TW200844102A - Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms - Google Patents
Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms Download PDFInfo
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- TW200844102A TW200844102A TW097107239A TW97107239A TW200844102A TW 200844102 A TW200844102 A TW 200844102A TW 097107239 A TW097107239 A TW 097107239A TW 97107239 A TW97107239 A TW 97107239A TW 200844102 A TW200844102 A TW 200844102A
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- Taiwan
- Prior art keywords
- phenyl
- isopropyl
- dihydroxy
- ylmethyl
- isoxazole
- Prior art date
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
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- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
- C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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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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- C07D—HETEROCYCLIC COMPOUNDS
- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
- C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D261/18—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
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Description
200844102 九、發明說明： 【發明所屬之技術領域】 本發明係關於5-(2,4-二羥基-5-異丙基-苯基）_4_(4•嗎啉_ 4-基曱基··苯基兴異噁唑-3_甲酸乙醯胺之新穎鹽形式及多晶 型物、該等新穎鹽形式之水合物及多晶型物以及包含該等 鹽形式之新穎調配物。 【先前技術】 分子伴侣之HsP90家族包括四個已知成員：皆存於胞質 溶膠中之HsP90a及Ηδρ90β、存於内質網中之以卟々及存於 線粒體中之trap-Ι。HsP90係變性或，，未經折疊，，蛋白質之 ATP依賴性再折疊及細胞對細胞外因子之生長反應中所涉 及多種關鍵蛋白之構象成熟所需的豐富細胞分子伴侣。該 等蛋白質（稱為客體蛋白）包括類固醇受體以及各種蛋白激 酶。Hsp90對真核細胞存活至關重要且在許多腫瘤中過度 表現。癌症細胞似乎對Hsp90 Ατρ酶活性之短暫抑制敏 感，此表明HsP90抑制劑可具有作為抗癌藥物之潛力。每 個Hsp90豕私成員在其N末端結構域具有保守Ατρ結合位 .·，、占此僅在少數其他ΑΤΡ結合蛋白中發現。Hsp9〇與各種 共分子伴侣蛋白之交互作用可刺激其弱Ατρ酶活性。諸如 格爾德黴素（geldanamycin)或根赤殼菌素（radicic〇1)等若干 天然化合物結合在HsP90之ATP結合位點上而抑制其Ατρ酶 活H。在細胞系統中及在體内，該等藥物在與邮％結合 後可阻止客體蛋白折疊，該等客體蛋白隨後在蛋白酶體中 降解。在階段I臨床實驗中檢驗17_烯丙基胺基脫甲氧 129123.doc 200844102 基格爾德黴素（17-AAG)(格爾德黴素衍生物）。使用17· AAG之初始臨床經歷已提供初步證據證明可在毒性可财受 之情況下在人類中達成與臨床前系統中活性相關之藥物濃 度，且提供在至少某些替代物及腫瘤區室中調節&初步 證據。17_AAG之劑量限制性毒性係肝毒性。17-AAG之弱 溶解性使其難以調配/投與且其合成很困難（其一般係藉由 發酵來獲得）。因此業内需要具有較佳物理化學特性且可 ( 具有較尚特異性（17-AAG抑制所有該四種Hsp90種内同源 物）之替代化合物。WO 2004/072051揭示該等替代化合 物，更具體而言揭示一系列對熱休克蛋白具有抑制特性之 異噁唑衍生物。 【發明内容】 5-(2,4-二羥基異丙基-苯基）-4-(4-嗎啉_4_基甲基-苯 基）-異噁唑-3-甲酸乙醯胺係w〇 2〇〇4/〇72〇51 (實例78)中所 述之Hsp90抑制劑。舉例而言，可根據該公開文獻所揭示 Q 内容製備該化合物。5-(2,4-二羥基-5-異丙基-苯基）-4-(4- 嗎琳-4-基甲基-苯基異噁唑-3_甲酸乙醯胺弱水溶性化合 物’其水溶解度低於〇·；[ mg/ml。在0·1 N HC1中游離鹼之 溶解度為約丨-2.5 mg/ml。此外，游離鹼具有輕度吸水性， 、 其在80%之相對濕度（r.h·)及25°C下之最大吸水度為1.8%。 令人驚訝的，發現5_(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎琳-4_基甲基-苯基 >異噁唑曱酸乙醯胺之新穎鹽形式 包括鹽酸鹽、酒石酸鹽、磷酸鹽、半富馬酸鹽及曱磺酸 鹽。發現該等鹽及游離鹼為晶體，此使得該等形式尤其適 129123.doc 200844102 用於醫藥研發。 务見（’4 一說基-5-異丙基-苯基）-4-(4-嗎琳基f基-苯基）_異噁唑甲酸乙醯胺甲磺酸鹽及5-(2,4-二羥基-5-異 丙基-苯基）-4-(4-嗎啉_4_基甲基_苯基）_異噁唑_3_甲酸乙醯 , 胺鹽酸鹽二者皆不具有吸水性。 / 此外，與游離鹼及其他鹽相比，發現5-(2,4-二羥基-5-異 =基^苯基）-肛（4-嗎啉_4-基甲基_苯基）_異噁唑_3_甲酸乙醯 ( _甲酉夂鹽之溶解度較佳。除了顯示高水溶性之優點外， 甲石戸、&L鹽亦適於以清楚之酸/驗比例重複製造。此發現使 甲磺酸鹽尤其適合用於口服液體調配物及靜脈内調配物 中〇 與游離鹼相比，所有5_(2,4_二經基_5_異丙基_苯基）_4_ (4-馬啉-4-基甲基_苯基異噁唑_3_甲酸乙醯胺鹽皆顯示較 高溶解度。 鹽酸鹽在水中之溶解度為2·5_5 mg/ml，在pH 5下溶解度 Q 為約 ^2·5 mg/ml且在 〇.1 NHC1 中低於 1 mg/ml。 酒石酸鹽在水中之溶解度高於2 mg/ml。 麟酸鹽在水中只溶解度為約0.5-1.0 mg/ml。 ·· 半富馬酸鹽在水中之溶解度為約0.1-0.25 mg/m卜
*· 甲尹、酉夂鹽在PH 5下之〉谷解度為約1 _2·5 mg/ml且在〇· 1 N HC1中為1〇_20 mg/ml。發現在pH 4之水中之溶解度為33 5 mg/ml。 除上述外’已發現可以水合物形式獲得％(2,4_二羥基_5_ 異丙基-笨基）-4-(4-嗎琳-4-基曱基-苯基）_異噁唾-曱酸乙 129123.doc 200844102 醯胺甲«鹽。·變體八係5_(2,二經基：異丙基-苯基 (4-嗎琳-4-基甲基-苯基）_異。惡唾|甲酸乙醯胺甲石黃酸鹽之 無水形式且形式ΗΑ及ΗΒ係5-(2,4-二羥基-5-異丙基-苯基）_ 4- (4-嗎啉-4-基甲基-苯基異噁唑_3_甲酸乙醯胺曱磺酸鹽 / 之水合形式。 • 在本發明另一態樣中，發現可獲得5-(2,4-二羥基-5-異丙 基笨基）4-(4-嗎琳-4-基甲基-苯基）_異噁唾_3_甲酸乙醯胺 之游離鹼及甲磺酸鹽之不同晶體形式。 最後，發現在所施用條件範圍内晶體形式的5_(2,4-二羥 基-5-異丙基-苯基）-4-(4-嗎啉-4-基曱基-苯基）_異噁唑-3_曱 酉文乙胺鹽酸鹽不隨懸浮液中之平衡而變化。對於被指定 作為藥物經研發之固體形式而言，缺少多晶型係有益特 性。 因此’在第一態樣中，本發明係關於5_(2,4_二羥基-5-異 丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）-異噁唑-3-甲酸乙醯 I 胺之新鹽，更具體而言係關於5-(2,4-二羥基-5-異丙基-苯 基）-4-(4-嗎啉-4-基甲基-苯基）_異噁唑-3-甲酸乙醯胺曱磺 酸鹽、5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基_ " 苯基）_異噁唑-3-曱酸乙醯胺鹽酸鹽、5-(2,4_二羥基-5-異丙 ·· 基-苯基）-4-(4-嗎啉-4-基曱基-苯基）-異噁唑-3-曱酸乙醯胺 酒石酸鹽、5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基 甲基-苯基）-異噁唑_3_曱酸乙醯胺磷酸鹽及5_(2,4-二羥基_ 5- 異丙基-苯基）_4_(4_嗎啉基曱基-苯基）_異噁唑_3-甲酸 乙酉&胺半富馬酸鹽。 129123.doc 200844102 在第二態樣中，本發明係關於5_(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）_異噁唑_3_甲酸乙醯胺甲 磺酸鹽之新穎晶體形式及水合物。 在第三態樣中，本發明係關於5_(2,4-二羥基-5-異丙基-苯基）-4-(4_嗎啉-4-基甲基-苯基異噁唑_3·曱酸乙醯胺游 離鹼之新穎晶體形式。 此外，本發明係關於5_(2,4_二羥基異丙基-苯基）_4_ (4-嗎琳-4-基甲基-苯基）_異噁唑甲酸乙醯胺曱磺酸鹽、 5-(2,4-二羥基_5_異丙基-苯基嗎啉_4_基甲基-苯基）_ 異嚼唾-3 -曱酸乙醯胺鹽酸鹽、5_(2,4-二羥基_5_異丙基-苯 基）-4-(4-嗎琳-4-基甲基-苯基）_異噁唑_3_甲酸乙醯胺酒石 酸鹽、5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基- 苯基）-異。惡嗤-3 -曱酸乙醯胺磷酸鹽及5-(2,4-二羥基-5-異丙 基-苯基）-4-(4-嗎啉-4-基甲基-苯基）_異噁唑_3_甲酸乙醯胺 半富馬酸鹽之用途，其用於製造治療由Hsp9〇介導之病症 之藥物。 除非另外說明，否則在本揭示内容之上下文中上文及下 文所用通用術語較佳具有以下含義。 本文所用短語’’由Hsp90所介導之病症，，表示諸如腫瘤疾 病等病症，其係由HsP90之過度表現、活化或失調而引 發，或其中該過度表現、活化或失調具有顯著作用。 本文所用短語”不含任何其他鹽，，意指既不存在作為等滲 劑之衍生自無機或有機酸之任何鹽（例如氯化鈉）亦不存在 任何緩衝鹽。據觀察在該等其他鹽存在下，遲早會形成晶 129123.doc -10- 200844102 體’、使Ό，4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基曱 基苯基）-異噁唑_3_甲酸乙醯胺甲磺酸鹽溶液不穩定，且 y、對4曰疋用於靜脈内投與之調配物而言係尤其不可接受之 風險。
本+文所用短語，，化學上穩定”意指5_(2,4_二羥基_5_異丙 基-本基）-4-(4-嗎啉基甲基-苯基）_異噁唑_3_甲酸乙醯胺 不、經歷任彳可彳卜風C： rfc J 1匕予反應，例如溶劑分解反應，尤其不經歷水 解、重排或氧化。 在較佳實施例中 5 -（2,4-二經基-5-異丙基-苯基）-4-(4- 馬琳冰基甲基·笨基l·異嚼唾·3-曱酸乙醯胺之基本上純淨 之甲烷石尹、§文鹽之形式1顯示圖7中所示之X射線繞射圖。
極佳者亦可為5-(2,4-二羥基_5_異丙基-苯基）_4_(4_嗎啉_ 土 土-本基）_異噁唑_3-甲酸乙醯胺甲烷磺酸鹽之形式 1 ’其顯示圖7中所示類型之X射線繞射圖，其中在以下2-Θ 值處具有顯著峰強度：16.7、19.4及22·7±0·2度。在不含任 何額外材料（其他晶體形式、水合物 、賦形劑）之樣品中， 可能觀察到以 下 2-Θ 值：8.0、11.9、13.9、14.2、 16.7 > 18.5 19·4、22.7、23·3±0·2度。 在另較佳實施例中，5-(2,4-二羥基-5-異丙基-苯基>4- G馬κ基曱基-苯基）-異鳴U-甲酸乙醯胺之基本上純 爭之甲烷、酸鹽之形式Ηα顯示圖8中所示X射線繞射圖。 4極佳者亦可為5_(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉_ 基甲基-笨基）_異噁唑甲酸乙醯胺曱烷磺酸鹽之形式 Ha’其顯示圖8中所示類型之X射線繞射圖，其中在以下2_ 129123.doc 200844102 ㊀值處具有顯著峰強度：18」及2〇 5，±〇2度。在不含任何 額外材料之;u γ 像叩（其他晶體形式、無水物、賦形劑）中， 能觀察到以下2 a姑·，t Λ 卜 值· 11·0、Π·6、14·1、18.1、20.1、 2〇·5 21」、21·7、21.9、25·8±〇·2度。 在另一較佳實施例中，5-(2,4-二羥基-5-異丙基-苯基）_4_ (4-嗎琳基甲其贫盆 ^ Τ I-本基）_異噁唑_3_甲酸乙醯胺之基本上純 #之甲燒〜酸鹽之形式ηβ顯示圖9中所示X射線繞射圖。
極佺者亦可為5_(2,4_二羥基巧_異丙基_苯基）_‘（4_嗎啉_ 4-基曱美_笑装、 土 土）-異噁唑_3_甲酸乙醯胺甲烷磺酸鹽之形式 Ηβ其顯不圖9中所示類型之X射線繞射圖，其中在25·4 ±〇·2度之2-Θ值處具有顯著峰強度。在不含任何其他材料 (其他晶體形式、無水物、賦形劑)之樣品中，可能觀察到 乂下 2Θ值· 6,2、1〇,1、126、145、18〇、185、19〇、 20.4、2G.9、21.8、22.2、25.4±G.2度。 在另一較佳實施例中，5_(2,4_二羥基_5_異丙基_苯基）_各 (4馬啉-4-基甲基_苯基）_異噁唑_3•甲酸乙醯胺之基本上純 >尹之鹽酸鹽顯示圖1〇中所示X射線繞射圖。 極佳者亦可為5_(2,4-二羥基_5_異丙基-苯基）_4_(4_嗎啉_ ‘基甲基—苯基）_異噁唑-3-甲酸乙醯胺鹽酸鹽，其顯示圖1〇 所示類型之X射線繞射圖。 在另一較佳實施例中，5气2,4-二羥基_5-異丙基_苯基）_4_ 嗎啉基甲基-苯基）-異噁唑-3-甲酸乙醯胺之基本上純 淨之酒石酸鹽顯示圖11所示X射線繞射圖。 極佳者亦可為5_(2,4-二羥基-5-異丙基_苯基）-4-(4-嗎啉- 129123.doc -12- 200844102 4-基曱基-苯基）-異噁唑_3_曱酸乙醯胺酒石酸鹽，其顯示圖 11所示類型之X射線繞射圖。 在另一較佳實施例中，5-(2,4-二羥基-5-異丙基-苯基）-4-(4胃嗎啉-4-基甲基_苯基）_異噁唑甲酸乙醯胺之基本上純 • 淨之磷酸鹽顯示圖12中所示X射線繞射圖。 • 極佳者亦可為5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉- 4-基甲基_苯基）_異噁唑曱酸乙醯胺磷酸鹽，其顯示圖12 、 中所示類型之X射線繞射圖。 C、 在另一較佳實施例中，5-(2,4-二羥基-5_異丙基-苯基）-4-(4-嗎琳-4-基曱基_苯基）_異噁唑曱酸乙醯胺之基本上純 淨之富馬酸鹽顯示圖丨3中所示X射線繞射圖。 極“者亦可為5_(2，4-二^基-5-異丙基-苯基）-4-(4-嗎琳_ 心基甲基—本基）_異°惡。坐-3 -曱酸乙醯胺富馬酸鹽，其顯示圖 13中所示類型之X射線繞射圖。 在本發明上下文中術語”基本上純淨”可理解為尤其意指 〇 至少90重量❶/❶、較佳至少95重量％、且最佳至少99重量〇/〇 之5-(2，4-二經基_5_異丙基-苯基）-4-(4 -嗎琳-4-基甲基-苯 基l·異噁唑_3_甲酸乙醯胺之酸加成鹽晶體以本發明晶體形 ·· 式存在。 ·· 在本發明另一態樣中提供包含5-(2,4-二羥基-5-異丙基_ 苯基）-4-(4-嗎啉_4_基甲基-苯基）_異噁唑甲酸乙醯胺甲 磺酸鹽之新穎調配物。更具體而言，本發明提供不含任何 其他鹽之包含％(2,4_二羥基_5_異丙基-苯基>4_(4_嗎啉-心 基甲基-苯基）-異噁唑-3_甲酸乙醯胺甲磺酸鹽之水溶液。 129123.doc -13- 200844102
較佳地’水溶液之pH介於3.2與52之間D 車父佳地，調配物中每毫升溶液包含約4·8至$·2毫克5· (2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基_苯基）_異 噁唑-3-曱酸乙醯胺曱磺酸鹽溶液，更佳為每毫升溶液包含 5.〇毫克。此溶液之PH為約4.2且在此pH下之甲磺酸鹽具有 最大穩定性。此驚人發現使得溶液尤其適用於醫藥用途。 具體而s ’其因此可在不含任何其他穩定藥物物質之賦形 W (例如緩衝液）情況下使用該溶液。此外，鐾於其高穩定 性’可對每毫升溶液包含約4.8至5.2 mg 5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）-異噁唑-3-曱酸乙 酸胺甲磺酸鹽之溶液實施高壓蒸汽滅菌法（例如在約2巴壓 力下加熱至約120 °C並保持20至40分鐘（例如30分鐘）），且 不導致任何顏色變化或降解產物。 在一實施例中，由5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉基曱基-苯基）-異噁唑-3 -曱酸乙醯胺之等滲水溶液 之曱績酸鹽及5% w/w葡萄糖或甘露醇組成調配物。後項實 施例之其他優點在於即使經過更長儲存時間（例如若干月） 後，仍可避免晶體形成。此外，此調配物中之甲磺酸鹽在 化學上穩定。此外，此溶液之pH可在高壓蒸汽滅菌期間防 止5%葡萄糖溶液在中性pH下可能發生變色之美拉德 (Maillard)反應。 鑒於上文所列驚人發現，本發明提供 • 包含5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲 基-苯基）-異σ惡唑_3 -曱酸乙醯胺曱石黃酸鹽之調配物， 129123.doc •14· 200844102 其較佳為包含5-(2,4-二羥基-5-異丙基_苯基）_4-(4_嗎 啉-4-基甲基-苯基）_異噁唑甲酸乙醯胺甲磺酸鹽且 不含任何其他鹽之水溶液，其pH較佳介於3.2與52之 間； •尤其由5-(2,4·二羥基-5-異丙基-苯基）_4-(4_嗎啉_4_基 曱基-苯基）-異噁唑-3-甲酸乙醯胺甲磺酸鹽之等滲水 溶液及5% w/w葡萄糖或甘露醇組成之調配物； •及尤其以約4.8至5·2 mg/ml之濃度包含5-(2,4-二羥基-5-異丙基-苯基）-‘（4-嗎啉-4-基甲基-苯基）-異噁唑-3-曱酸乙酿胺曱磺酸鹽之水性調配物。 本文中上述水溶液尤其可用於5_(2,4_二羥基異丙基_ 苯基）-4-(4-嗎啉-4-基曱基-苯基異噁唑_3-曱酸乙醯胺甲 石黃酸鹽之靜脈内投與。 此外，令人驚訝地發現5_(2,4_二羥基異丙基-苯基 (4-嗎啉-4-基甲基-苯基）_異噁唑_3_甲酸乙醯胺曱磺酸鹽之 固體及溶液形式皆具有光敏性。因此，在另一實施例中， 本發明提供填充有本文上述藥物物質或水性調配物之琥拍 色玻璃容器。 此外’本發明提供治療由Hsp9〇介導之病症之方法，其 包括向需要其之溫血動物投與治療有效量的5-(2,4-二輕 基-5-異丙基-本基）_4-(4-嗎琳_4_基曱基-苯基）-異嚼嗤-3-曱 酸乙醯胺甲磺酸鹽或5_(2,4_二羥基異丙基-苯基）_‘（4 一 嗎啉-4-基甲基-苯基）_異噁唑-3·曱酸乙醯胺鹽酸鹽。 【實施方式】 129123.doc -15- 200844102 實例 下述實例闡述本發明。 以攝氏度（°c)量測溫度。除非另有說明，否則反應在室 溫下發生。 縮略語
EtOAc 乙酸乙酯 r.h 相對濕度 RT 室溫 TBME 曱基第三丁基醚 實例1 : 5-(2,4-二羥基-5-異丙基-苯基嗎啉-4-基甲 基-苯基）-異嗔峻-3-甲酸乙醯胺鹽酸鹽
在緩慢加熱下將5-(2,4-二羥基-5-異丙基-苯基）-4-(4_嗎 琳-4-基曱基-苯基）-異。惡唾-3-甲酸乙醯胺（4.19 g， 9 mmol) 溶解於無水醇（19·7 ml)中。攪拌5 min後，在RT(約25°C)下 添加6N鹽酸水溶液（1·5 ml，9 mmol)。用極微量5-(2,4-二羥 基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）-異噁唑-3-曱 酸乙醯胺鹽酸鹽對澄清溶液實施引晶且添加乙酸乙酯（2 ml)，之後混合物慢慢變渾濁。1 h後，分部分添加EtOAc (5 ml)，且在RT下將懸浮液攪拌過夜。添加更多EtOAc (2 ml)。將懸浮液攪拌約5 h且將其過濾。用無水醇/EtOAc 129123.doc -16 - 200844102 ^(ν/ν)洗滌濾餅且在45°c及低壓下將其乾燥16 h以獲得呈 白色粉末形式之標題化合物。
溶點（DSC) ·· 237°C 實例2 : 5-(2,4·二羥基-5-異丙基·苯基）-4-(4-嗎啉-4-基甲 基-苯基）-異噁唑-3-甲酸乙醯胺甲磺酸鹽_條件（A)
將存於丙酮（15 ml)中之5-(2,4-二羥基_5_異丙基-苯基）-4-(4-嗎啉-4-基曱基-苯基）_異噁唑_3_甲酸乙醯胺（7.76 g，15 mmol，包含約9 wt% TBME)經攪拌懸浮液加熱至35°C。在 20 min内向混合物中添加存於水（3.33 g)中之甲石黃酸（1.43 g，14.85 mmol)溶液。15 min後，將溶液加熱至45。(：且將其 澄清過濾至溫燒瓶（約45°C )中。用丙酮/水9:1 (v/v，12 ml) 沖洗過濾器。在30 min内用丙酮（53 ml)稀釋45°C溫濾液且 用5-(2,4-二經基-5-異丙基-苯基）-4-(4 -嗎琳-4-基曱基-苯 基）-異°惡σ坐-3 -曱酸乙酿胺甲石黃酸鹽（4 m g)引晶，之後結晶 作用開始。1 h後在45°C下添加丙酮（30 ml)。在45°C下將 、 懸浮液撥拌1 h，之後在90 min内使其冷卻至24 °C。添加 TBME(20 ml)，且在約24°C下將懸浮液攪拌15 h。另外添 加兩部分TBME(每部分20 ml)，且添加每部分後擾拌2 h。 此後’在將懸浮液過濾前使其冷卻至〇 - 5 °C並搅拌3 h。用 丙酮/曱基第三丁基醚3:1 (v/v)洗滌濾餅且在低壓及5 〇下 129123.doc 17 200844102 使其乾燥約17 h以獲得7.18 g (85%)呈白色晶體粉末形式之 標題化合物。 溶點：23 3。(： 若省略引晶，所形成晶體具有相同形式但可包含高奚 1·5 wt%之丙酮。 實例3 : 5-(2,4—二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲 基-苯基）-異噁唑-3-甲酸乙醯胺甲磺酸鹽-條件（B) 將 186.2 mg (0.4 mmol) 5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）_異噁唑_3_曱酸乙醯胺曱烷磺酸溶 解於〇·75 ml丙酮中。在rt下添加154 mg甲烷磺酸（0.4 mmo1)水溶液（25% w/w)，獲得藍色溶液。攪拌2 h後，添 加3·5 ml丙酮及〇·5 ml TBME。將溶液另外攪拌12 h後，緩 慢添加另外3 ·5 ml TBME，且繼續再攪拌12 h。過濾所獲 得乳液且用〇·5 ml TBME洗滌所得固體。在5〇°C及20 mbar 下將固體乾餘16 h以提供1 8 0 m g標題化合物。 實例4· 5-(2，4 -二輕基-5-異丙基-苯基)-4-(4-嗎琳-4-基甲 基-苯基）-異嚼峻-3-甲酸乙醯胺之游離驗、曱烧績酸鹽及 鹽酸鹽之吸水性 使用動態水吸收（Dynamic Water Sorption) (DVS)裝置量 測吸水性。在25 °C下使用約8-10 mg物質實施量測。如下 所述以10% r.h.之梯度改變r.h· : 40-0-95-0-40% r.h·。最短 階段時間為60 min，最長為180 min，若在1〇 min時間内之 變化小於0,002%/min，則將r.h.改變為下一梯度。 發現5-(2,4-二羥基-5-異丙基-苯基嗎啉_4_基甲基- 129123.doc -18- 200844102 笨基）-異。惡。坐_3 -甲酸乙醯胺曱石黃酸鹽及5_(2,4_二經基_5_異 丙基-苯基）-4-(4-嗎啉-4-基曱基_笨基）_異噁唑曱酸乙醯 胺鹽酸鹽皆不具有吸水性。游離鹼具有輕度吸水性，在 80%相對濕度（r.h·)及25°C下其顯示丨·8%之水的最大吸收。 實例5:在安瓶瓶中製造5〇 mg/10 mL 5_(2,4·二羥基_5-異 丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）_異噁唑-3-曱酸乙醯 胺甲磺酸鹽之液體 將391.95 g AUY922曱磺酸鹽（其對應於325 g游離鹼）及 3.25 kg葡萄糖溶解於65 L水中以供注射。獲得無色至輕度 微黃色溶液，其具有20°C下之1.018 士 0.005 g/mL之密度、 315±15 mOsm/kg之克分子滲透壓濃度及4·2±1·0之pH。經 由0·22 μιη過濾溶液。將10.5土0.4 mL溶液填充至琥珀色安 瓿瓶中。在氮氣氛下密封安瓿瓶且在121°C下將其高壓蒸 汽滅菌3 0 min。 實例6 :稀釋50 mg/10 mL實例5濃縮物 用市售250 mL 5%葡萄糖溶液稀釋mL實例5之50 mg/10 mL安瓶，且經由重量輸注管線將其靜脈内投與患 者。 實例7 : 5·(2,4-二經基-5-異丙基-苯基）-4_(4-嗎琳-4·基甲 基-苯基）-異噁唑-3-甲酸乙醢胺甲確酸鹽之溶解度 測定不同水性介質中5-(2,4-二沒基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）-異噁唑甲酸乙醯胺（AUY922)甲 磺酸鹽之溶解度且發現其為如了所述： 水（飽和溶液 ρΗ=3·6) - 3 7.5 mg/mL; 0.9% NaCl 溶液- 129123.doc -19- 200844102 12·8 mg/mL ; 5%葡萄糖溶液_ 39 mg/mL ; 5%甘露醇溶液 -39 mg/mL ; 5%葡萄糖溶液（pH 4) _ 35.6 mg/mL ; 5% 葡萄 糖溶液（pH 7) - 37.5 mg/mL ;緩衝溶液：pH 4.0(乙酸鹽緩 衝液）-14.6 mg/mL ; PH 5·0(乙酸鹽緩衝液）-3.2 mg/mL ; ρΗ 6·〇(填酸鹽緩衝液）-0.6 mg/mL ; pH 7.0(磷酸鹽緩衝 液）-0.7 mg/mL ; pH 8.0(棚酸鹽緩衝液）-1 ·8 mg/mL。 發現葡萄糖及甘露醇溶液具有高溶解度。在緩衝溶液中 pH 4導致最南溶解度。 實例8 : 5-(2,4_二羥基_5_異丙基-苯基）-4_(4_嗎啉-4-基甲 基-苯基）-異噁唑_3_甲酸乙醯胺甲磺酸鹽之溶液或懸浮液 中之應力測試 在應力條件（4週，在50°C下）下測定AUY922曱磺酸鹽在 不同水性介質中之穩定性，且發現以下外觀/内含物回收 率/副產物及降解產物之總和： 水：無色溶液/97·0%/0·32% ; 0.9% NaCl :溶液無色溶液 /98·5%/〇·34% ; 5%葡萄糖溶液：無色溶液/99.6%/0.34%。 緩衝溶液pH 1.0 (HC1):無色溶液/96·7%/2·83% ; pH 2.0 (檸檬酸鹽緩衝液）：無色溶液/97.8%/0·58% ; pH 3·0(擰檬 酸鹽緩衝液）··無色溶液/99·2%/0·47% ; pH 4.0(乙酸鹽緩 衝液）：無色溶液/1〇〇·5%/〇·36% ; pH 5·0(乙酸鹽緩衝液）： 無色溶液/99.1%/0.50%;?«[6.0(磷酸鹽緩衝液）：無色懸 浮液/96·2%/〇·49% ; ΡΗ 6·8(磷酸鹽緩衝液）：無色懸浮液/ 96·3%/〇·79% ; pH 8.0(硼酸鹽緩衝液）：無色懸浮液/88.5%/ 0.26% 〇 129123.doc -20- 200844102 此數據證實在pH 4下AUY922曱磺酸鹽具有最大穩定 性。此外顯示與其他水性介質相比，5%葡萄糖溶液獲得 最大穩定性。 【圖式簡單說明】 圖1至13係5_(2,4·二經基-5-異丙基-苯基）4-(4-嗎琳-4-基 - 曱基-苯基l·異噁唑-3-甲酸乙醯胺之游離鹼、曱烷石黃酸 鹽、鹽酸鹽、酒石酸鹽、磷酸鹽及半富馬酸鹽之晶體形式 之X射線繞射圖。在X射線圖中，繞射角2 0繪於水平軸（X € 軸）’相對譜線強度（經背景校正之峰強度）緣於垂直軸（y 軸）。用Cu K輻射源（K1韓射，波長=1.54060埃）量測X射線 粉末繞射模式。 圖1顯示5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲 基-苯基）-異噁唑-3-曱酸乙醯胺游離鹼（形式I)之X射線繞射 圖。 圖2顯示5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基曱 ^ 基-苯基）-異噁唑-3-曱酸乙醯胺游離鹼（形式II)之X射線繞 射圖。 圖3顯不5-(2,4-二罗里基-5-異丙基-本基）-4-(4-嗎琳-4 -基甲 基-苯基）-異噁唑-3-曱酸乙醯胺游離鹼（形式III)之X射線繞 • 射圖。 圖4顯示5-(2,4-二經基-5-異丙基-苯基）-4-(4 -嗎琳-4-基曱 基-苯基）-異噁唑-3-甲酸乙醯胺游離鹼（形式IV)之X射線繞 射圖。 圖5顯示5-(2，4-二經基-5-異丙基-苯基）-4-(4-嗎琳-4-基甲 129123.doc -21 - 200844102 基-苯基）-異噁唑-3-曱酸乙醯胺游離鹼（形式V)之χ射線繞 射圖。 圖6顯示5-(2，4-二經基-5-異丙基-苯基）-4-(4-嗎琳-4-基曱 基-苯基）-異噁唑-3-甲酸乙醯胺游離鹼（形式VII)之X射線繞 射圖。 圖7顯示5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基曱 基-苯基）-異噁唑-3-甲酸乙醯胺甲烷磺酸鹽之形式1之乂射 線繞射圖。 圖8顯示5-(2，4-二經基-5-異丙基-苯基）-4-(4-嗎琳-4-基曱 基-苯基）-異噁唑-3-曱酸乙醯胺甲烷磺酸鹽之水合物形式 HA之X射線繞射圖。 圖9顯示5-(2,4-二經基-5-異丙基-苯基）-4-(4-嗎琳-4-基曱 基-苯基）-異噁唑-3-甲酸乙醯胺曱烷磺酸鹽之水合物形式 HB之X射線繞射圖。 圖10顯示5-(2,4-二羥基異丙基-苯基）-4-(4-嗎啉-4-基 曱基-苯基）-異噁唑-3 -曱酸乙醯胺鹽酸鹽之X射線繞射圖。 圖11顯示5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基 曱基-苯基）-異噁唑-3-甲酸乙醯胺酒石酸鹽之X射線繞射 圖。 圖12顯示5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎琳-4-基 甲基-苯基）-異噁唑-3-曱酸乙醯胺磷酸鹽之X射線繞射圖。 圖13顯示5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎琳-4-基 曱基-苯基）-異噁唑-3-甲酸乙醯胺半富馬酸鹽之X射線繞射 圖。 129123.doc -22-
Claims (1)
- 200844102 十、申請專利範圍： 1· 一種以5-(2,4-^一經基_5_異丙基-苯基）-4-(4 -嗎琳-4 -基甲 基-苯基）-異噁唑-3 -甲酸乙醯胺甲石黃酸鹽、5-(2,4_二經 基-5-異丙基-苯基）-4-(4-嗎琳-4-基曱基-苯基）_異。惡嗤_3-甲酸乙醯胺鹽酸鹽、5-(2,4-二羥基-5-異丙基-苯基）-4-(4- 嗎琳-4-基甲基-苯基）-異喔嗤_3-曱酸乙醯胺酒石酸鹽、 (2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基曱基_苯基）_ 異°惡°坐-3-曱酸乙醯胺填酸鹽或5-(2,4-二經基-5-異丙基-笨基）-4-(4-嗎琳-4-基曱基-苯基）_異。惡峻_3_曱酸乙醯胺半 富馬酸鹽於製造供治療由Hsp90介導之病症之藥物上之 用途。 2.如請求項1之用途，其中使用5-(2,4-二羥基-5-異丙基-苯 基）-4-(4-嗎琳-4-基甲基-苯基）-異噁唑_3_甲酸乙醯胺甲石黃 酸鹽。 3 ·如請求項2之用途，其中該藥物係靜脈内投與。 4· 一種治療由Hsp90介導之病症之方法，其包括向有此需 要之溫血動物投與治療有效量之5-(2,4_二羥基—5-異丙 基·•笨基）-4-(4-嗎啉-4-基甲基-苯基）-異噁唑-3 -曱酸乙醯 胺甲磺酸鹽、5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4_基甲基-苯基）-異噁唑-3 -甲酸乙醯胺鹽酸鹽、5-(2,4-二 沒基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）-異噁唑-3_甲酸乙醯胺酒石酸鹽、5-(2,4-二羥基-5-異丙基-苯基）-4_(4-嗎啉-4-基甲基-苯基）-異噁唑—3-甲酸乙醯胺磷酸鹽 或5-(2,4-二羥基-5-異丙基-苯基）_4-(4-嗎啉-4-基甲基-苯 129123.doc 200844102 基）-異噁唑_3_甲酸乙醯胺半富馬酸鹽。 5. —種5-(2,4_二經基-5-異丙基-苯基）-4-(4-嗎琳-4-基甲基-苯基）-異"惡唑甲酸乙醯胺甲磺酸鹽。 6. 一種5-(2,4-二•基-5-異丙基-苯基）-4-(4-嗎琳-4-基甲基-苯基）_異噁唑_3_甲酸乙醯胺鹽酸鹽。 7· —種5-(2,4-二經基-5-異丙基-苯基）-4-(4-嗎琳-4-基甲基- 苯基）-異噁唑甲酸乙醯胺酒石酸鹽。 8· —種5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基-苯基）-異噁唑-3-甲酸乙醯胺磷酸鹽。 9· 一種5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基_ 苯基:l·異噁唑-3-甲酸乙醯胺半富馬酸鹽。 10. —種5-(2,4-二羥基-5-異丙基-苯基）-4_(4-嗎啉-4-基甲基_ 苯基）-異噁唑-3-甲酸乙醯胺甲磺酸鹽之晶體形式。 1 1.如請求項10之晶體形式，其係5-(2,4-二經基-5-異丙基_ 苯基）-4-(4-嗎琳_4_基甲基-苯基）_異噁唑-曱酸乙醯胺曱 績酸鹽無水物。 12· —種5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲基- 苯基）-異噁唑-3-甲酸乙醯胺曱磺酸鹽無水物之晶體形式 卜 13·如請求項13之晶體形式，其X射線繞射圖型如圖7所示， 其中與圖7所示圖中相對峰強度相比，各峰之相對峰強 度之偏離程度不超過1 〇〇/0。 14.如清求項10之晶體形式，其係5_(2,4_二羥基異丙美 苯基）-4-(4-嗎啉-4-基甲基-苯基）_異噁唑甲酸乙醯胺曱 129123.doc 200844102 磺酸鹽之水合物。 15· —種5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲義 苯基）-異噁唑-3-甲酸乙醯胺甲磺酸鹽之水合物形式只八。 16·如請求項15之水合物形式，χ射線繞射圖型如圖8 τ戶斤 示’其中與圖8所示圖中相對峰強度相比，各峰之相對 峰強度之偏離程度不超過1 〇〇/0。 17· —種5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉_4_基甲基 苯基l·異噁唑-3-甲酸乙醯胺甲磺酸鹽之水合物形式。 18·如請求項17之水合物形式，其χ射線繞射圖型如圖$中所 不’其中與圖9所示圖中相對峰強度相比，各峰之相辦 峰強度之偏離程度不超過1 〇〇/0。 19· 一種5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉j基甲基 苯基）-異噁唑-3-甲酸乙醯胺鹽酸鹽之晶體形式。 20.如請求項19之晶體形式，其χ射線繞射圖型如圖1〇中所 示，其中與圖10所示圖中相對峰強度相比，各峰之相對 峰強度之偏離程度不超過10%。 21· —種5-(2,4-二羥基-5-異丙基_苯基）-4-(4-嗎啉-4-基甲基_ 苯基異噁唑-3-甲酸乙醯胺酒石酸鹽之晶體形式。 22·如請求項21之晶體形式，其χ射線繞射圖型如圖丨丨中所 示’其中與圖11所示圖中相對峰強度相比，各峰之相對 峰強度之偏離程度不超過10〇/〇。 23. —種5-(2,4-二羥基-5-異丙基-苯基>4_(4_嗎啉基甲基· 苯基）-異噁唑-3 -甲酸乙醯胺磷酸鹽之晶體形式。 24·如請求項23之晶體形式，其χ射線繞射圖型如圖12中所 129123.doc 200844102 不，其中與圖12所示圖中相對峰強度相比，各峰之相對 峰強度之偏離程度不超過1 〇%。 25· —種5_(2,4-二羥基-5-異丙基-苯基）_4_(4_嗎啉_4_基甲義 苯基異噁唑-3-甲酸乙醯胺半富馬酸鹽之晶體形式。 26·如請求項25之晶體形式，其χ射線繞射圖型如圖13中所 示，其中與圖13所示圖中相對峰強度相比，各峰之相對 峰強度之偏離程度不超過1 〇〇/。。 27· —種調配物，其包含5_(2,4_二羥基_5_異丙基·苯基）_私 嗎琳-4-基甲基-苯基）-異噁唑甲酸乙醯胺甲磺酸鹽。 28.如請求項27之調配物，其係包含5-(2,4-二羥基_5_異丙 基-苯基）-4-(4-嗎啉-4-基曱基_苯基）_異噁唑_3_曱酸乙醯 胺甲磺酸鹽且不含任何其他鹽之水溶液。 29·如請求項28之調配物，其pH介於3 ·2與5.2 pH之間。 30· —種調配物，其係由5-(2,4-二羥基-5-異丙基-苯基;M-d 嗎琳-4-基曱基-苯基）-異嚼ϋ坐曱酸乙酸胺曱石黃酸鹽之 等滲水溶液及5% w/w葡萄糖組成。 31. —種調配物，其由5_(2,4_二羥基-5-異丙基-苯基）-4-(4-嗎 琳-4-基甲基-苯基）-異嚼n坐-3 -甲酸乙酷胺曱石黃酸鹽之等 滲水溶液及5% w/w甘露醇組成。 32·如請求項28至30中任一項之調配物，其包含約4.8至5.2 mg/ml 5-(2,4-二羥基-5-異丙基-苯基）-4-(4-嗎啉-4-基甲 基-苯基）-異噁唑-3 -曱酸乙醯胺曱磺酸鹽。 33. —種琥珀色玻璃容器，其填充如請求項27至31中任一項 之調配物。 129123.doc
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| JP5845193B2 (ja) | 2010-01-21 | 2016-01-20 | アプレア エイビー | 過増殖性疾患、自己免疫疾患、および心疾患の治療のための３−キヌクリジノンを含有する水溶液 |
| US20120309750A1 (en) * | 2010-02-17 | 2012-12-06 | Ildong Pharm Co., Ltd. | 5-membered heterocycle derivatives and manufacturing process thereof |
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| WO2013015661A2 (en) * | 2011-07-28 | 2013-01-31 | Ildong Pharm Co.,Ltd. | Novel prodrugs of 5-(2,4-dihydroxy-5-isopropylphenyl)-n-ethyl-4-(5-methyl1-1,2,4-oxadiazol-3-yl)isoxazole-3-carboxamide |
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