IE44807B1 - Method for combatting swine dysentery - Google Patents

Abstract

Process for obtaining substituted quinoxalines, of formula (* see image I), in which R is hydrogen or lower alkyl.

Description

This invention relates to compositions useful for, and a method of, combatting swine dysentery. In a particular aspect, this invention 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.

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 rapidly becoming a prime disease problem for swine producers.

The earlier consensus was that Vibrio coli was the urinary causative 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 feeding of antibacterial agents with therapy based on use of higher levels of these drugs. Such drugs include furazolidone, neomycin, oxytetracycline, tylosin, carbadox, virginiamycin and arsanilic acid. Unfortunately these drugs give erratic results, 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. · It is an object of this invention to provide a composition for, and method -2-44807 of, combatting swine dysentery.

It is another object of this invention to provide a method of combatting 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 prophylactic or therapeutic administration of a substituted quinoxaline which selectively combats the swine dysenterycausing organisms without deleterious ly affecting the balance of other organisms desired in an environment, e.g., in the internal biological system of swine, e.g., 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 composition for and method of cambatting swine dysentery by administering to animals likely to be exposed to dysentery-producing organisms, or to animals suffering from the disease, a substituted quinoxaline (hereafter the “C-Compounds) dioxide represented by the formula: wherein R is hydrogen or lower alkyl of 1 to 5 carbon atoms, i.e. methyl, ethyl, 2o propyl, butyl, pentyl. The compounds are especially useful for prophylactic administration prior to development of symptoms of dysentery.

According to the method of the present 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 -3, 448°17 combatting dysentery; in this respect, it can be incorporated in the swine rations generally at a level of from about 25g/ton to about 500g/ton. The preferred level, however, particularly in the absence of the disease, is about 100 to 200g/ton for prophylaxis, advantageously for a period of 3 to 21 days. However if there has g 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 500g/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 swine.

The compounds useful in the practise of the present invention include but are not limited to CO-1 2 - (2- (2 - amino - 4 - pyrimidinyl)ethenyl) - quinoxaline 1,4 dioxide (this same compound was designated in the first of the U.S. Patent applications from which priority is claimed 2-(2 - amino - 6 - methyl - 4 - pyrimidinyl) ethenvl) - quinoxaline 1,4 dioxide (this same compound was designated in the first of two U.S. Patent applications from which priority is claimed as 2-(2-(2- mino - - methyl - 5 - pyrimidinyl)ethenyl) - quinoxaline 1,4 - dioxide).

These compounds can 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 wherein R has the same meaning as defined above. -44480? The reaction is advantageously 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 reaction takes place at reaction temperatures sufficient to effect the reaction and these temperatures can range from ambient, e.g. Οθ C. to elevated temperatures,,e.g., 80° C. or more and preferably, e.g., at from about 25° to 50° C. or more, when the reaction is complete e.g., after about 10 to 24 hours, the product is advantageously recovered by crystallizing it from water.

Catalysts suitable for the practise of this invention are generally known as strong acids and any strong acid known in the art can be used. Suitable strong acids include but are not limited to hydrochloric, hydrobromic, sulfuric, nitric, aryl sulfonic, e.g., toluene sulfonic acid, trichloroacetic acid, etc. The acids are 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 for preparing the compounds of the present invention is known in the art. It can be prepared according to the procedure of Haddadin et al., British Patent 1,305,138, Example XIII.

The pyrimidine compounds used as starting materials are similarly known in the art. They are commercially available and the usual commercial grade is suitable. Preferably they should 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 intimately 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 provided 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 -5throughout. However it is also contemplated that it could be sprinkled on the daily food supplies in the form of a powder or as pellets. Thus it is not intended that the invention 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 9955 formic acid, 1.15 g of 9655 sulfuric acid, 1.09 g (0.01 mole) of 2 - amino - 4 - methyl pyrimidine, and 2.36 g (0.01 mole) of quinoxaline -di - N - oxide- 2 - carboxyaldehyde dimethylacetal. The mixture was heated to 45-50° C. and maintained at that temperature 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 l. 8 g of 2 -)2.- (2- amino - 4 pyrimidinyl) - ethenyt/ quinoxaline 1,4 - dioxide, m. p. 237-239° C. with decomposition (this same compound had been designated in the first of the two U.S. Patent applications from which priority is claimed as 2 ./2 -(2 - amino - 3- pyrimidinyl) - ethenyl/ quinoxaline 1,4 - dioxide.

The product, designated CO-1 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 together with some corresponding results from Example 3. . .

Tests were also run to see if the compound was effective against Vibrio cholerae El Tor Ogawa 6 in the presence of sewage. Sewage samples were obtained from the sewer system of the city of Moderna, Italy- They were centrifuged-to separate solids and the supernatant liquid was used in the tests. The results are given in Table 2. -6448 07 Same degree of growth as in untreated control experiments.

TABLE 2 Effect After Sample Concentration of C0-1 24 hrs. 48 h.rs. 5 days Control + Vibrion +++ +++ +++ Sewage ..- — — — Sewage + Vibrion - +++ +++ +++ Sewage_+ Vibrion 5y/ml — — Sewage + Vibrion lOy/ml — — — Sewage + Vibrion 20y/ml — — Sewage + Vibrion 30y/ml — — At lOpg/ml of CO-1 there was no growth of 3 of the organisms after 48 hours, and only marginal growth of the remaining two at 100 pg/ml.

CO-1 was tested in vitro against Treponema hyodysenteriae by a known method.

The minimum inhibitory concentration (the lowest concentration of compound in a dilution series where growth is inhibited) was 0.1 jug/ml. The minimum bacteriocidal concentration (the lowest concentration of comoound in which no viable treponemes are observed upon dilution and subculture from the broth onto blood agar plates) was greater than 0.1 jjg/ml but less than 1 jug/ml.

The compound was tested for acute toxicity be several modes of administration in four soecies, namely mice, rat, guinea pig and rabbit. The compound was found to be of a low order of toxicity. The test results are given below in tables 3, 4, 5 and 6. -8TABLE 3 Acute Toxicity of CO-1 in Female Mice Dead/Treated Animals after Dosage, mg/kg 1 day 2 days 4 days 7 days Endoperitoneal Administration 2000 6/6 6/6 1000 6/6 6/6 500 6/12 250 0/18 Esophageal Administration (x) 0/6 4000 1/12 1/12 2000 0/12 1000 0/12 (x) By gastric gavage and receiving only the vehicle. -907 V) ro x c+ 3· O < Φ 3* —j· O «w O £ Oi V) 0) CU i-ι m mm 3 3 w vr rt- c+ Ο O -s -Ϊ-3Τ3 03 03 S’3“ Ό Ό 0» W Φ O IQ © ·$ -s· ro ro -I· -J. ro P ct· <+ ** —* O O 3 3 ro ro βί ro i-ι t—i m m 3 3 (/) -(/) c+c+O O *? too 0ί βί 3*3* T3 Ό βί 0» ro ro © to -5 “5 ro ro w. -ι. βί OJ C+ t+ —* o o 3 3 ro ro o> 0) u»33 3 O -i. c (/) Ctrl- ro. ro o (+ rt) to ro o o CL m X Ό ro rt· 3* Φ < ro 3* m m m m m m mm 333 3 0)(/)(/)(/) CUO.Q.O.O Ο Ο O Ο Ο O ΟΌΌΌ© οόόό 3* 3· 3*3· rorororororororo -$ ι -S *?©©©© -j. •j· —>· φ ro ro ro rt· rt· c+ c+ ro ro ro ro oooo —j—i—*—» 3 3 3 3 ro ro ro ro ro ro ro ro > o. s & -j. o -s o ro -h rt· tn o o o _ oo © © S? .->4* tn cn ο o oooo oooo £ O ->.ro c+- ro. TO.

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-TO O o 4ϋ O o JS. .0» -Ρ» 4* ro ro ro ro —»ro ro ro o o to to oo o w to -ο σι o -P* © —j to -> uirooororo*4tn I+I+I+I+I+I+W- + 4^couicnto4^to—* ......* to to -4 *4 ro © ro -u · co rorototororotoro ui co no -j to to —* co toai4^4*oco-^co uiootooroo-M 1+((+1+1+1 + + + -4 ro co —· —* -j o —* • *4· ©ΟΓΟ· CO •siro*4· · · · • tour—> oo £ o -J. o c+ro 3* Δ. —i . -t roro -U£U rt· 0-0 ro a. $ -J. CO 3 © ,CL © << ro © ·* 3· rt- <+ ro 1? 3 W ro m c+ 3X to -j. © to -»· e+ -h ro +<+ n Acute Toxicity of GO-1 in the Rat '-IO» **8θγ TABLE 5 Acute Toxicity of CO-1 in the Guinea Pig By Esophageal Administration Dosage, mg/kg Dead/Treated within 21 days 500 0/4 1000 1/4 2000 5/6 4000 6/6 ο (χ) 0/13 (x) Only the vehicle was administered.

TABLE 6 Acute Toxicity of CO-1 in the Rabbit By Esophageal Administration Dosage, mg/kg Dead/Treated within 7 days Body weight in g. Start m + SE) Termination 2000 0/2* 2250-2150 2180-2140 1000 0/4 2037 + 104.3 1922.5 + 71.5 0 (X) 0/4 2135 + 75 2262 + 215 500 0/2 2000 - 2100 1650 - 1550 (x) Only the vehicle was administered.

* There were two dead out of seven treated animals, within 4 days.

In view of the favourable acute toxicity data, the compound was administered orally in sub-acute, but relatively 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. -11TABLE 7 Subacute Toxicity of CO—1 in the Mouse Daily Dose: 500 mg. CO-1 By gastric gavage for 15 days.

Oral Treatment Dead/Treated % Body Height Change (m+SE) Fresh. Organ-to-Body Height Ratio Liver Kidneys Vehicle 0/10 20.4 + 4.2 5.2 + 0.2 1.4 + 0.1 CO-1; 500 mg/kd/day 0/10 -8.1 + 3.9 5.3 + 0.3 1.5 + 0.1 a. Mortality and Body Weight Daily Dose: 1 g/fcg/day for 15 days. - - Oral Treatment Dead/Treated jS Body Height Change Vehicle (HgO) 0/12 24.54 + 0.64. CO-1 in HgO, 1 g/kg/day . 2/12 18.5 + 0.75 Vehicle (adraganth gum) (x) 0/12 25.04 + 1.18 CO-1 in adraganth gum 3/12 15.27 + 1.31 b. SGOT AND SGPT (24 hrs. after last dose).

Units/ml Oral Treatment SGOT SGPT Vehicle: Water 115 4 Adraganth gum 119 6 CO-1 in water 124 9 CO-1 in sdragan'th gum “132 10 -1244807 TABLE 8 Subacute Toxicity of CO-1 in Female Rats Daily Dose: 2g/kg/day of CO-1 by gastric gavage for 21 days.

OralTreatment Body Weight in g (ni + SE) Termination Dead/Treated Start Vehicle 2/6 (x) 200.0 = 4.1 233.Z + 5.1 CO-1, 2 g/kg/day 1/6 (x) 204.1 + 2.0 210.6 + 9.6. (x) Death caused by a mistake in esophagus incannalutation. This diagnosis was confirmed at the post-mortem examination. Daily Dose: 2g/kg/day of CO-1 by gastric gavage for 21 days. Average Percent Weight of Fresh Organs (m + SE) Oral Treatment Lung Liver Kidneys Vehicle 0.85 + 0.06 3.45 + 0.07 0.95 + 0.04 (3 animals) CO-1 1.07 + 0.09 NS 4.54 + 0.10 NS(x) 1.04 + 03 NS (5 animals) (x) Death caused by a mistake in esophagus incannalutation. This diagnosis was confirmed at the post-mortem examination.

In view of the favorable sub-acute toxicity, the chronic toxicity in female mice was studied.

The results are given in Table 9. -13J 44807 TABLES Chronic Toxicity in the Female Mouse Daily treatment by gastric gavage for 18 weeks (4.5 months) a. Mortality and Body Weight Oral Treatment Dead/Treated Body Weight in g (m + 1.1 Start Termination Vehicle 3/10 28.2 + 1 33.0 + 1.1 CO-1, 500 mg/kg/day 2/10 30.4 + 0.9 30.0 + 0.7 C0-1, 250 mg/kg/day 0/10 27.3 + 0.5 26.7 + 0.7 b. Urine excretion. Urine amount excreted by 6 animals in 6 hours Oral Treatment^-~ Urine Amount (ml) Controls 6 CO-1, 500 mg/kg/day 7 CO-1, 250 mg/kg/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-1, 500 mg/kg/day 1.06 C0-1, 250 mg/kg/day 1.10 d. SGPT and SGOT. Mean values for 6 animals. Blood samples were taken 24 hours after the last dose Units/ml Oral Treatment SGOT SGPT Controls 125 5 C0-1, 500 mg/kg/day 159 6 C0-l', 250 mg/kg/day118 5 ' -1444807 TABLE 9 (Continued) Chronic Toxicity of CO-1 in the Female Mouse e. Fresh Weights of Organs Fresh Organ-to-Body-Weight Ratio (m + SE, 4 animals) Oral Treatment Kidneys Heart Li ver Lungs Controls 0.938 + 0.044 0.481 + 0.055 4.57 + 0.15 0.674 + 0.044 CO-1, 500 mg/kg/day 1.07 + 0.04 0.47 + 0.02 4.66 + 0.91 i.on + o.no CO-1, 250 mg/kg/day 0.87 + 0.08 0.60 + 0.08 4.57 + 0.25 0.731 + 0.035 In view of the favorable results on chronic toxicity, a tertogenetic 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 group were observed. The data are given in Table 10. -1544807 o o 3 cf· CO-1 a cr X 0 0 3 ch CO-1 O “5w 3 > s: 0 3 w 3 - o fi) 3 zr 3 O a> ro ro —J ro —j tn cn 3* ch ch in cn o —1 fi) 3* ΖΓ 0 rt - 3 . ro ro 3 s ro 3 3 ro IQ fi) tn cr to fi) -fe c+ ΤΖΓ 0 ro -fe. ch TC 3 ro 0 tn pr 3 to ro 0 1 to ro -fe 3 rt tn 3 Q_ ch ro CL ch 0) tn 0) O P> << 0 rt << ch C O to fi) C Oi 3 ch << S I TZJ CL rt cn 3 ro rt -5 0) ro 3 ro 3 < ro ro to. ro , ro X to 3· 3 Ό > 3 on fej ft) ro Ch ro VO CO 3 εο •fe. 3 X tn 3 -fe •fe. 3 3 ch Ό —J —J 3 rt o o fi) -fe ro TZ) ro 0 0 fi) -fe. _j —1 3 3 3 rt in -$ ro 0 tn 3 ro 3* to ro X ro ft) ro 3 fe·* 0) ch 3 ro ch ro ch 3 ch ro CL fi> n 3 CL —* << ro «Ο ο O cr 3 O CL < ro ch —J. 3 σ cj O ro ro 2 . ro z 3 in —·* rt O O Tt o tn c vo 0 ro • ro < ch co CO < ch fi) ch 0 co ro ez O ro c Q _ tn ,3 tn rt 1 + 1 + << in ro rt £ 3 1 + IP << ro CA- r* o w Γ* _<· to’ 0 0e _4> ch 3 3 TS < _J co 3 *o < 3 ch vo Ov 1 + ro -j· PC σ\ ro -)· 3 3 IP 3 3 ch. cr cn Ό tSi to ΖΓ · ro Irt m ro *—* 0 3 cu 0 tn c C tn fi) ro __l On -4 o 03 rt -) -1. 0 CO 3 rt o zr 3 rt 0 CO ro O 00 to rt << ro P OV P ro to rt <5* ro in ro 1 + 1 + |? ch c s: ro rt c 1 + IP 1+ ch cz- T“ ro o o cn tn _>· CL 0 0 cn tn —j. n ro (Q s • • m ro to _ps tn O’ 0 0 tn 3* O vo Ch in fej cn ch O c _4 CL cr ro 3 rt 3 3 rt fi) ro ro fi) ro ch Ό ch rt C Z! ro rt c s: e? tn o ro O (fl 0 o o ~s ro ch 0 O 3 ro • 3 tn ro 3 tn fi) . o CL fi) 0 ch rt ch '£ rt ch o’ ch O O rt 3 zr ' 3 - 3· tn CL tn ro ch ro O fi) rt ro fi) ch Φ ch rt O co cl (di TO CD o c tn ro 0) ro 0) CL Teratogenetic Study •16 *4807 EXAMPLE 2.

Compound CO-1 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-1 or other drug. Many members of the herd develop symptoms 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 1.15 g of 965! sulfuric acid dissolved in 25 ml acetic acid, 1.23 g (0.01 mole) of 2 - amino4,6 - dimethyl pyrimidine and 1.9 g (0.01 mole) of 2 - formyl - quinoxaline - di15 N - oxide. The mixture was heated at 40°C. for 16 hours, then cooled, diluted with water and adjusted to pH 5 with sodium bicarbonate solution. The resulting yellow, crystalline precipitate was filtered and washed to give, in 71% yield, 2.1 g of 2 - Ui - (2 - amino-6 - methyl - 4 - pyrimidinyl) - ethenylj7 - quinoxaline 1,4 - dioxide (this same compound has been designated in the first of the 2( two U.S. Patent applications from which priority is claimed as 2 - ^T-(2-amino-3 methyl- 5 - pyrimidinyl) - ethenyljj-quinoxaline 1,4 - dioxide) designated CO-2 for convenience. It melted with decomposition at 240°C.

The product was tested against the five strains of Vibrio cholerae as described in Example 1. The results are given in:.Table 1. There was no growth after 48 hours of 3 of the organisms at 10 ug/ml of CO-2, only marginal growth of the remaining two at 100 ug/ml.

Compound C0-2 is tested against Treponema hyodysenteriae as described in Example 1, The minimum inhibitory concentration is about 0.1 ug/ml. and the minimum bacteriocidal concentration is less than 1.0 ug/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 ccmpound is -174480^ suitable for prophylactic or therapeutic treatment of-swine dysentery. ’ ‘ ι · Example 4.

Compound CO-2 is mixed with swine rations at a leyel 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 C0-2 or other drug. Many members of the herd develop 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 ranging from about 12 to percent pro te'in ori a weight basis. Table 11 sets forth examples.of starter, grower and finished swine rations. -1844807 TABLE Π Starter , (30-75 lb) 1 Grower . (75-130 lb)' Finisher (130-220 lb) Ground Corn ff 2 1478 lb 1620 lb 1697 lb SBOM, 44% 454 324 257 Dical ciurn Phosphate 20 18 14 Ground Limestone 23 17 15 Iodized Salt 10 8 7 0 Vitamin Premix4 10 8 5 0 Trace Mineral Mix 5 5 5 1 Weight of Pig.

Vitamin Premix Vitamin A (30,000 IU/gm) 1000 gm Vitamin Dg (200,000 IU/gm) 20 gm BY-24 (Riboflavin) 300 gm CaPantothenate, 45% 150 gm Niacin, 98% 200 gm Choline 25 4600 gm Proferm 20 (Vit. Β·^) 3600 gm Perma E (20,000 IU/lb.-Vit.E) 2270 gm Biotin 1 gm Ground Corn 33129 gm TOTAL 45360 gm (100 lb.) Trace Mineral Premix CCC Trace Mineral 4536 gm Zinc Oxide 600 gm 5136 gm Ground Corn 17544 gm TOTAL 22680 gm (50 lb.) -1944807 To one ton of the preceding grower ration is added 200 grams of compound CO-2 by the following procedure: 200 grams of CO-2 are mixed with a five pound aliquot of the ration, which in turn is succssively mixed into or with larger aliquots until the CO-2 is essentially uniformly mixed with the whole ration which is a feeding composition. The feeding composition so prepared supplies 200 grams of compound CO-2 per ton of finished ration.

The same procedure is essentially followed to provide starter and finisher rations containing CO-2.

Example 6.

CO-1 compound is advantageously administered to swine by incorporating it 10 in drinking water provided for swine in swine dysentery-inhibiting amounts, generally these amounts are of about 25 to 500 parts per million of water, for instance from about 25 to 200 parts per million for prophylaxis and 200 to 500 parts per million forr theraphy.

Claims (26)

CLAIMS 4 48θγ

1. A method of combatting swine dysentery comprising the prophylactic or therapeutic administration of a compound represented by the formula: N wherein R is hydrogen or lower alkyl.

2. The method of claim 1 wherein R is hydrogen.

3. The method'of claim 1 wherein R is methyl.

4. The method of any one of claims 1 to 3 wherein said compound is incorporated in the feed rations at a level of from 25 to 500 g/ton.

5. The method of claim 4 wherein the level of said compound is from 100 to 200 g/ton.

6. The method of claim 4 wherein the level is from 200-500 g/ton.

7. A swine feed composition comprising a nutritional source for swine and as an active ingredient, a substituted quinoxaline represented by the formula 15 where R is hydrogen or lower alkyl.

8. The composition of claim 7 where R is hydrogen.

9. The composition of claim 7 where R is methyl.

10. The composition of any one of claims 7 to 9 wherein the nutritional source -214.48«^ . is a swine ration containing from 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. ί

11. The composition of claim 10 wherein the level of said quinoxaline is from 100 to 200 g/ton. 5

12. The composition of claim 10 wherein the level of said quinoxaline is from 200 to 500 g/ton.

13. A method of combatting swine dysentery by administration to swine exposed, or likely to be exposed, to a swine dysentery-producing organism an effective amount of a substituted quinoxaline represented by the formula 0 . wherein R is hydrogen or lower alkyl.

14. The method of claim 11 wherein the swine dysentery-producing organism is a Vibrio or Treponema organism.

15. The method of claim 13 or claim 14 where R is hydrogen. 15

16. The method of claim 13 or claim 14 where R is methyl.

17. The method of any one of claims 13 to 16 wherein the quinoxaline is prophylactically administered for a time sufficient to combat swine dysentery.

18. The method of claim 17 wherein the prophylactic administration includes the administration of a swine feed ration containing from 12 to 18 percent by weight 20 protein and having swine dysentery-inbihiting amounts of the quinoxaline. I

19. The method of claim 18 wherein the amounts of quinoxaline incorporated in the feed is at a level of 25 to 500 g/ton of feed.

20. The method of claim 1 or claim 13 wherein said compound is incorporated in drinking water provided for and consumed by swine in swine dysentery-inhibiting 25 amounts. -22. 44807

21. The method of claim 20 wherein these amounts range from about 25 to 500 parts per million of water.

22. The method of claim 21 wherein these amounts range from about 25 to 200 parts per million for prophylaxis. 5

23. The method of claim 21 wherein these amounts range from 200 to 500 parts per million for therapy.

24. The method of claim 1 substantially as herein described and exemplified.

25. The composition of claim 7 substantially as herein described and exemplified,

26. The method of claim 13 substantially as fieretn described and exemplified.