CA1092027A - Method of combatting swine dysentery - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE Compositions and method for combatting swine dysentery using substituted quinoxaline represented by the formula: where R is hydrogen or lower alkyl of 1 to 5 carbon atoms, e.g., methyl and pentyl, are provided.

Description

lO9~Z7 This invention relates to compositions useful for, -and a method of, combatting swine dysentery. In a particular '~
aspect, this lnvention relates to a method of combatting swine dysentery by administration to swine, exposed or likely to be exposed to dysentery-producing organisms, a member of a class of certain substituted quinoxalines.

BACKGROUND OF THE INVENTION

Swine dysentery (also known as vibrionic dysentery, bloody scours, or hemorrhagic dysentery) is an enteric ~
disease primarily characterized by muco-hemorrhagic diarrhea `~ -with lesions usually restricted to the large intestine. The disease is worldwide and rapldly becoming the prime disease problem among swine producers in this country. ,;`
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- ` ~LO~ZOZ7 . i The earlier consensus wa~ that Vibrio coli was the pri-mary CAUS~tiVe agent. Recent evidence suggests, however, that a spirochete, Treponema hyodysenteriae is involved with ~.
the disease and may in fact be the primary etiologic agent.
Currently, control measures are based on constant feed~
ing of antibacterial agents with therapy based on~use-of higher .
levels of these drugs. Such drugs include furozolidone, neo- . .
mycin, oxytetracycline, tylosin, carbadox, virginiamycin and arsanilic acid. Unfortunately these drugs give erratic re-sults, even when used at abnormally high levels. .
Accordingly there is a continuing need for new drugs of . ..
low toxicity and high potency to combat swine dysentery.

. SUMMARY OF THE INVENTION
It is an object of this invention to provide a composi-tion or, and method of, combatting swine dysentery.
It is another object of this invention to provide a method of co~batting swine dysentery by prophylatic or ~ :
therapeutic administration of a substituted quinoxaline. : - -It is a further object of this invention to provide a ~;
composition for, and method of, combatting~swine dysentery by. ~;
the prophylatic or therapeutic administration ~f a substituted . .
quinoxaline which selectively combats the swine dysentery- `
causing organisms without deleterously afecting the balance of other organisms desired in an environment, e.g., in the ;
internal biological system of swine, e.y., the intestinal flora.
Other objects will be apparent to those skilled in the ~.
art from the disclosure herein. .
It is the discovery of this invention to provide a compo-, .:: .
sition for and meth~d of combatting swine dysentery by admin-30 isteriny to ~nimals likely to be exposed to dysenteryeproducing . e2-. .

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organisms, or to ani~als suffering from the disease, a sub-stituted ~uino~aline (hereafter the "C-Compounds") dioxide ;
represented by the for~ulà:

N~2 'I`` I ~
N ~ ~ ~ `

~ ~ CH=CH ~ H

wherein R is hydro~en or lower alkyl of 1 to 5 carbon atoms, e.g. methyl, ethyll propyl, butyl, pentyl, and the like.
The compounds are especially useful for prophylactic adminis-tration prior to development `o symptoms of dysentery. `

DET;~ILED DISCLOSURE
According to the method of the p~esent invention, a C-. .
Compound(s) is administered to swine in amounts effective to ~`
combat dysentery. It can be advantageously~incorporated in a -swine ration to provide a swine feed composition for combat- ;
ting dysentery; in this aspect, it can be incorporated in the swine ration~i generally at a level of from about 25 g/ton to about 500 g/ton. The preferred level, however, particularly in the absence of the disease, is about 100 to 200 g/ton for prophylaxis, advantageously for a period of 3 to 21 days.
However if there has been an outbreak of the disease, or if new animals whose history is not known have been introduced ;~
into a herd, the higher level of 200 to 500 g/ton is preferred until the health of the herd is assured. Generally, however, the prophylatic treatment is continued until the animals are ready for market. The C-Compounds can also be administered by incorporation into drinking water provided for sw:ine.
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The compounds useful in the practice of the present invention include but are not limited to ``
C0-1 2-[2-(2-amino 4-pyrimidinyl)ethenyl]-quinoxaline 1,4-dioxide and C0-2 2-[2-(2-amino-6-methyl-4-pyrimidinyl)ethenyl]-quinoxaline 1,4-dioxide.
These compounds may be prepared by reacting, advantageously in an approximately 1:1 mole ratio, quinoxaline di-N-oxide-2-carboxyaldehyde dimethylacetal and a compound represented by the formula /~ , .
N N
H3C ~\ ~ R

wherein R has the same meaning as defined above.
The reaction may advantageously be conducted in the presence of a strong acid catalyst and a suitable solvent, e.g., a lower alkanoic acid such as formic acid or acetic acid. The rPaction takes place at reaction temperatures sufficient to effect the reaction and these temperatures can range from ambient, e.g., 0C to elevated temperatures, e.g., 80C, or more and preferably, e.g., at from about 25 to 50C. or more. When the reaction is complete, e.g., after about 10 to 24 hours, the product may advantageously be recovered by crystallizing it from water. Suitable strong acid catalysts -may be any strong acid known in the art. Suitable strong acids include hydrochloric, hydrobromic, sulfuric, nitric, aryl sulfonic acids, e.g., toluene sulfonic acid, trichloro-acetic acid, etc. The acids may be generally used in a ratio of about 0.5-2 moles of acid per mole of quinoxaline starting compound.
The quinoxaline di-N-oxide-2-carboxyaldehyde dimethyl-acetal used as a starting material is known in the art. It can be prepared according to the procedure of Haddadin et al.

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The pyrimidine compounds used as starting materials are similarly known in the art. They are commercially available and the usual commercial grade is suitable. Perferably they ~ ishould be of good quality, free from deleterious material. ~
The C-Compounds are useful for combatting swine dysentery- -causing organisms, e.g., dysentery caused by Vibrio or Treponema organisms, or both. The C-Compounds are of a low order of toxicity and are suitable for use by oral administration for prophylactic or therapeutic treatment of dysentery.
A swine feed ration for oral administration of C-Compounds according to this invention can be readily prepared by inti-mately admixing a C-Compound alone or as a premix with a conventional swine feed composition to provide a homogeneous ~ `
feed product. -The term feed rations is intended to mean the food pro-vided for the swine, and it is not intended that the invention be limited thereby. Preferably a C-Compound is thoroughly mixed with the feed ration so that it is uniformly dispersed throughout. However it is also contemplated that it could be sprinkled on the dàily food supplies in the form of a powder or as pellets. Thus it is not intended that the inven-tion be limited to any particular mode of administration.
The invention will be better understood with reference -to the following examples. It is understood however that the examples are intended for illustration only and it is not intended that the invention be limited thereby.
Example 1 To a reaction vessel there was added 15 ml of 99% formic acid, 1.15 g of 96 sulfuric acid, 1.09 g (0.01 mole) of 2-~''' - - 5 - ~;

9;~z7 amino-4-methyl pyrimidine, and 2.36 g (0.01 mole) of quino-xaline -di-N-oxide-2-carboxyaldehyde dimethylacetal. The mixture was heated to 45-50C. and maintained at that temper-ature for 10 hours. It was then cooled, diluted with 35 ml of cold water and the pH was adjusted to about 5 with sodium bicarbonate. A yellow, crystalline precipitate was formed.
It was filtered and washed with water. There was obtained in 64% yield 1.8 g of 2-[2-(2-amino-4-pyrimidinyl)-ethenyl]
quinoxaline 1,4-dioxide, m.p. 237-239C. with decomposition.
This product, designated CO-l for convenience, was -tested against five strains of Vibrio cholerae at concentrations of 10, 30 and 100 micrograms per milliliter. The results are given in table 1.
Tests were also run to see if the compound was effective against Vibrio cholerae ~l Tor Ogawa 6 in the presence of sewage. Sewage samples were obtained from the sewer system of the city of Modena, Italy. They were centrifuged to sep-arate solids and the supernatant liquid was used in the tests.
The results are given in table 2.

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Table 2 , Sample Concentration _ Effect After of CO-l 24 hrs. 48 hrs. 5 days .. ... .. ... . .. . . . . . ...... . . .. .
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lO9ZOZ7 At 10 ~g/ml of CO-l there was no growth of 3 of the organisms after 48 hours, and only marginal growth of the remaining two at 100 ~g/ml. ..
CO-l was tested in vitro against Treponema _~_ ysenteriae ;
by a known method. The minimum inhibitory concentration ~the lowest concentration of compound in a dilution series "~
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where grow-th is in~ibited) was Q.l ~g/ml. The minimum bac~ .. :
teriocidal concentration (the lowest concentration o~ compound :
in which no viable treponemes are observed upon dilution and .. :-subculture from the broth onto blood agar plates) was grea~er - ~ . -than 0.1 ~g/ml but less than 1 ~g/ml. .
The compound was tested for acute toxicity by several -. .--.
modes o administration in four species, nameIy mice, rat, .~. ~
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guinea pig and rabbit. The compound was found to be of a low j. : - . .
order of toxicity. The test results are given below in tables ~i..
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Table 3 . Acute ToXicity of CO-l in.Female Mice .
,: , ~osage, Dead/Treated Animals after ~ ~ .
20~g/kg l day . 2 day.s 4 days 7 days Endoperitoneal Administration .::
2000 6/6 6/~

500 6/12 ~
250 0/18 . .
Esophageal Administration ~:.
O(x) 0/6 .
4000 1/12 1/12 ~i 301000 0/12 .. .
(x) By gas~ric gavage and receiving only the vehicle.

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Acute~Toxicity of CO-l' in the Guinea Pig - . ' ' By Esophageal Administration :'" ~ ."
Dosage, Dead/Treated within 21 days - .:.
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- . Table' 6 Ac'ute Toxi'city ~of C,O-l in~he Rabbit 'By Esopha'geal ~dmin:istration Dosage,Dead/Treated Body Weight in g. :(m+SE~ , :
mg/kg'-wi'thin 7 days Start : Termination. : .
2000 '0/2* 2250-2150 ~ '~2180-2140 .' ', 1000 0/4 ' 2037+104.3 1922.5~71.5 '. ,.
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500, .' '., 0/2 , 2000-2100 165~-1550 :' ' ' (x) Only the vehicle was administered.
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~L09Z(~27 -~~ In view of the favo~able acute toxicity data, the com-pound was administered orally in sub-acute, but rela-tively large doses, to mice and rats for 15 days. Data were collected on the effects on death rate, weight, liver and kidneys. The data are given in Tables 7 and 8. `

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, Subacute Toxic-ty of CO-l in Female Rats ~ ~.
Daily Dose: 2 g~kg/day of CO-1 by gastric gavage for 21 days.
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Oral I`reàtmentDead~: Body ~leight in g-(m+SE) ~, '': Treated' ''' Start -' ' Ter~ination Vehicle2/6(x) 200.0~4.1 233.2+5.1 - .
CO-l, 2 g~kgjday 1/6(x) .204.1+2.0 - 210.6+9.6 .
(x) Death caused by a mistake in esophagus incannalu- -tation. This diagnosis was confixmed at the .
post-mortem examination. ~
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Daily Dose: 2 g/kg/day of CO-l by gastric gavage for 21 days. . ..
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Oral Average Percent We'ight of Fresh Organs (m+SE) Treatment ' Lung ' ' - LiVer~ ' ~. Kidneys Vehicle '. . 0.8$+0.06 3.~5+0.07 0'.95~0~04 (3 animals) .; :
CO-l - 1.07i0.09 N5 4.54~0.10 NS(x) 1.04+03 NS `~
~5 animals? '. ,,... ,....... . ' - ' '' ' ' (x) Death caused'by a mlstake in esophagus incannalutation. . ,~
This diagnosis was confi~med at the post-mortem.examina- ~
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In view of the favorable sub-acute toxicity, the chronic ~ ' toxicity in female mice was studied. The results are given in ' :
Table 9.

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~' Table 9 Chronic Toxicity in the E~emale ~ouse Daily treatment by gastric gavage for 18 weeks (4.5 months) ' . ~ ' a. Mortality and Bod~ Weigh-k Oral Treatment Dead/ Body Weight in g (m~SE) Treated Start Termination -Vehicle 3/10 28.2+1 33.0~
CO~l, 500 mg/kg/day 2/10 30.4+0-9 30.b-~0.7 CO~l, 250 mg/kg/day 0fl0 27.3+0.5 26.7~0.7 -b. Urine excretion. Urine amount excreted by 6 animals in 6 hours `
Oral Treat~ent - Urine Amount (ml) -~,;, Controls 6 -CO-l, 500 mg/kg/day 7 CO-l, 25C ~g!ky/day _ 6.5 .... ~ .
c Blood glucose. Mean values for 6 animals. Blood samples were taken 24 hours after the last dose Oral Treatment _ Blood Glucose Controls - 1.14 CO-l, 500 mgjkg/day 1.06 ;
O-l, 250 ~g/kg/day _ 1.10 0 d. SGPT and SGOT. Mean values for 6 animals. Blood samples Were ~aken 24 hours after the last dose Oral Treatment Units/ml SGOT SGPT
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Controls 125 5 CO-l, 500 mg/kg/day 159 6 CO-l, 250 mg/kg!day 118 5 ~;

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1~9Z027 - In view of the favorable results on chronic toxicity, a teratoyenetic study was conducted with male and female mice and rats. The number of young delivered live at birth was comparable with controls.` No malformations in either yroup were observed. The data are given in Table 10.

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Example 2 Compound CO-l is mixed with swine rations at a level of 200 g/ton and is fed to swine housed in an area where there has been a previous outbreak of swine dysentery~ The members of the herd remain free from symptoms during the duration of their stay. Another herd is housed in a similar area where there has been a previous outbreak of dysentery.
They are fed the same rations as the first herd but with no CO-l or other drug. Many members of the herd develop symp- `
toms of dysentery. CO-1 is then mixed with the rations at a level of 400 g/ton. The spread of the disease is halted and the diseased members become free from symptoms.
Example 3 To a reaction vessel there was delivered a solution of 1.15gof96% sulfuric acid dissolved in 25 ml acetic acid, 1.23 g (0.01 mole) of 2-amino-4, 6-dimethyl pyrimidine and 1.9 g (0.01 mole) of 2-formyl-quinoxaline-di-N-oxide. The mixture was heated at 40C. for 16 hours, then cooled, di-luted with water and adjusted to pH 5 with sodium bicarbon- ~
ate solution. The resulting yellow, crystalline precipi- ~;
tate was filtered and washed to give, in 71% yield, 2.1 g of 2-[2-(2-amino-6-methyl-4-pyrimidinyl)-ethenyl]-quinoxaline ~;
1,4-dioxide which melted with decomposition at 240C. This product, designated C0-2 for convenience, was tested against the five strains of Vibrio cholerae as described in Example 1.
The results were given in table 1. There was no growth after 48 hours of 3 of the organisms at 10 pg/ml of C0-2, only marginal growth of the remaining two at 100 pg/ml.

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~IL09Z(~27 Compound C0-2 is tested a~ains~ Treponema hyodysenteriae as described in Example 1. The minimum inhibitory concentra- ~ !
tion is about 0.1 ~g/ml and the minimum bacteriocidal con- ~;
centration is less than 1.0 ~g/ml.
Compound C0-2 is tested for toxicity in the same manner as described for C0-1 in Example 1. Comparable results are obtained showing that the compound is suitable for prophylactic or therapeutic treatment of swine dysentery.

Example 4 Compound C0-2 is mixed with swine rations at a level -of 200 g~ton and is fed to swine housed in an area where there has been a previous outbreak of-swine dysentery. The members of the herd remain free from symptoms during the duration of their stay. Another herd is housed in a simi- ;
lar area where there has been a previous outbreak of dysen-., tery. They are fed the same rations as the first her~d but with no CQ-2 or other drug. Many members of the herd de- -velop symptoms of dysentery. C0-2 is then mixed with the - ~ :
rations at a level of 400 g/ton. The spread of the disease is halted and the diseased members become free from symptoms. ~ ~ -EXample 5 Swine rations typically contain a protein content rang-ing from about 12 to 18 percent protein on a weight basis.
Table 11 sets forth examples of starter, grower and finisher swine rations.

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Starter Grower Finisher (.30-75 lb)l (.75-130 lb)l ~130-220 lb) Ground Corn ~21478 lb 1620 lb 1697 lb SBOM, 44% 454 324 257 ;~
Dicalcium Phosphate 20 18 14 Ground Limestone23 17 15 Iodized Salt 20 8 7 ..
Vitamin Premix2 3 10 8 5 :
Trace Mineral Mix 5 5 5 .
1 Weight of Pig- -~

2 Vitamin Premix ;;~
Vitamin A (30,000 IU/gm) iooo gm Vitamin D3 (200,000 IU/gm~ 20 gm .
*BY-24 ~Riboflavin) 300 gm CaPantothena-te, 45~150 gm Niacin, 98~ 200 gm *Choline 25 4600 gm ~ :
*Proferm 20 (Vit. B12)3600 gm *Perma E (20,000 IU/lb.-Vit. E) 2270 gm Biotin 1 gm ;~
Ground Corn 33129 gm TOTAL45360 gm (100 lb.) :
. . .

3 Trace Mineral Premix CCC Trace Mineral4536 gm Zinc Oxide 600 gm 5136 gm Ground Corn 17544 gm TOTAL22680 gm (50 lb.) * Tradenames '.
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'. ., .' To one ton of the preceding grower ration is added 200 ~rams of compound C0-2 by the following procedure: 200 :
grams of C0-2 are mixed with a five pound aliquot of the rakion, which in turn is successively mixed into or with larger aliquots until th~ C0-2 is essentially uniformly mixed with the whole ration which is a feeding composition. The feeding composition so prepared supplies 200 grams of compound C0-2 per ton of finished ration.
The same procedure is essentially foilowed to provide starter and finisher rations containing CO-2. . .

. EXample 6 , CO-l compound is advantageou~ly administered to swine by incorporating it in drinking water provided for swine in swine dysentèry-inhibiting amounts, gener~lly these amounts are of about 25 to 500 parts per million of water, for in-. ~. . . .
stance from about 25 to 200 parts per million for prophylaxis and 200 to 500 parts per miLlion for therapy.

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Claims (20)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A composition comprising, as an active ingredient, a swine dysentery-inhibiting amount of a substituted quinoxaline represented by the formula where R is hydrogen or lower alkyl, in admixture with a suitable carrier or diluent therefor.

2. The composition of claim 1 where R is hydrogen.

3. The composition of claim 1 where R is methyl and the composition contains swine dysentery-inhibiting amounts of the quinoxaline active ingredient.

4. The composition of claim 1 which is in the form of a swine feed composition providing a nutritional source for swine.

5. The composition of claim 4 wherein the nutritional source is a swine ration containing from about 12 to 18 percent by weight protein and the quinoxaline is incorporated in the feed at a level of from 25 to 500 g/ton.

6. The composition of claim 5 wherein the level of said quinoxaline is from 100 to 200 g/ton.

7. The composition of claim 5 wherein the level of said quinoxaline is from 200 to 500 g/ton.

8. The composition of claim 4 where the quinoxaline active ingredient is represented by the said formula wherein R is hydrogen.

9. The composition of claim 5, 6 or 7 where the quinoxaline active ingredient is represented by the said formula wherein R is hydrogen.

10. The composition of claim 4 where the quinoxaline active ingredient is represented by the said formula wherein R is methyl.

11. The composition of claim 5, 6 or 7 where the quinoxaline active ingredient is represented by the said formula wherein R is methyl.

12. The composition of claim 1 which is in the form of a premix composition suitable for use as an addition to, or as part of, a swine feed composition.

13. The composition of claim 1 wherein the diluent or carrier is a solid.

14. The composition of claim 1 wherein the diluent or carrier is a liquid.

15. The composition of claim 14 wherein the liquid is water.

16. The composition of claim 15 wherein the quinoxaline active ingredient is incorporated in drinking water provided for and consumed by swine in swine dysentery-inhibiting amounts.

17. The composition of claim 16 wherein the amounts range from about 25 to 500 parts per million of water.

18. The composition of claim 16 wherein the amounts range from about 25 to 200 parts per million.

19. The composition of claim 16 wherein the amounts range from 200 to 500 parts per million.

20. The composition of claim 12, 13 or 14 wherein the quinoxaline active ingredient is represented by the said formula wherein R is hydrogen or methyl.