JPH0223547B2 - - Google Patents

Description

[Detailed description of the invention]

(Industrial Application Field) The present invention relates to a novel ω-(1-imidazolyl)alkyloxybenzene derivative having excellent lipid-lowering effect and platelet aggregation-inhibiting effect. Furthermore, the compounds of the present invention are useful as intermediates in the synthesis of pharmaceutically useful derivatives. (Solution Means of the Invention) More specifically, ω- expressed by the following general formula
The present invention relates to (1-imidazolyl)alkyloxybenzene derivatives. The symbols in the formula have the following meanings. A: Does not form a fused ring with the imidazole ring,
When forming a condensed ring, phenyl ring R ₁ : Hydrogen atom or lower alkyl group, which are the same or different n : An integer from 1 to 10 R ₂ : Amino group, nitro group, hydroxy group, or benzyloxy group Here The above term “lower” refers to carbon atoms with a carbon number of 1 to 5.
Straight chain or branched chain. Therefore, lower alkyl means carbon chains such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, and the like. The target compounds of the present invention are capable of forming acid addition salts, and include pharmacologically acceptable acid addition salts. Suitable salts include hydrochloric acid,
Acid addition salts with inorganic acids such as hydrobromic acid and phosphoric acid; acid addition salts with organic acids such as formic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, benzoic acid, and benzenesulfonic acid; Examples include quaternary ammonium salts with alkyl halides such as methyl chloride. (Prior Art) The compound () of the present invention has an alkyloxy group having 4 to 10 carbon atoms and a 1-imidazolyl group at the end, and one of a nitro group, an amino group, a bidroxy group, and a benzyloxy group. It is a benzene derivative, and no known literature describing a compound having such a structure has been found. (Effect of the invention) The compound of the present invention is useful as a pharmaceutical ω-(1
-imidazolyl) is useful as a raw material for producing pentyloxybenzene derivatives. For example, the compound described in Japanese Patent Application No. 56-211058 has a lipid-lowering effect, particularly an excellent cholesterol and triglyceride-lowering effect, and also has an effect of inhibiting platelet aggregation, and is effective in preventing arteriosclerosis, cerebral infarction, and cancer. It is useful in the prevention and treatment of hyperischemic attack, angina pectoris, peripheral thrombosis and occlusion. In addition, the compounds of the present invention are disclosed in Japanese Patent Application No. 58-113988.
It is also useful as a raw material for the compounds described in No. 61-150078. Further, the compound of the present invention itself has a lipid-lowering effect and is useful as a medicine. Hereinafter, pharmacological data of the compounds of the present invention and the compounds described in Reference Examples produced using the compounds of the present invention as raw materials are listed.

[Table] Lipid-lowering effect: Sprague-Dawley at 3 weeks old
Dawley male rats were fed a diet containing 1.5% cholesterol and 0.5% bile acids for 7 days, and for the last 4 days, the compound of the present invention suspended in a 0.5% methylcellulose aqueous solution was administered once a day by oral probe. After an overnight fast, blood was collected under ether anesthesia, and serum total cholesterol and HDL levels were measured.
Cholesterol measurement is performed by “Schettler, G & N.
ssel；Arbeitsmed.Sozialmed.Pr¨a
ventivmed.10, 25 (1975)”, and HDL was measured using the method described in “TT Ishikawa
Platelet aggregation inhibition: The platelet-rich plasma (PRP) and platelet-poor plasma (PPP) used were obtained from the venous blood of Japanese white rabbits. Platelet aggregation ability was measured using “Born, GV
R; Nature., 194, 927 (1962)'', the platelet aggregation inhibiting effect of the compound on the platelet aggregation induced by arachidonic acid (final concentration 0.3mM) was measured using an aggregometer. (Manufacturing method) The compound of the present invention can be manufactured by the following method. (The symbols in the formula have the following meanings. A: Does not form a fused ring with the imidazole ring,
When forming a condensed ring, phenyl ring _R2 ': nitro group or benzyloxy group _R1 : hydrogen atom or lower alkyl group, which are the same or different from each other hal: halogen atom n: an integer from 4 to 10. ) To produce the target compound of the present invention, a step (first step) of reacting sodium phenoxide () with α,ω-dihalogenoalkyl () to produce ω-halogenoalkyloxybenzene (); Compound () is reacted with imidazole derivative () (1-imidazolyl alkyloxy)
The step of producing benzene ( ₁ ) (second step), and the reduction of the obtained compound ( ₁ ) to produce the corresponding [(1)
-imidazolyl)alkyloxy]aniline (or phenol) ( ₂ ) are carried out in sequence. Furthermore, useful derivatives can be obtained by reacting this compound ( ₂ ) with R'-NCO, alkylating it, or acylating it. The first step is 0-alkylation, which is carried out by reacting compounds () and () in a benzene-dimethylformamide mixture using a conventional method, or by using phenol instead of phenoxide in (). The reaction is carried out in a solvent such as methyl ethyl ketone or ethanol in the presence of an alkali (potassium carbonate, etc.). The reaction in the second step is carried out by heating the compound () and the imidazole derivative () in an inert solvent in the presence of a base. Bases used include alkali metal hydrides such as sodium hydride, alcoholates such as sodium methoxide, and the like. Further, examples of the inert solvent include benzene, toluene, xylene, dimethylformamide, and alcohol. The third step of reduction is reduction of a nitro group to an amino group or debenzylation, and this can be carried out by catalytic reduction in a conventional manner using, for example, palladium-carbonate as a catalyst. (Example) In order to explain the present invention more specifically, reference examples and examples are listed below. Reference Examples 1 to 13 describe the first step, Examples 1 to 13 describe the second step, and Examples 14 to 26 describe the third step, respectively. Reference Example 14 further shows a specific example of producing a useful derivative using the compound of the present invention as a raw material. Reference example 1 4-nitrophenol sodium 16.1g and 1,
28.8 g of 5-dibromopentane was dissolved in 150 ml of a benzene-dimethylformamide mixture (1:2 volume ratio), heated to 80°C, and reacted with stirring overnight. Pour this reaction solution into 500 ml of ice water, add 100 ml of benzene and stir, then separate the benzene layer, wash it sequentially with a 5% aqueous sodium hydroxide solution, water, and a saturated aqueous sodium chloride solution, and dry over anhydrous sodium sulfate.
The solvent was removed under reduced pressure and the remaining oil was subjected to silica gel column chromatography using an n-hexane-benzene mixture (2:1 volume ratio) as the eluent.
After removing the solvent, the residue was rectified under reduced pressure to obtain 21.5 g of 4-[5-bromopentyloxy]nitrobenzene. Boiling point 168-170℃ (0.5mmHg) Reference examples 2-10 In place of 4-nitrophenol sodium and 1,5-dibromopentane in Reference example 1, other phenol sodium compounds and α,ω-dibromoalkane compounds were used on one side. Or, by changing both of them and using them as raw material compounds, react in the same manner as in Reference Example 1.
Compounds of Reference Examples 2 to 10 were produced by processing.

【table】

[Table] Reference example 11 Add 1.8 g of N-acetyltyramine and 2.8 g of anhydrous potassium carbonate to 50 ml of anhydrous methyl ethyl ketone.
After heating to 90°C and stirring for 1 hour, 2.8 g of 1,8-dibromooctane was further added thereto, and the mixture was allowed to react under reflux for 3 days. The solvent is distilled off from the reaction solution, and 100 ml of chloroform and 100 ml of water are added to the residue, followed by stirring. The chloroform layer is separated, washed successively with water and a saturated aqueous sodium chloride solution, and then dried over anhydrous sodium sulfate. The white crystalline residue obtained after distilling off the chloroform was completely dissolved in 50 ml of methyl ethyl ketone by heating, and the mixture was allowed to stand for 1 hour under ice cooling to dissolve the by-produced 1,8-bis-[4
-(β-acetaminoethyl)phenoxy]octane crystals (melting point 171-172°C) are removed, and the solvent is distilled off from the liquid to obtain the desired N-acetyl-
2.6 g of white crystals of 4-[8-bromooctyloxy]phenethylamine were obtained. Melting point 57-58℃. Reference Examples 12-13 In place of 1,8-dibromooctane in Reference Example 11, another α,ω-dibromoalkane compound was used as a raw material compound, and the reaction treatment was carried out in the same manner as in Reference Example 11 to obtain Reference Examples 12-13. A compound was prepared.

[Table] Example 1 Sodium hydride (60% suspension in mineral oil) 0.8g
After washing with dry benzene, 60 ml of dry dimethylformamide are added thereto, and an additional 1.36 g of imidazole is added while stirring at room temperature. After the intense foaming subsided, the suspension was heated to 80°C.
Heat and stir for 30 minutes, then cool to room temperature. A solution of 5.25 g of 4-[5-bromopentyloxy]nitrobenzene obtained in Reference Example 1 dissolved in 10 ml of dry dimethylformamide was added to the mixture, and the mixture was heated and stirred at 80°C for 4 hours. After evaporating the solvent from the reaction solution under reduced pressure, the residue was dissolved in methylene chloride, washed successively with a 5% aqueous sodium bicarbonate solution, water, and a saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and a small amount of n was added to the remaining oil.
-Crystallize by adding hexane to obtain the desired 4-
[5-(1-imidazolyl)pentyloxy]nitrobenzene was obtained. Melting point 64-65℃. Examples 2 to 10 In place of 4-[5-bromopentyloxy]nitrobenzene in Example 1, the compounds produced in Reference Examples 2 to 10 were used as raw material compounds, and Example 1
Compounds of Examples 2 to 10 were produced by reacting and treating in the same manner as above.

【table】

[Table] Examples 10 to 11 Examples were prepared by using other methyl-substituted imidazole derivatives as raw material compounds in place of imidazole in Example 1, and reacting and treating in the same manner as in Example 1.
10-11 compounds were prepared.

[Table] Example 12 Benzimidazole was used instead of imidazole in Example 1, and 4-[6-
Bromhexyloxy]nitrobenzene was used as a raw material compound and reacted and treated in the same manner as in Example 1 to synthesize 4-[6-(1-benzimidazolyl)hexyloxy]nitrobenzene. Melting point 73-74℃. Example 13 Dissolve 3 g of 4-[5-(1-imidazolyl)pentyloxy]nitrobenzene in 30 ml of ethyl acetate, add 0.1 g of 10% palladium on carbon, and stir under normal pressure in a hydrogen atmosphere until the theoretical amount of hydrogen is absorbed. reacted to. After removing the palladium on carbon, the solvent was distilled off under reduced pressure to quantitatively obtain the desired 4-[5-(1-imidazolyl)pentyloxy]aniline. Melting point 55-56℃. Examples 14 to 24 Reactions and treatments were carried out in the same manner as in Example 13, using the compounds produced in Examples 2 to 12 as raw materials instead of 4-[5-(1-imidazolyl)pentyloxy]nitrobenzene in Example 13. Example
Compounds 14-24 were prepared.

【table】

【table】

[Table] Reference example 14 4-[5-(1-imidazolyl) obtained in Example 13
[Pentyloxy] 0.75g of aniline to dry pyridine
Add 0.5 ml of acetic anhydride to the 10 ml solution under ice-cooling and stirring.
Add. The mixture was left at that temperature for 1 hour, and then stirred and reacted at room temperature overnight. After pyridine was distilled off from the reaction solution under reduced pressure, the residue was poured into 50 ml of ice water and further stirred for 5 minutes.
Add 10 ml of % sodium bicarbonate aqueous solution and stir for about 1 hour. The reaction product was then extracted with chloroform, and the chloroform layer was washed successively with water and a saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate. After chloroform is distilled off, the remaining white solid is recrystallized from ethanol to obtain the desired 4-[5-(1
0.6 g of white crystals of -imidazolyl)pentyloxy]acetanilide were obtained. Melting point 148-149℃ Elemental analysis value (as C ₁₆ H ₂₁ N ₃ O ₂ ) C (%) H (%) N (%) Theoretical value 66.88 7.37 14.62 Experimental value 66.87 7.44 14.75

Claims (1)

[Claims] 1. General formula (The symbols in the formula have the following meanings. A: Does not form a fused ring with the imidazole ring,
When forming a condensed ring, phenyl ring _R1 : hydrogen atom or lower alkyl group, which are the same or different n: integer from 4 to 10 _R2 : amino group, nitro group, hydroxy group, or benzyloxy group) An ω-(1-imidazolyl)alkyloxybenzene derivative and a salt thereof.