CA1064038A - 3-(.alpha.-IMINOBENZYL)-4-HYDROXY-6-PHENYL-2(1H)PYRIDONE COMPOUNDS - Google Patents

Abstract

IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS

Abstract of the Disclosure The invention provides novel 3-(.alpha.-iminobenzyl)-4-hydroxy-2(1H)-pyridone derivatives, useful as sleep inducers and minor tranquillisers, and processes for their production.

Description

C~

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.

CANA~

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~

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 ~' ' . ' , .

~ ~ ' ',, . . -.

CANAD~

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

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 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~"~

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 ~' `' '

Claims (5)

The embodiments of the invention in which an exclusive privilege or property is claimed are defined as follows:

1. A process for the production of a compound of formula I

in which R1, R2 and R4, which may be the same or different, each signifies hydrogen, fluorine, chlorine, tri-fluoromethyl or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable base addition salts thereof, characterised by reducing a compound of formula II, II

in which R1, R2, R3 and R4 are as defined above, in an inert organic solvent and, where required, converting a resulting compound of formula I into a pharmaceutically acceptable base addition salt thereof.

2. A process according to claim 1, in which, in the compound of formula II, R1, R2 and R4 are all hydrogen, and R3 is methyl.

3. A process according to claim 1, in which, in the compound of formula II, R2 and R4 are both hydrogen, R3 is methyl and R1 is p-fluoro.

4. A process according to any one of claims 1 to 3, in which the reduction is effected by catalytic hydrogenation, and at a temperature of from 10° to 50°C.

5. A compound of the formula I

in which R1, R2 and R4, which may be the same or different, each signifies hydrogen, fluorine, chlorine, tri-fluoromethyl or alkyl or alkoxy of 1 to 4 carbon atoms, and R3 is alkyl of 1 to 4 carbon atoms, and pharmaceutically acceptable base addition salts thereof, whenever produced by the process according to claim 1 or an obvious chemical equivalent thereof.