Imidazo benzodiazepine

The first antagonist to be developed was the (imidazo)benzodiazepine, flumazenil. This compound blocks the actions of both agonists and inverse agonists in vitro. It will... 

Annelating the 1,2-bond of ring B with an additionai eiectron-rich (i.e., proton acceptor) ring, such as s-triazoie or imidazole, also results in pharmacologically active benzodiazepine derivatives with high affinity for the BZR (Fig. 22.17). For example, the s-triazolo-benzodiazepines triazolam, alprazolam, and estazolam and the imidazo-benzodiazepine midazolam are popularly prescribed, clinically effective anxiolytic agents (Fig. 22.16). 

Synthesis of imidazo[l,2-d]pyridazines and their interaction with central and peripheral-type (mitochondrial) benzodiazepine receptors 98JHC1205. 

Chemical Name 8-Nitro-1,2-dihydro-2-(N-methyl-piperazin-1 -yl)methylene-6-(o-chloro-phenyl)-1 H,4H-imidazo-[ 1,2-a] [ 1,4] -benzodiazepin-1 -one methanesulfonate... 

A mixture of this material with 500 ml of toluene end 30 g of manganese dioxide wes heated to reflux for 1 A hours. The mangenese dioxide wes seperated by filtration over Celite. The filtrate wes evaporated and the residue was crystallized from ether to yield 6-chloro-6-(2-fluorophenyl)-1 -methyl-4H-imidazo[1,5-a] [1, 4] -benzodiazepine, melting point 152°C to 154°C. The analytical sample was racrystallized from methylene chloride/hexane. 

A warm solution of 6.5 g (0.02 mol) of 6-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazo-[13-a] [1,4] -benzodiazepine in 30 ml of ethenol wes combined with a warm solution of 2.6 g (0.022 mol) of maleic acid in 20 ml of ethenol. The mixture was diluted with 150 ml of ether and heated on the steam bath for 3 minutes. After cooling, the crystals were collected, washed with ether and dried in vacuo to yield 8-chloro-6-(2-fluorophenyl)-1-methyl-4H-imidazoM, 5-a] [1,4] -benzodiazepine maleete, melting point 148°C to 151°C. 

CN 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[l,5-a][l,4]benzodiazepine-3-carboxylic acid ethyl ester... 

CN (Z)-6-(2-chlorophenyl)-2,4-dihydro-2-[(4-methyl-l-piperazinyl)methylene]-8-nitro-l//-imidazo[l,2-a][ 1,4]benzodiazepin- 1-one... 

CN 8-chloro-6-(2-fluorophenyl)-1 -methyl-4//-imidazo[ 1,5-a][l, 4]benzodiazepine monohydrochloride... 

Mellors JW, Im G-J, Tramontano E, Winkler SR, Medina DJ, Dutschman GE, Bazmi HZ, Piras G, Gonzalez CJ, Cheng Y-C. A single conservative amino acid substitution in the reverse transcriptase of human immunodeficiency virus-1 confers resistance to ( + )- (5S)-4,5,6,7-tetrahydro-5-methyl-6-(3-methyl-2-butenyl)imidazo[4,5,l-y ][l,4]benzodiazepin-2(lH)-thione (TIBO R82150). Mol Pharmacol 1993 43 11-16. 

Further new competitive AMPA antagonists include the imidazo-fused 23-benzodiazepine derivative 103. This compound showed excellent anticonvulsant activity and other activities indicative of possible therapeutic significance in human stroke and Parkinson k disease <00BMC2127>. An efficient synthesis of fluorine-containing H-1,4-diazepino[6,5-/t]quinolines has been described based on iV,/V-dimethyl-5,7-bis(trifluoroacetyl)-8-quinolylamine and an aromatic nucleophilic displacement with 1,2-ethylenediamine, followed by cyclocondensation <00S1822>. 

A series of imidazo[l,5-a]quinoxaline amides, carbamates, and ureas which have high affinity for the y-aminobutyric acid A/benzodiazepine receptor complex was developed. Compounds within this class have varying activities ranging from antagonists to full agonists. However, most analogs were found to be partial agonists as indicated by [ S]TBPS and Cl current ratios. Many of these... 

Imidazo[2,l-fl]isoindolone 187 is the product of an intramolecular a-aza-amidoalkylation of N-acyliminium species 186. Nevertheless, when the jS-substituent is an aromatic moiety, a competing a-amidoalkylation takes place and isoindolo[l,4]benzodiazepine 188 is obtained under thermodynamic control (Scheme 37 (2004T11029)). 

Amino methyl substituted pyrrolo-benzodiazepine 215 forms a cyclic aminal with aldehydes that can be further oxidized with Mn02 to fused 3-substituted imidazole 216. Alternatively, cyclic imine 217 can be submitted to TosMlC cycli-zation to afford unsubstituted 9H-benzo[e]imidazo[5,l-c]pyrrolo[l,2-fl][l,4]-diazepine 218 (Scheme 45, Section 3.1.1.2 (1993JHC749)). 

These spectra were routinely obtained for most of the compounds discussed in forthcoming sections. Specific studies were performed on selected compounds such as (i) (+)-(S )-4,5,6,7-tetrahydroimidazo-9-chloro-5-methyl-6-(3-methyl-but-2-enyl)imidazo [4,5,1 -jk [1,4] benzodiazepin-2(l//)-thione (9-chloro-TIBO)187 and (ii) series of metal chelates derived from l,2-dithiol-3-thion-4,5-dithiolate (dmt)188. The equilibria between 2-ethoxycarbonylthiolane-3-thiones and their (Z)-enethiol tautomers were also studied by these techniques189. It was found that the equilibrium is largely shifted in favor of the enethiols. NMR was also used to study the syn-anti conformational equilibria of seven A-(l-methoxycarbonylethyl)-A4-thiazoline-2-thiones with S conformation of the chiral rotor (43)190. A variety of substituents were used. 

Separately, 3.0 g (27.1 mmol) of potassium t-butylate are dissolved in 9.0 ml of dry dimethylformamide, cooled in an acetone/dry-ice bath, treated with 3.9 g (27.1 mmol) of t-butyl isocyanoacetate and the solution obtained is added dropwise at -15°C to the mixture obtained according to the preceding paragraph. The mixture is warmed to 15°C, neutralized with 1.5 ml of glacial acetic acid, poured into 100 ml of water and extracted four times with methylene chloride. The methylene chloride solution is washed twice with water, dried over magnesium sulfate, evaporated and the crude product obtained is chromatographed on silica gel using ethyl acetate for the elution. By recrystallization from ethyl acetate/n-hexane there is obtained t-butyl (S)-8-bromo-ll,12,13,13a-tetrahydro-9-oxo-9H-imidazo[l,5-a]pyrrolo[2,l-c] [ 1,4] benzodiazepine-1-carboxylate. 

Nitro-l,2-dihydro-2-(N-methylpiperazin-l-yl)methylene-6-(o-chlorophenyl)-lH,4H-imidazo[l,2-a][l,4]benzodiazepin-l-one Methanesulfonic acid... 

Chemical Name 8-Chloro-6-(2-fluorophenyl)-l-methyl-4H-imidazo-[l,5-a][l,4]benzodiazepine maleate... 

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