JPS58213770A - Novel 4,7-dimethoxybenzofuran derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to synthetic intermediates, and more particularly to benzofuran compounds useful as synthetic intermediates for pharmaceuticals and the like.

The compound of the present invention is specifically represented by the following general formula.

ct-t3 In the formula, A is a methylcarbamoyl group (-CONHCH,)
, B is a hydrogen atom (or a group -CHICC
Ht) iCL (where m is a digit of 1 or 2); when A is an acetyl group (-cocn,), the group -C'H2 (C夷') = -Ct (m is It represents an aminoethyl group or an aminopropyl group selected from the group having the above meaning; when A is a hydrogen atom, it represents an aminoethyl group or an aminopropyl group selected from the group.

All of these compounds of the present invention are useful as new synthetic intermediates for benzofuran drugs. These compounds of the present invention are specifically shown by the following structural formulas.

QC)13 OCR.

OCR.

OCR.

OCR.

00M.

The above-mentioned compounds all form a group of close compounds having 4,7-simethoxypenzofuran as the basic skeleton, and the compound represented by the following formula disclosed in French Patent No. 2178815, or the compound represented by the following formula: It can be produced using a compound represented by the following formula obtained by treatment with dilute hydrochloric acid as a starting material.

Furthermore, from the above-mentioned compounds (1) to 08), in the following formula 2, R8 and R7 both represent a methyl group or an ethyl group, or R1 and bird are combined together. Pyrrolidino group, piperidino group,
N-methylpiperazino group, hexamethyleneimino group or heptamethylene group is a monoalkylamino group (e.g.
monomethylamine, monoethylamine), dialkylamino group (eg dimethylamino) or cycloalkyleneimino group (eg piperidino).

4,7-Simethoxy-5-carbamoyl-mino-6-amizalkyloxybenzofuran can be obtained. 4 derived from compounds (1) to (18)
, 7-simethoxy-5-carbamoyl-6-aminoalkyloxybenzofuran all exhibit effects as excellent companion drugs.

The route from the above-described starting material to the final product via the intermediate of the present invention is shown as follows using a chemical structural formula.

-6: That is, the compound of the present invention can be derived from a common useful compound, and can also be produced from a common starting material (1) or [1) by addition reaction of isocyanate, alkylation reaction with a halogenated alkyl compound, dehydrochlorination reaction, etc. It can be obtained using conventional methods such as amination reaction with dilute hydrochloric acid and hydrolysis reaction with dilute hydrochloric acid, and is considered to be a group of compounds.

That is, compound (1) is prepared by adding methyl isocyanate to the starting material in chloroform! - can be produced by reacting with compounds (2) and (3
) can be obtained by reacting compound (1) with a compound represented by the general formula (where m is 1 or 2) at 90°C in an aqueous solution of 50-, or by reacting the compound (1) with a compound represented by the general formula (where m is 1 or 2) at 90°C, or by reacting the compound (1) with a compound represented by the general formula (where m is 1 or 2) at 90°C, or by (Here, m is 1 or 2) in the presence of potassium carbonate and acetone or acetonitrile by heating under reflux.

Compounds (4) and (5) can be obtained by reacting the starting material [Rei] with a compound whose general formula is represented by 2) in a 50% aqueous sodium hydroxide solution, or by reacting the compound whose general formula is BrCH1 (C
It can be obtained by reacting a compound represented by Ht4XVCt (where m is 1 or 2) in acetone or acetonitrile in the presence of potassium carbonate.

Compounds (6) to (14) are the thus obtained compounds (
4) Represents a methyl group or an ethyl group, or a group -
An amine represented by pyrrolidino, piperidino, hexamethyleneimino, heptamethyleneimino, 4-methylpyridino or N-methylpiperazino group, where N<7, can be obtained by reacting it in an autoclave using toluene as a solvent.

Compounds 05) to 08) are the compounds (6) thus obtained.
) to 04) by reacting dilute hydrochloric acid with the corresponding compound.

To the intermediate compound of the present invention obtained as described above and R
2 is as defined above) in an autoclave at 100-110°C using toluene as a solvent; and from intermediate 00-0, methyl isocyanate of,
By reacting in an autoclave with toluene/ as a solvent, or by reacting with dimethyl-2-carbamoyl chloride (ctcoNgcl(s)) in toluene at room temperature, the following formula; In, R1, a, and m each have the above-mentioned meaning.

The final product shown is derived. Other intermediate compounds (1) + (4) to 0 of the present invention are all the above-mentioned intermediate compounds (2) + (3) + (15) to
08), and since the final product mentioned above is a compound useful as a medicine, as shown in the test example below, these are also useful intermediates. You can say that.

The intermediate compounds (1) to 08) of the present invention are not limited to the above-mentioned final products, but also intermediates leading to various other useful compounds, as shown in the following synthesis examples, examples, and test examples. Needless to say, it is useful for the body.

Hereinafter, the present invention will be explained in more detail by showing Examples, Synthesis Examples, and Test Examples.

Example 1 20.9 F (0.1 mol) of 5-amino-4,7-dimethoxy-6-hydroxypenzofuran was dissolved in 20
5.7F (0.1 mol) of methyl incyanate was slowly added to the chloroform solution of 0-.

Stirred for 2 hours at room temperature, then the solvent was evaporated and the residue was crystallized from ether and filtered. 239 target compounds were obtained.

Yield: 89% Melting point: 110°C Specific formula: C1@H14N20B Example 2 C5-(N-methylcarbamoylamino)pene group Compound of 150f (0.56 mol) obtained in Example 1, 100d( A mixture of 1.2 mol) of 2-chloro-1-bromoethane and 207F (1.5 mol) of potassium carbonate was heated under reflux in 1.4 liters of acetonitrile for 4.5 hours.

This was filtered while heating, cooled, and the resulting precipitate was treated with F. 1151 of the desired product was obtained.

Yield rate; 62 chi Melting point: 14B℃ Expressive formula: C,, H,, CtN, o.

Synthesis Example 1 4.7- shi) ) #shi 6-(shiyuho otsumiku jiku I
Synthesis of benzofuran (code number: 770576) 1 1.5 t (0,035 mol) of 6 -(2-chloroethoxy)-4,7-simethoxy5
-(N-methylcarbamoylamino)benzofuran, 8
．． 21 (0.14 mol) of isopropylamine, 7.5
9 (0,05 mol) of sodium iodide and 48F (0,
A solution of 035 mol) of potassium carbonate in 200 ml of toluene was heated under reflux in an autoclave for 15 hours. Filter this. The filtrate was evaporated and recrystallized from ethyl acetate. 2.22 target compounds were obtained.

Yield: 18% Melting point: 140°C Specification formula: C+t)izsNsOs Synthesis Example 2 4 of 12t (+), 045 mol) obtained in Example 1
．． 7-Simethoxy5-(N-methylcarbamoylamino)-6-hydroxybenzofuran, 12r(0,06
A solution of 2-diisopropylamino-1-chloroethane hydrochloride (mol) and 21t (0.15 mol) of potassium carbonate in 100 g of acetonitrile was heated under reflux for 4 hours. This was filtered, the P liquid was evaporated, and the residue was recrystallized from a 50:50 mixture of ethyl acetate and isopropyl ether. The target compound 13.5f was obtained.

Yield: 77% Melting point -142°C Specification formula: Cgo Hsl'a'a Elemental analysis value Example 3 25.1F (0.1 mol) of 5-acetamide-4,7-
A solution of dimethoxy-6-piperidinoethoxybenzofuran was heated under reflux in 200-2N-HCt for 10 hours. It was then neutralized with concentrated caustic soda, extracted with ethyl acetate, the solvent was evaporated and the residue was taken up in acetone and 30-7N-HCt.ethanol was added. This was filtered and recrystallized from ethanol to obtain the desired product as a dihydrochloride.

Yield: 43% Melting point: 203°C Specific formula: CI? "!11 C10N104 Synthesis Example 3 16F (0.05 mol) obtained in Example 3 above and 5-amino-4,7-dimethoxy-6-biperidinoethoxybenzofuran and 3.2 td (0.055 mol) The mixture of methyl isocyanate was placed in an autoclave and heated to 500-
of toluene at 80-90°C for 3 hours. The solvent was evaporated and the resulting oil was crystallized from petroleum ether and recrystallized from isopropyl ether.

Yield: 37% Melting point: 120°C Specification formula: C1, Temperature ff Nl 05 Elemental analysis value Synthesis of Synthesis Example 4 4°7-Simethoxy of 8,5F (0,023 mol) obtained in Synthesis Example 3 above 5-(N-methylcarbamoylamino)-6-(2-piperidinoethoxy)benzofuran and 9
．． 1f (0.09 mol) of N-methylpiperazine in 10
A solution of 0- in toluene was heated under reflux for 20 hours. The solvent was evaporated, the residue was taken up in ethyl acetate, washed with water, the solvent was evaporated and the residue was crystallized from ether and recrystallized from ethyl acetate.

Yield: 25% Melting point: 138°C Specific formula: C,, H,, N, 0° Synthesis Example 5 2) First step of synthesis 4.7-Cynotoxy5-(N-methylcarbamoylamino)-6 -(1-piperidinocarbonylethoxy)0
4 of 1 3.3 F (0.05 mol) obtained in benzofuran Example 1
,7-Simethoxy5-(N-methylcarbamoylamino)-6-hydroxybenzofuran and 12F (0,0
68 moA, ) (7) A solution of 1-chloro-piperidinocarbonylethane and 1a,5r (o, i mole) of potassium carbonate in 120-acetonitrile was heated under reflux for 6 hours. This was then subjected to Fm, the p solution was evaporated and the residue was taken up in chloroform and filtered through a silica column. 8.5j'' (0.02 mol) of the target compound was obtained. The yield was 41%.

Second step 4.7-Simethoxy5-(N-methylcarbamoylamino)-6-(2-piperidino-1-methylethoxy)
Benzofuran The compound obtained in the above step was dissolved in 50-Tetrahydrofuran and the resulting solution was slowly added to a suspension of 2.3 t of lithium aluminum hydride in 100-Tetrahydrofuran 7 run. This was heated under reflux for 4 hours. Then, the hydrolyzed and filtered liquid F was evaporated,
The residue was chromatographed using a silica column.

Elution was performed using chloroform to obtain the target compound 5f. This was recrystallized from a mixture of 20 ethyl thiacetate and 80% isopropyl ether.

Yield: 50% Melting point: 147°C Specification formula: C1oH2,N, 0° Elemental analysis Example 4 25.1f (0.1 mol) of 5-acetamide-4,7-
Dimethoxy-6-hydroxybenzofuran and 22.2f
((1,15 mol) of 2-piperidinochloroethane and 4
A solution of 1.6 f (0.3 mol) of potassium carbonate dissolved in 250 molar acetone was heated under reflux for 2 hours. It was then filtered, the solvent was evaporated, the resulting residue was taken up in acetone and a 20-7 N-klct ethanol solution was added. This was filtered and recrystallized from 400-propateol to obtain the target compound as a hydrochloride.

Yield: 33% Melting point: 260°C Specific formula: C,,H,7CtN, 0°Example 5 5 of 25.1F (0.1 mol) produced in Example 4 above
-acetamido-4,7-simethoxy(2-piperidinoethoxy)benzofuran in 200-2N-KCl
The solution was heated under reflux for 10 hours. It was then neutralized with concentrated caustic soda, extracted with ethyl acetate, the solvent was evaporated, the residue was taken up again in acetate/and 30 ml of 7N KCl were added.

This was filtered and recrystallized from ethanol to obtain the target compound as a dihydrochloride.

Yield: 43% Melting point: 203 with formula "I?" 26C4N204 Elemental analysis value Synthesis example 6 5- of 16f (0.05 mol) produced in Example 5 above
Amino-4,7-simethoxy-6-(2-piperidinoethoxy)benzofuran and 3.2-(0,055 mol) methyl incyanate were heated to 80-90°C in 500-g of toluene for 3 hours in an autoclave. Heated. The solvent was evaporated, and the resulting nine oils were crystallized from petroleum ether and recrystallized from ethanol containing propatool.

Yield: 37% Melting point: 120°C Specific formula 200'27Ns Os Elemental analysis value Example 6 25.1? (0.1 mol) of 5-7 cetamide 4.7-
dimethoxy-6-hydroxybenzofuran to 15-5
An aqueous solution dissolved in an aqueous sodium hydroxide solution was heated to 90°C, and 21F (0.1 mol) of 2-chloroethanol tosylate was slowly added.

This was kept at 90℃ for 2 hours, diluted with 1 ton of water, and then
Recrystallized from ethanol.

Yield: 37% Melting point: 180 tl: Specific formula: C14)l111C6NOs Elemental analysis value Example 7 15.5 f (0.05 mol) produced in Example 6
5-acetami')'-6-(2-chloroethogycy)-
4,7-Simethoxypenzofuran and 15f (0.15 mol) of N-methylbiperazine were heated under reflux in 100-g of toluene for 8 hours. This was filtered, the V solution was evaporated under reduced pressure, the residue was taken up in alcohol, and hydrochloric acid alcohol was added. This was treated with F and recrystallized from absolute alcohol to obtain the target compound as a dihydrochloride hydrate.

Yield: 55% Melting point: 160°C Specific formula: C+5)12°C4N5o, +9/4
Synthesis of H,0 Example 8 According to the method of Example 2 and using the corresponding reagents, 6-(
3-chloropropoxy)-4,7-simethoxy5-(
, N-methylcarbamoylamino)benzofuran was obtained. The obtained compound had the following properties.

Melting point = 162℃ Significant formula "Cl1H1ll"N2N20SN spectrum (δp p m -DMSO) 7.92 and ?
, 03, d, (J=3Hs), 2 Pe/
Schifuran ring proton: 7.111"1 1 urea proton -CO-N (-CHa): 5.
98, d, (J = 5 Hz).

1 urea proton: -N-CO-NH (-C)
;3.85 and 3.96. s, 6 protons (2CH
, 0-): 3.92 (center) , m, 4 proto7
:-0-CH2-+-CH,-Ct: 2.10 (center), III, 2 protons: proton knee N-C)
f.

Synthesis Example 7 By the method of Synthesis Example 1 and using the corresponding reagents, code numbers 770602.770577 and '1705'18 were synthesized.
, and other compounds were obtained. These are shown in Table 1.

Synthesis Example 8 According to the method of Synthesis Example 2, a compound of code number 750819 was obtained using the corresponding reagent. These compounds are shown in Table 1.

Examples 9 to 15 Compounds (7), (8), (9), (
tt), (12).

(10), (13) (code number, 7 respectively)
50725°750761, 750762. 760
886. 760887. 750732 and 7701
'll compound) was obtained.

Examples 16-18 Compound (15) (code number Nia 60618) and compound (17) were prepared by the method of Example 5 using the corresponding reagents.
) (code number: 771275) and compound (18
) (code number: 781407) was obtained. The properties of the obtained compounds (16), (17) and compound (18) were as follows.

Compound (16): Melting point: 62°C Yield: z100 Characteristic formula: C1? H26NS'% Elemental analysis formula C,6N(2,C1,N20.; Molecular weight:
379.28: NMRy, vector (CDC4):
δPPm=6.82. d and? , 55, d (J=
3Hz), 2 hensifuran ring protons; 4
．． 41. m,-Nu! ; 3.95. a and 4.08.
a+ 20CHs: 4.20- and 2.80. L
Compound (18): Formula CI? H3N204; Oily substance; NMR spectrum (cncz3): δPPm=6.78; d
and 7.51, d (J=3Hz), 2 nohenzo75:/monkey protons: 3. '95, s and 4.50, a, -0CR,: 4.02°7/
\, and 2.68. t (J=7Hz), L)-C
B, cH, -N; Example 19 According to the method of Example 6, 5-acetamido-6-(2-chloropropoxy)-4,7-simethoxypenzofuran (compound (5) + Code number 7
80480) was obtained. The properties of this compound were as follows.

Expressive formula: C,,H,,C1N0. :Melting point: 100
°C; NMR spectrum (CDCt, ), Jppm=7.
52. d and 0:6.82, d (J=3 Hz
), 2 benzofuran jJ Bro) 7 : 7
．． 50. m, Np-C0: 3.95.1 and 4.0
5, IS.

2C) 130? 4.08, and 3.71,
t (J=7Hz).

,〆\, , /\, 0-CH,C1(,-C1: 2.08, m (J
=7Hx), OC enemy C1: 2-08 + a,
C Lou CO.

Next, compounds derived from the intermediates of the present invention (Synthesis Examples 1 to
Antiarrhythmia experiments were conducted on the compound obtained by 8) using experimental animals.

Test Example 1 Overdosing of Ouabain (30~
/Kgi,v,'l could be suppressed for more than 30 minutes by administration of the compound derived from the intermediate of the present invention.

Together with the results of the compounds of the present invention, compounds with known antiarrhythmic effects (ajimalin, quinidine, brocainamide, diisopyramide, amiodarone)
a, quinidine, proeainamid
s, diiao-pyramide, amidar
Table 3 shows the results using one). Each compound was injected intravenously 30 minutes after stabilization of the arrhythmia.

Test Example 2 A compound derived from the intermediate of the present invention was administered to a dog that had developed polymorphos arrhythmia 24 hours after its coronary artery was ligated by the Harris method to restore normal heartbeat.

Table 4 shows the results obtained using the compounds of the present invention as well as those using known antiarrhythmic agents (azimaline, quinidine, procainamide, diisoviramide, amiodarone).

Each compound was administered by intravenous injection or buccal administration via food.

From the results shown in Tables 4 and 5, it is clear that there is a sufficient difference between the therapeutically effective dose and the lethal dose, and the compounds derived from the intermediates of the present invention can be used as medicines.

It is clear that many of the compounds derived from the intermediates of the present invention have antiarrhythmic effects equivalent to or greater than those of reference compounds.

Compounds derived from the intermediates of the present invention are administered against tachycardia and heart rhythm irregularities.

Tablets and tablets containing active ingredients 1 to 2001q.

It may be administered orally (2 to 6 times a day) in the form of a capsule, or it may be administered subcutaneously, intravenously, or intramuscularly (1 to 4 times a day) in the form of an injection solution containing 5 to 100 wg of the active ingredient. ) may be performed.

Continuation of page 1 Priority claim 07/12/1976 ■ France (FR
)■76 21287

Claims (1)

[Claims] The following formula: In the formula, when A is a methylcarbamoyl group, B is a hydrogen atom or a group -CHI''-ct (herein, m
is 1 or 2); A represents an acetyl group;
When A is a hydrogen atom, it represents a BU group.