MEDICAMENT ET METHODE DE PREPARATION

MEDICINE AND ITS PREPARATION

Abrégé anglais

A B S T R A C T
The invention relates to the new N-[2-/4-fluoro-
-phenyl/-1-methyl]-ethyl-N-methyl-N-propyryl amine of the
general Formula I
<IMG> /1/
and isomers and salts thereof.
The compound of the Formula I is useful as
medicine.
The compound of the Formula I may be prepared
by methods known per se.

Revendications

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing N-[2-(4-fluorophenyl)-1-methyl]-
ethyl-N-methyl-N-propynyl amine of the formula I
<IMG>
or an isomer or salt thereof which comprises
a) in an amine of the formula I(a)
<IMG> I(a)
in which R2 stands for a radical which can be converted to fluorine
converting the group R2 into fluorine; or
b) in an amine of the formula I(b)
<IMG> I(b)
adding the propynyl group to the amino nitrogen atom; or
c) in an amine of the formula I(c)
28

<IMG>
I(c)
subjecting the amine to N-methylation; and if required converting
a propynyl amine of the formula I obtained into a salt formed with
a mineral or organic acid or setting free the base from a salt
thereof.
2. A process as claimed in claim 1 wherein a compound of
formula I(a) is obtained by reacting a 2-phenyl-isopropyl deriva-
tive of the formula II
<IMG> II
wherein R2 stands for a radical, which can be converted to fluorine
with a compound of the formula III
B-R1 III
wherein
A and B represent groups which on reacting with each
other form a bivalent group of the formula
<IMG>
or the groups A and B comprise the said bivalent group and A may
be attached to the carbon atom by a single or double bond, whereby
29

in the latter case the carbon atom cannot bear a hydrogen and
R1 represents methyl or propynyl or a group which can be
replaced by methyl or propynyl to obtain a compound containing an
N-methyl or an N-propynyl group and then N-propynylating or N-
methylating, respectively.
3. A process as claimed in claim 1 wherein a compound of
formula I(b) or I(c) is obtained by reacting a 2-phenyl-isopropyl
derivative of the formula II
<IMG> II
with a compound of the formula III
B-R1 III
wherein
A and B represent groups which on reacting with each
other form a bivalent group of the formula
<IMG>
or the groups A and B comprise the said bivalent group and A may
be attached to the carbon atom by a single or double bond, whereby
in the latter case the carbon atom cannot bear a hydrogen and
R1 represents methyl or propynyl or a group which can
be replaced by methyl or propynyl and if required N-methylating to
obtain a compound of formula I(b) or if required propynylating to
obtain a compound of formula I(c).

4. A process as claimed in claim 1 wherein a compound of
formula I(a) is obtained by reacting an amine of the formula VIII
<IMG> VIII
wherein
R4 represents hydrogen or an optionally halosubstituted
saturated or unsaturated aliphatic hydrocarbon group having 3 car-
bon atoms; and
R5 represents hydrogen or methyl
with either
a) a phenyl acetone derivative of the formula IX
<IMG> IX
wherein
R is as defined in claim 1; and
reducing the ketimine or oxyamine thus obtained; or
b) a phenyl isopropyl derivative of the formula X
<IMG> X
wherein
R2 is as defined in claim 1 and X is halogen or a
sulfonic acid ester group; and if required converting the R4 group
into a propynyl group or transforming the R5 group
31

into methyl, whereby the said two optional steps may be carried
out in any order.
5. A process as claimed in claim 1 wherein a compound of
formula I(a) is obtained by subjecting an amine of the formula XI
<IMG> XI
wherein
R2 is as defined in claim 1 to methylation and pro-
pynylation.
6. A process according to claim 1(b) wherein the propynyl
group is formed by reacting an amine of the formula I(b) as defined in claim
1 with formaldehyde and acetylene.
7. A process according to claim 5 wherein the propynylation
is carried out stepwise through the corresponding halopropyl and
propenyl derivative, respectively.
8. A process according to claim 7 wherein the propynylation
is carried out with 1,2-dibromo-propene and subjecting the 2-bromo-
propenyl derivative thus obtained to thermal effect or to a treat-
ment with a base to yield the required propynyl derivative.
9. A process according to claim 1 (c) wherein the N-methyla-
tion is carried out by an amine of the formula I (c) as defined
in claim 1 with a methyl ester or with formaldehyde and formic acid.
32

10. A process according to claim 9 wherein the methylation
is carried out with, methyl halide, dimethyl sulfate, methyl
sulfuric acid ortrimethyl phosphate.
11. A process according to claim 1, 2 or 3 wherein when R
represents a nitro, amino or diazonium group, converting the R
group into fluorine by converting the nitro group into an amino
group and transforming the amino group into a diazonium fluoro
borate.
12. A process according to claim 4 or 5 wherein when R2
represents a nitro, amino or diazonium group, converting the R2
group into fluorine by converting the nitro groups into an amino
group and transforming the amino group into a diazonium fluoro
borate.
13. A process according to claim 1, 2 or 3 wherein the start-
ing material used is an optically active compound.
14. A process according to claim 4 or 5 wherein the starting
material used is an optically active compound.
15. A process according to claim 1 which further comprises
the step of subjecting the compound obtained to resolution.
16. A process according to claim 15 wherein the resolution
is carried out by forming a diastereomeric pair of salts by means
of reacting with an optically active acid.
17. A process according to claim 1 wherein the compound of
the formula I, as defined in claim 1, obtained is converted into
33

a salt formed with a mineral or organic acid.
18. A process according to claim 1 wherein the compound of
the formula I, as defined in claim 1, obtained is converted into a
salt formed with hydrochloric acid, hydrogen bromide, sulfuric
acid, phosphoric acid, acetic acid, formic acid, maleic acid,
tartaric acid, lactic acid, 3,5-dinitro-benzoic acid, citric acid
or oxalic acid.
19. A process according to claim 1 further comprising the
step of resolving the starting material, or resolving an inter-
mediate formed during the process, or resolving a final product
to obtain the + isomer of a compound of the formula I or salt
thereof.
20. A process according to claim 1 further comprising the
step of resolving the starting material, or resolving an inter-
mediate formed during the process, or resolving a final product
to obtain the -isomer of a compound of the formula I or salt
thereof.
21. A process for preparing (+)-N-[2-(4-fluorophenyl)-1-
methyl]-ethyl-N-methyl-N-propynyl-amine which comprises reacting
(+)-N-methyl-[2-(4-fluorophenyl)-1-methyl]-ethylamine with
propargyl bromide.
22. N-[2-(4-fluorophenyl)-1-methyl]-ethyl-N-methyl-N-propynyl
amine of the formula I
34

(I)
<IMG>
or an isomer or a salt thereof.
23. The compound (+) -N-[2-(4-fluorophenyl)-1-methyl]-ethyl-
N-methyl-N-propynyl-amine or a salt thereof.
24. The compound (-) -N-[2-(4-fluorophenyl)-1-methyl]-ethyl-
N-methyl-N-propynyl-amine or a salt thereof.
25. The compound (+) -N-[2-(4-fluorophenyl)-1-methyl]-ethyl-
N-methyl-N-propynyl-amine.
26. The compound (-)-N-[2-(4-fluorophenyl)-1-methyl]-ethyl-
N-methyl-N-propynyl-amine.
27. A pharmaceutical composition comprising a pharmaceutically
acceptable compound according to claim 22 as active ingredient in
association with a pharmaceutically acceptable diluent or carrier.
28. A composition according to claim 27 wherein the active
ingredient is as defined in claim 23 or claim 25.
29. A composition according to claim 27 wherein the active
ingredient is as defined in claim 24 or claim 26.
30. A process for preparing a pharmaceutical composition
comprising a pharmaceutically acceptable compound according to

claim 22 as active ingredient which process comprises admixing
said active ingredient with a pharmaceutically acceptable diluent
or carrier.
36

Description

The present invention is related to a new medicine and
to is preparation which acts mainly as a selective MAO-B inhibitor
inhiblting the uptake of biogeneous amines and tyramine in the
organism.
The present invention is directed to the biologically
active compound of the formula (I)
f
fH2CH - N - CH~C--CH
O ~ (I)
salts of this compound as well as processes serving for the
preparation of the active ingredients and pharmaceutical
compositions containing the active ingredient or the salts thereof.
The substituents throughout the disclosure are as defined
below:
Rl stands for methyl or propynyl or a radical which can
be converted to methyl or propynyl,
R stands for fluorine or a radical which can be con-
verted to fluorine, for example, nitro,amino or diazonium,
A and B when reacted with each other can form a bivalent
radical of the formula
IRl
-N-
or the groups A and B comprise the said bivalent group,
R stands for hydrogen or C3 saturated or unsaturated
. ,~"

5~`7~
aliphatic hydrocarbon group which can be substituted by halogen,
R stands for hydrogen or methyl,
X stands for halogen or a sulphonic acid ester group.
In Hungarian Patent Specification Nos. 154,060 and
154,655 a process for the preparation of phenylisopropylamine
derivatives and their optically ac-tive derivatives is disclosed
and in Hungarian Patent Specification No. 154,060 the coronary
dilatatory, the hallucinogenic, depressant, tranquillant,
analgesic and slimming activity of the compounds whereas in
Hungarian Patent Specification No. 154,655 the monoamino oxydase
(MAO) inhibitory activity of the optically active compound is
disclosed.
The present invention relates to N-[2-(4-fluorophenyl)-
l-methyl]-ethyl-N-methyl-N-propynyl-amine, as well as isomers and
salts thereof which compounds have not been described in the
literature.
The compounds of the formula (I) and the isomers and
salts thereof are according to experimental data excellent MAO
inhibiting substances. Their MAO-B bloc~ing selectivity is good.
They also show a long-lasting aphrodisiac activity. Their
toxicity properties are also extremely good. It is very
significant that next to these activities the compounds possess
an activity inhibiting the uptake of biogeneous amines and
tyramine.
Due to the above properties the product according to
the invention is particularly suitable for the treatment of aged
people. At an elderly age by administration of the compound of
the formula (I), the mood elements can be improved, the sexual
- 2 -

'73
activity can be stimulated and the motor changes can be inhibited
by administrating the compound continuously, and thus the quality
of life of elderly people can be improved. The product represents
a drug which can be adopted to counteract the consequences of age-
related decrease in brain dopamine concentration. It facilitates
dopaminergic modulation in the brain without acting on the
postsynaptic dopamine receptor, remains efficient during years
of administration and is reasonably free of side-effects.
~nless otherwise emphasized that a special isomer or
salt is referred to throughout the specification the product
according to the invention includes all isomers and salts of the
formula (I).
~ ur present invention is based on the recognition that
in the compound group of N-alkyl-N-phenylalkylamines the position
of the substituents of the phenyl ring and the quality of the
substituents influence the molecule to such an extent that a
generalization could lead to errors.
Thus the special biological activity found in our
invention could not be expected on the basis of the compounds
which had been known from the state of prior art and which had
been explicitly disclosed.
According to a further feature of the present invention
there is provided a process for the preparation of N-[2-(4-fluoro-
phenyl)-l-methyl]-ethyl-N-methyl-N-propynyl-amine and isomers and
salts thereof which comprises
(a) in an amine of the formula (Ia)
- 3 -

7~
1 3 1 3
CH2-CH - N -CH2C-CH
O ~ (Ia)
in which R stands for a radical which can be converted to fluorine,
converting the g~oup R into fluorine; or
(b) in an amine of the formula (Ib)
1 3 1 3
CH2CH - NH
~ (Ib)
adding the propynyl group to the amino nitrogen atom; or
(c) in an amine of the formula (Ic)
ICH3
CH2-CH-NH-CH2C--CH
(Ic)
F
subjecting the amine to N-methylation; and if required converting
a propynyl amine of the formula (I) obtained into a salt formed
with a mineral or organic acid or setting free the base from a
;~ - 4

23305-1021
salt thereof.
The forma-tion oE the propynyl group in part (b) above may
be effected by reacting an amine of the formula (Ib) with formalde-
hyde and acetylene.
A compound of formula (Ia) can be obtained by reacting a
2-phenyl-isopropyl derlvative of the formula (II)
fH -C-----A
¦ H
~ (II)
wherein R stands for a radical which can be converted to fluorine;
with a compound of the formula (III)
B - R (III)
wherein A and B represent groups which on reacting with each other
form a bivalent group of the general formula
-N-
or the groups A and B comprise the said bivalent group and A may be
attached to the carbon atom by a single or double bond whereby in
the latter case the carbon atom cannot bear a hydrogen, and wherein

56'~;3
~ 5a - 23305-1021
R represents methyl or propynyl or a group which may be replaced
by methyl or propynyl.
A compound of Eormula (Ib) or (Ic) can be obtained by
reacting a 2-phenyl-isopropyl derivative of the formula (II)
- 5a -

5~-~7~,~
IEl3
CH2 - C~ A
3 (II)
F
with a compound of the formula (III)
B - Rl (III)
wherein
A and B represent groups which on reacting with each
other form a bivalent group of the formula
IRl
-N-
or the groups A a~d B comprise the said bivalent group and A may
be attached to the carbon atom by a single or double bond, whereby
in the latter case the carbon atom cannot bear a hydrogen and
Rl represents methyl or propynyl or a group which can be
replaced by methyl or propynyl and if required, N-methy]ating to
obtain a compound of formula (Ib) or if required, propynylating to
obtain a compound of formula (Ic).
A compound of the formula (Ia) can be obtained by
reacting an amine of the formula (VIII)
R5
HN - R4 (VIII)
wherein R4 stands for hydrogen or an optionally halosubstituted,
saturated or unsaturated aliphatic hydrocarbon group having 3
..
~ ; - 6 -

s~i 73
carbon atoms and R5 is hydrogen or methyl, with a phenyl acetone
derivative of the formu]a (IX)
CH2-CO-CH3
~ (IX)
wherein R2 is as defined above. In this reaction the corresponding
ketlmine or oxyamine is formed as intermediate which is thereafter
reduced. Reduction may be carried out by methods known per se.
Catalytic hydrogenation or nascent hydrogen may be used. In the
compound thus obtained the R4 group is converted into propynyl
and/or the R5 group into methyl, if necessary. The said reactions
may be carried out in any order.
According to another feature of the present invention,
a compound of the formula (Ia) can be obtained by reacting an
amine of -the formula (VIII) with a phenyl isopropyl derivative
of the formula (X)
fH3
fH2-CH-X
~X)
wherein R is as defined above and X stands for halogen or a
sulfonic acid ester group. X as halogen may be preferably chlorine,
bromine or iodine. X as sulfonic acid ester group may be preferably
- 7 -

~_~,,L73~ j 7~
an alkyl sulfonyloxy (e.g. methyl sulfonyloxy) or aryl sulfonyloxy
(preferably benzene sulfonyloxy, p-toluene-sulfonyloxy or p-bromo-
sulfonyloxy etc.). The reaction may be carried out advantageously
in the presence of an acid binding agent. In the compound thus
obtained R4 may be conver-ted into propynyl and/or R5 into methyl,
if necessary. The said reactions may be carried out in any order.
According to a still further feature of the present
invention a compound of the formula (Ia) can be obtained by
subjecting an amine of the formula (XI)
ICH3
fH2 ~ CH - NH2
/~
~ (XI)
wherein R is as defined above to methylation and propynylation.
The said reactions may be carried out in any order.
Propynylation may be accomplished stepwise by introducing
first a halopropyl or propenyl group into the molecule.
Thus one may proceed by reacting the amine of the formula
(XI) with 1,2-dibromo-propene and converting the 2-bromo-propenyl
derivative thus obtained into the desired propynyl derivative by
splitting off hydrogen bromide. This reaction may be carried out
by reacting the 2-bromo-propenyl derivative with a base or
subjecting the same to thermal treatment.
The methylation reaction according to the present inven-
tion may be carried out by reacting an amine of the formula (Ic)
- 8 -
.

with formaldehyde and formic acid. One may also proceed by
reacting an amine of the formula (Ic) with a methyl ester. As
methylating agent a me-thyl hallde (e.g. methyl bromide), dimethyl
sulfate, methyl sulfuric acid or trimethyl phosphate may be used.
According to ano-ther feature of the present invention,
a fluorine atom can be introduced into compounds which do not
contain fluorine at any suitable stage of the synthesis. One may
also proceed by using a compound wherein R stands for nitro,
amino or diazonium. The reaction may be carried out by reducing
the nitro group into an amino group, diazotizing the amino group,
converting the diazonium group into diazonium-fluoro-borate and
forming the fluorine substituent via the latter group.
The process of the present invention encompasses the
preparation of the compound of the formula (I) in racemic and
optically active form. If optically uniform antipodes are to be
prepared a resolution step is to be accomplished at any suitable
stage of the synthesis. Resolution may be carried out at the
initial stage of the synthesis on a starting material. In this
case a laevo- or dextro-rotatory starting material is used in the
synthesis [C.A. 14 (1920) 745; Hungarian Patent Specifications Nos.
154,635 and 169,844].
One may also proceed by subjecting a compound of the
formula (I) obtained to resolution. The reaction may be carried
out by methods known per se by forming a diastereomer pair of
salts by using a suitable optically active acid (e.g. tartaric
acid or dibenzoyl tartaric acid).
,- _ g _

-- 10 --
The oily, lipoid soluble compounds
according to the invention can be converted to water
soluble salts or the free bases can be set free from
the salts. Thus salts formed with hydrochloric acid,
hydrogen bromide, sulphuric acid, phosphoric acid,
acetic acid, formic acid, maleic acid, tartaric acid,
lactic acid, 3,5-dinitrobenzoic acid, citric acid,
oxalic acid can be prepared. The biologically inert
or acceptable salts or the free bases are suitable
for use in human medicines.
The present invention provides next to the
compounds of the Formula (I) pharmaceutical composi-
tions con-taining compounds of the ~ormula (I) and
salts thereof.
The pharmaceutical compositions can be
prepared by methods known per se in the form of
tablets, dragées, suppositories, capsules, solutions,
emulsions, injections and optionally additives,
carriers, lubrica-ting agents and filling agents can
be added.
A part of the starting materials mainlg
the fluoro substituted derivatives has not been
known from the literature and therefore the prepa-
ration of these compounds is briefly disclosed in
the examples.
The pharmaceutical compositions according
to the invention can be administered for adults as
follows: as geriatric med~cine 1-5 mg., as uptake
~ inhibiting ugtidc ~rceSssQ~n~r20-50 mg. and as a
6 '`~ medicine against Parkinson's disease 5-10 mg. pro
die is used.

~4~
11 --
Example 1
8.28 g. (0.0495 mole) of /+/-N-methyl-[2-
(4-fluoro-phenyl)-1-methyl]-ethyl amine (Jr ~m. Chem.
Soc. _ 1009-1011) are dissolved in 45 ml. of toluene.
To the solu-tion 0.078 g. of benzyl triethyl ammonium
chloride are added and paralle~y 6.48 g. (0.0545 mole)
of propargyl bromide and a solution of 2.17 g.
(0.0543 mole) of sodium hydroxide in 7.5 ml. of water
are added dropwise under stirring within 5 minutes.
The temperature of the reaction mi~ture rises from
23 C to 26 C. ~he reaction mixture is stirred at
26-28 C for 20 hours whereupon the two phases are
separated, the toluene layer is dried over anhydrous
sodium sulfate and evaporated. ~he residue is
distilled~ at 80-82 C/0.1 Hgmm. Thus 5.05 g. of
/+/~N-methyl-N-propynyl-L2-(4-fluoro-phenyl)-1-
methyl3-ethyL amine are obtained, nD = 1.5050.
~he hydrochloride melts at 132-133 C (from ethanol
and ether).
Analysis~ for the Formula C13H17NClF
Calc.o C % = 65.59, H % = 7.09, N % = 5.79, Cl %=14.66,
F % = 7.859
Found~ C % = 65.00, H % = 6.97, ~ % = 5.95, Cl %=14.90,
~ % = 8.01.
E~ample 2
3.38 g. (0.022 mole) of /+/-N-methyl-~2-
(4-fluoro-phenyl)-1-methyl3-ethyl amine are dissolved
in 35 ml. of acetone, whereupon 19 gO (0.14 mole) of
potassium carbonate are added and 2.95 g. (0.025 mole)
of distilled propargyl bromide are added dropwise
under stirring within 10 minutes~ The temperature of
the mixture rises from 22 C to 25 C. The reaction

~24~
- 12 -
mixture is heated at 55 C for -three hours and a
half under stirring. The reaction mixture is allowed
to stand overnight, filtered, washed three times
with 25 ml~ of acetone each and the acetone fil-trate
is evapora-ted. The residue is distilled off at 2
` ~ Hgmm. Thus 2.28 g. of /i/-N-methyl-N-propinyl-~2-(4
fluoro-phenyl)-l-methyl]-ethyl amine are obtained,
yleld 5].7 %. Bp.: 120-122 C/2 Hgmm., nD = 1.5050.
Example 3
30.97 g. (0.197 mole) of /+/~N-methyl~[2-
(4-fluoro-phenyl)-1-methyl]-ethyl arnine are dissolved
in 310 ml. of acetone whereupon 174.5 g. (1.26 mole)
f pOtasSiUm carbonate are added and a 68 % toluene
solution of propargyl bromide (39.7 g., 0.227 mole)
is added dropwise under stirring within 20 minutes.
The temperature of the mixture rises from 26 C to
40 C. The reaction mixture is stirred at 55 C for
six hours and a half, filtered, washed with acetone
and the acetone filtrate is evaporated. The residue
is distilled ~f a-t 0.6 Hgmm. Thus 16.25 g. of /+/-
N-methyl-N-propinyl-[2-(4-fluoro-phenyl)-1-methyl~-
ethyl amine are obtained, yield- 41.2 %. Bp. 90-92 C.
Example 4
7.4 g. (0.0443 mole) of /-/-N-methyl-[2-
-(4-fluoro-phenyl)-1-methyl~-ethyl amine ([~DO =
-3.44 ethanol)) are dissolved in 60 ml. of acetone
whereupon 28~9 g. (0.21 mole) of potassium carbonate
are added and a 60 % toluene solution of 7056 g.
(0.045 mole) of propargyl bromide is added dropwise
under stirring. The reaction mixture is stirred at
35-40 C for 3-4 hours, filtered, washed with acetone
and the acetone filtrate is evaporated. The residue

- 13 -
is distilled ~ at 2 HgmmO Thus 3.3 g. of /~/-N-
methyl~N-propinyl-L2-(4-fluoro-phenyl)-1-methyl]~
ethyl-arnine are obtalned, b~p~o 120-122 C, nD2 =
1.5052. The hydrochloride melts at 169-171 C.
L~]20 = -6~2 (ethanol, c=2.4) 9 ~JD2 = -10.98
(wa-ter, c = 2.9)
Example 5
~n aqueous solution of 10 g. (0.028 mole)
f /-S-N-methyl-~2-(4-fluoro-phenyl)-1-methyl7-ethyl
amine /+/-tartarate-dihydrate (mp.o 88-91 C) is made
alkaline with a 40 % aqueous sodium hydroxide solu-
tion (pH 12-13)~ The solution is extracted with di-
chloro methane and the dichloro methane extract is
dried over sodium sulfate~
To the above dichloro methane solution
22.5 g. (0016 mole) of potassium carbonate are added
whereupon 60 % toluene solution of 5.96 g. of propargyl
bromide is added dropwiseO The reaction mixture is
stirred at room temperature for 5 hours, filtered
and the filtrate is extracted first four times with
25 ml. of 20 % acetic acid each and thereafter four
times with 25 ml. of 10 % hydrochloric acid each. The
aqueous hydrochloric acid extracts are made alkaline
with a 40 % sodium hydroxide solution and extracted
with dichloro methane. The dichloro methane solution
is dried and gaseous hydrogen chloride is introduced.
On addition of petrolether 2.38 g. of /-/-N-methyl-
N-propinyl-~2-(4-fluoro-phenyl)-1-methyl]-ethyl amine
hydrochloride are obtainedO ~p.. 168-170 C.
~JDO = -10.89 (water, c=2.5). Yieldo 47.1 ~0.

73
~ 14 -
Example 6
~ rom 10 g. (0.028 mole) of /-/-N-methyl-
-l2-(4-fluoro-phenyl)-1-methyl~-ethyl amine-/+/-
tartrate dihydrate the base is set free as describedin Example 5 whereupon the dichloro methane solu-tion
is evaporated. The residue is dissolved in 60 ml. of
acetone, 22 5 g. (0.16 mole) of potassium carbonate
are added and a 60 % toluene solution of 5.96 g. of
propargyl bromide is added dropwise. The reaction
mixture is stirred at room temperature for 3 hours,
filtered and evaporated. The residue is dissolved in
toluene and extracted with a 10 % hydrohhloric acid.
The aqueous acidic extract is made al~aline with a
40 % sodium hydroxide solution to pH 12-13 and extract-
ed with toluene. The toluene solution is dried and
acidified with 31 ~0 ethanolic hydrogen chloride to
pH 3. The precipitated crystalline product is filtered,
washed with cold acetone and dried. Thus 2.05 g. of a
product are obtained which is identical with the
compound prepared according to Example 5. Yield-
40.6 %.
Example 7
To 10 g. (0.028 mole) of /-/ N-methyl-
~2-(4-fluoro-phenyl)-1-methyl~-ethyl amine /+/-
tartrate-dihydrate according to Example 5 a solu-
tion of 7.5 g~ of sodium hydroxide in 25 ml. of
water and 17 mlO of toluene are addedO The mixture
is stirred for 30 minutes. The phases are separated
and -the aqueous layer is extracted three times with
6 ml~ of toluer.e each.
The toluene solution thus obtained is
added to a solution of 1.37 g. of sodium hydroxide,

~ ~5~3
-15- 23305-1021
0.04 g. of benzyl triethyl ammonium chloride and 5 ml. of water.
To the mixture 4.1 g. of propargyl bromide are added dropwise and
the reaction mixture is stirred at room temperature for 15 hours.
The phases are separated, the toluene layer is extracted twice
with 7 ml. of 5 % acetic acid each and twice with 10 ml. of 10%
hydrochloric acid each. The aqueous-acidic extract is made
alkaline by adding a 40 % sodium hydroxide solution and is there-
after extracted with toluene. After drying the toluene solution
is acidified to pH 3 with 31 % ethanolic hydrogen chloride. The
crystalline product is filtered, washed with cold acetone and
dried. Thus 2.72 g. of a product are obtained which is identical
with the compound prepared according to Example 5.
Example 8
From 10 g. (0~028 mole) of /-/-N-methyl-[2-(4-fluoro-
phenyl) -l-methyl]-ethyl amine /+/-tartrate dihydrate the base is
set free as described in Example 7. To the dried toluene solution
24.7 g. (0.17 mole) of potassium carbonate are added whereupon
a 60 % toluene solution of 3.66 g. (0.03 mole) of propargyl
bromide is added dropwise. The reaction mixture is stirred at room
temperature and filtered. The toluene filtrate is extracted twice
with 7 ml of 5 % acetic acid each and twice with 10 ml. of 10 %
hydrochloric acid each. The aqueous acidic extract is worked up
according to Example 7. Thus 2.6 g. of a product are obtained
which is identical with the compound prepared according to Example
5.
Example 9
To a solution of 8.3 g (0.05 mole) of

'7~
-16- 23305-1021
/+/-N-methyl-[2-(4-fluoro-phenyl)-1-methyl]-ethyl amine, 5.4 g.
(0.01 mole) of propargyl aldehyde and 100 ml. of 96 % ethanol
3 g. of aluminium foils activated with mercuri chloride are added
in portions at 20-30C. The reaction mixture is stirred at room
temperature for 24 hours, filtered and the filtrate is evaporated.
The residue is also dissolved in a 10 % hydrochloric acid, extracted
with benzene, made alkaline with a 40 % sodium hydroxide solution
and extracted again with benzene. The benzene solution is dried
and evaporated. The residue is distilled off in vacuo at 2 Hgmm.
Thus 5.6 g. of /+/-N-methyl-N-propinyl-[2-(4-fluoro-phenyl)-1-
methyl]-ethyl amine are obtained. Bp.: 120-123C/2 Hgmm., nD
1.5055. The melting point of the hydrochloride salt is 130-132C.
Example 10
10 g. (0.065 mole) of 4-fluoro-phenyl acetone and 5.3 g.
(0.097 mole) of propargyl amine are dissolved in 55 ml.of 96 %
alcohol. The solution is stirred for half an hour at 60C where-
upon 1.75 g. of aluminium foils activated with mercuri chloride
are added. The reaction mixture is allowed to stand overnight,
whereupon 15 ml. of a 40% sodium hydroxide solution are added, the
alcohol is distilled off and the residue is extracted with benzene.
The benzene solution is extracted with 10 % hydrochloric acid, the
aqueous acidic phase is made alkaline and extracted with benzene.
After drying the benzene phase is evaporated and the residue is
distilled in vacuo. Thus 4.9 g. of /+/-N-propynyl-[2-(4-fluoro-
phenyl)-l-methyl]-ethyl amine are obtained, yield 36 % Bp.:
134-140C/17 Hgmm., nD = 1.5031.
~7

~ ~5 Ei~7~
-17- 23305-1021
4. g. of the above compound are dissolved in 25 ml. of
acetone whereupon 4 g. of potassium carbonate and 4 g. of methyl
iodide are added. The reaction mixture is refluxed for 2 hours,
filtered and evaporated. The residue is dissolved in 10%
hydrochloric acid, clarified, filtered, made alkaline with a
40 % sodium hydroxide solution and extracted with toluene. After
drying the toluene solution is acidified with ethanolic hydrogen
chloride, -the precipitated product is filtered and dried. Thus
3.1 g. of /~/-N-methyl-N-propinyl-[2-(4-fluorophenyl)-1-methyl]-
ethyl amine hydrochloride are obtained, melting point 131-133C.
Example 11
-
To a solution of 6.0 g. (0.036 mole) of /+/-N-methyl-
[2-(4-fluoro-phenyl)-1-methyl]-ethyl amine and 60 ml. of acetone
33.6 g. (0.24 mole) of potassium carbonate are added whereupon
7.45 g. (0.037 mole) of 2,3-dibromo-propene are added dropwise
at 25-30 C under stirring within 20-25 minutes. The reaction
mixture is refluxed for 6 hours, filtered and evaporated. The
residue is distilled in vacuo at 4-5 Hgmm. Thus 6.52 g. of
/+/-N-methyl-N-(2-bromo-propenyl-3)-[2-(4-fluoro-phenyl)-1-methyl]-
ethyl amine are obtained, yield 63.3 ~.
Bp.: 142-143 C, n20 = 1.5234.
2.5 g. of the above product are dissolved in 35 ml. of
ethanol whereupon 5 ml. of a 50 % potassiumhydroxide solution are
added. The reaction mixture is refluxed for 16 hours and
evaporated. The residue is taken up in water and extracted with
benzene. After drying the benzene solution is acidified with

'L~
-18- 23305-1021
ethanolic hydrogen chloride. The precipitated product is filtered
and dried. Thus 2.2 g. of /+/-N-methyl-N-propinyl-[2-(4-fluoro-
phenyl)-l-methyl]-ethyl amine hydrochloride a~e obtained,
mp.: 131-133 C.
Pharmacological Tests
-
The following symbols are used:
IA = /+/-N-methyl-N-[(2-propinyl)-2-(4-fluoro-phenyl)-1-methyl]-
ethylamine-hydrochloride
IB = /-/-N-methyl-N-[(2-propinyl)-2-(4-fluoro-phenyl)-1-methyl]-
ethylamine-hydrochloride
pClP = /+/-N-methyl-N-[(2-propinyl)-2-(4-chloro-phenyl)-1-methyl]
-ethylamine-hydrochloride
pBrP = /+/-N-methyl-N-[(2-propinyl)-2-(4-bromo-phenyl)-1-methyl]-
ethylamine-hydrochloride
1. Monoamine-oxydase (MAO) inhibitory activity
1.1. In vitro tests
1.1.1. Measured in rat brain and liver nucleus free
homogenate
Method: Biochem. Pharmacol. 1963, 12, 1417
1978, 27, 1739.
Substrates:
MAO-B: C-PEA: 0.2 mM; spec.act. 0.5 ~Ci/ml.
MAO-A: 14C-5HT: 5.0 mM; spec.act. 0.25 ~Ci/ml.
Results:

~-~45~
-~9- 23305-1021
Organ IB IA pCIP pBrP
IC50 brain 4.57xlO 8 4.17x10 8 1.48x10 3.98x10 7
MAO-B liver 1.98x10 ~ l.l9x10 8 lx10 7 1.64xlo 7
(M)
-
select liver 238.38 580.67 43.47 51.28
index
IC MAO-A
select.index = - 50
IC50 MAI-B
1.1.2. Measured on rat brain mltochondrium
Method: From the brain of male CFY rats weighing
200-250 g. mitochondria were prepared as follows:
after decapitation a tissue homogenate was
prepared in 0.25 M sucrose. It was centrifuged
at 1000 g. for 10 minutes and the supernatant
was further centrifuged for 15 minutes at 9000 g.
and the sediment was taken up in 0.25 M sucrose.
Substrates:
MAO-A: 6x10 4 M 5HT
MAO-B: 2x10 5 M PEA
Results: IC50 values (M) of IA compound:
MAO-A: 5x10 5
MAO-B: 3x10
1.2. In vivo test measured in rats brain and liver nucleus free
homogenizate
Method: the rats weretreated s.c. with different doses of the
substances and 4 hours after the administration of
the substance the organs were taken out and the

~L~45673
-20- 23305-1021
and the MAO activity was measured as disclosed
in 1.1.1.
Organ IB IA pBrP
ID50 brain0.104 0.076 5.61
MAO-B liver0.772 0.292 8.85
(mg/kg)
index liver148.8 168.6 13.33
ID50 MAO-A
select-indeX = ID50 MAO-B
After a treatment lasting for 21 days (daily dose 0.25
mg./kg. s.c./IA) the MAO-B inhibition was 92-94% expressed in the
% of the control and the MAO-A inhibition was 0%.
2. Tyramlne uptake inhibitory activity on arteria pulmonalis of
rabbits
Rabbitsof both sexes and weighing 2-4 kg. were used for the
experiments. The animals were killed by a blow on the neck and the
heart was immediately taken out and placed to an oxygenated Krebs
solution. Composition of the Krebs solution (mmole/1.): NaC1 111,
KCl 4.7, CaC12 2.52, MgSO4 1.64, NaHCO325, KH2PO4 1-2, glucose 11.
The blood vessel was purified from the connective tissue and an
1.5 mm. wide spiral had been cut out from the tissue. The so
obtained blood vessel segment was placed to a 5 ml. organ bath
containing a Krebs solution through which a gas mixture consisting
f 95% 2 + 5% C2 was passed through and which had been thermo-
stated at 37C. The mechanical activity was registered on a semi-
isometric compensograph by using 1 g. preloading

-21- 23305-1021
The tyramine uptake was inhibited on the above preparation by
compound lB dependently on the dose IC50 = 4 5 x 10 M.
3. Inhibition of the uptake of blogeneous amines (method: J. Pharm.
Exp. Ther. (1969) 165, 78-86)
Concentration IA
Ligand of the ligand Region IC50 (M)
NA SxlO 8 hypothalamus 8xlO
5I~T lxlO hippocampus 6xlO
DA lxlO striatum 2xlO
NA: 3H-noradrenaline
5HT: 3H-5-hydroxy-triptamine
DA: H-dopamine
4. Activities stimulating the activity of external phenethylamine
(PEA~ (in vivo MAO-B)
4.1. Activity stimulating the nictitating membrane of
anaesthetized cats
The nictitating membrane is contracted on administration
i.v. dose dependently by PEA. The PEA contraction
activity curves are dosis dependently shifted to the left
upon the intravenous administration of IA compound at a
dose of 0.1 or 0.25 mg./kg.
4.2. Increase of PEA induced stereotypic behaviour
Method: Arzneimittel Forsch. (Drug Research)
22, 1178 (1972)
Results:

$'~
-22- 23305-1021
Compound mg./kg. Max-score Total.score
Control - 0.5+0.22 1.17+0.54
IA 0.05 2.17tO.31 8.17+0.87
0.1 1.67+0.21 5.67+0.49
0.05 1.0+0.37 2.83+1.01
The 40 mg./kg. PEA activi-ty is potentiated by
the IA compound at a dosis 0.05-0.25 mg./kg.
s.c. depending on the dose.
5. Central nervous system tests
5.1. Modified junping test (MJT)
The compound IA does not inhibit the avoidance reflex
of the rats at a dose of 15 mg./kg. (method: Knoli 1963).
5.2. Metabolic rate test
The compound IA at a dose of 5 mg./kg. did not increase
the metabolism of rats (method: Issekutz 1942).
5.3. Testing the activity upon the food intake
The test were carried after 96 hours starvation on rats
(n=10-13). When administered~he compoundIA s.c. at a
dose of 5 mg./kg. mainly the 1 hour food intake was
significantly decreased and when using higher doses
(10-15 mg./kg. s.c.) the 5 hours food intake was
significantly decreased.
5.4. Effect on catalepsy
The catatonia induced by 3 mg./kg tetrabenazine was
inhibited depending on the dose both by compound IA and IB.

5~
-22a- 23305-1021
ED50-IA = 2.6 mg./kg-
ED50-I~ = 2.9 mg./kg.
6. Testing the sexual activity on male rats
on sluggish male rats compound IA proved to be a strong long-
lasting stimulant. The afrodisiac activity of one single dose
(0.1 mg./kg. and 0.25 mg./kg. rest) significantly increased the
number of ejaculations 24 hours and 2-3 and 4 weeks resp. after
the administration related to the control. (Method: Medical
science _3, 179--180, 1382).
0 7. Toxicity
The tests were per~ormed on CFY male and female albino rats
weighing 100-120 g. The compounds were administered i.v. and
animals were observed for 48 hours.

~ 3
- 23 -
IA IB pClP
LD50 60 64 35 ~g-/kg.
Pharmaceutical comeositions
Example l
The following component~ are uqed:O 10 g. /+/-N-methyl-N-propargyl-~2-(4-fluoro-phenyl)-
l-methyl]ethyl-amine-hydrochloride
6 g. talcum
6 g. magnesium-stearate
20 g. polyvidone
90 g. corn starch
160 g~ lactose
The components are homogenized and lO00 piece~ of
tablets were compressed from the mi~ture.
Example 2
The following components are blended:
llO g. /-/~-methyl-N-proparOyl-t2-(4-fl-;oro-phenyl)-
L-methy~ethyl-amine-hydrochloride
7 g. talcum
5 g. magnesium-stearate
20 g. polyvidone
lO0 g. potatoe-starch
150 g. lactose
The components are homogenized and lO00 pieces of
tablets are compressed from the mixture.

-- 24
~urt~ier chemical Examples ~ 567
Example 12
16,7 g of (~-N-methyl-/2-(4-fluoro-phenyl)-1-methyl/-ethyl-
-amine are dissolved in 150 ml of acetone and 69,2 9 of sodium-
-carbonate are added while stirring. On addition of 13,3 9 of
allyl-bromide the reaction mixture is refluxed for 8 hours,
cooled and filtrated. The filtrate is evaporated and distilled
in vacuo. 15,2 9 of (+)-N-methyl-N-(2-propinyl)-/2-(4-fluoro-
-phenyl)-l methyl/-ethylamine are obtained. The product is
dissolved in 100 ml of carbone tetrachloride and 11,8 9 of
bromine are added dropwise. After stirring for 8 hours the
solution is evaporated and the residue is dissolved in 400 ml
of ethanol. 100 ml of a 50 ~0 aqueous sodium hydroxide solution
are added and the reaction mixture is refluxed for 20 hours.
On evaporation of the ethanol, water is added and the mixture
is extracted with benzene. The benzene solution is extracted
with 2 N hydrochloric acid and on addition of a sodium
hydroxide solution the extraction with benzene is repeated.
The benzene extract is dried over sodium-sulphate, filtered
and evaporated. On distillation in vacuo of the residue 5,6 9
of (~)-N-methyl-N-(2-propinyl)-/2-(4-fluoro-phenyl)-1 methyl/-
-ethyl-amine are obtained.
Bp (0,6 Hgmm) 90-93 C.

lf~'~56
-- 25 --
Example 13
10 9 of 4-fluoro-phenylacetone and G,9 9 of N-methyl-propargyl
amine are dissolved in 60 ml of 9~,cO e-thanol. 1,8 9 aluminium
shect, /activated with mercury chloride/ are added at 60C and
the mixture is stirred for 10 hours, filtered and evaporated.
The residue is dissolved in l0,~o hydrochloride acid and extracted
with benzene. The aqueous layer is made alcaline and extracted
with benzene, whereupon the benzene extract is dried and
evaporated. The residue is distilled in vacuo. 5,1 ~ of (+) -
-N-methyl-N-(Z-propinyl)-/2-(4-fluoro-phenyl)-1 methyl/-ethyl-
amine are obtained.
Bp:(2 Hgmm)=120-123 C n20= 1,5058
~xamole 14
1,72 g of 1-(4-fluoro-phenyl)-2-chloro-propane /Acta Chim.Acad.
Sci.Hung~79 (1973) 433/ and 1,4 g of N-methyl-propargyl-amine
are hea~ed in a sealed tube for 5 hours. The reaction mixture
is dissolved in 30~' aqueous ethanol containing hydrochloric acid
and evaporated. F,-om the residue 0,35 9 cf (+)-N-methyl-N-(2-pro-
pinyl)-/2-(4-fluoro-phenylj-1-methyl/-ethyl~amine hydrochloride
are obtained.
Mp: 130-132 C

1~45673
Example 15
A solution of 802 g. (0005 mole) of
/+/~-methyl-2-(4-amino-phenyl)-1-methyl-ethyl amine
(h~J-PS 154,060) in 30 ml. 56 ~0 fluoroboric acid and
305 g. (0.051 mole) of sodium ~itrite in 25 ml.
water are simuLtaneously dropped into 100 ml. of
56 % fluoro boric acid under stirring and cooling at
-5 -(-7) C so 1,hat a small e~cess of nitrite solution
is maintained in the reaction mixture during the addi-
tionO ~he mi~t,ure is then stirred for ~ further 30
minute~ at -5 (-7) C and in small portions 2.5 g.
~eshly prepared copper/I/ chloride is added to the
solutionO ~he ai~ture is stirred for 2 hours at room
temperature and stirred for 80-90 G for 2 hours.
After cooling the mi~ture is extracted with ether
and the aqueous acid layer is alkalized witb conc.
ammonium hydro~ide and e~tracted with benzene. The
benzene e~tract is evaporated after drying and the
residue is distilled at 10 mmHg~ As a main cut 506 g.
~+/-~-methyl-2~(4-~luorophen~ methyl-ethyl-amine
(boiling point: 87-90 C/10 mmHg) obtained which are
rea~d according to ~a_ple 2 with propargv~l bromide
and processed according to Example 2. 308 g. /+/-N-
methyl-~-propynyl-2-(4~fluoro-phenyl)-1-methyl ethyl-
amine are obta:ined. ~pD 120-123 C/2 mmHg, nD =
1.5054.
ExarQple 16
To 7.65 g. ~0.05 mole) of /+/-2-(4-~luoro-
phenyl) l-methyl-ethyl-amine (BE-PS 609 630) in 25 mlO
of benzene 5.3 g. (0.05 mole) of 2istilled benz-
alde~yde are added ana the solution is allowed to
stand overnight and driedO To the dried solution
603 g. (0.05 mole) of dimethyl sulphate are add0d
and the mi~ture is allowed to boil under reflu~ for
3 hours a~d after cooling under stirring a ~olution

~ 5~73,
of 2 ml. conc. hydrochlorid aoid in 50 ml. of
wa.ter is addedc hfter stirrir.~ for 1 hour the two
layers are separated a~d the aqueous - acidic layer
is alkalized with sodium hydroxide and e~tracted
with benzene. The benzene solution is dried and
evaporated and the residue is distilled in vacuo~
- The main cut (4.15 g., bpo- 87-90 C/10 mmHg) is
dissolved in 40 mlO of toluene and after adding
23.5 g. (0.17 mole) of potassium carbonate a solu-
tion of 3065 g. (0.031 mole) propargyl bromide in
60 % toluene is added dropwise to the mi~ture and
it is stirred for 14 hours at xoom temperature~ The
mixture is then filtèred and the filtrate acidified
with 31 ~o ethanol containing HCl.until pH = 3. The
crystalli~e product is filtered and recrystallizedfrom a mi~ture of ethanol and etherO 2Ol g. of
/+/-~-methyl~ propynyl-2-(4-fluoro-phenyl)-1-
methyl-l-ethyl-amine hydrochloride are obtai.ned,
m.p O 130-132 CO