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US 4,225,715 AGranted
Preparation of 3-amino(or carbamyl)-5-(pyridinyl)-2(1H)-pyridinones
AssigneeSterling Drug Inc.
InventorsGeorge Y. Lesher, Chester J. Opalka, Jr.
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AssigneeSterling Drug Inc.
InventorsGeorge Y. Lesher, Chester J. Opalka, Jr.
Estimating the term…
Compounds useful as cardiotonic agents are 1-R-3-Q-5-PY-2(1H)-pyridinones (I) where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, Q is amino (preferred), lower-alkylamino, di-(lower-alkyl)amino or NHAc, Ac is lower-alkanoyl or lower-carbalkoxy, and PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents. The corresponding compounds where Q is nitro, carbamyl, cyano, halo or hydrogen are useful as intermediates and those where Q is hydrogen or cyano also are useful as cardiotonic agents. Said compounds are prepared: by reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagent capable of converting carbamyl to amino to produce 3-amino-5-PY-2(1H)-pyridinone (Ib); by reacting II or .alpha.-PY-malonaldehyde (II') with .alpha.-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) and partially hydrolyzing III to produce Ia; and, by heating 1,2-dihydro-2-oxo-5-PY-nicotincic acid (IV) with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce 3-nitro-5-PY-2(1H)-pyridinone (Ic) and then either reducing Ic to produce Ib or first reacting Ic with an alkylating agent to produce 1-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing Id to produce 1-R'-3-amino-5-PY-2(1H)-pyridinone (Ib) where R' is lower-alkyl or lower-hydroxyalkyl. Other derivatives of I where Q is amino are shown.
The process for preparing a 3-Q-5-PY-2(1H)pyridinone having the formula ##STR4## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents, and Q is carbamyl or amino, which comprises reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide and reacting 1,2-dihydro-2-oxo-5-PY-nicotinamide with an alkali metal hypohalite to produce 3-amino-5-PY-2(1H)-pyridinone, where R.sub.1 and R.sub.2 are each lower-alkyl.
The process which comprises reacting .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide having the formula ##STR5## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents, and R.sub.1 and R.sub.2 are each lower-alkyl.
The process which comprises reacting 1,2-dihydro-2-oxo-5-PY-nicotinamide having the formula ##STR6## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents, with an alkali metal hypohalite to produce the corresponding 3-amino-5-PY-2-2(1H)-pyridinone.
The process which comprises reacting either .alpha.-PY-.beta.-(R.sub.1 R.sub.2 N)acrolein or .alpha.-PY-malonaldehyde with .alpha.-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinonitrile and partially hydrolyzing 1,2-dihydro-2-oxo-5-PY-nicotinonitrile to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide having the formula ##STR7## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents, and R.sub.1 and R.sub.2 are each lower-alkyl.
The process which comprises the steps of heating 1-R-1,2-dihydro-2-oxo-5-PY-nicotinonitrile or 1-R-1,2-dihydro-2-oxo-5-PY-nicotinic acid with an aqueous mineral acid to produce 1-R-5-PY-2(1H)-pyridinone, reacting said 1-R-5-PY-2(1H)-pyridinone with halogen to produce the corresponding 1-R-3-halo-5-PY-2(1H)-pyridinone having the formula ##STR8## where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alkyl substituents, R is hydrogen or lower-alkyl and Q is halo, and reacting said 3-halo compound with a lower-alkylamine or a di-(lower-alkyl)amine to produce the corresponding respective 3-(lower-alkylamino)-5-PY-2(1H)-pyridinone or 3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone.
Dependencies are inferred from the claim text.