ABSTRACT
We report an efficient synthesis of 4H-benzo[b][1,4]thiazine 1,1-dioxides via unprecedented ring contraction of 2,5-dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides under mild conditions involving carbon-sulfur bond formation. 2,5-Dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides are easily accessible from commercially available building blocks, including Fmoc-protected amino acids, 2-nitrobenzenesulfonyl chlorides, and bromo ketones. Benzothiazine 1,1-dioxides represent pharmacologically relevant derivatives with biological, medicinal, and industrial applications.
Subject(s)
Benzodiazepinones/chemistry , Epoxy Compounds/chemistry , Nitrobenzenes/chemistry , Thiadiazines/chemistry , Thiazines/chemistryABSTRACT
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 (Kiâ¯=â¯6â¯nM, IC50â¯=â¯17.6â¯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 (MEDâ¯=â¯1 and 0.3â¯mg/kg, p.o, respectively). These effects were similar to those produced by intepirdine. Additionally, combination of inactive doses of compound 17 (0.1â¯mg/kg) and donepezil (0.3â¯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.
Subject(s)
Cognition/drug effects , Imidazoles/pharmacology , Pyridines/pharmacology , Receptors, Serotonin/metabolism , Animals , Dose-Response Relationship, Drug , HEK293 Cells , Humans , Imidazoles/chemical synthesis , Imidazoles/chemistry , Male , Molecular Structure , Pyridines/chemical synthesis , Pyridines/chemistry , Rats , Rats, Sprague-Dawley , Rats, Wistar , Structure-Activity RelationshipABSTRACT
Herein we report the polymer-supported synthesis of 3,4-dihydro-2H-1,4-oxazine-3-carboxylic acid derivatives using immobilized Fmoc-Ser(tBu)-OH and Fmoc-Thr(tBu)-OH as the starting materials. After the solid-phase-synthesis of N-alkyl-N-sulfonyl/acyl intermediates, the target dihydrooxazines were obtained using trifluoroacetic acid-mediated cleavage from the resin. This approach was also studied for the preparation of dihydrothiazines from immobilized Fmoc-Cys(Trt)-OH. Inclusion of triethylsilane in the cleavage cocktail resulted in the stereoselective formation of the corresponding morpholine/thiomorpholine-3-carboxylic acids. Stereochemical studies revealed the specific configuration of the newly formed stereocenter and also the formation of stable N-acylmorpholine rotamers.
Subject(s)
Carboxylic Acids/chemical synthesis , Morpholines/chemical synthesis , Polymers/chemistry , Solid-Phase Synthesis Techniques/methods , Carboxylic Acids/chemistry , Fluorenes/chemistry , Morpholines/chemistry , Oxazines/chemical synthesis , Oxazines/chemistry , Stereoisomerism , Thiazines/chemical synthesis , Thiazines/chemistryABSTRACT
Polymer-supported benzenesulfonamides prepared from various immobilized primary amines and 2/4-nitrobenzenesulfonyl chloride have been used as key intermediates in different chemical transformations, including unusual rearrangements to yield a number of diverse privileged scaffolds. This review summarizes individual strategies in their application to date.
Subject(s)
Nitrobenzenes/chemical synthesis , Solid-Phase Synthesis Techniques/methods , Sulfonamides/chemical synthesis , Amines/chemistry , Combinatorial Chemistry Techniques , Nitrobenzenes/chemistry , Polymers/chemistry , Sulfonamides/chemistryABSTRACT
A traceless polymer-supported synthesis of 4-benzoylquinazolines was developed using the following commercially available building blocks: Fmoc-α-amino acids, 2-nitrobenzensulfonyl chlorides and α-bromoacetophenones. The acyclic intermediates underwent base-catalyzed rearrangement involving C-C and N-N bond formation followed by ring expansion and yielded resin-bound dihydroquinazoline-2-carboxylic acids. After they were released from the resin by treatment with trifluoroacetic acid, base-mediated decarboxylation produced the target quinazolines in moderate-to-high yields and purities.
Subject(s)
Quinazolines/chemical synthesis , Acetophenones/chemistry , Amino Acids/chemistry , Fluorenes/chemistry , Molecular Structure , Nitrobenzenes/chemistry , Quinazolines/chemistryABSTRACT
The solid-phase synthesis of trisubstituted 2,5-dihydrobenzo[f][1,2,5]thiadiazepine 1,1-dioxides is reported. Acyclic polymer-supported intermediates were prepared using commercially available building blocks: Fmoc-protected amino acids, 2-nitrobenzenesulfonyl chlorides, and bromoketones. The acyclic precursors underwent acid-mediated release from the resin and the cyclization was completed in solution.
Subject(s)
Benzene Derivatives/chemical synthesis , Solid-Phase Synthesis Techniques/methods , Thiazepines/chemical synthesis , Amino Acids/chemistry , Benzene Derivatives/chemistry , Chlorides/chemistry , Cyclization , Fluorenes/chemistry , Halogenation , Ketones/chemistry , Nitrobenzenes/chemistry , Oxides/chemical synthesis , Oxides/chemistry , Thiazepines/chemistryABSTRACT
Simple solid-phase synthesis of 3,10-dihydro-2H-benzo[e]imidazo[1,2-b][1,2,4]thiadiazin-2-one 5,5-dioxides is described, with Fmoc-α-amino acids and 2-nitrobenzenesulfonyl chlorides (2-NosCls) being the key building blocks. Fmoc-α-amino acids were immobilized on Wang resin and transformed to the corresponding 2-nitrobenzenesulfonamides in two steps. After reduction of the nitro group, Fmoc-thioureas were synthesized followed by cyclization of the 1,2,4-benzothiadiazine-1,1-dioxide scaffold with diisopropylcarbodiimide (DIC). Cleavage of the Fmoc protecting group followed by spontaneous cyclative cleavage gave the target products in excellent crude purity.
Subject(s)
Fibrinolytic Agents/chemical synthesis , Quinazolines/chemical synthesis , Amino Acids/chemistry , Combinatorial Chemistry Techniques , Cyclization , Fibrinolytic Agents/chemistry , Fluorenes/chemistry , Quinazolines/chemistry , Solid-Phase Synthesis Techniques , Sulfinic Acids/chemical synthesis , Sulfinic Acids/chemistryABSTRACT
Solid-phase synthesis of 3,4-dihydro-benzo[e][1,4]diazepin-5-ones with three diversity positions is described. Various primary amines were used as the starting material and immobilized on the polystyrene resin equipped with different acid-labile linkers. Polymer-supported amines were converted to α-aminoketones with the use of their sulfonylation with the 4-nitrobenzensulfonylchoride (4-Nos-Cl) and subsequent alkylation with α-bromoketones. After the cleavage of the 4-Nos group, the corresponding α-aminoketones were acylated with various o-nitrobenzoic acids. Reduction of the nitro group followed by spontaneous on-resin ring closure gave the target immobilized benzodiazepines. After acid-mediated cleavage the products were obtained in very good crude purity and satisfactory yields, which makes the developed method applicable for simple library synthesis of the corresponding derivatives in a combinatorial fashion.