TWI812166B - 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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- TWI812166B TWI812166B TW111114267A TW111114267A TWI812166B TW I812166 B TWI812166 B TW I812166B TW 111114267 A TW111114267 A TW 111114267A TW 111114267 A TW111114267 A TW 111114267A TW I812166 B TWI812166 B TW I812166B
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Abstract
本發明係關於鞘胺醇-1-磷酸受體促效劑之晶型。更具體地，本發明係關於下式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
本發明係關於鞘胺醇-1-磷酸受體促效劑之晶型。更具體地，本發明係關於以下式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(S1P)係經由細胞內神經醯胺途徑所產生，其中神經醯胺係起始原料。神經醯胺係經由兩種途徑所產生，第一種係從頭(de novo)生物合成途徑。神經醯胺亦為藉由細胞中細胞膜成分之鞘磷脂的降解而產生。各組織中的S1P濃度係由兩種生物合成鞘胺醇激酶(SphK)和兩種可生物降解的S1P磷酸酶(S1P裂解酶和溶血磷脂磷酸酶)所控制。已知經由鞘胺醇激酶對鞘胺醇的磷酸化所產生的S1P可調控各種細胞反應，
例如細胞增殖、細胞骨架的組織和遷移、黏附和緊密連接(tight junction)組裝以及形態發生。S1P與包括白蛋白的血漿蛋白呈結合形式且以高濃度(100至1,000nM)存在於血漿中，而在組織中則為低濃度。
S1P與S1P受體(一種G-蛋白偶聯受體)結合，以顯示出各種生物學功能。作為S1P受體亞型，迄今為止已知S1P1至S1P5，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、神經細胞增殖、形態變化、遷移、內皮功能、血管調節和心血管發育。
與此同時，新穎藥物之物理與化學性質的研究，對於新穎藥劑有效率地和成功地開發係必要的。具體而言，藉由研究藥物的同質異晶物(polymorphs，或稱多形體)和假同質異晶物(pseudopolymorphs)的存在，以及各同質異晶物之間的物理和化學性質的差異，可從醫藥方面的角度，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)。當同質異晶物存在於溶液中時，其在化學上係相同的，但在固態下，其各自具有完全不同的X光繞射圖，且在各種物理和化學性質上表現出差異。具體而言，由於溶離率(dissolution rate)的差異，各個同質異晶物可具有生體可用率(bioavailability)上的差異，並且在熱力學穩定性方面表現出無法預期的性質。
當某種藥物以同質異晶物的形式存在時，在製備藥物的程序中，根據再結晶的條件，例如再結晶溶劑、藥物濃度、加熱及冷卻速度、溫度、攪拌速度等，可得到具有不同結構的晶型。因此，為了獲得相同的
晶型，需要特別注意製備程序的管理。晶體結構的差異可藉由X光繞射圖譜來區分。由於在水合物中只有物理性質(例如結晶度、吸濕性、熔點、溶解度、溶離率等)有所變化，而提供藥理作用的化學性質沒有任何改變，因此，其在醫藥方面具有非常重要的意義，如同質異晶物(Morris,K.R.等人，Int.J.Pharm.,108,1994,15-206)。
從與本發明所屬技術領域相關的各種參考文獻中所了解到的最新知識是，對於包含藥物穩定性及吸濕性等醫藥性質的改善沒有整體的趨勢。最終，必須藉由逐案不斷的研究才能確定個別化合物具有最佳的醫藥性質的形式，其係無法預期者，且屬於只能藉由反覆實驗才能證實的實驗領域。
本發明旨在提供具有優異醫藥性質的下式1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：
為了解決上述技術課題，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，本發明提供醫藥組成物，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。
本發明係詳細描述於下文中。
在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個或更多個、5個或更多個、7個或更多個、9個或更多個、或10個或更多個特徵峰(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：8.93±0.2°、9.17±0.2°、9.49±0.2°、13.36±0.2°、13.81±0.2°、15.04±0.2°、16.15±0.2°、17.41±0.2°、18.07±0.2°、18.59±0.2°、19.56±0.2°、20.75±0.2°、21.26±0.2°、21.70±0.2°、22.66±0.2°、24.72±0.2°、25.65±0.2°、27.19±0.2°及31.10±0.2°。在下文中，上述結晶形式稱為「晶型III」。
在根據本發明的一個實施態樣中，該晶型III具有選自以下X光繞射圖譜的3個或更多個、5個或更多個、7個或更多個、9個或更多個、或10個或更多個特徵峰(2θ)：8.93±0.1°、9.17±0.1°、9.49±0.1°、13.36±0.1°、13.81±0.1°、15.04±0.1°、16.15±0.1°、17.41±0.1°、18.07±0.1°、18.59±0.1°、19.56±0.1°、20.75±0.1°、21.26±0.1°、21.70±0.1°、22.66±0.1°、24.72±0.1°、25.65±0.1°、27.19±0.1°及31.10±0.1°。
當晶型III經受熱重分析時，在30至75℃觀察到約0.5%的重量損失(圖2)。當使用示差掃描量熱法(DSC)分析晶型III時，在約224℃(起始)觀察到吸熱(圖2)。
在根據本發明的一個實施態樣中，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、對甲苯磺酸以及萘磺酸所組成之群組。在根據本發明的一個實施態樣中，藥學上可接受的鹽可為氫氯酸。
根據本發明的又一個方面，其提供醫藥組合物，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的晶型III以及藥學上可接受的載體。
在本發明中，除了本發明的活性成分外，「醫藥組成物」還可包含其他組分，例如載體、稀釋劑、賦形劑等。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、賦形劑或其組合。該醫藥組成物有助於將化合物投予到體內。用於投予化合物的各種方法包括但不限於口服、注射、氣霧劑、腸胃外和局部給藥。
在本文中，「載體」係指促進化合物添加到細胞或組織中的化合物。例如，二甲亞碸(DMSO)係有助於將許多有機化合物投予到活細胞或組織中的常規載體。
在本文中，「稀釋劑」係指化合物，其不僅穩定生物活性形式，而且在溶解化合物的溶劑中稀釋。在緩衝液中溶解的鹽被用作所屬技術領域的稀釋劑。常規使用的緩衝液係模擬體液中鹽形式的磷酸鹽緩衝鹽
液。由於緩衝溶液可在低濃度下控制溶液的pH值，因此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」係指不損害化合物的生物活性和物理性質的特性。
根據本發明的化合物可配製成各種藥學給藥劑型。在本發明的醫藥組成物的製備中，考慮所要製備的劑型，把活性成分(具體而言，式1之化合物或其藥學上可接受的鹽的晶型III)與所選擇的藥學上可接受的載體混合。例如，本發明的醫藥組成物可根據需要配製成注射劑、口服製劑等。
本發明的式1之化合物之晶型可藉由常規方法，使用已知的醫藥載體和賦形劑配製，並注入一單元或複數單元容器中。製劑可為油性或水性溶劑中的溶液、懸浮液或乳液，且包括常規分散劑、懸浮劑或穩定劑。此外，該化合物可為例如乾粉形式，其在使用前溶解在經滅菌的無熱原水中。本發明的式1之化合物之晶型可藉由使用常規的栓劑基質(例如可可脂或其他甘油酯)來配製成栓劑。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。膠囊和錠劑是較佳的。錠劑和丸劑較佳地為腸溶衣。固體形式係藉由將本發明的式1之化合物之晶型與至少一種選自如蔗糖、乳糖或澱粉的惰性稀釋劑、如硬脂酸鎂的潤滑劑、崩解劑、黏合劑等的載體混合而得。此外，其可配製成經皮劑型，例如，作為洗劑、軟膏劑、凝膠劑、乳膏劑、貼劑或噴霧劑。
根據本發明的醫藥組成物係適用於預防或治療與鞘胺醇-1-磷酸受體相關的疾病。在根據本發明的一個實施態樣中，該醫藥組成物可使用於包括多發性硬化症的自身免疫疾病之治療。在根據本發明的一個實施態樣中，該醫藥組成物可使用於由與鞘胺醇-1-磷酸相關之非所欲之淋巴
細胞浸潤所致疾病之預防或治療。在根據本發明的一個實施態樣中，該醫藥組成物可使用於免疫調節疾患之預防或治療。在根據本發明的一個實施態樣中，免疫調節疾患的示例可為選自由全身紅斑性狼瘡、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、動脈粥狀硬化症、硬皮症和自體免疫性肝炎所組成之群組的自體免疫疾病或慢性發炎疾病，但不限於此。
在本文中，術語「預防」係指減少或消除感染疾病的可能性。
在本文中，術語「治療」係用於表示，在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III，具有作為鞘胺醇-1-磷酸受體促效劑的藥理學活性，且同時具有優異的藥理學性質，例如穩定性，如熱穩定性和儲存穩定性。
圖1係晶型III的X光粉末繞射(XRPD)光譜。
圖2係晶型III的熱重分析(TGA)/示差掃描量熱法(DSC)分析結果。
在下文中，藉由以下實施例更詳細地解釋本發明。然而，必須理解，本發明的保護範圍並不限於這些實施例。
製備實施例1：1-[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-羧酸氫氯酸鹽的合成
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-羧酸乙酯的合成，係按照國際專利申請公開第WO 2014/129796 A1號製備例153-1中所描述的方法，使用NaOH把酯水解，使用HCl把其酸化，然後進行結晶以得到氫氯酸鹽形式(以下稱為「化合物1」)。
製備實施例2：基本晶型的製備
把化合物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。在內部溫度45℃加熱60分鐘後，把內部溫度冷卻至28℃。把二氯甲烷(DCM)(340mL 1.5倍)添加到該反應混合物中後，在50分鐘內緩慢滴加6N HCl(167ml，1.00mol)以把溶液的pH酸化至2.5，然後添加乙酸乙酯(EtOAc)(0.23L，1倍)以進行結晶。把內部溫度冷卻至5℃後，將所獲得的產物靜置30分鐘，過濾並用水(1.13L，5倍)洗滌兩次，並使用甲基第三丁基醚(MTBE)(0.50L，3倍)洗滌一次以得到表1的具有X光粉末繞射(XRPD)圖之化合物1的結晶形式(以下稱為「晶型A」)(156g，兩步驟產率：69.0%)。
實施例1：晶型III之製備
把晶型A溶解在二甲亞碸中以製備溶液，然後向其中緩慢加入乙腈。此時，二甲亞碸和異丙醇以1：20的比例使用。在室溫攪拌1天後，把所獲得的產物冷藏3天。如果形成沉澱，則藉由0.45μm PVDF過濾器對其進行過濾。
實施例2：晶型III之分析
(1)XRPD(X光粉末繞射)
XRPD分析係藉由使用帶有銅輻射入射光束的PANalytical X’pert Pro繞射儀所進行。將約20至30mg的樣本壓實在玻璃樣本架上使其具有平整表面後，把設備的發電器設置為45kV(加速電壓)和40mA(燈絲發射)，然後用反射模式(非旋轉)進行測量。在4到40°範圍內的布拉格角(2θ)係以0.026°的步長和每步時間51秒的條件測量。XRPD圖係使用HighScore Plus 2.2c軟體分類和處理，結果如圖1和表2所示。
(2)DSC(示差掃描量熱法)
DSC係藉由使用Mettler Toledo DSC 1系統所進行。量秤約2至5mg的樣本，放置於40μL鋁坩堝(帶有一個針孔蓋的平底鋁鍋)中，並製成1個針孔。然後，以10℃/min的速率把樣本從25℃加熱到350℃以測量DSC。在測量期間，以70mL/min的速率向儀器內部供應氮氣，以防止氧氣和其他氣體的流入。使用軟體STARe進行資料收集和評估(圖2)。
(3)TGA(熱重分析)
TGA係藉由使用Mettler Toledo TGA/DSC 1模組所進行。量秤約4至8mg的樣本並置於100μL鋁坩堝(平底鋁坩堝)中。然後，以
10℃/min的速率將樣本從30℃加熱到350℃以測量TGA。在測量過程中，以80mL/min的速率向儀器內部供應氮氣，以防止氧氣和其他氣體的流入。使用軟體STARe進行資料收集和評估(圖2)。
(4)結果
作為XRPD分析的結果，其證實該化合物為結晶形式，且具體數值係表示於下表2中。
作為TGA測量的結果，在30至75℃觀察到約0.5%的重量損失。
作為DSC測量的結果，在224℃(開始)觀察到吸熱，其預期為係因晶型III的熔化。
Claims (6)
- 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-羧酸氫氯酸鹽之晶型，具有選自以下X光繞射圖譜的3個或更多個特徵峰(2θ)：8.93±0.2°、9.17±0.2°、9.49±0.2°、13.36±0.2°、13.81±0.2°、15.04±0.2°、16.15±0.2°、17.41±0.2°、18.07±0.2°、18.59±0.2°、19.56±0.2°、20.75±0.2°、21.26±0.2°、21.70±0.2°、22.66±0.2°、24.72±0.2°、25.65±0.2°、27.19±0.2°以及31.10±0.2°。
- 如請求項1所述之晶型，其具有選自以下X光繞射圖譜的3個或更多個特徵峰(2θ)：8.93±0.1°、9.17±0.1°、9.49±0.1°、13.36±0.1°、13.81±0.1°、15.04±0.1°、16.15±0.1°、17.41±0.1°、18.07±0.1°、18.59±0.1°、19.56±0.1°、20.75±0.1°、21.26±0.1°、21.70±0.1°、22.66±0.1°、24.72±0.1°、25.65±0.1°、27.19±0.1°以及31.10±0.1°。
- 一種用於包含多發性硬化症之自體免疫疾病之治療的醫藥組成物，其包含如請求項1中所定義之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-羧酸氫氯酸鹽之晶型，以及藥學上可接受的載體。
- 一種用於由與鞘胺醇-1-磷酸相關之非所欲之淋巴細胞浸潤所致疾病之預防或治療的醫藥組成物，其包含如請求項1中所定義之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-羧酸氫氯酸鹽之晶型，以及藥學上可接受的載體。
- 一種用於免疫調節疾患之預防或治療的醫藥組成物，其包含如請求項1中所定義之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-羧酸氫氯酸鹽之晶型，以及藥學上可接受的載體。
- 如請求項5所述之醫藥組成物，其中，該免疫調節疾患係選自由全身紅斑性狼瘡、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、硬皮症以及自體免疫性肝炎所組成之群組的自體免疫疾病或慢性發炎疾病。
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