TW201514180A - 一種ｊａｋ激酶抑制劑的硫酸氫鹽及其製備方法 - Google Patents
一種ｊａｋ激酶抑制劑的硫酸氫鹽及其製備方法 Download PDFInfo
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Abstract
本發明涉及一種JAK激酶抑制劑的硫酸氫鹽及其製備方法。更具體地，本發明涉及如式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽及其製備方法和用途。如式(I)所示的硫酸氫鹽可很好地作為JAK激酶抑制劑應用於臨床，用來治療風濕及類風濕性關節炎。
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Description
本發明涉及一種JAK激酶抑制劑的硫酸氫鹽及其製備方法。具體地說，本發明涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽及其製備方法。
關節炎是全世界最常見的慢性疾病，導致關節炎的原因很多，引起關節損傷也各有不同。目前，治療風濕性關節炎的主要藥物有美國雅培製藥公司的阿達木單抗(Humira)，輝瑞和安進公司共同研發的依那西普(Enbrel)以及Janssen製藥公司的英利昔單抗(Remicade)，這些藥物都是當前醫藥市場的暢銷藥物，但值得注意的是，這些暢銷藥物都只是注射型藥物，常用的口服藥甲胺蝶呤(methotrexate)，雖然藥效顯著，但毒性也非常大。
研究表明，在類風濕性關節炎(RA)病理生理學過程中，多重細胞因子信號通路失調發揮重要作用，一系列失控的細胞因子介導的炎症級聯反應導致RA相關的多種細胞，包括T細胞、B細胞、單核細胞、巨噬細胞和破骨細胞處於長期啟動狀態，從而引發持續炎症及關節結構性損傷。而Janus激酶(JAK)信號通
路對RA相關細胞的促炎活性有調控作用，其中JAK是炎症細胞因子網路信號傳導中樞蛋白，RA關節滑膜組織中JAK水準顯著增高。目前由輝瑞公司開發的tofacitinib(tasocitinib，CP-690550)為JAK1抑制劑。經臨床三期試驗結果，輝瑞tofacitinib藥物藥效明顯優於甲胺蝶呤(methotrexate)。在該實驗中，研究人員對患者進行隨機分組，其中一組患者服用5毫克/10毫克的tofacitinib藥物作為單一療法，另外一組患者則服用5毫克/10毫克劑量的甲胺蝶呤(methotrexate)。研究結果顯示，在六個月的時間裏，tofacitinib藥物在抑制人體內部結構損傷方面的藥效比甲胺蝶呤(methotrexate)略勝一籌，可以有效改善風濕性關節炎患者的各種綜合症。
我們從研製JAK激酶抑制劑的思路出發，緊跟國際上同類藥物發展方向，基於tofacitinib的結構，開發出一系列具有體內、外活性，高吸收的藥物，成功得到了JAK激酶抑制劑化合物(IV)，關於式(IV)所示化合物，其資訊已完整記載於申請人與他人共同申請的PCT專利申請PCT/CN2012/086922中，在此全文引入作為參考。
由於化合物(IV)的溶解度較低，為了進一步提高化合物的溶解度和生物利用度，我們對化合物(IV)進行了成鹽研究，考察的酸包括檸檬酸、鹽酸和硫酸，通過成鹽後產物的溶解
度及動物的藥物代謝實驗結果，令人驚喜地發現，式(I)化合物有望成為JAK激酶抑制劑的較佳化合物，在治療風濕及類風濕性關節炎方面，具有重要的研究意義。
本發明的目的是提供一種水溶性較好的、能增強其藥物代謝活性的JAK激酶抑制劑的鹽，具體來說是提供一種如式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽及其製備方法。
其中(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺與硫酸的化學配比為1：1。
本發明的另一方面提供了如式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽的製備方法，其包括化合物(IV)與硫酸成鹽的步驟，
上述反應可在溶劑中進行，所述的反應溶劑為碳原子數小於或等於3的鹵烷類與醇類的混合溶劑，較佳為二氯甲烷與甲醇的混合溶液。
上述反應的反應溫度較佳為10至30℃，反應時間較佳為0.5至4小時。
本發明的另一方面提供了一種醫藥組成物，其含有如式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽及藥學上可接受的載體。
本發明的另一方面提供了如式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽或包含上述硫酸氫鹽的醫藥組成物在製備治療風濕及類風濕性關節炎的藥物中的用途。
按照本發明的方法製備的式(I)硫酸氫鹽不含有或僅含有較低含量的殘留溶劑，符合國家藥典規定的有關醫藥產品殘留溶劑的限量要求，因而本發明的式(I)硫酸氫鹽可以較好地作為醫藥活性成分使用。
以下將結合實施例更詳細地解釋本發明，本發明的實施例僅用於說明本發明的技術方案，並非限定本發明的實質和範圍。
實施例1：式(IV)化合物的製備(引自PCT/CN2012/086922)式(IV)化合物可依如下路線製備：
其中化合物d的製備方法如下：
具體的，式(IV)化合物的製備包括如下兩個部分：
(3aR,5r,6aS)-5-(甲基磺醯氧基)六氫環戊並[c]吡咯-2(1H)-甲酸
第三丁酯
將(3aR,5r,6aS)-5-羥基六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯1d(9g，40mmol)溶於150mL二氯甲烷中，在0℃下加入甲磺醯氯(4.70mL，60mmol)和三乙胺(11.20mL，80mmol)，室溫下反應2小時。向反應液加入200mL飽和碳酸氫鈉溶液，分液，有機相用飽和氯化鈉溶液洗滌(200mL)，無水硫酸鈉乾燥，過濾，減壓濃縮濾液，得到標題產物(3aR,5r,6aS)-5-(甲基磺醯氧基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯2d(12.00g，黃色液體)，產率：98.4%。
(3aR,5s,6aS)-5-(甲基胺基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯
將(3aR,5r,6aS)-5-(甲基磺醯氧基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯2d(60mg，0.2mmol)溶解於10mL甲醇中，加入5mL甲基胺，於40℃下反應16小時。減壓濃縮反應液，得到粗品標題產物(3aR,5s,6aS)-5-(甲基胺基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯3d(60mg，褐色油狀物)，不經純化直接用於下一步反應。
MS m/z(ESI)：241.5[M+1].
(3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯
將(3aR,5s,6aS)-5-(甲基胺基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯3d(200mg，0.8mmol)和4-氯-7H-吡咯並[2,3-d]嘧啶4d(127mg，0.8mmol)溶解於5mL正丁醇中，滴加三乙胺(168mg，1.6
mmol)，於100℃下反應48小時。減壓濃縮反應液，加入10mL水和10mL乙酸乙酯，分液，合併有機相，無水硫酸鈉乾燥，過濾，減壓濃縮濾液，用HPLC製備得到標題產物(3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯5d(5mg，白色固體)，產率：5.0%。
MS m/z(ESI)：358.5[M+1]
1H NMR(400MHz,CDCl3)：δ 10.07(s,1H),8.31(s,1H),7.50(s,1H),6.55(s,1H),5.58-5.54(m,1H),3.65-3.62(m,2H),3.27-3.23(m,5H),2.86-2.81(m,2H),2.06-2.02(m,2H),1.93-1.91(m,2H),1.49(s,6H).
N-甲基-N-((3aR,5s,6aS)-八氫環戊並[c]吡咯-5-基)-7H-吡咯並[2,3-d]嘧啶-4-胺鹽酸鹽
將(3aR,5s,6aS)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲酸第三丁酯5d(1.5g，4.2mmol)溶解於20mL 1M氯化氫的甲醇溶液中，反應16小時。減壓濃縮反應液，得到粗品標題產物N-甲基-N-((3aR,5s,6aS)-八氫環戊並[c]吡咯-5-基)-7H-吡咯並[2,3-d]嘧啶-4-胺鹽酸鹽d(1.5g，褐色固體)。
MS m/z(ESI)：258.1[M+1].
3-甲氧基-1,2,4-噻二唑-5-基胺基甲酸苯酯
將3-甲氧基-1,2,4-噻二唑-5-胺a(500mg，3.82mmol)和氯甲酸苯酯b(600mg，3.82mmol)溶解於20mL二氯甲烷中，滴加三乙
胺(0.8mL，5.73mmol)，滴畢反應16小時。向反應液中加入30mL水稀釋，分液，水相用二氯甲烷萃取(20mL×2)，合併有機相，無水硫酸鈉乾燥，過濾，減壓濃縮反應液，用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題產物3-甲氧基-1,2,4-噻二唑-5-基胺基甲酸苯酯c(200mg，白色固體)，產率：20.8%。
MS m/z(ESI)：252.0[M+1].
(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺
將根據第一部分所述方法製備得到的化合物d(120mg，0.47mmol)溶解於15mL四氫呋喃中，加入3-甲氧基-1,2,4-噻二唑-5-基胺基甲酸苯酯c(117mg，0.47mmol)，滴加三乙胺(0.13mL，0.94mmol)，滴畢於60℃下反應5小時。向反應液中加入30mL水，用二氯甲烷萃取(50mL×3)，合併有機相，用飽和氯化鈉溶液洗滌(50mL×2)，無水硫酸鈉乾燥，過濾，減壓濃縮濾液，用矽膠管柱色譜法以洗脫劑體系A純化所得殘餘物，得到標題產物(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基))六氫環戊並[c]吡咯-2(1H)-甲醯胺(IV)(50mg，白色固體)，產率：25.9%。
MS m/z(ESI)：412.9[M-1].
1H NMR(400MHz,DMSO-d6)：δ 11.60(m,2H),8.08(s,1H),7.06-7.05(m,1H),6.53-6.51(m,1H),5.48-5.44(m,1H),3.90(s,3H),3.69-3.65(m,2H),3.37-3.32(m,2H),3.16(s,3H),2.90-2.88(m,2H),2.02-1.99(m,2H),1.80-1.77(m,2H).
實施例2：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽的製備(式I)
在10L反應瓶中投入化合物(IV)140g(0.34mol)，加入無水甲醇350g，二氯甲烷2.0kg，懸浮攪拌，室溫下緩慢滴加硫酸34.8g(0.36mol)，反應液溶清，攪拌反應30min。過濾除去不溶物，濾液減壓濃縮幹，乾燥，得目標產物135g至168g，產率：80至90%。
MS m/z(ESI)：415.1651[M+1].
1H NMR(400MHz,DMSO-d6)：δ 12.75(s,1H),11.04(s,1H),8.37(s,1H),7.41-7.42(t,1H),6.89(s,1H),5.15-5.19(m,1H),3.89(s,3H),3.68-3.70(m,2H),3.38-3.40(m,2H),3.29(s,3H),2.95(s,2H),2.09-2.16(m,2H),1.92-1.97(m,2H)
實驗例3：
(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺(式IV化合物)和其相應的檸檬酸鹽、鹽酸鹽、硫酸鹽和硫酸氫鹽在水、0.1N鹽酸中的溶解度比較試驗，結果表明成硫酸氫鹽後，溶解度大大提高，同時也遠遠大於其他鹽。詳細結果見表1。
實驗例4：
考察式(IV)化合物及其不同鹽形式在恒河猴體內的藥物動力學行為，詳細評價不同化合物形式的性質，試驗動物為4隻恒河猴，雌雄各半，單次給予恒河猴50mg/kg劑量；採用多交叉試驗設計給予動物不同藥物，每個週期恢復三天；分別於給藥前(0h)及給藥後0.25h、0.5h、1h、2h、4h、6h、8h和24h經股靜脈取血0.5mL，置肝素鈉抗凝化試管中，搖勻，3500rpm離心10min，分離血漿，並低溫保存，採用LC-MS/MS分別測定血漿中及肝臟中的藥物濃度並採用WinNonlin 5.3軟體分析藥物動力學參數，實驗結果如下：
結論：以上猴的藥物代謝試驗結果顯示，式(IV)化合物體內暴露量為41111ng/ml*小時，但個體差異較大，檸檬酸鹽暴露量和鹼類似，硫酸氫鹽的體內暴露量較鹼提高了50%，並且個體差異小，由此可以看出硫酸氫鹽形式體內暴露量高，個體差異小，適合藥用。
Claims (9)
- 一種式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽，
- 如申請專利範圍第1項所述的式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽，其中式(IV)所示的化合物與硫酸的化學配比為1：1，
- 一種如申請專利範圍第1項所述的式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽的製備方法，其包括化合物(IV)與硫酸成鹽的步驟，
- 如申請專利範圍第3項所述的製備方法，其中成鹽反應在溶劑中進行，該溶劑為碳原子數小於或等於3的鹵烷類與醇類的混合溶劑。
- 如申請專利範圍第4項所述的製備方法，其中該溶劑為二氯甲烷與甲醇的混合溶液。
- 如申請專利範圍第4或5項所述的製備方法，其中成鹽反應的反應溫度為10至30℃，反應時間為0.5至4小時。
- 一種醫藥組成物，其含有如申請專利範圍第1項所述的式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽及藥學上可接受的載體。
- 一種如申請專利範圍第1項所述的式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯並[2,3-d]嘧啶-4-基)胺基)六氫環戊並[c]吡咯-2(1H)-甲醯胺硫酸氫鹽的用途，其係用在製備治療風濕及類風濕性關節炎的藥物。
- 一種如申請專利範圍第7項所述的醫藥組成物的用途，其係用在製備治療風濕及類風濕性關節炎的藥物。
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| JP2023550363A (ja) | 2020-11-17 | 2023-12-01 | アーキュティス・バイオセラピューティクス・インコーポレーテッド | 深部皮膚薬物送達のための組成物および方法 |
| CN112457272B (zh) * | 2020-12-02 | 2022-04-19 | 上海再启生物技术有限公司 | (3-甲氧基-1,2,4-噻二唑-5-氨基)甲酸苯酯的制备方法 |
| WO2023114832A1 (en) | 2021-12-15 | 2023-06-22 | Arcutis Biotherapeutics, Inc. | Stable formulations of shr0302 |
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| DZ3359A1 (fr) * | 2000-06-26 | 2002-01-03 | Pfizer Prod Inc | DÉRIVÉS DE PYRROLO [2,3-d] PYRIMIDINE UTILES COMME AGENTS IMMUNOSUPPRESSEURS |
| GB0307856D0 (en) | 2003-04-04 | 2003-05-14 | Novartis Ag | Organic compounds |
| US7745462B2 (en) * | 2003-04-04 | 2010-06-29 | Novartis Ag | Quinoline-2-one derivatives for the treatment of airways diseases |
| RU2434871C2 (ru) * | 2005-02-03 | 2011-11-27 | Вертекс Фармасьютикалз Инкорпорейтед | Пирролопиримидины, применимые в качестве ингибиторов протеинкиназы |
| AU2011213198B2 (en) * | 2010-02-05 | 2014-04-24 | Zoetis Llc | Pyrrolo [ 2,3-d] pyrimidine urea compounds as JAK inhibitors |
| EP2721025B1 (en) * | 2011-06-16 | 2015-11-25 | Boehringer Ingelheim International Gmbh | New selective ccr2 antagonists |
| SI2796460T1 (sl) * | 2011-12-21 | 2018-10-30 | Jiangsu Hengrui Medicine Co. Ltd | Pirolni šestčlenski derivat heteroarilnega obroča, postopek priprave zanj in medicinske uporabe le-tega |
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| TWI717658B (zh) * | 2017-11-20 | 2021-02-01 | 大陸商江蘇恒瑞醫藥股份有限公司 | 局部給藥的藥物組合物及其製備方法 |
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| RU2015156142A3 (zh) | 2018-03-19 |
| KR20160032021A (ko) | 2016-03-23 |
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| TWI641609B (zh) | 2018-11-21 |
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| CA2913194A1 (en) | 2014-12-11 |
| HUE036533T2 (hu) | 2018-07-30 |
| US9422300B2 (en) | 2016-08-23 |
| CN104470927A (zh) | 2015-03-25 |
| AU2014277506B2 (en) | 2017-08-31 |
| BR112015029463A2 (pt) | 2017-07-25 |
| CA2913194C (en) | 2021-03-02 |
| EP3006445A1 (en) | 2016-04-13 |
| HK1206026A1 (zh) | 2015-12-31 |
| CN104470927B (zh) | 2016-05-04 |
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