Heterocyclics benzodiazepines

Stereodynamic properties of medium-ring benzo-fiised nitrogenous heterocycles Benzodiazepines, benzazepines, benzazocines, and benzazo-nines 13T10783. 

Other heterocycles which provide the CCC component in related ring transformations are benzodiazepine-3-carbonitrile (80CPB567), benzotriazepines (74T2765), azaxanthones (75JOC1734), acyloxiranes (61AP769) and oxetanones (65CPB248). 

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. 

Fusion of an additional heterocyclic ring onto that already present in the benzodiazepines has led to some medicinal agents with considerable activity. Treatment of an intermediate like 15 with phosphorus pentasulfide affords the corresponding thio-amide (37). Condensation of this intermediate with acetyl hydra-zide affords triazolam )37). The same agent can be prepared by reaction of the amidine, 38, ° with acetylhydrazide. ... 

A number of benzodiazepines have heterocyclic rings anne-lated to them. One such is the tranquilizer midazol am (94). Nitrosation (HONO) of secondary amine leads to the ] -nitroso analogue Nitrosoamidines, in the presence of carbanions,... 

Fusion of an additional heterocyclic ring onto a benzodiazepine is well known to considerably increase potency. This increase in potency is apparently maintained when the benzene ring is replaced by thiophene. Thiophene aminoketone 161 is converted to the benzodiazepine analogue 164 via chloroacetamide 162 and then glycine derivative 163 by the same sequence as that used in the benzene series. Treatment of the product 164 with phosphorus pentasulfide gives the thio-amide 165 reaction of that intermediate with hydrazine leads to the amino amidine 166. Conden-... 

The term benzodiazepine refers to a chemical structure, consisting of a heterocyclic ring system in which the two N atoms are mostly located in positions 1 and 4 (1,4-benzodiazepines), e.g., in diazepam (Fig. 1). 

A mass spectrometric study was carried out to establish tbe structure of compoimd 69. Its mass spectrum contains tbe molecular ion peak m/z 252 (16.98%) and a base peak (100%) at m/z 210, corresponding to 2-(2-hydroxypbenyl)benzimidazole (70). A tendency towards decreasing the heterocycle size is characteristic of the mass spectrometric behavior of 1,5-benzodiazepin-2-ones [61] and consequently the mass spectra of these compounds contains intense peaks of the corresponding benzimidazoles. It is also known that the mass spectrometric fragmentation of 1,5-benzodiazepines is similar to their thermal or acid decomposition. In fact, refluxing compound 69 in concentrated sulfuric acid yields benzimidazole 70 as the main product. 

An elegant two-step solution-phase methodology was developed for the synthesis of the benzodiazepine-2,5-diones (93 e.g. R1 = PhCH R2 = Me, R3 = Me, R4 = H, R5 = Me, 32%). The first step was a Ugi four-component reaction followed in the second step by a palladium-mediated intramolecular IV-arylation reaction. This methodology has considerable scope for further application in heterocyclic synthesis <06TL3423>. 

Microwave-promoted reactions continue to extend their reach in heterocyclic synthesis. Regioselective N4-aminoethylation of the l,4-benzodiazepin-2-one 94 was observed under microwave conditions in DMF/K2C03 to afford, for example, 96a and 96b in 64% and 67% yield respectively (Table 4). In contrast, the thermal reaction at 80 °C in DMF with K.2CC)3 as base gave the Nl-aminoethylation products (95a, 65%) and (95b, 76%). These results were... 

Many seven-membered ring heterocyclic derivatives show pharmacological activity, and many, for example the benzodiazepines, nevirapine (anti-HIV), trineptine (antidepressant) and artemisinin derivatives (anti-malarial) are used clinically. The number of papers reporting pharmacological activity of new compounds or pharmacological mode of action studies continues at a significant rate. 

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). 

There are many examples for seven-membered benzoannelated heterocycles that include benzazepines (332) [245, 454] benzothiazepines (333) [455, 456] and the very important pharmacological family of benzodiazepines (334) [285, 457, 458], which was the first class of small molecules synthesized on solid supports [459]. Benzoxazocines (335) [460] are examples for benzoannelated eight-mem-bered heterocycles obtained on solid supports (Fig. 3.14). 

Diazepines represent an important class of bicyclic seven-membered heterocycles. They are the basis of several tranquilizers and are accessible from a-amino acid esters and o-azidobenzoyl chloride in the presence of triethylamine. The A/ -(o-azidobenzoyl)amino esters (333) formed in this way (Scheme 121) are cyclized by Staudinger and aza-Wittig reactions to give 2-ethoxy-l,4-benzodiazepin-5-ones (334) (92MI2). 

This general strategy has been employed for the synthesis of several types of heterocycles, including diketopiperazines [29-32], ketopiperazines [29, 33], pyrro-lidinones [34], 1,4-benzodiazepines [29, 32, 35-37], dihydroquinoxalinones [29], hexahydropyrrolodiazepines [38], and oxetanones [27]. Figure 4 shows some selected examples. 

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]. 

Reactions of 4,5-disubstituted triazoles with appropriate substrates provide very useful methods for building triazolo fused bicyclic or tricyclic systems. 5-Azido-1,2,3-triazoles bearing an appropriate substituent (e.g., CHO, CN, CO2R) at the 4-position can be transformed with active methylene nitriles into tricyclic heterocycles (e.g., (368)) <86BSB679,87BSB587). A new tricyclic system, 5//-1,2,3-triazolo[5,l-c][l,4]benzodiazepine (e.g., (370) and (371)), is prepared by the intramolecular ring closure of triazoles (369) <89JHC1605). 

The basic chemical structure of the benzodiazepines consists of a benzene ring coupled to a seven-member heterocyclic structure containing two nitrogens (di-azepine) at positions 1 and 4 (Fig. 30.1). Of the 2,000 benzodiazepines that have been synthesized, approximately 15 clinically useful compounds are on the market in the United States (Table 30.1). 

Nitrile imines have been added to 1,4-diazepines (246) (143,144), 1,2, 4-triazepines (247) (145), 1-benzazepines (248) (146), 1,4-benzodiazepines (249-251) (147-149), 1,5-benzodiazepines (252, 253) (X = NH) (143,150-153), 1,5-benzothiazepines (253) (X=S) (153). Interest in this area has been stimulated by the known pharmacological activity of many compounds with five-membered heterocyclic rings fused to a benzodiazepine skeleton. 

Benzodiazepine derivates, seven-membered rings with 2 N atoms in 1,4 position are the pivotal structures of the benzodiazepine class of breakthrough CNS (central nervous system) drugs such as Librium and Valium. The most recent drug in this class, Sepracor s Lunesta (eszopiclone), is composed almost entirely of A-heterocyclics. Like most modern drugs, esczopi-clone also has a chiral center ... 

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