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Патент USA US3065139

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nited States Patent Office
3,065,132
Patented Nov. 20, 1952
1
2
3,065,132
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
1-(2-METHYL-4-AMENO - 5 - PYRIMIDYLMETHYL)
LOWER ALKYL PYRIDINIUM QUATERNARY
SALTS FOR TREATING COCCIDIOSIS
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
way, N.J., a corporation of New Jersey
c is 2. When more than one lower alkyl group is present
No Drawing. Original application July 28, 1959, Ser.
in the pyridine ring, i.e. when n is 2 or 3, such lower
No. 829,978. Divided and this application June 24,
alkyl groups may be the same or different. As described
196i), Ser. No. 38,451
more fully below, these anticoccidial compounds are pre
10
11 Claims. (Cl. 167—53.1)
Edward F. Rogers, Middletown, and Lewis H. Sarett,
Princeton, N..l., assignors to Merck & Co., line, Rah
pared by reaction of a 2-methyl-4-arnino-5-substituted
This invention relates generally to new chemical com
methyl pyrimidine with an appropriately alkylated pyri
, unds. More speci?cally, it is concerned with chemical
dine. As will be apparent from the above structural
“compounds which are useful in the prevention and the
formula, the anticoccidial compounds described herein
cure of coccidiosis. Still more particularly, it is con 15 may be considered as substituted pyridines. The pyridine
cerned with a group of new pyridinium quaternary salts
ring is substituted at the 1-position by a 2-methyl-4-amino
which are effective in controlling coccidiosis when fed
pS-pyrimidylmethyl
radical; in the preferred compounds,
in relatively small amounts to poultry. Still more spe
it is further substituted with one or more lower alkyl ‘
ci?cally, it relates to 1-(Z-methyl-4-amino-S-pyrimidyl
methyl)~loweralkyl pyridinium quaternary salts and with
methods of making such substances. It is further con
cerned with novel compositions containing such sub
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
stances.
need not, of course, be the same in any particular com- I
This application is a division of our copending applica
tion Serial No. 829,978, ?led July 28, 1959, now aban 25 pound.
The preferred compounds of the invention are 1-(2- '
doned, which in turn is a continuation-impart of our ap
plication Serial No. 805,688, filed April 13, 1959, now
abandoned.
methyl — 4 - amino - S-pyrimidylmethyl)-2-loweralkylated
pyridinium salts and 1-(2-1oweralkyl-4-amino-5-pyrimidyl- '
Coccidiosis is a common and Widespread poultry dis
ethyl)-4-loweralkylated pyridinium salts, i.e. compounds
ease caused ‘by several species of protozoan parasites of 30 having a lower alkyl radical at least at the 2 or 4 position
the genus Eimeria, such as E. tenella, E. necatrix, E.
in the pyridine ring. Included among these are 1-(2
acervulina, E. maxima, E. lzagani and E. brunetti. E.
methyl~4—amino-5-pyrimidylmethyl)-2—methyl pyridinium ,
tenella is the causative agent of a severe and often fatal
chloride hydrochloride, v1-(2-methyl~4-amino-5~pyrimidyl
methyl)-2-methyl-5~ethyl pyridinium chloride hydrochlo
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 coc
ride,
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?
cidiosis; ‘Related species of coccidia such as E. melagridis
(2-methyl-4- amino-S-pyrimidylmethyl) ~2-methyl pyridin
cidiosis lead to poor weight gain, reduced feed ef?ciency
and high mortality in fowl. The elimination or control
and the like, or‘ the anion of an organic acid such as ‘
and E. adenoides are causative organisms of coccidiosis 4.0 ium ‘bromide hydrobromide.
The quaternary anion may be an inorganic- anion such,‘
in turkeys. When left untreated, the severe forms of coc
aschloride, bromide, iodide, nitrate, sulfate, phosphate
of coccidiosis is, therefore, of paramount importance in
the poultry raising industry.
45
It has now been found that certain pyridinium quater
nary compounds are highly active against the protozoa
responsible for coccidiosis. One object of the invention
is to provide such compounds. Another object is to pro
vide a synthesis of such substances. A further object
is the provision of animal feeds and feed ‘supplements
and of water soluble compositions containing these py
ridinium 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 55
methyl - 4-amino-5-pyrimidylmethyl)-loweralkyl pyridin
citric, tartaric, acetic, picric, stearic, succinic, benzoic, "
phthalic, phenoxyacetic, embonic, abietic, Z-naphthalene f
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 amino’group.
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 ;
ium quaternary salts, and particularly those compounds
and an alkylated pyridine.
wherein the pyridine ring is substituted with from one to
three lower alkyl groups, are very effective in preventing
and treating coccidiosis. The compounds of the invention
are pyridinium quaternary salts of the formula
2-methyl-4-amino-5-halomethyl pyrimidine dihydrohalide,
According to one process, a
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 al
kanols, acetonitrile or an N,N-dilower alkyl alkanoamide
may be employed as the reaction medium. The tempera
ture 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 ?ltration or centrifugation. This proc
ess may be represented as follows:
ifmznx
N
H30
_j l
B. 1~(2-methyl-4-amino-S-pyrimidylmethyl)-2Lbs.
methyl pyridinium bromide hydrobromide___ 10.0
Nut+
onix + N/
\"
2
(R).
-—-—>
L
(Rh.
1130* \N/
where R is a lower alkyl radical, n is 1-3 inclusive and 10
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 pyrim 15
idine. Suitable esters are the methylsul?uate, p-toluene
sulfonate and nitrate esters. The quaternization may be
conducted so that the particular salt desired for treating
Corn distillers’ dried grains _______________ __ 90.0
C. l-(Z-methyl - 4 - amino - 5 - pyrimidylmethyl)-2
methyl-S-ethyl pyridinium chloride hydrochlo
ride _________________________________ __ 15.0
Wheat standard middlings ________________ __ 85.0
D. I-(Z-methyl - 4 - amino - 5 - pyrimidylmethyD-Z
methyl pyridinium chloride hydrochloride___ 20.0
Corn germ meal _________________________ __ 30.0
Corn distillers’ grains ____________________ __ 50.0
E. 1-(2»methyl - 4 - amino - 5 - pyrimidylmethyl)-4
coccidiosis is obtained directly. Alternatively, the qua
ethyl pyridinium bromide hydrobromide____ 12.0 ;
ternary salt recovered from the synthetic reaction me 20
Wheat standard middlings _________________ __ 88.0
dium may be conveniently metathesized to another salt
by techniques known in the art.
These and similar feed supplements are prepared by
In using the compounds of the invention in the treat
uniformly mixing the pyridinium quaternary salt with
ment and prevention of coccidiosis, they are conveniently
the carrier or carriers.
fed to poultry as a component of the feed of the animals 25
The feed supplements of the type illustrated herein
although they may also be given dissolved or suspended
above are usually further diluted with materials such as
in the drinking water. According to one aspect of the
corn meal or soybean meal before being incorporated in
invention, novel compositions are provided in which com
the animal feed. In this intermediate processing step the
pounds described above are present as an active anti
level of coccidiostat in the carrier is brought down to
coccidial ingredient. ‘Such compositions comprise the 30 from about 0.1% to about 1.0% by weight. This dilu
quaternary salts intimately dispersed in or admixed with
tion serves to facilitate uniform distribution of the sub
an inert carrier or diluent. By an inert carrier is meant
stance in the ?nished feed. The finished feed is one that
one that is nonreactive with respect to the quaternary salt
contains a source of fat, protein, carbohydrate, minerals,
and that may be administered with safety to the animals.
vitamins and other nutritional factors.
The carrier or diluent is preferably one that is or may 35
The amount of pyridinium quaternary salt required for’
be an ingredient of the animal feed.
control of coccidiosis in poultry will, of course, vary
The compositions which are a preferred feature of the
somewhat with the specific compound or compounds
invention are the so-called feed supplements in which
employed. The compounds of Formula 1 above are effec
the active ingredient is present in relatively large amounts
tive in preventing the disease when administered at levels
and which are suitable for addition to the poultry feed 4.0 of less than about 0.05 % by weight of the feed. With
either directly or after an intermediate dilution or blend
ing 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 ?our,
soybean mill feed, antibiotic mycelia, soya grits, crushed
limestone and the like.
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
The quaternary salts are in
of pyridinium salt. When the pyridinium salts are to be
timately ‘dispersed or admixed throughout the solid inert
employed as therapeutic agents, the higher levels are used
carrier by methods such as grinding, stirring, milling or 50 for relatively short periods of time. Thus, concentrations
tumbling. By selecting proper diluents and by altering
of about 0.02% to 0.05% by weight of the feed may be
the ratio of carrier to- active ingredient, compositions of
advantageously administered in treating an established out“
any desired concentration may be prepared. Formula
break of coccidiosis. It is desirable to employe the lowest
tions containing from about 1% to about 40% by weight,
that afford fully adequate control of coccidiosis in
and preferably from about 2—25% by weight of active in 55 levels
order to eliminate as far as possible any risk of side effects
gredient are particularly suitable for addition to poultry
that might appear on prolonged feeding of the compounds.
feeds, and compositions containing from about 5-15%
Many of these pyridinium quaternary salts are desir
by 'weight of coccidiostat are very satisfactory. The active
ably or advantageously administered to poultry by way of
compound is normally dispersed or mixed uniformly in
the drinking water of the birds. This method of treatment
the diluent but in some instances may be sorbed on the 60
is often employed in the therapeutic use of our compounds
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
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. Alter
supplement for each ton of ?nished feed, the preferred 65 natively, water-soluble powders may be prepared, in which
concentration of any one of our coccidiostats in a feed
supplement is partly a function of the level of active in
gredient desired in the ?nished feed.
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 concentra~
Examples of typical feed supplements containing a
pyridinium quaternary salt dispersed in a solid inert 70 tion of coccidiostat, and preparations containing from
1-25 % by weight of active ingredient are suitable.
carrier are:
Lbs.
EXAMPLE 1
A. I-(Z-methyl - 4 - amino - 5 ~ pyrimidylmethyl)-4
To
25
ml.
of
Z-methylpyridine
(e-picoline) was added
methyl pyridinium chloride hydrochloride-" 6.0
Wheat standard midlings _________________ __ 94.0 75 a solution of 20 grams of 2-methyl-4-amino-5-pyrimidyl
3,065,132‘
methyl bromide dihydrobromide in 100 ml. of methanol.
EXAMPLE 4
The pyridiniurn quaternary salts set forth in Table I
below were synthesized utilizing processes described in
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
preceding examples.
Table I
lYlHz. 2HX
I!“
/\
N
H~UHzX +
HgC-k\N/
Cpd. N o.
R‘
R5
N/
NH3+
—R4——>
N
R2 R3
R?
R3
R6
_
‘ CHz-N
R5
R6
——~R4 2X
|
Hack\N
R4
R5
/
R2 R3
X
Quaternary Melting Percent
Point
11
By Method
° 0.
Feed “
of Ex. N o.
Prepared
(dec.)
1
2
l
1
1
2
l
l
2
1
233-234
256-257
274
269
218
234
235
254
269
219
0. 006
0. 006
0. 05
0. 025
0.006
0. 006
0. 0125
0. 003
0. 003
0. 006
1
1
l
3
275
236
240
208
3
256
0. 05
O. 0125
0. 0125
0. 003
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
They were fed ad libitum a standard laboratory basal ration in which
graded levels of the pyridinium quaternary salt were intimately dispersed 0r blended. Normal
and infected control birds were fed basal ration containing no quaternary salt. On the second
(lay of test, the chicks were each orally inoculated with 50,000 sporulated oocysts ot' Eimeriw
tcnella. Papers under the cag es were examined on the sixth, seventh and eighth days of assay
cages with wire ?oors.
for the presence or absence 0 5 bloody droppings. A score of 0 was given if no bloody spots
were observed; scores of 1 , 2 or 4 were assigned for 1-3, 4-6 and >6 bloody spots, respec
tively.
On the eighth day of assay, the surviving birds were weighed, sacrificed and examined
grossly for cecal coccidiosis lesions. Normal ceca were scored
0, and ceca with detectable,
moderate or maximal lesions were scored 1, 2 and 4, respectively. When a bird died and cecal
coccidiosis lesions were present, a score of 5 was recorded.
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 com
pound 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
?ltration, washed with two 20 ml. portions of cold absolute
ethanol and dried. The small white crystals of 1-(2-meth
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
yl-4-amino-5-pyrimidylmethyl)-2-methylpyridinium bro~
mide 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 pyri
The coccidiostatic activity of two of the pyridinium
compounds of the invention was determined by the fol
lowing 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.
dinium chloride hydrochloride crystallized. This salt was 60
Other groups of ten chicks each were fed a similar
dissolved in 2 ml. of concentrated hydrochloric acid and
mash diet which contained no coocidiostat. These were
the solution slowly diluted with 40 ml. of acetone. The
also infected after 24 hours ‘and served as positive or
salt crystallized and on drying melted to 256-7° C. (deo).
infected controls. As positive controls, two to four
‘groups of ten chicks each were employed. Still other
EXAMPLE 3
0; Or groups of ten chicks each were fed the mash free of
coccidiostat and were not infected with coccidiosis.
To 7.5 parts of 2-methyl-4-amino-S-pyrimidylmethyl
bromide dihydrobromide in 50 parts of acetonitrile was
added 9 parts of 2,3-dimethyl pyridine. The mixture
These served as normal controls.
The diets were administered to the chicks for eight
days following the date of infection. At the end of
warmed and became clear. Shortly, l-(2-methyl-4-amino 70 this time, the infected birds still living were sacri?ced.
5 - pyrimidylmethyl) - 2,3 - dimethyl pyridinium bromide
The oocyst count was determined by a microscopic ex
hydrobromide began to crystallize. The crystals were
amination of the cecal homogenates.
collected after standing overnight, and recrystallized from
The results employing the indicated amounts of qua
50 parts of methanol and 150 parts of acetone, melting
ternary salt, and expressed as mean values, are set forth
point 208° C. (dec.).
75 in Table II.
3,065,132
Percent
Com-
Compound
pound
In Feed
8
4-amino-5-pyrimidylmethyl)-2-methyl pyridinium halide
hydrohalide.
Table 11
Percent
Mortality
6. An animal feedstuif having dispersed therein from
about 0.005% to about 0.05% by weight of 1-(2-methyl
No. of
Percent Oocysts
Weight X 10-s In
Gain
Surviving
4-amino-5-pyrimidylmethyl)-2-methyl-5-ethyl pyridinium
chloride hydrochloride.
Animals
7. A composition comprising an inert edible carrier
1 - (2 - methyl - 4 - amino — 5-
pyrimidylmethyl)
82
having dispersed therein a member of the class consisting
8
-
0. 003
0
78
methyl pyridinium bro-
0.006
0
Q6
3
0.0125
0
97
<0.1 10
-me
y
2
O
1 made hyglllrtibromide ______ _-
-
0. 0015
-4-amino-5-
-
'1
pyrimidylmethyl) - _2‘ -
8‘
niethylhi 5 ethlyll gyrnlililn-
0' 00B
0
97
<0‘ 1
ride ______________________ __
0. 0125
0
100
<()- 1
iumcorie
yoeo-
'
Infected Controls- _
Normal Controls _____________________ __
lg
19
0g
.
'
40
63
0
0
90
________ __
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
15 addition salts thereof.
8. A poultry feed supplement composition that com
prises a poultry feed additive having dispersed therein
Any departure from the above description which con
‘from about 1% to about 40% by weight of a member
forms to the present invention is intended to be included
of the class consisting of 1-(2-methyl-4-arnino-5-py
within the scope of the claims.
20 rimidylmethyl)-2-methyl pyridinium quaternary salt and
What is claimed is:
l - (2-methyl-4-amino-5-pyrirnidylmethyl)-2-methyl pyr
1. A poultry feed supplement composition that com
idinium quaternary salt having a lower alkyl group at
prises an edible carrier having dispersed therein from
one of the 3-, 4- and 5-positions of the pyridine ring,
about 1% to about 40% by weight of a quaternary coin
wherein the anion of the quaternary salt is a non-toxic
pound of the formula
25 anion; and non-toxic acid addition salts thereof.
9. A poultry feedstuii containing as an active anticoc
cidial ingredient a member of the class consisting of l-(2
methyl-4-arnino-5-pyrimidylmethyl)-2-methyl pyridinium
30
quaternary salt and l-(2-methyl-4~amino-5-pyrimidyl
methyD-Z-methyl pyridinium quaternary salt having a
lower alkyl group at one of the 3-, 4- and 5~positions
wherein R is methyl, and X is a non-toxic anion.
2. A composition useful against coccidiosis that com
of the pyridine ring, wherein the anion of the quaternary
salt is a non-toxic anion; and non-toxic acid addition
salts thereof.
prises an edible carrier having intimately dispersed there
10. The composition of claim 9 wherein the feedstuff
in from about 1% to about 40% by weight of a 1—(2 35 contains from about 0.005 % to about 0.05% by weight
methyl-4-arnino-5-pyrimidyhnethyl)~2-rnethyl pyridiniuni
quaternary salt, wherein the anion of the salt is a non
toxic anion.
3. A composition useful against coccidiosis that com
prises 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 py
ridinium chloride hydrochloride.
4. A composition useful against coecidiosis that com
prises 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 py
ridinium halide hydrohalide.
5. An animal feedstutf having dispersed therein from
about 0.005% to about 0.05% by weight of l-(2-rnethyl
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-methyl—4-amino-S-pyrimidylmethyl)~2
methyl pyridinium quaternary salt and l-(2-rnethyl-4
amino-S-pyrimidylmethyl)-2-methyl pyridinium quater
nary 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.
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