JPS5818366A - Novel 1-aryloxyethylimidazole derivative, its preparation and inhibitor of blood platelet agglutination containing the same - Google Patents

Abstract

NEW MATERIAL:A 1-aryloxyethylimidazole derivative expressed by formulaI(A is methine or N) and an acid addition salt thereof. EXAMPLE:1-[2-(2-Naphthyloxy)ethyl]imidazole. USE:An inhibitor of blood platelet agglutination, preventing agent for apoplexy, antiagglutinating agent of blood platelets, remedy for pulmonary embolism, endotoxic shock, asthma and cardiac infarction, vasodilator of coronary artery, antiarteriosclerotic agent, antiulcer agent, remedy for nephritis, etc. PROCESS:An aryloxyethyl halide expressed by formula II (X is Cl, Br or I) is reacted with imidazole in a solvent, e.g. N,N-dimethylformamide, in the presence of a base, e.g. NaH, at -20-+50 deg.C for 5min-24hr to give the compound expressed by formulaI.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel 1-7lyloxyethylimidazole derivative, a method for producing the same, and a platelet aggregation inhibitor containing the same. More specifically, the present invention has an anti-inflammatory effect and an anti-platelet aggregation effect.

tromboxane At (thromboxane A,
, hereinafter TXA.

A novel compound that has pharmacological effects related to inflammation such as biosynthesis inhibiting action and is therefore useful as a pharmaceutical.
7! The present invention relates to a +-luoxie+imidazole conductor, a pharmaceutically acceptable acid addition salt thereof, a method for producing the same, and a platelet aggregation inhibitor containing the same.

The novel 1-7lyloxyethylimidazole derivative of the present invention is represented by the following formula (i) (where A is a methine group or a nitrogen atom).

The compound of the present invention is a novel compound that has not been described in any literature, and exhibits anti-inflammatory activity, anti-platelet aggregation inhibiting activity, and TXA.

For example, these compounds have physiological effects such as inhibiting biosynthesis, so they are used as stroke preventive drugs.

Antiplatelet drug, pulmonary embolism drug, endotoxic shock drug, asthma drug, myocardial infarction drug.

It is useful as a coronary artery dilator, arteriosclerotic agent, anti-ulcer agent, nephritis treatment, etc.

In the above formula CI), A represents a methine group or a nitrogen atom. Specific examples of such compounds include:

For example, 1-[2-(2-naphthyloxy)ethylcoimidazole.

1-(2-(7-inquinolyloxy)ethylcoimidazole).

and their hydrochlorides, hydrobromides, and sulfates.

Bisulfates, phosphates, acid phosphates, acetates.

Maleate, fumarate, lactate, I! These include phosphate salts, esterates, gluconates, and succinates.

The compound of the present invention can be produced as follows. That is, it can be produced by reacting 7yloxyethylnolide represented by the following formula (III) with imidazole in the presence of a base, and optionally forming a pharmaceutically acceptable salt of the product.

The above formula CI [
] The aryloxyethylno\ride represented by the formula can be easily obtained via the corresponding alcohol derivative, for example, as shown in the synthetic route below.

Synthetic route The reaction in step 1 can be carried out using, for example, the method of Ishido et al. (Bull.

Chem, Soc, Japan, vol. 46, 555
(1975)) by reacting 5-ethylene carbonate in the presence of tetraethylammonium iodide. The reaction in step 2 is carried out by a method known per se, for example, using onyl chloride for the chloride, phosphorus tribromide or triphenylphosphine and carbon tetrabromide for the bromide, and red phosphorus and iodine for the iodide. It will be done.

The halide represented by the formula []II is as follows:
An example of bromide is 2-(2-naphthyloxy)ethyl bromide.

2-(7-inquinolyloxy)ethyl bromide.

etc.

The production method of the present invention can be carried out by reacting a halide represented by formula (n) with imidazole in the presence of a base. These rogenides represented by formula (II) are usually used in a stoichiometrically 1-fold molar amount relative to imidazole, but may be used in an amount ranging from 1.01-2 times the molar amount. In this invention (・
Solvents used include benzene and toluene 6
- aromatic hydrocarbons, ethereal solvents such as dinityl ether, tetrahydrofuran, dioxane, dimethoxyethane, N,N-dimethylformamide, N,N-
Solvents such as dimethyl 7ceto7mide, hexamethylphosphoric tri7mide.

Alternatively, a mixed solvent of any combination thereof can be used.

The base used in the present invention includes sodium hydride I
Hydrogenation of ionium, potassium hydride, etc. 7 Rulkali metals, sodium chloride, sodium chloride, lithium chlorate, lithium 7
Used are metal heptamides such as amide, sodium 11-ium amide, butyl lithium, methyl 114-ium, phenyl lithium, methyl i-danecaram pumite, and fulkyl gold X% such as phenylmagnesium bromide.

The amount of base used is usually -(0.2 to 1 of 4 dazole)
, 5 times the mole, preferably 0.5 to 12 times the mole.

The reaction temperature is carried out in the range of -78°C to 150°C,
It is preferably carried out at -20°C to 50°C. The reaction time varies depending on the solvent used, the degree of reaction of the base, etc., and is determined by tracking the reaction by thin layer chromatography, etc., and is usually about 5 minutes to 24 hours.

After reacting the h-loginide represented by the formula [■] with imidazole in this way, the product represented by the formula [I] is isolated by a commonly used method. After distilling off the reaction solvent if desired, an extraction operation is performed, followed by drying and concentration to obtain a crude product.This product is subjected to column chromatography, thin layer chromatography, and recrystallization.

By separating using purification means such as distillation, the product 1-7 lyloxyenal imidazole derivative represented by formula [I] can be obtained.

The compound represented by the formula CI) thus obtained can be converted into an acid phase m-, if desired. Those used to form acid addition salts include hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphoric acid.

Acetic acid, maleic acid, fumaric acid, lactic acid, tartaric acid.

Citric acid, gluconic acid, succinic acid, etc. are preferably used.

The reaction to form an acid addition salt is usually carried out in a suitable solvent, such as water, methanol, alcohol, ether, chloride/l.
This is carried out by dissolving the compound represented by formula [I] in s-lene, chloroform, etc., and adding 1 to 10 equivalents of the above-mentioned acid thereto.

The 1-7 lyloxyethyl imidazole derivative of the present invention obtained by such compression and its pharmaceutically acceptable acid addition salt have anti-inflammatory effects, platelet aggregation inhibiting effects, TXA,
It has physiological effects related to inflammation such as biosynthesis inhibition,
Stroke prevention drug.

Antiplatelet drugs, pulmonary embolism drugs, endotoxic shock drugs, asthma drugs, myocardial infarction drugs.

It is useful as a coronary artery dilator, arteriosclerotic agent, anti-ulcer agent, nephritis treatment, etc.

These compounds can be administered orally or non-orally, such as intrarectally, subcutaneously, intramuscularly, intravenously, etc., for the above purpose, but are preferably administered orally or intravenously. 1--Good.

For oral administration, it is formulated into solid or liquid preparations. The solid dosage form is 1 tablet or pill.

Available in powder or granule form. In such solid formulations, one or more active substances are mixed with at least one inert diluent, such as the commonly used sodium bicarbonate, calcium carbonate, potato starch, sucrose, mannitol, carboxymethylcellulose, etc. be done. The formulation is carried out according to conventional methods, but may contain additives other than diluents, such as lubricants such as calcium stearate, magnesium stearate, and glycerin.

Liquid preparations for oral administration include pharmaceutically acceptable emulsions, liquid solutions, suspensions, syrups or elixirs, containing a commonly used inert diluent such as water or a fluid. This is due to the fact that it contains paraffin, etc.

10- In addition to the inert diluent, the liquid preparation may also contain adjuvants 9 such as wetting agents, clouding agents, sweeteners, flavors, fragrances, stabilizers, or preservatives.

The liquid preparation may also be administered in capsules made of an absorbable material such as gelatin.

Solid preparations for rectal administration include herbal medicines containing one or more active substances and prepared by methods known per se.

Preparations for parenteral administration are sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Non-aqueous solutions or suspensions include, for example, propyl glycol, polyethylene glycol or vegetable oils such as opal oil, and injectable organic esters such as oleic acid. Such formulations also contain preservatives, wetting agents, and emulsifying agents.

Auxiliary agents such as dispersants and stabilizers may be included. These can be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of disinfectants, or by irradiation.

Alternatively, a sterile solid preparation can be prepared and used by dissolving it in sterile water or a sterile injection solvent immediately before use.

The dosage of the 1-7lyloxyethylimidazole derivative or pharmaceutically acceptable acid addition salt, which is the active compound of the present invention, is 0.01 to 200 M9 per body weight per day.
and preferably 0.1 to 100 . These dosages depend on the patient's medical condition.

Depends on body weight, age, and route of administration.

To show an example of specific efficacy evaluation of the novel 1-7lyloxyethylimidazole derivative of the present invention, for example, 1-7lyloxyethylimidazole derivative
(Evaluation of platelet aggregation inhibitory effect of 2-(2-s7tyloxy)ethylcoimidazole (tnvttro review 1lffi on 7-rachidonic acid aggregation in guinea pig blood) showed that the 50% inhibitory concentration (ICID) was 8.5μI. Ta.

The present invention will be specifically explained below with reference to Examples.

Implementation row 1 Imidazole (t 171/ , 17.1 mmoj
? ) was dissolved in dry N,N-dimethylformamide and hydrogenated under stirring under water cooling to give 11 um (0,
78, P.

16.4 mmol (containing 50% mineral oil) was added.

The mixture was stirred at room temperature for 30 minutes. This was cooled on ice again and 2-(2-
naphthyloxy)ethyl bromide (3,741,14
, 9rmnol) in 25 m dry N,N-dimethylformamide was added and stirred at room temperature for 15 hours. Ethyl acetate and water were added to this for extraction, and the organic layer was washed with water, dried, and condensed.

The obtained crude product was subjected to silica gel column chromatography and eluted with chloroform containing 2% methanol to obtain 1-C2-(2-naphthyloxy)ethyl).
I4 Crystals of tasol (2,911, 12.2 mmol, yield 82%) were obtained.

Melting point (ethanol reconsolidation); ias ~ 6°C Infrared absorption spectrum (KBr, Rho 1); 1630.1 (SOD, 15
12,1262,1259°1220.1205,11
82,1078,1052°842.819,752°13- Nuclear magnetic resonance absorption spectrum (CD C1a, 8 (
ppm) ); 4.20 (8,4H), 6.9-7.
9 (vn, 10H).

Example 2 l-C2-(2-naphthyloxy)ethylraimidazole (1,461,6,1 mmol) was dissolved in 50 d of methylene chloride, and excess hydrogen chloride in ether solution was added. After concentration, crystallization from ethyl acetate yields 1-C2-
(2-Naphthyloxy)ethylcoimidazole hydrochloride (
1.32 g, 4.8 mmol, 79%) of a white solid was obtained.

Example 3 l-(2-(2-7thyloxy)ethylcoimidazole (1,2Jil, 5.0mmoA!) and fumaric acid (580N, 5.Orrmol) were mixed with ether/-
The solution was dissolved in 2QmlK and heated for 10 minutes. Concentration gave a white solid, which was recrystallized from ethyl acetate to give 1-(2-(2
-naphthyloxy)ethyl) imidasil fumarate (
1,2/i, 3.4mmoAl*68%) was obtained.

Example 4 7-Hydrooxyisokihapone 16By, equilene carbonate t1211, and tetraethylammonium iodide 00■ were mixed in dimethylform 7! Five shoulders! 14 inside
Heated to 0°. After 45 hours, dimethylformamide was distilled off under reduced pressure.

Add 100% of the remaining oil and chloroform.

The dissolved portion was washed once with saturated deuterated water (3Qm) and then once with water (5Q1nl). After drying over anhydrous sodium sulfate, it was filtered, and the resulting solution was distilled off under reduced pressure to obtain oily substance t6I. This product was subjected to the next bromination reaction without purification. That is, 1.6 g of the crude product obtained above was dissolved in 501 LIKm of tetrahydrofuran, and 5.9/l of triphenylphosphine and 5.0/l of carbon tetrabromide were dissolved.
9 was added at room temperature and reacted for 45 minutes. After vacuum III compression.

Dissolved in 80ml of chloroform and saturated soy water.

Then washed with water, dried with anhydrous sulfuric acid (+1um),
After filtration, the solvent was distilled off under reduced pressure to obtain an oil.

Purified by column chromatography (SiII Kagel 709; chloroform/ethyl acetate = 9515) to give 80
01ap 2-(7-inquinolyloxy)ethyl bromide was obtained. The nuclear magnetic resonance spectrum of this substance is as follows.

NMR (CD C1, 8 (ppm)); 5.63
(2H, t, J=6Hz), 4.32 (2H, t.

J=6Hz), 7.0-7.86 (4H, m), 8.5
4CIH.

d, J=6Hz), 9.30 (IH,s
).

Next, 11 um of sodium hydride (50% oil dispersion) 150 ■
dimethylo, rumyomi Y2m1mWK ξmezol 1
85 was added under ice-cooling, and the mixture was stirred for 30 minutes. In that mixture,
2-(7-inquinolyloxy) obtained above, :C
A dimethylformamide 1d bath solution containing 0.651 tylpromide was added, and the mixture was allowed to react at room temperature for 3 hours. Then water 30rn
1, 50 ml of ethyl acetate was added, and the liberated IA
The layers were washed twice with water (20 mj). Sulfuric anhydride) 1
After drying at 1 μm, filtered with #J and evaporated under reduced pressure, the resulting red oil was subjected to column chromatography (silica gel 10I).
;Chloroform/methanol=9B/2) K-C purification to obtain the desired 1-(2-(7-inquinolyloxy)ethylcoimidazole α51).

Nuclear magnetic resonance spectrum tcDctt, δ (ppm)
); 4.27 (4H, a), 6.90-7.80 (7
H, m).

8JO (1H, d, J = 6) (z), 8.98 (IH,
s).

EXAMPLE 1 The in vitro platelet aggregation inhibitory effect of the 1-7 lyloxyethylimidazole derivative of the present invention was measured using PRP.

The results were expressed as 50% inhibitory concentration (IC,.) of platelet aggregation. As the flocculant, sodium 7-rachitonate with a final concentration of 0.1 M was used.

(Preparation of PRP, drug, M concentrate) Preparation weight of ill PRP (face platelet plasma) 300~
Citrus fluid (1 volume of 3.8% sodium citrate and 9 volumes of blood) was collected from a 400-year-old male Hartley guinea pig by cardiac puncture.

The obtained quenching surface was centrifuged at 1.00 Orpm for 10 minutes at room temperature, and the supernatant (PRP) was separated.

The obtained PRP was stored at room temperature and used only once as much as possible, and was not used more than 4 hours after preparation.

(Preparation of 21 drugs The test drug is generally dissolved in ethyl alcohol and diluted with physiological saline.
i/rrl, 0. ! 1' pi/Inl, 0
1al/ILl, Q, 03μ#/14', 0.01μm
1/at, 0.0 [13 μI/− solutions were prepared in 1 d each.

The result of the platelet aggregation inhibition test was 0.003μy/shoulder! (0.0005 in terms of final concentration) di/yLl) If the drug completely inhibits platelet aggregation, the drug solution is further diluted with physiological saline and each diluted solution is Furthermore, a platelet inhibition test was conducted.

(3) Preparation of flocculant 7-rachidonic acid (manufactured by Sigma) was dissolved in Suminum HCO, to prepare a 3.5 mM sodium arachidonic acid solution. This was diluted with physiological saline and used as a 1mMp solution. The 3.3 mM ffl solution was stored in a cool area as a stock mother liquor, and a 1 mM solution was prepared from this mother liquor before use.

[Platelet aggregation inhibition test]

(11 Blank Platelet Aggregation Aggregation of platelets was achieved by adding 2511 physiological saline and 25 pl of MI concentration solution to 200 μl of PR'P pre-warmed in a 37°C cuette of a blank alibometer. The aggregation curve was recorded for 5 minutes using an aggregometer manufactured by Rika Denki Co., Ltd. The maximum aggregation degree in this platelet aggregation was taken as the maximum aggregation degree of the blank.

(2) Platelet aggregation inhibition test Add 25 μl of test drug solution to 200 μl of PRP,
After pre-incubation at 37°C for 2 minutes in the same manner as in step 11 above, 25μ of arachidonate solution was added and the aggregation curve was recorded for 5 minutes, and the degree of platelet agglutination was determined within that time. [-The inhibition rate is calculated using the following formula, and the minimum degree of drug whose inhibition rate exceeds 50% is IC,
. Shown as a value.

1-(2-(
IC of 2-naphthyloxy)imidazole.

The value was 8.5 μfi/nl.

Example 6 (Tablet formulation) One tablet was manufactured having the following composition.

Active ingredient 200j9 lactose
280 ■ Dimoid starch 80 m 9 vol vinyl hydrolidone 11 ■ Magnesium stearate
5~576~ Mix the active ingredient, lactose and potato starch, evenly moisten it with a 20% ethanol solution of 11 tons of polyvinylpyro, pass through a 20 m mesh, 45
℃ and passed again through a 15 m mesh. The granules thus obtained were mixed with magnesium stearate and compressed into one tablet.

The compounds of Examples 1 and 4 were typically used as active ingredients.

Example 7 (Capsule formulation) Hard gelatin capsules were prepared, one capsule containing the following composition:

Active Ingredients 20ON9 Microcrystalline Cellulose 195 ■ Amorphous Silicic Acid 5 Da 400 Da The active ingredient in finely powdered form, microcrystalline cellulose and unpressed amorphous silicic acid were thoroughly mixed and packed into hard gelatin capsules.

The compounds of Examples 1 and 4 were typically used as active ingredients.

21 - Example 8 (Formulation of Ampoules) One ampoule (51 volumes) IC7 containing the following composition:
Manufactured a bundle.

Active Ingredients 200 Soku Poly Technic Hand Astragalus II Call 6 on 20 0 Mouse 9 Steam
Distilled Water Total 501 Polyethylene glycol and active ingredient were dissolved in water under nitrogen, which was boiled, cooled under nitrogen and distilled. Pretreated water was added to this solution to give a volume of 1 trL, and the production was carried out under sterile conditions with KF under diffused light.

Filling is carried out in a nitrogen stream and sterilization is carried out at 121°C for 2 hours.
This was done for 0 minutes.

Note that the compounds of Examples 1 and 4 were used as the above active ingredients.

Example 9 (Preparation of ampoule) 10 Da of 1-(2-(2-naphthyloxy)ethylcoimidazole (compound obtained in Example 1) was mixed with 5 dabs of ethanol.
trrlic fm, sterilized through a bacteria retention filter 22-filter, 1m/m/capacity amble α
1Wll each was added and 7 tubes were sealed. The contents of the ampoule were diluted to 1 ml with a pH 8.6 To-11-HCl buffer and used for injection.

Patent applicant Teijin Ltd. 1) Jun Hiroshi 23- Continuation of page 1 (C author: Atsuo Hanari 3-5-18 Tamadaira, Hino City (C author: Kenji Manabe 3-5-18 Tamadaira, Hino City @ Originator: Tsuyoshi Tenba 3-18-4 Tamadaira, Hino City □□□Author: Kenzo Watanabe 3-5-18 Tamadaira, Hino City 0 shots Akira Seiji Kurozumi Higashitokura l-2-28, Kokubunji City ([Co., Ltd.] Founder Akira Otsu 3-13-35 Inumon, Ome City ・9 shots: Fukuyoshi Kamimoto 3-18-4 Tamadaira, Hino City

Claims (1)

[Scope of Claims] t A novel 1-7lyloxyethylimidazole derivative represented by the following formula CI) and a pharmaceutically acceptable acid addition salt thereof. 2. An aryloxyethyl halide represented by the following formula (IF) is reacted with imidazole in the presence of a base. A novel 1-7 aryloxyethylimidazole derivative represented by the following formula (I) (wherein A is the same as the above definition), which forms a pharmaceutically acceptable salt, if desired, and its Method for producing pharmaceutically acceptable acid addition salts. l A platelet aggregation inhibitor comprising an effective amount of a novel 1-7lyloxyethylimidazole derivative represented by the above formula CI) and/or a pharmaceutically acceptable acid addition salt thereof and a pharmaceutically acceptable carrier. .