US3065132A - 1-(2-methyl-4-amino-5-pyrimidylmethyl)-lower alkyl pyridinium quaternary salts for treating coccidiosis - Google Patents
1-(2-methyl-4-amino-5-pyrimidylmethyl)-lower alkyl pyridinium quaternary salts for treating coccidiosis Download PDFInfo
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/32—One oxygen, sulfur or nitrogen atom
- C07D239/42—One nitrogen atom
Definitions
- This invention relates generally to new chemical specids. More specifically, it is concerned with chemical compounds which are useful in the prevention and the cure of coccidiosis. Still more particularly, it is concerned with a group of new pyridinium quaternary salts which are effective in controlling coccidiosis when fed in relatively small amounts to poultry. Still more specifically, it relates to 1-(Z-methyl-4-amino-S-pyrimidylmethyl)-loweralkyl pyridinium quaternary salts and with methods of making such substances. It is further concerned with novel compositions containing such substances.
- Coccidiosis is a common and Widespread poultry disease caused by several species of protozoan parasites of the genus Eimeria, such as E. tenella, E. necatrix, E. acervulina, E. maxima, E. lzagani and E. brunetti.
- E. tenella is the causative agent of a severe and often fatal infection of the ceca of chickens which is manifested by extensive hemorrhage, accumulation of blood in the ceca, and the passage of blood in the droppings.
- E. neczarrix as well as certain other species attack the small intestine of the chick causing what is known as intestinal coccidiosis;
- Related species of coccidia such as E. melagridis and E.
- adenoides are causative organisms of coccidiosis in turkeys. When left untreated, the severe forms of coccidiosis lead to poor weight gain, reduced feed efficiency and high mortality in fowl. The elimination or control of coccidiosis is, therefore, of paramount importance in the poultry raising industry.
- pyridinium quaternary compounds are highly active against the protozoa responsible for coccidiosis.
- One object of the invention is to provide such compounds.
- Another object is to provide a synthesis of such substances.
- a further object is the provision of animal feeds and feed supplements and of water soluble compositions containing these pyridinium quaternary salts.
- Other objects will be appar ent from the following discussion of our invention.
- 1-(2- methyl 4-amino-5-pyrimidylmethyl)-loweralkyl pyridinium quaternary salts are very effective in preventing and treating coccidiosis.
- the compound of the invention are pyridinium quaternary salts of the formula wherein R is a lower alkyl radical, n has a value of l, 2 or 3, and X is an anion; b and c are positive numbers having values such that the positive charge of b moles of cation is neutralized by c moles of anion X.
- X is a monovalent anion such as a halide
- b is 1 and c is 2.
- c is 2 or 3
- these anticoccidial compounds are prepared by reaction of a 2-methyl-4-arnino-5-substituted methyl pyrimidine with an appropriately alkylated pyridine.
- the anticoccidial compounds described herein may be considered as substituted pyridines.
- the pyridine ring is substituted at the 1-position by a 2-methyl-4-amino- S-pyrimidylmethyl radical; in the preferred compounds,
- lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl and amyl groups, such substituents being in at least the 2, 3 and/or 4 positions of the ring.
- the lower alkyl groups present in the pyridine ring of these compounds need not, of course, be the same in any particular com- I pound.
- the preferred compounds of the invention are 1-(2- methyl 4 amino S-pyrimidylmethyl)-2-loweralkylated pyridinium salts and 1-(2-1oweralkyl-4-amino-5-pyrimidylethyl)-4-loweralkylated pyridinium salts, i.e. compounds having a lower alkyl radical at least at the 2 or 4 position in the pyridine ring.
- 1-(2- methyl-4amino-5-pyrimidylmethyl)-2methyl pyridinium chloride hydrochloride 1-(2-methyl-4-amino-5-pyrimidylmethyl)-2-methyl-5-ethyl pyridinium chloride hydrochloride, 1 (2 methyl-4-amino-5-pyrimidylmethyl)-4-ethyl 1 pyridinium bromide hydrobromide, l-(2-methyl-4-amino- S-pyrimidylmethyl)-4-methyl pyridinium acetate and 1 (2-methyl-4- amino-S-pyrimidylmethyl) -2-methyl pyridinium bromide hydrobromide.
- sulfonic or ethylenediamine tetracetic acids may also be the anion of a polymer such as a polyphosphate. or
- polystyrenesulfonate ion The nature of the anion is not critical and any anion may be employed as long as it is not unduly toxic for the poultry. It will be realized that an acid addition salt of the primary aminogroup. present in these compounds will also be formed concur- 1 rently with the quaternary salt.
- the compounds described herein are synthesized by reacting together an appropriately substituted pyrimidine and an alkylated pyridine. According to one process, a 2-methyl-4-amino-5-halomethyl pyrimidine dihydrohalide,
- the halogen is bromine or chlorine
- the alkylated pyridine is reacted directly with the alkylated pyridine.
- An excess of the liquid alkylated pyridine or alternatively organic solvents inert under the reaction conditions such as lower alkanols, acetonitrile or an N,N-dilower alkyl alkanoamide may be employed as the reaction medium.
- the temperature is not critical and it is preferred to carry out the process at about room temperature. After a short time the quaternary salt crystallizes and is recovered by known ⁇ Ma I 3 technique such as filtration or centrifugation. This process may be represented as follows:
- R is a lower alkyl radical
- n is 1-3 inclusive and X is chlorine or bromine.
- the quaternization may also be brought about with an ester of 2-methyl-4-amino-5-hydromethyl pyrimidine. Suitable esters are the methylsulfiuate, p-toluenesulfonate and nitrate esters.
- the quaternization may be conducted so that the particular salt desired for treating coccidiosis is obtained directly.
- the quaternary salt recovered from the synthetic reaction medium may be conveniently metathesized to another salt by techniques known in the art.
- compositions are provided in which compounds described above are present as an active anticoccidial ingredient.
- Such compositions comprise the quaternary salts intimately dispersed in or admixed with an inert carrier or diluent.
- an inert carrier is meant one that is nonreactive with respect to the quaternary salt and that may be administered with safety to the animals.
- the carrier or diluent is preferably one that is or may be an ingredient of the animal feed.
- compositions which are a preferred feature of the invention are the so-called feed supplements in which the active ingredient is present in relatively large amounts and which are suitable for addition to the poultry feed either directly or after an intermediate dilution or blending step.
- carriers or diluents suitable for such compositions are solid orally ingestable carriers such as distillers dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits, crushed limestone and the like.
- the quaternary salts are intimately dispersed or admixed throughout the solid inert carrier by methods such as grinding, stirring, milling or tumbling.
- compositions of any desired concentration may be prepared.
- Formulations containing from about 1% to about 40% by weight, and preferably from about 225% by weight of active ingredient are particularly suitable for addition to poultry feeds, and compositions containing from about -15% by 'weight of coccidiostat are very satisfactory.
- the active compound is normally dispersed or mixed uniformly in the diluent but in some instances may be sorbed on the carrier.
- the optimal concentration of coccidiostat in these feed supplements will depend to some extent on the particular compound employed. Since it is convenient for the feed manufacturer to use about one pound of feed supplement for each ton of finished feed, the preferred concentration of any one of our coccidiostats in a feed supplement is partly a function of the level of active ingredient desired in the finished feed.
- Examples of typical feed supplements containing a pyridinium quaternary salt dispersed in a solid inert carrier are:
- feed supplements are prepared by uniformly mixing the pyridinium quaternary salt with the carrier or carriers.
- the feed supplements of the type illustrated hereinabove are usually further diluted with materials such as corn meal or soybean meal before being incorporated in the animal feed.
- the level of coccidiostat in the carrier is brought down to from about 0.1% to about 1.0% by weight. This dilution serves to facilitate uniform distribution of the substance in the finished feed.
- the finished feed is one that contains a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.
- the amount of pyridinium quaternary salt required for control of coccidiosis in poultry will, of course, vary somewhat with the specific compound or compounds employed.
- the compounds of Formula 1 above are effective in preventing the disease when administered at levels of less than about 0.05 by weight of the feed. With the preferred compounds of the invention, i.e.
- the 1-(2-methyl-4-amine-5 pyrimidylmethyl) 2 lower alkyl pyridinium and 1-(Z-methyl-4-amino-5-pyrimidylmethyl)- 4-lower alkyl pyridinium salts good prophylactic results were obtained when from about 0.01% to about 0.05 by weight of the totalfeed consumed is administered; for most satisfactory results it is preferred that the poultry feed contain between about 0.005% and 0.025 by weight of pyridinium salt.
- concentrations of about 0.02% to 0.05% by weight of the feed may be advantageously administered in treating an established out break of coccidiosis. It is desirable to employe the lowest levels that afford fully adequate control of coccidiosis in order to eliminate as far as possible any risk of side effects that might appear on prolonged feeding of the compounds.
- pyridinium quaternary salts are desirably or advantageously administered to poultry by way of the drinking water of the birds. This method of treatment is often employed in the therapeutic use of our compounds since poultry with coccidiosis are apt to consume less solid feed than normal birds.
- the water-soluble quaternary salts may be added directly to the drinking water.
- water-soluble powders may be prepared, in which the coccidiostat is intimately admixed with a suitable carrier, such as dextrose or sucrose, and these powders added to the drinking water of poultry as necessary.
- a suitable carrier such as dextrose or sucrose
- Such water-soluble powders may contain any desired concentration of coccidiostat, and preparations containing from 1-25 by weight of active ingredient are suitable.
- e Anticoccidial activity of the compounds described in the above table was determined by the following test Straight run White Leghorn chicks, in groups of three each, were weighed and placed in cages with wire floors.
- EXAMPLE 3 The compounds described in Table I, when tested by this method, were found to be active (total score of 0-5) at the dose level indicated.
- EXAMPLE 5 The coccidiostatic activity of two of the pyridinium compounds of the invention was determined by the following method:
- the diets were administered to the chicks for eight days following the date of infection. At the end of this time, the infected birds still living were sacrificed. The oocyst count was determined by a microscopic examination of the cecal homogenates.
- Com- Percent Percent Oocysts Compound pound Mor- Weight X 10- In In Feed tality Gain Surviving Animals 1 (2 methyl 4 amino 5- 0. 0015 O 82 8 pyrimidylmethyl) 2 0. 003 78 19 methyl pyridinium bro- 0.006 0 Q6 3 1 made hyglllrtibromide 0.0125 0 97 0.1
- a poultry feed supplement composition that comprises an edible carrier having dispersed therein from about 1% to about 40% by weight of a quaternary coinpound of the formula wherein R is methyl, and X is a non-toxic anion.
- composition useful against coccidiosis that comprises an edible carrier having intimately dispersed therein from about 1% to about 40% by weight of a 1(2- methyl-4-arnino-5-pyrimidyhnethyl)-2-rnethyl pyridiniuni quaternary salt, wherein the anion of the salt is a nontoxic anion.
- composition useful against coccidiosis that comprises an inert edible carrier having intimately dispersed therein from about 1% to about 40% by weight of 1-(2- methyl-4-amino-5-pyrimidylmethyl)-2-methy1-5-ethyl pyridinium chloride hydrochloride.
- composition useful against coecidiosis that comprises an inert edible carrier having intimately dispersed therein from about 1% to about 40% by weight of 1-(2- methyl-4-amino-5-pyrimidylmethyl)-2-methyl-5-ethyl pyridinium halide hydrohalide.
- An animal feedstutf having dispersed therein from about 0.005% to about 0.05% by weight of l-(2-rnethyl- 8 4-amino-5-pyrimidylmethyl)-2-methyl pyridinium halide hydrohalide.
- a composition comprising an inert edible carrier having dispersed therein a member of the class consisting of 1 (2-methyl-4-arnino-5-pyrimidylrnethyl) 2 methyl pyridinium quaternary salt and l-(2-methyl-4-arnino-S- pyrimidylmethyl)-2-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and 5 positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
- a poultry feed supplement composition that comprises a poultry feed additive having dispersed therein from about 1% to about by weight of a member of the class consisting of 1-(2-methyl-4-arnino-5-pyrimidylmethyl)-2-methyl pyridinium quaternary salt and l (2-methyl-4-amino-5-pyrirnidylmethyl)-2-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and 5-positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
- a poultry feedstuii containing as an active anticoccidial ingredient a member of the class consisting of l-(2- methyl-4-arnino-5-pyrimidylmethyl)-2-methyl pyridinium quaternary salt and l-(2-methyl-4-amino-5-pyrimidylmethyD-Z-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and 5-positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
- composition of claim 9 wherein the feedstuff contains from about 0.005 to about 0.05% by weight of quaternary salt.
- a water-soluble powder comprising an edible water-soluble carrier having dispersed therein from about 1% to about 25% by weight of a member of the class consisting of 1-(2-methyl4-amino-S-pyrimidylmethyl)-2- methyl pyridinium quaternary salt and l-(2-rnethyl-4- amino-S-pyrimidylmethyl)-2-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and S-positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
Description
nited States Patent Office 3,065,132 Patented Nov. 20, 1952 1-(2-METHYL-4-AMENO 5 PYRIMIDYLMETHYL)- LOWER ALKYL PYRIDINIUM QUATERNARY SALTS FOR TREATING COCCIDIOSIS Edward F. Rogers, Middletown, and Lewis H. Sarett,
Princeton, N..l., assignors to Merck & Co., line, Rahway, N .J a corporation of New Jersey No Drawing. Original application July 28, 1959, Ser. No. 829,978. Divided and this application June 24, 196i), Ser. No. 38,451
11 Claims. (Cl. 16753.1)
This invention relates generally to new chemical comunds. More specifically, it is concerned with chemical compounds which are useful in the prevention and the cure of coccidiosis. Still more particularly, it is concerned with a group of new pyridinium quaternary salts which are effective in controlling coccidiosis when fed in relatively small amounts to poultry. Still more specifically, it relates to 1-(Z-methyl-4-amino-S-pyrimidylmethyl)-loweralkyl pyridinium quaternary salts and with methods of making such substances. It is further concerned with novel compositions containing such substances.
This application is a division of our copending application Serial No. 829,978, filed July 28, 1959, now abandoned, which in turn is a continuation-impart of our application Serial No. 805,688, filed April 13, 1959, now abandoned.
Coccidiosis is a common and Widespread poultry disease caused by several species of protozoan parasites of the genus Eimeria, such as E. tenella, E. necatrix, E. acervulina, E. maxima, E. lzagani and E. brunetti. E. tenella is the causative agent of a severe and often fatal infection of the ceca of chickens which is manifested by extensive hemorrhage, accumulation of blood in the ceca, and the passage of blood in the droppings. E. neczarrix as well as certain other species attack the small intestine of the chick causing what is known as intestinal coccidiosis; Related species of coccidia such as E. melagridis and E. adenoides are causative organisms of coccidiosis in turkeys. When left untreated, the severe forms of coccidiosis lead to poor weight gain, reduced feed efficiency and high mortality in fowl. The elimination or control of coccidiosis is, therefore, of paramount importance in the poultry raising industry.
It has now been found that certain pyridinium quaternary compounds are highly active against the protozoa responsible for coccidiosis. One object of the invention is to provide such compounds. Another object is to provide a synthesis of such substances. A further object is the provision of animal feeds and feed supplements and of water soluble compositions containing these pyridinium quaternary salts. Other objects will be appar ent from the following discussion of our invention.
According to tihs invention it has been found that 1-(2- methyl 4-amino-5-pyrimidylmethyl)-loweralkyl pyridinium quaternary salts, and particularly those compounds wherein the pyridine ring is substituted with from one to three lower alkyl groups, are very effective in preventing and treating coccidiosis. The compound of the invention are pyridinium quaternary salts of the formula wherein R is a lower alkyl radical, n has a value of l, 2 or 3, and X is an anion; b and c are positive numbers having values such that the positive charge of b moles of cation is neutralized by c moles of anion X. Thus when X is a monovalent anion such as a halide, b is 1 and c is 2. When more than one lower alkyl group is present in the pyridine ring, i.e. when n is 2 or 3, such lower alkyl groups may be the same or different. As described more fully below, these anticoccidial compounds are prepared by reaction of a 2-methyl-4-arnino-5-substituted methyl pyrimidine with an appropriately alkylated pyridine. As will be apparent from the above structural formula, the anticoccidial compounds described herein may be considered as substituted pyridines. The pyridine ring is substituted at the 1-position by a 2-methyl-4-amino- S-pyrimidylmethyl radical; in the preferred compounds,
it is further substituted with one or more lower alkyl groups, such as methyl, ethyl, propyl, isopropyl, butyl and amyl groups, such substituents being in at least the 2, 3 and/or 4 positions of the ring. The lower alkyl groups present in the pyridine ring of these compounds need not, of course, be the same in any particular com- I pound.
The preferred compounds of the invention are 1-(2- methyl 4 amino S-pyrimidylmethyl)-2-loweralkylated pyridinium salts and 1-(2-1oweralkyl-4-amino-5-pyrimidylethyl)-4-loweralkylated pyridinium salts, i.e. compounds having a lower alkyl radical at least at the 2 or 4 position in the pyridine ring. Included among these are 1-(2- methyl-4amino-5-pyrimidylmethyl)-2methyl pyridinium chloride hydrochloride, 1-(2-methyl-4-amino-5-pyrimidylmethyl)-2-methyl-5-ethyl pyridinium chloride hydrochloride, 1 (2 methyl-4-amino-5-pyrimidylmethyl)-4-ethyl 1 pyridinium bromide hydrobromide, l-(2-methyl-4-amino- S-pyrimidylmethyl)-4-methyl pyridinium acetate and 1 (2-methyl-4- amino-S-pyrimidylmethyl) -2-methyl pyridinium bromide hydrobromide.
sulfonic or ethylenediamine tetracetic acids. .It may also be the anion of a polymer such as a polyphosphate. or
polystyrenesulfonate ion. The nature of the anion is not critical and any anion may be employed as long as it is not unduly toxic for the poultry. It will be realized that an acid addition salt of the primary aminogroup. present in these compounds will also be formed concur- 1 rently with the quaternary salt.
The compounds described herein are synthesized by reacting together an appropriately substituted pyrimidine and an alkylated pyridine. According to one process, a 2-methyl-4-amino-5-halomethyl pyrimidine dihydrohalide,
in which the halogen is bromine or chlorine, is reacted directly with the alkylated pyridine. An excess of the liquid alkylated pyridine or alternatively organic solvents inert under the reaction conditions such as lower alkanols, acetonitrile or an N,N-dilower alkyl alkanoamide may be employed as the reaction medium. The temperature is not critical and it is preferred to carry out the process at about room temperature. After a short time the quaternary salt crystallizes and is recovered by known {Ma I 3 technique such as filtration or centrifugation. This process may be represented as follows:
i mznx Nut+ N onix N/ 2 j l (R). L
where R is a lower alkyl radical, n is 1-3 inclusive and X is chlorine or bromine.
Although the S-halomethyl pyrimidines are generally most conveniently employed for reaction with the alkyl pyridine, the quaternization may also be brought about with an ester of 2-methyl-4-amino-5-hydromethyl pyrimidine. Suitable esters are the methylsulfiuate, p-toluenesulfonate and nitrate esters. The quaternization may be conducted so that the particular salt desired for treating coccidiosis is obtained directly. Alternatively, the quaternary salt recovered from the synthetic reaction medium may be conveniently metathesized to another salt by techniques known in the art.
In using the compounds of the invention in the treatment and prevention of coccidiosis, they are conveniently fed to poultry as a component of the feed of the animals although they may also be given dissolved or suspended in the drinking water. According to one aspect of the invention, novel compositions are provided in which compounds described above are present as an active anticoccidial ingredient. Such compositions comprise the quaternary salts intimately dispersed in or admixed with an inert carrier or diluent. By an inert carrier is meant one that is nonreactive with respect to the quaternary salt and that may be administered with safety to the animals. The carrier or diluent is preferably one that is or may be an ingredient of the animal feed.
The compositions which are a preferred feature of the invention are the so-called feed supplements in which the active ingredient is present in relatively large amounts and which are suitable for addition to the poultry feed either directly or after an intermediate dilution or blending step. Examples of carriers or diluents suitable for such compositions are solid orally ingestable carriers such as distillers dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, Attapulgus clay, wheat shorts, molasses solubles, corn cob meal, edible vegetable substances, toasted dehulled soya flour, soybean mill feed, antibiotic mycelia, soya grits, crushed limestone and the like. The quaternary salts are intimately dispersed or admixed throughout the solid inert carrier by methods such as grinding, stirring, milling or tumbling. By selecting proper diluents and by altering the ratio of carrier toactive ingredient, compositions of any desired concentration may be prepared. Formulations containing from about 1% to about 40% by weight, and preferably from about 225% by weight of active ingredient are particularly suitable for addition to poultry feeds, and compositions containing from about -15% by 'weight of coccidiostat are very satisfactory. The active compound is normally dispersed or mixed uniformly in the diluent but in some instances may be sorbed on the carrier. The optimal concentration of coccidiostat in these feed supplements will depend to some extent on the particular compound employed. Since it is convenient for the feed manufacturer to use about one pound of feed supplement for each ton of finished feed, the preferred concentration of any one of our coccidiostats in a feed supplement is partly a function of the level of active ingredient desired in the finished feed.
Examples of typical feed supplements containing a pyridinium quaternary salt dispersed in a solid inert carrier are:
Lbs.
A. I-(Z-methyl 4 amino 5 pyrimidylmethyl)-4- methyl pyridinium chloride hydrochloride-" 6.0 Wheat standard midlings 94.0
B. 1-(2-methyl-4-amino-S-pyrimidylmethyl)-2- Lbs. methyl pyridinium bromide hydrobromide 10.0
Corn distillers dried grains 90.0 C. l-(Z-methyl 4 amino 5 pyrimidylmethyl)-2- methyl-S-ethyl pyridinium chloride hydrochloride 15.0
Wheat standard middlings 88.0
These and similar feed supplements are prepared by uniformly mixing the pyridinium quaternary salt with the carrier or carriers.
The feed supplements of the type illustrated hereinabove are usually further diluted with materials such as corn meal or soybean meal before being incorporated in the animal feed. In this intermediate processing step the level of coccidiostat in the carrier is brought down to from about 0.1% to about 1.0% by weight. This dilution serves to facilitate uniform distribution of the substance in the finished feed. The finished feed is one that contains a source of fat, protein, carbohydrate, minerals, vitamins and other nutritional factors.
The amount of pyridinium quaternary salt required for control of coccidiosis in poultry will, of course, vary somewhat with the specific compound or compounds employed. The compounds of Formula 1 above are effective in preventing the disease when administered at levels of less than about 0.05 by weight of the feed. With the preferred compounds of the invention, i.e. the 1-(2-methyl-4-amine-5 pyrimidylmethyl) 2 lower alkyl pyridinium and 1-(Z-methyl-4-amino-5-pyrimidylmethyl)- 4-lower alkyl pyridinium salts, good prophylactic results were obtained when from about 0.01% to about 0.05 by weight of the totalfeed consumed is administered; for most satisfactory results it is preferred that the poultry feed contain between about 0.005% and 0.025 by weight of pyridinium salt. When the pyridinium salts are to be employed as therapeutic agents, the higher levels are used for relatively short periods of time. Thus, concentrations of about 0.02% to 0.05% by weight of the feed may be advantageously administered in treating an established out break of coccidiosis. It is desirable to employe the lowest levels that afford fully adequate control of coccidiosis in order to eliminate as far as possible any risk of side effects that might appear on prolonged feeding of the compounds.
Many of these pyridinium quaternary salts are desirably or advantageously administered to poultry by way of the drinking water of the birds. This method of treatment is often employed in the therapeutic use of our compounds since poultry with coccidiosis are apt to consume less solid feed than normal birds. The water-soluble quaternary salts may be added directly to the drinking water. Alternatively, water-soluble powders may be prepared, in which the coccidiostat is intimately admixed with a suitable carrier, such as dextrose or sucrose, and these powders added to the drinking water of poultry as necessary. Such water-soluble powders may contain any desired concentration of coccidiostat, and preparations containing from 1-25 by weight of active ingredient are suitable.
EXAMPLE 1 To 25 ml. of Z-methylpyridine (e-picoline) was added a solution of 20 grams of 2-methyl-4-amino-5-pyrimidylmethyl bromide dihydrobromide in 100 ml. of methanol. A clear solution formed which became slightly warm. 100 ml. of absolute ethanol was added. In a short time crystals of 1-(2-methyl-4-amino-S-pyrimidylmethyl)-2- EXAMPLE 4 The pyridiniurn quaternary salts set forth in Table I below were synthesized utilizing processes described in preceding examples.
Table I lYlHz. 2HX I! R NH R R N/ N H-UHzX R N CHz-N -R 2X- H C-k R R Hack R2 R Quaternary Melting Percent Cpd. N o. R R R R R R X Prepared Point 11 By Method 0. Feed of Ex. N o. (dec.)
1 233-234 0. 006 2 256-257 0. 006 l 274 0. 05 1 269 0. 025 1 218 0.006 2 234 0. 006 l 235 0. 0125 l 254 0. 003 2 269 0. 003 1 219 0. 006 1 275 0. 05 1 236 O. 0125 l 240 0. 0125 3 208 0. 003 3 256 0. 006
e Anticoccidial activity of the compounds described in the above table was determined by the following test Straight run White Leghorn chicks, in groups of three each, were weighed and placed in cages with wire floors.
They were fed ad libitum a standard laboratory basal ration in which graded levels of the pyridinium quaternary salt were intimately dispersed r blended. Normal and infected control birds were fed basal (lay of test, the chicks were each orally inoculated with 50,000 sporulated oocysts ot' Eimeriw tcnella. Papers under the cag for the presence or absence 0 were observed; scores of 1 tively. On the eighth day coccidiosis lesions were es were examined bloody droppings. 2 or 4 were assigned of assay, the surviving birds were grossly for cecal coccidiosis lesions. moderate or maximal lesions were scored 1, 2 and 4, respectively.
present, a score of 5 was recorded.
ration containing no quaternary salt. On the second on the sixth, seventh and eighth days of assay A score of 0 was given if no bloody spots for 1-3, 4-6 and 6 bloody spots, respecweighed, sacrificed and examined Normal ceca were scored 0, and ceca with detectable, When a bird died and cecal It the total of the two scores was 0-5, the compound under test was rated active, if the total score was 6 or more, the compound was rated inactive at the concentration tested.
methylpyridinium bromide hydrobromide began to appear. The mixture was allowed to stand in the cold for about 15 hours. The crystalline material was then collected by filtration, washed with two ml. portions of cold absolute ethanol and dried. The small white crystals of 1-(2-methyl-4-amino-5-pyrimidylmethyl)-2-methylpyridinium bromide hydrobrornide thus obtained melt at 233-234 C. (dec.).
EXAMPLE 2 One gram of 1-(2-mcthyl-4-amin0-5-pyrimidylmethyl)- Z-methyl pyridinium bromide hydrobromide was dissolved in 4 ml. of concentrated hydrochloric acid. This solution was carefully diluted with 60 ml. of acetone whereupon 1-(2-merhyl-4-amino-5-pyrimidylmethyl) 2 methyl pyridinium chloride hydrochloride crystallized. This salt was dissolved in 2 ml. of concentrated hydrochloric acid and the solution slowly diluted with ml. of acetone. The salt crystallized and on drying melted to 256-7 C. (deo).
EXAMPLE 3 The compounds described in Table I, when tested by this method, were found to be active (total score of 0-5) at the dose level indicated.
EXAMPLE 5 The coccidiostatic activity of two of the pyridinium compounds of the invention was determined by the following method:
Groups of ten two-week old White Leghorn chicks were fed a mash diet containing various amounts of the compounds. The compounds were uniformly dispersed in the feed. After having been on this ration for 24 hours, each chick was inoculated with 50,000 sporulated oocysts of E. tenella.
Other groups of ten chicks each were fed a similar mash diet which contained no coocidiostat. These were also infected after 24 hours and served as positive or infected controls. As positive controls, two to four groups of ten chicks each were employed. Still other groups of ten chicks each were fed the mash free of coccidiostat and were not infected with coccidiosis. These served as normal controls.
The diets were administered to the chicks for eight days following the date of infection. At the end of this time, the infected birds still living were sacrificed. The oocyst count was determined by a microscopic examination of the cecal homogenates.
The results employing the indicated amounts of quaternary salt, and expressed as mean values, are set forth in Table II.
Table 11 Percent No. of
Com- Percent Percent Oocysts Compound pound Mor- Weight X 10- In In Feed tality Gain Surviving Animals 1 (2 methyl 4 amino 5- 0. 0015 O 82 8 pyrimidylmethyl) 2 0. 003 78 19 methyl pyridinium bro- 0.006 0 Q6 3 1 made hyglllrtibromide 0.0125 0 97 0.1
-me y -4-amino-5- '1 pyrimidylmethyl) 2 8 g 0 g niethylhi ethlyll gyrnlililn- B 0 97 1 iumcorie yoeoride 0. 0125 0 100 1 Infected Controls- 40 63 0 Normal Controls 0 90 Any departure from the above description which conforms to the present invention is intended to be included within the scope of the claims.
What is claimed is:
1. A poultry feed supplement composition that comprises an edible carrier having dispersed therein from about 1% to about 40% by weight of a quaternary coinpound of the formula wherein R is methyl, and X is a non-toxic anion.
2. A composition useful against coccidiosis that comprises an edible carrier having intimately dispersed therein from about 1% to about 40% by weight of a 1(2- methyl-4-arnino-5-pyrimidyhnethyl)-2-rnethyl pyridiniuni quaternary salt, wherein the anion of the salt is a nontoxic anion.
3. A composition useful against coccidiosis that comprises an inert edible carrier having intimately dispersed therein from about 1% to about 40% by weight of 1-(2- methyl-4-amino-5-pyrimidylmethyl)-2-methy1-5-ethyl pyridinium chloride hydrochloride.
4. A composition useful against coecidiosis that comprises an inert edible carrier having intimately dispersed therein from about 1% to about 40% by weight of 1-(2- methyl-4-amino-5-pyrimidylmethyl)-2-methyl-5-ethyl pyridinium halide hydrohalide.
5. An animal feedstutf having dispersed therein from about 0.005% to about 0.05% by weight of l-(2-rnethyl- 8 4-amino-5-pyrimidylmethyl)-2-methyl pyridinium halide hydrohalide.
6. An animal feedstuif having dispersed therein from about 0.005% to about 0.05% by weight of 1-(2-methyl- 4-amino-5-pyrimidylmethyl)-2-methyl-5-ethyl pyridinium chloride hydrochloride.
7. A composition comprising an inert edible carrier having dispersed therein a member of the class consisting of 1 (2-methyl-4-arnino-5-pyrimidylrnethyl) 2 methyl pyridinium quaternary salt and l-(2-methyl-4-arnino-S- pyrimidylmethyl)-2-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and 5 positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
8. A poultry feed supplement composition that comprises a poultry feed additive having dispersed therein from about 1% to about by weight of a member of the class consisting of 1-(2-methyl-4-arnino-5-pyrimidylmethyl)-2-methyl pyridinium quaternary salt and l (2-methyl-4-amino-5-pyrirnidylmethyl)-2-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and 5-positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
9. A poultry feedstuii containing as an active anticoccidial ingredient a member of the class consisting of l-(2- methyl-4-arnino-5-pyrimidylmethyl)-2-methyl pyridinium quaternary salt and l-(2-methyl-4-amino-5-pyrimidylmethyD-Z-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and 5-positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
10. The composition of claim 9 wherein the feedstuff contains from about 0.005 to about 0.05% by weight of quaternary salt.
11. A water-soluble powder comprising an edible water-soluble carrier having dispersed therein from about 1% to about 25% by weight of a member of the class consisting of 1-(2-methyl4-amino-S-pyrimidylmethyl)-2- methyl pyridinium quaternary salt and l-(2-rnethyl-4- amino-S-pyrimidylmethyl)-2-methyl pyridinium quaternary salt having a lower alkyl group at one of the 3-, 4- and S-positions of the pyridine ring, wherein the anion of the quaternary salt is a non-toxic anion; and non-toxic acid addition salts thereof.
References Cited in the file of this patent Fujita: J.B.C., 196, pages 297-303 and 313-320, 1952.
Claims (1)
- 5. AN ANIMAL FEEDSTUFF HAVING DISPERSED THEREIN FROM ABOUT 0.005% TO ABOUT 0.005% BY WEIGHT OF 1-(2-METHYL4-AMINO-5-PYRIMIDYLMETHYL)-2-METHYL PYRIDINIUM HALIDE HYDROHALIDE.
Priority Applications (11)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
BE587330D BE587330A (en) | 1959-04-13 | ||
US829979A US3020277A (en) | 1959-04-13 | 1959-07-28 | 1-(2-n-propyl-4-amino-5-pyrimidyl-methyl)-2(or 4)-methyl pyridinium salts |
GB3698/60A GB911551A (en) | 1959-04-13 | 1960-02-02 | 1-[2-(c alkyl)-4-amino-5-pyrimidylmethyl]-(c alkyl)-pyridinium quaternary salts and compositions containing them |
DEM44190A DE1149010B (en) | 1959-04-13 | 1960-02-03 | Process for the preparation of 1- [2-alkyl-4-aminopyrimidyl- (5) -methyl] -alkylpyridinium salts |
CH163960A CH381694A (en) | 1959-04-13 | 1960-02-15 | Process for the preparation of quaternary pyridinium salts |
FI0327/60A FI43598B (en) | 1959-04-13 | 1960-02-29 | |
FR820636A FR1291531A (en) | 1959-04-13 | 1960-03-07 | Manufacture of quaternary pyridinium salts such as 1- (2-alkylinferieur-4-amino-5-pyrimidylmethyl) -loweralkyl-quaternary pyridinium salts |
SE2942/60A SE308105B (en) | 1959-04-13 | 1960-03-23 | |
US38451A US3065132A (en) | 1959-04-13 | 1960-06-24 | 1-(2-methyl-4-amino-5-pyrimidylmethyl)-lower alkyl pyridinium quaternary salts for treating coccidiosis |
US38449A US3020200A (en) | 1959-04-13 | 1960-06-24 | 1-(2-alkyl-4-amino-5-pyrimidinylmethyl)-alkyl-pyridinium quaternary salts for treating coccidiosis |
SE7084/63A SE311801B (en) | 1959-04-13 | 1963-06-26 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US80568859A | 1959-04-13 | 1959-04-13 | |
US82997859A | 1959-07-28 | 1959-07-28 | |
US829979A US3020277A (en) | 1959-04-13 | 1959-07-28 | 1-(2-n-propyl-4-amino-5-pyrimidyl-methyl)-2(or 4)-methyl pyridinium salts |
US38451A US3065132A (en) | 1959-04-13 | 1960-06-24 | 1-(2-methyl-4-amino-5-pyrimidylmethyl)-lower alkyl pyridinium quaternary salts for treating coccidiosis |
US38449A US3020200A (en) | 1959-04-13 | 1960-06-24 | 1-(2-alkyl-4-amino-5-pyrimidinylmethyl)-alkyl-pyridinium quaternary salts for treating coccidiosis |
Publications (1)
Publication Number | Publication Date |
---|---|
US3065132A true US3065132A (en) | 1962-11-20 |
Family
ID=27534658
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US829979A Expired - Lifetime US3020277A (en) | 1959-04-13 | 1959-07-28 | 1-(2-n-propyl-4-amino-5-pyrimidyl-methyl)-2(or 4)-methyl pyridinium salts |
US38451A Expired - Lifetime US3065132A (en) | 1959-04-13 | 1960-06-24 | 1-(2-methyl-4-amino-5-pyrimidylmethyl)-lower alkyl pyridinium quaternary salts for treating coccidiosis |
US38449A Expired - Lifetime US3020200A (en) | 1959-04-13 | 1960-06-24 | 1-(2-alkyl-4-amino-5-pyrimidinylmethyl)-alkyl-pyridinium quaternary salts for treating coccidiosis |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US829979A Expired - Lifetime US3020277A (en) | 1959-04-13 | 1959-07-28 | 1-(2-n-propyl-4-amino-5-pyrimidyl-methyl)-2(or 4)-methyl pyridinium salts |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US38449A Expired - Lifetime US3020200A (en) | 1959-04-13 | 1960-06-24 | 1-(2-alkyl-4-amino-5-pyrimidinylmethyl)-alkyl-pyridinium quaternary salts for treating coccidiosis |
Country Status (8)
Country | Link |
---|---|
US (3) | US3020277A (en) |
BE (1) | BE587330A (en) |
CH (1) | CH381694A (en) |
DE (1) | DE1149010B (en) |
FI (1) | FI43598B (en) |
FR (1) | FR1291531A (en) |
GB (1) | GB911551A (en) |
SE (2) | SE308105B (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3246492A1 (en) * | 1981-12-18 | 1983-06-30 | Forest Laboratories Inc., 10022 New York, N.Y. | METHOD FOR PRODUCING THERAPEUTIC PREPARATIONS BASED ON HYDROXYPROPYLMETHYL CELLULOSE WITH EXTENDED RELEASE PROCESS |
CN105434362A (en) * | 2015-11-11 | 2016-03-30 | 浙江大洋生物科技集团股份有限公司 | Method for preparing high-purity granular type amprolium hydrochloride |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB984375A (en) * | 1962-09-06 | 1965-02-24 | Ici Ltd | Veterinary compositions of sulphaquinoxaline and pyrimidine derivatives |
DE1545721B1 (en) * | 1964-12-29 | 1971-01-21 | Chinoin Gyogyszer Es Vegyeszet | Process for the preparation of 1- (2-alkyl-4-amino-5-pyrimidylmethyl) pyridinium compounds |
US3374236A (en) * | 1965-08-23 | 1968-03-19 | Ciba Geigy Corp | Quaternary 5-ammoniummethyl-4-amino-2-alkylmercaptoalkylene pyrimidine salts |
GB1168801A (en) * | 1966-05-13 | 1969-10-29 | May & Baker Ltd | Quinoline Derivatives |
DE2251687A1 (en) * | 1971-11-01 | 1973-05-10 | Chinoin Gyogyszer Es Vegyeszet | NEW QUATERNAERE AMMONIUM COMPOUNDS AND METHOD OF MAKING THE SAME |
US4044133A (en) * | 1974-04-18 | 1977-08-23 | Merck & Co., Inc. | Anticoccidial compositions |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2587262A (en) * | 1952-02-26 | Chs chzghjoh | ||
US2895874A (en) * | 1953-03-27 | 1959-07-21 | Whitmoyer Lab Inc | Diamino-pyrimidine compositions for chemotherapy of coccidiosis |
US2823160A (en) * | 1955-03-29 | 1958-02-11 | Whitmoyer Lab Inc | Substituted pyrimidines compositions for chemotherapy of coccidiosis |
-
0
- BE BE587330D patent/BE587330A/xx unknown
-
1959
- 1959-07-28 US US829979A patent/US3020277A/en not_active Expired - Lifetime
-
1960
- 1960-02-02 GB GB3698/60A patent/GB911551A/en not_active Expired
- 1960-02-03 DE DEM44190A patent/DE1149010B/en active Pending
- 1960-02-15 CH CH163960A patent/CH381694A/en unknown
- 1960-02-29 FI FI0327/60A patent/FI43598B/fi active
- 1960-03-07 FR FR820636A patent/FR1291531A/en not_active Expired
- 1960-03-23 SE SE2942/60A patent/SE308105B/xx unknown
- 1960-06-24 US US38451A patent/US3065132A/en not_active Expired - Lifetime
- 1960-06-24 US US38449A patent/US3020200A/en not_active Expired - Lifetime
-
1963
- 1963-06-26 SE SE7084/63A patent/SE311801B/xx unknown
Non-Patent Citations (1)
Title |
---|
None * |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE3246492A1 (en) * | 1981-12-18 | 1983-06-30 | Forest Laboratories Inc., 10022 New York, N.Y. | METHOD FOR PRODUCING THERAPEUTIC PREPARATIONS BASED ON HYDROXYPROPYLMETHYL CELLULOSE WITH EXTENDED RELEASE PROCESS |
CN105434362A (en) * | 2015-11-11 | 2016-03-30 | 浙江大洋生物科技集团股份有限公司 | Method for preparing high-purity granular type amprolium hydrochloride |
CN105434362B (en) * | 2015-11-11 | 2018-01-19 | 浙江大洋生物科技集团股份有限公司 | The preparation method of high-purity granular pattern Amprolium Hydrochloride |
Also Published As
Publication number | Publication date |
---|---|
GB911551A (en) | 1962-11-28 |
BE587330A (en) | 1900-01-01 |
SE311801B (en) | 1969-06-23 |
DE1149010B (en) | 1963-05-22 |
FI43598B (en) | 1971-02-01 |
CH381694A (en) | 1964-09-15 |
US3020277A (en) | 1962-02-06 |
SE308105B (en) | 1969-02-03 |
FR1291531A (en) | 1962-04-27 |
US3020200A (en) | 1962-02-06 |
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