Dihydropyridine library

Scheme 12.27 Generation of a dihydropyridine library using automated sequential microwave processing.

The Hantzsch reaction that allows the synthesis of pyridine derivatives, is a condensation involving two equivalents of a yS-ketoester or a yS-ketoamide, one equivalent of an aldehyde and ammonia. The Hantzsch reaction was used by Patel et al. for the synthesis of a 300 member dihydropyridine library (Scheme 3.27) [287]. 

Figure 4.11 Structure of a nifedipine-inspired SP 1,4-dihydropyridine library LIO.

The Hantzsch synthesis of dihydropyridines represents a classical example of MCR, generating an array of diversely substituted heterocycles in a one-pot reaction procedure. Given that the reaction requires elevated temperatures and extended reaction times to proceed, acceleration of the process by microwave irradiation could be envisioned. Indeed, dielectric heating of aldehyde (aliphatic or aromatic) and 5 equivalents of /i-keloesler in aqueous 25% NH4OH (used both as reagent and solvent) at 140-150 °C for merely 10-15 min furnished 4-aryl-l,4-dihydropyridines in 51-92% yield after purification on a silica gel column [100]. The Hantzsch synthesis under reflux conditions ( 100 °C) featured a remarkably longer time (12 hours) and lower yields (15- 72%). To demonstrate the suitability of the procedure for the needs of combinatorial chemistry, a 24-membered library of 1,4-dihydropyridines (DHP) was prepared (Scheme 36). 

A focused SP library LIO of pools of 1,4-dihydropyridines (DHP) was reported by Gordeev et al. (45) and tested as a source of calcium channel blockers. The library consisted of 10 x 3 x 10 = 300 members prepared as 30 pools of 10 compounds (Fig. 4.11) whose deconvolution produced several new compounds of interest. The mono-... 

Recently Gordeev et al. reported (140, 141) the synthesis and iterative deconvolution of a 300-member focused library of 1,4-dihydropyridines L5 as potential calcium channel blockers inspired by the strucmre of nifedipine and other known bioactive compounds. The library was built on SP as 30 pools of 10 individuals, following the synthetic scheme shown in Fig. 7.18. Rink amine resin was deprotected, split into 10 portions (steps a and b), and treated with P-ketoesters (step c. Mi, 10 representatives A-J, Fig. 7.19) to give 10 discrete N-supported P-enaminoesters 7.30. The resin aliquots were then mixed (step d) and split again into 30 identical, 10-member pools (step e). Each resin portion was treated with a different combination of 1,3-dicarbonyls (M2, three representatives K-M, Fig. 7.19) and aldehydes (M3, 10 representatives N-W, Fig. 7.19) to give 30 pools of 10 open-chain precursors 7.31 (step f), which were cyclatively cleaved to give the final hbrary L3 (step g. Fig. 7.18). Library QC was performed by off-bead MS, identifying all the expected molecular ions in several pools. 

Figure 7.18 SP synthesis of the focused dihydropyridine pool library L5.

TABLE 8.3 Yields and Purity of the Dihydropyridine Discrete Library L8... 

Polysubstituted dihydropyridines were also considered as targets. Condensation of LI with enamino ester 9.16 and enamino nitrile 9.17 under standard Hantsch conditions only proved successful for the latter, furnishing the pyridine library L6 (1280 members). Oxidation of the initially formed dihydropyridines is presumably favored due to the highly conjugated system formed (Fig. 9.12). Hantsch condensation with cyclic enamino esters 9.18 and 9.19a-f was also successful, providing respectively the bicyclic libraries L7 (1280 members) and L8 (7680 members. Fig. 9.12). 

The Hantzsch dihydropyridine synthesis has been performed in a single-mode microwave cavity [199]. In comparison with both conventional methods and microwave-assisted reactions performed in a domestic oven, reaction times were shorter and yields were higher (Scheme 10.102). The improved yields under micro-wave conditions enabled the synthesis of a small library. 

Generally, Method A is better and more convenient, since it affords 53 in fair yields and in >80% average purity. In terms of purity. Method B is more suited within a library of 12 dihydropyridines 53, 11 were analytically pure (Scheme 30). 

It has also been found that there are privileged structures like benzimidazoles, spiropiperidines, or dihydropyridines, which show activity toward several target classes [76]. Analyses like this can be used to design compound libraries with a higher probability for success. However, it is questionable if there are many such structural features with selectivity for a certain target class [77], which is why this concept is certainly usefiil for building general compoimd collections, but maybe not selective ones. 

Another problem sometimes occurs where diversity-based company A has granted exclusive rights to license compounds in its libraries to several other companies, and two or more of these partners identify and claim the same compound. This can happen where partners have defined their fields of exclusivity by different mechanisms (e.g., partner B claims IL-IOR antagonists , while partner C claims dihydropyridine derivatives , or immune modulators ), or where the selected targets respond to the same compound (e.g., where new, poorly characterized receptors turn out to be related or identical). When this happens, one has partners converging on the same compound (or similar compounds). 

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