JPH04202127A - Interleukin-1 production-inhibiting agent - Google Patents

Abstract

PURPOSE:To provide the agent containing a zingerol derivative having a strong interleukin-I production-inhibiting activitiy as an active ingredient and moderating various symptoms mediated by the interleukin-I. CONSTITUTION:Agent containing a compound of formula I (R is H, lower alkyl; X is CH2-CH2, CH=CH; Y is methyl, CH=CH-(CH2)8-CH3, a group of formula II or III), e.g. 4-(3,4-dihydroxyphenyl)-3-butene-2-one as an active ingredient or further added with a conventional medicinal carrier, a conventional exicipient, etc., by a conventional method. The agent can be formed into a shape such as tablets, sugar-coated tablets, powder, capsules, granules, suspensions, emulsions or injections, etc. The dose of the compound of formula I is 100-3000mg, preferably 200-500mg a day for an adult. The compound of formula I has an interleukin-Ibeta production-inhibiting activity against human peripheral blood monocytes, thereby exhibits an antiinflammatory activity, and is active especially to chronic arthritic rheumatism.

Description

DETAILED DESCRIPTION OF THE INVENTION "Field of Industrial Application" The present invention relates to an interleukin production inhibitor containing a zincerol derivative as an active ingredient, and an anti-inflammatory agent that is particularly effective for rheumatoid arthritis.

[Prior art and problems to be solved by the invention] Interleukin-1 is a glycoprotein with a molecular weight of 17,000 that is produced by a wide variety of cells including macrophages, and has an isoelectric point of 50. There are α and β, which is 7.0, but as far as has been clarified to date, the effects of interleukin-1α and interleukin-1β are exactly the same.

Interleukin-1 is an important mediator of inflammation and plays an important role in inflammatory diseases, especially rheumatoid arthritis.

In particular, it is believed that rheumatoid arthritis is the main cause of joint destruction, which is the most serious condition of rheumatoid arthritis.

In addition to the above-mentioned diseases, interleukin-1 is also related to inflammatory dermatitis and psoriasis, and it also promotes the proliferation of vascular smooth muscle cells, leading to enlargement of the vascular wall. It has been revealed that it is involved in the development of atherosclerosis.

Therefore, it has been a challenge to find a substance that suppresses the production of interleukin-1 and is effective in treating these diseases.

The present inventors synthesized various gingerol derivatives and conducted intensive research on their interleukin-1 production inhibitory effects, and as a result, discovered that the gingerol derivatives according to the present invention have a strong interleukin-1 production inhibitory effect. The present invention has now been completed.

Although it has been known that gingerols have 5-lipoxygenase inhibitory activity, it is not known at all that they have interleukin-1 production inhibiting activity or anti-inflammatory effect thereof.

[Means for Solving the Problems] As a result of intensive research, the present inventors have found that certain gingerol derivatives have an effect of suppressing interleukin-1 production, and that they suppress inflammation and inflammation mediated by interleukin-1. They found that it is effective against sexual diseases, especially rheumatoid arthritis, and have completed the present invention.

The present invention will be explained in detail below.

Interleukin-1 represented by general formula (1) of the present invention
The production inhibitor has the following formula (II) [wherein R4 represents a methoxymethyl group or a hydrogen atom]
It can be obtained by performing a Claisen reaction between a benzylidene acetone derivative and capric acid imidazolamide or an aldol reaction with capric aldehyde, followed by a deprotection reaction. Further, these adducts can be obtained by further performing catalytic reduction and dehydration reactions.

The gingerol derivative represented by the formula (I) of the present invention is used as an interleukin-1 production inhibitor and an anti-inflammatory agent, and the dosage varies depending on the symptoms, but the daily dose for adults is generally 100 to 3000 mg, preferably 200 to 3000 mg. 50
It is preferably administered in 1 to 3 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 used in 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 formulated into tablets, sugar-coated tablets, powders, capsules, etc.
It can be applied in various forms such as granules, suspensions, emulsions, and injection solutions. Examples of carriers or excipients include calcium carbonate, calcium phosphate, starch, glucose, lactose, dextrin, alginic acid, mannitol, talc, magnesium stearate, and the like.

Next, the present invention will be specifically explained by showing compounds/synthesis examples and examples, but the present invention is not limited thereto.

[Compound 1] 4-(3,4-dihydroxyphenyl)-3-buten-2-one (manufactured by Aldrich) represented by the following formula (I[[)].

It was purchased and used in the following examples.

[Compound 2] 4-(4-hydroxy-3-methoxyphenyl)-3-buten-2-one (Aldo 1) shown in the following formula (TV)
・Manufactured by Sochi Co., Ltd.) was purchased and used in the following Examples.

[Synthesis Example 1] 0.50 g of 1-(3,4-dihydroxydiphenyl)-1-tetradecene-3,5-dione was mixed with methanol-J and lQ
After adding 0.10 g of 5% palladium on carbon and reacting in a hydrogen gas atmosphere for 5 hours, the reaction mixture was filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 1. -(3,4-dihydroxyphenyl)-3
, 0.36 g of 5-tetradecanedione (V) is obtained.

Spectroscopic data of this product support the structure of formula (V) below.

'HNMR (CDC13) δ: 0, 87 (311, t, J=5.01lz), 1.0
0-1. , 83 (1411, m), 2, 07-2.93
(6111m), 5.39 (III, s), 6,
27-6, 73 (3t1.m) [Synthesis Example 2] Under an argon atmosphere, 874g of diisopropylamine was dissolved in 200ml of dry tetrahydrofuran, and after cooling to -15°C, a hexane solution of 1.6M n-butyllithium 5 was added.
Add 5.7 ml dropwise. dry tetrahydrofuran 200
19.2 g of 4-(3,4-dimethoxymethyloxyphenyl)-3-buten-2-one dissolved in ml
After the dropwise addition at ℃, the mixture was stirred at the same temperature for 05 hours. After cooling to -78°C, 23.6 g of capricaldehyde dissolved in 5 Qml of dry tetrahydrofuran was added dropwise, and the mixture was stirred at the same temperature for 2.5 hours. After adding 30 ml of methanol, the mixture is returned to room temperature, saturated brine is added, the organic layer is separated, and the aqueous layer is extracted with diethyl ether. The organic layer is washed with 2N hydrochloric acid, a saturated aqueous sodium bicarbonate solution, and saturated brine, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 1-(
27.8 g of 3,4-dimethoxymethyloxyphenyl)-5-hydroxy-1-tetradecen-3-one are obtained.

After dissolving 19.3 g of titanium tetrachloride in 50 ml of methylene chloride and cooling to -78° C., 193 g of this aldol reaction adduct dissolved in 250 ml of methylene chloride was added dropwise and stirred at the same temperature for 0.5 hour.

After raising the temperature to room temperature, add 1500 ml of ethyl acetate and 50 ml of water.
0 ml is added, the organic layer is separated and the aqueous layer is extracted with ethyl acetate. The organic layer is washed with a saturated aqueous sodium bicarbonate solution and a saturated saline solution, dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure.

The obtained crude crystals were mixed with ethanol-methylene chloride (3:97
V/V) to obtain 8.33 g of 1-(3,4-dihydroxyphenyl)-5-hydroxy-1-tetradecen-3=one (VI). Spectroscopic data of this product support the structure of formula (VI) below.

'HNMR (DMSO-d6): 0, 85 (3H, t, J=511z), 1.03-]
,, 67 (1611, m), 2, 63 (211, d,
J=611z), 3.67-4.10(III, m
), 6, 38 (1, 11, d, J=16117), 6
．． 67-7, 10 (311, m), 7, 33 (l) I,
d. ．． oOg
After reacting for 15 hours under a hydrogen gas atmosphere, the reaction solution was filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, and 1-(3,4
5.94 g of -dihydroxyphenyl)-5-hydroxytetradecan-3-one (■) are obtained.

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

'HNMR (CD C13) δ ・0, 87 (
311,t, J=4.5Hz), 1.07-1.62
(1611, m), 2, 47 (21+, d, J=6
．． 0llz), 2.58-2.75 (411, m), 3
, 80-4.23 (IH, m), 6.20-6.8
0(3H,m), [Synthesis Example 4] Diisopropylamine 12°50g under argon atmosphere
was dissolved in 100 ml of dry tetrahydrofuran, -15
After cooling to °C, 82.37 ml of a hexane solution of 1.6M n-butyllithium was added dropwise, and the mixture was stirred at the same temperature for 10 minutes.

After cooling to -78℃, dry tetrahydrofuran 100ml
22.58 g of 4-(4-benzyloxy-3-methoxyphenyl)-3-buten-2-one dissolved in is added dropwise, and the mixture is stirred at the same temperature for 40 minutes. To this was added 19 ml of capricaldehyde dissolved in 30 ml of dry tetrahydrofuran.
．． Add 31 g dropwise and stir at the same temperature for 4 hours.

The reaction mixture is diluted with ether, saturated brine is added, the aqueous layer is separated, and the aqueous layer is extracted with ether. Combine the organic layers and add 2N hydrochloric acid, saturated aqueous sodium hydrogen carbonate solution,
After washing with saturated saline and drying with anhydrous magnesium sulfate,
The solvent is removed under reduced pressure.

The residue was subjected to silica gel column chromatography, and 1-(4-benzyloxy-3
18.87 g of -methoxyphenyl)-5-hydroxy-1-tetradecen-3-one are obtained. This 1-
(4-pencyloxy-3-methoxyphenyl)-5-
Hydroxy-1-tetradecen-3-one 11, '09
g was dissolved in 200 ml of methanol, and 1.0% palladium on carbon was added. After adding oOg and reacting for 15 hours under a hydrogen gas atmosphere, the reaction mixture was filtered and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography,
1-(4-hydroxy-3-
6.10 g of methoxyphenyl)-5-hydroxy-3-tetradecanone ([1,0]-gingerol) are obtained.

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

'HNMR (CD C13) δ: 0, 88 (3H, t, J=511z), 1.05-1
．． 58 (1611, m), 2, 50 (211, d, J
=6Hz), 2.65-2.95 (411, m), 3,
79 (311, s), [Synthesis Example 5] 330 g of 1-(3,4-hydroxyphenyl)-5-hydroxy-3-tetradecanone and 0.30 g of p-)luenesulfonic acid hydrate were mixed with methanol-benzene ( 1:1
0 V/V) in 66 ml and heated under reflux for 4 hours.

Add saturated aqueous sodium hydrogen carbonate solution to the reaction solution, =12
- Separate the organic layer, extract the aqueous layer with ethyl acetate, wash the organic layer with saturated aqueous sodium bicarbonate solution and saturated brine, dry over anhydrous magnesium sulfate, and then evaporate the solvent under reduced pressure. The residue was subjected to silica gel column chromatography, and 1-(3,4-dihydroxyphenyl)-4-tetradecen-3-one (Ix) was extracted from the methanol-methylene chloride (1:9 V/V) elution fraction. Get OOg. Spectroscopic data of this product support the structure of formula (IX) below.

'HNMR (CDCJ+) δ: 0, 86 (311, t, J=511z), 1.03-
2.38 (1611, m), 2,60-2.90 (41
1, m), 6.08 (III, d, 'J=1611z
), 6, 28-7.23 (411, m) [Synthesis Example 6] 1-(4-hydroxy-3-methoxyphenyl)-5-
0.90 g of hydroquine-3-tetradecanone and 010 g of p-toluenesulfonic acid hydrate are dissolved in 30 ml of benzene and heated under reflux for 3 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was removed. Distill under reduced pressure.

The residue was subjected to preparative TLC, developed with methylene chloride, and extracted from the band RfO, 2-04 with methylene salt tetrachloride to give 1-(4-hydroxy-3-methoxyphenyl)-4-tetradecene-3- 0.50 g of On ([10]-shogaol) is obtained. Spectroscopic data of this product supports the following structural formula (X).

'HNMR (CDC13) δ: 0, 87 (311, t, J=5+1z), 1.02-
1.60 (14H, m), 1, 90-2.37 (2) 1
．． m), 2.82 (411, br, s), 3
, 83 (311, s), 6.02 (Ill, d
, J=1611z), 6, 50-7.00 (411,
m) [Example] N-Ron-1 The inhibitory effect of the compounds of the present invention on the production of interleukin-1β from human peripheral blood-derived mononuclear cells was investigated.

Human peripheral blood was collected in the presence of heparin, red blood cells were separated using the dextran method, and Lymphoprep (specific gravity 1.007
) to separate mononuclear cells by specific gravity method.

- Interleukin-1 was measured by EIA method.

That is, mononuclear cells are suspended in RPM11640 medium supplemented with 2% bovine fetus, and then planted in a 96-well microplate.

Add the sample solution to this and leave at 37°C for 4 hours. Then,
Add LPS (final concentration: 1βg/ml) and incubate at 37°C.
Culture for 16 hours. After collecting the supernatant and diluting it at an appropriate ratio, the produced interleukin-1β was measured using a human interleukin-1β measurement kit (Otsuka Assay Institute).
1 amount was measured. The interleukin-1 production inhibition rate was calculated using the following formula, and IC5o (50% inhibition concentration) was determined.

The results are shown in Table 1.

IL-1 production suppression rate (%) = IL-1 (+): IL-1 production amount T when LPS is added
L-1(-): IL-1 production amount IL upon addition of LPS powder
-1(S): Sample/IL-1 production amount upon addition of LPS [TL-1 in the formula indicates interleukin-1.

] General formula (I) Table 1 Compound - Shipman RX Y
I C50 (IIM) Compound 1 m H-CH
=CH-CH3-0,95 Compound 2 TV CH
3-Cl=Cl1- C11s-3,2 Synthesis Example IVH-CIl□-CH2-01,9=CH2-C-(
Cl+2)++-CI+3 Synthesis Example 2 VI H-
CII=CH-0112,8-CHrC1+-(C11
2) s-Ctls synthesis example 3 ■ H-CH2-Cl+
2- O1+ 6.2=CH
2-C11-(CI+□)++-C1ls synthesis example 4 ■
CH3-Cl+2-Cl+2- 011
5.9■ =CH2-CH-(CI+□)8-CI+3 Synthesis Example 5
IX H−Cl+2−Cl+2− −C11=
CI+-(C112)8CH33,2 Synthesis Example 6 M
Cl+3 -CH2-Cl+2- -C11=C
11-(Cl+2)8-Cl+3 3.1 From the results in Table 1, it is clear that the gingerol derivative of the present invention has an effect of suppressing interleukin-1 production.

[Acute Toxicity] Even when the gingerol derivatives shown in Table 1 were administered intraperitoneally to male IRC mice at 500 m/kg, no toxicity, including a decrease in body weight, was observed.

[Effect of the invention]

Claims (1)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) [In the formula, R represents a hydrogen atom or a lower alkyl group, and X represents a
-CH_2-CH_2- or -CH=CH-,
Y is a methyl group or -CH=CH-(CH_2)_8
-CH_3 or ▲There are mathematical formulas, chemical formulas, tables, etc.▼ or -CH_2-CH-(CH_2)_8-CH_
3 is shown. ] An interleukin-1 production inhibitor.