CN1067381C - 新的4-咪唑烷酮化合物,其制备方法和含有它的药物组合物 - Google Patents
新的4-咪唑烷酮化合物,其制备方法和含有它的药物组合物 Download PDFInfo
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Abstract
式(Ⅰ)化合物:
及其与药物上可接受的酸或碱的加成盐。
Description
本发明涉及新的4-咪唑烷酮化合物,其制备方法和含有它的药物组合物。
本发明的化合物除了是新的这一事实外,还是与N-甲基-D-天冬氨酸(NMDA)受体相偶联的甘氨酸受***点(甘氨酸B受体)的有效的部分***。
L-谷氨酸和L-天冬氨酸有能力激活中枢神经***的神经元。许多研究表明,这些兴奋性氨基酸(EAA)与定义神经递质的标准相符合。为此,在治疗神经病和精神病中,与这些EAA有关的神经元活动的调节似乎是一个有利的目标。
在位于突触后和突触前的四类EAA受体中,NMDA受体与离子通道有关,这种离子通道可渗透一价和二价阳离子(包括钙离子)但被镁离子所阻滞。NMDA通道的开放受一些与该受体有关的位点的控制,并且特别是被甘氨酸启动,其效应对马钱子碱不敏感。这个甘氨酸位点是调节NMDA受体的激活的主要靶之一。
通过充当甘氨酸B受体的***,NMDA传导的正调节是一种从整体上改善学习和记忆功能的方式(J.B.Monahan et al.,Phar-macol.Biochem.&Behavior,34,649-653,1989;W.E.Müller er al.,Life Sciences,55,No.25/26,2147/2153,1994),以及改善与衰老过程、神经变性病、象早老性痴呆这样的痴呆、皮克病、亨廷顿舞蹈病、神经***症或焦虑-抑郁病有关的功能异常(A.Hashimoto et al.,J.Neurochem.,60,No.2,783-786,1993;P.Saransaari,Mechanismsof Ageing and Devel.,72,57-66,1993)。另外,甘氨酸B类的***或部分***活性在治疗惊厥,例如那些与癫痫有关的惊厥中(M.G.Baxter et a1.,CNS Drug Reviews,1,No.1,74-90,D.O.Nor-ris et al.,Pharmacol.Biochem.&Behavior,43.609-612,1992),在治疗疼痛中(A.H.Dickenson et al.,Neuroscience Lett.,121,263-266,1991;M.J.Millan et al.,Europ.J.Pharmacol.,238,445-447,1993),在控制精神***症的产生新组织的炎症和缺乏性症状中(M.Ishimaru et al.,Biol.Psychiatry,35,84-95,1994,A.O.Sherman etal.,Biol.Psychiatry,30,1191-1198,1991),在治疗焦虑中(R.Trul-las et al.,Europ.J.Pharmacol.,203,379-385,1991;J.T.Winslow etal.,Europ.J.Pharmacol.,190,11-21,1990)和治疗抑郁中(I.A.Paul et al.,Psychopharm.,106,285-287,1992;上文引用的R.Trul-las)以及治疗与滥用象乙醇(C.R.Breese et al.,Brain Research,674,82-90,1995;S.J.Deutsch et al.,Clinical.Neuropharmacol.,12,No.6,483-489,1989)和精神***(G.E.Evoniuk et al.,Psy-chopharm.,105,125-128,1991;E.Toth et al.,Neurochem.Re-search,11,No.3,393-400,1986)这样的药物有关的疾病中,都非常有用。
文献中很少描述过简单的4-咪唑烷酮衍生物,尽管如此,可以提到由R.E.Harmon等描述过的化合物(J.Het.Chem.,70,Vol.7(2),p439-442)。
现有技术中没有对这些化合物的具体药理学活性做过描述。
和其与药物上可接受的酸或碱的加成盐。
在药物上可接受的酸中,可以提到的作为非限制性例子的有盐酸、氢溴酸、硫酸、磷酸、乙酸、三氟乙酸、乳酸、丙酮酸、丙二酸、琥珀酸、戊二酸、富马酸、酒石酸、马来酸、柠檬酸、抗坏血酸、草酸、甲磺酸和樟脑酸等。
在药物上可接受的碱中,可以提到的作为非限制性例子的有氢氧化钠、氢氧化钾、三乙胺、叔丁胺等。
本发明还涉及制备这种化合物的方法,其特征在于,将式(Ⅱ)的甘氨酸异羟肟酸:
H2N-CH2-CO-NH-OH (Ⅱ)与甲醛水溶液反应,得到式(Ⅰ)化合物,合适的话,按照常规纯化技术对其进行纯化,如需要,将其转化为与药物上可接受的酸或碱的加成盐。
本发明的另一主题是仅含有作为活性成分的式(Ⅰ)化合物或含有式(Ⅰ)化合物与一种或一些无毒、惰性赋形剂或载体的组合的药物组合物。
在本发明的药物组合物中,更需特别提到的是那些适合口服、肠胃外或鼻腔施用的组合物,简单或糖衣片剂、***片、胶囊、锭剂、栓剂或乳膏、油膏、敷剂等。
有效剂量随病人年龄和体重、疾病的性质和严重程度以及施用途径而有所不同。施用途径可以是口服、鼻腔、直肠或肠胃外施用。一般说来,单位治疗剂量为1-1000mg,每24小时分1-3次施用。
下列实施例用于阐述本发明,而不以任何方式限制本发明。
已经用常用的波谱技术(核磁共振、红外线、质谱、X射线衍射等)证实了本发明化合物的结构。实施例1:3-羟基-4-咪唑烷酮
在20℃下,向保持在氮气气氛中、含有11mmol甘氨酸异羟肟酸的50ml乙醇溶液的溶液中一次性加入0.9ml40%甲醛水溶液。然后回流下加热混合物3小时,再冷却至20℃并在此温度下搅拌过夜。滤出所得的晶体残留物,用乙醇洗涤,再用***洗涤。再通过从乙醇中结晶来对目的产物进行纯化。熔点:147-148℃。元素微量分析:
C% H% N%计算值 35.29 5.92 27.44实测值 35.21 5.72 27.08
本发明化合物的药理学研究实施例2:关于[3H]-甘氨酸和[3H]-MK801结合到鼠脑膜上的研究材料和方法膜的制备(按照Yoneda等,J.Neurochem.,55,1,237-244,1990)
制备膜并以同样方式用于两种放射性配体。用无菌Milli-Q水(Millipore)制备缓冲液,这种水是去离子的并且就在使用之前在硝化纤维素滤器(0.45μm)上过滤过。
解剖之后,把得自鼠(Wistar雄性鼠,240-260g)的、除去了小脑的脑置于含有Tris-乙酸盐(1mM)、EGTA(1mM)和蔗糖(320mM),pH为7的冰冷的缓冲液中。把脑研碎,再用polytron匀化。将悬浮液在1000g下离心10分钟,回收含膜的上清液并在35000g下再离心20分钟。没有棕色环的沉淀物回收于含有Tris-乙酸盐(1mM)和EGTA(1mM)、pH为8的裂解冲液中。然后将悬浮液于4℃放置15分钟,再于35000g下离心20分钟。将沉淀物回收于pH7.4、含有0.08%Triton的Tris-乙酸盐(50mM)缓冲液中,并在4℃下放置30分钟。经接连两次离心之后,把沉淀物溶解在pH7.4的Tris-乙酸盐(50mM)缓冲液中,分成等份并于-80℃贮存。在实验当天,至多在制备后3周,用pH7.4的Tris-乙酸盐(50mM)缓冲液洗涤膜两次。
结合实验(按照Yoneda等人,J.Neurochem.,60,2,634-645,1993)
位点 | 放射性配体 | 非特异性结合 | 保温 |
甘氨酸B | [3H]-Glycine(10nM) | Glycine(10mM) | 4℃,20分钟 |
NMDA通道 | [3H]-MK 801(1nM) | PCP(10μM) | 20℃,120分钟 |
采用Brandle过滤装置,在用PEI(0.1%)预浸过的GF/B滤器上对游离放射性配体和结合放射性配体进行分离。在两种情况中,都采用冰冷的pH为7.4的Tris-乙酸盐(50mM)缓冲液(对使用[3H]-甘氨酸的实验而言,含有10mM MgSO4)快速进行过滤。对每个滤器都漂洗3次。用β计数器(Tricarb 1500,packard)测定放射性并以dpm表示。用GraphPad Prism软件(非线性回归)对所得曲线进行分析。结果(表1)
与甘氨酸B位点的结合反映出甘氨酸类产物(glycinergic prod-uct)对这一位点的亲和性(IC50)。甘氨酸这种内源性***配体、也推断为内源性***的D-丝氨酸(A.Hashimoto等人,J.Neu-rochem.,60,No.2,783-786,1993)以及拮抗物L701,324分别显示出大约为0.247μM、0.673μM和0.026μM的亲和性。
本发明的化合物显示出类似于部分***D-环丝氨酸和拮抗剂(+)-HA966的亲和性,即分别为6.8、7.4和7.3μM。NMDA受体复合体通道的开放受甘氨酸类位点的正调节。MK801是一种配体,它通过自身附着于通道内而发挥作用。这样,[3H]-MK801的结合受到甘氨酸类***的刺激,而受到甘氨酸类拮抗剂的抑制。因此,象甘氨酸、D-丝氨酸和D-环丝氨酸那样,本发明的化合物刺激[3H]-MK801的结合。应注意的是,对***而言,根据[3H]-MK801结合而获得的EC50值通常低于根据[3H]-甘氨酸结合而获得的IC50值。至于效果,甘氨酸产生一种59%最大刺激效果,该效果类似于D-丝氨酸;而部分***D-环丝氨酸仅产生22%的效果。本发明的化合物起到***的作用,其效果(46%)明显高于D-环丝氨酸,但稍低于甘氨酸和D-丝氨酸。就拮抗剂来说,所得抑制效果实际上是最大的。
表1
IC50抑制配体的结合达50%所需的产物浓度EC50刺激配体的结合达50%所需的产物浓度ME:以0%为基准、根据[3H]-MK801的结合而得到的产物最大效果:+=刺激而-=抑制。实施例3:药物组合物
[3H]-甘氨酸 | [3H]-MK 801 | |||
产物 | IC50(μM) | EC50(μM) | ME(%) | |
实施例1的化合物 | 6.812±0.545(7) | 4.330±1731(2) | +46±3在10μMF | |
***部分***拮抗剂 | 甘氨酸D-丝氨酸D-环丝氨酸(+)-HA966L701,324 | 0.247±0.024(19)0.673±0.198(8) | 0.068±0.013(4)0.161±83(2) | +59±6(4)在10μMF+69±20(2)在210μMF |
7.371±1.748(2) | 2.950±683(3) | +22±9在100μMF | ||
IC50(μM) | IC50(μM) | ME(%) | ||
7.343±1098(4) | 6.729(1) | -85±7(3)在100μM | ||
0.026±0.007(4) | 0.022(1) | -91±3(2)在1μMF |
制备1000片含10mg剂量的药片的配方:实施例1的化合物 10g羟丙基纤维素 2g小麦淀粉 10g乳糖 100g硬脂酸镁 3g滑石 3g
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FR9515223 | 1995-12-21 | ||
FR9515223A FR2742748B1 (fr) | 1995-12-21 | 1995-12-21 | Nouveau derive de 4-imidazolidinone, son procede de preparation et les compositions pharmaceutiques qui le contiennent |
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EP (1) | EP0780379B1 (zh) |
JP (1) | JPH09176128A (zh) |
CN (1) | CN1067381C (zh) |
AT (1) | ATE165349T1 (zh) |
AU (1) | AU705695B2 (zh) |
CA (1) | CA2193310C (zh) |
DE (1) | DE69600253T2 (zh) |
DK (1) | DK0780379T3 (zh) |
ES (1) | ES2118664T3 (zh) |
FR (1) | FR2742748B1 (zh) |
NO (1) | NO305753B1 (zh) |
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EP0319824A1 (en) * | 1987-12-01 | 1989-06-14 | G.D. Searle & Co. | D-cycloserine and its prodrugs as cognitive enhancers |
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EP0319824A1 (en) * | 1987-12-01 | 1989-06-14 | G.D. Searle & Co. | D-cycloserine and its prodrugs as cognitive enhancers |
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Publication number | Publication date |
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NO305753B1 (no) | 1999-07-19 |
NO965445D0 (no) | 1996-12-18 |
CA2193310A1 (fr) | 1997-06-22 |
DE69600253D1 (de) | 1998-05-28 |
ES2118664T3 (es) | 1998-09-16 |
NZ299984A (en) | 1997-11-24 |
CA2193310C (fr) | 2001-08-14 |
EP0780379B1 (fr) | 1998-04-22 |
CN1158847A (zh) | 1997-09-10 |
AU7547996A (en) | 1997-06-26 |
NO965445L (no) | 1997-06-23 |
FR2742748A1 (fr) | 1997-06-27 |
ZA9610804B (en) | 1997-06-30 |
DK0780379T3 (da) | 1999-01-25 |
DE69600253T2 (de) | 1998-11-12 |
ATE165349T1 (de) | 1998-05-15 |
FR2742748B1 (fr) | 1998-01-30 |
EP0780379A1 (fr) | 1997-06-25 |
US5677325A (en) | 1997-10-14 |
AU705695B2 (en) | 1999-05-27 |
JPH09176128A (ja) | 1997-07-08 |
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