JPS59206378A - Bisbenzofuranyl ketone derivative and its preparation - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R is -NHC(NH)NH2, -NHCOOCH2CH3, -OH, or -NHCSNH2; R1 is H, or SO3H; R2 is H, 1-3C lower alkyl, group shown by the formula II (m is 1-3; R3 and R3 are 1-3C lower alkyl), R1 and OR2 are replaced at any of 4-7 positions of benzofuran ring] and its salt. EXAMPLE:Bis(6-hydroxy-2-benzofuranyl) ketone guanylhydrazine. USE:An antiviral agent. Useful for colds caused by various kinds of viruses, pharyngitis, fever caused by swimming pool, pneumonia, zona, etc. PREPARATION:A bisbenzofuranyl ketone compound shown by the formula IIIis reacted through dehydration with an amino compound shown by the formula R-NH2 in a mixed solvent of methanol, ethanol, water, etc. at 25 deg.C- the reflux temperature for 30min-15hr, to give a compound shown by the formula I .

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel bisbenzofuranyl ketone derivatives, more specifically those represented by the general formula (1) [wherein R is -NHC(NH)NH2, NHCOOCH
2CH3, -OH group or -NHCSNH2, R1 is hydrogen or 503H, R2 is hydrogen, lower alkyl group having 1 to 3 carbon atoms, or formula (where m is an integer of 1 to 3, R3 and R4 are each represents a substituted aminoalkyl group represented by (represents a lower alkyl group having 1 to 3 carbon atoms), and the R1 group and OR2 group are substituted at any position of the 4, 5, 6 or 7 position of the benzobran ring] The present invention relates to bisbenzofuranyl ketone derivatives and salts thereof, and methods for producing them.

The compound of the present invention itself has antiviral activity and is useful as a medicine. Bis(6-hydroxy-2-benzofuranyl)ketone guanyl hydrazone, bis', has excellent antiviral activity.

(7-Medoxy 2-benzofuranyl) ketone guanylhydrazone, bis(6-medoxy 2-benzofuranyl) ketone guanyl hydrazone, bis(6-hydroxy-
Bisbenzofuranyl ketones such as 2-benzofuranyl) ketone thiosemicarbazone, bis(7-β-diethylaminoethoxy-2-benzofuranyl) ketone guanyl hydrazone, and bis(6-β-diethylaminoethoxy-2-benzofuranyl) ketone guanyl hydrazone. Derivatives and their salts are preferred.

The bisbenzofuranyl ketone derivative (1) of the present invention has the general formula (n) (In the formula, m is 1
represents a substituted aminoalkyl group represented by an integer of ~3, R3 and R4 each represent a lower alkyl group having 1 to 3 carbon atoms, and R1 group and OR2 group represent a substituted aminoalkyl group represented by [Substituted at any position]] is a bisbenzofuranyl ketone compound represented by the general formula (m)R-NH2(III) (wherein, R is -NHC(NH)NH2, -NHCOOC
It is easily produced by dehydration reaction with an amino compound represented by H2CH3, -01 (or -NHCSNH2).

Ethanol, methanol, water, or a mixed solution thereof is used as the solvent in the dehydration reaction, and as the catalyst, inorganic acids such as concentrated hydrochloric acid, concentrated sulfuric acid, concentrated sulfuric acid, or sodium hydroxide, potassium hydroxide, Alkali such as sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate, pyridine, etc.
It is used appropriately in a range of 1 drop to 10 equivalents. Further, the reaction temperature is set at a temperature in the range of 25° C. to reflux temperature, and the reaction time is suitably set at a time in the range of 30 minutes to 15 hours.

Starting material bisbenzofuranyl ketone compound (II
), examples of the lower alkyl group having 1 to 3 carbon atoms represented by R2 include methyl group, ethyl group, n-propyl group and isopropyl group, of which methyl group is preferred. Further, as the substituted aminoethyl alkyl group represented by R2, a β-dimethylaminoethyl group and a βi diethylaminoethyl group are particularly preferred.

In the present invention, bisbenzofuranyl ketone derivative (1
) can be changed to salt if desired, but such salts include:
Examples include addition salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid, or organic acids such as succinic acid and methanesulfonic acid, and alkali salts such as sodium salts and potassium salts. These salts can be prepared by conventional methods, for example, by reacting the bisbenzofuranyl ketone derivative (1) with a corresponding acid in a suitable organic solvent such as ethyl ether, methanol, or ethanol, or by reacting the bisbenzofuranyl ketone derivative (1) with a corresponding acid in a suitable organic solvent such as ethyl ether, methanol, or ethanol, or by reacting with sodium hydroxide or potassium hydroxide. It can be easily obtained by reacting with an alkaline aqueous solution such as

All of the bisbenzofuranyl ketone compounds (II) that are the starting materials in the present invention are new compounds, but among them, those in which R1 is hydrogen and R2 is a lower alkyl group have the general formula (IV) (in the formula, R5 represents a lower alkyl group) and salicylaldehyde (IV) and 1
, 3-dichloroacetone in a suitable solvent such as dioxane, acetone, water, etc. in the presence of a suitable deoxidizer such as sodium hydroxide, potassium hydroxide, potassium carbonate, etc. available. In addition, among the bisbenzofuranyl ketone compounds (n), those in which R1 and ]Rx are both hydrogen have the general formula ('V) obtained by the above reaction (wherein, R5 is the same as above). It can be easily obtained by dealkylating a bisbenzofuranyl ketone compound (V) represented by the following formula, in which the OR5 group is substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring.

The dealkylation reaction involves heating the bisbenzofuranyl ketone compound (V) in an appropriate solvent such as benzene, chlorobenzene, dichlorobenzene, acetic acid, methanol, or ethanol in the presence of an acid catalyst at room temperature or under reflux for several hours. This is preferably carried out by: Preferred examples of the acid catalyst used include anhydrous aluminum chloride, anhydrous tin (IV) chloride, Lewis acids such as boron trifluoride, mineral acids such as hydrochloric acid and hydrobromic acid, and pyridine hydrochloride.

Also, among the bisbenzofuranyl ketone compounds (II),
A compound in which R1 is 15O3H can be easily obtained by reacting the bisbenzofuranyl ketone compound (V) represented by the general formula (V) obtained by the above reaction with concentrated sulfuric acid.

Also, among the bisbenzofuranyl ketone compounds (II),
Those in which R1 is a substituted aminoalkyl group have the general formula (Vl) obtained by the above-mentioned dealkylation reaction (in the formula, -C11 group represents any position of the 4, 5, 6 or 7 position of the benzofuran ring). The bisbenzofuranyl ketone compound (VI) represented by the general formula (■) (wherein, X is halogen, m, R
2 and R3 have the same meanings as above) or a hydrochloride thereof.

The bisbenzofuranyl ketone derivatives (1) and their salts of the present invention are all new compounds that themselves have excellent antiviral activity and are useful as pharmaceuticals. For example, bisbenzofuranyl ketone derivatives (1) and their salts can be used to prevent various diseases caused by various viruses, such as the common cold, pharyngitis, pool fever, influenza, respiratory infections such as pneumonia, cystitis zoster, and keratitis. and therapeutically effective.

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

Reference Example 1 [Production of bis(7-medoxy 2-benzofuranyl) ketone] 3.4 g (0,022
mol) in dioxane 15IIIQ, 1 g (0,025 mol) of sodium hydroxide was added to this at room temperature with stirring, and the mixture was gradually heated and reacted at 75°C for 20 to 30 minutes.
Next, 1.3 g of 1,3-dichloroacetone (0,010
mol) was added little by little, and the mixture was further reacted at 80°C for 30 minutes. After cooling the reaction solution, 200 ml of water was added, and the resulting precipitate was collected by filtration, dried, and then recrystallized from 100 ml of ethanol to obtain bis(7-medoxy 2- benzofuranyl) ketone 1. O
I got g.

Calculated value as elemental analysis value "C1'1H1405: C7
0,80H4,38 Actual value: C71,09H4,09 Infrared absorption spectrum (Br tablet; cm-”) 31
50~2900 (νCH) ”1640 (乍C=0
) 1560.1490 (v C=0.aromati
c) 1170 (C-0) Reference Example 2 [Production of bis(6-medoxy-2-benzofuranyl)ketone] Same procedure as Reference Example 1 except that 4-methoxysalicylaldehyde was used in place of 3-methoxysalicylaldehyde. A yellowish brown crystalline bis(6-medoxy-2-benzofuranyl)ketone having a melting point of 191-193°C was obtained.

Calculated value as elemental analysis value “CIQH+40!”: C7
0,80H4,38 Actual value: C70,89H4,41 Infrared absorption spectrum (KBr tablet; cm-1) 3150
~2900 (νcH) 1615' (乍C=0) 1550.1490 (v C=O, aromati
c) 1160 (DaC-0) Reference Example 3 [Production of bis(7-hydroxy-2-benzofuranyl) ketone] 7.5 g of bis(7-medoxy-2-benzofuranyl) ketone obtained in Reference Example 1 (0, 023 mol) and 60 mm of chlorobenzene were mixed, and 9.3 g (0,069 mol) of anhydrous aluminum chloride was added little by little at room temperature while stirring. The reaction solution immediately turned into a red viscous liquid. Then, the mixture was gradually heated and reacted at 100° C. for 1 hour, and a reddish brown precipitate was deposited. After the reaction, the reaction product was poured into water and the precipitate was collected by filtration, dried, and then recrystallized from ethanol to give yellow crystalline bis(
5.7 g of 7-hydroxy-2-benzofuranyl) ketone
It was returned.

Elemental analysis value "Calculated value as c, 7u + oOr・N2.O: C65,39-H3,89 Actual measurement value: C65,17H3,94 Elemental analysis value" As CI'7HI005 (dried at 110°C for 7 hours) Calculated value: C69,39H3,43 Actual value: (1,69,51H3,21 infrared absorption spectrum (KBr tablet; am-1) 340073050
(ν0H) 3000~2950 (νCH) 1620 (YC=0) 1550.1490 (C=C, aromati
c) Reference Example 4 [Production of bis(6-hydroxy-2-benzofuranyl) ketone] Bis(6-medoxy-2-benzofuranyl) ketone obtained in Reference Example 2 was used instead of bis(7-medoxy-2-benzofuranyl) ketone. A yellow crystalline bis(6-hydroxy-2-benzofuranyl)ketone having a decomposition point of 256 to 258°C was obtained in the same manner as in Reference Example 3, except for the following procedure.

Elemental analysis value: C,7H,, Calculated value as 0Sel/2H2,O: C67,55H3,33 Actual value: C67,36H3,56 Infrared absorption spectrum (KBr tablet; am-1) 3400
~3250 (ν0H) 3100~2950 (YCH) 1625 (乍C20) 1550~1495 (V C=0', aroma
tic) 1170 (y C-0) Reference Example 5 [Production of bis(7-β-diethylaminoethoxy-2-benzofuranyl)ketone and its dihydrochloride] Reference Example 3
4.4 g (0.15 mol) of the resulting bis(7-hydroxy-2-benzofuranyl) ketone, anhydrous potassium carbonate 12
．． 4g (0,090 mol) and acetone 75m Q
After mixing and refluxing for 30 minutes, β-diethylaminoethyl chloride 4. sg (o, 033 mol) was added and the mixture was further refluxed for 3 hours. The reaction solution was cooled and filtered, and the filtrate was concentrated and the resulting oily substance was extracted with petroleum benzine. ) gained ketones.

The obtained crystals were dissolved in ethanol saturated with hydrochloric acid gas, and most of the ethanol was distilled off to precipitate crystals. Recrystallization of these crystals from ethanol yields 4.3 g of bis(7-β-diethylaminoethoxy-2-benzofuranyl)ketone dihydrochloride as pale yellow crystals with a melting point of 260-262°C (decomposition).
(yield 50.0%).

Elemental analysis value: C2 (lH3 et al. O, N2.・2HCt12
Calculated value as o: C59,69H6,91N 4.8
0 Actual value: C59,50H6,86N 4.80 Infrared absorption spectrum (KBr tablet; cm-1) 3100-29
0(1(ツCH) 2700~2400 (乍NH”) 1625 (νC=0) 1560.1495 (vc=c, aromat
ic) Reference Example 6 [Production of bis(6-β-diethylaminoethoxy-2-benzofuranyl)ketone and its dihydrochloride] Reference Example 4
The resulting bis(6-hydroxy-2-benzofuranyl) 1. After mixing Og ('0.035 mol), 3.0 g ('0.022 mol) of anhydrous potassium carbonate, and 15 mQ of dimethylformamide and heating at 80°C for 30 minutes, β-diethylaminoethyl chloride 1.0 g' (0
, (108 mol) was added and further heated at 80°C for 1 hour. After cooling the reaction solution, it was poured into water, and the precipitate precipitated was collected by filtration and dried to give bis(6-β
-diethylaminoethoxy-2-benzofuranyl)ketone was obtained.

Dissolve the obtained crystals in ethanol, add a small amount of diluted hydrochloric acid,
Then, the crystals obtained by slightly concentrating the ethanol were further recrystallized from an ethanol/ether fi liquid (1:4 volume ratio) to obtain yellow crystalline bis(6-
1.0 g (yield: 50.0%) of β-diethylaminoethoxy-2-benzofuranyl)ketone dihydrochloride was obtained.

Elemental analysis value "C2'l 83G 05N2・2HC to H20 Calculated value: C' 59.69 H6,9
1,N 4.80 Actual value: C59,74H6,75N
4.99 Infrared absorption spectrum (KBr tablet; cm-1)
3000-2900 (YCH) 2700-2450 (YNH) 1620
(乍C=0) 1560.1495 (y C=C, aromati
c) Reference Example 7 [Production of bis(7-medoxy 4-sulfo-2-benzofuranyl) ketone disodium salt] Bis(7-medoxy 2-benzofuranyl) ketone obtained in Reference Example 1 0.6
g (0,002 mol) and concentrated sulfuric acid 0.6 g,
After reacting at 100°C for 1 hour, the reaction solution was cooled, dissolved in ethanol, made alkaline with an aqueous sodium hydroxide solution, filtered the precipitate, and recrystallized from water to produce yellow crystalline bis with a melting point of 280°C or higher. (7-Medoxy 4-
0.6 g of sulfo-2-benzofuranyl) ketone disodium salt was changed.

Elemental analysis value: C+q H12011”2Na2.3H
Calculated value as 20: C39,32H3,13 Actual value: C39,20H3,12 Infrared absorption spectrum (KBr tablet; cm-1) 3150
~2900 (vCH) 1625 (YaC=0) 1590.1490 (v C=C, aromati
c) 1160.1050' (乍so) Example 1 [Production of bis[7-hydroxy-2-benzofuranyl) ketone guanyl hydrazone hydrochloride] Bis(7-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 3 0.6 g (0,002 mol), aminoguanidine bicarbonate 0.27 g (0,002 mol) and 20 m Q of ethanol were mixed, and concentrated hydrochloric acid 2~
After adding 2.51 and heating under reflux for 30 minutes, the reaction solution was cooled and concentrated under reduced pressure. The precipitate was reconstituted with MtMt from ethanol to give yellow crystalline bis(7-hydroxy) with a melting point of 136-138.5°C. -2-Benzofuranyl)ketone guanylhydrazone hydrochloride 0.52g was returned.

Elemental analysis value: CIgH,404N4・2)+20 Toshite calculation value: C51,13H4,53N 13.25
Actual value: C50,95H4,52N 13.38 Infrared absorption spectrum (am-1; KBr tablet) 3400~
3100 (νOH,vNH)3000~2900
(νcH) 250 (1~2300 (yNH”) 1685
(VC=N) 1640.1580 (SNC) 1560.14
90 (c=c, aromatic) 1150
(C-0) Example 2 [Production of bis(6-hydroxy-2-benzofuranyl) ketone guanyl hydrazone hydrochloride] Bis(6-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 4 was used instead of bis(7-hydroxy-2-benzofuranyl) ketone. -Hydroxy-'2-benzofuranyl)ketone was used, and the melting point was 146 to 148°C in the same manner as in Example 1, except that the reaction was carried out under heating and reflux for 8 hours.
0.8 g of yellow crystalline bis(6-hydroxy-2-benzofuranyl)ketone guanylhydrazone hydrochloride was obtained.

Elemental analysis value” CIg H1404N+・HCto2H2
Calculated value as 0: C51,1384,53N 13.2
5 Actual value: C51,01H4,44N 13.35 Infrared absorption spectrum (cm-1; KBr tablet) 3400~
3100 (YaOH, YaNH) 3000~2900
(νC1() 2500-2300 (νNH+) 1690 (νC=N) 1660.1620 (SiN-C) 1560.14
40 (v C=C, aromatic) 1150
(乍C-0) Example [Production of bis(7-medoxy 2-benzofuranyl) ketone guanyl hydrazone hydrochloride] 0.6 g (0,002 mol) of bis(7-medoxy 2-benzofuranyl) ketone obtained in Reference Example 1 , 0.2'7 g (0,002 mol) of aminoguanyl carbonate and 20 mQ of ethanol were mixed, and 2 to 2.5 m of concentrated hydrochloric acid was added thereto. After heating under reflux for 4 hours, the reaction solution was cooled and then reduced under reduced pressure. The precipitate deposited was filtered and recrystallized from ethanol containing concentrated hydrochloric acid to yield bis(7-medoxy-2-benzofuranyl)ketone guanylhydrazone hydrochloride in the form of pale yellow crystals with a melting point of 228-230°C. 8g was changed.

Elemental analysis value: C2゜JgOJ4・HCQ・3.5H20
Calculated value: C50,27H5,,48N 11.7
2 Actual value: C50,45H5,20N 12.00 Infrared absorption spectrum (c+o-1; KBr tablet) 3400
~3300 (YNH) 3000~2900 (V CH) 2550~2300 (YNH+) 1680 (乍C=N) 1620.1590 ('vN-C) 15801.1
490 (C=C, aromatic) Example 4 [Production of bis(6-medoxy 2-benzofuranyl) ketone guanyl hydrazone hydrochloride] Bis(7-medoxy 2-benzofuranyl) ketone was replaced with bis(7-medoxy 2-benzofuranyl) ketone prepared in Reference Example 2. Light brown crystalline bis(6-medoxy 2-benzofuranyl) ketone with a melting point of 124 to 126°C was prepared in the same manner as in Example 3, except that 6-medoxy 2-benzofuranyl) ketone was used and the reaction was carried out under heating and reflux for 14 hours. 0.5 g of guanylhydrazone hydrochloride was obtained.

Elemental analysis value 202°H + g04N4・ICt2H20 Calculated value: C53,28H4,92N 12.43 Actual value: C53,00H5,00N 12.63 Infrared absorption spectrum (cm-,'; KBr tablet) 340
0-3300 (νNH) 3000-2900 (乍C3) 2650-2300 (乍NH) 1685-1665 (νC=N) 1625.1590 (乍N-C) 1560.1490 (v C=C, aromati
c) Example 5 [Production of bis(7-hydroxy-2-benzofuranyl) ketone ethoxycarbonylhydrazone] Bis(7-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 3 0
．． 7g (0,0025 mol), ethyl carbazate 0.
26g (0,0025mol), 95% ethanol 6m
After mixing Q and one drop of concentrated hydrochloric acid and heating under reflux for about 5 hours, the reaction solution was cooled, poured into water, filtered the precipitate, and recrystallized from a mixture of acetone and water, resulting in a melting point of 158~
0.6 g of white powder bis(7-hydroxy-2-benzofuranyl)ketone ethoxycarbonyl hydrazone at 160°C (decomposed) was returned.

Elemental analysis value: Calculated value as C2oHIGOGN2・H2O: C60,30H4,55N 7.03 Actual value: C
60,53' H4,37N 7.08 Infrared absorption spectrum (c+n''; KBr tablet) 3400-3200
(Y0H) 3350 (YNH) 3100~2900 (YCH) 1730 (Y000) 1620 (t C=N) 1550.1485 (v C=C, aromati
c) 1160 (乍C-〇) Example 6 [Production of bis(7-medoxy-2-benzofuranyl)ketone ethoxycarbonylhydrazone] Bis(7-hydroxy-2-benzofuranyl)ketone was replaced with bis(7-hydroxy-2-benzofuranyl)ketone prepared in Reference Example 1. Example 5 except that 7-methoxy-2=benzofuranyl) ketone was used and the reaction was carried out under heating reflux for 8 hours.
Recrystallization from a mixture of benzene and petroleum benzine was carried out in the same manner as above to obtain 0.6 g of bis(7-medoxy-2-benzofuranyl)ketosoethoxycarbonylhydrazone in the form of a white powder with a melting point of 134-136°C (decomposition).

Calculated value as elemental analysis value 2C22H2゜06N2: C6
4,70H4,94N 6.86 Actual value: C64,9
1H5,03'N 6.58 Infrared absorption spectrum (
am-1; KBr tablet) 3200' (乍NH) 3000~2900 (νCH) 1710 (νC00) 1620 (YC=N) 1550.1480 (vC=C, aromatic
) Example 7 [Production of bis(6-hydroxy-2-benzofuranyl) ketoxime] 0.8 g (0,00275 mol) of bis(6-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 4, 0 hydroxylamine hydrochloride .3g (0,0043 mol),
Mix 10m Q of ethanol and 0.5mfl of water,
Add to this 0.77 g of sodium hydroxide (0,001375
After refluxing for 4 hours, the reaction solution was cooled, poured into water, acidified with dilute hydrochloric acid, and the precipitate was recrystallized from a mixture of ethanol and water to give a pale yellow powder with a melting point of 247-248°C (decomposition). 0.5 g of bis(6-hydroxy-2-benzofuranyl) ketoxime was recovered.

Elemental analysis value 201□H,,05N-H2O Calculated value: C62,39H4,00N 4.28 Actual value: C62
,18H3,98N 4.30 Infrared absorption spectrum (
cm-1; KBr tablet) 3400-3200 (ν0
H) 3100-2950 (乍CH) 1630 (VC=N) 1570.1490 (y C=C, aromati
c) 1150 (vC-0) Example 8 [Production of bis(7-hydroxy-2-benzofuranyl) ketoxime] Bis(7-hydroxy obtained in Reference Example 3) was used instead of bis(6-hydroxy-2-benzofuranyl) ketone. -2-Benzofuranyl)ketone, melting point 243-244, was carried out in the same manner as in Example 7, except that the reaction was carried out under heating and reflux for 12 hours.
Bis(7-hydroxy-2-
0.55 g of benzofuranyl) ketoxime was obtained.

Elemental analysis value: CI7H,, Calculated value as 0sN-H2O: C62,39H4,00'N 4.2B Actual value: C62,60H3,86N 4.39 Infrared absorption spectrum (cm-1; KBr tablet) 3400-320
0 (ν0H) 3050~2950 (νCH) 1600 (νC=N) 1550.1495 (C=C, aromatic
) 1175 (C-0) Example 9 [Production of bis(7-medoxy-2-benzofuranyl) ketoxime] Bis(7-medoxy 2 obtained in Reference Example 1) was used in place of bis(6-hydroxy-2-benzofuranyl) ketone. Recrystallization from ethanol in the same manner as in Example 7, except that -benzofuranyl) ketone was used, yielding bis(72methoxy-2-benzofuranyl) as white needle-like crystals with a melting point of 210-212°C.
Obtained 0.7 g of ketoxime.

Elemental analysis value: Calculated value as C+q H+s, OrN:
C67, 65H4, 48N 4.15 Actual value: C67,
9084,54N 4.07 Infrared absorption spectrum (C
m””; KBr tablet) 3000-2900 (ν
CH) 1610 (γC=N) 1550.14'90 (V C=C, aromat
ic) Example 10 [Production of bis(7-hydroxy-2-benzofuranyl) ketone thiosemicarbazone] 0.6 g (0,002 mol) of bis(7-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 3, 0.3 g (0,003 mol) of thiosemicarbazide and 40 rnQ of 95% ethanol were mixed, 4 to 5 drops of concentrated sulfuric acid were added thereto, and the mixture was heated under reflux for 4 hours. After cooling the reaction solution, the mixture was concentrated under reduced pressure. When the precipitate was poured into water and made weakly alkaline with a dilute alkaline aqueous solution and recrystallized from a mixture of ethanol and water, yellow crystalline bis(7-
0.5 g of hydroxy-2-benzofuranyl) ketone thiosemicarbazone was changed.

Elemental analysis value: Cl8H, 30, N3s・1/2H2,
OtoLte calculation value: C57, 44H4, 0'2 N 1
1.16 Actual value: C57,70H4,30N 11.4
0 Infrared absorption spectrum (cm-1; KBr tablet) 35
00~3300 (ν0H) 3150 (νNH) 3100~3000 (v CH) 1620 (v C=N) 1580.1490 (V C==C, aromat
ic) 1290 (νC=S) 1180 (C-〇) Example 11 [Production of bis(6-hydroxy-2-benzofuranyl) ketone thiosemicarbazone] Replacement with bis(7-hydroxy-2-benzofuranyl) ketone A yellow crystalline bis(6-hydroxy-2-benzofuranyl) ketone with a melting point of 172 to 174°C was prepared in the same manner as in Example 10, except that the bis(6-hydroxy-2-benzofuranyl) ketone obtained in Reference Example 4 was used.
0.5 g of hydroxy-2-benzofuranyl) ketone thiosemicarbazone was obtained.

Elemental analysis value: Calculated value as C, $H, 304N3S:
C58,8583,57N 11.44 Actual value: C58
,90H3,83N 11.23 Infrared absorption spectrum (am-1; KBr tablet) 3450-3250 (ShiOH
, YaNH2) 3150 (νNH) 3100~2950 (Ya-CH) 1625 (V C'= N) 1560.14
80 (vc=c, aromatic) 1270(ν
C=S) 1155 (C-0) Example 12 [Production of bis(7-medoxy-2-benzofuranyl) ketone thiosemicarbazone] In place of bis(7-hydroxy-2-benzofuranyl) ketone, in Reference Example 1 Recrystallization from ethanol yields a melting point of 203-205°C in the same manner as in Example 10 except that the obtained bis(7-medoxy-2-benzofuranyl) ketone was used.
yellow needle-like crystals of bis(7-methoxy-2-bendose)
I got g.

Calculated value based on elemental analysis value "C2D'1704NJ":
C60,75H4,33N 10. ．． 63 actual measurement value: C
60,93H4,37N' 10.36 Infrared absorption spectrum (cm-1; KBr tablet) 3400.3350
(v NH2) 3250 (y NH) 3100-3000 (ACH) 1610 (乍C=N) 1590.1470 (v C=C, aromati
c) 1290 (νC=S) Example 13 [Production of bis(6-medoxy-2-benzofuranyl) ketone thiosemicarbazone] Bis(7-hydroxy-2-benzofuranyl) ketone was replaced with bis(7-hydroxy-2-benzofuranyl) ketone prepared in Reference Example 2. When recrystallized from ethanol in the same manner as in Example 10 except that 6-medoxy (2-benzofuranyl) ketone was used, the melting point was 202-204°C.
Yellow crystalline bis(6-medoxy-2-benzofuranyl)ketone thiosemicarbazone 0,. I gained 4g.

Elemental analysis value: Calculated value as C2°H, 704N3S:
C60,75H4,33N 10.63 Actual value: C6
0,49H4,35N 10. ．． 55 Infrared absorption spectrum (cm-1; KBr tablet) 3450.3350
(νNH2) 3250 (νNH) 3100~2900 (YCH) 1620 (VC=N) 1600.1480 (VC=C, aromati
c) 1270 (vc=s) Example 14 [Production of bis(7-β-diethylaminoethoxy-2-benzofuranyl)ketone guanylhydrazone trihydrochloride] Bis(7-β-diethylaminoethoxy-2- benzofuranyl)ketone 1.14g (0,002
mol), aminoguanyl bicarbonate 0.28 g (0,00
2 mol) and 20 mQ of ethanol were mixed, 2 to 2.5 mQ of concentrated hydrochloric acid was added thereto, and after heating under reflux for 2.5 hours, the reaction solution was cooled and concentrated under reduced pressure, and the precipitate was mixed with methanol. When recrystallized from a mixture of ether, the melting point is 2.
Yellow crystalline bis(7-β-
0.9 g of diethylaminoethoxy-2-benzofuranyl) ketone guanyl hydrazone trihydrochloride was returned.

Elemental analysis value: C. Calculated value as H4,N604/3HCQ: C54,76H6,59N 12.77Actual value: C54,99,H6,73N 12.70Infrared absorption spectrum (cm""1; KBr tablet) 3300-3
150 (乍NH2, DANH) 3100-2900
(YCH) 2650~2400 (YNH) 1680 (νC=N) 1590.1490 (v C=C, aromati
c) Example 15 [Production of bis(6-β-diethylaminoethoxy-2-benzofuranyl)ketone guanyl hydrazone trihydrochloride] After adding bis(7-β-diethylaminoethoxy-2-benzofuranyl)ketone, the reaction mixture was prepared in Reference Example 6. Eta bis (6-β
Recrystallization from a mixture of ethanol and ether yields a yellow powder with a melting point of 144-146°C in the same manner as in Example 14, except that the reaction was carried out for 6.5 hours under heating and reflux using -diethylaminoethoxy-2-benzofuranyl) ketone. 0.6 g of crystalline bis(6-β-diethylaminoethoxy-2-benzofuranyl)ketone guanylhydrazone trihydrochloride was obtained.

Elemental analysis value: Calculated value as C3oH4°N, O, 3HCQ: C54,76H6,59N 12.77 Actual value: C54,51H6,70N 12.56 Infrared absorption spectrum (Cm-1; KBr tablet) 3400-3200
(YNH2, YNH) 3100~2900 (YCH) 2650~2450 (νNH") 1675 (C=N) 1580.1490 (v C=C, aromati
c) Example 16 [Production of bis(7-medoxy-4-sulfo-2-benzofuranyl)ketone guanyl hydrazone] Bis(7-β-
Water-containing methanol was prepared in the same manner as in Example 14, except that the bis(7-medoxy-4-sulfo-2-benzofuranyl) ketone disodium salt obtained in Reference Example 7 was used in place of diethylaminoethoxy-2-benzofuranyl) ketone. Recrystallization from a mixture of and ether yielded 0.8 g of bis(7-medoxy 4-sulfo-2-benzofuranyl) ketone guanyl hydrazone in the form of a white powder with a melting point of 280° C. or higher.

Elemental analysis value "C20HIs O+o Calculated value as N4S2: C44,6183,37N"10.40 Actual value: C44,8383,58N 10.53 Infrared absorption spectrum (am-"; KBr tablet) 3550-32
50 (y NH2, v NH) 3150-2900
(乍CH) 1690 (乍C=N) 1580.1490 (y C=C, aromat,
1c) 1160.1040 (νS03 H) Example 17 [Antiviral test in chicken fetal fibroblast cells] 10-1
A fetus from a 1-day-old embryonated chicken egg was tissue cultured by a conventional method, and 20
Influenza A-PR8 diluted with various concentrations of bisbenzofuranyl ketone compounds dissolved in methanol or water and culture medium on primary chicken fetal fibroblasts cultured for ~24 hours.
I challenged almost at the same time (last challenge m-o-
1=0.1-0.2). After that, incubation was carried out at 37°C, and after 48 hours, the amount of virus in the culture solution was determined by HA (hemagglutination) test, and the amount of virus in the cells was determined by heme atsorption, and the minimum concentration of the test compound expressing virus activity was determined. I asked for The cytotoxicity of the test compound was examined in the same experimental system as above without virus challenge, and the effectiveness coefficient was determined from the following formula.

For comparison, the same test as above was conducted on Amantadine, which has been conventionally used as an antiviral agent.

These results are shown in Table 1.

Claims (1)

[Claims] 1 General formula [wherein R is -NHC(NH)NH2, NHCOOCH
2CH3, -〇)I or -NHCSNH2, R1 is hydrogen or -503H, R2 is hydrogen, a lower alkyl group having 1 to 3 carbon atoms, or the formula (where m is an integer of 1 to 3, R3 and R4 are each represents a lower alkyl group having 1 to 3 carbon atoms), and the R1 group and OR2 group are substituted at any position of the 4, 5, 6 or 7 position of the benzofuran ring. ] Bisbenzofuranyl ketone derivatives and salts thereof 2 Bisbenzofuranyl ketone derivatives and salts thereof according to claim 1 which are bis(6-hydroxy-2-benzofuranyl)ketone guanyl hydrazone 3 Bis( Bisbenzofuranyl ketone derivatives and salts thereof according to claim 1 which are 7-medoxy 2-benzofuranyl) ketone guanyl hydrazone Claim 4 which is bis(6-medoxy 2-benzofuranyl) ketone guanyl hydrazone Bisbenzofuranyl ketone derivative and salt thereof according to claim 1 5 Bisbenzofuranyl ketone derivative and salt thereof according to claim 1 which is bis(6-hydroxy-2-benzofuranyl) ketone thiosemicarbazone 6 Bis(7-β-diethylaminoethoxy-2=benzofuranyl) ketone guanyl hydrazone, the bisbenzofuranyl ketone derivative and salt thereof according to claim 1 7 Bis(6-β-diethylaminoethoxy-2-benzofuranyl) Bisbenzofuranyl ketone derivatives and salts thereof according to claim 1, which are ketone guanylhydra 1 sine 8 General formula [wherein R1 is hydrogen or -5O3H, R2 is hydrogen, and has 1 to 3 carbon atoms] Represents a lower furkyl group or a substituted aminoalkyl group represented by the formula (wherein m is an integer of 1 to 3, R3 and R4 each represent a lower alkyl group having 1 to 3 carbon atoms), and R1 group and OR
2 groups are substituted at any position of the 4, 5, 6 or 7 position of the benzobran ring. NH)NH2,' NHCO
OCH2CH3, -OH group or -NHC5NH2) is reacted with an amino compound represented by the general formula (in the formula, R, R1 and R2 groups have the same meanings as above, R1 group and OR2 group). is 4.5 of the benzofuran ring.
Process for producing bisbenzofuranyl ketone derivatives and salts thereof represented by (substituted at any position of 6 or 7) 9 The process according to claim 8, wherein in general formula (n), R2 is hydrogen