CN106496233B - 吡咯并嘧啶类化合物、其制备方法及其用途 - Google Patents
吡咯并嘧啶类化合物、其制备方法及其用途 Download PDFInfo
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- CN106496233B CN106496233B CN201610852190.9A CN201610852190A CN106496233B CN 106496233 B CN106496233 B CN 106496233B CN 201610852190 A CN201610852190 A CN 201610852190A CN 106496233 B CN106496233 B CN 106496233B
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Abstract
本发明公开了一种通式I所示的吡咯并嘧啶类化合物及其药学上可接受的盐或药学上可接受的溶剂合物。本发明还公开了上述通式I所示的吡咯并嘧啶类化合物及其药学上可接受的盐或药学上可接受的溶剂合物的制备方法及其应用。本发明制备的吡咯并嘧啶类化合物在血浆中均能迅速转化为原药baricitinib;而且本发明与原药相比,有更好的溶解性,更高的生物利用度,增强了药效。
Description
技术领域
本发明属于有机化合物合成与医药应用技术领域,具体涉及吡咯并嘧啶类化合物、其制备方法及其用途。
背景技术
前药(Prodrug)是指一类在体外无活性或活性较小,在体内经一个或多个步骤的酶和化学种类的生物转化,释放出活性物质二产生药理作用的化合物,又称为生物可逆性药物。它常常是将有生物活性的药物分子(原药)与某种无毒性载体(暂时转运基团)相连接而形成的。按照化学结构,前药可分为载体连接前药、生物前药、大分子前药和药物抗体结合物4类。
前药是一种很有用的药物设计方法,广泛应用于多种药物分子的设计中。许多药物以前药的形式给予,与潜在的活性组分相比,所述前药表现出改善的生物利用度,例如改善的物理化学性质,更具体地说是溶解度、主动或被动吸收性质或组织特异性分布。通常通过前残基改善潜在活性组分的性质,且为了达到最佳的作用曲线,根据活性组分的性质、适应症、作用靶点与给药途径等特点,设计合理的前药残基以及理想的释放机制是十分必要的。
类风湿关节炎(rheumatoid arthritis,RA)是由多种免疫细胞(B淋巴细胞、T淋巴细胞及巨噬细胞等)及相关细胞因子参与介导的复杂疾病,发病机制尚未完全明确。研究表明,IL-2,IL-6,IL-17,IL-21,IFNs及GM-CSF等在RA滑膜细胞和滑膜组织中的水平明显升高,这些因子可通过不同途径激活JAK/STAT信号通路。例如:IL-6,IL-15和IFNs可与JAK1结合;GM-CSF,EGF,IFN-γ和IL-6可与JAK2结合;IL-15可与JAK3结合;IFN-α和IFN-β可与TYK2结合。不同通路在不同细胞或RA发病的不同阶段表现不同功能。IL-6是STAT3和STAT1的主要激活因子。Wang等发现RA滑液的单核细胞中,STAT3具有显著的DNA结合活性,并且RA滑液中的可溶性因子能有效激活STAT3。随后的动物模型中同样表明STAT3失调能够改变关节炎的炎症过程。Kasperkovitz等通过免疫组织化学方法对RA患者的滑液进行研究,结果表明STAT1的表达明显增加并主要分布在T细胞和B细胞中。STAT2与STAT1及IRF9形成异二聚体转录复合物,推测在RA发病过程中,STAT2与STAT1通过共同作用发挥功能。就STAT4而言,Th1细胞主要通过其传递IL-12信号,进而加速Th1和Th2之间的免疫失衡。IL-2对RA患者的T细胞中STAT5过度激活,引起了IL-2信号传导的异常放大效应,其在RA发病过程中同样发挥重要作用。在蛋白多糖诱导的关节炎模型表明,IL-4可通过STAT6调控炎症。JAK/STAT信号通路与RA发病机制具有重要关系,靶向该通路的RA治疗药物已获一定成效,特别是选择性JAK抑制剂。
巴瑞替尼(Baricitinib)其化学名称为1-(乙基磺酰基)-3-[4-(7H-吡咯并[2,3-D]嘧啶-4-基)-1H-吡唑-1-基]-3-氮杂环丁烷乙腈。由礼来公司与Incyte公司联合开发,为可口服的小分子JAK抑制剂,主要用于治疗RA、银屑病和糖尿病性肾病,同时也有治疗癌症、克罗恩病、溃疡性结肠炎、关节固定性脊柱炎、银屑病性关节炎和反应性关节炎(莱特尔综合征)等疾病的潜在功效。一种可选择性抑制JAK1和JAK2的新型和高效小分子药物,能抑制IL-6和IL-23等多种炎性细胞因子的细胞内信号传导。Baricitinib能优先抑制JAK1(IC50=5.9nmol·L-1)和JAK2(IC50=5.7nmol·L-1),对JAK1和JAK2的选择性较对Tyk2高10倍及对JAK3高70倍,且其能在全血中抑制IL-6刺激的STAT3磷酸化(IC50=128nmol·L-1)。
Baricitinib在专利WO2009114512中公开,但目前现有技术中均没有对吡咯环上的氨基进行修饰的报道。本发明人发现,通过对活性位点吡咯环上的氨基进行修饰获得的baricitinib前药,能够提高baricitinib的生物利用度,从而完成了本发明。
发明内容
发明目的:本发明的第一个目的是提供了一种通式I所示的吡咯并嘧啶类化合物及其药学上可接受的盐或药学上可接受的溶剂合物。本发明的第二个目的是提供一种通式I所示的吡咯并嘧啶类化合物及其药学上可接受的盐或药学上可接受的溶剂合物在制备治疗类风湿性关节炎药物方面的应用。
技术方案:为了解决上述技术问题,本发明提供了一种通式I所示的吡咯并嘧啶类化合物及其药学上可接受的盐或药学上可接受的溶剂合物:
其中,R选自-C(=0)R1、-C(=O)OR2、-CnOC(=O)R3、-C(=O)OC(R4)OC(=O)R5、-C1-C6烷基、-P(=O)(R6)2、-OP(=O)(R7)2;
R1为烷基、卤代烷基、或用羧基,氰基中的一种取代的烷基;
R2为氢、烷基、卤代烷基、或用羧基、氰基、酯基、氨基、烷氧基中的一种取代的烷基;
n取自1-5,R3为烷基、卤代烷基、或用羧基、氰基、酯基、氨基、烷氧基的一种取代的烷基;
R4为C1-C8烷基或酯基中的一种;
R5为氢、烷基、卤代烷基、或用羧基、氰基、酯基、氨基、烷氧基、羰基中的一种取代的烷基;
R6为烷基、环烷基、卤代烷基、钠盐或用羧基、氰基、酯基、烷氧基中的一种取代的烷基;
R7为烷基、环烷基、卤代烷基、钠盐或用羧基、氰基、酯基、烷氧基中的一种取代的烷基。
其中,R选自-C(=0)R1,-C(=O)OR2,-CnOC(=O)R3,-C(=O)OC(R4)OC(=O)R5,C1-C4烷基;
R1为烷基、卤代烷基、或用羧基、氰基中的一种取代的烷基;
R2为氢、烷基、卤代烷基、或用羧基、氰基、酯基、氨基、甲氧基中的一种取代的烷基;
n取自1-3,R3为烷基、卤代烷基,或用氰基、酯基、氨基、甲氧基中的转移取代的烷基;
R4为C1-C4烷基,酯基;
R5为氢、烷基、卤代烷基、或用羧基、氰基、酯基、氨基、甲氧基、羰基中的一种取代的烷基;
R6为烷基、环烷基、卤代烷基、钠盐或用羧基、氰基、酯基、烷氧基中的一种取代的烷基;
R7为烷基、环烷基、卤代烷基、钠盐或用羧基、氰基、酯基、烷氧基中的一种取代的烷基;
其中,R选自-C(=O)R1,-C(=O)OR2,-CnOC(=O)R3,-C(=O)OC(R4)OC(=O)R5,C1-C3烷基;
R1为甲基、乙基、丙基、异丙基、叔丁基、溴乙基、溴丙基、氯乙基、氯丙基、甲酸基、乙酸基、丙酸基或氰基甲烷基;
R2为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、羟基、氨基甲烷基、氨基乙烷基、甲氧基甲烷基、甲氧基乙烷基、甲氧基丙烷基、甲酸基、乙酸基、丙酸基或氰基甲烷基;
n取自1和2,R3为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、氨基甲烷基、氨基乙烷基、甲氧基甲烷基、甲氧基乙烷基或甲氧基丙烷基;
R4为甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基或乙酸甲酯基;
R5为氢、甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、戊基、甲酮基、乙酮基、丙酮基或丁酮基;
R6为甲基、乙基、丙基、异丙基、叔丁基、戊基、苯基或钠盐;
R7为甲基,乙基,丙基,异丙基,叔丁基,戊基,苯基或钠盐。
其中,所述通式Ⅰ的化合物为由以下通式之一表示的吡咯并嘧啶类化合物:
其中,所述通式Ⅰ的化合物为选自下列化合物中的一种化合物:
化合物与不同卤素取代的烷基发生取代反应为本领域的常规反应条件,通常在碱性条件下进行,碱可以为碳酸铯、碳酸纳、碳酸氢纳、碳酸钾、吡啶、哌啶或三乙胺,优选为碳酸钾或三乙胺。通常二者直接在反应液中反应,反应液一般选择二氯甲烷和甲苯。
上述的一种通式I所示的吡咯并嘧啶类化合物及其药学上可接受的盐或药学上可接受的溶剂合物在制备治疗类风湿性关节炎药物方面的应用。
有益效果:本发明具有以下优点:本发明制备的吡咯并嘧啶类化合物在血浆中均能迅速转化为原药baricitinib;而且本发明与原药相比,有更好的溶解性,更高的生物利用度,增强了药效。
具体实施方式
下面结合具体实施例对本发明作进一步阐述。这些实施例仅是出于解释说明的目的,而不限制本发明的范围和实质。
lH-NMR用WNMR-I-300/500MHz型仪测定,MS用Agilent 1100LC/MS仪测定,二氯甲烷、碳酸钾、乙腈等均购于安耐吉化学试剂公司。氘代氯仿,氘代DMSO均购于百灵威化学试剂公司。所有溶剂在使用前均经过重新蒸馏,所使用的无水溶剂均是按标准方法干燥处理获得;产品的纯化除说明外均使用硅胶(200-300目)柱色谱法;其中硅胶(200-300目)是由青岛海洋化工生产,薄层硅胶板由烟台江友硅胶开发有限公司生产。
本发明实施例中的化合物1(即原药baricitinib)即为申请号为201610080433.1的合成方法制备得到的化合物6。
实施例1 化合物A-1的制备
将化合物1(150mg,0.40mmol,1equiv)加入二氯甲烷和乙腈的混合溶剂使之溶解,再加入三乙胺(140mL,2.5equiv),将反应体系在冰水浴中反应15分钟,缓慢加入乙酰氯(0.044mL,0.60mmol,1.5equiv),缓慢升至室温,搅拌过夜。浓缩滤液,硅胶拌样,直接柱层析(二氯甲烷:甲醇=50:1)得化合物A-1(106mg),产率64%。lH-NMR(300MHz,DMSO-d6)δ:9.01(s,1H),8.96(d,J=5.3,1H),8.52(s,1H),8.13(d,J=4.1,1H),7.43(m,J=5.1,1H),4.61(d,J=9.2,2H),4.25(d,J=9.2,2H),3.69(s,1H),3.25(m,J=8.6,2H),3.00(s,3H),1.24(m,J=4.9,3H)
实施例2 化合物A-2的制备
将化合物1(150mg,0.40mmol,1equiv),加入二氯甲烷和乙腈的混合溶剂使之溶解,再加入三乙胺(140mL,2.5equiv),将反应体系在冰水浴中反应15分钟,缓慢加入异丁酰氯(0.084mL,0.60mmol,1.5equiv),缓慢升至室温,搅拌过夜。浓缩滤液,硅胶拌样,直接柱层析(二氯甲烷:甲醇=50:1)得化合物A-2(128mg),产率72%。lH-NMR(300MHz,DMSO-d6)δ:8.93(s,1H),8.44(s,1H),8.31(s,1H),8.01(d,J=4.1,1H),6.87(d,J=4.1,1H),4.62(m,J=6.1,2H),4.25(d,J=9.4,2H),3.41(s,2H),3.09(m,J=7.4,2H),1.41(d,J=7.4,3H),1.38(t,J=4.9,6H)
实施例3 化合物A-3的制备
除了用正丁酰氯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物A-3(125mg),产率70%。lH-NMR(300MHz,CDCL3)δ:8.93(s,1H),8.44(s,1H),8.31(s,1H),8.06(d,J=4.1,1H),6.86(d,J=4.2,1H),4.64(d,J=9.5,2H),4.25(d,J=9.5,2H),3.53(t,J=7.3,2H),3.41(s,2H),3.09(m,J=7.4,2H),1.88(m,J=7.4,2H),1.42(t,J=7.4,3H),1.11(t,J=7.4,3H)
实施例4 化合物A-4的制备
除了用异戊酰氯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物A-4(135mg),产率73%。lH-NMR(300MHz,CDCL3)δ:8.93(s,1H),8.44(s,1H),8.30(s,1H),8.06(d,J=4.1,1H),6.86(d,J=4.1,1H),4.64(d,J=9.5,2H),4.25(d,J=9.6,2H),3.44(t,J=9.2,2H),3.08(t,J=7.4,,2H),2.37(m,J=6.7,1H),1.42(t,J=7.4,3H),1.11(t,J=6.7,6H)
实施例5 化合物A-5的制备
除了用3,3-二甲基丁酰氯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物A-5(132mg),产率69%。lH-NMR(300MHz,CDCL3)δ:9.04(s,1H),9.00(s,1H),8.56(s,1H),8.20(d,J=4.1,1H),7.44(d,J=4.2,1H),4.64(d,J=9.2,2H),4.28(d,J=9.1,2H),3.73(s,2H),3.62(s,2H),3.27(m,J=7.3,2H),1.28(t,J=7.3,3H),1.13(s,8H)
实施例6 化合物A-6的制备
除了用戊酰氯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物A-6(138mg),产率75%。lH-NMR(300MHz,DMSO-d6)δ:8.98(d,J=15.1,1H),8.51(s,1H),8.13(d,J=4.1,1H),7.41(d,J=4.1,1H),4.61(d,J=9.1,2H),4.25(d,J=9.2,2H),3.70(s,2H),3.53(t,J=7.4,2H),3.24(m,J=7.3,2H),1.73(m,J=7.4,2H),1.25(t,J=7.3,3H),0.95(t,J=7.3,3H)
实施例7 化合物A-7的制备
除了用己酰氯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物A-7(141mg),74%。lH-NMR(300MHz,CDCL3)δ:8.91(s,1H),8.44(s,1H),8.30(s,1H),8.05(d,J=4.2,1H),6.85(d,J=4.2,1H),4.64(d,J=9.5,2H),4.25(d,J=9.6,2H),3.55(t,J=7.4,2H),3.41(s,1H),3.09(m,J=7.4,2H),1.86(m,J=7.4,2H),1.48(m,J=6.0,7H),0.95(t,J=7.1,3H)
实施例8 化合物B-1的制备
除了用氯甲酸甲酯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物B-1(155mg),90%。H-NMR(500MHz,DMSO-d6)δ:8.99(s,1H),8.93(s,1H),8.50(s,1H),7.99(d,J=3.9,1H),7.37(d,J=3.9,1H),4.61(d,J=9.1,2H),4.25(d,J=9.0,2H),4.04(s,3H),3.69(s,3H),3.23(m,J=7.3,2H),1.25(t,J=7.3,3H)
实施例9 化合物B-2的制备
除了用氯甲酸丙酯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物B-2(148mg),80%。lH-NMR(500MHz,DMSO-d6)δ:8.99(s,1H),8.94(s,1H),8.51(s,1H),7.99(d,J=4.1,1H),7.37(d,J=4.1,1H),4.61(d,J=9.1,2H),4.42(t,J=6.4,2H),4.25(d,J=9.1,2H),3.70(s,2H),1.81(m,J=7.0,2H),1.25(t,J=7.2,3H),1.05(t,J=7.3,3H)
实施例10 化合物B-3的制备
除了用氯甲酸丁酯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物B-3(152mg),83%。lH-NMR(500MHz,DMSO-d6)δ:8.99(s,1H),8.94(s,1H),8.51(s,1H),7.99(d,J=4.1,1H),7.37(d,J=4.1,1H),4.61(d,J=9.1,2H),4.42(t,J=6.4,2H),4.25(d,J=9.1,2H),3.70(s,2H),1.81(m,J=7.0,2H),1.25(t,J=7.2,3H),1.05(t,J=7.3,3H)
实施例11 化合物B-4的制备
除了用氯甲酸异丙酯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物B-4(162mg),85%。lH-NMR(500MHz,DMSO-d6)δ:8.99(s,1H),8.94(s,1H),8.50(s,1H),7.97(d,J=4.0,1H),7.35(d,J=4.0,1H),5.22(m,J=6.2,1H),4.60(t,J=9.2,2H),4.25(d,J=9.1,2H),3.69(s,2H),3.23(m,J=7.3,2H),1.43(d,J=6.2,6H),1.25(t,J=7.3,3H)
实施例12 化合物B-5的制备
除了用氯甲酸戊酯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物B-5(162mg),83%。lH-NMR(300MHz,CDCL3)δ:9.02(s,1H),8.45(s,1H),8.30(s,1H),7.80(d,J=4.0,1H),6.83(d,J=4.1,1H),4.63(d,J=9.2,2H),4.29(m,J=8.1,2H),3.41(s,2H),3.08(m,J=7.4,2H),2.20(m,J=6.7,2H),1.41(m,J=10.6,6H),1.09(d,J=6.7,6H)
实施例13 化合物B-6的制备
除了用氯甲酸异丁酯代替乙酰氯以外,采用与制备实施例1的合成化合物A-1相同的方法合成化合物B-6(129mg),产率68%。lH-NMR(300MHz,CDCL3)δ:9.02(s,1H),8.45(s,1H),8.30(s,1H),7.80(d,J=4.0,1H),6.83(d,J=4.1,1H),4.63(d,J=9.2,2H),4.29(m,J=8.1,2H),3.41(s,2H),3.08(m,J=7.4,2H),2.20(m,J=6.7,2H),1.41(m,J=10.6,6H),1.09(d,J=6.7,6H)
实施例14 化合物C-1的制备
将化合物1(150mg,0.40mmol,1equiv),加入二氯甲烷和乙腈的混合溶剂使之溶解,再加入三乙胺(140mL,2.5equiv),将反应体系在冰水浴中反应15分钟,缓慢加入NaH(0.1equiv),低温搅拌半小时,加入丁酸氯甲酯(0.077mL,0.60mmol,1.5equiv),缓慢升至室温,搅拌过夜。浓缩滤液,硅胶拌样,直接柱层析(二氯甲烷:甲醇=50:1)得化合物C-1(129mg),产率68%。
lH-NMR(300MHz,CDCL3)
δ:8.89(s,1H),8.45(s,1H),8.33(s,1H),7.51(d,J=3.8,1H),6.76(d,J=3.8,1H),6.26(s,2H),4.63(d,J=9.3,2H),4.25(d,J=9.5,2H),3.44(s,2H),3.09(m,J=7.4,2H),2.32(t,J=7.4,2H),1.63(m,J=7.4,2H),1.41(t,J=7.4,3H),0.90(t,J=7.4,3H)
实施例15 化合物D-1的制备
将化合物1(150mg,0.40mmol,1equiv),加入二氯甲烷和乙腈的混合溶剂使之溶解,再加入三乙胺(140mL,2.5equiv),将反应体系在冰水浴中反应15分钟,缓慢加入氯乙基氯甲酸酯(0.053mL,0.49mmol,1.1equiv),缓慢升至室温,搅拌过夜。旋干溶剂,用乙酸重新溶解,加入乙酸钾(60mg,0.60mmol,,1.5equiv),室温反应过夜。浓缩滤液,硅胶拌样,直接柱层析(二氯甲烷:甲醇=50:1)得化合物D-1(148mg),产率73%。[M+Na]:524
实施例16 化合物E-1的制备
将化合物1(150mg,0.40mmol,1equiv),加入二氯甲烷和乙腈的混合溶剂使之溶解,再加入三乙胺(140mL,2.5equiv),将反应体系在冰水浴中反应15分钟,缓慢加入NaH(0.1equiv),低温搅拌半小时,加入氯磷酸二甲酯(0.057mL,0.60mmol,1.5equiv),缓慢升至室温,搅拌过夜。浓缩滤液,硅胶拌样,直接柱层析(二氯甲烷:甲醇=50:1)得化合物E-1(132mg),产率68%。MS:524(M+Na)
实施例17 化合物E-2的制备
将化合物1(150mg,0.40mmol,1equiv),三偏磷酸钠(62mg,0.20mmol,0.5equiv)和碳酸钠(150mg,1.42mmol,3.5equiv)溶于水,45℃反应过夜。反应结束,加入氢氧化钠(16mg,0.40mmol,1equiv)除去未反应的原料,加入氢氧化钙(30mg,0.40mmol,1equiv)40℃搅拌过夜,离心除去沉淀,浓缩滤液。用0.2mol/L氢氧化钠水溶液与乙醇(体积比1:2)重结晶得化合物E-2(101mg),产率51%。MS:518(M+Na)
生物学实施例
采用下列实验甄别具有最佳程度的所需活性的那些化合物
1.目标化合物体外血浆实验
1.1 高效液相色谱测定条件
液相色谱仪:Waters 2489UV/Visible Detector,Waters 1525BinaryHPLC Pump
色谱柱:Kromasil 100-5-C18,Dim:4.6x150mm,Part/Serial:M05CLA15/E121514
流动相:水:乙腈(75:25)
流速:1mL/min 柱温30℃;
检测波长305nm 进样量10μL。
在流动相无干扰下,baricitinib保留时间约为7min。
1.2 样品制备
将目标化合物溶于DMSO溶剂中,浓度均按质量浓度折算为baricitinib 120mg/mL,取20μL该溶液加入1.18mL新鲜大鼠空白血浆中,37℃孵化得到样品。
1.3 样品预处理
在规定时间点每次精密吸取样品120μL,加入120μL乙腈,高速涡旋混合2min,10000r/min离心15min,吸取上清液,过13mm·0.45μm滤膜,即可测定。
1.4 原药baricitinib血浆稳定性试验
取20μLbaricitinib的DMSO溶液(120mg/mL),加入1.18mL新鲜大鼠空白血浆中,37℃孵化,分别于不同时间点取样120μL,按1.2方法样品预处理。用HPLC法测定,记录峰面积,计算药物浓度。结果如表1所示
表1
由表1中的数据表明,baricitinib在血浆中可以稳定存在。
1.4 目标化合物的体外血浆转化实验
按照1.3方法,我们对目标化合物进行了体外的血浆转化实验,测试化合物在不同时间点转化为baricitinib的转化率。结果如表2所示
表2
以上数据表明,除A5,A6,E1,E2外大部分目标化合物在血浆中均能迅速转化为原药baricitinib。
大鼠体内药物动力学实验:
取健康的SD雄性大鼠15只,体重200~220g,每天定时饲以大鼠标准配方颗粒饲料,实验前禁食12h,给药后4h恢复供食,实验前后和实验过程中均自由饮水。随机分成5组,第一组单剂量灌喂给药baricitinib,第二组单剂量灌喂给药实施例1制备的化合物;第三组单剂量灌喂给药实施例2制备的化合物;第四组单剂量灌喂给药实施例3制备的化合物;第五组单剂量灌喂给药实施例14制备的化合物。4组大鼠的给药剂量均按摩尔浓度折算为含baricitinib10mg/kg,分别于给药前(0h)和给药后0.5,1,2,4,6,8,10,24,48h由眼底静脉丛取血约0.2~0.3ml,肝素抗凝,离心分离血浆,准确量取0.1ml至EP管中,加入1.2ml乙酸乙酯,用涡旋混合器高速混匀5min,离心5min(8000r.min-1),收集上清液,与30℃氮吹仪上用氮气吹干溶剂,残余物用流动相100μl溶解,用涡旋混合器高速混匀10min,离心5min(14000r.min-1),转移80μl上清液至进样瓶,HPLC进样10μL检测,记录色谱图。结果如表4所示
表4
体内外的药理学实验表明目标化合物具有良好的生物利用度,优于baricitinib,作为baricitinib的前药具有进一步临床研究的潜力。
以上所述仅是本发明的优选实施方式,应当指出:对于本技术领域的技术人员来说,在不脱离本发明原理的前提下,还可以做出若干改进和润饰,这些改进和润饰也应视为本发明的保护范围。
Claims (2)
1.一种通式I所示的吡咯并嘧啶类化合物:
其中,所述通式Ⅰ的化合物为选自下列化合物中的一种化合物:
2.权利要求1所述的一种通式I所示的吡咯并嘧啶类化合物在制备治疗类风湿性关节炎药物方面的应用。
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