Note: Descriptions are shown in the official language in which they were submitted.
~04~137
The present invention relates to certain new derivatives
of phenylpropylamine, to a process for their preparation and to the
'~ use of these derivatives in pharmaceutical compositions.
,' ~
Thus, the present invention consists in compounds of -
general formula (I): -
El~A_CH2_NR R ' '
R
in which R is a hydrogen or halogen (fluorine, chlorine, bromine
or iodine, preferably chlorine) atom, R is a phenyl or cyclohexyl ;~
group, and is a cyclohexyl group when 1~2 is a halogen atom; A is a
CH2CH2 or CH=CH group; and R and R, which may be the same or s ;~
different are each a hydrogen atom or an alkyl group, preferably
ha-~ing from 1 'o 3 e..rbon atoms, provided that R3 and ~4 ma~r no
both be hydrogen atoms, or NR3R may represent a substituted or
unsubstituted heterocyclic group having from 5 to 7 atoms in the
heterocyclie ring and optionally containing a ~econd hetero atorr.; and
aeid addit1on salts of said compounds. ~ ~;
Aecording to one embod1ment of the invention, when N~3R4
lS a heterocyelie group, it may be unsubstituted or may have one ~or
more subst1tuents, preferably Cl-C5 alkyl groups or hydroxyalky1
.:
.,
~ : ' :'- '
,
: ~., : : .
..
5~3~7
groups having from 1 to 5 carbon atoms. E~camples of such
heterocyclic groups are: pyrrolidino; morpholino; thiomorpholino;
- 2, 6-dlmethylmorpholino; piperidino; 4-methylpiperidino; piperazino;
4~ hydroxyethyl)-piperazino; 4-methylpiperazino; and azepino groups.
:.
,: The acid addition salts of the present invention may be
prepared by mixing a compound of general formula (I) wii;h an organic
or inorganic acid; preferred acids are hydrochloric acid, hydrobromic
acid, hydroiodic acid, oxalic acid, succinic acid, maleic acid, fumaric -
acid, acetic acid, benzoic acid, citric acid, lactic acid, malic acid,
10 ascorbio acid, salicylic acid, glutamic acid, methanesulphonic acid and p- toluenesulphonic acid .
The compounds of formulà (I) may be prepared by condensin jg
an acetophenone of general forrrlula (II):
,
~CO-CH3 (Il)
:
(in which R and R are as defined above) in a Mannich reaction
.: . . ~
wi~th formald~ehyde and a primary or secondary amine, reducinjg the
amino-ketone thus formed to a 3-amino-1-phcnyl-propan-1-ol) and
subsequently dehydratlng this 3-amino-1-phenyl-propan-~-ol. The
.
' '' . . ':
,~
2 --
:: , . ::
.
.
1045~L3~7
compound so produced is of general formula (I) in which A is CH-C~
subsequently, if desired, this compound may be hydrogenated-to
produce a compound of formula (I) in which A is CH2CH2.
~' ' - .
Thus, the present invent;on further consists in a process
for the preparation of a compound of formula (I) (as hereinbefore
~ defined), which comprises the steps of~
. (a) condensing an acetophenone of formula (II) (as
!
: ~ hereinbefore defined) with formaldehyde and an amine of formula
HNR3R4 (R and R being as defined above) to form an amino-ketone;
(b) reducing said amino-ketone to a corresponding 3-amino- ~ : :
1-phenyl-propan-1-ol;
~ . .
~' (c) dehydrating said 3-amino-1-phenyl-propan-1-oI to : `
; a compound of formula.(I) in which A is CH-CH; and if des1red
;~ (d) hydrogenating said ~compound of formula ~I) in which A
~ 15 . is CH=CH to form a compound of:formula (I) in which A is CH2CH2. ~.
. . .
~ .The compound of formula (I) so produced may then be reacted with :
: an acid to form the acid addltion salt. : :. -
~: :
In step~(b) of the process, the reduction is preferably
effected by means of a hydride reducing agent, preferably at a . .
~: ~ 20 ~ temperature beluw 10 C and p~ eferably in the presence of an ~1coho1, ;.
Examples of hydricle reducing: agents are sodium borohydride, lithium
borohydride, llthlum aluminium hydride, and potassium borohydride,
- : . :
.
.
- 3 - ~
.. .
,
~ , .
~04S137
sodium borohydride being the preferred reducing agent.
,
v .
In step (c) of the process of the invention, the dehydration ~ :
is preferably effected by means of a dehydrating agent such as
p-toluenesulphonic acid. According to a preferred embodiment oî
. .
the invention, the dehydration is carried out by heating the 3-amino- ; -
Rropan-l-ol with p-toluenesulphonic acid in toluene at the reflux
temperature of the reaction medium, continuou61y withdrawing water, ; . '
until the reaction is substantially complete, which normally requires .:
approximately 20 hours.
The hydrogenation of step (d), if required, may be carried . ; .
out using a conventional hydrogenation catalyst, such as platinum
oxide, . . :
.
The sequence of reactions employed in the process of the . . ~
present invention is as follows: ~ ;
- , ;':,
, ...
:.
.
~: ' '
: .
~' ' .
:' '.:
10~5137
,;
R~CO CH HCHO 14~--Co-cH2-cH -N
HNR R R2>=/ R
(II) (a) (III)
NaBH4 Rl--~ 2 2 -H O
~' a>==/ R - 2 ~, . .
R :.
(b) (IV3 (c) . .:
.. ..
,,, ~,. . .
' ~ :,: ,:'
. . .
~, .
... ..
. . -
;~ R ~ 2-~lz-CY~
(d) (VI)
~: : - : .
` :~ :
~ ,
;;;; ~ i ~ .,,,...",.,...,,",.; .,.,".,~,~.,, ., ~,..,,.. i . ~ .,i,".., ~,"., . ;;,;,. ,,." "j,,,",; . ;"," ."," ,, ~ , ,,, ,""j, ,"" ,,, ",
~.....
~L04S~37 ; ~
The process of the invention is further illustrated with . .
reference to the following Examples.
. .
,~' . . ''
xample 1
. 3 -Chloro 4 - cyclohexyl- 1- ( 3 -diethylamix~o -propen -1 -yl) -benzene
(a) 54 g of diethylamine hydrochloride, 100 g of 3-chloro-4-
cyclohexyl-acetophenone and 15.1 g of paraformaldehyde in 75 ml of ::absolute ethanol were heated under reflux for 4 hours in the presence
of 1. 5 ml of lON hydrochloric acid. When the reaction was complete,..
the ~olvent was evaporated over a water bath under the vacuum producecl ...
. .
.by a water-jet pump, and the residue was then recrystallized from :
acetone. 116 g (a yield of 76, 5% of theory) of 3-chloro 4-cyclohexyl-
. 1-(3-diethy1amino-1-oxo-propyl)-benzene were obtained; the product :
had a melting point of 156-158C (with decomposition). -.
,;,. . ~
~ (b) 116 g of the product of step (a) were suspended m a
:.. mv~ture of 1 litre~of methanol and 60 ml of 40% sodium carbonate. ~ ~ : i s
40 g oi sodlum borohydrate were~then added slowly to this 6uspension, ;maintaining the temperature below 8C. .After all of the sodium ~
borohydrate had been added, the mixture was left for 12 hours at;
ambient temperature, after which:1. 5 litres of 5% soda solution were `.
. . ~ , . .
20~ added and the mixture; was extraot~ed with 700 ml of isopropyl ether. ..
The organic~ phase was washed with water, dried over sodium sulpllate
~and then evaporated to: dry~es6. 81~g ~yield 77% of theory) of
: ' . '
: :
~5137
3 -chloro-4 -cyclohexyl- 1- (3 -diethylamino -1 -hydroxy-propyl) -benzene
were obtained in the form of a yellow oil.
.
(c) 81 g of the compound produced in step (b) were dissolved
in 500 ml of toluene and, to the solution so produced, was added a
solution of 76 g of p-toluenesulphonic acid in the minimum quantity of
water. The mixture was heated under reflux for about 20 hours,
continuously removing ~e water formed. At the end of this time, the
solution was cooled and poured into 2 litres of water, to which ammonia
was added until the solution became alkaline. The organic phase was
then separated, washed with water and dried with sodium sulphate. ;
. . :
66 g (yield 86~1o) of 3-chloro-4-cyc~ohexyl-1-(3-diethylammo-propen-1-yl)-
benzene (hereinafter referred to as compound 933 CB) were obtained in
. .
the form of a light brown oil. This was disso~ed in ether and reacted
s'.rith B sufficient quantity of hydrochlorlc acid dissolved in the sarQe~
~5 001vent to produce 67 g of the hydrochloride having a melting point of
1 61C . , `
..
,,
: , . :,-.
Example 2 `;
;3-Chloro-4-cyclohexyl-1 -(3-dimethylamino-propen-1 -yl)-ben~ene
(a)~ Thc ~process was the same as described in step (a)
~; ` 20 ~ of Example 1, except that an equimolar quantity of dimethylamine
"
hydrochloride was used in place of the diethylamine hydr~chloride. --
The~hydrochloride~of 3-chloro-4-cyclohexyl-1-(3-dimethylamino-
l-oxo-propylj-benzene was~ obtained in a yield of 78% and had a melting
~: ~ : .
::
7 - :
,
, .,
~:
1~5~L37
point of 186-18~C (with decomposition).
(b) Following the method described in step (b) of Example 1,
the cornpound prepared in step (a) of this Example was used to produce
3-chloro-4-cyclohexyl-1 -(3-dimethy:larnino-1 -hydroxypropyl) -benzene . . .
- 5 in. a yield of 90%; the product was a brown oil.
. . ..
(c) From the compound produced in step (b) and fo]lowing
the method described in step (c) of Example 1, 3-chloro-4-cyclohexyl- i
1-(3-dimethylamino-propen-1-yl)-benzene was obtained in a yield of .
80%; this compound IS hereinafter referred to by the reference ... :
"31004 CB". Following-the procedure described in Example 1, the
, ~ .
- . ` hydrochloride of this compolmd was obtained qualltitatively and was ~:
. ,, ~
found to ha~e a melting point of 163-164C. ~ -
' ''.
Example 3
.: .
~` 3-Chloro-4-cyclohexyl-1-(3-morpholino-propen-1-yl)-benzene .:
; 15 ~ : (a) Following the procedure described ir. step (a) of Example 1,
except:~that diethylamine hydrochloride was replaced by an equimolar
- quantity of morpholine hydrochloride, the hydrochloride of 3-chloro-4-
cyclohe2~yl-1-t3-morpholino-l-oxo-propyl)-benzene was obtained in a~ ;
yield~of 73%; the melting point of this compound was 192-193 C.
~; 20 ; ~ ~ ~ (b j: Thi.s compound ~was then used in the process described .
8 -
..
:
:
~1134~37
in step (b) of Example 1 to produce 3-chloro-4-cyclohexyl-1-(3-
morpholino-l-hydroxy-propyl)-benzene in the form of a yellow oil
and in a yield of û6%. . :
,
(c) Following the process described in step (c) of Example 1,
the compound prepared in step (b) was then used to produce 3-chloro- .
4-cyclohexyl-1-(3-morpholino-propen-1-yl)-benzene in the form of a
yellowish oil and in a yield of 88%; this compound is hereinafter
referred to by the reference 't31013 CB". The hydrochloride of ~.
compound 31013 CB was prepared as described preYiously,in a yield ~:
of 95%,and was found to have a melting point of 198-200 C. :
- ' '',
`Example 4 . : ~:
3-Chloro-4-cyclohexyi-1-(3-pyrrolidino-propen l-yl)-benzene : .
(a) The process described in step (a) of Example 1 was
repeated, except that the diethylamine hydrochloride was replaced
: by an equimolar amount of pyrrolidine hydrochloride to produce~the
.: .
hydrochloride of 3-chloro-4-cyclohexyl-1-t3-pyrrolidino-1-oxo- -.
- ~ propyl)-benzene in a yield of 73~o. This compound had a melt:ing point
~ .
~ ~ of 189-190 C (with decomposition).
~, : . ,-
,
(b) Following the process described in step (b) of Example 1,
' .: ,
the compound prepared in step (a) above was used to produce 3-chloro-
4 -cyclohexyl- 1- (1~ hydroxy-3 -pyrrolidino-propylj-benzene in a yield ~ ~:
~ ' - , ~ ' ' ,',.,, ~ :''
: _ g ~ .: ,
: .:, ,
~O~S~3~
of 91%. The compound had a melting point of 90 C.
~` ., .
(c) This compoundwas then used in the process described
in step (c) of Example 1 to produce 3-chloro-4-cyclohexyl-1-
(3-morpholino-propen-1-yl)-benzene (referred to by the code "31015 CB")
jn a yield of 87%; from this the hydrochloride was prepared as described
~bove and was found to have a melting point of 1-61-162 C.
. .
:E:xample_5
4-(3-Diethylam_no-propen-l-yl)-biphenyl ~ ~
(a) 50 g of ~iphenyl methyl ketone, 10 g of paraformaldehyde ~ ~;
arid 30 g of diethylamine hydrochloride were heated under reflux for
6 hours in 200 ml of absolute ethanol and in the presence of 1 ml of
10 N hydrochloric aeid. On coolmg, a mixture of the reaction product
m the form of its hydrochloride and of the initial Isetone crystallized
from the reaction mixture. These were separated by treating the
mixture with 500 ml of ~0% hydrochloric acid and the aqueous solution
was extracted with ethyl acetate. The organic phase was disposed of ,
~nd the aqueous phase was made alkaline by the addition of ~0 N aqueous
.
~oda. The liberated base was~ finally extracted with ether. After
drying the ethereal solution with sodIum sulphate and evaporating the
~ ether, 4-(3-diethylamino l-oxo-propyl)-biphenyl was obtained in the
form of a yellow oil and in a yield of 55%,
. .
,,
..
- 10 _ ~
, ~, ` .
...... ,, .. , . ... , .. ,. ... , ~ . .. .
~0~S137
(b) This 4-(3-diethylamino-l-oxo-propyl)-biphenyl was
then used in the process described in step (b) of Example 1 to produce . .
4-(3-diethylamino-1-hydroxy-propyl)-biphenyl in the form of a brown
oil (yield 87%).
(c) This compound was then converted to 4-(3-diethylamino- : .
propen-1-yl)-biphenyl (compound "994 CB") following the method :-
described in step (c) of Example 1. The compound was obtained in a .
yield of 88% and was found to have a melting point of 60C. The
hydrochloride was then prepared in ether and was found to have a
melting point of 210-212 C; it was obtained in a yield of 87%.
- ' ' ' ' . ' . ' ` ' .
E~ample 6 . ~ :
4-(3 diethylamino-propyl)-biphenyl
The hydrochloride of 4-(3-diethylamino-propen-1-yl)-biphenyl
prepared in Example 5 was reduced in 10 volumes of ethanol and in
the presence of 1% (based on the weight of compound reduced) of
~.. .
platinwn oxideJ using hydrogen at ambient pre~sure. Aîter absorption
of hydrogen had ceased, the catalyst was separated, the alcohol .:
: evaporated and the residue recovered in anhydrous ether. The ~ -
. ~ hydrochloride of 4-~3-diethylamino-propyl)-biphenyl (compound "31001 CB"~ .:
. .:
20 : was obtained in a yield of 77%; its melting point was 140 C.
: . :
.
: .,.: .
- : ' '. . , ~ ' '
: ~ . . :,, . , :, .
, ~ ~ ''" '
,. ': .
~045137
:
Example 7 -
.` 3-Chloro-4-cyclohexyl-1-(3-diethylamino-propyl)-benzenc
,
This compound (reference "934 C13") was obtained in the
form of its hydrochloride in a yield of 83% after recrystallization
from ether, using the process described in Example 6 and starting
from the hydrochloride of compound 933 CB (prepared in Example 1).
~he hydrochloride had a melting point of 134C.
, ..
:E~xample 8
3-Chloro-4-cyclohexyl-1-(3-dimethylamino-propyl)-benzene ..
Starting from the hydrochloride of compound 31004 CB
(Example 2) and using the method described in Example 6, the
hydrochloride of 3-chloro-4-cyclohexyl-1 -(3-dimethylamino-propyl)- ,:
benzene (compound "31012 CB") was obtained in a yield of 86%
after recrystallization from ether; -the hydrochloride had a rnelting
point of 190-191C.
Example 9
::3-Chloro-4-cyclohexyl-1-(3-pyrrolidino-propyl)-benzene
The hydrochloride of this compound (compound "31016 CB") ,~ "
''.' ' '.
was obtained USillg the process of Example 6 and starting îrom the
~hydrochloride of compound 31015 CR (Example 4). A~ter recrystallization
from ether, the yie1d was 53% and the melting point of the hydrochloride
was 17$-117`'C. '
12 - .
, . . . .
.
, . ' ' '; . . . ! . ~ . ' . . , ,;, ,, ; '. ~
~L045~37
Example 10
4-Cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene
Following the procedure described in steps (a) to (c)
Example 1, except that 3-chloro-4-cyclohexyl acetophenone was .
replaced by an equimolar quantity of 4-cyclohexyl acetophenone,
the hydrochloride of 4-cyclohexyl-1-(3-diethylamino-propen-1-yl)- ~.
benzene (compound "31023 CB") was obtained after recrystallization
from ether; the hydrochloride had a melting point of 171-172 C.
Example 11
` 10 3-Fluoro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene - . .-
Following the procedure described in steps (a) to (c) of -
:: Example 1, except that 3-chloro-4-cyclohexyl acetophenone was .
replaced by an equimolar quantity of 3-fluoro-4-cyclohexyl ;.
acetophenone, the hydrochloride of 3-fluoro-4-cyclohexyl-1-(3-
diethylammo-propen-l-yl)-benzene was obtained after recrystallization ~:
: ~ from ethe;r. The hydrochloride had a melting point of 171-172C. ; . ~ .
. " - "
The following Table I summarizes the products obtained
in Examples 1 to 11~
~: ~ ~. ;',,
~513'7
TABLE I
...
. ._ . ._ . .
Ex . R R2 A- NR R Melting :
No.Code No. 1 3 4 point of :~ ~
. ___ _ h o ri~l e ~ :
1933 CB cyclohexyl Cl CH=CH ( 2H5)2161
23 1 , 004 CB cyclohexyl Cl CH=C~I - N(CH3)2 163 -164
331,013 CB cyclohexyl Cl CH-CH morpholino198-200
431, 015 CB cyclohexyl Cl CH=CH pyrrolidino 161-162
5994 CB phenyl H CH=CH ( 2 5)2210-212 `:: .
631,001 CB phenyl H CH2CH2 ( 2 5)2 14;0 ~ :
7934 CB cyclohexyl Cl CH2CH2 N(C2HS)2 134
.. 831, 012 CB cyclohexyl Cl CH2CH2 -N(CH3)2 190-191 :
931,016 CB cyclohexyl Cl CH2CH2pyrrolidino 175-177 :
~: 1031, 023 CB cyclohexyl 1~ CH=CH N(C2H5)2171~172 ;~
1131j (130 CB cyclohexyl F CH=CH _ _171-17 2
We have discovered that the compounds of formula (I) and
;`- ~ their non-toxic acid addition salts have useful pharmacological
; 20 ~ p~roperties, and speclfically have psycnostimulant, antispasmodic,
~ ~ , : . , ,
hypotensive and~analgesic properties. Accordingl~, the present ~ :
invention further consists m a pharmaceutical composition comprlsing
. a compound of formula (I) (as hereinbefore defined) or a non-toxic acid
: :
;..:
: : :
: ~ :::
~ .
.' ' ~
~1045::11L37
- .
. .
addition salt thereof in admixture with a pharmaceutically acceptable
excipient .
The psychopharmacological activity of the compounds c~f the
invention was demonstrated by the following tests:
ctivity test
.~ .
(Boissier J. R. and Simon P, "Archives Internationales de
Pharmacodynamie", 1965, 158, 212).
A mouse wa.s placed in a Plexiglass cage crossed by r" , ' ',
a plurality of beams of light actlng on phatoelectric cells. When the
mouse moved and thereby interrupted one of the beams, this caused
an electrical pulse which was registered on a couNter. The
measurements were carried out on batches of 6 treated anima]s and
.
6 control animals for a period of 20 minutes.
Traction test
(Courvoisier S., Ducrat R. and Julou L. "Psychotropic Drugs",
, .
Elsevier, 1957, p.373j
"
In this test, a mouse was hung by its front legs on a stretched
wire. The animal will normally recover by itself, by gripping with ~
~its rear Iegs within 5 seconds. However, when under the influence ~ -
of drugs acting on the central nervous system, the animals do not
~recover successfully. ~ -
15 - :
: .. :
, . . ~. . . . - ,
~o~s~
Balancing test
(33oissier J.R., Dumont C. and Ratouis R. "Thérapie", 1960,15, 1170)
. , .
In this test, mice were placed for 1 minute on a horizontal
wooden shaft which rotated steadily at 12 r.p.m. The mice will
normally counteract this movement using positional and balancing
.reflexes; if, however, the central nervous system is affected, these
reflexes are disturbed and a certain number of animals fall off. . .
:
-
Exploration test ~ , .
(:E3oissier J,R. and Simon P. "Archives Internationales de : :. .
~ - .
Pharmacodynamie", 1964, 147, 372).
,~ '
This test, using a plank with holes in it, makes it pcssible
:,, . ' .
to measure ohjective~y the anxiolytic activity of a compound by
nating the decrease in -the number of holes explored within a given
time by a treated mouse in comparis:on with a control mouse. The
~: , ,
animals are used in batches of ten and are aLlowed 5 minutes for : .
: ~ exploration . ~ : ~
. :
,:,.
Reserpine~ test: :
(Rubin B ., Malone M . H., Waugh M . ~I. and :Burke J. C .,
"Journal of Pharmacology and :Experimental Therapeutics", 1957, 120,125) ..
.:
:
..
.
1 6 -
. , .
: ~045137
:
Reserpine, administered subcutaneously to a mouse in a
dose of 5 mg/kg body weight, causes symptoms of. se-vere depression,
with absolute fixity, ptosis of the eyelids, hypothermia and catatonia;
the simultaneous administration of a substance having anti-depressive
properties leads to the progressive total or partial disappearance ..
of this depressed state.
". ,.
. :,.- :
The results obtained from the tests described above are
...
summarized in Table II; the figures given in this Table show the .. :
value of the median effective dose for each test. The method of ;
administration is indicated by "I. V. " for intravenous administration, . .-"I. P. " for intraperitoneal administration and "P. O. " for oral
administration.
, .,. ~.
' ' ;'
.. ..
. ~ .
... , ,~ :;,:
10~ l3~
TABLE II
. ~
. ~ . Te st
Compound ~ctivity Traction BaIancing Exploration Reserpme
. .. .... _ _ ._ _ _
933 CB 25 I.P. 50 I.P. 30 I.P. 25 I,P. 75 I.P. ~ -
. lOOP.O. lOOP.O. 50PØ 25P.O. lQOP.O. - :-
- .. __ . , __ _~
1004 CB 12.5 I.P. ~100 I.P. 100 I.P. 60 I.P. _ , .
__ . . __ ... _ , .,
31013 CB 50 I.P. _ 50 I.P. .
. _ --- .. . . . _ ~
31015 CB 20 I.P. 50 I.P. 50 I.P. 2S l.P. 50 I.I~. :` :
. __ __ ... . _ ~ . . _~
994 CB 100 I. P. 100 I. P. 50 I. P. 50 I. P. 50 I. P.
SO P.O. 50 P.~.
. ._ .. . _.__
31001 CB 50 I.P. 100 I.P. 100 I.P. ~ :.
... _ _ ... . ___ '-: .
934 CB 3 0 I . P . 12 . 5 I . P . 20 I . P . 50 I. P . .~
_ . . ~........... _ _ ~ ..
31012 CB 50 I.P. 100 I.P. 100 I.P. 50 I.P. _
. . . __ _ .. ___ ~_ : ' ': .-`'-
31016 CB12.5 I.P. _ 20 I.P. 50 I~P. : : :
. .. ~ ..
31023 C:B25 I. P. 25 I. P.30 ;. P. _ J
. . . ~ _ : ~ - I ~. , .
31030 100 I. P. ~50 I. P.25 I. P. ~ 50 I. P. : ~ :
__
-
Further experiments relating to the anticataleptic and : ~ -
antispasmodic activity were carried out.
: : -
,
The anticataleptic activity was examined using the ~ :~
~ prochlorperazine test described by Boissier J. R. and Simon P.
- 20 ("Thérapie" (1963), 18, 1257). Prochlorperazine, when administered
intraperitoneally in a dose OI 25 mg/kg to a rat, causes a state of
:: ,
~ ~ ~ catalepsy which is particularly characterized by the crossing of the
:
~. .
: - 18 - ~
lV45~37
homolateral legs: tllis criterion is used to assess the anticataleptic
activity of the compounds of the present invention. For each test
there were used 5 control and 5 rats treated with different doses ; -,
of the compound tested. Using compounds 933 CB and 994 CB,
respectivelyJ the effective dose by the intraperitoneal route was
25 mg/kg and per os was 30 xng/kg. The anti~epressant activity ~ :
was assessed using two tests:
:
- . ,.- - , ,
Reserpine-induced ulcer in the rat .
.`-'
(Blackman J. G. and Campion D. S., "British Journal of Pharmacology",
1959, 14, 112 116)
,:
`~
`
The'administration of reserpine (by the intraperitoneal
route in an amount of 5 mg/kg) causes a rat to develop gastric ulcers
at the end of from ;O to 20 hvurs. A~I~idepxessants of the imlpramine
type prevent the formation of the ulcers or decrease their mcidence
15 ; . or eeriousness. In th~s test, the effect1ve dose is, by way of example, ~ :
when using compound 933 CB 25 mg/kg by the intraperitoneal route ~ -
.::
and 50 mg/kg by the oral route,~ and, when using compound 994 CB,
0 mg/kg by the intraperitoneal route and lO0 mg/kg by the oral route.
Electroencephalographic study ; ~ -
~- - .. ..
ao ~ :(Sohmitt H. and Schmitt H., "Theraple", 19669 3, 675-6~4)
~;:
1 9
:
~04S~37
:
Electrical stimulation of the dorsal hippocanilpus (6 volts;
30 cycles per second; 5 seconds, extent: 1. 5 milliseconds) causes
electrical discharges in the rabbit which continue for several seconds
after cessation of electrical stimulation. These discharges last ~rom
15 to 19 seconds in a normal animal. When the rabbit is under the
influence of an antidepressant drug, these discharges last much longer. .. :-.
The e~perimen:t was carried out on batches of G conscious rabbits
implanted by the technique of Monnier M. and Gangloff H. ("~tlas
of Stereotaxic brain research on the conscious rabbit", Elsevier 1961), ;
the products being administered intravenously. The discharges were ; ~:increased by 60% when the rabbits were treated with compound 933 CB ~:
and by 20% when the rabbits were treated with compound 994 C:B. ~
~, ' .
,~
The antispasmodiF activity of the compounds of the invention
was also studied on the isolated ra:t duodenum, kept alive in an aer&ted
tyrode bath at 37C. Spasms were Induced by the administration of
: barium chloride in an amount of lOO~ug/litre. The compounds of the
.nvention were added, at various concentra:tions, to the tyrode bath
3 minutes before ~he addition cf the spasmogenic a~ent and the :
concentration determined~ of each which reduced by 50% the extent of
20 ~ the contractlon caused by thls sgent. The results using various compounds
accordlng to the~present invention are:~given in Table III.
~.
: - i :
~- : : ~ : ::
~ . . :
~ ,
:~45~37
: :
TABLE I:[I
.
_ .~ ~ , ,
Compound 50% effective concentration (~g/litre)
. _ _ . ._ __
93 3 CB 0 . 6 to 1 -
31004 CB 1 to 3 :~;
.31015 CB l to 3 .
994 C~3 3 .
31001 CB .1 : . .
934 CB 0. 6
31012 CB 3 . .
1031016 CB 0. 6 to 1 ~ . . .
Papaverine . . . :
.~ hydrochloride . 3
. . .. .__ ... . . . .-. :
In addition, compounds of lormula I ~as hereinbefore defined)
have æubstan:tial analgesic properties.
,....
~ ~ The toxicity of the compou~ds of the invention i6 generally .
:low, a6 r-ay be s66n from Table IV,~ which gives the LD50 m mg/kg ~ . :;.; .
in mice for some of the compounds of the invention.
:
. . .
:
: : -
.i . .
: '' . ..:
`~ lO~S~l3~7
TABLE IV
. . _
' LD50
Compound _ . _
. 5 -. I P. Orally
. ........................ . _ .,........... .. _ .. -,
' 933 CB 125 ~ 1075 ~:
. 31004 CB 125 ~ 750 .
31013 CB 500 > 7 50 .
31015 CB . 62.5 >750 .~ .
934 CB 125 to 250 ~ 750
31012 CB 250 to 300 >750
. 31016 CB 5û to 100 ~750
........ . - ~ ..... _ , ,~
.
The compounds of the invention have been success,.ully ;
: ~ used clinically to treat adynarnlc and depressive states, such as
melancholia, reactive depression6;6nd manic-depressive psychosls. ~::
The compounds of formula (1) may be formulated with
~: physiologlcally acceptable solid or liquid vehicles.
~ : . :
.
Where the veh cie ls a solfLd, the compositions of the ~ ~-
invenhon may comprls6 conv6ntl0nal~solid dosage units such as : ~ . .
: ao ~powder6~ c ~ompre66ed tablets, granules or dragees, or the vehicle
may~be contained in a capsule, especially a gelatin capsule, or may . ~ .
.: : ..
: ~ : . :, i
-- 22 -- . : .
..
;
;
~ 1045~3
comprise a suppository base. The vehicle may comprise one or
more diluents, perfumes, solubilizing agents, lubricants, binders,
surface active agents or disintegrating agents. The vehicle may
` also comprise one or more coating ~r encapsulating substances.
"' ~' :.
The compounds of formula (I) may be formulated as powders
in association with a finely divided solid vehicle. In compressed -
~ablets the compounds may be formulated in association with a
compressible solid vehicle which can release the compounds after
,, ,.,: ,.
the tablets have been administered. Powders and compress~ed tablets
may contain from l to go~lo by weight of the compound OI formula (I).
Examples of such sol1d vehicles are: magnesium carbonate;
magnesium stearate; talc; sucrose, glucose; lactose; pectin; dextrin; - `~
starch gelatin; gum tragacanth; methylcellulose; the sodium salt of
carboxymethyl cellulose; low melting point waxes; cocoa butter and
semi-s,ynthetic glycerides.
Where the vehic1e is a liquid the compositions of the
invention may, for example, take the form of an iniectible solution
suspenslon or~ emulsion comprising a compo~md of the in~rention
together with sterile pyrogen-free water or an injectible oil. The
20 ~ ~ vehicle may, for exarnple, be a suspension or emulsion containing
as one compon~nt an aqueous solution oi polyethylene glycol or
~ ~ : , ;,
polypropylene glyco1 and as the other component an oil, preferably
ollve oil,
23 -
: : ~ : : .
:
~ S~37
Alternatively, where the vehicle is a liquid the
composition of the invention may cornprise a compound of formula (I)
together with a carrier liquid and one or more pharmaceutical
adjuvants such as preservatives,flavouring agents, buffering agcnts,
colouring agents, thickening agen~s, sweetening agents or suspending
agents. The composition may take the form of a syrup, an elixir or
a linctus or may take the form of a solution or suspension of the , -
eompound of formula (I) in a carrler liquid contained in a capsule,
espeeially a soft gelatin capsule. Aqueous suspensions for oral use
may comprise thiekening agents and suspending agents, for e~ample
natural or synthetic gums or resins such as gum arabic; ion-exchange
resins; methylcellulose; or carboxyrnethylcellulose.
' ;''.'
The compounds of the present invention are preierably
formulated for oral administrahon or for injection. The compollnds --
of the invention are also suitable for reetal administration, ~or ` ~ ~ ~
.
oral administration, eompressed tablets, eaeh containing from 20 to
.
500 mg of active ingredient are recommended and for injection, ~ ~
ampoules each containing frorn 10 to 500 mg of active ingredient ;
~ ~ ... .. ...
are reeommended. Good results were obtained, especially for ~ ;;
compound 933 CB, when administering from 2 to 10 compressed
tablets, each eontaining 100 mg of the ecmpound, daily or when ~`
administermg from I to 5 injeetlble ampoules each containing 100 mg
of the eompound. ~
:` ~ . ' '
24 ~ - ~
:
~ ~: : ', ' ~ .
.. ~ .
.~ . .
' ~ ~ ' .i ~ ' '
~ 45~'37
Examples of suitable formulations are as follows: -
Compressed tablets:
.,
933 CB, hydrochloride 100 mg
Lactose 200 mg
Potassium polymethacrylate 30 mg.
Magnesium stearate 10 mg
, . ~ .
..: ',.~' .
Injectible ampoules: :
933 CB, hydrochloride 100 mg
Dishlled water q. s. f. 5 ml.
,,:
Capsules:
933 CB, hydrochloride10 mg
Talc q. s. f. 105 mg
.:,
duppoeitories~
933 CB, hydrochloride 15 mg :: . ;
:~ Mixture~of mono-, di- and
- triglycerldes of saturated fatty : :.
acids q. s.~f. ~ 3 g
.~, . : : ; ,' ~;;
25~
~ ~O~S~37
A clinical evaluation of 933 CB was carried out using a
sample of 30 severely depressed hospital patients who were
considering suicide or in some cases had attempted it. The sample
contained thirteen cases of nervous depression, ten cases of
5 reactional depression, seven cases of psychotic depression and
three cases of severe melancholia. A clear favourable action on
the depressive thymine occurred in 21 of the patients. Several
cases where a favourable response was noted had previously been ;-~
treated with tricyclic anhdepressants without success. The action -
was rapid, an improvement being noted in less than a week in
,~ ; ,
~ thirteen of the patients. The daily dose of the compound administered ~ -
, , .
to each patient varied from 20 to 200~mg, the most favourable results
being obtained with a dose of 40 to 60 mg.
. ..
.. ..
: ~`,'.''''. "
, i .
.
, . . ~.
-: : . .,-: .
e6~
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