United States Patent 1191
`Junggren et al.
`
`[11]
`[45]
`
`4,255,431
`Mar. 10, 1981
`
`[54] GASTRIC ACID SECRETION INHIBITING
`SUBSTITUTED
`2-(Z-BENZIMIDAZOLYL)-PYRIDINES,
`PHARMACEUTICAL PREPARATIONS
`CONTAINING SAME, AND METHOD FOR
`INHIBITING GASTRIC ACID SECRETION
`
`[75] Inventors: Ulf K. Junggren, Molnlycke; Sven E.
`Sjiistrand, Kungsbacka, both of
`Sweden
`
`[73] Assignee: Aktiebolaget Hassle, Molndal,
`Sweden
`
`OTHER PUBLICATIONS
`Berntsson et al., Chem. Abst., 1976, vol. 85, No.
`149139q.
`Hideg et a1., Chem. Abst., 1971, vol. 75, No. 98570g.
`Primary Examiner—Henry R. Jiles
`Assistant Examiner—Richard A. Schwartz
`Attorney, Agent, or Firm—Brumbaugh, Graves,
`Donohue & Raymond
`[57]
`ABSTRACT
`The present invention relates to novel compounds of
`the formula
`
`[21] App]. No.: 27,277
`
`[22] Filed:
`
`Apr. 5, 1979
`
`Foreign Application Priority Data
`[30]
`Apr. 14, 1978 [SE]
`Sweden .............................. .. 7804231
`
`[51] Int. 01.3 ............ .. A61K 31/44; 0071) 401/12
`[52] us. c1. .................................. .. 424/263; 546/271;
`546/301; 548/329
`[58] Field of Search ....................... .. 546/271; 424/263
`
`[56]
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,045,563
`4,045,564
`4,182,766
`
`3/1977 Berntsson et a1. ................. .. 546/271
`8/1977 Berntsson et a1.
`‘ .... .. 546/271
`1/1980 Krasso et al. .................. .. 546/271 X
`
`FOREIGN PATENT DOCUMENTS
`
`wherein R1 and R2 are the same or different and are
`each hydrogen, alkyl, halogen, carbomethoxy, carbe
`thoxy, alkoxy, or alkanoyl, R6 is hydrogen, methyl or
`ethyl, R3, R4 and R5 are the same or different and are
`each hydrogen, methyl, methoxy, ethoxy, methoxye
`thoxy or ethoxyethoxy whereby R3, R4 and R5 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.
`The compounds are potent gastric acid secretion inhibi
`tors.
`
`1804450 5/1970 Fed. Rep. of Germany ......... .. 546/271
`
`29 Claims, No Drawings
`
`

`

`GASTRIC ACID SECRETION INHIBITING
`SUBSTITUTED
`2-(2-BENZIMIDAZOLYL)-PYRIDINES,
`PHARMACEUTICAL PREPARATIONS
`CONTAINING SAME, AND METHOD FOR
`INHIBITING GASTRIC ACID SECRETION
`
`The present invention relates to new compounds
`having valuable properties in affecting gastric acid se
`cretion in mammals, including man, as well as the pro
`cess for their preparation, method of affecting gastric
`acid secretion and pharmaceutical preparations contain
`ing said novel compounds.
`The object of the present invention is to obtain com
`pounds which affect gastric acid secretion, and which
`inhibit exogenously or endogenously stimulated gastric
`acid secretion. These compounds can be used in the
`treatment of peptic ulcer disease.
`It is previously known that compounds of the formu
`las I and II
`
`R2
`
`“ fl
`“til
`\N
`5“
`
`(1)
`
`25
`
`30
`
`35
`
`45
`
`50
`
`55
`
`wherein R1 and R2 are each selected from the group
`consisting of hydrogen, alkyl, halogen, cyano, carboxyl,
`carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbam
`oyl, carbamoyloxy, hydroxy, alkoxy," hydroxyalkyl,
`tri?uoromethyl and acyl in any position, R3 is selected
`from the group consisting of hydrogen, alkyl, acyl,
`carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcar
`bamoyl, alkylcarbonylmethyl, alkoxylcarbonylmethyl,
`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 meth
`ylene group is present between S and the pyridyl group,
`and whereby the pyridyl group may be further substi
`tuted with alkyl or halogen, possess an inhibiting effect
`on gastric acid secretion.
`It has now, however, surprisingly been found that the
`compounds de?ned below possess a still greater inhibit
`ing effect than those given above.
`Compounds of the invention are those of the general
`formula III
`
`R2
`
`0 3
`
`R4
`
`5
`
`60
`
`(III)
`
`I
`R6
`
`N
`
`65
`
`N
`I
`
`1
`
`4,255,431
`
`2
`wherein R1 and R2 are same or different and are each
`selected from the group consisting of hydrogen, alkyl,
`halogen, carbomethoxy, carbethoxy, alkoxy, and alkan
`oyl, R6 is selected from the group consisting of hydro
`gen, methyl, and ethyl, and R3, and R5 are the same or
`different and are each selected from the group consist
`ing of hydrogen, methyl, methoxy, ethoxy, methoxye
`thoxy and ethoxyethoxy and R4 is methoxy, ethoxy,
`methoxyethoxy or ethoxyethoxy whereby R3, R4, and
`R5 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.
`Alkyl R1 and R2 of formula III are suitably alkyl
`having up to 7 carbon atoms, preferably up to 4 carbon
`atomsThus, alkyl R may be methyl, ethyl, n-propyl,
`isopropyl, n-butyl or isobutyl.
`Halogen R1 and R2 are chloro, bromo, fluoro, or
`iodo.
`Alkoxy R1 and R2 are suitably alkoxy groups having
`up to 5 carbon atoms, preferably up to 3 carbon atoms,
`such as methoxy, ethoxy, n-propoxy, or isopropoxy.
`Alkanoyl R1 and R2 have preferably up to 4 carbon
`atoms and are e.g. formyl, acetyl, or propionyl, prefera
`bly acetyl.
`A preferred group of compounds of the general for
`mula III are those wherein R1 and R2 are the same or
`different and are each selected from the group consist
`ing of hydrogen, alkyl, carbomethoxy, alkoxy, and al
`kanoyl, whereby R1 and R2 are not both hydrogen, R6
`is hydrogen, and R3, R4, and R5 are the same or differ
`ent and are each selected from the group consisting of
`hydrogen, methyl, methoxy, and ethoxy, whereby R3,
`R4, and R5 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.
`A second preferred group of compounds of the gen
`eral formula III are those wherein R1 and R2 are the
`same or different and are each selected from the group
`consisting of hydrogen, alkyl, halogen, carbomethoxy,
`carbethoxy, alkoxy, and alkanoyl, R6 is selected 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 R1 and R2 are the same or
`different and are each selected from the group consist
`ing of hydrogen, alkyl, halogen, carbomethoxy, carbe
`thoxy, alkoxy and alkanoyl, R6 is selected from the
`group consisting of hydrogen, methyl and ethyl, and R3
`is hydrogen, 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 gen
`eral formula III are those wherein R1 and R2 are the
`same or different and are each selected from the group
`consisting of hydrogen, alkyl, halogen, carbomethoxy,
`carbethoxy, alkoxy, and alkanoyl, R6 is selected from
`the group consisting of hydrogen, methyl and ethyl, R3
`and R5 are hydrogen and R4 is methoxy.
`A ?fth preferred group of compounds of the general
`formula III are those wherein R1 and R2 are the same or
`different and are each selected from the group consist
`ing of hydrogen, alkyl, halogen, carbomethoxy, carbe
`thoxy, alkoxy, and alkanoyl, R6 is selected from the
`group consisting of hydrogen, methyl and ethyl, and R3
`and R5 are methyl and R4 is hydrogen.
`A sixth preferred group of compounds of the general
`formula III are those wherein R1 and R2 are the same or
`different and are each selected from the group consist
`ing of hydrogen, alkyl, halogen, carbomethoxy, carbe
`
`

`

`wherein R1, and R2 have the same meanings as given
`above and Z1 is SH or a reactive esteri?ed hydroxy
`group, with a compound of the formula VIII
`
`(v11)
`
`(vm)
`
`4,255,431
`3
`thoxy, alkoxy, and alkanoyl, R6 is selected from the
`group consisting of hydrogen, methyl and ethyl, R3 and
`R5 are hydrogen and R4 is ethoxy, methoxyethoxy or
`ethoxyethoxy.
`A seventh preferred group of compounds of the gen
`eral formula III are those wherein R1 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.
`Other groups of compounds which may be used are:
`Compounds in which R1 is hydrogen, chloro, methyl,
`ethyl, methoxy, acetyl, carboethoxy or carbomethoxy;
`R2 is hydrogen or methyl; R6 is hydrogen, methyl or
`ethyl; R3 and R5 are methyl; and R4 is methoxy. Com
`pounds in which R1 is hydrogen, chloro, methyl, ethyl,
`methoxy, acetyl, carboethoxy or carbomethyl; R2 is
`hydrogen, methyl or ethyl; R4 is methoxy; and R3 is
`methyl and R5 is hydrogen or R3 is hydrogen and R5 is
`methyl.
`Compounds of formula III above may be prepared
`according to the following methods:
`(a) oxidizing a compound of formula IV
`
`wherein R6, R3, R4, and R5 have the same meanings as
`given above, and Z2 is a reactive esteri?ed hydroxy
`group or SH, to the formation of an intermediate of
`formula IV above, which then is oxidized to give a
`compound of formula III;
`(d) reacting a compound of the formula IX
`
`25
`
`R2
`
`Rl
`
`NHZ
`
`NH;
`
`("0
`
`35
`
`wherein R1 and R2 have the same meanings as given
`above with a compound of the formula X
`
`wherein R1, 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
`
`(V)
`
`45
`
`50
`
`wherein R1, R2, and R6 have the meanings given above
`and M is a metal selected from the group consisting of
`55
`K, Na and Li, with a compound of formula VI.
`
`R4
`
`(vn)
`
`R3 / R5
`
`Z \ N
`
`wherein R3, R4, and R5 have the same meanings as
`given above, Z is a reactive esteri?ed hydroxy group, to
`the formation of a compound of formula III;
`(e) reacting a compound of the formula VII
`
`65
`
`R4
`
`N
`
`’ HOOC- S-CH
`
`(X)
`
`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 therapeutically acceptable salts, if so
`desired.
`'
`In the reactions above, Z, Z‘, and Z2 may be a reac
`tive, esteri?ed hydroxy group which is a hydroxy group
`esteri?ed with strong, inorganic or organic acid, prefer
`ably a hyd'rohalogen 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. benzenesulfonic acid, 4-bromobenzenesulfonic
`acid or 4-toluenesulfonic acid.
`The oxidation of the sulfur atom in the chains above
`to sulfinyl (S—>O) takes place in the presence of an
`oxidizing agent selected from the group consisting of
`nitric acid, _ hydrogen peroxide, peracids, peresters,
`ozone, dinitrogentetraoxide, iodosobenzene, N-halosuc
`cinimide, l-chlorobenzotriazole, t-butylhypochlorite,
`diazobicyclo-[2,2,2,]-octane bromine complex, sodium
`metaperiodate, selenium dioxide, manganese dioxide,
`chromic acid, cericammonium nitrate, bromine, chlo
`
`

`

`20
`
`4,255,431
`5
`6
`rine, andsulfuryl chloride. The oxidation usually takes
`amount of active compound is between 0.1 to 95% by
`place in a solvent wherein the oxidizing agent is present
`weight of the preparation, between 0.5 to 20% by
`weight in preparations for injection and between 2 and
`in some excess in relation to the product to be oxidized.
`50% by weight in preparations for oral administration.
`Depending on the process conditions and the starting
`In the preparation of pharmaceutical preparations
`materials, the end product is obtained either as the free
`containing a compound of the present invention in the
`base or in the acid addition salt, both of which are in
`cluded within the scope of the invention. Thus, basic,
`form of dosage units for oral administration the com
`pound selected may be mixed with a solid, pulverulent
`neutral or or mixed salts may be obtained as well as
`hemi, mono, sesqui or polyhydrates. The acid addition
`carrier, such as lactose, saccharose, sorbitol, mannitol,
`starch, amylopectin, cellulose derivatives or gelatin, as
`salts of the new compounds may in a manner known per
`se be transformed into free base using basic agents such
`well as with an antifriction agent such as magnesium
`as alkali or by ion exchange. On the other hand, the free
`stearate, calcium stearate, and polyethyleneglycol
`bases obtained may form salts with organic or inorganic
`waxes. The mixture is then pressed into tablets. If
`acids. In the preparation of acid addition salts prefera
`coated tablets are desired, the above prepared core may
`bly such acids are used which form suitable therapeuti
`be coated with a concentrated solution of sugar, which
`cally acceptable salts. Such acids include hydrohalogen
`may contain gum arabic, gelatin, talc, titanium dioxide
`acids, sulfonic, phosphoric, nitric, and perchloric acids;
`or with a lacquer dissolved in volatile organic solvent
`aliphatic, alicyclic, aromatic, heterocyclic carboxy or
`or mixture of solvents. To this coating various dyes may
`sulfonic acids, such as formic, acetic, propionic, suc
`be added in order to distinguish among tablets with
`cinic, glycolic, lactic, malic, tartaric, citric, ascorbic,
`different active compounds or with different amounts of
`maleic, hydroxymaleic, pyruvic, phenylacetic, benzoic,
`the active compound present.
`p-aminobenzoic, antranilic, p-hydroxybenzoic, salicylic
`Soft gelatin capsules may be prepared which capsules
`or p-aminosalicylic acid, embonic, methanesulfonic,
`contain a mixture of the active compound or com
`ethanesulfonic, hydroxyethanesulfonic, ethylenesul
`pounds of the invention and vegetable oil. Hard gelatin
`fonic, halogenbenzenesulfonic, toluenesulfonic, naph
`capsules may contain granules of the active compound
`tylsulfonic or sulfanilic acids; methionine, tryptophane,
`in combination with a solid, pulverulent carrier as lac
`lysine or arginine.
`tose, saccharose, sorbitol, mannitol, potato starch, corn
`starch, amylopectin, cellulose derivatives or gelatin.
`These or other salts of the new compounds, as e.g.
`picrates, may serve as purifying agents of the free bases
`Dosage units for rectal administration may be pre
`obtained. Salts of the bases may be formed, separated
`pared in the form of suppositories which contain the
`from solution, and then the free base can be recovered
`active substance in a mixture with a neutral fat base, or
`they may be prepared in the form of gelatin-rectal cap
`from a new salt solution in a purer state. Because of the
`relationship between the new compounds in free base
`sules which contain the active substance in a mixture
`form and-their salts, it will be understood that the corre
`with a vegetable oil or paraf?n oil.
`Liquid preparations for oral administration may be
`sponding salts are included within the scope of the
`invention.
`prepared in the form of syrups or suspensions, e.g. solu
`tions containing from 0.2% to 20% by weight of the
`Some of the new compounds may, depending on the
`active ingredient and the remainder consisting of sugar
`choice of starting materials and process, be present as
`and a mixture of ethanol, water, glycerol and propylene
`optical isomers or racemate, or if they contain at least
`glycol. If desired, such liquid preparations may contain
`two asymmetric carbon atoms, be present as an isomer
`mixture (racemate mixture).
`colouring agents, ?avouring agents, saccharin and car
`The isomer ‘mixtures (racemate mixtures) obtained
`boxymethylcellulose as a thickening agent.
`Solutions for parenteral administration by injection
`may be separated into two stereoisomeric (diastereom
`eric) pure racemates by means of chromatography or
`may be prepared as an aqueous solution of a watersolu
`fractional crystallization.
`ble pharmaceutically acceptable salt of the active com
`The racemates bbtained can be separated according
`pound, preferably in a concentration from 0.5% to 10%
`by weight. These solutions may also contain stabilizing
`to known methods, e.g. recrystallization from an opti
`cally active solvent, use of microorganisms, reactions
`agents and/or buffering agents and may be manufac
`tured in different dosage unit ampoules.
`with optically active acids forming salts which can be
`separated, separation based on different solubilities of
`'Pharmaceutical tablets for oral use are prepared in
`the diastereomers. Suitable optically active acids are the
`the following manner: The solid substances are ground
`L- and D-forms of tartaric acid, di-o-tolyl-tartaric acid,
`or sieved to a certain particle size, and the binding agent
`malicv acid, mandelic acid, camphorsulfonic acid or
`is homogenized and suspended in a suitable solvent. The
`therapeutically active compounds and auxiliary agents
`quinic acid. Preferably the more active part of the two
`antipodes is isolated.
`are mixed with the binding agent solution. The resulting
`The starting materials are known or may, if they
`mixture is moistened to form a uniform suspension hav
`should be new, be obtained according to processes
`ing the consistency of wet snow. The moistening causes
`the particles to aggregate slightly, and the resulting
`known per se.
`In clinical use the compounds of the invention are
`mass is pressed through a stainless steel sieve having a
`administered orally, rectally or by injection in the form
`mesh size of approximately 1 mm. The layers of the
`mixture are dried in carefully controlled drying cabinets
`of a pharmaceutical preparation which contains an ac
`for approximately ten hours to obtain the desired parti
`tive component either as a free base or as a pharmaceuti
`cally acceptable, non-toxic acid addition salt, such as
`cle size and consistency. The granules of the dried mix
`hydrochloride, lactate, acetate, sulfamate, in combina
`ture are sieved to remove any powder. To this mixture,
`tion with a pharmaceutically acceptable carrier. The
`disintegrating, antifriction vand antiadhesive agents are
`65
`added. Finally, the mixture is pressed into tablets using
`carrier may be in the form of a solid, semisolid or liquid
`diluent, or a capsule. These pharmaceutical prepara
`a machine with the appropriate punches and dies to
`tions are a further object of the invention. Usually the
`obtain the desired tablet size. The pressure applied af
`
`55
`
`60
`
`35
`
`40
`
`45
`
`

`

`4,255,431
`
`8
`were added and the mixture was re?uxed for two hours.
`The sodium chloride formed was ?ltered off and the
`solution was evaporated in vacuo. The residue was
`dissolved in acetone and was treated with active car
`bon. An equivalent amount of concentrated hydrochlo
`ric acid was added, whereupon the mono-hydrochlo
`ride of 2-[2-(3,5-dimethyl)pyridylmethylthio]-4,6-dime
`thyl)benzimidazole was isolated. Yield 0.05 moles.
`This compound was then oxidized in accordance
`with Example 1 above to give the corresponding sul?
`nyl compound, melting point 50"—55° C.
`
`0
`
`7
`fects the size of the tablet, its strength and its ability to
`dissolve in water. The compression pressure used
`should be in the range 0.5 to 5 tons. Tablets are manu
`factured at the rate of 20.000 to 200.000 per hour. The
`tablets, especially those which are rough or bitter, may
`be coated with a layer of sugar or some other palatable
`substance. They are then packaged by machines having
`electronic counting devices. The different types of
`packages consist of glass or plastic gallipots, boxes,
`tubes and speci?c dosage adapted packages.
`The typical daily dose of the active substance varies
`according to the individual needs and the manner of
`administration. In general, oral dosages range from 100
`to 400 mg/day of active substance and intravenous
`dosages range from 5 to 20 mg/day.
`The following illustrates a preferred embodiment of
`the invention without being limited thereto. Tempera
`ture is given in degrees Centigrade.
`The starting materials in the examples found below
`were prepared in accordance with the following meth
`Ods:
`(1) a 1,2-diamino compound, such as o-phenylenedia
`mine was reacted with potassium ethylxanthate (ac
`cording to Org. Synth. Vol. 30, p. 56) to form a 2-mer
`captobenzimidazole; (2) the compound 2-chloromethyl
`pyridine was prepared by reacting 2-hydroxymethyl
`pyridine with thionylchloride (according to Arch.
`Pharm. V61. 26, pp. 448-451 (1956)); (3) the compound
`2-chloromethylbenzimidazole was prepared by con
`densing o-phenylenediamine with chloroacetic acid.
`
`EXAMPLE 32 (METHOD B)
`0.1 moles of 2-[Li-methylsul?nyl](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 re?uxed for two hours. The lithium
`chloride formed was ?ltered 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,S-dimethyDpyridyImethyl
`sul?nyl]-(5-acetyl-6-methyl)benzimidazole melting at
`171° C.
`
`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)
`phenylenediaminewere boiled for 40 minutes in 100 ml
`of 4 N‘HCl. The mixture was cooled and neutralized
`with ammonia. The neutral solution was then extracted
`with ethyl acetate. The organic phase was treated with
`active carbon and evaporated in vacuo. The residue was
`dissolved in acetone whereupon an equivalent of con
`centrated HCl was added. The precipitated hydrochlo
`ride was ?ltered off after cooling and the salt was re
`crystallized 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 oxidized‘ in accordance
`with Example 1 above, to give the corresponding sul?
`nyl derivative. M.p. 190° C.
`
`I EXAMPLE 34 (METHOD C)
`g of Z-mercapto-(S-acetyl-6-methyl)ben
`22.0
`zimidazole 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 20 ml of water
`were added, whereupon the solution was re?uxed for
`two hours. The sodium chloride formed was ?ltered 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 sul?
`nyl derivative..M.p. 158° C.
`
`30
`
`EXAMPLE 1
`
`40
`
`45
`
`28.9 g of 2-[2-(4,5-dimethyl)pyridylmethylthio]-(5
`acetyl-6-methyl)-benzimidazole were dissolved in 160
`ml of CHCl3, 24.4 g of m-chloroperbenzoic acid were
`added in portions while stirring and cooling to 5° C.
`After 10 minutes, the precipitated m-chlorobenzoic acid
`was ?ltered off. The ?ltrate was diluted with CH2Cl2,
`washed with Na2CO3 solution, dried over Na2SO4 and
`evaporated in vacuo. The residue crystallized when
`diluted with CH3CN, and 2-[2-(4,5-di-methyl)pyridyl
`methylsul?nyl]-(5-acetyl-6-methyl)benzimidazole was
`recrystallized from CH3CN. Yield 22.3 g; m.p. 158° C.
`
`EXAMPLES 2-30
`
`The preparation of compounds of formula III la
`belled 2-26 was carried out in accordance with Exam
`ple 1 above. The compounds prepared are listed in
`Table l which identi?es the substituents for these com
`pounds.
`
`55
`
`60.
`
`EXAMPLE 31 (METHOD C)
`0.1 moles of 4-6-dimethyl-Z-mercaptobenzimidazole
`were dissolved in 20 ml of water and 200 ml of ethanol
`containing 0.2 moles of sodium hydroxide. 01 moles of
`2-chloromethyl-(3,5-dimethyDpyridine hydrochloride
`
`65
`
`

`

`9
`
`4,255,431
`
`10
`
`R2
`
`R1
`
`EX.
`
`R1
`
`n2
`
`R4
`
`N
`
`s
`0 a
`R / R
`
`\ s-CH \
`l
`N
`
`|
`H
`
`-
`R6
`
`R3
`
`R4
`
`,
`
`R5
`
`M.p.
`‘‘C
`
`CH; 158
`CH; "
`H
`6-CH; H
`s-COCH;
`1
`CH; 163
`CH;
`H
`6-CH; H
`s-COOCH;
`2
`CH; 141
`H CH;
`H
`H
`s-COOCH;
`3
`H
`160
`6-CH3 H CH; CH;
`s-COCH;
`4
`H
`163
`cm; H CH; CH;
`s-COOCH;
`s
`CH; 50-55
`6-CH; H CH; H
`4;CH3
`6
`CH; 171
`cm; H
`CH; H
`s-COCH;
`1
`CH; 190
`6-CH3 H
`CH; CH;
`s-COCH;
`a
`H
`165
`cm; H
`H OCH;
`s-COCH;
`9
`H
`122
`mm H
`H
`OCH;
`4~CH3
`10
`CH; 156
`6-Cl-l3 H CH; OCH;
`s-COCH;
`11
`CH; 144
`6-CH; H CH; H
`s-COOCH;
`12
`CH; 185
`s-CooCH; mm H CH; CH;
`13
`H
`169
`s-COOCH;
`6-CH; H
`H
`OCH;
`14
`H
`148
`s-COOCH;
`6-CH; H
`H
`OCZH5
`is
`H
`175
`s-COOCH;
`cm; H CH; OCH;
`16
`CH; 15s
`s-COOCH;
`cm; H CH; OCH;
`17
`CH; 158
`s-COOCH;
`cm; H H OCH;
`18
`CH; 141
`s-COOCH;
`H
`H CH; H
`19
`CH; 142
`s-COOCH;
`H
`H
`CH; OCH;
`20
`CH; 162
`s-COCH;
`H
`H
`CH; OCH;
`21
`CH; 178
`22 mm;
`H
`H H OCH;
`CH; 156
`23
`s-OCH;
`H
`H CH; OCH;
`CH; 1x1
`24 mm
`H
`H
`CH; OCH;
`CH; 165
`25
`H
`H
`H
`CH; OCH;
`CH; 185
`26
`S-Cl
`H
`H CH; OCH;
`21
`s-CH;
`H
`H
`H OCZH4_OCH3 H 119
`28
`s-COOCZH;
`H
`H
`CH; OCH;
`CH; 150.5
`29
`s-COOCH;
`H
`CH; CH; H
`CH; 130
`30
`s-CH;
`H
`CH; CH; H
`CH; 152
`
`BIOLOGICAL EFFECT
`The compounds of the invention possess worthwhile
`therapeutic properties as gastric acid secretion inhibi
`tors as demonostrated by the following-tests. To deter
`mine 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 intradu
`odenal administration of the test compounds. After 18
`hours starvation and deprivation of water the dogs were
`given 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 titra
`
`tor and pH-meter (Radiometer, Copenhagen, Den
`mark). 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, suspendedv in 0.5% Methocel ® (methyl
`cellulose), were given intraduodenally in doses from
`4-20 umOl/kg when the secretory response to pentagas
`trin 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 described.
`
`R2
`
`R1
`
`TABLE 2
`
`R4
`
`0
`s
`s
`/I\ R / R
`
`>—S-CH \
`I
`N
`R‘
`
`N
`
`N
`l
`H
`
`Ex.
`1
`4
`7
`s
`9
`
`R‘
`s-COCH;
`s-COCH;
`s-COCH;
`5~C0CH3
`s-COCH;
`
`R6
`R2
`6-CH; H
`6-CH; H
`6-CH; H
`6-CH; H
`6-CH; H
`
`R4
`R3
`CH;
`H
`CH; CH;
`CH; H
`CH; CH;
`H
`OCH;
`
`R5
`CH;
`H
`CH;
`CH;
`H
`
`Dose
`umol/kg
`2
`1
`2
`4
`2
`
`Effect
`%inhibition
`90
`60
`100
`100
`9s
`
`

`

`4,255,431
`
`11
`TABLE 2-continued
`
`R4
`N i R / R
`
`1
`
`5
`
`>—S-—CH \
`I
`N
`R6
`
`N
`l
`H
`
`Dose
`
`Effect
`
`R2
`
`R1
`
`
`
`Ex. 11
`
`
`
`R1 5-CoCH;
`
`
`
`R6 R2 6-CH; H
`
`
`
`
`
`
`
`R4 R3 CH; OCH;
`
`CH;
`H
`6-CH; H
`s-COCH;
`'
`6-Cl-I3 H H H
`5-CoCH;
`'
`6-CH3 H H CH;
`s-coocH;
`2
`6-CH3 H
`CH; CH;
`5-C0oCH;
`s
`6-CH3 H CH; H
`5-CooCH;
`12
`6-CH3 H CH; CH;
`s-CooCH;
`13
`s-coocH; cm; H
`H
`oCH;
`14
`s-CooCH;
`6-CH3 H
`H OCgl-l;
`15
`s-coocH;
`6-CH; H CH; oCH;
`16
`s-coocH; cm; H
`CH; ocH;
`17
`5-CooCH;
`6-CH3 H H OCH;
`1s
`5-CooCH;
`6-CH3 H H
`H
`'
`5-CooCH;
`6-CH; H
`Br H
`'
`4-CH3
`6-CH3 H
`CH; H
`6
`10 mm
`G-CH; H
`H mm
`'
`4-CH;
`6-CH3 H
`H
`H
`*
`4-CH3
`6-CH; H
`H
`H
`3
`s-coocH; H
`H
`H
`CH;
`19
`s-coocH; H
`H
`CH; H
`2o
`5~C00CH3 H
`H CH; oCH;
`*
`s-coocH; H
`H H H
`'
`5-CO0CH; H
`H
`H
`H
`21
`s-cocH;
`H
`H
`CH; OCH;
`'
`s-cocH;
`H
`H H H
`22
`s-ocH;
`H
`H H OCH;
`23
`s-ocH;
`H
`H CH; OCH;
`'
`s-ocH;
`H
`H H CH;
`
`
`
`
`
`24 mm ' 5-CH;
`H H
`H H
`
`CH; oCH; H H
`
`H
`H
`H
`H
`5-COOC2H5 H
`5-C1
`H
`
`H CH; oCH;
`H
`H
`H
`H CH; oCH;
`H
`CH; oCH;
`
`25
`'f
`28
`26
`
`
`
`27 29
`
`
`
`R5 CH;
`
`H
`CH;
`CH;
`H
`CH;
`CH;
`H
`H
`H
`CH;
`CH;
`CH;
`H
`CH;
`H
`H
`CH;
`CH;
`CH;
`CH;
`CH;
`H
`CH;
`C2H5
`CH;
`CH;
`H
`
`CH; CH;
`
`CH;
`H
`CH;
`CH;
`
`
`
`umol/kg % inhibition _. 0.5 70
`
`
`
`20
`8
`2
`2
`2
`4
`2
`4
`0.5
`0.5
`
`4
`4
`4
`2
`4
`12
`4
`2
`0.5
`20
`20
`0.5
`20
`
`0.5
`20
`
`05 4
`
`0.5
`4
`0.5
`0.5
`
`
`
`0.5 0.5
`
`30
`so
`60
`90
`10
`s0
`100
`75
`65
`90
`
`50
`0
`4o
`40
`30
`5o
`100
`60
`65
`90
`50
`60
`40
`
`65
`, 10
`
`50, so
`
`60
`50
`so
`25
`
`
`
`30 40
`
`
`
`5-CH; s-coocH; H H
`
`
`
`
`
`H H OC2H4OCH3 H CH; CH; H CH;
`
`
`
`12
`
`.
`.
`
`J
`
`>
`
`._
`
`’
`
`.
`
`v
`
`.
`
`z
`
`,,
`
`. r.
`
`‘
`
`‘denotes a previously known compound
`
`EXAMPLE 35
`
`A syrup containing 2% (weight per volume) of active
`substance was prepared from the following ingredients:
`
`(S-acetyl-6-methyl)benzimidazole . HCl
`Saccharin
`Sugar
`Glycerin
`Flavouring agent
`Ethanol 96%
`
`2.0 g
`0.6 g
`30.0 g
`5.0 g
`0.l g
`l0.0 ml
`
`Distilled water (suf?cient to obtain a ?nal volume of 60
`100 ml) Sugar, saccharin and the acid addition salt were
`dissolved in 60 g of warm water. After cooling, glycerin
`and a solution of flavouring agents dissolved in ethanol
`were added. Water was added to the mixture to obtain
`a ?nal volume of 100 ml.
`The above given active substance may be replaced
`with other pharmaceutically acceptable acid addition
`salts.
`
`65
`
`45
`
`5O
`
`55
`
`_
`EXAMPLE 36
`2- 2- 3,4-dimeth 1
`rid lmel'th lsul?n l-5-acet l-6
`[ (
`y)1.>y y
`y
`y]
`y
`methyDbenzimidazoleIuHCl (250 g) was mixed with
`lactose (1775.8 g),.potato. starch (169.7v g) and colloidal
`silicic acid ‘(32
`The mixture was moistened with 10%
`solution of gelatin and was_..gro1i1nd through a l2-mesh
`sieve. After drying, potatostarch (160 g), talc (50 g) and
`magnesium stearate (5 g)-vve_re added and the mixture
`thus obtained was pressed into tablets (10.000), with
`each tablet containing 25 mg of active substance. Tab
`lets can be prepared that contain any desired amount of
`the active ingredient.
`
`EXAMPLE 37
`Granules were prepared from 2-[2-(3,5-dimethyl)
`pyridylmethylsul?nyl]-(5-acetyl-6-methyl)ben~
`zimidazole-p-hydroxybenzoate (250 g), lactose (175.9 g)
`and an alcoholic solution of polyvinylpyrrolidone (25
`g). After drying, the granules were mixed with talc (25
`g), potato starch (40 g), and magnesium stearate (2.50 g)
`and werepressed into 10.000 tablets. These tablets are
`first coated with a 10% alcoholic solution of shellac and
`thereupon with an aqueous solution containing saccha
`rose (45%), gum arabic (5%), gelatin (4%), and dyestuff
`
`

`

`4,255,431
`13
`14
`2-[2-(4-ethoxy)-pyridylmethylsul?nyl]-(5-carbome
`(0.2%). Talc and powdered sugar were used for pow
`thoxy-6-methyl)-benzirnidazole,
`dering after the ?rst ?ve coatings. The coating‘was then
`2-[2—(3-methyl-4-methoxy)-pyridylmethylsul?nyl]-(5
`covered with a 66% sugar syrup and polished with a
`carbomethoxy-6-methyl)-benzimidazole,
`solution of 10% carnauba wax in carbon tetrachloride.
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul
`?nyl]-(5-carbomethoxy-6-methyl)-benzimidazole,
`2-[2-(4-methoxy-5-methyl)-pyridylmethylsul?nyl]-(5
`carbomethyoxy-6-methyl)-benzimidazo1e,
`2-[2-(3,S-dimethyl-4-rnethoxy)-pyridylmethylsul
`?nyl]-S-carbomethoxy)-benzimidazole,
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul
`?nyl]-(5-acetyl)-benzimidazole,
`2-[2-(4-methoxy-5-methyl)-pyridylmethylsul?nyl]-(5
`methoxy)-benzimidazole,
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul
`?nyl]-(5-methoxy)-benzimidazole,
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul
`?nyl]-(5-methyl)-benzimidazole,
`2-[2-(3,S-dimethyl-4-methoxy)-pyridylmethylsul
`?nyl]-benzimidazole,
`2-[2-(3,5-dimethyl-4-methoxy)-pyridylmethylsul
`?nyl]-(5-chloro)-benzimidazole or a pharmaceuti
`cally acceptable salt thereof in a therapeutically
`effective amount is administered for inhibiting gas
`tric acid secretion.
`5. A compound of formula III
`
`EXAMPLE 38
`2~[2-(3,5-dimethyl)pyridylmethylsul?nyl]-(5-acetyl
`6-methyl)benzimidazole hydrochloride (1 g), Sodium
`chloride (0.6 g) and ascorbic acid (0.1 g) were dissolved
`in suf?cient 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 ?lling ampoules,
`which were steralized by heating at 120° C. for 20 min
`utes.
`We claim:
`1. A method of inhibiting gastric acid secretion by
`administering to mammals, including man, suffering
`from gastric acid secretion disturbances a compound of
`the formula III
`
`15
`
`25
`
`40
`
`or a pharmaceutically acceptable salt thereof in a thera
`peutically effective amount in which R1 and R2 are the
`same or different and are selected from the group con
`sisting of hydrogen, lower alkyl, halogen, carbome
`thoxy, carbethoxy, lower alkoxy, and lower alkanoyl in
`35
`any position, R6 is selected from the group consisting of
`hydrogen, methyl, and ethyl, R3, and R5 are the same or
`different and are each selected from the group consist
`ing of hydrogen, methyl, methoxy, ethoxy, methoxye
`thoxy, and ethoxyethoxy; and R4 is methoxy, ethoxy,
`methoxyethoxy and ethoxye