Central nervous system depressants. 15. 1,4-benzodiazepines

A number of 5-phenyl-1,4-benzodiazepines and a few 2-phenyl-1,4-benzodiazepines were prepared and screened for central nervous system activity in mice. Some were highly active. An unusual substitution of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one by trichloro-acetylisocyante is reported.     

An anomalous reaction of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine with sodium acetate and 1,1′-carbonyldiimidazole

The addition of 7-chloro-2-hydrazono-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 3 to a mixture of sodium acetate and 1,1′-carbonyldiimidazole 1 at room temperature gave, in moderate yields, carbonyl-1,1′-bis[7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ylidene hydrazone] 7 instead of the expected 2-acetylhydrazono-7-chloro-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepine 4 .     

Quinazolines and 1,4-benzodiazepines. XLVI. Photochemistry of nitrones and oxaziridines

The cyclic nitrones 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5a ) and 1,3-dihydro-7-methylthio-5-phenyl-2H-1,4-benzodiazepin-2-one 4-oxide ( 5b ) are photoisomerized to readily isolable oxaziridines, 7-chloro-4,5-epoxy-5-phenyl-1,3,4–5-tetrahydro-2H-1,4-benzodiazepin-2-one ( 6a ) and 4,5-epoxy-5-phenyl-1,3,4,5-tetrahydro-7-methylthio-2H-1,4-benzo-diazepin-2-one ( 6b ). Oxaziridine 6b upon further irradiation gave ring expansion and ring contraction products, 4,6-dihydro-2-phenyl-9-methylthio-5H-1,3,6-benzoxadiazocin-5-one ( 7b ) and 4-benzoyl-3,4-dihydro-6-methylthioquinoxalin-2(1H)-one ( 8b ) respectively. The ring contraction product, 4-benzoyl-6-chloro-3,4-dihydroquinoxalin-2(1H)-one ( 8a ), was obtained from irradiation of oxaziridine 6a .     

Control of electron demand in the cycloadditions of 2(H)-1,4-oxazin-2-ones

3-Methoxy-5-chloro-6-methyl-2(H)-1,4-oxazin-2-one 4, 3-methoxy-5-chloro-6-phenyl-2(H)-1,4-oxazin-2-one 5, 3-phenylsulfenyl-5-chloro-6-methyl-2(H)-1,4-oxazin-2-one 6, and 3-phenylsulfenyl-5-chloro-6-phenyl-2(H)-1,4-oxazin-2-one 7, are ambident dienes and undergo Diels-Alder cycloadditions with electron neutral, rich and deficient dienophiles.     

The m/z 91 rearrangement ion in the mass spectra of some 1,4-benzodiazepines

With the aid of isotope labeling and by substituent shifts, the relatively strong m/z 91 ion in the mass spectra of 7-chloro-2-methoxy-5-phenyl-3H-1,4-benzodiazepine and related compounds was shown to contain the 5-phenyl ring and the 3-CH₂ group. Mechanisms involving the opening of the 7-membered ring and the migration of the phenyl ring from C-5 to C-3 are postulated for the formation of this ion. This rearrangement ion was also observed in the mass spectra of some 1-alkyl-7-chloro-1,3-dhydro-5-phenyl-2H-1,4-benzodiazepin-2-ones.     

A NOVEL SERIES OF PALLADIUM(II) AND PLATINUM(II) COMPLEXES WITH 1,4-BENZODIAZEPINES AS LIGANDS

Abstract

The complexing behaviour towards palladium(II) and platinum(II) halides of some 1,4-benzodiazepines is reported. The ligands used in this study are 7-chloro-2-methylamino-5-phenyl-3H-1,4-benzodiazepin-4-oxide, 1,3-dihydro-7-nitro-5-phenyl-2H-1,4-benzodiazepin-2-one and 7-chloro-1-methyl-5-phenyl-3H-1,4-benzodiazepin-2-one. The complexes have been studied by means of magnetic susceptibility measurements, infrared and far infrared spectra, electronic spectra and conductivity measurements. The most convincing structural evidence for these complexes is a square planar stereochemistry with bridging ligands joining two metal ions and terminal halides in the 1:1 complexes and terminal ligands and terminal halides in the 1:2 derivatives. Assignments for the metal-ligand and metal-halide bands have also been made.     

2(H)-1,4-Oxazin-2-ones as ambident azadienes

3,5-Dichloro-6-phenyl-2(H)-1,4-oxazin-2-one 3, 5-chloro-3,6-dimethyl-2(H)-1,4-oxazin-2-one 4, 5-chloro-6-methyl-3-phenyl-2(H)-1,4-oxazin-2-one 5 and 5-chloro-3,6-diphenyl-2(H)-1,4-oxazin-2-one 7, are ambident azadienes reacting efficiently and selectively with both electron rich and electron poor dienophiles.     

Nuclear magnetic resonance of psychotherapeutic agents. IV—conformational analysis of 2,3-dihydro-1H-1,4-benzodiazepines

The lanthanide shift reagent (LSR)/¹H NMR study of some 7-chloro-5-phenyl-2,3-dihydro-1 H-1, 4-benzodiazepines shows that these compounds exist in CDCI₃ solution as two pseudo-boat conformers, rapidly interconverting at room temperature. Computer simulated lanthanide induced shifts (LIS) are consistent with LSR complexation by the imine nitrogen atom. The lanthanide shifts the conformational equilibrium towards conformer (a), with a pseudoequatorial 1-substituent: this effect may be the result of the greater basicity of 4-N when the 1-N lone pair is pseudoaxially directed, thus permitting an extended electron delocalization from 1- to 4-N through the fused benzene ring. The detection of H-9/1-Me through space spin-spin coupling in medazepam (7-chloro-1-methyl-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepine) supports the observed higher availability of conformer (a) to LSR. A LIS computer calculation to predict the population ratio results in reasonable agreement with the conformational changes based on the response of ³J(HH) to lanthanide addition. The electronic and steric effects which determine the greater stability of conformer (a) may be effective in the drug-receptor interaction.     

Diazepines I. A new synthesis of 6-phenyl-4H-imidazo[1,2-a] [1,4] benzodiazepines

6-Phenyl-4H-imidazo[1,2-a][1,4]benzodiazepines are obtained on reaction of 2-amino-7-chloro-5-phenyl-3H-1,4-benzodiazepine with α-bromoketones. In the cases of 3-bromo-2-butan-one and of 3-bromo-2-pentanone, 2-alkylimidazobenzodiazepine but not 1,2-dialkyl compound is the major product. A mechanism for the imidazole ring formation is presented.     

Synthesis and structure determination of isomeric 7- and 8-chloro-1,5-benzodiazepine derivatives

Reaction of 4-chloro-1,2-benzenediamine with 3,3-dimercapto-1-phenyl-2-propen-1-one afforded, as expected, a mixture of 7-chloro and 8-chloro-1,3-dihydro-4-phenyl-2H-1,5-benzodiazepine-2-thione. After separation of the two components and further reaction, their structure was established by chemical degradation of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine to 5-chloro-1,3-dihydro-1-methyl-2H-benzimidazol-2-one. The structure was also confirmed by single X-ray analysis of 7-chloro-2-(2-diethylaminoethylthio)-4-phenyl-3H-1,5-benzodiazepine.     

Nitration products of substituted 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones

Highly substituted, novel, 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-ones were obtained by direct nitration of the corresponding mono- or di-substituted 5-phenyl-1,4-benzodiazepines. Substituent effects and the orientation of aromatic substituents in the nitration products are discussed. The single-crystal X-ray structural data for one of these products, 18 , is given.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones. XII. Synthesis of N,N-disubstituted 4-amino-3-chloro-6-(2-methyl-l-propenyl) (2-phenylethenyl)-2H-pyran-2-ones

Cycloaddition of dichloroketene to N,N-disubstituted (E)-amino-5-methyl-1,4-hexadien-3-ones IV and (E,E)-1-amino-5-phenyl-1,4-pentadien-3-ones V occurred in moderate to good yield only in the case of aromatic N-substitution to give N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-6-(2-methyl-l-propenyl) (2-phenylethenyl)-2H-pyran-2-ones, which were dehydrochlorinated with DBN to afford in good yield N,N-disubstituted 4-amino-3-chloro-6-(2-methyl-propenyl)(2-phenylethenyl)-2H-pyran-2-ones. In the case of aliphatic N,N-disubstitution (dimethylamino group) of enaminones IV and V, the Cycloaddition led directly in low yield to 3-chloro-4-dimethylamino-6-(2-methyl-l-propenyl)(2-phenylethenyl)-2H-pyran-2-ones.     

1,4-Benzodiazepines III . Cyclization paths of hexaminium salts of 2-chioroacetamido-5-ehlorobenzophenone and its N-methyl derivative

This study reports the isolation and characterization of hexaminium salts of 2-chloroacetamido-5-chlorobenzophenone (I) and of 2-(N-methyl)chloroacetamido-5-chlorobenzophenone (II). The 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (VI) and 7-chloro-1,3-dihydro-1-meth-yI-5-phenyl-2H-1,4-benzodiazepin-2-one (VII), respectively are of pharmacodynamic importance. Based on chromatographic separation of some intermediates, and on spectrophotometric monitoring of cyclizations I → VI and II → VII, respectively, two different pathways for these reactions have been proposed. Since the slowest step in the reaction sequence II → VII follows the quasi first order rate law, intramolecular nucleophilic attack of the benzophenone carbonyl group on the hexamine moiety proved to be decisive for the cyclization (scheme II). However, cyclization I → VI seems to incorporate quite different solvolytic pathways in addition to one corresponding to the sequence II → VII. Isolated 4-imidazolidinone intermediates N,N' -methylene-bis[3-{2 -benzoyl-4-chIoro)phenyI]-4-imidazolidinone(III), and 3-(2 -benzoyl-4′-chlorophenyI)-4-imidazolidinone hydrochloride (IV) recyclize into the 1,4-benzodiazepine VI. The optimal reaction conditions have been found to be between pH 6-7.     

Reaction of ketenes with N,N-disubstituted α-aminomethyleneketones VIII. Synthesis of N,N-disubstituted 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones

The dipolar 1,4-cycloaddition of dichloroketene to N,N-disubstituted 3-amino-1-phenyl-2-propene-1-onesled directly to N,N-disubstituted 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones only in the case of an usual aliphatic N,N-disubstitution. In the case of partial or full aromatic N-substitution, N,N-disubstituted 4-amino-3,3-dichloro-3,4-dihydro-6-phenyl-2H-pyran-2-ones were instead obtained, which were dehydrochlorinated with DBN to the corresponding 4-amino-3-chloro-6-phenyl-2H-pyran-2-ones.     

Synthesis of 3-methoxy-5-oxo-6-phenyl-5,6-dihydro-4H-isothiazolo[5,4-b]-1,4-thiazine 7,7-dioxide,the first representative of a new heterocyclic system

When treated with an excess of MeONa in DMF, 5-benzylsulfonyl-3-chloro-4-methoxycarbonylaminoisothiazole undergoes cyclization into 3-methoxy-5-oxo-6-phenyl-5,6-dihydro-4H-isothiazolo[5,4-b]-1,4-thiazine 7,7-dioxide, the first representative of a new heterocyclic system. The starting 5-benzylsulfonyl-3-chloro-4-methoxycarbonylaminoisothiazole was prepared by the reaction of 5-benzylsulfonyl-4-carbamoyl-3-chloroisothiazole with PhI(OAc)₂ in methanol.     

Reaction of sulfene and dichloroketene with N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones. Synthesis of 1,2-oxathiino[6,5-E] indole and of pyrano[2,3-e] indole derivatives

The 1,4-cycloaddition of sulfene to N,N-disubstituted 5-aminomethylene-1,5,6,7-tetrahydro-2-methyl-1-phenylindol-4-ones afforded N,N-disubstituted 3,4,5,6-tetrahydro-8-methyl-7-phenyl-7H-1,2-oxathiino[6,5-e]indol-4-amine 2,2-dioxides only in the case of aliphatic N-substitution. The 1,4-cycloaddition of dichloroketene occurred normally only in the case of 1,5,6,7-tetrahydro-2-methyl-1-phenyl-5-piperidinomethyleneindol-4-one to give 3,3-dichloro-3,4,5,6-tetrahydro-8-methyl-7-phenyl-4-piperidino-7H-pyrano[2,3-e]indol-4-one. Attempted recrystallisation, dehydro-chlorination or treatment with palladium on carbon of this adduct, as well as reaction of similar enaminoketones with dichloroketene, gave instead the same product, namely 3-chloro-8-methyl-7-phenyl-7H-pyrano[2,3-e]indol-4-one, as a result of dehydrochlorination, dehydrogenation and subsequent hydrogenolysis of the C-NR₂ bond in the primary adduct.     

Chiral 1,4-benzodiazepines. XII. Conformation in a solution of 7-chloro-5-phenyl-3(S)methyl-1,3-dihydro-2H-1,4-benzodiazepine

Deuterium labeled congeners of 7-chloro-5-phenyl-3(S)-methyl-1,3-dihydro-2H-1,4-benzodiazepine ( 8 ), i.e., compounds 9 and 16-18 were prepared and their lis-nmr spectra run. For computational studies compounds 9 and 16 were chosen. The results of lis measurements revealed that 16 is present in more than 97% in the boat-like conformation I (Scheme 3).     

Mechanism of Alkaline Hydrolysis of Diazepam

Diazepam (1) is a frequently prescribed hypnotic/anxiolytic drug in worldwide use. Compound 1 is hydrolyzed in alkaline medium to form 2-methylamino-5-chlorobenzophenone imine (2) and 2-methylamino-5-chlorobenzophenone (3) ; the ratio of 2:3 increases with increasing NaOH concentration (J. Pharm. Sci. 85, 745–748, 1996). The mechanism in the conversion of 1 to 2 and 3 via various intermediates is the subject of this report. Results of hydrolysis kinetics and structural identification of some intermediate products indicated an initial hydroxide attack at the C2-carbonyl carbon of 1 , resulting in the formation of a dioxide ( 7 , 7-chloro-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2,2-dioxide). Compound 7 was characterized by proton NMR spectroscopy and via its monomethyl ether ( 8 , 7-chloro-1,3-dihydro-2-hydroxy-2-methoxy-l-methyl-5-pheny]-2H-1,4-benzodiazepine). The seven-member diazepine ring of 7 opened at the N1-C2 bond to form a glycinate [ 5 , 2-methylamino-5-chloro-α-(phenylhenzylidene)glycinate]. Compound 7 (and/or 5 ) underwent an additional hydroxide attack at the C5-N4 imine bond to form a tetrahedral intermediate, which decomposed to form 2 and 3 .     

The synthesis of oxazolo- and oxazino[3,2-d] [1,4]benzodiazepinones

Cyclization of 2′-benzoyl-4′-chloro-2-[(2-hydroxypropyl)amino]acetanilide (8) and 2′-bcnzoyl-4-ehloro-2-[(3-hydroxypropyl)amino]acetanilide ( 7 ) led to the respective oxazolo (3) and oxazino (5) analogs of 7-chloro-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one. Cyclization of 2′-benzoyl-4′-chloro-2-[2,3-dihydroxypropyl)amino]acetanilide ( 9 ) could produce either the oxazolo ( 4 ) or oxazino ( 10 ) analog. Data is presented to show that cyclization occurred to give the oxazolo (4) analog.     

Reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone derivatives and the properties of the obtained products

N′-(4-Oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides and N′-(3-methyl-4-oxo-1,4-dihydronaphthalen-1-ylidene)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides were synthesized by reactions of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 1,4-naphthoquinone or 2-methyl-1,4-naphthoquinone. The alkylated analogues of the above products were obtained using ethyl iodide. The interaction of 5-oxo-1-phenylpyrrolidine-3-carbohydrazides with 2,3-dichloro-1,4-naphthoquinone was followed by formation of N′-(3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)-1-phenyl-5-oxopyrrolidine-3-carbohydrazides. All these compounds were characterized using ¹H, ¹³C NMR, IR and mass spectra. Some of the new compounds were tested for the antimicrobial and antifungal activity.