Stimulant

The present invention relates to pharmaceutical and veterinary compositions for use as sex stimulants for mammals which comprise an active ingredient phenylethylamine substituted in the ortho or in the meta position by a methoxy group, a methylthio group, by a chlorine atom or by a bromine atom, as well as salts and complexes of these compounds. The invention further relates to the ortho- and meta- methoxyphenylethylamine and methylthiophenylethylamine compounds and to their salts and complexes as novel compounds.

FIELD OF THE INVENTION 
The invention relates to novel pharmaceutical compositions which are sex 
stimulants for mammals. This term includes both humans and animals, and 
more specifically domesticated mammals. Furthermore, the invention relates 
to certain novel compounds which are of use as active ingredients in such 
compositions, and to the preparation of these. Further aspects of the 
invention will become apparent hereinafter. 
BACKGROUND OF THE INVENTION 
It has been reported (Res. Comm. Psychol. Psychiat. Behav. 2, 161, 1977) 
that p-methoxyphenylethylamine is effective as sex stimulant when 
administered to mammals. The administration was during 2 days in large 
doses, or over a period of two weeks in smaller doses. 
p-Methoxyphenylethylamine is not suitable for use with humans as it 
results in changes of the blood pressure. It has been found that when 
administered i.v. to cats at 0.2 mg/kg, an increase of blood pressure 
results, while chronic oral administration of 50 mg/kg has a hypotensive 
effect on uninephrectomized DOCA-saline treated rats. The method used is 
described in Experientia 33, 1430, 1977. 
The method for quantifying sexual stimulation in female rats was described 
in Res. Comm. Psychol. Psychiat. Behav. 3, 359, 1978. 
SUMMARY OF THE INVENTION 
According to the present invention there are provided pharmaceutical and 
veterinary compositions for use as sex stimulants in male and female 
mammals comprising as active ingredient a compound of the general formula 
##STR1## 
where X designates --OCH.sub.3.--SCH.sub.3 or a halogen, the substituent 
being either in ortho or in meta position, as well as the salts and 
complexes of these. The term halogen in this context designates chlorine 
or bromine. 
The present invention further relates to the compounds defined above, 
wherein X is --SCH.sub.3, both in the ortho and in the meta position, 
which are novel per se, and to the preparation of these. 
The compounds wherein X is methoxy are known compounds, and these were 
prepared as described in literature. Their physical data are: 
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o-Methoxyphenylethylamine.HCl 
M.P. = 138-140.degree. C. 
m-Methoxyphenylethylamine.HCl 
M.P. = 134-141.degree. C. 
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The novel thiophenyl derivatives were prepared as follows: 
EXAMPLE 1: Preparation of o-Methylthiophenylethylamine.HCl 
The compound was prepared according to the following reaction scheme: 
##STR2## 
13 g of compound I (Christiaens et al. Bull. Soc. Chim. Belges. 79, 1970, 
235-243) dissolved in 50 cc THF was added to a stirred suspension of 5.0 g 
LiAlH.sub.4 so as to maintain a gentle reflux. After stirring over-night 
at room temperature, the mixture was cooled on an ice bath and water was 
slowly added, followed by a 20% NaOH solution. The insoluble salts were 
filtered off, and washed with two portions of ether. The combined 
filtrates were washed with water and dried over magnesium sulfate. After 
filtration gaseous HCl was bubbed through for 3 minutes and the resulting 
yellowish crystals were collected and washed with a little 
dichloromethane. 
Yield: (HCl) 5.5 g. M.P.=165.degree. C.-167.degree. C. (decomp.) 
EXAMPLE 2: Preparation of m-Methylthiophenylethylamine 
This compound was prepared in a manner corresponding to that of Example 1. 
Elemental analysis of the hydrochloride salt confirms its composition. 
EXAMPLE 3: Preparation of ortho-and meta-halogen substituted compounds 
These compounds were prepared as described in J.Med.Pharm.Chem. 5, 793 
(1962). The orth-chloro, meta-chloro, ortho-bromo and meta-bromo compounds 
were tested on animals and all of these were found to be effective sex 
stimulants. 
Results of Animal Tests: 
Typical results are presented in Table 1 which demonstrates the drastic 
difference between the ortho- and the meta-derivatives versus the 
para-derivative. 
The compounds of the present invention have no adverse side effect on the 
blood pressure of rats on oral administration. The compounds were tested 
on DOCA-saline treated rats and, even at 50 mg/kg per day for a week, no 
effect on blood pressure was observed. 
The compounds can be used as such, or in the form of physiologically 
acceptable salts or complexes. The pharmaceutical composition can be 
administered in the form of sustained release preparations or as implants. 
Preliminary tests with human volunteers have shown that the pharmaceutical 
compositions of the present invention exert a pronounced effect on human 
males. Tests have shown that o-methoxy- and o-methylthiophenylethylamine 
are effective in dosages of 35 to 50 mg when given per os as the 
hydrochloride salt. A preferred dose is in the range of from 5 to 10 mg, a 
number of times per day. The drug is advantageously administered per os in 
the form of capsules. The effect is obtained after a few hours to a few 
days. 
There may be used the free base, any pharmaceutically acceptable salt or 
complex. 
TABLE 1 
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Effect of Sustained Administration of Methoxy- and Methylthiophenylethylam 
ines* 
on the Sexual Behavior of Rats 
Minimal effective 
Male Female 
oral dose 
mountings/animal 
lordosis/mount 
Treatment mg/kg/day 
in first 15 minutes 
coefficient 
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Control -- 1 .+-. 1 
0.1 .+-. 0.03 
o-Methoxyphenylethylamine 
0.25 20 .+-. 4 
0.5 .+-. 0.05 
o-Methylthiophenylethylamine 
0.25 25 .+-. 5 
0.5 .+-. 0.05 
m-Methoxyphenylethylamine 
1.00 20 .+-. 4 
0.5 .+-. 0.05 
m-Methylthiophenylethylamine 
1.00 20 .+-. 4 
0.5 .+-. 0.05 
p-Methoxyphenylethylamine 
10.00 10 .+-. 2 
0.3 .+-. 0.05 
p-Methylthiophenylethylamine 
10.00 10 .+-. 3 
0.3 .+-. 0.05 
o-Chloro-phenylethylamine 
10.00 10 .+-. 2 
0.3 .+-. 0.05 
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*as hydrochloride salts