The Lateral Metalation of Isoxazolo[3,4-]pyridazinones towards Hit-to-Lead Development of Selective Positive Modulators of Metabotropic Glutamate Receptors.

Isoxazolo[3,4-] pyridazinones ([3,4-]s) were previously shown to have selective positive modulation at the metabotropic glutamate receptor (mGluR) Subtypes 2 and 4, with no functional cross-reactivity at mGluR, mGluR, or mGluR. Additional analogs were prepared to access more of the allosteric pocket and achieve higher binding affinity, as suggested by homology modeling. Two different sets of analogs were generated.

Synthesis and crystal structures of a bis-(3-hy-droxy-cyclo-hex-2-en-1-one) and two hexa-hydro-quinoline derivatives.

The title compound , 2,2'-[(2-nitro-phen-yl)methyl-ene]bis-(3-hy-droxy-5,5-di-methyl-cyclo-hex-2-enone), CHNO, features a 1,3-ketone-enol conformation which is stabilized by two intra-molecular hydrogen bonds. The most prominent inter-molecular inter-actions in compound are C-H⋯O hydrogen bonds, which link mol-ecules into a two-dimensional network parallel to the (001) plane and a chain perpendicular to (11). Both title compounds , ethyl 4-(4-hy-droxy-3,5-di-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-oxyl-ate, CHNO, and , ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, CHNO, share the same structural features, such as a shallow boat conformation of the di-hydro-pyridine group and an orthogonal aryl group attached to the di-hydro-pyridine.

Isoxazolo[3,4-d]pyridazinones positively modulate the metabotropic glutamate subtypes 2 and 4.

Isoxazolo[3,4-d] pyridazinones ([3,4-d]s) are selective positive modulators of the metabotropic glutamate receptors (mGluRs) subtypes 2 and 4, with no functional cross reactivity at mGluR, mGLuR or mGluR. Modest binding for two of the [3,4-d]s is observed at the allosteric fenobam mGluR site, but not sufficient to translate into a functional effect. The structure activity relationship (SAR) for mGluR and mGluR are distinct: the compounds which select for mGluR all contain fluorine on the N-6 aryl group.

Patenting the life sciences at the European Patent Office.

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3-(1,3-Di-phenyl-propan-2-yl)-4-methyl-6-phenyl-isoxazolo[3,4-d]pyridazin-7(6H)-one.

In the title compound, C27H23N3O2, the geminal benzyl groups branching out from the methine adjacent to the isoxazole group are both syn-oriented to the methyl group of the pyridazinone moiety, as reflected by C-C distances of 3.812 (2) and 4.369 (2) Å between the methyl carbon and the nearest ring carbon of each benzyl group.