Thiadiazole compounds useful as proton pump inhibitors

Novel thiadiazole compounds are provided, which are effective as proton pumps inhibitors, useful in treating peptic ulcers by inhibition of the proton pump enzyme H.sup.+ /K.sup.+ -ATPase. The compounds are 3-substituted 1,2,4-thiadiazolo 4,5-.alpha.!benzimidazole and 3-substituted imidazo1,2-d!-1,2,4-thiadiazoles corresponding to the general formula: ##STR1## where X and Z either represent an optionally substituted benzene ring fused to the diazole nucleus, or represent a variety of independent chemical groupings (hydrogen, lower alkyl, halo, etc.) and Y is an electronegative group.

FIELD OF THE INVENTION 
This invention relates to novel chemical compounds having pharmaceutical 
utility. More particularly, it relates to novel heterocyclic chemical 
compounds useful in the treatment of peptic ulcers in mammals, to methods 
for their synthesis and to compositions and uses thereof in peptic ulcer 
treatment in mammals. 
BACKGROUND OF THE INVENTION AND PRIOR ART 
Peptic ulcers are one of the most prevalent diseases in industrialized 
nations. Control of gastric acid secretion is the main therapy for peptic 
ulcers. Acid secretion is in turn brought about by the interaction of 
three physiological stimulants, gastrin, acetylcholine and histamine with 
their respective parietal cell receptors. Prior to the discovery of 
histamine H.sub.2 -receptor antagonists such as cimetidine and ranitidine, 
peptic ulcer treatment consisted of antacid therapy and anticholinergic 
drugs (eg. dicyclomine HCl). However, with the advent of H.sub.2 -receptor 
antagonists, treatment with anticholinergic agents has been largely 
supplanted by histamine H.sub.2 -receptor antagonist therapy. The 
development of this class of therapeutic entities presents one of the most 
important advances in the field of medicinal chemistry. 
Another major development in the treatment of peptic ulcers has been 
realized with the introduction of H.sup.+ /K.sup.+ -ATPase inhibitors e.g. 
omeprazole. The enzyme H.sup.+ /K.sup.+ -ATPase, which is also known as 
the proton pump, is located in the membrane of gastric parietal cells and 
is responsible for the transport of protons from blood to lumen, which in 
turn results in decreasing the pH of stomach contents which leads to 
aggravation of peptic ulcers. 
Omeprazole itself is in fact a prodrug which under acidic conditions 
converts to the active drug, namely its corresponding sulfenamide. The 
mechanism of action of omeprazole is well-studied and is known to involve 
a nucleophilic attack of one (or two) thiol group(s) of the H.sup.+ 
/K.sup.+ -ATPase on the sulfur atom of the chemically active sulfenamide. 
The resulting chemical modification of the thiol group(s) of the enzyme 
(formation of a disulfide bond between the H.sup.+ /K.sup.+ -ATPase sulfur 
and the sulfur of the benzimidazole pyridinium salt) causes the observed 
inhibition of the proton pump. The complex cascade of molecular events 
that lead to the inhibition of the H.sup.+ /K.sup.+ -ATPase is shown in 
FIG. 1. 
As shown in FIG. 1, the presence of acid is a prerequisite to the 
conversion of omeprazole to its chemically active sulfenamide. However, 
the resulting sulfenamide is a labile molecule which transforms further to 
a number of other compounds that are unreactive to nucleophilic attack by 
the H.sup.+ /K.sup.+ -ATPase thiol(s) and are therefore incapable of 
inhibiting the enzyme. These transformations are acid catalyzed. 
Accordingly, in a strict chemical sense, while acid is a prerequisite for 
the conversion of omeprazole to its active form, it also acts to its 
detriment. As a partial solution to this problem, omeprazole drug products 
are formulated to resist the acidic medium of the stomach by enteric 
coating. The coating is dissolved in the relatively neutral environment of 
the duodenum and omeprazole is absorbed into the blood stream which 
carries the prodrug to the proton pump. It should be emphasized however, 
that the conversion of the prodrug to the active enzyme inhibitor can only 
be achieved in acidic media which also results in substantial degradation 
of the active sulfenamide. In summary, the instability of omeprazole in 
acidic environments, which is a prerequisite to its activation into a 
proton pump inhibitor, is the major shortcoming of this drug. 
Acid instability of omeprazole not only decreases the bioavailability of 
the drug, but also creates considerable difficulty in its formulation, 
adding to the cost of the final drug product. 
These inherent problems are also observed in the large number of omeprazole 
analogues that have been synthesized to increase the acid stability of 
their corresponding sulfenamide. Two factors contribute to the instability 
of omeprazole in acidic media. First, as observed with other sulfoxides, 
omeprazole undergoes a characteristic acid catalyzed degradation known as 
the Pummerer rearrangement. Second, protonation of the trivalent nitrogen 
of sulfenamide followed by nucleophilic attack on the sulfur atom is 
another characteristic reaction of these compounds. Enzyme inhibition is 
observed only when the H.sup.+ /K.sup.+ -ATPase-S.sup.- acts as the 
nucleophile. On the other hand, sulfenamide degradation is caused when 
Cl.sup.- acts as the nucleophile. Accordingly, any slight gain in acid 
stability of the sulfenamide (or sulfoxide) that may be introduced by 
chemical modification (resistance to Cl.sup.- attack) is offset by a 
decrease in reactivity of the analogue to H.sup.+ /K.sup.+ -ATPase-S.sup.- 
attack. The net result is a less effective drug. 
Another shortcoming of omeprazole is its variability of action in different 
patients. There is clinical evidence of a variable response to omeprazole 
as determined by inhibition of gastric acid release in peptic ulcer 
patients, attributable to a high first pass effect for the 
biotransformation of omeprazole, and the fact that the metabolism of 
omeprazole appears to be under polymorphic genetic control, resulting in 
variable amounts of drug reaching the systemic circulation following a 
given dose. 
SUMMARY OF THE INVENTION 
It is an object of the present invention to provide novel pharmaceutical 
compounds, and compositions containing them, which are active as H.sup.+ 
/K.sup.+ -ATPase inhibitors, and hence useful in the treatment of peptic 
ulcers in mammals. 
It is a further object of the invention to provide methods for the 
synthesis of such compounds. 
The present invention is based upon the discovery of a class of new 
chemical compounds that are effective as H.sup.+ /K.sup.+ -ATPase 
inhibitors and are also acid stable. The new chemical compounds of the 
invention are characterized by an imidazo1,2-d!-thiadiazole nucleus, with 
different substituents attached to the 3-position of the thiadiazolo 
heterocyclic ring structure. 
Thus according to one aspect of the present invention, there are provided 
various 3-substituted 1,2,4-thiadiazolo4,5-a!benzimidazole compounds and 
imidazo1,2-d!-1,2,4-thiadiazole compounds corresponding to the general 
formula I: 
##STR2## 
The groups represented by X and Z can be chosen from a wide variety of 
independent chemical groupings (hydrogen, lower alkyl, halo, nitro, amino, 
hydroxy, lower alkoxy, lower alkylamino, lower dialkylamino, etc) as more 
fully described hereinafter, to provide imidazo1,2-d!-1,2,4-thiadiazoles. 
Alternatively, X and Z taken together can represent a benzene ring fused 
to the imidazo ring to form 1,2,4-thiadiazolo4,5-a!benzimidazole 
compounds, with the benzene ring thereof being optionally substituted with 
up to four substituents independently selected from a wide variety of 
chemical groupings (hydrogen, lower alkyl, halo, nitro, amino, hydroxy, 
lower alkoxy, lower alkylamino, lower dialkylamino, etc). 
The group Y at the 3-position of the thiadiazole nucleus is generally an 
electron withdrawing group, and can be any of the following groups: 
(1) groups of the formula: 
##STR3## 
in which R.sup.7 represents hydrogen, hydroxy, lower alkyl, lower 
cycloalkyl, lower alkoxy, lower alkenyl, lower alkynyl, aryl, lower 
arylalkyl, heterocyclyl, heterocyclyloxy, heterocyclyl-loweralkylene, a 
group NR'R" where R' and R" are independently selected from hydrogen, 
lower alkyl, aryl and lower arylalkyl, or R' and R" when taken together 
form with the N-atom a five or six membered heterocyclic ring 
##STR4## 
wherein n=4 or 5; and a group ANR'R", AOR' wherein A is an amino acid 
residue or a peptide of 2 to 3 amino acid residues and R', R" have the 
same definition as above 
(2) heterocyclyl, the heterocyclic ring being attached at any heteroatom or 
carbon atom which results in the creation of a stable structure, and the 
heterocyclic ring being optionally substituted with lower alkyl, lower 
acyl, lower alkoxycarbonyl, lower alkylsulfonyl or amido, with the proviso 
that the heterocyclyl is not 1-imidazolyl or substituted 1-imidazolyl; 
(3) NR'R" wherein R', R" have the same definition as above 
(4) ANR'R", AOR' wherein A is an amino acid residue or a peptide of 2 to 3 
amino acid residues and R', R" have the same definition as above 
(5) lower 2-(alkoxycarbonyl)alkyl 
(6) halo 
(7) groups of formula R.sup.8 -CHOH-- wherein R.sup.8 is hydrogen, lower 
alkyl, aryl, lower arylalkyl, lower cycloalkyl, lower alkenyl, lower 
alkynyl or heterocyclyl, the heterocyclic ring being attached at any 
heteroatom or carbon atom which results in the creation of a stable 
structure, 
(8) groups of formula R.sup.9 --C(.dbd.NOR.sup.10)-- wherein R.sup.10 is 
hydrogen, lower alkyl or lower arylalkyl, and R.sup.9 is lower alkyl, 
aryl, lower arylalkyl, lower cycloalkyl, lower alkenyl, lower alkynyl or 
heterocyclyl, the heterocyclic ring being attached at any carbon atom 
which results in the creation of a stable structure; 
(9) lower alkoxy, lower arylalkoxy, lower cycloalkoxy, lower 
heterocyclylalkoxy or heterocyclyloxy; 
(10) lower alkylsulfonyl, lower alkylsulfinyl, arylsulfonyl, arylsulfinyl, 
lower arylalkylsulfonyl, lower arylalkylsulfinyl, heterocyclylsulfonyl, 
heterocyclylsulfinyl; optionally substituted with 1 to 2 substituents 
selected from lower alkyl, halo, nitro, hydroxy, lower alkoxy, or groups 
of formula NR'R", OC(O)R', OC(O)OR', OC(O)NR'R", NR'(COR'), NHC(O)NR'R", 
NHC(O)OR' where R' and R" have the meanings given above; 
(11) groups of the formula --C(.dbd.NOH)COOR.sup.11 wherein R.sup.11 is 
lower alkyl; 
(12) lower alkyl, aryl, lower arylalkyl, lower cycloalkyl, each group being 
optionally substituted with 1 to 2 substituents selected from halo, nitro, 
amino, hydroxy, lower alkoxy, lower alkylamino, lower dialkylamino, NR'R", 
OC(O)R', OC(O)OR', OC(O)NR'R", NR'(COR'), NHC(O)NR'R", NHC(O)OR', with R' 
and R" having the meanings given above.

DESCRIPTION OF THE PREFERRED EMBODIMENTS 
One class of preferred compounds according to the invention are 
1,2,4-thiadiazolo4,5-a!benzimidazoles corresponding to the following 
formula II: 
##STR5## 
or pharmaceutically acceptable salts thereof, wherein: R.sup.1, R.sup.2, 
R.sup.3, R.sup.4 are independently hydrogen, lower alkyl, halo, nitro, 
amino, hydroxy, lower alkoxy, lower alkylamino, lower dialkylamino, NR'R", 
OC(O)R', OC(O)OR', OC(O)NR'R", NR'(COR'), NHC(O)NR'R", NHC(O)OR'. 
R', R" are independently hydrogen, lower alkyl, aryl, lower arylalkyl or R' 
and R" in NR'R" when taken together with the N-atom, can form a five or 
six membered heterocyclic ring N (CH.sub.2).sub.n wherein n=4 or 5; and 
Y is as previously defined. 
A second class of preferred compounds according to the present invention is 
imidazo1,2-d!-1,2,4-thiadiazole of the following formula III: 
##STR6## 
wherein R.sup.5 and R.sup.6 can have the same meanings as R.sup.1, 
R.sup.2, R.sup.3 and R.sup.4 in formula II above, and Y is as previously 
defined. 
While it is not intended that the present invention should be limited to 
any particular theory or mode of action, it is believed that the compounds 
of the present invention interact to inhibit the action of the proton pump 
enzyme, by reacting with sulfhydryl groups on surface cysteine residues of 
the enzyme. This is generally illustrated in FIG. 2 of the accompanying 
drawings. The S--N bond in 1,2,4-thiadiazoles has a high energy content 
which originates, at least in part, from non-bonded electron repulsion 
between sulfur atom d orbitals and nitrogen atom p orbitals. 
1,2,4-Thiazoles are therefore likely to be susceptible to nucleophilic 
attack. It has been reported over forty years ago that 1,2,4-thiadiazoles 
undergo S--N bond cleavage with reducing agents (Gordeler, Chem. Ber., 
1954, 87, 57). The thiol groups of H.sup.+ /K.sup.+ -ATPase appear to act 
as reducing agents (nucleophiles), thereby become chemically modified as 
shown on FIG. 2, with resulting inhibition of the enzymatic activity. 
Group Y at the 3-position of the thiadiazole nucleus, because of its 
electron withdrawing nature, activates the adjacent bonds to facilitate 
this reaction. 
A useful in vitro model for obtaining an indication of the reactivity of 
thiadiazole compound towards the proton pump enzyme for deactivation 
thereof is provided by the reactivity of the thiadiazole compound towards 
phenethylmercaptan. The chemical mechanism of this process, as applied to 
the thiadiazolobenzimidazole compounds of the present invention, is 
diagrammatically illustrated on FIG. 3 of the accompanying drawings. The 
first stage of reaction forms a disulfide compound by cleavage of the S--N 
bond of the thiadiazole ring. This disulfide X cannot be isolated, since 
it reacts very rapidly with a second mercaptan group to give the disulfide 
of phenethylmercaptan and intermediate XI. In connection with the actual 
enzyme, the second step involving attack of another thiol group would not 
happen because of steric factors inhibiting the approach of two enzymes, 
or would lead to the formation of a disulfide bond in the event that 
another proximal thiol group is present. In both cases, this would lead to 
the inhibition of the enzyme. In some cases, intermediate XI further 
degrades to 2-mercaptobenzimidazole VIII or 
1-cyano-2-mercaptobenzimidazole XII. A similar mechanism is followed by 
the imidazothiadiazoles of the present invention. Further description and 
discussion of this reaction and test method is included in the specific 
example section hereof. 
Preferred compounds of formula II according to the invention are those in 
which R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each either hydrogen or 
lower alkoxy; and Y is (2-pyridyl) carbonyl or 2-pyridyl with the pyridyl 
ring in each case being optionally substituted with one to three 
substituents selected from methyl and methoxy, or lower alkoxy; Y is NR'R" 
where R' and R" are as previously defined, heterocyclyl (e.g. piperazino 
or morpholino), R.sup.7 CO where R.sup.7 is lower alkyl, aryl, hydroxy or 
hydrogen. 
Particularly preferred compounds of formula II are those belonging to the 
following sub-classes: 
(a) R.sup.1, R.sup.3 and R.sup.4 are hydrogen, R.sup.2 is lower alkoxy, and 
Y is (2-pyridyl)carbonyl wherein the pyridine ring is either unsubstituted 
or optionally substituted with 1-3 substituents selected from methyl and 
methoxy; 
(b) R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each hydrogen, and Y is lower 
alkoxy, heterocyclyl especially nitrogen heterocyclyl, or R.sup.7 CO 
wherein R.sup.7 is alkyl, aryl, hydrogen or 2-pyridyl optionally 
substituted with up to 3 substituents selected from methyl and methoxy; 
(c) R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each hydrogen, and Y is 
piperazino, morpholino, R.sup.7 CO wherein R.sup.7 is lower alkyl, phenyl 
or hydroxy. 
The preferred compounds according to the present invention show specificity 
for the mercaptan functional group demonstrated by the fact that the 
imidazo1,2-d!-thiadiazole nucleus of these compounds show limited or no 
reactivity towards other nucleophiles present in vivo such as amines, 
hydroxide or iodide ions. In chemical model systems, the heterocyclic ring 
of 1,2,4-thiadiazolo4,5-a!benzimidazole in particular is unreactive 
towards these nucleophiles. 
Particularly preferred compounds of formula III according to the invention 
are those in which R.sup.5 and R.sup.6 are hydrogen, and Y is R.sup.7 CO 
wherein R.sup.7 is lower alkyl, aryl, hydrogen, or 2-pyridyl optionally 
substituted with 1 to 3 substituents selected from methyl and methoxy. 
As used herein: 
The term "lower", as applied for example to lower alkyl, means 1 to 8 
carbon atoms. 
The term "aryl", alone or in combination, means a phenyl or naphthyl 
radical which optionally carries one or more substituents selected from 
alkyl, alkoxy, halogen, hydroxy, amino and the like, such as phenyl, 
p-tolyl, 4-methoxyphenyl, 4-(tert-butoxy)phenyl, 4-fluorophenyl, 
4-chlorophenyl, 4-hydroxyphenyl, 1-naphthyl, 2-naphthyl and the like. 
The term "arylalkoxy carbonyl", alone or in combination, means a radical of 
the formula --C(O)--O-- arylalkyl, in which the term "arylalkyl" has the 
significance given below. An example of an arylalkoxycarbonyl radical is 
benzyloxycarbonyl. 
The term "arylalkyl" means an alkyl radical in which one hydrogen atom is 
replaced by an aryl radical, such as benzyl, phenylethyl and the like. 
The term "cycloalkylcarbonyl" means an acyl group derived from a monocyclic 
or bridged cycloalkanecarboxylic acid such as cyclopropanecarbonyl, 
cyclohexanecarbonyl, adamantanecarbonyl, and the like, or from a 
benz-fused monocyclic cycloalkanecarboxylic acid which is optionally 
substituted by, for example, alkylamino, such as 
1,2,3,4-tetrahydro-2-naphthoyl, 
2-acetamido-1,2,3,4-tetrahydro-2-naphthoyl. 
The term "arylalkanoyl" means an acyl radical derived from an 
aryl-substituted alkanecarboxylic acid such as phenylacetyl, 
3-phenylpropionyl, hydrocinnamoyl, 4-phenylbutyryl, (2-naphthyl)acetyl, 
4-chlorohydrocinnamoyl, 4-aminohydrocinnamoyl, 4-methoxyhydrocinnamoyl, 
and the like. 
The term "aroyl" means an acyl radical derived from an aromatic carboxylic 
acid. Examples of such radicals include aromatic carboxylic acid, an 
optionally substituted benzoic or naphthoic acids such as benzoyl, 
4-chlorobenzoyl, 4-carboxybenzoyl, 4-(benzyloxy)carbonyl!benzoyl, 
1-naphthoyl, 2-naphthoyl, 6-carboxy-2-naphthoyl, 6-(benzyloxy) 
carbonyl!-2-naphthoyl,3-benzyloxy-2-naphthoyl, 3-hydroxy-2-naphthoyl, 
3-(benzyloxy)formamido!-2-naphthoyl, and the like. 
The term "heterocyclyl", as used herein except where noted, represents a 
stable 5- to 7-membered mono or bicyclic or stable 7- to 10-membered 
bicyclic heterocyclic ring which is either saturated or unsaturated, and 
which consists of carbon atoms, and from one to three heteroatoms selected 
from the group consisting of N, O, S, and wherein the nitrogen and sulfur 
heteroatoms may be optionally oxidized, and the nitrogen atom may 
optionally be quaternized, and including any bicyclic group in which any 
of the above defined heterocyclic rings is fused to a benzene ring. The 
heterocyclic ring may be attached at any heteroatom or carbon atom which 
results in the creation of a stable structure. Examples of such 
heterocyclic elements, commonly known as heterocyclyl include piperidinyl, 
piperazinyl, 2-oxopiperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 
2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, 
pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, 
imidazolidinyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, 
oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, 
thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, 
quinolinyl, isoquinolinyl, benzimidazolyl, thiadiazolyl, benzopyranyl, 
benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, 
thienyl, benzothienyl, tetrahydroquinolinyl (e.g. 
1,2,3,4-tetrahydro-2-quinolinyl, etc.), 1,2,3,4-tetrahydroisoquinolinyl 
(e.g. 1,2,3,4-tetrahydro-1-oxo-isoquinolinyl etc.),quinoxalinyl, 
beta-carbolinyl, 2-benzofurancarbonyl, thiamorpholinyl, thiamorpholinyl 
sulfoxide, thiamorpholinyl sulfone, oxadiazolyl and the like. The 
heterocycle may be substituted in a manner which results in the creation 
of a stable structure. 
"Amino acid residues" means any of the naturally occurring alpha-, beta-, 
and gamma-amino carboxylic acids, including their D and L optical isomers 
and racemic mixtures thereof, and the N-lower alkyl- and N-phenyl lower 
alkyl-derivatives of these amino acids. The amino acid residue is bonded 
through a nitrogen of the amino acid. The naturally occurring amino acids 
which can be incorporated into the present invention include, but are not 
limited to, alanine, arginine, asparagine, aspartic acid, cysteine, 
cystine, glutamic acid, glutamine, glycine, histidine, isoleucine, 
leucine, lysine, methionine, ornithine, phenylalanine, proline, serine, 
threonine, thyroxine, tryptophan, tyrosine, valine, beta-alanine, and 
gamma-aminobutyric acid. Preferred amino acid residues include proline, 
leucine, phenylalanine, isoleucine, alanine, .gamma.-amino butyric acid, 
valine, glycine, and phenylglycine. 
All alpha-amino acids except glycine contain at least one asymmetric carbon 
atom. As a result, they are optically active, existing in either D or L 
form as a racemic mixture. Accordingly, some of the compounds of the 
present invention may be prepared in optically active form, or as racemic 
mixtures of the compounds claimed herein. 
The term "A" wherein A is an amino acid or peptide of 2 to 3 amino acid 
residues refers to an amino acid or a peptide diradical starting with the 
HN-- radical on the left hand side of A and terminated by the --C(O) 
radical on the right hand side. For example, the amino acid glycine is 
abbreviated HAOH wherein A is HN--CH.sub.2 --C(O). 
The term "aryloxyalkanoyl" means an acyl radical of the formula 
aryl-O-alkanoyl. 
The term "heterocyclyloxycarbonyl" means an acyl group derived from 
heterocyclyl-O--CO-- wherein heterocyclyl is defined above. 
The term "heterocyclylalkanoyl" is an acyl radical derived from a 
heterocyclyl-substituted alkane carboxylic acid wherein heterocyclyl has 
the same significance given above. 
The term "heterocyclylalkoxycarbonyl" means an acyl radical derived from a 
heterocyclyl-substituted alkyl-O--COOH wherein heterocyclyl has the same 
significance given above. 
The term "aminoalkanoyl" means an acyl radical derived from an 
amino-substituted alkanecarboxylic acid wherein the amino group can be a 
primary, secondary or tertiary amino group containing substituents 
selected from hydrogen, and alkyl, aryl, arylalkyl, cycloalkyl, 
cycloalkylalkyl radicals and the like. 
"Pharmaceutically acceptable, non-toxic salts" refers to pharmaceutically 
acceptable salts of the compounds of this invention which retain the 
biological activity of the parent compounds and are not biologically or 
otherwise undesirable (e.g. the salts are stable). Salts of the two types 
may be formed from the compounds of this invention: (1) salts of inorganic 
and organic bases from compounds of Formula I which have a carboxylic acid 
functional group. (2) Acid addition salts may be formed at the amine 
functional group of many of the compounds of this invention. 
Pharmaceutically acceptable salts derived from inorganic bases include 
sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, 
copper, manganous, aluminum, ferric, manganic salts and the like. 
Particularly preferred are the ammonium, potassium, sodium, calcium and 
magnesium salts. Pharmaceutically acceptable, non-toxic salts derived from 
organic bases include salts of primary, secondary and tertiary amines, 
substituted amines including naturally occurring substituted amines, 
cyclic amines and basic ion exchange resins. Such salts are exemplified 
by, for example, isopropopylamine, trimethylamine, diethylamine, 
triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 
tromethamine, dicyclohexamine, lysine, arginine, histidine, caffeine, 
procaine, hydrabramine, choline, betaine, ethylenediamine, glucosamine, 
metylglucamine, theobromine, purines, piperazine, piperidine, 
N-ethylpiperidine, polyamine resins and the like. Particularly preferred 
organic non-toxic bases are isopropylamine, diethylamine, ethanolamine, 
piperidine, tromethamine, dicyclohexylamine, choline and caffeine. 
Pharmaceutically acceptable acid addition salts are formed with inorganic 
acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric 
acid, phosphoric acid and the like and organic acids such as acetic acid, 
propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, 
malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, 
citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic 
acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the 
like. 
The term "animals" refers to humans as well as all other animal species, 
particularly mammals (e.g. dogs, cats, horses, cattle, pigs etc.), 
reptiles, fish, insects and helminths. 
The specific, most preferred compounds according to the present invention 
are the following: 
3-(1-oxoethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the 
following chemical formula: 
##STR7## 
3-(1-oxophenylmethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the 
following chemical formula: 
##STR8## 
3-(2-pyridyl)-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the 
following chemical formula: 
##STR9## 
3-(4-methyl-1-piperazinyl)-1,2,4-thiadiazolo-4,5-a!benzimidazole, which 
has the following chemical formula: 
##STR10## 
3-(4-morpholinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the 
following chemical formula: 
##STR11## 
3-(1-pyrrolidinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the 
following chemical formula: 
##STR12## 
3-bromo-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the following 
chemical formula: 
##STR13## 
3-(4-methoxy-3,5-dimethyl 
-2-pyridyl)oxomethyl!-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the 
following chemical formula: 
##STR14## 
3-carboxy-1,2,4-thiadiazolo-4,5-a!benzimidazole which has the following 
chemical formula: 
##STR15## 
7-methoxy-3-(4-methoxy-3,5-dimethyl 
-2-pyridyl)oxomethyl!-1,2,4-thiadiazolo4,5-a!benzimidazole, which has the 
following chemical formula: 
##STR16## 
3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolol4,5-a!benzimidazole, which 
has the following chemical formula: 
##STR17## 
3-(1-oxoethyl)imidazo1,2-d!-1,2,4-thiadiazole, which has the following 
chemical formula: 
##STR18## 
3-(oxophenylmethyl)imidazo1,2-d!-1,2,4-thiadiazole, which has the 
following chemical formula: 
##STR19## 
3-(4-acetyl-1-piperazinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole, which 
has the following chemical formula: 
##STR20## 
The present invention provides synthetic methods for preparing compounds 
according to the invention. Some of these methods involve conversion of 
one compound according to the invention into another, different such 
compound. The choice of method depends largely upon the desired Y group, 
i.e. the substituent on the 3-position in the final compound. 
In a first process, the corresponding 3-oxo compound of formula IV, 
carrying a lower alkyl or lower arylalkyl substituent at position 2 is 
reacted with YCN in an inert solvent. This method is appropriate for 
compounds in which Y is lower alkyl, aryl, arylalkyl, cycloalkyl, 
1-haloalkyl, 1,1-dihaloalkyl, heterocyclyl, lower alkylsulfonyl or 
arylsulfonyl. The reaction can be represented as follows: 
##STR21## 
The appropriate nitrile compounds YCN wherein Y is lower alkyl, arylalkyl, 
cycloalkyl, 1-haloalkyl, 1,1-dihaloalkyl, or heterocyclyl are for the most 
part commercially available e.g. from Aldrich Chemical Co. Alternatively, 
they can be prepared by methods known in the Art (see for example Chapter 
17 in Organic Functional Group Preparations, Vol. I by Sandler and Karo, 
Academic Press, 1983). Acetonitrile, benzonitrile, 2-cyanopyridine, 
cyclopentylcyanide, dibromoacetonitrile, 6-cyanopurine and 
p-toluenesulfonyl cyanide are some typical examples. The reaction normally 
takes place at elevated temperature between 70.degree. to 140.degree. C. 
in an inert solvent such as toluene, dimethylformamide for a period of 6 
to 24 hours, preferably 16 hours. In some cases, YCN is used as the 
solvent. The product is isolated by conventional means. 
Compounds of formula I in which Y is amino, lower alkylamino, lower 
dialkylamino, thioalkyl can also be prepared by using compounds of formula 
YCN wherein Y is amino, lower alkylamino, lower dialkylamino or lower 
thialkyl. Examples of YCN is this category are cyanamide, 
1-piperidinecarbonitrile, methyl thiocyanate which are commercially 
available. Compounds YCN can also be synthesized from cyanogen bromide 
according to literature procedures (see p.174, Fieser and Fieser, Reagents 
in Organic Synthesis, John Wiley and Sons, 1967). 
2-Alkyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-ones of formula IV are 
prepared from alkyl isocyanate and 2-mercaptobenzimidazole according to 
the procedure of Martin et al., Tetrahedron, 1983, 39, 2311. 
2-Alkylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-ones of formula IV are 
prepared from alkyl isocyanate and 2-mercaptoimidazole according to the 
procedure of Tittlebach et al., J. Prakt Chem. 1988, 330, 338-348. The 
2-mercaptobenzimidazoles are either commercially available, or can be 
prepared by methods well known in the art or readily available in the 
literature. Commercially available 2-mercaptobenzimidazoles includes 
5-methyl-2-mercaptobenzimidazole, 5-methoxy-2-mercaptobenzimidazole, 
5-chloro-2-mercaptobenzimidazole. Suitable 2-mercaptobenzimidazole which 
are not commercially available can be prepared by known methods. 
Preparative method include those of Billeter et al., Ber., 1887, 20, 231, 
Org. Synth., Coll. Vol. 4, 569, Futaki et al., J. Pharm. Soc. Jpn., 1954, 
74, 1365, Bucknall et al., Nature, 19670 213, 1099. 
In a second, similar process, applicable for the preparation of compounds 
in which group Y in the final compound is R.sup.7 --C.dbd.O and R.sup.7 is 
lower alkyl, aryl, lower arylalkyl, lower cycloalkyl, lower alkoxy, amino, 
lower alkylamino, lower dialkylamino, heterocyclyl, the heterocyclic ring 
being attached at any heteroatom or carbon atom which results in the 
creation of a stable structure, NR'R", ANR'R", AOR' wherein A is an amino 
acid residue or a peptide of 2 to 3 amino acid residues and R', R" have 
the same definition as above, a compound of general formula 
##STR22## 
is reacted with the corresponding 3-oxo compound carrying a lower alkyl or 
lower arylalkyl substituent at position 2, i.e. a compound of formula IV 
used in process A above, thus: 
##STR23## 
The reaction may be carried out in an inert solvent such as 
dichloromethane, tetrahydrofuran or dimethylformamide. The reaction takes 
place at room temperature over a period of 3 to 48 hours, usually about 6 
hours. The resulting solid is then isolated by conventional means. 
Most cyanoketones, cyanoester derivatives of formula V are commercially 
available. The cyanoketone derivatives used in this invention are either 
commercially available or can be prepared by methods known in the art. The 
commercially available cyanoketones include, benzoyl cyanide, acetyl 
cyanide, methoxycarbonyl cyanide. A list of commercially available cyanide 
derivatives is available (Chem Sources, U.S.A., 24th Ed., 1983, 
Directories Publishing Company Inc., Ormont Beach, Fla.). Appropriate 
cyanoketones, cyanoesters which are not commercially available can be 
readily prepared by methods known in the art such as the ones described in 
Mathieu et al., Formation of C--C Bonds, Vol I, p. 456-457, Georg Thieme 
Verlag, 1973, Stuttgart. Other suitable methods include those of Koenig et 
al., Tet. Lett., 1974, 2275 and Ando et al., Synthesis, 1983, 637. These 
methods include reacting an acid chloride with cuprous cyanide or 
potassium cyanide. 
Alternatively, compounds of formula I in which Y is R.sup.7 --C.dbd.O 
wherein R.sup.7 has the same definition as above can be prepared by the 
hydrolysis of compounds of formula I wherein Y is R.sup.7 --C(Hal).sub.2 
and wherein Hal is a halogen, preferably chlorine, bromine or iodine. Such 
an hydrolysis can be carried out in a strongly acidic media or in aqueous 
silver nitrate, and can be represented thus: 
##STR24## 
A third process for making the same end products as in the case of the 
second process described above, involves, as a final step, reacting a 
2-thioether diazole compound of formula VI with m-chloroperbenzoic acid 
(MCPBA) in an inert solvent, to effect cyclization to form the 
1,2,4-thiadiazole ring, and can be represented as follows: 
##STR25## 
A bromoheterocyclylacetonitrile derivative (VII) can be reacted with 
2-mercaptobenzimidazole (VIII) in base to give a compound of formula VI. 
Examples of those bases are sodium hydroxide or potassium hydroxide. The 
reaction takes place in a mixture of water and alcohol at room temperature 
for about 1 to 16 hours, preferably 8 hours, the product compound VI is 
isolated by conventional means. 
Compound VI reacts with m-chloroperbenzoic acid, in an inert solvent such 
as dichloromethane, or 1,2-dichloroethane to give the compound of formula 
I where Y is R.sup.7 --C.dbd.O. The reaction takes place at room 
temperature for about 3 to 8 hours, preferably 3 hours. The product is 
isolated by conventional means. 
The bromoheterocyclylacetonitrile (VII) derivative is in turn prepared by 
reacting a compound of formula IX with N-bromosuccinimide in an inert 
solvent such as carbon tetrachloride. 
A fourth process uses a compound of formula I in which Y is R.sup.7 
--C.dbd.O (formula IA) as the starting material, and derivatizes it to a 
compound of formula I in which Y is --CHOH--R.sup.7 (formula IB) or 
--C.dbd.(NOR.sup.10)--R.sup.7 (formula IC), or --COOH (formula ID), thus: 
##STR26## 
Compounds of formula IB can be prepared by the reduction of the 
corresponding compounds of formula IA wherein Y is R.sup.7 --C.dbd.O with 
sodium borohydride, or sodium cyanoborohydride in alcohol. Compound of 
formula IB is isolated by conventional means. 
Compounds of formula IC can be prepared by reacting compound of formula I 
wherein Y is R.sup.7 --C.dbd.O with hydroxylamine derivatives. Examples of 
hydroxylamines are hydroxylamine, methoxylamine, ethoxylamine, 
benzyloxylamine. The conversion of a ketone to an oxime is well-documented 
in the art (see, for example, Sandler and Karo, Organic Functional Group 
Preparations, 1989, Vol. III, Chapter 11). 
Compounds of formula ID in which R.sup.7 is hydroxy can be prepared by the 
base hydrolysis of the compounds of formula I wherein Y is R.sup.7 
--C.dbd.O and R.sup.7 is lower alkoxy. The reaction is carried out in 1M 
sodium hydroxide at room temperature in a mixture of water and an organic 
solvent such as methanol, ethanol, 1,4-dioxane or acetonitrile. The 
product is isolated by conventional means after neutralization of the base 
with diluted acid. 
A fifth process, applicable to the preparation of compounds of formula I 
according to the invention in which Y represents halogen, uses the same 
starting compound of formula IV as used in process A and process B, and 
reacts it with cyanogen halide, thus: 
##STR27## 
The reaction takes place in an inert solvent. The compound is isolated by 
conventional means. 
A sixth process uses as starting materials the compounds of formula I where 
Y represents halogen, compounds prepared according to process E above, and 
reacts them with a primary or secondary amine, or alcohol, to give a 
compound of formula I wherein Y is NR'R", AOR', ANR'R", OR'. R', R" have 
the same definition as above. This process proceeds best when Y in the 
starting material is bromine. It can be represented thus: 
##STR28## 
Nucleophiles such as lower alkoxides, aryloxides, lower arylalkoxides, 
lower cycloalkoxides, ammonia, lower alkylamines, lower dialkylamines, 
heterocyclic amines, HNR'R", HANR'R", HAOR', wherein A is an amino acid 
residue or a peptide of 2 to 3 amino acid residues, react with compounds 
of formula I wherein Y=bromide in an inert solvent to give compounds of 
formula I wherein Y is lower alkoxy, aryloxy, lower arylalkoxy, lower 
cycloalkoxy, amino, lower alkylamino, lower dialkylamino, NR'R", ANR'R", 
AOR', wherein A is an amino acid residue or a peptide of 2 to 3 amino acid 
residues. 
A seventh process uses as starting materials compounds of formula I 
according to the invention in which Y represents COOH (preparable by 
process D above), and reacts them with an amine to give a compound of 
formula I wherein Y is CO--R.sup.7, wherein is NR'R", AOR', ANR'R", thus: 
##STR29## 
In this way, compounds of formula I in which Y is R.sup.7 --C.dbd.O and 
R.sup.7 is NR'R", AOR', ANR'R" can be prepared by reacting the carboxylic 
acid compound of formula I wherein Y is COOH with an amino acid amide 
HANR'R", or amines HNR'R", or amino acid ester HAOR', in the presence of a 
dehydrating agent such as 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide 
(EDCI) and hydroxybenzotriazole in an inert solvent such as 
tetrahydrofuran, dimethylformamide, dichloromethane. 
An eighth process applicable to the preparation of compounds of Formula 1 
in which Y represents lower alkylsalkylsulfonyl, arylsulfonyl, 
heterocyclylsulfonyl, lower arylalkylsulfonyl, lower alkylsulfinyl, 
arylsulfinyl, heterocyclylsulfinyl or lower arylalkylsulfinyl comprises 
the reaction of the corresponding thioether compound with the 
predetermined stoichiometric amount of an oxidizing agent, thus: 
##STR30## 
where n is 1 or 2 and R.sup.12 represents lower alkyl, lower arylalkyl or 
aryl. A preferred oxidizing agent for use in this process is 
metachloroperbenzoic acid mCPBA, but there are many other, suitable such 
oxidizing agents. 
A significant feature of the preferred compounds of this invention is that 
these compounds are heterocycles with molecular weight less than 450. Low 
molecular weight compounds are generally more bioavailable. The spectrum 
of log P of these molecules, i.e. the partition coefficient between 
octanol and water, varies from 0.5 to 4.0 which covers the lipophilicity 
range of most known drugs. 
The specific, most preferred compound according to the present invention is 
7-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole. This molecule carries an electron-withdrawing group 
at the 3-position of the heterocyclic ring. It has limited solubility in 
water. A specific synthesis route for it, in accordance with the 
invention, is illustrated on FIG. 4 of the accompanying drawings. Its 
structure was proved by X-ray crystallography. .sup.1 H and .sup.13 C NMR, 
IR, mass spectrometry and elemental analysis provided additional evidence 
for the chemical identity of this compound. Further specific details of 
its preparation, characterization and properties are given in the specific 
examples below. It is active in the suppression of gastric acid secretion 
in animal model. 
For the treatment of peptic ulcers, the compounds of the invention may be 
administered orally, topically, or parenterally in dosage unit 
formulations containing conventional non-toxic pharmaceutically acceptable 
carriers, adjuvants and vehicles. The term parenteral as used herein 
includes subcutaneous injection or infusion techniques. In addition to the 
treatment of warm-blooded animals such as mice, rats, horses, cattle, 
sheep, dogs, cats, etc., the compounds of the invention are effective in 
the treatment of humans. 
For compositions, conventional non-toxic solid carriers include, for 
example, pharmaceutical grades of mannitol, lactose, starch, magnesium 
stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium 
carbonate, and the like may be used. The active compound as defined above 
may be formulated as liquid pharmaceutically administrable compositions 
can, for example, be prepared by dissolving, dispersing, etc. an active 
compound as defined above and optional pharmaceutically adjuvants in a 
carrier, such as, for example, water, saline, aqueous dextrose, glycerol, 
ethanol, and the like, to thereby form a solution or suspension. If 
desired, the pharmaceutical composition to be administered may also 
contain a minor amount of non-toxic auxiliary substances such as wetting 
or emulsifying agents and the like, for example, sodium acetate, sorbitan 
monolaurate, triethanolamine sodium acetate, triethanol-amine oleate, etc. 
Actual methods of preparing such dosage forms are known, or will be 
apparent to those skilled in this art: for example, see Remington's 
Pharmaceutical Sciences, Mack Publishing Company, Easton, Pa., 15th 
Edition, 1975. The composition of formulation to be administered will, in 
any event, contain a quantity of the active compound(s) in an amount 
effective to alleviate the symptoms of the subject being treated. 
The pharmaceutical compositions containing the active ingredient may be in 
a form suitable for oral use, for example, as tablets, troches, lozenges, 
aqueous or oily suspensions, dispersible powders or granules, emulsions, 
hard and soft capsules, or syrups or elixirs. Compositions intended for 
oral use may be prepared according to any method known to the art for the 
manufacture of pharmaceutical compositions and such compositions contain 
one or more agents from the group consisting of sweetening agents, 
flavouring agents, colouring agents and preserving agents in order to 
provide pharmaceutically elegant and palatable preparations. Tablets 
contain the active ingredient in admixture with the non-toxic 
pharmaceutically acceptable excipients which are suitable for the 
manufacture of tablets. The excipients may be for example, inert diluents, 
such as calcium phosphate or sodium phosphate; granulating and 
disintegrating agents, for example, corn starch, or alginic acid; binding 
agents, for example starch, gelatin or acacia, and lubricating agents, for 
example magnesium stearate, stearic acid or talc. The tablets may be 
coated by known techniques to delay the disintegration and absorption in 
the gastrointestinal tract and thereby provide a sustained action over a 
long period. For monostearate or glyceryl distearate may be employed. 
Formulations for oral use may also be presented as hard gelatin capsules 
wherein the active ingredients are mixed with an inert solid diluent, for 
example, calcium phosphate or kaolin, or as soft gelatin capsules wherein 
the active ingredient is mixed with water or an oil medium, for example 
peanut oil, liquid paraffin, or olive oil. 
Aqueous suspensions contain the active materials in admixture with the 
excipient suitable for the manufacture of aqueous suspensions. Such 
excipients are suspending agents, for example sodium 
carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, 
sodium alginate, polyvinylpyrrolidone, gum and gum acacia; dispersing or 
wetting agents may be a naturally-occurring phosphate, for example 
lecithin, or condensation products of an alkene oxide with fatty acids, 
for example polyoxyethylene stearate, or condensation products of ethylene 
oxide with long chain aliphatic alcohols, for example 
heptadecathyl-eneoxycetanol, or condensation products of ethylene oxide 
with partial esters derived from fatty acids and hexitol anhydrides, for 
example polyethylene sorbitan monooleate. The aqueous suspensions may also 
contain one or more preservatives, for example ethyl, or n-propyl, 
p-hydroxybenzoate, one or more colouring agents, such as sucrose or 
saccharin. 
Oily suspensions may be formulated by suspending the active ingredient in a 
vegetable oil, for example arachis oil, olive oil, sesame oil or coconut 
oil, or in a mineral oil such as liquid paraffin. The oily suspensions may 
contain a thickening agent, for example beeswax, hard paraffin or cetyl 
alcohol. Sweetening agents such as those set forth above, and flavouring 
agents may be added to provide a palatable oral preparation. These 
compositions may be preserved by the addition of an anti-oxidant such as 
ascorbic acid. 
Dispersible powders and granules suitable for preparation of an aqueous 
suspension by the addition of water provide the active ingredient in 
admixture with the dispersing or wetting agent, suspending agent and one 
or more preservatives. Suitable dispersing or wetting agents and 
suspending agents are exemplified by those already mentioned above. 
Additional recipients, for example sweetening, flavouring and colouring 
agents, may also be present. 
The pharmaceutical composition of the invention may also be in the form of 
oil-in-water emulsions. The oily phase may be a vegetable oil, for example 
olive oil or arachis oil, or a mineral oil, for example liquid paraffin or 
mixtures of these. Suitable emulsifying agents may be naturally-occurring 
phosphates, esters derived from fatty acids and hexitol anhydrides, for 
example sorbitan monooleate, and condensation products of the said partial 
esters with ethylene oxide, for example polyoxyethylene sorbitan 
monooleate. The emulsion may also contain sweetening and flavouring 
agents. 
Syrups and elixirs may be formulated with sweetening agents, for example 
glycerol, propylene glycol, sorbitol or sucrose. Such formulations may 
also contain a demulcent, a preservative and flavouring and colouring 
agents. The pharmaceutical compositions may be formulated according to the 
known art using those suitable dispersing or wetting agents and suspending 
agents which have been mentioned above. The sterile injectable preparation 
may also be a sterile injectable solution or suspension in a non-toxic 
parenterally-acceptable diluent or solvent, for example as a solution in 
1,3-butane diol. Among the acceptable vehicles and solvents that may be 
employed are water, Ringer's solutions and isotonic sodium chloride 
solution. In addition, fixed oils are conventionally employed as a solvent 
or suspending medium. For this purpose any bland fixed oil may be employed 
including synthetic mono- or diglycerides. In addition, fatty acids such 
as oleic acid find use in the preparation or injectables. 
Parenteral administration is generally characterized by injection, either 
subcutaneously, intramuscularly or intravenously. Injectables can be 
prepared in conventional forms, either as liquid solutions or suspension 
in liquid prior to injection, or as emulsions. Suitable excipients are for 
example, water, saline, dextrose, glycerol, ethanol or the like. In 
addition, if desired, the pharmaceutical compositions to be administered 
may also contain minor amounts of non-toxic auxiliary substance such as 
wetting or emulsifying agents, pH buffering agents and the like, such as 
for example, sodium acetate, sorbitan monolaurate, triethanolamine oleate, 
etc. 
The amount of active ingredient that may be combined with the carrier 
materials to produce a single dosage form will vary depending upon the 
host treated and the particular mode of administration of humans may 
contain from 0.5 mg to 5 gm of active agent compounded with an appropriate 
and convent amount of carrier material which may vary from about 5 to 
about 95% of the total composition. Dosage unit forms will generally 
contain between from about 1 mg to about 500 mg of an active ingredient. 
It will be understood, however, that the specific dose level for any 
particular patient will depend upon a variety of factors including the 
activity of the specific compound employed, the age, body weight, general 
health, sex, diet, time of administration, drug combination and the 
severity of the particular disease undergoing therapy. 
The invention is further described and illustrated in the following 
specific examples. 
SPECIFIC DESCRIPTION OF THE MOST PREFERRED EMBODIMENTS 
EXAMPLE 1 
Preparation of bromo(2-pyridyl)acetonitrile 
To a solution of (2-pyridyl)acetonitrile (12.0 g, 0.10 mole) in 150 ml of 
carbon tetrachloride, was added 18.1 g of N-bromosuccinimide (0.10 mole) 
at room temperature. The mixture was refluxed for 1.5 h. The resulting 
precipitate was removed by filtration and the solvent was removed under 
reduced pressure to give the crude product, which was recrystallized from 
hexane to yield 18.6 g (94%) of the title compound as red crystals: mp 
62.degree.-64.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.8.67 (d, 1H), 
7.97 (t, 1H), 7.70 (d, 1H), 7.51 (td, 1H), 5.60(s,1H) ppm; IR (KBr) 
.nu.3064, 2972, 1712, 1587, 1470, 1439, 1051, 993 cm.sup.-1 ; MS m/z 196, 
198 (M.sup.+), 117 (M.sup.- -Br); HRMS calcd for C.sub.7 H.sub.5 BrN.sub.2 
195.9630, found 195.9645. 
Proceeding in a similar manner, the following compound was made: 
bromo(4-methoxy-3,5-dimethyl-2-pyridyl)acetonitrile: 
mp 56.degree.-57.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.31 (s, 1H), 
5.67 (s, 1H), 3.81 (s, 3H), 2.37 (s, 3H), 2.30 (s, 3H) ppm; .sup.13 C NMR 
(CDCl.sub.3) .delta.164.84, 150.19, 149.56, 128.28, 125.59, 115.49, 
60.135, 27.99, 13.51, 11.05 ppm; IR (KBr) .nu.3415, 2988, 2210, 1568, 
1472, 1255, 997, 791 cm.sup.-1 ; MS m/z 255, 257 (MH.sup.+), 175 (M.sup.+ 
-Br). 
EXAMPLE 2 
Synthesis of (2-benzimidazolyl)thio!(2-pyridyl)acetonitrile 
A mixture of 2-mercaptobenzimidazole (0.30 g, 3.0 mmole), 
bromo(2-pyridyl)acetonitrile (0.59 g, 3.0 mmole) and potassium carbonate 
(0.37 g 3.0 mmole) in 50 ml of dry N,N-dimethylformamide was heated at 
60.degree. C. for 6 h. The solvent was evaporated. The residue was 
dissolved in ethyl acetate, washed with water and then saturated sodium 
chloride solution. The organic layer was dried over magnesium sulfate and 
evaporated to give a solid. The crude product was further purified by 
column chromatography on silica gel (100% ethyl acetate) to give 66 mg 
(10%) of the title compound as a solid; mp 166.degree.-167.degree. C.; 
.sup.1 H NMR (DMSO-d.sub.6) .delta.9.3 (m, 1H), 8.65 (m, 2H), 8.32 (m, 
1H), 7.78 (br s, 4H), 4.81 (br s, 2H) ppm; IR .nu.2206, 1512, 1465, 1432, 
1357, 1179, 740 cm.sup.-1. 
In a similar manner, by replacing 2-mercaptobenzimidazole with 
2-mercaptoimidazole, the following compound was made: 
(2-imidazolyl)thio!(2-pyridyl)acetonitrile: 
mp 203.degree.-204.degree. C. (dec); .sup.1 H NMR (CDCl.sub.3) .delta.8.51 
(d, 1H), 7.65 (t, 1H), 7.36 (d, 2H), 7.12 (d, 1H), 7.03 (dd, 1H), 6.33 (br 
s, 2H) ppm, .sup.13 C NMR (CDCl.sub.3) .delta.154.08, 148.23, 145.76, 
136.84, 134.95, 134.43, 119.15, 118.40, 109.32, 96.15 ppm; IR (KBr) 
.nu.3344, 3225, 2202, 1643, 1493, 1485, 1427 cm.sup.-1 ; 
EXAMPLE 3 
Synthesis of 
(5-methoxy-2-benzimidazolyl)thio!(4-methoxy-3,5-dimethyl-2-pyridyl)aceton 
itrile 
To a solution of 2-mercapto-5-methoxybenzimidazole (15.1 g, 0.14 mole) 
dissolved in 40 ml of 8.4% sodium hydroxide, was added 170 ml of methanol, 
followed by bromo(4-methoxy-3,5-dimethyl-2-pyridyl)acetonitrile(21.4 g, 
0.11 mole) at room temperature. The mixture was heated to reflux for 1 h 
under a nitrogen atmosphere. The resulting precipitate was removed by 
filtration and the methanol was evaporated. The residue obtained was 
extracted with chloroform, and the chloroform was washed 3 times with 
water and dried over magnesium sulfate. After evaporation of the solvent, 
the crude product was recrystallized from diethyl ether to give 22.6 g 
(90%) of the title compound as yellowish crystals: mp 
193.degree.-197.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.25 (s,1H), 
7.65 (dd, 1H), 7.30 (m, 1H), 6.90 (m, 1H), 6.30 (br s, 2H), 3.95 (s, 3H), 
3.75 (s, 3H), 2.50 (s, 3H), 2.20 (s, 3H) ppm. 
EXAMPLE 4 
Synthesis of 3-oxo(2-pyridyl)methyl!imidazo1,2-d!-1,2,4-thiadiazole 
To a solution of (2-imidazolyl)thio!(2-pyridyl)acetonitrile (30 mg, 0.14 
mmole) in 5 ml of chloroform, was added portionwise 0.12 g of 60% 
m-chloroperbenzoic acid (0.42 mmol). The mixture was stirred at room 
temperature for 10 h. The resulting mixture was washed with water and 
saturated sodium bicarbonate solution. The organic phase was then treated 
with charcoal, and filtered to give the crude product. Chromatography on 
silica gel (100% ethyl acetate) affords 22 mg (84%) of the title compound 
as a yellowish solid: mp 147.degree.-148.degree. C.; .sup.1 H NMR 
(CDCl.sub.3) .delta.8.87 (d, 1H), 8.30 (m, 2H), 7.95 (m, 1H), 7.57 (m, 
1H), 7.52 (m, 1H) ppm; IR (KBr) .nu.1700, 1660 cm.sup.-1 ; MS m/z 230 
(M.sup.+); HRMS calcd for C.sub.10 H.sub.6 N.sub.4 OS 230.0262, found: 
230.0267. 
EXAMPLE 5 
Synthesis of 
7-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole and 
6-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole 
To a solution of 
(5-methoxy-2-benzimidazolyl)thio!(4-methoxy-3,5-dimethyl-2-pyridyl)aceton 
itrile (5.31 g, 15 mmole) in 400 ml of chloroform, was added dropwise 60% 
m-chloroperbenzoic acid (8.62 g, 30 mmole) dissolved in 100 ml of 
chloroform at 0.degree.-5.degree. C. during a period of 1 h. After the 
addition was over, the reaction mixture was stirred at room temperature 
for 1 h. The resulting mixture was then washed with water and dried over 
magnesium sulfate. The solvent was evaporated to give the crude product. 
Chromatography on silica gel (ethyl acetate: hexane 1:1) yields 0.828 g 
(10%) of 
7-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole as a yellowish solid and 0.828 g (10%) of 
6-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole as a solid. 
7-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazolo 
4,5-a!benzimidazole: mp 170.degree.-171.degree. C.; .sup.1 H NMR 
(DMSO-d.sub.6) .delta.8.34 (s, 1H), 7.86 (d, 1H), 7.29 (d, 1H), 6.93 (dd, 
1H), 3.84 (s, 6H), 2.42 (s, 3H), 2.31 (s, 3H) ppm; IR (KBr) .nu.1684, 1654 
cm.sup.-1 ; MS m/z 369 (M.sup.+ +1). 
6-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazolo 
4,5-a!benzimidazole: mp 196.degree.-197.degree. C.; .sup.1 H NMR 
(DMSO-d.sub.6) .delta.8.34 (s, 1H), 7.67 (d, 1H), 7.34 (d, 1H), 7.10 (dd, 
1H), 3.84 (s, 3H), 3.74 (s, 3H), 2.44 (s, 3H), 2.31 (s, 3H) ppm; IR (KBr) 
.nu.1684 cm.sup.-1 ; MS m/z 369 (M.sup.+ +1). 
EXAMPLE 6 
Synthesis of dibromo(2-pyridyl)acetonitrile 
To a solution of (2-pyridyl)acetonitrile (6.0 g, 50.8 mmol) in 120 mL 
carbon tetrachloride was added N-bromosuccinimide (18.5 g, 104 mmol) at 
room temperature. The resulting mixture was heated to reflux for 2 h. 
After cooling, the precipitate was filtered. The carbon tetrachloride was 
evaporated to give 13.5 g (96%) of dibromo(2-pyridyl)acetonitrile as a 
dark-brown solid: mp 59.degree.-61.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.8.62 (d, 1H), 7.93 (d, 1H), 7.86 (dt, 1H), 7.35 (dr, 1H) ppm; 
.sup.13 C NMR (CDCl.sub.3) .delta.155.23, 148.94, 138.24, 125.38, 120.55, 
115.81, 30.81 ppm; HRMS calcd for C.sub.7 H.sub.4 N.sub.2 Br.sub.2 : 
273.8741, found: 273.8730. 
EXAMPLE 7 
Synthesis of 2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole -3(2H)-one 
The mixture of 2-mercaptobenzimidazole (29.30 g, 0.195 mole) and butyl 
isocyanate (48.3 mL, 0.33 mole) in a 500 ml of round-bottom flask equipped 
with a condenser was heated to 130.degree.-140.degree. C. in an oil bath 
for 45 min. After the reaction mixture was cooled to room temperature, the 
solid was filtered, washed with hexane, and dried under vacuum to give 
43.48 g (89%) of 1-(butylcarbamoyl)-1,3-dihydrobenzimidazole-2-thione as 
white crystals: mp 179.degree.-180.degree. C. 
To a solution of 1-(butylcarbamoyl)-1,3-dihydrobenzimidazole-2-thione 
(39.89 g, 0.16 mole) in 250 mL of chloroform, was added 25.57 g (0.16 
mole) of bromine, in 110 mL of chloroform, at 0.degree. C. After the 
addition was complete, triethylamine (44.6 mL, 0.32 mole), in 80 mL of 
chloroform, was added dropwise to the reaction mixture. The mixture was 
stirred at 0.degree. C. for an additional 4 h, and then stirred at room 
temperature for 14 h. The resulting mixture was washed with water and then 
with a 10% sodium sulfate solution. The organic layer was dried over 
magnesium sulfate and evaporated to give the crude product. 
Recrystallization from methanol gave 27.10 g (69%) of 
2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one as colourless 
crystals: mp 153.degree.-154.degree. C. (lit.: 156.degree.-157.degree. C., 
Martin et al. Tetrahedron 1983, 39, 2311). 
In a similar manner, by replacing n-butyl isocyanate with other alkyl 
isocyanates, the following compounds are made: 
2-ethyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one 
2-isopropyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one 
2-methyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one 
2-phenyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one 
2-benzyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one 
EXAMPLE 8 
Synthesis of 
3-dibromo(2-pyridyl)methyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
A mixture of 2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (2.0 
g, 8.1 mmol) and dibromo(2-pyridyl)acetonitrile (4.91 g, 17.8 mmol) in 50 
mL of dichloromethane was heated to reflux for 16 h. After cooling to room 
temperature, the precipitate was filtered, washed with dichloromethane and 
dried to give 2.76 g (80%) of the title compound as a light-brown solid: 
mp 195.degree. C. (dec); .sup.1 H NMR (CDCl.sub.3) .delta.8.25 (m, 2H), 
7.96 (dt, 1H), 7.76 (d, 1H), 7.32 (m, 2H), 6.95 (t, 1H), 6.92 (s, 1H) ppm; 
.sup.13 C NMR (CDCl.sub.3) .delta.166.08, 157.95, 150.34, 148.28, 147.71, 
38.31, 128.76, 124.79, 124.58, 122.94, 121.68, 119.49, 13.97, 54.37 ppm; 
HRMS calcd for C.sub.14 H.sub.8 Br.sub.2 N.sub.4 S: 421. 8836, found: 
421.8850. 
EXAMPLE 9 
Synthesis of 3-(oxophenylmethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
A mixture of 2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (6.0 
g, 24.3 mmole) and benzoyl cyanide (6.36 g, 48.5 mmole) in 80 mL of 
dichloromethane was stirred at room temperature for 24 h. The precipitate 
was filtered and washed with dichloromethane. The crude product was 
recrystallized from acetone to give 6.48 g (96%) of 
3-(oxophenylmethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole as yellow 
crystals: mp 190.degree.-191.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.8.35 (d, 3H), 7.82 (d, 1H), 7.73 (t, 1H), 7.59 (t, 2H), 7.50 (t, 
1H), 7.36 (t, 1H) ppm; .sup.13 C NMR (CDCl.sub.3) .delta.180.86, 163.69, 
150.82, 146.70, 134.79, 134.34, 131.22 (2C), 129.46 (2C), 128.74, 125.82, 
122.27, 119.49, 115.23 ppm; IR (KBr) .nu.1671 cm.sup.-1 ; HRMS calcd for 
C.sub.15 H.sub.9 N.sub.3 OS: 279.0466, found: 279.0475. Anal. Calcd for 
C.sub.15 H.sub.9 N.sub.3 OS: C, 64.50; H, 3.25; N, 15.04. Found: C, 63.93; 
H, 3.10; N, 14.53. 
In a similar manner, by replacing benzoyl cyanide with pyruvonitrile, the 
following compound was made: 
3-(1-oxoethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole: mp 
180.degree.-181.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.70 (d, 1H), 
7.80 (d, 1H), 7.50 (t, 1H), 7.38 (t, 1H), 2.83 (s, 3H); .sup.13 C NMR 
(CDCl.sub.3) .delta.187.02, 164.15, 150.69, 147.78, 129.63, 125.82, 
122.26, 119.27, 115.94, 26.74 ppm; IR (KBr) .nu.1703 cm.sup.-1. HRMS calcd 
for C.sub.10 H.sub.7 N.sub.3 OS: 217.0310, found: 217.0318. Anal. Calcd 
for C.sub.10 H.sub.7 N.sub.3 OS: C, 55.29; H, 3.25; N, 19.34. Found: C, 
55.31; H, 3.29; N, 19.46. 
In a similar manner, by replacing benzoyl cyanide with other cyanides, the 
following compounds are made: 
3-(1-oxopropyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(1-oxobutyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(1-oxo-2-phenylethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(cyclopentyloxomethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(1-oxo-2-phthalimidoethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
EXAMPLE 10 
Synthesis of 3-methyl-1,2,4-thiadiazolo4,5-a!benzimidazole 
2-Butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (1.00 g, 4.04 mmol) 
was refluxed in 100 mL acetonitrile for 18 h. The solvent was then 
evaporated and the residue was recrystallized from methanol to give 0.671 
g (88%) of the title compound: mp 192.degree.-193.degree. C.; .sup.1 H NMR 
(CDCl.sub.3) .delta.7.81 (dm, 2H), 7.47 (td, 1H), 7.34 (td, 1H), 2.92 (s, 
3H) ppm; IR (KBr) .nu.1564, 1481, 1453, 1430, 1304, 1208, 756, 745 
cm.sup.-1 ; MS m/z 189 (M.sup.+), 148 (M.sup.+ -CH.sub.3 CN). 
In a similar manner, by replacing acetonitrile with other alkyl nitriles, 
the following compounds are prepared: 
3-ethyl -1,2,4-thiadiazolo4,5-a!benzimidazole 
3-isopropyl-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(2-methylpropyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
EXAMPLE 11 
Synthesis of 
3-4-(methoxycarbonyl)phenyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
A mixture of 2-butyl -1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (0.3 
g, 1.2 mole) and methyl 4-cyanobenzoate (0.41 g, 2.5 mmole) in 7 mL of 
dichloromethane was heated to reflux for 20 h. The precipitate was 
filtered and washed with dichloromethane to give 0.16 g (48%) of 
3-4-(methoxycarbonyl)phenyl!-1,2,4-thiadiazolo 4,5-a!benzimidazole as a 
white solid: mp 204.degree.-206.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.8.33 (d, 2H), 7.98 (d, 2H), 7.83 (d, 1H), 7.49 (m, 2H), 7.20 (t, 
1H), 4.02 (s, 3H) ppm; .sup.13 C NMR (CDCl.sub.3) .delta.165.96, 165.30, 
151.08, 149.10,133.16, 132.55, 130.24(2C), 128.69(3C), 125.34, 121.58, 
119.96, 112.01, 52.56 ppm; IR (KBr) .nu.1729, 1508, 1448, 1275, 733 
cm.sup.-1 ; HRMS calcd for C.sub.16 H.sub.11 N.sub.3 O.sub.2 S, 309.0572 
found 309.05719. 
EXAMPLE 12 
Synthesis of 3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolo 
4,5-a!benzimidazole 
A mixture of 2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (10.0 
g, 40.4 mmole) and p-toluenesulfonyl cyanide (14.7 g, 81.0 mmole) in 120 
mL of dichloromethane was stirred at room temperature for 20 h. The 
precipitate was filtered and washed with dichloromethane to yield 12.2 g 
(91%) of 3-(4-methylphenylsulfonyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
as white powder: mp 231.degree.-234.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.8.53 (d, 1H), 8.04 (d, 2H), 7.82 (d, 1H), 7.56-7.44 (m, 4H), 2.53 
(s, 3H) ppm; .sup.13 C NMR (CDCl.sub.3) .delta.163.72, 150.38, 147.97, 
147.54, 132.48, 130.30(2C), 129.97(2C), 128.49, 126.14, 123.06, 119.70, 
114.67, 21.93 ppm; IR (KBr) .nu.1592, 1525, 1444, 1337, 1151, 1081, 735 
cm.sup.-1 ; HRMS calcd for C.sub.15 H.sub.11 N.sub.3 O.sub.2 S.sub.2 : 
329.0293, found: 329.0300. Anal. Calcd for C.sub.15 H.sub.11 N.sub.3 
O.sub.2 S.sub.2 : C, 54.70; H, 3.37; N, 12.76. Found: C, 54.29; H, 3.14; 
N, 14.59. 
EXAMPLE 13 
Synthesis of 3-(methoxycarbonyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
A mixture of 2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (4.0 
g, 16.2 mmole) and methyl cyanoformate (2.75 g, 32.4 mmole) in 30 mL of 
dichloromethane was stirred at room temperature for 21 h. The precipitate 
was filtered and washed with dichloromethane to give 3.36 g (84%) of 
3-(methoxycarbonyl)-1,2,4-thiadiazolo 4,5-a!benzimidazole as a colourless 
solid: mp 208.degree.-209.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.8.61 (d, 1H), 7.82 (d, 1H), 7.51 (t, 1H), 7.31 (t, 1H), 4.17 (s, 
3H) ppm; .sup.13 C NMR (CDCl.sub.3) .delta.164.02, 156.51, 150.67, 140.89, 
129.34, 125.93, 122.41, 119.48, 115.41, 54.04 ppm; IR (KBr) .nu.1733 
cm.sup.-1 ; HRMS calcd for C.sub.10 H.sub.7 N.sub.3 O.sub.2 S 233.0259, 
found 233.0262. Anal. Calcd. for C.sub.10 H.sub.7 N.sub.3 O.sub.2 S: C, 
51.50; H, 3.02; N, 18.02. Found: C, 51.41; H, 2.89; N, 18.16. 
In a similar manner, by replacing methyl cyanoformate with other 
cyanoformates, the following compounds are made: 
3-(ethoxycarbonyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(butoxycarbonyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(isopropoxycarbonyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(benzyloxy)carbonyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(cyclopentyloxy)carbonyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
EXAMPLE 14 
Synthesis of 3-(2-pyridyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
A mixture of 2-butyl -1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (15.0 
g, 60.7 mmole) and 2-cyanopyridine (13.3 g, 0.13 mole) in 150 mL of 
dichloromethane was stirred at room temperature for 72 h. The precipitate 
was filtered and washed with dichloromethane to give 10.4 g (68%) of 
3-(2-pyridyl)-1,2,4-thiadiazolo4,5-a!benzimidazole as a white solid: mp 
173.degree.-174.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.90 (d, 1H), 
8.70 (d, 1H), 8.30 (d, 1H), 7.99 (t, 1H), 7.80 (d, 1H), 7.57 (t, 1H), 7.47 
(t, 1H), 7.37 (t, 1H) ppm; .sup.13 C NMR (CDCl.sub.3) .delta.166.10, 
151.09, 150.11, 148.74, 147.73, 137.38, 130.50, 125.85, 125.24, 124.52, 
121.41, 119.11, 116.33 ppm; IR (KBr) .nu.3419, 3054, 1611, 1587, 1501, 
1463, 1446, 727 cm.sup.-1. HRMS calcd for C.sub.13 H.sub.8 N.sub.4 S 
252.0470, found 252.0882. Anal. Calcd for C.sub.13 H.sub.8 N.sub.4 S: C, 
61.89; H, 3.20; N, 22.21. Found: C, 61.48; H, 3.30; N, 22.24. 
EXAMPLE 15 
Synthesis of 3-amino-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a cooled solution of 
2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (2.00 g, 8.08 
mmole) in 25 mL dichloromethane, cyanamide (0.728 g, 16.2 mmole) Was added 
in one portion and the mixture was stirred for 48 h at room temperature. 
The resulting precipitate was filtered, slurried in methanol and 
subsequently washed with dichloromethane to give 1.01 g (66%) of 
3-amino-1,2,4-thiadiazolo4,5-a!benzimidazole as colourless crystals: mp 
255.degree.-256.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) 8 8.23 (d, 1H), 
7.71 (d, 1H), 7.43 (t, 1H), 7.54 (s, 2H), 7.32 (t, 1H) ppm; IR (KBr) 
.nu.3302, 3151, 1661, 1577, 1487, 1473, 1251, 1207, 810 cm.sup.-1 ; HRMS 
calcd for C.sub.8 H.sub.6 N.sub.4 S 190.0313, found 190.0293. Anal. Calcd 
for C.sub.8 H.sub.6 N.sub.4 S: C, 50.51; H, 3.18; N, 29.45. Found: C, 
50.26; H, 3.26; N, 29.38. 
EXAMPLE 16 
Synthesis of 3-bromo-1,2,4-thiadiazolo4,5-a!benzimidazole 
A mixture of 2-butyl-1,2,4-thiadiazolo4,5-a!benzimidazole-3(2H)-one (5.0 
g, 20.2 mmole) and cyanogen bromide (4.28 g, 40.4 mmole) in 100 mL of 
dichloromethane was stirred at room temperature for 26 h. The precipitate 
was filtered and washed with dichloromethane to yield 4.18 g (81%) of 
3-bromo-1,2,4-thiadiazolo4,5-a!benzimidazole as a white powder: mp 
189.degree.-190.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.23 (d, 1H), 
7.82 (d, 1H), 7.52 (t, 1H), 7.42 (d, 1H)ppm; .sup.13 C NMR (1:1 CDCl.sub.3 
:DMSO-d.sub.6): .delta.162.78, 149.67, 129.22, 125.53, 122.25, 119.48, 
117.25, 111.27 ppm; IR (KBr): .nu.3025, 2925, 1601, 1493, 1451, 1028, 757, 
701 cm.sup.-1 ; HRMS calcd for C.sub.8 H.sub.4 N.sub.3 SBr 252.9309, found 
252.9307. Anal. Calcd for C.sub.8 H.sub.4 N.sub.3 SBr: C, 37.81; H, 1.59; 
N, 16.54. Found: C, 37.44; H, 1.33; N, 16.57. 
In a similar manner, by replacing cyanogen bromide with other cyanogen 
halides, the following compounds are made: 
3-iodo-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-chloro-1,2,4-thiadiazolo4,5-a!benzimidazole 
EXAMPLE 17 
Synthesis of 3-oxo(2-pyridyl)methyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a solution of 
3-dibromo(2-pyridyl)methyl!-1,2,4-thiadiazolo4,5-a!benzimidazole (2.02 
g, 4.76 mmol) in 75 mL tetrahydrofuran was added a solution of silver 
nitrate (0.890 g, 5.24 mmol) in 75 mL water. The suspension was stirred 
for 2 days and then basified to pH 6 with aqueous sodium bicarbonate. 
After the addition of 1 mL saturated aqueous sodium chloride, the mixture 
was filtered on celite and the celite was washed with ethyl acetate. After 
extraction with water, the ethyl acetate was dried and evaporated to give 
a crude residue which was purified by flash chromatography using a mixture 
of chloroform/methanol 10:0.1 as the eluent. 1.05 g (78%) of the title 
compound was obtained as a yellow solid: mp 182.degree.-186.degree. C. 
(dec); .sup.1 H NMR (CDCl.sub.3) .delta.8.85 (m, 1H), 8.31 (dr, 1H), 8.19 
(d, 1H), 8.01 (td, 1H), 7.83 (d, 1H), 7.63 (ddd, 1H), 7.50 (ddd, 1H), 7.35 
(ddd, 1H) ppm; IR (film) 1673, 1511, 1444, 1235, 1057, 879, 733 cm.sup.-1 
; MS m/z 280 (M.sup.+), 148 (M.sup.+ -(2-pyridyl)C(O)CN). 
EXAMPLE 18 
Synthesis of 
3-bis(ethoxycarbonyl)methyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
A mixture of 3-bromo-1,2,4-thiadiazolo4,5-a!benzimidazole (0.2 g, 0.78 
mmole), diethyl malonate (0.15 g, 0.94 mmol) and triethylamine (0.13 mL, 
0.94 mmole) in 8 mL of THF was refluxed under a nitrogen atmosphere for 36 
h. The resulting mixture was extracted with ethyl acetate, washed with 
water and 10% aqueous sodium sulfate. The organic layer was dried over 
magnesium sulfate to give the crude product, which was purified by flash 
chromatography (35% ethyl acetate: 65% hexane) to afford 0.14 g (54%) of 
the title compound as a yellow oil: 
.sup.1 H NMR (CDCl.sub.3) .delta.9.48 (s, 1H), 8.06 (d, 1H), 7.63 (d, 1H), 
7.34-7.31 (m, 2H), 4.39 (q, 4H), 1.35 (t, 6H) ppm; IR (film) 1748 
cm.sup.-1. HRMS calcd for C.sub.15 H.sub.15 N.sub.3 O.sub.4 S 333.0783, 
found 333.0794. 
EXAMPLE 19 
Synthesis of 3-methoxy-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a cooled mixture of 3-bromo-1,2,4-thiadiazolo4,5-a!benzimidazole (4.55 
g, 17.9 mmole) in 50 mL of methanol, sodium methoxide (0.967 g, 17.9 
mmole) was added in one portion and stirred for 4 h at room temperature. 
The reaction mixture was evaporated to dryness under vacuum and the 
residue was taken-up in ethyl acetate and washed with water. The organic 
layer was dried with sodium sulfate, filtered and evaporated to yield 3.64 
g (94%) of 3-methoxy-1,2,4-thiadiazolo4,5-a!benzimidazole as colourless 
crystals: mp 172.degree.-175.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.7.83 (d, 1H), 7.75 (d, 1H), 7.42 (t, 1H), 7.27 (t, 1H), 4.32 (s, 
3H) ppm; .sup.13 C NMR (CDCl.sub.3) .delta.163.2, 150.3, 148.1, 128.2, 
124.9, 121.8, 119.2, 111.7, 57.5 ppm; IR (KBr) .nu.3418, 2942, 1595, 1492, 
1404, 1275, 1255, 1206, 1083, 755 cm.sup.-1. Anal. Calcd for C.sub.9 
H.sub.7 N.sub.3 OS: C, 52.67; H, 3.44; N, 20.49. Found: C, 52.28; 3.36; N, 
20.45. 
In a similar manner, by replacing sodium methoxide with other metal 
alkyloxides, the following compounds are made: 
3-ethoxy-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-propoxy-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-isopropoxy-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-butoxy-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-tert-butoxy-1,2,4-thiadiazolo4,5-a!benzimidazole 
3-(cyclopentyloxy)-1,2,4-thiadiazolo4,5-a!benzimidazole 
EXAMPLE 20 
Synthesis of 3-(dimethylamino)-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a cooled mixture of 3-bromo-1,2,4-thiadiazolo4,5-a!benzimidazole (15.44 
g, 0.0603 mole) in 100 mL dichloromethane, dimethylamine (40% solution in 
water) (5.44 g, 0.121 mole) was added dropwise. The reaction mixture was 
allowed to stir for 16 h at room temperature. It was then diluted with 
dichloromethane, washed with water, dried with sodium sulfate and 
evaporated under vacuum to give 10.47 g (80%) of 
3-(dimethylamino)-1,2,4-thiadiazolo4,5-a!benzimidazole as colourless 
crystals: mp 102.degree.-104.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.7.74 (t, 2H), 7.41 (t, 1H), 7.27 (t, 1H), 3.06 (s, 6H) ppm. Anal. 
Calcd for C.sub.10 H.sub.10 N.sub.4 S: C, 55.03; H, 4.62; N, 25.69. Found: 
C, 54.53; H, 4.90; N, 25.50. 
In a similar manner, by replacing dimethylamine with other amines, the 
following compounds were made: 
3-(ethylamino)-1,2,4-thiadiazolo4,5-a!benzimidazole: mp 
164.5.degree.-165.degree. C. (dec); .sup.1 H NMR (CDCl.sub.3) .delta.7.78 
(m, 2H), 7.65 (d, 1H), 7.43 (t, 1H), 7.21 (t, 1H) 3.68 (q, 2H), 1.45 (t, 
3H) ppm. 
3-(1-pyrrolyl)-1,2,4-thiadiazolo4,5-a!benzimidazole: mp 
118.degree.-119.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.7.77 (t, 2H), 
7.43 (t, 1H), 7.28 (t, 1H), 3.71 (m, 4H), 2.07 (m, 4H) ppm. 
3-(4-morpholinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole: mp 
140.degree.-142.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.7.78 (d, 1H), 
7.60 (d, 1H), 7.45 (t, 1H), 7.32 (t, 1H), 3.99 (m, 4H), 3.48 (m, 4H) ppm. 
3-(1-piperazinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole: mp 
116.degree.-118.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.7.76 (d, 1H), 
7.63 (d, 1H), 7.42 (t, 1H), 7.30 (t, 1H), 3.41 (m, 4H), 3.15 (t, 4H), 2.00 
(br s, 1H) ppm. 
3-(4-methyl -1-piperazinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole: mp 
158.degree.-158.5.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.7.77 (d, 
1H), 7.64 (d, 1H), 7.42 (t, 1H), 7.32 (t, 1H), 3.49 (m, 4H), 2.70 (m, 4H), 
2.43 (s, 3H) ppm. 
3-2-(methoxycarbonyl)methyl!amino!-1,2,4-thiadiazolo4,5-a!benzimidazole: 
mp 196.degree.-197.degree. C. Anal. Calcd for C.sub.11 H.sub.10 N.sub.4 
O.sub.2 S: C, 50.37; H, 3.84; N, 21.36. Found: C, 50.13; H, 3.96; N, 
21.26. 
In a similar manner, by replacing dimethylamine with other nucleophilic 
amines, the following compound is made: 
3-(methylamino)-1,2,4-thiadiazolo4,5-a!benzimidazole 
EXAMPLE 21 
Synthesis of 3-(hydroxyimino) 
phenylmethyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a solution of 0.5 g (1.79 mmol) of 
3-(oxophenylmethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole in 7 mL of 
ethanol was added 0.5 mL (6.46 mmol) of pyridine and 0.5 g (7.20 mmol) of 
hydroxylamine hydrochloride. The mixture was refluxed for overnight. The 
precipitate was collected by filtration, and washed with methanol and 
dichloromethane to give the crude product, which was recrystallized from 
methanol to yield 0.47 g (89%) of the title compound as white crystals. mp 
247.degree. C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.11.89 (s, 1H), 7.81 (d, 
1H), 7.73 (dd, 2H), 7.45-7.53 (m, 5H), 7.32 (t, 1H) ppm; .sup.13 C NMR 
(CDCl.sub.3) .delta.168.25, 155.24, 150.52, 147.95, 136.94, 135.67, 
134.30(2C), 133.03, 131.52(2C), 130.35, 127.26, 124.28, 116.91 ppm; IR 
(KBr) .delta.2731, 1549, 1475, 1450, 1251, 1194, 983, 753, 736 cm.sup.-1. 
HRMS calcd for C.sub.15 H.sub.10 N.sub.4 OS 294.0575, found 294.0583. 
EXAMPLE 22 
Synthesis of 3-(1-hydroxyethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a suspension of 3-(1-oxoethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
(729 mg, 3.36 mmol) in 200 mL methanol, was added sodium borohydride (140 
mg, 3.69 mmol). The mixture was stirred for 30 min and 0.1 mL of water was 
added. The methanol was evaporated and the residue was partitioned between 
ethyl acetate and 0.1M hydrochloric acid. The aqueous phase was extracted 
with ethyl acetate. The organic phases were combined, washed twice with 
brine, dried and evaporated. The crude residue was purified by 
chromatography using chloroform/methanol to give 
3-(1-hydroxyethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole. mp 
174.degree.-175.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.05 (d, 1H), 
7.80 (d, 1H), 7.47 (td, 1H), 7.36 (td, 1H), 5.39 (q, 1H), 2.76 (d, 1H), 
1.84 (d, 3H) ppm; IR (KBr) .nu.3136, 1544, 1494, 1478, 1451, 1374, 1250, 
1200, 1123, 1103, 1093, 752, 729, 711 cm.sup.-1 ; MS m/z 219 (M.sup.+), 
148 (M.sup.+ -CH.sub.3 CH(OH)CN). 
EXAMPLE 23 
Synthesis of 3-carboxy-1,2,4-thiadiazolo4,5-a!beuzimidazole 
To a 6 mL solution of 1N NaOH, 
3-(methoxycarbonyl)-1,2,4-thiadiazolo4,5-a!benzimidazole (1.0 g, 
4.3mmole) in 6 mL of dioxane, was added. The reaction mixture was stirred 
at room temperature until completion. The resulting mixture was then 
acidified with 3N HCl to pH .about.2.0, and stirred at room temperature 
for an additional 0.5 h. The solid was filtered, washed with water, and 
dried under vacuum at 60.degree. C. for 24 h to yield 0.74 g (78%) of the 
title compound as a colourless solid: mp 184.degree.-185.degree. C. (dec); 
.sup.1 H NMR (DMSO-d.sub.6) .delta.13.79 (br s, 1H), 8.59 (d, 1H), 7.78 
(d, 1H), 7.51 (t, 1H), 7.40 (t, 1H); IR (KBr) .nu.3435, 1705 cm.sup.-1 ; 
MS m/z 193 (M.sup.+ -OH), 175 (M.sup.+ -CO.sub.2). 
EXAMPLE 24 
Synthesis of sodium 3-carboxylato-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a suspension of 3-carboxy-1,2,4-thiadiazolo4,5-a!benzimidazole (10.00 
g, 45.62 mmol) in methanol (150 ml) and water (100 ml), 1M NaOH (45.6 ml) 
was added over a period of 1 h. After 4 h, the solution turned clear and 
the methanol was removed under reduced pressure. The aqueous solution was 
extracted with chloroform, the aqueous phase was freeze-dried to give the 
title compound (10.4 g, 95%) as a white solid: mp 225.degree.-227.degree. 
C.; .sup.1 H NMR (DMSO-d.sub.6) .delta.7.68 (d, 1H), 7.05 (d, 1H), 6.95 
(t, 1H), 6.80 (t, 1H) ppm; .sup.13 C NMR (DMSO-d.sub.6) .delta.167.20, 
161.76, 149.68, 148.84, 129.52, 126.23, 122.74, 118.37, 116.06 ppm; IR 
(KBr) .nu.3395, 3243, 1663, 1641, 1522, 1443, 1334, 827, 729 cm.sup.-1. 
EXAMPLE 25 
Preparation of 
3-(4-methyl-1-piperazinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
dihydrochloride 
To a clear solution of 
3-(4-methyl-1-piperazinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole (6.07 g, 
22.21 mmol) in 100 ml of dichloromethane, hydrogen chloride gas was 
bubbled through for 40 min. The solution became turbid with time. The 
suspension was filtered and dried under vacuum to give the title compound 
as a fine white powder 7.60 g (99%). mp 252.degree. C. (dec); .sup.1 H NMR 
(DMSO-d.sub.6 & D.sub.2 O) .delta.7.85 (d, 2H), 7.60 (t, 1H), 7.51 (t, 
1H), 3.86 (m, 2H), 3.56 (m, 6H), 2.91 (s, 3H) ppm; .sup.13 C NMR 
(DMSO-d.sub.6 & D.sub.2 O) .delta.164.39, 148.80, 144.27, 126.92, 126.12, 
123.41, 117.08, 113.20, 51.19, 45.87, 42.32 ppm; IR (KBr) .nu.3420, 1606, 
1571, 1475, 1461, 1225, 981, 761 cm.sup.-1. 
EXAMPLE 26 
Preparation of 2-butylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-Mercaptoimidazole (24.39 g, 0.244 mole) and butyl isocyanate (48.3 g, 
0.487 mole) were combined in a round-bottom flask and heated to 50.degree. 
C. for 30 min or until the reaction was complete by TLC. The reaction 
mixture was then cooled to room temperature and the solidified mass was 
triturated with 50 mL of hexane for 30 min. The beige solid was filtered, 
washed with a minimum amount of hexane and dried under reduced pressure to 
yield 44.96 g (93%) of 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-thione as 
beige crystals: mp 66.degree.-68.degree. C. 
To solution containing 1-(butylcarbamoyl)-1,3-dihydroimidazole-2-thione 
(4.73 g, 23.7 mmole) suspended in 15 mL of dichloromethane cooled to 
0.degree. C. under a nitrogen atmosphere, was added bromine (3.79 g, 23.7 
mmole) dissolved in 15 mL of dichloromethane, in a dropwise manner. After 
the addition was complete, triethylamine (4.81 g, 47.5 mmole) dissolved in 
15 mL dichloromethane was added such that the temperature of the reaction 
mixture never exceeded 0.degree. C. The reaction mixture was maintained at 
0.degree. C. for an additional 2 h and then stirred for 16 h at room 
temperature. It was then diluted with 150 mL of dichloromethane and washed 
twice with water and once with a saturated sodium chloride solution. The 
organic layer was then dried over magnesium sulfate and evaporated to 
dryness to yield 4.30 g (92%) of 
2-butylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one as an off-white powder: 
mp 142.degree.-143.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.7.40 (d, 
1H), 7.20 (d, 1H), 3.79 (t, 2H), 1.73 (m, 2H), 1.40 (m, 2H), 0.957 (t, 3H) 
ppm; IR (KBr) .nu.1702 cm.sup.-1. 
In a similar manner, by replacing butyl isocyanate with other selected 
isocyanates, the following compounds are made: 
2-methylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-ethylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-propylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-isopropylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-pentylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-hexylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-cyclohexylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
2-benzyl imidazo1,2-d!-1,2,4-thiadiazole -3(2H)-one 
EXAMPLE 27 
Synthesis of 3-(1-oxoethyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
To a cooled solution of 2-butylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
(2.49 g, 12.6 mmole) in 5 mL of dichloromethane, pyruvonitrile (1.74 g, 
25.2 mmole) was added dropwise and allowed to stir for 24 h. The 
precipitate was then collected by filtration, washed with dichloromethane 
and evaporated under reduced pressure to yield 0.662 g (31%) of 
3-(1-oxoethyl) imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one as yellow-green 
crystals: mp 142.degree.-144.degree. C.; .sup.1 H-NMR (CDCl.sub.3) 
.delta.8.23 (s, 1H), 7.51 (s, 1H), 2.78 (s, 3H) ppm; IR (KBr) .nu.3436, 
3168, 3106, 1516, 1408, 1363, 1229, 1136, 730 cm.sup.-1. Anal. Calcd for 
C.sub.6 H.sub.5 N.sub.3 SO: C, 43.11; H, 3.01; N, 25.13. Found: C, 43.11; 
H, 2.91; N, 25.27. 
In a similar manner, by replacing pyruvonitrile with benzoyl cyanide, the 
following compound was made: 
3-(oxophenylmethyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one: mp 
166.degree.-168.degree. C.; .sup.1 H NMR (CDCl.sub.3) .delta.8.44 (d, 2H), 
8.40 (s, 1H), 7.70 (d, 1H), 7.58 (t, 3H) ppm. 
In a similar manner, by replacing pyruvonitrile with other selected cyanide 
or nitriles, the following compounds are made: 
3-(1-oxopropyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
3-(1-oxobutyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
3-(1-oxopentyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
3-(1-oxohexyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
3-(cyclopentyloxomethyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
3-(1-oxo-2-phthalimidoethyl)imidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
EXAMPLE 28 
Synthesis 3-(methoxycarbonyl)imidazo1,2-d!-1,2,4-thiadiazole 
To a cooled solution of 2-butylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
(2.95 g, 15.0 mmole) in 25 mL dichloromethane, methyl cyanoformate (2.54 
g, 30 mmole) was added dropwise and the mixture was stirred for 16 h at 
room temperature. The precipitate was filtered and subsequently washed 
with dichloromethane to give 2.18 g (80%) of 
3-(methoxycarbonyl)imidazo1,2-d!-1,2,4-thiadiazole as colourless 
crystals: mp 164.5.degree.-165.degree. C.; .sup.1 H NMR (CDCl.sub.3) 
.delta.8.13 (s, 1H), 7.51 (s, 1H), 4.11 (s, 3H) ppm; IR (KBr) .delta.3440, 
1737, 1527, 1253, 1071 cm.sup.-1. Anal. Calcd for C.sub.6 H.sub.5 N.sub.3 
O.sub.2 S: C, 39.34; H, 2.75; N, 22.94. Found: C, 39.41; H, 2.51; N, 
22.94. 
In a similar manner, by replacing methyl cyanoformate with other 
cyanoformates, the following compounds are made: 
3-(ethoxycarbonyl)imidazo1,2-d!-1,2,4-thiadiazole 
3-(propoxycabonyl)imidazo1,2-d!-1,2,4-thiadiazole 
3-(butoxycabonyl)imidazo1,2-d!-1,2,4-thiadiazole 
3-(isopropoxycarbonyl)imidazo1,2-d!-1,2,4-thiadiazole 
3-(pentyloxy)cabonyl!imidazo1,2-d!-1,2,4-thiadiazole 
3-(cyclopentyloxy)cabonyl!imidazo1,2-d!-1,2,4-thiadiazole 
3-(benzyloxy)cabonyl!imidazo1,2-d!-1,2,4-thiadiazole 
EXAMPLE 29 
Synthesis of 3-bromoimidazo1,2-d!-1,2,4-thiadiazole 
To a cooled solution of 2-butylimidazo1,2-d!-1,2,4-thiadiazole-3(2H)-one 
(4.78 g, 0.0242 mole) in 25 mL dichloromethane, cyanogen bromide (5.13 g, 
0.0482 mole) was added in one portion and the mixture was stirred for 16 h 
at room temperature. The precipitate was filtered, slurried in 10 mL of 
methanol and subsequently washed with dichloromethane to give 4.45 g (90%) 
of 3-bromoimidazo1,2-d!-1,2,4-thiadiazole as a colourless powder: mp 
220.degree. C. (dec); MS m/z 205, 203 (M.sup.+). Anal. Calcd for C.sub.4 
H.sub.2 N.sub.3 SBr.1/2 H.sub.2 O: C, 22.55; H, 1.42; N, 19.72; O, 3.75; 
S, 15.02; Br, 37.50. Found: C, 22.79; H, 1.41; N, 19.42; O, 2.67; S, 
14.61; Br, 38.20. 
In a similar manner, by replacing cyanogen bromide with other cyanogen 
halides, the following compounds are made: 
3-iodoimidazo1,2-d!-1,2,4-thiadiazole 
3-chloroimidazo1,2-d!-1,2,4-thiadiazole 
EXAMPLE 30 
Synthesis of 3-methylsulfonyl-1,2,4-thiadiazolo4,5-a!benzimidazole 
To a solution of 3-methylthio-1,2,4-thiadiazolo4,5-a!benzimidazole (100 
mg, 0.45 mmole)in 10 mL dichloromethane was added m-chloroperbenzoic acid 
(287 mg, 0.95 mmole). The mixture was stirred at room temperature and the 
starting material was converted to the sulfoxide after a few hours; it was 
then further oxidized to the sulfone after 18 h. The solvent was than 
evaporated and the residue purified by chromatography using 
chloroform/methanol 10:0.1 as the eluent to yield 50 mg (44%) of 
3-methylsulfonyl-1,2,4-thiadiazolo4,5-a!benzimidazole as white solid: mp 
203.degree.-207.degree. C. (dec); .sup.1 H NMR (CDCl.sub.3) .delta.8.31 
(d, 1H), 7.84 (d, 1H), 7.54 (ddd, 1H), 7.43 (td, 1H), 3.63 (s,3H) ppm; IR 
(KBr) .nu.1530, 1487, 1444,1324, 1315, 1193, 1147, 1141, 735 cm.sup.-1, MS 
m/z 253 (M.sup.+), 174 (M.sup.+ -CH.sub.3 SO.sub.2), 148 (M.sup.+ 
-CH.sub.3 SO.sub.2 CN). 
EXAMPLE 31 
Acid stability of 
7-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole 
To examine acid stability of the captioned compound, the compound was 
dissolved in a minimum volume of methanol and the resulting solution was 
added to a 6 molar solution of hydrochloric acid. The compound was found 
to be very stable in acid and was totally recovered after stirring for 48 
hours at room temperature. Omeprazole, on the other hand, underwent 
complete decomposition in a few minutes under the above conditions. 
1,2,4-Thiadiazole derivatives are superior to omeprazole as a direct thiol 
trapping agent in acidic medium because they are stable in acid. 
EXAMPLE 32 
Reaction of 
3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazolo4,5-a!be 
nzimidazole with 3-mercaptopropionic acid. 
To a suspension of 250 mg of 
3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazolo4,5-a!be 
nzimidazole in 125 mL methanol and 38 mL 0.1M hydrochloric acid was added 
161 .mu.L of 3-mercaptopropionic acid. After complete degradation of the 
starting material, the mixture was neutralized to pH 6 with aqueous sodium 
bicarbonate and extracted with ethyl acetate. The ethyl acetate was dried 
on anhydrous magnesium sulfate and evaporated. The crude material was 
purified by chromatography to give 93 mg of 
2-imino-2-(2-mercapto-1-benzimidazolyl)-1-(4-methoxy-3,5-dimethyl-2-pyridy 
l) ethanone, 65 mg of 2-mercaptobenzimidazole and 61 mg of methyl 
2-(4-methoxy-3,5-dimethyl-2-pyridyl)-2-oxoacetate. 
2-Imino-2-(2-mercapto-1-benzimidazolyl)-1-(4-methoxy-3,5-dimethyl-2-pyridy 
l)ethanone: .sup.1 H NMR (CDCl.sub.3) .delta.10.55 (br s, 1H, NH or SH), 
10.35 (br s, 1H, NH or SH), 8.10 (d, 1H, J=7 Hz, ArH), 7.80 (s, 1H, H6 of 
pyridyl), 7.35-7.20 (m, 2H, 2.times.ArH), 7.10 (d, 1H, J=7.9 Hz, ArH), 
3.75 (s, 3H, OCH.sub.3), 2.60 (s, 3H, ARCH.sub.3), 2.15 (s, 3H, 
ArCH.sub.3) ppm; IR (KBr) .nu.3262, 1691, 1635, 1502, 1458, 1396, 1328, 
1272, 1247, 1004, 746 cm.sup.-1 ; MS (electrospray)m/z 341 (MH.sup.+), 191 
(MH.sup.+ -2-mercaptobenzimidazole). 2-Mercaptobenzimidazole: the material 
was found to be identical to an authentic sample purchased from Aldrich 
Chemical Co. by .sup.1 H NMR, IR and TLC. Methyl 
2-(4-methoxy-3,5-dimethyl-2-pyridyl)-2-oxoacetate: .sup.1 H NMR 
(CDCl.sub.3) .delta.8.45 (s, 1H, ArH), 4.1 (s, 3H, OCH.sub.3), 3.85 (s, 
3H, OCH.sub.3), 2.65 (s, 3H, ArCH.sub.3), 2.4 (s, 3H, ArCH.sub.3) ppm; IR 
(KBr) .nu.1747, 1703, 1468, 1394, 1310, 1242, 1206, 1120, 1004, 740 
cm.sup.-1 ; MS m/z 224 (M.sup.+ +H), 164 (M.sup.+ -CO.sub.2 Me), 136 
(M.sup.+ -CO.sub.2 Me-CO). 
EXAMPLE 33 
Reaction of 3-(dimethylamino)-1,2,4-thiadiazolo4,5-a!benzimidazole with 
phenethyl mercaptan. 
To a solution of 23 mg of 
3-(dimethylamino)-1,2,4-thiadiazolo4,5-a!benzimidazole in 10 mL of 
methanol was added 360 .mu.L of phenethyl mercaptan. After 1 min, the 
reaction is complete. The solvent was evaporated and the crude material 
was purified by chromatography to give 15 mg of N.sup.1, N.sup.1 
-dimethyl-2-mercapto-1-benzimidazolylamidine: .sup.1 H NMR (DMSO-d.sub.6) 
.delta.7.3-7.0 (m, 4H, 4.times.ArH), 3.35 (br s, 2H, NH, SH), 2.88 (s, 6H, 
2.times.NCH.sub.3) ppm; IR (KBr) .nu.3210, 1641, 1475, 1452, 1407, 1319 
cm.sup.-1 ; MS m/z 220 (M.sup.+), 150 (M.sup.+ -Me.sub.2 NC.dbd.NH). 
EXAMPLE 34 
Reaction of 3-bromo-1,2,4-thiadiazolo4,5-a!benzimidazole with phenethyl 
mercaptan. 
To a suspension of 500 mg of 3-bromo-1,2,4-thiadiazolo 4,5-a!benzimidazole 
in 50 mL methanol was added 790 .mu.L of phenethyl mercaptan. The solid 
rapidly dissolves. After completion of the reaction, the solvent was 
evaporated and the residue purified by chromatography to give 296 mg of 
2-mercapto-1-benzimidazolecarbonitrile:=H NMR (DMSO-d.sub.6) .delta.12.85 
(br s, 1H, SH), 7.5-7.2 (m, 4H, 4.times.ArH) ppm; IR (KBr) .nu.2259, 1509, 
1459, 1303, 1189, 752 cm.sup.-1 ; MS m/z 175 (M.sup.+), 150 (M.sup.+ -CN). 
EXAMPLE 35 
Reaction of 3-methoxy-1,2,4-thiadiazolo4,5-a!benzimidazole with phenethyl 
mercaptan. 
To a solution of 23 mg of 3-methoxy-1,2,4-thiadiazolo 4,5-a!benzimidazole 
in 10 mL of methanol was added 376 .mu.L of phenethyl mercaptan. After 1 
min, the reaction is complete. The methyl 
2-mercapto-1-benzimidazolecarboximidate was identified as the major 
reaction product of the reaction: .sup.1 H NMR (DMSO-d.sub.6) .delta.13.45 
(br s, 1H, SH or NH), 9.8 (s, 1H, NH or SH), 7.7 (d, 1H, J=8 Hz, ArH), 
7.35-7.2 (m, 3H, 3.times.ArH), 3.95 (s, 3H, OCH.sub.3) ppm; IR (KBr) 
.nu.3437, 3095, 1679, 1450, 1440, 1376, 1193, 735 cm.sup.-1 ; MS m/z=207 
(M.sup.+), 150 (M.sup.+ -MeOC.dbd.NH). 
EXAMPLE 36 
Reaction of 3-(oxophenylmethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole with 
phenethyl mercaptan 
To a suspension of 26 mg of 
3-(oxophenylmethyl)-1,2,4-thiadiazolo4,5-a!benzimidazole in 10 mL 
methanol was added 31 .mu.L of phenethyl mercaptan. It was found that the 
substrate undergoes complete conversion to 2-mercaptobenzimidazole by 
comparing with an authentic sample of 2-mercaptobenzimidazole purchased 
from Aldrich Chemical Co. 
EXAMPLE 37 
Reaction of 
3-hydroxy(4-methoxy-3,5-dimethyl-2-pyridyl)methyl!-1,2,4-thiadiazolo4,5- 
a!benzimidazole with phenethyl mercaptan. 
To a suspension of 25 mg of 
3-hydroxy(4-methoxy-3,5-dimethyl-2-pyridyl)methyl!-1,2,4-thiadiazolo4,5- 
a!benzimidazole in 10 mL methanol was added 250 .mu.L of phenethyl 
mercaptan. It was found that the substrate undergoes complete conversion 
to 2-mercaptobenzimidazole by comparing with an authentic sample of 
2-mercaptobenzimidazole purchased from Aldrich Chemical Co. 
EXAMPLE 38 
Reaction of 
3-(4-methylphenyl)sulfonyl!-1,2,4-thiadiazolo4,5-a!benzimidazole with 
phenethyl mercaptan. 
To a suspension of 31 mg of 
3-(4-methylphenyl)sulfonyl!-1,2,4-thiadiazolo4,5-a!benzimidazole in 10 
mL methanol was added 313 .mu.L of phenethyl mercaptan. It was found that 
the substrate undergoes complete conversion to 2-mercaptobenzimidazole by 
comparing with an authentic sample of 2-mercaptobenzimidazole purchased 
from Aldrich Chemical Co. 
EXAMPLE 39 
Effects of compounds of Formula I on Gastric Acid Secretions in Rats 
Fasted, adult (140-240 g), male, Sprague-Dawley rats were fasted for 24 h 
from food, but not water, and then treated by oral gavage with 1 to 1.5 mL 
total volume of compound of Formula I (300 .mu.mmol/Kg) on different days. 
Two hours later, rats were anesthetized with a combination of 
pentobartital and thiopental, the abdomen was opened and the pylorus was 
ligated, and tracheal, gastric, and peripheral venous canulas were placed. 
The stomachs were lavaged with 10 mL 0.9% saline every 10 min. for 30 min 
and the gastric effluent collected in receptacles to determine the basal 
acid secretion. Acid output was determined in each gastric effluent sample 
by back-titration to pH 7.0 using 0.02M NaOH. Then, 5 mL of an 8% peptone 
meal (pH 5.5) was instilled into the stomachs, mixed, and drained after 10 
min each time for 2 hours. Acid output was determined in each gastric 
effluent containing the peptone meal by back-titration to pH 5.5 using 
0.02M NaOH. 
In the controlled vehicle (n=6), 8% peptone stimulated acid output is noted 
at 160 mmol/30 min after 1 hr., while rats dosed with 
7-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole have an observed level of acid output at 20 
.mu.mmol/30 min after 1 h. 
7-Methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole demonstrated significant (p&lt;0.05) inhibition of 
meal-stimulated acid secretion at 300 .mu.mol/kg doses. 
EXAMPLE 40 
Effects of compounds of Formula I on Gastric Acid Secretions in Rats 
(Dose-dependent study) 
Fasted, adult (140-240 g), male, Sprague-Dawley rats were fasted for 24 h 
from food, but not water, and then treated by oral gavage with 1 to 1.5 mL 
total volume of 4 different doses (0.3, 3, 30, and 300 .mu.mol/kg) of each 
compound on different days. Two hours later, rats were anesthetized with a 
combination of pentobartital and thiopental, the abdomen was opened and 
the pylorus was ligated, and tracheal, gastric, and peripheral venous 
canulas were placed. The stomachs were lavaged with 10 mL 0.9% saline 
every 10 min. for 30 min and the gastric effluent collected in 
receptacles. Acid output was determined in each gastric effluent sample by 
back-titration to pH 7.0 using 0.02M NaOH. Then, 5 mL of an 8% peptone 
meal (pH 5.5) was instilled into the stomachs, mixed, and drained after 10 
min each time for 2 hours. Acid output was determined in each gastric 
effluent sample by back-titration to pH 7.0 using 0.02M NaOH. After 
measuring basal acid output for at least 30 minutes, acid output was then 
measured during a 2 h intravenous infusion of histamine (5 mg/kg). 
FIG. 5 shows gastric acid output (mmol/min) after administration of vehicle 
and after administration of 4 doses of 
7-methoxy-3-(4-methoxy-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazol 
o4,5-a!benzimidazole (0.3, 3, 30, and 300 mmol/kg) in anesthetized rats. 
7-methoxy-3-(4-methoxy 
-3,5-dimethyl-2-pyridyl)oxomethyl!-1,2,4-thiadiazolo4,5-a!benzimidazole 
demonstrated significant (p&lt;0.05 ) inhibition of histamine-stimulated acid 
secretion at 3, 30, 300 .mu.mol/kg doses. 
EXAMPLE 41 
In Vitro Inhibition of Gastric Acid Secretion By 
3-(4-methyl-1-piperazinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
dihydrochloride 
Acid secretion is measured indirectly by the accumulation of the weak base 
.sup.14 C-aminopyrine in the isolated murine gastric glands of mouse. The 
assay is performed in polypropylene eppendorf tubes containing 0.5 mL of 
resuspended mouse gastric glands. In addition, tubes contain the tested 
drug, acid secretagogues (e.g. histamine, di-butyryl cyclic AMP (cAMP), 
carbachol) and aminopyrine. Tubes are incubated for 60 min. at 37.degree. 
C. and continuously rotated. The reaction is stopped by centrifugation of 
the gland suspension for five min. at 1500 g. Supernatant is aspirated 
leaving the pellet containing intact gastric glands. The pellet is washed 
extensively and digested overnight in 1 mL of Protosol (Amersham). After 
neutralisation with acetic acid and addition of scintillation fluid, the 
radioactivity is counted in a beta-counter (Beckman). The amount of 
radioactivity trapped in the pellet corresponds directly with the amount 
of acid being secreted. Each experimental point is done in triplicate. In 
each experiment, energy independent consumption was estimated with 0.1 mM 
of dinitrophenol and basal acid secretion in the absence of acid 
stimulants. These values were then subtracted from corresponding results 
in order to calculate basal or secretagogue stimulated acid secretion. 
Mouse glands respond to a variety of conventional secretagogues and 
post-receptor mediators but not to gastrin. The maximum stimulation of 
acid secretion is achieved with 1 mM cAMP, 0.1 mM histamine, 0.1 mM IBMX, 
10 .mu.M carbachol, 10 .mu.M forskolin, 10 .mu.M calcium ionophore A23187, 
1 .mu.M thapsigarin. Each experiment is repeated a number of times and all 
results are expressed as a % of the maximum stimulation. For the purpose 
of comparing the relative potency of the compounds, each experiment 
contains positive controls using omeprazole for post-receptor/cAMP 
mediated responses and ranitidine which inhibits histamine mediated acid 
secretion. 
3-(4-Methyl-1-piperazinyl)-1,2,4-thiadiazolo4,5-a!benzimidazole 
dihydrochloride completely inhibited cAMP and histamine stimulated acid 
secretion at 100 .mu.M. Using the above procedure, the ED.sub.50 value for 
this compound was found to be 50 .mu.M.