1.5- Benzodiazepines, reaction with

People with LD, don t have higher pain thresholds, but may respond to much smaller drug doses than usual. They re more sensitive to paradoxical reactions with benzodiazepines, so use when necessary, but monitor closely. 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

The benzodiazepine fused azetes (353 R = Et, Pr) have been claimed as useful tranquilizers and sedatives (76BRP1448895). However, their stability and formation from benzodiazepines (352) by reaction with an aldehyde and base is hard to reconcile with the proposed structure. 

The 2,3-benzodiazepin-l-one 5c is transformed into the corresponding thione 18 by reaction with diphosphorus peniasuifide. 32... 

The action of nitrous acid on the benzodiazepine A -oxide 38 gives the nitrosoamino derivative 39,234 which reacts with alcohols, ethanethiol and various amino compounds, such as hydrazines and guanidine, by replacement of the methyl(nitroso)amino group.235 Reaction with aziridine affords the aziridinyl compound 40f or the 2-(aziridin-l-yl)ethylainino derivative 40g, depending on the conditions. 

Hydrazino-3//-l, 4-benzodiazepines, such as 14, are transformed into triazolobenzodiazepines 15 by reaction with ortho esters241 or with acyl chlorides and subsequent heating in acetic acid (see Houben-Weyl, Vol. E8d, p502fif).242... 

The methyl groups of 2,4-dimethyl-3//-l, 5-benzodiazepine are CH acidic reaction with benzal-dehyde gives a mixture of mono- and distyryl derivatives 13 and 14.256... 

Acetamido-l//-l,5-benzodiazepine-3-carbonitrilc forms the pyrimidine derivative 10 by reaction with methylamine.290... 

Benzodiazepin-2-ones are converted efficiently into the 3-amino derivatives by reaction with triisopropylbenzenesulfonyl (trisyl) azide followed by reduction <96TL6685>. Imines from these amines undergo thermal or lithium catalysed cycloaddition to dipolarophiles to yield 3-spiro-pyrrolidine derivatives <96T13455>. Thus, treatment of the imine 50 (R = naphthyl) with LiBr/DBU in the presence of methyl acrylate affords 51 in high yield. 

According to the H-NMR spectra in DMSO - de, benzodiazepine 69 exists as a 4 1 mixture of tautomers A and A. Benzodiazepin-2-one 69 is formed due to the substitution of the hydroxyl group of coiunarin 67 by one of the amino groups of o-phenylenediamine and the C - O bond cleavage in the py-rone ring upon reaction with the second amino group. 

Erker and Trinkl synthesized the tricycles 177 as novel GABA-A/benzodiazepine receptor ligands via synthesis of enol phosphates such as 175 and reaction with isocyanides 176 (Scheme 13) <2001H1963>. 

Impairment of memory, delirium and immobility are some of the adverse dmg reactions from benzodiazepines. Elderly patients in nursing homes often receive benzodiazepines inappropriately (Oborne et al. 2003). The frailest elderly, who are most susceptible to ADR from benzodiazepines, use these drugs and often for long term. In a Japanese study it was shown that benzodiazepines were prescribed for longer terms as patient age increased (Nomura et al. 2007). Sometimes elderly patients in nursing homes are treated with benzodiazepines without actually talking to their nurse or physician (Holmquist et al. 2005). This makes it hard evaluate the treatment. 

Alkylation of pyrrolo-benzodiazepine dione 244 with methyl iodide occurs on both positions N9 and ClOa, while reaction with 2-bromo diethylaminoethane leads to the low yield of the 4-substituted 248. Acylations with benzoyl and 2-chloroacetyl chlorides are directed exclusively to position 4 to afford 247 (Scheme 52, Section 3.1.1.4 (1992CE649, 2005H2451)). Alkylation of 5H-benzo[/]-pyrrolo[l,2-d][l,4]diazepin-6(7H)-one with a substituted phenethyl bromide has been reported (Scheme 36, Section 3.1.1.1 (1992BMCL1639)). 

Chorazepate Chorazepate, 7-chloro-2,3-dihydro-2,2-dihydroxy-5-phenyl-1H-1,4-benzo-diazepin-3-carboxylic acid (5.1.34), which is used in the form of a dipotassium salt, is synthesized by yet another interesting synthetic scheme. 2-Amino-5-chlorobenzonitrile is used as the initial compound, which upon reaction with phenyhnagnesiumbromide is transformed into 2-amino-5-chlorbenzophenone imine (5.1.32). Reacting this with amino-malonic ester gives a heterocyclization product, 7-chloro-l,3-dihydro-3-carbethoxy-5-phenyl-2H-benzodiazepin-2-one (5.1.33), which upon hydrolysis using an alcoholic solution of potassium hydroxide forms a dipotassium salt (5.1.34), chlorazepate [30-32]. 

There is no cross-tolerance of buspirone with benzodiazepines or other sedative medications. Withdrawal symptoms, occurring for example after stopping benzodiazepine use are influenced by buspirone only to a minor extend. Adverse effects include dizziness, light-headiness, agitation, headache, tinnitus and nausea but those reactions are generally mild. 

Both acute and chronic anxiety can be treated with benzodiazepines, although it is anticipated that for most anxiety disorders counseling will also play an important role. Benzodiazepines employed in the treatment of anxiety should be used in the lowest effective dose for the shortest duration so that they will provide maximum benefit to the patient while minimizing the potential for adverse reactions. For most types of anxiety, none of the benzodiazepines is therapeutically superior to any other. Choice of a particular agent is usually made on the basis of pharmacokinetic (Table 30.2) considerations. A benzodiazepine with a long half-life should be considered if the anxiety is intense and sustained. A drug with a short half-life may have advantages when the anxiety is provoked by clearly defined circumsfances and is likely to be of short duration. 

The oxidation of 3H- 1,2-benzodiazepines (90 R = Hor Me) with MCPB A gave both (91) and (92). The former have proved useful as precursors for 3-substituted 1,2-benzodiazepines via treatment with bases or acids. Thus (91) on reaction with alkoxides (R -) and CH(C02Et)2 gave respectively (93 X = OR1) and (93 X = CH(C02Et)2) in ca. 70% yields, and treatment with hydrogen chloride and with acetic acid gave (93 X = C1) and (94) respectively (78CPB1896). 

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