NZ198427A - 2-(di- or tri-methylpyrid-2-ylmethylthio) benzimidazoles - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number 1 98427 CASE KH 575-4 t 984 27i . 11^:7 f\ AWMg-Mtr.

Gomrj'i&'io SpsciEeation Fi'.cd Piib!ic£t'cn Oste P.O. Jcumsl No: 7.'M iw.wfi |£5f. iiliw Under the provisions of Regulation 23 (I) the Specification has been ante-datedi to .../<? 19_ Initials ■NEW ZEALAND ■PATENTS ACT 1953 COMPLETE SPECIFICATION "SUBSTITUTED PYRIDYLALKYLENETHIO BENZIMIDAZOLE COMPOUNDS" We, AKTIEBOLAGET HASSLE, a Swedish Company, of Fack, S-431 20 Molndal, Sweden, hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: 1 98427 The present invention relates to novel substituted pyridylalkylenethio benzimidazole compounds that are useful as intermediates in the preparation of di- and tri- methyl substituted pyridylalkylenesulphinyl benzimidazole compounds having valuable properties in affecting gastric acid secretion in mammals, as disclosed in New Zealand Patent Specification No. 198426, which is divided out of New Zealand Patent Specification No. 190203.

The specifications of New Zealand Patents Nos. 176671 and 179132 disclose respectively compounds of the formulas I and II below: (I) (II) 12 . wherein R and R are each selected from the group consisting of hydrogen, alkyl, halogen, cyano, carboxy, carboxyalkyl, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoyloxy, hydroxy, alkoxy, hydroxyalkyl, trifluoromethyl and acyl in any position, 3 R is selected from the group consisting of hydrogen, alkyl, acyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, and alkylsulphonyl, 4 and R 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 and the J 98427 pyridyl group, and whereby the pyridyl group may be further substituted with alkyl or halogen, possess inhibiting effect of gastric acid secretion.

Mew Zealand Patent Specification No. 190203, which is the parent of the present divisional specification, discloses the compounds of ttie general formula III as defined below and therapeutically acceptable salts thereof, having a still greater inhibiting effect of gastric acid secretion than the compounds of formula I and II above: I4 R2\ /N\ O RIVV R" 1 I II ^-s-ch-L., J] (III) N' I H 1 2 wherein R and R are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy, and alkanoyl, R6 is independently selected from the group consisting of 3 4 5 hydrogen, methyl and ethyl, and R , R and R are the same or different and are each independently selected from the group consisting of hydrogen, methyl, methoxy, ethoxy, methoxyethoxy 3 4 5 and ethoxyethoxy, provided: (i) that R , R and R are not all 3 4 hydrogen or not all methyl; (ii) that when two of R , R and 20 are methyl, the third of R^, R4 and R"* is not hydrogen; and (iii) that when two of R^, R4 and R"* are hydrogen, the third 3 4 5 of R , R and R is not methyl.

New Zealand Patent Specification No. 198426, which is also divided out of New Zealand Patent Specif ication No. 190203, 25 discloses di- and tri- methyl substituted pyridyl compounds of -3- «* 1984 27 the general formula IV as defined below and therapeutically acceptable salts thereof, that possess an unexpectedly greater inhibiting effect of gastric acid secretion than the mono-methyl substituted compounds disclosed in the specification of New Zealand Patent No. 179132: 4 R" R 5 R1- ' || y S-CH (IV) ■N I H 1 2 wherein R and R are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy, and alkanoyl, R^ is independently selected from the group consisting of 3 4 5 hydrogen, methyl and ethyl, and R , R and R are the same or different and are each independently selected from the group consisting of hydrogen and methyl, provided that at least two 3 4 5 of R , R and R are methyl.

The present invention is directed to the compounds of the general formula V: R4 I5 (V) 1 2 wherein R and R , preferably in 4 to 6 positions, are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy, and alkanoyl, R^ is independently selected from the group 1984 27 3 4 5 consisting of hydrogen, methyl and ethyl, and R , R and R are the same or different and are each independently selected from the group consisting of hydrogen and methyl, provided that at 3 4 5 least two of R , R and R are methyl, that are useful as 5 intermediates in the preparation of the compounds of formula IV above. 1 2 Alkyl R and R of formula V are suitably alkyl having up to 7 carbon atoms, preferably up to 4 carbon atoms. Thus, 1 2 alkyl R and R may be methyl, ethyl, n-propyl, isopropyl, n-10 butyl or isobutyl. 1 2 Halogen R and R is chloro, bromo, fluoro, or iodo. 1 2 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. 1 2 Alkanoyl R and R 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 1 2 V are those wherein R and R are the same or different and are each independently selected from the group consisting of hydrogen. alkyl, carbomethoxy, alkoxy and alkanoyl, provided that R"^ and R^ are not both hydrogen, R6 is hydrogen, and R3, R4 and R^ are' the same or different and are each independently selected from the group consisting of hydrogen and methyl, provided that at 3 4 5 least two of R , R and R are methyl.

A second preferred group of compounds of the general 1 2 formula V are those wherein R and R are the same or different and are each independently selected from the group consisting of 1 984 27 hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy and £ alkanoyl, R is selected from the group consisting of hydrogen, 3 5 4 . methyl and ethyl, R and R are methyl, and R is hydrogen.

A third preferred group of compounds of the general 1 2 formula V are those wherein R and R are the same or different 5 and are each independently selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, alkoxy and alkanoyl, R is selected from the group consisting of hydrogen, methyl 3 4 5 and ethyl, and R , R and R are all methyl.

Compounds of formula V above may be prepared according to the following methods: (a) reacting a compound of the formula VII: ,2 •N> ^ ' " (VII) 12 1 wherein R and R have the same meanings as given above, and Z is SH, or a reactive esterified hydroxy group, respectively, with a compound of the formula VIII: R4 5 RC - -R Z^-CH-kJ (VIII) I R6 wherein R^, R3, R4 and R"* have the same meanings as given above, 2 . and Z is a reactive esterified hydroxy group or SH, respectively, for the formation of a compound of formula V above; or (b) reacting a compound of the formula IX: R2 NH- ,!— (IX) nh2 /98427 12 wherexn R and R have the same meanings as given above, with «f a compound of the formula X: ,4 HOOC-S-CH I (X) wherein R®, R^, R4 and R"* have the same meanings as given above, 5 for the formation of a compound of formula V above. 12 In the reactions above, Z and Z may be a reactive, esterified hydroxy group, which is a hydroxy group esterified with a strong, inorganic or organic acid, preferably a hydro-halogen acid, such as hydrochloric acid, hydrobromic acid, or 10 hydroiodic acid, also sulfuric acid, or a strong organic sulfonic acid, such as a strong aromatic acid, for example, benzenesulfonic acid, 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid.

Some of the new compounds may, depending on the choice 15 of starting materials and process, be present as optical isomers or racemate, or if they contain at least two asymmetric carbon atoms, be present as an isomer mixture (racemate mixture). The isomer mixtures (racemate mixtures) obtained may be separated into two stereoisomeric (diastereomeric) pure racemates by 20 means of chromatography or fractional crystallization.

The racemates obtained can be separated according to known methods, for example, recrystallization from an optically active solvent; use of microorganisms; reactions with optically active acids forming salts which can be separated; or separation 25 based on different solubilities of the diastereomers. Suitable optically actjye^acids are the L- and D- forms of tartaric acid, 1984 27 di-o-tolyl-tartaric acid, malic acid, mandelic acid, 3- or 10-camphorosulfonic acid or quinic acid. Preferably 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.

The following examples illustrate preferred embodiments of the invention without being limited thereto. Temperature is given in degress Centigrade.

The starting materials in the examples below were prepared in accordance with the following methods: (1) a 1,2-diamino compound, such as o-phenylenediamine was reacted with potassium ethyl xanthate (according to Org. Synth. Vol. 30, p. 56) to form a 2.-mercaptobenzimidazole; (2) the compound 2-chloromethylpyridine was prepared by reacting 2-hydroxymethyl-pyridine 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 (Method a) : 0.1 mole of 4,6-dimethyl-2-mercaptobenzimidazole was dissolved in 20 ml of water and 200 ml of ethanol containing 0.2 mole of sodium hydroxide, 0.1 mole of 2-chloromethyl-(3,5-dimethyl) pyridine hydrochloride was 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-hydrochloride of 2-[2-(3,5-dimethyl)pyridylmethylthio]-(4,6-dimethyl)benzimidazole was isolated. Yield 0.05 mole. 198427 Example 2 (Method b): 23.4 g of 2-[2-(3,4,5-trimethyl)pyridylmethylthio]formic acid and 16.6 g of o-(5-acetyl-6-methyl)phenylene diamine were boiled for 40 minutes in, 100 ml of 4N HC1. 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 concentrated HC1 was added. The precipitated hydrochloride was filtered off after cooling and the salt was recrystallized from absolute ethanol and some ether, to yield 6.5 g of 2-[2-(3,4,5-trimethyl)pyridylmethyl-thio] -(5-acetyl-6-methyl)benzimidazole.

Example 3 (Method a); 22.0 g of 2-mercapto-(5-acetyl-6-methyl)benzimidazole and 19.5 g of 2-chloromethyl-(4-5-dimethyl)pyridine hydrochloride was dissolved in 200 ml of 95% ethanol. 8 g of sodium hydroxide in 20 ml of water was added, whereupon the solution was refluxed for two hours. The sodium chloride formed 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.

Cross reference is made to New Zealand Patent, Specification No. 198426, which like the present .?spedificaticnis divided out of New Zealand Patent Specification No. 190203, said New Zealand Patent Specification No. 198426 disclosing that the a sulfinyl compounds corresponding to the compounds of formula V of the present specification, possess an unexpectedly greater inhibiting effect of gastric acid secretion than the mono-methyl V / substituted compounds disclosed in New Zealand Pate^t^ Specification No. 179132. 18 OCT 1982

Claims (8)

1984 27 The matter contained in each of the following claims is to be read as part of the general description of the present invention. - 10 - 1 98427 ffhat we claim is: J A compound of formula V: R4 _ ,2 rVY i H 1 2 wherein R and R are the same or different and are each independently 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 3 4 5 hydrogen, methyl and ethyl, and R , R and R are the same or different and are each independently selected from the group consisting of hydrogen and methyl, provided that at least two 3 4 5 of R , R and R are methyl.

1 2

2. A compound according to claim 1 wherein R and R are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, carbomethoxy, alkoxy, 1 2 and alkanoyl, provided that R and R are not both hydrogen, 6 3 4 5 R is hydrogen, and R , R and R are the same or different and are each independently selected from the group consisting 3 4 of hydrogen and methyl, provided that at least two of R , R and R"* are methyl. 1 2

3. A compound according to claim 1 wherein R and R are the same or different and are each independently selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, carbethoxy, alkoxy, and alkanoyl, R^ is selected from the group 3 5 consisting of hydrogen, methyl and ethyl, R and R are methyl,

4 and R is hydrogen. V. !« 1~FEBI982*"\ V *l XWo / - li - 198427 1 2 A compound according- to claim 1 wherein R and R are i the same or different and are each independently selected from the group consisting of hydrogen, alkyl, halogen, carbomethoxy, alkoxy and alkanoyl, is selected from the group consisting 3 4 5 of hydrogen, methyl and ethyl, and R , R and R are all methyl.

5. A compound according to any one of claims 1 to 4 wherei-1 2 R and R are in the 4 to 6 positions.

6. A compound according to any one of claims 1 to 5, in the form of a stereoisomeric (diastereomeric) substantially pure racemate, when initially existing as optical isomer or racemate.

7. A process for preparing compounds of the general formula V: 4 (V) 1 2 wherein R and R are the same or different and are each 5 independently 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 3 4 5 hydrogen, methyl and ethyl, and R , R and R are the same or different and are each independently selected from the group 10 consisting of hydrogen and methyl, proyided that at least two 3 4 5 of R , R and R are methyl, characterized in: (a) reacting a compound of formula VII: ,2 - N. . Vz1 (VII) 198427 1 2 wherein R and R have the same meanings as given above, and 15 ,1 • is SH, or a reactive esterified hydroxy group, respectively, with a compound of formula VIII: R4 (VIII) 20 6 3 4 5 wherein R , R , R and R have the same meanings as given above 2 and Z is a reactive esterified hydroxy group or SH, respectively, for the formation of a compound of formula V; or (b) reacting a compound of formula IX: ,2 (IX) 25 1 2 wherein R and R have the same meanings as given above, with a compound of the_formula X: R4 „3 HOOC-S-CH 1,6 (X) wherein , R"*, R4 and R^ have the same meanings as given above, for the formation of a compound of formula V.

8. 1 2 A process according to claim 7 wherein R and R of the compound of formula VII or the compound- of formula IX are in the 4 to 6 positions. AKTIEBOLAGET HASSLE By Their Attorneys HENRY HUGHES LIMIT! BY r= - 13 -