JPS61106555A - Amide derivative and inhibitor against 5-lipoxygenase action containing same - Google Patents

Abstract

NEW MATERIAL:An amide derivative shown by the formula I [(R)<m> is 3,4- dihydroxy group, 3-methoxy-4-hydroxy group, 3,4-dimethoxy group, 3,5- dimethoxy-4-hydroxy group 3,5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4- toluoyloxy group, etc.; n is number of double bond in trans-configuration, 1 or 2; Y is group shown by the formula II (X is H, halogen, etc.; n is 2, or 3), group shown by the formula III, etc.]. EXAMPLE:N-[3-(3,4-Dihydroxyphenyl)-2-propenoyl]-N'-{3-[1-pheny-l- 1-(p-chloro phenyl)ethoxy]propyl}piperazine. USE:A drug useful for allergic asthma, allergic rhinitis, etc. as an inhibitor against 5-lipoxygenase action. PREPARATION:For example, a compound shown by the formula IV is subjected to condensation reaction and protecting group eliminating reaction, to give a compound shown by the formula I.

Description

Detailed Description of the Invention 10 Technical Field of the Invention The present invention relates to a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same. The amide derivative provided by the present invention has the activity of inhibiting the action of the enzyme 5-lipoxygenase. Leukotriene C4 (
Leukotrienes such as LTC4) and leukotriene D4 (LTD4) are synthesized from 7 rachidonic acid to 5 in vivo.
-Biosynthesized by the action of lipoxygenase. Therefore, the amide ffl conductor of the present invention, which exhibits 5-lipoxygenase inhibitory activity, suppresses the biosynthesis of the allergy-inducing factors, and is useful as an anti-allergy agent.

Prior Art Recently, it has been revealed that leukotrienes are produced from arachidonic acid by the action of 5-lipoxygenase, and that these leukotrienes are factors that cause allergies [Science, Vol. 220, p. 568, 1983; The American Association
Fore Advancement Ab Niens (1”
heAmeriCan A 530CiatiOn
for the ac+vancement of S
Published by Science).

As mentioned above, leukotrienes (LTC), which are 5-lipoxygenase products of arachidonic acid, are used to develop the allergic diseases allergic asthma and allergic rhinitis.
4, LTD4) is involved as an important factor, there is a strong desire for the development of a drug that has the activity of deactivating 5-lipoxygenase and inhibiting its action.

The present inventors synthesized various amide derivatives, and their 5-
As a result of intensive research on the inhibitory activity of lipoxygenase,
The present inventors have discovered that the amide derivatives of the present invention have a strong 5-lipoxygenase inhibitory activity, and have completed the present invention.

■Object of the Invention The present invention provides a novel amide derivative and a novel amide derivative containing the same.
- An object of the present invention is to provide an inhibitor of lipoxygenase action.

In accordance with the above object, the present invention provides general formula (I) (wherein (R)
1 is 3,4-dihydroxy group, 3-methoxy-4-hydroxy group, 3,4-dimethoxy group, 3,5-dimethoxy-4-hydroxy group, 3,5-tume-1-xy-4-toluoyloxy or 3,4.5-trimethoxy group.

n represents the number of double bonds in trans configuration, 1 or 2
is an integer. Y is a group represented by the general formula ([) [wherein X is a hydrogen atom, a halogen atom or a methoxy group, and n represents 2 or 3], a group represented by the general formula (I [[)], and a group represented by the general formula A group selected from the groups represented by (TV)] is an amide derivative represented by the following.

Further, the present invention provides a compound of the general formula (I> [wherein (R) is a 3.4-dihydroxy group, 3-methoxy-4-hydroxy group, 3.4-dimethoxy group, 3
．． It represents a 5-dimethoxy-4-hydroxy group, a 3,5-dimethoxy-4-toluoyloxy group, or a 3,4,5-trimethoxy group.

n represents the number of double bonds in trans configuration, 1 or 2
is an integer. Y is a group represented by the general formula (n)'' [wherein X is a hydrogen atom, a halogen atom or a methoxy group, and n represents 2 or 3], a group represented by the general formula (II), and a group represented by the general formula ( rV) is a 5-lipoxygenase action inhibitor containing an amide derivative represented by the following group.

The halogen atom represented by the formula (I) in the present invention is preferably furor, chloro or bromine. In the present invention, the 5-lipoxygenase action inhibitor means a preparation that has the action of suppressing the action of 5-lipoxygenase.

(6) Detailed Description of the Invention The amide derivative represented by the above formula (I) of the present invention is a carboxylic acid derivative represented by the following formula (V) as shown in the Examples. In the formula C, (R)1 is 3. 4-dihydroxy group, 3-methoxy-4-hydroxy group, 3.4-dimethoxy group, 3,
It represents a 5-dimethoxy-4-hydroxy group, a 3,5-dimethoxy-4-toluoyloxy group, or a 3.4.5-trimethoxy group.

n represents the number of double bonds in trans configuration, 1 or 2
is an integer. ) or, for example, by performing a synthesis reaction and a deprotecting group reaction on its reactive derivative (Vl)l [wherein the definitions of (R) and n are the same as the definitions of formula (V)-] .

The amide derivative of the present invention is used as a 5-lipoxygenase action inhibitor, that is, an antiallergic agent, and the dosage varies depending on the symptoms, but is generally ω10 to 2000 It per day for adults.
g, preferably 20 to 600 IItg, and is preferably administered in 1 to 3 divided doses depending on the symptoms. The administration method can take any form suitable for administration, and oral administration is particularly preferred, but intravenous injection is also possible.

The compound of the present invention can be used as an active ingredient or one of the active ingredients alone or mixed with a pharmaceutical carrier or excipient in a conventional manner, and can be used as a tablet, sugar-coated tablet, powder, capsule, granule, suspension, emulsion, or injection. It can be applied in various forms such as liquid formulations. Examples of carriers or excipients include calcium carbonate, phosphorus-tolerant sodium, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate, and the like.

EXAMPLES Next, the present invention will be explained in more detail with reference to Examples and Test Examples, but the present invention is not limited thereto.

Example 1 2M solution of phenylmagnesium bromide in tetrahydrofuran (74mioJl) under argon atmosphere
, p-chloroacetophenone 5.24 g (33,
9mmoj! ) was added and reacted at 0°C for 3 hours. After the reaction, saturated ammonium chloride aqueous solution was added and extraction was performed with chloroform. The organic layer was washed with water and concentrated under reduced pressure.

The resulting residue was subjected to silica gel column chromatography, and 1-phenyl-
6.99 g of 1-(p-chlorophenyl)ethanol (
30.0 mmojl) was obtained.

The alcohol compound 6.99 g (30.0 mmon
) of ethanol (80 ai solution with 5.00 g of concentrated sulfuric acid
d (93.8 mmoJ) was added and reacted for 1 hour. Water was added to the reaction solution and extracted with chloroform.

The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography to obtain 1-phenyl-1-
(p-chlorophenyl)ethylene6.14 SJ-(2
8.6 mmojl) was obtained.

Under an argon atmosphere, 1.87 g (8
,70mn+oρ) of 3-chloropropanol (21t
d) 7.04 g (22.1 mm) of mercuric acetate in solution
oN) was added and reacted at room temperature for 27 hours. Add 45 m of 3.4N hydrium hydroxide aqueous solution to the reaction solution and add sodium borohydride 8311FJ (22, OramofJ
) was added little by little. After reacting at room temperature for 2 hours, extraction was performed with benzene. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and 1-phenyl-1-(p-chlorophenyl)ethyl 3 was extracted from the chloroform-hexane (1:1) eluted fraction.
-chloropropyl ether 2.329 (7,50 mmo
J) was obtained.

2.32 g (7,50 mmoJl) of the ether compound
> Ethyl N-piperazinolupoxylate 2.50
m (17,1ml of J) was added and reacted at 150°C for 2 hours. Water was added to the reaction solution, the pH was adjusted to 11 with an aqueous sodium carbonate solution, and extraction was performed with chloroform.

The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform yielded 3.23 g of N-(3-M-phenyl-1-N)-chlorophenyl)ethoxy]propyl)-N'-(ethoxycarbonyl)piperazine. (7,50 mmoj)
I got it.

9.34 g (166 mmoJ) of potassium hydroxide was added to a solution of 3.23 g (7,50 mmofJ) of the amine compound in ethanol (12#+1) and water (6d).
Distant current was applied for 5 hours. Water was added to the reaction solution and extracted with n-butanol. The organic layer was washed with water and concentrated under reduced pressure.

The resulting residue was subjected to Sephadex column chromatography, and from the methanol elution fraction, 2.36 g (6,58 uoj) of N-(3-[1-phenyl-1-(p-chlorophenyl)ethoxy]propyl]perazine) was obtained. I got it.

A dry tetrahydrofuran solution of the piperazine compound 40019 (!M) ICN-(3-[3,4-di(p-methoxyethoxymethoxy)phenyl]-2-propenoyl)thiazolidine-2-'thione 510η (10#li of water was added, and the reaction was allowed to proceed for 2 hours at room temperature in an argon atmosphere.The reaction solution was concentrated, and a 2N aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform.The organic layer was concentrated, The obtained residue was subjected to silica gel column chromatography, and N-(3-[3
,4-di(β-methoxyethoxymethoxy)phenyl-2-propenoyl]-N'-(3-[1-phenyl-1-(p-chloro.:107":/L')Ito-1
"21701":'/u)t""""52'33511
tg was obtained.

186 η of p-toluenesulfonic acid hydrate was added to a methanol solution (10 ml) containing 335 μ of the amide compound, and the mixture was stirred at room temperature for 1.7 hours. A saturated aqueous solution of nine thorium carbon hydrogen was added to the reaction solution, and the mixture was diluted with ethyl acetate. The resulting residue was subjected to silica gel column chromatography, and N-
(3-(3,4-dihydroxyphenyl)-2-propenoyl)-N'-(3-(1-phenyl-1-(p-
Chlorophenyl)ethoxy]propyl)piperazine 50
We obtained η. The spectroscopic data of this is expressed by the following formula (Vl)
support the structure of

IRν product x (K B r): 3400.2935.1635° Example 2 1-phenyl-1-(p-chlorophenyl)ethylene 1.11 g (5,18 mmoρ) under argon atmosphere
Add 4.04 g (12,7imo1) of mercuric acetate to a 2-chloroethanol (10 m) solution of
Allowed time to react. 3.4N potassium hydroxide aqueous solution 25- was added to the reaction solution, and sodium borohydride 59
2η(15,7a+moj) ) was added little by little. After reacting at room temperature for 30 minutes, extraction was performed with benzene. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and 1-phenyl-
1.39 g (4,72 nimoj!) of 1-(p-O-lophenyl)ethyl 2-chloroethyl ether was obtained.

The ether compound 848 #Ig (2,87n+o+o
Jl) to ethyl N-biverazinolupoxylate 1
．． Add 00 m (6,83n+mojl) and heat to 150°C.
The reaction was carried out for 2 hours. Water was added to the reaction solution, and the mixture was made 1) Hll with an aqueous sodium carbonate solution and extracted with chloroform.

The organic layer was washed with water and concentrated under reduced pressure. , #R residue was subjected to silica gel column chromatography and chloroform-
N-(2-N-
Phenyl-1-(p-chlorophenyl)ethoxy]ethyl)-N'-(ethoxycarbonyl) was obtained.

To a solution of 1.19 g (2.85 u+oj!) of the amine compound in tanol (4d) and water (2d), 3.37 g (60.1+u+ojl) of potassium hydroxide was added and refluxed for 42 hours.

Water was added to the reaction solution and extracted with n-butanol.

The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to Sephadex column chromatography, and the methanol eluted fraction was N-(2-[1-phenylene/Iz-1-(p
-ri0lophenyl>ethoxy]ethyl]piperazine8
7 81! I! F (2.55 mmof>) was obtained.

Under an argon atmosphere, 29311 g of the piperazine compound (
N-(3-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-
2-propenoyl phthiazolidine 630Wg (1,64
mmoj ) in dry dimethylformamide (5 m) was added. After reacting at room temperature for 17 hours, it was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography and chloroform-methanol (100:1>N-(3-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl-2-propenoyl) was extracted from the eluted fraction. -N'-(2-[1-phenyl-1-(+)-chlorophenyl)ethoxy]ethyl)piperazine 486Rg(
0,798■01) was obtained.

The amide compound 486Irtg (0,798nmoj!
) in methanol (10ad) solution of p-toluenesulfonic acid-hydrate 153q (0,804110j1)
was added and refluxed for 30 minutes. Water was added to the reaction solution, the pH was adjusted to 11 with an aqueous sodium carbonate solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and from the eluted fraction chloroform-methanol <50:1), N
-(3-[3-methoxy-4-hydroxyphenyl)-
2-benoyl)-N'-(2-[1-phenyl-1
-(p-chlorophenyl)ethoxy]ethyl)piperazine 293 ml (0,562,111 iojl) was obtained. Spectroscopic data of this product support the structure (Vlll) of the following formula.

IRν product, (KBr): 3400.1642.1590 1) 1-NMR (deuterated chloroform) δ: 1.80 (3H
, S).

2.3-2.83 (6H, m).

3.17 to 3.97 (6H, m).

3.80 (3H, S).

8.62 (1H, d, J = 15) - 1z)
.

6.88 ~ 7.32 (12H, m) 7.55 (IH
, d, J = 15Hz) Example 3 Sodium hydride 400cm (60%
101a+oρ) was washed with dry hexane and dissolved in dimethyl sulfoxide 5111. The mixture was kept at a temperature of 70 to 75°C, stirred for 30 minutes, and then cooled to room temperature. 1.8 g (10 mm 5 oj) of theophylline was suspended in 5 d of dimethyl sulfoxide and stirred for 30 minutes. 1.2
-Dichloroethane 209 (200 in+ojl) was dissolved in dimethyl sulfoxide 10i+oj and added dropwise using a dropping funnel over 15 minutes. After stirring at room temperature for 16 hours, water was added and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (100:1) yielded 1.629 g of 7-(2-chloroethyl)theophylline.
(6,6811110Jl) Wiri.

Under an argon atmosphere, the theophylline derivative 1.003(
4,6611+1oj! ) with formylpiperazine 1.
289 was added and stirred at 80°C for 13 hours. The reaction solution was subjected to silica gel column chromatography, and 7-(
1.389 (4,65a+a+of) of 2-[4-(1-formyl)piperazino]ethyl)theophylline was obtained.

Under an argon atmosphere, this and perazine compound 240q (0,
81 mmojl) was dissolved in 10 m of ethanol.

Add 80% hydrazine humanate 507ay (
After adding 8,15IIaj) and heating under reflux for 36 hours, the mixture was allowed to cool to room temperature. 10 d of dimethylformamide was added to the residue after concentration under reduced pressure. Add N-(3-[3
-Methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]-2-thiothiazoline 3
30 Rg (0.81 mmon) was added and stirred at 80° C. for 1 hour. After concentrating this reaction solution under reduced pressure, a residue of 450
R9 was subjected to silica gel column chromatography, and from the chloroform-methaneol (100:3) elution fraction,
7-(2-[4-[3-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-bropenoylJpiperazi1-yl]ethyl]theophylline 276
#Iy(0,50a+moJ) 1'Jt;-.

Under an argon atmosphere, the theophylline derivative 276η(0
, 50mm+oJ) in methanol 10-, p
-Toluenesulfonic acid -hydrate 242Rg (1,28
m1ofJ) was added thereto, and the mixture was heated under reflux for 2 hours. After the reaction solution was allowed to cool to room temperature, a saturated aqueous sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was extracted with chloroform. Yes!
One layer was dried over anhydrous 1II 1tM sodium and concentrated under reduced pressure. Remaining a! 1200 ay was subjected to silica gel column chromatography and chloroform-methanol (5
7-(2-[4-[3-
(3-Methoxy-4-hydroxyphenyl)-2-propenoylcopiperazin-1-yl]ethyl]theophylline 100100Ir, 22+uoj! )Obtained. The cononomono spectroscopic theta 1,i supports the structure (IX) of the following formula.

・''((IX) IRν'5x (CHCN3): 3540.1705.1660 1H-NMR (weight roll form) δ: 2.3 to 2.8
(4H, m).

2.80 (2H, t, J=6Hz).

3.3-3.9 (4H, m).

3.39(3)-1,S), 3.57(3H,S
).

3.88 (3H, S).

4.40 (21-1, t, J=6Hz).

6.60 (IH, d, J=16Hz).

6.7-7.3 (3H, m).

7.53 (1H, d, J = 16 Hz).

7.58 (1H, S)
'Example 4 1-(3-[1-phenyl-1-(p -Chlorophenyl)ethoxy]propyl)piperazine 115η in dry tetrahydrofuran solution (2m) and stirred at room temperature under argon atmosphere for 1.5 hours.The reaction solution was concentrated, and a 2N aqueous sodium hydroxide solution was added to the resulting residue. The organic layer was concentrated and the resulting residue was subjected to silica gel column chromatography using chloroform-methanol (50:1'').
) 175 mg of N-(3-(3,4-dimethoxy)phenyl-2-propenoyl)-N'-(3-[1-phenyl-1-(p-chlorophenyl)ethoxy]propyl)piperazine was obtained from the elution fraction. Ta. Spectroscopic data of this product supports the structure shown in the following formula (X).

'H-NMR (ffirio form) 6 (ppal
): L83 (3f-1,8), 1.83 (2H,
m).

2.47 (6H, m).

3.27 (2H, t (J=6Hz)).

3.67 (4H, m), 3.88 (6H, S)
.

e, 73 (1H, d (J = 15 Hz))7.
0-7.43 (12H, m).

7.58 (1H, d (J = 15 Hz)) IR
ν” (KBr): I!1ax 2940.1645.1600゜Example 5 Under argon atmosphere, N-(2-[1-phenyl-1-(
p-chlorophenyl)ethoxy]ethyl)piperazine 3
A solution of 4311 g (0,995 mg+on) of dry dimethylformamide (3adt>N-(3-[3°5-
Dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl]thiazolidine 656 m
y (1,59n+ioJ) was added. 16 at room temperature
After reacting for an hour, the mixture was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography and chloroform-
N-(3-[
3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2-propenoyl)-N'-(2
-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine 412+y (0,645l+a
oJ) was obtained.

) The amide compound 412 #19 (0,64
To a solution of 5 mmoj ) of methanol (8 ad) was added 101 q of p-toluenesulfonic acid hydrate (
0,531 avoj! ) and centrifuged for 30 minutes.

Water was added to the reaction solution, the pH was adjusted to 11 with an aqueous sodium carbonate solution, and extraction was performed with ethyl acetate. The solid layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography using chloroform-methanol (50:
1) From the eluted fraction, N-(3-(3,5-dimethoxy-4-hydroxyphenyl)-2-propenoyl]-N
' -(2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl)piperazine 371η (0,67
3n1llofJ) was obtained. Spectroscopic data of this product support structure (XI) of the following formula.

IRL/'' (KBr): aX 3540.1647.1615 I H-NMR (deuterated chloroform) δ: 1.80 (3H
, S').

2.28-2.78 (6H, m).

3.12-4.02 (6H, m).

3.82 (6H, S).

6.60 (IH, d, J = 15 H2).

6.65(2)(,S).

6.97-7.35 (11H, m).

7.50 (1H, d, J = 15 Hz) Example 6 N-(3-(3,5-dimethoxy-4-β-methoxyethoxymethoxy)phenyl-2-propenoyl)thiazolidine-2-thione 574.8Rg 1-(3-[1-phenyl-1
-(p-chlorophenyl)ethoxy 170 pyru]piperazine 500 Irg in dry tetrahydrofuran solution (5 d
) was added and processed for 2 hours at room temperature under an argon atmosphere. The reaction solution is concentrated, a 2N aqueous sodium hydroxide solution is added to the resulting residue, and the mixture is extracted with chloroform. The residue obtained by concentrating the Ariiso layer was subjected to silica gel column chromatography using chloroform-methanol (50:1).
N-(3-(3,5-dimethoxy-4-β)
-methoxyethoxymethoxy)phenyl-2-propenoyl)-N'-(3-[1-phenyl-1-(p-chlorophenyl)ethoxy110pyr]piperazine 960
Got #+9.

A methanol solution (10 m
) was added with 280 μl of p-1-luenesulfonic acid hydrate and heated under reflux for 0.17 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The resulting residue was subjected to silica gel column chromatography, and N-(
3-(3゜5-dimethoxy-4-hydroxy)phenyl-2-propenoyl)-N'-(3-[1-phenyA
z-1-(p-chlorophenyl)ethoxy 110 pills]
563 mg of piperazine was obtained. Spectroscopic data of this product support the structure of the following formula (XII).

(XTI) 'H-NMR (deuterated chloroform) δ (ppU: 1.80
(3H, S), 1.80 (2H, m).

2.43 (6H, m).

3.23 (2H, t (J=6Hz>).

3.63 (4H, m), 3.83 (6H, S).

6.65 (1H, d (J = 15 Hz))
.

6.70 (2H, S).

7.17 to 7.33 (10H, m).

7.55 (I H, d (J=15Hz))IRν”
(KBr): ax Hl 3420,2940.164
0゜□“□' 1600.1513 Example 7 Under argon atmosphere, N-(2-[1-phenyl-1-(
p-chlorophenyl)ethoxy]ethyl]piperazine 3
141m! To a solution of F(0,9101 ion) in dry dimethylformamide (5d) was added N-(5-[3,4-bis(β-methoxyethoxymethoxy)phenyl]-2.4
-Pentagenoyl]thiazolidine 741■ (1,53
4poN) was added. After reacting at room temperature for 3 hours,
It was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography using chloroform-methanol (50:
1) N-(5-[3,4-bis(β-
methoxyethoxymethoxy)phenyl]-2,4-pentagenoyl)-N'-(2-[1-phenyl-1-
(p-O-lophenyl)ethoxy]ethyl)piperazine 620q (0,874i+moJl) was obtained.

The amide compound 620 #FF (0,874 avojl
185q (0,973 mmoj) of p-toluenesulfonic acid hydrate was added to a methanol (7d) solution of ) and refluxed for 20 minutes. Water was added to the reaction solution, the pH was adjusted to 11 with an aqueous sodium carbonate solution, and extraction was performed with ethyl acetate. The organic layer was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography and chloroform-
N-(5-(3,
4-dihydroxyphenyl)-2,4-pentagenoyl)-N'-(2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine 279q(
0,523in+oj) was obtained. Spectroscopic data of this product support the structure (XI[I) of the following formula.

α-1 1Rν (K B r): aX 3300.1635, 1610°I H-NMR (deuterated chloroform) δ: 1.78 (3H
,S).

2.25 ~ 2.82 (6H, m>.

3.12 to 3.88 (6H, m).

e, 2G (IH, d, J-141-11).

6.47~7.62 (15H, m).

Example 8 A solution of 536.8 JljJ of N-(5-(3,4-diβ-methoxyethoxoxydimethoxy)phenyl-2,4-pentagenoyl)thiacylydi-2-thione in dry tetrahydrofuran (1-(3 -[1-phenyl-1
Add 5 ml of a dry tetrahydrofuran solution of 400 q of -(p-chlorophenyl)ethoxy-1propyl]piperazine and stir at room temperature under an argon atmosphere for 1.5 hours. Concentrate the reaction solution, and add 2N sodium hydroxide to the resulting residue. Add an aqueous solution and extract with chloroform.The organic layer was concentrated and the resulting residue was subjected to silica gel column chromatography. -methoxyethoxymethoxy)phenyl-2,4-pentagenoyl] -
N'-(3-[1-phenyl-1-(p-chlorophenyl)ethoxy1propyl]piperazine 354.51R
I got g.

Methanol solution of the amide compound 354QF (101d
186 μl of p-toluenesulfonic acid hydrate was added to 1), and the mixture was stirred at room temperature for 1.7 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The resulting residue was subjected to silica gel column chromatography, and N-(
5-(3゜4-dihydroxy)phenyl-2,4-pentagenoyl)-N'-(3-[1-phenyl-1-
46 ml of (p-chlorophenyl)ethoxy-1propyl]piperazine was obtained. The spectroscopic data of this substance is expressed by the following formula (
XrV) structure is supported.

Kokusei (also ■) 1HFNMR (heavy chloroform) δ (ppm): 1,
'80 (3H, S), 1.80 (2H, m).

2.42 (6H, m), 3.23 (2H, b t
).

3.60 (4H, m).

6.33 to 7.33 (18H, m> IRν” (KBr): l1ax 3400.2940, 1638° Example 9 Under argon atmosphere, 7-(2-[4-(1-formyl)piperazino]ethyl]theophylline 690 Q (2
, 33 mmojl) to ethanol 37! dissolved in.

Add 2.92 g of 80% hydrazine hydratate to this solution.
(46,6110 J) was added, heated under reflux for 8 hours, and then allowed to cool to room temperature. Dimethylformamide 10 #11 was added to the residue after concentration under reduced pressure. added. Add N-(5
-[3,4-di(β-methoxyethoxymethoxy)phenyl]-2,4-pendagenoyl]-2-thiothiazoline 1.13 g (2,331 Tsuru 01) was added and stirred at 80°C for 2 hours. . After concentrating this reaction solution under reduced pressure, 2 g of the residue was subjected to silica gel column chromatography, and from the chloroform-methanol (100:3) eluted fraction,
7-(2-[4-[5-[3,4-di(β-methoxyethoxymethoxy)phenyl-2,4-pentagenoylcopiperazin-1-yl]ethyl]theophylline 790
q(1,20gvoj) ) It was.

Under an argon atmosphere, the theophylline derivative 79011!
F (1,20 mmojl) in methanol 12. ad!
p-Toluenesulfonic acid-hydrate 685I
Itg (3.6 mmoj!) was added and heated under reflux for 2 hours. After the reaction solution was allowed to cool to room temperature, a saturated aqueous sodium bicarbonate solution was added to adjust to I)H9, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure.The remaining 310#y was subjected to silica gel column chromatography, and from the fraction eluted with chloroform methanol (100:9), 7-[22 [4-[5-(3,4-dihydroxyphenyl)-2
,4-pentagenoylcopiperad-1-yl]ethyl]theophylline 5919 (0,121110jl) was obtained. The spectroscopic data of this substance is the structure of the following formula (XV
).

IRI15x (KBr): 3400.1705.1660 + 1-j-NMR (heavy pyridine) δ: 2.2-2.7
(4H, m).

2.78(2)1. t, J=6Hz).

3.2-3°8 (4 days, m).

3.43(3H,S), 3.53(3H,S
).

4.50 (2H, t, J="6H7).

6.5-7.7 (7H, m).

7.50 (1H,S) Example 10 Under argon atmosphere, N-(2-[1-7enyl-1-(
p-chlorophenyl)ethoxy]ethyl)piperazine 4
N-(5-[3-methoxy-4-
(β-methoxyethoxymethoxy)phenyl]-2.4
-Pentagenoyl]thiazolidine 618 mg (1,5
1 mmojl) was added. Room □, 1. ′″−6
8[i1″lゝ9°1!j, :I゛gJEflllllL
ゞ.

The resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (100:1) was N-(5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-penta Genoyl)-N'-(2-[1-phenyl-1-(p-chlorophenyl)ethoxy]ethyl]piperazine 736 ml
(L 16++voJ) ) was obtained.

To a solution of the amide compound 736 Itg (1,16m5+o#n) in methanol (15d) was added 225q (1,181,110 jl) of D-toluenesulfonic acid-hydrate and refluxed for 15 minutes.Water was added to the reaction solution and carbonic acid The pH was adjusted to 11 with an aqueous sodium solution and extracted with ethyl acetate.The organic layer was washed with water and concentrated under reduced pressure.The resulting residue was subjected to silica gel column chromatography and extracted with chloroform-
N-(5-(3-
methoxy-4-hytomixyphenyl)-2,4-pentagenoyl)-N'-(2-[1-phenyl-1-(
p-chlorophenyl)ethoxy]ethyl]piperazine 3
63IIg (0,664u+on) was obtained. Kono also (7) (7) Spectroscopic data 1- supports the structure <XVt> of the following formula.

3400, 1635.　1615゜ 1H-NMR (deuterated chloroform) δ: 1.80 (3H, S).

2.3 to 2.77 (6H, m>.

3.20 to 3.80 (6H, m>.

3.83 (3H, S).

6.32(1)-1,d, J=14H7).

6.60 to 7.57 (15H, m > Example 11 N-(5-(3-methoxy-4-β-methoxyethoxymethoxy)phenyl-2,4-pentagenoyl)thiazolidine-2-thione 553j 1-(3-[1-7enyl-1-(
A solution of 500 q of p-chlorophenyl)ethoxy]propyl]piperazine in dry tetrahydrofuran (5d) is added, and the mixture is stirred at room temperature under an argon atmosphere for 4 hours. The reaction solution was concentrated, a 2N aqueous sodium hydroxide solution was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was concentrated, the resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (50:1) was purified with N.
-(5-(3-methoxy-4-β-methoxyethoxymethoxy)phenyl-2,4-pentagenoyl)-N'
-(3-[1-phenyl-1-(p-chlorophenyl)
Ethoxy]propyl]piperazine 900 #ry was obtained.

To a methanol solution (10 m) of the amide compound 900 ~, 263 q of p-toluenesulfonic acid-hydrate was added.
, and heated under reflux for 11 hours. A saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted with ethyl acetate. The resulting residue was subjected to silica gel column chromatography, and N-(5
-(3-methoxy-4-humanOxy)phenyl-2,4
-Pentagenoyl)-N'-(3-[1-7enyl-1-(p-chlorophenyl)ethoxy]propyl]piperazine 328q was obtained.

Spectroscopic data of this product support the structure of the following formula (X■).

1H-NMR (deuterated chloroform) δ (ppm): 1.
83 (3H, m), 1.83 (2H, m).

, 2.45 (6H, m).

3.26 (2H, t (J-6H2)).

3.63 (4H, m), 3.87 (3H, S)
.

6.35 (IH, d (J-15H2)).

6.76-7.50(16)(,m)IRν5x(K
Br): 3400.2940,1640°1580, 1513 Example 12 Under an argon atmosphere, 7-(2-[4-(1-formyl)piperazino]ethyl]theophylline 564 N (1
, 90+uojl) was dissolved in 8 d of ethanol. Add to this solution 80% hydrazine hydrazine 596■ (9,
52 isoJ) and heated under reflux for 15 hours, then allowed to cool to room temperature. 10 ml of dimethylformamide was added to the residue after concentration under reduced pressure. To this solution, 778 tny (1,90a+moJ) of N-(5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentagenoyl]-2-thiothiazoline (1,90a+moJ) was added, and 80
Stirred at ℃ for 2 hours. After concentrating this reaction solution under reduced pressure,
The residue 1.229 was subjected to silica gel column chromatography and chloroform-methanol (100:3)? 7
From the F fraction, 7-(2-[4-[5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-
2,4-pentagenoyl]piperazi1-nyl1ethyl]theophylline 502 Ill (0,86gimo
jl) got it.

Under an argon atmosphere, the theophylline derivative 502 q(
0,8611041) in methanol 8d and p-
Toluenesulfonic acid-hydrate 360q (t, 9o11
) was added thereto, and the mixture was heated under reflux for 4 hours. After the reaction solution was allowed to cool to room temperature, a saturated aqueous sodium bicarbonate solution was added to adjust to pl-110, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The remaining 540jI9 was subjected to silica gel column chromatography, and chloroform-methanol (50:1
) From the elution fraction, 7-(2-[4-[5-(3-methoxy-4-hydroxyphenyl)-2,4-pentagenoyl]piperazin-1-yl)ethyl]theophylline 2
25 my (0,45 iioJ) was obtained. Spectroscopic data of this product support the structure (X■) of the following formula.

(XVl[[) , -1 1Rν (KBr): aX 3400.1700. 1655 1H-NMR (deuterated chloroform) δ: 2.3-3.0 (6H, m).

3.3-3.9 (4H, m).

3.37 (3H, S), 3.55 (3H, S).

3.85 (3H, S, ).

4.2 to 4.6 (2H, m).

6.3-7.8 (7H, m).

7.57(I H,S ) Example 13 N-(2-[1-phenyl-1-(
p-chlorophenyl)ethoxy]ethyl]piperazine 5
N-(5-[3°5-
dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentagenoyl) f-7'/ +
) 760 Itg (1,73 mmoj) was added. After reacting at room temperature for 67 hours, it was concentrated under reduced pressure.

The resulting residue was subjected to silica gel column chromatography, and N-(5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2 ,4-pentagenoyl)-N'-(2-[1-phenyl-1-(p
-chlorophenyl)ethoxy1ethyl]piperazine 61
8■ (0,929 mmon) was obtained.

To a solution of the amide compound 618η (0,929 mmoj) in methanol (10d) was added p-toluenesulfonic acid.-
Add 181 mol of hydrate (0,952 imojl) and 15
Refluxed for an hour. Add water to the reaction solution and add sodium carbonate 1:
'1 The pH was adjusted to 11 with an aqueous solution and extracted with chloroform. A'eiAH was washed with water and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and N-[5-(3,5-dimethoxy-4-hydroxyphenyl]-2,4-pentagenoyl) was extracted from the fraction eluted with chloroform-methanol (100:1). )-N'
-(2-[1-phenyl-1-(p-chlorophenyl)
ethoxy1ethyl]piperazine 422■ (0,766m
mojl) was obtained. Spectroscopic data of this product support the structure (XIX) of the following formula.

IRν:Rax(K8r): 3400.1640.1615° 1H-NMR (deuterated chloroform) δ: 1.85 (3H, S).

2.37-2.83 (6H, m).

3.20 to 3.93 (6H, m).

3.87 (6H, S).

6.33 (I H, d, J = 141-1 z
).

6゜53-7.67 (141-1, m) Example 14 Under argon atmosphere, 7-(2-[4-(1-formyl)
piperazinocoethyl) theophylline 455 N (1,
54u+ojl) was dissolved in 10mM ethanol.

Add 80% hydrazine hydrazine 960 II to this solution.
After adding tg (15,4a+1ojl) and heating under reflux for 23 hours, the mixture was allowed to cool to room temperature. To the residue concentrated under reduced pressure,
10ml of dimethylformamide was added. In this solution, N-
(5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentagenoyl)-2-thiothiazoline 680I1g (1,45in+
oj)) and stirred at 80°C for 4 hours.

After concentrating this reaction solution under reduced pressure, 1.2·Og of the residue was subjected to silica gel column chromatography, and the 7-(
2-[4-[5-[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentagenoyl]piperazi-1-nyl]ethyl]theophylline) 394ay (0, zellOI) was obtained.

Under an argon atmosphere, the theophylline derivative 3944 (0
, 6711110Jl) was dissolved in 12d of methanol, and 320q of p-toluenesulfonic acid-hydrate (1,6
8uoj! ) and heated under reflux for 2 hours. After the reaction solution was allowed to cool to room temperature, a saturated aqueous sodium bicarbonate solution was added to adjust the oI-I to 8, and the mixture was extracted with chloroform. Yes 11t! t was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The remaining 400η was subjected to silica gel column chromatography, and chloroform-methanol (5
0:1) From the elution fraction, 7-[2-[4-[5-
(3,5-dimethoxy-4-hydroxyphenyl)-
2,4-Pentagenoyl]ethyl]theophylline 25
211y (0.48g+*oN) was obtained. Spectroscopic data of this product support the structure <XX> of the following formula.

(XX) cIR-1 1Rν (chloroform): aX 3535.1705.1660 'H-NMR (deuterated chloroform) δ: 2.4-2.7 (4H, m>.

2.80 (2H, t, J=6Hz).

3.4-3.9 (4H, m).

3.40(3H,S), 3.58(3H,S)3
．． 89 (6H, S).

4.40 (2H, t, J-6Hz).

6.0-7.5 (6H, m>.

1 7.57 (1H,S)
Example 15 Under an argon atmosphere, 7-(2-[4-(1-formyl)piperazino 1 ethyl)theophylline 118IIg (0
, 40110jl) to ethanol 5mi! dissolved in. Add 250 jv of 80% hydrazine humanate to this solution.
(4,01 ion) was added, and the mixture was heated to reflux for 3611 IJ, and then allowed to cool to room temperature. Dimethylformamide 5ai! is added to the residue after concentration under reduced pressure. added. Add N-(
50(3,4,5-trimethoxyphenyl)-2,4-
pentagenoyl)-2-diothiazoline 153ay(
0.50imoJ) and stirred at 80°C for 1 hour.

After concentrating this reaction solution under reduced pressure, 340q of the residue was subjected to silica gel column chromatography, and chloroform-
From the methanol (5o:1) elution fraction, 7-(2-[
4-[5-(3°4.5-trimethoxyphenyl)2.
4-Pentagenoyl]piperazi1-nyl]ethyl
Theophylline 50q (0,091 moj) was obtained. (:
(7) Mo (7) (7) Spectroscopic data supports the structure (Xo) of the following formula.

(χxl) 1Rν crystal X (chloroform) 1705.1660 1H-NMR (deuterated chloroform) δ: 2.3-2.8 (4H, m).

2.80 (2H, t, J = 6 Hz).

3.3-3.9 (4H, m).

3.38 (3H, S), 3.57 (3H, S)
.

3.84 (9H, S).

4.39 (2H, t, J=6Hz).

6.0 to 7.5 (6F+, m).

7.58 (I H, S ) Example 16 Under argon atmosphere, 4-hydroxypiperidine s, 71
9 (56,5n+e+ojl) and N-(2-bromoethyl)phthalimide 5.28 g (20,8ma+ojl)
n) was reacted at 150°C for 1 hour. After cooling,
Water was added, extraction was performed with chloroform, and the organic layer was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography using chloroform-methanol (20:1).
1-(2-phthaloylaminoethyl)-4 from the elution fraction
-Hydroxypiperidine 3.60 g (13.1 mg
+oJl) was obtained.

3.60 g of the alcohol compound (13, In+mo
j) to penzhydryl chloride 10m (56,3u+
oN), potassium carbonate 3.47 g (25,1nu
++on) was added, and the mixture was reacted at 135°C for 4 hours.

Water was added to the reaction solution and extracted with chloroform.

After washing the organic layer with water, it was concentrated under reduced pressure and the resulting residue was subjected to silica gel column chromatography. 1-(2-phthaloylaminoethyl)- from the chloroform elution fraction
2.48 g of 4-benzhydroxypiperidine (5,6
4ma+oJ) was obtained.

Under an argon atmosphere, the pi'veridine compound 224q(0
, 509 mmoJl) of ethanol (5 ai), add hydrazine in the upper tray 1-50 sty (0,99
9 mmon) was added and refluxed for 1 hour. The reaction solution was concentrated under reduced pressure, and 2 m of dry dimethylformamide was added to the resulting residue.

Additionally, 527 Itg (1,37 mn+
oj! ) was added to the mixture in dry dimethylformamide (8IR1), and the mixture was reacted at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (50:1) was extracted with 1-(2-[3-[3-methoxy-4-(β-
Methoxyethoxymethoxy)phenyl-2-propenoyl]amineethyl)-4-benzhydroxypiperidine 292 Rg (0,508n++aoJl) was obtained.

The amide compound 292IQ (0,508 mmojl)
meta, :, /-)Lt (8d) l[p-”
″”′“′°Pa″″.

-hydrate 112IRy (0,589imoJl) was added and refluxed for 20 minutes. Water was added to the reaction solution, the mixture was diluted with an aqueous sodium carbonate solution, and extracted with ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and subjected to silica gel column chromatography. From the chloroform-methanol (50:1) elution fraction, 1-(2-[
3-(3-methoxy-4-hydroxyphenyl)-2-
Propenoylcoaminoethyl)-4-benzhydroxypiperidine 164jIIy (0,337anon) was obtained. The spectroscopic data of this substance is the structure of the following formula (XX
II) is supported.

IRν crystal x (KBr): 3300.1660, 1620°1H-NMR (weight Ro*JLzm) 6:1.57~3
．． 0 (10H, m).

3.43 (3H, m), 3.72 (3H, S)
.

5.42(1)1, S).

5.98 (IH, d, J-15Hz).

6.38-7.47 (15H, m) Example 17 Under argon atmosphere, 1-(2-phthaloylaminoethyl)-4-benzhydroxypiperidine 228aff (0
,518n+a+oj! ) in ethanol (5 m) solution was added hydrazine humanate 5019 (0,999 m
moJ) was added and refluxed for 1 hour. The reaction solution was concentrated under reduced pressure, and 6 m of dry dimethylformamide was added to the resulting residue. Zarani N-(3-[3,5-dimethoxy-4-(β
-methoxyethoxymethoxy)phenyl]-2-propenoyl]thiazolidine-2-thione 369 Rg(0,
8921111110J1) was added and reacted at room temperature for 400 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography. From the fraction eluted with chloroform-methanol (50:1), 1-(2-[3-
[3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl[-2-propenoylcoaminoethyl]-4-benzhydroxypiperidine 2761+9(0
, 456 mmon) was obtained.

The amide compound 27619 (0,4561m0Jl)
(7) Add p-toluenesulfonic acid hydrate 79 # (0,4151 ion) to a methanol (6ae) solution.
was added and refluxed for 20 minutes. Water was added to the reaction solution, the pH was adjusted to 11 with an aqueous sodium carbonate solution, and extraction was performed with ethyl acetate. After washing with water, the residue was concentrated under reduced pressure and subjected to silica gel column chromatography. Chloroform-methanol (20:1) elutes 1-(2-[
3-(3,5-dimethoxy-4- and droxyphenyl)
-2-10benoyl]aminoethyl)-4-benzhuman0xypiperidine 16211? (0,299mmoJI
). (7) Mo+7) +7) Spectroscopic data supports structure (XXIII) of the following formula.

! Rν crystal x (KBr): 3400, 1660.1620° 1H-NMR (deuterated chloroform) δ: 1.50-3.03 (10H, m).

3.47 (3H, m), 3.78 (6H, S)
.

5.38 (IH,S), 5.47 (1H,S)
.

6.07 (IH, d, J = 15 H2).

6.37-7.50 (14H, m) Example 18 Under argon atmosphere, 1-(2-phthaloylaminoethyl)-4-benzhuman oxypiperidine 777ay(1,
Hydrazine humanate 148q (2,911+sg*o) was added to an ethanol (16m) solution of
Jl) was added and allowed to flow far for 1 hour. The reaction solution was concentrated under reduced pressure, and 4ad of dry dimethylformamide was added to the resulting residue. Furthermore, N-(5-[3,4(β”
-zt-Yatse, ya, tsu, guy)7z:/Lz)
A solution of 1.33 g (2,75 u+on) of -2°4-pentagenoyl]thiazolidine-2-thione in dry dimethylformamide (10 d) was added and reacted at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography.
From the methanol (50:1) elution fraction, 1-(2-[
5-[3,4-bis(β-methoxyethoxymethoxy)
phenyl]-2,4-pentagenoyl J aminoethyl]-4-benzhydroxypiperidine 500 q(0,
741 meals (Wolf) were obtained.

The amide compound 5 Q Qq (0,741+uaoJ
) in methanol (10 m) solution of p-toluenesulfonic acid-hydrate 144 al! 1l (0,7571ioJ
) was added and refluxed for 35 minutes. Water was added to the reaction solution, the pH was adjusted to 11 with an aqueous sodium carbonate solution, and extraction was performed using ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and subjected to silica gel column chromatography.

Chloroform-methanol (10:1) elution fraction
' from 1- (2-[5-(3,4-dihydroxyphenyl)-2,4-pentagenoylcoaminoethyl]
-4-benzhydroxypiperidine 185my(0,3
531lasoj) was obtained. Spectroscopic data of this product support the structure (XXIV) of the following formula.

1Rν (KBr): aX 3300.1650.1590 'H-NMR (heavy pyridine) δ: 1.67-2.93 (10H, m).

3.57 (31-1, m), 5.60 (1H, S
).

6.25 (1H, d, J-15Hz).

6.73-7.67 (17H, m) Example 19 Under argon atmosphere, 1-(2-phthaloylaminoethyl)-4-benzhydroxypiperidine 508q(1,1
Hydrazine humanate 89 N (1,713++ n+o
n) was added and allowed to flow far for 1 hour. The reaction solution was concentrated under reduced pressure, and dry dimethylformamide 5Id was added to the resulting residue.

Furthermore, N-(5-[3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]22,4-pentagenoyl]thiazolidine-2-thione 856j19 (2,1
1+u+oJ) of dry dimethylformamide was reacted. The reaction solution was concentrated under reduced pressure, the resulting residue was subjected to silica gel column chromatography, and the 1-(2
- [5- [3-methoxy-4-(β-methoxyethoxymethoxy)phenyl]-2. 4-pentagenoylcoaminoethyl)-4-benzhydroxypiperidine 690Q (1.15u+oj)) was obtained.

The amide compound 6 9 Q my (1.15 mmoj
l) (7) m9/-l (14m>solution, p-
Toluenesulfonic acid-hydrate 212■ (1.12ms
+oρ) was added and refluxed for 25 minutes. Water was added to the reaction solution, the pH was adjusted to 11 with an aqueous sodium carbonate solution, and extraction was performed using ethyl acetate. The organic layer was washed with water, concentrated under reduced pressure, and subjected to silica gel column chromatography. 1 from the chloroform-methanol (50:1) elution fraction
- (2-[5-(3-methoxy-4-hydroxyphenyl)-2,4-pentagenoylcoaminoethyl]-
4-benzhydroxypiperidine 393 rRg(0,
7301100fJ> was obtained. Spectroscopic data of this product support the structure (XXv) of the following formula.

J-1 1Rν (KBr): ax 3300.1650.1590 1H-NMR (heavy pyridine) δ: :1;: 1.53-2.88 (10H, m).

3.58(3f-1,m), 3.67(3)-1
,S).

5.63 (11-1, 3).

6.33 (IH, d, J = 15 Hz).

6.75 to 7.63 (17H, m) Example 20 Under argon atmosphere, 1-(2-phthaloylaminoethyl)-4-benzhydroxypiperidine 508 a9 (
1,15sioJ) in ethanol (10d) solution,
Hydrazine humanate 85IRg (1,72111O
Add N > 1 o 1 i 13! I let it flow. The reaction solution was concentrated under reduced pressure, and 4 d of dry dimethylformamide was added to the resulting residue. Furthermore, N-(5-[3,5-dimethoxy-4-(
β-methoxyethoxymethoxy)phenyl]-2.4-
Pentagenoyl]thiazolidine-2-thione 895
A solution of tlQ (2,04sioJ) in dry dimethylformamide (6d) was added and reacted for 2 hours under warm and humid conditions.

The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to chromatography on a silica gel recolumn using chloroform-methanol (
50:1) 1-(2-[5-(3,5-dimethoxy-4-(β-methoxyethoxymethoxy)phenyl]-2,4-pentagenoylcoaminoethyl]-
4-benzhydroxypiperidine 374 # (0,5
93101) was obtained.

The amide compound 374 q (0,593 Intojl
120q (0,631 mmojl) of p-toluenesulfonic acid hydrate was added to a methanol (9Id) solution of ) and centrifuged for 30 minutes. Water was added to the reaction solution, the mixture was converted to DHII with an aqueous sodium carbonate solution, and extraction was performed using ethyl acetate. Yes1jIW! After washing J with water, it was concentrated under reduced pressure and subjected to silica gel column chromatography.

1 from the chloroform-methanol (50:1) elution fraction
- (2-[5-(3,5-dimethoxy-4-humanOxyphenyl)-2,4-pentagenoylcoaminoethyl]-4-benzhydroxypiperidine 314IIFI
(0,552 Intojl) was obtained. The spectroscopic data of this product is 84 (XXVI) of the following formula: 3350.
1610. 1590'H-NMR (deuterated chloroform) δ: 2.55 to 2.92 (10H, m).

3.42 (3H, m), 3.78 (61-1,3)
.

5.42 (IH, S).

5.80 (IH, d, J-15H2).

6.38 - 7.40 (16H, m) Test Example 5 - Lipoxygenase action inhibition activity Mouse-derived mastocytoma cell line P-815 was used by Eagle's basic trust [Gibco Laboratories] ) and diluted to 5×104 cells/I11 in a culture medium containing 90% of the product. After culturing the diluted solution in the air at 37° C. for 48 hours with shaking, the culture solution is cooled on ice and centrifuged to collect the cells. The cells are resuspended in p)-17,4 phosphate buffer to a concentration of 2×10 7 cells/d. After the suspension is treated with an ultrasonic cell disrupter, it is centrifuged at 10,000 rpm for 10 minutes, and the supernatant is used as a 5-lipoxygenase enzyme solution. Radioactive? ! Shiki Arachidonic Acid 10μ Cury/Ai Ri 2
Indomethacin (2 x 10-8 mol) and the amide derivative according to the invention to be tested are each placed in a test tube, and 0.45 ml of phosphate buffer is added to this. , the above enzyme solution 0
．． 45 al! Add 0.1 m of 8mM Ca C12 (calcium chloride) solution and react at 37°C for 5 minutes. After cooling with water, add 60 μl of 1N HCl (salt) and extract with 8 m of ethyl acetate. Concentrate the extract. The obtained concentrate was plated on a silica gel thin layer plate (Merck 60
F) Spot and develop. The inhibitory activity was measured using a radio thin-layer Omado scanner (Dunnschicht-Scanner I [
LB 2723, 3erthold
5-) IETE' (5-(S)-hydroxy-6,8,11,14[mura-eicosatetraene II), L, TB4, which is a 5-lipoxygenase product detected in
This is done by collecting the portion corresponding to (leukotriene B4) and measuring the radioactivity with a liquid scintillation counter. The inhibition activity of 5-lipoxygenase is confirmed by the decrease in the production amount of the 5-lipoxygenase product. As a result of the test, the famous 5
-Lipoxygenase action inhibitory activity was discovered. Also,
It was confirmed that amide derivatives according to the present invention not shown in Table 1 also have similar 5-lipoxygenase action inhibiting activity.

(SoA bottom @) In addition, the 50% inhibitory concentration in the table refers to the amount of 5-lipoxygenase produced by introducing the amide derivative, assuming that the production amount of 5-GETE and LTB4 without introducing the amide derivative is 100%. It means the concentration of amide derivative required to suppress the amount of product produced by 50%.

"Acute toxicity" An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks).The LDso values of the compounds of the present invention were all 1001119/b or higher, indicating higher safety than Effective M. was confirmed.

IV. Effects of the Invention According to the present invention, a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same are provided.

It has been revealed that the above-mentioned compound of the present invention has an activity of inhibiting the action of 5-lipoxygenase.

That is, by inhibiting the action of 5-lipoxygenase, the above compound inhibits LTC4, LTD, which is an allergy-inducing factor produced by the action of 5-lipoxygenase.
It is possible to suppress the production of leukotrienes such as 4. Therefore, the amide derivative can be effectively used as a 5-lipoxygenase action inhibitor against allergic asthma, allergic rhinitis, etc.

Claims (2)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, (R)^m is 3,4-dihydroxy group, 3-methoxy-4-hydroxy group, 3,4 -dimethoxy group, 3
, 5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4-toluoyloxy group or 3,4,5-trimethoxy group. n represents the number of double bonds in trans configuration, 1 or 2
is an integer. Y is a group represented by the general formula (II) ▲There are numerical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, X is a hydrogen atom, a halogen atom or a methoxy group, and n represents 2 or 3] (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) A group represented by (III) and a group selected from the general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (IV) ] An amide derivative represented by (2) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, (R)^m is 3,4-dihydroxy group, 3-methoxy-4-hydroxy group, 3,4 -dimethoxy group, 3
, 5-dimethoxy-4-hydroxy group, 3,5-dimethoxy-4-toluoyloxy group or 3,4,5-trimethoxy group. n represents the number of double bonds in trans configuration, 1 or 2
is an integer. Y is a group represented by the general formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (II) [In the formula, X is a hydrogen atom, a halogen atom, or a methoxy group, and n represents 2 or 3] (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III) Quantities represented by, and general formula (IV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(IV) A group selected from the groups represented by ] A 5-lipoxygenase action inhibitor containing an amide derivative represented by the following.