FI87069C - Process for the preparation of pharmaceutically active 2- / 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio / benzimidazole derivatives - Google Patents

Description

5,87069

Process for the preparation of pharmaceutically active 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole derivatives.

This invention relates to a process for the preparation of novel antiallergic 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole derivatives.

10 Certain types of cells, such as mast cells, release chemical mediators that mediate allergic reactions as a result of antigen-antibody reactions. As chemical mediators involved in the immediate allergic reaction, histamines and SRS-A (a slow-sensitizing agent) are considered important, but the latter is most important, especially in bronchial asthma.

SRS-A is a mixture of leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), which are 5-lipoxygenase metabolites of arachidonic acid. In general, drug research to prevent, ameliorate, and eliminate the symptoms of allergic reactions has focused on the development of drugs that release or counteract the effects of a chemical mediator. As a result, there are antihistamines (e.g., diphenhydramine, chloro-rifeniramine, etc.), SRS-A-releasing inhibitors (disodium cromoglycate), and the like on the market. However, the effect of the former against bronchial asthma is unreliable, and the latter has only a preventive effect but no effect when used internally.

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Therefore, drugs that antagonize the effect of SRS-A are expected to be useful antiallergic agents. Currently, only a few drugs are known to have such an effect, but none of them is known to have such an effect when used internally.

2 87069

ΕΡ-Α-0 061 800, EP-A-0 079 637, DE-A-2 454 670 and US-3 882 148 disclose a number of antiallergically active compounds containing a similar side chain 5 having a similar substituted phenyl group as shown below. compounds of formula I. However, these known compounds do not contain a benzimidate sol ring, such as the compounds of formula I.

EP-A-0 121 806 discloses certain pyrazolo-10 [1,5-a] pyridine derivatives whose pharmaceutical activity is based on the inhibitory activity of SRS-A biosynthesis, thus differing completely from the pharmaceutical activity of the compounds of formula I below, which is based on The antagonizing effect of SRS-A and the inhibitory effect of SRS-A-induced sensitization.

As a result of extensive research on antiallergic compounds, it has now been found that the compounds of formula (I) have an excellent antiallergic effect, in particular a very potent inhibitory effect on the sensitization which SRS-A can cause, even when used internally.

'/ - \ CH3CO - / ^ ^ 0CH2CH2CH2S (0) n 1

; :. 25 HO CH2CH2CH3 H

where n is an integer from 0 to 2.

The compounds of general formula I according to the invention can be prepared in such a way that a phenoxyalkyl derivative of general formula

ch3c ° -fy OCH2CH2CH2X III

B

HO CH2CH2CH3 3 87069 wherein X is a halogen atom is reacted with a compound of formula hs - \ ίΓΊ 11 5> 1 ''

B

to give a compound of formula

CH3Ca- / ~ -O-CH2CH2CH2S -IV

HO '^ CH2CH2CH3 H

And, if desired, oxidizing the compound of general formula IV to give a compound of general formula I wherein n is 1 or 2.

The reaction of a compound of formula (II) with a compound of formula (III) may be carried out in a suitable solvent, e.g. methanol, ethanol, tetrahydrofuran and the like, and in the presence or absence of a base such as potassium hydroxide, sodium hydride or the like.

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Compounds of formula (I) wherein n is 1 may be prepared by reacting a compound of general formula (IV) with an oxidizing reagent. These can typically be prepared by reacting a compound of general formula (IV) with a mild oxidizing reagent such as e.g.

with hydrogen peroxide in methanol, m-chloroperbenzoic acid in dichloromethane or one or more molar equivalents thereof.

Compounds of formula (I) wherein n is 2 may be prepared by reacting a compound of general formula (IV) with an oxidizing reagent in the same manner as above. They can typically be prepared by reacting a compound of formula (IV) with one or more molar equivalents of a mild oxidizing reagent in the same manner as above.

Compounds of the invention have shown a strong antagonistic effect on 5 ^ LTD induced contraction of isolated guinea pig ileum. It should be noted that all compounds are orally effective in an experimental model of bronchial asthma. Inhalation of the nebulized antigen causes anaphylactic bronchoconstriction in actively sensitized guinea pigs pretreated with indomethacin and tripelennamine, in which endogenously released SRS-A may play a predominant role. The compounds of the present invention strongly inhibit this anaphylactic bronchoconstriction at an oral dose of 20 mg / kg (Table 1). FPL55712, sodium 7- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) -2-hydroxypropoxy] -4-oxo-8-propyl-4H-1-benzopyran, has been reported 2-Carboxylate, a known SRS-A antagonist, is orally inactive (P. Sheard et al .; Monogr. Allergy, 20 pp. 244-248, S. Karger 1977). Thus, the compounds of the present invention are promising antiallergic agents with potent anti-SRS-A (leukotriene) activities. These compounds are considered to have prophylactic and / or therapeutic role in allergic diseases such as pulmonary asthma, allergic rhinitis and urticaria.

0

30 OH f I

/ = \ i - ~ H3C0C-Λ \ - 0CH2CHCH20 0 - COONa / \ ch2ch2ch3 • 35 HO CH2CH2CH3 FPL55712 β 87069 b

table 1

Inhibitory effect of anaphylactic bronchoconstriction

Example No. Oral dose Number of animals protected (5 mg / kg) / number of animals used_ 1 20 3/3 2 20 2/2 3 20 2/2 10

The invention is described in more detail below by way of exemplary embodiments.

Example 1 Preparation of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole

To a suspension of 1.2 g of 2-mercaptobenzimidazole in 30 ml of ethanol was added 580 g of potassium hydroxide with stirring and stirred at room temperature for 10 minutes.

To this solution was added 2.8 g of 3- (4-acetyl-3-hydroxy-2-propylphenoxy) propyl bromide in one portion and stirred at room temperature for 4 hours. The solvent was removed by distillation under reduced pressure, and the resulting residue was diluted with dichloromethane-water, then extracted with dichloromethane three times. The organic layer was combined, then washed with water saturated with sodium chloride and dried over anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was recrystallized from dichloromethane-n-hexane to give 2.5 g (yield 81%) of the desired compound as a colorless powder. Sp. 149-150 ° C. Analysis (%) for c 21 H 24 N 2 O 3 S: calculated (obtained): C 65.60 (65.71); H 6.29 (6.29); N 7.29 (7.24).

Example 2 Preparation of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] -benzimidazole S-oxide 87069 6 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] -benzimidazole (described in Example 1) was oxidized with m-chlorobenzoic acid in a manner similar to that described in Example 2 of strain application 860571 (Patent 83314) to give the desired compound (yield 60%). Sp. 172-173 ° C. Analysis (%) for C 21 H 24 N 2 O 4 S: Calculated (obtained): C 62.98 (62.89); H 6.04 (6.02); N 6.99 (7.08).

Example 3 Preparation of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylsulfonyl] -benzimidazole

To a solution of 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole (described in Example 1) was oxidized with m-chlorobenzoic acid in a manner similar to that described in Example 3 of strain application 860571 (Patent 83314). to give the desired compound (yield 43%). Sp. 179-180 ° C. Analysis (%) for C 21 H 24 N 2 O 5 S: Calculated (obtained): C 60.56 (60.36); H 5.81 (5.83); N 6.72 (6.78).

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Claims (4)

A process for the preparation of pharmaceutically active 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole derivatives of the general formula CH3CO- / \ -OCH2CH2CH2S (O) n 1 ίο M HO CH2CH2CH3 H wherein n is an integer from 0 to 2, characterized in that a phenoxyalkyl derivative of the general formula CH3COH (\ -och2ch2ch2x III HO CH2CH2CH3 20 wherein X is a halogen atom is reacted with a compound of the formula HS- <II II N - 25 H to give a compound of formula 30 ch3co - <^ ~ \ -o-ch2ch2ch2s -IV HO '' CH2CH2CH3 H35 and, if desired, oxidizing a compound of formula IV to give a compound of general formula I wherein n is 1 or 2 87069 For the preparation of a pharmaceutical active ingredient 2- [3- (4-acetyl-3-hydroxy-2-propylphenoxy) propylthio] benzimidazole derivative in the form of 5-CH3CO- (R) -OCH2CH2CH2S (O) 1 10 HO CH2CH2CH3 H color is not listed 0-2, the number of turns of which are phenoxy-cold derivatives with the formulation 15 ch3co - <^ ^) - och2ch2ch2x III HO CH2CH2CH3 color X is a halogen atom, the same as for-20 Meln HS II II H ... 25 for the benefit of the form "" <JHaok, s -Oo " 30 HO CH2CH2CH3 H och, om sä önskas, oxideras föreningen med formula IV IV förlandh av en förening med den allmänna formuleln I värv n är 1 eller 2. 35