pyrimidinones and tetrahydropyrimidinone

Endothelial lipase (EL) inhibitors have been shown to elevate HDL-C levels in pre-clinical murine models and have potential benefit in prevention and treatment of cardiovascular diseases. Modification of the 1-ethyl-3-hydroxy-1,5-dihydro-2H-pyrrol-2-one (DHP) lead, 1, led to the discovery of a series of potent tetrahydropyrimidinedione (THP) EL inhibitors. Synthesis and SAR studies including modification of the amide group, together with changes on the pyrimidinone core led to a series of arylcycloalkyl, indanyl, and tetralinyl substituted 5-amino or 5-hydroxypyrimidinedione-4-carboxamides. Several compounds were advanced to PK evaluation. Among them, compound 4a was one of the most potent with measurable EL

Topics: Animals; Cholesterol, HDL; Enzyme Inhibitors; Humans; Lipase; Mice; Models, Molecular; Pyrimidinones; Structure-Activity Relationship

Polysubstituted 3-arylaminoacrylate and tetrahydropyrimidin-2-one derivatives could be selectively produced from the one-pot domino reaction of arylamines, methyl propiolate, aromatic aldehydes, and urea in ethanol in the presence of FeCl3 as catalyst. Under similar reactions secondary amines such as morpholine and piperidine predominately afford tetrahydropyrimidin-2-one derivatives in good yields.

Topics: Aldehydes; Alkynes; Amines; Catalysis; Chemistry Techniques, Synthetic; Chlorides; Ferric Compounds; Propionates; Pyrimidinones; Urea

The synthesis of novel organocatalysts consisting of a pyrrolidine moiety and a thiohydantoin or a thioxotetrahydropyrimidinone ring is described. The compound combining the pyrrolidine with the thioxotetrahydropyrimidinone was found to be a highly effective catalyst for the Michael reaction. Low catalyst loadings (1-2.5%) can be employed leading to quantitative yields and excellent stereoselectivities in the reaction between cyclic ketones and nitroolefins.

Topics: Catalysis; Molecular Structure; Pyrimidinones; Pyrrolidines; Stereoisomerism; Sulfhydryl Compounds; Thiohydantoins

Electrochemical oxidation of a series of 20 substituted 2-oxo-1,2,3,4-tetrahydropyrimidin-5-carboxamides (THPMs) in acetonitrile has been studied using voltammetric methods at a glassy carbon electrode to investigate the influence of the substituents on the 4- and 5-positions of the heterocyclic ring. Analysis of the results shows that the electronic nature and steric hindrance of the substituents, especially their orientations toward the heterocyclic ring, determine their effects on the oxidation potential. Analysis of the computational results obtained at the DFT-B3LYP/6-31++G** level of theory suggests a mechanism in which the first electron removal occurs from either the N(1) of the heterocyclic ring or N(17) of the amide substitution. This process is followed by a fast proton removal resulting in the formation of stable allylic and/or benzylic radicals which then undergo further oxidation to the 2-oxo-1,2-dihydropyrimidin-5-carboxamides (DHPMs).

Topics: Acetonitriles; Amides; Biological Products; Carbon; Electrochemistry; Electrodes; Electrons; Isomerism; Models, Chemical; Oxidation-Reduction; Potentiometry; Protons; Pyrimidines; Pyrimidinones

Coagulation enzyme factor Xa (FXa) is a particularly promising target for the development of new anticoagulant agents. We previously reported the imidazo[1,5-c]imidazol-3-one derivative 1 as a potent and orally active FXa inhibitor. However, it was found that 1 predominantly undergoes hydrolysis upon incubation with human liver microsomes, and the human specific metabolic pathway made it difficult to predict the human pharmacokinetics. To address this issue, our synthetic efforts were focused on modification of the imidazo[1,5-c]imidazol-3-one moiety of the active metabolite 3a, derived from 1, which resulted in the discovery of the tetrahydropyrimidin-2(1H)-one derivative 5k as a highly potent and selective FXa inhibitor. Compound 5k showed no detectable amide bond cleavage in human liver microsomes, exhibited a good pharmacokinetic profile in monkeys, and had a potent antithrombotic efficacy in a rabbit model without prolongation of bleeding time. Compound 5k is currently under clinical development with the code name TAK-442.

Topics: Administration, Oral; Animals; Anticoagulants; Biological Availability; Bleeding Time; Drug Discovery; Factor Xa Inhibitors; Haplorhini; Humans; Microsomes, Liver; Pharmacokinetics; Pyrimidinones; Rabbits

Diastereoselective syntheses of 3-aryl-(S/R)-6-methyl-1-[(S/R)-1-phenylethyl)]-2-thioxotetrahydro pyrimidin-4(1H)-ones were achieved in good yields by the condensation of aryl isothiocyanates with ethyl 3-(1-phenylethylamino)butanoate in a one-pot reaction. Benzylation of these substrates illustrated that the orientations of the exocylic and endocylic groups determine the stereochemical outcome of the product formed.

Topics: Molecular Structure; Pyrimidinones; Stereoisomerism

An efficient protocol for the stereoselective synthesis of 1,3-syn and -anti-tetrahydropyrimidinones (syn- and anti-11a) is reported. The modular procedure is based on a stereodivergent cyclization of readily available urea-type substrates (10a) by intramolecular allylic substitution. The cyclization proceeds with excellent yield (up to 99%) and selectivity (up to dr > 20:1), purely based on substrate control. The product pyrimidines can be readily transformed into the corresponding free syn- and anti-amines.

Topics: Cyclization; Molecular Structure; Pyrimidinones; Stereoisomerism; Urea

A novel K-10 clay (nanoclay)-catalyzed expeditious synthesis of polyfunctionalized bicyclic pyrimidines using unprotected aldoses, 2-methyl-2-phenyl-1,3-oxathiolan-5-one and amidines/guanidine is reported. These polyfunctionalized bicyclic pyrimidines were obtained in excellent yields (72-93%) with high cis diastereoselectivity (>94%) at the ring junction via tandem condensation, mercaptoacetylative ring transformation and cyclization reactions. The process presents an excellent illustration of use of carbohydrates as renewable resources for the formation of pharmaceutically relevant fine chemicals employing solvent-free microwave irradiation conditions in a one-pot procedure.

Topics: Bridged Bicyclo Compounds; Catalysis; Cyclization; Pyrimidinones; Stereoisomerism

Seventeen compounds with either an imidazolin-2-one or a tetrahydropyrimidin-2(1H)-one scaffold were synthesized and evaluated for their immunosuppressive activity in a concanavallin A (ConA)-stimulated mouse splenocytes proliferation test. Three of these molecules exerted a significant activity at 90 microM. All the compounds of the tetrahydropyrimidin-2(1H)-one series have turned out to be inactive showing the crucial role of the imidazolidin-2-one scaffold in the induction of an immunosuppressive activity.

Topics: Animals; Cell Proliferation; Concanavalin A; Imidazolidines; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Pyrimidinones; Spleen; Structure-Activity Relationship

As part of an ongoing effort in understanding the role of hydrophobicity in the design of nonpeptidic HIV protease inhibitors, the QSAR study on P2/P2' tetrahydropyrimidinone is presented in this report. Our results suggest that the balance of hydrophobicity and a volume- dependent polarizability term plays a key role in the inhibition of the viral protease by these inhibitors. The size of the substituent of ligands at particular positions that induce steric fit is crucial. The role of hydrophobicity in the design of tetrahydropyrimidinone is discussed. It has been found that a sufficient spread in the data is required to observe the optimum value of ClogP for these inhibitors.

Topics: Drug Design; HIV Protease; HIV Protease Inhibitors; Hydrophobic and Hydrophilic Interactions; Ligands; Molecular Conformation; Pyrimidinones; Quantitative Structure-Activity Relationship