CN1103762C - 新的具有抗惊厥活性且4－位上含有二取代氨基的1－芳(烷)基咪唑啉－2－酮类化合物,以及它们的制备方法 - Google Patents

新的具有抗惊厥活性且4－位上含有二取代氨基的1－芳(烷)基咪唑啉－2－酮类化合物,以及它们的制备方法 Download PDF

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CN1103762C
CN1103762C CN96197801A CN96197801A CN1103762C CN 1103762 C CN1103762 C CN 1103762C CN 96197801 A CN96197801 A CN 96197801A CN 96197801 A CN96197801 A CN 96197801A CN 1103762 C CN1103762 C CN 1103762C
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tetrahydroglyoxaline
ketone
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phenyl
morpholino
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H·J·兰考
M·门泽尔
K·翁弗尔菲尔思
K·格瓦德
H·谢费尔
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    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract

本发明提供了具有抗惊厥活性的通式1化合物：其中：X＝氢，C1-C4烷基，C1-C4烷氧基，三氟甲基或卤素，R1和R2＝C1-C4烷基，环烷基或杂烷基。

Description

新的具有抗惊厥活性且4-位上 含有二取代氨基的 1-芳(烷)基咪唑啉-2-酮类化合物， 以及它们的制备方法
本发明涉及4-位上含有二取代氨基的1-芳(烷)基咪唑啉-2-酮类化合物，它们的制备方法以及它们作为治疗中枢神经系统疾病(特别是各种形式的癫痫病)的药剂的应用。
按照现有技术，4-位上具有氨基或甲氨基的1-芳(烷)基咪唑啉-2-酮类化合物可通过反应芳(烷)基氨基乙酰胺和溴化氰制备。N-烷基化按此方法制得的4-氨基-1-芳(烷)基咪唑啉-2-酮，则得到3-烷基-或1-亚氨基烷基-3-烷基-1-芳(烷)基咪唑啉-2-酮化合物，4-位上的氨基被互变成亚氨基。因此，通过进一步N-烷基化以得到通式1化合物是不可能的，因而按照这一方法不能制得本发明化合物[USP 4044021；DE 2251354]。
迄今为止，文献中尚没有描述过4-位上具有二取代氨基的1-芳(烷)基咪唑啉-2-酮类化合物。
尽管已知有众多化合物具有抗惊厥活性。然而，直至今日，也并不是所有的癫痫病都能得到令人满意的治疗。
因此，本发明的目的是提供一类具有有用的药理学性质的新化合物，它们可用作如具有抗癫痫活性的药物。
根据本发明，这些新化合物为具下述通式1结构的1-芳(烷)基咪唑啉-2-酮类化合物：
其中：
X＝氢，C1-C4烷基，C1-C4烷氧基，三氟甲基或卤素，
R1和R2＝C1-C4烷基，环烷基或杂烷基(heteroalkyl)，其中各个烷基含5-7个碳原子，
或者
R1和R2一同表示含有2-6个碳原子的亚烷基，其中-CH2-基团可被氧，氮或硫置换。
CH2基团的数量为0(1-芳基咪唑啉-2-酮)或1(1-芳烷基咪唑啉-2-酮)。
可提及的通式I化合物的实例包括：
1-苯基-4-吗啉代咪唑啉-2-酮
1-(4-甲氧基)-4-哌啶子基咪唑啉-2-酮
1-(4-氯苯基)-4-吗啉代咪唑啉-2-酮
1-(4-氯苯基)-4-哌啶子基咪唑啉-2-酮
1-(4-氯苯基)-4-二甲氨基咪唑啉-2-酮
1-(4-溴苯基)-4-吗啉代咪唑啉-2-酮
1-(3-氯苯基)-4-吗啉代咪唑啉-2-酮
1-(4-氯苯基)-4-六亚甲基亚氨基咪唑啉-2-酮
1-(4-氯苯基)-4-(4-甲基哌嗪子基)咪唑啉-2-酮
1-(4-甲基苯基)-4-吗啉代咪唑啉-2-酮
1-(4-氯苯基)-4-(环己基甲基氨基)咪唑啉-2-酮
1-(4-氟苯基)-4-吗啉代咪唑啉-2-酮
1-苄基-4-吗啉代咪唑啉-2-酮
根据本发明，通式1化合物可通过反应式2化合物与仲胺HNR1R2的新方法制备：
Figure C9619780100051
其中：
X＝氢，C1-C4烷基，C1-C4烷氧基，三氟甲基或卤素。
式1化合物的制备可以在50℃-160℃的温度下在溶剂中或者在过量仲胺中进行。合适溶剂优选为芳烃，例如苯，甲苯，氯苯或二氯苯。
上述反应优选在能结合水的物质(如沸石或硫酸钠)存在下进行。加入常规的缩合催化剂(如4-甲苯磺酸)能够促进反应。
本发明化合物适于制备药物组合物。所述药物组合物中可包含一种或多种本发明化合物。可使用常规的药物赋型剂和助剂来制备药剂。
药物可通过非肠道(例如静脉内，肌内，或皮下)或口服途径施用。
各种施用形式的药剂可用制药实践中一般公知的常规方法制备。
本发明化合物具有强有效的抗惊厥活性。
按照国际常规标准(Pharmac Weekblad，Sc.Ed. 14，132(1992)和抗癫痫药物(Antiepileptic Drugs)，第三版，Raven Press，New York(1989)，在腹膜内给药小鼠或大鼠(口服给药)后，测试本发明化合物的体内抗惊厥活性(表1)。
例如，对于化合物2(1-(4-氯苯基)-4-吗啉代咪唑啉-2-酮)，在大鼠中，最大电休克试验测得的ED50(口服)为21mg/kg，s.c.戊四唑试验测得的ED50为16mg/kg，而且测得神经毒性的NT50为＞400mg/kg。与此相比，已知的镇癫痫药或是仅在最大电休克模型中具有活性，或是仅在戊四唑试验中具有活性，或者在具有比较高的活性情形下，在PTZ试验中具有严重的神经毒性。表1
实施例化合物   log P2)    试验3)    剂量4)   活性5)
1 0.64     MESPTZ     100100     3030
2 1.48     MESPTZ     30030     3070
3 2.29     MESPTZ     100100     100100
4 0.48     MESPTZ     300300     3030
5 2.17     MESPTZ     300300     100100
6 1.61     MESPTZ     300100     10020
7 1.53     MESPTZ     300100     100100
8 1.45     MESPTZ     300100     30100
9 0.97     MESPTZ     100100     30100
10 1.28     MESPTZ     300300     1070
11 2.56     MESPTZ     300300     10040
    对比物质    试验3)    剂量4)    活性5)
氨甲酰氮     MESPTZ     100100     1000
丙戊酸盐     MESPTZ     100100     030
表1附注：
1)化合物的编号参见实施例
2)辛醇/水分配系数
3)小鼠腹膜内：MES＝最大电休克，PTZ＝s.c.戊四唑试验
4)以mg/kg为单位
5)以％受护动物数表示
本发明的通式1新化合物的制备借助下述实施例更详细说明。
实施例
制备表1中实施例1-11的式1化合物的一般方法。
变型方法A
将0.05mol通式2(n＝0)的1-芳基咪唑啉-2，4-二酮、200mg4-甲苯磺酸加到100ml合适的仲胺中。然后在索格利特提取器中加热回流混合物，抽提套管内预装有约25g能结合水的固体(氧化钙，硫酸钠，硫酸镁，NaOH，KOH，沸石是合适的)。反应8-30小时后，热过滤溶液并用旋转蒸发器蒸发至大约一半体积。将透明溶液用冰浴冷却并将所得的结晶膏状物与胺分离开。粗产物中所包含的原料物用50ml热丙酮提取。产物用正丙醇重结晶。
可以从分离出的胺中回收到大约0.02mol未反应的1-芳基咪唑啉-2，4-二酮。
变型方法B
将0.05mol通式2(n＝1)的1-芳烷基咪唑啉-2，4-二酮与方法A中所述的仲胺反应。反应8-30小时后，热过滤所得溶液，然后用旋转蒸发器浓缩至干。向残留物中加入50ml二氯甲烷和50ml 2NHCl。分出有机相，水相用二氯甲烷进一步提取两次。分离水相用50ml10％强度的NaOH调节至碱性，并用100ml二氯甲烷提取1-4-氨基-1-芳烷基咪唑啉-2-酮。醚提取液用硫酸钠干燥。蒸除二氯甲烷之后，将粗产物用乙醇或丙酮重结晶。
变型方法C
按方法A和B所述，反应0.05mol通式2的1-芳(烷)基咪唑啉-2，4-二酮和100ml二甲基氨基甲酸二甲基铵。反应40小时后，混合物按照变型方法A或B进行后处理。表2                1)计算产率时考虑回收的原料。

Claims (7)

1.通式1化合物：
Figure C9619780100021
其中：
X＝氢，C1-C4烷基，C1-C4烷氧基或卤素，
R1和R2＝C1-C4烷基，或者
R1和R2一同表示含有2-6个碳原子的亚烷基，其中-CH2-基团可被氧或氮置换。
2.根据权利要求1的化合物，所述化合物为：
1-苯基-4-吗啉代咪唑啉-2-酮
1-(4-甲氧基)-4-哌啶子基咪唑啉-2-酮
1-(4-氯苯基)-4-吗啉代咪唑啉-2-酮
1-(4-氯苯基)-4-哌啶子基咪唑啉-2-酮
1-(4-氯苯基)-4-二甲氨基咪唑啉-2-酮
1-(4-溴苯基)-4-吗啉代咪唑啉-2-酮
1-(3-氯苯基)-4-吗啉代咪唑啉-2-酮
1-(4-氯苯基)-4-六亚甲基亚氨基咪唑啉-2-酮
1-(4-氯苯基)-4-(4-甲基哌嗪子基)咪唑啉-2-酮
1-(4-氟苯基)-4-吗啉代咪唑啉-2-酮
1-苄基-4-吗啉代咪唑啉-2-酮
3.通式1化合物的制备方法，其特征是在50℃至160℃的温度下，使下述通式2化合物与仲胺HNR1R2反应：
Figure C9619780100031
其中：
X＝氢，C1-C4烷基，C1-C4烷氧基或卤素，
R1和R2具有如权利要求1所述的定义。
4.一种药物组合物，其特征在于含有至少一种作为活性成分的权利要求1的化合物和药物可接受的赋形剂。
5.根据权利要求4的药物组合物，其特征在于含有至少一种作为活性成分的权利要求2的化合物和药物可接受的赋形剂。
6.通式1的化合物在生产用于治疗癫痫病的药物中的用途。
7.根据权利要求6的用途，其中权利要求2的化合物在生产用于治疗癫痫病的药物中的用途。
CN96197801A 1995-09-05 1996-07-26 新的具有抗惊厥活性且4－位上含有二取代氨基的1－芳(烷)基咪唑啉－2－酮类化合物,以及它们的制备方法 Expired - Lifetime CN1103762C (zh)

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RU2014109079A (ru) 2011-08-12 2015-09-20 Бёрингер Ингельхайм Ветмедика Гмбх Фармацевтическая композиция с маскированным вкусом
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IL123333A (en) 2001-10-31
IL123333A0 (en) 1998-09-24
BG102287A (en) 1998-09-30
HK1015776A1 (en) 1999-10-22
EA000535B1 (ru) 1999-10-28
EA199800271A1 (ru) 1998-10-29
CN1200728A (zh) 1998-12-02
WO1997009314A1 (de) 1997-03-13
FR13C0049I1 (zh) 2013-09-27
PL188287B1 (pl) 2005-01-31
GEP20022652B (en) 2002-03-25
HUP9802941A2 (hu) 1999-09-28
NO980906D0 (no) 1998-03-02
FR13C0049I2 (fr) 2014-03-28
PT863880E (pt) 2004-04-30
SK284868B6 (sk) 2006-01-05
LT4482B (lt) 1999-03-25
HUP9802941A3 (en) 1999-10-28
JP4030578B2 (ja) 2008-01-09
LU92263I2 (fr) 2013-10-07
AU700602B2 (en) 1999-01-07
EE03562B1 (et) 2001-12-17
MX9801742A (es) 1998-08-30

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