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Synthesis of Spiro[cycloalkane-pyridazinones] with High Fsp3 Character Part 2*

[ Vol. 18 , Issue. 5 ]

Author(s):

Csilla Sepsey Für, Eszter Judit Horváth, Áron Szigetvári, Miklós Dékány, László Hazai, György Keglevich and Hedvig Bölcskei*   Pages 373 - 381 ( 9 )

Abstract:


An extended compound library of spiro[cycloalkane-pyridazinones] with a high Fsp3 character is targeted. There are two possibilities to improve the physicochemical parameters of a drug candidate molecules or building blocks, either to replace the aromatic systems with bioisoster heteroaromatic moieties, e.g. with one or two nitrogen containing ring systems (pyridines, pyridazines, pyrimidines, etc.), or to increase the Fsp3 character of the compounds. Using a new synthetic approach, the Grignard reaction of 2-oxaspiro[4.5]decane-1,3-dione and 2-oxaspiro[4.4]nonane-1,3-dione with p-halophenyl- or p-alkylphenyl-magnesium bromide resulted in the formation of the corresponding 2-oxoethyl-cycloalkanecarboxylic acids, which served as starting materials for the pyridazinones by reaction with hydrazine or phenylhydrazine. The pyridazinones obtained were alkylated with methyliodide or benzylbromide. 16 Novel 4-tolyl- or 4-halophenyl-2,3-diazaspiro[5.5]undec-3-en-1-one and 4-tolyl- or 4-halopyhenyl-7,8-diazaspiro[4.5]dec-8-en-6-one, and their N-methyl, N-benzyl, and N-phenyl derivatives were synthetized. The physicochemical parameters and the Fsp3 character of the novel compounds obtained were studied. A few of them showed excellent logP and clogP values, but the introduction of a further phenyl group seemed to be disadvantageous.

Keywords:

Grignard-reactions, fsp3 character, pyridazinone, spiro, 2-oxoethyl-cycloalkanecarboxylic acids, hydrazine.

Affiliation:

Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, Gedeon Richter Plc. Budapest X., Gyömrői út 19-21, Budapest 10. Pf.27. H-1475, Gedeon Richter Plc. Budapest X., Gyömrői út 19-21, Budapest 10. Pf.27. H-1475, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest, Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, H-1521 Budapest

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