JPH05306219A - Antiinflammatory and antiallergic agent - Google Patents

Abstract

PURPOSE:To obtain an antiinflammatory and antiallergic agent, comprising a sesquiterpene derivative as an active ingredient and having antileukotriene action and high safety. CONSTITUTION:The objective antiinflammatory and antiallergic agent comprises a compound expressed by formula I (R... is HO or O=), i.e., sec-cedrenol of formula II or cedrenone of formula III as an active ingredient. The compound expressed by formula II is obtained by oxidizing alpha-cedrene, present in cedar oil and expressed by formula IV in the presence of cobalt resinate or reacting the compound expressed by formula IV with a microorganism belonging to the genus Rhodococcus. On the other hand, the compound expressed by formula III is a constituent ingredient contained in the oil of Toona sinensis Roem. and can be separated and purified from the oil of the Toona sinensis Roem. according to a conventional method. Furthermore, this compound is obtained by oxidizing a compound expressed by formula IV in the presence of the cobalt resinate or oxidizing the compound expressed by formula II in the presence of chromic anhydride, pyridinium chlorochromate, etc., as a catalyst.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an anti-inflammatory / anti-allergic agent, and more particularly to a drug useful for treating various allergic inflammatory diseases such as eczema, urticaria, atopic dermatitis and allergic rhinitis. ..

[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 the type I allergy is the most frequent. Type I allergic reaction is expressed by the reaction of IgE antibody bound to the surface of mast cells with a specific antigen (antigen-antibody reaction), and the resulting chemical mediators such as histamine and leukotriene locally attack the target organs. .. Therefore, many drugs have been developed as antiallergic agents, such as drugs that suppress the release of chemical mediators, drugs that have an antagonistic effect on the released chemical mediators, and drugs that specifically suppress 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 antiallergic and antiinflammatory actions.

[0004]

In view of the above situation, the inventors of the present invention have diligently studied the pharmacological action of sesquiterpenes. As a result, the sesquiterpene derivative represented by the following general formula (1) has excellent antihistamine action and The inventors have found that they have an anti-leukotriene action, are highly safe, and are useful as anti-inflammatory / anti-allergic agents, and completed the present invention.

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

[0006]

[Chemical 2]

The present invention provides an anti-inflammatory / anti-allergic agent containing a sesquiterpene derivative represented by

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

[0009]

[Chemical 3]

The sec -cedrenol is α-
It can also be produced by reacting sedren with a microorganism belonging to the genus Rhodococcus.

On the other hand, cedrenone is a known compound as a constituent component of Camellia oil, and can be separated and purified from the Camellia oil by a conventional method. Further, it can be produced by oxidizing the above α-cedrene in the presence of cobalt resinate as in the following reaction formula [Kato, Fragrance No. 123, 3
1 , 1978], sec -Cedrenol can be also produced by oxidizing chromic anhydride, pyridinium chlorochromate or the like as a catalyst.

[0012]

[Chemical 4]

The sesquiterpene derivative (1) has excellent antihistamine action and antileukotriene action as shown in Examples described later and is highly safe, and therefore has eczema, urticaria, atopic dermatitis, allergic rhinitis, It is useful as a preventive and therapeutic agent for various pollinosis diseases. The fact that these sesquiterpenes have an antihistamine action and an antileukotriene action means that the chemical structures of conventional antihistamine agents and antiallergic agents [Kenji Tasaka et al., Therapeutics 18, 163-169 (198).
7)] is totally 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 agents such as tablets, capsules, granules, fine granules, powders and liquids, injections, external preparations, suppositories,
It can be administered by any of parenteral agents such as inhalants.

Examples of oral solid carriers include starch,
Lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like can be mentioned, and if necessary, further, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a flavoring agent, a coloring agent, a flavoring Etc. can be mentioned. More specifically, starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch, methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, 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 .; as a lubricant Talc, waxes, 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 dosage forms include flavoring agents, flavoring agents,
A colorant can also be added.

Further, as the parenteral liquid carrier, 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, a bactericidal agent, an antiseptic agent, a stabilizer, a tonicity agent, a soothing agent and the like can be added.

The anti-inflammatory / anti-allergic agent of the present invention can be administered orally or parenterally, and, for example, as an adult sesquiterpene derivative (1) per day per adult,
It is preferable to administer 1 to 20 mg / kg orally in 1 to 3 divided doses. Further, in an external preparation intended for the treatment of 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]

EXAMPLES The present invention will now be described in detail with reference to examples, but the present invention is not limited thereto.

Reference Example 1 Rhodococcus KSM-7358 strain (FERM BP-3
747) was cultured in a slant medium of the following medium A at 30 ° C. for 3 days. 0.5% of this in a 500 ml Sakaguchi flask
50 ml of the below-mentioned medium B containing α-cedrene was inoculated. Culturing was carried out at 30 ° C. for 2 days, and this was used as preculture.
0.5 ml of this preculture liquid was inoculated into 50 ml of medium B containing 0.5% α-cedrene, and shake culture was carried out 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 -cedrenol was 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 a total volume of 1 liter (pH after sterilization) 7.1-7.5). (Medium B) Na ₂ SO ₄ 0.71 g NH ₄ NO ₃ 3.5 g FeCl ₃ .6H ₂ O 0.01 g MgCl ₂ .6H ₂ O 0.17 g CaCl ₂ .2H ₂ O 0.1 g 50 mM phosphate buffer (PH 7) make the total volume 1 l.

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

(1) Morphological properties Bacteria having a size of 0.8 to 1.0 × 1.0 to 12 μm and having polymorphism. That is, at the initial stage of culture, branched hyphae are formed, and then the hyphae are ruptured to become short rod-shaped. Also,
This strain is non-motile and has no flagella. No spores were found, Gram positive, no acid resistance.

(2) Culture property (a) Flat culture of broth agar: It grows well and forms a milky white opaque, rough-surfaced, cone-shaped colony, and in the latter half of the culture, it is flesh-colored or pale orange. Present. The shape of the settlement is circular curly and wavy at the periphery. (B) Meat broth agar slope culture; grows well and exhibits milky white color. (C) Broth liquid culture; growth is weak, but it grows in both upper and lower layers of the surface of the culture solution. (D) Meat broth gelatin stab culture; grows well. No liquefaction is observed. (E) Litmus milk; liquefy only the upper layer. The litmus dye was changed from purple to pink, and a partial decolorization reaction was observed.

(3) Physiological properties (a) Nitrate reduction; 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) Utilization of citric acid; Coser medium: Positive Christensen culture: Positive (i) Utilization of nitrates; Positive (j) Utilization of ammonium salts Generation of positive (k) pigment; 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 Optimal growth temperature: 25 to 30 ° C (q) Attitude toward oxygen; Aerobic but still standing conditions Even below Can grow. (R) OF test; weak oxidative type (can be distinguished by Andrade indicator, but when BTB indicator is used, no change is observed even after 7 days of culture) (s) Growth in NaCl-containing medium; 5,
It grows in both% 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, +; used,-; not used.

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

Reference Example 2 A 200 ml four-necked flask equipped with a stirrer, a thermometer and a dropping funnel was charged with 1.95 g of pyridinium chlorochromate and 30 ml of dichloromethane and kept at 25 ° C. To this, 30 ml of a dichloromethane solution in which 1 g of sec -cedrenol was dissolved was added dropwise over about 10 minutes while stirring. The reaction solution was stirred at 25 ° C. for 1 hour, chromatographed on 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 using the isolated intestinal tract to examine the inhibitory effect on histamine-induced contraction. That is, the guinea pig (Ha
rtley strain, male, 250-400 g), and then the ileum was removed to prepare a ileal longitudinal muscle sample, which was then tensioned in a physiological saline solution at 37 ° C under oxygen gas aeration using an isotonic transducer. Was monitored and stabilized. The inhibitory effect of the sample solution on the contraction reaction by the addition of histamine diphosphate (0.5 μg / ml) was measured as the antihistamine activity. At this time, Terfenadine (25μ
g / ml) served as a positive control. As shown in Table 2, cedrenone was found to have superior antihistamine activity to Terfenadine.

[0030]

[Table 2]

Example 2 By using the isolated intestinal tract to examine the inhibitory effect on the contraction of leukotriene D ₄ (LTD ₄ ), sec −
The anti-LTD ₄ activity of cedrenol was measured. That is, guinea pigs (Hartley system, male, 250
~ 400g) and then lethal to bleeding, and the ileum is removed to prepare a longitudinal muscle specimen of ileum, and atropine, diphenhydramine,
The tension was monitored and stabilized using an isotonic transducer in a physiological saline solution containing indomethacin at 37 ° C. under aeration of oxygen gas. LTD ₄ (10ng / ml)
The effect of suppressing the sample solution on the contraction reaction by adding
It was measured as TD ₄ activity.

[0032]

[Table 3]

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

Example 4 Tablets were 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

(Manufacturing method) After thoroughly mixing the above components, a tablet machine was used to obtain a tablet having a diameter of 9 mm and a weight of about 320 mg of 10,000.
0 tablets were produced. *: Take 50 g of starch in a 2 liter container, add 900 ml of purified water, gradually heat while thoroughly stirring, boil and bring to 1000 ml.

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

[0038]

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

(Manufacturing method) The above components were diluted with distilled water for injection to a total amount of 1
It was made into ml and made into an injection according to a conventional method.

Example 6 A suppository was prepared according to the following formulation.

[0041]

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

(Manufacturing Method) The above ingredients were made into 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 Ethylparaben 3 mg sec -Cedrenol 3 mg (Phase B) 1,3-butylene Glycol 5 mg Glycerin 5 mg Purified water 439 mg

(Production Method) Phase A was melted by heating and added to phase B with stirring. After homogenizing with a homomixer, it was rapidly cooled to obtain a cream.

[0046]

EFFECTS OF THE INVENTION The sesquiterpene derivative (1) has excellent antihistamine action and antileukotriene action and is highly safe. Therefore, eczema, urticaria, atopic dermatitis, allergic rhinitis, hay fever, etc. It is useful for the prevention or treatment of various inflammatory and allergic diseases.

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[Procedure amendment]

[Submission date] May 27, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] 0025

[Correction method] Change

[Correction content]

(3) Physiological properties (a) Nitrate reduction; Negative (nitrate broth medium) (b) Denitrification reaction; Negative (c) MR test; Negative (d) VP test; Negative (e) Indole formation; Negative (f) Hydrogen sulfide production; Weak positive (g) Starch hydrolysis; Negative (h) Utilization of citric acid; Coser medium: Positive Christensen medium : Positive (i) Utilization of nitrates; Positive (j) Utilization of ammonium salts Generation of positive (k) dye; 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 Optimal growth pH: 5 to 9.0 (p) Growth temperature range; Growth temperature: 10 to 37 ° C Optimal growth temperature: 25 to 30 ° C (q) Attitude toward oxygen; Aerobic but still standing conditions It can grow well even underneath. (R) OF test; weakly oxidative type (can be distinguished by Andrade indicator, but when BTB indicator is used, no change is observed after 7 days of culture) (s) Growth in NaCl-containing medium; 5,
It grows in both% and 7%.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Shigeka Tanaka 9-1030 Sonobe, Wakayama City, Wakayama Prefecture (72) Inventor Susumu Ito 3441-64 Higashiminecho, Utsunomiya City, Tochigi Prefecture

Claims (1)

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