Sterling Drug Inc.

William B Dickinson

George Y Lesher

Baldev Singh

Marcia P Vaupotic

3-(NB)-4-Q-6-PY-pyridazines (I) or salts thereof, which are useful as cardiotonics, are prepared by reacting a 3-halo-4-Q-6-PY-pyridazine with an amine, H-NB, to produce I, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents and Q is cyano when NB is NHCH.sub.3 or N(CH.sub.3).sub.2, or Q is carbamyl when NB is NHCH.sub.3, or Q is hydrogen when NB is N(CH.sub.3).sub.2. Cardiotonic use of said 3-(NB)-4-Q-6-PY-pyridazines or salts is shown.

3-[methyl or dimethyl)amino]-6-(pyridinyl)pyridazines and their

4,5-Dihydro-4-R-6-(4-pyridinyl)-3(2H)-pyridazinone (IA) or pharmaceutically-acceptable acid-addition salt thereof, where R is hydrogen or methyl, is shown as the active component in cardiotonic composition and method for increasing cardiac contractility in a patient requiring such treatment. Also shown is the preparation of IA by reacting a lower-alkyl 2-R-4-(BN)-4-cyano-4-(4-pyridinyl)butanoate with hydrazine, where R is hydrogen or methyl, and BN is 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl.

Cardiotonic use of 4,5-dihydro-6-(4-pyridinyl)-3(2H)-pyridazinones

3-Hydrazino-6-PY-pyridazine or pharmaceutically-acceptable acid-addition salt thereof is useful as a cardiotonic agent, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents. 6-PY-3-pyridazinol is prepared by reacting 6-PY-3-pyridazinol with a chlorinating agent to produce 3-chloro-6-PY-pyridazine and reacting said 3-chloro compound with hydrazine to produce said 3-hydrazino compound. 3-Hydrazino-6-PY-pyridazine or pharmaceutically-acceptable acid-addition salt thereof is disclosed as the active component in cardiotonic compositions for increasing cardiac contractility and in the method for increasing cardiac contractility in a patient requiring such treatment. The novel intermediate 3-chloro-6-PY-pyridazine is prepared as noted above.

3-Chloro-6-(pyridinyl)-pyridazines

4-Amino-2-R-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as cardiotonics, where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents are prepared by: (a) reaction of 2-R-6-PY-3(2H)-pyridazinone (II) with hydrazine; (b) conversion from 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxamide (III); or, (c) conversion form 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (IV). Also shown are: the use of I or salts as cardiotonic agents; and, the preparation of intermediates.

Preparation of 4-amino-6-(pyridinyl)-3(2H)-pyridazinones from

2-R-4-R'-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as intermediates and some as cardiotonics, are prepared by reacting di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH.sub.2.nH.sub.x An (III) to produce lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia where R' is lower-carbalkoxy) and reacting Ia with hydrazine hydrate or anhydrous hydrazine to produce 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib where R' is aminocarbamyl), where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, R' is carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy, n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganic acid or an organic sulfonic acid. Also shown are: the preparation of II from PY-COCH.sub.3 (IV), the conversion of Ia to Ib (Id where R' is carboxy), and the use of 2-R-4-R'-6-PY-3(2H)-pyridazinones (I where R is lower-alkyl or lower-hydroxyalkyl and R' is carbamyl, aminocarbamyl or lower-carbalkoxy) as cardiotonic agents. Other intermediates are shown.

Di-(lower-alkyl)hydroxy-[2-oxo-2-(pyridinyl)ethyl]-propanedioates

2-R-4,5-dihydro-4-R'-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as cardiotonics, where R is lower-alkyl or 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, are prepared by reacting 4-oxo-4-PY-2-R'-butanenitrile with an N-R-hydrazine salt of a strong inorganic acid or organic sulfonic acid or by reacting a lower-alkyl 4-oxo-4-PY-2-R'-butanoate or lower-alkyl 4-(BN)-4-cyano-4-PY-2-R'-butanoate with N-R-hydrazine where BN is 4-morpholinyl, 1-piperidinyl or 1-pyrrolidinyl. Also shown are: (a) cardiotonic compositions and a method for increasing cardiac contractility using said compounds or salts where R is lower-alkyl (b) the use of I as intermediates in preparing the corresponding 2-R-4-R'-6-PY-3(2H)-pyridazinones; and, (c) the preparation of said lower-alkyl 4-(BN)-4-cyano-4-PY-2-R'-butanoates.

4,5-Dihydro-2-methyl-6-(4-pyridinyl)-3(2H)-pyridazinone and its use as a

4-Amino-6-(pyridinyl)-3(2H)-pyridazinones and their use as cardiotonics

3-Hydrazino-6-PY-pyridazine or pharmaceutically-acceptable acid-addition salt thereof is useful as a cardiotonic agent, where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substitutents. 6-PY-3-pyridazinol is prepared by reacting 6-PY-3-pyridazinol with a chlorinating agent to produce 3-chloro-6-PY-pyridazine and reacting said 3-chloro compound with hydrazine to produce said 3-hydrazino compound. 3-Hydrazino-6-PY-pyridazine or pharmaceutically-acceptable acid-addition salt thereof is disclosed as the active component in cardiotonic compositions for increasing cardiac contractility and in the method for increasing cardiac contractility in a patient requiring such treatment. The novel intermediate 3-chloro-6-PY-pyridazine is prepared as noted above.

3-Hydrazino-6-(pyridinyl) pyridazines and cardiotonic use thereof

2-R-4-R'-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as intermediates and some as cardiotonics, are prepared by reacting di-(lower-alkyl) hydroxy[2-oxo-2-PY-ethyl]propanedioate (II) with a hydrazine salt of the formula RNHNH.sub.2.nH.sub.x An (III) to produce lower-alkyl 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylate (Ia where R' is lower-carbalkoxy) and reacting Ia with hydrazine hydrate or anhydrous hydrazine to produce 2,3-dihydro-2-R-3-oxo-6-PY-4-pyridazinecarboxylic acid hydrazide (Ib where R' is aminocarbamyl), where PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, R' is carbamyl, carboxy, aminocarbamyl or lower-carbalkoxy, n is 1 or 2, x is 1, 2 or 3, and An is an anion of a strong inorganic acid or an organic sulfonic acid. Also shown are: the preparation of II from PY--COCH.sub.3 (IV), the conversion of Ia to Ib (Id where R' is carboxy), and the use of 2-R-4-R'-6-PY-3(2H)-pyridazinones (I where R is lower-alkyl or lower-hydroxyalkyl and R' is carbamyl, aminocarbamyl or lower-carbalkoxy) as cardiotonic agents. Other intermediates are shown.

4-Substituted-6-(pyridinyl)-3(2h)-pyridazinones and their use as

2-R-6-PY-3(2H)-pyridazinones (I) or salts thereof, which are useful as cardiotonics, where R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, are prepared by reacting 2-R-4,5-dihydro-6-PY-3(2H)-pyridazinone with a dehydrogenating agent. Also shown are: cardiotonic compositions and a method for increasing cardiac contractility using I or salts; and, the preparation of the corresponding intermediate 4,5-dihydro compounds.

6-(Pyridinyl)-3(2H)-pyridazinones and their use as cardiotonics

4,5-Dihydro-6-(4-pyridinyl)-3-pyridazinol or pharmaceutically-acceptable acid-addition salt thereof is useful as a blood pressure lowering agent. 4,5-Dihydro-6-(4-pyridinyl)-3-pyridazinol is prepared by reacting .gamma.-oxo-.gamma.-(4-pyridinyl)butyronitrile with a hydrazine salt of a strong inorganic or organic sulfonic acid. Said 4,5-dihydro-6-(4-pyridinyl)-3-pyridazinol or pharmaceutically-acceptable salt thereof is shown as the active ingredient in pharmaceutical compositions for lowering blood pressure and in the method for lowering blood pressure in a patient having elevated blood pressure.

4,5-Dihydro-6-(4-pyridinyl)-3-pyridazinol and salts, their preparation

N-(4-Amino-2-butynyl)imides are prepared from N-propargylimides, paraformaldehyde and the appropriate secondary amine. The compounds are useful as stimulants or depressants of the central nervous system.

N-(4-Amino-2-butynyl)imides

Lower-alkyl (5-R.sub.5 -2-pyridyl)carbamodithioates, prepared by reaction of a 5-R.sub.5 -2-aminopyridine with carbon disulfide in the presence of a tri-lower-alkylamine and reaction of the resulting tri-lower-alkyl ammonium (5-R.sub.5 -2-pyridyl)carbamodithioate with a lower-alkyl halide, where R.sub.5 is chloro, lower-alkyl or di-lower-alkylamino, are useful as anthelmintic agents.

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Albany, NY, United States of America

William B Dickinson