CA1127158A - 2-pyridylmethylsulfinyl-benzimidazole compounds - Google Patents

2-pyridylmethylsulfinyl-benzimidazole compounds

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Publication number
CA1127158A
CA1127158A CA325,188A CA325188A CA1127158A CA 1127158 A CA1127158 A CA 1127158A CA 325188 A CA325188 A CA 325188A CA 1127158 A CA1127158 A CA 1127158A
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Prior art keywords
methyl
hydrogen
benzimidazole
methoxy
dimethyl
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CA325,188A
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French (fr)
Inventor
Ulf K. Junggren
Sven E. Sjostrand
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Hassle AB
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Hassle AB
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents

Abstract

Abstract The present invention relates to novel compounds of the formula

Description

~` 1127158 AB H~SSLE
Molndal/SWEDEN

`~ Inventors: U Junggren and S E Sjostrand UI/LB/EMH

Gastric acid sscretion agents . ~ .
The present invention relates to new compounds having valuable properties in affecting gastric acid secretion in ~ mammals, including man, as well as the process for their ~ preparation, method of affecting gastric acid secretion and pharmaceutical preparations containing said no~el compounds.

The object of the present invention is to obtain compound5 which affect gastric acid secretion, and which inhibit exogenously or endogenously stimulated gastric acid secre-tion. These compounds can be used in the treatment of peptic ~ ~ ulcer disease.
`,:
i It is previously known that compounds of the formulas I and II

~, ;

, . .
~ .

llZ715~
~2 Rl ~ ~ S R4 ~ (I~

Rl ~ \ ~ S-R4 ~ ( I I ) wherein Rl and R2 are each selected from the group consist-ing of hydrogen, alkyl, halogen, cyano, carboxy, carboxy- :
` 15 alkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoyl-oxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl in any position, R3 is selected from the group con-: sisting of hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, and alkylsulphonyl, and R4 is selected ~ from the group consisting of straight and branched alkylene ;~ groups having 1 to 4 carbon atoms, whereby at most one methylene group is present between S and the pyridyl ~roup, and whereby the pyridyl group may be further substituted ZS with alkyl or halogen, possess inhibiting effect of gastric :: acid secretion.

It has now, however, surprisingly been found that the compounds defined belaw possess a still ~reater inhibiting effect than those given abave.

: Campaunds af the inventian are those af the general formula ~ 35 ~ ~ R5 ~ (III~

'! H

'~ ' ' ' ~'' ~, L ~

llZ715~3 in which Rl and R2 are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy and alkanoyl in any position, R is selected from the group consisting of hydro-gen, methyl, and ethyl, R3, R4 and R5 are the same or different and are each selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy, and ethoxyethoxy, with the proviso that R3, R4 and R5 are not all hydrogen, and the further proviso that when two of R , R and R are hydrogen, the third of R3, R4 and R5 is not methyl.
The invention also extends to therapeutically acceptable salts of compounds of formula III.
Alkyl R and R of formula III are suitably alkyl having up to 7 carbon atoms, preferably up to 4 carbon atoms. Thus, alkyl R may be methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.
Halogen R and R is chloro, bromo, fluoro or iodo.
Alkoxy R and R are suitably alkoxy groups having up to 5 carbon atoms, preferably up to 3 carbon atoms, as methoxy, ethoxy, n-propoxy or isopropoxy.
Alkanoyl Rl and R2 have preferably up to 4 carbon atoms and are e.g. formyl, acetyl or propionyl, preferably acetyl.
A preferred group of compounds of the general formula III are those wherein Rl and R2 are the same or different and are each selected from the group consisting of hydrogen, alkyl, carbomethoxy, alkoxy, and alkanoyl, whereby R and R2 are not both hydrogen, R is hydrogen, and R3, R4 and R
are the same or different and are each selected from the group consisting of hydrogen, methyl, methoxy and ethoxy, whereby R3, R4 and R are not all hydrogen, and whereby when two of R3, R4 and R5 are hydrogen the third of R3, R4 and R5 is not methyl.

~lZ715~

..
A second preferred group of compounds of the general formula III are those wherein Rl and R2 are the same or different and are each selected from the group consisting of hydrogen, alkyl, halogen, caroomethoxy, carbethoxy, alkoxy, and alkanoyl, 5 R6 is select'ed from the group consisting of hydrogen, methyl, and ethyl, R3 is methyl, R4 is methoxy, and R5 is methyl.

A third preferred group of compounds of the general formula III are those wherein Rl and R2 are the same or different 10 and are each selscted from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, caroethoxy, alkoxy and alkanoyl, R is selected from the group consisting of hydrogen, methyl and ethyl~ and R3 is hydrDgen, R4 is methoxy and R5 is methyl or R3 is methyl, R4 is methoxy and R5 is hydrogen.
A fourth preferred group of compounds of the general formula III are those wherein Rl and R2 are the same or different and are each selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy, and alkanoyl, 20 R6 is selected from the group consisting of hydrogen, methyl and ethyl, R3 and R are hydrogen and R4 is methoxy.
.
A fifth preferred group of compounds of the general formula III are those wherein Rl and R2 are the same or different J . -:
.' 25 and are each selected from the group consisting of hydrogsn, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy, and alkanoyl, R6 is selected from the group consisting of hydrogen. methyl and ethyl, and R3 and R5 are methyl and R4 i9 hydrogen.
... .
30 A sixth preferred group of compounds of the general formula III are those wherein Rl and R2 are the same or different and are each selected from the group consisting of hydrogen, alkyl, halogenJ carbomethoxy, carbethoxy, alkoxy, and alkanoyl~
'~i R is selected from the group consisting of hydrogen, methyl 35 and ethyl, R and R are hydrogen and R4 is ethoxy. methoxy-ethoxy or ethoxyethoxy.

~ .

11~7158 A seventh prefPrred group of compounds o-F the general formula III are thnse wherein Rl and R2 are the same or different and are each selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, alkoxy, and alkanoyl, R6 is selected from the group consisting of hydrogen, methyl, and ethyl, R3, R4, and R5 are all methyl.

Compounds of formula III above may be prepared according to the following methods:
a) oxidizing a compound of formula IV

Rl ~ N ~ RS R5 (IV~

wherein R , R2, R6, R3. R4, and R5 have the meanings given, to the formation of a compound of formula III.
b) reacting a compound of the formula V '.

.5 Rl ~ ~ S-l -M (V) 1~1 .~ .

wherein Rl, R2, and R6 have the meanings given above and M is a metal selected from the group consisting of K, Na and Li, with a compound of formula VI.

~ (~

11~715~

wherein R3, R4, and R5 have the same meanings as given above, Z is a reactive esterified hydroxy group, to the formatinn of a compound of formula III;

c) reacting a compound of the formula VII
~2 R~ VII) wherein Rl, and R2 have the same meanings as given above and zl is SH or a reactive esterified hydroxy group, with a compound of the formula VIII

R3 ~ R5 ~VIII) Z2-lH ~ J

; wherein R6, R3, R4, and R5 have the same meanings as given above, and z2 is a reactive esterified hydroxy group or SH, to the formation of an intermediate of formula IV above, which then i5 oxidized to give a compound of formulà III;

d) reacting a compound of the formula IX
- R~
., 1 ~NH2 R ~ NH2 (IX~

wherein Rl and R2 have the same meanings as given above with a compound of the formula X
`~ 35 11~715~

R3`~ R5 (X) HOOC-S-~H - ~

wherein R6, R3, R4, and R5 have the same meanings as given above, to the formation of an intermediate of formula IV
above, which then is oxidized to give a compound of formula III, which compound may be converted to its therapeutical~y ; acceptable salts, if so desired.

In the reactions above, z, zl, and z2 may be a reactive, esterified hydroxy group which i5 a hydroxy group esterified with strong, inorganic or organic acid, preferably a hydro-halogen acid, such as hydrochloric acid, hydrobromic acid, or hydroiodic acid, also sulfuric acid or a strong organic sulfonic acid as a strong aromatic acid, e.g. benzene-~ sulfonic acid, 4-bromobenzenesulfonic acid or 4-toluene-; 20 sulfonic acid.

The oxidation of the sulfur atom in the chains above to sulfinyl (S-~0) takes place in the presence of an oxidizing I agent selected from the group consisting of nitric acid, ,f ` 25 hydrogen peroxide, peracids, peresters, ozone, dinitrogen-tetraoxideJ iodosobenzene, N-halosuccinimide, l-chlorobenzo-triazole, t-butylhypochlorite, diazobicyclo-r2,2,2]-octane bromine complex, sodium metaperiodate, selenium dioxide, . manganese dioxide, chromic acid, cericammonium nitrate, bromineJ chlorine, and sulfuryl chloride. The oxidation usually takes place in a solvent wherein the oxidizing agent i5 present in some excess in relation to the product to be oxidized. -~:
j 35 Oepending on the process conditions and the starting mater`
ials, the end product is obtained either as the free base or in the acid addition salt, both of which are included within the scope of the invention. Thus, basicJ neutral or or mixed salts may be obtained as well as hemiJ monoJ sesqui llZ7~S~

or polyhydrates. The acid addition salts of the new compounds may in a manner known per se be transformed into free base using basic agents such as alkali or by ion exchange. On the other hand, the free bases obtained may form salts with organic or inorganic aoids. In the prepara-tion of acid addition salts preferably such acids are used which form suitable therapeutically acceptable salts. Such acids include hydrohalogen acids, sulfonic, phosphoric, nitric, and perchloric acids; aliphatic, alicyclic, aromatic, heterocyclic carboxy or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, antranilic, ` ~p-hydroxybenzoic, salicylic or p-aminosalicylic acid, embonic, methanesulfonic, ethanesulfonic, hydroxyethane-sulfonic, ethylenesulfonic, halogenbenzenesulfonic, toluene-sulfonic, naphtylsulfonic or sulfanilic acids; methionine, tryptophane, lysine or arginine.

, ,20 These or other salts of the new compounds, as e.g. picrates, may serve as purifying agents of the free bases obtained.
Salts of the bases may be formed, separated from solution, and then the free base can be recovered from a new salt solution in a purer state. Because of the relationship between the new compounds in free base form and their salts, it will be understood that the corresponding salts are ':
included within the scope of the invention.

'Some of the new compounds may, depending on the choice of ;`30 starting materials and process, be pressnt as optical isamers or racemate, or if they contain at least two asymmetric carbon atoms, be present as an isomer mixture tracemate -~ mixture).
" ~
Ths isomer mixtures (racemate mixtures) obtained may be separated into two stereoisomeric ~diastereomeric) pure racemates by means of chromatography or -Fractional crystal-.

.

15~3 g lization.

The racemates obtained can be separated according to knownmethods, e.g. recrystallization from an optically active solvent, use of microorganisms, reactions with optically active acids forming salts which can be separated, separa-; tion based on different solubilities of the diastereomers.
Suitable optically active acids are the L- and D-forms of tartaric acid, di-o-tolyl-tartaric acid, malic acid, mandelic acid, camphorsulfonic acid or quinic acid, Prefer-ably the more active part of the two antipodes is isolated.

The starting materials are known or may, if they should be new, be obtained according to processes known per se.
In clinical use the compounds of the invention are administ-ered orally, rectally or by injection in the form of -a pharmaceutical preparation which contains an active component either as a free base or as a pharmaceutically acceptable, , 20 non-toxic acid addition salt, such as hydrochloride, lactate, acetate, sulfamate, in combination with a pharmaceutically acceptable carrier. The carrier may be in the-form of a solid, semisolid or liquid diluent, or a capsule. These pharmaceutical preparations are a further object of the 25 ~invention. Usually the amount of active compound is between 0.1 to 95 % by wèight of the prsparation, between 0.5 to 20 % by weight in preparations for injection and between 2 and 50 ~O by weight in preparations for oral administration.

i 30 In the preparation of pharmaceutical preparations containing a compound of the present invention in the form of dosage ~` units for oral administration the compound selected may be ~, ~ mixed with a solid, pulverulent carrier, such as lactose, saccharose, sorbitol, mannitol, starch, amylopectin, i 35 cellulose derivatives or gelatin, as well as with an anti-friction agent such as magnesium stearate, calcium stearate.
and polyethyleneglycol waxes. The mixture is then pressed ~1~715~3 into tablets. If coated tablets are desired, the above prepared core may be coated with a concentrated solution of sugar, which may contain gum arabic, gelatin, talc, titanium dioxide or with a lacquer dissolved in volatile organic solvent or mixture of solvents. To this coating various dyes may be added in order to distinguish among ; tablets with different active compounds or with different amounts of the active compound present.

Soft gelatin capsulss may be prepared which capsules contain a mixture oF the active compound or compounds of the invention and vegetable oil. Hard gelatin capsules may contain granules of the active compound in co~bination with a solid, pulverulent carrier as lactose, saccharose, sorbi-tol, mannitol, potato starch, corn starch, amylopectin,cellulose derivatives or gelatin.

Dosage units for rectal administration may be prepared in the form of suppositories which contain the active substance in a mixture with a neutral fat base, or they may be prepared in the form of gelatin-rectal capsules which contain the active substance in a mixture with a vegetable oil or paraffin - oil.

Liquid preparations for oral administration may be prepared in the form of syrups or suspensions, e.g. solutions contain-ing from O.Z % to 20 % by weight of the active ingredient and the remaindar consisting of sugar and a mixture of ethanol, water, glycerol and propylene glycol. If desired, such liquid preparations may conta`in colouring agents, flavouring agents, saccharin and carboxymethylcellulose as a thickening agent.

Solutions for parenteral administration by injection may be prepared as an aqueous solution of a watersoluble pharma-ceutically acceptable salt of the active compound, prefer-ably in a concentration from 0.5 % to 10 % by weight. These solutions may also contain stabilizing agents and/or 11~7~58 buffering agents and may be manufactured in different dosage unit ampoules.

Pharmaceutical tablets for oral use are prepared in the following manner: The solid substances are ground or sieved to a certain particle size, and the binding agent is homo-genized and suspended in a suitable solvent. The therapeut-ically active compounds and auxiliary agents are mixed with the binding agent solution. The resulting mixture is moistened to form a uniform suspension having the consist-ency of wet snow. The moistening causes the particles to aggregate slightly, and the resulting mass is pressed through a stainless steel sieve having a mesh size of approximately 1 mm. The layers of the mixture are dried in carefully controlled drying cabinets for approximately ten hours to obtain the desired particle size and consistency. The granules of the dried mixture are sieved to remove any powder. To this mixture, disintegrating, antifriction and antiadhesive agents are added. Finally, the mixture is pressed into tablets using a machine with the appropriate punches and dies to obtain the desired tablet size. The pressure applied affects the size of the tablet, its strength and its ability to dissolve in water. The compression ; pressure used should be in the range O.S to 5 tons. Tablets are manufactured at the rate of 20.000 to 200.000 per hour.
The tablsts, especially those which are rough or bitter, may be coated with a layer of sugar or some other palatable substance. Thay are then packaged by machines having elect-ronic counting devices. The different types of packages ; 30 consist of glass or plastic gallipots, boxes, tubes and specific dosage adapted packages.

The typical daily dose of the active substance varies according to the individual needs and the manner of adminis-tration. In general, oral dosages range from 100 to 400mg/day of active substance and intravenous dosages range -from 5 to 20 mg/day.

.

11;~7158 The following illustrates a preferred embodiment of the invention without being limited thereto. Temperature is given in degrees Centigrade.
:
The starting materials in the examples found below were prepared in accordance with the following methods:
- ~1) a 1,2-diamino compound~ such as o-phenylenediamine was reacted with potassium ethylxanthate ~according to Org.
Synth. Vol. 30, p. 56) to form a 2-mercaptobsnzimidazole;
~2) the compound 2-chloromethylpyridine was prepared by reacting 2-hydroxymethylpyridine with thionylchloride ~according to Arch. Pharm. Vol. 26, pp. 448-451 ~1956));
(3) the compound 2-chloromethylbenzimidazole was prepared by condensing o-phenylenediamine with chloroacetic acid.
Example 1 ~, .
28.9 g of 2-[2-~4,5-dimethyl)pyridylmethylthio]-(5-acetyl--6-methyl)-benzimidazole were dissolved in 160 ml of CHC13, . 20 24.4 g of m-chloroperbenzoic acid were added in portions while stirring and cooling to 5C. After 10 minutes, the precipitatsd m-chlorobenzoic acid was filtered off. The filtrate was diluted with CH2C12, washed with Na2C03 solu-tion~ dried over Na2S04 and evaporated in vacuo. The residue crystallized when diluted with CH3CN, and 2-[2-~4,5-di-methyl)pyridylmethylsulfinyl~-(5-acetyl-6-methyl)benzimid-azole was recrystallized from CH3CN. Yield 22.3 g; m.p.
158C.
;' ~ ' ' - 30 Examples 2-30 The preparation of compounds of formula III labelled 2-26 was carried out in accordance with Example 1 above. The compounds prepared are listed in Table 1 which identifies the substituents for these compounds.

I

11~7158 Example 31 ~method c) 0.1 moles of 4-6-dimethyl-2-mercaptobenzimidazole were dissolved in 20 ml of water and Z00 ml of ethanol contain-ing 0.2 moles of sodium hydroxide. 0.1 moles of Z-chloro-methyl-(3,5-dimethyl)pyridine hydrochloride were added and the mixture was refluxed for two hours. The sodium chloride formed was filtered off and the solution was evaporated in vacuo. The residue was dissolved in acetone and was treated with active carbon. An equivalent amount of concentrated hydrochloric acid was added, whereupon the mono-hydro-; chloride of 2-[2-(3,5-dimethyl)pyridylmethylthio]-(4,6-di-methyl)benzimidazole was isolated. Yield 0.05 moles.

This compound was then oxidized in accordance with Example 1 above to give the corresponding sulfinyl compound, melting point 50-55C.

Example 32 (method b) 0.1 moles of 2-rLi-methylsulfinyl](5-acetyl-6-methyl)-benzimidazole were dissolved in 150 mls of benzene. 0.1 moles
2-chloro-(3,5-dimethyl)pyridine were added and the mixture was refluxed for two hours. The lithiumchloride formed was filtered off, and the solution was evaporated in vacuo.
The residue was crystallized from CH3CN, and recrystallized from the same solvent. Yield 0.82 moles of 2-[2-(3,5-di-methyl)pyridylmethylsulfinyl~-(5-acetyl-6-methyl)benzimid-a~ol-e melting at 171C.
Example 33 (method d) 23.4 g of 2-[2-(3,4,5-trimethyl)pyridylmethylthio] formic acid - and 16.6 g of o-(5-acetyl-6-methyl)phenylenediamine were boiled for 40 minutes in 100 ml of 4N HCl. The mixture was cooled and neutralized with ammonia. The neutral solution was then extracted with ethyl acetate. The organic phase was !

11'~,715~3 . .
`treated with active carbon and evapQrated ln _acuo. The residue was dissolved in acetone whereupon an equivalent of concentrated HCl was added. The precipitated hydro-chloride was filtered off after cooling and the salt was - 5 recrystallized from absolute ethanol and some ether. Yield of 2-[2-(3,4,5-trimethylpyridyl)methylthio]-(5-acetyl-6-methyl)benzimidazole was 6.5 g.

This compound was then oxidizèd in accordance with Example 1 above, to give the corresponding sulfinyl derivative.
M.p. 190C.

Example 34 (method c) .'. ~ ~ .
22.0 g of 2-mercapto-(5-acetyl-6-methyl)benzimidazole and 19.5 g of chloromethyl(4,5-dimethyl)pyridine hydrochloride were dissolved in 200 ml of 95 % ethanol. 8 g of sodium hydroxide in 2~ ml of water were added, whereupon the solu-tion was refluxed for two hours. The sodium chloride formed , 20 was filtered off and the solution was evaporated in vacuo.
The residue, 2-[2-(4,5-dimethyl)pyridylmethylthio]-(5-acetyl-6-methyl)benzimidazole, was recrystallized from 70 ~ ethanol.
Yield 10.6 g.
' This compound was then oxidized in accordance with Example 1 above, to give the corresponding sulfinyl derivative.
M.p. 158C;

` '', ~ ~ .

~ ~ ~ RB

Ex. Rl R2 R6 R3 R4 R5 M.p.
C
.. .
3 5-COOCH3 H H H CH3 CH3 141 : ~ 15 5 COCH3 6 CH3 H C.H3. CH3. H 160 :. 5 5-COOCH3 6-CH3 H CH3 ~ CH3. H 163 : 6 4-CH3 6-CH3 H CH3 H CH3 50-55 7 5-COCH3 6-CH3 H CH3 H ` CH3 171 8 5-COCH3 6 CH3 H CH3 EH3 ~ CH3 190 , 20 9 5-COCH3 6-CH3 H H OCH3 H 165
4-CH3 6-CH3 H H OCH3 H 122 .
., 11 5 COCH3 6 CH3 H CH3 OCH3 CH3 156 .` . 12 5-COOCH3 6-CH3 H CH3 H CH3 144 13 H3 6 GH3 H CH3 CH3 CH3 lB5 . 25 14 5-COOCH3 6-CH3 H H OCH3 H 1.69
5-COOCH3 6-CH3 H H OC2H5 H 148 . 17 5-COOCH3 6-CH3 H CH3 OCH3 CH3 155 .. 30 19 5-COOCH3 H H CH3 H CH3 141 5-COOCH3 H H CH3 OCH~ CH3 142 . 21 5-COCH3 H H CH3 0CH3 ` CH3 162 . ~ 22 5-OCH3 H H H OCH3 CH3 178 . . 23 5-OCH3 H H CH3 OCH3 CH3 156 '. 35 24 5-CH3 H H CH3 OCH3 CH3 181 . , 26 5-Cl H H CH~ OCH3 CH3 185 5-CH3 3 3.. _ CH3 152 .

~1~7~5~

.
Biological e~fect The compounds of the invention possess worthwhile thera-peutic properties as gastric acid secretion inhibitors as demonstrated by the following tests. To determine the gastric acid secretion inhibitory properties, experiments have been performed on conscious dogs provided with gastric fistulas of conventional type and duodenal fistulas, the latter ones used for direct intraduodenal administration of the test compounds. After 18 hours starvation and depriv-; ation of water the dogs were givsn a subcutaneous infusion of pentagastrin (1-4 nmol/kg, h) lasting for 6-7 hours.
Gastric juice was collected in consecutive 30 minutes ; samples. An aliquot of each sample was titrated with 0.1 N
NaOH to pH 7.0 for titrable acid concentration using an automatic titrator and pH-meter (Radiometer, Copenhagen, Denmark). Acid output was calculated as mmol H /60 minutes.
The percent inhibition compared to control experiments was calculated for each compound and the peak inhibitory effect is given in Table 2 below. The test compounds,--suspended in 0.5 % Methocel~ (methyl cellulose), were given intraduoden-ally in doses from 4-20 ~mol/kg when the secrstory response to pentagastrin has reached a steady level.
~`:
. : :
In the test prior known compounds were compared with the compounds of the present invention as will be evident from ~-~ the Table 2 below.
, ~ .
.~ ~ . , .

, The following gastric acid inhibiting effect data were obtained for a number of compounds tested according to the . method dsscribed.

- i ~

. I .

~i27158 Table 2 R

H

~`
Ex. Rl R2 R6 R3 R4 R5 Dose Effect -~mol/k~ % inhibition _ .

a 5 COCH3 6 CH3 H CH3 CH3 CH3 4 100 5 COCH3 6-CH3 H CH3 OCH3 CH3 0.5 70 x 5-COCH3 6-CH3 H H CH3 H 20 30 x 5-COCH3 6-CH3 H H H CH3 8 80 ., 20 2 5-COOCH3 6-CH3 H H CH3 3 60 ;' 5 5-COOCH 6-CH H CH3 CH H 2 90 . ' 12 5-COOCH3 6-CH3 H CH3 H CH3 2 70 .
: 13 5 C CH3 6 CH3 H CH3 C 3 3 4 RO

: 25 15~ 5-COOCH3 6-CH3 H H OC~H5 H 4 75 : 16 5-COOCH3 6-CH3 H CH3 OCH3 H 0.5 65 : 17 5-COOCH3 6-CH3 H CH3 OCH3 CH3 0.5 90 18 s-cOOCH3 6-CH3 H H OCH3 CH3 30 x 5-COOCH3 6-CH3 H Or H H 4 a ~: ' .

, oont.

:~ ;

.

11~71S8 ] ~
Ex Rl R2 R6 R3 R4 R5 Dose Effect ~mol/kg % inhibition 5 ~20 5-COOCH3 H H CH3 OCH3 CH3 0 5 65 x 5-COOCH3 H H H H CH3 20 90 x 5-COOCH3 H H H H H 20 50 10 x 5-COCH3 H H H H C2H5 20 40 23 5-OCH3 H H CH3 OCH3 CH3 0~5 65 . x 5-OCH3 ' H ~ H CH3 ~ 20 10 : 15 24 5-CH H H CH3 OCH3 CH3 0.5 50 x 5-CH3 H H H H CH3 4 50 ; . x H H H H H H 4 50 . 20 2B. 5-COOC2H5 H H CH3 OCH3 CH~ 0.5 50 26 5-Cl H H CH3 OCH3 CH3 0-5 25 27 5-CH H H H OC2H4ocH3 H 0.5 30 . .

: x denotes a previously known compound ~

.:, ... .. . .. ~ .
Example 35 A syrup containing 2 % (weight per volume~ of acti~e substance was prepared from the following ingredients:

2-[2-(4,5-dimethyl)pyridylmethylsulfinyl]--(5-acetyl-6-methyl)benzimidazole HCl 2.0 g Saccharin 0.6 g Sugar 30.0 g 35 Glycerin - 5.0 g Flavouring agent 0.1 g Ethanol 96 % 10.0 ml Distilled water (sufficient to obtain a final volume of 100 ml~

~lZ7~58 Sugar, saccharin and the acid addition salt were dissolved in 60 g of warm water. After cooling, glycerin and a solu-tion of flavouring agents dissolved in ethanol were added.
To the mixture water was added to obtain a final volume of 100 ml.

The above given active substance may be replaced with other pharmaceutically acceptable acid addition salts.

Example 36 2-[2-~3,4-dimethyl)pyridylmethylsulfinyl]-~5-acetyl-6--methyl)benzimidazole HCl (250 g~ was mixed with lactose (175.8 g), potato starch (169.7 g) and colloidal silicic acid (32 g). The mixture was moistened with 10 % solution of gelatin and was ground through a 12-mesh sieve. After drying, potato starch (160 g), talc (50 g) and magnesium ; ~ stearate (5 g) were added and the mixture thus obtained was pressed into tablets (10.000), with each tablet containing , 20 25 mg of active substance. Tablets can be prepared that i contain any desirsd amount of the active ingredient.
;
Example 37~

Granules were prepared from 2-[2-(3,5-dimethyl)pyridyl-methylsulfinyl]-(5-acetyl-6-methyl)benzimidazole-p-hydroxy-benzoate (250 g), lactose (175.9 g) and an alcoholic solu-` tion of polyvinylpyrrolidone (25 g). After drying, the granules were mixed with talc t25 g), potato staroh t40 g), and magnesium stearate ~2.50 g) and were pressed into 10.000tablets. These tablets are first coated with a 10 % alcoholic solution of shellac and thereupon with an aqueous solution ~ ~ containing saccharose (45 %), gum arabic (5 ~), gelatin (4%), -~ and dyestuff (0.2 %). Talc and powdered sugar were used for powdering after the first five coatings. The coating was then ; covered with a 66 % sugar syrup and polishsd with a solution of 10 % carnauba wax in carbon tetrachloride.

11~7158 Example 3~

2-[2-(3,5-dimethyl)pyridylmethylsulfinyl~-(5-acetyl-6--methyl)benzimidazole hydrochloride (1 g)J sodium chloride (0.6 g) and ascorbic acid (0.1 g~ were dissolved in sufficient amount of distilled water to give 100 ml of solution. This solution, which contains 10 mg of active substance for each ml, was used in filling ampoules, which were sterilized by heating at 120C for 20 minutes.

, .
, -!
' '`'~

.

' !
,~, : , ~ J~
..,~ 1, ~':~: i ' .

Claims (89)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of the general formula III

III

or a therapeutically acceptable salt thereof in which R1 and R2 are the same or different and are selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy and alkanoyl in any position, R6 is selected from the group consisting of hydrogen, methyl, and ethyl, R3, R4 and R5 are the same or different and are each selected from the group consist-ing of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy, and ethoxyethoxy, with the proviso that R3, R4 and R5 are not all hydrogen, and the further proviso that when two of R3, R4 and R5 are hydrogen, the third of R3, R4 and R5 is not methyl, which process comprises:
(a) oxidizing a compound of formula IV

IV

wherein R1, R2, R6, R3, R4 and R5 are as defined above to form a compound of formula III; or (b) reacting a compound of the formula V

V

wherein R1, R2 and R6 are as defined above, and M is a metal selected from the group consisting of K, Na, and Li with a compound of formula VI

VI

wherein R3, R4 and R5 are as defined above, and Z is a reactive esterified hydroxy group, to form a compound of formula III; or (c) reacting a compound of formula VII

VII

wherein R1 and R2 are as defined above and Z1 is SH, or a reactive esterified hydroxy group, respectively, with a compound of formula VIII

VIII

wherein R6, R3, R4 and R5 are as defined above and Z2 is a reactive esteri-fied hydroxy group or SH, respectively to farm an intermediate of formula IV, which then is oxidized to give a compound of formula III; or (d) reacting a compound of formula IX

IX

wherein R1 and R2 are as defined above with a compound of the formula X

X

wherein R6, R3, R4 and R5 are as defined above, to form an intermediate of formula IV, which then is oxidized to give a compound of formula III, and, if required, converting a salt to the free base or converting a free base to a therapeutically acceptable salt.
2. A process according to claim 1(a) wherein the compound of formula IV is obtained by reacting a compound of formula VII

VII

wherein R1 and R2 are as defined in claim 1 and Z1 is SH, or a reactive esterified hydroxy group, respectively, with a compound of formula VIII

VIII

wherein R6, R3, R4 and R5 are as defined in claim 1 and Z is a reactive esterified hydroxy group or SH, respectively.
3. A process according to claim 1(b) wherein the compound of formula IV is obtained by reacting a compound of formula IX

IX

wherein R1 and R2 are as defined in claim 1 with a compound of the formula X

X

wherein R6, R3, R4 and R5 are as defined in claim 1.
4. A process according to claim 1, 2 or 3 in which R1 is hydrogen, chloro, methyl, ethyl, methoxy, acetyl, carbethoxy or carbomethoxy, R2 is hydrogen, or methyl, R6 is hydrogen, methyl or ethyl, R3 and R5 are methyl, and R4 is methoxy.
5. A process according to claim 1, 2 or 3 in which R1 is hydrogen, chloro, methyl, ethyl, acetyl, methoxy, carbethoxy or carbomethoxy, and R2 is hydrogen, methyl or ethyl, R6 is hydrogen, methyl or ethyl, R4 is methoxy and R3 is hydrogen and R4 is methyl, or R3 is methyl and R5 is hydrogen.
6. A process according to claim 1, 2 or 3 wherein R1 is methyl in the 4-position, acetyl in the 5-position, carbomethoxy in the 5-position or carbethoxy in the 5-position, R2 is methyl in the 6-position, R6 is hydrogen, R3 is hydrogen or methyl, R4 is hydrogen, methyl, methoxy or ethoxy and R5 is hydrogen or methyl.
7. A process according to claim 1, 2 or 3 wherein R1 is hydrogen, methyl in the 5-position, chlorine in the 5-position, methoxy in the 5-position, carbomethoxy in the 5-position, carbethoxy in the 5-position, R2 is hydrogen, R6 is hydrogen or methyl, R3 is hydrogen or methyl, R4 is hydrogen, methyl, methoxy or methoxyethoxy and R5 is hydrogen or methyl.
8. A compound of formula III as defined in claim 1 or a therapeuti-cally acceptable salt thereof when prepared by a process according to claim 1 or an obvious chemical equivalent thereof.
9. A process according to claim 1, 2 or 3 wherein R1 is 5-COCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is methyl and R5 is hydrogen.
10. A process according to claim 1, 2 or 3 wherein R1 is 4-CH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is hydrogen and R5 is methyl.
11. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is hydrogen, R6 is hydrogen, R3 is hydrogen, R4 is methyl and R5 is methyl.
12. A process according to claim 1, 2 or 3 wherein R1 is 5-COCH3, R2 is 6-CH3, R6 is hydrogen, R3 is hydrogen, R4 is methyl and R5 is methyl.
13. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is hydrogen, R4 is methyl and R5 is methyl.
14. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is methyl and R5 is hydrogen.
15. A process according to claim 1, 2 or 3 wherein R1 is 5-COCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is hydrogen and R5 is methyl.
16. A process according to claim 1, 2 or 3 wherein R1 is 5-COCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is methyl and R5 is methyl.
17. A process according to claim 1, 2 or 3 wherein R1 is 5-COCH3, R2 is 6-CH3, R6 is hydrogen, R3 is hydrogen, R4 is OCH3 and R5 is hydrogen.
18. A process according to claim 1, 2 or 3 wherein R1 is 4-CH3, R2 is 6-CH3, R6 is hydrogen, R3 is hydrogen, R4 is OCH3 and R5 is hydrogen.
19. A process according to claim 1, 2 or 3 wherein R1 is 5-COCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
20. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is hydrogen and R5 is methyl.
21. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is methyl and R5 is methyl.
22. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is hydrogen, R4 is OCH3 and R5 is hydrogen.
23. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is hydrogen, R4 is OC2H5 and R5 is hydrogen.
24. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is hydrogen.
25. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
26. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is 6-CH3, R6 is hydrogen, R3 is hydrogen, R4 is OCH3 and R5 is methyl.
27. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is hydrogen, R6 is hydrogen, R3 is methyl, R4 is hydrogen and R5 is methyl.
28. A process according to claim 1, 2 or 3 wherein R1 is 5-COOCH3, R2 is hydrogen, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
29. A process according to claim 1, 2 or 3 wherein R1 is 5-COCH3, R2 is hydrogen, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
30. A process according to claim 1, 2 or 3 wherein R1 is 5-OCH3, R2 is hydrogen, R6 is hydrogen, R3 is hydrogen, R4 is OCH3 and R5 is methyl.
31. A process according to claim 1, 2 or 3 wherein R1 is 5-OCH3, R2 is hydrogen, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
32. A process according to claim 1, 2 or 3 wherein R1 is 5-CH3, R2 is hydrogen, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
33. A process according to claim 1, 2 or 3 wherein R1 is hydrogen, R2 is hydrogen, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
34. A process according to claim 1, 2 or 3 wherein R1 is 5-Cl, R2 is hydrogen, R6 is hydrogen, R3 is methyl, R4 is OCH3 and R5 is methyl.
35. A process for preparing 2-[2-(3,4-dimethyl)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,4-dimethyl)-pyridylmethylthio]-(5-acetyl-6-methyl)-benzimidazole with m-chloro-perbenzoic acid.
36. The compound 2-[2-(3,4-dimethyl)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole when prepared by a process according to claim 35 or an obvious chemical equivalent thereof.
37. A process for preparing 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(4,6-dimethyl)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl)-pyridylmethylthio]-(4,6-dimethyl)-benzimidazole with m-chloroperbenzoic acid.
38. The compound 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(4,6-di-methyl)-benzimidazole when prepared by a process according to claim 37 or an obvious chemical equivalent thereof.
39. A process for preparing 2-[2-(4,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbomethoxy)-benzimidazole which comprises oxidizing 2-[2-(4,5-dimethyl)-pyridylmethylthio]-(5-carbomethoxy)-benzimidazole with m-chloroperbenzoic acid.
40. The compound 2-[2-(4,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbo-methoxy)-benzimidazole when prepared by a process according to claim 39 or an obvious chemical equivalent thereof.
41. A process for preparing 2-[2-(4,5-dimethyl)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(4,5-di-methyl)-pyridylmethylthio]-(5-acetyl-6-methyl)-benzimidazole with m-chloro-perbenzoic acid.
42. The compound 2-[2-(4,5-dimethyl)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole when prepared by a process according to claim 41 or an obvious chemical equivalent thereof.
43. A process for preparing 2-[2-(4,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(4,5-dimethyl)-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidazole with m-chloroperbenzoic acid.
44. The compound 2-[2-(4,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbo-methoxy-6-methyl)-benzimidazole when prepared by a process according to claim 43 or an obvious chemical equivalent thereof.
45. A process for preparing 2-[2-(3,4-dimethyl)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,4-dimethyl)-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidazole with m-chloroperbenzoic acid.
46. The compound 2-[2-(3,4-dimethyl)-pyridylmethylsulfinyl]-(5-carbo-methoxy-6-methyl)-benzimidazole when prepared by a process according to claim 45 or an obvious chemical equivalent thereof.
47. A process for preparing 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole which comprises reacting 2-[Li-methyl-sulfinyl]-(5-acetyl-6-methyl)-benzimidazole with 2-chloro-(3,5-dimethyl)-pyridine.
48. The compound 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole when prepared by a process according to claim 47 or an obvious chemical equivalent thereof.
49. A process for preparing 2-[2-(3,4,5-trimethyl)-pyridylmethylsul-finyl]-(5-acetyl-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,4,5-trimethyl)-pyridylmethylthio]-(5-acetyl-6-methyl)-benzimidazole with m-chloroperbenzoic acid.
50. A process according to claim 49 wherein the 2-[2-(3,4,5-trimethyl)-pyridylmethylthio]-(5-acetyl-6-methyl)-benzimidazole is obtained by reacting 2-[2-(3,4,5-trimethyl)-pyridylmethylthio] formic acid with o-(5-acetyl-6-methyl)-phenylenediamine.
51. The compound 2-[2-(3,4,5-trimethyl)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole when prepared by a process according to claim 49 or 50 or an obvious chemical equivalent thereof.
52. A process for preparing 2-[2-(4-methoxy)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(4-methoxy)-pyridylmethylthio]-(5-acetyl-6-methyl)-benzimidazole with m-chloroperbenzoic acid.
53. The compound 2-[2-(4-methoxy)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole when prepared by a process according to claim 52 or an obvious chemical equivalent thereof.
54. A process for preparing 2-[2-(4-methoxy)-pyridylmethylsulfinyl]-(4,6-dimethyl)-benzimidazole which comprises oxidizing 2-[2-(4-methoxy)-pyridylmethylthio]-(4,6-dimethyl)-benzimidazole with m-chloroperbenzoic acid.
55. The compound 2-[2-(4-methoxy)-pyridylmethylsulfinyl]-(4,6-dimethyl)-benzimidazole when prepared by a process according to claim 54 or an obvious chemical equivalent thereof.
56. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethyl-sulfinyl]-(5-acetyl-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-acetyl-6-methyl)-benzimidazole with m-chloroperbenzoic acid.
57. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-acetyl-6-methyl)-benzimidazole when prepared by a process according to claim 56 or an obvious chemical equivalent thereof.
58. A process for preparing 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl)-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidazole with m-chlorobenzoic acid.
59. The compound 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbo-methoxy-6-methyl)-benzimidazole when prepared by a process according to claim 58 or an obvious chemical equivalent thereof.
60. A process for preparing 2-[2-(3,4,5-trimethyl)-pyridylmethylsul-finyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,4,5-trimethyl)-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimi-dazole with m-chlorobenzoic acid.
61. The compound 2-[2-(3,4,5-trimethyl)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole when prepared by a process according to claim 60 or an obvious chemical equivalent thereof.
62. A process for preparing 2-[2-(4-methoxy)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(4-methoxy-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidazole with m-chlorobenzoic acid.
63. The compound 2-[2-(4-methoxy)-pyridylmethylsulfinyl]-(5-carbo-methoxy-6-methyl)-benzimidazole when prepared by a process according to claim 62 or an obvious chemical equivalent thereof.
64. A process for preparing 2-[2-(4-ethoxy)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(4-ethoxy}-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidzole with m-chlorobenzoic acid.
65. The compound 2-[2-(4-ethoxy)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole when prepared by a process according to claim 64 or an obvious chemical equivalent thereof.
66. A process for preparing 2-[2-(3-methyl-4-methoxy)-pyridylmethyl-sulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3-methyl-4-methoxy)-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidazole with m-chlorobenzoic acid.
67. The compound 2-[2-(3-methyl-4-methoxy)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole when prepared by a process according to
claim 68 or an obvious chemical equivalent thereof.

68. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridyl-methylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidazole with m-chlorobenzoic acid.
69. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole when prepared by a process according to claim 68 or an obvious chemical equivalent thereof.
70. A process for preparing 2-[2-(4-methoxy-5-methyl)-pyridylmethyl-sulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole which comprises oxidizing 2-[2-(4-methoxy-5-methyl)-pyridylmethylthio]-(5-carbomethoxy-6-methyl)-benzimidazole with m-chlorobenzoic acid.
71. The compound 2-[2-(4-methoxy-5-methyl)-pyridylmethylsulfinyl]-(5-carbomethoxy-6-methyl)-benzimidazole when prepared by a process according to claim 70 or an obvious chemical equivalent thereof.
72. A process for preparing 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbomethoxy)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl)-pyridylmethylthio]-(5-carbomethoxy)-benzimidazole with m-chlorobenzoic acid.
73. The compound 2-[2-(3,5-dimethyl)-pyridylmethylsulfinyl]-(5-carbo-methoxy)-benzimidazole when prepared by a process according to claim 72 or an obvious chemical equivalent thereof.
74. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethyl-sulfinyl]-(5-carbomethoxy)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-carbomethoxy)-benzimidazole with m-chlorobenzoic acid.
75. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-carbomethoxy)-benzimidazole when prepared by a process according to claim 74 or an obvious chemical equivalent thereof.
76. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethyl-sulfinyl]-(5-acetyl)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-acetyl)-benzimidazole with m-chlorobenzoic acid.
77. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-acetyl)-benzimidazole when prepared by a process according to claim 76 or an obvious chemical equivalent thereof.
78. A process for preparing 2-[2-(4-methoxy-5-methyl)-pyridylmethyl-sulfinyl]-(5-methoxy)-benzimidazole which comprises oxidizing 2-[2-(4-methoxy-5-methyl)-pyridylmethylthio]-(5-methoxy)-benzimidazole with m-chloro-benzoic acid.
79. The compound 2-[2-(4-methoxy-5-methyl)-pyridylmethylsulfinyl]-(5-methoxy)-benzimidazole when prepared by a process according to claim 78 or an obvious chemical equivalent thereof.
80. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridyl-methylsulfinyl]-(5-methoxy)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-methoxy)-benzimidazole with m-chlorobenzoic acid.
81. A process according to claim 80 wherein the 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-methoxy)-benzimidazole is obtained by reacting 5-methoxy-2-mercaptobenzimidazole with 2-chloromethyl-3,5-dimethyl-4-methoxy-pyridine.
82. A process according to claim 80 wherein the 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-methoxy)-benzimidazole is obtained by reacting 2-[2-(3,5-dimethyl-4-methoxy-pyridylmethylthio] formic acid with o-(4-methoxy)-phenylene-diamine.
83. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-methoxy)-benzimidazole when prepared by a process according to claim 80, 81 or 82 or an obvious chemical equivalent thereof.
84. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridyl-methylsulfinyl]-(5-methyl)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-methyl)-benzimidazole with m-chloro-benzoic acid.
85. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-methyl)-benzimidazole when prepared by a process according to claim 84 or an obvious chemical equivalent thereof.
86. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridyl-methylsulfinyl]-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-benzimidazole with m-chlorobenzoic acid.
87. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-benzimidazole when prepared by a process according to claim 86 or an obvious chemical equivalent thereof.
88. A process for preparing 2-[2-(3,5-dimethyl-4-methoxy)-pyridyl-methylsulfinyl]-(5-chloro)-benzimidazole which comprises oxidizing 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylthio]-(5-chloro-benzimidazole with m-chlorobenzoic acid.
89. The compound 2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsulfinyl]-(5-chloro)-benzimidazole when prepared by a process according to claim 88 or an obvious chemical equivalent thereof.
CA325,188A 1978-04-14 1979-04-09 2-pyridylmethylsulfinyl-benzimidazole compounds Expired CA1127158A (en)

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IE790785L (en) 1979-10-14
US4255431A (en) 1981-03-10
NO1995005I1 (en) 1995-06-14
JPS6034956B2 (en) 1985-08-12
DK150510B (en) 1987-03-16
MY8500074A (en) 1985-12-31
ZA791586B (en) 1980-04-30
IE48370B1 (en) 1984-12-26
AU529654B2 (en) 1983-06-16
SU895292A3 (en) 1981-12-30
NO791227L (en) 1979-10-16
JPS58192880A (en) 1983-11-10
SE7804231L (en) 1979-10-15
NZ190203A (en) 1984-03-16
DD142882A5 (en) 1980-07-16
NO152785C (en) 1985-11-20
EP0005129B1 (en) 1981-04-29
DK151179A (en) 1979-10-15
LU88305I2 (en) 1994-05-04
LU88307I2 (en) 1994-05-04
SG63383G (en) 1984-07-27
JPS54141783A (en) 1979-11-05
NO152216C (en) 1985-08-21
NO840112L (en) 1979-10-16
FI791219A (en) 1979-10-15
ATA273279A (en) 1983-09-15
NL930075I1 (en) 1993-09-16
NL930074I1 (en) 1993-09-16
SU878196A3 (en) 1981-10-30
DK150510C (en) 1987-12-07
NO1995006I1 (en) 1995-06-14
HU179022B (en) 1982-08-28
NL930075I2 (en) 1994-02-16
US4508905A (en) 1985-04-02
NO152216B (en) 1985-05-13
JPS6353191B2 (en) 1988-10-21
AT374471B (en) 1984-04-25
EP0005129A1 (en) 1979-10-31
CY1232A (en) 1984-06-29
ATA290483A (en) 1989-08-15
CS261851B2 (en) 1989-02-10
NO152785B (en) 1985-08-12
HK15284A (en) 1984-03-02
LT2274B (en) 1993-12-15
AU4602779A (en) 1979-10-18
NO1994027I1 (en) 1994-12-21
NL930074I2 (en) 1994-02-16
FI65067C (en) 1984-03-12
SU873880A3 (en) 1981-10-15

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