 MS ( CI+ ) m/z : 241 ( ΜΗ+ ) 參 C13H15F202 ( MH+)之 HRMS ( CI+):計算値 " 2 4 1.1 0 4 0，實測値 241.1012 〇
步驟IV
[(1/3,3α，4α ) -3,4-二氟基環戊基]甲醇 如在參考竇例9之步驟V中，該反應係使用苯甲酸[ (1/3,3α，4a ) -3,4-二氟基環戊基]甲酯（34 9毫克）來 進行，以供應[(1/5,3α，4α ) -3,4-二氟基環戊基]甲醇（ 184毫克）。 -55- 200831081 MS ( CI+ ) m/z : 137 ( MH+ ) C6HHF20 ( MH+)之 HRMS ( CI+):計算値 1 37.0778 ，實測値 1 3 7.0 7 5 4。
步驟V (1/3,3α，4α ) -3,4_二氟基環戊基甲基碘 如在參考實例9之步驟VI中，該反應係使用[(1 /3，3 α，4α ) -3，4·二氟基環戊基]甲醇（3.46公克）來進行， 以供應（1沒，3 α，4 α ) -3,4-二氟基環戊基甲基碘（4.72 公克）。 MS ( El ) m/z ： 246 ( M+ ) C6H9F2I ( M+ )之 HRMS ( El)：計算値 245.97 1 7， 實測値245.9749。 試驗實例1 : GK活性試驗 GK活性試驗係藉由測量在以蔔萄糖-6-脫氫酶催化之 共軛反應中所生產的NADH量來測定，而不是直接測量在 以葡糖激酶催化之反應中所生產的葡萄糖-6-磷酸鹽量。 (重組體GK的製備作用） 選殖人類肝臟或胰臟葡糖激酶及彼之重組體蛋白 以人類肝臟 GK序列（基因庫登錄號（GenBank Accession Number) ： NM_033507 )及人類胰臟 GK 序列 (基因庫登錄號：NM_000 1 62 )爲基準，PCR係使用 -56- 200831081
PyTobest DNA聚合酶（TaKaRa)及使用人類肝臟cDNA ( Clontech)與人類胰臟cDNA(Clontech)作爲模板來執行 。選殖之基因表現在作爲以His-標籤之融合蛋白的可溶性 部分中的大腸桿菌中，該蛋白係在C-末端上以6xHis-標 籤化。將細胞以聲波化溶解，並將溶解物離心及收集上層 清液。使上層清液接受以金屬螯合親和層析法純化。 將純化之酵素在-80°C下貯存在含有12.5mM HEPES、 72mM KC1、0.5mM MgCl2、0.5mM DTT、2.5mM 葡萄糖及 50%甘油的HEPES緩衝液中。. (GK活性分析） GK活性係在25°C下使用一半面積的96-井平底盤（ Costar)來分析。所製備之培育混合物包括25mM HEPES 緩衝液（pH 7.1 ) ( Invitrogen ) 、25mM KC1 ( Wako Pure
Chemical Industries) 、2mM MgCl2 ( Wako Pure Chemical Industries ) 、5mM D-蔔萄糖(Wako Pure Chemical
Industries) 、ImM ATP ( Roche) 、ImM NAD ( Sigma) 、ImM 二硫蘇糖醇（Wako Pure Chemical Industries)、 5 單元 /毫升之 G6PDH ( Sigma ) 、0 · 1 % B S A ( S igma )及 試驗化合物或5% DMSO與GK。 將每一試驗化合物溶解在DMSO中。將2微升該溶液 加入含有 HEPES 緩衝液（pH 7·1) 、KC1、MgCl2、D-葡 萄糖、ATP、NAD及二硫蘇糖醇的20微升溶液中。接著 加入含有G6PDH、BSA及重組體GK的18微升溶液，以 -57- 200831081 引發反應。加入GK，所以在5% DMSO的存在下於1分鐘 之內增加的吸收率爲0.002至0.003。在340奈米下增加 的吸收率係使用SPECTRAmaxl90微量盤分光光度計在反 應開始之後測量1 5分鐘。使用在前1 〇分鐘所測量的增加 値評估活性。 結果是肝臟GK活性係在1 0从Μ之化合物第1 1號或 第14號的存在下增加至150%或更高，並在ΙΟ/iM之化 合物第1號至第1 〇號、第12號、第13號、第1 5號至第 17號、第20號、第21號、第23號、第25號、第27號 、第30號、第31號、第33號至第36號、第43號至第 46號、第48號、第50號、第54號、第55號、第60號 、第61號、第68號、第69號、第71號、第73號至第 75號及第79號至第82號的存在下增加至200 %或更高， 其係相對於不含有該等化合物的井所觀察的肝臟GK活性 而言。 試驗實例2 :降血糖活性試驗 每一試驗化合物對血液葡萄糖値的效應係使用7-至9-週齡大的 ICR 公鼠（Charles River Laboratories Japan) 來觀察。特別將每一化合物溶解在 GeUcire44/14 ( Gatefosse )與PEG400以60 ; 40之混合物中，並在2小 時禁食期之後，經口服投予動物（3 0毫克/公斤，1 〇毫升/ 公斤）。在投予之前（前値），投予之後〇·5、2及4小 時，立即使用以伸乙二胺四乙酸二鉀塗佈之試管從尾靜脈 -58- 200831081 收集血液樣品。將血液樣品離心（4°C，3,600 g，3分鐘 )，獲得血漿樣品。 將每一樣品以生理食鹽水稀釋5倍，並使用葡萄糖 CII-test Wako ( Wako Pur eChemical Industries)測量血液 葡萄糖値。將10微升各個樣品之一、生理食鹽水及100 毫克/公合之標準的葡萄糖溶液（將200毫克/公合之標準 的蔔萄糖溶液以生理食鹽水稀釋2倍）放入96井平盤的 每一井中。將150微升色彩形成溶液加入每一井中及將平 盤留置在.37 °C下5分鐘，允許溶液顯色。使用Lucy 2發 光讀取機（Aloka)在0D = 492奈米處取得測量値。降低 的Σ葡萄糖（在每一血液收集點上相對於前値而言平均降 低的蔔萄糖値）係從每一血液收集點上相對於前値而言降 低的葡萄糖値來測定。 以試驗證明以化合物第1號、第2號、第3號、第17 號、第27號、第30號、第35號、第36號、第46號、 第54號、第55號及第74號中每一者使Σ葡萄糖値降低 3 0 %或更多，反之，參考化合物第2號、第7號及第8號 中沒有一者造成Σ葡萄糖降低超過15%。 試驗實例3:活體內藥物動力學試驗 每一試驗化合物的口服生物利用率係使用6週齡大的 ICR 公鼠（Charles River Laboratories Japan)來評估。特 別將每一試驗化合物溶解在二甲基亞颯（DMSO，Sigma) 中及將溶液加入1/15M之磷酸二氫鈉水溶液（Wako Pure -59 - 200831081
Chemical Industries)中，成爲 200 /ζ Μ 濃度。DMSO 加至 3 0 %之最終濃度。將所得溶液投予動物。將禁食隔夜的 ICR公鼠組以試驗化合物溶液（1微莫耳/公斤，5毫升/公 斤）注射彼之尾部靜脈，當作靜脈注射組。在靜脈投予之 後5、15及30分鐘與1、2、4、8及24小時，使用以肝 素塗佈之毛細試管從每一隻動物的眼底收集血液樣品。將 血液樣品離心，獲得血漿樣品。將公鼠組強迫口服投予相 同的溶液（2微莫耳/公斤，10毫升/公斤），當作口服投 予組。在口服投予之後15及30分鐘與1、2、4、8及24 小時，從眼底收集血液樣品，並離心，獲得血漿樣品。將 10微升分開的血漿以100微升生理食鹽水及10微升二甲 基亞颯（Sigma )稀釋，並以配備液相層析法的三段四極 桿串聯式質譜儀（API-30 00，Applied Biosystem)就未改 變之產品的血漿濃度來分析。在血漿濃度·時間曲線（ AUC )下的面積係以梯形法測定。試驗化合物的生物利用 率係藉由將劑量校正之口服投予組的平均AUC除以靜脈 內投予組的平均AUC來測定。化合物第1號顯示50%或 更高的生物利用率。 試驗實例4 :試管內肝微粒體代謝穩定性試驗 將每一試驗化合物在玻璃試驗管中以含有人類肝微粒 體（Xenotech)或鼠科動物來源的肝微粒體（源自於7週 齢大的 ICR 公鼠所製備；Charles River Laboratories Japan)之溶液在37°C下培育5分鐘，以評估化合物的代 -60- 200831081 謝穩定性。培育混合物包括10OmM磷酸鉀緩衝液（pH 7.4 ，Wako Pure Chemical Industries ) 、3mM MgCl2 c Wako
Pure Chemical Industries ) 、5mM 葡萄糖-6-磷酸鹽（
Roche ) 、ImM EDTA ( Tokyo Chemical Industry ) 、1 Ι·υ·葡萄糖-6-磷酸鹽脫氫酶（R0Che)及1毫克/毫升之肝 微粒體。將試驗化合物溶解在DMSO中及將溶液加入反應 混合物中，成爲1 μ Μ最終濃度。代謝法係藉由加入 NADPH ( Roche )溶液成爲1 mM最終濃度而開始，並在5 分鐘之後，藉由加入等體積的乙腈（Fischer )而終止。在 代謝法終止之後，將上層清液離心分開，及以液相層析法 的質譜儀（SHIMADZU 2010A，Shimadzu )就未改變之產 品的濃度來分析。化合物第1號、第2號及第3號中每一 者在人類及小鼠二者中的代謝清除率爲0.0 6毫升/分鐘/毫 克之蛋白質或更低。 產業利用性 本發明的化合物充當有效的GK活化劑或降血糖劑， 且引起較少的副作用（如QT間隔的延長及低血糖症）， 並有用於治療或預防糖尿病、肥胖症及其他病症。 -61 -

Claims (1)

  1. 200831081 十、申請專利範圍 1. 一種以下列通式（1 )代表的化合物’或其醫藥上 可接受之鹽： (化學式1)
    (其中以*表示之碳原子具有R組態；R1及R2各自獨立爲 氫原子、鹵素原子、胺基、羥基、羥胺基、硝基、氰基、 胺磺醯基、Ci-C^烷基、Ci-C6烷氧基、Ci-Cs烷硫基、Ci_ c6院基亞擴醯基或c 1 - C 6院基礦醯基；及A爲經取代或未 經取代之雜芳基）。 2·根據申請專利範圍第1項之化合物，或其醫藥上可 接受之鹽，其中R1爲氫原子及112爲CrG烷基磺醯基。 3 ·根據申請專利範圍第1項之化合物，或其醫藥上可 接受之鹽，其中R1爲氫原子及R2爲甲基磺醯基。 4.根據申請專利範圍第1至3項中任一項之化合物， 其係以下列通式（1 a )代表，或其醫藥上可接受之鹽： -62- 200831081 (ft學式2)
    • 5.根據申請專利範圍第1至3項中任一項之化合物， 其係以下列通式（1 b )代表，或其醫藥上可接受之鹽： (化學式3)
    (其中以*、R1、R2及A如上述所定義）。 6 ·根據申請專利範圍第1項之化合物，或其醫藥上可 接受之鹽，其中A爲未經取代或經鹵素原子' 烷基 、院氧基、硝基、氰基或_(CH2) / (ο) 〇R3 (其 中R3爲氫原子或CpC6烷基，及m爲〇至2之整數）單 取代之雜芳基。 6 7·根據申請專利範圍第 接受之鹽，其中Α爲未經取 單取代之雜芳基。 8 ·根據申請專利範圍第 1項之化合物，或其醫藥上可 代或經鹵素原子或c 1 -c 6院基 或7項之化合物’或其醫藥 -63« 200831081 上可接受之鹽，其中A爲未經取代或經單取代之雜芳基， 其爲含有1至3個選自硫原子、氧原子及氮原子之雜原子 的5 -或6 -員芳香族雜環狀環，雜原子之一爲與環鍵聯原子 鄰接之氮原子。 9 ·根據申請專利範圍第6或7項之化合物，或其醫藥 上可接受之鹽，其中A爲未經取代或經單取代之雜芳基， 其爲稠合之雜環狀環，該環包括含有i至3個選自硫原子 、氧原子及氮原子之雜原子的5 -或6-員芳香族雜環狀環， 雜原子之一爲與環鍵聯原子鄰接之氮原子。 10·根據申請專利範圍第6或7項之化合物，或其醫 藥上可接受之鹽’其中A爲未經取代或經單取代之雜芳基 ，其係選自下列者： -64« 200831081 (化學式4)
    11·一種（R) -3- ( ( lr，3R，4S ) -3,4-二氟基環戊基 )-2- ( 4-(甲基磺醯基）苯基）-N-(噻唑-2-基）丙醯胺 ，（R) -3- ( ( lr，3R54S) -3,4_二氟基環戊基）-2- ( 4-( 甲基磺醯基）苯基）-N- ( 5-氟基噻唑-2-基）丙醯胺，（R )-3- ( ( lr,3R，4S ) -3,4-二氟基環戊基）-2- ( 4-(甲基磺 醯基）苯基）-N- ( 1-甲基吡唑-3-基）丙醯胺，（R)-3-((lr，3R，4S) -3,4-二氟基環戊基）-2-(4-(甲基磺醯基 )苯基）-N-(吡啶並[3,2-d]噻唑-2-基）丙醯胺或（R )- -65- 200831081 3-((11：，3尺，4 8)-3,4-二氟基環戊基）-2-(4-(甲基碌醯 基）苯基）-N- ( 3-甲基噻二唑-5-基）丙醯胺，或其醫藥 上可接受之鹽。 12· — 種（-)-3-[(1<^，3〇:，461：)-3,4-二氟基環戊基 )-2- ( 4-(甲基磺醯基）苯基）-N-(噻唑-2-基）丙醯胺 ，或其醫藥上可接受之鹽。 13. —種（-)-3-[(1(2,3(2,4〇：)-3,4-二氟基環戊基 )-2- ( 4-(甲基磺醯基）苯基）-N- ( 5-氟基噻唑_2-基） 丙醯胺，或其醫藥上可接受之鹽。 14. 一種（-)-3-[(1〇：，30，4〇^)-3,4-二氟基環戊基 )-2· ( 4-(甲基磺醯基）苯基）-N- ( 1-甲基吡唑-3-基） 丙醯胺，或其醫藥上可接受之鹽。 15. — 種（-)-3-[(1〇:，30，4〇：)-3,4-二氟基環戊基 )-2- ( 4-(甲基磺醯基）苯基）-N-(吡啶並[3,2-d]噻唑_ 2-基）丙醯胺，或其醫藥上可接受之鹽。 16. — 種（-)-3-[(10，3〇:，4〇：)-3,4-二氟基環戊基 )_2_ ( 4-(甲基磺醯基）苯基）-N- ( 3-甲基噻二唑-5-基 )丙醯胺，或其醫藥上可接受之鹽。 17. —種根據申請專利範圍第1至1 6項中任一項之化 合物或其醫藥上可接受之鹽的用途，其係用於製造供治療 人類疾病之醫藥劑。 1 8 . —種根據申請專利範圍第1至1 6項中任一項之化 合物或其醫藥上可接受之鹽的用途，其係用於製造供治療 或預防糖尿病之醫藥劑。 -66 - 200831081 19.一種醫藥組成物， 至16項中任一項之化合物〕 20·—種以下列通式（3 其包含根據申請專利範圍第1 t醫藥上可接受之載體。 )代表的化合物， (化學式5) e
    (其中以*表示之碳原子具:ϊ 氫原子、鹵素原子、胺基、 胺磺醯基、H6烷基、Cr c6烷基亞磺醯基或CrCe院 21.根據申請專利範圍| 原子及R2爲甲基磺醯基。 (3) f R組態；R1及R2各自獨立爲 羥基、羥胺基、硝基、氰基、 C6烷氧基、Ci-Cs烷硫基、Cr 基磺醯基）。 ;20項之化合物，其中R1爲氫 -67- 200831081 七、指定代表圖： (一） 、本案指定代表圖為：無 (二） 、本代表圖之元件代表符號簡單說明：無
    八、本案若有化學式時，請揭示最能顯示發明特徵的化學 式： (化學式1)
    -4-
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CN101668743A (zh) 2010-03-10
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CL2007003722A1 (es) 2008-08-22
EP2116535A4 (en) 2013-05-29
CA2672088A1 (en) 2008-07-03
AU2007337382A1 (en) 2008-07-03
EP2116535B1 (en) 2014-06-11
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CN101668743B (zh) 2012-06-20
US20100016304A1 (en) 2010-01-21
JP5248327B2 (ja) 2013-07-31
EP2116535A1 (en) 2009-11-11
WO2008078674A1 (ja) 2008-07-03
BRPI0719470A2 (pt) 2014-02-11
US8173649B2 (en) 2012-05-08
CA2672088C (en) 2014-11-25

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