CA1315783C - Hydroxystyrene derivative - Google Patents

Abstract

Abstract of the Disclosure A hydroxystyrene derivative represented by the formula (I):

(I) wherein when R1 and R2 are the same or different and each is phenyl group, benzyl group or phenethyl group, or R1 is a group having the formula: R5O- in which R5 is hydrogen atom, an alkyl group having 1 to 5 carbon atoms or benzyl group and R2 is benzyl group or group having the formula: PhSCH2, R3 and R4 are taken together to represent a group having the formula: -CONH-CS-S-, a group having the formula: -CONH, a group having the formula: -CONHSO2- or a group having the formula:

in which R6 is a group having the formula: [in which X1 is hydrogen atom, a halogen atom, methyl group, ethyl group, an alkoxyl group having the formula: R7O- (in which R7 is methyl or ethyl group), nitro group, aminosulfonyl group or amino group, and m1 is 1 or 2], pyridyl group, furyl group or thienyl group, and n1 is 0 or an integer of 1 to 3; when R1 and R2 are the same or different and each is phenyl group, benzyl group or phenethyl group, or R1 is a group having the formula: R5O- in which R5 is as defined above, and R2 is benzyl group, R3 is cyano group and R4 is a carbamoyl group, or R3 and R4 are taken together to represent a group having the formula: -CO-Y-CH2CH2- in which Y is oxygen atom or -NH-, or a group having the formula:
-CO-?-NH-CO-; and when R1 and R2 are the same or different and each is an alkyl group having 1 to 3 carbon atoms, R3 and R4 are taken together to represent a group having the formula:

Description

3 ~
HYDROXYSTYRENE DERIV~TIVE

BACKGROUND OF THE INVENTION
The present invention relates to a novel hydroxystyrene derivative or a salt thereof, which has antiallergic activity, 5-lipoxygenase inhibiting activity, antibacterial activity, tyrosine kinase inhibiting activity, ultraviolet (hereinafter referred to as "W") absorbing activity and reverse transcriptase inhibiting activity and is useful as an intermediate for preparing various organic compounds, and relates to an antiallergic agent, a 5-lipoxygenase inhibiting agent, an antibacterial agent, a tyrosine kinase inhibiting agent, an W ab~orber and a reverse transcriptase inhibiting agent containing the same as an active ingredient.
The compound of the present invention is a novel compound which has not yet been reported in a literature and is first synthesized by the present inventors.
~ he objects of the present invention will become apparent from the description hereinafter.

SUMMARY OF THE INVENTION
. . _ . . .
It has now been found that a novel hydroxystyrene derivative of the present invention is a useful intermediate for preparing various organic compounds and has itself antiallergic activity, 5-lipoxygenase inhibiting activity, antibacterial activity, tyrosine kinase inhibiting activity, W absorbing activity and reverse transcriptase inhibiting activity.
In accordance with the present invention, there is provided a hydroxystyrene derivative represented the formula (I~:

Rl R3 HO ~ CH=C (I) R2-~-' \R4 ,~,

- 2 - ~.3 ~
wherein when Rl and R2 are the same or different and each is phenyl group, benzyl group or phenethyl group, or is a group having the formula: R50- in which R5 is hydrogen atom, an alkyl group having 1 to 5 carbon atoms or benzyl group and R2 is benzyl group or a group of PhSCH2 in which Ph is phenyl group, hereinafter the same, R3 and R4 are taken together to represent a group having the formula: -CONH-CS-S-, a group having the formula:

-CONH ~ , a group having the formula: -CONH ~ S02-or a group having the formula: -CO-N=C-S- in which NH(CH2)nlR6 R6 is a group having the formula: ~ (Xl)ml [in which xl is hydrogen atom, a halogen atom, methyl group, ethyl group, an alkoxyl group having the formula: R70~ (in which R7 is methyl group or ethyl group), nitro group, aminosulfonyl group or amino group, and ml is 1 or 2], pyridyl group, furyl group or thienyl group, and nl is O
or an integer of 1 to 3; when Rl and R2 are the same or different and each is phenyl group, ben~yl group or phenethyl groupr or Rl is a group having the formula:
R50- in which R5 is as defined above, and R2 is benzyl group, R3 is cyano group and R4 is carbamoyl group, or R3 and R4 are taken together to represent a group having the formula: -CO-Y-CH2CH2- in which Y is oxygen atom or -NH-, or a group having the formula: -CO-N-NH-CO-; and when Rl and R2 are the same or different and each is an alkyl group having 1 to 3 carbon atoms, R3 and R4 are taken together to represent a group having the formula:
-CO-N=C-S- in which nl and R6 are as defined above, NH(CH2)nlR6 or a salt thereof.
Also, in accordance with the present invention~
there is provided an antiallergic agent, a 5-lipoxygenase inhibiting agent, an antibacterial agent, a tyrosine _ 3 ~ 3 ~ ~ 7 ~ ~
kinase inhibiting agent, an W absorber or a reverse transcriptase inhibiting agent containing the hydroxystyrene derivative (I) or a pharmaceutically acceptable salt thereof as an active ingredientO

DETAILED DE _RIPTION
The compound having the formula (I) of the present invention can form a salt with a base or an acid. The salt of the present invention may be any which can be formed from the compound of the present invention and the base or the acid.
~ xamples of the salt with the base are, for instance, (1) a salt with metal, especially an alkali metal salt, an alkaline earth metal salt and a salt with aluminum; (2) an ammonium salt; and (3) an amine salt, especially a salt with methylamine, ethylamine, diethylamine, triethylamine, pyrrolidine, piperidine, morpholine, hexamethyleneimine, aniline or pyridine, and the like.
Examples of the salt with the acid are, for instance, (1) a salt with an inorganic acid, especially a salt with hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid or carbonic acid; (2) a salt with an organic acid, especially a salt with a carbo~ylic acid such as formic acid, acetic acid, propionic acid, succinic acid, oxalic acid, tartaric acid, maleic acid, lactic acid, benzoic acid, anthranilic acid or salicylic acid; a salt with a sulfonic acid such as p-toluenesulfonic acid or methanesulfonic acid; a salt with an amino acid such as glycine, methionine or lysine; and the like.
When the salts are employed for the antiallergic agent, the 5~1ipoxygenase inhibiting agent, the antibacterial agent, the tyrosine kinase inhibiting agent, the W absorber or the reverse transcriptase inhibiting agent, the pharmaceutically acceptable salts should be employed.
As typical examples of the compounds of the :~ 3 ~

invention, the compounds (1) to (45) are shown in Table 1 by showing the groups Rl, R2, R3 and R4 in the formula (I), and further, exemplifying the group R6 and nl in case that R3 and R4 are taken together to represent a group having the formula: -CO-N=C-S- . Also, the NH(CH2)nlR6 molecular formula, molecular weight, melting point, and data of elementary analysis of each compound of (1) to (45) are shown in Table 1. The results of lH-NMR
spectrum analysis and IX spectrum analysis of the compounds (1) to (45) are shown in Table 2.

~3~ 3 ~ , ~.~ ~ ~ ~n ~
~ ~U) ^ U~ _ ~ _ ~ _ ~ _ s 0 3~ o n2 Ln o ~ O ~ O ~ ,~
o In o u~ z ~r Z ~r Z Ln JJ
Z ~ ~:
n a~ na r~ O
~ ~ m~ CO m~ m U
U
~1 0 ~o ~:

I I . I

~, ~! ~ 1~ ~ ~o~

~ o o o o o , C~ ,u Y C' N ~ Uc S

~`J
s m ~ ~uq ~ ~ r n O O
U Z

- 6 - ~ J
_ o In o ~_ ~ .
Z E4d-~
.~n . l ~q ~ co a~
t~ _ C~
.
c m _ ~ r ~ ~: - a~ ~ o ~o 1`
~_ ~ 0~
c~ O~

~ ~ ~ r~l oo O
~ V _ ~ ~ ~~1 ~
o o o oo X ~ o O ~ o ~1 ~ Z

_~ l 0V ~
~ .,, u~ cn ~ u~ cn :~
a~
0 3 o ~r O a~ O ~1 0 O ~) ., Z In Z ~ Z ~o Z ~D Z ~ -L~
r~ 1 O
~: o ~ r~ ~ o ~ ~ ,~
~: ~

~ l l l l l ~D~

1:~ I U~
U C~
~; O Z Z O

D~

~; Ln ~
~a ~
~1 ra cO~ ~ ~ o o o c~ z - 8 - ~ 3 .
~, ~p t~
~-Z ~_ oo ~ o ~_ .U~ .
u~ ~ u~ 1 o o o ~
:C
, ~ o E o _ ~ ~ ~ ul m 1~
.
In C
_ U~
.
-- ~o ~ ~ CO
C~ In U~
C~
r~ ~ oo oo l`
~ _ ~ ~ o o O _ ~
~ Lr~

,1 ~ ~ oa~
.,, ~ _ ~: C) O O O O O
O -- ~ .1~
~: ~ o a~ o ~ a~
a~
.~ ~U~
C~
O O
C) Z

~ 9 ~JJ l 0 3 ~ 0~1` otY) ~ 0~ a~ ~-- ~
~1 Z ~ Z U') Z ~1 Z ~ Z ~ ~
o O
~ ~ m ~ m Ln ;~ r ~
a~
O N -- N -- N -- N

~ l ~D~ l l l l l ~r ~ O
~ o o o o Z

t`l S .C p~ P ~ .

~ ~r S
~:
a ~
O ~ Z ~

- 10 - :~3~ b~ ~

~ ~''1 .-1 N ~1 ~) ~) _ I` o a~ Il) ~1 .
~_ ~ CO ~
.,1 z ~a v ~: ~ ~ l N ~--1 O
O ~ ~ O a~ In C~
~ ~ l .Ul .
o~ ~ r~
~ C) ~p u~
ra C~ ~
m ~ ~ 0 V ~ _ O _ E~
.
~a ~ ~ O 1`
_ ~ a~
o~ ~
-- o c~ r~ l` ~ I` t`

~o o ~ ,~
_ ~ 0 E4- o ~r r oo r~

~ 0 a~ ~ ~ co a~
~: ~ ~ N
-~ V _ V S:: ~) O O O O O
O V V .1_~ V ~1 O O --X R~ o IJ7 0 1~
~ 11') ~ 0 r-'1:1 ~1 ~I N r~l r l .~
~:
O O ,~ ~ ~ ~ n ~1 , O O
Z

e ~ N ~ ~
~ a~ O -- ~-- O ^ O ^ O -- ~::
0 3 ~ N O In Z ~ N 00 N ~ ,1 r ~ r~ r Z Lr~ V
s~ ~ ~ O ~ ~~ ~ ~ O O
~ ,1 tq ~ m ~ D v :~ V ~r r~ N t~ ~ r~ --O

~ l ll l l l l~ I I t m O

Z O Zo Z;_s Z_~
o o ~;

~: ~

~: ~

V E~ ,1 ,1 ,1 ~I N
l ~o~ z;

~ o a~ l ~ _ ~ r o.
C~- ~ ~

Z ~ 0 o ~J ~ ~::
~_ a~ w ~_ ~ I
,~n .
ul ~ I~ a~ co ~o In dP
u~ Ln ~ ~r Lr m _ ~ ~0- In Ln E~

CJ ~ ~ O
~ ~ C~
~ I~
c) ~ ~ o a~
~0- ~ co ~

co ~o n ~ o o o o o o o --~: ~ o 1~
Ln U~ ~ o 'JJ
O O ~ I~ o U ~ ~
O O
U Z

- 13 ~ P) ~ `'i _ I

r~) r~l r~
~ Q~O -- O -~ O ~ O -- ~ ^ r 0 3r~ In r~ ~ ~ O ~ --I O 1` .
q~Z~ ~r) Z~D r`') Z'~' ~ Z~ . Z ' ~
fl~ _I N ~I r~ ,1 ~ ,~ ~ r~ ~ O
tC ~ tC o ~ rl~ r~7 ~o U
:~ rl~ r~) co r~ ~ r~7 r~
U ,~
~ ~01 U ~ l O ~

~; I I I I S

O O 0 5, ~ C~
r~ Z Z Z Z ~ Z
C~ C~ C) y O

r~l ~ ~ ~
~ m P:~ :r w ~

o o ~ Lt~ r~) O ~0 p, .~ ~
O O ,1 ~ r~
U O O r~ r~l r~l r~ r~

~l 3 ~

~ o~ ~
dP ~ U~ ~ O
~- CO
::

Z ~ o ~ co ~ - ~ o ~o- o~
,tQ .
~ ~ ~ ~ o o o ~1 U _ ~D N 0~ 1~ CO
.
~a ~ ~ Ln u~
~ ~I
~a ~ 1 ~ ~ dP
a~ ~o - u~
W
.
O ~ 0~ ~ ,1 C~ dP 01) ~
~ -- o o a~
O

~ _ Ln O W
O _ O O ~
~ I~

~ r~ o ~ u~ n .,~ ~ _ ~1 ~'d ~ N ~I
O O O O O
a) o -- J~
~ Q~ ~
a) .,, ~a O O ~
c~ O O N N N N N
O Z

- 1 5 - ~ 3 ~
_ I
~ ~ ~ ~ ~ .~s ~ ~ ~ U~ ~
o 3 O ~t) o ~ o ~I o ~ o ,_1 ._~
~D ~ ~ ~ ~D ~ U~ ~ U~ .
~ ~ Z Z ~ Z~ Zco ~r oD N O
11~ ~1t~ C)~ ~ ~~ I` t`J O N t` t) ,, :: m~
~ a a~ ~o1 U C~

~ P, ~0 s ~ s ~r ~ ~`J ~ N N
~ m U~
--æ c3_t¢
o C~ C~ Uo s '~ m tl ~ S C

,~ m m ~~
~o ~ U

O O ~ I` OD cr~ o r~
l C~ Z

:~ 3 ~

~:i ~
V _ ~ Lr) ~o In In U-:~
Z r S~ _ ~ O U~ D ~O~
~_ Lr .U~ .
_ ~1 ~ ~ .
~

h trl ~ ~_ ~ o 0 ~P .
~ ~ _ Ln .
~_ o ~
~ -- In C~
r~

,~
O _ U~ O U~ ~ ~
IL~ ~

~ ~P ~ a~ I` ~r .~ ~ ~ ~
~ ~ C~ O O O O O
,1.. -1 0 ~ ~ ~ J~
a) o --u~ ~ ~ In ~Y
~r ~ ~ I` ~
~ . f`~
.
O O w 1~ 0 a~ o C~ O O ~
~ Z

- 1 7 ~ 3 1~1~ l ~I C U~ ~

0 3O r-l O OO IY) O 1-'1 0 N C
LIN 1~ ~ 1N 11'1 ~i In N Lt7 C
~ la ~ ~ ~ o ~ tl ~ O
~ ~(~ ~ t~ I o N r-l U
~ ~m ~ m ~
~ ~a~
O a) N N N N N
~I) o c,~ V l~
~0 ~

~1 0 ~D~ ~ S
\~
U~
C C ~ C C
, m e~
u~
-)~Z u--~ Z C~_r Z Z Z Z iZ
~ O ~ O o I

m m~

O
mN
C~; y '' y Y

::~; ~C
C :1 O O
o ~
o o ~ Z

~ 3 ~

~ ~ l C) ~ ,~
U~
. ~
.
Z ~ u~ c c ,_ a~ o a~ ~
~0,-,u~ ~
~n :~ t~
a c~

m ~a r~ o oo ~ ~P
V ~ Ul ~ U~ O
~0 -O ~ ~ ~ o In C~
0 _ ~ a~ o o ~D
C~
ro ~
o ~_ ~r ~ o o ~D

r~
C ~ ~1 OD ~r r_ .~ .,. _ V C U o o o o o .~.
~
U) ~1 00 ~ 1 ~a V :~
O O ~ ~ ~ ~ In u e u zo 1 9 ~

~'3 ~ O~Ln O~ oP~l 3 ~J O a~ o~ z~ u) zOJ U~ z ~

O U UN U UN N O
~ ,1 ~1 ~t 'I 'I

~ ~ ~ U ~ o ~

~ U~ U~ U~ U~ U~

t ~Y U~
~ ~ ~ ,1 ,1 o e~ O ~ O

- 2 0 _~ e~ ~ ~ 7 ~, o ~ _ ~ o .t. ~o ~ l ~ ~ o U- ~
.
Z ~_ ~ o ~0 ,u~ .
~? ~a t~ ~ u~
a 0 ~0~ - U~ 9 Ul ~ t':
~ ~ ~0 ~ ~ C;~,~
.u ~ _a~
~ O-' In L~
.
~_~ O ~ O ~O
~1 ~P .
0 _ ~ Cl~
C~ ~

~a ~ o ~: _ 1~
d~ . . . . .
o _ ~ a~ I~ o ~

~ ~ o~
-~ JJ _ U
,~ ) - ~ ,U U
aJ O -- ~_ 1 ~1 ~ co O O ~ r~ o c~ o o ~
~ z ~J- l e .~ ~ n ~
h 11~ ~ G
0 3 O ~ O U~ O t~O O Lt~ O ~ ,~
~J Z ~ Z Z Z Z
u t~ ~ o 1~) It O
(lS ~1 ~ 1~ ~ O ~ O~
~ ~ ~ ~ :q ~ ~' ~ O ~ ~ ~
~

Z~ I
~o~$ ~ ~O~C,Q<~Z

~ O
~r ~
m~ ' qN I ~ I m~
-z ~ x ~_~
Z Z Z Z; Z
~) C) O o P~
~ .Y, .Y, .' .Y, .Y, _1~ pr~ m~
Y Y ~' Y Y
.r~

c~
l ~ Z

22 - ~ 3 .
~ ~ CO
U- ' '` ~

Z ~ CO
~ _ ~

~n .
_ un .
U -~:
r~
_ ~ ~ _ Ln .
I~D ~ a~
c~ ~ ~
~ _ ~
U Ln U
~ ~ I~
o _ co r~

~ ~O ~ OD 00 ~1 .~ ~ _ C~
~ ~ o ~ o o o ,,-,, O ~ ~a ~ ~ ~
~ Ln a~ o o ~O o t~ a~
~a .
O O ,~
~ O O
~ Z

~ 23 Table 2 Compound lH-~MR spectrum IR spectrum No. ~ (ppm) (cm 1) 1 CDCQ3/DMSO-d6 = 1/1;7.3-7.7(13H,m), KBr; 3540, 3150l 9.01(1H,br~, 13.4(1H,br) 3050, 1700, 1590 2 CDCQ3/DMSO-d6 = 1/1;4.03(4H,s), 7.0- KBr; 3330, 3300, 7.4(13H,m), 9.27(1H,br), 13.55(1H,br) 1680, 1570

3 CDCQ3/DMSO-d6 = 1/1;6.7-7.8(16Hrm), KBr; 3550, 3180, 8.33(1H,s), 8.6(1H,br), 10.4(1H,br) 3050, 1695, 1620,

4 CDCQ3/DMSO-d6 = 1/1;4.05(4H,s), 6.5- KBr; 3380, 3200, 7.3(16H,m), 7.45(1H,s), 9.0(1H,br), 1685, 1585 10.2(1H,br) CDCQ3/DMSO-d6 = 1/1;3.97(4H,s), 7.1- KBr; 3450, 3200, 7.8(16H,m), 7.75(1H,s), 9.5(1H,br) 3060, 1680, 1600 6 CDCQ3/DMSO-d6 = 2/1;1.40(3H,t), 4.10(2H, q), 4.16(2H,s), 4.70(2H,d), 7.0-7.7(15H, m), 9.1-9.6(1H,br), 9.7-lO.O(lH,br) 7 CDCQ3/DMSO-d6 = 1/1;4.15(2H,s), 6.9 KBr; 3440,3260, (2H,s), 7.0-8.6(8H,m), 10.0(2H,br~ 1670,1575 8 CDCQ3/DMSO-d6 = 1/1;4.18(2H~s), 5.18 KBr; 3520, 3120, (2H,s), 6.8-7.6(13H,m), 9.7(lH,br) 3050, 2850, 1675, 9 CDC~3/DMSO-d6 = 1/1;0.98(3H,t), 1.2- KBr; 3480, 3130, 1.9(4H,m), 4.05(2H,t), 4.17(2H,s), 3050, 2850, 1675, 6.97(2H,s), 7.0-7~3(5H,m), 7.42(1H,s), 1570 9.45(1H,br), 13.4(1H,br) CDCQ3/DMSO-d6 = 1/1;0.95(3H,t), 1.3- KBr; 3480, 3130, 2.0~4H,m), 3.93(2H,s), 4.02(2H,t), 3020, 2950, 2850, 6.8-7.4(7H,m), 7.45(1H,s), 9.28(1H,br) 1685, 1570 11 CDCQ3/DMSO-d6 = 1/1;4.19(2H,s), 6.7- KBr; 3420, 3180, 7.8(12H,m), 9.3(2H,br), 1003(1H,br) 1705, lS90 .
- continued 3 ~

- continued .
Compound lH-NMR spectrum IR spectrum No. ~ (ppm) (cm 1) 12 CDCQ3/DMSO-d6 = 1/1;4.22(2H,s), 5.25 KBr; 3505, 3150, (2H,s), 6.7-7.7(16H,m), 8.87(1H,d), 3080, 3050, 3020, 9.3(1H,br), 10.3(1~,br) 1670, 1615, 1580 13 CDCQ3/DMSO-d6 = 1/1;3.97(3H,s), 4.00 KBr; 3400, 3170, (2H,s), 6.7-7.6(11H,m), 8.77(1H,d), 3060, 1690, 1620, 9.2(1H,br), 10.4(1H,br) 1610, 1580 14 CDCQ3/DMSO-d6 = 1/1;0.94(3~,t), 1.3- KBr; 3160l 3130, 1.9(4H,m), 3.94(2H,s), 4.00(2H,t), 6.5- 3060, 3020, 2950, 7.5(12~,m), 8.9(1H,br), 10.4(1H,br) 1685, 1610 CDCQ3/DMSO-d6 = 1/1;7.3-7.8(12H,m), KBr; 3500, 3475, 7.85(2H,s), 8.15(1H,s), 9.25(1H,s) 3300, 3200, 2205, 1710, 15~0 16 CDC~3/DMSO-d6 = 1/1;4.00(4H,s), 7.1- KBr; 3400, 3320, 7.3(10H,m), 7.4(2H,br), 7.57(2H,s), 2205, 1660, 1565 7.90(1H,s), 9.5(1H,br) 17 CDCQ3/DMSO-d6 = 1/1;2.93(2H,t-d), 4.00 KBr; 3360, 1720 (4H,s), 4.30(2H,t), 7.0-7.3(13H,m), 1645, 1590 9.0(1~,br) 18 CDCQ3/DMSO-d6 = 1/1;2.77(~H,m), 3.30 KBr; 3400, 3200, (2H,m), 3.97(4H,s), 6.8-7.5(13H,m), 2900, 1685, 1640, 7.8(1H,br), 8.8(1H,br) 1600, 1580 19 CDC~3/DMSO-d6 = 1/1;7.0-8.0(16H,m), KBr; 3530, 3220, 8.48(1H,s), 8.53(1H,s), 9.3(1H,br) 3080, 1720, 1660, 1620, 1570 CDCQ3/DMSO-d6 = 1/1;4.00(4H,s), 7.0- KBr; 3150, 3060, 7.9(16H,m), 8.3(1H,s), 8.35(1H,s), 3020, 1700, 1655, 9.8(1H,br) 1620, 1570 21 CDCQ3/DMSO-d6 = 1/1;1.43(3H,t), 3.97 KBr; 3520, 3380, (2H,s), 4.12(2H,q), 7.1-7.3(6H,m), 3170, 2205, 1685, 7.43(2H,br), 7.60(1H,d), 8.00(1H,s), 1575 9.30(lH,br) - continu~d ~ 3 ~ J ~

- continued CompoundlH-NMR spectrum IR spectrum No. ~ ~ppm) (cm 1) 22 CDCQ3/DMSO-d6 = 1/1;3.87(3H,s), 3.93 KBr; 3500, 3370, (2H,s), 7.1-7.3(6H,m), 7.40(2H,br), 3170, 2200, 1665, 7.60(1H,d), 7.98(1H,s), 9.5(1H,br) 1570 23 CDCQ3/DMSO~d6 = 1/1;3.92(2H,s), 7.06 KBr; 3440, 3310, (lH,d), 7.1-7.3(5H,m), 7.4(2HIbr), 3250, 2210, 1660, 7.53(1H,d), 7.87(1H,s), 9.4(2H,br) 1590, 1570 24 CDCQ3/DMSO-d6 = 1/1;3.90(2H,s), 7.1- KBr; 3480, 31~0, 7.8(12H,m), 8.38(1H,dd), 9.9(2H,br) 1710, 1650, 1600, 25 CDCQ3/DMSO-d6 = 1/1;4.75(2H,d), 7.3- KBr; 3570, 3200, 7.7(18H,m), 8.8(1H,br), 9.84(1H,t) 2850, 1690, 1635, 1610, 1570 26 CDCQ3/DMSO-d6 = 1/1;4.00(4H,s), 4.82 KBr; 3300r 3200, (2H,d), 7.1-7.3(18H,m), 9.0(1H,br), 3010, 2880, 1660, 9.78(1~,t) 1610, 1590, 157 27 CDCQ3/DMSO-d6 = 1/1;4.13(2H,s), 4.72 KBr; 3550, 3180, (2H,s), 6.37(2H,d), 6.90(2H,s), 7.2- 2800, 1660, 1620, 7.5(6H,m), 7.57(1H,d), 9.8(3H,br) 1580 28 CDCQ3/DMSO-d6 = 2/1;1.40(3H,t), 4.10(2H, q), 4.16(2H,s), 4.70(2H,d), 7.03-7.73 (15H,m), 9.10-9.60(1H,br), 9.7-lO.O(lH,br) 29 CDCQ3/DMSO-d6 = 1/1;0.97(3H,t), 1.3- KBr; 3520, 3200, 2.0(4H,m), 4.03(2H,t), 4.13(2H,s), 3050, 2950, 2880, 4.72(2H,s), 6.9-7.5(13H,m) 1680, 1615, 1595 30 CDCQ3/DMSO-d6 = 1/1;1.02(3H,t), 1.3- KBr; 3520, 3200, 1.9(4H,m), 4.03(2H,s), 4.08(2H,t), 3020, 2900, 2870, 4.59(2H,s), 6.88(2H,s), 7.1-7.7(11H, 1670, 1590 m), 8.0(1H,br) 31 CDCQ3/DMSO-d6 = 1/1;4.17(2H,s), 4.87 KBr; 3500, 3200, (2H,s), 5.17(2H,s), 6.9-7.6(16H,m), 3060, 2770, 1680, 9.8(2H,br) 1630, 1610, 1590 . . . _ . . .
- continued P' rd~
- continued _ _ . . .. . _ . _ . _ Compound lH-NMR spectrum IR sp~ctrum No. ~ (ppm) (cm 1) _ _ _ 32 CDcQ3~l.3o(l2H,d)f 3.12(2H,m), 7.10 (2H,d), 7.41(2H,s), 7.52(1H,br), 7.90 (lH,s), 10.21(1H,br) 33 CDCQ3/DMSO-d6 = 10/1;1.20(12H,d), 3.30 (2H,m), 4.70(2H,s), 7.13(2H,s), 7.30 (5H,m), 7.56(1H,s), 9.30-9.80(1H,br) 34 CDCQ3/DMSO-d6 = 10/1;1.23(12H,d), 2.96(2H,t), 3.40(2H,m), 3.80(2H,q), 7020-7.40(7H,m), 7.53(1H,s), 8.40-8.70(1H,br), 9.46(1H,t) CDCQ3;1.23(12H,d), 3.36(2H,m), 4.76 (2H,d), 6.86-7.50(6H,m), 7.67(1H,s), 7.90-8.40(1H,br), 9.23-9.66(1H,br) 36 CDCQ3/DMSO-d6 = 10/1;1.26(12H,d), 3.36(2H,m), 4.70(2H,s), 7.20(2H,s), 7.33(4H,s), 7.07 (lH,s), 8.00-8.40(1H,br), 9.10-9.70(1H,br) 37 CDCQ3/DMSO-d6 = 10/1;1.23(12H,d), 3.33 (2H,m), 4.70(2H,d), 7.20 7.47(5H,m), 7.67 (l~,s), 7.80-8.20(1H,br), 9.20-9.60(1H,br) 38 CDCQ3/DMSO-d6 = 10/1;1.16(12H,d), 3.33 12H,m), 3.73(3H,s), 4.70(1H,s), 6.80~2H, d), 7.16(2H,s), 7.30(2H,d), 7.60(1H,s), 7.85-8.20(1H,br), 9.00-9.60(1H,br) 39 CDCQ3/DMSO-d6 = 10/1;1.23(12H,d), 2.33(3H,s), 3.36(2H,m), 4.70(2H,d), 7.06-7.26(6H,m), 7.66(1H,s), 8.0-8.3(1H,br), 9.30(1H,t) 40 CDCQ3/DMSO-d6 = 10/1;1.23(12H,d), 3.36 (2~,m), 4.87(2H,d), 7.16(2H,s), 7.50 (lH,s), 7.60(2H,d), 8.20(2H,d), 8.2-8.6 (lH,br), 9.67(1H,br) - continued - 27 - ~ 3 1.~ 3 - continued _ CompoundlH-NMR spectrum IR spectrum No. ~ (ppm) !cm~l) . _ . . . _ . . .
41 CDCQ3/DMSO-d6 = 10/1;1.23(12H,d), 3.16(2H,s), 3.33(2H,m), 4.80(2H,s), 6.96-7.90(7H,m), 8.0-8.4(1H,br), 9.63-9.76(1H,m) 42 CDCQ3/DMSO-d6 = 10/1;1.26(12H,d)~ 3.30 (2H,s), 3.36(2H,m), 4.66(2H,d), 6.63 (2H,d), 7.06(2H,d), 7.20(2H,s), 7.56 (lH,s), 8.4-8.8(1H,br), 9.5-9.7(1H,br) 43 CDCQ3/DMSO-d6 = 10/1jl.27(12H,d), 3.36 (2H,m), 4.80(2H,d), 6.36(2H,s), 7.26 (2H,s), 7.43(1H,s), 7.73(1H,s), 7.8-803 (l~,br), 9.1-9.5(1H,br) 44 CDcQ3/DMso-d6 = 10/1;1.26(12H,d), 3.36 (2H,m), 4.96(2H,d), 6.9-7.3(5H,m), 7O73 (lH,s)~ 7.8-8.4(1H,br), 9.40(1~,t) 45 CDC~3;1.23(12H,d), 3.2312E,m), 4.86 (2H,d), 7.06-7.46(5H,m), 7.66(1H,d), 7.76(1H,s), 8.50(1H,d), 8.7-9.1(lH,br) . , . _ . . _ . _ _ ~

The compound having the formula (I) of the present invention can be prepared by any processes as far as the compound can be obtainedl and there are exemplified the following processes (a), (b) and (c) as the preparation processes.
(a) The compound having the formula (I) can be prepared by a condensation reaction of a benzaldehyde having the formula tII):

Rl OO--~CHO ( I I ) R

wherein R8 and R9 are the same or different and each is an alkyl group having 1 to 3 carbon atoms, phenyl group, benzyl group or phenethyl group , or R8 is a group having the formula: RllO- in which Rll is hydrogen atom, an alkyl group having 1 to 5 carbon atoms or benzyl group, and R9 is benzyl group or a group: PhSCH2, and R10 is hydrogen atom, an alkyl group having 1 to 3 carbon atoms, an alkyl group substituted with ethers, e.g.
methoxymethyl group or methoxyethoxymethyl group, benzyl group, an acyl group having the formula: COR12 in which R12 is hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or a trialkylsilyl group such as trimethylsilyl group or tert-butyldimethylsilyl group;
and a compound having the formula (III):
~ R13 C~2 (III) ~Rl 4 wherein R13 is cyano group and R14 is carbamoyl group, or R13 and R14 are taken together to represent a group:
-CO-Y-CH2CH2- in which Y is oxygen atom or a group:
N(CoR15)- in which R15 is hydrogen atom or an alkyl group having 1 to 3 carbon atoms, a group:

~ 3 ~ 3 -CO-N~N~CO-, a group: -CON~-CS-S-, a group: -CO~

or a group: -CON~ ~ SO2-;

or a compound having the formula: (IV):

N ~ NU(C~2~n2R16 ~IV) wherein R16 is a group having the formula: ~ (X2)m2 [in which x2 is hydrogen atom, a halogen atom, methyl group, ethyl group, an alkoxyl group having the formula:
R17O- (in which R17 is methyl group or ethyl group), nitro group, aminosulfonyl group or amino yroup/ and ml is 1 or 2]l pyridyl group, furyl group or thienyl group, and n2 is 0 or an integer of 1 to 3;
in the absence or presence of an acid or a base as a catalyst.
Examples of the acid used as the catalyst in the above-mentioned reaction are, for instance, a proton acid such as sulfuric acid, benzenesulfonic acid or p-toluenesulfonic acid, a Lewis acid such as boron trifluoride, and the like.
Examples of the base used as the catalyst are, for instance, ammonium or its salt, an or~anic base such as piperidine, pyrrolidine, monoethanolamine, p~ridine, morpholine or 1,8-azabicyclo [5.4.0] undeca-7-ene or a salt thereof~ an alkali metal salt of or~anic acid such as sodium acetate or potassium acetate, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide, an alkali metal amide such as lithium diisopropylamide, an alkali metal alcoholate such as sodium methylate or potassium butylate, an alkali metal hydride such as sodium hydride or potassium hydride, and the like.
When R10 in the starting material is remained in the obtained product as an alkvl, an alkyl group substituted with ethers, ben~yl, an acyi, or trialkylsilyl group due to noncatalytic reaction or the kind of catalyst employed, the desired compound can be obtained by eliminating R10~ For eliminating R10~ when R10 is an alkyl group or an alkyl grou~ substituted with _~~e_~ cleavage re-c-ion which is carried out by using a Lewis acid such as aluminum chloride~ boron trifluoride or bo-ron tribromide or a proton acid such as hydrogen bromide or trichloroacetic acid, other ether bond cleavage reaction, or the like can be adopted. When R10 is benzyl group, catalytic reduction reaction can be employed which is carried out by using a noble metal catalyst such as palladium carbon, as well as the above-mentioned ether bond cleavage reaction. When R10 is an acyl group, R10 can be eliminated by hydrolysis reaction which is carried out by using a base such as an alkali metal hydroxide such as sodium hydroxide or an alkaline earth metal hydroxide such as barium hydroxide. ~hen R10 is trialkvlsily~ grou~, R10 c2n be eliminated with water, me_hanol, an acld, fluorine ion, or the like.
When the reaction is carried out by employing an N-acyllactam and an acyl group is remained in the obtained product, the acyl group can be eliminated by hydrolysis reaction using a base such as alkali metal hydroxide such as sodium hydroxide to give the desired compound.
(b) The compound having the formula (I) can be pre?ared, according to O. Ister et al. [~elvetica Chimica Acta (~elv. Chim. Acta), 40, 1242(1957)], G. A. Howie et 21. ~Journal of Medicinal Chemistry (J. Med. Chem.), 17, 840~1974)], ~. Wamhoff et al. [Synthesis, 331(1976)], and the like, by reacting a benzaldehyde having the formula (V):

~0 ~C~O (V) Rl9 s~
- 31 ~
wherein R18 and R19 are the same or different and each is an alkyl group having 1 to 3 carbon atoms, phenyl group, benzyl group or phenethyl group, or R18 is a group: R200-in which R20 is hydrogen atom, an alkyl group having 1 to

5 carbon atoms or ben2yl group, and R19 is benzyl group or the group: PhSC~2;
with an ylide having the formula (VI~:

(Ar)3P ~ (VI) wherein Ar is an aryl group, R21 is a cyano group, and R22 is carbamoyl group, or R21 and R22 are talcen together to represent a group having the formula:
-CO-Z-C~2C~2- in which Z is oxygen atom or -NH-, a group having the formula: -COI-N~-CO-, a group having the Ph formula: -CON~-CS-S-, a group having the formula:
-CONH ~ or a group having the formula: -CONH ~ S02-;

or an ylide having the formula (VII):

(Ar)3P1 S
O~`N ~ NH(CH2)n3R23 (VII) wherein R23 is a group having the formula: ~ (X )m3 [in which X3 is hydrogen atom, a halogen atom, methyl group, ethyl group, an alkoxyl group having the formula:
R240- (in which R24 is methyl group or ethyl group), nitro group, aminosulfonyl group or amino group, and m3 is 1 or 2], pyridyl group, furyl group or thienyl group, and n3 is O or an integer of 1 to 3.
The above-mentioned reaction (b) is carried out according to the so-called Wittig reaction. For the ylide in the reaction (b), a ylide derived from a trialkyl phosphine such as tributyl phosphine or a triaryl arsine such as triphenyl arsine can also be used as well as the above-mentioned ylide (VI) or (VII~.
(c) The compound, which is one of the embodiments of the present invention, having the formula (VIII):

HO ~ CH S (VIII) R26 O~N~N:E~(CH2)n4R27 wherein R25 and R26 are the same or different and each is an alkyl group having 1 to 3 carbon atoms, phenyl group, benzyl group or phenethyl group, or R25 is a group having the formula: R23O- in which R28 is hydrogen atom, an alkyl group having 1 to 5 carbon atorns or benzyl group, R26 is benzyl group or the group: PhSCH2, R27 is a group having the formula:

~ (X )m [in which X4 is hydrogen atom, a halogen atom, methyl group, ethyl group, an alkoxyl group having the formula: R29O- (in which R29 is methyl group or ethyl group), nitro group, aminosulfonyl group or amino group, and m4 is 1 or 2], pyridyl group, furyl group or thienyl group, and n4 is 0 or an intenger of 1 to 3, can be prepared, according to M. T. Omar et al. [Acta Chimica Academiae Scientiorum ~ungaricae (Acta Chim. Budapest)], 83, 359(1974); Indian Journal of Chemistry (Ind. J.
Chem.) 20B, 849(1981)], by reacting a compound having the formula (IX):

HO ~ CH ~ S (IX) R31 O N ~ S
H
wherein R30 and R31 are the same or different and each is an alkyl group having 1 to 3 carbon atoms~ phenyl group, benzyl group or phenethyl group, or R30 is a group having - 33 - ~ 3 ~
the formula: R32O- in which ~3~ is hydrogen atom, an alkyl group having 1 to 5 carbon atoms or benzyl group, and R31 is benzyl group or a group: PhSC~2;
or a compound having the formula (X):

HO~C~-r -- S ( X ) R34 ~ N ~ SR35 wherein R33 and R3~ are the same or different and each is an alkyl group having 1 to 3 carbon atoms, phenyl group, benzyl group or phenethyl group, or R33 is a group having the formula: R36O- in which R36 is hydrogen atom, an alkyl group having 1 to 5 carbon atoms or benzyl group, R34 is benzyl group or a group: PhSCH2, and R35 is an alkyl group having 1 to 3 carbon atoms;
with an amine having the formula (XI~:

H2N(C~2)n5R37 (XI) wherein R37 is a group having the formula~ )m5 [in which X5 is hydrogen atom, a halogen atom, methyl group, ethyl group, an alkoxyl group having the Cormula:
R38O- (in which R38 is methyl group or ethyl group), nitro group, aminosulfonyl group or amino group, and m5 is 1 or 2], pyridyl group, furyl group or thienyl group, and n5 is 0 or an integer of 1 to 3.
The novel hydroxystyrene derivative (I) of the present invention or a salt thereof is useful as an intermediate for preparing various organic compounds, and also useful as an antiallergic agent/ 5-lipoxygenase inhibiting agent, an antibacterial agent, a tyrosine kinase inhibiting agent, an W absorber or a reverse transcriptase inhibiting agent.
That is, the hydroxystyrene derivative can be expected to be used as an antiallergic agent and the like, by its antiallergic activity. By its 5-lipoxygenase inhibiting activity, it can be expected to - 3~ - ~3~
be used as an antiasthmatic agent, an antiinflammatory agent, agents for the treatments of psoriasis, nephritis and myocardial infarction, an agent for preventing myocardial infarction and the like. By its antibacterial activity, it can be expected to be used as an antibacterial agent. By its tyrosine kinase inhibiting activity, it can be used as an antiasthmatic agent, an antiinflammatory agent, an anti~cancer agent, a carcinogenesis preventing agent, a metastasis-preventing agent, an agent used for the treatment of mental disease and the like. By its W absorbing activity, it can be expected to be used for the prevention of erythema solare, used for preventing the deterioration of materials of organic high molecular weight compounds due to ultraviolet rays, and the like. Also, by its reverse transcriptase inhibiting activity, it can be expected to be used as an agent for preventing virus infections.
The above-mentioned activities of the compound of the present invention are specifically described by the following tests. In Tables 3 to 9, each compound No.
corresponds to the compound No. in Tables 1 and 2.
The antiallergic activity of the compound of the invention is proved by the tests of inhibitory activity against passive cutaneous anaphylaxis (hereinafter referred to as "PCA") reaction, inhibitory activity against antigen-induced anaphylactic shock and inhibitory activity against antigen~induced airway constriction.
(1) Inhibitory activity against homologous PCA reaction in rats Antiserum was prepared according to I.
Mota [Immunology, 7, 681(1964)] and the PCA reaction was conducted according to Maruyama et al. [Folia Pharmacologica Japonica, 74, 179(1978)].
Preparation of antiserum An ovalbumin solution dissolved in physiological saline (2 mg/mQ) was injected intramuscularly into both thighs of male Wistar rats ~ 35 ~ ~ 3 ~
weighing 200 to 260 g in a volume of 0.5 mQ/lOO g body weight, and pertussis vaccine tsordetella pertussis, 2 x 10l/mQ, Chiba Serum Institute) was intraperitoneally administered at 1 mQ/rat. Twelve days after sensitization, blood was taken from posterior aorta under ether anesthesia and antiserum was obtained and stored at -80C until use.
PCA reaction Groups of 4 male Wistar rats each, weighing 180 to 210 g, were used. Back of the rats was shaved and each 0.05 mQ of antiserum diluted 32 times with physiological saline was injected intradermally at four sites on the back. After 48 hours, 1 mQ of a mixture of ovalbumin (2 mg/m~) as an antigen and Evans blue (10 mg/mQ) in the volume ratio of 1 : 1, which was dissolved in physiological saline was injected intravenously into the tail. Thirty minutes later, the rats were bled to death under ether anesthesia and the back skin of the rats was removed. The blue-dyed area formed by pigment exudation was measured and an inhibition rate (%) was calculated as compared with control according to the following equation.

A - B
Inhibition rate (~ x 100 A

A: Blue-dyed area in the control group B: Blue-dyed area in the test compound group A test compound suspended in a 2.5 ~ aqueous solution of gum arabic containing 0.2 % Tween 80 was administered orally in a volume of 0.5 mQ/lO0 g body weight l hour before the injection of antigen. To the control group, only the vehicle was administered.
Tranilast which was a positive control compound was administered orally 30 minutes before the injection of antigen. The result shown in Table 3 proves that the compound of the present invention shows an excellent PCA

reaction inhibitory activity.

~able 3 _ _ 5Compound No. Dose (mg/kg)Inhibition rate ~) 15tranilast 300 40 (2) Inhibitory activity against antigen-induced anaphylactic shock in actively sensitized guinea pigs Antigen-induced anaphylactic shock death was observed according to John P. Devlin [Pulmonary and Antiallergic Drugs~ John Wiley & Sons, 155(1985~]
employing actlvely sensitized guinea pigs.
Each 100 mg/kg of body weight ovalbumin dissolved in physiological saline was injected into gluteus and into peritoneal cavity of male guinea pigs weighing 250 to 350 g. Three days later, the animals were further injected intraperitoneally with ovalbumin (100 mg/kg body weight) to conduct booster. Those animals were employed for testing 3 to 4 weeks after the sensitization.
Groups of 4 or more actively sensitized guinea pigs each were pretreated by subcutaneously injecting pyrilamine (1 mg/kg body weight) 30 minutes before antigen inhalation to suppress histamine-dependent response and propranolol (1 mg/kg body weight) to enhance the response induced by other than histamine 10 minutes before the antigen inhalation.

r~

The animal was placed in a desiccator with a capacity of about 5 Q and 0.5 % aqueous solution of ovalbumin in the state of aerosol was inhaled with ultrasonic type nebulizer for five minutes. ~naphylactic shock death was observed and the animals survived for 90 minutes or more after antigen inhalation were estimated to be protected. All the animals of the control group died due to anaphylactic shock. The results are shown in Table 4. The compounds of the present invention and therapeutic antiasthmatic agent (tranilast, theophylline) were administered orally 30 minutes before the antigen inhalation. The result shown in Table 4 proves that the compounds of the present invention shows an excellent inhibitory activity against anaphylactic shock.
Table 4 . _ _ Compound No.Dose (mg/kg) Protecting effect*
. . _ 38 100 1/~
39 100 1~4 tranilast 100 0/4 theophylline 30 2/4 control - 0/20 ... . . _ . _ _ _ .. . .
(note) * Number of survivors/Number of animals used (3) Inhibitory activity against antigen-induced airway constriction in actively sensitized guinea pigs According to Orange and Moore [Journal of Immunology (J. Immunol.), 116, 392(1976)], an emulsion of a solution of ovalbumin dissolved in phvsiological saline (2 mg/mQ) and Freund's complete adjuvant (Difco Laboratories), mixed in the equal volume was injected ~^3~cr ~;~

into peritoneal cavity of guinea pigs in the volume of 1 mQ/guinea pig to sensitize them. Three or four weeks later, airway contraction caused by antigen-antibody reaction was measured in accordance with Konzett Rossler [Archiv f~r Experimental Pathologie und Pharmakologie (Arch. Exp. Path. Pharmak.), 195, 71(19~0)]. That is, the sensitized guinea pigs (5 guinea pigs/group) were provided with artificial respiration by inserting a tracheal cannula under urethane anesthesia (1.5 g/kg body weight, intraperitoneal administration), and then, gallamine at 1 mg/kg body weight was injected intravenously) to stop spontaneous respiration of the guinea pigs. Inhalation of 0.5 % aqueous solution of ovalbumin was conducted using a nebulizer for 1 minute to increase antigen-induced airway constriction, at the same time, airway pressure was recorded through a transducer. Test compound was administered into jugular vein (i.v.) of the guinea pig 3 minutes before the antigen inhalation or administered orally (p.o.) 2 hours before the antigen inhalation. The control group received the vehicle. As a positive control compound, theophylline which was a drug for anti-asthma was used.
The effect of the compound was estimated bY calculating the maximum value of airway constriction (%) in comparison with the control group, according to the following equation.

A - B
Inhibition rate (%) = ~-- x 100 A

A: Maximum value of airway constriction iII the con-trol group B: Maximum value of airway constriction iII the test compound group The result shown in Table 5 proves that the compounds of the present invention shows excellent - 39 - ~ t~
inhibitory activity against antigen-induced airway constriction.
Table 5 . _ . . .
Compound ~oute of Dose Inhibition rate No. administration (mg/kg) (~) . . _ _ . . _ 7 i.v. 1 25 8 i.v. 1 43 9 i.v. 1 20 11 i.v. 1 52 11 p.o. 30 26 12 i.v. 1 32 26 i.v. 1 68 15 3~ i.v. 2 23 33 i.v. 2 26 37 i.v. 1 21 39 i.v. 1 59 42 i.v. 5 33 20 ~3 i.v. 5 21 i.v. 1 42 theophylline i.v. 1 31 _ ... .. . _ 5-Lipoxygenase inhibiting activity of the compound of the present invention was measured referring to the method for measuring 5-lipoxygenase activity by K.
Ochi et al. [Journal of Biological Chemistry (J. Biol.
Chem.), 258, 5754(1983)].
Sterilized 2 % solution of casein (pH 7) was injected intraperitoneally into Hartley guinea ~igs in a volume of 5 mQ/100 g body weight. Fifteen hours later, the guinea pigs were killed and peritoneal exudate cells thereof were collected. After the exudate cells were washed with 17 mM Tris-HCQ buffer (pH 7.4) containing O.74 ~ ammonium chloride to remove contaminating erythrocytes, the residual cells (leukocytes) were washed with buffer A (130 mM NaCQ, 1 mM EDTA, 25 mM sodium phosphate, pH 7.4). The washed cells were suspended in bufer B (50 mM sodium phosphater 1 mM EDTA, Ool gelatin, pH 7.~) at 108 cells/mQ, sonicated and centrifuged a~ 10,000 x g for 20 minutes under the cold atmosphere. The obtained supernatant was further centrifuged at 105,000 x g for 60 minutes under the cold atmopshere. The cytosol fraction was obtained and used as an enzyme solution of 5-lipoxygenase.
The enzyme solution was preincubated with the test compound in the presence of lmM CaCQ2, 1 mM reduced glutathione (GSH) and 2n~ ATP at 30C for 5 minutes in 0.2 m~ of a reaction mixture and the mixture was further incubated at 30C for 5 minutes by adding 20 ~M [1-14C]
arachidonic acid t0.1 yci) thereto. The test compounds were dissolved in ethanol to give the reaction mixture containing 2 % ethanol as a final concentration. Only ethanol was added to the reaction mixture as a control group.
To the reaction mixture were added 2.~ m~ of a mixture of chloroform and methanol (2/1 by volu~e) and 0.3 m~ of 40 mM citrate to stop the reaction. The mixture was vortexed and an organic solvent layer was evaporated to dryness under nitrogen gas. After dissolving the dried organic layer in a fixed amount of the mixture of chloroform and methanol 12/1 by volume~, it was spotted on a silica gel plate (Kiesel gel 60F254, E. Merck) and 5-lipoxygenase products were separated using the solvent system of an organic solvent layer of ethyl acetate/water/2,2,4-trimethylpentane/acetic acid =
30 11/10/5/2 by volume. After the radioactive position of the product was determined by means of a radioautography, an area equivalent to that of 5-hydroxyeicosatetraenoic acid (hereinafter referred to as ''5-HETE'I) was scraped off, and then its radioactivity was measured with a liquid scintillation counter. With regarding the amount of the generated 5-HETE as the 5-lipoxygenase inhibiting activity, the inhibition rate (%) in comparison with the control group was calculated according to the following ~ 3 ~

equation.

A - B
Inhibition rate (~ ~~~ x 100 A
A: Value of radioactivity in the control group B: Value of radioactivity in the test compound group The 5-lipoxygenase inhibiting activity of the compounds of the present invention is shown in Table 6.
The result shown in Table 6 proves that the compounds of the present invention sufficiently inhibits 5-lipoxygenase activity.

Table_6 . . . _ . . _ Compound Concentration* Inhibition rate 20No. (lIM) (~6) _ _ _ . . ... _ 1 ~3 _ _ _ _ _ - continued - ~2 - ~ 3 ~ ~y .~
- continued .. _ _ . ... _ _ ..
Compound Concentration* Inhibition rate No. (~M) -- . . . _ _.
23 10 ~5 ~9 43 ~ 53 _ _ . . . _ _ _ _ ., _5 (note) * Concentration of the test compound in the reaction mi~ture The antibacterial activity against Gram-positive bacteria of the compound of the present 30 invention was measured according to a standard method of Nippon Kagaku Ryoho Gakkai [Nippon Kagaku Ryoho Gakkaishi tJournal of the Chemical therapy of Japan), 29, 76(1981) ] .
As for gram-positive bacteria, after 35 cultivation in Mueller Hinton broth medium (made by Difco Co., Ltd.), there was prepared a bacterial suspension for inoculation containing about 106 of the bacteria per 1 mQ
of the medium. On the other hand, the test compound was ~ 3 ~
- ~3 added to Mueller Hinton ager medium (made by Difco Co., Ltd.) so as to give a serial dilution ager medium. Then, the above-mentioned bacterial suspension for inoculation was streaked to each agar medium for about 2 cm with a nichrome wire (inner diameter: about 1 mm).
After that the each agar medium was cultured at 37C for lB to 20 hours~ the growth of the test bacteria was determined. The minimum concentration of the test compound, which completely inhibited the growth of the test bacteria, was decided as a minimal inhibitory concentration (hereinaf-ter referred to as "MIC").
As for acid-fast bacteria, after cultured in glycerol broth medium, there was prepared a bacterial suspension for inoculation containing about 106 of the bacteria per 1 mQ of the medium. On the other hand, there were prepared some glycerol Czapek agar plating media with adding the test compounds, and thereto the bacterial suspension for inoculation was streakedO
After the each agar plating medium, to which the acid-fast bacteria was streaked, was cultured at 37C
for 40 to 42 hours, MIC was determined as defined above.
As the result, each MIC of the test compounds (1)l (2), (4), (11), (15), (16), (19) and (20) against 25 Micrococcus luteus IFO 13867 was not more than 6 ~g/mQ, not more than 6 ~g/mQ, not more than 6 ~g/mQ, 12 ~g/mQ~
60 ~g/mQ, not more than 15 ~g/mQ, 50 ~g/mQ and not more than 50 ~g/mQ respectively; each MIC of the test compounds (1), (2), (11), (15), (16), (19), (20) and (41) 30 against Bacillus subtilis IFO 3134 was not more than 6 ~g/mQ, not more than 6 ~g/mQ~ not more than 6 ug/mQ, 100 ~g/mQ, not more than 15 ~g/mQ, 100 ~g/mQ, 50 ~g/mQ and 25 ~g/mQ respectively; each MIC of the test compounds (1), (2), (11), (15), (16), (19), (20) and (41) against 35 Staphylococcus aureus IFO 12732 was 12 ~g/mQ, 12 ~g/mQ, 25 ~g/mQ, 60 ~g/mQ, not more than 15 ~g/mQ, 100 ~g/m~, 100 ~g/mQ and 50 ~g/mQ respectively; and each MIC of the test compounds (1), (15), (16), (19), (28), (30), (31), - 44 ~ i3 (32), (33), (34), ~35), (41), (42), (43), (44) and (45) against Mycobacterium sme~matis ATCC 607 was 6 ~g/mQ, not more than 15 ~g/mQ, not more than 15 ~g/mQ, not more than 5 ~g/mQ, not more than 15 ~g/mQ, not more than 6 ~g/mQ~
not more than 6 ~g/mQ, not more than 6 ~g/mQ, not more than 15 ~g/mQ, not more than 6 ~g/m~, 15 ~g/mQ, 25 ~g/mQ, not more than 15 ~g/m~, not more than 6 ~g/m~, 2 ~/mQ
and not more than 6 ~g/mQ respectively.
Consequently, it was found that the compounds of the present invention were effective on both gram-positive and acid-fast bacteria.
Tyrosine kinase inhibiting activity of the compound of the present invention was measured referring to a method for measuring tyrosine kinase activity by G.
Carpenter or by S. Cohen et al. [J. Biol. Chem.~ 254, 4884(1979); J. Biol. Chem., 257, 1528(1982)].
Cell line A-431 derived from human epidermoid carcinoma (ATCC CRL1555) was cultured at 37C under the condition of 5 % CO2 in Dulbecco's modified Eagle's medium (made by NISSUI PHARMACEUTIC~L CO., LTD.) containing 10 ~ by volume fetal bovine serum, 50 ~g/mQ of streptomycin, 50 IU/mQ of penicillin G and 50 ~g/mQ of kanamycin. The obtained cel]s were treated according to the above-mentioned method of Cohen or Carpenter et al.
to give membrane preparation containing epidermal growth factor receptor-tyrosine kinase complex (hereinafter referred to as "membrane preparation"). The membrane preparation was employed in the following measurement without solubilization.
A test compound dissolved in dimethylsulfoxide (hereinafter referred to as "DMSO") was added to a mixture of 20 mM of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid buffer (pH 7.4), 1 mM of MnC~2, 7.5 ~g of bovine serum albumin and the membrane preparation (10 ~g as protein). After incubation at 0C for 5 minu-tes, 100 ng of epidermal ~rowth factor (hereinafter referred to as "EGF") was added thereto and the mixture was further incubated at 0C for 15 minutes. [r-32P]RTP

(3000 Ci/mmol, 0.1 ~Ci~ was added thereto to make final volume of 70 ~Q. After incubation at 0C for 15 minutes, 50 ~Q of the reaction mixture was soaked into Whatman 3 MM filter paper (made by Whatman Ltd.) and immediately S the reaction was stopped by an aqueous solution of 10 by weight trichloroacetic acid containing 10 mM sodium pyrophosphate. The filter paper was sufficiently washed with the same solution and then washed with ethanol, and dried. Radioactivity present in the filter paper was measured by liquid scintillation counter (A). Also, radioacti~ity was measured in case of the reaction without EGF (B), the reaction without the test compound (C), and the reaction without both EGF and the test compound (D) as a control.
Tyrosine kinase inhibition rate (%) was calculated by the following equation.

(C - D) - ~A - B) Innhibition rate (~ - x 100 C - D

The result proves that the compounds of the present invention shows excellent tyrosine kinase inhibitory activity.
There is shown each tyrosine kinase inhibition rate of the compounds of the present invention in Table 7.

*Trade-mark ~ 3 ~

Table 7 .
Compound Concentration* Inhibition rate No. t~M3 _ (%) _ . . . _ _ . __ . _ . _ _ _ 1 l 23 7 lO S9 8 lO 69 9 lO 50 11 lO 52 14 1 ~3 l 100 16 l lO0 l 46 21 l 98 26 lO 62 31 lO ~1 - continued ~ 3 ~ ~ t)~~

- continued Compound Concentration* Inhibition rate No. (llM) (%) _ ~0 10 21 ~3 10 95 .. .. _ .
(note) * Concentration of the test compound in the reaction mixture Additionally, the compounds of the precent invention have W absorbing activity and thus there are expected to use the compounds as the W absorber in order to prevent a living body from dermatitis solaris (generally called as sunburn), prevent organic high molecular materials (e.g. plastics, gum, paints and the like) from declining by W -ray or prevent photographs and pictures from discoloring by UV-ray.
Each W absorption spectrum of the compounds of the present invention was measured according to the conventional method, in which methanol was used as a solvent, and thereby molar extinction coefficient thereof was calculated. The results were shown in Table 8. It is found that, as shown in Table 8, the compounds of the present invention rather strongly absorb W -ray~

- ~8 Table 8 . _ . . . _ ~
Compound ~ max molar extinction No. (nm) coefficient 4 257 1.87 x 104 361 1.80 x 104 . _ . . _ _ . _ 271 2.04 x 104 348 2.11 x 10 . . ~ . _ . ._ 249 1.51 x 104 347 2.40 x 104 .. . . _ 18 304 1~87 x 104 _ _ . _ There was found the following point by using reverse transcriptase derived from Moloney-Murine Leukemia Virus (hereinafter referred to as "M-MLV").
The compound of the present invention was dissolved in DMSO to give a 100 mM solution thereof.
Then, the solution was diluted with water containing DMSO
to give a solution of the test compound having a defined concentration. A mixed ratio of DMSO and distilled water was adjusted so that the concentration of DMSO at this time is 10 % by volume and a final concentration of DMSO
at the beginning of a reaction is 1 % by volume.
The thus prepared solution of the test compound 0 was added to a solution containin~ 50 mM of Tris-~CQ
buffer (pH 8.3), 8 mM of MgCQ2, 30 mM of NaCQ, 50 mM of dithio threitol (made by Wako Pure Chemical Industries Ltd.), 0.2 mM of thymidine-5'-triphosphate (m~de by Pharmacia K. K.) and 6 U/mQ of reverse transcriptase derived from M-MLV (made by Pharmacia K. K.) at 37C for 30 minutes. After there was added thereto 10 ~g/mQ of polyadenylic acid, 0.01 U/m~ of oligodeoxy thymidylic acid (made by Pharmacia K. K.) and 10 ~Ci/mQ of [methyl-' i ."

3~] thymidine-5'-triphosphate (made by ~mersharn ~apan Co., Ltd., 47 Ci/mmol) to give a reaction mixture, the mixture was further incubated at 37C for 30 minutes, followed by cooling with ice to stop the reaction.
The radioactivity incorporated into deoxyribonucleic acids was measured according to the method of Linteril et al (Science, 170, ~47 to 449 (1967)) After 50 ~Q of the reaction mixture was soaked into DE-81 filter paper (made by Whatman Ltd.), the filter paper was washed with 5 % by weight of Na2HP04 solution for three times, distilled water and ethanol successively by one and then dried. Radioactivity contained in the filter paper was measured by liquid scintillation counter to give the each radioactivity of the test solution groups.
On the other hand, the same procedure as above was carried out using DMSO-distilled water without the test compound instead of using the test solution, to give the value of radioactivity of a control group.
Reverse transcriptase derived from M-MLV
inhibition rate (%) was calculated by the following equation.

A - B
Inhibition rate (%) = x 100 A: radioactivity of the control group B: radioactivity of the test solution group The typical examples of reverse transcriptase derived from M-MLV inhibiting aclivity of the compounds of the present invention are shown in Table 9.
The results proves that the compounds shown in Table 1 have strong inhibiting activity against reverse transcriptase derived from M-MLV and thus it can be expected that the compounds show sufficient growth inhibiting effect on retrovirus having reverse ~ ~ 6 transcriptase.

Table 9 5CompoundConcentration*Inhibition rate No. (~M) (%) . _ _

6 10 98

7 1 98

8 1 98

9 1 73 _ _ _ _ _ (Note) * Concentration of the test compound in the reaction mixture Acute toxicity test Groups of 6 female ICR mice each, each mouse weighing 23 to 26 g, were employed. The compounds (1) to (45) suspended in an aqueous solution of 2.5 % gum arabic containing 0.2 % Tween 80 were administered orally to each mouse in a volume of 0.1 m~/10 g body weight. The general symptoms of the mice were observed for two weeks after the administration. The LD50 (mg/kg) values were estimated from the ratio of the number of dead mice to the number of mice used. ~s a result, there were observed no dead mice at a dose of 500 mg/lcg. The LD50 of the compounds (1) to (45) of the present invention was estimated to be not less than 500 mg/kg, which proved a low toxicity of the compounds of the present invention.
Preparations and Dosage The antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agents~ tyrosine kinase inhibiting agents, W absorber or reverse transcriptase inhibiting agents of the present invention can be administered orally, rectally, or parenterally in pharmaceutical dosage form, for example, tablets, capsules, fine subtilaes, syrups, suppositories, ointments, injections and the like.
For an excipient of the antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agent,tyrosine kinase inhibiting agents, W absorber or reverse transcriptase inhibiting agents o~ the present invention, organic or inorganic phar~aceutically acceptable excipient material is employed in a solid or liquid state, which is usually inactive and suited for oral, rectal or parenteral administration~ Examples of such excipient are, for instance, crystalline cellulose, gelatin, lactose, starch, magnesium stearate, talc, vegetable or animal fat and oil, gum, polyalkyleneglycol, and the like~ The ratio of the compound of -the present invention having the formula (I), contained in the antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agents, tyrosine kinase inhibiting agents, W absorber or reverse transcriptase inhibiting agents as an active ingredient in the formulation may vary in the range from 0.2 to 100 %.
The antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agents, the tyrosine kinase inhibiting agents, W absorber or reverse transcriptase inhibiting agents of the present invention may contain other antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agents, tyrosine kinase inhibiting agents, W absorber, reverse transcriptase inhibiting agents or any other drugs, which are compatible with the agents of the present invention. In this case, it is needless to say that the antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agents, tyrosine kinase inhibiting agents, W absorber or reverse transcriptase inhibiting agents of .he present invention may not be the principal ingredients in the formulation.
The antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agent, the tyrosine ~inase inhibiting agents, W absorber or reverse transcriptase inhibiting agents of the present invention are administered at a dose where the desired activity is generally achieved without any side effects.
Though a practical dose should be determined by a physician, the compound of the present invention having the formula (I), which is an active ingredient of the agents of the present invention, is generally administered at a dose from 10 mg of 10 9, preferably from 20 mg to 5 g, for an adult a day. The antiallergic agents, 5-lipoxygenase inhibiting agents, antibacterial agents, tyrosine kinase inhibiting agents, W absorber or reverse transcriptase inhibiting agents of the present invention can be administered as a pharmaceutical formulation which contains 1 mg to 5 gl preferably 3 mg to 1 g of the compound having the formula (I) as an active ingredient.
The present invention is more specifically described and explained by means of the following Examples. It is to be understood that the present invention is not limited to Examples, and various changes and modifications may be made in the invention without departing from the spirit and scope thereof.

Example 1 [Preparation of the compound (1)]
In 100 mQ of benzene were dissolved 1.37 g of 3,5-diphenyl-4-hydroxybenzaldehyde and 0.82 g of ~ 3 ~

rhodanine, and thereto 0.1 m~ of piperidine and 0.5 m~ of acetic acid were added. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. After cooling, the deposited crystals were filtered and subjected to crystallization from a mixed solvent of benzene and acetone to give 1.2 g (yield: 62 ~) of the compound (1).
The melting point and data of elementary analysis of the obtained compound (1) are shown in Table 1. And results of lH-NMR and IR of the obtaine~ compound (1~ are shown in Table 2.

Examp~
[Preparation of the compound (4)]
In 70 mQ of benzene were dissolved 1.51 g of 3,5-dibenzyl-4-hydroxybenzaldehyde and 0.67 g of oxyindol, and thereto 0.1 m~ of piperidine and 0.5 mQ of acetic acid were added. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. After cooling, the solvent was distilled away under reduced pressure. The obtained residue was dissolved in 200 m~ of chloroform, washed with water and dried with sodium sulfate. Chloroform was distille~ away under reduced pressure, the residue was subjected to crystallization from ethanol to give 600 mg (yield: 29 ~) of the compound (4).
The melting point and data of elementary analysis of the obtained compound (4) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (4) are shown in Table 2.

Example 3 [Preparation of the compound (5)]
In 70 mQ of benzene were dissolved 0.61 g of 3,5-dibenzyl-4-hydroxybenzaldehyde and 0.39 g of 2~-1,4-benzothiazine-3(4H)-one-1,1-dioxide, and thereto 0.1 mQ
of piperidine and 0.5 m~ of acetic acid were added. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. After cooling, the solvent was dlstilled away under reduced pressure.
~he obtained residue was subjected to a column-chromatography (carrier: silica-gel) and eluted with mixed solvent of chloroform/methanol (98/2: v/v).
fraction containing the desired compound was concentrated and the obtained residue was subjected to crystallization from benzene to give 180 m~ (yield: l9 %) of the compound (5).
The melting point and data of elementary analysis of the obtained compound (5) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (5) are shown in Table 2.

Example 4 [Preparation of the compound (7)]
To lO0 mQ of benzene were added 2.6 9 of 5-phenylthiomethylprotocatechuic aldehyde, l.33 g of rhodanine, O.l mQ of piperidine and 0.5 m~ of acetic acid. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced.
After cooling, the deposited crystals were filtered off from the reaction mixture and the obtained crystals were recrystallized from ethanol to give 2.78 g (yield: 74 %) of the compound (7).
The melting point and data of elementary analysis of the obtained compound (7) are shown in Table 1. And results of l~-NMR and IR of the obtained compound (7) are shown in Table 2.
Example 5 [Preparation of the compound (ll)]
In 70 mQ of benzene were dissolved 0.78 g of 5-phenylthiomethylprotocatechuic aldehyde and 0.4 g of oxyindol, and thereto O.l m~ of piperidine and 0.5 m~ of acetic acid were added. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. Af ter cooling, the deposited crystals o~

were filtered off from the reaction mixture and washed with benzene. And the obtained crystals were recrystalliæed from a mixed solvent of benzene and acetone to give 1.0 g (yield: 90 ~) of the compound (11).
The melting point and data of elementary analysis of the obtained compound (11) are shown in Table 1. And results of l~-NMR and IR of the obtained compound (11) are shown in Table 2.

Example 6 [Preparation of the compound (12)]
A condensation of 0.7 9 of 3-benzyloxy~4 hydroxy-5-phenylthiomethylbenzaldehyde and 0.27 g of oxyindol was carried out in the same manner as in the above Example 1. And the obtained residue was subjected to a column-chromatography (carrier: silica~gel) and eluted with mixed solvent of chloroform/methanol (98/2:
v/v). After a fraction containing the desired compound was concentrated under reduced pressure, the fraction was subjected to crystallization from ethanol to give 0.62 g (yield: 66 ~) of the compound (12).
The melting poin~ and data of elementary analysis of the obtained compound (12) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (12) are shown in Table 2.

Example 7 [Preparation of the compound (15)]
In 200 mQ of benzene were dissolved 2.90 g Gf 3,5-diphenyl-4-hydroxybenzaldehyde and ~40 mg of -cyanoacetoamide, and thereto 0.1 m~ of piperidine and 0.5 mQ of acetic acid were added. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. After the solvent was distilled away under reduced pressure, the obtained residue was subjected to a column-chromatography (carrier: silica-gel) and eluted with a mixed solvent of chloroform/methanol (98/2: v/v). A fraction containing ~ 56 the desired compound was concentrated and the obtained residue was subjected to crystallization from a mixed solvent of benzene and acetone to give 11.15 g (yield: 32 %) of the compound (15).
The melting point and data of elementary analysis of the obtained compound (15) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (15) are shown in Table 2.

Example 8 [Preparation of the compound (17)~
To 50 mQ of acetonitrile were added 760 mg of 3,5-dibenzyl-4-hydroxybenzaldehyde and 1.04 g of ~-triphenylphosphoranylidene-y-butyrolactone. The mixture was heated and stirred overnight at 80C. After cooling, the deposited crystals were filtered and subjected to crystallization from ethanol to give 450 mg (yield: 48 %) of the compound (17).
The meltin~ point and data of elementary analysis of the obtained compound (17) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (17) are shown in Table 2.

Example 9 [Preparation of the compound (18)]
In 50 mQ of dried benzene was suspended 0.6 g of sodium hydride under nitrogen atomosphere, to which a solution of 1.73 g of 3,5-dibenzyl-4-methoxymethoxy-benzaldehyde and 1.27 g of N-acetylpyrrolidone dissolved in 20 mQ of benzene was added dropwise r subsequently heated and stirred overnight at 50C. After cooling, the reaction solution was added to an ice water and extracted with chloroform. The solvent was distilled away from the obtained extract under reduced pressure. The obtained residue was dissolved in 50 mQ of dried methylene chloride, which was added with ~ mQ of trifluoroacetic acid and stirred for 3 hours at room temperature. The solvent was distilled away from the solution under reduced pressure, the obtained residue was subjected to a column-chromatography (carrier: silica-gel) and eluted with mixed solvent of chloroform/methanol (98/2: v/v). A
fraction containing the desired compound was concentrated and the obtained residue was sub~ected to crystallization from ethanol to give 450 mg (yield: 21 %) of the compound (18).
The melting point and date of elementary analysis of the obtained compound (18) are shown in Table 1. And results of l~-NMR and IR of the obtained compound (18) are shown in Table 2.

Example lO
[Preparation of the compound (l9)]
In lO0 mQ of benzene were dissolved 1.37 g of 3,5-diphenyl-4-hydroxybenzaldehyde and 0.88 g of l-phenyl-3,5-pyrazolidinedion, and thereto 0.1 mQ of piperidine and 0.5 mQ of acetic acid were added. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. After cooling, the deposited crystals were filtered and subjected to crystallization from ethanol to give 600 mg (yield: 28 %) of the compound (l9).
The melting point and data of elementary analysis of the obtained compound (l9) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (l9) are shown in Table 2.

Example 11 [Preparation of the compound (25)]
To lO0 mQ of benzene were added 1.37 g of 3,5-diphenyl-4-hydroxybenzaldehyde, 0.82 g of rhodanine, 0.1 mQ of piperidine and 0.5 m~ of acetic acid. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. The deposited crystals was filtered off from the reaction mixture.
After drying, the deposited crystals were heated under reflux for 5 hours with l.l mQ of benzylamine in 50 mQ of 58 ~ 3~
ethanol. After cooling, the solvent was distilled away under reduced pressure. The residue was subjected to a column-chromatography (carrier: silica-gel) and eluted with mixed solvent of chloroform/methanol t100/2: v/v).
After a fraction containing the desired compound was concentrated under reduced pressure, the fraction was subjected to crystallization from ethanol to give 0.60 g (yield: 26 ~) of the compound (25).
The melting point and data of elementary analysis of the obtained compound (25) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (25) are shown in Table 2.

Example 12 [Preparation of the compound (26)]
To 100 mQ of benzene were added 3.02 g of 3,5-dibenzyl-4-hydroxybenzaldehyde, 1.33 g of rhodanine, 0.1 mQ of piperidine and 0.5 mQ of acetic acid. The mixture was heated under reflux for 5 hours in Dean-Stark apparatus while removing water produced. The deposited crystals were filtered off from the reaction mixture.
After drying, the deposited crystals were heated under reflux for 5 hours with 2.2 mQ of benzylamine in 100 mQ
of ethanol. After cooling, the solvent was distilled away under reduced pressure. The obtained residue was subjected to a column-chromatography ~carrier: silica-gel) and eluted with mixed solvent of chloroform/methanol (100/2: v/v). ~fter a fraction containing the desired compound was concentrated under reduced pressure, the fraction was subjected to crystallization from ethanol to give 2.0 g (yield: 41 %) of the compound (26~.
The melting point and data of elementary analysis of the obtained compound (26) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (26) are shown in Table 2.

Example 13 [Preparation of the compound (28)]

59 - ~ 3 ~ ~ d~~
To lO0 mQ of ethanol were added ~.04 g of 5-(3-ethoxy-4-hydroxy-5-phenylthiomethylbenzylidene)-rhodanine obtained by the condensation reaction of 5-phenylthio-methylethylvanillin and rhodanine in the same manner as S above and 2.2 m~ of benzylamine. The mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled away under reduced pressure. The obtained residue was subjected to a column-chromatography (carrier: silica-gel) and eluted with chloroform. AEter a fraction containing the desired compound was concentrated under reduced pressure, the fraction was subjected to crystallization from ethanol to give 1.36 g (yield: 38 %) of the compound (28).
The melting point and data of elementary analysis of the obtained compound (28) are shown in Table 1. ~nd results of lH-NMR and IR of the obtained compound (28) are shown in Table 2.

Example 14 [Preparation of the compound (30)]
To 50 mQ of ethanol were added 0.80 g of 5-(3-n-butyloxy-4-hydroxy-5-benzylbenzylidene)-rhodanine obtained by the condensation reaction of 3-n-butyloxy-4-hydroxy-5-benzylbenzaldehyde and rhodanine in the same manner as above and 0.44 m~ of benzylamine. The mixture was heated under reflux for 5 hours. After cooling, the solvent was distilled away under reduced pressure. The obtained residue was subjected to a column-chromatography (carrier: silica-gel) and eluted with a mixed solvent of chloroform/methanol (lO/l: v/v). After a fraction containing the desired compound was concentrated under reduced pressure, the fraction was subjected to crystallization from ethanol to give 0.72 g (yield: 76 %) of the compound (30~.
The melting point and data of elementary analysis of the obtained compound (30) are shown in Table 1. And results of lH-NMR and IR of the obtained compound ~30) are shown in Table 2.

- 60 - 1 .3 ~
Example 15 [Preparation of -the compound (33)]
In 30 mQ of ethanol was dissolved 966 mg of 5-(3,5-diisopropyl-4-hydroxybenzylidene~-rhodanine, and thereto 624 mg of benzylamine was added. The mixture was heated under reflux for 5 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was dissolved in chloroform. After washing with water, the solution was concentrated to dryness. The obtained concentrate was subjected to a column-chromatography (carrier: silica-gel) and eluted with chloroform. A
fraction containing the desired compound was collected, concentrated and dried to give 660 mg (yield: 56 %~ of the compound (33).
The melting point and data of elementary analysis of the obtained compound (33) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (33) are shown in Table 2.

Example 16 [Preparation of the compound (34)]
In 30 mQ of ethanol was dissolved 966 mg o~ 5-(3,5-diisopropyl-4-hydroxyben~ylidene)-rhodanine, and thereto 726 mg of phenethylamine was added. The mixture was heated under reflux for 12 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was dissolved in chloroform. After washing with water, the solution was subjected to a column-chromatography (carrier: silica-gel) and eluted with chloroform. A fraction containing the desired compound was collected, concentrated, dried and subjected to crystallization to give 600 mg (yield: 68 %) of the compound (34).
The melting point and data of elementary analysis of the obtained compound ~3~) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (34) are shown in Table 2.

~ J3 E~ample 17 [Preparation of the compound (35)]
In 30 m~ of ethanol was dissolved 966 mg of S-(3,S-diisopropyl-4-hydroxybenzylidene)-rhodanine, and thereto 773 mg of p-fluorobenzylamine. The mixture was heated under reflux for 7 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was dissolved in chloroform. After washing with wa-ter, the solution was subjected to a column-chromatography (carrier: silica-gel) and eluted with chloroform. A
fraction containing the desired cornpound was collected, concentrated and dried to give 660 mg (yield: 52 %) of the compound (35).
The melting point and data of elementary analysis of the obtained compound (35) are shown in Table 1. And results of lH-NMR and IR of the obtained compound ~35) are shown in Table 2.

Example 18 ~Preparation of the compound (39)]
In 30 mQ of ethanol was dissolved 966 mg of 5-(3,5-diisopropyl-4-hydroxybenzylidene)-rhodanine~ and thereto 726 mg of p-methylbenzylamine was added. The mixture was heated under reflux for 12 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was dissolved in chloroform. After washing with water, the solution was subjected to a column-chromatography (carrier: silica-gel) and eluted with chloroform. A frackion containing the desired compound was collected, concentrated, dried and subjected to crystallization to give 900 mg (yield: 30 %) of the compound (39).
The melting point and data of elementary analysis of the obtained compound (39) are shown in Table 1. And results of l~-NMR and IR of the obtained compound (39) are shown in Table 2.

Example 19 [Preparation of the compound (41)]
In 30 mQ of ethanol was dissolved 966 mg of 5-(3,5-diisopropyl-4-hydroxybenzylidene)-rhodanine, and thereto 681 mg of p-aminosulfonylbenzylamine hydrochloride and 606 mg of triethylamine. The mixture was heated under reflux for 6 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was dissolved in chloroform. After washing with water, the solution was subjected to a column-chromatography Icarrier: silica-gel) and eluted with a mixed solvent of chloroform/ethanol (9/1: v/v). A
fraction containing the desired compound was collected, concentrated and dried to give 400 mg (yield: 27 %) of the compound (41).
The melting point and data of elementary analysis of the obtained compound (41) are shown in Table 1. And results of l~-NMR and IR of the obtained compound (41) are shown in Table 2.

Example 20 [Preparation of the compound (42)]
In 30 mQ of ethanol was dissolved 1.61 g of 5-(3,5-diisopropyl-4-hydroxybenzylidene)-rhodanine, and thereto 1.30 g of p-aminobenzylamine was added. The mixture was heated under reflu~ for 5 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was subjected to a crystallization f rom chloroform to give 570 mg (yield: 56 %) of the compound (~2).
The melting point and data of elementary analysis of the obtained compound (~2) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (42) are shown in Table 2.

Example 21 [Preparation of the compound (44)]
In 30 mQ of ethanol was dissolved 966 mg of 5-(3,5-diisopropyl-4-hydroxybenzylidene)-rhodanine, and ~ ~Q~ ~)~

thereto 707 mg of 2-aminomethylthiophene w~s added. The mixture was heated under reflux for 3 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was dissolved in chloroform. After washin~ with water, the solution was subjected to a column-chromatography ~carrier: silica-gel) and eluted with chloroform. A fraction containing the desired compound was collected, concentrated and dried to give 300 mg (yield: 24 %) of the compound (44).
The melting point and data of elementary analysis of the obtained compound (44) are shown in Table 1. And results of lH-NMR and IR of the obtained compound ~44~ are shown in Table 2.

Example 22 [Preparation of the compound (45)]
In 30 mQ of ethanol was dissolved 966 mg of 5-(3,5-diisopropyl-4-hydroxybenzylidene)-rhodanine, and thereto 648 mg of 2-aminomethylpyridine was added. The mixture was heated under reflux for 4 hours. Ethanol was distilled away under reduced pressure, and the obtained residue was dissolved in chloroform. After washing with water, the solution was subjected to a column-chromatography (carrier: silica-gel) and eluted with a mixed solvent of chloroform/ethanol (20/1: v/v). A
fraction containing the desired compound was collected, concentrated and dried to give 200 mg (yield: 17 ~) of the compound (45).
The melting point and data of elementary analysis of the obtained compound (45) are shown in Table 1. And results of lH-NMR and IR of the obtained compound (45) are shown in Table 2.

In addition to the ingredients used in the Examples, other ingredients can be used in the Examples as set forth in the specification to obtain substantially the same results.

Claims (10)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A hydroxystyrene derivative represented by the formula (I) (I) wherein when R1 and R2 are the same or different and each is phenyl group, benzyl group or phenethyl group, or R1 is a group having the formula R5O- in which R5 is hydrogen atom, an alkyl group having 1 to 5 carbon atoms or benzyl group and R2 is benzyl group or a group having the formula PhSCH2, R3 and R4 are taken together to rep-resent a group having the formula -CONH-CS-S-, a group having the formula -CONH, a group having the form-ula -CONHSO2- or a group having the formula in which R6 is a group having the for-mula [in which X1 is hydrogen atom, a halogen atom, methyl group, ethyl group, an alkoxyl group having the formula R7O- (in which R7 is methyl or ethyl group), nitro group, aminosulfonyl group or amino group, and m1 is 1 or 2], pyridyl group, furyl group or thienyl group, and n1 is 0 or an integer of 1 to 3;

when R1 and R2 are the same or different and each is phenyl group, benzyl group or phenethyl group, or R1 is a group having the formula R50- in which R5 is as de-fined above, and R2 is benzyl group, R3 is cyano group and R4 is carbamoyl group, or R3 and R4 are taken together to represent a group having the formula -CO-Y-CH2CH2- in which Y is oxygen atom or -NH-, or a group having the formula -CO-?-NH-CO-; and when R1 and R2 are the same or different and each is an alkyl group having 1 to 3 carbon atoms, R3 and R4 are taken together to represent a group having the formula in which n1 and R6 are as defined above, or a salt thereof.

2. The hydroxystyrene derivative of claim 1, wherein R1 and R2 are the same or different and each is phenyl group, benzyl group or phenethyl group, or R1 is a group having the formula R5O- in which R5 is defined as in claim 1, and R2 is benzyl group or PhSCH2 group, and R3 and R4 are taken together to represent a group having the formula -CONH-CS-S-, a group having the formula -CONH, a group having the formula -CONHSO2- or a group having the formula in which n1 and R6 are defined as in claim 1, or a salt thereof.

3. The hydroxystyrene derivative of claim 1, wherein R1 and R2 are the same or different and each is phenyl group, benzyl group or phenethyl group, or R1 is a group having the formula R5O- in which R5 is defined as in claim 1, and R2 is benzyl group, and R3 is cyano group and R4 is carbamoyl group, or R3 and R4 are taken together to represent a group having the formula -CO-Y-CH2CH2- in which Y is defined as in claim 1, or a group having the formula -CO-?-NH-CO-, or a salt thereof.

4. The hydroxystyrene derivative of claim 1, wherein R1 and R2 are the same or different and each is an alkyl group having 1 to 3 carbon atoms, and R3 and R4 are taken together to represent a group having the form-ula in which n1 and R6 are defined as in claim 1, or a salt thereof.

5. An antiallergic agent containing a hyd-roxystyrene derivative, as defined in claim 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, toge-ther with a pharmaceutically acceptable carrier there-for.

6. A 5-lipoxygenase inhibiting agent con-taining a hydroxystyrene derivative, as defined in claim 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

7. An antibacterial agent containing a hyd-roxystyrene derivative, as defined in claim 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, toge-ther with a pharmaceutically acceptable carrier there-for.

8. A tyrosine kinase inhibiting agent con-taining a hydroxystyrene derivative, as defined in claim 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

9. An ultraviolet absorber containing a hydroxystyrene derivative, as defined in claim 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.

10. A reverse transcriptase inhibiting agent containing a hydroxystyrene derivative, as defined in claim 1, 2, 3 or 4, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically accept-able carrier therefor.