JPS5951547B2 - benzofuran derivatives - Google Patents

Description

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

The compound of the present invention has the general formula RHC□CH2■HCH2NHR1(I) (wherein R is a hydrogen atom, a lower alkyl group or a phenyl group, R1 is a lower alkyl group, and the substituted proboxyl group is 3, 4, , substituted at any position of 5, 6 or 7) and acid addition salts thereof.

The lower turkyl group contained in R in the general formula 1 is a group having 1 to 4 carbon atoms such as methyl, ethyl, n-procell, isopropyl, n-butyl, isobutyl, sec-butyl, etc.
straight-chain or branched alkyl groups.

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 tert-butyl, particularly those having 3 to 4 carbon atoms. 4 branched alkyls. ν
Groups are preferred. Examples of acid addition salts include inorganic acid salts such as hydrochloride, sulfate, and nitrate, and organic acid salts such as acetate, oxalate, succinate, and malate.

The compounds of the present invention exhibit adrenergic β-receptor blocking activity, and are less toxic than known compounds that exhibit this activity, and are useful as preventive and therapeutic agents for heart diseases such as arrhythmia and angina pectoris, and hypertension. It is. The benzofuran derivative 1 of the present invention has the general formula (wherein R' is a lower alkyl group, a lower alkoxy group, or a phenyl group, R1 represents the same as described above, and the monosubstituted propoxy group is the 3-substituted propoxy group of the benzofuran ring. , 4, 5
．． , substituted at any position of 6 or 7) or an acid addition salt thereof.

The lower alkyl group included in R in the general formula () is methyl, ethyl, n-propyl, itpropyl, n-
Number of carbon atoms such as butyl, isobutyl, Sec-butyl, etc.
Four straight-chain or branched alkyl groups are mentioned, and lower alkoxy groups include methoxy, ethoxy, proboxy, isoproboxy, n-butoxy, and isobutoxySe.
Examples include c-butoxy and tert-butoxy.
Examples of the acid addition salts of the benzofuran derivative () include those similar to those for the benzofuran derivative (I). The reduction reaction is suitably carried out using a conventional reducing agent under conventional reducing conditions. For example, the following reduction method is suitable. (1) A method using lithium aluminum hydride, sodium borohydride, diporan, etc. as a reducing agent. As a reaction solvent, methanol, ethanol, dioxane, tetrahydrofuran, or a mixed solvent thereof is usually used. (2) A method using a metal or metal alkoxide as a reducing agent.

In particular, aluminum ethoxide, aluminum isopropoxide, and aluminum tert-butoxide are preferably used, and alcohols or hydrocarbons are used as the reaction solvent. (3) Catalytic reduction method.

As the catalyst, any of the usual catalytic reduction catalysts such as Raney nickel and palladium on carbon can be used, and either normal pressure or pressurized pressure can be used. As the reaction solvent, methanol, ethanol, dioxane-tetrahydrofuran, 9-cyclohexane, water, and a mixed solvent thereof are usually used. (
4) As a reducing agent, an enzyme (aromatic aldehyde ketone reductase) that is widely distributed in the liver, kidney, blood, intestinal tract, etc. of rabbits, hamsters, mice, rats, etc. is used, and reduction is performed under appropriate pH and temperature conditions. Method.

Note that the above reduction reaction also occurs when the benzofuran derivative (rho alkali aqueous solution is allowed to stand).

In the reduction reaction, R' of the benzofuran derivative
When R is a lower alkyl group and a phenyl group, a benzofuran derivative (I) in which R is a corresponding lower alkyl group and a phenyl group is obtained, and when R' is a lower alkoxy group, a benzofuran derivative (I) in which R is a hydrogen atom is obtained. I) can be obtained. The obtained benzofuran derivative (I) can be converted into an acid addition salt according to a conventional method, for example, by reacting with the corresponding acid in a suitable organic solvent.

Since there are 1 to 4 asymmetric carbon atoms in the compounds of the invention and stereoisomers exist, the invention relates to the individual stereoisomers and mixtures thereof. Penzofuran derivatives used as starting materials in the present invention (
), for example, by the method described in Japanese Patent Publication No. 50-2σ0'63, that is, the general formula (wherein R' represents the same as above, and the hydroxyl group is 3,4,5,
A benzofuran derivative (substituted at any position of 6 or 7) is reacted with epichlorohydrin to obtain a general formula (wherein R' represents the same as above, and 2,3 - The epoxypropoxy group is substituted at any position of the 3, 4, 5, 6 or 7 position of the benzofuran ring).
2NR} (in the formula, R1 represents the same thing as above).

Both the benzofuran derivative (1) and its acid addition salt of the present invention are new compounds, have excellent pharmacological effects, and are useful as medicines.

For example, these compounds not only improve the electrocardiogram in hypoxia or isoprotenol loading, but also suppress the isoprotenol-induced increases in contractile force and heart rate and the drop in blood pressure, thus reducing 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 compounds also have known adrenergic β
It is less toxic than single receptor blockers. The compounds of the present invention exhibit their excellent medicinal efficacy when administered in doses of about 10 to 200 doses per day.

The administration method may be oral, subcutaneous injection, or intravenous injection. The compounds of the present invention can be formulated into capsules, tablets, granules, and injections by conventional methods using carriers commonly used in formulations.

Next, the present invention will be explained with reference to Examples and Test Examples.

Example 1 [2-(1-Hydroxy)ethyl 2-hydroxy-3-Sec-butylamino)propoxybenzofuran]2-acetyl-3-Sec-
Butylamino) propoxybenzofuran 0.61f! was dissolved in a mixture of dioxane 20a and water 2 ml, and 0.059 ml of sodium borohydride was added under ice cooling, followed by stirring at room temperature for 1 hour.

The obtained reaction solution was poured into ice water 100a, which was extracted with ethyl acetate while salting out.The organic layer was dehydrated over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from benzene/petroleum ether (3:2 volume ratio) to yield 0.549 g of a white powdery compound with a melting point of 88-90°C.
Elemental analysis values, infrared absorption spectra, thin layer chromatograms (Rf values) and NMR spectra (δ values) of the obtained compound were measured to determine whether the compound was 2-(1-hydroxy)ethyl-2-hydroxy- 3-Se′c
-butylamino)propoxybenzofuran.

Note that the Rf value is determined using Kiesel Gel H manufactured by Talc as a carrier.
This is the value when F254 is used and developed with benzene triethanol: 28% aqueous ammonia = 6:4:0.3 (
Same below). Also, the δ value is 100MH in deuterochloroform.
This is the value measured at z (the same applies below). Below are elemental analysis values, characteristic infrared absorption spectrum (unit: Cfn-1), R
The f value and δ value are shown. Note that the numbers in brackets after the δ value represent the number of protons and the multiplicity (the same applies below). Elemental analysis value: Cl7H25O4N Theoretical value (to): C66.42H8.2ON4.56 Actual value %: C66.7lH8.3ON432 Characteristic infrared absorption spectrum: ν0H3375,3325 νNH325O νC=Cl627,l62O,l589. Rf value: 0.41 δ value: 0.92 (3H, t), 1.11 (3H, d), 1.5
0 (2H, q), 1.65 (3H, d), 2.50-3
．． 20 (6H, m), 4.20 (3H, m), 5.06
(1H, q), 6.64 (1H, S), 6.80-7.
40(3H,m) Example 2 [2-(1-Hydroxy)ethyl-Jyo-i2-hydroxy-3-Tert-butylamino)propoxybenzofuran]2-acetyl-Jyo-i2-hydroxy-3-Te
rt-butylamino)propoxybenzofuran 0.61
9 with 20ml of dioxane and 22ml of water! ! L! , and added 0.059 g of sodium borohydride under ice cooling, followed by stirring at room temperature for 1 hour.

The obtained reaction solution was treated in the same manner as in Example 1, and the obtained residue was recrystallized from benzene to obtain 0.499% of a white powdery compound with a melting point of 126-127°C. Elemental analysis value: Cl
Theoretical value 2 as 7H2, O4N: C66.42H8.2
ON4.56 Actual value O: C66.28H8.37N4.
6l characteristic infrared absorption spectrum: ν0H3375 νNH32OO νC=Cl635,l6O5,l595Rf value: 0.33 δ value: 1.14 (9H,S), 1.63 (3H,d), 2
．． 60-3.20 (5H, m), 4.19 (3H,
m), 5.04 (IH, q), 6.62 (IH, S)
, 6.80-7.50 (3H, m) Example 3 [2-
(1-Hydroxy)ethyl-Jyo-i2-Hydroxy-3
-isopropylamino)propoxybenzofuran]2-
Acetyl-7-(2-hydroxy-3-isopropylamino)propoxybenzofuran 0.589 to dioxane 201n1! The mixture was dissolved in a mixture of 2" and 2" of water, and 0.059% of sodium borohydride was added under ice cooling, followed by stirring at room temperature for 1 hour.

The obtained reaction solution was treated in the same manner as in Example 1, and the obtained residue was recrystallized from benzene-petroleum ether (1:1 volume ratio) to obtain a white powdery compound with a melting point of 77-81°C.
I got 539. Elemental analysis value: C, 6H23O4N Theoretical value %: C65.5lH7.9ON4.78 Actual value%
:C65.43H7.94N4.83 Characteristic infrared absorption spectrum: ν0H3375 νNH335O νC=Cl627,l6OO,l589Rf value: 0.25 δ value: 1.06 (6H, d), 1.58 (3H, d), 2
．． 60-3.00 (3H, m), 3.43 (3H, S)
, 3.90-4.30 (3H, m), 4.98 (IH,
S), 6.67 (IH, S), 6.75-7.15 (
3H,m) Example 4 [2-(1-hydroxy)ethyl-7-(2
-Hydroxy-3-isopropylamino)propoxybenzofurano hydrochloride] 0.1 g of 2-(1-hydroxy)ethyl-7-(2-hydroxy-3-isopropylamino)propoxybenzofuran obtained in Example 3 was added to 10 g of ethyl ether. The resulting white precipitate was collected in an oven and then recrystallized from ethyl acetate to obtain colorless needle-like hydrochloride with a melting point of 83-88°C.
Got 089.

Example 5 [2-(1-hydroxy)ethyl-7-(2
-hydroxy-3-isopropylamino)propoxybenzofuran acetate] 2-(1-hydroxy)ethyl-7-(2-hydroxy-3 obtained in Example 3)
-isopropylamino)propoxybenzofuran 0.7
59 to ethyl acetate 20! ! Dissolve in Le, add 2 acetic acid to this
Add 0.0mfi and 10g of ether and leave in a cool place overnight to dissolve 0.89% of colorless needle-like acetate with a melting point of 104-107°C.
I got it.

Example 6 [2-(1-hydroxy)ethyl-4
-(2-hydroxy-3-isopropylamino)propoxybenzofuran]2-acetyl-4-(2
-Hydroxy-3-isopropylamino)propoxybenzofuran 0.589 is dissolved in a mixture of 20 g of dioxane and 2" of water and 0.0 g of sodium borohydride is dissolved under ice-cooling.
59 was added thereto, and the mixture was stirred at room temperature for 1 hour.

The obtained reaction solution was treated in the same manner as in Example 1, and the obtained residue was recrystallized from ether-petroleum ether (1:1 volume ratio) to obtain a white powdery compound with a melting point of 64-66°C.
I got 319. Elemental analysis value: Cl6H23O3N Theoretical value W: C65.5lH7.9ON4.78 Actual value O
:C65.73H7.9lN4.59 Characteristic infrared absorption spectrum: ν0H3350 νNH328O νC=Cl6O9,l595R f value: 0.27 δ value: 1.26 ( 6H, d), 1.73 ( 3H, d), 2
．． 50-3.20 (6H, m), 4.00-4.20 (
3H, m), 5.04 (IH, q), 6.64 (IH,
dd), 6.68 (IH, S), 7.1-7.4 (2H
, m) Example 7 [2-(1-hydroxy)ethyl-5-(2
monohydroxy-3-Secbutylamino)propoxybenzofuran]2-acetyl-5-(2-hydroxy-3
-Sec-butylamino)propoxybenzofuran 0.
619 was dissolved in 20a of dioxane and 2a of water, and 0.059% of sodium borohydride was added while cooling with ice, followed by stirring at room temperature for 1 hour.

The obtained reaction solution was treated in the same manner as in Example 1, and the obtained residue was recrystallized from acetone-petroleum ether (1:1 volume ratio) to obtain a white powdery compound with a melting point of 94-96°C. 4
I got 59. Elemental analysis value: Theoretical value as Cl7H25O4N: C66.42H8.2ON4.56 Actual value %: C66.78H7.98N4.49 Characteristic infrared absorption spectrum: ν0H3360 νNH328O νC=Cl6l2,l6O8R f value: 0.38 δ value : 0.99 (3H, t), 1.09 (3H, d), 1.4
7 (2H, d), 1.61 (3H, d), 2.50-3
．． 20 (6H, m), 3.90-4.20 (3H, m)
, 5.01 (1H, q), 6.57 (1H, S), 6.
86 (1H, d), 6.99 (1H, dd), 7.39
(1H, d) Example 8 [2-(1-hydroxy)ethyl-6-(2-hydroxy-3-Tert-butylamino)propoxybenzofuran]2-acetyl-6-(2-hydroxy-3-Te
rTobutylamino)propoxybenzofuran 0.61f
I was dissolved in a mixture of dioxane 20a and water 2a, and 0.059% of sodium borohydride was added under ice cooling, followed by stirring at room temperature for 1 hour.

The obtained reaction solution was treated in the same manner as in Example 1, and the obtained residue was recrystallized from benzene to give a melting point of 129 to 131°C.
0.54f of white powdery compound! I got it. Elemental analysis value: Cl, theoretical value % as H25O4N: C66.42H
8.2ON4.56 Actual value (to): C66.54H8.
l3N4.8O characteristic infrared absorption spectrum: ν0H33
25 νNH3275 νC=Cl628, l588Rf Value: 0.27 δ value: 1.16 (9H, S), 1.62 (3H, d), 2.6
0-3.00 (5H, m), 3.90-4.10 (3H
, m), 5.030H, q), 6.58 (1H, S),
6.93 (1H, dd), 7.07 (1H, d), 7.
47 (1H, d) Example 9 [2-(1-Hydroxy)Butyl-J 2-Hydroxy-3-Tert-butylamino)propoxybenzofuran]2-Butyryl-J 2-Hydroxy-3-Te
rt-butylamino)propoxybenzofuran 0.66
Dissolve g in a mixture of dioxane 201n1 and water 2a,
0.059 ml of sodium borohydride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour.

The obtained reaction solution was treated in the same manner as in Example 1 to obtain 0.43 fl of a yellow oily compound. Elemental analysis value: Cl, H2
, Theoretical value (to) as O4N: C68. O3H8.7lN4. l8 Actual value (to): C68.57H8.63N4.24 Characteristic infrared absorption spectrum: ν0H3375 νNH33OO νC=Cl622,l6O2,l59ORf value: 0.35 δ value: 0.93 (3H, t), 1.11 (9H , S), 1.4
6 (2H, m), 1.91 (2H, q), 2.75 (2
H, d), 3.70 (3H, S), 4.23 (3H, m
), 4.81 (1H, t), 6.60 (1H, S), 6
．． 75-7.40 (3H, m) Example 10 [2-(1
-Hydroxy)ethyl 2-hydroxy-3-isopropylamino)propoxybenzofuran]2-acetyl 2-hydroxy-3-isopropylamino)propoxybenzofuran 0.619 was added to the 1059 centrifuged supernatant of rabbit liver homogenate 80f1. The obtained enzyme fraction was mixed with coenzyme (NADPH) at pH 7.4 and temperature 37°C.
generation system) for 30 minutes.

The reaction was stopped by adding 2N aqueous sodium hydroxide solution, the product was extracted with ether, the solvent was distilled off, and the resulting residue was recrystallized from benzene-petroleum ether (1:1 volume ratio) to give a solution with a melting point of 77-81. A white powdery compound was obtained at 0.49 °C.

This product has the same elemental analysis value as that obtained in Example 3,
Characteristic infrared absorption spectra, Rf values and δ values are shown. Example 11 [2-(1-hydroxy)ethyl-7-(2
-Hydroxy-3-isopropylamino)propoxybenzofuran]2-acetyl-7-(2-hydroxy-3-isopropylamino)propoxybenzofuran 0.619 dissolved in 100 g of ethanol A solution of 0.059 Raney Nickel was placed in a reaction vessel. The mixture was shaken under normal pressure in a hydrogen stream for about 10 hours.

The reaction solution was filtered to remove the catalyst, and then the solvent was distilled off under reduced pressure. The resulting residue was diluted with benzene-petroleum ether (1:
1 volume ratio) to yield 0.419 of a white powdery compound with a melting point of 77-81°C. This product showed the same elemental analysis values, characteristic infrared absorption spectrum, Rf value and δ value as those obtained in Example 3. Example 12 [2-(α-hydroxy)benzyl-7-(2-
Hydroxy-3-isopropylamino)propoxybenzofuran] 0.2f1 of 2-benzoyl-7-(2-hydroxy-3-isopropylamino)propoxybenzofuran was dissolved in 20g of dioxane, and 0.029g of sodium borohydride was added under ice-cooling. The mixture was then stirred at room temperature for 1 hour.

The obtained reaction solution was treated in the same manner as in Example 1, and the obtained residue was recrystallized from acetone-petroleum ether (1:1 volume ratio) to obtain a white powdery compound with a melting point of 135-139°C. I got it. Elemental analysis value: C2lH2, O4N, theoretical value O: C7O. 96H7. O9N3.94 actual value%
:C7O. 88H7. l6N3.79 characteristic infrared absorption spectrum: ν0H3330 νNH328O νC=Cl63O,l6OO,l59ORf value: 0.39 δ value: 1.12 (6H, d), 2.70-3.20 (3H
, m), 3.40 (3H, S), 4.41 (3H, m)
,5.96(IH,S),6.40(IH,S),6
．． 60-7.60 (8H, m) Example 13 [2-hydroxymethyl-7-(2-hydroxy-3-isopropylamino)propoxybenzofuran and its acetate] 2-ethoxycarbonyl-7-(2-
Dissolve 0.619 hydroxy-3-isopropylamino)proboxybenzofuran in 301 ml of tetrahydrofuran, and add 0.05 ml of lithium aluminum hydride under ice cooling.
9 was added and then stirred at room temperature for 3 hours.

The resulting reaction solution was poured into 150 g of ice water, extracted with ethyl acetate under salting out, and the organic layer was dehydrated over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a pale yellow oily compound with 0.0%.
I got 48I. 0.489 of the obtained compound was treated in the same manner as in Example 5 to obtain 0.49 of acetate in the form of a white powder with a melting point of 144-147°C.

Elemental analysis value: Cl7H2, theoretical value % as O6N: C6O. l6H7.43N4. l3 Actual value O
:C59.87H7.2lN4.38 Example 14 [2
-(1-Hydroxy)ethyl-7-(2-hydroxy-3-isopropylamino)propoxybenzofuran]2-acetyl-7-(2-hydroxy-3-isopropylamine)propoxybenzofuran 0.619 and aluminum isopropoxide 0. 21
9 to isopropanol 30! It was dissolved in Ne and stirred with heating.

During this time, acetone produced was distilled off, and reflux was continued while dropping isopropanol as needed. When acetone was no longer distilled off, the reaction solution was poured into ice water and extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from benzene-petroleum ether (3:2 volume ratio) to give a melting point of 77~
0.51g of a white powdery compound having a temperature of 81°C was obtained. This product showed the same elemental analysis values, characteristic infrared absorption spectrum, Rf value and δ value as those obtained in Example 3. Example 15 Each compound obtained in Examples 1 to 9 and 12 to 13 was used as an active ingredient, and the active ingredient and carrier ingredient were mixed in the following proportions, and the resulting mixture was filled into capsules. I got some medicine.

Example 16 Each compound obtained in Examples 1 to 9 and 12 to 13 was used as an active ingredient, and 0.25% by weight of this was added to physiological saline.
Injections were prepared by dissolving the mixture in the following proportions:

Test Example [Experiment 1] Using anesthetized rats as test animals, the above-mentioned Examples 1 to 3 and 6 were conducted on blood pressure reduction due to isoproterenol loading.
- Compounds obtained in 9 (hereinafter referred to as compounds 1-3 and 6-
9) was investigated.

The dose of isoproterenol is 1 μf! /Kf, and the test drug was administered by intravenous injection. For comparison, a similar experiment was conducted using propranolol (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] Acute toxicity of compounds 1 to 3 and 6 to 9 (
LD5O) was investigated.

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

The healing coefficient (LD5O/ED,O) and strength ratio (relative ratio when the healing coefficient of propranol is set to 1) were determined from the ED5O (5LD50) obtained in Experiments 1 and 2 above.

Claims (1)

[Claims] 1 General formula ▲ Numerical formula, chemical formula, table, etc. benzofuran derivatives (substituted at any position of the 3rd, 4th, 5th, 6th or 7th ring) and acid addition salts thereof. 2. The compound according to claim 1, which is 2-(1-hydroxy)ethyl-7-(2-hydroxy-3-sec-butylamino)propoxybenzofuran. 3. The compound according to claim 1, which is 2-(1-hydroxy)ethyl-7-(2-hydroxy-3-tert-butylamino)propoxybenzolan. 4. The compound according to claim 1, which is 2-(1-hydroxy)ethyl-7-(2-hydroxy-3-isopropylamino)propoxybenzofuran.