CN103420983B - 达比加群酯衍生物及其制备方法和用途 - Google Patents
达比加群酯衍生物及其制备方法和用途 Download PDFInfo
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- CN103420983B CN103420983B CN201210164265.6A CN201210164265A CN103420983B CN 103420983 B CN103420983 B CN 103420983B CN 201210164265 A CN201210164265 A CN 201210164265A CN 103420983 B CN103420983 B CN 103420983B
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- Prior art keywords
- pharmaceutically acceptable
- derivative
- dabigatran etexilate
- acceptable salt
- dabigatran
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- 150000003839 salts Chemical class 0.000 claims abstract description 24
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 67
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 34
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical class C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 claims description 24
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 claims description 8
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 8
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims 1
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Landscapes
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Abstract
本发明涉及苯并咪唑衍生物通式Ⅰ的制备方法,其中R1、R2和R3分别具有在说明书中限定的含义。本发明涉及通式Ⅰ所示的达比加群的酯衍生物及其非毒性药学上可接受的盐,以及含有这些化合物作为活性成分的药物组合物,以及所述化合物及药物组合物作为凝血酶抑制剂的用途。
Description
技术领域
本发明涉及药物合成领域,具体涉及达比加群的酯衍生物及其制备方法,含有这些衍生物的药物组合物以及所述化合物及药物组合物作为凝血酶抑制剂的用途。
背景技术
达比加群酯(Dabigatran)是德国勃林格殷格翰公司开发的具有多种特点的新型抗凝血药物。2008年4月,首先在德国和英国上市,商品名为Pradaxa,用于防治急性静脉血栓(VTE)。这是继华法林之后50年来首个上市的抗凝血口服新药,是抗凝血治疗领域和潜在致死性血栓预防领域的又一个里程碑。美国食品和药品监督管理局2010年10月19日批准Pradaxa胶囊(达比加群酯)为在有心律异常(心房颤动)患者中预防中风和凝血。
凝血酶是细胞外胰岛素样丝氨酸蛋白酶,在凝血过程中具有重要作用,一方面,其能使纤维蛋白原裂解成为纤维蛋白, 后者参与构成不溶性血栓基质;另一方面,其能诱导血小板活化和聚集,进而引发一系列次级凝血级联反应。达比加群酯为前药,在体内转化为有活性的达比加群,达比加群通过直接抑制凝血酶而发挥抗凝血效应。达比加群酯是一种新型的合成的直接凝血酶抑制剂,是用于口服的前体药物,属非肽类的凝血酶抑制剂。口服经胃肠吸收后,在体内转化为具有直接抗凝血活性的达比加群。药物结合于凝血酶的纤维蛋白特异结合位点,阻止纤维蛋白原裂解为纤维蛋白,从而阻断了凝血瀑布网络的最后步骤及血栓形成。
但是达比加群酯的口服生物利用度较低(<6.5%),因此有待进一步提高。
发明内容
本发明涉及由结构式Ⅰ所示的达比加群的酯衍生物及其非毒性药学上可接受的盐,以及含有这些化合物作为活性成分的药物组合物,以及所述化合物及药物组合物作为凝血酶抑制剂的用途。
因此本发明的第一个方面提供了式Ⅰ所代表的达比加群的酯衍生物及其可药用盐:
其中,
R1代表H或C1-C5的烷基;R2代表H或C1-C3的烷基;R3代表C1-C6的烷基或取代的烷基。
优选地,本发明提供式Ⅰ所代表的达比加群的酯衍生物或其可药用盐,其中R1代表H或C1-C2的烷基,R2代表H或CH3,R3代表C1-C6的烷基。
更优选地,本发明提供式Ⅰ所代表的达比加群的酯衍生物或其可药用盐选自如下结构式所代表的化合物:
具体目标化合物的各取代基分别定义如下:
I1:R1为-CH3,R2为-H,R3为-CH3;
I2:R1为-CH3,R2为-H, R3为-CH2CH3;
I3:R1为-CH3,R2为-H, R3为-CH2CH2CH3;
I4:R1为-CH3,R2为-H, R3为-CH2CH2CH2CH3;
I5:R1为-CH3,R2为-H, R3为-CH2CH2CH2CH2CH3;
I6:R1为-CH3,R2为-H, R3为-CH2CH2CH2CH2CH2CH3;
I7:R1为- CH2CH3,R2为-H,R3为R3-CH3;
I8:R1为- CH2CH3,R2为-H,R3为R3-CH2CH3;
I9:R1为- CH2CH3,R2为-H,R3为R3-CH2CH2CH3;
I10:R1为- CH2CH3,R2为-H,R3为R3-CH2CH2CH2CH3;
I11:R1为- CH2CH3,R2为-H,R3为R3-CH2CH2CH2CH2CH3;
I12:R1为- CH2CH3,R2为-H,R3为R3-CH2CH2CH2CH2CH2CH3;
I13:R1为-CH3,R2为- CH3,R3为-CH3;
I14:R1为-CH3,R2为- CH3, R3为-CH2CH3;
I15:R1为-CH3,R2为- CH3, R3为-CH2CH2CH3;
I16:R1为-CH3,R2为- CH3, R3为-CH2CH2CH2CH3;
I17:R1为-CH3,R2为- CH3, R3为-CH2CH2CH2CH2CH3;
I18:R1为-CH3,R2为- CH3, R3为-CH2CH2CH2CH2CH2CH3;
I19:R1为- CH2CH3,R2为- CH3,R3为R3-CH3;
I20:R1为- CH2CH3,R2为- CH3,R3为R3-CH2CH3;
I21:R1为- CH2CH3,R2为- CH3,R3为R3-CH2CH2CH3;
I22:R1为- CH2CH3,R2为- CH3,R3为R3-CH2CH2CH2CH3;
I23:R1为- CH2CH3,R2为- CH3,R3为R3-CH2CH2CH2CH2CH3;
I24:R1为- CH2CH3,R2为- CH3,R3为R3-CH2CH2CH2CH2CH2CH3;
本发明的第二个方面涉及药物组合物,其包括至少一种式Ⅰ所代表的达比加群的酯衍生物或其可药用盐,以及一种或多种药学上可接受的载体或赋形剂。
本发明的第二个方面涉及式Ⅰ所示的达比加群的酯衍生物及其非毒性药学上可接受的盐,以及包含式Ⅰ所示的达比加群的酯衍生物及其非毒性药学上可接受的盐作为活性成分的药物组合物作为抗凝血的用途。
式Ⅰ所代表的化合物可以与无机酸形成药用盐,例如硫酸盐、磷酸盐、盐酸盐、氢溴酸盐;也可以与有机酸形成药用盐,例如醋酸盐、草酸盐、柠檬酸盐、琥珀酸盐、葡萄糖酸盐、酒石酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、苯甲酸盐、乳酸盐、马来酸盐等。选择和制备适当的盐是本领域技术人员公知技术。
本发明化合物或其可药用盐可以单独或以药物组合物的形式给药。本发明药物组合物可根据给药途径配成各种适宜剂型。使用一种或多种生理学上可接受的载体,包含赋形剂和助剂,它们有利于将活性化合物加工成可以在药学上使用的制剂。适当的制剂形式取决于所选择的给药途径,可以按照本领域熟知的常识进行制备。
给药途径可以是口服、非肠道或局部给药,优选口服和注射形式给药。可以口服的药物制剂包括胶囊剂和片剂等。本发明化合物也可以配制用于肠胃外给药或者透皮给药或者经粘膜给药,或者采用栓剂或者埋植剂的方式给药。本领域技术人员可以理解,本发明化合物可以采用合适的药物释放***(DDS)以得到更有利的效果。
具体实施方式
下面的实施例可以使本专业技术人员更全面的理解本发明,但不以任何方式限制本发明。
首先参考文献(Hauel NH,Nar H,Priepke H,et al.Structure-Based Design of Novel Potent NopePtide Thrombin Inhibitors. J.Med. Chem.2002;45:1757-1766)方法合成达比加群酯及式Ⅰ所示的达比加群的酯衍生物:
R1 = H, -CH3, -CH2CH3; R2=H,CH3,R3 = C1-C6的烷基或取代的烷基。
以化合物1为起始原料,经酰胺化、缩合得到中间体2;将中间体2与氢氧化钠反应再与氯代烷烃反应得到中间体3,中间体3与乙酰氧肟酸反应得到中间体4,中间体4与不同取代的活化酯反应得到达比加群的酯衍生物(Ⅰ1-32)
实施例 1 3-(2-(((3-((甲氧羰基)氨基)苯并异恶唑-6-基)氧)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并咪唑-5-甲酰胺)丙酸甲酯(Ⅰ1)的制备
1)3-(2-((4-氰基-3-氟苯氧基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并咪唑-5-甲酰胺基)丙酸乙酯(2A)的合成
2-(4-氰基-3-氟苯氧)乙酸 ( 1.77 g, 0.0l mo1)、EDC1( 1.9g,0.01 mo1)、1-羟基苯并***( 1.35 g,0.01 mo1)溶于THF( 35 mL)和DMF( 5 mL)混合液中。冰水浴中搅拌35 min,升至室温,缓慢滴加1( 3.1 g,0.009 mo1)的THF(15 mL)溶液。加毕搅拌6 h。蒸去溶剂,加入二氯甲烷 (30 mL),用饱和盐水 (5 mLx 3)洗涤,经无水硫酸钠干燥后过滤,滤液浓缩至干,剩余物中加冰乙酸 (45 mL) ,加热回流 2 h,减压浓缩至干,剩余物中加入浓氨水( 15 mL),室温搅拌30 min 蒸去溶剂,剩余物中加入二氯甲烷 (25 mL),经饱和盐水(5 mL x 3 )洗涤,无水硫酸钠干燥后过滤,滤液浓缩至干,剩余物经柱色谱纯化,得无定形黄色固体3.1 g。
2)3-(2-((4-氰基-3-氟苯氧基)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并咪唑-5-甲酰胺基)丙酸甲酯(3Aa)的合成
将5.0 g中间体2A溶于200 mL乙醇中,加入1N的氢氧化钠溶液10 mL,室温下搅拌反应至水解完全,蒸干,以20 mL DMF溶解,加入1.86 g碘甲烷,室温搅拌24小时,浓缩,柱分离得到4.0 g目标中间体。
3)3-(2-(((3-氨基苯并异恶唑-6-基)氧)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并咪唑-5-甲酰胺基)丙酸甲酯(4 Aa)的合成
将4.0 g中间体3Aa溶于80 mL DMF中,取碳酸钾(4.8 g, 0.036mol)溶于24 mL水中加至上述溶液中,常温下搅拌。称取乙酰氧肟酸(1.632 g, 0.024 mol)加至上述反应液中,室温反应3天,滤出固体后蒸干溶剂,过柱得纯品2.5 g。
4)3-(2-(((3-((甲氧羰基)氨基)苯并异恶唑-6-基)氧)甲基)-1-甲基-N-(吡啶-2-基)-1H-苯并咪唑-5-甲酰胺)丙酸甲酯(Ⅰ1)的合成
将上步产物(4 Aa)溶解在四氢呋喃(50 mL)中,加入氯甲酸甲酯(0.519 g)和DIEA(3 mL),室温搅拌过夜,蒸干,柱层析纯化得到白色的目标产物1.8 g。1H NMR(DMAO-d6,400 MHz)δ: 2.68(t, J=7.1Hz, 2H, CH2), 3.68(s, 3H, CH3), 3.72(s, 3H, CH3), 3. 8(s, 3H, CH3), 4.22(t, J=7.1 Hz, 2H, CH2), 5.51(s, 2H, CH2), 6.34(s, 1H, NH), 6.89~6.95(m, 2H, ArH ), 7.09~7.12(m, 1H, ArH), 7.19~7.22(m, 2H, ArH), 7.47(d, J=8.4, 1H, ArH), 7.5~7.56(m, 2H, ArH), 7.67(d,J=8.4, 1H, ArH), 8.37(m, 1H), ESI-MS: m/z 559 [M+H]+。
实施例 2-24
参照实施例1的操作,区别在于选用不同的苯氧乙酸,不同的羧酸酯与不同的活化酯侧链反应,得到下述式Ⅰ的化合物。
实施例 25 抗凝活性评价-活化部分凝血活酶时间(aPPT)的测定
将质量18-20g的昆明小鼠,随机分组,每组10只,禁食过夜。将达比加群酯及待测目标化合物悬浮或溶解于1%的羧甲基纤维素钠的水溶液中,配成1mg/mL的浓度,按10mg/Kg的剂量(折合成达比加群计算)灌胃给药,半小时后通过心脏穿刺取血,加入4%枸杞酸钠溶液至0.4%终浓度抗凝,12000r/min离心5分钟,取血浆0.1mL,加入aPPT试剂0.1mL,37℃预温3分钟后,加入37℃预温的氯化钙溶液0.1mL,用血小板聚集凝血因子分析仪测定凝固时间,即为aPPT值。结果见表1.
表1 活化部分凝血活酶时间(aPPT)的测定结果
化合物 | aPPT(sec) |
生理盐水 | 21.4±4.3 |
达比加群酯 | 75.3±2.1 |
Ⅰ3 | 77.1±2.8 |
Ⅰ4 | 165.1±2.9 |
Ⅰ5 | 145.2±4.5 |
Ⅰ10 | 147.6±3.6 |
Ⅰ12 | 135.9±3.0 |
Ⅰ13 | 112.4±3.9 |
Ⅰ14 | 80.9±3.6 |
Ⅰ16 | 102.4±3.0 |
Ⅰ17 | 95.9±3.2 |
Ⅰ18 | 165.2±4.7 |
Ⅰ22 | 127.6±3.3 |
Ⅰ23 | 68.5±3.7 |
Ⅰ24 | 105.9±3.1 |
Claims (10)
1.具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐:
其中,
R1为H或C1-C5的烷基;R2为H或C1-C3的烷基;R3为C1-C6的烷基。
2.根据权利要求1所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐:
其中,
R1为H或C1-C2的烷基,R2为H或CH3,R3为C1-C6的烷基。
3.根据权利要求1-2任一项所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐,选自如下结构式所代表的化合物:
其中,R1、R2和R3分别定义如下:
I1:R1为-CH3,R2为-H,R3为-CH3;
I2:R1为-CH3,R2为-H,R3为-CH2CH3;
I3:R1为-CH3,R2为-H,R3为-CH2CH2CH3;
I4:R1为-CH3,R2为-H,R3为-CH2CH2CH2CH3;
I5:R1为-CH3,R2为-H,R3为-CH2CH2CH2CH2CH3;
I6:R1为-CH3,R2为-H,R3为-CH2CH2CH2CH2CH2CH3;
I7:R1为-CH2CH3,R2为-H,R3为-CH3;
I8:R1为-CH2CH3,R2为-H,R3为-CH2CH3;
I9:R1为-CH2CH3,R2为-H,R3为-CH2CH2CH3;
I10:R1为-CH2CH3,R2为-H,R3为-CH2CH2CH2CH3;
I11:R1为-CH2CH3,R2为-H,R3为-CH2CH2CH2CH2CH3;
I12:R1为-CH2CH3,R2为-H,R3为-CH2CH2CH2CH2CH2CH3;
I13:R1为-CH3,R2为-CH3,R3为-CH3;
I14:R1为-CH3,R2为-CH3,R3为-CH2CH3;
I15:R1为-CH3,R2为-CH3,R3为-CH2CH2CH3;
I16:R1为-CH3,R2为-CH3,R3为-CH2CH2CH2CH3;
I17:R1为-CH3,R2为-CH3,R3为-CH2CH2CH2CH2CH3;
I18:R1为-CH3,R2为-CH3,R3为-CH2CH2CH2CH2CH2CH3;
I19:R1为-CH2CH3,R2为-CH3,R3为-CH3;
I20:R1为-CH2CH3,R2为-CH3,R3为-CH2CH3;
I21:R1为-CH2CH3,R2为-CH3,R3为-CH2CH2CH3;
I22:R1为-CH2CH3,R2为-CH3,R3为-CH2CH2CH2CH3;
I23:R1为-CH2CH3,R2为-CH3,R3为-CH2CH2CH2CH2CH3;
I24:R1为-CH2CH3,R2为-CH3,R3为-CH2CH2CH2CH2CH2CH3。
4.根据权利要求1-2任一项所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐,所述的盐为通式Ⅰ结构的达比加群酯衍生物与有机酸或无机酸所成的盐。
5.根据权利要求3所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐,所述的盐为通式Ⅰ结构的达比加群酯衍生物与有机酸或无机酸所成的盐。
6.根据权利要求1或2所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐,所述的盐可以为硫酸盐、磷酸盐、盐酸盐、氢溴酸盐、醋酸盐、草酸盐、柠檬酸盐、琥珀酸盐、葡萄糖酸盐、酒石酸盐、对甲苯磺酸盐、苯磺酸盐、甲磺酸盐、苯甲酸盐、乳酸盐、马来酸盐。
7.一种药物组合物,其特征在于,包括至少一种如权利要求1-2任一项所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐,以及一种或多种药学上可接受的载体或赋形剂。
8.一种药物组合物,其特征在于,包括至少一种如权利要求3所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐,以及一种或多种药学上可接受的载体或赋形剂。
9.根据权利要求1-2任一项所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐在制备凝血酶抑制剂中的用途。
10.根据权利要求3所述的具有通式Ⅰ结构的达比加群酯衍生物或其药学上可接受的盐在制备凝血酶抑制剂中的用途。
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