Synthesis of Polysubstituted Pyridines and Pyrazines via Truce-Smiles Rearrangement of Amino Acid-Based 4-Nitrobenzenesulfonamides.

Immobilized l-glutamic acid ß-methyl ester was sulfonylated with 4-nitrobenzenesulfonyl chloride and alkylated with various α-haloketones. The resulting sulfonamides were reacted with potassium trimethylsilanolate. Then, upon cleavage from the polymer support, tetrasubstituted pyridines were produced as the result of one-step C-arylation, aldol condensation, and oxidation. When cleavage from the resin occurred before the trimethylsilanolate treatment, C-arylation was followed by enamination, which yielded trisubstituted pyrazines. Through the developed protocols, targeted synthesis of novel heterocyclic derivatives was performed using mild reaction conditions and a number of readily available starting materials.

Efficient synthesis of pentasubstituted pyrroles via intramolecular C-arylation.

Immobilized L-aspartic acid beta-methyl ester (Fmoc-Asp(OMe)-OH) was reacted with 4-nitrobenzenesulfonyl chloride, followed by alkylation with various α-haloketones. The resulting intermediates were treated with potassium trimethylsilanolate, which yielded tetrasubstituted pyrroles after a one-step transformation consisting of sequential C-arylation, aldol condensation and spontaneous aromatization. The discovered synthetic strategy enables fast and simple access to pentasubstituted and functionalized pyrroles from a number of readily available starting materials.

New imidazopyridines with phosphodiesterase 4 and 7 inhibitory activity and their efficacy in animal models of inflammatory and autoimmune diseases.

Herein, we describe the rapid synthesis of a focused library of trisubstituted imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine using the combination of solution-phase/solid-phase chemistry as new potential anti-inflammatory agents in the treatment of autoimmune diseases. Structure-activity relationship studies, followed by the structure optimization, provided hit compounds (17 and 28) which inhibited phosphodiesterase 4 (PDE4) with IC50 values comparable to rolipram and displayed different inhibitory potency against phosphodiesterase 7 (PDE7). Among them, compound 17 showed a beneficial effect in all the studied animal models of inflammatory and autoimmune diseases (concanavalin A-induced hepatitis, lipopolysaccharide-induced endotoxemia, collagen-induced arthritis, and MOG35-55-induced encephalomyelitis). In addition, compound 17 showed a favorable pharmacokinetic profile after intraperitoneal administration; it was characterized by a fast absorption from the peritoneal cavity and a relatively long terminal half-life in rats. It was found to penetrate brain barrier in mice. The performed experiments sheds light on the impact of PDE7A inhibition for the efficacy of PDE4 inhibitors in these disease conditions.

Synthesis of chiral 1,4-oxazepane-5-carboxylic acids from polymer-supported homoserine.

The preparation of novel 1,4-oxazepane-5-carboxylic acids bearing two stereocenters is reported in this article. Fmoc-HSe(TBDMS)-OH immobilized on Wang resin was reacted with different nitrobenzenesulfonyl chlorides and alkylated with 2-bromoacetophenones to yield N-phenacyl nitrobenzenesulfonamides. Their cleavage from the polymer support using trifluoroacetic acid (TFA) led to the removal of the silyl protective group followed by spontaneous lactonization. In contrast, TFA/triethylsilane (Et3SiH)-mediated cleavage yielded 1,4-oxazepane derivatives as a mixture of inseparable diastereomers. The regioselectivity/stereoselectivity depended on the substitution of the starting 2-bromoacetophenones and was studied in detail. Catalytic hydrogenation of the nitro group improved the separability of the resulting diastereomeric anilines, which allowed us to isolate and fully characterize the major isomers.

Novel non-sulfonamide 5-HT6 receptor partial inverse agonist in a group of imidazo[4,5-b]pyridines with cognition enhancing properties.

A small library of novel 3H-imidazo[4,5-b]pyridine and 1H-imidazo[4,5-c]pyridine derivatives was designed and synthesized as non-sulfonamide 5-HT6 receptor ligands. In vitro evaluation allowed to identify compound 17 (2-ethyl-3-(3-fluorobenzyl)-7-(piperazin-1-yl)-3H-imidazo[4,5-b]pyridine) as potent 5-HT6 receptor partial inverse agonist in Gs signaling (Ki = 6 nM, IC50 = 17.6 nM). Compound 17 displayed high metabolic stability, favorable cytochrome P450 isoenzyme (2D6, 3A4) profile, did not affect PgP-protein binding, without evoking mutagenic effects. It was orally bioavailable and brain penetrant. In contrast to intepirdine (SB-742457), which prevented 5-HT6R-elicited neurite growth and behaved as an inverse agonist of cyclin-dependent kinase 5 (Cdk5), compound 17 has no influence on neuronal differentiation. Compound 17 exerted significant pro-cognitive properties in novel object recognition (NOR) task in rats reversing both phencyclidine- and scopolamine-induced memory deficits (MED = 1 and 0.3 mg/kg, p.o, respectively). These effects were similar to those produced by intepirdine. Additionally, combination of inactive doses of compound 17 (0.1 mg/kg) and donepezil (0.3 mg/kg) produced synergistic effect to reverse scopolamine-induced memory deficits. Accordingly, investigating putative divergence between inverse agonists and neutral antagonists as cognitive enhancers in neurodegenerative and psychiatric disorders is certainly of utmost interest.

Synthesis of Novel N9-Substituted Purine Derivatives from Polymer Supported α-Amino Acids.

Solid-phase synthesis of purine derivatives bearing an α-amino acid motif in position 9 is described herein. Polymer supported amines were acylated with various Fmoc-α-amino acids and, after cleavage of the protecting group, arylation with 4,6-dichloro-5-nitropyrimidine or 2,4-dichloro-5-nitropyrimidine was performed. The second chlorine atom was replaced with various amines. Subsequent reduction of the nitro group, followed by reaction with aldehydes, afforded the purine scaffold. After cleavage from the polymer support, the target compounds were obtained in very good crude purity, good overall yields, and excellent enantiomeric purity. The anticancer activity of prepared compounds was tested in vitro against human cancer cell lines MCF7 and K562, and they were found to have mild, but clear dose-dependent effects.

Directed solid-phase synthesis of trisubstituted imidazo[4,5-c]pyridines and imidazo[4,5-b]pyridines.

An efficient method is described for the solid-supported synthesis of imidazo[4,5-b]pyridines and imidazo[4,5-c]pyridines from 2,4-dichloro-3-nitropyridine. The key pyridine building block was reacted with polymer-supported amines, followed by replacement of the second chlorine with amines, nitro group reduction, and imidazole ring closure with aldehydes. Depending on the combination of polymer-supported and solution-phase reagents, the strategy allowed for the simple preparation of the target trisubstituted derivatives with variable positioning of the pyridine nitrogen atom. Additionally, after a slight modification of the method, the preparation of strictly isomeric imidazopyridines was possible.

Regioselective incorporation of backbone constraints compatible with traditional solid-phase peptide synthesis.

A protected aldehyde was attached via a two-carbon spacer to a peptide backbone amide nitrogen during a traditional Merrifield solid-phase synthesis. Acid-mediated unmasking of the aldehyde triggered the regioselective formation of cyclic N-acyliminiums between the aldehyde and the neighboring peptide amide nitrogen. In the absence of an internal nucleophile, the cyclic iminiums formed dihydropyrazinones, a six-membered peptide backbone constraint between two peptide amides. In the presence of an internal nucleophile, tetrahydropyrazinopyrimidinediones or tetrahydroimidazopyrazinediones were formed via tandem N-acyliminium ion cyclization-nucleophilic addition. The outcome of this nucleophilic addition was dependent on the substituent on the nitrogen nucleophile.

Solid-phase synthesis of 4,7,8-trisubstituted 1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones.

Solid-phase synthesis of 1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-ones with use of polystyrene resin is described. The starting material was polymer supported 1,2-diaminoethane and as a key synthon, 4-chloro-2-fluoro-5-nitrobenzoic acid was used. The synthetic approach allows the preparation of derivatives with variable substitution at positions 4 and 8. Additionally, a skeletal diversity was increased when the nitro group was reduced and some benzene fused heterocycles were prepared. An expansion of a diazepinone to a benzodiazocinone scaffold was also successful although some limitations in a diversity of target derivatives were observed.