ANTIMICROBIAL ANIMAL FEED ADDITIVE COMPOSITIONS

Abstract: Antimicrobial animal feed additive compositions con­ taining substituted 1-(aminophenyl)-2-aminoethanols and a method for increasing feed efficiency and antilipogenic activity when said animal feed additive combinations are orally administered to food-producing animals.

Description: ANTIMICROBIAL ANIMAL FEED ADDITIVE COMPOSITIONS Background of the Invention The present invention relates to antimicrobial edible animal feed additive compositions and antimicrobial edible animal feedstuff compositions containing certain substituted l-caminophenyl)-2-aminoetbanols, or the pharmaceutically-acceptable acid-addition salts thereof, in combination with certain antimicrobial agents. Additionally, this invention relates to a method for increasing the feed efficiency of warm-blooded animals and improving the lean meat to fat ratio of said animals. Several references disclose the use of 1 (aminodihalophenyl)-2-aminoethanols and their derivatives. For instance, United States Patent 3,536,712 specifically discloses methods for preparing such compounds, as well as the use of such compounds in warm-blooded animals for enhancing blood circulation, as bronchodilators, analgesics, sedatives and antipyretics. Other such l-(aminodihalophenyl)-2-aminoethanols and their derivatives are useful as analgesics, broncholytics, anti-inflammatives, uterine spasmolytics, S- mimetics and/or B-blockers, body fat mobilizers and antiallergics (Japanese Kokai 77 83,619; German Offenlegungsschrift 2,804,625 (1979); German Offenlegungsschrift 2,157,040 (1973); German Offenlegungsschrift 2,261,914 (1974); European Patent Application 8,715 (1980); and Netherlands Patent Application 7,303,612 (1973)). However, these references fail to disclose, teach or suggest the animal teed additive combinations of the present invention. United States Patents 4,404,222 and 4,407,819 do relate to methods for depressing fat deposition in warm-blooded animals by administering effective amounts of l-(aminophenyl)-2-aminoethanes, substituted products thereof or certain acid-addition salts. Although these compounds are disclosed as antilipogenics, these references fail to specifically disclose the compatability of these aminoethanols in combination with antimicrobial agents. But even more importantly, these references fail to recognize that animal feed additives or edible animal feeds containing formula (I) compounds with antimicrobials will increase feed efficiency, while reducing fat deposition, resulting in a larger, yet leaner foodproducing animal. Summary of the Invention The present invention, therefore, relates to animal feed additive compositions and edible animal feedstuff compositions used for increasing feed efficiency and improving the lean meat to fat ratios of warm-blooded animals comprised of certain substituted l-(aminophenyl)- 2-aminoethanols, or the pharmaceutically-acceptable acidaddition salts thereof, represented by the following structural formula (I): EMI2.1 wherein R1 is hydrogen or C1-C14 alkyl; R2 is hydrogen or methyl, provided that when R1 is C2-C14 alkyl, then R2 is hydrogen; R3 and R4 are each hydrogen or C1-C6 alkyl; X and Y are each hydrogen, bromine, chlorine, fluorine, iodine or cyano; Z is preferably hydrochloric, phosphoric, acetic, propionic, citric, gluconic, abietic, oleic, linoleic, linolenic, tall oil fatty acids, or mixtures thereof; and n is an integer of 0 or 1; and antimicrobial agents such as anticoccidials, growthpromoting antimicrobials and therapeutic antimicrobials, or mixtures thereof. It is an object of the present invention to provide said composition useful as animal feed additive compositions as well as edible animal feedstuff compositions themselves. Furthermore, it is also an object of this invention to provide a method for increasing feed efficiency, while reducing the level of body fat, in domestic and farm animals administered said animal feed additives or edible animal.feedstuff compositions. Description of the Invention Substituted l-(aminophenyl)-2-aminoethanols The present invention contains certain substituted l-(aminophenyl)-2-aminoethanols and the pharmaceutically-acceptable acid-addition salts thereof, represented by formula (I) below: EMI3.1 wherein R1 is hydrogen or C1-C14 alkyl; R2 is hydrogen or methyl, provided that when R1 is C2-C14 alkyl, then R2 is hydrogen; R3 and R4 are each hydrogen or C1-C6 alkyl; X and Y are each hydrogen, bromine, chlorine, fluorine, iodine or cyano; Z is preferably hydrochloric, phosphoric, acetic, propionic, citric, gluconic, abietic, oleic, linoleic, linolenic, tall oil fatty acids, or mixtures thereof; and n is an integer of O or 1. The preferred acid addition salts of the substituted l-(aminophenyl)-2-aminoethanols include abietic acid, linolenic acid, linoleic acid, oleic acid, acetic acid, tall oil fatty acids, and mixtures thereof. The preferred formula (I) compounds include 4 amino-a[tert-butylamino)methyli-3,5,dichlorobenzyl alcohol and 5-[l-hydroxy-2-(isopropylamino)ethyl] anthranilonitrile, with the 5-!l-hydroxy-2-(isopropylamino)- ethyllanthranilonitrile being the most preferred. When these compounds are used in animal feed additive compositions, in amounts to increase feed efficiency and improve lean meat to fat ratio, about 0.00001% to 0.0001% (0.10 to 10.0 ppm), by weight, of the compound or the desired acid-addition salt is present in the final edible animal feedstuff composition. Antimicrobials Antimicrobials useful in the present invention include three types, anticoccidials, growth-promoting antimicrobials and therapeutic antimicrobials. Some suitable anticoccidials include prinicin, salinomycin, monensin, naracin, lasalocid, robinedine, aprinocid, amprolium, nicarbazine, among others, or mixtures thereof, with prinicin being preferred. Examples of growth-promoting antimicrobials useful in the present compositions are avoparcin, bacitracin methylene disalicylate, bacitracin zinc, virginiamycin, penicillin, chlorotetracycline, tylosin, bambermycins, oxytetracycline, erythromycin, roxarsone, nitrovin, carbadox, or mixtures thereof, with penicillin being preferred. The therapeutic antimicrobials used in the compositions of the present invention include tiamulin, lincomycin, oleondomycin, neomycin, dimetridazole, furazolidone, sulfa drugs such as sulfamethazine and sulfamethoxy pyridizine, or mixtures thereof, with tiamulin being preferred. About 0.0001% to 0.02 (1 to 200 ppm) of these antimicrobials should be present in the final edible animal feedstuff compositions of the present invention. In a preferred embodiment of the present invention, an edible animal feed additive composition (Pre-mix) containing 0.00001% to 0.0001%, by weight, of 5-[l-hydroxy2-(isopropylamino)ethyl]anthranilonitrile, or the pharmaceutically-acceptable acid-addition salt thereof, and 0.0001% to 0.02%, by weight, of an antimicrobial agent are administered in an edible animal feedstuff composition to seven-day old animals. Likewise, in another preferred embodiment of the present invention, 0.0001% to 0.02%, by weight, of the antimicrobial agent and 0.00001% to 0.0001%, by weight, of 4-amino-a-[ tert-butyl-.amino)methyl]-3,5- dichlorobenzyl alcohol, or the pharmaceuticallyacceptable acid-addition salt thereof, is mixed into a suitable edible animal feedstuff composition and administered to a food-producing animal when said animal is seven days old. It has been unexpectedly discovered that the animal feed additive compositions of the present invention result in healthy, leaner, yet larger, animals when feed is administered to animals at seven days of age. The present invention is further illustrated by the following non-limiting examples. EXAMPLE 1 Oleic acid salt of 4-amino-a-[(tert-butylamino)methyl]- 3,5-dichlorobenzyl alcohol A solution of oleic acid (5.65 grams, 0.02'mol) in methylene chloride (5 ml) is added to a warmed-up slurry of 4-amino-a-[(tert-butylamino)methyl]-3,5- dichlorobenzyl alcohol (5.54 grams, 0.02 mol) in methylene chloride (30 ml). The mixture is stirred for a few minutes, and the resultant solution is filtered and evaporated to dryness to afford the title product, a slightly sticky solid, mp 540C - 56 0C. The product is soluble in ether, hexane, methanol, chloroform, and ethylene dichloride. EXAMPLE 2 Oleic acid salt of 5-t1-hydroxy-2-(isopropylamino)ethyl3 anthranilonitrile A warmed solution of oleic acid (3.43 grams, 0.012 mol) in methanol (105 ml) is added to a warmed solution of 5-[l-hydroxy-2-(isopropylamino)ethyl]- anthranilonitrile (2.66 grams, 0.012 mol) in methanol (210 ml). The mixture is stirred for a few minutes at just below boiling, and the resulting solution evaporated to dryness to afford the title product as a solid, mp 75 C - 80 C. EXAMPLE 3 Evaluation of combinations - chick study One day old Hubbard X Hubbard broiler chicks from Kerr Hatcheries, Frenchtown, New Jersey are sorted into equal weight outcome groups of five males and five females per pen. Starting and ending body weights per pen for the 17-day test period are obtained at seven and 24 days of age, respectively. The basal diet used in these studies is Broiler Ration No. 453 (see description below) which is supplied ad libitum and to which the present animal feed additive composition is added. DIET Broiler Ration No. 453 Component Percent by Weight Ground yellow corn 53.45 Soybean oil meal (49%) 28.00 Menhaden fish meal (60%) 5.00 Corn gluten meal (60%) 5.00 Dehydrated alfalfa mear (17%) 2.00 Stabilized fat 4.00 Dicalcium phosphate 1.20 Ground limestone 0.50 Sodium chloride 0.30 Trace minerals mixture 0.05 Vitamin premix 0.50 100.00 1.5 kg of diet containing an antimicrobial agent is prepared for each pen for day one to day seven feeding. 10 kg of diet containing representative samples of antimicrobial agent in combination with a formula (I) substituted l-(aminophenyl)-2-aminoethanol is prepared for each pen for the following 17-day test period, chick ages of seven to 24 days. Feed is withheld from the chicks approximately 12 hours before sacrifice. Representative (200 g) whole ground bird tissue samples are obtained for each test replicate (four pens of 10 birds) and frozen for protein, moisture, and fat content analyses. Resultant data are reported in Table I. TABLE I Effect of Antimicrobials and Oleate Salts of (A) 5-[1-hydroxy-2-(isopropylamino)ethyl]anthranilonitrile and (B) 4-amino-&alpha;-[Tert-butylamino)methyl]-3,5dichlorobenzyl alcohol in Animal Feed Additive Percent Percent Enhancement in Percent Reduction in Improvement in Feed Efficiency Compound Dose (ppm) Fat Fat Feed Efficiency as Percentage Control - 11.91 - - (A) 0.25 11.40 7.3 1.9 Penicillin 200 13.10 - 7.1 Penicillin/(A) 200/0.25 11.64 11.14 8.6 21.4 Chlorotetracycline 50 11.56 - 4.5 Chlorotetracycline/(A) 50/0.25 11.27 2.50 4.6 2.2 Bacitracin methylene disalicylate 50 11.63 - 6.4 Bacitracin methylene disalicylate/(A) 50/0.25 11.62 - 8.3 29.7 Avoparcin 10 12.20 - 2.8 Avoparcin/(A) 10/0.25 11.80 3.27 5.5 96.4 Virginiamycin 10 12.18 - 6.9 Virginiamycin/(A) 10/0.25 11.66 4.26 6.0 -13.0 Bambermycins 2 10.07 - 1.5 Bambermycins/(A) 2/0.25 9.50 5.66 3.3 12.0 Tiamulin 5 10.59 - 1.1 Tiamulin/(A) 5/0.25 9.40 10.39 1.6 45.4 TABLE I (Continued) Percent Percent Enhancement in Percent Reduction in Improvement in Feed Efficiency Compound Dose (ppm) Fat Fat Feed Efficiency as Percentage Tylosin 100 10.89 - 2.8 Tylosin/(A) 100/0.25 9.99 8.26 7.8 178.6 Dimetridazole 200 10.49 - 2.7 Dimetridazole/(A) 200/0.25 9.71 7.44 4.2 55.6 Carbadox 25 10.49 - 6.5 Carbadox/(A) 25/0.25 9.44 10.00 5.1 -21.5 Monensin 121 - - 1.42 Monensin/(A) 121/0.25 - - 3.53 148.0 Penicillin 200 10.94 - 5.5 Penicillin/(B) 200/1 10.11 7.6 7.6 38.2 Chlorotetracycline 50 10.67 - 5.2 @ Chlorotetracycline/(B) 50/1 9.88 7.4 5.3 1.9 Bacitracin methylene disalicylate 50 10.10 - 3.4 Bacitracin methylene disalicylate/(B) 50/1 9.81 2.9 4.9 44.1 Avoparcin 10 10.32 - 5.2 Avoparcin/(B) 10/1 9.31 9.8 6.6 26.9 Virginiamycin 10 11.08 - 6.7 Virginiamycin/(B) 10/1 10.23 8.2 7.0 4.5 TABLE I (Continued) Percent Percent Enhancement in Percent Reduction in Improvement in Feed Efficiency Compound Dose (ppm) Fat Fat Feed Efficiency as Percentage Bambermycins 2 10.28 - 5.7 Bambermycins/(B) 2/1 9.75 5.1 6.2 8.8 Nitrovin 10 10.22 - 5.1 Nitrovin/(B) 10/1 9.60 6.1 5.2 1.9 As can be seen, the data in Table I demonstrate improvements in feed efficiency concomitant with reduction of fat deposition. Surprisingly, this effect is more evident when the combination bf the invention is given to animals which contain a higher percentage of fat. For example, in Table I, the percent fat reduction of animals fed only ethanolamine is only 7.3%, whereas, birds fed penicillin in comparison to penicillin with ethanolamine increases this fat reduction to 11.14%. Thus, this indicates an improvement in reducing the fat to lean meat ratio in larger birds, an unexpected result.

Claims: WHAT IS CLAIMED IS: 1. An edible animal feedstuff composition used for increasing feed efficiency and improving the lean meat to fat ratios of warm-blooded animals, said composition characterized by an antimicrobial agent; and a substituted l-(aminophenyl)-2-aminoethanol, or the pharmaceutically-acceptable acid-addition salts thereof, represented by structural formula (I), EMI12.1 wherein R1 is hydrogen or C1-C14 alkyl; R2 is hydrogen or methyl, provided that when Rl is C2-C;4 alkyl, then R2 is hydrogen; R3 and R4 are each hydrogen or C1-C6 alkyl; X and Y are each hydrogen, bromine, chlorine, fluorine, iodine or cyano; Z is an acid which results in pharmaceutically-acceptable acid-addition salts thereof; and n is an integer of O or 1. 2. An edible animal feedstuff composition according to Claim 1, wherein said antimicrobial agent is present in amounts, on a weight basis, of about 0.0001% to 0.02% (1 to 200 ppm) and said substituted l-(aminophenyl)-2-aminoethanol, or the pharmaceutically-acceptable acid-addition salts thereof, is present in amounts, on a weight basis, of about 0.0000001% to 0.001% (0.001 to 10.0 ppm); and wherein Z is hydrochloric, phosphoric, acetic, propionic, citric, gluconic, abietic, oleic, linoleic, linolenic, tall oil fatty acids, or mixtures thereof; and n is 1. 3. An edible animal feedstuff composition according to Claim 2, wherein said formula (I) compound is 4-amino-a[tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol; wherein said formula (I) pharmaceuticallyacceptable acid-addition salt is ioleic acid; wherein said formula (I) compound is 5-[1-hydroxy-2-(isopropylamino)- ethyl]anthranilonitrile; or wherein Z is oleic acid when formula (I) is 5-[l-hydroxy-2-(isopropylamino) ethyl]anthranilonitrile. 4. An edible animal feedstuff composition according to Claim 3, wherein said antimicrobial agent is selected from anticoccidials, growth-promoting antimicrobials, therapeutic antimicrobials, or mixtures thereof. 5. An edible animal feedstuff composition according to Claim 4, wherein said anticoccidials are selected from prinicin, salinomycin, monensin, naracin, lasalocid, robinedine, aprinocid, amprolium, nicarbazine, or mixtures thereof; wherein said growth-promoting antimicrobials are selected from avoparcin, bacitracin methylene disalicylate, bacitracin zinc, virginiamycin, penicillin, chlorotetracycline, tylosin, bambermycin, oxytetracycline, erythromycin, roxarsone, nitrovin, carbadox, or mixtures thereof; wherein said therapeutic antimicrobials are selected from tiamulin, lincomycin, oleandomycin, neomycin, dimetridazole, furazolidone, sulfa drugs such as sulfomethazine and sulfamethoxy pyridizine, or mixtures thereof. 6. An edible animal feedstuff composition according to Claim 5, wherein said anticoccidial is prinicin; wherein said growth-promoting antimicrobial is penicillin; or wherein said therapeutic antimicrobial is tiamulin. 7. An animal feed additive composition useful in an edible animal feedstuff composition for use in increasing feed efficiency and improving the lean meat to fat ratios of warm-blooded animals, said animal feed additive composition characterized by an edible animal feedstuff; an antimicrobial agent; and a substituted 1 (aminophenyl)-2-aminoethanol, or the pharmaceuticallyacceptable acid-adition salts thereof, represented by structural formula (I), EMI14.1 wherein R1 is hydrogen or C1-C14 alkyl; R2 is hydrogen or methyl, provided that when R1 is C2-C14 alkyl, then R2 is hydrogen; R3 and R4 are each hydrogen or C1-C6 alkyl; X and Y are each hydrogen, bromine, chlorine, fluorine, iodine or cyano; Z is an acid which results in pharmaceutically-acceptable acid-addition salts thereof; and n is an integer of O or 1. 8. An animal feed additive composition according to Claim 7, wherein said antimicrobial agent, when used in said edible animal feedstuff, is present in amounts, on a weight basis, of about 0.0001% to 0.02% (1 to 200 ppm) and said substituted l-(aminophenyl)-2-aminoethanol, or the pharmaceutically-acceptable acid-addition salts thereof, when used in said edible animal feedstuff composition, is present in amounts, on a weight basis, of about 0.0000001% to 0.001% (0.001 to 10.0 ppm); and wherein Z is hydrochloric, phosphoric, acetic, propionic, citric, gluconic, abietic, oleic, linoleic, linolenic, tall oil fatty acids, or mixtures thereof; and n is 1. 9. An animal feed additive composition according to Claim 8, wherein said formula (I) compound is 4-amino-a[ tert-butylamino)methyl ]-3 , 5-dichlorobenzyl alcohol; wherein Z is oleic acid; wherein said formula (I) compound is 5[1-hydroxy-2-(isopropyl-amino)ethyl]anthranilonitrile; or wherein Z is oleic acid when formula (I) is 5[1-hydroxy-2-(isopropyl-amino)ethyl]anthra- nilonitrile. 10. An animal feed additive composition according to Claim 9, wherein said antimicrobial agent is selected from anticoccidials, growth-promoting antimicrobials, therapeutic antimicrobials, or mixtures thereof. 11. An animal feed additive composition according to Claim 10, wherein said anticoccidials are selected -from prinicin, salinomycin, monensin, naracin, lasolocid, robinedine, aprinocid, amprolium, nicarbazine, or mixtures thereof; wherein said growth-promoting antimicrobials are selected from avoparcin, bacitracin methylene disalicylate, bacitracin zinc, virginiamycin, penicillin, chlorotetracycline, tylosin, bambermycin, oxytetracycline, erythromycin, roxarsone, nitrovin, carbadox, or mixtures thereof; or wherein said therapeutic antimicrobials are selected from-tiamulin, lincomycin, oleondomycin, neomycin, dimetridazole, furazolidone, sulfa drugs such as sulfomethazine and sulfamethoxy pyridizine, or mixtures thereof. 12. An animal feed additive composition according to Claim 11, wherein said anticoccidial is prinicin; wherein said growth-promoting antimicrobial is penicillin; or wherein said therapeutic antimicrobial is tiamulin. 13. A method for increasing feed efficiency and improving the lean meat to fat ratios of warm-blooded animals, said method characterized by administering a feed-efficiency-increasing-and-lean-meat-to-fat-ratioimproving amount of an edible animal feedstuff composi tion containing an antimicrobial agent; and a substituted l-(aminophenyl)2-aminoethanol, or the pharmaceuticallyacceptable acid-addition salts thereof, represented by structural formula (I), EMI16.1 wherein R1 is hydrogen or C1-C14 alkyl; R2 is hydrogen or methyl, provided that when R1 is C2-C14 alkyl, then R2 is hydrogen; R3 and R4 are each hydrogen or C1-C6 alkyl; X and Y are each hydrogen, bromine, chlorine, fluorine, iodine or cyano; Z is an acid which results in pharmaceutically-acceptable acid-addition salts thereof; and n is an integer of O or 1; to said warm-blooded animals when seven days of age. A A method according to Claim 13, wherein said antimicrobial agent is present in amounts, on a weight basis, of about 0.0001% to 0.02% (1 to 200 ppm) and said substituted l-(aminophenyl)-2-aminoethanol, or the pharmaceutically-acceptable acid-addition salts thereof, is present in amounts, on a weight basis, of about 0.0000001% to 0.001% (0.001 to 10.0 ppm); and wherein Z is hydrochloric, phosphoric, acetic, propionic, citric, gluconic, abietic, oleic, linoleic, linolenic, tall oil fatty acids or mixtures thereof; and n is 1. 15. A method according to Claim 14, wherein said formula (I) compound is 4-amino-a-[tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol; wherein said formula (I) pharmaceutically- acceptable acid-addition salt is oleic acid; wherein said formula (I) compound is 5-[1- hydroxy-2-(isopropylamino)ethyl]anthranilonitrile; or wherein Z is oleic acid when formula (I) is 5-[l-hydroxy- 2-(isopropylamino)ethyl]anthranilonitrile. 16. A method according to Claim 15, wherein said antimicrobial agent is selected from anticoccidials, growth-promoting antimicrobials, therapeutic antimicrobials, or mixtures thereof. 17. A method according to Claim 16, wherein said anticoccidials are selected from prinicin, salinomycin, monensin, naracin, lasalocid, robinedine, aprinocid, amprolium, nicarbazine,- or mixtures thereof; wherein said growth-promoting antimicrobials are selected from avoparcin, bacitracin methylene disalicylate, bacitracin zinc, virginiamycin, penicillin, chlorotetracycline, tylosin, bambermycin, oxytetracycline, erythromycin, roxarsone, nitrovin, carbacox, or mixtures thereof; or wherein said therapeutic antimicrobials are selected from tiamulin, lincomycin, oleandomycin, neomycin, dimetridazole, furazolidone, sulfa drugs such as sulfomethazine and sulfamethoxy pyridizine, or mixtures thereof. 18. A method according to Claim 17, wherein said anticoccidial is prinicin; wherein said growthpromoting antimicrobial is penicillin; or wherein said therapeutic antimicrobial is tiamulin.

Inventors: BECK, JOHN RICHARD, INGLE, DONALD LEE
Applicants: AMERICAN CYANAMID COMPANY
Application year: 1984
Main classification: A23K1
IPC codes: A23K1