Benzo diazepines

Similar ring contractions in which the nitrogen-nitrogen bond is cleaved are found in the reductive ring contractions of pyridazines to pyrroles [148, 149], phthalazines to isoindoles [150], 5,6-diphenyl-1,2,4-triazinones to imidazolones [151], benzo-l,2,4-triazines to benzimidazoles [71], benzo-l,2,3-triazinone to indazolone [la, 152], benzo-l,2,3-triazin-3-oxide to indazole [la], benzo-2,3-diazepines to isoquinolines [153], benzo-l-pyrano-[4,3-e ]-as-triazin-3-one to benzopyranoimidazolone [154], and 2-methyl-4,5-dihydropyridazin-3-ones to pyrrolin-2-ones [155]. 

Treatment of benzopyrilium perchlorates (159) with excess hydrazine hydrate in refluxing EtOH has provided 5/f-benzo-2,3-diazepines (160) in 63-75% yield (Scheme 23) <93KGS1475>. Reaction of (159 R = Me, R = C02Et, CN) with one equivalent of hydrazine hydrate aflbrds 2-amino-isoquinolinium perchlorates (161) in 90% yield, which, in the case of the 4-cyano compound, proceeds to the benzodiazepine (160 R = Me, R = CN) in 73% yield. 

A careful and NMR study of 1,5-benzoxazine and 1,5-benzo-diazepine shows that these compounds exist in the amino-thione forms 55 and 56, respectively. Compound 55 displays a solvent-dependent amino/imino tautomerism (92MRC673).Tricyclic compounds 57, analogous to the bicyclics discussed above have been described they exist in the tautomeric form shown below (87BSB399,92BSB995,96BSB345). 

Removal of the solvent gave an oil which was taken up In ether and filtered through a pad of Woelm grade I alumina. The eluent was concentrated and the residue was crystallized from methylene chloride/hexane yielding 1-methyl-7-nitro-5-(2-fluorophenyl)-3H-1,4-benzo-diazepin-2(1 H)-one as pale yellow needles melting at 166° to 167°C. 

B) Preparation of 7-Chloro-1,2,3,4-Tetrahydro-1-Methyl-6H-1,4-Bemodiazepin-5-one A mixture of 25.25 g (0.1 mol) of 4-acetyl-7-chloro-1,2,3,4-tetrahydro-1-methyl-5H-1,4-benzo-diazepin-5-one, 33.3 ml (0.1 mol) of 3 N sodium hydroxide and 350 ml of ethanol was heated under reflux for 15 minutes and then concentrated to dryness in vacuo. The residue was treated with 500 ml of water, collected and washed with ethanol to give 20.2 g... 

B) Add to a suspension of 34 g of 3-acetoxy-7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzo-diazepin-2-one in 80 ml of alcohol, 6 ml of 4N sodium hydroxide. Allow to stand after complete solution takes place to precipitate a solid. Redissolve the solid by the addition of 80 ml of water. Acidify the solution with acetic acid to give white crystals. Recrystallize from ethanol to obtain 7-chloro-1,3-dihydro-3-hydroxy-5-phenyl-2H-1 4-benzodiazepin-2-one, melting point 203°Cto 204°C. 

The 1/7-1,2-benzodiazepines 6 react with lead(IV) acetate to give 3-acetoxy-3//-l, 2-benzo-diazepines 5 with mcthanolic copper(II) nitrate, the 3-methoxy-3//-l,2-benzodiazepines 7 arc formed.123... 

An analogous reaction of (2-acylphenyl)acetic acids with hydrazine or substituted hydrazines in refluxing benzene, xylene or butanol with azeotropic removal of water gives 3//-2,3-benzo-diazepin-4(5//)-ones 3.128,129... 

The bromo derivative 16 reacts with phenylmagnesium bromide in diethyl ether, followed by workup with 5% aqueous hydrobromic acid, to give 2-methyl-4,5-diphenyl-2//-2,3-benzo-diazepin-l(5//)-one (17) in 55% yield.137 No further details were reported. 

The identification of the HIV-1-specific non-nucleoside reverse transcriptase inhibitors (NNRTIs) as a separate class of HIV inhibitors was heralded by the discovery of the tetrahydroimidazo[4,5,1 -// .][ 1,4]benzo-diazepin-2(l //)-onc and -thione (TIBO) derivatives (Fig. 7) [58,59] and 1 -(2-hydroxyethoxymethyl)-6-(phenylthio)thymine (HEPT) derivatives (Fig. 8) [60,61]. The first TIBO derivatives (R82150, R82913) were the first NNRTIs [58] postulated to act as inhibitors of HIV-1 RT [59], For the HEPT derivatives it became evident that they also interact specifically with HIV-1 RT after a number of derivatives (i.e., E-EPU, E-EBU, and E-EBU-dM) had been synthesized that were more active than HEPT itself [62,63]. Following HEPT and TIBO, several other compounds, i.e., nevirapine, pyridinone, and bis(heteroaryl)piperazine (BHAP), were... 

The drug diazepam may serve as an illustrative example. Chemically, this compound is called 7-chloro-l,3-dihy-dro-1 -methyl-5-phenyl-2H-l, 4-benzo-diazepin-2-one, a term too unwieldy for everyday use. A simpler name is diazepam. This is not a legally protected name but a generic (nonproprietary) name. An INN (= international nonproprietary name) is a generic name that has been agreed upon by an international commission. 

A Bischler-Napieralski intramolecular cyclization involving aryl acetyl chlorides in phosphoryl chloride affords 4-arylmethyl-4H-pyrrolo[l,2-fl][l,4]benzo-diazepines 236 (Scheme 50 (1995EJM593)). 

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]. 

Cyclic secondary amines with pyrrolo[2,l-c][l, 4]-benzodiazepine rings were oxidised with TPAP/NMO/PMS/CH3CN to the corresponding imines. Thns (llaS)-1,2,3,10,ll,lla-hexahydro-5H-pyrrolo[2,l-c][l, 4]-benzodiazepine-5-one gave (llaS)-l,2,3,lla-tetrahydro-5H-pyrrolo[2,l-c][l, 4]benzo-diazepine-5-one [23]. 

Garanti et al. (30a) reported a synthesis of the l,2,3-triazolo[l,5-a][4.1]benzox-azepine 149 via an intramolecular cycloaddition of an aryl azide with an acetylene (Scheme 9.30). By using a similar strategy, the l,2,3-triazolo[l,5-a][l,4-l ]benzo-diazepine 150, an analogue of Flumazenil, was also reported (30b,c). As an extension of this method, the l,2,3-triazolo[l,5-a][l,4]benzodiazepine-6-one 153 was synthesized using an intramolecular 1,3-dipolar cycloaddition of an azide with a cyano group (30d). 

A new method for the synthesis of 4(3//)-qumazolinones 822 and 1,4-benzo-diazepine-2,5-diones 823 from reaction of 4-aryhnethylene-2-methyl- 821 (Rj = Me) or 4-arylmethylene-2-phenyl-5(4/i/)-oxazolones 821 (Rj = Ph) with o-aminobenzamide has also been reported (Scheme 7.254). ... 

Beta blockers provide symptomatic relief by decreasing the symptoms due to sympathetic overactivity e.g. palpitation, tremors, rise in BP, etc. They may be used as adjuvant to benzo-diazepines. 

In a simple microwave-assisted and solvent-free approach, substituted isatoic anhydrides were reacted with 4-substituted prolines to afford fused 1,4-benzodiazepine derivatives67. The reactions proceeded in less than 3 min and the fused 1,4-benzo-diazepine products were obtained in very good yields (Scheme 3.42). This condensation reaction represents a practical alternative approach to the typical traditional methods. 

An intramolecular reaction with primary amine as the nucleophile that was prepared in situ by the reduction of the nitro group in pyrrole 1319 resulted in the pyrrolo[2,Tf]benzo[/ ]diazepine 1320, which indicates that the amino group reacts via condensation with the aldehyde group rather than via substitution of the chloro group (Equation 287) <2005T5831>. 

A linkage strategy was used for the solid-phase synthesis of a range of 1,4-benzo-diazepine derivatives . It was demonstrated that the germanium route is superior to the silicon route because numerous functional groups are tolerated and the demetallation using trifluoroacetic acid or bromine is easier for germanium compounds. In Scheme 52... 

More recently, Fitos and Simonyi (41) used the work of Brown et al. to attempt to explain the observation that the S-enantiomer of warfarin is able to induce an allosteric enharKement in the binding of certain (S)-benzo-diazepines at site 11, whereas its antipode apparently is not. Their hypothesis was that a particular orientation of binding of the coumarin nucleus was responsible for the allosteric coupling between the two binding... 

Social anxiety avoidance Social phobia, panic disorder Antidepressants, beta blockers, benzo diazepines... 

The sedative and hypnotic effects of benzo diazepines are accentuated by other drugs acting on the gamma-aminobutyric acid, (GABA ) receptor, especially barbiturates and alcohol. However, there are fewer drug... 

Clonazepam. Clonazepam, chemically 5-(2-chlorophenyl) -1,3-dihydro- 7-nitro-2ff-1,4-benzo-diazepin-2-one(4b), is closely related to nitrazepam (4e), differing only at position 5 with the o-chloro substituent. Only 0.5% of the original drug is recovered unchanged in the urine after 24 h, indicating extensive bio-... 

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