IE56844B1 - Phenethanolamine derivatives in weight control in animals - Google Patents

Description

This invention relates to phenethanolamine derivatives in weight control in animals.

The chemist ry and use oi ^-phen&th&nol&mines has been extensively investigated. European Patent Specification Ho. 6p7a6 describes the use of phenethanolamine derivatives in promoting the loss of weight in animals.

This invention provides a method for increasing weight gain in domestic animals and improving the efficiency of feed utilisation fend the quality of the carcass. The invention is more particularly directed to a method for promoting growth, improving feed efficiency or leanness comprising administering a cos^ound having the toraula (ϊ) 0H CH.

HO OH (X) Our Patent discloses or an acid addition salt thereof.

Specification No. λ ///< c, the use of related compounds.

This invention also provides an animal feed 20 premix comprising a β-phenethanolamine of the above formula together with a suitable carrier therefor.

The compound of formula (I) is disclosed as having utero-relasting activity by Van Dijk et al. in Recueil, 92 1281 (1973>.

The compound of formula (X) can be prepared by reaction of a styrene oxide with & 3-pheny Ipropylamine derivative.

An alternative method for preparing the 0^phenethanolamine comprises reacting a mandelic acid derivative with a 3-pheny Ipropy lamine derivative to provide an eamidetf which upon subsequent reduction compound of the &bove formula * A similar, yet alternative, method of synthesis comprises reacting a phenethaaoXamiae with a phenyl Thus, 2»bydroxy2-(4-hydroKyphuyX)$thylemino 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 5¾ palladium on carbon, provides 1- (4-hydroxyphenyl) -2® (l-methyi-3- (4~hydro2cy~ phenyl) propy lamino) ethanol.

Xt should be noted that the compounds to be employed in this invention possess two asymmetric centers ® Since employment of individual optical isomsrs necessitates preparing the e-pheMthanolamines from optically active starting materials, or using costly separation procedures, a preferred embodiment of this invention for veterinary purposes (employs a mixture of optical isomers<. Thus, 1- (4-hydroxyphenyl )-2-( 1-methy I® 3- (4-hydroxyphenyl) propyXamino)ethanol is preferably prepared from racemic- mixtures of starting materials, e.go dl-l-methy 1-=3-(4-hydroxyphenyl>propylamine and dl-4-hydroxy styrene oxide, to provide a t mixture of all four possible optical isomers of the product. The mixture of optical isomers is employed in the method without subsequent separation of isoxvers® Since the 0-phenethanolamine to be employed in the present method is inherently basic, it readily forms acid addition salts with any number of inorganic and organic acids® These salts can be employed in the invention, and often are preferred to the free base since they generally ©re more soluble in solvents such as water and are store conveniently formulated as an animal feedstuff.

Acids eo5feroaly es^ployed to form ©cid addition salts include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric &cid, perchloric acid and the like? and organic acids such as acetic acid. citric acid, succinic acid, para*t©Xuene sulfonic acid. methanesulfonic acid, lactic ecid &nd the like. Preferred salts to be employed in the present method include the hydrochlorides &nd hydrobromides.

Th^ method of promoting growth &nd improving leanness and feed efficiency provided by this invention is practised by administering an effective amount of & · compound of formula (1) to a domesticated animal that receives a nutritionally adequate diet. The term domesticated animal as used herein includes those * warm-blooded animals raised for human meat consumption, for exaaple grouer/finisher swine, poultry, ruminants and the like, but excludes such animals as rats. In a preferred embodiment, the growth of pigs, chickens and turkeys is promoted employing a β-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 docs 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 β-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 the amount that is effective in causing * g a promotion of growth, or an improvement in the efficiency of utilisation of food, or an improvement in carcass guality of the animal, for instance in the form of less fatty tissue and improved leanness. The effec5 tive amount to be administered will vary somewhat depend» ing upon the particular animal species being treated and the particular active ingredient employed, hut 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 β-phen» ethanolamine is preferably admixed with suitable carriers or diluents commonly employed in animal husbandry. Animal feed premixes comprising a p=-phenethanolamine as defined herein are provided as a further embodiment of this invention. Typical carriers and diluents commonly employed in such feedstuffs include com meal, soybean meal, alfalfa meal, rice hulls, soybean mill run, cottonseed oil meal, bone meal, ground com, 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 β-phenethanolamines can be admixed with conventional carriers such as com 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-re™ lease 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. β 5 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 mobilise 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 f 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.

Example 1 Preparation of dl-4~(benzyloxy)mandelic acid A solution of 5.0 g of dl-4-hydroxy mandelic acid, 11.0 g of benzyl chloride and 10.0 g of potassium carbonate in 50 ml of methanol was heated to reflux and stirred for seventy-two hours. The reaction mixture was cooled to room temperature and diluted with 50 ml of water. The aqueous solution was washed twice with 50 ml portions of benzene, and then was acidified with concentrated hydrochloric acid. The aqueous acid solution was extracted three times with 50 ml portions of ethyl acetate. The organic extracts were combined, washed with water and with saturated sodium chloride solution and dried. Removal of the solvent by evaporation under reduced pressure provided 5.7 g of a solid which was then recrystallized from 300 ml of toluene to afford 5.33 g of 31-4-(benzyloxy)mandelic acid. itf.P. 153-155°C.

Analysis calc, for C15H14O4 Theory: C, 69.76; H, 5.46; Found : C, 69.96; H, 5.33.

Example 2 Resolution of 31-4~(benzyloxy)mandelic acid to provide R(-)“(4-benzyloxy)mandelic acid To a stirred solution of 185.6 g of dl-4benzyloxy)mandalic acid in 2500 ml of ethyl acetate at 80°C was added in one portion 43.6 g of R(*)-a-methylbenzylamine. The reaction mixture was cooled to room temperature, and the precipitated solid which had formed was collected by filtration and washed with frssh ethyl acetate. The solid was recrystallised twice from a solution of ninety percent ethanol in water to provide 91.4 g of the RpJ-ff-raethylbensylamiae salt of R(-)”4-(hensyloxy)aandelic acid. W.P. 208.5“ 209,5°C. [Q -38.6°, [«]365 -155.3° (HeOB) Analysis calc, for C23H25ftOA Theory: 0, 72.80; H, 6.54; H, 3.69; Found : C, 72.95; H, 6.83; H, 3.95.

To a stirred suspension of 91.4 g of the above-named salt in 2000 ml of ethyl acetate was added 150 ml of ten percent aqueous hydrochloric acid solution. The aqueous acid solution was separated, and the organic layer washed with water and dried. Removal of the solvent by evaporation under reduced pressure afforded 54.5 g of H(-)-4-(bensyloxy)mandelic acid, ie. R( - )-2- (4-benzyloxyphenyl, -2-hydroxyacetic acid. v?. P. 155-161°C. [a]D -102.2°; f365 -410.6° (^eOH) Analysis calc, for C15H14°4 Theory: C, 69.76; H, 5.46; Found : C, 69.67; H, 5,41.

Example 3 Preparation of dl«l«methyl^3”(4-benzyloxyphenyl)propyl-’ amine A solution of 40.0 g of methyl 2“(4-bensyloxyphenylJethyl ketone and 160 ml of anhydrous ammonia in 300 ml of ethanol was heated at 75°C and stirred for two hours. After cooling the reaction mixture to room temperature, 4.0 g of Raney nickel was added in one portion, and the reaction mixture then was stirred at 25°C for twelve hours under a hydrogen atmosphere at 300 psi. The reaction mixture next was filtered and the filtrate was concentrated by evaporation of the solvent under reduced pressure to provide an oil. The oil was dissolved in 120 ml of 3W hydrochloric acid, from which the product as a hydrochloride salt precipitated. The salt so formed was collected by filtration and recrystallized from methanol and toluene to provide 36.2 g of dl-l~methyl-3~(4-benzy loxyphenyl )propylaminium chloride, M.P. 195-197.5°C.

Example 4 Resolution of dl«l-methyl-3-(4~benzyloxyphenyl)propylamine to provide R-(-)-1 -methyl-3-(4-benzyloxyphenyl)“ propylamine A solution of 629,3 g of dl-l®methyl-3-(4bensy loxyphenyl )propylaminium chloride was converted to the free amine by reaction with 95 g of sodium hydroxide in 400 ml of water. The free aiaine was then dissolved in 2000 ml of methylene chloride and added to a solution of 328 g of 0-(-)-mandelic acid in 1000 ml of methanol.

The mandelic acid salt of the free amine precipitated out of solution and was recrystal lised three times from methanol to provide 322 g of the R-mandelic acid salt of R-l-methyl-3«(4-bensyloxypheayl)propylamine. H.P. X66~167°C. (a]D -30°, [365^ 119° (MeOH).

The salt so formed was converted to R~X*methyl-3°(4-bensyloxypheayl )propylamine as the free base by reaction with aqueous sodium hydroxide.

Example 5 R, r-k- [2- (4-Bensyloxyphenyl )-2-hydroxy-l-oxoethyl) -115 methyl-3 (4~bensy!oxypheayX )propylamine A solution of 93.9 g of Ρ-1«Β©ΐΛιγ1<*3-(4benzyloxyphenyl)propylamine in 500 ml of N,N~dimethyl« formamide containing 63.0 g of 1-hydroxybenzotriazole and 104.6 g of n-2-(4«bensyloxyphenyl)-2-hydroxyacetic acid was cooled to 0°C and stirred while a solution of 83.6 g of N,Ν'-dicyclohexylcarbodiimide in 300 ml of dimethylformamide was added dropwise over one hour.

The reaction mixture was stirred for twelve hours at 3°C and then was diluted with 10 ml of water, stirred for an additional hour, and then cooled to -30°C in an ice-acetone bath. The reaction mixture was filtered to remove dicyclohexylurea, and then the filtrate was concentrated by evaporation of the solvent under reduced pressure. The concentrated solution was diluted with ethyl acetate and washed with saturated aqueous sodium carbonate solution, with water, with 300 ml of IN hydrochloric acid, and again with water. The organic layer was dried and the solvent was removed by evaporation under reduced pressure to provide the product as a white solid. The solid was recrystallized once from acetonitrile and again from methanol to provide 159.7 g of R, R-N- [ 2™(4-bensy loxyphenyl) -2-hydroxy-l-oxoethyl ] methyl-3-(4-bensyloxyphenyl Jpropylamine. M.P. 145-148°C. [a]D “15.9°, [a)365~50.1° (MeOH).

Analysis calc for C32S33^°4 Theory: C, 77.55? H, 6.71? N, 2.83; Found : C, 77.04; H, 6.84; N, 2.53.

Example 6 R,R«N~[2-(4-Benzyloxyphenyl)-2-hydroxyethyl]-1-methyl3 - (4-bensy loxyphenyl )propylamine To a stirred solution of 10.0 g of R,R-N-[2(4-benzyloxyphenyl) -2-hydroxy~l-oxoethyl ] ~l-methyle3” (4-benzyloxyphenyl )propylamine in 500 ml of freshly distilled tetrahydrofuran under a nitrogen gas atmosphere was added dropwise over thirty minutes 41 ml of 2 molar borane-dimethyl sulfide complex in tetrahydro13 furan- The reaction mixture was stirred at 25°C for twenty hours, and then was heated to reflux and stirred for an additional three hours. After cooling the reaction mixture to 25°C and stirring for another eighteen hours, the excess borane was decomposed by the slow portion-wise addition of 400 ml of methanol. The solvent was then removed from the reaction mixture by evaporation under reduced pressure to provide the product as an oil. The oil so formed was dissolved in 250 ml of hot methanol, and after concentrating the volume to 125 ml, the product began crystallising out of solution. The crystalline product was collected by filtration and recrystallised twice from methanol to provide 6.65 g of 8,R-N-[2-(4~bensyloxyphenyl) ’2-hydroxyethyl ] ®l-methyl-3-(4-bensyloxyphenyl )propylamine.

M.P* 119-123.5°C.

The amine so formed was dissolved in methanol and a^dded to a solution of ethereal hydrogen chloride, thereby providing 6,49 g of R,R™N-[2“(4-benzyloxyphenyX)2-hydroxyethyl ] “l=-methyl-3- (4-benzyloxyphenyl )propylaminium chloride. H.P. 214.5-216eC. [cr]p -13-4°, [ff]365 “30.2° (MeOH).

Analysis calc, for C^H^itfO^Cl Theory: C, 74,19; H, 7.00; N, 2.70; Cl, 6.84; Found : C, 74.20; H, 6.98; W, 2.65; Cl, 6.63. id Example 7 R,R-l-(4~Hydroxyphenyl)-2-[l~methyl-3-(4»hydroxyphenyl)* propylamino]ethanol hydrochloride, also named as R,R-M(2~(4«Hydroxyphenyl)-2-hydroxyethyl ] -1-methyl-3- (4hydroxyphenyl )propylaminium chloride A mixture of 51.6 g of R,R^M~[2“(4-benzyloxyphenyl)“2-hydroxyethyl]l“methyl-3-(4benzyloxy- » phenyl)propylaminium chloride and 5.0 g of Raney nickel in 2 liters of ethanol and 2 liters of ethyl acetate was stirred at 25°C for four and one-half hours under a hydrogen atmosphere of 60 psi. The reaction mixture was then filtered to remove the residual Raney nickel, and the filtrate was concentrated to an oil by evaporation of the solvent under reduced pressure, and the oil was crystallized from fresh ethanol and diethyl ether to provide 29.8 g of R,R-N-(2-(4-hydroxyphenyl)-2hydroxyethyl]l-methyl-3- (4-hydroxyphenyl)propylaminium chloride. M.P. 176-176.5eC. (dec.) (α]ρ -22.7°, (ff]365 -71.2° (3.7 mg/ml MeOH).

Analysis calc, for C18H24NO3C^ Theory: C, 63.99; H, 7.16; M, 4.15; Found : C, 63.70; H, 7.26; H, 4.32. is Example 6 As pointed out above, & preferred embodiment of this invention employs a mixture of all four optical isomers of the compound of Example 7. This racemic mixture can be prepared by the method described above by reaction of dl'-4“(bensoyloxy)mandelic acid with dl1- methyl-3-(4-bea3yloxyphenyl)propylamiae in the presence of DCC to give racemic l»(4*bensyloxyphenyl)-2-oxo2- [ 1-methyl-3- (4-benxyloxyphenyl )propylamino ] ethanol.

Reduction of the latter compound and subsequent removal of the bensyl groups provides racemic 1®(4-hydroxyphenyl) -2- [l-methyl-3- (4-hydroxyphenyl Ipropylamino] ethanol. This compound is more preferably prepared by the following procedure.

A solution of 32.8 g (0.2 m) of methyl 2-(4hydroxyphenyl)ethyl ketone and 42.6 g (0.2 in) of 1-(4hydroxyphenyl)-2-aminoethanol in 380 ml of ethanol containing 3.8 g of five percent palladium on carbon was stirred for sixteen hours at 60°c under hydrogen at 55 psi. The reaction mixture was then filtered, and the filtrate was diluted by addition of 350 ml of water.

The aqueous mixture was concentrated to a volume of about 400 ml, and then washed with dlchloromethane.

The aqueous mixture was acidified by addition of 50 ml of cone, hydrochloric acid. After standing at room temperature for two hours, the aqueous acid mixture was filtered and the filter cake was washed with 40 ml of IS ice water find dried et 50cC in vacuum to provide 47 g of l-(4‘*hydroxnjheny2“2H-mn»ethy3“3~Hhydroxyphenyl )propylamino)ethanol hydrochloride. M.F. 124-129CC.

Analysis c&lc. for Theory: C. 63.99; H. 7.16: H, 4.15; Cl, 10.49. Found: C, 63.77; Η, δ.Θ0; W, 3.91; Cl. 10.66. 13 C NMR studies demonstrated the product to be com- prised of 51^ RR,$S diastereamer and $9% RS, SR diastereomer. gxample, 9 Fremix for $v«ne Ingredient X by weight 1»(4-hydroxyphenyl)-2~(1-methylθ 10 3-(4~hydroxyphenyl)propylamino] ethanol hydrochloride Soybean mill run €$ Mineral oil _2 100 The above ingredients are blended tc uniformity to provide a dry flowable premix that can be admixed with a typical animal feed ration at a rate to provide about 20 ppm of active ingredient in the final feed ration. For example, the premix can be added tc the following swine grower ration for convenient oral administration of the f^pbenethanolamine to swine.

Ingredient Tt, by wijjoht Ibs/Ton l9/t Corn, yellow, ground 76.70 153« 767 Soybean Oil Keel, solvent extracted, detailed 19.35 387 194 5 Calcium Carbonate 1.20 24 12 4 Dicaleium Phosphate, feed grade 1.20 24 12 Salt (sodium chloride) 0.30 IO $ Trace mineral premix, A$~03“ o.io 2 1 w 10 Swine Vitamin Premia, sw-032 0.65 13 7 Vitamin & Premia, 3M use units/lb.3 0.05 1 <£> 0.5 Methionine Hydroxy Analogue, 93% 0.2Q 4 2 15 Selenium Premix^ 0.006 .....1 0.5 100.00 2000 1000 ^Eoch Kg of premia contains: 50 g manganese as manganese sulfate; 100 g sine as sine carbonate; 50 g iron as ferrous sulfate; S g copper os copper oxide; 1.5 g iodine as potassiiyn iodide and 150 g maximum and 130 g minimum calcium, as calcium carbonate. “i “Each Kg of prexix contains: 77,161 10 Vitamin D2; 2.205 IU Vitamin E; 411 ©g riboflavin; 1,520 mg pantothenic acid; 2,205 mg niacin; 4.4 mg vitamin BiS; 441 mg Vitamin K; 19,100 mg choline; 110 mg folic acid; 165 mg pyridoxine; 110 sg thiamine; 22 sg biotin.

Each Kg of premix contains 6,613,800 XU vitamin A.

^Each Kg of preaix contains 200 mg of selenium as sodium selenite. ϊ@ A ten day in vivo study was employed to determine the effect of β-phenethanelamines on feed efficiency and rate of growth. In these studies, barrows and gilts weighing approximately 60 Mg were maintained in individual pens. Each treatment was replicated six times in randomly assigned animals, with each test animal forming an experimental unit. A group of control animals received a normal swine grower feed ration comprising the following ingredients: Inorodient 1 by weight Ground yellow corn 76.70 Soybean oil meal 19.35 Calcium carbonate 1.20 Dicaleium phosphate 1.20 Sait 0.50 Trace mineral premix 0.10 Swine Vitamin premia 0.65 Vitamin A premia, 3K USP units/lb. 0.05 Methionine Hydroxy analogue, 93% 0.20 Selenium premix20S 100.00 The test animals received the same feed ration plus the test compound. All animals received feed and «ater ad libitum. All animals were weighed on day 1 and again on day 10, and feed consumption was measured by recording all feed issued and any remaining feed on day 10. The results of two series of this XQ day test are given in Table L In the © ί Table, the column labelled AIX” is the average daily weight gain in kilograms and pounds; mA£)Fw is the average daily feed consumption (in kilograms and pounds) by the test animals; and F/G is the feed efficiency calculated as ADF divided by ADG.

I e Cj © rtj fe cs cs |oa cm © tfi •«4 W fO &> r· c* OM · · xlo © © © •op O' «— CM © A to EW Xi © © fe Ό C »5 C c £ aa &, £ aJ u C o The β-phenethanol amines to be employed in the method of this invention can be administered in combination with other compounds known to have a beneficial effect upon animals. typical compounds to be co-edmin5 istered with 'the p-pheaetbanolami&eo include antibiotics, for exanple any of the tetracyclines· tylosin, penicil® lins. cephalosporins, polyether antibiotics, glyeopeptides, orthosoaycins &nd related compounds commonly administered to swine, poultry, ruminants and the like.

A preferred combination to be employed in the present method is an antibiotic such as tylosin or a t^tra® eyeline, together with 1®(4-hydroxyphenyl)®2-[1-methyl® 3»(4«hydroxypbenyl)p?opylamino)ethanel - Such combinations will comprise the respective components in a ratio of about 1 to about 2 parts by weight ©f P<»phenethanolaaine and about 1 to about 10 parts by weight of the partner component.

A total of 100 crossbred barrows and gilts, averaging approximately 134 pounds starting weight, were used to determine the effect of oral administration of Example.- 6 at 5 or 20 ppm on growth performance &nd carcass characteristics of finishing pigs. Ths pigs were fed a 16X crude protein corn-soy diet during the experiment fend wers boused in fen on25 closed commercial type swine building with concrete slatted floors. The effect of treatments on average daily gain (ADG), average daily feed (AX>F) and feed/gain are shown in Table 11. The treatment effects on the carcass composition of the pigs presented in Table XSS. <ί) ·Η «) «ϊ Ο «Α « η ng ca <1 η Ό ca *< Α» ο «η «» η Ci η αι β Η «Λ ΙΑ ιπ fe- ι ο «0 Ω ng> Ο «V «ζ • • 4<1 «Μ 04 ca 03 oa ΑΙ ΐΑ Μ> fM| • β . g «-4 6* 1 <9 fA η 51 ♦0 Α» ο» • Ο Ο Ο «Μ f*i ΑΙ «0 «J *Η| ο <Ά rn •Η <[» β» «— f*ft 44 Α ·*4 • <0 E* C ff*a si »-β· 1 V? CJ VS 03 Μ» >»© ε=μ Μ &* «4 «J C ι3 © « & U *** •eft fiX «s? tS3 » «μ» >> ki Φ A £ F~1 S Ή G ο & CM «— C Ο © fi£ α α α α ΙΑ ο 03 α> βΜ Φ φ Ο «Η •Η fcjf α α £J ε ε £ «Β <9 0 Κ « υ Μ ea A >1 β <8 (Ε α jSj •c=4 Ο «§* W Φ 09 ΛΜ .υ «J 0 <3 β Φ C (3 5^ ,.pj &J GS « J0 η Ο £ & Μ © > >, υ ο fel C «Ο A 40 Φ Β* £ «Η 44 ·*4 © «9 ¢3 £ Φ 44 ε «Φ ο β υ 6= ο 0 Θ) & Ό «© Μ <1> Φ ω W Ν & > <Η <Μ & S A ¢-1 φ Μ> ί® 44 5 ε <3 & •Η Φ ρ»4 β U Μ < ΑΑ & (Μ Sm • ρ=4 0 » «3 38 T? & Τ> θ 3 c «—a Q «3 & & β '·© •βΜ Ο ο β Μ φ & €\3 « S3 (Z& .

• J » 5- ** co t*J & SE • O &?j ¢3 m co » m £ «; Ef j £rj · «£ & <*! «Α sB fej β ol co fe. ft TA3LE III • · « t^l fsl fe3 fi. mJ > S’ » nc «e I K «C fo W OOM ec 2 <3 ta) X o u G ra ra a k Q I © Cm ΜΊ la) H »J 1 e • > > L·) («il © raw ^M <4 <£ Μ 1 Ρ» Pfo r. fo 1 ra raW © ra •M J M > **. > Μ O «2 *J feS €9 Ifl gi ra «Η ¢£.

•M i»)O IH w § Gti) &» >8 ά* (3 *C3 <0 (M 10 fe. <8 ca fe <8 t=4 «3 0 « fja oM ¢0 «) » & S9 &· (0 m X «; ¢9 tei /« ffl HI III fol «, &4 e fo o fo ejI e to Ml «5 («3 &3 Additional studies have been carried out to demonstrate the anabolic effect of p-phenetbanolamines in swine. The effect of the compounds on nitrogen retention in finishing barrows was determined. nitrogen retention is the difference between nitrogen intake and nitrogen excreted. Increased nitrogen retention is 'mown to he associated with increased anabolic activity, resulting in improved carcass muscling and leanness.

In a typical study, harrows weighing about 172 pounds (78 Kg) were orally administered various doses of l”(4hydrcxyphenyl)-2“ll-methyl®3-(4«hydroxyphenyl )propvlejnino]ethanol hydrochloride (Compound A). All animals received ^eter and e constant emount of normal swine feed ration. The results of this study are presented in Table iv, and show that all p^phenethanol amine treatments improved nitrogen retention compared to controls.

Table iv Treatment Nitrogen detention Animals per Ki treatment trogen Retained (g/ Control Compound A (5 g/T) Compound A (10 g/T) Compound A (20 g/T) 21.0 23.5 23.9 .0 As pointed out ftbovs, the method of this invention can be practiced with individual isomers of β-pbenethanolamnes or with mixtures of isomers and diastereomers. in a study to determine the effect on weight gain and feed efficacy pf various mixtures of diastereomers, borrows initially weighing about 177 pounds (80 kg) were fed a normal swine diet plus & @-phen~ ethanolamine at 20 g/T oi feedstuff. Each treatment was replicated in twelve individually fed animals. The results are presented in Table V ©nd show that growth performance was improved by both p-phenethanolemiae treatments with very little change ia feed intake. •«Μ φ & e? Θ' ss Φ Ε GJ «3 > Ο &* <=« OS O*r*J JZ Βί9> Ο tft θ' « CD CD Ο > & ι=4: & IU ί >) 1 <3 Ο C' ν& & .Qto & & φ ®-«Γ· • • θ' fcf» tn tn (3 Ό ϊτί Φ φ Φ > k, «£ σ^> ο MD -hike νο VD 04 03 04 ι~< χρ Ο 1 C 1 <η < ΓΛ FM I ~ 1 0 «j -4 C >ι φ ?ι <3 /«.* *=» iS tS Χ3 ο ij Aj Φ C φ φ β — S <-”“ » β 1 0 ^4 40 m e = ι=1 «—•pi 1 >1 ι e 03 Ω, 03 <3 1 Ο 1 ¢=-4 Κ»» &4 >, ί-Μ {X ΐΗ·-* >o C £ M φ > φ a «£: s <&M *** δ' Ift & X£·* O S ea w 0 Φ k k « o β te ki XI © w es ·© 0»M £S w Ή &.F-9 w m («-1 t£i H &£ « 3^i £ϊ te • 0 £*3 0 & K u & yj to o >O X β o o es κ *> ς? £ ut &n ^1 h s *3* 1 *U . • ·«.·©«© o fl >1 8 ^i>> P* n u P-ί ·-*-«£ <^9 <^jj ω * The data in Table V demonstrates that the method of improving feed effieency ,md promoting growth ean he practiced with aay desired mixture of 0*phen» ©thanolamine optical isomers.

The efficacy of the 9*pherathanolestine£ described herein also has been demonstrated in poultry. In a typical study, broilers that were twenty^oae days old were administered an oral dosing of a ^pheneth&nol® amine in their normal daily feed ration. All animals received the following broiler finisher ration: Ingredients X by wejoht Ibs/T jtq/t Ground yellow corn 66.40 1328.00 664.00 Animal-vegetable fat 1.63 30.60 15.30 Corn Glut, meal (60%) 4.00 80.00 40.00 Soybean meal (48%) 19.19 383.80 191.90 Fish meal«menhaden 2,50 50.00 25.00 Dicaleium phosphate 1.01 34.20 17.10 Feather meal-Hydr. 2.50 50.00 25.00 Ground limestone 0.83 16.60 8.30 Salt 0.30 6.00 3.00 Vitamin Prenix1 0.50 10.00 5.00 Trace mineral premix3 0.10 2.00 1.00 Methionine Hyd. Anal. 0.15 3.00 1.50 Lysine HCl 0.29 5.80 2.90 100.00 2000.00 1000.00 1 . * Vitamin premix provides ICU of vitcimin Ds, 40 mg 3000 IU of vitamin A, of vitamin E, 0.7 mg 900 of vitamin κ, 1000 a»g of choline, 70 mg of niacin, ag of pantothenic acid, 4 mo of riboflavin, 100 meg of vitamin 31St 100 meg of biotin and 125 mg of ethoxyguin per kg of complete feed.

Trace mineral premix provides 75 ag of manganese, mg of zinc,'25 mg of iron and 1 mg of iodine per kg of complete feed.

Test animals received with the above ration varying doses of l“(4-hydroxyphenyi)-2-[l-methyl-3-(4-hydroxyphenyl)propylaaino] go* ο fo O' es s ¢9 0 am y > y o e fci 0 0 u •rt (rt Q •b5 Eg *0 © C © •rt fe ¢9 0 0 •rt ea X. eJ fo 9 <9 © gj fi£ irt ©> •rt' fe 0 u ga nJ £ fcj & o Is esq © J> © > u C © © •pH fo *-4 <3 «9 O t£& β 0 ε «ϋ w •rt 0 «J lu x H btf © pH & o x« X» KO 3ff Ei O ¢8 &j fo O *=* 6? ω < 0 0 *3* O' Φ © O' © ϊ=1 ^=J I=j wgt M> CM CM t-3 & fi* CM n CM CM « CM CM CM CM CM CM Φ tM *Ί f* eA cn cn «Α cn O σ* i- ca e-J M3 -© &n «0 tn «0 »rt frt fM fM rtC coo© «-i CM *& <9 fo (¢3 < < < < O £ es £ £ 0 S3 3 3 S3 fo 0 0 0 0 <5} 0* Wi ex ex £ 65 8= C: IK 0 O O 0 0 u U 0 u » The results of this study demonstrate that the g-phenethanolamines described herein ere effective in promoting growth and improving feed efficiency in poultry.

The compounds of the invention also hove demonstrated efficacy in ruminants. Forty-eight cross® bred wether lambs were employed in a test designed to show the effects of Compound A (l-(4®hydroxyphenyl)2® Il“methyl-3“H-hydroxyphenyl )propyl amino] ethanol hydrochloride) st varying doses. Sixteen animals were held as controls, while sixteen received 40 ppm of Compound A, and another sixteen received 00 ppm of Compound A. All animals received a normal daily feed ration and water ad libitum. Average daily weight gain and average daily feed consumption after twenty^eight days is given below in Table Vll. The data demonstrates that a p^phenethanolamine as defined herein is effective in promoting growth and improving feed efficiency in ruminants.

Table vii Growth Performance of Lambs Treatment Dose i£2Si ADG (feg/lbs) ADF (kg/lbs) F/G 25 Control 0 0.188 0.414 1.869 3.68 8.89 Compound A 40 0.190 0.418 1.637 3-61 8.64 Compound A @0 0.214 0.472 1.619 3.57 7.56 *

Claims (11)

1. A method for promoting the growth, improving th® efficiency of feed utilisation or improving the leanness of © clousstieatecs animal e which comprises admin» 5 istering to said animal a costpound of the formula O): O’) os* an acid addition salt thereof·

2. O A method according to claim 1, for growth promotion» 10

3. method according to claim 1, for improving the efficiency of feed utilisation»

4. A method according to claim 1, for improving the leanness of a domesticated animal.

5. » A method according to any one of claims 1 to 15 wherein the compound of fonaula (I) is 1~ (^-hydroxyphenyl) -2« (l®methyl*=3“ (® -hydroKypheny 1) propy lamino J ethanol, hydrochloride.

6. A sietbod according to any one of claims 1 to 5 which comprises administering an active compound of 20 formula (X ) to pigs.

7. A nethod according to any one of claims 1 to 5 which comprises administering an active compound of formula (X) to cattle.

8. Φ An animal feed presaix comprising a g-phen25 ethanolamine of the formula (1) s or an acid addition salt thereof, associated with a suitable carrier therefor.

9. An animal feed premix as claimed in claim· 8, wherein the compound of formula (1) is in the form of 5 its hydrochloride.

10. A method according to claim l for promoting the growth, improving the efficiency of feed utilisation or improving the leanness of a domesticated animal, substantially as hereinbefore described and exemplfied. 10

ll. An animal feed premix according to claim 8, substantially as hereinbefore described and exemplified.