49738-24-1

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LDH1A1, one of 19 NAD(P)+-dependent aldehyde dehydrogenases, participates in multiple metabolic pathways and has been indicated to play an important role in obesity and diabetes. In this study, a series of 1,3-dimethylpyrimidine-2,4-diones were designed, synthesized and evaluated as novel selective aldehyde dehydrogenase 1A1 inhibitors. Among them, compounds 46, 50, 53, 56 and 57 exhibited excellent inhibitory activity against ALDH1A1 with IC50 values in the low nanomolar range and high selectivity over ALDH1A2, ALDH1A3, ALDH2 and ALDH3A1. Furthermore, in vitro study demonstrated that compound 57 effectively improved glucose consumption in HepG2 cells compared to compound 1 (CM026).

Background: Many synthetic and natural uracil derivatives have biological activity. Furthermore, many of these derivatives have pro- and antioxidant properties, but the mechanism of these processes is far from being understood. Methods: Oxygen-uptake kinetics and computational methods (CBS-QB3, M062X/MG3S and SMDM05/MG3S) were combined to study the reaction of peroxyl radicals with five organic-soluble derivatives: 5-amino- and 5-hydroxy-1,3-dimethyluracil, 5-amino- and 5-hydroxy-1,3,6-trimethyluracil, and 5-hydroxy-1,3-dimethyl-6-phenyluracil in chlorobenzene. Results: The studied uracil derivatives should be classified as inhibitors of medium reactivity kin= (1-10) × 10-4M-1s-1. The methyl group in the 6-position of the pyrimidine ring increases the rate constant of the reaction with peroxyl radicals by 3-4 times and the stoichiometric coefficient of inhibition. The calculation of the reaction barrier heights at the SMD-M05/MG3S level of theory for the hydrogen abstraction is in good agreement with experimental data. Conclusion: 1,3-Dimethyl-5-aminouracil is transformed by the addition of a methyl group at the 6-position into a favic-like pyrimidine, while the 5-hydroxy derivative becomes a more effective antioxidant. The bound dissociation energy (O-H or N-H) and the IP for the reactivity forecasting of uracil derivatives were used, but it was found that this methodology did not lead to good correlation between experimental and theoretical results. The SMD-M05/MG3S method provided the most accurate calculations of the reaction barrier heights for hydrogen abstraction from uracil derivatives by peroxyl radical.

The invention relates to compounds of formula (I): (I) as described herein, pharmaceutical preparations comprising such compounds, uses and methods of use for such compounds in the treatment of a disorder or a disease mediated by the activity of MDM2 and/or MDM4, and combinations comprising such compounds.

A C-H bond of electron-rich heterocycles is transformed into a C-N bond in a reaction sequence comprising the formation of heteroaryl(phenyl)iodonium azides and their in situ regioselective fragmentation to heteroaryl azides. A Cu(I) catalyst ensures complete regiocontrol in the fragmentation step and catalyzes the subsequent 1,3-dipolar cycloaddition of the formed azido heterocycles with acetylenes. The heteroaryl azides can also be conveniently reduced to heteroarylamines by aqueous ammonium sulfide. The overall C-H to C-N transformation is a mild and operationally simple one-pot sequential multistep process.

Nfr-A1, a Bacillus subtilis nitroreductase, catalyzes the nitroreduction of a large panel of aromatic and heterocyclic nitro compounds, except those belonging to nitrouracil class of molecules. Besides nitroreduction, Nfr-A1 exhibits a strong NADH oxidase activity in the presence of oxygen, leading to high concentration of H2O2 (up to 200 μM). In the presence of (N,N)-dimethyl-5-nitrouracil 1 (dim-NU), Nfr-A1 achieves the reduction of dim-NU double bond to compounds 2 and 3 and in parallel the oxidation of dim-NU to the denitrated five membered derivatives 4 and 5. The reduction is catalyzed by the reduced flavin Fl-Red and resembles those catalyzed by dihydropyrimidine dehydrogenases (DPD), during the catabolism of pyrimidines. The oxidative denitration is catalyzed in part by hydrogen peroxide generated through the NADH-oxidase activity, and certainly by the peroxyflavin intermediate Fl-OOH for the other part. The mechanisms of reaction were proposed according to experimental data and literature. These findings together with our previous results on the potential biological role of Nfr-A1, confirm the large spectrum of catalysis supported by this enzyme. The oxidative denitration is sporadically reported in literature and represents a safe and green alternative for the remediation of nitro-compounds.

The invention described herein relates to novel fused pyrimidinediones derivatives of formula (I) which are TRPA (Transient Receptor Potential subfamily A) modulators. In particular, compounds described herein are useful for treating or preventing diseases, conditions and/or disorders modulated by TRPAl (Transient Receptor Potential subfamily A, member 1). This invention also provides processes for preparing compounds described herein, intermediates used in their synthesis, pharmaceutical compositions thereof, and methods for treating or preventing diseases, conditions and/or disorders modulated by TRPAl. Formula (I)

An inexpensive and novel method of caffeine synthesis starting from uracil in six simple steps is described. Uracil 1 is first converted to I, 3-dimethyluracil 2, followed by nitration, reduction, and cyclization to theophylline and finally methylation of theophylline forms caffeine.

Diethylamine (DEA) and triethylamine (TEA) can function as sources for the two-carbon component in the reverse azadiene synthesis.Reaction of 5,7-dimethylpyrimido-1,2,4-triazene-6,8-dione, 6,8-dimethylpyrimido--1,2,4-triazine-5,7-dione, or 1

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