1, 5 Benzodiazepines: Overview of Properties and Synthetic Aspects
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Research Journal of Chemical Sciences ______________________________________________ ISSN 2231-606X Vol. 3(7), 90-103, July (2013) Res. J. Chem. Sci. Review Paper 1, 5 Benzodiazepines: Overview of Properties and Synthetic Aspects Pareek Aastha 2*, Kumar Navneet 1, Agarwal Anshu 2, Sharma Pratima 2 and Kishore Dharma 2 1Raj Kumar Goel institute of Technology, Ghaziabad, UP, INDIA 2Banasthali University, Department of Chemistry, Banasthali, Rajasthan, INDIA Available online at: www.isca.in Received 20 th April 2013, revised 10 th May 2013, accepted 9th June 2013 Abstract Heterocyclic compounds occur widely in nature and quite a few of these are essential to life processes. The literature on heterocyclic compounds is replete with examples of a large number of synthetic methods of naturally occurring systems which are pharmacologically active. Their practical applications range from clinical use to field as diverse as agriculture, photography, biocide formulations and polymer science. The range of known compounds is virtually limitless, encompassing an impressive spectrum of physical, chemical and biological properties. Extensive applications of these compounds in medicine has led to the chemistry of these materials to expand exponentially in the past few decades, so much so that virtually a limitless series of structurally novel compounds with a broad spectrum of reactivity and stability has been developed . The heterocyclic compounds containing nitrogen has expanded exponentially in the past decades due to their uniquephysical properties , specific chemical reactivity and their remarkable potential biological activities 1,2 .A survey of literature on the nitrogen heterocycles reveal that pyrazole, isoxazole, carbazol, pyrimidine , diazepines and oxazepines tc., are important constituents of a wide variety of natural products with pharmacodynamic application. Keywords: Heterocyclic compounds, uniquphysical properties, pharmacodynamic application. Introduction benzodiazepines are prone to cause tolerance, physical dependence, and, upon cessation of use after long term use, a The core structure of benzodiazepines. "R" labels denote withdrawal syndrome. Due to adverse effects associated with common locations of side chains, which give different the long-term use of benzodiazepines, withdrawal from 1,2 benzodiazepines their unique properties . A benzodiazepine benzodiazepines, in general, leads to improved physical and (sometimes colloquially "benzo"; often abbreviated "BZD") is a mental health. The elderly are at an increased risk of suffering psychoactive drug whose core chemical structure is the fusion from both short- and long-term adverse effects. Withdrawal of a benzene ring and a diazepine ring. The first benzodiazepine, from a long term benzodiazepine addiction may cause tinnitus chlordiazepoxide (Librium), was discovered accidentally by Leo as a side effect 6. Sternbach in 1955, and made available in 1960 by Hoffmann– La Roche, which has also marketed diazepam (Valium) since 1963 3. Benzodiazepines enhance the effect of the neurotransmitter gamma-amino butyric acid (GABA-A), resulting in sedative, hypnotic (sleep-inducing), anxiolytic (anti- anxiety), anticonvulsant, and muscle relaxant properties; also seen in the applied pharmacology of high doses of many shorter-acting benzodiazepines are amnesic-dissociative actions. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures. Benzodiazepines are categorized as either short-, intermediate- or long-acting. Short- and intermediate-acting There is controversy concerning the safety of benzodiazepines benzodiazepines are preferred for the treatment of insomnia; in pregnancy. While they are not major teratogens, uncertainty longer-acting benzodiazepines are recommended for the remains as to whether they cause cleft palate in a small number treatment of anxiety 4. In general, benzodiazepines are safe and of babies and whether neurobehavioural effects occur as a result effective in the short term, although cognitive impairments and of prenatal exposure, they are known to cause withdrawal paradoxical effects such as aggression or behavioral symptoms in the newborn. Benzodiazepines can be taken in disinhibition occasionally occur 5. Long-term use is controversial overdoses and can cause dangerous deep unconsciousness. due to concerns about adverse psychological and physical However, they are much less toxic than their predecessors, the effects, increased questioning of effectiveness and because barbiturates, and death rarely results when a benzodiazepine is International Science Congress Association 90 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606X Vol. 3(7), 90-103, July (2013) Res. J. Chem. Sci. the only drug taken; however, when combined with other central 3H etc., In dihydro and tetrahydro benzodiazepines the odd nervous system depressants such as alcohol and opiates, the hydrogen is given the lowest possible number. potential for toxicity and fatal overdose increases7. Benzodiazepines are bicyclic heterocyclic compounds in which This is however, complicated by the fact that, first consideration benzene nucleus is fused to a seven membered ring containing is given to the position of a functional group which is expressed two nitrogen atoms. The term benzodiazepine implies a as a suffix to the name of the compound 10 . maximum degree of unsaturation due to the presence of three double bond in the seven membered ring. Considering the Biological Importance of 1, 5-Benzodiazepines relative position of nitrogen atom in the heterocyclic ring, benzodiazepines are classified as 1, 2; 1, 3; 1, 4; 1, 5 and 2, 4 Benzodiazepines and their polycyclic derivatives are an benzodiazepines 8,9. (figure 1) important class of bioactive compounds. They have attracted H attention of chemist in field of drug and pharmaceutical. Their N N 11 N clinical use has been reported by Palfai and Janbiewiz . According to their report, roughly 800 tons of benzodiazepines N are consumed every year with 53 million prescriptions for valium only. 1.001 1.002 The compounds of this class have been widely used as anticonvulsant, antianxiety, analgesic, sedative, antidepressive, N N hypnotic and anti-inflammatory agents. They are also used to relieve pain of skeletal muscle joints and the spasticity resulting from cerebral palsy and paraplegia, athetosis and stiff-man syndrome. Recently they have been reported to show N N antileukamic, antiplatelet, antilucer, endothelia antagonists and 1.003 1.004 vasopressin antagonist activity 12 . Their role in the control and treatment of AIDS has also been recently demonstrated. Benzodiazepines enhance the effect of the neurotransmitter N N gamma-aminobutyric acid (GABA), which results in sedative, 13 N hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic action. These N properties make benzodiazepines useful in treating anxiety, 1.005 1.006 insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental Figure-1 procedures. Most are administered orally; however, they can History: The first benzodiazepine, Chlordiazepoxide (Librium) also be given intravenously, intramuscularly or rectally. (1.007), was discovered accidentally by Leo Sternbach in 1955, Benzodiazepines are not FDA (Food and Drug Administration) and made available in 1960 by Hoffmann-La Roche, which also approved for long term use. They are approved only for the marketed diazepam (Valium) (1.008) since 1963. Oxazepam short-term use for several conditions. Benzodiazepine (1.009) was synthesized in 1961, nitrazepam (1.010) in 1962, derivatives are also commercially used as dyes for acrylic fibres. and temazepam (1.011) and nimetazepam (1.012) in 1964. In Moreover 1, 5-benzodiazepines derivatives are valuable 1965 came flurazepam and nordazepam. Benzodiazepines are synthons that can be used in preparation of other fused ring categorized as either short-, intermediate- or long-acting drugs. compounds such as triazolo-, oxadiazolo-, oxazino-,or furano- Short- and intermediate-acting benzodiazepines are preferred for benzodiazepines. the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety. Chemistry The 1, 4-benzodiazepine ring system. 5-phenyl-1H- Nomenclature of Benzodiazepines benzo[ e][1,4]diazepin-2(3 H)-one forms the skeleton of many of Benzodiazepines are numbered as shown in figure 3 the the most common benzodiazepine pharmaceuticals, such as numbering of these benzodiazepines proceeds in the opposite diazepam (7-chloro-1-methyl substituted) (figure 4). direction to that used for the unsaturated diazepines. The position of the odd hydrogen atom (even if occupied by another mono or divalent substituent) is indicated by the term 1H, 2H, International Science Congress Association 91 Research Journal of Chemical Sciences ___________________________________________________________ ISSN 2231-606X Vol. 3(7), 90-103, July (2013) Res. J. Chem. Sci. CH3 H O O N N H C N N OH Cl Cl Chlordiazepoxide (Librium) Diazepam (Valium) Oxazepam 1.007 1.008 1.009 CH3 O O N N H O OH N Cl N O2N N N O2N C6H5 Nitrazepam Temazepam Nimetazepam 1.010 1.011 1.012 Figure-2 that form the receptor, the chloride (Cl -) ion channel pore at the 5 R 6 center, the two GABA active binding sites at the α1 and β2 N 7 4 interfaces