JPH01165563A - Isoprenoid derivative and 5-lipoxygenase action inhibitor containing said derivative - Google Patents

Abstract

NEW MATERIAL:A compound shown by formula I (R is H or CH3; n is number of double bonds of trans-configuration and is 1 or 2; m is 0-3). EXAMPLE:5-(4'-Hydroxy-3'-methoxyphenyl)pentadienoic acid prenylamide. USE:A remedy for asthma, rhinitis, nephritis, hepatitis, rheumatism or gastric ulcer. PREPARATION:A compound shown by formula II [(R)<l> is 3,4- dimethoxymethyloxy, etc.)] and a compound shown by formula III are subjected to hydrazine decomposition to give isoprenylamine shown by formula IV, which is condensed and deprotected to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel isoprenoid derivative and a 5-lipoxygenase action inhibitor containing the same. The isoprenoid derivative provided by the present invention has an activity of inhibiting the action of the enzyme 5-lipoxygenase.

[Problems to be solved by the prior art and the invention] Leukotriene C4 (LT), which is an allergy onset factor
Leukotrienes such as C4), leukotriene o, and (LTD4) are 5-derived from arachidonic acid in vivo.
It is biosynthesized by the action of IJ poxygenase.

Recently, it has been revealed that leukotrienes are involved not only in allergies but also in the development of pathological conditions such as nephritis, hepatitis, rheumatism, and gastric ulcers.

Therefore, it has been a challenge to find substances that suppress the biosynthesis of leukotrienes and are effective in treating these diseases.

The present inventors synthesized various isoprenoid derivatives and conducted intensive research on their 5-lipoxygenase action inhibitory activity.
-We have discovered that it has lipoxygenase action inhibiting activity and have completed the present invention. The isoprenoid derivatives of the present invention having 5-lipoxygenase action inhibiting activity suppress leukotriene biosynthesis and are useful for treating allergic diseases such as asthma and rhinitis, as well as nephritis, hepatitis, rheumatism, and gastric ulcers.

Therefore, an object of the present invention is to provide a novel isoprenoid derivative and a 5-lipoxygenase action inhibitor containing the same.

[Means for solving problems]

The present invention in accordance with the above object provides - Maximum (1) (wherein R represents a hydrogen atom or a methyl group, n represents the number of double bonds in trans configuration, and is 1 or 2; m is O-3 is an integer of ).

Furthermore, the present invention is based on the general formula (I) (wherein R represents a hydrogen atom or a methyl group, n represents the number of double bonds in the trans configuration, and m is 1 or 2, and m is 0 to 2.
This is a 5-lipoxygenase action inhibitor containing an isoprenoid derivative represented by (an integer of 3).

In the present invention, the 5-lipoxygenase action inhibitor means a preparation that has the action of suppressing the action of 5-lipoxygenase.

The isoprenoid derivative represented by the formula (I) of the present invention is a carboxylic acid derivative represented by the following formula (n) (wherein (R) 1 is a 3,4-dimethoxymethyloxy group).

3-methoxy-4-methoxymethyloxy group, 3゜4-
Represents a dihydroxy group or 3-methoxy-4-hydroxy group. n represents the number of double bonds in trans configuration, and is 1 or 2. ) and isoprenylamine (IV) obtained by hydrazine decomposition of isoprenyl phthalimide (in the formula, m is an integer of O to 3) represented by the following formula (I[[) (in the formula, m is an integer of O to 3) is an integer of ) and a deprotecting group reaction.

The isoprenoid derivative of the present invention is used as a 5-lipoxygenase action inhibitor, and the dosage varies depending on the symptoms, but the daily dose for adults is generally 10 to 2000 mg.

The dose is preferably 20 to 600 μl, and the dose may be divided into 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 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, calcium phosphate, starch, sugar, milk powder, dextrin, alginic acid, mannitol, talc,
Examples include magnesium stearate.

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 N-prenylphthalimide 10.0 under argon atmosphere
5 g and 2.92 g of 80% hydrazine hydrate in ethanol 5
Dissolve in a solution of 0.0 and reflux for 2 hours. Add 5% of concentrated hydrochloric acid to the reaction mixture.
ml, and the precipitated crystals are filtered and washed four times with 5 d of ethanol. The filtrate and washing liquid were combined and the solvent was distilled off under reduced pressure until the volume was about 10%. Add 50 mft of water to the residue,
After filtration, the filtrate was distilled off under reduced pressure to obtain prenylamine hydrochloride. After adding 7 d of a 40% aqueous sodium hydroxide solution, potassium carbonate was added until saturation, the organic layer was taken, dried over sodium hydroxide, and prenylamine 1.3
Obtain 0g.

Under an argon atmosphere, 2.20 g of 5-(4''-hydroxy-3°-methoxyphenyl)pentadienoic acid is suspended in 50 volumes of methylene chloride and cooled to -10''C. Add 2.92 d of triethylamine and 2.16 g of ethyl chlorocarbonate.

After stirring for 1 hour, a solution of 8 g of prenylamine hydrochloride dissolved in 10-methylene chloride was added, and the mixture was stirred at -10°C to 0°C for 3 hours. The reaction mixture was poured into water and extracted with chloroform. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and prenyl 5-(4'-ethoxycarbonyloxy-3'-methoxyphenyl)pentadienoate was extracted from the fraction eluted with methylene chloride-methanol (99:1). 2.91 g of amide are obtained.

5-(4'-Ethoxycarbonyloxy-31-methoxyphenyl)pentadienoic acid prenylamide 1.34g
was dissolved in 10 d of methanol, 2.8 ml of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred for 15 minutes at room temperature. IN-hydrochloric acid was added to the reaction mixture to make it acidic, and then extracted with chloroform. Wash the organic layer with water and dry with sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and 5-(4'-hydroxy-3'-methoxyphenyl) was extracted from the fraction eluted with methylene chloride.
0.77 g of pentadienoic acid prenylamide (V) is obtained. Spectroscopic data of this product support the structure of formula (V) below.

n+ar(CDCl3)δ: 5.96(III, d
, J=15Hz) 3.91 (2H, t, J=8Hz) 3.77 (3H, s) 1.66 (6H, bS) Example 2 3.00 g of N-geranylphthalimide and 80% hydrazine hydrate 0 Dissolve .80 g in 60 d of ethanol and reflux for 3 hours. The solvent was distilled off under reduced pressure to obtain a mixture of geranylamine and hydrazide. Meanwhile, under an argon atmosphere, 5-(
2.33 g of 4'-hydroxy-3'-methoxyphenyl)pentadienoic acid was suspended in 50 m2 of methylene chloride,
Cool to 0"C. Add triethylamine 2.95-ethyl chlorocarbonate 2.03mff1. After stirring for 30 minutes, add a solution of a mixture of geranylamine hydrazide suspended in methylene chloride. -1o"C-O"C The reaction mixture is filtered and the precipitate is washed with methylene chloride.The filtrate and washing liquid are combined, washed with water and then with saturated brine, and dried over anhydrous sodium sulfate.The solvent is distilled off under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 2.61 g of 5-(4'-ethoxycarbonyloxy-3'-methoxyphenyl)pentadienoic acid genyralamide from the chloroform eluted fraction.

5-(4'-Ethoxycarbonyloxy-3°-methoxyphenyl)pentadienoic acid geranylamide 1.61
g was dissolved in 25 d of methanol, 10 d of 2N aqueous sodium hydroxide solution was added, and the mixture was stirred for 1 hour at room temperature. IN-hydrochloric acid is added to the reaction mixture to make it acidic and then extracted with chloroform. Wash the organic layer with water and dry with sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
1.20 g of (4'-hydroxy-3-methoxyphenyl)pentadienoic acid geranylamide (VI) is obtained. Spectroscopic data of this product support the structure of the following formula (Vl).

nmr (CDCl3)δ: 5.83 (IH, d,
J=15)1z) 3.83 (3H, s) 1.65 (6H, s) 1.57 (311, s) Example 3 (E, B)-N~Farnesylphthalimide 2.10 g
and 0.49 g of hydrazine hydrate were dissolved in 40% ethanol and refluxed for 3 hours. The solvent was distilled off under reduced pressure to obtain a mixture of E,E)-farnesylamine and hydrazide.

Meanwhile, under an argon atmosphere, 1.32 g of 5-(4'-hydroxy-3'-methoxyphenyl)pentadienoic acid was suspended in 30 d of methylene chloride and cooled to -10'C. Add 1.67 d of triethylamine and 1.15 d of ethyl chlorocarbonate. After stirring for 30 minutes, a solution of a mixture of (E,E)-farnesylamine and hydrazide suspended in methylene chloride is added. Stir at -1H°C to 0°C for 3 hours. The reaction mixture is filtered and the precipitate is washed with methylene chloride.

The filtrate and washing solution are combined, washed with water and then saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 5-(4°-ethoxycarbonyloxy-3'-methoxyphenyl)pentadienoic acid (E, E) from the fraction eluted with methylene chloride.
-2.06 g of farnesylamide are obtained.

Dissolve 2.06 g of 5-(4'-ethoxycarbonyloxy-3°-methoxyphenyl)pencacienic acid (E,E)-farnesylamide in 40 d of methanol,
Add 20 d of N-sodium hydroxide aqueous solution and stir at room temperature for 1 hour. The reaction mixture was made acidic by adding IN-hydrochloric acid and extracted with chloroform. The organic layer is washed with water and dried over sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and 5-(4''-hydroxy-3''-methoxyphenyl)pentadiene M (E, E)-farnesylamide (■) 1. Obtain 67g. Spectroscopic data of this product support the structure of the following formula (■).

nmr (CDC13) δ: 5.81 (IH, d, J=
15Hz) 3.83 (3H, s) 1.64 (68, bs) 1.55 (6H, bs) Example 4 2.62 g of N-geranylphthalimide and 0.70 g of hydrazine hydrate were dissolved in 40 d of ethanol, Reflux for 3 hours. The solvent was distilled off under reduced pressure to obtain a mixture of geranylamine and hydrazide.

On the other hand, under an argon atmosphere, 1.80 g of ferulic acid was salted,
Suspend in methylene chloride 40Id and cool to -10''C.

Triethylamine 2.58-Ethyl chlorocarbonate 1.77
Add 1d. After stirring for 30 minutes, a solution of a mixture of geranylamine and hydrazide suspended in methylene chloride is added.

Stir at -10°C to 0°C for 3 hours. The reaction mixture is filtered and the precipitate is washed with methylene chloride. The filtrate and washing solution are combined, washed with water and then saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
1.44 g of -ethoxycarbonyloxy-3-methoxycinnamic acid geranylamide are obtained.

Dissolve 1.44 g of 4-ethoxycarbonyloxy-3-methoxycinnamic acid geranylamide in 25 ml of methanol, add 2N aqueous sodium hydroxide solution (14), and stir at room temperature for 1 hour.

IN-hydrochloric acid is added to the reaction mixture to make it acidic, and then extracted with chloroform. The organic layer is washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to obtain 0.70 g of 4-hydroxy-3-methoxycinnamic acid geranylamide (■) from the chloroform elution fraction. Spectroscopic data of this product support the structure of the following formula (■).

nmr (CDCII 3) δ: 7.45 (IH, d,
J=15Hz)6.2011-1. d, J=151(x
) 3.73 (38, s) 1.70 (6H, bs) 1.50 (3H, bs) Example 5 2.50 g of N-geranylphthalimide and 0.66 g of hydrazine hydrate were dissolved in 50 ml of ethanol, Reflux for an hour. The solvent was distilled off under reduced pressure to obtain a mixture of geranylamine and hydrazide.

Meanwhile, under an argon atmosphere, 2.60 g of 5-(3", 4°-dimethoxymethoxyphenyl)pentadienoic acid was suspended in 30 d of methylene chloride and cooled to -10°C. 1.23 d of triethylamine and 0.85 d of ethyl chlorocarbonate. - is added. After stirring for 30 minutes, a solution of a mixture of geranylamine and hydrazide suspended in methylene chloride is added.

Stir at -10°C to 0°C for 3 hours. The reaction mixture is filtered and the precipitate is washed with methylene chloride. The filtrate and washing solution are combined, washed with water and then saturated saline, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and 5-(3°, 4''-dimethoxymethoxyphenyl) was extracted from the chloroform elution fraction.
2.12 g of pentagenic acid geranylamide was obtained.

1.96 g of 5-(3", 4"-dimethoxymethoxyphenyl)pentadienoic acid geranylamide was added to 40 g of methanol.
Dissolved in P-) luenesulfonic acid monohydrate 0.09
g and stirred at 50'C for 3 hours. Pour the reaction solution into water and extract with chloroform. The organic layer is washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using chloroform-methanol (99:1) from the t8 fraction.
- (3',4'-dihydroxyphenyl)pentadienoic acid geranylamide F 1.40 g (IX) is obtained. Spectroscopic data of this product support the structure of formula (IX) below.

no+r (CDC1s) δ: 5.81 (18, d,
J=15Hz) 1.63 (6H,S) 1.57 (3H,S) [Test example] 5-lipoxygenase action inhibition activity Rat-derived basophilic leukemia cell line RBL-1 was lO in basal medium [manufactured by Gibco Laboratories]
Cells are suspended in a culture solution containing 5% FC5 and cultured at 37°C in an incubator, and then the culture solution is centrifuged at 4°C to collect the cells. The cells were resuspended in a phosphate buffer solution at pH 7.4 to a cell density of 1.0 to 3. OX 10' pieces/
Let it be d.

After treating the floating cells with an ultrasonic cell disrupter, 15. Centrifuge at OOOrpm 4°C and remove the supernatant at 5°C.
- Make it a lipoxygenase enzyme solution. Radioactively labeled arachidonic acid (20 μ2 of 10 μC/1+11) and the isoprenoid derivative according to the present invention to be tested were placed in test tubes, and 0.40 d of phosphate buffer, 0.10 d of the above enzyme solution, and 100 mM CaCf z ( Add 5d of calcium chloride solution and react at 37°C for 15 minutes.

After cooling with water, 1 drop of IN-HCf (hydrochloric acid) was added, and the mixture was extracted with 2 d of ethyl acetate. The concentrated solution obtained by concentrating the extract was placed on a silica gel thin layer plate (Merck 60
Fzs4) and develop. Measurement of inhibitory activity is
Radio thin layer chromatography scanner (Dunnschich
5-HETE (5-(S)-hydroxy-6,8,11,14-eicosatetraenoic acid), a 5-lipoxygenase product detected with t-Scanner IILB2723, manufactured by Berthold. This is done by collecting the corresponding portions 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. Test results,
As shown in Table 1 below, remarkable 5-lipoxygenase action inhibitory activity was found. Furthermore, it was confirmed that isoprenoid derivatives according to the present invention not shown in Table 1 also have similar 5-lipoxygenase action inhibiting activity.

(Left below) In addition, the 50% inhibitory concentration in the table refers to the amount of 5-HETH produced when the isoprenoid derivative according to the present invention is not introduced.
00χ means the concentration of isoprenoid derivative required to suppress the production amount of the 5-lipoxygenase product to 50% by introducing the isoprenoid derivative.

[Acute toxicity] An acute toxicity test was conducted by oral administration using ICR male mice (5 weeks old). LD of the compounds of the invention. All values were over 100 μ/kg, confirming high safety compared to the effective dose.

〔Effect of the invention〕

According to the present invention, a novel isoprenoid derivative and a 5-lipoxygenase action inhibitor containing the same are provided.

The above compounds of the present invention have remarkable activity of inhibiting the action of 5-lipoxygenase. That is, the above compound inhibits the action of 5-lipoxygenase, thereby reducing LTC4 and LTD4 produced by the action of 5-lipoxygenase.
It is possible to suppress the production of leukotrienes. Therefore, the isoprenoid derivative can be used as a 5-lipoxygenase action inhibitor to treat asthma, which is an allergic disease.
It can be effectively used for rhinitis, gastritis, hepatitis, rheumatism, gastric ulcers, etc.

Claims (2)

[Claims] (1) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a hydrogen atom or a methyl group, n represents the number of double bonds in trans configuration, 1 or 2 is.m is 0
is an integer of ~3). (2) General formula (I) ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, R represents a hydrogen atom or a methyl group, n represents the number of double bonds in trans configuration, 1 or 2 is.m is 0
A 5-lipoxygenase action inhibitor containing an isoprenoid derivative represented by (an integer of ~3).