CA1264053A - Cyclopropylmethyloxybenzimidazoles - Google Patents

Abstract

CYCLOPROPYLMETHYLOXYBENZIMIDAZOLES

ABSTRACT OF THE DISCLOSURE

Benzimidazole derivatives of the general formula [I]
are provided:

Description

)53 CYCLOPROPYLMETHYLOXYBENZIMIDAZOLES

BACKGROUND OF THE INVENTION
(1) Field of the Invention The present invention relates to benzimidazole derivatives having a cyclopropylmethyloxy group on the benzene ring, processes for preparing ~uch compounds, and p~armaceutical compositions such a compound as an active in~redient. The benzimidazole derivatives according to the present invention exhibit excellent stability during ~torage and can be u~ed for the treatment of gastric and duoden~l ulcers.

(2) Description of the Prior Art In recent years, the behavior of the potassium ion-dependent adenosine triphosphatase [hereinafter referred to as ~(H t R )-ATPase~], which takes part in the production of hydrochloric acid in the vesicles of gastric endoplasmic reticulum, has received attention in the pathologic physiology of gastric and duodenal ulcers, and the a~tivity of inhibi~ing the enzyme has become an indicator for antiulcer agents tGastroenterology, Vol. 1, pO 420 (1943); and ibid-, Vol. 73, p 921 (1977)~ From the above viewpoint, extenRive clinical investigation has been made on 5-methoxy-2-[2-(4-methoxy-3,5-dimethyl)-pyridylmethyl~ulfinyl]benzimidazole (hereinafter referredto as ~omeprazole~) [Japanese Patent Laid-Open No. 141,783/79; ~nd ~riti6h Medical ~ournal, Vol. 287, p. 12 (1983~].
~owever, a problem ari~es on the ~tability of o~eprazole, ~ince it i~ degraded at an unexpectedly high rate when ~tored without any special precaution6 being taken. In order to solve this problem, i~ is required to convert omeprazole into its ~al s ~Japanese Patent Laid-Gpen No. 167,587~84).
SUMMARY OF T~E INVENTION
_, _ In view o~ the abov~, the lnventors have conducted int~n~ive inve~ti~ation~ on v~riou omeprazole-related c~pounBs, ~s a result~ it h~s been found that benz-!

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t)53 imidazole derivatives having a cyclopropylmethyloxy group on the benzene ring possess a sufficient stability during storage even in the cases where they are not converted into their salts. It has also been found that the S benzimidazole derivatives, when orally administered, provide a gastric antisecretory effect based on its (H + K )-ATPase inhibition activity which is superior to that of omeprazoleO The present invention has been accomplished on the basis of the above findings~
According to one feature of the present invention, there is provided a benzimidazole derivative represented by the following General Formula 1I]:

R2 Rl ~ C~2 ~ ~ S - CH ~ R3 [I~

(wherein Rl is a hydrogen atom, a methyl group or a methoxy group, and R2 and R3 each is a hydrogen atom or a methyl ~roup, at least one of said Rl, R2 and R3 groups being a member other than a hydrogen atom~.
According to another feature of the present inYention ~ there is provided a process for preparing benzimidazole derivatives represented by the above General Formula ¦I].
According to still another feature o~ the present invention, there is provided a pharmaceutical composition cont~ining a benzimidazole derivative represented by the above General Formula [I~, as an active ingredi0nt.
According to another feature of the present invention, there is provided a sulfide compound represented by general formula L~:
~ .

' - 2a -~ CH2 ~ ~ S- CH2 ~ ~ R3 ]- wherein R i5 a hydrogen atom, a methyl group or a methoxy group, and R a~d R each i~ a hydrogen atom or a methyl group, at leas-t one of said R , R and R groups be:ing a memher o-ther than a hy~rogen a~om.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The benzimidazole derivatives represented by the above~described General Formula 1I] (hereinafter referred to briefly a~ the present compounds [IJ) can be prepared by oxidizing a sulfide compound represented by the following General Formula [II]:

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~ ~ Y~ r S -CH ~ R3 [II]

(wherein Rl, R2 and R3 haYe the same meanings as above) by use of an oxidizing agent in the presence of a solvent. As examples of usable solvents, mention may be made of halogenated hydrocarbons, ~uch as chloroform and dichloromethane; ~lcohols, ~uch as methanol, ethanol, prop~nol and butanol; and mixtures of two or more of these solvents. The use of chloroform or dichloromethane can be pref~rable with regard to yield attainable. As examples of usable oxidizing agents, mention may be made of peroxides, such as m-chloroperbenzoic acid, perbenzoic acid and peracetic acid. Of these peroxides, m-chloro-perbenzoic acid can be preferable with regard to stability. In ~aid oxidation reaction, there may be used 1.0 to 1.3 moles of oxidizing agen~s, per mole of said ~ulfide compounds [II]. The reaction may be carried out at a temperature of from -70 to 30 C, preferably from -20 to 10 DC ~ for a period of from 1 minute to 24 hours, preferably from 5 minutes to 1 hour.
~0 The sulfide compounds III] can be prepared by condensing a ~hiol compound represented by the following General Formula [IIIl:

~ ~ SH

with a pyridine compsund represented by the following General Formula [IV3:

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R~ ~CH2CQ
1 ~ \\
R ~ N-HCQ [IV]

(wherein Rl, R2 and R3 have the same meanings as ab~ve) in a reaction solvent in the presence of a base. As examples of usable reac~on 601vents, mention may be made of alcohols, ~uch a~ methanol~ ethanol, propanol and butanol; polar aprotic solvents, ~uch as dimethyl-formamide ~nd di~ethylsulfoxide; wa~er; and mixtures of two or more of these r~action solvents. As examples of usa~le bases, mention may be made of 80~iUm hydrogen carbonate, ~odium carbonate, potassium carb~nate~ sodium hydroxide ~nd pota~sium hydroxide. In said condensation reaction, there may be used about 1 mole of said pyridine compounds lIV] and about 2.0 to 3.0 moles of bases, per mole of said thiol compounds [IIIl. The reaction may be carried ~ut at a temperature o~ from 10 to 200 ~C, preferably from 60 to 80 C, for a period of from 1 minute to 12 hours, prefer~bly from 5 minutes to 4 hours.
The ~tarting materials, or thiol compounds tIII]/
can be prepared by reacting 3- or 4-cyclopropylmethyloxy-o-phenylenediamine with potassium xanthogenate in accordance with the method described in Organic Syntheses Collective Vol. 4, p. 569 (1963).
The ~tability during storage, the (H ~ K~ TPa~e inhibition ~ctivity, the gastric ant~secret~ry effect and 25 the acu~e tQXiCity of the pre~ent compound lIl will h~reinafter be explained in detail. The following ~ests ~ere ~arried out by u6ing typical examples of the pres~nt compounds ~I] ~hereinafter referred to a8 test ~ompounds), : wh~se nam~s ~re ~et forth below with their example numbcr~ $n p~rentheses.
2-[2-~3,5-dimethyl)pyridyl~ethylsulfinyl]-5 cyclo~
propyl~ethyloxybenzimidazole (~xample 1~;
2-t2 (~-Dethyl)pyridylmethylsulfinyl3-5-cyclo-; ~

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propylmethyloxybenzimidazole (Example 2);
2-[2-(3,5-dimethyl)pyridylmethylsulfinyl]-4-cyclo-propylmethyloxybenzimidazole (Example 3);
2-[2-(3,4,5-trimethyl)pyridylmethylsulfinyl] 5-cyclopropylmethyloxybenzimidazole (Example 4);
2-[2-(3,4,5-~rimethyl)pyridylmethylsulfinyl]-4-cyclopropylmethyloxybenzimidazole (Example 5);
2-[2-(4-methoxy-3,5-dimethyl)pyridylmethylsulfinyl]-4-cyclopropylmethyloxybenzimidazole (Example 6~;
2-t2-!4-methoxy-3,5-dimethyl)pyridylmethylsulfinyl]-5-cyclopropylmethyloxybenzimidazole (Example 7);
2-12-(4 methoxy-5-methyl)pyridylmethylsulfinyl]-5-cyclopropylmethyloxybenzimidazole (Example 8), and 2-[2-(4-methoxy-5-methyl)pyridylmethylsulfinyl]-4-cyclopropylmethyloxybenzimidazole (Example 9).(a) Stability During Storage The stability during storage of the present compounds [Il was t~sted by allowing each of the test com~ounds to s~and under severe conditions (at a temperature of 60 C
~nd at a relative humidity of 75~) for 6 days and then determining their residual rate6 by means of thin layer densitometry in accordance with the method described in Bunseki Kagaku Vol. 23, No. 9, p. 1016 (1974). In the thin layer densitometry, spots ~ach containing lO0 ~9 of a test sample were app~ied onto thin layer plates. ~he ~pots were developed with a mixture of chloroform and ethanol (lO:l, by volume). As the thin layer plates, TLC
Plate Silica Gel 60 F254 (lO x 20 cm, 0.25 mm in thickn~ss, a product of Merck & Co., Inc.~ was used. The di~tance of developmen~ was 15 cm. The densitometry was cffected by use of a ~himadzu Dichroic ~hromato~canner CS-~lO ~anufactured by Shimadzu Corporationl ~t a wavelength of 280 vr 300 nm.
~ The results obtained are shown in Table l. In the t~bl~ ~8 ~l~o ~hown, for the purpose of comparison, the residual r~te of omeprazole which was determined in the ~me manner as abov~

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Table 1 _ . _ ___ Stability During Storage (-D ~r., 7~ ~ D~ys) Compounds Residual Rate ( ~ ) ~neprazole 5 Example l 9l Example 2 59 Example 3 88 Example 4 94 Example 5 86 Example 6 67 Example 7 37 Example 8 32 Example 9 _ 76 It would be apparent from Table l that the presen~
compounds [I] - have far greater ~tability during storage than that of omeprazole.

- ~b-l) (H ~ K ) ATPase Inhibi ~ A~tivity The ~H ~ R ~-ATPase ~ nhibiting activity of the present compounds [I~ was determined in the following ~anner: A methanol or ethanol solution of a te ~ compound was added to a solution containing 300 to 500 ~g (reduced to protein) of said enzyme, so as to make a solu~ion in concentration ranging from 1 x lO 2M ts l x lO 4M of the test compound; the re~ulting solution was incubated at a temperatura of rom 35 to 37 C for a period of from 5 to 30 minut~s to allow the r~action to procecd; and the residual ac~ivity of (~ ~ K )-ATPase contained in the react~on ~ixture was determined.
The (H + R )-~TPase u~ed in the above test wa~
~repar~d fro~ the fundus ventriculi of fre~h hog ~tomachs ~n accordance w1t~ the ~ethod of Saccomani et al. [The Journal of Biological Chemistry, Vol- 251, No- 23v p. 7690 (l976)1~ The r~idu~l activity of (~ ~ K )-~TP~e w~s determin~d by incorporating magnesium chloride .

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and potassium chloride into the reaction mixture, adding ~denosine triphosphate thereto, inGubating the resulting mixture at a ~emperature of 37 ~C for a period of 5 to 15 minutes to allow the enzymatic reaction to proceed, and then colorimetrically determining the liberated inorganic phosphoric acid by the use of ammonium molybdate. The initial concentra~ions of magnesium chloride, potassium chloride and adenosine triphosphate were 2 mM, 2D mM and 2 mM, respectiv01y. The colorimetric measurement was effected at a wavelength range of from 360 to 400 nm. As ~ control experiment, the residual activity of (H J' K )-ATPase wa8 determined in the same manner as abuve without addition of any test compounds. The inhibiting effect was evaluated by the amount of test compound required to inhibit 50~ of the (B~ t X+)-~TPase activity (hereinafter referred to ~s nIC50~). To be more specific, the di~ference between the colorimetric reading obtained in the control experiment and the colorimetric reading obtained wi h a te~t compound is calculated at various molar concentrations, and the difference is divided by the reading of the control experiment to give a rate of inhibition. With inhibition rates thus obtained, a density-inhibition rate curve is plotted, and the IC50 value i~ determined based on the curve. The results obtained are ~hown in Table 2. In th~ table is also shown, for the purpose of comparison, the (H ~ K~)-ATPase inhibiting ~ctivity of omeprazole determined in the ~ame manner as above.

~6~53 Table 2 _ (H ~ K )-ATPase Inhibiting Activity Compounds IC50 (Molar Concentration) Omeprazole 1.8 x 10 3 Example 1 1.8 x 10 3 Example 2 2.1 x 10 3 Example 3 9.0 x 10 4 Example 4 1.0 x 10 3 Example 5 1.9 x 10 3 Example 6 1.9 x 10 3 Example 7 1.7 x 10 3 Ex~mple 8 3.0 x 10 4 Example 9 _4.3 x 10 4 (b-2? Gastric Antisecretory Effect The gastric ~cid secretion inhibiting effect of the present comp~unds lI] was tested in the following manner:
1 to 100 mg/kg of a test compound was or~lly administer~d at ~n interval of S minutes to a group of 5 male Wistar rat~ (body weight: ca. 200 ~) which had been fasted overnlght~ Exactly 1 hour ~fter the completion of the administration, the pyloric regions of their stomachs were ligated. After 4 hour~, the total acid contained in the gastric juice of each rat was determined.
In the above determination, the test compounds were used in $he form of a ~uspension in a 1:1 (by volume~
~ixture of polyethylene ~lycol ~nd aqueous 0.5% carboxy-

3~ ~ethylcellulose. To collect the gastric juice, the ra~swere killed, and their ~tomachs ~ere cu~ open. The total acid in the ga~tric juice was detenmined by titra~ing the ~uice with ~gueous 0.1 N ~odium hydroxide solution until ~t5 p~ reached 7Ø ~ a control experiment, the ~otal acid cont~ined ln the ga~tric juice of rat~ not a~mini~t~ra~ ~ith the co~pounds was ~180 de~ermined in the same manner ~s ~bove. The ~tric ~nti6ecr~tory " ~ . ' :: ~ . ::-: :

i, L'l ~353 g effect was evaluated by the dosage (mg/kg) required to inhibit the ~ecretion of gastric acid, or total gastric acid, by 50~ ~hereinafter referred to as ED50). In order to determine the ED50 value, the difference in total aeid between a ~roup of rats administered with a test compound and a group of rats not administered with any of the test compsunds was calculated, and the difference was then divided by the total acid of the latter ratsl so as ~o obtain a r~te of inhibition. With inhibition rates thus obtained, a dosage-effect curve was plotted, and the ED50 value was determined on the basis of the curveO The results obtained are shown in Table 3. In the table is also ~hown, for the purpose of comparison, the ED50 value of omepr~zole determined in the same manner as above.
Table 3 , Gastric Antisecretory Effect Compounds ED50 (mg/kg) [po]
Omeprazole 30.5 Example 1 17.8 ~xample 3 19.5 Example 4 22.1 Example 8 25.9 It would be apparent rom Tables 2 and 3 that the present compounds tI3 have marked (H ~ K )-ATPase inhibiting activities and, when orally administered, exert gastric acid secretion inhibiting effects ar ~reater than that of omeprazole.
(c) Acute Toxic ty Using 5 weeks old male ~i~tar rats, acute toxicity (LD50) of two repre~entative compounds (compounds obtainad in Examples 1 and 8) of he pres~nt compounds lIJ was tested. LD50 values of the two compounds were not les~ than ~.0 g/kg.when admini~tered orally ~nd not le~ than S00 mg/kg when ~dministered intraperi~oneally.

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Taking into consideration the above test results on the stability during ~torage, (H+ + ~ ~-ATPase inhibiting activity, gastric antisecretory effect and acute toxicity, it can be said that the present compounds [I]
can be a medicament for treating gastric and/or duodenal ulcers, which medicament is free from deactivation during storage~
The presen~ compounds ~I] can be incorpora~ed with physiologically harmless solid or liguid pharm~ceutical carriers to prepare pharmaceutical compositions. The compositions can be in the form of ~olid formulations, such as tablets, capsules, powders, p~rticles and granules, ~s well as liquid formulations, such as ~olutions, emulsions and ~uspen6ions. In the case where the oompositions are ~olid formulations, they may be provided with coatings, so as to make them soluble in the intestines. Any pharmaceutical carriers normally employed for such formulations may be used therefore, including, or example, excipients, binding agents or 20 disintegrators, ~uch as corn 6tarch, dextrins, ~ or ~-cyclodextrin, glucos~, lactose, cucrose, methyl celluloses, ~thyl celluloses, carboxymethyl ~elluloses calcium, cryst~lline celluloses, magnesium stearate, ~odium alginate, Witepsole W35, Witepsole E85, polyvinyl alcohols and ~ynthetic aluminum 6ilicate; lubricating agents or coating agents, such as talc, waxes, hydroxy-propyl celluloses, hydroxypropyl ~ethyl celluloses, hydroxyethyl ~ethyl celluloses, cellulose acetate phthalates, hydroxypropyl methyl cellulose phthalates, polyvinyl alcohol phthalates, styrene-maleic anhydride copolymers and polyvinyl ~cetal diethylamino~cet~tes;
æolubilizing atents, ~uch ~s glycerol, propylene glycol ~nd mannitol; emul~ifiers or ~uspensions, ~uch ~ poly-oxyethylene ~tearates, polyoxyethyl~ne cetyl ~lcohol ethers, polyethylen~ glycols and polyvinyl pyrrolidones;
~tab~lizer~, ~uch as ~orbitol, Twesn 80, Span 60, fats and oilB; and v~rious ~olvents.
In the above pharmaceutical compositions, the .
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present compound ~I] can be used at an oral dosage of 0.5 to 2,000 mg, preferably 3 to 200 mg, per day. The thus prepared pharmaceutical compositions according to the invention can be ~dministered 1 to 6 times, preferably 1 S to 3 times, a day within the above dosage.
The present invention is urther illustrated by the following Reference Example, Examples and Prepsration Examples.
Reference Example: (Preparation of sulfide compounds [II]) To 70 ml of ethanol ~olution of 0.80 9 (0.02 mole) of ~odium hydroxide were added 2~20 y (~.01 mole) of 2 mercapto-5-cyclopropylmethyloxybenzimidazole and 1.92 9 tO.01 mole) of 2-chloromethyl-3,5-dimethylpyridine hydrochloride, and the resulting mixture was heated under reflux for 3 hours. After the reaction mixture had been cooled to room temerature, the insoluble materials contained therein were filtered off, and ~he filtrate was condensed under reduced pressurel The residue obtained was dissolved in 100 ml of chloroform and washed with 100 ml of ~queous 5% ~odium hydroxide solution. The chloroform layer was dried over anhydrou~ ~odium 6ulfate and evaporated to dryness under reduced pressure. The residue obtained was purified by means of silica gel column ~hromato~raphy employing chloroform as the development solvent to give 2.99 9 of oily 2~12-(3,5-dimethyl)pyridylmethylthio]-5-cyclopropylmethyloxybenz-imidazole. Yield: 8801~.
The following 8 compounds were prepared in the same manner ~6 ~bove, exeept that corresponding thiol compound~ lIII] (0.01 mole~ and pyridine compounds [IV]
lO~01 mole~ were used in place of 2-mercapto-5 cyclo-propylmethyloxybenzimidazole (0.01 mole~ and 2-chloro ~ethyl-3,5-dimethylpyrldine hydrochloride ~0.01 mole)~
2-[2~ methyl)pyridyl~ethylthiol-5-cyclopropyl-methyloxybenzimida~ole: oily ~ub~tance;
2-[2-~3,5 di~ethyl)pyridylmethylthio3-4-cyc~opropyl-~ethyloxybenzim~d~zole: 91~Q8Y ~ub~tance;

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4~i3 2-~2-(3,4,5-~rimethyl)pyridylmethylthio~-5-cyclo-propylmethyloxyb~nzimidazole: crystals, m.p. 163-165 C
(reerystallized from a mixture of ethyl acetate and hexane);
2-[2-(3,4,5 trimethyl)pyridylmethylthio]-4-cyclo-propylmethyloxybenzimidazole: glassy substance;
2-~2-(4-methoxy-3,5-dimethyl)pyridylmethylthio~-4-cyclopropylmethyloxybenzimidazole: glassy ~ubstance;
2-[2-(4-methoxy-3,5-dimethyl)pyridylmethylthio]-5-cyclopropylmethyloxybenzimidazole: crystals, m.p. 133~134 C (recrystallized from a mixture of ethyl acetate and hexane);
2-t2 (4-methoxy-5-mQthyl)pyridylmethylthio]-5-cyclo-propylmethyloxybenzimidazole: oily substance; and 2-[2-~4-methoxy-5-methyl)pyridylmethylthio3-4-cyclo-propylmethyloxybenzimidazole: crystals, m.p. 142-143 C
(recrystalli~ed from a mixture of ethyl acetate and hexane)~

ExamPle 1 In 100 ml of chloroform was dissolved 2.72 g (0.008 mole) of 2-(2-(3,5-dimethyl)pyridylmethylthio]-5-cyclo-propylmethyloxybenzimidazole. To this was gradually added 1.38 9 (0.008 mole3 of m-chloroperbenzoic acid for a period of 15 minutes at 5 to 10 ~C. After the completion of the addition, the reaction mixture was stirred for additional 30 minutes at the ~ame temperature and then washed wi~h 100 ml of aqueous 10% sodium carbonate solution. ~he chloroform layer was separa~ed, dried over anhydrous ~odium sulfat~, and ~hen evaporated to dryness under r~duced pressure. The residue obtained was subjected to silica gel ¢olumn chromatography employing chloroform as the development ~olvent, and ~he ractions containing the desired compound ~ere collected~
The fractions were ev~porated to dryness under rzduced pres~ure. Tha res$due obtalned was recrystall~zed from a ~ixture of chloroform and ~thyl ather to give 2.06 9 (yield: 72.4~) of colorl0ss cry~tals ~f 2-12-(3,5-: "'' -' , o~

dimethyl~pyridylmethyl~ufinyl]-5-cyclopropylmethyloxy-benzimidazole.
Mel~ing point: 132-133 C.
IR absorption ~pec~rum ~KBr, cm ):
1010 (S=O) Elementary analysis (~):
Calcd. for ClgH21N3O2S: C, 64.20; H, 5.96; N, 11.82 Found ~ C, 64.16; H, 5.83; N, 11.79 The compounds shown in Examples 2 to 5 were prepared in a ~imilar manner as above, except that correqponding sulfide ~ompounds [II~ (0.008 mole) were used in place of 2-~2-~3,5-dimethyl)pyridylmethylthio~-5-cyclopropyl-methyloxybenzimidazole (0.008 mole) and minor changes were made on the reaotion temperature and the reaction time.
Example 2 2-[2-(4-methyl)pyridylmethyl~ulfinyl]-5-cyclopropyl-methyloxybenzimidazole.
Colorless crystals; Yield, 1.79 9 (65.5~) Melting point: 93-94 C (recrystallized from ethyl ether) IR ~bsorption ~pectrum (KBr, cm 1):
1030 (S=0) Elementary analysis (~:
~5 Calcd. for C18HlgN3O2S: C, 63.32; H, 5.61; N, 12.31 Found : C, 63.41; H, 5O57; N, 12.25 Example 3 2-[2-(3,5-dimethyl)pyridylmethyl~ulfinyl3-4-cyclo-propyl~ethyloxybenzimidazole.
Colorle~s cryfitals; Yield, 2.44 9 (8508~) Mel~ing point: 139-141 ~C (recrystallized from ethyl ether) IR ~bsorp~ion spectrum (RBr~ cm.l):
10~0 (SYO) Elementary analysi~
Calcd. for C19~21N3O2S: C, 64.20; ~, ~.96; N, 11.82 ~und s C, 64.28; H, 5.81; ~, 11.76 :

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2-~2-(3,4,5-trimethyl~pyridylmethylsulfinyl]-5-cyclopropylmethyl~xybenzimidazole.
Light brown crys~als; Yield, 2.12 9 (71.7%) Melting poin~: 181-185 C (recrystallized from a S mixture of chloroform and ethyl ether) IR absorption spectrum (RBr, cm 1):
1~10 ( S=O ) Elementary analysis (~):
Calcd. for C20H23N3O2S: C, 65.01; H, ~.27; N, 11~38 Found : C, 64.94; H, S.l9; N, 11.41 ExamPle 5 2-[2-(3,4,5-trimethyl)pyridylmethyl~ulfinyl]-4-cyclopropylmethyloxybenzimidazole.
Colorless crystals; Yield: 2.18 9 (73.7%) Melting p~intr 1~6-169 C (recrystallized from a mixture of chloroform and ethyl ether) IR absorption spectrum (KBr, cm 1):
10~ ~5-0) Elementary analysis (~):
C~lcd. for C20H23N3O2S: C, 65.01; H, 6.27; N, 11.38 F~und : C, 65.23; ~, 6.35; N, 11.12 Example 6 In 80 ml of dichloromethane was dissolved 2.96 9 (0.008 mole~ of 2-[2-(4-methoxy-3,5-dimethyl)pyridyl-methylthio]-4-cyclopropylmethyloxybenzimidazole. To this was added 40 ml of dichloromethane ~olution of 1.33 g (0.008 mole1 of m-chloroperbenzoic acid for a period of 5 3~ ~inutes at a ~onstant temperature of -5 'C. After the Gompletion of the addition, the reaction mixture was ~tirred for additional 10 ~inu~e~ at the ~ame tamperature and hen washed with 50 ml o aqueous 1~ sodium hydroxide ~olut~cn. The dichloromethane layer was 6epara~ed, dried over anhydrou~ ~odiu~ ~ulf~te, condensed under reduced pres~ure, and then ~dde~ with an appropri~te a~ount of a ~i~ture of p~troleum ~th~r and ethyl ~ther to precipitate cry~tal~ The thus obtained ery~t~ls ~ere recry~tallized _ . . .
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5;3 from a mixture of chloroform and ethyl ether to give 2.32 g (yield- 75.3~) of colorless crystal6 of ~ [2-(4-methoxy-3,5-dimethyl)pyridylmethylsulfinyl]-4-cyclo-propylmethyloxybenzimidazole.
Melting point: 142-146 C.
IR absorption ~pectrum (~Br, cm 1):
1040 (S=0) Elementary analysis (~):
Calcd. for C20H23N3O3S: C, 62.31; H, 6.01; N, 10.90 Found : C, 62.28; H, 6.09; N, 10.99 The compounds shown in Examples 7 to 9 were prepared in a similar manner as above, except that corresponding ~ulfide compounds lII] (0.008 m~le) were u ed in place of 2-[2-(4-meth~xy-3,5-dimethyl)pyridylmethylthio]-4-cyclopropylmethyloxybenzimidazole (0.008 mole) and minorchanges were made on the reaction temperature and the reaction ~ime.
Example 7 2-[2-(4-methoxy-3,5-dimethyl~pyridylmethylsulfinyl]-5-cyclopropylmethyloxybenzimidazole~
Colorless cry~tal~; Yield: 2.51 g (81.4%) Melting p~int: 107-108 ~C (recrystallized from a mixture of chloroform and ethyl ether~
IR absorpti~n 6pectrum (RBr, cm 1):
1000 (S=O) Elementary analysis (%):
Calcd. for C20H23N3O3S: C~ 62.31; ~, 6.01; N, 10.90 Found s Cr 62.19; H, 5.94; N, 10.84 Example_8 2-[2-~4-methoxy~5-methyl)pyridylmethyl~ul~inyl]-5-cyclopropylmethyloxybenzimidazole.
Colorless cry6tals; Yield: 1.73 g (58 D 2%) Melting point~ 139-141 C (recry~t~llized from a mixture of chloroform and . ethyl eth~r) IR ~b~orption 6pectrum ~Br, cm 1 1030 ~nd lOS0 (S~O) ~4~15~

Elementary analysis (%):
Calcd. for ClgH21N3O3S: C, 61.43; H, 5.70; N, 11.31 Found : C, 61.32; ~, 5.63; N, 11~40 Example 9 2-[2-(4-methoxy-5-methyl)pyridylmethylsulfinyl]-4-cyclopropylmethyloxybenæimidazole.
Colorless crystals; Yield: 2.35 g (79.1~) Melting point: 150-15~ ~C (recrystallized from a mixture of chloroform and ethyl ether) IR absorption spectrum (KBr, cm l);
1040 and 1050 (S~O) Elementary analysis (~):
Calcd. for ClgH21N3O3S: C, 61.43; H, 5.70; N, 11~31 Found : C, 61.51; B, 5.64; N, 11.42 Preparation Exam~e 1: (Tablets) % By Wei~ht (1) Compound prepared in Example 1 25 (2) Lactose 41 (3) Corn starch powders 15 (4) Crystalline cellulose 15 (5) Hydroxypropyl cellulose 3 l6) Magnesium ~tearate ~

~5 The above ingredients (1) to (S) were mixed, granulated with the addition of water, and then dried.
The thus obtained granules were regulated, mixed with the ingredient (6), and then formed with compression into t~blets of 100 ~9.

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Preparation Example 2: (Capsules) .

~lj Compound prepared in Example 8~5 (2) Lactose 50 (3~ Corn starch powders 20 (4) ~ydroxypropyl cellulose 3 (5~ Synthetic aluminium silicate

(6) Magnesium ~tearate lû
C;ranules were prepared from the above ingredients according to conventional method. Capsules containing 100 mg of the ~ranules were prepared therefrom.

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Claims (12)

What is claimed is:

1. A sulfide compound represented by general formula wherein R1 is a hydrogen atom, a methyl group or a methoxy group, and R2 and R3 each is a hydrogen atom or a methyl group, at least one of said R1, R2 and R3 groups being a member other than a hydrogen atom.

2. A compound as claimed in claim 1 wherein the cyclopropylmethoxy group is substituted at the 4 or 5 position of the benzimidazole ring.

3. A compound as claimed in claim 2 wherein the substituted pyridyl group represented by general formula is selected from the group consisting of 2-(3,5-dimethyl)-pyridyl, 2-(4-methyl)pyridyl, 2-(3,4,5-trimethyl)pyridyl, 2-(4-methoxy-3,5-dimethyl)pyridyl and 2-(4-methoxy 5-methyl)pyridyl.

4. 2-[2-(3,5-dimethyl)pyridylmethylthio] 5-cyclo propylmethyloxybenzimidazole.

5. 2-[2-(4-methyl)pyridylmethylthio]-5-cyclo-propylmethyloxybenzimidazole.

6. 2 [2-(3,5-dimethyl)pyridylmethylthio]-4-cyclo-propylmethyloxybenzimidazole.

7. 2-[2-(3,4,5-trimethyl)pyridylmethylthio]-5-cyclopropylmethyloxybenzimidazole.

8. 2-[2-(3,4,5-trimethyl)pyridylmethylthio]-4-cyclopropylmethyloxybenzimidazole.

9. 2-[2-(4-methoxy-3,5-dimethyl)pyridylmethylthio]-4-cyclopropylmethyloxybenzimidazole.

10. 2-[2-(4-methoxy-3,5-dimethyl)pyridylmethylthio]-5-cyclopropylmethyloxybenzimidazole.

11. 2-[2-(4-methoxy-5-methyl)pyridylmethylthio]-5-cyclopropylmethyloxybenzimidazole.

12. 2-[2-(4-methoxy-5-methyl)pyridylmethylthio]-4-cyclopropylmethyloxybenzimidazole.