Note: Descriptions are shown in the official language in which they were submitted.
42~4~
This invention relates to 6~tlower-alkyl)-5-(pyridinyl)-2(1~l)~
pyridinones, their use as cardiotonic agents, and their preparation.
Lesher and Opalka [United States Patents 4,004,012, issued
January 18, 1977, and 4,072,7~6, issued February 7, 1978~ show as cardiotonic
agents 3-amino~or cyano)-5-~pyridinyl)-2(lH)-pyridinones and also 3-unsub-
stituted-5-(pyridinyl)-2(1H)-pyridinones, which were prepared by hea~ing the
corresponding 3-cyano compounds with aqueous sulfuric acid, first forming
the 3-carboxylic acids, i.e., 1,2-dihydro-2-oxo-5-(pyridinyl)nicotinic acids,
which are then decarboxylated. No cardiotonic activity is shown for said
1,2-dihydro-2-oxo-5-(pyridinyl)nicotinic acids. The disclosure of United
States Patent 4,072>746 also is shown in Lesher and Opalka United States
Patents 4,107,315, 4,137,233, 4,199,586 and 4,225,715.
The present invention provides, as new compounds, the compounds
having formula I
R; O
where Rl is hydrog~n, tCl-C6)-alkyl or (C2-C6)-hydroxyalkyl having its
hydroxy ~roup and its connecting linkage on different carbon atoms, R is
(Cl-C6)-alkyl and PY is 4- or 3- or 2-pyridinyl or ~- or 3- or 2-pyridinyl
having one or two (Cl-C6)-alkyl subs~ituents, or pharmaceutically-acceptable
acid-addition or cationic salts thereof. The compounds of formula I are
useful as cardiotonic agen~s, as determined by standard pharmacological
evaluation procedures. The compounds of formula I also are useful as inter-
mediates for preparing the corresponding 3-halo compounds whose preparation
is shown in said copending application Serial No. (Agent's Docket No.
3678A), filed October 20, 1980. Preferred embodiments are those of formula
I where PY is 4-pyridinyl or 3-pyridinyl and R is me~hyl or ethyl. Part-
-1- ,~
;. ~
9~
icul~rly preferred embodiments are 6-methyl-5-~4-pyridinyl)-2~111)-pyridinonc
(I wllere Rl is H, PY is 4-pyridinyl and R is methyl) and 6-ethyl-S-
(4-pyridinyl)-2~1H)-pyridinone tI where Rl is H, PY is 4-pyridinyl and R is
ethyl), or pharmaceutically-acceptable acid-addition salt thereof. These
particularly preferred embodiments were ~ound to have significantly higher
cardiotonic activity than the corresponding known 6-(desalkyl) compound,
5-(4-pyridinyl~-2(lH)-pyridinone.
According to the invention, there is provided a process for pro-
ducing a l-Rl-5-PY-6-R-2~111)-pyridinone of formula (I), or a pharmaceutic-
ally-acceptable acid-addition or cationic salt thereof, which comprises
heating a l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinonitrile of the formula III
PY ~ CN
~ J III
R N ~
, 1
or a l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-nicotinic acid of the formula IV
PY ~ COOII
~ J ~ IV
R N
Rl
with an aqueous mineral acid, and where required converting a compound of
formula ~I) so obtained into a pharmaceutically-acceptable acid-addition or
cationic salt thereof.
The invention also provides, as new compounds, the compounds hav-
ing formula II
., ,
i
~z~
PY ~ ~ ~ COOR'
R ~ N /
Rl
where Rl and PY are defined as in formula I above, R is tCl-C6)-alkyl and
R' is hydrogen or (Cl-C6)-alkyl, or pharmaceutically-acceptable acid-addi-
tion or cationic salts thereof. The compounds of formula II are useful as
cardiotonic agents, as determined by standard pharmacological evaluation
procedures. Preferred embodiments are those of formula II where PY is 4-
pyridinyl or 3-pyridinyl and R is methyl or ethyl.
The invention accordingly also provides a process for preparing a
l-Rl-1,2-dihydro-2-oxo-5-PY-6-[(Cl-C6)-alkyl]nicotinic acid or ~Cl-C6)-alkyl
ester thereof of formula II, or a pharmaceutically-acceptable acid-addition
or cationic salt thereof, which comprises hydrolyzing a l-Rl-1~2-dihydro-2-
oxo-5-PY-6-R -nicotinonitrile of formula III to produce l-Rl-1,2-dihydro-2-
oxo-5-PY-6-R -nicotinic acid of formula IV, and where required esterifying
said nicotinic acid with a ~Cl--C6~-alkanol to produce a compound of formula
II where R' is lower-alkyl, and where required converting a cornpound of
formula (II) so obtained into a pharmaceutically-acceptable acid-addition or
cationic salt thereo.
The compounds of formula (I) and their pharmaceutically-acceptable
acid-addition or cationic salts may be formulated as cardiotonic composi-
tions for increasing cardlac contractility, such a composition comprislng apharmaceutically-acceptable carrier and, as the active component thereof, a
cardiotonically-effective amount of a l-Rl-5-PY-6-R-2(1~ pyridinone having
formula I, where Rl, PY and R are each defined as in formula I or pharmaceu-
tically-acccptable acid-addition or cationic sal~ thereof.
These compounds may be employed for increasing cardiac contract-
ility in a patient requiring such trea~ment by administering to such patient
a car~iotonically-effective amount of a l-Rl-5-PY-6-R-2~ )-pyridinone hav-
ing formula I, where Rl, PY and R are each defined as in formula I, or
pharmaceutic~lly-acceptnble acid-addition or cationic salt thereo~.
The compounds of formula II and their pharmaceutically-acceptable
acid-addition or cationic salts may be formulated as cardiotonic composi-
tions for increasing cardiac contractility, such a composition comprising a
pharmaceutically-acceptable carrier and, as the active componen~ thereo~, a
cardiotonically-effective amount of a l-Rl-1,2-dihydro-2-oxo-5-PY-6-R -
nicotillic acid or (Cl-C6)-alkyl ester thereof having formula II where Rl, PY
and R are each defined as in formula II or pharmaceùtically-acceptable acid-
addition or cationic salt thereof.
Tllese compounds also may be employed for increasing cardiac con-
tractility in a patient requiring such treatment by administering to such
patient a cardiotonically-effective amount of a l-Rl-1,2-dihydro-2-oxo-5-PY-
6-R -nicotinic acid or (Cl-C6)-alkyl ester thereof having i`ormula II where
Rl, PY and R are each defined as in formula II or pharmaceutically-accept-
able acid-addition or cationic salt thereof.
The lower-alkyl radicals having from 1 to 6 carbon atoms which can
be arranged as straight or branched chains, e.g., as the meaning of R ,
as one of the meanings of Rl, or R', or as a substituent for PY in formula I
or II, are illustrated by methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-
butyl, tert.-butyl, isobutyl, n-amyl, n-hexyl, and the like.
The lower-hydroxyalkyl radicals having from two to six carbon
atoms and having the hydroxy group and the connecting linkage on different
carbon atoms, e.g., as one of the meanings for Rl in formula I or II, are
illustrated by 2-hydroxyethyl, 2-hydroxypropyl7 3-hydroxypropyl, 2-hydroxy-
2-n~ethylyropyl, 2-hydroxy-1,1-dimethylethyl, 4-hydroxybutyl, 5-hydroxy-
pentyl, 6-hydroxyhexyl7 and the like.
Illustrative of PY in formula I or II where PY is 4-7 3- or
2-pyridinyl having 1 or 2 (Çl-C6)-alkyl substituents are the following:
,. . ~,,
2-methyl-4-pyridiny:L, 2,6-dimethyl-4-pyridinyl, 3-methyl-4-pyridinyl,
2-methyl-3-pyridinyl, 6-methyl-3-pyridinyl (alternatively named 2-methyl-5-
pyridinyl), 4-methyl-2-pyridinyl, 6-methyl-Z-pyridinyl, 2,3-dimethyl-4-
pyridinyl, 2,6-dimethyl-4-pyridinyl, 4,6-dimethyl-2-pyridinyl, 2-ethyl-4-
pyridinyl, 2-isopropyl-4-pyridinyl, 2-n-butyl-4-pyridinyl, 2-n-hexyl-4-
pyridinyl, 2,6-diethyl-4-pyridinyl, 2,6-diethyl-3-pyridinyl, 2~6-diisopropyl-
4-pyridinyl, 2,6-di-n-hexyl-4-pyridinyl, and the like.
The compounds of formulas I and II are use~ul both
in the free base form and in the form of acid-addition
salts, and, both forms are within the purview of the inven-
tion. I`he acid-addition salts are simply a more convenient
form for use; and in practice, use of the salt form inherently
amounts to ùse of the base form. The acids which can be
used to prepare the acid-addition salts include preferably
those which produce, when combined with the free base,
pharmaceutically-acceptable salts, that is, salts whose
anions are relatlvely innocuous to the animal organism in
pharmaceutical doses of the salts, so that the beneficial
cardiotonic properties inherent in the free base are not
vitiated by side effects ascribable to the anions. In
practicing the invention, it is convenient to use the free
base form; however, appropriate pharmaceutically-acceptable
salts within the scope of the invention are those deri~ed
from mineral acids such as hydrochloric acid, sulfuric acid,
phosphoric acid and sulfamic acid; and organic acids such as
acetic acid, citric acid, lactic acid, tartaric acid~
methanesulfonic acid, ethanesulfonic acid, benzenesulfonic
acid, p-toluenesulfonic acid, cyclohexylsulfamic acid,
quinic acid, and the li~e, giving the hydrochloride, sul-
fate, phosphate, sulfamate, acetate, citrate, lactate,
tartrate, methanesulfonate, ethanesulfonate, benzenesul-
fonate, p-toluenesulfonate, cyclohexylsulfamate and quinate,
respectively.
The acid-addition salts of said basic compound (I
or II) are prepared either by dissolving the free base in
aqueous or aqueous-alcohol solution or other suitable
"~
~.~J
solvents containing the appropriate acid and isolating the
salt by evaporating the soll~tion, or by reacting the free
base and acid in an organic solve~t, in ~Ihich case the salt
separates directly or can be obtained by concentration of
the solution.
Although pharmaceutically-acceptable salts of said
basic compound (I or 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 ~esired only as an
intermediate product as for example when the salt is formed
only for purposes of purification or identifica~ion, or when
it is used as an intermediat, in preparing a pharmaceutically-
acceptable salt by ion exchan~e procedures.
1~ Other pharmaceutically-acceptable salts of said
c~ompound of formula I or II are those cationic salts derived
from stroncJ inorganic or organic bases, e.g., sodium hydroxide,
potassium hydroxide, trimethylammonium hydroxide, to produce
the corresponding 1~ or N-cationic salt, e.g., sodium,
~ potassium, trimethylammonium salt, respectively, tha~ is,
the cationic ion be-ng attached to ~he 1- or N-position of
the 2(1~1)-pyridinone ring. Also, the compound of formula II
where R' is hydrogen can react with a second mole o~ said
strong base to form an O-cationic salt of the 3-carboxylic
acid group.
The molecular structures of the compounds of
formulas I and II were assigned on the basis of evidence
pr~vided by infrared, nuclear magnetic resonance and mass
spectra, and by the correspondence of calculated and found ,,
values for the elemental analysis. I
The manner o~ making and using the instant invention
will now be generally described so as to enable a person skilled
in the art of pharmaceutical chemistry ~o make and use the same,
as follows.
The preparation of the intermediate l-Rl-1,2-dihydro-
2-oxo-5-PY-6-R-nicotinonitriles are described in the next -three
paragraphs. These intermediate nicotinonitriles are disclosed
and claimed as cardiotonics in copending Canadian application
Serial No. 365,406 (see also United States Patent 4t313~951).
The preparation of l-PY-2-(dimethylamino)ethenyl lower-
alkyl ketone by reacting PY-methyl lower-alkyl ketone with di-
methylformamide di(lower-alkyl) acetal is carried out by mixing
the reactants in the presence or absence of a suitable solvent.
The reaction is conveniently run at room temperature, i.e.,
about 20-25C., or by warming the reactants up to about 100C.,
preferably in an aprotic solvent, conveniently hexamethylphos-
phoramide because of the method used to prepare the PY-methyl
lower-alkyl ketone, as noted below in Example A-l. Other suit-
able solvents include tetrahydrofuran, dlmethylform~mide, aceto-
nitrile, ether, benzene, dioxane, and the like. ~lso, the
reaction can be run without solvent, preferably using an excess
of dimethylformamide di-(lower-alkyl)acetal~ This procedure is
further illustrated hereinbelow in Examples A-l through A-17.
- 8 --
~ iL429~9
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); Uni~ed States
Patent 3,133,077 ~5-12-64); Bull. Soc. Chim 1968, 4132; Chem.
Abstrs. 79, 8539h (1973); Chem. Abstrs. 81, 120,~01a (197~;
J. Org. Chem. ~9, 3834 (1~74); Chem. Abstrs. 87, 6594q
(1977); J. Org. Chem. ~3, 2286 (1978)].
The reaction of l-PY-2-(dimethylamino)ethenyl
lower-alkyl ketone with N-Rl-~-cyanoacetamide to produce 1-
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 o 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. Alter-
natively, methanol and sodium 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, li~hium diethylamide, lithium
diisopropylamide, and the like, in an aprotic solvent, e.g.,
tetrahydrofuran, acetonitrile, ether, benzene, diox~ne, and
the like. This procedure is further illustrated herembelow
in Examples B-l through B-21.
The conversion of l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-
nicotinonitrile to l-Rl-5-PY-6-R-2(lH)-pyridinone (I, Q is
hydrogen) is carried out by heating said nicotinonitrile
with an aqueous mineral acid, preferably 50% sulfuric acid,
first to form the corresponding nicotinic acid (II, R' = l-l)
and then continue heating for a longer period whereupon the
nicotinic acid is decarboxylated to produce I. This pro-
cedure is further illustrated hereinbelow in Examples C-l
through C-21.
The hydrolysis of l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-
nicotinonitrile to produce l-Rl-1,2-dihydro-2-oxo-5-PY-6-R-
nicotinic acid (II, R' is H) is conveniently run by heating
said nicotinonitrile on a steam bath with an aqueous mineral
acid, preferably 50% sulfuric acid. This procedure is
further illustrated hereinbelow in Examples D-l through D-
21.
The esterification of l-R1~1,2-dihydro-2-oxo-5-PY-
6-R-nicotinic acid (II, R' is ~1) to produce lower-alkyl 1-
Rl-1,2-dihydro-2-oxo~5-PY-6-R-nicotinate (II, R' is lower-
alkyl) is carried by heating the acid (II, R' is H) ~ith a
lowe-r-alkanol at about 25C to 150C, preferably about
50C to 100C preferably in the presence of a suitable
solvent, e.g., excess lower-alkanol, and in the presence of
an acid catalyst, e.g., a strong inorganic acid or an
organic sulfonic acid such as hydrochloric acid, sulfuric
acid, msthanesulfonic acid, p-toluenesulfonic acid, and the
like. This procedure is further illustrated hereinbelow in
Examples E-l through E-l9.
- 10 -
The following examples will ~urther illustrate the
invention without, however, limiting it thereto.
A. l-PY-2- (DIM~T~NLAMINO)~THENYL LOWER ALKYL KETONeS
A~ 1-(4-Pyridinyl~-2-(dimethylamino~ethenyl
methyl ketone - A mixture containing 20 g of ~4-pyridinyl)-
methyl methyl ketone [alternatively named 1-(4-pyridinyl)-2-
propanone] and 30 c~of hexamethylphosphoramide was diluted
with 65 cc of dimethylformamide dimethyl acetal and the
resulting mlxture 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 temperatuTe). 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 weighing 24 g. The residue was
purifiéd by continuous chromatographic extraction on alumina
(about 150 g) using chloroform (recycled by distillation
onto the alumina) as eluant. After 1 and 1/2 hours, the
extract was heated _n vacuo to remove the chloroform,
thereby leaving, as a light yellow crystalline material,
23.2 g of 1-~4-pyridinyl)-Z-(dimethylamino)ethenyl methyl
ketone, alternatively named 4-dimethylamino-2-(~-pyridinyl)-
3-buten-2-one.
The above preparation can be carried out using in
place of hexamethylphosphoramide other solvents, e.g.,
dimethylformamide~ acetonitrile 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-
~2~4~
aration: To a stirred solution containing 70 cc oE freshly
distilled diisopropylamine and 200 cc of tetrahydrofuran at
0 C under nitrogen was added dropwise over 20 minutes 210
cc of 2.4 M n-bu~y~ithium 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 cc of dry hexamethylphosphoramide (no temperature
change) and a resulting light yellow solution was stirred
for 15 minutes. To the cold solution at 0C was added a
solution of 50 cc of 4-picoline in 150 cc of dry tetra-
hydrofuran over a 15 minute period and stirring was con-
tinued for 30 minutes at 0C. Next, a mixture containing 50
cc of dry ethyl acetate and 150 cc of tetrahydrofuran was
added over a 15 minute period ~temperature rose from 0 to
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
of the reaction mixture rose to about 25C. The reaction
mixture was then cooled in an ice bath and to it was added
60 cc of acetic acid over a period of about 30 minutes.
The tetrahydrofuran was distilled off using a rotary evap-
orator in vacuo. The remaining mixture was diluted with 400
cc of water ~Id the aqueous mixture was extracted suc-
cessively with two 250 cc portions of isopropyl acetate and
three 80 cc 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-
Z~4~
tities was carried out as above except after the addition
of 60 cc of glacial acetic acid, the mixture was diluted
with only 200 cc of water, the phases were separated, alld
the aqueous phase was extracted with five 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
hexamethylphosphoramide was combined with the above 137 g
of the same mixture and the combined mixture was distilled
under reduced pressure to yield the following fractions: I.
63 g, b.p. of 110-112 C at 4 mm; II. 59 g of pale
yellow oil, b.p. 113-115 C at 3 mm; and, III. 69 g of
pale yellow oil, b.p. 115-118 C at 2.5 mm. Examination of
fraction III by NMR showed it to consist of a 2:3 mixture by
weight of ~-pyridinyl)methyl methyl ketone and hexamethyl-
phosphoramide.
~cid-addition salts of l~ pyridinyl)-Z-~dimethyl-
amino)ethenyl methyl ketone are conveniently prepar~d by
adding to a mixture of 5 g of 1-(~-pyridinyl)-2-(dimethyl-
amino)ethenyl methyl ketone in about 100 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 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-(~-pyridinyl)-2-(dimethylamino)ethenyl
r,.~ 3GS~
methyl ketone and -the appropriate acid, e.g., lactic acid or
hydrochloric acid, to prepare respectively the monolactate
or monohydrochloride salt in aqueous solution.
~-2. - 1-(4-Pyric1inyl)-2-(dimethylamino)ethenyl
ethyl ketone - A mixture containing 87.5 g. of (4-pyri-
dinyl)methyl ethyl ketone [alternatively named 1-(4-pyri-
dinyl)-2-butanone~ and 160 cc. of hexamethylphosphoramide
was diluted with 100 g. of dimethylformamide dimethyl acetal
and the resulting mixture was stirred under nitrogen at room
temperature for 45 minutes. The methanol formed by the
reaction was distilled 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. a-t
0.5 l~n. and the second at 90-95C. at 0.5 mm. After Tl,C
analysis showed predominantly a single spot for each fraction,
the two Eractions were coinbined (135 ~.) and taken up in 600
cc. of chloroform. The resulting solution was washed with
two 300 cc. portions of water and the water was back extracted
with three 100 cc. portions of chloro~orm. The combined
chloroform solution was dried over anhydrous sodium sulfate
and purified by continuous extraction chromatography on 300
cc. of alumina using chloroform (recycled by distillation
onto the alwnina) as the eluant. The chloroform was dis-
tilled off ln vacuo to yield a red oil which crystallized 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, 1-(~-pyridinyl)-2-(dimethyl-
amino)ethenyl ethyl ketone. Another 11 y. of crvstalline
r
Z9~1
product w~s obtained from the mother liquor by continuous
extractioll chromatography on alumina using chloroform (reeycled
by distillation onto the alumina) as the eluant.
The above intermediate (4-pyridinyl)methyl ethyl
ketone was obtainecl in a Inixture with hexamethylphosphoramide
as follows: To a mixture containing 200 ec. of tetrahydro-
furan and 70 cc. of diisopropylamine under nitl-ogen at 0~
5C. was added 210 cc. of 2.4N n-butyllithium in n-hexane
and the resulting mixture was stirrecl for 30 minutes. Next
was added over a 10 minute period 90 cc. of hexamethylphos-
phoramide follo~ed by stirring of the mixture for 15 minutes.
Then was added over a 15 minute period a solution of 48 cc.
of 4-picoline in 150 cc. oE tetrahydrofuran followed by
stirrincJ for 30 minutes at about O~C. The ice/acetone bath
cooliny the reaction mixture was replaced with a dry
ice/acetone bath and to the reaction mixture was added over
a 20 minute period a mixture of 75 cc. of ethyl propionate
in an equal volume of tetrahyclrofuran. The reaetion mixture
was then allowed to warm up to room temperature over a
~0 periocl of about 90 minutes and then was warmed at abou-t
35C. for 30 minutes. The mixture was next eooled in an
icejacetone bath and to it was added 60 ec. of glaeial
acetic acid over 30 minutes. The resulting pale yell,ow
suspension was diluted with 200 cc. of water. The mixture
was extrac~ed with three 150 cc. portions of ethyl acetate
and the ethyl acetate extract was back washed with saline
solution. I~he extract was heated in vacuo to remove the
ethyl acetate and the residue was taken up ayain with ethyl
- 15 -
I).IJ
31~4~
acetate. Ti-,e solution was washecl with water and then heated
in vacuo to remove the ethyl acetate followed by heating the
_
residue in vacuo at 50~C. for about 30 minutes to yield 100
g. of pale yellow oil. The pale yellow oil was combined
with corresponding samples obtained from two additional runs
and th~n distilled _n vacuo to yield a 256 g. fraction, b.p.
85-105C. at 0.5-1.0 mm. The NM~ of this fraction showed it
to be a mixture of (~-pyridinyl)methyl ethyl ketone and
hexamethylphosphoramide in a respective molar ratio of
1:1.55, t}iat isI 35% or .35 ~ 256 = 90 g. of said ketone.
~-3. 1-(4-Pyridill~1)-2-(dimethylamino)ethenyl
n-propyl ketone - A mixture containing 80 g. of (4-pyri-
dinyl)me~hyl n-propyl ~etone [a1ternatively named l-(4-pyri-
diny1)-2-~el~tanone~ and ~h cc. of he~amethylphosphoramide
1~ was dilu~e(1 with 250 cc. of acetonitrile. rrO the mixture
was added 90 cc. of dimet]lylformamide dimethyl acetal and
the resultinc~ reaction mixtur~ w~s lleated on a steam bath
for ninety minutes and thell distilled under vacuum at about
2 n~m. to remove volatile materials, includin~ methanol,
acetonitrile and hexamethylphosphoramide. The remaining
residue was diluted with ethyl acetate and washed with
water. The combined water washin~s were extracted with five
150 cc. portions of ethyl ace~ate. The combined ethyl
acetate solutions were washed with saline solution) dried
over anhydrous sodium sulfate, filtered and evaporated to
dryness. l`he residue crystallized while standing in a
freezer. The crystalline product was slurried with cyclo-
hexane, fil-tered and dried overnight at 30~C. to produce, as
- 16 -
~2~
a yellow crystalline product, 97 g. of 1~ pyridinyl)-2-
(dimethyl~rnino)ethenyl n-propyl ketone, m.p. 48-50C.
The a~ove intermediate (~-pyridinyl)methyl n-
propyl ketone was obtained in a mixture with hexamethyl-
phosphoramide as follows: To a st~rred solution of 70 cc.
of ~iisopropylamine in 200 cc. of tetrahydrofuran under
nitrogen at about 0C. (use of ice bath) was added 210 cc.
of 2.4N n-butyllithium over twenty minutes and the resulting
mixture was stirred for 30 minutes at about 0C. to the
~- mixture was added with stirring over ten minutes 90 cc. of
hexamethylphosphoramide and the resulting mixture was
stirred for another ten minutes. Next 45 cc. of 4-picoline
in 140 cc. of tetrahydrofuran was added dropwise over
fifteen to twenty minutes. ~he resulting dark orange-brown
solution was stirred at O~C. for thirty min~ltes and then
treated dropwise over an eiyhteen mlnute period a solution
consistin~ of 68 cc. of ethyl butyrate in 68 cc. of tetra-
hydrofuran, the temperature rising Erom -8C. to -~ to 10C.
The reacti~n 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 cc. of glacial acetic
acid. ~ pale yellow soli~ separated, resulting in a sus-
pension. The suspension was diluted with water and extracted
with two 200 cc. portions of ethyl acetate. The ethyl
acetate extract was washed with three 100 cc. portions of
saline solution, dried over anhydrous sodium sulfate and
evaporated in vacuo to yield 107 g. of a mixture consisting
- 17 -
~ . 3~,s'~
Z~
primarily of (4-pyridiny])lnethyl n-propyl ketone and hexa-
methylphosphoramide. The mixture obtained in this run ~7as
combined with corresponding mixtures obtained in -two other
runs and the combined mixtures were distilled under vacuum
to produce, as the major ~raction, b.p. 80-90C. at 0.2 mm.,
a mixture consisting of 80 ~J. of (4-pyridinyl)methyl n-
propyl ketone and 46 g. of hexamethylphosphoramide.
Following the procedure described in Example A-2
but using a molar equivalent quantity of the appropriate PY-
~0 methyl lower-alkyl ketone i,n place of (4-pyridinyl)methyl
ethyl ketone, it is contemplated that the corresponding l-
PY-2-(dimethylamino)ethenyl lower-alkyl ketones of Examples
~-4 thru ~ can be obtained.
~-q. 1-(3-Pyriclillyl)-2-(~imethylamino)ethenyl
methyl ketone USi llCJ ( 3-py~-iclinyl)methy] methyl ketone.
~-5. l-(2-Pyrldinyl)-2-(dimethylarnino)ethenyl
methyl ketone usincJ (2-pyridinyl~methyl methyl ketone.
~-6. l-(~-Pyridillyl)-2-(climethylclmino~ethenyl
isopropyl ketone using (4-pyridinyl)methyl isopropyl ketone.
~0 ~-7. 1-(4-Pyr:i~inyl)-2-(dimethylamino)ethenyl n-
butyl ketone using (4-pyridinyl)methyl n-butyl ketone.
~-8. l-(4-Pyridinyl)-2-(dimethylamino)ethenyl
i sobutyl ketone using (4-pyridinyl)methyl isobutyl ketcne.
~-9. l-(4-Pyridinyl)-2-(dimethylamino)ethenyl
t_.-butyl ketone using (4-pyridinyl)methyl tert.-butyl
ketone.
A-lO. 1-(4-Pyridinyl)-2-(dimethylamino)ethe~yl n-
'pentyl ketone using (4-pyridinyl)methyl n-pentyl ketone.
- 18 -
. 3~J~
~2~4~
A-ll. 1~(2-Me-thyl-4-p~ridinyl)-2-(dimeth~rlamino)-
ethenyl ethyl ketone usincJ (2-methyl-4-pyridinyl)methyl
ethyl ketone.
~-12. 1-(5-Methyl-2-pyriclinyl~-2-c1imethylamino)-
ethenyl methyl ketone using (5-methyl-2-pyridinyl)methyl
methyl ketone.
~-13. 1-(5-Ethyl-2-pyridinyl)-2-(dimethylamino)-
ethenyl ethyl ketone uslng (5-ethyl-2-pyridinyl~methyl ethyl
~etone.
A-14. 1-(3-Pyridinyl)-2-(dimethylamino)ethenyl
ethyl ketone using (3-pyridinyl)methyl ethyl ketone.
A-15. 1-(4,6-Dimethyl-2-pyridinyl)-2-~dimethyl-
amino)ethenyl methyl ketone using (~,6-dimethyl-2-pyri-
c~inyl)methyl methyl ke~one.
~-16. 1-t6-Methyl-2-pyriclinyl)-2~(dimethylamino)-
ethenyl isopropyl ketone usiny (6-methyl--2-pyridinyl)methyl
isopropyl ketolle.
~-17. 1-(2~Pyridinyl)-2-(dimethylamino)ethenyl n-
hexyl ke~one using (2-pyriclinyl)methyl n-hexyl ketone.
B. l-Rl 1,2-DLHYD~0-6-(l,OWE~-ALKYL)-2-OY.0-5-PY-NICOTINO-
-
NITRILES
B~ 1,2-Dlhydro-6-methyl-2-o~o-5-(4-pyri-
dinyl)nicotlnonitrile, alternatively named 1,6-dihydro-2-
methyl-6-oxo-[3,4'-bipyridine]-S-carbonitrile - To a mixture
containinc3 23 y. of 1-(4-pyridinyl)-2-(dimethylamino)ethenyl
methyl ketone and 11 g. of ~-cyanoacetamide dissolvea in 400
cc. of dime~hylformamide was added with stirring 14 y. of
sodium methoxide and the resulting reaction mixture was
he~ted in an oil bath uncler yentle reflux for one hour. TLC
- 19 -
r~ , , f~ 5 7/~.
9~1
analysis showed no startincJ m.-lterial in the reaction rnixture
whicll ~Jas then concentraked in vacuo on a rotary evaporator
to a volume of about 80 cc. l'he concentrate was treated
with about 160 cc. of acetonitrile and the resulting mixture
was stirred on a rotary evaporator with warming until ho~o-
~enuous and then cooled. Tlle crystalline product was
collected, rinsed successively with acetonitrile and ether,
- and dried overnight at 55C. to yield 2g g. of tan crystal-
line produc~, namely, sodium salt of 1,2-dihydro-6-methyl-2-
oxo-5-(9-pyriclinyl)nicotinonitrile, the presence of cyano
being con~irllled by IR analysis. ~n 8 ~. portion of said
sodium salt was dissolved in 75 cc. of hot water, the
a~lueous solution treated with decolorizin~ charcoal fil-
tered, the filtrate a~ain treclted with decolorizing charcoal
lS and filtered, and the filtrate acidified with 6N-hydro-
chloric acid by dropwise acldition to a pll of 3. l'he acidic
mixture was diluted with e~hanol and cooled. The crys-
talline product was collected, clried, recrys~allized from
dimethylformamide-water and clriec1 to procluce 3.75 g. of 1,2-
dihydro-G-me~hyl-2-oxo-5-(~-pyridinyl)nicotirlonitrlle, m.p.
>300C.
~cid-addition salts of 1,2-dihydro-6-methyl-2-oxo-
5-(4-pyridinyl)nicotinonitrile are conveniently prepared by
adding to a mixture of 2 q. of 1,2-dihydro-6-methyl-2-oxo-5-
(4-pyridinyl)nicotinonitrile in about 40 ml. of aqueous
methanol the appropriate acid, e.~., methanesulfonic acid,
concentrated sulfuric acid, concentrated phosphoric acid, to
a pH of about 2 to 3, chillin~J the mixture after partial
evaporation and collecting the precipitated salt, e.~
dimethanesulfonate, sulfate, phosphate, respectively. Also,
- 20 _
~ 1 . 3 fi ~
the c~cid-cld(lition s~lt i5 conveniently prepared in aqueous
solution by adding to water with StirrinCJ molar equivalent
quantities each of 1,2-dihydro-6-metllyl-2 ox~-5-(4-pyri-
dinyl)nicotinonitrile ancl the appropriate aci.d, e.g ,
lactic acid or hydrochloric acid, to prepare respectively
the monol~lctate or monohydrochloride salt in aqueous solution.
B-2. - 6-~thyl-1,2-dihydro-2-ox~-5-~-pyridinyl)nicotinc)-
nitrile, alternatively named 2-ethyl-1,6-dihydro-6-oxo-
~3,4'-bipyridine]-5-carhonitrile, m.p. ,300C., 11.6 g., was
~re~ared ~ollowing tl-e pl^oceclure clescribed above in Example
B-l usin~ 20 L~ of 1-(4-pyriclinyl)-2-(dimethylamino)ethenyl
etllyl ~etone, 8.9 c3. oE ~-cyanoacetamide, 16.2 g. of sodiuM
methoxide and 250 cc. of climetllylclcetamide (as solvent in
place of dilnethylforlllclnlide).
~-3. - 1,2~ ycll-~-,-oxo-~
dinyl)nicotinon _rile, alternatively named 1,6-dihydro-6-
oxo-2-n-propyl-[3,4'-bipyridine]-5-carbonitrile, m.p. 232-
239C., 9.g c~., waC; prepared followinc3 ~hc procedure clescrib~cl
al)ove in L;:~ample L3-1 usincJ ~35 c~. of ]-(9 pyriclinyl)-2- l
(clinlethylamino)ethenyl n-propyl ~et.one, 36.5 g. of ~-cyano- i
ace~amide, 50 cJ. of soclium metlloxicle and 800 cc. of dimethyl-
acetamide.
13-4. - 1,2-Dihydro-1,6-dimethyl--2-oxo-5-(4-pyri-
dinyl)nicotinonitrile, alternatively named 1,6-dihydro-1,2
._
dimethyl-6-oxo-(3,4'-bipyridine) 5-carbonitrile, m.p. 295-
29~C., 32.3 g., was prepared ~ollowing the procedure
described above in Example B-l usinc3 42.5 g. of 1-(4-pyri-
dinyl~-2-(dimethylamino)ethenyl methyl ketone, 23.5 g. of N-
methyl-~-cyanoacetamlde, 6.7 cJ. of sodiurrl methoxide, 400 ml.
of methanol arl(l a re~luxincJ period of two hours.
L, 1 ), 3 f-, r~
94~l
l;c~ll()wirlcJ the procedurc clescribed in ~xample ~-2
but using cl m~lar equivalent quantity o~ -tlle appropriate 1-
~Y-2-(dimethylamino)ethenyl lower-alkyl ketone (III) in
place of 1-(9-pyridinyl)-2-(dinlethylamino)ethenyl ethyl
ketone aricl the apyropriate N-r~ ~cyanoacetamidel i-t is
contemplated tha-t the correspondin~ l-Rl-1,2-dihydro-2-oxo-
5-PY-6-R-nicotinonitriles of Ixamplcs B-5 thru B-21 can be
obtained.
B-5. 1,2-Dihydro-6-rnethyl-2-oxo-5-(3-pyridinyl)-
nicotinonitrile, uslng 1-(3-pyridirlyl)-2-(dimethylamino)ethenyl
methyl keLone and ~-cyanoacetamide.
B-6. 1,2-Dilly~ro-6-methyl-2-oxo-5-(2-pyridinyl)-
nicotinoni~rile, using 1-(2-pyridinyl)-2-(dimethylamino)ethenyl
~____
thyl ~ nd ~-c~nc)~c(~t.l~lic~c.
13-7. 1,2-Dihy~ o G-isopropyl_2-o~o-5-(4-pyri-
dinyl)nicotinonitrile, USillCJ ~ -pyridinyl)-2-(dimethyl-
_~ i
mi3l0)eth~nyl isopropyl ketone and q-cy~noacetamide.
L3-~. 6-n-Butyl-1,2-dihydro-2-oxo-S- (4-pyr~.-
dinyl)l cotil~onitrile, usinc3 1-(4-pyridinyl)-2~(dimethyl-
amino)ethenyl n-butyl ketone and ~-cyanoacetamide.
E3-9. 1,2-Dihydro-6-isobutyl-2-oxo~5-(4-pyri-
dinyl)nico~inonitrile, usiny 1-(4-pyridinyl)-2-(dimethyl-
amino)ethenyl isobutyl ketone and ¢-cyanoacetamide~
B-10. 1,2-Dihydro-2-oxo-5-(4-pyridinyl)-6-tert.-
butylnicotinonitr , usin~ 1-(4-pyridinyl)-2-(dimethyl-
amino)ethellyl tert.-butyl ketone and ~-cyanoacetamide.
B-ll. 1,2-Dihydro=2-oxo-6-n-pentyl-5-(4-pyri-
dinyl)nicotinonitrile, usiny 1-14-pyridinyl)-2-ldimethyl-
amino)ethenyl n-pentyl ketone and d-cyanoacetamide.
- 2~ -
~ J f,r7~t~
4~
T~ 12. 6-~thyl-l,2-dihydro-5-(2-methyl-~-pyri-
diny1~-2-oxonicotirlonitrile, using l-(2-methyl~4-pyridinyl)-
2-(dimethylamino)ethenyl ethyl ketone and d-cYanoacetamid0.
1~-13. l,2-~ihydro-6-methyl-5-(5-methyl-2-pyri-
dinyl)-2-oxonicotinonitrile, usincJ l-(S-methyl-2-pyridinyl)-
2-(dimethylarnino)ethenyl methyl ketone and ~-cyanoacetamide.
B-19. 6-~thy]-5-(S-ethyl-2-pyridinyl)-l,2-dihydro-
2-oxonicotinonitrile, usin~ l-(5-ethyl-2-pyridinyl)-2-
~dimethylamino)ethenyI ethyl letone and ~-cyanoacetamide.
1~ ~-l5. ~ 2-dihydro-2-oxo-5-(3-pyri-
dinyl)nicotinonitrile, usiny ~-(3-pyridiny])-2-(dimethyl-
amino)ethenyl ethyl ketone and ~-cyanoacetamide.
13-lfi. 1,2-Dihydro-S-(q,G-dimethyl-2-pyridinyl)-6-
lnethyl-2-oxon cotino2l]tr~le, nsin~ ,6-dimethyl-2-pyri-
dinyl)-2~(din~ethylamirlo)ethellyl n~et.hyl ketc~ne and c~-cyano-
acetamide.
~-17. l,2-Dihydro~G-isopropyl-5-(6-methyl-2-
pyridinyl)-2-oxo-nicotinonitrile, usin~ l (6-methyl-2-pyri-
dinyl)~2-(dimethylamino)etllenyl isopropyl ]setone and ~-
~ cyanoacetalllicle.
B-18. l,2-Dihydro-6-n-hexyl-2-oxo-5-(2-pyri-
din _ nicotinonitrile using 1-(2-pyridinyl)-2-(dimethyl-
amino)ethenyl n-hexyl ketone and ~-cyanoacetamide.
B-19. 6-Ethyl-l,2-dihydro-l-(2-hydroxyethyl)-2-
oxo-5-(4-pyridinyl)nicotinonitrile, using l-(4-pyridinyl)-2-
(dimethylamirlo)ethenyl ethyl ketone and N-(2-hydroxyethyl)-
q-cyanoacetamide.
r3-20. l-F-thy~-1,2-(lil-ydro-G-methyl-2-oxo-5-(4-
~yridinyl)l~icotinonitrile, usin~J 1-(4-pyr1dinyl)-2-dimethyl-
3~ arnino)ethenyl methyl ketone alld N-ethyl-c~-cyanoacetamide.
- 23 -
9~
B-21. 1,6-Diethyl-1,2-dihydro-2-oxo-5-(4-Pyri-
dinyl)nicotinonitrile, using 1-(4-pyridinyl~-2-tdimethyl-
amino)ethenyl ethyl ketone ~nd N-ethyl-~-cyanoacetamide.
C. l-Rl-6-(LOWER-ALKYL)-5-PY-2(lH)-PYRIDINONES
C-l. 6-Methyl-5-(4-pyridinyl)-2(1H)-pyridinone,
alternatively named 2-methyl-[3,4'-bipyridin]-6(1H)-one - A
mixture of 5.3 g of 1,2-dihydro-6-methyl-2-oxo-5-~4-pyri-
dinyl)nicotinonitrile and 30 cc of ~5% sulfuric acid was
heated to about 195C, gently refluxed for twenty-four
hours, cooled and added to ice. The aqueous mixture was
brought to a pH of 8 by addition of concentrated aqueous
sodium hydroxide solution. The resulting precipitate
~product plus Na2S04) was treated with chloroform and the
chloroform solution filtered. The filtrate was concentrated
in vacuo to remove the chloroform and the resulting crys-
talline residue was recrystallized from methylene dichloride-
ether and dried at 75 C for four hours to produce 4.1 g o:E
6-methyl-5-~4-pyridinyl)-2(1H)-pyridinone, m.p. 287-288C.
Acid-addition salts oE 6-methyl 5-~4-pyridinyl)-
2~1~1)-pyridinone are conveniently prepared by adding to a
mixture of 5 g of 6-methyl-5-~4-pyridinyl)-2~lH)-pyridinone
in about 100 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 col-
lecting the precipitated salt, e.g., dimethanesulfonate,
sulfate, phosphate, respectively. Also, the acid-addition
salt is con~eniently prepared in aqueous solution by adding
to water with stirring molar equivalent quantities each of
6-methyl-5-(4-pyridinyl)-2(lH)-pyridinone and the appro-
- 24 -
priate acid, e.g., lac~ic acid or hydrochloric acid, to
prepare respectively the monolactate or monohydrochloride
salt in aqueous solution.
C-2. 6-Ethyl-5-~4-pyridinyl)-2~lH)-pyridinone,
alternatively named 2-ethyl-[3,4'-bipyridin]-6(1H~-one - A
mixture containing 9 g of 6-ethyl-1,2-dihydro-2-oxo-5-(4-
pyridinyl)nicotinonitrile and 50 ml of concentrated sulfuric
acid was hea~ed with stirring at 200C for twenty-four
hours, cooled to about 40C and quenched in 200 ml of lce
water. After the aqueous solution had been basified with
concentrated ammonium hydroxide, the separated solid was
collected, recrystallized from isopropyl alcohol ~70 ml),
and dried at 60C in vacuo to yield 3 g of 6-ethyl-5-(4-
pyridinyl)-2~1H)-pyridinone, m.p. 226-228C. A second crop
of 0.4 g, m.p. 225-227C, was obtained by concentrating
the filtrate to about 20 ml.
C-3. 6-n-P_opyl-5-~4-pyridinyl)-2(lH)-pyridinone~
alternatively named 2-(n-propyl)-[3,4'-bipyridin]-6(1H)-one,
m.p. 179-180C, 3.4 g, was obtained following the pro-
cedure d~scribed in Example C-2 but using lO g of 1,2-
dihydro-6-n-propyl-2-oxo-5-(4-pyridinyl)nicotinonitrile,
42.5 cc of 85% sulfuric acid, and recrystallization from
methylene dichloride-ether.
Following the procedure described in Example C-2
but using in place of 6-ethyl-1,2-dihydro-2-oxo-5-(4-pyri-
dinyl)nicotinonitrile a molar equivalent quantity of the
corresponding l-Rl-1,2-dihydro-2-oxo-5-PY~6-(lower~alkyl)-
- 25 --
nicotinonitrile, it is contempl~ted that there c~n be obtained the l-Rl-5-
PY-6-(lower-alkyl)-2(1H)-pyridinones of Examples C-~ through C-Zl.
C-4. 6-Methyl-5-(3-pyridinyl)-2(lH)-pyridinone.
C-5. 6-Isopropyl-5-~-pyridinyl)-2(1H)-pyridinone.
C-6. 6-n-Butyl-5-(4-pyridinyl)-2(lH)-pyridinone.
C-7. 6-Isobutyl-5-(4-pyridinyl)-2(lH)-pyridinone.
C-8. 5-(4-Pyrldinyl)-6-tert.-butyl-2(lH)-pyridinone.
C-9. 6-n-Pentyl-5-(4-pyridinyl)-2(lH)-pyridinone.
C-10. 6-Ethyl-5-~2 methyl-4-pyridinyl)-2(lH)-pyridinone.
C-ll 6-Ethyl-5-(3-pyridinyl)-2(1H)-pyridinone.
C-12. 1,6-Dimethyl-5-(4-pyridinyl)-2(1H)-pyridinone, m.p. 164-165C.
C-13. 6-Ethyl-1-(2-hydroxyethyl)-5-(4-pyridinyl)-2tlH)-pyridinone.
C-14. 1-E~hyl-6-methyl-5-(4-pyridinyl)-2(lH)-pyridinone.
C-15. 1,6-Diethyl-5-(4-pyridinyl)-2(1H)-pyridinone.
C-16. 6-Methyl-5-~2-pyridinyl)-2(lH)-pyridinone.
C-17. 6-Methyl-5-(5-methyl-2-pyridinyl)-2(lH)-pyridinone.
C-18. 6-Ethyl-5-(5-ethyl-2-pyridinyl)-2(1H)-pyridinone.
C-l9. 6-Methyl-5-(4,6-dimethyl-2-pyridinyl)-2(lH)-pyridinone.
C-20. 6-Isopropyl-5-~6-methyl-2-pyridinyl)-2(1H)-pyridinone.
C-21. 6-n-Hexyl-S-~2-pyridinyl)-2~lH)-pyridinone.
- 26 -
~ .
41
D. l-Rl-1,2-DIHYDRO-6-~LOWER-A~KYI.)-2-OXO-5-PY-NICOTINIC
-
ACIDS
D-l. 1,2-Dihydro-6-methyl-2-oxo-5-~4-pyridinyl~nic~tinic Acid,
alternatively named 1,6-dihydro-2-methyl-6-oxo[3,4'-bipyridine]-5-carboxylic
acid - A 30 g portion of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyljnicotino-
nitrile was added with stirring to a hot solution containing 220 cc of water
and 145 cc of concentrated sulfuric acid. The reaction mixture was ~efluxed
for seven hours ~about 122C) and then allowed to stand over the weekend at
room temperature. It was then diluted with water, cooled in an ice bath and
treated dropwise with stirring with ammonium hydroxide to neutral pH. The
resulting crystalline precipitate was collected, rinsed successively with
three 100 cc portions of water and several times with acetone and then ether,
and dried at 80C. The crystalline material was slurried with 200 cc of
chloroform and 200 cc o~ methanol for thirty minutes and the mixture concen-
trated in vacuo to a volume of 150 cc. The crystalline product was collect-
ed and dried at 95C over P2O5 to yield about 24 g oE product. A 10 g
sample of product was heated with 200 cc of water at incipient boiling, the
mixture cooled and the solid collected and dried at 80C to yield 9 g of
1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinic acid, m.p. >260C.
Pollowing the procedure described in Example D-l but using in place
of 1,2-dihydro-6-methyl-2-oxo-5-(4-pyridinyl)nicotinonitrile a molar equival-
ent quantity of the corresponding l-Rl-1,2-dihydro-2-oxo-5-PY-6-(lower-alkyl3-
nicotinonitrile, it is contemplated that there can be obtained the l-Rl-1,2-
dihydro-2-oxo-5-PY-6-(lower-alkyl)nicotinic acids of Examples D-2 through
D-21.
- 27 -
; i, !~
L).~l. 3~;,1,
D-2 . G-~thyl-1,2-di-hydro~2-oxo-5-~4-pyridinyl)-
ni.cotinic ~ci{l.
D-3. 1,2-Dihyclro-G-methyl-2-oxo-5-(3-pyridinyl)-
nicotinic ~cid.
5D-4. 1,2-Dihydro-2-oxo-~-n-propyl-5-(4-pyri-
dinyl)nicotinic acicl.
D-5. 1,2-Dihyclro-2-oxo-6-isopropyl-5-(4-pyri-
dinyl)nicotinic acid.
V-6. 6-n-Butyl-1,2-dihydro-2-oxo-5-(4-pyridinyl)-
10nicotinic acid.
l)-7. 1,2-Dihydro-6-isobutyl-2-oxo-5-(4-pyri-
dinyl)nicoti.llic acid.
D-~. 1,2-Dihyclrc)-2-oxo-5-(4-pyridinyl)-6-tert.-
~u~ylnicot~ ic acid.
15D-9. 1,2-Dihydro-2-oxo-G-n-perltyl-5-(4-pyri-
di.nyl~llicotinic acicl.
1)-10. 6-~thyl-1,2-dillydro-5-(2-TIlethyl-4-pyri-
C~ yl ) - 2- OXOIliCOtilliC aci.cl.
D-ll. 6-l,thyl-1,2-dillydro-2-oxo-5-(3-pyridinyl)-
2~nicotinic acid.
D-12. 1,2-Dihydro-1,6-dimethyl-2-oxo--5~(4-pyri-
dinyl)nicotinic acid.
D-13. 6-Ethyl.-I,2-dihydro-1-(2-hydroxyethyl)-2-
oxo-5-(4-pyridinyl)nicotinic acid.
25D-14. 1-Ethyl-1,2-dihydro-6~methyl-2-oxo-5-(4-
pyridinyl)nicotinic acid.
D-15. 1,6-Diethyl-1,2-dihydro-2-oxo-5-(4-pyri-
dinyl)rlicoti.nic acicl.
D-16. 1,2-Dihyclro-6-methyl-2-oxo-5-(2-pyri--
30dinyl)ni~otinic Icid.
- 28 -
3G$3/i
~- :17 . 1, 2 - DihyclL-o- ~-m~thyl-5-(5-methyl~2-pyri-
dinyl)-2-oxonicotinic acid.
D-18. 6-Ethyl-5-(5-ethyl-2-pyridinyl)-1,2-
dihydro-2-oxonicotinlc acid.
D-19. 1,2 Dihyclro-~.-methyl-5-(4,6-dimethyl-2-
pyridinyl~-2-oxonicotinic acid.
D-20. 1,2-Dihydro-6-isopropyl-5-~6-methyl-2-pyri-
dinyl)-2-oxonicotinic acid.
D-21. 1,2-Dihydro-G-n-hexyl-2-oxo 5-(2-pyri-
dinyl)nicotinic acid.
E. LOWEI~-~Li;YL 1-l~l-6-(IOW~I~-AL~l.)-1,2-DIHYDRO-2-OXO-5-
PY-NICOTIN~TES
1-1. ~t~lyl ],2-d:ihydro-6-methyl-2-oxo-5-(4-
l~yridinyl)llico~inate - ~ 4 ~ ortion of lr2-c1ihydro-6-
methyl-2-oxo-5-(4-pyridinyl)nicotinic acid is heated in 200
cc. of ref1uxill~ ethanol with 1 c3. of methanesulfonic acid
for eic3hteen hours. q~he excess ethanol is distilled off in
v~cuo and tl~e residue is recrystall:ized froll~ dirnekhylform-
amide tG l~rocl-lce ethyl 1,2-dihydro-6-rnethyl-2-oxo-5-(4-pyri-
dinyl)nicotinate as its metllanesulfonic acid salt. The salt
is dissolved in warm water all(l the solution made basic with
excess aclueous potassium carbonate solution. The solid that
separates is collected, ~ried, recrystallized from isopropyl
alcohol and dried to procluce ethyl 1,2-dihydro-6-methyl-2-
oxo-5-(4-pyridinyl)nicotinate.
Acid-addition salts of ethyl 1,2-dihydro-6-methyl-
2-oxo-5-(4-pyridinyl)nicotinate are conveninetly prepared by
adding to a mixture of 5 g. of ethyl 1,2-dihydro-6-methyl-2-
oxo-5-(4-pyridinyl)nicotinat2 in about 100 ml of aqueous
methanol the appropriate acid, e.c3. r methan~sulfonic acid,
- 29 -
~ r/3~
concentral:e(:l sulf-lric aci~1, concentrated phosphoric acid, tc
a pll of about 2 to 3, chillin~ the mixtu~e after partial
evaporation and coll~ctiny the precipitat~d salt, e.g.,
dimethanesulfonate, s~llfate, phosphate, respectively. Also,
the acid-aclditioll salt is conve~ ntly prepared in aqueous
solution by adding tc~ water ~-ith stirrincJ molar equivalent
~uan~itie~ ~ach of ethyl 1,i`-clihydro-6-methyl-2-oxo~5~(4-
pyridinyl)nicotinate and the appropriate acid, e.~., lactic
acid or hydrochloric acic1, to prepare respectively the
monolactate or monohydrochloride salt in aqueous solution.
rollowincJ tlle procedure described in Example E-l
but usinc3 i31 place of 1,2-clihydro-f)-methyl-2-oxo-5-l4-
pyridinyl)nicotinic acid and ethanol molar ecluivalent
qu~ntitit-:s of the appropriat~ ]-1,2-dihyclro-2-oxo~5~PY-6-
~lower-alkyl)nicotillic a~id ancl low~r-alkanol, it is con-
t~mplated L]lat there can be obtainecl the low~r-alkyl 1-R1-
l,2-dihyclrc)-2-oxo-5-PY-G-(lower-al}~yl)nicotinates o~
F.xalllples l:-2 thl~ugh F-19.
~-2. Metl~yl 1,2-dihydro-6-metllyl-2~oxo-5-(4-
pyriclinyl)nicotinate, m.p. 204-206CC.
E-3. ~thyl 6-~thy]-1,2-dihydro-2-oxo-5-(4-pyri-
dinyl)nic~t:inate.
E-4. n-Propyl 1,2-dihydro-6-methyl-2-oxo-5-t3- i
pyl-idillyl) nicotlnate. I
E-5. E:thyl 1,2-clihyclro-2-oxo-6-n-propyl-5-(4-
~yridinyl)nico~inate.
~ -6. Isopro~yl l,2-dihydro-2-oxo 6-isopropyl-5-
~4-pyridinyl) lliCOti nate.
~ 7. ~thyl 6-n-butyl-1,2-dihydro-2-oxo-5-(4-
pyridinyl)rlicoti]-~ate.
~0 --
"ll 3~3
~ thy]. 1,2-dihyclro--~,-isobutyl-2-oxo-5~(4-
pyridinyl)nicotinate.
1.-9. Methyl 1,2-dihydro-2-oxo-5-(~-pyridinyl)-6-
tert.-~utylni.cotinate.
~-10. Methyl 1,2-dihyd.ro-2-oxo-6-n-pentyl-5-(4-
pyridinyl)rlico~inate.
E-ll. n-Butyl ~-cthyl-1,2-dihydro-5-(2-methyl-4-
pyridinyl)-2-oxonicotlnate.
~-12. Ethyl 6-ethyl-1,2-dihydro-2-oxo-S-(3-pyri-
dinyl)nicotinate.
~-13. Ethyl 1,2-dihydro-1,6-dimethyl-2-oxo-5-(4-
p~ridinyl)nico~inate.
E-14. Ethyl 6-ethyl-1,2-dihydro-1-(2-hydroxy-
ethyl)-2-oxo-rj-(4-pyric11rly~ icoti.nate.
15. ~`thyl 1,6-~iethyl-1,2-dihydro-2-oxo-5~(4-
pylidillyl)nicotinate.
~-16. n-~lexyl 1,2-dihydro~6-m~thyl-2-oxo-5-~-
pyridinyl)nicoti.nate.
E-17. Methyl G~el:llyl-5-(5-ethyl-2--pyridirlyl)-1,2-
~0 dihydro-2-oxollicotillate.
~ . Ethyl 1,2-dihydro-6-methyl-5-(4,6-dimethyl
2-yyridinyl)-2-oxonicotinate.
E--19. Ethyl 1,2-dihydro-6-n-hexyl-2-oxo-5-(2-
pyridinyl)nicotinate.
The usefulness of the compounds of formula I or II
or salt thereo as cardiotonic agents is de~onstrated by
their effectiveness in standard pharmacological test pro-
cedures, for example, in causing a signiicant increase in
contractile ~orce in ~he Isolated Cat Atria and Papillary
- 31 -
, rJ ~ /,
r~luscle l~rocec1ure an~1 in causing a significant increase in
cardiac corltractile force i.n the ~.nesthetized ~og Procedure
with low or minioal changes in heart rate ancl blood pressure.
Detailed descriptions of these test procedures appear in
U.S. Patent 4,072,746, issued l;ebruary 7, 1980.
~hen tested by tl1e above-notecl Isolated Cat Atria
and Papillary ~1uscle ~roced~1re, thc compounds of formula I
and II when tested at doses of 3, lO or 30 ~g./ml., were
found to cause a significant increase, that is, greater than
25~, in papillary nluscle ~orce and a significant increase,
that is, yre.1ter than 25~, in right atrial force, while
causing ol1ly a low percenta~e increase (about one-third or
less thal1 the percentacJe increase in ri~ht atrial force or
~apillary l~-luscle forcc) in ricJht atrial rate. ~10reover, the
~5 G-(lo~er-al~yl) compou11ds of formula I unexpectedly were
found to be nlarkec1ly mol-e active as cardiotonics when tested
~y this procedure in comparison with the corresponding pr.ior
~r~ 6-des-(lower-al~;yl) compounds. ~lso, the compounds of
formula 1I whel-e R~ is hyc1rogen were found to be active as
2~) cardiotonics whereas, in contlast, the corresponding prior
art 6-des-(lower alkyl) compoun(1s are shown only as inter- j
mediates, not as having c~rdiotonic properties.
The markedly higher cardiotonic activity of the 6-
(lower-alkyl) compounds of formula I ov~r the corresponding
prior art 6-unsubstituted compounds is illustrated by the
following comparisons of test data obtained using said
isolated cat atria and papillary muscle procedure: the
yercentage increases irl papillary muscle force and right
- 32 -
atrial force for 6-methyl-5-~4-pyridinyl)-2~1ll)-pyridinone
were found to be 115% and 48% when tested at 10 ~g/ml
compared with corresponding respective increases of 48~ and
51% for prior art 5-(4-pyridinyl3-2~1ll)-pyridinone tes~ed at
100 ~g/ml, that is, ten times the dose; the percentage
increases in papillary muscle force and right atrial force
for 6-ethyl-5-(4-pyridinyl)-2(1H)-pyridine were found to be
106% and 50% when tested at 30 ~g/ml compared with corre-
sponding increases of 48% and 51% for 5-(4-pyridinyl)-2~lH)-
pyridinone tested at 100 ~g/ml, that is, more than three
times the dose.
As illustrative of a cardiotonically-active
compound of formula II where Rl is hydrogen whereas the
corresponding prior art 6-des-~lower-alkyl) compounds are
shown only as intermediates and not as cardiotonic agents,
1,2-dihydro-6-methyl-2-oxo-5-~4-pyridinyl)nicotinic acid
when tested by the similar in vitro guinea pig atria and
papillary muscle test (comparison with corresponding _n
vitro cat atria and papillary muscle test given in the
immediately following paragraphs) was found to show per-
centage increases in papillary muscle force and right atrial
force of 36% and 27% at 30 ~g/ml respectively and 44% and
69% respectively at 100 ~g/ml.
Cat or guinea pig atria papillary muscle test -
Cats of either sex weighing 0.6 to 2.7 kg were anesthetized
with sodium pentobarbital, 30 mg/mg i.v. and exsanguinated.
Hartley guinea pigs of either sex weighing 650 to 800 g
were stunned with a sharp blow ~o the head and exsanguinated.
Both ca~s and guinea pigs and their tissues were handled by
the following procedures. The chest was opened rapidly, the
- 33 -
heart excised, rinsed in Tyrode's solution, and the right
atrium and one or more small thin right ventricular papillary
muscles were excised. The tissues were transferred to a
large Petri dish filled with modified Tyrode's solution
oxygenated with 95% 2~ 5% C02. A silver wire was attached
to each of two opposite ends of the papillary muscle or the
atrial preparation. The wire from the nontendonous end of
the papillary muscle was attached to a glass covered platinum
electrode which was connected to the cathode of a Grass
Model SD~ stimulator. The pouch end of the atrium was
attached to the curved end of a glass rod. The preparations
were mounted in organ baths (40 ml for papillary muscles
and 50 ml for atrial) filled with modified Tyrode's solution
maintained at 37C and oxygenated with 95~ 2' 5% C02. The
wire on the tendonous end of the papillary muscle was looped
and tied to a force-displacement transducer ~Grass, PT03C)
and then connected to the anodal terminal of the stimulator.
The second wire on the right atrium was tied to a force-
displacement transducer and the atrium allowed to beat
spontaneously. The transducer is connected to a Grass model
7 polygraph. The resting tension on each muscle was adjusted
to produce a maximum contractile force ~Starlings Law) and
the muscle stimulated electrically at a rate of 120 beats/min
by a suprathreshold (1.5 x threshold) rectangular pulse, 0.5
msec in duration.
After Starlings and voltage adjustment, the prep-
arations were washed and allowed to equilibrate for 15
minutes before a test dose of dopamine (1.0 ~g/ml) or
isoproterenol ~0.0003 ~g/ml) was added and the response
- 34 -
" I
~ I
I').II. ~'~,';3~
monitored. Next, the test druy di,ssolved in vehicle or the
vehicle alone was aclcled to tlle tis~ue baths and the responses
recorcled. 'l'he tissues wer~ w~shec~ at least tw~ times af-ter
e~ch dose or unti 1 the pre-~lru~ coll trol lev~l in developed
~ensioll ar,(l rate was obtain~d. l;'ive or six doses of drug
were given to tlle preparatiolls over a period of 4-5 hours.
The modified Tyrode's solution bathing the prep-
aration had tlle following composition (in mM): NaCl, 136.9,
~Cl, 5.4; MaH2PO4, 0.4; CaC12, 1.~ gC12~6H2O, 1.0; NaC~IO3,
iO 11.9 glucose, 5.5; ~DTA, 0.04. The solution was equili-
brated with a gas mixture consisting of 95~ 2 and 5~ CO2,
and the pll was 7.3-7.4 at 37('.
'l'issue Differences - A comparison of cat and
yuinea pig tissue characteristics is presented as follows:
'rIle cat p~l)illc1ry muscles use('l ~veraged 5.12 ~ .20 mm in
lenc;th ancl weicJhed 7.0] + .G4 ~g. with a mean cross sectional
area of 1.31 Mm2 (N=~6, N beincJ the numher of preparations),
G~Iinea ~icI papillary muscle~s averaged 6.fiO + .18 mm in
lerIcJth an(l weiclIled 9.09 ~ .~7 mc,~. Theil- mecLn cross sectional
area was 1.31 ~Im (N--60). 'I'he restiny tension (tension
applied ~o tIle muscle to obtain maximum contractile force,
Starling's Law) applied to cat papillary muscles averaged
1.5 ~ .09 g. (N=34) while the resting tension applied to
guinea pig papillary muscles was 1.01 ~ .042 g. (N=56). Cat
papillary muscle control active tension at the start of thè
day averaged 0.62 ~ .05 c~. (N=34); the guinea pig papillary
muscles averaged .213 + .011 g. (N=62). A comparison of cat
and guinea pig papillary muscle active tension per mg. of
ti (control active tenslon in mg) indicated that for
wet welght of tlssue ln mg
their weic~ht cat papillary muscles are almost 4 times
- 35 -
a4~
stronger than guinea pig papillary muscles. The cat right
atria weighed more than guinea pig right atria; 306 * 15 mg
(N=2~1) and 76.5 + mg (N=~l) respectively. The average
right atrial rate for cat atria was 133 + 3 beats/min
(n=34) while the rate for guinea pig atria was 167 + 3
beats/min ~n=57). The applied resting tension on guinea
pig atria averaged 1.95 + .06 g (N=117); on cat right atria
the resting tension averaged 2.21 + .10 g (N=34). A com-
parison of guinea pig and cat right a-trial control active
tension indicates that, similar to the papillary muscles
from the two species, the cat m~scle was stronger; 1.93 +
.10 g (N=34~ active tension for cat atria and 0.742 + .0~
g (N=34) active tension for guinea pig atria. Because of
the lower control active tensions of guinea pig tissues the
percent change from control values for both rate and Force
responses is elevated. Thus, whereas cardiotonic activity
is ascertained with a papillary muscle force or right atrial
force increase of 26% and greater in the cat test, corre-
sponding activity in the guinea pig test is designated with
a papillary muscle force or ri~ht atrial force increase of
31% and greater.
When tested by the above-noted Anesthetized Dog
Procedure, compounds of formula I when administered intra-
venously as a single bolus injection of 0.01, 0.03, 0.10
mg/kg and higher caused a significant lncrease, that is,
greater than 25%, in cardiac contractile force or caTdiac
contractility with only low or minimal changes ~less than
25%) in heart rate and blood pressure. Moreover, the 6-
(lower-alkyl) compounds of formula I were found to be
- 36 -
,L~
markedly more active as cardiotonics when tested by this pro-
cedure in comparison with the corresponding prior art 6-
des-(lower-alkyl) compounds, as evidenced by the following
illustrations: the percen~age increase on the cardiac
contractile forces or cardiac contractilities for 6-methyl-
5-(4-pyridinyl)-2(lH)-pyridinone when tested as indicated in
the anesthetized dog at 0.01, 0.03 and 0.10 mg./kg. intra-
venously were found to be 28.8%, 53.5% and 124.6% respectively
compared with 41%, 70% and 92% for the corresponding prior
art 6-desmethyl compound, that is, 5-~4-pyridinyl)-2(lH)-
pyridinone, when tested at one hundred times the doses, that
is, at 1, 3 and 10 mg./kg. intravenously, respectively.
In clinical practice a compound of the invention
-37-
or salt thereo~ will normally be administered orally or
parenterally in a wide variety of dosage forms.
So~id composltions 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, flavouring, perfuming and preserving agents.
According to the invention, the compounds for oral admin-
istration 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 o~ organic solvents or suspending media are propyl-
ene glycol, polyethylene glycol, vegetable oils such as
olive oil and injectable organic esters such as ethyl
oleate. These compositions may also contain adjuvants such
as stabilising, preserving, wetting, em~lsifying and dis-
persing agents.
- 38 -
94~L
They may be sterilized, for example by filtration through a bac-
teria-retaining filter, by incorporation of sterilising agents in the compo-
sitions, by irradiation or by heating. They may 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 percentages of active components in the said co~position and
method for increasing cardiac contractility may be varied so that a suitable
dosage is obtained. The dosage administered to a particular patient is vari-
able, 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 de-
termined by the clinician considering all criteria and utilizing the best
judgement on the patient's behalf.
- 3~ -
