JPS5951548B2 - Method for producing benzofuran derivatives - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method for producing novel benzofuran derivatives useful as pharmaceuticals.

The object compound of the present invention has the general formula (1) RHC□OCH2■HCH2NHR1 IOH(l) (wherein, R is a hydrogen atom, a lower alkyl group or a phenyl group, R1 is a lower alkyl group, and the substituted propoxy group is a benzofuran ring. benzofuran derivatives (substituted at any position of 3, 4, 5, 6 or 7)
) and their acid addition salts.

The lower alkyl group contained in R in the general formula (1) is methyl, ethyl, n-propyl, isopropyl, n-
Examples include linear or branched alkyl groups having 1 to 4 carbon atoms, such as butyl, isobutyl, Sec-butyl, and tert-butyl.

In addition, the lower alkyl group represented by R1 is methyl,
Examples include straight-chain or branched alkyl groups having 1 to 4 carbon atoms, such as ethyl, n-propyl, isopropyl, n-butyl, isobutyl, Sec-butyl, and terdobutyl. 3 to 4 branched alkyl groups are preferred. Examples of acid addition salts of the target compound include inorganic acid salts such as hydrochloride, sulfate and hexanitrate, and organic acid salts such as acetate, oxalate, succinate and malate.

These acid addition salts can be easily obtained according to conventional methods, for example, by reacting with the corresponding acid in a suitable organic solvent. The object compound of the present invention is an adrenergic β
It exhibits a receptor-blocking action, and has lower toxicity than known compounds that exhibit this action, and is useful as a preventive and therapeutic agent for heart diseases such as arrhythmia and angina pectoris, and hypertension.

According to the production method of the present invention, the benzofuran derivative (1) of the target compound represented by the general formula (1) is prepared by the general formula (1).
A novel benzofuran derivative (1) represented by the formula (wherein R represents the same as above, and the substituted hydroxyl group is substituted at any position of the 3, 4, 5, 6, or 7 position of the benzofuran chain) and a propanol derivative () represented by the general formula (2) (in which X represents a halogen atom and R1 represents the same as defined above) or an acid addition salt thereof.

The benzofuran derivative (1) represented by the general formula (1) used as one of the raw materials in the present invention is a new compound, and is a new compound represented by the general formula () (wherein R2 is a lower alkyl group, a lower alkoxy group or represents a phenyl group,
The substituted hydroxyl group is 3,4,5,6 of the benzofuran ring.
or substituted at any position of the 7-position) by reducing the benzofuran derivative () using a conventional reducing agent under conventional reducing conditions.

In the general formula (), the lower alkyl group contained in R2 is methyl, ethyl, n-propyl, isopropyl,
Examples include linear or branched alkyl groups having 1 to 4 carbon atoms such as n-butyl, isobutyl, and Sec-butyl. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, and isobutoxy. , Sec-butoxy, Tert-butoxy, and the like. Suitable methods for reducing such benzofuran derivatives include, for example, methods using lithium aluminum hydride, sodium borohydride, diborane, etc. as reducing agents. In this case, methanol, ethanol, dioxane, tetrahydrofuran, or a mixed solvent thereof is usually used as the reaction solvent.
The novel benzofuran derivatives () thus obtained include, for example, 2-hydroxymethyl-hydroxybenzofuran, 2-(1-hydroxy)ethyl-hydroxybenzofuran, 2-(1-hydroxy)-n-propyl-
Hydroxybenzofuran, 2-(1-hydroxy)-n
-Butyl-hydroxybenzofuran, 2-(1-hydroxy)isobutyl-hydroxybenzofuran, 2-(1
-Hydroxy)-n-pentyl-hydroxybenzofuran, 2-(3-methyl-1-hydroxy)-n-butyl-hydroxybenzofuran, 2-(2-methyl-1-hydroxy)-n-butyl-hydroxybenzofuran, 2 -(α-hydroxy)benzyl-hydroxybenzofuran and the like.

The other raw material used in the method of the present invention is a propanol derivative () represented by the general formula (2) or an acid addition salt thereof, in which R1 represents the same as above, and X is chlorine, Represents a halogen atom such as bromine or iodine.

Such propanol derivatives include, for example, 1-methylamino-3-chloro-2-propanol, 1
-ethylamino-3-chloro-2-propanol,
1-n-propylamino-3-chloro-2-propanol, 1-isopropylamino-3-chloro-2-propanol, 1-n-butylamino-3-chloro-
2-propanol, 1-isobutylamino-3-chloro-2-propanol, 1-Sec-butylamino-3-
Chlor-2-propanol, 1-Tert-butylamino-3-chloro-2-propanol, 1-methylamino-3-bromo-2-propanol, 1-ethylamino-3-bromo-2-propanol, 1-n -Propylamino-3-bromo-2-propanol, 1-isopropylamino-3-bromo-2-propanol, 1-n
-butylamino-3-bromo-2-propanol, 1
-isobutylamino-3-bromo-2-propanol,
1-Sec-butylamino-3-bromo-2-propanol, 1-Tert-butylamino-3-brom-2
-propanol, 1-methylamino-3-iodeine-2-propanol, 1-ethylamino-3-iodeine-2-propanol, 1-n-propylamino-3
-iodeine-2-propanol, 1-isopropylamino-3-iodeine-2-propanol, 1-n
-Butylamino-3-iodeine-2-propanol, 1-isobutylamino-3-iodeine-2-propanol, 1-Sec-butylamino-3-iodeine-2-propanol, 1-Tert-butylamino-3-iodeine-2 - Examples include propanol. Among these, propanol derivatives having a branched alkyl group having 3 to 4 carbon atoms are particularly preferred. In addition, acid addition salts of such propanol derivatives () include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and nitrate;
Alternatively, organic acid salts such as acetate, oxalate, succinate, and malate may be mentioned.

Such acid addition salts can be easily obtained according to conventional methods, for example, by reacting with the corresponding acid in a suitable organic solvent. The method of the present invention is to synthesize the benzofuran derivative represented by the general formula (l) by heating and reacting the benzofuran derivative (I) and the propanol derivative () in approximately equimolar ratios as described above. ,
The preferred heating temperature range is 60 to 120°C, particularly 80 to 100°C.

In addition, in order to neutralize the generated acid and promote the reaction, an alkali such as potassium hydroxide, sodium hydroxide, anhydrous potassium carbonate, sodium hydride, sodium amide, etc. is added to the reaction system according to a conventional method. You can also do that. However, this reaction is usually completed in about 5 to 24 hours. In addition, examples of reaction solvents that are suitably used include methanol, ethanol, dimethylformamide, acetone, diglyme, methyl ethyl ketone, hexamethylphosphonylamide, and the like. The benzofuran derivative (□) which is the object compound of the present invention thus obtained
and its acid addition acid are both new compounds,
It has excellent pharmacological effects and is useful as a medicine.

For example, these target compounds not only improve the electrocardiogram in hypoxia or isoproterenol stress, but also suppress the increase in contractile force and heart rate and the drop in blood pressure produced by isoproterenol, thus reducing the adrenergic β It exhibits receptor blocking action and is useful as a preventive and therapeutic agent for heart diseases such as arrhythmia and angina pectoris, and hypertension. These target compounds also have lower toxicity than known adrenergic β-receptor blockers. Next, the present invention will be explained with reference to Reference Examples, Examples, and Test Examples, but the present invention is not limited to these.

Reference example 1 2-acetyl-4-hydroxybenzofuran 1.769
was dissolved in 20 mj of methanol, 0.42 g of sodium borohydride was slowly added under ice cooling, and the mixture was allowed to react at room temperature for 5 minutes.

After the reaction, methanol was distilled off, and the residue was mixed with 10 d of water and 1 d of glacial acetic acid.
wL1 was added and extracted five times with 10 ml of ethyl acetate. The ethyl acetate layer was then thoroughly washed with saturated aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off under reduced pressure at 40°C or lower. The residue was recrystallized with benzene-acetone (9:1) to obtain colorless needle-like crystals of 2-(1-hydroxy)ethyl-4-hydroxybenzofuran used as a starting material in the present invention. The melting point of this thing is 138
~140°C, and showed the following elemental analysis values. Elemental analysis value: ClOHlOO3 Theoretical value (existence): C67.4lH5.66 Actual value (7): C67.64H5.5l Reference examples 2 to 4 2-acetyl-5-hydroxybenzofuran 1.769
(Reference Example 2), 2-acetyl-6-hydroxybenzofuran 1.769 (Reference Example 3) and 2-acetyl-6-hydroxybenzofuran
[2-(1-Hydroxy)ethyl-5-hydroxybenzofuran 1.169 used as a starting material in the present invention was prepared in substantially the same manner as in Reference Example 1 using 1.769 hydroxybenzofuran (Reference Example 4).
(Melting point 120.5-122.5°C), 2-(1-hydroxyno(ha)ethyl-6-hydroxybenzofuran) 0.
98 g (melting point 82-84°C) and 1.509 g of 2-(1-hydroxy)ethyl hydroxybenzofuran (
The melting point was 159-161°C).

All of these showed the same elemental analysis values as 2-(1-hydroxy)ethyl-4-hydroxybenzofuran obtained in Reference Example 1. Example 1 [Production of 2-(1-hydroxy)ethyl-4-(2-hydroxy-3-isopropylamino)propoxybenzofuran] 2-(1-hydroxy)ethyl-4-hydroxybenzofuran obtained in Reference Example 1 3.6 g, 1-isopropylamino-3-chloro-2-propanol hydrochloride (3.89 g), and potassium hydroxide (3.4 f1) were added to 100 w11 ethanol and heated at 100° C. for 10 hours in a sealed tube.

After the reaction was completed, the reaction solution was filtered through a P filter, and the P solution was distilled off under reduced pressure, and the resulting residue was extracted with ether 300d. After the extract was purified with a silica gel column, ether and petroleum ether (
1:1) to obtain 0.8 g of the target compound in the form of a white powder with a melting point of 64-66°C. The elemental analysis values are shown below. Elemental analysis value: Theoretical value ω as Cl6H23O4N:
C65.5lH7.9ON4.78 Actual value (7): C6
5.73H7.9lN4.59 Example 2 [2-(1-
hydroxy) ethyl J yo 2-hydroxy-3-Te
Production of rt-butylamino)propoxybenzofuran]
2-(1-hydroxy)ethyl J obtained in Reference Example 4
Me[hydroxybenzofuran 3.69, 1-Tert-
Butylamino-3-chloro-2-propanol hydrochloride 4
．． 1f1 and 2.49 ml of sodium hydroxide were added to 100 ml of ethanol, and the mixture was reacted by heating at 100° C. for 10 hours in a sealed tube.

After the reaction was completed, the reaction solution was filtered through P, and the P solution was distilled off under reduced pressure. 500ml of the ether extract of the resulting residue was concentrated, purified with a silica gel column, and then recrystallized with benzene to obtain 0.95f of the desired compound as a white powder with a melting point of 126-127°C.
! I got it. The elemental analysis values are shown below. Elemental analysis value:
Theoretical value (1) as Cl7H25O4N: C66.42
H8.2ON4.56 Actual value ω: C66.28H8.3
7N4.6l Example 3 [Production of 2-(1-hydroxy)ethyl-6-(2-hydroxy-3-Tert-butylamino)propoxybendufuran] 2-(1-hydroxy) obtained in Reference Example 3 ) Dissolve 3.6 g of ethyl-6-hydroxybenzofuran in 50 ml of dimethylformamide, add 8.19 g of anhydrous potassium carbonate, and heat to 80-100°C with stirring to dissolve 1-tert-butylamino-2-hydroxy. -3-Chlorpropane hydrochloride 4
f! was slowly added dropwise and allowed to react for 8 hours.

After the reaction was completed, the reaction solution was filtered through a p-filter, and the P solution was distilled off under reduced pressure. The resulting residue was extracted with 800 ml of ether. The extract was purified with a silica gel column and then recrystallized with benzene to obtain the desired compound as a white powder with a melting point of 129-131°C (0.69°C).
I got it. The elemental analysis values are shown below. Elemental analysis value: C
Theoretical value Ω as l7H25O4N: C66.42H8.2ON4.56 Actual value ω
:C66.54H8. l3N4.8O Example 4 [2-
(1-hydroxy)ethyl-5-(2-hydroxy-3
Production of -Sec-butylamino)propoxybenzofuran] Potassium salt of 2-(1-hydroxy)ethyl-5-hydroxybenzofuran obtained in Reference Example 2 4.359
and 1-Sec-butylamino-2-hydroxy-3-chloro-propane 8.25f! was added to 100 d of ethanol and reacted in a sealed tube at 100°C for 7 hours.

After the reaction was completed, the reaction solution was filtered through P, and the P solution was distilled off under reduced pressure. The ether extract of the resulting residue (500ml) was concentrated, purified using a silica gel column, and then recrystallized from acetone-petroleum ether (1:1) to obtain 1.2f1 of the target compound in the form of a white powder with a melting point of 94-96°C. I got it. The elemental analysis values are shown below. Elemental analysis value: C,7H25O4N Theoretical value (1): C66.42H8.2ON4,56 Actual value ω: C66.78H7.98N4.49 Example 5 [2-(1-hydroxy)ethyl -Production of 3-isopropylamino)propoxybenzofuran] Potassium salt of 2-(1-hydroxy)ethyl-J-hydroxybenzofuran obtained in Reference Example 4 4.3
59 and 1-isopropylamino-2-hydroxy-3-
7.69 ml of chloropropane was added to 100 ml of ethanol and reacted under reflux for 24 hours.

After the reaction was completed, the reaction solution was filtered with P, the P solution was distilled off under reduced pressure, the resulting residue was concentrated to 400 ml of ether extract, purified with a silica gel column, and purified with benzene-petroleum ether (1
:1) to obtain 0.459 of the target compound in the form of a white powder with a melting point of 77-81°C.

The elemental analysis values are shown below. Elemental analysis value: Cl6H2
Theoretical value ω as 3O4N: C65.5lH7.9ON4
．． 78 Actual measurement value ω: C65.43H7.94N4.83 Test example [Experiment 1] Using anesthetized rats as test animals, the target compounds obtained in Examples 1 to 5 above (hereinafter referred to as The inhibitory effects of compounds 1 to 5) were investigated.

The dose of isoproterenol was 1 μ9/Kg, and the test drug was administered by intravenous injection. For comparison, a similar experiment was conducted using propranolol, which is commonly used as an adrenergic β-receptor blocker.

The results are shown in Table 1.

In Table 1, the inhibitory effect is shown as 50% inhibition value (ED5O). [Experiment 2] The acute toxicity (LD, O) of Compounds 1 to 5 was investigated using mice.

The test drug was administered intravenously as a physiological saline solution. For comparison, a similar experiment was conducted with propranolol.

From the ED5O and LD5O obtained in Experiments 1 and 2, the healing coefficient (LD5O/ED5O) and strength ratio (relative ratio when the healing coefficient of propranolol is set to 1) were determined.

Claims (1)

[Claims] 1 General formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R
is a hydrogen atom, a lower alkyl group or a phenyl group,
The substituted hydroxyl groups are 3, 4, 5, and 6 of the benzofuran ring.
There are benzofuran derivatives represented by general formula (II) ▲ mathematical formulas, chemical formulas, tables, etc. ▼ (II) (where X is a halogen atom, R^
General formula (III) characterized by reacting with a propanol derivative represented by (1 is a lower alkyl group) or its acid addition salt▲There are mathematical formulas, chemical formulas, tables, etc.▼
(III) (In the formula, R and R^1 represent the same as above, and the substituted propoxy group is 3, 4, 5 of the benzofuran ring.
, substituted at any position of the 6 or 7 position) and an acid addition salt thereof. 2. The manufacturing method according to claim 1, wherein the reaction is carried out at a temperature in the range of 60 to 120°C. 3. The manufacturing method according to claim 1, characterized in that 2-(1-hydroxy)ethyl-hydroxybenzofuran is used as the benzofuran derivative represented by general formula (I). 4. The production method according to claim 1 or 3, characterized in that 1-alkylamino-3-chloro-2-propanol is used as the propanol derivative represented by general formula (II).