TW201706259A - 結晶形式 - Google Patents
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Abstract
本發明係關於化合物(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之結晶形式。
Description
本發明係關於化合物(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇(該化合物在下文中亦稱為「化合物」)之結晶形式。
(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之製備及其醫藥用途係闡述於公開之PCT申請案WO 2011/007324及WO 2013/175397中。(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇亦可如以下實例1中所闡述來製備。
本發明之目標係提供化合物之結晶形式且具體而言具有有利的性質之結晶形式。此等有利的性質可包括較高熔點、較佳流動性質、較高熱力學穩定性、較低吸濕性、不同溶解性、較高純度、製造中之較佳再現性(例如較佳過濾參數及較佳固體形成之再現性)、明確形態學及/或較佳長期穩定性。現已發現如本文所述化合物之結晶形式A具有有利的性質。
圖1顯示呈結晶形式A之化合物之X-射線粉末繞射圖,其中X-射線粉末繞射圖係針對Cu Kα1輻射展示。圖中折射角2θ繪製於水平軸上且計數繪製於垂直軸上。X-射線繞射圖顯示,在所指示之折射角2θ處具有相較於圖中最強峰之以下百分比之相對強度(相對峰強度於括
號中給出)之峰(報告在3-30° 2θ範圍內具有大於10%之相對強度之經選擇峰):4.0°(18%)、4.2°(46%)、5.4°(100%)、8.0°(59%)、8.5°(68%)、9.1°(12%)、10.8°(72%)、12.7°(31%)、13.4°(18%)、13.6°(15%)、14.4°(28%)、16.0°(18%)、17.0°(31%)、17.3°(15%)、17.7°(22%)、19.0°(15%)、19.3°(17%)、20.4°(47%)、21.0°(22%)、21.3°(26%)、21.8°(22%)、22.8°(23%)、25.0°(20%)及25.5°(19%)。
圖2顯示呈結晶形式B之化合物之X-射線粉末繞射圖,其中X-射線粉末繞射圖係針對Cu Kα1輻射展示。圖中折射角2θ繪製於水平軸上且計數繪製於垂直軸上。X-射線繞射圖顯示在所指示折射角2θ處具有相較於圖中最強峰之以下百分比之相對強度(相對峰強度在括號中給出)之極寬峰(報告3-30° 2θ範圍內具有大於10%之相對強度之經選擇峰):5.9°(74%)、7.1°(70%)、8.1°(35%)、11.9°(61%)、14.6°(48%)、20.1°(65%)及21.5°(100%)。
圖3顯示呈結晶形式C之化合物之X-射線粉末繞射圖,其中X-射線粉末繞射圖係針對Cu Kα1輻射展示。圖中折射角2θ繪製於水平軸上且計數繪製於垂直軸上。X-射線繞射圖顯示在所指示之折射角2θ處具有相較於圖中之最強峰之以下百分比之相對強度(相對峰強度在括號中給出)之峰(報告3-30° 2θ範圍內具有大於10%之相對強度之經選擇峰):3.7°(11%)、6.4°(55%)、7.4°(100%)、9.8°(77%)、12.8°(49%)、13.2°(28%)、14.7°(15%)、17.0°(24%)、19.5°(24%)、20.5°(22%)、21.2°(19%)、23.3°(17%)及25.9°(20%)。
圖4顯示呈非晶形狀態之化合物之X-射線粉末繞射圖,其中X-射線粉末繞射圖係針對Cu Kα1輻射展示。圖中折射角2θ繪製於水平軸上且計數繪製於垂直軸上。X-射線繞射顯示如針對非晶形材料所獲得之典型圖。
為避免任何疑問,上文所列示之峰闡述圖1至3中所示之X-射線
粉末繞射之實驗結果。應理解,與上文峰清單相比,僅需要選擇特徵峰以充分且明確表徵本發明呈各別結晶形式之化合物。
1)本發明之第一實施例係關於化合物(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之結晶形式(例如基本上純結晶形式),其特徵在於在X-射線粉末繞射圖中在以下折射角2θ處存在峰:5.4°、8.5°及10.8°。
2)在另一實施例中,本發明係關於如實施例1)之結晶形式,其特徵在於在X-射線粉末繞射圖中在以下折射角2θ處存在峰:4.2°、5.4°、8.0°、8.5°及10.8°。
3)在另一實施例中,本發明係關於如實施例1)之結晶形式,其特徵在於在X-射線粉末繞射圖中在以下折射角2θ處存在峰:4.2°、5.4°、8.0°、8.5°、10.8°、12.7°、14.4°、17.7°、20.4°及21.3°。
4)在另一實施例中,本發明係關於如實施例1)至3)中任一項之結晶形式,其基本上顯示如圖1中所繪示之X-射線粉末繞射圖案。
5)在另一實施例中,本發明係關於如實施例1)至4)中任一項之結晶形式,其具有如藉由差示掃描量熱法使用如本文所述方法來測定之約79℃之熔點。
6)在另一實施例中,本發明係關於化合物(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之結晶形式(例如基本上純結晶形式),其可藉由以下獲得:
i)將20mg呈非晶型之(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇溶解於0.1mL乙酸乙酯中;ii)歷經1h逐漸添加0.9mL正庚烷;及iii)使其在20-25℃下封閉靜置過夜;或
iv)將25-30mg呈非晶型之(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇與5mL乙酸乙酯/正庚烷1/9(體積/體積)混合並加熱至70℃;及v)使溶液冷卻至20-25℃且將其在4℃下儲存過夜。
7)在另一實施例中,本發明係關於如實施例6)之結晶形式,其特徵在於在X-射線粉末繞射圖中在以下折射角2θ處存在峰:5.4°、8.5°及10.8°。
8)在另一實施例中,本發明係關於如實施例6)之結晶形式,其特徵在於在X-射線粉末繞射圖中在以下折射角2θ處存在峰:4.2°、5.4°、8.0°、8.5°及10.8°。
9)在另一實施例中,本發明係關於如實施例6)之結晶形式,其特徵在於存在X-射線粉末繞射圖中在以下折射角2θ處在峰:4.2°、5.4°、8.0°、8.5°、10.8°、12.7°、14.4°、17.7°、20.4°及21.3°。
10)在另一實施例中,本發明係關於如實施例6)之結晶形式,其基本上顯示如圖1中所繪示之X-射線粉末繞射圖案。
11)在另一實施例中,本發明係關於如實施例6)至10)中任一項之結晶形式,其具有如藉由差示掃描量熱法使用如本文所述之方法所測定之約79℃之熔點。
12)在另一實施例中,本發明係關於如實施例1)至5)中任一項之結晶形式,其可藉由實施例6)之方法獲得。
基於如上文中所揭示之不同實施例1)至12)之依賴性,以下實施例由此係可能的且意欲呈個別化形式且以個別化形式明確揭示於此:1、2+1、3+1、4+1、4+2+1、4+3+1、5+1、5+2+1、5+3+1、5+4+1、5+4+2+1、5+4+3+1、6、7+6、8+6、9+6、10+6、11+6、11+7+6、11+8+6、11+9+6及11+10+6。同樣,實施例12)係關於以個別化形式明確揭示於此之以下實施例:可藉由6獲得之1、可藉由6獲
得之2+1、可藉由6獲得之3+1、可藉由6獲得之4+1、可藉由6獲得之4+2+1、可藉由6獲得之4+3+1、可藉由6獲得之5+1、可藉由6獲得之5+2+1、可藉由6獲得之5+3+1、可藉由6獲得之5+4+1、可藉由6獲得之5+4+2+1及可藉由6獲得之5+4+3+1。
在上述清單中,數字係指根據上文所提供其編號之實施例,而「+」指示與另一實施例之依賴性。不同個別化實施例由頓號隔開。換言之,例如,「5+4+1」係指實施例5)依賴於實施例4),該實施例4)依賴於實施例1),即,實施例「5+4+1」對應於特徵進一步在於實施例4)及5)之特徵之實施例1)。此外,「可藉由6獲得」意指所指示之個別化實施例可藉由實施例6)之方法獲得。
除非另外明確闡述之定義提供更廣或更窄之定義,否則本文所提供之定義意欲一致地適用於如實施例1)至12)中任一項及(已作必要的修正)貫穿整個說明及申請專利範圍中所定義之標的物。應充分理解,術語或表述之定義或較佳定義獨立於(及與之組合)如本文所定義任一或所有其他術語或表述之任一定義或較佳定義來定義且可替代各別術語或表述。
術語「基本上純」在本發明之上下文中應理解為尤其意指結晶形式A中存在至少90、較佳至少95且最佳至少99重量%之(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇。
當定義(例如)X-射線粉末繞射圖中峰之存在時,常見方式係藉助S/N比率(S=信號,N=雜訊)來進行。根據此定義,當闡述X-射線粉末繞射圖中必須存在一峰時,應理解X-射線粉末繞射圖中之該峰之定義為S/N比率大於x(x為大於1之數值),通常大於2,尤其大於3。
在闡述結晶形式基本上顯示如圖1中所繪示之X-射線粉末繞射圖案之情況下,術語「基本上」意指該圖中所繪示圖形至少必須存在主
要峰,亦即彼等相較於圖中最強峰之相對強度大於10%、尤其大於20%之峰。然而,熟習X-射線粉末繞射之技術者將認識到,X-射線粉末繞射圖中之相對強度可能由於較佳取向效應而產生較強的強度變化。
除非使用時涉及溫度,否則在本申請案中置於數值「X」前之術語「約」係指自X-X之10%延伸至X+X之10%之區間,且較佳係指自X-X之5%延伸至X+X之5%之區間。在溫度之特定情形下,在本申請案中置於溫度「Y」前之術語「約」係指自溫度Y-5℃延伸至Y+5℃之區間,且較佳係指自Y-3℃延伸至Y+3℃之區間。
當在本申請案中指定峰之繞射角2西塔(2θ)時,應理解所給出之值應理解為自該值-0.2°至該值+0.2°且較佳自該值-0.1°至該值+0.1°之區間。
本發明結晶形式A可用作藥劑,例如呈用於經腸或非經腸投與(例如尤其經口投與)之醫藥組合物形式,且適用於減少循環淋巴球之數目且用於預防及/或治療哺乳動物(例如尤其人類)中與活化之免疫系統相關之疾病或病症。
醫藥組合物之製造可依熟習此項技術者熟悉之方式(參見例如Remington,The Science and Practice of Pharmacy,第21版(2005),第5部分,「Pharmaceutical Manufacturing」[由Lippincott Williams & Wilkins出版])藉由將本發明結晶形式A(視情況與其他有治療價值之物質組合)連同適宜無毒惰性醫藥上可接受之固體或液體載劑材料及(若需要時)常用醫藥佐劑製成蓋侖製劑(galenical)投與形式來達成。
化合物之結晶形式A可呈單一組份使用或呈與化合物之其他結晶形式或非晶型之混合物使用。
可使用本發明結晶形式A來治療及/或預防之與活化之免疫系統相關之疾病或病症係闡述於(例如)WO 2011/007324中。
欲使用本發明結晶形式A來治療及/或預防之較佳疾病或病症選自由以下組成之群:移植器官(例如腎、肝、心臟、肺、胰臟、角膜及皮膚)排斥;移植物抗宿主疾病;自體免疫症候群,包括薛格連氏症候群(Sjögren's syndrome)、脊椎關節病/僵直性脊椎炎、幼年型關節炎、亞急性皮膚狼瘡、盤狀紅斑狼瘡、狼瘡性腎炎、全身性硬化、彌漫性皮膚全身性硬化、血管炎(例如韋格納(M.Wegener))、巨細胞動脈炎、貝切特氏病(Behcet disease)、非傳染性眼色素層炎、古巴士德氏症候群(Goodpasture syndrome)、葛瑞夫茲氏病(Grave's disease)、格林-巴利症候群(Guillain Barré syndrome)、原發性膽汁性肝硬化、原發性硬化性膽管炎、自體免疫肝炎、多發性肌炎、皮肌炎、微小性結腸炎、乳糜瀉、類肉瘤病、白斑症、斑禿、慢性發炎性去髓鞘型多發性神經病變(CIDP)、羅氏腦炎(Rasmussen's encephalitis)、類風濕性關節炎、多發性硬化、諸如克羅恩氏病(Crohn's disease)及潰瘍性結腸炎等發炎性腸病、牛皮癬、牛皮癬關節炎、諸如橋本氏甲狀腺炎(Hashimoto’s thyroiditis)等甲狀腺炎、眼色素層視網膜炎及全身性紅斑狼瘡;異位性疾病,例如鼻炎、結膜炎及異位性皮膚炎;氣喘;I型糖尿病;及包括風溼熱之感染後自體免疫疾病。
極佳地,本發明結晶形式A用於治療全身性紅斑狼瘡。
本發明亦係關於用於預防或治療本文所提及或WO 2011/007324中所提及之疾病或病症之方法,其包含將醫藥活性量之本發明結晶形式A投與個體(尤其人類個體)。
此外,本發明結晶形式A亦與一或若干種免疫調節劑組合以用於預防及/或治療本文所提及之疾病及病症。根據本發明之較佳實施例,該等試劑選自由以下組成之群:免疫抑制劑、皮質類固醇、非類固醇抗發炎藥物、細胞毒性藥物、分子黏附抑制劑、細胞介素、細胞介素抑制劑、細胞介素受體拮抗劑及重組細胞介素受體。
本發明亦係關於本發明結晶形式A之用途,其用於製備視情況與一或若干種免疫調節劑組合用於預防或治療本文所提及或WO 2011/007324中所提及之疾病及病症的醫藥組合物。
(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇可(例如)如公開之PCT申請案WO 2011/007324(具體而言參見實例2)中所闡述或藉由使用如公開之PCT申請案WO 2013/175397中所揭示之製備方法來製備。具體而言,化合物亦可如下文所述來製備。
實驗部分
以下實例更詳細地闡釋本發明。溫度係以攝氏度給出。若未另外闡明,則室溫係在18-25℃範圍內且百分比係以重量計來給出。
如本文所用縮寫:
所用方法:
1
H-NMR
400MHz,Bruker;化學位移係相對於所用溶劑以ppm給出。
X-射線粉末繞射分析
X-射線粉末繞射圖案係於配備有使用CuKa輻射以反射模式(偶合2θ/θ)操作之Lynxeye檢測器之Bruker D8 Advance X-射線繞射儀上收集。通常,X-射線管在40kV/40mA下運行。施加在3-50° 2θ之掃描範圍內之0.02°(2θ)之步長及76.8秒之步時。發散狹縫設定為固定的0.3。以0.5mm之深度將粉末輕微壓至矽單晶樣品架中且在量測期間使試樣在其自身平面上旋轉。在使用儀器評估軟體(EVA)去除Kα2組
份之後,使用Cu Kα1(λ=1.5406Å)來報告繞射數據。如本文所提供之2θ值之準確度在+/- 0.1-0.2°範圍內,如習用記錄之X-射線粉末繞射圖案通常存在之情形。
差示掃描量熱法(DSC)
於配備有34位自動取樣器之Mettler Toledo STARe系統(DSC822e模組,具有陶瓷感測器及9.20版STAR軟體之量測單元)上收集DSC數據。使用標準銦對儀器之能量及溫度進行校準。通常將1-5mg之各試樣在自動穿刺之鋁盤中以10℃ min-1(除非另外闡明)自-20℃加熱至280℃。在試樣上方維持20mL min-1之氮吹掃。峰溫度係針對熔點報告。
實例1
(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之製備
a)(R)-N-((2-環戊基-6-甲氧基異菸鹼醯基)氧基)-4-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-3-乙基-5-甲基苯甲脒
向30L反應器中添加2-環戊基-6-甲氧基-異菸鹼酸(1.27kg,1當量;可(例如)如WO 2013/175397中所闡述來製備)、DMF(17mL)及DCM(18L)。在20℃下經30min向懸浮液中添加草醯氯(534mL,1.1當量)。將混合物攪拌30min。藉由LC-MS分析來確認反應完全。在<30℃下經20min之時段將(R)-4-(2,2-二甲基-[1,3]二氧戊環-4-基甲氧基)-3-乙基-N-羥基-5-甲基-苯甲脒(1.77kg,1當量;可如WO 2011/007324中所述來製備)及TEA(1.78L,2.2當量)於DCM(4L)中之溶液添加至醯基氯中。在攪拌15min後,藉由LC-MS分析來確認反應完全。用水(7L)洗滌反應混合物。在55℃及減壓下移除溶劑(18L)。添加EtOH(26L),將懸浮液冷卻至0℃並過濾。用EtOH(7L)洗滌濾餅。將固體在50℃下於旋轉蒸發器上乾燥以獲得灰白色固體。產率:
2261g(77%)。LC-MS:純度:100% a/a,tR=1.886min,[M+1]+=512;1H-NMR(CDCl3):δ 7.43(s,2 H),7.34(s,1 H),7.12(s,1 H),5.16(s,2 H),4.52(quint,J=5.8Hz,1 H),4.21(dd,J 1=8.3Hz,J 2=6.9Hz,1 H),3.98(s,3 H),3.96(m,1 H),3.83(m,2 H),3.19(m,1 H),2.70(m,2 H),2.33(s,3 H),2.06(m,2 H),1.85(m,4 H),1.71(m,2 H),1.46(d,J=21.3Hz,6 H),1.25(t,J=7.6Hz,3 H)。
b)(R)-5-(2-環戊基-6-甲氧基吡啶-4-基)-3-(4-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-3-乙基-5-甲基苯基)-1,2,4-噁二唑
將(R)-N-((2-環戊基-6-甲氧基異菸鹼醯基)氧基)-4-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-3-乙基-5-甲基苯甲脒(2150g,1當量)於甲苯(10L)中之混合物加熱回流4h。將水收集於Dean Stark裝置中。將溶液在70℃及減壓下濃縮至乾燥以獲得黃色油。產率:2116g(102%)。LC-MS:純度:96% a/a(4% a/a甲苯),tR=2.665min,[M+1]+=494;1H-NMR(CDCl3):δ 7.87(d,J=6.3Hz,2H),7.50(s,1 H),7.30(s,1 H),4.55(quint,J=5.8Hz,1 H),4.23(dd,J 1=8.4Hz,J 2=6.5Hz,1 H),4.01(m,4 H),3.90(m,2 H),3.24(m,1 H),2.77(m,2 H),2.40(s,3 H),2.09(m,2 H),1.88(m,4 H),1.73(m,2 H),1.50(s,3 H),1.48(d,J=22.0Hz,6 H),1.32(t,J=7.5Hz,3 H)。
用於步驟a)及b)中之LC-MS方法:
Agilent G1956B(MS,電離:ESI+,APCI),Agilent G1312B Bin Pump,Agilent G1315C DAD,Agilent G1316B(恒溫管柱隔室),Agilent G1367C(自動取樣器)。注射體積:2μL;管柱:Kinetex C18,2.6μm,2.1×50mm;溫度:40℃;流速:1mL/min;梯度:水/乙腈:2.8min內95:5至5:95,然後0.2min內95:5。
c)(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇
向30L Büchi反應器中添加(R)-5-(2-環戊基-6-甲氧基吡啶-4-基)-3-(4-((2,2-二甲基-1,3-二氧戊環-4-基)甲氧基)-3-乙基-5-甲基苯基)-1,2,4-噁二唑(2.28kg,1當量)及EtOH(5L)。將溶液加熱至45℃且添加1N HCl(3L,0.75當量)。將所得混合物在45℃下攪拌1h且在減壓(400毫巴)下再攪拌3h。將混合物用32% NaOH(300mL,0.75當量)中和且在60℃及減壓下濃縮直至達到最小攪拌體積(約2L)為止。將反應器用氮氣設定為正常壓力。用EtOAc(20L)稀釋殘留物。用水(2×10L)洗滌混合物。將有機層在60℃及減壓下濃縮以獲得黃色油。
產率:2053g(98%)。產生第二批;產率:1907g(98%)。
結晶:
在Pyrex燒瓶中將兩批(2053g+1907g)合併並溶解於EtOAc(5.5L)中(API溶液)。向30L反應器中添加呈結晶形式A之(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇(14g)及正庚烷(30L)。將懸浮液加熱至40℃且在40℃下經1h之時段添加API溶液。將懸浮液再攪拌0.5h,冷卻至20℃且經30L Büchi吸濾器過濾。用正庚烷(6L)洗滌產物。將產物於施加輕柔氮氣流之吸濾器上乾燥2天。
產率:3300g(83%),純度(HPLC方法):99.51% a/a;熔點:約79℃(DSC),呈結晶形式A之化合物(圖1)。
1H-NMR(D6 DMSO):δ 7.78(s,2 H),7.53(s,1 H),7.26(s,1 H),4.98(d,J=4.6Hz,1 H),4.65(s,1 H),3.94(s,3 H),3.86(m,2 H),3.75(m,1 H),3.50(t,J=5.4Hz,2 H),3.28(m,1 H),2.75(d,J=7.5Hz,2 H),2.35(s,3 H),2.03(m,2 H),1.81(m,4 H),1.69(m,2 H),1.22(t,J=7.5Hz,3 H)。
HPLC方法:
HPLC系統Agilent 1100;注射體積:5μL;管柱:Zorbax Eclipse
XDB C18,3.5μm,150mm×4.6mm;溫度:30℃;流速:1mL/min;檢測波長:250nm;梯度:水/乙腈:2.8min內95:5至5:95,然後0.2min內95:5。溶析劑:溶析劑A:水/MeOH/TFA(95/5/0.05),溶析劑B:水/MeOH/TFA(5/95/0.05);梯度:0-1min40% A,7-22min 0% A,22.1-27min 40% A。
非晶形化合物之製備:
非晶形化合物可藉由針對公開之PCT申請案WO 2011/007324之實例2所闡述之製程獲得。該製程係如下:
a)向2-環戊基-6-甲氧基-異菸鹼酸(162mg,0.732mmol)於DMF(2mL)及THF(10mL)中之溶液中添加DIPEA(189mg,251μL,1.46mmol),隨後添加TBTU(235mg,0.732mmol)。將混合物在室溫下攪拌10min,然後添加(R)-4-(2,2-二甲基-[1,3]二氧戊環-4-基甲氧基)-3-乙基-N-羥基-5-甲基-苯甲脒(226mg,0.732mmol)。將混合物在室溫下攪拌1h,然後將其用EtOAc稀釋且用水洗滌。分離有機層並濃縮。將殘留物(375mg)溶解於二噁烷(10mL)中並將混合物加熱至105℃持續18h。將混合物冷卻至室溫,濃縮且於製備性TLC板(矽膠,0.5mm)上使用含有10%甲醇之DCM純化粗產物以獲得黃色油形式之4-{3-[4-((R)-2,2-二甲基-[1,3]二氧戊環-4-基甲氧基)-3-乙基-5-甲基-苯基]-[1,2,4]噁二唑-5-基}-2-環戊基-6-甲氧基-吡啶(396mg);LC-MS:tR=1.39min,[M+H]+=494.31。
b)將4-{3-[4-((R)-2,2-二甲基-[1,3]二氧戊環-4-基甲氧基)-3-乙基-5-甲基-苯基]-[1,2,4]噁二唑-5-基}-2-環戊基-6-甲氧基-吡啶(390mg,790μmol)於4M HCl於二噁烷(16mL)中之溶液在室溫下攪拌90min,然後將其濃縮。於製備性TLC板上使用含有10%甲醇之DCM來純化粗產物以獲得灰白色泡沫形式之(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇(80
mg);LC-MS:tR=1.20min,[M+H]+=454.32;1H-NMR(400MHz,CDCl3):δ 7.91(d,J=2.0Hz,1 H),7.89(d,J=2.0Hz,1 H),7.53(d,J=0.8Hz,1 H),7.32(d,J=1.0Hz,1 H),4.16-4.22(m,1 H),4.03(s,3 H),3.96-3.99(m,2 H),3.93(dd,J 1=4.3Hz,J 2=11.3Hz,1 H),3.88(dd,J 1=5.5Hz,J 2=11.3Hz,1 H),3.21-3.31(m,1 H),2.79(q,J=7.6Hz,2 H),2.74(s br,1 H),2.43(s,3 H),2.07-2.17(m,2 H),1.85-1.96(m,4 H),1.70-1.81(m,2 H),1.34(t,J=7.5Hz,3 H);XRPD圖如圖4中所顯示。
在製備非晶形化合物之上述描述中,化合物係由 1 H-NMR(Bruker Avance II,400MHz UltraShieldTM,400MHz(1H),100MHz(13C);化學位移係以百萬分率(ppm)相對於四甲基矽烷(TMS)來報告且多重性係以s(單峰)、d(雙峰)、t(三重峰)、q(四重峰)、quint(五重峰)、h(六重峰)、hept(七重峰)或m(多重峰)形式給出,br=寬,偶合常數係以Hz給出);及/或由LC-MS(Finnigan MSQTM plus或MSQTM測量器(Dionex,瑞士)與Agilent G4220A幫浦及AGilent G4212A DAD(Agilent,瑞士),管柱:Zorbax RRHD SB-AQ,1.8μm,3.0×20mm(Agilent);梯度:1.2min內5-95%含有0.04%三氟乙酸之水中之乙腈,流速:1.6mL/min;tR係以min給出)來表徵。
藉由塗佈有矽膠60 F254(0.5mm)之製備性TLC玻璃板來純化化合物。
實例2:形式A之製備
將20mg呈非晶型之化合物溶解於0.1mL EtOAc中且經1h逐漸添加0.9mL正庚烷。在20-25℃下封閉靜置過夜後收集所形成之固體且其由呈結晶形式A之化合物組成。或者,將25-30mg呈非晶型之化合物與5mL EtOAc/正庚烷1/9(體積/體積)混合且加熱至70℃。使溶液冷卻至20-25℃且然後在4℃下儲存過夜。收集所獲得固體且該固體係呈
結晶形式A之化合物。藉由DSC觀察到在約66℃至約88℃範圍內之寬的吸熱事件,其中峰在約79℃(結晶形式A之熔點)處。
實例3:形式B之製備
將0.5g呈結晶形式A之化合物、2.5mL DCM及3mL正庚烷混合並過濾至培養皿(具有約9cm之直徑)中。使溶液在20-25℃下蒸發過夜。收集固體殘留物且在真空下乾燥(2毫巴持續1h)。如此獲得之固體殘留物係呈結晶形式B之化合物,如圖2中所示。藉由DSC觀察到在約44℃至約63℃範圍內之寬的吸熱事件,其中峰在約58℃(結晶形式B之熔點)處。
實例4:形式C之製備
在15mL褐色玻璃小瓶中將266mg呈結晶形式A之化合物及36mg尿素溶解於10mL甲醇中。將小瓶在20-25℃下敞口靜置用以蒸發溶劑。一旦所有溶劑蒸發且最晚在1週後即刻添加10mL水且藉由磁力攪拌在20-25℃下將試樣攪拌5天。過濾懸浮液且將回收之固體在2毫巴下乾燥1h。如此獲得之固體殘留物係呈結晶形式C之化合物,如圖3中所顯示。藉由DSC觀察到在約30℃至約60℃範圍內之寬的吸熱事件,其中峰在約48℃(結晶形式C之熔點)處。
實例5:呈結晶形式A、B及C之化合物之吸濕性之比較
方法:
重量蒸汽吸附(GVS)分析:
在於25℃下在以步進模式操作之多試樣儀器SPS-100n(Projekt Messtechnik,Ulm,德國)上對呈結晶形式A、B及C之化合物同時實施量測。使試樣在40% RH下平衡,然後開始施加預定濕度程式(40-0-95-0-95-40% RH,步進為5% △RH且每步最大平衡時間為24小時)。使用約20mg至30mg之各試樣。根據歐洲藥典技術指南(European Pharmacopeia Technical Guide,1999,第86頁)進行吸濕性分類,即,
不吸濕:質量增加少於0.2%質量/質量;輕微吸濕:質量增加少於2%且等於或大於0.2%質量/質量;吸濕:質量增加少於15%且等於或大於2%質量/質量。慮及在首次吸附掃描中介於40%相對濕度與80%相對濕度之間之質量變化。
形式A:<0.2%質量增加:不吸濕
形式B:0.5%質量增加:輕微吸濕
形式C:0.8%質量增加:輕微吸濕
實例6:含有0.5mg、1mg、2mg及4mg呈結晶形式A之化合物之膠囊
由於活性物質(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之極低水溶解性(水中約0.06μg/mL)及差的潤濕能力,原料藥包衣作為第一步驟。在此程度上,將甲基纖維素(METHOCELTM A15 Premium LV,懸浮劑)、十二烷基硫酸鈉及二棕櫚醯基磷酯醯膽鹼(潤濕劑)在攪拌下相繼添加至純化水中:各賦形劑僅在前一者完全溶解後添加。將API(即
呈結晶形式A之化合物)經由篩孔大小40篩分,添加至甲基纖維素溶液中並攪拌3h,直至形成完全均勻懸浮液為止。將懸浮液噴霧乾燥(出口空氣溫度40-50℃,乾燥氣體流速110kg/h,霧化N2氣體流速8kg/h,N2霧化壓力0.7巴),此產生經包衣API。包衣使得活性物質溶解性增加(水中約29μg/mL)。
經包衣後,測定經包衣之原料藥中之原料藥含量且最後相應地校正用於下一步驟中之材料之量。
將經包衣API與甲基纖維素(METHOCELTM A15 Premium LV)、十二烷基硫酸鈉及一部分之甘露醇(EMPROVE® Parteck® M 200甘露醇)一起篩分並混合。在篩分後在2步內將更多份甘露醇添加至摻合物中,每次皆隨後進行混合。然後將膠態二氧化矽(AEROSIL® 200)與其餘甘露醇一起篩分並添加至粉末摻合物中。將最終混合物進一步摻和。然後將粉末填充入「0」型白色不透明HPMC膠囊(VCaps+®)中。
Claims (17)
- 一種化合物(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之結晶形式,其特徵在於在X-射線粉末繞射圖中在以下折射角2θ處存在峰:5.4°、8.5°及10.8°。
- 如請求項1之結晶形式,其中在該X-射線粉末繞射圖中在以下折射角2θ處存在峰:4.2°、5.4°、8.0°、8.5°及10.8°。
- 如請求項1之結晶形式,其中在該X-射線粉末繞射圖中在以下折射角2θ處存在峰:4.2°、5.4°、8.0°、8.5°、10.8°、12.7°、14.4°、17.7°、20.4°及21.3°。
- 如請求項1至3中任一項之結晶形式,其基本上顯示如圖1中所繪示之X-射線粉末繞射圖案。
- 如請求項1至4中任一項之結晶形式,其具有如藉由差示掃描量熱法所測定之約79℃之熔點。
- 一種化合物(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇之結晶形式,其可藉由以下獲得:i)將20mg呈非晶型之(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇溶解於0.1mL乙酸乙酯中;ii)經1h逐漸添加0.9mL正庚烷;及iii)使其在20-25℃下封閉靜置過夜;或iv)將25-30mg呈非晶型之(S)-3-{4-[5-(2-環戊基-6-甲氧基-吡啶-4-基)-[1,2,4]噁二唑-3-基]-2-乙基-6-甲基-苯氧基}-丙烷-1,2-二醇與5mL乙酸乙酯/正庚烷1/9(體積/體積)混合並加熱至70℃;及 v)使溶液冷卻至20-25℃且在4℃下將其儲存過夜。
- 如請求項6之結晶形式,其中在X-射線粉末繞射圖中在以下折射角2θ處存在峰:5.4°、8.5°及10.8°。
- 如請求項6之結晶形式,其中在X-射線粉末繞射圖中在以下折射角2θ處存在峰:4.2°、5.4°、8.0°、8.5°及10.8°。
- 如請求項6之結晶形式,其中在X-射線粉末繞射圖中在以下折射角2θ處存在峰:4.2°、5.4°、8.0°、8.5°、10.8°、12.7°、14.4°、17.7°、20.4°及21.3°。
- 如請求項6之結晶形式,其基本上顯示如圖1中所繪示之X-射線粉末繞射圖案。
- 如請求項6至10中任一項之結晶形式,其具有如藉由差示掃描量熱法所測定之約79℃之熔點。
- 如請求項1至5中任一項之結晶形式,其可藉由請求項6之方法獲得。
- 一種醫藥組合物,其包含如請求項1至12中任一項之結晶形式及醫藥上可接受之載劑。
- 如請求項1至12中任一項之結晶形式或如請求項13之醫藥組合物,其用作藥劑。
- 如請求項1至12中任一項之結晶形式或如請求項13之醫藥組合物,其用於預防或治療與活化之免疫系統相關之疾病或病症。
- 如請求項1至12中任一項之結晶形式或如請求項13之醫藥組合物,其用於預防或治療選自由以下組成之群之疾病或病症:移植器官(例如腎、肝、心臟、肺、胰臟、角膜及皮膚)排斥;移植物抗宿主疾病;自體免疫症候群,包括薛格連氏症候群(Sjögren'ssyndrome)、脊椎關節病/僵直性脊椎炎、幼年型關節炎、亞急性皮膚狼瘡、盤狀紅斑狼瘡、狼瘡性腎炎、全身性硬 化、彌漫性皮膚全身性硬化、血管炎(例如韋格納(M.Wegener))、巨細胞動脈炎、貝切特氏病(Behcet disease)、非傳染性眼色素層炎、古巴士德氏症候群(Goodpasture syndrome)、葛瑞夫茲氏病(Grave's disease)、格林-巴利症候群(Guillain Barré syndrome)、原發性膽汁性肝硬化、原發性硬化性膽管炎、自體免疫肝炎、多發性肌炎、皮肌炎、微小性結腸炎、乳糜瀉、類肉瘤病、白斑症、斑禿、慢性發炎性去髓鞘型多發性神經病變(CIDP)、羅氏腦炎(Rasmussen's encephalitis)、類風濕性關節炎、多發性硬化、諸如克羅恩氏病(Crohn's disease)及潰瘍性結腸炎之發炎性腸病、牛皮癬、牛皮癬關節炎、諸如橋本氏甲狀腺炎(Hashimoto’s thyroiditis)之甲狀腺炎、眼色素層視網膜炎及全身性紅斑狼瘡;異位性疾病,例如鼻炎、結膜炎及異位性皮膚炎;氣喘;I型糖尿病;及感染後自體免疫疾病,包括風溼熱。
- 如請求項1至12中任一項之結晶形式或如請求項13之醫藥組合物,其用於治療全身性紅斑狼瘡。
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