DIARYLALKYLAMINES PRIMAIRES AYANT UNE ACTION ANTIDEPRESSIVE

PRIMARY DIARYLALKYL AMINES HAVING ANTIDEPRESSIVE ACTIVITY

Abrégé anglais

Abstract of the Disclosure
A limited number of useful compounds having anti-depressive or
tranquilizing activity are known. The present invention expands upon the
known compounds by providing a compound of the general formula
<IMG> I
wherein the dotted line represents an optional double bond and Ar represents
the group
<IMG>
wherein Y is bound in the 2-, 3- or 4-position and represents a lower alkyl or
lower alkoxy group, a halogen, a trifluoromethyl group or an amino, mono- or
di-lower alkylamino group, or Ar represents a pyridyl group bound in the 2-,
3- or 4-position, X represents hydrogen, a lower alkyl or lower alkoxy group,
a halogen, a trifluoromethyl group or an amino, mono- or di-lower alkylamino
group, R represents a lower alkyl group; and R1 represents hydrogen or a
lower alkyl group, whereby "lower" indicates a group having up to 3 carbon
atoms; or a pharmaceutically acceptable acid addition salt thereof, in
anhydrous form or in any degree of hydration possible. Such compound also
have an anti-depressive or tranquilizing effect.

Revendications

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 of the general
formula
<IMG> I
wherein the symbol <IMG> represents either a single or double
bond and Ar represents the group
<IMG>
wherein Y is bound in the 2-, 3- or 4-position and represents a
lower alkyl or lower alkoxy group, a halogen or a trifluoromethyl
group or Ar represents a pyridyl group bound in the 2-, 3- or 4-
position, X represents hydrogen, a lower alkyl or lower alkoxy
group, a halogen or a trifluoromethyl group, R represents a lower
alkyl group, n is 0 or 1 and A is an anion of a pharmaceutically
acceptable acid wherein "lower" indicates a group having up to 3
carbon atoms, provided that when the symbol <IMG> represents a
single bond, X and Y are both fluorine atoms in the 4-position
and R is a methyl group n is not zero, which process comprises
a) reducing a compound of the formula
<IMG> II
wherein Ar, X and R have the meaning as defined above and R' is
a hydrogen atom or an alkyl, an acyl or an alkylsulfonyl group
32

having 1 - 3 carbon atoms, to obtain a compound of formula Ia, or
b) reacting a reactive ester of an alcohol of the formula
<IMG> I
wherein Ar, X and R have the meaning defined above, with ammonia
or
c) reducing a compound of the formula
<IMG> Ib
wherein Ar, X and R have the meaning defined above or
d) reacting a ketone of the formula
<IMG> IV
wherein Ar, X and R have the meaning defined above with ammonium
formate or methyl ammonium formate according to Leuckert-Wallach,
e) dehydrating a carbinol of the formula
<IMG> VII
to a compound of formula Ib, as defined above
f) reacting a compound of the formula
<IMG> VIII
33

wherein Ar, X and R have the meaning defined above and Z is a leaving group
with ammonia or a derivative thereof to form a primary amine of formula Ib
above, or
(g) oxidizing the benzylic carbon atom of a compound of the
formula
<IMG> IX
wherein Ar, X and R have the meaning defined above and R" and R"' are pro-
tective groups for the amino function, followed by elimination of the group
formed by oxidation at the benzyl carbon atom, giving a compound of the
formula
<IMG> X
which is transformed into the compound of formula Ib by removing the pro-
tective groups R" and R"'; and, if required, converting the primary amine ob-
tained into a therapeutically acceptable acid addition salt thereof in anhy-
drous form or any degree of hydration possible, by reaction with an acid HA
wherein A is as defined above.
2. A process according to claim 1 wherein process (b) is used and the
reactive ester is obtained by reacting the alcohol of formula III with a
halogenating agent.
3. A process according to claim 1 wherein process (b) is used and the
reactive ester is obtained by reacting the alcohol of formula III with thionyl
chloride, thionyl bromide, phosphorus tribromide or p-toluenesulphonyl
chloride.
34

4. A process according to claim 1 wherein process (c) is used and the
starting material of formula Ib is obtained by process (e), (f) or (g) of
claim 1.
5. A process according to claim 1 wherein X and Y are not both fluorine
atoms in the 4-position of respective phenyl groups.
6. A process according to claim 1 or 5 wherein process (a), (b), (c)
or (d) is used to obtain a compound of formula I in which the symbol <IMG>
represents a single bond.
7. A process according to claim 1 or 5 wherein process (a), (b), (c)
or (d) is used to obtain a compound of formula I in which the symbol <IMG>
represents a single bond and wherein X is hydrogen.
8. A process according to claim 1 or 5 wherein process (e), (f) or (g)
is used to obtain a compound of formula I in which the symbol <IMG> represents
a double bond.
9. A process according to claim 1 wherein X is hydrogen and Y is
fluorine, bromine or a methoxy group.
10. A compound of formula I as defined in claim 1 when prepared by a
process according to claim 1 or an obvious chemical equivalent thereof.

11. A process according to claim 1 wherein R is methyl, X is hydrogen
and the symbol ? represents a single bond.
12. A process according to claim 11 wherein Y is a phenyl ring substi-
tuted in the 4-position by a fluorine atom.
13. A process according to claim 11 wherein Y is a phenyl ring substi-
tuted in the 4-position by a bromine atom.
14. A process according to claim 11 wherein Y is a phenyl ring substi-
tuted in the 4-position by a methoxy group.
15. A process according to claim 11 wherein Y is a phenyl ring substi-
tuted in the 3-position by a bromine atom.
16. A process according to claim 11 wherein Y is a phenyl ring substi-
tuted in the 2-position by a bromine atom.
17. A process according to claim 1 wherein R is methyl X is hydrogen,
the symbol ? represents a double bond and Y is a phenyl ring substituted
in the 3-position by a bromine atom.
18. A process according to claim 1 wherein R is methyl, X is methoxy in
the 4-position, the symbol ? represents a double bond and Y is a phenyl
group substituted in the 4-position by a methoxy group.
19. A process for preparing (.beta.)-3-(4-fluorophenyl)-1-methyl-3-phenyl-
propylamine or its hydrochloride salt which comprises reducing 4-(4-fluoro-
phenyl)-4-phenylbutan-2-one oxime and, if required, reacting the product with
hydrogen chlcride to obtain the hydrochloride salt.
20. A process for preparing (.beta.)-3-(4-bromophenyl)-1-methyl-3-phenyl-
propylamine or its maleate salt which comprises reducing 4-(4-bromophenyl)-
4-phenylbutan-2-one oxime and, if required, reacting the product with maleic
acid to obtain the maleate salt.
21. A process for preparing (.alpha.)-3-(4-methoxyphenyl)-1-methyl-3-phenyl-
36

propylamine or its maleate salt which comprises reclucing 4-(4-methoxyphenyl)-
4-phenylbutan-2-one oxime and, if required, reacting the product with maleic
acid to obtain the maleate salt.
22. A process for preparing (.beta.)-3-(3-bromophenyl)-1-methyl-3-phenyl-
propylamine or its fumarate salt which comprises reducing 4-(3-bromophenyl)-
4-phenylbutan-2-one oxime and, if required, reacting the product with fumaric
acid to obtain the fumarate salt.
23. A process for preparing (.beta.)-3-(3-bromophenyl)-1-methyl-3-phenyl-
propylamine or its maleate salt which comprises reacting 4-(3-bromophenyl)-
4-phenylbutan-2-one with formamide, and, if required, reacting the product
with maleic acid to obtain the maleate salt.
24. A process for preparing (.alpha.)-3-(2-bromophenyl)-1-methyl-3-phenyl-
propylamine or its maleate salt which comprises reducing 4-(2-bromophenyl)-
3-phenylbutan-2-one oxime and, if required, reacting the product with maleic
acid to obtain the maleate salt.
25. A process for preparing (E)-3-amino-1-(3-bromophenyl)-1-phenyl-
butene or its hydrochloride salt which comprises reacting (E)-3-phthalimido-
1-(3-bromophenyl)-1-phenylbutene with hydrazine hydrate and, if required,
reacting the product with hydrogen chloride to obtain the hydrochloride salt.
26. A process for preparing (Z)-3-amino-1-(3-bromophenyl)-1-phenylbut-
l-ene or its maleate salt which comprises reacting (Z)-3-phthalimido-1-(3-
bromophenyl)-1-phenylbutene with hydrazine hydrate and, if required, reacting
the product with maleic acid to obtain the maleate salt.
27. A process for preparing 3-amino-1,1-di-(4-methoxyphenyl)-1-butene
or its fumarate salt which comprises dehydrating 3-amino-1-hydroxy-1,1-di-(4-
methoxyphenyl)-butane and, if required, reacting the product with fumaric
acid to obtain the fumarate salt.
28. A process for preparing the hydrochloride salt of 3,3-di-(4-
fluorophenyl)-1-methylpropylamine which comprises reducing 3,3-di-(4-fluoro-
37

phenyl)-1-methyl-allylamine in the presence of hydrochloric acid.
29. A process for preparing (.beta.)-3-(4-methoxyphenyl)-1-methyl-3-phenyl-
propylamine or its maleate salt which comprises reducing 4-(4-methoxyphenyl)-
4-phenylbutan-2-one oxime and, if required, reacting the product with maleic
acid to obtain the maleate salt.
30. A process for preparing (E)-3-amino-1-(4-bromophenyl)-1-phenyl-
butene or its oxalate salt which comprises reacting (E)-3-phthalimido-1-(4-
bromophenyl)-1-phenylbutene with hydrazine hydrate and, if required, reacting
the product with oxalic acid to obtain the oxalate salt.
31. The compound (.beta.)-3-(4-fluorophenyl)-1-methyl-3-phenylpropylamine or
its hydrochloride salt when prepared by a process according to claim 19 or
an obvious chemical equivalent thereof.
32. The compound (.beta.)-3-(4-bromophenyl)-1-methyl-3-phenylpropylamine or
its maleate salt when prepared by a process according to claim 20 or an ob-
vious chemical equivalent thereof.
33. The compound (.alpha.)-3-(4-methoxyphenyl-1-methyl-3-phenylpropylamine or
its maleate salt when prepared by a process according to claim 21 or an ob-
vious chemical equivalent thereof.
34. The compound (.beta.)-3-(3-bromophenyl)-1-methyl-3-phenylpropylamine or
its fumarate or maleate salt when prepared by a process according to claim 22
or 23 or an obvious chemical equivalent thereof.
35. The compound (.alpha.)-3-(2-bromophenyl)-1-methyl-3-phenylpropylamine or
its maleate salt when prepared by a process according to claim 24 or an ob-
vious chemical equivalent thereof.
36. The compound (E)-3-amino-1-(3-bromophenyl)-1-phenylbutene or its
hydrochloride salt when prepared by a process according to claim 25 or an
obvious chemical equivalent thereof.
37. The compound (Z)-3-amino-1-(3-bromophenyl)-1-phenylbut-1-ene or its
38

maleate salt when prepared by a process according to claim 26 or an obvious
chemical equivalent thereof.
38. The compound 3-amino-1,1-di-(4-methoxyphenyl)-1-butene or its
fumarate salt when prepared by a process according to claim 27 or an obvious
chemical equivalent thereof.
39. The hydrochloride salt of 3,3-di-(4-fluorophenyl)-1-methylpropyl-
amine when prepared by a process according to claim 28 or an obvious chemical
equivalent thereof.
40. The compound (.beta.)-3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine
or its maleate salt when prepared by a process according to claim 29 or an
obvious chemical equivalent thereof.
41. The compound (E)-3-amino-1-(4-bromophenyl)-1-phenylbutene or its
oxalate salt when prepared by a process according to claim 30 or an obvious
chemical equivalent thereof.
39

Description

The present invention is related to new compounds of the diarylalkyl-
amine type having therapeutic. activity, to methods for preparing such compounds,
to pharmaceutical preparations comprising such compounds and to methods of
treatment employing such compounds. The invention is also related to inter-
mediates useful in preparation of such therapeutically active compounds.
The object of the invention is to obtain compounds having a therapeu-
tical activity in the central nervous system, especially an anti-depressive or
a tranquilizing activity.
British Patent 1429068 discloses compounds corresponding to the
general formula:
Br ~
: Rl ~\ fCH3
~ CH-CH2 -CH2 -N~
N
having anti-depressive activity. Belgian Patent 835.802 discloses compounds
of the general formula:
Br
R ~ / C=CH-CH2-N
having anti-depressive activity.
Compounds following ~ithin the general formula
H~
C RIII
CH2
CH-CH
NHR
are disclosed by prior publications as follows: R =CH30, R =OH, R =RIV=H
and R =Cl, R =OH~ R =CH3~ R V=H having hypotensive properties, by British
Patent 765~881; RI=RII=RIII=RIV=H by French Patent 2~215~973; R =R sR =H~
RIV=tertiary butyl having spasmolytic properties, by British Patent 923~942;
R =R =R =H, R V=CH3 having spasmolytic properties, by U.S. Patent 2~46~522.
r - 2 -
,"~
.

South African Patent 62/~15~ discloses i.a. a compound having theformula
CF
/ \
CH3 CH3-N(CH3)2
claimed to have a therapeutic utility especially as an anti-tussive.
In J. Med. Chem. 1~ 161 (1971) a compound of the formula
~`lCI~
H CH3-NHCH3
is disclosed as an antidepressant.
General Outline of the Invention
According to the present invention it has been found that compounds
of the general formula below have advantageous, therapeutic properties:
Ar R
Cll.... CH2-CH-NH2(HA)n
X
In these compounds the dotted line represents an optional double
bond. These compounds may be divided into two groups defined by the formulae
Ar R
~ CH-cH2-cH-NH2(HA)n Ia
X
Ar R
- C=CH-CH-NH2~HA)n Ib
X
- 3 -
-

41
.. .
. In the compounds of formula I Ar represents the group
wherein Y is bound in the 2-, 3- or 4-position and represents a lower alkyl
group, a lower alkoxy group, a halogen, a trifluoromethyl group, or Ar
represents a pyridyl group bound in the 2-, 3- or 4-position, X represents
hydrogen, a lower alkyl group, a lower alkoxy group, a halogen, a trifluoro-
methyl group, R is a lower alkyl group, n is zero or 1 and A is an anion of
a pharmaceutically acceptable acid, provided that when the symbol
represents a single bond, X and Y are both fluorine atoms in the 4-position
`~ 10 and R is a methyl group~ n is not zero. By lower alkyl and alkoxy groups
are meant groups comprising up to 3 carbon atoms. Halogen may be any of the
elements F, Cl, Br or I. Therapeutically acceptable salts and bioprecursors
of the compounds of the invention as well as differently hydrated or anhydrous
forms of such compounds or salts are within the scope of the invention. By a
bioprecursor of a therapeutically active compound is meant a compound which
is structurally different from the therapeutically active compound but which
~ on administration to an animal or human is converted in the body to the
; therapeutically active compound.
The compounds of formula Ia above wherein Ar is identical to the
group
~ X
contain one asymmetric carbon atom. The remaining compounds of formula Ia
; contain two asymmetric carbon atoms and can therefore exist in two diastereo-
; meric forms which can be separated by methods known in the art. Further the
: compounds of formula Ia above may be resolved into their optical enantiomers
by using optically active acids such as i.a. tartaric acid, mandelic acid,
dibenzoyl tartaric acid as known in the art. The compounds of the invention
may be used as mixtures of diastereomeric forms or as racemic mixtures of the
pure diastereomers or as the pure
4 -
- : , , .
.-: ,' . :- ~ - :
.: .. . : -

.
enantiomers mentioned above. The therapeutic properties may reside to a
greater or lesser extent in one of the enantiomers or mixtures mentioned
above.
Due to the lack of free rotation in the double bond the compound
of formula Ib in which the group Ar is not identical with the group
X~
may exist in different stereoisomeric forms, that is in cis-trans isomers or,
according to the IUPAC nomenclature ~J. Org. Chem. 35, 2849-2867, September
1970), in an E-form and a Z-form. The compound may be used therapeutically
as a mixture of geometrical isomers or in pure E or Z form. The pure geo-
metrical isomers may be prepared from an isomer mixture, from an isomer-pure
starting material or directly by a stereoselective synthesis.
It should be noted that in the IUPAC nomenclature compounds of
formula Ib in the form of pure geometrical isomers which are similar in
structure may be named the E-form for one subgroup of compounds and the Z-
form for another subgroup. The two structural formulas below illustrate
this fact.
Br
f H / CH-NH
CH3 CH3
E-form Z-form
5 _
: :: ::
- ,.

4 ~
;
All the compounds of formula Ib further contain one asymmetric carbon atom.
The compounds of formula Ib may be resolved into their optical enantiomers
by using optically active acids such as i.e. tartaric acid, mandelic acid,
dibenzoyl tartaric acid as known in the art. The compounds of formula Ib
may be used as mixtures especially racemic mixtures, or as the pure enantio-
mers of the geometrical isomers mentioned above. The therapeutic properties
may reside to a greater or lesser extent in one of the enantiomers or mix-
tures mentioned above.
The compounds of the invention show an activity in the central
1~ nervous system which makes them useful as neuropharmacological agents for
treatment of various diseases in animals including man. The compounds are
expected to be especially useful as anti-depressive, anxiolytic or tranquil-
. izing agents in man.
~; Preferred embodiment of the inventionOf the compounds of the invention defined by formula I above those
wherein Ar is
are to be specially mentioned. Of those the compounds ~herein X is hydrogen
are preferred and especially those wherein Y is F, Br or CH30-.
As preferred individual compounds should be mentioned:
~)-3-~4-~lurophenyl)-1-methyl-3-phenylpropylamine,
~)-3-~4-bromophenyl)-1-methyl-3-phenylpropylamine,
` ~a)-3-~4--methoxyphenyl)-1-methyl-3-phenylpropylamine, and
~)-3-~3-bromophenyl)-1-methyl-3-phenylpropylamine
being non-selective inhibitors of neuronal noradrenaline and 5-hydroxytryp-
tamine uptake;
~a)-3-~2-bromophenyl)-1-methyl-3-phenylpropylamine,
.
~,~
'

(E)-3-amino-1-(3-bromophenyl)-1-phenylbutene, and
~Z)-3-amino-1-~3-bromophenyl)-1-phenylbutene
being selective inhibitors of neuronal noradrenaline uptake; and
3-amino-1,1-di-~4-methoxyphenyL)-l-butene,
3,3-di-(4-fluorophenyl)-1-metllylpropylamine,
` - 6a -
- ~ . :: ' : ' ~ ' :

3-(4-methoxyphenyl)-1-methyl-3-phenylpropylamine, and
(E)-3-amino-1-(4-bromophenyl)-1-phenylbutene,
being selective inhibitors of neuronal 5-hydroxytryptamine uptake; as well as
salts and precursors of said compounds. The neuronal uptake mechanisms are
discussed further in the chapter "Pharmacological evaluation" below.
Generally preferred in all classes of the compounds of the invention
are those wherein R represents a methyl group.
Methods of Preparation
The compounds of the invention may be prepared by
(a) reducing a compound of the formula
Ar R
CH-CH -C=N-OR' II
wherein Ar, X and R have the meaning defined above and R' is a hydrogen atom
or an alkyl, an acyl or an alkylsulfonyl group having 1 to 3 carbon atoms, to
obtain a compound of formula Ia. The reduction may be carried out by known
methods e.g. employing a hydride reagent such as lithium aluminium hydride,
(b) reacting a reactive ester of an alcohol of the formula
Ar R
-CH2-CH-H III
.~ X
wherein Ar, X and R have the meaning defined above and reacting the ester
obtained with ammonia. The reactive ester may be obtained by treating the
alcohol with a halogenating agent such as thionyl chloride, thionyl bromide
or phosphorus tribromide, or with an arylsulphonyl halide such as p-toluene-
sulphonyl chloride,
(c) reducing a compound of the formula
Ar R
X C=CH-CH-NH2 Ib
~ .
,~,1

41
wherein Ar, X and R have the meaning defined above. The reduction may be
carried out by methods known in the art e.g. by catalytical hydrogenation
using catalysts SUC}I as Raney nickel, palladium on charcoal, platinum dioxide
or rhodium,
(d) reacting aketone of the formula
Ar R
~ CH-C}12-C--O IV
.' X
wherein Ar, X and R have the meaning defined above, with ammoniumformate or
methylammoniumformate according to Leuckart-~allach. The formate may be
added as such, or obtained by formation in situ from formamide or methyl
formamide, or from formic acid and ammonia or methylamine.
The intermediates of formulae II, III, and IV above are novel.
The intermediates of formula II may be prepared by reacting the
ketone of the formula IV above with a hydroxylamine derivative of formula
NH20R', wherein R' has the meaning defined above.
The intermediate of formula III may be prepared by hydride reduc-
tion of the compound of formula IV which, in turn, may be obtained by
1) reacting an alpha, beta-unsaturated ketone of the formula
X ~ CH=CH-C=O
wherein X and R have the meaning defined above, with a metal-organic reagent,
such as magnesium, lithium or sodium derivative of an arylhalide of the
formula Ar-Y', wherein Ar has the meaning defined above and Y' is a chlorine,
bromine or iodine atom, in the presence of catalytic amounts of cuprous ions,
2) reacting a diarylcarbinol of the formula
H-Ar VI
X OH
wherein Ar and X have the meaning defined above, first withthionylchloride,
then with ethyl acetoacetate in the presence of suitable condensation catalyst
such as sodium acetate or the like.
~'
i ~ - 8 -

4:L
The compounds of formula Ia are preferably prepared by method a).
The reaction according to method a) is preferably performed in diethyl ether
with a slight excess of lithium aluminium hydride under inert atmosphere.
The new compounds of :Eormula Ia may be used therapeutically as the
racemic mixtures of ~+)- and (-)-forms, which in the usual case are obtained
; at the synthesis. Isomer mixtures obtained may be resolved by methods known
per se into the corresponding optically active modifications. If desired,
the optically active modification may be prepared by way of direct synthesis,
e.g. via an optically active compound as described above.
; 10 The compounds of the formula I of the invention may be prepared by:
~e) Dehydration of a carbinol of the formula
Ar R
~ 1 2 2 VII
X 0}1
to a compo~md of formula Ib.
The dehydration of the starting material may be done by means of
treatment with hydrochloric acid HCl and heating of the reacting mixture.
The dehydration of the starting material may also be done by means of other
types of acid-catalysis, such as by means of sulfuric acid H2S04, phosphoric
acid H3P04, potassium hydrogen sulphate KHS04, or oxalic acid ~COOH)2. Other
methods for the dehydration of the starting material to the formation of a
compound of the formula I are dehydration using phosphoroxichloride POC13
in pyridine, and dehydration with thionylchloride, SOC12, in pyridine. Also
a catalytic dehydration of the starting material may be used. The dehydration
is in this case carried out at a temperature of about 300 to 500~C using a
catalyst such as kaolin, alumina or aluminium oxide.
~ _ 9 _

(f) Reaction of a compo~md of the formula
Ar R
X ~ C=CH-CH-Z VIII
wherein Z is a leaving group such as F, Cl, Br, I, OS02R , wherein R is
alkyl, aralkyl or aryl, with ammonia or with a derivative thereof such as
hexamethylenetetraamine, alkaliphtalimide, lithium bisbenzenesulfeneamide,
guanidine, sodium cyanate, sodium azide, a carboxamide or a sulfoneamide.
IVhen an amine derivative is alkylated the product obtained is subsequently
hydrolyzed or in some other way converted into a primary amine of formula Ib.
A preferred amine derivative is potassium phtalimide.
This reaction is also useful for preparation of the compounds of
formula Ia by employing as a starting material a saturated compound corres-
ponding to the compound of formula VIII.
(g) Oxidation (halogenation) of the benzylic carbon atom of a com-
pound of formula IX
Ar R R"
~ CH-CH2-CH-N / IX
X R"'
e.g. with N-bromosuccinimide, R", R"' being protective groups for the amino
function preferably joined as the group
R~ .
: O
or alternatively corresponding to one of the amine derivatives specified
under f) above, followed by elimination of the group formed by oxidation at
the benzyl carbon atom, giving a compound of the formula
- 1 0 -

Ar R R"
C=CII-CH-N
X R"'
which is transformed into the compound of formula Ib by splitting off the
groups R" and R"', e.g. by hydrolysis or hydrazinolysis. In this manner it
is possible to synthesize the compounds of formula Ib from the corresponding
saturated compo~mds of formula Ia, by introducing in those compounds protec-
tive groups R" and R"~ in a kno~n manner to the obtention of a compound of
formula IX.
Obtained compounds of formula I can be converted, if required, into
therapeutically acceptable acid addition salts, in anhydrous form or in any
10degree of hydration, by reaction with an acid HA wherein A is as defined
above.
The intermediates of formulae VII, VIII, IX and X above are novel.
.: The intermediate of formula VII may be obtained by preparing a
Grignard or lithium compound from a halobenzene of the formula
.; ~ Hal Hal = Br, Cl
: X
and reacting it with an ester of the formula
0 R
Il I
.~ R" - 0-C-CH2-CH-NH2
wherein R" is an alkyl, aralkyl or aryl group.
The intermediate of formula VII may be isolated (cf. Example 14)
20and subsequently dehydrated or alternatively the crude product in the prepar-
ation of formula VII may be dehydrated directly (cf. Example 16).
The intermediate of formula VIII may be obtained fro~ a compound of
formula
X ~ C=CH-CH -R XI
-- 11 --
~ . . .--

wherein X, Ar and R haYe the meaning defined above, by oxidation of the
allylic carbon to the formation of a compound of the formula
Ar R
X ~ C=cH-cll-zl III:l
wherein Z represents Z or OH, e.g. by reaction with N-bromosuccinimide
(Z = Br) or selenium dioxide ~zl = OH). The latter compound may be trans-
formed to a reactive derivative III by treatment with an agent such as SOC12,
SOBr2 or PBr3 or with ClS02Rl.
Pharmaceutical preparations
In clinical practice the compounds of the present invention will
normally be administered orally, rectally or by injection, in the form of
pharmaceutical preparations comprising the active ingredient either as a free
base or as a pharmaceutically acceptable non-toxic, acid addition salt, e.g.
the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulphate, sul-
phamate, citrate, tartrate, oxalate and the like in association with a phar-
maceutically acceptable carrier. Accordingly, terms relating to the novel
compounds of this invention whether generically or specifically are intended
to include both the free amine base and the acid addition salts of the free
base, unless the context in which such terms are used, e.g. in the specific
examples would be inconsistent with the broad concept. The carrier may be a
solid, semi-solid or liquid diluent or capsule. These pharmaceutical pre-
parations constitute a further aspect of this invention. Usually the active
substance will constitute from 0.1 to 99 % by weight of the preparation, more
specifically between 0.5 and 20 % by weight for preparations intended for in-
jection and between 2 and 50 % by weight for preparations suitable for oral
administration.
To produce pharmaceutical preparations containing a compound of
the invention in the form of dosage units for oral application the selected
- 12 -

39
':
- compound may be mixed with a solid pulverulent carrier, e.g. lactose, sac-
charose, sorbitol, mannitol, starches such as potato starch, corn starch or
amylopectin, cellulose derivatives, a binder such as gelatine or polyvinyl-
pyrrolidone, and a lubricant such as magnesium stearate, calcium stearate,
polyethylene glycol waxes, and the like, and then compressed to form tablets.
If coated tablets are required, the cores, prepared as described above, may
be coated with a concentrated sugar solu-tion which may contain, e.g. gum
arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the
tablet can be coated with a lacquer dissolved in a readily volatile organic
1~ solvent or mixture of organic solvents. Dyestuffs may be added to these coat-
ings in order to readily distinguish between tablets containing different
active substances or different amounts of the active compounds.
~or the preparation of soft gelatine capsules (pearlshaped closed
capsules) consisting of gelatine and for example, glycerol or similar closed
capsules, the active substance may be admixed with a vegetable oil. Hard
gelatine capsules may contain granulates of the active substance in combina-
tion with solid, pulverulent carriers such as lactose, saccharose, sorbitol,
mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose
derivatives or gelatine.
Dosage units for rectal application can be prepared in the form
of suppositories comprising the active substance in admixture with a neutral
fatty base, or gelatine rectal capsules comprising the active substance in
admixture with vegetable oil or paraffin oil.
Liquid preparations for oral application may be in the form of
syrups or suspensions, for example, solutions containing from about 0.2 % to
about 20 % by weight of the active substance herein described the balance
being sugar and a mixture of ethanol, water, glycerol, and propyleneglycol.
Optionally such liquid preparations may contain colouring agents, flavouring
agents, saccarine and carboxymethylcellulose as a thickening agent.
Solutions for parenteral applications by injection can be prepared
in an aqueous solution of a water-soluble pharmaceutically acceptable salt of
- 13 -
.

the active substance preferably in a concentration of from about 0.5 % to
about 10 % by weight. These solutions may also contain stabilizing agents
and/or buffering agents and may conveniently be provided in various dosage
unit ampoules.
Suitable daily doses of the compounds of the invention in thera-
peutic treatment is 25 to 250 mg for peroral administration, preferably 50
- to 150 mg, and 5 to 50 mg for parenteral administration preferably 10 to 30
mg. A preparation in dosage unit form for oral administration may contain
10 to 50 mg, preferably 10 to 25 mg of active substance per dosage unit.
~orking examples
Example 1. PTeparation of 4-(3-bromophenyl)-4-phenylbutan-2-one
To 2.4 g ~0.10 mol) of magnesium turnings, covered with 20 ml of
anhydrous diethyl ether and treated with some crystals of iodine under nitro-
gen atmosphere, 23.5 g ~0.10 mol) of 1.3-dibromobenzene in 80 ml of ether
was added. The rate of addition was adjusted, to maintain a gentle reflux of
the solvent. When the Mg turnings had disappeared ~30 min) 0.75 g ~0.005
mol) of cuprous bromide was added and the mixture was stirred for 10 min at
room temperature. A solution of 13.6 g (0.09 mol) of benzalacetone in 100
ml of ether was added dropwise at ~10C. Then the reaction mixture was al-
lowed to reach room temperature for 2 h. The mixture was poured into 400 ml
of a 10 % aqueous solution of ammonium chloride, the aqueous layer was sep-
arated and the product was extracted with 2 x 200 ml of ether. The ethereal
layer was washed with water, dried with Na2S04 and the solvent was evaporated.
The crude 3-~3-bromophenyl)-3-phenylbutan-2-one obtained (26.5 g, 0.086 mol)
was added to a solution of 20 g ~0.28 mol) of hydroxylamine hydrochloride in
300 ml of ethanol and 100 ml of anhydrous pyridine. The mixture was heated
under reflux for 4 h. After cooling the solvent was evaporated in vacuo and
the ketoxime was extracted with ether from an aqueous solution. Washing of
the extract with water and drying followed by evaporation of the solvent gave
27.5 g of 4-~3-bromophenyl)-4-phenylbutan-2-one oxime.
- 14 -
. X

Example 2. Preparation of 3-~3-bromophenyl)-1-methyl-3-phenyl-
propylamine oxalate. (Method a)
To the oxime obtained according to Example 1 ~27.5 g) 100 ml of
carbon tetrachloride was added and evaporated twice in order to remove traces
of water. The residue was dissolved in a mixture of 300 ml of anhydrous ether
and 150 ml of anhydrous tetrahydrofuran. To the stirred mixture 3.5 g ~0.0086
mol) of lithium al~1minum hydride was added in portions under nitrogen atmo-
sphere at room temperature. The reaction mixture was stirred for 8 h. Then
25 ml of 2 M NaOH was dropwise added and the precipitated inorganic salts
were removed by filtration. The filtrate was shaken with 3 x 300 ml of 1 M
HCl and the combined aqueous layers were made alkaline by addition of 35 ml
of 30 % NaOH. Extraction with 3 x 200 ml of methylene chloride, washing, dry-
ing and evaporation of the solvent gave 8.9 g of the primary amine as an oil.
To a hot solution of 7.9 g ~0.026 mol) of the amine in 100 ml of isopropyl-
alcohol 1.1 g (0.014 mol) of oxalic acid in 10 ml of ethanol was added. 6.2
g of the diamine oxalate was collected. Recrystallization from 160 ml of a
mixture of ethanol and isopropylalcohol ~1:1) yielded 4.43 g, mp 134-138C.
Analysis: C calcd 58.5 %, found 58.7 %; H calcd 5.48 %, found
5.80 %; N calcd 4.01 %, found 4.07 %.
Example 3. Separation of 3-~3-bromophenyl)-1-methyl-3-phenyl-
propylamine into its diastereomers.
The free amine ~2.9 g, 0.009 mol) obtained from 3.8 g of the oxa-
late prepared according to Example 2, was dissolved in 40 ml of ethyl acetate.
A hot solution of 1.1 g ~0.009 mol) of maleic acid in 20 ml of ethanol was
added. There was obtained 1.3 g of the maleate. Recrystallization from 18
ml of isopropylalcohol gave 0.65 g of the pure alpha isomer, mp 163-165 C.
The high field part of the NMR spectrum ~COC13) displayed a triplet at 4.1
ppm ~J=7.8 Hz), a quartet at 2.8 ppm ~J=6.2 Hz), a double dublet at 2.0 ppm
ttwo protons) and a dublet at 1.5 ppm ~J=6.1 Hz) ~three protons).
Analysis: C calcd 57.15 %, found 57.45 %, H calcd 5.28 %, found
5.35 %; Br calcd 19.01 %, found 19.05 %; N calcd 3.33 %, found 3.20 %; O calcd
15.23 %, found 15.00 %.
- 15 -

4 i
The solvents of the first mother liquors of the diamine oxalate
prepared accordin~ to example 2 were evaporated and the residue was extracted
with ether from an alkaline solution. There was obtained 1.2 g of free amine.
The fumarate was prepared in ethyl acetate from half an equivalent of fumaric
acid and recrystallized twice from acetonitrile-isopropylalcohol affording
0.28 g of the pure beta isomer as the diamine fumarate, mp 184-186C.
Analysis: C calcd 59.7 %, found 60.3 %, H calcd 5.6 %, found 5.7 %;
N calcd 3.9 %, found 3.7 %.
Example 4
~a)-3-~4-fluorophenyl)-1-methyl-3-phenylpropylamine oxalate, mp
186-188 C ~EtOH-EtOAc, 1:1) and ~)-3-~4-fluorophenyl)-1-methyl-3-phenyl-
propylamine hydrochloride, mp 171-172C ~EtOAc) were prepared from 4-~3-
fluorophenyl)-4-phenylbutan-2-one oxime in accordance with Examples 2 and 3.
Example 5
~a)-3-~4-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp
168-170 C ~EtOH-EtOAc, 1:1) and ~)-3-(4-bromophenyl)-1-methyl-3-phenyl-
propylamine maleate; mp 161-162C ~i-PrOH-EtOAc, 3:1) were prepared from 4-
~4-bromophenyl)-4-phenylbutan-2-one oxime in accordance with Examples 2 and 3.
Example 6
~a)-3-~4-methoxyphenyl)-1-methyl-3-phenylpropylamine maleate, mp
146-148C ~i-PrOH) and ~)-3-~4-methoxyphenyl)-1-methyl-3-phenylpropylamine
maleate, mp 124-133C ~EtOAc) were prepared from 4-~4-methoxyphenyl)-4-phenyl-
` butan-2-one oxime in accordance with Examples 2 and 3.
Example 7
~a)-l-methyl-3-~4-trifluoromethylphenyl)-3-phenylpropylamine maleate,
mp 165-166C.
; and ~ l-methyl-3-(4-trifluoromethylphenyl)-3-phenylpropylamine maleate, mp
165-167C.
were prepared from 4-~4-trifluoromethylphenyl)-4-phenylbutan-2-one oxime in
accordance with Examples 2 and 3.
- 16 -

Example 8. Preparation of 4-(2-bromophenyl)-4-phenylbutan-2-one
To a solution of 24.3 g ~0.13 mol) of 2-bromobenzaldehyde in 80 ml
of acetone, 1.0 ml of 10 M NaOH was slowly added at OC. The reaction mixture
was allowed to reach room temperature and stirred for another 2 h. Then it
was poured into 400 ml of water, to which 10 ml of 2 M HCl had been added.
- Extraction with ether, drying and evaporation of the solvent gave 18.9 g of
2-bromobenzalacetone as an oil. This was dissolved in 150 ml of ether and
added to a Grignard reagent prepared from 1,1 g (0.045 mol~ of magnesium
turnings 6.6 g ~0.042 mol) of bromobenzene and 0.2 g of CuBr in 150 ml of
ether. The mixture was stirred under nitrogen atmosphere for 2 h. It was
poured into 450 ml of ice-water to which 18 g of ammonium chloride had been
added. Extraction with ether gave 11.0 g of the desired ketone as an oil.
Example 9
(~)-3-~2-bromophenyl)-1-methyl-3-phenylpropylamine maleate, mp 145-
146 C ~i-PrOH) and ~)-3-(2-bromophenyl)-1-methyl-3-phenyl-propylamine
maleate, mp 135-137C ~EtOH-EtOAc, 1:4) were prepared from 4-~2-bromophenyl)-
4-phenylbutan-2-one oxime in accordance with Examples 2 and 3.
Example 10. Preparation of 3-(3-bromophenyl)-1-methyl-3-phenyl-
propylamine ~Method d)
A mixture of 22.1 g ~0.074 mol) of 4-(3-bromophenyl)-4-phenylbutan-
2-one and 230 ml o~ formamide was heated for 8 h at 180C. After cooling
water was added and the product was taken up in ether. Drying and evaporation
of the solvent gave 30.5 g of a residue.
To this residue 85 ml of conc. hydrochloric acid was added and the
mixture was heated under refluxing conditions for 3 h. Water was added and
the non basic materials were removed by shaking the reaction mixture with 100
ml of ether. The aqueous layer was separated and made alkaline by addition
of 120 ml of 10 M NaOH. Extraction with 3 x 200 ml of ether, drying ~Na2SO4)
and evaporation of the solvent gave 12.9 g of the desired amine.
,~

o~
The maleate was prepared by addition of a hot ethanolic solution
of 4.9 g of maleic acid into a warm solution of the amine in 100 ml of ethyl
acetate. P.ecrystallization from EtOH-EtOAc gave 8.4 g of the maleate, mp
158-161C.
Analysis: C calcd 57.2 %, found 57.5 %; H calcd 5.28 %, found
5.35 %; Br calcd 19.0 %, found 19.1 %; N calcd 3.33 %, found 3.20 %; O calcd
15.2 %, found 15.0 %.
Example 11. Preparation of 3,3-di-~4-fluorophenyl)-1-methyl-
propylamine hydrochloride (Mekhod c)
3,3-di-~4-fluorophenyl)-1-methylallylamine (0.9 g, 0.003 mol) as
dissolved in 100 ml of ethanol and transferred to a Parr hydrogenation flask.
1.0 ml of concentrated hydrochloric acid was added followed by 0.2 g of 5 %
palladium on charcoal. The hydrogenation was effectuated at a pressure of
3.9 atm for 5.5 h. The reaction mixture was filtered to remove the catalyst
and the solvent of the filtrate was evaporated. Crystallization from EtOAc-
i-Pr2O gave 0.75 g of the desired product, mp 225-229C.
Analysis: C calcd 64.5 %, found 64.5 %; H calcd 6.09 %, found
6.11 %; C1 calcd 11.9 %, found 11.8 %; F calcd 12.8 %, found 12.7 %; N calcd
4.70 %, found 4.55 %.
By the same method there were prepared from the appropriate ally-
lamines:
Example 12.
By the method of Example 11 3,3-di-(4-methoxyphenyl)-1-methyl-
propylamine fumarate, mp 153-157C, (~tOH-i-Pr2O) was prepared from the cor-
responding allylamine.
Example 13.
By the method of Example 11 1,3', 3"-trimethyl-3,3-diphenyl-propy-
lamine oxalate, mp 214-215C, (EtOH-EtOAc) was prepared from the corresponding
allylamine.
- 18 -

Example 14~ ~reparation of 4,4-di~(4-bromophenyl)-4-hydroxy-2-
butylamine oxalate
A solution of 81.5 g ~0.35 mol) 1,4-dibromobenzene in 500 ml of
diethyl ether was added to a stirred mixture of 8.3 g ~0.35 mol) magnesium
turnings in 25 ml diethyl ether at such a rate that reflux was maintained.
After an additional stirring for 1.5 h at room temperature the mixture was
cooled in an ice-bath and a solution of 11.3 g ~0.11 mol) of ethyl 3-amino-
butyrate in 25 ml of diethyl ether was added during 15 min.
The mixture was stirred for 1.25 h at ice-cooling and then for 2.5
h at reflux. An aqueous cold solution of 25 g ammonium chloride was slowly
added, and after stirring ~he mixture was extracted twice with ether. The
ethereal layer was dried over sodium sulphate and the amine was precipitated
~10.9 g, 20 % yield) with oxalic acid dissolved in ether. M.p. 191-194C.
Elemental analysis: C18lll9Br2NO5: Found: C 44.5, H 4.0, N 2.7,
and D 16.8 %. Calculated: C 44.20, H 3.91, N 2.86 and 0 16.35 ~.
Examp-le 15. Preparation of 3-amino-1,1-di(4-bromophenyl)-1-butene
hydrochloride_~hlethod e)
A solution of 3.8 g 4,4-di(4-bromophenyl)-4-hydroxy-2-butylamine
oxalate, 25 ml acetic acid and 5 ml conc. aqueous hydrogen chloride was heated
under reflux for 30 min. The solvent was evaporated and the residue was made
alkaline with sodium hydroxide and extracted twice with ether. The ethereal
layer was dried over sodium sulphate and the solvent was evaporated. Ace-
tonitrile and hydrogen chloride in ether were added and the hydrochloride of
the title compound (1.7 g) was obtained after recrystallization from ace-
tonitrile/ether. M.p. 216-220 C.
Elemental analysis: C16H16Br2ClN; Found: C 46.7, H 3.9, Cl 8.8
and N 3.1 %. Calculated: C 46.02, 11 3.86, Cl 8.49 and N 3.35 %.
Example 16. Preparation of 3-amino-1 1-di(4-methoxyphenyl)-1-
.
butene fumarate (Method e)
A solution of 58.0 g (0.31 mol) of 4-bromoanisole in 300 ml diethyl
ether was added dropwise to a stirred mixture of 7.78 g (0.32 mol) magnesium
- 19 -

turnings in 250 ml of diethyl ether during 2 h. The mixture was stirred at
room temperature for another 1.5 h and then he&ted under reflux for 1.5 h.
The mixture was cooled in an ice-ba~h and a solution o~ 10.3 g ~0.10 mol)
ethyl ~-aminobutyrate in 25 ml diethyl ether was added during 20 min. After
stirring over night at room temperature an aqueolls solution of 16.6 g (0.31
mol) ammonium chloride was slowly added. The mixture was stirred and then
; made alkaline and filtered. After separation of the ether phase the aqueous
phase was extracted with ether. The combined ethereal layers were extracted
twice with 2 M hydrogen chloride. The aqueous phase was made alkaline and
extracted with ether and dried over sodium sulphate. After evaporation of
the solvent 10.1 g of yellow oil was obtained, which was dissolved in 75 ml
of acetic acid and 15 ml of conc. aqueous hydrogen chloride.
The solution was heated under reflux for 30 min and then the solvent
was evaporated. The residue was made alkaline and extracted with ether. The
ethereal layer was washed with water and extracted with 0.5 M hydrogen chlo-
ride. The aqueous phase was washed with ether, made alkaline and extracted
with ether. After drying over sodium sulphate the ether was evaporated to
give 5.9 g of the title compound as an oil in 21 % yield.
The amine was converted to the fumarate, which was recrystallized
twice from ethanol/ethyl acetate/hexane to give 6.2 g (17 % yield) of the
fumaric acid salt in the form C18H21N2 3/4C4H~04- M-p- 167-167-5 C-
Elemental analysis: C21H24NO5: Found: C 67.8, H 6.52, N 3.89and 0 21.5 %. Calculated: C 68.09, H 6.53, N 3.78 and 0 21.60 %.
Example 17
3-amino-1,1-di-(4-fluorophenyl)-1-butene fumarate was prepared
according to Example 16. M.p. 225-231C.
Example 18
3-amino-1,1-di-(3-methyiphenyl)-1-butene hydrochloride was prepared
according to Example 16. M.p. 216-217.5C.
- 20 -
.~
'

Example 19. Preparation of l-(4-bromophenyl~ phenyl-butene
Sodium dimethylsulfoxide in DMS0, prepared by heating 3.8 g (0.08
mol) sodium hydride (50 ~ in oil) in lO0 ml dimethylsulfoxide at 80C for 40
min, was mixed with 27.0 g (0.07 mol) propyltriphenyl-phosphonium bromide,
prepared by heating propylbromide and triphenyl-phosphine in toluene at re-
flux temperature for 14 h. The mixture was stirred under nitrogen atmosphere
at room temperature for 1.5 h. Then a solution of 13.1 g (0.05 mol) of 4-
bromobenzophenone, in a mixture of 100 ml dimethylsulfoxide and 100 ml of
anhydrous tetrahydrofuran was added at room temperature. The reaction mix-
ture was stirred for 2 h, then it was poured into l.000 ml of ice-water.
The product was extracted with 3 x 300 ml of ether, the combined ethereal
layer was washed with 100 ml of water. Vrying (Na2S04) and evaporation of
the solvent gave 18 g of oily residue. After trituration with lO0 ml of di-
isopropylether crystals of triphenyl-phosphinoxide was separated by filtration.
Distillation of the filtrate at 4 Pa gave 12.2 g of 1-(4-bromophenyl)-1-phenyl-
butene, b.p. 120-130C. Yield 85 %.
Example 20. Preparation of 3-(4-bromophenyl)-3-phenyl-1-methyl-
- allylbromide.
To a solution of 22.6 g (0.0786 mol) of 1-(4-bromophenyl)-1-phenyl-
butene in 800 ml of carbontetrachloride 14.0 g (0.0787 mol) of N-bromo-
succinimide was added. The mixture was heated to reflux temperature after
the addition of 0.7 g of alpha, alpha-azabis-butyronitrile. After 3.5 h all
NBS had been consumed and the reaction mixture was cooled and filtered. 7.8
g of succinimide was separated and the volume~of the filtrate was reduced to
50 ml by evaporation at 35 C. TLC of a sample on silica in diisopropyl-
etherhexane (1:1) showed a new spot at Rf 0.62 (the starting olefin had Rf
0.55). The material was being used without further isolation or purifica-
tion due to its hi~h reactivity with nucleophilic agents.
- 21 -
': ' :

:
Example 21. Preparation of 3~ phtalimido)~ 4-bromophenyl)-
l-phenylbutene ~Method f)
A solution of crude 3-~4-bromophenyl)-3-phenyl~l-methylallyl-
bromide (29 g, 0.08 mol) in 50 ml carbon tetrachloride was mixed with 15.0 g
(0.08 mol) of N-potassiumphtalimide and 120 ml of anhydrous dimethylformamide.
The mixture was stiTTed at 50 C foT 14 houTs.
Dilution with wateT ~excess) and extTaction of the product with
diethylether gave 18 g of an oil after drying and evapoTation of the solvent.
Column chromatogTaphy on silica with diisopropyletheT as the eluent afforded
the geometrical isomers: 2.6 g of the ~Z)-form, R~ = 0.30, and 3.7 g of the
(E)-form, Rf = 0.26 in diisopropylether-hexane ~1:1).
Example 22. PTepaTation of ~Z)-3-amino-1-~4-bromophenyl)-1-
phenylbutene maleate
To a stirTed solution of 0.43 g ~0.001 mol) of ~Z)-3-phtalimido-
1-~4-bTomophenyl)-l-phenylbutene in 30 ml of methanol 0.25 g ~0.005 mol) of
hydTazine hydrate was added at Toom temperatuTe. In ordeT to dissolve all
the phtalimide 10 ml of carbon tetTachloride was added. The mixture was
stirred and heated at 60C for 2 h. After cooling the solvent was removed
in vacuo and the residue was taken up in ether. The product was extracted
with 3 x 50 ml of 0.5 M HCl, the combined aqueous layer was made alkaline
with 10 M NaOH and extracted with 2 x 50 ml of ether. Drying and evaporation
of the solvent gave 0.23 g of the title compound as an oil. The maleate had
m.p. 174-176C from ethanol. The UV spectrum in ethanol had ~ max 237 nm.
Elemental analysis: C20H20BrN04; Found: C 57.1, H 4.80, BT 20.3,
N 3.10 and 0 15.2 %. Calculated: C 57.43, H 4.82, BT 19.10, N 3.35 and
0 15.30 %.
Example 23
~E)-3-amino-1-~4-bTomophenyl)-l-phenylbutene oxalate was prepared
fTom the coTresponding phtalimide according to Example 22. M.p. 145-148 C.
- . ' :
.

Example 24. Preparation of (Z)-3-amino-1-(3-bromophenyl)-1-
phenylbut-l-ene maleàte (Method f)
To a stirred solution of 0.43 g (0.001 mol) of (Z)-3-phtalimido-
1-~3-bromophenyl)-1-phenylbutene in 40 ml of methanol 0.35 g (0.007 mol) of
hydrazine hydrate was added at room temperature. The mixture was heated
under reflux for 2.5 h. The solvent was evaporated and the residue was taken
up in ether. Extraction with 3 x 25 ml of 0.5 M IICl followed by alkalization
of the combined aqueous layer with 10 M NaOH and extraction with 2 x 50 ml
of ether gave 0.19 g of residue after drying and evaporation of the solvent.
The maleate was prepared from 15 ml ethylacetate - ethanol (2:1) to give
0.12 g (28 %~. M.p. 198-200C.
Elemental analysis: C20H20BrN04; Found: C 56.3, H 4.7, and N 3.2
%. Calculated C 57.43, H 4.82 and N 3.35 %.
Example 25
(E)-3-amino-1-(3-bromophenyl)-1-phenylbutene hydrochloride was pre-
pared from the corresponding phtalimide according to Example 24. M.p. 118-
123C.
Example 26
(Z)-3-amino-1-(4-bromophenyl)-1-(3-pyridyl)-butene oxalate was pre-
pared from the corresponding phtalimide according to Example 24. M.p.
Example 27. Preparation of 3-(N-Phtalimido)-1-(4-bromophenyl)-1-
phenylbutane
3-(4-bromophenyl)-1-methyl-3-phenylpropylamine as the free base
(41.2 g, 0.136 mol) was dissolved in 350 ml of acetic acid. Phtalic anhydride
(20.0 g, 0.136 mol) was added and the mixture was heated with stirring under
refl~x (bath temperature 120C) for 2 h. After cooling the solvent was evap-
orated in vacuo. The residue was shaken with a mixture of 800 ml of ether
and 500 ml of 2 M Na3H. The ethereal layer was separated and washed with 100
ml 1 M hydrochloric acid. Drying and evaporation gave 49.5 g of a tan oil.
Thin layer chromatography on silica in diisopropylether showed one spot of
:

Rf 0.42. NMR showed a four proton multiplet at 7.7 ppm from T~S, character-
istic of phtalimides. The material was used without further purification.
Yield 83 %.
Example 28 Preparation of 3-~N-phtalimido)-1-(4-bromophenyl)-
` l-phenylbut-l-ene ~Method g)
To a stirred solution of 24.6 g ~0.057 mol) 3-~N-phtalimido)-l-
~4-bromophenyl)-1-phenylbutane in 400 ml of carbon tetrachloride 10.0 g (0.057
mol) of N-bromosuccinimide was added. The mixture was stirred and 0.5 g of
alpha, alpha-azaisobutyronitrile was added as radical initiator. Stirring
was continued under reflux temperature for 2.5 h. The reaction mixture was
cooled and filtered. Upon evaporation of the solvent 32.4 g of a residue
Nas obtained. NhlR of a sample in COC13 showed a double quartet at 5.0 ppm
from T~S and a doublet at 6.6 ppm. TLC on silica in diisopropylether showed
a spot with Rf 0.28, identical with the Rf-value of the material prepared
according to Example 22.
The following examples illustrate how the compound of the present
invention may be included in pharmaceutical preparations.
Example 29. Preparation of soft gelatin capsules.
500 g of active substance were mixed with 500 g of corn oil, where-
upon the mixture was filled in soft gelatin capsules, each capsule containing100 mg of the mixture ~i.e. 50 mg of active substance).
Example 30. Preparation of soft gelatin caRsules.
` 500 g of active substance were mixed with 750 g of peanut oil, where-
; upon the mixture was filled in soft gelatin capsules, each capsule containing
125 mg of the mixture ~i.e. 50 mg of active substance).
Example 3l. Preparation of tablets.
` 50 kg of active substance were mixed with 20 kg of silicic acid of
the trade mark Aerosil. 45 kg of potato starch and 50 kg of lactose were
mixed therewith and the mixture was moistened with a starch paste prepared
from 5 kg of potato starch and distilled water, whereupon the mixture was gran-
ulated through a sieve. The granulate was dried and sieved, whereupon 2 kg
of magnesium stearate was mixed into it. Finally the mixture was pressed in-

to tablets each weighing 172 mg.
Example 32. Preparation of an emulsion.
100 g of active substance were dissolved in 2500 g of peanut oil.From the solution thus obtained, 90 g of ~lm arabic, aroma och colouring
agents (q.s.) and 2500 g of water an emulsion was prepared.
Example 33. Preparation of a syrup.
100 g of active substance were dissolved in 300 g of 95 % ethanol,
whereupon 300 g of glycerol, aroma and colouring agents (q.s.) and 1000 ml
; of water were mixed therein. A syrup was obtained.
Example 34. Preparation of a solution.
100 g of active substance were dissolved in 2000 g o~ polyoxyethy-
lene sorbitane monooleate, whereupon flavouring agents and colouring agents
(q.s.) and water to 5000 ml was mixed therein. A drop solution was obtained.
Example 35. Preparation of effervescing tablets.
100 g of active substance, 140 g of finely divided citric acid,
100 g of finely divided sodium hydrogen carbonate, 3.5 g of magnesium stear-
ate and flavouring agents (q.s.) were mixed and the mixture was pressed into
tablets each containing 100 mg of active substance.
Example 36. Preparation of a drop solution.
100 g of active substance were mixed with 300 g of ethanol, where-
upon 300 g of glycerol, water to 1000 ml, aroma and flavouring agents (q.s.)
and 0.1 N sodium hydroxide solution (to pH 4.5 to 5.5) was added while stir-
ring. A drops solution was obtained.
Example 37. Preparation of a sustained release tablet.
200 g of active substance were melted together with 50 g of stearic
acid and 50 g of carnauba wax. The mixture thus obtained was cooled and
ground to a particle size of at most 1 mm in diameter. The mixture thus ob-
tained was mixed wilth 5 g of magnesium stearate and pressed into tablets each
weighing 305 mg. Each tablet thus contains 200 mg of active substance.
- 24a -
" ~

Phar~acological evaluation
Depressions are considered to be connected with changes in the bio-
chemical processes of the brain which processes control the mood. The nature
of these biochemical processes are largely unkno~in but in depressive states
there is evidence for a decreased activity of
- 24b -

~5
monoaminergic brain neurons. The monoamines, noradrenaline (NA),
dopamine (DA) and 5-hydroxytryptamine (5-HT), are of great interest
in this respect.
It has been demonstrated that NA, DA and 5-~T is localised in
three different types of neurons and may function as transmittors
in the central nervous system. The monoamines are stored in special
structures, granules, situated in enlargements of the nerve endings,
varicosities. The varicosity is separated from the effector neuron
by a space, the synaptic cleft or spatium. As-a result of a nerve
stimulation the transmittor is released from the granule into the
synaptic cleft and reaches the receptor of the eFfector neuron and
generates a nerve impulse. After impulse generation the amines are
inactivated by mainly two mechanisms: a re-uptake mechanisrn at the
cell membrane and enzymatic conversion by catechol-0-methyltransferas
to form methylated metabolites. There is also an inactivating
enzyme within the varicosities, monoamine oxidase (MA0), that is
stored in the mitochondria and inactivates the amines intracellular-
ly. I
When MA0-inhibitors are administered, an increased amount of
transmittor substance becomes available for release at the nerve
ending.
Another way o-f increasing the amine levels at the receptor
is exerted by the tricyclic antidepressants. It has been shown
that this type of compOund~inhibits the re-uptake mechanism of NA
and 5-HT, and the antidepresseive action is assumed to be related
to the uptake inhibition of NA and 5-HT.
It has been proposed, that some depressions are caused by
deficiency in either one of the neurotransmittors and so~e of
deficiency in both.
- An antidepressant effect should thus be obtained with compounds
which are able to inhibit the re-uptake of one or both NA and
5-HT.
Pharmacological methods
The test method described in Europ.J. Pharmacol. 17, 107, 1972.
This method involves the mesurement of the decrease in the uptake
- of 14C-5-hydroxytryptamine (14C-5-HT) and H-noradrenaline
~3H-NA) in brain slices from mice after in vivo and in vitro administ
ration of the test substance.
'' .
,

~6
Inhibition of the uptake o-F 14C-5-HT and 3H-NA in vitro and
i~n vivo
The test substances were administered intraperitoneally half
an hour before the animals were killed. The midbrain was taken ou-t,
sliced and incubated in a mixture consisting of 0.2 nmole of
14C-5-HT, 0.2 nmole of 3H-NA and 11 ~umole of glucose in Z ml of Krebs
Henseleit-buffer, pH 7.4,per 100 mg of brain slices. The in- ;
cubation time was 5 minutes with 5 minutes of preincubation
before the labelled amines were added.The slices were diSsolved in
Soluene@ and the amounts of radioactive amines taken up were
determined by liquid scintillation. The doses producing 50 per cent
decrease of the active uptake ~ED50) of 14C-5-HT and 3H-NA were
- determined graphically from dose response curves. Active uptake is
defined as that part of the radioactive uptake which is inhibited
by a high concentration of cocaine.
: In the vitro administration method slices of mouse midbrain
were preincubated for 5 minutes with solutiOn of the compound to be
tested and then incubated as described above. The concentration
producing 50 per cent inhibition of the active uptake IC50 f
14c-5 HTand 3-H-NA was determined graphically from dose response
curves.
The test results are given in Table I.

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` The pharmacological tests show that the compounds are able -to
inhibit the uptake of noradrenaline and 5-hydroxytryptamine.
A pronounced non-selective activity is shown for -the compounds
having codes CPK 170, CPK 171, CPK 130 and CPK 184. A pronounced
selective activity on uptake of noradrenaline is seen in compounds
CPK 185, CPK 215 and CPK 217 while a pronounced selective activity
on uptake of 5-hydroxytryptamine is seen in compounds FLA 611,
FLA 615, CPK 198 and CPK 204.
A strong non-selective activity is considered to be especially
advantageous, as compounds having such activity may be employed in
the treatment of depressions in which the neurotransmittor 1.
deficiency is unknown as well as in those cases wherein it is
established that the deficiency pertains to both noradrenaline and
5-hydroxytryptamine .
. .
.