DK141122B - Analogous process for the preparation of substituted benzimidazoles or acid addition salts thereof. - Google Patents

Description

(fin \ Ra / (11) PUBLICATION PUBLICATION 141 122 DENMARK (ex intci.3 c 07 d 401/12 '(21) Application No 54Ο / 75 (22) filed on 14 Feb 1975 (23) Day 14) © b. 1975 (44) The application presented and

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DIRECTORATE OF

PATENT AND TRADE MARKET (3 °) Spent requested from 18 Feb. 1974, 7402101, SE (71) AB HAESSLE, Fack, S-4j51 20 Moelndal 1, SE.

(72) Inventor: Peder Bernhard Bernt's son, Flugsnapparegatan 17A, S-431 55. Moelndal, SE: Stig Åke Ingemar Carlsson, Vallmovaegen 5, S-455 00 Moeln «lyeke, SE: Lars Erik Garberg, HSdavaegen 70, S-435 00 Moelnlycke, SE:

Ulf Krister Junggren, Damravaegen 7, S-4j50 62 Pixbo, SE: Sven Erik SJoe «beach, BlåkTintsvaegen 71, S-434 00 Kungsbacka, SE: Gunhild Wika von Wittken Sundeli, Sollidsvaegen 2, S-45 & 00 Aakim, SE.

(74) Plenipotentiary during the week:

Office of Industrial Eneret v. Svend Schønnlng. _. (54) Analogous process for preparing substituted benzimidazoles or acid addition salts thereof.

The present invention relates to an analogous process for the preparation of novel substituted benzimidazoles having the general formula I shown in the preamble of claim 1, wherein R, R, 4 R, A and Het have the same meanings stated, or acid addition salts thereof. The compounds I and their acid addition salts have valuable properties in influencing gastric acid secretion in mammals, including humans. A particularly advantageous property of the compounds of the invention is that they inhibit exogenously or endogenously stimulated gastric acid secretion. peptic ulcer.

q

For example, alkyl groups R and R of the general formula I may be methyl, ethyl, n-propyl, isopropyl, n'-butyl or isobutyl.

3 141122 2

Halogen atoms R and R may be fluorine, iodine, bromine or chlorine, preferably bromine or chlorine.

3

Carboxy groups R and R are the group HOOC-.

3

Carboalkoxy groups R and R are alkyl-O-OC- groups, wherein the alkyl group contains 1-4 carbon atoms, preferably up to 2 carbon atoms. Examples of carboalkoxy groups R and R are carbomethoxy (CH 2 OOC-) and carboxy oxy (C 1 H 2 OOC-).

For example, alkoxy groups R and R 2 may be methoxy, ethoxy, n-propoxy or isopropoxy.

3

Hydroxyalkyl groups R and R having up to 4 carbon atoms may be straight or branched and may be, for example, hydroxymethyl, 1-hydroxypropyl-2, 1-hydroxyethyl-2 or 1-hydroxy-2-methylpropyl-2.

3

For example, alkanoyl groups R and R may be formyl, acetyl or propionyl, i. j), ^ or 0 HC- CH3C- CH3CH2C-

The alkanoyl group Ryl may be, for example, one of the same groups, ie for example formyl, acetyl or propionyl.

4

A carboalkoxy group R is a group of alkyl-0-00 wherein the alkyl group contains 1-4 carbon atoms, preferably 1-2 carbon atoms; it is, for example, a carbomethoxy group (CH3OOC-) or carbethoxy group (CjHgOOO).

The heterocyclic group Het is a 2-pyridyl group which may be further substituted by alkyl or halogen. Such alkyl groups are lower alkyl groups such as methyl, ethyl or propyl.

. Halogen substituents are preferably chlorine or bromine.

The process according to the invention is characterized by the characterizing part of the claim.

In particular, a reactive esterified hydroxy group Z or in reaction a) is a hydroxy group esterified with a strong inorganic or organic acid, preferably a hydrohalogenic acid such as hydrochloric acid, hydrobronic acid or iodine hydrochloric acid, in addition there may be sulfuric acid or a strong organic sulfonic acid such as a strong acid, e.g., benzenesulfonic acid, 4-bromobenzene sulfonic acid or ± 4-to-luenesulfonic acid. Thus, Z or Z ^ is preferably chlorine, bromine or iodine.

Depending on the process conditions and the starting material, the final product is obtained either as a free base or in the form of an acid addition salt thereof, and the formation thereof is included in the invention. Thus, for example, basic, neutral or mixed salts can be formed as well as hemiamino, Besqui or polyhydrates. Acid addition salts of the subject compounds can be converted into the free base in a manner known per se by, for example, basic agents such as alkali or ion exchangers. On the other hand, the formed free bases can form salts with organic or inorganic acids. In the preparation of acid addition salts, such acids are preferably used which form suitable therapeutically acceptable salts. Such acids are, for example, halohydrides, sulfonic acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, malic acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid, tartaric acid ; ; methionine, tryptophan, lysine or arginine.

These and other salts of the compounds of the present invention, for example picrates, can also serve as detergents for the obtained free bases by first converting these free bases into salts, separating them and finally releasing the salts from the salts again.Because of the close relationship between the new compounds in question in the free form and in the form of their salts will be understood by the foregoing and also by the following that in most cases the mention of the free compounds and their effects also applies to the corresponding salts, unless otherwise stated.

Some of the novel compounds in question may, depending on the choice of starting materials and process, be available as optical antipodes or racemates, and if they contain at least two asymmetric carbon atoms, they may exist as an isomer mixture (racemate mixture).

The obtained isomer mixtures (racemate mixtures) can, depending on physicochemical differences between the components, be separated into the two stereoisomeric (diastereomeric) pure racemates, for example by chromatography and / or fractional crystallization · 4 141122

The obtained racemate can be separated by known methods, for example, by recrystallization from an optically active solvent, by microorganisms or by reaction with optically active acids which form salts with the compounds and then separate the salt thus formed, for example, using their different solubility. in the diastereomers from which the antipodes can be released under the action of a suitable agent.

Suitable optically active acids for the purpose are, for example, the L and D forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quinic acid. Preferably, the most active portion of the two antipodes is isolated.

The starting materials are known or, in the cases where they are new, can be prepared in a manner known per se.

Some examples serve to elucidate the method of the invention.

The starting materials of the Examples were prepared according to the following:

A 1,2-diamino compound such as o-phenylenediamine is reacted with potassium methyl xanthate (according to Org. Synth, Vol. 30, page 56) to give a 2-mercaptobenzimidazole.

2-Chloromethylpyridine was prepared by reacting 2-hydroxymethylpyridine with thionyl chloride (see Arch. Pharm vol. 26, pages 448-451 (1956)).

2-Chloromethylbenzimidazole was prepared by condensing o-phenylenediamine with chloroacetic acid.

Example 1 Dissolve 0.1 mole of 4-methyl-2-mercaptobenzimidazole in 20 ml of water and 200 ml of ethanol containing 0.2 mole of sodium hydroxide. 0.1 mole of 2-chloromethylpyridine hydrochloride was added and the mixture was refluxed for 2 hours. The resulting sodium chloride was filtered off and the solution evaporated in vacuo. The residue was dissolved in acetone and treated with activated charcoal. An equivalent amount of concentrated hydrochloric acid was added and the monohydrochloride of (2-pyridylmethylthio) -4-methyl-2-benzimidazole was isolated. Yield 0.05 mol, m.p. 137 ° C.

5 141122

Example 2-27

The preparation was carried out in accordance with Example 1.

The compounds prepared are listed in Table 1 below.

Example 28 13.5 g (0.05 mole) of 2- (2-pyridylmethylthio) benzimidazole hydrochloride, 3.9 g (0.05 mole) of acetyl chloride and 10.1 g (0.1 mole) of triethylamine were dissolved in 100 ml of acetonitrile. The mixture was heated in a 40 ° C hot water bath for 30 minutes. After cooling, the crystals formed were filtered off and suspended in water to dissolve the triethylamine hydrochloride. The residue, 2- (2-pyridylmethylthio) -N-acetylbenzimidazole, was filtered off. Yield 7.2 g (51%), m.p. 119-124 ° C as a base.

Example 29 2- (2-Pyridylmethylthio) -N-methoxycarbonylbenzimidazole was prepared in the manner described in Example 28.

Example 30 17.2 g of 2-pyridine methylthiocarboxylic acid and 12.2 g of 4-methyl-o-phenylenediamine were boiled for 40 minutes in 100 ml of 4N HCl. The mixture was cooled and neutralized with ammonia. The neutral solution was extracted with ethyl acetate. The organic phase was washed with activated carbon and evaporated in vacuo. The residue was dissolved in acetone and an equivalent amount of concentrated HCl was added. The precipitated hydrochloride was filtered off after cooling and the salt was recrystallized from absolute ethanol and some ether. The yield of 2- (2-pyridylmethylthio) - (4-methyl) -benzimidazole was 5.3 g. 137 ° C (HCl).

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Biological effect

The compounds of the present invention have valuable therapeutic properties such as gastric acid-acting compounds.

Thus, in a test series, in tests with dogs, a technique is used for compounds with secretory activity. The experiments were performed with dogs with experimentally induced acute (not chronically) acidic stomach by a modified perfusion technique.

The stomach of the anesthetized dog was provided with one tube through the esophagus to introduce fluid and another tube via the ligated pylorus through the duodenum to drain the fluid. Saline was introduced at a volume of 5 ml / kg body weight and the installation fluid changed every fifteen minutes.

The collected samples were titrated to pH 7.0 with 0.04 N NaOH using an automatic titrator labeled "Radiometer" and the acid yield per ml. 15 minutes were calculated (collection periods).

Stomach acid secretion was induced by pentagastrin in amounts of 1-2 µg / kg and hour, resulting in a submaximal secretory response.

Test compounds were administered in 0.5% metocel suspension, being administered into the duodenum close to the ligature at least 2 hours after the insertion of the stimulation, as the secretion had reached a stable level for three consecutive 15-minute periods.

The gastric secretion response was noted, showing that all of the compounds listed in the above examples were gastric acid secretion inhibitors.

Some of the compounds of the process according to the invention have gastric acid secretion inhibitory effect as compared to N-methyl-N'-2- (5-methyl-4-imidazolyl) methylthioethyl thiourea known as gastric acid secretion inhibitory compound from NO. Patent Specification 133,196.

Said compound, designated in Table 2 below A, is compared with the compounds prepared according to Examples 1, 3 and 9 above; the study was done on vigilant dogs with ventricular fistula and their gastric acid secretion was stimulated with pentagastrin. The secreted amount of gastric acid for administration of the compound under study was determined titremetrically, then the compound was administered and the gastric acid secretion was again determined.

In Table 2, the inhibition is given in% relative to the basal secretion, and in addition, the amount of test compound administered is expressed in mg / kg body weight.

Table 2

Connection fire% inhibition after

Dose 1 _2_3 hours_ A 2 mg / kg 50 30 20

Ex.1 "50 60 65

Ex. 3 „50 6 0 6 5

Ex.9 "50 60 65 A 1 mg / kg 15 0 0

Ex.1 "20 25 25

Ex. 3 "20 25 25

Ex.9 "20 25 25

As can be seen from the foregoing, the initial inhibition obtained with the known and the compounds prepared by the process according to the invention, respectively, is of uniform size. In contrast, the compounds prepared by the process of the invention exhibit significantly better duration, even with improved inhibition after 2 and 3 hours.

Table 3 below shows the inhibition of the acid secretion obtained by the screening test described above for a number of compounds identified by the examples by which they were prepared.

Table 3

Compound 1 3 5 9 15 27 28 according to Ex.% Inhibition, 10 mg / kg 89 86 40 70 50 80 76

It is evident that the compounds exhibit a markedly reducing effect on gastric acid secretion.

Claims (2)

An analogous process for the preparation of substituted benzimidazoles of the general formula R 1 R 4 wherein R and R are the same or different and each represents hydrogen, an alkyl group, a halogen atom, a hydroxy, carboxy, C , C1-4 hydroxyalkyl or C1-4 alkanoyl group, R4 represents hydrogen or an alkanoyl or 2-S carboalkoxy group, A represents -SCH2- or -SCH (CH3) - and Het represents an optionally C1-3 alkyl or halogen substituted 2-pyridyl group, although R and R 5-CH3 and 6-CH3 and may not be hydrogen and 5-Cl if Het is a 2-pyridyl group, A is "SCH2 ~ and R4 is hydrogen, or acid addition salts thereof, characterized by a) reacting a compound with the general Formula II L II K 3 4 wherein R, R and R have the above meanings and Z is SH or a reactive esterified hydroxy group, with a compound of general formula III Z1-CH2Het III where Het has the above meaning and Z is a reactive esterified hydroxy group or a group SH, respectively; or b) reacting a compound of general formula IV