JPH10120657A - Imidazole derivative and its production - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a safe imidazole derivative having excellent antihyperlipemic activity and therapeutic/preventive effect on arteriosclerosis, and having no side effects. SOLUTION: This compound is shown by formula I (X is F, Cl or trifluoromethyl: (n) is 2 or 3), e.g. 1- 4-[2-(4-chlorophenylsulfonylamino) ethoxy]phenylmethyl}imidazole. The compound of formula I is obtained by reaction of a compound of formula II (M is H or an alkali metal) with a compound of formula III (L is an eliminable group), when needed, in the presence of a catalyst (e.g. p-toluenesulfonic acid) and/or a solvent (e.g. anhydrous tetrahydrofuran). The reaction temperature is pref. 0 deg.C to the boiling point of the solvent when the solvent is used, while 80-200 deg.C in the absence of any solvent.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an imidazole derivative having cholesterol biosynthesis inhibitory activity and useful as a medicament, and a method for producing the same.

[0002]

2. Description of the Related Art In recent years, anti-hyperlipidemic drugs which suppress cholesterol and triglycerides affecting arteriosclerosis and the like have attracted attention, and pravastatin (Pra
vastatin), simvastatin (Simvastin)
atin) are known. As compounds similar to the present invention, the following compounds are described in JP-A-6-199791 as antiallergic agents.

[0003]

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The compounds of the present invention are described in WO95 / 291.
The compounds described in the claims of No. 63 are included in the general concept, but are not specifically mentioned in the detailed description of the invention.

[0005]

DISCLOSURE OF THE INVENTION The present invention has an excellent antihyperlipidemic effect, a therapeutic and preventive effect for arteriosclerosis,
Another object of the present invention is to provide an imidazole derivative which is safe and free from side effects, and an industrially advantageous production method thereof.

[0006]

That is, the present invention relates to a compound represented by the general formula [I] or a pharmaceutically acceptable salt thereof and a method for producing the same.

[0007]

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In the formula, X represents a fluorine, chlorine or trifluoromethyl group. Of these, a fluorine or chlorine atom is particularly preferred. In addition, n represents 2 or 3, and a compound in which n is 2 is particularly preferable.

The pharmaceutically acceptable salts of the present invention include:
Examples thereof include inorganic salts such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and organic acids such as acetic acid, propionic acid, lactic acid, succinic acid, tartaric acid, citric acid, benzoic acid, salicylic acid, nicotinic acid and heptagluconic acid.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION The compound of the present invention can be produced by the following production methods. (Production method 1)

[0011]

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(Wherein, X and n have the same meanings as described above, M represents a hydrogen atom or an alkali metal, and L represents a leaving group.) A preferred leaving group L is a halogen such as chlorine or bromine. Atoms, a methanesulfonyloxy group, a sulfonyloxy group such as a p-toluenesulfonyloxy group, and a hydroxy group.

In this production method, imidazole [II] is reacted with a compound represented by the general formula [III]. Solvents that can be used in the reaction include aromatic hydrocarbons such as benzene and toluene, ethers such as diethyl ether, dioxane, THF, and 1,2-dimethoxyethane, alcohols such as ethanol, and D.
Organic solvents such as MF, amides such as hexamethylphosphoric acid triamide, and water, and the like. The reaction is 0
° C to the boiling point of the solvent used, preferably from room temperature to the boiling point of the solvent used, or 80 ° C to 200 ° C without solvent.
C., preferably at a temperature of 100 ° C. to 180 ° C., and p-toluenesulfonic acid. It proceeds smoothly in the presence or absence of a catalyst such as copper powder and alkali iodide.

The imidazole can be used in the free state or in the form of an alkali salt which can be obtained from imidazole and alkali hydride, alkali amide, alkali alcoholate, alkali hydroxide and the like.

(Production Method 2) The compound of the present invention can also be produced by the following reaction.

[0016]

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(Wherein, X and n have the same meanings as described above,
Hal represents a halogen atom. That is, this production method comprises N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DM
A), amide solvents such as N-methylpyrrolidone, ethers such as tetrahydrofuran, diethyl ether and 1,2-dimethoxyethane, aromatic hydrocarbons such as benzene and toluene, and saturated hydrocarbons such as hexane and heptane; In an inert organic solvent such as dimethyl sulfoxide (DMSO) and acetonitrile, a hydride such as sodium hydride, an alkoxide such as potassium-t-butoxide and sodium ethoxide, a carbonate such as potassium carbonate, sodium hydroxide, and potassium hydroxide In the presence of an organic base such as hydroxide, pyridine, triethylamine, etc., from -20 ° C to the boiling point of the solvent used, preferably from room temperature to the boiling point of the solvent used, preferably from room temperature to 30 minutes under mild heating conditions. This is performed over several tens of hours.

(Production method 3) Further, the compound of the present invention can also be produced by the following reaction.

[0019]

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(Wherein X and n represent the same meaning as described above,
Hal represents a halogen atom. ) A reaction of an amine represented by the formula [IV] with a sulfonyl halide represented by the formula [V]. The reaction is carried out in an inert solvent such as DMF, DMSO, chloroform, methylene chloride, preferably triethylamine,
The reaction is carried out in the presence of a base such as 1,8-diazabicyclo [5,4,0] -unde-7-ene (DBU) in a temperature range from −20 ° C. to the boiling point of the solvent to be used for 30 minutes to several tens of hours. .

The starting compounds used in the above production can be produced, for example, according to the following reaction formula (where n has the same meaning as described above, and Hal represents a halogen atom).

[0022]

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When the reaction is carried out by any of the above-mentioned methods, the target product can be obtained by carrying out a usual post-treatment after completion of the reaction. The structure of the compound of the present invention is IR, NMR, M
Determined from ASS etc.

[0024]

Next, the present invention will be described in more detail with reference to examples.

Reference Example 1 Production of 1- (4-cyanomethoxyphenylmethyl) imidazole

[0026]

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In 500 ml of DMF, 11.5 g of sodium hydride (NaH) was added, and 1-
(4-hydroxyphenylmethyl) imidazole 50g
Was added and stirred at 100 ° C. for 30 minutes. The reaction solution was returned to room temperature, and 35 g of bromoacetonitrile was added.
Stirred at C for 1 hour. The reaction solution was poured into water and extracted with chloroform. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off and the solvent was distilled off under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 35 g of the title compound.
I got

Example 1 Preparation of 1- [4- [2- (4-chlorophenylsulfonylamino) ethoxy] phenylmethyl] imidazole

[0029]

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Anhydrous tetrahydrofuran (THF) 20 m
During l, added lithium aluminum hydride 0.71g (LiAlH _4), thereto the 2.0 g 1-(4
-Cyanomethoxyphenylmethyl) imidazole 20
The ml THF solution was added dropwise at room temperature over 5 minutes, and after completion of the addition, the mixture was further stirred at room temperature for 1 hour. Pour the reaction solution into water,
The insolubles were filtered off using Celite, and the filtrate was concentrated under reduced pressure. Methanol and benzene were further added to the obtained residue, followed by concentration under reduced pressure again to obtain 1.6 g of a crude product. 1.6 g of the obtained 1- [4- (2-aminoethoxy) phenylmethyl] imidazole was dissolved in 20 ml of DMF, and 1.1 g of triethylamine was added thereto. Next, 1.6 g of 4-chlorobenzenesulfonyl chloride was added under ice cooling, and the mixture was returned to room temperature and stirred for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 0.8 g of the title compound. Melting point: 140-141 ° C

The compounds of the present invention, including the above Examples, are shown in Table 1.

[0032]

[Table 1]

The compounds of the present invention are useful as antihyperlipidemic drugs, therapeutic and prophylactic drugs for arteriosclerosis. Administration of the compound of general formula [I] or a pharmaceutically acceptable salt thereof in pure form or as a suitable pharmaceutical composition thereof comprises:
It can be done in any of the accepted modes of administration for agents having similar utility. That is, the method of administration can be, for example, oral, nasal, parenteral, topical, transdermal or rectal, solid, semi-solid, lyophilized powder or liquid dosage forms, such as tablets, suppositories, pills, soft And as hard capsules, powders, solutions, suspensions, aerosols and the like, preferably in unit dosage forms suitable for simple administration of precise dosages.

The compositions contain the customary pharmaceutical carriers or excipients and the compounds of the general formula [I], alone or as one active ingredient, but additionally contain other drugs, pharmaceutical ingredients, A carrier, an adjuvant and the like can be included. In general, depending on the intended mode of administration, a pharmaceutically acceptable composition comprises one or more of the compounds of general formula [1] or a pharmaceutically acceptable salt thereof, about 1%.
-99% by weight, and 99-1% by weight of a suitable pharmaceutical excipient. The composition preferably contains about 5 to 75% by weight of one or more compounds of the general formula [I] or a pharmaceutically acceptable salt thereof, the balance being suitable pharmaceutical excipients. .

The preferred route of administration is oral, using a convenient daily dosage standard prepared according to the degree of hypercholesterolemia, hyperlipidemia and arteriosclerosis to be treated.

For such oral administration, a compound of the general formula [I]
A pharmaceutically acceptable composition containing one or more of the compounds of Formula I or a pharmaceutically acceptable salt thereof may be prepared using any of the commonly used excipients, such as pharmaceutical mannitol,
It is formed by adding lactose, starch, gelatinized starch, magnesium stearate, sodium saccharin, talc, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like.

Such compositions are in the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like. It is preferably in the form of a capsule, cashew or tablet. Accordingly, diluents such as lactose, sucrose, dicalcium phosphate, etc., disintegrants such as croscarmellose sodium or its derivatives, lubricants such as magnesium stearate, binders such as starch, gum arabic, polyvinylpyrrolidone, gelatin, cellulose ether Derivatives are also contained.

The compound of the general formula [I] or a pharmaceutically acceptable salt thereof may be, for example, a carrier that slowly dissolves in the body, for example, polyoxyethylene glycol and polyethylene glycol (PEG), for example, PEG1
000 (96%) and PEG 4000 (4%) can be formulated into a suppository using about 0.5% to about 50% of the active ingredient dispersed therein.

Liquid compositions that can be administered as medicaments include, for example, one or more compounds of the general formula [I] (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and An arbitrary pharmaceutical adjuvant can be produced by dissolving or dispersing in a carrier, for example, water, saline, aqueous dextrose solution, glycerol or ethanol, or the like, to give a solution or suspension.

The pharmaceutical composition of the compound of the present invention may contain, if desired, a small amount of auxiliary substances such as wetting or emulsifying agents.
H buffers, antioxidants and the like, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene and the like can also be added.

[0041] The actual method of preparing such dosage forms is conventional, for example, Remington's Phar.
medical Sciences, 18th edition, M
ack Publishing Company, Ea
manufactured according to Ston, Pennsylvania, 1990.

The composition to be administered, in any event, when administered in accordance with the teachings of the present invention, comprises a therapeutically effective amount of a general formula for the purpose of ameliorating hypercholesterolemia, hyperlipidemia and arteriosclerosis. It contains one or more compounds of [I], or a pharmaceutically acceptable salt thereof.

In general, the compound of general formula [I] or a pharmaceutically acceptable salt thereof is administered to the individual and to the pathological condition characterized by hypercholesterolemia, hyperlipidemia and arteriosclerosis to be treated. Will be administered in a therapeutically effective amount that will vary depending on the dosage. Usually, the therapeutically effective daily dose is 1 kg body weight
Approximately 0.14 mg to about 1 compound of formula [I]
4.3 mg / day, preferably about 0.7 mg / kg to about 10 mg / kg body weight, most preferably 1 kg body weight
About 1.4 mg to about 7.2 mg / g / day. For example, when administered to a human weighing 70 kg, the dose range of the compound of the general formula [I] or a pharmaceutically acceptable salt thereof is about 10 mg to about 1.0 g per day, preferably about 50 mg to about 1.0 mg per day. 700 mg, most preferably about 10 per day
0 mg to about 500 mg.

[0044]

【The invention's effect】

Pharmacological Test Example 1 Inhibition of Cholesterol Biosynthesis by Cell-free (1) Preparation of Enzyme System Preparation of an enzyme system for rat cholesterol biosynthesis is Bio.
chimica etBiophysica Acta
486, 70-81 (1977). That is, SD female rats (body weight 110-
130 g) was fed a 2% cholestyramine-added feed for 7 to 10 days to increase cholesterol biosynthesis activity.
After killing by exsanguination at midnight, the liver was removed and doubled in volume to 1
Contains 5 mM nicotinamide and 2 mM magnesium chloride
0.1M potassium phosphate buffer (pH 7.4) was added,
Homogenized with efitting Teflon homogenizer. The supernatant obtained by centrifugation at 12000 × g for 30 minutes was further centrifuged at 105000 × g for 90 minutes to separate the microsome fraction and the supernatant. The obtained supernatant was used as a 40% to 80% ammonium sulfate precipitation fraction (soluble fraction).
The soluble fraction and the microsomal fraction were treated with 0.1 M potassium phosphate buffer (pH 7.4) at 1 ml / g liver and 1 ml, respectively.
/ 3g liver was prepared and used in the test described below as an enzyme solution having a mixing ratio of 16: 1.

(2) Method for Measuring Cholesterol Biosynthesis Activity Cholesterol biosynthesis activity was measured by Biochimica e.
t Biophysica Acta 486, 70-
Performed according to the method described on page 81 (1977).
50 μl of the enzyme solution prepared in (1), 0.1 M potassium phosphate buffer (pH 7.4), 1 mM ATP, 5 mM glucose-1-phosphate, 6 mM glutathione, 6 mM magnesium chloride, 0.04 mM coenzyme A, 0.1 mM 25
mM NAD, 0.25mM NADP, 1mM 2- 14
2 μl of a dimethyl sulfoxide solution of the test drug in a solution consisting of sodium C-acetate (111 MBq./mmol)
Was added to a total volume of 0.2 ml, and the mixture was shaken at 37 ° C. for 90 minutes. 15m potassium hydroxide-ethanol solution 1m
The reaction was stopped by adding 1 and heating at 75 ° C. for 1 hour.
The non-saponifiable substance was extracted with n-hexane, concentrated to dryness, and dissolved in a small amount of chloroform-methanol (1: 2). Chloroform-methanol solution was added to Pre-co
spotted on Silicagel TLC,
It was developed with benzene-ethyl acetate (9: 1). The cholesterol portion was cut off, the radioactivity was measured with a liquid scintillation counter, and the 50% inhibitory concentration (IC ₅₀ value) of the compound of the present invention was determined. The results are shown in Table 2.

[0046]

[Table 2]

Pharmacological Example 2 In Vivo Cholesterol Biosynthesis Inhibition Test Male Crj: ICR mice aged 7 to 9 weeks were used. The mouse was in an environment where the lighting was reversed day and night (7 am to 7 pm,
(Dark) 2% cholestyramine-added feed was ingested for 7 to 10 days. The test drug was dissolved or suspended in distilled water or a 1% aqueous solution of polyoxyethylene hydrogenated castor oil and orally administered at 10:30 AM. One hour after the administration of the test drug, the mice were given 5 μCi / 0.5 m of ¹⁴ C-sodium acetate.
1 / mouse was administered intraperitoneally. Two hours later, under anesthesia with ether, blood was collected from abdominal vena cava into a plastic test tube containing a serum separating agent, and after about 30 minutes to 1 hour, 10,000 rpm
Centrifuged and separated the serum. To 0.5 ml of serum was added 1 ml of a 20% potassium hydroxide-ethanol solution, and the mixture was added at 75 ° C. for 3 hours.
Heated for hours. The non-saponifiable substance was extracted with n-hexane, concentrated to dryness, and dissolved in a small amount of chloroform-methanol (1: 2). Chloroform-methanol solution was applied to Pre-coated Silicagel TLC
And developed with benzene-ethyl acetate (9: 1). Cut cholesterol moiety, the radioactivity in a liquid scintillation counter to obtain the cholesterol biosynthesis inhibitory concentration 50% of the present compound (ID ₅₀ value), it showed the results in Table 2.

Pharmacological Example 3 Acute toxicity test A single dose was orally administered to male mice, followed by observation for 7 days to determine the mortality. The results are shown in Table 2.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Nobuhiro Umeda 345 Takada, Odawara-shi, Kanagawa Nippon Soda Co., Ltd.Odawara Research Laboratories (72) Inventor Yumi Ichihara 345 Takada, Odawara-shi, Kanagawa Nippon Soda Co., Ltd.

Claims (5)

[Claims] 1. A compound of the general formula [I] (Wherein X represents a fluorine, chlorine or trifluoromethyl group, and n represents 2 or 3) or a pharmaceutically acceptable salt thereof. 2. A compound of the general formula [II] (Wherein, M represents a hydrogen atom or an alkali metal) and a compound represented by the general formula [III]: (Wherein, X and n have the same meanings as described above, and L represents a leaving group). The compound represented by the general formula [I]: (Wherein, X and n have the same meanings as described above). 3. A compound of the general formula [IV] And a compound represented by the general formula [V]: Reacting with a compound represented by the general formula [I]: A method for producing a compound represented by the formula: 4. A compound of the general formula [I] (Wherein X and n have the same meanings as described above) or a pharmaceutically acceptable salt thereof as an active ingredient. 5. A compound of the general formula [I] (Wherein, X and n have the same meanings as described above) or a pharmaceutically acceptable salt thereof as an active ingredient.