CH616160A5 - Process for the preparation of novel compounds which affect gastric acid secretion - Google Patents

Description

The present invention relates to a process for the preparation of new compounds which have valuable properties for influencing gastric acid secretion in mammals, preferably in humans. The compounds obtainable according to the invention can be used in the form of pharmaceutical preparations which contain the new compounds in free form or in the form of their pharmaceutically acceptable, non-toxic acid addition salts.

The state of the art can be divided into two groups:

a) Compounds with a structural formula similar to formula I are known, but they are used for other purposes. For example, DE-OS 1 804 450 describes compounds of similar formulas, but the compounds described in this invention are expressly excluded from patent claim 1 given there. The compounds set out in the cited publication show tuberculostatic and bacteriological effects; but they are also suitable as insecticides, fungicides and as compounds with antiviral, anthelmintic and antimetabolic activity.

b) Compounds which have an inhibitory effect on gastric acid secretion. Such connections are e.g. known from Swedish patent application S / N 2933/72. You have the general formula like this

Xr

X

AC- (CH2) i-Y- (CH2) m -NH-C ss X2 ^ NHRi in which A is formed such that it forms an unsaturated, heterocyclic ring with 5 to 6 atoms, at least one of these atoms being nitrogen. Xi and X2 are the same or different and each is either hydrogen, acyl, trifluoromethyl, hydroxy, benzyl, halogen, amino or

6S

- (CH2) i-Y- (CH2) mNHC

y

• Xi and X2

NHRi

3rd

616160

but can also form another ring together with two other atoms that occur in group A. For example, they can form the benzene or pyrimidine ring. 1 and m are integers from 0 to 4, the sum of 1 and m being 3 or 4. Y is S, O or NH, E is O, S or, if A is not a pyridine ring, NR2, Ri is hydrogen, alkyl,

Acyl or dialkylaminoalkyl and R2 is hydrogen, cyano or nitro.

The inventive method for producing new benzimidazoles (I) is specified in claim 1.

The new compounds which can be prepared according to the invention inhibit exogenously or endogenously stimulated gastric acid secretion, as a result of which they are suitable for the treatment of, for example, gastric ulcers or similar diseases. These compounds have the formula I.

3rd

R

■ A-Het

R

wherein R and R3, which are the same or different, are hydrogen, alkyl, halogen, carboxy, carbalkoxy, hydroxy, alkoxy, hydroxyalkyl or acyl in any position, where the alkyl radicals each have 1 to 4 carbon atoms, R4 is hydrogen, acyl or carbalkoxy, A the group - S - CHa— or - S —CH (CH3) - and Het are an optionally further substituted 2-quinolyl or 2-pyridyl radical, where, when Het is 2-pyridyl and A is -SCH2, R4 is hydrogen and R and R3 does not simultaneously represent hydrogen, not 5-CHs and 6-CH3 and not hydrogen and 5-Cl; the compounds can be present as free bases or in the form of their pharmaceutically acceptable acid addition salts.

When R and R3 are halogen, they are preferably bromine or chlorine.

When the groups R, R3 and R4 are carbalkoxy, the alkyl groups preferably have 1 or 2 carbon atoms, i. H. they are preferably carbomethoxy (CH3OOC—) or carboethoxy (C2H5OOC—).

Hydroxyalkyl groups of the substituents R and R3 are preferably hydroxymethyl, l-hydroxypropyl- (2), 1-hydroxy-ethyl- (2) or l-hydroxy-2-methylpropyl- (2).

Acyl radicals of the substituents R, R3 and R4 are preferably formyl, acetyl or propionyl.

The heterocyclic group Het can preferably be further substituted with alkyl groups or halogen atoms. Such alkyl groups are preferably lower alkyl groups, especially methyl, ethyl or propyl. Halogen substituents are preferably chlorine or bromine. The heterocyclic group Het is preferably attached in the 2-position.

The process according to the invention for the preparation of the new benzimidazoles of the formula I is characterized in that a compound of the formula IV

wherein R, R3 and R4 have the meanings given above and Z - SH or a reactive, esterified hydroxyl group, with a compound of the formula V, Z ^ B-Het, where Het has the meaning given above, B the group --CH2— or - is CH (CH3) - and Z1 is a reactive, esterified hydroxyl group or - SH, is reacted.

A reactive, esterified hydroxyl group is, in particular, a hydroxyl group which has a strong inorganic or organic acid, preferably a hydrohalic acid, in particular hydrochloric acid, hydrobromic acid or hydroiodic acid or else sulfuric acid or a strong, organic sulfonic acid, preferably a strong, aromatic acid, in particular benzenesulfonic acid , 4-bromobenzenesulfonic acid or 4-toluenesulfonic acid, is esterified. Z and Z1 are preferably chlorine, bromine or iodine. Depending on the process conditions and the starting materials used, the end product is either in the form of a free base or in the form of its acid addition salt. These are also within the scope of the present invention. For example, basic, neutral or mixed salts as well as hemiamino, sesqui or polyhydrates can be obtained. The acid addition salts of the new compounds obtainable according to the invention can be converted into the free base in a manner known per se using, for example, basic agents or alkalis or ion exchangers. On the other hand, the free bases obtained can form salts with organic or inorganic acids. In the production of acid addition salts, preference is given to using those acids which form therapeutically permissible salts. Such salts are u. a. Hydrochloric acids, sulfonic acids, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, especially formic, acetic, propionic, amber, glycolic, milk, apple, wine, lemon, Ascorbic, maleic, hydro-xymaleic or pyruvic acid, phenylacetic, benzoic, p-aminobenzoic, anthranilic, parahydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulfonic, ethansulfonic, hydroxyethanesulfon , Ethylene sulfonic acids, halobenzenesulfonic, toluenesulfonic, naphthylsulfonic or sulfanilic acid, methionine, tryptophan, lysine or arginine.

These or other salts of the new compounds obtainable according to the invention, such as, for example, picrates, can serve as cleaning agents for the free bases obtained by converting the free bases into the salts, by separating them and then by liberating the bases from the salts again be set. Because of the close relationship between the new compounds in free form and in the form of their salts, it is understood from the foregoing and the following that the corresponding salts are included in the free compounds, if possible.

Depending on the choice of the starting materials and the process, some of the new compounds obtainable according to the invention can be present in the form of optical antipodes or in the form of racemates, or - if they contain at least two asymmetric carbon atoms - they can be present as a mixture of isomers (racemate mixture).

Depending on the physico-chemical differences of the components, the isomer mixtures obtained (racemate mixtures) can be split into pure racemates in the two stereoisomers (diastereomers), for example by means of chromatography and / or fractional crystallization.

The racemate obtained can be broken down by methods known per se, for example by recrystallization from an optically active solvent, by means of microorganisms or by reaction with optically active

5

10th

15

20th

25th

30th

35

40

45

SO

55

60

65

616160

4th

Acids which form salts with the compound, separation of the salts thus obtained, for example by means of their different solubility in the diastereomers, and release of the antipodes by means of a suitable reagent. Suitable optically active acids that can be used are, for example, L and D forms of tartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphor sulfonic acid or quinic acid. The more active part of the two antipodes is preferably isolated.

The starting materials are known per se or, if they should be new, they can be produced by processes known per se.

In clinical use, the compounds obtainable according to the invention are normally administered orally, rectally or parenterally by injection in the form of a pharmaceutical preparation which is an active component either as a free base or as a pharmaceutically acceptable, non-toxic acid addition salt, for example as hydrochloride, lactate, acetate, sulfamate or the like, in combination with a pharmaceutically acceptable carrier. The mention of the new compounds obtainable according to the invention means both the free amine base and the acid addition salt of the free base, even if the compounds are described in general or in particular, provided that the context in which the terms are used, e.g. in the examples, does not conflict with this broad meaning. The carrier can be a solid, semi-solid or liquid diluent or a capsule. The amount of active compound is usually between 0.1 and 95% by weight of the preparation, preferably from 0.5 to 20% by weight in the case of preparations for injection and from 2 to 50% by weight in the case of preparations for oral administration .

The starting materials required for carrying out the process according to the invention can be obtained by the following processes:

A 1,2-diamino compound, such as o-phenylenediamine, is reacted with potassium methylxanthate (according to Org. Synth. Volume 30, p. 56) to form a 2-mercaptobenzimidazole.

2-chloromethylpyridine is prepared by reacting 2-hydroxymethylpyridine with thionyl chloride (according to Arch. Pharm. Volume 26, pp. 448-451 [1956]).

2-chloromethylbenzimidazole can be prepared by condensing o-phenylenediamine with chloroacetic acid.

example 1

0.1 mol of 4-methyl-2-mercaptobenzimidazole was dissolved in 20 ml of water and 200 ml of ethanol containing 0.2 mol of sodium hydroxide. 0.1 mole of 2-chloromethylpyridine hydrochloride was added and the mixture was heated to reflux for 2 hours. The sodium chloride formed was filtered off and the solution was evaporated to dryness in vacuo. The residue was dissolved in acetone and treated with activated carbon. An equivalent amount of concentrated hydrochloric acid was added and the monohydrochloride was isolated from 2- [2-pyridylmethylthio] -4-methyl-2-benzimidazole. Yield: 0.05 mol; Melting point F. 137 ° C.

Examples 2 to 16 and 19 to 30 The preparation was carried out by the method described in Example 1. The compounds prepared are listed in Table I below.

15

20th

25th

Table I

Compounds of formula I produced

A-Het

Ex.

R3

R

R "

A

Het

F.

(° C)

l

H

4-CH3

H

-SCH2-

2-pyridyl

137-83

(2.HC1)

2nd

6-CH3

4-CH3

H

-SCH2-

2-pyridyl

230

(HCl)

3rd

H

5-C2H5

H

-SCH2-

2-pyridyl

180

(HCl)

4th

6-cl

4-CH3

H

-SCH2-

2-pyridyl

180

(HCl)

5

H

5-OCH3

H

-SCH2-

2-pyridyl

155-95

(2.HC1)

6

H

5-OH

H

-SCH2-

2-pyridyl

190-200

(HCl)

7

H

5-COCH3

H

-SCH2-

2-pyridyl

144

(Base)

8th

H

5-COOH

H

-SCH2-

2-pyridyl

268

(Base)

9

H

5-COOC2H5

H

-SCH2-

2-pyridyl

180-90

(2.HC1)

10th

H

H

H

-SCH2-

2- (6-methylpyridyl)

121

(HCl)

11

H

H

H

-SCH2-

2- (6-chloropyridyl)

145

(Base)

12

H

H

H

—SCH2—

2- (4-chloropyridyl)

13

H

H

H

-SCH2-

2- (5-methylpyridyl)

134

(HCl)

14

H

H

H

-SCH2-

2-quinolyl

144-63

(HCl)

15

H

5-CH2OH

H

-SCH2-

2-pyridyl

190

(HCl)

16

H

H

H

- S-CH (CH3) - 2-pyridyl

165

(HCl)

19th

H

4-COOCH3

H

-SCH2-

2-pyridyl

182

(Base)

20th

H

4-C2H5

H

-SCH2-

2- (5-methylpyridyl)

158

(HCl)

21st

H

4-CH3

H

—SCH2-

2- (4-methylpyridyl)

130

(Base)

22

5-cl

6-OCH3

H

-SCH2-

2-pyridyl

75

(Base)

23

H

4-CH3

H

-SCH2-

2- (5-methylpyridyl)

120

(Base)

5 616160

Table 1 (continued)

Ex.

R3

R

R4

A

Het

F.

(° C)

24th

H

4-CH3

H

-SCH (CH3)

2-pyridyl

99

(Base)

25th

H

5-CH3

H

-SCH (CH3)

2-pyridyl

140

(Base)

26

H

5-OCH3

H

-SCH2-

2 - (5-methylpyridyl)

105

(Base)

27th

4-CH3

6-CH3

H

-SCH2-

2- (5-methylpyridyl)

01

(Base)

28

H

5-C3H7

H

-SCH2-

2-pyridyl

160-65

(HCl)

29

H

5 — ÌS0C3H7

H

-SCH2—

2-pyridyl

145

(HCl)

30th

H

5-t.QH9

H

-SCH2-

2-pyridyl

130-35

(HCl)

Biological effectiveness The compounds obtainable according to the invention have valuable therapeutic properties by influencing the gastric acid formation. They were therefore tested using a test method for testing compounds with secretory activity in dogs. The test was carried out using special dog experiments using a modified perfusion technique. 20th

The stomach of the anesthetized dog was provided with a tube for the instillation of fluid through the esophagus and with another tube over the tied gatekeeper through the duodenum for the drainage of fluid. In an amount of 5 ml / kg body weight 25, saline was dropped and the dropping liquid was changed every 15 minutes.

The collected samples were titrated with 0.04 sodium hydroxide solution using a "Radiometer" automatic titrator to a pH of 7.0, from which the acid release per 15 minutes was calculated (collection periods).

Gastric acid secretion was caused by "pentagastrin" in an amount of 1 to 2 (ikg-h), with almost maximum secretion effect.

Test compounds were given in 0.5% "Methocel" suspension at least 2 hours after the start of stimulation, if the secretion had reached a uniform level within 3 consecutive 15-minute periods, close to the pinch in the duodenum .

The response to gastric acid secretion was recorded, and it was found that all of the compounds of the above examples inhibited gastric acid secretion.

B

Claims (2)

616160 2nd PATENT CLAIMS 1. Process for the preparation of new benzimidazoles of the formula I A-Het (I) and their therapeutically permissible salts, where in formula (I) R and R3, which are the same or different, are hydrogen, alkyl, halogen, carboxy, carbalkoxy, hydroxy, alkoxy, hydroxyalkyl or acyl in any position, the alkyl radicals in each case 1 have up to 4 carbon atoms, R4 is hydrogen, acyl or carbalkoxy, A is the group - S — CTfc— or - S - CH (CH3) - and Het is an optionally further substituted 2-quinolyl or 2-pyridyl radical, where, when Het 2 -Pyridyl, R4 are hydrogen and A - SCH2—, R and R3 are not simultaneously hydrogen, not 5-CH3 and 6-CH3 and not hydrogen and 5-Cl, characterized in that compounds of the formula IV (IV) 10th 15 25th wherein R, R3 and R4 have the meanings given above and Z - SH or a reactive, esterified hydroxyl group, with compounds of the formula V, Z ^ B-Het, wherein Het has the meaning given above, B the group --CH2— or - CH (CH3) - and Z1 is a reactive, esterified hydroxyl group or - SH, are converted into compounds of the formula (I) and these are converted into the therapeutically permissible salts if necessary. 2. The method according to claim 1, characterized in that the hydroxyl group is esterified with a hydrohalic acid, preferably with hydrochloric acid. 3. The method according to claim 1, characterized in that a compound of formula I, wherein R is hydrogen, hydroxy, hydroxymethyl, methyl, ethyl, methoxy, acetyl, carboxy or carbethoxy, R3 is hydrogen, methyl or chlorine, R4 is hydrogen, acetyl or carbomethoxy , A - SCH2— and Het are 2-pyridyl or 2-quinolyl optionally substituted by methyl or chlorine, or a therapeutically permissible salt thereof. 4. The method according to claim 1, characterized in that a compound of formula I, wherein R and R3 are hydrogen, or a therapeutically permissible salt thereof is prepared. 5. The method according to claim 1, characterized in that a compound of formula I, wherein R and R3 are hydrogen, A - S — CH (CH3) - and Het 2-pyridyl, or a therapeutically permissible salt thereof is prepared. 6. The method according to claim 1, characterized in that 40 2- [2-pyridylmethylthio] - (4-methyl) -benzimidazole, 2- [2-pyridylmethylthio] - (4,6-dimethyl) -benzimidazole, 2- [2-pyridylmethylthio] - (5-ethyl) -benzimidazole, 2- [2-pyridylmethylthio] - (4-methyl-6-chloro) benzimidazole, 2- [2-pyridylmethylthio] - (5-methoxy) benzimidazole, 2- [2-pyridylmethylthio] - (5-hydroxy) - benzimidazole, 2- [2-pyridylmethylthio] - (5-acetyl) benzimidazole, 2- [2-pyridylmethylthio] - (5-carboxy) benzimidazole, 2- [2-pyridylmethylthio] - (5-carbethoxy) benzimidazole, 2- [2- (6-methyl) pyridylmethylthio] benzimidazole, 2- [2- (6-chloro) pyridylmethylthio] benzimidazole, 2- [2- (4-chloro) pyridylmethylthio] benzimidazole, 2- [2- (5-methyl) pyridylmethylthio] benzimidazole, 2- [2-quinolylmethylthio] benzimidazole, 2- [2-pyridylmethylthio] - (5-hydroxymethyl) benzimidazole, 2- [2-pyridyl- (methyl) -methylthio] -benzimidazole, 2- [2-pyridylmethylthio] - (N-acetyl) -benzimidazole, 2- [2-pyridylmethylthio] - (N-methoxycarbonyl) -benzimidazole, or a therapeutically permissible salt of the compounds mentioned.