201240985 六、發明說明： 【發明所屬之技術領域】 表示的（ls)-(-)-N-[(i_ 乙 •N-(6-異丙基吡啶_3_ 經分離晶形：201240985 VI. Description of the invention: [Technical field to which the invention pertains] (ls)-(-)-N-[(i_ B-N-(6-isopropylpyridine_3_ separated crystal form:
本發明關於一種由以下式⑴所 基-1H-。比唑-4-基）甲基；經基 基）-1，2,3,4-四氫萘-1-醯胺之新賴、 其製造方法與其醫藥用途。 【先前技術】 N-[(l-乙基-1Η-°比唾-4-基）甲| 3 A ^ 1 ? W卜 甲基卜5-羥基-N-(6-異丙基吡 定基)_1，2,3,4·四虱萘]_酿胺為-已知化合物（專利文獻 1及2)。其8形異構物叫(_)幕[(1 文獻 甲基Η-經基-N-(6_異丙基吼咬_ 胺具有優異的C5a受體 土 ，，，四虱奈-1-醯 、 體拮抗作用，且可用作為疾病之預防 性及/或治療性藥物，該 m 4疾病為由⑸與C5a受體之結合 k成者’例如自體免疫疾病 戾届（啫如類風濕性關節炎、全奋 性紅斑狼瘡與類似者）、 母 敗血症、成人呼吸窘迫症候群、 慢性阻塞性肺部疾病^ ^ ^ ^ 、 ▲〆 职：注疾病（諸如氣喘與類似者）、 動脈粥狀硬化 '心梗塞、 腦梗塞、牛皮癬、阿茲海默症、 由缺血再灌注、創傷、 70备、外科侵入性手術及類似者所 造成的白血球法各&播 斤導致的嚴重器官傷害（例如肺炎、腎 201240985 炎、肝炎、騰臟炎及類似者）；更甚者，因C5a具有強烈 的發炎誘發作用，該S異構物可用作為抗發炎藥物，而且 進一步地’作為用於由透過C5a受體入侵的細菌或病毒所 造成的感柒性疾病的預防性及/或治療性藥物。專利文獻2 描述（lS)-(-)-N-[(i_乙基_1H-吡唑_4_基）甲基]·5-羥基-N-(6-異丙基吡啶-3-基）4,2,3,4-四氫萘-1-醯胺之兩種自由晶形。 文件列表 專利文獻 專利文獻 1 : WO 2002/2255 6 專利文獻 2 : WO 2006/82975 【發明内容】 本發明欲解決之問題 本發明之一目標為提供均勻的、純的且更穩定的晶 體。具體言之’本發明之一個目相 之一個目標為提供呈經分離及/或純The present invention relates to a group -1H- which is represented by the following formula (1). Bisazol-4-yl)methyl; a novel basis of the base-1,2,3,4-tetrahydronaphthalen-1-anthracene, a process for its production and its medical use. [Previous technique] N-[(l-ethyl-1Η-° than sal-4-yl)-methyl | 3 A ^ 1 ? W-bu-methyl 5-hydroxy-N-(6-isopropylpyridyl)_1, 2,3,4·tetradecylnaphthalene]-bristamine is a known compound (Patent Documents 1 and 2). Its 8-isomer is called (_) curtain [(1 literature methyl hydrazine-transcarbyl-N-(6_isopropyl octapeptide _ amine has excellent C5a receptor soil,,, 虱 虱 -1-醯, antagonism, and can be used as a prophylactic and/or therapeutic drug for diseases. The m 4 disease is caused by (5) binding to the C5a receptor, such as autoimmune diseases (such as rheumatoid arthritis). Arthritis, generalized lupus erythematosus and similar), maternal sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary disease ^ ^ ^ ^, ▲ dereliction of duty: injection of disease (such as asthma and similar), atherosclerosis 'Heart infarction, cerebral infarction, psoriasis, Alzheimer's disease, severe organ damage caused by white blood cells caused by ischemia, reperfusion, trauma, 70, surgical invasive surgery and the like (eg Pneumonia, kidney 201240985 inflammation, hepatitis, visceral inflammation and the like); even worse, because C5a has a strong inflammatory-inducing effect, the S-isomer can be used as an anti-inflammatory drug, and further 'as used for transmission through C5a Inductive bacteria or viruses caused by receptors Prophylactic and/or therapeutic drug for disease. Patent Document 2 describes (lS)-(-)-N-[(i_ethyl_1H-pyrazole-4-yl)methyl]·5-hydroxy-N Two free crystal forms of -(6-isopropylpyridin-3-yl)4,2,3,4-tetrahydronaphthalen-1-ylamine. Document List Patent Literature Patent Literature 1: WO 2002/2255 6 Patent Literature 2: WO 2006/82975 SUMMARY OF THE INVENTION Problems to be Solved by the Invention An object of the present invention is to provide a uniform, pure and more stable crystal. In particular, one of the objectives of the present invention is to provide Separated and / or pure
供該晶體的製造方法。A method of producing the crystal.
因此，當 201240985 將結晶物質用作為醫藥品之有效成分時，纟晶體係欲為均 勻的、純的且更穩定的。 為了確保一致的功效表現及副作用表現，對於醫藥應 用而：咸欲得到化合物之單一且穩定的晶體。咸亦欲提: 能夠安全地且有效率地ί以卫t規模提供該日曰曰體的製造方 法。 解決問題之方法 在研究及開發本化合物之後，N [(1_乙基_1H_吡唑-心 基）甲基]·5-經基-N-(6_異丙基吡啶_3_基）]，2,3,4_四氫萘-卜 醯胺之新穎晶體被分離出來。該新穎晶體已被證實較傳統 已知晶體為穩定。此外，該新穎晶體已被發現可選擇性地 以均勻晶體形式製造，其係藉由使用水或具有兩個或以上 的碳數之有機溶劑結晶，溶劑溫度在從不低於該溶劑之融 點至不高於6 0 °C之範圍内。 在本發明一具體實例中，提供（13)_(·)·Ν_[(卜乙基]h_ 比坐4-基）甲基]經基·Ν-(6 -異丙基D比咬_3_基）_ 1,2,3，4 -四 氫萘-1-醯胺之經分離晶體，其中該晶體於粉末χ光繞射圖 譜中，在至少約 4.6。± 0.2。' 1〇.9。± 〇_2。、13.2。± 〇 2。 及16.6。± 0.2。之繞射角2θ處具有訊號峰。 在一具體實例中，該晶體於粉末χ光繞射圖譜中，在 至少約10.5。± 〇_2。及14.0。± 0.2。之繞射角20處具有訊 號峰。 该晶體在微差掃描熱量法測量中，可於i 43_丨49(外 推起始溫度）及171-1771 (外推起始溫度）具有吸熱峰。 6 201240985 此外’該晶體可具有以下A及/或B的理化性質：a為 具有如圖1所示之粉末X光繞射圖樣之訊號峰，而B為具 有如圖2所示之微差掃描熱量法曲線。 在本發明一具體實例中，提供一製造前述晶體的方 法’其中將溶劑溫度設定落於自不低於水或具有兩個或以 上的碳數之有機溶劑之融點至低於60°C的範圍内、形成；容 於水或該有機溶劑中之（lS)-(-)-N-[(l-乙基-1H-吡唑基） 甲基]-5-經基_N_(6_異丙基吡啶-3_基）_1，2,34_四氫萘_1、酿 胺晶體、及回收該晶體。 在本發明另一具體實例中，提供一種包含前述晶體之 醫藥品’其中該晶體具有至少95%之純度。 在另一具體實例中，提供一種包含前述晶體及醫藥上 可接受添加物之醫藥組成物。 在另—具體實例中，提供一種治療由C5a與C5a受體 之、° 口所造成之疾病之方法，其中對需要其之個體投予有 效量之前述晶體。 在另—具體實例中，提供一治療由C5a與C5a受體之 了口所造成之疾病之方法，其中該由C5a與C5a受體之妗 合所造成之疾病為下述之_ :自體免疫疾病、敗血症、成 人呼吸碧迫症候群、慢性阻塞性肺部疾病、過敏疾病、動 脈粥狀硬化、心肌梗塞、腦梗塞、牛皮癬、阿兹海默症、 及由缺血再灌注 '創傷、燒傷、外科侵人性手術所造成的 白血球活化所導致的嚴重器官傷害。 在另一具體實例中，提供一種治療發炎之方法，其中 201240985 對需要其之個體投予有效量之包含 在另-具趙實例中，提供一=晶雜之抗炎劑= 法’其中對需要其之個體投予有效量之々療感染性疾病之方 受體拮抗劑。 1含前述晶體之C5a 在另一具體實例中，提供— 法，盆中兮β* 稷化療感染性疾病之方 其中3亥感染疾病為由透過C5a受- 所造成。 體入侵的細菌或病毒 在另一具體實例中，提供一種 太、土#丄 〇療類風濕性關節炎之 方法，其中對需要其之個體投予有 欠之 丁，政里之前述晶體。 物丄另一具體實例中’提供一種預防性及/或治療性藥 此藥物用於由C5a與C5a受體之έ士人 ^ 、 且包含前述晶體。 成之疾病， 此^另—具體實例中，提供—預防性及/或治療性藥物， 此樂物用於由C5a愈^ .〇 、 5a又體之結合所造成之疾病，且嗜 由C5a與C5a受體 人 ^ :、·、σ 口所&成之疾病為下述之一 ··自體 疫疾病、敗血症、成人呼吸窘迫症候群、慢性阻塞性肺 '、病㉟敏疾病、動脈粥狀硬化、心肌梗塞、腦梗塞、 ，癬、阿茲海默症、及由缺血再灌注、創傷、燒傷、外 金又入!生手術所造成的白血球活化所導致的嚴重器官 害0 體 在另-具體實例中，提供—種抗炎劑，其包含前述 曰曰 另’、體實例中，提供一種預防性及/或治療性藥 物此藥物用於感染性疾病，且包含前述晶體。 8 201240985 在另一具體實例中，提供一種預防性及/或治療性藥 物，此藥物用於感染性疾病，其中該感染性疾病為由透過 C5a受體入侵的細菌或病毒所造成導致。 在另一具體實例中，提供一種預防性及/或治療性藥 物，此藥物用於類風濕性關節炎，且包含前述晶體。 在另一具體貫例中，提供一種C5a受體拮抗劑，其包 含前述晶體。 本發明之功效 本發明之晶體於低於6(rc之條件下為穩定的，且具有 對作為醫藥產品之原料藥較佳的性質。此外，本發明之製 造方法可安全地、長久地以工業規模提供本發明之晶體。 以上概述著重於本發明之部分方面。本發明其它目 的、方面和具體實例見於本發明之實施方式。 【實施方式】 參照以下圖式並與下列詳細說明連結，可得到對本發 明更佳之了解，並可輕易獲得對本發明更完整之理解及許 多本發明伴隨的優點。 具體實例之描述 除非特別定義，本文中使用之所有技術及科學術語， 二有與熟習藥學及醫學科學領域者所通常了解者相同之意 義0 彳有與本文中所描述者類似或相等之方法與材料，以 本文中描述之適合的方法和材料，可用於實施或測試本發 201240985 明。 本發明之晶體可藉由1)根據（舉例而說）專利文件2 中描述之方法’當而設定反應溶液之溫度於不低於溶劑之 融點且低於6 0 °C時合成該晶體，2)結晶該化合物，及3)回 收該晶體。結晶之方法並無限制，且可使用如冷卻反應混 合物之溫度、於濃縮反應混合物之後沈積、持續攪拌、加 入晶種或類似者。此外，化合物N-[(l-乙基-1H-吡唑-4-基） 甲基]-5-羥基-N-(6-異丙基吡啶-3-基）_i，2,3,4-四氫萘·ι·醯 胺並不須完全溶解於溶劑中’仍能藉由（舉例來說）將溶 劑加入專利文獻2實施例3所描述之自由晶型〗晶體以得到 懸浮液且於不低於溶劑融點且低於6(rc的溶劑溫度持續攪 拌此懸浮液而製造其晶體。 雖然用於獲得晶體之溶劑溫度之範圍並無特定限制 (只要其為自不低於該溶劑之融點至低於6〇。匚時，以水而 言，較佳其為自不低於至低於6〇t，且更佳其為自不 低於10 C至低於;以有機溶劑而言，通常較佳A為自 不低於-听至低於6代，且更佳其為自不低於低於 雖然製造該晶體可用之溶劑並無特別限制（只要其為 水或具有兩個或以上的碳數之有機溶劑），使用於製造醫 樂產品可接受之溶劑為所欲的。具有兩個或以上的碳數之 有機溶劑意謂組成溶劑之分子 例包含乙醇、乙酸、乙产、丙;有兩個或以上的碳數。其 欠乙猜丙嗣、二甲基甲醯 2-丙醇'“丁醇、2-丁醇、2_甲基_2_丙醇、2_甲基· 10 201240985 乙酸乙醋、1-戊醇、2-Λ隨 . 知、3-戊醇、3 -曱基-1-丁醇、甲基 異丁基酮、己院、甲笨、贫 本甲醚、庚烧及四氫呋喃。於本 文’其較佳例包含乙醇、> 内_、1-丙醇、2 -丙醇、2 -丁醇、 2 -甲基-2-丙醇、乙酸乙酷、，m 3'甲基-1-丁醇、甲苯、苯曱謎、 庚院及四氫°夫喃。此外，介 亦可使用其混合溶劑’舉例來說， 水和乙醇之混合溶劑、乙醆 知和庚烷之混合溶劑及類似者。 本發明因此所知之晶體在粉末χ光繞射圖譜中，於約 4.6° + 02°' 10Q°+ .一 〇·2 、13.2°± 0.2° 及 16.6°± 0.2。的 繞射角20處顯示訊號峰’且進一步的於約1〇 5。土 〇 2。 14’0 ± 〇·2的繞射角2θ處顯示訊號峰。這些訊號峰並 未在專利文獻2實施例3描述之晶體（型j晶體）及實施例 22中描述之晶體（们1晶體）中觀測到。此外，本發明之 晶體在微差掃描熱量法測量中，於⑷七代（外推起始溫 度）及1 7 1 · 1 77〇C (外推起弘、、田谇、老曰+ , 愁始，皿度）處具有吸熱峰。雖然粉 末X光繞射及微差掃描熱量法之測量條件無特定限制，較 佳以本說明書所描述之測量條件進行測量。 -般而言’在晶體之技術領域中，不論晶型為何，粉 末X光繞射圖譜於繞射角20處之訊號峰會根據樣本分析 期間之溫度及相對濕度及樣本中所含水和類似者之量的改 變而變動’且因此’於20處訊號峰值之± 〇.2、變化並不 影響本發明之晶體的鑑定。因此， 心口此本發明不僅包含訊號峰 值完全相符之晶體，亦包含訊號峰值顯示之土 〇2。的差異 者。 、 本說明書所使用之部分術語如以下定義 201240985 預防性藥物」意謂在疾 之藥物，亦即，舉例來說，為 之藥物。 病欲發病前對健康個體投+ 預防疾病發病之目的所招：+ 療性藥物」意謂對醫生診斷已發展為疾病之個骨 (病患）技予之藥物，亦即’舉例來說，以減緩疾病或^ 狀、或回復健康為目的而投予之藥物。當對病患投予藥來 時’即:吏技予之目的為預防疾病或症狀之加重或預防扇 作，該藥物仍為治療性藥物。 結合至C5a受體之物質」意謂C5a、C5a*解產物（例 如C5a desArg ’其巾C5a幾基端之精胺酸已被移除）、及 (除C5a以外）對⑸受體具有親合性之已知或未知之物 質。 C5a文體拮抗劑」為抑制C5a受體與「結合至C5a 受體之物質」結合之物質。 「&受體括抗作用」意謂藉由「結合至C5a受體之物 質」透過C5a又體與表j見C5a受體之細胞之結合抑制造成 某些生理變化（例如細胞内Ca2 +增加及類似者）之反應的 作用。 本發明之晶體可以純化的及/或經分離的形式使用。於 本發明之—具體實例中，㈣「純的」或「純化的」意謂 基於在-經分離晶體混合物中所發現之目標晶體之總質量 至少具50〇/〇純度。另外，於本發明之該具體實例中，「純 的」或「純化的」進一步涵蓋以下範圍：至少6〇% '至少 70/〇至夕75/〇、至少8〇%、至少85%、至少9〇〇/〇、至少 12 201240985 %%、至少98%、至少99%、及至少w 本發明呈晶型之化合物顯示〜受體拮抗作用 用於作為預防或治療由C5a#…受體之結 病的藥物，該疾病舉例來說為， ^之疾 濕性嶋、全身性紅斑狼瘡、與類似者、敗血症、：： 呼吸奢迫症候群、慢性阻塞性肺部疾病、過敏性疾病 如氣喘與類似者、動脈粥狀硬化、讀塞、腦梗塞^ 癣、阿兹海默症、由缺血再灌注、創冑、燒傷、外科侵入 性手術及類似者所造成的白▲球活化所導致的嚴重琴 害（例如肺炎、腎炎、肝炎、騰臟炎及類似者）、與類似 者。於本文’自體免疫疾病之較佳例子包含類風濕性關節 炎。因⑸具有強烈的發炎誘導作用，本發明呈晶型之化 合物可用於作為抗發炎劑’且進—步的’作為預防及/或治 療由透過C5a受體人侵的細菌或病毒所造成之感染性疾病 之的藥物。 當本發明呈晶型之化合物作為前述之預防性及/或治療 性藥物使用時’其通常以全身性或局部性且^服或非經腸 投予有效量。給予病患之劑量根據年紀、體重、性別、一 般健康狀況 '療效、飲食、投予時間、投予方法、清除率、 藥物的組合、治療下之疾病狀況及類似者而變化。成人以 口服投予-日-至數次每劑自〇.lmg至5〇〇mg之範圍，或 成人以非經腸投予（較佳為靜脈内投予）_日一至數文每 劑自〇·〇1 mg至200 mg之範圍通常是所欲的。劑量根^ 患之狀況適當地增加或減少更是所欲的。 201240985 枣發明呈晶型之 -小，、瓜/切驭眾劑（例 如粉末、顆粒、錠劑、丸劑、膠囊、糖漿、馳劑、懸浮液、 溶液及類似者，其中至少一本發明呈晶型之化合:可單獨 使用或於摻加醫藥上可接受之載劑（賦型劑、黏合劑、崩 解劑、矯正劑（COrrigent)、矯味劑（c〇rrective) '乳化 劑、稀釋劑及/或助溶解劑及類似者）後㈣）口服或㈣ 腸（舉例而言，藉由吸入、直腸投予、局部投予及類似者 使用。 醫藥組成物可根據一般方法製備。在本說明書中，藉 由非經腸的係意謂皮下注射、靜脈内注射、肌肉内注射： 腹膜内注射、點滴及類似者。注射用之組成物，諸如注射 用無菌懸浮液和油懸浮液，可根據技術領域中已知之方法 使用適合的分散劑、潤濕劑、或懸浮劑製備。 口服投予用之固體组忐铷夕香&认 ’ 貫例為鍵劑、丸劑、膠囊' 粉末、顆粒及類似者。於上述 K固體組成物中，一或多種 活性化合物可與至少一種添加劑混合。 此外，上述組成物可進一步包含 _ L 3请如潤滑劑、防腐劑、 抗氧化劑'崩解劑、穩定劑、助 助/合解劑、黏合劑、增稠劑、 甜味劑、風味劑、香料及類似者之添加劑。 當必要時，錠劑和丸劑可 ^ 愛佈上月可溶解或腸道材料 之薄膜，或可塗佈二或多層。 口服投予用之液體組成物肖 ^ x奶包含醫樂上可接受之溶液、 乳劑、糖漿、驰劑及類似者， 雜由， 且可含有常用不具活性之稀 釋劑。此組成物除了不具活性 注之稀釋劑以外，可包含助劑， 14 201240985 *‘、、、’門齊i、懸浮劑、及類似者、增甜劑、風味劑、香料 及防腐劑。其他用於口服投予之組成物為（舉例而言）包 含-或多種活性物質且以本身已知的方法製造之噴劑。 非經腸投予用之注射之組成物可包含無菌之水或非水 溶液、懸浮液及乳劑。上述之組成物可進-步包含助劑， ^ 冑齊丨’閏濕劑、乳化劑、分散劑、穩定劑及助溶解 劑。此等可藉由f無a, γ 、 稭由C舉例而言）通過滯留細菌之濾器過濾、 加入殺菌劑或照射而殺菌。 t射用之組成4勿亦可藉由製造無菌m组成物並在 使用刖命冑（舉例而言’於無菌水或注射用無菌溶劑中的 凍乾之產物）而使用。 其他非經腸投予用之組成物包含外用溶液、軟膏、擦 齊J栓劑及類似者’其包含一或多種活性物質且以傳統方 法調配。 直腸投予用之栓劑可藉由將該藥物摻與適合的非刺激 t生媒劑（諸如周圍溫度下為固體、但於腸道溫度下顯示液 體性質、且於直腸内融解以釋放該藥物的物質）以製造。 實施例 本發明藉由參考非限制性之實施例及實驗實施例而於 以下更明確地解釋’該等實施例不應被認定為不適當地限 制本發明。 實施例1 :本發明晶體之製造方法（i) 向根據專利文獻2實施例3描述之方法合成之 15 201240985 (lS)-(-)-N-[(l -乙基 _1H-0比唾 基。比啶-3-基）-l,2,3,4-四氫萘-1 ，比唑-4-基）甲基]_5_羥基_N_(6_異丙Therefore, when 201240985 uses crystalline materials as an active ingredient in pharmaceuticals, the twin system is intended to be homogeneous, pure, and more stable. In order to ensure consistent efficacy and side-effect performance, for pharmaceutical applications: salty to obtain a single and stable crystal of the compound. Salt also wants to mention: It is safe and effective to provide the manufacturing method of the Japanese carcass in a safe and sturdy manner. Solution to the problem After the research and development of the present compound, N [(1_ethyl_1H_pyrazole-cardio)methyl]·5-carbyl-N-(6-isopropylpyridine_3_yl) )], the novel crystal of 2,3,4_tetrahydronaphthalene-diazolamine was isolated. This novel crystal has been shown to be more stable than conventionally known crystals. Further, the novel crystal has been found to be selectively produced in a uniform crystal form by crystallization using water or an organic solvent having two or more carbon numbers, and the solvent temperature is never lower than the melting point of the solvent. Not higher than 60 °C. In a specific embodiment of the present invention, (13) _(·)·Ν_[(iethyl]h_ is more than 4-yl)methyl]-based Ν-(6-isopropyl D-bit _3_ base is provided a crystalline form of 1,2,3,4-tetrahydronaphthalen-1-anthracene, wherein the crystal is at least about 4.6 in a powder calender diffraction pattern. ± 0.2. '1〇.9. ± 〇_2. 13.2. ± 〇 2. And 16.6. ± 0.2. The diffraction angle 2θ has a signal peak. In one embodiment, the crystal is at least about 10.5 in the powder calender diffraction pattern. ± 〇_2. And 14.0. ± 0.2. The diffraction angle 20 has a signal peak. The crystal has an endothermic peak at i 43_丨49 (extrapolation onset temperature) and 171-1771 (extrapolation onset temperature) in the differential scanning calorimetry measurement. 6 201240985 In addition, the crystal may have the following physical and chemical properties of A and/or B: a is a signal peak having a powder X-ray diffraction pattern as shown in FIG. 1, and B is a differential scanning as shown in FIG. Thermal method curve. In a specific embodiment of the present invention, there is provided a method of producing the aforementioned crystals wherein the solvent temperature is set to fall from a melting point of not less than water or an organic solvent having two or more carbon numbers to less than 60 ° C. Within the range, formed; contained in water or the organic solvent (lS)-(-)-N-[(l-ethyl-1H-pyrazolyl)methyl]-5-pyridyl_N_(6_ Isopropylpyridine-3-yl)_1,2,34-tetrahydronaphthalene_1, alanine crystal, and the crystals were recovered. In another embodiment of the present invention, there is provided a pharmaceutical product comprising the foregoing crystals wherein the crystal has a purity of at least 95%. In another embodiment, a pharmaceutical composition comprising the foregoing crystals and a pharmaceutically acceptable additive is provided. In another embodiment, a method of treating a disease caused by the C5a and C5a receptors is provided, wherein an effective amount of the aforementioned crystal is administered to an individual in need thereof. In another embodiment, a method of treating a disease caused by the C5a and C5a receptors is provided, wherein the disease caused by the combination of the C5a and C5a receptors is as follows: autoimmune Disease, sepsis, adult respiratory syndrome, chronic obstructive pulmonary disease, allergic disease, atherosclerosis, myocardial infarction, cerebral infarction, psoriasis, Alzheimer's disease, and ischemia, reperfusion, trauma, burns, Severe organ damage caused by white blood cell activation caused by surgical invasive surgery. In another embodiment, a method of treating inflammation is provided, wherein 201240985 comprises an effective amount to an individual in need thereof, and is provided in another example, providing an anti-inflammatory agent of the formula = method The individual is administered an effective amount of a receptor antagonist for the treatment of an infectious disease. 1 C5a containing the aforementioned crystals In another specific example, the method of providing 兮β* 稷 chemotherapy for infectious diseases in a pot is caused by the passage of C5a. Invasive Bacteria or Virus In another embodiment, a method for treating rheumatoid arthritis is provided, wherein the individual in need thereof is administered with the aforementioned crystals. In another embodiment, the present invention provides a prophylactic and/or therapeutic drug which is used by a gentleman of the C5a and C5a receptors, and which comprises the aforementioned crystals. In the case of the disease, in the specific example, a prophylactic and/or therapeutic drug is provided, which is used for the disease caused by the combination of C5a, 5, 5a and body, and is susceptible to C5a and C5a receptors ^ :, ·, σ 口所& The disease is one of the following: · Autoimmune disease, sepsis, adult respiratory distress syndrome, chronic obstructive pulmonary ', disease 35 sensitive disease, atherosclerosis Sclerotherapy, myocardial infarction, cerebral infarction, sputum, Alzheimer's disease, and severe organ damage caused by ischemia-reperfusion, trauma, burns, and extra-gold! The activation of white blood cells caused by surgery is another In a specific example, an anti-inflammatory agent is provided, which comprises the aforementioned sputum, and provides a prophylactic and/or therapeutic drug for use in an infectious disease, and comprises the aforementioned crystal. 8 201240985 In another embodiment, a prophylactic and/or therapeutic drug is provided for use in an infectious disease caused by a bacterium or virus invaded by a C5a receptor. In another embodiment, a prophylactic and/or therapeutic drug is provided for use in rheumatoid arthritis and comprising the aforementioned crystals. In another specific example, a C5a receptor antagonist is provided which comprises the aforementioned crystals. EFFECTS OF THE INVENTION The crystal of the present invention is stable under conditions of less than 6 (rc) and has properties preferable for a drug substance as a pharmaceutical product. Further, the production method of the present invention can be industrially safely and permanently The above summary is focused on some aspects of the invention. Other objects, aspects and specific examples of the invention are found in the embodiments of the invention. A better understanding of the present invention, as well as a more complete understanding of the present invention, and many of the advantages of the present invention will be readily obtained. The description of the specific examples, unless otherwise defined, all the technical and scientific terms used herein, and are familiar with pharmacy and medical science. Those skilled in the art will generally appreciate that the methods and materials that are similar or equivalent to those described herein can be used in the practice or testing of the methods and materials described herein. The crystal can be set by 1) according to the method described in the patent document 2 (for example) The solution temperature should be not lower than the melting in the point of the solvent and lower than the crystal synthesized when 6 0 ° C, 2) of the crystalline compound, and 3) recovering the crystals. The method of crystallization is not limited, and a temperature such as cooling of the reaction mixture, deposition after concentration of the reaction mixture, continuous stirring, addition of seed crystals or the like can be used. Further, the compound N-[(l-ethyl-1H-pyrazol-4-yl)methyl]-5-hydroxy-N-(6-isopropylpyridin-3-yl)_i, 2, 3, 4 - tetrahydronaphthalene·methaneamine does not have to be completely dissolved in the solvent'. It is still possible to obtain a suspension by, for example, adding a solvent to the free crystal form crystal described in Example 3 of Patent Document 2 to obtain a suspension. No less than the melting point of the solvent and less than 6 (the solvent temperature of rc is continuously stirred to produce crystals thereof. Although the range of the solvent temperature for obtaining the crystal is not particularly limited (as long as it is not lower than the solvent) The melting point is less than 6 〇. When 匚, in terms of water, it is preferably from not less than less than 6 〇t, and more preferably it is not less than 10 C to below; In general, it is preferred that A is not lower than - heard to be lower than 6 generations, and more preferably it is not lower than lower than the solvent which is usable although the solvent is used (as long as it is water or has two Or an organic solvent having a carbon number as described above, and a solvent acceptable for use in the manufacture of a medical product is desirable. An organic solvent having two or more carbon numbers means a molecular example comprising a solvent. Ethanol, acetic acid, ethyl acetate, C; there are two or more carbon numbers. It is a B-propion, dimethylformam-2-propanol 'butanol, 2-butanol, 2-methyl-2 _propanol, 2_methyl· 10 201240985 Acetate, 1-pentanol, 2-indole, 3-pentanol, 3-mercapto-1-butanol, methyl isobutyl ketone, In the present case, the preferred examples include ethanol, > internal, 1-propanol, 2-propanol, 2-butanol, 2-methyl- 2-propanol, ethyl acetate, m 3 'methyl-1-butanol, toluene, benzoquinone, Gengyuan, and tetrahydrofuran. In addition, the medium can also be used as a mixed solvent 'for example, A mixed solvent of water and ethanol, a mixed solvent of acetamidine and heptane, and the like. The crystal thus known in the present invention is in a powder calender diffraction pattern at about 4.6 ° + 02 ° ' 10 Q ° + . · 2, 13.2 ° ± 0.2 ° and 16.6 ° ± 0.2. The diffraction angle 20 shows the signal peak 'and further about 1 〇 5. The soil 〇 2. 14'0 ± 〇 · 2 diffraction angle 2θ Display signal peaks. These signal peaks are not crystals described in Example 3 of Patent Document 2. The crystal of the type j) and the crystal described in Example 22 (the crystal of one) are observed. In addition, the crystal of the present invention is measured by the differential scanning calorimetry in (4) seven generations (extrapolation onset temperature) and 17 1 · 1 77〇C (external push from Hong, Tian, and Lao, +, beginning, dish) has an endothermic peak. Although there are no specific restrictions on the measurement conditions of powder X-ray diffraction and differential scanning calorimetry, Preferably, the measurement is performed under the measurement conditions described in the present specification. - Generally speaking, in the technical field of crystals, regardless of the crystal form, the signal peak of the powder X-ray diffraction pattern at the diffraction angle 20 is based on the sample analysis period. The temperature and relative humidity and the change in the amount of water and the like in the sample vary 'and thus' ± at the peak of the signal at 20, and the change does not affect the identification of the crystal of the present invention. Therefore, the present invention encompasses not only the crystal whose signal peak value is completely matched, but also the soil peak of the signal peak display. The difference. Some of the terms used in this specification are as defined below. 201240985 "Preventive drugs" means drugs in the case of diseases, that is, for example, drugs. For the purpose of preventing the onset of disease before the onset of the onset of illness: + Therapeutic drugs means "drugs for the diagnosis of a bone (patient) that has developed into a disease, that is, for example, A drug that is administered for the purpose of slowing down a disease or a disease, or returning to health. When a drug is administered to a patient, the drug is still a therapeutic drug for the purpose of preventing the disease or the aggravation of the disease or preventing the fan. "Substance bound to C5a receptor" means C5a, C5a* decomposed products (eg C5a desArg 'the arginine at the basal end of C5a has been removed), and (except C5a) have affinity for (5) receptor A substance known or unknown. The C5a Sterling Agent is a substance that inhibits the binding of the C5a receptor to a substance that binds to the C5a receptor. "&Resistance" means that certain physiological changes (such as intracellular Ca2+ increase) are caused by inhibition of binding of C5a to cells of the C5a receptor by "substance bound to the C5a receptor". And the effect of the reaction). The crystals of the invention may be used in purified and/or isolated form. In the present invention, (4) "pure" or "purified" means having a total mass of at least 50 Å/〇 based on the total mass of the target crystals found in the separated crystal mixture. In addition, in this embodiment of the invention, "pure" or "purified" further encompasses the following range: at least 6〇% 'at least 70/〇 to 75/〇, at least 8%, at least 85%, at least 9〇〇/〇, at least 12 201240985%%, at least 98%, at least 99%, and at least w. The crystalline form of the compound exhibits ~receptor antagonism for use as a prophylaxis or treatment by a C5a#...receptor The disease drug, for example, is a disease of phlegm, systemic lupus erythematosus, and the like, sepsis,:: respiratory motility syndrome, chronic obstructive pulmonary disease, allergic diseases such as asthma and the like , atherosclerosis, occlusion, cerebral infarction, sputum, Alzheimer's disease, severe sputum activation caused by ischemia, reperfusion, trauma, burns, surgical invasive surgery, and the like Psychic damage (such as pneumonia, nephritis, hepatitis, visceral inflammation and the like), and the like. Preferred examples of autoimmune diseases herein include rheumatoid arthritis. Since (5) has a strong inflammatory inducing effect, the compound of the present invention in a crystalline form can be used as an anti-inflammatory agent 'and as an anti-inflammatory agent' as an agent for preventing and/or treating infection caused by bacteria or viruses invaded by a C5a receptor. Drugs for sexual diseases. When the compound of the present invention is used as a prophylactic and/or therapeutic drug as described above, it is usually administered in an amount effective or systemically and parenterally or parenterally. The dose administered to a patient varies according to age, weight, sex, general health status, efficacy, diet, time of administration, method of administration, clearance rate, combination of drugs, disease condition under treatment, and the like. Adults are administered orally - daily - to several times per dose from the range of .1 mg to 5 mg, or adults are administered parenterally (preferably intravenously) - one to several times per dose 〇·〇1 mg to 200 mg range is usually desirable. It is more desirable to appropriately increase or decrease the condition of the dose. 201240985 Jujube invention is a crystalline, small, melon/cutting agent (such as powder, granules, tablets, pills, capsules, syrups, granules, suspensions, solutions and the like), at least one of which is crystallized Combination of the formula: can be used alone or in combination with a pharmaceutically acceptable carrier (excipient, binder, disintegrant, correcting agent (COrrigent), flavoring agent (c〇rrective) 'emulsifier, diluent and / or cosolvents and the like) (4)) Oral or (4) Intestines (for example, by inhalation, rectal administration, topical administration, and the like. The pharmaceutical composition can be prepared according to a general method. In this specification By parenteral means subcutaneous injection, intravenous injection, intramuscular injection: intraperitoneal injection, drip and the like. Compositions for injection, such as sterile suspensions for injection and oil suspensions, according to the technique Methods known in the art are prepared using suitable dispersing agents, wetting agents, or suspending agents. Oral administration of solid group E. sinensis & amps are examples of bonding agents, pills, capsules, powders, granules and the like. .to In the K solid composition, one or more active compounds may be mixed with at least one additive. Further, the above composition may further comprise _L 3 such as a lubricant, a preservative, an antioxidant 'disintegrant, a stabilizer, a helper. Additives, binders, thickeners, sweeteners, flavors, flavors, and the like. When necessary, tablets and pills can be used to dissolve the film of the last month or the intestinal material, or It can be applied in two or more layers. The liquid composition for oral administration includes milk, a solution, an emulsion, a syrup, a granule and the like, and may contain a commonly used non-active diluent. In addition to the diluent which is not active, this composition may contain adjuvants, 14 201240985 *',,, 'doors, suspensions, and the like, sweeteners, flavors, flavors, and preservatives. Others The composition for oral administration is, for example, a spray comprising - or a plurality of active substances and produced by a method known per se. The composition for injection for parenteral administration may comprise sterile water or non-aqueous Aqueous solution Floats and emulsions. The above-mentioned composition may further comprise an auxiliary agent, a hydrazine, a emulsifier, a dispersing agent, a stabilizer and a solubilizing agent. These may be a, γ, The straw is sterilized by, for example, C) filtration through a filter for retaining bacteria, addition of a bactericide or irradiation. The composition of the t-ray 4 can also be used by making a sterile m composition and using a sputum hydrazine (for example, a lyophilized product in sterile water or a sterile solvent for injection). Other compositions for parenteral administration include topical solutions, ointments, rubs, and the like which contain one or more active substances and are formulated in a conventional manner. A suppository for rectal administration can be prepared by incorporating the drug with a suitable non-irritating t-agent (such as a solid at ambient temperature but exhibiting liquid properties at intestinal temperature and melting in the rectum to release the drug). Material) to manufacture. EXAMPLES The present invention is more specifically explained below by reference to the non-limiting examples and experimental examples. The examples should not be construed as unduly limiting the invention. Example 1: Method for producing crystal of the present invention (i) 15 synthesized according to the method described in Example 3 of Patent Document 2 201240985 (lS)-(-)-N-[(l-ethyl_1H-0 is more than saliva Bispin-3-yl)-l,2,3,4-tetrahydronaphthalene-1, bisazol-4-yl)methyl]_5_hydroxy_N_(6_isopropyl
且授拌混合物8分鐘以使白色固體結晶。 1 水（12 · 6 m 1 )， 。確認固體，並於 15°C下撥拌混合物2小時。加熱至2(rc後㈣混合物i小 時，冷卻至12°C並攪拌丨小時，於1(rc下，於5小時中逐 滴加入水（81.4 ml )，並於同樣溫度攪拌混合物丨5小時。 過慮懸浮液，以從乙醇（10.0 ml )及水（20 〇 ml )製備之 溶液洗滌固體，且於減壓下於45。〇乾燥16小時而獲得呈晶 體（純度99.97% ,光學純度100%ee)之白色固體（19 6 g)。 使獲得之晶體在以下條件下接受粉末X光繞射（XRD ) 分析： 儀器.RINT-TTR III (Rigaku Corporation) 條件： X光真空管：Cu 電流：300 mA 電壓：50 kV 掃描速度：2°/min 掃描範圍：2 Θ = 2-40。 粉末X光繞射圖樣顯示於圖1，且當於16。的繞射角2 0之訊號峰強度定為1 〇〇時，有相對強度不低於1 5之訊號 峰’及其相對強度顯示於表1。 16 201240985 表1 2Θ(°) 相對強度 4.6 73 10.5 15 10.9 26 13.2 21 14.0 17 16.3 67 16.6 100 17.3 59 18.1 27 18.7 40 20.2 53 21.1 43 22.5 59 24.3 17 24.6 33 25.3 25 25.6 32 26.0 21 28.8 15 實施例1獲得之晶體之特徵訊號峰於繞射角2 0處為 4.6°、10.5°、10.9°、13.2°、14.0° 及 16.6° (分別 ± 0.2°)。 這些特徵峰並未於型I晶體及型II晶體中觀測到，且因此， 實施例1所獲得之晶體為（lS)-(-)-N-[(l-乙基-1H-。比唑-4-基） 17 201240985 甲基]-5-經基-N-(6-異丙基吡咬_3_基…，认四氫萘小醯 胺之一種新穎晶體。 接著’將實施例i所得之晶體（1.59叫）放置於微差 掃描熱量計DSC· i ( METTLER_T〇LED〇製），並於代— 的掃描上升速度下測量（25·3崎、乾燥氮氣则紅―、 紹槽室容m。結果，於145X:(外推起始溫度）發現第一 炫解峰，且於148〇c發現第一炼解峰之最大峰高。此外，於 觀察第-料峰後’觀察到與轉變成M !晶體相關之吸孰 峰’且進-步的，於176t (外推起始溫度）觀測到型工晶 體之溶解峰。微差掃描熱量法（DSC)曲線顯示於圖2。 實驗實施例1 :晶體之穩定度測試（i) 將型I晶體、型II晶體及根據上述實施例丨描述之方 法所得之晶體之三種晶體各自放置於樣品瓶中，且開放保 存於4〇t/75Q/„RH。結果，型j晶體及根據上述實施例t描 述之方法所得之晶體即使在六個月過後仍無改變。然而， 型II晶體於八天後轉變成型ί晶體（見圖3_5 ) 此結果展不根據上述貫施例1描述之方法所於得之本 發明之晶體，即使於4(TC /75%RH的條件下保存六個月後仍 沒有轉變成不同晶體，且與型II晶體相比於長期保存下具 有更優越的穩定度。 實驗實施例2及實施例2 :晶體之穩定度測試（2)及本 發明晶體之製造方法（2) 18 201240985 將水（6 ml)加入型I晶體（1 g)，日 混合物。攪拌2。小時後，收集一部二 的晶體在類似於實施例1之條件下接典# "使濕 - γ . A ，、下接又粉末X光測量。 中扩述方 '’’圖樣比較’型1晶體部分轉變為實施例1 所得之晶體。本發明呈晶型之化合物可用於作 樂…活性成分。-般而言，f藥品被調配成製劑 及於市場上配售，而水大多用於饭成展劑 夕用於調配步驟期間。 因此，當型1晶體作為活性成分使用時，於調配步驟其 間可能發生部分之晶體轉換，此轉換可能導致功效及副作 用的表現m而可能導致無法預期之情況。另一方 面’本發明之晶體作為活性成分使㈣，如此問題可以被 壓制，且可獲得更均勻的製劑。 實驗實施例3及實施例3:晶體之穩定度測試（3)及本 發明晶體之製造方法（3) 將根據上述實施例1描述之方法所獲得的晶體及型1 晶體加入溶劑中，將混合物攪拌至懸浮液狀態。其後，收 集部分懸浮液，使懸浮液中之晶體在類似於實施例丨之條 件下接受粉末X光測量。加入溶劑之晶體重量、使用之溶 劑、溶劑之溫度及攪拌時間如表2所示。結果如表4所示。 表2 溶劑 晶 溫度 攪拌時間 乙醇4 ml 每種1.5 g 50°C 1.5小時 乙醇4 ml 每種3.5 g 70°C 1.5小時 乙醇3 ml +水1 ml 每種2.5 g 50°C 1.5小時 19 201240985 乙醇1.5 ml + 水 0.5 ml 每種2.0 g 60°C 1.5小時 乙醇1 ml +水3 ml 每種0.5 g 50°C 1.5小時 乙醇1 ml +水3 ml 每種2.0 g 60°C 1.5小時 乙醇0.5 ml + 水 1.5 ml 每種0.5 g 65 °C 1.5小時 乙醇4 ml 每種0.8 g 10°C 1.5小時 乙醇3 ml +水1 ml 每種0.8 g 10°C 1.5小時 乙醇1 ml +水3 ml 每種0.5 g 10°C 1.5小時 水2 ml 每種0.25 g r.t. 1.5小時 丙酮1 ml 每種0.25 g r.t. 1.5小時 曱醇1.5 ml 每種0.25 g r.t. 1.5小時 甲酸1 ml + 水1 ml 每種0.5 g r.t. 1.5小時 苯甲醛1.5 ml 每種0.25 g r.t. 1.5小時 2-丁醇 2 ml 每種0.25 g r.t. 1.5小時 3-甲基-1-丁醇2 ml 每種0.25 g r.t. 1.5小時 庚烧3 ml 每種0.25 g 50°C 6.5小時 甲苯2 ml 每種0.25 g 50°C 1小時 2-曱基-2-丙醇2 ml 每種0.25 g 50°C 1小時 乙醇0.5 ml + 庚炫0.5 ml 每種0.25 g 50°C 1小時 1·丙醇1 ml + 庚烧1 ml 每種0.25 g 50°C 1小時 2-丙醇1 ml + 庚烧1 ml 每種0.25 g 50°C 1小時 2-丁醇 1 ml + 庚烧1 ml 每種0.25 g 50°C 1小時 2-甲基-2丙醇1 ml + 庚烧1 ml 每種0.25 g 50°C 1小時 3-曱基-1-丁醇 1 ml + 庚院1 ml 每種0.25 g 50°C 1小時 四氫呋喃1 ml + 庚烧1 ml 每種0.25 g 50°C 1小時 乙酸_乙酯1 ml + 庚烧1 ml 每種0.25 g 50 V 1小時 (表2中「r.t·」意謂室溫） 另外，當將表3所示之混合溶劑維持於70°C時，將根 20 201240985 據上述實施例1描述之方法所獲得的晶體及型Γ晶體（分別 為250 mg )加入混合溶劑中，且攪拌混合物5分鐘至懸浮 液狀態。收集40至60 “ ！之懸浮液，使懸浮液中之晶體在 類似於實施例1之條件下接受粉末χ光測量。此外，在剩 餘懸浮液之溫度確定達到6〇r後，進一步加入根據上述實 施例1描述之方法所獲得的晶體（5至丨〇 mg )，且維持懸 浮液温度於60°C下攪拌混合物10分鐘。收集4〇至 之懸浮液，使懸浮液中之晶體在類似於實施例丨之條件下 接受粉末X光測量。此外，將根據上述實施例丨描述之方 法所獲得的晶體（大約20 mg )進一步加入剩餘之懸浮液’ 維持懸浮液溫度於6(TC下攪拌混合物1小時且於室溫下授 拌過夜。而後，使懸浮液中之晶體在類似於實施例1之條 件下接受測量。結果如表4所示。 表3 乙醇0.5 ml +庚院0.5 ml 2- 丁醇 0.5 ml + 庚烷 0.5 ml 3- 甲基 1-丁醇 10.5 ml + 庚烷 0.5 ml 乙酸乙醋0.5 ml +庚烧0.5 ml 21 201240985 寸啭 70°C 1 x (型 I) 1 1 1 1 1 1 1 1 1 1 1 X (型 I) 1 1 X (型 I) 1 X (型 I) 1 X (型 I) 65〇C 1 1 1 X (型 I) 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 60°C 1 1 X (型 I) X (型 I) 1 1 1 1 1 1 1 1 1 X (型 I) 1 1 X (型 I) 1 X (型 I) 1 X (型 I) 50°C 1 〇 〇 〇 1 1 1 1 1 1 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 〇 1 1 1 〇 X (型 II) X (型 II) 〇 〇 〇 1 1 1 〇 1 1 〇 1 〇 1 〇 10°C 1 〇 〇 〇 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 乙醇 75%乙醇水溶液 25%乙純水溶液 丙酮 甲醇 50%甲酸水溶液 苯曱醛 2-丁醇 3-曱基-1-丁醇 庚烧 ί4 ¢- 2-曱基-2-丙醇 乙醇/庚烷 1-丙醇/庚烷 2-丙醇/庚烷 2-丁醇/庚烷 2-甲基-2-丙醇/庚烷 3-甲基-1-丁醇/庚烷 四氫呋喃/庚烷 乙酸乙酯/庚烷 -nngs#艏琮某贺采χ+4傘忘匣羿韜吨ΙΙ1Η铽玫鹚ΙΓΦ9「(II到)X」< 韜<銮#艏琮茶^βχχ-条客Isl要nmsM刹铼杷*晚靶踩艄「(I别) X」*韜吨忘#餒m^^-^x-K龕《匣羿韜<》改鹚茫丧柃^:靖锶^1军嫜駟^^鳍塔破杯砘瞭鹚輮艄「〇」*賴榈鰥艄「.1」」-+寸<咩 ττ 。^茛^刼<輮裥「-」叫 201240985 此等結果清楚地展示當該化合物用具有碳數丨之溶劑 (諸如甲醇、甲酸及類似者）結晶時，僅得到型π晶體； 當該化合物用水或具有碳數2或以上之有機溶劑、於不低 於60。(：之條件下結晶時’僅得到型！晶體；且當該化合物 用水或具有碳數2或以上之有機溶劑、於不低於溶劑融點 且低於60 C之條件下結晶時，僅選擇性地獲得本發明曰 體。一般而言，當溶劑溫度增加時固體之溶解度變高。因 此，為以高產率獲得晶體，結晶較佳係於低溶劑溫度進行。 另外，當製造工人面臨接觸高溫溶劑時，工人可能受傷（例 如！傷等）。為確保製造工人們之安全，溶劑溫度較佳為 低。為了單獨（即不含其他晶體）製造純的型r晶體，溶劑 溫度需不低於6(TC。為了以經分離的及/或純的形式製造本 發明之晶體，可使用較低溫度溶劑。因此，本發明之晶體 相比於型I晶體可較安全地且有效率地製造。另外，因相比 於型I晶體，本發明之晶體於室溫下更穩定，且於調配步: 及類似者期間不轉變為其他晶體，故其易於掌握且作為 料醫藥產品具有優異性質。 ‘ ” 產業利用性 因本發明之晶體於低於6(rc條件下穩定且不轉變成其 他曰曰體，相比於其他先前已鑑定之晶體可用作為醫藥產: 之原料藥。另外，本發明之製造方法可並安全地、有效: 並選擇性地選擇性製造本發明之晶體。 i 本發明之上文敘述提供製造及使用其之方法及製程 使任何所屬技術領域_具有通常知識者可以製、Α 衣k且使用 23 201240985 其，此可據以實施性牲 i色性特別針對所附之申請專 成原始敘述之一部分π μ 1 图（具構 刀）之禚的提供。用於本文，片語^ 自由…所組成之群 「 。 ' 選自」及類似者包含指定物之混 合物。當本文提及數傕HP生 值限制或範圍時，包含端點。另外， 視同明確記載，一邀插PP庄丨 数值限制或範圍内的所有值與子範圍皆 被明確地涵蓋。 本申請案係基於美國臨時申請案第61/437,949號該 臨時申請案全文以引用方式納入本文中。 【圖式簡單說明】 圖1顯示本發明晶體之粉末X光繞射圖樣。 圖2顯示本發明晶體之微差掃描熱量法（DSC)之結果。 圖3顯示專利文獻2實施例3描述之晶體（型I晶體） 經保存前及保存後之粉末X光繞射圖樣，保存條件為於4〇 C /75〇/〇RH六個月，其中縱軸顯示強度（cps )。 圖4顯示專利文件獻2實施例22所描述之晶體（型II 明體）經保存前、保存1天、3天及8天後之粉末X光繞射 圖樣’保存條件為於4(TC /75%RH 8天；及專利文獻2實施 例3描述之晶體（型I晶體）之粉末X光繞射圖樣，其中 縱軸顯示強度（CPS )。 圖5顯示本發明之晶體經保存前後之粉末X光繞射圖 樣’保存條件為於4〇。〇 /75〇/〇RH六個月，其中縱軸顯示強度 (CPS) 〇 24 201240985 【主要元件符號說明】 無 25The mixture was stirred for 8 minutes to crystallize the white solid. 1 water (12 · 6 m 1 ), . The solid was confirmed and the mixture was stirred at 15 ° C for 2 hours. After heating to 2 (rc) (4) mixture for 1 hour, cooled to 12 ° C and stirred for 1 hour, water (81.4 ml) was added dropwise at 1 (rc) over 5 hours, and the mixture was stirred at the same temperature for 5 hours. The suspension was washed, and the solid was washed with a solution prepared from ethanol (10.0 ml) and water (20 〇ml), and dried under reduced pressure at 45 〇 for 16 hours to obtain crystals (purity: 99.97%, optical purity 100% ee). White solid (19 6 g). The obtained crystal was subjected to powder X-ray diffraction (XRD) analysis under the following conditions: Instrument. RINT-TTR III (Rigaku Corporation) Condition: X-ray vacuum tube: Cu current: 300 mA Voltage: 50 kV Scanning speed: 2°/min Scanning range: 2 Θ = 2-40. The powder X-ray diffraction pattern is shown in Figure 1, and the signal peak intensity at the diffraction angle of 20 is set to 1 When 〇〇, the signal peaks with relative strength not less than 15 and their relative intensities are shown in Table 1. 16 201240985 Table 1 2Θ(°) Relative strength 4.6 73 10.5 15 10.9 26 13.2 21 14.0 17 16.3 67 16.6 100 17.3 59 18.1 27 18.7 40 20.2 53 21.1 43 22.5 59 24.3 17 24.6 33 25.3 25 25.6 32 26.0 21 28.8 15 The characteristic peaks of the crystals obtained in Example 1 are 4.6°, 10.5°, 10.9°, 13.2°, 14.0° and 16.6° (± 0.2° respectively) at the diffraction angle of 20 0. These characteristic peaks are Not observed in the Form I crystal and the Form II crystal, and therefore, the crystal obtained in Example 1 was (lS)-(-)-N-[(l-ethyl-1H-.pyrazol-4-yl) 17 201240985 methyl]-5-carbyl-N-(6-isopropylpyridyl_3_yl..., a novel crystal of tetrahydronaphthalene berbamine. Next, the crystal obtained in Example i 1.59)) placed in the differential scanning calorimeter DSC·i (METTLER_T〇LED〇), and measured at the scanning ascending speed of the generation (25·3, dry nitrogen, red –, and the volume of the chamber). At 145X: (extrapolation onset temperature), the first peak is found, and the maximum peak height of the first refining peak is found at 148 〇c. In addition, after observing the first peak, 'observed and converted to M! The crystal-related absorption peak' and the step-by-step, the dissolution peak of the shape crystal was observed at 176t (extrapolation onset temperature). The differential scanning calorimetry (DSC) curve is shown in Fig. 2. Experimental Example 1: Crystal Stability Test (i) Three crystals of the crystal obtained by the type I crystal, the type II crystal, and the method described in the above Example 丨 were each placed in a sample vial and kept open at 4 〇t /75Q/„RH. As a result, the crystal of the type j and the crystal obtained by the method described in the above Example t did not change even after six months. However, the type II crystal was transformed into a crystal after eight days (see Fig. 3_5). This result shows that the crystal of the present invention obtained according to the method described in the above-mentioned Example 1 does not convert into a different crystal even after being stored for four months under the condition of TC / 75% RH, and the type The II crystal has superior stability compared to long-term storage. Experimental Example 2 and Example 2: Crystal Stability Test (2) and Process for Producing Crystal of the Invention (2) 18 201240985 Water (6 ml) Add a type I crystal (1 g), a daily mixture. After stirring for 2 hours, collect a portion of the crystal under the conditions similar to the example 1 and then make the wet- γ. A, and then the powder. X-ray measurement. Medium expansion square ''' pattern comparison 'type 1 crystal Partial conversion to the crystal obtained in Example 1. The compound of the present invention in the form of a crystal can be used as an active ingredient. In general, the f drug is formulated into a formulation and marketed, and water is mostly used for rice exhibiting agents. It is used during the compounding step. Therefore, when the type 1 crystal is used as an active ingredient, a partial crystal transition may occur during the compounding step, which may result in an effect of efficacy and side effects, which may lead to unpredictable conditions. Aspect 'The crystal of the present invention is used as an active ingredient to make (4), the problem can be suppressed, and a more uniform preparation can be obtained. Experimental Example 3 and Example 3: Crystal Stability Test (3) and Process for Producing Crystal of the Present Invention (3) The crystal obtained according to the method described in the above Example 1 and the crystal of the type 1 are added to a solvent, and the mixture is stirred to a state of suspension. Thereafter, a part of the suspension is collected to make the crystal in the suspension similar to the implementation. The powder X-ray measurement was carried out under the conditions of the sample. The weight of the crystal added to the solvent, the solvent used, the temperature of the solvent and the stirring time are shown in Table 2. The results are shown in Table 4. Table 2 Solvent Crystal Temperature Stirring Time Ethanol 4 ml Each 1.5 g 50 ° C 1.5 hours Ethanol 4 ml Each 3.5 g 70 ° C 1.5 hours Ethanol 3 ml + water 1 ml Each 2.5 g 50 °C 1.5 hours 19 201240985 Ethanol 1.5 ml + water 0.5 ml each 2.0 g 60 ° C 1.5 hours ethanol 1 ml + water 3 ml each 0.5 g 50 ° C 1.5 hours ethanol 1 ml + water 3 ml each 2.0 g 60 °C 1.5 hours ethanol 0.5 ml + water 1.5 ml each 0.5 g 65 °C 1.5 hours ethanol 4 ml each 0.8 g 10 ° C 1.5 hours ethanol 3 ml + water 1 ml each 0.8 g 10 ° C 1.5 hours ethanol 1 Ml + water 3 ml each 0.5 g 10 ° C 1.5 hours water 2 ml each 0.25 g rt 1.5 hours acetone 1 ml each 0.25 g rt 1.5 hours sterol 1.5 ml each 0.25 g rt 1.5 hours formic acid 1 ml + water 1 ml each 0.5 g rt 1.5 hours benzaldehyde 1.5 ml each 0.25 g rt 1.5 hours 2-butanol 2 ml each 0.25 g rt 1.5 hours 3-methyl-1-butanol 2 ml each 0.25 g rt 1.5 Hg every 3 ml each 0.25 g 50 ° C 6.5 hours toluene 2 ml each 0.25 g 50 ° C 1 hour 2-mercapto-2-propanol 2 ml each 0.25 g 50 ° C 1 hour ethanol 0.5 ml + Geng Xuan 0.5 ml Each 0.25 g 50 ° C 1 hour 1 · Propanol 1 ml + Geng 1 ml Each 0.25 g 50 ° C 1 hour 2-propanol 1 ml + Geng 1 ml Each 0.25 g 50 ° C 1 hour 2-butanol 1 ml + heptane 1 ml each 0.25 g 50 ° C 1 hour 2-methyl-2 propanol 1 ml + heptane 1 ml each 0.25 g 50 ° C 1 hour 3-曱1-butanol 1 ml + Gengyuan 1 ml Each 0.25 g 50 ° C 1 hour tetrahydrofuran 1 ml + heptane 1 ml each 0.25 g 50 ° C 1 hour acetic acid 1 ethyl ester 1 ml + heptane 1 ml Each 0.25 g 50 V for 1 hour ("rt·" in Table 2 means room temperature) In addition, when the mixed solvent shown in Table 3 is maintained at 70 ° C, the root 20 201240985 is described according to the above embodiment 1. The crystals obtained by the method and the ruthenium crystals (250 mg, respectively) were added to the mixed solvent, and the mixture was stirred for 5 minutes to the suspension state. The suspension of 40 to 60" was collected, and the crystals in the suspension were subjected to powder calendering measurement under conditions similar to those of Example 1. Further, after the temperature of the remaining suspension was determined to reach 6 Torr, further addition was carried out according to the above. The crystals obtained by the method described in Example 1 (5 to 丨〇mg) were stirred and the mixture was stirred at 60 ° C for 10 minutes. The suspension was collected 4 Torr to make the crystals in the suspension similar. The powder X-ray measurement was carried out under the conditions of Example 此外. Further, the crystal obtained by the method described in the above Example 丨 (about 20 mg) was further added to the remaining suspension'. The suspension temperature was maintained at 6 (TC stirring mixture) The mixture was allowed to stand overnight at room temperature for 1 hour, and then the crystals in the suspension were subjected to measurement under conditions similar to those in Example 1. The results are shown in Table 4. Table 3 Ethanol 0.5 ml + Gengyuan 0.5 ml 2- Butanol 0.5 ml + heptane 0.5 ml 3-methyl 1-butanol 10.5 ml + heptane 0.5 ml Acetate vinegar 0.5 ml + heptane 0.5 ml 21 201240985 inch 啭 70 ° C 1 x (type I) 1 1 1 1 1 1 1 1 1 1 1 X (Type I) 1 1 X (Type I) 1 X (Type I ) 1 X (Type I) 65〇C 1 1 1 X (Type I) 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 60°C 1 1 X (Type I) X (Type I) 1 1 1 1 1 1 1 1 1 X (Type I) 1 1 X (Type I) 1 X (Type I) 1 X (Type I) 50°C 1 〇〇〇1 1 1 1 1 1 〇〇〇〇 〇〇〇〇〇〇〇〇1 1 1 〇X (Type II) X (Type II) 〇〇〇1 1 1 〇1 1 〇1 〇1 〇10°C 1 〇〇〇1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 Ethanol 75% ethanol aqueous solution 25% ethyl pure aqueous solution acetone methanol 50% aqueous formic acid phenyl aldehyde aldehyde 2-butanol 3-mercapto-1-butanol glycerol ί4 - 2-曱2-propanol ethanol/heptane 1-propanol/heptane 2-propanol/heptane 2-butanol/heptane 2-methyl-2-propanol/heptane 3-methyl-1- Butanol/heptane tetrahydrofuran/heptane ethyl acetate/heptane-nngs#艏琮######### #艏琮茶^βχχ-条客 Isl wants nmsM brakes* night target hi-hat "(I don't) X"*韬吨忘#馁m^^-^xK龛 "匣羿韬<" change Funeral ^: Jing Jing ^1 Army 嫜驷 ^^ Fin tower broken cup 砘 "〇" * 赖鳏艄 鳏艄 ".1"" - + inch < ττ. ^茛^刼<輮裥"-" is called 201240985. These results clearly show that when the compound is crystallized with a solvent having a carbon number such as methanol, formic acid and the like, only the type π crystal is obtained; It is not less than 60 with water or an organic solvent having a carbon number of 2 or more. (: Crystallized under conditions of 'only type! crystal; and when the compound is crystallized with water or an organic solvent having a carbon number of 2 or more, at a temperature not lower than the melting point of the solvent and lower than 60 C, only the crystal is selected. The steroid of the present invention is obtained. Generally, the solubility of the solid becomes high as the temperature of the solvent increases. Therefore, in order to obtain crystals in a high yield, crystallization is preferably carried out at a low solvent temperature. In addition, when the manufacturing worker is exposed to high temperatures In the case of solvents, workers may be injured (for example, injuries, etc.). To ensure the safety of the workers, the solvent temperature is preferably low. In order to produce pure type r crystals alone (ie, without other crystals), the solvent temperature is not lower than 6 (TC. In order to produce the crystal of the present invention in isolated and/or pure form, a lower temperature solvent can be used. Therefore, the crystal of the present invention can be manufactured safely and efficiently compared to the type I crystal. In addition, since the crystal of the present invention is more stable at room temperature than the type I crystal, and is not converted into other crystals during the compounding step: and the like, it is easy to grasp and has a medical product as a material. Excellent properties. ' ” Industrial Applicability The crystal of the present invention is stable under the rc condition and does not transform into other steroids, and can be used as a drug substance for pharmaceutical production compared to other previously identified crystals. The manufacturing method of the present invention is safe and effective: and selectively produces the crystal of the present invention. i The above description of the present invention provides methods and processes for making and using the same. It is possible to make, coat, and use 23 201240985, which can be used to provide the singularity of the π μ 1 figure (with a knife) for the attached application. In this article, the phrase "free" consists of a group ". 'selected from" and the like contains a mixture of specified substances. When the reference to the number limit or range of HP values is included in this article, the endpoint is included. It is stated that all values and sub-ranges within the limits or ranges of the invitations are explicitly covered. This application is based on the US Provisional Application No. 61/437,949. BRIEF DESCRIPTION OF THE DRAWINGS [Brief Description of the Drawings] Fig. 1 shows a powder X-ray diffraction pattern of the crystal of the present invention. Fig. 2 shows the results of the differential scanning calorimetry (DSC) method of the crystal of the present invention. The crystal described in Example 3 (type I crystal) The powder X-ray diffraction pattern before and after storage was stored at 4 〇C / 75 〇 / 〇 RH for six months, wherein the vertical axis shows the intensity (cps) Figure 4 shows the powder X-ray diffraction pattern of the crystal (type II body) described in Example 22 of the patent document before storage, storage for 1 day, 3 days and 8 days. The storage condition is 4 (TC). /75% RH for 8 days; and a powder X-ray diffraction pattern of the crystal (type I crystal) described in Example 3 of Patent Document 2, wherein the vertical axis shows the intensity (CPS). Fig. 5 shows a powder X-ray diffraction pattern of the crystal of the present invention before and after storage. The storage conditions were 4 Å. 〇 /75〇/〇RH for six months, where the vertical axis shows the intensity (CPS) 〇 24 201240985 [Main component symbol description] None 25