CA1245673A - Medicine and its preparation - Google Patents

Abstract

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

/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.

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~

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) ~ (Ib) adding the propynyl group to the amino nitrogen atom; or (c) in an amine of the formula (Ic) (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 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) 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) ~ (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 ~_~,,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) 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) .

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 _ 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~

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~

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 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.

~ 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 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~

/+/-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~

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~

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 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 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 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 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:

$'~

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 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.

~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 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

Claims (30)

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

or an isomer or salt thereof which comprises a) in an amine of the formula I(a) 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) I(b) adding the propynyl group to the amino nitrogen atom; or c) in an amine of the formula I(c) 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

II

wherein R2 stands for a radical, which can be converted to fluorine with a compound of the formula III

wherein A and B represent groups which on reacting with each other form a bivalent group of the formula 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 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

II

with a compound of the formula III

wherein A and B represent groups which on reacting with each other form a bivalent group of the formula 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

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

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

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 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

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.

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 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

(I) 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.