Benzodiazepines derivatives

Dimethyl malonate was reacted with 2-(iV-nitrosomethylamino)-1,4-benzodiazepines (502, R = H, F n = 0, 1) in the presence of potassium tm-butoxide in DMF under nitrogen to give (1,4-benzo(6)diazepin-2-ylidene)malonates (503, R = H, F n = 0, 1) (75JOC153 83USP4401597). A dichloro derivative of (1,4-benzodiazepin-2-ylidene)malonate (503, R = Cl, = 0) was prepared in the reaction of a 1,4-benzodiazepine derivative (504) and dimethyl malonate under the previous conditions (83USP4401597). 

A A,A-dimethylcarboxamido group attached to other aromatic systems can be hydrolyzed enzymatically as demonstrated by the metabolism of the ring-opened 1,4-benzodiazepine derivative 4.84 in dogs and rats [53], Here also, hydrolysis was shown to proceed via the secondary and primary amide formed by A-demethylation. 

Some 1,4-benzodiazepine derivatives, loosely regarded as cyclic versions of basic anilide analgesics, antagonize pethidine in the rat tail-flick test [246]. Activity orders are about 200 times below that of nalorphine for some 4-allyl... 

Marcaccini S, Miliciani M, Pepino R (2005) A facile synthesis of 1, 4-benzodiazepine derivatives via Ugi four-component condensation. Tetrahedron Lett 46 711-713... 

Flumazenil is one of several 1,4-benzodiazepine derivatives with a high affinity for the benzodiazepine binding site on the GABAa receptor that act as competitive antagonists. It blocks many of the actions of benzodiazepines, zolpidem, zaleplon,... 

The Negishi coupling was also effective in the functionalization of 1,4-benzodiazepine derivatives. The imidoyl chloride subunit of the 5-chloro-... 

Although the Sonogashira-coupling of heterocycles is usually limited to their bromo and iodo derivatives, in certain cases the cross-coupling might also be achieved on activated chloro compounds. The chloro derivative shown in 8.23. was coupled with trimethylsilylacetylene.32 In another example the imidoyl chloride subunit of the 5-chloro-1,4-benzodiazepine derivative shown in 8.27. coupled efficiently with phenylacetylene to give the expected disubstituted acetylene derivative.15... 

Bunin, B. A., Ellman, J. A. (1992) A general and expedient method for the solid phase synthesis of 1,4-benzodiazepine derivatives./ Am ChemSoc 114, 10997-10998. 

Plunkett, M. J. Ellman, J. A. Solid-Phase Synthesis of Structurally Diverse 1,4-Benzodiazepine Derivatives Using the Stille Coupling Reaction, J. Am. Chem. Soc. 1995,117, 3306-3307. 

SCHEME 52. Solid-phase synthetic strategy for 1,4-benzodiazepine derivatives using a germanium linker strategy i) polymer support linkage, ii) solid-phase synthesis, iii) product release... 

Plunkett MJ, Ellman JA, Solid-phase synthesis of structurally diverse 1,4-benzodiazepine derivatives using the Stille coupling reaction, J. Am. Chem. Soc., 117 3306-3307, 1995. 

The oxidation of A-alkoxyamides (e.g., 364) with [bis(trifluoroacetoxy)iodo]benzene provides an efficient route to 1,4-benzodiazepine derivatives 365 under mild conditions (Scheme 200) <2005JOC2256>. This cyclization has been used to prepare synthetic precursors to the antitumor antibiotic ( + )-DC-81 <2003T7103, 2005JOC2256>. 

The oxidation of 2,3-dihydro and l,3,4,5-tetrahydro-5-phenyl-2//-1,4-benzodiazepine derivatives has been investigated. Oxidation of compounds of the type 192 (R4 = R5 = H) with chromium trioxide in glacial acetic acid gave compounds of the type 199.214,215 Similar results were obtained with selenium dioxide or silver oxide.215 Oxidation of the 1-methyl analog of 192 gave the 2,3(lf/)dione.215 Oxidation of 2,3-dihydro-5-phenyl-lff-l,4-benzodiazepine also gave... 

The interest in compounds with potential medicinal activity has stimulated the appearance of a number of additional reports on 1,4-benzodiazepines.219a The antibiotic anthramycin has been recently shown to be a 1,4-benzodiazepine derivative (206a).219b... 

A solid-phase synthesis of biaryls has been described by Forman and Sucholeiki [133] they used both phenyltrialkyltins with polymer-supported aryl iodides or the reverse technique involving polymer-supported aryltributyltins and aryl iodides or triflates. The fonmer approach was preferred, even though overall yields were poor. Related chemistry has been reported by Plunkett and Ellmann [134], who prepared 1,4-benzodiazepine derivatives via an initial solid-phase reaction between an aryltin moiety and acid chlorides (Scheme 4-38). 

Some of the solubility differences obviously arise from differences in the pH of the salt solutions, which in the case of compound XIX ranged from 2.4 to 5.8 pH units. This is not atypical. The pH of solutions of salts of a 3-oxyl-1,4-benzodiazepine derivative at 5 mg cm ranged from 2.3 for its dihydrochloride, to 4.3 for the maleate, and to 4.8 for the methane sulfonate. 

Tarri-Kellou, S., Cartier, A., Maouche, B. and Maigret, B. (2001) Electronic descriptors of the 1,4-benzodiazepine derivatives related to the antagonist activity on cholecystokinin receptors. /. Mol. Struct. (Theochemj, 571, 207—223. 

A large amount of activity on 1,4-benzodiazepine derivatives was reported in 2004. Tetrahydro-l,4-benzazepin-2-one derivatives are of interest as P-turn peptidomimetics and their solid-phase synthesis was reported by Kim et al. <04JC0207>. The diasteroselective synthesis of two enantiopure tetrahydro-l,4-benzodiazepin-5-ones was also achieved based on intramolecular azide cycloaddition and subsequent stereoselective reduction of the 1,4-benzodiazepinone products <04TA687>. A different approach to tetrahydro-1,4-benzodiazepin-5-ones 80 involves the 1,2-thiazine 1-oxides 77 as key intermediates. These intermediates were then converted to the nitroaryl amides 78 (R , R, R = H or Me) which could be cyclised to 80 after hydrogenation of the nitro group via the intermediates 79 <04T3349>. 

Other novel isoquinolino-fused 1,4-benzodiazepine derivatives have been reported in connection with studies on their DNA recognition potential. The approach to these derivatives was based on the l,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 109, and functional group interconversions to set up the groups for the eventual cyclisation of 110 to the fused 7-membered system 111 <04BMCL4371>. 

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