三唑杂环衍生物的合成及其抗癫痫活性研究
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摘要
本文以7-烷氧基-4H-苯并[b][1,2,4]三唑并[4,3-d][1,4]噻嗪(Ⅵ)为先导化合物,应用扩环、缩环,电子等排和环裂解等原理对先导化合物进行结构改造,设计合成了7个系列(T1-T7)共113个三唑类化合物。
所有化合物经IR、1H-NMR和MS等方法确证结构并对其进行了抗癫痫活性的评价。本文主要使用最大电休克发作实验(MES),评估化合物的抗癫痫活性,以旋转法来评估神经毒性。采取循序渐进的方案,淘汰活性低的化合物,对于活性突出的化合物进行了深入活性评价,得出其半数有效剂量EDso、半数中毒剂量TD50和保护指数PI值(PI=TD50/ED50)。并对部分化合物进行了化学物质诱导惊厥实验,以进一步考察化合物的广谱抗癫痫活性和推测其可能的作用机制。
药理实验结果显示,设计合成的113个化合物大部分具有不同程度的抗癫痫活性。其中,最低有效剂量为300mg/kg,100mg/kg和30mg/kg的化合物百分比分别为34.6%,32.3%和23.8%,只有9.3%的化合物在300mg/kg的剂量下没有显示出活性。在这些化合物中,出现了具有一定开发价值的候选化合物。譬如化合物T1g的EDso为8.0mg/kg, PI值为15.0,其抗癫痫活性和安全性都要优于阳性药卡马西平、苯妥英钠和丙戊酸钠；化合物T4i的EDso等于19.7mg/kg, PI值达到34.8。虽然其活性要略低于卡马西平和苯妥英钠(强于丙戊酸钠),但由于其神经毒性很低,导致其具有很高的安全性,它的保护指数分别是丙戊酸钠、卡马西平和苯妥因钠的22、7.7和5.0倍。
此外,化合物T1g, T3f, T4i和T7h在化学物质(包括戊四唑,3-巯基丙酸和荷包牡丹碱)诱发的惊厥实验中,表现出了较好的活性,表明了这些化合物在对电惊厥模型有效的同时,又对化学致惊厥模型有效。这在一定程度上说明该化合物具有广谱抗惊厥活性。同时,基于这几种化学物质诱发惊厥的原因,初步推测了它们在体内的作用机制,即这些化合物可能是通过增加GABA能神经递质水平或GABA的活性,以及调节GABAa受体而发挥抗惊厥活性的。
总之,通过对先导化合物的结构改造,并对所合成的化合物进行抗惊厥活性的筛选,丰富了三唑类化合物抗癫痫活性的构效关系,得到一些药理性质优于临床药物的候选化合物,这一工作为开发出新抗癫痫药物奠定了基础。
In this study, eight series of triazole derivatives (T1-T7) were designed and synthesized using7-alkoxy-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]thiazine (Ⅵ) as leading compounds, based on ring-expanding/reducing, bioisosterism and dissociation of a fused ring system.
All the structures of the synthesized compounds were characterized by1H-NMR, IR and MS. We use the maximal electroshock seizure test (MES) and the rotarod test to evaluate the anticonvulsant activity and neurotoxicity of these compounds, respectively. From the preliminary screens, the compounds holding promising potency were subjected to phase II trials for quantification of their anticonvulsant activity and neurotoxicity (indicated by ED50and TD50). In addition, some compounds were tested against convulsions induced by chemical substances with the aim to further investigate their anticonvulsant activity and speculating the possible mechanism of anticonvulsant activity.
The pharmacological results showed that most of the target compounds showed the anticonvulsant activity in different levels in the MES screens. Among which, the percentage of compounds which were active at minimum dose of300,100and30mg/kg were34.6%,32.3%and23.8%respectively. Only9.3%of compounds prepared were found absence of anticonvulsant activity at300mg/kg. In this study, some candidate compounds with certain development value were obtained. For examp.le, compound T1g, with an EDso value of8.0mg/kg and a protective index (PI=TD50/ED50) value of15.0, showed better anticonvulsant activity and higher safety than clinical drugs carbamazepine, phenytoin sodium and valproic acid sodium; compound T4i, though showed weaker activity than carbamazepine and phenytoin sodium (better than valproic acid sodium) with an ED50value of19.7mg/kg, exhibited a very low neurotoxicity, providing this compound a big safety margin with a PI value of34.8. This value was22folds,7.7folds and5folds of that of valproic acid sodium, carbamazepine and phenytoin sodium, respectively.
In addition, compounds T1g, T3f, T4i and T7h exhibited strong inhibitory activity in chemical (pentylenetetrazole,3-mercaptopropionic acid and bicuculline) induced seizures models, which further confirmed the broad-spectrum anticonvulsant activity of these compounds. Base on the known knowledge of the seizures induced by these chemical, the mechanism of anticonvulsant activity of enhancing GABAergic activity/level or modulating the GABAA receptor were suggested.
In a word, a process screening novel potential anti-epilepsy drugs was stated in the paper. The structure-activity relationships of triazole derivatives as anti-epilepsy drugs were enriched and several compounds with better pharmacological properties than clinic drugs were found. This study lays the foundation for the development of new anti-epilepsy drugs.
所有化合物经IR、1H-NMR和MS等方法确证结构并对其进行了抗癫痫活性的评价。本文主要使用最大电休克发作实验(MES),评估化合物的抗癫痫活性,以旋转法来评估神经毒性。采取循序渐进的方案,淘汰活性低的化合物,对于活性突出的化合物进行了深入活性评价,得出其半数有效剂量EDso、半数中毒剂量TD50和保护指数PI值(PI=TD50/ED50)。并对部分化合物进行了化学物质诱导惊厥实验,以进一步考察化合物的广谱抗癫痫活性和推测其可能的作用机制。
药理实验结果显示,设计合成的113个化合物大部分具有不同程度的抗癫痫活性。其中,最低有效剂量为300mg/kg,100mg/kg和30mg/kg的化合物百分比分别为34.6%,32.3%和23.8%,只有9.3%的化合物在300mg/kg的剂量下没有显示出活性。在这些化合物中,出现了具有一定开发价值的候选化合物。譬如化合物T1g的EDso为8.0mg/kg, PI值为15.0,其抗癫痫活性和安全性都要优于阳性药卡马西平、苯妥英钠和丙戊酸钠；化合物T4i的EDso等于19.7mg/kg, PI值达到34.8。虽然其活性要略低于卡马西平和苯妥英钠(强于丙戊酸钠),但由于其神经毒性很低,导致其具有很高的安全性,它的保护指数分别是丙戊酸钠、卡马西平和苯妥因钠的22、7.7和5.0倍。
此外,化合物T1g, T3f, T4i和T7h在化学物质(包括戊四唑,3-巯基丙酸和荷包牡丹碱)诱发的惊厥实验中,表现出了较好的活性,表明了这些化合物在对电惊厥模型有效的同时,又对化学致惊厥模型有效。这在一定程度上说明该化合物具有广谱抗惊厥活性。同时,基于这几种化学物质诱发惊厥的原因,初步推测了它们在体内的作用机制,即这些化合物可能是通过增加GABA能神经递质水平或GABA的活性,以及调节GABAa受体而发挥抗惊厥活性的。
总之,通过对先导化合物的结构改造,并对所合成的化合物进行抗惊厥活性的筛选,丰富了三唑类化合物抗癫痫活性的构效关系,得到一些药理性质优于临床药物的候选化合物,这一工作为开发出新抗癫痫药物奠定了基础。
In this study, eight series of triazole derivatives (T1-T7) were designed and synthesized using7-alkoxy-4H-benzo[b][1,2,4]triazolo[4,3-d][1,4]thiazine (Ⅵ) as leading compounds, based on ring-expanding/reducing, bioisosterism and dissociation of a fused ring system.
All the structures of the synthesized compounds were characterized by1H-NMR, IR and MS. We use the maximal electroshock seizure test (MES) and the rotarod test to evaluate the anticonvulsant activity and neurotoxicity of these compounds, respectively. From the preliminary screens, the compounds holding promising potency were subjected to phase II trials for quantification of their anticonvulsant activity and neurotoxicity (indicated by ED50and TD50). In addition, some compounds were tested against convulsions induced by chemical substances with the aim to further investigate their anticonvulsant activity and speculating the possible mechanism of anticonvulsant activity.
The pharmacological results showed that most of the target compounds showed the anticonvulsant activity in different levels in the MES screens. Among which, the percentage of compounds which were active at minimum dose of300,100and30mg/kg were34.6%,32.3%and23.8%respectively. Only9.3%of compounds prepared were found absence of anticonvulsant activity at300mg/kg. In this study, some candidate compounds with certain development value were obtained. For examp.le, compound T1g, with an EDso value of8.0mg/kg and a protective index (PI=TD50/ED50) value of15.0, showed better anticonvulsant activity and higher safety than clinical drugs carbamazepine, phenytoin sodium and valproic acid sodium; compound T4i, though showed weaker activity than carbamazepine and phenytoin sodium (better than valproic acid sodium) with an ED50value of19.7mg/kg, exhibited a very low neurotoxicity, providing this compound a big safety margin with a PI value of34.8. This value was22folds,7.7folds and5folds of that of valproic acid sodium, carbamazepine and phenytoin sodium, respectively.
In addition, compounds T1g, T3f, T4i and T7h exhibited strong inhibitory activity in chemical (pentylenetetrazole,3-mercaptopropionic acid and bicuculline) induced seizures models, which further confirmed the broad-spectrum anticonvulsant activity of these compounds. Base on the known knowledge of the seizures induced by these chemical, the mechanism of anticonvulsant activity of enhancing GABAergic activity/level or modulating the GABAA receptor were suggested.
In a word, a process screening novel potential anti-epilepsy drugs was stated in the paper. The structure-activity relationships of triazole derivatives as anti-epilepsy drugs were enriched and several compounds with better pharmacological properties than clinic drugs were found. This study lays the foundation for the development of new anti-epilepsy drugs.
引文
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[1]Achgill R K, Call L W. Process for the preparation of tricylagol. GB 2,027,700 A, February 27,1980.
[2]Voitenko Z V, Egorova T V, Kovtunenko V A. TRIAZOLO-AND TETRAZOLOISOINDOLES. Chemistry of Heterocyclic Compounds,2002,38,9
[3]Abdel-Hafez A A, Elsherief H A, Kurokawa M Jo M, et al. Synthesis and evaluation of anti-HIV-1 and anti-HSV-1 activities of 4H-[1,2,4]-triazolo[1,5-a]pyrimidin-5-one derivatives. Arzneimittelforschung,2002,52,833-9.
[4]White H S. Preclinical development of antiepileptic drugs:past, present, and future directions. Epilepsia,2003,44 (Suppl.7),2-8.
[5]Levy R H, Mattson R H, Meldrum B S. (Eds.), Raven Press:New York,1995, p 99-110.
[6]Loscher W, Nolting B. The role of technical, biological and pharmacological factors in the laboratory evaluation of anticonvulsant drugs. IV. Protective indices. Epilepsy Res,1991,9,1-10
[7]Kupferberg H J. Antiepileptic Drug Development Program:A Cooperative Effort of Government and Industry. Epilepsia,1989,30, S51
[8]Okada R, Negishi N, Nagaya H. The role of the nigrotegmental GABAergic pathway in the propagation of pentylenetetrazol-induced seizures. Brain Res.1989,480,383-387
[9]Gale K. GABA and epilepsy:basic concepts from preclinical research. Epilepsia, 1992,33,S3-S12.
[10]Loscher W.3-Mercaptopropionic acid:convulsant properties, effects on enzymes of the gamma-aminobutyrate system in mouse brain and antagonism by certain anticonvulsant drugs, aminooxyacetic acid and gabaculine. Biochem. Pharmacol., 1979,28,1397-1407.
[11]Macdonald R L, Barker J L. Specific antagonism of GABA-mediated postsynaptic inhibition in cultured mammalian spinal cord neurons:a common mode of convulsant action. Neurology,1978,28,325-330.