CN101863900A - 新型一氧化氮供体型噻吩并吡啶衍生物、其制备方法和用途 - Google Patents
新型一氧化氮供体型噻吩并吡啶衍生物、其制备方法和用途 Download PDFInfo
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- CN101863900A CN101863900A CN 201010212471 CN201010212471A CN101863900A CN 101863900 A CN101863900 A CN 101863900A CN 201010212471 CN201010212471 CN 201010212471 CN 201010212471 A CN201010212471 A CN 201010212471A CN 101863900 A CN101863900 A CN 101863900A
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- compound
- acetate
- ester
- pyridines
- tetramethylene sulfide
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Abstract
本发明属于抗高血压药物技术领域,提供具有式I结构的一类一氧化氮供体型噻吩并吡啶衍生物及其盐,其中R1,R2,R3同时或分别为:氢,卤素,C1-C4烷基,C1-C4烷氧基,硝基;R4为C1-C6直链或支链烷基。本发明还涉及上述化合物的制备方法,并同时公开了以该化合物或其药学上可接受的盐作为活性有效成分的药物组合物,以及它们在作为抗高血压药物方面的应用。
Description
技术领域
本发明属于医药技术领域,更确切地说,是涉及一类具有抗高血压作用的化合物及其制备方法、含有它们的药物组合物和作为抗高血压药物的用途。
背景技术
一氧化氮在室温下是一种无色气体,微溶于水。它具有(σ1)2(σ*)2(σ2,Л)6(Л*)的电子构型。配对电子表明,一氧化氮是一种形式上的自由基,并决定了该分子具有独特的性质。NO分子中,N原子外层有5个电子,O原子外层有6个电子,形成共价键后,在分子轨道上还有1个不成对电子,化学性质极不稳定,半衰期短,脂溶性强,容易弥散通过细胞膜,扩散到邻近组织中,凭其活泼的化学性质,很快与靶物质反应,产生生物学效应。
生物体内的NO来源包括内源性、外源性两个方面。内源性是指以L-精氨酸作为底物,通过NO合成酶的作用,生成NO和L-瓜氨酸。外源性NO供体是指具有释放NO性质的不同结构的化合物,它们的化学活性取决于相关氮原子的氧化状态,控制着生理性转化NO的速度和程度。理想的NO供体药物是在体内能自发稳定地释放NO,且释放简单,无需细胞代谢,长时间应用不易产生耐受性,有不同作用时间和不同作用强度的品种供选用。
外源性NO的重要来源是NO供体,即在体内能释放NO的化合物。化学上根据与NO释放部位相连的原子的不同,将NO供体分为六类:C-NO供体,N-NO供体,O-NO供体,S-NO供体,杂环-NO供体和过渡金属-NO供体。到目前为止,数量最多,研究较深入的NO供体是O-NO供体。主要包含有机硝酸酯和有机亚硝酸酯,其NO的释放机制尚存在争议。
近年来无论是在基础研究还是应用研究方面,一氧化氮供体都有较显著的发展,NO与某些药物相连,不仅可以增强药效,增加新的适应性而且可以显著降低其不良反应。
随居民日常生活水平的日益提高,日常生活和饮食习惯的改变,我国高血压患者人数呈逐年上涨的趋势。高血压严重威胁人们的身心健康,甚至危害生命。
近年来被世界卫生组织列为首选并被广泛临床应用的降压药物有五大类:利尿降压药、β-受体阻滞剂、钙离子拮抗剂、血管紧张素转换酶抑制剂(包括血管紧张素II受体拮抗剂)、α-受体阻滞剂。这些降压药都有肯定的疗效,但各有缺点。
高血压是心血管患病率和死亡率最常见的危险因子,是多种致病因素共同作用的结果,并受基因、环境等因素影响,尽管人们已做出巨大的努力控制血压,但目前仍有35%的高血压患者血压控制不良。在采用了各种降压药物血压控制较好的人群中,只有1/3的患者可免于中风和心脏事件。因此,寻找新的具有特色的降压药仍是长期的研究热点。
发明内容
本发明的一个目的在于,公开了一类一氧化氮供体型噻吩并吡啶衍生物及其药用盐。
本发明的另一个目的在于,公开了以一类一氧化氮供体型噻吩并吡啶衍生物及其药用盐为主要活性成分的药物组合物。
本发明的再一个目的在于,公开了一类一氧化氮供体型噻吩并吡啶衍生物及其药用盐的制备方法。
本发明还有一个目的在于,公开了一类一氧化氮供体型噻吩并吡啶衍生物及其药用盐作为抗高血压药物方面的应用。
现结合本发明目的,对本发明内容进行详细阐述。
本发明具体涉及通式I结构的化合物及其药学上可接受的盐:
其中:
R1,R2,R3同时或分别为:氢,卤素,C1-C4烷基,C1-C4烷氧基,硝基;
R4为C1-C6直链或支链烷基。
本发明涉及的具有式I结构的化合物,代表化合物如下:
I-1 2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-2 2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(3-硝氧基丙醇)酯;
I-3 2-苯基-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-4 2-(3-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-5 2-(3-硝基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-6 2-(4-氟苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-7 2-(2,3-二氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-8 2-(3,4,5-三甲氧基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯。
本发明中具有式I结构的化合物,其盐系指:本发明化合物与无机酸、有机酸成盐。特别优选的盐是:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、富马酸盐、牛磺酸盐、葡萄糖酸盐、氨基酸盐,等等。
式I化合物的制备路线如下:
其中X为溴或氯。
具体可以通过两种方法制备化合物I:
①α-溴代取代苯基苯乙酸(1)与卤素取代烷基醇(2)以甲苯为溶剂,以对甲苯磺酸为催化剂,加热回流制得酯类中间体(3)。(3)再与4,5,6,7-四氢噻吩并[3,2-c]吡啶(4)在三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠或氢氧化钾等缚酸剂存在下,以二氯甲烷、三氯甲烷、乙腈或甲苯为溶剂,15~100℃反应制得关键中间体(5)。然后将(5)溶于乙腈,室温下滴加硝酸银和乙腈的混合液,搅拌反应可得式I化合物;
②(6)与(2)在DCC和DMAP存在下,以二氯甲烷或三氯甲烷为溶剂,-5~25℃反应制得关键中间体(5)。然后将(5)溶于乙腈,室温下滴加硝酸银和乙腈的混合液,搅拌反应可得式I化合物。
将反应制得各种中间体或所得产物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,滴加无机酸或有机酸的溶液,制成药学上可接受的盐。
具体是将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,于冰水浴下滴加盐酸乙醚溶液至pH=2,制成盐酸盐;或将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,加入等摩尔柠檬酸,加热搅拌得其柠檬酸盐;抑或将各种化合物溶于乙醚、DMF、丙酮、甲醇、乙醇、乙酸乙酯或DMSO中的一种,于冰水浴下滴加浓硫酸至pH=3,制成硫酸盐,等等。
此类化合物对于治疗人类因高血压引起的疾病是有效的。尽管本发明的化合物可以不经任何配置直接给药,但所述的各种化合物优选以药物制剂的形式使用,给药途径可以是非肠道途径(如静脉、肌肉给药)及口服给药。
本发明化合物的药物组合物制备方法如下:使用标准和常规的技术,使本发明化合物与制剂学上可接受的固体或液体载体结合,以及使之任意地与制剂学上可接受的辅助剂和赋形剂结合制备成微粒或微球。固体剂型包括片剂、分散颗粒、胶囊、缓释片、缓释微丸等等。固体载体可以是至少一种物质,其可以充当稀释剂、香味剂、增溶剂、润滑剂、悬浮剂、粘合剂、崩解剂以及包裹剂。惰性固体载体包括磷酸镁、硬脂酸镁、滑粉糖、乳糖、果胶、丙二醇、聚山梨酯80、糊精、淀粉、明胶、纤维素类物质例如甲基纤维素、微晶纤维素、低熔点石蜡、聚乙二醇、甘露醇、可可脂等。液体剂型包括溶剂、悬浮液例如注射剂、粉剂等等。
药物组合物以及单元剂型中含有的活性成份(本发明化合物)的量可以根据患者的病情、医生诊断的情况特定地加以应用,所用的化合物的量或浓度在一个较宽的范围内调节。通常,活性化合物的量范围为组合物的0.5%~90%(重量),另一优选的范围为0.5%~70%。
本发明的具有式I结构的化合物及其药学上可接受的盐,在抗高血压方面有明显的效果。
下面通过药效学实验进一步说明本发明化合物的抗高血压作用。
对大鼠肾性高血压模型作用试验
1.实验动物:
Wistar大鼠:(160±20)g,雌雄各半,中国医学科学院实验动物研究所提供,许可证号SCXK(京)2005-0013。
2.实验药物:
发明化合物及其盐(均由发明人自制提供)。
3.实验方法与结果:
造模:以两肾一夹型手法造模,空白组除外,各组术前禁食12h,不禁水,3%戊巴比妥钠(40mL/kg)腹腔注射麻醉后,将大鼠仰卧位固定,常规备皮,消毒,铺巾。于腹中纵行切口,依次暴露肾脏,在腹膜后近主动脉钝性分离左肾动脉,并用内径0.2mm银夹钳夹,右肾动脉不触及。逐层关腹,术后注射青霉素钠盐10万U/只,常规饲养。假手术组行手术而不上银夹,其余处理同造模组。待造模4周后,以尾动脉收缩压较术前升高22.6mmHg以上,超过135mmHg者为造模成功。
分组及给药:筛选造模成功的大鼠32只,随机分为4组,每组8只,另有空白组8只。造模后第5周起各鼠每日灌胃给药1次,其中化合物组均以100mg/kg灌服,模型组给予同容积生理盐水溶液。灌胃容积均为10mL/kg,连续1周。
血压测定:采用尾动脉波动法,在干燥、通风、安静的环境中将大鼠置25W灯下加温,预热10min使大鼠尾动脉充分扩张,待大鼠短暂躁动停止后,测血压。结果见下表。
对双肾一夹大鼠肾性高血压模型的影响
结果显示,本发明化合物有明显的抗高血压作用。
具体实施方式
下面结合实施例对本发明做进一步地说明。实例仅为解释性的,决不意味着它以任何方式限制本发明的范围。所述的化合物经高效液相色谱(HPLC),薄层色谱(TLC)进行检测。随后可采用诸如红外光谱(IR),核磁共振谱(1H-NMR),质谱(MS)等进一步确证其结构。
参考实施例1:
参考专利US 5,036,156A1(Bouisset et al.)的方法即可制备化合物(1)。反应通式如下:
参考实施例2:
2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(6-1)的制备
向反应瓶中加入20.17g(0.066mol)硫酸氢氯吡格雷,用约60ml蒸馏水溶解。在冰水浴条件下滴加碳酸氢钠饱和溶液,滴加过程中,有白色絮状物生成。至pH为7~8时停止滴加。用二氯甲烷萃取几次,合并二氯甲烷层并用无水硫酸钠干燥,过滤,蒸干得浅黄色油状液体。向其中加入约50mL甲醇,加热至回流。加入10mL 30%氢氧化钠溶液,继续回流至反应完全(点板控制反应进程)。蒸干得白色蜡状固体。向反应瓶中加大量水,用二氯甲烷洗涤水层,合并有机层,干燥,过滤,蒸干得白色固体产物。
实施例1:
2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-溴乙醇)酯(中间体5-1)
在装有搅拌器、冷凝器、分水器的反应瓶中加入α-溴代邻氯苯乙酸5.0g(0.020mol),2-溴乙醇7.06g(0.110mol),对甲苯磺酸1.0g,甲苯50mL,加热回流。反应过程中将分水器中的水分出至明显无水生成时,补加少量醇,若仍无水分出可认为反应完全。冷却至室温,用饱和碳酸氢钠溶液洗涤2次,蒸馏水洗涤2次,取有机层无水硫酸钠干燥,过滤,蒸干得浅黄色油状液体。将上步产物装入干燥单口瓶中,用20mL甲苯溶解,加入无水碳酸钾5.0g(0.036mol),室温搅拌下滴加4,5,6,7-四氢噻吩并[3,2-c]吡啶3.07g(0.022mol),点板控制反应进程。反应完全后过滤蒸干溶剂,用快速制备色谱分离得无色透明晶体,收率94.0%,m.p.93.4~94.2℃。1H-NMR(CDCl3,400MHz)δ:2.854~2.953(m,4H),3.455~3.512(t,2H),3.669(d,J=14Hz,1H),3.749(d,J=14Hz,1H),4.395~4.463(m,2H),4.942(s,1H),6.665(d,J=5.2Hz,1H),7.052(d,J=5.2Hz,1H),7.231~7.303(m,2H),7.384~7.407(q,1H),7.681~7.704(q,1H)。IR ν:3097,3077,3057,2959,2929,2901,2842,1743,1203,1183,1150,1047,1015,761cm-1。EI-MSm/z(%):414(5),262(100),138(47),110(39),89.1(9)。
实施例2:
2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(3-溴丙醇)酯(中间体5-2)
在装有干燥管的反应瓶中加入(6-1)3.44g(0.011mol),二氯甲烷50mL,3-溴丙醇5.07g(0.07mol),DCC 2.54g(0.012mol),DMAP 1.37g(0.011mol),室温下搅拌反应。3h后,过滤,加36%盐酸少量,洗涤2次,饱和碳酸氢钠溶液洗涤2次,饱和氯化钠溶液洗1次,取有机层干燥过滤,蒸干溶剂。快速制备色谱分离得无色透明晶体,收率91.8%,m.p.78.1~78.5℃。1H-NMR(CDCl3,400MHz)δ:2.066~2.178(m,2H),2.869~2.907(q,4H),3.261~3.326(m,2H),3.644(d,J=14.4Hz,1H),3.757(d,J=14Hz,1H),4.176~4.290(m,2H),4.889(s,1H),6.662(d,J=4.8Hz,1H),7.050(d,J=5.2Hz,1H),7.227~7.302(m,2H),7.382~7.405(q,1H),7.670~7.694(q,1H)。IR ν:3071,3020,2963,2947,2920,2836,1741,1200,1176,1047,1037,747,708cm-1。EI-MS m/z(%):428(3),262(100),138(18),110(7)。
实施例3:
2-苯基-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-氯乙醇)酯(中间体5-3)
参照实施例1的方法,(1-3)与2-氯乙醇反应产物,再与4,5,6,7-四氢噻吩并[3,2-c]吡啶反应,即可方便制得中间体5-3。收率87.6%,m.p.86.7~88.0℃。
实施例4:
2-(3-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-氯乙醇)酯(中间体5-4)
参照实施例1的方法,(1-4)与2-氯乙醇反应产物,再与4,5,6,7-四氢噻吩并[3,2-c]吡啶反应,即可方便制得中间体5-4。收率84.9%,m.p.90.1~91.3℃。
实施例5:
2-(3-硝基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-溴乙醇)酯(中间体5-5)
参照实施例1的方法,(1-5)与2-溴乙醇反应产物,再与4,5,6,7-四氢噻吩并[3,2-c]吡啶反应,即可方便制得中间体5-5。收率89.1%,m.p.92.3~93.2℃。
实施例6:
2-(4-氟苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-(4H)-基)乙酸(2-氯乙醇)酯(中间体5-6)
参照实施例1的方法,(1-6)与2-氯乙醇反应产物,再与4,5,6,7-四氢噻吩并[3,2-c]吡啶反应,即可方便制得中间体5-6。收率84.7%,m.p.96.8~97.9℃。
实施例7:
2-(2,3-二氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-溴乙醇)酯(中间体5-7)
参照实施例1的方法,(1-7)与2-溴乙醇反应产物,再与4,5,6,7-四氢噻吩并[3,2-c]吡啶反应,即可方便制得中间体5-7。收率83.6%,m.p.91.4~92.9℃。
实施例8:
2-(3,4,5-三甲氧基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-氯乙醇)酯(中间体5-8)
参照实施例1的方法,(1-8)与2-氯乙醇反应产物,再与4,5,6,7-四氢噻吩并[3,2-c]吡啶反应,即可方便制得中间体5-8。收率93.5%,m.p.97.1~98.3℃。
实施例9:
2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯(化合物I-1)
取中间体(5-1)5.0g(0.012mol)用乙腈溶解,室温下滴加含硝酸银2.25g(0.013mol)的乙腈溶液,滴加完毕后室温下搅拌12h。过滤,蒸干,快速制备色谱分离得淡黄色油状液体,收率81.1%,Rf=0.45[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。1H-NMR(DMSO-d6,400MHz)δ:2.790~2.891(m,4H),3.662(d,J=4.4Hz,2H),3.805~3.952(t,2H),4.351~4.387(q,2H),4.892(s,1H),6.759(d,J=4.8Hz,1H),7.259(d,J=4.8Hz,1H),7.361~7.393(m,2H),7.479~7.503(q,1H),7.596~7.619(q,1H)。IR ν:3419,3108,2987,1741,1600,1258,1196,1187,721。EI-MS m/z(%):400(5),262(100),138(63),110(50),46.0(12),36.0(38)。
实施例10:
2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(3-硝氧基丙醇)酯(化合物I-2)
取中间体(5-2)5.0g(0.017mol)用乙腈溶解,室温下滴加含硝酸银2.55g(0.019mol)和乙腈的混合液,滴加完后室温下搅拌12h。过滤,蒸干,快速制备色谱分离得淡黄色油状液体,收率82.6%,Rf=0.48[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。1HNMR(CDCl3,400MHz)δ:2.882(d,J=4Hz,4H),3.638(d,J=14.4Hz,1H),3.758(d,J=14Hz,1H),4.192~4.234(q,2H),4.327(q,2H),4.892(s,1H),6.660(d,J=5.2Hz,1H),7.052(d,J=5.2Hz,1H),7.241~7.283(m,2H),7.385~7.408(q,1H),7.658~7.682(q,1H)。IR ν:3423,3117,2996,1739,1618,1278,1216,1196,720。EI-MS m/z(%):410(2),262(100),138(54),110(50),46.0(14),36.0(34)。
实施例11:
2-苯基-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯(化合物I-3)
参照实施例9的方法,中间体(5-3)与硝酸银反应,即可方便制得化合物I-3的淡黄色油状产物,收率76.8%,Rf=0.46[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。
实施例12:
2-(3-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯(化合物I-4)
参照实施例9的方法,中间体(5-4)与硝酸银反应,即可方便制得化合物I-4的淡黄色油状产物,收率79.5%,Rf=0.48[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。
实施例13:
2-(3-硝基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯(化合物I-5)
参照实施例9的方法,中间体(5-5)与硝酸银反应,即可方便制得化合物I-5的黄色油状产物,收率73.6%,Rf=0.47[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。
实施例14:
2-(4-氟苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯(化合物I-6)
参照实施例9的方法,中间体(5-6)与硝酸银反应,即可方便制得化合物I-6的浅黄色油状产物,收率83.1%,Rf=0.49[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。
实施例15:
2-(2,3-二氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯(化合物I-7)
参照实施例9的方法,中间体(5-7)与硝酸银反应,即可方便制得化合物I-7的黄色油状产物,收率75.9%,Rf=0.50[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。
实施例16:
2-(3,4,5-三甲氧基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯(化合物I-8)
参照实施例9的方法,中间体(5-8)与硝酸银反应,即可方便制得化合物I-8的浅黄色油状产物,收率76.2%,Rf=0.48[展开剂:v(石油醚)∶v(乙酸乙酯)=2∶1]。
实施例17:
化合物I-1成盐酸盐:取I-1油状产物2.0g,溶于10mL无水乙醚。冰水浴冷却至0℃,滴加25%盐酸乙醚溶液至pH为2,继续于冰水浴下搅拌约1h。过滤,得浅黄色固体。
实施例18:
化合物I-5成柠檬酸盐:取I-5油状产物2.0g,溶于15mL无水乙醇。加热至回流后加入等摩尔柠檬酸,继续于回流下搅拌反应约2h。反应完毕,于室温下静置24h。过滤,得黄色固体。
实施例19:
化合物I-8成硫酸盐:取I-8油状产物2.0g,溶于20mL无水甲醇。冰水浴冷却至5℃,滴加浓硫酸溶液至pH为3,继续于冰水浴下搅拌约0.5h。过滤,得浅黄色固体。
为了更充分地说明本发明的一氧化氮供体型噻吩并吡啶酯衍生物的药物组合物,下面提供下列制剂实施例,所述实施例仅用于说明,而不是用于限制本发明的范围。所述制剂可以使用本发明化合物中的任何活性化合物及其盐。
实施例20:
用下述成分制备硬明胶胶囊:
用量/囊
化合物I-2 74mg
预胶化淀粉 100mg
泊洛沙姆 4mg
羧甲基淀粉钠 10mg
硬脂酸镁 20mg
10%聚维酮乙醇溶液 适量
制备工艺:将原辅料预先干燥,过100目筛备用。按处方量将上述成分混匀,过60目筛三次,加适量10%聚维酮乙醇(95%)溶液制软材,过18目筛制粒,40℃干燥,过16目筛整粒,填充入硬明胶胶囊中。
实施例21:
用下述成分制备片剂:
用量/片
化合物I-6 68mg
淀粉 45mg
微晶纤维素 40mg
羧甲基淀粉钠盐 4.5mg
硬脂酸镁 1mg
滑石粉 1mg
泊洛沙姆 3mg
制备工艺:将原辅料预先干燥,过100目筛备用。先将处方量的辅料充分混匀。将原料药以递增稀释法加到辅料中,每次加时充分混匀2-3次,保证药与辅料充分混匀,过20目筛,在55℃通风烘箱中干燥2h,干颗粒过16目筛整粒,测定中间体含量,混合均匀,在压片机上压片。
实施例22:
注射液的制备:
化合物I-1的盐酸盐 45mg
丙二醇 100mg
聚山梨酯80 适量
蒸馏水 300mL
制备方法:取活性成分加入到已溶解山梨醇和丙二醇的注射用水中,加入药用碱调节pH值至4~8使其溶解。加入活性炭,搅拌吸附30min,除炭、精滤、灌封、灭菌。
实施例23:
注射用冻干粉的制备:
化合物I-5的柠檬酸盐 50mg
药用碱 0.1-7.0%
甘露醇 55-80%
制备方法:取活性成分加入注射用水,用药用碱调节pH值至4~8使其溶解。再加入甘露醇,按注射剂的要求进行高压灭菌,加入活性炭,采用微孔滤膜过滤,滤液进行分装,采用冷冻干燥法,制得疏松块状物,封口,即得。
Claims (7)
2.如权利要求1所述的通式I化合物,代表化合物如下:
I-1 2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-2 2-(2-氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(3-硝氧基丙醇)酯;
I-3 2-苯基-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-4 2-(3-甲基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-5 2-(3-硝基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-6 2-(4-氟苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-7 2-(2,3-二氯苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯;
I-8 2-(3,4,5-三甲氧基苯基)-2-(4,5,6,7-四氢噻吩并[3,2-c]吡啶-5(4H)-基)乙酸(2-硝氧基乙醇)酯。
3.如权利要求1所述化合物,其药学上可接受的盐指:化合物与无机酸、有机酸成盐。
4.如权利要求3中所述的式I化合物药学上可接受的盐,优选:盐酸盐、氢溴酸盐、氢碘酸盐、硫酸盐、硫酸氢盐、磷酸盐、磷酸氢盐、乙酸盐、丙酸盐、丁酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、马来酸盐、苯甲酸盐、琥珀酸盐、酒石酸盐、柠檬酸盐、富马酸盐、牛磺酸盐、葡萄糖酸盐、氨基酸盐。
5.权利要求1中式I化合物的制备方法,其特征在于:
具体可以通过两种方法制备:
①α-溴代取代苯基苯乙酸(1)与卤素取代烷基醇(2)以甲苯为溶剂,以对甲苯磺酸为催化剂,加热回流制得酯类中间体(3)。(3)再与4,5,6,7-四氢噻吩并[3,2-c]吡啶(4)在三乙胺、吡啶、碳酸钾、碳酸钠、碳酸氢钠、碳酸氢钾、氢氧化钠或氢氧化钾等缚酸剂存在下,以二氯甲烷、三氯甲烷、乙腈或甲苯为溶剂,15~100℃反应制得关键中间体(5)。然后将(5)溶于乙腈,室温下滴加硝酸银和乙腈的混合液,搅拌反应可得式I化合物;
②(6)与(2)在DCC和DMAP存在下,以二氯甲烷或三氯甲烷为溶剂,-5~25℃反应制得关键中间体(5)。然后将(5)溶于乙腈,室温下滴加硝酸银和乙腈的混合液,搅拌反应可得式I化合物。
其中X为溴或氯。
6.一种抗高血压的药物组合物,它包含治疗有效量的式I化合物或其盐及一种或多种药用载体、赋形剂或稀释剂。
7.权利要求1~4中式I化合物及其盐在用于制备抗高血压药物方面的应用。
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CN103626722A (zh) * | 2012-08-27 | 2014-03-12 | 天津药物研究院 | 一氧化氮供体型降血糖化合物、其制备方法和用途 |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1998040385A1 (en) * | 1997-03-07 | 1998-09-17 | Novo Nordisk A/S | 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE |
CN1221407A (zh) * | 1996-04-13 | 1999-06-30 | 英国阿斯特拉药品有限公司 | 氨基异喹啉和氨基噻吩并吡啶衍生物及其作为抗炎剂的用途 |
DK200000513A (da) * | 2000-03-27 | 2000-03-30 | Novo Nordisk As | 4,5,6,7-Tetrahydro-thieno 3,2-c pyridine Derivatives |
CN1923797A (zh) * | 1999-08-12 | 2007-03-07 | 尼科克斯公司 | 药用化合物 |
-
2010
- 2010-06-29 CN CN2010102124710A patent/CN101863900B/zh not_active Expired - Fee Related
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1221407A (zh) * | 1996-04-13 | 1999-06-30 | 英国阿斯特拉药品有限公司 | 氨基异喹啉和氨基噻吩并吡啶衍生物及其作为抗炎剂的用途 |
WO1998040385A1 (en) * | 1997-03-07 | 1998-09-17 | Novo Nordisk A/S | 4,5,6,7-TETRAHYDRO-THIENO[3,2-c]PYRIDINE DERIVATIVES, THEIR PREPARATION AND USE |
CN1923797A (zh) * | 1999-08-12 | 2007-03-07 | 尼科克斯公司 | 药用化合物 |
DK200000513A (da) * | 2000-03-27 | 2000-03-30 | Novo Nordisk As | 4,5,6,7-Tetrahydro-thieno 3,2-c pyridine Derivatives |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103626722A (zh) * | 2012-08-27 | 2014-03-12 | 天津药物研究院 | 一氧化氮供体型降血糖化合物、其制备方法和用途 |
CN103626722B (zh) * | 2012-08-27 | 2016-06-01 | 天津药物研究院 | 一氧化氮供体型降血糖化合物、其制备方法和用途 |
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