Note: Descriptions are shown in the official language in which they were submitted.
3S33
Case 100~5374
_ .
2 (lH)-PYRIDI~OM.E DERIVP.TIVES, THEIR PREPARP~TION A2~D
PHAR~lAC~lJ'rICAL COMPOSITIONS CONTAINING THEM
, . .. _ ._ . ,
The prPsent invention relates to 2(lH)-pyridone
derivatives, their preparation and pharmace~tical
compositions containing them.
In particular, the invention provides compounds
of formula I,
Rl~NH2
R2~}1.?,
wherein
Rl and R2 independently are hydrogen, alkyl or option-
10 . ally substituted monocyclic aryl
wlth the provisos that
a) at ].east one of Rl and R2 is aryl andb) when R2 is hydrogen,
3533
- 2 - 100-5374
then Rl is other than 2-, 3-- or 4-pyridinyl, un-
substituted or substituted by one or t~o lower
alkyl groups,
hereinafter referred to as "the compounds of the
invention".
It is to be appreciated that for the sake of
simplicity the compounds of the inventions are
defined with reference to the tautomeric form of
formula I. However, the invention extends to all
tautomeric forms of ~he compounds, e.g. the iminol
form.
As used herein, the term "monocyclic aryl"
indicates a radical bonded through an unfused aromatic
ring. The ring may be carbocyclic, such as phenyl, or
heterocyclic contalning up to 3 h teroato~s. As
indicated, the raclical may be substituted or
unsubstituted.
~ ~3~33
~ 3 - 100-5374
In accordance with the invention, there are
especially provided compounds of formula Ia,
1 ~ ~ ~ 2 Ia
R2a 1 0
wherein
Rla and R2a independently are
i) hydrogen or alkyl of 1 to 4 carbon atoms,
ii) phenyl, phenyl monosubstituted by di-
alkylamino of independently 1 to 4 carbon
atoms in each alkyl moiety or phenyl mono-
or independently disubstituted by alkyl of
1 to 4 carbon atoms, alkoxy of 1 to 4
carbon atoms or halogen o atomic number of
from 9 to 35 or
~ iiij pyrrolyl, furanyl, thienyl, thiazolyl,
imidazolyl~ pyrazolyl, pyridinyl, pyri-
midinyl, pyridazinyl or pyrazinyl
with the pro~isos that
a ) at least one of Rl and R2a has the above signi-
ficance ii) or iii) and
b ) when R~ is hydrogen,
then Rl is other than 2-, 3- or 4-pyridinyl.
~L835~3
~ 0-537~
Alkyl of 1 to 4 carbon atoms and alkoxy of 1
to ~ carbon atoms preferably are of 1 or 2, especially
1 carbon atom. Halogen preferably is chlorine or
bromine, especially chlorine. In dialkylamino the t~70
alkyl moieties preferably are identical. Pyrrolyl
preferably is 3-pyrrolyl. Furanyl preferably is
3 furanyl. Thienyl preferably is 3-thienyl. Thiazolyl
preferably is 4 -thiazolyl. Imidazolyl preferably is
4 -imidazolyl. Pyrazolyl prefer~bly is 3-pyrazolyl.
Pyridinyl preferably is 2- or 4-, especially 4-pyri-
dinyl. Pyrimidinyl preferably is 4-pyrimidinyl.
Pyridazinyl preferably is 4-pyridazinyl. Pyrazinyl
preferably is 2-pyrazinyl.
Rl preferably is alkyl or has the above sig-
nificance ii) or iii). Rl especially has significanceii). R2a preferab]y has the above significance i~, it
especially is ~et:hyl. Significance i) preferably is
alkyl. Significance ii) preferably is unsubstituted
or monosubstituted phenyl. When ~t is monosubstituted
phenyl, the substituent preferably is in the m- or p-,
especially in the p-position. h~hen it is disubstituted
phenyl, the su~stituents preferably are in the m-and p-
posltions.They preferably are identical. Pre'erred
substituents of the phenyl group are alkoxy and
halogen, especially alkoxy. Slgnificance iii) prefer-
ably is pyrrolyl, furanyl, th~enyl, pyridinyl,
pyrimidinyl, pyridazinyl or pyrazinyl, especially
furanyl, pyridinyl, pyrimidinyl or pyrazlnyl,
~3~33
~ 5 ~ 100-537
especially pyrimidinyl or pyridinyl, especially
pyrimidinyl. Preferably one of Rla and R2a has signi-
ficance i).
In one group of compounds of formula Ia Rl
and R2 are other than pyridinyl. In a subgroup they
have a significance other than significance iii).
A preferred group of compounds of formula Ia
is the compounds of formula Iaa,
aa
~ Iaa
H3~1 0
wherein
Rala has siginificance ii) or iii) indicated above.
In one group of compounds of formula Iaa
Rlaa is other than pyridinyl. In a subgroup Rlaa has
slgnificance li) indicated above.
. . . .. . . . . .. . . . . . . . . ..
A further group of compounds of formula Ia is
the compounds of_formula Ipa
1 ~ H2 Ipa
RP o
H
3~3~
- 6 - 100-537
wherein
a is i) phenyl, phenyl monosubstituted by dialkyl-
amino of independently 1 to 4 carbon atoms
in each alkyl moiety or phenyl mono- or indepen
~dently disubstituted by alkyl of 1 to 4 carbon
atoms, alkoxy of 1 to 4 carbon atoms or
halogen of atomic number of from 9 to 35,
or
ii) pyrrolyl, furanyl, thienyl 7 pyridinyl,
pyrimidinyl, pyridazinyl or pyrazinyl and
Rpa is alkyl of 1 to ~ carbon atoms.
A further group of compounds of formula Ia is the
compounds of formula Ipb,
~pb ~ H2 ' Ipb
RP~/
wherein
5 RPlb i5 hydrogen or alkyl of 1 to 4 carbon atoms and
R2b has the significance indicated above for RPa .
A further group of compounds of formula Ia is the
compounds of formula Ipc,
3~3;~
- 7 - 100-5374
1 ~H2
ll I Ipc
H
wherein RlPC with the exception of ~yridinyl. has the
significance indicatea above for RP
In accordance with the invention, a compoun~l of
the invention may be obtained by a process comprisins
aminating a corresponding compound of formula II,
1 ~ X
R2 ~ ~0
1 II
wherein Rl and ~2 are as defined above and Rx is a
group capable of conversion to a primary amino group.
-
The amination process may be effected inconventional manner for the production of analogous
3-amino~2~lH)-pyridinone derivatives. Rx may be a
conventional radical used for conversion to a
primary amino group, such as nitro and especially
carbamoylO For example, when Rx is carbamoyl, the
~3~33
- ~ - 100 5374
reaction conditions of a Hofmann degradation may be
used. The reaction preferably is effected under
strong alkaline conditions, e~g. in the presence
of an alkali metal hydroxide and bromine. P~ferably
water is used as a solvent. Suitable reaction ~em-
peratures may be from about 50 to about 100C,
conveniently about 100C.
The compounds of formula I may be isolated from
the reaction mixture and purified in a manner ana-
logous to kno~m methods.
The compounds of the invention may exist in free
base form or in salt form. Pree base forms may be
converted into salt forms in conventional ~anner and
Yice-versa. Suitable acids for acid addition salt
formation include hydrochloric, malonic, p-toluene-
sulfonic and methanesulfonic acid. Suitable bases
for anionic salt formation include sodium and
potassium hydroxide~
The starting materials may be obtained in
known manner.
33
- 9 - 100-5374
. . .
In particular, a.compound of formula II ,
wherein R is carbamoyl, may e.g. be obtained by
partial hydrolysis of a corresponding compound of
formula III,
lWC~
~2 1 ~ III
H
wherein Rl and P~2 are as defined above, e.g. wi~h
sulfuric or phosphoric acid.
A compound of formula III may e.g. be obtained
by reacting a co:rresponding compound of formula IV,
R
1~ NAlk2
~ IV
wherein Rl and R2 are as defined above and Alk is
lower alkyl, peferably methyl, with cyanacetamide.
The reaction may e.g. be effected in the presence
of acetic acid, in which case a:.compound oi formula
II may be directly obtained~
~3~33
- 10 ~ 100-5374
A ~ompound of formula IV may e.g. be obtained
by reacting a corresponding compound of ~ormula V,
Rl~
V
R2/ ~0
wherein Rl and R2 are as defined above, with an~,N-
di(lo~er)alkyl formamide di(lower~alkyl acetal, prefer-
ably N,~-dimethylformamide dimethyl or diethyl acetal.
Insofar as the preparation of any particular
starting material is not particularly described,
this may be effected in conventional manner or in
analogous manner to that desCribed herein.
In the following Examples all temperatures are
in degrees Centigrade and are uncorrec~ed.
~3~:i33
100-537
3-Amino-6-methyl-S-phenyl-2(1H
pyridinone
2.1 ml of bromine are addea dropwise at 0 to
a stirred solution of B.4 g of sodium hydroxide in 125
ml of water. 7~3 ~ of 1,2-dihydro-~-methy-1-2~
oxo-S-phenyl~nicotinamide are then _
added and the mix~ure heated under stirring to 100
for 3 hours. After cooling to room temperature the
resultant solution is carefully acidified with 6N hy-
10 droc~loric acid and stirring continued for 30 minutes.
The resulting precipitate is filtered off under
vacuum and recrystallized from methanol. The title
compound is obtained (M.P. 260-263; M.P. of the
mesylate salt form: 220-222 [dec.]).
The starting ma~erial i5 obtained as follows:
Benzylmethylketone and N,N-dimethYlformamide
dimethyl acetal are heated to 80 for 5 hours. The
so-obtained crude 4-dimethylamino-3-phenyl-3-buten-
2-one is then reacted with cyanacetamide at koiling t~
perature in the presence of sodium ethoxide. The
so-ohtained 1,2-dihydro-6-methyl-2-oxo-5-phenylpyridin-
3-carbonitrile ~M.P. 290-294 - from methanolJ is then
partially hydrolysed with 90 ~ sulfuric acid at
100 to give 1,2 dihydxo-6-methyl-2-oxo-5-phenyl
nicotinamide ~M.P.~ 300 - from dimethylformamide~.
35~31
- 12 - 103~5374
The following compounds of formula I may be
obtained by reaction of the appropriate com.pound of
formula II, wh-erein Rx is carbamoyl, in analogous
manner to Example 1~
~33~:i33
- 13 - 100-5374
, , _~
Example Rl R2 .
, . _ . ~___
2 m-tolyl Me ~ 245-250 ~dec.
3 p-Cl-phenyl ~le ms 231-234
4 p-MeO phenyl Me b 256 260
m-,p diMeO-phenyl ~Ie b 218~220
6 phenyl Et b 192-194
7 o-tolyl Me .b 231-232
8 Me phenyl b 174-176
9 pyrimidin-4-yl H b 283-287
phenyl H ch 240-243
11 pyrazin-2-yl H b 262-264
12 I phenyl ?henyl b 296-299
13I furan-2-yl Me b 189 191
14¦ pyridin-2-yl ~phenyl b 239-242
15`I m-MeO-phenyl I Me b 244-245
16¦ pyridi.n~4-yl , Me I b 290-295
17j o-MeO-phenyl ' Me ¦ b 224-226
b = in free base form
ch = in hydrochloride salt form
ms = in mesylate salt form
Et = ethyl
Me = methyl dec. = decomposition
MeO = methoxy
~3~i~3
- 14 - 1~0-5374
The compounds of the invention possess pharma-
cological activity.
The compounds possess cardiotonic activity,
as indicated by standard tests. For example, in the
normotonic Numal anaesthetized dogl an increase in the
contractile force of the left ventricle is observed
upon intravenous administration of from about 0.02
to about 2 mg/kg.
The test method is as follows:
Dogs of either sex weighing from 10 to 15 kg
are used. Numal in a dosis of 65 mg/kg i.v. is used
as an anaesthetic. The animal is attached in supine
position on the operation table. After the usual
preparations have been effec~ed, a heparini7ed catheter
is introduced along the Arteria carotis dextra into
the left ventricle under radiological control and the
transmission of the pressure is registered with a
donor membrane (Gould Statham P 23 Gb). The increase
in pressure as a function of time is computed and
registered wi~h an HSE-physiodifferentiator. The
pressure increase in the left ventricle is a measure
of the contractile force of the heart. The magnitude
of the pressure differential is indicated in mm ~g/sec
A suitable body temperature (about 36 to 37C) i8
maintained constant. After a control period of about
40 minutes the test substance is injected into the
Vena femoralis and it~ effect on the registered or
computed parameters observed.
3533
- 15 ~ 5374
The compounds are therefore indicated for use
as cardiotonic agents, e.g. for ~he treatment of
heart insuLficiency.
Preferred in this indlcatlon are the compounds
cf Examples 1 and 4, especially the compound of
Example 1.
~ n indicated daily dose is from about 10 ~g
to about 500 mgt suitably administered,e g. orally,
in divided dosages of from about 2.5 mg to about
250 mg of the compounds two ~o four times daily, or
in re~ard form. An example of a daily dosage is from
10 to 100 mg.
The compoun~s may be administered in pharma-
ceutically acceptable salt form, preferahly acid
addition salt form. Such sal~ forms exhibit the same
order of activity as the free forms and are readiiy
prepared in conventional manner. The present invention
also provides a pharmaceutical composition comprising
a compound of the invention in free form or in phar-
maceutically acceptable salt formr in associationwith a pharmaceutical carrier or dlluent. Such
compositions may bP in the form of, for example, a
solution or a tablet.
