JPH01186835A - Isoprenoid derivative and medical preparation containing the same - Google Patents

Abstract

NEW MATERIAL:An isoprenoid derivative of formula I (R is H, methyl; n is the number of double bonds of trans configuration, 1 or 2; m is 0-3). EXAMPLE:1-(4'-Hydroxy-3'-methoxyphenyl)-9-methyl-1,3,8-decatriene-5-one. USE:Medicine. 5-lipoxygenase inhibitor and antiulcerative. It inhibits the biosynthesis of leucotriene and is useful in allergic diseases, asthma, rhinitis as well as in treatment for nephritis, hepatitis, rheumatism and gastric ulcer. PREPARATION:The aldol condensation reaction between an aldehyde derivative of formula II [(R)<l> is 3,4-dimethoxymethyloxy, 3-methoxy-4-methoxymethyloxy, 3,4-dihydroxy; p is the number of trans double bonds, 0 or 1] is followed by dehydrogenation and deprotection to give the compound of formula I.

Description

Detailed Description of the Invention [Industrial Application Field] The present invention relates to a novel isoprenoid derivative and a 5-lipoxygenase action inhibitor and an antiulcer agent containing the same.Isoprenoid derivatives provided by the present invention has the activity of inhibiting the action of the enzyme 5-lipoxygenase.

[Problems to be solved by the prior art and the invention] Leukotriene Ca (LTC
a) Leukotrienes such as leukotriene DJ (LTDa) are biosynthesized in vivo from arachidonic acid by the action of 5-lipoxygenase.

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, rheumatoid arthritis, 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. Another challenge was to find a substance with antiulcer activity that suppresses gastric ulcers.

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

The isoprenoid derivatives of the present invention having anti-ulcer activity are also useful for treating ulcers such as gastric ulcers.

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

[Means to solve the problem]

The present invention in accordance with the above-mentioned object has the following advantages: (integer) is an inbrenoid derivative.

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

In the present invention, the 5-lipoxygenase action inhibitor means a preparation that has the action of suppressing the action of 5-lipoxygenase. In the present invention, the term "antiulcer agent" refers to a preparation that has the effect of suppressing ulcers such as gastric ulcers.

The isoprenoid derivative' represented by the formula (1) of the present invention is an aldehyde derivative represented by the following formula (II).

(In the formula, (R) j is a 3,4-dimethoxymethyloxy group.

3-methoxy-4-methoxymethyloxy group, 3゜4-
Represents a dihydroxy group or a 3-methoxy-4-hydroxy group, p represents the number of double bonds in trans configuration, and is O or 1. ) and polyisoprenylacetone (in the formula, n is an integer of O to 3) represented by the following formula (1), by performing an aldol reaction, followed by a dehydration reaction and a deprotection reaction.

The isoprenoid derivative of the present invention is used as a 5-lipoxygenase action inhibitor and an antiulcer agent, and the dosage varies depending on the symptoms, but is generally 10 to 2000 μ per day for adults, preferably 20 to 600 μ per day, depending on the symptoms. It is preferable to administer the drug in 1 to 3 divided doses if necessary.The administration method can be any form suitable for administration, and oral administration is particularly desirable, 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, 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 Under an argon atmosphere, 1.25 g of diisopropylamine was dissolved in 40 d of anhydrous tetrahydrofuran, cooled to -15°C, and 1.6 M n-butyllithium in hexane solution 8. Add OOd and stir for 10 minutes. 1.56g of prenylacetone and 10ml of anhydrous tetrahydrofuran! Add the solution dropwise at -15°C and stir for 10 minutes. -78℃
A solution of 2.50 g of 3'-methoxy-4''-methoxymethyloxycinnamaldehyde in 10 affi of anhydrous tetrahydrofuran was added dropwise, and the mixture was heated at -78°C for 20
Add saturated brine to the reaction mixture, stir for 0 minutes, separate the organic layer, extract the aqueous layer with ethyl acetate, wash the organic layer with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution, saturated brine, and anhydride. Dry with magnesium sulfate.

The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and the aldol adduct 3-hydroxy-1-(3'-methoxy-4'-methoxymethyloxyphenyl) was detected from the chloroform elution fraction. 1.93 g of -9-methyl-1,8-decadien-5-one are obtained.

1.93 g of this aldol adduct was dissolved in 501 methanol, 10 Ild of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. Methanol is distilled off under reduced pressure, saturated brine is added and extracted with methylene chloride, and the organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. Remove the solvent under reduced pressure.
The residue obtained by distillation was subjected to silica gel column chromatography, and 1-(4°-hydroxy-3°-methoxyphenyl)-9-methyl-1 was extracted from the fraction eluted with methylene chloride.
,3,8-decatrien-5-one (IV) 1.25
get g. The spectroscopic data of this is given by the following formula (IV)
supports the structure of

NMR (CDCl3) δ: 1.51-1.80 (6
H, +++) 3.89 (31, a) 5.07 (IH, br, t, J = 6Hz) 6.15 (
IH, d, J = 15 Hz) Example 2 Under an argon atmosphere, 0.73 g of diisopropylamine was dissolved in 20° of anhydrous tetrahydrofuran, cooled to -15°C, and a 1.6 M hexane solution of n-butyllithium was added to the solution. Add 65d and stir for 10 minutes. Geranylacetone 1.40 g of anhydrous tetrahydrofuran 5I! 11
Add the solution dropwise at -15°C and stir for 10 minutes. -7
Cool to 8°C, add dropwise a solution of 1.46 g of 3'-methoxy-4'-methoxymethyloxycinnamaldehyde in anhydrous tetrahydrofuran 5Id, and stir at -78°C for 40 minutes. Add saturated brine to the reaction mixture, separate the organic layer, extract the aqueous layer with ethyl acetate, wash the organic layer with 2N hydrochloric acid, saturated aqueous sodium bicarbonate solution, and saturated aqueous hydrochloric acid, and dry over anhydrous magnesium sulfate. do. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using hexane-methychloride L/7 (1: IV/V
) 9.13-dimethyl-3-hydroxy- from the elution fraction
1.31 g of 1-(3''-methoxy-4°-methoxymethyloxyphenyl)-1,8,12-tetradecatrien-5-one are obtained.

1.23 g of this aldol adduct was dissolved in 401d methanol, 10H1 of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 4 hours. Methanol is distilled off under reduced pressure, saturated brine is added, and extraction is performed with methylene chloride. The organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography using hexane-methylene chloride (1: IV/V
) 9,13-dimethyl-1-(4'-hydroxy-3°-methoxyphenyl)-1,3,8,12 from the elution fraction
0.75 g of -tetradecatetraen-5-one (V) is obtained. Spectroscopic data of this product support the structure of formula (V) below.

NMR (CDC42s) δ: 1.45-1.72 (9
H, m) 3.86 (3H, s) 4.83-5.23 (2H, Mongolia) 6.12 (111, d, J-15Hz) Example 3 Under an argon atmosphere, 0.66 g of diisopropylamine was anhydrous. The mixture was dissolved in 20°C of tetrahydrofuran, cooled to -15°C, 4.20ml of a 1.6M n-butyllithium hexane solution was added thereto, and the mixture was stirred for 10 minutes. trans
.

A solution of 1.70 g of trans-farnesylacetone in 51 d of anhydrous tetrahydrofuran was added dropwise at -15°C.
Stir for 10 minutes. Cool to -78°C, 3°-methoxy-4′-methoxymethyloxycinnamaldehyde 1.
A solution of 31 g of anhydrous tetrahydrofuran (5 m) was added dropwise, -
Add saturated brine to the reaction mixture, stir at 78°C for 45 minutes, separate the organic layer, extract the aqueous layer with ethyl acetate, and wash the organic layer with 2N hydrochloric acid, saturated aqueous sodium bicarbonate, and saturated brine. Dry with anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography using hexane-methylene chloride (1: IV
/V) From the elution fraction, it is an aldol adduct. 3-Hydroxy-1-(3'-methoxy-41-methoxymethyloxyphenyl)-9゜13.17-)trimethyl-
1.54 g of 1,8,12,16-octazocatetraen-5-one are obtained.

1.45 g of this aldol adduct was dissolved in 50M1 methanol, 10-6N hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. Methanol is distilled off under reduced pressure, saturated brine is added and extracted with methylene chloride, and the organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography using hexane-methychloride 7L' (1: IV/
V) 1-(4'-hydroxy-3'-methoxyphenyl)-9,13,17-trimethyl-1,3 from the elution fraction
,8,12,16-octazocapentaen-5-one (
Vl) 1.11 g is obtained. Spectroscopic data of this product support the structure of the following formula (Vl).

NI'1R (CDCJ! *) δ: 1.52-1.8
2 (12H, m) 3.84 (38, s) 4.88-5.30 (311, s) 6.14 (LH, b, J-15,5 Hz) Example 4 Under argon atmosphere, diisopropylamine 0 .49g was dissolved in anhydrous tetrahydrofuran 20511 and heated to -15°C.
3.14 Jd of a 1.6 M n-butyllithium hexane solution was added thereto, and the mixture was stirred for 10 minutes. A solution of 0.61 g of prenylacetone and anhydrous tetrahydrofuran is added dropwise at -15° C. and stirred for 10 minutes. -78
Cool to 5°C and add 3", 4°-dimethoxymethyloxybenzaldehyde to 1.0 Hg of anhydrous tetrahydrofuran.
solution was added dropwise and stirred at -78°C for 20 minutes.

Saturated brine was added to the reaction mixture, the organic layer was separated, the aqueous layer was extracted with ethyl acetate, and the organic layer was added with 2N hydrochloric acid.

Wash with saturated aqueous sodium bicarbonate solution and saturated brine, and dry over anhydrous magnesium sulfate. Under reduced pressure.

The solvent was distilled off, the residue was subjected to silica gel column chromatography, and the aldol adduct was obtained from the methylene chloride elution fraction. 0.86 g of 1-(3°,4°-dimethoxymethyloxyphenyl)-1-hydroxy 7-methyl-6-octen-3-one was obtained.

0.86 g of this aldol adduct was dissolved in 25 m methanol, 10 M1 of 6N hydrochloric acid was added, and the mixture was stirred at room temperature for 5 hours. Methanol is distilled off under reduced pressure, saturated brine is added and extracted with methylene chloride, and the organic layer is washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography, and 1-(3', 4''
-dihydroxyphenyl)7-methyl-1,6-octacyen-3-one (■) 0.51 g is obtained. Spectroscopic data of this product support the structure of the following formula (■).

N? 1R(CDCfi3)δ: 1.50-1.
80 (6H, s) 5, 07 (IH, dr, t, J
-6Hz) 6.42 (IH, d, J-16Hz) 7.38 (IH, d, J-16Hz) [Test Example] (1) Rat-derived basophilic leukemia cell line with inhibitory activity on 5-lipoxygenase RBL-1 as Eagle (Eag)
le) basal medium [Gibco Laboratories (Gibco
Laboratories, Inc.) in a culture solution containing 10% PCS, and incubated in a 5% CO8 incubator for 3 hours.
After culturing at 7°C, the culture solution is centrifuged at 4°C to collect cells. The cells are resuspended in a phosphate buffer solution of pH 7.4 to a cell density of 1.0 to 3.0×10′ cells/d.

After the floating cells were treated with an ultrasonic cell disrupter, they were centrifuged at 15.00 rpm for 30 minutes at 4°C, and the supernatant was
Make it a lipoxygenase enzyme solution. Arachidonic acid 50μg
and the isoprenoid derivative according to the present invention to be tested were placed in test tubes, and 0.30 m of phosphate buffer solution,
The above enzyme solution 0.20ai, 100mM CaCj! .

Add 5 μl of (calcium chloride) solution and react at 37° C. for 15 minutes. After ice cooling IN-FICj! (Hydrochloric acid) 1
Add a drop and extract with 2 d of ethyl acetate. After concentrating the extract to dryness, add 100 pj of methanol! was added and used as a sample.

The sample was injected into octadecylsilane (ODS)-based reverse phase high performance chromatography (HPLC), and methanol:acetonitrile:acetic acid-15:45:35:0
．． The 5-lipoxygenase product, 5-HETE (5
-(s)-hydroxy-6,8,11,14-eicosatetraenoic acid) is measured. , the inhibitory activity of 5-lipoxygenase is confirmed by the decrease in the peak height of the 5-lipoxygenase product. As a result of the test, remarkable 5-lipoxygenase action inhibitory activity was found as shown in Table 1 below. 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-HHTE 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.

(2) Anti-ulcer effect After fasting for 24 hours, the isoprenoid derivative of the present invention was orally administered to Wistar male rats (body weight 150-200 g), and 1 hour later, ethanol-hydrochloric acid (60% ethanol containing 15 hM hydrochloric acid) was administered to It was administered orally at a volume of .5yd/100g body weight.

After 1 hour, the animals were killed with ether, the stomach was removed and treated with formalin, and the length of the damage (■) generated in the glandular stomach was measured.
The total damage per animal was calculated as the ulcer coefficient (Un!cer In
dex).

As shown in the test results table (■), a remarkable anti-ulcer effect was found. It was also confirmed that isoprenoid derivatives according to the present invention not shown in Table 1 have similar anti-ulcer effects.

Table ■ Ulcer effect In addition, the ulcer formation inhibition rate (%) in the table is the value obtained by dividing the ulcer coefficient of rats to which the isoprenoid derivative according to the present invention is orally administered by the ulcer coefficient of rats that are not orally administered, multiplied by 100. It is.

・ [Acute toxicity] The LDso values of the compounds of the present invention, which were tested by oral administration using ICR male mice (5 weeks old), were all 2000 ■/kg or more, which was lower than the effective dose. High safety was confirmed.

〔Effect of the invention〕

According to the present invention, novel isoprenoid derivatives and 5-lipoxygenase action inhibitors and antiulcer agents containing the same are provided.

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

That is, by inhibiting the action of 5-lipoxygenase, the above compound can suppress the production of leukotrienes such as LTC4 and LTDa produced by the action of 5-lipoxygenase. Isoprenoid derivatives are used as 5-lipoxygenase inhibitors to treat allergic diseases such as asthma and rhinitis, as well as gastritis and
It can be effectively used for hepatitis, rheumatism, gastric ulcers, etc.

Furthermore, since the compound of the present invention can suppress ulcers, it can be effectively used as a therapeutic agent for gastric ulcers and the like.

Claims (3)

[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). (3) 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
an integer of ~3).