Methods and compositions for increasing feed intake of animals using tertiary alcohols

.Iadd.This application is a reissue of U.S. Pat. No. 3,852,473 issued Dec. 3, 1974 from Ser. No. 328,235 filed Jan. 31, 1973. .Iaddend.

This invention relates to animal feed compositions and to novel methods of increasing the feed intake of growing or "fattening" animals by administering as the active ingredients in these compositions and methods certain tertiary alcohols and derivatives thereof. More specifically, this invention relates to a method of increasing feed intake in immature animals beyond satiety by administering internally the active ingredient, a tertiary alcohol or derivative thereof, as such or distributed uniformly in the feed of the animals. Oral or implant administration is preferred from a practical viewpoint.

Increasing the feed intake in meat producing animals, particularly ruminants, is an important commercial objective. Immature sheep and cattle are commonly fed for maximum growth rate in feed lots until they reach a marketable weight. When the desired weight is achieved, the animal is sold for slaughter. There is a normal feed intake for most animals due to both physical and metabolic factors. Animals become naturally satiated and thereafter will not feed voluntarily until the hunger drive again becomes dominant.

It has been unexpectedly found that, when certain tertiary alcohols or their urea, ureide, oxyurea or carbamate derivatives are administered to animals, polyphagic activity is induced, i.e., they eat more and gain weight at a faster rate resulting in better overall efficiency to the grower.

The practical effect of this invention is to induce meat producing animals, preferably sheep or cattle, to eat past the point of satiety or to induce polyphagia in the immature animal by administering internally, preferably by implant or orally, the active ingredients of this invention. The active ingredients are most conveniently dispersed uniformly throughout the normal feed of the subject animal in effective but nontoxic quantities.

The increased feed intake and concomitant weight gain of animals is accomplished in accordance with this invention by a method which comprises administering internally to the animal a compound of the following basic structure formula: ##EQU1## in which:

R is lower alkyl of from 1-9, preferably 1-5, carbon atoms or hydroxy lower alkyl of from 1-9, preferably 2-5, carbon atoms;

R' is lower alkyl of from 1-9, preferably 1-5, carbon atoms, or halo such as fluoro, chloro or bromo;

R" is lower alkyl of from 1-9, preferably 1-5, carbon atoms, lower alkenyl of from 2-9, preferably 2-5, carbon atoms, lower alkynyl of from 2-9, preferably 2-5, carbon atoms and, when R and R' are hydrogen or lower alkyl, phenyl; and,

X is --OH, --NHCONH 2 (ureido), --ONHCONH 2 (oxyureido), --OCONH 2 (oxycarbamyl) or --CONHCONH 2 (carbonylureido).

A preferred group are those compounds of Formula I in which R, R' and R" are lower alkyl of from 1-5 carbon atoms. It will be recognized that certain of the active ingredients are not truly "tertiary alcohols" but this generic term is most conveniently used to describe the invention because the tertiary alcohols are the nub of the invention.

One skilled in the medicinal art will recognize that certain of the basic compounds of Formula I have been known to have medicinal effects in humans, especially hypnotic effects, such as phenylacetyl urea; 3-methyl-1-pentyne-3-ol [Meparfynol], carbamic acid 1-ethyl-1-methyl-2-propynyl ester [Meparfynol carbamate], (α-bromo-α-ethylbutyryl)-urea [Carbromal] and 1-ethyl-1-1-methylpropyl carbamate [Emylcamate]. In the compositions and methods of this invention, the quantities of active ingredients are much below the hypnotic effect in animals, especially on a dose per unit of body weight basis. In fact, if the dose approaches the hypnotic effect, the very opposite action may be achieved, that is, the animal may become disinterested in food because of a general central nervous system depression. If sleepy or sedated the animal will not eat enough to satisfy its appetite and certainly not enough to cause a polyphagic effect. This effect has been noted in the test data presented hereafter. Therefore, in the context of this disclosure an overt pharmacodynamic or therapeutic effect such as hypnosis or sedation is classified as a toxic effect.

It will be recognized therefore that the active ingredients of this invention are old compounds known to the art. The tertiary alcohols are usually liquids and in the formulation of premixes or supplemented feeds this must be taken into account using standard techniques of the art. The alcoholic derivatives, for example the ureas, oxyurea, acylureas (ureides) or carbamates, are particularly useful because of their solid or crystalline state. The compounds which are the basis of this invention are notable for their very low chemical cost. Certain members of the groups are by-products of fermentation or chemical synthetic procedures.

Among the individual compounds most useful in the invention are benzyloxyurea, 1-ethyl-1-methylpropyl carbamate, 3-methyl-3-pentanol, 1-ethyl-1-methyl propyloxyurea, N-(1-ethyl-1-methylpropyl)urea, 3-methyl-1-pentyne-3-ol, carbamic acid 1-ethyl-1-methyl-2-propynyl ester and (α-bromo-α-ethylbutyryl)-urea. The solid nitrogen derived derivatives are preferred.

The compounds can be administered to growing meat producing animals intramuscularly or subcutaneously in the form of solutions for injection or preferably pellet implants. Most usually, the compounds can be mixed with conventional animal feed compositions. The feed compositions are then fed to ruminant or monogastric animals, according to methods well known to the agricultural art. The compounds are particularly advantageous when incorporated into the normal feeds of meat producing animals. Preferably the compounds are incorporated into fattening ruminant feeds.

The animal feeds most generally used in conjunction with the method of this invention are either various grain mixtures and/or roughage feeds such as hay commonly fed to meat producing animals especially cattle or sheep feeds. The amount of additive used to supplement such feeds will be in an amount sufficient to induce polyphagia, i.e., to increase feed intake and/or thereby to improve the feed efficiency of the animal but not to have a toxic or noxious effect; within the broad range of from about 10 g. to 2 kg. per ton of feed, preferably from about 100 g. to about 1 kg./ton. An average sheep will ingest about 3-4 lbs. of feed daily; an average feed lot steer about 20-25 lbs. Therefore, the preferable broad range of dosage for ruminants by any method of internal administration will range approximately from 50 mg. to 10 g. per day depending on the potency of the ingredient for these purposes. It will be appreciated that the exemplary dose ranges given are for a generic group of chemical compounds having varying potencies. The gist of the invention claimed is that certain sub-therapeutic or sub-hypnotic quantities of the chemical compounds administered as described have a polyphagic effect.

For commercial use, the active ingredients usually are most readily used as premix formulations in which the chemical is distributed uniformly throughout a standard animal organic or inorganic feed carrier in a concentrated form which is conveniently packaged and shipped to the feed mixer. This premix or concentrate is then in turn mixed uniformly with a normal diet for the animal as desired by the grower or the feed mixer. Examples of such carriers for premix compositions are soybean meal, corn oil, ground corn, barley, wheat, mineral mixtures such as vermiculite, diatomaceous earth, corn gluten meal, corn distillers solubles or soyflour. The active ingredient will be in amounts to satisfy the criteria set forth above for whole feed. The active ingredient will usually be present in from about 1-75 percent by weight of the premix composition.

If the ingredients are liquids or unstable materials, they may optionally be adsorbed on silica, kieselguhr, etc. or coated with a solid, absorbable fat or resin by standard spray drying or congealing techniques (See U.S. Pat. No. 3,660,562).

The animal feeds themselves may also contain roughages such as cellulose, hay, straw, silages, corn stalks, cotton seed hulls, oats, barley and cereal brans; natural oils such as animal fats, fish oils, safflower oil, peanut oil, and cottonseed oil; antioxidants, minerals, vitamins, antibiotics, anthelmintics; and other appropriate medicaments.

Examples of typical prepared animal feed is as follows:

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R R' R" X Dose(mg.)

%(120 min.)

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C.sub.2 H.sub.5

Br C.sub.2 H.sub.5

CONHCONH.sub.2

31 142

62 164

125 136

500 77

C.sub.2 H.sub.5

CH.sub.3

C.tbd.CH

OH 31 100

62 164

125 148

500 226

CH.sub.3

CH.sub.3

C.tbd.CH

OH 31 110

62 97

125 130

500 70

(n)C.sub.5 H.sub.11

CH.sub.3

C.tbd.CH

OH 62 104

125 157

500 0

C.sub.2 H.sub.5

CH.sub.3

C.sub.2 H.sub.5

OH 62 138

125 154

300 185

600 127

C.sub.2 H.sub.5

C.sub.2 H.sub.5

CH.sub.3

OCONH.sub.2

62 146

125 203

250 193

500 319

750 272

CH.sub.3

CH.sub.3

CH.sub.3

OCONH.sub.2

500 109

1500 139

CH.sub.3

CH.sub.3

CH.sub.3

NHCONH.sub.2

250 129

CH.sub.3

CH.sub.3

C.sub.6 H.sub.5

OH 62 66

125 131

500 88

H H C.sub.6 H.sub.5

CONHCONH.sub.2

31 123

62 144

125 167

200 141

500 133

H H C.sub.6 H.sub.5

ONHCONH.sub.2

300 122

H H C.sub.6 H.sub.5

OCONH.sub.2

125 133

250 73

H CH.sub.3

iso-C.sub.4 H.sub.9

OH 125 85

500 127

823 77

iso-C.sub.3 H.sub.7

CH.sub.3

CH.sub.3

OH 125 105

500 123

C.sub.2 H.sub.5

C.sub.2 H.sub.5

C.sub.2 H.sub.5

OH 125 124

500 143

CH.sub.3

CH.sub.3

C.sub.2 H.sub.5

OH 125 123

500 172

CH.sub.3

C.sub.2 H.sub.5

C.sub. 4 H.sub.9

OH 31 95

125 115

CH.sub.3

CH.sub.3

C.sub.4 H.sub.9

OH 62 71

125 121

500 50

CH.sub.3

CH.sub.3

C.sub.5 H.sub.11

OH 31 148

62 91

125 109

2- CH.sub.3

CH.sub.3

OH 62 56

(OH)C.sub.3 H.sub.6 125 144

500 126

CH.sub.3

CH.sub.3

CH.sub.2 =CH.sub.2 CH.sub.2

OH 62 99

125 151

250 155

CH.sub.3

iso-C.sub.3 H.sub.7

C.sub.2 H.sub.5

OH 62 144

125 195

500 104

CH.sub.3

CH.sub.3

CH.sub.3 C.tbd.C

OH 125 103

500 211

1000 166

CH.sub.3

CH.sub.3

C.sub.2 H.sub.5

NHCONH.sub.2

250 110

500 106

CH.sub.3

CH.sub.3

iso-C.sub.4 H.sub.9

OH 62 104

125 145

500 38

CH.sub.3

C.sub.2 H.sub.5

CH.sub.2 =CH

OH 125 123

500 160

100 78

iso-C.sub.3 H.sub.7

iso-C.sub.3 H.sub.7

CH.tbd.C

OH 62 110

125 170

C.sub.2 H.sub.5

ClCH=CH

CH.tbd.C

OH 31 45

62 160

125 105

CH.sub.3

C.sub.2 H.sub.5

CH.tbd.C

OCONH.sub.2

31 112

62 54

125 139

CH.sub.3

C.sub.2 H.sub.5

C.sub.2 H.sub.5

NHCONH.sub.2

62 153

125 147

250 221

500 142

CH.sub.3

C.sub.2 H.sub.5

BrC=CBr OH 62 85

125 162

500 119

CH.sub.3

C.sub.2 H.sub.5

CH.tbd.CC.sub.5 H.sub.10

OH 125 150

500 78

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R R' R" X Dose(mg.)

%(120 min.)

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CH.sub.3

C.sub.2 H.sub.5

C.sub.2 H.sub.5

OCONH.sub.2

625 133

1250 128

H H C.sub.6 H.sub.5

ONHCONH.sub.2

1000 113

H H C.sub.6 H.sub.5

CONHCONH.sub.2

250 103

375 77

375 270

750 165

1500 100

1500 179

150 108

CH.sub.3

C.sub.2 H.sub.5

C.sub.2 H.sub.5

OH 1250 84

1500 103

2500 100

3750 149

CH.sub.3

C.sub.2 H.sub.5

C.sub.2 H.sub.5

NHCONH.sub.2

300 80

600 87

1250 113

1250 117

CH.sub.3

C.sub.2 H.sub.5

C.tbd.CH

OH 1250 154

C.sub.2 H.sub.5

Br C.sub.2 H.sub.5

CONHCONH.sub.2

625 100

1250 94

2500 129

iso-C.sub.3 H.sub.7

iso-C.sub.3 H.sub.7

C.tbd.CH

OH 1250 102

CH.sub.3

CH.sub.3

C.sub.6 H.sub.5

OH 1250 120

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