Bioorganic & Medicinal Chemistry 15 (2007) 4009–4015 Synthesis and pharmacological investigation of novel 4-benzyl-1-substituted-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones V. Alagarsamy,a,* V. R. Solomonb and M. Muruganc aMedicinal Chemistry Research Laboratory, Dayananda Sagar College of Pharmacy, Kumaraswamy Layout, Bangalore 560 078, India bMedicinal & Process Chemistry Division, Central Drug Research Institute, Lucknow 226 001, India cMedicinal Chemistry Research Laboratory, Arulmigu Kalasalingam College of Pharmacy, Anand Nagar, Krishnankovil 626 190, India Received 16 February 2007; revised 31 March 2007; accepted 3 April 2007 Abstract—A series of novel 1-substituted-4-benzyl-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-ones were synthesized by the cyclization of 2-hydrazino-3-benzyl-3H-quinazolin-4-one with various one-carbon donors. The starting material 2-hydrazino-3-benzyl-3H-quinaz-olin-4-one was synthesized from benzylamine by a new innovative route. When tested for their in vivo H1-antihistaminic activity on guinea pigs, all the test compounds protected the animals from histamine induced bronchospasm significantly. The compound 1-methyl-4-benzyl-4H-[1,2,4]triazolo[4,3-a]quinazolin-5-one (II) emerged as the most active compound of the series and it is more potent (percent protection 76%) when compared to the reference standard chlorpheniramine maleate (percent protection 71%). Compound II showed negligible sedation (7%) when compared to chlorpheniramine maleate (30%). Hence it could serve as proto-type molecule for further development as a new class of H1-antihistamines. � 2007 Elsevier Ltd. All rights reserved.
that do not possess the above-mentioned pharmaco-phore for H1-antihistamines gave way for the discovery The first generation antihistamines penetrate the blood– of many novel antihistamines temelastineand mango- brain barrier and also possess anticholinergic properties stiA literature survey reveals excellent antihistaminic and this has led to the development of a second genera- activity in quinazolines and condensed quinazolines.
of H1-antagonists such as terfenadine, cetirizine, In view of these facts and to continue our effoin and astemizole. A common feature of first generation the search of quinazoline derivatives as potent antihista- compounds includes two aryl or heteroaryl rings linked mines with least sedation, we aimed at preparing a series to an aliphatic tertiary amine via the side chain(e.g., of 1,2,4-triazolo-4H-[4,3-a]quinazolin-5-ones containing Diphenhydramine and Pheniramine), the second-gener- benzyl substitution at position 4 and alkyl/alicyclic ation compounds (Terfenadine and Cetirizine) also con- amine substitution at position 1. The title compounds tain many of the common structural features of first were synthesized by the cyclization of 3-benzyl-2-hydra- generation compounds. The real breakthrough of non- zino-3H-quinazolin-4-one 6 with various one-carbon sedative antihistamines came in the early eighties of donors. The 3-benzyl-2-hydrazino-3H-quinazolin-4-one twentieth century when the discovery of modern antihis- 6 was synthesized from benzylamine 1 by a new innova- tamines was found to exhibit potent antihistaminic tive route (). Spectral data (IR, NMR, and activity without sleep-inducing Condensed het- mass spectra) confirmed the structures of the synthesized erocycles containing new generation of H1-antihista- compounds; the purity of these compounds was ascer- mines (e.g., Loratadine, Azelastine, and Flazelastine) tained by microanalysis ). The synthesized com-pounds were tested for their in vivo H1-antihistaminic activity on conscious guinea pigs. As sedation is one of the major side effects associated with antihistamines, the test compounds were also evaluated for their seda- Keywords: Quinazoline; Pyrimidine; Antihistamine. * Corresponding tive potentials, by measuring the reduction in locomotor 0968-0896/$ - see front matter � 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmc.2007.04.001


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