Synthesis of 2-amino-3-hydroxy- and of 2,3-diamino-3H-1,4-benzodiazepines

A new synthesis of 7-chloro-2,3-diamino-5-phenyl-3H-1,4-benzodiazepines is described, which allows for the preparation of compounds bearing the same or different substituents at the 2 and 3 positions, starting from 2-amino-7-chloro-3-hydroxy-5-phenyl-3H-1,4-benzodiazepines.     

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.     

Expedient one-pot synthesis of novel chiral 2-substituted 5-phenyl-1,4-benzodiazepine scaffolds from amino acid-derived amino nitriles

An efficient and stereocontrolled synthesis of phenylalanine- and tryptophan-derived 5-phenyl-1,4-benzodiazepines is described. This new methodology involves, as a key step, the synthesis of 5-phenyl-2,3-dihydro-1H-1,4-benzodiazepines by a one-pot cyano reduction and reductive cyclization of the appropriate amino nitrile, which were obtained via a modified Strecker reaction of N-protected alpha-amino aldehydes with 2-aminobenzophenone and trimethylsilyl cyanide. The subsequent reduction of these 2,3-dihydro-1H-1,4-benzodiazepines, followed by regioselective alkylation or acylation at position 4, led to 2,4-disubstituted-5-phenyl-2,3,4,5-tetrahydro-1H-1,4-benzodiazepine.     

Quinazolines and 1,4-benzodiazepines XXXVI . The formation of 1,3-dihydro and 1,5-dihydro-1,4-benzodiazepines from tosyl and Mesyl - substituted 1,3,4,5-tetrahydro-5-phenyl- 1,4-benzodiazepine derivatives

The treatment of 4-sulfonyl derivatives of 5-phenyl-1,3,4,5-tetrahydro-1,4-benzodiazepin-2-ones (I) with base was shown to result in the formation of 1,3-dihydro or 1,5-dihydro-1,4-benzodiazepin-2-ones (III and II respectively) depending upon the conditions used. The base treatment of 1-sulfonyl substituted 2,3-dihydro-1,4-benzodiazepines (V) was shown to give the vinylimines VI.     

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.     

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 .     

1,4-Benzodiazepines and their cyclic homologs and analogs

5-Difluoromethylsulfonyl-2-aminobenzophenone was synthesized by condensation of p-difluoromethylsulfonylaniline with benzoyl chloride. 5-Difluoromethoxy- and 5-difluoromethylthio-2-aminobenzophenones were obtained by condensation of phenylacetonitrile with the appropriate p-substituted nitrobenzenes and subsequent reduction of the resulting anthranils. 7-Difluoromethoxy-, 7-difluoromethylthio-, and 7-difluoromethylsulfonyl-5-phenyl-1,2-dihydro-3H-1,4-benzodiazepin-2-ones were obtained by the successive action of bromoacetyl bromide and ammonia on the 2-aminobenzophenone derivatives or by reaction of 2-aminobenzophenones with aminoacetyl chloride hydrochloride. The structure of the 1,4-benzodiazepines was confirmed by a study of the UV, IR, PMR, and mass spectra.     

Quinazolines and 1,4-benzodiazepines. XCV. Synthesis of 1,4-benzodiazepines by ring expansion of 2-chloromethylquinazolines with carbanions

1,4-Benzodiazepines bearing a carbon substituent at the 2-position were obtained by reaction of 2-chloromethylquinazoline 3-oxides with stabilized carbanions. The carbanions of alkyl acetates, N,N-disubstituted acetamides, acetonitrile, dimethylsulfone, N,N-dimethyl methanesulfonamide and 2-methylpyridine were successfully applied. The conversion of some of the 2-carbon substituted 1,4-benzodiazepines to imidazo[1,5-a][1,4]benzodiazepines and [1,2,5]oxadiazino[5,4-a][1,4]benzodiazepines is described.     

Gas-phase fragmentation of protonated benzodiazepines

Protonated 1,4-benzodiazepines dissociate in the gas phase by the common pathway of CO elimination and by unique pathways dictated by the substituents; the latter typically differentiate one benzodiazepine from another. Protonated 3-dihydro-5-phenyl-1,4-benzodiazepin-2-one, the base diazepam devoid of substituents, dissociates by eliminating CO, HNCO, benzene, and benzonitrile. Mechanisms of these reactions are proposed with ionic products being resonance stabilized. The abundant [MH-CO]+ ion dissociates to secondary products via elimination of benzene, benzonitrile, the NH2 radical, and ammonia, yielding again ionic products that are stabilized by resonance.     

Quinazolines and 1,4-benzodiazepines. XCIII. Synthesis of imidazo[1,5-a][1,4]benzodiazepines from nitrooximes

The displacement of the nitro group in nitrooximes by other nucleophiles was used to prepare various 2-(hydroxyimino)methyl- and 2-(methoxyimino)methyl-1,4-benzodiazepines. These compounds were converted to imidazo[1,5-a][1,4]benzodiazepines bearing a tertiary amine, methoxy or thiomethyl group in the 3-position.     

Über die Synthese von 4-Phenyl-[1,4]-diazepino[6,7,1-kl]phenthiazin-1(2H)-on

The preparation of 4-phenyl-[1.4]-diazepino[6.7.1-kl]phenothiazin-1(2H)-one (5) is described and some of its properties are compared with those of 1.4-benzodiazepines.     

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.     

Quinazolines and 1,4-benzodiazepines LVII. 1H-1,4-benzodiazepines

The preparation of the title compounds 3 and 4 using two different methods of synthesis is described. These compounds are readily reduced to 2,3-dihydro-1H-derivatives 5 . Oxidation of 2-alkylthio-1H-1,4-benzodiazepines leads to the corresponding sulfoxides and sulfones. The oxidative rearrangement of sulfones 9 to a 2H-1,4-benzodiazepin-2-one derivative 10 is also given. The “normal” addition of azodicarboxylate together with an unusual addition of two moles of acetylenedicarboxylate to the enamine double bond of 1H compounds is discussed.     

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. LXI. Syntheses of 7-Acetyl-1,4-benzodiazepines

Methods for the synthesis of the biologically active 7-acetyl-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 6 ) are described. This includes two new methods for the preparation of 5-acetyl-2-aminobenzophenone ( 4 ). The crucial steps in these syntheses involve, respectively, the oxidation of an ethyl group to an acetyl group with permanganate or ceric ions ( 2 → 3; 5 → 6 ), the selective reaction of methyl lithium with the cyano group of 7-cyano-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one ( 8 ) and the efficient condensation of benzyl cyanide with the ethylene ketal of p-nitroacetophenone to form the anthranil 11 .     

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.     

Acyl Indoles. III. The synthesis of [1,4] diazcpino [6,5-b ] indoles

The synthesis of 1,3,4,6-letrahydro-6-metliy]-2H,5H-[1,4]diazepino[6,5-b] indole-2,5-diones and 5-phenyl-3,6-dihydro[1,4]diazepino[6,5-b ]indole-2(lH)one is described. Also detailed is the, preparation of a 3-amino-2-benzoylindole.     

Versatile synthesis of chiral 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines as novel scaffolds for peptidomimetic building

The stereocontrolled synthesis of phenylalanine and tryptophan derived 5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepine derivatives is described. This new methodology involves a modified Strecker reaction of N-Boc protected amino aldehydes and methyl anthranilate, reduction of the resulting α-amino nitriles, and lactamization. The resulting 2-substituted-5-oxo-1,2,3,4-tetrahydro-5H-1,4-benzodiazepines were further functionalized at position 4 by alkylation or acylation reactions. One of these new tryptophan-derived 1,4-benzodiazepines showed significant selective binding affinity at cholecystokinin CCK₁ receptors (IC₅₀=156.5±33.2 nM).     

Mikrochemischer Nachweis und Unterscheidung von fünf Tranquilizern aus der Klasse der 5-Phenyl-1,4-Benzodiazepine mit Hilfe der dünnschicht-chromatographischen TRT-Technik

An analysis method for the separation and detection of five 5-phenyl-1,4-benzodiazepines (Chlorazepate, Chlordiazepoxid, Diazepam, Medazepam, Nitrazepam) is described. After separation in the first dimension of two-dimensional thin-layer chromatograms, the benzodiazepines may be converted to benzophenone derivatives by means of treatment with hydrochloric acid. The subsequent separation in the second dimension provides structural information and permits exact specification by way of R_f-values and Bratton-Marshall detection. With this method contents as low as 0.02 μg can be detected.     

Mikrochemischer Nachweis und Unterscheidung von fünf Tranquilizern aus der Klasse der 5-Phenyl-1,4-Benzodiazepine mit Hilfe der dünnschicht-chromatographischen TRT-Technik

An analysis method for the separation and detection of five 5-phenyl-1,4-benzodiazepines (Chlorazepate, Chlordiazepoxid, Diazepam, Medazepam, Nitrazepam) is described. After separation in the first dimension of two-dimensional thin-layer chromatograms, the benzodiazepines may be converted to benzophenone derivatives by means of treatment with hydrochloric acid. The subsequent separation in the second dimension provides structural information and permits exact specification by way of R_f-values and Bratton-Marshall detection. With this method contents as low as 0.02 μg can be detected.