JPS6036476A - Novel bisbenzofuranyl ketone derivative and its production - Google Patents

Abstract

NEW MATERIAL:A bisbenzofuranyl ketone derivative of formula I (R is lower alkyl, pyridyl, aminoacid residual group; R1 is H, halogen, R1 and RCOO are in any positions among 4, 5, 6, or 7 positions on the benzofuran ring). and its salt. EXAMPLE:Bis(6-acetoxy-2-benzofuranyl)ketone. USE:A drug having antiviral action. PREPARATION:The reaction of a novel benzofuranyl ketone of formula II with an acid chloride of R2COCl or acid anhydride of formula III, if desired, followed by debenzylcarbonylation, gives a compound of formula I . The compound of formula II is obtained by dealkylation of a compound of formula V resulting from the reaction between a compound of formula IV (R3 is alkyl) and 1,3-dichloroacetone.

Description

DETAILED DESCRIPTION OF THE INVENTION Kikanaki is a novel conductor of the general formula (1), in which [ri is a lower argyl group, biridyl group, (or amino acid Remaining J1 (,1, represents hydrogen element 1゛J: take halogen j]; shi f゛, 1<, base? and tic(1
(11,1; l:l]\4.5 of the soprano ring, [;
The second is the bisbensofuranilke 1 hexagonal conductor J-i and its salts, and ('JL et al.) Concerning the manufacturing method.

+< I in the general formula (1), (wherein, as lower alkyl, the number of carbon atoms + -: 3 QI'・l is 1)
Direct, i, iJi, or branched alkylno, 1 is
Among them, methyl J1 (amino acid IN j+', where r < J, t:
Examples include decarboxylated A residues of amino acid 2 such as glycine, aluminum, valine, leucine, isoleucine, phenylalanine, lysine, glycine, β-alanine, methionine, etc. I'll do it for you (I?). Also 1<, J. (of which halogen; -f
How about fluorine? 1L (4, 8J);
t",suyo4;atom,you,(・,)hl,"I"KaageraAshin,I.

The LJ-like compound of the present invention has the following properties: 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 1, 2, 3, 3, 3, 4, 5, 5, 5, 5, 1, 5, 1, 5, 1, 5, 1, 1, 1, 5, 1, 5, 1, 1, 1, 1, 5, 1, 1, 1, 1, 5
At the point, bis(ra-acel-Shen-:2-benzofuranyl)keyne, bis(
7-Atel-xy-2-benzofuran: -l)keyne, bis(7-2'thinoyloxy-2-benzofuranyl)noJ'1-n, his(〇-alanyloxy-2-benz') his(7-alanyloxy-2-benzofuranyl)keyne, bis(6-phenylalanyloxy-2-hensofuranyl)keyne, bis(7-phenylalanyloxy) -2=hensofuranyl)/rl-n, his([,i-lysylAxy2-henn'furanyl)getone, his(7-lysyloxy-2
Bisbensofuranylgeton poetry guide book such as -benzofuranyl)keyne, bis(7-methionyloxy-2-benzofuranyl)keyne, etc.: J3, Kamizo J Shirano Jsu1
j or a lot of fj.

Bisbenzofuranylketone +'A conductor of the present invention (1)
is the general formula (0) (in the formula, 1<) represents a water source r- or a halogen l+j; :The 7th place child 7σ, of (1
Bisbenzofuranyl ketonization r>4', 4. −.

General formula (II+) or (1) "J-' compound or acid represented by I"
! <u 4 <4'η Easily obtained by reaction (optionally with dependylation and carbonylation): 1ξ.

Said (II+): 1 mouth or (IV) in which vertical core; f;
+-J: 'I'' 6 medium is j4! (water pyridine, Ml, water acid resistance 1.4, ether, or l'1
lfX6 etc. use 64F,, /l! +! As necessary, what should I do? ) 1 p; to 1 (n (, perchloric acid, acid resistant triu 11, west 1 ° self a potash ・] 11, biinosine or 17., i i ni self 11! nail; A, rika 1, commercial 11, use A.Also, the reaction lA+! degree is 110°C-1i0° (61N degree between 1.i of ゛, and the reaction 111 is 1 hour to Ii 11.'1 The range between 11'I° is adopted as appropriate.

-C, +<, J, l; is N-benzyl Agisicarponyl-amino acid residue 1 (5), if the reaction is gill A, N-benzyl Agisicarponyl-amino acid residue A is For example, the compound is 25%,'
2 II: The compound of the present invention can be obtained by removing benzyl carbonylation using old hydrogen solution.

In the present invention, bisbenzofuranyl getone derivative (1
) is place I′? 1. However, such salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, or succinic acid, fumaric acid, maleic acid, etc. Jj, the fish are being attacked. These salts can be easily obtained according to conventional methods, for example, by reacting bisbenzofuranylketone talolopol 11 with a correspondingly dichlorotic acid in a suitable organic solvent such as ethanol or methanol.

All of the bisbenzofuranylgetone compounds (11), which are the starting materials in the invention, are new compounds, but they are represented by the general formula (V) (where 1<, represents lower alkyl with I, :). Salicylaldehyde (V) represented by 1,; The general formula (Vl) selected from 9 by reacting at the lower right of the presence of helium 11, potassium hydroxide 11, potassium carbonate, etc. (in the formula, 1<, is 1); represents the same as in f, ul
+. By dealkylating a hischenzofuranylkene compound (Vl) represented by +no1 (substituted at the 4, 5, 6 or 7 position of the henzofuran ring, σ) It's easy to do gills.

In the dealkylation reaction, the hisbenzofuranyl ketone compound (Vl) is mixed in a suitable solvent such as benzene, chlorohensen, dichlorobenzene, acid-resistant, methanol, and ethanol in the presence of an acid agent and a solvent (at room temperature in the presence of an acidic medium). This is suitably carried out by heating to 1 to reflux for 1 to 1 hours.The acid catalysts used include Lewis acids such as anhydrous aluminum chloride, anhydrous soot(IV) chloride, and porcelain difluoride. ,
Preferred examples include mineral acids such as hydrochloric acid, odor fb, /l acid, and pyridine hydrochloride.

The hissofuranyl ketone derivative (T) and its salts of the present invention are novel compounds which themselves have excellent antiviral activity and are useful as medicines. For example, bisbennefuranyl ketone derivative (1) and its salts can be used to treat common colds, pharyngitis, pool fever, influenza, pneumonia, etc. caused by various viruses): (
Infectious disease 11: It is effective in preventing and treating various diseases such as herpes zoster, genital herpes, herpes labialis, and herpetic keratitis.

The present invention will now be described with reference to reference examples and examples.

Reference Example I [Bis(7-me1-xy-2-hensofuranyl)ke1-
1-Me-1-xysalicylaldehyde: 1.71 g (0
,022 mol) of dioxane] was added to 5 ml of dioxane, and to this was added 1-lium Ig(0,
025 mol) and gradually heated at 75°C to 20-3
Reacted for 0 minutes, then added 1.3 g (0,010 mol) in small portions and further reacted for 1 minute (at 1'C).
0m Q is added, and the resulting precipitate is dissolved by r + M, .
',L Is mountain'+L/teh'+ii,-',j
14. '! 144 ” (-, 0) e'H' N!
His (7-Me1-xy-2-henzofuranyl) 1. I got nine.

Elemental analysis (target: (', Hq II (40 evenings and 2
Tea God Value: C70,80II 71. :Ill actual value=(-71,0!l II l+,O!1neζExample 2~
11: (-me1~C4-me1 instead of xisalicylaldehyde
- Gysisalicylaldehyde, 5-MeI-A (tritylaldehy 1~, L3-Me1 hexysalicylaldehyde 1, etc.) 5 Example 1 and intermediary SoA and it (
Reference example 2) Bis(ni-me-1-gyshi-2-hensofuranyl)-J1-
Yellow m color viscous crystal, 111 points 1! l]~19;1
℃ Original Nu・S analysis value: C, 9I+, 4(] +5 and lit value: C70,801+ 4.:18 Actual a++
Meteki: C71ノ, 8! J 14 /1.41 (Reference Example ゛3) Bis(5-me-1-xy-2-pentufuranyl) PJ'1
-N yellow viscous crystal, -1 point 173-174℃ Elemental analysis value: (II, q II, 40 da and 17 da
Calculated value: C70,801+ 4. :18 real 41j1 value:
IT 70.417 11) 1.50 (Reference Example 4) Bis(4-me-1-xy-2-benzfuranyl) γ1~
yellow viscous, #Ji, j', <181-1811"
C + S + l'i value: (2, q II, 40 da as I; 1 calculated value: C10, 80114,: i8 real d1
Value: t-, 70,71It 4.2R was obtained. .

Reference 2ぢfσ115 [Production of bis(4-chloro-7-meI-xy-',)-henzofuranyl) 1-ene] Reference ζ''Example 1 ) Ke1hen: 1.2.. (0, old mole) is dissolved in Chloropol \30m Q, and this is loosened)
Crab + 5 sulfuryl chloride 3. O, ;(0,0
22 mol) in chloroform 6nIG'('j'f F
)'+i L solution was gradually added dropwise over a period of about 3 (1 minute).
I continued the ball style. Reactions 21 were cooled and the precipitated crystals were collected by JB and 1f1 (! points 218-220''(':
, +2 +', /j (!vcrystalline bis(/1-noLJU-7-me1hegysy2-henzofuranyl)ke1-
Nl, :i+zushitita. This thing: Main Haroken's constant ('l yi t, knee, : de l; i, + 1' l u・
, Yashi 2, and infrared absorption spectrum and nuclear iron part 1
n:+, n) II (Subek I・ru was measured and it was confirmed that the compound Cd・100).

Elemental content υ1 value: (', 1q II 1□05(2Q
2, 11 go i1i'f: +-,51i
, :l:l It', t, I)ri (', 11. 1
8. 12 fruit d1 1st shift: C5LI6 If: 1
．． : Eye r(! 18.:II Reference example [3 [Bis(7-hi1~roxy2-]\nsofranil) U1henno1to2Jkichi] Part-9 Example 1-?' Obtained bis( 7-mei-xy-;(
−・＼nzofuranil) 1 to 7.5 to 2 (0, (+2
:t mol) Dori IJ L, l -＼zen60m1+,
Do the d-cinema and then go to the room! ! u! , Jr'i J'1
41・Anhydrous aluminum chloride Uno! J, :1g (0
, 069 mol) was added. The reaction solution immediately turned red and viscous. Then gradually add nj1
1. After reacting for 1 hour at 100°L, a reddish-brown precipitate was precipitated. After the reaction was completed, the reactant was poured into water for 21°, and the precipitate was dried in an incubator, and then recrystallized from ethanol. 5.7 g of yellow crystalline bis(7-hydroxy-2-benzfuranyl)ketone with a decomposition point of 268-2 (i!IT) was recovered.

Elemental analysis value: C,,7+1. , (] 5-1+20
J1 calculated value as: C65,39II: i, li! J
Real at! I value: C65,17II:1. Old elemental analysis value: C, 7H. 0 DE (dried at 110°C for 7 hours) Calculated value: C (i!1.3911: 1./l:1 Actual value: C69, Fi] II: 1.21 Reference Example 7 [Bis(6-H) Production of 1-roxy-2-benzofuranyl)ketone] Bis(e-me-1-xy-2-benzofuranyl)ketone obtained in Reference Example 2 was used in place of bis(7-meth-hexy-2-benzofuranyl)ketone. Otherwise, yellow crystalline bis(6-
Hydroxy(2-benzofuranyl)keyne was obtained.

Elemental analysis value: C17111,Oy・]/2112 (calculated value as 1: C67,55H3,33 Actual value: C67,3611:1.56 Reference Example 8 [Bis(5-hydroxy-2-pentufuranyl)ke1-
Same as Reference Example 6 except that bis(5-methoxy-2-benzofuranyl)ketone obtained in Reference Example 3 was used instead of bis(7-methoxy-2-benzofuranyl)ketone. Yellow crystalline bis(5-
1-roxy-2-benzofuranyl)keyne was obtained.

Elemental analysis value: C,711,005・lI20 Estimated value: C65,39II 3.87 Actual 11111 value:
C65,39If: 3.72 Reference Example 9 [Bis(4-hydroxy-2-benzofuranyl)ke 1~
Production of Reference Example 6 except that bis(4-methoxy-2-benzofuranyl)/rl produced in Reference Example 4 was used instead of bis(7-medoxy-2-benzofuranyl) Yellow crystalline bis(4-hydroxy-2-benzofuranyl)ketone with a decomposition point of 2, 15 to 2, and 7 was obtained.

Elemental analysis value: C17! IF calculated value as I 1005: C69,:μl II 3. II: 1 actual illumination value:
C61,17II:1. : i22 Reference 10 [Production of his(/l-riUlow7-hy(~L'xy-2-benzofuranyl)keyne) J''7:1 Bis(4-ri1 obtained in Reference Example 5) Low 7-Me 1-Ki-
2-henzofuranyl) 4. (+), 01 mol) dissolved in 50 mQ of benzene A? ' L, room temperature, stirring bar anhydrous, aluminum oxide 11 times; (0,
0: (mol) was added and heated at 5°75 to 80°C for 30 minutes. After the reaction was completed, the reaction product was cooled, placed in ice water for 11 minutes, and the precipitate precipitated was collected, dried, and then recrystallized from ethanol to obtain a solution with a melting point of 295°C.
The orange-yellow crystalline bis(11-chloro-7-hy-1)
-1"xy-2-benzofuranyl)keyne;)g was obtained.

Elemental analysis value: (:+7tl g OsCQZ do at f, 'J + straight: I-, 5ri, 2:l I
f 2.22 1”11. I!], 52 fruit; U
++ value: C5Li, 07 II 2.42 (20.
1! ! , 21 Reference Example 11 [Production of bis(4,6-dipromo-7-hydroxy-2-penzofuranyl-1-one)] Reference f row [') 2. ! ]g(0,0
1 mol) of r1 acid was dissolved in 60IIIQ of r1 acid and added with 60% of bromine under cooling. /Ig (0.04 mol) and 1″i1 acid 7+
ul! I want 11 times more rL fluid. Negative for l quotient j ′・;mi (at 1; After 30 minutes of loss J1, soak the reaction ?1!! in water.

The precipitated precipitate was washed with d (January 1'), and the decomposition point was 285.
~287°
2.5g was changed.

Elemental analysis value: c+71+ 6 (l r l-1++
・11□0doshi, crystal IQ, value: (', :12.5
2 If 1.28 fir ,'+(1,!l!real-
11 value: C32, (il II 1.+3!j ll
r! 'i0.11! 'i Example 1 [His(7-ace1-xene = henzofuranyl) ke 1
[Manufacture of] his(7-bitroxy-2-benzofuranyl)keyne 0.5IX (0,0017 mol) obtained in Reference Example 6,
Combine anhydrous acid-resistant 5ni and (J1), cool in ice water, and then add 1 to 2 drops of sulfuric acid. Immediately, the substance turns from yellow to light brown. Leave to cool for 1 hour. After the reaction,
The reaction mixture was poured into ice water (11).The precipitate produced was collected by filtration and washed with water.
When crystallized, r,'tI: point 212-2I at 71 DEG C. 1 product of his(7-ace-1-xy-2-hensofuranyl)ke 1-0.4 was obtained.

几、(・3 analytic value 2C, II 1407 as li
1 Calculated value: C6f3.67 If: 1.7: No. Actual I Rule I Direct: CG6.79 II: L62 Infrared Absorption 11
'Jsubeta1~le(Kllll';l:;cm-'
):3200~2!100 (νC11) 1765(ν
C(10) 16/+5 (νCO) +5(i5.1480 (vC=C, riromaLi
c) Real J blood series f 2 [bis(6-ace1-xy-2-hensofuranyl)ke[
Production of his(5-hyroxy-2-penenfuranyl) prepared in Reference Example 7 instead of bis(7-hyroxy-2-penenfuranyl)
The same procedure as in Example 1 was carried out except that Lll (point 227 to 229°C) was used, except that Lll (point 227 to 229°C) was used.・Eta.

Yuan, (・; minute i fi ll/i: ; Cyu, 1114
(510 value as 17: c 6 + 3.67 11:
1.7:1 real, ]1 value: (', 66.78 II
:1. G5 infrared viscosity (absorption subekir) (111 tablets;
(:m-');(n00~2!100 (y C1
1) l 755 (TSC00) I()7IO(νC()) 1555.1llRO(wc=c, aromaLic)
Example 3 [Bis(5-ace1-xy-2-henzofuranyl)ke1
Production of hemp] Instead of bis(7-hy1-roxy-2-henzofuranyl) ketone, bis(5-hy1-roxy2-
A light brown crystalline bis(5-ace1-xy-2-henzofuranyl)keyne with a melting point of 203-2 (14°C) was obtained in the same manner as in Example 1, except that hensofuranyl)keyne was used. .

9, +5 minutes 4f1 value: Calculated value as C21111407: CGG, GI II: 1.73 actual measurement (l+'I:
C, 66, /+2 II: 1. ! 'i8 Infrared Infrared Absorption Spell 1-le; ←l1l-'' ), (
N[)0~2!100 (νC11)1770~17(
io (νCO(1)l 1i 55(νC(1) i5!i5j/1180 (C=c, 11ru+ll
;+1. ic) Example 4 (l varnish (・1-adji1-quin-2-hensofuranyl)
[Production of compounds 1 to 1] Same as Example 1 except that his(4-hydroxy-2-pentufuranyl)ben obtained from Reference Example 9 was used in place of bis(7-hydroxy-2-hensofuranyl)ben. Similarly, f, 41i point +61-16:l"(':'s/,
: Color
hensofuranil) ge[・nQ got.

Elemental analysis value: (6 mouths as □111+407": lj
'i: 2G [J, GI If: L73 actual value:
+-,66,80It 3. ,'+:1 infrared absorption spectrum (Kllr#:i: ; cm-') 32U
tl-2ri00 (YaC11) 17ra5 (νCO(1) l Li 55(νC0) 1':+(i!'i, 14!],'+(ν(-,=C,
rIr+-+Illi+1. i() Example 5 [X of bis(4-talolo-7-ace1-gin-2-hensofuranyl)]! '1. ! J] hiss (7-hi 1
-loxy 2-hensofuranyl) instead of ken 1-? Example J except that bis(4-chloro-7-hyI-roxy-2-henzofuranyl)keyne obtained in Example 10 was used.
At the same 4If, crystallization from a /iL solution of taloloform l\ and ethyl 61ate gives a melting point of 245 to 2/16.
Bis(4-taloro7-ace1~
xy-2-benzofuranyl) gene was obtained.

Elemental analysis 1] 1°1: C, 11112 (17c Qz
Then 'C811 value: C56,4(l If 2.
70 CQ 15.85 Actual Rule I Direct: (':',)6
．． N7 If 2.7! l C,Q 15. li3 infrared absorption spectrum (nillr<u;cm-'):
32 [River~2!100 (νC11) 1785~+77
(+ (Ya fi (1(1)1ra55 (νself)) 151ノ5.I/l!10(ν(２(,・)人)口]a
1. i(:)Ij :l! 'i (Sit--+Q) In the example
2-・＼Sofranil) K1~N's small 212i j Hiss (7-Hi1~Logyscene-/\NSofranil 9ke I)
I
Same as in Example 19-1, except that 19-1 was used, but with lumpy eyes and ethyl chloride: 1.13 points when one hundred village items from jL71; 2 to 2! 'i3,! i'C story
7-acetoxy-2-benzofuranyl)keyne was obtained.

Elemental analysis value: As Czl It Ipo 7 nr4! ! l”!j value: C; 16.,'15 If 1.
45 11r 4fi, Ofi real i! I'l f direct:
C: 16.5 (i II 1.60 fir 46.
It infrared rays 1 unit (old II tablet; tllll)
-') 3200~2! ] Oo (νC11)17
! 10 (11COO) 16! 'i 5(νL' (1) 1565, 1470 (C=C,arnm;+l 1
c) 575 (C-fir) Example 7 [+1 VJ notice of his(7-nicotyyl-2-hennofuranyl)cane and its hydrochloride] Reference column 1 [
5teel: +Jtdahis(7-hydroxy2-pensofuranyl)ken1-1sen (0,01,15 mol), Ij
, 7. Acid nicotine acid loli l' 1.81ζ (0.01 mol) (1.1. The scale is 1ζ, the precipitated precipitate is cooled, and the wave number of the precipitated substance is determined as: λshiba k
121, melting, point 2113~245° (hiss (7-
Nicotinoyl A (xene-penzofuranyl) was dissolved in chloroform, and hydrochloric acid residue was introduced.
151. After +11, when it dries, it becomes 1. “1'l
! Points 18/l~18 G'(','s yellow paddy mid-autumn bis(7-2) chinoyl 71 = S' scene-henzofuranyl) nor r l-n lj,, j cup' J request 1.5 g It was returned.

Noi:・;minute4h' fll(: (',,II,4(
1, rN2・2+1C0 bow (/211.0, it
'O: (Direct: C57, (i:! If: 1.
50 N'1. et al;Bird actual measurement value I C,57,:! fj
If: 1.41 N +1. ,'+2 infrared decay spectrum (1(llr#-; Cl1l-')
;315θ~280 rin (ν(11) 700hen, '100 (y i~・1)) 17fi
l-1(νf-(ll) lfi, itJ (t・(0) 1 !'i('', 1.l 49(1(νf, former 11th ir) Example 8 [Bis(6 -Nicotine rruno]゛kin; 7-hensoftsunil)su 1 hen o, the top is so no! fj n'i 4's Xj, 11 ill;
-/\nzofuranyl) 1~In place of ζExample 7
The procedure was the same as in Example 7 except that the decomposition point 28 was used.
5” (-, the price of the conversation (6-go, cochino, rruoxy2-/＼sofranil)/r1henwoe,i)
(Same stroke as Example 7 (Nishi C minute 1'ii', ・, -<
28 (1°(: Yellow 1'fl terminal form (6-
nicotinol) I-i-scene-benzofuranyl)
1, n1,1.1・Adventure +4,4 went. .

Maru,'? I molecule jl'lll'1. : (2q I
I 16 [17Nz-', 4110)・(1□(] doshigokichi 1 ), 2l', f1-i : [', 58 5
0 It ::, :l! l ki + 4.70', i'
l fi white: i 5+1.28 II; 1.5.
'l \ ・I n) 8 Red Sun 11 "1; 1 and 11 (),
・＼′,)1 hell (formerly “′i′rL; (kawa-゛)
', (lficl--'10(1(νC1))27 [
1(]~;!:j00 (νN11)l 75('l~
17:10 (ν(:(lfl)1ii,'(fi (
ν(0) 1545.1,1ltn (v(-,=L-,,;+r
om;
No: j+'11,',11r J hiss (7-hi I・rokin-2-・＼insou)wool)su1, think of n in place of n rol+8゛゛た hino, 0-hi1- 11 hesi 2-pentufuranyl) and 1-one (1 Same as Example 7 (I(nishiko f, i':! point old "j-device de(:'s shim white 1 sensai 5) Terminal bis(5-nicotinoylfucoxy-2-hensofuranyl)keyne was obtained, and then Example 7
The same as (1,11 points in fl, 208-210"C (molecule Lf1' point 222-224°(")). 1-n'AA t'ItQ ノ+τ1^ eno°
two.

Original, 4・; Analysis value: (−, 2q111407N2・Hatill・I/211□0 and 711() I11'
1 2 C5!1.40 II :t, 27 N no L
71 + actual d1 value: C! 'i! 1.6:l If:
ri,'llll N /1.81! Infrared absorption spectrum (Kll/tablet; (・l1l-'): 1200-2850
(νC11) 2700~2300 (νN11) 1760~175 (1(ν("(10) 1640 (yaC0) 15G5.1470 (t+ C=f-,;+rom
++1. i (→Example IO [bis(4-nicotinoylsuccinic-2-pentufuranyl) quinone and its like] (Preparation of 1S acids jj, fi)
Bis(7-hiI~roxy2-benzofuranyl)ke1-
Bis(・1-hydroxy-2 obtained in Example 9 instead of
Hogaha fruit 1fJ1 using benzofuranyl)
Set it to the same 1k as f column 7. 1. 1.141 points 2; 32~2
(White color at 4°C) Remove the unpaid his(4-nicotinoyl 2-hensofuranyl) carbon, then fail in the same manner as in Example 7; Point 20;)~205°C) pale color, 1'171 bis(/l-nicotine 1'lua 1x-2-)benzofuranyl) ketene hydrochloride.

Nine, (gu analysis value: (-,2q1116(17N2・2
+1 Cit・II2 (l + 1 stone 1 value: C58
,50If 3. :l! I N 4.7i', 1 real 7 rules 1 shift: C, 58, 55II: 1. ]7 N +1
．． Fi! 'i Red eye absorption spectrum (3111 tablets;
(:l11-'):1200~2850 (YaC1
1) 2700-2:101] (vNll)1760
(ν(200) 1()110~1G:io (νI: (1)!560
．． 1 no 190 (ν C=[-,,;+rom,+
1. ic) Example 11 [1.1 Preparation of bis(7-phenylalanylmegcy-2-benzofuranyl)ke-1-hen-odor-1-arsenic acid salt] Reference Example 6
The resulting bis(7-hydroxy-2-benzofuranyl)ge 1-1, , (0,01 mol), ~-benzyloxycarbonyl-1,-phenylalanyl 6, G
(<(0,022 mol)) Then, combine 1!1.Q water pyridine l 00 Ill 1 no, l (1”
(', -5°(゛nirei 11shi, IvJ I'14
l' Nichi y'r2/l/ri Urai 1: I, 'l
m-9 a little, 5-J, Ikawae, sat゛) to -5
Tehe・θ°(: after reaction between r lLj,]1(in, i
, a precipitate or 111 comes out. Filter this precipitate,
: After stuttering, +fi- crystallizes from ethanol and melts, l
,';I, 11]7・~I! 11! His(7-(N-bencylno)oxycarbonyl-) as a pale yellowish white powder at 1°C.
Phenylalanyl 21゛gish)-2-Benzofuranyl moss 1~7.21ζ was changed, and then this was mixed with 25γ, concrete water; After the reaction, a precipitate is precipitated by adding ether to cold ethanol.
When the mountain crystallizes from the T solution, the molecule p'f point 2: His(7-phenylalanyl 2]
-Benzofuranyl)kene hydrobromide.

0! Two hatched.

9J min A11 value: Cz5 It1g07Nz ' 2
1111+- ii1' i, > value: C56,0
2II 4.0: I N : 1.73 Actual t1 value: C
56,18fl 4.28 N :L51 Red Sun L jl
'a absorption smooth 1~ru(1(Ilrl', :i: ;
+...'''I)1200□=2800 (v C11)2
7(10-2:lt, IO(vNll)+77(1
(νcod) 1 [I/l II (νC0) 15riO,1480(乍C=(',,+n()mal
ic) Example 12 [His(()-phenylalanyloxone-hennofuranyl)keyone odor 1 arsenic 1'la 4'7j+''h] bis(7-di1-logycy 2- pentufuranyl)
In addition to using the bis(6-hydroxy-2-benzofuranyl) ketone obtained in Example 7 in place of the ketone,
IA! ! , +r', < 123-125℃υμ%, ?
U, color jjl JJ-like hiss ([1-(N-・\nshiluo; ■cycarbonyl-phenylalanyl ■shi)-2-
Henzofuranil, 1 ketone was obtained, which was then added to Example 11 in 17 minutes at a PtI' point of 240 to 241°C.
brown powdered bis(6-phenylalanylmegcy 2)
-benzfuranyl)kene% hydrohydric acid Ji1A was obtained.

Elemental analysis value: c,,'ll1g0+yN,' 21
111r and 17 total Φ [Direct: C56,02If
411:l ~ 3.7:+ Actual value: L-, 5, +
, ! )8 114.15igu1.70 infrared absorption smooth (Kll≦“;t; (…-1):t 200~
2800 (ν[:11)27 (l I)~2:(0
0 (v Nll ) 1750 (ν white) 0) 1630 (ν own)) 1550, +47. ”) (Sit-=LId r L month 11 + 1.ic) Execution roll l : 3 j3! ] N',E-hensyl-giso-luponyl-1,-lysine was used in place of tJ-hensyl apoxycarbonyl-lanine. “(Second I:
2, [7-(N,N-Shihensol Agisicarbonylurisyloxy)-n-hen>sofranil] 'r' l-ngaeJ゛)re , Next, conduct A to β 11 and same 1'r7, and divide J4i' point 2; Ru 2: Bis(°7-lysyl Agicy 2-benzofuranyl) ke! in the form of yellowish brown powder at 18°C!
～Nbrominated wood>! ': f'j6 I+'+X was λ.

yuan, (demin() lIII'I: 1 yuq 11 3407
N4・41111- Toshi-C:ll”!.7. 1
111j: ('. '.1!1.84 II 4.
:', 8 N +i lI + real (11li Il white
: (, :+:+.71+ n ・1.1:l N c
i. :In infrared' to 'lj 1' + ψ collection smooth (K
llr-≦'l: : +:m-' ):1 2 0
0~2 +1 0 1) (νCll) 2700~2:
I (1 0 (νN11)177(1 (νf':
0 (1 ) 1(+25(νself)) 1,"+6(1, 111310(ν("=(,,■
()11・II, H. ') Example 1/1 [His (b-lysyl A xy 2-Henso]'I nyl)
/J゛1~Preparation of a certain chemical wood acid deficiency] ~Hensyl 7j W socarponyl-1,-phenylalanine was replaced with N, N-sibensilfurine l-Y-carponyl-1,-lysine. Same as Shi Ding 112 (r
.

2, then reaction 111 for 2 11. Reaction for 11 -4
Orange-yellow (!v'D) with a melting point lfi7~16.1℃
) Unpaid bis[6-(N', ~6] \nnor A'xycarbonyl lysil λYkin)-'!ー，゛＼゛゛゛ゅfuranyl〕ketone is obtained, and then it is fruited/jin rp
Similar to H I2, decomposition point 204~20G”C
orange-yellow 1'n unpaid bis(6-lysyloxy-2-
Benzofuranyl) ketone hydrobromide was obtained.

Elemental analysis value: Cyu9113 cattle (]qN4・411O r
Calculated value of a1 as: C: 39.84 11 4.3
8 N (i.4I actual value: C 39.89 If
4.56 N 6. (i9 infrared absorption spectrum 1 her (1 tablet; cm-1) 3200-2800 (νC11) 2700-2: +00 (1 interval) +760 (νCOO) 1615 (νCO) 1550, 1480 (v C=: C, aromaL
．． ic) Example 15 [Bis(7-alanyloxy-2-henzofuranyl)hydrobromide 1j1. This +li9th No. N-benzyloxycarbonyl-lanine was replaced with N-penzylmexycarbonyl-1.

- The same ffl as in Example 11 was used except that alanine was used. In is a yellow-white powdery bis(7
-(N-benzyloxycarbonyl-alanyloxy-
2-Benzofuranyl] was obtained, and then strained in the same manner as in Example 11 to obtain bis(7-alanyloxy-2-benzofuranyl) as a pale yellow powder with a decomposition point of 244-245°C. - Obtained hydrobromide.

Original g3 minute IJr lllt: [:23 11:L
o07N2・21111r To L -U311″111
Straight: C 46.18 Il 3.71 N Il.
G8Hss; ut+ value: C 4C+. 07 it
3.88 N 4.51 Red Sun 1. <11. Absorption spectrum (1 (llr tablet; cm −'): l 2 L
l o~28(10 (νCll)2 '7 0 (1
~2: lUO (νN11)+770 (νCOO) 1G4+1~I G 2 5 (νCO) 15Ci (1,
14110 (v C=C, ++-omal:j.
c) Example 1G [Bis(6-alanyloxy-2-benzofuranyl)keyne bromide A (manufacture of acid salt)] Instead of N-benzyloxycarbonyl-L-phenylalanine, N-penzylleo-Ndicarbonyl- [6-(N
-penzylmexyl-alanyloxy)-2-
Benzofuranyl]ketone was first filtered and then strained in the same manner as in Example 12 for minutes/'ii' point 2; 12-2; 34°C.
A yellow-brown powder of bis(6-7ranyloxy-2-penzofuranyl)phene bromide Δ(J acid Jl!A) was obtained.

Original R'3 'y) Near value: Czy If zo f+7
N z ' 21111r-HowlVi calculated value: ['
: /16.111 11 :1. '71 N/1.
6Fl Real 1 ((1 value: C/16.37 It :il
(/l N 4.76 infrared absorption spectal (1(l)
lr tablet; cm −' )3200-2800 (νC
11) 2700~2 :lOO(vNII) 1 'I G 5 (νCf1(1) l(l20 (νC(+) 155!i, ]480 (ν(=(,・II'(l old 1
．． i ＜: )-1 Example 17 [bis(7-mediA-nilo''Y-2-henzofuranyl)kene hydrobromide] N-pendyloxycarbonyl 1 ) 5 (+1 point
A light brown powder of bis[7-(N-benzyloxycarbonyl-methionyloxy)-2-benzofuranyl moss] at 95-197°C was poured into gills A, and then the sieves were mixed as in Example II. Same rank) and 442 with Kotanor and Ether
Step ka J to IIi, tllI crystal do decomposition point 2 () 5 to 2
(Pale yellow at 17°C 4'8) Unpaid bis(7-methine]nyl A xy-2-pentufuranyl) Ge 1-I;
-j (gained acid 1).

Original; (3 minutes 1f1 value: C, xgII z+(17N2
S2...! lll] + How do i'il calculation value: +'
4:L4! ] o: 1.8o N 4. (16 fruits (
1 yen straight: C43,:10 11:l98 N
/1. υO infrared i′iδ absorption 11v spectrum (K 11
r tablet; [:Ill-'): 12 (IO to 28 (1
0(νC11) 270(1-2:10(1(vNII)
1 '77 (1(νC00) I G 40~I G :l O(乍C0)l!'1(
i(1,14115(vc=c,+rnmX+1.i+
:) Example 18 [Bis(6-ace1-xy-2-benzofuranyl) getone! II'li 冑]
Suspend (mol) in 1 mQ of ether, add Bucha (water pyridine (0,013 mol)) and cool in ice water.
Acetyl chloride 1.0. , (0°01:1 mol) and 3 mQ ether solution was gradually added dropwise.

Gradually bring the temperature to room temperature, and then react for 3 hours in room JIA, then pour into ice water, remove any precipitate, wash with water, and prepare 1 point of iTj crystallization from ethyl sulfate. 2
27~229°
-=Y-2-penzonolanyl) gene 0.251ζ
It was hatched.

Original '7'l Analysis value: C,,If,+(1-,,l
-L TeI? +! 71st shift: C6G, 67 If:
1.7:1 Real jllsj(It,: C(3, GOI
T: 1.811 Infrared cotton absorption Subek 1 Hell (formerly 1r!?
i: :(:l11-'):1200~2900(ν
C11) 1755(νC(1(+) 1640 (νC0) 1555.141'IO(v+-,=(',,++ro
Block +1. ic) Example (9 [15 Fetal Vaginal Fibers 51: Anti-Trust Test in 4111 Follicles] Fetuses from embryonated chicken eggs of 10 to 110 instars were cultured using a conventional method, and 20-2411.71 ftl j (
f Mustard (1) First generation'f'i fetus 4'K 411: g'
l' 4111 #a, add a concentrated solution of bishenshifuran compound dissolved in methanol or water to
Influenza diluted with nutrient solution (approximately 8 to 1
I challenged 1.1 (last part 1)〉'ji m-o-
i=0. I~0.2). Then 37T: Nite(n'V Yuhel-shi, 4811.'Ill t'i
I((N 71!', Nakanotsu(rus g4+1A(red+r)
It Ll? iQ 4 reactions) Tes I-d J1. Tel
') The minimum concentration at which the anti-russ activity of the compound 1' was determined.

Welcome friend i! # ('L is the same as the above without Wools challenge, 1; In the experimental system, (Kanayama 1, (r effect coefficient 1.) is the following formula, -1 is calculated.

jltl cell) ; Binary spell minimum, and) Antiviral agent binding for nail comparison f (i; l from Ir
・I, j III A, amantadine (,1m order-adi++e), followed by the same ITi as above, ``J
To; Takumi played 1.

The results of these studies are shown in Table 1.1-0 Table 1 Example 20ゞtsu, rrus (circle t-
1+) is a rod public road ni 1i′: tIR shi 2, IQj ii”
'! t': n'3 11'4! did. Il! ! Thrifty (L, n f = + IJ.

l U'! 4 J'''/L' 7 ''' lz water; r1 liquid nirinta<shi, lj3 f4b t! ．． 4[
Between I and 9 [1, I l'l 1 Dokei 11 throw rj, U
Ta. (・11,110 animals) The effect is '6' life extension! I;
What happened? Child's accomplishment ;:I! ! ! 81)% of mice infected with t+If mice were infected by 2011111.
, again (inter/ ,, cJ n-(du-ley, 'U /J'.ll I'J IL 'U I
'jJorone(]1lOuB;/J) administration group's mouth Y↑' 1.1? IO':! ．． There was.

On the other hand, the In
d(!
) (20UnBζ/1 hit) J1n'j Ii'1'te LJ. 4 0'; ζ・mice just left the north exit (Jteariaki I) Kanani + effect 1'1 was observed 11. Ta,.

Claims (1)

[Scope of Claims] 1 General formula (wherein () represents a lower argyl group, a pyridyl group, or an amino acid residue, Rt represents a hydrogen atom or a halogen atom, and R1 and RCOO groups represent 4.5% of the benzofuran ring.
．． Bisbenzofuranyl ketone derivatives (substituted at any position of 6 or 7) and salts thereof. 2. The bisbenzofuranyl ketone derivative according to claim 1, which is 2-bis(6-acetoxy-2-benzofuranyl)ketone. 3. The hisbenzofuranylkene derivative according to claim 1, which is 3bis(7-ace1hexy-2-benzofuranyl)kene. 4. The bisbenzofuranyl ketone derivative and its salt according to claim 1, which is bis(7-nicotinoyloxy-2-benzofuranyl)ketone. 5 Bis(6-alanyloxy-2-benzofuranyl)
The bisbenzofuranyl ketone derivative and salt thereof according to claim 1, which is a ketone. 6 Bis(7-alanyloxy-2-benzofuranyl)
The bisbenzofuranyl ketone derivative and salt thereof according to claim 1, which is a ketone. 7. The bishenzofuranyl ken aA core according to claim 1, which is 7 bis(6-phenylalanyloxy-2-henzofuranyl) ken and salts thereof. 8. The bishensofuranyl ketone derivative and its salt according to claim 1, which is bis(7-phenylalanyloxy-2-benzofuranyl)ketone. 9 Bis(6-lysyloxy-2-benzofuranyl)'
r I-nte, 46 le 4. h] 5-sought range vj1 1st
'Jl +ij 1lffl Novischenfuranilkane1-Ah 'j'X I)
;. 10 Bis(7-lysylmegicy 2-benzofuranyl)
K1-C The hishenzofuranylkene derivatives and salts thereof according to claim 3ii, paragraph 1. 11 Bis(7-methionyloxene-benzofuranyl) 4, I'5 1? year of blue dreams u 17
1J No. 1 'J11fL14 Oni no Bisbensofuranilken 1-+'A 4l body and its 1st story. 12 general formula (in the formula, R, + is water 2j 7M or halodenka 11
+< , J, t; and 011 J, l
; is substituted at any position of the 11.5.6 or 7-position of the benzofuran ring). Lower alkyl J, (, pyridyl I, (,
or N-hensyloxycarbonyl-representing an amino acid residue) is characterized by reacting with an acid chloride or a substance (optionally followed by dehensyloxycarbonylation). General formula (wherein 1<, and I (means the same as the above,
The R1 group and 1(C) are the 4.5. groups of the pentufuran ring.
Bisbenzofuranylkene derivatives (4\ and its ζ
7 people made of 1A.