TWI284641B - Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same - Google Patents
Glucopyranosyloxybenzylbenzene derivatives and medicinal compositions containing the same Download PDFInfo
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- TWI284641B TWI284641B TW090124049A TW90124049A TWI284641B TW I284641 B TWI284641 B TW I284641B TW 090124049 A TW090124049 A TW 090124049A TW 90124049 A TW90124049 A TW 90124049A TW I284641 B TWI284641 B TW I284641B
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- group
- general formula
- benzene derivative
- fluorenyl
- solvent
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- 239000000203 mixture Substances 0.000 title description 9
- 125000003545 alkoxy group Chemical group 0.000 claims abstract description 28
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 17
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- HOVAGTYPODGVJG-UHFFFAOYSA-N methyl beta-galactoside Natural products COC1OC(CO)C(O)C(O)C1O HOVAGTYPODGVJG-UHFFFAOYSA-N 0.000 description 1
- 125000005484 neopentoxy group Chemical group 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- LYGJENNIWJXYER-UHFFFAOYSA-N nitromethane Chemical compound C[N+]([O-])=O LYGJENNIWJXYER-UHFFFAOYSA-N 0.000 description 1
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000002923 oximes Chemical class 0.000 description 1
- 125000005429 oxyalkyl group Chemical group 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 235000019369 penicillin G sodium Nutrition 0.000 description 1
- 229940056360 penicillin g Drugs 0.000 description 1
- 125000004115 pentoxy group Chemical group [*]OC([H])([H])C([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- NTTOTNSKUYCDAV-UHFFFAOYSA-N potassium hydride Chemical compound [KH] NTTOTNSKUYCDAV-UHFFFAOYSA-N 0.000 description 1
- 229910000105 potassium hydride Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012746 preparative thin layer chromatography Methods 0.000 description 1
- 238000002203 pretreatment Methods 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 125000002572 propoxy group Chemical group [*]OC([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- QQONPFPTGQHPMA-UHFFFAOYSA-N propylene Natural products CC=C QQONPFPTGQHPMA-UHFFFAOYSA-N 0.000 description 1
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 description 1
- UKPBXIFLSVLDPA-UHFFFAOYSA-N propylhydrazine Chemical compound CCCNN UKPBXIFLSVLDPA-UHFFFAOYSA-N 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000001007 puffing effect Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- SBYHFKPVCBCYGV-UHFFFAOYSA-N quinuclidine Chemical group C1CC2CCN1CC2 SBYHFKPVCBCYGV-UHFFFAOYSA-N 0.000 description 1
- 230000009103 reabsorption Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- FTIMWVSQXCWTAW-UHFFFAOYSA-N ruthenium Chemical compound [Ru].[Ru] FTIMWVSQXCWTAW-UHFFFAOYSA-N 0.000 description 1
- 239000012898 sample dilution Substances 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 239000002689 soil Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000000638 solvent extraction Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 150000003432 sterols Chemical class 0.000 description 1
- 229960002385 streptomycin sulfate Drugs 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- LZOZLBFZGFLFBV-UHFFFAOYSA-N sulfene Chemical compound C=S(=O)=O LZOZLBFZGFLFBV-UHFFFAOYSA-N 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 1
- 125000004354 sulfur functional group Chemical group 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- UWHCKJMYHZGTIT-UHFFFAOYSA-N tetraethylene glycol Chemical compound OCCOCCOCCOCCO UWHCKJMYHZGTIT-UHFFFAOYSA-N 0.000 description 1
- 229940124597 therapeutic agent Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 125000004149 thio group Chemical group *S* 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- RMVRSNDYEFQCLF-UHFFFAOYSA-N thiophenol Chemical class SC1=CC=CC=C1 RMVRSNDYEFQCLF-UHFFFAOYSA-N 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000009466 transformation Effects 0.000 description 1
- 210000005239 tubule Anatomy 0.000 description 1
- 239000011534 wash buffer Substances 0.000 description 1
Classifications
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- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
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- A61P3/00—Drugs for disorders of the metabolism
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- 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
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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Description
1284641
【技術領域】 本發明與有用為醫藥品 含該衍生物之醫藥組成物 之比喃葡糖基經爷基苯衍生物及 有關。 詳言之丄本發明與有用於糖尿病、糖尿病性併發症、
肥胖症等咼血糖症狀引起之痂、忘笙 X 此η尺嗖（疾病專之預防或治 人SGLT2活性抑制作用，以下列一般式 贫川”有
(式中R為低級烷基、低級烷氧基、低級烷硫基、低級燒氧 低級烧基、低級烧氧低級烧氧基、或低級烧氧低級烧硫 基）代表之咄喃葡糖基羥苄基苯衍生物為活性本體，以下 列一般式
(式中P為構成前體藥物之基，R為低級烷基、低級烷氧 基、低級烷硫基、低級烷氧低級烷基、低級烧氧低級烷氧 基、或低級烧氧低級烧硫基）代表之吼喃葡糖基經节基苯
C:\2D-CODE\90-12\90124049.ptd 第6頁 1284641 五、發明說明（2) ,生物及含該衍生物之醫藥組 【習知技術】 λ物有關。 糖尿病為以飲食生活之 慣病之一種。因此或運動不足為背景 、 U此對糖尿病患者告# △ 月尽之生活習 j，但如無法充分控制或繼續實扩Γ人食療法或運動療 前有縮二胍藥（Blguanid 胺/則併用藥物療法。目 2·“)、及抗姨島素善尿藥素上、 樂❶但細—胍藥有乳酸酸中毒、庐^ 用為糖尿病治療 胰島素改善藥有浮腫等副作用，i f尿素藥有低血糖、抗 慮。因此為消除此等問題，期望σϋ促進肥胖化之 之糖尿病治療劑。 #卷依據新穎機制與作用 、近年，有關在腎臟抑制再吸收過剩之糖， 泄、使血糖值減低斩〗 進尿糖排 丨f唐值減低之新型糖尿病治療藥之研發在推 (J.=. In:st.’vol.79, ρρ·151…5 1 5 ( 1 98 7))。 取k報告於腎臟近翊泌尿小管S1領域存在有SGLT2 (鈉 賴（0Γ相關）性葡萄糖輸送體2)，該SGL丁2主要與被腎小球又 過濾之糖之再吸收有關（J. Clin· Invest.， v〇193/ 此亦可期待其防止肥胖化之效果 PP. 397 - 404 ( 1 994 ))。是故，如能抑制人SGLT2以抑制 腎臟再吸收過剩之糖，則可由尿排泄過剩之糖使血糖值正 常化。因此期望早日開發具有強大人SGLT2活性抑制作用 之新穎機制與作用之糖尿病治療藥。同時由於此種尿糖排 泄促進劑能使過剩之糖由尿排泄，減少體内糖之蓄積，因 其防止肥胖化之效果。 1284641 五、發明說明（3) 本發明者等為發現具ASGLT2活性抑制作用之化合物專 了研m ’獲知前述以—般式⑴代表之化合物，如下 述於生體内被轉換為活性本體、即被轉換為以前述一般式 ()代表之吡喃葡糖基羥苄基苯衍生物，而顯示優異之抑 制人SGLT2活性乃完成本發明。 本發明提供在生體内發揮人SGLT2活性抑制作用’以抑 制腎臟再吸收糖、排泄過剩之糖於尿中，而表現優異降低 血糖作用之下述吡喃葡糖基羥辛基苯衍生物及含該衍生物 之醫藥組成物。 亦即本發明與以一般式
(式中P為構成前體藥物之基’R為低級烧基、低級烧氧基 、低級烧硫基、低級烧氧低級烧基、低級烧氧低級燒氧 基、或低級烧氧低級院硫基）代表之σ比喃葡糖基經爷基苯 衍生物有關。 本發明與含上述以一般式（I )代表之π比喃葡糖基羥辛基 苯衍生物為有效成分之醫藥組成物有關。 ^ 本發明與含上述以一般式（I )代表之Π比喃葡糠基經辛基 苯衍生物為有效成分之人SGLT2抑制劑有關。
1284641
本發明與含上述以 苯衍生物為有效成分 療劑有關。 一般式（I)代表之口比喃巧她甘 , 南®糖基羥苄基 之起因於高血糖症狀+ L卞丞 狀疾病之預防及治 本發明與投給（0r投予）有 之吼喃葡糖基羥爷基苯衍生 疾病之預防及治療方法有關 效量之上述以—般式（1)代表 物所形成之起因於高血糖症狀 醫 苄 本發明與為製造起因於 藥組成物而使用上述以 基苯衍生物有關。 高血糖症狀疾病之預防及治療用 省 一般式（I)代表之D比喃葡糖基羥 於本發明’則體樂物（Prodrug)乃指在生體内轉換成活 ，生本體之上述以一般式（11)代表之。比喃葡糖基羥苄基笨鲁 生物之化合物而言，構成前體藥物之基如低級醯基、低每 燒氧低級醯基、低級院氧幾低級醯基、低級烷氧幾基、仓 級垸氧低級烧氧魏基等通常使用於前體藥物以保護經基4 保護基。 又於本發明，低級烷基為曱基、乙基、丙基、異丙基、 丁基、異丁基、另丁基、特丁基、戊基、異戊基、新戊 基、特戊基、己基等碳原子數1〜6之直鏈狀或分枝狀烷 基，低級炫氧基為曱氧基、乙氧基、丙氧基、異丙氧基、 丁氧基、異丁氧基、另丁氧基、特丁氧基、戊氧基、異戊 氧基、新戊氧基、特戊氧基、己氧基等碳原子數1〜6之直 鏈狀或分枝狀烷氧基’低級烧硫基為甲硫基、乙硫基、丙 硫基、異丙硫基、丁硫基、異丁硫基、另丁硫基、特丁硫 基、戊硫基、異戊硫基、新戊硫基、特戊旒基、己硫基等
第9頁 1284641 五、發明說明（5) 碳原子數1〜6之直鏈狀或分枝狀烷硫基。低級烷氧低級烷 基為被上述低級：)：完氧基取代之上述低級烷基，低級烷氧低 級院氧基為被上述低級烷氧基取代之上述低級烷氧基，低 級烷氧低級烷硫基為被上述低級烷氧基取代之上述低級烷 硫基。低級醯基為乙醯基、丙醯基、丁醯基、異丁醯基、 特戊醯基:己醯基、環己羰基等碳原子數2〜7之直鏈^或 ，枝狀或環狀醯基，低級烷氧基低級醯基為被上述低級烷 乳基取代之上述低級醯基。又低級烷氧羰基為、 « 之：丙氧幾基、異丁氧幾基、環己氧幾基等；原 . # Α & Q直鏈狀或分枝狀或環狀烷氧羰基，低級烷氧妒 = (乙氧幾基）㈣基等被上述低級院氧Λ =級酸基，低級院氧低級烧氧幾基為2甲氧基 i二基J，上:：級烷氧基取代之上述低級烷氧羰基。 數1〜4之直鏈狀^級烧基或低級烧氧基較好，以碳原子 分枝狀烧氧基更:V刀枝狀烧基或碳原子數1〜3之直鏈狀或 p，以低級醯基或V並以乙基或甲氧基最好。於取代基 數4〜6之直鏈妝/級烷氧羰基較好。低級醯基以碳原子 更好。低級烷氧ί ί枝狀醯基較好’ &以丁醯基或己醯基 氧幾基較好，^基^碳原子數2〜5之直鏈狀或分枝狀烧 本發明之化八从甲氧幾基或乙氧幾基更好。 羥基保護基，導可依常法將一般在前體藥物可能使用之 辛基苯衍生4勿之麵t述以一般式（1 1)代表之吼°南»糖基經 (1)代表之化合物基而製成。例如本發明之上述以—般式 物，可使用上述以一般式（11)代表之
第10頁 1284641 五、發明說明（6) 葡糖基經苄基苯衍生物，依下列方法製造
OH
HO
p-x (in) HO、' OH (II) (I) (式中X為溴 義） 使用上述 劑存在下或 乙胺、曱基 1，2, 2, 6, 6-類保護上述 物之經基， 之溶劑如二 仿、四氫呋 丁醇、及此 流溫度，反 但通常為3 0 使用為上 (II)代表之 原子、氯原子等消除取代基，R及P如同前述定 以一般式（111)代表之保護化試藥，在惰性溶 無溶劑存在下，以咄啶、三乙胺、N，N -二異丙 吡啶、二曱基咄啶、三甲基吼啶、奎寧環、 五曱基哌啶、1，4-二氮二環[2· 2· 2]辛烷等鹼 以一般式（I I)代表之吼喃葡糖基羥窄基苯衍生 製成上述以一般式（I )代表之前體藥物。使用 氯曱烷、乙腈、醋酸乙酯、二異丙基醚、氯 喃、1，2 _二曱氧乙烷、1，4 -二Df烷、丙酮、特 等之混合溶劑等，反應溫度一般為-4 0 °C〜迴 應時間因使用原料、溶劑、反應溫度等而異， 分鐘〜2日。 述製造方法起始物質之本發明之上述以一般式 化合物，可舉例如依下列方法製造。
90124049.ptd 第11頁 1284641
1284641
步驟1 生2 ϋ:劑中’縮合上述以-般式(ιν)代表之苯甲駿衍 生物與=以一般式(v)代表之格利雅試劑(g
Recent)或鋰試劑、或上述以一般式（ιν)代表之格雅 劑或鋰試劑與上述以一护泞 # J雅4 叙式（V)代表之本甲醛衍生物， : 以一般式（VI)代表之化合物。使用溶劑如四氫呋 喃1一5醚、或其混合溶劑等，反應溫度-般為— 781 迴紈溫度，反應時間因使用原才斗、溶劑、反應溫度等而 異，但通常為10分鐘〜1曰。 步驟2
、在u n /谷劑中使用j)ess — Martin試劑氧化上述以一 般式（VI)代表之化合物，可製成上述以一般式（νι ^代表 之化二物。使用溶劑如二氯甲烧、氯仿、乙腈、或其混合 溶劑等，反應溫度一般為01〜迴流溫度，反應時間因使 用原料、溶劑、反應溫度等而異，但通常為丨小時〜丨曰。 步驟3 在情性溶劑中，鹽酸等酸存在或不存在下，使用鈀/ 碳（Pd-C)粉等鈀系催化劑催化還原上述以一般式（VI)代表 之化合物後，依需要以常法消除保護基，可製成上述以一 般式（V I I I )代表之化合物。使用於催化還原之溶劑如甲 醇、乙醇、四氫呋喃、醋酸乙酯.、醋酸、異丙醇、或其混 合溶劑等’反應溫度一般為室溫〜迴流溫度，反應時間因 使用原料、溶劑、反應溫度等而異，但通常為3 〇分鐘〜i 曰。又上述以一般式（V111)代表之化合物可依常法轉換為
1284641 五、發明說明（9) 鈉鹽、鉀鹽等之鹽。 步驟4 依常法消除上述以一般式（VII)代表之化合物之保護 後，在惰性溶劑中，三乙胺、二異丙基乙胺、4 _ (N，N _ 二曱胺）。比啶等鹼類存在下，與氯甲酸曱酯縮合得碳酸酯 衍生物’再用氫硼納等還原劑還原即製成上述以一般式 (VIII)代表之化合物。使用於縮合反應之溶劑如四氫呋 喃、二氣曱烷、乙腈、醋酸乙酯、二乙醚、或其混合溶劑 等，反應溫度一般為〇 t：〜迴流溫度，反應時間因使用原 料、溶劑、反應溫度等而異，但通常為30分鐘〜i日。使 用於還原反應之溶劑如四氫呋喃與水之混合溶反應 、：度：ί ΐ0 V迴流溫度’反應時間因使用原料、溶 鈉、反應溫度等而異，但通常為i小時〜】 一
般式（V I I I)代表之化合物可依常法 ；L 鹽。 〜J m吊/云轉換為鈉鹽、鉀鹽等之 步驟5 使二上上以—般式(IX)代表之2, 3, 4, 6-四-〇-乙酿+〇 二亞广代乙醯i_D_吡喃葡糖、I 2, 3 五♦乙醯 糖4 6 η2,3,4,6—四一乙酿-㈣-漢化口比喃葡 糖、d，4, b -四-〇—乙醢一 a』盔 1冷一D—鼠化咄喃葡糖等糖給予體 (Sugar donor )，在條丨μ：、、六兔,丨丄 人铷-翁儿 在h性，谷劑中，三氟化硼-二乙醚配位化 Ψ # #笠i π 銀虱化亞知、三甲基硅烷基三氟化 甲石頁酸#活化劑存在下 . 一般式（VIII)代表之架美^ 、 yc〇sldation)上述以 矛之卞基本齡衍生物或其鹽，製成上述以
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五、發明說明（ίο) 'B 一般式（X)代表之糖苷。使用溶劑如二氯甲烷、甲苯、乙 月青、硝基甲烷、醋酸乙酿、二乙醚、氯仿、或其混合溶劑 等，反應溫度一般為-30T：〜迴流溫度，反應時間因使用 原料、溶劑、反應溫度等而異’但通常為1〇分鐘〜}曰。 步驟6 美二述以一般式⑴、代表之糖苔以消除經基保護 :衣#田w以一般式（11)代表之吡喃葡糖基羥苄基苯衍 生物。使用溶劑如水、甲醇、乙醇、 溶劑等，使用鹼性物質如氫氧化η:南或其混合 方法如分級；結:付：：：之化合物’使用習用分離 法、固相萃取法等分離純化精梦：純化精製法’溶劑萃取 包含水合 物ίϊ:醇；二發明之前體藥物 被轉換成其活性本體、即上W之前體藥物’在生體内 糠基羥苄基苯衍生物，而At於4般式（丨丨）代表之咄喃葡 作用。又上述以一般式（I)W揮優異之人sglt2活性抑制 經改善其經口吸收性，故)八代兮表^之本發明之前體藥物’已 經口投給製劑亦具有高户；;亥：體藥物< 醫藥"物當做 當做糖尿-病 '糖尿病性；性。因此本發明之前體藥物 起之疾病等之預防或治=為=胖症等高血糖症狀引 第15頁 1284641
用 明之醫藥組成物於實際治療時，因應用法而使 劑ΞϊΓ如粉劑、顆粒劑、細粒劑、無水糖浆劑、ί 等，並㈣ΐ射劑、液劑、軟膏劑、检塞劑、貼付劑 等 並以口或非經口投藥。 此寻醫藥組成物，因應其劑$，以 與適當之賦形劑、分魬南丨私入α 蜊于上便用之方法 ^ ^ ^ 刀解J、黏合劑、潤滑劑、稀釋劑、緩 i九丨：ί壓劑、:?腐劑、濕潤劑、乳化劑、分散劑、 二；仴十丨：劑等醫藥品添加物適當混合或稀釋·溶解， 依常法调劑製造之。 ^ 使用本發明之醫藥組成物於實際治療時，其有效成分 本^月之化5物之投藥量，依患者之年齡、性別、體重、 疾病及治療程度等而適宜決定，但經口投藥時成人每曰約 0· 1〜ljOOmg範圍，非經口投藥時則成人每曰約〇· 〇1〜 3OOmg範圍，並以每曰}次或分成數次適當投藥。 【實施例】 ” 以下以參考例、實施例及試驗例再詳細說明本發明之内 容，但本發明不受該内容之限制。 參考例1 2-（4-異丁苄基）苯祕 由2-芊氧基-1-溴基苯（〇.20g)、金屬鎂（〇,〇26g)、碘 (催化劑量）、及四氫呋喃（1 mL)依常法調製格利雅試劑 (Grignard reagent)。加該格利雅試劑於4 -異丁基苯曱 醛（0· 1 6g)之四氫呋喃（2mL)溶液，於室溫攪拌3〇分鐘。此 反應混合物以胺丙基石夕膠管柱色析法（洗出溶劑：四氪口夫
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喃）製得二苯基甲醇體（0.23g)。溶解該二苯基甲醇體於 f酵3mL)及濃鹽酸（〇.lmL)，並加催化劑量之1〇%鈀_碳' m溫及氣氣存在下授拌一夜。濾除催化劑後減壓濃 細。殘渣以矽膠管柱色析法（洗出溶劑：二氯 = 1/1)純化得2-(4-異丁苄基）苯酚（(Kl〇g)。 ^-NMRCCDClg) (ippm ： 〇.89(6H，d，J = 6.6HZ)，1.75-1.90(lH，m)，2 43 ( 2H d J-7 Hz),3.97(2H,s),4.66(lH,s),6.75 -6.85 (lH,m),6.85-6： 5(1H，m)，7· 00-7. 20(6H，m) 參考例2
2-（4-異丙氧芊基）茉祕 與參考例1相同方法並以4 -異丙氧基笨甲駿取代& _異丁 基本曱I合成得標題化合物。 ^-NMR (CDC13) (5 ppm : 1. 31(6H, d, J = 6. 1Hz),3. 93C2H,s), 4. 50(1H,heptet, J = 6. 1
Hz)，4· 72(1H，s), 6· 75-6.85 ( 3H，m)，6. 85-6. 95(1H，m)7· 0 5 - 7.20(4H，m) ’ ’ 參考例3 2 -（4 一乙氧笮基）笨祕 由1-溴基-4-乙氧基苯（1· 5g)、金屬鎂（〇· i9g)、碘（催 , 化劑量）、及四氫呋喃（2mL)依常法調製格利雅試劑。滴加 2-苄氧基苯曱醛（1· ig)之四氫呋喃（i5mL)溶液於該格利 雅試劑’在室溫攪拌3 〇分鐘。加飽和氣化錢水溶液（1 〇 m [) 及水（20mL)後以醋酸乙g旨（i〇〇mL)提取（extract)。提取液
第17頁 1284641 五、發明說明（13) 以水（20mL)及飽和食鹽水（2〇mL)洗淨。用無水硫酸鈉乾燥 後減壓餾除溶劑。殘渣以矽膠管柱色析法（洗出溶劑：己 燒/醋酸乙酯=5/1)精製得二苯基甲醇體（1. 7g)。溶解 該二苯基曱醇體（1.7g)於乙醇（25mL)，並加濃鹽酸 (〇· 42mL)及催化劑量之1〇%鈀-碳粉，於室溫及氫氣存在 下攪拌1 8小時。濾除催化劑後減壓濃縮。加醋酸乙酯 (1 0OmL)於殘渣後用飽和小蘇打水（3〇mL)及飽和食鹽水 (3OmL)洗淨。有機液相以無水硫酸鈉乾燥後減壓餾除溶 劑。殘渣以矽膠管柱色析法（洗出溶劑：己烷/醋酸乙酯 = 8/1)純化得2-(4-乙氧窄基）苯酚（〇.85g)。 4-NMR(CDC13) 5ΡΡΠ1 ： 1. 39(3H, t, J = 7. 1Hz), 3. 93(2H,s), 4. 00(2H, q, J = 7. 1Hz), 4 • 72(lH，s)，6.75-6.85(3H，m)，6.85-6.95(lH，m)，7.05-7.2 〇(4H, m) 參考例4 2-（4-乙石危窄基）笨齡 由1-漠基-4~乙硫基苯（l.ig)、金屬錢（〇.12g)、填（催 化劑量）、及四氫呋喃（5mL)依常法調製格利雅試劑。加2 -（曱氧甲氧基）苯曱醛（〇.56g)之四氫呋喃（12mL)溶液於該 格利雅試劑，在6 5 °C攪拌1 0分鐘。冷卻至室溫，加飽和氯 化銨水溶液（51111〇及水（2〇11^)後以醋酸乙酯（8〇1111〇提取。 提取液以水（2OmL)及飽和食鹽水（2 OmL)洗淨，用無水硫酸 鈉乾燥後減壓餾除溶劑。殘渣以矽膠管柱色析法（洗出溶 劑：己烷/醋酸乙酯= 4/1)精製得二苯基曱醇體（0. 9 lg)。溶
第18頁 1284641 五、發明說明（14) 解該二苯基曱醇體（0· 90g)於二氯曱烷（1 5ml )後加Dess-Martin 試劑（1，1，1-triacetoxy-1，1-dihydro-1，2-benziodoxol-3(lH)-one)(1.5g)，於25°C 攪拌26小時。加 二乙醚（75mL)與lmol/L氫氧化鈉水溶液（30mL)於該反應混 合物並激烈攪拌後分取有機液相。此有機液相以1 mo 1 /L氫 氧化鈉水溶液（30mL)、水（30mL X 3次）、飽和食鹽水 (3OmL)洗淨，用無水硫酸鈉乾燥後減壓餾除溶劑。殘渣以 矽膠管柱色析法（洗出溶劑：己烷/醋酸乙酯= 15/1〜9/1) 精製得甲酮體（0.82g)。此甲酮體（0.81g)、p-曱苯磺酸1 水合物（0· 10g)、及甲醇（14mL)之混合物於60 °C攪拌4小 時。冷卻至室溫後，減壓濃縮反應混合物。殘渣以矽膠管 柱色析法（洗出溶劑：己烷/醋酸乙酯=1 5 / 1)精製得脫保護 體（0.69g)。溶解此脫保護體（〇.68g)於四氫呋喃（llmL)， 加三乙胺（0· 41mL)與氯曱酸甲酯（0· 22mL)，於25 °C攪拌1 小時。接著加入三乙胺（0 . 1 1 mL)及氯曱酸曱酯（0 . 0 6 1 mL ) 攪拌3 0分鐘。過濾此反應混合物，減壓濃縮其濾液。殘渣 溶解於四氫咬喃（14mL)與水（7mL)後加氫硼鈉（0.40g)，於 25 °C攪拌7小時。滴加1 mo 1 /L鹽酸（1 5mL)，以醋酸乙酯 (75mL)提取。提取液以水（20mL)、飽和小蘇打水（20mL)及 飽和食鹽水（20mL)洗淨，用無水硫酸鈉乾燥後減壓餾除溶 劑。殘渣以矽膠管柱色析法（洗出溶劑：己烷/醋酸乙酯 = 8/1)純化得2-(4-乙硫芊基）苯酚（0.62g)。 ^-NMR (CDC13) δ ppm : 1. 29(3H, t, J = 7. 3Hz), 2. 90(2H, q, J = 7. 3Hz), 3. 96(2H, s),
第19頁 1284641 五、發明說明（15) 4.62(lH,s)56.75~6.80(lH,m),6.85-6.95(lH,in),7.05-7· 20(4H,m), 7·20-7· 30(2H,m) 參考例5 曱氧苄基）笨基2, 3, 4, 6-四-〇- r」醯基-/3 -D-吼喃葡 糖苷 加三氟化硼-二乙醚配位化合物（〇. 〇33mL)於2_(4—曱氧
爷基）苯酚（46mg)與2, 3, 4, 6-四乙醯基-1-0-三氣亞胺 代乙醯基-a _D-吼喃葡糖（〇· 1 3g)之二氣曱烷（2mL)溶液， 在室溫攪拌1小時。反應混合物以胺丙基矽膠管柱色析法 (洗出溶劑··二氯甲烷）純化得2-（4-甲氧苄基）苯基2, 3, 4, 6 -四-0-乙醯基-咄喃葡糖苔（〇· iig)。 1 H-NMR (CDC 13) δ ppm 1· 91(3H，s)，2· 03(3H，s)，2· 05(3H，s)，2· 08(3H，s)，3· 77(3 H，s)，3.80-3.95(3H，m)，4.17(lH，dd，J = 2.5，12.2Hz)，4 29 (1H，dd，J = 5· 5, 12. 2Hz)，5. 11(1H，d，J = 7· 5Hz)，5· 10一5· 25( 1Η，πι)，5·25-5·40(2Η，ιη)，6·75'6·85(2Η，ιη)，6·95 — 7ΐ〇(5Η ,m), 7. 10-7. 25(1H,m) · 參考例6
與參考例5相同方法並以2-( 4-曱苄基）苯酚取代2〜 曱氧辛基）苯酚合成得標題化合物。 一 ^-NMRCCDC^) 5ppm ： 1.89(3H,s),2.03(3H,s),2.05(3H,s),2.07(3H ο 〇 〇 η，s j，2 · 3 0 ( 3
第20頁 1284641 五、發明說明（16) H，s)，3· 80-3· 95(3H，m)，4· 17(1H，dd，J = 2· 5, 12· 3Hz)，4. 28 (1H，dd，J = 5.5,12.3 Hz), 5.11(lH，d，J = 7.5Hz ),5.10 - 5.25( lH，m)，5.25-5.40(2H，m)，6.90-7.20(8H，m) 參考例7 2_-（4-乙竽某）笨基2,3,4,6-四-〇-乙醯某-石-0-吡喃葡差 與參考例5相同方法並以2-(4-乙苄基）苯酚取代2-(4-甲氧爷基）苯酚合成得標題化合物。 1 Η - N M R ( C D C 13 ) d p p m : 1· 20(3H，t，J = 7· 6Hz)，1·87(3H，s)，2· 03(3H，s)，2·05(3H, s )，2.08(3H，s)，2.60(2H，q，J = 7.6Hz)，3·80-4·00(3Η，ιη)， 4· 18(1H，dd，J = 2· 3, 12· 2Hz)，4· 28( 1H，dd，J = 5· 4, 12· 2Hz)， 5.11(lH,d,J = 7.5Hz),5.10-5.25(lH,ra),5.25-5.40(2H,m) ，6. 90-7. 25 ( 8H，m) 參考例8 HI—異丁芊基）笨某2· 3· 4. fi-四-〇-乙醯基-D-吡喃葡 糖苷 與參考例5相同方法並以2-(4-異丁亨基）苯酚取代2-(4 -曱氧辛基）苯酚合成得標題化合物。 ^-NMR (CDC13) 5 ppm : 〇.88(6H,d,J = 6.6Hz),1.75-1.90(lH,m),1.87(3H,s),2.03 (3H,s),2.05(3H,s),2.08(3H,s),2.42(2H,d,J = 7.2Hz),3. 80 - 3·95(3Η，πι)，4.18(lH，dd，J = 2.4，12·3Ηζ ),4.29(1 H，dd， J = 5.5, 12·3Ηζ)，5· ll(lH，d，J = 7.6Hz)，5· 10-5.25(lH，m)，5
C: \2D-00DE\90-12\90124049.ptd 第21頁 1284641 五、發明說明（17) • 25-5·40(2H，m)，6· 90-7·25(8H，m) 參考例9 乙氧爷苯基2·3·4,6 -四乙醯基-吡喃葡 糖苷 與參考例5相同方法並以2-(4-乙氧苄基）苯酚取代2-(4 -曱氧辛基）苯酚合成得標題化合物。 H-NMR (CDC13) δ ppm · 1.39(3H，t，J = 7.0Hz)，1.91(3H，s)，2.03( 3H，s)， 2.05(3H，s) 2.07(3H，s), 3.80-3.95 ( 3H，m)，3.99(2H，q， J = 7.0Hz)，4.18(lH，dd，J = 2.5，12.3Hz)，4.28(lH，dd，J = 5· L· 6，12.3Hz)，5.1〇(lH，d，J = 7.7Hz)，5.15-5.25(lH，m)，5.25 -5.40(2H,m),6.75-6.85( 2H,m),6.95-7.10(5H,m),7.10-7. 20(1H,m) 參考例1 0 K4 -異丙氧苄基)一苯基2, 3, 4, 6 -四-〇-乙醯基Ί])_吡喃 葡糖苷 與參考例5相同方法並以2-(4 -異丙氧苄基）笨酚取代2-(4-甲氧苄基）苯酚合成得標題化合物。 -NMR (CDC13) 5 ppm : 1.30(6H,d,J = 6.0Hz), 1.90(3H,s), 2.03(3H,s), 《齡 2.05(3H,s),2.08(3H,s), 3.80-3.90(3H,m), 4.18 (1H, dd, J = 2. 3, 12. 3Hz), 4. 28(1H, dd, J = 5. 5, 12. 3Hz), 4. 48(1 H, heptet, J = 6. 0Hz), 5. 1 0( 1 H, d, J = 7. 7Hz), 5. 10-5. 25(lH,m),5.25-5.40(2H,m),6.70-6.85( 2H,m), 6.90-7. 10
C:\2D-C0DE\90-12\90124049.ptd 第 22 頁 1284641
(5H，m)，7· 10-7· 20(1H，m) 參考例11 2 -（4-曱氧辛基）苯基/5 - D-吼n南葡糠苔 加甲醇鈉（28%曱醇溶液、〇. 12mL)於2一（4—曱氧爷基）苯 基2, 3, 4, 6-四-0-乙醯基-々—D—咄喃葡糖誓（〇· Ug)土之曱 醇溶液（4mL)，在室溫攪拌3〇分鐘。減壓餾除溶劑，殘渣 以矽膠管柱色析法（洗出溶劑··二氣曱烷/甲醇=1〇/1)純化 得2-（4_曱氧爷基）苯基/5 - D-u比喃葡糖苔（65mg)。 !H - NMR(CD30D) 6 ppm : 3·35 - 3.55(4H,m)，3.69(lH，dd，J = 5.1，12.1Hz)，3.73(3H，s _ )，3.8 0-4.00(2H，m)，4.03(lH，d，J=15.1Hz)，4.91(lH，d，J = 7. 4Hz), 6. 75-6. 85 ( 2H,m), 6. 85-6. 9 5 ( 1 H,m), 6. 95-7. l〇(l H, m), 7. 10-7. 20(4H, m) 參考例1 2 2-（4一甲芊基）笨基/3—D - 口比喃葡糖苷 與參考例11相同方法並以2_(4_曱苄基）苯基2, 3, 4, 6 -四-0-乙醯基-/3 -D-吼喃葡糖苷取代2-（4-曱氧苄基）苯基 2, 3, 4, 6 -四-0-乙醯基-/5-D-吡喃葡糖苷合成得標題化合 物。 l-NMRCCDsOEOSppm:*· 2.27(3H,s),3.35-3.55(4H,m)53.69(lH,dd,J = 5.2,12.0Hz )，3·80 - 3.90(lH，m)，3_94(lH，d，J = 15.0Hz)，4.05 (lH，d，J = 15.0Hz)，4.85-4.95(lH，m)，6.85-6.95(lH，m)， 6· 95-7· 20(7H，m)
第23頁 1284641 五、發明說明（19) 參考例1 3 2 -（4一乙辛基）苯基汐- D-p比°南fe糖誓 與參考例11相同方法並以2-(4-乙苄基）苯基2，3，4，6 -四-0-乙醯基-石-D -吼喃葡糖苷取代2-(4-曱氧辛基）苯基 2, 3, 4, 6-四-0-乙醯基-/3 -D —吼喃葡糖苷合成得標題化合 物。 ^-NMR (CD30D) (5 ppm ： 1· 15-1·25(3Η，πι) ,2.50 - 2.65(2H，m)，3.35-3· 55( 4H，m)， 3.65-3.75(lH,m),3.80-4.00(2H,m), 4.06 (lH，d，J = 14_9Hz), 4·85-5·00(1Η，π〇,6·85-7·00(1Η，πι)， 7· 00-7· 20(7H，m) 參考例1 4 2-（4 一異丁节基）笨基/9 一 D —。比喃葡糖苔 與參考例11相同方法並以2-(4-異丁辛基）苯基2，3，4，6 -四一 0-乙酉盔基一 /3—D - σ比喃葡糖苔取代2 -（4一曱氧罕基）苯 基2, 3, 4, 6-四-0-乙醯基-冷-D-吼喃葡糖苷合成得標題化 合物。 ^-NMR (CD3OD) (5 ppm ： 0.80-0.95(6H,m),1.70-1.90(lH,m),2.41(2H,d,J = 7.1Hz) ,3.30-3.55(4Η,ιη),3.60-3.75(1Η,ιη),3.80-3.95(1Η,πι),3 .95(lH,d,J = 15.0Hz),4.〇6(lH,d,J = 15.0Hz),4. 85-4. 95(1 Η，m), 6· 80-7· 20(8Η, m) 參考例1 5 2 -（4-乙氣爷基）笨基- D-吼17南葡糖誓
第24頁 1284641 五、發明說明（20) 與參考例1 1相同方法並以2-(4-乙氧苄基）苯基2, 3, 4, 6 -四-0-乙醯基_ /5 - D-咄喃葡糖：¾:取代2-(4_甲氧辛基）苯基 2，3, 4, 6 -四_0-乙醯基-召一 D-吼喃葡糖苷合成得標題化合 物。 4 - NMR(CD3OD) 6 ppm : 1.35(3H,t,J = 6.8Hz),3.35-3.55(4H,m),3.60-3.75(lH,m) ,3.80-4.10(5H,m)54.90(lH,d,J = 7.1Hz),6.70-6.85(2H,m ),6.85-6.95(lH,m),7.〇〇-7.20(5H,m) 參考例1 6 2 -（4 一異丙氧苄基）苯基汐一 D—p比喃葡糖答 與參考例1 1相同方法並以2 _( 4 -異丙氧窄基）苯基 2, 3, 4, 6-四一0-乙醯基一 /5-D-咣喃葡糖苷取代2-（4 一甲氧罕 基）苯基2, 3, 4, 6 -四-0-乙醯基-冷-D-吼喃葡糖苷合成得標 題化合物。 ]H-NMR (CD3OD) 5 ppm ： 1.27(6H,d,J = 6.0Hz),3.35-3.55(4H,m),3.69(lH,dd,J = 5.4,12.1Hz),3.88(lH,dd,J = 2.0,12.1Hz),3.91(lH,d,J = l 5.0Hz),4.02(lH,d,J = 15.0Hz),4.51(lH,heptet,J = 6.0Hz) ，4· 91(1H，d，J = 7· 7Hz), 6· 70-6· 85(2H, m), 6· 85-6· 95(1H，m )，7· 00-7· 10(1H，m)，7· 10-7· 20(4H，m) 參考例1 7 2-U- L疏苄基）笨基；S-D-。比喃葡糖苷 加三氟化硼-二乙醚配位化合物（〇· 78mL)於2-(4-乙硫笮 基）苯酚（〇· 51mg)與1，2, 3, 4, 6-五-0-乙醯基-；3 - D-吡喃葡
第25頁 1284641 五、發明說明（21) 糖（2· 4g)之甲苯（6· 3mL)與二氣曱烷（2· 7mL)溶液，在室溫 攪拌9小時。加醋酸乙酯（7〇mL)及飽和小蘇打水（25mL)於 該反應混合物，分取有機液相。此有機液相以飽和食鹽水 (2 5mL )洗淨，無水硫酸鈉乾燥後，減壓餾除溶劑。殘渣溶 解於甲醉（10. 5mL)後加甲醇鈉（28°/。曱醇溶液、〇· 〇8mL)， 於25 C攪拌18小時。加醋酸乙酯（75mL)及水（2〇mL)於該 反應混合物’分取有機液相。此有機液相以飽和食鹽水 (2 0mL )洗淨，無水硫酸鈉乾燥後，減壓餾除溶劑。殘渣以 石夕膠管柱色析法精製（洗出溶劑：二氣曱烷/甲醇=1〇/1)。 減壓顧除溶劑，加二乙醚於殘渣，濾取析出物。所得無色 固体以二乙驗洗淨後減壓乾燥得2 - (4 -乙硫苄基）苯基/3 一 D -吼喃葡糖苷（〇 · 5 1 g)。 ^-NMR (CD3OD) (5 ppm ： 1. 24(3H, t, J = 7. 3Hz),2.88(2H, q, J = 7.3Hz),3.3 5-3. 5 5 ( 4H ，πι)>3. 69(1H, dd ,J = 5.0, 12. 2Hz), 3. 88(lH,dd, 1 = 2.0,12.2
Hz),3.95(lH,d,J = i5.iHz),4.08(lH,d,J = 15.1Hz),4.91(i H,d,J = 7. 3Hz), 6.85-7.0 0 ( 1 H,m), 7. 0 0-7. 10(1H, m), 7· 10-7. 30(6H, m) 實施例1 2 -2基6 - 0 -乙__氧羰基-_ D -吡喃葡糖苷 室溫下’加氯甲酸乙酯（〇· 〇4mL)於2 -（4-甲氧苄基）笨基 万D 口比。南葡糖誓（〇75g)之2,4,6 -三甲基吡啶（2mL)溶 液。於室溫授拌1 6小時後，加飽和檸檬酸水溶液於此反應 混合物並以醋酸乙酯提取。提取物以水洗淨後，用無水硫
第26頁 1284641 五、發明說明（22) 酸納乾燥，減壓鶴除溶劑。殘渣以製備（p r e p a r a t i v e)石夕 膠薄層色析法純化（洗出溶劑：二氯曱烷/甲醇= 10/1)得無 定形2-(4-甲氧苄基）苯基6-0-乙氧羰基-yS -D-咄喃葡糖苷 (〇· 〇32g) ^-NMR (CD3OD) (5 ppm ： 1.23(3H,t,J = 7.1Hz),3.30-3.65(4H,ra),3.74(3H,s),3.93 (1H，d，J = 15.1 Hz ),4.02(1 H, d，J = 15.1 Hz ),4.05-4.20(2H，m )，4· 29(1H，dd，J = 6· 4, 11· 7Hz)，4. 4 5(1H，dd，J = 2. 2, 11· 7Hz )，4.89(1 H，d，J = 7.4Hz ),6.75 - 6·85(2Η，πι)，6·86-7·05(2Η， m)，7· 05-7. 20(4H，m) 實施例2 2-（1二曱氧芊基）笨基6-0-甲氮羰基一厶一D-咄喃葡糖苷 與實施例1相同方法並以氣曱酸曱酯取代氯曱酸乙酯合 成得標題化合物。 ^-NMR (CD3OD) δ ppm : 3· 30-3· 65(4H，m)，3· 71(3H，s)，3· 74(3H，s)，3· 93(1H，d，J = 15. 1Hz), 4. 0K1H, d, J = 15. 1Hz), 4. 30(1H, dd, J = 6. 4, 11. 7H z),4.45(lH,dd,J-2.1,ll.7Hz),4.89(lH5d,J = 7. 4Hz), 6. 7 5-6.85(2H,m),6.85~7.05(2H,m),7.05-7.20(4H,m) 實施例3 二-甲氧节基）苯基6一〇一「2一（甲氧基）乙氧羰基卜s-d — 口比喃葡糖苷 與實施例1相同方法並以氯曱酸2-（曱氧基）乙酯取代氣 曱酸乙S旨合成得標題化合物。
C:\2D-00DE\90-12\90124049.ptd 第27頁 1284641 五、發明說明（23) ]H-NMR (CD3OD) (5 ppm ： 3. 3 0-3. 65(9H, m), 3. 74(3H, s), 3. 9 2(1H, d, J = 15. 1Hz), 4. Ο 2(lH,d,J = 15.1Hz),4.10-4.25(2H,m),4.30(lH,dd,J = 6.33 11. 7Hz),4.47(1H,dd, J = 2. 1, 11. 7Hz),4.89(1H,d,J = 7.4Hz )，6· 70-6. 85(2H，m)，6.85-7· 05(2H，m)，7· 05-7.20(4H，m) 貫施例4 甲氣芊某）装基6-0-己醯基-/3 一d-吼喃葡糖苷 於〇°C加己醯氣（〇.〇72g)於2 -（4-甲氧苄基）苯基/5-D -^比喃葡糖苷（〇· l〇g)之2, 4, 6-三曱基吡啶（2mL)溶液，擾拌 3小犄。加1 〇 %彳争檬酸水溶液於此反應混合物並以醋酸乙酯 提取。有機液相以1 0%檸檬酸水溶液及飽和食鹽水洗淨。 = f =乾燥•，減壓館除溶劑。殘渣以製 備矽膠溥層色析法（洗出溶劑：二氯曱烷/ 曱氧…基6♦己酿基-…㈣/ ^-NMR (CD3OD) δ ppm : 0.80 °·95(3Η,πι),1. 20-1. 35(4H,m),l. 50-1. 65(2H,m))2. -2 35 ( 2H,m), 3. 30-3. 65 ( 4H,m), 3. 74( 3H, s), 3. 92( 1 H d ，=1 .lHz),4.01(lH,d5j = 15.1H2))4.22(lH,dd,J = 6 7 il .8 z),4.42(lH,dd,J = 2.2,11.8H2),4.85-4.95(lH,；) 6 5-6.85(2H)m),6.85-7.05 ( 2H,n〇,7.05-7.20 (4H,m) 實施例5 ’ 氧苄基）苯基6-咄喃葡嫉^ 與實施例4相同方法並以丙醯氣取代己醯氣合成得標題
第28頁 1284641 五、發明說明（24) 化合物。 ^-NMR (CDgOD) 5ppm ： 1.08(3H，t，J = 7.6Hz)，2.25-2.40(2H，m)，3.30-3.55(3H，m) ，3.55-3.65(lH，m)，3.74(3H，s)，3.93(lH，d，J = 15.1Hz)，4· 01(1H，d，J = 15· 1Hz)，4· 23(1H，dd，J = 6. 7, 11· 8Hz)，4· 40(1H ，dd，J:2.1，11.8Hz)，4.85-4.95(lH，m)，6.75-6.85(2H，ni)， 6.85- 7.05(2H,m),7.05~7.20(4H,m) 實施例6 2-（4-甲氧芊基）茉某6-0-丁醯基二比直葡轉 與實施例4相同方法並以丁醯氯取代己酿氣合成得標題 化合物。 ]H~NMR (CD3OD) δ ppm ^ 0.90(3H,t,J = 7.4Hz),1.50~1.70(2H,m)>2.20-2.35(2H,m) ,3.30~3.65(4H,m),3.74(3H,s),3.93(lH,d,J = 15.1Hz),4. 0K1H, d, J = 15. 1Hz), 4. 22(1H, dd, J = 6. 7, 11. 8Hz), 4. 42(1 H ,dd, J = 2. 2, 11. 8Hz), 4. 85-4. 95(lH,m), 6. 75-6. 85 (2H,m), 6.85- 7.05(2H,m),7.05-7.20(4H,m) 實施例7 2二（4-曱氧苄基）苯某6-0-乙醯基-沒-D-咄喃葡糖苷 與實施例4相同方法並以乙醯氣取代己醯氣合成得標題 化合物。 ^-NMR (CD3OD) 5 ppm ：
2.02(3H,s),3.30-3.65(4H,m),3.74(3H,s),3.93(lH,d,J = 15. 1Hz), 4. 0K1H, d, J = 15. 1Hz), 4. 24(1H, dd, J = 6. 5, 11. 9H
C:\2D-C0DE\90-12\90124049.ptd 第29頁 1284641 五、發明說明（25) z)，4.38(lH，dd，J = 2e2, 11.9 Ηζ )，4·85-4·95(1Η，πι)，6.75 -6.85(2H,m),6.85-7.05(2H,m),7.05-7.20(4H,m) 實施例8 2-（4-曱氧芊基）笨基6-0-異丁醯基->5-D-吼喃葡糖苷 與實施例4相同方法並以異丁醯氯取代己醯氯合成得標 題化合物。 ^-NMR (CD30D) (5 ppm ： l.ll(3H,d,J = 7.0Hz),1.12(3H,d5J = 7.0Hz), 2.45-2.60C1H ，m)，3.30-3.65(4H，m)，3.74(3H，s)，3.93(lH，d，J = 15.1Hz) ，4.00(lH，d，J = 15.1Hz)，4.19(lH，dd，J = 6.9，11.8Hz)，4.43 一 (lH,dd,J = 2.1,11.8Hz),4.85-4.95(lH,m),6.75-6.85(2H, m),6.85~7.05(2H,m),7.05-7.20(4H,m) 實施例9 2-（4-曱氧芊基）笨基6-0-乙基丁二醯基_万-D-吼喃葡糖苷 與實施例4相同方法並以乙基丁二醯基氣取代己醯氯合 成得標題化合物。 ^-NMR (CD3OD) (5 ppm ： 1.19(3H,t,J = 7.1Hz),2.50-2.70(3H,m),3.30-3.65(4H,m) ,3.74(3H,s),3.93(lH,d,J = 15.1Hz),4.02(lH,d,J = 15.1Hz ^ ),4.08(2H,q,J = 7.1Hz),4.2 2(lH,dd,J = 6.7,11.8Hz),4.44 _ (lH,dd,J = 2. 1,11.8 Hz ),4.85-4. 95(lH,m), 6. 75-7. 25(8H, m) 實施例1 0 2-（4-甲氣爷基）笨基6-0-異丙氡羰基-/3-D-吼喃葡糖苷
C:\2D-CODE\90-12\90124049.ptd 第 30 頁 1284641 五、發明說明（26) _ 於0 °C加三碳醯氯（又稱三* 於異丙醇（0· 12g)之2, 4 6Γ二氣、Triph〇sgene)(0· 0 2 2S) 之。1小時後再加2-(4-甲氧^曱基咄啶（2mL)溶液並攪拌 (0. 075g),於室溫攪拌1夜。卞基）苯基々一卜吡喃葡糖苷 、曰入輪怂丨、/鉍缺7t 加1 〇%棒檬酸水溶液於此反應 混合物後以醋酸乙酯提取。右拖>， 、 ’機液相以1 0 %棒樣酸水溶液 及水洗淨，用無水硫酸鎂乾燥後，減壓餾除溶劑。殘渣以 製備矽膠薄層色析法（洗出溶劑：二氣甲烷/甲醇=1 〇 / 1)純 化得2 -（4-甲氧芊基）苯基6 - 0-異丙氧獄基-/3 - D-^b。南葡糖 苷（0· 024g)。
'H-NMR (CD3OD) 5 ppm ： I. 21(3H，d，J = 6.3Hz)，1.23(3H，d，J = 6.3Hz ),3.30 -3·65(4Η ，m)，3.74(3H，s)，3-93(lH，d，J = 15. lHz)，4.02(lH，d，J = 15. 1Hz), 4. 28(1H, dd, J = 6. 4, 11. 7Hz), 4. 43(1H, dd, J = 2. 2, II. 7Hz),4.70~4.85(lH,m),4.85-4.95(lH,m),6.75-7.20( 8H，m) 實施例11〜2 2 與實施例1或2相同方法並使用參考例1 2〜1 7製得之化合 物合成得下列表1記載之化合物。 «
第31頁 1284641 五、發明說明（27) [表1] 實施例 R Ρ 11 甲基 乙氧羰基 12 甲基 曱氧羰基 13 乙基 乙氧羰基 14 乙基 曱氧羰基 15 異丁基 乙氧羰基 16 異丁基 曱氧羰基 17 乙氧基 乙氧羰基 18 ^乙氧基 甲氧羰基 19 異丙基 乙氧魏基 20 異丙基 曱氧羰基 21 乙硫基 乙氧羰基 22 备你Μ 乙硫基 甲氧羰基 « 人SGLT2活性抑制作用禮認試驗 1)製造表現人SGLT2之質·體載體 使用 SUPERSCRIPT Preamplification System (Gibco -BRL : LIFE TECHNOLOGIES製品、前置放大系統），將人腎 臟來源之全RNA(total RNA)(0ri gene公司製品）以〇iig〇 dT(寡聚去氧胸誓）為引子（primer)反轉錄，製成PCR (Polymerase Chain Reaction、聚合酶鏈鎖反應）放大用 cDNA基因庫。上述人腎臟cDNA基因庫為模板（template)，
C:\2D-C0DE\90-12\90124049.ptd 第32頁 1284641 五、發明說明（28) 下列以序列編號1及2表示之寡核苔酸0702F及071 2R為引 子，以使用Pfu DNA 聚合酶（Pfu DNA Polymerase、 Stratagene公司製品）之PCR反應，放大編碼人SGLT2之DNA 片段。依選殖用載體pCR - Blunt(Invitrogen公司製品） 之套件（ki t)之標準方法將被放大之DNA片段與選殖用載體 pCR - Blunt連接（ligation)。以常法將其導入大腸桿菌 HB1 01競爭細胞（competent cel 1、東洋紡股份有限公司製 品）中後，用含卡那黴素（Kanamycin)50//g / mL之LB洋菜 培養基選取被轉形菌株。取其中1轉形菌株，萃取純化質 體DNA，下列以序列編號3及4表示之寡核苷酸〇71 4F及 0715R為引子’以使用pfu DNA聚合酶（Stratagene公司製 品）之PCR反應，放大編碼人SGLT2之DNA片段。用限制酶 Xho I與Hind I I I消化此被放大之DNA片段後，以Wizard Purification System (Pr omega公司製品、純化DNA 用套 件）純化。此純化之D N A片段插入融合蛋白質表現用載體 ?〇0 — 3.1(-）^1乂〇:/1^3-8(111¥11：1'〇忌611公司製品）之對應限制 酶位點（site)。以常法導入大腸桿菌HB1 〇1競爭細胞（東洋 紡股份有限公司製品）中後，用含安比西林（Ampici丨in) 1 00 # g / mL之LB洋菜培養基選取轉形菌株。由該轉形菌 株萃取純化質體DNA，檢查插入載體pcdnA3. 1 (_)Myc /
His - B多選殖位點之DNA片段之鹼基序列（Base sequence)。如與Wells 等Am. J. Physiol.， ν〇1·263，ΡΡ· 459-465 ( 1 992 ))報告之人SGLT2比較時，本選殖系（clone) 具有1驗基之改變（第433編碼異白胺酸之ATC取代為GTC)。
C:\2D-CODE\90-12\90124049.ptd 第33頁 1284641 五、發明說明（29) 於是獲得第433殘基之異白胺酸改變為纈胺酸之選殖系。 在羧基末端方最後之殘基丙胺酸之後，融合以下列序列編 號5表示之胜肽之表現人SGLY2之質體載體命名為KL29。
序列編號1 ATGGAGGAGCACACAGAGGC
序列編號2 GGCATAGAAGCCCCAGAGGA
序列編號3 A A CCTCGAG ATGGAGGAGCACACAGAGGC
序列編號4 AACAAGCTTGGCATAGAAGCCCCAGAGGA
序列編號5 KLGPEQKLISEEDLNSAVDHHHHHH 2)調製人SGLT2暫時性表現細胞（Transient Expression
Cell)
用電氣穿孔法導入人SGLT2表現質體KL29於C0S-7細胞 (RIKEN CELL BANK RCB0 5 3 9 )中。電穿孔法使用 Genepulser I I(Bio - Rad Laboratories 製品、基因脈 衝器），在含 5 0 0 /zL 0PTI - MEM I 培養基（Gibco - BRL ·· LIFE TECHNOLOGIES 製品）、COS - 7 細胞2x 106 個、及20 β g KL29 之 0.4cm 比色管（cuvette)中以 0.290 kV 、975 //F 條件下進行。基因導入後之細胞以遠心分離回收，加1 m L OPT I - MEM I培養基於1比色管份細胞使其懸浮。分注該 細胞懸浮液於9 6孔微量培養板（9 6 - w e 11 m i c r ο p 1 a t e)，每 孔125//L。在37°C、5%C02條件下培養1夜後每孔加125 //L 含10%牛胎兒血清（三光純藥股份有限公司製品）、1〇〇
units/mL 青黴素 G 鈉（Gibco - BRL : LIFE TECHNOLOGIES 製 品）、100 //g/mL 硫酸鏈黴素（Gibco - BRL : LIFE TECHNOLOGIES 製品）之 DMEM 培養基（Gibco - BRL : LIFE
第34頁 1284641
TECHNOLOGIES製品）。培養至翌日供測定抑制嵌入 (incorporation )曱基-α一d-咄喃葡糖普活性之用。 3 )測定抑制嵌入甲基—α —D-咄喃葡糖苷之活性 ^溶解供試化合物於二甲亞砜，以嵌入用緩衝液（含“MM 氯化鈉、2mM氣化鉀、1 mM氯化鈣、1 mM氣化鎂、甲美一 二-D-咄喃葡糖苔、10mM 2-[4 一（2 一羥乙基）一 i 一哌啶醯广乙一 石頁酸、5mM三羥曱基胺基甲烷，ρΗ7· 4)稀釋製成測定抑制 活性用樣品。去除（上述培養板各孔中之）、S(JLT2暫時性 表現細胞COS-7之培養基，每孔加20() 前處理用緩衝液
(含140mM氯化膽鹼、2mM氣化鉀、1祕氣化鈣、lmM氣化 鎂、lOinM 2-[4-（2-羥乙基）-卜哌啶醯]乙磺酸、5mM三羥 曱基胺基曱烷，ΡΗ7·4)，於37t靜置10分鐘。去除前處理 用緩衝液，再加同一緩衝液2 〇 〇 # L，於3 7 〇◦靜置丨〇分鐘。 取上述（測定抑制活性用）樣品各5 2 5 各加曱基一 α -D -（U - 14C)咄口南葡糖 KAmersham Pharmacia Biotech 製
，）7 // L製成測定用緩衝液。另調製不含供試化合物之測 定用緩衝液為對照組用。又為供試化合物不存在下及鈉不 ，在下之基本嵌入測定用，調製含14〇mM氯化膽鹼以取代 ^化納之基本嵌入測定用緩衝液。去除前處理用緩衝液， 每孔加75 # L測定用緩衝液，於37 °C靜置2小時。去除測定 用緩衝液，每孔加2〇〇 洗淨用緩衝液（含i4〇mM氯化膽 產双、2mM氯化鉀、ImM氣化鈣、ImM氣化鎂、i〇mM甲基- α -D-吼味葡糖苷、ι—μ 2-[4一（2 -羥乙基）一卜哌啶醯]乙磺 酸、5mM三經甲基胺基曱烷，ρΗ7· 4)並立即去除。此洗淨
第35頁 1284641 五、發明說明（31) 操作再進行2次後，每孔加7 5 # L 0 · 2 N氫氧化鈉使細胞溶 液化。移此細胞溶液於PiC0 —Plate (Packard製品、微微量 培養板）’加 150//L Microscint-40(Packard 製品、樣品 稀釋計數用溶液）後，以微量閃爍計數器 (Microscintillation counter) TopCount (Packard 製 口口）測定放射活性。對照組之嵌入量減去基本嵌入量之值 為1 0 0 %，由濃度-抑制曲線以最小自乘法（平方法）計算抑 制5 0%嵌入量之濃度（丨^值）。結果如下列表2所示。w [表2] 供試化合物 IC50 值（ηΜ) 參考例1 1 350 參考例1 2 450 參考例1 3 140 參考例1 4 Ί 500 參考例1 5 330 參考例1 6 370 參考例1 7 110 試驗例2 經口吸收性碹認試脍
1 )以尾靜脈内投藥製造測定藥物濃度用樣品 使用絕食1夜之SD系家鼠（日本可樂亞製、雄性、5週 齡、體重140〜170g)為實驗動物。溶解或懸浮供試化合物 60mg於乙醇1.8mL後，加聚乙二醇PEG-4〇〇 72mL&生理食 鹽水9mL，溶解後調製成含3· 3mg/mL之溶液。測定家鼠體
第36頁 1284641 五、發明說明（32) 重後’以供試化合物溶液3mL/kg用量（即1 Omg/kg)，在無 麻醉下投給尾靜脈内。尾靜脈内投藥使用26G注射針與lmL 注射筒。於尾靜脈内投藥後2、5、1〇、20、30、60、120 分鐘分別採取血液。血液經遠心分離後以血漿為測定血中 藥物濃度用樣品。 2 )以經口投藥製造測定藥物濃度用樣品 使用絕食1夜之SD系家鼠（曰本可樂亞製、雄性、5週 齡、體重140〜170g)為實驗動物。供試化合物以〇· 5%羧甲 基纖維素鈉溶解或懸浮使成為含1 m g / m L活性本體之溶液。 測定家鼠體重後，以上述供試化合物溶液1〇mL/kg用量（以 活性本體為1 〇 m L / k g)經口投藥。經口投藥使用家鼠用探 針（Sonde)及2.5mL注射筒。經口投藥後15、30、60、120 、2 4 0分鐘分別採取血液。血液經遠心分離後以血漿為測 定血中藥物濃度用樣品。 4 )測定藥物濃度 取於上述1 )及2 )所得各血聚〇 · 1 m L，加參考例1 5記載 之2-(4-乙氧苄基）苯基- D-吼喃葡糖笞1 為内標準物 質後，再加甲醇1 mL以去除蛋白質。遠心分離後，在氮氣 氣流下蒸發甲醇液層並乾涸。隨後用移動相（m〇bi 1 e phase) 30 0 //L 稀釋，取其 30#L 注入 HPLC(High Performance Liquid Chromatography、高效液相色析 儀）。血中藥物濃度依下列條件用hplc法測定。 管柱：Inertsil 0DS - 2(4.6 X 250mm) 移動相：乙腈/1〇11^磷酸緩衝液（1)}] 3.0 ) = 25:75(>/乂）
1284641 五、發明說明（33) 管柱溫度：5 0 °C 流量：1.〇1111/分鐘（111丨11) 測定波長：UV232nm 標準曲線為取空白血漿〇 · 1 m L，以添加參考例1 5記載之2 -（4-乙氧窄基）苯基冷一D—咄喃葡糖笞1 #忌及參考例丨丨記載 之2-（4-曱氧苄基）苯基々一 d—咄喃葡糖苷各、〇.5、 〇· 2、〇· 1、〇· 〇5、或〇· 〇2 為内標準物質，與上述相同 方法製成。 由HPLC所得各時間之血漿濃度，用WinN〇niin
^andard(體内藥物動態解析軟體、扑訂幻 Corporation公司制口、本％知 經口投藥之血號中濃V時門：:式化合物尾靜脈内投藥; curve)，根據下式計算生B曲線下之面積（Area under 示。 1用率（％)。結果如下列表3戶; 度-時間曲線下之面 漿中濃度-時間曲線 生物利用率U)=(經口投藥之血漿中^ 積/尾靜脈内和雄 下之面積）X 1〇〇 ^又樂之i [表3]
1284641
使用未絕食之SD系家鼠（日本SLC、雄性、8週齡、體重 27 0〜3 2 0g)為實驗動物。懸浮供試化合物於〇· 5%羧甲基纖 維素鈉水溶液，調製成〇· 3及1· 3mg/mL懸浮液。測定家鼠 體重後，以供試化合物懸浮液l〇mL/kg用量（3、10、
3 0mg/kg)經口投藥。對照組則只以〇· 5%羧曱基纖維素納 水溶液1 OmL/kg用量經口投藥。經口投藥使用家鼠用探針 (Sonde)及2· 5mL注射筒。各處理組與對照組之重複數為5 至6隻。經口投藥終了後即開始在測定代謝用飼養籠中進 行採尿。採尿時間為經口投藥後24小時。採尿終了後記錄 尿量，測定尿中所含葡萄糖濃度。葡萄糖濃度使用臨床檢 查用套件· π葡萄糖B測試和光’’（g 1 u c 〇 s e B T e s t W a k 〇、 曰本和光純藥公司製品）進行定量。由尿量、尿中葡萄糖 濃度、及體重計算24小時、體重2 0 0g之尿糖排泄量。結果 如下列表4所示。 [表4] —供試化合i 用量（mg/kg) 尿糖排泄量(mg/24小時· 200g體重） 實施例1 3 52 10 239 30 513
試驗例4 急性毒性試<»蜂 取雄性、8週齡ICR系家鼠（日本可樂亞製、體重22〜 28g、1組5隻），經絕食4小時後以i〇mL/kg用量（600mg/ kg) ’經口投給（or投）供試化合物加0. 5%羧曱基纖維素調
C:\2D-C0DE\90-12\90124049.ptd 第39頁 1284641
五、發明說明（35) 製成之懸浮液（60mg/mL)。結果如下列| 一 十你丨。 幻表5所示，未發生死 [表5] 供試化合物 死亡例 實施例1 0/5 【產業上利用之可能性】 本發明之上述以-般式⑴代表之吼 何生物已被改善其經口吸收性，經口 ％ 土規卞基苯 其活性本體 '即上述以一般式（，後在肢内轉換’
基苯衍生物，而發揮優旦之=2代舌\之南葡糖基經 恭昍二 叙评1雯共之人1 Z，舌性抑制作用。因本 “：可提供當做經口投藥製劑亦適宜之糖尿病、糖尿e 療劑]症、因肥胖症等高血糖症狀引起疾病等之預防或；
第40頁 1284641
C:\2D-C0DE\90-12\90124049.ptd
Claims (1)
- ι· 一種咄喃葡糖基羥节基 般式 本何生物，其特徵為以 下列 1284641； -^^wJI〇124049 六、申請專利範圍(式中R為C1/t烧某、r ^ ^ 其Γ ρΛ CH烷虱基、或Ch烷硫基，ρι Α 基:C燒氧叫6酿基、c2 4燒氧幾基、或c“為土醯 乳斂基）代表之吡喃葡糖基羥节基苯衍生物。土 Ch烷 2·:申凊專利範圍第i項之吡喃葡糖基羥苄基 物，其中以下列一般式 本何生(式中R1為(^_4燒基或cw烧氧基，P1為C2_6醯基、C2_4燒氧幾 Cl6醯基、Cm烷氧羰基、或Ci_4烷氧基C2_4烷氧羰基）代表之 吼喃葡糖基羥芊基苯衍生物。 3·如申請專利範圍第1項之咄喃葡糖基羥苄基苯衍生 物，其中以下列一般式C: \總檔\90\90124049\90124049(替換）-1. 第42頁 1284641 案號 90124049 年月曰 修正 六、申請專利範圍(式中R為q_4烷基、Cw烷氧基、或Q_4烷硫基，P2為C2_6醯基 或C2_4烷氧羰基）代表之咄喃葡糖基羥苄基苯衍生物。 4.如申請專利範圍第2項之吼喃葡糠基羥苄基苯衍生 物，其中以下列一般式.R1 (式中R1為(^_4烷基或(^4烷氧基，P2為C2_6醯基或C2_4烷氧羰 基）代表之吼喃葡糖基羥苄基苯衍生物。 5.如申請專利範圍第4項之吼喃葡糖基羥苄基苯衍生 物，其中以下列一般式 ch3ch2^HO、、 och3 OHC: \總檔\90\90124049\90124049(替換）-1 .ptc 第43頁 1284641代表之吼喃葡糖基羥爷基苯衍生物。 物，复t明專利耗圍第4項之咄喃葡糖基羥苄基苯行生 物，其中以下列一般式 盘本何生代表j吼喃葡糖基經辛基苯衍生物。 由!ϊ =於人SGLT2活性抑制劑之醫藥組成物，其特徵 tl::利範圍第1至6項中任-項之吼喃葡糖基經。 本何生物為有效成分。 該醫藥組成物 其中起因於高 〇 ，其中起因於ί 8如申？專利範圍第？項之醫藥組成物， -&因於向血糖症疾病之預防或治療劑。 •如申請專利範圍第8項之醫藥組成物， 潘症之疾病為糖尿病或糖尿病性併發症 〇·如申請專利範圍第8項之醫藥組成物 血糖症之疾病為肥胖症。
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| SI (1) | SI1329456T1 (zh) |
| SK (1) | SK287811B6 (zh) |
| TW (1) | TWI284641B (zh) |
| UA (1) | UA73606C2 (zh) |
| WO (1) | WO2002028872A1 (zh) |
| ZA (1) | ZA200302283B (zh) |
Families Citing this family (67)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1020944C (zh) | 1990-01-30 | 1993-05-26 | 阿图尔-费希尔股份公司费希尔厂 | 紧固件 |
| CN1293087C (zh) | 2000-09-29 | 2007-01-03 | 橘生药品工业株式会社 | 吡喃葡糖氧基苄基苯衍生物及其药物组合物 |
| US7053060B2 (en) * | 2000-11-30 | 2006-05-30 | Kissei Pharmaceutical Co., Ltd. | Glucopyranosyloxybenzylbenzene derivatives, medicinal compositions containing the same and intermediates in the production thereof |
| TWI255817B (en) | 2001-02-14 | 2006-06-01 | Kissei Pharmaceutical | Glucopyranosyloxybenzylbenzene derivatives and medicinal use thereof |
| CN1307190C (zh) | 2002-03-22 | 2007-03-28 | 橘生药品工业株式会社 | 吡喃葡糖基氧代苄基苯衍生物的晶体 |
| CA2478889A1 (en) * | 2002-08-09 | 2004-02-19 | Taisho Pharmaceutical Co., Ltd. | Aryl 5-thio-.beta.-d-glucopyranoside derivatives and therapeutic agents for diabetes containing the same |
| JP4651934B2 (ja) * | 2002-12-04 | 2011-03-16 | キッセイ薬品工業株式会社 | ベンジルフェノール誘導体、それを含有する医薬組成物およびその医薬用途 |
| CA2507665A1 (en) * | 2002-12-04 | 2004-06-17 | Kissei Pharmaceutical Co., Ltd. | Preventive or remedy for diseases caused by hyperglycemia |
| DE10258007B4 (de) * | 2002-12-12 | 2006-02-09 | Sanofi-Aventis Deutschland Gmbh | Aromatische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
| DE10258008B4 (de) * | 2002-12-12 | 2006-02-02 | Sanofi-Aventis Deutschland Gmbh | Heterocyclische Fluorglycosidderivate, diese Verbindungen enthaltende Arzneimittel und Verfahren zur Herstellung dieser Arzneimittel |
| UA86042C2 (en) * | 2003-08-01 | 2009-03-25 | Янссен Фармацевтика Н.В. | Substituted indazole-o-glucosides |
| EP2360164A3 (de) * | 2004-03-16 | 2012-01-04 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituierte Benzol-Derivate, diese Verbindungen enthaltende Arzneimittel, deren Verwendung und Verfahren zu ihrer Herstellung |
| US20070185197A1 (en) * | 2004-03-31 | 2007-08-09 | Hideki Fujikura | Phenol derivative, medicinal composition containing the same, and medicinal use thereof |
| US20080045466A1 (en) * | 2004-07-21 | 2008-02-21 | Kenji Katsuno | Progression Inhibitor For Disease Attributed To Abnormal Accumulation Of Liver Fat |
| TW200606129A (en) | 2004-07-26 | 2006-02-16 | Chugai Pharmaceutical Co Ltd | Novel cyclohexane derivative, its prodrug, its salt and diabetic therapeutic agent containing the same |
| ES2314743T3 (es) * | 2004-12-16 | 2009-03-16 | Boehringer Ingelheim International Gmbh | Derivados de benceno sustituidos con glucopiranosilo, medicamentos que contienen a este tipo de compuestos, su uso y procedimiento para su fabricacion. |
| TW200637869A (en) | 2005-01-28 | 2006-11-01 | Chugai Pharmaceutical Co Ltd | The spiroketal derivatives and the use as therapeutical agent for diabetes of the same |
| JP5073948B2 (ja) * | 2005-01-31 | 2012-11-14 | 田辺三菱製薬株式会社 | 医薬組成物 |
| DE602006009772D1 (de) * | 2005-02-23 | 2009-11-26 | Boehringer Ingelheim Int | Glucopyranosylsubstituierte ((hetero)arylethynyl-benzyl)-benzenderivative und deren verwendung als inhibitoren des natriumabhängigen glucose-cotransporters typ 2 (sglt2) |
| ATE453656T1 (de) * | 2005-04-15 | 2010-01-15 | Boehringer Ingelheim Int | Glucopyranosyl-substituierte (heteroaryloxy- benzyl)-benzen-derivate als sglt-inhibitoren |
| UA91546C2 (uk) * | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | КРИСТАЛІЧНА ФОРМА 1-ХЛОР-4-(β-D-ГЛЮКОПІРАНОЗ-1-ИЛ)-2-[4-((S)-ТЕТРАГІДРОФУРАН-3-ІЛОКСИ)-БЕНЗИЛ]-БЕНЗОЛУ, СПОСІБ ЇЇ ОДЕРЖАННЯ ТА ЇЇ ЗАСТОСУВАННЯ ПРИ ПРИГОТУВАННІ ЛІКАРСЬКИХ ЗАСОБІВ |
| US7723309B2 (en) * | 2005-05-03 | 2010-05-25 | Boehringer Ingelheim International Gmbh | Crystalline forms of 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
| US7772191B2 (en) | 2005-05-10 | 2010-08-10 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives and intermediates therein |
| AR054871A1 (es) * | 2005-07-27 | 2007-07-25 | Boehringer Ingelheim Int | Derivados de (hetero)cicloalquiletinil-bencil)-benceno sustituidos con glucopiranosilo, medicamentos que contienen dichos compuestos, sus uso y proceso para su fabricacion |
| ATE484499T1 (de) * | 2005-08-30 | 2010-10-15 | Boehringer Ingelheim Int | Glucopyranosyl-substituierte benzyl-derivate, medikamente mit solchen verbindungen, ihre verwendung und herstellungsverfahren dafür |
| NZ566787A (en) * | 2005-09-08 | 2010-02-26 | Boehringer Ingelheim Int | Crystalline forms of 1-chloro-4-(beta-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene, methods for its preparation and the use thereof for preparing medicaments |
| AR056195A1 (es) * | 2005-09-15 | 2007-09-26 | Boehringer Ingelheim Int | Procedimientos para preparar derivados de (etinil-bencil)-benceno sustituidos de glucopiranosilo y compuestos intermedios de los mismos |
| EP1989191B1 (en) * | 2006-02-15 | 2011-07-20 | Boehringer Ingelheim International GmbH | Glucopyranosyl-substituted benzonitrile derivatives, pharmaceutical compositions containing such compounds, their use and process for their manufacture |
| PE20080697A1 (es) * | 2006-05-03 | 2008-08-05 | Boehringer Ingelheim Int | Derivados de benzonitrilo sustituidos con glucopiranosilo, composiciones farmaceuticas que contienen compuestos de este tipo, su uso y procedimiento para su fabricacion |
| PE20110235A1 (es) | 2006-05-04 | 2011-04-14 | Boehringer Ingelheim Int | Combinaciones farmaceuticas que comprenden linagliptina y metmorfina |
| DE102006028862A1 (de) | 2006-06-23 | 2007-12-27 | Merck Patent Gmbh | 3-Amino-imidazo[1,2-a]pyridinderivate |
| TW200817424A (en) | 2006-08-04 | 2008-04-16 | Daiichi Sankyo Co Ltd | Benzylphenyl glucopyranoside derivatives |
| US20080109178A1 (en) * | 2006-11-03 | 2008-05-08 | Nikon Corporation | Method and system for predicting and correcting signal fluctuations of an interferometric measuring apparatus |
| EP2325182A1 (en) | 2006-12-06 | 2011-05-25 | Glaxosmithkline LLC | Bicyclic compounds and use as antidiabetics |
| DE102007008420A1 (de) | 2007-02-21 | 2008-08-28 | Merck Patent Gmbh | Benzimidazolderivate |
| PE20090938A1 (es) * | 2007-08-16 | 2009-08-08 | Boehringer Ingelheim Int | Composicion farmaceutica que comprende un derivado de benceno sustituido con glucopiranosilo |
| DE102007048716A1 (de) | 2007-10-11 | 2009-04-23 | Merck Patent Gmbh | Imidazo[1,2-a]pyrimidinderivate |
| CL2008003653A1 (es) | 2008-01-17 | 2010-03-05 | Mitsubishi Tanabe Pharma Corp | Uso de un inhibidor de sglt derivado de glucopiranosilo y un inhibidor de dppiv seleccionado para tratar la diabetes; y composicion farmaceutica. |
| WO2009096503A1 (ja) * | 2008-01-31 | 2009-08-06 | Daiichi Sankyo Company, Limited | ベンジルフェニルグルコピラノシド誘導体 |
| DE102008017590A1 (de) | 2008-04-07 | 2009-10-08 | Merck Patent Gmbh | Glucopyranosidderivate |
| AR072511A1 (es) | 2008-07-15 | 2010-09-01 | Theracos Inc | Derivados deuterados de bencilbenceno y metodos de uso. composicion farmaceutica. |
| CN102149717B (zh) * | 2008-08-28 | 2014-05-14 | 辉瑞大药厂 | 二氧杂-双环[3.2.1]辛烷-2，3，4-三醇衍生物 |
| LT2395983T (lt) | 2009-02-13 | 2020-07-10 | Boehringer Ingelheim International Gmbh | Farmacinė kompozicija, apimanti sglt2 inhibitorių, dpp-iv inhibitorių ir, pasirinktinai, papildomą priešdiabetinį agentą, bei jos panaudojimas |
| KR101921934B1 (ko) * | 2009-02-13 | 2018-11-26 | 베링거 인겔하임 인터내셔날 게엠베하 | 글루코피라노실 디페닐메탄 유도체를 포함하는 약제학적 조성물, 이들의 약제학적 용량형, 이들의 제조방법 및 환자에서의 개선된 당 조절을 위한 이들의 용도 |
| WO2011039108A2 (en) | 2009-09-30 | 2011-04-07 | Boehringer Ingelheim International Gmbh | Processes for preparing of glucopyranosyl-substituted benzyl-benzene derivatives |
| PH12012500633B1 (en) * | 2009-09-30 | 2017-12-13 | Boehringer Ingelheim Int | Method for the preparation of a crystalline form of 1-chloro -4- (beta -d- glucopyranos -1-yl) -2- (4-((s)- tetrahydrofuran -3- yloxy) benzyl) benzene |
| UY32919A (es) * | 2009-10-02 | 2011-04-29 | Boehringer Ingelheim Int | Composición farmacéutica, forma de dosificación farmacéutica, procedimiento para su preparación, mé todos para su tratamiento y sus usos |
| BR112012008924A2 (pt) | 2009-10-20 | 2019-09-24 | Novartis Ag | derivado de glicosídeo e usos do mesmo |
| US8163704B2 (en) | 2009-10-20 | 2012-04-24 | Novartis Ag | Glycoside derivatives and uses thereof |
| WO2011051864A1 (en) | 2009-11-02 | 2011-05-05 | Pfizer Inc. | Dioxa-bicyclo[3.2.1]octane-2,3,4-triol derivatives |
| AR079438A1 (es) | 2009-12-09 | 2012-01-25 | Panacea Biotec Ltd | Derivados de azucar, composiciones farmaceuticas y sus usos |
| WO2011107494A1 (de) | 2010-03-03 | 2011-09-09 | Sanofi | Neue aromatische glykosidderivate, diese verbindungen enthaltende arzneimittel und deren verwendung |
| WO2012025857A1 (en) | 2010-08-23 | 2012-03-01 | Hetero Research Foundation | Cycloalkyl methoxybenzyl phenyl pyran derivatives as sodium dependent glucose co transporter (sglt2) inhibitors |
| UY33937A (es) | 2011-03-07 | 2012-09-28 | Boehringer Ingelheim Int | Composiciones farmacéuticas que contienen inhibidores de dpp-4 y/o sglt-2 y metformina |
| EP2697240B1 (en) | 2011-04-14 | 2015-09-16 | Novartis AG | Glycoside derivatives and uses thereof |
| US8614195B2 (en) | 2011-04-14 | 2013-12-24 | Novartis Ag | Glycoside derivatives and uses thereof |
| US9555001B2 (en) | 2012-03-07 | 2017-01-31 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition and uses thereof |
| US9192617B2 (en) | 2012-03-20 | 2015-11-24 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| EP2774619B1 (de) | 2013-03-04 | 2016-05-18 | BioActive Food GmbH | Zusammensetzung zur Behandlung von hyperglykämischen Erkrankungen |
| RU2641014C2 (ru) | 2013-03-14 | 2018-01-18 | Марс, Инкорпорейтед | Ароматизирующая композиция, содержащая глюкозиды hmg |
| US11813275B2 (en) | 2013-04-05 | 2023-11-14 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| PT2981271T (pt) | 2013-04-05 | 2019-02-19 | Boehringer Ingelheim Int | Utilizações terapêuticas de empagliflozina |
| CA2812519A1 (en) | 2013-04-05 | 2014-10-05 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
| HK1213818A1 (zh) | 2013-04-05 | 2016-07-15 | 勃林格殷格翰国际有限公司 | 依帕列净的治疗用途 |
| EA033286B1 (ru) | 2013-04-18 | 2019-09-30 | Бёрингер Ингельхайм Интернациональ Гмбх | Способ лечения или отсрочки развития хронической болезни почек |
| EP2944311A1 (de) | 2014-05-16 | 2015-11-18 | BioActive Food GmbH | Kombination von biologisch aktiven Substanzen zur Behandlung von hyperglykämischen Erkrankungen |
| JP7625363B2 (ja) | 2016-11-10 | 2025-02-03 | ベーリンガー インゲルハイム インターナショナル ゲゼルシャフト ミット ベシュレンクテル ハフツング | 医薬組成物、治療方法及びその使用 |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2549476B1 (fr) * | 1983-07-20 | 1986-04-25 | Rech Ind | Benzyl-phenyl-osides, procede de preparation et utilisation en therapeutique |
| US5731292A (en) * | 1992-11-12 | 1998-03-24 | Tanabe Seiyaku Co., Ltd. | Dihydrochalcone derivatives which are hypoglycemic agents |
| CA2102591C (en) * | 1992-11-12 | 2000-12-26 | Kenji Tsujihara | Hypoglycemic agent |
| HUP0300057A3 (en) * | 2000-03-17 | 2003-09-29 | Kissei Pharmaceutical | Glucopyranosyloxy benzylbenzene derivatives, pharmaceutical compositions containing the same and intermediates for the preparation of the derivatives |
| US6683056B2 (en) | 2000-03-30 | 2004-01-27 | Bristol-Myers Squibb Company | O-aryl glucoside SGLT2 inhibitors and method |
| CN1293087C (zh) | 2000-09-29 | 2007-01-03 | 橘生药品工业株式会社 | 吡喃葡糖氧基苄基苯衍生物及其药物组合物 |
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