CA1195870A - Phenylethanolamine derivatives and acid addition salts thereof for the depression of fat deposition in warm-blooded animals - Google Patents

Abstract

PHENYLETHANE DERIVATIVES AND
ACID ADDITIION SALTS THEREOF FOR INCREASING
LEAN MEAT DEPOSITION AND/OR IMPROVING LEAN
MEAT TO FAT RATIO IN WARM BLOODED ANIMALS

ABSTRACT OF THE DISCLOSURE
A method for increasing lean meat deposition and/-or improving lean meat to fat ratio in poultry, domestic pets, sheep, swine, rabbits, goats and cattle by administer-ing, orally or parenterally, to said animals an effective amount of a phenylethane derivative or acid salt thereof.

Description

PHENYLETHANE DERIVATES AND
AClD ADDITION SALTS THEREOF FOR INCREASIN~
LEAN MEAT DEPOSITION AND/OR IMPROVING LEAN
MEAT ~O FAT RATIO IN WARM BLOODED ANIMALS

SUMMARY OF THE INVENTION
5ubs~ ution products o~ certain l~-(aminodihalo-phenyl)-2-amlno ethanes and the acid addition salts thereo~
are disclo~ed ln United States Patent 3,536,712g issued on October 27, 1970. Specifically, patentee~ disclose methods for the synthesls o~ said compounds and state 20 that said compounds are useful ~or enhancing the blood clrculation, and a~ bronchodllators, analgesics, sedatives~
antipyretlcs ~ antiphlogistics and antitussives in warm-blooded ~ m~ 1 S, Other related 1 aminodihalophenyl)-2 amino-ethanols and their derivates are disclosed in Japanese Kokal 77 83,619 (Chemical Abstracts~ 87, 201061r), ~erman O~enlegungsschrift 2,804,625 (1979), German O~enlegungsschri~t 2,157,040 (1973)~ German Offenlegung-~schrift 2,261,914 (1974), European Patent Applicat~on 8~715 ~198~)~ Netherlands Patent Application 7,303,612 ~1973). ~hese applications dlscloss uses selected from analgeslcs, broncholytic~ antlinflamm~tory, uterin~
spasmolytic 9 ~mlmetlc and~or ~blocking ~etivities, antispasmolytic ackivlty on cross~s~riped muscle structure, for tocology, reduc~ng blood pressure by peripheral ~asodilation and moblllzing body fat3 and ~or treatlng allergies.

5~7~

The patentees and authors referred to above do not, however, indicate or suggest that said compounds are useful for increasing lean meat deposition and/or improving the lean meat to fat ratio in warm~blooded animals, particularly farm and domestic animals, such as s~ine, poultry, dogs, sheep, goats, rabbits, cats and ca~tle. The term lean meat is used hereaf~er interchangeably with the amount of muscle or protein measured.
It is, therefore, surprising to find that a compound having a formula selected from the group consisting of:

y ~ CH - CH ~ NR2R3 (I) X ,Rl Y ~ CH N-R (Ia) X ,1 CH~ (Ib) O O

wherein X is hydrogen, halogen, or -CN;

Y is hydrgen,NRgRg or NHCORs;

~ is halogen, OH, CF3, CN,COORl, CONH2, Cl-C4 alkyl, Cl-C4 alkoxy, nitro, or Cl-C4 dialkylaminomethyl;

Rl is hydrogen or Cl-C4 alkyl;

R2 is hydrogen, methyl, ethyl, C2-Cs alkanoyl or 7q~

~o;

R3 is Cl-Cs alkyl, C3-C4 alkenyl, C3-Cs cycloalkyl, 2-hydroxy-ethyl, ~,~-dimethylphenethyl, ben~yl, 3-phenylpropyl or 3-(~
carbomethoxyphenyl) propyl;
R4 is hydrogen, OR6 or SRll;
Rs is hydrogen, Cl-C4 alkyl, Cl-C~ alkoxy, Rlo R o ~ CH20 ~ CO, or N(R1)2;

R6 is hydrogen, Cl-C6 alkyl, C3-C4 alkenyl, C2-Cs alkanoyl, Rlo Rlo R~o ~ ~ CO ~ CH2;

R7 is hydrogen, Cl-C4 alkyl or phenyl;

R8 .is hydrogen, Cl-C4 allcyl or C3-C4 alkenyl; Rg is hydrogen, Cl-C6 alkyl, C4-C6 cycloalkyl, C3-C4 alkenyl, or benzyl;
Rlo is hydrogen chloro, dichloro, methyl~ dimet.hyl, methoxy, dimethoxy or nitro;
Rll is Cl-C6 alkyl, phenyl, or ben~yl;
and when R8 and Rg are taken together with the nitrogen to which 37~1 ..., ~

they are a~tached, they may represent pyrrolidino;
with the provisos that when R3 is ~,~-dimethylphenethyl, C3-C6 cycloalkyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl, R2 is hydroyen, C2-Cs alkanoyl or benzoyl;
and when R3 is hydroxyethyl, R2 and R~ are hydrogen and the compound is (I);
and when R6 is C2-Cs alkanoyl or Rlo ~CO, R2 and R3 are substituents other than hydrogen, except when R3 is an alkyl or substituted alkyl group which contains a tertiary carbon attached to nitrogen;
and when Y is hydrogen, and X and Z are halogen, R2 is hydrogen, C2-Cs alkanoyl or Rlo CO

R3 is isopropyl, 2-butyl or tert-butyl;
and when Z is OH, X and Y are hydrogen;
and when X is -CN, Z is -CN;
and when Rs is N (R1)2, R6 is hydrogen;
and when R~ is Cl-C4 alkyl or C3-C4 alkenyl, Rg is Cl-C4 alkyl or C3-C4 alkenyl;
or racemic mixtures of the above~identified compounds and the optically active isomers, and non-toxic acid addition salts 7~

thereof, when administered to swine, poultry, such as chickens and turkeys, cattle, sheep, goats or domestic pets, increases the lean meat deposition on said animals, improves the lean meat to fat ratio thereof and enhances the dressed carcass weight of said animals. Moreover, in the treatment of swine it is particularly effective to administer the compounds of the invention to pigs being prepared for market and weighing between 30 kg and marke~
weight which could be in excess of 125 or 150 kg~
A preferred group of compound~ of formula I for use in the method of this invention have the above structure wherein X is hydrogen or halogen; Y is hydrogen, NR8Rg or NH-CORs; 2 is halogen, OH, CN or CE3; Rl is hydrogen or C1-C4 alkyl; racemic mixtures of the above-identified compounds and the optically active isomers and non-toxic, pharmacologically acceptable acid addition salt thereof.

- 4a -'~

~95~37~
, Another preferred group o~ compounds of ~ormula I ~or use ln ~he method Or this in~ention have the above structure wherein X is hydrogen, chlorine and bromine; Y is hydrogen or NR8R9; Z is chlorine~
C bromlne~ CN or CF3~ Rlls hydrogen; R~ is H, OR6 whereln R6is hydrogen, Cl~C6 alkyl, Cl-C6 alkanolyl or benzoyl; racemic mix~ures of the above-identif~ed compounds and the op~ically actlve lsomers and non-toxic, pharmacologically acceptable acid addition salt thereo~. ..
It ls-found that, in addition to the me~hods of preparation disclosed ln the cited art, the formula (I) compounds (wherein Y is hydrogen) may also be prepared by the condensatlon of an approprla~ely substituted styrene presence o~ an inert solvent~ such as a lower alcohol at or near the boiling point o~ same, as shown below:
X .

HN~ 2 ethanol X

2~ ~ Cl H2 N~R

whereln X and Z are halogen, R~ and R3 are as hereina~ove dePln~d and Y is hydrogen. Thus 9 ~or in~tance 9 one mole o~ 3,5--dichlorostyrene oxide can be reacted with fin equlmolar or exce~s amo~nt o~ tbùtylamlne in ethanol at re~lux ~rom about 1 to about 8 hour~, or until the reaction 18 essentiallg complete and the desired ~-Ct~-butylamino)methy~ 3 9 ~dichlorob~nzyl alcohol is obtalned~

~ ~5~

The ~tyrene oxide intermediate can be prepared by reduclng th~ corresponding phenacyl ~omide with NaBH4 at 5C or lower in the presence o~ an anhydrous lower alcohol, such as ethanol. Th~ phenacyl bromlde irltermediate . in turn i5 prepare~ by brominat~ng the approprlately 5 substituted acetophenone ~ith cupric bromide ln the presence ~ chloroform and ethyl acetate. The above sequence may ~e graphlcally lllustrated as follows;

Cl Cl

3 C~C13/~OAC ~ ~ C-~H2Br Cl Cl EtOH ~ O~
Cl Alternatlvely, ~ormula-(I) compound~ above wherein Y i~ hydrogen may be prepa~ed ~rom the corre~-25 pondlng formul (I3 compound wherein Y i8 ~mino, via .a deamina~lon reaction, as follows:
The amine ls dlssolved in 50-52~ aqueous hypophosphorous acid (H3PO2~9 the ~olutlon i~ chllled below 10C 9 an~ an equimolar or e~ce ~ amount o~ ~odlum 30 nitrite 1~ added a~ an aqueou~ 801ution wit~ ~tlrring over a perlod o~ time9 On completlon o~ the additlon9 the r~actlon mixture 18 warmed to room temperature ~nd ~tlrred for an addltional period o~ tlme~ The product ,, , ls then recoYered from the reac~ion mixture by standard laboratory procedures and purified if so desired.
~ he preparation o~ 4-substituted amino-acetophenones required for the preparation of 4-substituted phenylethanolamines by co~ventional means,which are now ~ound to be use~ui ~or raising meat-producing ~n~m~ls, is exemplified as follows:

F ~ O-CH3 ~ RgRgNH - ~ R8R9N ~ CO-CH3 (Excess~
The fluorine displacement is carried out with excess amlne in the presence Or a solvent and i~ a solvent is required, water appears to be the most use~ul. With volatil* amines, the reaction is conducted in a sealed vessel and generally tempera~ures of 50-100C are sufflcient ~o complete the reaction.
Chlorination and bromination o~ $hese amino-acetophenones may be conducted with N chlorosuccinimide and N-bromosuccinlmide in toluene, chlorobenzene or dichlorobenzene at 90-100C. Iodination may be conducted with NaI/N,N-dichlorobenzenesulfonamide or iodlne mono-chloride in acetic acid.
By reactlng these acetophenones with bromine in chloro~orm or methylene chlorlde, the corresponding phenacyl bromides are preparedD These phenacyl bromides are then reacted with R2R3N amlnes and the aminoketones are reduced with NaBH4 or NaCNBH3 by conventional teahnlques descrlbea in re~erences cited hereinbe~ore.
halogenatlon IX
R8RgN ~ COCH3 8 9 ~ COCH3 7~

Br2 X
RaRgN ~ COCH3 ~~~~ 8 9 ~ COCH2Br ~r R8R9N-'~ COCH2NR~R3 ~ 8 9 ~ fH H2 N 2 3 OH

whereln X and Z are hydrogen; chlorine, bromine or 1~ iodine and R2 and R3 are hydrogen; C1-C4 alkyl, or C2-C3 alkenyl groups.
The compounds of formula I, wherein R8 and Rg are groups other than bo~h belng hydrogen are also pr~epared by the following general scheme:

NH2 ~ COCH3 + ~R'CO)2 pyrldine~ R~ ~C NEI ~ COCX3 Z Z
(R9'CO ~

~ Pyridine BH3/TH~
~ N ~ COCH3 R "CO
Z

R8NH--~fH-CH3 ~ 3/ z OH

~95~
_ g _ ~0]

5~8R9N~3 I H-CH3 R8NH~ CH3 OH z o 1 ) SeO2 10 ~] ~ 2 3 \~

89~ C-CH3 ~8N ~8H-CH2-NR2 13 S~O2 2 ) R;~R3NH/NaBH4 R8RgN ~I H CH2 N~2R3 z OH

3 The methods utilized in the above æcheme are either repor~ed in references ~ited hereinbe~ore or by conventional m~thodæ. ûxida~i on of the alcohol may be - 10 - ~

co~ducted with chromic acid (Jones Reagent2, MnO2, pyridinium chlorochromat~, or other oxidlzing agents.
Where X or Z are the BH3-reducible groups CN, COOR, or CONH2g the appropriate acetophenones are prepared by displacemen~ of X or Z represented by bromine w~th CuCN/DMF at 100-150C by the conventional method after reduction of the acylated aminoacetophenones in the first step followed by re oxidation in ~he second step of the above procedure~ The cyano substituted-amino-acetophenones are then converted to their corresponding ethanolamines, which are then converted to the des~red esters, acids and amides by conventional me~hods, such as RlOHfacid ~ esters, hydrolyses~ acids and partial hydrolyses ~ amides.
Furthermore, compounds of khe ~ollowlng structure are prepared by allowing-the corresponding ethanolamines to react with an equivalent or slight excess o~ the acid anhydrides with or without organic bases, such as tertiary amines or pyridine. The reactlons are conducted in inert solvents Y ~ CH-CH-NR2R3 6 2~ y ~ CH~C -NR~R3 O-~-R~
such as chlorinated hydrocarbons, aromatic s~olvents at 0-25C. Reaction o~ the anhydrlde at the hydroxyl group proceed~ well provlded R2 and R3 are groupR other khan hydrogen and when R2 is hydrogen, R3 is a substituent cont~n~n@ a ~ertiary carbon attached to nltrogen.

137~

Compounds of the following structure whlch contain alkanoyl or aroyl groups on the ethanolamine molety are readily prepared by using 2 equivalents or more of the acid anhydrides in the presence of a tertlary amine~ such as triethylam.ine, or pyridine in an inert solvent (CH2C12, C~IC13, toluene~ etc.) at 50-100C.
X
y ~-CH-CH-NHR3 + (R6C-)20 base~ y ~ CH-N-R3 10 Z OH Rl X C-R6 C-R6 Additionally, Formula I compounds, wherein R8 and R~ are selec~ed from hydrogen ana C3-C4 alkenyl, are prepared by alkenylation of 4-amino-3,5-disubstituted phenacy.l bromides in dimethylformamide (DMF) in th~
presence of an acid acceptor, such as triethylamine or sodium carbonate, at 70-100C to afford mono and di~ke~ylate products which are separated and converted to I by conventional methods~ The following scheme illu~trates above-described general method:
Cl H2 ~ COCH2Br + CH~-CH-CH2Br 2 5 3 . C:l CZ~ c,~
25CH2=CH-CH2-NH ~ COC~2Br ~ (CH2=CH-CH2)2N ~ OCH~Br Cl Cl J~ t-BUNE2/NaBH4 .gC
CH~CH-CH2-N ~ CH-CH3-NH-C(CH~3 OH
Cl Formula ~I~ compounds wherein R4 is OR6 and SRll, wherein R6 and Rll are as hereinabove defined, may be prepared by converting the alcohol CR4=OH~ wlth thionyl ~hloride under an inert blanket Or gas such as nitrogen at a temperature ran~e of ~rom about 0 C
to 10C, and preferably a~ 0 to 59C ~or a reac~lon period sufficient to essentially comple~e the reaction.
The ~hus obtained halo compound is lsolated ~y con-ventional me~hods and is then reacted w~th t~e appropriate alcohol or mercap~an, under an lnert blanket of gas, such as nitrogen at a temp~rature range o~ ~rom about 0 to 50C. The formula ~I) product thus obtained is then ~olatedby standard ~aboratory methods and purified, i~ so desired. The above reaction se~uence may be graphically illustrated a~ follow~:

Y~ 7H-CH2-NR2R3 SOC12 >
z OH .(HCl)o 1 2 X~ X
Y~3CH-CH2-NR2F~3 1~60H ~ Y~_C~ CH2 NR2R3 ~ HCl)l 2 z 6 .(ECl~l 2 9J RllSH

. .

~ H CH2 NR2R3 z S~ HCl~l 2 wherein X, Y, Z9 R2, R6, and Rll are as hereinabove defined.

7'~
, .
~ 13 -These dlsplacement reactions may also be performed by uslng an excess of alkoxide (R60 ~ or mercaptide (R11S ~ in an inert solvent such as tetra-drofuran to afford ~he above ethers and thioethers in a s~mi1~r manner.
Alternati~ely, a formula (I) compound wherein R4 is OR6 may be prepared by dissolving the corresponding R60H alcohol and satura~ing the thus obtained solution wi~h dry HCl gas. The reaction mixture is then stirred at room temperature for a period of time sufficient to essentially complete the reaction and the product ls then isolated by standard laboratory procedures ~nd purif~ed if so desired. This reaction sequence may be illustrated as follows:
X
Y ~ t 2 2 3 6 ~ 2 3 Z OH HCl gas z OR6 (I) wh~rein X, Y~ Z~ ~2~ R3 and R6 are as hereinabove defined.
Amon~ the acid a;dditlon salts which can be prepared and used in accord~nce with the presen~ invention are the hydrochloric acid~ phosphorlc aeidg acetic acid, citri.c acid, gluconlc ~cid and propionic acid additlon salts. In accordance with t.he process o~ the invention, it has been ~ound that the increase in lean meat deposition and lmprovemPnt in lean meat to fat ratio in swine 3 poulkry3 sheep, goats, cattl~ and domestic pets can be achle~ed by ~m~nl sterlng to sald ~n~ an effectlve amount of a formula I phenyletha~olamine,or the acid addltion salt thereo~, ln the ~nlm~l ~eed. Th~
phenylethane~ or acid additlon salt~ may also b~
~flm~n~stered in the form of an ~n~m~l f'eed ~oncen~rate as a top dressing for the ~n1m~1s daily ration ~r it may be a~m~nl~tered as a subcut2neous implant in the ~orm o~ paste or pellet~.

~5~7~

~ 1 feed compositions effective ~or increasing lean meat deposltion and for improving lean meat to fat ratlo in poultry, swine~ sheep, goats, domestic pets and cattle are generally prepared by admixing a ~ormula ~I) phenylethane derivative or acid addition salt thereof or an ~n~m~l feed supplement containing said compound with a sufficient amount o~
~n~m~l feed to provide from about 1 to 1000 ppm of said compound ln the ~eed.
Animal ~eed supplements can be prepared by admixing about 75% to 95% by weig~t of a formula I
phenylethane derivatlve o~ acld addltion salt thereof with about 5% to 25% by weight o~ a sui~able carrier or dlluent. Carriers suitable for use to make up the feed supplement compositions include the following: alralfa meal, soybean meal, cottonseed oil meal, linseed oil meal, sodil~ chloride, cornmeal, cane molasses, urea, bone meal, corncob meal and the like~ The carrier promotes a uniform distribution of the active ingredients in the finished feed into which the supplement is blended.
It thus performs an important function by en~uring proper dlstribution of the active ingredient throughout the ~eed.
I~ the supplement i~ used as a top dressing ~or feed, it likewise helps to ensure uniformlty o~
d~trlbution of the active material across the top of the dressed feed.
The preferred medlcated swine 9 cattle, sheep and goat ~eed generally contaln ~rom 0.01 to 400 grams of actl~e ingredient per ton of ~eed, the optimum amount ~or these ~n~m~ls usually being about 50 to 300 grams per ton o~ ~eed.
The pre~erred poultry and domes~lc pet feeds usually contain about 0oOl to 400 grams and prererably 10 to 400 grams of active lngredient per ton Or ~eed.

513'~

~or parenteral administration the pehnylethane deriyative ~ay be prep~red in the fo~m of a paste or pellet and admlnist~red as an implant, usual~y under the skin of the head or ear of the animal in whlch increase in lean meat deposition ~nd improvement in lean meat to fat ratlo i5 sought.
In general parenteral administxation involves in~ection o~ a su~icient amount of the above-said phenylethane derivat~ve to provide the ~n~m~l with O . 001 to 100 mg/kg/day o~ body welght of the active ingredient.
The pre~erred dosage ~or swineg cattlej sheep and goats is in the range of ~rom .001- to 50 mg/kg/day o~ body weight o~ the actlve phenylethane derivatlve; whereas, the preferred dose level of said p~enylethane derivative for poultry and domestic pets is usually in the ran~e o~ from .001 to 35 mg/kg/day of body we~ght.
Paste formulations can be ~repared by dispersing ~he active phenylethane derivative ln a pharmaceutically acceptable oil such as peanut oilg ses~ne oil, corn oil or the likeO
Pellets cont~1 n~ ~g an effective level o~ the phenylethane deri~ative can be.prepared by admixing the above-sald active ingredient with a diluent such as carbowax~ carnuba wax, or the 11ke, and a lubricant, sUch as magnesium or calcium stearate, can be added to lmprove the pelleting process.
It is 3 of course, recognized that more than one pellet may be administered to an ~n~m~l to achieve the desired dose le~el whlch wlll provlde the increase in lean meat desposit~on and imp~o~ement in lean meat to fat ratlo de~ired. Moreoverg ~t has been round ~at ~mplants may also be made periodically during the ~nlm~l treatment period ln order to maintain the proper drug level in the ~nlm~l 'æ body.

7~
, . ~

The method o~ the present invention has several advan~a~es; for the pet owner or yeterinarian who wishes to increase leaness and ~rim unwanted fat from pet ~n~m~ls~ the present invention provides the means by which this can be accomplished. For the poultry men and swine raisers, using the method of the present lnvention yields leaner ~n~l s which command higher prices from the meat industry. Surprisingly, it is also noted that feed efficiency and/or ~n~m~l growth rate are signifi-cantly enhanced when the compounds of the presentinvention are adminis~ered ~o swine and poultry at selected do~e levels~
These and other advantage~ will become apparent ~rom ~he example~ set ~orth below. Such examples are provided only for exemplification of the lnvention and are not to be considered as limiting the invention.
Percent Body Fat Determination of Mice A. Preparation of Carcasses:
Stomach and intestines are removed from each -' mouseO All othex viscera, includins s~in and fur, rem2in intact. Each cage of mice (lO) are weighed and added to a lO00 ml beaker and ~utocalved at 120C (1,05 kg cm 2 pressure~ for 30 minutes. Carcasses from each cage are then blended and homogenizedO The homogenate is ~eighed an~ duplicate 5~gram samples are removed ~or ~nalysisD
B. ~a~ Analysis:
Fif~een mi1liliters (ml) of concentrated hydro-chloric acid is added to each 5-gr~m sa~ples and mixed well.
Samples are heated in an 8~C water bath for 2 ho~rs. TG
extract the fat, thirty ml of oetroleum ether is added to each sample, 15 ml at a time, and m.ixe~ well on a Vortex mixer~ The aqueous and organic phases are separated by low speed centrifugation and t~e ether la Jer ~containins fat) is extracted into tared 30 ml beaXers. Aftèr e~a-porating to dryness the beaker containing f2t is reweig~edto determine grams of fat per five grams of nomosenate.
Total body fat in the carcass is calcula~ed as follows.
;

~s~

grams fat grams total in s2mple homogenate Fat = - - - X 100 gram weight carcass weight of samDle of mice ~g) - Antilipogenic Evaluation of test compounds - Mouse Study CFI female mice, 55 days old, are weighed in groups of 10 and allotted to cages to minimize weigh~
variation a~ong cages~ Treatments are randomly assigned to cages.
Each of the txea~ments are tested in 3 replicates, i q e o ~ in 3 cages of 10 mice each~ There are 10 cages of 10 control mice each. Drugs are mixed in thc diet at tne d~saye level indicated. ~eed and water are offered ad libitum for 12-day test period. Feed spilled is col-lected during the test period. At the end of the test per-iod, the collected feed is weighed and the mean feed consump-tion per cage of ten mice is determined for each treatment.
The mice are weighed as a group of 10 and the weight gain determined~ The mice axe sacrificed by cervical dislocation.
The right uterine fat pad of each mouse is removed. The fat pads for each cage of 10 mice are weighed as a unit.
To establish the correlation between the percent re-duction in fat pad weights of treated animals and percent reduction in total body fat of treated animals, animals from several treatment groups are evaluated for total body .at using the body fat determination described in r.xample 1.
Data o~tained axe reported in Table II for those groups upon which such determination had been made, From percent reduction in fat pad weight and the total -at determinations for the groups tested, it can be seen that a reduction in fat pad weights of animals is generally indicative 0! a re-duction o total body fat of the treated 2nim~1s.

TA~ II
~mOOFNI~ F~lATJJATJff~ aF TEgr ~ ~ g~OY
- DOSAGE X REWCl'ION IN FAT
C~ ' (P~M)PAD WElrRI~ VS:~ROTS
(q~ert~uty~no)n ethyl~-3, 5~chl~4-d~methyl~mi3~Z00 ~i6 .1 b2n~yl alccilol 50 -14.8 3,~c~-{~(3{)henyl~opy1)~no~nethy1) 200 ~il.l b~yl alcoh~l 50 -36.2'

4~3,~dlc121~ phpnpt~ ] 200 -1301 .
D~thyl)ber~ lco ol hydr~l~orlde -13.9 ~-C (~)met~ -3~ ~ethY~o- 20D -51, 0 .ben~yl ~lco~l . 50 . -41.9 - 4 ~ 1~ N t -h~tyl-3,~dlcbla~1~. ~ U~rlam1ne 200 -57.0 .--17 . 0 Il r n~ N t -~utyl-3,5~ch:1~ro B ~ amlr~ 200 . -33.7 ~o!hc~le 5 . -15.3 T~ TT ~r ~
.3VA~IA~'7 OF q~ COMPa~7 ~ .~;E ~
71J7~ 1 ~ FAT
(PPM) . PAD ~Q~7 ~1 4 ~ (11; 3,5-dlc~ B ~ ~1,141) 200 -27.7 ~ r7~qf~,~ 50 -11l.6 .~thyl-4-C2-~te~7~yl ' ~ ,h~". b~ 1~-2,15-.t l Pf 4 50 -23 . 5 4'-[;~ " ~ ~1]-~"6~ci21~ 200 -27.1 p~ nt l~ .7 50 ~

lnr7~f.rlle 200 -45.9 -10.4 ~ ~1 cn a ~79~ ~tert-butyl-3,5dlchl~ 2Q0 -~4.2 0 1P ' - h~d~ . 50 -18.4 -a-~(f~butyl8mlno)1retl~r1]-3,5-dichlc~4-~7n~pyl~ n9t~ng~rl 200 -52,5 7~ 5 -22 6 - 3 -25.5 ..

., TAEtE 11 (C~tln~
A~C ~VALU.. ~ N v~F ~r l~u~ E ~DY
D05AGE % l1~1Uf,~ 1 FAT
- ~ (PPM) PAD w~a~ vs co~r~
4 C2~ V1P ) lh~ ,61- 200- -33~2 dlchla~v~l~ll~ SG . ~6.1 8enzyl-4-~2-( e~uty~amlno)-l~,.h~,.,~ ~,1]-2J6~1chlvL~&~a~e 50 --19.6 ~kehyl-5~t2~ Y~ ]- 2C0 . ~ 5'9 3-chlo~ 3ste ~chlor~ide 50 . ~ 5.8

5-L2-tTert~tylf~rv)-l h"l~.~ '~l~ant}nanilo- 200. ~ 5 ~ nltrile~ ~ 50 ~ ~10.3 4-[h ~i_~tyl-3,5-dic~v ~ "lt.h~r~) 200 -28~9 tl~,~ ~chlor~de 50 -16~2 N-te~-butyl-3,5~i~hls~v G~ e 200 . ~22.5 kYdrvcblo~de 50 -19~4 5~

hXæ~LE 2 Evaluation of test compounds for increasin~ the muscle and/or protein in swine and improving the lean mea~ ~o fat r~io thereof.
Barrows, weighing approximately 45 kg axe placed in pens and offered swine ~inishi~g feed con-taining 0.2% by weight of a chlortetracycline (50 g/lb) premix in soybean meal, and water ad libitum. When the pigs have reached 57 kg body weight, they are rAndom1y divided into groups of 6 and placed in pens.
Four pens Der trea~ment are used for the evaluations.
Control animals are offered an unmedicated finishing feed and water ad libitum throughout the trials. Medicated swin~ are offered the same diet cont~ining the test drug at the levels indicated in the table below and water ad libitum. The swi~e are weighed ~t the beginning and on com~letion of the experiment. Feed is weighed ~ach day and unconsumed fe~d collected rec~vered and weighed in order to determine the amount of ~eed consumed.
The experiment i conducted over`a ~2 day period at the end of which the pigs are sacri~iced by st~nn;~g and exsangui~ation. The head is ~ .o~ed and the ~n;~ eviserated. The dressed carcass is split in half lengthwise, weigh~d and hung overnight at 32F.
The split carcass is measured and then cut in cross-section a~ the 6th-7~h rib interface and at the lOth-llth ~` rib inter~ace. The loin eye (~ongissim~s dorsi~ cross-sectional area i5 traced onto paper and the area in the cm2 deterr~ne~ by overlaying a p~e-narked grid~

7(~
,, ~

The v~lues thu~ obt~iped are used to calculate the muscle and fat composition.
Half of each carcass is ground twice in a meat grinder and samples taken and analyzed for protein, mo sture and fat~
The diet employed in these tests is as follows~
DIET
SWINE FINI5~ER
Ingrediant %
Corn, Ground 83.15 Soybean Meal (49%~ 12.50 Meat & Bone Meal (50~) 2.50 15 DiCalcium Pho~phate (18.5% P3 0.75 Iodized Salt 0.50 Limestone ~33% Ca) 0.35 NI Vitamin-Minera} Mix* (Cyanamid) 0.20 Selenium Premix* (Cyanamid~0.05 7~
,,. ~

NI SWI~E VITAMIN-MINERA:L PREMIXa Furnishl3s the ~ollowing per 1000 kg ~2200 lb~ Diet Die~
Type Fini~her NI Premix.A~ded (%~ ~ ~n Vitamins:

Vit~in AM.I,U,b 3.52 Vitamin D3kl,I,U. ,88 Yitamin ET.I~U,C 2,2 Riboflavin g 2.6 d-Pantothenic Acid ~ 7.3 Niacin g 17,6 Clloline ~ ~ 76, vit~min ~12 m~ . 15,4 ~l~na~ione (K3) ~linerals:
Iodi~e (I) g .2,4 Cobalt (Co~ g 1.2 Copper (Cu) g 4.0 Iron (l`e~ . 8 4~0 ~ian~ane~ In)~ ~4.0 2inc t2n~ ~ 64.0 ~gne~iu~ 12.0 ~otssslum (K)~ 4 . 0 5ELE2~I~nq PREHIX
Addition of 0 . 05% or 0 . 5 kg per 1000 kg ~2200 lb) furnishes 0.1 ppm selenium in the finished diet, 37~
"

Moisture Determination Moisture content in the groun~ carcass samples ~5 determined by weighinq out ap~roximately 10 g samples~ pl~cing said sam21es in alumin~n foil pans and weighing the samples and pan. These samples are then placed in a forced air oven, dried overnight and the dry weight of the pan and sample determined the following day.
Protein Deter~ination i~ Protein content is determined by the macro-Kjieldahl method, using 1 y.sam~les of the ground carcass.
Fat Determination Approximately 5 g samples of the ground S carcass are weighed intc 50 ml centrifuge tubes.
Fifteen ml of concentrated hydro hloric acid are added to each sample and the samples digested by heating at 80C for 2 hours.
The samples are then extracted twice with 2G 15 ml of petroleum ether. The samples are agitated in a vor~ex mixer and the~ centri~uyed at 1500 rpm for 10 minutes. The ether layer is separated from the solids and the ether layers fro~ each extraction combined. The ether is evaporated and the r~m~; ni ng ~5 residue weighed to dsterm;ne the amount of fat in each ~ampleO
Data obtained are reported in ~able IV
below.

30 `

TABLE IV
Evaluat~oA of Test Compounds for.Increasing the Muscle and/or Protein in Swine and Improving the Lean Meat to Fat Ratio Thereof Compcund 4-amino-a- 1 ~tert-butylaminc~metbyl]~3,5-dichlorobe~2yl- alcohol-ppm i~ diet ppl~
Av./P~g 0 2 10 50 100 I~it. wk~ ~) 53.5 53.8 53,6 53.8 53.2 ' Final wt. ~q) 84.0 78.6 75.4 77.8 78.9 Ic~al Fbod ~b~s~icn(~g) 1~5 84 84 88 88 ~ Yd ~ b~(k~ ~1.4 57.8 56.1 57.9 58.0 qoka~ muscl~ 33.4 35.8 36.3 34.1 3~.~
~btal fat ~g~ 16.4 11.1 9.9 12.5 12.1 Eee~u~cle 3.1 2.4 2.3 206 2.5 TA~LE V
Evaluation of Test Compounds for Increasi31g Muscle Tissue an~/or Pro~ein in ~wine and Improving the Lean Meat to Fat Ratio Th reof Compound 4-amino~ ert~butyl ~i no ) methyl 1 - 3, 5-dichlorobenzyl alcohol-ppm in diet ~a'ca fr~ t ~ reps (heaviest pigs t ;n;~qt~ of~ d.y) Av~pig 0 Q. 5 2 10 Ini~. wt. ~k~) Sl.9 61.. 8 61.8 61.9 Final wt. (3~j 100.0 100.2 99.1 97.~
~3ys to ~ Jl-l Pr 45 51 64 56 ~) .~ inn (tot.kg) 128 126 129 124 N ~no. O~v.~ 12 13 . 11 lC
l~r~ ~L~Ss wi:. (kg3 74.98 76.98 76.95 75.~5 Total ~scle (kg) 39.!~4 43~25 44.35 43~85 Total ~at ~ 2G.84 19.05 17.95 17.25 P~ le 3 . 21 2. 91 2 . 91 2. 83 ~ i~pscv~t . - (+9.496) 1+9.4~) (+ll.R9~) ~) T~BLE V (Continued Compound 4-amino~ tert-butylamino)methyl~o3~5-dichlorobenzyl alcohol-ppm in diet D~ta ~æn 3r~ ~rd 4~ ps ~ tefit p~g~ at init~ ~ of ~y) ~E3n .
Av/pig O O . 5 2 10 Init. wt.(kg) 53 . 9 53 . 7 53 0 9 53 . 7 F~n21 wt~g) 100.4 98.3 95.8 98.8 , G~
Days to E~ JT~ 5S.1 63.0 ~9.~ 70.3 ~ed ~s~ ot~kg) 154 151 15a 142 N ~n~. a~v~ ) 12 10 8 9 ~e~3~ . ~r~ wt. (hg) 76.2 76.5 7409 7601 To~al mus~ (kg) 4t)~) 44.2 43.7 43.3 Ibtal fat ~kg) 21~7 19.9 1701 1708 scle . , 3.85 3.42 3.43 3.2~
?~t 1III~L~ (+~ %) (t 10~ 9~ 50 8%) ~513~
,_ ~

-2~-Example 3 Growth Enhancement, Feed ~fficiency Improvement, Increased Deposition of Muscle Tissue andjor Protein and Improvement in Carcass Composition ~o determine the effect of feeding experimental compounds to ruminants, wether lambs are randomly allotted to pens in group~ o~ ~ourO Five replications per treatment are usedO The sheep are weighed and permitted feed and wa~e~ ad libitum. The feed is weighed daily, and uneaten feed from the previous day is collected and weighed. Test lambs receive the same diet as control ani~als, but with ~he ~ddition of experimen~al compound at a concentration of rom 1 to 100 ppm. The tests are conducted for a period of eight weeks at the end of which the lambs are aga;n weighed, and the feed consumed calculated~ The lamb~, - are then necropsied. Ten animals per treatment are dressed, and the average cross-~ectlonal area of the longissimus dorsi mea~ured at ~he 12th rib and at the 7th lumbar vertebra measureda The data obtained ~re repor~ed in Table IX.

7~

-29- .

Example 4 N-tP~t-butYl-3,5-dichloro- ~methox~-4-methylamino-phenethylamine h~drochloride A 7 ~ ample of ~ r(tert-butylamino)methyl~
-3,5-~ichloro-4-methylaminobenzyl aloohol is added to 70 ml o~ thionyl chloride under N2 a~mosphere and the mixture is ~tirred for two hours. Exces~ thionyl chloride is removed i cuo, ~nd the glassy ~esidue is dissolved in ~0 ml of methanol4 ~he ~olution is stirred for 1.5 hours and evaporated to dryness.
The residue ~s dissolved in 100 ml of ~2 and extrac ed with 2 x 50 ml of C~2C12. ~he agueous layer is neutra-lized with solid ~a~CO3 and extr~cted with C~L~.
The extrac is dried ~MgSO~) and evaporated to dryness 15 in acuo to give 4.1 g of semi-solid, ~hich after trituration w~th ethyl ether affords 1.07 g o~ the title co~pound, mp 220 - 221Co . . Similarly, the ~ollowing ethers ~re prepared;

C 3 ~ C~2 ~ NH -~u~
I

Cl Alcohol R .
eth~nol ~2~5 l-propansl l-C3~
2-propanol 2-C3~7 1 butanol l~C4~9 2~bu~anol 2-C4~9 l-hexanol ~ C6~13 benzyl alcohol b~nzyl allyl alcohol allyl 1() 4-methoxybenzyI alcohol 4-methoxybenzyl 4 chlorobenzyl al~ohol 4-~hlorobenzyl 4-nitrobenzyl alcohol 4-nitrobenzyl 4-~ethylbenzyl alcohol 4-methylbenzyl 3,4-dimethylbenzyl lS ~lcohol - 3,4-dimeghylbenzyl 3~4-dimethoxybenzyl alcohol 3,4-dimethoxybenzyl 3,4-dichlorobenzyl alcohol 3,4-dichlorobenzyl , 2-chlorobenzyl alcohol 2-chlorobenz~l 2~- 2-methylbenzyl al~ohol 2-m~thylben~yl Example 5 ~-tert-Butyl-3,5-dic~loro~ -metho~yphenetbyla~in~
hydrochlor~de 25 ~ ~xture ~ontai~in~ 6.55 g of 4~ no-N-tert~butyl-3,5-d~hloro-~-metho~ypbenethylamine hydrochlor~de ~ 66 ~l o~ 50~ hypopho~phorous ~cid 18 cooled to 5C ~nd 1~52 g of NaN02 ~a lS ~l of ~2 ~8 added dropw~s~ pl~ foaming o~cur~ ~FO~
30 gas evolution and a~ter 0.5 houx~ at 5C~ the ~ ur~
~s ~tirred $urther ~ E~0~ te~pe~a~ur ~or two ~oursO
~t l~ the~ ~aae ~lk~lln~ ~t~ 50~ aqueou~ ~aO~ 80~ution~
~nd the m~xture 18 kep~ a~ ~elow 25 & ~lth ~ddi~on of lcec ~he mixtur~ x~r~c~ed ~t~ 3 ~ lOO ~l 35 of C~2C12 and the combined organ~c ph~ses ar~ washe~

~5~

wi~h ~00 ml of brine, dried ~gSO4~, and eYaporated to dryness in vacuo to give 5.1 g of ~he title compound in the form of ~he free baseO This product is dissolved in ~0 ml of EtOH and acidified at 5 with 4N HCl to afford a light orange precipita~e, which is collected.
This gives 3O36 g, mp 278 - 280 dec, o~ the title compound ~hich is re~rys~allized from i~opropanol to give 2O35 g, mp ~80C dec.
~ imila~ly, ~-isopropyl-3,5 dichloro- pmethoxy-phenethylamine hydro~hloride is prepared from 4-amino-N~isopropyl 3,5-dichl~ro- ~chlorophenethylamine hydro-chloride~
Example 6 ~
~n the mann2r des~ribed in ~xamplP 19, the ollowing ethers are prepared by su~stituting the corresponding alcohol~ for methanol.

. ~1 ~;1 .

~N ~ C~ N~ ~ C(C~3)3 Cl R m~
Ethyl ~ ~Cl) 180-182 2-~ropyl 117-121 benzyl 19 0-19 3 allyl 57- 59 l~hexyl 4-m~thoxybenzyl ~ chl~robenzyl 4-ni~roberl2yl ~-~nethylbenzyl 3, 4-dimethylbenæyl 3 ~ 4 -d ~ me thoxybenzyl 3, ~-dichlorobenæyl phenyl oi 1 ~ 4-chlorophenyl 4-me~hoxyphenyl ~-~ethylphenyl 2-c:hlorophenyl 4-nitropherlyl 13xample 7 ~-~ert-Xutyl-3-chloro-S~cyano~-Jnel:hoxy ~uninophenethyl-am~ne hydrochlcr ide In th~ nneE descr~lDea ~n ~x~rdple 4 25 ss- I t~er~ ~u'cy~ ~m~ ~ol~ethyl] -4 ~lno 3-chloro-S-cyano-benzyl alcohol 18 Gonverted Pnto the 'c~tl~ ~ompound~
~n~ m~l~rly, the following ~re alRo prep~re ~ ~ 2 ~ 3~ EICl ~9S~3~7~
.

~r 4-amino 3,5-dicyanophenyl t-butyl 4~amino-3-chloro-5~trifluoro-methylphenyl t-butyl 4-amino~3-chloro~5~rifl~oro-me~hylphenyl i-propyl 4-acet~mido-3,5-dichlorophenyl t-butyl 4-acetamidophenyl t-butyl 4-amiAo-3-chloro-5-H N-CO-phenyl ~ . t-butyl 4 amino-3-chloro-5-~O CO~
phenyl t-bugyl 4-amino-3-chloro-5~methyl phenyl t-butyl 4-amino-3~hloro-5-methoxy-phenyl t-butyl 4-amino-3-chloro-5-nitro-phenyl t butyl 4-amino-3-chloro-S-C~ O-CO-phenyl 3 . ~-butyl 4-amino-3-chloro-5 di~ethyl-ami~omethylphenyl t-butyl 4-amino-~-cyano-phenyl t-bu~yl . Example. 8 .
$-t4amino-3~5-di~hlorophenyl3-3-tert-butyl-2-oxazolidinone ~ .
~n :10 ml o CEI;2C~;, 005 g of ~-amin~
25 t (ter~ ~utyla~ino)methyl]-3,5-dicl lcirobenzyl alcohol ~s st~rred with 1 ml o~ 3N ~ 5& and 2 ml o~
~2.S~ COCl;~ In ~enzene,~S ml o C~ 2 i~ ~dded over lS minu'c~ rh~ re~ult~ng ~uspension lr~ed 20 ~inutes al~ l~C ~n~ allowed to war~ 'co room temperature 30 w~h fitirring or 1.5 hour~. ~he m~x~u~2 ~ evaporated to dryne~ nd t:h@ resi~ue 15 chromatogr~phed on yel w~th 1P1 ~exane~2C~2 to afford Ool 9 c~gE

7~

oil which crystallizes to yive ~he ~ltle compound, mp 97 - 103~C.
In the ~ame manner, ~-[(allylamino)methyl]
-4-amino-3,5-dichlorobenzyl alcohQl is allowed to reac~ with phosgene to afford 5~4-amino-3,5-dichloro-phenyl~ 3-allyl-2-oxazolldinone.
Likewise, the following compounds are prepare~
by this manner:

Ar-lR- 1~2 \C ~
Il.

Ar ~3 . . .
3,5-dichlorophenyl ~-butyl 3~5-dichlorophenyl i-propyl 4-acetamidophenyl t-butyl 4-amino-3-chloro-S-~yanophenyl ~-butyl ~-~mino-3 chloro ~-trifluoro~
~ethylphe~yl . t~but~l .3-~hloro-4-~etam~dophenyl t-butyl 3 J 5~ hloro-4-methxlæmino-:25 phenyl . t~butyl 3,5-diehloLo-4 e~hyl~mino-phenyl t-butyl 3,5-~lchloro 4-~-propyl~
~minophenyl t-butyl 3 9 5-d~¢hlors 4-acetam~do~
phenyl t butyl 3,5-d~chloro-4;~ethox~-~ar~nylaminophenyl t-butyl 305~ hloro-4-be~zylo~y-carbonylaMinophenyl t butyl 7~9 3,5 dichloro-4~methyl-carbamoylaminophenyl ~-butyl 4-amino-3-chloro~5-.
methylphenyl t-butyl 4-ami~o-3-cyanophenyl ~-butyl 4-aminc)-3-trifll3oroMethyl-phenyl t-butyl 4-amino-3-chloro-S-NH CO-phenyl 2 t butyl 4-amino-3-chlo~o-5 ~00C
phenyl t~butyl 4 a~ino-3-chloro-S-CX3OOC-phenyl t-butyl 4-amino-3-chloro-5-(C~332NCH2~phenyl t-butyl 15 1 4-amino-3,5-dicyanophenyl t-butyl . Example 9 4-Amino- ~ L Itert-butylamino~methyl]-3,5-dich}orobenzyl~
alcohol acetate A mixture containing 1 9 of 4-amino-o-[(tert~
bu~ylaminoJmethyl~-3,5-dichlorobenzyl alcohol in 1 35 ml of C~Cl~ a~ lO - 15~C is ~kirr~d, snd 0.37 g of Ac2Q and 0O5 ~l of ~t3N ~r~ ~dded dropwi~e. The ~ react~on ~xture lfi then allowe~ to war~ to room ~emperature, and the seaction i8 ~ollowed by ~hin-l~yer chro~tography to .o~pletr~on. Tbe ~ ura i~ evapor~t~d to dryneR~ In vacuo~ and the yellow P~GOU8 liguld ~1~5 g) 1~ st~r~e~ ~ith 50 ~1 of ethyl ~0 ~5~37C~

ether to afford a yell~w ~olid (~.8~ 93, mp 12~ - 131C~
This material i~ ~hown by nuclear magnetic resonan~P
~pectroscopy and by neutralization with ~lkali to be the acetic acid salt. On treating 100 mg of this ~alt in 30 ml of C~2C12 with 30 ml of 10~ aqueous NaQ~, the salt i~ neutralized. ~he C~2C12 ~olution is dried (MgSO4~ and evaporated to dryness in vacuo to afford the viscous title compound. Analysis-Cl~R2DO~N~C12~ C, 52.67; ~f 6.32; ~ 8 78;
Found: Cr ~2~38; ~ So51; N, 8.88.
In the 6ame manner, propionic anhydride~
butyric anhydride, pivalic anhydride, and benzoic an~ydride are allowed to react with 4-am~no~ -[~tert- -butylamino)methyll 3,S-dichlorobenzyl alcohol (A~ and a-l(tert-butylaminol~e thyl]-3, 5-dichloro-4-~ethylamino benzyl ~lcohol (B) respectively~ to af~ord the propionate, butyrat~, pivalate a~d benzoate~ of A and B.
ExamPlelO
The following e~ter~ are prepared by the method of ~xample 9 by u~ing the appropriate acid anhydr ide~

)--8R9M ~ C~2-N~-C ~c}~3~ 3 ~_ .
~ S
E:l' I
,~

~8 ~9 6 ~ 3 ~3 C2R~ ~33 n-C3~7 ~H3 2-C3~I7 C~3 benzyl C~3 R . allyl 1 ~I3 c~3 ~H3 ~H3 Il C E[3 : G2 ~3~? CO C~3 E[ C~3NH-CO ~3 B CH3 n-C4 C2~5 ~ c~3 n-S:4~9 n-CA~ 3 ~C~ C ~E13) 3 ~, 5~37g~

-~8-Ar ~6 ~,5-dichlorophenyl 2-C3H7 4-amino-3-chloro-S-~yanophenyl C~3 4-amino~3-chloro-5-trifluoro-methylphenyl CR3 4-amino~3-chloro-5~ CO-phenyl CH3 4 amino-3-ehloro-5-~ooc phenyl CH~
4-amino-3-chloro-5-methylphenyl C~3 4-amino~3-bromo 5-cyanophenyl CH3 4-amirlo-3chlsr~-S-CH30CO-phenyl CH3 4-amino-3-chloro-5-(C~3)~
NCR2-phenYl . ~3 4-amino-3,5-dicyanophenyl C~3 4~amino-3-cyanophenyl t C4~9 Example 11 , ~ N-~4-amino-3,5-dichloro-5-hyaroxyphene~hyl)-~-tert ~butylacetamide ac~tate A m~xture ~onta~ning 2.5 9 of 4~ami~o~ tert-butyl-am~no)~ethyl]-3~5-dichlor~benzyl alcohol, 25 ml of pyridine ~nd 10 ~1 of acet~c anhydride ~8 ~tirred ~or th~ee hours and evaporated to dryness in va~uo ~ith heat~ng up to 70~ The ~e~idu~ ~ treated ~th ~C~, 100 ~1 o~ C~2~12 and 50 ~1 of 10~ NaO~ ~ol~tfon.

7~
, The CR2C12 phase is ~ep~rated, and the agueous por~ion is fur~her extracted with CH2C12 (2 x 50 ml)- The combined C~2C12 ~olutions are dried 5Na25O~) and evaporated to dzyness ~o afford ~ solid af~er scratching.
The solid is washed with hexane and colle~ted to ~fford 2.61 9 of the ~i~le rompound, mp 126 - 136C.
Similarly~ by substituting the appropriate acid anhydrides, the following compounds are prepared.

~1 R8RgN ~ C~ - C~ - N C~CH ) Cl o--COR6 1~ R6 ~8 ~9 ~6 C~3 c~3 . - C2~s c~3 ~ 2 ~3~7 ~3 _~4~9 C~3 ~3 C~3 ~3 C~3O-~O ~3 CB3N~-CO c~3 CB~eO ~3 ~ ~3 ~2 3~ S2~5 ~5 Ar T~cH2 - 7 C(CH3~3 O COR~ ~R6 Ar R~
4-amino-3,5-dicyanophenyl C2~5 4-amino-~-chloro-t-dimethyl-amino methylphenyl C~3 4amino-3-chloro-5-C~300C-~henyl 2~5 4 amino-~-chloro-5-methylphenyl C~3 3,S-dichlorophenyl C~3 4-~mino-3-chloro-5-cyanophenyl C~3 4-amino-3 chloro~5 trifluoro methylphenyl C~3 4-amino-3-chlo20-5-~2NCO-phenyl CH3 4-amino-3-ehloro 5-~0-CO-phenyl CH3 Example 12 4-Acetamido-~-[(tert-bu~ylamlno)methyl]~3~5-dichloro-~en~yl alco~ol ~ce~ate In 15 ~1 of C~2cl2~ 1057 g of ~-~cetamido ~ t~er~obutylamino)me~hyll~3~dichloroben2yl ~lcohol ~ ~uspended and stirred ~hile lo 2 9 o tr~ethyl~mine ~n 30 ~1 o~ 30 ml of C~2C12 1~ added, ~ollowed by 007 g o~ acet~ anhydrlde ~n 1~ ~1 of C~2CL2. ~he ~ixtur~ 1~ 8~r~ed ~r 20 hou~s and the~ a~hed wl~h 100 ~1 o~ 10~ NaO~ ~o~utloaQ The orqan~ ph~&e ~8 8~parated, dr~ed (~a2SO~3 ~d evapor~ed to drynes~
In vacuo~ ~h~ resi~u~ ~5 dissol~ed in 30 ml of et ~n~ a tr~e of B29 ~8 ~dde~ followed ~y 10~ ~Cl to ~di~o The ~ixtur~ $s evaporated to drynes~
~n ~a~o and th~ ~e~idue ~ Grystall~ed ~rom aceto~e/
hex~ne ~30 ~1/5 ~l)o ~h~ ord~ 1.35 9, mpO 25 257 & aee., of the tltle ~ompoundO

~s~

-4~-Similarly, by replacing acetic anhydride with ~ropionic ~nhy~ridet butyric anhydride, pivaliç
anhydride, and benzoic anhydride, the ~orresponding propionate, butyrate, pivalate, and benzoate es~ers are prepared.
~ xample 13 N-Isopropyl-m-hydroxy-~-me~hox~phenethylamine hydro-chloride . In 425 ml of ethanol, 64 g of 3-benzyloxy--~henacyl bromide and 212 ml of iso-propylamine are stirEed at SC under N2 a~mosphere, and the temperature i5 allowed to rise to 12C~ After 0.75 minutes;
the ~lear ~olution is pour~d into 2 liters o crushed ice containing 500 ml of ~oncentrated ~Cl and 1.5 liters of ~0. The mixture is stirred for 20 minutes~ filtered and the solid ~s w~shed with water to a~ord 3'-~benzyloxy) -2-~sopropylamino-acetophenone hydrochloride, mp -213 - 215C de~,~ A 5 g - ~ample of this materi~l is ~tirred ~n 50 ~1 of methanol, and the mixture is cooled in ice and neutralized with 10% N~OH until a clear eolution is obtained. To this ~olution~
2 9 of Na~4 i8 ~dded and.~ft~r 0~75 hours of ~tirr~ngr ~he ~ix~ure i5 ~v~porated in ~a~uo, ~nd ~he result~ng ~olid 1~ ~olle~ted and w~shed w~th ~2 Thi~ gi~es, ~fter drylng~ ~.4 9 o~ ~-(ben2yloxy~ [(isopropyl no)~lethyl]beJ3zy3. 81coholt l~lp ~t3 ~ 85~Co ~ hi~ ohol 1~ then tr~ated ln th~ ~a~ner de~cribed ln Example 19 to a~for~ ~-f~opropyl-m~
benzyloxy ~-~ethox~ph~nethylam~e hyd~ochlor~de, ~hi~h ~ then deben2yl~té~ ~ith ~5~ palladium ~arbon ~t 50 p~ Og- in 2-~ropanol- ~fter f~lt~rln~ an~
evaporatlng to ~ryne ~, thi~ procedure ~ffords ~-i~opropyl-m hydroxy~methoxyphenethyl~lne hydrochlorid~.

~ ~15~7~

In the ~ame mann~r, N-tPrt-butyl-m hydroxy-~-~ethoxyphenethylamino hydrochloride is prepared ~tarting with 3'~(benzyloxy)-2-~ert-butylaminoa~etophenone.
Example 14 ~-t~tert-Butylamino)methyl]-m hydroxybenzyl alcohol ac~ta~e In the manner described in Example 12 -~benzyloxy)-c-[(tert-butylamino~methyl~benzyl alcohol ~s converted to m-tbenzyloxy9~ er~-butylamino)-1~ methyl~benzyl al~ohol aceta~e~ Thi~ ma~erial i then debenzylated by the prucedur~ of Example 28 to glv~ ter~-butylamino)methyI]-m~hydroxybenzyl alcohol acetate.
Example 15 5-~-Aminopbenyl~-3-tert-butyl-2-oxa201idinone In 270 ml of C~2C12, 12.97 g of u-l~tert butylamino~methyl~ nitrobenzyl alcohol ~s dissolved~
The solution i8 cooled to ~5C and 54 ~1 o~ 12.5%
pho~gene in benzene is added ~lowly. ~f~er th~ addition is comple~ed, the ~ixture i ~tirreæ for 3~5 hours and poured on ~c~0 The ~rganic ph~s~ eparatedO
and t~e ~queou~ l~yer ~ extracted w~th C~2el2 ~2 X 100 ml).
The combined organic layer~ ar~ wa~hed with Eatur~ted r~ro3 solution (2 X 250 ml), 100 ml o ~2 and dr~ed over ~gSO4. ~he zolut~on ~ evapora~ed to aryness to giv~ 16.3 ~, which ~fi ree~y~t~llized rom ~eO~
~wice to ~ford 12.S8 g of 3~ger~-butyl~ nitro-phenyl)-2-oxa201~dinone~ ~p 123 125 & ~ ~h~ product ~1~ g 3 i~ dis~olved ln 200 ~1 of ~eO~ ~nd hydrogena~ed 3'7~
. -43-over 6 g of Raney nickelat 51 p.s.i~g at 40C to give, after ~iltra~ion and evaporation, 8.21 q of 5-aminop~enyl) 3-tert-butyl-2~oxazolidinoneO
mp 125 - 129C7 Example 16 ~-[~tert~butylamino)-methyl]305-dicbloro-4-dimethyl-aminobenzyl alcohol A mixture con~aining 50 9 of ~-fluoroaceto-phenone and 150 ~1 of ~0% a~ueous dimethylamine is warmed in ~ pressure bottle a~ 90 - 100C. ~fter two hour~, ~ pale yellow oil i~ formed. The mixture is cooled~ ~nd the oil ~olidifies. ~he solid is oollected and wa~hed well with ~2 to give 54.93 of ~-dimethylaminoacetophenone, ~p 101 - 103C, af~er hep~ane reGrystallizat~on, ~ 72 g sample of this ~cetophe~one is heated with 129 g of M~chlorosuccinimide in 700 ml of toluene to reflux ~emperature and maintalned at this temperature for 35 minutes. ~he mixture i~ cooled and filtereda The ~ilter ~ake is washed with 200 ~ of ~o~u~ne, and the filtrate ~nd wash ~olution ar~ evaporated to dryn~ss in Yacuo to afford 66 g o~ oil. Thi~ oil ~s ch~omatographed on SiO2 with 40~ hexane/C~2C12 to q~ve 38~9 9 a 305-di~hloro 4-d~methylam~noaeetophenone ~8 ~ yellow oll. ~ ~.22 g ~ample o~ th~s ol~ dded por~ivnwise ~o 2.75 g of SeO2 in 20 ~1 of d~ox~ne and 0O7 ml o~ ~O at 55 ~ 60~o This ~ixture ie hea~d at reflux ~emperature or 4.5 hours, ~ooled a~d fil~gred ~hrou~h 8ill ~u8 ~arth. ~he ilter cake 18 wa~he~ w~th 20 ~1 of ~ioxane.
The ~oxane ~ol~tlon~ are coolea to 15C ~nd 2.77 9 of t-butyl~m~ne i added dropwise ~Q afford ~ tan prec~p~ta~e. ~fter stlrring 1~ ~inute~ ~ room ~emperature, ~s~

the mixture is diluted with 200 ml of ethanol, cooled 'co 5C and 7 9 of NasEl4 is added portionwiseO After 15 hours, the ~ixture is ~rea ed wi~h 300 - 400 g of ice and 20û ml of ~2 at below 10C. The mixture is ~tarred ~o dissolve all solids and extracted with of ~H2~12. ~he C~2C12 layer ls washed with 103 ml of ~0, dried (MgS04~ and evapora~ed to dryness in vacus to slive 5 ., 6 g of oran~e oil, This oil is di~solved in ethyl ether, dec~slorized with a~tiva ed 10 carbon and conc:entrated to 15 ml. On cooling, crystals are ob ained. The title product is collel:ted as white Grystals f mp 96 - 99oc.

Claims (13)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. An animal feed composition comprising an edible animal feed containing from 0.01 grams to 400 grams of a compound, based on one ton of feed, having the general formula selected from the group consisting of:

(I) (Ia) (Ib) wherein X is hydrogen, halogen, or -CN;
Y is hydrogen, NR8R9 or NHCOR5;

Z is halogen, OH, CF3, CN, COOR1, CONH2, C1-C4 alkyl, C1-C4 alkoxy, nitro, or C1-C4 dialkylaminomethyl;
R1 is hydrogen or C1-C4 alkyl;
R2 is hydrogen, methyl, ethyl, C2-C5 alkanoyl or R3 is C1-C5 alkyl, C3-C4, alkenyl, C3-C5 cycloalkyl, 2-hydroxy-ethyl, .alpha.,.alpha.-dimethylphenethyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl;
R4 is hydrogen, OR6 or SR11;
R5 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, R6 is hydrogen, C1-C6 alkyl, C3-C4 alkenyl, C2-C5 alkanoyl, R7 is hydrogen, C1-C4 alkyl or phenyl;
R8 is hydrogen, C1-C4 alkyl or C3-C4 alkenyl; R9 is hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, C3-C4 alkenyl, or benzyl;
R10 is hydrogen, chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro;
R11 is C1-C6 alkyl, phenyl, or benzyl;
and when R8 and R9 are taken together with the nitrogen to which they are attached, they may represent pyrrolidino; with the provisos that when R3 is .alpha.,.alpha.-dimethylphenethyl, C3-C6 cycloalkyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl, R2 is hydrogen, C2-C5 alkanoyl or benzoyl;
and when R3 is hydroxyethyl, R2 and R6 are hydrogen and the compound is (I);

and when R6 is C2-C5 alkanoyl or R2 and R3 are substituents other than hydrogen, except when R3 is an alkyl or substituted alkyl group which contains a tertiary carbon attached to nitrogen;
and when Y is hydrogen, and X and Z are halogen, R2 is hydrogen, C2-C5 alkanoyl or R3 is isopropyl, 2-butyl or tert-butyl;
and when Z is OH, X and Y are hydrogen;
and when X is -CN, Z is -CN;
and when R5 is N (R1)2, R6 is hydrogen;
and when R8 is C1-C4 alkyl or C3-C4 alkenyl, R9 is C1-C4 alkyl or C3-C4 alkenyl;
or racemic mixtures of the above-identified compounds and the optically active isomers, and non-toxic acid addition salts thereof.

2. An animal feed supplement comprising about 10% to 25% by weight of a compound having the general formula selected from the group consisting of (I) (Ia) (Ib) wherein X is hydrogen, halogen, or -CN;
Y is hydrogen,NR8R9 or NHCOR5;
Z is halogen, OH, CF3, CN,COOR1, CONH2, C1-C4 alkyl, C1-C4 alkoxy, nitro, or C1-C4 dialkylaminomethyl;
R1 is hydrogen or C1-C4 alkyl;
R2 is hydrogen, methyl, ethyl, C2-C5 alkanoyl or R3 is C1-C5 alkyl, C3-C4 alkenyl, C3-C5 cycloalkyl, 2-hydroxy-ethyl, .alpha.,.alpha.-dimethylphenethyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl;
R4 is hydrogen, OR6 or SR11;
R5 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, R6 is hydrogen, C1-C6 alkyl, C3-C4 alkenyl, C2-C5 alkanoyl, R7 is hydrogen, C1-C4 alkyl or phenyl;
R8 is hydrogen, C1-C4 alkyl or C3-C4 alkenyl; R9 is hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, C3-C4 alkenyl, or benzyl;
R10 is hydrogen, chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro;
R11 is C1-C6 alkyl, phenyl, or benzyl;
and when R8 and R9 are taken together with the nitrogen to which they are attached, they may represent pyrrolidino;
with the provisos that when R3 is .alpha.,.alpha.-dimethylphenethyl, C3-C6 cycloalkyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl, R2 is hydrogen, C2-C5 alkanoyl or benzoyl;
and when R3 is hydroxyethyl, R2 and R6 are hydrogen and the compound is (I);
and when R6 is C2-C5 alkanoyl or R2 and R3 are substituents other than hydrogen, except when R3 is an alkyl or substituted alkyl group which contains a tertiary carbon attached to nitrogen;
and when Y is hydrogen, and X and Z are halogen, R2 is hydrogen, C2-C5 alkanoyl or R3 is isopropyl, 2-butyl or tert-butyl;
and when Z is OH, X and Y are hydrogen;
and when X is -CN, Z is -CN;
and when R5 is N (R1)2, R6 is hydrogen;
and when R8 is C1-C4 alkyl or C3-C4 alkenyl, R9 is C1-C4 alkyl or C3-C4 alkenyl;
or racemic mixtures of the above-identified compounds and the optically active isomers, and non-toxic acid addition salts thereof.

3. A composition according to claim 1 or 2 wherein X is hydrogen, chlorine or bromine; Z is CN; Y is NH8R9 wherein R9 is hydrogen or C1-C4 alkyl; R1 and R2 are each hydrogen; R3 is iso-propyl or tert-butyl; and R4 is OH.

4. A composition according to claim 1 or 2 wherein the compound is 5-[1-hydroxy-2(isopropylamino)ethyl]anthranilo-nitrile.

5. A composition according to claim 1 or 2 wherein the compound is 3-chloro-5-[2-isopropylamino)-1-hydroxyethyl]anthra-nilonitrile.

6. A composition according to claim 1 or 2 wherein the compound is 3-bromo-5-[2-(tert.-butylamino)-1-hydroxyethyl]anthra-nilonitrile.

7. A parenteral formulation in the form of a paste or pel-let for subcutaneous implantation in meat-producing animals there-by to increase lean meat deposition and to improve the lean meat to fat ratio which comprises an effective amount of a compound having the general formula selected from the group consisting of:

(I) (Ia) (Ib) wherein X is hydrogen, halogen, or -CN;
Y is hydrogen,NR8R9 or NHCOR5;
Z is halogen, OH, CF3, CN, COOR1, CONH2, C1-C4 alkyl, C1-C4 alkoxy, nitro, or C1-C4 dialkylaminomethyl;
R1 is hydrogen or C1-C4 alkyl;
R2 is hydrogen, methyl, ethyl, C2-C5 alkanoyl or R3 is C1-C5 alkyl, C3-C4, alkenyl, C3-C5 cycloalkyl, 2-hydroxy-ethyl, .alpha.,.alpha.-dimethylphenethyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl;
R4 is hydrogen, OR6 or SR11;
R5 is hydrogen, C1-C4 alkyl, C1-C4 alkoxy, or N(R1)2;

R6 is hydrogen, C1-C6 alkyl, C3-C4 alkenyl, C2-C5 alkanoyl, R7 is hydrogen, C1-C4 alkyl or phenyl;
R8 is hydrogen, C1-C4 alkyl or C3-C4 alkenyl; R9 is hydrogen, C1-C6 alkyl, C4-C6 cycloalkyl, C3-C4 alkenyl, or benzyl;
R10 is hydrogen, chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro;

R11 is C1-C6 alkyl, phenyl, or benzyl;
and when R8 and R9 are taken together with the nitrogen to which they are attached, they may represent pyrrolidino; with the provi-sos that when R3 is .alpha.,.alpha.-dimethylphenethyl, C3-C6 cycloalkyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl, R2 is hydrogen, C2-C5 alkanoyl or benzoyl;
and when R3 is hydroxyethyl, R2 and R6 are hydrogen and the compound is (I);
and when R6 is C2-C5 alkanoyl or R2 and R3 are substituents other than hydrogen, except when R3 is an alkyl or substituted alkyl group which contains a tertiary carbon attached to nitrogen;
and when Y is hydrogen, and X and Z are halogen, R2 is hydrogen, C2-C5 alkanoyl or R3 is isopropyl, 2-butyl or tert-butyl;
and when Z is OH, X and Y are hydrogen;
and when X is -CN, Z is -CN;
and when R5 is N (R1)2, R6 is hydrogen;
and when R8 is C1-C4 alkyl or C3-C4 alkenyl, R9 is C1-C4 alkyl or C3-C4 alkenyl;
or racemic mixtures of the above-identified compounds and the optically active isomers, and non-toxic acid addition salts there-of in admixture with a non-toxic, pharmaceutically acceptable oil or wax.

8. The formulation according to claim 7 wherein X is hydro-gen, chlorine or bromine; Z is CN; Y is NH8R9 wherein R9 is hydro-gen or C1-C4 alkyl; R1 and R2 are each hydrogen; R3 is isopropyl or tert-butyl; and R4 is OH.

9. The formulation according to claim 7 wherein the com-pound is 5-[1-hydroxy-2(isopropylamino)ethyl]anthranilonitrile.

10. The formulation according to claim 7 wherein the com-pound is 3-chloro-5-[2-isopropylamino)-1-hydroxyethyl]anthranilo-nitrile.

11. The formulation according to claim 7 wherein the com-pound is 3-bromo-5-[2-(tert.-butylamino)-1-hydroxyethyl]anthra-nilonitrile.

12. The composition according to claim 1 or 2 wherein the compound is 5-[1-hydroxy-2(tert.-butylamino)ethyl]anthranilo-nitrile.

13. The formulation according to claim 7 wherein the compound is 5-[1-hydroxy-2(tert.-butylamino)ethyl]anthranilo-nitrile.