TW202115064A - 神經激肽-1拮抗劑 - Google Patents
神經激肽-1拮抗劑 Download PDFInfo
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- TW202115064A TW202115064A TW109121881A TW109121881A TW202115064A TW 202115064 A TW202115064 A TW 202115064A TW 109121881 A TW109121881 A TW 109121881A TW 109121881 A TW109121881 A TW 109121881A TW 202115064 A TW202115064 A TW 202115064A
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- alkyl
- groups
- aryl
- cycloalkyl
- compound
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- 229940127387 Neurokinin 1 Antagonists Drugs 0.000 title abstract 2
- 150000001875 compounds Chemical class 0.000 claims abstract description 150
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Abstract
本公開中提供了神經激肽-1拮抗劑。具體而言,本公開中提供一種式II所示化合物或其藥學上可接受的鹽,及其製備方法。本公開中式II所示化合物是神經激肽-1受體的拮抗劑,可用於與這種受體有關的疾病的治療中,可避免藥物的溶血作用,降低藥物給藥時的副作用。
Description
本公開中涉及一種神經肽神經激肽-1(NK1或NK-1)受體的拮抗劑。
速激肽是神經激肽受體的肽配體。神經激肽受體,比如NK1,NK2和NK3,與各種生物過程有關。可在哺乳動物的神經和循環系統以及在周圍組織中發現它們。因此,這類受體的調節已被研究用於潛在地治療或預防哺乳動物的各種疾病。典型的神經激肽受體拮抗劑和它們的用途包括:US5760018(1998)(疼痛,炎症,偏頭痛和嘔吐),US5620989(1997)(疼痛,傷害感受和炎症),WO95/19344(1995),WO 94/13639(1994)和WO 94/10165(1994)。其它NK1受體拮抗劑的種類還包括:Wu等人,Tetrahedron 56,3043-3051(2000);Rombouts等人,Tetrahedron Letters 42,7397-7399(2001);和Rogiers等人,Tetrahedron 57,8971-8981(2001)。
US7049320提供一種有效的、選擇性的、和具有有益的治療和藥理學性質和良好代謝性穩定性的NK1拮抗劑(5S,8S)-8-[{(1R)-1-(3,5-雙-(三氟甲基)苯基)-乙氧基}-甲基]-8-苯基-1,7-二氮雜螺[4.5]癸-2-酮(式I化合物),該化合物可採用游離鹼形式或藥學上可接受的鹽形式,適合胃腸外給藥的製劑,
US9101615提供式I化合物的前藥,即,式I化合物游離胺(或兩個胺)的氫被選自-Y、-X的基團置換的前藥及其鹽,其中Y選自-P(O)(OH)2、-S(O)n1R1、-C(O)(C1-6烷基)X、-C(O)(C1-6烷基)(芳基)、-C(O)OR4;X選自-NR2R3、-P(O)(OH)2或-S(O)n1R1;R1是H或C1-6烷基;R2是H或C1-6烷基;R3是H或C1-6烷基;R4是H或C1-6烷基;n1是0-4。該前藥可用於合適的液體製劑(包括或不包括所述胃腸外遞藥載體)中治療需要其治療的患者。
另一方面,藥物溶血性是藥物進入人體後免疫因素導致的紅細胞大量破壞引起的,臨床上出現了貧血、黃疸、醬油和尿液等溶血現象。藥物性溶血性貧血可分為以下三種類型:(1)藥物性免疫,導致抗體介導的溶血性反應;(2)藥物作用於具有遺傳酶缺陷的紅細胞(例如G6PD缺陷);(3)藥物對異常血紅蛋白的溶血反應。治療這種疾病的關鍵在於停止使用相關藥物,控制溶血的發生,以防止併發症的發生。為了解決式I化合物在生理pH溶劑度低的問題,研究人員採用含有Captisol、丙二醇和乙醇的共溶劑基製劑明顯提高化合物1的溶解度,但是共溶劑製劑在靜脈內給藥後有明顯的溶血作用。CN102573475公開了一種改進處方,含有聚乙二醇15-羥基硬脂酸酯、中鏈甘油三酯。但醫藥組成物的溶血作用仍然沒有徹底解決,即便將式I化合物製備成含有磷酸酯的前藥。
本申請提供一種新的對治療各種生理失調、病徵和疾病有效而副作用最小的NK1拮抗劑前藥化合物。
其中,X選自氫、雜環基、芳基、雜芳基、-C(O)OAmR3、-C(O)NR4AmR3、-Am[C(R1)(R2)]C(O)OAnR3、-AmOC(O)[C(R1)(R2)]AnR3、-AmC(O)NR4AnR3、-AmNR4C(O)AnR3或-AmR5,該雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
Y選自氫、-C(O)OAmR3、-C(O)NR4AmR3、-Am[C(R1)(R2)]C(O)OAnR3、-AmOC(O)[C(R1)(R2)]AnR3、-AmC(O)NR4AnR3、-AmNR4C(O)AnR3或-AmR5;
A獨立地選自-C(R1)(R2)(B)p-或-(B)qC(R1)(R2)-,
R1、R2或R4各自獨立地選自氫、烷基、環烷基、雜環基、芳基或雜芳基,該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
R3選自氫、烷基、環烷基、雜環基、芳基、雜芳基、聚(伸氧基
伸乙氧基)()、聚(伸乙氧基)()、ORO(R6)2、
PO(R6)2、OSO2(R6)2、SO2(R6)2、OC(O)R6或C(O)OR6,該烷基、環烷基、雜環基、
芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
R6各自獨立地選自氫、羥基、烷基、環烷基、雜環基、芳基、雜芳基、烷氧基、羥烷基或NR'(R"),該烷基、羥烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
R7各自獨立地選自烷基、羥基、環烷基、雜環基、芳基、雜芳基、羥烷基或NR'(R"),該烷基、羥烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
R'或R"獨立地選自氫、羥基、烷基(較佳選自C1-12烷基,包括但不限於甲基、乙基或異丙基)、烷氧基(較佳選自C1-12烷氧基)、烯基、醯基;
B各自獨立地選自O,N,SC(O)
m,n,o各自獨立地選自1~10,可為1、2、3、4、、5、6、7、8、9或10;p,q各自獨立地選自0或1;
且,X和Y不同時為氫。
本公開式II所示化合物具有優於母藥式I化合物的溶解度,因此,可適用於靜脈內給藥。另外,前述化合物製成靜脈製劑進入人體後,在生理條件下降解並釋放母藥,延緩藥物的釋放,延長藥物的釋放週期。
在本公開可選實施方案中,式II所示的化合物,其中X選自氫、雜環基、芳基、雜芳基、-C(O)O[C(R1)(R2)(O)p]mR3、-C(O)NR4[C(R1)(R2)(O)p]mR3、-[C(R1)(R2)(O)p]mC(O)[C(R1)(R2)(O)p]nR3、-[C(R1)(R2)(O)p]m[C(R1)(R2)]C(O)[(O)qC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]mR5,該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基(較佳選自C1-12烷基,包括但不限於甲基、乙基或異丙基)、環烷基(較佳選自C1-12環烷基,如環已烷基、環戊烷基)、烷氧基(較佳選自C1-12烷氧基)、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
Y選自氫、-C(O)O[C(R1)(R2)(O)p]mR3、-C(O)NR4[C(R1)(R2)(O)p]mR3、-[C(R1)(R2)(O)p]mC(O)[C(R1)(R2)(O)p]nR3、-[C(R1)(R2)(O)p]mC(O)[(O)qC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]mR5,且X和Y不同時為氫。
在本公開可選實施方案中,式II所示的化合物,其中Y選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3、-[C(R1)(R2)N]m C(O)[C(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[OC(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[NC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]nR5,X為氫、3至6員雜環基。
在本公開可選實施方案中,式II所示的化合物,其中Y選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3、-[C(R1)(R2)N]m C(O)[C(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[OC(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[NC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]nR5,X為氫、3至6員雜環基;m,n,o各自獨立地選自1、2、3、4、5或6;p,q各自獨立地選自0。
在本公開可選實施方案中,式II所示的化合物,其中Y選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3、-[C(R1)(R2)N]m C(O)[C(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[OC(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[NC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]nR5,X為氫、3至6員雜環基;m,n,o各自獨立地選自1、2、3、4、5或6;p,q各自獨立地選自1。
在本公開可選實施方案中,式II所示的化合物,其中Y選自-C(O)O[C(R1)(R2)]R3、-C(O)NR4[C(R1)(R2)]R3、-[C(R1)(R2)O]C(O)[C(R1)(R2)]R3、-[C(R1)(R2)]C(O)[OC(R1)(R2)]R3、-[C(R1)(R2)N]C(O)[C(R1)(R2)]R3、[C(R1)(R2)N]C(O)[OC(R1)(R2)]R3、[C(R1)(R2)N]C(O)[NC(R1)(R2)]R3、-[C(R1)(R2)(O)p]C(O)NR4[C(R1)(R2)(O)p]R3或-[C(R1)(R2)(O)p]R5,X為氫、3至6員雜環基。
在本公開可選實施方案中,式II所示的化合物,其中Y選自-C(O)O[C(R1)(R2)]2R3、-C(O)NR4[C(R1)(R2)]2R3、-[C(R1)(R2)O]2C(O)[C(R1)(R2)]2R3、-[C(R1)(R2)]2C(O)[OC(R1)(R2)]2R3、-[C(R1)(R2)N]2C(O)[C(R1)(R2)]2R3、[C(R1)(R2)N]2C(O)[OC(R1)(R2)]2R3、[C(R1)(R2)N]2C(O)[NC(R1)(R2)]2R3、-[C(R1)(R2)(O)p]2C(O)NR4[C(R1)(R2)(O)p]2R3或-[C(R1)(R2)(O)p]2R5,X為氫、3至6員雜環基。
在本公開可選實施方案中,式II所示的化合物,其中X選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3或-[C(R1)(R2)]nR5,Y為氫。
在本公開可選實施方案中,式II所示的化合物,其中X選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3或-[C(R1)(R2)]nR5;Y為氫;m,n,o各自獨立地選自1、2、3、4、5或6;p,q各自獨立地選自0。
在本公開可選實施方案中,式II所示的化合物,其中X選自-[C(R1)(R2)]C(O)[OC(R1)(R2)]R3、-C(O)O[C(R1)(R2)]R3、-C(O)NR4[C(R1)(R2)]R3、-[C(R1)(R2)O]C(O)[C(R1)(R2)]R3、-[C(R1)(R2)]C(O)NR4[C(R1)(R2)]R3或-[C(R1)(R2)]R5,Y為氫。
進一步地,在本公開可選實施方案中,式II所示的化合物,其
中R3選自氫、聚(伸氧基伸乙氧基)()、聚(伸乙氧基)
()、OPO(R6)2、PO(R6)2、OSO2(R6)2、SO2(R6)2、OC(O)R6或C(O)OR6,
R6如式II所示化合物中所定義。
在本公開可選實施方案中,式II所示的化合物,其中Y選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3、-[C(R1)(R2)N]m C(O)[C(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[OC(R1)(R2)]nR3、[C(R1)(R2)N]m C(O)[NC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]nR5,X為氫、3至6員雜
環基;R3選自氫、聚(伸氧基伸乙氧基)()、聚(伸乙氧基)
()、OPO(R6)2、PO(R6)2、OSO2(R6)2、SO2(R6)2、OC(O)R6或C(O)OR6,
R6如式II所示化合物中所定義。
在本公開可選實施方案中,式II所示的化合物,其中Y選自[C(R1)(R2)(O)p]nR5,R5選自C6-10雜環基、OPO(R6)2、OSO2R6、SR'、SO2R'、
、OC(O)R7或NR'(R")。
在本公開可選實施方案中,式II所示的化合物,其中Y選自
[C(R1)(R2)]nR5,R5選自C6-10雜環基、OPO(R6)2、OSO2R6、SR'、SO2R'、、
OC(O)R7或NR'(R")。
在本公開可選實施方案中,式II所示的化合物,其中Y選自[C(R1)(R2)O]nR5,R5選自C6-10雜環基、OPO(R6)2、OSO2R6、SR'、SO2R'、
、OC(O)R7或NR'(R")。
進一步地,式II所示的化合物,其中該R6選自氫、C1-6烷基、C3-6環烷基、3至6員雜環基(如派啶)、OR'或NR'(R"),R'、R"如式II所示化合物中定義。
在本公開可選實施方案中,式II所示的化合物,其中R'、R"選自氫或烷基,該烷基較佳選自C1-10烷基,更優自C1-6烷基,如甲基、乙基、丙基、異丙基。
在本公開可選實施方案中,式II所示的化合物,其中m=1、2、3或4,n=1、2、3或4,o=1~8。
在一些實施方案中,式II所示化合物,其中R6和R7各自獨立地選自
一些實施方案提供II所示化合物中R3選自OPO(R6)2,R6選自羥基、C1-6烷基、C3-7環烷基、C1-6烷氧基或3至7員雜環基。
另一些實施方案提供II所示化合物中m=1、2、3或4。
另一些實施方案提供II所示化合物中R1或R2各自獨立地選自氫、C1-6烷基或C3-7環烷基。
在另一些實施方案中,其中式II所示化合物為
其中,R1或R2各自獨立地選自氫、烷基、環烷基、雜環基、芳基或雜芳基,該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
R'或R"獨立地選自氫、羥基、烷基、烷氧基、烯基、醯基;
m=1、2、3或4。
在一些實施方案中,式II所示化合物中R6選自
在另一些實施方案中,式III所示化合物為
其中,R1或R2各自獨立地選自氫、烷基、環烷基、雜環基、芳基或雜芳基,該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
R6各自獨立地選自氫、羥基、烷基、環烷基、雜環基、芳基、雜芳基、烷氧基、羥烷基或NR'(R"),該烷基、羥烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;
R'或R"獨立地選自氫、羥基、烷基、烷氧基、烯基、醯基。
進一步地,在可選實施方案中,式IV所示化合物中R6選自C1-12烷基(包括但不限於甲基、乙基、丙基或異丙基)、C3-12環烷基(包括但不限於環丙基、環戊基、環己基)、3至12員雜環基(包括但不限於吡咯基)、C6-12芳基(包括但不限於苯基、萘基)、3至12員雜芳基(包括但不限於吡啶、哌啶)、C1-12烷氧基(包括但不限於甲氧基、乙氧基、丙氧基或異丙氧基)、C1-12羥烷基或NR'(R"),該烷基、羥烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自C1-6烷基、C3-6環烷基、3至12員雜環基、C1-12烷氧基、C1-6羥烷基、C2-4烯基、C2-4炔基、C6-10芳基、3至10員雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;R'或R"獨立地選自氫、C1-6烷基、C1-6烷氧基、C2-4烯基、C1-6烷醯基(如乙醯基、甲醯基)、苯甲醯基、對甲苯醯基。
在本公開較佳實施方案中,式IV所示化合物,其中該R6選自氫、C1-6烷基、C3-6環烷基、3至6員雜環基(如派啶)、OR'或NR'(R")。
在本公開可選實施方案中,式IV所示的化合物,其中R'、R"選自氫或烷基,該烷基較佳選自C1-10烷基,更佳選自C1-6烷基,如甲基、乙基、丙基、異丙基。
在一些實施方案中,式IV所示化合物中R6選自
在本公開較佳實施方案中,式IV所示化合物,其中該R6選自氫、C1-6烷基、C3-6環烷基、3至6員雜環基(如派啶)、OR'或NR'(R")。
在本公開可選實施方案中,式IV所示的化合物,其中R'、R"選自氫或烷基,該烷基較佳選自C1-10烷基,更佳選自C1-6烷基,如甲基、乙基、丙基、異丙基。
在另一些實施方案中,式IV所示化合物中R6選自
式II所示典型化合物,包括但不限於:
另一方面,本公開化合物相比已知化合物具有更高溶解度、體內轉化更為優異。在一些實施方案中,本公開化合物具有低溶血作用,降低在給藥時藥物的副作用,利於提高患者給藥順從性。
本公開中還提供了一種醫藥組成物,包括至少一種治療有效量的前述化合物或其可藥用的鹽以及藥學上可接受的載體、稀釋劑或賦形劑。
另一方面,本公開所述化合物的官能團中氫可被氘代,獲得相應氘代化合物,氘代化合物保留了與氫類似物相當的選擇性和潛力;氘鍵更穩定,使得"ADME"即"毒藥物動力學"不同,從而提供臨床上有益效果。
毒藥物動力學,指機體對外源化學物的吸收(absorption)、分佈(distribution)、代謝(metabolism)及排泄(excretion)過程。
本公開中還涉及上述方案中所述化合物或其可藥用鹽,或醫藥組成物在製備治療患者中的生理失調,病症或疾病的藥物中的用途,其中生理失調、病症或疾病是呼吸道疾病、咳嗽、炎性疾病、皮膚障礙、眼科障礙、抑鬱症、焦慮、恐怖症,雙向障礙,酒精依賴,對神經起顯著作用的物質濫用,癲癇,傷害感受,精神病,精神分裂症,阿爾茨海默氏病,與AIDs有關的癡呆,Towne′s疾病,與緊張有關的障礙,強迫性/強制性障礙,暴食症(bulimia),神經性厭食症,瘋狂進食,狂躁,經前期綜合症,胃腸機能紊亂,動脈粥樣硬化,纖維化障礙,肥胖,II型糖尿病,頭痛,神經性疼痛,動作後疼痛,慢性疼痛綜合症,膀胱障礙,泌尿生殖器障礙,嘔吐或噁心。進一步地,用於製備治療哮喘,嘔吐,噁心,憂鬱症,焦慮,咳嗽或偏頭痛的藥物的用途。
另一方面,化合物的可藥用鹽選自無機鹽或有機鹽,本公開所述化合物與酸如三氟乙酸反應成相應鹽,該酸選自但不限於乙酸、鹽酸、水楊酸、蘋果酸、抗壞血酸、磷酸、檸檬酸、苯甲酸或富馬酸。本公開所述化合物
與鹼如N-甲基-D葡甲胺或二環已胺反應成相應鹽,該鹼選自但不限於鈉、鹼土金屬、胺基酸(如精胺酸、賴胺酸)。
另一方面,本公開還包括與本公開中記載的那些相同的,但一個或多個原子被原子量或質量數不同於自然中通常發現的原子量或質量數的原子置換的同位素標記的本申請化合物。可結合到本申請化合物的同位素的實例包括氫、碳、氮、氧、磷、硫、氟、碘和氯的同位素,諸如分別為2H、3H、11C、13C、14C、13N、15N、15O、17O、18O、31P、32P、35S、18F、123I、125I和36Cl等。
本公開的化合物可以在一個或多個構成該化合物的原子上包含非天然比例的原子同位素。例如,可用放射性同位素標記化合物,比如氚(3H),碘-125(125I)或C-14(14C)。又例如,可用重氫取代氫形成氘代藥物,氘與碳構成的鍵比普通氫與碳構成的鍵更堅固,相比於未氘化藥物,氘代藥物有降低毒副作用、增加藥物穩定性、增強療效、延長藥物生物半衰期等優勢。本申請的化合物的所有同位素組成的變換,無論放射性與否,都包括在本申請的範圍之內。
此外,用較重同位素(諸如氘(即2H))取代可以提供某些由更高的代謝穩定性產生的治療優點(例如增加的體內半衰期或降低的劑量需求),並且因此在某些情形下可能是較佳的,其中氘取代可以是部分或完全的,部分氘取代是指至少一個氫被至少一個氘取代。
術語解釋:
“烷基”指飽和的脂族烴基團,包括1至20個碳原子的直鏈和支鏈基團。較佳含有1至12個碳原子的烷基,更佳含有1至6個碳原子的烷基。非限制性實施例包括甲基、乙基、正丙基、異丙基、正丁基、異丁基、第三丁基、第二丁基、正戊基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基,及其各種支鏈異構體等。烷基可以
是取代的或未取代的,當被取代時,取代基可以在任何可使用的連接點上被取代,較佳為一個或多個以下基團,獨立地選自芳基、雜芳基、鹵素所取代。“烯基”包括具有2至12個碳原子的支鏈和直鏈烯烴或含有脂族烴基團的烯烴。例如“C2-6烯基”表示具有2、3、4、5或6個碳原子的烯基。烯基的實例包括但不限於,乙烯基、烯丙基、1-丙烯基、1-丁烯基、2-丁烯基、3-丁烯基、2-甲基丁-2-烯基、3-甲基丁-1-烯基、1-戊烯基、3-戊烯基及4-己烯基。
術語“環烷基”指飽和或部分不飽和單環或多環環狀烴取代基,環烷基環包含3至20個碳原子,較佳包含3至12個碳原子,更佳包含3至6個碳原子。單環環烷基的非限制性實例包括環丙基、環丁基、環戊基、環戊烯基、環己基、環己烯基、環己二烯基、環庚基、環庚三烯基、環辛基等;多環環烷基包括螺環、稠環和橋環的環烷基。
該環烷基環可以稠合於芳基、雜芳基或雜環烷基環上,其中與母體結構連接在一起的環為環烷基,非限制性實例包括茚滿基、四氫萘基、苯并環庚烷基等。環烷基可以是視需要取代的或非取代的,當被取代時,取代基較佳為一個或多個以下基團,其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。
術語“雜環基”指飽和或部分不飽和單環或多環環狀烴取代基,其包含3至20個環原子,其中一個或多個環原子為選自氮、氧或S(O)m(其中m是整數0至2)的雜原子,但不包括-O-O-、-O-S-或-S-S-的環部分,其餘環原子為碳。較佳包含3至12個環原子,其中1~4個是雜原子;更
佳包含3至6個環原子。單環雜環基的非限制性實例包括吡咯烷基、咪唑烷基、四氫呋喃基、四氫噻吩基、二氫咪唑基、二氫呋喃基、二氫吡唑基、二氫吡咯基、哌啶基、哌嗪基、嗎啉基、硫代嗎啉基、高哌嗪基等,較佳哌啶基、吡咯烷基。多環雜環基包括螺環、稠環和橋環的雜環基。
雜環基可以是視需要取代的或非取代的,當被取代時,取代基較佳為一個或多個以下基團,其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、側氧基、羧基或羧酸酯基。
“炔基”包括具有2至12個碳原子的支鏈和直鏈炔基或含有脂族烴基的烯烴,或若規定指定碳原子數,則意指該特定數目。例如乙炔基、丙炔基(例如1-丙炔基、2-丙炔基)、3-丁炔基、戊炔基、己炔基及1-甲基戊-2-炔基。
術語“芳基”指具有共軛的π電子體系的6至14員全碳單環或稠合多環(也就是共享毗鄰碳原子對的環)基團,較佳為6至12員,例如苯基和萘基。該芳基環可以稠合於雜芳基、雜環基或環烷基環上,其中與母體結構連接在一起的環為芳基環,其非限制性實例包括:
芳基可以是取代的或非取代的,當被取代時,取代基較佳為一個或多個以下基團,其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基,較佳苯基。
術語“雜芳基”指包含1至4個雜原子、5至14個環原子的雜芳族體系,其中雜原子選自氧、硫和氮。雜芳基較佳為6至12員,更佳為5員或6員,例如咪唑基、呋喃基、噻吩基、噻唑基、吡唑基、噁唑基、吡咯基、四唑基、吡啶基、嘧啶基、噻二唑、吡嗪基等,較佳為咪唑基、吡唑基、嘧啶基或噻唑基;更佳為吡唑基或噻唑基。該雜芳基環可以稠合於芳基、雜環基或環烷基環上,其中與母體結構連接在一起的環為雜芳基環,其非限制性實例包括:
雜芳基可以是視需要取代的或非取代的,當被取代時,取代基較佳為一個或多個以下基團,其獨立地選自烷基、烯基、炔基、烷氧基、烷硫
基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。
術語“烷氧基”指-O-(烷基)和-O-(非取代的環烷基),其中烷基的定義如上該。烷氧基的非限制性實例包括:甲氧基、乙氧基、丙氧基、丁氧基、環丙氧基、環丁氧基、環戊氧基、環己氧基。烷氧基可以是視需要取代的或非取代的,當被取代時,取代基較佳為一個或多個以下基團,其獨立地選自烷基、烯基、炔基、烷氧基、烷硫基、烷基胺基、鹵素、巰基、羥基、硝基、氰基、環烷基、雜環烷基、芳基、雜芳基、環烷氧基、雜環烷氧基、環烷硫基、雜環烷硫基、羧基或羧酸酯基。
術語“羥烷基”指被羥基取代的烷基,其中烷基如上所定義。
術語“鹵代烷基”指被鹵素取代的烷基,其中烷基如上所定義。
術語“氘代烷基”指被氘原子取代的烷基,其中烷基如上所定義。
術語“羥基”指-OH基團。
術語“鹵素”指氟、氯、溴或碘。
術語“胺基”指-NH2。
術語“氰基”指-CN。
術語“硝基”指-NO2。
“視需要”或“視需要地”意味著隨後所描述地事件或環境可以但不必發生,該說明包括該事件或環境發生或不發生地場合。例如,“視需要被烷基取代的雜環基團”意味著烷基可以但不必須存在,該說明包括雜環基團被烷基取代的情形和雜環基團不被烷基取代的情形。
“取代的”指基團中的一個或多個氫原子,較佳為最多5個,更佳為1~3個氫原子彼此獨立地被相應數目的取代基取代。不言而喻,取代基僅處在它們的可能的化學位置,本領域技術人員能夠在不付出過多努力的情況下確定(藉由實驗或理論)可能或不可能的取代。例如,具有游離氫的胺基或羥基與具有不飽和(如烯屬)鍵的碳原子結合時可能是不穩定的。
“醫藥組成物”表示含有一種或多種本文所述化合物或其生理學上可藥用的鹽或前體藥物與其他化學組分的混合物,以及其他組分例如生理學可藥用的載體和賦形劑。醫藥組成物的目的是促進對生物體的給藥,利於活性成分的吸收進而發揮生物活性。
本公開中的已知的起始原料可以採用或按照本領域已知的方法來合成,或可購買自AcrosOrganics或AldrichChemicalCompany等公司或參考文獻CN102775401A中方法獲取。
化合物的結構是藉由核磁共振(NMR)或/和質譜(MS)來確定的。NMR位移(δ)以10-6(ppm)的單位給出。NMR的測定是用BrukerAVANCE-400核磁儀,測定溶劑為氘代二甲基亞碸(DMSO-d6),氘代氯仿(CDCl3),氘代甲醇(CD3OD),內標為四甲基矽烷(TMS);ESI-MS的測定用FINNIGANLCQAd(ESI)質譜儀(生產商:Thermo,型號:FinniganLCQadvantageMAX),LCMS採用高效液相色譜(生產商:Agilent,型號:1200)進行梯度洗脫,以正離子模式掃描,質量掃描範圍為100~1500。
[圖1]係實施例5化合物於人血漿中轉化的趨勢圖。
以下結合實施例進一步描述本公開中,但這些實施例並非限制本公開中的範圍。
本公開中實施例中未註明具體條件的實驗方法,通常按照常規條件,或按照原料或商品製造廠商所建議的條件。未註明具體來源的試劑,為市場購買的常規試劑。
實施例1:
第一步:
在N2保護下,於100mL三口瓶中稱取化合物1(2.43g,4.86mmol,1eq)溶於二氯甲烷(36mL)中,加入二異丙基乙胺(5g,38.76mmol,8eq),冷卻到-30℃,加入三甲基氯矽烷(1.36g,12.52mmol,2.6eq),室溫下攪拌2h。再冷卻到-25℃,滴加氯甲酸氯甲酯(0.77g,6mmol,1.23eq)的二氯甲烷溶液,控溫-20℃~-5℃攪拌至反應完畢,將反應液
倒入冰水中,分液,二氯甲烷萃取,加入水和1N的鹽酸溶液,分液,再依次用食鹽水、飽和碳酸氫鈉水溶液和食鹽水洗滌,無水硫酸鈉乾燥,過濾,濃縮,得到3.0g黃色膠狀物,收率104%。
第二步:
在N2保護下,於500mL三口瓶中加入化合物2(2.8g,4.53mmol,1eq),四丁基碘化銨(1.68g,4.55mmol,1eq),磷酸二第三丁酯鉀鹽(5.63g,22.67mmol,5eq)和二噁烷(84mL),加熱至55℃下攪拌4h。反應液降溫,倒入乙酸乙酯和水中,分液,用乙酸乙酯萃取,用亞硫酸鈉的水溶液洗滌,再依次用水、食鹽水洗滌,無水硫酸鈉乾燥,過濾,濃縮得到3.73g黃色泡沫,收率107%。
第三步:
在N2保護下,於100mL單口瓶中加入化合物3(1.95g,2.543mmol,1eq)溶於二氯甲烷(40mL)中,冰水冷卻下緩慢加入三氟乙酸
(1.45mL,19.52mmol,8eq),攪拌至反應完畢,濃縮,得到2.29g油狀物,分離純化得到1.39g白色泡沫狀固體,收率83.5%。
1H-NMR(400MHz,CD3OD):δ(ppm)7.89(s,2H),7.86(s,1H),7.41-7.27(m,5H),5.66(d,J=12Hz,1H),5.50-5.47(m,1H),4.60(d,J=8Hz,1H),4.20-3.88(m,3H),2.51-2.10(m,5H),1.86-1.66(m,3H),1.44-1.31(m,4H).
第四步:
於50mL單口瓶中加入化合物4(111mg,0.17mmol),葡甲胺(59.6mg,0.305mmol)溶於甲醇(5mL)中,室溫下攪拌1.5h,濃縮,得到174mg白色固體鹽。
實施例2:
第一步:
將化合物1(5g,10mmol,1eq)置於250mL的三口瓶中,加入50mL的二氯甲烷,N2置換,加入二異丙基乙基胺(5.1g,40mmol,4eq),冷卻至0℃,慢慢滴入氯甲酸-3-氯丙酯(4.71g,30mmol,3eq)攪拌至反應完畢,反應液用20mL×2水洗,用無水硫酸鈉乾燥後濃縮,粗品用20mL的第三丁基甲醚打漿,過濾乾燥後得到5.3g產品,白色固體,收率85.5%,HPLC純度95.2%。
第二步:
將化合物2(500mg,0.833mmol,1eq)置於25mL的圓底燒瓶中,加入5mL的二甲基甲醯胺、5mg碘化鉀和二第三丁酯磷酸四丁基季銨鹽(564mg,1.25mmol,1.5eq),升溫至100℃反應完畢,濃縮,高效液相製備得到370mg產品,收率57.8%,HPLC純度97%。
第三步:
化合物3(2g,2.52mmol)溶於鹽酸二噁烷溶液(25mL,4M),室溫攪拌反應30min後減壓蒸乾,得到化合物4(1.4g,2.05mmol),收率81%。
第四步:
25℃下將化合物4(700mg,1.025mmol),葡甲胺(310mg,2mmol)用甲醇(10mL)溶解,攪拌反應1h,減壓濃縮乾得到化合物5粗品(1.1g),將其用甲基第三丁基醚打漿並過濾抽乾,得到化合物5的純品(1g,0.932mmol),收率91%。
1H-NMR(400MHz,CD3OD):δ 7.90-7.84(m,3H),7.32-7.25(m,5H),4.14-3.61(m,25H),2.81(m,5H),2.47-2.29(m,12H),1.79-1.63(m,5H),1.46-1.29(m,3H),1.21-1.12(m,6H).
實施例3:
在25ml燒瓶中,加入2毫升丙酮和100毫克化合物1,開啟攪拌;分批加入固體碳酸鉀(42mg,0.3mmol,1.5eq)後,室溫攪拌半小時;將36毫克的化合物2加入到反應瓶裡,室溫攪拌反應完畢,約18小時,管柱層析純化得50毫克3(產率40.8%)。
1H-NMR(400MHz,CDCl3):δ=7.79(s,1H),7.72(s,2H),7.42-7.40(d,J=8Hz,2H),7.31-7.27(m,2H),7.27-7.21(m,1H),5.58(s,1H),4.55-4.53
(m,1H),4.06-3.99(m,2H),3.69-3.67(d,J=8Hz,1H),3.53-3.49(d,J=16Hz,1H),3.25-3.21(d,J=16Hz,1H),2.77-2.74(d,J=12Hz,1H),2.59-2.57(d,J=8Hz,1H),2.34-2.31(m,3H),1.97-1.71(m,7H),1.46-1.45(d,J=4Hz,3H).
實施例4:
第一步:
在氮氣氛圍下,將750mg的化合物1、2.1ml二異丙基乙胺加入到三口瓶中,然後加入12毫升的無水二氯甲烷,降溫到-40℃,滴入0.5ml三甲基氯矽烷完畢後,室溫並攪拌反應兩個小時。再降溫到-30至-20℃,將0.024毫升的氯甲酸氯乙酯溶於3毫升的無水二氯甲烷裡,滴入到反應液中完畢後,在-20至5℃攪拌至反應完畢,加入水淬滅反應,分液,依次用濃度為1N的稀鹽酸、飽和食鹽水、飽和碳酸氫鈉水溶液,飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾,減壓濃縮,真空乾燥得1克白色固體2。
第二步:
將1g化合物2以及0.99g碘化鈉溶於10毫升的二甲基甲醯胺中,加入1.15ml二異丙基乙胺以及0.75ml甲基哌嗪,加熱至90℃攪拌反應完畢,反應液直接濃縮後經高效液相製備得430mg化合物3。
1H-NMR(400MHz,CDCl3):δ7.77(s,1H),7.73(s,2H),7.37-7.26(m,5H),6.56(s,1H),4.44-4.40(m,1H),4.29-4.24(m,2H),4.10-4.07(m,1H),3.90-3.87(d,J=12Hz,1H),3.79-3.76(d,J=12Hz,1H),3.01-2.97(d,J=16Hz,1H),2.52-2.32(m,15H),1.93-1.65(m,6H),1.29-1.28(d,J=4Hz,3H).
實施例5:
第一步:
氮氣氛圍下,取750mg化合物1以及2.1ml二異丙基乙胺溶於13ml無水二氯甲烷裡,冷卻到-10℃,逐滴加0.5ml三甲基氯矽烷,加完後升到室溫並攪拌三個小時,再次降溫到-10℃,滴加3ml氯甲酸氯甲酯(0.288g)的二氯甲烷的溶液,滴完後,在-10℃反應完畢,水淬滅反應,分液,依次用稀鹽酸、飽和食鹽水、飽和碳酸氫鈉水溶液、飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾,減壓濃縮,純化得400毫克白色固體化合物2。
第二步:
將147mg化合物3以及203mg碘化鈉加入到2毫升的二甲基甲醯胺中,隨後加入136毫克的碳酸氫鉀,室溫攪拌半個小時,隨後將溶於10ml二甲基甲醯胺的400mg化合物2滴入到反應體系裡,反應過夜,加入水淬滅反應,乙酸乙酯萃取兩次,有機相合併,無水硫酸鈉乾燥過濾濃縮後,過矽膠管柱純化得450mg油狀化合物4。
第三步:
將405mg化合物4溶於18ml二氯甲烷裡,冰浴冷卻下滴加4.5ml三氟醋酸,滴完後反應升到室溫,攪拌兩個小時,濃縮後經管柱層析純化得330mg產物化合物5,產率80%。
1H-NMR(400MHz,CDCl3):δ 8.34(s,1H),7.72(s,1H),7.63(s,2H),7.40-7.28(m,5H),6.19(s,1H),5.68-5.67(d,J=4Hz,1H),4.30-4.29(d,J=4Hz,1H),4.20-4.17(d,J=12Hz,1H),3.99-3.91(m,2H),3.79(s,1H),2.70-2.67(d,J=12Hz,1H),2.49-2.21(m,8H),1.83-1.70(m,4H),1.29-1.28(m,3H),1.09-1.07(m,6H).
實施例6:
第一步:
將1.294g三光氣溶於7.5ml無水四氫呋喃裡,冰浴冷卻,氮氣置換三次。隨後逐滴加入0.33ml吡啶。滴完後,再將溶於7.5ml無水四氫呋喃的
500mg化合物1溶液滴入到反應液裡,滴完後反應在5℃攪拌3個小時。加入30ml二氯甲烷稀釋,依次用稀鹽酸、水和飽和食鹽水洗滌,無水硫酸鈉乾燥,過濾,濃縮得粗品700mg。
第二步:
將128mg化合物3加入到2ml無水四氫呋喃裡,氮氣保護下置換三次。反應冷卻到-65攝氏度左右,滴入0.28ml六甲基二矽胺基鋰(1摩爾每升,溶於正己烷)並攪拌半個小時。另取前一步的粗品60mg化合物2溶於1ml無水四氫呋喃裡,氮氣保護下置換三次後冷卻到-65℃。將前面製取化合物3的鋰鹽轉移進醯氯化合物2反應瓶裡,加完後在-65℃反應完畢,加入飽和氯化銨水溶液淬滅,乙酸乙酯萃取,有機相濃縮後直接過管柱純化得62mg化合物4。
第三步:
將62mg化合物4以及31mg 20%濕的氫氧化鈀一起加入到1.5ml乙酸乙酯裡,開啟攪拌,氫氣球置換三次後室溫攪拌5個小時,過濾,濾餅用乙酸乙酯洗滌,濾液濃縮後製備得41mg白色固體化合物5。
1H-NMR(400MHz,CDCl3)δ=7.72(s,1H),7.57(s,2H),7.50-7.41(m,5H),4.80-4.59(m,3H),4.17-4.13(d,J=16Hz,1H),3.83-3.80(d,J=12Hz,1H),3.62-3.59(d,J=12Hz,1H),3.26-3.22(d,J=16Hz,1H),2.60-2.47(m,4H),2.26-2.18(m,2H),1.85-1.80(m,2H),1.45-1.43(d,J=8Hz,3H),0.89-0.83(m,1H).
實施例7:
將碳酸鉀(11.7g,84.66mmol,8.47eq)溶於水(40mL)中備用。在N2保護下,化合物1(5.55g,10mmol,1eq)懸浮於乙酸乙酯(80mL)中,冰浴冷卻下滴加上述碳酸鉀水溶液,攪拌下反應液逐漸澄清,再滴加Cbz-Cl(1.7mL,12mmol,1.2eq),加完攪拌10min,室溫攪拌反應過夜,將反應液分液,用乙酸乙酯提取,合併有機相,無水硫酸鈉乾燥,過濾,濃縮,管柱層析得到4.3g白色固體,收率56%。
實施例8:
氮氣保護下,於50mL單口瓶中加入化合物1(317mg,0.5mmol)和THF(7.2mL),攪拌溶解並冷至-20℃。滴加NaHMDS(2M,0.5mL,1mmol),攪拌至反應完全,飽和氯化銨淬滅反應,甲基第三丁基醚萃取,飽和食鹽水洗,無水硫酸鈉乾燥,濃縮,經管柱層析純化得化合物2(250mg),收率68%。
於50mL單口瓶中,加入化合物2(250mg,0.34mmol)、甲醇(10mL),鈀碳(10%,250mg),室溫下氫氣氛圍下攪拌至反應完畢,過濾,濃縮得化合物3(150mg),收率74%。
LCMS:601[M+1]。
實施例9:
在N2保護下,於50mL反應瓶中加入化合物1(215mg,0.339mmol,1eq),無水碳酸鉀(55mg,0.396mmol,1.1eq)、多聚甲醛(37mg,1.23mmol,3.3eq)和THF(5ml),加熱攪拌至反應完畢,過濾,濃縮得到粗品,管柱層析純化得到216mg油狀物2,收率95%。
在N2保護下,於反應瓶中加入化合物2(66mg,0.1mmol,1eq)和THF(5ml)中,冰浴冷條件下滴加LiHMDS(1M in THF,0.2ml,0.2mmol,2eq),再加入化合物3(40mg,0.37mmol,3.7eq),攪拌至反應完畢,乙酸乙酯萃取,濃縮得到粗品,管柱層析純化得到27mg油狀物粗品4,收率36%。
室溫下,反應瓶中加入化合物4(27mg,0.367mmol,1eq),Pd/C(33mg)和甲醇(5ml)中,氫氣氛圍下攪拌至反應完畢,過濾,濃縮得到粗品,經管柱層析得13mg油狀物5,收率58.8%。
LCMS:602[M+1]。
實施例10:
按照實施例5的方法,以氯甲酸氯丙酯代替氯甲酸氯甲酯,合成得到該目標化合物。LCMS:702[M+1]。
實施例11:
按照實施例5的方法,以氯甲酸氯乙酯代替氯甲酸氯甲酯,合成得到該目標化合物。LCMS:688[M+1]。
實施例12:
按照實施例5的方法,以N-Boc-甘胺酸代替Boc-L-纈胺酸,合成得到該目標化合物。LCMS:632[M+1]。
實施例13:
按照實施例5的方法,以Boc-L-丙胺酸代替Boc-L-纈胺酸,合成得到該目標化合物。LCMS:646[M+1]。
實施例14:
按照實施例5的方法,以1-氯乙基氯甲酸酯代替氯甲酸氯甲酯,合成得到該目標化合物(異構體大約1/1)。LCMS:688[M+1]。
實施例15:
按照實施例5的方法,以Boc-L-蛋胺酸代替Boc-L-纈胺酸,合成得到該目標化合物。LCMS:706[M+1]。
實施例16:
按照實施例5的方法,以Boc-L-脯胺酸代替Boc-L-纈胺酸,合成得到該目標化合物。LCMS:672[M+1]。
實施例17:
按照實施例5的方法,以(S)-2,6-二第三丁基羰基胺基己酸代替Boc-L-纈胺酸,合成得到該目標化合物。LCMS:703[M+1]。
實施例18:
按照實施例5的方法,以Boc-D-纈胺酸代替Boc-L-纈胺酸,合成得到該目標化合物。LCMS:674[M+1]。
測試例1:水溶性數據和化學穩定性
1.1 配製試劑
試劑:NaH2PO4.2H2O
1.2 配製方法
按100ml規格配製如下:
pH=3.0:磷酸鹽緩衝溶液:100ml 20mmol/L NaH2PO4,0.1M H3PO4調節pH至3.0。
pH=4.0:磷酸鹽緩衝溶液:100ml 20mmol/L NaH2PO4,0.1M H3PO4調節pH至4.0。
pH=7.0:超純水
pH=9.0:磷酸鹽緩衝溶液:100ml 20mmol/L Na2HPO4,0.1M NaOH溶液調節pH至9.0
1.3 測試方法
精確稱取適量待測化合物,少量多次加入溶液攪拌等待化合物溶解,測定溶液中化合物含量。數據見表1。
2.1 化合物穩定性實驗
稱取約1mg樣品至小瓶中,放置真空袋中抽真空,再放入裝有變色矽膠的容器內,密封,平行配製兩份。按取樣時間點配製足夠的份數,分別放置在4度和室溫下。數據見表1。
備註:較好 放置7天,純度降低<0.5%;中等 放置7天,純度降低0.5%~2.0%;較差 放置7天,純度降低>2.0%
測試例2:血漿代謝評價
試驗方案
1.1 試驗藥品
實施例5化合物和式I化合物。
1.2 試驗血漿
人新鮮血漿由志願者在之情同意下捐獻。
1.3化合物溶液配製
稱取一定量實施例5化合物,加入DMSO配製成30mM儲備液,取一定體積儲備液,用DMSO稀釋成濃度為1600μM的溶液I;再取一定體積的1600μM的溶液I用45%的甲醇稀釋成濃度為16μM的工作溶液II。用上述方法配製式I化合物30mM儲備液和1600μM的溶液II。
1.4樣本孵育
取16μM實施例5化合物的工作液5μL,分別加入到75μL的血漿中,使化合物的終濃度為1μM。樣本於37℃水浴中孵育0,15,30,60,90,120,180min。孵育結束後加入240μL含內標的乙腈,然後搖床800rpm搖10min,離心機3700rpm,4℃離心20min,上清採用LC-MS分析,進樣體積為2μL。
1.5標準曲線的配製
取之前稀釋好的1600μM溶液I,用乙腈稀釋製備標準曲線工作液,濃度為160,400,1600,4000,8000,16000,32000ng/mL,QC工作液濃度設為480,1920,25600ng/mL。分別取標準曲線及QC工作液5μL加入到75μL血漿中,得終濃度分別為10,25,100,250,500,1000,2000ng/mL的標準曲線樣本和終濃度為30,120,1600ng/mL的QC樣本;迅速加入240μL含內標的乙腈,然後搖
床800rpm搖10min,離心機3700rpm,4℃離心20min。取上清採用LC-MS分析,進樣體積為2μL。
用上述方法準備式I化合物標準曲線及QC樣本。
2.結果
本發明實施例5化合物在人新鮮血漿中轉化情況如下,數據見表2:
結論:在人新鮮血漿中30min左右全部轉化為式I化合物。
測試例3:血漿穩定性試驗
1.1 試驗藥品
實施例4、實施例6、實施例10和實施例11化合物
1.2 試驗血漿
人新鮮血漿由志願者在知情同意下捐獻
1.3 實驗步驟
1)表3中待測化合物分別用DMSO配成30mM的儲備液備用。
2)用DMSO溶液將濃度30mM的儲備液稀釋成濃度為1600μM的溶液I,再用乙腈(ACN),將濃度為1600μM的溶液I稀釋成濃度為16μM的工作溶液II。
3)實驗設置0、15、30、60、90、120、180min 7個時間點,每個時間點設兩個平行樣,反應體系是每個化合物分兩組,各加入75μL血漿,5μL上述配製好的濃度為16μM的工作溶液II,37℃孵育,計時開始到時的時候,用含內標的ACN的溶液300μL終止反應。離心機3700rpm離心10min,取上清分析。
4)標準曲線配置:取之前稀釋好的1600μM的溶液I用乙腈稀釋到1.5μM/mL的溶液III作為標準曲線備用;標準曲線濃度設為0.32、0.8、1.6、4.0、8、12、16、42uM;標準曲線各濃度稀釋好後,分別75μL血漿加入5μL各濃度點,使終濃度分別為為0.02、0.05、0.1、0.25、0.75、1.0、1.5uM,迅速加入300μL終止液,離心機3700rpm離心10min,取上清LC-MSMS分析。數據見表3。
註:a實施例中化合物在血漿濃度,b實施例化合物代謝後羅拉匹坦在血漿濃度。
結論:實施例4、實施例10和實施例11中化合物在血漿中較穩定,代謝時間較長,但是該三種化合物在血漿中只有少數的被代謝為羅拉匹坦。實施例6中化合物在血漿中能代謝為羅拉匹坦,但從上述數據看來,其在血漿整體代謝量較少。
測試例4:
參照測試例2中試驗方法分別測試實施例1、實施例2和實施例8化合物在小鼠(Mouse)、大鼠(Rat)和人的血漿中的代謝情況,數據見表4。
註:a實施例中化合物在血漿濃度,b實施例化合物代謝後羅拉匹坦在血漿濃度。
結論:實施例8化合物在小鼠、大鼠和人的血漿中均可轉化為羅拉匹坦,尤其在人的血漿中轉化率近46%,而實施例1和實施例2化合物在人的血漿中基本沒有轉化為羅拉匹坦,或者只有稍許轉化。
測試例5:大鼠體內藥物代謝動力學測試
以大鼠為受試動物,應用LC/MS/MS法測定了注射給予實施例1和實施例2化合物後不同時刻血漿中的藥物濃度。研究該化合物在大鼠體內的藥物代謝動力學行為,評價其藥動學特徵。
藥物配製
稱取一定量實施例1和實施例2化合物,用20mmol/L磷酸二氫鈉配製成pH=4.0溶液,以備用。
1.1 給藥
靜脈推注,推注時間約5min,給藥劑量2mg/kg,給藥濃度0.4mg/ml,給藥體積5ml/kg。
1.2 操作
給藥前及給藥結束後5min、0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h和48h,經眼眶靜脈採血,每個樣品採集約0.6mL,肝素鈉抗凝,採集後馬上放置冰上。血液樣本採集後放置於標記好的離心管中,離心分離血漿(離心條件:離心力2200g,離心10min,2-8℃)。
1.3藥物代謝動力學參數結果
註:a實施例中化合物在大鼠體內藥物代謝動力參數,b實施例化合物代謝為羅拉匹坦在大鼠體內藥物代謝動力參數。
結論:雖然實施例1化合物在體外血漿,尤其是人的血漿中基本沒有代謝為羅拉匹坦活性物,但是在大鼠體內中卻能表現出優異的羅拉匹坦藥物代謝動力學數據,說明實施例1化合物在體內已經被代謝為羅拉匹坦,且從AUC0-∞、AUC0-t和T1/2數據來看,化合物1給藥後體內代謝週期長、吸收和暴露水平與羅拉匹坦相當。
測試例6:化合物在食蟹猴中的藥物代謝動力學測試
以食蟹猴為受試動物,應用LC/MS/MS法測定了注射給予實施例5化合物後不同時刻血漿中的藥物濃度。研究該化合物在食蟹猴體內的藥物代謝動力學行為,評價其藥動學特徵。
藥物配製
稱取一定量實施例5化合物,用20mmol/L磷酸二氫鈉配製成pH=4.0溶液,以備用。
1.1 給藥
靜脈滴注,推注時間約30min,給藥劑量2mg/kg,給藥濃度0.4mg/ml,給藥體積5ml/kg。
1.2 操作
給藥前及給藥結束後5min、0.25h、0.5h、1h、2h、4h、6h、8h、10h、24h和48h,經股靜脈採血,每個樣品採集約0.6mL,肝素鈉抗凝,採集後馬上放置冰上。血液樣本採集後放置於標記好的離心管中,離心分離血漿(離心條件:離心力2200g,離心10min,2-8℃)。
應用LC/MS/MS測定血漿樣品中的實施例5化合物和羅拉匹坦的含量。
1.3 藥物代謝動力學參數結果
結論:實施例5化合物在食蟹猴體內藥物代謝動力學研究中,在食蟹猴絕大部分迅速轉化為活性代謝產物羅拉匹坦,其具有良好的藥物代謝動力學性質。
實施例19:
參照實施例1中步驟1-2製備獲得化合物3,再在在N2保護下,於500mL單口瓶中加入化合物3(6.65g,8.67mmol,1eq)溶於二氯甲烷(200mL)中,冰水冷卻下緩慢加入三氟乙酸(9.89g,86.7mmol,10.0eq),攪拌至反應完畢,濃縮,得到2.29g油狀物,經反相矽膠管柱(C18)純化(A溶液:20mmol NH4HCO3水溶液,B溶液:乙腈)純化,再用1M磷酸調節pH=1~2,用二氯甲烷萃取,飽和鹽水洗滌,無水硫酸鈉乾燥,過濾,濃縮得目標產物2.7g。
測試例7:溶解度
參數測試例1溶解度測試方法,測得實施例19化合物在不同pH值下溶解度,數據如下:
測試例8:溶血作用
紅血球(RBC)隨機地從兔頸靜脈或耳中央動脈採取(EDTA全血)10ml,放入玻璃珠的三角燒瓶中振搖10分鐘,除去纖維蛋白原,使成脫纖血液。加入氯化鈉注射液約10倍量,搖勻,1500轉/分鐘離心10分鐘,除去上清液,沉澱的紅細胞再用氯化鈉注射液按上述方法洗滌3次,至上清液不顯紅色。將所得紅細胞用氯化鈉注射液配成2%(v/v)的混懸液,以備用。
取測試樣品(實施例5化合物和實施例19化合物)分別溶於PBS(pH 7.4或pH 5),過濾,配製0.4mg/ml、0.8mg/ml、1.2mg/ml、1.6mg/ml和2mg/ml,以備用。
取一定量的測試樣品溶液加入上述血紅蛋白在上清液中測試。
若試管中的溶液呈澄明紅色,管底無細胞殘留或有少量紅細胞殘留,表明有溶血發生;如紅細胞全部下沉,上清液體無色澄明,表明無溶血發生。若溶液中有棕紅色或紅棕色絮狀沉澱,輕輕倒轉3-5次仍不分散,表明可能
有紅細胞凝聚發生;應進一步置顯微鏡下觀察,如可見紅細胞聚集為凝聚。本公開提供的化合物採用該方法測定溶血作用。
結論:實施例19化合物在濃度高至2mg/ml都沒有出現溶血作用,實施例5化合物在0.04mg/ml及以上濃度出現溶血作用。
測試例9:羅拉匹坦乳劑溶血性作用
參照CN102573475中方法製備羅拉匹坦乳劑(處方為:4.4%聚乙二醇-15羥基硬脂酸酯、1.1%中鏈甘油三酸酯和0.66%大豆油),用PBS配製0.18mg/ml、0.09mg/ml、0.045mg/ml、0.023mg/ml、0.011mg/ml、0.056mg/ml和0.028mg/ml,以備用。
參照測試例8中方法測定溶血作用。
結論:所有濃度的羅拉匹坦乳劑均存在溶血作用。
測試例10:食蟹猴中的藥物代謝動力學測試
以食蟹猴為受試動物,應用LC/MS/MS法測定了注射給予參照實施例19方法製備的化合物後不同時刻血漿中的藥物濃度。研究該化合物在食蟹猴體內的藥物代謝動力學行為,評價其藥動學特徵。
藥物配製
稱取一定量待測化合物,用20mmol/L磷酸二氫鈉配製成pH=4.0溶液,以備用。
1.1 給藥
靜脈滴注,推注時間約30min,給藥劑量3.54mg/kg,給藥濃度2mg/ml,給藥體積5ml/kg。
1.2 操作
給藥前及給藥結束後5min、0.25h、0.5h、1h、2h、4h、6h、8h、10h和24h,經股靜脈採血,每個樣品採集約0.6mL,肝素鈉抗凝,採集後馬上放置冰上。血液樣本採集後放置於標記好的離心管中,離心分離血漿(離心條件:離心力2200g,離心10min,2-8℃)。
應用LC/MS/MS測定血漿樣品中的實施例24化合物和羅拉匹坦的含量。
1.3 藥物代謝動力學參數結果
註:a實施例中化合物在食蟹猴體內藥物代謝動力參數,b實施例化合物代謝為羅拉匹坦在食蟹猴體內藥物代謝動力參數。
結論:該化合物在食蟹猴體內藥物代謝動力學研究中,在食蟹猴絕大部分迅速轉化為活性代謝產物羅拉匹坦,其具有良好的藥物代謝動力學性質。另外,相比實施例5化合物,該化合物在食蟹猴體內生物利用度更高。
Claims (14)
- 一種式II化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中,X選自氫、雜環基、芳基、雜芳基、-C(O)OAmR3、-C(O)NR4AmR3、-Am[C(R1)(R2)]C(O)OAnR3、-AmOC(O)[C(R1)(R2)]AnR3、-AmC(O)NR4AnR3、-AmNR4C(O)AnR3或-AmR5,該雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;Y選自氫、-C(O)OAmR3、-C(O)NR4AmR3、-Am[C(R1)(R2)]C(O)OAnR3、-AmOC(O)[C(R1)(R2)]AnR3、-AmC(O)NR4AnR3、-AmNR4C(O)AnR3或-AmR5;A獨立地選自-C(R1)(R2)(B)p-或-(B)qC(R1)(R2)-,R1、R2或R4各自獨立地選自氫、烷基、環烷基、雜環基、芳基或雜芳基,該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;R3選自氫、烷基、環烷基、雜環基、芳基、雜芳基、聚(伸乙氧基) ()、聚(伸氧基伸乙氧基)()、OPO(R6)2、PO(R6)2、 OSO2(R6)2、SO2(R6)2、OC(O)R6或C(O)OR6,該烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、 芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;R6各自獨立地選自氫、羥基、烷基、環烷基、雜環基、芳基、雜芳基、烷氧基、羥烷基或NR'(R"),該烷基、羥烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;R7各自獨立地選自烷基、羥基、環烷基、雜環基、芳基、雜芳基、羥烷基或NR'(R"),該烷基、羥烷基、環烷基、雜環基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;R'或R"獨立地選自氫、羥基、烷基、烷氧基、烯基、醯基;B各自獨立地選自O,N,SC(O);m,n,o各自獨立地選自1~10;p,q各自獨立地選自0或1;且,X和Y不同時為氫。
- 如請求項1所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中X選自氫、雜環基、芳基、雜芳基、-C(O)O[C(R1)(R2)(O)p]mR3、-C(O)NR4[C(R1)(R2)(O)p]mR3、-[C(R1)(R2)(O)p]mC(O)[C(R1)(R2)(O)p]nR3、-[C(R1)(R2)(O)p]m[C(R1)(R2)]C(O)[(O)qC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]mR5,該環烷基、雜環 基、芳基或雜芳基視需要被一個或多個選自烷基、環烷基、烷氧基、羥烷基、烯基、炔基、芳基、雜芳基、硝基、腈基、羥基、鹵素、SR'、NR'(R")、COOR'或CONR'(R")所取代;Y選自氫、-C(O)O[C(R1)(R2)(O)p]mR3、-C(O)NR4[C(R1)(R2)(O)p]mR3、-[C(R1)(R2)(O)p]mC(O)[C(R1)(R2)(O)p]nR3、-[C(R1)(R2)(O)p]mC(O)[(O)qC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]mR5,且X和Y不同時為氫。
- 如請求項1或2所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中Y選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3、-[C(R1)(R2)N]mC(O)[C(R1)(R2)]nR3、[C(R1)(R2)N]mC(O)[OC(R1)(R2)]nR3、[C(R1)(R2)N]mC(O)[NC(R1)(R2)]nR3、-[C(R1)(R2)(O)p]mC(O)NR4[C(R1)(R2)(O)p]nR3或-[C(R1)(R2)(O)p]nR5,X為氫、3至6員雜環基。
- 如請求項1至3中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中X選自-C(O)O[C(R1)(R2)]mR3、-C(O)NR4[C(R1)(R2)]mR3、-[C(R1)(R2)O]mC(O)[C(R1)(R2)]nR3、-[C(R1)(R2)]mC(O)[OC(R1)(R2)]nR3或-[C(R1)(R2)]mC(O)NR4[C(R1)(R2)]nR3或-[C(R1)(R2)]mR5,Y為氫。
- 如請求項1至5中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中R3選自OPO(R6)2,R6選自羥基、C1-6烷基、C3-7環烷基、C1-6烷氧基或3至7員雜環基。
- 如請求項1至4中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中m=1、2、3或4。
- 如請求項1至3中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中R1或R2各自獨立地選自氫、C1-6烷基或C3-7環烷基。
- 如請求項1所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物,其中m=1、2、3或4,n=1、2、3或4,o=1~8。
- 一種醫藥組成物,包括至少一種治療有效量的如請求項1至11中任一項所述的化合物或其可藥用的鹽或其立體異構體、旋轉異構體或互變異構體或其氘代物以及藥學上可接受的載體、稀釋劑或賦形劑。
- 一種請求項1至11中任一項所述的化合物或請求項12所述的醫藥組成物的用途,其用在製備治療患者中的生理失調,病症或疾病的藥物,其中生理失調、病症或疾病是呼吸道疾病、咳嗽、炎性疾病、皮膚障礙、眼科障礙、抑鬱症、焦慮、恐怖症、雙向障礙、酒精依賴、對神經起顯著作用的物質濫用、癲癇、傷害感受、精神病、精神分裂症、阿爾茨海默氏病、與AIDs有關的癡呆、Towne′s疾病、與緊張有關的障礙、強迫性/強制性障礙、暴食症(bulemia)、神經性厭食症、瘋狂進食、狂躁、經前期綜合症、胃腸機能紊亂、動脈粥樣硬化、纖維化障礙、肥胖、II型糖尿病、頭痛、神經性疼痛、動作後疼痛、慢性疼痛綜合症、膀胱障礙、泌尿生殖器障礙或嘔吐或噁心。
- 如請求項13的用途,其選自用於治療哮喘,嘔吐,噁心,憂鬱症,焦慮,咳嗽或偏頭痛。
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- 2020-06-28 MX MX2021015827A patent/MX2021015827A/es unknown
- 2020-06-28 US US17/623,205 patent/US20220380393A1/en active Pending
- 2020-06-28 JP JP2021577929A patent/JP2022539570A/ja active Pending
- 2020-06-28 WO PCT/CN2020/098460 patent/WO2020259675A1/zh active Application Filing
- 2020-06-28 CA CA3144247A patent/CA3144247A1/en active Pending
- 2020-06-28 BR BR112021026554A patent/BR112021026554A2/pt unknown
- 2020-06-28 EP EP20831251.2A patent/EP3991730A4/en active Pending
- 2020-06-29 TW TW109121881A patent/TW202115064A/zh unknown
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Publication number | Publication date |
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WO2020259675A1 (zh) | 2020-12-30 |
AU2020308397A1 (en) | 2022-02-17 |
JP2022539570A (ja) | 2022-09-12 |
EP3991730A1 (en) | 2022-05-04 |
EP3991730A4 (en) | 2023-08-09 |
CN113905735A (zh) | 2022-01-07 |
CN113905735B (zh) | 2024-03-15 |
BR112021026554A2 (pt) | 2022-05-24 |
KR20220054287A (ko) | 2022-05-02 |
US20220380393A1 (en) | 2022-12-01 |
MX2021015827A (es) | 2022-04-11 |
CA3144247A1 (en) | 2020-12-30 |
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