2-[2-(di-lower-alkylamino-1-propenyl]-6-methoxy-3-pyridinecarbonitriles, useful as intermediates for cardiotonic agents.

BACKGROUND OF THE INVENTION 
a. Field of the Invention 
This invention relates to 
5-[1H-(5-membered-N-aromatic-heteryl-1-yl)]-1,6-naphthyridin-2(1H)-ones, 
their cardiotonic use, their preparation and intermediates. 
b. Information Disclosure Statement 
Lesher and Singh in U.S. Pat. No. 4,415,580, issued Nov. 15, 1983, show as 
cardiotonic agents 5-(loweralkyl)-1,6-naphthyridin-2(1H)-ones (I) and 
their preparation by reacting a 
5-(lower-alkanoyl)-6-methyl-2(1H)-pyridinone with 
di-(lower-alkyl)formamide di-(lower-alkyl) acetal to produce 
5-(lower-alkanoyl)-6-[2-(di-lower-alkylamino)ethenyl]-2(1H)-pyridinone 
(II) and reacting II with formamidine or ammonia or salt thereof to 
produce I. 
Czuba et al., Pol. J. Chem. 52, 2369-76 (1978), show as intermediates 
4-bromo-1,6-naphthyridin-2(1H)-one and 
4-hydrazino-1,6-naphthyridin-2(1H)-one. This reference also shows the 
preparation of 4-bromo-1,6-naphthyridin-2(1H)-one by heating 
2,4-dibromo-1,6-naphthyridine with 20% hydrobromic acid and the 
preparation of 4-hydrazino-1,6-naphthyridin-2(1H)-one by heating 
4-bromo-1,6-naphthyridin-2(1H)-one with hydrazine. 
Paudler et al., J. Heterocyclic Chem. 2 (4), 393-8 (1965), show the 
synthesis and NMR spectra of various 4-substituted-1,6-naphthyridines, for 
example, the reaction of 4-hydroxy-1,6-naphthyridine with POBr.sub.3 or 
POCl.sub.3 to obtain 4-bromo-1,6-naphthyridine or 
4-chloro-1,6-naphthyridine, respectively. Also shown is the reaction of 
4-bromo-1,6-naphthyridine with dimethylamine to produce 
4-dimethylamino-1,6-naphthyridine and the reaction 
4-chloro-1,6-naphthyridine with piperidine or hydrazine to produce 
4-(1-piperidinyl)-1,6-naphthyridine or 4-hydrazino-1,6-naphthyridine, 
respectively. 
Rooney et al. U.S. Pat. No. 3,993,656, issued Nov. 23, 1976, shows various 
substituted-1,8-naphthyridin-2(1H)-ones having bronchodilating and 
hypotensive properties, including 
6-(2-imidazolyl)-1,8-naphthyridin-2(1H)-one and its preparation from 
2-amino-6-(2-imidazolyl)-1,8-naphthyridine. 
SUMMARY OF THE INVENTION 
In a composition of matter aspect the invention resides in 
5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-7-R'-1,6-naphthyridin-2(1H)-on 
e having the formula I 
##STR1## 
or acid-addition or cationic salt thereof, where R is hydrogen, halo or 
lower-alkyl, R' is hydrogen or methyl, R.sub.1 is hydrogen, lower-alkyl, 
hydroxymethyl, halo, trifluoromethyl, nitro or phenyl, Z is N, C--H, 
C-(lower-alkyl), C-halo, C-hydroxymethyl or C-phenyl, and Y is N, C--H, 
C-halo, C-(lower-alkyl) or C--NO.sub.2, at least one of Y or Z being N. 
The compounds of formula I are useful as cardiotonic agents, as determined 
by standard pharmacological evaluation procedures. 
A composition aspect of the invention resides in the cardiotonic 
composition for increasing cardiac contractility which comprises a 
pharmaceutically acceptable carrier and, as the active component thereof, 
a cardiotonically effective amount of 
5-[1H-(5-membered-N-heteryl)-1-yl)]-7-R'-1,6-naphthyridin-2(1H)-one having 
the formula I or pharmaceutically acceptable acid-addition or cationic 
salt thereof. 
A method aspect of the invention resides in the method for increasing 
cardiac contractility in a patient requiring such treatment which 
comprises administering orally or parenterally in a solid or liquid dosage 
form to such patient a cardiotonically effective amount of 
5-[1H-(5-membered-N-heteryl)-1-yl]-7-R'-1,6-naphthyridin2(1H)-one having 
the formula I or pharmaceutically acceptable acid-addition or cationic 
salt thereof. 
In another composition of matter aspect, the invention resides in 
5-X-7-R'-1,6-naphthyridin-2(1H)-one having the formula II 
##STR2## 
or pharmaceutically acceptable acid-addition or cationic salt thereof, 
where X is bromo, chloro or hydrazino and R' is methyl. The compounds of 
formula II where X is bromo or chloro, are useful as cardiotonic agents, 
as determined by standard pharmacological procedures, and also are useful 
as intermediates for preparing the compounds of formula I hereinabove, the 
compound where X is bromo being preferred when used as an intermediate. 
The compound of formula II where X is hydrazino is useful as an 
intermediate for preparing the compounds of formula I where Y is N, Z is 
C--H and R' is methyl. 
Another composition aspect of the invention resides in the cardiotonic 
composition for increasing cardiac contractility which comprises a 
pharmaceutically acceptable carrier and, as the active component thereof, 
a cardiotonically effective amount of 5-X-7-R'-1,6-naphthyridin-2(1H)-one 
having the formula II or pharmaceutically acceptable acid-addition or 
cationic salt thereof, where X is bromo or chloro and R' is methyl. 
A method aspect of the invention resides in the method for increasing 
cardiac contractility in a patient requiring such treatment which 
comprises administering orally or parenterally in a solid or liquid dosage 
form to such patient a cardiotonically effective amount of 
5-X-7-R'-1,6-naphthyridin-2(1H)-one having the formula II or 
pharmaceutically acceptable acid-addition or cationic salt thereof, where 
X is bromo or chloro and R' is methyl. 
In another composition of matter aspect, the invention resides in 
2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile 
having the formula IIIa 
##STR3## 
and acid-addition salt thereof, where R.sub.2 and R.sub.2 are each 
lower-alkyl. 
In a process aspect the invention resides in the process which comprises 
reacting hydrogen bromide or hydrogen chloride with 
2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile to 
produce 5-(bromo or chloro)-2-methoxy-7-methyl-1,6-naphthyridine and 
treating said 2-methoxy compound with aqueous sodium or potassium 
hydroxide solution to produce 5-(bromo or 
chloro)-7-methyl-1,6-naphthyridin-2(1H)-one. 
DETAILED DESCRIPTION INCLUSIVE OF PREFERRED EMBODIMENTS 
Intermediates for the compounds of formula I are the 
5-X-7-R'-1,6-naphthyridin-2(1H)-ones having the formula II 
##STR4## 
where X is bromo, chloro or hydrazino and R' is hydrogen or methyl. A 
preferred compound of formula II as an intermediate is the compound where 
X is bromo and R' is hydrogen or methyl. The compound of formula II where 
X is hydrazino is useful as an intermediate for preparing the compounds of 
formula I where Y is N and Z is C--H. 
Intermediates for the compounds of formula II where X is bromo or chloro 
and R' is hydrogen are the 
1,6-dihydro-2-[2-(di-lower-alkylamino)ethenyl]-6-oxo-3-pyridinecarbonitril 
es having the formula III 
##STR5## 
and acid-addition salts thereof, where R.sub.2 and R.sub.3 are each 
lower-alkyl. 
The reaction of hydrogen bromide or hydrogen chloride with 
1,6-dihydro-2-[2-(di-lower-alkylamino)-ethenyl]-6-oxo-3-pyridinecarbonitri 
le of formula III produces 5-bromo(or 
chloro)-7-R'-1,6-naphthyridin-2(1H)-one of formula II above where X is 
bromo or chloro and R' is hydrogen. 
The intermediate for the preparation of the compounds of formula II where X 
is bromo or chloro and R' is methyl is 
2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile of 
the formula IIIa 
##STR6## 
or acid-addition salt thereof, and R.sub.2 and R.sub.3 are each 
lower-alkyl. 
The reaction of 6-methoxy-2-methyl-3-pyridinecarbonitrile with 
N,N-(di-lower-alkyl)acetamide dimethyl acetal produces 
2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile of 
formula IIIa and the reaction of the compound of formula IIIa with 
hydrogen bromide or hydrogen chloride followed by alkaline hydrolysis of 
the resulting 5-(bromo or chloro)-2-methoxy-7-methyl-1,6-naphthyridine 
produces 5-(bromo or chloro)-7-methyl-1,6-naphthyridin-2(1H)-one of 
formula II where R' is methyl 
The reaction of 5-bromo(or chloro)-7-R'-1,6-naphthyridin-2(1H)-one with 
1H-(5-membered-N-aromatic)-heteryl compound having the formula IV 
##STR7## 
where Y, Z, R', R.sub.1 and R are defined as in formula I, produces the 
5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-7-R'-1,6-naphthyridin-2(1H)-on 
e of formula I. 
The reaction of 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile with 
bis(di-lower-alkylamino)-t-butoxymethane of formula V 
EQU (R.sub.2 R.sub.2 N).sub.2 CHOC(CH.sub.3).sub.3 V 
produces 
1,6-dihydro-2-[2-(di-lower-alkylamino)-ethenyl]-6-oxo-3-pyridinecarbonitri 
le of formula III. 
The reaction of 5-bromo(or chloro)-7-R'-1,6-naphthyridin-2(1H)-one (formula 
II where X is Br or Cl and R' is hydrogen or methyl) with hydrazine 
hydrate produces the corresponding 
5-hydrazino-7-R'-1,6-naphthyridin-2(1H)-one (formula II where X is 
hydrazino and R' is hydrogen or methyl). 
The reaction of 5-hydrazino-7-R'-1,6-naphthyridin-2(1H)-one (formula II 
where X is hydrazino and R' is hydrogen or methyl) with 
1,1,3,3-tetramethoxypropane produces 
5-(1H-pyrazol-1-yl)-7-R'-1,6-naphthyridin-2(1H)-one of formula I where Y 
is N, Z is C--H, R' is hydrogen or methyl and R.sub.1 and R are each 
hydrogen. 
Preferred compounds having formula I are those where Y is CH when Z is N, 
R.sub.1 and R are each hydrogen or methyl and R' is hydrogen, or Y is N 
when Z is CH, R' is hydrogen and, R.sub.1 and R are each hydrogen, or Y 
and Z are each N when R', R.sub.1 and R are each hydrogen. 
The term "lower-alkyl" as used herein, e.g., one of the meanings for R or 
R.sub.1 in formula I, as C-(lower-alkyl) for one of the meanings of Z or Y 
in formula I, or as the meaning of R.sub.2 or R.sub.3 in formulas III, 
IIIa and IV means alkyl radicals having from 1 to 4 carbon atoms which can 
be arranged as straight or branched chains, illustrated by methyl, ethyl, 
n-propyl, isopropyl, n-butyl, sec.-butyl, tert.-butyl and isobutyl. 
The term "halo" as used herein, e.g., as one of the meanings for R or 
R.sub.1 in formula I or in C-halo as one of the meanings for Y or Z in 
formula I, preferably means bromo or chloro. 
The compounds of formulas I and II 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 inherently 
amounts to use of the base form. The acids which can be used to prepare 
the acid-addition salts of the compounds of formulas I and II include 
preferably those which produce, 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. 
Appropriate pharmaceutically acceptable salts within the scope of the 
invention are those derived from mineral acids such as hydrochloric acid, 
hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid; and 
organic acids such as lactic acid, acetic acid, citric acid, tartaric 
acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, 
p-toluenesulfonic acid, cyclohexylsulfamic acid, quinic acid, and the 
like, giving the hydrochloride, hydrobromide, sulfate, phosphate, 
sulfamate, lactate, acetate, citrate, tartrate, methanesulfonate, 
ethanesulfonate, benzenesulfonate, p-toluenesulfonate, cyclohexylsulfamate 
and quinate, respectively. 
The acid-addition salts of said basic compounds of formulas I and II 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 the 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 concentration of the solution. 
Although pharmaceutically acceptable salts of said basic compounds of 
formulas I and II are preferred, all acid-addition salts are within the 
scope of the invention. All acid-addition salts are useful as sources of 
the free base form even if the particular salt per se is desired only as 
an intermediate 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. 
Other pharmaceutically acceptable salts of said compound of formulas I and 
II are those cationic salts derived from strong inorganic or organic 
bases, e.g., sodium hydroxide, potassium hydroxide, monobasic or dibasic 
lower-alkylamines, tetra-(lower-alkyl)ammonium hydroxides. 
The molecular structures of the compounds of formulas I, II, III, IIIa and 
IV were assigned on the basis of evidence provided by infrared, 
ultraviolet, nuclear magnetic resonance and mass spectra, by the 
correspondence of calculated and found values for the elemental analyses, 
and by their method of preparation. 
The manner of making and using the instant invention will now be generally 
descibed so as to enable a person skilled in the art of pharmaceutical 
chemistry to make and use the same. 
The reaction of 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile with 
bis(di-lower-alkylamino)-t-butoxymethane to produce 
2-[2-(di-lower-alkylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitril 
e of formula III is carried out by heating the reactants at about 
100.degree. C. to 160.degree. C., preferably in a suitable aprotic 
solvent. The reaction is conveniently run by refluxing the reactants in 
dimethylformamide or dioxane (p-dioxane), preferably using 
bis(dimethylamino)-t-butoxymethane. 
The intermediate bis(di-lower-alkylamino)-t-butoxymethanes of formula V are 
known compounds or are prepared by conventional means. 
Alternatively, the compounds of formula III where the lower-alkyl groups 
R.sub.2 and R.sub.3 have from 2 to 4 carbon atoms are conveniently 
prepared by refluxing the compound of formula III where R.sub.2 and 
R.sub.3 are each methyl with an excess of the appropriate amine of the 
formula R.sub.2 R.sub.3 NH in methanol. 
The preparation of said intermediate 
1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile is shown in CibaGeigy AG 
German Patent Publication No. 2,256,288, published May 24, 1973. 
3-Aminocrotononitrile is reacted with 3-ethoxyacrylic acid chloride at 
-15.degree. C. to -10.degree. C. in a mixture of pyridine, tetrahydrofuran 
and dimethylformamide, and then the reaction mixture is treated with 
water. As shown hereinbelow, 
1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile was conveniently 
prepared by refluxing a mixture of 3-aminocrotrononitrile and methyl 
propiolate in dimethylformamide. 
The reaction of 6-methoxy-2-methyl-3-pyridinecarbonitrile with 
di-(lower-alkyl)acetamide dimethyl acetal to produce 
2-[2-(di-lower-alkylamino)-1-propenyl)]-6-methoxy-3-pyridinecarbonitrile 
of formula IIIa is carried out by heating the reactants in a suitable 
aprotic solvent, preferably dimethylformamide, at about 
120.degree.-140.degree. C., preferably using dimethylacetamide dimethyl 
acetal. 
The reaction of hydrogen bromide or hydrogen chloride with 
2-[2-(di-lower-alkylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridine-carbonitri 
le of formula III to produce 5-bromo(or chloro)-1,6-naphthyridin-2(1H)-one 
of formula II where X is bromo or chloro and R' is hydrogen is carried out 
by bubbling gaseous hydrogen bromide or hydrogen chloride into a chilled 
and stirred solution containing III in a suitable solvent, e.g., a mixture 
of chloroform and acetic acid, and then stirring the reaction mixture at 
room temperature. 
The reaction of hydrogen bromide or hydrogen chloride with 
2-[2-(di-lower-alkylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile of 
formula IIIa to produce 5-(bromo or 
chloro)-2-methoxy-7-methyl-1,6-naphthyridine is carried out as in the 
immediately preceding paragraph and then said 2-methoxy compound is 
treated with aqueous sodium or potassium hydroxide solution at room 
temperature to produce 5-(bromo or 
chloro)-7-methyl-1,6-naphthyridin-2(1H)-one of formula II where X is bromo 
or chloro and R' is methyl. 
The reaction of 5-bromo(or chloro)-7-R'-1,6-naphthyridin-2(1H)-one with a 
1H-(5-membered-N-aromatic)heteryl compound of formula IV to produce the 
5-[1H-(5-membered-N-aromatic-heteryl)-1-yl]-7-R'-1,6-naphthyridin-2(1H)-on 
e of formula I is carried out by heating the reactants at about 125.degree. 
C. to 225.degree. C., preferably about 140.degree. C. to 180.degree. C. in 
a suitable inert solvent in the presence or absence of an acid-acceptor. 
Illustrative solvents are dimethylformamide, N-methylpyrrolidinone, and 
illustrative acid-acceptors are anhydrous potassium carbonate, sodium 
methoxide, sodium hydride, and the like. The reaction is preferably run 
using N-methylpyrrolidin-one as solvent and using a two-to-four fold 
excess, preferably three fold excess, of 
1H-(5-membered-N-aromatic)-heteryl compound of formula IV per mole of 
5-bromo-7-R'-1,6-naphthyridin-2(1H)-one in the absence of an 
acid-acceptor. 
The intermediate 1H-(5-membered-N-aromatic)-heteryl compounds of formula IV 
are known compounds which are prepared by conventional means or are 
commercially available. 
The reaction of 5-hydrazino-7-R'-1,6-naphthyridin-2(1H)-one with 
1,1,3,3-tetramethoxypropane to produce 
5-(1H)-pyrazol-1-yl)-7-R'-1,6-naphthyridin-2(1H)-one is carried out by 
heating the reactants in a suitable solvent, e.g., ethylene glycol, at 
about 150.degree. C. to 200.degree. C., preferably about 160.degree. C. to 
180.degree. C. 
5-Hydrazino-7-R'-1,6-naphthyridin-2(1H)-one is conveniently formed by 
heating 5-bromo(or chloro)-7-R'-1,6-naphthyridin-2(1H)-one with hydrazine 
hydrate.

The following examples will further illustrate the invention without, 
however, limiting it thereto. 
1. 
2-[2-(Dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile--To 
a stirred mixture containing 6.7 g of 
1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile in 100 ml of 
dimethylformamide was quickly added 11.5 ml of 
bis(dimethylamino)-t-butoxymethane and the reaction mixture was heated 
with stirring for 3 hours at 110.degree. C. After a tlc analysis had shown 
some of the starting material still present, another 2.3 ml of 
bis-(dimethylamino)-t-butoxymethane was added, the reaction mixture was 
heated with stirring to reflux for 90 minutes, and then allowed to cool to 
room temperature and stand overnight. The mixture was chilled and the 
separated product was collected, washed with chilled ethanol and dried in 
a vacuum oven at 90.degree. C. to yield 8.2 g of 
2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile, 
m.p. 298.degree.-300.degree. C. 
The above intermediate 1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile 
was prepared as follows: a mixture containing 85% 3-amino-2-butenenitrile 
and 8.4 g of methyl propiolate was heated on a steam bath for about 15 
minutes whereupon a vigorous exothermic reaction ensued. External heating 
was stopped until the reaction subsided. To the reaction mixture was added 
25 ml of dimethylformamide and the reaction mixture was refluxed for 8 
hours, allowed to cool to room temperature and then stand overnight. The 
separated solid was collected, washed with ethanol and dried in a vacuum 
oven at 90.degree. C. to yield 3.4 g of 
1,6-dihydro-2-methyl-6-oxo-3-pyridinecarbonitrile, m.p. &gt;300.degree. C. 
Acid-addition salts of 
2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile are 
conveniently prepared by adding to a mixture of 2 g of 
2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile in 
about 40 ml of methanol or ethanol the appropriate acid, e.g., 
methanesulfonic acid, concentrated sulfuric acid, concentrated phosphoric 
acid, to a pH of about 2 to 3, chilling the mixture after partial 
evaporation and collecting the precipitate, e.g., dimethanesulfonate, 
sulfate, phosphate, respectively. 
2. 2-[2-(Diethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile, 
m.p. 218.degree.-220.degree. C., was prepared by refluxing 
2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile with 
a 3 to 4 molar excess of diethylamine for about 70 hours; the reaction 
mixture was allowed to cool; and, the precipitated product was collected, 
recrystallized from isopropyl alcohol and dried in a vacuum oven at 
90.degree. C. 
Also, 2-[2-(diethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile 
can be prepared following the procedure described in Example 1 using a 
molar equivalent quantity of bis(diethylamino)-t-butoxymethane in place of 
bis(dimethylamino)-t-butoxymethane. 
3. 
2-[2-(Di-n-propylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile, 
m.p. 154.degree.-155.degree. C., was prepared as in Example 2 but using an 
excess of di-n-propylamine in place of diethylamine. 
4. 5-Bromo-1,6-naphthyridin-2(1H)-one--Hydrogen bromide was bubbled for 
about 25 minutes into a stirred suspension containing 9.5 g of 
2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile in 
400 ml of chloroform cooled in an ice bath. The reaction mixture was 
stirred in the ice bath for 1 hour, allowed to warm up to room temperature 
and stirred at room temperature overnight. A tlc analysis using 7:2:1 of 
diethyl ether:methanol:triethylamine showed only starting material and no 
final product. To the reaction mixture was added 150 ml of acetic acid and 
hydrogen bromide was bubbled into the reaction mixture at room temperature 
with stirring whereupon the reaction mixture turned a lighter yellow 
color. The reaction mixture was then stirred at room temperature overnight 
and then concentrated on a rotary evaporator to dryness. The residue was 
stirred in an ice bath with about 300 ml of 10% aqueous potassium 
carbonate. The solid was collected by filtering the mixture through a 
sintered glass funnel, washed with water and dried in a vacuum oven at 
50.degree. C. to yield 10.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, m.p. 
278.degree.-280.degree. C. 
In subsequent runs the reaction was run starting with a mixture of 
chloroform and acetic acid, illustrated as follows: Into a mixture 
containing 40 g of 
2-[2-(dimethylamino)ethenyl]-1,6-dihydro-6-oxo-3-pyridinecarbonitrile, 400 
ml of chloroform and 202 ml of acetic acid, the mixture chilled in an ice 
bath, was bubbled hydrogen bromide for 45 minutes whereupon the reaction 
mixture changed from dark yellow to off white. The reaction mixture was 
stirred in the ice bath for 15 minutes, allowed to warm up to room 
temperature and then stirred at room temperature over the weekend. The 
precipitate was collected, washed with chloroform and dried in vacuum oven 
at 60.degree. C. to yield 83 g of solid which contained some inorganic 
material. The solid was slurried in water along with the concentrate 
obtained by evaporating the mother liquor on a rotary evaporator and the 
mixture was stirred at room temperature. The solid was collected, washed 
with water and dried in a vacuum oven at 90.degree. C. to yield 41.2 g of 
5-bromo-1,6-naphthyridin-2(1H)-one, m.p. 272.degree.-274.degree. C. 
Acid-addition salts of 5-bromo-1,6-naphthyridin-2(1H)-one are conveniently 
prepared by adding to a mixture of 2 g of 
5-bromo-1,6-naphthyridin-2(1H)-one in about 40 ml of aqueous methanol the 
appropriate acid, e.g., methanesulfonic acid, concentrated sulfuric acid, 
concentrated phosphoric acid, to a pH of about 2-3, chilling the mixture 
after partial evaporation and collecting the precipitate, e.g., 
dimethanesulfonate, sulfate, phosphate respectively. Also, the 
acid-addition salt is conveniently prepared in aqueous solution by adding 
to water with stirring molar equivalent quantities of 
5-bromo-1,6-naphthyridin-2(1H)-one and the appropriate acid, e.g., lactic 
acid or hydrochloric acid, to prepare respectively the monolactate or 
monohydrochloride salt in aqueous solution. 
Cationic salts of 5-bromo-1,6-naphthyridin-2(1H)-one are conveniently 
prepared by reaction with an equivalent quantity of the appropriate base, 
e.g., sodium hydroxide, potassium hydroxide or tetramethylammonium 
hydroxide, to produce the corresponding respective sodium, potassium or 
tetramethylammonium salt. The salts are prepared in solution or in solid 
form by suspending equivalent quantities of 
5-bromo-1,6-naphthyridin-2(1H)-one and base in water or water-methanol to 
form the solution of salt or by evaporating the solvent from the solution 
to obtain the salt in solid form. 
5. 5-Chloro-1,6-naphthyridin-2(1H)-one--Following the procedure described 
in Example 4 using a molar equivalent quantity of hydrogen chloride in 
place of hydrogen bromide, it is contemplated that 
5-chloro-1,6-naphthyridin-2(1H)-one can be obtained. 
6. 5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)one--Io a solution containing 
15 g of imidazole dissolved in 200 ml of dimethylformamide was added with 
stirring 2.7 g of sodium hydride and the resulting mixture stirred at room 
temperature for 10 minutes. To the reaction mixture was then added 11.3 g 
of 5-bromo-1,6-naphthyridin-2(1H)-one and the reaction mixture was 
refluxed overnight. The reaction mixture was concentrated on a rotary 
evaporator to remove most of the solvent. To the concentrate was added 
water plus 7.5 ml of concentrated hydrochloric acid and the mixture 
allowed to stand at room temperature. The solid that separated was 
collected, washed successively with water and n-hexane, and dried in a 
vacuum oven at 90.degree. C. to yield 4.5 g of off-white powder. The 
powder was recrystallized from hot methanol, washed with methanol and 
dried in a vacuum oven at 90.degree. C. to yield 4.0 g of 
5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
291.degree.-292.degree. C. 
Acid-addition salts of 5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one are 
conveniently prepared by adding to a mixture of 2 g of 
5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one in about 40 ml of aqueous 
methanol the appropriate acid, e.g., methanesulfonic acid, concentrated 
sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, 
chilling the mixture after partial evaporation and collecting the 
precipitate, e.g., dimethanesulfonate, sulfate, phosphate, respectively. 
Also, the acid-addition salt is conveniently prepared in aqueous solution 
by adding to water with stirring molar equivalent quantities of 
5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one and the appropriate acid, 
e.g., lactic acid or hydrochloric acid, to prepare respectively the 
monolactate or monohydrochloride salt in aqueous solution. 
Cationic salts of 5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one are 
conveniently prepared by reaction with an equivalent quantity of the 
appropriate base, for example, sodium hydroxide, potassium hydroxide, 
ethylamine, trimethylamine or tetramethylammonium hydroxide, to form the 
corresponding respective sodium, potassium, ethylammonium, 
trimethylammonium or tetramethylammonium salt. The salts are prepared in 
solution or in solid form by suspending a equivalent quantities of said 
5-(1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one and base in water or 
water-methanol to form the solution of salt or by evaporating the solvent 
from the solution to obtain the salt in solid form. 
7. 5-(4-Methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A mixture 
containing 6.75 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 7.0 g of 
4-methyl-1H-imidazole and 100 ml of dimethylformamide was refluxed with 
stirring for 33 hours and then concentrated on a rotary evaporator. The 
residue was slurried in water, the mixture treated with a small quantity 
of acetic acid. The solid was collected, washed with water and dried in a 
vacuum oven at 90.degree. C. The solid was dissolved in boiling isopropyl 
alcohol, the hot solution treated with decolorizing charcoal and filtered. 
The hot filtrate was concentrated and cooled. The separated solid was 
collected, washed successively with isopropyl alcohol and ether and dried 
in a vacuum oven at 90.degree. C. to yield 1.9 g of product which was 
recrystallized a second time from isopropyl alcohol and dried under 
reduced pressure at 105.degree. C. to yield 1.1 g of 
5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1 H)-one as a compound 
with 2-propanol (4:1) and water (4:1), m.p. 257.degree.-259.degree. C. 
A 19.6 g portion of 
5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one as a compound 
with one-fourth mole each of isopropyl alcohol and water per mole of said 
compound was recrystallized from 1.3 liters of ethanol and the 
recrystallized solid was dried at 115.degree. C. in a drying pistol 
(Abderhalden) at &lt;1 mm pressure for two days. The resulting compound, 
weighing 15.1 g, contained one-fourth mole of ethanol per mol of said 
compound. This 15.1 g portion was recrystallized from about 2500 ml of 
water and dried at 125.degree. C. in a drying pistol at &lt;1 mm pressure for 
three days to produce 12.0 g of 
5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
263.degree.-264.degree. C. 
Acid-addition salts and cationic salts of 
5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one are prepared as 
in Example 6 following the procedures described therein. 
8. 5-(2-Methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A mixture 
containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 8 g of 
2-methyl-1H-imidazole, 25 ml of N-methylpyrrolidinone, 3.4 g of anhydrous 
potassium carbonate and 50 mg of copper powder was refluxed for 6 hours, 
allowed to cool to room temperature and then poured into 100 ml of water. 
The resulting solution was neutralized by adding acetic acid and the 
resulting solution was allowed to stand overnight at room temperature. The 
solid that separated was collected, recrystallized from dimethylformamide 
and dried in a vacuum oven at 90.degree.-95.degree. C. to yield 2.4 g of 
5-(2-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
&gt;310.degree. C. 
9. 5-(2-Methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A 
mixture containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 12.7 g of 
2-methyl-5-nitro-1H-imidazole, 3.45 g of anhydrous potassium carbonate and 
50 ml of N-methylpyrrolidinone was refluxed for 5.5 hours, cooled and 
concentrated in vacuo to remove most of the solvent. To the concentrate 
was added 100 ml of water and 10 ml of 35% aqueous sodium hydroxide; and, 
the mixture was treated with decolorizing charcoal and filtered. The 
filtrate was acidified with acetic acid and the precipitate was collected, 
washed with water, dried, recrystallized from dimethylformamide, and dried 
in a vacuum oven at 90.degree.-95.degree. C. to yield 4.5 g of 
5-(2-methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
&gt;300.degree. C. 
10. 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one--To a mixture containing 
5-hydrazino-1,6-naphthyridin-2(1H)-one monohydrochloride monohydrate 
suspended in 100 ml of methanol was added 1.35 g of sodium methoxide and 
the mixture stirred at room temperature for 20 minutes and then stripped 
to dryness in vacuo to produce 5-hydrazino-1,6-naphthyridin-2(1H)-one in 
free base form. To the residue was added 6.15 g of 
1,1,3,3-tetramethoxypropane and 25 ml of ethylene glycol; and, the 
resulting mixture was heated with stirring to about 170.degree. C., 
allowing the methanol boil off from the reaction mixture. The reaction 
mixture was allowed to stand at room temperature over the weekend and was 
then concentrated on a rotary evaporator. The residue was slurried in 
boiling methanol; and, the mixture was cooled and filtered. The solid was 
slurried in water, collected and dried in a vacuum oven at about 
90.degree. C. The solid was dissolved in boiling dimethylformamide, the 
hot solution treated with decolorizing charcoal and filtered, and, the 
filtrate allowed to cool. The separated product was collected, washed with 
methanol and dried in a vacuum oven at 90.degree. C. to yield 2.8 g of 
5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. &gt;300.degree. C. 
Acid-addition salts of 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one are 
conveniently prepared by adding to a mixture of 2 g of 
5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one in about 40 ml of aqueous 
methanol the appropriate acid, e.g., methanesulfonic acid, concentrated 
sulfuric acid, concentrated phosphoric acid, to a pH of about 2 to 3, 
chilling the mixture after partial evaporation and collecting the 
precipitate, e.g., dimethanesulfonate, sulfate, phosphate, respectively. 
Also, the acid-addition salt is conveniently prepared in aqueous solution 
by adding to water with stirring molar equivalent quantities of 
5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one and the appropriate acid, 
e.g., lactic acid or hydrochloric acid, to prepare respectively the 
monolactate or monohydrochloride salt in aqueous solution. 
Cationic salts of 5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one are 
conveniently prepared by reaction with an equivalent quantity of the 
appropriate base, for example, sodium hydroxide, potassium hydroxide or 
tetramethylammonium hydroxide, to form the corresponding respective 
sodium, potassium or tetramethylammonium salt. The salts are prepared in 
solution or in solid form by suspending a equivalent quantities of said 
5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one and base in water or 
water-methanol to form the solution of salt or by evaporating the solvent 
from the solution to obtain the salt in solid form. 
The above intermediate 5-hydrazino-1,6-naphthyridin-2(1H)-one as its 
monohydrochloride monohydrate was prepared as follows. A mixture 
containing 30 g of 5-bromo-1,6-naphthyridin-2(1H)-one and 20.2 ml of 
hydrazine hydrate was heated to reflux and then heated for an additional 2 
hours. The reaction mixture was concentrated on a rotary evaporator and 
the residue was slurried in concentrated hydrochloric acid. The solid was 
collected, washed with concentrated hydrochloric acid, dried in a vacuum 
oven at 75.degree. C. The solid was then slurried in water, collected by 
filtration, washed with water and dried in a vacuum oven at 90.degree. C. 
to yield 25.2 g of 5-hydrazino-1,6-naphthyridin-2(1H)-one 
monohydrochloride monohydrate, m.p. &gt;310.degree. C. with decomposition. 
11. 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin2(1H)-one--A mixture 
containing 5.6 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 100 ml of 
dimethylformamide and 6.9 g of 1,2,4-triazole was refluxed on an oil bath 
for 21 hours and then allowed to cool. The separated solid was collected, 
washed with ethanol and dried in a vacuum oven at 90.degree. C. to yield 
2.8 g of 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
&gt;300.degree. C. 
Acid-addition salts of 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one 
are conveniently prepared by adding to a mixture of 2 g of 
5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one in about 40 ml of 
aqueous methanol the appropriate acid, e.g., methanesulfonic acid, 
concentrated sulfuric acid, concentrated phosphoric acid, to a pH of about 
2 to 3, chilling the mixture after partial evaporation and collecting the 
precipitate, e.g., dimethanesulfonate, sulfate, phosphate, respectively. 
Also, the acid-addition salt is conveniently prepared in aqueous solution 
by adding to water with stirring molar equivalent quantities of 
5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one and the appropriate 
acid, e.g., lactic acid or hydrochloric acid, to prepare respectively the 
monolactate or monohydrochloride salt in aqueous solution. 
Cationic salts of 5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one are 
conveniently prepared by reaction with an equivalent quantity of the 
appropriate base, for example, sodium hydroxide, potassium hydroxide or 
tetramethylammonium hydroxide, to form the corresponding respective 
sodium, potassium or tetramethylammonium salt. The salts are prepared in 
solution or in solid form by suspending a equivalent quantities of said 
5-(1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one and base in water or 
water-methanol to form the solution of salt or by evaporating the solvent 
from the solution to obtain the salt in solid form. 
12. 5-(4,5-Dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A mixture 
containing 12.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 300 ml of 
dimethylformamide, 13.8 g of anhydrous potassium carbonate, 10.8 g of 
4,5-dimethylimidazole and 200 mg of cuprous bromide was refluxed with 
stirring for eight hours. About 20 ml of the solvent was distilled off 
using a water separator to remove any moisture from the reaction mixture. 
The remaining reaction mixture was concentrated on a rotary evaporator. 
The residue was dissolved in water, acidified with acetic acid and 
evaporated to dryness on a rotary evaporator. The residue was treated with 
50 ml of water and the brown solid was collected, washed with water, 
recrystallized from ethanol in the presence of decolorizing charcoal. The 
resulting pale yellow solid was dried at 80.degree.-85.degree. C. to yield 
6.4 g of 5-(4,5-dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
m.p. 256.degree.-258.degree. C. 
13. 5-(4-Phenyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A mixture 
containing 11.3 g of 5-bromo1,6-naphthyridin-2(1H)-one, 18 g of 
4-phenylimidazole and 500 ml of dimethylformamide was refluxed with 
stirring for ninety hours and the solvent then distilled off in vacuo. The 
gummy residue was slurried with a mixture of 250 ml of water and 250 ml of 
ether until no gum remained. The remaining solid was collected, washed 
successively with water and ethanol, and dried in vacuo at 85.degree. C. 
to yield 10.8 g of solid. This solid was suspended in 375 ml of boiling 
absolute ethanol and dissolved using a small amount of hot 
dimethylformamide. The solution was allowed to cool in a refrigerator 
overnight. The white solid was collected, washed with a small quantity of 
cold absolute ethanol and dried in vacuo at 90.degree. C. to yield 5.0 g 
of 5-(4-phenyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
263.degree.-265.degree. C. Another 1.9 g of product, m.p. 
263.degree.-265.degree. C., was obtained from the mother liquor. 
Following the procedure described in Example 4 but using in place of 
imidazole a corresponding molar equivalent quantity of the appropriate 
substituted 1Himidazole, it is contemplated that the compounds of Examples 
14-24 can be obtained. 
14. 5-(2,4-Dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
2,4-dimethyl-1H-imidazole. 
15. 5-(2,4,5-Trimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
2,4,5-trimethyl-1H-imidazole. 
16. 5-(4-Methyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4-methyl-5-nitro-1H-imidazole. 
17. 5-(2,4-Dimethyl-5-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 2,4-dimethyl-5-nitro1H-imidazole. 
18. 5-(2-Ethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
2-ethyl-1H-imidazole. 
19. 5-(2-Isopropyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
2-isopropyl-1H-imidazole. 
20. 5-(4-Ethyl-1H-imidazol-1-yl)-1,6-naphthyridin-(1H)-one, using 
4-ethyl-1H-imidazole. 
21. 5-(4,5-Diethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4,5-diethyl-1H-imidazole. 
22. 
5-(2-Methyl-4,5-di-n-propyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 2-methyl-4,5-di-n-propyl-1H-imidazole. 
23. 5-(4-Tert-butyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4-tert-butyl-1H-imidazole. 
24. 5-(4,5-Di-n-butyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4,5-di-n-butyl-1H-imidazole. 
Following the procedure described in Example 4 but using a molar equivalent 
quantity of the corresponding substituted-1-H-pyrazole in place of 
imidazole, it is contemplated that the compounds of Examples 25-32 can be 
obtained. 
25. 5-(3,4-Dimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3,4-dimethyl-1H-pyrazole 
26. 5-(3,5-Dimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3,5-dimethyl-1H-pyrazole. 
27. 5-(3-Methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-methyl-1H-pyrazole 
28. 5-(4-Methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2 (1H)-one, using 
4-methyl-1H-pyrazole. 
29. 5-(3,4,5-Trimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3,4,5-trimethyl-1H-pyrazole. 
30. 5-(4-Ethyl-3,5-dimethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 4-ethyl-3,5-dimethyl1H-pyrazole. 
31. 5-(3-n-Propyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-n-propyl-1H-pyrazole. 
32. 5-(3-Phenyl-1H-pyrazol-1-yl)-1,6-naphthyridin2(1H)-one, using 
3-phenyl-1H-pyrazole. 
Following the procedure described in Example 6 using a molar equivalent 
quantity of the appropriate substituted-1H-1,2,4-triazole in place of 
1H-imidazole, it is contemplated that the compounds of Examples 33-39 can 
be obtained. 
33. 5-(3,5-Dimethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 3,5-dimethyl-1H-1,2,4-triazole. 
34. 5-(5-Methyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
5-methyl-1H-1,2,4-triazole. 
35. 5-(3-Methyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-methyl-1H-1,2,4-triazole. 
36 5-(3-Phenyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-phenyl-1H-1,2,4-triazole. 
37. 5-(3-Ethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-ethyl-1H-1,2,4-triazole. 
38. 5-(3-n-Propyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-n-propyl-1H-1,2,4-triazole. 
39. 5-(3,5-Diethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)--one, 
using 3,5-diethyl-1H-1,2,4-triazole 
40. 5-(3-Methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one--A stirred 
mixture containing 13.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 18 ml of 
3-methyl-1Hpyrazole and 75 ml of N-methylpyrrolidinone was heated in an 
oil bath at 170.degree.-180.degree. C. for 18 hours, after which a tlc 
analysis indicated some remaining starting material. The temperature of 
the oil bath was raised to 200.degree. C.; and, the reaction mixture was 
heated for an additional 5 hours and then poured into water. The solid 
that separated was collected, dried and combined with 1.7 g of 
corresponding material obtained in another run starting with 2.25 g of 
5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids were 
recrystallized from dimethylformamide and dried in an oven for three days 
at 100.degree. C. to yield 6.6 g of 
5-(3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. &gt;300.degree. 
C. 
41. 5-(3-Methyl-1H-1,2,4-triazole-1-yl)-1,6-naphthyridin-2(1H)-one--A 
stirred mixture containing 13.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 
20 g of 3-methyl-1H-1,2,4-triazole and 75 ml of N-methylpyrrolidinone was 
heated in an oil bath at 170.degree.-180.degree. C. for 18 hours and then 
cooled to room temperature whereupon a tan solid crystallized out. The 
mixture was diluted by adding 125 ml of water and the separated solid was 
collected, washed with water, air-dried and combined with another 1.2 g 
sample of the same material obtained in another run starting with 2.25 g 
of 5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids were 
recrystallized from dimethylformamide and dried in an oven at 
95.degree.-100.degree. C. for three days to yield 6.1 g of 
5-(3-methyl-1H-1,2,4-triazole-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
&gt;300.degree. C. 
42. 5-[4-(Hydroxymethyl)-1H-imidazol-1-yl]-1,6-naphthyridin-2(1H)-one --A 
mixture containing 22.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 31.4 g of 
4-(hydroxymethyl)-1H-imidazole and 75 ml of N-methylpyrrolidinone was 
heated with stirring in an oil bath at 135.degree.-150.degree. C. for 38 
hours. The reaction mixture was cooled to room temperature, diluted with 
water and when no precipitate separated the dark solution was filtered The 
filtrate was concentrated in vacuo to yield a brown viscous oil which was 
further concentrated on a rotary evaporator to yield a brown semi-solid. 
Residual N-methylpyrrolidin-one was removed by heating the semi-solid 
residue under reduced pressure in an oil bath heated at 
120.degree.-130.degree. C. to yield 75.4 g of a semi-solid. To this 
material was added 50 ml of water and the mixture was allowed to stand at 
room temperature for two days whereupon some light orange product 
crystallized. This material was collected, washed with cold water and 
dried. This material was recrystallized several times from water and 
finally from methanol, and dried in an oven at 90.degree.-95.degree. C. to 
yield 4.5 g of 
5-[4-(hydroxymethyl)-1H-imidazol-1-yl]-1,6-naphthyridin-2(1H)-one, m.p. 
259.degree.-261.degree. C. 
43. 5-(4-Bromo-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A stirred 
mixture containing 11.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 16.6 g 
of 4-bromo-1H-imidazole and 100 ml of N-methylpyrrolidinone was heated in 
an oil bath at 135.degree.-140.degree. C. for 22 hours. The reaction 
mixture was cooled and diluted with 200 ml of water. The resulting 
precipitate was collected, washed with water, air-dried, combined with 1.5 
g of 5-(4-bromo-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one prepared in 
another run starting with 1.58 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 
recrystallized twice from dimethylformamide and dried in an Abderhalden 
drying pistol at 90.degree. for 22 hours, after which the sample still 
contained 0.2 mol of dimethylformamide per mol of product. The material 
was then dissolved in 100 ml of 5% aqueous sodium hydroxide solution, the 
solution filtered and the filtrate solidified with acetic acid. The 
cottony solid that crystallized out was collected, washed with distilled 
water and dried in an oven at 100.degree. C. over the weekend to produce 
10.3 g of 5-(4-bromo-1H-imidazol-1-yl)-1,6 -naphthyridin-2(1H)-one, m.p. 
278.degree.-280.degree. C. 
44. 
5-[(4-(Trifluoromethyl)-1H-imidazol-1-yl)]-1,6-naphthyridin-2(1H)-one--A s 
tirred mixture containing 2.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 4.1 
g of 4-(trifluoromethyl)-1H-imidazole, 4.15 g of potassium carbonate in 
100 ml of dimethylformamide was refluxed for 12 hours and then allowed to 
cool to room temperature. The insoluble inorganic material was filtered 
off and the filtrate was concentrated in vacuo to yield a brown gummy 
residue which was dissolved in 150 ml of acetonitrile, the solution 
treated with decolorizing charcoal and filtered, and then the filtrate 
concentrated to a volume of about 75 ml. The solution was chromatographed 
on silica gel using ether:methanol:triethylamine mixture (7:2:1) as the 
eluant to yield 1.1 g of the crude product. 
The above preparation was repeated but changing the heating period from 12 
hours to 39 hours and following the workup as above, 800 mg of the crude 
product was obtained. 
In a third run a mixture containing 3.5 g of 
5-bromo-1,6-naphthyridin-2(1H)-one, 8.5 g of 
4-(trifluoromethyl)-1H-imidazole, 8.7 g of potassium carbonate and 150 ml 
of dimethylformamide was refluxed with stirring for 29 hours and following 
a work-up procedure as described in the preceding paragraphs, 1.9 g of the 
crude product was obtained. The three fractions of product were combined, 
recrystallized three times from isopropyl alcohol and dried in an oven at 
100.degree. C. for two days to yield 1.95 g of 
5-[(4-trifluoromethyl)-1H-imidazol-1-yl)]-1,6-naphthyridin-2(1H)-one, m.p. 
216.degree.-218.degree. C. 
45. 2-2-(Dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile--A 
mixture containing 47.2 g of 6-methoxy-2-methyl-3-pyridinecarbonitrile, 
100 ml of dimethylacetamide dimethyl acetal and 100 ml of 
dimethylformamide was heated with stirring in an oil bath at 130.degree. 
C. for 1 hour and 45 minutes. The temperature of the oil bath was raised 
to 150.degree. C. and the methanol formed by the reaction was distilled 
off using a 12" distillation column (Vigreux) while continuing the heating 
at 150.degree. C. for 14 hours. The reaction mixture was concentrated, 50 
ml of ether was added to the concentrated solution whereupon the product 
crystallized out. The mixture was chilled and the crystalline solid 
collected. The solid was washed with cold ether, dried and recrystallized 
from ethyl acetate using decolorizing charcoal to yield 33.5 g of 
2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile, m.p. 
103.degree.-104.degree. C. 
The above intermediate 6-methoxy-2-methyl-3-pyridinecarbonitrile was 
prepared as follows. A 69 g portion of 
6-chloro-2-methyl-3-pyridinecarbonitrile was dissolved in 700 ml of warm 
methanol. To the solution was added with stirring 27 g of sodium methoxide 
whereupon an exothermic reaction ensued. After allowing the solution to 
cool, an additional 5 g of sodium methoxide was added and the mixture was 
refluxed for 15 minutes. The precipitated sodium chloride was filtered off 
and to the filtrate was added about 400 ml of ether, the ether solution 
treated with decolorizing charcoal and filtered. The filtrate was 
evaporated to dryness in vacuo to yield 64 g of 
6-methoxy-2-methyl-3-pyridinecarbonitrile, m.p. 80.degree.-80.5.degree. C. 
46. 5-Bromo-7-methyl-1,6-naphthyridin-2(1H)-one--Into a solution containing 
10.8 g of 
2-[2-(dimethylamino)-1-propenyl]-6-methoxy-3-pyridinecarbonitrile dissolve 
d in a mixture of 25 ml of acetic acid and 150 ml of chloroform cooled in 
an ice-ethanol bath was bubbled hydrogen bromide gas, keeping the reaction 
mixture below 20.degree. C. A solid separated and the mixture was stirred 
at ambient temperature for 2 hours. The solid 
(5-bromo-2-methoxy-7-methyl-1,7-naphthyridine) was collected, dried, 
suspended in 200 ml of water and neutralized by stirring with about 20 ml 
of 2N aqueous potassium hydroxide solution. The separated product was 
collected, dried and recrystallized from dimethylformamide to yield 9.0 g 
of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one, m.p. 
276.degree.-278.degree. C. 
47. 7-Methyl-5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A 
mixture containing 9.56 g of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one, 
8.2 g of 4-methyl-1H-imidazole and 22 ml of N-methylpyrrolidin-one was 
heated with stirring in an oil bath at 140.degree. C. for 20 hours. The 
reaction mixture containing some separated solid was diluted with about 
150 ml of water and the solid was collected, triturated with water, washed 
with ethanol and dried to give 6.0 g of 
7-methyl-5-(4-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
307.degree.-308.degree. C. 
48. 5-(4-Nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one--A stirred 
mixture containing 13.2 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 20.4 g of 
4-nitro-1H-imidazole and 50 ml of N-methylpyrrolidinone was heated for 
eight hours in an oil bath at 170.degree.-180.degree. C. The reaction 
mixture was cooled and diluted with 200 ml of water. The solid that 
separated was collected, washed with water and dried. The dried solid was 
dissolved in 350 ml of boiling dimethylformamide, the hot solution treated 
with decolorizing charcoal and filtered, and the filtrate concentrated on 
a rotary evaporator. The residue was recrystallized from 
dimethylformamide, dried in an oven at 90.degree.-95.degree. C. over the 
weekend to give 20.4 g of product containing some starting 
4-nitro-1H-imidazole. The mixture was treated with 400 ml of 5% aqueous 
potassium carbonate solution for thirty minutes and then filtered. The 
insoluble material was filtered off and washed with water. The washings 
and filtrate were combined and acidified with acetic acid. The solid that 
separated was collected, washed with water, air-dried and recrystallized 
from dimethylformamide to yield 6.8 g of 
5-(4-nitro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. 
298.degree.-300.degree. C. 
Following the procedure described in Example 43 but using in place of 
4-bromo-1H-imidazole a molar equivalent quantity of the corresponding 
appropriate substituted 1H-imidazole, it is contemplated that the 
following compounds of Examples 49-51 can be obtained. 
49. 5-(4-Chloro-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4-chloro-1H-imidazole. 
50. 5-(4-Chloro-5-methyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 4-chloro-5-methyl-1H-imidazole. 
51. 5-(2-Bromo-4,5-dimethyl-1H-imidazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 2-bromo-4,5-dimethyl-1H-imidazole. 
Following the procedure described in Example 40 but using in place of 
3-methyl-1H-pyrazole a molar equivalent quantity of the corresponding 
appropriate substituted 1H-pyrazole, it is contemplated that the compounds 
of Examples 52-55 can be obtained. 
52. 5-(4-Nitro-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4-nitro-1H-pyrazole. 
53. 5-(4-Chloro-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4-chloro-1H-pyrazole. 
54. 5-(4-Hydroxymethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
4-hydroxymethyl-1H-pyrazole. 
55. 5-(3-Trifluoromethyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-trifluoromethyl-1H-pyrazole. 
Following the procedure described in Example 41 but using in place of 
3-methyl-1H-1,2,4-triazole a molar equivalent quantity of the 
corresponding appropriate substituted-1H-1,2,4-triazole, it is 
contemplated that the compounds of Examples 56-60 can be obtained. 
56. 5-(3-Bromo-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-bromo-1H-1,2,4-triazole. 
57. 5-(3-Bromo-5-methyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 3-bromo-5-methyl-1H-1,2,4-triazole. 
58. 5-(5-Chloro-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
5-chloro-1H-1,2,4-triazole. 
59. 5-(3-Nitro-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, using 
3-nitro-1H-1,2,4-triazole. 
60. 5-(3-Trifluoromethyl-1H-1,2,4-triazol-1-yl)-1,6-naphthyridin-2(1H)-one, 
using 3-trifluoromethyl-1H-1,2,4-triazole. 
61. Following the procedure described in Example 10 but using in place of 
5-hydrazino-1,6-naphthyridin-2(1H)-one a molar equivalent quantity of 
5-hydrazino-7-methyl-1,6-naphthyridin-2(1H)-one, it is contemplated that 
7-methyl-5-(1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one can be obtained. 
The intermediate 5-hydrazino-7-methyl-1,6-naphthyridin-2(1H)-one can be 
prepared by the procedure described in Example 10 for preparing 
5-hydrazino-1,6-naphthyridin-2(1H)-one but using a molar equivalent 
quantity of 5-bromo-7-methyl-1,6-naphthyridin-2(1H)-one in place of 
5-bromo-1,6-naphthyridin-2(1H)-one. 
The usefulness of the compounds of formulas I and II as cardiotonic agents 
is demonstrated by their effectiveness in standard pharmacological test 
procedures, for example, in causing a significant increase in contractile 
force of the isolated cat or guinea pig atria and papillary muscle and/or 
in causing a significant increase in cardiac contractile force in the 
anesthetized dog with lower or minimal changes in heart rate and blood 
pressure. Detailed descriptions of these test procedures appear in U.S. 
Pat. No. 4,072,746, issued Feb. 7, 1978. 
Cardiotonic activity in said isolated cat or guinea pig atria and papillary 
muscle procedure, is indicated by a significant increase, that is, greater 
than 25% (cat) or 30% (g.pig) in papillary muscle force and a significant 
increase, that is, greater than 25% (cat) or 30% (g.pig) in right atrial 
force, with a lower percentage increase (about one-half or less than the 
percentage increase in right atrial force or papillary muscle force) in 
right atrial rate. Because of the lower control active tensions of guinea 
pig tissues, the percent change from control values of both rate and force 
responses is elevated slightly, i.e., 5%. Thus, whereas cardiotonic 
activity is ascertained with a papillary muscle force or right atrial 
force increase of 26% and greater in the cat test, corresponding activity 
in the guinea pig test is designated with a papillary muscle force (PMF) 
or right atrial force (RAF) increase of 31% or greater. Representative 
examples of the compounds of Formulas I and II were tested by said guinea 
pig atria and papillary muscle procedure with the following results: 
______________________________________ 
Dose % Change from Control 
Example .mu.g/ml 
RAF PMF 
______________________________________ 
6 3 70 55 
10 68 90 
30 142 96 
7 0.3 28 53 
1 49 66 
3 88 87 
8 10 39 34 
30 117 69 
100 221 100 
9 10 15 24 
30 16 43 
100 116 103 
10 10 38 43 
30 102 121 
100 168 203 
11 3 28 51 
10 31 76 
30 140 108 
12 3 7 13 
10 14 49 
30 50 92 
13 10 33 25 
30 24 34 
100 1* 36 
47 1 37 46 
3 46 48 
10 158 164 
42 1 -2 9 
3 8 48 
10 37 112 
44 10 35 30 
30 36 31 
100 101 69 
43 1 35 47 
3 43 71 
10 56 128 
41 1 29 36 
3 37 56 
10 67 124 
40 3 26 24 
10 89 64 
30 84 97 
4 3 57 73 
10 49 85 
30 134 110 
48 10 18 37 
30 42 71 
100 170 107 
46 1 41 44 
3 92 67 
10 59 114 
______________________________________ 
*Precipitated in bath. 
When tested by said anesthetized dog procedure, the said cardiotonically 
active compounds of formulas I and II at doses of from about 0.030 to 3.0 
mg/kg administered intravenously are found to cause significant increases, 
that is, 25% or greater, in cardiac contractile force or cardiac 
contractility with lower changes in heart rate and blood pressure. 
Representative examples of the invention were tested by this procedure and 
found to cause increases in contractile force as follows: 
______________________________________ 
Dose % Increase In 
Example mg/kg Contractile Force 
______________________________________ 
4 0.100 135 
7 0.030 34 
0.100 96 
0.300 124 
12 1.00 54 
3.00 136 
13 1.00 40 
3.00 87 
47 0.100 71 
0.300 125 
1.00 183 
______________________________________ 
The present invention includes within its scope a cardiotonic composition 
for increasing cardiac contractility, said composition comprising a 
pharmaceutically acceptable carrier and, as the active component thereof, 
the compound of formula I or II or pharmaceutically acceptable 
acid-addition or cationic 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 a 
cardiotonically effective amount of said cardiotonically active compound 
of formula I or II. In clinical practice said compound will normally be 
administered orally or parenterally in a wide variety of dosage forms. 
Solid compositions for oral administration include compressed tablets, 
pills, powders 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 carbonate, 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 commonly used in the art, such as water and 
liquid paraffin. Besides inert diluents such compositions may also contain 
adjuvants, such as wetting and suspending agents, and sweetening, 
flavoring, perfuming and preserving agents. According to the invention, 
the compounds for oral administration also include capsules of absorbable 
material, such as gelatin, containing said active component with or 
without the addition of diluents or excipients. 
Preparations according to the invention for parenteral administration 
include sterile aqueous, aqueous-organic, and organic solutions, 
suspensions and emulsions. Examples of organic solvents or suspending 
media are propylene glycol, polyethylene glycol, vegetable oils such as 
olive oil and injectable organic esters such as ethyl oleate. These 
compositions can also contain adjuvants such as stablilizing, preserving, 
wetting, emulsifying and dispersing agents. 
They can be sterilized, for example by filtration through a 
bacterial-retaining filter, by incorporation of sterilizing agents in the 
compositions, by irradiation or by heating. They can also be manufactured 
in the form of sterile solid compositions which can be dissolved in 
sterile water or some other sterile injectable medium immediately before 
use. 
The percentage of active component in the said composition and method for 
increasing cardiac contractility can be varied so that a suitable dosage 
is obtained. The dosage administered to a particular patient is variable, 
depending upon the clinician's judgement using as the criteria: the route 
of administration, 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.