Certain N-(.beta.-phenyl-.beta.-hydroxyethylamino)propiophenones as lipolysis promoters

Certain N-(.beta.-phenyl-.beta.-hydroxyethylamino)propiophenones promote lipolysis in swine.

DESCRIPTION OF THE INVENTION 
It has been found that lipolysis in swine is promoted by certain 
N-(.beta.-phenyl-.beta.-hydroxyethylamino)propiophenones, of the formula: 
##STR1## 
wherein n is zero, one or two, X is hydroxy, alkoxy of from one to four 
carbon atoms, chlorine or nitro, and R and R.sup.1 each is hydrogen or 
methyl, and their physiologically acceptable acid addition salts. 
Preferred of this genus of compounds is the subgenus wherein n is zero or 
one, X is hydroxy or methoxy and both of R and R.sup.1 are hydrogen. 
Suitable salts are those of such acids as acetic, succinic, maleic, 
fumaric, propionic, citric, lactic, hydrochloric, sulfuric and phosphoric 
acids. 
Included in the invention are the individual optically active isomers, and 
diastereomers, as well as mixtures thereof, that promote lipolysis. 
The compounds of Formula I are known: they, and methods for their 
preparation, are described in U.S. Pat. No. 3,644,525. 
The compounds of Formula I have been found to promote--i.e., 
stimulate--lipolysis in swine tissue. The manner in which they cause this 
effect has not been established. Their effectiveness for this purpose has 
been ascertained by the following procedure. 
A mixture of (a) 150 milligrams of slices of pig adipose tissue, 
approximately 0.3 millimeter thick, (b) 3 milliliters of a Krebs-Ringer 
bicarbonate solution, pH=7.4, containing one-half the usual calcium ion 
concentration, 4% fatty acid-free bovine serum albumin, 6.6 milligrams of 
L-ascorbic acid per milliliter, 2 milligrams of glucose per milliliter, 
and (c) sufficient of a solution or suspension of the test compound in 
dimethyl sulfoxide (DMSO), so that the final DMSO concentration in the 
mixture was 5%, and the test compound was present at a concentration of 
one microgram per milliliter of the mixture was incubated for 90 minutes 
at 37.degree. C. Two replicates, taken from the tissue of one pig, were 
tested. The rate of lipolysis was determined by titration of the fatty 
acids that had been released to the medium: the tissue was removed by 
filtration through cheesecloth; to 0.5 milliliter of the filtrate was 
added 0.5 milliliter of 0.9% sodium chloride solution and 5 milliliters of 
a solution consisting of (by volume) 40 parts of isopropanol, 10 parts of 
heptane and 1 part of 1 N sulfuric acid. The mixture was allowed to stand 
for 5 minutes at room temperature. Then 3 milliliters of heptane and 2 
milliliters of water were added. The mixture was shaken for 10 minutes, 
then was held until the liquid phases separated. Duplicate 1.5 milliliter 
aliquots of the upper phase were titrated with tetra N-butyl ammonium 
hydroxide, using 0.5 milliliter of methanolic Phenol Red as indicator. The 
basal rate of lipolysis (no test compound present) was subtracted. Test 
compound activity was expressed as the percent of maximal activity, 
estimated for each test as the activity in the presence of 16 micromolar 
epinephrine (L-epinephrine bitartrate). Each test compound was 
independently evaluated twice using tissue from two different pigs, and 
the percent of maximal activity indicated is the average of the two 
experiments.

The hydrochloride salts of the following individual species of the 
compounds of Formula I were tested. (For simplification, the species are 
characterized in terms of Formula I, the number preceding the moiety, X, 
indicating its position on the ring.): 
______________________________________ 
Compound 
No. n X R R.sup.1 
______________________________________ 
1 1 4-(CH.sub.3 O--) 
H H 
2 1 2-(HO--) H H 
3 0 -- H H 
______________________________________ 
The results are reported in the following table: 
______________________________________ 
Compound Percent 
No. Stimulation 
______________________________________ 
1 95 
2 102 
3 92 
______________________________________ 
The compounds of Formula I can be used to promote lipolysis in swine by 
administering an effective amount of one or a mixture of two or more of 
the compounds orally or parenterally to the animal. They may be 
administered as such, or as an active ingredient of a conventional 
pharmaceutical formulation. They may be administered orally by any 
convenient means. Thus, they may be orally administered as a drench, by 
intubation, in the animal's food and water, in a food supplement or in a 
formulation expressly designed for administration of the drug. Suitable 
formulations include solutions, suspensions, dispersions, emulsions, 
tablets, boluses, powders, granules, capsules, syrups and elixirs. For 
parenteral administration, they may be in the form of a solution, 
suspension, dispersion or emulsion. They can be administered in the form 
of an implant or other controlled sustained release formulation. Inert 
carriers, such as one or more of water, edible oil, gelatin, lactose, 
starch, magnesium stearate, talc or vegetable gum can be used. The dosage 
of the compound needed to promote lipolysis will depend upon the 
particular compound used, and the particular animal being treated. 
However, in general, satisfactory results are obtained when the compounds 
are administered in a dosage of from about 1 to about 500 milligrams per 
kilogram of the animal's body weight. The compound can be administered in 
a single dose or in a series of doses in the same day, or over a period of 
days. For any particular animal, a specific dosage regimen should be 
adjusted according to the individual need, the particular compound(s) used 
as the promoters and the professional judgment of the person administering 
or supervising the administration of the promoter. It is to be understood 
that the dosages set forth herein are exemplary only, and that they do 
not, to any extent, limit the scope or practice of the invention.