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PubMed1982

New anticancer agents: synthesis of 1,2-dihydropyrido[3,4-b]pyrazines (1-deaza-7,8-dihydropteridines).

Reaction of alpha-aminoacetophenone oximes (2) with ethyl 6-amino-4-chloro-5-nitropyridine-2-carbamate (1) gave ethyl 6-amino-5-nitro-4-[(2-oxo-2-phenylethyl)amino]pyridine-2-carbamate oximes (3), which were hydrolyzed under acidic conditions to give the corresponding ketones (4). Related pyridines substituted with a keto side chain were prepared from 1 and 1,3-diaminopropanone oximes and by oxidation of the side-chain hydroxy group of ethyl 6-amino-4- [[3-(N-methyl-N-phenylamino)-2-hydroxypropyl]amino]-5-nitropyridine-7- carbamates (6). Catalytic hydrogenation of the nitro group of 4 over Raney nickel in a large volume of ethanol gave the 1-deaza-7,8-dihydropteridines (7). Several of the oximes 3 were successfully hydrogenated to give 7 directly. The resulting 1-deaza-7,8-dihydropteridines showed potent cytotoxicity against cultured L1210 cells and significant anticancer activity against lymphocytic leukemia P-388 in mice. These biological activities are attributed to the accumulation of cells at mitosis.

Animals↗
PubMed2004

Imidazoquinoxaline Src-family kinase p56Lck inhibitors: SAR, QSAR, and the discovery of (S)-N-(2-chloro-6-methylphenyl)-2-(3-methyl-1-piperazinyl)imidazo- [1,5-a]pyrido[3,2-e]pyrazin-6-amine (BMS-279700) as a potent and orally active inhibitor with excellent in vivo antiinflammatory activity.

A series of novel anilino 5-azaimidazoquinoxaline analogues possessing potent in vitro activity against p56Lck and T cell proliferation have been discovered. Subsequent SAR studies led to the identification of compound 4 (BMS-279700) as an orally active lead candidate that blocks the production of proinflammatory cytokines (IL-2 and TNFalpha) in vivo. In addition, an expanded set of imidazoquinoxalines provided several descriptive QSAR models highlighting the influence of significant steric and electronic features. The H-bonding (Met319) contribution to observed binding affinities within a tightly congeneric series was found to be significant.

Animals↗
PubMed2000

Indeno[1,2-b]pyrazin-2,3-diones: a new class of antagonists at the glycine site of the NMDA receptor with potent in vivo activity.

Indeno¿1,2-bpyrazin-2,3-diones have been identified as a novel series of potent ligands on the glycine site of the NMDA receptor. To improve their in vivo activities, an acetic acid-type side chain was introduced to the 5-position, giving water-soluble compounds when formulated as the sodium salt (>10 mg/mL). Introduction of a chlorine atom in the 8-position led to a dramatic improvement of anticonvulsant activity and this was surprising since this change did not improve binding affinity. A plausible explanation is a reduced recognition by a Na(+),K(+)-ATPase active transport system responsible for the excretion of these compounds from the brain and kidney. This promising new chemical series led to the optically active isomer (-)-10i (RPR 118723), a glycine/NMDA antagonist with nanomolar binding affinity and in vivo activity in animal model of convulsions and electrophysiology at doses in the range of 2-3 mg/kg following iv administration.

Animals↗
PubMed2005

Intervalence charge transfer in a "chain-like" ruthenium trinuclear assembly based on the bridging ligand 4,7-phenanthrolino-5,6:5',6'-pyrazine (ppz).

The IVCT characteristics of the mixed valence forms of the trinuclear complex [{Delta-Ru(bpy)2}2{Delta(t)-Ru(bpy)(mu-ppz)2}]n+ (n = 7, 8; t = trans), and the diastereoisomers (meso and rac) of the dinuclear complex [{Ru(bpy)2}2(mu-ppz)]5+, display a marked dependence on the nuclearity and extent of oxidation of the assemblies. The dinuclear species are classified as borderline localised-delocalised mixed valence species while the two mixed valence states of the trinuclear complex exhibit localised behaviour. One-electron oxidation of a terminal Ru centre in the trinuclear case gives rise to a broad, low intensity IVCT band for the +7 mixed valence species which is composed of two underlying Gaussian-shaped bands. The transitions are identified as adjacent and remote IVCT transitions, with the former dominating the intensity of the IVCT manifold. The +8 mixed valence species exhibits a single dominant IVCT band arising from the equivalent IVCT transitions from the central Ru(II) to peripheral Ru(III) centres.

Chemistry↗