Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
This invelltion rela-tes to the preparation of 3-amino-5-
(pyridinyl)-2~ 1)-pyridillolles, which are cardiotonics.
Lesher ancl Opallca United States Patents 4,004,012, issued
January 18, 1977, and 4,n72,746, issued February 7, 1978, show as cardio-
tonic agents 3-amino-5-(pyridinyl)-2(111)-pyridinones and their preparation
from the correspolldillg 3-carbamyl compounds. Said 3-carbamyl-5-~pyridinyl)-
2~1~1)-pyridinones, alternatively named 1,2-dihydro-2-oxo-5-(pyridinyl)-
nicotinamides, were shown only as intermediates.
The present invention provides the process which comprises
reacting N-hydroxy-l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide with
polyphosphoric acid to produce l-Rl-3-amino-5-PY-6-R-2~1~l)-pyridinone,
where R is hydrogen or lower-alkyl, Rl is hydrogen, lower-alkyl or (C2-C6)-
hydroxyalkyl having its hydroxyl group and its connecting linkage on dif-
Eerent carbon atoms, and PY is 4- or 3-pyridinyl or 4- or 3-pyridinyl
having one or two lower-alkyl substituents.
The invention also provides the process which comprises
reacting l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile with hydroxylamine
to produce N-hydroxy-l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide and
reacting said N-hydroxy nicotinimidamide with polyphosphoric acid to
produce 1-Rl-3-amino-5-PY-6-R-2(111)-pyridinone, where R is hydrogen or
lower-alkyl, Rl is hydrogen, lower-alkyl or lower-hydroxyalkyl, and PY is
4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl sub-
stituents.
Preferred embodiments are those where PY is 4- or 3-pyridinyl
and/or Rl is hydrogen and R is hydrogen~ methyl or ethyl.
The term "]ower-alkyl" as used herein, e.g., as one of the
meanings of R or Rl or as a substituent for PY in formula I, means an alkyl
radical 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,
-1- ~
and the like.
(C2-C6)-llydroxyalkyl radical havillg :its hydroxy group and
its free valence bond (or connectillg linkage) on diEferent carbon atoms,
is illustrated by 2-hydroxyethyl, 2-hyclroxypropyl, 3-hydroxypropyl, 2-
hydroxy-2-methylpropyl, 2-hydroxy-1,1-dimetllylethyl, 4-hydroxybutyl, 5-
hydroxypentyl, 6-hydroxyhexyl, and the like.
Illustrative c)f PY in formula I where PY is 4- or 3-pyridinyl
having 1 or 2 lower-alkyl substituents are the following: 2-methyl-4-
pyridinyl, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl, 2-methyl-3-
pyridinyl, 6-methyl-3-pyridinyl (alternatively named 2-methyl-5-pyridinyl),
2,3-dimethyl-4-pyridinyl, 2,6-dimethyl-4-pyridinyl, 2-ethyl-4-pyridinyl,
2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-pyridinyl,
2,6-diethyl-4-pyridinyl, 2,6-die-thyl-3-pyridinyl, 2,6-diisopropyl-4-
pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the like.
The molecular structures of the N-hydroxy-l-Rl-1,2-dihydro-2-
oxo-5-PY-6-R-nicotinimidamides were assigned on the basis of evidenced pro-
vided by infrared, nuclear magnetic resonance and mass spectra, and by the
correspondence of calculated and found values for the elemental analysis.
The manner of making and using the instant invention will now
be generally described so as to enable a person skilled in the art of
pharmaceutical chemistry to make and use the same, as follows.
The preparation of the intermediate l-Rl-1,2-dihydro-2-oxo-5-
PY-6-R-nico-tinonitriles where R is lower-alkyl are described in the next
three paragraphs. These intermediate nicotinonitriles are disclosed and
claimed as cardiotonics in copending application Serial No. 365,406 filed
November 25, 19~0.
The preparation of l-PY-2-(dimethylamino)ethenyl lower-alkyl
ketone by reacting PY-methyl lower-alkyl ketone with dimethylformamide di-
(lower-alkyl) acetal is carried out by mixing the reactants in the presence
or absence of a sui-table solvent. The reaction is convelliclltly run at room
temperature, i.e., about 20-25C., or by warming the reactants up to about
100C., preferably in an aprotic solvent, convenielltly hexamethylphosphor-
amide because of the method used to prepare the PY-methyl lower-alkyl
ketone, as noted below in Example A-l. Other suitable solvents include
tetrahydrofuran, dimethylformamide, acetonitrile, ether, benzene, dioxane,
and the like. Also, the reaction can be run without solvent, preferably
using an excess of dimethylformamide di-(lower-alkyl)acetal. ihis pro-
cedure is further illustrated hereinbelow in Examples A-l through A-ll.
The intermediate PY-methyl lower-alkyl ketones are generally
known compounds which are prepared by known methods [e.g., as given in
Rec. trav. chim 72, 522 (1953); United States Patent 3,133,077 (5-12-64);
Bull. Soc. Chim 1968, 4132; Chcm. Abstrs. 79, 8539h (1973); Chem. Abstrs.
81, 120,401a (1974) ; J. Org. Chem. 39, 3834 (1974); Chem. Abstrs. 87,
6594q (1977); J. Org. Chem. 43, 2286 (1978)].
The reaction of l-PY-2-(dimethylamino)ethenyl lower-alkyl
ketone with N-Rl-~-cyanoacetamide to produce l-Rl-1,2-dihydro-2-oxo-5-PY-
6-R-nicotinonitrile is carried out preferably by heating the reactants
in a suitable solvent in the presence of a basic condensing agent. The
reaction is conveniently run using an alkali lower-alkoxide, preferably
sodium methoxide or ethoxide, in dimethylformamide. In practicing the
invention, the reaction was carried out in refluxing dimethylformamide
using sodium methoxide. Alternatively, methanol and sodiwn methoxide or
ethanol and sodium ethoxide can be used as solvent and basic condensing
agent, respectively; however, a longer heating period is required. Other
basic condensing agents and solvents include sodium hydride, lithium
diethylamide, lithium diisopropylamide, and the like, in an aprotic solvent,
e.g., tetrahydrofuran, acetonitrile, ether, benzene, dioxane, and the
like. This procedure is further illustrated hereinbelow in Examples B-l
through B-15.
~ 3~~
The intermediate l-R1-1,2-dihydro-2-oxo-5-PY-6~R-
nicotinonitriles where R is hydrogen are known, e.g., IJnited
States Patents 4,004,012 and 4,072,746, noted hereinabove.
The reaction of l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-
nicotinonitriles with hydroxylamine to produce N-hydroxy-l-
Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide by heating
the reactants at about 50C. to 100C., preferably at about
60C. to 65C. and preferably in an appropriate solvent.
The reaction was conveniently run in refluxing methanol.
The reaction of N-hydroxy-l-Rl-1,2-dihydro-2-oxo-
5-PY-6-R-nicotinimidamide with polyphosphoric acid to
produce 1-~1-3-amino-5-PY-6-R-2(1H) -pyridinone was caxried
out by heating the reactants at about 50C. to 100C.,
preferably about 95C. to 100C.
The following examples will furtller illustrate
the invention without, however, limiting it thereto.
A. l-PY-2-(DIMETHYLAMINO)ETHENYL LOWER-ALKYL KETONES
-
A-l. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl
methyl ketone - A mixture containing 20 g. of (4-pyr.dinyl)-
me-thyl methyl ketone ~alternatively named 1-(4-pyridinyl)-2-
propanone~ and 30 cc. of hexamethylphosphoramide was diluted
with 65 ml. of dimethylformamide dimethyl acetal and the
resulting mixture was refluxed for 30 minutes. TLC analysis
showed a single spot, thereby indicating completion of the
reaction (in another run, the reaction appeared to be
complete after 30 minutes at room temperature). The reaction
mixture was evaporated under reduced pressure using a rotary
evaporator and a pressure of about 15 mm., thereby resulting
in a crystalline residue weiyhing 24 g. The residue was
purified by continuous chromatographic extraction on alumina
(about 150 g.) using chloroform (recycled by distillation
onto the alumina) as eluant. ~fter l and l/2 hours, the
extract was heated _ vacuo to remove the chloroform,
thereby leaving, as a light yellow crystalline material,
23~2 g. of 1-(4-pyridinyl)-2-~dimethylamino)ethenyl methyl
ketone~ alternatively named 4-dimethylamino-2-(4-pyridinyl)~
3-buten-2-one.
The above preparation can be carried out using in
place of hexamethylphosphoramide other solvents, e.g.,
dimethylformamide, ace-tonitrile or others noted above or in
the absence of a solvent; however, hexamethylphosphoramide
was conveniently used since (4 pyridinyl)methyl methyl
ketone was conveniently prepared as a mixture together with
hexamethylphosphoramide, as seen by the following prep-
aration: To a stirred solution containing 70 ml. of freshly
distilled diisopropylamine and 200 ml of tetrahydrofuran a~
0C. under nitrogen was added dropwise over 20 minutes 210
cc. of 2.4 M n-butyllithium in n-hexane and the reaction
mixture was stirred for about 35 minutes at about 0-5C. To
the cold solution was added dropwise over a period of 10
minutes 90 ml. of dry hexamethylphosphoramide (no temper-
ature change) and a resulting light yellow solu~ion was
stirred for 15 minutes. To the cold solution at 0C. was
added a solution of 50 ml. of 4-picoline in 150 ml. of dry
tetrahydrofuran over a 15 minute period and stirring was
continued fbr 30 minutes at 0C. Next, a mixture containing
50 ml. of dry ethyl acetate and 150 ml. of tetrahydrofuran
-- 5 --
was added over a 15 minute period (temperature rose from 0
~o about 6C.) and the resulting mixture was stirred for 20
minutes at 0C. The ice bath was then removed and stirring
continued for another 90 minutes whereupon the temperature
S of the reaction mixture rose to about 25C. The reaction
mixture was then cooled in an ice bath and to it was added
60 ml. of acetic acid over a period of about 90 minutes.
The tetrahydrofuran was distilled off using a rotary
evaporator in vacuo. The remaininy mixture was diluted with
, .
400 ml. of water and the aqueous mixture was extracted
successively with two 250 ml. portions of isopropyl acetate
and three 80 ml. portions of chloroform. The solvents were
distilled off under reduced pressure to yield about 137 g.
of a mixture consisting primarily of the desired product and
hexamethylphosphoramide. Another run using the same quan-
tities was carried out as above except after the addition of
60 ml. of glacial acetic a~id, the mixture was diluted with
only 200 ml. of water, the phases were separated, and the
aqueous phase was extracted with fi~e 100 ml. portions of
chloroform. The chloroform extract was washed with saline
solution and the chloroform was distilled off in vacuo. The
remaining mixture of the desired ketone and hexamethyl-
phosphoramide was combined with the above 137 g. of the same
mixt~re and the combined mixture was distilled under reduced
pressure to yield the following fractions: I. 63 g., b.p.
of 110-112C. at 4 mm.; II~ 59 g. of pale yellow oil, b.p.
113~115C. at 3 mm.; and, III. 69 g. of pale yel~ow oil,
b.p. 115-118C. at 2.5 mm. Examination of frac~ion III by
NMR showed it to consist of a 2:3 mixture by weight of (4-
pyridinyl)methyl methyl ketone and hexamethylphosphoramide.
Acid-additlon sal-ts of 1-(4-pyridinyl)-2-(di-
methylamino)ethenyl methyl ketonc are conveniently prepared
by adding to a mi~ture o~ 5 g. of 1-(4-pyridinyl)~2-(dimethyl-
amino)ethenyl methyl ketone in about 100 ml. of aqueous
methanol the app~opriate acid, e.g., methanesulfonic acid,
concentratcd sulfuric acid~ concentrated phosphoric acid, to
a pH of about 2 to 3, chilling the mixture after partial
evaporation and collecting the precipitated salt, 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 each of l-(4-pyridinyl)-2-(dimethylamino)ethenyl
methyl ketone and the appropriate acid, e.g., lactic acid or
hydrochloric acid, to prepaxe respectively the monolactate
or monohydrochloride salt in aqueous solution.
A-2. ~ 1~(4-Pyridinyl)-2-(dimethylamino)ethenyl
ethyl ketone - A mixture containing 87.5 g. of (4-pyri~
dinyl)methyl ethyl ketone [alternatively named l-(4-pyri-
dinyl)-2~butanone~ and 160 ml. of hexamethylphosphoramide
was diluted with 100 g. of dimethylformamide dimethyl acetal
and the resulting mixture was stirrPd under nitrogen at room
temperature for 45 minutes. The methanol formed by the
..
reaction was dis-tilled off in vacuo using a rotary evaporator
and the remaining material was distilled under reduced
pressure to yield two fractions, one boiling at 45-80C. at
0.5 mm. and the second at 90-95C. at 0.5 mm. After TLC
analysis showed predominantly a single spot for ~ach frac-
tion, the two fractions were combined (135 g.) and ta];en up
in 600 ml. of chloroform. The resulting solution was
-- 7 --
washed with two 300 ml. portions of water and the water wa~
back extracted with three 100 ml. portions of chloroform.
The combined chloroform solution was dried over anhydrous
sodium sulfate and purified by continuous extraction chroma-
~ography on 300 ~1. of alumina using chloroform (recycled by
distillation onto the alumina) as the eluant. The chloro-
form was distilled off in vacuo to yield a red oil which
.
crystalli~ed on standing overnight in an ice bath. The
crystalline material was dissolved in carbon tetrachloride,
cyclohexane was added and the mixture cooled to yield 64 g.
of the resulting yellow crystalline product, l-(4-pyri-
dinyl)-2-(dimethylamino)ethenyl ethyl ketone. Another 11 g.
of crystalline pxoduct was obtained from the mother liquor
by continuous extract.ion chromatography on alumina using
chloroform (recycled by distillation onto the alumina) as
the eluant.
The above intermediate (~-pyridinyl)methyl ethyl
ketone was obtained in a mixture with hexamethylphosphor-
amide as follows: To a mixture containing 200 ml. of
tetrahydrofuran and 70 ml.of diisopropylamine under nitrogen
at 0-5C. was added 210 ml. of 2.4N n-butyllithium in n-
hexane and the resulting mixture was stirred for 30 minutes.
Next was added over a 10 minute period 90 ml. of hexamethyl-
phosphoramide followed by stirring of the mixture for 15
minutes. Then was added over a 15 minute period a solu~ion
of 48 ml. of 4-picoline in 150 ml. of tetrahydrofuran
followed by stirring for 30 minutes at about 0C. The
ice/acetone bath cooling the reaction mixture wa~ replaced
with a dry ice/acetone bath and to the reaction mixture was
added over a 20 minute period a mixture of 75 ml. of ethyl
,
.. . . . . .. . . . . . . . . .
~ 3~ c~
propionate in an equal volume of ~etrahydrofuran. The
reaction mixture was then allowed to warm up to room temper-
at~ er a p~riod of about n9 minutes and then was warmed
at abou~ 35C. for 30 minutes. The mi~ture was next cooled
in an ice/acetone bath and to it was added 60 ml. of glacial
acetic acid over 30 minutes. The resulting pale y~llow
suspension was diluted with 200 ml. of water. The mixture
was extracted with three 150 ml. portions of ethyl acetate
and the ethyl aceta~e extract was back washed with saline
solution. The extract was heated ln vacuo to remove the
ethyl acetate and the residue was taken up again with ethyl
acetate. The solution was washed with water and then heated
in vacuo to remove the ethyl acetate followed by heating the
residue in vacuo at 50C. for about 30 minutes to yield 100
g. of pale yellow oil. The pale yellow oil was cQmbined
with corresponding samples obtained from two additional runs
and then distilled in vacuo to yield a 256 g. fraction, b.p.
85-105C. at 0.5-1.0 mm. The NMR oE this fraction showed it
to be a mixture of (4-pyridinyl~methyl ethyl ketone and
hexamethylphosphoramide in a respective molar ra~io of
1:1.55, that is, 35~ or .35 x 256 = 90 g. of said ke~one.
_ 9 _
~-3. 1-(4-Pyridinyl)-2-(dimethylamlno)ethenyl
., " , _ _
n-propyl ketone - A mixture containing 80 g. of (4~pyri-
dinyl)methyl n-propyl ketone [~lternatively named l-(4-pyri-
dinyl)-2-pentanone] and 46 cc. of hexameth~lphosphoramide
was diluted with 250 ml. or acetonitrile. To the mixture
was added 90 ml. of dimethylformamide dimethyl acetal and
the resulting reaction mixture was heated on a steam bath
for ninety minutes and then distilled under vacuum at about
2 mm~ to remove volatile materials, including methanol,
acetonitrile and hexamethylphosphoramide. The remaining
residue was diluted with ethyl acetate and washed with
water. The combined water washings were extracted with five
150 cc. portions of ethyl acetate. The combined ethyl
acetate solu~ions were washed with saline solution, dried
over anhydrous sodium sulfate, filtered and evaporated to
dr~ness. The residue crystallized while standing in a
freezer. The crystalline product was slurried with cyclo-
hexane, filtered and dried overnight at 30C. to produce, as
a yellow crystalline product, 97 g. o~ 1-(4-pyridinyl)-2-
(d~methylamino)ethenyl n-propyl ketone, m.p. 48-50C.
The above intermediate (4-pyridinyl)methyl n-
propyl ketone was obtained in a mixture with hexamethyl-
phosphoramide as follows: To a stirred solution of 70 ml~
of diisopropylamine in 200 ml. of tetrahydrofuran under
nitrogen at about O~C. (use of ice bath) was added 210 cc.
of 2.4N n-butyllithium over twenty mlnutes and the resulting
, .
-- 10 --
~-~p~p'~
mi~ure was stirred for 30 minutes at about 0C. to the
mixture was ~dded with stirring over ten minu~es 90 ml. of
hexamethylphosphoramide and the resulting mixture was
s~irred for another ten minutes. Next 45 ml. of 4-picoline
in 140 ml. of tetrahydrofuran was added dropwise over
fifteen to twenty minutes. The resulting dark orange-brown
solution was stirred at 0C. for thirty minutes and then
treated dropwise over an eighteen minute period a solution
consisting of 68 ml. of ethyl butyrate in 68 ml. of tetra-
hydrofuran, the temperature rising from -8C. to +8 to 10C.
The reaction mixture was removed from the ice bath and
allowed to warm up to room temperature for over seventy-five
minutes. The reaction mixture was re-cooled and to it was
added dropwise over fifteen minutes 60 ml. of glacial acetic
acid. A ~ale yellow solid separated, resulting in a suspension.
The suspension was diluted with water and extracted with two
200 ml. portions of ethyl acetate. The ethyl acetate
extract was washed with three 100 ml. portions of saline
solution, dried over anhydrous sodium sulfate and evaporated
in vacuo to yield 107 g. of a mixture consisting primarily
of (4-pyrldinyl)methyl n-propyl ketone and hexamethylphos
phoramide. The mixture obtained in this run was combined
wi~h corresponding mixtures obtained in two other runs and
the combined mixtures were distilled under vacuum to produce r
as the major fraction, b.p. 80-90C. at 0.2 mm., a mixture
conslsting of 80 g. of (4-pyridinyl~methyI n-propyl ketone
and 46 g. of hexamethylphosphoramide.
- 11 -
Following the procedure de~cribed in Example A-2
but using a molar equivalent quantity of the appropriate PY-
methyl lower alkyl ketone in place of (4-pyridinyl)methyl
ethyl ketone, it is contemplated that the corresponding 1-
PY-2-(dimethylamino)ethenyl lower-alkyl ketones of Examples
A-4 ~hru A-ll can be obtained.
A-4. 1-(3-Pyridinyl)-2~(dimethylamino)ethenyl
methyl ketone using (3-pyridinyl)methyl methyl ketone.
A-5. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl
isopropyl ketone using (4-pyridinyl)methyl isopropyl ketone.
A-6. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-
hutyl ketone using (4-pyridinyl)methyl n-butyl ketone.
A-7. 1-(4-Pyridinyl)-2~(dimethylamino)ethenyl
isobutyl ketone using (4-pyridinyl)rnethyl isobu-tyl ketone.
A-8. l-(4-Pyridinyl)-2-(dimethylamino)ethenyl
tert-butyl ketone using (4-pyridinyl)methyl tert.-butyl
ketone.
A-9. 1-(4-Pyridinyl)-2-(dimethylamino)ethenyl n-
pentyl ketone using (4-pyridinyl)methyl n-pentyl ketone.
A-10. 1-(2-Methyl-4-pyridinyl)-2-(dimethylamino)-
ethenyl ethyl ketone using ~2-methyl-4-pyridinyl)methyl
ethyl ketone~
A-ll. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl
ethyl ketone using (3-pyridinyl)methyl ethyl ketone.
B. l-R -1,2-DI~YDRO-6-(LOWER-ALKYL)-2-OX0-5-PY-NICOTINO-
NITRIL~S
-
B-l. 1,2-UihYdro-6-me'hy~-2-oxo-5-(4-pyri-
_ _ _ _ _ _
dinyl)nicotinonitrile, al-ternatively named 1,6-dihydro-2-
methyl-6-oxo-[3,4'-bipyridine]-5-carbonitrile - To a mixture
- 12 -
3 /~df.~ ;~
containing 23 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl
methyl ketone and 11 g. of ~-cyanoacetamide dissolved in 400
ml. of dimethylformamide was added with stirring 1~ g. of
sodium methoxide and the resulting reaction mixture was
heated in an oil bath under gentle reflux for one hour. TLC
analysis showed no starting material in the reaction mixture
which was then concentrated in vacuo on a rotary evaporator
to a volume of about 80 ml. The concentrate was treated
with abou~ lS0 ml. of acetonitrile and the resulting mixture
10 ~as ~tir~ed on a rotary evaporator with warming until
homogenuous and then cooled. The crystalline product was
collec~ed, rinsed successively with acetonitrile and ether,
and dried overnight at 55Co to yield 28 g. of tan crys-
~alline product, namely, sodium salt of 1,2-dihydro-6-
15 methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, the presence of
cyano ~eing confirmed by IR analysis. An 8 g. portion of
said sodium salt was dissolved in 75 ml. of hot water, the
aqueous solution treated with decolorizing charcoal fil-
~ered, ~he filtrate again treated with decolorizing charcoal
20 and filtexed, and the filtrate acidified with 6N-hydro-
chloric acid by dropwise addition to a pEI of 3~ The acidic
mixture was diluted with ethanol and cooled. The crys-
talline product was collected, dried, recrystallized from
dimethylformamide-water and dried to produce 3.75 g. of 1,2-
25 dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile, m.p.,
>300C.
Acid-addition salts of 1,2-dihydro-6-methyl-2-oxo~
5-(4-pyridinyl)nicotinonitrile-are conveniently prepared by
- 13 -
adding to a mixture of 2 g. oE 1,2-dihydro-6-1nct}ly]-2-oxo-5-(~-
pyridinyl)nico-tinonitrile in abou-t 40 m]. oE aqueous methanol the
appropriate acid, e.g., methanesulfollic acid, concentrated sul-
furic acid, concentrated phosphoric acid, to a p~l of about 2 to 3,
chilling the mixture after partial evaporation and collecting the
precipitated salt, e.g., dimethanesulfonate, sulfate, phosphate,
respectively. Also, the acid-addition salt is conveniently pre-
pared in aqueous solution by adding to water with stirring molar
equivalent qucmtities each of 1,2-dihydro-6-methyl-2-oxo-5-~4-
pyridinyl)nicotinonitrile and the appropriate acid, e.g., lclctic
acid or hydrochloric acid, to prepare respectively the monolactate
or monohydrochloride salt in aqueous solution.
B-2. 6-Ethyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotino-
nitrile, alternatively named 2-ethyl-1,6-dihydro-6-oxo- [3,4'-bipyri-
dine]-5-carbonitrile, m.p. 300 C., 11.6 g., was prepared following
the procedure described above in Example B-l using 20 g. of 1-(4-
pyridinyl)-2-(dimethylamino)ethenyl ethyl ketone, 8.4 g. of c~-cyano-
acetamide, 16.2 g. of sodium methoxide and 250 ml. of dimethyl-
acetamide (as solvent in place of dimethylformamide).
B-3. 1,2-Dihydro-2-oxo-6-n-propyl-5-(4-pyridinyl)-
nicotinonitrile, alternatively named 1,6-dihydro-6-oxo-2-n-propyl-
[3,4'-bipyridine]-5-carbonitrile, m.p. 232-234 C., 9.9 g., was pre-
pared following the procedure described above in Example B-l using
85 g. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl n-propyl ketone,
36.5 g. of cl-cyanoacetamide, 50 g. o-f sodium methoxide and 800 ml.
of dimethylacetamide.
- 14 -
3~PJ(~
-
B-4 1,2-Dihydro-1,6-dimeth~1-2-oxo-5-(4-~yrl-
dinyl)nicotinonitrile, alternatively named 1,6 dlhydro-1,2-
dimethyl-6-oxo-(3,4'-bipyridine)-5-carbonitrile, m.p. 245-
248~C~, 32.3 g. , was prepared following the procedure
described above in Example B-l using 42.5 g. of 1-(4-pyri-
dinyl)-2-(dimethylamino)ethenyl methyl ketone, 23.5 g. of N
methyl-~-cyanoacetamide, 6.7 g. of sodium methoxide, 400 ml.
of methanol and a refluxing period of two hours.
Following the procedure described in Example B-2
but ~sing a molar equivalent quantity of the appropriate 1-
PY-2-~dimethylamino)ethenyl lower-alkyl ketone in place of
1-(4-pyridinyl)-2-(dimethylamino)ethenyl ethyl ke~one and
the appropriate N-Rl-~-cyanoacetamide, it is contemplated
that the corresponding l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-
nicotinonitriles of Examples B-5 thru B-15 can be obtained.
B-5. 1,2-Dihydro-6-methyl-2-oxo-5-(3-pyridinyl?-
nicotinonitrile, using l-(3-pyridinyl)-2-(dimethylamino)ethenyl
methyl ketone and ~-cyanoacetamide.
B-6. 1,2-Dihydro-6-isopropyl-2-oxo-5-(4-pyri-
dinyl)nicotinon trile, using 1-t4-pyridinyl)-2-(dimethyl-
amino)ethenyl isopropyl ketone and q-cyanoacetamide.
B-7. 6-n-Butyl-1,2-dihydro-2-oxo-$-(4-pyri-
. .
dinyl?nicotinonit_ile, using 1-(4-pyridinyl~-2-(dimethyl-
amino)ethenyl n-butyl ketone and ¢-cyanoacetamide.
B-8. 1,2-Dihydro-6-isobutyl-2-oxo-5-(4-pyri-
dinyl)nicotinonitrile, using l-(4-pyridinyl)-2-(dimethyl-
amino)ethenyl isobutyl ketone and ~-cyanoacetamide.
B-9. 1,2-Dihydro-2-oxo-5-(4-pyridlnyl)-6-tert.-
utylnicotinonitrile, using 1-(4-pyridinyl)-2-(dimethyi-
amino)ethenyl tert.-butyl ketone and ~-cyanoacetamide.
- 15 -
;P L~ C~
~-10. 1,2-Dihyclro-2-oYo-6-n pentyl-5-t4-pyri-
dinyl)nicotinonitrile, using 1-(4-pyridinyl)-2-(dimethyl-
amino)ethenyl n-pentyl ketone and ~-cyanoacetamide.
~-11. 6-E~hyl-1,2 dihydro-S-(2~methyl-4-pyri-
dinyl)-2-oxonicotinonitrile, using 1-(2-methyl-4-pyridinyl)-
2-(dime~hylamino)ethenyl ethyl ketone and d-cyanoacetamide.
B-12. 6-~thyl-1,2-dihydro-2-oxo-5-(3-pyri-
dinyl)nicotinonitrile, using 1-(3-pyridinyl)-2-(dimethyl
a~ino~ethenyl ethyl ketone and a-cyanoacetamide.
~-13. 6-Ethyl-1,2-dihydro-1=(2-hvdroxyethyl)-2-
oxo-5-~4-pyridinyl)nicotinonitrile, using 1-(4-pyridinyl)~2-
~dimethylamino)ethenyl ethyl ketone and N-(2-hydroxyethyl)-
o~cyano~cetamide.
B-14. 1-Ethyl-1,2-dihydro-6-methyl-2-oxo-5-(4=
pyridinyl)nicotinonitrile, using 1-(4-pyridinyl)-2-dimethyl-
a~jnolethenyl methyl ketone and N-ethyl-~-cyanoacetamide.
B-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5-(4-pyri-
dinyl)nicotinonitrile, using 1-(4~pyridinyl)-2-(dimethyl-
amlno~ethenyl ethyl ketone and N-ethyl-d-cyanoacetamide.
C. N-~YDROXY-l-Rl-1,2-DIHYDRO~2-OXO-5-PY-6-R-NICO'rIN-
IMID~SID~S
C-l. N-HyDRoxy-l~2-DIHyDRo-2-oxo-5-(4~pyRI-
DINYL~NICOTINIMIDAMIDE, alternatively named N-hydroxy-1,6-
dihydro-6-oxo-[3,4'-bipyridin]-5-carboximidamide - To a
solution containing 8.0 g. of sodium hydroxide dissolved in
500 ml. of absolute methanol was added with stirring 15.9 g.
of hydroxylamine hydrochloride. To the resulting stirred
mix~ure containing precipitated sodium chloride was added
- 19.7 g. of 1,2-dihydro-2-oxo-5-(4-pyridlnyl)nicotinonitrile
l ~ ..
- 16 -
and the resultin~ suspension was xefluxed with stirring on a
steam bath for forty-three hours. The resulting bright
yellow solld that separated was collected, washed with a
small quantity of fresh methanol and was ~hen triturated
t~ice with wa~er to remove sodium chloride. The remaining
product was dried in a vacuum oven at 90C. ~o yield 20.6 g.
of N-hydroxy-1,2-dihydro-2-oxo-5-t4-pyridinyl)nicotinimid-
amide m.p. 228C. with decomposition.
Acid-addition salts of N-hydroxy~1,2-dihydro-2-
oxo-5-(4-pyridinyl)nicotinimidamide are convenien~ly pre-
pared by adding ~o a mixture of 2 g. of N-hydroxy-1,2-
dihydro-2~oxo-5-(4-pyridinyl)nicotinimidamide in about 40
ml. of aqueous methanol the appropriate acid, e.g., methane-
sulfonic acid, concentrated sulphuric acid, concentra~ed
lS phosphoric acid, to a pH of about 2 to 3, chilling the
mixture after partial evaporation and collectin~ the pre-
cipitated salt, ~.g., dimethanesulfona~e, sulfate, phos-
phate, respectively. Also, the acid-addition sa~t is
conveniently prepared in aqueous solution by adding to water
with stirring molar equivalent quantities each of N-hydroxy-
1,2-dihydro-2-oxo-5-(4-pyridinyl)nicotinimidamide and the
appropriate acid, e.g., lactic acid or hydrochloric acid, to
prepare respectively the monolactate or monohydrochloride
salt in aqueous solution.
Following the procedure described in Example C-l
but using a molar equivalent quantity of the appropriate 1-
Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile in place of
1,2-dihydro-2 oxo-5-(4-pyridinyl)nicotinonitrile, it is
contemplated that the corresponding N-hydroxy-l--Rl-1,2-
dihydro-2-oxo-5-PY-6-R-nicotinimidamides of Examples C-2
thru C-13 can be obtained.
- 17 -
C-2. N-Hydroxy-1,2-dihydro-6-methyl-2-oxo-5-
.
(3-pyridinyl)nicotinimidamide, using 1,2-dihydro-6-methyl-2-
oxo-5-(3-pyridinyl)nicotinonitrile.
C-3. N-~lydroxy-1,2-dihydro-6-isopropyl-2-
oxo-5-(4-pyridinyl)nicotinimidamlde, using 1,2-dihydro-6-
isopropyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
C-4. N-6-n-butyl-1,2-dihydro-2-oxo-5-(4-pyri-
dinyljnicotinimidamide~ using 6-n-butyl-1,2-dihydro-2-oxo-S-
(~-pyridinyl)nicotinonitrile.
C-5. N-E~ydroxy-1,2-dihydro-6-isob~ltyl-2-oxo-
5-(4-pyridinyl)nicotinimidamide, using 1,2-dihydro-6-iso~
butyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
C-6. N-Hydroxy-1,2-dihydro-2-oxo-S-(4-pyri~
dinyl)-6-tert.-butylnicotinimidamide, using 1,2-dihydro-2-
oxo-5-(4 pyridinyl)-6-tert.-butylnicotinonitrileO
C-7. N-Hydroxy-1,2-dihydro-2-oxo-6-n-pentyl-
5-(4-pyridinyl)nicotinimidamide, using 1,2-dihydro-2 oxo-6-
n-pentyl-5-(4-pyridinyl)nicotinonitrile.
C-8. N-Hydroxy-6-ethyl-1,2-dihydro-5-(2-methyl-
4-pyridinyl)-2-oxonicotinimidamide, using 6~ethyl-1,2-
dihydro-5-(2-methyl-4-pyridinyl)-2-oxonicotinonitrile.
C-9. N-Hydroxv-6-ethyl-1,2-dihydro-2-oxo-5-
(3-~yridinyl)nicotinimidamide, using 6-ethyl-1,2-dihydro-2-
oxo-5-(3-pyridinyl)nicotinonitrile.
C-10. N-Hydroxy-6-ethyl-1,2-dihydro-1~(2-
hydroxyethyl)-2-oxo-5-(4-pyriclinyl)nicotinimidamide, using
6-ethyl-1,2-dihydro-1-(2-hydroxyethyl)-2-oxo-5-(4-pyri
dinyl)nicotinonitrile.
- 18 -
C~ll. N-~lydroxy-1,2-dihydro-6-methyl-2-o~o
5-(4-pyridinyl)nicotinimidamide, using 1,2-dihydro-6-methyl-
2-oxo-5-(~l-pyridinyl)nico~inonitrile.
C-12. ~-~lydro~y--1-ethyl-1,2-dihydro~6-methyl-2
o~o-5-(4-pyridinyl)nicotinimidamide, using 1-ethyl-1,2-
dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile.
C-13. N-Hvdroxy-1,6-diethyl-1,2-dihydro-2-
__ _ _.
oxo-5-(4-p~ridinyl)nicotinimidamide, using 1,6-diethyl-1,2-
dihydro-2-oxo-5-~4-pyridinyl)nicotinonitrile.
~- 1-Rl-3-~MINO-5-PY-6-R-2(lII)-PYRIDINO~lES
D-l. 3-Amino-5-(4-pyridinyl)-2(1II)pyridinone - A
mixture containing 2.0 g. of N-hydro~y-1,2-dihydro-2-oxo-5-
(4-pyridinyl)nicotinimidamide and 16 g. of polyphosphoric
acid was stirred with a glass rod until a stiff paste was
~tained. The mixture was then heated on a steam bath with
occasional stirring for 12 hours and then allowed to stand
at room temperature over the weekend. The reaction mixture
was warmed a little to soften the viscous mixture which was
then treated with about 100 ml. of water and mixed well to
dissolve the excess polyphosphoric acidO A yellow solid
material that separated was collected, suspended in fresh
water and to the suspension was added ammonium hydroxide
until the mixture was distinctly alkaline. The solid which
did not dissolve was collected, washed with a little water
and dried in a vacuum oven at 90C. to produce 0.9 g. of 3-
amino-5-(~ pyridinyl)-2(lII)pyridinone, m.p. 293-295~C. with
decomposi~ion. This product was identical with a sample of
amrinone, that is, 3-amino-5-(~-pyridinyl)-2(1~)pyridinone
which had been prepared from its corresponding 3-carbamyl
precursor as shown in U.S. Patent 4,072,746.
- 19 -
~ A ~
Following -the procedure described in Example D-l
but using a molar equivalent quantity of the appropriate N-
hydroxy-l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinimidamide in
place of N-hydroxy-1,2--dihydro-2-oxo-5-(4-pyridinyl)nico-
tinimidamide, it is contemplated that the corresponding 1-
-3-amino-PY-6-R-2(11l)-pyridinones of Examples D-2 thru D-
12 can be obtained.
D-2. 3-Amino-G-methyl-5-(3-pyridinyl)-2(lH)-
pyr~dinone, using N-hydroxy 1,2-dihydro-6-methyl-2-oxo-5-(3
pyridinyl~nicotinimidamide.
D-3. 3-Amino-6-isopropyl-5-(4-pyridinyl)-
2(1H)pyrldinone, using N-hydroxy-1,2-dihydro-6-isopropyl-2-
oxo-5-(4-pyridinyl)nicotinimidamide.
D-40 3--Amino-6-n-butyl-5-(4-pyridinyl)-
2(1~1)pyridinone, using N-hydroxy-6-n-butyl-1,2-dihydro-2-
--
oxo-5-54-pyridinyl)nicotinimidamlde.
D-5. 3-Amino-6-isobutyl-5-54-pyridinyl)-
2SlH)pyridinone, using N-hydroxy-1,2-dihydro-6-isobutyl-2-
o~o-5-(4-pyridinyllnicotinimidamide.
D-6. 3-Amino-5-(4-pyridinyl)-6-tert.-butyl-
2(1~pyridinone, using N-hydroxy-1,2-dihydro-2-oxo-5-(4-
pyridinyl)-6-tert.-butylnicotinimidamide.
D-7. 3-Amino-6-n-pentyl-5-(4-pyridinyl)-~(lH)~yri-
dinone, UsinCJ N-hydroxy-1,2-dihydro-2-oxo-6-n-pentyl-5-(4-
pyridinyl)nicotinimidamide.
D-8. 3-Amino-6-ethyl-5-(2-methyl-4-pyridinyl)-
2(1~)p~rldi_one, usincJ N-hydroxy-6-ethyl-1,2-dihydro-5-(2-
methyl-4-pyridinyl)-2-oxonicotinimidamide.
- 20 -
D-3. 3-Amino-6-ethyl-5-(3-pyridinyl)-2(1H)pyr1-
dinone, using N-hydroxy-6-ethyl-1,2-dihydro-2-oxo-5~(3-pyri-
dinyl)nicotinimidamide.
D-10. 3-Amino-6-ethy1-1-(2-hydroxyethyl)-5~
(4-pyridinyl)-2(1H)pyridinone, using N-hydroxy-6-ethyl.-1,2~
dihydro-1-(2-hydroxyethyl)-2-o~o-5-(4-pyridinyl)nicotinimid-
amide.
D-ll. 3- ino-1-ethyl-6-methyl-5-(4-pyri-
dinyl)-2(1~I)pyridinone, using N-hydroxy-l-ethyl-1,2-dihydro-
6-methyl-2-oxo-5-(4-pyridinyl)nicotinimidamide.
D-12. 3-Amino-1,6-diethyl-5-(4-pyridinyl)-
2(lH)pyridinone, using N-hydroxy-1,6-diethyl-1,2-dihydro-2-
o~o-5-(4-pyridinyl)nicotinimidamide.
The usefulness of the compounds of formula I or
salts thereof as cardiotonic agents is demonstrated by their
effectiveness in standard pharmacological test procedures,
for example, in causin~ a significant increase in contrac-
tile force in the Isolated Cat Atria and Papillary Muscle
Procedure and in causing a significant increase in cardiac
contractile force in the Anesthetized Dog Procedure with low
or minimal changes in heart rate and blood pressure.
Detailed descriptions of these test procedures appear in
U.S~ Patent 4,072,746, issued February 7, 1980.
, When tested by the above-noted Isolated Cat Atria
and Papillary ~usclc Procedure, the compounds of formula I
when tested at doses of 100 or 300 ,ug./ml., were found to
cause a significant increase, that is, greater than 25%, in
papillary muscle force and a significant increase, that is,
greater than 25%, in right atrial force, while causing a
- 21 -
lower percentage increase (about one-hal.f or less than the per-
eentage increase in right atrial force or papillary muscle
force) in right atrial rate; for example, N-hydroxy-1,2-dihydro-
2-oxo-5-(4~pyridinyl)nicotinimidamide (Example C-l), when tested
by said proceduxe was found to cause a 25~ increase in each of
papillary muscle force and right a~rial force at lOO ~g/ml and
48% and 43~ increases respectively in papillary muscle force and
right atrial force at 300 ~g/ml.
In cli~iOE~ practice the N-hydroxy-l-Rl-l,2-dihydro-
2-oxo-5-PY-6-R-nicotini~idamide (I) or pharmaceutically-
acceptable acid-addition or cationic salt thereof will normally
be administered orally or parenterally in a wide variety of dos-
~ge 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
admiY.ed with at least one inert diluent such as starch,
calcium carbonate, sucrose or lactose. These compositions
can also contain additional substances other than inert
diluents, e.g., lubrica-ting 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
~o~monly used in the art, such as water and liquid paraffin.
Besides inert diluents such compositons can also con~ain
adjuvants, such as wetting and suspending agents, and
sweetening, flavouring, perfuming and preserving agents.
Ac~ording to the invention, the compounds for oral admin-
is~ration also include capsules of absorbable material, such
as ge~atin, con~aining said active component with or without
the addition of diluents or excipients.
Preparations according to the invention for
parenteral administration include sterile aqueous, aqueous-
or~anic, and organic solutions, suspensions and emulsions.
E~ples of organic solvents or suspending media are pro-
pylene 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 stabilising, preserving, wetting, emulsifying and
dispersing agents.
They can be sterilized, for example by filtration
through a bacteria-retaining filter, by incorporation of
sterilising agents in the compositions, by irradiation or by
heating. They can also-be manu actured in the ~orm of
- 23 -
:
sterile solicl compositions which can be dissolved in sterlle
water or some other sterile injectable medium immediately
before use.
The percentages of active components in the ~aid
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
trea~nent, 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 the best judgement on the patient's
behalf.
- 24 -
