JP3236657B2 - Anti-inflammatory and anti-allergic agents - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an anti-inflammatory and anti-allergic agent, and more particularly to a medicament useful for treating various allergic inflammatory diseases such as eczema, hives, atopic dermatitis, allergic rhinitis and the like. .

[0002]

2. Description of the Related Art Allergic reactions in the human body are generally classified into type I (immediate type) to type IV (delayed type), but type I allergy is most frequently occurring. In the type I allergic reaction, a specific antigen reacts with an IgE antibody bound to the surface of mast cells (antigen-antibody reaction), and the resulting chemical mediators such as histamine and leukotriene locally attack target tissues and are expressed. . Therefore, a large number of pharmaceuticals have been developed as antiallergic agents, such as drugs that suppress the release of chemical mediators, drugs that antagonize the released chemical mediators, and drugs that specifically inhibit IgE production. However, these conventional antiallergic agents have problems such as insufficient efficacy and many side effects, and further development of new agents is desired.

On the other hand, some sesquiterpenes have various pharmacological actions, but few have an antiallergic action and an antiinflammatory action.

[0004]

Means for Solving the Problems In view of such circumstances, the present inventors have conducted intensive studies on the pharmacological action of sesquiterpenes, and found that the sesquiterpene derivative represented by the following general formula (1) has excellent antihistamine action and The present inventors have found that they have an anti-leukotriene effect, are highly safe, and are useful as anti-inflammatory and anti-allergic agents, and completed the present invention.

That is, the present invention provides the following general formula (1)

[0006]

Embedded image

An anti-inflammatory and anti-allergic agent comprising a sesquiterpene derivative represented by the following formula as an active ingredient:

[0008] The sesquiterpene derivative (1) used as an active ingredient in the present invention is specifically sec -sedrenol or cedrenone. Of which, sec-
Cedrenol is a known compound, and can be produced, for example, by oxidizing α-cedren present in seder oil in the presence of cobalt resinate according to the following reaction formula [Kato, Perfume No. 123, 31 , 1978).

[0009]

Embedded image

[0010] The sec -sedrenol is α-
It can also be produced by allowing a microorganism belonging to the genus Rhodococcus to act on cedren.

On the other hand, cedrenone is a constituent component of persimmon oil.
Is a known compound.
can do. Also, as shown in the following reaction formula,
Oxidizing α-cedrene in the presence of cobalt resinate
[Kato, Fragrance No. 123,3
1, 1978],sec-Cedrenol to chromic anhydride
Oxidation using pyridine or pyridinium chlorochromate as a catalyst
Can also be manufactured.

[0012]

Embedded image

The sesquiterpene derivative (1) has excellent antihistamine and anti-leukotriene effects and is highly safe as shown in the Examples below, so that eczema, hives, atopic dermatitis, allergic rhinitis, It is useful as a prophylactic and therapeutic agent for various hay fever and the like. The fact that such sesquiterpenes have an antihistamine action and an anti-leukotriene action is based on the chemical structure of conventional antihistamines and antiallergic drugs [Kenji Tasaka et al., Therapeutics 18,163-169 (198)
7)], it is completely unexpected.

The sesquiterpene derivative (1) can be administered as it is or in various dosage forms. The administration form of the anti-inflammatory / anti-allergic agent of the present invention is not particularly limited, and oral preparations such as tablets, capsules, granules, fine granules, powders, and liquids, injections, external preparations, suppositories,
It can be administered by any parenteral preparation such as an inhalant.

Examples of solid carriers for oral use include starch,
Lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts, etc., and, if necessary, further a binder, a disintegrant, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, and a fragrance. And the like. More specifically, starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol, etc. as binders; Starch, hydroxypropyl starch, sodium carboxymethylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose, low-substituted hydroxypropylcellulose, etc .; sodium lauryl sulfate as a surfactant, soybean lecithin, sucrose fatty acid ester, polysorbate 80, etc .; Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, aluminum stearate, polyethylene Recall the like; light anhydrous silicic acid as flow promoters, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate and the like can be used.

Examples of oral liquid preparations include suspensions, emulsions, syrups, and elixirs. These various forms include flavoring agents, flavoring agents,
Coloring agents may be included.

Further, the parenteral liquid carrier includes distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection,
Sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. are used,
Further, if necessary, bactericides, preservatives, stabilizers, tonicity agents, soothing agents and the like can be added.

The anti-inflammatory and anti-allergic agents of the present invention can be administered orally and parenterally. For example, 0.1 mg of sesquiterpene derivative (1) per adult per day.
It is preferable to orally administer 1 to 20 mg / kg in 1 to 3 divided doses. Further, in an external preparation for treating eczema, urticaria, atopic dermatitis, etc., it is preferable to contain the sesquiterpene derivative (1) in an amount of 0.1 to 5% by weight.

[0019]

Next, the present invention will be described in detail with reference to examples, but the present invention is not limited to these examples.

Reference Example 1 Rhodococcus KSM-7358 strain (FERM BP-3)
747) was cultured at 30 ° C. for 3 days in the following slant culture medium A. 0.5% of this in a 500 ml Sakaguchi flask
50 ml of the following medium B containing α-cedrene was inoculated. Culture was performed at 30 ° C. for 2 days, which was used as preculture.
0.5 ml of this preculture solution was inoculated into 50 ml of medium B containing 0.5% α-cedrene, and cultured with shaking at 30 ° C. for 4 days. The resulting culture was extracted with hexane, to quantify the hexane Kayo fraction by gas chromatography, se
25 mg of c -sedrenol were obtained.

[0021]

(Medium A) Polypeptone (casein peptone) 17 g Polypeptone S (soybean peptone) 3 g K ₂ HPO ₄ 2.5 g Glucose 2.5 g NaCl 5 g Agar 15 g Purified water to make a total volume of 1 liter (pH after sterilization: 7.1-7.5). (Medium _{B) Na 2 SO 4 0.71g NH} 4 NO 3 3.5g FeCl 3 · 6H 2 O 0.01g MgCl 2 · 6H 2 O 0.17g CaCl 2 · 2H 2 O 0.1g 50mM phosphate buffer (PH 7) Make the total volume 1 liter.

The Rhodococcus KSM-
The mycological properties of strain 7358 are as follows.

(1) Morphological properties Bacteria having a cell size of 0.8 to 1.0 × 1.0 to 12 μm and having polymorphism. That is, in the early stage of the culture, a branched hyphae is formed, and then the mycelium is torn and becomes a short bacillus. Also,
This strain is non-motile and has no flagella. No spores are found, Gram positive, no acid resistance.

(2) Cultural properties (a) Gravy agar flat culture; grows well, forms a milky white opaque, rough surface, colony-shaped colony, and has a flesh-colored or pale orange color at the later stage of culture. Present. The shape of the settlement is circular curly hair and the periphery is wavy. (B) Gravy agar slant culture; grows well and exhibits milky white color. (C) Liquid broth culture; growth is weak, but it grows in the upper layer or lower layer of the culture solution. (D) A broth gelatin stab culture; grows well. No liquefaction is observed. (E) Litmus milk; only the upper layer is liquefied. The litmus pigment changes from purple to pink, and a partial decolorization reaction is observed.

(3) physiological properties (a) reduction of nitrate; negative (nitrate broth medium) (b) denitrification reaction; negative (c) MR test; negative (d) VP test; negative (e) indole formation; Negative (f) Hydrogen sulfide formation; Weak positive (g) Starch hydrolysis; Negative (h) Use of citric acid; Coser medium: Positive Christensen medium : Positive (i) Use of nitrate; Positive (j) Use of ammonium salt Positive (k) dye production; King A medium: negative King B medium: negative (l) urease; positive (m) oxidase; negative (n) catalase; positive (o) growth pH range; growth pH: 3-10 Optimum growth pH: 5 to 9.0 (p) Growth temperature range; Growth temperature: 10 to 37 ° C. Optimum growth temperature: 25 to 30 ° C. (q) Attitude to oxygen; It can sufficiently grow even under. (R) OF test; weakly oxidized type (can be discriminated with an Andrade indicator, but when a BTB indicator is used, no change is observed even after culturing for 7 days) (s) Growth in a NaCl-containing medium; Grow at both 5% and 7%.

(T) Utilization of carbon source; L-arabinose-D-xylose-D-glucose + D-mannose + (weak) D-fructose + D-galactose-maltose + (weak) sucrose + lactose-trehalose + (Weak) D-sorbitol + D-mannitol + inositol + glycerol + (weak) starch-D-ribose + However, +; use,-; do not use.

(4) Chemotaxonomic properties (a) Glycolate test glycolyl type (b) Cell wall cross-linked amino acid meso -2,6-diaminopimelic acid (c) Cell wall constituent sugars Arabinose and galactose are detected, but xylose Is not detected. (D) Menaquinone system MK-8 (H ₂ )

Reference Example 2 1.95 g of pyridinium chlorochromate and 30 ml of dichloromethane were placed in a 200 ml four-necked flask equipped with a stirrer, a thermometer and a dropping funnel, and kept at 25 ° C. To this, 30 ml of a dichloromethane solution in which 1 g of sec -sedrenol was dissolved was added dropwise with stirring over about 10 minutes. After the reaction solution was stirred at 25 ° C. for 1 hour, it was chromatographed over 50 g of silica gel, and the obtained filtrate was concentrated to obtain 0.8 g of cedrenone.

Example 1 The antihistamine activity of cedrenone was measured by examining the inhibitory effect on histamine-induced contraction using an isolated intestinal tract. That is, guinea pigs (Ha
rtley strain, male, 250-400 g) after bleeding and death, the ileum is removed to prepare an ileum longitudinal muscle preparation, and tension is determined using an isotonic transducer in a physiological saline solution at 37 ° C under oxygen gas ventilation. Was monitored and stabilized. The inhibitory effect of the sample solution on the contraction reaction due to the addition of histamine diphosphate (0.5 μg / ml) was measured as antihistamine activity. At this time, Terfenadine (25μ)
g / ml) was used as a positive control. As shown in Table 2, cedrenone was found to have better antihistamine activity than Terfenadine.

[0030]

[Table 2]

Example 2 Using an isolated intestinal tract, the effect of inhibiting the contraction by leukotriene D ₄ (LTD ₄ ) was examined to determine the sec −
Anti LTD ₄ activity Sedorenoru was measured. That is, guinea pigs (Hartley strain, male, 250
４００400 g) after bleeding to death, the ileum is removed to make an ileum longitudinal muscle specimen, and atropine, diphenhydramine,
The tension was monitored and stabilized using an isotonic transducer under aeration of oxygen gas in a physiological saline solution at 37 ° C. to which indomethacin was added. LTD ₄ (10 ng / ml)
The effect of the sample solution on the shrinkage reaction caused by the addition of
It was measured as a TD ₄ activity.

[0032]

[Table 3]

Example 3 Acute toxicity test: Male ICR mice (5 mice per group; 5 weeks old) were administered once with cedrenone or sec -sedrenol, and the acute toxicity was examined. As a result, no deaths were observed after oral administration of 1 g / kg (observation period 7
Days).

Example 4 A tablet was prepared according to the following formulation.

[0035]

(Table 4) (Composition) Cedrenone 119 g Lactose 3000 g Starch paste (5%) * Appropriate amount Magnesium stearate 5 g

(Preparation method) After thoroughly mixing the above-mentioned components, a tablet machine having a diameter of 9 mm and a weight of about 320 mg was used for the preparation of 10,000 tablets.
0 tablets were manufactured. *: 50 g of starch is placed in a 2 liter container, 900 ml of purified water is added, and the mixture is gradually heated while stirring well, and then boiled to make 1000 ml.

Example 5 An injection was prepared according to the following formulation.

[0038]

(Table 5) (Composition) Cedrenone 50 mg Hardened castor oil 200 mg Propylene glycol 150 mg Glucose 100 mg

(Preparation method) The above components were dissolved in distilled water for injection in a total amount of 1
ml, and used as an injection according to a conventional method.

Example 6 Suppositories were prepared according to the following formulation.

[0041]

[Table 6] (Composition) Cedrenone 20 mg Hard fat 880 mg

(Preparation method) The above-mentioned components were used as suppositories according to a conventional method.

Example 7 A cream was prepared according to the following formulation.

[0044]

(Phase A) Stearyl alcohol 40 mg Squalane 400 mg Beeswax 30 mg Reduced lanolin 50 mg Stearic acid monoglyceride 20 mg Polyoxyethylene (20) sorbitan monopalmitate 20 mg Ethyl paraben 3 mg sec -Cedrenol 3 mg (B phase) 1,3-butylene Glycol 5 mg Glycerin 5 mg Purified water 439 mg

(Preparation method) The phase A was dissolved by heating and added to the phase B with stirring. After granulation with a homomixer, the mixture was quenched to obtain a cream.

[0046]

EFFECTS OF THE INVENTION The sesquiterpene derivative (1) has excellent antihistamine and anti-leukotriene effects and is highly safe, so that eczema, urticaria, atopic dermatitis, allergic rhinitis, pollinosis, etc. It is useful for the prevention or treatment of various inflammatory and allergic diseases.

────────────────────────────────────────────────── ─── Continued on the front page (72) Inventor Narika Tanaka 1030-9, Sonobe, Wakayama City, Wakayama Prefecture (72) Inventor Susumu Ito 3441-64, Higashimine-cho, Utsunomiya City, Tochigi Prefecture ⁷ , DB name) A61K 31/045 A61K 31/122 A61P 29/00 A61P 37/08 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. The following general formula (1): An anti-inflammatory / anti-allergic agent comprising a sesquiterpene derivative represented by the following formula as an active ingredient: