[p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]-ethyl]phenoxy]acetic acid and its physiologically compatible salts, which have catabolic activity and can be used for the treatment of obesity, of diabetes and of conditions which are associated with increased protein breakdown or as feed additives for fattening animals, as described. The compounds are prepared starting from esters corresponding to the aforementioned acid.

BRIEF DESCRIPTION OF THE INVENTION 
The invention relates to phenoxypropanolamines, a process for their 
preparation and pharmaceutical compositions based on-the referred to 
compounds, as well as the use of the compounds in the control or 
prevention of illnesses. 
The phenoxypropanolamines are 
[p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]acetic acid 
(referred to hereinafter a HPA) and its physiologically compatible salts. 
DETAILED DESCRIPTION OF THE INVENTION 
The invention relates to phenoxypropanolamines, a process for their 
preparation and pharmaceutical compositions based on the referred to 
compounds, as well as the use of the compounds in the control or 
prevention of illnesses. 
The phenoxypropanolamines are 
[p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]acetic acid 
(referred to hereinafter a HPA) and its physiologically compatible or 
pharmaceutically acceptable salts. Examples of such salts are alkali 
metal, alkaline earth metal, ammonium and alkylammonium salts, such as, 
Na, K, Ca, trimethylammonium and ethanolammonium salts as well as salts of 
HPA with mineral acids, such as, hydrochloric acid, hydrobromic acid, 
sulfuric acid or phosphoric acid or with organic acids, such as, oxalic 
acid, methanesulfonic acid, acetic acid, propionic acid, citric acid, 
maleic acid, succinic acid, malic acid fumaric acid phenylacetic acid or 
salicylic acid. HPA hydrochloride is preferred. 
The phenoxypropanolamines can be prepared by cleaving an ester 
corresponding to the 
[p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]acetic acid and, 
if desired, converting the acid obtained into a salt. 
As esters there come into consideration for example, lower-alkyl esters or 
the benzyl ester of HPA. The lower-alkyl esters can be cleaved by 
saponification under acidic or basic conditions for example, with a strong 
acid, such as, hydrochloric acid, sulfuric acid or phosphoric acid, 
conveniently at a temperature between 20.degree. and 110.degree. C., in a 
polar solvent, such as, water, a C.sub.1-4 -alkanol, for example, methanol 
or ethanol; or with a base, such as, sodium or potassium hydroxide, 
conveniently at a temperature between 10.degree. and 110.degree. in a 
suitable solvent, such as, a C.sub.1-4 -alkanol. The benzyl ester of HPA 
can be cleaved by catalytic hydrogenation. Conveniently, the HPA can be 
isolated from the reaction mixture in the form of a salt. The free HPA can 
be isolated by extraction from the aqueous reaction medium with an organic 
solvent, such as, methylene chloride or chloroform, at pH 6 to 7. 
The ester starting material can be prepared in a known manner, for example, 
starting from (S)-phenyl glycidyl ether and tyramine via 
p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol and reacting this 
phenol with a lower alkyl haloacetate, such as, methyl bromoacetate. The 
latter reaction can be carried out for example, in a solvent, such as, 
dimethyl sulfoxide in the presence of a base, such as, potassium 
t-butylate at a temperature up to the reflux temperature of the reaction 
mixture. Alternatively, the ester starting material can be prepared by 
reacting (S)-phenyl glycidyl ether with a lower-alkyl 
p-[2-aminoethyl]phenoxyacetate. 
The compounds in accordance with the invention can be used as active 
substances in pharmaceutical preparations for the treatment of obesity 
and/or of diabetes mellitus, especially of obese adult diabetics. In an 
animal experiment, an increased catabolism, primarily of fat, has been 
observed upon the administration of the compounds of the invention. 
Furthermore, it has been observed that the compounds of the invention 
stimulate the formation of brown adipose tissue in rats and 
obese-hyperglycemic mice. It is known that defects of the brown adipose 
tissue play a substantial role in the origin of obesity. In 
obese-hyperglycemic mice and in streptozotocin-diabetic rats, the 
compounds of the invention have a pronounced anti-diabetic effect, that 
is, they have hypoglycemic activity and reduce glycosuria. The compounds 
of the invention exhibit only a slight activity on the working of the 
heart and circulation. The dosage can amount to 0.5-1000 mg, preferably 
2-200 mg, per day for an adult depending on the strength of activity of 
the individual compounds and on the individual requirements of the 
patients, whereby the dosage can be administered as a single dose or in 
several divided doses over the day. 
In addition, in an animal experiment utilizing the compounds of the 
invention, an increase in the protein content of the body and a decrease 
in the fat content of the body could be detected. The compounds in 
accordance with the invention therefore lead to an increase in the lean 
composition of the body at the expense of fat. Accordingly, the compounds 
of the invention can be used in human medicine for the treatment of 
conditions which are associated with an increased protein breakdown, for 
example, in convalescence after operations. In latter case, the dosages 
administered are the same as in the case of the treatment of obesity 
and/or diabetes mellitus. 
The compounds of the invention can also be used in the maintenance of 
fattening animals, such as, beef cattle, pigs, sheep and poultry. In this 
case, the dosage administered and the dosage forms administered can be the 
same as in the case of vitamins. The compounds of the invention can also 
be used as feed additives in dosages of 0.01-100 mg/kg depending on the 
substance, kind of animal and age. 
The pharmaceutical compositions contain the active substance together with 
a compatible pharmaceutical organic or inorganic carrier material, for 
example, water, gelatin, gum arabic, lactose, starch, magnesium stearate, 
talc, vegetable oils, polyalkylene glycols and the like. The 
pharmaceutical compositions are preferably administered orally, for 
example, in the form of tablets, capsules, pills, powders, granulates, 
solutions, syrups, suspensions, elixirs and the like. The administration 
can, however, also be carried out parenterally, for example, in the form 
of sterile solutions, suspensions or emulsions The pharmaceutical 
compositions can be sterilized and/or can contain ingredients, such as, 
preserving agents. stabilizers, wetting agents, emulsifiers, salts for 
varying the osmotic pressure and buffer substances. 
The activity of the compounds of the invention is demonstrated and evident 
from the test results which follow: 
ACTIVITY ON OXYGEN CONSUMPTION 
Male albino rats weighing 160-180 g were placed in metabolic cages after 
fasting for 24 hours. The cages were ventilated with a constant 6 liters 
room air/minute which was equilibrated at a dew point of 11.degree. C. 
Samples of the spent air were collected in each case during periods of 14 
minutes after again equilibrating and the oxygen content and CO.sub.2 
content were analyzed. After an adaptation time of 4 hours, the animals, 
divided into groups of 6, received either placebo (5% gum arabic) or the 
test substance, namely HPA hydrochloride (suspended in 5% gum arabic), per 
oz. Thereafter, the determinations were carried out for a period of 12 
hours. In the following Table there is given the percentage of the average 
oxygen consumption after medication during the first 3 hours and the 
entire test duration (12 hours) of the oxygen consumption of the 
adaptation period, corresponding corrections for variations in the placebo 
group having been taken into consideration. 
TABLE 
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Oxygen consumption 
Dosage (% of the value of the pre-period) 
(.mu.M/kg) 1st to 3rd hour 
1st to 12th hour 
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0.03 114 105 
0.1 132 105 
0.3 152 117 
1 169 129 
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A slight chronotropic effect (tachycardia) occurred only in the case of the 
administration of about 100 .mu.M/kg.

The following Examples illustrate further the invention. 
EXAMPLE 1 
1.90 g of methyl 
[p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]acetate were 
heated to 50.degree. C. for 90 minutes with 80 ml of 5% methanolic 
potassium hydroxide and 80 ml of water. The reaction solution was cooled, 
poured on to ice-water and extracted with ether. The aqueous-alkaline 
phase was acidified to pH 2 with concentrated hydrochloric acid and 
evaporated to dryness in a vacuum at 40.degree. C. The residue was 
evaporated with toluene in a vacuum. The residue was triturated with 150 
ml of a mixture of ethanol-methanol 2:1. The precipitate was removed by 
filtration and the filtrate was evaporated in a vacuum. The residue was 
dissolved in 20 ml of methanol and treated with 20 ml of ether, whereby 
1.5 g of [p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]acetic 
acid hydrochloride crystallized, melting point 194.degree.-196.degree. C. 
(dec.), [.alpha.].sub.D.sup.20.degree. =-18.degree. (c=0.5 in methanol). 
The starting material was prepared as follows: Reaction of S-phenyl 
glycidyl ether with tyramine gave 
p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenol of m.p. 
118.degree.-119.degree. C. This was reacted with methyl bromoacetate and 
potassium t-butylate in dimethylsulfoxide at room temperature to give 
amorphous methyl 
[p-[2-[[(S)-2-hydroxy-3-phenoxypropyl]amino]ethyl]phenoxy]acetate. This 
was crystallized from acetone as the hydrochloride of m.p. 
167.degree.-168.degree. C., [.alpha.].sub.D.sup.20.degree. =-16.degree. 
(c=1.0 in methanol). 
EXAMPLE 2 
382 mg of HPA hydrochloride were dissolved in 16 ml of ethanol and 4 ml of 
methanol and treated with 80 mg of sodium hydroxide. The solution was 
stored in a refrigerator for 1 hour, whereby there were obtained 270 mg of 
HPA sodium salt, melting point 200.degree.-201.degree. C., 
[.alpha.].sub.D.sup.20.degree. =-4.5.degree. (c=0.5 in methanol). 
EXAMPLE 3 
382 mg of HPA hydrochloride were dissolved in 5 ml of hot methanol, treated 
with 40 mg of sodium hydroxide and cooled. The separated sodium chloride 
was removed by filtration and the filtrate was treated with 130 mg of 
maleic acid. 15 ml of ether were then added thereto and the mixture was 
left to crystallize in a refrigerator. There were obtained 300 mg of HPA 
maleate of melting point 163.degree.-166.degree. C., 
[.alpha.].sub.D.sup.20.degree. =-15.degree. (c=0 6 in methanol). 
EXAMPLE 4 
Tablets of the following composition are prepared in the usual manner: 
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[p-[2[[(S)-2-Hydroxy-3-phenoxypropyl]amino]- 
250 mg 
ethyl]phenoxy]acetic acid hydrochloride 
Lactose 200 mg 
Maize starch 300 mg 
Maize starch paste 50 mg 
Calcium stearate 5 mg 
Dicalcium phosphate 45 mg 
850 mg 
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