A compound of the formula ##STR1## or a pharmaceutically effective salt thereof in which R.sup.1 and R.sup.2 are hydrogen or lower alkyl and R.sup.3 is halogenoalkenyl or propinyl. The compounds have pharmacological effects similar to those of phenylethylamine but are free from the amphetamine effect with an excellent therapeutic index and selectivity especially with respect to inhibition of monoaminooxidase.

This invention relates to new amines. More particularly it is concerned 
with new N-2-(2-furyl)-ethyl-amine derivatives compositions comprising the 
same. 
According to an aspect of the present invention there are provided 
compounds of the formula I 
##STR2## 
and salts thereof (wherein R.sup.1 and R.sup.2 are hydrogen or lower 
alkyl, and R.sup.3 is halogenoalkenyl or propynyl). 
It is known that furyl-ethyl amines exhibit a pharmacological effect 
similar to that of phenyl-ethyl amine [J. Pharmacol. 72, 265 (1941)]. The 
new compounds of the formula I are free of the undesired "amphetamine" 
effect, but are capable of selective inhibition of monoaminooxidase. Some 
known compounds of different chemical structure are described to have 
selective monoaminooxidase inhibiting effect. (Biochemical Pharmacology 
18, (1969) 1447; Br. J. Pharmacology 45, (1972) 490). The said compounds 
inhibit however mainly the oxidation of 5-hydroxy-tryptamine. It is known 
that N-alpha-dimethyl-N-beta-phenyl-N-propynylamine (British Pat. No. 
1,031,425) inhibits the oxidation of benzyl amine (Br. J. Pharmacology 45, 
490 (1972)). The compounds of the formula I possess however more favorable 
properties than the phenyl-ethyl-propynyl amine derivatives mentioned 
above. 
The compounds of the formula I possess a chiral carbon atom and may be 
present either in racemic or in optically active forms. The present 
invention encompasses both the racemic and optically active forms of the 
compounds of the formula I and the preparation thereof. 
The term "lower alkyl group" means straight or branched chain alkyl groups 
having 1-4 carbon atoms (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, 
isobutyl, etc.) The alkyl group preferably can be a methyl group. The 
halogenoalkenyl group can comprise 2 or 3 carbon atoms and preferably 
chlorine or bromine as halogen (e.g. bromopropenyl). 
The salts of the compounds of the formula I may be formed with inorganic or 
organic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric acid, 
phosphoric acid, maleic acid, tartaric acid, fumaric acid, succinic acid, 
lactic acid, etc.). 
According to a further aspect of the present invention there is provided a 
process for the preparation of compounds of the formula I 
##STR3## 
which comprises 
(a) reacting a compound of the formula 
##STR4## 
with a compound of the formula III 
EQU B-R.sup.3 (III) 
(wherein A and B stand for groups, which on reacting with each other are 
capable of the formation of the bivalent 
##STR5## 
radical) and if desired converting a halogeno alkenyl group in the 
obtained product into a propynyl group; or 
(b) condensing a compound of the formula IV 
##STR6## 
with formaldehyde and acetylene and if desired converting a compound of 
the formula I thus obtained into its acid addition salt or setting free a 
compound of the formula I from its acid addition salt and if desired 
separating a racemic compound of the formula I into its optically active 
isomers. 
According to an embodiment of method (a) of our process a compound of the 
formula IV is reacted with a compound of the formula III, wherein R.sup.3 
is propargyl and B is halogen or a sulfonic acid ester group, e.g. an 
alkylsulfonyloxy or arylsulfonyloxy group, such as chlorine, bromine, 
benzenesulfonyloxy, p-toluenesulfonyloxy or methanesulfonyloxy. The 
reaction may be carried out in a solvent or without solvent. It is 
preferred to add an acid binding agent to the reaction mixture. As the 
acid binding agent, inorganic or organic bases, such as alkali or alkali 
earth metal hydroxides, carbonates or tertiary amines can be used. An 
excess of the amine of the formula IV can also serve as acid binding 
agent. In this case it is preferred to use the excess of amine both as 
acid binding agent and reaction medium. The reaction may be accomplished 
preferably at a temperature between 20.degree. and 120.degree. C. As 
solvent aliphatic and aromatic hydrocarbons, such as gasoline, benzene and 
its homologues, alkanols (e.g. ethanol, methanol, butanol, etc.) ketones 
(e.g. methyl-ethyl-ketone, cyclohexanone, etc.) can be used. According to 
a particularly preferred embodiment of this reaction variant an amine of 
the formula IV is dissolved in toluene and propargyl bromide and an 
aqueous sodium hydroxide solution are added simultaneously dropwise. The 
reaction is completed by heating if necessary. 
The product is recovered from the reaction mixture by addition of an alkali 
and subsequent extraction. If the reaction is carried out in a 
water-immiscible solvent, it is preferred to remove this solvent by 
distillation and adding the aqueous sodium hydroxide to the residue. The 
two-phase mixture is extracted with a water-immiscible solvent (e.g. ether 
or benzene), the extract is dried, evaporated and the residue is purified 
by fractionated distillation. 
If the compound of the formula I thus obtained is a tertiary base (R.sup.2 
is alkyl) the product may be advantageously purified by the acylation of 
the evaporation residue. In this case the unreacted starting material of 
the formula IV (secondary base) is acylated, the acylated product thus 
obtained is insoluble in diluted acids and the tertiary base of the 
formula I can be recovered by extraction with diluted acid in pure form. 
Acylation may be carried out with conventional acylating agents (e.g. acid 
anhydrides or acid chlorides such as acetic anhydride or benzoyl chloride) 
in the presence of an alkali. After acylation the reaction mixture is 
extracted with cold diluted hydrochloric acid, whereupon the acidic 
extract is made alkaline, the precipitated tertiary amine of the formula I 
is extracted with a solvent, dried, evaporated and the residue is 
distilled off. The product may be converted into a salt formed with an 
organic or inorganic acid. 
According to an other embodiment of process (a) a compound of the formula 
IV is reacted with propargyl aldehyde under simultaneous or subsequent 
reduction. One may proceed by reacting the compound of the formula IV with 
propargyl aldehyde in a solvent or without solvent. As reaction medium 
preferably water-immiscible solvents (e.g. benzene and its homologues, 
such as toluene, xylene, petrol, etc.) may be used. In this case the water 
formed in the reaction is separated and this shifts the reaction equation 
towards the formation of the Schiff-base. This product is then reduced 
into the corresponding compound of the formula I. One may also proceed by 
carrying out condensation and reduction simultaneously. Reduction is 
preferably accomplished with the aid of nascent hydrogen. 
According to a further embodiment of method (a) a 2-furyl-acetone of the 
formula VI 
##STR7## 
is reacted with an amine of the formula V. with simultaneous or 
subsequent reduction. The reduction can be accomplished preferably with 
the aid of nascent hydrogen. 
According to a further embodiment of method (a) a compound of the formula 
VII 
##STR8## 
(wherein X is halogen or a sulfonic acid radical, e.g. an alkylsulfonyloxy 
or arylsulfonyloxy group, such as chlorine, bromine, methanesulfonyloxy, 
phenylsulfonyloxy or p-toluenesulfonyloxy) is reacted with an amine of the 
formula V. The reaction can be carried out in the presence or absence of a 
solvent. As reaction medium hydrocarbons (e.g. benzene and its homologues, 
petrol etc.) alcohols or ketones may be used. An excess of the amine 
component can also serve as the reacting medium. The reaction is 
preferably accomplished in the presence of an acid binding agent. For this 
purpose organic or inorganic bases or an excess of the amine of the 
formula V may be used. The reaction can be carried out at a temperature 
between 20.degree. and 130.degree. C. The recovery and purification of the 
product may be carried out by known physical methods (e.g. extraction, 
distillation, crystallization). 
According to method (b) a compound of the formula IV is reacted with 
paraformaldehyde and acetylene. The reaction is carried out in an ether of 
high boiling point (e.g. butylether or dioxane) in the presence of cuprous 
acetylide. The reaction is performed preferably at a temperature of 
80.degree. to 150.degree. C. One may proceed preferably by dissolving the 
compound of the formula IV in dioxane, adding cuprous acetylide or a 
compound capable of forming cuprous acetylide (e.g. cuprous -- chloride) 
and introducing acetylene into the mixture under heating and stirring. The 
compound of the formula I may be isolated by methods known per se. 
The propinyl group may also be formed by subsequent modification of a 
halogenopropenyl derivative. Thus one may proceed by reacting a compound 
of the formula IV with an 1,2-dihalogeno-alkene (e.g. 1,2-dibromo-propene) 
and splitting off hydrogen halide from the halogens-propenyl derivative 
thus obtained with an alkali hydroxide, alkaline earth metal hydroxide, or 
an organic base. 
The compounds of the formula I thus obtained may be converted into a 
pharmaceutically acceptable acid addition salt formed with an inorganic or 
organic acid. The product may also be purified through the salts under 
utilising the fact that the salts are crystalline, readily crystallisable 
substances. After purification the base is set free from the salt by 
treatment with an alkali. For salt-formation hydrochloric acid, 
hydrobromic acid, sulfuric acid, phosphoric acid, maleic acid, lactic 
acid, citric acid, scorbic acid, etc. may be used. 
Compounds of the formula I in which R.sup.1 is an alkyl group contain a 
chiral carbon atom and may exist in racemic or optically active forms. The 
racemate may be subjected to resolution by conventional method. The 
optically active compound of the formula I may also be prepared by using 
an optically active amine of the formula IV in the reactions (a) and (b). 
According to a further feature of the present invention there are provided 
pharmaceutical compositions comprising as active ingredient a compound of 
the formula I or its salt in admixture with suitable inert solid or liquid 
carriers or diluents. The compositions may be finished in solid (e.g. 
tablets, pills, coated pills, capsules, dragees, powder mixtures) or 
liquid (e.g. aqueous solution or suspension) forms. The compositions are 
suitable for oral, or parenteral administration. The compositions contain 
conventional carriers, e.g. talc, calcium carbonate, magnesium stearate, 
water, vaseline, polyalkylene glycols, etc. The compositions are prepared 
by methods of pharmaceutical industry known per se. 
The N-methyl-N-[2-(furyl-2)-ethyl]-propynyl amine in an in vivo dose of 
6.25 mg./kg. inhibits in the liver the oxidation of benzyl amine to an 
extent of 79% and the oxidation of thyramine only by 44%. In a dose of 5 
mg./kg. N-methyl-N-[1-methyl-2-(furyl-2)-ethyl]propynyl amine inhibits in 
the brain the oxidation of benzylamine to an extent of 53% and that of 
5-hydroxy-tryptamine only by 2%. On the other hand the known compound 
N,alpha-dimethyl-N-beta-phenyl-ethyl-N-propynyl amine shows in the same 
dose an inhibition of 80% of the oxidation of benzylamine in the brain, 
while the inhibition of the oxidation of 5-hydroxy-tryptamine is 15%. The 
said known phenyl derivative when administered in a dose of 10 mg/kg. 
inhibits the oxidation of benzylamine in the liver by 78%, and the 
oxidation of 5-hydroxy tryptamine by 56%. The above data show that the 
compounds of the formula I exhibit a more selective monoaminooxidase 
inhibiting effect, than the known phenyl derivatives. According to in 
vitro tests the selectivity is more pronounced. 
The reserpine depression antagonizing antidepressive effect of the 
compounds of the formula I is significantly stronger than that of the 
phenyl analogues. 
The toxicity of the compounds of the formula I is smaller, than that of the 
known phenyl derivatives, and therefore the new compounds of the present 
invention possess a more advantageous therapeutic index and a broader 
spectrum of activity.

Further details of the present invention are to be found in the Examples 
without limiting the scope of our invention to the Examples. 
EXAMPLE 1 
7.9 g. (0.0568 moles) of N-methyl-N-[1-methyl-2-(furyl-2)-ethyl]-amine are 
dissolved in 142 ml. of toluene, whereupon at 45.degree. to 50.degree. C. 
6.7 g. (0.0568 moles) of propargyl bromide and 11.4 ml. of a 5 N aqueous 
sodium hydroxide solution are added at the same time under stirring. The 
reaction mixture is refluxed under stirring for 3 hours. After cooling 
14.8 ml. of a 10 N sodium hydroxide solution are added and the phases are 
separated. The aqueous layer is extracted twice with benzene, whereupon 
the benzene and toluene solutions are united, dried over anhydrous 
potassium carbonate and evaporated. The residue is dissolved in 50 ml. of 
benzene and refluxed with 6 g. of acetic anhydride for an hour. After 
cooling the solution is washed with a 20% sodium carbonate solution until 
the evolution of carbon dioxide ceases. The mixture is washed with water 
and extracted with 5% hydrochloric acid at 0.degree. C. The hydrochloric 
acid solutions are united, the mixture is allowed to stand at a 
temperature below 10.degree. C., and made alkaline. The separated oil is 
extracted with ether, the ether extract is dried over potassium carbonate 
and evaporated. On subjecting the residue to vacuum destillation 6.5 g. of 
N-methyl-N-[1-methyl-2-(furyl-2)-ethyl]-propynyl-amine are obtained. Bp.: 
115.degree. -117.degree. C./20 Hgmm; n.sub.D.sup.20 =1.4922. 
EXAMPLE 2 
The process according to Example 1 is carried out except that 12.5 g. of 
N-methyl-N-2-(furyl-2)-ethyl amine 11.9 g. (0.1 mole) of propargyl bromide 
are reacted in 70 ml. of toluene and 20 ml. of a 5 N sodium hydroxide 
solution. Thus 11.2 g. of N-methyl-N-[2-(furyl-2)-ethyl]-propynyl amine 
are obtained. Bp.: 105.degree.-106.degree. C./20 Hgmm; n.sub.D.sup.20 
=1.4891. The melting point of the hydrochloride amounts to 
106.degree.-108.degree. C. (from a mixture of ethanol and ether). 
EXAMPLE 3 
To 13.9 g. (0.1 mole) of N-methyl-N-[1-methyl-2-(furyl-2)-ethyl]amine 10 g. 
(0.05 moles) of 1,2-dibromo-propene are added dropwise, the reaction 
mixture is heated at 100.degree. C. for 7 hours, whereupon it is cooled to 
room temperature and dissolved in 5% hydrochloric acid. The acidic 
solution is extracted with ether and made alkaline with 40% sodium 
hydroxide. The precipitated oil is extracted with ether, the extract is 
dried and evaporated. To the residual brown oil 60 ml. of 40% sodium 
hydroxide and 30 ml. of benzoyl chloride are added parallelly dropwise 
within 30-45 minutes in order to benzoylate the unreacted 
N-methyl-N-[methyl-2-(furyl-2)-ethyl] amine. During the addition the 
temperature of the reaction mixture rises to 50.degree.-60.degree. C. The 
addition having been completed the reaction mixture is stirred at this 
temperature for an hour, whereupon it is cooled to room temperature and 
benzene is added. The mixture is shaken and the benzene phase is separated 
and extracted with 5% hydrochloric acid. The 
N-methyl-N-[1-methyl-2-(furyl-2)-ethyl]-N-2-bromopropenyl amine dissolves 
in the acidic phase, while the 
N-methyl-N-[1-methyl-2-(furyl-2)-ethyl]-benzoyl amine remains in the 
benzene solution. The hydrochloric acid layer is made alkaline, the 
precipitated N-methyl-N-[1-methyl-2-(furyl-2)-ethyl]-N-2-bromo-propenyl 
amine is extracted with benzene, dried and evaporated. The residue is 
distilled off in vacuo. Thus 7.1 g. of 
N-Methyl-N-[1-methyl-2-(furyl-2)-ethyl]-N-2-bromo-propenyl amine are 
obtained. The product is dissolved in 100 ml. of ethanol and 14 ml. of an 
50% aqueous potassium hydroxide solution are added. The reaction mixture 
is refluxed for 16 hours, whereupon the ethanol is distilled off and the 
residue is admixed with water and extracted with benzene. The benzene 
solution is dried over anhydrous potassium carbonate and evaporated. The 
residue is distilled off in vacuo. Thus 4.9 g. of 
N-methyl-N-[1-methyl-2-(2-furyl)-ethyl]-propynyl amine are obtained. Bp.: 
114.degree.-115.degree. C./20 Hgmm; n.sub.D.sup.20 =1.4915. 
EXAMPLE 4 
12.5 g. (0.1 mole) of N-methyl-N-2-(2-furyl)-ethyl amine are reacted with 
10 g. (0.05 moles) of 1,2-dibromo-propene according to Example 3. Thus 7.6 
g. of N-methyl-N-[2-(2-furyl)-ethyl]-2-bromo-propenyl amine are obtained, 
which is reacted with 14 ml. of 50% aqueous potassium hydroxide in 100 ml. 
of ethanol under heating to boiling as described in Example 3. Thus 5.1 g. 
of N-methyl-N-[2-(2-furyl)-ethyl]-propynyl amine are obtained. Bp.: 
105.degree.-106.degree. C./20 Hgmm; n.sub.D.sup.20 =1.4890. The melting 
point of the hydrochloride amounts to 107.degree.-108.degree. C. (from a 
mixture of ethanol and ether). 
EXAMPLE 5 
12.4 g. (0.1 mole) of 2-furyl-acetone are dissolved in 100 ml. of ethanol, 
whereupon 7.25 g. (0.105 moles) of methyl-propinyl amine are added. 3.5 g. 
of aluminium foiles are degressed with ethanol and thereafter activated 
with a solution of 1 g. of mercuric chloride and 15 g. of sodium chloride 
in 30 ml. of water. The activating solution is decanted after 6-8 minutes 
and the activated aluminum foils are washed with cold water and added to 
the alcoholic solution previously prepared under stirring. An exothermic 
reaction takes place and the temperature is kept at 15.degree. to 
30.degree. C. by cooling. The reaction mixture is stirred for 24 hours, 
whereupon 30 ml. of 40% sodium hydroxide are added. The two phases are 
separated, the lower aqueous phase is extracted three-times with benzene. 
The benzene solutions are united with the previously separated alcoholic 
phase and evaporated. The residue consists of an organic oily layer and an 
aqueous phase which is extracted with benzene and the benzene solution is 
dried over potassium carbonate. The benzene is removed and the residue is 
distilled off in vacuo. Thus 6.7 g. of 
N-methyl-N-[1-methyl-2-(2-furyl)-ethyl]-propynyl amine are obtained. BP.: 
113.degree.-115.degree. C./20 Hgmm; n.sub.D.sup.20 =1.4905. 
EXAMPLE 6 
13.9 g. (0.1 mole) of N-methyl-N-[1-methyl-2-(2-furyl)-ethyl] amine and 7 
g. (0.184 moles) of propargyl aldehyde are reacted in 100 ml. of ethanol 
in the presence of 3.5 g. of aluminium foils as described in Example 5. 
Thus 6.1 g. of N-methyl-N-[1-methyl-2-(2-furyl)-ethyl]-propynyl amine are 
obtained. Bp.: 114.degree.-115.degree. C./20 Hgmm; n.sub.D.sup.20 =1.4910. 
EXAMPLE 7 
13.9 g. (0.1 mole) of N-methyl-N-[1-methyl-2-(2-furyl)-ethyl] amine are 
dissolved in 80 ml. of dioxane, whereupon 6 g. of paraformaldehyde and 1 
g. of cuprous chloride are added and gaseous acetylene is introduced into 
the solution at 80.degree. C. under stirring for 30 hours. The reaction 
mixture is filtered and the filtrate is evaporated. The residue is 
dissolved in benzene, the benzene solution is washed with water, dried 
over potassium carbonate and evaporated. The residue is distilled off in 
vacuo. Thus 6.8 g. of N-methyl-N-[1-methyl-2-(2-furyl)-ethyl]-propynyl 
amine are obtained. Bp.: 114.degree.-116.degree. C./20 Hgmm; 
n.sub.D.sup.20 =1.4910. 
EXAMPLE 8 
12.8 g. (0.1 mole) of 1-methyl-2-(2-furyl-ethyl)chloride and 15 g. (0.208 
moles) of methyl-propinyl amine are heated in a sealed bomb tube at 
70.degree. to 80.degree. C. for 4 hours. The reaction mixture is cooled, 
30 ml. of 40% sodium hydroxide are added and the mixture is extracted with 
benzene. The benzene solution is dried, evaporated and the residue is 
distilled off in vacuo. Thus 9.8 g. of 
N-methyl-N-[1-methyl-2-(2-furyl)-ethyl]-propynyl amine are obtained. Bp.: 
113.degree.-115.degree. C./20 Hgmm; n.sub.D.sup.20 =1.4904. 
EXAMPLE 9 
11.45 g. (0.1 mole) of 2-furyl-ethyl-chloride are reacted with 15 g. (0.208 
moles) of methyl-propinyl amine according to the method described in 
Example 8. Thus 8.8 g. of N-methyl-N-[2-(furyl-2)-ethyl]-propynyl amine 
are obtained. Bp.: 104.degree.-105.degree. C./20 Hgmm; n.sub.D.sup.20 
=1.4868.