Tetrahydroquinoline scaffold

Derivatization of functional groups in a natural-product scaffold can also be effectively performed on the solid-phase. An example of this is the synthesis of a small compound collection (27-compounds) based on the tetrahydroquinoline scaffold. A chiral tetrahydroquinoline scaffold was synthesized in solution from 5-hydroxy-2-nitrobenzaldehyde (Scheme 4). The synthesis involved a key asymmetric aminohydroxylation step. This building block was anchored to the solid support with a Wang linker and diversity was introduced by selective deprotection and derivatization of the protected hydroxyl and amino substituents. 

Scheme 4. Synthesis of a compound library based on the tetrahydroquinoline scaffold.

The tetrahydroquinoline scaffold was investigated by Lilly [169]. Good ERa affinity and 4-fold ERa selectivity was observed for compound 132. However, poor MCF-7-inhibitory activity was noted. Introduction of a methylene hinge in the BSC (134) did not affect ERa affinity, but slightly increased ERa selectivity. A further increase to 27-fold ERa selectivity was observed when using a carbonyl hinge (133), but in this case ERa affinity was 6-fold lower. No improvement in MCF-7 inhibitory activity was observed, indicative for problematic cellular uptake or stability. For this reason, the tetrahydroquinoline series do not look promising. 

Couve-Bonnaire, S. et al., A solid-phase, library synthesis of natural product-hke derivatives from an enantiomerically pure tetrahydroquinoline scaffold, J. Comb. Chem., 6, 73, 2004. 

Numerous y-secretase inhibitors featuring sulfonamide- and sulfone-based scaffolds have been disclosed. Bicyclononane thiophene sulfonamide 40 reduced brain Ap in transgenic mice by 50% after a dose of 100 mg/kg [100]. High potency (A p IC50 = 0.5 nM) and improved oral activity (ID50 = 17 mg/kg) was found in a series of related sulfamides represented by 41 [101]. Tetrahydroquinoline (42) and piperidine (43-44) sulfonamides have been developed [102-104]. Elaboration of the piperidine series with the cyclopropyl substituent present in 44 improved in vitro potency (Aft IC50 = 2.1 nM in membrane assay) and in vivo activity in transgenic mice (plasma Ap = 2% of control after oral dose of 30 mg/kg). Reductions of A p in the cortex were reported to be comparable to those observed in plasma. 

A series of diamine amides based on the phenoxypropyl amine scaffold was reported. Amide 26 displayed an hH3 Ki of 1 nM and was selective versus other histamine receptors [73]. The chirality was removed via cyclic diamines to produce tetrahydroisoquinolines, tetrahydroquinolines, benzazepines and indolines [74]. The benzazepine 27 displayed picomolar hH3 binding affinity. Pharmacokinetic issues were also identified with this diamine series, with i.v. half-lives of 10-12 h in the rat. A strategy to remove the diamine skeleton and prepare new H3... 

Baylis-Hillman adducts such as 55 and 56 derived from 2-nitrobenzaldehydes were shown to function as useful precursors to functionalized (1H)-quinol-2-ones and quinolines. Treatment of 55 and 56 with iron and acetic acid at 110 °C afforded 57 and 58, respectively <02T3693>. A variety of other cyclization reactions utilized in the preparation of the quinoline scaffold were also reported. An iridium-catalyzed oxidative cyclization of 3-(2-aminophenyl)propanols afforded 1,2,3,4-tetrahydroquinolines <02OL2691>. The intramolecular cyclization of aryl radicals to prepare pyrrolo[3,2-c]quinolines was studied <02T1453>. Additionally, photocyclization reactions of /rans-o-aminocinnamoyl derivatives were reported to provide 2-quinolones and quinolines <02JHC61>. Enolizable quinone and mono- and diimide intermediates were shown to provide quinolines via a thermal 6jt-electrocyclization <02OL4265>. Quinoline derivatives were also prepared from nitrogen-tethered 2-methoxyphenols. The corresponding 2-methoxyphenols were subjected to a iodine(III)-mediated acetoxylation which was followed by an intramolecular Michael addition to afford the quinoline OAc O... 

Fig. 17.14 (a) The binding of tetrahydroaminoquinoline scaffold-based small molecules (65 and 66) with Bcl-XL using fully N-labeled NMR experiments, (b) The interactions tetrahydroquinoline derivative, 66 with Bcl-XL (NMR and in silico)... 

The parallel synthesis of several tens of compounds with two complementary SP routes employing a multicomponent reaction and producing diverse tetrahydroquinolines as decorated, biologically relevant scaffolds (101-103) was realized using simple laboratory equipment and commercially available reagents as monomers. The assessment work to produce compounds 6.14 and 6.25 with the optimized reaction conditions was deemed to be sufficientiy robust to pass immediately to library production. This... 

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