CN86102285A - 新的二胺衍生物的制备方法 - Google Patents
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Abstract
本文中公开了具有如下通式的化合物或其盐及其制备方法:(式中R1和R2各为具有1到3个碳原子的烷基,它们可以相同或不相同;R3是氢原子或具有1到3个碳原子的烷基;R4和R5各为氢原子或具有1到8个碳原子的烷基,它们可以相同或不相同;m和n各为1到7中的整数,它们可以相同或不相同;但R4和R5不同时是氢原子)。
该化合物具有所希望的强治疗心律不齐效果,不希望的副作用极小,故可用于治疗心律不齐。
Description
本项发明是关于用在治疗心律不齐方面的新的二胺衍生物。
本发明所要求保护的各化合物是新的并从未在文献中报道过。
目前临床上应用的抗心律不齐药包括:利多卡因、达舒平以及普鲁卡因酰胺。在临床应用上,利多卡因适用于静脉内或肌内给药。《英国医学杂志》,1970年第二期第29-30页及“莫克索引”,1983年第10版,第5304页)而不适于口服,这是因为血液中的药物浓度太低,以致于不能达到所要求的效果。达舒平由于口服时显出长效性而很适用于临床,但它却产生种种所不希望的副作用。〔见“chiryogaku(Therapeutics)”1983年第11卷,第4号512页;及“莫克索引”1983年第十版3378页〕。由达舒平所产生的副作用有:口渴(hydrodipgia)、尿闭、便秘、眩晕、视力模糊和呕吐,凡此种种均可能是由于达舒平的抗胆碱能作用所引起的。发现由于患糖尿病而引起前列腺肥大与神经性膀胱的患者的尿闭发生率很高。达舒平还有心肌抑制作用,故对于患有心力衰竭或可能有潜在性心力衰竭的患者一定要谨慎用药。
已知普鲁卡因酰胺具有如下缺点:它显示抗胆碱能及导致心肌无力,并能引起低血压(Medicina,Vol.20,No.7,p.1115,1983;和Gekkan Yakuji,V.ol.26,No.5,p.155,1984)。
本发明者们共同致力于开发一种副作用最小而抗心律不齐作用强的药物。结果发现,本发明所要求保护的化合物没有上述现存的诸种抗心律不齐药物的一切缺点。
本发明的式(Ⅰ)化合物可通过在有一种碱存在下,在惰性溶剂中由式(Ⅱ)的N-氯烷酰基苯胺衍生物与式(Ⅲ)的二胺衍生物起反应来制备。反应式可表示如下:
(式中R1与R2可以相同或不同,它们各为具有1-3个碳原子的烷基;R3是氢原子或具有1-3个碳原子的烷基;R4及R5可以相同或不同,它们各为氢原子、具有3-8个碳原子的烷基或具有1-8个碳原子的环烷基;m与n亦可相同或不同,它们各为1-7中的整数;但上式中R4及R5不能同时是氢原子)。
尽管用于N-氯烷酰苯胺(Ⅱ)和二胺(Ⅱ)之间的反应的溶剂可包括象二氯甲烷、氯仿、乙酸乙酯等溶剂-这些溶剂通常可用于和上述反应相似的反应,但不是以苯、甲苯和二甲苯为好。
该反应最好是在回流温度下,在含有三乙胺的甲苯中进行。
更具体地说,式(Ⅰ)中的R1与R2可以是甲基或乙基,以甲基为好;R3可以是氢原子或甲基,以氢原子为好;R4及R5可以是氢原子、甲基、乙基、异丙基、正丁基、异丁基、叔丁基、正己基或环辛基,以甲基、乙基、异丙基、异丁基较佳;m可以是2到5中的一个整数,以2或3较好;n可以是2到7中的一个整数,以2或3较好。
本发明中的化合物可以通过常用的方法转变为相应的盐类。
为说明本项发明,提供下列参考例及实施例,但决不能认为这些例子是对本发明的限制。
参考例
3-氯-2′,6′-二甲基丙酰苯胺的合成:
将(60.5克)2,6-二甲基苯胺与(45克)碳酸钾的混合物溶解于(1200毫升)乙酸乙酯与水(3∶1)的混合液中。往冰冷却的混合物中在搅拌下滴入100毫升含有(52.5毫升)氯丙酰氯的乙酸乙酯溶液。在室温下将此反应混合物搅拌3小时,随后分离出水层。有机层用饱和碳酸氢钠水溶液与饱和氯化钠水溶液洗涤,然后用芒销干燥。真空下蒸馏除去溶剂后,得到无色粉末。用乙醇重结晶,得到96.5克无色针状体(产率:90.8%)。熔点131℃。
NMR(CDCl3)δ:2.10(3Hx2,s,PhCH3),2.68(2H,t,J=7.0HzC-2H),3.74(2H,t,J=7.OHz,C-3H),6.92(3H,s,PhH),7.40(1H,宽峰s,NH)
实施例1
3-(二异丙氨乙氨基)-2′,6′-二甲基丙酰苯胺(1号化合物)的合成:
将100毫升含有(6.1克)N,N-二异丙基乙二胺、(3.6克)3-氯-2′,6′-二甲基丙酰苯胺和(2.0毫升)三乙胺的混合物的甲苯溶液回流加热6小时。冷却后,在真空下蒸馏除去反应溶剂。于残余物中加入200毫升氯仿,混合物用饱和碳酸氢钠水溶液和饱和氯化钠水溶液洗。用芒销盐类干燥后,在真空下蒸馏除去溶剂,得到淡黄色粉末。用正己烷重结晶,得3.0克无色针状体(产率:66.9%)。熔点:78.8℃。
元素分析:
按C19H33N3O计算(%):C71.43,H 10.41,N 13.15。
实测(%)C71.25,H 10.44,N 13.17。
NMR(CDCl3)δ:0.94(3Hx4,d,J=6.0Hz,CHCH3),2.18(3Hx2,s,PhCH3),2.40-2.70(2Hx3,m,NCH2),2.75-3.20(1Hx2,m,
),2.96(2H,t,J=6.Hz,COCH2),6.96(3H,s,PhH),10.00(1H,宽峰s,NH)
将得到游离碱的乙醇溶液用HCl饱和的乙醚处理,得到一无色针状体(有吸湿性的,双盐酸盐),熔点198.3℃。
同样游离碱的乙醇溶液用磷酸处理,得无色针状体(双磷酸盐),熔点212.0℃。
元素分析:
按C19H33N3O·2H3PO4计算(%):
C 44.27,H 7.63,N 8.15
实测(%):C 44.47,H 7.68,N 8.24。
实施例2:
3-(二甲氨丙氨基)-2′,6′-二甲基丙酰苯胺(2号化合物)的合成:
将60毫升含有(3.74毫升)N,N-二甲基-1,3-丙二胺、(2.12克)3-氯-2′,6′-二甲基丙酰苯胺与(2.0毫升)三乙胺的混合物的甲苯溶液按实施例1所述方法进行处理,得到重2.29克的无色油状物(产率:82.7%)。
NMR(CDCl3)δ:2.12,2.16(各为3Hx2,s,PhCH3,NCH3),2.96(2H,t,J=5Hz,COCH2),6.95(3H,s,PhH),9.66(1H,宽峰s,NH)。
此化合物的盐酸盐是无色针状体(具有吸湿性),其熔点为201.3℃。同一化合物的磷酸盐是一种熔点为219.8℃的无色针状物。
元素分析:
按C16H27N3O·2H3PO4计算(%):
C 40.60,H 7.03,N 8.88。
实测(%):C 40.48,H 7.03,N 8.93。
实施例3
3-(二乙氨丙氨基)-2′,6′-二甲基丙酰苯胺(3号化合物)的合成:
将60毫升含有(4.73毫升)N,N-二乙基-1,3-丙二胺、(2.12克)3-氯-2′,6′-二甲基丙酰苯胺及(2.0毫升)三乙胺的混合物的甲苯溶液按实施例1所述方法处理,得到2.2克无色油状物(产率:72.1%)。
NMR(CDCl3)δ:2.18(3Hx2,s,PhCH3),2.30-3.10(2Hx5,m,NCH2),2.96(2H,t,J=5Hz,COCH2),6.97(3H,s,PhH),9.80(1H,宽峰s,NH)
此化合物的盐酸盐为一种无色粉末(收湿的),熔点为81.3℃。同样化合物的磷酸盐是熔点为187.2℃的无色针状物。
元素分析:
按C18H31N3O·2H3PO4·4/3H2O计算(%):
C 41.11,H 7.61,N 7.97。
实测(%):C 40.95,H 7.48,N 8.47。
实施例4
3-(异丙氨乙氨基)-2′,6′-二甲基丙酰苯胺(4号化合物)的合成:
将300毫升溶有(20.0克)N-异丙基-1,2-乙二胺、(13.9克)3-氯-2′,6′-二甲基丙酰苯胺以及(10毫升)三乙胺的混合物的甲苯溶液按实施例1所示方法处理,得到淡黄色粉末。用正己烷重结晶后,得到11.5克无色针状体(产率:63.2%)。熔点:69.5℃。
元素分析:
按C16H27N3O计算(%):C 69.28,H 9.81,N 15.15
实测(%):C 69.46,H 9.81,N 15.07
该化合物的磷酸盐为熔点135.8℃的无色针状物。
元素分析:
按C16H27N3O·2H3PO4·H2O计算(%):
C 39.11,H 7.18,N 8.55
实测(%):C 39.61,H 6.90,N 8.71
表1所示的5至51号化合物可通过重复实施例1所述的方法制备。
本发明的化合物显示显著的抗心律不齐作用,其副作用较小。
下述是一些实验结果,进行这些实验是为了说明这些化合物的优点,除另有说明者外,这些化合物均采用其相应盐的形式。
实验1
抗由氯仿诱导的大鼠心律不齐的活性:
下述方法实际上是按Erker与Baker的方法进行的(见Arch.Int.Pharmacodyn.,1980年,243期,97-102页)。按20毫克/公斤的剂量给两组平均体重为100克的Sprague-Dowley雄性大鼠(每组7只,3-4周龄)肌内注射氨基非林,一组已禁食24小时,另一组则未经禁食。注射30分钟后,将这些大鼠放入一个4000毫升的玻璃烧杯中,其盖有用200毫升氯仿浸渍的纱布。50分钟后,将大鼠从杯中复原,切开它们的胸部,检查它们心脏心室的纤维性颤动的存在。用心电图检查它们心律的特征。若观察不到显著纤维性颤动,则用镊子触动心脏。当胸部切开或机械刺激后,在各心室表面出现迅速而无规律的收缩并持续至少5秒钟时,心脏可判断为纤维性颤动。
用氯仿处理30分钟前,将悬浮于3%阿拉伯胶中的选定的化合物按不同剂量给大鼠口服(P.O)或腹膜内给药(i.P.)。对每只大鼠测定心室纤维性颤动的预防百分率。对于对照组的大鼠,则只给予3%的阿拉伯胶。实验结果如表2所示:
表2
实验2
抗乌头碱所致大鼠心律不齐的作用:
用平均体重约350克的Sprague-Dowlex雄性大鼠(9-10周龄,每组二只)基本按照Vargftig等人的方法(见Europ.J.Pharmacol.,1969年第六期,第49页)进行了下述实验。
按1克/公斤的剂量对大鼠腹膜内给予尿烷将其麻酬。将一根聚乙烯导管插入每只大鼠的股动脉和股静脉;通过股静脉给药,同时测量股动脉的血压。
将乌头碱溶液按1微克/公斤/分钟的速率不断注入到静脉中,同时,每隔5分钟从静脉内给予选定之化合物。为防止乌头碱引起的呼吸困难干扰实验结果,对每只大鼠静脉内给予0.2毫克/公斤的d-筒箭毒碱,然后通过一根插入到气管中的导管对其进行人工呼吸(每分钟呼吸80次,通过单独的换气装置供给4毫升空气)。
在第二诱导期内通过做心电图辨别心律不齐;极度向下偏移的QRS波群的出现可用做判断心室心律不齐的标志,继续观察直至心室纤维性颤动出现。实验结果是用室性期外收缩和心室纤维性颤动出现所需之时间表示的,如表3所示:
表3
实验3
抗豚鼠的乌巴因所致心律不齐的作用:
按1.2克/公斤的剂量,将尿烷腹膜内给予平均体重为350克的Hartly雄性豚鼠(5-6周龄,每组2只)而使其麻醉。将聚乙烯插管同时插入其颈静脉和颈动脉;通过颈静脉给药,同时测量颈动脉的血压。在按“J.Pharmacol.Exp.Ther”,1962年第136期第227页上所述方法持续地静脉内注射乌巴因溶液前5分钟给予选定的实验用化合物。
在第二诱导期通过做心电图辨别心律不齐;向下极度偏移QRS波群用做判断心室心律不齐的标志,继续观察直至心室纤维性颤动出现和心跳停止为止。实验结果是用室性期外收缩、心室纤维性颤动以及心跳停止三者出现所需时间表示的,如表4所示:
表4
实验4
抗乙酰胆碱的作用(Ⅰ):
将SD/Slc雄性大鼠(10月龄,每组4只)用棍棒打死,并立即提取其回肠。将该回肠以一克之量悬浮于在27℃用95%氧气和5%二氧化碳的混合物氧化的克-汉二氏溶液中,并用等渗法检测回肠反应。
实验用的每种化合物的抗胆碱能活性是用对10-6M的乙酰胆碱(引起最大乙酰胆碱收缩反应的60-70%)的收缩反应之抑制百分比表示的。实验结果如表5所示:
表5
实验5
抗乙酰胆碱作用(Ⅱ):
将戊巴比妥(35毫克/公斤)以静脉内给药方式将小猎
犬麻醉。按照Sato等人的方法进行了下述试验(“Tohoku J.Exp.Med.,1982年,108期,377-388页)。切开每条狗的左下颌骨以辨别出下颌下腺、自该腺分泌出唾液的分泌管以及为该腺提供养份的动脉。先将一根聚乙烯导管插入分泌管。再将一根管子插入控制动脉的下颌下腺,该腺即被灌入来自股动脉的动脉血。将插入唾液分泌管的导管与一个滴数计数器相连,记录所分泌的唾液。唾液的分泌是由于动脉内给予乙酰胆碱而引起的。
在给予乙酰胆碱前一分钟,将100微克(0.1毫升)选定的一种化合物动脉内给药并检查其抑制唾液分泌的功能。本实验结果如表6所示:
表6
实验6
对环己烯巴比妥钠所致睡眠时间的影响:
按每公斤50或100毫克的剂量给ddy/Slc雄性大鼠(5-6周龄,每组10只)口服本发明的某种选定化合物。一小时后,对每只大鼠腹膜内给予2.5毫克/公斤的环己烯巴比妥,使之失去正交反射机能。测量每只大鼠恢复正交反射机能所需的时间。
作为对照药物,口服给予50或100毫克/公斤的达舒平和5毫克/公斤的安定。结果如表7所示:
表7
**p<0.05(与未经处理组睡眠时间有显著差异)
实验7
对血糖含量的影响:
将SD/Slc雄性大鼠(体重250克,每组6只)断食一夜后,在未麻醉下从每只大鼠的尾静脉中抽取20微升血样。记录每份血样的糖含量。选定一种本发明中的化合物,将其悬浮在3%阿拉伯胶中并将该悬浮液按每公斤50或200毫克的剂量给每只大鼠口服。分别在服药药后2小时、4小时和6小时抽取血样并测量血糖含量。采用“新血糖试验法”(Boehringer,Mannheim)来测定血糖含量。
给对照组服用3%的阿拉伯胶溶液,并将达舒平作为对比药物给药。结果如表8所示。
正如上述实验结果表明的,本发明诸化合物对于治疗源于心室和心房的心律不齐具有多种效果。尤其是这些化合物呈现出一个延长了时间的持续的抗心律不齐活性。它们没有治疗心律不齐时所不希望有的诸如抗胆碱能作用、中枢神经抑制作用以及血糖降低作用等副作用。因此,本发明诸化合物具有作为高度安全而有效的抗心律不齐药物的潜在用途。
Claims (7)
2、根据权利要求1的方法,其中R1和R2是甲基或乙基,R3是氢或甲基,m是2到5中的整数,n是2到7中的整数。
3、根据权利要求1的方法,其中R1和R2是甲基,R3是氢原子,m和n各为整数2或3,它们可以相同或不相同,R4和R5各为甲基、乙基、异丙基或异丁基,它们可以相同或不相同。
4、根据权利要求1的方法,其中所说的反应是在升温条件下于惰性溶剂中,在碱存在下进行。
5、根据权利要求4的方法,其中所说的惰性溶剂选自苯、甲苯、二甲苯、二氯甲烷、氯仿和乙酸乙酯,而所说的碱选自三甲胺、三乙胺、吡啶、碳酸钾和碳酸钠。
6、根据权利要求5的方法,其中所说的反应在从20℃到150℃的温度下进行。
7、根据权利要求5的方法,其中所说的反应是在回流温度及三乙胺存在下,在甲苯中进行的。
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DE2915250A1 (de) * | 1979-04-14 | 1980-10-30 | Basf Ag | Salze von alpha -aminoacetaniliden |
IT1150959B (it) * | 1980-06-10 | 1986-12-17 | Simes | Sostanze datate di attivita' antispastica vasale e procedimenti per la loro preparazione |
US4562201A (en) * | 1982-07-26 | 1985-12-31 | American Hospital Supply Corporation | Aminomethyl benzanilides |
US4536346A (en) * | 1983-05-06 | 1985-08-20 | American Cyanamid Company | Aralkanamidophenyl compounds |
-
1986
- 1986-03-18 US US06/840,681 patent/US4855497A/en not_active Expired - Fee Related
- 1986-03-25 AU AU55210/86A patent/AU593240B2/en not_active Ceased
- 1986-03-26 CA CA000505233A patent/CA1290347C/en not_active Expired - Fee Related
- 1986-03-27 ZA ZA862348A patent/ZA862348B/xx unknown
- 1986-03-28 JP JP61070094A patent/JPS6230746A/ja active Granted
- 1986-04-01 DE DE8686104386T patent/DE3662039D1/de not_active Expired
- 1986-04-01 ES ES553600A patent/ES8706615A1/es not_active Expired
- 1986-04-01 AT AT86104386T patent/ATE40677T1/de active
- 1986-04-01 HU HU861337A patent/HU196357B/hu not_active IP Right Cessation
- 1986-04-01 CN CN86102285A patent/CN1021908C/zh not_active Expired - Fee Related
- 1986-04-01 EP EP86104386A patent/EP0196648B1/en not_active Expired
- 1986-04-01 SU SU864027259A patent/SU1500155A3/ru active
- 1986-04-02 KR KR1019860002508A patent/KR940005917B1/ko active IP Right Grant
Also Published As
Publication number | Publication date |
---|---|
ATE40677T1 (de) | 1989-02-15 |
CA1290347C (en) | 1991-10-08 |
EP0196648B1 (en) | 1989-02-08 |
HUT40999A (en) | 1987-03-30 |
HU196357B (en) | 1988-11-28 |
ZA862348B (en) | 1986-11-26 |
US4855497A (en) | 1989-08-08 |
JPH0466476B2 (zh) | 1992-10-23 |
AU5521086A (en) | 1986-10-09 |
ES553600A0 (es) | 1987-06-16 |
JPS6230746A (ja) | 1987-02-09 |
KR860008123A (ko) | 1986-11-12 |
ES8706615A1 (es) | 1987-06-16 |
SU1500155A3 (ru) | 1989-08-07 |
EP0196648A1 (en) | 1986-10-08 |
DE3662039D1 (de) | 1989-03-16 |
CN1021908C (zh) | 1993-08-25 |
AU593240B2 (en) | 1990-02-08 |
KR940005917B1 (ko) | 1994-06-24 |
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