JPH078864B2 - 2-alkyl-3-benzoylbenzofuran - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel alkylbenzoylbenzofuran and a pharmaceutically acceptable salt thereof.

[Problems to be Solved by Prior Art and Invention]

Heart arrhythmias are an important cause of death from myocardial infarction or other lesions. To date, the drugs used to control this disease, such as quinidine, lidocaine, and procainamide, have significant and significant drawbacks. Goodman and Gilman (The Pharmacolo
According to gic Basis of Therapeutics, 7th edition, pp. 761-770), it is described as follows. That is, "About one-third of patients receiving quinidine will have the side effect of requiring immediate treatment interruption. Procainamide is useful in the treatment of various arrhythmias, and the procainamide can be administered by various administration methods. Unfortunately, its effectiveness and versatility are impaired due to its short duration of action and the occurrence of high side effects when used chronically. Lidocaine has a narrow antiarrhythmic spectrum. The main side effects relate to the central nervous system. Higher concentrations may result in hearing loss, disorientation, muscle spasms, convulsions or respiratory arrest. Thus, there is a great need for improved antiarrhythmic agents.

Gubin et al. (Eur.J.Med.Ghem.-Chim.Ther. (1974) 9,19
-25), 2-alkyl-3- (4-hydroxy-3,5-dialkylbenzoyl) benzofuran, wherein the 3,5-dialkyl groups each have 1 to 3 carbon atoms, is Corresponding 2-alkyl (aminoalkoxy-
It is a useful intermediate for the preparation of anti-angina agents consisting of 3,5-dialkylbenzoyl) benzofuran. As is well known, angina is due to the narrowing of coronary vessels (usually due to plaque buildup), while arrhythmias, or irregular heartbeats, are the result of one problem with natural pacemakers.

[Means for Solving the Problems, Actions and Effects of Invention]

The object of the present invention is to provide novel compounds having an improved antiarrhythmic effect.

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

The object of the present invention is, as will be apparent from the following description, the following formula I: (Wherein, R C ₂ -C ₄ is an alkyl group) it has been achieved by that finding the salts which may be acceptable as new 2-alkyl-3-benzoyl-benzofuran and its pharmaceutically represented by.

The Applicant has found that said compounds of formula I show a high antiarrhythmic effect and thus provide an improved method for the treatment of arrhythmias.

Formula I (wherein, R C ₂ H _5, a n-C ₃ H ₇ and n-C ₄ H ₉₎ compounds are preferred.

The preparation of compounds of formula I according to the invention is carried out by the following reaction sequence A or B:
Is achieved according to either.

Reaction series A: According to the A series of reactions, compounds of formula I are obtained by Friedel-Crafts acylation of 2,6-di-tert-butylanisole with benzofurancarboxylic acid (II) chloride. The resulting methyl ether intermediate (III) decomposes to the corresponding phenol (I) with pyridine hydrochloride.

Alternatively, the compound of the present invention is, as shown in Reaction Sequence B, a condensation reaction of 2-alkylbenzofuran and 4-hydroxy-3,5-tert-butylbenzoyl chloride using a Friedel-Crafts type SnCl ₄ catalyst. Is obtained by

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

For example, the compound of formula I (wherein R is C ₂ H ₅ ) exhibits an excellent effect of suppressing ventricular tachycardia in a rat model of coronary ligation, as compared with lidocaine, and also attacks. It was also excellent in promoting the survival of target animals.

Thus, the compounds of formula I of the present invention have improved levels of antiarrhythmic activity with reduced side effects.

The compounds of formula I having antiarrhythmic activity can be formulated for oral or parenteral administration. For urgent administration, arrhythmic dosage forms containing the pharmaceutically acceptable salt as the active ingredient, eg, the sodium, potassium or calcium salt in an aqueous vehicle compatible with body fluids, are usually used.
For such uses, the sterilized isotonic solution consists of a pyrogen-free, soluble salt of the active drug dissolved in water at pH 10-11.5. Preservatives such as benzyl alcohol can be used to maintain sterility, especially in many dosage forms. A typical intra-arrhythmic formulation will contain 10-100 mg of active ingredient per ml of solution, calculated as base.
By the intra-arrhythmic method of administration, the administration of 0.5 to 10 mg of active ingredient per kg of body weight is continued until a satisfactory cardiac rhythm is established.

Chronic treatment is usually carried out with oral tablets or capsules containing 10-200 mg of the compound of formula I per dose. As is usual in the art, the active ingredient is admixed with a lubricant and dispersant such as stearic acid, magnesium stearate, silica, etc. in an amount necessary to provide the appropriate dosage form disintegration and solubility properties. It is mixed with excipients such as lactose, starch, Avicel and the like.

The usual antiarrhythmic maintenance dose is in the range of 1 to 100 mg of active ingredient per kg of body weight of the patient, given in 3 to 4 divided doses or in a single sustained release dose.

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

〔Example〕

Example 1 2-Ethyl-3- (4-hydroxy-3,5-di-tert-butylbenzoyl) benzofuran 50 g (0.2 mol) of 3,5-
Di-tert-butyl-4-hydroxybenzoic acid was dissolved in 250 ml of warm methanol and then 8 g (0.
(2 mol) NaOH aqueous solution for 30 minutes. The mixture is evaporated to dryness then the residual sodium salts are triturated and dried. 300 ml petroleum ether are added, the mixture is stirred, cooled to 5 ° C. and then 100 ml thionyl chloride are added. After refluxing for 3 hours, 200 ml of dichloroethane are added and the mixture is distilled to remove unreacted thionyl chloride. The addition of dichloroethane and the distillation of excess thionyl chloride are repeated two more times, then the solution is cooled to room temperature. 29.2 g (0.2 mol) of 2-ethyl-benzofuran dissolved in 100 ml of dichloroethane are added, then 0.4 mol of anhydrous stannic chloride is added dropwise with stirring. The reaction mixture is stirred at room temperature overnight. After cooling to 0 ° C., 1000 ml of water are added carefully, the mixture is stirred for 1 hour and separated. The aqueous phase is extracted 3 times with 100 ml of dichloroethane, the combined organic phases are dried over Na ₂ SO ₄ , filtered and evaporated to dryness. The residual brown oil was recrystallized from petroleum ether, 28 g of white crystals with a melting point of 95-100 ° C (37% yield).
To get

Example 2 Synthesis of 2-n-butyl-3- (4-hydroxy-3,5-di-tert-butylbenzoyl) benzofuran The procedure of Example 1 is followed except that 2-n-butylbenzofuran is replaced by 2-ethyl. Using benzofuran, melting point 118-1
2-n-butyl-3- (4-hydroxy-) having a temperature of 20 ° C
Yield of 3,5-di-tert-butylbenzoyl) benzofuran 3
Get at 8%.

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

2-n-butyl-3- (4-hydroxy-3,5-di-tert-butylbenzoyl) sodium salt of benzofuran 1.0g sodium chloride 0.9g amount of sodium hydroxide or citric acid sufficient to make pH 8-10 In order to prepare a 100 ml iv sterile solution of pyrogen-free water, which has been sterilized with benzofuran, 2-n-butyl-3- (4-hydroxy-3,5-di-tert-butylbenzoyl) benzofuran is dissolved in benzofuran. Up to residual water without pyrogens. Adjust the pH of the solution to 8-10 by adding sodium hydroxide or citric acid, and then add a sufficient amount of sodium chloride to obtain isotonicity and further add sufficient pyrogen-free distilled water. Make 100 ml. After thorough mixing, filter through sterile Millipore (0.4 μc) into sterile containers and then into ampoules and / or vials.

Example 4 Formulation of 100 mg / ml Intravenous Solution An intravenous solution containing 100 mg / ml of the compound of the invention is prepared by the procedure mentioned in Example 3 with the following ingredients.

2-n-butyl-3- (4-hydroxy-3,5-di-tertiary-butylbenzoyl) benzofuran potassium salt 10.0g sodium chloride 0.8g pH 8 ~ 10 Sodium hydroxide or citric acid sufficient 100 ml of pyrogen-free water sterilized in Example 5 Tablets containing 50 mg of 2-n-butyl-3- (4-hydroxy-3,5-di-tert-butylbenzoyl) benzofuran per tablet Prepare with the following ingredients: To obtain tablets, blend 3- (4-hydroxy-3,5-di-tertiary-butylbenzoyl) benzofuran with lactose, then use a medium mill with a size 2B stainless steel screen in front of the medium mill. Pulverize at the speed of. The milled powder is transferred to a V blender, then the prescreened starch and magnesium stearate are added. The resulting mixture was blended for 20 minutes, then transferred to a tablet machine and 301.
Pressurize 5 mg of 10.3 mil flat surfaced tablets.

 ─────────────────────────────────────────────────── ─── Continued Front Page (72) Inventor Morris Stoller, Israel, 8413 Tel Aviv, Neot Ofeka, Sheronski Street 49 (72) Inventor Ron Breman Israel, 69345, Tel Aviv, University Street 89

Claims (3)

[Claims] 1. The following formula: (In the formula, R is a C _{2 to} C ₄ alkyl group) 2-alkyl-3-benzoylbenzofuran and a pharmaceutically acceptable salt thereof. 2. A 2-alkyl-3-benzoylbenzofuran according to claim 1, wherein R is an ethyl, n-propyl or n-butyl group. 3. A method according to claim 1, wherein R is an ethyl group.
2-Alkyl-3-benzoylbenzofuran according to the item.