JPH06321884A - Sesquiterpene derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful e.g. as a treating agent for allergic inflammatory diseases, hyperlipemia, etc. CONSTITUTION:A compound of formula I (R is H or lower alkyl), e.g. cedrenone oxime. The compound of formula I can be obtained by reaction of cedrenone with hydroxylamine or an alkoxylamine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel sesquiterpene derivative and a medicament containing the same, more specifically, eczema,
The present invention relates to a novel sesquiterpene derivative useful for treating various allergic inflammatory diseases such as urticaria, atopic dermatitis, allergic rhinitis and hyperlipidemia.

[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, blood lipids represented by cholesterol are important risk factors for arteriosclerosis, and treating hyperlipidemia is important for preventing arteriosclerosis and hypertension. As such a therapeutic agent for hyperlipidemia, various agents such as clofibrate are known, but they have drawbacks such as many side effects on the liver and gallbladder system, and further development of new agents is desired.

On the other hand, some sesquiterpenes have various pharmacological actions, but anti-allergic agents,
No anti-inflammatory agent having a sufficient effect has been found yet, and no anti-inflammatory agent having a therapeutic effect on hyperlipidemia is known.

[0005]

In view of the above situation, the present inventors have synthesized sesquiterpenes and conducted diligent studies on their pharmacological actions. As a result, a novel sesquiterpene derivative represented by the following general formula (1) was obtained. It has excellent antihistamine action, antileukotriene action and blood cholesterol lowering action, and is highly safe, and was found to be useful as an anti-inflammatory / anti-allergic agent and a therapeutic agent for hyperlipidemia, and completed the present invention. did.

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

[0007]

[Chemical 2]

The present invention provides a sesquiterpene derivative represented by the formula [wherein R represents a hydrogen atom or a lower alkyl group].

The present invention also provides an anti-inflammatory / anti-allergic agent and a therapeutic agent for hyperlipidemia, which comprises the sesquiterpene derivative represented by the general formula (1) as an active ingredient.

In the above general formula (1), R represents a lower alkyl group, and examples of the lower alkyl group include linear or branched alkyl groups having 1 to 6 carbon atoms. Specific examples of the lower alkyl group include methyl group, ethyl group and n-
Propyl group, isopropyl group, n-butyl group, sec-
Butyl group, tert-butyl group, n-pentyl group, n-
A hexyl group and the like can be mentioned.

The sesquiterpene derivative (1) of the present invention is
For example, it is manufactured according to the following reaction formula.

[0012]

[Chemical 3]

[Wherein R is the same as above]

That is, the sesquiterpene derivative (1) of the present invention is produced by reacting cedrenone (2) with hydroxylamine or alkoxylamine (3).

Cedrenone used as a raw material here is a compound known 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 α-cedrene in the presence of cobalt resinate [Kato, Fragrance No. 123, 31 , 197
8], can also be produced by oxidizing sec -cedrenol using chromic anhydride, pyridinium chlorochromate or the like as a catalyst. Furthermore, Cedrenone is α
It can also be produced by reacting sedrene with a microorganism belonging to the genus Rhodococcus and oxidizing the produced sec -cedrenol.

The reaction of cedrenone (2) with hydroxylamine or alkoxylamine (3) is carried out in the presence of a base such as pyridine according to a conventional oxime production method.
It is preferably carried out at 0 ° C. for 5 to 100 hours.

The sesquiterpene derivative (1) is isolated from the reaction mixture by a conventional method, for example, recrystallization, extraction, chromatography and the like.

The sesquiterpene derivative (1) has excellent antihistamine action, antileukotriene action and blood cholesterol lowering action as shown in Examples below, and since it is highly safe, it has eczema, urticaria and atopic skin. It is useful as a preventive and therapeutic agent for inflammation, allergic rhinitis, various pollinosis, hyperlipidemia and the like. Such sesquiterpenes have antihistamine action and antileukotriene action,
Chemical structures of conventional antihistamines and antiallergic agents [Kenji Tasaka et al., Therapeutics 18,163-169 (1987)]
It's totally unexpected.

The sesquiterpene derivative (1) can be administered as it is or in various dosage forms. There is no particular limitation on the administration form of the anti-inflammatory / anti-allergic agent and the therapeutic agent for hyperlipidemia of the present invention, and oral agents such as tablets, capsules, granules, fine granules, powders and liquids, and injections, It can be administered by any of parenteral agents such as external preparations, suppositories, and 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 agent. 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 a 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, a preservative, a stabilizer, an isotonic agent, a soothing agent and the like can be added.

The anti-inflammatory / anti-allergic agent and the therapeutic agent for hyperlipidemia of the present invention can be administered orally or parenterally. For example, the adult sesquiterpene derivative (1) is 10 to 200 mg / day. It is preferable to administer 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 3% by weight.

[0024]

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 solution 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.

[0026]

[Table 1] (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 polymorphism. That is, in the early stage of culture, branched hyphae are formed, and then they are ruptured and 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 properties (a) Flat culture of broth agar; good growth, opaque milky white, rough surface and conical ridge-like colonies are formed. 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 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 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 under You can grow separately. (R) OF test; weak oxidation type (can be discriminated 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) Chemo-taxonomic 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 and chromatographed on 50 g of silica gel, and the obtained filtrate was concentrated to obtain 0.8 g of cedrenone.

Example 1 Synthesis of cedrenone oxime: Hydroxylamine hydrochloride 1.8 g (25 mmol), cedrenone 3. in a 100 ml round bottom flask equipped with a Dimroth and a dropping funnel under a nitrogen stream.
3 g (15 mmol) and 50 ml of ethanol were added, and 2.4 g (30 mmol) of pyridine was added dropwise at room temperature in about 10 minutes. Then, the mixture was stirred under reflux for 12 hours. After cooling the reaction mixture, ethanol was distilled off with an evaporator, 100 ml of hexane and 50 ml of water were added, and the mixture was washed with water. The hexane layer was further washed twice with 50 ml of water, and then hexane was distilled off to give 3.5 g (15 mmol, yield 100%) of cedrenone oxime.
Got

IR (KBr); 693, 882, 921, 1160, 1280, 13
65, 1380, 1443, 1632, 2872,2956, 3070, 3370cm ^-1 .NMR (200MHz, CDCl ₃ ); 1.01 (s, 3H), 1.06 (s, 3H), 1.29 (d,
J = 7Hz, 3H), 1.92 (d, J = 2Hz, 3H), 1.3-2.2 (m, 9H), 6.56 (b
rs, 1H), 8.1-8.5 (br.s, 1H) ppm.GC-MS (M ⁺ ); 233 mp .; 97.8 ℃

Example 2 Synthesis of cedrenone oxime methyl ether: 0.84 g (10 mmol) of methoxyamine hydrochloride, 1.20 g (5.5 mmol) of cedrenone in a 100 ml round bottom flask equipped with a Dimroth and a dropping funnel under a nitrogen stream. 30 ml of methanol
Was added, 1.0 g (13 mmol) of pyridine was added dropwise at room temperature, and the mixture was further stirred at room temperature for 60 hours. After methanol was distilled off from the reaction mixture under reduced pressure, column chromatography (silica gel 60 g, hexane: ethyl acetate = 98:
Purification was performed in 2) to obtain 1.24 g (5.0 mmol, yield 91%) of cedrenone oxime methyl ether.

IR (KBr); 840, 864, 873, 1026, 1056, 11
58, 1281, 1374, 1464, 1629, 2812, 2872, 2944, 3050c
m ^-1 .NMR (200MHz, CDCl ₃ ); 1.00 (s, 3H), 1.05 (s, 3H), 1.30 (d,
J = 7Hz, 3H), 1.88 (d, J = 2Hz, 3H), 1.3-2.2 (m, 9H), 3.81 (s,
3H), 6.39 (br.s, 1H) ppm. GC-MS (M ⁺ ); 247 mp .; 68.5 ℃

Example 3 The antihistamine activity was measured by using the isolated intestinal tract to examine the inhibitory effect on histamine-induced contraction. That is, according to a conventional method, guinea pig (Hartley)
System, male, 250-400 g), and then the ileum was removed to prepare a ileal longitudinal muscle specimen, and the tension was adjusted using an isotonic transducer in a physiological saline solution at 37 ° C. under oxygen gas aeration. 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 (25 μg / ml)
Was used as a positive control. As shown in Table 2, it was found that the compound of the present invention has an antihistamine activity superior to that of Terfenadine.

[0039]

[Table 2]

Example 4 A hypercholesterolemic mouse prepared by feeding 6 mice in each group with a high-cholesterol feed for 7 days was divided into halves on the 6th and 7th days, and a total of 300 mg / kg of the sample was added thereto. It was orally administered. After administration, the animals were fasted for a whole day and night, the serum cholesterol content was averaged, and compared with that in hypercholesterolemic mice (control). As a result, the compound obtained in Example 1 reduced the serum cholesterol content by 31% as compared with the control group.

Example 5 (Acute toxicity test) Cedrenone oxime methyl ether was administered once to male ICR mice (5 mice per group, 5 weeks old) to examine acute toxicity. No deaths were observed after oral administration of 1 g / kg (observation 7 days).

Example 6 Tablets were prepared according to the following formulation.

[0043]

Table 3 (Composition) Compound of Example 1 119 g Lactose 3000 g Starch paste (5%) * Appropriate amount Magnesium stearate 5 g

(Manufacturing method) After the above ingredients were thoroughly mixed, a tablet having a diameter of 9 mm and a weight of about 320 mg was 1.00 using a tableting machine.
0 tablets were produced. *: Take 50 g of starch in a 2 liter container, add 900 ml of purified water, heat gradually while thoroughly stirring, boil and bring to 1000 ml.

Example 7 An injection was prepared according to the following formulation.

[0046]

Table 4 (Composition) Compound of Example 2 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 8 A suppository was prepared according to the following formulation.

[0049]

(Composition) Compound of Example 2 20 mg Hard fat 880 mg

(Manufacturing method) The above-mentioned components were made into suppositories according to a conventional method.

Example 9 A cream was prepared according to the following formulation.

[0052]

Table 6 (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 Example 1 compound 3 mg (Phase B) 1,3 -Butylene glycol 5 mg Glycerin 5 mg Purified water 424 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.

[0054]

The sesquiterpene derivative (1) has excellent antihistamine action, antileukotriene action and blood cholesterol lowering action, and is highly safe.
Eczema, urticaria, atopic dermatitis, allergic rhinitis,
It is useful for preventing or treating various inflammatory and allergic diseases such as hay fever and hyperlipidemia.

Claims (3)

[Claims] 1. The following general formula (1): A sesquiterpene derivative represented by the formula: wherein R represents a hydrogen atom or a lower alkyl group. 2. An anti-inflammatory / anti-allergic agent comprising the sesquiterpene derivative according to claim 1 as an active ingredient. 3. A therapeutic agent for hyperlipidemia, which comprises the sesquiterpene derivative according to claim 1 as an active ingredient.