JPS6347710B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel imidazole derivatives represented by the following general formula (), salts thereof, and methods for producing them. [The symbols in the formula have the following meanings. A; single bond, formula - (CH ₂ ) mCONH (CH ₂ ) n
―, ―(CH ₂ )m―O―, or

Group represented by [Formula] R; formula

Group represented by [Formula] m; integer of 1 to 6 n; integer of 0 or 1 to 5 R ₁ ; hydrogen atom or lower alkyl group l; integer of 0 or 1 to 5 R ₂ , R ₃ and R ₄ ; Same or different hydrogen atoms or lower alkyl groups. The same applies hereinafter] In the definition of the group of the general formula in this specification, "lower"
The term means a straight or branched carbon chain having 1 to 5 carbon atoms. Therefore, specific examples of lower alkyl groups include methyl group, ethyl group, propyl group,
Isopropyl group, butyl group, isobutyl group, sec
-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert
-pentyl group, etc. The compound represented by the above general formula () forms a salt. The present invention also includes salts of compound ().
Particularly suitable salts include inorganic acids such as hydrochloric acid, sulfuric acid, hydrobromic acid, phosphoric acid, formic acid, acetic acid, lactic acid, oxalic acid, succinic acid, fumaric acid, maleic acid, methanesulfonic acid, ethanesulfonic acid, and benzene. Examples include acid addition salts with organic acids such as sulfonic acids, and quaternary ammonium salts with alkyl halides such as methyl iodide. Further, the compounds of the present invention include compounds in which geometric isomers and various optical isomers (racemic forms, optically active forms, etc.) exist, and the present invention includes all of these isomers. Representative compounds of the present invention are illustrated below. (1) 5-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethyl-pentanoic acid methyl ester (2) 5-[p-[2-[4-(1-imidazolyl)] butyramide]ethyl]phenoxy]-2,
2-Dimethylpentanoic acid ethyl ester (3) 5-[p-[6-(1-imidazolyl)hexanamide]phenoxy]-2,2-dimethylpentanoic acid ethyl ester (4) 2-[p-(1-imidazolyl) Phenoxy]-2-methylpropionic acid ethyl ester (5) 5-[p-[N-[4-(1-imidazolyl)]butyl-N-methylamino]phenoxy]
-2,2-dimethylpentanoic acid ethyl ester (6) 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoic acid (7) 7-[p-[3-( 1-Imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoic acid methyl ester (8) 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoic acid ethyl ester (9) ) 5-[p-[6-(1-imidazolyl)hexyloxy]phenoxy]-2,2-dimethylpentanoic acid methyl ester (10) 7-[p-[2-[4-(1-imidazolyl)butyramide]ethyl [Phenoxy]-2,
2-dimethylheptanoic acid ethyl ester (11) 7-[p-[6-(1-imidazolyl)hexamide]phenoxy]-2,2-dimethylheptanoic acid ethyl ester (12) 5-[p-[7-(1 -imidazolyl)heptanamide]phenoxy]-2,2-dimethylpentanoic acid ethyl ester (13) 7-[p-[N-[4-(1-imidazolyl)]butyl-N-methylamino]phenoxy-2,2- Dimethylheptanoic acid ethyl ester (14) 5-[p-[6-(1-imidazolyl)hexanamide]phenoxy]pentanoic acid ethyl ester (15) 5-[p-[6-(1-imidazolyl)hexanamide]phenoxy]- 2-Methylpentanoic acid ethyl ester (16) 5-[p-[6-(1-imidazolyl)hexanamide]phenoxy]-2-pentylpentanoic acid ethyl ester The compound of the present invention has a lipid-lowering effect, particularly excellent cholesterol and It has a triglyceride-lowering effect as well as a platelet aggregation-inhibiting effect, and is useful for the prevention and treatment of arteriosclerosis, cerebral infarction, transient ischemic attack, angina, peripheral thrombosis, and occlusion. According to animal experiments, the object compound of the present invention has excellent cholesterol and triglyceride lowering effects and high density lipoprotein (HDL) in the blood.
The selective increasing effect of HDL is
It is a substance whose amount decreases during arteriosclerosis compared to normal times, and which is known to prevent excessive accumulation of cholesterol in arterial walls and promote the flow of cholesterol from arterial walls. . Furthermore, the object compound of the present invention has an effect of inhibiting platelet aggregation induced by arachidonic acid. This effect, together with the lipid-lowering effect, is effective in preventing and treating the above-mentioned diseases such as arteriosclerosis. The pharmacological effects of the present invention were confirmed as follows. Lipid-lowering effect: Sprague-Dawley at 4 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 carried out by Schütler, G. &Nüssel; Arbeitus Medicin Social Medicin Preventive Medicine Vol. 10, p. 25, 1975.
(Schettler, G &HU¨ssel; Arbeitsmed.
HDL was measured by the method described in Sozialmed.Praventived. 10 25 (1975), Lipid Vol.
Lipids; 11 628 (1976)). Table 1 shows the lipid-lowering effects of representative compounds of the present invention. Platelet aggregation inhibitory effect: Platelet-rich plasma (PRP) and platelet-poor plasma (PPP) used were prepared from venous blood of Japanese white rabbits. Bone GV is used to measure platelet aggregation ability.
R.; Nature Vol. 194, p. 927, 1962 (Born, GV
R; Nature, 194 , 927 (1962)), and the platelet aggregation inhibiting effect of the compound on the platelet aggregation induced by arachidonic acid (final concentration 0.2mM) was measured using an aggregometer (Paint Co., Ltd.). (manufactured by). Table 1 shows the platelet aggregation inhibiting effects of representative compounds of the present invention.

[Table] Drugs containing the compound represented by the general formula () or a salt thereof as a main component can be prepared by a method commonly used in the field using pharmaceutical carriers, excipients, etc. commonly used in the field. It can be prepared by Administration may be in the form of oral administration in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration in the form of injections such as intravenous or intramuscular injections, suppositories, etc. The dosage is appropriately determined depending on the individual case, taking into consideration the symptoms, the age and gender of the recipient, but usually 1 to 100 mg/day for adults, preferably 5 to 25 mg/Kg per day for oral administration. can be,
This can be administered once or in 2 to 4 divided doses. According to the present invention, the present compound () and its salt can be produced by the method exemplified below. Among the compounds of the present invention, the acid amide compound represented by the general formula (a) can be produced by reacting an imidazolylalkanoic acid represented by the general formula () or a reactive derivative thereof with an amine represented by the general formula (). I can do it. Reactive derivatives of compound () include acid halides such as acid chlorides and acid bromides; acid azides; active esters such as N-hydroxybenzotriazole esters, p-nitrophenyl esters, and p-chlorophenyl esters; Type acid anhydride: Mixed acid anhydride, such as an alkyl carbonate mixed acid anhydride obtained by reacting an alkyl carbonate halide such as isobutyl carbonate chloride, methyl carbonate chloride, or ethyl carbonate bromide with the compound (). When compound () is reacted with a free carboxylic acid, it is advantageous to carry out the reaction in the presence of a condensing agent such as N,N'-dicyclohexylcarbodiimide or 1,1-carbonyldiimidazole. In addition, when reacting with a reactive derivative, a tertiary base such as triethylamine, pyridine, picoline, lutidine, N,N-dimethylaniline, potassium carbonate, sodium carbonate, sodium hydroxide, hydroxide, etc. It may be advantageous to work in the presence of a base such as potassium. The solvent, temperature conditions, etc. are appropriately selected and set depending on the type of reactive derivative used. Commonly used solvents include organic solvents such as pyridine, benzene, toluene, dimethylformamide, dioxane, ether, tetrahydrofuran, chloroform, dichloromethane, and dichloroethane, and mixed solvents thereof. (In the reaction formula, R ₆ is a lower alkyl group, or the formula

In the group represented by the formula, M represents a hydrogen atom or an alkali metal, and X represents a halogen atom. The same applies hereinafter) Among the compounds of the present invention, the ether compound represented by the general formula (b) can be prepared by adding the corresponding phenol compound (,M=H) in the presence of a base or an alkali metal phenoxide (,M=alkali metal).
can be produced by reacting with an alkyl halide represented by the general formula (). In addition, examples of the halogen atom include an iodine atom, a bromine atom, and a chlorine atom, and as the alkali metal, sodium and potassium are preferable. The reaction involves alcohols such as methanol and ethanol, dimethyl sulfoxide, dimethyl formamide, benzene, toluene, xylene, ether,
It is advantageous to carry out the reaction in an organic solvent inert to the reaction, such as tetrahydrofuran, at room temperature or with heating. Potassium carbonate, sodium amide, sodium hydroxide, etc. are suitable as the base for directly reacting the phenol compound (, M=H) and the alkyl halide (). The compound of the present invention () is imidazole (, M=
H) can be synthesized by reacting it with a halide represented by the general formula () in the presence of a base or as an alkali metal salt of imidazole (,M=alkali metal). The reaction involves alcohols such as methanol and ethanol, dimethyl sulfoxide, dimethyl formamide, benzene, toluene, xylene, ether,
It is preferable to carry out the reaction in an organic solvent inert to the reaction, such as tetrahydrofuran, at room temperature or with heating. The base used is preferably an alkali metal hydride such as sodium hydride, an alkali metal alcoholate such as sodium ethoxide, or an organic lithium compound such as n-butyllithium. (In the reaction formula, R ₇ means a lower alkyl group.
The same applies hereinafter) In the compound of the present invention, p represented by general formula (c)
-Substituted-N-lower alkyl-N-imidazolylalkylaniline derivatives have the corresponding p-substituted-N
-It can be synthesized by N-alkylation in which an imidazolylalkylaniline derivative () is reacted with a lower alkyl halide () in the presence of a base. The reaction is usually carried out in an alcohol such as methanol or ethanol, or an organic solvent such as dimethyl sulfoxide, dimethyl formamide, benzene, toluene, xylene, ether, or tetrahydrofuran in the presence of a base at room temperature or at elevated temperatures. Bases used include potassium carbonate, sodium carbonate, sodium hydroxide, and the like. The compounds of the present invention produced by these various methods are isolated and purified in their free form or as their salts. Isolation and purification are performed by methods commonly used in the art, such as crystallization, distillation, extraction, various chromatography, and recrystallization. The present invention will be explained in more detail with reference to Examples below. Note that the raw material compounds of the present invention also include novel substances, and reference examples of such compounds will be listed and their manufacturing methods will be clarified. Note that the target product of Reference Example 1 (4) is used as the raw material compound () in the above C production method. Reference example 1 After washing 5.0 g of sodium hydride (60% suspension in mineral oil) with dry benzene, add 100 ml of dry NN-dimethylformamide, and add 25 g of p-hydroquinone benzyl ether while stirring at room temperature. After the vigorous foaming subsided, the suspension was heated and stirred at 80° C. for 30 minutes, and then cooled to room temperature. A solution of 75 ml of dibromopropane dissolved in 40 ml of dry NN-dimethylformamide is added to this, and the mixture is heated and stirred at 60°C for 4 hours. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in methylene chloride, washed successively with a 5% aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, the remaining oil was subjected to silica gel column chromatography, the target product was eluted using a benzene-n-hexane mixture (2:3) as an eluent, and the solvent was removed from the eluent under reduced pressure. The target p-(3
-bromopropoxy)phenylbenzyl ether is obtained as an oil. Nuclear magnetic resonance spectrum ( _CDCl3 ) (internal standard
TMS) δ (ppm); 1.9 (quint, 2H, -C-CH~ ₂ -C-, J = 7.2) 3.4 (t, 2H, Br-CH _{~ 2} -C-, J = 7.2) 3.9 (t, 2H,

[Formula] J=7.2) 4.98(s, 2H,

【formula】) 6.7~6.9 (m, 4H,

【formula】) 7.2~7.5 (m, 5H,

【formula】) Add 100 ml of n-butyllithium (15 w/w, n-hexane solution) to 15 g of diisopropylamine dissolved in 75 ml of dry tetrahydrofuran at -5 to 0.
After dropping at ℃ and stirring for 30 minutes at the same temperature, add isobutyric acid.
Drop 6.7g. After stirring at the same temperature for 1 hour, a solution of 20 g of p-(3-bromopropoxy)phenylbenzyl ether dissolved in 60 ml of dry tetrahydrofuran was added dropwise to the solution. After 30 minutes, the mixture is allowed to warm to room temperature and stirring is continued for 16 hours. The mixture is cooled, 250 ml of water is added, and the aqueous layer is washed with ether, acidified with 6N hydrochloric acid, extracted twice with 70 ml of methylene chloride, and the extract is washed with saturated brine and dried over anhydrous sodium sulfate. After drying, the solvent is distilled off under reduced pressure and the residue is recrystallized from ethyl acetate to obtain the desired 5-[p-benzyloxyphenyloxy)-2,2-dimethylpentanoic acid. Melting point 112-113℃ Elemental analysis value (as C ₂₀ H ₂₄ O ₄ ) C (%) H (%) Theoretical value 73.15 7.37 Experimental value 73.34 7.40 5-(p-benzyloxyphenyloxy)-
9 g of 2,2-dimethylpentanoic acid was dissolved in 100 ml of tetrahydrofuran and treated with a diazomethane-ether solution in a conventional manner to obtain 5-(p-benzyloxyphenyloxy)-2,2-dimethylpentanoic acid methyl ester. The ester obtained here was dissolved in 200 ml of methanol, 10% palladium on carbon was added, and the mixture was reacted under normal pressure with stirring in a hydrogen atmosphere until the theoretical amount of hydrogen was absorbed. When the palladium on carbon is removed and the solvent is distilled off under reduced pressure, the target 5
-(p-hydroxyphenyloxy)-2,2-
Dimethylpentanoic acid methyl ester is obtained as crystals. Melting point 53-54℃ Elemental analysis value (as C ₁₄ H ₂₀ O ₄ ) C (%) H (%) Theoretical value 66.65 7.99 Experimental value 66.53 8.01 In Reference Example 1 (1), 5-[p-
(3-bromopropoxy)phenyloxy)-2,
2-dimethylpentanoic acid methyl ester was obtained. Nuclear magnetic resonance spectrum ( _CDCl3 ) (internal standard
TMS) δ (ppm); 1.18 (s, 6H,

[Formula]) 1.4~2.0 (m, 4H, Br-C-CH~ ₂ -C-, O-
C-CH~ ₂ -C) 2.0~2.3(m, 2H,

[Formula]) 3.58 (t, 2H, Br-CH~ ₂ -, J=6.5Hz) 3.62 (s, 3H, CH~ ₃ OOC-) 3.7-4.0 (m, 4H,

【formula】) 6.76(s, 4H,

[Formula]) Reference example 2 N-[4-(1-imidazolyl)butyl]-4
- Dissolve 12.3 g of (cis-p-menthan-8-yloxy)aniline in 100 ml of ethanol, add 4.65 g of anhydrous potassium carbonate while stirring, then dropwise add 4.7 g of methyl iodide, stir at room temperature for 4 hours, and then reflux. Continue stirring at bottom for 2 hours. After cooling, the solvent is distilled off from the reaction mixture, and the residue is dissolved in methylene chloride, washed successively with a 5% aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography and purified using chloroform as an eluent to obtain the desired N-[4
-(1-imidazolyl)butyl]-4-(cis-
p-menthan-8-yloxy)-N-methylaniline is obtained as an oil. Nuclear magnetic resonance spectrum ( _CDCl3 ) (internal standard
TMS) δ (ppm) 0.98 (d, 3H,

[Formula] J =7.2Hz) 1.36(s, 6H,

【formula】) 1.2~2.0 (m, 14H,

[Formula] C-CH~ ₂ CH~ ₂ -C) 2.84 (s, 3H, N-CH~ ₃ ) 3.24 (t, 2H, N-CH~ ₂ -C, J=6.5Hz) 3.93 (t, 2H ，

[Formula] J =6.5Hz) 6.54(d, 2H,

[Formula] J=9 Hz) 6.82(d, 2H,

[Formula] J=9Hz) 6.88, 7.04 (s, 1H,

【formula】) 7.43(s, 1H,

[Formula]) Example 1 After washing 210 mg of sodium hydride (suspended 60% in mineral oil) with dry benzene, add 20 ml of dry NN-dimethylformamide and, with stirring, add 360 mg of imidazole. After the vigorous foaming subsides, the suspension is heated and stirred at 80° C. for 30 minutes, and then cooled to room temperature. To this, 1.8 g of 5-[p-(3-bromopropoxy)phenyloxy]-2,2-dimethylpentanoic acid methyl ester was added to the dried NN-
Add a solution dissolved in 5 ml of dimethylformamide.
Continue stirring at 60°C for 4 hours. Thereafter, the solvent was distilled off from the reaction solution under reduced pressure, and the remaining oil was dissolved in methylene chloride, washed successively with 5% sodium bicarbonate, water, and saturated brine, and dried over anhydrous sodium sulfate.
After drying, the solvent was distilled off under reduced pressure, the remaining oil was subjected to silica gel column chromatography, the target product was eluted using a chloroform-methanol mixture (50:1) as an eluent, and the solvent was distilled off from the eluent under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to obtain the desired 5-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2.
-Dimethylpentanoic acid methyl ester is obtained. Melting point 47-49℃. Elemental analysis value (as C ₂₀ H ₂₈ N ₂ O ₄ ) C (%) H (%) N (%) Theoretical value 66.64 7.83 7.77 Experimental value 66.75 7.94 7.73 Example 2 Dry 1.6 g of 4-(1-imidazolyl)butyric acid and 1.4 g of 1-hydroxybenzotriazole.
40% solution dissolved in 100ml of dimethylformamide
Heating to ~50°C, adding 2.1 g of NN-dicyclohexylcarboimide with stirring and continuing stirring for about 30 minutes, added ethyl 5-[p-(2-aminoethyl)phenyloxy]-2,2-dimethylpentanoate. A solution of 3.0 g of ester dissolved in 15 ml of dry NN-dimethylformamide is slowly added dropwise. Stirring was continued for about 1 hour at the same temperature, and after confirming the completion of the reaction, the precipitated dicyclohexylurea was removed, the solvent was distilled off under reduced pressure, the remaining oil was dissolved in chloroform, and this was dissolved in a 5% aqueous sodium bicarbonate solution. ,
Wash sequentially with water and saturated saline and dry over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the remaining oil was subjected to silica gel column chromatography to elute the target product using chloroform-methanol (9:1) as an eluent.The solvent was distilled off from the eluate under reduced pressure to obtain the desired product. 5-[p-[2-[4-(1-imidazolyl)butyramido]ethyl]phenyloxy]-2,2-dimethylpentanoic acid ethyl ester is obtained as an oil. Nuclear magnetic resonance spectrum ( _CDCl3 ) (internal standard
TMS) δ (ppm) 1.25 (t, 3H, CH~ ₃ -, J=7.2Hz) 1.20 (s, 6H,

[Formula]) 1.6~1.8 (m, 4H, N-C-CH~ ₂ C, -O
-C-CH~ _H2 -C) 2.0~2.2(m, 4H,

【formula】

【formula】) 2.75(t, 2H,

[Formula] J = 7.2Hz) 3.49 (q = 2H, CONH-CH~ ₂ -C, J =
7.2Hz) 3.8~4.1(m, 4H,

【formula】

[Formula]) 4.12 (q, 2H, COOCH~ ₂ -C, J=7.2Hz) 5.60 (broad t, 1H, -CONH~ -C) 6.8 (d, 2H,

[Formula] J=9 Hz) 7.8(d, 2H,

[Formula] J=9 Hz) 6.85, 7.03, 7.36 (s, 1H,

[Formula]) Reference example 3 6-(1-imidazolyl)-4'-(cis-p-
Menthan-8-yloxy)hexaneanilide 10
After stirring g in 200 ml of 3N hydrochloric acid at room temperature for 15 hours, the reaction solution was washed with ether and the aqueous layer was concentrated under reduced pressure. The obtained crystals are recrystallized from water and used for the purpose.
4'-hydroxy-6-(1-imidazolyl)hexaneanilide hydrochloride is obtained. Melting point 178-179℃. Elemental analysis value (as C ₁₅ H ₂₀ N ₃ O ₂ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 58.16 6.51 13.56 11.44 Experimental value 58.04 6.58 13.58 11.59 Reference example 4 N-[4-(1-imidazolyl)butyl]-4
-(cis-p-menthan-8-yloxy)-N
- Stir 11.5 g of methylaniline in 200 ml of 6N hydrochloric acid at room temperature for 15 hours. After the reaction, the reaction solution was washed with ether and neutralized with 6N-sodium hydroxide aqueous solution.
Extract with chloroform, remove the chloroform layer with water,
Wash sequentially with saturated saline and dry with anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate to obtain the desired P.
-[N-[4-(1-imidazolyl)butyl]-
N-methylamino]phenol is obtained. Melting point 117-118℃. Elemental analysis value (as C ₁₄ H ₁₉ N ₃ O) C (%) H (%) N (%) Theoretical value 68.54 7.81 17.13 Experimental value 68.66 8.08 17.13 Example 3 Suspend 3 g of 4'-hydroxy-6-(1-imidazolyl)hexaneanilide hydrochloride in 50 ml of ethanol, and add 2.8 g of anhydrous potassium carbonate and 2.4 g of 5-bromo-2,2-dimethylpentanoic acid ethyl ester while stirring. Stir and heat under reflux for an hour. The solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in ethylene chloride, and a 5% aqueous sodium hydrogen carbonate solution was added.
After sequentially washing with water and saturated saline, drying with anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from ethyl acetate to obtain the desired 5-[p-[6-(1-imidazolyl)].
Hexanamide]phenyloxy]-2,2-dimethylpentanoic acid ethyl ester is obtained. melting point 81
~82℃. Elemental analysis value (as C ₂₄ H ₃₅ N ₃ O ₄ ) C (%) H (%) N (%) Theoretical value 67.11 8.21 9.78 Experimental value 66.93 8.44 9.79 Example 4 Dissolve 1.6 g of p-(1-imidazolyl)phenol in 50 ml of ethanol and 1.4 g of anhydrous potassium carbonate.
Then, 2.1 g of α-bromoisobutyric acid ethyl ester was added dropwise with stirring, and the mixture was heated under reflux for 20 hours while stirring was continued. After cooling to room temperature, the solvent was distilled off from the reaction mixture, and the residue was dissolved in methylene chloride, washed successively with 5% sodium bicarbonate, water, and saturated brine, and then dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, and the remaining oil was subjected to silica gel column chromatography using chloroform-methanol (9:
The target product is eluted using 1) as an eluent, and the solvent is distilled off from the eluent under reduced pressure to obtain the target 2-[p-(1
-imidazolyl)phenyloxy]-2-methylpropionic acid ethyl ester is obtained as an oil. Nuclear magnetic resonance spectrum ( _CDCl3 ) (internal standard
TMS) δ (ppm) 1.26 (t, 3H, -CH~ ₃ , J=5.5Hz) 1.62 (s, 6H,

[Formula]) 4.26 (q, 2H, COOCH~ ₂ -C, J=5.5Hz) 6.92 (d, 2H,

[Formula] J = 7.6Hz) 7.1~7.3 (m, 4H,

【formula】) 7.72(s, 1H,

[Formula]) Example 5 In Example 3, 4'-hydroxy-6-(1-
The desired 5-[p-[N ―
[4-(1-imidazolyl)]butyl-N-methylamino]phenyloxy)-2,2-dimethylpentanoic acid ethyl ester is obtained as an oil. Nuclear magnetic resonance spectrum ( _CDCl3 ) (internal standard
TMS) δ (ppm) 1.22 (s, 6H,

[Formula]) 1.24 (t, 3H, -C-CH~ ₃ , J=6.5Hz) 1.5~1.9 (m, 4H, N-C-CH~ ₂ CH~ ₂ -C
--) 1.9~2.1 (m, 2H,

[Formula]) 3.24 (s, 3H, N-CH~ ₃ ) 3.6~4.2 (m, 4H,

【formula】

[Formula]) 4.44 (broad t, 2H,

[Formula]) 4.12 (q, 2H, COOCH ~ ₂ -, J = 6.5Hz) 6.92 (d, 2H,

[Formula] J=9 Hz) 7.40, 7.52 (broad s, 2H

【formula】) 7.74(d, 2H,

【formula】) 9.64(s, 1H,

[Formula]) Example 6 After adding 300 ml of ethanol to 35 g of P-[5-(1-imidazolyl)pentyloxy]phenol and 39 g of potassium carbonate, the mixture was heated and stirred at 60°C.
Then cool to room temperature. To this, 6-bromo-2,
Add 43 g of 2-dimethylhexanoic acid ethyl ester dissolved in 50 ml of ethanol, and heat to reflux with stirring overnight. The solvent was distilled off from the reaction solution under reduced pressure, and the residue was dissolved in chloroform, washed successively with a 1N aqueous sodium hydroxide solution, water, and saturated brine, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure, the remaining oil was subjected to silica gel column chromatography, the target product was eluted using a chloroform-methanol mixture (30:1) as an eluent, and the solvent was removed from the eluate under reduced pressure. The residue was recrystallized from ethyl acetate-n-hexane to obtain the desired 6-[p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoic acid ethyl ester. get. Melting point 40-41℃ Elemental analysis value (as C ₂₄ H ₃₆ N ₂ O ₄ ) C (%) H (%) N (%) Theoretical value 69.20 8.71 6.72 Experimental value 69.11 8.94 6.67 Ethyl acetate containing 1.5 g of hydrogen chloride gas 6 to 85ml
- Add 17 g of [p-[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylhexanoic acid ethyl ester. After heating to melt, cool on ice and collect the precipitated solid. The obtained solid was recrystallized from ethyl acetate to give 6-[p-[5-
(imidazolyl)pentyloxy]phenoxy]
-2,2-dimethylhexanoic acid ethyl ester
15.9 g of hydrochloride was obtained. Melting point 121-123℃ Elemental analysis value (as C ₂₄ H ₃₇ N ₂ O ₄ Cl) C (%) H (%) N (%) Cl (%) Theoretical value 63.63 8.23 6.18 7.83 Experimental value 63.59 8.24 6.18 8.04 Mass spectrometry Value (m/z): 416, 343, 259, 137 Infrared absorption spectrum (KBr) cm ^-1 1724,
1512, 1230, 1210 Nuclear magnetic resonance spectrum (CDCl ₃ ) (internal standard
TMS) δ (ppm); 1.16 (6H, s), 1.20 (3H, t), 3.88
(4H, t), 4.08 (2H, q), 4.36 (2H, t)
6.76 (4H, s), 9.72 (1H, s) Example 7 In Example 6, the same reactions and treatments as in Example 6 were carried out using 7-bromo-2,2-dimethylheptanoic acid ethyl ester as a raw material compound instead of 6-bromo-2,2-dimethylhexanoic acid ethyl ester. Then, saturated hydrogen chloride methanol was added to the obtained oil, the solvent was distilled off under reduced pressure, and the residue was recrystallized with ethyl acetate to obtain the desired 7-[p-
[5-(1-imidazolyl)pentyloxy]phenoxy]-2,2-dimethylheptanoic acid ethyl ester hydrochloride is obtained. Melting point 123-124℃. Elemental analysis value (as C ₂₅ H ₃₉ N ₂ ClO ₄ ) C (%) H (%) N (%) Cl (%) Theoretical value 64.29 8.42 6.00 7.59 Experimental value 63.99 8.48 5.88 7.59 Example 8 In Example 6, P-[5-(1-imidazolyl)pentyloxy]phenol was replaced by P-[5-(1-imidazolyl)pentyloxy]phenol.
- [3-(1-imidazolyl)propoxy]phenol, and 7-bromo- in place of 6-bromo-2,2-dimethylhexanoic acid ethyl ester.
Using 2,2-dimethylheptanoic acid ethyl ester as a raw material compound, the same reaction and treatment as in Example 6 were carried out to obtain the desired 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2, 2-
Dimethylheptanoic acid ethyl ester is obtained as an oil. Nuclear magnetic resonance spectrum (CD ₃ OD + DMSO-d ₆ + DCl) (internal standard
TMS) 1.24 (3H, t, J=7.2Hz, -COO- _CH2 -CH~ ₃ ) 4.10 (2H, q, J=7.2Hz, -COOCH ₂ -CH~ ₃ ) Example 9 After washing 110 mg of sodium hydride (60% suspension in mineral oil) with dry benzene, add 10 ml of dry dimethylformamide and add imidazole while stirring.
Add 190mg. After vigorous foaming subsides, the suspension is heated and stirred at 80° C. for 30 minutes, and then cooled to room temperature. To this was added a solution of 870 mg of 7-[p-(3-bromopropoxy)phenyloxy]-2,2-dimethylheptanoic acid methyl ester dissolved in 10 ml of dry dimethylformamide, and the mixture was heated at 60℃ for 5 minutes.
Continue stirring for an hour. Thereafter, the solvent is distilled off from the reaction solution under reduced pressure, and the remaining oil is dissolved in benzene, washed successively with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, and dried over anhydrous sodium sulfate. After drying, the solvent was distilled off under reduced pressure and the remaining oil was subjected to silica gel column chromatography, the target product was eluted using a chloroform-methanol solution (50:1) as an eluent, and the solvent was removed from the eluate under reduced pressure. The residue was distilled off to obtain the desired 7-[p-[3-(1-imidazolyl)propoxy]phenoxy]-2,2-dimethylheptanoic acid methyl ester as an oil. Nuclear magnetic resonance spectrum ( _CDCl3 ) (internal standard
TMS) 3.64 (3H, s, COOCH~ ₃ ) Example 10 4-(1-imidazolyl)butyric acid 0.62g and 1
-Dissolve 0.59 g of hydroxybenzotriazole in 20 ml of dry dimethylformamide, and add 0.91 g of dicyclohexylcarbodiimide to this solution while stirring at 40-45°C. After dicyclohexylurea was precipitated in the reaction solution, 5-(p-amino)phenoxy-2,2-dimethylpentanoic acid ethyl ester dissolved in 5 ml of dimethylformamide was added dropwise at the same temperature, and the mixture was stirred at the same temperature for 1 hour. do. After removing the dicyclohexylurea, the solvent is distilled off under reduced pressure. Ice water is added to the residue, extracted with chloroform, and the chloroform layer is washed successively with saturated sodium bicarbonate, water, and saturated brine, and then dried over anhydrous magnesium sulfate. Chloroform is distilled off under reduced pressure, and the resulting residue is subjected to silica gel column chromatography. The target product was eluted using a chloroform-methanol mixture (40:1 volume ratio) as an eluent, the solvent was distilled off from the eluate under reduced pressure, and the remaining white solid was recrystallized from an ether-benzene mixture to give 5. -[p-[4-(1-
imidazolylbutyramide] phenoxy]-2,
White crystals of 2-dimethylpentanoic acid ethyl ester were obtained. Melting point 92-93℃ Elemental analysis value (as C ₂₂ H ₃₁ N ₃ O ₄ ) C (%) H (%) N (%) Theoretical value 65.81 7.78 10.47 Experimental value 65.80 7.68 10.38 Examples 11-15 In addition to the raw material compounds used in Example 10, 5-(1-imidazolyl)pentanoic acid with m=4 and p-aminophenoxycarboxylic acid ethyl ester compounds with l=3,4,5 were combined. The mixture was changed and used as the raw material compound, and the reaction was carried out in the same manner as in Example 10.
The compounds of Examples 11-15 were prepared by processing.

[Table] Example 16 1.37 g of p-hydroxy-6-(1-imidazolyl)hexaneanilide and anhydrous potassium carbonate
Add 0.69g to 20ml of ethanol and heat under reflux.
Stir for 30 minutes. After cooling, add 6-bromo to this product.
2,2-dimethylhexanoic acid ethyl ester 1.26
g was added, and the mixture was allowed to react under heating and reflux overnight. The solvent was distilled off from the reaction solution under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The chloroform layer is washed successively with 1N aqueous sodium hydroxide solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the resulting residue is subjected to silica gel column chromatography. The target product was eluted using a chloroform-methanol mixture (50:1 volume ratio), the solvent was distilled off under reduced pressure, and the resulting crystals were recrystallized from a mixed solvent of n-hexane-ethyl acetate to give 6-[ p-[6-(1-imidazolyl)hexaneamide]phenoxy]-2,2
-White crystals of dimethylhexanoic acid ethyl ester were obtained. Melting point 64-65℃ Elemental analysis value (as C ₂₅ H ₃₇ N ₃ O ₄ ) C (%) H (%) N (%) Theoretical value 67.69 8.41 9.47 Experimental value 67.48 8.65 9.46 Example 17 In Example 16, 7-bromo-2,2-dimethylheptanoic acid ethyl ester was used as a raw material compound instead of 6-bromo-2,2-dimethylhexanoic acid ethyl ester, and the reaction treatment was carried out in the same manner as in Example 16 to obtain 7. -[p-[6-(1-imidazolyl)
Hexanamido]phenoxy]-2,2-dimethylheptanoic acid ethyl ester was obtained. Melting point 58-59℃ Elemental analysis value (as C ₂₆ H ₃₉ N ₃ O ₄ ) C (%) H (%) N (%) Theoretical value 68.24 8.59 9.18 Experimental value 68.28 8.72 9.10 Example 18 Add 1.00 g of 6-[p-[4-(1-imidazolyl)butyramide]phenoxy]-2,2-dimethylhexanoic acid ethyl ester to 10 ml of ethanol, 1N
-Dissolved in 10ml of sodium hydroxide solution at 40℃
After continued stirring for 16 hours, ethanol was distilled off under reduced pressure and the aqueous layer was washed with chloroform. Next, 10 ml of 1N hydrochloric acid was added to the aqueous layer, and the precipitated crystals were collected by filtration and recrystallized from isopropyl alcohol to obtain the desired 6-p-[4-(1-imidazolyl)butyramide]phenoxy]-2,2. - Obtain dimethylhexanoic acid. Melting point 149.5℃～150.5℃ Elemental analysis value (as C ₂₁ H ₂₉ N ₃ O ₄ ) C (%) H (%) N (%) Theoretical value 65.10 7.54 10.84 Actual value 64.97 7.77 10.87 Example 19 6-[p-[4-(1
-imidazolyl)butyramide]phenoxy]-
2,2-dimethylhexanoic acid ethyl ester 10.0
After dissolving g in 100 ml of ethanol, 5 ml of ethanol containing 1.42 g of hydrochloric acid was added under stirring, and after stirring for 1 hour, the solvent was distilled off under reduced pressure, and the residue was recrystallized from ethanol-ethyl acetate. 6-
[p-[4-(1-imidazolyl)butyramide]
[phenoxy]-2,2-dimethylhexanoic acid ethyl ester hydrochloride was obtained. Melting point 131-132℃ Elemental analysis value (as C ₂₃ H ₃₄ N ₃ O ₄ Cl) C(%) H(%) N(%) Cl(%) Theoretical value 61.12 7.58 9.30 7.84 Calculated value 61.01 7.75 9.29 7.97

Claims (1)

[Claims] 1. General formula [The symbols in the formula have the following meanings. A; single bond, formula - (CH ₂ ) mCONH (CH ₂ ) n
-, -(CH ₂ )m-O-, or a group represented by the formula R; a group represented by the formula m; an integer of 1 to 6 n; an integer of 0 or 1 to 5 R ₁ ; hydrogen An imidazole derivative or a salt thereof, wherein the atom is a lower alkyl group l; 0 or an integer of 1 to 5 R ₂ , R ₃ and R ₄ are the same or different hydrogen atoms or lower alkyl groups. 2 General formula (In the formula, M means a hydrogen atom or an alkali metal. The same applies hereinafter.) Imidazole or its alkali metal salt represented by the general formula [The symbols in the formula have the following meanings. A; single bond, formula - (CH ₂ ) mCONH (CH ₂ ) n
-, -(CH ₂ )m-O-, or a group represented by the formula R; a group represented by the formula m; an integer of 1 to 6 n; an integer of 0 or 1 to 5 R ₁ ; hydrogen Atom or lower alkyl group l: 0 or an integer of 1 to 5 R ₂ , R ₃ and R ₄ ; the same or different hydrogen atom or lower alkyl group X: halogen atom. The same applies hereinafter] A general formula characterized by reacting with a halide represented by A method for producing an imidazole derivative shown in