JPS60152454A - Amide derivative and 5-lipoxigenase inhibitor containing said derivative as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (when R<1> is H, R<2> is piperidyl, morpholyl, 4-oxopiperidyl, etc.; when R<1> is methyl, R<2> is morpholyl, 2-hydroxycarbonylanilino, 4-oxopiperidyl, etc.). EXAMPLE:N-Caffeoyl piperidine. USE:Useful as an inhibitor for 5-lipoxigenase activity, i.e. an antiallerigic agent (e.g. remedy for allergic asthma, allertic rhinitis, etc.). It suppresses the production of leucotrienes which are critical factors of allergy. PREPARATION:The compound of formula I can be prepared by reacting the compound of formula II (R<1> is methoxyethoxymethyl or methyl) with an amine such as piperidine, and eliminating the methoxyethoxymethyl group with hydrous acetic acid, trifluoroacetic acid, etc.

Description

Detailed Description of the Invention (1) Background Technical Field of the Invention The present invention relates to a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same as an active ingredient. The amide derivative provided by the present invention has activity of inhibiting the action of 5-lipoxygenase. Leukotriene C4 (LTC4), a factor that causes allergies
Leukotrienes such as leukotriene D4 (LTD4) are biosynthesized in vivo from arachidone 6 by the action of 5-lipoxygenase. Therefore, the amide derivatives of the present invention having 5-lipoxygenase action inhibiting activity are useful as antiallergic agents.

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, p. 220, 56]
8 pages, 1983 The American Association for the Advancement of the Year: x,
7 The American As5ocia
tion for the Advancement o
As mentioned above, leukotrienes (LTC4, LTD4), which are 5-lipoxygenase products of arachidonic acid, are important factors in the development of allergic asthma and allergic rhinitis, which are allergic diseases. Therefore, there is a strong desire for a drug that has the activity of deactivating 5-lipoxygenase and inhibiting its action.

The present inventors have synthesized many amide derivatives, and their 5-
The result of intensive research into the inhibitory activity of lipoxygenase,
The inventors have discovered that amide derivatives have strong K5-IJ poxogenase inhibitory activity and have completed the present invention.

(2) Purpose of the Invention The object of the present invention is to provide a novel amide derivative and a 5-lipoxygenase action inhibitor containing the same as an active ingredient.

(2) Detailed Description of the Invention The present invention, which achieves the above objects, has the following features: (wherein R1 is hydrogen, R2 is piperidyl, morpholyl, 4-oxopiperidyl, 2-hydroxyethylamino, 4-acetamidobutylamino.

represents a group selected from 4-hydroxyanilino, R1
When is a methyl group, it is an amide derivative represented by RQj: a group selected from morpholyl, 4-oxopiperidyl, 4-hydroxyanilino, and 2-hydroxycarbonylanilino.

Further, the present invention provides (wherein R1 is hydrogen, R2 is bi-1-nodyl-2-ethylamino, 4-acetamidobutylamino.

represents a group selected from 4-hydroxyanilino, R1
is a methyl group, R2 represents a group selected from morpholyl, 4-orquinpiperidyl, 4-hydroxyanilino, and 2-hydroxycarbonylanilino) 5-lipoxygenase action inhibitor containing as an active ingredient an amide derivative represented by It is a drug.

The amide derivative represented by the general formula (1) of the present invention is:
It can be obtained by reacting the following formula θI) with an amine, and then removing the methoxyethoxymethyl group with hydrous acetic acid, P-)luenesulfonic acid, or trifluoroacetic acid. The amines include piperidine, morpholine, 4
-Biperidone monohydrate, 2-hydroxyethylamine, putrescine, 4-hydroxyaniline, etc. are preferred. Further, if desired, the amide derivative represented by the formula (1) can be obtained by condensing the carboxylic acid derivative represented by the formula (@) with an amine using a condensing agent, and then converting the acetyl group or methoxyethoxymethyl group into piperidine or hydrated acetic acid, respectively. Detach using. As the condensing agent, dicyclohexyl carboxyamide, 2-chloro-1-methylpyridinium iodide, 2-chloro-1-methylpyridinium tosylate, etc. are preferably used. As the amines, piperidine, forporin, 4-piveridone monohydrate, 4-hydroxyaniline, anthranilic acid methyl ester, etc. are preferable.

(In the formula, R1 is a methoxyethoxymethyl group or a methyl group.) (In the formula, when R' is a methyl group, R2 is a methoxyethoxymethyl group. When R1 is an acetyl group, R2 is an acetyl group. R1 is a methoxyethoxymethyl group. (In the case of R2 is a methoxyethoxymethyl group) 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 severity of the symptoms, but in general, the daily dose for adults is 20 to 2,000 μl. , preferably 50-1
It is best to administer it in 91 to 3 doses depending on the symptoms. Method of Administration: Any form suitable for administration can be taken, with oral administration being particularly preferred, but intravenous injection is also possible.

The compounds of the present invention may be used alone or mixed with pharmaceutical carriers or excipients in a conventional manner to form various formulations such as tablets, sugar-coated tablets, powders, capsules, granules, suspensions, emulsions, and injection solutions. It can be applied in Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol,
talc.

Magnesium stearate etc. can be used.

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 Diacetyl caffeic acid 531 r under argon atmosphere
n? (2,01 mmol) in dry acetonitrile (
2-chloro-1-methylpyridinium iodide 1.66f (6,50
mmol), triethylamine 0.340 ml
(2,44 mmol) and reacted at room temperature for 1 hour and 40 minutes, then 0.240 m (2,43 mmol) of piperidine
mmol) was added and reacted at 0°C for 1 hour. The reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with chloroform. The organic layer was dried with sulfuric acid) and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform was extracted with N-diacetyl cafnioyl piperidi 7332 q (1
,00 mmol) was obtained.

70.370 mg (3,74 mmol) of piperidine was added to a solution of 542 ml (1,64 mmol) of the amide compound dissolved in tetrahydrofuran (20 mg) and water (5-).
1) was added and reacted at 0°C for 1 hour and 15 minutes. After the reaction solution was concentrated under reduced pressure, water was added to the resulting residue, and the mixture was extracted with ethyl acetate.

The organic layer was dried over sodium sulfate and then concentrated under reduced pressure to obtain an extracted residue. This was subjected to silica gel column chromatography, and N-cafnioylpiperidine 252 m9 (
1,02 mmol) was obtained. The spectroscopic data of this substance supports the structure of the following formula (goods)〇IRνfipr
(Confucianism: 3470.1645.1600'H-NM
R (heavy pyridine) δ: 8.10 (IH, ci, J
=15Hz) 17.63(IH,s), 7.23(2
H, s), 7.13 (IH, d, J=15Hz), 3.
60 (4H, bs).

1.43 (6H, bs) Example-2 Under argon atmosphere, diacetylcaffeic acid 2.069
(7,80 mmo 1) was dried with acetonitrile (1
2-chloro-1-methylpyridinium iodide in a solution dissolved in 4.99 ? (19,5 mmo
1), triethylamine 2.20 ml (1
After adding 5,8mmol) and reacting at room temperature for 1 hour, morpholine 0.730+d (8,37mmol
) was added and reacted at 0°C for 4 hours and 40 minutes. The reaction solution was concentrated under reduced pressure, water was added to the resulting residual solution, and the mixture was extracted with chloroform. Dry the organic layer with sodium sulfate and reduce pressure f.
IJk shrunk. The obtained extraction residue was subjected to silica gel column chromatography, and the chloroform eluted fraction was separated from the silica gel column chromatography.
-Diacetyl cafnioylmorpholine 1.58 f
(4,74 mmo 1 ) was obtained.

To a solution of 1.58 f (4,74 mmol) of the amide compound dissolved in tetrahydrofuran (60 m/) and water (15 d) was added 1.20 mg (12,1 mmol) of piperidy.
mmo 1 ) was added and reacted at 0° C. for 9 hours and 30 minutes. The reaction oil was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was concentrated under reduced pressure, and the resulting residue was recrystallized from ethyl acetate to obtain N-cafnioylmorpholine 456 #v (1,83 mrno 1 ). Spectroscopic data of this product support the structure of formula (V) below.

Engineering Ru, Hr: (-m'): 3400, 165
0, 1605'H-NMR (ipyridine) δ: 8.
10 (IH, d, J=15Hz).

7.63 (IH, 8), 7.23 (2H, s).

7.08 (IH, d, J=15Hz), 3.
63 (8H.

bs) Example-3 Under argon atmosphere, diacetylcaffeic acid 2.2Of
(8,33 mmo 1) was dried with acetonitrile (1
2-chloro-1-methylpyridinium aiodide 6.41F (25.1 mmo
l), triethylamine 4.60ml (33,0mm
o 1) and reacted at room temperature for 2 hours, 4-
Piperidone monohydrate hydrochlorite 1.38
f (8,98 rnmol) was added and reacted at 0°C for 6 hours. The reaction solution was concentrated under reduced pressure, water was added to the obtained residue, and the mixture was extracted with chloroform. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The obtained extraction residue was subjected to silica gel column chromatography, and chloroform-
From the methanol (40:1.) elution fraction, 1.40 f (4
, 03 mmol) was obtained.

The amide form 1.40? (4,03 mmol) in tetrahydrofuran (80fn1.) and water (20mmol).
) in a solution of 1.00 me piperidine (1.00 me
0.1n+m o 1 ) was added and reacted at 0°C for 5 hours and 30 minutes. 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 (10:1) was concentrated with 1.05% of N-caffeoyl-4-piperidone. (4,02 mmol)
I got it. Spectroscopic data of this product supports the structure of the following formula (○).

IRv", :', Ccm'): 3475, 17
35'*1645, 1600 IH-NMR (heavy pyridine) δ: 8.13 (LH, d, J=15H7).

7.65 (IH, s), 7.23 (2H, s)
, 7.17 (IH, d, J=”'15H7),
3.93 (4H, t.

J=6Hz), 2.47(4H,t, J=6
Hz) Example-4 N-3-43,4-di(β-methoxyethoxymethoxy)phenyl]-propenoyl-2-thio-thiazolidine 203 to (0,44 mmo 1 ) was dissolved in 5 m7 of tetrahydrofuran! A solution of ethanolamine 32~ (0.52 mmo 1 ) dissolved in tetrahydrone 1~ was added under an argon atmosphere to a solution dissolved in
It was allowed to react for 0 minutes. IN-sodium hydroxide water bath solution 10- was added to the reaction mixture, and the mixture was extracted three times with dichloromethane. The extracted layer was washed with water and anhydrous sulfuric acid). After drying with IJum, the solvent was distilled off under reduced pressure to give N-3-(3,4-di(β-methoxyethoxymethoxy)phenylcupropenoylethanolamine 152 W (0, 38 mmol) was obtained.

N-3-[3,4-di(β-methoxyethoxymethoxy)phenylcupropenoylethanolamine 71~(
0.18 mmo 1 ) was dissolved in an 80% aqueous acetic acid solution and reacted at 99 to 102° C. for 2 hours and 30 minutes under an argon atmosphere. The solvent was distilled off from the reaction mixture under reduced pressure to obtain a residue 54#v. This was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (95:5) contained 1υN-3-(3,4-dihydroxyphenyl)-propenoylethanolamine 23"! (0.10 mm
ol) was obtained. All optical data of this product support the structure of formula (6) below. .

IRvy”: H<cm 1): 3425.3325.
3155.1660.1590.

1550, 1450, 1380 lH, -NMR (heavy pyridine) δ: 3.90 (2H
, t, J=4.8Hz).

4.00 (2H, t, J = 4.8Hz), 6.88 (,
H(.

d, J=15.5Hz), 7.20 (2H, bs).

7.55 (IH, bs), 8.1.2 (HLd, J=1
5.5Hz) Example-5 Under argon atmosphere, ■,4-diaminobutane 815 m
N-3-[3,4-di(β
-methoxyethoxymethoxy)phenyl]-propenoyl-2-thio-thiazolidine 499 m9(1-,09
mmol) dissolved in 4 ml of tetrahydrofuran was added, and the mixture was reacted at room temperature for 5 minutes. IN to the reaction mixture
- 30 aqueous sodium hydroxide solutions were added and extracted four times with chloroform. The extracted layer was washed with water, dried over anhydrous sulfuric acid, and then the solvent was distilled off under reduced pressure to obtain extraction residue 536. To a solution of this in 10 ml of dry pyridine was added 3-acetic anhydride under an argon atmosphere at a room source, and the mixture was reacted overnight at room temperature. The solvent was distilled off from the reaction mixture under reduced pressure, leaving a residue of 540
I got ~. This was subjected to silica gel column chromatography, and N-acetyl-N'-3-(3,4-di(β-
methoxyethoxymethoxy)phenyl]-furope,/yl-1,4-sheer, minobutane 228■ (0,49r
nmol) was obtained.

N-acetyl-N'-3-[3,4-di(β-methoxyethoxymethoxy)phenyl]-flobenoyl-1,4
-diaminobuta 7100 '11 (0,21mrno
1) was dissolved in 80% acetic acid aqueous solution (3 me) and reacted for 2 hours and 30 minutes at 100 to 105°C under an argon atmosphere.

The solvent was distilled off from the reaction mixture under reduced pressure to obtain a residue 87++v. This was subjected to silica gel column chromatography,
The chloroform-methanol (9:1) elution fraction was
Acetyl-N'-3-(3,4-dihydroxyphenyl)-propenoyl-1,4-diaminobutane 40~(0
, 14 mmol) was obtained. Spectral IRv of this,
H:rx(tM+): 3285, 1660, 1
5951' 1540, 1525.

1.440.1375 ”H-NMR (m pyridine) δ: 1.71 (4H,b
s), 2.07 (3H.

s), 3.43 (2H, t, J=5.9Hz), 3.
62 (2H, t, J = 5.9Hz) 6.88 (IH, d
, J=15.5Hz), 7.22 (2H, bs), 7.
59(II(.

bs), 8.13 (IH, d, J = 15.5 Hz) Example-6 Caffeic acid 5004■ (27,7
8+nmo1. ), sulfuric acid-ethanol 2: 230
Mixed solvent of 100+n/! The mixture was heated to reflux and reacted for 3 hours and 20 minutes. The reaction mixture was allowed to cool to room temperature and diluted with 100ml of drained water, and extracted three times with a mixed solvent of chloroporum and methanol (19:1). After washing the extracted layer with water and drying with anhydrous sulfuric acid, the solvent was distilled off under reduced pressure to obtain an extraction residue of 5,910~. This was subjected to silica gel column chromatography and chloroform-methanol (9
7:3) elution fraction, ethyl cicaffeate 5600
q (26,90 mmo 1 ) was obtained.

Ethyl caffeate 3847'? (18,48mm
o l) in dry 1,2-dichloroethane (80+n/) under argon atmosphere, add 9.28 mj of β-methoxyethoxymethyl chloride under water cooling. (81
, 28 mmol) followed by N.

N-diisopropylethylamine 14.16 me (
81.30rnmol) was added. Subsequently, this was reacted under heating under reflux for 3 hours. After the reaction mixture was allowed to cool to room temperature, water was added and extracted three times with dichloromethane. The extracted layer was washed with water, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to obtain an extracted residue 18010~. This was subjected to silica gel column chromatography, and 3
-[3,4-di(β-methoxyethoxymethoxy)phenylcupropenate ethyl 7100v (18,48m
mol) was obtained.

A solution of 7,100 mq (18,48 mmo+) of the ester compound dissolved in 160 scraps/Ic of methanol under an argon atmosphere was added with 40 ml of water at room temperature. Sodium hydroxide 11.8
51' (295 mmol) was added, followed by reaction at 40°C for 1 hour and 30 minutes.

Add 200% of water to the reaction mixture, and adjust the pH with 6N hydrochloric acid under water cooling.
4, and then extracted three times with dichloromethane.

The extracted layer was washed with water and anhydrous sulfuric acid). After drying with IJum, the solvent was distilled off under reduced pressure and 3-(3,4-di(β-methoxyethoxymethoxy)phenyl)propenoic acid 6371 wsi
(17.88 mmo 1 ) was obtained. The carboxylic acid 2
2-Mercaptothiazoline 683 W9 (
5,73 mmol), 4-dimethylaminopyridine 64ray (0,524 mmol), followed by dicyclohexylcarbodiimide 1288Iny (6,
24 mmol) were added in order and reacted at room temperature for 1 hour and 10 minutes. After filtering off the resulting precipitate, 30% of IN-sodium hydroxide aqueous solution was added to the mother liquor, and this was diluted with dichloromethane.
Extracted twice. The extracted layer was washed with water, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to obtain an extraction residue 2930#.

This was subjected to silica gel column chromatography, and the chloroform eluted fraction was
2-thio-thiazolidine 2162”? (4,73m
mol) was obtained. N-3-[3,4-di(β-methoxyethoxymethoxy)phenylcupropenoyl-2
- Thiazolidine 300'9 (0,66mmo
l) in tetrahydro7 run 6d at room temperature under an argon atmosphere.
19 (0.98 mmol) was added thereto, followed by reaction under heating and reflux for 21 hours. The reaction mixture was allowed to cool to room temperature, added with drained water, and extracted three times with dichloromethane. The extracted layer was washed with water, dried over anhydrous sodium itate, and then the solvent was distilled off under reduced pressure to obtain extraction residues 304-. This was subjected to silica gel column chromatography and chloroform-methanol (
98:2) N-3-C3,4-di(β-methoxyethoxymethoxy)phenylcupropenoyl-
4-aminophenol 173 ml (0.39 mmo
l) was obtained.

N-3[3,4-di(β-methoxyethoxymethoxy)
phenyl]-flopenoyl-4-aminephenol 10
5'9 (0.23 mmol) was dissolved in 80 thiacetic acid aqueous solution 4- and left at room temperature under an argon atmosphere overnight.
React at 100-105℃ for 2 hours! Ta. The solvent was distilled off from the reaction mixture under reduced pressure to obtain residue 71. This was subjected to silica gel column chromatography, and chloroform-
The methanol (95:5) elution fraction was purified with N-3-(3,4
-dihydroxyphenyl)-propenoyl-4-aminephenol 35q (0.13 mmol) was obtained. Spectroscopic data of this product support the structure of formula (K) below.

IR number: (LM-RE: 3305.1655.160
5.1590.1540.

1515, 1440, 1365 IH-NMR (heavy pyridine) δ: 6.99 (IH, d
, J-15,5Hz).

7.18 (2H, be), 7.22 (2H, d, J=
9Hz).

7.55 (IH, bs), 8.10 (2H, d, J
=9Hz).

8.23 (IH, d, J = 15.5 Hz) Example-7 165q (0
, 699 mmol) in dry acetonitrile (4 ml)
2-chloro-1-methylpyridinium iodide 357'f (1,40 mmol) in the K-dissolved solution
) ethylamine 0.390wt (2,80mm
After adding 0.610 d (7,00 mmol) of morpholine and reacting at room temperature for 45 minutes, the mixture was reacted at room temperature for 200 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and 175-(0,601 mmol) of N-feruloylmorpholine was obtained from the chloroform elution fraction. The physicochemical data of this ~ support the structure (3) of the following formula.

IR, ni: 2 (bei-'): 3535, 1645
, 1600F HNMR (CDCL3) δ: 7
．． 65 (IH, d, J=15Hz), 7.13-6.8
7 (3H, m), 6.67 (IH, d, J=15Hz
), 6.28 (IH, bs), 3.90 (3H, s).

3.70 (8H, a) Example-8 Acetylferrin & 832111 under full-bodied atmosphere i
F (3,52 mmol) was dissolved in dry acetonitrile (
26d) 2-chloro-1-methylviridiram iodide in a solution of 2.03 ? (7,95mm
l), triethylamine y 2.50ml (17
, 9 mmol) and reacted at room temperature for 300 minutes, 4-biperidone monohydrate hydrochlorite 596~ (3.88 mmol) was added and reacted at 0°C for 6 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and extraction was performed with chloroform. The organic layer was dried over sulfuric acid and concentrated under reduced pressure. The obtained extraction residue was subjected to silica gel column chromatography and N-acetylferuloyl-4-piperide 71.11? (
3,50n+mol) was obtained.

To a solution of 327 ml (1,03 mmol) of the amide compound dissolved in tetrahydrofuran (10 ml) and water (2,5 ml), piperidine 0.115 ml (1,16 ml) was added.
mmol) was added and reacted at room temperature for 27 hours. The reaction solution was concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography to obtain 147 tons (0,897 rnmo 1 ) of N-feruloyl-4-pipe IJ. The spectroscopic data of this product supports the structure of the following formula (to) ○IRv::;(c+n-li: 3250.1725.1
647.1600'H-NMR (heavy pyridine) δ: 8
．． 15 (LH, d, J = 15H7).

7.48-7.15 (4H, m), 3.97 (4H, t
.

J = 6Hz), 3.72 (3H, s), 2.45 (4H
.

t, J=6H7) Example-9 Ethyl ferulate 5.00 r(
0,024 mol) to 1.2-diO/l/1 y(
7oi), add 3.60 ml (0,032 mol) of β-methoxyethoxymethyl chloride to the solution dissolved in
, followed by N,N-diisopropylethylamine 5.5
7 ml (0,032 mol) was added. Subsequently, this was reacted under heating under reflux for 2 hours. The reaction solution was allowed to cool to room temperature, and 100 + + +/- of drained water was added, extracted with chloroform, and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and benzene-ethyl acetate :1) Elution fraction: 0-methoxyethoxymethyl ethyl ferulate 6.1
2F(0,021mo 1 ) was obtained. Next, in an argon atmosphere, 5.92f(0,
020mol) in methanol (100+++t), add 25mg of water and 10ml of sodium hydroxide (Q
, 25 mol) and reacted at room temperature for 1 hour.

After adding 6N hydrochloric acid to this reaction solution to adjust the pH to 4,
It was diluted with 50 ml of water and extracted with ethyl acetate.

The organic layer was dried with sulfuric acid) and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the fraction eluted with chloroform-methanol (19:1) was purified with 0-methoxyethoxymethylferulic acid. 4.9
3 f (0,019 mol) was obtained.

Next, the carboxylic acid 703'? (2,63 mmol
) in 1,2-dichloroethane 1 under an argon atmosphere.
740my (0.33mmol) of 4-dimethylaminopyridi, fk460tr9 (3.05mmol) of anthranilic acid were added to a solution dissolved in 0rnl at room temperature.
, Dicyclohexylcarbodiimide 620
wry (3.01 mmol) was added and reacted at room temperature for 4 hours. After filtering off the resulting precipitate, the mother liquor was concentrated under reduced pressure.
The obtained residue was subjected to silica gel column chromatography, the benzene-ethyl acetate (9:1) eluate fraction was concentrated under reduced pressure, and the residue was further subjected to Sephadex LH-20 column chromatography, and the methanol eluted fraction was N
-(0-Methoxyethoxymethyl)feruloyl anthranilate methyl 234"? (0,586 mmol
) was obtained.

Next, 190 ml (0,476 mmol) of the amide compound
) in methanol (10 ml) under an argon atmosphere, add water 2-1 sodium hydroxide 0.5F (12
, 5rnmol) and reacted at room temperature for 45 minutes. 6N hydrochloric acid was added to this reaction solution to adjust the pH to 4, and the mixture was diluted with 10 ml of water to precipitate crystals. Take this crystal, recrystallize the obtained crystal from dilute methanol, and obtain 160 ml (0,416 mmol) of N-(0-methoxyethoxymethyl)feruloyl anthrael.
) was obtained.

Next, the amide compound 110”f (0,286 mmol
) under argon atmosphere, l,4-dioxane (], m
l) 5 ml of a mixed solution of acetic acid-water (4:'1) was added to the K-dissolved solution, and the mixture was reacted at 100°C for 1 hour.

When water was added to this reaction solution, crystals were precipitated. The crystals were taken and recrystallized from dilute methanol, yielding 75~(0,253 mmol) of N-feruloyl anthranilic acid.
) was obtained.

Spectroscopic data of this amide support the structure of the following formula (2).

IR+' company: (cm-li: 3525.1681.16
64.1602.1582.

520'H-NMR (heavy acetone) δ: s, 97 (IH, d
, J=8Hz).

8.19 (IH, dd, J=8.2Hz),
7.80-6.85 (5H, m), 7.71 (IH, d
, J=16Hz).

6.69 (IH, d, J=16Hz), 3.9
7 (3H.

S) Example-10 Under an argon atmosphere, 468 mg (1,76
mmol) dried 7-k)=)'Jle(10+d)
K dissolved at room temperature P-amine phenol 196! (
1,80! .

mmol), 2-chloro-1-methylpyridinium iodide 460 +119 (1,80 mmol
), then triethylamine 0.5 mg (3,5
8 mmol) was added and reacted for 2 hours. The reaction solution was diluted with water and extracted with chloroform. The organic layer was dried with sulfuric acid) and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the N-(0
-Methoxyethoxymethyl)-fershou-4-aminophenol 290 ”?
) was obtained.

Next, the amide compound 210 m? (0,588 mmol
) in 1,4-dioxane (1 ml) under argon atmosphere.
) and a mixed solution of acetic acid and water (4:1) 5
ml was added and reacted at 100°C for 1 hour. After the reaction solution was allowed to cool to room temperature, it was diluted with 10 ml of water and extracted with ethyl acetate. The organic layer was dried with sulfuric acid) and concentrated under reduced pressure. The resulting residue was subjected to Sephadex LH-20 column chromatography, and N-feruloyl-4-aminophenol 108 'I' was extracted from the methanol elution fraction. 9 (0,401 mmol) was obtained. Spectroscopic data of this amide support the structure of the following formula (E).

IRνH Koni (crn-li: 3340, 1670
, 1620, 1610, 1590'H-N
MR (heavy acetone) δ: 9.02 (IH, Il, 7
．． 48 (IH.

d, j=16Hz), 7.48(2H, d, J=8H
z).

6.97 (2H, d, J=8Hz), 6.
78-6.63 (3H, m), 6.55 (IH, d,
J=16Hz).

3.80 (3H1s) Test Example 5 - Lipoxygenase action inhibition activity Mouse-derived mastocytoma cell line P-815 Ly-
5 x 10' cells/m/! in a culture solution containing 90% of Eagle's basal medium (manufactured by Gibco Laboratories). Dilute so that Diluted solution' in air at 37°C
After culturing with shaking for an hour, the culture solution is cooled on ice and centrifuged to collect the cells. The cells are resuspended in pH 7.4 phosphate buffer to a concentration of 2 x 10' cells/ml. After treating the suspension with an ultrasonic cell disrupter, the suspension was heated at 10.00 Orr for 10 minutes.
Centrifuge at pm and use the supernatant as a 5-lipoxygenase enzyme solution. Radioactively labeled arachidonic acid (10 μl/m
Put 20 μt of 7.0%, indomethane (2×10'mol) and the amide conductor to be tested into test tubes, and add 0.45#+7! of phosphate buffer to the test tubes. , the above enzyme solution 0.4
Add 5 ml of SmMcactz (calcium chloride) solution 0.1- and react at 37°C for 5 minutes. After cooling on ice, 60 μt of 1N-HC1 (hydrochloric acid) is added, and the mixture is extracted with ethyl acetate 8-. The concentrated solution obtained by concentrating the extract was placed on a silica gel thin layer plate (Merck 60 F
ist) and expand it. Measurement of inhibitory activity is
Radio thin layer chromatography scanner (Diinnschic
ht-3canner! 5- detected with ILB 2723 (manufactured by Berthold)
5-HETE (5(
8)-hydroxy-6,8,11,14-eicosatetraenoic acid).

This is done by collecting a portion corresponding to LTB4 (leukotriene B4) and measuring the radioactivity using a liquid scintillation counter. The inhibitory activity of 5-lipoxygenase is confirmed by the decrease in the production amount of the 5-riboxygenase product. As a result of the test, remarkable 5-riboxygenase inhibitory activity was found as a representative example as shown in Table 1 below. Indeed, it was confirmed that the amide derivatives according to the present invention shown in Table 1 also have similar 5-lipoxygenase action inhibiting activity.

In addition, the 50% inhibitory concentration in the table refers to the case where the amide derivative is not introduced. It means the concentration of amide visiting conductor required to suppress it to 50%.

■Specific effects of the invention According to the present invention, novel amide derivatives are provided.

As shown in the above test example, the above compound of the present invention has 5-
It was revealed that it has riboquinogenase action inhibiting activity. That is, by inhibiting the action of 5-lipoxygenase, the above compound inhibits LTC, which is an allergy-inducing factor produced by the action of 5-lipoxygenase.
4. Production of leukotrienes called LTD4 can be suppressed. Therefore, the amide derivative can be effectively used as a 5-riboquinogenase action inhibitor for allergic asthma, allergic rhinitis, and the like.

Patent applicant: Terumo Corporation

Claims (2)

[Claims] (1) General formula (+) (In the formula, when R1 is hydrogen, RZ is selected from piperidyl, morpholyl, 4-oxypiperidyl, 2-hydroxyethylamide), 4-acetamidobutylamino. 4-hydroxyanilino represents a group, R1
is a methyl group, R2 represents a group selected from morpholyl, 4-oxopiperidyl, 4-hydroxyanilino, and 2-hydroxycarbonylanilino). (2) General formula (+) (wherein, when R1 is hydrogen, R2 is a group selected from piperidyl, morpholyl, 4-oxopiperidyl, 2-hydroxyethylamino, 4-acetamidobutylamino, and 4-hydroxyanilino) Representation, R1
is a methyl group, R2 represents a group selected from morpholyl, 4-oxopiperidyl, 4-hydroxyanilino, and 2-hydroxycarbonylanilino) A 5-lipoxygenase action inhibitor containing as an active ingredient an amide derivative represented by .