CN108299397A - 一种用于降血压的活性药物及其制备方法 - Google Patents
一种用于降血压的活性药物及其制备方法 Download PDFInfo
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- CN108299397A CN108299397A CN201810234007.8A CN201810234007A CN108299397A CN 108299397 A CN108299397 A CN 108299397A CN 201810234007 A CN201810234007 A CN 201810234007A CN 108299397 A CN108299397 A CN 108299397A
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- C—CHEMISTRY; METALLURGY
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- C07D—HETEROCYCLIC COMPOUNDS
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种用于降血压的活性药物，所述药物为血管紧张素转换酶抑制剂，本发明还涉及所述药物的制备方法。体外试验结果表明，本发明化合物对于ACE具有良好的抑制活性，其IC50均在100nm以下。动物试验表明，本发明化合物对于自发性高血压大鼠具有明显的降血压作用，其降压效果与尼群地平大致相当。
Description
技术领域
本发明涉及药物领域，特别地，本发明涉及一种用于降血压的活性药物，所述药物为血管紧张素转换酶抑制剂，本发明还涉及所述药物的制备方法。
背景技术
高血压是我国最常见的心血管疾病，其发生率在成年人中高达20％，高血压患者由于动脉血压长期高于正常血压，不仅能引起头痛、头昏、心悸等症状，而且能引起患者心、脑、肾等器官损害，导致出血性脑卒中、心肌梗死、心力衰竭和脑血栓并发症，使患者偏瘫或死亡，明显降低患者生活质量。当前常见的治疗高血压的药物有以下六种：利尿剂(可能引起低血钾症，影响糖代谢，使糖耐量下降)，β-阻滞剂(可带来中枢神经系统、消化系统以及血管系统的不良反应)，α-阻滞剂、钙拮抗剂(会导致水肿、头痛、潮红、多尿、低血压以及心脏传导受阻)，血管紧张素II受体阻滞剂(可引起干咳、血钾高、甚至血管性水肿)和血管紧张素转换酶抑制剂(ACEI)。
ACEI具有诸多优点：其具有降压的作用、具有保护心脏的作用、具有保护肾脏的作用、不良反应少等，因此适用于治疗各种类型高血压，特别适用于急进型高血压，尤其适用伴有高脂血症、糖尿病和冠心病的高血压患者。
目前上市的ACEI类药物已超过30种，例如卡托普利(captopril)、佐芬普利(zofenopril)、阿拉普利(alacepril)、依那普利(enalapril)、赖诺普利(lidinopril)、希拉普利(cilazapril)、雷米普利(ramipril)、贝那普利(benazepril)、喹那普利(quinapril)、福辛普利(fosinpril)等。它们在与ACE结合强度、生物利用度、半衰期、体内分布等方面各有所不同。尽管ACEI以具有多方面的优点，如降压效果好而持久、治疗范围广、副作用小，但是仍存在一些负面作用，如有些患者服用后，出现了干咳、哮喘以及骨髓抑制、血管神经性水肿、瘙痒及嗜酸细胞增多症等不良反应。如何寻找和合成优秀的ACEI是研究降血压药的活跃领域。
发明内容
本发明一方面涉及一种式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体：
其中：
R1、R2、R3、R4选自氢、卤素、羟基、氰基、硝基、氨基、C1-C4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷氧羰基或C1-4烷基羰基；
R5、R6选自氢、卤素、C1-C4烷基，或者R5、R6一起形成羰基；
Cy表示杂环基，其任选被一个或更多个选自卤素、羟基、氰基、硝基、氨基、C1-C4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷氧羰基或C1-4烷基羰基的基团取代；
L表示C1-C8亚烷基，其任选被一个或更多个选自卤素、羟基、氨基、C1-4烷氧基的基团取代；
M1、M2选自N或CR；
R表示氢、卤素、羟基、氰基、硝基、氨基、C1-C4烷基、C1-4烷氧基、C1-4烷基氨基或C1-4烷基羰基；
其中，所述C1-C4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷氧羰基或C1-4烷基羰基中的C1-C4烷基任选被一个或更多个选自卤素、羟基、氨基、C1-2烷氧基的基团取代。
在本发明的一个实施方案中，所述R1、R2、R3、R4优选为氢、卤素、羟基、氰基、硝基或C1-C4烷基。
在本发明的一个实施方案中，所述R5、R6优选为氢或C1-C4烷基，或者R5、R6一起形成羰基。
在本发明的一个实施方案中，所述Cy优选为吡啶基、噻吩基、吡咯基、嘧啶基、噻唑基、吡咯烷基或哌啶基。
在本发明的一个实施方案中，所述L优选为-CH2-、-CH2CH2-、-CH2CH2CH2-或-CH2CH(OH)CH2-。
在本发明的一个实施方案中，所述M1、M2优选为N或CH。
在本发明的一个实施方案中，所述化合物选自：
本发明中，术语卤素表示氟、氯、溴或碘。
本发明中，术语烷基表示直链状或分支链状的碳数为1-4的烷基，例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基。
本发明中，术语杂环基表示以下(1)或(2)：
(1)具有1-4个选自N、O和S的杂原子的五或六元的芳环基或者它们的苯稠合环基，所述的成环原子为N或S时，所述的N、S可以形成氧化物。例如，可以例举吡咯基、吲哚基、呋喃基、苯并呋喃基、噻吩基、苯并噻吩基、噻唑基、苯并噻唑基、咪唑基、苯并咪唑基、三唑、四唑、吡啶基、吡唑基、嘧啶基、吡嗪基、三嗪基等。
(2)具有1-4个选自N、O和S的杂原子的四至八元环的饱和环基或它们的苯稠合环基，所述的成环原子为N或S时，所述的N、S可以形成氧化物。例如，可以例举哌啶基、哌嗪基、均哌嗪基、吗啉基、硫代吗啉基、吡咯烷基、吡咯烷基、四氢呋喃基、四氢噻吩基、吡唑烷基。
术语“药学上可接受的盐”，是指本发明化合物的药学上可接受有机或无机盐。示例性的盐包括硫酸盐、乙酸盐、草酸盐、氯化物、溴化物、碘化物、硝酸盐、异烟酸盐、乳酸盐、水杨酸盐、琥珀酸盐、马来酸盐、延胡索酸盐、甲酸盐和甲磺酸盐等。
本发明化合物可作为前体药物形式被给予。因此，自身可能具有很少药理学活性或不具有药理学活性的某些衍生物当被给予到体内或体上时，通过例如水解裂解而转化为具有所需活性的本发明的化合物。这种衍生物被称为“前体药物”。
溶剂合物是指本发明化合物与一个或多个溶剂分子的结合物或络合物。形成溶剂合物的溶剂的示例包括但是不局限于水、异丙醇、乙醇、甲醇、二甲亚砜、乙酸乙酯、乙酸和乙醇胺。
本发明化合物可以以异构体以及其混合物的形式存在；例如互变异构体、光学异构体、对映异构体、非对映异构体。本发明化合物可以例如包含不对称碳原子，并因此可以对映异构体或非对映异构体及其混合物的形式存在，例如以外消旋物的形式。本发明化合物可以以(R)-、(S)-或(R，S)-构型存在，优选在化合物的特定位置上为(R)-或(S)-构型。
本发明还公开了制备式1化合物的方法，可以按照以下的路线以及步骤进行：
(1)步骤一：将式II化合物与式III所示的异氰酸酯类化合物反应生成式IV化合物；
(2)步骤二：将式IV化合物与式V所示的唑类化合物反应生成式I化合物；
其中，R1-R6、L、Cy、M1、M2的定义如本文所述，X表示卤素，优选氯、溴或碘。
本发明的另一方面提供了一种药物组合物，包含一种或多种所述的式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体，以及药学上可接受的载体、稀释剂、赋形剂或它们的组合。
本发明可以以任意方便的给药形式施用化合物，例如，片剂、粉末、胶囊、溶液、悬浮液、糖浆、喷雾剂、栓剂、凝胶、乳剂、贴剂等。这样的组合物可以含有药物制剂的常规组分，例如载体、稀释剂、赋形剂、pH调节剂、甜味剂、填充剂和其他活性剂。如果需要胃肠外给药，组合物是无菌的，且是适合注射或者输注的溶液或悬浮液形式。
典型的组合物是通过将本发明化合物和载体、稀释剂或赋形剂混合来制备。适宜的载体、稀释剂或赋形剂可以例举如：碳水化合物、蜡类、水可溶或可膨胀聚合物、亲水性或疏水性材料、明教、油类、溶剂、水等。所用的具体载体、稀释剂或赋形剂将取决于本发明化合物被应用的方式和目的。作为上述载体、赋形剂和稀释剂，具体可包含例如:水、乳糖、右旋糖、果糖、蔗糖、山梨糖醇、甘露醇、聚乙二醇、丙二醇、淀粉、橡胶、明胶、海藻酸盐、硅酸钙、磷酸钙、纤维素、糖水、甲基纤维素、聚乙烯基吡咯烷酮、对羟基苯山梨酸烷基酯、滑石、硬脂酸镁、硬脂酸、甘油、芝麻油、橄榄油、大豆油等。
所述的组合物还可以包括一种或者多种缓冲剂、增溶剂、表面活化剂、润湿剂、润滑剂、乳化剂、混悬剂、防腐剂、抗氧剂、遮光剂、助流剂、着色剂、增甜剂、芳香剂、调味剂和其他已知的添加剂。
对于成人患者，本发明的化合物能够以口服或非口服的方式将作为1次的给予量的0.001～500mg、1天1次或分为数次来给予。应予说明，该给予量可根据治疗对象的疾病的种类、患者的年龄、体重、症状等适当增减。
本发明的化合物可以单独使用，或者与其他治疗剂联合使用。联合治疗可以提供协同作用，即当活性成分一起使用时达到的效果，大于分别使用所述化合物所产生效果的加和。
所述联合治疗可以以同时或连续的方案施用。当连续施用时，所述组合可以以两种或多种用法来施用。化合物可以再单一的药物组合中一起施用，或分开施用，且当分开施用时，可以同时地或以任意次序先后地进行。
本发明的另一方面提供了所述的式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体在制备药物中的用途，所述药物用于预防或治疗高血压。
本发明的另一方面提供了所述的式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体在制备血管紧张素转换酶抑制剂中的用途。
本发明的另一方面提供了所述的式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体在制备降血压剂中的用途。
体外试验结果表明，本发明化合物对于ACE具有良好的抑制活性，其IC50均在100nm以下。动物试验表明，本发明化合物对于自发性高血压大鼠具有明显的降血压作用，其降压效果与尼群地平大致相当。
具体实施方式
在下文中更详细地描述了本发明以有助于对本发明的理解。
所属领域的技术人员将认识到：本发明所描述的化学反应可以用来合适地制备许多本发明的其他化合物，且用于制备本发明的化合物的其它方法都被认为是在本发明的范围之内。例如，根据本发明那些非例证的化合物的合成可以成功地被所属领域的技术人员通过修饰方法完成，如适当的保护干扰基团，通过利用其他已知的试剂除了本发明所描述的，或将反应条件做一些常规的修改。另外，本发明所公开的反应或已知的反应条件也公认地适用于本发明其他化合物的制备。
实施例1：2-((1H-咪唑-1-基)甲基)-N-(吡啶-4-基)-3,4-二氢喹啉-1(2H)-甲酰胺(化合物1)的合成
取2-氯甲基-1,2,3,4-四氢喹啉10mmol溶解于100ml的二氯甲烷中中，加入等当量的4-异氰酸基-吡啶，在室温搅拌12小时。然后加入二氯甲烷稀释反应液，再加入2M盐酸100ml，有机层用2M HCl洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，最后用无水硫酸钠干燥，减压除去溶剂，真空干燥得到粗品，不经纯化直接投入下一步反应。
将上述干燥的产物溶解于120ml THF中，加入20mmol的NaOH水溶液20ml，然后再滴加10mmol咪唑溶于20ml THF中的溶液，升温至回流搅拌6h。减压除去溶剂，加入甲苯100ml溶解，然后用饱和碳酸氢钠洗涤，饱和氯化钠洗涤，最后用无水硫酸钠干燥，减压除去溶剂，残余物用硅胶柱色谱分离，以乙酸乙酯/石油醚(1/5)作为洗脱剂，最后分离得到目标产物2.52g，两步总收率76.4％。
质谱(ESI)：334[M+H]+
氢谱(400MHz，CDCl3)δ8.93(s,1H),8.53(d,2H),7.95(s,1H),7.15-7.34(m,6H),6.83(d,1H),6.72(d,1H),4.03(d,2H),3.63(m,1H),2.84(t,2H),1.94(m,2H)。
实施例2：2-(2-羟基-3-(1H-咪唑-1-基)丙基)-N-(吡啶-4-基)-3,4-二氢喹啉-1(2H)-甲酰胺(化合物2)的合成
取1-氯-3-(1,2,3,4-四氢喹啉-2-基)丙烷-2-醇10mmol溶解于100ml的二氯甲烷中中，加入等当量的4-异氰酸基-吡啶，在室温搅拌10小时。然后加入二氯甲烷稀释反应液，再加入2M盐酸100ml，有机层用2M HCl洗涤，饱和碳酸氢钠洗涤，饱和氯化钠洗涤，最后用无水硫酸钠干燥，减压除去溶剂，真空干燥得到粗品，不经纯化直接投入下一步反应。
将上述干燥的产物溶解于100ml乙醇中，加入20mmol的NaOH水溶液20ml，然后再滴加10mmol咪唑溶于20ml乙醇中的溶液，升温至回流搅拌8h。减压除去溶剂，加入甲苯100ml溶解，然后用饱和碳酸氢钠洗涤，饱和氯化钠洗涤，最后用无水硫酸钠干燥，减压除去溶剂，残余物用硅胶柱色谱分离，以乙酸乙酯/环己烷(1/8)作为洗脱剂，最后分离得到目标产物2.60g，两步总收率68.9％。
质谱(ESI)：378[M+H]+
氢谱(400MHz，CDCl3)δ8.92(s,1H),8.54(d,2H),7.96(s,1H),7.18-7.33(m,6H),6.83(d,1H),6.73(d,1H),4.83(s,1H),4.13(d,2H),3.59(m,1H),3.24(m,1H),2.89(t,2H),1.92(m,2H),1.65(m,2H)。
按照实施例1类似的方法，合成以下化合物：
测试实施例1：ACE的体外抑制活性
使用如下文所述体外分析测定化合物对人类ACE的抑制活性。
重组人类ACE为市售商品(阿迪系统(R&D Systems)，明尼阿波利斯(Minneapolis)，MN，目录编号分别为929-ZN)。使用荧光肽底物Mca-B K2(Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp)-OH；约翰逊(Johnson)等人(2000)分析生物化学(Anal.Biochem.)286:112-118)(来自安娜贝克(Anaspec)，圣何塞(San Jose)，CA)。
在384-孔白色不透明平板中在室温下使用相应的荧光肽以10μM的浓度于分析缓冲剂(50mM Tris/HCL在25℃下，100mM NaCl，0.01％吐温(Tween)-20，1μM Zn，0.025％BSA)中实施分析。人类ACE是以可在室温下于20分钟内获得5μM Mca-BK2定量蛋白酶解的浓度使用。
通过向12个浓度(10μM至20pM)的12.5μL测试化合物中添加25μL酶来开始分析。使抑制剂与酶平衡10分钟，然后添加12.5μL荧光底物以开始所述反应。通过在培育20分钟后添加10μL 3.6％冰醋酸来终止反应。借助荧光计在激发波长和发射波长分别设定为320nm和405nm时读取平板。
根据使用ACE抑制剂时的平均高读数(无抑制，100％酶活性)和平均低读数(完全抑制，最高抑制剂浓度，0％酶活性)将原始数据(相对荧光单元)归一化为％活性。使用单位点竞争模型(格拉夫帕德软件公司，圣地亚哥，CA)实施归一化数据的非线性回归。将数据报告为IC50值。结果记于以下表1中：
表1化合物对ACE的体外抑制活性
试验结果表明，本发明化合物对于ACE具有良好的抑制活性，因此可用作降压药，用于预防和治疗高血压。
测试实施例2：降压作用研究
使用如下文所述动物试测定化合物对自发性高压压大鼠(SHR)的降压作用
将40周龄、体重250-300克的雄性SHR(北京维通利华实验动物技术有限公司)共72只，随机分成12组，每组6只动物，分别为阴性对照组(0.5％CMC-Na)、阳性对照组(尼群地平)、以及化合物1-10组(所有化合物均配制在0.5％CMC-Na中)，其中阳性对照组和化合物1-10均以2mg/Kg的剂量给药；阴性对照仅给予安慰剂。用尾套法(BP2010A无创血压仪)测定大鼠给药前、灌胃给药后1h的血压，分别测三次取平均值，并将结果进行统计学处理。结果记于以下表2中：
表2化合物对自发性高压压大鼠的降压作用(n＝6)
试验结果表明，本发明化合物对于自发性高血压大鼠具有明显的降血压作用，其降压效果与尼群地平大致相当。
以上描述了本发明优选实施方式，然其并非用以限定本发明。本领域技术人员对在此公开的实施方案可进行并不偏离本发明范畴和精神的改进和变化。
Claims (10)
1.一种式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体：
其中：
R1、R2、R3、R4选自氢、卤素、羟基、氰基、硝基、氨基、C1-C4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷氧羰基或C1-4烷基羰基；
R5、R6选自氢、卤素、C1-C4烷基，或者R5、R6一起形成羰基；
Cy表示杂环基，其任选被一个或更多个选自卤素、羟基、氰基、硝基、氨基、C1-C4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷氧羰基或C1-4烷基羰基的基团取代；
L表示C1-C8亚烷基，其任选被一个或更多个选自卤素、羟基、氨基、C1-4烷氧基的基团取代；
M1、M2选自N或CR；
R表示氢、卤素、羟基、氰基、硝基、氨基、C1-C4烷基、C1-4烷氧基、C1-4烷基氨基或C1-4烷基羰基；
其中，所述C1-C4烷基、C1-4烷氧基、C1-4烷基氨基、C1-4烷氧羰基或C1-4烷基羰基中的C1-C4烷基任选被一个或更多个选自卤素、羟基、氨基、C1-2烷氧基的基团取代。
2.根据权利要求1所述的化合物,其特征在于，所述R1、R2、R3、R4优选为氢、卤素、羟基、氰基、硝基或C1-C4烷基。
3.根据权利要求1所述的化合物,其特征在于，所述R5、R6优选为氢或C1-C4烷基，或者R5、R6一起形成羰基。
4.根据权利要求1所述的化合物,其特征在于，所述Cy优选为吡啶基、噻吩基、吡咯基、嘧啶基、噻唑基、吡咯烷基或哌啶基。
5.根据权利要求1所述的化合物,其特征在于，所述L优选为-CH2-、-CH2CH2-、-CH2CH2CH2-或-CH2CH(OH)CH2-。
6.根据权利要求1所述的化合物,其特征在于，所述化合物选自：
7.根据权利要求1所述的式I化合物的制备方法，其包括以下步骤：
(1)步骤一：将式II化合物与式III所示的异氰酸酯类化合物反应生成式IV化合物；
(2)步骤二：将式IV化合物与式V所示的唑类化合物反应生成式I化合物；
其中，R1-R6、L、Cy、M1、M2的定义如权利要求1中所述，X表示卤素，优选氯、溴或碘。
8.一种药物组合物，包含一种或多种根据权利要求1所述的式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体，以及药学上可接受的载体、稀释剂、赋形剂或它们的组合。
9.根据权利要求1所述的式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体在制备药物中的用途，所述药物用于预防或治疗高血压。
10.根据权利要求1所述的式I化合物或其药学上可接受的盐、前药、溶剂化物以及包括其各种比例混合物在内的立体异构体在制备血管紧张素转换酶抑制剂或降血压剂中的用途。
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| WO2008136457A1 (ja) * | 2007-04-27 | 2008-11-13 | Dainippon Sumitomo Pharma Co., Ltd. | 含窒素芳香族誘導体 |
| WO2009005002A1 (ja) * | 2007-06-29 | 2009-01-08 | Dainippon Sumitomo Pharma Co., Ltd. | キノロン誘導体 |
| WO2015150995A1 (en) * | 2014-04-04 | 2015-10-08 | Pfizer Inc. | Bicyclic-fused heteroaryl or aryl compounds and their use as irak4 inhibitors |
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| US3983121A (en) * | 1974-07-01 | 1976-09-28 | Council Of Scientific And Industrial Research | 1-Substituted 4-(β-2-quinolylethyl)piperazines and 1,2,3,4-tetrahydroquinolyl-ethyl analogues thereof |
| US4855291A (en) * | 1984-08-15 | 1989-08-08 | The Boots Company Plc | 1,4dihydroquinoline-3-carboxamides |
| CN1564820A (zh) * | 2001-10-05 | 2005-01-12 | 瑞蔻达蒂股份有限公司 | 用于治疗泌尿道疾病的杂环化合物 |
| WO2008136457A1 (ja) * | 2007-04-27 | 2008-11-13 | Dainippon Sumitomo Pharma Co., Ltd. | 含窒素芳香族誘導体 |
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