Benzodiazepine Ring Research Articles

Synthesis and nitration of 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one

Analysis of the UV spectra of the reaction products shows that in the nitration of 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one the nitro group is directed to the benzodiazepine ring rather than to the phenyl ring to give a 7-nitro derivative.

Quinazolines and 1,4‐benzodiazepines LXVIII. 5‐Heterocyclic‐substituted benzodiazepinones

AbstractThe synthesis of a number of new 1,4‐benzodiazepin‐2‐ones containg the 2‐thiazolyl, 5‐isothiazolyl, 1‐rnethyl‐2‐imidazolyl. 1‐methyl‐5‐pyrazolyl, and 3,5‐dimethyl‐4‐isoxazolyl groups in the 5‐position of the benzodiazepine ring are described.

Studies on the fate of flurazepam. 2. The metabolism of flurazepam in rat

The metabolic fate of Flurazepam hydrochloride, 7-chloro-1-(2-diethylaminoethyl)-5-(2-fluorophenyl)-1, 3-dihydro-2H-1, 4-benzodiazepin-2-one monohydrochloride, having a sleep-inducing effect, was examined in a rat after oral administration of this compound labeled with 14C at the C-5 position. Radioactive metabolites in bile and urine were fractionated to be identified. Less than 3% of the bilary 14C could be extracted with ethyl acetate at pH 9.0 and no appreciable amount of intact Flurazepam was detected in this extract. In bilary metabolites, N-dealkylated compounds (>NCH2CH2NHC2H5, >NCH2CH2NH2), thier conjugates, and the conjugate of N1-ethanol (>NCH2CH2OH) were found. In urinary metabolites, N1-acetic acid (>NCH2COOH) was found in addition to the bilary metabolites. One of major metabolites in both bile and urine remained unidentified, but it was evident that this unidentified metabolite was soluble in water, had no acidic group, kept a benzodiazepine ring structure, and had an N1-aminoethyl group (>NCH2CH2N<). From these results, the pathway of Flurazepam in rat was postulated as shown in Chart 4.

Thermische spaltung und massenspektrometrie der benzodiazepinalkaloide (−)-cyclopenin und (−)-cyclopenol

(−)-Cyclopenine (I) and (−)-cyclopenol (II) are benzodiazepine derivatives formed by Penicillium viridicatum Westling and P. cyclopium Westling. They are easily transformed to the quinoline alkaloids viridicatine (III) and viridicatol (IV) respectively by a general acid catalysis or an enzyme of P. viridicatum called cyclopenase. Mass spectrometric investigations suggest that both benzodiazepine compounds may be converted to viridicatine and viridicatol by thermic degradation. In fact, by heating (−)-cyclopenine and (−)-cyclopenol in various solvents to 220–240°C they readily rearrange by loss of methyl isocyanate to viridicatine and viridicatol. Besides this major route of degradation there is a minor one giving rise to 3-methyl-3,4-dihydroquinazolone-(4), carbonmonoxide and benzaldehyde or m-hydroxybenzaldehyde. The pyrolysis presumably starts with the homolytic fission of the epoxide ring between the oxygen and either C-atom 10 or 3 and follows the route shown in Schemes 1 and 2. Degradation of biosynthetically labelled (−)-cyclopenol-2- 14C, -3- 14C and -5- 14C supports the mechanisms proposed. It was possible to show that the carbonyl group of the methyl isocyanate derives from C (5) and the carbon monoxide from C (2) of the benzodiazepine ring. In the 3-methyl-3,4-dihydroquinazolone-(4) C-atoms 3 and 5, in the viridicatol C-atoms 2 and 3 of this ring remain (Table 1). By mass spectrometric degradation of (−)-cyclopenine and (−)-cyclopenol a set of peaks is obtained which corresponds to the molecular ions of viridicatine or viridicatol and their fragmentation products (Figs. 1–4). In addition there seem to be other fragmentation routes probably connected in part with a hydrogen shift from the side chain to the benzodiazepine moiety (Schemes 3 and 4), In spite of this 3-methyl-3,4-dihydroquinazolon-(4) may be formed in small quantities. Conversion of cyclopenine and cyclopenol to 3-methyl-1,2,3,4-tetrahydroquinazolindione-(2,4) was not detectable.