| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | May 20, 1997 |
| PATENT TITLE |
Growth promotion |
| PATENT ABSTRACT | beta.-Phenethanolamines are effective in promoting growth and improving feed efficiency and leanness in animals |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | May 25, 1995 |
| PATENT REFERENCES CITED |
Dijk, et al., Recueil 92, pp. 1281-1297 (1973). Fed. Proc. 42 #3 (1983). Fed. Proc. 42 #4 (1983). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A composition useful for treating a domesticated warm blooded animal to promote growth, improve feed efficiency, or improve leanness, which comprises both of (1) a first compound having the formula ##STR4## wherein: R.sup.1 is hydrogen, hydroxy, or methoxy; R.sup.2 is hydrogen or fluoro; R.sup.3 is hydrogen or C.sub.1 -C.sub.2 alkyl; R.sup.4 is hydrogen or methyl; R.sup.5 is hydrogen, fluoro, nitro, hydroxy, SO.sub.2 CH.sub.3 or CONH.sub.2 ; provided that R.sup.1 is hydrogen only when R.sup.5 is nitro or SO.sub.2 CH.sub.3, or an acid addition salt thereof; and (2) a second compound which is a tetracycline, tylosin, penicillin, cephalosporin, polyether, glycopeptide, or orthosomycin, in a ratio of about 1 to about 2 parts by weight of the first compound and about 1 to about 10 parts by weight of the second compound. 2. The composition of claim 1 wherein the first compound is 1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)propylamino)ethanol or an acid addition salt thereof. 3. The composition of claim 2 where the second compound is tylosin. 4. The composition of claim 2 wherein the second compound is a polyether. 5. A method for treating a domesticated warm blooded animal to promote growth, improve feed efficiency, or improve leanness, which comprises administering to the animal both of (1) a first compound having the formula ##STR5## wherein: R.sup.1 is hydrogen, hydroxy, or methoxy; R.sup.2 is hydrogen or fluoro; R.sup.3 is hydrogen or C.sub.1 -C.sub.2 alkyl; R.sup.4 is hydrogen or methyl; R.sup.5 is hydrogen, fluoro, nitro, hydroxy, SO.sub.2 CH.sub.3 or CONH.sub.2 ; provided that R.sup.1 is hydrogen only when R.sup.5 is nitro or SO.sub.2 CH.sub.3, or an acid addition salt thereof; and (2) a second compound which is a tetracycline, tylosin, penicillin, cephalosporin, polyether, glycopeptide, or orthosomycin, in amounts which in combination are effective. 6. The method of claim 5 wherein the first compound is 1-(4-hydroxyphenyl)-2-(1-methyl-3-(4-hydroxyphenyl)-propylamino)ethanol or an acid addition salt thereof. 7. The method of claim 6 wherein the second compound is tylosin. 8. The method of claim 6 wherein the second compound is a polyether. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION The chemistry and use of .beta.-phenethanolamines has been extensively investigated. A number of these compounds have been reported to have beneficial cardiac activities; see U.S. Pat. No. 3,987,200. Such compounds also are known to have sympathomimetic activity, and have found utility as utero-relaxing agents; Van Dijk et al., Recueil, 92, 1281 (1973). More recently, a group of .beta.-phenethanolamines have been reported as possessing anti-hyperglycemic activity, and have been found effective in promoting the loss of weight in animals, EPO 6735 published Jan. 9, 1980. An object of this invention is to provide a new use for certain .beta.-phenethanolamines. This invention provides a method for promoting the growth of domesticated animals employing .beta.-phenethanolamines. SUMMARY OF THE INVENTION This invention provides a method for increasing weight gain in animals and improving the efficiency of feed utilization and the quality of the carcass. The invention is more particularly directed to a method for promoting growth and improving feed efficiency and leanness comprising administering an effective amount of a compound having the formula ##STR1## wherein: R.sup.1 is hydrogen, hydroxy, or methoxy; R.sup.2 is hydrogen or fluoro, R.sup.3 is hydrogen or C.sub.1 -C.sub.2 alkyl; R.sub.4 is hydrogen or methyl; R.sup.5 is hydrogen, fluoro, nitro, hydroxy, SO.sub.2 CH.sub.3 or CONH.sub.2 ; provided that R.sup.1 is hydrogen only when R.sup.5 is nitro or SO.sub.2 CH.sub.3 ; and the acid addition salts thereof. A preferred method for promoting growth and improving feed efficiency and leanness according to this invention employs a compound of the above formula wherein R.sup.1 is hydroxy, R.sup.2 is hydrogen, R.sup.3 is hydrogen or methyl and R.sup.4 is methyl. The method is most preferably practiced employing a compound wherein R.sup.1 and R.sup.5 both are hydroxy and R.sup.2 and R.sup.3 both are hydrogen and R.sup.4 is methyl. When R.sup.1 is hydroxy or methoxy, it preferably is in the para position. When R.sup.5 is other than hydrogen, it also is preferably in the para position. This invention also provides an animal feed-stuff comprising a .beta.-phenethanolamine of the above formula together with a suitable carrier therefor. DETAILED DESCRIPTION OF THE INVENTION The compounds employed in the method provided by this invention are either known in the art or are readily prepared by well known synthetic procedures. A particularly preferred method employs 1-(3-hydroxy-phenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]-ethanol. This .beta.-phenethanolamine is disclosed in South African Patent No. 673,994 published in May, 1967. The most preferred embodiment of this invention employs 1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)-propylamino]ethanol, a compound disclosed as having utero-relaxing activity by Van Dijk et al. in Recueil, 92 1281 (1973). The compounds to be employed in the method of this invention are readily prepared by reaction of a styrene oxide with a 3-phenylpropylamine derivative. For example, a styrene oxide such as 2-fluorostyrene oxide can be reacted with about an equimolar quantity of an amine such as 1-methyl-3-(4-nitrophenyl)propyl-amine in an unreactive organic solvent such as ethanol, methanol, 5-propanol, dioxane, or the like. The reaction generally is carried out at a temperature of about 50.degree. to about 120.degree. C., and at such temperature the reaction routinely is substantially complete within about 6 to about 10 hours. The product, a .beta.-phenethanolamine, is readily isolated by simply removing the reaction solvent, for instance by evaporation under reduced pressure, and further purification can be accomplished if desired by standard techniques, including crystallization, chromatography, acid-base extraction, and the like. An alternative method for preparing the .beta.-phenethanolamines to be employed in the present method comprises reacting a mandelic acid derivative with a 3-phenylpropylamine derivative to provide an amide, which upon subsequent reduction provides a compound of the above formula. For example, a phenylpropylamine derivative such as 1-methyl-3-(3-fluorophenyl)propylamine can be reacted with an acylating agent such as a hydroxy protected mandelic acid halide, or preferably simply reacted with a mandelic acid in the presence of a common peptide coupling reagent such as N,N'-di-cyclohexylcarbodiimide, carbonyldiimidazole, N-ethoxy-carbonyl-2-ethoxy-1,2-dihydroquinoline, commonly referred to as EEDQ. The direct coupling reaction generally is conducted in an organic solvent such as benzene or N,N-dimethylformamide, and normally is complete after about 2 to 48 hours when carried out at about -30.degree. to about 100.degree. C. The product is an amide that is readily isolated by simply filtering the reaction mixture and then removing the reaction solvent. The amide thus formed is next reduced by reaction with a common reducing agent such as diborane or the like to provide a .beta.-phenethanolamine defined by the above formula. A similar, yet alternative method of synthesis comprises reacting a phenethanolamine with a phenylethyl ketone to provide a Schiff base, which upon reduction gives a compound to be employed in the present method. For example, a phenethanolamine such as 2-hydroxy-2-(4-hydroxyphenyl)ethylamine can be reacted with a ketone such as methyl 2-(4-hydroxyphenyl)ethyl ketone to provide the corresponding imine, which upon reduction, for instance with 5% palladium on carbon, provides 1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propylamino]ethanol. It should be noted that the compounds to be employed in the method of this invention possess at least one asymmetric center (i.e. the carbinol center), and when R.sup.3 and R.sup.4 differ, the compounds possess two asymmetric centers. Since employment of individual optical isomers necessitates preparing the 6-phenethanolamines from optically active starting materials, or using costly separation procedures, a preferred embodiment of this invention employs a mixture of optical isomers. For example, 1-(4-hydroxyphenyl)-2-[1-methyl-3-(4-hydroxyphenyl)propytamino]ethanol is preferably prepared from racemic mixtures of starting materials, e.g. dl-1-methyl-3-(4-hydroxyphenyl)propyl-amine and dl-4-hydroxystyrene oxide, to provide a mixture of all four possible optical isomers of the product. The mixture of optical isomers is employed in the method without subsequent separation of isomers. Since the .beta.-phenethanolamines to be employed in the present method are inherently basic, they readily form acid addition salts with any number of inorganic and organic acids. These salts can be employed in the method of the invention, and often are preferred to the free base since they generally are more soluble in solvents such as water and are more conveniently formulated as an animal feedstuff. Acids commonly employed to form acid addition salts include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric acid, perchloric acid and the like; and organic acids such as acetic acid, citric acid, succinic acid, para-toluene sulfonic acid, methanesulfonic acid, lactic acid and the like. Preferred salts to be employed in the present method include the hydrochlorides and hydrobromides. Typical .beta.-phenethanolamines to be employed in the method of this invention include the following: 1-(3-hydroxyphenyl)-2-[1-methyl-1-ethyl-3-(4-aminocarbonylphenyl) propylamino]ethanol; 1-(2-fluoro-4-hydroxyphenyl)-2-[1-methyl -3-(4-fluorophenyl) propylamino]ethanol; 1-(4-hydroxyphenyl)-2-[3-(3-nitrophenyl) propylamino]ethanol; 1-(3-hydroxy-2-fluorophenyl) -2-[3-(4-methyl-sulfonyl) propylamino]ethanol; 1-(4-methoxyphenyl) -2-[1-methyl-3-(4-hydroxyphenyl) propylamino]ethanol; 1-phenyl-2-[1,1-dimethyl-3-(3-methylsulfonylphenyl) propyl amino]ethanol; 1-(4-hydroxyphenyl)-2-[1,1-dimethyl-3-(4-hydroxyphenyl) propylamino]ethanol hydrochloride; 1-(phenyl)-2-[1-methyl-3-(4-nitrophenyl)-propylamino]ethanol; 1-(3-hydroxyphenyl)-2-[1-methyl-3-(4-fluorophenyl) propylamino]ethanol succinate; 1-(4-hydroxyphenyl)-2-[1-methyl-1-ethyl-3-(4-aminocarbonylphenyl) propylamino]ethanol; 1-(4-hydroxyphenyl)-2-[1,1-dimethyl-3-phenyl-propylamino]ethanol hydrobromide; and d-1-(4-hydroxyphenyl) -2-[1,1-dimethyl-3-(4-hydroxyphenyl)propylamino]ethanol. The method of promoting growth and improving leanness and feed efficiency provided by this invention is practiced by administering an effective amount of a compound defined above to a warm-blooded animal that receives a nutritionally adequate diet. The method generally will be practiced on domesticated animals raised for human meat consumption, for example grower/finisher swine, poultry, ruminants and the like. In a preferred embodiment, the growth of pigs, chickens and turkeys is promoted employing a .beta.-phenethanolamine. Another preferred embodiment is practiced in ruminants such as cattle, sheep and goats. The method of improving leanness is not limited to meat producing animals, and can be practiced on other warm-blooded animals, including dogs and cats. This latter embodiment is particularly useful when it is desired to maintain mature animals in a relatively lean physical state. The method of the invention is preferably practiced by orally administering an effective amount of a .beta.-phenethanolamine to an animal. Other routes of administration can be employed, for instance intra-muscular or intravenious injection; however, such routes are less practical. The amount to be administered to an animal is an amount that is effective in causing a promotion of growth, or an improvement in the efficiency of utilization of food, or an improvement in carcass quality of the animal, for instance in the form of less fatty tissue and improved leanness. The effective amount to be administered will vary somewhat depending upon the particular animal species being treated and the particular active ingredient employed, but generally will be from about 1 to about 1000 parts per million (ppm) of total daily feed intake. Such amount will provide a dosage of about 0.05 to about 50 mg/kg. A preferred embodiment employs about 1 to about 200 ppm, and more preferably from about 5 to about 100 ppm. A typical amount of active ingredient to be administered to swine will be from about 5 to about 40 ppm. For example, when practicing the method in animals such as ruminants or swine, the compound will be added to the daily feed ration at about 5 to about 100 parts per million of the daily feed ration. For oral administration, the active .beta.-phenethanolamine is preferably admixed with suitable carriers or diluents commonly employed in animal husbandry. Animal feedstuffs comprising a .beta.-phenethanolamine growth promoter as defined herein are provided as a further embodiment of this invention. Typical carriers and diluents commonly employed in such feedstuffs include corn meal, soybean meal, alfalfa meal, rice hulls, soybean mill run, cottonseed oil meal, bone meal, ground corn, corncob meal, sodium chloride, urea, cane molasses and the like. Such carriers promote a uniform distribution of the active ingredient in the finished feed ration into which such compositions are added, thereby ensuring proper distribution of the active ingredient throughout the feed. The feedstuff composition provided by the invention will contain about 5 to about 95 percent by weight of active ingredient, and more typically about 10 to about 50 percent by weight. As already noted, the acid addition salts of the active phenethanolamines are generally preferred for oral administration, and are thus the preferred form of active ingredient for the feedstuff compositions of the invention. While the preferred method for orally administering the growth promoters is via the daily feed rations, the compounds can be incorporated into salt blocks and mineral licks, as well as being added directly to drinking water for convenient oral consumption. The compounds can additionally be formulated with polymorphous materials, waxes and the like for long-term controlled release, and administered to an animal as a bolus or tablet only as needed to maintain the desired daily payout of active ingredient. For parenteral administration, the .beta.-phenethanolamines can be admixed with conventional carriers such as corn oil, sesame oil, carbowax, calcium stearate and the like. Such formulations can be molded into pellets and administered as an injection or as a slow-release subcutaneous implant. Such administrations can be made as often as needed to ensure the proper dosing of active ingredient to obtain the desired rate of growth promotion and improvement in leanness and feed efficiency. While the compounds described herein are effective in promoting average daily weight gain and improving feed efficiency in animals, they also cause observable improvement in the quality of the meat produced. For example, the compounds appear to mobilize free fatty acids from fatty tissue and depress the deposition of fat as the animals gain weight. This reduction of fat is beneficial since the animal being treated according to the invention gains weight in the form of more useable lean meat, thereby reducing waste and improving the value of the animal thus treated. Also, mature animals that are not subject to additional weight gain can be maintained in a desirably lean form by administering a compound as described herein. The practice of the present invention is more fully illustrated by the following detailed examples. |
| PATENT EXAMPLES | available on request |
| PATENT PHOTOCOPY | available on request |
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