IE873337L - Phenethanolamine derivative - Google Patents

Description

® 8 4 % This Invention relates to phenethanolaraine derivatives in weight control in animals. chemistry and use of ® - ph® na thano laaii ne s has besii «itt.<ansively investigated. European Potent 5 Specification Bto. S„ 766 describes the use of phene thrnia 1 ®@ina derivatives is> promoting she loss ot weight in animals.

Shis invention provides a method ios .increasing weight gain in domestic aniraals fend improving the 10 efficiency of £®afi utilisation and the quality of the carcass. The invent ion is aora particularly directed so a laethod fox ptrosaoting growth, improving Seed efficiency or Ismiasss comprising edroiniatax'iag a cosspound having a he gosusala CD or an acid addition salt thereof. Our Patent Specification No. a >■ /< q discloses the use of related compounds.

This invention elso provides en animal feed 20 preadx cosaprisiag a g-phenethanolaaiine of the above formula together with a suitable carrier therefor.

The compound of forsula (I) is disclosed as having utero-Eelexing activity by Van Dijk at al. in Recuail, 92 1231 (1073).

'She compound of foraula (X) can be prepared by yaeetion of a styrens oxide with a 3-phesiyIpropyleunine derivative.

An alternative method for preparing the 3-fshsasvathajioXasaine comprises reacting e siandelic acid 30 derivative with a 3-%>henylpropyl%atine derivative to provide on eatiitSa, which upon subsequent reduction iasfo^Mas a eomg>ouad of fcha rfjova fosmule« A similar, yet alternatiwe, ssethod of synthesis comprises reacting & phem&thanoi&tnine wish a phenylethyl ketone to provide a Schifg bass, which epoa sredluctioa gives a compound so l>a ®mploy®d in tha present invssition.

Thus, 2"hydrosy~2™ (4-hy&sre}:yphenyI.)i!5thylamia<s can be reactsd wit.h a tetos»<a such as matinr 1 a-ti-hy&roaypheayl)-ethyl Ketone to provi<9e the eorraspoiidia© imiae, which upon reduction, for instance with 5% pallafliua on earfeon, provides !=■ («»hyteojtyphenyI) -2™ [i-8saftlsy3,'--3- (4--SiydroKy"-10 phenyl) prog>y lagiino J ethcao.1 „ it should be noted that the compounds to be employed in this indention possess two asyKsaatffic canters. Since employment os: individual optical iseasssrs necessitates preparing the @ ~phsm£'tiiaaoJe«nin®s froai optically active 15 starting states-ials, or using eootly separation procedures, a prer'err®d asaboflisaaat of this invention fior ^terinary purposes employs a sniscture of optical igosars. flius, 1- (4»hydrojsyphenyl) -2~ [ l~saathy 1-3- (4™hy&rosyphanyl) propyl-aiaino)ethanol is preferably prepared ssrosa racamic- fixtures 20 of starting materials, e.g„ dl-l-methyl-a-^-hydrostyphenylJ-propylamine and <31-4-hydroi:ystys:eae osiide, to provide a mixture of all four possible optical isososrs of the product. i'he mixture of optical isosiers is employed in the method without subsequent separation of isouars. 25 Since the 8-phenethanolaaiins to be employed in the present method is inherently basic, it readily forms acid addition salts with feny number of inorganic and organic acids. These salts can be employed in the invention, and often are preferred to the free base since 30 they generally are more soluble in solvents such as water and are sore conveniently formulated as en animal feedstuff. &cids eonsioaly employed to fora acid acMitioa salts include mineral acids such as hydrochloric acid, sulfuric acid, phosphoric seid, perchloric acid and the lifts; and 35 organic acids such as acetic acid. 4 citric acid, succinic acid, para-toluene sulfonic acid. eiethar.esulfonic acid, lactic acid and the like. Fre» fersee salts to be ampleyed in the present asethod include the hydrochlorides and hydrobsroaidas.

The siathod of promoting growth and improving leanness and fssed efficiency provided by this invention is practised by administering an affective amount of a • compound of formula (!) to a domesticated animal that receives a nutritionally adequate diet. The tana 10 "domesticated animal" as used herein includes those * wani«b.1.ooded enisie ,ls raised for hujuan meat consumption, for example grower/finisher s^ine, poultry, ruminants and the like, but excludes such animals as rats. In a preferred embodiment, the grot?th of pigs, chickens and 15 turkeys is promoted employing a p-phensth&nolawine.

Another preferred embodiment is practiced in ruminants such as cattle, sheep and eoats. The method of improving leanness is not limited to meat producing anisaals, and can b® 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 25 of a fl-pheneth&no!amine to an animal. Other routes of administration can be employed, for instance intra" siuscular or iatrovenious injection; however, such routes s?e less practical. The amount to be administered to an animal is the aaouat that is effective in causing B a promotion of growth, or an improvement in the efficiency of utilisation of food, or an improvement in carcass quality of the animal, for instance in the form of less fatty tissue and improved leanness. liie 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 rag/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 0-phen-ethanolamine is preferably admixed with suitable carriers or diluents commonly employed in animal husbandry. Animal feed premises comprising a p-phenethanolaraine 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 com, corncob meal, sodium chloride, urea, cane molasses and the like.

Sucb 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 p-phen-ethanolamines 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-release subcutaneous implant. Such administrations can be made as oftea 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 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 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 3 stirred for seventy-two hours. The reaction mixture was cooled to room temperature and diluted with SO ml of water. The aqueous solution was washed twice with 50 ml portions of bensene, and then was acidified with concentrated hydrochloric acid. The aqueous acid solution was extracted three times with 50 ml portions of ethyl ace» tate. 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 recrystallised from 300 ml of toluene to afford 5.33 g of dl-4-(bensyloxy)mandelic acid. M.P. 153-155°C.

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

Example 2 Resolution of dl~4-(benzyloxy)mandelic acid to provide R(-)-(4-benzylosy)mandelic acid To a stirred solution of 185.6 g of dl-4-benzyloxy)mandelic acid in 2500 ml of ethyl acetate at 80°C was added in one portion 43.6 g of R(-s-)-o-methyl-benzylamine. The reaction mixture was cooled to room temperature, and the precipitated solid which had formed was collected by filtration and washed with s fresh ethyl acetate. The solid was recrystallised twice from a solution of ninety percent ethanol in water to provide 91.4 g of the R (<-)-<* -methylbensylamine salt of R (-)-4-(beaaylojjy )mandelic acid. M.P. 208.5-5 209.5°C. [a]Q -38.6°, [a]365 -155.3° (rfeOH) Analysis calc. for C23H25M0^ Theory: C, 72.80; H, 6.64; H, 3.69; Found : C, 72.95; H, 6.83; H, 3.95.

To a stirred suspension of 91.4 g of the 10 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 15 afforded 54.5 g of H(«)-4-(benzyloxy)mandelic acid, ie. R(-)-2-(4«benzyloie.yphenyl)»2-hydroxyacetic acid. ri.P. 155-161°C. for]D -102.2°; t«1365 -410.6° (MeOH) Analysis calc. for C15H14°4 C, 69.76; H, 5.46; C, 69.67; H, 5,41.

Theory: Found : I iO Example 3 Preparation of dl-l»a<athyl-3~(4-ben3ylosyphenyl)propyl~ amine A solution of 40.0 g of methyl 2-(4»bensyl~ oxyphenyl)ethyl 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 3M hydrochloric acid, from which the product as a hydrochloride salt precipitated. The salt so formed was collected by filtration and recrys'callized from methanol and toluene to provide 36.2 g of dl-l-methyl-3»(4-benzyloxyphenyl)propyl-aminium chloride. M.P. 195~197.5°C.

Example 4 Resolution of dl»l-methyl-3=(4-benzyloxyphenyl)propyl-amine to provide R» (-) -methyl™3 - (4~beMyloxyphenyl) -propylamine A solution of 629.3 g of dl-l-methyl-3~(4-benayloxyphenyl)propylaminium chloride was converted to Si the free amine by reaction with 95 g of sodium hydroxide in 400 ml of water. The free amine was then dissolved in 2000 ml of methylene chloride and added to a solution of 328 g of D~(-)-=mandelic acid in 1000 ml of methanol. 5 The mandelic acid salt of the free amine precipitated out of solution and was recrystallized three times from methanol to provide 322 g of the R-mandelic acid salt of R-l-methyl-3"(4"bensylo3syph®ayl)propylamine. M.P. 166-167°C. [«]D "30°, [eJ365„ 119° (MebH). 10 The salt so formed was converted to R-l~ methyl-3~(4-benayloxyph£ayl)propylamitte as the free base by reaction with aqueous sodium hydroxide.

Example 5 R,R-H-[2-(4-Bensyloxypheayl)-2-hydro3Ey™l-oxoethyl]-1-15 methyl-3-(4-bensyloxyphenyl)propylamine A solution of 93.9 g of R-l~methyl-3-(4-benzyloxyphenyl)propylamine in 500 ml of H,W--dimethyl= formamide containing 63.0 g of 3,-hydroxybenzotriasole and 104.6 g of R-2-(4-=b®&syl03fs|>henyl) -2-hydroxy ace tic 20 acid was cooled to 0°C and stirred while a solution of 83.6 g of N.H'-dicyclohejsylcarbodiimide 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 25 for an additional hour, and then cooled to -30°C in an ice-acetone bath. The reaction mixture was filtered to 12 remove dicyclohessylurea, 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 1M 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 aceto-nitrile and again from methanol to provide 159.7 g of R,[2-(4~benzyloxyphenyl)-2-hydroxy-l-oxoethyl]-1" methyl-3-{4-bengyloxyphenylpropylamine. M.P. 145»148°C. [or]D -15.9°, [a]365-50.1° (MeOH).

Analysis calc for C32H33N04 Theory: C, 77.55; H, 6.71; W, 2.83; Found : C, 77.04; H, 6.84; M, 2.53.

Example 6 R,R-M-[2~(4»Bensyloxyphenyl)-2-hydroxyethyl]=1-methyl-3-(4-bensyloxyphenylpropylamine To a stirred solution of 10.0 g of R,R-N-[2~ (4-benzyloxyphenyl)-2-hydrojcy-l-oxoethyl]™l-methyl-3-(4=henzyloxyphenylpropylamine in 500 ml of freshly distilled tetrahydrofuran under a nitrogen gas atmosphere was added dropwise over thirty minutes 41 ml of 2 molar borane-dimsthyl sulfide complex in tetrahydro- 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 5 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 10 250 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 recrystallized twice from methanol to provide 6.65 g of B.,R-0-[2- (4~ben2yloxyphenyl)«'2-hydroxy« 15 ethyl]®1-methyl-3-(4-benzyloxyphenyl)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-W-[2-(4-benzyloxyphenyl)» 20 2-hydroxysthy1]-l-methyl-3-(4-benzyloxyphenyl)propyl-aminium chloride. M.P. 214.5~216°C. [a]D -13-4°, [<*]365 -30.2° (»30H).

Analysis calc. for Theory: C, 74.19; H, 7.00; N, 2.70; CI, 6.84; Found : C, 74.20; H, 6.98; W, 2.65; CI, 6.63. 14 Example 7 R,R-l"(4™Hydroxyphenyl)-2-[l-methyl-3-(4~hydroxyphenyl)-propylamino]ethanol hydrochloride, also named as R,R-M-[ 2- (4»Hyelroxyphenyl) -2-hydroxyethyl J -1 -methyl -3 ™ (4-5 hydroxyphenyl)propylaminium chloride A mixture of 51.6 g of R,R-N"[2-(4-benzyloxyphenyl )™2™hydroxyethyl] '-l-methyl-3-(4=benzyloxy» phenyl)propylaminium chloride and 5.0 g of Raney nickel in 2 liters of ethanol and 2 liters of ethyl acetate 10 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 15 was crystallized from fresh ethanol and diethyl ether to provide 29.8 g of R,R-N-[2-(4=hydroxyphenyl)=2-hydroxyethyl]-1-methyl~3-(4"hydroxyphenyl)propylaminium chloride. M.P. 176-176.5°C. (dec.) [a]D -22.7°, [a]365 -71.2° (3.7 mg/ml MeOH).

Analysis calc. for c18H24N03c1 Theory: C, 63.99; H, 7.16; N, 4.15; Found : C, 63.70; H, 7.26; N, 4.32. 1 s Esamale 8 As pointed out: above, a preferred embodiment of this invention employs a mixture of all four optical isomers of the compound of Example 7. This racaaic 5 mixture can be prepared by the method described above by reaction of dl-4-(benzoy1oxy)mandelie acid with dl-1-methyl-3-(4.-be:a3yloxyphenyl)propylaraiae in the presence of QCC to give raceiaic l-(4-bensylo^yphenyl)"2-o3so-2" [ l-methyl-3- (4-bea3yl0JEypheayl) propyl amino ] ethanol. 10 Reduction of the latter compound and subsequent reaoval of the beasyl groups provides racemic l-(4-hydrojsy-phenyl)-2-[l-methyl-3-(4~hydroxyphenyl)propylamiao]-ethanol. This compound is more preferably prepared by the following procedure.

A solution of 32.8 g (0.2 m) of methyl 2-(4- hydroxyph&nyl)ethyl ketone and 42.6 g (0.2 in) of l-(4~ hydroxyphenylJ-S-aminoethanol in 380 ml of ethanol con= taining 3.8 g of five percent palladium on carbon was stirred for sixteen hours at 60°c under hydrogen at 20 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 dichloromethane. The aqueous mixture was acidified by addition of 50 ml 25 of conc. 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 It® ice water and dried at 50eC in vacuum to provide 47 g of (■S-hydrojiyphenyl-5» 12-me-thy.!-3-(*3-hydrexyphe:iyl)~ propylana noMethanol hydrochloride. ft.F. 124»129CC.

Analysis calc. for CigH^MO^Cl Theory: C. 63.99; H. 7.16; M. 4.15; CI. 10.49.

Found: C, 63.77; H, S.80; M, 3.91; CI. 10.66. 13 C WMK studies demonstrated the product to be cobs™ prised of 51% RR.SS di aster earner and <§9% IRS.SR dissterecraer. gxamsle 9 Fremix for S^'ine Ingredient i - (^-hydroxyphenyl )-2- [ 1-tnethyl- 10 3-(4-hydroxyphenyl)propylami no] 15 ethanol hydrochloride Soybean mill run SB Mineral oil 2 100 The above ingredients are blended to uni-20 forraity to provide a dry flcwable presr.ix that can be edir.iaed with a typical aniaal feed ration at s rate to provide about 20 pprc of active ingredient in the final feed ration. For a it ample, "chs premiss can be added tc the following swine grower sration for convenient oral 25 administration of the 0-phenethanolair.ine to swine. 17 Jnersdient % bv waioht lbs/Ton M/S Corn, yellow, ground 7S.70 1534 7S7 Soybean Oil Keel, solvent ffiatractsd, dehullefi 19.35 387 154 Caleiust earbonats 1.30 24 12 4 Diealeiusn Phosphate, fssd grade 1.20 0^4 : T2 Salt (sodium chloride) 0.50 Trace saiaeral preaia, ASS-OS" 0.10 2 1 '< 10 Svioe ^itiania Fresia, SW-032 0.65 13 7 yiimiti A Presaia, 3M US? units/lb.3 o.os 1 0.5 Methionine Hydroxy Analogs®, §3% 0.20 At «3 2 Selenium PxemiJ!^ o.oos 1 0.5 3.00.00 2000 1000 ^Eech Kg of pre»ia contains: 50 g w&aganese as manganese sulfate; 100 g siac as sine earbonats; 50 g iron as ferrous sulfate; S g eoppez os copper oxide; 1.5 q iodine as potassium iodide and 150 g maximim end 130 g s?iinisi\jjr. ca.lcius;. as ealcius carbonate.

"Eaeh Kg of preniK contains: 77,161 JU Vitair.jn !>«; 2.205 IU Vitamin E; 411 a§ riboflavin; 1,630 gig pantothenic acid; 2,205 ag niacin; 4.4 sag vitesrin E,a; 441 ae Vitwin K; 19.100 ag choline; 110 ag folic acid; 165 sag pyridoxins; 110 sag thiamins,- 22 mg biotin. 3Each Kg of prenix contains 5,613.000 XU vitear.in A. rsgach Kg of prsais contains 200 ag of sal anion as sodium selenite. 18 k ten day in vivo study was employed to determine the effect of p-phsmsthanolasr.ines on feed (efficiency and rate of growth. In these studies, barrows ane gilts weighing flpproaimetely SO kg were aaintainsd in ,indi-5 vidual pens. Each treatment was replicated sis tiaes in randomly assigned animals, with «ach test enieal forming «n experimental unit, A group o£ control animals received a nonaal swine grower feed ration comprising the following ingredients: Ingredient % by weiqht Ground yellow corn 76.70 Soybean oil seal 19.35 Calcium carbonate 1.20 Dicoleiva phosphate 1.20 Salt o o Trace mineral preir.ix 0.10 Swine Vitamin preaix 0 * 65 Vitamin A preais, 3K USP uni ts/lb. 0.05 Methionine Hydroxy analogue. 93% 0.20 Selenium prefix .05 100.00 The test anisals received the same feed ration plus the test compound. All aniaals received feed and water ad libitum. All anisaals were weighed on day 1 and again on 25 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 ?=.Q day test, ate given in Table X. In the Table, the column labelled "&E>G" is the average daily weighs gain in kilograms and pounds; "ADFB is the average daily feed consumption (in kilograms and pounds) by the test animals; and P/G is the feed efficiency calculated 5 as AOF divided by ADG.

Table E Growth Piomoi.ion and Feed Efficiency Ss nn h *=*=* \~£HrHxHHC-rMzrM*-K ,» \ / L 1 dus a1 a2 a3 ;i5 doss wm adg adf f/g lb kg lb Sus M Control 1.60 5773 477 j.f 2.90 © Compound of formula (I) 2.19 0.59 5.0 2.3 2.3.» & a The p-phenethanol amines to las "ssaployed ia the aeihod e;f this invention e&n be administered in eosibing-tion with other compounds teiovrei to have a bsn@fi.cial >s££<sct tspon animals. Tfpic&l eosipoua&s to t#g eo-ad®iii-iatsrefl with the (3-pheaethisnol esaines iaelufis antibiotic?;;, for esasnplffi any of the t®traeyeliises. tylosis, penicillins. cephalosporins, polyether antibiotics, glycopep-tidas, ©rtftososiyeins and .related eospouisfc eosnaonly ads)iaist«r©fi to swine, poultry, ruaisisnts and the like. A preferred combination te be employed ia the present gasthod is an antibiotic s«eh as tylosis* os « tetracycline, together with (4-hydroJi^henyl)-2-[ l-rjethyl~ 3»($»hyfirojtypbenyl)propylffiiaiae}<sthanol • Such combinations will eoraprisa the respective coiapoaents ia a ratio of about 1 to about 3 parts by weight of p^pheneth&aol-asaine and about 1 to about 10 parts by «sight of ths partner component.

A total of 3.80 crossbred barrows and gilts, Averaging approximately 334 pounds starting weight, ware used to determine the effect of oral administration of Example, e at 5 or 20 ppm on growth performance and carcass characteristics ©f finishing pigs. ™hs j)igs were fed a 1$% crude protein cora-soy diet during the experiment and vers boused in an enclosed comir.ereial type swine building with concrete slatted floors. The effect of treatments on average daily gain (ftOG), average daily feed (ADF) and feed/gain are shown in Table 23. The treatment 'effects on the eercass composition of the pigs ©re presented ia TablffiSXX.

Table II £asa©eur»8S Number Animal m.

Puna Iniii«sl wt.

ADC AD T Fead, Cain Kg lb kg lb *S .

JLb Control J9 4 SI 3<1 0.S8 1.53 2.40 ,30 3.50 Ssasnpl© 6 ppm 4 f>2 133 0.73 1.62 2.38 .25 3,23 Example B ppm j5 4 52 U6 0.73 1.62 2.41 .38 3;26 S3 Anitaals were slnughtered on's weight constant 5>asis at approximately 230 pounds. Animals were on test an av©r®ge of 30 days. The control fesd snd all treated feeds contained Tylosin st 44 ppm (40 g/t).

S3 • »> »i f- «o O 9 im fes gi f-3| 6?a £ <sj &r-J E-l • es or •a! CO si ES) sliS <M id CO <5* © C9 ca G* S"» <? M * N o ort P> «<? CSS) v^J o « © w tn 6f* tr» «=» » © «f\ €9 •s S3" sn C2> w C«k « €H o to <7* i> o p o ©* fe-» «M *•4 © • W N esa • • • (U| fal £3 Ch x.| > » • nc 4 <t A ul I U. «: h W «C c-> h.

U U H ee a ^1 c ta si U^JO • » Q blHJ > > Eal <«S <4 < M o © ca * M pJ fel > -^1 > M O «2 «J feil €9 (H m p 64.

Sfa *=4 <a s% <W fiii y «*4 e»J fej flbGH is,0 e# (6 u « £ «9 O W w g RJ "S3 &* «0 •a (6 IGJ 05 Ba «3 0 $MJ cW «J « &• (Q ID «: (S3 (!) (9 HI Ill a o (£4 (fe g=a §•*> to «5 (*} &3 &a <g 3 4 Additional studies have been carried out to demonstrate the anabolic effect ©f p-phenethanolamines in s«ia«. The affect of the compounds ©n nitrogen retention in finishing barlows was determined. Nitrogen 5 retention is the difference between nitrogen intake and nitrocer. excreted. Increased nitrogen retention is known to be associated with increased anabolic activity, resulting in improved carcass muscling and leanness. in a typical study, barrows weighing about 10 172 pounds (70 Kg) wers orally administered various doses of 1-(4-hydroxyphenyl)-2-ll-»ethy3.-2-(^-hydro3iy-phsnyl)propvlej»ino]ethanol hydrochloride (Compound A). All aniraals received fe-eter and a constant eraount of normal suine feed ration. The results o£ this study 15 are presented ir. Table iv, and show that all p-phen-ethanolair.ine treatments improved nitrogen retention compared to controls.

Table IV Hitrogen Retention Animals per Nitrogen Retained Treatment treatment (q/dav) Control 6 21.0 Compound A (5 g/T) 3 23.6 Compound A (10 g/1) 3 33.0 Compound A (20 g/T) 3 25.0 As pointed out above, the aethod of this invention can be practiced with individual isosaers of |i «p.henethenolai;iines or with Kii situ res of isoaers and diastereomers. Iti a study to determine the effect on 30 weight gain and feed efficacy of various sniatures of diastesreosBers, borrows initially weighing about. 177 pounds (80 kg) were fed a normal swine diet plus a (3-phen- ethafiolair.iaffi at 20 g/T of feedstuff. Eaeh treanaeat: was replicated ia twelve individually fed aaianls. The results are presented ia Table V ®a«3 show that perferiaaae® was isaproved both p -^h<ga«sh&n»l esai&e tsreatssnts with very little ehange ia £®g-d iataks.

Table V Average Daily &vsrag8 Daily Treatment Feed Gain kg lb fcg lb Control 2.5"? S7S3 0.T2 1/58 l»(4°hydroxyphenyH-2-f l*iaethyl-3- 2.69 5.94 0.98 2.15 {4~hydroxyphenylJpropylasninoJethanol hydrochloride 57.5% RR.SS 42.5% aS,5H l°(4°hydroxyphenyl5-2-(l-siethyl-3-(4- 2.66 5.36 0.88 1.95 hydroxyphenyl)propylaroino1ethanol hydrochloride 47% SiR.SS m S3% SJS.Stl ® The dlatei ia Table V demonstrates that zha issthod ef improving £«ed effieenew «ad prosiotiag $ro«th essi he psraeiieecl with any fiesirsfl mixture of §-=phen» ethanolassaiae optical isoasrs.

The efficacy ©t the ^-phsacthanelesiiaes descjri&ed hejrsiii also has been iesnosisfcratsti ia poultry. In a typical gtsdy, broilers tJsst «®re t«snty-ons days old wers administered an erel tloaing of a p-pheneth&nol~ amine ia their Ke.tsnei daily fssd nation. All snivels received ths following broiler finishes ration: Z8 Ingredients X fey weight Ibs/T ftq/t 664.00 Grouad yellow corn 66.40 1326.00 Animal-vegetable fat 1.53 .60 .30 Corn Glut., meal (60%) ■ft. 00 .00 40.00 s Soybean meal (&3%) 19.19 383.80 191 .90 Fish mee 1 -menhaden 2.50 50.00 .00 Dicaleiujn phosphate 1.01 34.20 17.10 Feather aesi-3yds:. 2.50 50.00 .00 Ground limestone 0.83 lfi.60 8.30 Salt 0.30 3.00 3.00 Vitamin Prewis1 0.50 .00 .00 Trace sainsrel premix3 0.10 2.00 1 .00 Methionine Hyd. Anal. 0.15 3.00 1 .50 Lysine BCl 0.29 .80 2.90 100.00 2000.00 1000.00 "Vitamin premis provides 3000 IU of vitamin A, 900 ICU of vitcsaia Ds, 40 mg of vitamin E, 0.7 mg of vitamin k, 1000 a>g of choline, 70 ag of niacin, 4 »g of pantothenic acid, 4 uq of riboflavin, 20 100 meg of vitamin B12, 100 meg of biotin and 125 mg of ethoxyguin per kg of complete feed. 2 Xrace mineral premix provides 75 lag of manganese, 50 sng of sine, 25 «ng of iron and 1 sag of iodine per Itg of complete feed.

Test animals received with the above ration varying doses of l=-(3-hydtroKyphenyl)-2»[l~methyl"3= (^-hydroxy-phenylJpropylasiinoJethanol hydrochloride (compound A). Each treatment w.s ^splicfited sixteen times, and the test was terminated when the animals reached fifty-sis 30 days of age. The animals were analysed for "eight gain end feed csffieieney. The results of tins test ia broilers is pseseatefi ia Tfsble ^'1 as mean weight gain and asaa feed to gsisa ratios.

Traatoaitt Control Compound A Compound A Compound A Cospsisnti! A Doss iq/n 20 40 SO Table VI Growth PerTcrro^ce of Sroilsrs Faed EfCicisr.cv Weight Gain Fssd/Gain % cUtasigs grass % iaorovemsnt Ratio from control 1473 0 2.336 0 1535 7.6 2.292 1.9 1613 9.5 2.253 1.® 1550 5.2 2.212 1.0 1669 13.3 2.221 4.9 The results of this study demonstrate that the g-phenethanolamines described herein ere effective in promoting growth end improving feed efficiency in poultry.

The compounds of the invention also have demonstrated efficacy in ruminants. Forty-eight crossbred wether lambs were employed in a test designed to show the effects of Compound A (l-(4-hydrosyphenyl)'-2~Jl-s>ethyl-3-(4-hydroJiyphenyl )propylamino]ethanol hydrochloride) at varying doses. Sixteen animals were held as controls, while sixteen received 40 ppra of Compound A, and another sixteen received 30 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 VII. The data demonstrates that a p~phenethanolaroine as defined herein is effective in promoting growth and improving feed efficiency in ruminents.

Table vii Growth Performance of Lamfcs Dcse ADG ADF F/G Treatment (kg/lbs) (kg/lbs) Control 0 0. 138 0.414 1 .369 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 (4)

1. CLftZHS 1. a method £osr pKOiaoting she growth, improving the afgiciency of Stead u'eilisatiea or istprov.iag the leanness of ® doeissticatetJ aairaal „ wh.ieli eosipyjses adsiin-5 istering to said ffiaisnal a eosigjotsties of alia foi-mule O): or an acid aelfiitiosi salt tJvareos;*
2. 2, A uethod according no claisn 1, fosr growth promotion. the efficiency of feed isti 11 session. 4. & method accog-diag to claim 1. fosr improving she leanness of a tHoBtasticasad sniEusl. 5. h stathod accordiacf to any one of cla jjas 1 to 15 4, wherein the cosupoand of gorsaula (I) is S-(4-hydro*y- phenyl) -2= [ l-a»8thyl-3- (S-hy&rosiyphianyl) propylasniiaoj ethanol, hydrochloride. 6. A method according to any one of claims 1 to 5 which comprises adaiiaisteriag an active compound of 20 fossiula (I) to pigs. 7. A natiiod according to any one of claims 1 to 5 which comprises adjaiaistering an active compound of formula (1) to cattle.
3. 3. &n fanisaal feed p?esaix comprising ti g-phen-25 ethanolesiiae of ths fosrsrala (X)° 10 3. & aafcjiod iaeeesTdiag to eleisn 1, for Sjap^oviitg eo S* or an acid addition salt thereof, associated with a suitable carrier therefor. S. An animal feed premix as claimed in claim' 8, wherein the compound of formula (I) is in the form o£ its hydrochloride. 10. A method according to claim 1 for promoting the growth, improving the efficiency of feed utilisation or improving the leanness of a domesticated animal, substantially as hereinbefore described and exemplfied. 11. An animal feed premix according to claim 8, substantially as hereinbefore described and exemplified. Dated this the 8th day of December, 1987. F. R. KELLY & CO. 27, Cl^de Road, Ballsbridge, Dublin
4. 4. AGENTS FOR THE APPLICANTS.