International Journal of Pharma and Bio Sciences ISSN 0975-6299 1,5
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Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 Review Article Medicinal Chemistry International Journal of Pharma and Bio Sciences ISSN 0975-6299 1,5-BENZODIAZEPINE: A VERSATILE PHARMACOPHORE P.S. SALVE* AND D.S. MALI Department of Pharmaceutical Chemistry, KLE University’s College of Pharmacy, Belgaum, Karnataka, India. ABSTRACT Diazepines are an eminent class of drugs owing to their psychotherapeutic activities. Among these, 1,5-benzodiazepines are regarded as privileged structures due to their clinical importance and commercial success. Although immense work has been carried out on the benzodiazepine nucleus, it continues to receive a great deal of attention. Due to their vast range of biological properties the benzodiazepine nucleus has fascinated many investigators to synthesize and screen the analogues for all possible activities through all possible routes. This current review article mainly covers the various routes of synthesis utilized, the numerous solvents employed, catalysts used and the different pharmacological activities exhibited by 1,5-benzodiazepine derivatives. This review encompasses the research work that has been accomplished since the past decade. KEYWORDS: 1,5-Benzodiazepines, o-Phenylenediamines, Synthesis, Catalyst, Diazepines P.S. SALVE Department of Pharmaceutical Chemistry, KLE University’s College of Pharmacy, Belgaum, Karnataka, India. *Corresponding author This article can be downloaded from www.ijpbs.net P - 345 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 INTRODUCTION Benzodiazepines are an important class of activities.1,2 They have also been used in nitrogen containing heterocyclic compounds treatment of viral diseases3,4, cardiovascular acting mainly on the central nervous system. disorders5 and as cholecystokinin (CCK) They have attracted much attention in the field receptor antagonists.6,7The 1,5-benzodiazepine of medicine and pharmaceuticals due to their scaffold is extremely versatile and has featured broad spectrum of biological activities. in a number of clinically used drugs. Out of Immense research has been done on the which about five 1,5-benzodiazepines are in benzodiazepine nucleus. A lot of work has therapeutic use for their sedative, anxiolytic been carried out to synthesize and screen its and anticonvulsant activities viz. clobazam, analogues for all possible activities due to its arfendazam, lofendazam, triflubazam and CP- wide range of pharmacological 1414S.Clobazam has been marketed as an activities.Recently 1,5-benzodiazepines have anxiolytic since 1975 and as an anticonvulsant attained huge clinical importance and since 1984.8 It is marketed under the brand commercial success. It has proved to be a very names frisium, urbanol and onfi. Clobazam has versatile moiety as various derivatives of proved useful in the treatment of epilepsy, benzodiazepines have shown various activities anxiety and also as a short term adjunctive like anticonvulsant, anti-anxiety, analgesic, agent in schizophrenia and other psychotic sedative, antidepressant and hypnotic disorders to manage anxiety or agitation. Clobazam Arfendazam has sedative and anxiolytic effects. It produces muscle relaxant effects at very high doses.9,10 It is closely related to clobazam and produces an active metabolite lofendazam, which is thought to be responsible for part of its effects. Arfendazam Lofendazam Triflubazam and CP-1414S are closely related to clobazam. Triflubazam has sedative and anxiolytic effects.11,12 CP-1414S is an experimental drug and shows primarily anxiolytic and anticonvulsant effects. Its potency is roughly equal to that of clobazam, but with more pronounced sedation.13 This article can be downloaded from www.ijpbs.net P - 346 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 Triflubazam CP-1414S The present article is a review of most of the recent work that has been accomplished on the 1,5- benzodiazepine nucleus since the past decade based on the various routes of synthesis utilized, the numerous solvents employed, catalysts used and the different pharmacological activities exhibited by 1,5-benzodiazepine derivatives. ROUTES OF SYNTHESIS EMPLOYED Investigators have synthesized 1,5-benzodiazepine derivatives through different routes of synthesis using various starting materials like α,β-unsaturated compounds, ketones, β-diketones, β-ketoesters, triazines, coumarins, etc. Various routes used have been described as follows. From chalcones Bhatia et al.14 carried out synthesis of 2,4-disubstituted-1,5-benzodiazepines from chalcones. The yields of the products were good (70-88%) Sharma N et al.15 synthesized a new series of 2,4-disubstituted-2,3-dihydro substituted-1,5- benzodiazepine derivatives from various substituted chalcones under solvent free microwave irradiation. This article can be downloaded from www.ijpbs.net P - 347 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 Srivastava YK et al.16 synthesized some novel benzimidazole assembled 1,5-benzodiazepine derivatives from substituted chalcones. From ketones Reddy BM et al.17 carried out synthesis of 2,3-dihydro-1H-1,5-benzodiazepines from various ketones in the presence of a versatile solid superacid catalyst ‘sulfated zirconia’ under solvent free conditions. The yields obtained were good to excellent (80-96%). Kuo CW et al.18 synthesized 1,5-benzodiazepine derivatives from enolizable ketones by using 2,4,6-trichloro-1,3,5-triazine as a catalyst. The products were obtained in excellent yields through simple and mild reaction conditions. This article can be downloaded from www.ijpbs.net P - 348 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 From quinoline carbaldehyde Basavaraju B et al.19 synthesized transition metal complexes of methylquinolino [3,2-b] [1,5]benzodiazepine from 2-chloro-6-methylquinoline-3-carbaldehyde. From β-diketones/β-ketoesters Kumar R et al.20 synthesized 3H-1,5-benzodiazepine derivatives from β-diketones/β-ketoesters by using p-toluenesulfonic acid as catalyst. Vibhute A et al.21 synthesized a series of 2-methyl-4-(substituted phenyl)-1,5-benzodiazepine derivatives from β-diketones. Pathak VN et al.22 synthesized a series of 3H-1,5-benzodiazepine derivatives from 2-arylidene- 1,3-diketones and 4-chloro-1,2-phenylenediamine. This article can be downloaded from www.ijpbs.net P - 349 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 Tsoleridis CA et al.23 carried out a facile synthesis of 4-phenyl-1H-1,5-benzodiazepines from o- phenylenediamines and 1,3-diketones in the presence of a catalytic amount of acetic acid has been achieved, in excellent yields, under microwave irradiation. From β-ketoesters Murai K et al.24 demonstrated a novel one-pot three-component reaction of aromatic aldehydes, 1,2-phenylenediamine and β-ketoesters, which efficiently produced 1,5-benzodiazepine derivatives. From triazine Insuasty B et al.25 synthesized a new 2,3-dihydro-1H-1,5-benzodiazepine derivative by reaction of o-phenylene diamine and trazine. From β-aminoketones Roman G et al.26 synthesized 2,3-dihydro-1,5-benzodiazepines by base catalysed cyclocondensation of β-aminoketones. This article can be downloaded from www.ijpbs.net P - 350 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 From isoxazole Kapoor KK et al.27 synthesized a series of novel 2,3-dihydro-1H-1,5-benzodiazepines from isoxazole derivatives and o-phenylenediamine, under solvent free conditions. From coumarins Kusanur RA et al.28 synthesized spiro[indolo-1,5-benzodiazepines] from acetyl coumarins. From indane diones Aggarwal P et al.29 synthesized some novel 1,5-benzodiazepin-7-ones from corresponding indane- 1,3-diones in excellent yields. This article can be downloaded from www.ijpbs.net P - 351 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 From α-tetralone Sharma S et al.30 synthesized some ethoxypthalimide derivatives of tetrahydro-naphtho[1,2- e][1,5]benzodiazepine by using α-tetralone and 4-substituted benzaldehyde as starting materials. From dimedone Nedjar Kolli et al.31 demonstrated high yielding synthesis off a series of amino-1,5-benzodiazepine derivatives bearing a dimedone moiety. VARIOUS SOLVENTS USED Apart from the commonly used solvents i.e. alcohols, the following solvents have also been used in the synthesis of 1,5-benzodiazepines. This article can be downloaded from www.ijpbs.net P - 352 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 Ionic liquids Srinivasan KV et al.32 used ionic liquid 1,3-di-n-butylimidazolium bromide and afforded 1,5- benzodiazepines in excellent isolated yields in the absence of a catalyst at ambient temperature. Yadav AK et al.33 synthesized novel 1,5-benzodiazepine ribofuranosides by using various ionic liquids as catalyst at room temperature. The yields of the targeted compounds are excellent (72- 90%). Glycerol Radatz CS et al.34 have performed a catalyst-free synthesis of 1H-1,5-benzodiazepines by using glycerol as solvent, which can be easily re-utilized for further condensation reactions up to four times without lost of activity. This proved to be a simple and efficient method for obtaining the products in good yields. This article can be downloaded from www.ijpbs.net P - 353 Int J Pharm Bio Sci 2013 July; 4(3): (P) 345 - 370 Acetonitrile Varala R et al.35 synthesized 1,5-benzodiazepine derivatives in good isolated yields (62-92%) under mild conditions using acetonitrile as solvent at ambient temperature in the presence of p- nitrobenzoic acid as catalyst. 2-methoxyethanol Zangade S et al.36 synthesized 1,5-benzodiazepines in the presence of 2-methoxyethanol as an alternative reaction solvent under microwave irradiation. The clean reaction conditions, easy work-up, time saving and higher yields are notable advantages of present method. VARIETY OF DIFFERENT CATALYSTS USED A large variety of different catalysts are employed for synthesizing 1,5-benzodiazepine derivatives. Most of the reactions utilizing the various catalysts are solvent free thus ensuring much more efficient and expeditious synthesis of the desired compounds.