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• 105-54-4 butanoic acid ethyl ester 

Relevant academic research and scientific papers

Bipyridine Cardiotonics: The Three-Dimensional Structures of Amrinone and Milrinone

The cardiotonic drug milrinone (1,6-dihydro-2-methyl-6-oxo--5-carbonitrile) is superior to its analogue amrinone (5-amino--6(1H)-one) by virtue of its greater potency and reduced side effect profile.We confirmed initial reports on the potencies of milrinone and amrinone and found that after intravenous administration to phenobarbital anesthetized dogs, the drug had cumulative inotropic ED50's of 37 and 1891 μg/kg, respectively; relative effects on heart rate and blood pressure were comparable.There are two structural differences between amrinone and milrinone: (1) milrinone has a pyridone 2-methyl substituent and (2) the pyridone 5-amino substituent of amrinone is replaced with a nitrile in milrinone.We confirmed structure-activity studies that indicated that the 2-methyl substituent appears to be primarily responsible for the dramatic difference in the potencies of amrinone and milrinone.A plausible explanation for the effect of the methyl substituent is an altered molecular topology resulting from its steric interaction with the 3',5'-hydrogen atoms.Consequently, we probed the three-dimensional structures of these two compounds by X-ray crystallography.The dihedral angle between the planes formed by the two aromatic rings of amrinone was 1.3 deg.In marked contrast, the corresponding angle for milrinone was 52.2 deg.Moreover, 1H NMR studies revealed conformational differences in solution.Whereas the 2-methyl substituent undoubtedly produces some electronic and hydrophobic perturbations in the bipyridine cardiotonic series, the most significant effect, from a global viewpoint, is the altered molecular topology.

3-Substituted-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones, their cardiotonic use and intermediates therefor

1-R1 -3-[amino, cyano, carbamyl, halo, lower-alkylamino, di-(lower-alkyl)amino or lower-acylamino]-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones or pharmaceutically-acceptable acid-addition or cationic salts thereof are useful as cardiotonic agents, where R1 is hydrogen, lower-alkyl or lower-hydroxyalkyl. 1-R1 -3-amino-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by hydrolyzing the corresponding 3-cyano compounds to produce the corresponding 3-carbamyl compounds and reacting the latter with a reagent capable of converting carbamyl to amino. The 1-R1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones are prepared by reacting (pyridinylmethyl) lower-alkyl ketones with dimethylformamide di-(lower-alkyl) acetal to produce 1-(pyridinyl)-2-(dimethylamino)ethenyl lower-alkyl ketone and reacting said ketones with N-R1 -α-cyanoacetamide to produce the 1-R1 -3-cyano-6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones. Also shown are the conversions: of the 3-cyano compounds to the 3-H compounds; of the 3-H compounds to the 3-halo compounds; of the 3-halo compounds to the 3-[mono-(lower-alkyl)- or di-(lower-alkyl)-amino]compounds; and, of the 3-amino compounds to the 3-lower-acylamino or 3-[mono-(lower-alkyl)- or di-(lower-alkyl)amino] compounds.

5-(Pyridinyl)pyridine-2-hydrazines, their preparation and their cardiotonic use

2-[R1 NHN(R)]-3-Q'-5-Py-6-Q-pyridines or pharmaceutically-acceptable acid-addition salts thereof are useful as cardiotonic agents, where Q is hydrogen or lower-alkyl, PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, Q' is hydrogen or halo, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and R1 is hydrogen or when R is other than hydrogen R1 is the same as R. These compounds are prepared by reacting a 2-halo-3-Q'-5-PY-6-Q-pyridine with R1 NHNHR where 2-halo is bromo or chloro. Also shown are: the use of said 2-[R1 NN(R)]-3-Q'-5-PY-6-Q-pyridines as cardiotonic agents; and, the intermediates, 2,3-dihalo-5-PY-6-Q-pyridines, and their preparation from 3-nitro-5-PY-6-Q-2(1H)-pyridinones.

N-Hydroxy-1,2-dihydro-2-oxo-5-(pyridinyl)-nicotinimidamide and their cardiotonic use

N-Hydroxy-1-R1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamides or pharmaceutically-acceptable acid-addition salts thereof, useful as cardiotonic agents, are prepared by reacting 1-R1 -1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitriles with hydroxylamine and are converted by reaction with polyphosphoric acid to the corresponding cardiotonically useful 1-R1 -3-amino-5-PY-6-R-2(1H)-pyridinones, where R1 is hydrogen, lower-alkyl and lower-hydroxyalkyl, R is hydrogen or lower-alkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents.