Note : Les descriptions sont présentées dans la langue officielle dans laquelle elles ont été soumises.
~o70685
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IMPROVEMENTS IN OR RELATING TO ORGANIC COMPOUNDS
The present invention relates to morphanthridine
derivatives.
The present invention provides compounds of
formula I,
~ ~ N ~
~NJ
2 ~ ~ ~ ~ I
CHz
wherein Rl is hydrogen, alkyl of 1 to 4 carbon atoms,
or hydroxyalkyl of 1 to 4 carbon atoms, and
R2 is hydrogen or halogen.
When Rl is alkyl, it is preferably methyl. When
Rl is hydroxyalkyl, this preferably has 2 to 4 carbon
atoms. The hydroxy group is preferably bound to the
terminal carbon atom away from the nitrogen atom to which
Rl is bound. Rl is, for example, ~-hydroxyethyl. Rl is
preferably hydrogen or alkyl.
~` When R2 is halogen, it is fluorine, chlorine or
bromine, especially fluorine or chlorine.
The present invention also provides a process
for the production of a compound of formula I, as defined
~ .
'.' 1 ' O
'' ` '
` ` 1070685
' ..
above, whlch comprises reacting a compound of formula II,
,; ' ~
R2 ~ ~ ~ ~ ~ II
~, CH2
....
wherein R2 ls as deflned above, and
X 18 chlorlne,
with a co~pound of formula,III,
.~-N ~ N-Rl III
1, , .
;- 5wherein Rl is a3 defined above.
The process may be effected ln known manner for
~i ~ 8uch condens ation~.
.. The reaction may be convenlently effected ln an
.
i lnert organlc/solvent, for example, xylene o~ dioxane,
,
.
~'':' .. ' "
.; ~ -
~ 2 -
.,, . ~ ~ . , ~ .
.
107~85
`: . .. .
. .
at temperature~ between 50 and 170 C, preferably between
100 and lqO C.
The re~ulting compounds of formula I may be l~olated
and purlfled ln conventlonal manner,
~:,. s .A compound of formula II, used as startlng material
. may be obtained by
..;
. a) reactlng a compound of formula IV,
" .,
,. A2 ~ ' ~ ' ? IV
;
O
. .:
r~
;~ wherein R2 18 as deflned above,
,~ with a compound of formula V,
,....
...... .
~f ~ CH3-Mgy V
.. ,;.'~ , . . .
;~. lO whereln Y is chlorine, bromine or lodlne,
.
ospeclally bromlne,
under conventlonal condltlons for a Grlgnard reactlon,
b) hydrolysing the resultlng reactlon complex to glve a
:
: . ;
. ~ .~ . .
: .
.,. .
- .
? ,~
. - 3 -
',:
. .
.
~ r 1070685
.
. ll-methyl-ll-hydroxy reactlon product,
c) dehydratlng the ll-methyl-ll-hydrox~ reactlon product
ln conventional manner to give a compound of formula VI,
- ~
R ~ NH-Co
- 2 ~ VI
, .. .
: , CH2
,~ .
. . .
whereln R2 is a~ deflned above, and
. S d) converting the compound of formula VI ln conventional
.1 , .
manner lnto a com*ound of formula II~
Insofar as the preparatlon of any startlng
fjl . materlal 18 not partlcularly degcribed, this is known or
`. may be produced and purlfled ln known manner or in
analogous manner to methods described here$n or ln
: analogous manner to known processe~.
: Free base form~ of compound~ of formula I may be
converted into a~id addition ~alt ~orm in conventional
manner and vlce versa. Suitable acld3 ~or ~alt formation
include hydrochloric acld, methane-~ulphonlc acid or
.~ maleic acld.
., , ~ .
. ~
_ 4 _ -
~ r!~
. ~ ....
.. ....
,
07~685
~ . . _ . ,
;~
,
: In the following Examples all temperatures are
... .
... ~ uncorrected and are in degrees Centigrade.
,,
., .
.~
,,
.
: '.
:
,',..~ -
.
:
:-
. _ 5 _
:
-
.
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EXAMPLE 1~ Methylene-6-(4-methyl~i~erazin-1-yl)-
mor~hanthridlne
a~ 6-Chloro-ll-methylene-mor~hanthridine
_ _ _ _ _ .
8 g of S,6-dihydro-11-methylene-morphanthridin-6-one are
boiled for 2 hours with 3 ml of N,N-dimethylaniline and
80 ml of phosphoryl chloride. The resulting
dark solution is concentrated in a vacuum. The residue
is treated with xylene and once again the mixture is
evaporated in a vacuum. The residue is dissolved in
80 ml of xylene and the solution is poured onto ice-
water. The mixture is extracted twice with xylene. The
xylene extracts are combined, washed in turn with dilute
hydrochloric acid, water and a saturated sodium chloride
aqueous solution, dried over sodium sulphate and treated
with active charcoal. The xylene solution is filtered
through aluminium oxide and concentrated to a volume
of about 100 to 150 ml in a vacuum. This solution contains
6-chloro-11-methylene-morphanthridine which is used
directly in step b).
b) 11 Methylene~6-(4-methyl~i~erazln-~-yl)-mor~hanthridine
The xylene solution of 6-chloro~ methylene~morphanthridine
is treated with 8 g of N-methylpiperazine and the mixture
is boiled for 4 hours. The hydrochloride salt of
N-methylpiperazine precipitates out of solution. The
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mixture is treated with water and 25 ml of a concentrated
sodium hydroxide aqueous solution. The organic phase is
- shaken twice with ether, washed with water and extracted
: with 2N hydrochloric acid.
The acid extract is made alkaline with 2N aqueous
sodium hydroxide solution and the resulting oily phase
which separates out is extracted twice with ether. The
ether extracts are combined,.washed with water and a
saturated aqueous sodium chlorlde solution, dried over
sodium sulphate, tre.ated with active charcoal and then
filtered through aluminium oxide. Recrystallization from
ether/petrol.eum ether yields ll-methylene-6-~4-methyl-
piperazin-l-yl)-morphanthrldine as prisms; M.Pt. 119 -
120.
In analogous manner to that described in Example
1 using the appropriate starting materials of formulae
II and III the following compounds of formula I are
obtained, wherein:-
Ex.No. Rl ~ M.Pt.
2 H H fil90-195oc 1)2)
~208-2lloc 1)3)
3 H0-CH2-CH2- H 151-155C
2 2 Cl 147-149C
H Cl 130-138C
6 CH3 Cl 162-164C
7 H F 125-126C
8 CH3 F 138-140C
-- 7
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1) decomposition
2) maleate salt form.
3) methane sulphonate salt form
The production of the 5,6-dihydro-3-halo-11-
methylene-morphanthridin-6-ones used as starting materials
of formula IV may be effected as follows_-
a) 5 6-dihydro-3-fluoro-morehanthridin-6,11-dione
_L_____ ________________ _____________________
A solution o~ 88 g of chromium (VI) trioxide in 60 ml of
water is added dropwise over 4 hours to a stirred solution
of 5,6-dihydro-3-fluoro-morphanthridin-6-one in 1.5 Iitres
of acetic acid warmed to 60C. The mixture is then-heated
for 1 hour under reflux, cooled and then poured onto ice-
water. The crystals formed are separated off and washed
with water. After drying the heading compound M.Pt. 282-
285C (sublimation) is obtained.
In analogous manner 3-chloro-5,6-dihydro-morph-
anthridin-6,11-dlone is obtained, melting at 293-295~C.
b) 5 6-Dihydro-3-fluoro-11-meth~lene-mor~hanthridin-6-one
_L_____ ____ ____ __ __ __ ____ _ __ ___ __ _ ____ ___ ______ __
150 ml of absolute tetrahydrofuran is added in portions
with an exothermic reaction to a Grignard solution of
5.6 g of magnesium, 30.6 g of methyl iodide and 80 ml
of ether. The solution is cooled to 10C. In a nitrogen
gas atmosphere this solution is treated in small portions
-- 8 --
. . ~.
.
1C~70685
with a suspension of l9 g of 5,6-dihydro-3-fluoro-morph-
anthridin-6,11-dione in 200 ml of absolute tetrahydro-
furan. The mixture is stirred for 4 hours at room
temperature and then poured onto an ice-cold ammonical
ammonium chloride aqueous solution. The mixture is then
extracted with ether. The ether extracts are washed with
brine and concentrated to dryness. The hard residue
containing 5,6-dihydro-3-fluoro~ hydroxy-ll-methyl-
morphanthridin-6-one is dissolved in a little acetone,
treated with 18 g of pyridine hydrochloride and warmed
in the presence of a stream of nitrogen. ~fter the acetone
is removed, the mixture is warmed for 90 minutes to
130 - 140C, cooled somewhat, treated with water,
separated from the water and dried. After recrystallization
lS from acetone/petroleum ether the heading compound melting
at 220 - 230C (crystal change from 160C) is obtained.
In analogous manner 3-chloro-5,6-dihydro-ll-
methylene-morphanthridin-6-one melting at 247 - 249C
is obtained.
_ g _
.. . - , . , : .
- .
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The compounds of formula I exhibit pharmacological
activity. In particular, the compounds of formula I (a)
inhibit the locomotor activity in mice in a test carried
out according to the principles of Caviezel and Baillod,
Pharma Acta E~elv. 33, 465-484 (1958), (b) inhibit the
arousal reaction of xabbits as determined by electro-
encephalography in a test carried out according to the-
method of Stille et al., Int. J. Neuropharmacology 4~
375-391 (1965) and/or (c) have a significant effect on
the sleep of rats, significantly increasing the deep
sleep phase, in a test carried out according to the
method of Stille et al, Ps~chopharmacologica 28, 325-
337 (1973).
As a result of their activity in tests a) and b)
the compounds are therefore indicated for use as anti-
psychotics. An indicated daily dose is from about 5 to
about 500 mg, conveniently administered in dlvided doses
2 to 4 times a day in unit dosage form containing from
about 1 to about 250 mg or in sustained release form.
The compounds of formula I, wherein R2 is halogen,
especially the compound of Example 6, exhibits especially
interesting activity in tests a) and b).
As result of their activity in test c) the compounds
are indicated for use as hypnotics. An indicated daily
dose is from about 1 to 100 mg, conveniently administered
-- 10 --
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in a single dose shortly before the time when sleep is
required.
The compounds of formula I, wherein R2 is hydrogen,
especially the compound of Example 2, exhibit particularly
interesting activity in test c).
The compounds of formula I may be administered
in pharmaceutically acceptable acid addition salt form.
Such acid addition salt forms exhibit the sam~ order
of activity as the free base forms and are readily
prepared in conventional manner. The present invention
also provides a pharmaceutical composition comprising
a compound of formula I, in free base form or in
pharmaceutically acceptable acid addition salt form,
in association with a pharmaceutical carrier or diluent.
Such cOTnpOSitiOnS may be in the form of, for example,
a solution or a tablet.
.
