Phenylethanolamine derivatives and acid addition salts thereof for enhancing the growth rate in meat-producing animals

237;3~7 PHENYLETHANE DERIVATIVES AND ACID ADDITIOM SALTS THEREOF FOR ENHANCING T~E GROWTH RATE OF ~EAT-PRODUCING ANIMALS AND/OR IMPROVING T~E EFFICIENCY OF FEED UTILIZATION T~E~EBY SUMMARY OF THE INVENTION Substitution products of l-(amino-dihalophenyl) -2-aminoethanes, and the acid addition salts thereof, are disclosed in United States Patent 3,536,712, issued October 27, 1970.

Specifically, methods for the synthesis of said compounds are disclosed as useful for enhancing the blood circulation, and as bronchodilators, analgesics, sedatives, antipyretics, antiphlogistics and antitussives ~ in warm-blooded animals. ~owever, only the analgesic '`''`` ` ~e~ ea~ utility is ei~q~ he~.

The preparation of other related 1-(amino-dihalophenyl)-2 aminoethanols and their deriYatives are di~closed in Japan~se Rokai 77 83,619 (C~emical Abstracts, 87,2D1061r), German Offenlegunysschrif~ 2,804,625 (1979), German Offenlegungs ichrift 2,1~7,040 (1973), German Offenlegungsshrift 2,261,914 ~1974), 20 Europen Patent Applicat~on 8,715 tl980), Netherlands Patent Applicat~on 7~303,612 (19~3). ~hese appllca~lons . ~5 ~;~3~;73~ --2- disclose uses selected from analgesics, broncholytic, antiinfla~matory, uterine spasmolytic, ~-blocking activities, antispa~olytic activity on cross-striped muscle structure, for tocology, reducing blood pressure by peripheral vasodilation and mobilizing body fat, and for treating allergies. There is no indication or suggestion in any Of these disclosures that said compounds are effective as growth-promoting agents for meat-producing animals, such as poultry,~cattle, sheep or the like; nor is there any suggestion that said compounds improve the efficiency oE feed utilization by said meat-producing animals.

In accordance with the process of the invention, it has been found that the growth rate of meat-producing animals such as chickens, turkeys, rabbits, sheep, goats and cattle, including calves, can be increased and/or the efficiency of feed utilization thereby measurably improved by the oral.or parenteral administration to said animals of an effective amount of a compound selected from the group consisting of:

- .

2~ ~_ (I) Y ~ ~H-~H-NR2R3 3~ . ~3~ ~3~3~7 (Ia) ll _~CE~ Z O CHR7 ; and t Ib ) X C/ \ 1 ~ O wherein, X is hydrogen, halogen or -CN;

Y is hydrogen, NR8Rg or NHCOR5;

Z is hydrogen, halogen, OH, CN, CF3, COORl, CONH~, Cl-C4 alkyl, Cl-C4 alkoxy, NO2, Cl-C4-dialkylaminomethyl or hydroxymethyl;

Rl is hydrogen or Cl-C~ alkyl;

25 R2 is hydrogen, Cl-C~ alkyll C3-C4 alkenyl, C2-C5 alkanoyl or Rlo ~0;

R3 i~ hydrogen, Cl-C~ alkyl, C3~-C6 cyoloalkyl, met~e~yprop~l, C3-C4 alkenyl, phenyl, 2-hydroxye~hyl, ~ 30 dimethylphenethyl, benzyl, 3-phenylpropyl or 3-(4 carbomethoxyphenyl)propyl; and when R2 and R3 are ~aken together with the nitrogen to which they are attached~ they represent morpholino or N'-Cl-C4 alXylplpera~ino;

R~ ~ hydrogen~ O~, OR~ or SRll;

35 X5 ~ hydroqent Cl-C4 alkyl.

Cl 4 Rlo ~ 10 ~-' 20 ' ~ or N(Rl)2 _4_ ~373~ 7 R6 is Cl-C6 alkyl, C2-C5 alkanoyl, Rlo 10 ~10 ~ ~ o or ~ C~2 R7 is hydrogen, Cl-C4 alkyl or phenyl;

R8 is hydrogen, Cl-C4 alkyl or C3-C4 alkenyl;

Rg is hydrogen, Cl-C6 alkyl, C4-Cs cycloalkyl, C3-C~ alkenyl, or benzyl; and when ~8 and R9 are taken together with the nitrogen to which they are attached, they represent pyrrolidino; Rlo is chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro; Rll is Cl-C6 alkyl, phenyl or benzyl; with the provisos that when R3 is phenyl, 2-hydroxyethyl, ,~-dimethylphenethyl, C3-C6 cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl, or 3-(4-carbomethoxyphenyl)propyl, R2 is hydrogen;

and when R3 is hydroxyethyl, R4 is Aydroxyl and the compound is (I); and when R6 is alkanoyl or Rlo ~ C~ , R2 ~nd R3 are substituents other than hydro~en, e~cept when R3 is an ~lkyl or substitutPd alkyl group which contains a tertiary carbon attached to nitrogen; and 3~ when Y is hydrogen, X ~nd Z are ha}ogen, and R~ is hydrogen, C3-C5 alkanoyl or Rlo ~CO, R3 i5 ~sopso~yl, ~-butyl, or t-~utyl; and when R8 ~ Cl-C~ ~llkyl or C3-C~ alkenyl~ Rg ~s hydrogen~ 37317 Cl-C4 alkyl or C3-C4 alkenyl; and when Z is OH, X and Y are hydrogen; and that at least one of X, Y and Z represents a substituent other than hydrogen, and when X is -CN, Z is -CN; and when Z is hydroxymethyl, R4 is OH; and when Z is a group other than halogen, Y is NR8Rg or NHCOR5; and when R5 is N(Rl)2, R4 is OH;

and further provided that when X is hydrogen or halogen, and Y is hydrogen, NH2 or NHCOR5, and Z is hydrogen, halogen or OH, then R4 cannot be hydrogen, OH or OR6 where R6 is Cl-C6 alkyl; racemic mixtures of the above-identiEied compounds and the optically active isomers, and non-toxic acid addition salts thereoE.

Accordingly, there is provided an animal feed supplement comprising about 10~ to 75~ by weight of a compound having the above structure, and about 90 to 25% of an edible diluent. In another aspect, there is provided an animal feed composition comprising an edible feed containing from 0.01 gram to 300 grams per ton of feed of a compound having the above structure. In yet another aspect, there is provided a parenteral formulation in the form or a paste or pellet or subcutaneous implantation in meatproducing animals thereby to enhance the growth rate and imp^ove the efficiency of feed utilization, which comprises an effective amount of a compound having the above struc-ture in admixture with a non-toxic pharmaceutically acceptable oil or wax.

A preferred group of compounds for use in the method of this invention have the above formula I structure wherein X is hydrogen or halogen; Y is hydrogen, NR8R~ or NHCOR5; Z is halogen, OH, CN, CF3, COORl, CON~12, methyl, methoxy, NO2, Cl-C4 dia kylaminome-thyl, or hydroxy-methyl; and the remaining groups are as hereinbefore defined; or a non-toxic acid addition salt thereof.

~3~ Another preferred group of compounds for use in the method of this invention have the above formula I structure wherein X is hydrogen, chlorine, or bromine, Y is hydrogen or NR8Rg; Z is chlorine, bromine, CN, CF3; Rl is hydrogen or methyl; R4 is - 5a .

~37~7 OH, OR6, SRll; R6 is Cl-C6 alkyl, benzyl, C2-C5 alkanoyl, or benzoyl; or a non-toxic, acid addition salt thereof.

A fur-ther preferred group of compounds have the formula I structure wherein X is hydrogen, chlorine or bromine; Z is CN; Y is NHRg wherein Rg is hydrogen or Cl-C4 alkyl; Rl and R2 are each hydrogen; R3 is isopropyl or tert-butyl; and R4 is OH.

The most preferred compounds for use in enhancing the growth rate of meat-producing animals and/or for improving the efficiency of feed u-tilization -thereby are: hydrochloride, 4-amino-N-tert butyl-3, 5-dichloro-~-methoxyphenethylamine hydrochloride,N -[(ter-t-butylamino)methyl~-3,5-dichloro-4-me-thylamino-benzyl alcohol; ~~[t _ -butylamino)-methyl}3,5-dichloro-4-isopropylaminobenzyl alcohol; ~-[(tert-bu-tylamino)-methyl]-3,5-dichloro-4ethylamino-benzyl alcohol; 5-[2-(tert-bu-tylamino-1-hydroxyethyl]-3chloro-anthranilonitrile; N-tert-butyl-3,5-dichloro-~-methoxy-4methylaminophenethylamine; 3-chloro-5- [2- (tert-butylamino)-lhydroxyethyl]anthranilonitrile.

Although it is evident from the above discussion that certain compounds represented by formula I above are described in the literature, many compounds represented by formula I are new and unobvious. The novel and unobvious compounds of the present invention are represented by the structure of formula I, 11 ~3'7;~7 --7- 5 wherein X is hydrogen, halogen or -C~1;

Y is hydroyen, ~R3Rg or NHCOR5;

Z is halo9en, -CN, CF3, COORl, CONH2, Cl-C,~ alkyl, Cl-C4 alkoxy, NO2 or Cl-C~ dialkylaminomethyl;

Rl is hydrogen or Cl-C4 alkyl;

10 R2 is hydrogen, Cl-C~ al~yl, C3-C6 cycloalkyl, C3-C~ alkenyl, C2-C5 alkanoyl or Rlo ~CO R3 is hydrogen, Cl-C6 al~yl, C3~C6 cycloal~yl, C3-C, lS a'kenyl, phenyl or ben~yl;

R4 is OH, OR6 or SRll;

R5 is hydrogen, Cl-C,~ alkyl, Cl-C~ alkoxy, Rlo Rlo ~ H2O , ~ or N (Rl) 2 R6 is Cl-C6 al~yl, C2-C5 al~anoyl, Rlo Rlo Rlo ~ Co or ~ C~2 R8 is hydrogen, Cl-C4 alkyl or C3-C~ albenyl; - - ~9 is hydrogen, Cl-C6 alkyl, C~-C6 cycloal~yI, C3-C~ alkenyl, or benzyl; Rlo is hydrosen, chlorot dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro;

~ll is Cl-C6 al~yl, phenyl, benzyl; with the provisos that when Y is N~ , NHC~3, ~HC2~I5 or N~COR5, R~ is OR6 or SRll; and when Y is hydrogen, X and 3 are halogen, R~ is hydrogen, C2-C5 al~anoyl or 1l0 g - C3 ~3~73~L~ and R3 is isopropyl, 2-butyl or t-butyl; and when X is -CN, Z is -CN; and when R6 is aIkanoyl or Rlo /~ CO, \ R2 and R3 are substituents other than hydrogen, except when R3 is`an alkyl or a substituted aLkyl group which con-tains a tertiary carbon attached to ni.-tro-gen; and when R8 is Cl-C4 alkyl, or C3-C4 alkenyl, Rg is hydrogen, Cl-C4 alkyl or C3-C~ alkenyl; when Z is OH, X and Y a.re hydrogen; and that at least one oE X, Y and Z represents a substi-tuent other than hydrogen; and when X is -CN, Z ls -CN; and when Z is hyclroxymethyl, Rq .is Oll; and wllen Z is a group other than haLocl~n, Y is NR~ o.r NIICOR5; and when R5 ls N(.~)2, Rq i5 OH; and further p.rovicbc1 that when X is hyd.rvcJen or halocJen, and Y is hyclrogen, N112 or NEIOOR5, and Z is hydrogen, halogen or OH, then R4 cannot be hyclrogen, OH orOR6 where R6 is Cl-C6 aLkyl; racemic mixtures of the above iclentified c~rnpounds and the opticaLly active isorrers, and nontoxic acid addition sc~lts thereoE.

~ preferred group of the novel compounds of this invention have the abo~e structure wherein X = hyclrogen or halogen; Y is hydrogen, NR8R9, or NH-COR5; Z is halocJen, CN, CF3, COOR, CCNH2, rrethyl, methoxy, N02, Cl-C4 dic~Lkylaminon-ethyl; ~ is hydrogen, or rrethyl, R2 is hydrogen, Cl-C4 alkyl, C3-C4 alkenyl, C~-C4 alkanoyl or benzoyl; R3 is hydrDgen, Cl-C6 aIkyl, C3-C~ cycloalkyl, Cl-C4 alkenyl, benzyl; with the above provisos, and further providedthat when X and Z are halogen and Y is hydrogen or Ntl2, -then R4 cannot ba hydrogen, OH or O~ when R6 is Cl-C6 alkyl.

~ most pre~arred group o.E novel compo~ds o:E this invention have the above struct~e wherein X = hydrogen, chlorine, bronine; Z is chlorine, bromine, CN, CF3, COOEII COCCH3, COCC2H5, CONH2; ~ is hydrogen; ~ is hydrogen, Cl-C4 alkyl; .R3 is hydrogen, Cl-C4 aIkyl; with the c~bo~-a provisos, and Eiuther provided that wh~l X and Z are halogen and Y is hydrogen or N~12, then R4 cannot ~ - 8 ~` ~3~3~L~ be hydrogen, OH or O~ where R6 is Cl~C6 c~Ikyl.

It is found, that formulca (I) compounds below (wherein Y is hydrogen) can be prepared by the condensation of an appropriately substituted styrene oxide with thR appropriately substituted anine in the presence of an inert solvent, such as a lower alcohol at or near the boiling point of same, as hown below:

A " - 8a ~237~317 g , _ ~ ~ R ethanol >

X (I) ~ fH-CH - ~ 2 0 z wherein X and Z are halogen, R2 and R3 are as hereinabove defined and Y is hydrogen. Thus, 3,5-dichlorostyrene - oxide can be reacted with an equimolar or molar excess of t-butylamine in ethanol at reflux from ab~ut one to a~out eight hours, or until the rea~tion is essentially complete and ~he desired ~-[(t-butylamino)methyl~-3~5dichlorobenzyl alcohol is obtained as illus~rated ~~ below.

Cl Cl + ~2NCgHg~t EtOH ~ ~ CH CH~ NH-C4H9 t Cl ~1 .

-10- ~ ~ 3 ~ 3 1 ~ 5 The thus obtained product can be purified by known procedures, such as chromatography or recrystallization of salts thereof.

The above styrene oxide is made by reducing the corresponding phenacyl bromide with NaBH4 at or below 5C in the presence of an anhydrous lower alcohol, such as ethanol. The phenacyl bromide intermediate is prepared by brominating the appropriately substituted acetophenone with CuBr2 in the presence of chloroform and ethyl acetate. The above sequence may be g~aphically illustrated as follows:

Cl Cl 20 ~ C-CX CuBr2 ~ 11-CH2Br O CHCl3/EtO~c ~ ~ O Cl Cl 2~ Sl NaB~I4 ~7 Cl Alterna~ively, a formula (I) compound wherein Y ls hydr~gen may be prepared from the corrPsponding formula (I) compound wherein Y is amino, ~ia a deamination reaction, by dissolving the amin~ in 50;52% aqueous ~ 3 ~ 3 ~ ~ S hypophosphorous acid ~H3PO2). The solution is chilled below 10C, and an equimolar or excess amount of sodium nitrite is added to an aqueous solution with stirring over a period of time. On completion of the addition, the reaction mixture is warmed to room temperature and stirred for an additional period of time. The product is then recovered from the reaction mixture by standard laboratory procedures and purified if so desired.

The preparation of 4-substituted aminoacetophenones required for the preparation of 4-substituted phenylethane derivatives which are now found to be useful for raising meat-producing animals, is exemplified as follows:

F ~ O - C~3 + R8RgNH ~ R8R9N ~ - CO - CH3~excess) The fluorine displacement is carried out with excess amine in the presence or absence of a solvent; and, if a solvent is requ;red, water appears to be the ^ most useful. With volatile amines~ the reaction is conducted in a sealed vessel and generally temperatures of 50 - 100C are sufficient to complete the reaction.

3~ Chlorination and bromination of these amino acetophenones may be conducted with N-chlorosuccinimide and N-brolllosuccinimide in toluene, chlorobenzene or dichloroben2ene at 90 - 100C. Iodination may be conducted with NaI/N,N-dichlorobenzenesulfonamide 35 or iodine monochloride in acetic acid.

1~:373~7 -12 By reacting these acetophenones with bromine in chloro~orm or methylene chloride, the corresponding phenacyl bromides are prepared.

These phenacyl bromides are then reacted with R2R3N amines and the aminoketones are reduced with NaBH4 or NaCNBH3 by conventional techniques described in references cited hereinbefore.

Naturally, compounds which contain groups reactive to halogen, such as when R8 is alkenyl, require other approaches that are discussed below.

R8R9N ~ COCH 2` R R N ~ - COCH~Br R2R3N~ R8R9N--~ CCH2NR2R3 ~ R8RgN ~ H CH~ -~R2R3 z OH wherein X and Z are hydrogen, chiorine, or bromine 35 and R2 and R3 are hydrogen, Cl-C~ alkyl, or ~-C3 alkenyl groups.

i .

3~'7 -13 The compounds of formula I, wherein R8 and R9 are groups other than both being hydrogen are al.so prepared by the following general scheme:

NH ~ OCH3 + (R'Co) 2 ~ridine R'-C-NH ~ COCH3 (R'CO) O 2 ~ ~ BH /THF ~ 3 pyridine X L~ R~NH~fH-CH3 20 R'C ~ COCH Z OH R"CO ~ 3 ~ [O] X 25 ¦ BH3/THF ~ ~-CH3 R8RgN ~ ~H-CH3 ¦ 1) SeO 30¦ H v 2~ R2R3NH/NaBH~ ] R8NH~CH CH? NR2P~3 X dH RgN ~ , ~ fi-CH3 Z 35 a 1) SeO2 - X 2) R2R3NH/N~BH4 8 9 ~ C~-C~2-~2R 2 OH ~L~373~L7 -14 The methods utilized in the above scheme are either reported in references cited hereinbefore or by conventional methods.

Oxidation of the alcohol may be conducted with chromic acid ~Jones Reagent), MnO2, pyridinium chlorochromate, or other oxidizing agents. Where X or Z are the BH3-reducible groups, C~, COOR, or CONH2, the appropriate acetophenones are prepared by displacement of X or Z represented by bromine with CuCN/DMF at 100 - 160C by the conventional method, after reduction of the acylatecl aminoace~ophenones in the first step followed by re~oxidationin the second step of the above procedure. The cyano substituted-amino-acetophenones are then converted to their corresponding ethanolamines, which are then converted to the desired esters, acids, and amides by conventional methods, such as RlOH/acid-~esters, hydrolyses~ ~acids and partial hydrolyses-_,~amides.

Furthermore, compounds of the following structure are prepared by allowing the corresponding ethanolamines to react with an equivalent or slight excess of the acid anhydrides with or without organic bases such as tertiary amines or pyridine. The reactions are conducted in inert solvents O X (~6~- )2 X ~rl IH NR2R3 ~ Y~ --NR2R3 O -15- ~2373~7 such as chlorinated hydrocarbons, or aromatic solvents at 0 - 25C, Reaction of the anhydride at the hydroxyl group proceeds well provided R2 and R3 are groups other than hydrogen and when R2 is hydrogen, R3 is a substituent containing a tertiary carbon attached to nitrogen.

Compounds of the following structure which contain alkanoyl or aroyl groups on ethanolamine moiety are readily prepared by using two equivalents or more of the acid anhydrides in the presence of a tertiary amine, such as triethylamine, or pyridine in an inert solvent tCH2C12, CHC13, toluene, etc.) at 50 - 100C.

~ ~ H-fH-NH~3 + (R6C-)2 bas~ Y- ~ H-CH-N-R3 Z OH R z 1 6 6 Additionally, Formula I co~pounds, wherein R8 and Rg are selected from hydrogen and C3-C4 alke-nyl, are prepared by alkenylation of 4-amino-3,5-disubstituted phenacyl bromides in dimethylformamide (DMF) in the presence of an acid acceptor, such as triethylamine or sodium carbonate, at 70 - 100C to afford monoand dialkenylated products which are separated and converted to I by conventional methods.

The following scheme illustrates above-described general method:

-16- ~ 2 ~ ~31 7 Cl H2N~ COCH2Br +CH2=CH -cH2sr C2H5.)3N r (excess) D~ Cl Cl Cl CH2=CH--CH2-NH ~ -cQcH2Br + (CH2=CH=CH2)2 N~ COCH2Br ¦ t~ BuNH2/NaBH4 \/ Cl CH2=CH- CH2-NH- ~ fH CH2 - NH - C(CH3)3 Cl OH Formula (I) compounds wherein R~ is ORS and SRll, wherein R6 and Rll are as he.reinabove defined, may be prepared by converting the alcohol (R4=OH) wi~h thionyl chloride under an iner~ blanket o~ gas such as nitrogen at: a temperature range of from about 0 to 10C 35 and preferably at 0 ~o 5C for a reaction period suffici~nt ~o essen~ially complete the reaction~ The ~hus obtained -17- ~ ~ 3 7 ~ 1 ~ 5 halo compound is isolated by conventional methods and is then reacted with the appropriate alcohol or mercaptan, under an inert blanket of gas, s~ch as nitrogen at a temperature range of from about 0 to 50C. The formula (I) product thus obtained is then isolated 10 by standard laboratory methods and purified, if so desired. The above reaction sequence may be graphically illustrated as follows:

y ~ H - CH2 - NR2R z OH (HC1)o,l,2 y ~ - CH-CH2-NR2R3 ~ ~fH - CH - NR R z c 1 OR6 . (HCl~l 2 ~ RllS~ ~ F 2 NR2R3 SRll (HCl)l 2 7~ - -18 5 wherein Xf Y, Z~ ~2~ R3, RS and Rll are as hereinabov2 defined, These displace~ent reactions may also be performed by using an excess o~ alkoxide (~6 ) or mercaptide (RllS ) in an inert solvent such as tetra10 hydrofuran to afford the above ethers and thioethersin a similar manner.

Alternatively, a formula (I) compound wherein R4 is OR6 may be,prepared by dissolving the corresponding formula (I) compound wherein R4 is OH in the corresponding 15 R6OH alcohol and saturating the thus obtained solution with dry HCl gas. The reaction mixture is then stirred at room temperature for a period of time suEficient to essentially comple~e the reaction and the product is then isolated by standard laboratory procedures 20 and purified, if so desired. This reaction sequence may be illustrated as follows: , X X ~ ¦ 2 2 3 HCl gas ~ Y43CH-CH2NR~R3 . HCl OH OR, : (I) wherein X, Y~ Z~ R2, R3 and R6 are as hereina~ove 30 defined, In the present specification and cl~lms, the term ~ o~dimethylphenethyl means a ~tructure having the following configurat~on:

~ CH-C- I CH3 .

-19- ~:3~L7 When orally administered in the feed, generally about 0.01 to 300 grams per ton of feed of the aboveidentified phenylethane derivative or acid addition salt thereof, is effective for enhancing the growth rate and improving the efficiency of feed utilization by the above-mentioned meat-producing animals.

Since the effective and preferred dietary levels of the active ingrec~ient vary somewhat from species to species in the above-mentioned animals, said levels for each animal species are listed in Table I below on a gram per ton o feed b~sis:

TAB1E I Effective Prefer~ed Feed Level Level Compound g/Ton g/Ton Animal Formula (I) 0.1-200 1-100 Sheep, Goats _ 0.01-50 0.1-10 Chickens, Rabbits 0.01-50 0.1-10 Turkeys 0.1-30~ 1-100 Catt~e Animal feed compositions which will provide the desired growth promotion and feed efficiency in the abovementioned animals can be prepared by admixing the phenylethane derivative or acid addition salt thereof~ or ananimal eed supplement containing said compound, with a sufficienl: quantity of an appropriate animal feed to provide the desired level of active compound in said feed.

~:37~ -20 Animal feed supplements can be prepared by admixing abo~t 10~ to 75~ by weight of the phenylethane derivative acid addition salt thereof, with about 90~ to 25% by weight of a suitable carrier or diluent.

Carriers suitable for use to make up the feed supplement compositions include the following: alfalfa meal, soybean meal, cottonseed oil meal, linseed oil meal sodium chloride, cornmeal, can molasses, urea, bone meal, corncob meal and the like.

The carrier promotes a uniform distribution of the active ingredient in the finished feed into which the supplement is blended. It thus performs an important function by ensuring proper distribution oE the active ingredient throughout the feed.

If the supplement is used as a top dressin~ for feed, it likewise helps to ensure uniformity of distribution of the active material across the top of the dressed feed.

For parenteral administration, the phenylethane derivative may be prepared in the form of a paste or pellet and administered as an implant, usually under the skin of the head or ear of the animal in which enhanced growth rate and~or improved efficiency of feed utilization is sought.

In practice, parenteral administration generally involves injection of a sufficient amount of ~he abovesaid phenylethane derivative to provide the animal with from 0.001 to 50 mg/kg of body weight of the active ingredient. The preferred dosage level for cattle is the range of from 0.001 to ~5 mg/kg of body weight of the active phenylethane derivative. The pre~erred dose level of said phenylethane derivative for poultry is about 0.001 to 35 mg/~g of animal ~ody weight and the pre~erred ~ose l~vel o~ said phenylethane derivatiYe for sheep an~ goa~s is 0~1 to 40 ~g~kg of a~imal ~ody wei~h~.

The preelre~ ~ose le~el for r~b~its ~5 0 . ~01 to 3~ my~kg of ani~a~ body weight.

~LZ3~3~7 Paste ~ormulations can be prepared by dispersing the active phenylethane derivative in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like.

Pellets containing an effective level of the phenylethane derivative can be prepared by admixing the above-said active ingredient with a diluent such as carbowax, biodegradable polymers, carnauba wax, or the like. A lubricant, such as magnesium stearate or calcium stearate may be added to improve the pelleting process if desired It is, of course, recognized that more than one pellet may be administered to an animal to achieve the desired dose level which will provide the increased growth rate and/or improve efficiency of feed utilization by said animal. Moreover, it has been found that additional implants may also be introducted periodically during the treatment period in order to maintain the proper drug release rate in the animal's body.

In addition to enhanced growth promotion and improved efficiency of feed utilization ~y meatproducing animals, the compounds of the present invention have the added advanta~e that, at selected levels of administration, they increase the deposition of lean meat (i.e., muscle or protein) in said animals and improve the carcass quality thereof by increasing the ratio of lean meat to fat in the animals receiving them. This biological response has substantial advantage to poultrymen, cattlemen, and swine, sheep and goat producers since administration o~ said compounds at selected levels yields leaner animals which command premium prices from the meat in~us~ryr ~3~7317 -~2 ~rhese and other advantages of the present invention will become apparent from the examples set forth below.

Such examples are provided only by way of exemplification and are not intended to be expressions of limitations on the invention.

EXAMPLE l Evaluation of Test Compounds as Animal Growth Promoters CFI female mice from Carworth Farms are received when they are six weeks old.

They are housed ten to a cage in air-conditioned rooms (72F to 76F~ 15 with automatically controlled lights, 14 hours on and 10 hours off.

The basal diet used in these st~dies is Purina Laboratory Chow (see description below), which is supplied ad libitum.

Water is allowed ad libitum.

Thirteen days after arrival, the mice are weighed in groups of ten and assigned at random to the different treatments.

The concentration of the different compounds in the diet is indicated in the following tables.

Twelve days later the mice are 25 weighed again, and the experiment ~erminated. Test data are provided in Table II below wherein data ar~ reported as percentage gain over controls. The following is description of the diet to which the growth-promoting compounds were added.

DIET Guaranteed AnalYsis Crude protein not less than23.0 Crude ~at not less ~an 4.5 Crude fiber no~ mor~ than ~.0~ Ash ~ot m~re ~an 9.03 -23- ~ % 3 ~ 3 Ingredients Meat and bone meal, dried skimmed milk, wheat germ meal, fish meal, animal liver meal, dried beet pulp, ground extruded corn, ground oat groats, soybean meal, dehydrated alfalfa meal, cane molasses, animal fat preserved with BHA, vitamin B12 supplement, calcium pantothenate, choline chloride, folic acid, riboflavin supplement, brewe.r's dried yeast, thiamin, niacin, vitamin A supplement, D-activated plant sterol, vitamin E supplement, calcium carbonate, dicalcium phosphate, iodized salt, ferric ammonium citrate, iron oxide, manganous oxide, cobalt carbonate, copper oxide, zinc oxide.

-24- ~23~317 O r l C~ ~ O~ ~ ~I L'l ~ ~J l'_ r~ I~ O I_ ~ I~ O C 0~ +i + ++ ~ ~ ~ CO ~ _~ O ~ 0 ~ O C a~ ~ 0 --I ~1 L'~ ~ E ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ .

C:J ~ O g g L--~ ~_1 ~0~ ~ 1 t`~ ~ C~ . ~ ~ ~ ~ D r C O C e _ l c ~ ~,~ CJ r-l _ C L'~ E--~ O v o_ ,_ - c i ~ o C lU ~ ~ ~ ~o .... . _ ~ . ~ ......... _ __.... _.. ___ ....... . . _ .. _.. .. _____ _.. ._.. ..

... ; .. _ .. ..... ... _ _.. . _---- _ _. _ ...... .. . ......... _ .. . . .. . .. . .... ... . . . .... .......

-25- ~L~3~331.

a~ O ~1 C cn ~O -1 , ~ Ln U~ ~D r~ a~ ~D ~ ~ o~ * + ~ ~o o ~ o oE P~ ~ 3 C: E~ o ~ o~ ~ ~ 0 o~ a~ ~ O O ~ ~ r-l ~0 0 0~ ~ ~ O Ul N ~ tJ~ _~1 t~--¦ ~I N r~ 1 -1 N ~I N ~I N N ~1 ~ E ~1 ~: ~ n I E o oo o o o o o o o o o u 8 ~ N N N N O ul N ~ ~,) h O O O ~J a s: .c l l Iv E-~ V_I ~ ~ ct~ C~l O N O 1 .~1 0 U~ S 0 0 O :~ _~ t) _ , ~0 _~ ~ O ~~ ~ ~ .~: ~a ~ ~ ~ u In Q) u~ ~ ` Q~ 1~7 ~: ~ ~ .Q ~ ~ C ~ _ 5;?_ N ~-- --~ _I ~1 ~--I 91 S r~ 1~0 C: ~.1~ O ~ ~1--I ~t C --I E ~ ~O ~ ~ N ~ ~t ~--~ = ~ u ~ n_1~ ~ ~ .n ~ a t> a) ~ I ~ .

--E~ ~ O J ~ V ~ _~ r_ ~ ~ L~ Q~ P.I Ll . x l _ r~ aJ~ o~ a)~ ~; ~ O ~ ~ :~ E~ ~ oQ~ -E~ ~ 0~ ~ ~ :~0 -2~ 3731.~ o ol ~ _I N ~ N O ~D O cr~ Ll O r` r~ o r~ co ~D ~ a~ u~ o v ~ r) ~ cr~ Il'~ ~r) r~ _o + ~* +~ ++ +++t Vo O Ll P~ ra . ~ ~ ~ N ~D ~r U~ ~ O O~ ' I ~ -( ~ r~ V~ N N .~p ~ ~ r-tO~ _ N N N N N N N N N N N ~ ~ a~ _ ~ ~,_ c ~n~ ~o c~o oo oo oo~ a a-- u. N N O u') N D~.

~a c ~ ~c1 l o ~¢ X ~ t In E~ ~ ~ ~ Ll _l ~ _l a~ h ~ O ~ ~ a~ .C 0 ~ C O ~ 9 ::>1 :~. o ~ e I a) ~ o QS `~-1 ~ _~ ~ :~ ~ i U r~ O ~ SO ~ ~.C ~ ~ O I O :~ h c: ,1~ ,s:: ~ ~ ra _~ ~8 ~ I ~ _l ~ I .s: s ~n ô ~ I ~ æ :~ ~ ~ ~ ~ o -~ _ ~:

O ~ ~ ~ e~ 5: ~: ~ _ N ~Q O ~ V ~rl O ~ O ~ ~ ~ R~ a~ ~ ~I O ~ O ~ ~ ~ .,1 ~l ~ _I ~ _~ ~ ~ ~î ~ ~ ~1 ~ O S J~ O ~ 0 N .S: ~3 C ~ V :J ~.1 ~ ).1 ~ ~J _I _ _~ ~1 o ~ a~ s~ ''1 I 'lD I r-l N I ~ .f; i S:- _ N ~ l o I O .

~_ l ~ O O L~ .. ~ ~ O dJ t~ :~ ,q ~ ~D I V ~ ~ ~ C~ I . _ I t) ~P' ~J .. ~ I ~ ~ e I ~n I ~i~373~L7 --27- O'r N 0~ 0 N O ~ CO N . .

C ~o~ ~-1 1~ ,(e~ o ~`1It~ u~ o o Vc~ ~ N ~D + f ~ ~ O _ .c E~ ~ e~ ~1~ ~_l ~ ~ I~ ~ ~ ~ ~ o~ ~r o ~D ~ U~ ~ U~ O ~ _ N N N N N N N t~ N N N l~l .) ~O O NO O O O O N H ¦ O . ~ m~L~ l 1~ ~ o E~ V ~ K U _ u u r K C O 1 0 O ~ U ~ 0 _ ~ ~ V~ 'O _ I E~ 3 l E~ ~i ~E~ C O (~l O O _l _l Rl ~1 ~1 ~ t~l ra ~:

,~; 1~1-- v " c .... ,. u v D u '1~ ~ "1 .Q D. i~ ~ ~ o ~o ~ ~ I_ :~ ~ O ~ O .~ ~ O ~ ~:

~) o N.~: ~ U . ~ ~ rI ~l~c ~ ~b ~ ~ ~ ~ I n v ~' ~lo ~_~ _ ~ ul -2~ 373~L~ ~ I Lf~ 3(~ '~DO ~li\ r~ ~o O ~ _' O ~ ~ Lr~ ~ CO ~ ++l C~ :+C~ +Ct- +t c ~ !3~ ~o ~3 ~_0 ~ .. ~ r O c~ C~ 3 ~ c) b~ ~ ~ ~ 1 ~ .~ ~ ~ 0 0 O 0 0 0 00 0 ~ U~ P. O U~ OO Lf~ O ~ O U~ O O ~ ~ ~ ~' ~ .

.~ ~ .1 Ir~ ~ O X ~J A r--1 O ~-1 ~ ~ ~ O ~I ¦ .~ E ~ RE ~ ~¦ 3 ~1 ~ ¦' 3 1 N .0 _ C~ lR Q~ -1 ~¦ I ~ I s~ J~l ~d S ~ ~ ~ _l ~0 ~_ ~ I O ~ _ ,0 ~ IJ I o I c~ E a~ I S I c~ If ~ r--l ~ -1 t~5 .0 (~) ~ Nm o C o ~ N 3 O ~ ~ a R ~:373~L7 29 O ¦ H H ~~J L~`\ ~o CO ~ S~ O t-- ^O L^\ ~ ~ ~ =r ~O ( rl ~ t~ N ~0 H CO 1~ (~ ~ _ L'~ ~ ++ ++ ++ ++ ++ P~ ~ ~ ~ ~o o ,~ ~o ~ ~ r-- ~ =~ S ~ ~ co ~ cO r~ c~ o =r co U~ ~O S~ C~ r-l~l ~ ~1~ 1~~ ~1~ .

bO J~ ~ OO OO OO OO OO S:~U~ U~ D~ O L~\ O L'~ O Ir~ O L'~ O L c~ a~ ~ ~_~ ~1 ~ ~\J ~J .

H O O~ O ~;

C ~ l O U~ l l H Lr~ a) ~ s~ l s ~-1 ~ X c:O L~ a~ S O ~r-l ~ ~ ls I a~ E~ ~ ?~ X~r~~ C) ~_ ::~ sl S ~ ~ s ~ s ~ ~ ~1 L~ ~ ~ ~1 ~i ~ l ~ ~ I~ ~ Q~ ~ o ~:: ~ s ~ o ~ :~ ~ ~ I C~ ~ ~ ~ tQ o ~ ~ ,~ s s ~! ~' ~ C~ ~ o ~ o ~ l ~ S S F ~ ~, ~) ~ o ~ _~ :~ ~ S~ ~rl '~I ~ ' I C~ ~~ u\ E E~ N Q~ ~ ~ ~ ~ ~ ~ ~ C) ~) r-l r-J (I) Q~ ~1 I ~i N r~ ~ :~ Q ~ S S~ ~' ?~ ~S O ~ O I rl~ ~Q S: l c) ~ a) Lr~ ~1~ 5~ I .~ ~ ~1 a~ Q Q a)~ E~ I ~ ~1 0 ~0 ~_~ S~ ~ ~ ~ r-l N O O F~ ~ O ~ :~ ~ ~ H ~ S V ~ `--X E N a~ S m ~ ~ .~ , ~ ¢ ~ m c~ I ~ I ~ I S I ~ I ~rl (~ ~ Z ~ ~ ~' a~ Q ~ ~ ~L~23731.'7 --30- ¦ O CJ~ cs~ ~ ~ ~r ~ ~J S~ O X , o~ ~ O .~ ~ =r o ~,~ ++ ++ ++ ,~+ ++ ~ ,~ LO~D (~ ~ ;~ ~0 S ~ ~ ~ CS:~ ~ O ~ L-~ ~D CO U~ C~ ~IL` ~ ~I r~ N (~J ~J ~ r~ ~) ~ t~ E o o o o o o o o o o U~ U~ ~ O U~ O LS~ O L~ O U~ O U~ o~ ~ ~ ~U ~ ~ ~ .~ o ~ ~ C~ l .~ ~ o l U~ I o l S _ ,~ ~D~S r~ ~o ;~ l , ~ ~ s~' ,o rr~ ~ S s~ ~ ~ ~ l a~ ô a 3 ,~ ~ ~: ~ a) 5~ a r~ ~ X ~ X J~ X ~ ~ o E o u~ o u~ ~ ~ ~ ~ ,~ ~_, ~ '~ ~¦ l ~ s~ s~ ~o ~ Q~l'o ~o~ ~, ~ , 8 ~ s~ ,~ ,~.

=r a I ~ ,D ~ O ~ Q ~ ^ ~ V ~ -- ~ ~ l ~1 ' x ~ a) ~ a) ~ c) O r~ !~ ~ ~ O ~Q C\l ~-~ i~ ~-1 r~ ~ S ~1 cS~ ~ S .=r, ~>

S~ 3~ I ;~ _ ~ ~ -31- ~3~317 ~o o ~ ~ ~ U~ _ ,, ~ ~ L~C~ ~ ~ ~ + + V C~ ~ ~ ,~o ~ O C N r1 ~1 ~ ~ g~O 00 ~ L~ C~ l O O h r~l ~ S ~ C) O ~) ~ ~ 1~0 ~1 ~U E ~1 ~ ,~ ~ O ~ ~ ~1~ . :>, ~5 E _3~ 31~ The procedure described above is repeated for the evaluation of each of the following compounds usins different control animals for each test.

Twelve days after the tests are started, the animals are weighed and the test terminated.

The results of each test are reported in Table II~ below as weight gains for each test group and percent gain for each test group over the weight gains obtained by the control animals in the specific test in which the compound is evaluated.

lS ~ ` _33_ ~3731~ L~ o .

l o a~ ~D ~ r~ In ~n ~ ~ G~ ~ ~ ~ CO ~ ~ ~ ~1 ~ ~--O O ~D ~ ~r C~ O ~ ~ ~ ~n r~ . ~ co ~ U~ dP~ + ++ ++ I+ ++ +l o P.

s _ o a~' a~a~ ~r ~ ~ a~o~ ~ o 3 .,~ ~ ~,1 ~D~ ~-r ~o ~ ~ o~ ~ Cl ~t~ ,~ ,_1 ~1~ ~1~ ~(~ ~ ~ ~: ~_ oo oo oo oo oo oo U~ Q O U~) O 11) O U~ O Ll') O 11'1 O 1~ H~ a~ ~ E O O ~ ~ O O Q) U~ r-l r-l I V ~) S ~: l l 111 r . ~) i ~) ~ I O ~ ~~1 ~1 ._I l ~ O O N W ra ~ ~ ~ ~ ~ S l ~h ~--1 ~ t~ o O ~ O O L~ ~ D ' ,~.C: ~ ~ ~ ,~ O S~ O ~ O ~--1 ~ ~ S ,1 O ~1 I S I a I r--I V r~ S -r~ . ~_ O ~1 ~_ O ~~rl t.) ro p~ r--l r)~' r~l --1 S IC5 ~ O I O :~1 _ ~ ::~ O l I 1.~ L~ ~ ::~ ~ al ~ ~ .~: O11'~ Q~ U') ~ ` ro ~ I ~: V ~1~ ~` :~ ~ _ u C~ ~ ~ ~ ~ n~~ ~ ~ s I O ,~ ~ I ~ ~ t E~ l O ~:

~ O_ No__~ ~ r~l l'a ~ C~1 PO C~J ~I O ~1 ~~'1 C s: ~ O ~ C N ~ :~ ~,~ E~ O~ 0~1 ~ ~ ::1 S~ E~ n5 E O s v E~ c~ s~ v ~ ~a I ,1 c v ~ ~ ~I a~I ~1 .r1.~1 F~. r-l OV C~) ~ ~ S F~~ r_ ~ ~ alLl ~ --~ V I o J~ a~ s~ v I cJ U7 ~ :~ ~_,~ ~~ aJ I ~I C ._~~ 1~: ~ ~ I ~ Z x æ ~ I ~ I ~ v ~ I OI C: ~Q~ ~ O ^ L~ SO PJO Q~ I >~1 t~) f~C r-l a~ .U ~: O ~: ~t r--l X E~ ,~~ :~ ~ a~.r~ ~.~ ~ :~ O _, ~~ Q~ ~ E~ QE~ O s _ I ~ O _ ~ ~ O I ~ I ~ I ~r~ U)I v I ~ ~ ~ I ~~r ~ ~ c:

- 3 4 - ~;~3~3~L7 ~,~ co ~ a~ O~D oa~ o o . . . . . . .

., o ~` r` o r~ o:~ ~D N ~ u~ o cr ~ ~r ~ ) u~ ~0 + -~ ++ ++ ++++ U~ o .C C ~ a~ co ~r r~ ~ ~D ~r ~D ~ O r~ 3 ~ ~ 1` ~t ~) 1~ ~ t~l N ~r ~ C~ I O ~ _ ~ ~J ~ ~ ~ ~ ~ ~`I ~ N N ~-~ ~ O 00 Oo 00 oo~r~ H C 1~~ u~ 0 1~7O 11 ) N O u ) ~1 H O ~: ~ ~ ~ ~ l o E~ J~ x ?1 o _. ~ S a) ~ ~, ~ .c I ~ c.

E~ ~ ~ ~ ~ ~ ,~ .,~ ~0 l 0 :~ ~O ~ _.

I a~ ~ ~ o ~a s ~rt 0 1~ r ~ h ~ O ~ O C~l ~ :~ ~ ~ ~ O ~) _ rt I Q~ ~ ~ ro ~t O (~ ~ C ~1~ I 1_1~) ::~/lr-l ~_1 Q I ~ ~t ~ Z ~ S l~ ~1 ~>1 ~ O ~rt ~ ~)I a~ C) r-l r~ ~~ 1 1 O-rt tL~ O~ V ~rt 1~1 C C ~-rt ~ N Q~ O E~ ~) .r~ oX E~ O C ~I ~ I a~ E~ O I~S o~ o ,,, v (a rt~ 1~1~rt ~ Oh ~_1~ /~ ~ ~::~ :~ E~ O (1~ C JJ O ~ la N C 0 C ~ V ~ h ~ h C ~ ~1 ~1 _ rt ~ O ~ ~a) a,)~ E~ I ~:1 I ~1 R ~ ~ C ~ r~S ~`3 1 J~ r! I ~ --a~ --- ~D h ~ J~ ~I _C: ~ :~1 11~ ~rt ~.1 Oa2 ~ I ~1 ~ C`l E-~ ,~ Q~ 1.1 I O ~) O _ ~ E~ OO ~`J LJ )-~ r_ I _ _ ~ ~ O ~ P.

~1 r--¦~ D t Srt r~l E-~ O S ~ __ ~ ~ U E c: ~_ ~ C I _ _ I ~¢ U ~trt al ~J - N 1 ~1 ~ Il) ~ I tl~ I~ '0 ~ ~ ~L23~3~L'7 -35 O ~ N a \ G~ N O ~ 01~ ~ ¦ ~) c: ~ a~ ~ ~ ~ :, o N Il~ U~ O O J t-- CO 'r N Il ) ~D U) 1~ ) U ) C~ ~0 ++ ++' +~ + ++ +1 V O h P. ,_ ~ ~ u~ a~ ~ ~ ~ r ~1 ~ l u~ co 3C tl~ C~ a~ ~r O ~ ~D V') U~ n V U-- t~ N N N ~ N ~ N ~ N N ~1 G) _ 00 00 00 O 00 00 ~ U) ~ O U~O U~ O U~ In O U~ O U~ ~ a-- N N N N . ~ .~ O a) ,~5 ~¢ v r X ~1 O O :~ E~ ~ ~ U ~ ~ ~ X GJ~ O ~ ~ U~ O :>~I ~J ~1 l r~ ~ .C ~` O X.-1 ~ X ~I ~ S ~ I ~ O I Ll~ .~: ~1 _ ~) 1~ E~ O ~ O ~ O ~ ~ 1: I a) ~ ~ ~ ~ cr~ ,~ .,1 ~ ~ ~ .,~ .,1 I E~ I Ll I .,1 ~ ~ O ~ O O ~1(~ -1 ~ 1 a ~ c: ~1 Ll ~ ~1 C: l ~1' ~.~ ~1~ 'E~ O.c:

O ~ ~ O la ~ 1~ ":s ~ ~ o o ~ ~ ~ ~ ~ ~ u ~ u u Q .,~Q S ~ ~1 n o :~ , ~ I ~ ~ ~ I O r~ ~~ ~ ~ ~a ~ o ~ ~ I ,c ) .~ ~~ ~ r~ ~ ~ ,~ Q ~QI In Q~ O ~1 0 ~ ~ I ~_ J~ hJ-l ~J ~) ) 1 ~) U J~ O ~ J~_ O :~ O _ ~ ~ ~1 I Q~lI ~1 Q~I I ~ a) ~ ~ I 1:~1 ,~::I ~C . ~ ~ ~J >1 1~1 ~ U1-~ t.~ ~ I r-l h ~ l l ~-J ,1 I ~ Z a)~n ~~ ra ~ ~I I ~ L~ ~ t:: ~ I E~ l l l O ~ I JJ _ ~~._ l _ .-1~ s: a~ ~ Q~ :~ ~ ~ ~D ~ -1 ~ E~ L~ N .1: .5:: ~ ~ ~ N ~1 F: -- ~ 5 VV ~::I _ S:: ~ ~ I ~ Q~ 1~) ~ - N a~ J~l I Ct:~ l C:

~ Q~ ~ I ~:q Q) ~ I Z -36- ~373~ Example 2 Evaluation of test compounds as animal feed additives for (1) the enhancement of the growth rate of poultry, (2) lmprovement in feed utilization thereby, (3) increase in the deposition of muscle tissue or protein in said birds and (4) improvement in the carcass quality of treated birds One day old Hubbard & Hubbard Crossbred Chicks ar~ employed in the following tests; eight pens of chicks are used for each treatment level and the druy is administered in the chick diet for three weeks, i.e., from the start of week five through week seven.

The experiment is terminated when the birds are seven weeks old. The weight of the chicks is determined at the beginning and on completion of the experiment, ; ~e,'~ and the ~ gains and the amount of feed consumed calculated. In addition, 19 males and 10 females from each group are randomly selected and sacrificed by decapitation. The defeathered carcass, with visera intact, were ground. Samples of the ground carcasses were then analyzed for protein, fat and moisture content.

The results of these tests are reported in Table VIII below where it can be seen that chicks receiving from 0.25 to 4.0 ppm of the test compound showed an increase in growth rate, improvement in utilization of their feed, increased deposition of muscle -tissue or protein and improved overall carcass ~uality.

Moisture was determined by placing 10 gram samples in aluminum foil pans, and the weights of sample and pan recorded. These samples were dried overnight in a forced air oven, and the dry weight of the pan and sample recorded.

:~3~ 7 -37 .

Protein content was determined by a Macro Kjeldahl method, using 1 gram samples of the ground samples.

Fat was determined by digesting S gram samples of the ground birds in 50 ml plastic centrifuge tubes and digesting the samples with 5 ml of concentrated 10 hydrochloric acid at 80C for 120 minutes. The digested samples were treated with 15 ml o~ petroleum ether, mixed and centrifuged at 1500 rpm for 10 minutes, and the ether layer separated from the solids. The sample was extracted again in the same manner, and 15 the ether layers mixed. The ether was then evaporated, and the remaining residue weighed to determine the amount o~ fat in the sample.

- 3 8- ~2373~ a) o ,, ~.

.,, u .C E~ D v D o ~ O- P~ O E~ h O :~ O O o I ~ ~ u~ ~ . ~1~ + ~ ~ + ++ ~,?

.~ V ,, ~o t~ ~ ,~a ~ ~ ~ ~ ~ ~ ~ + ~ + ~ + ', p:; ~1 ~ E,--p .C ~ O E, t: O o 3 v o o ~ ~ r~ ~1 0 u~ ~ 1~ o o~ ~1 ~ O ~1 :~ ~ O ~ ~ ~ ~o ~ ~ Ln O 0 H ~: a c ~1~ + + ~ ++ ~ ~J a) u~ )J 2 c ~ ~ ~ ~ o~ ~ c c~ o l ~ ~ N ~ 11~ OQ V ~ aJ H C .C: O O 1~ C:: ~ o~ ~ ~ . ~ 1~ ~ :~ O C ~ ou a E a a O 0 ~n o c Q O ~ ~1 ~a ~ ~- v .Q s:: o ~:1 o o ta ~4 ~ ~1 y C~ P O 39- ~373~7 Example_3 5 Growth Enhancement, Feed Efficiency Improvement, Increased Deposition of Muscle Tissue and/or Protein and Improvement in Carcass ComEosition To determine the effect of feeding experimental compounds to ruminants, wether lambs are randomly 10 allotted to pens in groups of four. Five replications per treatment are used. The sheep are weighed and permitted feed and water ad libitum. The feed is weighed daily, and uneaten feed from the pxevious day is collected and weighed. Test lamhs receive 15 the same diet as control animals, but with the addition of experimental compound at a concentration of from 1 to 100 pp~. The tests are conducted for a period of eight weeks at the end of which the lambs are again weighed, and the feed consumed calculated. The lambs 20 are then necropsied. Ten animals per treatment are dressed, and the average cross-sectional area of the longissimus dorsi measured at the 12th rib and at the 7th lumbar vertebra measured. The data ob~ained are reported in Table IX.

_~ --40-~L~3731~ N .,1 L~ . a) o ~ c JJ ~ 'O O U~ C u7 ~ o ~ ~ o~ O ~ Ul O ~ ~ ~ O + l~ C E~ 5: ~ ~ + + P;

O ~ U~ JJ ~, _. ~ a) o ~ G~ O ,_a ~ n o ~I O ~ PC ~ ~ ~ ~ r~ u~ O ~ U~ r o ~ ~: C s-~ . ~ 3 ~ E3 E~ O O U~ ~0 O a o ~ o .

Y O ~ ~ o ~1 ~r In u~ ~' V ~ O ~ ,~ J~ ~ r-l c ~ ~ ~1 ~) o c~ H ¦ 1/7 U .a tl~ ~) dt Ct~ I + ~ ~1 ~ C m u ~ ~ a) '¢H C _ ~ U W l 'Uo O ~ ~1 C C Lrl 1;~ .~ o ~ ~ Ir) u ~ ; ~ ~ O ~ aQ O C: ~ ~'l e~ cn ~ cc~ I I ~`I _l I ~-1 tl) '~O V _ O .~ 4' ~ 1~ ~ O Q O ~ ~ O ~ ~ ~ ~ V O C ~ U~ ~ , _~ C: ` ~ ~ ~1 1~' J-~ ,1 ~ -1 0 ~ l O E~ O /V O ~1~ ~ O O O O t~ O a~.c ~_1 ~ E3 ~1 3: _ ~ ra ~ v t~ Q ~ 1~ C C lU /1) ~ ~ H C r~ 1--l -- O ~) O O ~n _I ~ O ~:1 1¢ ~ c ~ $~ au~ ~:1 H h ~¢ ~ S4 -41- ~ ~3~3~ Example _4 N~ butyl-3,5 dichloro- ~methoxy-4-methylaminophenethylamine hYdrochlorlde A 7 9 sample of ~[(tert-butylamino)methyl] -3,5-dichloro-4-methylaminobenzyl alcohol is added to 70 ml of thionyl chloride under N~ atmosphere and the mixture is stirred for two hours. Excess thionyl chloride is removed in vacuo, and the glassy residue is dissolved in 50 ml of methanol. The solution is stirred for 1.5 hours and evaporated to dryness.

The residue is dissolved in lQ0 ml of H2O and extracted with 2 x 50 ml of CH2C12.

The aqueous laver is neutralized with solid NaHCO3 and extracted with CH2CL2.

The extract is dried (MgSO~) and evaporated to dryness n vacuo to give 4.1 g of semi-solid, which after trituration with ethyl ether affords 1.07 g of the title compound, mp 220 - 221 C.

Similarly, ~he .followin~ ethers are prepared:

Cll CH3NH~--CH--CH2--NH--BU--t -^ Cl OR -42- ~373~ Alcohol R ethanol C2H5 l-propanol 1 C3H7 2-propanol 2 C3H7 l-butanol l~C4H9 2-butanol ~ C4H9 l-hexanol n-C6H13 benzyl alcohol benzyl allyl alcohol allyl 4-methoxybenzyl alcohol 4-methoxybenzyl 4-chlorobenzyl alcohol 4-chlorobenzyl 4-nitrobenzyl alcohol 4-nitrobenzyl 4-methylbenzyl alcohol 4-methylbenzyl 3,4-dimethylbenzyl alcohol 3,4-dimethylbenzyl 3,4-dimethoxybenzyl alcohol 3,4-dimethoxybenzyl 3,4-dichlorobenzyl alcohol 3,4-dichlorobenzyl 2-chlorobenzyl alcohol 2-chlorobenzyl 2-methylbenzyl alcohol 2-methylbenzyl Example 5 N-tert-Butyl-3,5-dichloro~ -methoxyphenethylamine hydrochloride A mixture containing 6.55 9 of 4-amino N-tert-butyl-3,5-dichloro-~-methoxyphenethylamine hydrochloride in ~6 ml of 50% hypophosphorous acid is cooled to 5C and 1.5~ 9 of NaNO2 in 15 n,l of H2O is added dropwise. Rapid foaming occurs from gas evolution and after 0.5 hours at 5C, the mixture is stirred further at room temperature for two hours.

It is then made alkaline with 50~ aqueous NaO~ solution, and the mixture is kept at belo~ 25C with addition of ice. The mixture is extracted with 3 x 100 ml o~ C~Cl~ and the combined organlc phases are washed .

.

' _43_ ~37~1~ with 200 rnl of brine, dried (MgSO~), and evaporated to dryness _ vacuo to give 5.1 9 of the title compound in the form of the free base. This product is dissolved in 50 ml of EtOH and acidified at 5 with 4N HCl to afford a light orange precipitate, which is collected.

This gives 3.36 g, mp 278 - 280 dec, of the title compound which is recrystallized from isopropanol to give 2.35 g, mp 280C dec.

Similarly, N-isopropyl-3,5-dichloro-~-methoxy phenethylamine hydrochloride is prepared from 4~amino N-isopropyl-3,5-dichloro-~-chlorophenethylamine hydrochloride.

Example 6 In the manner described in Example 4 , the following ethers are prepared by substituting the corresponding alcohols for methanol.

Cl H2N - ~ - CH - CH2 - NH - C(CH3)3 -^ Cl OR ~3~317 R mpC Ethyl (~HCl) 180-182 2-Propyl . 117-121 benzyl 190-193 allyl 57- 59 l-hexYl 4-methoxybenzyl 4-chlorobenzyl 4-nitrobenzyl 4-methylbenæyl 3,4-dimethylbenzyl 3,4-dimethoxybenzyl 3,4-dichlorobenzyl phenyl oil 4-chlorophenyl 4-methoxyphenyl 4-methylphenyl 2-chlorophenyl 4-nitrophenyl Example 7 N-tert-Butyl-3-chloro-5-cyano-B-methoxy-4-aminophenethylamine hydrochloride In the manner described in Example 4-, ~-[(tert-butylamino)methyl~-4-amino-3-chloro-5-cyano3~ ben2yl alcohol is converted into the title compound;

and, similarly, the following are also prepared:

Ar-C~-C~2-NH~ Cl OC~ .

~, ~ -~5- ~ 3 ~ 3 Ar R 4-amino-3,5-dicyanophenyl t-butyl 4-amino-3-chloro-5-trifluoro methylphenyl t-butyl 4-amino-3-chloro-5-trifluoro methylphenyl i-propyl 4-acetamido-3,5-dichlorophenyl t-butyl 4-acetamidophenyl t-butyl 4-amino-3-chloro-5-H2N-CO phenyl t-butyl 4-amino-3-chloro-5-HO-CO~ phenyl t-butyl 4-amino-3-chloro-5-methyl phenyl t-butyl 4-amino-3-chloro-5-methoxy phenyl t-butyl 4-amino-3-chloro-5-nitro phenyl t-butyl 4-amino-3-chloro-5-CH30-CO phenyl ~-butyl 4-amino-3-chloro-S-dimethyl- aminomethylphenyl t-butyl 4-amino-3-cyano-phenyl t-butyl Exampl~ 8 5-(4-amino-3,5-dichlorophenyl)-3-ter,-butyl-2-oxa~olidinone In 10 ml of CH2CL2, 0.5 g of 4-amino- [(tert-butylamino)methyl~-3,5-dichlorobenzyl alcohol is stirred with 1 ml of Et3N at -5C and 2 ml of 12.5~ COC1~ in benzene~5 ml of CH2CL2 is added over 15 minutes. The resulting suspension is stlrred 20 minutes at 1C and allowed to warm to room temperature with stirring for 1~5 hours. The mixture is evaporated 3~ to dryness, and the residue is chromatographed on silica ge.'~ with 1:1 hexane/CH2CL~ to afford 0.1 g of 3~L~ oil which crystallizes to give the title compound, mp 97 - 103C.

In the same manner, ~-[(allyla~ino)methyl] -4-amino-3,5-dichlorobenzyl alcohol is allowed to react with phosgene to afford 5-(4-amino-3,5-dichloro phenyl)-3-allyl-Z-oxazolidinone.

Likewise, the following compounds are prepared by this manner:

Ar-CH- CH2 1 ~ O \ N-R3 Il o Ar R3 3,5-dichlorophenyl t-butyl 3,5-dichlorophenyl i-propyl 4-acetamidophenyl t-butyl 4-amino-3-chloro-5-cyanophenyl t-butyl 4-amino-3-chloro-5-trifluoromethylphenyl t-butyl 3-chloro-4-acetamidophenyl t-butyl 3,5-dichloro-4-methylamino phenyl t-butyl 3,5-dichloro-4-ethylamino phenyl t-butyl 3,5-dichloro-4-i-propyl aminophenyl t-butyl 3,5~ ichloro-4-acetamido phenyl t-butyl 3,5-dichloro-4-methoxy carbonylaminophenyl t-butyl 3,5-dichloro-4-benzyloxy carbonylaminophenyl t-butyl -47 : L23'73~ Ar R3 3,5-dichloro-4-methylcarbamoylaminophenyl t-butyl 4-amino-3-chloro-5~ methylphenyl t-butyl 4-amino-3-cyanophenyl t-butyl 4-amino-3-trifluoromethyl phenyl t-butyl 4-amino-3-chloro-5-NH2CO phenyl t-butyl 4-amino-3-chloro-5-HOOC phenyl t-butyl 4-amino-3-chloro-5 CH3OOC-phenyl t-butyl 4-amino-3-chloro-5 (CH3)2NCH2-phenyl t-butyl 4-amino-3,5-dicyanophenyl t-butyl Example 9 4-Amino- ~[(tert-butylamino)methyl]-3,5-dichloro~enzyl - alcohol acetate A mixture containing 1 g of 4-amino-o-[(tertbutylamino)methyl]-3,5-dichlorobenzyl alcohol in 35 ml of C~2C12 at 10 - 15C is stirred, and 0.37_9 o~ Ac2O and 0.5 ml of Et3N are added dropwise. The reaction mixture is then allowed to warm to room 3~ temperature, and the reaction is followed by thin layer chromatography to completion. The mixture is evaporated to dryness in vacuo, and the yellow viscous liquid (1.5 9) is stirred with 50 ml of ethyl ~3~3~7 ether to afford a yellow solid (0.84 g), mp 128 - 131C.

This material is shown by nuclear magnetic resonance spectroscopy and by neutralization with alkali to be the acetic acid salt.

On treating 100 mg of this salt in 30 ml of CH2Cl~ with 30 ml of 10~ aqueous NaOH, the salt is neutralized. The CH2C12 solution is dried (MgSO4) and evaporated to dryness in vacuo to afford the viscous title compound. Analysis:

Calcd for C14H20~N2C12 C, 5 .67;

Found: C, 52.38; H, 6.51; N, 8.88.

In the same manner, propionic anhydride, butyric anhydride, pivalic anhydride, and benzoic anhydride are allowed to react with 4-amino-~-[~tertbutylamino)methyl]-3,5-dichlorobenzyl alcohol (A) and ~-[~tert-butylamino)methyl]-3,5-dichloro-4-methylaminobenzyl alcohol (B) respectively, to afford the propionate, butyrate, pivalate and benzoates of A and B.

Exam~le ln The following esters are prepared by the method of Example g by using the appropriate acid anhydride.

Cl R8R9N- ~ C~-C~2-N~-C(CH3)3 O-C-R6 Cl 11 o -49 ~237~ R8 Rg R6 H CH3 CH3 H C2H5 CH3 ~ c3 7 CH3 H 2-C3H7 CH3 H benzyl CH3 H allyl CH3 CH3 CH3 CH3 H CH3 C~H5 H CH30-C0- CH3 H CH3NH-Co CH3 H CH3 n-C4Hg C2~5 C2H5 CH3 n C4Hg n-C4Hg CH3 Ar-CH ~ H2 -NH - C(CH3)3 0 - C - R o 6 -50~3~3~ Ar R - 6 3,5-dichlorophenyl 2 C3H7 4-amino-3~chloro-5-cyanophenyl CH3 4-amino-3-chloro-5-trifluoro methylphenyl CH3 4-amino-3-chloro-5-H2NCO-phenyl CH3 4-amino-3-chloro-5-HOOC-phenyl CH3 4-amino-3-chloro-S-methylphenyl CH3 4-amino-3-bromo-5~cyanophenyl C~3 4-amino-3-chloro-5-CH30CO phenyl CH3 4-amino-3-chloro-5-(CH3)2 NCH2-phenyl CH3 4-amino-3,5-dicyanophenyl CH3 4-amino-3-cyanophenyl t~C4Hg Example 11 N-(4-amino-3~5-dichloro-~-hydroxyphenethyl)-N-tert -butylacetamide acetate A mixture containing 2.5 g of 4-amino-~-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol, 25 ml of pyridine and 10 ml of acetic anhydride is stirred for three hours and evaporated to dryness in vacuo with heating up to 70C. ~he residue is treated with ice, 100 ml of CH Cl and 50 ml of 10% NaOH solution.

~ -51- ~23731~ 5 The CH2C1,~ phase is separated, and the aqueous portion is furthe,r extracted with CH2CL2 (2 x 50 ml). The combined CH~CL~ solutions are dried (Na2S04) and evaporated to dryness to afford a solid a~ter scratching.

The solid is washed with hexane and collected to afford 2.61 9 of the title compound, mp 126 - 136C.

Similarly, by substituting the appropriate acid anhydrides, the following compounds are prepared.

.

Cl ~ R8RgN ~ CH CH2~ C(CH3)3 Cl 0-~COR6 R6 R8 Rg R6 H CH3 CH3 . C2H5 CH3 H 2-C3H7 CH3 ~ n-c4H9 CH3 C~3 CH3 C~3 H CH30-C0 CH3 H C~3NH-C0 CH3 ~ C~3C0 CH3 H CH3 C2H5 C2H5 C2H5 n-C4Hg -52- ~373~ S Ar - C~ - C~2 - N C(CH~)3 O--COR6 COR6 Ar R6 4-amino-3,5-dicyanophenyl C2H5 4-amino-3-chloro-t-dimethyl amino methylphenyl CH3 ~-amino-3-ch~oro-5-CH300C-phenyl C2~5 4-amino-3-chloro-5-me~hylphenyl CH3 3,5-dichlorophenyl CH3 4-amino-3-chloro-5-cy'anophenyl CH3 4-amino-3-chloro-5-trifluoromethylphenyl CH3 4-amino-3-chloro-5-H2NCO-phenyl CH3 EX ample 12 4-Acetamido-~-[~tert-butylamino)methyl]-3,5 dichlorobenzyl alcohol acetate In 15 ml of C~I2CL2, 1.57 g of 4-acetamido (tert-butylamino~methyl] 3,5-dichlorobenzyl alcohol is suspended and stirred while 1.2 9 of triethylamine in 30 ml of 30 ml of CH2C12 is added, followed by 0.7 9 of ace~ic anhydride în 15 ml of C~2CL~.

The mixture is stirred for 20 hours and then is washed with 100 ml of 10% NaOH solutionO The organic phase is separa~ed, dried (Na2S04) and eYaporated to dryness in vacuo. The residue is dissol-ved in 30 ml of ethanol . __ and a tra~e ~ ~2 is added, followed by 10~ ~Cl to acidify. The mi~ture is evaporated to dryness in vacuo and ~he residue is crystallized from acetone~ hexane (30 ml~5 ml). This affords 1.35 ~, mp. 254 257c dec.~ of the title compound.

_53_ ~23~7 Similarly, by replacing acetic anhydride with propionic anhydride, butyric anhydride, pivalic anhydride, and benzoic anhydride, the corresponding propionate, butyrate, pivalate, and benzoate esters are prepared.

Example l3 N-IsoproPyl-n-hydroxy-~-methoxy~henethYlamine hydrochloride In 425 ml of ethanol, 64 9 of 3-benzyloxyphenacyl bromide and 212 ml o iso-propylamine are stirred at 5C under N2 atmosphere, and the temperature is allowed to rise to 12C. After 0.75 minutes, the clear solution is poured into 2 liters of crushed ice containing 500 ml of concentrated HCl and 1.5 liters of H2O. The mixture is stirred for 20 minutes, filtered and the solid is washed with water to afford 3'-~benzyloxy) -2-isopropylamino-acetophenone hydrochloride, mp 213 - 215C dec.. A 5 9. - sample of this material is stirred in 50 ml of methanol, and the mixture is cooled in ice and neutralized with 10~ NaOH until a clear solution is obtained. To this solution, 2 g of N~BH4 i5 added and after 0.75 hours of stirring, the mixture is evaporated ~n vacuo, and the resulting solid is collected and washed with ~2 This gives, . after drying, 4.4 g of m-(benzyloxy)-~[~isopropyl 3~ amino)methyl]benzyl alcohol, mp 83 - 85C.

This alcohol is then treated in the manner described in Example 4 to afford N-isopropyl-mben~yloxy-~-methoxyphenethylamine hydrochloride, which is then deben2ylated with ~2/5~ palladium-carbon at 50 p.s.i.g. in 2-propanol. After filtering and evaporating to dryness t this procedure affords Nlso~rcpy~-m-hydroxy-~-methoxyphenethylamine hydrochloride.

,~ ,.

3~ 7 -54 [n the same manner, N-tert-butyl-m-hydroxy~-methoxyphenethylamino hydrochloride is prepared starting with 3'-(benzyloxy)-2-tert-butylaminoacetophenone.

Example 14 ~-[(tert-Butylamino)methyl]-m-hydroxybenzyl alcohol acetate In the manner described in Example 12 m-(benzyloxy) ~ -[(tert-butylamino)methyl]benzyl alcohol is converted to m-(ben2yloxy)~ -[(tert-butylamino)methyllbenzyl alcohol acetate.

This material is then debenzylated by the procedure of Example 13 to give ~-[(tert-~utylamino)methyl]-m-hydroxybenzyl alcohol acetate.

Example 15 5-(~-Aminophenyl)-3-tert-butyl-2-oxazolidinone In 270 ml of CH~C12s 12.97 9 of ~-[(tertbutylamino)methyl]-D-nitrobenzyl alcohol is dissolved.

The solution is cooled to -5C and 54 ml of 12.5% phosgene in benzene is added slowly. After the addition is completed, the mixture is stirred for 3.5 hours and poured on ice. The organic phase is separated, - and the aqueous layer is extracted with CH2C12 (2 X 100 ml).The combined organic layers are washed with saturated NaHCO3 solution (2 X 250 ml), 100 ml of H2O and dried over ~gSO4. The solution is evaporated to dryness to give 16.3 9, which is recryst.allized from ~eO~ twice to afford 12.58 g of 3-tert-butyl-5-(~-nitrophenyl)-2-oxa~olidinone, mp 123 - 125C. This product ~10 9 ) is dissolved in 200 ml of MeOH and hydrogenated 3~ ~ .~ _55~ 37317 f~ j cke/ over 6 g of Raney f~ff~ at 51 p.s.i.g at 40 C to give, after filtration and evaporation, 8.21 9 of 5-(p_ aminophenyl)-3-tert~butyl-2-oxazolidinone, mp 125 - 129C.

Example 16 ~-[(tert-butylamino)-methyl}3,5-dichloro-4-dimethylaminobenzyl alcohol A mixture containing 50 g of ~-fluoroacetophenone and 150 ml of 40~ aqueous dimethylamine is warmed in a pressure bottle at 90 - 100C. After two hours, a pale yellow oil is formed. The mixture is cooled, and the oil solidifies. The solid is collected and washed well with ~2 to give 54.93 of ~-dimethylaminoacetophenone, mp 101 - 103C, after heptane recrystallization A 72 g sample of this acetophenone is heated with 129 g of N-chlorosuccinimide in 700 ml of toluene to reflux temperature and maintained at this temperature for 35 minutes. The mixture is cooled and filtered. The filter cake is washed with ~00 ml of toluene, and the filtrate and wash solution are evaporated to dryness in vacuo to afford 66 9 of oil. This oil is chromatographed on SiO~ with 40~ hexane/CH2C12 to give 38~9 g of 3.5-dichloro~ 4-dimethylaminoacetophenone as a yellow oil. A 5.22 g 3~ sample of this oil is added portionwise to 2.75 g of SeO2 in 20 ml of dioxane and 0.7 ml f ~2 at 55 - 60C. This mixture is heated at reflux temper~ture for 4.5 houxs, cooled and filtered through siliceous earth. The filter ~ake ;s washed with 20 ml of dioxane.

The dioxane solutions are cooled to 15C and 2.77 9 of t-butylamine is added dropwise to afford a tan precipitate~ After s~irring 15 minutes at room tempera~ure, ~37~17 -56 S the mixture is diluted with 200 ml of ethanol, cooled to 5C anc3 7 g of NaBH4 is added portionwise. After 15 hours, the mixture is treated with 300 - 400 g of ice and 200 ml of H2O at below 10C. The mixture is stirred to dissolve all solids and extracted with 300 ml of CH2C12.

The CH2C12 layer is washed with 100 ml of H2O, dried (MgSO4) and evaporated to dryness in vacuo to give 5.6 9 of orange oil. This oil is dissolved in eth~l ether, decolorized with activated carbon and concentrated to 15 ml. On coolin~, crystals are obtained, The title product is collected as white crystals, mp g6 - 99C.

. ..

._ -57- ~3~3~7 EXA~LE 17 5-(4-amino-3,5-dibromophenyl)-3-tert-butyloxazolidine .

A mixture containing 2 g o~ 4-amino-3,5dibromo-~-[(tert-butylamino)methyl]benzyl alcohol and 5 ml of 37~ formalin solution in 20 ml of toluene containing a few crystals of p-toluene sulfonic acid is heated at reflux to azeotrope water. After three hours, the mixture is cooled, diluted to 75 ml with CH2C12 and washed with ~0% aqueous NaOH solution (2x20 ml). The aqueous portion is further extracted with 10 ml of CH2C12 and the combined organic e~tracts are dried ~MclSO4) and evaporated to dryness ln vacuo to afford 1.6 g of clear brown oil. A chemical ioni~ation mass spectrographic analysis gives a Mass + H of 377, which is correct for the title compound. The nuclear magnetic resonance proton spectrum reveals a singlet at ~S4.53 in CDC13 indicative of the O-CH2-N group in the title compound.

In the same manner, the following oxazolidines are prepared by substituting the corresponding arylethanolamines for 4-amino-3,5-dibromo-~-[tertbutylamino)methyl]benzyl alcohol. ^~ Ar-CH ~ ---CH2 \ ~ -C~CH)3 C H2 :~2373~7 -58 Ar . _ 4-amino-3,5-dichlorophenyl 4-methylamino-3,5-dichlorop~enyl 4-amino-3-chloro-5-cyanophenyl 4-amino-3-chloro-5-trifluromethylphenyl 4-amino-3-chloro-5-methylphenyl 4-amino-3-bromo-5-M~2-CO-phenyl 4-amino-3-bromo-5-HOOC-phenyl 4-acetamido-3,5-dichlorophenyl 3,5-dichloro-4-methoxycarbonylaminophenyl 3,5-dichloro-4-methylcarbamoylamino~henyl 4-amino-3-cyanophenyl 4-amino-3-trifluromethylphenyl 4-amino-3,5-dicyanophenyl EXAMPL~ 18 4-Benzylamino-~-[te-t-butylamino)meth~1)-3,5-dichlorobenzyl alcohol In the manner described in Example 16, the title compound is prepared to give mp 86-89C.

EXP~l~LE 19 4'-~2-(tert-butylamino)-1-hydroxyethyl]-2',6'-dichloro .. _ . . . . .

- benzanilide A mixture containing ~.04 g of 4-amino-3,5dichloroacetophenone an~ 0.25 ml of triethylamine in 10 ml of benzoyl chlori~e is stirred and heated at 130-135 for two hours. The mixture is cooled, filtered and the product is washed with ether. This amide is further oxidi.zed with SeO2 in the manner described in Example 16 to eventually a~ord the title compound, mp 177-182C.

~59- ~237317 EXAMPLE 20 -[tert-butylamino)methyl]-3,5-dichloro-4-methylamino_ benzvl alcohol p-Methylaminoacetophenone is prepared and chlorinated by method described in E~am21e 16 to give 10 3,5-dichloro-4-methyla~inoacetophenone. This ketone (18 g) in 200 ml of CHC13 is stirre~ and 4.65 ml of Br2 in 50 ml of CHC13 is added dropwise. After the addition is completed, the mixture is stirred an additional 20 minutes and warmed to reflux temperature for 25 minutes.

15 The mixture is cooled, 100 ml of H2O is added and saturated Na2CO3 solution is added carefully until the mixture is n~utral. The CHC13 layer is separated and the aqueous layer is fùrther extracted with 100 ml of CH2C12. The combined extracts are dried (MgSO4) and 20 eva?orated to dryness to afford 16.3 g of the phenacyl bromide. This material (16 g) in 80 ml of EtOH is s.irred zt 12-15C and 40 ml of t-~utylamine is added dropwise. After the addition is completed the mixture is stirred for 10 minutes at 12-15C and then cooled to 25 5 and 4 g of NaBH4 is carefully added. After stirring for 0.5 hours, the mixture is allowed to warm to roo~ temperature and stirring is continued foI 0.75 hours.

The mixture is poured on 300 ml of ice with stirring and the resulting mixture is extracted with 300 ml of 30 CH2C12. The CH2C12 extract is dried (MgSO4) and evaporated to dryness ~n vacuo to give a yellow oil.

Trituration of this residue with ethyl ether affords 7.45 g of the title compound, which melts at 98-101C after recrystallization from ethyl ether~ . ~ ,~!:.~ . .: , ` ' . _ ~23~3~7 -60 EXAMPLE 21 5-[2~ -butylamino)-l-hydroxyethyl}anthran71anitrile A mixture containing 48.~6 g of ~-aminoacetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide is added in portions over 0.5 hours at below 40Q C.

After 15 minutes, the mixture is washed with H20 (4xlOO ml).

The solution is dried (MgS04) and evaporated to dryness to afford 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62C. A 35 ~ sample of this material in 180 ml of dry dimethylEormamide is stirred and heated at reflu~ with 17.57 g of Cu~(CN)2 for 6 hours under N2 atmosphere.

Subsequently, 180 ml of FeC13/HCl solution (40 g FeC13.6H20/10 ml concentrated HCl/60 ml H2) is added and the mixture is heated for 20 minutes at 60-70C and poured into 350 ml of H20.

The aqueous mixture is extracted with CH2C12 and the extracts are washed with H20, sa-turated NaHC03 solution and H20, respectively. The CH2C12 solution is evaporated to dryness in vacuo and the residue is recrystallized from 95% EtOH to afford 14.25 g, m~ 155-159C, of 4-amino-3-cyanoacetophenone. A 4.8 g sam~le of this product in 100 ml of EtOAc and 100 ml of CHC13 containing 13.32 g of CuBr2 is heated at reflux temperature for 20 minutes. The mixture is further heated after 20 ml of EtOH is added and then filtered while still hot. The ~ilter cake is washed with 50 ml of hot 20% MeOH/CH2C12 and the combined organic solutions are eva~orated to dryness in vacuo. The residue is stirred in 25 ml of _._ CH2C12 and the solid is collected and washed with CH2C12 to give 8~08 g of the Dhenacyl bromide. This material is added to 50 ml of t-Bu~H2 in 100 ml of ~3~3~'7 -61 EtOH at 5 under N2 atmosphere. After 10 minutes of stirring, the mixture is allowed to warm to 30C to give a solution. This solution is cooled to 10 and 4 g of NaBH4 is added in portions. After 45 minutes, the mixture is allowed to warm ~42C) and kept at 20C until 1~ the exotherm subsides. The mixture is then evaporated to dryness and the residue is washed with H2O. The residue is dried and treated with 200 ml of boiling MeOH and the hot MeOH solution is filtered. The ilter cake is further washed with hot MeOH and the combined filtra-tes are concentrated to afford cxystals. This solid is recrystallized from MeO~1/2-PrOH to afford 2.08 g, mp lB4-186C, of the title compound.

In a similar manner, the following related compounds are prepared starting with the appropriate acetophenone:

R8RgN ~ IH_CH2_NHR3 ~^ OH CN -62- ~373~7 R~ Rg ~3 X H H 2 C3~17 H H CH3 t-butyl H CH3 CH3 t-butyl H H C2~5 t-butyl H H n C3 7 _-butyl H H 2-C3H7 t-butyl H H n-C4Hg t-butyl H H CH3 C3 7 H H benzyl t-butyl H C2H5 C2H5 t-butyl Cl n-C3H7 _-C3H7 t-butyl Cl n-C4Hg n-C4Hg t-butyl Cl EXAMPLE 22 3-chloro-5-[2-(tert-butylamino)-1-hydroxyethyl] anthranilonitrile - In 100 ml of toluene, 5 g of 4-amino-3 cyanoacetopnenone is heated at reflux temperature for 20 minutes with 4.2 g of N-chlorosuccinimide.

The mixture is cooled and filtered. ~he filtrate is ~^ further heated at reflux temperature for 2 hours.

The precipitate is collected and washed with H2O. The remaining solid is treated with 0.75 ml of Br2/14 ml of CHCl3 added to 75 ml of CHC13 and 4.9 ml of EtOH. The ~ixture is evaporated to dryness and the residue is slurried with CH2C12, collected and washed with CH2C12 to afford 2.84 q of the p~e~acyl bromide. This material is allowed to react with t-BuNH2 ~nd reduced with NaBH4 by the procedure of ExamDle 21 to afford the title compound, mp 128-138C.

. ~ 1 ~:37317 -63 5In a similar manner, the following compounds are prepared:

Cl R8Rgll~--CH-C~ -R3 R8 Rg R3 H H 2-propyl H CH3 t-butyl CH3 C~13 t-butyl H C2H5 t-butyl H 2-propyl t-butyl H n-butyl t-butyl H benzyl t-butyl 2~ EXA~PLE 23 5-[2-(tert-butylamino)-1-hydroxyethyl]-3-chloroanthranilic acid, methyl ester, hvdrochloride A mixture containing 1.36 g of 5-[2-~tertbuty~amino)-l-hydroxyethyl]-3-chloroanthranilonitrile ~5 in 21 ml of 50% aqueous NaOH and 21 ml of EtOH is stirred under N2 for 0.5 hours. The mixture is -~ evaporated to remove EtOH and acidified to pH 3 and further evaporated to dryness ~n vacuo. The residue treated several times with MeOH and evaporated to dryness. The solid is then treated with a,solution which is prepared from 40 ml of ~leOH and 2 ml of acetyl ch.loride. Ater allowing to stand overnight, the mixture is filtered and the filtrate is evaporated to dryness. The filter cake is a~so washed with MeOH and added to preceding filtrate. The rasidue is dissolved in acetone, filtered, and evaporated to dryness. The solid is triturated with Et20 and filtered to give 1.49 g, mp 95-115C, of the title compound.

-64- lZ37317 In a similar manner, the following related esters are prepared;

Cl R8R9N~3~H-CH2-NH-R3 H COOCH3 R8 Rg R3 H ~ H 2-pr~pyl H CH3 t-butyl CH3 CH3 t-butyl H C2H5 t-butyl H n-propyl t-butyl H n-butyl t-butyl H benzyl t-butyl H allyl _-butyl C2H5 C2H5 t-butyl n-C4Hg _-C4Hg t-butyl n C3 7 n~C3H7 t-butyl EX~i~LE 2 4 2-Amino-3-bromo-5-[2-(tert-butylamino)-1-hydroxyethyl]benzamide A mixture containing 1.~2 g of 3-bromo-5~2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile in 25 ml of H20, 5 ml of 50% NaOH and 30 ml of EtOH is stirred and heated at 55-65C under N2 atmosphere for 1.25 hours.

The mixture is evaporated to remove EtOH and extracted with CHC13.

The CHC13 extract is washed wit~ 25 ml of 2% NaOH, dried (MgSO4) and evaporated to dryness to afford 0.74 g~ This solid is stirre~ with pentane and filtered to afford 0.6 g, mp 135-14~C, of the title compound.

.

.

~3~3~7 -65 Similarly, the following compounds are prepared: CONH2 R8RgN ~ ~H-cH2-NH-c(cH3)3 X R8 Rg X H CH3 Cl H . H Cl H C2H5 Cl CH3 CH3 Cl H 2-C3H7 Cl H n-C4Hg Cl H CH3 Br ~ benzyl Cl C2H5 C2H5 Cl n-C3H7 -C3H7 Cl _-C~H9 n-C4Hg Cl EXA~LE 25 3-bromo-5-[2-(tert-butylamino)-l-hydroxyethyl]anthranilic acid A mixture containing 2 g of 3-bromo-512-(tert-butylamino)-l-hydroxyethyl~anthranilonitrile in l0 ml of 50% NaOH, 50 ml of H2O and 60 ml of EtOH is stirred and heated to reflux temperature under N2 for an hour. The EtOH is evapo~ated and the aqueous mixture mixed with 50 ml of H2O and 50 ml o CHC13.

The CHCl3 layer is removed and the interfacial brown oil is collected, added to l0 ml of MeOH, 5 ml of H2O and this mixture is acidified to-pH 5. After stirring for an hour, the of-white solid is collected, washed with H2O ~:Ind dried to give 0.8 g, mp 221.5C dec., o the ti1:le compound.

~L~3~73~7 -66 Similarly, the following compounds are prepared:

COOH R8RgN ~ ~H-cH2-NH-c(cH3)3 ~ H R8 R9 X H H Cl H CH3 Cl CH3 CH3 Cl H CH3 ~r H 2-C3H7 Cl H n-C~Hg Cl H benzyl Cl C2H5 C2H7 Cl n~C3H7 n~C3H7 Cl n~C4H9 n-C4Hg Cl EXAMPLE 26 5-~3-hydroxyphenyl~-3-tert-butyl-2-oxazolidinone In the manner described in Example. 8 - m-benzyloxy)- a- [tert-butylamino)methyl]benzyl .

alcohol is coverted to the oxazolidinone compound by treatment with phosgene. Subsequently debenzylation is completed by the method of Example~ 1to give the title compound.

EXAMPLE 27 5-(3-hydroxyphenyl)-3-tert-butyloxazolidine .

In the manner described in Example m-(benzyl~xy)-~-[(tert-butylamino)methyl]benzyl alcohol i~, reacted with formaldehyde to afford the oxazolidine derivative, which is debenzylated by the proceduxe o Example 13 to give the title compound.

-67- ~ 23731~ EXA~LE 28 4-amino-N-tert-butyl-3,5-dichloro-B-(methylthio) pnenethylamine hydrochloride In the manner described in Example ~, N-tert-butyl-3,5-dichloro-~-chloro-4-aminophenethylamine hydrochloride is prepared. An ll g sample of this product is portionwise added to 5 ml of methyl mercaptan in 100 ml of dry ethylenedichloride at -10C to 0C. The mixture is stirred and allowed to rise gradually to room temperature over a four day perio~. The mixture is filtered, the ilter cake is washed with ethylenedichloride (2x500 ml). The solid is dispersed in 200 ml of H2O, cooled to 5C and basified with 6N NaOH solution to give a white oil, which is extracted with CH2Cl2 (3x100 ml). The CH2C12 extract is dried (MgSO4) and evaporated to dryness to give 6.41 g of dark green oil. This oil is stirred in HCl/isopropanol and the mixture is evaporated to dryness. The residue is stirred in 35 ml of ethyl eiher for 16 hours and filtered to give 3.63 g, mp 178-181C dec. This solid is heated in refluxing ethyl acetate and filtered to give 2.07 g, mp 188-193C.

Recrystallization ~rom 75 ml of ethylenedichloride affords 1.45 g of the title compound, mp 191-196C.

The title compound is also obtained by adding 5-10 fold excess ~f sodium mercaptide in tetrahydrc,uran at 0-10C and by following the above workup.

-68~2373~7 EXA~LE 29 In the same manner as described in Example ~8, the following thioethers are prepared by substituting methyl mercaptan wi.h the corresponding mercaptans:

Cl H2N - ~ CIH-CH2-NH-R3 SR HCl Cl R R3 methyl 2-propyl ethyl t-butyl 2-propyl t-butyl n-butyl t-butyl t-butyl t-butyl n-hexyl t-butyl phenyl t-butyl benzyl 2-propyl EXAMP1E 30 In the manner described in Example 28, substitution of-the corresponding chloro compound for N-tert-butyl-3,5-dichloro-~-chloro-4-aminophenethylamine hydrochloride and adding the appropriate mercaptans afford the following thioethers:

Ar-fH~ C~2-NH-R3 ~ RSH ~ Ar-fH-C~2-NHR3 Cl SR ~3733L~ Ar R R3 4-amino-3-cyanophenyl methyl 2-propyl 4-methylamino-3,5-dichlorophenyl methyl t-butyl 4-amino-3-chloro-5-trifluoromethyl methyl t-butyl 4-amino-3-chloro-5-cyanophenyl methyl t-butyl 4-amino-3-chloro-5-cyano~henyl ethyl t-butyl 4-acetamido-3,5-dichlorophenyl methyl t-butyl 4-amino-3-chloro-5-H2NCO-phenyl methyl t-butyl 4-amino-3~-chloro-5-HOCO-phenyl methyl t-butyl 4-amino-3-chloro-5-methylphenyl ethyl t-butyl 4-amino-3~chloro-5-metho~yphenyl n-butyl t-butyl 4-amino-3-chloro-5-nitrophenyl methyl t-butyl 4-amino-3-chloro-5-CH30-CO-phenyl methyl t-butyl EXAMPLE 31 3,5-dichloro-4-(N,N-diethylamino)acetophenone A sample (2.5 g) of 4-amino-3,5-dicllloroacetophenone in 10 ml of acetic anhydride and 25 ml of pyridine is stirred and heated at reflux temperature for 20 hours.

The mixture is evaporated to dryness, and the residue is treated Wi~l ice and 10~ NaOH solution and extracted with CH2C12 (3x~0 ~1).

The extracts are dried (Na2S04) and evaporated to dryness to give 2.42 g of semisolid, which is purified by chromatography over SiO2 using CH2C12 as eluent to afford 1.06 g of 4-(N,N-diacetyamino)3,5-dichloroacetophenone as an oil.

This material is dissolved in 10 ml o tetrahydrofuran (THF) under N2 atmosph.ere and 18 ml of lM BH3~ THF is added dropwise.

The mixture is stirred until the reaction is complete and H20 is added cautiously.

The mixture -70- ~ Z37317 is evaporated to remove THF and 20 ml of ~2 and 10 ml of 1~ NaOH are added.

This aqueous mlxture is extracted with CH2C12 (3x25 ml) and the extracts are dried (Na2SO4) and evaporated to dryness ~o yield 0.68 g the desired alcohol.

This product (0.3 g) in 2 ml of CH~C12 is added to 0.32 g of pyridinium chlorochromate ~PCC) in 2 ml of CH2C12.

After 1.25 hours, an additional 0.3 g of PCC is added and after another 0.5 hours, the solution is decanted and the residue is washed with 10 ml o~ CH2C12.

The combined CH2C12 solutions are diluted with 50 ml of CH2C12 and washed with 10 ml of saturated Na2CO3 solution 2,nd 10 ml of H2O and dxied (Na2SO4).

The solution is evaporated to dryness to afford a residue which is chromatographed on SiO2 with C~2C12 as eluent to yield 0.0~ g of the title compound as an oil (NMR in CDC13: ~1.0 (~H, triplet), 2.5 (3H, sing]et), 3.25 (4H, quartet), 7.83 (2H, singlet~.

The monoethylaminoacetophenone is also obtained as a solid (~.12 g) as the second component.

This 3,5-dichloro-ethylaminoacetophenone is further reacted with propionic anhydride, reduced and reoxidized in the above manner to afford 3,5- -~ dichloro-N-ethyl-N-propylaminoacetophenone.

In a similar manner the following 4-(N,Ndial~ylamino-acetophenones which are required for preparing 4-(N,N-disubstituted amino) compounds of formula I are prepared:

X B8 9 ~ CO-CH3 -71- ~2373~7 R8 Rg ~ ~ - 3 7 - 3.7 Cl Cl n-C4Hg n-C4H~ Cl Cl C2H5 n~C3H7 Cl Cl C2H5 C2H5 Cl C~3 C2H5 C2H5 Cl CF3 C2H5 C2H5 Cl No2 C2H5 C2H5 C1 Br C2H5 C2H5 Cl OCH3 EXA~LE 32 ~-[(tert-butylamino)methyl]-3,5-dichloro-4-diethyl .

amlnobenzyl alcohol In the manner described in Example 16, 3,5-dichloro-4-diethylaminoacetophenone is oxidized with SeO2 and reductively alkylated with t-BuNH2/NaBH4 to afford the title compound, mp 93-96 C.

Similarly, a- [ tert-butylamino)methyl]-3,5dichloro-4-(_-dipropyl)aminobenzyl alcohol and ~-[(tert-butylamino)methyl]-3,5-dichloro-4-(_-dibutyl)aminobenzyl alcohol are prepared.

E~LE 33 ~2-bromo-3',5'-dichloro-4' diallylaminoacetophenone and 4'-(allylamino)-2-bromo-3',5'-dichloroacetophenone Cl (CH2=C~CH2)2N~ Co-CH2B Cl ~ CH2-CHCH2NH ~ CO-CH2Br Cl 1~:37;3~ -72 Triethyla~ine (17.0 g, 0.168 mol) is added in c)ne portion to allyl bromide (105.9 g, 0.875 mol~ under a nitrogen atmosphere.

The resulting white emulsion gives an exotherm to 70C and becomes a thick white solid mass within 5 minutes.

The solution formed with the addition of ~lO0 ml of DMF is stirred for l hour at 70-95C. A solution of 4'-amino-2-bromo-3',5'-dichloroacetophenone (25.0 g, 0.088 mol) in 50 ml of D~ is added in one portion and the resulting brown xeaction mixture is maintained at 80-90C for 2 hours.

The orogress of the reaction is frequently checked by thin layer chromatogxaphy(SiO2~CH2Cl2/hexanes (l/l)) since prolonged heating results in the decomposition of both starting material and products.

The reaction mixture is ooured into 1.51 of H2O and is stirred for 0.5 hours.

After a second aqueous trituration, the r~sidual brown semi-solids are stirred with ~150 ml of CCl4 for 0.5 hours to form a suspension.

The yellowish-brown solids are collected by filtration and are air dried to give 14.9 g (59.6%) of recovered phenacyl bromide starting material.

The CCl~ filtr~ate is stirred with MgSO4, filtered and concentrated to yield 9.42 g of a brown syrup.

Gradient elution (hexanes/CH2Cl~ (lO/0 ~ 8/2) flash chromatography on a 9"x2" column of Silica Gel 60 gives two major fractions:

tA) 1.82 g (5.7%) o~ a faster moving amber syrup, identified as 2-bromo-3',5'-dichloro-4'diallylaminoacetophenone by IR(neat) 1680 cm l;

NMR (CDCl~) ~7.93 (s, 2, AR-H), 6.25-5.55 (complex m, 2, CH=~, 5~40-4.95 (complex m, 4, CH2=), 4.40 (s, :2, CH2Br) and 3~87 (m resembling d, 4, J=6Hz, CH~N); chemical ionization mass spectr~n (M ~ H) = 3.62; and _73- ~3~317 (B) 3.49 g (]2.2%~ of a slower moving brown syruo, ideitified as 4'-(allyamino)-2-bromo3',5'-dichloroacetophenone by IR(neat) 3330, 1670cm 1;

NMR(CDC13) ~7.83 (s, 2, AR-H), 6.35-5.65 (com~lex m, 1, CH=), 5.50-5.00 ~complex m, 2, CH2=), 4.8~ (br t, 1, NH), 4.37 (s, 2, CH2Br) and 4.20 (br m, 2, CH2N); chemical ionization mass s~ectrum (~ + H) = 322.

EX~PLE .34 4-(Allyamino)-a-[(tert-butylamino)methyl]-3,5dichloroben~yl alcohol Cl CH2=cHcH2~H ~ CHCH2NHC(CH3)3 1 OH A solution of 4'-(allylamino)-2-bromo3',5'~dichloroacetophenone (2.88 g, 8.92 mmol) in 10 ml is added dropwise over 1 hour to a stirred solution of t-butylamine (1.34 g, 18.3 mmol) in 20 ml of THF.

The reaction tem~erature is maintained at -2d-13C by cooling in a dry iceCC14 bath.

The resultin~ amber suspension is warmed to room temperature over 30 minutes and is stirred~ at 21-22C for 1.5 hours.

Sodium cyanoborohydride (2.80 gt 44.6 mmol) is added in two portions over 5 minutes to give a thick tan suspension with an exotherm from 22-25.C. G1acial acetic acid ~10 ml) is added dropwise to graduàlly form a yellow solution which is stirred at room temperature for 3 days.

The reaction mixture is poured into a solution o 100 ml of H2O and 100 ml of saturated aqueous NaCl which is -hen adjusted to pH7 with 10~ Na2CO3 and extracted three times with Et20.

The combined -74~ extracts are shaken with two portions of diluted aqueous ~Cl which are combined, neutralized with 10~ Na2C~3 to pH8 and extracted three times with Et20.

After stirring the combined extracts with anh. K2C03, the pale yellow-green solution is filtered and concentrated to yield 2.04 g (72.1%) of a pale yellow syrup, identified as 4-(allylamino)~-[(tert-butylamino)methyl}-3,5-dichlorobenzyl alcohol by IR(neat) 3400 cm ; NMR(CDC13) ~7.32 (s, 2, Ar-H), 6.35-5.60 (complex m, 1, CH=), 5.45-4.95 (complex m, 2, CH2=), 4.5 (d of d, 1, Ar-CH), 3.97 (overlapping m, 3, Ar-NHCH2), 3.03 (br s, 2, ~H and OH), 2.68 (m, ~, CH2N) and 1.13 (s, 9, CtCH~)3); chemical ionization mass s~ectrum (M + ~I) = 317.

Tlle CH~C12/CH30H/conc. NH40H (~0/19/1)) shows one major spot (~f = 0.6) with nine trace impurities.

The syrup gradually crystallizes to a tan solid on standing.

E ~ ~LE 35 N-tert-butyl-_-hydroxy-B-methylthiophenethylamine hydrochloride By using the procedure of Example 4 and_ substituting methyl mercaptan for me,hanol as in Example 28, the title compound is prepared.

~ EXAMPL~ 36 3D The following compounds are pre~ared b the method of Example 16:

Cl R~RgN ~ H-CH2-NH-C(CH3)3 ~ Il OH ~L2,3731~ -75 R8 9 o C~ ~ l-C4Hg oil H 1 C6P13 62-64 H C2H5 209 (HCl salt) H benzyl 85-89 H cyclopentyl oil H cyclohexyl 194-198 (HCl salt) -CH2-CH2-cH2 CH2 EXA~LE 37 ~-[(tert-butylamino)methyl]-3,5-dichloro-4diallylaminobenzyl alcohol . (CH2=CHCH2)2-N ~ THC~ -NH-C(C~3)3 Cl OH The title compound is pre~ared usins the procedure described for the preDaration of 4-(allylamino)-~-[(tert-butylamino)methyl]-3,5dichlorobenzyl alcohol (Example30 ). The pale yellow syrup, which graduallv crystallizes on standing, is ~ identified by IP~neat) 3300 and 1630 cm 1;

N,~R(CDC13) ~7.26 (s, 2, AR-H), 6.23-5.54 (complex m, 2, CH=), 5.32-4.87 (complex m, 4, CH2=), 4.48 ~m, 1, AL-CH), 3.78 (m resembling d, 4, J-6Hz, Ar-NCH2), ;3.4-2.0 (br s, 2, NH and OH), 2.62 (m, 2, CH2N~ and 1~13 (s, 9, C(CH313); chemical ionization mass spectrum ~M + H)~ = 357, corresponding to that expected of the title compound.