JPS6396149A - Novel terpene compound and anti-inflammatory agent containing the same - Google Patents

Abstract

NEW MATERIAL:11-Hydroxy-3,7,11-trimethyldodecanoic acid of formula VI. USE:A medicine. An anti-inflammatory agent. It can be administered by oral or parenteral administration. PREPARATION:The objective compound of formula VI can be produced by (1) reacting geranylacetone of formula V with formic acid and water in the presence of a catalytic amount of an alkali compound at 0 deg.C - room temperature, (2) subjecting the resultant compound of formula I and the compound of formula II (R<1> is lower alkyl) to Harmer reaction in the presence of a base such as NaH at 0-100 deg.C, (3) converting the obtained unsaturated carboxylic acid ester of formula III to the compound of formula IV by the catalytic hydrogenation with H2 in the presence of a catalyst such as Pd/C and (4) saponifying the product with NaOH in a solvent using a conventional saponification reaction process.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides a novel compound, 11-hydroxy-3,7
, 11-trimethyldodecanoic acid and an anti-inflammatory agent containing the same.

[Conventional technology]

11-Hydroxy-3,7,11-trimethyldodecanoic acid according to the present invention is a new compound, and anti-inflammatory agents containing it are also unknown.

[Problem that the invention seeks to solve]

The object of the present invention is to develop novel compounds containing 11-hydroxy-
An object of the present invention is to provide 3,7,11-)limethyldodecanoic acid and an anti-inflammatory agent containing the same.

[Means for solving problems]

The present inventors have newly synthesized 11-hydroxy-3,7,11-trimethyldodecanoic acid represented by the formula +4coOHH, and this compound has excellent anti-inflammatory effects as evidenced by the test examples described below. The present invention was completed based on the discovery that the present invention has the following properties.

The compound of the present invention, 11-hydroxy-3,7゜11-
Trimethyldodecanoic acid is produced by Homer reaction (Ber, 95) with a compound represented by the formula % [wherein R1 represents a lower alkyl group].

581 ('62) by the method known as
In the formula, R1 is the same as above. After synthesizing a phosphoric acid ester, it can be obtained by catalytic hydrogenation to obtain a compound represented by the formula [wherein R1 is the same as above], and finally saponification by a normal saponification reaction. .

Below, 11-hydroxy-3゜7.1 obtained by the above method
1-) The synthesis reaction of lymethyldodecanoic acid is shown as a representative example according to the synthesis scheme shown below.

[In the formula, R1 is the same as above] 1) Synthesis of compound r Ranyl acetone and 10 to 100 equivalents, preferably 20 to 50 equivalents of formic acid and about 1/3 weight of formic acid ShiL can be obtained by reacting a mixture of water and a catalytic amount of alkali at 0° C. to room temperature. As the alkali, sodium hydroxide, potassium hydroxide, sodium formate, etc. are used.

2) Synthesis of compound Compound 2 and a base such as sodium hydride or sodium methylate in an amount of 0.8 to 1.5 equivalents, preferably 1.0 to 1.1 equivalents thereof, are mixed in a solution of benzene, toluene, etc. After reacting in the presence of a hydrocarbon solvent, an ether solvent such as diethyl ether, diisopropyl ether, tetrahydrofuran, dimethoxyethane, etc. at 0°C to Miyazaki temperature,
Compound 3 is obtained by adding 0.8 to 1.2 equivalents of the compound obtained in 1) to the reaction mixture and reacting at 0°C to 100°C.

3) Synthesis of compound 4 Unsaturated monohydroxycargenic acid x obtained in 2)
/Cte/I/3t'y 0, 1 of commonly used hydrogenation catalysts such as nickel, nickel-diatomaceous earth, palladium-activated carbon, and 9 radium-calcium carbonate.
~10% by weight, hydrogen pressure 1 ~ 100V secondary 2. Compound 4 is obtained by hydrogenation at room temperature to 200°C. This reaction can be carried out using ester solvents such as ethyl acetate and inbutyl acetate, ketone solvents such as acetone and methyl ethyl ketone, alcohol solvents such as ethanol and isopro/9-ol, and ether solvents such as diisopropyl ether and tetrahydro-7rane. It can be carried out in the presence or absence of a solvent.

4) Synthesis of 3,7.11-)dimethyl-11-hydroxy-dodecanoic acid 1.0 to 2.0 equivalents of alkali and water to Compound 4
In the presence of a water-containing organic solvent such as methanol, water-ethanol, water-improvil alcohol, water-acetone, etc., from room temperature to
After reacting at 100°C, the 11-hydroxy-3
,7,11-trimethyldodecanoic acid can be obtained. As the alkali, an alkali metal hydroxide such as sodium hydroxide or potassium hydroxide can be used, and as the acid, a mineral acid such as sulfuric acid or hydrochloric acid or an organic acid such as p-)luenesulfonic acid can be used.

Next, the compound of the present invention, 11-hydroxy-3,7,
1 shows an anti-inflammatory effect test on 11-trimethyldodecanoic acid and its results.

Test Example 1, Ultraviolet erythema suppression effect Hartlay male guinea pig (weight cotton 3009)
were preliminarily bred for one week, and healthy ones were used for testing.

These guinea pigs were randomly divided into groups of 5, their abdomens were removed the day before the test, and 11-hydroxy-3, 11-hydroxy-3,
A quantity of hydrophilic petrolatum ointment containing 2 parts (by weight) of 7,11-trimethyldodecanoic acid was applied. The application site was then covered with Saran wrap for 1 hour, and the ointment was then gently wiped off from the application site. A bandage with three small holes of 6 cm in diameter made at intervals of 1.5 strokes was applied to the hair removal area, and ultraviolet rays were irradiated for 1 minute from a height of 15 cPn using an ultraviolet lamp. After irradiation, the degree of erythema was visually observed every hour, and the degree of erythema was expressed as an index using the following erythema coefficient, and the erythema suppression rate was calculated.

Erythema index: 0: No erythema observed 1: Mild erythema with unclear borders observed 2: Moderate erythema with unclear borders observed 3: Erythema with clear borders but without swelling Recognized 4: Test results in which erythema with sharp borders and swelling are observed in the group where indomethacin was applied as a control drug in the same manner as 11-hydroxy-3,7,11-trimethyldodecanoic acid, and 11-hydroxy-3,7,11
Figure 1 shows a comparison with the results of a control group (no treatment) in which a hydrophilic petrolatum ointment containing trimethyldodecanoic acid was not applied to the skin surface.

2. Carragesnin edema suppression effect Wlster
Male rats (weight 180 g) were preliminarily bred for one week, and healthy rats were used for the test. Rats were randomly divided into groups of 6 and treated with 11-hydroxy-3,7,1.
A suspension of 0.5% by weight aqueous gum arabic solution containing 1-trimethyldodecanoic acid was added to the rat's body weight ioo, y. It was administered orally at a rate of 91.0 m7. 3 of this administration
After 0 minutes, 0 and 1 d of a suspension of Carrageen ln in distilled water for injection was injected into the sole of the rat's foot to induce inflammation. The constant volume of the rat was measured 1 hour, 2 hours, 3 hours, 4 hours, and 5 hours after Carrageenin injection, and this paw volume value and Carrageenin
The edema rate was calculated using the following formula from the rat's paw volume before injection.

Constant volume value test results before Carrag@enin injection,
As a control drug, indomethacin was treated with 11-hydroxy-3,
Figure 2 shows a comparison between the results of a group administered with 7,11-trimethyldodecanoic acid in the same manner and a control group not administered with 11-hydroxy-3,7,11-trimethyldodecanoic acid.

Based on the results of the above pharmacological tests, 11-hydroxy-3,7
, 11-trimethyldodecanoic acid is useful as a drug for the treatment of inflammation. Furthermore, this compound was confirmed to have low toxicity in toxicity tests.

According to the present invention, a pharmaceutical composition containing 11-hydroxy-3,7,11-trimethyldodecanoic acid is provided. Administration of the pharmaceutical composition may be either oral or parenteral. Oral dosage forms include powders, tablets, emulsions,
Capsules, granules, liquids (including tinctures, liquid extracts, spirits, suspensions, limonases, syrups, etc.)
Examples include. In addition, parenteral dosage forms include injections,
Examples include drops, ointments, plasters, liquids (including alcoholic preparations, tinctures, lotions, etc.), poultices, liniments, sprays, dusting agents, liniments, creams, emulsions, and solvents. It will be done.

The dosage varies depending on the symptoms, but in the case of oral preparations, injections, and infusions, it is 25 to 500 Da per day for adults, preferably 50 Da as 11-hydroxy-3,7゜11-trimethyldodecanoic acid. ~100rn9, and this dosage can be administered once a day or in divided doses. In the case of parenteral and external use, 11-hydroxy-3,7,11-trimethyldodecanoic acid has 0.
The concentration may be 0.01 to 10%, preferably 0.1 to 3.
It is best to use it as a preparation.

11-Hydroxy-3,7,11-trimethyldodecanoic acid is a pharmaceutical composition suitable for molding into the various dosage forms mentioned above according to conventional methods using an appropriate pharmacologically acceptable diluent (or carrier). It can be a thing. Diluents for use in pharmaceutical compositions (eg granules) adapted for forming into tablets and capsules include, for example: (a) Fillers and thickening agents, such as starch, sugar,
(b) Binders such as carboxymethylcellulose and other cellulose derivatives, alginates, gelatin, I-lipinylpyrrolidone, etc.'
(e) a wetting agent, such as glycerin; (d) a disintegrant;
Examples include agar, calcium carbonate, and sodium bicarbonate:
(,) Dissolution delaying agents, such as roughin; (f) Resorption promoters, such as quaternary ammonium compounds; Excellent) Surface active agents, such as cetyl alcohol, glycerin monostearate, etc.; Ql) Adsorption carriers, For example, kaolin, bentonite, etc.; (1) Lubricants, such as Merck, calcium stearate, magnesium stearate, solid polyethylene glycol, etc. The tablets and capsules obtained by molding the pharmaceutical compositions of the present invention may contain commonly used coatings, envelopes and protective matrices, which may contain opacifying agents. Coatings, envelopes and protective matrices can be made, for example, from polymeric substances or waxes. Diluents used in pharmaceutical compositions suitable for formulation into herbal medicines include, for example, common water-soluble or water-insoluble diluents. , for example polyethylene glycols, fats (e.g. cocoa oil, higher esters such as C44-alcohol esters of C16-fatty acids) or mixtures of these diluents.In ointments, liniments and creams. Certain pharmaceutical compositions include, for example, common diluents such as animal or vegetable fats, waxes, craffins, starches, tragacanth, cellulose* derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc, oxidants. Zinc or mixtures of these substances, etc. can be included.

Pharmaceutical compositions which are powders and sprays can, for example, contain common diluents such as 2ctose, talc, silicic acid, aluminum hydroxide, calcium silicates, polyamide powder or mixtures of these substances. Aerosol sprays can include, for example, common propellant bases such as chlorofluorohydrocarbons. Pharmaceutical compositions that are solutions and emulsions may, for example, contain common diluents such as solvents, solubilizers, and emulsifying agents. Representative examples of such diluents include water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (such as peanut oil), Examples include fatty acid esters of glycerin, tetrahydrofurfuryl alcohol, I-lyethylene glycol, or sorbitol, or mixtures thereof. Pharmaceutical compositions which are solutions and emulsions for parenteral administration are sterile and suitably blood isotonic. For pharmaceutical compositions that are suspensions, common diluents such as water, ethyl alcohol, propylene glycol, liquid dilutions of surfactants (such as ethoxylated isostearyl alcohol, I-lyoxyethylene solpit, sorbitan esters, etc.) are used. agents such as microcrystalline cellulose, aluminum metahydroxide, bentonite, agar, tragacanth, or mixtures thereof. All pharmaceutical compositions of the present invention may also contain colorants, preservatives, aroma and flavor additives (eg peppermint oil, eucalyptus oil, etc.), sweeteners (eg saccharin, etc.), and the like.

〔Example〕

The present invention will be specifically explained below using examples. Note that the present invention is not limited to these examples.

11-hydroyac-3,7 according to the synthetic scheme below
, 11-trimethyldodecanoic acid was synthesized.

OH2/ 1) NaOH-H20/l Tanol OH3t 1) Synthesis of compound 1 Geranyl acetone 250,! i' (1,29 mol
e) A mixture of 10,100 O of 99 thiformic acid, 300 d of water and 0.6 g of sodium hydroxide was stirred at room temperature for 20 hours.

After the reaction was completed, the mixture was extracted with 500 g of diisozorobyl ether. After sequentially washing the organic layer with water, 5-chloride sodium bicarbonate solution, and water,
The solvent was removed by evaporation to obtain 199 g of a residue. A mixture of this residue, 305' of hydroxide, 135' of water, and methanol was stirred at 55° C. for 20 minutes. After the reaction was completed, the mixture was extracted with noisoderovir ether 500, the organic layer was washed with water, and the solvent was removed by evaporation. The obtained residue was subjected to vacuum distillation to obtain 103 g as a fraction at 108° C./Q and 1 mHg.

According to GLC analysis, this compound had a purity of 98.4%.

2) Synthesis of Compound 2' A mixed solution of 7.2 jp of sodium hydride and 400 d of toluene was cooled to 5°C with ice water, and then triethylphosphonoacetate (68. ! A mixed solution of i+ and 50 g of toluene was gradually added dropwise. After the addition was completed, the mixture was further stirred for 1 hour at Vc. Compound 11 obtained in 1) was added to the reaction solution obtained in the following manner.
01.4 g were mixed and reacted at room temperature for 12 hours. After the reaction was completed, 100+++/ml of water was added, the layers were separated, the organic layer was washed with water, and the toluene was removed by evaporation under reduced pressure. The resulting residues 7B and 79 were subjected to vacuum distillation at 124°C/0.15
57.6 g of mHg fraction was obtained. According to GLC analysis, this product was Compound 2' with a purity of 99.1%.

3) Synthesis of Compound 3' To a mixed solution of 5 x g of the compound z with a purity of 99.1% obtained in 2) and 100 ml of ethyl acetate was added 0.5 g of radium-carbon supported on 50 to 60°C under a hydrogen pressure of 20 mL. The hydrogenation reaction was carried out for 18 hours under the following two conditions. After the reaction was completed, the reaction mixture was cooled to room temperature, the catalyst was removed by filtration, and then ethyl acetate was removed by evaporation.

The resulting residue was distilled under reduced pressure to obtain 49.8 g as a fraction with a concentration of 10.1 μHg at 122°C. According to GLC analysis, this product was Compound 3' with a purity of 98.5%.

4) Engineering 1-hydroxy-3,7,11-trimethy/1
/dodecanoic acid 4' 32.5 g of compound 3' with purity of 98.5% obtained from 3)
and 6 g of sodium hydroxide, and 100 yJ of methanol.

A mixed solution of H2O20rILt was heated and reacted for 30 minutes under methanol reflux conditions. Then, after cooling to room temperature 5
After adding 150 d of sulfuric acid water, add 100 d of ethyl acetate to 2
After extraction was carried out twice and the obtained organic layer was washed with 10% brine, ethyl acetate was removed by evaporation.

The obtained residue was subjected to molecular distillation at 120°C10. I I
16.04 g of ram Hg fraction was obtained. The results of this analysis are shown below.

FD-Mass spectrum: 259C(M+1
)+]'H-NMR spectrum (90MHz) δCD
Cts■MS 6.27 (bs, 2H): 2.07-2.27 (m
, 2H): 1.83-2.17(m, IH
); 1.17-1.50 (m, 22H): 0
．． 93(d, J=6.0Hz, 3M): 0.80(d
, J=6.0Hz, 3H) The analysis results confirmed that the above fraction was 11-hydroxy-3,7,11-trimethyldodecanoic acid. As a result of GLC analysis, the purity of this compound in the fraction was 98.8%.

Next, examples of formulations containing 11-hydroxy-3,7,11-trimethyldodecanoic acid of the present invention will be shown.

Example 2 Tablet 11-dihydroxy-3,7,11-trimethyldodecanoic acid
10I cornstarch 65.
9 Calgexycellulose 20
．． 9 Polyvinylpyrrolidone
3g calcium stearate
2g00g Tablets each weighing 100 cm were prepared by a conventional method. One tablet contains 10 μ of 11-hydroxy-3,7,11-trimethyldodecanoic acid.

Example 3 Cream weight % (1) Stearic acid
9.0 cetanol
3゜5 whale 0u
2.5 lanolin
2.0 Polyoxyethylene sorbitan monostearate 3.0-Lioxyethylene sorbitan monooleate 1.0 2-octyldodecyl myristate
10.0 (2) Mother's oxybenzoic acid ester Appropriate amount of propylene glycol
3.0 triethanolamine
0.5 distilled water
61.5 Mix and heat each component in (2) above (75 to 80°C) to dissolve, and then mix and heat each component in (1) (75 to 80°C).
) was added and emulsified, and then the emulsion was cooled to room temperature.

Example 4 Ointment weight I (1) Aracel C2,5 Ceresin 7
．． 5 Vaseline
10.0 lanolin
10,0(2) Distilled water
25.0 Mix and heat each component in (1) above (7
5 to 80°C) and then heated to 80°C (2
) was mixed with stirring and cooled to room temperature.

〔Effect of the invention〕

11-Hydroxy-3°7.1 provided by the present invention
1-) Limethyldodecanoic acid has an excellent anti-inflammatory effect, as is clear from the results of the drug trial described above.

[Brief explanation of the drawing]

Figure 1 shows a group to which a hydrophilic petrolatum ointment containing 11-hydroxy-3,7,11-trimethyldodecanoic acid was applied to the skin surface (the present invention), a group to which indomethacin (control drug) was applied, and a group to which no treatment was applied ( The results of comparing the inhibitory effects of ultraviolet erythema over time for the control group) are shown. Second
The figure shows a group in which a suspension of aqueous gum arabic solution containing 11-hydroxy-3,7,11-trimethyldodecanoic acid was orally administered (the present invention), a group administered with indomethacin (control drug), and a group not administered ( The results of comparing the inhibitory effects of caladanin on edema over time with respect to the control group) are shown. In FIGS. 1 and 2, (1) shows the results of indomethacin, (2) shows the results of the control group, and (3) shows the results of the present invention.

Claims (1)

[Scope of Claims] 1,11-hydroxy-3,7,11-trimethyldodecanoic acid Anti-inflammatory agent containing 2,11-hydroxy-3,7,11-trimethyldodecanoic acid