CA1045137A - Phenylpropylamine derivatives - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds having useful psychostimulant, anti-spasmodic, hypotensive and analgesic properties are disclosed.
The compounds have the formula:
(I) in which R2 is selected from the group consisting of a hydrogen atom and a halogen atom;
is selected from the group consisting of q cyclohexyl group and a phenyl group, and is a cyclohexyl group when R2 is a halogen atom;
A is selected from the group consisting of CH2CH2 and CH=CH groups; and is selected from the group consisting of an alkylamino group, a dialkylamino group and a heterocyclic ring containing from 5 to 7 atoms in the ring, said ring optionally having one or more substituents and optionally containing a second hetero-atom; and acid addition salts of said compound.
Theymay be prepared by condensing an acetophenone in a Mannich reaction with formaldehyde and a primary or secondary amine, reducing the amino-ketone thus formed to a 3-amino-1-phenyl-propan-1-ol, subsequently dehydrating the 3-amino-4-phenyl propan-1-ol to give a compound of formula (I) in which A is CH=CH which may if desired be hydrogenated to a compound of formula (I) in which A is CH2-CH2 and/or converted to an acid addition salt.

Description

~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 .
' '' . . ':
,~

:: , . ::
.
.

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 .

..

:

:
~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) ..

.:
:

..
.

. , .

: ~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) ~;:

:

~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, : : ~ : : .

:

~ 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.
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Claims (26)

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

1. A process for preparing a compound having the formula:
(I) in which:
R2 is selected from the group consisting of a hydrogen atom and a halogen atom;
R1 is selected from the group consisting of a cyclohexyl group and a phenyl group, and is a cyclohexyl group when R2 is a halogen atom;
A is selected from the group consisting of CH2CH2 and CH=CH groups; and wherein NR3R4 is selected from the following group:
NR3R4 has the form NHR3 wherein R3 is an alkyl with 1 to 4 carbon atoms;
NR3R4 has the form NR3R4 wherein R3 and R4 are independently selected alkyls with 1 to 4 carbon atoms;
NR3R4 is a nitrogenous heterocycle group with 5, 6 or 7 atoms; or wherein the group NR3R4 represents a heterocycle radical containing 6 ring atoms, one of which is the aforementioned N, the heterocycle radical also containing a second hetero atom selected from N and O at the 4-position with respect to the aforementioned N;
said process comprising the steps of:

(a) condensing an acetophenone of formula (II) (in which R1 and R2 are as previously defined) with formaldehyde and an amine of formula HNR3R4 (wherein R3 and R4 are as previously defined) to form an amino ketone;
(b) reducing said amino-ketone to the corres-ponding 3-amino-1-phenyl-propan-1-ol;
(c) dehydrating said 3-amino-1-phenyl-propan-1-ol to a compound of formula (I) in which A is CH=CH;
(d) if desired hydrogenating the compound of formula (I) in which A is CH=CH to a compound of formula (I) in which A is CH2CH2; and (e) if desired reacting the compound of formula (I) with an acid to form a pharmaceutically acceptable acid addition salt.

2. The process of Claim 1, wherein said amino ketone is reduced in step (b) to said corresponding 3-amino-1-phenyl-propan-1-ol using a reducing agent selected from the group consisting of sodium borohydride, lithium borohydride, lithium aluminium hydride, and potassium borohydride.

3. The process of Claim 1, wherein said 3-amino-1-phenyl-propan-1-ol is dehydrated in step (c) to a compound of formula (I) by heating with p-toluenesulphonic acid in a toluene medium at the reflux temperature of said medium and continuously withdrawing water formed in the dehydration reaction from said medium.

4. The process of Claim 1, in which 3-chloro-4-cyclohexyl-1-acetophenone is reacted in steps (a) to (c) with formaldehyde and diethylamine hydrochloride to produce 3-chloro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

5. The process of Claim 1, in which 3-chloro-4-cyclohexyl-acetophenone is reacted in steps (a) to (c) with formaldehyde and dimethylamine hydrochloride to produce 3-chloro-4-cyclohexyl-1-(3-dimethylaminopropen-1-yl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

6. The process of Claim 1, in which 3-chloro-4-cyclohexyl acetophenone is reacted in steps (a) to (c) with formaldehyde and morpholine hydrochloride to produce 3-chloro-4-cyclohexyl-1-(3-morpholino-propen-1-yl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

7. The process of Claim 1, in which 3-chloro-4-cyclo-hexyl-acetophenone is reacted in steps (a) to (c) with formaldehyde and pyrrolidine hydrochloride to produce 3-chloro-4-cyclohexyl-1-(3-pyrrolidino-propen-1-yl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

8. The process of Claim 1, in which biphenyl methyl ketone is reacted in steps (a) to (c) with formaldehyde and diethylamine hydrochloride to produce 4-(3-diethylamino-propen-1-yl)-biphenyl which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

9. The process of Claim 1, in which biphenyl methyl ketone is reacted in steps (a) to (d) with formaldehyde and diethylamine hydrochloride to give 4-(3-diethylamino-propyl)-biphenyl which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

10. The process of Claim 1, in which 3-chloro-4-cyclohexyl-acetophenone is reacted in steps (a) to (d) with formaldehyde and diethylamine hydrochloride to produce 3-chloro-4-cyclohexyl-1-(3-diethylamino-propyl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

11. The process of Claim 1, in which 3-chloro-4-cyclohexyl-acetophenone is reacted in steps (a) to (d) with formaldehyde and pyrrolidine hydrochloride to produce 3-chloro-4-cyclohexyl-1-(3-pyrrolidino-propyl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

12. The process of Claim 1, in which 4-cyclohexyl-acetophenone is reacted in steps (a) to (c) with formaldehyde and diethylamine hydrochloride to produce 4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

13. The process of Claim 1, in which 3-fluoro-4-cyclohexyl-acetophenone is reacted in steps (a) to (c) with formaldehyde and diethylamine hydrochloride to produce 3-fluoro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene which may if desired be reacted with an acid to form a pharmaceutically acceptable acid addition salt.

14. A compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 1, or an obvious chemical equivalent thereof.

15. A compound of formula (1) or a pharmaceutically acceptable addition salt thereof when prepared by the process of Claim 2, or an obvious chemical equivalent thereof.

16. A compound of formula (1) or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 3, or an obvious chemical equivalent thereof.

17. 3-chloro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 4, or an obvious chemical equivalent thereof.

18. 3-chloro-4-cyclohexyl-1-(3-dimethylaminopropen-1-yl)-benzene or a pharmaceutically acceptable acia addition salt thereof when prepared by the process of Claim 5, or an obvious chemical equivalent thereof.

19. 3-chloro-4-cyclohexyl-1-(3-morpholino-propen-1-yl)-benzene or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 6, or an obvious chemical equivalent thereof.

20. 3-chloro-4-cyclohexyl-1-(3-pyrrolidino-propen-1-yl)-benzene or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 7, or an obvious chemical equivalent thereof.

21. 4-(3-diethylamino-propen-1-yl)-biphenyl or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 8, or an obvious chemical equivalent thereof.

22. 4-(3-diethylamino-propyl)-biphenyl or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 9, or an obvious chemical equivalent thereof.

23. 3-chloro-4-cyclohexyl-1-(3-diethylamino-propyl)-benzene or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 10, or an obvious chemical equivalent thereof.

24. 3-chloro-4-cyclohexyl-1-(3-pyrrolidino-propyl)-benzene or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 11, or an obvious chemical equivalent thereof.

25. 4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene or a pharmaceutically acceptable acid addition salt thereof when prepared by the process of Claim 12, or an obvious chemical equivalent thereof.

26. 3-fluoro-4-cyclohexyl-1-(3-diethylamino-propen-1-yl)-benzene or an acid addition salt thereof when prepared by the process of claim 13 or an obvious chemical equivalent thereof.