Library benzodiazepines

Immunoaffinity Extraction (lAE) This method combines immunoaffinity extraction with two HPLC columns online with either mass spectrometry or tandem mass spectrometry. These systems have been used to characterize benzodiazepine libraries [103]. To isolate them from the library, benzodiazepines were trapped in an lAE column that was packed with antibodies specific to these molecules. 

To speed the process of drug discovery, combinatorial chemistry> has been developed to prepare what are called combinatorial libraries, in which anywhere from a few dozen to several hundred thousand substances are prepared simultaneously. Among the early successes of combinatorial chemistry is the development of a benzodiazepine library, a class of aromatic compounds much used as antianxiety agents. 

A benzodiazepine template was also reported by researchers at GlaxoSmithKline [85]. The lead molecule GW405212, (40), was identified from a 1,296-member library of 1,4-benzodiazepines prepared on Tentagel beads and screened initially in pools of 30 against CHO cells expressing the human oxytocin receptor. It is a highly potent inhibitor of oxytocin binding with a K of 8nM [86]. However, all attempts to improve the pharmacokinetic properties of this molecule were unsuccessful. It appears that the functionality responsible for the oxytocin activity is distributed around the periphery... 

The same approach was readily adaptable to solid-phase synthesis. A small library of unnatural derivatives of 140 was prepared with variation of the configuration and nature of R1 and R4 and with substitution on the benzene ring <2000JC0186>. Three natural alkaloids, Verrucine A, B, and Anacine, were synthesized by a similar pathway and the pyrazino[2,l- ]quinazoline as opposed to the benzodiazepine structure of Anacine was proved <2001JNP1497>. Fiscalin B and other derivatives were prepared by solid-phase synthesis using polyethylene glycol (PEG) resin <2002USP6376667>. 

Only the particle-beam interface produces El spectra for direct comparisons with computerized library spectra of fragmentation patterns. The other systems enable the relative molecular mass (RMM) of analytes up to 105 and above to be established. An example of an HPLC-APCI separation and identification of some benzodiazepine tranquillizers is shown in Figure 4.39. The most appropriate choice of LC-MS interface for a particular... 

Cyclative cleavage strategies release the final compound into solution following intramolecular attack of a nucleophile or electrophile upon the linkage site. Synthesis byproducts and intermediates do not incorporate the necessary nucleophile or electrophile therefore only the desired products are released into solution to yield high purity materials. Seminal examples of this approach are the library syntheses of benzodiazepines and hydantoins (Scheme 3). 

Kratzsch C, Tenberken O, Peters FT, Weber AA, Kraemer T, et al. 2004. Screening, library-assisted identification and validated quantification of 23 benzodiazepines, flumazenil, zalepone, zolpidem and zopiclone in plasma by liquid chromatography/mass spectrometry with atmospheric pressure chemical ionization. J Mass Spectrom 39 856. 

One of the first cross-coupling reactions performed on solid supports was the Stille reaction [250] which is a paUadium-catalyzed reaction of a trialkylaryl or trialkylalkenyl stannane with an aromatic iodide, bromide or triflate. In contrast to the process in liquid-phase, the organotin reagent is easily removed from the solid-phase because of the subsequent washing processes. Immobilized aryl halides have been frequently coupled with aryl and alkenylstannanes, whereas stan-nanes attached to the solid support have been used less frequently for the StiUe reaction. An example is the synthesis of a benzodiazepine library by EUman et al. Recently, a Stille cross-couphng reaction has been employed in the synthesis of al-kenyldiarylmethanes (ADAM) series of non-nucleoside HlV-1 Reverse Transcriptase Inhibitors (Scheme 3.14) [251]. 

Hulme C, Peng J, Tang S-Y, Bums CJ, Morize I, Labaudiniere R (1998) Improved procedure for the solution phase preparation of 1, 4-benzodiazepine-2, 5-dione libraries via Armstrong s convertible isonitrile and the Ugi reaction. J Org Chem 63 8021-8023... 

Tempest P, Pettus L, Gore V, Huhne C (2003) MCC/SNAr methodology. Part 2 Novel three-step solution phase access to libraries of benzodiazepines. Tetrahedron Lett 44 1947-1950... 

Intramolecular cyclization is the final step in the preparation of the scaffold for a 66-member C2-aryl pyrrolo[2,l-c][l,4]benzodiazepine library (2007JCC437). 

C. G. Burow, K. M. Thompson, L. A. Ellman, J. A. Solid-Phase Synthesis of 1,4-Benzodiazepine-2,5-diones. Library Preparation and Demonstration of Synthesis Generality, Boojamra, J. Org. Chem. 1997,62, 1240. 

The famous Ugi reaction, the one-pot condensation of a carboxylic acid, an amine, an aldehyde or ketone and an isocyanide to yield an a-acylaminoamide, have recently been used as an efficient method for the synthesis of diverse libraries of small organic molecules such as benzodiazepines, pyrroles, lactams and diketopiperazines2. Even though some solution-phase Ugi reactions proceed rapidly, such reactions on solid phase have been found to take between one and several days. In 1999, Hoel and Nielsen17 performed the first microwave assisted, solid phase Ugi four-component condensation (see Scheme 5.5). 

Scheme 35 Synthesis of benzodiazepine-fused P-lactam library...

Benzodiazepines were the first class of heterocyclic compounds to be synthesized on the SynPhase surface. In 1994, Ellman and co-workers24 reported a 192 member library of structurally diverse 1,4-benzodiazepines. These compounds were prepared on Mimotopes pins that were grafted with polyacrylic acid, the surface originally used for antibody epitope elucidation.10 Ellman and co-workers25 subsequently synthesized a 1680-member 1,4-benzodiazepine library on SynPhase Crowns that were grafted with a methacrylic acid/dimethylacrylamide copolymer, one of the first SynPhase surfaces designed for solid-phase synthesis. The synthesis was performed on a preformed linker-template system in order to avoid low aminobenzophenone incorporation in this case the HMP acid-labile linker... 

The directed sorting approach has been widely applied both in industry and in academia. Two examples are detailed in this chapter. Some other recently published examples include a benzopyran library synthesized using the Nanokan system,15 libraries derived from phenolic amino acid scaffolds prepared with the Accutag system,16 and libraries of l,5-benzodiazepine-2-one derivatives.17... 

Scheme 1. Synthetic route for the preparation of 1,4-benzodiazepine libraries.

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