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TWI344465B - Crystalline form of 1-chloro-4-(β-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,a method for its preparation and the use thereof for preparign medicaments - Google Patents

Crystalline form of 1-chloro-4-(β-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,a method for its preparation and the use thereof for preparign medicaments Download PDF

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TWI344465B
TWI344465B TW095115586A TW95115586A TWI344465B TW I344465 B TWI344465 B TW I344465B TW 095115586 A TW095115586 A TW 095115586A TW 95115586 A TW95115586 A TW 95115586A TW I344465 B TWI344465 B TW I344465B
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crystalline form
solution
pharmaceutical composition
preparation
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Frank Himmelsbach
Sandra Schmid
Martin Schuehle
Hans-Juergen Martin
Matthias Eckhardt
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Boehringer Ingelheim Int
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Description

M4465 九、發明說明： 【發明所屬之技術領域】 本發明係關於1-氣-4-(p-D-葡萄哌喃糖 四奇 用糖-卜基）-2-[4-(〇 =喃·3·基氧基Μ基]•苯之結晶型 '其製備方法 其用於製備藥物之用途。 【先前技術】 。南^物1备喃糖+基）_2·[4·⑽-四氣咬 土氧基）-苄基]-苯（在下列係指「 4利中請書WQ 湖助並具有如“之化學結構：
°χ>
A SGLT 1心述之化合物對於鈉~依賴葡萄糖共運輸蛋白 ”：定而言為SGLT2’具有重要抑制作用。化編 泉k方法如文中描述並不會產生結晶型。 前特二：醫藥活性為同樣藥物在商業上證實可作為藥物 而醫藥活性劑進行㈣時之當然基本Μ條件。缺 等it多種額外之需求是醫藥活性劑必須遵循之條件。該 二:r各種與其本身活性物質之性質有關之參數為基 條件又有限制下’該等參數之實例為活性劑在各種環境 及之穩定性、在醫藥調配物製造期間之該穩定性，以 …生劑在最終醫藥品組合物之穩定性。用於製備醫藥組 1〇9742.d〇, 1344465 合物之醫藥活性物質應儘可能 情況下其長期保存之穩定性。 避免使用含有其分解產物之醫 等案例中’醫藥品中之活性物 含量。 純粹且必須保證在各種環境 除了含有確實活性物質外， 藥組合物是最基本的。在該 質含量可能少於特定物質之 该醫樂品在調配物中均質分佈為關鍵因素，特…為 當醫樂品必須以低劑量給予時。A了確定均質分佈，活性 物質之顆粒大小可利用例如磨碎而減少至適合量。由於要 儘可能避免醫藥活性物質因為麻 馮磨碎（或微粉化）而造成分解 之副作用’儘管在製造期間需要銀困之料，活性物質在 整個磨碎難應為高度穩以最基本的。対當活性物質 在磨碎過程中；1夠穩定，才可能產生均質之醫藥調配物， 其經常以可重製之方式含有特定量之活性物質。 在用以製備期望醫藥調配物之磨碎過程可能產生之另一 個問題為由該過程引發之能量輸人以及在結晶表面之壓 力。這在特㈣境中可能引發多形性改變、晶質化或在晶 格之改變。由於醫藥調配物之醫藥品質需要的是活性物質 應該總是具有相同之晶體形態'，因此由同樣之觀點看來， 對於結晶活性物質之穩定性和性質同樣易於具有嚴格之需 求。 醫藥活性物質之穩定性在醫藥組合物中用於決定特定醫 藥品之保存期限亦很重要；保存期限係指該醫藥品可投藥 而不會有任何危險期間之時間長短。因此上述醫藥組合物 中之醫藥品在各種儲存條件下具有高穩定性對病人和製造 109742.doc 1344465 商兩者來說皆為一額外之好處。 • 濕氣之吸收降低醫藥活性物質之含量，主要是因 ；取會造成體重之增加。易於吸收濕氣之醫藥組合物: =期間必須利用例如其他適用之乾燥劑或利用將藥物儲 子-防湖之環境中而加以保護以防潮濕。因此較佳而今， 醫藥活性物質應只具有輕微吸濕性。 再者，良好定義結晶之可獲性使得藥物物質可利用再择 φ 晶之方式得到純化。 、、。 除了上述所示之H 一般應該牢記的{，對於醫藥租 合物之固體狀態來說，能夠改善其物理和化學穩定性之任 . ㈣變’對於較不穩定形式之相同醫藥品能提供重要之好 . 處。 因此本發明之目標為提供化合物A之穩定結晶型，其能 滿足上述對於醫藥活性物質所提出之重要需求。 〃 【發明内容】 _ 在第一方面本發明係關於化合物A之結晶型。 在第二方面，本發明係關於化合物A之結晶型，其係具 有包含18.84、20.36和25.21度2Θ(±0.05度2Θ)波峰之乂光粉 末繞射圖，其中該X-光粉末繞射圖為㈣射所製 得。 在第三方面，本發明係關於化合物A，其中至少5〇%之 該物質係以如前文和下文定義之結晶型形式存在。 從化合物A之醫藥效率來看，本發明第四方面係關於包 έ如刖文和下文疋義之結晶型之醫藥組合物或醫藥品。 109742.doc 在第五方面本發明係關於如前文和下文
療或預防。 月1J文和下文所定義可用於製 ’其適用於疾病或症狀之治 藉由抑制鈉-依賴葡萄糖共 可用於 本發明係關於如前文和下文所定義可用於 之結晶型之用途，其適用於代謝疾病之治 在第七方面’本發明係關於如前文和下文所定義可用於 製備醫藥組合物之結晶型之用途，其可用於抑制鈉-依賴 葡萄糖共運輸蛋白SGLT2。 在第八方面，本發明係關於如前文和下文所定義可用於 製備醫藥組合物之結晶型之用途，其可用於預防胰島素p 細胞之退化和/或用於改善和/或恢復胰島素p細胞之功能 在第九方面，本發明係關於如前文和下文所定義可用於 製備醫藥組合物之結晶型之用途，其可用於預防、減緩、 延遲或治療本身需要之病人因不正常肝脂肪累積所造成之 疾病或症狀。 在第十方面，本發明係關於可用於製造如前文和下文所 定義之結晶型之方法，該方法包含下列步驟： (a) 將化合物A溶解在溶劑或溶劑混合物中以形成飽和或 幾乎飽和之溶液； (b) 較佳為以冷卻該溶液之方法加以儲存，以沉澱出該 結晶型並因此產生懸浮液； 109742.doc 1344465 »* (C)將沉澱物和懸浮液分離；、 及 (d)將沉澱物乾燥直到 合物為止。 除去任何過量 之該溶劑或溶劑混 本發明另一方面熟習此項技藝 方式以及實例中變得更為了解。 【實施方式】 令人驚言牙地，吾人發現复φ左 凡，、干存在有化合物A之結晶型，
其可執行本文前述之重要雹卡。m ,, 某表 因此本發明係關於化合物 A之結晶型。 該結晶型可藉由該等特性化之x_光粉末繞射（xrpd)圖 之方法而加以鑑定。 該結晶型可藉由X-光粉末繞射圖加以特性化，其係含有 在18.84、20.36和25.21度2Θ(±0.05度2Θ)之波峰，其中該 X-光粉末繞射圖可利用CuKa 1輕射製得。 特定而言’該X-光粉末繞射圖包含在14 69 ' ι8 84、
者可從下列本發明 之實施 19.16、19.50、20.36 和 25.21 度 2Θ(±0.05 度 2Θ)之波峰，其 中該X-光粉末繞射圖可利用CuKal轄射製得。 更特定而言，該結晶型可利用X-光粉末繞射圖加以特性 化’可利用CuKal輻射製得，其包含如表1中所包含之度 2Θ (±0_05度 2G))之波峰。 表1 :結晶型之X-光粉末繞射圖（僅列出在2Θ中高達30度之波峰）： 2Θ ΙΊ d-值 ίΑΐ 強度Ι/Ι〇 ί%1 4.46 19.80 8 9.83 8.99 4 109742.doc 1344465
---——. -—U-68 7,57 4 -___L3.35 6.63 14 --15-69 6.03 42 -i5.73 5.63^ 16 --16.20 5.47 8 ___17.95 30 ~—ij-31 4.84~^~ 22 -—i^.43 4.8Ϊ〜 23 --1^-84 4.7Γ~~~ 100 42 -__19.5〇 A~5S 31 --20.36 "— 4.36 74 --20.55 --------- 4.32 13 --21.18 .rr-»«««--- 4.19 11 __21.46 4.14 13 --22.09 4.02~~·s 19 __22.22 ioo---- 4~ --22.71 -------- 3.91 28 ---23.44 3.79~~~~ 27 --23.72 3.75 3 ___24.〇9 r~~r—_ 3.69 3 --2433 ***--- 3.66 7 ——-_24.81 - 24 --25.21 3.53 46 __^5.65 Ϊ47 23 __26.40 -- 3.37 2 __26.85 332 8 ___27.26 1 3.27~^~~ 17 ___27.89 3.20 2 __28.24 ------ 3.16 3 ___29.〇l 3.〇T~· 4 29.41 3^〇T~~ 18 甚至更特定而言，該結晶型可利用x_光粉末繞射圖而定 出特徵，該X-光粉末繞射圖係利用CuKa]輻射製得，其在 2Θ(±〇.〇5度20)包含如圖1所示之波峰。 由^化&物”型可藉由約149°㈤t之炫點（經 由吻決定；經評估作為起始溫度；加熱速㈣ 定出特徵。得到之DSC曲線顯示在圖2中。 里) I09742.doc 1344465 在本發明範疇内，利用ST〇E_SRAD〗p_繞射儀，以裝置 有區域敏感偵測器（〇ED)和Cu_陽極作為1光源 射，λ= 1.54056 A，40 kV，40 ηιΑ)之傳輸模式，記錄χ· 光粉末繞射圖。在表1中，該等值"2Θ[。]"之上代表單位為 度之繞射角度且"d[Α]"代表在晶格平面之間的a中之特定 距離。圖1顯示之強度單位為cps(每秒鐘之次數）。 為了允許實驗誤差，上述2Θ應考慮必須準確至土〇〇5度 • 2Θ。也就是說，當評估一給定之化合物八之結晶樣本是否 為根據本發明之結晶型時，經實驗觀察到樣本之2@值，如 落在特性化值之土 0.05度2〇中，應同樣具有上述之特性化 值。 * 熔點可藉由微差掃描熱量儀（Differential Scanning
Cal〇rimetry ; DSC)利用 Dsc 821 (Meuler T〇ied〇)而加以決 定。 本發明另一方面係關於可用於製造如前文和下文所定義 Φ 之結晶型之方法，包含下列步驟： (a)將化合物A溶解在溶劑或溶劑混合物中以形成飽和或 幾乎飽和之溶液； ⑻較佳為以冷卻該溶液之方法加以儲存，以沉殿出該 結晶型並因此產生懸浮液； (c)將沉澱物和懸浮液分離；以及 ⑷將沉殿物乾燥直到除去任何過量之該溶劑或溶劑混 合物為止。 飽和」或「幾乎飽和」係關於在步驟中所使用 術語「 109742.doc 物A之起始物質。例如對 說飽和溶液可由其結晶型得到超飽和 適用之溶劑較佳為選自C丨.4-烷醇類、水、乙酸乙賴、乙 ^丙酮、二乙㈣兩種或多種該等溶劑之混合物組成之 更佳之溶劑為選自曱醇、乙醇、異丙醇、乙酸乙酯、二 :^丙_、水及：❹種㈣溶劑之混合物㈣而言為 $夕種該等有機溶劑和水之混合物組成之群。 特定而言較佳之溶劑係選自乙酸乙0|、乙醇、異丙醇及 乙醇和/或異丙醇和水之混合物組成之群。 —一 J中才木用水和-或多種CM·貌醇類之混合物，特 二而：為 '醇、乙醇和/或異丙醇’最佳為乙醇之混合 7 .烷醇較佳之體積比為在範圍從約i ·· 4至4 · ! 佳為從約1 : 2至2: 1 ;甚至更佳為從約2: 3至3 : 2。， 較佳地步驟⑷在約室溫下（約2〇t)或在提高溫度至約使 用洛劑或溶劑混合物之沸點下發生。 牛:二Γ合物A在溶液中之溶解度，可在步驟⑷和/或 。二 或多個抗溶劑或非溶劑，較佳地為在步驟 =或、❹驟⑻之開始”“適用抗溶劑或非溶劑之 =針=劑或非溶劑或其混合物之量較佳為經選擇以獲 仔超飽和或幾乎超飽和之溶液。 2步驟附將溶㈣存—段㈣Μ 在步驟（b)中該溶液之溫产 于 中。度為大約相同或低於在步驟⑷ U間’較佳為降低含有化合物A之溶液溫度較 I09742.doc vS) •13- 1344465 佳至一溫度範圍2(TC至Ot或甚至更低。該步驟（b)可在攪 拌或無攪拌中發生。如熟習此項技藝者已知，由於在步驟 (b)中該時間週期及不同之溫度，獲得結晶之大小、形狀和 -質會有所不同。再者，結晶化作用可藉由熟習此項技藝 者已知之方法引發，例如利用刮取或摩擦之方法。視情況 地可將種晶接種至該（幾乎）飽和溶液令。 你灭锁（c)中，可利用 ________
傾析或離心法，從沉澱物中除去該（等）溶劑- 在步驟（d)中，可利用熟習此項技藝者已知之方法例如 利2降低該（等）溶劑之分壓，較佳為在真空中，和/或利用 在同於約20 C下加熱，較佳為在溫度範圍低於80°C甚至更 佳為低於50。(：，從沉澱物中除去過量之該（等）溶劑。 化e物A可利用如在國際申請案w〇 中描述
或提及之特定和/或一般之方法加以合成。再者化合物A之 生物性質可如國際中請案WO 2⑽5/G92877所描述而加以谓 測，其係以整體引用之方式併入本文中。 根據本發明之結晶型較佳為以實質上純粹之形式，用以 2為藥物活性物質，也就是說本質上游離之其他結晶型化 “勿A。除非另有說明’否則本發明亦涵蓋如本文中定義 =結晶型或形式混合之結晶型。藥物活性物質應為結 :型之混合物，較佳…該等物質包含至少5〇%如本文 中所描述之結晶型。 根據本發明之結晶型 有受到S G LT活性特定 關於抑制SGLT活性之該等能力， 適用於製備可用於治療和/或預防所 109742.doc 1344465 .龕, 而言為SGLT-2活性之抑制所影響之該等症狀或疾病之醫藥 物因此D亥結晶形特定而言適用於製備醫藥組合 物，其可用於預防或治療疾病，特定而言為代謝失調症， 或症狀例如第1型和第2型糖尿病、糖尿病之併發症（例如 視網膜病變、腎病或神經病變、糖尿病腳、潰瘍、大血管 病變）、代謝性酸中毒或綱中毒、反應性低血糖症、高胰 島素血症、葡萄糖代謝失調症、姨島素抗性、代謝性症候 群、不同起源之血脂異常、動脈粥狀硬化及相關疾病、肥 胖症、高血壓、慢性心臟衰竭、水腫和多尿症。該結晶型 亦適用於製備可用於預防β'細胞退化例如之肤雜細胞之 死亡或/周零之醫藥組合物。該結晶型亦適用於製備可用於 改：或恢復胰臟細胞功能性以及同時可增加胰臟"田胞之 里和大小之醫藥組合物。根據本發明之結晶型亦可用於 ^ Τ $以作為利尿劑或抗高血壓並適用於預防和治療急 性腎衰竭之醫藥組合物。 在肝臟中脂肪之不正常累積可藉由根據本發明結晶型之 j藥而加以降低或抑制。目此根據本發明另—方面，可提 供用於預防、減緩、延遲或治療因不正常肝臟脂肪堆積在 其經特性化需投予根據本發明醫藥組合物藥物之病人身上 所造成之疾病或症狀之方法。會造成不正常肝臟脂肪堆積 之疾病或症狀特定而言係選自由一般脂肪肝、非酒精性脂 7肝（NAFL)、非酒精性脂肪肝炎（NASH) '高營養療法引 么月曰肪肝、糖尿病性脂肪肝、酒精引發脂肪肝或毒性脂肪 肝組成之群。 '09742.doc 1344465 付疋而言 w發明之結晶型適用 “療糖尿病特定而言為第】型和第 了用於預防 病併發症之醫藥組合物。 糖尿病和/或糖尿 型係特別適用於預狀—、，α 士 a頂防或治療體 第Π類和/或第ΙΠ類肥胖症）、 此外’根據本發明之結晶 重過重、肥胖症（包括第I類、 軀幹肥胖症和/或腹部肥胖症
人達=於治療或預防之對應活性所需之劑量通常視病 、：丙，症狀之本性和嚴重性以及投藥之方法和頻率而 定’而且是由醫師來決定。有❸也，該劑量係藉由靜脈注 射至100 mg，幸乂佳為U 30 ，而藉由口服為1至 mg ’較佳為1至！ 〇〇 mg，且在各案例中每天投藥^至4次。 為了該目的，根據本發明之醫藥組合物較佳為包含結晶型 共同加上一或多種惰性習用載劑和/或稀釋劑。該醫藥組 合物可s周配成習用之蓋备氏製備物，例如一般錠劑或膜衣 錠劑、膠囊、粉劑、懸浮液或栓劑。 下列合成實例可作為說明製備化合物A及其結晶型之方 法。其可視為僅作為以實例之方式描述之可能方法，而非 限制本發明至其内容中。 起始化合物之製備：
實例I CI 0
109742.doc -16- 1344465 (5-溴-2-氣-苯基）_(1_甲氧基_苯基）_甲嗣 將38.3 草醯基氣和〇_8 二甲基〒醯胺加到i〇〇 § 5_ ' 溴-2_氣-苯甲酸在5〇〇如二氣甲烷中之混合物中。將反應 • ⑥合物攪拌丨4小時’然後過遽並在旋轉蒸發器中分離出所 有揮發性成分。將殘餘物溶解在15〇刎二氯甲烷，將溶液 冷部至-5°C ’並加入46.5 g苯甲越。然後將515 8三氣化紹 逐批加入，以便使得溫度不會超過5 t。將該溶液於1至$ 0 C下再授拌I小時，然後並將溶液倒到碎冰中。將有機相 刀離，並利用二氣甲烷萃取水相三次。將結合之有機相利 用1 Μ氫氣酸水溶液清洗，再用〗河氫氧化鈉水溶液清洗兩 人並用鹽水清洗。然後將有機相乾燥，將溶劑除去並在乙 ' 醇中將殘餘物再結晶。 產量·· 86.3 g(64%之理論值） 質譜（ESI + ) : m/z = 325/327/329 (Br+Cl) [M+H] +
實例II
•17· 1 -溴_1-氣-2-(4-甲氧基-苄基）_苯 將86.2 g (5->臭-2-氣-苯基）-(4_甲氧基_笨基）_甲酮和5 ml二乙基矽烷在75 二氣曱烷中之溶液和150 ml乙腈冷卻 至1 〇 c。然後攪拌加入50.8 mI三氟化硼合乙醚使得溫度不 會超過20C。在另外之9 ml三乙基矽烷和4,4 ml三氟 109742.doc T合㈣加人前’將溶液於環境溫度下揽拌14小時。將 冷液於45至5(rc另外攪拌3小時，然後並冷卻至環境溫 度將28 g氫氧化卸在7〇如水中之溶液加入並將得到之 混合物攪拌2小時。然後將有機相分離除去並將水相利用 一異丙醚另外萃取三次。將結合之有機相利用2 Μ氣氧化 =水♦液清洗兩：欠並用鹽水清洗一次，然後利用硫醆納乾 燥在除去浴劑後，將殘餘物在乙醇中清洗、在度分離並 在6 0 °C乾燥。 產量：50.0 g(理論值之61〇/〇) f tt(ESI+) : m/z = 310/312/314 (Br+Cl) [M + H] +
實例III
Cl
4-(5-溪-2-氣-节基）_酚 將14.8 g 4|m(4-曱氧基-节基）.苯在15〇 mi二氣 甲烷之冷液中在冰浴中冷卻。然後將5〇之i河三溴化硼 在-氣甲烷中之溶液加入，並於環境溫度下將溶液攪拌2 J、時。然後將溶液再度置於冰浴中冷卻並將飽和碳酸钟水 ’合液滴加到溶液中。於環境溫度下，㈣】m氫氣酸水溶 液將=合物調整至pH=1，分離有機相，並利用乙酸乙醋另 卜再萃取水相二次。將結合之有機相以硫酸鈉乾燥並將溶 劑完全除去。 109742.doc 1344465 產量：13.9 g(理論值之98%)
質譜（ESI·) : m/z = 295/297/299 (Br+Cl) [M-H]· 實例IV
[4-(5-溴-2-氣-苄基）_苯氧基卜第三-丁基_二甲基_矽烷 將13.9 g 4-(5-溴-2-氣-苄基）-酚在140 ml二氣甲烷中之溶 液在冰浴中冷卻。然後將7.54 g氣化第三-丁基二曱基矽 院在20 ml二氣曱烧中之溶液加入，接著加入9.8 ml三乙胺 和0.5 g 4-二甲基胺基吡啶。將溶液於環境溫度下攪拌16小 時，然後並利用1 00 ml二氣曱烷稀釋。將有機相利用1 M氫 氣酸水溶液清洗兩次並用碳酸氫鈉溶液清洗一次，然後利 用硫酸納乾燥。將溶劑除去後，將殘餘物經由矽膠（環己 烷/乙酸乙酯100:1)過遽。 產量：16.8g(理論值之87〇/〇) 質譜（El) : m/z = 410/412/414 (Br+Cl) [M] +
實例V
2,3,4,6-肆-0-(三甲基矽烷基）_〇-糖吡喃酮 109742.doc 19 1344465 將20 g D·葡萄糖酸-1%内酯和98 5 m]沁曱基嗎啉在2〇〇 四氧夫喃之溶液冷卻至_5ec。然後將85 ml氣化三甲基 石夕燒基滴加到溶液中’使得溫度不會超過5。(：。然後將溶 液於環境溫度下攪拌丨小時，於35〇C攪拌5小時並於環境溫 度下再攪拌14小時。將300 ml曱苯加入後，在冰浴中將溶 液冷卻，並將500 ml水加入溶液中，使得溫度不會超過 10°C °然後將有機相分離並利用磷酸二氫鈉水溶液、水和 鹽水各清洗一次《將溶劑除去，將殘餘物溶解在25〇 ml甲 苯中’並將溶劑再度完全除去。 產量·· 52.5 g(大約90%純度） 質譜（ESI + ) : m/z = 467 [M+HJ +
實例VI
1-氮葡萄略喃糖-1-基）-2-(4_經基苄基）-苯 將4.0 g[4-(5-溴-2-氣-苄基）_苯氧基]•第三-丁基-二甲基_ 矽烷在42 ml乾二乙基醚之溶液於氬氣下冷卻至_8〇它。將 11.6 ml之1 ·7 Μ第三丁基鋰在戊烷中之溶液緩慢滴加到冷 卻溶液中，然後並將溶液於-80°C攪拌30分鐘。然後將利 用乾冰冷卻之該溶液經由雙頭針滴加到冷卻至-80。〇之4.78 g 2,3,4,6-肆-〇_(二甲基矽烷基）_D-糖吡喃酮在38 ml二乙基 醚之溶液中。將得到之溶液於-78°C攪拌3小時。然後加入 109742.doc -20· 1344465 二1酸在35 醇中之溶液並於環境溫度授拌 卜“後將該溶液利用®體碳酸氫鋼中*，加入乙酸 乙S旨並和乙喊共同將甲薛除本。 山 /、 ' 。將奴酸氫鈉水溶液加到剩 餘浴液中，並將得到之混合物利用乙酸乙料取四次。 將有機相利用硫酸納乾燥並進行蒸發。將殘餘物溶解在30 心腈和30 ml二氣甲統中並將溶液冷卻至镇。將4 4 乙基石夕院2.6 ml三敗化硼合乙趟（b〇_㈣窗)以 ★瞻）滴加到溶液中，使得溫度不會超過-rc。在添加 完成後將溶液於_5至書⑽拌5小時，然後利用加入碳酸 氫納水，液使溶液驟冷。將有機相分離，並將水相利用乙 西夂乙西曰卒取四次。將結合之有機相利用硫酸納乾燥，將溶 劑除去，並將殘餘物利用層析法在石夕膠上進行純化（二氯 甲烧/甲醇l.G.〉3:l)。然後得到之產物為約㈣之_混合 物，其可利用經基基團與乙酸針和吼咬在二氣甲烧令之總 體乙醯化作用轉化成純β_差向異構體並將產物從乙醇中進 行再結晶作用。因此將得到之產物利用在甲醇中之去乙感 化作用和4Μ氫氧化_水溶液轉化成標題化合物。 產量：1.6 g(理論值之46%) 質譜（ESI + ) : m/z = 398/400 (C1)[M+H] + 化合物A之製備
Ο 109742.doc 1344465 I氣-4-(p-D-葡萄哌喃糖·1_基）_八丨4_((8)·四氫呋喃_3基 基）·苄基]-苯 • 將〇·19 g(穴)-3-(心甲基苯基磺醯基氧基）-四氫呋喃加到 〇·2〇 g 1-氣-4-(β-ϋ-葡萄哌喃糖-基苄基）苯和 0.29 g碳酸鉋在2.5 ml二曱基甲醯胺之混合物中。將混合物 於75 C下攪拌4小時，接著另外加入〇 29 g之碳酸鉋和〇 19 g(/?)-3-(4-甲基苯基磺醯基氧基）_四氫呋喃加入前。在75它 • 另外攪拌14小時後將混合物冷卻至環境溫度並加入鹽水。 將得到之混合物利用乙酸乙酯萃取，將結合之有機萃取物 利用硫酸鈉乾燥並將溶劑除去。將殘餘物利用層析法在矽 ' 膠上純化（二氯曱烷/曱醇1:0 -> 5:1)。 ' 產量：0.12 g(理論值之49%) 質谱（ESI，）： m/z = 451/453 (Cl) [M+H] + 結晶型之製備： 變化型1 : 鲁 30 mg 1_氣-4-(P_D葡萄哌喃糖-1-基）-2-[4_(〇四氫呋 基氧基）-苄基]-笨（如上述而得）加熱至約5〇。〇而溶解 在m丨之乙酸乙酯（含有〇 5_3%水）中。將溶液緩慢冷卻 1至3小時）至約2(rc。在48小時後利用過濾分離出結晶 色、aa。利用將結晶儲存在升高溫度（4〇至$ 〇。(〕）約3 至4小時而將過量之溶劑除去。 變化型2 : 將1 g氣-4-(β·〇-葡萄哌喃糖-丨·基）-2_[4·(⑻-四氫呋 南·3-基氧基）-节基]•苯加熱至約抓*溶解在$ w水/乙醇 109742.doc -22- (§) 混合物（2: 3體積比卜將8 ml水加人溶液中並使溶液在！至 3小時内冷部至約2(TC。在16小時後利用過遽分離出結晶 型之白色H利用將結晶儲存在升高溫度（概坑）約4 至6小時而將過量之溶劑除去。 變化型3 : 將1 g 1-氣-Μβ-D·葡萄哌喃糖小基“[心⑽-凹氫呋 α南-3-基氧基Η基]•苯加熱至約5Q<t而溶解在n mi異丙醇 中。將溶液在1至3小日夺内冷卻至約2〇〇c。在16小時後利用 °心刀離出’”。aa型之白色結晶。Μ用結晶儲存在升高溫度 (40至50 C)約4至6小時而將殘餘溶劑除去。 變化型4 : 將8.9 g 1-氣-4-(β·ϋ-葡萄哌喃糖基）_2_[心⑽四氫呋 南基氧基苄基]-苯加熱至約50。(：而溶解在60 ml水/乙 酵、δ物中（2 ’ 3體積比）。使溶液在3小時内冷卻至約2〇 c並將結晶化合物利用過濾分離。將分離出之白色固體於 俄乾燥16小時得到約6 g之結晶型。 【圖式簡單說明】 圖1顯示該結晶型之X-射線粉末繞射圖。 圖2顯示該結晶型經由Dsc之熱分析及熔點之決定。 109742.doc

Claims (1)

1344465 第095115586號專利申請案 -中文申請專利範圍替換本餘）| 1、申請專利範圍： -種1-氣-4’-D-葡萄哌喃糖·!·基)·2·[4_⑽-四氫呋喃_ 3-基氧基）·_基].苯之結晶型，其具有在18 84、2〇3_ 25.21度2Θ(±0_05度2Θ)含有波峰之χ•光粉末繞射圖其 中該X-光粉末繞射圖係利用CuKal輻射製得。 ” 2. 如請求項！之結晶型，其中x_光粉末繞射圖另於14 69、
竹年"月期修(更)正替換頁 19.丨6和丨9_5〇度20(±〇.〇5度2Θ)含有波峰，其中該χ光粉 末繞射圖係利用CuKal輻射製得。 乃 3. —種1-氣_4_(p_D_葡萄哌喃糖_丨·基）_2_[4_(〈幻·四氫呋喃_ 3-基氧基）_节基卜苯’其中該物f至少·係存在如請求 項1或2之結晶型形式。 4. 一種醫藥組合物，其包含如請求項1或2之結晶型。 5. 種如吻求項1或2之結晶型之用途，其係用於製備適用 於冶療可藉由抑制納-依賴葡萄糖共運輸蛋白sgl丁而受 到影響之疾病或症狀之醫藥組合物。 6. —種如請求項丨或2之結晶型之用途，其係用於製備適用 於治療代謝失調症之醫藥組合物，該代謝失調症係選自 下列組成之群：第1型和第2型糖尿病、糖尿病之併發 症、代謝性酸令毒或酮中毒、反應性低血糖症、高胰島 素灰症、葡萄糖代謝失調症、姨島素抗性 '代謝性症候 群不同起源之血脂異常、動脈粥狀硬化及相關疾病、 肥胖症、兩血麼、慢性心臟衰竭、水腫和多尿症。 7.種如凊求項】或2之結晶型之用途，其係用於製備用以 抑制納_依賴葡萄糖共運輸蛋白SGLT2之醫藥組合物。 109742-991126.doc 1344465 8， 一種如請求項〖或2之結晶型之用途，其係用於製備用於 改善及/或恢復胰臟β細胞功能性之醫藥組合物。 9. 一種製造如請求項1或2之結晶型之方法，該方法包含下 列步驟： (a) 將1-氣-4-(β-〇-葡萄哌喃糖_丨_基）_2_[4_(〇_四氫呋 喃-3-基氧基）·苄基μ苯溶解在溶劑或溶劑混合物中，以 形成飽和或幾乎飽和之溶液； (b) 儲存溶液，以便從溶液中沉澱出如請求項丨、2或3 之该結晶型’並因此產生懸浮液； (c) 自懸浮液分離沉澱物；及 (d) 乾燥沉澱物，直到除去任何過量之該溶劑或溶劑混 合物。 109742-991126.doc 1344465 第095115586號專利申請案 _，t 中文圖式替換本(99年11 & Hi 十一、圖式： 1--1
圖2 l09742-991126.doc
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