Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
C~
600-6697
IMPROVE~IENTS IN O~ RELATING_TO ORGANIC CO~SPOUNDS
This invention relates to 3-(a-iminobenzyl~-4-hydroxy-
2(1H)-pyridone derivatives.
More particularly, this invention provides compounds
of formula I;
in which Rl, R2 and R4, which may be the same or
different, each signifies hydrogen,
fluorln~, chlorine, trifluorome.hyl or
alkyl or alkoxy of 1 to 4 carbon atoms,
and R3 is alkyl of 1 to 4 carbon atomsO
1 The invention also provides a process for the pro-
duction of compounds of formula I t comprising reducing a
compound of formula II~
.
-- 1 .
.
.
.. , ' . . .. ~........ ..
:~ .
' . '.
. .
6~0-6697
CANADA
~ 9~
1 ~ II
~ n ~hich Rl J R2~ X3 and R~ are as deined above,
in an inert organic solvent.
The process may be effected in conventional manner, for
example by catalytic hydrogenation. Suitable catalysts
include palladium on carbon, platinum oxide and raney
nickel, preferably palladium on carbon. An inert organic
solvent r such as a lower alkanol, e.g. methanol org pref-
erably ethanol, is suitably employed. The hydrogenation
is conveniently effected at a temperature of from 10 to
50C, preferably 20 to 30C, and the reaction time may
vary, for example from 1 ~o 10 hours~ more usually 2 to 3
hours.
The resulting compounds of formula I may be isolated and
puri~ied using conventional techniques. ~here required, free
hydroxy forms of the compounds may be converted into base
addition salt forms in conventional manner, and vice versaO
As will be appreciated, ~he compounds of formula I
may exist in tautomeric forms of ~ormulae Ia, Ib and Ic,
.
.... . . . ; ......... . ...... . ........ .... .. .__ .... _, __.. ,
.
e 600-6697
CAN~DA
O O
Rl--~C -~-R3 ~ R ~3--C ~N-R3 ~j 2
W o~L ~ ,} o~L R"
Ia Ib
OH
OJ~R
Ic
in which Rl, R2, R3 and R4 are as defined above,
Whils reference is made above and hereinafter solely
to the form of formula I, or the corresponding chemical
name, it is to be understood that the invention is not
intended to be limited to, or to the production or use of,
any particular form of the compounds.
~ he compounds of formula II may be produced by cyclising
a ~ompound of formula III,
/ ~ X CU -C ~ III
O ,4
., ., . . . . . . ... . .. ., . . . . . ............... . ... ~ ~.. . . .. ... .
~ ' ' , .
.
`~ , CAN,~D,~
600-66~7
in which Rl, R~, R3 and R4 are as defined above,
in the presence of an acid and a solvent~
The cyclisation may be effected in conventional manner,
for example by treatment of the co~pound of formula III
S with an acid, such as hydrochloric, ~-toluenesulphonic,
polyphosphoric or, preferably,sulphuric acid, ancl suitably
in an inert solvent, such as an aromatic hydrocarbon,
e.g. benzene or toluene. Preferably, however, an excess
of the acid may be employed to provide the reaction medium.
The process is suitably effected at a temperature of from
80~- to 150C, preferably at the reflux temperature of the
- reaction mixture, and the reaction time may, Eor example,
vary from 12 to 36, more usually 20 to 36 hours.
- The resulting compounds of foxmula II may be isolated
ana purified using conventional techniques.
The compounds of formula III may be produced by oxid-
ising a compound cf formula IV,
O
1 ~ H2-CH ~ R2 IV
OH
in ~Ihich Rl, R~ R3 and R4 are as defined above.
- 4 -
CANA~
600-6637
The o~idation may be effected in conventio:nal manner,
for example with potassium permanganate or, preferably,
chxomium trio~ide, and under aqueous ac.idic conditions.
The preferred acids include mineral acids, such as sulph
uric or hydrochloric acid and, prefe:rably, organic acids~
in particular acetic acid. The reaction temperature is
conveniently from 10 to 50~C, preferably from 20D to 30C~
and the reaction time may, for example~ vary from 1 to 5,
more usually 1.5 to 2.5 hours.
The resulting compounds of formula III may be isolated
and purified using conventional techniques.
The compounds of formula IV may be produced by reacting
a compound of formula V0
l~`CH2(~ 3 V
in which Rl an~ R3 axe as defined above,
with a compound of formula VI,
.~
n VI
.
5 ~
.~ ' .
, . . . . ... . _. .. ...
; .
`- c~
600-G697
L~
in which R2 and R~ are as aefined above~
in an ine.rt organic solvent.
The reaction is suit~ly effected at a temperature of
~xom -75 to -55~C, preferably -bS to -60C and suitable
solvents include aliphatic hydrocarbons, such as pentane,
hexane and heptane, and, preferably, ethers~ such as diethyl
ether or, in particular, tetrahydrofuran. The reaction
time may, for example, varv from 1 to 5, particularly 2.5
to 3.5 hours~ The compounds of formula V are desirably
produced in situ in conventional manner from the corres-
ponding 3-phenyl-N-alkyl-5-methyl-isoxazole-4-carboxamide
by reaction with, for example, a Cl 4 alkyl lithium,
particularly n-butyllithium under ~he conditions, for
example, of the subsequent step for producing compounds
~V. - .
The resulting compounds of formula IV ma~ be lsolated
and purified using con~entional techniques.
The compounds of ~ormula VI and the necessary starting
~aterials for producing compounds of foxmula V are either
kno~m or may be produced in conventional manner from
available materials.
The compounds of formula I possess pharmacoloyical
activity. In particular, they possess sleep inducing and
~' ' . ' , .
- 6 -
~ ~ ' ',, . . -
.
CANAD~
600-6697
minor tranquillising activity as indi.cated 1) by the
hexobarbi.tal reinduction method of Winter, ~. :Pharmacol.
and Exp. Therap. 94 7-11, (1948)~ 2) by their ability
to produce docility in behaviour test:s in mice given 25
to 200 my/kg of animal body weight, i.p., o~ the test com-
pound according to the 30~word adjective check sheet
system basically as described by Irwin S. (Gordon Research
Conference, Medicinal Chemistry, 1959) and Chen [Symposium
on Sedative and Hypnotic Drugs, l~illiams and Wilkins,
(1954)~; 3) by their ability to antagonize chlonic
convulsions and death in mice given about 35 mg/kg of the
test compound followed immediately by 45 to 2~0 mg/k~,
i.p~,of N-sulfamoylazepine; and 4) by scoring for loss
of righting reflex accordin~ to the method of Reed-Muench
[(~merican 30urnal of Hygiene 27, 493-497, (1938)], in
which mice are administered 12.5 mg/kg, i.p., of Thioridazine,
immediately after which the test compound is administered
at dosages of S to 100 mg/k~ in a volume of 0.1 ml/10 g of
body weight. Sixty minutes after dosing, the mice are
scored for loss of righting reflex; and 5) by their ability
to reduce conflicts as defined in the Geller Conflict Test
tIxving Geller, Psychopharmacologia, I~ 4~-492 (1960)].
~ he compounds of formula I are therefore indicated for
use as sleep inducers and minor tranquillisers~ For the
sleep~inducing indication~ an indicated suitable daily
- 7 ~
:......... . ... . . . . . ...... . ..
(~r~
6~-6697
dosage is from 35 to 1000 mg, which may be a~ministered
in divided doses of rom about 8 to S00 mg, two to four
times daily, but which is preferably administered as a
sinyle dose at bed-t.ime. For the minor tranquillisin~
activity, an indicated s~itable daily dosage is from
30 to 1500 mg, sui.tably administered in divided dosages
of from 7.5 to 750 mg, two to four times daily~ or in
retard ~orm~
The compounds may be administered in free hydroxy form
or in the form of pharmacologically acceptable base addition
salts, which salt forms have the same order of activity
as the free forms. Suitable salt forms include alkali
metal forms, in particular lithium, sodium and potassium
salt forms, and alkaline earth metal forms, in particular
magnesiwm or calcium salt forms.
The compounds may be admixed with conventional pharm-
aceutically acceptable diluents and carriers, and, option-
ally, other excipients, and administered in such forms as
hard-filled capsules and tablets.
~0The preferred compounds of formula I are those in
which Rl to R4 have the following significances:-
: Rl = hydrogen, chloxine, flucrine, trifluoromethyl, methyl
or methoxy, particularly hydrogen or chlorine, more
particulariy hydrogen;
. .
~, ' ' - ' .
`
CANA~A
600-6697
R2 ~ hydro~en;
R~ = hydrogen, chlorine, fluorine, trifluoromethyl, methyl,
or methoxy, particularly hydrogen, chlorine, trif-
fl.uoromethyl, methyl or me-thoxy;
R3 = methy~. .
More preferred compounds are those having a combination
of the above preferred significances. I'he most preferred
compound is 3~(a-iminoben~yl)-4-hydroxy-6-phenyl-1-methyl-
2~1H)-pyridone.
The following Examples illustrate the inventionO
_ g _
C~NADA
600-~697
EXAMPLE 1: 3-(a-Iml:nobenzyl)-4-hydroxy--6-E~e~y- l-met ~ -
c~
a) 3-Phenvl-5-(R-hvdroxyPhenethv~)-M-methyli~oxazole-4
c~rboxamide [compound IV]
A suspensi.on of 75 g (0.348 mole) of 3-phenyl-5,N-di-
methy~-isoxazole-4-carboxamide and 1 liter o tetrahydro-
furan is cooled ~o -65C and 478 ml of 1.6M n-butyl-
lithium in hexane (0.765 mole) is added, dropwise, main-
taining the temperature between -60 and 70C~ After .
the addition is complete, the orange suspension is stirred
for 11/~ hours at -60 to -70C, and then 37.2 g (0.350 .:
mole) of benzaldehyde in 375 ml of tetrahydrofuran is
added, drop~ise, maintaining the temperature between
-60 and -70C. After addition is complete/ the mixture
is stirred for 11/2 hours at -60 to -70~C and then warmed
to -30C and-quenched by the addition of saturated ammon-
ium chloride solution. The mixture is further diluted
with tetrahydrofuran and the la.yers are separated. The
tetrahydrofuran layer is washed twice with 50~ brine, and
once with brine, dried over anhydrous magnesi.um sulphate,
filtered, and evaporated in vacuo. The solid residue is
triturated with a 50:50 mixture of ether:petroleum ether,
filtered and washed with cold ether to g~ve th~ heading.
compound, m.p. 183~-184C.
'
... . . , . _ . .. . . . _ _
;
: - ~ , . , . ~:
C~ANA[) q
600-6697
b) N-~lethyl-5-~henac~l-3-~henyllsoxazole~4-carb-oxamide
[compound III]
A suspension of 50 g (0.155 mole) of 3-phenyl-5-
(~-hydrox~rphenethyl)-M-methyl-isoxazole-4-carboxamide and
800 ml of acetic acid, at room temperature, is treated,
~ropwise, ~ith 18.4 g (0.185 mole) of chromium trioxide
. . .
in 185 ml of water. The resulting solution is stirred
for 2 hours at room temperature and a portion of the
acetic acid is removed in vacuo. The remainder is poured
onto ice water and extracted with methylene chloride.
The methylene chloride iayex is washed with 2N sodium
hydroxiae, dried over anhydrous magnesium sulphate~ fil-
tered and evaporated in vacuo. The solid residue is
triturated with hot ether, cooled to O~C and filtered
to give the heading compoundJ m.p. 125-128C.
c) 5-Methyl-3L6-di~h_nyl-isoxazolo~4~5-c]~yridin-d~5H~
one tcompound II]
A mixture of 26.1 g ~0~0815 mole) of N-methyl-5-
phenacyl-3-phenylisoxazole-4-carboxamide and 261 ml of
2M sulphuric acid is refluxed for 24 hours The mixture
is cooled and extracted with methylene chloride. The
methylene chlorlde layer is washed with watex and then
brine, dried over anhydrous magnesium sulphate, filtered
- and evapoxated in vacuo~ The residue is triturated with
. .
.... , .~.. , ,,, , ,; , ,
:, . .
G,^.1`,;`~r~"~
600-6697
ether and then recrystallised from ethanol to give the
heading compound, m.pi 149-151.5C.
d) 3-~~Iminobenzvl)-a-hydroxv-6-~henyl~ me-thY1~2(1H)-
___.___________._______ ____ ___ __~ ~_______________
~ridone [compouncl I]
_ _ _ _
A mixture of 16.5 y ~0.0545 molle) of N-n~ethyl-3,6-
diphen~l-isoxazolo[~5-c]pyridin-4(5H~-one, 330 ml of
ethanol and 1.65 g of 10~ palladium on carbon is hydrog-
enated at 50 p.s.i. and room temperature. The hydrogen-
ation is ceasea after 1 equivalent of hydrogen is absorbed
Sca. 2.5 hours). The mixture is treated ~7ith methylene !,
chloride and the catalyst is removed by filtration.
The solvents are removed in vacuo to a volume of ca. 50
ml and then ether is adaed to precipitate.solids which
are removed b~ ~iltration to give the heading compound,
mOp. 238~-240~C. The above compound is dissolved in
methanol and treated with ~odium hydroxide solution to
yield after evaporation the sodium salt of 3-(a~imino-
benzyl~-4-hydroxy 6-phenyl-1-methyl-2(lH)-pyridone.
EXAMPLE 2:
__ .
In manner analogous to Example 1, and employing
- appropriate starting materials in approximately equivalent
amountsjr the compounds of formula IV~ III, II and I, in
w~ich Rl, R2, R3 and R~ have the significances indicated
1~ ~he following Table, may bP obtained.
.. .. _ . . . _ .. ..
-- -- ~
ul
C~
~I~ ~ o ~n co ~
H I
~D~D ~1 oo ~ 1
c~ ~ ~ ~ ~ r~ ~
~ ~ ~ ~I N r l 1~1
_ ~
In
. . ,U~ ~1
~D O ~D
I 1~ U~ ~ ~ I
O H ~1U) ~ l r I r-l Lll
H
r~
1:~
rl r3~1 ~Ir l ~1 r~l ~1
P~ _ _ _ ~t :
~ ~ i
.~J H ~ Irl
r-J H ~
al H tl7 r t a~ ~ O
~ 1~
~I r l r~ ~1 ~1
. --~' ~~ u~ ~ ~--'~-- '~' i
. ~ ~ o o In ,~ ~
- .
H ~ .
t~
I~ 00 ~D ~ ~r ~ r~
-1 I-J ~I r-l r l r-l r~l
__ ~
m ~ ~ ,~ r-l
~r ~ .) U C.~ C,.)
m ~ o l ~ b~
r7 ~ ~ ~ ~ ~ ~ ~ ~
~ ~ m $ P~ x ~ ~ m I
_~
~c~ $ x 5: m m ~ :~ m
~ ~ .
~ ........................ ~ ~ ~
m ~' $ ~: ~ m 3 5 :
' ~: _ . ~_
'~
~ Z ~ ~ ~ _~ _~ _~ ~_ _ ~ ~ _ ~ _
~ _~ ~
, .
:: -- 1 3
~'
`' '
