NZ196249A

NZ196249A - Animal feed compositions containing 1-(aminodihalophenyl)-2-aminoethane derivatives

Info

Publication number: NZ196249A
Application number: NZ196249A
Authority: NZ
Inventors: P K Baker; J A Kiernan
Original assignee: American Cyanamid Co
Priority date: 1980-08-25
Filing date: 1981-02-12
Publication date: 1984-09-28
Also published as: LU83580A1; AT379055B; ATA368581A; KR830005656A; RO85450B; DK374381A; GR75746B; DK171124B1; HU188686B; PT73560B; KR860001829B1; RO85450A; PT73560A; DD208758A5

Description

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number 1 96249 No.: Date: COMPLETE SPECIFICATION 1-(AMINODIHALOPHENYL)-2-AMINOETHANE DERIVATIVES FOR ENHANCING THE GROWTH AND FOR THE DEPRESSION OF FAT IN WARM-BLOODED ANIMALS f^We, AMERICAN CYANAMID COMPANY, a corporation organized and existing under the laws of the State of Maine, United States of America, of Wayne, New Jersey, United States of America, * hereby declare the invention for which Jlxfcwe pray that a patent may be granted to CCflC^us, and the method by which it is to be performed, to be particularly described in and by the following statement:- v - 1 - /•Followed Vw lal la- 196249 PHENYLETHANE DERIVATIVES AND ACID ADDITION SALT THEREOF FOR ENHANCING THE GROWIH RATE OF MEAT-PRODUCING ANIMALS, IMPROVING THE EFFICIENCY OF FEED UTILIZATION THEREBY AND/OR IMPROVING TEE LEAN MEAT TO FAT RATIO THEREOF 5 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 27r 1970. Specifically, methods for the synthesis 1° 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. Bowever, only the analgesic utility is examplified. The preparation of other related 15 i-(amino-dihalophenyl)-2-aminoethanols and their derivatives are disclosed in Japanese Xokai 77 83,619 (Chemical Abstracts, 8_7, 201061r) and European Patent Application 8 ,715 (1980).. These applications 20 25 -2- disclose uses selected from analgesics, broncholytic, 5 antiinflammatory, uterine spasmolytic, ^-blocking activities, antispasmolytic 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 10 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 of feed utilization by said meat-producing 15 animals. it has been found that the growth rate of meat-producing animals such as chickens, turkeys, rabbits, sheep, swine, goats and cattle, including calves, can be increased, 20 "the efficiency of feed utilization thereby measurably inproved, and the lean meat to fat ratio improved by the oral or parenteral administration to said animals of an effective amount of a compound selected from the group consisting of: In accordance with the process of the invention 25 (1) Z 4 ~1 ; 30 35 1962 4 9 -3- 10 15 Ri (la) „ I * ca *-0-^ r"3 Z O CHR? (lb) i* -£>- CHV / \ CH I —R. sO and wherein, X is hydrogen, halogen or -CN? Y is hydrogen, NRQRQ or NHCOR-; 20 o » 3 Z is hydrogen, halogen, OH, CN, CF^, COOR^, CONH2, Cj-C4 alkyl, alkoxy, N02, Cj-C^-dialkylaminomethyl or hydroxymethyl; R^ is hydrogen or Cj^-C^ alkyl; 25 R2 is hydrogen, C^-Cg alkyl, C3-C^ alkenyl, C2~C5 alkanoyl or R10 0-CO ; R3 is hydrogen, C^-Cg alkyl, C^rCg cycloalkyl, methexy-propyl, C3-C4 alkenyl, phenyl, 2-hydroxyethyl, o,a-30 dimethyIphenethyl, benzyl, 3-phenylpropyl or 3-(4- carbornethoxyphenyl)propyl; and when Rj and R^ are taken together with the nitrogen to which they are attached, they represent aorpholino or N'-C^-Cj alkylpiperazino* R^ is hydrogen, OB, ORg or SR^f 35 R5 is hydrogen, C^-Cj alkyl, alkoxy. *10 *io O- or 196249 -4- Rg is Cj^-Cg alkyl, C2~C5 alkanoyl fl>V-CH-. or C -C, alkenyl; R7 is hydrogen, C^-C4 alkyl or phenyl; Rg is hydrogen, C^-C^ alkyl or C3-C4 alkenyl; Rg is hydrogen, C^-Cg alkyl, C4-Cg cycloalkyl, C3-C4 alkenyl, or benzyl; and when Rg and Rg are taken together with the nitrogen to which they are attached, they represent pyrrolidine; R1Q is chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro; R^ is C^-Cg alkyl, phenyl or benzyl; with the provisos that when R3 is phenyl, 2-hydroxyethyl, ora-dimethylphenethyl, C3-Cg cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl, or 3-(4-carbomethoxyphenyl)propyl, R2 is hydrogen; and when R3 is 2-hydroxyethyi, r^ is hydroxyl and the compound is (I); and when Rg is alkanoyl or R2 and R3 are substituents other than hydrogen, except when R^ is an alkyl or substituted alkyl group which contains a tertiary carbon attached to nitrogen; and when X is hydrogen, X and Z are halogen, and Rj is hydrogen, C2-C5 alkanoyl or R3 is isopropyl, 2-butyl, or t-butyl; and when Rg is alkyl or C3-C4 alkenyl, R^ is hydrogen. CD 196249 -5- 5 C1~C4 or c3"c4 alkenyl? and when Z is OB, X and Y are hydrogen; and that at least one of X, Y, and Z represents a substituefit other than hydrogen; and when X is -CN, Z is -CN; and when Z is hydroxymethyl, R4 is OH; and when ^ is a group other than halogen, Y is 10 NRgRg or NHCORg; and when Rg is R4 is OH; and further provided that when X is hydrogen or halogen, and Y is hydrogen, NH2 or NHCOR5 where R5 is hydrogen or C^-C^ alkyl, and Z is hydrogen, halogen or OH, then R4 cannot be hydrogen, OH or ORg where R^ is alkyl; racemic mixtures of the above-identi- 25 fied compounds and the optically active iscmers, and non-toxic, pharmacologically acceptable acid addition salts thereof. 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,NRgRg or 20 NHCOR5; Z is halogen, OH, CN, CF3, COOR^ CONH2, methyl, methoxy, N02, ci~c4 dialkylaminomethyl, or hydroxy-. methyl; and the remaining groups are as hereinbefore defined; or a non-toxic, pharmacologically acceptable acid addition salt thereof. 25 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 NRgRg; Z is chlorine, bromine, CN, CF3j R^ is hydrogen or methylj R4 is 30 OH, OR6, SR1]l» Rg is Cj-Cg alkyl, benryl, C2-C5 alkanoyl, or benzoyl} or a non-toxic, pharmacologically acceptable acid addition salt thereof. The most preferred compounds for use in this invention are: N-tert-butyl- -T OFFICE 2 4 NOV 1983 196249 3,5-dichloro-g-methoxy-4-methylaminophenethylamine; a—[ (tert-butylamino) methyl] -3 , 5-dichloro-4-isopropyl-aminobenzyl alcohol; 5-[2-(tert-butylamino)-1-hydroxy-ethyl]-3-chloroanthranilonitrile; 5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile; methyl-5-[2-(tert-butylamino) -1-hydroxyethvl]-3-chloroanthronilate; benzyl-4-[2-(tert-butylamino)-1-hydroxyethyl]-2,6-dichlorocarban-ilate; 4-amino-N-tert-butyl-3,5-dichloro-3-(methylthio)-phenethylamine; a-[(tert-butylamino)-methyl]-3,5-dichloro-4-methylaminobenzyl alcohol; a-[(tert-butylamino)methyl-3,5-dichloro-4-dimethylaminobenzyl alcohol; 4-amino-3,5-dichloro-a-{[(3-phenylpropvl)amino]methyl}benzyl alcohol; methyl-£-{3-[(4-amino-3,5-dichloro-g-hydroxyphenethyl)-amino]propylJbenzoate; methyl-4-[2-(tert-butylamino)-1-hydroxyethyl]-2,6-dichlorocarbanilate; 5-[2-(tert-butylamino) -1-hydroxyethyl]-3-chloroanthranilonitrile; 4-amino-g-(benzyloxy)-N-tert-butyl-3,5-dichlorophenethyl-amine and the non-toxic, pharmaceutically acceptable acid addition salts thereof. 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, 1S6249 -7- wherein X is hydrogen, halogen or -CN; Y is hydrogen, NRgR9 or NHCOR5; 2 is halogen, -CN, CF3, COOR^ CONH2, C1-C4 alkyl, A M * I M M ^ I 10 W X X X "1 C1~C4 alkoxy, N02 or C1~C4 dialkylaminomethyl; R^ is hydrogen or C1-C4 alkyl; R2 is hydrogen, C^-C4 alkyl, C3~Cg cycloalkyl, alkenyl, C2-C^ alkanoyl or C3~C4 *10 6- ; is hydrogen, C^-Cg alkyl, C3~Cg cycloalkyl x v 15 alkenyl, phenyl or benzyl; R4 is OH, ORg or R5 is hydrogen, C1~C4 alkyl, c3-c4 crc4 alkoxy, 20 110 6- *10 5g is C^-Cg alkyl, C2~C5 alkanoyl, 25 10 CO or 110 CH, 30 35 Rg is hydrogen, alkyl or C3~C4 alkenyl; Rg is hydrogen, Cj-Cg alkyl, C4-Cg cycloalkyl, C3-C4 alkenyl, or benzyl; R^q is hydrogen, chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro; is Cj-Cg alkyl, phenyl, benzyl; with the provisos that when Y is HH2 , NHCH3, NHC2H5 or KHCORg, R4 is ORg or SR^; and when Y is hydrogen, X and z are halogen, R2 is hydrogen, Cj-C^ alkanoyl or PlO /TV N.Z. PATENT bfoffi? 24mm nrnm 1SG249 - 8 - and is isopropyl, 2-butyl or t-butyl; and when X is -CN, Z is -CN; and when Rg is alkanoyl or ^LO CO , Rj and R^ are substituents other than hydrogen, except when R^ is an alkyl or a substituted alkyl group which contains a tertiary carbon attached to nitrogen; and -when Rg is C-^-C^ alkyl, or C^-C^ alkenyl, R^ is hydrogen, C-^-C^ alkyl or C^-C^ alkenyl; and further provided that when X and Z are halogen and Y Is hydrogen or NH^, then R^ cannot be hydrogen, OH or ORg where Rg is C-^-Cg alkyl. Racemic mixtures of the above identified conpounds and the optically active isomers, and nontoxic pharmacologically acceptable acid addition salts thereof. A preferred group of the novel conpounds of this invention have the above structure wherein X = hydrogen or halogen; Y is hydrogen, NRgR^, or NH-COR^; Z is halogen, CN, CF^, COOR^, CONK^, methyl, methoxy, N02, C^-C^ dialkylaminomethyl; R^ is hydrogen, or methyl, R2 is hydrogen, C^-C^ alkyl, C^-C^ alkenyl, alkanoyl or benzoyl; R^ is hydrogen, C^-Cg alkyl, C^-Cg cycloalkyl, C^-C^ alkenyl, benzyl; with the above provisos, and further provided that when X and Z are halogen and Y is hydrogen or NH2, then cannot be hydrogen, OH or ORg when Rg is C-^-Cg alkyl. A most preferred group of novel compounds of this invention have the above structure wherein X = hydrogen, chlorine, bromine; Z Is chlorine, bromine, CN, CF^, COOH, COOCH^, COOC^i^, CONH2; R-^ is hydrogen; R2 is hydrogen, C-^-C^ alkyl; R^ is hydrogen, C-^-C^ alkyl; with the above provisos, and further provided that when X and Z are halogen and Y is hydrogen or NH2, then R^ cannot be hydrogen, OH or ORg where Rg is C-^-Cg alkyl. It Is found, that formula (I) conpounds below (wherein Y is hydrogen) can be prepared by the condensation of an appropriately substituted styrene oxide with the appropriately substituted amine in the presence of an inert solvent, such as a lower alcohol,,at^or * ' - - i_j- -• Oi-.ricg near the boiling point of same, as shown below: ^ ' ,, ,v.„ ; 2 4 jW 8983 9- 1S6249 wherein X and Z are halogen and r„ and are as 20 i ^ hereinabove defined. Thus, 3,5-dichlorostyrene oxide can be reacted with an equimolar or molar excess of t-butylamine in ethanol at reflux from about one to about eight hours, or until the reaction is essentially complete and the desired a-[ (t-butylamino)methyl]—3#5— 25 dichlorobenryl alcohol is obtained as illustrated below: 35 -10- 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 NaBH^ at or 10 below 5°C 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 graphically 15 illustrated as follows: Alternatively, a formula (I) compound wherein 7 is hydrogen nay be prepared from the corresponding formula (Z) compound wherein Y is amino* via a deamination ^ reaction, by dissolving the amine in 50-521 aqueous -11- ^ /° V ' ■ " -V is' V.;- 5 hypophosphorous acid (H^POj). The solution is chilled below 10°C, 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 10 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 aminoaceto-15 phenones 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: 20 25 30 35 CO—CH3 + RgRgNH ^ RgRgN—C0—CH3 (excess) The fluorine displacement is carried out with excess amine in the presence or absence of a solvent; andr if a solvent is required, water appears to be the most useful. With volatile amines, the reaction is conducted in a sealed vessel and generally temperatures of 50 - 100°C are sufficient to complete the reaction. Chlorination and bromination of these amino-acetophenones may be conducted with N-chlorosuccinimide and N-bromosuccinimide in toluene, chlorobenzene or dichlorobenzene at 90 - 100°C. Iodination may be conducted with Nal/N,N-dichlorobenzenesulfonamide or iodine monochloride in acetic acid. 196 2 -12- 5 By reacting these acetophenones with bromine in chloroform or methylene chloride, the corresponding phenacyl bromides are prepared. These phenacyl bromides are then reacted with R2R3N amines and the aminoketones are reduced with NaBH^ or NaCNBH^ by conventional 10 techniques described in references cited hereinbefore. Naturally, compounds which contain groups reactive to halogen, such as when Rg is alkenyl, require other approaches that are discussed below. X X 15 Z Z X z X 25 Z OH 30 wherein X and Z are hydrogen, chlorine, or bromine 22 and Rj and R^ are hydrogen, C^-C^ alkyl, or Cj-C^ alkenyl groups. 1 8 f w 13- 5 The compounds o£ formula I, wherein Rg and R are groups other than both being hydrogen are also prepared by the following general scheme: RgRgN CH-CH~-NR,R_ I 223 OH 5 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), ^ Mn02, pyridiniuro chlorochromate, or other oxidizing 10 agents. Where X or Z are the BH^-reducible groups, CN, COOR, or CONH2, the appropriate acetophenones are prepared by displacement of X or Z represented by bromine with CuCN/DMF at 100 - 160°C by the conventional method, after reduction of the acylated aminoaceto-15 phenones in the first step followed by re-oxidation in 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 20 by conventional methods, such as R^OH/acid-festers, . 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 25 excess of the acid anhydrides with or without organic bases such as tertiary amines or pyridine. The reactions are conducted in inert solvents 30 35 nr2r3 / / / 5 such as chlorinated hydrocarbons, or aromatic solvents at 0 - 25°C. Reaction of the anhydride at the hydroxyl group proceeds well provided R2 and R^ are groups other than hydrogen and when R2 is hydrogen, R^ is a substituent containing a tertiary carbon attached 10 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 15 amine, such as triethylamine, or pyridine in an inert solvent (CH2C12, CHCl^, toluene, etc.) at 50 - 100°C. A 0 20 Y—^~^)-CH-CH-NHR, + (R,C-) ,0 ^ase. Y-^-CH-CH-N-R3 y=S\ | 3 6 2 —^ | I R-1 I Z OH R., Z I 1 I 1 CO-R-. CO-R. 25 Additionally, Formula I compounds, wherein R8 and Rg are selected from hydrogen and C^-Cj alkenyl, are prepared by alkenylation of 4-amino-3,5-disubstituted phenacyl bromides in dimethyIformamide (DMF) in the presence of an acid acceptor, such as triethylamine 30 or sodium carbonate, at 70 - 100°C to afford mono-and dialkenylated products which are separated and converted to I by conventional methods. The following scheme illustrates above-described general method: 35 -16- 1962 49 cl H i2N—COCH2Br + CH2=CH—CH2Br C2H5*3N ^ p7 (excess) DMF ' Cl 10 C1 Cl ch2»ch—ci^-nh-$^-coch2br + (ch2=ch=ch2) 2 n—coch2br ct 15 Is —BuNH2/NaBH4 Cl ch2«ch—ch2-nh— ch—ch2—nh—c (ch3) 3 r '* 25 Formula (I) compounds wherein R^ is ORg and SR^, wherein Rg and *11 are as hereinabove defined, may be prepared by converting the alcohol (R^«OH) with thionyl chloride under an inert blanket of gas such as nitrogen at a temperature range of from about 0 to 10°C 35 o and preferably at 0 to 5 C for a reaction period sufficient to essentially complete the reaction. The thus obtained <£iso -17- 5 halo compound is isolated by conventional methods and is then reacted with the appropriate alcohol or mercaptan, under an inert blanket of gas, such as nitrogen at a temperature range of from about 0 to 50°C. 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: x 25 f—V V-CH—CH,— 2" NR2R3 —CH—CH2—KHjRJ SR11 30 * 35 18- 5 wherein X, Y, Z, R2, Rj* Rg and 8ii are as hereinabove defined. These displacement reactions may also be performed by using an excess of alkoxide (RgO~) or mercaptide (R^S~) in an inert solvent such as tetra-10 hydrofuran to afford the above ethers and thioethers in a similar manner. Alternatively, a formula (I) compound wherein R4 is ORg may be .prepared by dissolving the corresponding formula (I) compound wherein Rj is OH in the corresponding 15 RgOH alcohol and saturating the thus obtained solution with dry BC1 gas. The reaction mixture is then stirred at room temperature for a period of time sufficient to essentially complete 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 RgQH ^^-3 HCI gas > T-CW3 \ OH Z wherein X, 7* X, R2* and Rg are as hereinabove 2Q defined. Zn the present specification and claims, the tern a, ordimethylphenethyl means a structure having the following configuration! o-E (2) / -19- 196240 10 15 When orally administered in the feedr generally about 0.01 to 400 grams per ton of feed of the above-identified 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 ingredient 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 of feed basis: TABLE I Compound Effective Peed Level Preferred Level Animal 20 25 Formula (I) 0.1-200 1-100 Sheep, Goats 0.01-50 0.1-10 Chickens, Rabbits 0.01-50 0.1-10 Turkeys 0.1-300 1-100 Catt£e & Swine Animal feed compositions which will provide the desired growth promotion and feed efficiency in the above-mentioned animals can be prepared by admixing the phenyl-30 ethane derivative or acid addition salt thereof, or an animal feed supplement containing said compound, with a sufficient quantity of an appropriate animal feed to provide the desired level of active compound in said feed. 35 5 10 15 20 25 30 196240 -20- Animal feed supplements can be prepared by admixing 75% to 95% by weight'of the phenylethane derivative or acid addition salt thereof, with 5% 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 of the active ingredient throughout the feed. If the supplement is used as a top dressing 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 the above-said 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 25 mg/kg of body weight of the active phenylethane derivative. The preferred dose level of said phenylethane derivative for poultry is about 0.001 to 35 mg/kg of animal body weight and the preferred dose level of said phenylethane derivative for sheep and goats is 0.001 to 40 ag/kg of animal body weight. The preferred dose level for rabbits is 0.001 to 35 mg/kg of animal body weight. 11 -21- 5 Paste formulations can be prepared by dispersing the active phenylethane derivative in a pharmaceutical^ acceptable oil such as peanut oil, sesame oil# corn oil or the like. Pellets containing an effective level of 10 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 15 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 20 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 25 and improved efficiency of feed utilization by meat- producing animals, the compounds of the present invention have the added advantage that, at selected levels of administration, they increase the deposition of lean meat (i.e., muscle or protein) in said animals 30 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 of. said compounds at 35 selected levels yields leaner animals which command premium prices from the meat industry. 22- 1 96 2 4 9 5 These 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. 10 EXAMPLE 1 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 (72°F to 76°F) 15 with automatically controlled lights, 14 hours on and 10 hours off. The basal diet used in these studies is Purina Laboratory Chow (see description below), which is supplied ad libitum. Water is allowed ad libitum. 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 terminated. Test^ data are provided in Table ZZ below wherein data az% reported as percentage gain over controls. Different control animals are used for each test. The following is description of the diet to which the growth-promoting compounds were added. 20 Thirteen days after arrival, the mice are 30 DIET Guaranteed Analysis 35 Crude protein not less than Crude fat not less than- -Crude fiber not sore than Ash not more than 23.0% 4.51 €.0% 9.0% J -23- 5 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 ^ 10 preserved with BHA, vitamin B^2 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, 15 iodized salt, ferric ammonium citrate, iron oxide, manganous oxide, cobalt carbonate, copper oxide, zinc oxide. 20 25 * 30 #1. 35 / / TABLE II Evaluation of Teat Compounds as Animal Growth Promotera Dosage Gain X Gain Over Compound (ppm) (grams) Controls 0 A'-12- (tert-butylamlno)-l-hydroxyethyn-2'-chloro- 200 . 16.8 +107.9 acetanlllde 100 18.A +127.7 4-Amlno-a-J (tert-butylaralno)methyl]-3,5-diiodobenzyl 200 21.1 +27.1 alcohol hydrochloride 100 20,0 +20.5 TABLE II (continued) Evaluation of Test Compounds as Animal Growth Promoters Compound Dosage (PPm) Gain (grams) % Gain Over Controls a-f(Tert-butylamino)methyl]-3,5-dichloro -4-dimethylaminobenzyl alcohol 200 50 16.0 21.9. 0 +36.9 4-Amino-3,5-dichloro-a-{{(3-phenyl-propyl)amino]methyl}benzyl alcohol 200 50 16.9 18.9 + 5.6 +18.1 a-1(Ter t-butylamino)methyl]-3,5-d ichloro -4-methylaminobenzyl alcohol 200 50 19.4 24.4 +21.3 +52.5 Methyl-g-{3-t(4-amino-3,5-dichloro- - 200 24.3 +22.6 hydroxyphenethyl)amino]propylJbenzoate 50 19.0 - 4.1 TABLE II (continued) Evaluation of Test Compounds as Animal Growth Promoters Compound Dosage (ppm) Gain (grams) % Gain Over Controls Methyl-4-12-(tert-butylamino)-1-hydroxyethyl] -2,6-dichlorocarbanilate 50 27.9 +40.8 5-[2-(Tert-butylamino)-1-hydroxyethvll -3-chloroar^hranilonitrile 200 50 27.3 26.2 +90.9 +83.2 4-Amino-B-(benzyloxy)-N-tert-butyl-3,5-dichlorophenethylamine hydrochlor ide 200 50 22.6 22.4 +58.0 +56.6 a-J (Tert-bubylamino)methyl]-3,5-dichloro-4-iBopropyLiminobenzyl alcohol 200 50 12 3 24.6 24.3 28.0 27.3 +72.0 +69.9 +95.8 +90.8 TABLE II (continued) Evaluation of Test Compounds as Animal Growth Promoters Compound Dosage (ppm) Gain (grams) % Gain Over Controls 5-[2-(Tert-butylamino)-1-hydroxyethyl]-anthranilonitrile 200 50 29.6 29.9 +79.4 +81.2 Methyl-5-[2-(tert-butylamino)-1-hydroxy-ethyl]-3-chloroanthranilate hydrochloride 200 50 24.4 20.1 +47.9 +21.8 Benzyl-4-f2-(tert-butylamino)-1-hydroxyethyl] -2,6-dichlorocarbanilate 50 25.1 +52.1 4-Amino-N-tert-butylamino-3,5-dichloro -8-(methylthio)phenethylamine hydrochloride 200 50 25.4 25.3 +55.8 +55.2 TABLE II (continued) Evaluation of Test Conpounds as Animal Growth Promoters Compound Dosage (ppm) Gain (grams) % Gain Over Controls 3-Bromo-5-[2-(tert-butylamino)-1-hydroxyethyl]-anthranilonitrile 200 50 16.1 24.2 +50.5 +126.2 4-Amino-a-[(tert-butylamino)methyl]-3-methyl-benzyl alcohol 100 20.8 +94.5 4-(Butylamino)-a-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol 200 50 19-3 19.4 +80.4 +81.3 2-Amino-3-bromo-5-[2-(tert-butylamino)-1-hydroxyethy1]benzamide 200 50 17.4 19-8 +62.6 +85.0 4-Amino-a-[(tert-butylamino)methylJ-3,5-dichloro-benzyl alcohol acetate (ester) 200 50 14.6 19.1 +36.4 +78.5 v£> o N) TABLE II (continued) Evaluation of Test Conpounds as Animal Growth Pranoters Dosage Gain % Gain Over Compound (ppm) (grams) Controls 3-Bromo-5-[2-tert-butylamlno)-1-hydroxyethyl]~ 200 18.2 +70.1 anthranilic acid 50 13-6 +27.1 N-tert-butyl-3,5-dichloro-3-methoxy-4miethy1- 200 18.0 +68.2 aminophenethylamine hydrochloride 50 23.1 +115-9 a-[(tert-butylamino)methyl]-3,5-dichloro-4- 200 19.6 +83.2 (hexylamino)benzyl alcohol 50 20.7 +93-5 4-Amino-a-[(tert-butylamino)methyl]-3,5-dichloro- 200 14.4 +34.6 benzyl alcohol acetate (ester), acetate 50 18.7 +74.8 4-Benzylamino-a-[(tert-butylamino)methy1]-3,5- 200 15-7 +46.7 dichlorobenzyl alcohol 50 16.4 +53.3 TABLE II (continued) Evaluation of Test Conpounds as Animal Growth Pranoters Dosage Gain % Gain Over Compound (ppm) (grams) Controls (allyloxy)-4-amino-N-tert-buty1-3,5-dichloro- 200 21.5 +100.9 phenethylamine 50 19-6 +83.2 41-[2-(tert-butylamino)-1-hydroxyethyl]-2',6'- 200 18.3 +71.0 dichlorobenzanilide 50 13-9 +29-9 4-(allylamino)-a-[(tert-butylamino)metbyl]-3,5 200 20.2 +88.8 dichlorobenzyl alcohol 50 21.9 +104.7 4'-[3-(tert-butylamino)-1-hydroxyethyl]-2',6'- 200 25.8 +141.1 dichloroacetanilide acetate (ester), hydrochloride . 50 16.2 +51.4 N-(4-amino-3,5-dichloro-3-hydroxyphenethy1)-N- 200 18.7 +74.8 tert-butylacetamide acetate (ester) 50 15-0 +40.2 TABLE II (continued) Evaluation of Test Conpounds as Animal Growth Promoters ■Compound a-[(tert-Butylamlno)methyl]-3,5-dichloro-4-cyclohexylaminobenzyl alcohol a-[(tert-Butylamlno )methy1]-4-amino-3-chloro-5-methylbenzyl alcohol, hydrochloride Dosage Gain % Gain Over (ppm) (grams) Controls 100 23.0 +115.0 200 16.5 +54.2 50 19.7 +84.1 -32- 5 EXAMPLE 2 Antlllpogenlc Evaluation of Test Conpounds - Mouse Study CFI female mice, 55 days old, are weighed in groups of 10 and allotted to cages to minimize weight variation among cages. Treatments are randomly assigned 10 to cages. Each of the treatments are tested in 3 replicates, i.e., in 3 cages of 10 mice each. There are 10 cages of 10 control mice each. Drugs are mixed in the diet at the dosage level indicated. Feed and water are offered ad 15 libitum for 12-day test period. Peed spilled is collected during the test period. At the end of the test period, the collected feed is weighed and the mean feed comsunp-tion per cage of ten mice is detemrlned for each treatment. The mice are weighed as a group of 10 and the weight gain 20 determined. The mice are 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. Data obtained are reported in Table III. Data are reported as percent reduction in fat pad weight. Reduction 25 in fat pad weights of animals is generally indicative of reduction of total body fat of the treated animals. 30 35 si'' jO 'rn < rn O ro j ** rn O < H c 3 -n OO •n o* a m TABLE III ANTILIPOGENIC EVALUATION OP TEST COMPOUNDS - MOUSE STUDY COMPOUND a-[(Itert-butylamlno)methy1]-3»5-dlchloro-4-dlmethylamlno benzyl alcohol DOSAGE (PCT4) 200 50 % REDUCTION IN PAT PAD WEIGHT VS CONTROLS -46.1 -14.8 4-Amino-3,5-dichloro-a-{[(3-phenyl-propyl) amino]methyl} benzyl alcohol 200 50 -41.1 -36.2 U> U> a-[ (Tert-butylamino )methyl]-3.5-dlchloro-4-methylainlno-benzyl alcohol 200 50 -51.0 -41.9 CO ro CO • • • • ^ ; ^ 1 ye \ I a'- ' Q i .■ 1 -P ' I ^ l \ \ O Irn ' 3 1 "H 1° \ OS I "N 1 \ **» TABLE III (Continued) AMT3LIP0GENIC EVALUATION OF TEST COMKXJNDS - MOUSE STUDY DOSAGE % REDUCTION IN FAT COMPOUND (PPM) PAD WEIGHT VS COOTROLS Methyl-4-(3-[(4-amino-3,5-dichloro-6-hydroxyphenethyl) amino]propylJbenzoate 200 50 a-[ (Tert-butylamino )methyl]-3,5-dichloro-4-isopropylaminobenzyl alcohol 200 50 12 3 -27.7 -14.6 Methyl-4-[2-(tert-butylamino)-1-hydroxyethyl] -2,6- dichlorocarbonilate 50 -23.5 i co , „ ^ 5-[2-Tert-butylamino-l-hydroxyethyl]-3-chloroanthranilonitrile 200 50 -45.9 -10.4 1 4-Amino-6-(benzyloxy)-N-tert-butyl-3,5-dichloro- 200 -24.2 phenethylamine hydrochloride 50 -18.4 -37.6 -13.7 -6.7 -21.3 CD cb CO TABLE-III (Continued) ANTILIPOGENIC EVALUATION OP TEST COMPOUNDS - MOUSE STUDY DOSAGE % REDUCTION IN PAT COMPOUND (PFM) PAD WEIGHT VS CONTROLS Benzyl-4-[2-(tert-butylamino)-l-hydroxyethyl]- 2,6-dichlorocarbanilate 5° -19.6 Methy1-5-[2-(tert-butylamino)-1-hydroxyethyl]- 200 - 5.9 3-chloroanthranilate hydrochloride 50 - 5.8 5-C 2-(Tert-butylamino)-1-hydroxyethyljanthranilo- 200 -'11.5 nitrile 50 -10.3 4-[Amino-N-tert-butyl-3,5-dichloro-6-(methylthio) 200 -28.9 phenethylamine hydrochloride 50 -16.2 Example 3 N-t&E±»-butyl-3,5-dichloro- e-methoxy-4-methylamino-phenethylamine hydrochloride -3,5-dichloro-4-methylaminobenzyl alcohol is added to 70 ml of thionyl chloride under N2 atmosphere and the mixture is stirred for two hours. Excess thionyl chloride is removed in vacuo, and the glassy residue is dissolved in SO ml of methanol. The solution is stirred for 1.5 hours and evaporated to dryness. The residue is dissolved in 100 ml of H20 and extracted with 2 x 50 ml of CH2C12. The aqueous layer is neutralized with solid NaHCOj and extracted with CB2CL2. The extract is dried (MgSO^) and evaporated to dryness in 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, the following ethers are prepared: A 7 g sample of a- [(tert-butylamino)methyl] CHjNH— CH—CH2—NH—Bu—t OR Cl 1962 4 9 -37- 10 15 20 25 Alcohol ethanol 1-propanol 2-propanol 1-butanol « 2-butanol 1-hexanol benzyl alcohol allyl alcohol 4-methoxybenzyl alcohol 4-chlorobenzyl alcohol 4-nitrobenzyl alcohol 4-methylbenzyl alcohol 3,4-dimethylbenzyl alcohol 3,4-dimethoxybenzyl alcohol 3,4-dichlorobenzy1 alcohol 2-chlorobenzyl alcohol 2-methylbenzyl alcohol Example 4 c2H5 1-C3H7 2-C3H7 1"C«89 2-c4H9 —"*C6H13 benzyl allyl 4-methoxybenzyl 4-chlorobenzyl 4-nitrobenzyl 4-methylbenzyl 3,4-dimethylbenzyl 3,4-dimethoxybenzyl 3,4-dichlorobenzyl 2-chlorobenzyl 2-methylbenzyl Zn the Banner described in Example 3, the following ethers are prepared by substituting the corresponding alcohols for methanol. 30 35 Cl E. H— \Jy— fH—CHj—MB— C (CHj) j Cl 38 - R benzyl allyl 190-193 57- 59 4-methoxybenzyl 4-chlorobenzyl 4-nitrobenzyl 4-methylbenzyl 3,4-dimethylbenzyl 3,4-dimethoxybenzyl 3,4-dichlorobenzyl phenyl oil 4-chlorophenyl 4-methoxyphenyl 4-methylphenyl 2-chlorophenyl 4-nitrophenyl Example 5 N-tert-Butyl-3-chloro-5-cyano-B-methoxy-4-aminophenethyl-amine hydrochloride Zn the manner described in Example 3, o-[(tert-butylamino)methyl]-4-amino-3-chloro-5-cyano-benzyl alcohol is converted into the title compoundt and, similarly, the following are also prepared: Ar-CH-CH,-NH-R»HC1 i 2 och3 - 39 - 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 ^-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-C0- phenyl e-butyl 4-amino-3-chloro-5-dimethyl- aminomethylphenyl t-butyl 4-ami no-3-cyano-pheny1 t-butyl Example A. 5-(4-amino-3,5-dichlorophenyl)-3-tert-butyl-2-oxazclidinone In 10 Hi of CH2CL2» 0.5 g of 4-amino- a -[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is stirred with 1 ml of Et^N at -5°C and 2 ml of 12.5% C0C12 in benzene/5 ml of CH2CL2 is added over 15 minutes. The resulting suspension is stirred 20 minutes at 1°C and allowed to warm to room temperature with stirring for 1.5 hours. The mixture is evaporated to dryness, and the residue is chromatographed on silica gel with lxl hexane/CH^CI^ to afford 0.1 g of - no - oil which crystallizes to give the title compound, mp 97 - 103°C. In the same manner, a-I(allylamino)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 CH, 1 1 1 C) N-R-, 3 II 0 Ar 3 3,5-d ichlorophenyl t-butyl 3,5-dichlorophenyl i.-propyl 4-acetamidophenyl t-butyl 4-amino-3-chloro-5-cyanophenyl t-butyl 4-amino-3-chloro-5-tr ifluoro- nethylphenyl t-butyl 3-chloro-4-acetarnidopheny1 t-butyl 3,5-dichloro-4-methylamlno- phenyl t-butyl 3,5-dichloro-4-ethylamino- phenyl t-butyl 3,5-dichloro-4-i.-propyl- "aminophenyl "" t-butyl 3,5-dichloro-4-acetamido pheny 1 ^ t-butyl 3,5-dichloro-4-»ethoxy- carbonylaminophenyl t-butyl 3,5-d ichloro-4-benzyloxy- carbonylaminophenyl t-butyl 1 10 15 20 - 4l - Ar ^3 3,5-dichloro-4-methyl-carbamoylaminophenyl t-butyl 4-amino-3-chloro-5-v 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-CH-jOOC-phenyl t-butyl 4-amino-3-chloro-5-(CH3)2NCH2-phenyl t-butyl 4-amino-3,5-dicyanophenyl t-butyl 25 30 Example 7 4-Amino- <*-[ (tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol acetate A mixture containing 1 g of 4-amino-a-l(tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol in 35 ml of CH2C12 at 10 - 15°C is stirred, and 0.37 J? of Ac20 and 0.5 ml of Et^N are added dropwise. The reaction mixture is then allowed to warm to room temperature, and the reaction is followed by thin-layer chromatography to completion. The mixture is evaporated to dryness jta vacuo, and the yellow viscous liquid (1.5 g) is stirred with 50 ml of ethyl 35 / I " * i ^ ^ o / - 42 - ether to afford a yellow solid (0.84 g), mp 128 — 131°C. 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 CH2CI2 with 30 ml o£ 10% aqueous NaOH, the salt is neutralized. The CI^Clj solution is dried (MgSO^) and evaporated to dryness i_n vacuo to afford the viscous title compound. Analysis: Calcd for C14H20O2N2Cl2: c» 52.67? H, 6.32; N, 8.78; Found: C, 52.38; B, 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-a-[(tert-butylamino) methyl]-3,5-dichlorobenzyl alcohol (A) and a-[(tert-butylamino)methyl]-3,5-dichloro-4-methylamino-benzyl alcohol (B) respectively, to afford the propionate, butyrate, pivalate and benzoates of A and B. Example 8 The following esters are prepared by the method of Example by using the appropriate acid anhydride. Cl - 43 - 5 . Kg ^9 ^6 H CH3 CH3 H C2H5 CH3 10 H n~C3H7 CH3 H 2"C3H7 CH3 H benzyl CH3 H allyl CH3 15 CH3 CH3 CH3 H ch3 C2H5 H CH30-C0- CH3 H CH3NH-CO CH3 H CH3 n-C4Hg CjHJ CjHJ CH3 n-C4Hg n-C4H9 CH3 20 25 Ar—CH CH2"—NH—C (CH^) 3 O—C—Rc II s 0 30 35 1 962 4 9 - i»4 - 5 — ^6 3,5-dichlorophenyl 2-C^H^ 4-amino-3-chloro-5-cyanophenyl CH3 4-amino-3-chloro-5-tr ifluoro-methylphenyl CH3 4-amino-3-chloro-5-H2NCO-phenyl CH3 4-amino-3-chloro-5-BOOC-phenyl CH3 4-amino-3-chloro-5-methylphenyl CH3 15 4-araino-3-bromo-5-cyanophenyl CH3 4-amino-3-chloro-5-CH,OCO-phenyl CH3 4-amino-3-chloro-5-(CH,)-NCH2-phenyl J * CH3 20 4-amino-3,5-dicyanophenyl CH3 4-amino-3-cyanophenyl t-C^Hg Example 9 N-(4-amino-3,5-dichloro-B-hydroxyphenethyl)-N-tert 25 -butylacetamide acetate ——————— A mixture containing 2.5 g of 4-amino-o-[(tert-butrl-amino)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 beating up to 70°C. The residue is treated with ice# 100 ml of and 50 ml of 10% NaOH solution. 35 - 45 - 5 The CH2CI2 phase is separated, and the aqueous portion is further extracted with CH2CL2 (2 x 50 ml). The combined C^CI^ solutions are dried (Na2SO^) and evaporated to dryness to' afford a solid after scratching, The solid is washed with hexane and collected to 10 afford 2.61 g of the title compound, mp 126 - 136°C. Similarly, by substituting the appropriate acid anhydrides, the following compounds are prepared. Cl 15 I rgrgn—ff —ch—ch2—n—c (ch3) 3 I 0—COR* io—R 20 25 30 Cl 6 h Rg ^6 h ch3 ch3 h C2H5 CH3 b 2-c3h7 ch3 B n-C4B9 cb3 ch3 CT3 cb3 B ch3o-co cb3 B ch3nh-co cb3 B cb3c0 cb3 B cb3 C2H5 C2H5 C2H5 n-c4B, 35 - 46 - Ar—CH CH2—N C (CH3) 3 •CH CH,—N I I 0—CORg CORg 4-amino-3,5-dicyanophenyl C2H5 4-amino-3-chloro-t-dimethylamlno methylphenyl CH3 4-amino-3-chl,oro-5-CH3CXX:-phenyl C2H5 15 4-amino-3-chloro-5-methylphenyl CH3 3,5-dichlorophenyl CH3 4-amino-3-chloro-5-cyanophenyl CH3 4-amino-3-chloro-5-trifluoro- 2Q methylphenyl CH3 4-amino-3-chloro-5-H2NCO-phenyl CH3 30 Example 10 25 4-Acetamido-a- [(tert-butylamino) methyl] -3,5-dichloro-Benzyl alcohol acetate In 15 ml of CH2CI>2, 1*57 g of 4-acetamido -$-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is suspended and stirred while 1.2 g of triethylamine in 30 ml of 30 ml of CH2C12 is added, followed by 0.7 g of acetic anhydride in 15 ml of CH2CL2* The mixture is stirred for 20 hours and then is washed with 100 ml of 10% NaOH solution. The organic phase is separated, dried (Na2S0^) and evaporated to dryness 35 in vacuo. The residue is dissolved in 30 ml of ethanol and a trace of H20 is added, followed by 10% HCI to acidify. The mixture is evaporated to dryness in vacuo and the residue is crystallised from acetone/ hexane (30 ml/5 ml). This affords 1.35 g, up. 254 -257°c dec., of the title compound. 1 96 2 -47- 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 11 o-[(tert-Butylamino)methyl]-m-hydroxybenzyl alcohol acetate In the manner described in Example 10 m-(benzyloxy) -a-[(tert-butylamino)methyl]benzyl alcohol is converted to m-(benzyloxy)-«-[(tert-butylamino)-methyl]benzyl alcohol acetate. This material is then debenzylated to give a -[(tert-butylamino)methyl]-m-hvdroxvbenzyl alcohol acetate. Example 12 5-(£-Aminophenyl)-3-ter t-butyl-2-oxazolldinone In 270 ml of CH^Cl2, 12.97 g of o- [ (tert-butylamino) methyl]-£-nitrobenzyl alcohol is dissolved. The solution is cooled to -5°C 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 CB2C12 (2 X 100 ml) The combined organic layers are washed with saturated KaHCO^ solution (2 X 250 ml), 100 ml of fi20 and dried over MgSOj. The solution is evaporated to dryness to give 16.3 g, which is recrystallized from MeOH twice to afford 12.58 g of 3-tert-butyl-5-(£-nitro-phenyl)-2-oxazolidinone, Bp 123 - 125°C. This product (10 g ) is dissolved in 200 b1 of MeOH and hydrogenated 1 •7 -43- 5 over 6 g of Raney nicke at 51 p.s.i.g at 40°C to give, after filtration and evaporation, 8.21 g of 5-(g_ aminophenyl)-3-tert-butyl-2-oxazolidinone, mp 125 - 129°C. Example 13 o-I(tert-butylamino)-methyl)3,5-dichloro-4-dimethyl-aminobenzyl alcohol A mixture containing 50 g of 2-fluoroaceto- 15 20 25 30 35 phenone and 150 ml of 40% aqueous dimethylamine is warmed in a pressure bottle at 90 - 100°C. 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 H20 to give 54.93 of £-dimethylaminoacetophenone, mp 101 - 103°C, 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 200 ml of toluene, and the filtrate and wash solution are evaporated to dryness in vacuo to afford 66 g of oil. This oil is chromatographed on SiC^-with 40% hexane/CH2Cl2 to give 38.9 g of 3.5-dichloro-4-dimethylaminoacetophenone as a yellow oil. A 5.22 g sample of this oil is added portionwise to 2.75 g of Se02 in 20 ml of dioxane and 0.7 ml of E20 at 55 - 60°C. This mixture is heated at reflux temperature for 4.5 hours, cooled and filtered through siliceous earth. The filter cake is washed with 20 ml of dioxane. The dioxane solutions are cooled to 15°C and 2.77 g of t-butylamine is added dropwise to afford a tan precipitate. After stirring 15 minutes at room temperature -49- the mixture is diluted with 200 ml of ethanol, cooled to 5°C and 7 g of NaBHj is added portionwise. After 15 hours, the mixture is treated with 300 - 400 g of ice and 200 ml of HjO- at below 10°C. The mixture is stirred to dissolve all solids and extracted with 300 ml of C^C^* The CH2Cl2 layer is washed with 100 ml of B2O, dried (MgS04) and evaporated to dryness in vacuo to give 5.6 g of orange oil. This oil is dissolved in ethyl ether, decolorized with activated carbon and concentrated to 15 ml. On cooling, crystals are obtained. The title product is collected as white crystals, mp 96 - 99°C. <! -50- 5 EXAMPLE 14 5-(4-amino-3,5-dibromophenyl)-3-tert-butvloxazolidine A mixture containing 2 g of 4-amino-3,5-dibromo-a-[(tert-butylamino)methyl]benzyl alcohol and 5 ml of 37% formalin solution in 20 ml of toluene 10 containing a few crystals of £-toluene sulfonic acid is heated at reflux to azeotrope water. After three hours, the mixture is cooled, diluted to 75 ml with CH2Cl2 and washed with ]0% aqueous NaOH solution (2x20 ml). The aqueous portion is further extracted 15 with 10 ml of CH2CI2 and the combined organic extracts are dried (MgS04) and evaporated to dryness in vacuo to afford 1.6 g of clear brown oil. A chemical ionization mass spectrographic analysis gives a Mass + H+ of 377, which is correct for the title compound. The nuclear 20 magnetic resonance proton spectrum reveals a singlet at «4.53 in CDClj indicative of the O-CHj-N group in the title compound. """""" In the same manner, the following oxazolidines are prepared by substituting the corresponding 25 arylethanolamines for 4-amino-3,5-dibromo-o-Ctert-butylamino) methyl] benzyl alcohol. Ar-CH ^h2 30 & ^N-C(CH)3 35 1 96 2 4 9 -51- 5 - Ar 4-amino-3,5-dichlorophenyl 4-methylamino-3,5-dichlorophenyl 4-amino-3-ch1oro-5-cyanopheny1 4-amino-3-chloro-5-trifluromethylphenyl 10 4-amino-3-chloro-5-methylphenyl 4-amino-3-bromo-5-NH2-CO-pheny1 4-amino-3-bromo-5-HOOC-phenyl 4-acetamido-3,5-dichlorophenyl 3,5-dichloro-4-methoxycarbonylaminophenyl 15 3,5-dichloro-4-methylcarbamoylaminophenyl 4-amino-3-cyanopheny1 4-amino-3-trifluromethylphenyl 4-amino-3,5-dicyanophenyl EXAMPLE 15 20 4-Benzylamino-a-ftert-butylamino)methyl]-3,5-dichloro-benzyl alcohol In the manner described in Example 13 the title compound is prepared to give mp 86-89°C. EXAMPLE 16 25 4'-[2-(tert-butylamino)-1-hydroxyethyl]-2 *,6'-dichloro- benzanilide A mixture containing 2.04 g of 4-amino-3,5-dichloroacetophenone and 0.25 ml of triethylamine in 10 ml of benzoyl chloride 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 oxidized with Be02 in the manner described in 35 Example f3 to eventually afford the title compound, mp 177-182°C. 1 4 9 -52- EXAMPLE 17 a-[tert-butylamino)methyl]-3,5-dichloro-4-methylamino-benzyl alcohol p-Methylaminoacetophenone is prepared and chlorinated by method described in Example 29 to give 3,5-dichloro-4-methylaminoacetophenone. This ketone (18 g) in 200 ml of CHCl^ is stirred and 4.65 ml of Br2 in 50 ml of CHCl^ is added dropwise. After the addition is completed, the mixture is stirred an additional 20 minutes and warmed to reflux temperature for 25 minutes. The mixture is cooled, 100 ml of H20 is added and saturated Na^O^ solution is added carefully until the mixture is neutral. The CHCl^ layer is separated and the aqueous layer is further extracted with 100 ml of CH2C12. The combined extracts are dried (MgSO^) and evaporated to dryness to afford 16.3 g of the phenacyl bromide. This material (16 g) in 80 ml of EtOH is stirred at 12-15°C and 40 ml of t-butylamine is added dropwise. After the addition is completed the mixture is stirred for 10 minutes at 12-15°C and then cooled to ^ 5° and 4 g of NaBH^ is carefully added. After stirring for 0.5 hours, the mixture is allowed to warm to roonu temperature and stirring is continued for 0.75 hours. The mixture is poured on 300 ml of ice with stirring and the resulting mixture is extracted with 300 ml of CHjClj. The CH2CI2 extract is dried (MgSOj) and evaporated to dryness in vacuo to give a yellow oil. Trituration of this residue with ethyl ether affords ' 7.45 g of the title compound, which melts at 98-101°C after recrystallization from ethyl ether. 35 '• /" ' / . /V J ^ ' 1 «/ -53- EXAMPLE 18 5-f2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile A mixture containing 48.86 g of o-amino-acetophenone in 490 ml of toluene is stirred while 64.5 g of N-bromosuccinimide is added in portions over X0 0.5 hours at below 40° C. After 15 minutes, the mixture is washed with H20 (4x100 ml). The solution is dried (MgSO^) and evaporated to dryness to afford 70.53 g of 4-amino-3-bromoacetophenone, mp 59-62°C. A 35 g sample of this material in '180 ml of dry dimethylformamide is 15 stirred and heated at reflux with 17.57 g of Cu2(CN)2 for 6 hours under N2 atmosphere. Subsequently, 180 ml of FeCl^/HCl solution (40 gFeCl3.61^0/10 ml concentrated HC1/60 ml H2) is added and the mixture is heated for 20 minutes at 60-70°C and poured into 350 ml of H20. 20 The aqueous mixture is extracted with CH2C12 and the extracts are washed with H20, saturated NaHCO^ 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, mp 155-159°C, of 25 4-aroino-3-cyanoacetophenone. A 4.8 g sample of this product in 100 ml of EtOAc and 100 ml of CHCl^ 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 30 filter cake is washed with 50 ml of hot 20% MeOH/CHjC^ and the combined organic solutions are evaporated to dryness in vacuo. The residue is stirred in 25 ml of CH2CI2 and the solid is collected and washed with CH2Cl2 to give 8.08 g of the phenacyl bromide. This 35 material is added to 50 ml of t-BuNH^* in 100 ml of 54- 5 EtOH at 5° under Nj atmosphere. After 10 minutes of stirring, the mixture is allowed to warm to 30°C to give a solution. This solution is cooled to 10° and 4 g of NaBH^ is added in portions.' After 45 minutes, the mixture is allowed to warm (42°C) and kept at 20°C until 10 the exotherm subsides. The mixture is then evaporated to dryness and the residue is washed with H20. The residue is dried and treated with 200 ml of boiling MeOH and the hot MeOH solution is filtered. The filter cake is further washed with hot MeOH and the combined 15 filtrates are concentrated to afford crystals. This solid is recrystallized from MeOH/2-PrOH to afford 2.08 g, mp 184-186°C, of the title compound. In a similar manner, the following related compounds are prepared starting with the appropriate 20 acetophenone: X 30 35 /' 1SG249 -55- 5 " Rg Rg R3 X M.P. H H 2~C3H7 H 155-159°C H CH3 t-butyl H CH3 CH3 t-butyl H 2q H ^2H5 t_-butyl H H n-C3H? t-butyl H H 2~C3H7 t-butyl H H n'-C.HQ t-butyl H 15 20 25 30 '4 "9 H CH3 2"C3H7 H H benzyl t-butyl H C2H5 C2H5 t-butyl Cl n-C3H7 n-c3H7 t-butyl Cl 168-168.5°G n-C^Hg n-C^Hg t-butyl Cl EXAMPLE 19 3-chloro-5-[2-(tert-butylamino)-1-hydroxyethyl]-anthranilonitrile In 100 ml of toluene, 5 g of 4-amino-3-cyanoacetophenone is heated at reflux temperature for 20 minutes with 4.2 g of N-chlorosuccinimide. The mixture is cooled and filtered. The filtrate is further heated at reflux temperature for 2 hours. The precipitate is collected and washed with H20. The remaining solid is treated with 0.75 ml of Br2/14 ml of CHCl^ added to 75 ml of CHCl^ and 4.9 ml of EtOH. The mixture is evaporated to dryness and the residue is •lurried with C^C^, collected and washed with CH2C12 to afford 2.84 g of the phenacyl bromide. This material is allowed to react with t-BuNH2 and reduced with NaBH. by the procedure of Example 18 to afford the 35 o title compound, mp 128-138 C. N,Z.PATENT OFFICER 2 4 NOV 1983 RECEIVED- 19 -56- 10 15 20 25 30 35 In a similar manner, the following compounds are prepared: Cl r8r9n 8 H H CH, H H H H h-ch2-nh-r3 H ch3 ch3 C2Hs 2-propyl n-butyl benzyl EXAMPLE 20 2-propyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl 5-[2-(tert-butylamino)-1-hydroxyethyl3-3-chloro-anthranilic acid, methyl ester, hydrochloride A mixture containing 1.36 g of 5-[2-(tert-butylamino)-1-hydroxyethyl]-3-chloroanthranilonitrile 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 in 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 MeOH and 2 ml of acetyl chloride. After allowing to stand overnight# the mixture is filtered and the filtrate is evaporated to dryness. The filter cake is llso washed with MeOH and added to preceding filtrate. The residue is dissolved in acetone, filtered, and evaporated to dryness. The solid is triturated with Et20 and filtered to give 1.49 g, mp 95-115°C, of the title compound. -57- In a similar mannerf the following related esters are prepared: r8r9n— —ff n— ch-ch--nh-r, VMh cooch3 r8 *9 r3 h h 2-propyl 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 t-butyl C2H5 C2H5 t-butyl E-C4H9 a-C4h9 t-butyl n~C3H7 n-C3H7 example 21 t-butyl 2-Amino-3-bromo-5-[2-(tert-butylamino)-1-hydroxyethyl]- - ' -a* benzamide A mixture containing 1.02 g of 3-bromo-5-[2- (tert-butylamino)-1-hydroxyethyl]anthranilonitrile in 25 ml of B20, 5 ml of 50% NaOB and 30 ml of EtOH is stirred and heated at 55-65°C under N2 atmosphere for 1.25 hours. The mixture is evaporated to remove EtOH and extracted with CHCl^. The CHCl^ extract is washed with 25 ml of 2% NaOH, dried (NgSO^) and evaporated to dryness to afford 0.74 g. This solid is stirred with pentane and filtered to afford 0.6 g, mp 135-145°Cf of the title compound. Similarly, the following compounds are R8 r9 x H ch3 Cl H H Cl H C2H5 Cl ch3 ch3 Cl H 2-C3H7 Cl H n-C4H ' Cl H ch3 Br H benzyl Cl C2H5 C2H5 Cl —~C3H7 n-C3H7 Cl n-C4H9 e"C4H9 Cl example 22 3-bromo-5- [2- (tert-butylamino)-1-hydroxyethyl]-anthranilic acid A mixture containing 2 g of 3-bromo-5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile in 10 ml of 50% NaOH, 50 ml of H20 and €0 ml of EtOH is stirred and heated to reflux temperature under N2 for an hour. The EtOH is evaporated and the aqueous mixture mixed with 50 ml of B20 and 50 ml of CHCl^. The CHCl^ layer is removed and the interfacial brown oil is collected, added to 10 ml of MeOH, 5 ml of H20 and this mixture is acidified to*pH 5. After stirring for an hour, the off-white solid is collected, washed with H20 and dried to give 0.8 g, mp 221.5°C dec., of the title compound. 10 15 20 25 1 96 2 49 - 59 - Similarly, the following compounds are prepared: cooh rgrgn ft ch-ch2-nh-c(ch3)3 >h R8 R9 X h h Cl h ch3 Cl CH3 CH3 Cl h ch3 Br h 2-C3H7 Cl h n-C4H9 Cl h benzyl Cl C2H5 °2H7 Cl £~C3H7 E~C3H7 Cl n-C4H9 n~C4H9 Cl EXAMPLE 2^ 5-(3-hydroxyphenyl)-3-tert-butyl-2-oxazolidinone In the manner described in Example 8, m-benzyloxy)-o- [tert-butylamino) methyl] benzyl alcohol is coverted to the oxazolidinone compound by treatment with phosgene. Subsequently debenzyla-30 tion is.completed ; to give the title compound. EXAMPLE 24 5-(3-hydroxyphenyl)-3-tert-butyloxazolidine In the manner described in Example 12, 35 m-(benzyloxy)-a-[(tert-butylamino)methyl)benzyl alcohol is reacted with formaldehyde to afford the oxazolidine derivative, which is debenzylated by the procedure of Example 10 to give the title compound. 1 96 2 4 example 25 5 4-amino-N-tert-buty1-3,5-dichloro-6-(methylthio)-phenethylamine hydrochlorid¥ In the manner described in Example 3, N-tert-butyl-3,5-dichloro-g-chloro-4-aminophenethyl-amine hydrochloride is prepared. An 11 g sample of 10 this product is portionwise added to 5 ml of methyl mercaptan in 100 ml of dry ethylenedichloride at -10°C to 0°C. The mixture is stirred and allowed to rise gradually to room temperature over a four day period. The mixture is filtered, the filter cake 15 is washed with ethylenedichloride (2x500 ml). The solid is dispersed in 200 ml of H20, cooled to 5°C and basified with 6N NaOH solution to give a white oil, which is extracted with CH2C12 (3x100 ml). The CH2C12 extract is dried (MgSO^) and evaporated to 20 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 ether for 16 hours and filtered to give 3.63 g, mp 178-181°C dec. This solid is heated 25 in refluxing ethyl acetate and filtered to give 2.07 g, mp 188-193°C. Recrystallization from 75 ml of ethylenedichloride affords 1.45 g of the title compound, mp 191-196°C. The title compound is also obtained by 30 adding 5-10 fold excess of sodium mercaptide in tetrahydrofuran at 0-10°C and by following the above workup. 35 / .'n c \_j) - 61 - 10 15 EXAMPLE 26 In the same manner as described in Example 25, the following thioethers are prepared by substituting methyl mercaptan with the corresponding mercaptans: Cl h-ch2-nh-r3 •HCI 20 25 30 methyl ethyl 2-propyl n-butyl t-butyl n-hexyl phenyl benzyl 2-propyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl 2-propyl EXAMPLE 27 In the manner described in Example 25 » substitution of-the corresponding chloro compound for N-tert-butyl-3,5-dichloro-g-chlor o-4-aminophene thy lamine hydrochloride and adding the appropriate mercaptans afford the following thioethers': 35 Ar-CH-CH2-NH-R3 + RSH T Cl Ar-CH-CH,- r sr 2-nhr3 - 62 - 1 96 2 4 9 10 15 20 25 30 Ar R 4-amino-3-cyanophenyl methyl 4-methylamino-3,5-dichlorophenyl methyl 4-amino-3-chloro-5-trifluoromethyl methyl 2-propyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl t-butyl 4-amino-3-chloro-5-cyanophenyl methyl 4-amino-3-chloro-5-cyanophenyl ethyl 4-acetamido-3,5-dichlorophenyl methyl 4-amino-3-chloro-;5-H2NCO-phenyl methyl 4-amino-3-chloro-5-H0C0-phenyl methyl 4-amino-3-chloro-5-methylphenyl ethyl 4-amino-3-chloro-5-methoxyphenyl n-butyl 4-araino-3-chloro-5-nitrophenyl methyl 4-amino-3-chloro-5-CH20-C0-phenyl methyl EXAMPLE 28 3,5-dichloro-4-(N,N-diethylainino)acetophenone A sample (2.5 g) of 4-amino-3,5-dichloro-acetophenone 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 with ice and 10% NaOH solution and extracted with CH2CI2 (3x50~nl). The extracts are dried (Na2804) and evaporated to dryness to give 2.42 g of semisolid, which is purified by chromatography over Si02 using CH2C12 as eluent to afford 1.06 g of 4-(N, N-diacety amino)-3,5-dichloroacetophenone as an oil. This material is dissolved in 10 ml of tetrahydrofuran (THF) under Nj atmosphere and 18 ml of 1M BH^THF is added dropwise. The mixture is stirred until the reaction is complete and HjO is added cautiously. The mixture 35 Q/L 7 A J - 63 - 5 is evaporated to remove THF and 20 ml of H20 and 10 ml of 10% NaOH are added. This aqueous mixture is extracted with C^Clj (3x25 ml) and the extracts are dried (Na2S04) and evaporated to dryness to yield 0.68 g the desired alcohol. This product (0.3 g) in 10 2 ml of CH2Cl2 is added to 0.32 g of pyridinium chlorochromate (PCC) in 2 ml of CHjClj. After 1.25 hours, em 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 of C^C^. The 15 combined CH2Ci2 solutions are diluted with 50 ml of CH2Cl2 and washed with 10 ml of saturated Na2C03 solution and 10 ml of HjO and dried (NajSO^. The solution is evaporated to dryness to afford a residue which is chroroatographed on Si02 with 20 CH2CI2 as eluent to yield 0.04 g of the title compound as an oil (NMR in CDCl^s rtl.O (6H, triplet), 2.5 (3H, singlet), 3.25 (4H, quartet), 7.83 (2H, singlet) The monoethylaminoacetophenone is also obtained as a solid (0.12 g) as the second component. 25 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,N-30 dialkylamino-acetophenones which are required for preparing 4-(N,N-disubstituted amino) compounds of formula I are prepared: 35 *8*9* - 6k - 10 15 25 30 35 *8 R9 X Y n-C3H? 5TC3H7 C1 C1 H-C4H9 C1 C1 CjH n~C3H7 Cl Cl C2H5 C2H5 C1 CH3 C2H5 C2H5 C1 CF3 c2h5 c2h5 cl n02 C2H5 C2H5 Cl Br c2h5 c2k5 cl och3 example 29 a-[(tert-butylamino)methyl]-3,5-di chloro-4-diethy1-aminobenzyl alcohol In the manner described in Example 13, 3,5-dichloro-4-diethylaminoacetophenone is oxidized 2Q with Se02 and reductively alkylated with t-BuNH2/NaBH4 to afford the title compound, mp 93-96°C. Similarly, a-[tert-butylamino)methyl]-3,5-dichloro-4-(n-dipropyl)aminobenzyl alcohol and a-I(tert-butylamino)methyl]-3,5-dichloro-4-(n-dibutyl)-aminobenzyl alcohol are prepared EXAMPLE 30 : -rs. 2-bromo-3',5 *-dichloro-4'-diallylaminoacetophenone and 4' - (allylaiaino) -2-bromo-3', 5' -dichloroacetophenone (CH^CHCH^^N-^ >\-CO-CH2Br Cl CH2«CHCH2NH-^ x>—CO-CH2Br Cl 19 - 65 - Triethylamine (17.0 g, 0.168 mol) is added in one portion to allyl bromide (105.9 g, 0.875 mol) under a nitrogen atmosphere. The resulting white emulsion gives an exotherm to 70°C and becomes a thick white solid mass within 5 minutes. The solution formed with the addition of *100 ml of DMF is stirred for 1 hour at 70-95°C. A solution of 4,-amino-2-bromo-3',5'-dichloroacetophenone (25.0 g, 0.088 mol) in 50 ml of DMF is added in one portion and the resulting brown reaction mixture is maintained at 80-90°C for 2 hours. The progress of the reaction is frequently checked by thin layer chromatography(Si02/CH2Cl2/hexanes (1/1)) since prolonged heating results in the decomposition of both starting material and products. The reaction mixture is poured into 1.51 of H20 and is stirred for 0.5 hours. After a second aqueous trituration, the residual brown semi-solids are stirred with *150 ml of CClj 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^ filtrate is stirred with MgSO^, filtered and concentrated to yield 9.42 g of a brown syrup. Gradient elution (hexanes/CH2Cl2 (10/0 » 8/2) flash chromatography on a 9"x2" column of Silica Gel 60 gives two major fractions: (A) 1.82 g (5.7%) of a faster moving amber syrup, identified as 2-bramo-3f,5'-dichloro-41-diallylaminoacetophenone by IR(neat) £680 cm'^j NMR (CDC13) <7.93 (s, 2, AR-H), £.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, CH2N)t chemical ionization mass spectrum (M + H)+ - 3.62; and 5 (B) 3.49 g (]2.2%) of a slower moving brown syrup, ideitified as 4'-(allyamino)-2-bromo-3',5'-dichloroacetophenone by IR(neat) 3330, 1670cm"1; NMR(CDC13) S7.83 (s, 2, AR-H), 6.35-5.65 (complex m, 1, CH=), 5.50-5.00 (complex m, 2, CH2»), 4.84 10 (br t, 1, NH), 4.37 (s, 2, CH2Br) and 4.20 (br m, 2, CHjN); chemical ionization mass spectrum (M + H)+ « 322. example 31 4-(Allyamino)-a-[(tert-butylamino)methyll-3,5-15 dichlorobenzyl alcohol" CH2=CHCH2NH—(/ (JHCH2NHC (CH3) 3 :i 0H 20 A solution of 4'-(allylamino)-2-bromo- 35'-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 temperature is main-25 tained at -24°-13°C by cooling in a dry ice- CC14 bath. The resulting amber suspension is warmed to room temperature over 30 minutes and is stirred-at 21-22°C for 1.5 hours. Sodium cyanoborohydride (2.80 g, 44.6 mmol) is added in two portions over 30 5 minutes to give a thick tan suspension with an exotherm from 22-25°C. Glacial acetic acid (*10 ml) is added dropwise to gradually form a yellow solution which is stirred at room temperature for 3 days. The reaction mixture is poured into a solution of 35 100 ml of H20 and 100 ml of saturated aqueous NaCl which is then adjusted to pH7 with 10% Na2C03 and extracted three times with Et20. The combined - 67 - 5 extracts are shaken with two portions of diluted aqueous HCI which are combined, neutralized with 10% NajCOj to pH8 and extracted three times with Et20. After stirring the combined extracts with anh. K2C03, the pale yellow-green solution is 10 filtered and concentrated to yield 2.04 g (72.1%) of a pale yellow syrup, identified as 4-(allylamino)-o-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol by IR(neat) 3400 cm"1; NMR(CDC13) <57.32 (s, 2, Ar-H), 6.35-5.60 (complex m, 1, CH=) , 15 5.45-4.95 (complex m, 2, CH2=), 4.52 (d of d, 1, Ar-CH), 3.97 (overlapping m, 3, Ar-NHCH2), 3.03 (br s, 2, NH and OH), 2.68 (m, 2, CH2N) and 1.13 (s, 9, CtCH,)^); chemical ionization mass spectrum (M + M) = 317. The CH2Cl2/CH30H/conc. 5JH4OH 20 (80/19/1)) shows one major spot (Rf «* 0.6) with nine trace impurities. The syrup gradually crystallizes to a tan solid on standing. example 32 N-tert-butyl-m-hydroxy-g-methylthiophenethylamine 25 hydrochloride By using the procedure of Example 3 and substituting methyl mercaptan for methanol as in Example 25 the title compound is prepared. EXAMPLE 33 30 The following compounds are prepared by the method of Example 13 : Cl 35 RgRgN ft V\—CH-CH2-NH-C (CH3) Cl 0H </div>

Claims

<div class="application article clearfix printTableText" id="claims"> % 1 96 2 4 9 - 68 - R8 R9 mp °C: 10 H X'CAH9 oil H l-CgH13 62-64 H C2H5 209 (HCI salt) H benzyl 85-89 H cyclopentyl oil H cyclohexyl 194-198 (HCI salt) -ch2-ch2-ch2-ch2- EXAMPLE 34 o-[(tert-butylamino)methyl]-3,5-dichloro-4- diall ylaminobenzyl alcohol Cl 15. (ch2«chch2 ) 2-n chch2-nh-c (ch3 ) 3 20 C1 08 The title compound is prepared using the procedure described for the preparation of 4-(allylamino)-a-[(tert-butylamino)methyl]-3,5- , dichlorobenzyl alcohol (Example 31) • The pale yellow 25 syrup, which gradually crystallizes on standing, is identified by XR(neat) 3300 and 1630 cm**1; NMR(CDC13) 67.26 (s, 2, AR-H), 6.23-5.54 (complex m, 2, CH»), 5.32-4.87 (complex a, 4, CH2»), 4.48 (m, 1, Ar-CH), 3.78 (m resembling d, 4, J-6Hz, 30 Ar-NCH2), 3.4-2.0 (br 8, 2, NH and OB), 2.62 (m, 2, CH2N) and 1.13 (s, 9, C(CH3)3)j chemical ionization mass spectrum (H + H)+ ■ 357, corresponding to that expected of the title compound. 35 196249 -69- WHAT WE CLAIM IS: 1.
An animal feed composition comprising a balanced diet and from 0.01 to 400 grams per ton of feed of a compound having a formula selected from the group consisting of: ji_NR2R3 (1)5 (la); and (lb) wherein X is hydrogen, halogen or -CN; Y is hydrogen, NRgR^ or NHC0R5; Z is hydrogen, halogen, OH, CN, CF^ COOf^, CONH^ C-j-C^ alkyl, ci-C4 alkoxy, NO^, C^-C^-dialkylamincmethyl or hydroxy-methyl, is hydrogen or C^-C^ alkyl; R2 is hydrogen, C^-Cg alkyl, C^-C^ alkenyl, C2~C^ alkanoyl or R1Q ; R^ is hydrogen^ 0-co C^-Cg alkyl, cycloalkyl, roethoxypropyl, C^-C^ alkenyl3 phenyl, 2-hydroxyethyl, a ,a -dimethylphenethyl, benzyl, 3-phenylpropyl or 3-(4-carbomethoxyphenyl) propyl; and when an^ are taken together with the nitrogen to which they are attached, they represent morpholino or N1—alkylplpera zino; is hydrogen, OH, ORg or SR^; R,_ is hydrogen, alkyl, C.^ alkoxy, R1Q , R.q S-vh? O- or N(R1). R6 is C1~°S aIky]L» C2"C5 \o » *ko <m^co, ^-CH2 q.- or C^-C^alken N ,z. patek 2 -70- 136249 Rj is hydrogen, alkyl or phenyl; Rg is hydrogen, C-^-C^ alkyl or alkenyl; is hydrogen, C^-Cg alkyl, C^-Cg cycloalkyl, alkenyl, or benzyl; and when Rg and R^ are taken together with the nitrogen to which they are attached, they represent pyrrolidine; R-^ is chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro; and is C^-Cg alkyl, phenyl or benzyl; with the provisos that when R^ is phenyl, 2-hydroxyethyl,a,a-dimethyl-phenethyl, C^-Cg cycloalkyl, benzyl, methoxypropyl, 3-phenylpropyl, or 3-(4-carfcomethoxyphenyl)propyl, is hydrogen; and when R^ is 2-hydroxyethyl, R^ is hydroxyl and the compound is (I); and when Rg is alkanoyl or PL q , R2 and R^ are substituents other than <g)_C0 hydrogen, except when R^ is an alkyl or a substituted alkyl group which contains a tertiary carbon attached to nitrogen; and when Y is hydrogen, X and Z are halogen, and R^ is hydrogen, alkanoyl or R^Q • , R^ is isopropyl, 2-tutyl or t-butyl; and when ^-C0 Pig is alkyl or C^-C^ alkenyl, R^ is hydrogen, C^-C^ alkyl or alkenyl; and when Z is OK, 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 hydroxyinethyl, is OK; and when Z is a group other than halogen, Y is NRgR^ or NHCGRj.; and when R^- is NCR^^, Rjj is OH; and further provided that when X is hydrogen or halogen,, and Y is hydrogen-, NH^ or nhcor^ where R<_ is hydrogen or Cl-C4 alky1' 2 hydrogen, halogen or Cii, then cannot be hydrogen, OH or OR, where R is C-. -Cr alkyl; racemic mixtures of the 6 6 16 above-identified conpounds and the optically active isomers, and nontoxic, pharmacologically acceptable acid addition salts thereof. 2.
A methed for the preparation of an animal feed canpos;-ition comprising admixing an animal feed with from 0.01 to *100 grams per ton of feed of a canpound having a structure selected from the group consisting of: X -ck ch—(i). ">f i { ' * *5 MAY 1984 ■ -71- 136249 Y- (la); and Y- (lb) wherein X, Y, Z, R^, R2, R^, R^ and Rp are as defined in claim 1 above. compound is selected from the group consisting of: N-tert-butyl-3,5-dichloro-B-methoxy-4-methylamir.ophenethylainiiie; a-[(tert-butylamino )methyl]-3,5-dichloro-A-isopropylaminobenzyl alcohol; 5-[ 2- (tert-butylamino )-1-hydroxyethyl ]-3-chloroanthranilonitrile; 5-[2-(tert-butylamino)-1-hydroxyethyl]anthranilonitrile; methyl -5-[ 2- (tert-butylamino) -1-hydroxyethyl) -3-chloroanthranilat e; benzyl-4- [ 2- (tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarban-ilate; 4-amino-N-tert-butyl- 3,5-dichloro- 0- (methylthio) phenethyl-amine; a- [ (tert-butylamino) -methyl] -3,5-dichloro-4-methylaraino-benzyl alcohol; a-[ (tert-butylamino)methyl]-3,5-dichloro-4-dimethyl-aminobenzyl alcohol; 4-amino-3/5-dichloro-a-{ [ (3-phenylpropyl)-amino]methyl}benzyl alcohol; methyl-g-{3-[ (4-amino-3,5-dichloro-g-hydroxyphenethy1) amino]propyl}benzoate; methyl-4-[2-(tert-butylamino) -1-hydroxyethyl] -2,6-dichlorocarbanilate; 5- [2- (tert-butylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile; 4-amino-f}- (benzyloxy) -N-tert-butyl-3,5-dichlorophenethylamine and the non-toxic, pharma-ceutically acceptable acid addition salts thereof.
4. A composition according to claim 1 wherein said compound is 5- [2- (isopropylamino) -1-hydroxyethyl] anthranilonitrile.
5. A composition according to claim 1 wherein said compound is 5- [2- (isopropylamino) -1-hydroxyethyl] -3-chloroanthranilonitrile.
6. A composition according to" claim 1 wherein said compound is 5- [ 2- (tert-butylamino) -1-hydroxyethyl] -3-bromoanthranilonitrile. 3. A conposition according to claim 1 wherein said 1S6240 -72-
7. An animal feed supplement useful for enhancing the growth rate and lean meat deDosition in warm-blooded animals can-prising from 75% to 95% \by weight of a compound having formula selected fron the group consisting of: K '2*3 (i); f1 CHFt, /ii I (la); and (lb) wherein X, Y, Z, R^, R2, R^, and R^, are as defined in claim 1 above and from 5% to 25% by weight of a suitable carrier or diluent.
8. An injectable composition useful for enhancing the growth rate and lean meat deposition .in warm-blooded animals ccm-prising as an active ingredient a compound having a formula selected frcrn the group consisting of: : NR^ (i), irti (la); and 136249 -73- * -r3 (ib) -c=o wherein X, Y, Z, R^, R^, R^, R^ and R^, are as defined in claim 1 above, and a pharmaceutically acceptable carrier > suitable for injectable canpositions.
9. A composition according to claim 8 wherein the active ingredient is administered to warm-blooded animals in an amount sufficient to provide said animals with..from-0.001-to-100 mg/kg/day of body weight of the active ingredient having the formula: -CH CH NR^ 4 A wherein X, Y, Z, R^, R^, R^j and R^, are as defined in claim 1 above.
10 . An implant useful for increasing the dressed carcass weight of meat-producing animals and enhancing the lean meat to fat ratio thereof canprising as the active ingredient a compound having the structure: Cj| Cjl NR^ wherein X, Y, Z, R^, R2, R^ and R^ are as defined in claim 1 above, and a pbaraaceutically acceptable carrier suitable for implants.
11. A compound of the formula: -CH CH- R1 R] r4 r1 -NR^ 136349 -7k- wherein X Is hydrogen, halogen or -CN; Y is hydrogen, NRgR^ or NBCOFU; Z is halogen, -CN, CF^, CCOR^ CCNH^ C^—alkyl, C-j-C^ alkoxy, NC>2 or ■ C-j^-C^ dialkylaminomethyl; is hydrogen ar C-j-C^ alkyl; is hydrogen, C-^-Cjj alkyl, C^-Cg cycloalkyl, C^-C^ alkenyl, ^-Cj- alkanoyl or R.Q ; R^ is hydrogen, C-j-Cg alkyl, C^-Cg cycloalkyl, C^-C^ alkenyl, phenyl or benzyl; is OH, ORg, or SR^; R^_ is hydrogen, C^-C^ alkyl, C-^-C^ alkoxy, R10 or R ; ^-CH2° 0- Rg is C^-Cg alkyl, C^-C^ alkanoyl, R1Q , R,Q or JLQ ; Rg is S- iy0 S-^ hydrogen, C^-C^ alkyl or C^-C^ alkenyl; R^ is hydrogen, C-^-Cg alkyl, Cj^g cycloalkyl, C^-C^ alkenyl or benzyl; R^ is hydrogen, chloro, dichloro, methyl, dimethyl, methoxy, dimethoxy or nitro; and R11 is Cj-Cg alkyl, phenyl, benzyl; with the provisos that when Y is NHCH^, NHC2H-, R^ is ORg'or SR.^; and when Y is hydrogen, X and Z are halogen, R2 is hydrogen, C2~C^ alkanoyl or FLq • and R^ is isopropyl, 2-butyl <^3y~C0 or t_-butyl; and when X is -CN, Z is -CN; and when Rg is alkanoyl or R-, n , R_ and R_ are substituents other than hydrogen, except when |10 d 3 is an alkyl or a substituted alkyl group which contains a tertiary carton attached to nitrogen; and when Rg is C^-C^ alkyl or alkenyl, Rg is alkyl or ^-C^ alkenyl; and further provided that when X and Z are halogen and Y is hydrogen or NH^ then cannot be hydrogen, OH or OR,, where R, is C..-C alkyl; racemic b bio mixtures of the above-identified compounds and the optically active isomers, and non-toxic pharmacologically acceptable acid addition salts thereof. - 75 - 3-3624$
12. A compound according to claim 11 wherein said compound is: N-tert-butyl-3,5-dichloro- B-methoxy-4-irethylaminophenethylamine ; a- [ (tert-butylamino) methyl] -3,5-dichloro-4-isopropylaminobenzyl . alcohol; 4-amino-N-tert-buty 1- 3,5-dichloro- p- (methylthio) phen-ethylamine; a- [ (tert-butylamino) methyl] -3,5-dichloro-4-dimethy 1-aminobenzyl alcohol; 4-amino- Q- (benzyloxy) -N-tert-butyl-3,5-dichlorophenethylamine; 4- (allyl amino) -N-[ (tert-butylamino) methyl] -3,5-dichlorobenzyl alcohol, and the non-toxic, pharmaceutically acceptable acid addition salts thereof. J, or oated this s cnkl A j park & son v, -E« /V- <=• ^ 1 ,gemts foi applicants 25MAY1984 $ </div>