CN1053895C - 取代磺酰胺,其制备方法以及含有它们的药物组合物 - Google Patents
取代磺酰胺,其制备方法以及含有它们的药物组合物 Download PDFInfo
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- CN1053895C CN1053895C CN95102144A CN95102144A CN1053895C CN 1053895 C CN1053895 C CN 1053895C CN 95102144 A CN95102144 A CN 95102144A CN 95102144 A CN95102144 A CN 95102144A CN 1053895 C CN1053895 C CN 1053895C
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Abstract
式I的取代的磺酰胺及其生理耐受盐,其中:A、R1和D如说明书中所定义,以及其用作药物用途。
Description
本发明涉及新的取代的磺酰胺,其制备方法以及含有它们的药物组合物。
也就是说该化合物中磺酰胺官能团总是与苯环连接,而该苯环本身可以是取代或未取代的。
本发明涉及:
其中:
-R1表示:
a)氢原子,
b)含1-7个碳原子的直链烷基以及可以被一个或多个甲基、苯基、吡啶基或噻吩基取代的含1-7个碳原子的直链烷基,其本身可以任意地或者被一个或多个卤原子取代、或者被羟基取代,
c)含3-7个碳原子的链烯基(例如-CH2-CH=CH2),或者
d)含3-7个碳原子的炔基(例如-CH2-C≡CH);以及
-D表示:
a)含2-6个碳原子的饱和直链烃链,它被一个或多个氧或硫原子间隔,或者被环戊烷环间隔,或者被偕二甲基取代,或者
在本发明最接近的现有技术的EP0330065A中进行了说明,它涉及下式的磺酰胺:
参考文献0330065A没有包括或提示上述式I中所定义的所有式A的双环基,因此该参考文献不能影响本申请的专利性。
本申请还涉及式I化合物的制备方法,其特征在于:将式II的磺酰氯
A-SO2Cl (I)
(其中A如上所定义)
其中R1和D如上所定义。
此外,可以在合适的溶剂(例如N,N-二甲基乙酰胺)中通过其中R1仅仅是氢原子的式I化合物(即式I″化合物)与氢化钠反应:其中A和D如上所定义,然后与式II″的卤化物反应:
A和D如上所定义,并且R′1表示α)含1-7个碳原子的直链烷基以及可以被一个或多个甲基、苯基、吡啶基或噻吩基取代的含1-7个碳原子的直链烷基,其本身可以任意地或者被一个或多个卤原子取代、或者被羟基取代,β)含3-7个碳原子的链烯基(例如-CH2-CH=CH2),或者χ)含3-7个碳原子的炔基(例如-CH2-C≡CH)。
式I化合物可以用生理耐受的酸转化为加成盐,因此该盐也是本发明的一部分。可用于形成那些盐的可提及的酸是例如:无机酸如盐酸、氢溴酸、硝酸、硫酸和磷酸,有机酸如乙酸、丙酸、马来酸、富马酸、酒石酸、草酸、苯甲酸甲磺酸和羟乙磺酸。
所有用作原料的式II磺酰氯已在文献中描述。如下列实施例中所述,式III的原料是按照已知的方法,根据D和R1的含义由已知产物制备的。
本发明的化合物具有有价值的生理性质和治疗性质。尤其是下面所证明的那些化合物的性质:·在体外—一方面;
其抗缺氧活性,该活性在缺氧—再氧合作用的过程中可防止离体大鼠心脏机能障碍,并且限制因缺氧所致的心细胞坏死。—另一方面:
其防止过量细胞内钙的能力:由此可以防止因钙异常所致大鼠心细胞坏死;以及·在体内:
其在猪内因冠状狭窄所致心肌局部缺血中的抗局部缺血活性。
这些活性使得本发明化合物适于用作防止或治疗局部缺血疾病(特别是在心血管领域:心绞痛、心肌梗塞和局部缺血心脏病后遗症(节律疾病、心机能不全))和外周血管疾病的药物。
本发明化合物也可以用于脑领域,特别是用于治疗脑血管意外和与慢性脑循环疾病有关的缺乏现象;用于眼科学领域;尤其是用于治疗因血管造成的视网膜疾病;以及用于局部缺血造成的感觉神经疾病。
剂量是可以变化的,尤其是根据患者的年龄和体重、给药途径、疾病的性质和有关的治疗改变,其范围是1-200mg活性成分,每天1-3次。
本发明还涉及药物组合物,它含有式I.化合物或其生理耐受盐作为活性成分,该活性成分与一种或多种合适的药物赋形剂混合或结合。
所得到的药物组合物通常是含1-200mg活性成分的剂型。它们可以是例如片剂、糖衣丸、明胶胶囊、栓剂或可注射或可饮用的溶液,并且可以根据情况通过口、直肠或肠道途径给药。
下列实施例用于说明本发明。除非另外说明,所有熔点均采用Kofler热板测定。实施例1N-乙基-N-(3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基〕丁基〕-(异喹啉-5-基)磺酰胺:
1)在搅拌下,向0.1mol N-(2,3,4-三甲氧基苄基)-哌嗪和0.1mol三乙胺在250ml苯中的混合物中滴加0.1mol 3-氯-2,2-二甲基丙酰氯。搅拌反应一夜后,将该混合物转入烧瓶中,并用水洗涤。分离下式的所需产物,为油状,产率为54%。
2)将0.053mol所得产物与0.063mol碘化钠在600ml甲乙酮中加热回流24小时。经HPLC监测后,再加入0.063mol碘化钠,然后再回流24小时。使其回复到室温,蒸发,溶于乙醚,并用常规(Normal)硫代硫酸钠洗涤。得到下式的所需产物,为油状,产率为95%。
3)在搅拌下、于100℃,将上述获得的碘化的化合物与两个当量的氰化钠在100ml二甲基甲酰胺中加热6小时。蒸发掉二甲基甲酰胺,将残余物溶于水中,并用乙醚萃取。不需进一步纯化,即可以使用如此得到的腈(产率为54%,为油状)。
4)特上述得到的腈溶于250ml四氢呋喃中,并将所得到的溶液与10当量的甲硼烷-二甲硫反应。将该反应混合物加热回流6小时。用25ml甲醇溶剂分解后,蒸发,并用在80ml甲醇中的40ml浓盐酸水解,将其蒸发,溶于水中,并用乙醚萃取,将水相碱化,并用乙酸乙酯萃取。得到油状的所需胺,产率为90%。
5)在室温,向在65ml二氯甲烷中的0.017mol上述得到的胺和0.034mol三乙胺中分批加入0.017mol(异喹啉-5-基)磺酰氯;盐酸盐。将反应物搅拌过夜,然后转入烧瓶中,用于100ml常规氢氧化钠溶液洗涤,将有机相干燥。然后在二氧化硅柱上干CH2Cl2/CH3OH(95∶5)体系中进行色谱,收集6.3克所需产物,为油状。
6)将上一步骤中制备的2.8g(0.005mol)磺酰胺溶于30ml二甲基乙酰胺中,并与化学计量量的60%氢化钠反应。当气体停止发生时,加入0.005mol碘乙烷,并将反应混合物搅拌过夜。用水充分稀释该混合物,用乙醚萃取,干燥并蒸发,得到油状的实施例1的标题产物,产率为64%。N-乙基-N-(3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基〕丁基〕-(异喹啉-5-基)磺酰胺二富马酸盐的熔点为143-146℃。实施例2-5
按照与实施例1所述方法类似的方法制备下列实施例的目的化合物:2)N-苄基-N-{3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基〕丁基}-(异喹啉-5-基)磺酰胺,相应的2,5-富马酸盐的熔点是174-176℃。3)(1R)-N-乙基-N-(3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基〕丁基}-10-莰佛磺酰胺,相应的二盐酸盐的熔点是243-245℃。4)(1S)-N-乙基-N-{3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基〕丁基}-10-莰佛磺酰胺,相应的二盐酸盐的熔点是243-245℃。5)(1R)-N-苄基-N-(3,3-二甲基-4-〔4-(2.,3,4-三甲氧基苄基)-哌嗪-1-基〕丁基}-10-莰佛磺酰胺,相应的二盐酸盐的熔点是188-191℃。实施例6N-苄基-N-{〔4-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基〕苯基〕甲基}-(异喹啉-5-基)磺酰胺
1)在100℃和搅拌下,将0.2mol氟苄腈、0.2mol碳酸钾和0.2mol N-(2,3,4-三甲氧基苄基)哌嗪加热8小时。然后用水稀释,并用乙醚萃取,用常规盐酸萃取有机相,合并水相,并在冷却条件下用浓氢氧化钠溶液使其碱化,用乙醚萃取。得到状的所需腈,产率为40%。
2)用在150ml四氢呋喃中的1当量氢化铝锂还原所得到的腈。分解后,用CH2Cl2/CH3OH/NH4OH(95∶5∶0.5)作洗脱剂,将所得到的油进行闪式色谱。得到油状的所需胺,产率为37%。
3)按照实施例1第5)段所述方法将上述得到的胺与(异喹啉-5-基)磺酰氯偶合。按照实施例1第6)段所述方法,用苄基溴代替碘乙烷进行烷基化作用。由此得到实施例6的实物,其盐酸盐的熔点为152-155℃。实施例7顺-N-乙基-N-{2-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基甲基〕环丙基甲基}-(异喹啉-5-基)磺酰胺
将0.5mol丙烯腈和0.5mol氯乙酸甲酯的混合物倒入50ml甲苯和0.5mol氢化钠的悬浮液中。将该反应混合物搅拌一夜,然后用含16ml甲醇的150ml乙醚极缓慢地使其分解。将其转入烧瓶中,用乙醚稀释,用饱和氯化钠溶液洗涤,干燥并蒸发。
将11.7g(0.093mol)上述得到的2-氰基环丙-1-基甲酸甲酯与100ml当量氢氧化钠溶液和50ml乙醇搅拌过夜使其水解。蒸发掉乙醇,加入100ml当量盐酸,将其蒸发干燥至恒重。
将沉淀溶于100ml乙腈,滤掉氯化钠,并蒸发。得到顺/反2-氰基环丙-1-基甲酸混合物,熔点为80-90℃(产率为81%)。
将12.2g(0.075mol)羰基二咪唑一次加入8.4g(0.075mol)2-氰基环丙-1-基甲酸和50ml CH2Cl2的悬浮液中,在气体停止发生后搅拌2小时。滴加在100ml CH2Cl2中的20g(0.075mol)4-(2,3,4-三甲氧基苄基)哌嗪,并将其撑拌一夜。将其全部倒入烧瓶中,用水洗涤,干燥并蒸发。经闪式色谱得到8.3g(35%)反式异构体(油状)和11.1g(47%)顺式异构体,熔点为108-110℃。
4)制备顺-2-{〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕甲基}环丙-1-基甲基胺:
·在搅拌下将22.7g(0.3mol)甲硼烷-二甲硫滴加至8.3g上面得到的顺式腈在315ml四氢呋喃中的溶液中。将其加热回流6小时,恢复到室温,用20ml甲醇缓慢地分解,并保持回流,直到气体停止发生。然后将其蒸发,并溶于50ml甲醇10ml浓盐酸中,加热回流,直到气体停止发生。
蒸发掉乙醇,在冷却条件下将水相碱化,用乙醚萃取,干燥并蒸发。产量为2.3g(29%)。
向2.3g(0.008mol)顺-{{2-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕甲基}环丙-1-基}甲基胺和0.8g三乙胺在25mlCH2Cl2中的溶液中分批加入1.1g(0.004mol)(异喹啉-5-基)磺酰氯。将反应物放置一夜,然后转入烧瓶中,用当量氢氧化钠溶液洗涤,然后用水洗涤,并蒸发。用CH2Cl2/CH3OH(95∶5)作洗脱剂进行闪式色谱,得到1.2g所需产物,产率为57%。
6)制备实施例7的标题化合物:
用0.1g 60%氢化钠处理在15ml二甲基乙酰胺中的1.2g(0.0024mol)上面5)得到的磺酰胺。然后加入0.4g碘乙烷,将该混合物在室温搅拌一夜。将其用水稀释,并用乙醚萃取。用CH2Cl2/CH3OH(95∶5)作洗脱剂进行闪式色谱,得到1g所需物质(产率为80%)。将其溶于5ml乙酸乙酯,并向其中加入在乙醚中的3当量盐酸,形成盐。将其过滤、干燥,并在5ml甲基氰中结晶该产物,得到顺-N-乙基-N-{2-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基甲基〕环丙基甲基}-(异喹啉-5-基)磺酰胺三盐酸盐,熔点为175℃。实施例8
按照与实施例7所述类似的方法,制备反-N-乙基-N-{2-〔4-2,3,4-三甲氧基苄基)-哌嗪-1-基甲基〕环丙基甲基}-(异喹啉-5-基)磺酰胺,不同的是从第4)段开始,用相应的反式化合物代替顺式化合物。实施例8标题产物的三盐酸盐在162-165℃熔融:实施例9
如实施例7所述方法制备顺-N-苄基-N-{2-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基甲基〕环丙基甲基}-(异喹啉-5-基)磺酰胺,不同的是在第6)段用苄基溴代替碘乙烷。
由此得到顺-N-苄基-N-{2-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基甲基〕环丙基甲基}-(异喹啉-5-基)磺酰胺三盐酸盐,其熔点为202-204℃:实施例10N-(吡啶-3-基甲基)-N-〔3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕丁基〕-(异喹啉-5-基)磺酰胺:1)制备下式的胺:
将7.3g(0.02mol)实施例1第4)段所得到的胺与2.14g(0.02mol)3-吡啶甲醛(pyridinecarbonaldehyde)在80ml乙醇中加热回流。待该混合物恢复到室温后,分批加入0.8g硼氢化钠。气体发生停止后,将反应物放置4小时,然后用水稀释,用乙醚萃取。干燥并蒸发后,得到6.5g油状所需产物,该产物不需进一步纯化即可使用。
2)制备实施例10的标题混合物:
按照实施例1第5)段所述方法,将上面得到的胺与(异喹啉-5-基)磺酰氯盐酸盐缩合,得到实施例10的标题化合物,其四盐酸盐在高于260℃熔融。实施例11-14
按照实施例10所述方法制备下列实施例的目的产物:
11)用2-吡啶甲醛代替实施例10第1)段的3-吡啶甲醛,制备N-(吡啶-2-基甲基)-N-(3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕丁基〕-(异喹啉-5-基)磺酰胺。所得到的游离碱在110-113℃熔融。
12)用4-吡啶甲醛代替实施例10第1)段的3-吡啶甲醛,制备N-(吡啶-4-基甲基)-N-{3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕丁基}-(异喹啉-5-基)磺酰胺。标题产物的四甲磺酸盐在143-146℃熔融。
13)用2-噻吩甲醛(thiophenecarbonaldehyde)代替实施例10第1)段的3-吡啶甲醛,制备N-(噻吩-2-基甲基)-N-{3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕丁基}-(异喹啉-5-基)磺酰胺。标题产物的三盐酸盐在188-190℃熔融。
14)用3-噻吩甲醛代替实施例10第1)段的3-吡啶甲醛,制备N-(噻吩-3-基甲基)-N-{3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕丁基}-(异喹啉-5-基)磺酰胺。标题产物的三盐酸盐在158-160℃熔融。实施例15N-乙基-N-{{4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕甲基}苄基}-(异喹啉-5-基)磺酰胺:
向25g(0.17mol)对氰基苯甲酸在250ml二氯甲烷中的悬浮液中加入27.6g(0.17mol)羰基二咪唑。当气体停止发生后,使反应物再反应2小时。然后将其快速滴加到至溶于100ml二氯甲烷中的45.3g(0.17mol)1-(2,3,4-三甲氧基苄基)哌嗪溶液中。将反应混合物在室温放置过夜后,用水洗涤,然后用氢氧化钠洗涤,然后再用水洗涤。用硫酸镁干燥并蒸发,得到65.8g油状所需产物。
用大约15分钟,向溶于280ml四氢呋喃中的10g(0.0278mol)前一步骤得到的产物中滴加21ml甲硼烷-二甲硫。将其回流一夜,使其冷却,然后用含有几滴硫酸的43.7ml甲醇溶剂分解。回流4小时后,将其蒸发至干,溶于二氯甲烷中,用水洗涤,并用硫酸镁干燥。蒸发得到5g油状所需产物。
按照实施例1第5)段所述方法,将上面得到的胺〔15g(0.014mol)〕与(异喹啉-5-基)磺酰氯盐酸盐缩合,用CH2Cl2/CH3OH)95∶5)作洗脱剂、在二氧化硅上经闪式色谱纯化,得到2.4g纯化合物。
(4)按照实施例1,段6)中描述的操作方法处理上面得到的2.48(0.004mol)化合物。在硅胶上用CH2Cl2/CH2OH(95∶5)作洗脱剂通过闪式色谱纯化后,得到2.1g游离碱,将其用3.5ml 3.5N盐酸乙醚溶液处理,得到该标题化合物的三盐酸盐,熔点为220-222℃。实施例16药理学研究
证明本发明产物的心保护活性;在体外·一方面对受缺氧—再氧合循环作用的离体大鼠心脏以及对缺氧坏死所影响的大鼠心细胞的活性,·另一方面对过量细胞内钙模型:因钙异常所致心细胞坏死的活性,以及在体内:
其在猪内因冠状狭窄所致心肌局部缺血中的活性。A一体外研究1—材料与方法1.1.—离体大鼠心脏的缺氧—再氧和作用
在静脉注射肝素(1ml/kg)后,将通过腹膜内用戊巴比妥钠(30mg/kg,腹膜内注射)麻醉的雄性Wistar大鼠(325-375g,Charles River品种)的心脏取出,在76mmHg恒压下按照Lan-gendorff的技术快速灌注,并用铂电极以5Hz进行电刺激。通过与压力敏感器(P23-Gould)连接并插入左心室的聚乙烯气囊记录等容量收缩,同此得到10mmHg的舒张压。
所使用的生理溶液保持在37℃,其组成如下(mM):NaCl,118;KCl,4.7;KH2PO4,1.2;MgCl2,1.2;CaCl2,1.3;NaHCO3,25;葡萄糖,8;pH7.4;95% O2+5% CO2。
稳定20-30分钟后,使心脏缺氧60分钟(用95% N2+5%CO2进行,PO2<60mmhg),然后使其再氧合30分钟;在事先将用。于试验的化合物保温15分钟,用于缺氧过程中。对于离体试验,该化合物在动物被处死前3小时经口服(1ml/kg)给药。1.2.—对大鼠心细胞的研究
从新生大鼠的心脏得到心肌细胞一级培养物。在放入培养基中后第4-6天使用该心细胞。1.2.1.缺氧所致大鼠心细胞坏死
在37℃和压力室中,在氮气氛下,将缺氧细胞培养3或4小时。仅仅在基缺氧时用于试验分子处理该细胞。通过分光光度法测量培养3或4小时后的上清液中释出乳酸脱氢酶的细胞百分数,估测缺氧所致的细胞坏死。1.2.2.因钙异常所致心细胞坏死
首先在补充有1mM EDTA的无钙或镁的缓冲液中将所有心细胞培养30分钟。除去上清液后,将细胞在3.8mM钙离子缓冲液中培养4小时。将该细胞用试验分子处理两次:此时加至EDTA缓冲液中,然后转入3.8mM Ca2+缓冲液中。2—结果2.1.对受缺氧—再氧合作用的离体大鼠心脏的影响
表1示出了本发明化合物,所用浓度(10-6M,3×10-7M或5×10-7M),缺氧60分钟后发生收缩从20%减少到63%,再氧合30分钟后发生收缩从35%减少到95%。它们还改善了再氧合过程中心功能的恢复:所处理心脏的室压实际上达到了其缺氧前初始值的48%-89.7%,而对照心脏的室压限制在其初始值的22.5%-33.5%。
表2表明,与对照动物的心脏比较,接受口服实施例2化合物治疗的大鼠心脏受到了保护,防止了因离体进行的缺氧—再氧合所致的改变:
1.与对照动物的心脏相比,缺氧60分钟后和再氧合30分钟后所发生的收缩分别减少了50%和37%;
2.比对照动物(其初始值33.5%)更早恢复心脏室压(其初始值的33.5%)。
表1:本发明化合物对受缺氧—再氧合作的离体大鼠心脏的收缩及
功能恢复的影响
表2:给大鼠口服实施例2化合物对复到离体缺氧—再氧合作用的离体心脏的收缩及功能恢复的影响
2.2.—对心细胞的研究2.2.1.—对缺氧所致大鼠心细胞坏死的影响
化合物 | 浓度(M) | n | 收缩(mmHg) | 左心室压缺氧前初始值的% | |
缺氧60分钟 | 再氧合30分钟 | 再氧合30分钟 | |||
对照 | 7 | 48.0±7.1 | 29.3±8.0 | 33.5±8.2 | |
实施例1 | 10-6 | 8 | 32.3±1.6 | 7.8±3.4 | 72.4±9.4 |
对照 | 12 | 50.2±4.6 | 27.7±4.6 | 22.5±6.2 | |
实施例10 | 5×10-7 | 3 | 18.7±5.8 | 1.3±1.3 | 89.7±11.8 |
实施例15 | 3×10-7 | 5 | 40.0±6.2 | 18.0±7.2 | 48.1±4.9 |
化合物 | n | 收缩(mmHg) | 左心室压缺氧前初始值的% | |
缺氧60分钟 | 再氧合30分钟 | 再氧合30分钟 | ||
对照 | 5 | 47.6±2.4 | 19.2±4.8 | 33.5±8.2 |
实施例210mg/kg口服 | 7 | 23.7±6.1 | 12.0±6.6 | 56.6±7.6 |
表3表明,本发明化合物从10-6M开始以浓度依赖的方式减少缺氧坏死。根据具体的化合物,最大的保护为49.4-76.4%。
表3
因缺氧所致大鼠心细胞坏死
浓度(M)化合物 | 0 | 10-6 | 10-5 | 10-4 |
实施例2 | 100 | 56.8 | 23.6 | 47.1 |
实施例10 | 100 | 83.2 | 91.6 | 46.5 |
实施例15 | 100 | 75.7 | 67.7 | 50.6 |
结果以百分数表示,它仅与缺氧所致细胞坏死有关(坏死指数为100)。2.2.2—对因钙异常所致大鼠心细胞坏死的影响
表4表明,该化合物限制因钙异常所致坏死。在10-6M或10-5M浓度的最大保护达到70-93%。
表4:因钙异常所致大鼠心细胞坏死
浓度(M)化合物 | 0 | 10-7 | 10-6 | 10-5 |
实施例2 | 100 | 70.8 | 30.1 | 35.3 |
实施例15 | 100 | 103.7 | 15.7 | 6.8 |
结果以百分数表示,它仅与钙异常所致细胞坏死有关(坏死指数为100)。B—体内研究1—材料与方法
该研究在3个月的重18-23公斤的雌性和雄性“LargeWhite”猪上进行。
用Zoletil(15mg/kg,肌内注射(麻醉动物。通过灌注6-8mg/kg/小时硫喷妥钠保持麻醉。
立即插管,并用空气+O2的混合物换气。
通过纵向切开胸骨以及在第4和第5根肋骨之间切口,施行“T”胸廓切开术。
切开心包使心脏悬于心包支架上,并将心脏固定在胸肌的四个点上。
将电磁流环置于左冠状室间支脉前的水平,并将可充气的气囊立即置于该环的下游,此二者设计为通过流量控制影响冠状狭窄。将与Triton微弦音计(sonomicrometer)连接的压电晶体,依垂直于心轴的环状面植入左心室壁的心内膜下。那些晶体用于记录由狭窄的冠状动脉所供应的区域中心内ECGs值。2—实验方案
通过给气囊充气,使冠状流量减少50-60%,造成心肌缺血。
施行具有可再生和可逆作用的两个同样的3分钟狭窄,通过间隔55分钟的恢复分离。
在狭窄前10分钟通过5分钟静脉输注进行治疗:·在第一次狭窄前输注溶剂·在第二次狭窄前输注产物或溶剂。3—研究的参数·局部缺血区域心内ECGs值的变化在于所测量的ST部分的增加,以毫伏(mV)计。4—结果
在对照组进行的两个冠状狭窄造成了同样的心电图变化。与第一次冠状狭窄的影响相比,在第二次冠状狭窄前通过静脉内施用1或3mg/kg本发明化合物,使得心内心电图的ST部分的增加减少了48-66%。
化合物 | 心内ST增加(mV) | |
狭窄1 | 狭窄2 | |
对照 | 1.9 | 1.9 |
实施例2 1mg/kg | 1.5 | 0.6 |
对照 | 2.8 | 2.9 |
实施例10 3mg/kg | 2.5 | 1.3 |
实施例15 3mg/kg | 1.5 | 0.5 |
Claims (8)
2.根据权利要求1的化合物,该化合物是N-苄基-N-{3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)-哌嗪-1-基〕丁基}-(异喹啉-5-基)磺酰胺或其富马酸盐。
3.权利要求1的化合物,该化合物是N-(吡啶-3-基甲基)-N-{3,3-二甲基-4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕丁基}-(异喹啉-5-基)磺酰胺或其四盐酸盐。
4.权利要求1的化合物,该化合物是N-乙基-N-{{4-〔4-(2,3,4-三甲氧基苄基)哌嗪-1-基〕甲基}苄基}-(异喹啉-5-基)磺酰胺或其三盐酸盐。
7.权利要求1-4中任一项的化合物用于制备治疗心肌局部缺血疾病,脑血管意外和与慢性脑循环疾病有关的缺乏现象的药物的用途。
8.适用于治疗心肌局部缺血疾病、脑血管意外和与慢性脑循环疾病有关的缺乏现象的药物组合物,它含有至少一种权利要求1-4中任一项的化合物作为活性成分与一种或多种合适的药用赋形剂结合。
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- 1995-02-23 EP EP95400384A patent/EP0669322B1/fr not_active Expired - Lifetime
- 1995-02-23 US US08/393,452 patent/US5565457A/en not_active Expired - Fee Related
- 1995-02-23 CA CA002143249A patent/CA2143249C/fr not_active Expired - Fee Related
- 1995-02-23 AT AT95400384T patent/ATE184597T1/de not_active IP Right Cessation
- 1995-02-23 AU AU13449/95A patent/AU682428B2/en not_active Ceased
- 1995-02-23 DK DK95400384T patent/DK0669322T3/da active
- 1995-02-23 DE DE69512104T patent/DE69512104T2/de not_active Expired - Fee Related
- 1995-02-24 JP JP7036490A patent/JPH07258217A/ja active Pending
- 1995-02-24 NZ NZ270567A patent/NZ270567A/en unknown
- 1995-02-24 ZA ZA951577A patent/ZA951577B/xx unknown
- 1995-02-24 CN CN95102144A patent/CN1053895C/zh not_active Expired - Fee Related
- 1995-02-24 NO NO950716A patent/NO302571B1/no unknown
-
1999
- 1999-09-20 GR GR990402350T patent/GR3031256T3/el unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0330065A1 (en) * | 1988-02-18 | 1989-08-30 | Kowa Company, Ltd. | Sulfonamide compounds |
WO1992014712A1 (fr) * | 1991-02-13 | 1992-09-03 | Asahi Kasei Kogyo Kabushiki Kaisha | Derive de sulfonamide substitue ou composition pharmaceutique contenant ce derive |
Also Published As
Publication number | Publication date |
---|---|
EP0669322A1 (fr) | 1995-08-30 |
FI110364B (fi) | 2002-12-31 |
NO950716L (no) | 1995-08-28 |
ES2139156T3 (es) | 2000-02-01 |
FR2716679A1 (fr) | 1995-09-01 |
GR3031256T3 (en) | 1999-12-31 |
ZA951577B (en) | 1995-12-12 |
NO302571B1 (no) | 1998-03-23 |
DK0669322T3 (da) | 2000-03-27 |
FI950818A0 (fi) | 1995-02-22 |
EP0669322B1 (fr) | 1999-09-15 |
NZ270567A (en) | 1996-05-28 |
FI950818A (fi) | 1995-08-26 |
AU682428B2 (en) | 1997-10-02 |
AU1344995A (en) | 1995-09-07 |
US5565457A (en) | 1996-10-15 |
JPH07258217A (ja) | 1995-10-09 |
NO950716D0 (no) | 1995-02-24 |
FR2716679B1 (fr) | 1996-04-05 |
DE69512104D1 (de) | 1999-10-21 |
DE69512104T2 (de) | 2000-04-20 |
CN1120537A (zh) | 1996-04-17 |
CA2143249C (fr) | 2002-02-26 |
CA2143249A1 (fr) | 1995-08-26 |
ATE184597T1 (de) | 1999-10-15 |
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