Animal feed and process

A process for increasing production in meat-producing, egg-laying or milk-producing animals comprising feeding a compound of the formula: ##STR1## wherein R is a member selected from the group consisting of hydrogen, R.sub.5, ##STR2## wherein R.sub.5 is alkyl of from 1 to 8 carbon atoms, inclusive, including isomeric forms thereof; alkenyl of from 2 to 8 carbons, inclusive, including isomeric forms thereof, cycloalkyl of from 3 to 7 carbon atoms; or R is lower acyl wherein acyl is up to and including 5 carbon atoms; R.sub.1 is a member selected from the group consisting of R.sub.5 and ##STR3## wherein R.sub.6 is selected from the group consisting of hydrogen, ##STR4## or lower acyl wherein acyl is up to and including 5 carbon atoms; R.sub.2 is a member selected from the group consisting of hydrogen, R.sub.5, bromo or chloro; R.sub.3 and R.sub.4 are the same or different and are selected from the group consisting of hydrogen, provided that R.sub.3 and R.sub.4 are not both hydrogen; R.sub.5, cycloalkyl of from 3 to 8 carbon atoms, alkyl substituted cycloalkyl of the formula ##STR5## wherein n is an integer of from 2 to 7, inclusive and R.sub.7 is a member selected from the group consisting of hydrogen and alkyl of from 1 to 5 carbon atoms, inclusive, including isomeric forms thereof; alkenyl of from 2 to 8 carbon atoms, inclusive, including isomeric forms thereof, aralkyl wherein Ar is a member selected from the group consisting of phenyl, substituted phenyl wherein 1 or 2 hydrogens are replaced with chlorine, fluorine, bromine, iodine, R.sub.5, --OR.sub.5 or --CF.sub.3 and the substituents can be the same or different, and alkyl is from 1 to 4 carbon atoms, inclusive, including isomeric forms thereof; and R.sub.3 and R.sub.4 taken together with ##STR6## is a heterocyclic moiety of from 4 to 8, inclusive, ring atoms and 1 or 2 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur or substituted heterocyclic moiety wherein 0, 1, 2 or 3 of the carbon atoms of the heterocycle are substituted with R.sub.5 in combination with a nutrient feed.

DESCRIPTION 
BRIEF SUMMARY OF THE INVENTION 
Broadly the present invention encompasses a nutritionally adequate animal 
feed having dispersed therein a compound of the Formula Ia and Ib in 
sufficient concentration to provide increasing productivity and feed 
efficiencies in healthy meat-producing, milk-producing or egg-laying 
animals. The invention also includes the process of administering the 
composition to meat-producing, milk-producing, egg-laying or 
wool-producing animals. 
BACKGROUND OF THE INVENTION 
It has been found in recent years that meat-producing animals will gain 
more weight and gain it faster when various classes of compounds such as 
vitamins, minerals, estrogens, antibiotics, and tranquilizers are added to 
the diet. Although the presently available compounds are useful, new 
materials are still being sought that would produce weight gains more 
rapidly, to a greater extent, more efficiently with respect to feed intake 
at a lower cost and without undesirable side effects. 
The active compounds of the present invention of the Formula Ia or Ib are 
known and have previously been used systemically in treating hypertension 
to cause vasodilation. Additionally, the compounds have been applied 
topically to cause hair growth. 
DETAILED DESCRIPTION OF THE INVENTION 
It is now possible by use of the present invention to obtain unexpected 
results in the feeding of meat-producing, milk-producing, or egg-laying 
animals; that is to say, an increased rate of weight gain, an increased 
amount of weight gain, an increase in milk production enhanced wool 
production, or increased rate of egg laying, as well as increased feed 
efficiency, can be obtained by the addition of minute quantities of a 
compound of the Formula Ia or Ib to the animals usual nutrient feed. 
The active compounds pyrimidine 3-oxides are represented by the structure 
Ia or Ib: 
##STR7## 
wherein R is a member selected from the group consisting of hydrogen, 
R.sub.5, 
##STR8## 
wherein R.sub.5 is alkyl of from 1 to 8 carbon atoms, inclusive, including 
isomeric forms thereof; alkenyl of from 2 to 8 carbons, inclusive, 
including isomeric forms thereof, cycloalkyl of from 3 to 7 carbon atoms; 
or R is lower acyl wherein acyl is up to and including 5 carbon atoms; 
R.sub.1 is a member selected from the group consisting of R.sub.5 and 
##STR9## 
wherein R.sub.6 is selected from the group consisting of hydrogen, 
##STR10## 
or lower acyl wherein acyl is up to and including 5 carbon atoms; R.sub.2 
is a member selected from the group consisting of hydrogen, R.sub.5, bromo 
or chloro; R.sub.3 and R.sub.4 are the same or different and are selected 
from the group consisting of hydrogen, provided that R.sub.3 and R.sub.4 
are not both hydrogen; R.sub.5, cycloalkyl of from 3 to 8 carbon atoms, 
alkyl substituted cycloalkyl of the formula 
##STR11## 
wherein n is an integer of from 2 to 7, inclusive, and R.sub.7 is a member 
selected from the group consisting of hydrogen and alkyl of from 1 to 5 
carbon atoms, inclusive, including isomeric forms thereof; alkenyl of from 
2 to 8 carbon atoms, inclusive, including isomeric forms thereof, aralkyl 
wherein Ar is a member selected from the group consisting of phenyl, 
substituted phenyl wherein 1 or 2 hydrogens are replaced with chlorine, 
fluorine, bromine, iodine, R.sub.5, --OR.sub.5 or --CF.sub.3 and the 
substituents can be the same or different, and alkyl is from 1 to 4 carbon 
atoms, inclusive, including isomeric forms thereof, and R.sub.3 and 
R.sub.4 taken together with 
##STR12## 
is a heterocyclic moiety of from 3 to 8, inclusive, ring atoms and 1 or 2 
hetero atoms selected from the group consisting of nitrogen, oxygen or 
sulfur or a substituted heterocyclic moiety wherein 0, 1, 2 or 3 of the 
carbon atoms of the heterocycle are substituted with R.sub.5. 
The compounds of the Formulas Ia or Ib exist in tautomeric forms. It is to 
be understood that the compounds of this invention are likely to be 
mixtures of tautomeric forms, the compositions of which are dependent on 
such factors as the nature of R, R.sub.1, and R.sub.2 and the environment. 
In some instances, one form or another may predominate. 
Compounds of the Formulas Ia or Ib can be prepared by methods disclosed in 
U.S. Pat. Nos. 3,910,928 (Oct. 7, 1975), 4,032,559 (June 28, 1977). 
The pyrimidine 3-oxides of Formulas Ia and Ib are amines, and exist in the 
non-protonated or free base form, or in the protonated or acid addition 
salt form, depending on the pH of the environment. They form stable 
protonates, i.e., mono- or diacid addition salts, on treatment with 
suitable acids, for example, hydrochloric, hydrobromic, sulfuric, 
phosphoric, nitric, acetic, benzoic, salicylic, glycolic, succinic, 
nicotinic, tartaric, maleic, malic, pamoic, methanesulfonic, 
cyclohexanesulfamic, picric, and lactic acids, and the like. 
Examples of alkyl are methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, 
octyl, and isomeric forms thereof. Examples of alkenyl are allyl, 
1-methylallyl, 2-methylallyl (methallyl), 2-butenyl (crotyl), 3-butenyl, 
1,2-dimethylallyl, 1,1-dimethylallyl, 2-ethylallyl, 1-methyl-2-butenyl, 
2-methyl-2-butenyl, 3-methyl-2-butenyl, 3-pentenyl, 
2,3-dimethyl-2-butenyl, 1,1,2-trimethylallyl, 1,3-dimethyl-2-butenyl, 
1-ethyl-2-butenyl, 4-methyl-2-pentenyl, 2-ethyl-2-pentenyl, 
4,4-dimethyl-2-pentenyl, 2-heptenyl, 2-octenyl, 5-octenyl, 
1,4-dimethyl-4-hexenyl, and the like. Examples of cycloalkyl are 
cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 
2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 
2-methylcyclobutyl, 3-propylcyclobutyl, 2,3,4-triethylcyclobutyl, 
cyclopentyl, 2,2-dimethylcyclopentyl, 3-pentylcyclopentyl, 
3-tert-butylcyclopentyl, cyclohexyl, 4-tert-butylcyclohexyl, 
3-isopropylcyclohexyl, 2,2-dimethylcyclohexyl, cycloheptyl, cyclooctyl and 
the like. Examples of aralkyl are benzyl, phenethyl, 1-phenylethyl, 
2-phenylpropyl, 4-phenylbutyl, 5-phenyl-2-methylpentyl, 1-naphthylmethyl, 
2-(1-naphthyl)ethyl, 2-(2-naphthyl)ethyl and the like. Examples of acyl 
are acetyl, propionyl, butanoyl, pentanoyl and the like. Examples of 
alkoxycarbonyl are carbomethoxy, carboethoxy and the like. Examples of 
heterocyclic moieties of the present invention are piperidino, 
pyrrolidinyl, morpholino, 2,4,4-trimethylazetidinyl, 
2,3,4-trimethylazetidinyl, 2-methylpyrrolidinyl, 3-butylpyrrolidinyl, 
2-isohexylpyrrolidinyl, 2,3-dimethylpyrrolidinyl, 
2,2-dimethylpyrrolidinyl, 2,5-diethylpyrrolidinyl, 
3-tert-butylpyrrolidinyl, 2,3,5-trimethylpyrrolidinyl, 
3,4-dioctylpyrrolidinyl, 2-methylpiperidino, 3-methylpiperidino, 
4-methylpiperidino, 3-isopropylpiperidino, 4-tert-butylpiperidino, 
2-methyl-5-ethylpiperidino, 3,5-dipentylpiperidino, 
2,4,6-trimethylpiperidino, 2,6-dimethylpiperidino, 
2,6-dimethyl-4-octylpiperidino, 2,3,5-triethylpiperidino, 
2-ethylhexahydroazepinyl, 4-tert-butylhexahydroazepinyl, 
3-heptylhexahydroazepinyl, 2,4-dimethylhexahydroazepinyl, 
3,3-dimethylhexahydroazepinyl, 2,4,6-tripropylhexahydroazepinyl, 
2-methylheptamethylenimino, 5-butylheptamethylenimino, 
2,4-diisopropylheptamethylenimino, 3,3-diethylheptamethylenimino, 
2,5,8-trimethylheptamethylenimino, 3-methyloctamethylenimino, 
2,9-diethyloctamethylenimino, 4-isooctyloctamethylenimino, 
2-ethylmorpholino, 2-methyl-5-ethylmorpholino, 3,3-dimethylmorpholino, 
2,6-di-tert-butylmorpholino, 4-methylpiperazinyl, 4-isopropylpiperazinyl, 
2-methylaziridinyl, 2-ethylaziridinyl, 2-butylaziridinyl, 
2,3-dimethylaziridinyl, 2,2-dimethylaziridinyl, 2-methylazetidinyl, 
3-methylazetidinyl, 2-octylazetidinyl, 2,2-dimethylazetidinyl, 
3,3-diethylazetidinyl and the like. 
Unless otherwise specified, all percentages are given on a weight-to-weight 
basis. The pound (lb) weights given are avoirdupois units. 
Administration of the compositions of the present invention can commence 
for birds shortly after hatching and in the case of mammals, during the 
creep-feeding period of suckling animals when they are starting on solid 
food and, of course, after weaning. Feeding of the compositions is 
continued throughout the growing period, lactation period, or egg-laying 
period. In addition to feeding the active ingredient in combination with 
the feed, the active compounds can alternatively be administered in 
combination with the animals drinking water or in combination with a 
pharmaceutical carrier by injection or implantation. 
The total concentration of the compound of the Formula Ia or Ib in the feed 
composition is determined with regard to the species of animal, sex, age, 
weight, and average amount of feed consumed daily. Preferably the compound 
of the Formula I is employed in the finished feed that will supply the 
animal with a daily intake of from about 0.02 mg to about 200 mg per head, 
per day. 
The following table illustrates the range of compound of Formula Ia or Ib 
in milligrams daily dose, per head, per day for representative animals. 
______________________________________ 
Range Preferred 
Animal Daily Dose/Head, mg 
Daily Dose, mg 
______________________________________ 
Swine (birth to 0.5-20.0 10.0 
8 weeks) 
Swine (40 to 200 
1.0-140.0 50.0 
lbs) 
Chickens (growing 
0.02-2.0 0.05 
0-8 weeks) 
Hens (laying) 0.1-2.0 1.0 
Turkeys (growing 
0.1-5.0 2.0 
0-24 weeks) 
Beef Cattle 0.5-50.0 10 
(fattening) 
Calves 1.0-40.0 10 
(0-12 weeks) 
Dairy Cattle 5.0-200.0 10 
(lactation) 
Lambs 1.0-20.0 10 
(fattening) 
______________________________________ 
The foregoing dosages can generally be accomplished by providing from about 
50 mg to about 20,000 mg of a compound of the Formula Ia or Ib per ton of 
finished feed. 
Advantageously a compound of the Formula Ia or Ib is supplied in the form 
of a liquid or solid premix wherein the concentration is 100-2,000 times 
greater than the desired final concentration in the feed. For example, the 
compound of Formula Ia or Ib can be dissolved or suspended in a fluid 
vehicle such as corn oil, cottonseed oil, molasses, distillers solubles 
and the like to prepare a fluid premix. Alternatively, a solid premix can 
be prepared by mixing a compound of the Formula Ia or Ib with an edible 
solid diluent such as sucrose, lactose, starch, corn meal, flour, calcium 
carbonate, soybean meal and the like.

EXAMPLE 1 
A diet for fattening lambs is prepared from the following types and amounts 
of ingredients: 
______________________________________ 
Ground ear corn 82.05% 
Alfalfa meal 10.0% 
Soybean oil meal 44% 
7.0% 
Ground limestone 0.3% 
Salt 0.3% 
Trace mineral mixture.sup.1 
0.05% 
______________________________________ 
.sup.1 Contains the following percent of minerals: Mn, 12; Co, 0.08; Fe, 
5.0; Cu, 0.4; I, 0.24; Zn, 0.7. 
The above feed to be mixed, pelleted and offered to fattening lambs 
free-choice in conjunction with hay. 
To 999 parts of the preceding feed is added 1 part of a premix composition 
prepared by mixing 7 gm of 2,4-diamino-6-piperidinopyrimidine-3-oxide with 
sufficient corn meal to make one pound. 
The feeding composition so prepared supplies 7.0 mg of 
2,4-diamino-6-piperidinopyrimidine-3-oxide per pound or 15.4 parts per 
million. 
The foregoing composition is usefully fed to lambs for increased rate of 
weight gain and improved utilization of feed. 
EXAMPLE 2 
A chicken feed for broilers is prepared from the following types and 
amounts of ingredients: 
______________________________________ 
Yellow corn meal 67.35% 
Soybean oil meal 24.00% 
Menhaden fish meal 6.00% 
Steamed bone meal 1.00% 
Ground limestone 1.00% 
Iodized salt .34% 
25% Choline chloride 
.13% 
Vitamin B.sub.12 supplement 
(6 mg/lb) .10% 
Manganese sulfate .02% 
Supplemental vitamin mix.sup.1 
.06% 
______________________________________ 
.sup.1 Consisting of 16.0 gm Vitamin A supplement (10 units/mg); 3.6 gm 
Vitamin D.sub.3 supplement (15,000 units/gm); 7.1 gm riboflavin supplemen 
(1 gm riboflavin per ounce); 500 mg niacin. 
To 999 parts of the preceding feed is added 1 part of a premix composition 
prepared by mixing 0.08 gm of 2,4-diamino-6-piperidinopyrimidine-3-oxide 
with sufficient soybean mill feed to make 1 pound. 
The feeding composition so prepared supplies 0.08 mg of 
2,4-diamino-6-piperidinopyrimidine-3-oxide per pound, or about 0.18 parts 
per million. 
The foregoing composition is usefully fed to chickens for increased rate of 
weight gain and improved utilization of feed. Similarly the composition 
can be fed to turkeys, ducks and geese. 
EXAMPLE 3 
A fattening feed for 800 pound yearling cattle is prepared from the 
following types and amounts of ingredients: 
______________________________________ 
Ground ear corn 89.75% 
Soybean oil mean, 44% 
9.0% 
Ground limestone 0.7% 
Salt 0.5% 
Trace mineral mixture.sup.1 
0.05% 
______________________________________ 
.sup.1 Contains the following percent of minerals: Mn, 12, Co, 0.08; Fe, 
5.0; Cu, 0.4; I, 0.24; Zn, 0.7. 
To 999 parts of the preceding feed is added 1 part of a premix composition 
prepared by mixing 0.5 gm of 2,4-diamino-6-piperidinopyrimidine-3-oxide 
with sufficient wheat flour to make 1 pound. 
The feeding composition so prepared supplies 0.5 mg of 
2,4-diamino-6-piperidinopyrimidine-3-oxide per pound, or about 11.0 parts 
per million. 
Cattle are to receive the foregoing feed ad libitum together with 5 lbs. of 
hay, per head, per day and when so fed have an increased rate of weight 
gain and improved utilization of feed. 
EXAMPLE 4 
A swine diet for growing hogs of 40 to 100 pounds body weight is prepared 
from the following types and amounts of ingredients: 
______________________________________ 
Corn, ground 78.15% 
Soybean oil meal, 44% 
17.0% 
Meat and bone scraps, 50% 
3.0% 
Oyster shell flour 0.4% 
Bone meal 0.5% 
Salt 0.5% 
Trace mineral mixture.sup.1 
0.05% 
Zinc oxide 0.01% 
Vitamin A and D Supplement.sup.2 
0.25% 
Vitamin Supplement.sup.3 
0.25% 
Vitamin B.sub.12 supplement.sup.4 
0.09% 
______________________________________ 
.sup.1 Contains the following % of minerals: Mn, 12; Co. 0.08; Fe, 5.0; 
Cu, 0.4; I, 0.24; Zn, 0.7. 
.sup.2 Contains 300 USP units D.sub.2 /Gm. and 1500 I.U. of A./Gm. 
.sup.3 Contains per lb.: Riboflavin, 2000 mg.; calcium pantohenate, 4000 
mg.; niacin, 9000 mg.; and choline chloride 10,000 mg. 
.sup.4 Contains 6 mg. Vitamin B.sub.12 per lb. 
To 999 parts of the preceding feed is added 1 part of a premix composition 
prepared by mixing 10 mg of 2,4-diamino-6-piperidinopyrimidine-3-oxide 
with sufficient ground limestone to make one pound. 
The feeding composition so prepared supplies 10 mg of 
2,4-diamino-6-piperidinopyrimidine-3-oxide per pound or about 22 parts per 
million. 
The foregoing composition is usefully fed to hogs for increased rate of 
weight gain and improved utilization of feed. 
EXAMPLE 5 
A regimen of 2,4-diamino-6-piperidinopyrimidine-3-oxide in water is 
prepared simply by adding the compound to the drinking water as specified 
below. The animals are allowed to ingest the water on an ad lib basis 
______________________________________ 
mg/l 
______________________________________ 
Swine Birth to 8 weeks 
2.5 
Swine 40-200 lb 7.0 
Chickens 0-8 weeks 0.3 
Hens 5.0 
Turkeys 0-24 weeks 3.2 
Beef cattle 0.2 
Calves 0-12 weeks 1.0 
Dairy cattle 0.9 
Lambs 5.0 
______________________________________ 
EXAMPLE 6 
Following the procedure of the preceding Examples 1 to 5, inclusive, animal 
feeds are similarly prepared substituting equimolar amounts of: 
2,4-diamino-6-pyrrolidinopyrimidine 3 oxide, 
2,4-diamino-6-diethylaminopyrimidine 3 oxide, 
2,4-diamino-6-(2-methylpiperidinopyrimidine 3-oxide, 
2-amino-4-methyl-6-pyrrolidinopyrimidine 3-oxide, 
2-amino-4-methyl-6-piperidinopyrimidine 3-oxide, or 
2,4-diamino-6-dialkylaminopyrimidine 3-oxide, 
for the 2,4-diamino-6-piperidinopyrimidine-3-oxide of the example. 
An added advantage was observed in the feeding of sheep. The sheep produced 
an increased amount of wool. This increase in wool production was 
attributable to the increase in body size (and weight).