CA1059815A - Imidazole derivatives - Google Patents

Abstract

ABSTRACT

Imidazole derivatives of the general formula:

Description

~135~3~
THIS IMVENTION relates to a new me-thod for the treatment of swine dysentery.
Swine dysentery~ which is also known as bloody dysentery, bloody scoursg vibrionic dysentery and mucohemorrnagic diarrhoea, is a highly infectious disease of pigs b~lieved to be transmitted by contact with infected pigs or their faeces, which was firs~
described b~ Whiting et al, Purdue Univ~ l~gr. ~xp. St. Bull, 257, 1-15 (1921) and since d.iagnosed. in many parts of the world., Many papers have appeared which describe its clinical diagnosis and economlc importance and discuss its aetiology, for example T.J,L.
Alexander and. D~Jo Tayler~ Vet, Rec, 85, 59-63 (1969). It is usually, but not lnvariably, characterised. by dysentery of varyin~ :
degrees of severity which is frequently severe and mucoh3morrhagic~
weight loss and., in severe cases, emaciation and morbidity. The :~
1~ disease may occur in pigs of all ages but is particularly prevalent in animals aged. from 10 to 16 weeks and most commonly when they are ::
reared. under intensive cond.itions in large herds in fattening units, : ~ :
The rate at which the disease spread.s d.epend.s on its severity and.
the standards of husbandry applied to the herd but is ~requently ..
very rapid. The condition of infected p-.gs deteriorates rapidly and recovery is slow. Morbid.ity rates as high as 50% may be encounterod iII severe outbreaks and even wi~h mild outbrea~s a ~.
significant loss in weight gain may be encountered.. In consequence, swine dysentery is ~n im~ortant cause of economic 103S in the commercial rearing of pigs, The aetiology of swine dysentery has been widely inve~tigated but remains obscure at th~ pxesent moment~
The involvement of ~orrella sp., Vi~rio coli and Treponema sp. is, however, suspected.
~s a result of rese~rch and.experimentation, it has been found. that the administration of imid.azole d.erivatives o~ the general formula:-.,,. ~

' ' :

C~

2~ ~ I R1 I .
0~ :

wherein R and R1~ which may be the same or different~ eachrepresent a hydrogen atom or a straight- or branched.-chain alkyl group containing from.l to 4 carbon atoms~ and. non-toxic acid. :
addition salts thereof, is highly efective agains~ ~wine d.~entery.
Imidazole derivatives within the ~cope of general formula I have hitherto been di~clo~ed. as possessing antiprotozoal activity, for ~xample against trichomoniasis and histomoniasis (a d.isease in turkeys caused. ~y the protozoan parasite Histomonas ~ 9E~
and. antibacterial activity 9 cf a the ~peci~ication of our British Patent 1006334 and. the speci~ication of United States Patent 3652579 granted. to M. ~fer and At ~ Donal~O
Accord.ing to the present invention there is provid.ed.
a method of treating or preventing swine d.ysentery which comprise~
admini~tering to pigs an ~ffective amount of at least one compound. ~.
qelected from imid.azole d.erivativc~ of general formula I, and more particularly 2-hydroxymethyl~l-methyl-5-nitroLmidazole, and their non-to~ic acid. add.ition salts. By the term "non-toxic acid. .
add.ition salts" is meant salts the anions of which are rel~tively innocuous to pig9 when used. at d.osage which are effective against wine dysentery ~o that the beneficial properties of the imidazole derivatives of general formula I are not vitiated by sid.2-effects ~ ~
a~crihable to the anions~ Suitable salts includ.e the hyd.rochloride, ~ :
nitrato and. bisulphate.
2$ The ~uantitie3 of the compounds o general formula I and.
their non-toxic acid. addition salts admunistered. will d.epend. upon the severi~y of the in~ection, the length of treatment and the method.of administr~tion~ In general, the compounds of general ormula I and. their non~toxic acid. addition salts are highly .

; ~:2 ~.
;~

:~D5~ 5 ~ffective in tr~ating ~wine dyse~-~ery when administered orally in drinking water to pig5 in dosages of from about 5 to 85 mg~ and preferably ~rom a~out 10 to 40 mg.~ o~ the compounds of yencral formula I per kg of animal bod.y weight per day for up to 5 d.ays~
When used to pr~vent swine dysent~ry~ ~.ore particularly by routine administra~ion over a period. of time9 the administration to pigs Oc feed. containing from ab~ut 0.001 to about 0.01% ~/W3 and preferably about 0 0025 to about 0.005% w/w, to give a daily intake of from about 0.5 mg. to about 5~0 mg ~ of the compounds of general formula I per kg. of animal body weight is generally eff2ctive in preventing outbreaks of the disease, For use in the treatment or prevention of swine dysentery~
particularly when continuous administration over a period. is .
d.esired.~ the compound.s of general formula I or their non-toxic acid. ad.d.ition salts may be administered.dispersed. in~ or mixed.
with, pig feed.stuffs, d.rinking water and.other liquids normally consumed. by the pigs, or in compositions containing the compounds of general foxmula I or their non-toxic acid ad.dition salts d.ispersed.in or mixed.with any othex suitable inert physiolo~ically 20 innocuous carrier or diluent which is orally administrabl~. By ~:
the term "inert physiologically innocuous carrier or diluent" is meant a carrier or diluent which is substantially non-reactive with the active ingredient and. is not harmful to pig5 on oral administration. Such compositions may be administered.in the form of powd.ers, pellets, solutions~ suspensions and.emulsions, to the pigs to supply the d.esired.d.o3age of the compounds of general ~ormula I or used. as concentrat~s or supplements to be : diluted. with ad.ditional carrier, feed.stuff, drin]cing wator or other liquids normally consumed by the pigs, befoxe administration.
Suitable inert physiologically innocuous carriers or diluents ; include wheat flour or meal~ maize gluten, lactose, glucose, sucxose, talc, kaolin, calcium phosphate, potassium sulphate and.
d.iatomaceous earths such as kieselguhr. Concentrates or .

~i~5~
~upplement~ in~elldecl for incorporation into drinking water or other liquids normally consumed by the pigs to give solu-tions, emul3ions or stable suspensions, may also comprise the active ingredient in association with a surface-active wetting, dispersing or emulsifying agent such as Teepol ("Teepol" is a registered Trade Mark), polyoxyethylene(20)sorbitan mono-oleate or the condensation product of naphthalenesulphonic acid with formaldehyde, with or without a physiologically innocuous, preferably water-soluble, carrier or diluent, for example, sucrose, glucose or an inorganic salt such as potassium sulphate, or concentrates or supplembnts in the form of stable disperc~ions or solutions obtained by mixing the aforesaid concentrates or supplements with water or some other suitablè
physiologically innocuous inert liquid carrier or diluent, or mixtures thereof.
I'he compositions described above may be prepared by mixing the compounds of general formula I or their non-toxic acid addition ; salts with the inert physiologically innocuous carriers or diluents in any manner known to the art. Solid compositions are conveniently prepared by intimately mixing or dispersing the compounds of general formula I or their non~toxic acid add;ition salts uniformly throughout the feedstu~fs or other solid carrier or diluent by methods such as grinding, stirring, milling or tumbling or by dissolving the imidazole compound in a solvent, e.g. water or suitable organic solvent, dispersing the solution so obtained in the feedstuff or other carrier or diluent and removing the solvent by any means known to the art. Medicated feedstuffs may also be prepared by mixing in concentrates or supplements containing higher concentrations of active ingredi~nt to give feedstuffs throughout which the imidazole compound is uniformly distributed at the desired concentration. The desired concentration of active ingredient in the compositions of the present invention is obtained by the selection of an appropriate ratio of imidazole compound to carrier or diluent.

Medicated feedstuffs will normally contain between 0.001%

,:

3LC3~ r3 and 0.01% by weicJht of thc imi~azole doxivativos of general formulcl I or their non-to~ic acid addition salts to give the requir~d d.osago. Cor-c~ntrates and supplements will nonmally contain betwe~n 5% and. 90/~, pr~f~rabl~f 5% to 50%, by weig~t of the imidazole compound.~ being~ if dcsired 9 sui~ably dilute~d as hereinbefore described. to give the re~uired. dosage.
The' compouncl.s of gcneral formula I and. their non-toxic acid. ad.dition salts may also be convenicntly administered. against swine d.ysentery in th~ form of compositions in a unit dosage form which comprise, as active ingrediont~ a compound. of general formula I or a non-toxic acid.ac3dition salt thereof in association with a significant amount o~ a pharmaceutically-accoptabl2 carrier or ooatiny~ especially such compositions mad.e up for oral administration~
for ~ample a ~ablet9 pill~ capsulo~ bolus~ paste~ gel or d.rench~
Solid. compositions for oral administration include com-pressod. table~s~ pills~ ~o'uses and. granules~ which may optionally be coated.with a pharmacQutically acceptable alkali-stable or acid.-stable material (e.g~ an entQric coa~ing) and.dispersible powd.ers In such solid. compo~itions onc- or more of the active compound.s is 7 or are 7 admixed. with at least one inert diluent such as potato starch~ alginic acid~ sucrose~ lactose~ or a resin~ ~he compositions may also comprise9 as is normal practice~
ad.d.itional substances other than inext d.iluents~ elg~ lubricating agents such as magnesium stearate~ Semi-solid compositions for oral administration include paste~ and. gols containing the active substances and. a suitablc inert diluent such as polyethylone glycol . (6000). Liquid. compositions for oral administration include :~
pharmaceutically acceptable emulsions, solutions 3 suspensions~
syrups and elixirs containing inert diluents commonly used. in the art, suc~ as water and.liquid. paraffin. Besides inert diluents such compositions may also comprise compatible ad.juvants such as wetting~ su~pending and. emulsifying a~ents and stabilIsing~
thickening~ perfuming7 sweetening and. flavouring agents~ and.

- 5 ~

;' ~ ~ ' ' ' ~ 5~8~15 an~i-oxidan~s, e.g ascorbic acid.. CO~POSitiOI19 suitable for oral administration also incl.uclc~ capsule3 of absorbable material such as g~latin containing on~ or more of the active substanccs with or without tho add.ition of d.iluents or cxcipients~
Pr~parations for p~renteral administration includ.e sterile aqueous, aqu~ous-organic and organic solutions~ suspensions and.
emulsions, Example~ of oryanic solvan-t5 or suspending med.ia are propylenc glycol 7 polyethylene glycol~ vegetable oils such as oliva oil ~nd.in~ect~ble organic esters such as etl~yl oleate~
mcse com~ositions may also contain ad.juvants such as stabilising, preserving, wetting, emulsifying and.dispersing agents or anti-o~id.ants. They may be sterilised 9 for e~aml~le~ ~y filtration through a b~cteria-r~taining filt~r, ~y incorporation in the com~ositions of st~rilising agents~ or hy hcating, ~ley may also be manufactured. in the ~rm of sterile solid compositions, which can b~ dissolv~d. in sterile water or some other steril~ injectabl~
m~dium immed.iat~ly beforc use, -.
l~c percentage of ~he compouncl.s of general formula I
or their non-toxic acid. ad.d.ition salts in the above compositions may ~e varied~ it b~ing necessary tha~ i~ should. constitute a proportion such that a suitable dosage for the therapeutic effect dQsired. shall b2 obtained.~ In general~ compositions containing from about 5% to about 90% by weight of active ingredient are satisfactory. ~-The ~ollowing Exampl~s illustrate the present invention.
EXAMPLE 1 .
; 2-Hydroxymethyl-l-methyl-5-nitroimid.azole ~0 625 g ) was mixed. tho~oughly~ using a p2stle and. mortar~ with wheat flour and.
then with a commercial weaner pig ration in meal form to a total weight of about 100 g. The concentrat~ thus obtained was then mechanically mixed with 25 kg. of the commercial weaner ration to gi~e medicated ration suitable for ~dministration to pigs to preve~nt swi.ne dysontery containing a concentration o 0.0025% w/w -~ 6 ~

of 2--hydroxymethyl-1-methyl-5-~itroirnida~ole.
The commercial weaner ration in meal form utilised consisted of 2 parts w/w of a co~nercially available concentrate (Seemeel Concentrate No. 4 con-taining 55% w/w protein, 5% w/w oil, 5% w/w fibre, 0.125% w/w copper), 2 parts w/w wheat, 5 parts w/w middling and 11 parts w/w barley. "Seemeel" is a registered Trade Mark.

An experiment on the prevention of swine dysentery was carried out as follows:-Infective material was prepared by removing, immediately after d~ath, the caecum, colon and rectum from a pig acutely infected with swine dysentery. After a light wash in tap water, the mucosae from infected portions were stripped-off and the material pooled, diluted in phosphate-buffered saline (pH 7.0) and macerated. The infective material was then either u~ed immediately to infect susceptible pigs or stored in 20 ml. portions at -20C.
Eight susceptible weaner pi~s (10 to 20 kg. live weight) aged from 6 to 8 weeks, purchased in litters, were fed to appetite -twice daily on a commercial weaner pig ration in meal form containin~ copper but no antibiotics or other growth additlves.
The animals were divided randomly into 2 groups of 4 pigs each and each animal was dosed twice orally with 20 ml. of the infective material described above with an interval of 12 hours between each dos~ and after fasting for at least 6 hours immediately prior to the fixst dose. Immediately after the second infection , the groups of pigs were offered either the unmedicated ration c~ .
(untreated control group) or rations in which had been incorporated a concentration of 0.0025% w/w of 2-hydroxymethyl-1-methyl-5-nitroimidazole prepared as described in Example 1 (treated group).
Feeding was then continued as previously, i.e. to appetite twice daily, feeding of the medicated ration to the treated group being continued until clinical symptoms of swine dysentery became manifest in the untreated control group (7 day~). The condition r ~

-of all pi~s and faecal consistency wa.~ observed daily and. the live w~ights xecorded twic~ wo~klyO Faoces from pigs with unformed skools wore checked Eor the pr~sence o~ nematod.e egg9 and.
Ralantidium coli and bacteriologicall~ for haemolytic Escherichia coli and.salmon~lla, Measurements of food. consumed were made to enable the mean d.aily intak~ of 2-hydroxymethyl-7-methyl-5-nitroimidazol~ in th~ treatcd group to be calculat~d..
Animals were regarded as having d.~veloped.swine d.ysentcry if th~y exhibited. thc clinical symptoms of swino d.ys~ntcry d.efined.

by G. Lussicr9 Can, VetO J. 39 228 ~1962) 9 iOe. :-1. Per acute pigs which d.ie showing no symptoms or an acute diarrhoea, 2. Acut~ pigs with severe d.iarrhoea which d.evelops early in the course o~ tho inf~ction. Faeces are yellowish lS or grey dnpend.iny on -the presence of blood. ~lucoid.
material may be pres~nt in the f~eces. Pigs exhibit tenesmus and. soiling of the hind. legs and. tail from ~owel d.ischarges. Polyd.ypsia i9 evid.ent. Pigs rapid.ly b~comc gaunt~ em~ciated. and. cache~ic if the course of the disca~e is prolonged,

3. Suk-acuto thc pred.omin~nt signs are unthriftiness and los~
of weight, Diarrhoea occurs later in the course of most infections,

4, Chronic a longstanding fluid.diarrhoea containing n~crotic ~ragments o~ sloughed. mucos~. The af~ected pigs became progr~ssively emaciated. and. d.ehydr~ted. with a f~ll in food cons~ption~
In this experiment~ the pig~ which succumbed. to 3wine ; d.ys~ntery exhibited.clinical s~mptoms of acute or sub-acute inXection.
A satisfactory response to 'creatment was defined as protection from diarrhoea d.uriny the period. of treatment with no loss of appetitc~ fall in the rate of liveweight gain or relapse durin~ 14 days ~ftGr the withdrawal of mad.ication.
Th~ results obt~in~d ~re s~t out in the following Tabl~ and. claarly show th~t 2-hydro~cyme~hyl-1-me~thyl 5-nitroimidazola i~ uscful in comb~tting swinc~ dyscntcry.

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rJ,s:: O ~1 ~ ::~ O ~ cD
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5~ ~n a~
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a~ 1 r~J ~ ~ .
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a)~,1 O~r~ Q O_ o_ O~'J 3 ~ . _ a) ~ ~1 a U t~ a~
~: rJ ~ 3~r~ tQ d~ r~
i :~ O ~
r~ ~ O O
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O ~ O ~ ~
0~ Q ~ O O
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X ~ >q :~ O rJ~ ,a I
c~ S ~ E3 ~ ~ ,~ ~ ~ ~ ~1 ~-~1 ra a) ~ O

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h 0 1~ ~ C) ~ ~
..
rl O ~ O ~ ~13 O`--~ ~ t~
rJ ~ h 3~ C~ ~ ~ O u~
U S~ 0 0 O rl h ~rl S-i ~ rJ ;j:., ~ Q~
h 0 ~ tn u~ ~ ~ G) R S~ 1 a).s~ r~
~ UI g a) ~ u~ h E~ ~ ~ d~
~ o ,1 a~ ~ d' ~i 3 ~ ~ 0 3 ~ ~5 o r~ _ _ _ _ ta I,~ 3 ~,_ U ~ ,~ ~ h 0 ~ O ~) O
h ~ ~ ~ N (D ~ C: O
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.

Com~ounds of general formula I may be pr~pared by the Lollo~ing ~rocesses:~
(a) reaction of 1 methyl-5-nitroimid,azole with formaldehyde und.er pressure to give the com~ound ol general formula I
wherein R and. Rl each represent a hydrogen atom 3 i.e. 2-hydroxymethyl-l_methyl-5-nitroimid,azole, 1-Methyl-5-nitroimid.AZole may be ~repared. as described. in British Patent Speci~ication 96990~
(b) N-methylation of compound.s o~ the general formula:-(wherein R and, Rl are as hereinbefore d.efined.] by known method.s for the N-methylation of 4(or 5)-nitroimid.azoles~fox exarnple by treatment with dimethyl sulphate~ i~ d,esired in an inert organic solvent, for example an aromatic hydrocl~rbon~ e.g. xylene, preferably at an elevated. temperature~ e~g. 120-130C.
By the term "known methods" as used. in the present specification is meant method.s heretofore used. or d.escribed. in `'-the chemical literature.
Compound.s of general formula II may be prepared by the ""- :
d.eiod.ination of compound.s of ~he general formula:-; 2 ~
H i : .
(wherein R and. Rl are as hereinbefore defined.) by treatment with sodium or potassium ~oxohyd.ride in an alkaline aqueous med.ium, ~ :
which may optionally contain a lower aliphatic alcohol, at from ~' 25 about 25C. to about 60Co and preferably at -5 to SC.
Compounds of general formula III may be prepared by thc nitration of compounds of the general formula:-' ~ r I ~ I L c_Rl IV
I

H OH
(whcrein R and Rl are as hercinbeforc d.efilled~ b~ known mcthods for the ni~ration of imid.azole3~ for example by treatment wi-th a mixture of concentrated. nitric acid. and concent~aked sulphuric acid at a temperature~ betwccn -25C. and. about 60C.
Compounds of general formula IV may be prepared. by thc iodination of compoulld~ of the general formula:

?,1 V
N
H OH

(wl~erein R and Rl are as hcreinbefor~ d.efin~d) by known methods fox the iod.inati.on of imidazoles~ for exam~le by trcatmont with an alkaline aqueous solution of iodine ~nd sodium iod.ide a-t a t~mp~rature between 10C. and 50C.
Compounds of general formula V may be pr~pc~red. by known..
methods for the preparation of imidazole d.erivatives, for exa~plc lg by reaction of com~ounds o~ the goneral formula:-OCH--C--OH

(wherein R and Rl are as her~inbeforo d.efined.) with glyoxal and ammonia a~ a temperature botwecn -20~C. and 20Co and preferably between -10C, and.~20C.
Tl~e prepar~tion of th~ compound. of general formul~
wherein P and. R each r~prc~ent ~ methyl group ? i . C . l~methyl-2-(l-methyl-l-hydroxyeth~ 5~nitroimidazole by the N-methylation with dimethyl sulphat~ o~ the corre~ onding compound o~ general formula II whorein R and. R cach xcpresen~ a methyl group~ i~eO 2~
~ethyl-1-hydr~y~th~ 5~ni~roimid~zol~, ha~ been de~cribed in Unitcd.

Stat~s Patent 3652579, which also dcscribes the preparation of 2 (1-methyl-1-hyd.ro~eth~13-5-nitroimid.azole starting from a-nydroxyisobutyraldehyde~ am~onia and. ylyoxal via the correspond.ing compcunds of general formula V~ IV and,III wherein R and R each repr~sent a methyl group by the proc~dures d.escribed above.
Acid ad.d.ition salts of the compounds of general ormula I may be preparcd. by trea~ing the cornpounds of formula I with the appropriate strong acid., e.g, hydrochloric, nitric or sulphuric acid~ in a suitable solvent~ for c~amplc water~ eth2nol, aqueous ethanol or an aroma~ic hyd.rocarbon~ e.g, benzene, and. isolating the salt prod.uccd by filtration or d.ecantation~ if nec2ssary after concentration of its solution.
The compounds of general ormula I wherein R represents a straight or bxanched.-chain al~yl group cont2ining from 2 to 4 carbon atoms and Rl reprcsents a straiqht- or branched.-~hain alkyl grou~ containing 1 to 4 carbon atoms~ and non toxic acid addition salts thereo~ arc new compounds and. as such they~ and.
a~orementioned processes for their preparation, form features of ~-the present invention.

~ 13 -

Claims (14)

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

1. Pig feedstuff suitable for use in the treatment or prevention of swine dysentery comprising pig feedstuff containing from 0.001% to 0.01%, by weight of the feedstuff, of at least one imidazole derivative of the general formula:

wherein R and R1, which may be the same or different, each represent a hydrogen atom or a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, or a non-toxic acid addition salt thereof.

2. Pig feedstuff according to claim 1 in which the concentration of imidazole ingredient is from 0.0025 to 0.005%
by weight of the feedstuff.

3. Pig feedstuff according to claim 1 or 2 in which the imidazole ingredient is 2-hydroxymethyl-1-methyl-5-nitroimidazole or a non-toxic acid addition salt thereof.

4. Pig feedstuff according to claim 1 or 2 in which the imidazole ingredient is 1-methyl 2 (1-methyl-1-hydroxyethyl)-5-nitroimidazole or a non-toxic acid addition salt thereof.

5. Pig feedstuff according to claim 1 or 2 in which the non-toxic addition salt of the imidazole derivative is the hydrochloride, nitrate or bisulphate.

6. Pig feedstuff according to claim 1 or 2 in which the imidazole ingredient is the hydrochloride, nitrate or bisulphate of 2-hydroxymethyl-1-methyl-5-nitroimidazole.

7. Pig feedstuff according to claim 1 or 2 in which the imidazole ingredient is the hydrochloride, nitrate or bisulphate of 1-methyl-2-(1-methyl-1-hydroxyethyl)-5-nitroimidazole.

8. A concentrate suitable for addition to pig feedstuff and drinking water for administration to pigs to treat or prevent swine dysentery comprising 5% to 90%, by weight of the concentrate, of at least one imidazole derivative of the general formula specified in claim 1, or a non-toxic acid addition salt thereof, and a surface active wetting, dispersing or emulsifying agent.

9. A concentrate according to claim 8 which comprises, in addition, a physiologically innocuous carrier.

10. A concentrate according to claim 8 or 9 in which the imidazole ingredient is 2-hydroxymethyl-1-methyl-5-nitroimidazole or a non-toxic acid addition salt thereof.

11. A concentrate according to claim 8 or 9 in which the imidazole ingredient is 1-methyl-2-(1-methyl-1-hydroxyethyl)-5-nitroimidazole or a non-toxic acid addition salt thereof.

12. A concentrate according to claim 8 or 9 in which the non-toxic acid addition salt of the imidazole derivative is the hydrochloride, nitrate or bisulphate.

13. A concentrate according to claim 8 or 9 in which the imidazole ingredient is the hydrochloride, nitrate or bisulphate of 2-hydroxymethyl-1-methyl-5-nitroimidazole.

14. A concentrate according to claim 8 or 9 in which the imidazole ingredient is the hydrochloride, nitrate or bisulphate of 1-methyl-2-(1-methyl-1-hydroxyethyl)-5-nitroimidazole.