CN1172908C - N-取代苄基或苯基芳香磺酰胺化合物及其用途 - Google Patents

N-取代苄基或苯基芳香磺酰胺化合物及其用途 Download PDF

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CN1172908C
CN1172908C CNB99124236XA CN99124236A CN1172908C CN 1172908 C CN1172908 C CN 1172908C CN B99124236X A CNB99124236X A CN B99124236XA CN 99124236 A CN99124236 A CN 99124236A CN 1172908 C CN1172908 C CN 1172908C
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substituted benzyl
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白东鲁
陈维洲
卜运新
王逸平
董月丽
康爱丽
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Shanghai Institute of Materia Medica of CAS
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Abstract

N-(3,5-双-二取代氨甲基-4-羟基)苄基芳香磺酰胺和N-(3,5-双-二取代氨甲基-4-羟基)苯基芳香磺酰胺化合物在动物试验中有预防和治疗心律失常的作用。这些化合物由相应的带有各种取代基的芳香磺酰氯与对羟苄胺、对氨基苯酚等缩合生成相应的芳香磺酰胺,再与甲醛和仲胺通过曼尼希反应制得相应的二胺。也可由芳香磺酰氯与4-氨基-2,6-双-二取代氨甲基苯酚直接反应制得二胺。二胺化合物再与各种酸生成盐。

Description

N-取代苄基或苯基芳香磺酰胺化合物及其用途
本发明涉及N-取代苄基或苯基芳香磺酰胺化合物即N-(3,5-双-二取代氨甲基-4-羟基)苄基(或苯基)芳香磺酰胺化合物及其生理可接受的盐。
李良泉曾报导常咯啉 1的合成及它的抗心律失常活性(李良泉等,中国科学,1997,7,723;陈维洲等,药学学报,1979,14,710)后,国内外科学家又相继对常咯啉的化学结构进行改造并进行了生理活性的研究(孙存济等,药学学报,1981,16.564;1986,21,692;林木兰等,药学学报,1982,17,212;DM,Stour等J.Med.Chem.,1983,26,808;1984,27,1347;1985,28,295;1989,32,1910;R.J.Chorvat等,J.Med.Chem.,1993,36,2494.)。
Figure C9912423600031
虽然常咯啉是一个有效抗心律失常药,给心律失常患者口服后,2-3天可使室性早搏消失。静脉注射或滴注可使室性早搏、室性心动过速明显减少,甚至消失。但口服一个月以上,患者的皮肤可逆性色素沉着,停药后可逐渐消退。这与常咯啉的结构中某些基团在皮下氧化或在溶液中不稳定有关。
本发明目的是为了寻找抗心律失常一类效果优于常咯啉并能克服常咯啉不足之处的新药。
一类N-取代苄基或苯基芳香磺酰胺化合物通式为:
Figure C9912423600032
1.当R’=H,n=0或1时,化合物通式为
Figure C9912423600041
Ar=烷基、烷氧基、硝基、卤素、乙酰基、取代氨基所取代的苯基或萘基;
NR2=N(CxH2x+1)2
Figure C9912423600042
等,m=4、5或6,x=1或2。
2.当R’=烷基,n=0时,化合物通式为
Figure C9912423600043
Ar=烷基、烷氧基、硝基、卤素、乙酰基、取代氨基所取代的苯基或萘基
NR2=N(CxH2x+1)2等,m=4、5或6。
化合物 2通过以下方法获得
化合物 3通过以下方法获得:
也可采用先进行曼尼希反应然后再与取代的磺酰氯反应获得,具体步骤如下:
Figure C9912423600052
再制成人体可接受的盐。
实施本发明较为详细描述如下:
I.通式
Figure C9912423600053
Ar=烷基,烷氧基,硝基,卤素,取代氨基的苯基和萘基
NR2=N(CnH2n+1)2等,m=4,5,6 n=1,2,
制备步骤为:
1、将取代的芳香磺酰氯与羟苄胺反应生成相应的芳香磺酰胺 4
2、磺酰胺 4再与甲醛和仲胺进行曼尼希(Mannich)反应得二胺化合物 2
3、上述所得的二胺化合物 2与无机或有机酸生成相应的盐 5
II.通式
Ar=烷基,烷氧基,硝基,卤素,取代氨基的苯基和萘基
NR2=N(CnH2n+1)2
Figure C9912423600063
等,m=4,5,6
制备步骤为:
1、将取代的芳香磺酰氯与4-氨基-2,6-双-二取代氨甲基苯酚 6直接缩合,生成磺酰胺 3
2、磺酰胺 3再与酸生成生理可接受的盐 7
化合物 6可由取代的氨基苯酚与甲醛和仲胺经曼尼希反应制得
Figure C9912423600071
也可通过制备通式 的相似步骤获得。
即:
1、由芳香磺酰氯与对氨基苯酚缩合,生成相应的磺酰胺 4(n=0);
2、磺酰胺 4(n=0)再与甲醛和仲胺反应,生成二胺 3
3、二胺3最后与酸生成盐 7
采用上述方法分别可获得通式
Figure C9912423600073
的化合物
见表1
                   表1
Figure C9912423600081
化合物编号    Ar         n    NR2
B-86808 
Figure C9912423600082
    0 
B-86810 
Figure C9912423600084
     0 
Figure C9912423600085
B-86816 
Figure C9912423600086
 0 
Figure C9912423600087
B-86818    0 
B-87822   1 
B-87823 
Figure C99124236000812
  1 
Figure C99124236000813
B-87828 
Figure C99124236000814
   1 
B-87829 
Figure C99124236000816
    1 
B-87835       0 
Figure C99124236000819
B-87836 
Figure C99124236000820
     0 
通式为
Figure C99124236000822
的化合物见表2
                    表2
Figure C99124236000823
化合物编号      Ar      R′     NR2
B-86809  
Figure C99124236000824
  Et  
B-87825     Me  
B-87826    Me  
Figure C99124236000829
B-87827   Me  
B-87830       Me  
本发明对通式为
Figure C9912423600091
的各化合物制成生理可接受的盐酸盐,采用实验性心律失常动物模型研究它们的抗心律失常活性,实验模型和结果如下:
1、采用麻醉大鼠,开胸暴露心脏,结扎冠状动脉前降枝,造成急性心肌缺血诱发心律失常模型(药理实验方法学,人民卫生出版社,北京,1991年第二版1022页)中化合物B-87823能明显降低室性早搏(有效率77%),抑制室性心动过速发生率73%,而常咯啉抑制室性早搏的发生率为50%。
2、北草乌头碱诱发大鼠心律失常模型(陈维洲等,中国药理学报,1983, 4,247.)中,化合物B-87823的预防性给药的ED50为2.8mg/kg,预防指数为37;治疗性给药的治疗剂量为5.9±0.5mg/kg,治疗指数为18,常咯啉ED50为3mg/kg。
3、在哇巴因诱发豚鼠心律失常模型(陈维洲等,中国药理学报,1983,4,247)中,化合物B-87823和常咯啉均能显著提高哇巴因诱发室性早搏,室性心动过速和心室颤动所需哇巴因的用量。
4、对缺氧-再给氧引起豚鼠离体心脏灌流(董月丽等,药学学报,1995,30,577)所诱发的心率失常B-87823也有显著的抑制作用。
5、化合物B-87823也能对抗北草乌头碱诱发离体豚鼠乳头肌异位节律(陈红专等,上海第二医科大学学报,1989,9,105)。对Ames试验呈阴性。各化合物药理作用见表3。
6、在豚鼠乳头状肌细胞快反应动作电位模型中(药理实验方法学,人民卫生出版社,北京,1991年第2版563页),测得化合物B-87823能降低动作电位幅度和零相最大除极速率,延长动作电位复极90%的时程和有效不应期(见表4)。
7、在兔窦房结优势起搏细胞慢反应动作电位模型中(药理实验方法学,人民卫生出版社,北京,1991年第2版563页),化合物B-87823可使零相最大除极速率和4相自动复极速率降低,减少动作电位幅度(见表5)。
8、在清醒狗Harris二期结扎冠状动脉诱发迟发性心律失常模型中(Harris,A.S.Delayed development of ventricular ectopic rhythms followingexperimental coronary occlusion.Circulation Res 1950;1:1318-1328),测得化合物B-87823口服给药能显著减少结性和室性早搏,明显减少阵发性室性心动过速(见表6)。
9、在豚鼠离体心脏缺血再灌注损伤模型中(Woodward,B.A model ofventricular fibrillation in the isolated rat heart.J Pharmac Meth 1981;6:219-231),化合物B-87823能明显抑制再灌注损伤引起的室颤(见表7)。
表3
Figure C9912423600111
对抗大鼠心律失常的作用
化合物编号    Ar         R′        n   NR2  预防指数      治疗指数
B-86808 
Figure C9912423600112
    H          0 
Figure C9912423600113
  5.6           20.4
B-86809      Et         0 
Figure C9912423600115
  1.1           4.0
B-86810 
Figure C9912423600116
     H          0    5.3           ——
B-86816   H          0 
Figure C9912423600119
  1.9           ——
B-86817     B-86816的对乙酰氨基苯磺酸酯        4.0           ——
B-86818 
Figure C99124236001110
   H          0   5.5           ——
B-87822    H          1   3.2           ——
B-87823 
Figure C99124236001114
   H          1   37            18
B-87825 
Figure C99124236001116
    Me         0 
Figure C99124236001117
  20.5          3.7
B-87826     Me         0 
Figure C99124236001119
 12.6          6.1
B-87827 
Figure C99124236001120
  Me         0   3.0           2
B-87828 
Figure C99124236001122
     H          1   3.8           12
B-87829       H          1 
Figure C99124236001125
  55            8.6
B-87830 
Figure C99124236001126
     Me         0 
Figure C99124236001127
  3.9           ——
B-87835        H          0 
Figure C99124236001129
  20            5.2
B-87836 
Figure C99124236001130
      H          0   33.5          9.7
表4:87823对豚鼠乳头状肌细胞快反应动作电位的电生理作用
     ( x±SD,n=6,*P<0.05,**P<0.01)
表5:87823对兔窦房结优势起搏细胞慢反应动作电位的电生理作用
     ( x±SD,n=5,*P<0.05,**P<0.01)
Figure C9912423600122
表6:87823口服给药对清醒狗Harris二期结扎冠状动脉诱发迟发性心律失常的作用( x±SD,n=6,**P<0.01)
表7:对豚鼠离体心脏缺血再灌注损伤引起的室颤的作用
  药物     n   室颤发生率
  ouM     17     100%
  louM     10     10%
表3的预防指数与治疗指数是通过大鼠急性毒性试验,求出半数致死量(LD50),再用大鼠乌头碱心律失常模型分别进行预防性试验求出半数有效量(ED50);治疗性试验求出有效量(ED)。然后以LD50∶ED50的值作为预防指数,LD50∶ED的值作为治疗指数来考察这些化合物的抗心律失常活性,从表3中可以看出B-87823盐酸盐的预防和治疗指数为最高。
下面用制备实施例进一步说明本发明,但不限制本发明。
实施例1
N-[3,5-双(1-哌啶甲基)-4-羟基]苯基-1-萘磺酰胺(B-87836)
1、1-萘磺酰氯(4,4g)的二氧六环(20ml)溶液在搅拌下滴加至对氨基酚(4.5g)的二氧六环(40ml)溶液中,在室温继续搅拌4.5小时。将反应液倒入水中,固体过滤,用乙醇重结晶,活性炭脱色,得N-(对羟基苯基)-1-萘磺酰胺(4.2g),mp195-196℃。
2、N-(对羟基苯基)-1-萘磺酰胺(2.0g),37%甲醛水溶液(4.5g)和哌啶(5.6g)在乙醇(100ml)中加热回流50小时,蒸除乙醇加入氯仿。有机层用水洗后经无水Na2SO4干燥。减压蒸除氯仿,残留物加水括擦即成固体,用乙醇重结晶得产物(1.4g),mp197-198℃
HNMR(CDCl3):1.30-1.50(m,12H),2.10-2.21(m,8H),3.28(S,4H),6.45(S,2H),
             7.24-8.04(m,6H),8.56(m,1H)
元素分析:C28H35N3O3S 理论值%:C 68.12;H 7.15;N 8.51
                             实验值%:C 67.96;H 7.16;N 8.56
          B-86835也由上述步骤制得。
实施例2
N-[3,5-双(1-吡喀烷甲基)-4-羟基]苯基-4-氯苯磺酰胺(B-86810)
将对氯苯磺酰氯(1.0g)的四氢呋喃(5ml)溶液滴加至2,6-双(1-吡咯烷甲基)-4-氨基苯酚(1.3g)的四氢呋喃(5ml)溶液中,在室温继续搅拌4小时。减压蒸除溶剂,残渣溶于水后用2N KOH溶液中和,混合物用乙酸乙酯提取。有机层先后用水、NaCl溶液洗涤,无水Na2SO4干燥。减压除去溶剂,残留物经硅胶柱层析(CH3COOEt∶CH3OH∶NH4OH=9∶1∶0.05),所得固体用乙酸乙酯重结晶,得产物(1.3g),mp187-188℃。
HNMR(CDCl3):1.72-2.08(m,8H),2.56-2.88(m,8H),3.88(S,4H),6.90(S,2H),
             7.36(d,2H),7.64(d,2H),10.18(brS,2H)
元素分析:C22H28N3ClO3S 理论值%:C 58.71;H 6.27;N 9.34;Cl 17.88
                               实验值%:C 58.87;H 6.39;N 9.44;Cl 17.79
用上述步骤也可制备B-86808,B-86816,B-86818
实施例3
N-[3,5-双(1-吡咯烷甲基)-4-羟基]苯基-N-乙基-4-甲基苯磺酰胺(B-86809)
1、在搅拌下将2,6-双(1-吡啶烷甲基)-4-乙酰氨基苯酚(5.6g)的四氢呋喃(5ml)溶液滴加至氢化铝锂(2.7g)的四氢呋喃(25ml)溶液中,加热回流5小时。在冰浴冷却下向反应物滴加水和20%NaOH水溶液,吸滤,滤渣用四氢呋喃洗涤。洗滤液合并减压除去溶剂,残留物经硅胶柱层析(CH3COOEt∶CH3OH∶NH4OH=5∶1∶0.1)得2,6-双(1-吡咯烷甲基)-4-乙氨基苯酚(3.9g)。
HNMR(CDCl3):1.16(t,3H),1.44-1.94(m,8H),2.24-2.66(m,8H),2.98(q,2H),
             3.52(s,4H),6.17(s,2H)
2、2,6-双(1-吡咯烷甲基)-4-乙氨基苯酚(2.6g)和对甲苯磺酰氯(1.1g)溶于四氢呋喃(20ml)中,在60℃搅拌反应3小时。处理和纯化方法同实施例2。固体用乙酸乙酯重结晶得产物(1.9g),mp 119-120℃。
HNMR(CDCl3):1.21(t,3H),1.60-2.12(m,8H),2.51(s,3H),2.68-3.20(m,
             10H),3.85(s,4H),6.92(s,2H),7.39(d,2H),7.77(d,2H)
元素分析:C25H15N3O4S 理论值%:C 65.61;H 7.70;N 9.18
                             实验值%:C 65.46;H 7.80;N 8.95
实施例4
N-[3,5-双(1-吡咯烷甲基)-4-羟基]苄基-4-氯苯磺酰胺(B-87829)
1、向对羟苄胺(0.68g)乙醇(10ml)溶液分别加入三乙胺(0.77ml)和对氯苯磺酰氯(1.2g)。反应混合物在室温搅拌4小时后减压蒸除溶剂。残留固体用水洗后用乙醇重结晶,得N-(4-羟基苄基)-对氯苯磺酰胺(1.2g),mp 187-189℃。
2、N-(4-羟基苄基)-对氯苯磺酰胺(0.74g)、吡咯烷(0.68ml)和37%甲醛水溶液(0.85ml)在乙醇(5ml)中加热回流3小时。减压蒸除溶剂,残留物经硅胶柱层析(CH3COOEt∶CH3OH∶NH4OH=9∶1∶0.05),所得固体用乙醇重结晶,得产物(0.84g);mp 112-113℃。
HNMR(CDCl3):1.57-1.97(m,8H),2.33-2.72(m,8H),2.63(s,4H),3.97(s,2H),
             6.81(s,2H),7.42(d,2H),7,75(d,2H)
元素分析:C23H30N3ClO3S 理论值%:C 59.53;H 6.52;N 9.06;Cl 7.64
                               实验值%:C 59.50;H 6.63;N 8.99;Cl 7.57
实施例5
N-[3,5-双(1-吡咯烷甲基)-4-羟基]苄基-4-甲氧基苯磺酰胺(B-87823)硫酸盐
1、对羟苄胺(59g)的二甲基甲酰胺(410ml)溶液在冰水冷却下加入对甲氧基苯磺酰氯(100g),混合物搅拌至固体溶解。在10℃以下滴加入三乙胺(76ml),加毕继续搅拌1小时。反应物倾入水(51)中,搅匀后将析出固体抽滤,水洗。滤饼悬浮在水(11)中,用30%NaOH溶液调节PH至12,混合物过滤后滤液用浓盐酸调节PH至2-3。静置30分钟后,析出的固体经抽滤、水洗、干燥、得N-(4-羟基苄基)-对甲氧基苯磺酰胺(112g),系白色固体,mp 161-162℃。
HNMR(CD3OD):3.70(s,3H),3.76(d,2H),6.48(d,2H),6.82(d,2H),6.86(d,
             2H),7.56(d,2H)
元素分析:C14H15NO4S 理论值%:C 57.34;H 5.12;N 4.78
                          实验值%:C 57.22;H 5.16;N 4.65
2、将N-(4-羟基苄基)-对甲氧基苯磺酰胺(50g)的乙醇(300ml)溶液、吡咯烷(36g)和37%甲醛水溶液(65ml)的混合物加热回流3小时。减压蒸除溶剂所得油状物溶于氯仿(200ml)中,用稀盐酸萃取,酸水溶液用氯仿洗涤后加入过量浓氨水。析出油状物用氯仿提取数次,合并有机相用无水Na2SO4干燥。减压蒸除溶剂后的油状物用丙酮-乙醚重结晶,得N-[3,5-双(1-吡咯烷甲基)-4-羟基]苄基-4-甲氧基苯磺酰胺(65g),mp 102-103℃。
HNMR(CDCl3):1.77-1.86(m,8H),2.53-2.63(m,8H),3.68(s,4H),3.86(s,3H)
             3.97(s,2H),6.86(s,2H),6.95(dd,2H),7.78(dd,2H)
元素分析:C24H33N3O4S 理论值%:C 62.72;H 7.24;N 9.14
                             实验值%:C 62.67;H 7.49;N 9.22
化合物B-87822,B-87828,B-87829也用上述步骤制得。
3、上述游离碱(75g)在2M硫酸中生成硫酸盐(86g),含3分子结晶水,可用水-异丙醇重结晶,mp 125-140℃。
HNMR(D2O):2.00-2.13(m,4H),2.14-2.25(m,4H),3.12-3.22(m,4H),3.45
           -3.55(m,4H),3.90(s,3H),4.20(s,2H),4.33(s,4H),7.02(d,
           2H),7.28(s,2H),7.66(d,2H)
元素分析:C24H33N3O4S·H2SO4·3H2O
          理论值%:C 47.06;H 6.70;N 6.86;S 10.48
          实验值%:C 47.00;H 6.98;N 6.87;S 10.65
实施例6
N-[3,5-双(1-吡咯烷甲基)-4-羟基]苯基-N-甲基-4-乙酰氨基苯磺酰胺(B-87827)
1、等克分子量对甲氨基苯酚硫酸盐和对乙酰氨基苯磺酰氯与加倍克分子量三乙胺在乙醇中室温反应4小时。减压蒸除溶剂后残留物加入乙醚提取,醚层分别用2N盐酸、饱和NaHCO3水溶液和水洗涤。有机层经无水Na2SO4干燥,蒸除溶剂后的固体用乙醇重结晶,得N-(4-羟基苯基)-N-甲基-对乙酰氨基苯磺酰胺,mp 202-203℃。
HNMR(CDCl3):2.07(s,3H),3.03(s,3H),6.64(d,2H),6.82(d,2H),7.36(d,
             2H),7.70(d,2H)
元素分析:C15H16N2O4S 理论值%:C 56.23;H 5.03;N 8.75
                             实验值%:C 56.21;H 4.99;N 8.74
2、按实施例4相同操作N-(4-羟基苯基)-N-甲基-对乙酰氨基苯磺酰胺与吡咯和甲醛水溶液在乙醇中室温反应5小时,所得固体用水-乙醇重结晶,得产物,mp 96-97℃。
HNMR(CDCl3):1.64-1.89(m,8H),2.17(s,3H),2.39-2.68(m,84H),3.09(s,
             3H),3.64(s,4H),6.73(s,2H),7.43(d,2H),7.57(d,2H),
             8.02(brs,1H)
元素分析:C25H34N4O4S·1/2 H2O 理论值%:C 60.58;H 7.12;N 11.30
                                       实验值%:C 60.58;H 7.18;N 11.42
上述步骤也可用于化合物B-87825,B-87826,B-87830的制备。

Claims (6)

1.一类化学结构如通式所示的N-取代苄基或苯基芳香磺酰胺化合物及其盐:
Figure C991242360002C1
Ar=烷基、烷氧基、硝基、卤基、酰基氨基所取代的苯基或萘基,n=0或1;
NR2=N(CxH2x+1)2
Figure C991242360002C2
m=4、5或6,x=1或2;
R’=H或烷基。
2.根据权利要求1所述的N-取代苄基或苯基芳香磺酰胺化合物,其中R’=H。
3.根据权利要求1所述的N-取代苄基或苯基芳香磺酰胺化合物,其中R’烷基,n=0。
4.根据权利要求2所述的N-取代苄基或苯基芳香磺酰胺化合物的制备方法,其特征在于:
(1)将取代的芳香磺酰氯与对-羟苄胺反应生成相应的芳香磺酰胺4;
(2)芳香磺酰胺4再与甲醛和仲胺进行曼尼希反应得二胺化合物2;
(3)二胺化合物2与无机或有机酸生成相应的生理可接受的盐5。
5.根据权利要求3所述的N-取代苄基或苯基芳香磺酰胺化合物的制备方法,其特征在于:
(1)将取代的芳香磺酰氯与4-氨基-2,6-双-二取代氨甲基苯酚6直接缩合成磺酰胺3;
(2)磺酰胺3再与酸生成生理可接受的盐7。
6.根据权利要求1所述的N-取代苄基或苯基芳香磺酰胺化合物在预防和治疗心律失常药物制备中的应用。
CNB99124236XA 1999-12-10 1999-12-10 N-取代苄基或苯基芳香磺酰胺化合物及其用途 Expired - Lifetime CN1172908C (zh)

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PCT/CN2000/000187 WO2001042204A1 (fr) 1999-12-10 2000-07-03 Composes sulfamides aromatiques phenyle ou benzyle n-substitues et leurs applications
DE60025270T DE60025270T2 (de) 1999-12-10 2000-07-03 N-substituierte benzyl oder phenyl arylsulfamide und ihre verwendung
JP2001543505A JP4015853B2 (ja) 1999-12-10 2000-07-03 N−置換ベンジルまたはフェニル芳香族スルホンアミド化合物及びその用途
EP00941870A EP1245561B1 (en) 1999-12-10 2000-07-03 N-substituted benzyl or phenyl aromatic sulfamides compounds and the use thereof
AT00941870T ATE314345T1 (de) 1999-12-10 2000-07-03 N-substituierte benzyl oder phenyl arylsulfamide und ihre verwendung
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