JPH045286A - 2-alkyl-3-benzoylbenzofuran - Google Patents

Abstract

NEW MATERIAL: A compound of formula I (R is a 2-4C alkyl).

EXAMPLE: 2-Ethyl-3-(4-hydroxy-3,5-di-tertiary butyl benzoyl)benzofuran.

USE: Drugs for arrhythmia. Having high antiarrhythmic action.

PROCESS: First of all, a compound of formula II is reacted with thionyl chloride in the presence of petroleum ether under a reflux condition, to form 4- hydroxy-3,5-tertiary butyl benzoyl chloride of formula III. Then the compound and 2-alkylbenzofuran of formula IV are condensation-reacted in dichloroethane in the presence of stannic chloride anhydride catalyst.

COPYRIGHT: (C)1992,JPO

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention provides novel alkylbenzoylhensifurans, more specifically novel 2-alkyl-3-(4-hydroxy-35- The present invention relates to di-tert-butylbenzoyl)-benzofurans, pharmaceutical compositions containing these benzofurans, and methods for treating cardiac arrhythmia using the compounds.

PRIOR ART AND PROBLEM TO BE SOLVED BY THE INVENTION Cardiac arrhythmia is an important cause of myocardial infarction or other pathologies leading to valve failure. To date, medicines used to suppress this disease, such as quinidine,
Lidocaine, and procainamide, have significant and serious drawbacks. Gundmann and Gilman (The
Pharmacologic Ba5is ofTh
erapeutics, 7th edition, pages 761-770), it is described as follows. That is, r
Approximately 173 of the patients receiving quinidine will experience side effects that require immediate discontinuation of treatment.

Procainamide is useful in the treatment of a variety of arrhythmias, and the procainamide can be administered by a variety of methods of administration. Unfortunately, their effectiveness and versatility are compromised by their short duration of action and high incidence of side effects when used chronically. Lidocaine has a narrow antiarrhythmic spectrum.

The main side effects are related to the central nervous system. At higher concentrations,
This may result in hearing loss, disorientation, muscle contractions, spasticity, or respiratory arrest. ”Therefore, there is a great need for improved antiarrhythmic agents.

Gubin et al. (Eur, J, Med, Chem, -Chi
2-alkyl-3-(4-hydroxy3,5-dialkylbenzoyl)benzofuran (where 3,5-
each dialkyl group has 1 to 3 carbon atoms)
It is a useful intermediate for the preparation of anti-angina agents consisting of the corresponding 2-alkyl(aminoalkoxy-3,5-dialkylbenzoyl)benzofurans. As is well known, angina is caused by narrowing of the coronary blood vessels (usually due to plaque buildup), while arrhythmia, or irregular heartbeats, is the result of a problem with the natural pacemaker.

[Means for solving the problem, action and effects of the invention]

An object of the present invention is to provide new compounds with improved antiarrhythmic activity.

A particular object of the present invention is to provide new 2-alkyl-3-benzoylbenzofurans with improved antiarrhythmic activity.

A further object of the present invention is to provide a novel pharmaceutical composition useful for the treatment of arrhythmia.

Another object of the invention is to provide a new and improved method of treating arrhythmia.

These and other objects are achieved according to either of the following formulas: A or B, as will become clear from the description below.

Reaction sequence A: Achieved by the discovery of a novel 2-alkyl-3-benzoylhensifuran and its pharmaceutically acceptable salts, represented by .

Applicants have found that the compounds of formula I above exhibit high antiarrhythmic activity and therefore offer an improved method for the treatment of arrhythmias.

Preference is given to compounds of formula I above, where R is CzHs, n-CJt and nC=Hq.

The preparation of the compounds of formula I of the present invention can be accomplished by following the reaction sequence A
According to the series, compound No. 2 is obtained by Friedel-Crafts acylation reaction of 2,6-di-tert-butylanisole using chlorinated benzofurancarboxylic acid (It).

The resulting methyl ether intermediate (I[l) is decomposed to the corresponding phenol (1) with pyridine hydrochloride.

Alternatively, compounds of the invention can be prepared from Friedel-Crafts type 5nCE from 2-alkylhensifurane and 4-hydroquine-3,5-tert-butylhendiyl chloride, as shown in Reaction Scheme B.

Obtained by a condensation reaction using a catalyst.

Reaction series B: The compounds of the invention have improved antiarrhythmic activity.

For example, the compound of formula I (wherein R is CJs) shows superior activity in suppressing ventricular tachycardia when compared to lidocaine in the rat coronary ligation model, and also in aggressive animals. They also excelled at promoting survival.

Thus, the compounds of the present invention have an improved level of antiarrhythmic activity with reduced side effects.

Compounds of Formula I exhibiting antiarrhythmic activity can be formulated for oral or parenteral administration. For emergency administration, intravenous dosage forms are usually used which contain the active ingredient as a pharmaceutically acceptable salt, such as a sodium, potassium or calcium salt in an aqueous vehicle compatible with body fluids.

For such applications, the sterile isotonic solution consists of a pyrogen-free, soluble salt of the active drug dissolved in water with a ptno ~ 11.5. Preservatives, such as benzyl alcohol, can be used to maintain sterility, particularly in many dosage forms. A typical intravenous formulation contains from 10 to 100 μ of active ingredient per d of solution, calculated as base. By intravenous administration, administration of 0.5 to 10 μ/kg body weight of active ingredient is continued until a satisfactory heart rhythm is established.

For chronic treatment, the dose of compound 10-200
It is usually carried out using oral tablets or capsules containing (1). The active ingredients may be combined with lubricants and dispersants such as stearic acid, magnesium stearate, silica, etc. in amounts necessary to impart suitable disintegration and solubility to the dosage form, as is conventional in the art. Excipients such as lactose, starch, AVicel
mixed with etc.

Usual antiarrhythmic maintenance doses range from 1 to 100 μg of active ingredient per kg of patient body weight, given in 3 or 4 divided doses or in a single sustained-release dose. .

The present invention will be further explained below with reference to Examples, but it goes without saying that the present invention is not limited thereto.

〔Example〕

Example 1 50 g (0.2 mol) of 3,5-di-tert-butyl 4-hydroxybenzoic acid were dissolved in a 250'd hot pot and then 8 g (0.2 mol) of N dissolved in 40 d of water.
Mix thoroughly with aqueous solution of aOH for 30 minutes.

The mixture is evaporated to dryness and the remaining thorium salt is crushed and dried. 3001d of petroleum ether is added, the mixture is stirred and cooled to 5°C, then 100-thionyl chloride is added. After refluxing for 3 hours, 200 m of dichloroethane is added and the mixture is distilled to remove unreacted thionyl chloride. The addition of dichloroethane and distillation of excess thionyl chloride is repeated two more times and the solution is then cooled to room temperature.

29.2 g (0
, 2 mol) of 2-ethyl-hensifuran are added and then, with stirring, 0.4 mol of anhydrous stannic chloride is added dropwise with cooling. The reaction mixture is stirred at room temperature overnight.

After cooling to 0° C., 1000 d of water are carefully added, the mixture is stirred for 1 hour and separated. The aqueous phase was extracted three times with 100-dichloroethane, and the combined organic phases were extracted with Na25-dichloroethane.
Dry with O, filter and evaporate to dryness. The residual brown oil is recrystallized from petroleum ether to give 28 g (37% yield) of white crystals with a melting point of 95-100°C.

Example 2 The procedure of Example 1 is followed, except that 2-ethylbenzofuran is used instead of 2-n-butylbenzofuran, melting point 118
2-n-Butyl 3-(4-hydroxy-3,5-di-tert-butylbenzoyl)benzofuran having a temperature of ~120°C is obtained in a yield of 38%.

Example 3 An intravenous solution containing compound 10/relative of the present invention is prepared using the following ingredients.

Sodium chloride 0.9gp
2-n-butyl-3 (4-hydroxy-3,5 - di-tert-butylbenzoyl) benzofuran is added to pyrogen-free distilled water until the benzofuran is dissolved. Adjust the pH of the solution to 8-10 by adding sodium hydroxide or citric acid, followed by the addition of sufficient sodium chloride to achieve isotonicity, and the addition of sufficient pyrogen-free distilled water. 100F! Let it be IIl.

After thorough mixing, sterilized Millibo
re) (0.4 μC), placed in sterile containers and then placed in ampoules and/or vials.

Example 4 An intravenous solution containing 100M1 of the compound of the present invention, Example 3
Prepared using the following ingredients according to the procedure mentioned in .

Sodium chloride 0.8gp
Amount of sodium hydroxide or citric acid to make H8-10 Sufficiently sterilized pyrogen-free water 100ai!
Example 5 50 μ of 2-n-butyl-3-(4-
Tablets containing hydroxy-3,5-di-tert-butylhendiyl)benzofuran are prepared using the following ingredients: Add sium. The resulting mixture was blended for 20 minutes, then transferred to a tablet machine and added 301 tablets per tablet.
．． Press into 5 ■ 10.3 mil flat surfaced tablets.

Lactose D, C, 200,00 Corn starch 50.00 Magnesium stearate 1.50 Total weight 301.50

Claims (1)

[Claims] 1. 2-alkyl-3-benzoylbenzofuran represented by the following formula: ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (wherein R is a C_2 to C_4 alkyl group) and its pharmaceuticals Acceptable salt. 2. 2-alkyl-3- according to claim 1, wherein R is ethyl, n-propyl or n-butyl group.
Benzoylbenzofuran. 3. The 2-alkyl-3-benzoylbenzofuran according to claim 1, wherein R is an ethyl group. 4. A pharmaceutical composition useful in the treatment of cardiac arrhythmia, comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 5. A pharmaceutical composition useful in the treatment of cardiac arrhythmia, comprising an effective amount of a compound according to claim 3 and a pharmaceutically acceptable carrier. 6. A pharmaceutical composition useful for the treatment of cardiac arrhythmia in the form of a tablet for oral administration, comprising an effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier.