Pyrimidylalkylthio benzimidale compounds, pharmaceutical compositions and use

This invention relates to 2- and 4-pyrimidinylmethylsulphinyl(and thio)benzimidazoles in which the pyrimidyl group is substituted by an optionally substituted amino group. These compounds inhibit exogenously and endogenously stimulated gastric acid secretion.

The present invention relates to novel substituted benzimidazole 
derivatives, intermediates useful in their preparation, pharmaceutical 
compositions containing them and a method of inhibiting gastric acid 
secretion by administering them. 
Substituted benzimidazole derivatives that are capable of inhibiting 
gastric acid secretion are known in the art. For example, GB No. 1500043 
and GB No. 1525958 disclose a series of 2-pyridylalkylthio- and 
2-pyridylalkylsulphinyl benzimidazoles in which the pyridyl group is 
optionally mono-substituted by an alkyl or a halogen group. Further, EP 
Nos. 5129B, 74341A and 80602A disclose series of 2-pyridylalkylsulphinyl- 
and 2-pyridylalkylthio-benzimidazoles in which the pyridyl group is 
optionally substituted by 1 to 3 substituents selected from methyl, ethyl, 
methoxy, ethoxy, methoxyethoxy or ethoxyethoxy; and GB No. 2134523A 
discloses further such compounds in which the pyridyl group is optionally 
substituted by 1 to 3 groups. Such compounds are believed to exert their 
effects by inhibition of the gastro-intestinal H.sup.+ -K.sup.+ ATPase 
enzyme. (Fellenius E., Beglindh T., Sachs G., Olke L., Elander B., 
Sjostrand S. E. and Wallmark B., 1981, Nature, 290, 159-61). 
In addition, U.S. Pat. No. 4,359,465 discloses the cytoprotective action of 
certain 2-pyridylalkylthio- and 2-pyridylalkylsulphinyl-benzimidazoles and 
their use in the treatment or prevention of gastro-intestinal inflammatory 
disease. 
It has now been found that 2- or 4-pyrimidylalkylsulphinyl (and thio) 
benzimidazoles in which the pyrimidyl group is substituted by an 
optionally substituted amino group inhibit exogenously and endogenously 
stimulated gastric acid secretion. 
The present invention therefore provides, in a first aspect, a compound of 
structure (I) 
##STR1## 
in which, 
R.sup.1 to R.sup.4 are the same or different and are each hydrogen, 
C.sub.1-6 alkyl, halogen, trifluoromethyl, C.sub.1-6 alkoxy, C.sub.1-6 
alkanoyl, C.sub.1-6 alkoxycarbonyl, RCF.sub.2 O, an ethoxy group 
substituted by 3 to 5 fluorine atoms, or R.sup.2 and R.sup.3 together form 
a group --O(CR.sub.2).sub.m O-- where m is 1 or 2, and each group R is 
hydrogen or fluorine; 
n is 0 or 1; 
R.sup.5 and R.sup.6 are the same or different and are each hydrogen, 
C.sub.1-6 alkyl or C.sub.3-6 cycloalkyl, or R.sup.5 and R.sup.6 together 
with the nitrogen atom to which they are attached form an azetidino, 
pyrrolidino, piperidino, piperazino, N--C.sub.1-4 alkylpiperazino or 
morpholino group; and 
one of X and Y is a nitrogen atom, and the other is a group CR.sup.7 where 
R.sup.7 is hydrogen, C.sub.1-6 alkyl or NH.sub.2 ; 
or a pharmaceutically acceptable salt thereof. 
Suitably, R.sup.1 to R.sup.4 are all hydrogen. More suitably, R.sup.1 and 
R.sup.4 are hydrogen, one of R.sup.2 and R.sup.3 is hydrogen and the other 
is halogen, trifluoromethyl, RCF.sub.2 O, an ethoxy group substituted by 3 
to 5 fluorine atoms, C.sub.1-6 alkoxycarbonyl or C.sub.1-6 alkanoyl. 
Preferably, R.sup.1 and R.sup.4 are hydrogen, one of R.sup.2 and R.sup.3 
is hydrogen, and the other is C.sub.1-6 alkyl or C.sub.1-6 alkoxy; or 
R.sup.1 and R.sup.4 are hydrogen and R.sup.2 and R.sup.3 are the same or 
different and are each C.sub.1-6 alkyl or C.sub.1-6 alkoxy or together 
form a group --O(CR.sub.2).sub.m O--. 
Suitably, ethoxy groups substituted by 3 to 5 fluorine atoms are, 
2,2,2-trifluoroethoxy, 1,1,2-trifluoroethoxy, 1,2,2-trifluoroethoxy, 
1,1,2,2-tetrafluoroethoxy, 1,2,2,2-tetrafluoroethoxy, and perfluoroethoxy. 
Suitably, groups --O(CR.sub.2).sub.m O-- in which m is 1 are for example, 
difluoromethylene dioxy (--OCF.sub.2 O--); preferably methylenedioxy 
(--OCH.sub.2 O--); suitably, groups --O(CR.sub.2).sub.m O-- in which m is 
2 are ethylenedioxy (--OCH.sub.2 CH.sub.2 O--) and trifluoroethylenedioxy 
(--OCHFCF.sub.2 O--). 
Suitably n is 0. Preferably n is 1. 
Suitably one of R.sup.5 and R.sup.6 is hydrogen and the other is C.sub.3-6 
cycloalkyl. Preferably R.sup.5 and R.sup.6 are the same or different and 
are each hydrogen or C.sub.1-6 alkyl. 
Suitably R.sup.5 and R.sup.6 together with the nitrogen atom to which they 
are attached form an azetidino group. Preferably, R.sup.5 and R.sup.6 
together with the nitrogen atom to which they are attached form a 
morpholino, pyrrolidino, piperazino, NC.sub.1-4 alkylpiperazino or 
piperidino group. 
Suitably R.sup.7 is NH.sub.2. Preferably R.sup.7 is hydrogen or C.sub.1-6 
alkyl. 
C.sub.1-6 Alkyl groups alone or as part of another group (for example 
C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl or C.sub.1-6 alkanoyl), can be 
straight or branched, for example methyl, ethyl, n-propyl, i-propyl, 
i-butyl, s-butyl, n-butyl, n-pentyl, i-pentyl or n-hexyl. Preferably 
C.sub.1-6 alkyl groups are methyl or ethyl. 
Preferably, C.sub.1-6 alkoxy groups are methoxy or ethoxy. 
Preferably C.sub.1-6 alkoxycarbonyl groups are methoxycarbonyl or 
ethoxycarbonyl. 
Preferably C.sub.1-6 alkanoyl groups are methanoyl or ethanoyl. 
C.sub.3-6 Cycloalkyl groups are cyclopropyl, cyclobutyl, cyclopentyl and 
cyclohexyl. Preferably, C.sub.3-6 cycloalkyl groups are cyclopentyl or 
cyclohexyl. 
Examples of compounds of the present invention include, 
(i) compounds of structure (I) in which X is nitrogen, Y is CR.sup.7 and n 
is 1, for example, 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
5-methoxy-2-(4-morpholino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazo 
le 
5-methoxy-2-(4-piperidino-5-methyl-2-pyrimidinylmethylsulphinyl)-(1H)-benzi 
midazole 
5-methoxy-2-(4-piperidino-5-amino-2-pyrimidinylmethylsulphinyl)-(1H)-benzim 
idazole 
5-methoxy-2-(4-dimethylamino-5-methyl-2-pyrimidinylmethylsulphinyl)-(1H)-be 
nzimidazole 
5-methoxy-2-(4-dimethylamino-5-amino-2-pyrimidinylmethylsulphinyl)-(1H)-ben 
zimidazole; 
(ii) compounds of structure (I) in which X is CR.sup.7, Y is nitrogen and n 
is 1, for example, 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzi 
midazole 
5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylsulphinyl)-(1H)-benz 
imidazole 
5-methoxy-2-(5-methyl-6-morpholino-4-pyrimidinylmethylsulphinyl)-(1H)-benzi 
midazole 
5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylsulphinyl)-(1H)-be 
nzimidazole 
5-methoxy-2-(6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazo 
le; and 
(iii) the corresponding thioethers of the foregoing compounds, ie the 
analogous compounds in which n is 0. 
Compounds of structure (I) in which n is 0, can form pharmaceutically 
acceptable acid addition salts with suitable organic and inorganic acids, 
the nature of which will be apparent to persons skilled in the art. For 
example, pharmaceutically acceptable salts can be formed by reaction with 
hydrochloric, sulphuric, sulphonic or phosphonic acids; aliphatic, 
alicyclic, aromatic or heterocyclic carboxyl or sulphonic acids; 
methionine, tryptophan, lysine or arginine and the like. 
Compounds of structure (I) in which n is 1 can also form pharmaceutically 
acceptable acid addition salts, but in aqueous solution the salts are less 
stable than those formed with the compounds of structure (I) in which n is 
0. 
Compounds of structure (I) in which n is 1 can form basic salts by reaction 
with an appropriate base. Such salts include, for example the sodium, 
potassium, lithium, calcium and magnesium salts, which can be prepared by 
methods well known to those skilled in the art; for example, the sodium, 
potassium and lithium salts can be prepared by reaction with sodium, 
potassium or lithium hydroxide in an aqueous or non-aqueous medium, and 
the calcium salts can be prepared by reaction of the sodium, lithium or 
potassium salts with calcium chloride in an aqueous or non-aqueous medium. 
Compounds of structure (I) in which n is 0 can also form basic salts but 
less readily than the compounds of structure (I) in which n is 1. 
Compounds of structure (I) in which n is 1 have an asymmetric centre at the 
S atom and are thus optically active compounds. As such, these compounds 
exist as two optical isomers (enantiomers). In addition, compounds of 
structure (I) in which one or more of R.sup.1 to R.sup.8 is a branched 
C.sub.3-6 alkyl group (either alone or as part of another group) may 
contain an additional asymmetic centre(s) due to the presence of the 
C.sub.3-6 alkyl group(s). Again, such compounds will exist aas two (or 
more) optical isomers. 
Both the pure enantiomers, racemic mixtures (50% of each enantiomer) and 
unequal mixtures of the two are included within the scope of the present 
invention. Further, all diasteriomeric forms possible (pure enantiomers 
and mixtures thereof) are within the scope of the invention. 
It should be noted that for all the compounds of the present invention, the 
substituents R.sup.1 and R.sup.4 as well as R.sup.2 and R.sup.3 are 
considered to be equivalent at room temperature in solution. This is due 
to the tautomerism of the benzimidazole nucleus causing an equilibrium 
between the 2 possible forms. 
Processes for the preparation of compounds of structure (I) and 
pharmaceutically acceptable salts thereof comprise 
(a) reacting a compound of structure (II) 
##STR2## 
with a compound of structure (III) 
##STR3## 
in which R.sup.1 to R.sup.6, X and Y are as described for structure (I) 
and one of L.sup.1 and L.sup.2 is SH and the other is a leaving group 
displaceable by a mercaptan; 
(b) reacting a compound of structure (IV) 
##STR4## 
in which R.sup.1 to R.sup.4 are as described for structure (I), with a 
compound of structure (V) 
##STR5## 
in which R.sup.5, R.sup.6, X and Y are as described for structure (I), 
X.sup.1 is CO.sub.2 H or CSX.sup.2 and X.sup.2 is halogen or C.sub.1-4 
alkoxy; 
(c) reacting a compound of structure (VI) 
##STR6## 
in which R.sup.1 to R.sup.4 are as described for structure (I), R.sup.9 is 
hydrogen or a protecting group and M is an alkali metal atom, with a 
compound of structure (VII) 
##STR7## 
in which R.sup.5, R.sup.6, X and Y are as described for structure (I) and 
Z is a leaving group; 
(d) reacting a compound of structure (VIII) 
##STR8## 
in which R.sup.1 to R.sup.4 are as described for structure (I), R.sup.9 is 
hydrogen or a protecting group and Y is a leaving group, with a compound 
of structure (IX) 
##STR9## 
in which R.sup.5, R.sup.6, X and Y are as described for structure (I) and 
M' is an alkali metal atom or the equivalent of an alkali metal atom, 
and, optionally, where desired: 
(i) oxidising a compound of structure (I) so formed in which n is 0 to a 
compound of structure (I) in which n is 1; 
(ii) reducing a compound of structure (I) so formed in which n is 1 to a 
compound of structure (I) in which n is 0; 
(iii) removing any protecting group R.sup.9 ; 
(iv) forming a pharmaceutically acceptable salt. 
Suitable leaving groups L.sup.1 displaceable by mercaptan include halogen, 
for example chloro, bromo or iodo, arylsulphonyloxy for example 
toluenesulphonyloxy, alkylsulphonyloxy for example methanesulphonyloxy, 
alkylmercapto, for example methylmercapto, alkylsulphinyl, for example 
methylsulphinyl, or alkylsulphonyl for example methylsulphonyl. 
Suitable leaving groups L.sup.2 are as described for L.sup.1, and may also 
be C.sub.1-4 acyloxy, for example acetoxy, or hydroxy. 
Suitable alkali metal atoms M include, for example lithium, sodium or 
potassium. 
Suitable leaving groups Z include, for example, halogen (preferably chloro) 
any hydroxy activated by esterification with, for example, an aryl or 
alkane sulphonic acid. Suitable sulphonic acids will be apparent to those 
skilled in the art, for example p-toluenesulphonic acid or 
methanesulphonic acid. 
Suitable leaving groups Y are those groups which form a reactive sulphinic 
acid derivative together with the sulphinyl group to which it is attached, 
and include for example, C.sub.1-4 alkoxy, di-C.sub.1-4 alkylamino and 
C.sub.1-4 alkylmercapto. 
Suitable groups M' which are equivalent to a metal atom include, for 
example, alkali earth metal atoms, (for example magnesium) which are 
substituted by a halogen atom (for example, bromine). 
Suitable protecting groups R.sup.9 are those conventional in the art for 
example as described in "Protective Groups in Organic Synthesis" T. W. 
Greene 1981 (Wiley). It will be appreciated that the group R.sup.9 should 
not be cleavable under the conditions of reaction of compounds of 
structure (VIII) and (IX). Such groups include for example benzyl or 
trityl groups. 
The reaction between compounds of structure (II) in which L.sup.1 is SH and 
compounds of structure (III) in which L.sup.2 is a leaving group can be 
carried out under basic conditions in the presence of an inert solvent at 
a temperature between ambient and the reflux temperature of the solvent. 
Suitable solvents include lower alkanols, for example methanol or ethanol, 
mixtures of lower alkanols with water, or ethers, for example 
dimethoxyethane or tehrahydrofuran. 
Suitable bases will be apparent to those skilled in the art and include for 
example, alkali metal hydroxides, for example, sodium or potassium 
hydroxide, alkali metal alkoxides, for example potassium t-butoxide, 
alkali metal hydrides, for example sodium or potassium hydride, or organic 
tertiary amines, for example triethylamine. 
Preferably the reaction is carried out at ambient temperature in ethanol as 
solvent, in the presence of sodium hydroxide solution. 
It is to be noted, and will be apparent to persons skilled in the art that 
under basic conditions L.sup.2 should be a group other than hydroxy or 
acetoxy, for example halogen, preferably chlorine. 
Further, the reaction can be carried out under neutral conditions in the 
presence of an inert solvent at the reflux temperature of the solvent. 
Suitable solvents include those hereinbefore described. 
Alternatively, when L.sup.2 is hydroxy or C.sub.1-4 acyloxy, for example 
acetoxy, the reaction can be carried out under acidic conditions. Suitable 
acidic conditions will be well known to those skilled in the art, for 
example, under reflux in hydrobromic acid, optionally in the presence of 
acetic acid. 
The reaction between compounds of structure (II) in which L.sup.1 is a 
leaving group and compounds of structure (III) in which L.sup.2 is SH can 
be carried out under basic conditions as described for the reaction 
between compounds of structure (II) in which L.sup.1 is SH and compounds 
of structure (III) in which L.sup.2 is a leaving group. 
The reaction between compounds of structure (IV) and compounds of structure 
(V) can be carried out under acidic conditions in a suitable solvent at a 
temperature between ambient and reflux temperature of the solvent used. 
Suitably the reaction is carried out in polar solvents, for example, lower 
alkanols, dimethyl sulphoxide, acetone, dimethylformamide or acetonitrile, 
optionally in the presence of water. Preferably the reaction is carried 
out in ethanol. 
Suitably the reaction is carried out in the presence of a strong acid, for 
example hydrobromic dor hydrochloric acid. Preferably the reaction is 
carried out in the presence of hydrochloric acid. 
Preferably the reaction is carried out at the reflux temperature of the 
solvent. 
The reaction between a compound of structure (VI) and a compound of 
structure (VII) can be carried out in an inert solvent at ambient or 
elevated temperature depending on the nature of groups M and Z. Suitable 
solvents include those solvents usually employed for the reaction of 
enolate ions with alkylating agents, for example, tetrahydrofuran, 
diethylether, benzene or toluene. Preferably, when M is lithium and Z is 
chlorine, the reaction is conducted in benzene at reflux temperature. 
The reaction between a compound of structure (VIII) and a compound of 
structure (IX) can be carried out in an organic solvent, for example, 
tetrahydrofuran or diethylether, under conditions normally used for 
organometallic reactions as will be well known to those skilled in the 
art. 
The products of reactions (a) to (c) are compounds of structure (I) in 
which n is 0. These products can be oxidised to compounds of structure (I) 
in which n is 1 by reaction with an oxidising agent. Suitable oxidising 
agents include, for example, nitric acid, hydrogen peroxide, peracids, 
peresters, ozone, dinitrogen tetroxide, iodosobenzene, N-halosuccinamide, 
1-chlorobenzotriazole, hypohalites, for example sodium hypochlorite or 
t-butyl hypochlorite, diazabicyclo[2,2,2]-octane bromine complex, sodium 
metaperiodate, selenium dioxide, manganese dioxide, chromic acid, ceric 
ammonium nitrate, bromine, chlorine, or sulphury chloride. Preferably the 
oxidising agent is m-chloroperbenzoic acid. 
The oxidation reaction is carried out under conditions known in the art for 
the oxidation of thiols to sulphoxides. Suitably, the reaction is carried 
out in an inert solvent at a temperature of between -70.degree. and the 
boiling point of the solvent used. Suitable solvents include aromatic or 
chlorinated hydrocarbons, for example benzene, toluene, dichloromethane or 
chloroform, esters, for example ethyl acetate, or ethers, for example 
dioxan. Preferably, the reaction is carried out in dichloromethane at a 
temperature of between -50.degree. and +20.degree. C. 
The compounds of structure (I) are obtained either as the free base, or in 
the form of a salt depending on the choice of starting materials and 
reaction conditions. If the free compound is obtained it can be converted 
into a salt by standard techniques well-known to those skilled in the art, 
for example by dissolving the compound in a suitable solvent and adding 
the desired acid or base; alternatively, if a salt is obtained it can be 
converted into the free compound, again by standard techniques, for 
example by treatment with an appropriate acid or base. 
Racemic mixtures may be produced and can be separated by standard 
techniques e.g. recrystallisation from optically active solvent or by high 
performance liquid affinity chromatography as described by S. Allenmark, 
B. Bomgren, H. Baren and P-O Lagerstrom in Analytical Biochemistry, 136, 
293-7, 1984. 
The intermediates of structure (IV) and the intermediate benzimidazole 
structures (II), (VI) and (VIII) are known or can be prepared by methods 
analogous to those known in the art. For example, compounds of structure 
(II) in which L.sup.1 is SH can be prepared by reacting the corresponding 
compounds of structure (IV) with carbon disulphide in the presence if 
alkali metal hydroxides, or with potassium ethylxanthate (Org. Syn., 30, 
56) or thiophosgene. Compounds of structure (II) in which L.sup.1 is a 
leaving group, for example halogen can be obtained from the corresponding 
compounds of structure (II) in which L.sup.1 is hydroxy by treatment with 
for example, phosphorous oxychloride. The compounds of structure (II) in 
which L.sup.1 is hydroxy can be prepared by reacting compounds of 
structure (IV) with phosgene. Compounds of structure (IV) can be prepared 
by methods analogous to those described in EP No. 127763A, DE No. 2848531, 
CA, 60, 13352h, 1964 and Liebigs Ann. Chem., 730, 16-30, 1969. 
Compounds of structure (VI) can be prepared by methylation, oxidation and 
protection (i.e. introduction of the group R.sup.9) of compounds of 
structure (II) in which L.sup.1 is SH. 
Compounds of structures (III), (V), (VII) and (IX) are novel and provide a 
further aspect of the invention. They can be prepared by methods analogous 
to those well known in the art, for example, compounds of structure (III) 
in which L.sup.2 is a leaving group displaceable by mercaptan and R.sup.7 
is NH.sub.2 can be prepared from the corresponding compounds of structure 
(III) in which R.sup.7 is hydrogen, by: 
(i) reaction of a compound of structure (III) in which R.sup.7 is hydrogen 
and L.sup.2 is, for example, methoxy, with nitric acid and sulphuric acid 
to give a compound of structure (III) in which R.sup.7 is a nitro group. 
Reduction of the intermediate nitro derivative so formed, gives a compound 
of structure (III) in which R.sup.7 is NH.sub.2 and L.sup.2 is methoxy. 
Deprotection of the group L.sup.2 with, for example, boron tribromide 
gives a compound of structure (III) in which L.sup.2 is hydroxy. The 
hydroxy group can then be converted to other suitable groups L.sup.2 using 
standard procedures, for example, reaction with p-toluenesulphonyl 
chloride gives a compound of structure (III) in which L.sup.2 is 
O-toluenesulphonyl; or reaction with thionyl chloride gives a compound of 
structure (III) in which L.sup.2 is chlorine; or 
(ii) reaction of a compound of structure (III) in which R.sup.7 is hydrogen 
and L.sup.2 is, for example, methoxy with, for example, bromine to give a 
compound of structure (III) in which R.sup.7 is bromine. Reaction of the 
intermediate so formed with ammonia gives the required compound of 
structure (III) in which R.sup.7 is NH.sub.2 and L.sup.2 is methoxy. 
Reaction of the compound of structure (III) so formed with, for example, 
boron tribromide gives the corresponding compound of structure (III) in 
which L.sup.2 is hydroxy. The group L.sup.2 can then be modified by 
standard procedures, for example, as described in (i) above. 
Compounds of structure (III) in which R.sup.7 is hydrogen can themselves be 
prepared by methods analogous to those known in the art. For example, by 
reaction of a compound of structure (X) 
##STR10## 
in which R.sup.8 is halogen, for example chlorine or bromine, and L.sup.2 
is methoxy or hydroxy, with a suitable amine of structure R.sup.5 R.sup.6 
NH in which R.sup.5 and R.sup.6 are as described for structure (I). 
Suitable conditions include heating in a suitable inert solvent, for 
example tetrahydrofuran in the presence of an excess of amine. 
Compounds of structure (X) can be prepared by methods well known to those 
skilled in the art, for example by reaction of the corresponding compounds 
in which R.sup.8 is hydroxy with, for example, phosphorus oxychloride to 
form a compound of structure (X) in which R.sup.8 is chlorine. 
Compounds of structure (X) in which R.sup.8 is hydroxy can be prepared by 
reaction of an appropriately substituted amidine with an appropriately 
substituted .beta.-keto-ester. For example, reaction of methoxyacetamidine 
hydrochloride and ethyl formyl acetate sodium salt gives a compound of 
structure (X) in which X is nitrogen, Y is CH and L.sup.2 is methoxy; and 
reaction of formamidine acetate and 3-keto-4-methoxybutyric acid ethyl 
ester gives a compound of structure (X) in which X is CH, Y is nitrogen 
and L.sup.2 is methoxy. 
Compounds of structure (III) in which L.sup.2 is SH can be prepared from 
compounds of structure (III) in which L.sup.2 is a leaving group, for 
example, halogen by reaction with, for example NaSH. 
Compounds of structure (V) can be prepared from the corresponding compounds 
of structure (III); for example, compounds of structure (V) in which 
X.sup.1 is CSCl can be prepared by reaction of a compound of structure 
(III) in which L.sup.2 is SH with thiophosgene. 
Compounds of structure (VII) can be prepared by methods analogous to those 
described in Roszniki Chem., 35, 475, 1961. 
The compounds of structure (I) and their pharmaceutically acceptable salts 
inhibit exogenously and endogenously stimulated gastric acid secretion and 
are useful in the treatment of gastro-intestinal diseases in mammals, in 
particular humans. Such diseases include, for example, gastric and 
duodenal ulcers, and Zollinger-Ellison Syndrome. 
Further, the compounds of structure (I) can be used in the treatment of 
other disorders where a cytoprotective and/or anti-secretory effect is 
desirable, for example, in patients with gastritis, NSAID induced 
gastritis, gastritis associated with a history of chronic and excessive 
alcohol consumption, gastric ulcers, acute upper gastrointestinal 
bleeding, for the prophylaxis of upper gastrointestinal haemmorage in 
patients at risk of the development of stress-related lesions of the 
gastric mucosa, and in the reduction of risk factors, for example gastric 
acidity and volume associated with pulmonary aspiration. 
It is believed that, after administration to mammals, compounds of 
structure (I) in which n is 0 exert their anti-secretory and 
cytoprotective activities after conversion into compounds of structure (I) 
in which n is 1. 
Furthermore it is believed that compounds of structure (I) in which n is 1, 
after administration to mammals, exert their anti-secretory activity after 
transformation under acid conditions into another chemically reactive 
species. Active species so generated from compounds of structure (I) are 
within the scope of the present invention. 
In therapeutic use, the compounds of the present invention are usually 
administered in a standard pharmaceutical composition. The present 
invention therefore provides in a further aspect pharmaceutical 
compositions comprising a compound of structure (I) or a pharmaceutically 
acceptable salt thereof and a pharmaceutically acceptable carrier. 
Compounds of structure (I) and their pharmaceutically acceptable salts can 
be administered in standard manner for example, orally, parenterally, 
rectally, transdermally, via inhalation or via buccal administration. 
The compounds of structure (I) and their pharmaceutically acceptable salts 
which are active when given orally can be formulated as liquids, for 
example syrups, suspensions or emulsions, tablets, capsules and lozenges. 
A liquid formulation will generally consist of a suspension or solution of 
the compound or pharmaceutically acceptable salt in a suitable liquid 
carrier(s) for example, ethanol, glycerine, non-aqueous solvent, for 
example polyethylene glycol, oils, or water with a suspending agent, 
preservative, flavouring or colouring agent. 
A composition in the form of a tablet can be prepared using any suitable 
pharmaceutical carrier(s) routinely used for preparing solid formulations. 
Examples of such carriers include magnesium stearate, starch, lactose, 
sucrose and cellulose. 
A composition in the form of a capsule can be prepared using routine 
encapsulation procedures. For example, pellets containing the active 
ingredient can be prepared using standard carriers and then filled into a 
hard gelatin capsule; alternatively, a dispersion or suspension can be 
prepared using any suitable pharmaceutical carrier(s), for example aqueous 
gums, celluloses, silicates or oils and the dispersion or suspension then 
filled into a soft gelatin capsule. 
Compounds of structure (I) in which n is 1 are susceptible to decomposition 
in acid media, and thus tablets and capsules containing such compounds are 
preferably provided with an enteric coating to protect the compound from 
acid degradation in the stomach or capsules used which are inherently acid 
resistant. Alternatively, the enteric coating can be provided by coating 
pellets containing the active ingredient before filling them into the hard 
gelatin capsule. Suitable enteric coating materials are those well known 
in the art of pharmacy and include for example shellac or anionic-film 
forming polymers such as cellulose acetate phthalate and 
hydroxypropylmethyl cellulose phthalate and the like, optionally in the 
presence of a plasticizer. 
It will be apparent to those skilled in the art that other standard 
techniques for enhancing the stability of such compounds can be used. The 
nature of such techniques will depend on the route of administration and 
include, for example, the formation of stable complexes with, for example 
.beta.-cyclodextrin. 
The compounds of structure (I) and their pharmaceutically acceptable salts 
which are active when administered parenterally (i.e. by injection or 
infusion) can be formulated as solutions or suspensions. 
A composition for parenteral administration will generally consist of a 
solution or suspension of the active ingredient in a sterile aqueous 
carrier or parenterally acceptable oil, for example polyethylene glycol, 
polyvinyl pyrrolidone, lecithin, arachis oil or sesame oil. Alternatively, 
the solution can be lyophilised and then reconstituted with a suitable 
solvent just prior to administration. 
A typical suppository composition comprises a compound of formula (I) or a 
pharmaceutically acceptable salt thereof which is active when administered 
in this way, with a binding and/or lubricating agent such as polymeric 
glycols, gelatins or cocoa butter or other low melting vegetable or 
synthetic waxes or fats. 
A typical transdermal formulation comprises a conventional aqueous or 
non-aqueous vehicle, for example, a cream, ointment lotion or paste or in 
the form of a medicated plaster, patch or membrane. 
A typical composition for inhalation comprises a solution, suspension or 
emulsion that may be administered in the form of an aerosol using a 
conventional propellant such as dichlorodifluoromethane or 
trichlorofluoromethane. 
Preferably the composition is in unit dose form. Each dosage unit for oral 
administration contains preferably from 1 to 250 mg (and for parenteral 
administration contains preferably from 1 to 150 mg) of a compound of the 
formula (I) or a pharmaceutically acceptable salt thereof calculated as 
the free base. 
The present invention provides a method of inhibiting gastric acid 
secretion which comprises administering to a mammal in need thereof an 
effective amount of a compound of structure (I) or a pharmaceutically 
acceptable salt thereof. 
The present invention also provides a method for the treatment of 
gastro-intestinal diseases and other conditions caused or exacerbated by 
gastric acidity which comprises administering to a mammal in need thereof 
an effective amount of a compound of structure (I) or a pharmaceutically 
acceptable salt thereof. 
The daily dosage regimen for an adult patient may be, for example, an oral 
dose of between 1 mg and 500 mg, preferably between 1 mg and 250 mg, or an 
intravenous, subcutaneous, or intramuscular dose of between 1 mg and 500 
mg, preferably between 1 mg and 150 mg, of the compound of the formula (I) 
or a pharmaceutically acceptable salt thereof calculated as the free base, 
the compound being administered 1 to 4 times per day. Suitably the 
compounds will be administered for a period of continuous therapy, for 
example for a week or more. 
In addition, the compounds of the present invention can be co-administered 
with further active ingredients, such as antacids (for example magnesium 
carbonate or hydroxide and aluminium hydroxide), non-steroidal 
antiflammatory drugs (for example indomethacin, aspirin or naproxen), 
steroids, or nitrite scavengers (for example ascorbic acid or 
aminosulphonic acid), or other drugs used for treating gastric ulcers, for 
example pirenzipine, prostanoids for example 16,16 dimethyl PGE.sub.2 or 
histamine H.sub.2 -antagonists, for example cimetidine.

The following examples illustrate the invention. Temperatures are recorded 
in degrees centigrade. 
EXAMPLE 1 
Preparation of 
5-Methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(i) A mixture of methoxyacetamidine hydrochloride (57 g) and ethyl formyl 
acetate sodium salt (150.5 g) in water (670 ml) were stirred at room 
temperature for 3 days. The volume was reduced and the solution acidified, 
saturated with sodium chloride and extracted with chloroform. After drying 
(MgSO.sub.4), the extracts were stripped to a solid which was triturated 
with ether to give 2-methoxymethyl-4-pyrimidone (53.5 g) m.p. 
125.degree.-7.degree.. 
(ii) A mixture of 2-methoxymethyl-4-pyrimidone (1.73 g) and phosphorus 
oxychloride (20 ml) were heated together under reflux for 30 minutes. The 
mixture was stripped, ice/water added and the pH raised to 14 (NaOH). The 
solution was extracted with chloroform, the extracts dried (MgSO.sub.4) 
and stripped to give 2-methoxymethyl-4-chloropyrimidine (1.72 g) as an oil 
which was used without further purification. 
(iii) Piperidine (6.17 ml) in dichloromethane (40 ml) was added dropwise to 
a solution of 2-methoxymethyl-4-chloropyrimidine (4.71 g) in 
dichloromethane (40 ml). After standing overnight at room temperature the 
mixture was heated under reflux for 1 hour. After cooling the solution was 
washed with water, dried and stripped. The residue was chromatographed 
(silica gel, CHCl.sub.3) to give 2-methoxymethyl-4-piperidinopyrimidine 
(4.49 g) as an oil. 
(iv) Boron tribromide (6.1 ml) was added dropwise to a stirred solution of 
2-methoxymethyl-4-piperidinopyrimidine (3.35 g) in dichloromethane (60 ml) 
at 0.degree.-5.degree. under nitrogen. After a further 30 minutes the 
mixture was poured onto ice, the pH raised to 13 (NaOH) and extracted with 
chloroform. The combined extracts were dried (K.sub.2 CO.sub.3) and the 
volume reduced. Ether was added to give 
2-hydroxymethyl-4-piperidino-pyrimidine (2.78 g) as a crystalline solid, 
m.p. 92.degree.-3.degree.. 
(v) Thionyl chloride (3.01 ml) was added dropwise to a stirred solution of 
2-hydroxymethyl-4-piperidino-pyrimidine (2.66 g) in chloroform (20 ml) 
cooled in an ice/salt bath. The mixture was allowed to warm to room 
temperature and stirred for a further 2.5 hours. The solution was poured 
onto ice, the pH raised to ca. 8 (NaOH), and extracted with chloroform. 
The extracts were dried and stripped to give 
2-chloromethyl-4-piperidino-pyrimidine (2.92 g) as an unstable oil which 
was used immediately. 
(vi) A mixture of 2-chloromethyl-4-piperidino-pyrimidine (2.89 g) and 
2-mercapto-5-methoxybenzimidazole (2.46 g) in ethanol (40 ml) and 1N 
sodium hydroxide (15 ml) was stirred at room temperature for 16 hours. 
After stripping the residue was washed with water and recrystallised from 
acetonitrile to give 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole (3.5 
g) m.p. 145.degree.-147.degree.. 
EXAMPLE 2 
Preparation of 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
A solution of m-chloroperbenzoic acid (1.69 g) in dichloromethane (25 ml) 
was added to a stirred solution of 
5-methoxy-2-[4-piperidino-2-pyrimidinylmethylthio]-(1H)benzimidazole (3.48 
g) in dichloromethane (75 ml) cooled to between -30.degree. and 
-35.degree.. After 1.5 hours at -20.degree. a further quantity of 
m-chloroperbenzoic acid (0.34 g) was added. After a further 30 minutes 
ammonia was passed through the reaction mixture and the precipitated solid 
filtered off. The filtrate was washed with aqueous sodium carbonate, which 
was back washed with chloroform. The combined organic phases were dried 
(K.sub.2 CO.sub.3) stripped and the residue purified by column 
chromatography (silica gel, 2% MeOH-NH.sub.3 /CHCl.sub.3) to give 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
(3.28 g) as an oil. 
EXAMPLE 3 
Preparation of 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
Calcium Salt 2.5H.sub.2 O 
5-Methoxy-2-(4-piperidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
(3.28 g) was partitioned between dichloromethane (20 ml), water (20 ml) 
and 1N sodium hydroxide (8.83 ml). The organic phase was separated off and 
the aqueous phase filtered and treated with a solution of calcium chloride 
(6H.sub.2 O, 0.97 g) in water (10 ml). The precipitate was filtered off 
and dried to give the title compound (1.89 g) m.p. 204.degree.-6.degree. 
(dec). 
C.sub.36 H.sub.40 CaN.sub.10 O.sub.4 S.sub.2.2.5H.sub.2 O: Found C, 52.30; 
H, 5.43; N, 16.71; S, 7.71% Requires C, 52.34; H, 5.19; N, 16.96; S, 
7.76%. 
EXAMPLE 4 
Preparation of 
5-methoxy-2-(4-morpholino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(i) A solution of morpholine (12.67 g) and 
2-methoxymethyl-4-chloropyrimidine (7.69 g) in tetrahydrofuran (100 ml) 
was heated under reflux for 1 hour. On cooling, the mixture was treated 
with water (100 ml), the pH adjusted to 8 (conc HCl) and extracted with 
chloroform. After drying (K.sub.2 CO.sub.3) the extracts were stripped, 
and the residue purified by chromatography (silica gel, CHCl.sub.3 
/methanol) to give 2-methoxymethyl-4-morpholinopyrimidine (5.4 g) as an 
oil. 
(ii) A solution of boron tribromide (9.02 ml) in dichloromethane (100 ml) 
was added dropwise to a stirred solution of 
2-methoxymethyl-4-morpholinopyrimidine (4.99 g) in dichloromethane (50 ml) 
at -25.degree. under nitrogen. After 15 minutes the mixture was allowed to 
warm to 0.degree.-5.degree., and left to stand for 2 hours at this 
temperature. After pouring onto ice, the pH was raised to 14 (NaOH), and 
the organic phase separated off. The aqueous phase was further extracted 
with chloroform, and the combined extracts dried (K.sub.2 CO.sub.3) and 
stripped. The residue was triturated with ether to give 
2-hydroxymethyl-4-morpholinopyrimidine (3.16 g) as a crystalline solid, 
m.p. 76.degree.-8.degree.. 
(iii) Thionyl chloride (3.4 ml) was added dropwise to a stirred solution of 
2-hydroxymethyl-4-morpholinopyrimidine in chloroform (30 ml) cooled in an 
ice bath. The mixture was allowed to warm to room temperature and left to 
stand for a further 1.5 hours. The solution was reduced to low volume, and 
ether added with stirring to give 2-chloromethyl-4-morpholinopyrimidine 
hydrochloride (3.8 g) as a crystalline solid, m.p. 214.degree.-6.degree.. 
(iv) 5N sodium hydroxide (6.42 ml) was added dropwise to a stirred mixture 
of 2-chloromethyl-4-morpholinopyrimidine hydrochloride (3.65 g) and 
2-mercapto-5-methoxybenzimidazole (2.63 g). Stirring was continued for 1.5 
hours and the mixture was allowed to stand for a further 16 hours. After 
stripping, the solid residue was washed with water and recrystallised from 
acetonitrile to give 
5-methoxy-2-(4-morpholino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(4.09 g), m.p. 188.degree.-92.degree.. 
EXAMPLE 5 
Preparation of 
5-methoxy-2-(4-morpholino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
Substituting 
5-methoxy-2-(4-morpholino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(3.53 g) for 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole and 
using corresponding molar proportions of the other reagents in the method 
of Example 2 gave 
5-methoxy-2-(4-morpholino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
(2.58 g), m.p. 154-6 (dec), from acetonitrile. 
C.sub.17 H.sub.19 N.sub.5 O.sub.3 S: Found C, 54.85; H, 5.11; N, 18.64; S, 
8.61. Requires C, 54.68; H, 5.13; N, 18.76; S, 8.59. 
EXAMPLE 6 
Preparation of 
5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(i) Substituting pyrrolidine (8.51 ml) for piperidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 1(iii), gave 
5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(8.49 g) as an oil. 
(ii) substituting 2-methoxymethyl-4-pyrrolidino-pyrimidine (8.31 g) for 
2-methoxymethyl-4-piperidino-pyrimidine and using corresponding molar 
proportions of the other reagents in the method of Example 1(iv), gave 
2-hydroxymethyl-4-pyrrolidino-pyrimidine (6.72 g), m.p. 
114.degree.-6.degree., from ether. 
(iii) Substituting 2-hydroxymethyl-4-pyrrolidino-pyrimidine (3.0 g) for 
2-hydroxymethyl-4-morpholino pyrimidine and using corresponding molar 
proportions of the other reagents in the method of Example 4(iii), gave 
2-chloromethyl-4-pyrrolidino-pyrimidine hydrochloride (3.72 g), m.p. 
186.degree.-9.degree.. 
(iv) Substituting 2-chloromethyl-4-pyrrolidino-pyrimidine hydrochloride 
(3.61 g) for 2-chloromethyl-4-morpholino-pyrimidine hydrochloride and 
using corresponding molar proportions of the other reagents in the method 
of Example 4(iv), gave 
5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(4.03 g), m.p. 199.degree.-202.degree., from ethanol. 
EXAMPLE 7 
Preparation of 
5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazol 
e 
Substituting 
5-methoxy-2-(4-pyrrolidino-2-pyrimidinyl-methylthio)-(1H)-benzimidazole 
(3.92 g) for 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole and 
using corresponding molar proportions of the other reagents in the method 
of Example 2 gave 
5-methoxy-2-(4-pyrrolidino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidazol 
e (2.88 g), m.p. 175.degree.-7.degree. (dec) from acetonitrile. 
C.sub.17 H.sub.19 N.sub.5 O.sub.2 S: Found C, 57.01; H, 5.35; N, 19.50; S, 
9.08. Requires C, 57.12; H, 5.36; N, 19.59; S, 8.97. 
EXAMPLE 8 
Preparation of 
5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(i) A 33% w/w solution of dimethylamine in ethanol (45 ml) was added 
dropwise to a stirred solution of 2-methoxymethyl-4-chloropyrimidine (7.54 
g) in ethanol (100 ml), cooled over an ice bath. The mixture was allowed 
to warm to room temperature, and left to stand for 16 hours. After 
stripping, the residue was treated with water (100 ml), and extracted with 
chloroform. The extracts were dried (K.sub.2 CO.sub.3) and stripped to 
give 2-methoxymethyl-4-dimethylaminopyrimidine (7.41 g) as an oil. 
(ii) Substituting 2-methoxymethyl-4-dimethylaminopyrimidine (7.2 g) for 
2-methoxymethyl-4-piperidinopyrimidine and using corresponding molar 
proportions of the other reagents in the method of Example 1(iv), gave 
2-hydroxymethyl-4-dimethylaminopyrimidine (5.7 g), m.p. 
83.degree.-4.degree., from ether. 
(iii) Substituting 2-hydroxymethyl-4-dimethylaminopyrimidine (5.55 g) for 
2-hydroxymethyl-4-morpholinopyrimidine and using corresponding molar 
proportions of the other reagents in the method of Example 4(iii), gave 
2-chloromethyl-4-dimethylaminopyrimidine hydrochloride (7.39 g), m.p. 
204.degree.-6.degree. from ether. 
(iv) Substituting 2-chloromethyl-4-dimethylaminopyrimidine hydrochloride 
(3.7 g) for 2-chloromethyl-4-morpholinopyrimidine hydrochloride and using 
corresponding molar proportions of the other reagents in the method of 
Example 4(iv), gave 
5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(4.41 g), m.p. 182.degree.-3.degree., from ethanol. 
EXAMPLE 9 
Preparation of 
5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidaz 
ole 
Substituting 
5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylthio)-(1H)-benzimidazole 
(4.25 g) for 
5-methoxy-2-(4-piperidino-2-pyrimidinylmethylthio)-(1H)-benzimidazole and 
using corresponding molar proportions of the other reagents in the method 
of Example 2 gave 
5-methoxy-2-(4-dimethylamino-2-pyrimidinylmethylsulphinyl)-(1H)-benzimidaz 
ole (2.67 g), m.p. 138.degree.-40.degree. (dec) from acetonitrile. 
C.sub.15 H.sub.17 N.sub.5 O.sub.2 S: Found C, 54.46; H, 4.97; N, 21.07; S, 
9.56. Requires C, 54.36; H, 5.17; N, 21.13; S, 9.68. 
EXAMPLE 10 
Preparation of 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole 
(i) 2-Methyl-3-keto-4-methoxybutyric acid ethyl ester (60 g) and 
formamidine acetate (39.06 g) were dissolved in methanol (150 ml) and 
treated, under nitrogen, with a sodium methoxide solution, prepared from 
sodium (17.42 g) and methanol (225 ml). The mixture was stirred at 
50.degree. for 23 hours, stripped, water added and the pH lowered to 7 
(HCl). The solution was extracted with chloroform, extracts dried 
(MgSO.sub.4) and stripped to a residue, which was triturated with diethyl 
ether to give 4-methoxymethyl-5-methyl-6-hydroxypyrimidine, 38.72 g, m.p. 
139.degree.-140.degree.. 
(ii) 4-Methoxymethyl-5-methyl-6-hydroxypyrimidine (38.40 g) was stirred 
with phosphorus oxychloride (275 ml) at room temperature for 24 hours. The 
mixture was stripped, ice/water added and the pH raised to 11.5 (NaOH). 
The solution was extracted with chloroform, extracts dried (MgSO.sub.4) 
and stripped to give 4-methoxymethyl-5-methyl-6-chloropyrimidine, 38.23 g, 
as an oil, which solidified on cooling to 5.degree. (m.p. 
37.degree.-38.degree.). It was used without further purification. 
(iii) Piperidine (15 ml) in tetrahydrofuran (40 ml) was added dropwise to a 
solution of 4-methoxymethyl-5-methyl-6-chloropyrimidine (5 g) in 
tetrahydrofuran (40 ml). The mixture was heated under reflux for 7 hours 
and then allowed to stand overnight at room temperature. It was filtered, 
stripped, and water added to the residual oil. The pH was lowered to 7.5 
(HCl) and extracted with chloroform. Extracts were dried (K.sub.2 
CO.sub.3) and stripped to give 
4-methoxymethyl-5-methyl-6-piperidinopyrimidine, 6.08 g, as an oil, which 
solidified on cooling to 5.degree. (m.p. 45.degree.-47.degree.). It was 
used without further purification. 
(iv) Boron tribromide (8.9 ml) in dichloromethane (25 ml) was added 
dropwise, under nitrogen, to a stirred solution of 
4-methoxymethyl-5-methyl-6-piperidinopyrimidine (5 g) in dichloromethane 
(100 ml) at 0.degree.-5.degree.. After a further 2 hours the mixture was 
poured onto ice, the pH raised to 13 (NaOH) and extracted with chloroform. 
Extracts were dried (K.sub.2 CO.sub.3) and stripped to a residue, which 
was triturated with diethyl ether to give 
4-hydroxymethyl-5-methyl-6-piperidinopyrimidine, 3.80 g, as a crystalline 
solid, m.p. 79.degree.-81.degree.. 
(v) Thionyl chloride (4.5 ml) in chloroform (30 ml) was added dropwise to a 
stirred solution of 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine (4.24 
g) in chloroform (30 ml) cooled in an ice-salt bath. The mixture was 
allowed to warm to room temperature and stirred for a further 22 hours. 
The solution was stripped to a residual glass which was triturated with 
diethyl ether to give 4-chloromethyl-5-methyl-6-piperidino-pyrimidine 
hydrochloride, 5.24 g, m.p. 182.degree.-184.degree.. 
(vi) A mixture of 4-chloromethyl-5-methyl-6-piperidino pyrimidine 
hydrochloride (4.63 g) and 2-mercapto-5-methoxybenzimidazole (3.18 g) in 
ethanol (180 ml) were heated at 50.degree. for 5 hours. The solution was 
stripped to a residual glass, to which water was added, the pH raised to 
13 (NaOH), and extracted with chloroform. Extracts were dried (K.sub.2 
CO.sub.3) and stripped to a residual glass which crystallised from ethyl 
acetate to give 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole, 5.67 g, m.p. 94.degree.-96.degree.. 
EXAMPLE 11 
Preparation of 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benz 
imidazole 
A solution of m-chloroperbenzoic acid (2.16 g) in dichloromethane (40 ml) 
was added to a stirred solution of 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole (4.0 g) in dichloromethane (110 ml) cooled to between -40.degree. and 
-50.degree.. After a further hour at -40.degree., ammonia was passed 
through the reaction mixture and the precipitated solid filtered off. The 
filtrate was stripped, and the residual glass triturated with acetonitrile 
to give 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benz 
imidazole, 2.66 g, m.p. 87.degree.-89.degree.. 
C.sub.19 H.sub.23 H.sub.5 O.sub.2 S0.5H.sub.2 O: Found C, 58.22; H, 5.87; 
N, 17.78; S, 8.43. Requires C, 57.93; H, 6.12; N, 17.78; S, 8.14. 
EXAMPLE 12 
Preparation of 
5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimid 
azole 
(i) Substituting pyrrolidine (12.20 ml) for piperidine, 1,4-dioxan as 
solvent for tetrahydrofuran, and using corresponding molar proportions of 
the other reagents, in the method of Example 10(iii), gave 
4-methoxymethyl-5-methyl-6-pyrrolidinopyrimidine, 5.52 g, as an oil. It 
was used without further purification. 
(ii) Substituting 4-methoxymethyl-5-methyl-6-pyrrolidino pyrimidine (5.4 g) 
for 4-methoxymethyl-5-methyl-6-piperidinopyrimidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 10(iv), gave 4-hydroxymethyl-5-methyl-6-pyrrolidinopyrimidine, 
4.11 g, m.p. 112.degree.-114.degree., from diethyl ether. 
(iii) Substituting 4-hydroxymethyl-5-methyl-6-pyrrolidino pyrimidine (3.90 
g) for 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 10(v), gave 4-chloromethyl-5-methyl-6-pyrrolidinopyrimidine 
hydrochloride, 4.88 g, m.p. 173.degree.-175.degree.. 
(iv) Substituting 4-chloromethyl-5-methyl-6-pyrrolidinopyrimidine 
hydrochloride (4.80 g) for 4-chloromethyl-5-methyl-6-piperidinopyrimidine 
hydrochloride in the method of Example 10(vi) and using corresponding 
molar proportions of other reagents, gave 
5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrrolidino-4-pyrimidinylmethylthio) 
-(1H)-benzimidazole, 5.78 g, m.p. 104.degree.-106.degree., from 
acetonitrile. 
EXAMPLE 13 
Preparation of 
5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylsulphinyl)-(1H)-ben 
zimidazole 
Substituting 
5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimid 
azole for 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylmethylthio)-(1H)-ben 
zimidazole and using corresponding molar proportions of other reagents in 
the method of Example 11 gave 
5-methoxy-2-(5-methyl-6-pyrrolidino-4-pyrimidinylmethylsulphinyl)-(1H)-ben 
zimidazole 3.33 g, m.p. 144.degree.-146.degree. (dec), from acetonitrile. 
C.sub.18 H.sub.21 N.sub.5 O.sub.2 S: Found C, 58.14; H, 5.70; N, 18.66; S, 
8.57. Requires C, 58.20; H, 5.70; N, 8.85; S, 8.63. 
EXAMPLE 14 
Preparation of 
5-methoxy-2-(5-methyl-6-morpholino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole 
(i) Substituting morpholine (12.9 ml) for piperidine, 1,4-dioxan as solvent 
for tetrahydrofuran, and using corresponding molar proportions of the 
other reagents, in the method of Example 10(iii), gave 
4-methoxymethyl-5-methyl-6-morpholinopyrimidine, 5.81 g, as an oil. It was 
used without further purification. 
(ii) Substituting 4-methoxymethyl-5-methyl-6-morpholinopyrimidine, (5.77 
g), for 4-methoxymethyl-5-methyl-6-piperidinopyrimidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 10(iv), gave 4-hydroxymethyl-5-methyl-6-morpholinopyrimidine, 3.46 
g, m.p. 66.degree.-68.degree., from petroleum ether (40/60). 
(iii) Substituting 4-hydroxymethyl-5-methyl-6-morpholinopyrimidine (3.35 g) 
for 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 10(v) gave 4-chloromethyl-5-methyl-6-morpholinopyrimidine 
hydrochloride, 4.22 g, m.p. 188.degree.-190.degree. (dec), from diethyl 
ether. 
(iv) Substituting 4-chloromethyl-5-methyl-6-morpholinopyrimidine 
hydrochloride (4.17 g) for 4-chloromethyl-5-methyl-6-piperidinopyrimidine 
hydrochloride and using corresponding molar proportions of the other 
reagents in the method of Example 10(vi) gave 
5-methoxy-2-(5-methyl-6-morpholino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole, 4.51 g, m.p. 129.degree.-131.degree., from ethyl acetate. 
EXAMPLE 15 
Preparation of 
5-methoxy-2-(5-methyl-6-morpholino-4-pyrimidinylmethylsulphinyl)-(1H)-benz 
imidazole 
Substituting 
5-methoxy-2-(5-methyl-6-morpholino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole for 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole and using corresponding molar proportions of other reagents in the 
method of Example 11 gave 
5-methoxy-2-(5-methyl-6-morpholino-4-pyrimidinylmethylsulphinyl)-(1H)-benz 
imidazle, 2.67 g, m.p. 176.degree.-178.degree. (dec), from acetonitrile. 
C.sub.18 H.sub.21 N.sub.5 O.sub.3 S: Found C, 55.74; H, 5.40; N, 17.96; S, 
8.17. Requires C, 55.80; H, 5.46; N, 18.08; S, 8.28. 
EXAMPLE 16 
Preparation of 
5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzim 
idazole 
(i) Substituting 4-methoxymethyl-5-methyl-6-chloropyrimidine (5.0 g) for 
2-methoxymethyl-4-chloropyrimidine, and using corresponding molar 
proportions of the other reagents, in the method of Example 8(i), gave 
4-methoxymethyl-5-methyl-6-dimethylaminopyrimidine, 4.77 g, as an oil. It 
was used without further purification. 
(ii) Substituting 4-methoxymethyl-5-methyl-6-dimethylaminopyrimidine (4.7 
g) for 4-methoxymethyl-5-methyl-6-piperidinopyrimidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 10(iv), gave 4-hydroxymethyl-5-methyl-6-dimethylaminopyrimidine, 
3.52 g, m.p. 46.degree.-48.degree., from petroleum ether (40-60). 
(iii) Substituting 4-hyroxymethyl-5-methyl-6-dimethylaminopyrimidine (3.35 
g) for 4-hydroxymethyl-5-methyl-6-piperidinopyrimidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 10(v), gave 4-chloromethyl-5-methyl-6-dimethylaminopyrimidine 
hydrochloride, 4.30 g, m.p. 176.degree.-178.degree., from diethyl ether. 
(iv) Substituting 4-chloromethyl-5-methyl-6-dimethylaminopyrimidine 
hydrochloride (4.20 g) for 4-chloromethyl-5-methyl-6-piperidinopyrimidine 
hydrochloride and using corresponding molar proportions of the other 
reagents in the method of Example 10, gave, after chromatography (silica 
gel, CHCl.sub.3 /MeOH), 
5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzim 
idazole, 5.28, g, as a glass. 
EXAMPLE 17 
Preparation of 
5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylsulphinyl)-(1H)-b 
enzimidazole 
Substituting 
5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzim 
idazole (3.86 g) for 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole and using corresponding molar proportions of other reagents in the 
method of Example 11, gave 
5-methoxy-2-(5-methyl-6-dimethylamino-4-pyrimidinylmethylsulphinyl)-(1H)-b 
enzimidazole, 3.36 g, m.p. 141.degree.-143.degree. (dec), from 
acetonitrile. 
C.sub.16 H.sub.19 N.sub.5 O.sub.2 S: Found C, 55.43; H, 5.64; N, 20.14; S, 
9.25. Requires C, 55,63; H, 5.54; N, 20.27; S, 9.28. 
EXAMPLE 18 
Preparation of 
5-methoxy-2-(6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 
(i) Substituting 3-keto-4-methoxybutyric acid ethyl ester (35.75 g) for 
2-methyl-3-keto-4-methoxybutyric acid ethyl ester and using corresponding 
molar proportions of the other reagents in the method of Example 10(i), 
gave 4-methoxymethyl-6-hydroxypyrimidine, 13.35 g, m.p. 
159.degree.-161.degree., from diethyl ether. 
(ii) Substituting 4-methoxymethyl-6-hydroxypyrimidine (15.40 g) for 
4-methoxymethyl-5-methyl-6-hydroxypyrimidine and using corresponding molar 
proportions of the other reagents in the method of Example 10(ii), gave 
4-methoxymethyl-6-chloropyrimidine, 16.77 g, m.p. 34.degree.-36.degree.. 
It was used without further purification. 
(iii) Substituting 4-methoxymethyl-6-chloropyrimidine (4.0 g) for 
4-methoxymethyl-5-methyl-6-chloropyrimidine and using corresponding molar 
proportions of the other reagents in the method of Example 10(iii) gave 
4-methoxymethyl-6-piperidino-pyrimidine, 4,88 g, as an oil. It was used 
without further purification. 
(iv) Substituting 4-methoxymethyl-6-piperidinopyrimidine (4.70 g) for 
4-methoxymethyl-5-methyl-6-piperidinopyrimidine and using corresponding 
molar proportions of the other reagents in the method of Example 10(iv) 
gave 4-hydroxymethyl-6-piperidinopyrimidine, 3.67 g, m.p. 
70.degree.-72.degree., from diethyl ether. 
(v) Substituting 4-hydroxymethyl-6-piperidinopyrimidine (3.56 g) for 
4-hydroxymethyl-5-methyl-6-piperidinopyrimidine and using corresponding 
molar proportions of the other reagents in the method of Example 10(v) 
gave 4-chloromethyl-6-piperidinopyrimidine hydrochloride, 4.55 g, m.p. 
187.degree.-189.degree., from diethyl ether. 
(vi) Substituting 4-chloromethyl-6-piperidinopyrimidine hydrochloride (4.47 
g) for 4-chloromethyl-5-methyl-6-piperidinopyrimidine hydrochloride and 
using corresponding molar proportions of the other reagents in the method 
of Example 10(vi) gave, after chromatography (silica gel, CHCl.sub.3 
/MeOH), 
5-methoxy-2-(6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, 
5.72 g, as a glass. 
EXAMPLE 19 
Preparation of 
5-methoxy-2-(6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
Substituting 
5-methoxy-2-(6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 
(4.12 g) for 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole and using corresponding molar proportions of other reagents in the 
method of Example 2, gave 
5-methoxy-2-(6-piperidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazole 
, 2.44 g, m.p. 98.degree.-101.degree., from ethyl acetate. 
C.sub.18 H.sub.21 N.sub.5 O.sub.2 S 0.33 EtOAc 0.18H.sub.2 O: Found C, 
57.44; H, 5.93; N, 17.29; S, 7.90. Requires C, 57,47; H, 5.99; N, 17.36; 
S, 7.95. 
EXAMPLE 20 
Preparation of 
5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 
(i) Substituting pyrrolidine (10.4 ml) for piperidine and using 
corresponding molar proportions of the other reagents in the method of 
Example 18(iii), gave 4-methoxymethyl-6-pyrrolidino pyrimidine, 4.65 g, as 
an oil. It was used without further purification. 
(ii) Substituting 4-methoxymethyl-6-pyrrolidinopyrimidine (4.60 g) for 
4-methoxymethyl-5-methyl-6-piperidinopyrimidine and using corresponding 
molar proportions of the other reagents in the method of Example 10(iv), 
gave 4-hydroxymethyl-6-pyrrolidinopyrimidine, 3.84 g, m.p. 
136.degree.-139.degree., from diethyl ether. 
(iii) Substituting 4-hydroxymethyl-6-pyrrolidinopyrimidine for 
4-hydroxymethyl-5-methyl-6-piperidinopyrimidine and using corresponding 
molar proportions of the other reagents in the method of Example 10(v), 
gave 4-chloromethyl-6-pyrrolidinopyrimidine hydrochloride, 4.66 g, m.p. 
180.degree.-182.degree. (dec), from diethyl ether. 
(iv) Substituting 4-chloromethyl-6-pyrrolidinopyrimidine hydrochloride for 
4-chloromethyl-5-methyl-6-piperidinopyrimidine hydrochloride and using 
corresponding molar proportions of the other reagents in the method of 
Example 10(vi), gave 
5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, 
6.41 g, as a glass. 
EXAMPLE 21 
Preparation of 
5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazol 
e 
Substituting 
5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 
(4.0 g) for 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole and using corresponding molar proportions of other reagents in the 
method of Example 11, gave 
5-methoxy-2-(6-pyrrolidino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidazol 
e, 2.79 g, m.p. 95.degree.-97.degree. (dec), from acetonitrile. 
C.sub.17 H.sub.19 N.sub.5 O.sub.2 S 0.04CH.sub.2 Cl.sub.2 0.67H.sub.2 O: 
Found C, 55.01; H, 5.68; N, 18.72; S, 8.54. Requires C, 54.85; H, 5.52; N, 
18.78; S, 8.59. 
EXAMPLE 22 
Preparation of 
5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 
(i) Substituting 4-methoxymethyl-6-chloropyrimidine (4.0 g) for 
2-methoxymethyl-4-chloropyrimidine, and using corresponding molar 
proportions of the other reagents, in the method of Example 8(i), gave 
4-methoxymethyl-6-dimethylaminopyrimidine, 4.1 g, as a low melting solid, 
m.p. 42.degree.-44.degree.. It was used without further purification. 
(ii) Substituting 4-methoxymethyl-6-dimethylaminopyrimidine (4.06 g) for 
4-methoxymethyl-5-methyl-6-piperidinopyrimidine and using corresponding 
molar proportions of the other reagents in the method of Example 10(iv), 
gave 4-hydroxymethyl-6-dimethylaminopyrimidine, 3.05 g, m.p. 
137.degree.-139.degree., from diethyl ether. 
(iii) Substituting 4-hydroxymethyl-6-dimethylaminopyridine (2.95 g) for 
4-hydroxymethyl-5-methyl-6-piperidinopyrimidine and using corresponding 
molar proportions of the other reagents in the method of Example 10(v), 
gave 4-chloromethyl-6-dimethylaminopyrimidine hydrochloride, 3.97 g, m.p. 
225.degree.-226.degree. from diethyl ether. 
(iv) Substituting 4-chloromethyl-6-dimethylaminopyrimidine hydrochloride 
(3.90 g) for 4-chloromethyl-5-methyl-6-piperidinopyrimidine hydrochloride 
and using corresponding molar proportions of the other reagents in the 
method of Example 10(vi), gave 
5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzimidazole, 
5.80 g, as a glass. 
EXAMPLE 23 
Preparation of 
5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidaz 
ole 
Substituting 
5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylthio)-(1H)-benzimidazole 
(4.0 g) for 
5-methoxy-2-(5-methyl-6-piperidino-4-pyrimidinylmethylthio)-(1H)-benzimida 
zole and using corresponding molar proportions of other reagents in the 
method of Example 11, gave 
5-methoxy-2-(6-dimethylamino-4-pyrimidinylmethylsulphinyl)-(1H)-benzimidaz 
ole, 3.06 g, m.p. 104.degree.-106.degree., from acetonitrile. 
C.sub.15 H.sub.17 N.sub.5 O.sub.2 S 0.23 CH.sub.3 CN: Found C, 54.45; H, 
5.33; N, 21.51; S, 9.23. Requires C, 54,48; H, 5.24; N, 21.50; S, 9.41. 
EXAMPLE A 
A tablet for oral administration is prepared by combining 
______________________________________ 
Mg/Tablet 
______________________________________ 
Compound of structure (I) 
100 
Mannitol 153 
Starch 33 
polyvinylpyrrolidone 
12 
microcrystalline cellulose 
30 
magnesium stearate 2 
330 mg 
______________________________________ 
into a 9 mm tablet. If the active ingredient is a compound of structure (I) 
in which n is 1 then the tablet is provided with an enteric coating. 
EXAMPLE B 
A pellet formulation for oral administration may be prepared by formulating 
the following into pellets by standard techniques 
______________________________________ 
% w:w 
______________________________________ 
Compound of structure (I) 
80 
microcrystalline cellulose 
10 
sodium carboxymethylcellulose 
2 
lactose 8 
______________________________________ 
If the active ingredient is a compound of structure (I) in which n is 1, 
the pellets are first enteric coated before being filled into hard gelatin 
capsules. 
EXAMPLE C 
An injection for parenteral administration is prepared by combining 
______________________________________ 
% w:w 
______________________________________ 
Compound of example 1 
1-5 
polyethylene glycol 
40 
ethanol 10 
water for injection EP to 
100 
______________________________________ 
The solution is then sterilised by an appropriate method and sealed into 2 
ml and 5 ml ampoules and vials. 
EXAMPLE D 
A reconstitutable lyophilisate for parenteral administration is prepared 
from: 
______________________________________ 
% w:w 
______________________________________ 
Compound of structure (I) as a salt 
1-5 
Mannitol 3 
NaCl sufficient to make 
reconstituted 
solution isotonic 
water to 100 
______________________________________ 
The solution is sterilised by an appropriate method, 5 ml portions 
dispensed into 5 ml vials and the solution lyophilised. The lyophilisate 
can be reconstituted with a suitable carrier, for example water, a 
buffered solution or a co-solvent mixture. 
Biological Data 
Inhibition of gastric acid secretion is demonstrated by the following test 
procedures: 
A. K.sup.+ Stimulated ATPase Activity 
The effects of a single high concentration (1 mM) of a compound of 
structure (I) on H.sup.+ -K.sup.+ -ATPase were determined at pH 6.1 and pH 
7.4. Preferred compounds of structure (I) were also tested over a range of 
concentrations to determine IC.sub.50 values at pH 6.1 and 7.4. 
(i) Preparation of Lyophilised Gastric Vesicles (H.sup.+ -K.sup.+ -ATPase) 
H.sup.+ -K.sup.+ -ATPase was prepared from the lyophilised gastric vesicles 
of pig fundic mucosa after the method of Saccomani et. al. (Biochem and 
Biophys. Acta., 465, 311, 1977). 
(ii) K.sup.+ Stimulated ATPase Activity 
Compounds of structure (I) were pre-incubated with H.sup.+ -K.sup.+ -ATPase 
preparation 30 .mu.g protein/ml from (i) in 10 mM Pipes/Tris buffer pH 6.1 
and pH 7.4. 
After 30 minutes at 37.degree. the pre-incubation was diluted 5-fold with 
assay buffer to start the ATPase reaction. The conditions in the assay are 
100 mM Pipes/Tris, 2 mM MgCl.sub.2, 10 mM KCl, 5 .mu.g/ml nigericin, 2 mM 
Na.sub.2 ATP, pH 7.0. After an incubation at 37.degree. for 15 minutes the 
inorganic phosphate released was determined by the method of Yoda & Hokin 
(Biochem. Biophys. Res. Com. 40, 880, 1970). Nigericin was dissolved in 
methanol, which at the final concentration of 0.5%, did not affect the 
enzyme activity. 
The effect of the same concentration of compound of structure (I) 
(pre-incubated with H.sup.+ -K.sup.+ -ATPase preparation at pH 7.4 as 
described above) on the recovery of 100 nmole of inorganic phosphate was 
also determined. 
Compounds of structure (I) were initially dissolved in dimethyl sulphoxide, 
polyethylene glycol (Type 400) or Pipes/Tris buffer. None of these 
solvents affects K.sup.+ -ATPase activity at the concentrations used. 
(iii) Results 
The compound of Example 3 was found to inhibit potassium stimulated H.sup.+ 
-K.sup.+ ATPase at pH6.1 and 7.4. 
B. Aminopyrine (AP) accumulation in intact gastric glands 
The effect of a single concentration (100 .mu.m) of a compound of structure 
(I) on dibutyryl cAMP stimulated AP metabolism in rabbit intact gastric 
glands was determined. Preferred compounds of structure (I) were tested 
over a range of concentrations to determine the IC.sub.50 value. 
(i) Preparation of intact gastric glands. 
Intact gastric glands were prepared from New Zealand white rabbits by the 
method of Berghindh et al. (Acta. Physio. Scand. 96, 150, 1976). Gastric 
mucosal scrapings were digested at 37.degree. C. for 45-60 min. with 
Collagenase (100 U, Type 1, Sigma), and glands harvested by coarse 
filtration and sedimentation. 
(ii) AP accumulation 
Test compound was incubated with glands and 300 .mu.M dibutyryl cAMP for 30 
minutes at 37.degree. C. Incubating medium contained 132.5 mM NaCl, 5.4 mM 
KCl, 1.0 mM NaH.sub.2 PO.sub.4, 5.0 mM Na.sub.2 HPO.sub.4, 1.2 mM 
MgSO.sub.4, 1.0 mM CaCl.sub.2, 11.1 mM glucose, 2.0 mg/ml rabbit albumin, 
10 .mu.g/ml phenol red, approximately 0.3 uM[.sup.14 C] aminopyridine (110 
mCi/mmole), pH 7.4. 
After incubation, glands were centrifuged and the supernatant removed. The 
glands were dried, weighed and dissolved in NaOH. The distribution of 
radioactivity between the supernatant and glands is then used to calculate 
the AP ratio after the method of Berglindh et al. (Acta. Physiol. Scand. 
97, 401, 1976). 
The IC.sub.50 value is the amount of compound required to inhibit the 
stimulated accumulation of aminopyrine by 50%. 
(iii) Results 
______________________________________ 
Compound of Example 
IC.sub.50 (.mu.M) 
______________________________________ 
3 16.00 
7 2.44 
9 1.20 
11 6.15 
13 0.32 
15 5.00 
17 3.33 
19 2.64 
______________________________________ 
C. Rat: Lumen perfused stomach (histamine stimulated gastric acid 
secretion). 
Using a modification of the procedure described by Ghosh and Schild (Br. J. 
Pharmacology, 13, 54, 1958), ED.sub.50 values after either intraduodenal 
(i.d) or intravenous (i.v) administration were obtained as follows: 
______________________________________ 
Route of ED.sub.50 
Compound of Example 
Administration 
.mu.mol/kg 
______________________________________ 
3 i.v. 1.4 
9 i.d. 2.4 
13 i.d. 2.8 
______________________________________ 
No overt signs of toxicity were observed in any of the foregoing tests.