HISTORY:

The first benzodiazepine, Chlordiazepoxide (Librium), was synthesized in 1955 by Leo Sternbach while working at Hoffmann–La Roche on the development of tranquilizers. The pharmacological properties of the compounds prepared initially were disappointing, and Sternbach abandoned the project. Two years later, in April 1957, co-worker Earl Reeder noticed a "nicely crystalline" compound left over from the discontinued project while spring-cleaning in the lab. This compound, later named chlordiazepoxide, had not been tested in 1955 because of Sternbach's focus on other issues. Expecting the pharmacology results to be negative and hoping to publish the chemistry-related findings, researchers submitted it for a standard battery of animal tests. However, the compound showed very strong sedative, anticonvulsant, and muscle relaxant effects. These impressive clinical findings led to its speedy introduction throughout the world in 1960 under the brand name Librium^[28]. Following chlordiazepoxide, diazepam was synthesized in 1959 and marketed by Hoffmann–La Roche under the brand name Valium in 1963 and for a while the two were the most commercially successful drugs. Oxazepam was synthesized in 1961, nitrazepam in 1962, and temazepam and nimetazepam in 1964. In 1965 flurazepam and nordazepam came. The introduction of benzodiazepines led to a decrease in the prescription of barbiturates, and by the 1970s they had largely replaced the older drugs for sedative and hypnotic uses^[29].

In 2010, formerly classified documents from a Medical Research Council (UK) meeting of experts emerged and revealed that the MRC was aware of research 30 years ago that suggested that benzodiazepines could cause brain damage in some people similar to that which occurs from alcohol abuse and failed to follow-up with larger clinical trials. The MRC turned down research proposals in the 1980s by Professor Lader and also proposals by Professor Ashton in 1995 to study whether benzodiazepines had permanent effects on the brain. The MRC responded that it has always been open to research proposals in this area that meet required standards. It was further alleged that the MRC documents were relevant to a large class action lawsuit, which started in the mid-1980s against drug companies and one solicitor stated that it was strange that the MRC had 'hidden' the documents. Jim Dobbin, MP and chair of the All-Party Parliamentary Group for Involuntary Tranquillizer Addiction, described the documents as a "huge scandal," given the large number of people who experience symptoms such as physical, cognitive and psychological problems as a result of benzodiazepine use, which can persist even after withdrawal^[30].

1. INTRODUCTION:

A benzodiazepine (Figure 1) is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first benzodiazepine, Chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and was made available in 1960 by Hoffmann–La Roche, which has also marketed diazepam (Valium) since 1963^[1]. Benzodiazepines enhance the effect of the neurotransmitter gamma-aminobutyric acid (GABA), which results in sedative, hypnotic (sleep-inducing), anxiolytic (anti-anxiety), anticonvulsant, muscle relaxant and amnesic action^[2]. These properties make benzodiazepines useful in treating anxiety, insomnia, agitation, seizures, muscle spasms, alcohol withdrawal and as a premedication for medical or dental procedures^[3]. Benzodiazepines are categorized as either short-, intermediate- or long-acting. Short- and intermediate-acting benzodiazepines are preferred for the treatment of insomnia; longer-acting benzodiazepines are recommended for the treatment of anxiety^[4].

Fig. 1 Benzodiazepine

The chemical structure of “benzodiazepine” is common to numerous molecules which differ by the presence of varying substitutes. Molecules which do not have the benzodiazepine chemical structure can however have the same properties, the same mechanism of action and the same effects as benzodiazepines^[7]. Benzodiazepines act on the central nervous system, produce sedation and muscle relaxation, and lower anxiety levels. Benzodiazepines are commonly abused. Benzodiazepines abuse is partially related to the toxic effects that they produce and also to their widespread availability. Death and serious illness rarely result from benzodiazepine abuse alone. However, they are frequently taken with either alcohol or other medications. The combination of benzodiazepines and alcohol can be hazardous^[5].

1.1. Classification of benzodiazepines:

Benzodiazepines are usually classified into three groups

a. Hypnotic:- Diazepam, Flurazepam, Nitrazepam, Alprazolam, etc,.

b. Antiaanxiety:- Diazepam, Chlordiazepoxide, Oxazepam, Lorazepam, etc,.

c. Anticonvulsant:- Diazepam, Lorazepam, Clobazam, etc,.

d. Anaesthetics:- Medazolam, etc^[6],.

1.1.1 Hypnotic:

The sedating effect of benzodiazepines is recognized; they induce sleep and in general prolong its duration. During a sustained use, their hypnotic effect attenuates but does not seem to disappear like that of barbiturates. The sleep obtained under benzodiazepines has electroencephalographic features close to those of natural sleep. This point should not be used as argument to widen their prescription, because a sustained use produces an addiction. Moreover, the quality of hypnotic is not judged only on sleep, but on the state of the subject on awakening and during day, drowsiness or not, etc, and on the possibility of adverse effects.

1.1.2 Antianxiety:

The first benzodiazepine introduced in therapeutics in 1960 was chlordiazepoxide, under the name of LIBRIUM*. Its anxiolytic properties, called then tranquillizing, were well highlighted in animals and in human beings. In animals, benzodiazepines decrease aggressiveness, exploratory behaviour in a new environment, physiological reactions to stress. In human beings, anxiolytic effects of benzodiazepines are clearly documented. However, the pathophysiology of anxiety is poorly understood and it is not proven that it results from a disturbance of the GABA-ergic system. Anxiolytic drugs must be regarded as symptomatic treatments, used to relieve patients and to facilitate their adaptation to a difficult situation.

1.1.3 Anticonvulsant:

Clonazepam is a benzodiazepine and has their general properties, with a predominant anticonvulsive effect. It is used by oral route for the treatment of different types of epilepsy resistant to other drugs and of myoclonus. For the treatment of status epilepticus it is used by injectable route.

1.1.4 Anaesthetic:

Midazolam is a benzodiazepine indicated for induction of narcosis in general anesthesia. It has an instantaneous and a short duration effect. Its amnesic effect can be beneficial^[7]. There is convincing evidence that most of the pharmacological and clinical effects of the benzodiazepines are medicated via benzodiazepine specific receptors present in the central nervous system of most vertebrate species including man. Furthermore the affinity of the benzodiazepines for these receptor site seems to be the major determinant potency of benzodiazepine drugs^[8].

2. CHEMISTRY:

The term benzodiazepine is the chemical name for the heterocyclic ring system (see figure to the right), which is a fusion between the benzene and diazepine ring systems^[9]. Under Hantzsch–Widman nomenclature, a diazepine is a heterocycle with two nitrogen atoms, five carbon atom and the maximum possible number of cumulative double bonds. The "benzo" prefix indicates the benzene ring fused onto the diazepine ring^[9]. Benzodiazepine drugs are substituted 1,4-benzodiazepines, although the chemical term can refer to many other compounds that do not have useful pharmacological properties. Different benzodiazepine drugs have different side groups attached to this central structure. The different side groups affect the binding of the molecule to the GABA_A receptor and so modulate the pharmacological properties^[10]. Many of the pharmacologically active "classical" benzodiazepine drugs contain the 5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one substructure (Fig. 2 )^[11]. Nonbenzodiazepines also bind to the benzodiazepine binding site on the GABA_A receptor and possess similar pharmacological properties. While the nonbenzodiazepines are by definition structurally unrelated to the benzodiazepines, both classes of drugs possess a common pharmacophore, which explains their binding to a common receptor site^[12].

Figure 2 Left: The 1,4-benzodiazepine ring system. Right: 5-phenyl-1H-benzo[e][1,4]diazepin-2(3H)-one forms the skeleton of many of the most common benzodiazepine pharmaceuticals, such as diazepam (7-chloro-1-methyl substituted).

Five-atom heterocyclic fused benzodiazepine ring systems occupy a prominent place among drugs for treatment of CNS disorders^[13]. The introduction of alprazolam, triazolam and midazolam (Fig. 3) in chemotherapy has enhanced the interest in the preparation of novel five-atom heterocyclic fused benzodiazepine ring systems. Numerous analogs of alprazolam, triazolam and midazolam have been described, and they have shown different pharmacological profiles related to those of their parent compounds^[14].

Figure 3

2.3 Structure Activity relationship:

2,3-Benzodiazepines (BZDs) (Figure 4) are members of a series of chemical entities that have been synthesized by changing the position of nitrogen atoms in the classical structure of 1,4-BZDs. 2,3-BZDs with anxiolytic and antipsychotic characteristics were found and minor structural changes led to development of novel dopamine transporter inhibitors^[19]. It was shown that methyleneor ethylenedioxy groups in 7, 8-position or chlorine in C-8 position and amino group in para position at the phenyl ring are requirement for blocking AMPA receptors^[20].

Figure 4 Benzodiazepine

Substitution of 2, 3-BZD with cyclopropyl-carbamoyl group in C3 position further increases AMPA receptor antagonistic properties. Additional substitution of the phenyl ring with a methyl group in meta position enhanced the time-course of AMPA receptor blocking action. Although a series of modification in the molecular structures of AMPA receptor antagonist BZDs resulted in increased efficacy, lack of correlation was found between in vivo and in vitro pharmacological potencies. 2,3-BZDs with AMPA receptor-blocking activity may have therapeutic value in a wide range of CNS disorders such as Parkinson's disease, stroke, epilepsy, multiple sclerosis or motoneuron disease. Furthermore, lengthening the spacer between the phenyl and BZD rings led to the discovery of 2,3-BZDs containing stryryl double bond^[21]. These changes resulted in anxiolytic compounds that devoid of binding to AMPA receptors. Some stryryl-BZDs may exert anxiolytic effect acting on GABA_A receptor subunits, their effect; however differ from that of 1,4-BZDs. Thus, the stryryl-2,3-BZD EGIS-8858, which exhibits anxiolytic effects in the elevated plus maze and the Vogel test, is not sedative, does not induce dependency, or amnesia and is not anxiogenic upon withdrawal^[19].

3.4. Synthesis of Benzodiazepine and its various derivatives:

Various methods for synthesis of benzodiazepine and synthesis of its derivatives are available in number of books and journals. From this we are going to discuss some of the important methods.

3.4.1. Synthesis of benzodiazepine analogue; 8-chloro-6-(2-fluorophenyl)-1-(aryl)-4H- [1,2,4] triazolo[4,3-a][1,4] benzodiazepine (5a–f) using 2-amino-4-chloro- 2′ fluorobenzophenone as a starting compound.

Various methods are known for the synthesis of 1,4-benzodiazepines^{[15, 16, 17]}. In the present synthesis, 2-amino-4-chloro-2′-fluorobenzophenone is converted to 2-(2-chloroacetyl) amino-4-chloro-2′-fluorobenzophenone (1) by treating it with chloroacetyl chloride following a literature reported procedure^{[18, 17]}. 2-(2-Chloroacetyl)amino-4-chloro-2′-fluorobenzophenone on treatment with hexamine yields 7-chloro-5-(2- fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (2). Compound (2) on treatment with P₂S₅ in pyridine results in the formation of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-thione (3). Then react 7-Chloro-5-(2-fluorophenyl)- 1,3-dihydro-2H-1,4-benzodiazepine-2-thione (3) with aromatic acid hydrazides (4a–f) by refluxing in n-butanol with catalytic amount of acetic acid which results in the formation of 8-chloro-6-(2-fluorophenyl)-1-(aryl)-4H- [1,2,4]triazolo[4,3-a][1,4] benzodiazepine (5a–f). Aromatic acid hydrazides (4a–f) can be prepared by treating the ethyl esters of respective aromatic acids with hydrazine hydrate in methanol. Scheme 1 illustrates the reaction scheme.

3.4.2 The solid-phase synthesis of pyrrolo[2,1-c][1,4]benzodiazepines involving reductive cleavage:

Solid-phase combinatorial chemistry has presently become a very useful methodology for the generation of libraries of new molecules with biological properties^[22]. Natural product derived heterocyclic compounds offer a high degree of structural diversity and thus may lead to useful therapeutic agents.

The pyrrolo[2,1-c][1,4]benzodiazepines (PBDs) are a group of potent, naturally occurring, antitumour antibiotics produced by various Streptomyces species^[23]. These compounds bind selectively in the minor groove of DNA while a covalent aminal bond between the electrophilic C-11 position of the PBD and the nucleophilic N₂- amino group of a guanine base^[5], possibly results in the biological activity. A number of naturally occurring and synthetic compounds based on this PBD ring system, such as anthramycin, chicamycin, abbeymycin, DC-81 and its dimmers²⁴ have shown varying degrees of DNA binding affinity and anticancer activity. Treat (4-bromomethylphenoxy) methyl polystyrene 1 (1.4 mmol/g, 100–200 mesh, 1% DVB) with potassium thioacetate in DMF. The formation of thioester 2 is indicated by a strong carbonyl stretching vibration at 1680 cm^-1 in the IR spectrum. The reduction of 2 using LiBH₄ in THF at room temperature gives the thiol Wang resin 3 (Scheme 2). The precursor BOC protected proline acid chloride 6 can be preapared by using polystyrene triphenylphosphine in CCl₄ (Scheme 3)²⁵. Link resin 3 to BOC protected proline acid chloride 6 by using triethylamine in dichloromethane to afford BOC protected proline thioester resin 7. After the deprotection of the BOC group using TFA, couple the corresponding 2-azidobenzoic acid in the presence of TBTU and DIPEA to provide the required resins (8a–h), as indication by IR spectra that shows a strong azide stretching vibrations in the range between 2080 and 2170 cm^-1. Treatment of 8a–h with excess of PPh₃ in dry toluene at room temperature produces the corresponding resins of iminophosphoranes (9a–h). Finally, treat the resins 9a–h were with DIBAL-H in dry dichloromethane at 78°C for 12 h to afford the desired PBD imines (10a–h)^[26] (Scheme 4) in good yields (57–65%). The thiol form of resin 3 can be recovered, and could be reused for the preparation of 7.

3.4.3. Synthesis of 1,4-Benzodiazepines:

As described for the synthesis of l-methyl substituted 1,4-benzodiazepines ^{[27, 28]} with a functionalized side chain at carbon 2, the open chain amides 1 cyclize at 80- 130°C in POCl, to yield a mixture of the 7- and 8-membered ring compounds 2 and 3. The crude mixture of 2 and 3 is reacts subsequently either with methylamine or with aqueous NaOH to yield 4 or 5, respectively, as main products (Scheme 5).

3.4.4. The synthesis of 1,5-benzodiazepines using polyaniline-sulfate salt as an efficient and reusable catalyst:

Stirr well a mixture of O-phenyldiamine (1 mmol), ketone (2.2 mmol) and dichloroethane (5 ml) solvent in presence polyaniline (20 wt% with respect to OPD) catalyst at reflux condition for 3 h; monitored the reaction by TLC. Filter the reaction mixture in order to recover the catalyst and dry the filtrate with sodium sulfate, concentrate in vacuum. Purify the crude product by column chromatography (Scheme 6)^[31].

Scheme 6

3.4.5. The synthesis of 1,5-benzodiazepines under solvent-free conditions using silica supported fluoroboric acid as a novel, efficient and reusable catalyst:

A mixture of o-phenylenediamine (2.5 mmol) and acetone (6 mmol) was stirred at room temperature in the presence of 100 mg (2 mol%) HBF₄–SiO₂ catalyst. After completion of the reaction (TLC), the reaction mixture was diluted with ethyl acetate (10 ml) and filtered. The catalyst was washed with ethyl acetate (3×5 ml). The organic layer was dried over anhydrous sodium sulphate and concentrated in vacuum. If required, purified by column chromatography (silica gel, Merck 60–120 mesh, petroleum ether: ethyl acetate 9:1) to afford pure product in 96% yield and structure was confirmed by IR, ¹H-NMR and Mass spectroscopy. The recovered catalyst was activated by heating at 80°C for 2 h under vacuum and reused for four times in the case of model reaction of o-phenylenediamine and acetone resulting in excellent yield of the corresponding product in 92, 90, 85 and 80% in short reaction time 30, 30, 35 and 40 min, respectively (Scheme 7)³².

3.4.6. Catalytic synthesis of 2,3-dihydro-1H-1,5-benzodiazepines by ferric perchlorate:

The reactions can be carried out at room temperature for 15–35 min by taking a 1:2.5 mol ratio mixture of o-phenylenediamine and the ketone in the presence of 2 mol% Fe(ClO₄)₃ in solvent-free condition to give the desired product i.e. Benzodiazepine (Scheme 7) in excellent yields. Both aromatic and aliphatic ketones equally undergoes the conversion well^[33].

4. PHARMACOLOGY:-

Benzodiazepines are the most potent drugs in preventing and interrupting experimental convulsions in animals and various forms of human epilepsy. They are the drugs of choice in the emergency treatment of status epilepticus and tetanus and are useful in the chronic treatment of various special and mixed types of epilepsy. Phenobarbitone is the oldest and still the most widely used antiepileptic. The topic of this contribution is the part played by GABA in the anticonvulsant action of benzodiazepines and barbiturates.

Investigation of the synaptic pharmacology of benzodiazepines began in 1967, when Schmidt et al., studying the recently discovered process of presynaptic inhibition, observed that diazepam enhanced presynaptic inhibition of the monosynaptic excitation of motoneurones in the spinal cat and increased the intensity of primary afferent depolarization induced by peripheral stimuli, measured by the amplitude of the so-called segmental dorsal root potential. This effect of diazepam on presynaptic inhibition was remarkable as such and became even more interesting by the failure of the drug to affect postsynaptic inhibition of spinal motoneurones. Schmidt et al.^[34] proposed that enhancement of presynaptic inhibition may contribute to the muscle relaxant action of diazepam in addition to its depressant effect on spinal monosynaptic and polysynaptic reflexes. The anticonvulsant potency of the benzodiazepines is dependent on the seizure variable measured. Forelimb clonus duration has previously been identified as a sensitive measure of benzodiazepine anticonvulsant action which shows a good correlation with other behavioral and EEG seizure variables^[35].

4.1. Mechanisam of action:

γ-Aminobutyric acid (GABA) is known to be the major inhibitory neurotransmitter in the brain^[36,37]. Receptors for GABA are divided into three categories. They are GABA_A, GABA_B, and GABAc according to their pharmacological and functional make up^[39]. In addition to this, a fourth receptor, GABA, is thought to exist^[39]. The GABA_A receptors are responsible for the actions of the benzodiazepines^[38]. The benzodiazepines act as agonists at only the GABA_A receptors and do not exert an effect at the other GABA receptors. It is believed that the GABA_A receptor may be a subset of receptors rather than a single entity. Four subunits of the GABA_A receptor have been identified; alpha, beta, gamma, and sigma (α, β, γ and σ)^[38]. GABA binds to a specific subunit of the receptor, the β subunit. The α subunit is the binding site for the benzodiazepines^[36,38]. The benzodiazepines alone lack the ability to initiate GABA mimetic effects^[38]_.

4.2. Uses of benzodiazepines:

a. Cardiovascular

As a class of drugs, the benzodiazepines display minimal cardiovascular depression. Diazepam and midazolam are used for the induction of anesthesia in patients with known cardiovascular disease, and result in minimal hemodynamic changes^[40].

b. Cerebral:

The benzodiazepines have strong anticonvulsant effects and will prevent or stop generalized seizure activity^[40]. Midazolam causes a reduction in the cerebral metabolic requirements and cerebral blood flow^[36].

4.3. Toxicity of Benzodiazepines:

4.3.1. Abuse:

Patients are found 2 be prone to be abused by benzodiazepines. And at the same time some evidence suggests alprazolam is distinguishable from other benzodiazepines in terms of its abuse potential. First, individuals with a history of alcohol and opiate abuse prefer alprazolam to other benzodiazepines (e.g., chlordiazepoxide and oxazepam), and report alprazolam produces a greater "high"^[43,44]. Second, 75% of drug-abuser-experienced physicians reported alprazolam as having a greater potential for abuse than other benzodiazepines^[42]. Third, emergency room admissions involving alprazolam increased by 50% between 1985-1988. Finally, admissions to substance abuse treatment clinics for alprazolam dependence increased during this same period, with three-fold increases reported in some clinics^[41].

4.3.2. In elderly patients:

Differences in cerebral response among elderly patients are significant. Psychomotor performance studies of regular dosing indicated that the elderly, especially those with dementia, hypoalbuminemia, or chronic renal failure are most at risk for prolonged sedation. Swift describes the changed pharmacokinetics in the elderly, which also affect response: decreased plasma clearance of those benzodiazepines requiring oxidative metabolism, increased volume of distribution of the drug caused by increased proportion of total body fat to lean body mass, and subsequent lowered peak plasma concentration and prolonged plasma half-life^[45].

4.3.3. Genetic toxicity:

CDZ is mutagenic as well as clastogenic in vivo mammalian systems because of its ability to form NO-CDZ in the presence of nitrite in the stomach. Hence, the positive mutagenic and clastogenic effects of this compound in vivo may be due to the formation of NO-CDZ in vivo^[46].

4.3.4. Carcinogenecity:

The results of epidemiological studies performed before 1996 on the carcinogenic risk to human of seven benzodiazepines diazepam, doxefazepam, estazolam, oxazepam, prazepam, ripazepam, and temazepam are reported by IARC^[47]. Diazepam has been the benzodiazepine most extensively investigated, and some studies on unspecified tranquillizers or hypnotics were included in the evaluation of its carcinogenic risk to humans because the dominance of this benzodiazepine among those prescribed. No positive association was found in five case–control studies concerning breast cancer, the relative risk ranging from 0.7 to 1.1. One case–control study of ovarian cancer reported an increased risk (odds ratio 1.8) that was not confirmed by another study (odds ratio 0.9). Too few were the subjects that had used oxazepam to allow analysis of this drug as a separate category, but no elevated risk was associated with the general category “sustained use of other benzodiazepines” for any cancer, including cancer of the large bowel (relative risk 1.5), malignant melanoma (relative risk 0.7), lung cancer (relative risk 1.4), breast cancer (relative risk 0.8), endometrial cancer (relative risk 0.8).

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3. Olkkola KT, Ahonen J (2008). "Midazolam and other benzodiazepines". Handb Exp Pharmacol 182 (182): 335–60. doi:10.1007/978-3-540-74806-9_16. PMID 18175099.

4. Dikeos DG, Theleritis CG, Soldatos CR (2008). "Benzodiazepines: effects on sleep". In Pandi-Perumal SR, Verster JC, Monti JM, Lader M, Langer SZ (eds.). Sleep Disorders: Diagnosis and Therapeutics. Informa Healthcare. pp. 220–2. ISBN 0-415-43818-7.

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9. IUPAC, the Blue Book; Oxford: Blackwell Science (1993). ISBN 0-632-03488-2. Online edition: [1]. pp. 40–3.; Moss GP (1998). "Nomenclature of fused and bridged fused ring systems (IUPAC Recommendations 1998)". Pure Appl Chem 70 (1): 143–216. doi:10.1351/pac199870010143. http://media.iupac.org/publications/pac/1998/pdf/7001x0143.pdf.

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11. CAS registry number:2898-08-0 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one; other names: Ro 05-2921, dechlorodemethyldiazepam

12. Madsen U, Bräuner-Osborne H, Greenwood JR, Johansen TN, Krogsgaard-Larsen P, Liljefors T, Nielsen M, Frølund B (2005). "GABA and Glutamate receptor ligands and their therapeutic potential in CNS disorders". In Gad SC. Drug Discovery Handbook. Hoboken, N.J: Wiley-Interscience/J. Wiley. pp. 797–907. ISBN 0-471-21384-5.

13. J.A. Vida, Principles of Medicinal Chemistry, M.W. Wolf, A. Burger, Eds.; Wiley, New York (1981)144–170 b) R.I. Frier, Comprehensive Heterocyclic Chemistry, Vol 3, C. Hansch, Ed. Pergamon Press, New York (1990) 539 c) J.B. Hester, A.B. Rudzik, B.V. Kamdar, J. Med. Chem, 14 (1971) 1078 d) A. Walser, L.E. Benjamin, T. Flynn, C. Mason, R. Schwarts, R.I. Fryer, J. Org. Chem, 43 (1978) 936–944.

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16. L.H. Sternbatch, R. Ivan Fryer, W. Metlesics, E. Reeder, G. Sach, G. Saucy, A. Stempel, J. Org. Chem, 27 (1962) 3788–3796.

17. G.A. Archer, E. Fells, L.H. Sternbatch, US patent Appl.3422091.

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19. Szenasi, G., Harsing, L. G.: Drug Discovery Today, 2004, 1, 69-76.

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21. Kapus, G., et al.: Pharmaceutical Res., 2004, 21, 317-323.

22. Thompson, L. A. Curr. Opin. Chem. Biol. 2000, 4, 324– 337; (b) Lou, B. Drug Discovery Today 2001, 6, 1288–1294.

23. Thurston, D. E. In Molecular Aspects of Anticancer Drug– DNA Interactions; Neidle, S., Waring, M. J., Eds.; Macmillan: London, 1993; p 54.

24. (a) Thurston, D. E.; Bose, D. S. Chem. Rev. 1994, 94, 433– 465; (b) Kamal, A.; Rao, M. V.; Laxman, N.; Ramesh, G.;Reddy, G. S. K. Curr. Med. Chem-Anti-Cancer Agents 2002, 2, 215–254.

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26. Preparation of compound 10a: To a suspension of resin 8a (1.4mmol) in dry toluene, TPP (1.47 g, 5.6mmol) was added and the mixture allowed to stir for 3h at room temperature to give the resin 9a. This was carefully filtered, rinsed with toluene and dichloromethane under dry conditions, and dried in vacuo. To the suspension of resin 9a in dry dichloromethane (10mL) was added DIBAL-H (2.8 mL of 1M solution in hexane, 2.8mmol) dropwise at 78 °C under nitrogen, and the mixture stirred at the same temperature for 12 h. The reaction was quenched by the addition of 5% HCl. The resin was filtered and washed with dichloromethane (3·10 mL). The combined filtrates were evaporated to afford the crude product, which was further purified by column chromatography (silica, ethyl acetate– hexane, 95:5) to get 10a (182mg, 65% yield from initial loading of Wang bromo polystyrene). 1H NMR (200MHz,CDCl3): d = 2.02–2.16 (2H, m), 2.26–2.38 (2H, m), 3.36– 3.94 (3H, m), 7.28–7.38 (2H, m), 7.53 (1H, t, J = 6.69 Hz), 7.79 (1H, d, J = 4.46 Hz), 8.05 (1H, d, J = 7.43 Hz). MS (EI): m/z 200 [M+]; ½a_26D þ343 (c 0.4, CHCl3).

27. Liepmann H., Milkowski W. and Zeugner H. (1976) Eur. J. Med. Chem. Chim. Ther. 11, 501. Milkowski W., Liepmann H., Zeugner H., Ruhland M. and Tulp M. (1985) Eur. J. Med. Chem. Chim. Ther. 20, 345.

28. Sternbach LH (1979). "The benzodiazepine story". J Med Chem 22 (1): 1–7. doi:10.1021/jm00187a001. PMID 34039. "During this cleanup operation, my co-worker, Earl Reeder, drew my attention to a few hundred milligrams of two products, a nicely crystalline base and its hydrochloride. Both the base, which had been prepared by treating the quinazoline N-oxide 11 with methylamine, and its hydrochloride had been made sometime in 1955. The products were not submitted for pharmacological testing at that time because of our involvement with other problems".

29. Shorter E (2005). "Benzodiazepines". A Historical Dictionary of Psychiatry. Oxford University Press. pp. 41–2. ISBN 0-19-517668-5.

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31. Polyaniline-sulfate salt as an efficient and reusable catalyst for the synthesis of 1,5-benzodiazepines and 2-phenyl benzimidazoles U. Srinivas a, Ch. Srinivas a, P. Narender a, V. Jayathirtha Rao a, S. Palaniappan b,* a Organic Chemistry Division-II, Indian Institute of Chemical Technology, Hyderabad 500007, India b Organic Coatings and Polymers Division, Indian Institute of Chemical Technology, Uppal Road, Tarnaka, Hyderabad 500007, India.

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