Benzodiazepine formation

Benzodiazepines, advances in chemistry and pharmacology of 83MI16. Benzodiazepines, formation from N-imides of cyclic amines 83YZ373. Benzodiazepines, historical aspects 79WCH641. 

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. 

A decrease in the basic properties of the reagent in going from 1,2-diaminoethane to 1,2-diaminobenzene leads, in the case of ynaminoketones (X = Me), to the 1,3-orientation of binucleophile and the formation of the benzodiazepines 356, suggesting that the carbonyl group is also involved in the heterocyclization. 

The action of triethylamine or 4-methylmorpholine on the imidazole derivatives 1 results in the formation of 4,5-dihydro-l/f-l,2-benzodiazepines 2, which eliminate imidazole on heating with ethanolic sodium ethoxide to give H-, 2-benzodiazepines 3.121 Details for compound 3 (R1 = Ph, R2 = Me) only were reported it was stated that other derivatives were obtained similarly but details were not given. 

Alkaline hydrolysis of 1/7-1,4-benzodiazepin-2(3//)-one 4-oxides results in ring opening, e.g. formation of l.223-224... 

For the formation of 3//-l,5-benzodiazepine-2,4-diamine from 4-amino-l//-l,5-diazcpinc-3-carbonitrile see below. 

Benzodiazepines undergo addition of dichlorocarbene, produced from chloroform and sodium hydroxide under phase-transfer conditions (see Houben-Weyl, Vol. El9b, p 1 523 fif) to give 2H-bisazirino[l,2-a 2, Y-d 1,5]benzodiazepines, e.g. formation of 28.301... 

Benzodiazepines react with methoxyketene, generated from methoxyacetyl chloride by the action of triethylamine (see Houben-Weyl, Vol. El 5, p2827fi), to give mixtures of cycloadducts and their acylation products, e.g. formation of 29 and 30.302... 

Methyl-17/-l,5-benzodiazepin-2(37/)-one undergoes addition to nitrile imines at the 4,5-bond, e.g. formation of 33.-10 1... 

The lactam moiety in benzodiazepines is active toward nucleophiles and numerous analogues have been made by exploiting this fact. For example, heating demoxepam (3) with N-cyclopropylmethylamine leads to amidine formation, the minor tranquilizer cyprazepam... 

It is interesting to note that some 1,5-benzodiazepines such as 29 also possess CNS depressant activity. Treatment of substituted diphenylamine 26 with methyl malonyl chloride and reduction with Raney nickel led to orthophenylenediamine analogue 27. Sodium alkoxide treatment led to lactam formation (28), and alkylation in the usual way with NaH and methyl iodide produced clobazam (29). °... 

Several different changes in mitochondria occur during apoptosis. These include a change in membrane potential (usually depolarization), increased production of reactive oxygen species, potassium channel activation, calcium ion uptake, increased membrane permeability and release of cytochrome c and apoptosis inducing factor (AIF) [25]. Increased permeability of the mitochondrial membranes is a pivotal event in apoptosis and appears to result from the formation of pores in the membrane the proteins that form such permeability transition pores (PTP) may include a voltage-dependent anion channel (VDAC), the adenine nucleotide translocator, cyclophilin D, the peripheral benzodiazepine receptor, hexokinase and... 

Cycloreversion with nitrile oxide formation is known not only in furoxans but also in isoxazolines, 1,2,4-oxadiazoles, furazans, and some other live-membered heterocycles (76). Such process, eliminating nitrile oxide fragment 3-R CeHiC N+Cr ", was observed mass spectrometrically in 3a,4,5,6-tetrahydro-[ 1,2,4 oxadiazolo[4,5-a J [ 1,5 benzodiazepine derivatives 11 (83). 

The basis for this technique lies in the competition between the test antigen and a labelled antigen for the available binding sites on a fixed amount of antibody. While the binding sites are traditionally associated with an antibody, any source of specific reversible binding sites may be used to create an assay in this format. Examples of such are specific transport proteins such as thyroxine-binding globulin and certain cellular receptors such as opiate or benzodiazepine receptors. Under these circumstances the equilibrium mixture may be represented thus ... 

---