ACTIVATEURS DE L'IMMUNISATION DANS LES INFECTIONS BACTERIENNES

IMMUNE STIMULANTS IN BACTERIAL INFECTIONS

Abrégé français

Des infections bactériennes chez le bétail et les cochons peuvent être prévenues par l'administration de composés répondant aux formules I à VIII telles que définies ici. Des infections bactériennes chez le bétail et les cochons peuvent être prévenues ou traitées par l'administration des composés répondant aux formules I à VIII en combinaison avec un antibiotique.

Abrégé anglais

Bacterial infections may be prevented in cattle and swine by administration of the compounds of formulae (I) to (VIII), as defined
herein. Bacterial infections may be prevented or treated in cattle and swine by administration of the compounds of formulae (I) to (VIII)
in combination with an antibiotic.

Revendications

-19-
CLAIMS
1. A method for the prevention of bacterial infections in cattle or swine
which comprises administering to a subject an effective amount of a compound of the
formula
(1)
<IMG>
I
or a pharmaceutically acceptable acid addition salt thereof,
wherein X is S or NH; Y is CH, CCH3 or N;R is hydrogen, hydroxymethyl, alkyl
of 1 to 6 carbon atoms, -(CH2)nAr,-NH2,-NHR1 or -NH-COR1, wherein R1 is alkyl of 1
to 6 carbon atoms or -(CH2)mAr;n is an integer from 2 to 4; m is zero or an integer from
1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to
3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH
and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or
-(CH2)nAr;
(2)
<IMG> I I
wherein
R is NHR1 or NR2R3;
R1 is (C7-C12)alkyl, (C6-C11)pyridylalkyl or (C11-C12)phenylalkyl, optionally
monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C1-
C3)alkoxy or trifluoromethyl; and

-20-
R2 and R3 are each independently (C1-C12)alkyl or (C7-C12)phenylalkyl, optionally
monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C1-
C3)alkyl, (C1-C3)alkoxy or trifluoromethyl; or
R2 and R3 are taken together with the nitrogen to which they are attached to
form a pyrrolidone, piperidine, perhydro-1H-azepine, or morpholine ring,
or a pharmaceutically acceptable acid addition salt thereof;
(3)
<IMG> I I I
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is NH and Y is CH or N,or
X is S and Y is CH;
R1 is a straight or branched chain (C4-C10)alkyl, (R3)2C6H3 or (R3)2Ar(CH2)n
wherein n is an integer from 1 to 4, the R3 groups are the same or different and are H,
F, Cl, Br, 1, CH3, CH3O, NO2, NH2, OH, CN, COOR5, or OCOR5 and R5 is (C1-C3)alkyl;
and Ar is the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl,
or imidazolyl group;
R2 is H or (C1-C4)alkyl;
or when R1 and R2 are taken together with the nitrogen atom to which they are
attached, they form pyrrolidino, piperidino, morpholino or 4-methyl-piperazino; and
R4 is H, (C1-C5)alkyl, NH2 or CH2OH;
(4)
I V
<IMG>
wherein A is such that there is formed together with the carbon atom shown an
unsaturated heterocyclic nucleus, said unsaturated heterocyclic nucleus being an

-21-
imidazole, pyrazole, pyrimidine, pyrazine or pyridazine ring; X1 is hydrogen, lower alkyl,
hydroxy, trifluoromethyl, benzyl, halogen, amino or
<IMG>
in which E' is NH or N-cyano; X2 is hydrogen or when X1 is lower alkyl or halogen; k is
0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4;
Y is oxygen, sulphur or NH; E is NR2; R1 is hydrogen, lower alkyl, or di-lower
alkylamino-lower alkyl; and R2 is hydrogen, nitro or cyano, or a pharmaceutically
acceptable addition salt thereof; with the proviso that X1 is
<IMG>
only when E is NH or N-cyano;
<IMG> V
or a physiologically acceptable salt thereof, N-oxide or hydrate thereof in which R1 and
R2 which may be the same or different represent hydrogen, lower alkyl, cycloalkyl, lower
alkenyl, aralkyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy
or halo or lower alkyl interrupted by an oxygen atom or a group
<IMG>
in which R4 represents hydrogen or lower alkyl;
R3 is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl;
X is -CH2-, O or S;
Y represents =S, =O, =NR5 or =CHR6;

-22-
Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;
R5 is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or
halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl
substituted by alkyl, alkoxy or halo;
R6 represents nitro, arylsulphonyl in which the aryl portion is phenyl or phenylsubstituted by alkyl, alkoxy, halo or alkylsulphonyl;
m is an integer from 2 to 4; and
n is 1 or 2; or when X=S, or -CH2-, n is zero, 1 or 2;
(6)
<IMG>
VI
wherein R represents a hydrogen atom or a lower alkyl group, R1 represents an amino
group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group
which is unsubstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono-
or di-lower alkylamino group, an arylamine group or an aralkylamino group, R2
represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower
alkynyl group, Y represents a sulfur atom or a methylene group, m and n, each
represents an integer of 1-3, or a pharmacologically acceptable acid addition salt
thereof;
(7)
<IMG>
V I I
wherein R1 represents a hydrogen atom or a methyl or ethyl group, R2 and R3,
independently from each other, represent a lower alkyl group, or together form a linear
alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a
hydroxyl or hydroxymethyl group, and R4 represents a hydrogen atom or a group of the
formula -R5-Z in which R6 represents a lower alkylene group, and Z represents a

-23-
hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino,
lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy,
benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof; or
(8)
<IMG>
V I I I
wherein each of R1 and R2 are individually H or (C1-C3)alkyl, one of R1 and R2 can be
benzyl or benzoyl, and when taken together with the nitrogen to which they are
attached, represent piperidino, pyrrolidino or morpholino; except that only one of R1
and R2 can be H when Z is CH2;
R3 is H or (C1-C3)alkyl;
Z is O, S, SO or CH2;
n is 2 or 3 when Z is O, S or SO and n is 1 , 2 or 3 when Z is CH2;
R5 is H or CH3;
m is 1, 2 or 3;
Q is
<IMG>
<IMG> or
wherein A is N-CN, N-NO2, CH-NO2, S, O, NH, N-SO2-aryl, N-SO2-(C1-C3)alkyl, N-CO-
NH2, N-CO-(C1-C3)alk, N-CO2-(C-1-C3)alkyl; CH-SO2-aryl or CH-SO2-CH3, wherein aryl
is phenyl, halo-phenyl, (C1-C3)alkylphenyl or (C1-C3)alkyloxyphenyl; and
B is NH-R when Q is
<IMG>

-24-
and NH-R or YR4 when Q is
<IMG>
wherein Y is S or O and R is H or R4 wherein R4 is (C1-C3)alkyl, (C3-C6)cycloalkylmethyl,
hydroxy(C1-C5)alkyl, (C3-C6)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyl wherein the
total number of carbons is less than 8; and there is at least a two carbon chainbetween the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof.
2. A method according to claim 1 wherein said compound is 2-guanidino-4-
(2-imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)4-(2-methyl-4-imidazolyl)thiazole.
3. A method for the prevention of bacterial infections in cattle which
comprises administering to a subject an effective amount of 2-guanidino-4-(2-methyl-4-
imidazolyl)thiazole, 2-guanidino-4-(2-N-n-hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl-
N'-guanidino)4-(2-methyl-4-imidazolyl)thiazole, ranitidine, cimetidine, famotidine,
roxatidine or nizatidine.
4. A method for the prevention of bacterial infections in swine which
comprises administering to a subject an effective amount of 2-guanidino-4-(2-methyl-4-
imidazolyl)thiazole, 2-guanidino-4-(2N-n-hexylamino-4-imidazolyl)thiazole, ranitidine,
cimetidine, famotidine, roxatidine or nizatidine.
5. A composition for the prevention or treatment of bacterial infections in
cattle or swine which comprises an antibiotic and a compound of the formula
(1)
<IMG> I
or a pharmaceutically acceptable acid addition salt thereof,
wherein X is S or NH; Y is CH, CCH3 or N; R is hydrogen, hydroxymethyl, alkyl
of 1 to 6 carbon atoms, -(CH2)nAr, -NH2, -NHR1 or-NH-COR1, wherein R1 is alkyl of 1
to 6 carbon atoms or -(CH2)mAr; n is an integer from 2 to 4; m is zero or an integer from
1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to

-25-
3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH
and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or
-(CH2)nAr;
(2)
<IMG> I I
wherein
R is NHR1 or NR2R3;
R1 is (C7-C12)alkyl, (C8-C11)pyridylalkyl or (C11-C12)phenylalkyl, optionally
monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C1-
C3)alkoxy or trifluoromethyl; and
R2 and R3 are each independently (C1-C12) alkyl or (C7-C12) phenylalkyl, optionally
monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C1-
C3)alkyl, (C1-C3)alkoxy or trifluoromethyl; or
R2 and R3 are taken together with the nitrogen to which they are attached to
form a pyrrolidone, piperidine, perhydro-1H-azepine, or morpholine ring;
or a pharmaceutically acceptable acid addition salt thereof;
(3)
<IMG> I I I
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is NH and Y is CH or N, or
X is S and Y is CH;

-26-
R1 is a straight or branched chain (C4-C10)alkyl, (R3)2C6H3 or (R3)2Ar(CH2)n where
n is an integer from 1 to 4, the R3 groups are the same or different and are H, F, Cl, Br,
1, CH3, CH3O, NO2, NH2, OH, CN, COOR5, or OCOR5 and R5 is (C1-C3)alkyl; and Ar is
the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, or
imidazolyl group;
R2 is H or (C1-C4)alkyl;
or when R1 and R2 are taken together with the nitrogen atom to which they are
attached, they form pyrrolidino, piperidino, morpholino or 4-methyl-piperazino; and
R4 is H, (C1-C5)alkyl, NH2 or CH2OH;
(4)
I V
<IMG>
wherein A is such that there is formed together with the carbon atom shown an
unsaturated heterocyciic nucleus, said unsaturated heterocyclic nucleus being animidazole, pyrazole, pyrimidine, pyrazine or pyridazine ring; X, is hydrogen, lower alkyl,
hydroxy, trifluoromethyl, benzyl, halogen, amino or
<IMG>
in which E' is NH or N-cyano; X2 is hydrogen or when X1 is lower alkyl or halogen; k is
0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4;
Y is oxygen, sulphur or NH; E is NR2; R1 is hydrogen, lower alkyl, or di-lower
alkylamino-lower alkyl; and R2 is hydrogen, nitro or cyano, or a pharmaceutically
acceptable addition salt thereof; with the proviso that X1 is
<IMG>
only when E is NH or N-cyano;

-27-
(5)
<IMG> V
or a physiologically acceptable salt thereof, N-oxide or hydrate thereof in which R1 and
R2 which may be the same or different represent hydrogen, lower alkyl, cycloalkyl, lower
alkenyl, aralkyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy
or halo or lower alkyl interrupted by an oxygen atom or a group
<IMG>
in which R4 represents hydrogen or lower alkyl;
R3 is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl;
X is -CH2-, O or S;
Y represents =S, =O, =NR5 or =CHR6;
Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;
R5 is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or
halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl
substituted by alkyl, alkoxy or halo;
R6 represents nitro, arylsulphonyl in which that aryl portion is phenyl or phenyl
substituted by alkyl, alkoxy or halo or alkylsulphonyl;
m is an integer from 2 to 4; and
n is 1 to 2; or when X=S, or -CH2-, n is zero, 1 or 2;
(6)
<IMG> V I

-28-
wherein R represents a hydrogen atom or a lower alkyl group, R1 represents an amino
group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group
which is unsubstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono-
or di-lower alkylamino group, an arylamino group, or an aralkylamino group, R2
represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower
alkynyl group, Y represents a sulfur atom or a methylene group, m and n, each
represents an integer of 1-3, or a pharmacologically acceptable acid addition salt
thereof;
(7)
<IMG>
V I I
wherein R1 represents a hydrogen atom or a methyl or ethyl group, R2 and R3,
independently from each other, represent a lower alkyl group, or together form a linear
alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a
hydroxyl or hydroxy-methyl group, and R4 represents a hydrogen atom or a group of
the formula -R5-Z in which R5 represents a lower alkylene group, and Z represents a
hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino,
lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy,
benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof; or
(8)
<IMG>
V I I I
wherein each of R1 and R2 are individually H or (C1-C3)alkyl, one of R1 and R2 can be
benzyl or benzoyl, and when taken together with the nitrogen to which they are

-29-
attached, represent piperidino, pyrrolidino or morpholino; except that only one of R1
and R2 can be H when Z is CH2;
R3 is H or (C1-C3)alkyl;
Z is O, S, SO or CH2;
n is 2 or 3 when Z is O, S or SO and n is 1, 2 or 3 when Z is CH2;
R5 is H or CH3;
m is 1, 2 or 3;
Q is
<IMG>
<IMG> or
wherein A is N-CN, N-NO2, CH-NO2, S, O, NH, N-SO2-aryl, N-SO2-(C1-C3)alkyl, N-CO-
NH2, N-CO-(C1-C3)alk, N-CO2-(C1-C3)alkyl; CH-SO2-aryl or CH-SO2-CH3, wherein aryl is
phenyl, halo-phenyl, (C1-C3)alkylphenyl or (Cl-C3)alkyloxyphenyl; and
B is NH-R when Q is
<IMG>
and NH-R or YR4 when Q is
<IMG>
wherein Y is S or O and R is H or R4 wherein R4 is (C1-C3)alkyl, (C3-C6)cycloalkylmethyl,
hydroxy(C1-C5)alkyl, (C3-C6)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyl wherein the
total number of carbons is less than 8; and there is at least a two carbon chainbetween the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof.
6. A composition according to claim 5 wherein said compound is 2-
guanidino-4-(2-imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)-4-(2-methyl-4-
imidazolyl)thiazole.
7. A composition according to claim 5 wherein said antibiotic is a
quinolone, .beta.-lactam, tetracycline, macrolide, aminoglycoside, or a sulfa combination.
8. A composition for the prevention or treatment of bacterial infections in
cattle or swine which comprises an antibiotic and a compound selected from the group

-30-
consisting of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-N-n-
hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)-4-(2-methyl-4-
imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine.
9. A method for the prevention or treatment of bacterial infections in cattle
or swine which comprises administering to a subject an effective amount of a
combination of an antibiotic and a compound of the formula
(1)
<IMG> I
or a pharmaceutically acceptable acid addition salt thereof,
wherein X is S or NH; Y is CH, CCH3 or N; R is hydrogen, hydroxymethyl, alkyl
of 1 to 6 carbon atoms, -(CH2)nAr, -NH2, -NHR, or -NH-COR1, wherein R1 is alkyl of 1
to 6 carbon atoms or -(CH2)mAr; n is an integer from 2 to 4; m is zero or an integer from
1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to
3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH
and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or
-(CH2)nAr;
(2)
<IMG> I I
wherein
R is NHR1 or NR2R3;

-31-
R1 is (C7-C12)alkyl, (C6-C11)pyridylalkyl or (C11-C12)phenylalkyl, optionally
monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C1-
C3)alkoxy or trifluoromethyl; and
R2 and R3 are each independently (C1-C12)alkyl or (C7-C12)phenylalkyl, optionally
monosubstituted or disubstituted on the phenyl group with chloro, bromo, fluoro, (C1-
C3)alkyl, (C1-C3)alkoxy or trifluoromethyl; or
R2 and R3 are taken together with the nitrogen to which they are attached to
form a pyrrolidone, piperidine, perhydro-1H-azepine, or morpholine ring;
or a pharmaceutically acceptable acid addition salt thereof;
(3)
I I I
<IMG>
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is NH and Y is CH or N, or
X is S and Y is CH;
R1 is a straight or branched chain (C4-C10)alkyl,(R3)2C6H3 or (R3)2Ar(CH2)n where
n is an integer from 1 to 4, the R3 groups are the same or different and are H, F, Cl, Br,
1, CH3, CH3O, NO2, NH2, OH, CN, COOR5, or OCOR5 and R5 is (C1-C3)alkyl; and Ar is
the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, or
imidazolyl group;
R2 is H or (C1-C4)alkyl;
or when R1 and R2 are taken together with the nitrogen atom to which they are
attached, they form pyrrolidino, piperidino, morpholino or 4-methyl-piperazino; and
R4 is H, (C1-C5)alkyl, NH2 or CH2OH;

-32-
(4)
I V
<IMG>
wherein A is such that there is formed together with the carbon atom shown an
unsaturated heterocyclic nucleus, said unsaturated heterocyclic nucleus being animidazole, pyrazole, pyrimidine, pyrazine or pyridazine ring; X1 is hydrogen, lower alkyl,
hydroxy, trifluoromethyl, benzyl, halogen, amino or
<IMG>
in which E' is NH or N-cyano; X2 is hydrogen or when X1 is lower alkyl or halogen; k is
0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4;
Y is oxygen, sulphur or NH; E is NR2; R1 is hydrogen, lower alkyl, or di-lower
alkylamino-lower alkyl; and R2 is hydrogen, nitro or cyano, or a pharmaceutically
acceptable addition salt thereof; with the proviso that X1 is
<IMG>
only when E is NH or N-cyano;
(5)
<IMG> V
or a physiologically acceptable salt thereof, N-oxide or hydrate thereof in which R1 and
R2 which may be the same or different represent hydrogen, lower alkyl, cycloalkyl, lower

-33-
alkenyl, aralkyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy
or halo or lower alkyl interrupted by an oxygen atom or a group
<IMG>
in which R4 represents hydrogen or lower alkyl;
R3 is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl;
X is -CH2-, O or S;
Y represents =S, =O, =NR5 or =CHR6;
Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;
R5 is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or
halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl
suhstituted by alkyl, alkoxy or halo;
R6 represents nitro, arylsulphonyl in which that aryl portion is phenyl or phenyl
substituted by alkyl, alkoxy or halo or alkylsulphonyl;
m is an integer from 2 to 4; and
n is 1 to 2; or when X=S, or -CH2-, n is zero, 1 or 2;
(6)
<IMG>
V I
wherein R represents a hydrogen atom or a lower alkyl group, R1 represents an amino
group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group
which is unsubstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono-
or di-lower alkylamino group, an arylamino group, or an aralkylamino group, R2
represents a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower
alkynyl group, Y represents a sulfur atom or a methylene group, m and n, each
represents an integer of 1-3, or a pharmacologically acceptable acid addition salt
thereof;

-34-
(7)
<IMG>
V I I
wherein R1 represents a hydrogen atom or a methyl or ethyl group, R2 and R3,
independently from each other, represent a lower alkyl group, or together form a linear
alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a
hydroxyl or hydroxy-methyl group, and R4 represents a hydrogen atom or a group of
the formula -R6-Z in which R5 represents a lower alkylene group, and Z represents a
hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino,
lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy,
benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof; or
(8)
<IMG>
V I I I
wherein each of R1 and R2 are individually H or (C1-C3)alkyl, one of R1 and R2 can be
benzyl or benzoyl, and when taken together with the nitrogen to which they are
attached, represent piperidino, pyrrolidino or morpholino; except that only one of R1
and R2 can be H when Z is CH2;
R3 is H or (C1-C3)alkyl;
Z is O, S, SO or CH2;
n is 2 or 3 when Z is O, S or SO and n is 1, 2 or 3 when Z is CH2;
R5 is H or CH3;
m is 1, 2 or 3;
Q is

-35-
<IMG> or <IMG>
wherein A is N-CN, N-NO2, CH-NO2, S, O, NH, N-SO2-aryl, N-SO2-(C1-C3)alkyl, N-CO-
NH2, N-CO-(C1-C3)alk, N-CO2-(C1-C3)alkyl; CH-SO2-aryl or CH-SO2-CH3, wherein aryl is
phenyl, halo-phenyl, (C1-C3)alkylphenyl or (C1-C3)alkyloxyphenyl; and
B is NH-R when Q is
<IMG>
and NH-R or YR4 when Q is
<IMG>
wherein Y is S or O and R is H or R4 wherein R4 is (C1-C3)alkyl, (C3-C6)cycloalkylmethyl,
hydroxy(C1-C5)alkyl, (C3-C6)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyl wherein the
total number of carbons is less than 8; and there is at least a two carbon chainbetween the hetero atoms, or a pharmaceutically acceptable acid additional salt thereof.
10. A method according to claim 9 wherein said compound is 2-guanidino-4-
(2-imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)4-(2-methyl-4-imidazolyl)thiazole.
11. A method for the prevention or treatment of bacterial infections in cattle
which comprises administering to a subject in need of such treatment an effective
amount of a combination of an antibiotic and a compound selected from the group
consisting of 2-guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-N-n-
hexylamino-4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)-4-(2-methyl-4-
imidazolyl)thiazole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine.
12. A method for the prevention or treatment of bacterial infections in swine
which comprises administering to a subject an effective amount of a combination of an
antibiotic and a compound selected from the group consisting of 2-guanidino-4-(2-
methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-M-n-hexylamino-4-imidazolyl)thiazole,
ranitidine, cimetidine, famotidine, roxatidine and nizatidine.
13. A method according to claim 9 wherein said antibiotic is a guinolone, .beta.-
lactam, tetracycline, macrolide, aminoglycoside, or a sulfa combination.

Description

~wo 94/~98 2 1 6 5 3 4 4 PCT/IB94/00082
H2-Antagon~sts as ~mmune st1mulants ~n bacter~al ~nfect~ons of cattle or
sw~ne.
The present invention relates to the prevention of l,acterial infections in cattle
and swirle by administering an effective amount of certain known compounds
previously used as H2-antagonists. The invention also relates to the prevention or
treatment of bacterial i.,te~,~iGns in cattle and swine by administering said known
10 compounds together with an antibiotic.
The col~"~ounds of the invention and their H2-antagoni~l activity are ~;~closed
in United States ~lelll 4,374,843, 4,435,396, 4,560,690, 3,950,333, 4,128,658,
4,283,40~, 4,293,557 and 4,375,547, each of which are incorporated by reference.The present use of these compounds in cattle and swine to prevent bacterial
15 infections is not ~lisclosed.
The invention relates to the prevention of bacterial infections in cattle or swine
by admin;;.le,i"g to a subject an effective amount of a compound of the formula
(1) R
N~
N H N~ (~ \X
H2NCNH ~
S
or a ,l~l,an.,~ceutic~lly acceptable acid addition salts thereof,
wherein X is S or NH; Y is CH, CCH3 or N; R is hydrogen, hydroxymethyl, alkyl
of 1 to 6 carbon atoms, -(CH2)nAr, -NH2, -NHRl or-NH-COR1, wherein Rl is alkyl of 1
to 6 carbon atoms or -(CH2)n,Ar; n is an integer from 2 to 4; m is zero or an integer from
1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to
3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is NH
and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or
~(CH2)nAr;
J

WO 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082 ~
(2)
R
~< ,
NH
NH N~/ I I
I I 1~ \\
H2N-C-NH~\S/
wherein
R is NHRl or NR2R3;
R1 is (C,-Cl 2)alkyl, (C6-C1 1 )pyridylalkyl or (C1 1-Cl 2)phenylalkyl, optionally
monosl ~hstituted or ~lis~hstitl~ted on the phenyl group with chloro, bromo, fluoro, (Cl-
C3)alkoxy or trifluoromethyl; and
R2 and R3 are each independently (C1-Cl 2)alkyl or (C7-C~ 2)phenylalkyl, optionally
15 monos~hstituted or ~is~hstituted on the phenyl group with chloro, bromo, fluoro, (C1-
C3)alkyl, (C,-C3)alkoxy or trifluoromethyl; or
R2 and R3 are taken together with the nitrogen to which they are attached to
form a py"olidone, piperidine, perhydro-1 H-azepine, or morpholine ring,
or a pharmaceutically acceptable acid addition salt thereof;
(3)
S
N~\N/~ N I I I
R1R2N NH2 \X R4
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is NH and Y is CH or N, or
X is S and Y is CH;
R' is a ~laiyll~ or branched chain (C4-C,O)alkyl, (R3)2C~H3 or (R3)2Ar(CH2)"
wherein n is an integer from 1 to 4, the R3 groups are the same or di~ r~:nl and are H,
F, Cl, Br, l, CH3, CH30, NO2, NH2, OH, CN, COOR5, or OCOR5 and R5 is (C,-C3)alkyl;

~wo 94/28898 2 1 ~ 5 3 4 4 PCT/IB94/00082
and Ar is the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl,
or i.,. -'n~olyl group;
R2 is H or (Cl-C4)alkyl;
or when R' and R2 are taken together with the nitrogen atom to which they are
5 atl~cl,ed, they form pyrrolidino, piperidino, ~,or~,holino or 4-methyl-piperazino; and
R~ is H, (C,-C5)alkyl, NH2 or CH20H;
(~)
Xl ~ C- ( CHz ) kY ( CH2 )mNHC I V
J
w:,erei" A is such that there is formed together with the carbon atom shown an
unsaturated heterocyclic nucleus, said unsaturated heterocyclic nucleus being an 15 i.,.idazole, pyrazole, pyrimidine, pyrazine or pyridazine ring; Xl is hydrogen, lower alkyl,
hydroxy, trifluoromethyl, benzyl, halogen, amino or
~E '
( C H 2 ) 4 Y ( C H z ) m N H C
NHCH3
in which E' is NH or N-cyano; X2 is hydrogen or when Xl is lower alkyl or halogen; k is
O to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4
Y is oxygen, sulphur or NH; E is NR2; R1 is hydrogen, lower alkyl, or di-lower
alkylamino-lower alkyl; and R2 is hydrogen, nitro or cyano, or a pharmaceutically
25 acceptat)le addition salt thereof; with the proviso that Xl is
~E '
( CH2 )4Y ( CH2 )mNHC
NHCH3
30 only when E is NH or N-cyano;

-
wo 94,288g8 2 1 6 5 3 4 4 PCT/IB94/00082 ~
(5)
/N-Rlk~ \~ (CH2)nX(CH2)mNHCNHR3
Rz
or a physiologically accep~ '-le salt thereof, N-oxide or hydrate thereof in which R, and
R2 which may be the same or di~reren~ represent hydrogen, lower alkyl, cycloalkyl, lower
alkenyl, aralkyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy0 or halo or lower alkyl interrupted by an oxygen atom or a group
N
R4
in which R4 represe,lt~ hydrogen or lower alkyl;
R3 is hydrogen, lower alkyl, lower alkenyl or alkoxy-alkyl;
X is -CH2-, O or S;
Y lepreser,ls =S, =0, =NR5 or =CHRB;
Alk denotes a straight or branched alkylene chain of 1 to 6 carbon atoms;
R5 is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or
20 halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl
substituted by alkyl, alkoxy or halo;
R6 represents nitro, arylsulphonyl in which the aryl portion is phenyl or phenyl s~hstihlted by alkyl, alkoxy, halo or alkylsulphonyl;
m is an integer from 2 to 4; and
n is 1 or 2; or when X=S, or -CHz-, n is zero, 1 or 2;
(6)
NSOz-
R N H N /( C Hz ) m--Y--( CH2 ) n--C\
C=N~/ ~J N H--R 2 V I
H2N S

~wo 94/~98 2 1 6 5 3 4 4 PCT/IB94/00082
-5-
wherein R repres6r,l~ a hyJloyen atom or a lower alkyl group, Rl represents an amino
group, n lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group
which is unsuhstituted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono-
or di-lo~wer alkylamino group, an arylamine group or an aralkylamino group, R2
5 r~rese~ a hyJIugen atom, a lower alkyl group, a lower alkenyl group or a loweralkynyl group, Y represents a sulfur atom or a methylene group, m and n, each
epresel~t~ an integer of 1-3, or a ph~""acologically accept ' le acid aJJiliGn salt
ll ,ereof,
(7)
\N--CH~\0-CHz-CH2-CH2-NH-C-R4 V I I
15 vl:,erei., R1 repr~se,.ls a hydrogen atom or a methyl or ethyl group, R2 and R3,
independently from each other, represent a lower alkyl group, or together form a linear
alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a
hydroxyl or hydroxymethyl group, and R4 represents a hydrogen atom or a group of the
formula -R5-Z in which R5 represents a lower alkylene group, and Z represen~j a
20 hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino,
lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy,
benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceplable salt thereof; or

wo 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082
-6-
(8)
R3 l I CH2~Z~(CH2)nNH~~~B
S N
\~ Rl
( C H R 5 ) m - N V I I I
R2
wherein each of Rl and R2 are individually H or (Cl-C3)alkyl, one of Rl and R2 can be
10 benzyl or benzoyl, and when taken together with the nitrogen to which they are
attached, represe"~ piperidino, pyrrolidino or morpholino; except that only one of
and R2 can be H when Z is CH2;
R3is H or (Cl-C3)alkyl;
Z is O, S, SO or CH2;
n is 2 or 3 when Z is O, S or SO and n is 1, 2 or 3 when Z is CH2;
R5is H or CH3;
m is 1 , 2 or 3;
Q is
O=C C=O
ll or l l
C --C C--
wherein A is N-CN,N-NO2, CH-NO2,S, O, NH, N-so2-aryl~N-so2-(cl-c3)alkyl~ N-CO-
NH2, N-CO-(Cl-C3)alk, N-CO2-(C-l-C3)alkyl; CH-SO2-aryl or CH-SO2-CH3, wherein aryl
is phenyl, halo-phenyl, (Cl-C3)alkylphenyl or (Cl-C3)alkyloxyphenyl; and
B is NH-R when Q is
O=C C=O
l l
--C C--
and NH-R or YR4 when Q is
Ic

~wo 94/288g8 2 1 6 5 3 4 4 PCT/IB94/00082
w: ,er~,i., Y is S or O and R is H or R4 wherein R4 is (Cl-C3)alkyl, (C3-C6)cycloalkylmethyl,
hydroxy(C,-C5)alkyl, (C3-C~)cycloalkyl or alkyloxyalkyl or dialkylami. ,oalkyl wherein the
total number of c6rL,Gr,s is less than 8; and there is at least a two carbon chain
betweerl the hetero atoms, or a pha, ll ,Aceutic~lly accept~ble acid addiliGnal salt thereof.
Ir~ a specific embodiment of the invention said cGmpound is 2-guanidino4-(2-
n~glyl)ll 1- e_ - Ie or 2-(N-benzyl-N'-guanidino)4-(2-methyl4-i" ,iJ~olyl)thiazole.
lhe invention also relates to the prevention of baulerial infections in cattle by
adminhleli"g to a subject an effective amount of 2-guanidi"o4-(2-methyl4-
i" ,i '~olyl)thiazole, 2-guanidino4-(2-N-n-hexylamino4-imidazolyl)thiazole, 2-(N-pentyl-
N'-guankJi"o)4-(2-methyl4-;"~ olyl)thiazole, ranitidine, cimetidine, famotidine,roxatidine or n i,~lidi"e, and the prevention of bacterial infections in swine by
administering to a subject an effective amount of 2-guanidino4-(2-methyl4-
glyl)ll ,iazole,2-guanidino4-(N-n-hexylamino4-i",idazolyl)thiazole,ranilid;.,e or
famotidine.
The invention further relates to a combination of an antibiotic and a compound
of the formula
('1)
R
N~
N H N ~ ~ X
HzNCNH ~
or a phar,l,aceutically accept~ble acid addition salt thereof,
w: ,er~i" X is S or NH; Y is CH, CCH3 or N; R is hydrogen, hydroxymethyl, alkyl
of 1 to 6 carbon atoms, -(CH2)nAr, -NH2, -NHRl or-NH-CORl, wherein Rl is alkyl of 1
to 6 carbon atoms or -(CH2)mAr; n is an integer from 2 to 4; m is zero or an integer from
1 to 4; Ar is phenyl or phenyl monosubstituted with chloro, bromo, fluoro, alkyl of 1 to
3 carbon atoms or alkoxy of 1 to 3 carbon atoms; provided that when Y is N, X is N
and m is other than zero; and when X is S, R is other than hydroxymethyl, alkyl, or
~(CH2)nAr;

WO 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082 ~
(2)
R
N~<
6 ~/NH
H2N-C-NH S
wherein
R is NHRl or NR2R3;
R' is (C7-C,2)alkyl, (C~-C")pyridylalkyl or (Cl1-Cl2)phenylalkyl, optionally
monos~ ~hstitl~ted or ~isuhstituted on the phenyl group with chloro, bromo, fluoro, (C,-
C3)alkoxy or trifluoromethyl; and
R2 and R3 are each independently (Cl-Cl 2)alkyl or (C7-Cl2)phenylalkyl, optionally
15 monosubstituted or ~isuhstituted on the phenyl group with chloro, bromo, fluoro, (Cl-
C3)alkyl, (C,-C3)alkoxy or trifluoromethyl; or
R2 and R3 are taken together with the nitrogen to which they are attached to
form a py"~ ne, piperidine, perhydro-1 H-azepine, or morpholine ring;
or a pharmaceutically acceptable acid addition salt thereof;
(3)
N/\N/~ N I I I
R1R2N NHz \X R4
or a pharmaceutically acceptable acid addition salt thereof, wherein
X is NH and Y is CH or N, or
XisSandYisCH;
R' is a sl,~i~hl or branched chain (C4-C,O)alkyl, (R3)2C~H3 or (R3)2Ar(CH2)n where
n is an integer from 1 to 4, the R3 groups are the same or .Ji~eler,l and are H, F, Cl, Br,
l, CH3, CH30, NO2, NH2, OH, CN, COOR5, or OCOR5 and R5 is (Cl-C3)alkyl; and Ar is

~WO 94/28898 2 t 6 5 3 ~ 4 PCT/IB94100082
the residue of a phenyl, naphthyl, furyl, thienyl, pyridyl, pyrimidinyl, thiazolyl, or
;"~ 75)1yl group;
R2 is H or (C1-C4)alkyl;
or when R' and R2 are taken toy~ll ,er with the r,il,ogen atom to which they are
5 c.Lhched, they form pyrrolidino, piperidino, morpholino or 4methyl-piperæino; and
R~ is H, (C1-C5)alkyl, NH2 or CH20H;
(4)
~E
X1~ C-(CH2)kY(CH2)mNHC \ IV
~ I NHR1
J
wherein .A is such that there is formed together with the carbon atom shown an
unsatural:ed heterocyclic nucleus, said unsaturated heterocyclic nucleus being an
15 imidazole, pyrazole, pyrimidine, pyrazine or pyridazine ring; X, is hydrogen, lower alkyl,
hydroxy, trifluGru,,,~l,yl, benzyl, halogen, amino or
~E '
(CH2)~,,Y(CH2)mNHC
NHCH3
in which l ' is NH or N-cyano; X2 is hydrogen or when X1 is lower alkyl or halogen; k is
0 to 2 and m is 2 or 3, provided that the sum of k and m is 3 or 4;
Y is oxygen, sulphur or NH; E is NR2; R1 is hydrogen, lower alkyl, or di-lower
alkylamino-lower alkyl; and R2 is hydlo5~en, nitro or cyano, or a pharm~celltic~y
25 accepttlble addition salt thereof; with the proviso that Xl is
~E '
(CH2)4Y(CH2)mNHC
NHCH3
30 only when E is NH or N-cyano

WO 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082 ~
-10-
(5)
/N - R I k~ ( C H 2 ) n X ( C H 2 ~ m N H C N H R 3 V
S R2
or a physiologically accept lhle salt thereof, N-oxide or hydrate thereof in which R1 and
R2 which may be the same or di~el`erll represent hydrogen, lower alkyl, cycloalkyl, lower
alkenyl, aralkyl in which the aryl portion is phenyl or phenyl substituted by alkyl, alkoxy0 or halo or lower alkyl interrupted by an oxygen atom or a group
N
R4
in which R4 represerll~ hydrogen or lower alkyl;
R3 is hy.l,ogen, lower alkyl, lower alkenyl or alkoxy-alkyl;
X is -CH2-, O or S;
Y represents =S, =O, =NR5 or -CHR~;
Alk denotes a sl-ai~l,l or branched alkylene chain of 1 to 6 carbon atoms;
R5 is H, nitro, cyano, lower alkyl, phenyl, phenyl substituted by alkyl, alkoxy or
20 halo, alkylsulphonyl, or arylsulphonyl in which the aryl portion is phenyl or phenyl
s~ ~hstit~ted by alkyl, alkoxy or halo;
Ro represents nitro, arylsulphonyl in which that aryl portion is phenyl or phenyl
substituted by alkyl, alkoxy or halo or alkylsulphonyl;
m is an integer from 2 to 4; and
n is 1 to 2; or when X=S, or -CH2-, n is zero, 1 or 2;
(6)
NSO2-R
R NH N /(CHz)m--Y--(CH2)n--C~
C=N~/~ NH--R2 VI
/ S~
H2N
wherein R represents a hydrogen atom or a lower alkyl group, Rl represents an amino
group, a lower alkyl group, a halogeno lower alkyl group, a phenyl or naphthyl group

~WO 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082
which is uns~ ~hstn~ted or substituted by halogen, hydroxyl, amino, or alkoxy, a mono-
or di-lower alkylamino group, an arylamino group, or an aralkylamino group, R2
I~epl~se:~lb a hydrogen atom, a lower alkyl group, a lower alkenyl group or a lower
alkynyl group, Y r~presel,l~ a sulfur atom or a methylene group, m and n, each
5 represe"ll~ an integer of 1-3, or a pha""acologically acceptable acid addition salt
tl ,er~o~,
(7)
/N--CH ~ \0-CH2 CH2 CH2 NH C-R4 Vll
1~3 Rl
wherein R, represents a hydrogen atom or a methyl or ethyl group, R2 and R3,
i. ,depender,lly from each other, represer" a lower alkyl group, or together form a linear
15 alklylene group having 4 to 7 carbon atoms which may be optionally substituted by a
hydroxyl or hydroxy-methyl group, and R4 represents a hydrogen atom or a group of
the formula -R5-Z in which R5 l~presenls a lower alkylene group, and Z represents a
hydrogen atom or an amino, mono- or di-(lower alkyl)amino, hydroxy lower alkylamino,
lower alkanoylamino, hydroxyl, lower alkoxy, lower alkanoyloxy, phenoxy, halophenoxy,
20 benzoyloxy or halobenzoyloxy group, or a pharmaceutically acceptable salt thereof.
(~)
R3 l I CH2~Z~(CH2)nNH~~~B
\ C7HR5 ) -N/ V I I I
w:,erei.. each of R1 and R2 are individually H or (C,-C3)alkyl, one of Rl and R2 can be
30 benzyl or benzoyl, and when taken together with the nitrogen to which they are
attachedl, represer,l piperidino, pyrrolidino or morpholino; except that only one of R
and R2 can be H when Z is CH2;
R3 is H or (Cl-C3)alkyl;

wo 94,28898 2 1 6 5 3 4 ~ PCT/IB94100082 ~
-12-
Z is O, S, SO or CH2;
nis20r3whenZisO,SorSOandnis1,20r3whenZisCH2;
R5 is H or CH3;
m is 1, 2 or3;
6 Qis
R 0=C C=0
or l l
C --C C--
wherein A is N-CN, N-NO2, CH-NO2, S, O, NH, N-SO2-aryl, N-SO2-(C,-C3)alkyl, N-CO-
NH2, N-CO-(Cl-C3)alk, N-CO2-(Cl-C3)alkyl; CH-SO2-aryl or CH-SO2-CH3, wherein aryl is
phenyl, halo-phenyl, (C1-C3)alkylphenyl or (Cl-C3)alkyloxyphenyl; and
B is NH-R when Q is
O=C--C=O
l l
--C C--
and NH-R or YR4 when Q is
11
wherein Y is S or O and R is H or R4 wherein R4 is (Cl-C3)alkyl, (C3-C~,)cycloalkylmethyl,
hydroxy(Cl-C5)alkyl, (C3-C~)cycloalkyl or alkyloxyalkyl or dialkylaminoalkyl wherein the
total number of carbons is less than 8; and there is at least a two carbon chainbetween the hetero atoms, or a pharmaceutically accepl~ble acid additional salt thereof.
In a specific er"bod;"~ent of the invention said compound is 2-guanidino4-(2-
i",i'~olyl)lhi~ole or 2-(N-benzyl-N'-guanidino)4-(2-methyl4-imidazolyl)thiazole.The invention further relates to a combination of an antibiotic and a compound
selected from the group consi~li"g of 2-guanidino4-(2-methyl4-imidazolyl)thiazole, 2-
guanidino4-(2-N-n-hexylamino4-imidazolyl)thiazole, 2-(N-pentyl-N'-guanidino)4-(2-
methyl4-i"~id~olyl)ll ,i~ole, ranitidine, cimetidine, famotidine, roxatidine and nizatidine.
The invention yet further relates to the prevention or treatment of bacterial
i"fe.,tions in cattle by admi"isleri"g to a subject an effective amount of said
co" Ibil lalion of said antibiotic and said compound of any one of said formulae I through
Vlll. In a specific embodiment of such prevention or treatment said compound is 2-

~WO 94/28898 2 1 6 5 3 4 4 PCT/IBg4/00082
guanidino 4-(2-imidazolyl)thiazole or 2-(N-benzyl-N'-guanidino)-4-(2-methyl4-
imidazolyl)ll e~ ~ le
The invention also relates to the prevention or l,t:al."er,l of bacterial infections
in cattle by administering to a subject in need of such treatment an effective amount
S of a combination of an antibiotic and a col"pound selected from the group consiali"g
of 2-guanidino~-(2-methyl4-imidazolyl)lhi~olE, 2-guanidino~-(2-N-n-hexylamino~-
i",.~'n7slyl~U ~le, 2-(N-pentyl-N'guanidino)~(2-methyl~i".-'o~olyl)U :'e, ranitidine,
cimetidin~, famotidine, roxatidine and ni~lidi. ,e, and to the prevention or treatment of
bacterial infections in swine by admi"i~leli"g to a subject an effective amount of a
10 combination of an antibiotic and a compound selected from the group consisting of 2-
guanidino-4-(2-methyl-4-imidazolyl)thiazole, 2-guanidino-4-(2-M-n-hexylamino-4-i",. '-~olyl)thiazole, ranitidine and famotidine.
The above-described compounds of formulae 1, Il, lll, IV, V, Vl, Vll and Vlll are
descriL,eci in, respectively, United States Patents 4,374,843, 4,435,396, 4,560,690,
15 3,950,333, 4,128,658, 4,283,408, 4,293,557, and 4,375,547. The preparation of these
active compounds and their ~char,nAceutic~lly accept~ble salts, if any, is disclosed in
these pater)~s. It is noted that the compounds of formulae I to Vlll herein are described
sul,sl~lnlially in accordance with the terminology used in the respective U.S. patents.
The compounds of formulae I to Vlll and any pharmaceutically acceptable salts
20 thereof, when used alone, are useful in the prevention of bacterial infections in cattle
and swine. The infections may be from a broad spectrum of bacteria, particularly, in
cattle, r~sp..~loly pathogens, such as Pasteurella haemolytica. Pasteurella multocida
and Haemophilus sornnus. and bacteria associated with ",a~lilis: Streptococcus sp.,
StaPhylococcus sp., KJebsiell~ sp., Escherichia coli., and Enterobacter sp., and in
swine, I-s,~ lory pathogens, such as Actinobacillus pleuropneumoniae, Pasteurella
multocida, MvcoPlasma sP., HaemoPhilus suis, and HaemoPhilus Parasuis, enteric
pathogens, such as Escherichia coli, Salmonella sp., or Treponema hyodesenteria, and
other pathogens, such as Staphylococcus sP., Streptococcus sp., Corynebacterium sp.,
Leutosl~yla sp., and ErvsiPelothrix rhuseopathiae.
The cor"pounds of formulae I to Vlll and any pharmaceutically acceplable salts
thereof, when used in combination with an antibiotic, are useful in the prevention or
treatment of bacterial infections in cattle and swine. In such use, each of the active
cG",pounds of formulae I to Vlll and the antiobiotic agent may be used at a dose

WO 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082 ~
-14-
similar or equal to the dose used for each agent alone. Since the active compounds
and the antibiotic agent are known, the doses for each are known as well. Dependent
on the dose for each agent, the ratio of antibiotic to active compound may vary greatly,
e.g., from about 0.1:1 to 50:1. The antibiotics of use in the invention include
5 Ln~ lial quinolones, such as danofloxacin, enrofloxacin, flumequine, ~liflox~in,
nGIrloxacin, sar~flsx~rin, tem~floxP~cin, tos~floY~in, and ih~flox~rin; 13 I&ct~ls, such
as ceftiof~r, cefquinome, cefoperazone, cephalexin, cephapirin, cefazolin, ampicillin,
amoxicillin, sulbactam-ampicillin, clavulinic acid-amoxicillin, and penicillin G;
tetracyclines, such as oxytetracycline, doxycycline, and chlortetracycline; macrolides
10 such as erythromycin, lil~ os.." ~itl,r~,l"ycin, and tylosin; aminoglycosides, such as
pirlimycin, gentamycin, and lincomycin; sulfa combinations, such as
baquiloprim/sulfadimethoxine, and trimethoprim/s~llf~ ine; and florfenicol.
The compounds of the invention may be admini~,lered to the cattle or swine
alone, but will generally be administered in admixture with a pharmaceutical carrier
15 sel~.ted with regard to the intended route of administration and standard
phhr",aceutical practice. For example, they can be admi"i ,lared orally or in the form
of tablets cor,l~i"i"g such exc;~iEnl~, as starch or lactose, or in cnrsules either alone
or in admixture with excipients, or in the form or elixirs or suspensions containing
flavoring or coloring agents. They are advantageously contained in an animal feed or
20 drinking water in a concentration of about 5-500 ppm, preferably about 25-100 ppm.
They can be injected pare,)ler~lly, for example, intramusc~ rly, intravenously or
subcutaneously. For pare"leral a.l",i"i~ lion, they are best used in the form of a
sterile aqueous solution which can contain other solutes, for example, enough salt or
glucose to make the solution isotonic. The compounds can be administered to the
25 cattle or swine intramusc~ rly or sllhcutnneously at dosage levels of about 0.1-50
mg/kg/day, advantageously about 0.2-10 mg/kg/day in cattle, for instance 2-10
mg/kg/day, and advantageously about 0.1 to 10 mg/kg in swine, given in single ormultiple daily doses.
The activity of compounds of formulae I to Vlll against bovine respiratory
30 .li;en^~ in immunosuppressed calves may be determined as follows. Three to four
month old I IGI~,le;~ ~ r~iSia~ calves free of clinical rlise~ce sy" ,ptor"s and weighing about
100 kg are used in these experiments. About five animals are randomly allotted to each
treatment on the day of trial initiation. F~perimental compounds are administered

~W0 94/28898 2 1 6 5 3 4 4 PCT/IBg4/00082
-15-
psr~nterally 24 hours prior to challenge. All animals except the saline controls are
- treated once daily for three consecutive days with 0.05 mg/kg of the synthetic
CO; I;CG:~Ie~ jd dexamethasone (Azium~) bey;l ,ni. ,g 24 hours prior to challenge. Animals
are cl,~l~nged endotracheally with 50 ml of saline conl~i.,ing 8x10~ cfu of Pasteurella
haemolvtica Type 1. All animals are observed daily for symptoms of acute 1~5F .alory
seAce. Body temperatures and illness scores are recorded daily. Animals which die
during the course of the study are necropsied and the lungs are removed and
exarnined grossly for pneumonic lesions. The perce"lage of lung volume exl,iLili.,g
lesions is recGrded. Surviving animals are weighed, euthanized and necropsied 5 days
after challenge and the percent lung lesions are recorded. Active compounds reduce
the severity of disease in treated animals relative to animals treated with corticosteroid
alone.
The prophylactic activity of compounds of formulae I to Vlll against naturally
induced bovine r~.j i.dt~ry disease, may be determined as follows. Animals are
tr~, ISpGi led for about a thousand miles overnight before initiation of the study. Mixed-
breed beef cattle free of clinical ~liseAce symptoms and weighing about 125 kg are
used. Upon arrival, the calves are weighed and mean body temperatures and illness
scores measured. Approxi.nalely twelve animals are allotted to each treatment. The
ex~.eri",ental compounds are administered parenterally as single or multiple doses
beginning within 2 to 4 hours of arrival. All animals are observed daily for symptoms
of acute respiratory disease. Body temperatures and illness scores are recorded daily.
Animals which die during the course of the study are weighed to determine gain or loss
and necropsied. The lungs are removed and examined grossly for pneumonic lesionsand the percentage of lung volume exhibiting lesions is recorded. Samples of lung
tissue are collected for bacteriological culture. Surviving animals are weighed
euthanized and necropsied 10 days after arrival and the percent lung lesions arerecorded. Active compounds reduce the incidence and/or severity of disease in treated
animals as compared to non-medicaled controls.
11 he therapeutic efficacy of experimental compounds against naturally induced
30 bovine l espi. atory disease may be deter" li"ed as follows. Compounds are
&I~,.i ,i~lered either alone or in conjunction with antibiotics. Animals are llansported
about 1000 miles ovemight before the study is begun and allotted to treal",ents upon
the onset of clinical r~iseAce sy" ,pto" ,s. Animals treated with active compounds exhibit
-

wo 94,288g8 2 1 6 5 3 4 4 PCTIIB94/00082 ~
-16-
a reduction in clinical symptoms relative to the day of allotment. Combination therapy
with an antibiotic and an effective immune stimulant results in reduced clinicalsy""~tolns and/or a reduction in relapse rates relative to animals treated with &r,l i lic
alone.
Mixed-breed beef cattle free of clinical symptoms of disease and weighing about
125 kg are used in these experiments. Upon arrival, the calves are weighed and mean
body temperatures and illness scores are determined. During the first seven days after
arrival, animals are randomly allotted to treatments when they exhibit a body
temperature equal to or more than 104F and at least one clinical symptom of
10 I- :atOly di-ease. Each treatment group contains about 20 animals.
Experimental compounds are typically ad" ,i. ,i~tered parenterally as either single
or multiple doses at the day of allotment.
All ar,i"~als are observed daily for sy"~ptG" ,s of acute respiratory disease. Body
temperatures and illness scores are recorded daily. Animals which die during thecourse of the study are weighed to determine gain or loss and necropsied. The lungs
are removed and examined grossly for pneumonic lesions and the percentage of lung
volume exhiLili"g lesions is recorded. Samples of lung tissue are collected for
bacteriological culture. Surviving animals are weighed euthanized and necropsied 10
days after allotment and the percent lung lesions are recorded.
The activity of compounds of formulae I to Vlll against swine respiratory disease
induced by A. pleuropneumoniae may be evaluated as follows. About twenty cross-
bred swine free of clinical dise~ce s~"nptoms and weighing about 10 kg are randomly
allotted to drug treatment groups on the day before the trial starts. Experimental
co",pounds are & I",i.,istered parenter~lly to the healthy swine immediately before
introduction of swine which have been challenged with bacteria. The challenged
animals are inocc~ t~d intranasally with 6 ml of a saline suspension containing about
3 X 107 cfu (colony-forming units) of A. Pleuropneumoniae placed in the pens
containing the treated animals, and removed two days later. All treated animals are
observed daily for sy" ~ptOI "s of r espi, atory ~lise~ce, and body temperatures and illness
scores are recorded daily. The swine within the experimental treatment groups are
e~,ll,a~ ed and neclopsied. The lungs are removed and examined grossly for
pneumonic lesions. The percentage of lung volume exhibiting lesions is recorded.

~WO 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082
Example 1
The above protocol to determine immune stimulant activity in cattle was used
with the test col"pounds 2-guanidino4-(N-n-hexylamino4-imidazolyl)thiazole (CP-
61,146), 2-guanidino-4-(2-methyl-4-i",i Is~olyl)thiazole (CP-57,361) and ranitidine.
The results of these experiments indicated that animals treated with CP-61,146,
CP-57,361 and ranitidine twenty four hours before ch~ e showed sig"i~icant
,~,rote-;tion from infection when co,~"~ar~d to controls using Azium. For instance, the
treated animals showed a 40 to 60% reduction in mean pneumonic lung volume
coi"pared to the Azium controls.
ÉxamPle 2
The prophylactic activities of both single and multiple doses CP-57,361 were
determined in naturally infected calves.
Sixty-six calves weighing about 125 kg were shipped about one thousand miles.
Upon arrival, thirty six ~ ;. "als were allotted to one of three treatment groups containing
12 calvex each. Animals in the first group served as saline controls. Animals in the
seconcl group were treated once intramusc~ rly with 2 mg/kg of CP 57,361 on the day
of arrival. Animals in the third treatment group were treated intramuscularly with 2
mg/kg of CP 57,361 once daily for three consecutive days beginning on the day ofarrival. Illness scores and body ter"pe,~lures were l~cGrcled daily. The variousl,~l."erll:, were started on the day of arrival. Illness scores and body temperatures
were recorded daily.
Animals were weighed upon arrival and on the tenth day to assess gain or loss.
Half of the animals in each treatment group were euthanized and necropsied on days
11 and 12. Lung lesion scores were recorded and samples for bacteriologic culture
were collected.
Saline-treated calves developed moderately severe pneumonia with an overall
morbidit~ rate of about 75%. Both P. haemolvtica and P. multocida were isol~ted from
the lungs of ill animals. These results are consistent with those normally observed for
natural infection studies.
30 Results obtained with both regimens of CP 57,361 indicated that these
treatments reduced both the incidence and severity of lisease relative to the saline
controls. Animals treated with CP 57 361 showed a 40% reduction in mean pneumonic
lung volume relative to the saline controls.

WO 94/28898 2 1 6 5 3 4 4 PCT/IB94/00082 ~
-18-
Animals treated with CP 57,361 gained more weight during this study than the
non-medicated cGIllluls.
All of the meJic~tecl animals and particularly those treated with the single dose
of CP 57,361 exhibited decreased illness scores relative to the non-med;caled CGnllulS.
5 Evaluation of the mean daily temperature data indicated the various treatments yielded
relatively small reductions relative to the saline co"l-ols. Both regimens of CP 57,361
su~,pressed the te" ,pel alures of treated animals relative to the saline c~r,l, ols
particularly during the first 5 days.
In summary, this study shows that prophylactic administration of CP-57,3610 provides efficacy against natural respi,alory disease.
Example 3
The prophylactic efficacy of various doses of CP-57,361 ranging from 1-4 mglkg
was evaluated using the above test d~ler,l,il,i"g the ability of a tested compound to
prevent the ll~nslnission of A. Pleuropneumoniae-induced pneumonia from infected15 swine to healthy swine. The results of this experiment inrlico~ed that swine treated with
a single intramusc~ r injection of CP-57,361 exhibited significantly decreased morbidity
relative to swine treated with saline. Morl,idity rates for ani" ,als treated with CP-57,361
ranged from 5-20% as opposed to 60% for the saline treated swine. Using lung lesion
scores as an indicator of disease severity, animals treated with CP-57,361 exhibited a
20 dose-dependent reduction in d;sease severity relative to the saline-treated swine.
In a sllhsequent experiment using the above test, the prophylactic efficacy of
CP-57,361 and CP-61,146 was evaluated using a dose of 4 mg/kg. The compounds
were adminislc~red as either a single intramusc~ r injection or by oral gavage. Animals
treated with CP-57,361 by either route of administration exhibited significant reductions
25 in morbidity (25%) relative to animals treated with saline (50%). Oral administration of
CP-61,146 also provided significant protection from infection similar to that observed
with CP-57,361.
The prophylactic efficacy of ranitidine, cimetidine, nizatidine, roxatidine and
famotidine was also evaluated using the above test by intramuscu~s~r administration as
30 a single injection at a dose of 4 mglkg. The results of this experiment indic~ted that
ani" .als treated with these active agents exhibited reduced morbidity relative to animals
treated with saline.