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Synthesis of Pyrazine Substituted 1, 3, 4-Thiadiazole Derivatives And

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Synthesis of Pyrazine Substituted 1, 3, 4-Thiadiazole Derivatives And Hindawi Publishing Corporation Organic Chemistry International Volume 2013, Article ID 631723, 8 pages http://dx.doi.org/10.1155/2013/631723 Research Article Synthesis of Pyrazine Substituted 1,3,4-Thiadiazole Derivatives and Their Anticonvulsant Activity Kikkeri P. Harish,1 Kikkeri N. Mohana,1 and Lingappa Mallesha2 1 Department of Studies in Chemistry, University of Mysore, Manasagangotri, Mysore 570 006, India 2 PG Department of Chemistry, JSS College of Arts, Commerce and Science, Ooty Road, Mysore 570025, India Correspondence should be addressed to Kikkeri N. Mohana; [email protected] Received 1 April 2013; Revised 13 September 2013; Accepted 13 September 2013 Academic Editor: Ashraf Aly Shehata Copyright © 2013 Kikkeri P. Harish et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The synthesis of new pyrazine substituted 1,3,4-thiadiazole derivatives was carried out in good yield by the reaction of pyrazine 1 substituted 1,3,4-thiadiazoles with various sulfonyl chlorides. A chemical structure of all the new compounds was confirmed by H NMR and mass spectral data. The new compounds were screened for their anticonvulsant activity against maximal electroshock (MES) seizure method. Rotarod method was employed to determine the neurotoxicity. Few compounds showed significant changes in anticonvulsant activity. The same compounds showed no neurotoxicity at the maximum dose administered (100 mg/kg). 1. Introduction antiparkinsonism [11], antihistaminic [15], and antiasthmatic [16]. Thiazolidin-4-one derivatives are also known to exhibit Epilepsy has been recognized as a neurological disorder, diverse bioactivities such as anticonvulsant [17], antidiarrheal affecting a large section of people across the world. The word [18], antihistaminic [19], antidiabetic [20], cardioprotective epilepsy usually describes a group of common chronic neu- [21], and anticancer [22]. Similarly, 2,5-disubstituted 1,3,4- rological disorders characterized by recurrent unprovoked thiadiazoles also display wide spectrum of activities such seizures due to excessive neuronal firing or synchronous as antibacterial [23]andanticonvulsant[24]. In the present neuronal activity in the brain [1, 2]. Seizures may vary from study, a series of new pyrazine substituted 1,3,4-thiadiazole the briefest lapses of attention or muscle jerks to severe derivatives 7(a–o) have been synthesized and their anticon- and prolonged convulsions [3]. The maximal electroshock vulsant effects are determined through maximal electroshock (MES)testisapredictorofcompoundsthatareactiveagainst (MES) seizure test. seizures [4]. The anticonvulsant drug design is based on the presumption that at least one phenyl or similar aromatic groupincloseproximitytotwoelectrondonoratomsinthe 2. Materials and Methods compound is required for the activity in MES [5, 6]. Newer drugs such as flupirtine [7], topiramate [8], zonisamide [9], 2.1. Chemistry. Melting range was determined by Veego and vigabatrin [10] have emerged as promising anticonvul- Melting Point VMP III apparatus. Elemental analyses were 1 sants. recorded on VarioMICRO superuser V1.3.2 Elementar. H Pyrazines and its derivatives play an important role in the NMR spectra were recorded on Bruker DRX-500 spectrom- drug discovery realm. In particular the structural analogue of eter at 400 MHz using DMSO-d6 as solvent and TMS as purines derivatives presents various pharmacological activi- an internal standard. Mass spectral data were obtained by ties such as antibacterial [11], anti-inflammatory [12], antide- LC/MSD Trap XCT. Silica gel column chromatography was pressant [13], and antiproliferative activities [14]. Thiadiazoles performed using Merck 7734 silica gel (60–120 mesh) and exhibit a broad spectrum of biological effectiveness such as Merck-made TLC plates. 2 Organic Chemistry International 2.1.1. Preparation of 1,3,4-Thiadiazole-2-ylamine (2). Thi- 4 N HCl in dioxane (80.0 mL) was added. The reaction was osemicarbazide (1,50.0g,0.5486mol)wastakenin100mL stirred at room temperature for 10 hr. The solid was filtered, formic acid and the reaction was stirred at room temperature washed with diethyl ether, and packed in air tight container for1hr.Thereactionwascooledand100mLconc.hydro- toyieldtheabovecompoundaspaleyellowhygroscopicsolid 1 chloric acid was added. Reaction completion was monitored 6 ∘ (16.73 g, 90%). H-NMR(400MHz,DMSO-d ): 3.22 (t, J = by TLC. The reaction was cooled to 0 C and basified with 3.75 Hz, 4H), 3.73 (t, J = 4.30 Hz, 4H), 8.83 (d, J =2.00Hz, ammonium hydroxide solution. The solid formed was fil- 1H), 8.94 (d, J = 2.00 Hz, 1H), 9.27 (s, 1H), 9.72 (s, 2H). MS tered, washed with water, and dried to yield the above (ESI) m/z:292.05. 1 compound as off white solid (Yield: 45.50 g, 82%). H- NMR (400 MHz, DMSO-d6): 4.21 (s, br, 2H), 9.31 (s, 1H). 2.1.6. General Procedure for the Synthesis of Pyrazine Substi- MS (ESI) m/z:102.14. tuted 1,3,4-Thiadiazole Derivatives 7(a–o). To a mixture of 6 (1.0 eq) and triethyl amine (4.5 eq) in dichloromethane (10 2.1.2. Preparation of 5-Bromo-1,3,4-thiadiazol-2-amine (3). volume), substituted sulphonyl chloride (2.4 eq) was added at ∘ To a stirred solution of 2 (40.0 g), sodium acetate (64.89 g) in 5–10 C and stirred overnight at room temperature. Reaction ∘ 200 mL acetic acid (4.0 vol) at 10 C, bromine was added drop completion was confirmed through TLC. The reaction was wise (37.92 g). The reaction was stirred at room temperature poured into separating funnel, washed with water followed for 3 hours. The reaction was concentrated and basified with by brine solution, and dried over anhydrous sodium sulphate. saturated sodium bicarbonate solution. The compound was Crude product was purified by crystallization using ethyl extracted with ethyl acetate and the ethyl acetate layer was acetate to yield the thiadiazole substituted sulfonamide as off washed with water followed by brine, dried over sodium whitetopaleyellowsolids. sulphate. The crude product was crystallized using ethyl acetate to yield the above compound as off white solid (Yield: (1) N-(5-(4-((1,l’-Biphenyl)sulfonyl)piperazine-1-yl)-1,3,4-thia- 1 ( ) 53.4 g, 75%). H-NMR (400 MHz, DMSO-d6): 4.21 (s, br, diazole-2-yl)pyrazine-2-carboxamide 7a . Yield: 70% (White 1 2H). MS (ESI) m/z:181.10. solid); H-NMR(400MHz,DMSO-d6): 3.18 (t, J =4.10Hz, 4H), 3.67 (t, J = 5.02 Hz, 4H), 7.40–7.52 (m, 3H), 7.64–7.87 2.1.3. Preparation of tert-Butyl 4-(5-amino-1,3,4-thiadiazole- (m, 6H), 8.81 (d, J = 2.35 Hz, 1H), 8.90 (d, J =2.45Hz,1H), 2-yl)piperazine-1-carboxylate (4). To a stirred solution of 3 9.26 (s, 1H), 12.2 (s, 1H). MS (ESI) m/z: 508.6. Anal. Calcd. for (25.0 g, 0.1388 mol), potassium carbonate (57.57 g, 0.4165 C23H21N7O3S2:C,54.42;H,4.17;N,19.32;Found:C,54.13;H, mol) in dimethyl formamide (250 mL) and mono boc piper- 4.32; N, 19.52%. azine (31.03 g, 0.1666 mol) were added and stirred the (2) N-(5-(4-((2,4-Dimethylphenyl)sulfonyl)piperazine-1-yl)-1, reaction for 10 hr at room temperature. The reaction was 3,4-thiadiazole-2-yl)pyrazine-2-carboxamide (7b). Yield: 72% quenched into ice water (2.0 L) and stirred at room temper- 1 ature for 1 hr. Solid formed was filtered and dried to yield (Off white solid); H-NMR (400 MHz, DMSO-d6): 2.34 (s, the above compound as off white solid (Yield: 33.6 g, 85%). 3H), 2.37 (s, 3H), 3.21 (t, J = 4.01 Hz, 4H), 3.68 (t, J =4.90Hz, 1 4H), 7.22 (s, 1H), 7.42 (d, J = 6.35 Hz, 2H), 8.70 (d, J =2.25Hz, H-NMR (400 MHz, DMSO-d6): 1.41 (s, 9H), 3.10 (t, J = 1H), 8.81 (d, J = 2.46 Hz, 1H), 9.16 (s, 1H), 12.3 (s, 1H). MS (ESI) 4.80 Hz, 4H), 3.77 (t, J = 5.36 Hz, 4H), 4.21 (s, 2H). MS (ESI) m/z: 460.60. Anal. Calcd. for C19H21F6N7O3S2:C,49.66;H, m/z: 286.03. 4.61; N, 21.34; Found: C, 49.75; H, 4.68; N, 21.46%. 2.1.4. Preparation of tert-Butyl-4-(5-(pyrazine-2-carbox- (3) N-(5-(4-(Methylsulfonyl)piperazine-1-yl)-1,3,4-thiadiazole amido)-1,3,4-thiadiazol-2-yl)piperazine-1-carboxylate (5). To -2-yl)pyrazine-2-carboxamide (7c). Yield: 72% (White solid); a stirred solution of 4 (25.0 g, 0.0876 mol), in dichloro- 1 H-NMR (400 MHz, DMSO-d6): 2.35(s,3H),3.23(t,J = methane (250 mL), triethyl amine (26.59 g, 0.2628 mol), 3.86 Hz, 4H), 3.72 (t, J = 4.31 Hz, 4H), 8.83 (d, J =2.00Hz, pyrazine-2-carboxylic acid (13.04 g, 0.1051 mol) and TBTU 1H), 8.94 (d, J =2.00Hz,1H),9.27(s,1H),12.1(s,br,1).MS (33.75 g, 0.1051 mol) were added. The reaction was stirred (ESI) m/z: 370.40. Anal. Calcd. for C12H15N7O3S2:C,39.01; overnight at room temperature and the reaction completion H,4.09;N,26.54;Found:C,38.97;H,3.96;N,26.74%. was monitored by TLC. The reaction was washed with saturated bicarbonate solution followed by 1.0 N HCl, water, (4) N-(5-(4-((2,5-Dichlorothiophen-3-yl)sulfonyl)piperazine- andbrine.Theorganiclayerwasdriedoversodiumsulphate, 1-yl)-1,3,4-thiadiazole-2-yl)pyrazine-2-carboxamide (7d).
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