COMPOSES DE PHENYL AMINOPROPANE TRIFLUOMETHYLE

TRIFLUOROMETHYLATED-PHENYL-AMINOPROPANE COMPOUNDS

Abrégé anglais

ABSTRACT
The present invention is concerned with novel
trifluoromethylated-phenyl aminopropanes, processes
for the production thereof and pharmaceutical compositions
having a content of same as active constituent. The
compounds have desirable anorectic properties and show
little or no central nervous system stimulation.

Revendications

The embodiments of the invention in which an
exclusive property or privilege is claimed are defined as
follows:
1. A process for the preparation of a 1-(trifluoro-
methylphenyl)-2-aminopropane compound of the formula II':
<IMG> ......(II')
wherein R represents a hydrogen atom,
Alk represents a lower alkylene group and,
X represents a di-(loweralkyl)amino, morphilino,
piperidino, pyrrolidino or a N-methylpiperazino
group and non-toxic acid addition salts thereof,
comprising reacting a phenylacetone of the
formula IV:
<IMG> ...... (IV')
with a diamine of the formula V:
H2N-Alk-X ....... (V)
wherein Alk and X are as defined above, and reducing the
so-obtained Schiff's base of the formula III':
<IMG> ......(III')

wherein Alk and X are as defined above, and, when
necessary or desired, converting the so-formed free base
into a non-toxic acid addition salt thereof.
2. A process for preparing a compound of the formula:
<IMG> ......(IIa')
wherein n is an integer from the group 1, 2, 3 and 4,
R1 and R2, taken individually each represents
a hydrogen atom or a lower alkyl group, and when
taken with the nitrogen atom to which they are
attached, together represent morpholino,
piperidino, pyrrolidino or N-methylpiperazino
and non-toxic acid addition salts therof which
comprises reacting a phenylacetone of the
formula IV':
<IMG> ......(IV')
with a diamine of the formula:
<IMG> ......( Va)
wherein n, R1 and R2 have the same significance as
defined above, and reducing the so-obtained Schiff's base
of the formula.
<IMG> ......(IIIa')
21

wherein n, R1 and R2 have the same significance as
defined above and, when necessary or desired,
converting the free base of the formula IIa'
into a non-toxic acid addition salt.
3. A process as claimed in Claim 1 wherein the
reduction is effected by reaction with a metal hydride.
4. A process as claimed in Claim 2 wherein the
reduction is effected by reaction with a metal hydride.
5. A process as claimed in Claim 3 or 4 wherein
the metal hydride is sodium borohydride or lithium
aluminum hydride.
6. A process as claimed in Claims 3 or 4 wherein the
reaction is conducted in a lower alkanol solvent and at
the reflux temperature thereof.
7. A process as claimed in Claim 1 for the preparation
of1-(3'-trifluoromethylphenyl)-2-(N,N-dimethylamino-
propyl)-aminopropane and non-toxic acid addition salts
thereof which comprises reacting m-trifluoromethyl-
phenylacetone and N,N-dimethyl-1,3-propane diamine and
reducing the so-obtained 1-(3'-trifluoromethylphenyl)-2-
(N,N-diemthylaminopropylimino)- propane with sodium
borohydride and, when necessary or desired, converting the
free base into non-toxic acid addition salts thereof.
8. A process as claimed in Claim 1 for the preparation
of 1-(3'-trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl)-
aminopropane and non-toxic acid addition salts thereof
which comprises reacting m-trifluoromethylphenylacetone and
22

N,N-dimethylethylene diamine and reducing the so-obtained
1-(3'-trifluoromethylphenyl)-2-(N,N-dimethylaminoehtylimino)
propane with sodium borohydride and, when necessary or
desired, converting the free base into non-toxic addition
salts thereof.
9. A process as claimed in Claim 1 for the
preparation of 1-(3'-trifluoromethylphenyl)-2-(N-morpholino-
ethyl)-aminopropane and non-toxic acid addition salts
thereof which comprises reacting m-trifluoromethyl-
phenylacetone and N-(2-aminoethyl)-morpholine and
reducing the so-obtained 1-(3'trifluoromethylphenyl)-2-
(N-morpholinoethylimino)-propane with sodium borohydride and,
when necessary or desired, converting the free base into non-
toxic acid addition salts thereof.
10. A process as claimed in Claim 1 for the preparation
of 1-(3'-trifluoromethylphenyl)-2-(N-piperidinoethyl)-
aminopropane and non-toxic acid addition salts thereof
which comprises reacting m-trifluoromethylphenylacetone
and N-(2-aminoethyl)piperidine and reducing the so-
obtained 1-(3'-trifluoromethylphenyl)-2-(N-piperidino-
ethylimino)- propane with sodium borohydride and, when
necessary or desired, converting the free base into
non-toxic acid addition salts thereof.
11. A process as claimed in Claim 1 for the
preparation of 1-(3'-trifluoromethylphenyl)-2-(4"-methyl-
piperazinopropyl)-aminopropane and non-toxic acid
addition salts thereof which comprises reacting
m-trifluoromethylphenylacetone and N-methyl-N'-(3-amino-
propyl)-piperazine and reducing the so-obtained
23

1-(3'-trifluoromethylphenyl)-2-(4"-methylpiperazino-
propylimino)-propane with sodium horohydride and, when
necessary or desired, converting the free base into non-
toxic acid addition salts thereof.
12. A process as claimed in Claim 1 for the preparation
of 1-(3'-trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)-
aminopropane and non-toxic acid addition salts thereof
which comprises reacting m-trifluoromethylphenylacetone
and N,N-diethylethylene diamine and reducing the so-
obtained 1-(3'-triofluoromethylphenyl)-2-(N,N-diethyl-
aminoethylimino)-propane with sodium borohydride and,
when necessary or desired, converting the free base into
non-toxic acid addition salts thereof.
13. A process as claimed in Claim 1 for the preparation
of 1-(3'-trifluoromethylphenyl)-2-(1"-ethyl-2"-pyrrolidino-
methyl)-aminopropane and non-toxic acid addition salts
thereof which comprises reacting m-trifluoromethylphenyl-
acetone and 1-ethyl-2-aminomethylpyrrolidine and
reducing the so-obtained 1-(3'-trifluoromethylphenyl)-2-
(1"-ethyl-2"-pyrrolidinomethylimino)-propane with
sodium borohydride and, when necessary or desired,
converting the free base into non-toxic acid addition
salts thereof.
14. A 1-(trifluoromethylphenyl)-2-aminopropane
compound of the formula:
<IMG> ...... (II')
24

wherein R represents a hydrogen atom ,
Alk represents a lower alkylene group, and
X represents a di-(loweralkyl)amino, morpholino,
piperidino, pyrrolidino or a N-methylpiperazino
group and non-toxic acid addition salts thereof
whenever prepared by a process as claimed in
Claim 1 or an obvious chemical equivalent
thereof.
15. A compound of the formula:
<IMG> ...... (II')
wherein n represents an integer from the group 1, 2, 3
and 4, and
R1 and R2, taken individually each represents
a hydrogen atom or a lower alkyl group, and taken
with the nitrogen atom to which they are attached
together represent morpholino, piperidino,
pyrrolidino or N-methylpiperazino and non-toxic
acid addition salts thereof whenever prepared by
a process as claimed in Claim 2 or any obvious
chemical equivalent thereof.
16. 1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylamino-
propyl)-aminopropane and non-toxic acid addition salts
thereof whenever prepared by a process as claimed in
Claim 7 or any obvious chemical equivalent thereof.

17. 1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylamino-
ethyl)-aminopropane and non-toxic acid addition salts
thereof whenever prepared by a process as claimed in
Claim 8 or any obvious chemical equivalent thereof.
18. 1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-
aminopropane and non-toxic acid addition salts thereof
whenever prepared by a process as claimed in Claim 9 or
any obvious chemical equivalent thereof.
19. 1-(3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-
aminopropane and non-toxic acid addition salts thereof
whenever prepared by a process as claimed in Claim 10, or
any obvious chemical equivalent thereof.
20. 1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylamino-
ethyl)-aminopropane and non-toxic acid addition salts
thereof whenever prepared by a process as claimed in
Claim 12 or any obvious chemical equivalent thereof.
21. 1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazino-
propyl)-aminopropane and non-toxic acid addition salts
thereof whenever prepared by a process as claimed in
Claim 11 or any obvious chemical equivalent thereof.
22. 1-(3'-Trifluoromethylphenyl)-2-(1"ethyl-2"-
pyrrolidinomethyl)-aminopropane and non-toxic acid addition
salts thereof whenever prepared by a process as claimed
in Claim 13, or any obvious chemical equivalent thereof.
26

Description

6.30.5537
~`~r~
1041505
This invention relates generally to new organic
compounds possessing significant pharmacolo~ical activity
and to processes for preparing such compounds. In
particular, this ~nvention is concerned with novel
trifluoromethylated-phenyl-aminopropane derivatives.
Certain trifluoromethylated-phenyl-aminopropane
compounds are known in the art. For instance, United States
patent specification No. 3,198,833 describes a broad class
of such compounds having the formula:
CF ~ CH2- CH- CH3
\ / I -----.-(I)
~ - / NH
R
wherein R is a lower alkyl group containing from 1 to 5
carbon atoms. In the specification, the compounds of the
foregoing formula I are said to be useful pharmaceutically
in that they exhibit anoroctic and/or sedative activity.
Probably the best known of such compounds at the present
tlme 18 1-(3'-trifluoromethylphenyl)-2-ethylaminopropane,
commonly known as fenfluramine, which is useful pharmaceuti-
I cally as an appetite inhibitor that may be employed in the
treatmont of obe~ity. In this role, the fenfluramine
typlcally in the form of the hydrochloride salt, is
associated in pharmaceutical compositions with pharmaceuti-
cally acceptable organic or inorganic solid or liquid
diluents or carriers. It has been recognized (cf. British
patent No. 1,182,557) that such compounds, in addition to
the desired anorectic properties, tend to have central
nervous system stimulating and pressor activity which is
:~,
- 1 -
~'

- ~041SU5
undesirable when patients are treated for obesity.
It is, accordingly, an o~ject of the present invention
to provide novel trifluoromethylated-phenyl-aminopropane
compounds which possess the desirable anorectic properties
but show little or no central nervous stimulation, as
evidenced by standard pharmacological evaluation, for example,
by animal tests.
According to the invention therefore, in one of its
aspects, there are provided, as new compounds,
trifluoromethylated-phenyl-amir.opropanes of the general formula:
CF3 ~ c~ -C~ -CK3
- R - N - Alk- X ............ (II)
.- ~ '' . '
and the acid addition salts thereof, wherein R represents ~
a hydrogen atom or a lower alkyl group, Alk represents a -
lower alkylene group and X represent9 substituted or un-
substituted amino group.
The terms "lower alkyl" and "lower alkylene" as employed
herein, connote both straight and branched chain radicals
containing not more than 6 carbon atoms.
In the above compound~ wherein R represents a lower
alkyl group, this group may, for example, be methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, secondary butyl or
tertiary butyl.
The divalent lower alkylene group,represented by the
symbol Alk in the compounds of Formula II, is a
saturated aliphatic hydrocarbon rad~cal derived from a
straight or branched-chain hydrocarbon residue such as, for
example, ethylene, propylene, butylene, trimethylene, ~-
,
. .

lO'~ 9~
tetra~ethyl~ne or l-metil;~lethylcne. ~uch al~ylen~ groups
may include substitutes.
The symbol X is defined as being a primary, secondary
or tertiary amino group of the following general designations:
it will be noted that some of the general designations are
further explained by reference to specific compounds falling
within the scope of the designation which are not to be
construed as being limited to such specific compounds.
The symbol X is therefore defined as an unsubstituted
amino(-NH 2 ); ( lower alkyl)-amino; di-(lower alkyl)-aminoi
(lower alkenyl)-amino; di-(lower alkenyl)-amino; phenylamino;
(hydroxy-lower alkyl)-amino; di-(hydroxy lower-alkyl)-amino;
(amino-lower alkyl)-amino; di-(amino-lower alkyl)-amino
heterocyclic groups of less than 12 carbon atoms as exemplified
by piperidino; (lower alkyl)-piperidino, e.g. 2-,3-, or
4-(lower alkyl)-piperidino; di-(lower alkyl)-piperidino;
(lower alkoxy)-piperidino; pyrrolidino; (lower alkyl)-
pyrrolidino; di-(lower alkyl)-pyrrolidino; (lower alkoxy)-
pyrrolidino; morpholino; (lower alkyl)-morpholino; di-(lower
alkyl)-morpholino; (lower alkoxy)-morpholino; thiomorpholino;
(lower alkyl)-thiomorpholino; di-(lower alkyl)-thiomorpholino;
piperazino; (lower alkyl)-piperazino (e.g. C or N- methyl
piperazino); di-C-(lower alkyl)-piperazino; (lower alkoxy)-
piperazino and (lower carbalkoxy)-piperazino and R3-(lower
alkyl)-amino wherein R3 is a 5- or 6- membered heterocyclic
ring containing nitrogen, oxygen or sulphur and 0-2
ethylenic double bonds.
One pharmaceutically preferred group of compounds in
view of their favorable utility are compounds of the general
formula: .
. ~ CH2-CH-CH3
NH ~ ..................... (IIA)
CF3 ~CH2)n-N~
and acid addition salts thereof, wherein R~ and R2
individually repre~nt a methvl, an ethyl, a ~ro~yl or an
isopropyl group or, taken together with the nitrogen atom to
.: ~

10415(~S
which they are attached, together represent a 5- or 6-
membered ~-heterocyclic rin~ such as, for example,
morpholino, piperidino, pyrrolidino, piperazino or
N-methyl-piperazino and n is 1, 2, 3 or 4.
Another pharmaceutically preferred group of compounds,
again in view of their favorable utility, are compounds of
the general formula:
~C~ CII-C~13
NH
~ - I ..... (IIb )
CF3 (CH2)n -NH-(CH2)m~ R3
and acid addition salts thereof, wherein R3 represents a
5- or 6- member heterocyclic ring containing an atom
selected from the group nitrogen, oxygen or sulfur and up
to 2 ethylenic double bonds, and n and m, which may be the
same or different, are 1, 2, 3 or 4.
; With regard to the acid-addition salts, when the
compounds are to be used as intermediates for preparing
other compounds or for any othèr non-pharmaceutical use,
the toxicity or non-toxicity of the salt is usually immaterial.
When the compounds are to be used as pharmaceuticals, they
are most conveniently used in the form of water-soluble,
non-toxic, acid-addition salts. Both toxic and non-toxic
~ salts are, therefore, within the purview of this invention.
The acids which can be used to prepare the preferred non-
toxic, acid-addition salts are those which produce, when
combined with the free bases, salts whose anions are
30 relatively innocuous to the animal organism in therapeutic
:,..
.
: . - . ' . ' ~ ' : ~ -
- - --:: -
- , . ~.
. . .~ , , - .

1041~0S
doses of the salts, so that the beneficial physiological
properties inherent in the free bases are not vitiated by
side-effects ascribable to the anions. Appropriate acid-
addition salts are those derived from mineral acids such as,
for example, hydrochloric acid, hydrobromic acid, hydriodic
acid, nitric acid, boric acid and phosphoric acid; and organic
acids such as, for example, acetic acid, tartaric acid, citric
acid, succinic acid, lactic acid and maleic acid.
The compounds of this invention can be prepared by a
variety of processes, some of which are further described
hereinafter. In the Formulae III to VIII, Alk and X have
the same significance as in Formula II.
Process A
By subjecting an imine or Schiff's base of the formula:
, . .
CF ~ CH2-C - CH3
N- Alk -X ................ (III)
wherein X has the same significance as defined with
reference to Formula II above to reduction by known methods.
For example, reduction may be effected with a hydride, ~-
preferably with a complex metal hydride such as sodium
borohydride or lithium aluminum hydride. This reduction
- can be carried out at room temperature or at temperatures
; below room temperature or with the application of heat,
deyending upon the particular reagents employed. For
instance, using sodium borohydride, it is preferably
carried out by heating the reaction mixture under reflux ~- -
conditions. The reduction is preferably carried out in an
organic solvent such as, for example, methanol, etnanol,
dioxan or tetrahydrofuran.
-- 5 --
'
.~ , . .
.

1(~41~0~
~rl~e term "known" as applied to the reduction and alkyla~i
r~actions in this specification and appended claims refer~
to methods presently or heretofore in actual use and/or
described in the literature on the subject.
Process B
-
By subjecting an imine or Schiff's base of the
Formula III to a catalytic hydrogenation, preferably with
a nickel, platinum or palladium catalyst.
The imine or Schiff's base starting compounds of
Formula III for Processes A and B may themselves be
prepared by known methods such a~ by reacting a phenyl-
acetone compound of the formula:
CF3 ~
CH2 C CH3 ..... (IV)
:'
with a diamine of the formula:
X- Alk -NHz ..... (V)
,~ wherein X has the same significance as defined with
reference to Formula II above. Advantageously, the
reaction is effected in a lower alkanol solvent preferably
at tne reflux temperature thereof.
The resulting Schiff's ba8e need not be isolated from the
reaction mixture prior to use in the reduction reactions of
processes A and B.
Process C
By reacting a phenyl-2-halo-alkane of the formula:
CF, ~ CN~_ CH_ C3~
Y .................................................... (VI)
.

~04lsas
wherein Y represents a halogen atom, preferably a chlorine
or bromine atom with an amine of Formula V above wherein all
but one of the amino hydrogen atoms are preferably replaced
by a protective group such as, for example, benzyl and
and toluene-sulfonyl, ~hiCh is.~eadily remoYed by reduction
or hydrolysis subsequent to th~ reaction.
Process D
By subjecting a phenylacetone of the Formula IV to
catalytic hydrogenation, preferably using a nickel, platinum
or palladium catalyst, in the presence of a diamine of the
Formula V.
Process E
By subjecting a phenylacetone of the Formula IV to
reductive amination with a hydride, preferably using a
complex metal hydride such as sodium borohydride, in the
presence of a diamine of the Formula V.
Process F
.
By reacting a phenylacetone of the Formula IV with a
diamine of Formula V in the presence of a formic acid,
obtained, say, by using formic acid itself, or a formic
acid salt or a formyl compound of the diamine of Formula V.
The phenylacetone compounds of Formula IV may
themselves be prepared according to conventional methods,
such as by oxidizing a l-phenyl-2-propanol into the
corresponding ketone
CF~_ CU2--CHOH--CH3 ~ ~3CI:2--CO--Cl:3 ~ ~
3~ . :
- 7 _ :
- . '` ' , ' ~ ~ . ~ .
.: : , .,' : ` .

1041~S
~r~cess C
By subjecting an oxime of the formula:
CF3
CH2- C -CH3 ..... (VII)
NOH
to catalytic reduction, preferably with a nickel or cobalt
catalyst, followed by reaction of the primary amine so-
obtained with a halide of the general formula:
Hal- Alk -X ............... (VIII)
wherein Hal represents a halogen atom, preferably in the
presence of an acid-binding agent.
Process H
By subjecting an oxime of the Formula VII to reduction
with a hydride, preferably with a complex metal hydride
such as sodium borohydride or lithium aluminum hydride,
followed by reaction of the primary amine so-obtained with a
halide of the general formula:
Hal- Alk- X ............... (YIII)
wherein ~al represents a halogen atom, preferably in the
presence of an acid-binding agent.
The oximes of Formula VII used as starting materials
in Processes G and H may themselves be prepared by known
methods, conveniently by reacting a phenylacetone of
Formula IV with hydroxylamine. ~ -
As a modification to the above processes A to H, when
compounds of the formula Il wherein R represents a lower
alkyl group are desired, the above processes are modified
to include a step wherein the appropriate R substituent is
introduced into the molecule by known alkylation procedures.
This may be conveniently achieved by the following procedures
8 --

104150S
with particular reference to Process A described above.
In Process A, the alkyl group R can be introduced by
alkylation of the Schiff's base to form a quaternary ammonium
compound which can then be reduced by known methods to
yield the desired tertiary amine. Alternatively, the
Schiff's base can be reduced as described above, and the
reduced compound subjected to an alkylation reaction to
introduce the substituent R. The choice of alkylating
agent required to introduce a selected group R to form the
desired product will be apparent to one skilled in the art.
Representative new compounds and processes for their
preparation are illustrated more fully by the following
examples which are not to be construed as limiting the
' invention since many modifications in materials and
procedures will be readily apparent to those skilled in the
art. In these examples, the melting point data was obtained
by the capillary tube method, and all temperatures are in
degrees centigrade.
~xample l
Part A
1-(3'-Trifluoromethylphenyl)-2--(N,N-dimethylaminopr'opyl)- '
.
a~ nopropane ~ ,.
A solution comprising 1 g. (0.005 mole) of m-trifluoro- -methylphenylacetone and 0.51 g. (0.005 mole) of N,~-dimethyl-
; 1,3-propane diamine in 10 ml. of ethanol was heated under
reflux for 3 hours. After cooling, 0.19 g. (0.005 mole) of
sodium borohydride was slowly added to the solution
containing the Schiff's base [1-(3'-trifluoromethylphenyl)-
2-(N,N-dimethylaminopropylimino)-propane] and the resultant
suspension stirred at ambient temperature for 1 hour and,
.' ' .
_ g _
,
.. ; : , - . : :

104150S
sodium borohydride was slowly added and the resultant
suspension stirred at ambient temperature for 1 hour and,
thereafter, heated under reflux for 3 hours. Dilute hydro-
chloric acid was added slowly to the cooled solution until an
acidic pH was obtained, whereupon the ethanol was distilled
off under reduced pressure. The aqueous residue was
extracted with ether, basi~ied with 20% aqueous sodium
hydroxide solution and then extracted twice with methylene
chloride. The extracts were washed with water, dried and
evaporated to give the desired product, 1-(3'-trifluoro-
methylphenyl)-2-(N,N-dimethylaminopropyl)-aminopropane,
in the form of a pale yellow oil.
~ Part B
- 1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminopropyl)-
minoproPane dihydrochloride monohydra*e
The free base of Part A was trans~ormed into the
dihydrochloride monohydrate salt by treatment with methanolic
hydrogen chloride followed by addition of acetone to precipitate
the salt. The salt, in good yield and in the form of a
~; while crystalline solid, was isolated by filtration. An
analysis sample was recrystallized from acetone/methanol.
Melting point: 208 to 212C.
Elementary analysis:
C(%) H(%) Cl(%) N(%)
Calculated 47.50 7.18 18.69 7.39
C~sH23F3N22HCl. H20
Found 47.32 6.88 18.53 7.64
Solubility: Very soluble in water, ethanol, dimethylsulfoxide
and propylene glycol.
:
-- 10 --

10415(~5
Example 2
Part A
1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl)-
aminopropane
This free base was obtained following essentially the
same procedure as set forth in Part A of Example 1 by
reacting together m-trifluoromethylphenylacetone and N,N- .
dimethyl-1,2-ethylenediamine.
Part B
1-(3'-Trifluoromethylphenyl)-2-(N,N-dimethylaminoethyl~-
aminopropane dihydrochloride
The free base obtained in Part A was converted into the
corresponding dihydrochloride salt following essentially
the same procedure as set forth in Part ~ of Example 1. An
analysis sample was recrystallized from acetone/methanol.
Melting point: 224 to 226.
Elementary analysis:
C(%) H(%) C1~%) N(%)
Calculated 48.42 6.68 20.42 8.Q7
Cl4H2lF3N22HCl
~ound 48.21 6.90 20.13 8.30
Solubility: Very soluble in water, ethanol, dimethylsulfoxide
and propylene glycol.
Example- 3
Part A
1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-Aminopropane.
.. .
The free base was obtained following essentially the
same procedure as set forth in Part A of Example 1 by reacting
together m-trifluormethylphenylacetone and N-(2-aminoethyl~-
- J morpholine.
- 11 -
.
- : - , ~:
. , , :
- - , . . - ' --

1041S05
Part B
1-(3'-Trifluoromethylphenyl)-2-(N-morpholinoethyl)-
aminopropane dihydrochloride.
The free base obtained in Part A was converted into the
corresponding dihydrochloride salt following essentially the
same procedure as set forth in Part B of Example 1. An
analysis sample was recrystallized from acetone/methanol.
Melting point: 222 to 225.
Elementary analysis:
C(%) H(~) Cl(~) N(%)
Calculated 49.36 6.47 18.22 7.20
Cl 6H2 3F3N20.2HCl
Found 48.98 6.27 18.56 7.52
Solubility: Very soluble in water, dimethylsulfoxide and
- propylene glycol; soluble in ethanol.
Example 4
Part A
,
1-~3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-
aminopropane
The free base was obtained following essentially the
same procedure as set forth in Part A of Example 1 by
reacting together m-trifluoromethylphenylacetone and
N-(2-aminoethyl)-piperidine.
Part B
1-(3'-Trifluoromethylphenyl)-2-(N-piperidinoethyl)-
aminopropane dihydrochloride.
The free base obtained in Part A was converted into the
- corresponding dihydrochloride salt following essentially the
- same procedure as set forth in Part B of Example 1. An
-G analysis sample was recrystallized from acetone~methanol.
. ~ .

10415US
Melting point: 238 to 242.
Elementary analysis:
C(%) H(%) Cl(~) N(%)
Calculated 52.71 7.03 18.31 7.23
. .
Cl7H2sF3N2.2HCl
Found 52.52 7.04 17.96 7.52
Solubility: Very soluble in water, dimethylsulfoxide and
propylene glycol, soluble in ethanol.
Example 5
-~ 10 Part A
1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazinopropyl)-
aminopropane
; The free base was obtained following essentially the
same procedure as set forth in Part A of Example 1 by reacting
together m-trifluoromethylphenylacetone and N-methyl-N'-(3-
aminopropyl)-piperazine.
Part B
1-(3'-~rifluoromethylphenyl)-2-(4"-methylpiperazino~ropyl)
aminopropane trihydrochloride
The free base obtained in Part A was converted into the
corresponding trihydrochloride salt following essentially
the same procedure as set forth in Part B of Example 1.
An analysis sample was xecr~stallized from methanol.
: Melting point: 297 to 305 (decomposition)
.
Elementary analysis:
C(%) H(%) Cl(%) N(%)
Calculated 47.74 6.90 23.49 9.28 ~ .
C~aH2aF3N3.3HCl
Found 47.49 7.12 23.35 9.49 : :
_O
- 13 -
' ,
.
'
:
. - .

~041505
Solubility: Very soluble in water and propylene glycol;
slightly soluble in dimethylsulfoxide; and
insoluble in ethanol.
Example 6
Part A
1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)-
-
aminopropane
The free base was obtained following essentially the
same procedure as set forth in Part A of Example 1 by
reacting together m-trifluoromethylphenylacetone and N,N-
diethyl-ethylenediamine.
Part B
.
1-(3'-Trifluoromethylphenyl)-2-(N,N-diethylaminoethyl)-
aminOprOpane dihydrochloride monohydrate
The free base obtained in Part A was converted into the
corresponding dihydrochloride salt following essentially the
same procedure as set forth in Part B of Example 1. An
analysis sample was recrystallized from acetone/isopropanol.
Melting point: 126 to 131.
Elementary analysis:
C(%) H(%) Cl(%) N(%)
Calculated 48.85 7.43 18.03 7.12
C18H2sF9N2.2HCl.H20
Found 48.60 7.65 17.87 7.50
Solubility: Very soluble in water, ethanol, dimethyl
sulfoxide and propylene glycol.
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104150S
- Example 7
1-(3'-Trifluoromethylphenyl)-2-(l"-ethyl-2"-pyrrolidinomethyl)
aminopropane
The free base was obtained following essentially the
same procedure as set forth in Part A of Example 1 by
reacting together m-trifluoromethylphenylacetone and l-eth~l-
2-aminomethylpyrrolidine.
Part B
1-(3'-Trifluoromethylphenyl~-2-(1"-ethvl-2"-pyrrolldinomethyl)-
dminopropane dihydrochloride
The free base obtained in Part A was converted into thecorresponding dihydrochloridemonohydrate salt following
e~sentially the same procedure as set forth in Part B of Example 1.
An analysis sample was recrystallized from acetone/methanol.
Melting point:
Elementary analysis:
- C(%~ H(%) N(~)
- Calculated 50.37 7.21 6.91
C 1 7H2 sF3N 2 2HCl.H20
Found 50.26 7.31 7.02
':
. . - .
, .
As indicated hereinbefore, it has been found in accordance
with this invention that the novel compounds of the formula
II and salts thereof have interesting pharmacological
properties. More particularly, such compounds when subjected
- 15 -
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.

1()4i~ 5
to standaxd pharmacologica~ evalu~tion,for example, by
animal tests, exhibit marked anorexigenic activity coupled
with very low central nervous system stimulating activity.
Compounds acting in this way may be expected to be of use for
curbing the appetites of warm-blooded animals.
Accordingly, this invention further provides in another
of its aspects a pharmaceutical composition comprising
as an essential active ingredient at least one active compound
of the Formula II or an acid addition salt thereof in
association with a pharmaceutically acceptable carrier
therefor.
The compositions of the present invention are
preferably administered either orally or rectally.
Advantageously, the composition is in a dosage unit form
appropriate to the desired mode of administration. For
example, the dosage unit may be a tablet, capsule, pill,
powder, packet, granule, wafer, elixir, suppository, or a
measured quantity of a suspension, solution, a syrup or
segregated multiples of the foregoing. The term "dosage
unit form" as used herein refers to physically discrete
units suitable as unitary dosages for human subjects and
animals, each unit containing a predetermined quantity of active
material calculated to produce the desired therapeutic
effect in admixture, or otherwise ln association, with a
pharmaceutical carrier therefor, the quantity of the active
ingredient being such that one or more units are normally
required for a single therapeutic administration or that, in
the case of severable units such as scored tablets, at
least one fraction such as a half or a quarter of a severable
unit is required for a single thera~eutic administration.
Advantageously, the compositions of this invention
- lG -

1041SU5
contain the active ingredient in an ~mount of at least 0.5~
and not more than 95~ by weight based on the total weight of
the composition. Conveniently, the compositions of the
invention when in dosage unit form contain 0.5 mg. to
1000 mg., and more conveniently from 5 mg. to 250 mg., of the
active ingredient of formula I.
The compositions of the present invention will
normally consist of at least one compound of formula I,
typically in the form of an acid addition, say, hydrochloride
or maleate salt thereof admixed with a carrier, or diluted by
a carrier, or enclosed or encapsulated by a carrier in the
form of a capsule, sachet, catchet, paper or other
container. A carrier which ser~es as a vehicle, excipient
or diluent medium for the therapeutically active ingredient
may be a solid, semi-solid or a sterile liquid.
Some examples of the carriers which may be employed in
the pharmaceutical compositions of the invention are lactose,
dextrose, sorbitol, mannitol, starches such as wheat, corn,
, , . -
or potato starch, gum acacia, calcium phosphate, liquid
paraffin, cocoa butter, oil of theobroma, alginates,
tragacanth, gelatin, syrup B.P., methyl cellulose,
polyoxethylene sorbitan monolaurate, methyl and propyl
hydroxybenzoateS, sterile pyrogen-free water and substantially
isotonic saline solution. The choice of carrier is determined
by the preferred form of administration~ the solubility of
the compound and standard pharmaceutical practice. In the
case of tablets a lubricant may be incorporated to prevent
sticking and binding of the powdered ingredients in the dies
and on the punch of the tabletting machine. For such purpose,
there may be employed, for example, talc, aluminum,
17 -
: . ,

1~141SOS
magnesium or calcium stereates or polyethylene glycols
(Carbowaxes) of suitable molecular weight.
The pharmaceutical compositions of this invention may
contain, in addition to the active ingredient of the general
Formula II,one or more other pharmacologically active
ingredients which elicit desirable complementary effects.
Two examples of suitable pharmaceutical compositions
according to this invention are presented below for the
purpose of facilitating a better understanding of this
aspect of the invention.
Example A
For oral administration, sugar coated tablets of the
following composition were prepared following standard
pharmaceutical practice.
Formulation:
Ingredient Content (gms.)
1-(3'-Trifluoromethylphenyl)-2-(4"-methylpiperazinopropyl)-
aminOpropane trihydrochloride ............................ 25
Lactose .................................................. 60
Sugar .................................................... 75
Talc ...................................................... 5
Magnesium stearate ........................................ 5
Example B
Hard gelatin capsules were made following standard
pharmaceutical practice from a mixture of the following
ingredients:
Formulation:
Ingredient Content (gms.)
1-(3'-Trifluoromethylphenyl~-2-(N-morpholinoethyl)-
aminopropane dihydrochloride ................. ,........... 100
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1~415(JS
Calcium ph~sphate ~,,,.,,.,.,~..,.,,,.,.,..,,..,..,,.... 20
In the foregoing Examples A and B, the active ingredient
specified may be wholly ox partly replaced by another
pharmacologically active compound of the invention.
The novel method of the invention for curbing appetites
in warm blooded animals comprises administering to the
animals an anorexigenically effective amount of at least one
compound of the ~rmula II and their non-toxic
pharmaceutically acceptable acid addition salts. The usual
effective dose of said compounds is between about 0.01 to ~-
5 mg./kg of body weight of the warm-blooded animals.
While in the foregoing specification various embodiments
of this invention have been ~et forth and specific details
elaborated upon for the purpose of illustration, it will be
apparent to those skilled in the art that this invention is
susceptible to other embodiments and that many of the details
- may be varied widely without departing from the spirit and
scope of the invention as defined in the appended claim~.
:
- ~ . ...