CN101279974A - 吡唑并嘧啶酮衍生物及其制备方法和应用 - Google Patents
吡唑并嘧啶酮衍生物及其制备方法和应用 Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- DOTPSQVYOBAWPQ-UHFFFAOYSA-N pyrazolo[4,3-d]pyrimidin-3-one Chemical class N1=CN=C2C(=O)N=NC2=C1 DOTPSQVYOBAWPQ-UHFFFAOYSA-N 0.000 title 1
- 150000003839 salts Chemical class 0.000 claims abstract description 20
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- 239000003814 drug Substances 0.000 claims abstract description 9
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- 125000000217 alkyl group Chemical group 0.000 claims abstract description 4
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- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 5
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- 229940045803 cuprous chloride Drugs 0.000 claims 1
- KRFJLUBVMFXRPN-UHFFFAOYSA-N cuprous oxide Chemical compound [O-2].[Cu+].[Cu+] KRFJLUBVMFXRPN-UHFFFAOYSA-N 0.000 claims 1
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- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
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- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及如式(I)表示的吡唑并嘧啶酮衍生物或其药用盐及其制备方法,其中R1代表H、氰基、4-甲基哌嗪基、或烷氧基;R2代表氨基、4-甲基哌嗪基、NHR3,其中,R3代表烷基、C(O)NHR4、或C(O)OR4,R4代表C1-C6烷基。所述的吡唑并嘧啶酮衍生物或其药用盐具有抑制磷酸二酯酶V的作用,可用于制备治疗阳痿疾病的药物。
Description
技术领域
本发明涉及一类磷酸二酯酶V的抑制剂,具体而言,是涉及一种吡唑并嘧啶酮衍生物及其制备方法和应用。
背景技术
勃起功能障碍(Erectile Dysfunction,英文简称ED)指持续时间不能达到或维持充分的勃起以获得满意的性生活。目前大约有7-8%的成年男性受到不同程度的勃起功能障碍困扰。由于患ED机率随年龄增长而增大,随着人口老龄化时代的到来,ED患者将越来越多。
1998年美国辉瑞公司研发的磷酸二酯酶V(PDE5)抑制剂西地那非(sildenafil,万艾可,Viagra)成功上市,用于治疗男性勃起功能障碍,使得人们开始关注这类新型药物。例如式A中的一类吡唑并嘧啶酮衍生物。中国专利申请CN1168376A、CN1246478A公开了西地那非的制备方法。中国专利申请CN1124926A、CN1393444A、CN1325398A、CN1966506A公开了5-取代苯基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮类磷酸二酯酶V抑制剂在治疗男性勃起功能障碍方面的用途及相应化合物的制备方法。CN1378547A公开了5-(2-取代的-5-杂环基磺酰基吡啶)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮类磷酸二酯酶V抑制剂在治疗男性勃起功能障碍方面的用途。WO0103644、US6077841公开了5-(3-取代的-5-取代噻吩基)-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮类磷酸二酯酶V抑制剂在治疗男性勃起功能障碍方面的用途。
尽管已上市的几个磷酸二酯酶V抑制剂类治疗男性性功能障碍(阳痿疾病)的药物取得了较显著的临床疗效,但是其临床表现出的头痛、潮红、视觉模糊等副作用仍未得到彻底解决。要减少或者克服这些副作用,开发具有高效、低副作用治疗男性性功能障碍药物就必须寻找具有新结构可作为磷酸二酯酶V抑制剂的化合物。
式A
发明内容
本发明的目的是提供一类新的具有式(I)结构的吡唑并嘧啶酮衍生物及其盐,其对磷酸二酯酶V具有显著的抑制作用。
解决上述技术问题的技术方案为:
如式(I)表示的吡唑并嘧啶酮衍生物或其药用盐,
其中R1代表H、氰基、4-甲基哌嗪基、或烷氧基;
R2代表氨基、4-甲基哌嗪基、或NHR3,其中,R3代表烷基、C(O)NHR4、或C(O)OR4,R4代表C1-C6烷基。
优选为:所述吡唑并嘧啶酮衍生物或其药用盐选自以下化合物:
5-(5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-甲氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-氰基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-(4-甲基哌嗪基)-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-丁氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-异丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮。
本发明的另一目的是提供了一种上述式(I)吡唑并嘧啶酮衍生物或其药用盐用于制备治疗阳痿疾病的药物。
本发明式(I)化合物能够以可药用盐的形式使用,尤其是酸加成盐,采用可药用的游离酸来制备,如氢氯酸、硫酸、柠檬酸、酒石酸等。
一种治疗阳痿疾病的药物组合物,其含有有效量的作为活性成分的上述吡唑并嘧啶酮衍生物或其药用盐和可药用载体。
本发明的另一目的是提供上述吡唑并嘧啶酮衍生物或其药用盐的制备方法。
一种制备权利要求1所述吡唑并嘧啶酮衍生物或其药用盐方法,该方法包括下列反应步骤:
(1)以2-溴噻吩-3-甲酸为起始原料,用二氯亚砜酰氯化,得到酰氯化合物II;
反应式(1)
(2)将化合物II和4-氨基-1-甲基-3-正丙基吡唑-5-甲酰氨在4-二甲基氨基吡啶的催化下偶联得到化合物III;
反应式(2)
(3)将化合物III在碱的作用下关环得到化合物IV,所用碱可以是NaOH、或KOH或醇钠、醇钾有机碱;
反应式(3)
(4)将化合物IV用氯磺酸处理后分别与N-甲基哌嗪和氨水反应得到化合物V和VI;ClSO3H可以单独作为溶剂和反应试剂,也可与SOCl2、PCl5、POCl3混和作为溶剂和反应试剂使用;
反应式(4)
(5)将化合物V在催化剂作用下取代-Br,得到所述吡唑并嘧啶酮衍生物或其药用盐;
或将化合物VI在催化剂作用下反应得到所述吡唑并嘧啶酮衍生物。概括地,反应式如下:
本发明所述的吡唑并嘧啶酮衍生物或其药用盐具有抑制磷酸二酯酶V的作用,可用于制备阳痿疾病的药物。本发明的化合物对阳痿的治疗具有良好的效果,副作用较小,为临床提供治疗阳痿疾病的药物更多的选择。
本发明所提供的制备方法具有简单,易操作等优点。
具体实施方式
下列实施例进一步解释了本发明的化合物及其中间体的合成方法,但并不限制本发明的范围。
一、仪器与药品
核磁共振仪 Mercury-Plus300(美国VARIAN)
质谱仪 LCMS-2010A(日本 岛津)
熔点仪 X-4显微数字熔点仪(北京泰克科学仪器有限),未校正
红外光谱分析仪 330FT-IR(美国Thermo公司)
化学试剂购自广州东征化学品公司,Alfar-Asar公司,Aldrich公司;
柱层析用硅胶购自青岛海洋化工厂。
实施例一:5-(2-溴-3-噻吩基)-1-甲基-3丙基-1,6-二氢-7H-吡唑并[4,3-d]嘧啶-7-酮的合成
将2-溴噻吩-3-甲酸(414mg 2mmol)加入到20mL CH2Cl2中,于冰水浴中加入5mLSOCl2及5滴DMF,加热回流搅拌4小时。反应完毕后减压蒸除SOCl2,于冰水浴中向剩余物加入5mL吡啶,然后滴加4-氨基-1-甲基-3-正丙基吡唑-5-甲酰氨盐酸盐(654mg,3mmol)的CH2Cl2(10mL)溶液,滴毕,加热搅拌回流2小时。反应完毕,将反应混合物倒入冰水中,用含5%甲醇的CH2Cl2萃取3次。将萃取液合并,用无水硫酸钠干燥。干燥完毕后减压蒸除溶剂,得到固体初产物III,直接用于下一步的合成中。
将化合物III的初产品加入到叔丁醇(25mL)中,向其中加入叔丁醇钾(672mg 6mmol),将反应液加热至回流,搅拌4小时。反应完毕,减压整除大部分叔丁醇,剩余物加入到冰水中,用CH2Cl2萃取三次。合并萃取液,用无水Na2SO4干燥。干燥完毕蒸除有机溶剂,粗产物用快速柱层析分离提纯,得白色固体产品(317mg,两步总收率45%)
Mp:165-166℃;1H NMR(300MHz,CD3SOCD3)δ0.93(t,J=7.1,3H,CH3),1.72-1.79(m,2H,CH2),2.76(t,J=7.2,2H,CH2),4.14(s,3H,NCH3),7.32(d,J=5.5,1H),7.70(d,J=5.5 1H),12.34(s,1H,NH);13C NMR(CD3SOCD3)δ13.76,21.59,27.10,37.77,113.0,124.1,127.4,128.5,134.1,137.2,144.7,145.4,153.8;IR(KBr):3434,3152,2965,2928,1693,1591;ESI-MS(-):353[M-H]-.Anal.Calcd for C13H13BrN4OS:C:44.20;H:3.71;N:15.86;Found:C:44.38;H:3.71;N:15.87.
实施例二:5-(2-溴-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成(化合物V)
在干燥的圆底烧瓶中加入1mLSOCl2和3mL氯磺酸,混匀后于冰水浴中加入化合物IV。待固体溶解完全后,升温至40℃搅拌2小时。反应完毕后将反应液滴入碎冰中,用氯仿萃取两次。合并萃取液,将溶剂减压蒸馏浓缩至25mL。冰水浴中搅拌滴加155mg三乙胺(1.5mmol)和75mg N-甲基哌嗪(0.75mmol).滴加完毕之后升至室温,搅拌过夜。减压蒸除溶剂,柱层析分离提纯(CHCl3∶CH3OH=20∶1).得209mg白色固体产率81%。
Mp:213-215℃;1H NMR(CD3SOCD3)δ0.93(t,J=7.2,3H,CH3),1.72-1.80(m,2H,CH2),2.18(s,3H),2.43(br s,4H),2.77(t,J=7.2,2H,CH2),3.04(br s,4H),4.15(s,3H,NCH3),7.86(s,1H),12.55(br s,1H,NH);13C NMR(CD3SOCD3)δ13.77,21.61,27.09,37.81,45.06,45.65,53.22,120.4,124.3,133.1,134.6,135.0,137.0,144.1,144.9,153.7;IR(KBr):3435,2959,2852,1681,1582;ESI-MS(-):513,515;Anal.Calcd for C18H23BrN6O3S2:C,41.94;H,4.50;N,16.30;Found:C,41.86;H,4.60;N,16.25.
实施例三:5-(2-溴-5-(氨基磺酰基)-3噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成(化合物VI)
在干燥的圆底烧瓶中加入1mLSOCl2和3mL氯磺酸,混匀后于冰水浴中加入化合物IV。待固体溶解完全后,升温至40℃搅拌2小时。反应完毕后将反应液滴入碎冰中,用氯仿萃取两次。合并萃取液,将溶剂减压蒸馏浓缩至5mL。将此溶液滴加至冰冷的20mL氨水中,室温搅拌过夜。减压蒸除溶剂,柱层析分离提纯(CHCl3∶CH3OH=15∶1).得183mg白色固体产品化合物V,产率:85%。
Mp:267-268℃;1H NMR(300MHz,CD3SOCD3)δ0.93(t,J=7.2,3H,CH3),1.71-1.78(m,2H,CH2),2.76(t,J=7.2,2H,CH2),4.15(s,3H,NCH3),7.71(s,1H),7.90(br s,2H,SONH2);13C NMR(75MHz,CD3SOCD3)δ13.78,21.64,27.08,37.81,117.88,124.3,130.3,134.4,137.0,144.5,144.8,145.3,153.7;IR(KBr):3434,2960,1676,1581cm-1;ESI-MS:m/z=432[M-H]-;Anal.Calcd for C13H14BrN5O3S2:C,36.12;H,3.26;N,16.20;Found:C,36.05;H,3.26;N,16.38.
实施例四:5-(5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成
将60mg化合物V(0.12mmol)溶于20mL甲醇中,搅拌,加入23mg锌粉(O.36mmol)和0.2mL甲酸。室温搅拌过夜。反应完毕,过虑除去多余锌粉,将虑液减压蒸馏,除去溶剂得粗产品,柱层析分离提纯(CHCl3∶CH3OH=20∶1)。得45mg白色固体产品,产率:85%。
Mp:239-240℃;1H NMR(300MHz,CD3SOCD3)δ0.95(t,J=6.8,3H,CH3),1.72-1.79(m,2H,CH2),2.25(s,3H,NCH3),2.55(br s,4H),2.79(t,J=6.9,3H),3.05(br s,4H),4.14(s,3H,NCH3),8.20(s,1H),8.78(s,1H),12.54(br s,1H);13C NMR(125MHz,CD3SOCD3)δ13.70,21.43,26.93,37.75,45.03,45.61,53.21,124.2,131.5,133.6,135.5,135.9,137.3,144.86,144.91,154.2;IR(KBr):3418,3093,2934,1682,1578cm-1;ESI-MS:m/z=435[M-H]-.Anal.Calcd for C18H24N6O3S2:C,49.52;H,5.54;N,19.25;Found:C,49.67;H,5.60;N,19.13.
实施例五:5-(2-甲氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成
将92mg(4mmol)金属钠溶解到20mL甲醇中,待溶解完全后,加入5mg CuI和130mg化合物V(0.25mmol)。氮气保护下于油浴锅中加热至回流,搅拌6个小时。反应完毕后,减压蒸去大部分溶剂。将剩余物倒入30mL水中,用含5%甲醇的CH2Cl2萃取两次。合并萃取液,用无水Na2SO4干燥。干燥完毕蒸除有机溶剂,粗产物用快速柱层析分离(CHCl3∶CH3OH=40∶1)提纯,得55mg白色固体产品,产率:47%。
Mp:264-265℃;1H NMR(300MHz,CDCl3)δ1.03(t,J=7.2,3H,CH3),1.79-1.87(m,2H,CH2),2.32(s,3H,NCH3),2.56(br s,4H),2.89(t,J=7.2,2H,CH2),3.20(br s,4H),4.25(s,3H,NCH3),4.26(s,3H,OCH3),8.09(s,1H),9.90(s,1H);13C NMR(75MHz,CDCl3)δ14.13,22.48,27.72,38.37,45.74,46.12,53.98,63.03,115.3,121.0,124.1,132.6,138.1,143.8,146.6,153.5,167.7;IR(KBr):3352,2965,1711,1584cm-1;ESI-MS:m/z=465[M-H]-;Anal.Calcdfor C19H26N6O4S2:C,48.91;H,5.62;N,18.01;Found:C,49.85;H,5.70;N,18.13.
实施例六:5-(2-乙氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成
合成方法与制备5-(2-甲氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮方法相同,不同之处在于将钠的甲醇溶液换为钠的乙醇溶液。提纯后得79mg白色固体产品产率66%。
Mp:193-194℃;1H NMR(300MHz,CD3SOCD3)δ0.93(t,J=7.2,3H,CH3),1.44(t,J=6.3,3H,CH3),1.71-1.78(m,2H,CH2),2.16(s,3H,NCH3),2.41(br s,4H),2.75(t,J=7.2,2H,CH2),3.00(br s,4H),4.12(s,3H,NCH3),4.32-4.36(m,2H,OCH2),7.76(s,1H);13C NMR(75MHz,CD3SOCD3)δ13.78,14.36,21.51,27.15,37.69,45.12,45.68,53.27,72.40,115.9,118.1,124.0,132.3,137.5,144.3,144.9,154.2,168.3;IR(KBr):3363,2930,1699,1588cm-1;
ESI-MS:m/z=481[M+H]+;Anal.Calcd for C20H28N6O4S2:C:49.98;H:5.87;N:17.49;Found:C:49.85;H:5.96;N:17.38.
实施例七:5-(2-氰基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成
将65mg(0.13mmol)化合物V溶于5mL DMF中,随后加入17mgCuCN(0.19mmol)。在氮气保护下升温至150℃,搅拌6小时。反应完毕后冷却至100℃,将反应液倾入FeCl36H2O(81mg0.3mmol)的盐酸溶液中。加热至60℃搅拌20分钟冷却至室温,用含5%甲醇的CH2Cl2萃取两次。合并萃取液,用无水Na2SO4干燥。干燥完毕蒸除有机溶剂,粗产物用快速柱层析分离(CHCl3∶CH3OH=15∶1)提纯,得12mg白色固体产品,产率:20%。
Mp:234-235℃;1H NMR(300MHz,CD3SOCD3)δ0.92(t,J=7.0,3H,CH3),1.77-1.84(m,2H,CH2),2.18(s,3H,NCH3),2.43(br s,4H),2.79(t,J=7.0,2H,CH2),3.11(br s 4H),4.16(s,3H,NCH3),8.39(s,1H);13C NMR(75MHz,CD3SOCD3)δ13.59,21.34,27.12,37.78,44.98,45.59,53.20,112.0,112.1,113.6,130.9,136.9,141.3,142.3,143.0,145.5,153.9;IR(KBr):3430,2927,2217,1680,1578cm-1;ESI-MS:m/z=460[M-H]-;Anal.Calcd forC19H23N7O3S2:C,49.44;H,5.02;N,21.24;Found:C:49.53;H:5.09;N:21.13.
实施例八:5-(2-(4-甲基哌嗪基)-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮
将65mg化合物V(0.13mmol)溶于5mLDMF中,加入3mg Pd(OAc)2(0.013mmol),,14mgDPPF(0.026mmol),42mg Cs2CO3(0.13mmol),和16mg N-甲基哌嗪基(0.16mmol)。在氮气保护下升温至120℃,搅拌6个小时。反应完毕,冷却至室温。将反应混和物倒入50mL水中,用150mL乙酸乙酯萃取,萃取液用水洗三次,有机相用无水Na2SO4干燥。干燥完毕蒸除有机溶剂,粗产物用快速柱层析分离(CHCl3∶CH3OH=20∶1)提纯,得55mg白色固体产品,产率:79%。
Mp:187-188℃;1H NMR(300MHz,CD3SOCD3)δ0.96(t,J=7.2,3H,CH3),1.71-1.78(m,2H),2.19(s,3H,NCH3),2.23(s,3H,NCH3),2.43(br s,4H),2.50(br s,4H),2.77(t,J=7.2,2H,CH2),3.00(br s,4H),3.13(br s,4H),4.14(s,3H,NCH3),7.70(s,1H),12.14(s,1H);13CNMR(75MHz,CD3SOCD3)δ13.82,21.71,27.05,37.74,45.05,45.32,45.63,52.23,53.25,53.68,117.4,119.9,124.0,134.1,137.2,144.5,145.5,153.5,163.1;IR(KBr):3432,2940,1698,1582cm-1;ESI-MS:m/z=533[M-H]-;Anal.Calcd for C23H34N8O3S2:C:51.66;H:6.41;
N:20.96;Found:C:51.76;H:6.38;N:20.91.
实施例九:5-(2-乙氧基-5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成VIA
合成方法同实施例六5-(2-乙氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成方法相同。不同之处在于起始反应物为化合物VI。提纯后得56mg白色固体,产率56%。
Mp:255-256℃;1H NMR(300MHz,CD3SOCD3)δ0.94(t,J=6.8,3H,CH3),1.46(t,J=6.3,3H),1.73-1.78(m,2H,CH2),2.76(t,J=7.0,2H,CH2),4.13(s,3H,NCH3),4.34(m,2H,OCH2),7.69(s,1H),7.69(br s,2H,SONH2),11.37(s,1H,NH2);13C NMR(75MHz,CD3SOCD3)δ13.79,14.41,21.59,27.10,37.79,72.36,113.7,123.8,128.5,129.6,137.4,144.5,144.6,153.2,166.3;IR(KBr):3332,3089,2969,1684,1587cm-1;ESI-MS:m/z=396[M-H]-;Anal.Calcd forC15H19N5O4S2:C,45.33;H,4.82;N,17.62;Found:C,45.29;H,4.75;N,17.70.
实施例十:5-(5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成VII
将200mg化合物VI(0.46mmol)溶于20mL甲醇中,搅拌,加入90mg锌粉(1.38mmol)和0.2mL甲酸。室温搅拌过夜。反应完毕,过虑除去多余锌粉,将虑液减压蒸馏,除去溶剂得粗产品,柱层析分离提纯(CHCl3∶CH3OH=20∶1)。得133mg白色固体产品,产率:82%。
Mp:307-308℃;1H NMR(300MHz,CD3SOCD3)δ0.95(t,J=6.9,3H,CH3),1.73-1.80(m,2H),2.79(t,J=7.2,2H),4.14(s,3H,NCH3),7.83(br s,2H),8.15(s,1H),8.63(s,1H),12.51(br s,1H);13C NMR(75MHz,CD3SOCD3)δ13.78,21.54,37.77,124.1,129.0,130.4,134.5,137.2,144.6,145.0,146.2,154.1.IR(KBr):3294,2958,1680,1579cm-1;ESI-MS:m/z=352[M-H]-;Anal.Calcd for C13H15N5O3S2:C:44.18;H:4.28;N:19.82;Found:C:44.15;H:4.20;N:19.86.
实施例十一:5-(5-(N-丁氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成
将65mg化合物VII(0.18mmol)溶于4mL吡啶中,加入44mg(0.36mmol)4-二甲氨基吡啶。将此溶液于冰浴中冷却,搅拌下加入40μL氯甲酸正丁酯(0.31mmol)。加完后升至室温搅拌过夜。反应完毕后将反应液倾入50mL 1N HCl中,用乙酸乙酯萃取(2×50mL)。合并有机层,分别用1N盐酸,饱和食盐水和水洗。无水Na2SO4干燥后,减压蒸去有机溶剂,粗产物用快速柱层析分离(CHCl3∶CH3OH=30∶1)提纯,得50mg白色固体产品,产率:61%。
Mp:317-318℃(dec.);1H NMR(500MHz,CD3SOCD3)δ0.83(t,J=7.2,3H,CH3),0.95(t,J=6.9,3H,CH3),1.23-1.30(m,2H,CH2),1.49-1.54(m,2H,CH2),1.73-1.80(m,2H,CH2),2.79(t,J=7.2,2H,CH2),4.04(t,J=5.7,2H,OCH2),4.14(s,3H,NCH3),8.30(s,1H),8.78(s,1H),12.55(s,1H);13C NMR(125MHz,CD3SOCD3)δ13.26,13.69,18.20,21.46,26.97,29.91,37.75,65.75,124.3,132.6,133.8,134.6,137.3,140.5,144,8,144.9,151.0,154.2;IR(KBr):3437,2961,1755,1681,1584cm-1;ESI-MS:m/z=452[M-H]-;Anal.Calcd for C18H23N5O5S2:C,47.67;H,5.11;N,15.44;Found:C,47.54;H,5.17;N,15.45.
实施例十二:5-(5-(N-丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成VIIA
合成方法同实施例十一5-(5-(N-丁氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成方法相同。不同之处在于使用了氯甲酸正丙酯代替氯甲酸正丁酯。分离提纯后得到白色固体,产率65%。
Mp:312-313℃(dec.);1H NMR(300MHz,CD3SOCD3)δ0.84(t,J=6.9,3H,CH3),0.95(t,J=6.6,3H,CH3),1.52-1.59(m,2H,CH2),1.72-1.79(m,2H,CH2),2.79(t,J=6.6,2H,CH2),4.00(t,J=5.4,2H,CH2,OCH2),4.14(s,3H,NCH3),8.31(s,1H),8.79(s,1H),12.57(s,1H);13C NMR(125MHz,CD3SOCD3)δ9.84,13.69,21.31,21.47,26.96,37.74,67.50,124.3,132.7,133.8,134.7,137.3,140.5,144.8,144.9,151.0,154.2;IR(KBr):3429,2963,1748,1681,1584cm-1;ESI-MS:m/z=438[M-H]-;Anal.Calcd for C17H21N5O5S2:C,46.46;H,4.82;N,15.93;Found:C,46.35;H,4.85;N,15.87.
实施例十三:5-(5-(N-异丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成
合成方法同5-(5-(N-丁氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮的合成方法相同。不同之处在于使用了氯甲酸异丙酯代替氯甲酸正丁酯。分离提纯后得到白色固体,产率57%。
Mp:309-310℃(dec.);1H NMR(500MHz,CD3SOCD3)δ0.95(t,J=6.9,3H,CH3),1.17-1.19(m,6H),1.72-1.79(m,2H,CH2),2.79(t,J=6.9,2H,CH2),4.13(s,3H,NCH3),4.79-83(m,1H,OCH),8.30(s,1H),8.78(s,1H),12.54(s,1H);13C NMR(125MHz,CD3SOCD3)δ13.70,21.32,21.50,26.98,37.75,70.27,124.3,132.7,133.6,134.6,137.3,140.7,144.8,144.9,150.5,154.2;IR(KBr);3444,2961,1746,1682,1584cm-1;ESI-MS:m/z=438[M-H]-;Anal.Calcd for C17H21N5O5S2:C,46.46;H,4.82;N,15.93;Found:C,46.55;H,4.76;N,15.82.
实施例十四:磷酸二酯酶5(PDE5)抑制活性实验
本文所合成的PDE5抑制剂的动力学性质使用了全长的PDE5A1进行测试。将PDE5A1加入到由20mM Tris HCl,HCl,pH 7.5,10mM MgCl2,0.5mM DTT,3H cGMP(20,000cpm/assay)组成的反应混和液中于室温下反应15分钟。然后加入0.2M ZnSO4和0.2M Ba(OH)2终止反应。产物3H GMP在BaSO4作用下沉淀出来,而未反应的3H cGMP则保留在上清液中,清液中的放射活性采用液滴闪烁计数测定。为了测定抑制剂的抑制活性,我们测定了至少六组在不同抑制剂及底物浓度下的数据。IC50值为抑制率达到50%时的抑制剂浓度。
按照实施例十四所介绍的方法测定了本发明的部分式(I)结构的吡唑并嘧啶酮衍生物或其药用盐对PDE5的抑制活性,测定结果如下:
上述化学物质(Inhibitors)1-10的化学名称分别如下:
5-(5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-甲氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-氰基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-(4-甲基哌嗪基)-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-丁氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-异丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮。
Claims (9)
2.权利要求1的所述吡唑并嘧啶酮衍生物或其药用盐,其特征是,其选自以下化合物:
5-(5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-甲氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-氰基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-(4-甲基哌嗪基)-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(2-乙氧基-5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-丁氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;
5-(5-(N-异丙氧羰基氨基磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮。
3.权利要求1所述吡唑并嘧啶酮衍生物或其药用盐在制备治疗阳痿药物中的应用。
4.一种治疗阳痿的药物组合物,其含有有效量的作为活性成分的权利要求1所述吡唑并嘧啶酮衍生物或其药用盐和可药用载体。
5.一种制备权利要求1所述吡唑并嘧啶酮衍生物或其药用盐方法,该方法包括下列反应步骤:
(1)以2-溴噻吩-3-甲酸为起始原料,用二氯亚砜酰氯化,得到酰氯化合物II,
反应式如下:
(2)将化合物II和4-氨基-1-甲基-3-正丙基吡唑-5-甲酰氨在4-二甲基氨基吡啶的催化下偶联得到化合物III,
反应式如下:
(3)将化合物III在碱的作用下关环得到化合物IV,所用碱是NaOH、KOH、醇钠有机碱、或醇钾有机碱;
反应式如下:
(4)将化合物IV用氯磺酸处理后分别与N-甲基哌嗪和氨水反应得到化合物V和VI;ClSO3H单独作为溶剂和反应试剂,或与SOCl2、PCl5、POCl3混和作为溶剂和反应试剂使用,
反应式如下:
(5)化合物V或VI在过渡金属催化剂作用下进行偶联反应或脱卤反应,得到所述吡唑并嘧啶酮衍生物。
6.根据权利要求5所述的制备方法,其特征是:步骤(5)化合物V在催化剂作用下进行脱卤反应为:将化合物V在金属催化剂作用下氢化脱卤得到5-(5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮,金属催化剂为Zn或Pd。
7.根据权利要求5所述的制备方法,其特征是:步骤(5)化合物V在催化剂作用下进行偶联反应为:化合物V和甲醇钠或乙醇钠在碘化亚铜、溴化亚铜、氯化亚铜、或氧化亚铜催化下发生偶联反应得到5-(2-甲氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮或5-(2-乙氧基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮。
8.根据权利要求5所述的制备方法,其特征是:步骤(5)化合物V在催化剂作用下进行偶联反应为:将化合物V和氰化亚铜反应得到5-(2-氰基-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮;或将化合物V和N-甲基哌嗪在碘化亚铜或醋酸钯催化下得到5-(2-(4-甲基哌嗪基)-5-(4-甲基哌嗪基-1-磺酰基)-3-噻吩基)-1-甲基-3-丙基-1,6-二氢-7H-吡唑[4,3-d]嘧啶-7-酮。
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CN105085526A (zh) * | 2014-05-15 | 2015-11-25 | 重庆圣华曦药业股份有限公司 | 一种改进的西地那非制备方法 |
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CN105085526A (zh) * | 2014-05-15 | 2015-11-25 | 重庆圣华曦药业股份有限公司 | 一种改进的西地那非制备方法 |
CN105085526B (zh) * | 2014-05-15 | 2017-08-01 | 重庆圣华曦药业股份有限公司 | 一种改进的西地那非制备方法 |
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