TW202302563A - 鞘胺醇-1-磷酸酯受體促效劑之晶型 - Google Patents
鞘胺醇-1-磷酸酯受體促效劑之晶型 Download PDFInfo
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Abstract
本發明關於鞘胺醇-1-磷酸酯受體促效劑之晶型。更具體地,本發明關於下式1的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型:
Description
本發明關於鞘胺醇-1-磷酸酯受體促效劑之晶型。更具體地,本發明關於下式1的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型:
鞘胺醇-1-磷酸酯(S1P)係藉由細胞內神經醯胺(ceramide)路徑生成,神經醯胺為其起始原料。神經醯胺藉由兩種路徑產生,第一種為從頭生物合成路徑(de novo biosynthetic pathway)。神經醯胺亦藉由神經鞘磷脂(細胞中的細胞膜成分)的降解而生成。各組織中的S1P含量係由兩種生物合成鞘胺醇激酶(sphingosine kinases,SphKs)及兩種生物可降解的S1P磷酸酶(S1P裂解酶及水解磷酯磷酸酶)所控制。已知經由
鞘胺醇激酶對鞘胺醇的磷酸化而生成之S1P可調節各種細胞反應,例如細胞增生、細胞骨架的組織及遷移、黏著及緊密連接(tight junction)組裝以及形態發生。於血漿中,S1P以與包括白蛋白之血漿蛋白的結合形式以高含量(100至1,000nM)存在,而於組織中則以低含量存在。
S1P與S1P受體(一種G-蛋白偶聯受體)結合,以展現各種生物功能。S1P1至S1P5是迄今已知的S1P受體亞型,分別被命名為內皮分化基因(endothelial differentiation gene,EDG)受體1、5、3、6及8。已知S1P受體參與各種生物功能,例如白血球再循環、神經細胞增生、形態變化、遷徙、內皮功能、血管調節及心血管的發育。
與此同時,欲有效率地和成功地開發新藥,針對新藥的物理和化學性質的研究至關重要。具體而言,藉由研究藥物的同質異晶物(polymorphs)及假同質異晶物(pseudopolymorphs)之存在以及各同質異晶物之間的物理和化學性質之差異,可基於製藥面向來選擇藥物的較佳晶型(Remington’s Pharmaceutics,Chapter 75 Preformulation);(Byrn,S.R.,Solid State Chemistry of Drugs,Academic Press,New York,1982)。當同質異晶物處於溶液中時,其於化學上是完全等同的,但在固態下,其各自具有明顯不同的X光繞射圖譜,並且於各種物理及化學性質上展現出差異。具體而言,由於溶離率(dissolution rate)的差別,各同質異晶物在生體可用率(bioavailability)上可能具有差異,且於熱力學穩定性方面表現無法預期之特性。
當某種藥物以同質異晶物形式存在時,於藥物製備程序中可依諸如再結晶溶劑、藥物濃度、加熱及冷卻速度、溫度、攪拌速度等再結
晶條件得到具有不同結構之晶型。因此,為獲取相同之晶型,需特別留意製造程序的管理。晶體結構之差異可藉由X光繞射圖譜加以區分。由於在水合物中僅有物理性質的改變,如結晶度、吸濕性、熔點、溶解度、溶離率等,而沒有提供藥理作用的任何化學性質之改變,因此如同質異晶物,其於製藥方面具有非常重要的意義(Morris,K.R.等人,Int.J.Pharm.,108,1994,15-206)。
基於從本發明所屬技術領域的各種參考文獻中了解到的最新知識,包括藥物穩定性、吸濕性等藥物性質於整體上並沒有改善的趨勢。最終仍須藉由視情況不斷的研究以確立針對個別化合物具最佳藥學性質的形式,此為無法預期者,屬於僅能藉由反覆實驗才得以確定的實驗領域。
本發明旨在提供具有優異藥學特性的下式1的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型:
為解決上述技術課題,本發明提供1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型。
此外,本發明提供一種醫藥組成物,其包含作為活性成分之1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型,以及藥學上可接受的載體。
以下詳細描述本發明。
根據本發明的一個方面,其提供具有選自以下X光繞射圖譜的3個以上、5個以上、7個以上、9個以上或10個以上的特徵峰(2θ)的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型:9.15±0.2°、12.19±0.2°、13.68±0.2°、14.48±0.2°、15.37±0.2°、15.93±0.2°、17.32±0.2°、19.53±0.2°、21.56±0.2°、22.64±0.2°、23.20±0.2°、23.66±0.2°、24.51±0.2°、27.12±0.2°、27.60±0.2°及30.87±0.2°。以下,將上述晶型稱為「晶型A」。
於本發明的一個實施態樣中,晶型A具有3個以上、5個以上、7個以上、9個以上或10個以上或更多選自以下X光繞射圖譜之特徵峰(2θ):9.15±0.1°、12.19±0.1°、13.68±0.1°、14.48±0.1°、15.37±0.1°、15.93±0.1°、17.32±0.1°、19.53±0.1°、21.56±0.1°、22.64±0.1°、23.20±0.1°、23.66±0.1°、24.51±0.1°、27.12±0.1°、27.60±0.1°及30.87±0.1°。
當對晶型A進行熱重分析(thermogravimetric analysis,TGA)時,從環境溫度至100℃觀察到約0.7%的重量損失,且於約230℃觀察到TGA熱譜圖的斜率發生顯著變化,其最可能與原料的降解有關(圖
2)。當使用示差掃描量熱法(differential scanning calorimetry,DSC)分析晶型A時,於約221℃(起始)處觀察到吸熱(圖3)。基於高溫載台顯微鏡分析(hot stage microscopy,HSM)的觀察(熔化範圍:217.1至226.4℃),該吸熱係歸因於原料的熔點(圖5)。根據HSM觀察,熔化與分解同時發生。以晶型A的動態水分吸附(dynamic vapor sorption,DVS)分析的結果,觀察到從5%到95%RH的吸附過程中重量增加了2.58%,而從95%到5%RH的去吸附過程中重量減少了2.49%(圖6)。DVS後回收之固體顯示XRPD圖譜與初始的相似。於加速及嚴苛條件下,晶型A物理/化學地穩定2週。
根據本發明的另一方面,其提供具有選自以下X光繞射圖譜的3個以上、5個以上、7個以上、9個以上或10個以上的特徵峰(2θ)的1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型:8.87±0.2°、12.53±0.2°、13.40±0.2°、14.10±0.2°、15.22±0.2°、15.64±0.2°、16.09±0.2°、17.06±0.2°、17.62±0.2°、18.91±0.2°、20.67±0.2°、21.05±0.2°、22.64±0.2°、23.59±0.2°、24.22±0.2°、25.52±0.2°、26.05±0.2°及27.09±0.2°。以下,將上述晶型稱為「晶型D」。
於本發明的一個實施態樣中,晶型D具有3個以上、5個以上、7個以上、9個以上或10個以上或更多選自以下X光繞射圖譜之特徵峰(2θ):8.87±0.1°、12.53±0.1°、13.40±0.1°、14.10±0.1°、15.22±0.1°、15.64±0.1°、16.09±0.1°、17.06±0.1°、17.62±0.1°、18.91±0.1°、20.67±0.1
°、21.05±0.1°、22.64±0.1°、23.59±0.1°、24.22±0.1°、25.52±0.1°、26.05±0.1°及27.09±0.1°。
根據本發明的一個實施態樣,該藥學上可接受的鹽可選自由氫氯酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸、酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富馬酸、馬來酸、甲磺酸、苯磺酸、對甲苯磺酸及萘磺酸所組成的群組。根據本發明的一個實施態樣,該藥學上可接受的鹽可為氫氯酸。
本發明的又另一方面提供一種醫藥組成物,其包含1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型A及/或晶型D,以及藥學上可接受的載體。
在本發明中,「醫藥組成物」可包含除了本發明的活性成分以外之載體、稀釋劑、賦形劑等其他成分。因此,視需要,該醫藥組成物可包括藥學上可接受的載體、稀釋劑、賦形劑或其結合。該醫藥組成物有助於將化合物投予至體內。用於投予化合物的各種方法包括但不限於口服、注射、噴霧劑(aerosol)、腸胃外和局部給藥。
在本文中,「載體」係指促進將化合物添加至細胞或組織中的化合物。例如,二甲基亞碸(DMSO)為一種有助於將許多有機化合物投予至活體細胞或組織中的常規載體。
在本文中,「稀釋劑」係指不僅能穩定具生物活性形式且於溶解化合物的溶劑中稀釋的化合物。溶解於緩衝液中的鹽於所屬技術領域中用作稀釋劑。常規使用的緩衝液為模擬體液中鹽形式的磷酸鹽緩衝液
(PBS)。由於緩衝溶液可於低濃度下控制溶液的pH值,故緩衝稀釋劑幾乎不會改變化合物的生物活性。
在本文中,「藥學上可接受的」係指具有不損害化合物的生物活性和物理性質的特性。
本發明的化合物可配製成各種給藥劑型。在本發明醫藥組成物的製備中,考慮欲製備的劑型,將活性成分(具體而言為式1化合物或其藥學上可接受的鹽之晶型A及/或晶型D)與所選擇之藥學上可接受的載體加以混合。舉例而言,本發明的醫藥組成物可視需要配製為注射劑、口服製劑等。
本發明的式1化合物之晶型可藉常規方法,以已知的藥物載體和賦形劑進行配製,並注入一單元或複數單元的容器中。該製劑可為油性或水性溶劑中的溶液、懸浮液或乳液,並且包括常規的分散劑、懸浮劑或穩定劑。此外,該化合物可例如為乾粉形式,並於使用前溶解於經滅菌的無熱原水中。本發明的式1化合物之晶型可藉由使用如可可脂或其他甘油酯之常規栓劑基質配製為栓劑。用於口服給藥的固體形式包括膠囊、錠劑、丸劑、粉劑和顆粒劑,較佳為膠囊和錠劑。錠劑和丸劑較佳為腸溶衣。固體形式係藉由將本發明的式1化合物之晶型與至少一種選自如蔗糖、乳糖或澱粉之惰性稀釋劑、如硬脂酸鎂之潤滑劑、崩解劑、接著劑等的載體混合而製備。此外,其可配製為經皮劑型,例如洗劑、軟膏劑、凝膠劑、乳膏劑、貼劑或噴霧劑。
本發明之醫藥組成物適用於預防或治療與鞘胺醇-1-磷酸酯受體相關的疾病。於本發明一實施態樣中,該醫藥組成物可用於治療包括
多發性硬化症在內的自體免疫疾病。於本發明一實施態樣中,該醫藥組成物可用於預防或治療與鞘胺醇-1-磷酸酯有關的非所欲之淋巴細胞浸潤所引起之疾病。於本發明一實施態樣中,該醫藥組成物可用於預防或治療免疫調節疾患。於本發明一實施態樣中,免疫調節疾患之示例可選自由全身性紅斑狼瘡、慢性類風濕性關節炎、發炎性腸道疾病、多發性硬化症、肌萎縮性脊髓側索硬化症(ALS)、動脈硬化症、動脈粥樣硬化症、硬皮症及自體免疫性肝炎所組成群組之自體免疫疾病或慢性發炎疾病,但不限於此。
在本文中,「預防」係指減少或消除感染疾病的可能性。
在本文中,「治療」表示於表現出疾病症狀的個體中阻止、延遲或改善疾病的進展。
1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型A及/或晶型D具有作為鞘胺醇-1-磷酸酯受體促效劑之藥理活性,且同時具有良好的藥學性質,例如穩定性,如熱穩定性及儲存穩定性。
圖1係晶型A之X光粉末繞射(XRPD)光譜。
圖2係晶型A之熱重分析(TGA)結果。
圖3係晶型A之示差掃描量熱儀(DSC)分析結果。
圖4係晶型A之核磁共振(NMR)光譜。
圖5係晶型A之高溫載台顯微鏡分析結果。
圖6係晶型A之動態水分析吸附分析結果。
圖7係晶型A之物理穩定性(XRPD)分析結果。
圖8係晶型D之X光粉末繞射(XRPD)光譜。
圖9係非晶型之X光粉末繞射(XRPD)光譜。
圖10係非晶型之熱重分析(TGA)/示差掃描量熱儀(DSC)分析結果。
圖11係非晶型之溫度循環DSC結果。
在下文中,藉由以下實施例更詳細地闡釋本發明。然而,必須理解,本發明的保護範圍並不限於該等實施例。
製備實施例:1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸鹽酸鹽的合成
1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸乙酸乙酯之合成係參照國際專利公開WO2014/129796A1的製備實施例153-1中所述方法,將該酯以NaOH水解,再以HCl酸化,然後結晶以獲得鹽酸鹽形式(以下簡稱「化合物1」)。
實施例1:晶型A的製備
將化合物1(226g,0.46mol)、乙醇(1.13L,5倍)、水(0.57L,2.5倍)及NaOH(32g,0.80mol)加入反應器。於內部溫度45℃下加熱60分鐘後,將內部溫度冷卻至28℃。將二氯甲烷(DCM)(340mL 1.5倍)添加至反應混合物中後,於50分鐘內緩慢滴加6N HCl(167
ml,1.00mol)以酸化溶液pH至2.5,再添加乙酸乙酯(EtOAc)(0.23L,1倍)以進行結晶。將內部溫度冷卻至5℃後,將獲取之產物保持30分鐘,經過濾並以水(1.13L,5倍)洗滌兩次及以甲基第三丁基醚(MTBE)(0.50L,3倍)洗滌一次以獲得晶型A(156g,兩步驟產率:69.0%)。
實施例2:晶型A的分析
(1)XRPD(X光粉末繞射)
藉由使用帶有銅輻射入射光束的PANalytical X’ pert Pro繞射儀進行XRPD分析。於玻璃樣本架上壓實約20至30mg的樣本使其表面平整後,將該設備的產生器設置為45kV(加速電壓)及40mA(燈絲發射),然後以反射模式(非旋轉)進行量測。在4到40°範圍內的布拉格角(2θ)以0.026°的步長及每步時間51秒的條件測量。使用HighScore Plus 2.2c軟體進行分類及處理XRPD圖,其結果如圖1及表2所示。
(2)TGA(熱重分析)
使用TA Instruments Q5000 IR熱重分析儀進行TGA。密封樣本並於密封蓋上打針孔,然後將製備好的樣本放入TG爐中,於氮氣下以10℃/min之速率從25℃加熱到最高350℃。結果如圖2所示。
(3)DSC(示差掃描量熱儀)
藉由使用Mettler-Toledo DSC 3+示差掃描量熱儀進行DSC。將樣本置於密封的鋁製DSC盤中,準確記錄重量。然後,將盤蓋刺穿,將樣本放入DSC單元中進行測量。於氮氣下以10℃/min之速率從30℃加熱到最高250℃。結果如圖3所示。
(4)NMR(1H核磁共振光譜法)
使用Bruker 500MHz NMR光譜儀於溶解在氘化DMSO中的溶液狀態以收集質子NMR光譜,各樣本的測量參數顯示於NMR光譜中(圖4)。
1H NMR(500MHz,DMSO-d6)δ:1.47(d,6H、1.80~2.10(m,4H)、2.55~2.70(m,3H)、2.80(m,2H)、3.10(m,2H)、3.50(m,2H)、4.00(m,2H)、5.00(m,1H)、5.30(s,2H)、7.0(s,2H)、7.55-7.66(m,2H)、7.80(m,2H)、10.2(br,1H)、12.6(br,1H)
(5)HSM(高溫載台顯微鏡分析)
藉由使用帶有TMS93控制器及Linkman高溫載台(型號FTIR 600)的Leica DM LP顯微鏡執行高溫載台顯微鏡分析。藉由使用具有正交偏光鏡的λ板以10×0.22或20×0.40放大率觀察樣本。將樣本放在蓋玻片上,並將另一個蓋玻片放在樣本上。於加熱載台目視觀察樣本。於某些情況下,可能會在樣本中加入一滴礦物油以研究釋氣作用。使用帶有SPOT軟體v.4.5.9的SPOT Insight彩色數位相機擷取圖像(圖5)。
(6)DVS(動態水分析吸附)
於DVS Intrinsic儀器(表面測量系統)上收集水分吸附/去吸附數據。樣本於分析前未乾燥。於氮氣下,以10% RH增量在5%至95%RH範圍內收集吸附及去吸附數據。分析中使用的平衡標準是5分鐘內重量變化小於0.0100%,且最大平衡時間為3小時。樣本的初始水分含量資料未經校正。結果如圖6所示。
(7)穩定性測試(XRPD、肉眼觀察、HPLC)
為研究晶型A的穩定性,於加速(40℃/75%RH)及嚴苛(80℃)條件下儲存2週後,藉由肉眼觀察及XRD測量確認物理穩定性(圖7),而藉由使用HPLC分析樣本純度以確認化學穩定性(表3)。HPLC設備及分析方法如表1所示。
(8)結果
作為XRPD分析結果,已確認該化合物為結晶形式,具體數值如下表2所示。
根據TGA,從環境溫度至100℃觀察到約0.7%的重量損失。於約230℃觀察到TGA熱譜圖的斜率發生顯著變化,其最可能與原料的降解有關。
於DSC結果,於約221℃(起始)處觀察到吸熱,其為由於基於HSM觀察的原料的熔點(熔化範圍:217.1至226.4℃)。根據HSM觀察,熔化與分解同時發生。
依DVS之結果,從5%到95%RH的吸附過程中重量增加了2.58%,而從95%到5%RH的去吸附過程中重量減少了2.49%。DVS後回收之固體顯示XRPD圖與初始的相似。
本發明之晶型A於加速條件(40℃,75%RH)及嚴苛條件(密封狀態,80℃)下展現出2週的化學穩定性,而由於XRPD中的晶型沒有變化,因此確認了其物理/化學穩定性,如圖7所示。
實施例3:晶型D的製備
晶型D藉由以下三種方法製備。
(1)將晶型A於60℃的甲醇溶劑中溶解成溶液,然後藉由0.2μm尼龍過濾器以冷的甲基第三丁基醚過濾。此時甲醇與甲基第三丁基醚的比例為1:4。以反溶劑過濾後,沒有形成固體,且保持溶液狀態,而溶液於冷凍狀態下保持5天以獲取白色固體。
(2)將晶型A於60℃的甲醇溶劑中溶解成飽和或濃縮溶液,藉由預熱的0.2μm尼龍過濾器過濾,然後放入預熱相同溫度的小瓶中。然後,關閉加熱並將獲取之產物於加熱板上緩慢冷卻至室溫。於此狀態下,
沒有形成固體。依此,冷卻至2至8℃3天後,將所得產物置於冰箱中19天以獲取固體。
(3)將含有晶型A的玻璃小瓶放入裝有甲醇溶劑的小瓶中並蓋上蓋子。然後,將小瓶於室溫下儲存21天以獲取白色固體。
實施例4:晶型D的分析
以與實施例2相同之方式進行XRPD分析(圖8)。
對於XRPD分析結果,確認該化合物為結晶形式。
實施例5:非晶型的製備
非晶型藉由以下三種方法製備。
(1)晶型A(60mg)溶解於10mL TFE(2,2,2-三氟乙醇)中,藉由0.2μm PVDF過濾器過濾至透明圓底燒瓶中。將燒瓶連接到旋轉蒸發器並浸入60℃水浴中,於真空下將溶劑快速蒸發至乾燥。於XRPD檢測之前,樣本於室溫下在真空烘箱中乾燥1天。
(2)晶型A(810mg)溶解於120mL TFE(2,2,2-三氟乙醇)中,藉由0.2μm PVDF過濾器過濾至透明圓底燒瓶中。將燒瓶連接到旋轉蒸發器並浸入60℃水浴中,於真空下將溶劑快速蒸發至乾燥。於XRPD檢測之前,樣本於室溫下在真空烘箱中乾燥1天。
(3)晶型A(1.03g)溶解於150mL TFE(2,2,2-三氟乙醇)中,藉由0.2μm PVDF過濾器過濾至透明圓底燒瓶中。將燒瓶連接到旋轉蒸發器並浸入60℃水浴中,於真空下將溶劑快速蒸發至乾燥。於XRPD檢測之前,樣本於40℃在真空烘箱中乾燥1天。
實施例6:非晶型的分析
(1)XRPD(X光粉末繞射)
以與實施例2相同之方式進行XRPD分析(圖9)。
(2)TGA/DSC組合(熱重分析/示差掃描量熱法)
使用Mettler-Toledo TGA/DSC 3+分析儀進行TGA/DSC組合分析。將樣本置於開口鋁盤中,並將盤密封。將盤蓋刺穿後,將樣本插入TG爐中。於氮氣下以10℃/min之速率從30℃加熱到最高250℃。結果如圖10所示。
(3)溫度循環DSC(示差掃描量熱儀)
藉由使用Mettler-Toledo DSC 3+示差掃描量熱儀進行溫度循環DSC。將樣本置於密封的鋁製DSC盤中,準確記錄重量。然後,將盤蓋刺穿,將樣本放入DSC單元中進行測量。於氮氣下依以下方式進行實驗。以20℃/min的速率從-30℃加熱至140℃後,以20℃/min的速率從140℃冷卻至-30℃,然後再以20℃/min的速率從-30℃加熱至200℃。結果如圖11所示。
(4)穩定性測試(XRPD、肉眼觀察、HPLC)
以與實施例2相同之方式進行穩定性測試。
(5)結果
依XRPD之結果,觀察到顯示無尖峰的典型非晶型光暈圖案(圖9)。依TGA之結果,樣本從49℃至160℃顯示出約4.3%的重量損失。於221℃(起始)時重量逐漸減輕可表示HCl的損失。假設揮發性物質為HCl,該階段周圍的重量損失約為6.4%,其相當於約1莫耳HCl。
進行溫度循環DSC以測定Tg。在初始加熱循環期間觀察到約69℃(峰值)處的寬吸熱,其係由於預期中的殘留溶劑/水分損失所致。於最終加熱循環期間,在約89℃觀察到熱流訊號之階躍變化,其通常表示Tg。
於嚴苛條件下(80℃)2週後,觀察到該非晶型為自由流動顆粒,當撞擊時破碎,且以肉眼觀察為氣泡狀黃色塊狀物。儘管非晶型於80℃下至少可保持2週的物理穩定性,但於此條件下樣本中雜質含量會增加(表4)。
Claims (10)
- 一種1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型,其具有選自以下X光繞射圖譜之3個以上特徵峰(2θ):9.15±0.2°、12.19±0.2°、13.68±0.2°、14.48±0.2°、15.37±0.2°、15.93±0.2°、17.32±0.2°、19.53±0.2°、21.56±0.2°、22.64±0.2°、23.20±0.2°、23.66±0.2°、24.51±0.2°、27.12±0.2°、27.60±0.2°及30.87±0.2°。
- 如請求項1所述之晶型,其具有選自以下X光繞射圖譜之3個以上特徵峰(2θ):9.15±0.1°、12.19±0.1°、13.68±0.1°、14.48±0.1°、15.37±0.1°、15.93±0.1°、17.32±0.1°、19.53±0.1°、21.56±0.1°、22.64±0.1°、23.20±0.1°、23.66±0.1°、24.51±0.1°、27.12±0.1°、27.60±0.1°及30.87±0.1°。
- 一種1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型,其具有選自以下X光繞射圖譜之3個以上特徵峰(2θ):8.87±0.2°、、12.53±0.2°、、13.40±0.2°、、14.10±0.2°、15.22±0.2°、15.64±0.2°、16.09±0.2°、17.06±0.2°、17.62±0.2°、18.91±0.2°、20.67±0.2°、21.05±0.2°、22.64±0.2°、23.59±0.2°、24.22±0.2°、25.52±0.2°、26.05±0.2°及27.09±0.2°。
- 如請求項3所述之晶型,其具有選自以下X光繞射圖譜之3個以上特徵峰(2θ):8.87±0.1°、12.53±0.1°、13.40±0.1°、14.10±0.1°、15.22±0.1°、15.64±0.1°、16.09±0.1°、17.06±0.1°、17.62±0.1°、18.91±0.1°、20.67±0.1°、21.05±0.1°、22.64±0.1°、23.59±0.1°、24.22±0.1°、25.52±0.1°、26.05±0.1°及27.09±0.1°。
- 如請求項1或3所述之晶型,其中,該藥學上可接受的鹽選自由氫氯酸、硫酸、硝酸、磷酸、氫溴酸、氫碘酸、酒石酸、甲酸、檸檬酸、乙酸、三氯乙酸、三氟乙酸、葡萄糖酸、苯甲酸、乳酸、富馬酸、馬來酸、甲磺酸、苯磺酸、對甲苯磺酸及萘磺酸所組成的群組。
- 如請求項5所述之晶型,其中,該藥學上可接受的鹽為氫氯酸。
- 一種用於治療包括多發性硬化症之自體免疫疾病的醫藥組成物,其包含如請求項1或3所述之1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型,以及藥學上可接受的載體。
- 一種用於預防或治療由與鞘胺醇-1-磷酸酯有關的非所欲之淋巴細胞浸潤所引起之疾病的醫藥組成物,其包含如請求項1或3所述之1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型,以及藥學上可接受的載體。
- 一種用於預防或治療免疫調節疾患的醫藥組成物,其包含如請求項1或3所述之1-[1-氯-6-(3-氯-1-異丙基-1H-吲唑-5-基甲氧基)-3,4-二氫-萘-2-基甲基]-哌啶-4-羧酸或其藥學上可接受的鹽之晶型,以及藥學上可接受的載體。
- 如請求項9所述之醫藥組成物,其中,該免疫調節疾患選自由全身性紅斑狼瘡、慢性類風濕性關節炎、發炎性腸道疾病、多發性硬化症、肌萎縮性脊髓側索硬化症(ALS)、動脈硬化、動脈粥樣硬化、硬皮症及自體免疫性肝炎所組成群組之自體免疫疾病或慢性發炎疾病。
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