JPS61218582A - Benzofuran derivatives, their production methods, and antihypertensive agents containing them as active ingredients - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (X is acetyl or lower alkoxycarbonyl; R is lower alkoxy or lower alkyl substituted arbitrarily to o-, m- or p-position relative to piperazinyl; the group of formula IV is substituted arbitrarily to 4-7-position of benzofuran ring) or its salt. EXAMPLE:2-Acetyl-5-{2-hydroxy-3-[4-(2-methylphenyl)piperazinyl-]p-ropoxy} benzofuran. USE:Effective as a hypotensor, a remedy for stenocardia, an agent for improving peripheral circulation and an agent for improving cerebral circulation. It has decreased side effects, strong beta-adrenalin blocking action and Ca-antagonistic action. PREPARATION:The compound of formula I can be produced, e.g. by reacting a 2,3-epoxypropoxybenzofuran derivative of formula II (some of which are novel) with an N-phenylpiperazine derivative of formula III or its salt in an organic solvent such as dioxane at room temperature - 100 deg.C for 15min-10hr.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel 2-hydroxy-3-(4
-Phenylbiverazinifre) propoxybenzofuran derivative, its production method, and an antihypertensive agent containing the same as an active ingredient.

[Prior Art] Various cardiovascular drugs having a benzofuran ring have already been developed. However, an antihypertensive agent that has not only β-blocking action but also multiple pharmacological actions such as α-blocking action and Ca antagonism, and has reduced side effects has not yet been found.

[Purpose of the Invention] The present inventors focused on antagonists at the level of sympathetic nervous system receptors, and as a result of extensive research, we found that they have strong α-adrenergic blocking effects and Ca antagonistic effects, and have fewer side effects. The new compound 2-hydroxy-3-(4-
They discovered a phenylpiperazinyl) propoxybenzofuran derivative and completed the present invention.

[Structure of the Invention] That is, the present invention is based on the general formula (■): H (wherein, X is an acetyl group or a lower alkoxycarbonyl group, and R is a lower alkoxy group.

or a lower alkyl group, R is any one at the 1st position (ortho position, same below), to position (meta position, same below) or p1 position (para position, same below) with respect to the piperazinyl group. 2-Hydroxy-3-(4-phenylpiperazinyl)propoxybenzofuran, which is substituted at any of the 4-, 5-, 6-, and 7-positions of the benzofuran ring. A derivative or a salt thereof, a method for producing the same, and an antihypertensive agent containing the same as an active ingredient are provided.

[Embodiments of the invention] In the present invention, the above term "lower" has 1 to 3 carbon atoms.
means a straight or branched carbon chain. Therefore, when R is a lower alkyl group, R is a methyl group, ethyl group, n-propyl group or isopropyl group,
Particularly preferred is a methyl group. In addition, when R is a lower alkoxy group, R is a methoxy group, an ethoxy group, n
-propoxy group or isopropoxy group, particularly preferably methoxy group.

Further, R may be substituted at any of the ○1-position, m-1 position, and p-position with respect to the piperazinyl group, but substitution at the ○1-position is particularly preferred.

The substituent H bonded to the benzofuran ring may be substituted at any of the 4th, 5th, 6th, and 7th positions of the ran ring, but in particular, those that are substituted at the 5th or 7th position are preferable.

Examples of the substituent X include an acetyl group and a lower alkoxycarbonyl group.

The 2-hydroxy-3-(4
-Phenylpiperazinyl) propoxybenzofuran derivatives are pharmaceutically acceptable salts of mineral or organic acids, such as hydrochlorides, sulfates, nitrates, acetates, oxalates, tartrates, citrates, Examples include lactate.

Furthermore, since the 2-hydroxy-3-(4-phenylpiperazinyl)propoxybenzofuran derivative of the present invention has one asymmetric carbon atom, the compound of the present invention can be used as a compound of each optically active form and a mixture of each optically active form. All-encompassing.

Compound (1) of the present invention is produced by the first and second methods shown below.

(First method) H (wherein, This is a method for producing the target compound (1).

The reaction is usually carried out in an organic solvent by reacting Compound I with an equimolar amount to 1.5 times the molar amount of Compound I. When Compound I is used in the form of an acid addition salt in the above reaction, an equimolar amount to 1.5 times the molar amount of a base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, etc. and added to the reaction system. Examples of organic solvents used include methanol, ethanol, 2-
BuOpanol, acetonitrile, tetrahydrofuran,
Examples include dioxane, dimethoxyethane, and dimethylformamide.

The reaction temperature and reaction time are not particularly limited, and it is sufficient to carry out the reaction usually at a temperature of about room temperature to about 100°C for about 15 minutes to about 10 hours.

Isolation and purification of the target compound (I) can be carried out by conventional treatment methods such as extraction with a solvent, separation by chromatography,
This may be done by crystallization or the like.

2,3-epoxypropoxybenzofuran derivative ([1
When X is a lower alkoxycarbonyl group,
This is a new compound that has not been described in any literature (when x is an acetyl group: see Japanese Patent Publication No. 50-20063).

A novel 2.3-epoxypropoxybenzofuran derivative (If) is a hydroxybenzofuran derivative (3) represented by the general formula If required, it can be obtained by heating and refluxing in the presence of a suitable catalyst (for example, piperidine hydrochloride, piperidine, or trifluoride).

(Second method) H (I) (wherein, This is a method for producing the target compound (Il), which is characterized by condensation.

The reaction is usually carried out in an organic solvent by reacting compound N in an equimolar amount to 1.5 times molar amount. When compound (2) is used in the form of an acid addition salt in the above reaction, an equimolar amount to 1.5 times the molar amount of a base, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, trimethylamine, Add triethylamine etc. to the reaction system. As for the reaction means itself, for example, a reaction means such as heating and reacting Compound (1) and Compound (1) using any organic solvent in a sealed tube, or heating and refluxing using any organic solvent is employed. Examples of organic solvents that can be used include ethanol, propatool, 2-propanol, butanol, 2-butanol, acetonitrile, tetrahydrofuran, dioxane, dimethoxyethane, and dimethylformamide.

Further, the reaction temperature and reaction time are not particularly limited, and it is sufficient to carry out the reaction usually at a temperature of about 50 to 150°C for about 30 minutes to 15 hours.

In the reaction, the target compound (I) is produced in the form of a hydrochloride. This salt may be isolated as is, or may be treated with sodium hydroxide, potassium hydroxide, etc. and isolated in the form of a free base.

Isolation and purification of the target compound (1) can be carried out by conventional treatment means, such as extraction with a solvent, separation by chromatography,
This may be done by crystallization or the like.

3-chloro0 used as starting material in the above reaction
In the -2-hydroxy-propoxybenzofuran derivative column, when X is a lower alkoxycarbonyl group, it is a new compound that has not been described in the literature (when X is an acetyl group: see Japanese Patent Publication No. 50-20062). reference).

The novel 3-chloro-2-hydroxy-propoxybenzofuran derivative (1) is obtained by shaking a chloroform solution of the 2,3-epoxypropoxybenzofuran derivative [11] obtained by the first method with concentrated hydrochloric acid at room temperature for 30 minutes to 1 hour. It can be obtained by doing.

[Effect of the invention] Compound (I) of the present invention has excellent α-blocking action (test example (
1)) and Ca antagonism (see Test Example (2)), and has excellent antihypertensive activity (see Test Example (2)) that does not cause an increase in heart rate in mammals, that is, does not cause tachycardia when lowering blood pressure. (See Test Example (3)). Therefore, the compound (I) of the present invention can be used as an excellent antihypertensive agent with few side effects.

Furthermore, the compound (I) of the present invention is effective as a therapeutic agent for angina pectoris, an agent for improving peripheral circulation, and an agent for improving cerebral circulation.

[Industrial Applicability of the Invention] When the compound (1) of the present invention is used clinically, it is usually administered intravenously or orally as a free base or as an addition salt with the above-mentioned pharmaceutically acceptable licoric acid. . The dosage for adults is 0.1-5011g/dose for intravenous injection.
10-200mM for oral administration in divided doses several times a day
It is appropriate to divide the treatment into 1 to 3 times a day.

Next, the present invention will be explained with reference to Examples and Test Examples, but the present invention is not limited to these.

Among the symbols indicating the physicochemical properties of the products in the examples, m
p means melting point, Ana I means elemental analysis value, IR means infrared absorption spectrum, NHR means nuclear magnetic resonance spectrum, and 88 means mass spectrum.

The solvent listed after the crystal form indicates the recrystallization solvent.

(Example 1a) [Production of 2-acetyl-5-(2-hydroxy-3-[4-(2-methylphenyl)piperazinyl]benzofuran and its salts by the first method) 2-acetyl-5-(
1.2 g of 2,3-epoxypropoxy)benzofuran was dissolved in dioxane 5I11, then 1.1 g of 1-(2-methylphenyl)piperazine hydrochloride was added, and the mixture was heated under reflux for 1.5 hours. After repulsion, the solvent was distilled off under reduced pressure, and the resulting concentrated residue was crystallized from ethyl acetate.

Yield: 1.39 (60%) Peng p: 125-126'p (pale yellow crystalline powder)
Anal: Actual value as C24H28N 204 (
Goods): C70,33, H6,99, N 6.59 Calculated value diagram: C70,5B, H6,91, N 6.86N
OR6 (CD (J3): 2.15 (3N, S)
, 2,42 (3H, s), 2.49-2,85 (10H, m), 3.73-4.00 (3H, m),
6.45 ~ 7,06 (8H, Ml) 83 l/e: 408 (M”), 268
, 219, 189, 131 g of the free base thus obtained.
was heated and dissolved in 10 d of ethanol, and an equal amount of concentrated hydrochloric acid was added while hot. The solvent was then distilled off under reduced pressure, and the resulting residue was crystallized from ethanol and ether.

Yield: 1.1g (83%) IP: 207-210°C (pale yellow crystalline powder) IR
ν"rts-': 320G ~3600.2200
~280G, ax H3l/e: 408 (M”), 189.176 (
Example 1b) [Production of 2-7cetyl-5-(2-hydroxy-3-[4-(2-methylphenyl)verazinyl]propoxy)benzofuran and its salts by second method] 2-acetyl-5-( 1.3 g of 3-chloro-2-hydroxypropoxy)benzofuran and 1.1 g of 1-(2-methylphenyl)piperazine were added to 10 #ti of dioxane!
The mixture was dissolved in water and heated under reflux for 6 hours. After the reaction, a 2N aqueous sodium hydroxide solution was added to convert the target product into a free base, and then
Extracted with chloroform. The mixture was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was crystallized from ethyl acetate.

Yield: 1.5g (73%) The physicochemical properties were the same as in Example 1a.

(Example 2a) [2-ethoxycarbonyl-5-(2-
Production of hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propoxy)benzofuran and its salt] 1.3 g of 5-(2,3-epoxypropoxy)-2-ethoxycarbonylbenzofuran and 1-(2-methoxy) Example 1a except that 1.0 g of phenyl)piperazine was used.
The reaction was carried out in the same manner. The obtained concentrated residue was purified by silica gel column chromatography (elution solvent: methylene chloride).

Yield: 1.9 g (88%) Colorless oil Anal: Actual value as C25H3ON 204 (
): C70,81, H7,23, N 6.35 Calculated value diagram: C71,06, H7,16, H6,63IR series
“tax-”: 3450.1120m&X NHRδ(CDCl3): 1.34(3)1
, t, J=7H2), 2.30-3.05 (1081
m), 3.61 (3N, S), 3,68~4.00 (3N
, n+), 4.14 (2H, Q, J-7Hz), 6.
30-7.05 (8H.

m) H8l/e: 454 (M”), 205.190 2.4 g of the free base thus obtained was mixed with 20 Id of ethanol.
While hot, an equal amount of concentrated hydrochloric acid was added.

Ethanol was then distilled off under reduced pressure, and the resulting residue was crystallized from ethanol and a small amount of ether.

Yield: 2g (78%) 11): 197-201°C (colorless crystalline powder) IR
L/KBras-': 3150-3600.17
25nax 83 m/e: 454 (in M), 409
, 205, 190 (Example 2b) [2-ethoxycarbonyl-5-(2-
Production of hydroxy-3-[4-(2-methoxyphenyl)piperazinyl]propoxy)benzofuran] 1.3 g of 2-ethoxycarbonyl-5-(3-chloro-2-hydroxypropoxy)benzofuran and 1-(2-
The reaction was carried out in the same manner as in Example 1b, except that 1.1 g of methoxyphenyl)piperazine was used.

Yield: 1.5g (73%) The physicochemical properties were the same as in Example 2a.

(Example 3a) [2-ethoxycarbonyl-5-(2-
Production of hydroxy-3-[4-(2-methylphenyl)piperazinyl]propoxy)benzofuran and its salt] 1.3 g of 5-(2,3-epoxybroboxy]-2-ethoxycarbonylbenzofuran was added to 3 ml of ethanol. Then, a suspension mixture of 1.1 g of 1-(2-methylphenyl)piperazine hydrochloride, 0.56 g of triethylamine, and 2 d of ethanol was added, and the mixture was heated under reflux for 1.5 hours.The reaction solution was concentrated, and it was subjected to silica gel column chromatography. The product was purified by chromatography (eluting solvent: methylene chloride).

Yield: 1.5y (65%) Colorless oil Anal: Actual value as C25H3ON 203 (
B): C73,62, H7,63, ~6.77 Calculated value■: C73,86, H7,44, N 6.89IRv
”&t2-1: 3450.1720ax NHRδ(CDCl2): 1.34(3H,t
, J=7H2), 2.16 (3H, S), 2.4
0-2.85 (10H, m), 3.73-3.90 (3H, m), 4.13 (2H, Q.

J-7H2), 6.45 to 7.10 (8H, g+)
83 i/e: 438(M”), 20
5,190 2.2 g of the free base thus obtained was dissolved in 20 d of ethanol, and an equal volume of concentrated hydrochloric acid was added while hot.

Ethanol was then distilled off under reduced pressure, and the resulting residue was crystallized from ethanol and a small amount of ether.

Yield: 1.7g (71%) Temperature: 172-175°C, (colorless crystalline powder) IR
Shishias-': 3150-3600.1125H5
m/e: 438 (M"), 393,
205, 190 (Example 3b) [2-Ethoxycarbonyl-5-(2-
Production of hydroxy-3-[4-(2-methylphenyl)piperazinyl-1propoxy)benzofuran and its salt] 1.3 g of 2-ethoxycarbonyl-5-(3-chloroO-2-hydroxypropoxybenzofuran) and 1-(2-hydroxypropoxybenzofuran) The reaction was carried out in the same manner as in Example 1b, except that 1.1 g of -methoxyphenyl)piperazine was used.

Yield: i, 59-P73) The physicochemical properties were the same as in Example 3a.

(Example 4) Tablets each weighing 100 m9 were prepared according to the following formulation.

Ingredients η2-acetyl-5-(2-hydroxy-3-(4-(2-methylphenyl)piperazinyl]buOboxy)benzofuran hydrochloride 10Lactose
25 cornstarch
45 Crystalline cellulose 1
5 Methyl cellulose 3 Calcium stearate 2 (Example 5) Mixed ingredients of 1 ooIRg with 5
Capsules were prepared by filling No. 2 capsules.

Ingredients ■2-
Acetyl-5-(2-hydroxy-3-[4-(2-methylphenyl) and verazinyl]propoxy)benzofuran 10 Lactose
45 cornstarch
35 crystalline cellulose
8 Calcium stearate 2 (Example 6
) Each component was mixed according to the following recipe, a core was made using a slug machine, and then pulverized and sized. Continued Tc
- Masking with 5R (film coating agent) 2
Granules of 500q were prepared with 0 to 40 meshes.

Ingredients η2-acetyl-5-(2-hydroxy-3-[4-(2-methylphenyl)piperazinyl]propoxy)benzofuran hydrochloride 10 Lactose
355 Calcium Hydrogen Phosphate
80 crystalline cellulose
40 Calcium stearate 5Tc-58
10 (Example 7) According to the following recipe, operate in exactly the same way as for granules, change the screen at the time of grading, and apply 50 to 10G.
500q of fine granules were prepared in mesh.

Ingredients η2-acetyl-5-(2-hydroxy-3-[4-(2-methylphenyl)piperazinyl]propoxy)benzofuran hydrochloride 10 Lactose
365 Calcium Hydrogen Phosphate
80 crystalline cellulose
30 Calcium stearate 5Tc-5
810 (Example 8) 2-acetyl-5-(2-hydroxy-3-[4-(2
-Methylphenyl)piperazinyl]propoxy)benzofuran hydrochloride (1q) was dissolved in 1m of physiological saline, pH 7,
0 to prepare an injection.

(Test Example 1) [α-Adrenaline Blocking Effect] Using vas deferens specimens isolated from 6 male Wistar rats at an appropriate age, the contraction response due to noradrenaline was determined as a dose-response curve by the Magnus method, and the antagonistic effect of each test compound was determined by the 1lAz value ( The negative logarithm of the dose of antagonist required to shift the agonist dose-response curve to higher concentrations by a factor of 2). For comparison, phentolamine (
phento+am+ne), labetalol (Labetalol, which is commonly used as an a-β-adrenergic blocker)
A similar experiment was conducted for talol. The results are shown in Table 1.

(Test Example 2) [Calcium antagonism] Hartly male guinea pig (400
Using a linear blood vessel specimen extracted from the thoracic aorta of ~600 g), the contraction response due to calcium was determined as a dose-response curve by the Magnus method, and the antagonism caused by each test compound was expressed as the I) A2 value. For comparison, diltiazem (Dil), which is commonly used as a calcium antagonist,
A similar experiment was conducted for tiazel. The results are shown in Table 1.

[Margins below] (Test Example 3) [Effect on hypotensive action and heart rate in spontaneously hypertensive rats (SHR)] An experiment was conducted using SHR with a systolic blood pressure of 170 hHQ or higher. Blood pressure was measured without anesthesia using a tail artery blood pressure and heart rate recorder (PS-802) manufactured by Riken Kaihatsu, and heart rate was also measured at the same time.

The test compound was dissolved or suspended in a 5% by weight aqueous gum arabic solution and orally administered once to SHH who had fasted overnight. Blood pressure and heart rate were measured before administration, 1 hour, 3 hours, 5 hours and 7 hours after administration, and compared with the pre-administration values to determine the maximum change value.

For comparison, similar experiments were conducted with the aforementioned labetalol and diltiazem.

Regarding the dose of the test compound, 100q/Kg
The test was conducted by administering 9 to 10 μg/day. The results are shown in Table 2.

(Test Example 4) [Acute toxicity test (LD50 value)] Experiments were conducted using 66-week-old ddy male mice.

The test compound was suspended in a 5% by weight aqueous gum arabic solution, and was forcibly administered once orally using a stomach probe. Patients were continuously observed for up to 6 hours from the start of administration, and thereafter every 24 hours for 7 days, and the cumulative number of deaths up to the 7th day was calculated.

LD value is Litchfield-Wilcoxson (Litc
Calculated according to the Mield-Wilcoxon method. The results are shown in Table 3.

Table 3

Claims (1)

[Claims] 1 General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X is an acetyl group or a lower alkoxycarbonyl group, and R is a lower alkoxy group or a lower alkyl group. A group in which R is substituted at any position of the ortho, meta, and para positions with respect to the piperazinyl group. ▲ Numerical formulas, chemical formulas, tables, etc. are available. ▼ The group is substituted at the 4th and 5th positions of the benzofuran ring. , 2-hydroxy-3-(4-
phenylpiperazinyl) propoxybenzofuran derivative or its salt. 2. The derivative or salt thereof according to claim 1, wherein in the general formula (I), X is an acetyl group. 3 2-acetyl-5-{2-hydroxy-3-[4-
(2-methylphenyl)piperazinyl]propoxy}benzofuran or a salt thereof according to claim 2. 4. The derivative or salt thereof according to claim 1, wherein in the general formula (I), X is a lower alkoxycarbonyl group. 5 2-ethoxycarbonyl-5-{2-hydroxy-
4. The derivative according to claim 4, which is 3-[4-(2-methoxyphenyl)piperazinyl]propoxy}benzofuran or a salt thereof. 6 2-ethoxycarbonyl-5-{2-hydroxy-
4. The derivative according to claim 4, which is 3-[4-(2-methylphenyl)piperazinyl]propoxy}benzofuran or a salt thereof. 7 General formula (II): ▲Mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, 2,3-epoxypropoxybenzofuran derivatives represented by (substituted at any positions of 5th, 6th, and 7th positions) and general formula (III): ▲Mathematical formulas, chemical formulas, tables, etc. are available▼(III) ( In the formula, R is a lower alkoxy group or a lower alkyl group,
, wherein R is substituted at any position of the ortho, meta, and para positions with respect to the piperazinyl group) or a salt thereof. Formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) 2-hydroxy-3-(4-phenylpiperazinyl)-propoxybenzofuran represented by (in the formula, X and R are the same as above) Process for producing derivatives or their salts. 8 General formula (IV): ▲Mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, X is an acetyl group or a lower alkoxycarbonyl group, and the 3-chloro-2-hydroxypropoxy group is the 4 3-chloro-2-hydroxypropoxybenzofuran derivatives represented by the general formula (III
): ▲Mathematical formulas, chemical formulas, tables, etc.▼(III) (In the formula, R is a lower alkoxy group or a lower alkyl group, and is located at any position of ortho, meta, or para to the piperazinyl group.) N- indicated by
General formula (I) characterized by reacting with a phenylpiperazine derivative or a salt thereof: ▲There are numerical formulas, chemical formulas, tables, etc.▼(I) (wherein X and R are the same as above) 2 -Production method of hydroxy-3-(4-phenylpiperazinyl)-propoxybenzofuran derivative or salt thereof. 9 General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, X is an acetyl group or a lower alkoxycarbonyl group, R is a lower alkoxy group or a lower alkyl group, and R is substituted at any position of the ortho, meta, and para positions relative to the piperazinyl group. ▲ Numerical formulas, chemical formulas, tables, etc. are available. ▼ The groups are substituted at the 4th, 5th, 6th, and 7th positions of the benzofuran ring. 2-hydroxy-3-(4-
An antihypertensive agent containing a phenylpiperazinyl) propoxybenzofuran derivative or its salt as an active ingredient.