Sterling Drug Inc.

Other

Donald F Page

George Y Lesher

Chester J Opalka, Jr

Ruthann M McGarry

Monte D Gruett

Disclosed and claimed is the cardiotonic use of 1-R.sub.1 -5-(3-R'-4-R'-phenyl)-6-R-2(1H)-pyridinones (II), where R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl, R is lower-alkyl or hydrogen, and, R' and R' are each hydrogen, amino or hydroxy, at least one of R' or R' being other than hydrogen, or where R' is nitro when R' is hydroxy, or pharmaceutically acceptable acid-addition salts thereof where at least one of R' and R' is amino. Also disclosed and claimed are 1-R.sub.1 -5-(3-R'-4-R'-phenyl)-6-R-2(1H)-pyridinones (I), where R.sub.1, R' and R' are defined as above and R is lower-alkyl and acid-addition salts thereof where at least one of R' and R' is amino. Also shown and claimed is the process which comprises reacting 1-R.sub.1 -1,2-dihydro-2-oxo-5-(3-R'-4-R'-phenyl)-6-R-nicotinonitrile, where R.sub.1 and R are defined as above for II, R' is hydrogen, hydroxy, methoxy or amino and R' is hydroxy, methoxy or hydrogen, preferably at least one of R' and R' being methoxy, or where R' is nitro and R' is hydrogen or methoxy, preferably methoxy, with 85% phosphoric acid to produce 1-R.sub.1 -5-(3-R'-4-R'-phenyl)-6-R-2(1H)-pyridinone, where R.sub.1 and R are defined as above for II, R' is hydrogen, hydroxy or amino and R' is hydroxy or hydrogen, at least one of R' and R' being hydroxy, or where R' is nitro and R' is hydroxy.

Preparation of 5-(hydroxy- and/or

1-R.sub.1 -3-amino-5-(3-R'-4-R'-phenyl)-6-R-2(1H)-pyridinones or salts thereof, which are useful as cardiotonics, where R.sub.1 is hydrogen, lower-alkyl, or lower-hydroxyalkyl, R is hydrogen or lower-alkyl, and, R' and R' are each hydrogen, hydroxy or amino at least one of R' or R' being other than hydrogen, are prepared by reacting the corresponding 3-carbamyl compound with a reagent capable of converting carbamyl to amino or by first reacting the corresponding 3-carbamyl compound where R' and R' are each hydrogen, nitro or lower-alkoxy at least one of R' and R' being other than hydrogen with a reagent capable of converting carbamyl to amino and then reacting the resulting 3-amino compound where R' and/or R' are/is lower-alkoxy and/or nitro with a reagent capable of converting lower-alkoxy to hydroxy and/or with a reagent capable of converting nitro to amino. Preparation of the corresponding 3-carbamyl and 3-cyano compounds is shown, the latter including cardiotonically active novel 1-R.sub.1 -1,2-dihydro-5-(3-R.sub.2 -4-R.sub.3 -phenyl)-6-R-nicotinonitriles where R.sub.1 and R are defined as above, and R.sub.2 and R.sub.3 have the above given definitions for R' and R' or where R.sub.2 is nitro and R.sub.3 is hydroxy. Also shown are cardiotonic compositions and cardiotonic method of use of above-said compounds.

1,2-Dihydro-2-oxo-5-(hydroxy-and/or amino-phenyl)-nicotinonitriles and

3-Amino-5-(hydroxy- and/or

Disclosed and claimed is the cardiotonic use of 1-R.sub.1 -5-(3-R'-4-R'-phenyl)-6-R-2(1H)-pyridinones (II), where R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl, R is lower-alkyl or hydrogen, and, R' and R' are each hydrogen, amino or hydroxy, at least one of R' or R' being other than hydrogen, or where R' is nitro when R' is hydroxy, or pharmaceutically acceptable acid-addition salts thereof where at least one of R' and R' is amino. Also disclosed and claimed are 1-R.sub.1 -5-(3-R'-4-R'-phenyl)-6-R-2(1H)-pyridinones (I), where R.sub.1, R' and R' are defined as above and R is lower-alkyl and acid-addition salts thereof where at least one of R' and R' is amino. Also shown and claimed is the process which comprises reacting 1-R.sub.1 -1,2-dihydro-2-oxo-5-(3-R'-4-R'-phenyl)-6-R-nicotinonitrile, where R.sub.1 and R are defined as above for II, R' is hydrogen, hydroxy, methoxy or amino and R' is hydroxy, methoxy or hydrogen, preferably at least one of R' and R' being methoxy, or where R' is nitro and R' is hydrogen or methoxy, preferably methoxy, with 85% phosphoric acid to produce 1-R.sub.1 -5-(3-R'-4-R'-phenyl)-6-R-2(1H)-pyridinone.

5-(Hydroxy- and/or amino-phenyl)-6-(lower-alkyl)-2-(1H)-pyridinones,

5-PY-6-Q-pyridin-2-amines (I) or pharmaceutically acceptable acid-addition salts thereof are useful cardiotonics, where Q is hydrogen or lower-alkyl, and PY is 4-pyridinyl or 4-pyridinyl having one or two lower-alkyl substituents. Their preparation from the corresponding 5-PY-6-Q-2(1H-pyridinones via the corresponding 2-halo-5-PY-6-Q-pyridines is shown.

5(Pyridinyl)pyridin-2-amines

2-(NB)-3-R-6-PY-5-Q-3H-imidazo[4,5-b]pyridines (I) and salts, useful as cardiotonics, where NB is amino or dimethylamino, R is lower-alkyl, Q 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 a 2-RNH-3-amino-5-PY-6-Q-pyridine with a di-(lower-alkyl) 2-methylthiopseudourea-1,3-dicarboxylate to produce 2-carbo(lower-alkoxy)amino-3-R-6-PY-5-Q-3H-imidazo[4,5-b] pyridine and hydrolyzing the latter to produce I where NB is amino and by reacting a 2-RNH-3-amino-5-PY-6-Q-pyridine with dichloromethylene-N,N-dimethylammonium chloride to produce I where NB is dimethylamino. Cardiotonic use of I is disclosed and claimed.

2-Amino-6-(pyridinyl)-3H-imidazo[4,5-b]pyridines and their cardiotonic

Disclosed and claimed are a cardiac composition and a method for increasing cardiac contractility using an effective amount of a cardiotonic 4-[4-(or 3)-AcNH-phenyl]-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -pyridine (I) or pharmaceutically-acceptable salt thereof, where R.sub.2 is hydrogen, methyl, ethyl or hydroxyl, R.sub.6 is hydrogen, methyl or ethyl, R.sub.3 and R.sub.5 are each hydrogen or methyl, and Ac is hydrogen, hydroxyacetyl, acetoxyacetyl, .alpha.-hydroxypropionyl, .alpha.-acetoxypropionyl, methyoxyacetyl, 2-butenoyl or carbamyl or when NHAc is attached to the 4-position of the phenyl ring Ac also is formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-carboxypropanoyl or when NHAc is attached to the 3-position of the phenyl ring Ac also is acetyl. Novel compounds shown and claimed are 4-[4-(or 3)-Ac'NH-phenyl]-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -pyridines (II) or pharmaceutically-acceptable acid-addition salts thereof, where R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are defined as above for I and Ac' is hydroxyacetyl, acetoxyacetyl, .alpha.-hydroxypropanoyl, .alpha.-acetoxypropionyl, methoxyacetyl, 2-butenoyl or carbamyl or where Ac'NH is attached to the 4-position of the phenyl ring Ac' is formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-carboxypropanoyl. Also disclosed and claimed is the process for preparing said novel compounds (II).

Use of 4-[4(or 3)-aminophenyl]pyridines as cardiotonic agents

Disclosed and claimed are N-R-N-40 [4-(4-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -4-pyridinyl)phenyl]ureas (I) or pharmaceutically-acceptable acid-addition salts thereof, where R is hydrogen, methyl or ethyl, R.sub.2 is hydrogen, methyl, ethyl or hydroxyl, R.sub.6 hydrogen, methyl or ethyl, and R.sub.3 and R.sub.5 are each hydrogen or methyl, their cardiotonic use and their preparation.

N-[4-(4-Pyridinyl)phenyl]ureas and their cardiotonic use

Shown is a process for preparing cardiotonically active 1,3-dihydro-3-R-6-PY-5-Q-2H-imidazo[4,5-b]pyridin-2-ones, where Q is hydrogen or lower-alkyl, R is lower-alkyl, lower-hydroxyalkyl, lower-alkoxyalkyl or Y-NB where Y is lower-alkylene and NB is di-(lower-alkyl)amino or 4-morpholinyl, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two substituents, by reacting a 2-RNH-5-PY-6-Q-nicotinamide with an alkali metal hypohalite. Also shown are cardiotonic compositions and a method for increasing cardiac contractility using 2-RR'N-5-PY-6-Q-nicotinamides or pharmaceutically acceptable acid-addition salts thereof, where R' is hydrogen or methyl. Also shown is the process for preparing said 2-RR'N-5-PY-6-Q-nicotinamides by reacting a 2-halo-5-PY-6-Q-nicotinamide with an amine of the formula RR'NH.

2-Substituted amino-5-(pyridinyl)-nicotinamides and their cardiotonic use

Shown are cardiotonically active 2-RR'N-5-PY-6-Q-nicotinonitriles where R is methyl or ethyl, R' is hydrogen or methyl, PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two substituents, and Q is hydrogen or methyl, the latter only when R' is hydrogen, or pharmaceutically acceptable acid-addition salts thereof. Also shown are cardiotonic compositions and a method for increasing cardiac contractility using as active components 2-RR'N-5-PY-6-Q-nicotinonitriles or pharmaceutically acceptable acid-addition salts thereof, where R, R', PY and Q are defined as above. Also shown is the process for preparing said 2-RR'N-5-PY-6-Q-nicotinonitriles by reacting a 2-halo-5-PY-6-Q-nicotinonitrile with an amine of the formula RR'NH.

2-(Substituted-amino)-5-(pyridinyl-nicotinonitriles, and their

2-[R.sub.1 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 R.sub.1 is hydrogen or when R is other than hydrogen R.sub.1 is the same as R. These compounds are prepared by reacting a 2-halo-3-Q'-5-PY-6-Q-pyridine with R.sub.1 NHNHR where 2-halo is bromo or chloro. Also shown are: the use of said 2-[R.sub.1 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.

Pyridinyl-pyridines

2-[R.sub.1 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 R.sub.1 is hydrogen or when R is other than hydrogen R.sub.1 is the same as R. These compounds are prepared by reacting a 2-halo-3-Q'-5-PY-6-Q-pyridine with R.sub.1 NHNHR where 2-halo is bromo or chloro. Also shown are: the use of said 2-[R.sub.1 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.

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

1-R.sub.1 -4- or 5-[4-pyridinyl-(CH.sub.2).sub.n ]-1H-indole-2,3-dione 3-Q derivatives, useful as cardiotonics, bronchodilators, anti-asthmatics, anti-allergics and anti-cholinergics, are prepared by cyclization of N-{3- or 4-[4-pyridinyl-(CH.sub.2).sub.n ]phenyl}glyoxalamide oxime with acid; reaction of the product thus obtained with a carbonyl reactive reagent to prepare a compound where Q is other than O; and reaction of a compound where Q is either O or other than O with a lower-alkyl, hydroxy-lower-alkyl or di-lower-alkylamino-lower-alkyl ester of a strong mineral acid or with a carbo-lower-alkoxy-lower-alkyl halide to prepare compounds where R.sub.1 is other than hydrogen.

1H-Indole-2,3-dione derivatives

Disclosed and claimed are a cardiac composition and a method for increasing cardiac contractility using an effective amount of a cardiotonic 4-[4-(or 3)-AcNH-phenyl]-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -pyridine (I) or pharmaceutically-acceptable salt thereof, where R.sub.2 is hydrogen, methyl, ethyl or hydroxyl, R.sub.6 is hydrogen, methyl or ethyl, R.sub.3 and R.sub.5 are each hydrogen or methyl, and Ac is hydrogen, hydroxyacetyl, acetoxyacetyl, .alpha.-hydroxypropionyl, .alpha.-acetoxypropionyl, methyoxyacetyl, 2-butenoyl or carbamyl or when NHAc is attached to the 4-position of the phenyl ring Ac also is formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-carboxypropanoyl or when NHAc is attached to the 3-position of the phenyl ring Ac also is acetyl. Novel compounds shown and claimed are 4-[4-(or 3)-Ac'NH-phenyl]-2-R.sub.2 -3-R.sub.3 -5-R.sub.5 -6-R.sub.6 -pyridines (II) or pharmaceutically-acceptable acid-addition salts thereof, where R.sub.2, R.sub.3, R.sub.5 and R.sub.6 are defined as above for I and Ac' is hydroxyacetyl, acetoxyacetyl, .alpha.-hydroxypropanoyl, .alpha.-acetoxypropionyl, methoxyacetyl, 2-butenoyl or carbamyl or where Ac'NH is attached to the 4-position of the phenyl ring Ac' also is formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-carboxypropanoyl. Also disclosed and claimed is the process for preparing said novel compounds (II).

4-[4(or 3)-Acylaminophenyl]pyridines and their use as cardiotonics

1-R.sub.1 -6-(lower-alkyl)-5-(pyridinyl)-2(1H)-pyridinones or 1-R.sub.1 -1,2-dihydro-2-oxo-6-(lower-alkyl)-5-(pyridinyl)nicotinic acids or lower-alkyl esters thereof or pharmaceutically-acceptable acid-addition or cationic salts thereof are useful as cardiotonic agents, where R.sub.1 is hydrogen, lower-alkyl or lower-hydroxyalkyl. These compounds are prepared by hydrolyzing the corresponding 3-cyano compounds to produce the corresponding 3-carboxylic acids and then either by decarboxylating or esterifying the acids.

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East Greenbush, NY, United States of America

Donald F Page