CA1103254A - Pyridinyl-2(1h)-pyridinones and preparation - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds useful as cardiotonic agents are 1-R-3-Q-5-PY-2(1H)-pyridinones of Formula I (herein) 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 sub-stituents. 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.-(R1R2N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting Ia with a reagent cap-able 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-nicotinic acid (IV) with a mix-ture 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.

Description

This invention relates to 3-amino-5-(pyridinyl)-

2[1H)-pyridinones, useful as cardiotonic agents, to their preparation and to intermediate~; used therein.
British Patent 1,322,318 discloses as inter-mediates 1,2-dihydro-2-oxo-6-(4 or 3-pyridinyl1-nicotino-nitrile, 6-(~- or 3-pyridinyl)-2(1H)-pyridinone and 6-(4-or 3-pyridinyl)-2-pyridinamine. United States Patent 3,838, 156, discloses as intermediates 1,2-dihydro-2-oxo-6-Q'''-nicotinic acids where Q "' is 4(or 3)-pyridinyl or 4(or 3)- "' pyridinyl having one or two lower-alkyl substituents~
Japanese Patent 20,295/67, published October 11,1967, shows l-(x'-amino-2'-pyridinyl)-2-pyridinones as having "analgesio and anti-phlogistic activity". Specifically shown is 1-~5'-amino-2'-pyridinyl)-2-pyridinone.
The invention resides in the compounds having formula I

PY ~.
\ ~ ...I

where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or ~wo lower-alkyl substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl, and Q is nitro, cyano, hydrogeln, carbamyl, halo, amino, lower-alkylamino, di-~lower-alkyl)amino, NHAc where Ac is lower-alkanoyl or 2- ~ .

~ ~ 3 2~ ~

lower-carbalkoxy, or -NHCH-C(COOR~)2 where R4 is lower alkyl, or pharmaceutically-acceptable acid-addition salt thereof. The compound of formula I where Q is amino, lower alkylamino, di-~lower-alkyl]amino~ or ~IAc are useful as cardiotonic agents, as determined by standard pharmacological evaluation procedures. The compounds of formula I where Q is nitro or carbamyl are useful as intermediates for preparing the said compounds where Q is amino and those where O is halo are useful as intermediates in the preparation of the compounds where Q is lo~er-alkylamino and di-(lower-alkyl}amino. Pre-ferred embodiments are those of formula I where Q is amino, R is hydrogen and PY is ~-pyridinyl or 3-pyridinyl. A
particularly preferred embodiment is 3-amino-5-(4-pyridinyl)-2(lH)-pyridinone. A preferred embodiment when Q is the last possibility above is diethyl N-~1,2 -dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]amino-methylenemalonate.
The compounds having formula I where Q is hydrogen or cyano are not only useful as intermediates for preparing the compounds of formula I where Q is amino, but also are useful as cardiotonic agents and, also, where Q is hydrogen, are useful as bronchodilators, as determined by standard pharmacological procedures.
One can produce a 3-amino-5-PY-2(lH)-pyridinone (Ib) by reacting a-PY-~-(RlR2N)acrolein (II) with malonamide to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) and reacting 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia~ with a re-agent capable of converting carbamyl to amino to produce

3-amino-5-PY-:2(1H)-pyridinone (Ib), where PY is defined as in I above, and Rl and R2 are each lower-alkyl, preferably methyl or ethyl.

~,`~i' Another process comprises reacting either ~~PY-~-(RlR2N)acrolain (II) or a-PY-malonaldehyde (II') with a-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotino-nitrile (III=I, Q is CN, R is H) and partially hydrolyzing 1,2-dihydro-~-oxo-S-PY-nicotinonitrile (III) to produce 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia), where PY is defined as in I above, and Rl and R2 ar~e each lower-alkyl, preferably methyl or ethyl.
One can produce a 3-amino-1-R-5-PY-2(1H)-pyridinone (I~) by first heating 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) with a mixture of concentrated sulfuric acid and con-centrated nitric acid to produce 3-nitro-5-PY-2(lH)-pyridinone (Ic~ and ~hen either reducing 3-nitro-S-PY-2(lH)-pyridinone (Ic) to produce 3-amino-5-PY-2(lH)-pyridinone (Ib), where R
is hydrogen in said compounds, or first reacting 3-nitro-5-PY-2(lH)-pyridinone (Ic) with an alkylating agent of the formula R'-An to produce l-R'-3-nitro-5-PY-2(1H)-pyridinone (Id) and reducing l-R'-3-nitro-S-PY-2(lH)-pyridinone ~Id) to produce l-R'-3-amino-5-PY-2(1H)-pyridinone (Ib~, where R and PY have the same meanings given hereinabove for formula I, and R' is lower-alkyl or lower-hydroxyalkyl and An is an anion of a strong inorganic acid or an organic sulfonic acid.
Alternatively the alkylation step can be carried out on any of the compounds of Formulas I, III and IV where R is hydrogen to prepare the corresponding aompound where R is R', such as prior to any of the conversion steps described.
The above processes are illustrated by the following flow sheet whi.ch al90 shows the conversion of 1,2-dihydro-2-oxo-5-PY-nicol:inonitrile (III) to 1,2-dihydro-2-oxo-5-PY-nicotinic acicl ~IV) by hydrolysis with a~ueous sulfuric acid:

, . ,... .. :: ~ ., .

2~

~ CHO ,~f CHO
\CHO ~ CHNRlR2 II ~ / II
2C 2 2 2 CH2 (CONH2~ 2 PY I CN ~ PY ~ ~CONH2 \~ Conc 112504 ~/
R'-An H ~ / R
III III Ia aq.~H2S04 R=R' PY t COOH ~ \ ~ NH2 IV ~ Ib /~ ~

Conc~ H S04 /
Conc~ H~03 / H 2 PY ~ Ic, R=P

7 R'-An R R' Ic Id S Alternatively, using the process described below 1,2-dihydro-2-oxo-S-PY-nicotinonitrile ~III) is converted to 3-nitro-5-ElY-2~lH)-pyridinone tIc) via 5-PY-2(lH3-pyridinone (Ie) by first refluxing III with aqueous sulfuric acid to produoe 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV3 _5_ .. ~ .

~ ~ 3 ~ ~ ~

then refluxing IV in solution (without i.solation~ to produce Ie which is then heated with a mixture of concentrated sul-furic acid and concentrated nitric acid to produce Ic.
A further process comprises heating 1,2-dihydro- !
2-oxo-5-PY-nicotinonitrile ~III) or 1,2-dihydro~2-oxo-5-PY-nicotinic acid ~IV) with an aqueous mineral acid, pre-ferably aqueous sulfuric acid, t:o produce 5-PY-2~1H~-pyridinone (Ie) upon hydrolysis of III and decarboxylation of IV, reacting Ie with halogen, preferably bromine or chlorine, to produce the corresponding 3-halo-S-PY-2~1H]-pyridinone ~If) and reacting If with a lower-alkylamine ~RlNH2) or a di-~lower-alkyl)amine (RlR2NH) to produce the corresponding 3-~lower-alkylamino)-5-PY-2(lH)-pyridinone lIg where Rl is lower-alkyl and R2 is hydrogen) or 3-[di-(lower-alkyl)amino]-5-PY-2(lH)-pyridinone (Ig whPre each of Rl and R2 is lower-alkyl~.
An alternati~e process for preparing Ig comprises reacting 3-amino-5-PY-2~lH)-pyridinone with one or two molar equivalents of a lower-alkylating agent. A preferred 2Q ~mbodiment of this alternative process comprises reacting 3-amino-5-PY-2~1H)-pyridinone with a methylating mixture of formic acid and formaldehyde to produce 3-dimethylamino-5-PY-2(lH)-pyridinone where PY is defined as above for I.
The above processes are illustrated by the follow-ing additional flow sheet which also shows the conversionof 1 R-3-amino-5-PY-2~lH~-pyridinone (Ib~ to di-~lower-alkyl) N-[1,2-dihydro-1-R-2-oxo-5-PY-3-pyridinyl3-amino-methylenemalonate (V):

py coo~ py ll I Aq H~S04 ~¦

¦ ~0 ¦ ~O
R R

IV Ie lX2 py ~N~Rl py~,/X

N ~ 1 2 I O
R R
Ig If NH2 PY ~ ~ NHCH=C(COOR4)2 R30CH=C(COOR4) o R R
Ib V ~I,Q- -NHCH=
C(COOR4) In the ormulas of above ~low sheet PY has the meaning given hereinabove for formula I, Rl is lower-alkyl, R2 is hydrogen or lower-alkyl, and R3 and R4 are each lower-alkyl.
In another aspect the invention resides in the process of producing l-R-3-Q'-S-PY-2(lH)-pyridinone 1~ which comprisc~ reacting 1-R-3-amino-5-PY-2(1H)-pyridinOne ~Ib) with a lower-alkanoylating agent or lower-carbalkoxy-lating agent, where PY and R have the meanings given here-i4 inabove for the compounds of Formula I and Q' is NHAc whareAc is lower-alkanoyl or lower-carbalkoxy, respectively.
In accordance with the present invention there is pro-vided a process for preparing a 2(:lH)-pyridinone having the Formula I where PY is 4- or 3- or 2-pyridinyl or 4- or 3- or 2-pyridinyl having one or two lower-alk~l substituents, R is hydrogen, lower-alkyl or lower-hydroxyalkyl and Q is nitro, carbamyl or halo, or a pharmaceutically-acceptable acid-addition salt thereof, which comprises:
a. reacting a compound Formula II wherein Rl and R2 are each lower-alkyl with malonamide to prepare a compound of Formula I where R is hydrogen and Q is carbamyl or b. reacting either a compound of Formula II' or II with ~-cyanoacetamide where Rl and R2 are each lower-alkyl to prepare a compound where R is hydrogen and Q is cyano, and (1) partially hydrolyzing a compound of Formula I
obtained where Q is cyano to obtain the corresponding compound where Q is carbamyl, ~2) hydrolyzing said compound of Formula I obtain~d where Q is cyano with aqueous mineral acid to obtain a compound of Formula IV;
if desired, with sufficient heating to produce a com-pound of Formula I where Q is hydrogen, and heating a compound of Formula IV obtained with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce a compound of Formula I where Q is nitro or decarboxylating said compound of Formula IV to obtain a compound of Formula I where Q is hydrogen;
and reacting a compound of Formula I obtained where Q is hydrogen wi~h a halogen to obtain the corresponding com-pound where Q is halo;
if desired, reacting a compound obtained wherein R is hydrogen with an alkylating agent of the Formula R'-An where R' is lower-alkyl or lower-hydroxyalkyl and An iq an a~ion of a strong inorganic acid or an organic sulfonic acid to prepare the corresponding compound where R is R' and, if desired, reac~ing a compound of Formula I obtained where Q is hydrogen with a halogen to obtain the corresponding compound where Q is halo;
if desired, converting a free base obtained to a pharmaceutically acceptable acid-addition salt thereof.
Certain compounds of the inven~ion are useful in a cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically-acceptable carrier. The active component of such a composition is a cardiotonic l-R-3-Q-5-PY-2~1~)-pyridinone having the Formula I
where PY and R are each dPfined as in Formula I and Q is cyano, hydrogen, amino, lower-alkylamino, di-(lower-alkyl)amino or NHAc where Ac is lower-alXanoyl, lower-carbalkoxy, or -NHCH=C
(COOR4)2, or pharmaceutically-acceptable acid-addition salt thereof.
The above active compounds can be used for increasing cardiac contractility in a patient requiring such treatment which comprises administering to such patient an effective amount of a cardiotonic l-R-3-Q-5-PY-2(lH)-pyridinone having Formula I where PY and R are each defined as in Formula I and Q is cyano, hydrogen, amino, lower-alkylamino, di~(lower-alkyl) amino or NHAc where Ac i5 lower-alkanoyl or lower-carbalkoxy, or pharmaceutically-acceptable acid addition salt thereof.
The term "lower-alkyl" as used herein, e.g., as one of the meanings for R or as a substituent for PY in Formula I
or as used in the Q subs~ituent when lower-alkylamino -q or di- (lower-alkyl) amino, means alkyl radicals having from one to six carbon atoms which can be arranged as straight or branched chains, illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl, and the like.
The term "lower-hydroxyalkyl", as used herein, e.g., as one of the meanings for R in formula I, means hydroxyalkyl radicals having from two to six carbon atoms and having its hydroxy group and its free valence bond (or connecting linkage) on different carbon atoms, illustrated by 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxy-2-methylpropyl, 3-hydroxypropyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxyamyl, 6-hydroxyhexyl, and the like.
Illustrative of PY in formula I where PY is 4-,3-or 2-pyridinyl having one or two lower-alkyl substituents are the following ~note that "pyridinyl" as used herein is the same as "pyridyl", the former now being the preferred tarm used in Chemical Abstracts]: 2-methyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyL-4-pyridinyl, 2-methvl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively named 2-me~hyl-5-pyridinyl), 4-methyl-2-pyridinyl, 6-methyl-2-pyridinyl, 2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl,

4,6-dimethyl-2-pyridinyl, 2-ethyl-4-pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyr~dinyl, 2,6-diethyl-4-pyridinyl~ 2,6-diethyl-3-pyridinyl, 2,6-di-isopropyl-4-p~yridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the like.
The term "lower-alkanoyl", as used herein, e.g., as one of the meanings for Ac in formula I, meanS alkanoyl radicals having from one to 9iX carbon atoms, including the straight- and branch-chained raclicals, illustrated by formyl, acetyl, propionyl (N~propanovl), butyryl (n-butanoyl), isobutyryl (2-methyl-n-propanoyl) and caproyl (n-hexanoyl), The term "lower-carbalkoxy", as used herein, e.g., as one o the meanings for Ac in formula I, means carbalkoxy radicals where the alkoxy portion can be straight- or branch-chained and has from one to six carbon atoms, as illustrated by carbomethoxy, carbetho~y, carbo-n-propoxy, carbisopropoxy, carbo-n-butoxy, carbo-tert~-butoxy and carbo-n-hexoxy.
The compound~ of formulas I and V are useful both in the free base form and in the form of acid-addition salts; and, both forms are within the purview of the invention, The acid-addition salts are simply a more convenient form for use; and in practice, use of the salt form inherentlv amounts to use of the base form. The acids which can be used to prepare the acid-addition salts include preferably those which produca, when combined with the free base, pharmaceutically-acceptable salts, that is, salts whose anions are relatively innocuous to the animal organism in pharmaceutical doses of the salts, so that the beneficial cardiotonic properties inherent in the free base are not vitiated by side effects ascribable to the anions. In practicing the invention, it was found convenient to form the sulfate, phosphate, methanesulfonate or lactate. However, other appropriate pharmaceutically-acceptable salts within the scope of the invention are those derived from mineral acids such as hydrochloric acid and sulfamic acid; and organic acids such as acetic acidj citric acid, tartaric acid, ethanesulfonic acid, benzenesulfonic acid, .'~ ...
, . ~ .
-

5~25~

p-toluenesulfonic acid, cyclohexylsulfamlc acid, quinic acid, and the like, giving the hydrochloride, suliamate, acetate, citrate, tartrate, sthanesulfonate, benzenesulfonate, ~-toluenesulonate, cyclohexylsulfamate and quinate, respec-tively.
The acid-addition salts of said basic compound are prepared either by dissolving the free base in aqueous or aqueous-alcohol solution or other suitable solvents containing the appropriate acid and isolating the salt by evaporating ~he solution, or by reacting the free base and acid in an organic solvent, in which case the salt separates directly or can be obtained by COnCentratlOn of the solutionO
Although pharmaceutically-acceptable salts oi said basic compounds are preferred, all acid-addition salts are within the scope of our invention. All acid-addition salts are useful as sources of the free base form even if the particular salt ~ se is desired only as an intermedlate product as for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate in preparing a pharmaceutically-acceptable salt by ion exchange procedures.
The molecular structures of the compounds ~I) of the invention were assigned on the basis of evidence provided by infrared, ultraviolet, nuclear magnetic resonance and mass spect:ra, by chromatographic mobilities, andi by the correspondence~ of calculated and found values for the elementary analyses for representative examples~
The manner of making and using the instant invention will now be ge~nerally described so as to enabLe a person skilled in the~ art of pharmaceutical chemistry to maXe and u$e the same, as follows:

t. :' ~ ~ 3 ~S ~

The preparation of 1,2-dihydro-2-oxo-S-PY-nicotinamide (Ia) by reacting ~-PY-~-tRlR2N~acrolein (II) with malonamide i~ carried out preferably by mixing the reactants in a suitable solvent in the presence~ of a basic condensing agent. The reaction is convenie!ntly run using a lower-alkanol as the solvent, preferably methanol or ethanol, and an alkali lower-alkoxide, preferably sodium methoxide or sodium ethoxide, respectively, as the basic condensing agent. In practicing the invention~ the reaction was carried out in refluxing methanol using sodium methoxide.
Other basic condensing agents include sodium hydride, lithium diethylamide, lithium diisopropylamide, and the like, in an aprotic solvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the like.
The above-noted intermediate ~-PY-~-(RlR2N)acroleins~
(II) are generally known and are prepared by conventional methods.
Eor example, II is produced by reacting an ~-PY-acetic acid witn the reaction product obtained by reacting dimethylformamide with a phosphorus oxyhalide, preferably the oxychloride or oxy-~romide. The reaction of dimethylformamide with the phosphorus oxyhalide is run preferably below 10C. and the resulting reac-tion product is heated with the ~-PY-acetic acid at about 50 to 8~C. to produce II. The intermediate ~-PY-acetic acids are generally known compounds which are prepared by conventional methods; for example, they are produced readily by heating the corresponding acetylpyridine of the formula PY-COCH3 with sulfur and morpholine to produce the corresponding PY-thioacetomorpholi-namide which on refluxing with 12N hydrochloric acid yield the ~-PY-acetic acid, e.g., ~-t3-ethyl-4-pyridinyl)acetic acid, is produced from 4-acetyl-3-ethylpyridine via 3-ethyl-4-pyridinyl-. . .

-~ ~ 3 ~ ~ ~

thioacetomorpholinamide LJain et al., Indian Journal of Chemistry 10, 455 (19~2)~. The acetylpyridines, i.a., PY-COCH3, also are ~enerally known compounds which are prepared by conventional procedures, e.~., production from the corresponding ayanopridines, i.e., PY-CN, [Reilly Tar ~ Chem Corp. British Patent ~20,303, published March 6, 1963; Case et al., J. Am. Chem. Soc. 78, 5842 (1956~].
The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinamide (Ia) to 3-amino-5-PY-2(1H~-pyridlnone tlb) is carried out by reacting Ia with a reagent capa~le of converting carbamyl to amino. This reaction is conveniently run by heating an aqueous mixture containing an alkali metal hypohalite, preferably hypobromite such as by using bromine and an alkali metal hydroxide or hypochlorite, and Ia, and then acidifying the reaction mixture, preferably with an aqueous mineral acid, e.g., hydrochloric acid. The reaction can be carried out from about 25C. to lOO~C., preferably about 60C. to 100C.
The reaction of ~-PY-B-~RlR2N~acrolein ~ with ~-cyanoacetamide to produce 1,2-dihydro-2-oxo-5-PY-nicotino-nitrile (III) is carried out preferably by mixing the reactants in a suitable solvent in the presence of a basic condensing agent. The reaction is conveniently run using a lower-alkanol as a solvent, preferably methanol or ethanol, and an alkali lower-alkoxide, preferably sodium methoxide or sodium ethoxide, respectively, as the basic condensing agent. In practicing the invention, the reaction was carried out in refluxing methanol using sodium methoxide. O~her basic condensing agants include sodium hydride, lithium diethyl-amide, lithium diisopropylamide, and the like, in an aproticsolvent, e.g., tetrahydrofuran, acetonitrile, ether, benzene -14~

2~

dioxane, and thQ like.
The raaction of ~-PY-malonaldahyde (II') with a-cyanoacetamide to produce 1,2-dihydro-2-oxo~5-PY-nicotino-nitrile ~III) is carried out by heating the reactants in the presence of a catalytic conden~ing agent, preferably morpholine or piperidine and/or its acetate. The reaction is conveniently carri-d out by refluxing a benzlene solution containing the reactants in the presence of morpholine, piperidine, morpholine acetate, piperidine acetate or mixture3 thereof, preferably lQ with a water separator attached to the reaction vessel ~o collect the wa'cer produced by the reaction.
The partial hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotinonitrile (III) to produce 1,2-dihydro-2-oxo-5-PY
nicotinamide (Ia) is carried out by heating III with con-centrated sulfuric acid. While the reaction is convenientlyand preferably run by heating the reactants on a steam bath, the temperature range for the reaction can vary from about 25 to 135C. Alternatively, the conversion of III to Ia can be carried out by heating III at about 100 to 17SC. with polyphosphoric acid for about one to five hours.
The hydrolysis of 1,2-dihydro-2-oxo-5-PY-nicotino-nitrile (III~ to produce 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) is conveniently run by heating III on a staam bath with an aqueous mineral acid, preferably S0~ sulfuric acid.
The conversion of 1,2-dihydro-2-oxo-5-PY-nicotinic acid (IV) to 3-nitro-5-PY-2~lH)-pyridinone (Ic) is carxied out by heating IV with a mixture of concentrated sulfuric acid and concentrated nitric acid. The heating of the reactants is conducted at a~out 60 to 100C., preferably at about 70 to 90C. Al~hough it might be presumed that the nicotinic acid (IV) is first decarboxylated to produce the I

5~

corresponding 3-unsubstituted-5-PY-2(1H)-pyridinone, which is then nitrated at the 3-position, it is noted, as shown above, that heating the corresponding nicotinonitrile (III~
with conc~ntrated sul~uric acid alone results in partial hydrolysis yielding the corresponding nicotinamide ~Ia).
Alternatively, 1,2-dihydro-2-oxo-5-PY-nicotino-nitrile (III) is readily converted step-wise to 3-nitro-5-PY-2(1H)-pyridinone ~Ic) by first heating III with aqueous sulfuric acid for a longar period (supra) than required to forml,2-dihydro-2-oxo-5-Py-nicotinic acid ('IV~ whereupon IV
if first formed and then is decarbo~ylated on continued heating to produce 1,2-dihydro-2-oxo-5-PY-pyridine which is then nitrated under the same reaction conditions noted above for converting IV to Ic, that is, by heating 1,2-dihydro-2-oxo-5-PY-pyridine with a mixture of concentrated sulfuric acid and concentrated nitric acid to produce 3-nitro-5-PY-2(lH)-pyridinone (Ic).
The reaction of 3-nitro-5-PY-2tlH~-pyridinone ~Ic~
with a lower-alkylating agent to produce l-R'-3-nitro-5-PY-2(lH)-pyridinone (Id) is generally carried out by reacting Ic with a lower-alkyl or a lower-hydroxyalkyl ester of a strong inorganic acid or an organic sulfonic acid, said ester having the formula R'-An, where An is an anion of a strong inorganic acid or an organic sulfonic acid, e.g., chloride, bromide, 'iodide, sulfate, methanesulfonate, benzenesulfonate, and para-toluenesulfonate (or tosylate3, and R' is lower-alkyl or lower-hydroxyalkyl. This alkylation is preferably run using a slight excess of the alkylating agent although equimolor quantities give satisfactory results.

The chloride, bromide, iodide or tosylate is preferred because of the ready availabilit~ of the requisite lower-!~;j ~3~

alkyl halides or tosylates; and, the reaction i9 carried outpreferably in the prasence of an acid-acceptor. The acid-acceptor is a basic substance which preferably forms freely water-soluble by-products easily separable from the product of the reaction, including for e~xample, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium al~oxides, potassium alkoxides, sodium amide, and the like. The acid-acceptor picks up the hydrogen halide or tosylate (or HAn) which is split out during the course of the reaction. The reaction is preferably carried out in the presence of a suitable solvent which is inert under the rraction conditions, e,g., a solvent such as lower-alkanol, acetone, dioxane, dimethylformamide, dimeth~l sulfoxide, hexamethyl phosphoramide, or a mixture of solvents, e.g., a mixture of water and a lower-alkanol. The reaction is generally carried out at a temperature between about room temperature (about 20-25C.) and 150C , preferably heating on a steam bath in a stirred mixture of dimethylformamide and anhydrous potassium carbonate.
The reduction of 3-mtro-5-PY-2-(lH)-pyridinone or 1-R'-3-nitrG-5-PY-2(lH)-pyridinone (Id) to produce l-R-3-amino-5-PY-2(1H)-pyridinone (Ib) can be carried out either by catalytic or chemical reductive means. In practicin~ the invention, the hydrogenation of Ic or Id to produce Ib was conveniently run in a suitable solvent, e.g., dimethyl-formamide, in the presence of a hydrogenation catalyst, e.g. palladium-on-charcoal, at room temperature (about 20 to 25C.) un~il the uptake of hydrogen ceased~ Other suitable solvents include tetrahydrofuran, dioxane, methanol, ethanol, water (containing a base, e.g., sodium hydroxide, potassium hydroxide, triethylamine, etc.), and the like.

Other suitable hydrogenation catalysts include Raney nickel, platinum oxide, and the li~e. Chemical reducing agents useful in the reduction of Ic or Id to produce Ib include iron and acetic acid, zinc and hydrochloric acid, and the like.
The acylation of l-R-3-amino-5-PY-2(lH)-pyridinone (Ib) to produce the corresponding l-R-3-Q'NH-5-PY-2(1H) pyridinone (Ie) is carried out by reacting Ib with a lower-alkanoylating agent or a lower-carbalkoxylating agent, a~g., a lower-alkanoyl halide, preferably chloride, a lower-alkanoic anhydrids, a lower-alkyl haloformate, and the like, preferably in the presence of an acid-acceptor, as illustrated hereinabove for the lower-alkylation reaction. The lower-carbalkoxylation reaction can be carried out step-wise by first reacting the 1-R-3-amino-5-PY-l-R-2(lH)-pyridinone (Ib~ with l,l'-carbonyldiimidazole in the presence of a suitable solvent, e.g., dimethylformamide, to produce N-(l-R-1,2-dihydro-2-oxo-5-PY-3-pyridinyl)-imidazole-1-carboxamide which is then heated with a lower-alkanol to yield the corresponding lower-alkyl N-~1-R-L,2-dihydro-2-oxo-5-PY-3-pyridinyl)carbamate.
The reaction of 5-PY-2(lH)-pyridinone (Ie) with halogen to produce 3-halo-5-PY-2(lH)-pyridinone (If) is carried out preferably by mixing the reactants in an appropriate ~5 solvent inert under the reaction conditions, a preferred solvent being acetic acid. The reaction is conveniently run at room temperature or by heating at moderate temperatures up to about 100C. Preferred halogenq are bromine and chlorine. Any inert solvent can be used, e.g., dimethyl-formamide, chloroform, ethanol, and the like.
The reaction of 3-halo-5-PY-2(lH)-pyridinone (If~

'': "':' 3~

with a lower-alkylamine or a di-~lower-alkyl~amine to produce the corresponding 3-(lower-alkylamino)-5-PY-2(lH)-pyridinone ~Ig; Rl is lower-alkyl and R2 i~ hydrogen~ or 3-[di-(lower-alkyl)amino]-5-PY-2(1H)-pyridinone (Ig; Rl and R2 are each lower-alkyl), respectively, is carried out by heating the reactants in an autoclave at about 100-180C., preferably about 125-160C. and preferably using a suitable solvent, e.g., water, dimethylformamide, dioxane, 1,2-dimethoxyethane, and the like, or mixtures thereof.
A preferred method of preparing the 3-dimethylamino-5-PY-2(lH)-pyridinone is carried out by reacting 3-amino-5-PY-2(lH)-pyridinone (Ib) with a mixture of formàldehyde and formic acid ~o effect dimethylation o the primary 3-amino group. This reaction is conveniently carried out by refluxing the 3-amino-5-PY-2(1H)-pyridinone (Ib) with an excess sach of formaldehyde, preferably an aqueous solution thereof, and formic acid, preferably mora than a two-fold molar excess o each.
The conversion of l-R-3-amino-5-PY-2~lH~-pyridinone (Ib) to di-(lowar-alkyl) l-R-N{1,2-dihydro-2-oxo-5-PY-3-pyridinyl]aminomethylenemalonate ~V) is conveniently carried out by stirring at room temperature (about 20-25C.) or by heating up to a temperature of about 80-120C. the reactants, l-R-3-amino-5-PY-2(lH)-pyridinone (Ib) and di-(lower-alkyl~ ~-(lower-alkoxy-methylene)malonate of the formula R30CH=C(COOR4), pre-ferably in a molor ratio of 1:1 and preferably in the presence of a suitable inert solvent, eOg., a lower-alkanol, preferably methanol or ethanol. Other inert solvents can be used, e.g., acetonitrile, isopropyl alcohol, dimethylformamide, benzene, and the like.

. .J

2S~

Alternati~ely, this reaction can be carried out by preparing the reactant di-(lower-alkyl) ~-(lower-alkoxymethylene)malonate ~n s u without its actual isolation by heating a mixture of equimolar quantities of 1-R-3-amino-5-PY-2(lH)-pyrid:inone, tri-~lower-alkyl) orthoformate, preferably the triethyl ester, and di-(lower-alkyl) malonate using reaction conditions similar to those presented above are although here the reactants preferably are heated in a suitable inert solvent, preferably a lower-alkanol, e.g., ethanol, at about 60~90C.
The following examples will further illustrate the invention without, however, limiting it thereto.

A. 1`, 2-DIHYDRO-2-0xo-5- (PYRIDINYL) NICTINONITRILES
A-l. 1,2-Dihydro-2-oxo-5-~4-pyridinyl)nicotino-nitrile - A reaction mixture containing 35 g. of ~-(4-pyridinyl)-~-dimethylaminoacrolein, 21.6 g. of sodium methoxide, 500 ml. of methanol and 17 g. of ~-cyanoacetamide was heated to reflux with stirring whereupon an exothermic reaction ensued sufficient to cause the reaction mixture to reflux without the use o external heat. The reaction mixture was then refluxed with stirring for an additional thirty minutes, with solid precipitating afte about five minutes of refluxing. The reaction mixture was cooled and the precipitate was collected, washed with ethyl ether and dried. The solid product was recrystallized from methanol and dried n vacuo at 80C. to yield 13 g. of 1,2-dihydro-2-oxo-5-(4-pyriclinyl)nicotinonitrile as its sodium salt, m.p.
~300C. Subsequent concentrations of the mother liquor yielded additional fractions of 10 g., 6,6 g. and 3 g. of the product, thereby resulting in a total of 32.5 g. of said sodium salt which is readily converted by treatment with 5~

hydrochloric acid as in Example A-2 to the corresponding N-H compound, that is, 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicot~no-nitrile.
An alternative method of preparing 1,2-dihydro-2-oxo-5-(4-pyridinyl)nico~inonitrile is given as ~ollows:
A mixture containing 15 g. of ~-(4-pyridyl~malonaldehyde, 9.3 g. of ~-cyanoacetamide, 11 g. of morpholine, 13 g. of acetic acid and 1 liter of benzene was refluxed for about twenty-four hours with a water separator connected to ths reaetion vessel, then allowed to stand over the weekend.
The solid which had separated was collected, reerystallized from dimethylformamide and dried in vacuo at 90C. for about fifteen hours to ~eild 5 g. of 1,2-dihydro-2-oxo-5-t4-pyridinyl)nicotinonitrile, m.p. >300C.
A-2. 1~2-Dihydro-2-oxo-5-(3-pyrldinyl)nicotino-nitrile - A mixture containing 93 g. of ~-(3-pyridinyl)-~-dimethylaminoacrolein, 54 g. of a-cyanoacetamid~, 65 g. of sodium methoxide and 900 ml. of methanol was refluxed with stirring for two hours and then allowed to stand at room temperature overnight. The resulting semi-solid eake was eooled and the solid was eolleeted, washsd with isopropyl aleohol and then ethyl ether and dried. The solid ~sodium salt) was dissolved in water, the aqueous solution neutralized with 6N hydroehlorie aeid, and the aeidie solution was eooled. The separated solid was eollected, washed sueeessively with isopropyl aleohol and ether and dried in vaeuo at 8~C, to yield 41 g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nieotino-nitrile, m.p. ~300C.
Th~ above intermediate ~-t3-PYridinYl)-~-dimethYl-aminoaerolein was prepared as follows: to 740 ml. of dimethylformamide kept below 10C. was added dropwise with stirring 294 g. o~ phosphorus oxychloride and stirring wascontinued for another fifteen minutes then thera was added 88 g. of ~-~3-pyridinyl)acetic acid and the re9ulting reaction mixture was stirred at room temperature for one hour and then heated with stirring at about 70C. for two hours and then cooled, The reaction mixture was then evaporated in vacuo to remove all of the volatile materials and the residue was added slowl~r to 1.24 liters of saturated potassium carbonate solution ancl 500 ml. of benzene with cooling. The mixture was allowed to stand overnight and then extracted with four portions of 50/50 (v/v) of ben-~ene/ethanol. The combined extracts were dried over anhydrous potassium carbonate and evaporated in vacuo to remove the solvent and thereby yield 136 g. of dark oily material conta~ning ~-(3-pyridinyl)-~-dimethylacrolein.
A-3. 1,2-Dihydro-2-oxo-5-~2-pyridinyl)nicotino-nitrile - A mixture containing 51 g. of ~-(2-pyridinyl)-~-dimethylaminoacrolein, 24 g, of ~-cyanoace~amide, 31 g. of sodium methoxide and 500 ml. of methanol was refluxed with stirring for four hours and then allowed to stand at room temperature overnight. The mixture was filtered and the filtrate evaporated in vacuo to remove the volatile materials, The residue was diluted with water and the mixture neutrali~ed with 6N hydrochloric acid. The separated solid was collected, washed successively with water, ethanol and ether and then dried at 80C,, in vacuo to yiald 18 g. of 1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile.
The above intermediate ~-(2-pyridinyl)-~-dimethyIamino-acrolein was prepared following the procedure described in Example A-2 using 50 g. of ~-(2-pyridinyl)acetic acid hydrochloride, 336 ml. of dimethylformamide and 80 ml. of ~3;~

phosphorous oxychloride.
Following the procedure de3cribed in Example A-2 but using in place of ~-(3-pyridinyl)-~-dimethylaminoacrolein a molar equivalent ~uantity of the appropriate ~-py-~dimeth aminoacrolein, the 1,2-dihydro-2-oxo-5-PY-nicotinonitrile of Example A-4 thru A-7 are obtained~ The intermediate ~-PY-~-dimethylaminoacroleins used in E:xamples A-4 thru ~-7 are prepared by following the procedure describ~d in the second paragraph of Example A-2 to produce a-(3-pyridinyl~-~-dimethylaminoacrolein but using in place of ~-~3-pyriclinyl)acetic acid a molar equivalent quantity of the appropriate ~-PY-acetic acid.

nicotinonitrile using a-(2-methyl-3-pyridinyl)-B-dimethyl-minoacrolein,in turn prepared from ~-(2-methyl-3-pyridinyl~-acetic acid.
A-5. 1~2-Dihydro-2-oxo-5-~5-methyl-3-pyridinyl~-nicotinonitrile using a-(5-methyl-3-pyridinyl~-~-dimethyl-aminoacrolein, in turn prepared from ~-(5-methyl-3-pyridinyl)-acetic acid.
A-6. 1,2-_ihyc~-2-oxo-5-(3-ethyl-4-~yridinyl3-nicotinonitrile using a-(3-ethyl-4-pyri~inyl)-~-dimethyl-aminoacrolein, in turn prepared from ~-(3-ethyl-4-pyridinyl3-acetic acid.
A-7. 1,2-Di ~ ro-2-oxo-5-(4~6-dimethyl-2-pyridinyl) nicotinonitril_ using ~-(4,6-dimethyl-2-pyridinyl)-~-dimethylaminoacrolein, in turn prepared from a-~4,6-dimethyl-2-pyridinyl)acetic acid.
B. 1,2-DIHYD~0-2-OXO-5-(PYRIDINYL)NICOTINIC ACIDS

B-l. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinic a _ - A mixture containing 227 g. of 1,2-dihydro-2-oxo-5-~4-pyridinyl)nicotinoitrile and 2.6 lit~rs of 50% aqueous , ; . . . -:

sulfuric acid was refluxed for five hours and then allowed to stand at room temperature overnight (about fifteen hours).
The reaction mixture was then poured into 1 liter of water and the mixture cooled. The precipitate wa~ collected, washed successively with water, athanol and ether, and dried overnight in a vacuum oven at 80C. to yeild 206 g. of the crude product as a pink solid. A 40 g. portion of the crude product was mixed with water and the mixture neutralized by addition of potassium carbonate. The solid was collected, washed successively with water, methanol, and ether, and then recrystallized from dimethylformamide followed by successive washing with methanol and ether, and then drying in vacuo at 8~C. to yeild, as a white solid, 27 g. of 1,2-dihydro-~-oxo-5-(4-pyridinyl)nicotinic acid, m.p, ~300C.
lS B-2. 1,2-Dihydro-2-oxo-5-(3-pyridin~l)nicotinic acid - A mixture containing 41 g. of 1,2-dihydro-2-t3xo-5-~3-pyridinyl~nicotinonitrile and 410 ml. of 50~ aqueous sulfuric acid was refluxed for two hours and then poured into 1.5 kg.
of a mixture of ice and water. The acidic mixture was ~0 neutralized with 35% aqueous sodium hydroxide solution ~nd the mixture cooled. The separated solid was collected, washed with water and dried in vacuo at 80C. to ~ield 47 g.
of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid which was used directly without urther purification in the next step described below as Example C-2.
B-3. L,2-Dihydro-2-oxo-5-(2-~ridin~l)nicotinic acid, 14 g., was obtained following the procedure described in Example B2 using 18 g. of 1,2-dihydro-2-oxo-5-(2-pyridinyl~-nicotinonitrile, 180 ml. of 50% aqueous sulfuric acid and a rt3flux period of four ht~urs.
Fol:Lowing the procedure described in Example B-2 but using in place of 1,2~dihydro-2-oxo-5-(3-pyridinyl)-nicotinonitrile a molar equivalent quantity of a 1,2-dihydro-2-oxo-5-PY-nicotinoni~rile, the corresponding 1,2-dihydro-2-oxo-5-PY-nicotinic acids of Examples B-4 thru B-7 are obtained.
B-4 1,2-Dih~dro-2-oxo-5-~2-meth~1-3-pyridinyl)-nicotinic acid using 1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl~-nicotinonitrile.
B-5. 1,2-Dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinic acid using 1,2-dihydro-2-oxo-5-(5-meth~l-3-pyridinyl)-nico~inonitrile.
B-6. 1,2-Dihydro-2-oxo-5-(3-ethyl-4-pyridinyl~-.

nicotinic acid using 1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridin~l)-nicotinonitrile.
B-7. 1!2-Dihydro-2-oxo-5-(4,6-dimeth~l-2-pyridinyl)-nicotinic acid using 1,2-dihydro-2-oxo-5-~4,6-dimethyl-2-pyridinyl)nicotinonitrile.
C. 3-NITR0-5-(PYRIDINYL)-2(lH)-PYRIDINONES
C-l. 3-Nitro-5-~4-pyridinyl)-2(1~-p~ridinone -To a stirred solution kept at 5-10C. and containing 154 g.

of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinic ac-d in 450 ml.
of concentrated sulfuric acid was added dropwise a solution containing 45 ml. of concentrated sulfuric acid ~ind 160 ml.
of 90~ nitric acid. The reaction mixture was heated cautiously at 80C. for three hours and then poured into 3.3 liters of a mixture of ice and water. The mixture was filtered and the precipitate washed with water. The combined filtrates were added slowly to one liter of 10% aqueous potassium carbonate solution with stirring. The solution was neutralized by adding potassium carbonate and then made alkaline by adding 5~ a~ueous sodium bicarbonate solution. The precipitated product was collected, washed succes~ively with a small amount of cold water, isopropyl alcohol and ether, and thendried in vacuo at 80C~ to yeild 89 g. of the product. A
30 g. portion of the product was recrystallized from dimethyl~
formamide to yield 20 g. of 3-nitro-5-~4-pyridinyl)-2(1H)-pyridinone, m.p. >300C.
Alternatively, 3-nitro-5-(4-pyridinyl)-2(lH)-pyridinone is prepared step-wise starting with 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile as follows: A mixture containing 197 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile, 600 ml. of concentrated sulfuric acid and150 liters of water was refluxed for twenty-four hours, cooled and poured into 10 liters of a mixture of ice and water. The mixture was neutralized with ammoni~m hydro~ide and the separated precipitate was collected, washed with a ~mall amount of cold water and dried ln vacuo at 80C. to yield 148 g. of 5-(4-pyridinyl)-2(lH)-pyridinone, m.p. 258-260C. An 80 g. portion of 5-(4-pyridinyl)-2(lH)-pyridinone was added to 288 ml. of concentrated sulfuric acid and the mixture heated to 70C. To this stirred solution kept at 70-80C. was added dropwise a mixture containing 102 ml. of ~0% nitric acid and 29 ml. of concentrated sulfuric acid.
The reaction mixture was heated at about 80C. for three hours after addition of the mixture of acids. The reaction mixture was then cooled and poured into a mixture of ice and water with stirring. The precipitate was collected and dried. It was then slurried with water and neutralized with 10~ aqueous potassium bicarbonate solution. The precipitate was collected, washed with water and dried in vacuo at B0C.
to yield 56 g. of 3-nitro-5-(4-pyridinyl)-2(lH)-pyridinone.
Following ~he procedure"described in'the im~ately prece~ing paragraph but starting with a molar'equivalent ~ ntity of the"app~opriate 1,2-dihyd~2-oxo-5-(4-pyridinyl)nicotu~nitrile in place of 1,2-dihydro-2_oxo-5-tpyrid~yl)-nicotinonitrile, there are obtained first the following 5-PY-2(1H)-pyridmones: 5-~3-pyridinyl)-2(1H)pyridmones; 5-(2-pyridinyl)-2(lH)-pyridinone; 5-(2-methyl-3-p~ridinyl)-2(lH)-pyridinone; 5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone;
5-(3-ethyl-4-pyridinyl)-2(1H)-pyrldinone; and, 5-~4,6-dimethyl-2-pyridinyl~-2(1H)-pyridinone. In the subsaquent second step, that is, the treatment of the appropriate 5-PY-2(lH~-pyridinone with concentratad sulfuric acid and con-centrated nitric acid as above, there are obtalned thecorresponding respective 3-nitro compounds.
C-2. 3-Nitro-S-(3-pyridinyl)-2(lH)-pyridinone, 14 g., m.p. >300C., was prepared following the procedure described in Example C-l using 25 g. of 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinic acid, 76.4 ml. of concentrated sulfuric acid, 26.6 ml. of 90% nitric acid and 7.6 ml. of concentrated sulfuric acid.
C-3. 3-Nitro-5-~2-pyridinyl~-2~1H~-pyridinone, 10 g., m.p. >300C., was prepared following the procedure described in Example C-1 using 14 g. of 1,2-dihydro-2-oxo-5-(2-pyridinyl~nicotinic acid, 44 ml. of concentrated sulfuric acid, 15 ml. of 90% nitric acid and 4.4 mL. of concentrated sulfuric acid.
C-4. 1-Methyl-3-nitro-5-(4-~yridinyl)-2(lH)-pyridinone - A mixture containing 4.3 g. of 3-nitro-5-(4-pyridinyl)-2(lH)-pyridinone, 2.8 g. of anhydrous potassium carbonate and 40 ml. of dry dimethylformamide was stirred under nitrogen and heated on a steam bath for thirty minutes.
The resulting fine suspension was cooled to room temperature and to it was added dropwise with stirring 3.7 g. of methyl tosylate. The resulting mixture was then stirred at room 2~

temperature ~or eighteen hours, at steam bath temperaturefor ninety minutes, cooled and then poured onto ice. The separated solid was collected, washed well with water and dried at 60C. and one-third a~losphere for eight ho~rs. The resulting powder (3,2 g.~ was cxystallized from 50% aqueous ethanol to yield ~ine needles wh~ich were washed well with water and dried in vacuo for three hours at lOO~C. and 10 mm. to yield 2.2 g. of 1-methyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 250-252C~ In order to prove that the product obtained here was ~he N-methyl compound and not the O-methyl compound the following experiment was conducted:
To 300 mg. of the product dissolved in 10 ml. of glacial acetic acid was added 2 ml. of 48% hy~rogen bromide and the resulting clear solution was heated on a steam bath ~or a~out seventy-five minutes, cooled and the solvents distilled-of under reducad pressure. The residual yellow solid was triturated with dilute a~ueous ammonium hydroxide solution, collected by filtration, washed with water and dried at 80C. and one third atmosphere for twenty hours to--yieId 0.30 g. of the starting material, m.p, 252-254C. Had the product been the O-methyl compound, that is, 2-methoxy-3-nitro-S-~4-pyridinyl)pyridine, the foregoing refluxing with hydrogen bromide in acetic acid would have produced the demethylated compound namely, 3-nitro-5-~4-pyridinyl)-2(lH)-pyridinone.
In another run following the above-described procedure there was obtained 11.2 g. of 1-methyl-3-nitro-5-(4-pyridinyl)-2(lH)-pyridinone, m.p. 151-152C~, using 21.7 g. of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 13.8 g.
of anhydrous potassium carbonate, 300 ml. of dimethylformamide, 18.6 g. of methyl tosylate in 50 ml. o~ dimethylformamide 2~

added in one portion, and recrystallization from aqueous ethancl.
C-5. 1-Ethyl-3 nit o-5-(4-pyridinyl)-2-~lH)-pyridinone - A mixture containing 21.7 g of 3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone, 13.8 g. of anhydrous potassium carbonate and 400 ml. of dry dimethylformamide was stirred at room temperature for one howr on a steam bath for one hour and then allowed to cool to room temperature. To the stirred yellow suspension was added a solution containing 20 g. of ethyl tosylate in 10 ml~ of dimethylformamide and the resulting mixture was stirred at toom temperature overnight tabout fifteen hours) and then on a steam bath for ninety minutes. The mixture was cooled and iltered. The filterate was concentrated to near dryness under reduced pressure and 400 ml of water was added. The yellow solid was collected by filtration, washed with water and dried at 50C. in vac~o ~or eighteen hours to yield 5.5 g. of pale yellow needles, m.p. 124-126C. (see below for recrystallization and identifi-cation~ The filtrate was stored at 0C~ and the resulting yellow crystalline precipitate was collected and dried at 100C.
and 10mm. for four hours to ~ield 8O0 g. of the product, 1-ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridlnone, mOp. 175 176C, A sample of this product was recrystallized from 95 ethanol to produce the yellow crystalline l-ethyl compound, m.p. 175-176C., whose nuclear magnetic resonance spec~rum (10~ in CF3COOD) is consistent with the assigned N-ethyl structure. A portion of the above-noted pale yellow needles melting at 124-126C. was recrystallized from ethanol-water (3/1, v/v) to yield white needles, m.p. 126-127C., which was identifield by its nuclear magnetic resonance spectrum (10~ in CF3COOD) as 2-ethoxy-3-nitro-5-(4-pyridinyl)pyridine.

~;
,~

~`3~

Following the procedure descxibed in Example C-l -~ut using in place of 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinic acid a molar e~uivalent quantity of the appropriate 1,2-dihydro-2-oxo-5-PY-nicotinic acid, the corresponding 3-nitro-5-PY 2~1H)-pyridinones of Examples C-6 thru C-9 are obtained.
C-6 3-Nitro-5-(2-m~thyl-3-pyridinyl) 2(lH)-_ pyridinone using 1,2-dihydro-2-oxo-5-(2-methyl-3-pyridinyl)-nicotinic acid.
C-7. 3-Nitro-5-(5-methyl-3-pyrldlnyl)-2~1H)-pyridinone using 1,2-dihydro-2-oxo-5-(5-methyl-3-pyridinyl)-nicotinic acid.
C-8. 3-Nitro-5-(3-ethyl-4-pyridinyl)-2(1H)-pyridinone using 1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinic acid.
C-9. 3-Nitro-5-(4,6-dimethyl-2-pyri_inyl)-2(1H)-pyridinone using 1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinic acid.
Following the procedure described in Example C-5 but using in place of ethyl tosylate a molar equivalent quantity of the appropriate lower-alkyl tosylate or other lower-alkylating agents the corresponding l-(lower-alkyl~-3-nitro-5-PY-2(lH)-pyridinones of Examples C-10, C-ll, C-12 and C-13 are obtained.
C-10, 3-Nitro-l-n-propyl-5-(4-pyridinyl)-2(lH)-yridinone using 3-nitro-5-(4-pyridinyl)-2(lH)-pyridinone and n-propyl tosylate.
C-ll. l-Isobutyl-5-(2-methyl-3-pyridinyl)-3-nitro-2(1H)-pyridinone using 5-(2-methyl-3-pyridinyl)-3-nitro-2(lH)-pyridinone and isobutyl tosylate.
C-12. 1-n-Hexyl-3-nitro-5-(4-pyridinyl)-2~lH)-~ 3~

pyridinone using 3-nitro-5~(4-pyrldinyl)-2 ~lH) -pyridinone and n-hexyl tosylate.
C-13O 1-(2-H~droxyethx1)-3-nitro-5-(4-pyridlnyl~-2(1Hl-pyridinone using 3-nitro-5-(4-pyridinyl)-2(lH)-pyridinone and 2-hydroxyethyl tosylate.
C-14. 3-Nitro-l-n-~ropyl-5-(4-pyridinyl)-2~1~)-p~ridinone - A suspension containing 62.5 g. of anhydrous potassium carbonate and 1 liter o dimethylormamids was stirred and heated on a st~am bath for thirty minutes. The reaction mixture was then cooled to about 40C. and 51.0 g.
of n-propyl iodide was added in one portion and the resulting mixture was stirred at room temparature for ninety minutes and then at 100C~ for four hours. The reaction mixture was filtered and the filtrate was concentrated to about one-third of its volume under reduced pressure. The resultingmixture was poured into 1 liter of cold water whereupon a red viscous oil separated. The mixture was extracted with three 150 ml. portions of chloroform and the combined extracts were w~shed successively with two 150 ml~ portions of water and two 150 ml. portions of saturated brine and then dried over anhydrous magnesium sulfate, treated with decoloriz-ing charcoal and filtered. The filtrate was distilled under reduced pressure to remove the chloroform, thereby leaving 66.5 g. of dark viscous oil. A 60 g. portion of said dark viscous oil was dissolved in 200 ml. of glacial acetic acid 100 ml. of 48~ hydrogen bromide was added, and the solution was stirred on a steam bath for six hours. After distilling off most o the solvents under reduced pressure, there was added 200 ml. of water and 200 ml. of methylene dichloride and the mixture was made basic (pH of about 10) with 2N
potassium hydroxide solution. The layers were separated and the aqueous layer was extracted with two 100 ml. portionsof methylene dichloride. The combined organic layers were shaken with brina and dried over anhydrous magnesium sulfate.
The methylene dichloride was distilled off under reduced S pressure to leave 35.6 g. of pa:Le yellow, viscous cil which crystallized completely on standing at room temperature.
The crystalline product was recrystallized rom boiling water and dried at 80C. and on~-third atmosphere for eighteen hours to yield a first crop of 30.2 g. of 3-nitro-10 1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 139-140C.
A second crop of 3 8 g. of product, m.p. 138-140C., also was obtained.

D. 3-AMINO-5-(PYRIDINYL)-2(1H)-PYRIDINONES (From 3-nitro compounds) D-l. 3-Amino-5-(4-pyridinyl)-2~1H) -pyridinone - P
mixture containing 10 g. of 3-nitro-5-(4-pyridinyl) -2(1H)-pyridinone, 200 ml. of dimethylformamide and 1.5 g~ of 10%
palladium-on-charcoal was hydrogenated under pressure (50 p,s.i.) at room temperature until the uptake of hydrogen ceased (about thirty minutes~. The reaction mixture was filtered through infusorial earth and the filtrate was heated _ vacuo to remove the solvent. The residual material was crystallized from dimethylformamide, washed successively with ethanol and ether, and dried in a vacuum oven at 80C.
25 for eight hours to yield 6 g. of 3-amino-5-(4-pyridinyl) -2(1H)-pyridinone, m.p. 294-297C. with decomposition.
The preparations or several acid-addition salts of 3-amino-5-(4-pyridinyl) -2(lH)-pyridinone ara given in the following paragraphs.

Me thanesulfonate - A 20 g~ portion of 3-amino-5 t4-pyridinyl~ -2(lH)-pyridinone was suspended in 250 ml, of .
' ' warm methanol and methanesulfonic acid was added in a fine stream until the pH of tha mixture dropped to about 2 to 3.
The m~xture was chilled and the separated orange solid was collected. The crystalline solid was recrystallized twice from aqueou~ meth~l to yield, a~ golden crystals, 14 g. of 3-amino-5-(4-pyridinyl)-2(lH)-pyridinone methanesulfonate, m.p. 280-282C. with decomposition, after drying in acuo at 80C.
Sulfate - To a solution containin~ 10 g of 3-~0 amino-5-(4-pyridinyl)-2(lH)-pyridinone in about 250 ml. of aqueous methanol was added carefully concentrated sulfuric acid until the pH of the solution became 3. A yellow solid formed and the mixture was chillad. The separated solid was collected, recrystallized from water and dried at 80C. and 0.11 mm. to yield 16.0 g. of 3-amino-5-(4-pyridin~1)-2(1H)-pyridinone sulfate, m.p. 287-288C. with decomposition.
Phosphate - A 10 g. portion of 3-amino-5-(4-pyridinyl)-2(1H)-pyri`dinone was dissolved in methanol-water and the solution made acidic by adding concentrated phosphoric acid to a pH of 2 and the mixture was stirred well and then allowed to stand over the weekend. The mixture was chilled;
the separated solid was collacted and washed successively with ethanol and ether, and then dried in vacuo at 70C. to yield 4 g. of 3-amino-5-~4-pyridinyl)-2~lH)-pyridinone phosphate, m.p. 270-272C. with decomposition.
D-2. 3-Amino-5-~3-pyridinyl)-2~1H)-pyridinone -A mixture containing 14 g. of 3-nitro-5-~3-pyridinyl)2(1H)-pyridinone, 300 ml. of dimethylformamide and 1.75 g. of 10 palladium-on-charcoal was hydrogenated under pressure (5~
p.s.i.) at room temperature for two hours and then filtered.

The solvent wlas distilled off in vacuo and the residue was slurriad wi~h isopropyl alcohol. The solid was collected byfiltration and washed with ether and then dried. The solid was dissolved in dilute a~ueous hydrochloric acid; the solution was treated with decolori~ing charcoal and filtered;
and, the ~iltrate was evaporatecl in vacuo. The r~sidue was slurried with isopropyl alcohol; the solid collected by filtration, washed with ether and dried at 80C. in vacuo to produce 11 g. of 3-amino-5-(3-pyridinyl)-2(1H)-pyridinone as its dihydrochloride, m.p. 280-290C. with decomposition.
D-3. 3-Amino-5-~2-pyrid nyl)-2~1H~-p~ridinor.e - A
mixture containing 10 g. of 3-nitro-5-(2-pyridinyl)2-tlH)-pyridinone, 150 ml. of dimethylformamide and 1.5 g, of 10%
palladium-on-charcoal was hydrogenated under pressure (50 p.s.i.) at room temperature for one hour and filtered. The filter cake was washed with dimethylformamide. The combined filtrate and washings were evaporated in vacuo and the residual material was taken up in 6N aqueous hydrochloric acid. The acidic solution was evaporated in vacuo and the residue was recrystallized from dimethylformamide, washed successi~ely with isopropyl alcohol and ether, and dried at 80C. in vacuo to yield 2 g. of 3-amino-5-(2-p~ridinyl~-2~lH)-pyridinone as its monohydrochloride, m.p. 259-262C. with decomposition.
n-4 . 3-Amino-l-methyl-5-(4-pYridinyl)-211H~-pyridinone - A mixture containing 10.7 g. of 1-methyl-3-nitro-5-(4-pyridinyl)-2~1H)-pyridinone and 200 ml. of dimethylformamide was warmed to dissolve the nitro-pyridinone and the solution was filtered through infusorial earth.
The filtrate was charged into a 500 ml. ~arr bottle with 1.2 g. of 10% palladium-on-charcoal catalyst and the mixture was shaken uncler 40 p.s.i. of hydrogen at room temperature or three hours, after which time no further hydrogen was ~3;Z~L

taken up. The reaction mix~ure was filtered and thefiltrate was concentrated to dryness under reduced pressure (o.l mm.) on a water bath at 40C. leaving 10.1 g. of ~rown crystalline solid. The solid was recrystallized S three times from benzene-ethanol, the third time using ~' decolorizing charcoal, to yield 4.5 g. of 3-amino-1-methyl-5-(4-pyridinyl)-2(lH)-pyridinonP, m.p. 175-176C. after drying at room temperature in acuo for twenty hours, D-5. 3-~o-1-ethyl-5-(4-pyridinyl)-2(lH)-pyridinone - A solution containing 8.3 g. of 1-ethyl-3-nitro-5-(4-pyridinyl)-2(1H)-pyridinone in 200 ml. of ethyl acetate and 50 ml, of 95% ethanol was charged into a 500 ml. Parr bottle with 1.8 g. of 10% palladium-on-charcoal and the mixture was shaken under 42 p.s,i, of hydrogen at ~oom temperature for fifty minutes after which time no further hydrogen was taken up. The catalyst was filtered off and the solution was evaporated in vacuo to leave 7,5 g, of white crystalline solid. The solid was recrystallized from benzene to produce, as white needles, S,8 g, of 3-amino-1-ethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m,p, 181-182C, after drying at room temperature in vacuo for fifty hours and at 55C. and 0.001 mm. for five hours.
Following the procedure described in Example D-4 but using in place of l-methyl-3-nitro-5-(4-pyridinyl)-2~lH)-pyridinone a molar equivalent ~uantity of the appropriate l-R-3-nitro-5-]PY-2(lH)-pyridinone, the l-R-3-amino-5-PY-2(1H)-pyridinones of Examples D-6 thru D-13 are obtained.
D 3-Amino-l-n-pro~1-5-~4-py-ridinyl)-2(lH)-pyridinone using l-n-propyl-3-nitro-5-(4-pyridinyl)-2(lH)-pyridinone, D-7 3-Amino-l-isobutyl-5-(4-pyridinyl)-2(1H)-pyridinone using l-isobutyl-3~nitro-5-(4-pyridinyl)-2(1H)-pyridinone.
D-8. 3-Amino-1-n-hexyl-5-~4-pyridinyl)-2(1H)-~ .
~ yridinone using l-n-hexyl-3-nit:ro-5-(4-pyridinyl)-2~1H)-pyridinone.
D-9. 3-Amino-5-(2-methyl-3-pyridinyl)-2(lH)-pyridinone using 3-nitro-5-(2-methyl-3-pyridinyl)-2(1H)-pyridinone.
D-10, 3-Amino-5-(5-methyl-3-pyridinyl)-2(lH)-pyridinone using 3-nitro-5-(5-methyl-3-pyridinyl)-2~1H)-pyridinone.
D-ll. 3-Amino-5-(3-ethyl-4-p~ridinyl)-2(lH)-pyridinone using 3-nitro-5-(3-ethyl-4-pyridinyl)-2(lH)-pyridinone.
D-12 _3_Am no-5-(4~6-dimethyl-2-pyridinyl)-2~1H?-pyridinone using 3-nitro-5-(4,6-dimethyl-2-pyridinyl)-2~1H)-pyridinone.
D-13. 3-A ino-1-~2-hydroxyethyl~-5-(~-pyridinyl)-2(lH)-pyridinone using 1-~2-hydroxyethyl~-3-nitro-5-~4~pyridinyl)-2~lH)-pyridinone.
D-14. 3-Amino-l-n-propyl-5-(4-pyridinyl3-2~lH)-pyridinone - A solution containing 15.1 g. of 3-nitxo-l-n-propyl-5-(4-pyridinyl)-2(lH)-pyridinone in 400 ml. of dry dimethylformamide was charged into an 800 ml. Paar bottle with 1.5 teaspoons cf Raney nickel and the mixture was shaken under 650 p.s.i. of hydrogen at room temperature four hours, during which time the reaction temperature was no more than 50C. The catalyst was filtered off; the filtrate was treated with decolorizing charcoal and filtered;
and, the solvent was distilled off under reduced pressure to leave 12.7 g. of crystalline solid. The solid was recrystallized ..~

from methanol to yield 7.2 g. of crystalline 3-amino-1-n-propyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 171-173C.
after drying at 70C and 0 001 ~Nm. for six hours.
E. 1,2-DIHYDRO-2-OXO-5-(PYRI~INYL)NICOTINAMIDES
E-l. 1,2-Dih~dro-2-oxo-5-t4-pyridinyl)nicotinamide (optionally named 1,6-dihydro-6-oxc[3,4'-bipyridin]-5-carboxamide) - A mixture containing 10 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile and 100 ml. of 90% sulfuric acid was heated on a steam bath for one hour and then poured into ice. The acidic solution was neutralized with 35~
aqueous sodium hydroxide solution and then made basic with 10% potassium bicarbonate solution. The separated product was collected, washed with water, dried, recrystallized from dimethylformamide, washed successively with ethanol and ethyl ether, and dried in vacuo at 80C. to yield 8.5 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. >300C.
In another run using 68 gO of 1,2-dihydro-2-oxo-4-(4-pyridinyl)nicotinonitrile, 700 ml. of 90~ sulfuric acid~
a heating period of two hours on a steam bath, isolation as above, recrystallization from dimethylformamide and washing with methanol and ether followed by drying, there was obtained a quantative yield, 80 g. of the product, 1,2-dihydro-2-oxo-5-(4-pyridinyl~nicotinamide, m.p. 300C.
E-2. 1,2-Dihydro-5-~ yridinyl)nicotinamide - A
25 reaction mixture containing 17.6 g. of a-(4-pyridinyl)-~- -dimethylaminoacrolein, 10.0 g. of malonamide, 10.8 g. of ~odium methoxide and 200 ml. of methanol was refluxed for thirty minutes and allowed to cool. The separated product was collected and dried to yield "A". The mother liquor was concentratad in vacuo to remove the solvent and the residuaI
material was diluted with water. The mixture was neutralized ~3~

with acetic acid and the solid was collected, washed withwater and dried to yield "B". "A" was dissolved in water and the solution was neutralized with acetic acid and the mixture cooled. The separated solid was collected, washed with water and dried. "A" and "B" were combined and re-crystallized from 400 ml. of dirnethylformamide to yield 13 g. of 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinamide, m.p. >300C. The product obtained by this procedure was identical with the compound obtained in the i~nediataely preceding Example E-l.

-3~-, ~}3~5~

Following the procedure described in Example E-l but using in place of l,2-dihydro-2 oxo-5-~4-pyridinyl)-nicotino-nitrile a molar equivalent quanl:ity of the appropriate 1,2~
dihydro-2-oxo-5-PY-nicotinonitrlle, the 1,2-dihydro-2-oxo-5-P~-nicotinamides of Examples E-3 thru E-8 are obtained.
E-3. 1,2-Dihydro-2-oxo-5-~3~y___iny~L~_cotinamide using l,2-dihydro-2-oxo-5-~3-pyxidinyl)nicotinonitrile.
E-4. 1,2-Dihydro-2-oxo-5-~2-~yridinyl)nicotinamide using 1,2-dihydro-2-oxo-5-(2-pyridinyl)nicotinonitrile.
E-5. 1,2-Dihydro-2-oxo-5-(2-met~yl-3-pyridinyl)-nicotinamide using l,2-dihydro-2-oxo-5-~2-methyl-3-pyridinyl)-~ .
nicotinonitrile.
E-6. 1,2-Dihydro-2-oxo-5-~5-methyl-3-~ridinyl)-nicotinamide using l,2-dihydro-2-oxo-5-methyl-3-pyridinyl)-nicotinonitrile.
E-7. 1,2-Dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-~ nicotinamide using 1,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinonitrile.
E-8. 1,2-Dihydro-2-oxo-5-(4~6-dimethyl-2-pyridinyl)-nicotinamide using 1,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinonitrile.
The products of E-3 thru E-8 also are produced by following the procedure described in Example E-2 using in place of ~-(4-pyridinyl)-~-dimethylacrolein a molar equivalent quantity of the appropxiate ~-PY-~-dimethyl-acrolein, e.g., 1,2-dihydro-2-oxo-5-(3-pyridinyl)nicotinamide using a-(3-pyridinyl)-~-dimethylaminoacrolein, and the like.

F. 3-AMINO-S-tPYRIDINYL)-2- ~lH)-PYRIDINONES ~From 3-CONH2 compounds~
F-l. 3~ L~ L ~idinAyl~-2~1H)-pYridinone - To a solution containing 90 g. of sodium hydroxide in 1300 ml. of water kept at 0C. was added dropwise with stirring 23 ml. of bromine. To the reaction mixture was than added 80 g. o 1,2-dihydro-2-oxo~5-(4-pyridinyl)nicotinamide and the resulting reaction mixture was heated on a steam bath for three hours.
The reaction mixture was cooled to room temperature, acidified slowly with 6N hydrochloric acid and the resulting acidic mixture was stirred for an additional thirty minutes. The acidic mixture was neutralized with 10~ aqueous potassium bicarbonate solution and the mixture cooled. The precipitate was collected, washed with water and dried. The solid product was recrystallized from dimethylfon~ude, washed successively with methanol and ethyl ether and dried in vacuo at 80C. to yield 35 g. of 3-amino-S-~4-pyridinyl)-2-(lH)-pyridinone, m.p. 295-297C with decom-position. Another 7 g. of the product was obtained by diluting the mother liquor with ethyl ether.
Following the procedure described in Examples F-l but using in place of 1,2-dihydro-2-oxo-5-~4-pyridinyl)-nicotinamide a molar equivalent quantity of the appropriate l,2-dihydro-2-oxo-5-PY-nicotinamide, the 3-amino-5-PY-2~lH)-pyridinones of Examples F-2 thru F-7 are obtained.
F-2. 3-Ami ~ , ridinone using 1,2-dihydro-2-oxo-5-t3-pyridinyl)nicotinamide.
F-3, 3-Amino-5-~2-pyridinyl)-2-~lH)-pyridinone using 1,2-dihydro-2-oxo-5-~2-pyridinyl)nicotinamide.
F 4. 3-Amino-5-~2-methyl-3-pyridinyl)-2-~lH)-pyridinone using 1,2-dihydro-2-oxo-5-~2-methyl--3-pyridinyl)-nicotinamide.

~Ls ~3~5~

F-5. 3-Amino-5-(5-methyl-3-~yridinyl)-2(1H)-pyridinone using 1,2-dihydro-2-oxo-S-(5-methyl-3-pyridinyl)-nicotinamide.
F-6. 3-Amino-5-(3-ethy~4-pyridinyl?-2tlH)-p~rldinone using l,2-dihydro-2-oxo-5-(3-ethyl-4-pyridinyl)-nicotinamide.
F-7 3-Amino-5-(4,6-dimethyl-2-pyridinyl)-2(1H)-_ pyrldinone using l,2-dihydro-2-oxo-5-(4,6-dimethyl-2-pyridinyl)-nicotinamide.
G. 1,2-DIHYDRO-3-(ACYLAMIDO~-5-( PY~IDIUYL~ -Z- ~iHI -rYRIDIwoN~
G-l. N-[1,2-Dihydro-2-oxo-5-(4-pyridlnx1?-3-py-idiny]
acPtamide - A mixture containing 9.4 gO of 3-amino-5-(4-pyridinyl)~
2~1Hl-pyridinone, 5.6 g. of acetic anhydride and 120 ml. of pyridine was heated on a steam bath for one hour and th~n allowed to cool. The separated product was collected, washed with ether and dried, and recrystallized twice from dimethylformamide to yield 8 g. of N-[1,2-dihydro-2-oxo-5-(4-pyridinyl~-3-pyridinyl]
acetamide, m.p. >300C.
G-2. Methyl N-[1,2-dihydro-2-oxo-5-(4-pyridinyl~-3-pyridinyllcarbamate - A mixture containing 10 g. of 3-amino-5-(4-pyridinyl)-2-(lH)-pyridinone, 100 ml. of dimethylformamide and 24 g. of l,l'-carbonyldiimidazole was stirred at room tem-perature for two hours and the solvent then distilled off in vacuo Cold water was added to the residue and the mixture was stirred until the evolution of carbon dioxide stopped~ The solid was collected, washed with water and dried. The solid was next slurried with acetone, collected and dried. The solid was dis-solved in 200 ml. of dimethylformamide, the solution treated with decolorizing charcoal and the mixture filtered. The fil-trate was heatl~d in vacuo to remove the dimethylformamide. The remaining material, which consisted primarily of N-~1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-imidazole-1-carboxamide, was !

~3~

heated with methanol whereupon a reaction ensured. The reaction mixture was allowed to cool and the separated product was collected and dried to yield 3.S g of methyl N-[1/2-dihydro-2-oxo-5-~4-pyridinyl)-3-pyridinyl]carbamate, m.p. >300C.
Following the procedure described in Example G-l but using in place of ace~ic anhydride a molar equivalent quantity of the appropriate acylating agent, the compounds of Examples G-3 thru G-5 are obtained.
G-3. N-[1,2-Dihydro-2-oxo-5-14-pyrid1nyl)-3-pyridinyl]
propionamide using propionic anhydride.
G-4. N-~1,2-Dihydro-2-oxo-5-~4-pyridinyl)-3-pyridin~]
isobutyramide using isobutyric anhydride .

G-5. N-[1~2-Dihydro-2=oxo-5-(4-Fy~idinyl~-3-pyrid~ l]
caproamide using caproic anhydride.
Following the procedure described in Example G-2 but first using in place of 3-amino-5-(4-pyridinyl)-2(lH)-pyridinone a corresponding molar equivalent quantity of the appropriate 3-amino-5-PY-2(lH)-pyridinone to produce the corres-ponding N-(1,2-dihydro-2-oxo-5-PY-3-pyridinyl)-imidazole-1-~ar-boxamide and then reacting said imidazole-l-carboxamide with the appropriate alkanol in place of methanol, there are obtained the corresponding lower-alkyl N-(1,2-dihydro-2-oxo-5-PY-3-pyridinyl) carbamates of Examples G-6 thru G-8.
G-6. Ethyl N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate first using 3-amino-5-(4-pyridinyl)-2(1H)-pyridinone and then using ethanol.
G-7. n-Hexyl N-[1!2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]carbamate using 3-amino-5-(4-pyridinyl~-2(lH)-pyridinone and then reacting the resulting N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-imidazole-1-carboxamide with n-hexanol.

5~

G-8. Isobutyl N-[1,2-dihydro-2-oxo-5-(4-pyrldinyl)-3-pyridinyl]carbamate ~irst using 3-amino~5-(4-pyridinyl)-2(lH)-pyridinone and then reacting the resulting N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]-1-imidazole-1-carboxamide with isobutyl alcohol.
G-9. N-[1,2-Dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl~
formamide (also named N-(1,6-dihydro-6-oxo-t3l4~-bipyridine]-5-yl)formamide) - A reaction mixture containing 28 g. o 3-amino-5-(4-pyridinyl)-2(lH)-pyridinone and 200 ml of 97% formic acid was heated on a steam bath for three hours, cooled and the excess formic acid distilled-off under reduced pxessure. The residue was dissolved in water and the aqueous solution was made alkaline with ammonium hydroxide. The precipitated product was collected, washed with water, dried, recrystallized from dimethylformamide, washed with ether and dried to yield 26 g of N-[1,2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]formamide, m.p. 299-300~C. with decomposition.
H. 3-HALO-5-(PYRIDINYL)-2(lH)-PYRIDINONES
H-l. 3-Bromo-5-(4-pyridinyl)-2-(lH)-pyridinone (also named 5-bromo-[3,4'-bipyridin]-6(1H~-one) - A mixture con-taining 51.6 g. of 5-(4-pyridinyl)-2(lH)-pyridinone and 600 ml~
of acetic acid was heated to about 60C. to effect complete solution. The heat was removed and 52.8 g. of bromine was added dropwise over a period of about twenty minutes whereupon a solid separated during the addition. The mixture was stirred at room temperature for about thirty mi~utes, diluted with ether and the mixture then chilled in ice, The solid was collected, washed with ether, dried, slurried with water and neutralized with 10~
potassium bicarbonate solution. The solid was collected, washed with water and dried. The solîd was then dissolved in dilute hydrochloric acid and isopropyl alcohol was added to the solution s~

to precipitate the hydrochloride salt which was recrystallizedfrom water and dried to yield 55 g. of 3-bromo-5-(4-pyridinyl)-(lH) -pyridinone as its hydrochloride, m p. >300CO
H-2, 3-Chloro-St9-pyridinyl)-2(1H)-pyridinone (also named 5-chloro~3,4'-bipyrldin]-6(lH)-one) - A mixture con-taining 17 g. of 5-(4-pyridinyl)-2(lH)-pyridinone and 200 ml.
of acetic acid heated on a steam bath was treated by bubbling chlorine into it for four hourQ. After allowing the reaction mixture to cool to room temperature, the solid was collected, washed with ether and dried. The solid was dissolved in water and the aqueous solution was neutralized with 2N aqueous potas-sium hydroxide solution and the mixture cooled. The separated solid was collected~ washed with water, dried, and recrystallized from ethanol to yield 6O5 g. of 3-chloro-5-(4-pyridinyl)-2-(lH)-pyridinone, m.p. 295-297C.
H-3. 3-Chloro-5-(3-pyridin~l)-2-(lH?-pyridinone is obtained following the procedure described in Example H-2 but using a molar equivalent quantity of 5-(3-pyridinyl)-2(lH)-4-pyridinone in place of 5-(4-pyridinyl)-2(lH)-pyridinone.
H-4. 3-~hloro-5-(3-ethyl-4-pyridinyl~-2-tlH)-pyridinone is obtained following the procedure de3cribed in Example H-2 using a molar equivalent quantity of 5-(3-ethyl-4-pyridinvl)-2(lH)-pyridinone in place of 5-(4-pyridinyl)-2(lH)-pyridinone.
H-5. 3-Bromo-5-(5-methyl-3-pyridinyl)-2(1H)-pyridinone is obtained following the procedure described in Example H-l using 5-(5-methyl-3-pyridinyl)-2(lH)-pyridinone in place of 5-(4-pyridinyl)-2(1H)-pyridinone.

~3~

I, 3-(LOWER-ALKYLAMINO)-AND 3- [DI-(LOWEg-~KYL)-AMINO] 5-(PYRIDINYL)-2(lH)-PYRIDINONES
..... .....
I-l. 3-Meth~lamino-5-(4-pyridln~ 2~lH)-pyrldinone (also named 5-methylamino[3,4'-bipyridln]-6-~lH)one) - A mixture 5 containing 55 g. of 3-bromo-5-~4-pyridinyl)-2~1H)-pyridinone, 200 ml~ of 40% aqueous monomethylamlne and 500 ml. of water was autoclaved at 140C. for one hundred and twenty hours. After allowing the reaction mixture to cool to room temperature,.the solid was collected, wash~d with water, dried, recrystallized from dimathylformamide, washed successively with methanol and ether, and dried to yield 10 g. of 3-methylamino-5-~4-pyridinyl)-2~lH)-pyridinone, m.p. 296-299C. with decomposition. Another 8 g. of product was obtained by stripping under reduced pressure the aqueous filtrate from the reaction mixture, slurrying the remaining compounds of Examples I-3 through I-7 are obtained:
residue with a small amount of water, collecting the solid and recrystallizing it from dimethylformamide I-2.
~also named 5-~dimethylamino)-[3,4-bi~yridin]-6-~lH)-one) - A
2Q mixture containing 36 g of 3-amino-5-(4-pyridinyl~-2~lH)-pyridinone, 40 ~. of 30~ aqueous formaldehyda solution and 400 ml of formic acid was refluxed for two and one-half hours and cooled, The reaction mixture was heated in vacuo to remove the excess formaldehyde and formic acid and th2 remaining material was neutralized with 10% potassium bicarbonate solution and allowed to stand at room temperature over the weekend. The aqueous mixture was extracted with three 150 ml. portions of methylene dichloride and the combined extracts were dried over anhydrous magnesium sulfate and treated with decolorizing charcoal, fill:ered and the filtrate heated ln vacuo to remove the methylene dichloride. The residue was recrystallized twice ~j from acetonitrile, washed with ether ancl dried in a vacuum oven at 80C. to yield 11.5 g. of 3-dimethylamino-5-~4-pyridinyl)-2 (lH)-pyridinone, m.p. 190-194C.
Following the procedur~ descri~ed in Example I-l but in place of 3-bromo-5-(4-pyridinyl)-2(1H)-pyridinone and/or mono-methylamine respective molar equivalent ~uantities of the appro-priate 3-halo-5-(pyridinyl)-2(lH)-pyridinone and/or lower-alkyl-amine or di-(lower-alkyl)amine, the compounds o Examples I-3 thru I-7 are obtained:
I-3. 3-Eth~lamino-5-1-3-pyridinyl)-2~1H)-pyridinone using 3-chloro-5-~3-pyridinyl)-2(1H)-pyridinone and monoethyl-amine.

~ e using 3-bromo-5-(4-pyridinyl)-2~1H)-pyridinOne and diethylamine.
I-5. _3-n-Propylamino-5-(3-ethyl-4-~yridinyl)-2~lH) pyridinone using 3-chloro-5-~3-ethyl-4-pyridinyl)-2~1H)-pyridinone and n-propylamine.
I-6. 3-~Diisopropylamino)-5-~5-methyl-3-pyridinyl)-2(lH)-pyridinone using 3-bromo-5-~5-methyl-3-pyridinyl)-2 (lH)-pyridinone and diisopropylamine.
I-7._ 3-n-Hexylamino-5-~4-pyridinyl)-2-(lH)-pyridinone using 3-bromo-5-(4-pyridinyl)-2~lH)-pyridinone and mono-n-hexylamine.
J. DI-~LOWER-ALKYL? N-[l, 2-DIHYDRO-2-OXO-5-~?YRIDINYL)-3-3-PY RIDINYL]AMINOMETHYLENEMALONATE
J-l. Diethyl N-~l, 2-dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate ~also named diethyl [1,6-dihydro-6-oxo-~3,4'-bipyridin)-5-ylaminomethylene]propanedioate)-A mixture containing 9.4 g. of 3-amino-5-~4-pyridinyl)-2~lH)-pyridinone, 10.8 g. of diethyl ethoxymethylenemalonate and 100 ml. of ethanol was refluxed with stirring on a steam bath for six and one-half hours. The reaction mixture was filtered through infusorial earth and the filtrate was distilled ln vacuo to remove the solvent. The solid residue wa~ recrystallized once from ethanol and then once from methanol uqin~ decolorizing charcoal, washed successively with isopropyl alcohol and ether, and then dried to yield 22 g. of diethyl N-[1,2 dihydro-2-oxo-5-(4-pyridinyl)-3-pyridinyl]aminomethylenemalonate, m.p. 218-222C.
Following the procedure described in ~xample J-l but using in place of diethyl ethoxymethylPnemalonate a molar equiv-alent quantity o~ the appropriate di- (lower-alkyl) (lower-alkoxy) methlenemalonate and/or using in place of 3-amino-5-~4-pyridinyl)-2llH)-pyridinone a molar equivalent quantity of the appropriate 3-amino-5-(pyridinyl)-2(lH)-pyridinone, the compounds of Examples J-2 thru J-6 are obtained:
J-2. Dimethyl N-[1,2-dihydro-2-oxo-5-(2-methyl-4-pyridinyl)-3-pyridinyl]aminomethylenemalonate using dimethyl methoxymethylenemalonate and 3-amino-5-(2-methyl-4-pyridinyl)-2(lH)-pyridinone J-3 Diethyl N-[1,2-dihydro-2-oxo-5-~3-pyridinyl)-3-pyridinyl]aminomethylenemalonate using diethyl ethoxymethylene-malonate and 3-amino-5-(3-pyridinyl)-2(lH)-pyridi~one J-4. Diisopropyl N-~1,2-dih~dro-2-oxo-5-(5-methyl-3-pyridinyl)-3-pyridinyl]aminomethylenemalonate using diisopropyl isopropoxymethylenemalonate and 3-amino-5-(5-methyl-3-pyridinyl) 2(1H)-pyridinone.
J-5. Di-n-butyl N-[1,2-dihydro-2-oxo-5-(2-methyl-4-pyridinyl)-3-py--ridinyl]aminomethylenemalonate using di-n-butyl n-butoxymethyllenemalonate and 3-amino-5-(2-methyl-4-pyridinyl)-2(lH)-pyridinone.

~3~

J-6. Di-n-hexyl N-[1,2-dihydro-2-oxo-5-~2,6-dimethyl-4-pyridinyl)-3-p~ridin~l]aminomethylenemalonate using di-n-hexyl n-hexoxymethylenemalonate and 3--amino-5-~2,6-dimethyl-4-pyridinyl)-2(lH)-pyridinone.
The usefulness of the ~ounds of Formula I where Q
is amino (preferred), lower-alkylamino, di-~lower-alkyl)-amino, NHAc, hydrogen or cyano and the compounds of Formula V as car-diotonic agents is demonstrated by their eff0ctiveness in standard pharmacological test p~ocedures, for example, in causing a significant increase in the contractile force of the isolated cat atria and papillary muscle and in causing a significant in-crease in the cardiac contractile force in the anesthetized dog with low or minimal changes in heart rate and blood pressure.
These test procedures are described in the following paragraphs.
X-l. Isolated Cat Atria and Papillary Muscle_Pxocedure -Cats of both sexes, weighing 1.5 to 3.5 kg. are each anesthetized ~ith 30 mg./kg. iop~ of sodium pentobarbital and exsanguinated.
The chest of each cat is opened, the heart excised, rinsed with saline, and the two atria and one or more small, thin papillary muscle from the right ventricle are dissected. The tissues are then transferred to a Petri dish filled with cold modified Tyrode's solution and bubbled with 2 A silver wire i5 attached to each of two opposite ends of the tissue and one of the wires is hooked to a glass electrode. The preparation is then imme-diately mounted in a 40 or 50 ml. organ bath filled with modifiedTyrode's solution at 37C. The second wire is attached to a force-displaclement transducer and the tension is adjusted to obtain a maximum contractile force (papillary muscle 1.5~0.5 g., left atria 3.0~0.6 g. right atria 4.5+0.8 g.). The transducer is connected to a Grass polygraph and the force and rate of con-traction is recorded continuously. The right atrium is beating .'' :- ' 5~

spontaneously due to the presence of the qino-atrial node, while the left atrium and the papillary muscle are stimulated elec-trically at a rate of 2 beats/sec~ by a suprathreshold rectangular pulse of 0.5 millise!cond duration~
S The modiEisd Tyrode's soluticn bathing the preparation is of the following composition (in millimoles): NaCl 136.87, KC1 5.36, NaH2PO~ 0.41. CaCl2 1.8, MgC12 6H2O 1.05, NaHCO3 11~9, glucose 5.55 and EDTA 0.04 The solution is equilibrated with a gas mixture consisting of 95~ 2 and 54 CO2 and the pH is adjusted to 7.4 with dilute solution of sodium bicarbonateO
The preparation is left to equilibrate or one hour before any compound is administered, and the bathing fluid is changed 3 to 4 times during the equilibration time. The comp~und dissolved in a vehicle ~e.g., Tyrode's solution or aqueous solu-tion of acid-addition salt of compound tested) or the vehicle alone is added to the tissue bath and the full responsQ is recorded. The tissues are washed between doses until pre-drug control values of rate and force of contraction are obtained.
Four to six doses are given to the same preparation over a period of 4 to 6 hours When tested by the above-described Isolated Cat Atria and Papillary Muscle Procedure, the compounds of Formula I where Q is amino, NHAc, lower-alkylamino, di(lower-alkyl)amino, NHAc, hydrogen or cyano and the compounds o Formula V, when tested at doses of 3 to lO0 ~g./ml., were found to cause significant increase, that: is, greater than 25% in papillary muscle orce and a significant increase, that is, greater than 25%, in right atrial force, while causing only a low percentage increase (about one-third or less than the percentage increase in right atrial or papillary muscle force) in right atrial rate.

~53~

-2. Anesthetized Dog Procedure - Mongrel dogs of both sexes weighing 9-15 kg. are used in this procedure. The dogs are each anesthetiz~d with 30 mg./kg. i.v. sodium pentobarbital Supplemental doses o~ pentobarbltal are administered whenever necessary. An intra-tracheal cannula is inserted and ventilation is carried out by means of a Harvard constant-volume, positive pressure pump using room air. The right femoral artery is can-nulated and the cannula is attached to a Statham P23A pressure transducer for the measurement of arterial blood pressure. The right femoral vein is cannulated and used for intravenous admin-istration of compounds to be tested. Pin electrodes are attached to the right forelimb, right hindlimb and left hindlimb, and lead II electrocardiogram is monitored.
A ventro-dorsal incision at the third inter-costal space is made, the heart is exposed and a Walton-Brodie strain guage is sutured to the wall of the right ventricle for the measurement of cardiac contractile force, that i9, cardiac con-tractility. Aortic and coronary blood flow are mea~ured with a pulsed field electromagnetic flow probe ~Carolina Medical Electronics) inserted around the blood vessel in questionO
Aortic blood flow is used as an approximate index of cardiac output and total peripheral resistence is calculated from aortlc flow and mean arterial pressure. All the above parameters measured are recorded simultaneously on a multi-channel Grass polygraph.
A g-ven compound is infused into the femoral vein at a rate of from 0.03 to 0.10 mg./kg.~minute untll a maximum inotropic eff~sct is obtained. The infusion of the compound is then continued for ten more minutes to maintain an equilibrium at this maximal inotropic effect. At the end of the equilibrium time the infu;sion is stopped and the rate of decline in cardiac ~?32~

contractile force is observed. Alternatively, the compound isadministered intravenously as a single bolus injection of 0.30 to 30 mg./kg.
When tested by the above-described Anesthetized ~og Procedure, the compounds of Formula I where Q is amino (pre-ferred), lower-alkylamino, di-(lower-alkyl)amino, NH~c, hydrogen or cyano and the compounds of Formula V, when admlnistered intra-venously at a rate of about 0.03 to 0.10 mg./kg./min. or as a single bolus injection of 0.30 to 30 mg./kg. caused a significant increase, that is, greater than 25~, in cardiac contractile force or cardiac contractility with only low or minimal changes (less than 25~) in heart rate and blood press~re.
The actual determination of the numerical cardiontonic data definitive for a particular compound of the invention is readily obtained according ~o the above-described standard test pro~edures by technicians versed in pharmacological test pro-cedures, without any need for any extensive experimentati~on.
Preferred embodiments are subjected to further standard test procedures. For example, 3-amino-5-(4-pyridinyl)-2-(lH)~
pyridinone, a particularly preferred embodiment, when tested orally in the unanestheti~ed dog at a dose of 1.9, 3.8, 7.5 or 10 mg./kg. was found to cause, respectively, a 39, 44, 47 or 98 increase in cardiac contractile force with a duration of action of more than three hours; no significant changes in bl!ood pressure were observed with these doses and a significant in-crease in heart rate was observed only at the highest dose of 10 mg./kg. p.o The present invention includes within its scope a cardiotonic composition for increasing caxdiac contractility, said composition comprising a pharmaceutically-accaptable carrier and, as the active component thereo~, a cardiotonic l-R-3-Q-5-PY-2(lH)-pyridinone of Formula I where Q is amino (preferred), lower-al~ylamino, di-(lower-alkyl)amino, NHAc, hydrogen or cyano, or a cardiotonic di-~lower-alkyl) N-[1,2-dihydro-2-oxo-5- (pyridinyl)-3-pyridinyl]aminomethylenemalonate o Formula V, or pharmaceutically-acceptable acid-addition salt thereof. The invention also includes within its scope the method for increasing cardiac contractility in a patient requiring such treatment which comprises administering to such patient an effective amount of said l-R-3-Q-5-PY-2-(lH)-pyridinone of ~ormula I where Q is amino (preferred), lower-alkylamino, di-(lower-alkyl)amino, NHAc, hydrogen or cyano, or a cardiotonic di-(lower-alkyl) N-[1,2-dihydro-2-oxo-5-(pyridinyl)-3-pyridinyl]
aminomethylenemalonate of Formula V, or pharmaceutically-accept-able acid-addition salt thereof. In clinical practice the said compounds of Formula I or V will normally be adminstered orally or parenterally in a wide variety of dt~sage forms.
Solid ct~ositions for oral administration include com-pressed tablets, pills, pt~wders and granules. In such solid compositions, at least one of the active compounds is admixed with at least one inert diluent such as starch, calcium car-bonate, sucrose or lactose. These compositions may also contain additional substances other than inert diluents, e.g., lubricating agents, such as magnesium stearate talc and the like.
Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commt~nly used in the art, such as water and liquid paraffin. hesides inert dil-uants such compositions may also contain adjuvants, such as wetting and suspending agents, and sweetening,flavoring, per-fuming and preserving agents. According to the invention, the compounds for oral administration also include capsules of ~, : .. .

~u~

absorbable material, such as gslatin, containing said active componPnt with or without the addition of diluents or excipients.
Preparations according to the invention for parenteral administration include sterile aqueous, aqueous-arganic, and S organic solutions, suspensions and emulsions Example of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as oliva oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilising, preserving, wetting, emulsifying and dispersing agents.
They may be sterilized, for example by filtration through a bacteria-retaining filter, by incorporation of ster-ilizing agents in the compositions, by irradiation or by heating.
They may also be manufactured in the form of sterile solid com-lS positions which can be dissolved in sterile water or some othersterile injectable medium immediately before use The percentage of active component in the said com-position and method for increasing cardiac contraotility may be varied so that a suitable dosage is obtained. The dosage admin-istered to a particular patient is variable, depending upon theclinician's judgement using as the criteria: the route of admin-istration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response thereto. An effective dosage amount of active component can thus only be determined by the clinician considering all criteria and utilizing his best judgement on the patient's behalf.

Claims (7)

The ambodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for preparing a 2(1H) pyridinone having the Formula I

, . . I

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, lower-alkyl or lower-hydroxyalkyl and Q is cyano or hydrogen or a pharmaceutically-acceptable acid-addition salt thereof, which comprises reacting either a compound of Formula II': or II: with .alpha.-cyanoacetamide where R1 and R2 are each lower-alkyl to prepare a compound where R is hydrogen and Q is cyano, if desired, hydrolyzing a compound obtained where Q
is cyano with aqueous mineral acid to obtain a compound of Formula IV

either with sufficient heating to produce a compound of Formula I where Q is hydrogen or with subsequent decar-boxylating of the compound of Formula IV obtained to obtain a compound of Formula I where Q is hydrogen;
if desired, reacting a compound-obtained wherein R
is hydrogen with an alkylating agent of the Formula R'-An where R' is lower-alkyl or lower-hydroxyalkyl and An is an anion of a strong inorganic acid or an organic sulfonic acid to prepare the corresponding compound where R is R'; and if desired, converting a free base obtained to a pharmaceutically acceptable acid-addition salt thereof.

2. A process according to claim 1, wherein Q is cyano and R is hydrogen, no alkylation stsp being carried out.

3. A process according to claim 1, wherein Q is hydrogen and R is hydrogen, no alkylation step being carried out.

4. A process according to claim 1, for preparing 1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile in which .alpha.-(4-pyridinyl)-.beta.-dimethylaminoacrolein or .alpha.-(4-pyridyl) malonaldehyde is reacted .alpha.-cyanoacetamide.

5. A process according to claim 4, for preparing 5-(4-pyridinyl)-2(1H)-pyridinone which comprises reacting the 1,2-dihydro-2-oxo-5-(4-pyridinyl)-nicotinonitrile obtained with aqueous sulfuric acid with sufficient heating.

6. A compound of Formula I as defined in claim 1, 2 or 3, when prepared by the process according to claim 1, 2 or 3, respectively,or by an obvious chemical equivalent thereof.

7. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)nicotinonitrile or 5-(4-pyridinyl)-2(1H)-pyridinone, when prepared by the process according to claim 4 or 5, respectively,or by an obvious chemical equivalent thereof.