TWI826599B - (3s)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1h-咪唑-5-基]-7-[5-氯-2-(1h-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1h)-酮的新穎結晶 - Google Patents
(3s)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1h-咪唑-5-基]-7-[5-氯-2-(1h-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1h)-酮的新穎結晶 Download PDFInfo
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Abstract
本發明係提供一種(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮的新穎結晶形態。
本發明係提供一種(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)。
Description
本發明係關於(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮的新穎結晶等。
血栓及其併發症之血栓栓塞(以下稱為血栓栓塞性疾病)係與癌症一同佔據成人死亡原因的上位,近年來已成為重要的問題。血栓栓塞性疾病是由於在血管傷害部位形成血栓,或者該血栓游離並順著血流被送往其他血管內並阻塞血管而產生。血栓栓塞性疾病例如包含深部靜脈血栓與肺栓塞的總稱之靜脈血栓栓塞、中風、心絞痛、心肌梗塞、其他各種動脈及靜脈血栓等。
因血管的損傷等而顯現於血管壁之組織因子乃成為血液凝固級聯反應的起點,並與微量地存在於血中之血液凝固第VII因子形成複
合體。本複合體係活化血液凝固第IX因子及血液凝固第X因子,經活化的血液凝固第X因子將凝血酶原(Prothrombin)轉換為凝血酶(Thrombin)。凝血酶將纖維蛋白原(Fibrinogen)轉換為纖維蛋白(Fibrin),最終形成不溶性纖維蛋白(開始期)。此過程中所產生之凝血酶可考量為促進開始期的血栓形成,對於止血乃為重要,但亦有報導顯示會活化血液凝固第XI因子,並經介經活化的血液凝固第XI因子(以下亦稱為FXIa)而引起凝血酶的爆發性產生(增幅期),其結果使血栓增大(參考非專利文獻1至3)。
血栓栓塞性疾病的治療及/或預防一般是採用抗凝固藥劑,惟既有的抗凝固藥劑雖顯示出優異的抗血栓作用,但出血併發症之嚴重的副作用亦成為問題,或者為了不引起出血併發症而限制投藥量,可能無法發揮足夠的抗血栓作用。在此狀況下,需開發出一種可抑制病態性血栓的成長或增大並且不會影響止血血栓的形成之具有新穎的作用機轉之血栓或血栓栓塞的治療劑及/或預防劑。近年來,FXIa係作為該標的之一而受到矚目。血液凝固第XI因子為參與血液凝固的調節之血漿中絲胺酸蛋白酶(Serine Protease)之一,並藉由經活化的血液凝固第XII因子、凝血酶或本身而成為FXIa。FXIa於古典的血液凝固級聯反應中是稱為內因系或接觸系之血液凝固路徑的構成因子之一,藉由選擇性切斷Arg-Ala與Arg-Val間的肽鍵來活化血液凝固第IX因子。FXIa的安全性在稱為血友病C之人類的血液凝固第XI因子缺損症中,主要是從以術後或外傷後之輕度至中等程度的出血為特徵之觀察結果中得到支撐。再者,對於FXIa的效果與安全性之高度,除了人類之血液凝固第XI因子缺損症的觀察結果之
外,亦可從使用血液凝固第XI因子缺損小鼠之實驗性血栓及出血模式中的實驗結果以及使用猴子或兔子之實驗性血栓及出血模式中之抗血液凝固第XI因子中和抗體或反義的實驗結果中得到證明(參考非專利文獻4至8)。
從以上結果來看,可得知FXIa對於開發出抗血栓治療劑及/或預防劑者為無出血的副作用之極具魅力的標的,FXIa抑制劑乃令人期待成為不具有出血等的不良副作用之極強力且安全的抗血栓治療劑或預防劑。
於專利文獻1中係記載了(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(lH)-酮為選擇性血液凝固第XIa因子抑制劑,且有用於作為血栓栓塞疾病等治療藥。
[先前技術文獻]
[專利文獻]
[專利文獻1]日本國際公開第2016/093285號手冊
[非專利文獻]
[非專利文獻1]Blood Coagulation and Fibrinolysis, 2006年, 第17卷, 251-257頁
[非專利文獻2]Science, 1991年, 第253卷, 909至912頁
[非專利文獻3]Blood, 2003年, 第102卷, 953至955頁
[非專利文獻4]Journal of Thrombosis and Haemostasis, 2005年, 第3卷, 695至702頁
[非專利文獻5]Journal of Thrombosis and Haemostasis, 2006年, 第4卷, 1982至1988頁
[非專利文獻6]Blood, 2012年, 第119卷, 2401至2408頁
[非專利文獻7]Blood, 2009年, 第113卷, 936至944頁
[非專利文獻8]Journal of Thrombosis and Haemostasis, 2006年, 第4卷, 1496至1501頁
醫藥品的原藥較佳是容易處理且吸濕性、經口吸收性優異之結晶。於調查專利文獻1所記載之(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮的物性時,可得知游離體及二鹽酸鹽的結晶性顯著較低。此外,二水合物雖是結晶,但如後述般可得知其吸濕性高且經口吸收性低。從此等內容來看,係期待可取得一種能夠形成結晶且容易作為醫藥品來處理之優異的新穎原藥形態(鹽、溶劑合物或共結晶等)。因此,本發明之課題在於提供一種能夠以(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮的鹽、溶劑合物或共結晶來形成結晶,並且低吸濕性及/或經口吸收性優異之原藥形態。
本發明者們係為了解決上述課題而進行探討,結果發現到(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮在許多構形異構物(coformer)中,係與特定的構形異構物,亦即α-雷鎖酸(α-Resorcylic Acid)、龍膽酸(Gentisic Acid)、菸鹼醯胺及3-羥基苯甲酸形成結晶。此外,在進行更進一步的探討後,結果發現到在此等之中,(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)(以下有時略稱為化合物A或本發明化合物)之低吸濕性及/或經口吸收性優異,因而完成本發明。
本發明例如提供下述實施樣態。
[1]一種化合物,其係(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1);
[2]如前述[1]所述之化合物,其為結晶形態;
[3]如前述[2]所述之化合物,其為:於粉末X射線繞射光譜中,於約9.4、約14.1、約15.8、約16.5、約17.4、約18.4、約20.6以及約22.4度的繞射角(2θ)中具有至少2個繞射峰值之結晶形態;
[3-1]如前述[2]所述之化合物,其為:於粉末X射線繞射光譜中,於約9.4、約14.1、約15.8、約16.5、約17.4、約18.4、約20.6以及約22.4度的繞射角(2θ)中具有至少3個繞射峰值之結晶形態;
[3-2]如前述[2]所述之化合物,其為:於粉末X射線繞射光譜中,於約9.4、約14.1、約15.8、約16.5、約17.4、約18.4、約20.6以及約22.4度的繞射角(2θ)中具有至少4個繞射峰值之結晶形態;
[3-3]如前述[2]所述之化合物,其為:於粉末X射線繞射光譜中,於約9.4、約14.1、約15.8、約16.5、約17.4、約18.4、約20.6以及約22.4度的繞射角(2θ)中具有至少5個繞射峰值之結晶形態;
[3-4]如前述[2]所述之化合物,其為:於粉末X射線繞射光譜中,於約9.4、約14.1、約15.8、約16.5、約17.4、約18.4、約20.6以及約22.4度的繞射角(2θ)中具有繞射峰值之結晶形態;
[4]如前述[2]所述之化合物,其為:於粉末X射線繞射光譜中,於約9.4、約13.3、約14.1、約14.7、約15.1、約15.8、約16.5、約17.4、約17.7、約18.0、約18.4、約18.9、約19.3、約19.8、約20.6、約20.9、約22.4、約22.8、約23.2、約24.2、約25.0、約25.5、約25.8、約26.3、約27.2、約27.6、約27.9、約28.6、約29.5以及約31.0度的繞射角(2θ)中具有繞射峰值之結晶形態;
[5]如前述[2]所述之化合物,其為以第5圖所示之粉末X射線繞射光譜圖為特徵之結晶形態;
[6]如前述[2]至[5]或[3-1]至[3-4]中任一項所述之化合物,其為:於微差掃描熱量分析中,起始溫度約214℃或放熱峰值溫度約215℃之結晶形態;
[7]如前述[6]所述之化合物,其為以第10圖所示之微差掃描熱量分析圖為特徵之結晶形態;
[8]如前述[1]至[7]或[3-1]至[3-4]中任一項所述之化合物,其為共結晶;
[9]一種醫藥組成物,其係含有如前述[1]至[8]或[3-1]至[3-4]中任一項所述之化合物;
[10]如前述[9]所述之醫藥組成物,其為血液凝固第XIa因子抑制劑;
[11]如前述[10]所述之醫藥組成物,其為血液凝固第XIa因子相關疾病的預防及/或治療劑;
[12]如前述[11]所述之醫藥組成物,其中血液凝固第XIa因子相關疾病為血栓栓塞疾病;
[13]如前述[12]所述之醫藥組成物,其中血栓栓塞疾病為動脈性心血管血栓栓塞性障礙、靜脈性心血管血栓栓塞性障礙、動脈性腦血管血栓栓塞性障礙、靜脈性腦血管血栓栓塞性障礙、或者心腔或末梢循環中的血栓栓塞性障礙;
[14]如前述[12]所述之醫藥組成物,其中血栓栓塞疾病為中風、腦血栓、腦栓塞、靜脈血栓、靜脈血栓栓塞、深部靜脈血栓、或者因血液暴露於人工物表面之治療所引起之血栓及/或血栓栓塞;
[15]一種血栓栓塞疾病的預防及/或治療方法,其特徵為:將如前述[1]至[8]或[3-1]至[3-4]中任一項所述之化合物的有效量投藥至哺乳動物;
[16]如前述[1]至[8]或[3-1]至[3-4]中任一項所述之化合物,其係使用在血栓栓塞疾病的預防及/或治療;
[17]一種如前述[1]至[8]或[3-1]至[3-4]中任一項所述之化合物的使用,其係用於血栓栓塞疾病的預防及/或治療劑的製造;
[18]一種如前述[1]至[8]或[3-1]至[3-4]中任一項所述之化合物的製造方法,其特徵為:於製造步驟中使用乙酸乙酯;
[19]一種化合物,其係如下述結構式所示之化合物;
[20]一種化合物,其係(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮與3-羥基苯甲酸之共結晶。
[20-1]一種化合物,其係(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)。
[20-2]如[20-1]所述之化合物,其為結晶。
[20-3]如[20-2]所述之結晶,其於粉末X射線繞射光譜中,於約9.4、約14.1、約15.8、約16.5、約17.4、約18.4、約20.6以及約22.4度的繞射角(2θ)中具有至少2個繞射峰值。
[20-4]如[20-2]所述之結晶,其於粉末X射線繞射光譜中,於約9.4、約13.3、約14.1、約14.7、約15.1、約15.8、約16.5、約17.4、約17.7、約18.0、約18.4、約18.9、約19.3、約19.8、約20.6、約20.9、約22.4、約22.8、約23.2、約24.2、約25.0、約25.5、約25.8、約26.3、約27.2、約27.6、約27.9、約28.6、約29.5以及約31.0度的繞射角(2θ)中具有繞射峰值。
[20-5]如[20-2]所述之結晶,其係以第5圖所示之粉末X射線繞射光譜圖為特徵。
[20-6]如[20-2]或[20-3]所述之結晶,其於微差掃描熱量分析中,起始溫度約214℃或放熱峰值溫度約215℃。
[20-7]如[20-6]所述之結晶,其係以第10圖所示之微差掃描熱量分析圖為特徵。
[20-8]如[20-1]所述之化合物,其為共結晶。
[20-9]如[20-1]至[20-7]中任一項所述之結晶,其為共結晶。
[20-10]一種醫藥組成物,其係含有如[20-1]所述之化合物或如[20-2]所述之結晶。
[20-11]如[20-10]所述之醫藥組成物,其為血液凝固第XIa因子抑制劑。
[20-12]如[20-10]所述之醫藥組成物,其為血液凝固第XIa因子相關疾病的預防及/或治療劑。
[20-13]如[20-12]所述之醫藥組成物,其中血液凝固第XIa因子相關疾病為血栓栓塞疾病。
[20-14]如[20-13]所述之醫藥組成物,其中血栓栓塞疾病為動脈性心血管血栓栓塞性障礙、靜脈性心血管血栓栓塞性障礙、動脈性腦血管血栓栓塞性障礙、靜脈性腦血管血栓栓塞性障礙、或者心腔或末梢循環中的血栓栓塞性障礙。
[20-15]如[20-13]所述之醫藥組成物,其中血栓栓塞疾病為中風、腦血栓、腦栓塞、靜脈血栓、靜脈血栓栓塞、深部靜脈血栓、或者因血液暴露於人工物表面之治療所引起之血栓及/或血栓栓塞。
化合物A係有用於作為可形成結晶且低吸濕性及/或經口吸收性優異之醫藥品原藥。
第1圖表示實施例1(11)之化合物的粉末X射線繞射光譜圖表(縱軸表示強度(counts),橫軸表示2θ(度))。
第2圖表示實施例2之化合物的粉末X射線繞射光譜圖表(縱軸表示強度(counts),橫軸表示2θ(度))。
第3圖表示實施例3之化合物的粉末X射線繞射光譜圖表(縱軸表示強度(counts),橫軸表示2θ(度))。
第4圖表示實施例4之化合物的粉末X射線繞射光譜圖表(縱軸表示強度(counts),橫軸表示2θ(度))。
第5圖表示實施例5之化合物的粉末X射線繞射光譜圖表(縱軸表示強度(counts),橫軸表示2θ(度))。
第6圖表示實施例1(11)之化合物的微差掃描熱量分析(DSC:Differential Scanning Calorimetry)圖表(縱軸表示熱通量(W/g),橫軸表示溫度(℃))。
第7圖表示實施例2之化合物的微差掃描熱量分析(DSC)圖表(縱軸表示熱通量(W/g),橫軸表示溫度(℃))。
第8圖表示實施例3之化合物的微差掃描熱量分析(DSC)圖表(縱軸表示熱通量(W/g),橫軸表示溫度(℃))。
第9圖表示實施例4之化合物的微差掃描熱量分析(DSC)圖表(縱軸表示熱通量(W/g),橫軸表示溫度(℃))。
第10圖表示實施例5之化合物的微差掃描熱量分析(DSC)圖表(縱軸表示熱通量(W/g),橫軸表示溫度(℃))。
第11圖表示實施例1(11)之化合物的熱重分析(TG:Thermogravimetric Analysis)圖表(縱軸表示重量的變化率(Weight(%)),橫軸表示溫度(Temperature(℃)))。
第12圖表示實施例2之化合物的熱重分析(TG)圖表(縱軸表示重量的變化率(Weight(%)),橫軸表示溫度(Temperature(℃)))。
第13圖表示實施例3之化合物的熱重分析(TG)圖表(縱軸表示重量的變化率(Weight(%)),橫軸表示溫度(Temperature(℃)))。
第14圖表示實施例4之化合物的熱重分析(TG)圖表(縱軸表示重量的變化率(Weight(%)),橫軸表示溫度(Temperature(℃)))。
第15圖表示實施例5之化合物的熱重分析(TG)圖表(縱軸表示重量的變化率(Weight(%)),橫軸表示溫度(Temperature(℃)))。
第16圖表示實施例1(11)之化合物(二水合物)、實施例2之化合物(RES)、實施例3之化合物(GEN)、實施例4之化合物(NIA)以及實施例5之化合物(3HBA)的等溫吸附曲線(縱軸表示乾燥質量的變化(%),橫軸表示相對濕度(RH)(%))。
第17圖表示實施例1(11)之化合物(二水合物)、實施例4之化合物(NIA)以及實施例5之化合物(3HBA)的共結晶於猴子經口投藥時(1mg/kg)之血中濃度變遷(縱軸表示血漿中的化合物濃度(ng/mL),橫軸表示時間(h))。
以下詳細說明本發明。
於本發明中,所謂(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮,意指以下列結構式所表示之化合物。
(式中,記號
表示α配置,
表示β配置)
此外,如專利文獻1的實施例2(10)所記載,以上述結構式所表示之化合物亦可命名為(3S)-3-[2-(6-胺-2-氟-3-吡啶基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫-5(1H)-吲嗪酮。
於本發明中,所謂(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1),意指以下列結構式所表示之化合物。
(式中,所有記號表示與前述相同涵義)
此外,以上述結構式所表示之化合物亦可命名為:
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1:1)、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-一-3-羥基苯甲酸合物、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1:1)、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-一-3-羥基苯甲酸合物、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮‧-3-羥基苯甲酸(1/1)、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮‧-3-羥基苯甲酸(1:1)、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮‧一-3-羥基苯甲酸合物、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮‧-3-羥基苯甲酸、
(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸、或者
(3S)-3-[2-(6-Amino-2-fluoropyridin-3-yl)-4-fluoro-1H-imidazol-5-yl]-7-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]-2,3-dihydroindolizin-5(1H)-one mono-3-hydroxybenzoate。
化合物名的表記上,(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮與3-羥基苯甲酸之間的連字符(-),如下述第1表所示般有時以全形短劃(em Dash)來表示,有時以兩個連字符(--)來表示。
化合物A的某形態例如為加成物。所謂加成物,意指兩個不同的分子(A)與(B)係以鍵結的性質雖產生變化但不論何方的分子皆無原子的增減之形式直接鍵結(加成)所產生之新穎的化學種類(AB)。加成物包含鹽或共結晶。
化合物A於一實施形態中,為(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮與3-羥基苯甲酸之加成物。
化合物A於一實施形態中,為(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮與3-羥基苯甲酸之共結晶。化合物A係藉由以下(a)及(b)的至少一種物理化學資料而賦予特徵。較佳係藉由(a)及(b)兩者的物理化學資料而賦予特徵。(a)(i)第5圖所示之粉末X射線繞射光譜,(ii)第5圖所示之粉末X射線繞射光譜的繞射角(2θ),(iii)具有與第6表所示之繞射角(2θ)
實質上相同的繞射角(2θ)(約9.4、約13.3、約14.1、約14.7、約15.1、約15.8、約16.5、約17.4、約17.7、約18.0、約18.4、約18.9、約19.3、約19.8、約20.6、約20.9、約22.4、約22.8、約23.2、約24.2、約25.0、約25.5、約25.8、約26.3、約27.2、約27.6、約27.9、約28.6、約29.5以及約31.0度)之粉末X射線繞射光譜,(iv)於選自與第6表所示之繞射角(2θ)實質上相同的繞射角(2θ)之繞射角(2θ)中具有至少1個、2個、3個、4個、5個或超過5個峰值之粉末X射線繞射光譜,或(v)於選自約9.4、約14.1、約15.8、約16.5、約17.4、約18.4、約20.6以及約22.4度之繞射角(2θ)中具有至少1個、2個、3個、4個、5個或超過5個峰值之粉末X射線繞射光譜,(b)為第10圖所示之微差掃描熱量分析(DSC)、或者具有起始溫度約214℃或放熱峰值溫度約215℃之放熱峰值。
[同位素標識化]
化合物A可藉由同位元素來取代1個以上的原子,經同位素標識化之化合物A,例如嵌入有放射性同位素之化合物A在藥物及/或基質的組織分布研究等乃為有用。上述同位元素例如可列舉出2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、35S、18F、36Cl、123I、125I等。
[毒性]
由於化合物A的毒性低,所以可安全地使用。
[對醫藥品之適用]
化合物A具有強力的FXIa抑制活性。因此,本發明化合物對於血栓栓塞性疾病,例如動脈性心血管血栓栓塞性障礙、靜脈性心血管血栓栓塞性障礙、動脈性腦血管血栓栓塞性障礙、靜脈性腦血管血栓栓塞性障礙、或者心腔或末梢循環中的血栓栓塞性障礙之預防及/或治療為有用。
動脈性心血管血栓栓塞性障礙例如可列舉出冠狀動脈疾病、缺血性心肌症、急性冠心症候群、冠狀動脈血栓、不穩定心絞痛及非Q波心肌梗塞的缺血性併發症、經醫學性管理或伴隨著經皮冠狀動脈介入治療之ST上升型及/或非ST上升型急性心肌梗塞、穩定(勞作性)心絞痛等之心絞痛、異型心絞痛、不穩定心絞痛、心肌梗塞(初次心肌梗塞或再發性心肌梗塞等)、急性心肌梗塞、冠狀動脈繞道手術後的血管再阻塞及狹窄、經皮經管的血管形成術、心臟/經冠狀動脈支架留置手術後或用於冠狀動脈之血栓溶解療法後的再阻塞及狹窄或缺血性猝死等。
靜脈性心血管血栓栓塞性障礙例如可列舉出主要的一般外科手術、腹部手術、人工股關節置換術、膝關節置換術、股關節骨折手術、多發骨折、多發外傷、外傷、脊髓損傷、燒傷時或重症管理室入室時之深靜脈血栓(DVT:Deep Vein Thrombosis)及/或肺栓塞(PE:Pulmonary Embolism)、身體活動顯著受限之急性內科疾病患者之DVT及/或PE、癌化學療法施行患者之DVT及/或PE、中風患者之DVT及/或PE、不論有無PE之症候性或無症候性的DVT等。
動脈性腦血管血栓栓塞性障礙例如可列舉出中風、缺血性中風、腦梗塞急性期、非瓣膜症性心房顫動或瓣膜症性心房顫動患者之中
風、大腦動脈血栓、腦梗塞、暫時性腦缺血(TIA:Transient Ischemic Attack)、陷窩性梗塞、粉瘤性血栓性腦梗塞、Branch atheromatous disease(BAD:分支動脈粥狀硬化)、大腦動脈栓塞、腦血栓、腦血管障礙、無症候性腦梗塞或腦血管性認知症等。
靜脈性腦血管血栓栓塞性障礙例如可列舉出頭蓋內靜脈血栓、腦栓塞、腦血栓、腦靜脈洞血栓、頭蓋內靜脈洞血栓或海綿靜脈洞血栓等。
心腔或末梢循環中的血栓栓塞性疾病例如可列舉出靜脈血栓、全身性靜脈血栓栓塞、再發性靜脈血栓栓塞、血栓性靜脈炎、非瓣膜症及瓣膜症性心房顫動、心原性栓塞、散播性血管內凝血症候群(DIC:Disseminated Intravascular Coagulation)、敗血症、急性呼吸窘迫症候群(ARDS:Acute Respiratory Distress Syndrome)、急性肺損傷(ALI:Acute Lung Injury)、慢性阻塞性肺疾病、抗磷脂質抗體症候群、肝栓塞、肝靜脈阻塞(VOD:Veno-Occlusive Disease)、腎臟栓塞、腎靜脈血栓、腎動脈阻塞、由膜性腎症或巢狀腎絲球硬化所導致之腎病、脾靜脈血栓、上腸繫膜動脈阻塞、門脈血栓、視網膜靜脈阻塞、粉瘤性動脈硬化、粉瘤血栓、末梢動脈阻塞性疾病(PAOD:Peripheral Arterial Occlusive Disease)、末梢動脈疾病、動脈栓塞、糖尿病及代謝症候群以及此等之續發症、或者因血液暴露於促進血栓形成之人工物(醫療用植入物、醫療用裝置、導管、支架、人工心臟閥、人工心肺或血液透析器等)的表面之治療所引起之血栓等。
血栓栓塞性疾病較佳可列舉出冠狀動脈疾病、不穩定心絞痛、急性冠心症候群、心房顫動、心肌梗塞(初次心肌梗塞或再發性心肌梗塞等)、缺血性猝死、暫時性腦缺血發作、中風、末梢動脈疾病、粉瘤性動脈硬化、末梢阻塞性動脈疾病、靜脈血栓、靜脈血栓栓塞、深部靜脈血栓、血栓性靜脈炎、動脈栓塞、冠狀動脈血栓、大腦動脈血栓、腦栓塞、腎臟栓塞、門脈血栓、肺栓塞、肺梗塞、肝栓塞、肝靜脈阻塞(VOD)/肝竇阻塞候群(SOS:Sinusoidal Obstruction Syndrome)、血栓性微血管障礙症(TMA:Thrombotic Microangiopathy)、散播性血管內凝血症候群(DIC)、敗血症、急性呼吸窘迫症候群(ARDS)、急性肺損傷(ALI)、抗磷脂質抗體症候群、起因於冠狀動脈繞道移植(Graft)手術之血栓或者因血液暴露於促進血栓之人工物(醫療用植入物、醫療用裝置、導管、支架、人工心臟閥、人工心肺或血液透析器等)的表面之治療所引起之血栓等。
於本說明書中,心房顫動、粉瘤性硬化症或敗血症包含由心房顫動、粉瘤性硬化症或敗血症所引起之血栓栓塞性疾病。
血栓栓塞性疾病尤佳可列舉出中風、腦血栓、腦栓塞、靜脈血栓、靜脈血栓栓塞、深部靜脈血栓、或者因血液暴露於人工物表面之治療所引起之血栓及/或血栓栓塞。
靜脈血栓栓塞(VTE:Venous Thromboembolism)中,係包含深靜脈血栓(DVT)、肺栓塞(PE)或伴隨著深靜脈血栓之肺栓塞。VTE的預防及/或治療包含深靜脈血栓及肺血栓栓塞的治療及/或再發抑制、下肢整形外科手術(人工膝關節全置換術、人工股關節全置換術或股關節骨折
術等)施行患者之VTE的發症抑制、身體活動顯著受限之急性內科疾病患者之DVT及/或PE的發症抑制、腹部外科手術施行患者於術中及/或術後之VTE的發症抑制、癌化學療法施行患者之DVT及/或PE的發症抑制。
缺血性中風的預防及/或治療中,係包含非瓣膜症性心房顫動患者之缺血性中風及全身性栓塞的發症抑制及/或治療、無法特定出栓塞源之栓塞性中風(ESUS:Embolic Stroke of Undetermined Source)患者之再發性中風及全身性栓塞的發症抑制及/或治療、共併了急性冠心症候群(ACS:Acute Coronary Syndrome)之心房顫動患者之缺血性中風及全身性栓塞的發症抑制及/或治療、伴隨著慢性腎臟病(CKD:Chronic Kidney Disease)或末期腎衰竭之心房顫動患者之缺血性中風及全身性栓塞的發症抑制及/或治療、分支動脈粥狀硬化(BAD)的再發抑制及/或治療、缺血性中風(排除心源性腦栓塞)後的再發抑制及/或治療。
因血液暴露於促進血栓形成之人工物表面之治療所引起之血栓栓塞性疾病的預防及/或治療中,係包含人工閥置換術施行患者之血栓栓塞性疾病的預防及/或治療、植入型、全置換型、經皮性或體外設置型等之輔助人工心臟的裝著患者之血栓栓塞性疾病的預防及/或治療、冠狀動脈支架留置患者之血栓栓塞性疾病的預防及/或治療。
急性冠心症候群(ACS)、冠狀動脈疾病、末梢動脈疾病的預防及/或治療中,係包含急性冠心症候群(ACS)患者之心血管事件的抑制、冠狀動脈疾病或末梢動脈疾病患者之心血管事件的抑制、心血管風險高之糖尿病患者(尤佳為第二型糖尿病患者)之心血管事件的抑制。
此外,由於化合物A具有血漿血管舒緩素抑制作用,故有用於血漿血管舒緩素所參與之疾病的預防及/或治療。
血漿血管舒緩素所參與之疾病例如可列舉出視網膜病變、糖尿病性視網膜病變、高血壓性視網膜病變、增殖性或非增殖性視網膜病變、老年性黃斑部病變(AMD:Age-related Macular Degeneration)、血腫的預防及/或治療、與血管穿透性增加相關之障礙、水腫相關疾病、遺傳性血管水腫(HAE:Hereditary Angioedema)、糖尿病性黃斑水腫(DME:Diabetic Macular Edema)、有臨床意義黃斑水腫(CSME:Clinically Significant Macular Edema)、黃斑囊樣水腫(CME:Cystoid Macular Edema)、視網膜水腫、神經膠原相關水腫、腦水腫、淋巴水腫、血管水腫、外傷性腦障礙、出血性中風、腦內出血、腦動脈瘤、動靜脈畸形、脊髓損傷、缺血再灌流傷害、缺血、腦缺血、疼痛、伴隨發炎因子之障礙、腦炎、多發性硬化症、搔癢、關節炎、發炎性腸疾病、痛風、乾癬、星狀細胞活化相關疾病、阿茲海默症、帕金森氏症、肌肉萎縮性側索硬化症、庫賈氏病、癲癇、原發性高血壓、與糖尿病或高血脂相關之血壓上升、腎衰竭、慢性腎疾病、心臟衰竭、蛋白尿或手術時的失血等。
血漿血管舒緩素所參與之疾病較佳可列舉出水腫相關疾病、遺傳性血管水腫、黃斑水腫、腦水腫、視網膜病變、與缺血再灌流傷害相關之水腫形成、心肺繞道或冠狀動脈繞道移植等之手術中的失血等。
在將化合物A適用在醫藥時,不僅可將本發明化合物以單劑來使用,例如亦可與:
(1)其預防、治療及/或症狀改善效果的補足及/或增強,
(2)其動態及吸收改善、投藥量的降低,以及/或者
(3)用於減輕其副作用之其他成分之例如以下所列舉之藥劑等組合使用。
在將化合物A使用在血栓栓塞性疾病的預防及/或治療之情形下,與化合物A組合使用之藥劑例如可列舉出抗凝固劑、抗血小板劑、血栓溶解劑、纖維素溶解劑、絲胺酸蛋白酶抑制劑、彈性蛋白酶抑制劑、類固醇或此等之組合等。
抗凝固劑可列舉出凝血酶抑制劑、抗凝血酶III活化劑、肝素補足因子II活化劑、其他FXIa抑制劑、血漿及/或組織血管舒緩素抑制劑、血漿蛋白原活化抑制因子(PAI-1)、凝血酶活化纖維溶解抑制劑(TAFI:Thrombin-Activatable Fibrinolysis Inhibitor)抑制劑、第VIIa因子抑制劑、第VIIIa因子抑制劑、第IXa因子抑制劑、第Xa因子抑制劑、第XIIa因子抑制劑或此等之組合等。
抗血小板劑可列舉出GPII/IIIa阻斷劑、蛋白酶活化受體(PAR-1)拮抗劑、PAR-4拮抗劑、磷酸二酯酶III抑制劑、其他磷酸二酯酶抑制劑、P2X1拮抗劑、P2Y1受體拮抗劑、P2Y12拮抗劑、凝血脂素受體拮抗劑、凝血脂素A2合成酶抑制劑、環氧合酶-1抑制劑、磷脂酶D1抑制劑、磷脂酶D2抑制劑、磷脂酶D抑制劑、醣蛋白質VI(GPVI)拮抗劑、醣蛋白質Ib(GPIB)拮抗劑、GAS6拮抗劑、阿斯匹靈或此等之組合等。
與化合物A組合使用之藥劑較佳為抗血小板劑。
抗血小板劑較佳可列舉出氯吡格雷(Clopidogrel)、普拉格雷(Prasugrel)、替格瑞洛(Ticagrelor)、坎格雷洛(Cangrelor)、依諾格雷(Elinogrel)、西洛他唑(Cilostazol)、沙格雷酯(Sarpogrelate)、依洛前列素(Iloprost)、貝拉前列素(Beraprost)、利馬前列素(Limaprost)及/或阿斯匹靈或此等之組合等。
與化合物A組合使用之藥劑較佳為殺鼠靈(Warfarin)、未區分肝素、低分子量肝素、依諾肝素(Enoxaparin)、達肝素(Dalteparin)、貝米肝素(Bemiparin)、亭扎肝素(Tinzaparin)、和司莫肝素(Semuloparin)、鈉(AVE-5026)、達那肝素(Danaparoid)、合成五醣、磺達肝素(Fondaparinux)、水蛭素(Hirudin)、二硫酸根合水蛭素(Disulfatohirudin)、來匹盧定(Lepirudin)、比伐盧定(Bivalirudin)、地西盧定(Desirudin)、阿加曲班(Argatroban)、阿斯匹靈、布洛芬(Ibuprofen)、萘普生(Naproxen)、舒林酸(Sulindac)、吲哚美辛(Indometacin)、甲芬那酸(Mefenamate)、屈昔康(Droxicam)、雙氯芬酸(Diclofenac)、磺胺吡唑酮(Sulfinpyrazone)、匹洛西卡(Piroxicam)、噻氯匹定(Ticlopidine)、氯吡格雷、普拉格雷、替格瑞洛、坎格雷洛、依諾格雷、西洛他唑、沙格雷酯、依洛前列素、貝拉前列素、利馬前列素、替羅菲班(Tirofiban)、伊巴肽(Eptifibatide)、阿昔單抗(Abciximab)、美拉加群(Melagatran)、希美加群(Ximelagatran)、達比加群(Dabigatran)、利伐沙班(Rivaroxaban)、阿哌沙班(Apixaban)、里先安(Edoxaban)、達雷沙班(Darexaban)、貝曲沙班(Betrixaban)、TAK-442、組織胞漿素原活化因子、改變型組織胞漿素原活化因子、阿尼普酶(Anistreplase)、尿激酶
(Urokinase)、鏈激酶(Streptokinase)、加貝沙酸酯(Gabexate)、甲磺酸加貝沙酸酯(Gabexate Mesilate)、萘莫斯他(Nafamostat)、西維來斯他(Sivelestat)、西維來斯他鈉水合物、Alvelestat(AZD-9668)、ZD-8321/0892、ICI-200880、Human Elafin(tiprelestat)、彈力素(Elafin)、α1-抗胰蛋白酶(A1AT)、可體松(Cortisone)、倍他米松(Betamethasone)、地塞米松(Dexamethasone)、氫可體松、甲基潑尼松龍(Methyl Prednisolone)、潑尼松龍及去炎松(Triamcinolone)或此等之組合。
於其他實施形態中,與化合物A組合使用之藥劑例如可列舉出鉀通道開口劑、鉀通道阻斷劑、鈣通道阻斷劑、氫鈉交換輸送體抑制劑、抗心律不整劑、抗動脈硬化劑、抗凝固劑、抗血小板劑、抗血栓劑、血栓溶解劑、纖維蛋白原拮抗劑、利尿降壓劑、ATP酶抑制劑、電解質腎上腺皮質素受體拮抗劑、磷酸二酯酶抑制劑、抗糖尿病劑、蛋白酶抑制劑、彈性蛋白酶抑制劑、抗發炎劑、抗氧化劑、血管新生調節物、骨質疏鬆症治療劑、賀爾蒙補充療法、賀爾蒙受體調節物、經口避孕藥、抗肥胖藥、抗憂鬱藥、抗焦慮劑、抗精神病劑、抗增殖劑、抗腫瘤劑、抗潰瘍及胃食道逆流劑、成長賀爾蒙劑及/或成長賀爾蒙分泌促進物質、甲狀腺模仿藥、抗感染劑、抗病毒劑、抗菌劑、抗真菌劑、膽固醇/脂質異常症治療藥及脂質分布改善療法、以及虛擬缺血性預處理及/或心肌頓抑劑或此等之組合等。
於其他實施形態中,與化合物A組合使用之藥劑例如可列舉出抗心律不整劑、抗高血壓劑、抗凝固劑、抗血小板劑、血栓溶解劑、
纖維素溶解劑、鈣通道阻斷劑、鉀通道阻斷劑、膽固醇/脂質降低劑、絲胺酸蛋白酶抑制劑、彈性蛋白酶抑制劑、抗發炎劑或此等之組合等。
抗心律不整劑可列舉出IKur抑制劑、彈性蛋白酶抑制劑、絲胺酸蛋白酶抑制劑、類固醇等。
抗高血壓劑可列舉出ACE抑制劑、AT-1受體抑制劑、β-腎上腺素受體拮抗劑、ETA受體拮抗劑、雙重ETA/AT-1受體拮抗劑、血管肽酶抑制劑等。
於較佳實施形態中,與化合物A組合使用之藥劑為抗血小板劑或此等之組合。
與化合物A組合使用之藥劑可以於1個製劑中調配有兩成分之調配劑的形態來投藥,或者設為在同一投藥路徑或不同投藥路徑中將各別的製劑投藥之形態。在將各別的製劑投藥之情形下,不一定需同時投藥,可視需要對投藥賦予時間差。此外,在對投藥賦予時間差之情形下,投藥的順序並無特別限制,以可得到期望的藥效之方式來適當地調節即可。
與化合物A組合使用之此等其他藥劑的投藥量,係可以該藥劑或類似藥於臨床上所使用之用量為基準來適當地增減。此外,本發明化合物與其他藥劑之調配比可考量投藥對象的年齡或體重、投藥方法、投藥時間、對象疾病、症狀等來適當地調節。相對於1重量份的本發明化合物,大致上可組合0.01至100重量份的其他藥劑。其他藥劑可使用複數種。此外,其他藥劑除了上述所列舉之外,亦可為與其具有相同機轉之藥物。此藥物不僅是至目前為止尚未發現者,亦包含往後所研發出者。
化合物A通常是全體性或局部性地以經口或非經口的形式來投藥。經口劑例如可列舉出內服用液劑(例如酏劑、糖漿、藥劑上所容許之水劑、懸浮劑、乳劑)、內服用固形劑(例如錠劑(包含舌下錠、口腔內崩解錠)、丸劑、膠囊劑(包含硬膠囊、軟膠囊、明膠膠囊、微膠囊)、散劑、顆粒劑、口含劑)等。非經口劑例如可列舉出液劑(例如注射劑(玻璃體內注射劑、皮下注射劑、靜脈內注射劑、肌肉內注射劑、腹腔內注射劑、點滴劑等)、點眼劑(例如水性點眼劑(水性點眼液、水性懸浮點眼液、黏性點眼液、可溶化點眼液等)、非水性點眼劑(非水性點眼液、非水性懸浮點眼液等)等)、外用劑(例如軟膏(眼軟膏等))、點耳劑等。此等製劑可為速釋放性製劑、緩釋放性製劑等之釋放控制劑。此等製劑可藉由一般所知的方法,例如日本藥典所記載之方法等來製造。
作為經口劑的內服用液劑例如可藉由使有效成分溶解、懸浮或乳化於一般所使用之懸浮劑(例如純化水、乙醇或此等之混合液)而製造。再者,此液劑可含有濕潤劑、懸浮化劑、乳化劑、甘味劑、風味劑、芳香劑、保存劑、緩衝劑等。
作為經口劑的內服用固形劑例如可將有效成分與賦形劑(例如乳糖、甘露醇、葡萄糖、微晶纖維素、澱粉等)、結合劑(例如羥丙基纖維素、聚乙烯吡咯啶酮、偏矽酸烏敏酸鈉等)、崩解劑(例如纖維素甘醇酸鈣等)、潤滑劑(例如硬脂酸鎂等)、穩定劑、溶解輔助劑(麩胺酸、天門冬胺酸等)等混合,並依循常用方法而製劑化。此外,可視需要以塗覆劑(例如白糖、明膠、羥丙基纖維素、羥丙基甲基纖維素鄰苯二甲酸酯等)來被覆,此外亦可由2層以上的層來被覆。
作為非經口劑的外用劑可藉由一般所知的方法或通常所使用之處方來製造。例如,軟膏劑可使有效成分研磨混合或熔融於基礎劑而製造。軟膏基礎劑可選自一般所知或通常所使用者。例如可單獨或混合2種以上之選自高級脂肪酸或高級脂肪酸酯(例如己二酸、肉豆蔻酸、棕櫚酸、硬脂酸、油酸、己二酸酯、肉豆蔻酸酯、棕櫚酸酯、硬脂酸酯、油酸酯等)、蠟類(例如蜜蠟、鯨蠟、精製地蠟等)、界面活性劑(例如聚氧乙烯烷基醚磷酸酯等)、高級醇(例如鯨蠟醇、硬脂醇、鯨蠟硬脂醇等)、矽油(例如二甲基聚矽氧烷等)、烴類(例如親水凡士林、白色凡士林、精製羊脂膏、流動石蠟等)、二醇類(例如乙二醇、二乙二醇、丙二醇、聚乙二醇、聚乙烯二醇等)、植物油(例如蓖麻油、橄欖油、芝麻油、松節油等)、動物油(例如貂油、蛋黃油、角鯊烷、角鯊烯等)、水、吸收促進劑、抗斑疹劑者而使用。再者,亦可含有保濕劑、保存劑、穩定化劑、抗氧化劑、香味劑等。
作為非經口劑的注射劑中,係包含溶解或懸浮於溶液、懸浮液、乳化液及用時溶解型溶劑而使用之固形的注射劑。注射劑例如使有效成分溶解、懸浮或乳化於溶劑而使用。溶劑例如可使用注射用蒸餾水、生理食鹽水、植物油、丙二醇、聚乙二醇、乙醇般之醇類等及此等之組合。再者,此注射劑亦可含有穩定劑、溶解輔助劑(麩胺酸、天門冬胺酸、Polysorbate 80(註冊商標)等)、懸浮化劑、乳化劑、無痛化劑、緩衝劑、保存劑等。此等於最終步驟中進行殺菌或者藉由無菌操作法來製造。此外,亦可製造無菌的固形劑,例如凍結乾燥品並在其使用前溶解於無菌化或無菌的注射用蒸餾水或其他溶劑而使用。
以上述目的來使用化合物A或者化合物A與其他藥劑時,通常是全體性或局部性地以經口或非經口的形式來投藥。投藥量因年齡、體重、症狀、治療效果、投藥方法、處理時間等而有所不同,通常成人每人每次於1ng至1000mg的範圍內一日一次至數次經口投藥,或者成人每人每次於0.1ng至10mg的範圍內一日一次至數次非經口投藥,或者是一日於1小時至24小時的範圍內持續投藥至靜脈內。當然如前述般,由於投藥量因各種條件而變動,所以有時以少於上述投藥量之量即足夠,有時亦須超過範圍來投藥。
於本發明中,(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮或其鹽、溶劑合物或共結晶等,例如可藉由後述實施例以及依據此等之方法來製造。於進行再結晶時,可使用或不使用種晶。
[實施例]
以下係藉由實施例來詳細說明本發明,惟本發明並不限定於此等。
由層析法所分離之處以及以TLC所示之括弧內的溶劑係表示所使用之溶出溶劑或擴展溶劑,比率表示體積比。
NMR之處所顯示之括弧內係表示測定所使用之溶劑。
本說明書中所使用之化合物一般係採用依據IUPAC的規則來進行命名之電腦程式,Advanced Chemistry Development公司ACD/Name(註冊商標),或依據IUPAC命名法所命名者。
以下實施例中的LC/MS分析中所使用之測定時間、溶劑及管柱條件如以下所示。tR意指保持時間。
條件a.管柱YMC-Triart C18、2.0mm×30mm、1.9μm;管柱溫度30℃;移動相(A液)0.1%三氟乙酸水溶液及(B液)0.1%三氟乙酸乙腈溶液;流速1.0mL/min;分析時間1.5分;梯度:0分(A液/B液=95/5)、0.1分(A液/B液=95/5)、1.2分(A液/B液=5/95)、1.4分(A液/B液=5/95)、1.41分(A液/B液=95/5)、1.5分(A液/B液=95/5)
條件b.管柱Waters ACQUITY UPLA(註冊商標)BEH C18、2.1mm×30mm、1.7μm;管柱溫度40℃;移動相(A液)0.1%甲酸水溶液及(B液)0.1%甲酸乙腈溶液;流速1.0mL/min;分析時間1.5分;梯度:0分(A液/B液=95/5)、0.1分(A液/B液=95/5)、1.2分(A液/B液=5/95)、1.4分(A液/B液=5/95)、1.41分(A液/B液=95/5)、1.5分(A液/B液=95/5)
[實驗例]
實施例1(1):6-氟-5-碘-2-吡啶胺
於冰冷卻下將N-碘琥珀醯亞胺(56.5g)分批投入(3次)於6-氟-2-吡啶胺(25.6g)的N,N-二甲基甲醯胺(200mL)溶液。於室溫下攪拌3小時後,將自來水(0.5L)加入於反應液。藉由乙酸乙酯/己烷(1/1、300mL)萃取3次,並以飽和亞硫酸水溶液(0.5L)、飽和碳酸鈉水溶液(0.5L、2次)、自來水(0.5L)、飽和食鹽水(0.5L)來洗淨有機層,進行乾燥後濃縮。將己烷/乙酸乙酯(3/1、150mL)加入於所得到之殘渣,於室溫下進行漿液洗淨並
過濾。乾燥所得到之固體而得到具有以下的物性值之標題化合物(36.7g)。
TLC:Rf 0.56(乙酸乙酯:己烷=1:2)
實施例1(2):雙(2-甲基-2-丙基)(6-氟-5-碘-2-吡啶基)醯亞胺二碳酸酯
將二碳酸二(三級丁基)酯(74.0g)的乙腈(100mL)溶液加入於實施例1(1)中所製造之化合物(36.7g)與4-二甲基胺吡啶(0.9g)的乙腈(300mL)溶液,於室溫下攪拌3小時。將反應溶液濃縮並將所得到之殘渣溶解於乙酸乙酯(500mL),以飽和氯化銨水溶液(400mL)洗淨並藉由乙酸乙酯(200mL)來萃取水層。將所調配之有機層乾燥後濃縮。藉由二氧化矽凝膠管柱層析來精製(乙酸乙酯:己烷=5:95→10:90)所得到之殘渣,而得到具有以下的物性值之標題化合物(45.06g)。
1H-NMR(CDCl3):δ 8.14(t,1H),7.03(dd,1H),1.47(s,18H)。
實施例1(3):2-甲基-2-丙基(5-氰基-6-氟-2-吡啶基)胺甲酸酯
於減壓下對實施例1(2)中所製造之化合物(9.1g)、氰化鋅(II)(7.32g)、肆(三苯基膦)鈀(0)(1.2g)的1-甲基-2-吡咯啶酮(60mL)溶液進行脫氣。在微波照射下於130℃攪拌1小時後放置冷卻。藉由乙酸乙酯(100mL)稀釋反應溶液後,藉由矽藻土過濾來去除不溶物並藉由乙酸乙酯(50mL)來洗淨不溶物。將濾液分液並藉由乙酸乙酯(100mL)對水層進行再萃取。調配有機層並於乾燥後濃縮,藉由二氧化矽凝膠管柱層析來精製
(乙酸乙酯:己烷=5:95→80:20)所得到之殘渣,而得到具有以下的物性值之標題化合物(2.1g)。
TLC:Rf 0.25(乙酸乙酯:己烷=10:90)
實施例1(4):2-甲基-2-丙基[6-氟-5-(N-羥基甲脒基)-2-吡啶基]胺甲酸酯
將N,N-二異丙基乙胺(2.84mL)加入於實施例1(3)中所製造之化合物(1.56g)與羥基胺鹽酸鹽(0.91g)的乙醇(40mL)溶液,於40℃攪拌一整晚。將反應溶液濃縮並將所得到之殘渣溶解於乙酸乙酯(50mL),加入自來水(50mL)並洗淨後,將有機層乾燥後濃縮而得到具有以下的物性值之未精製的標題化合物(1.93g)。
LC/MS tR 0.60分;MS(ES+)m/z 271(M+H)(條件a)。
實施例1(5):2-甲基-2-丙基(5-甲脒基-6-氟-2-吡啶基)胺甲酸酯 乙酸鹽
將乙酸酐(0.75mL)加入於實施例1(4)中所製造之化合物(1.93g)的乙酸(10mL)溶液,於室溫下攪拌1小時。將氫氧化鈀(II)(20%、250mg)加入於反應液,並在氫氣環境下於室溫下攪拌3小時。藉由矽藻土來過濾反應液並將濾液減壓濃縮而得到具有以下的物性值之未精製的標題化合物(2.99g)。
LC/MS tR 0.59分;MS(ES+)m/z 255(M+H)(條件a)。
實施例1(6):2-甲基-2-丙基(5-甲脒基-6-氟-2-吡啶基)胺甲酸酯 鹽酸鹽
將10%氯化氫/甲醇(6.5mL)溶液加入於實施例1(5)中所製造之化合物(2.6g)的甲醇(10mL)溶液,於室溫下攪拌10分鐘。將甲苯加入於反應液並濃縮而得到具有以下的物性值之未精製的標題化合物(2.63g)。
LC/MS tR 0.58分;MS(ES+)m/z 255(M+H)(條件a)。
實施例1(7):(3S)-3-(氯乙醯基)-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫-5(1H)-吲嗪酮
於冰冷卻下將1-氯-N,N,2-三甲基-1-丙烯-1-胺(1.33mL)加入於(3S)-7-[5-氯-2-(1H-1,2,3,4-四唑-1-基)苯基]-5-側氧-1,2,3,5-四氫吲嗪-3-羧酸(記載於日本國際公開第2013/093484號手冊的實施例9)(3.0g)的二氯甲烷(15mL)溶液,於0℃攪拌40分鐘。加入三甲基矽基重氮甲烷(2M己烷溶液、8.4mL)後,更於0℃攪拌1小時。於冰冷卻下加入濃鹽酸(0.87mL)並於室溫下攪拌20分鐘。將自來水(50mL)加入於反應液並藉由二氯甲烷(50mL)萃取2次。將有機層乾燥後濃縮,並藉由二氧化矽凝膠管柱層析來精製(乙酸乙酯:己烷=40:60→100:0)所得到之殘渣,而得到具有以下的物性值之標題化合物(2.32g)。
LC/MS tR 0.80分;MS(ES+)m/z 390(M+H)(條件a)。
實施例1(8):2-甲基-2-丙基[5-(5-{7-[5-氯-2-(1H-四唑-1-基)苯基]-5-側氧-1,2,3,5-四氫-3-吲嗪基}-1H-咪唑-2-基)-6-氟-2-吡啶基]胺甲酸酯
將碳酸鉀(0.70g)加入於實施例1(6)中所製造之化合物(1.5g)及實施例1(7)中所製造之化合物(1.0g)的乙腈(50mL)溶液,於80℃攪拌17小時。
藉由乙酸乙酯(100mL)稀釋反應溶液後,以自來水(100mL)、飽和食鹽水(200mL)來洗淨並進行乾燥後濃縮。藉由二氧化矽凝膠管柱層析來精製(乙酸乙酯:己烷=50:50→100:0,接著為甲醇:乙酸乙酯=5:95)所得到之殘渣,而得到具有以下的物性值之標題化合物(1.11g)。
LC/MS tR 0.81分;MS(ES+)m/z 590(M+H)(條件a)。
實施例1(9):2-甲基-2-丙基[5-(5-{(3S)-7-[5-氯-2-(1H-四唑-1-基)苯基]-5-側氧-1,2,3,5-四氫-3-吲嗪基}-4-氟-1H-咪唑-2-基)-6-氟-2-吡啶基]胺甲酸酯以及2-甲基-2-丙基[5-(5-{(3R)-7-[5-氯-2-(1H-四唑-1-基)苯基]-5-側氧-1,2,3,5-四氫-3-吲嗪基}-4-氟-1H-咪唑-2-基)-6-氟-2-吡啶基]胺甲酸酯
將1-氯甲基-4-氟-1,4-重氮雙環[2.2.2]辛烷雙(四氟硼酸酯)(selectfluor(註冊商標))(95mg)加入於實施例1(8)中所製造之化合物(264mg)及碳酸鈉(118mg)的乙腈(10mL)/四氫呋喃(5mL)懸浮液,於冰/食鹽浴的冷卻下攪拌3小時。藉由乙酸乙酯(20mL)稀釋反應溶液並加入亞硫酸鈉水溶液(40mL)。藉由乙酸乙酯(50mL)來萃取水層2次,並將所調配之有機層乾燥後濃縮。藉由二氧化矽凝膠管柱層析來精製(胺基二氧化矽、乙酸乙酯:己烷=50:50→100:0,接著為甲醇:乙酸乙酯=5:95)所得到之殘渣,而得到實施例1(9)的S體化合物與R體化合物之混合物(71.2mg)。藉由光學分割(DAICEL、CHIRALFLASH(註冊商標)IC管柱、(粒徑:20μm;管柱長度:100×30mm I.D.)流速:24mL/min;管柱溫度:室溫、移動相(A):乙腈;移動相(B):甲醇;等度(移動相(A):移動相(B)=90:10)20分;檢測器:UV Yamazen UV-254W UV-
Detector)來精製所得到之混合物(20mg),而得到標題化合物(實施例1(9)的S體化合物:7.9mg、實施例1(9)的R體化合物:7.7mg)。藉由上述條件來進行光學分割時之標題化合物的保持時間分別為13分鐘(實施例1(9)的S體化合物)及9.5分鐘(實施例1(9)的R體化合物)。
藉由下述括弧內的液相層析條件來分析各標題化合物時之物性值如以下所示。
實施例1(9)的S體化合物:
LC tR 10.4分(管柱DAICEL、CHIRALPAK(註冊商標)IC 5μm 4.6mm×250mm、移動相乙腈/甲醇=90/10、流速:1.0mL/min)。
實施例1(9)的R體化合物:
LC tR 7.95分(管柱DAICEL、CHIRALPAK(註冊商標)IC 5μm 4.6mm×250mm、移動相乙腈/甲醇=90/10、流速:1.0mL/min)。
實施例1(10):(3S)-3-[2-(6-胺-2-氟-3-吡啶基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫-5(1H)-吲嗪酮
將濃鹽酸(2mL)加入於實施例1(9)的S體化合物之乙酸乙酯(6mL)懸浮液,於室溫下攪拌20分鐘。於減壓下將反應溶液濃縮並將
所得到之殘渣再次溶解於四氫呋喃(10mL)。將飽和碳酸氫鈉水溶液(20mL)加入於該溶液並藉由乙酸乙酯(20mL、2次)來進行萃取。調配有機層並進行乾燥後濃縮。藉由二氧化矽凝膠管柱層析來精製(胺基二氧化矽、甲醇:乙酸乙酯=0:100→5:95)所得到之殘渣,而得到具有以下的物性值之標題化合物(321mg)。此外,本化合物的絕對立體配置係使用本化合物與FXIa之複合體的單晶,藉由X射線結晶結構解析來決定。
TLC:Rf 0.60(甲醇:乙酸乙酯=5:95);
1H-NMR(CD3OD):δ 9.31(s,1H),7.91(dd,1H),7.74-7.65(m,3H),6.44(dd,1H),6.21(s,1H),6.03(s,1H),5.83(dd,1H),3.39-3.06(m,2H),2.62-2.48(m,2H);
LC tR 22.5分(管柱DAICEL、CHIRALPAK(註冊商標)IC 5μm 4.6mm×250mm、移動相己烷/乙酸乙酯=30/70、流速:1.0mL/min);
[α]25 D=+44.1°(CH3OH、c=1.00)。
實施例1(11):(3S)-3-[2-(6-胺-2-氟-3-吡啶基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫-5(1H)-吲嗪酮二水合物
於75℃將實施例1(10)的化合物(100mg)加熱溶解於乙腈(1.0mL)及水(0.018mL),然後於40℃攪拌2小時,於室溫下攪拌30分鐘,濾取所生成之析出物並進行減壓乾燥而得到標題化合物(76mg)。
1H-NMR(CD3OD):δ 9.31(s,1H),7.91(dd,1H),7.74-7.65(m,3H),6.44(dd,1H),6.21(s,1H),6.03(s,1H),5.83(dd,1H),3.39-3.06(m,2H),2.62-2.48(m,2H);
LC/MS tR 0.82分;MS(ES+)m/z 508(M+H)(條件a)。
實施例1(12):(3R)-3-[2-(6-胺-2-氟-3-吡啶基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫-5(1H)-吲嗪酮
使用實施例1(9)的R體化合物來取代實施例1(9)的S體化合物並進行與實施例1(10)相同之操作,而得到具有以下的物性值之標題化合物。
1H-NMR(CD3OD):δ 9.31(s,1H),7.91(dd,1H),7.71-7.68(m,3H),6.44(dd,1H),6.20(s,1H),6.03(s,1H),5.84(dd,1H),3.37-3.06(m,2H),2.61-2.53(m,2H)。
實施例1(13):(3R)-3-[2-(6-胺-2-氟-3-吡啶基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫-5(1H)-吲嗪酮二水合物
使用實施例1(12)的化合物來取代實施例1(10)的化合物並進行與實施例1(11)相同之操作,而得到具有以下的物性值之標題化合物。
1H-NMR(DMSO-d6):δ 11.70(s,1H),9.64(s,1H),7.89-7.75(m,4H),6.75(brs,2H),6.38(dd,1H),6.01(d,1H),5.92(s,1H),5.69(dd,1H),3.18-3.00(m,2H),2.50-2.24(m,2H)。
[結晶化探討]
以下進行實施例1(10)的化合物之結晶化探討。於以下的探討中,關於光學異向性不會對結果帶來影響之實驗,係使用實施例1(12)或實施例1(13)的化合物來進行者。
首先使用實施例1(10)的化合物來探討實施例1(10)的化合物之鹽的結晶化之可能性。
使用11種酸性(鹽酸(1當量)、硫酸(1當量)、甲烷磺酸(1當量)、4-甲苯磺酸、乙烷磺酸(1當量)、羥乙基磺酸(1當量)、乙烷二磺酸(1/2當量)、1,5-萘二羧酸(1/2當量)、環己基氨基磺酸(1當量)、硝酸(1當量)),並使用12種溶劑(甲醇、乙醇、2-丙醇、丙酮、乙腈、乙酸乙酯、甲基三級丁醚(MTBE:Methyl Tert-butyl Ether)、四氫呋喃、庚烷、甲苯、二氯甲烷、水),藉由自動結晶化裝置(Freeslate公司製Core Module(X))的蒸發濃縮法(40℃加熱、室溫蒸發)來探討實施例1(10)的化合物之鹽的結晶化。
本探討之結果,可得知於各種上述條件下並未得到實施例1(10)的化合物之鹽的結晶。
接著進行游離體(實施例1(10)的化合物)之結晶化探討。
使用實施例1(13)的化合物,並使用51種溶劑(甲醇、乙醇、2-丙醇、丙酮、乙腈、乙酸乙酯、甲基三級丁醚(MTBE)、四氫呋喃、庚烷、甲苯、二氯甲烷、水、1,4-二噁烷、1-丙醇、1-丁醇、2-丁醇、2-甲基-1-丙醇、甲酸乙酯、乙酸甲酯、乙酸丙酯、乙酸異丙酯、氟苯、丁腈、丁酮、甲基異丁酮、二異丙醚、1,2-二氯乙烷、碳酸二甲酯、吡啶、1,2-二甲氧基乙烷、三級戊醇、環己烷、三乙胺、2,2,2-三氟乙醇、辛烷、2-己酮、乙酸丁酯、環戊酮、3-甲基-1-丙醇、氯苯、2-乙氧基乙醇、異丙苯、甲氧苯、N,N-二甲基甲醯胺、三甲苯、二甲基乙醯胺、二甲基亞碸、乙二醇、甲醯胺),使用自動結晶化裝置(Freeslate公司製Core Module(X))來探討游離體的結晶化。結晶化方法係設定漿液法(25℃及40℃)、沉澱法(室溫析出)、蒸發濃縮法(40℃或80℃加熱、室溫蒸發)的3條件,並組合溶劑及結晶化方法對各鹽設定576種的結晶化條件。
本探討之結果,可得知得到實施例1(12)作為結晶性良好的結晶者僅有二水合物(實施例1(13))。從本資料中,可得知即使在此鏡像體之實施例1(10)的化合物中,結晶性良好的結晶僅有二水合物(實施例1(11)),但由於實施例1(11)的化合物如後述般吸濕性高且經口吸收性低,所以無法直接選擇作為醫藥品的原藥。
由於在至目前為止之鹽及游離體的探討中無法得到與課題一致之結晶,所以如以下所述般進一步進行實施例1(10)的化合物之共結晶的結晶化探討。
使用實施例1(13)的化合物來進行共結晶的結晶化之可能性。
使用60種試藥(草酸、反丁烯二酸、己二酸、L-酒石酸、D-酒石酸、苯甲酸、2-羥基苯甲酸、3-羥基苯甲酸、4-羥基苯甲酸、2,3-二羥基苯甲酸、2,4-二羥基苯甲酸、2,5-二羥基苯甲酸、3,4-二羥基苯甲酸、3,5-二羥基苯甲酸、糖精、乳清酸、1-羥基-2-萘甲酸、L-焦麩胺酸、D-焦麩胺酸、苯甲醯胺、乙基麥芽醇、菸鹼醯胺、甘醇酸、山梨酸、L-樟腦二酸、D-樟腦二酸、脲、牛磺酸、丙二酸、L-苦杏仁酸、D-苦杏仁酸、順丁烯二酸、鄰胺苯甲酸、L-丙胺酸、D-丙胺酸、L-乳醯胺、D-乳醯胺、甘胺酸、L-色胺酸、D-色胺酸、N-乙醯基甘胺酸、L-纈胺酸、D-纈胺酸、抗壞血酸、檸檬酸、戊二酸、異抗壞血酸、半乳糖二酸、L-蘋果酸、D-蘋果酸、山梨醇、肌醇、葡萄醣醛酸、癸二酸、琥珀酸、D-組胺酸),並使用6種溶劑(甲醇、丙酮、乙腈、乙酸乙酯、甲苯、二氯甲烷),藉由自動結晶化裝置(Freeslate公司製Core Module(X))的蒸發濃縮法(40℃加熱、室溫蒸發)來探討共結晶的結晶化。
本探討之結果,可得知於各種上述條件下僅有3,5-二羥基苯甲酸、2,5-二羥基苯甲酸、菸鹼醯胺及3-羥基苯甲酸(以下有時分別略稱為RES、GEN、NIA及3HBA)的4種計數中形成結晶。關於3HBA係形成2種結晶。如下述所示般,4種計數中,於RES、GEN中從微差掃描熱量分析、熱重分析的物性資料中得知的吸濕性有疑慮。另一方面,此疑慮對於NIA及3HBA較少,所以製作S體並提供於往後的試驗。
實施例2:(3R)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-α-雷鎖酸(2/1)
將α-雷鎖酸(2.83mg)與乙腈(100μL)添加於實施例1(13)的化合物(20mg),於25℃攪拌1日。濾取所生成之析出物並於通風設備內進行乾燥,藉此得到具有以下的物性值之標題化合物的結晶。
1H-NMR(DMSO-d6):11.70,9.65,9.13,7.86-7.75,7.14-7.13,6.96-6.92,6.78-6.75,6.40-6.36,6.00.5.92,5.71,5.68,3.32,3.20-2.93,2.27-2.20。
實施例3:(3R)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-龍膽酸(2/1)
將龍膽酸(2.83mg)與乙腈(100μL)添加於實施例1(13)的化合物(20mg),於25℃攪拌1日。濾取所生成之析出物並進行減壓乾燥,藉此得到具有以下的物性值之標題化合物的結晶。
1H-NMR(DMSO-d6):12.67,11.70,9.65,9.53,7.89-7.75,6.78-6.75,6.40-6.37,6.00,5.92,5.71-5.68,3.32,3.17-2.93,2.26-2.20。
實施例4:(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-菸鹼醯胺(2/1)
將實施例1(11)的化合物(500mg)與菸鹼醯胺(56.1mg)、乙腈(5mL)混合,於25℃攪拌1日。濾取所生成之析出物並進行減壓乾燥,藉此而得到具有以下的物性值之標題化合物(465mg)。
1H-NMR(DMSO-d6):δ 11.71,9.65,9.11-8.89,8.79-8.60,8.24-8.09,7.90-7.72,7.61,7.53-7.44,6.75,6.38,6.00,5.93,5.74-5.65,3.20-2.93,2.29-2.19。
實施例5:(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)
將實施例1(11)的化合物(500mg)與3-羥基苯甲酸(127.0mg)、乙酸乙酯(5mL)混合,於25℃攪拌1日。濾取所生成之析出物並進行減壓乾燥,而得到具有以下的物性值之標題化合物(529mg)。
1H-NMR(DMSO-d6):12.82,11.71,9.73,9.65,7.90-7.72,7.40-7.22,7.02-6.93,6.75,6.38,6.00,5.92,5.74-5.65,3.20-2.93,2.29-2.19。
實施例6:(3R)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(2/1)
將實施例1(12)的化合物(500mg)與3-羥基苯甲酸(63.5mg)、乙腈(5mL)混合,於25℃攪拌1日。濾取所生成之析出物並進行減壓乾燥,而得到具有以下的物性值之標題化合物(5mg)。
1H-NMR(DMSO-d6):11.70,9.73,9.65,7.89-7.75,7.35-7.27,7.00-6.96,6.75,6.38,6.00,5.92,5.70-5.68,3.32,3.17-2.93。
[物性資料的測定]
對於可取得結晶之實施例1(11)、2、3、4及5的化合物,於下述條件下測定物性資料。
(1)粉末X射線繞射光譜:
裝置:Rigaku公司製SmartLab
標靶:Cu
電壓:45kV
電流:200mA
(2)微差掃描熱量分析(DSC):
裝置:Mettler Toledo公司製DSC822e微差掃描熱量分析裝置
試樣量:約1mg
試樣單元:鋁盤40μL
氮氣流量:40ml/min
升溫速度:10℃/min
(3)熱重分析(TG):
裝置:Mettler Toledo公司製TGA851e熱重分析裝置
試樣量:約2mg
試樣單元:鋁單元(無蓋)
氮氣流量:60mL/min
升溫速度:10℃/min
於本發明中,(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮的鹽、溶劑合物或共結晶之各結晶形態是藉由本說明書中所記載之物理化學資料來特定者,但由於各光譜資料的性質多少會有所改變,故不應嚴格地解釋。
例如,粉末X射線繞射光譜資料就其性質上於結晶之同一性的認定中,繞射角(2θ)或全體性的模式乃為重要,相對強度則因結晶成長的方向、粒子的大小、測定條件而多少有所改變。
此外,於DSC資料中,於結晶之同一性的認定中,全體性的模式亦為重要,且因測定條件的不同而多少有所改變。
因此,於本發明化合物中,粉末X射線繞射光譜或DSC與模式分別全體性地類似者,係包含於本發明化合物者。
於本說明書中,粉末X射線繞射光譜中之繞射角(2θ(度))以及DSC分析中之溫度(℃)的記載,意指包含該資料測定中通常所被容許之誤差範圍,意指大致上為其繞射角及其溫度。例如,粉末X射線繞射光譜中之繞射角(2θ(度))的「約」或「實質上相同」,於某樣態中為±0.2度,於其他樣態中為±0.1度。DSC分析中之起始溫度(℃)及吸熱峰值溫度(℃)的「約」,於某樣態中為±10℃,於其他樣態中為±5℃,於另外的樣態中為±2℃。
實施例1(11):(3S)-3-[2-(6-胺-2-氟-3-吡啶基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫-5(1H)-吲嗪酮二水合物的資料
於粉末X射線繞射光譜中,係表示出第1圖所示之粉末X射線繞射光譜圖、第2表所示之繞射角(2θ)及相對強度。
於微差掃描熱量分析中,如第6圖所示之圖表所述般,從約室溫至約87℃的範圍內顯示吸熱,從約155℃開始顯示吸熱及放熱。
於熱重分析中,如第11圖所示之圖表所述般,從約室溫至約60℃為止顯示約6.5%(相當於水1.7個分子)的重量減少。
實施例2:(3R)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-α-雷鎖酸(2/1)的資料
於粉末X射線繞射光譜中,係表示出第2圖所示之粉末X射線繞射光譜圖、第3表所示之繞射角(2θ)及相對強度。
於微差掃描熱量分析中,如第7圖所示之圖表所述般,從約室溫至約90℃的範圍內顯示廣泛的吸熱,從約175℃開始顯示吸熱及放熱。
於熱重分析中,如第12圖所示之圖表所述般,從約室溫至約63℃為止顯示約1.1%的重量減少。
實施例3:(3R)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-龍膽酸(2/1)的資料
於粉末X射線繞射光譜中,係表示出第3圖所示之粉末X射線繞射光譜圖、第4表所示之繞射角(2θ)及相對強度。
於微差掃描熱量分析中,如第8圖所示之圖表所述般,從約室溫至約100℃的範圍內顯示廣泛的吸熱,從約155℃開始顯示吸熱及放熱。
於熱重分析中,如第13圖所示之圖表所述般,從約室溫至約56℃為止顯示約1.0%的重量減少。
實施例4:(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-菸鹼醯胺(2/1)的資料
於粉末X射線繞射光譜中,係表示出第4圖所示之粉末X射線繞射光譜圖、第5表所示之繞射角(2θ)及相對強度。
於微差掃描熱量分析中,如第9圖所示之圖表所述般,從約144℃開始顯示吸熱及放熱。
於熱重分析中,如第14圖所示之圖表所述般,從約室溫至約65℃為止顯示約0.4%(未達1%)的重量減少。
實施例5:(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)的資料
於粉末X射線繞射光譜中,係表示出第5圖所示之粉末X射線繞射光譜圖、第6表所示之繞射角(2θ)及相對強度。
於微差掃描熱量分析中,如第10圖所示之圖表所述般,從約200℃至約234℃的範圍內顯示放熱。起始溫度為213.6℃,放熱峰值溫度為214.7℃。
於熱重分析中,如第15圖所示之圖表所述般,從約室溫至約156℃為止並未觀察到重量減少。
實施例5之化合物的單晶X射線結構解析資料如以下第7表至第10表所示。
[測定條件]
裝置:Rigaku股份有限公司製單晶X射線解析裝置SuperNova
標靶:Cukα(λ=1.54184Å)
測定溫度:100K
解析軟體:Olex2[1]
1. Dolomanov, O. V., Bourhis, L. J., Gildea, R. J., Haward, J. A. K. & Puschmann, H. (2009), J. Appl. Cryst, 42, 339-341.
結晶學上的資料如下所述。
一般而言,為了證明兩種成分作為共結晶而存在,必須顯示出a/b>1.08(Mol Pharm.2007 May-Jun;4(3):317-22)及/或ΔDc-o>0.08Å(Mol Pharm.2007 May-Jun;4(3):323-38)。
從由上述原子座標的表所導出之a/b及ΔDc-o之值分別為a/b≒1.091及ΔDc-o≒0.208者來看,可得知實施例1(10)的化合物與3-羥基苯甲酸係作為共結晶而存在。
在對從該單晶X射線結構解析資料所轉換之粉末X射線繞射光譜資料、與實施例5之化合物的實測粉末X射線繞射光譜資料進行比較時,由於散射峰值一致,故可得知實施例5的化合物為共結晶。
此外,從固體1H-NMR及13C-NMR(CP/MAS)(CP:cross-polarization、MAS:magic angle spinning)以及1H-13C CP-HETCOR(HETCOR:Heteronuclear Correlation Spectroscopy)的測定結果中,亦可確認到實施例1(10)的化合物與3-羥基苯甲酸作為共結晶而存在。
物理化學性實施例1:吸濕性評估
於以下條件下實施等溫吸附曲線測定(DVS:Dynamic Vapor Sorption)。
(條件)
裝置SMS公司製DVS Intrinsic
測定溫度:25℃
測定範圍:相對濕度0至95%
測定間隔:相對濕度5%
本評估之結果如第16圖所示,可得知實施例5的化合物之本評估中的重量變化率未達1%,且僅有3HBA的共結晶為低吸濕性。
物理化學性實施例2:溶解度評估
於以下條件下實施溶解度測定。
將本發明化合物約3mg量秤於試驗管,並將攪拌件與加溫至37℃之人工腸液(FaSSIF;參考文獻1:Pharmaceutical Research)、第20卷、1674-1680頁、2003年,參考文獻2:Biological &Pharmaceutical Bulletin)、第34卷、401-407頁、2011年)以及處方I液5mL加入於試驗管,並將試驗管密封拴緊。將試驗管設置在溶解度試驗裝置(Gilson,Quad-Z 215),於37℃、700rpm下攪拌。於0.25、0.5、1、3、6以及24小時後採集部分試驗管中的液體。以過濾器來過濾採集液並藉由乙腈將濾液稀釋2倍。人工腸液的稀釋液以3000rpm進行5分鐘的離心分離,並將其上清液用作為試樣溶液。處方I液係將稀釋液本身用作為試樣溶液,並藉由高速液相層析法來算出溶解度。
[測定條件]
裝置:Shimadzu HPLC NexeraXRseries
管柱:Waters Xbridge ShieldRP18(4.6mm內徑×50mm、3.5μm)
管柱溫度:40℃
移動相成分:20mM磷酸二氫鈉(pH3.0)/乙腈(0分:70/30、5分:25/75)
UV:285nm
流速:1.0mL/min
樣本架溫度:15℃
樣本注入量:10μL
測定時間:5分鐘
保持時間:2.6分鐘
24小時後之實施例1(11)、實施例4及實施例5之化合物的溶解度如以下第11表所示。
實施例1(11)的化合物對處方I液之溶解度為41μg/mL,實施例4及實施例5的化合物對處方I液之溶解度分別為77μg/mL及75μg/mL。此外,實施例1(11)的化合物對人工腸液之溶解度為47μg/mL,實施例4及實施例5的化合物對人工腸液之溶解度皆為60μg/mL。
物理化學性實施例3:經口吸收性評估
於以下條件下實施經口吸收性測定。
[調製、投藥及抽血方法]
調製實施例1(11)、實施例4及實施例5之化合物的懸浮液。懸浮液是以0.5%甲基纖維素水溶液來調製為0.33mg/mL(經游離鹼換算)。使用餵食針將各懸浮液強制性地投藥至預先從前一天開始禁食之猴子(食蟹獼猴/雄)的胃內。投藥量係因應猴子的體重以成為1mg/kg之方式來調製。
懸浮液(藥液)投藥後,於0.25、0.5、1、2、4、7及24小時後,使用加肝素用注射筒從橈側皮靜脈採集血液0.5mL。以10000G對所採集之血液進行5分鐘的離心分離以餾取血漿。於試驗化合物之經口吸收性的評估中,係使用在同投藥量(1mg/kg)下進行靜脈內投藥時之資料。經口吸收率(%)為將經口投藥時的AUC(血中濃度-時間曲線下面積)除以靜脈內投藥時的AUC之值,然後乘上100而算出。
[分析試樣的調製及分析]
將水/乙腈(19/1)200μL以及含有內部標準物質(實施例1(10)之化合物的結構類似物)之乙腈10μL添加於血漿10μL並攪拌。將全量添加於預先使乙腈200μL及純化水200μL通過之0asis HLB μElution Plate並進行減壓吸引。添加純化水200μL並進行減壓吸引而洗淨。添加乙腈200μL並進行減壓吸引,然後將溶出液回收至96孔盤。將溶出液10μL添加於0.1%甲酸水溶液/乙腈(2/1)290μL並攪拌,然後藉由LC/MS/MS來進行分析。
LC/MS/MS之分析係在以下的條件下進行。
[LC/MS/MS條件]
測定裝置:API-5000(Applied Biosystems/MDS SCIEX公司製)
分析管柱:Cadenza CD-C18(2.0mm I.D.×100mm、3μm)
流速:0.4mL/分
移動相成分:0.1%甲酸水溶液/乙腈(0分:65/35、4.0分:65/35、4.1分:10/90、5.0分:10/90、5.1分:65/35、7.0分:65/35)
掃描型式:MRM(多重反應監控;Multiple Reaction Monitoring)
Polarity:Positive
本評估之結果如第17圖所示。於實施例1(11)、實施例4及實施例5的化合物中,實施例1(11)、實施例4之化合物的經口吸收率分別為26%及44%。相對於此,實施例5之化合物的經口吸收率幾乎為100%。
[製劑例]
製劑例1:
含5mg化合物A錠劑
藉由常用方法將以下各成分混合後打錠,而得到於一錠中含有5mg的活性成分之錠劑1萬錠。
‧(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1):50g
‧羧甲基纖維素鈣(崩解劑):20g
‧硬脂酸鎂(潤滑劑):10g
‧微晶纖維素:920g
製劑例2:
含20mg化合物A注射劑
藉由常用方法將以下各成分混合後,藉由常用方法將溶液殺菌並以每5mL填充於安瓿,然後藉由常用方法進行凍結乾燥,而得到於1安瓿中含有20mg的活性成分之安瓿1萬根。
‧(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1):200g
‧甘露醇:20g
‧蒸餾水:50L
[產業上之可應用性]
化合物A除了具有極強力的血液凝固第XIa因子抑制活性之外,低吸濕性優異且經口吸收性亦優異,故極有用於作為醫藥品的原藥。
圖為實驗數據
Claims (15)
- 一種化合物,其係(3S)-3-[2-(6-胺-2-氟吡啶-3-基)-4-氟-1H-咪唑-5-基]-7-[5-氯-2-(1H-四唑-1-基)苯基]-2,3-二氫吲嗪-5(1H)-酮-3-羥基苯甲酸(1/1)。
- 如申請專利範圍第1項所述之化合物,其為:於粉末X射線繞射光譜中,於9.4±0.2、14.1±0.2、15.8±0.2、16.5±0.2、17.4±0.2、18.4±0.2、20.6±0.2以及22.4±0.2度的繞射角(2θ)中具有繞射峰值之結晶形態。
- 如申請專利範圍第1項所述之化合物,其為:於粉末X射線繞射光譜中,於9.4±0.1、13.3±0.1、14.1±0.1、14.7±0.1、15.1±0.1、15.8±0.1、16.5±0.1、17.4±0.1、17.7±0.1、18.0±0.1、18.4±0.1、18.9±0.1、19.3±0.1、19.8±0.1、20.6±0.1、20.9±0.1、22.4±0.1、22.8±0.1、23.2±0.1、24.2±0.1、25.0±0.1、25.5±0.1、25.8±0.1、26.3±0.1、27.2±0.1、27.6±0.1、27.9±0.1、28.6±0.1、29.5±0.1以及31.0±0.1度的繞射角(2θ)中具有繞射峰值之結晶形態。
- 如申請專利範圍第1項所述之化合物,其為以第5圖所示之粉末X射線繞射光譜圖為特徵之結晶形態。
- 如申請專利範圍第1項所述之化合物,其為:於微差掃描熱量分析中,起始溫度214±10℃或放熱峰值溫度215±10℃之結晶形態。
- 如申請專利範圍第5項所述之化合物,其為以第10圖所示之微差掃描熱量分析圖為特徵之結晶形態。
- 如申請專利範圍第2項所述之化合物,其為:於微差掃描熱量分析中,起始溫度214±10℃或放熱峰值溫度215±10℃之結晶形態。
- 如申請專利範圍第7項所述之化合物,其為以第10圖所示之微差掃描熱量分析圖為特徵之結晶形態。
- 如申請專利範圍第2至8項中任一項所述之化合物,其為共結晶。
- 一種醫藥組成物,其係含有如申請專利範圍第1至9項中任一項所述之化合物。
- 如申請專利範圍第10項所述之醫藥組成物,其為血液凝固第XIa因子抑制劑。
- 如申請專利範圍第11項所述之醫藥組成物,其為血液凝固第XIa因子相關疾病的預防及/或治療劑。
- 如申請專利範圍第12項所述之醫藥組成物,其中血液凝固第XIa因子相關疾病為血栓栓塞疾病。
- 如申請專利範圍第13項所述之醫藥組成物,其中血栓栓塞疾病為動脈性心血管血栓栓塞性障礙、靜脈性心血管血栓栓塞性障礙、動脈性腦血管血栓栓塞性障礙、靜脈性腦血管血栓栓塞性障礙、或者心腔或末梢循環中的血栓栓塞性障礙。
- 如申請專利範圍第13項所述之醫藥組成物,其中血栓栓塞疾病為中風、腦血栓、腦栓塞、靜脈血栓、靜脈血栓栓塞、深部靜脈血栓、或者因血液暴露於人工物表面之治療所引起之血栓及/或血栓栓塞。
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