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Synthesis and anticonvulsant activity of 8-alkoxy -5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives 8-烷氧基-5,6-二氢-4H-[1,2,4]三唑并[4,3-a]苯并氮卓-1-酮衍生物的合成及抗惊厥活性 Abstract A series of nolve 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives were synthesized using appropriate synthetic route. The newly synthesized compounds were characterized by IR, 1H NMR, mass and elemental analysis. All compounds were screened for their anticonvulsant activities by the maximal electroshock (MES) test and their neurotoxicity was evaluated by the rotarod neurotoxicity test (Tox).The MES test showed that compounds 3f and 3m were found to possess the most potential anticonvulsant activity but also had very low toxicity. In the anti-MES potency test, these compounds exhibited median effective dose (ED50) of 17.6 mg/kg, and median toxicity dose (TD50) both greater than 1117.4 mg/kg, resulting in a protective index (PI) of greater than 63.4 and 52.6, respectively, which is significantly greater than the PI of the marked antiepileptic drug carbamazepine.The possible structure-activity relationship was dischssed. 1. Introduction According to literature reports, currently available antiepileptic drugs (AEDs) provide adequate seizure control in many patients, still about 28–30% of patients are estimated to be poorly treated[1,2]. Therefore, continued search for safer and more effective AEDs is urgently necessary. Much efforts devoted in the recent years for the development of novel compounds as potential anticonvulsant agents[3-11]. Benzazepine derivatives have exhibit broad pharmacological activity[12-15]. Triazole compounds have wide variety of biological activities, the introduction of triazole ring to some activre molecules may significantly improve the biological activity of the parent molecule due to the superposition of biolegical activity[16-19]. In our search for new compounds with anticonvulsant activity, 1,3,4,5-tetrahydro-7- alkoxy-2H-1-benzazepin-2-one derivatives showed a moderate anticonvulsant activity, among which 1,3,4,5-tetrahydro-7- butyloxy -2H-1-benzazepin-2-one(1b), revealed as the best anticonvulsant activity with an effective dose of 52.8 mg/kg in the anti-MES test. In order to obtain compounds with better anticonvulsant activity, the target compounds were synthesized through a convenient synthetic sequence. The new compounds were evaluated as anticonvulsant agents in experimental epilepsy models, i.e., maximal electroshock test (MES) and neurotoxicity was evaluated by using the rotarod test. 2. Results and discussion 2.1. Chemistry Target compounds were prepared according to Scheme 1. The starting material 1,3,4,5-tetrahydro-7-hydroxy -2H-1-benzazepin-2-one wsa synthesized using the method described in a former paper of our group[12], which reacted with appropriate alkyl halide to produce the compounds 1a-1p[12].Compounds 1a–lp then reacted with phosphorus pentasulfide in acetonitrile in the presence of triethylamine under protection of nitrogen, and the resulting compound 2a–2p reacted further with methyl hydrazine carboxylate in n-butanol to produce the target compounds 3a-3p. The structures of all the new compounds were confirmed by IR, 1H NMR, MS and elemental analyses and their anticonvulsant activities have been initially screened. Scheme 1. The synthesis route of compounds 3a-3p. Reagents: (a) RX/C2H5OH, 80-92℃; (b) P2S5, (C2H5)3N /CH3CN, 86-92℃, 5-7 h; (d) H2NNHCOOCH3/ (CH3)(CH2)3OH, 140-150℃, 40-48 h R: 3a = n- C3H7 3e = n-C7H15 3i = CH2C6H4(m-Cl) 3m = CH2C6H4(p-F) 3b = n-C4H9 3f =n-C8H17 3j = CH2C6H4(p-Cl) 3o= CH2C6H4(p-CH3) 3c = n-C5H11 3g = CH2C6H5 3k = CH2C6H4(o-F) 3p= CH2C6H4(p-Br) 3d= n-C6H13 3h = CH2C6H4(o-Cl) 3l = CH2C6H4(m-F) 2.2. Pharmacology The results of preliminary (phase I) screening of compounds 3a–3p are summarized in Table 1. All the synthesized compounds exhibited anticonvulsant activity, among which twelve compounds 3c–3o possessed anticonvulsant activity against MES-induced seizure at the dose of 30 mg/kg, and then two compounds 3b and 3o, were active at the dose of 100 mg/kg. The remaining one compound 3a exhibited anti-MES effect only under the high dose of 300 mg/kg. As a result of preliminary screening, compounds 3b-3o were subjected to phase II trials for quantification of their anticonvulsant activity (indicated by ED50) and neurotoxicity (indicated by TD50) in mice (Table 2). Among these derivatives, the most potent compounds 3f and 3m exhibited similar activity with ED50 value of 17.6 mg/kg in the MES test, furthermore,they had significantly lower neurotoxicity (TD50＞1117.4 mg/kg, TD50＞931.2 mg/kg, respectively) than the marked antiepileptic drug carbamazepine. And their PI value (PI＞63.4, PI＞52.6, respectively) was superior to that of carbamazepine (TD50=71.6 mg/kg, PI=8.1) in the MES test. Analyzing the activities of the synthesized compounds the following structure–activity relationships (SAR) were obtained. Generally, the anticonvulsant activity of an organic compound might be increased remarkably after the introduction of a halogen atom. So, some halogen substituted derivatives were designed and synthesized in this paper. Comparison of the halogen substituted derivatives indicated that different halogen atoms contributed to the anticonvulsant activity in the order of F＞Cl＞Br; the introduction of F atom on the benzyl ring led to stronger activity. Comparing the derivatives with different F-substitution positions on the benzyl ring, their activity order was m-F＞o-F＞p-F, and activity order of the Cl- and Br- atom substituted derivatives was m-Cl＞o-Cl＞p-Cl＞p-Br. One electron donor derivative(3o) was also designed and prepared, and its activity was slightly low. Length of the alkyl chain appeared to have a direct impact on anticonvulsant activity of the 7-alkyloxyl derivatives. From compound 3a to 3g, as alkyl chain length increased, ED50 gradually increased with the compound 3f being the most active. The trend reversed, however, when the alkyl chain had more than seven carbon atoms. Among the 7-benzyloxy derivatives, the anticonvulsant activity of compounds containing substituted benzyloxy((o-F, m-F, p-F, m-Cl) was stronger than that of the compound with non-substituted benzyloxy (3h). The potency order of three F-substituted derivatives was m-F＞o-F＞p-F. The m-F-substituted derivative 3m exhibited the strongest anticonvulsant activity. The anticonvulsant activity of another four substituted-benzyl derivatives 3i, 3k, 3o and 3p was lower that of the compound with non-substituted benzyloxy (3h). 3. Conclusions A series of nolve 8-alkoxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one derivatives were synthesized. All synthesized compounds displayed anticonvulsant activity at 100 mg kg-1 except compound 3a, and their structure-activity relationship was discussed in the present study. In particular, we found that 8-heptyloxy-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3f) and 8-(3-Fluorobenzyloxy) -5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1]benzazepin-1-one (3m) possessed the most potential anticonvulsant activity with an ED50 value of 17.6 mg kg-1. Both compounds exhibited marked lower neurotoxicity. So a much larger protective index was observed for the two compounds in mice compared with the carbamazepin. They can be used as a lead for further development of more potent anticonvulsant agents. 4. Experimental section 4.1. Chemistry Melting points were determined on X-5 microscope melting point apparatus, which were uncorrected. IR spectra were recorded (in KBr) on a FT-IR (IRPRESTIGE-21). 1H-NMR spectra were measured on an AV-300 (Bruker, Switzerland), and all chemical shifts were given in parts per million relative to tetramethylsilane. Mass spectra were measured on a HP1100LC (Agilent Technologies, USA). Combustion analyses (C, H and N) were performed on a PE-2400 (SHIMADZU). Microanalyses of C, N, and H were performed using a Heraeus CHN Rapid Analyzer. The major chemicals were purchased from Alderich Chemical Corporation. All other chemicals were of analytical grade. General procedure for the preparation of 2a–2p Acetonitrile (1.0 ml) and triethylamine (0.6 ml) were placed in a three-necked round-bottomed flask, to which P2S5 (0.4 g, 1.9 mmol) was added slowly in an ice bath and stirred until dissolved. Then 1a–1p (1.7 mmol) was added while stirring. The mixture was refluxed for 4-6 h in a nitrogen atmosphere. After removing the solvent under reduced pressure, the residue was dissolved in 60 ml of dichloromethane, washed with water (60 × 3), and dried over anhydrous MgSO4. Evaporation of the solvents gave a crude product. General procedure for preparation of compounds 3a-3p Crude product 2a–2p (2 mmol) reacted with methyl hydrazine carboxylate (4mmol) in n-butanol 10 mL under nitrogen atmosphere for 40-48h, the solvent was removed under reduced pressure, and the residue dissolved with Ethy1 acetate and washed with water three times. The Ethy1 acetate layer was dried with anhydrous MgSO4, filtered, and concentrated the solvent, and the residue was purified by silica gel column chromatography (Dichloromethane : Methanol = 35 : 1) to afford target compounds 3a–3p. 4.2. Pharmacology The MES test and rotarod test were carried out by the Antiepileptic Drug Development Program (ADD), Epilepsy Branch, National Institutes of Health, Bethesda, MD, USA.[20-21]. All compounds were tested for anticonvulsant activity with Swiss mice in the 18–22 g weight range purchased from the Laboratory of Animal Research, College of Pharmacy, Yanbian University. The tested compounds were dissolved in DMSO. In phase I screening (Table 1) each compound was administered at three dose levels (30, 100, and 300 mg/ kg ip) with anticonvulsant activity and neurotoxicity assessed at 30 min intervals after administration. Anticonvulsant efficacy was measured in the MES test. In the MES test, seizures were elicited with a 60 Hz alternating current of 50 mA intensity in mice. The current was applied via corneal electrodes for 0.2 s. Abolition of the hind-leg tonic-extensor component of the seizure indicated protection against the spread of MES-induced seizures. Anticonvulsant drug-induced neurologic deficit was detected in mice by using the rotarod ataxia test. Anticonvulsant activity was expressed in terms of the median effective dose (ED50), and neurotoxicity was expressed as the median toxic dose (TD50). For determination of the ED50 and TD50 values, groups of 10 mice were given a range of intraperitoneal doses of the tested compounds until at least three points were established in the range of 10-90% seizure protection or minimal observed neurotoxicity. From the plots of these data, the respective ED50, TD50 values and 95% confidence intervals were calculated by means of Trimmed Spearman-Karber method[22]. Acknowledgment This work was supported by the National Natural Science Foundation of China (No. 30460151 and No. 30760290) and Important Item Foundation of Ministry of Education P.R. China (No. 20070422029). References [1] P. Yogeeswari, D. Sriram, R. Thirumurugan, J. Raghvendran, K. Sudan, R. Pavana, J. Stables, J. Med. Chem. 48 (2005) 6202–6211. [2] K.J. Meader, J. Clin. Psychiatry 64 (2003) 30–34. [3] M.Bialer, & H. Steve White, Nat. Rev. Drug Discovery. 9 (2010) 68-82. [4] E. Perucca, J.French, M.Bialer, Lancet Neurol. 6 (2007) 793-804. [5] M. Bialer, S. I. Johannessenb, H. J. Kupferbergc, R. H. Levyd, E. Peruccae, T. Tomsonf, Epilepsy Res. 73 (2007) 1-52 [6] W. Löschera, D. Schmidtb, Epilepsy Res. 69 (2006) 183–272 [7] Li-Ping Guan, Cheng-Xi Wei, Xian-Qing Deng, Xin Sui, Hu-Ri Piao, Zhe-Shan Quan*, Eur J Med Chem. 44 (2009) 3654–3657 [8] Nikhil D. Amnerkar, Kishore P. Bhusari*45 (2010) 149–159 [9] H. Stefan, T. Feuerstein, Pharmacol. Ther. 113 (2007) 165–183. [10] J.R. Pollard, J. French, Lancet Neurol. 5 (2006) 1064–1067. [11] E.J. Donner, O.C. Snead III, NeuroRX 3 (2006) 170–180. [12] C. X. Wei; W. Zhang; Z. S. Quan; R. B. Han; R. S. Jiang; F. Y. Piao*, Lett. Drug Des. Discov., 2009, 6, 548-553. [13] Felix M. Rivas; James P. Stables; Lauren Murphree; Rahul V. Edwankar; Chitra R. Edwankar; Shengming Huang; Hiteshkumar D. Jain; Hao Zhou; Samarpan Majumder; Subramanian Sankar; Bryan L. Roth; Joachim Ramerstorfer; Roman Furtmüller; Werner Sieghart and James M. Cook*., J. Med. Chem., 2009, 52, 1795–1798 [14] Jitender B. Bariwal; Kuldip D. Upadhyay; Atul T. Manvar; Jalpa C. Trivedi; Jyoti S. Singh; Kishor S. Jain; Anamik K. Shah*., European Journal of Medicinal Chemistry, 2008, 43, 2279-2290 [15] Isak Im; Thomas R. Webb; Young-Dae Gong; Jae-Il Kim and Yong-Chul Kim*., J. Comb. Chem., 2004, 2, 207–213 [16] Xian-Yu Sun; Lei Zhang; Cheng-Xi Wei; Hu-Ri Piao; Zhe-Shan Quan*, European Journal of Medicinal Chemistry, 2009, 44, 1265-1270 [17] Li-Ping Guan; Qing-Hao Jin; Guan-Rong Tian; Kyu-Yun Chai and Zhe-Shan Quan*, J. Pharm. Pharmaceut Sci., 2007, 3, 254-262 [18] Hong-Guang Jin; Xian-Yu Sun; Kyu-Yun Chai; Hu-Ri Piao and Zhe-Shan Quan*., Bioorganic & Medicinal Chemistry, 2006, 14, 6868–6873 [19] Xian-Yu Sun; Cheng-Xi Wei; Kyu-Yun Chai; Hu-Ri Piao and Zhe-Shan Quan, Arch. Pharm. Chem. Life Sci., 2008, 341, 288 – 293 [20] Krall, R. L.;Penry, J. K.;White, B. G.; Kupferberg, H. J.;Swinyard, E. A. Antiepileptic drug development:II.Anticonvulsant drug screening. Epilepsia., 1978, 19, 409-428. [21] Porter, R. J.;Cereghino, J. J.;Gladding, G. D.; Hessie, B. J.; Kupferberg, H. J.; Scoville, B. Antiepileptic drug development program. Cleveland Clin., 1984, 51, 293-305 [22] Okada, R.; Negishi, N.; Nagaya, H. The role of the nigrotegmental GABA ergic pathway in the propagation of pentylenetetrazolinduced seizures. Brain Res., 1989, 480, 383-387. |
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wypward(金币+1):谢谢参与 2010-09-06 21:30:48
hanjing011(金币+60, 翻译EPI+1):谢谢 2010-09-11 07:51:53
wypward(金币+1):谢谢参与 2010-09-06 21:30:48
hanjing011(金币+60, 翻译EPI+1):谢谢 2010-09-11 07:51:53
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感觉很地道，几个地方供参考： 1、 题目：anticonvulsant activity——anticonvulsant activities; 2、 and their neurotoxicity was evaluated----and their neurotoxicities were evaluated…. 3、 The possible structure-activity relationship was dischssed.----discussed? |
2楼2010-09-06 15:55:02
