KR790000939B1 - Process for the preperation of 3,4-dihydro carbo styril derivatives - Google Patents

Abstract

The title compds. (I; R = H, alkyl, aralkyl, R2= alkyl) were prepd. by treating II with epihalogenohydrin and alkylamine. Thus, 4.5g epichlorohydrin and 3 drops piperidine were added to 1.5g II (R1 = CH3), the mixt. heated to 90-95≰C for 2hr and treated with tert-butylamine for 5hr to give 0.5g I (R1 = CH3, R2 = tert-butyl). The I had β-adrenergic nerve blocking, hypotensive activity, and were useful as remedies for angina pectoris, arrhythmia, hyperpiesia.

Description

Preparation of 3,4-dihydro carbostyryl derivative

The present invention relates to a process for the preparation of the novel 3,4-dihydro carbostyryl derivatives. More specifically, the present invention is a novel 5- (3'-alkylamino-2'-hydroxy) pro, which has β-adrenergic nerve blocking action and hypotension, and is useful as an angi pectoris, arrhythmia and hypertension therapy. It relates to a method for preparing a foxy-8-substituted-3,4-dihydrocarabostyryl derivative.

It is already known that carbostyryl derivatives exhibit useful pharmacological action. Representatives of this type of compound are those described in Japanese Patent Publication Nos. 1182/1967 and 38,789 / 1971 and Chemical Abstracts, Vol. 62, 1b, 212e (1965) and the like. However, the above documents describe that compounds having a 3-substituted aminopropoxy group at the 5-, 6-, 7-, or 8-position of the carbostyryl component exhibit excellent blocking and β-adrenergic neuronal action. Not. In addition, Belgian Patent No. 794,669 describes 3,4-dihadedrocarabostyryl derivatives having the following general formula and pharmacologically acceptable acid addition salts thereof.

Wherein R ¹ is hydrogen, C ₁ -C ₄ alkyl, aralkyl or C ₂ -C ₄ alkenyl, R ² is hydrogen or a general formula 3COR ³ , wherein R ³ is C ₁ -C ₄ alkyl, phenyl or 3,4,5-trimethoxy phenyl) and R ¹ and R ^" are the same or different from each other and are hydrogen, C ₁ -C ₄ alkyl, aralkyl or cycloalkyl, or a nitrogen atom to which they are attached When taken together with, it is possible to form a heterocyclic tableware which may further contain a nitrogen atom or an oxygen atom as a ring member, provided that when substituted at the 5-position, R ¹ and R ² are hydrogen and R ^′ and R ^″ are not simultaneously hydrogen and C ₁ -C ₄ alkyl).

The 3,4-dihydrocarabostyryl derivative of the present invention has the following general formula

One of the metabolic products of the compound of the Bengi compound, wherein the beta-adrenergic neuroblocking action is lower than that of the compound described in the Belgian specification, but their hypotension action is greater than the former compound.

According to the present invention, the following general formula

Wherein R ₁ is hydrogen, C ₁ -C ₄ alkyl or aralkyl and R ₂ is C ₁ -C ₄ alkyl

A novel 3,4-dihydrocarabostyryl derivative represented by is prepared.

C ₁ -C ₄ alkyl groups in formula (I) are methyl, ethyl, propyl, isopropyl, sec-butyl, tert-butyl and the like.

Aralkyl groups are benzyl, phenethyl and the like.

The 3,4-dihydrocarabostyryl derivative of general formula (I) is a general formula

Wherein R ′ ₁ is C ₁ -C ₄ alkyl or aralkyl

3,4-dihydrocarabostyryl derivative represented by the general formula

Wherein X is halogen

A compound produced by reacting with epihalogenohydrin represented by

R ₂ -NH ₂ (Ⅴ)

(Wherein R ₂ is the same as above)

It is prepared by reacting with an alkylamine represented by and reducing the product as necessary.

The 3,4-dihydrocarabostyryl derivatives of the general formula (II) which can be used as starting materials in the present invention are novel compounds, for example, obtained by the following synthesis process.

1.Synthesis:

Wherein R ' ₁ is as defined above.

The known 8-hydroxy 3,4-dihydrocarabostyryl represented by the general formula (X) is first reacted with a nitriding agent such as a mixture of nitric acid, nitric anhydride or fuming nitric acid with acetic acid, acetic anhydride or sulfuric acid. 8-hydroxy-5-nitro-3,4-dihydrocarabostyryl is represented by General Formula (IX). The compound represented by formula (IX) is then reacted with a reducing agent such as tin 1 tin, tin, iron or zinc and a mixture of hydrochloric acid or sulfuric acid, or hydrogenated in the presence of a catalyst such as palladium-carbon 8-hydroxy-5-amino-3,4-dihydrocarabostyryl represented by general formula (VIII) is obtained. Oxidant, the compound represented by the general formula (VIII) to the next and ferric chloride, chromic acid, _{chromates, K 2 CrO 7 + H 2} SO 4 · KMnO 4 + H 2 O or MnO ₂ + H ₂ SO ₄ Is reacted with general formula (VII) to give 5,8-dioxo-3,4,5,8-tetrahydrocarabostyryl.

Next, the compound represented by the general formula (VII) is reacted with a reducing agent such as sulfur dioxide or sodium disulfide or zinc and acetic acid to give 5,8-dihydroxy-3,4-dihydro represented by the general formula (VI). Get gabostyryl.

Finally, the compound represented by the general formula (VI) is reacted with an alkylating agent such as methyl oxide or dimethyl sulfate or an aralkylating agent such as benzyl chloride to mono- or aralkylate the hydroxyl group at the 8-position. Alkylation or aralkylation usually occurs only at the 8-position but may occur at both the 5- and 8-positions. Thus, a 3,4-dihydrocarabostyryl derivative represented by formula (II) used as a starting material in the present invention is obtained.

The present invention reacts the 3,4-dihydrocarabostyryl derivative represented by the general formula (II) with epihalogenohydrin represented by the general formula (IV), and then generates the compound represented by the general formula (V). The reaction is carried out with an alkylamine represented by.

In the method of the present invention, the reaction of 3,4-dihydrocarabostyryl derivative of general formula (II) with epihalogenohydrin of general formula (IV) can be carried out in the presence of a basic compound. . As the basic compound, alkali metals such as metal sodium or metal potassium and their hydroxides and carbonates and amine compounds such as pyridine or piperidine can be used. In addition, this reaction is carried out in the absence of solvent or in the presence of a solvent. As the solvent, lower alcohols such as methanol, ethanol and isopropanol: ketones such as acetone and methyl ether ketone, ethers such as diethyl ether and dioxane and aromatic hydrocarbons such as benzene, toluene and xylene can be used. . Of these solvents, methanol and ethanol are suitable. In this reaction, the epihalogenohydrin of general formula (IV) may use 1 mole or more water per mole of 3,4-dihydro carbostyryl of general formula (II), but general formula (II) It is preferable to use it in the quantity of 5-10 mol per mol of 3, 4- dihydro carbon styryl. In addition, although this reaction can be performed at the temperature between 0-150 degreeC, it is preferable to carry out at the temperature between 50-100 degreeC.

By the reaction of the first step described above, the following general formula

여기서 X는 상기와 같음)이다.][Wherein R ' ₁ is C ₁ -C ₄ alkyl or aralkyl, Y is

Where X is the same as above.]

5- (2 ', 3'-epoxy) propoxy-3,4-dihydro carabostyryl derivative (III') or 5 '(3'-halogeno-2'-hydroxy) propoxy- 3,4-dihydrocarabostyryl derivative (III ') is obtained as an intermediate.

Usually, a mixture with the above-mentioned compounds (III ') and (III ") is obtained. The compound of formula (III') is predominantly prepared when the reaction is carried out in the presence of a strong base compound such as alkali metal and alkali hydroxide. The compound of the general formula (III ″) is predominantly prepared when the reaction is carried out in the presence of a weakly basic compound such as an organic base, especially with an excess of piperidine and epihalohydrin.

The products are separated from one another by conventional methods, for example, by fractional crystallization, but is preferably separated by column chromatography using a column filled with activated alumina salica gel or the like. These compounds can be converted into the compounds of the present invention by reaction with alkyl amines of the general formula (V) described later. Regardless of the ratio of compound (III ') to compound (III ") in the mixture, the mixture and the alkylamine react to form the compound of the present invention, and unnecessary reactions or effects, such as the formation of by-products or a decrease in yield It does not occur in this reaction, therefore it is not necessary to isolate the two compounds (III ') and (III') before reacting with alkylamines of general formula (V).

Thus, as a second step, the reaction between the intermediate product and the alkylamine of the general formula (V) can be carried out with or without isolating the electric intermediate from the reaction system of the first step. The reaction of the second step can be carried out in the absence of solvent or in a suitable solvent since the alkylamine of formula (V) used as the reactant can also act as a solvent. As the solvent, lower alcohol dioxanes such as ethanol, ethanol and isopropanol and ethers such as tetrahadifurfuran and aromatic hydrocarbons such as benzene and toluene can be used. Of these solvents, methanol and ethanol are suitable. The amount of alkylamine of formula (V) used in this reaction is suitable for ethanol in excess of the above intermediate product. The amount of alkylamine of the general formula (V) used in this reaction may be used in excess of the above intermediate product, but it is suitable to use alkylamine in an amount of 6 to 8 moles per mole of intermediate product. Although reaction is performed without heating, it is suitable to carry out reaction at the temperature near reflux temperature (50-80 degreeC is suitable).

By the said reaction, the 3, 4- dihydro carabostyryl derivative of general formula (I) which concerns on this invention is obtained. The compound may also be dissolved in acetone and then added with an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrochloric acid, or an organic acid such as hydrochloric acid, maleic acid, fumaric acid, dried acid, tartaric acid, citric acid, or ascolic acid to render the compound non-toxic. The water-soluble acid addition may be converted into a salt.

When a 5- (3'-alkylamino-2'-hydroxy) propoxy-8-hydroxy-3,4-dihydrocarabostyryl derivative is required, the 5- (3'-alkylamino thus obtained is obtained. -2'-hydroxy) propoxy-8-aralkyloxy-3,4-dihydrocarabostyryl derivative is reduced. In the case of 5- (3'-alkylamino-2'-hydroxy) propoxy-8-alkoxy-3,4-dihydrocarabostyryl, this is in the presence of excess HX (where X is halogen) at room temperature. The compound is stirred to perform dealkylation.

It is advantageous to carry out this reaction by hydrogenation in the presence of a known hydrogenation catalyst of this compound. As the hydrogenation catalyst, palladium black, palladium-carbon, ranickel, platinum dioxide, or the like can be used.

It is advantageous to carry out this reaction in a solvent. As the solvent, lower alcohols such as water, methanol, ethanol and isopropanol and acetic acid can be used. In addition, this reaction can be carried out at a temperature of 0 ~ 100 ℃ under the insertion pressure, but the temperature of 20 ~ 50 ℃ under normal pressure is preferred. Thus, the desired 5- (3'-alkylamino-2'-hydroxy propoxy-8-hydroxy-3,4-dihydrocarabostyryl can be readily prepared.

The compound is dissolved in a solvent such as isopropanol, followed by addition of an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or hydrochloric acid or an organic acid such as hydrochloric acid, maleic acid, fumaric acid, dried acid, tartaric acid, citric acid, or ascorbic acid. Can be converted to its nontoxic water soluble addition salts. The 5- (3'-alkylamino-2'-hydroxy) propoxy-8-hydroxy-3,4-dihydrocarabostyryl derivatives thus obtained are alkylated or aralkylylated as necessary to obtain A 5- (3'-alkylamino-2'-hydroxy) propoxy-8-alkoxy or -araloxy 3,4-dihydro carbostyryl derivative is obtained. In addition, the above dealkylation or dearalkylation may be carried out by the 5- (2 ', 3'-epoxy) propoxy-3,4-dihydrocarabostyryl derivative (III') 5- (3-halogeno-2- ' -Hydroxy) propoxy-3,4-dihydrocarabostyryl derivative (III ').

As described above, the 3,4-dihydrocarabostyryl derivatives of the general formula (I) and acid addition salts thereof obtained by the present invention are novel compounds having β-adrenal nerve blocking and hypotension. It is useful as a therapeutic agent such as factory, arrhythmia and hypertension.

For example, the antago-mistic activity of the 3,4-dihydrocarabostyryl derivative of the present invention (iso-mistic activity) (Table of β-adrenergic neuroblocking action) is known. D. Robson (R.D. bobson) and H. egg. According to the method described in H.R.Kaplan et al., "Pharmacological Experimental Paper," Volume 175, page 157 (1970), the following measurements were made.

Hybrid dogs of the same sex having a body weight of 9.7-19.0 kg were anesthetized behind their back with pentobarbital-Na (30 mg / kg.i.v.) And this anesthesia was 4 mg / kg / hr. Percentage of pentobarbital-Na was continued by continuous intravenous infusion. Arterial blood pressure was measured from the left femoral artery with a blood pressure transducer (Nihon Goden, RP-3). The left femoral vein was irrigated for intravenous injection. Heart rate was measured with a blood flow rate meter (San-ei, type 2130) braked by R waves of ECG (Lead II).

Blood pressure and heart rate were simultaneously recorded on an ink-recorder (San-ei, Type 145).

The test drug was cumulatively injected at 10 minute intervals after a regeneration test for positive cycle variability and hypotension of 0.3 μg / kg of the lowest dose of isoprofeterenol. When the blood pressure and heart rate response to these test drugs stabilized, that is, about 3 minutes after injection, 0.3 μg · kg of isoproterenol was injected again. From the difference between the response to isoproterenol before and after administration of the test drug, their antagonism was measured and expressed as% inhibition.

The results obtained are shown in the following table.

TABLE 1

The hypotensive action of the 3,4-dihydrocarabostyryl derivative of the present invention was estimated as follows.

Hybrid dogs of the same sex, all weighing 9.7-19.0 kg, were anaesthetized with pentobarbital-Na (30 mg / kgi.v.) Behind them, and the anesthesia was pentobarbital- at a rate of 4 mg / kg / hr. It was continued by continuous intravenous injection of Na.

A vinyl catheter was inserted into the left femoral vein and heparin sodium, 1,000 µg / kg, was injected to prevent blood coagulation. Arterial blood pressure was measured from the left femoral artery with a blood pressure transducer (Nihon Goden, RP-3). The test drug was dissolved in 0.9% saline solution and then administered intravenously in cumulative release at 5-10 minute intervals.

The results obtained are shown in the following table.

TABLE 2

As is clear from the above table, the 3,4-dihydro carabostyryl derivative (0.1-100 µg / kg) of the present invention showed a dose-dependent decrease in arterial blood pressure.

The acute toxicity of the 3,4-dihydrocarabostyryl derivatives of the present invention was found to be as follows.

TABLE 3

The following reference describes the preparation of 3,4-dihydro carbostyryl derivatives of general formula (II) for use as starting materials in the present invention.

[Reference Example]

First stage

16.3 g of 8-hydroxy-3,4-dihydrocarabostyryl was suspended in 75 ml of acetic anhydride and cooled to 0 ° C. A solution of 7.8 g of fuming nitric acid dissolved in 50 ml of glacial acetic acid was added dropwise to this suspension, while maintaining the temperature at this time at 5 ° C or lower. After completion of addition, the mixture was stirred at a temperature of 5 ° C. or less for 2 hours. 20 g of ice cubes were added thereto, and the separated precipitate was collected by filtration and recrystallized from dioxane. Thus, 8.5 g of a yellow amorphous material having a melting point of 300 ° C. or higher was obtained.

This product was identified as 5-nitro-8-hydroxy-3,4-dihydrocarabostylyl by analysis of NMR, IR (NO ₂ : 1.570 cm ^-1 , 1,320 cm ^-1 ) and elemental analysis.

2nd step

3 g of 1 st tin chloride was dissolved in 5 ml of concentrated hydrochloric acid, and 1 g of 5-nitro-8-hydroxy-3,4-dihydrocarabostyryl was added to this solution in a water bath where the solution was stirred with stirring. The separated precipitate was collected by filtration, washed with acetone and recrystallized with water. Thus, 0.9 g of acicular crystals having a melting point of 300 ° C. or higher were obtained. The product was analyzed by NMR, IR (NH ₂ hydrogen chloride: 3280, 2600, 1590, 1.500 cm ^-1 ) and elemental analysis. 5-amino-8-hydroxy-3,4-dihydro carbostyrylhydro It was identified as chloride.

3rd step

1.0 g of 5-amino-8-hydroxy-3,4-dihydro carbostyryl hydrochloride was dissolved in a mixture of 0.1 ml hydrochloric acid and 40 ml water. After dissolution, the solution was filtered directly by suction. The filtrate was cooled to room temperature. While stirring this solution vigorously, a solution of 3 g of ferric chloride dissolved in a mixture of 1 ml of hydrochloric acid and 3 ml of water was added to this solution at once. The mixture was stirred at rt for 1 h. The separated crystals were collected by filtration and recrystallized with ethyl acetate. Thus, 0.6 g of a yellow needle-like crystal having a melting point of 185 to 188C (decomposition) was obtained. This product was identified as 5,8-dioxo-3,4,5,8-tetrahydro carabostyryl by analysis of NMR, IR and elemental analysis.

4th step

0.8 g of 5,8-dioxo-3,4,5,8-tetrahydro carbostyryl was suspended in 30 ml of water, and sulfur dioxide was added to this suspension at room temperature with stirring. The separated crystals were collected by filtration and recrystallized with water. Thus, 0.5 g of colorless acicular crystals having a melting point of 228 to 230 ° C were obtained. This product was identified as 5,8-dihydroxy-3,4-dihydrocarabostyryl by analysis of NMR, IR, and elemental analysis.

5th step

1.8 g of 5,8-dihydroxy-3,4-dihydrocarabostyryl and 1.6 g of potassium carbonate were suspended in a mixture of 150 ml and 50 ml of water. 1.0 g of dimethyl sulfate was added to this suspension. This mixture was heated at reflux for 8 hours. After cooling, acetone was distilled off under reduced pressure. Water was added thereto and the reaction product was extracted with chloroform. The chloroform layer was washed with dilute aqueous sodium hydroxide solution and then with water. The chloroform layer was dried over anhydrous sodium sulfate and the chloroform was distilled off. The residue was recrystallized from methanol to give 0.5 g of colorless prismatic crystals having a melting point of 171 to 173.5 ° C. This product was identified as 5,8-dimethoxy-3,4-dihydro carabostyryl by analysis of NMR, IR and elemental analysis.

The washings were combined, acidified with concentrated hydrochloric acid, and then extracted with chloroform. The chloroform layer was washed with anhydrous sodium sulfate and the chloroform was distilled off. The residue was recrystallized with ethanol to obtain 1.0 g of a colorless needle crystal having a melting point of 202 to 204 캜. This product was identified as 5-hydroxy-8-methoxy-3,4-dihydrocarabostyryl by analysis of NMR, IR and elemental analysis.

The following examples illustrate the invention.

Example 1

To 1.5 g of 5-hydroxy-8-methoxy-3,4-dihydro carabostyryl, Epiclohydrin 4.5 and 3 drops of piperidine were added. This mixture was heated at 90-95 ° C. for 2 hours. The reaction liquid was concentrated under reduced pressure and the residue was dissolved in chloroform. The solution was washed with dilute aqueous sodium hydroxide solution and then with water and dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to obtain 1.2 g of intermediate product, which was separated into two components by chromatography, which was determined by analysis of NMR, IR, and elemental analysis. 5- (2 ', 3'-epoxy)- Propoxy-8-methoxy-3,4-dihydrocarabostyryl and 5- (3'-chloro-2'-hydroxy) propoxy-8-methoxy-3,4-dihydro carabostyryl Each was identified. Further, 1.2 g of the intermediate product was dissolved in 20 ml of methanol, and 2.5 g of tert-butyamine was added thereto. The mixture was heated to reflux for 5 hours. The reaction liquid was concentrated to dryness under reduced pressure. This residue was dissolved in dilute hydrochloric acid. The solution was washed with chloroform, neutralized with sodium bicarbonate and then concentrated under reduced pressure. This residue was extracted with ethanol and the ethanol was distilled off under reduced pressure. This residue was dissolved in acetone and a solution of maleic acid dissolved in acetone was added. The separated crystals were collected by filtration and recrystallized with ethanol to give 0.5 g of white powder powder crystals having a melting point of 201 to 202 캜 (decomposition). This product was analyzed by NMR, IR, and Elemental Analysis. 5- (3'-tert-butylamino'2'-hydroxy) propoxy-8-methoxy-3,4-dihydrocarabostyryl maleate Was identified as.

Example 2

8.5 g of epichlorohydrin and 10 drops of piperidine were added to 4.0 g of 5-hydroxy-8-benzyloxy-3,4-dihydro carbostyryl. This mixture was heated at 90-95 ° C. for 2 hours. The reaction solution was concentrated under reduced pressure and the residue was dissolved in chloroform. The solution was washed with dilute aqueous sodium hydroxide solution and then with water and then dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to obtain 4.0 g of an oily intermediate product, which was analyzed by NMR, IR, and elemental analysis. 5- (2 ', 3'-epoxy) propoxy-8-benzyloxy-3,4- It was identified as dihydrocarbobostyryl and 5- (3'-chloro-2'-hydroxy) -propox 8-benzyloxy-3,4-dihydrocarabobostyryl. Further, 4.0 g of the intermediate was dissolved in 40 ml of methanol, and 6.5 g of tert-butylamine was added thereto. This mixture was heated under reduced pressure for 3 hours. This residue was recrystallized with isopropanol to obtain 2.0 g of colorless scale-shaped crystals having a melting point of 124 to 126 ° C. This product was identified as 5- (3'-tert-butylamino'2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydrocarabostyryl by analysis of NMR, IR and elemental analysis. It became.

Example 3

4.0 g of the intermediate obtained in the same manner as in Example 2 were dissolved in 50 ml of methanol, and 6 g of isopropylamine was added thereto. This mixture was heated at reflux for 3 hours. Similar treatment as in Example 2 gave 2.0 g of a colorless plate-like crystal having a melting point of 132 to 135 ° C. This product was identified as 5- (3'-isopropylamino-2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydrocarabostyryl by analysis of NMR, IR and elemental analysis. It became.

Example 4

1.4 g of 5-hydroxy-8-benzyloxy-3,4-dihydro-3,4-carbostyryl was dissolved in 30 ml of methanol and 0.4 g of sodium ethylate was added thereto. The mixture was heated at reflux for 30 minutes, followed by the addition of 1.6 g of epichlorohydrin. This mixture was heated at reflux for hours. The reaction solution was concentrated under reduced pressure to dryness, and the residue was dissolved in chloroform. The solution was washed with dilute aqueous sodium hydroxide solution followed by water and then dried over anhydrous sodium sulfate. Chloroform was distilled off under reduced pressure to obtain 1.0 g of an oily intermediate product. The product was analyzed by NMR, IR, and elemental analysis. 5- (2 ', 3'-epoxy) propoxy-8-benzyloxy-3,4-dihydrocarabostyryl and 5- (3'-chloro -2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydro carbostyryl was identified as a mixture. In addition, 1.0 g of the above intermediate was dissolved in 20 ml of methanol, and 2 g of sec-butylamine was added thereto. This mixture was heated at reflux for 3 hours.

The reaction solution was concentrated to dryness under reduced pressure. This residue was recrystallized with isopropanol to give 0.6 g of colorless scale flakes having a melting point of 111 to 112 캜. This product was identified as 5- (3'-sec-butylamino-2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydrocarabostyryl by analysis of NMR, IR and elemental analysis. It became.

Example 5

1.5 g of 5- (3'-tert-butylamino-2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydrocarabostyryl is dissolved in 30 ml of methanol and 10% palladium-carbon at room temperature In the presence of 0.2 g, the solution was stirred while absorbing hydrogen. The catalyst was filtered off and the filtrate was concentrated under reduced pressure. The residue was dissolved in isopropanol, and thereto was added a solution of maleic acid dissolved in acetone. The separated crystals were collected by filtration and recrystallized with ethanol to obtain 1.0 g of a colorless needle-like crystal having a melting point of 187 to 190 ° C (decomposition). This product was identified as 5- (3'-tert-butylamino-2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydrocarabostyryl by analysis of NMR, IR and elemental analysis. It became.

Example 6

1.0 g of 5- (3'-isopropylamino-2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydrocarabostyryl is dissolved in 30 ml of methanol, and 10% palladium-carbon 0.15 at room temperature. The solution was stirred while absorbing hydrogen in the solution in the presence of g. Treatment similar to that described in Example 5 yielded 0.5 g of colorless needle crystals having a melting point of 162 to 165 캜 (decomposition). This product was analyzed as NMR, IR and elemental analysis to obtain 5- (3'-isopropylamino-2'-hydroxy) propoxy-8-hydroxy-3,4-dihydro carbostyrylmaleate. I was identified.

Example 7

0.2 g of 5- (3'-sec-butylamino-2'-hydroxy) propoxy-8-benzyloxy-3,4-dihydrocoabostyryl is dissolved in 20 ml of methanol, and 10% palladium-carbon at room temperature. The solution was stirred while absorbing hydrogen into the solution in the presence of 0.05 g. A treatment similar to that described in Example 5 yielded 0.1 g of a colorless needle-like crystal having a melting point of 175 to 178 캜 (decomposition). This product was obtained by analysis of NMR, IR and elemental analysis. 5- (3'-sec-butylamino-2'-hydroxy) propoxy-8-hydroxy-3,4-dihydrocarabostyryl maleate Was identified.

Claims (1)

Reacting the compound produced by reacting a compound of formula (II) with epihalogenohydrin of formula (IV) with an alkylamine of formula (V), and reducing the reaction product if necessary Characterized in the 3,4-dihydrocarabostyryl derivative of the general formula (I) and a method for producing an acid addition salt thereof

In each formula, R ₁ is hydrogen, C ₁ -C ₄ alkyl or R ₂ is C ₁ -C ₄ alkyl, R ₁ is C ₁ -C ₄ alkyl or aralkyl, X is halogen.