JPH05178793A - New compound and 5-lipoxygenase inhibitor comprising the same compound as active ingredient - Google Patents

Abstract

(57) [Summary] (Modified) [Objective] To provide a substance having a 5-lipoxygenase inhibitory action and useful as a drug such as an antiallergic agent. [Structure] Novel monoterpene [formula I] that can be isolated from crude drugs, a new compound [formula II] obtained by deriving it, a new C ₆ -C ₁ compound [formula III] and the above-mentioned compounds 5-lipoxygenase inhibitors containing the same as active ingredients.

Description

Detailed Description of the Invention [Industrial applications]

[0001] The present invention relates to a novel compound having a 5-lipoxygenase inhibitory action and useful as a drug effective for the prevention and treatment of allergic diseases.

[0002]

2. Description of the Related Art With the recent pollution problems and environmental changes in Japan, the number of patients with allergic diseases such as bronchial asthma and hay fever has increased, which has become a major social problem.

As a cause of these allergic diseases, the lipoxygenase pathway, which is one of the metabolic pathways of phospholipids, is drawing attention. The lipoxygenase pathway is a metabolic pathway in which arachidonic acid released from phospholipids by the action of phospholipase A ₂ or diacylglycerol lipase is converted into leukotrienes C ₄ , D ₄ , E ₄ and B ₄ .
One of the enzymes that catalyze the conversion of the lipoxygenase pathway
-Lipoxygenase, which is considered to be one of the rate-limiting enzymes in the pathway. Therefore, it has been desired to develop a drug that inhibits 5-lipoxygenase and is effective in preventing and treating allergic diseases.

[0004]

[Means for Solving the Problems] As a result of intensive studies to solve the above-mentioned problems, the present inventors have found that it is prescribed in Chinese herbs such as Shoseiryuto and Toki-Shigyakaku-Kurei-Gyozo-to. We succeeded in isolating novel monoterpenes and C ₁ -C ₆ compounds from crude herb medicines.

When the action of the compound was further investigated, it was found that it has the desired 5-lipoxygenase inhibitory action, and that it is possible to obtain a substance having higher activity by inducing the isolated compound. The present invention has been completed.

That is, the present invention is as follows.

The following formula I (In the formula, R ₁ represents a hydroxyl group, a para-bromobenzoyloxyl group or an acetoxyl group.) A novel monoterpene represented by the following formula II: And a new monoterpene derivative represented by the following formula III A novel C ₆ -C ₁ compound represented by the formula (hereinafter, the compounds represented by Formula I, Formula II and Formula III are collectively referred to as the compound of the present invention) and 5-lipoxygenase containing the compound of the present invention as an active ingredient. It is an inhibitor.

The compound of the present invention can be obtained, for example, by the following method.

The finely chopped spicy roots are extracted with one or more mixed solvents selected from water, methanol, ethanol, acetone and ethyl acetate under reflux at a temperature from 0 ° C to the boiling point of the solvent used, or Alternatively, ultrasonic extraction is performed at 0 ° C to room temperature to obtain an extract.

This extract was suspended in water, distributed and extracted using a low polar solvent such as benzene, chloroform, ether, n-hexane, cyclohexane, etc., and the remaining water-soluble portion from which low polar impurities were removed was removed. Partition extraction with ethyl acetate and / or n-butanol gives an extract.

The extract as it is or after being dried is subjected to column chromatography or high performance liquid chromatography once or several times and purified to obtain a fraction containing the compound of the present invention.

As the elution solvent for chromatography,
Water, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, acetonitrile, chloroform,
A single solvent or a mixed solvent such as benzene, ether, petroleum ether, and n-hexane can be used.

Specific examples of adsorbents for column chromatography or high performance liquid chromatography include:
Examples thereof include silica gel, ODS-silica gel, porous polymer gel and the like.

The thus obtained fraction containing the compound of the present invention can be recrystallized or powdered from a suitable solvent to obtain the compound of the present invention.

When recrystallizing or powdering, a single solvent or a mixed solvent of water, methanol, ethanol, acetone, ethyl acetate, tetrahydrofuran, benzene, chloroform, ether, petroleum ether, n-hexane, cyclohexane and the like is used. To do.

If necessary, the compound of the present invention can be obtained by appropriately acetylating or para-bromobenzoylating.

For the acetylation, a general acetylating agent can be used, and for example, acetylation with acetic anhydride in pyridine or N, N-dimethylaminopyridine is preferable.

For the para-bromobenzoylation, a general para-bromobenzoylating agent can be used, and for example, it is preferable to perform the para-bromobenzoylation with para-bromobenzoyl chloride in pyridine, N, N-dimethylaminopyridine.

Next, the fact that the compound of the present invention has an excellent 5-lipoxygenase inhibitory action and is useful as a drug such as an anti-allergic agent and an anti-inflammatory agent will be described with reference to experimental examples.

Experimental Example 1 RBL1 cultured cells were adjusted to 5 × 10 ⁶ cells / ml with 1 mM ethylenediaminetetraacetic acid (EDTA) and 10 mM.
50 mM phosphate buffer solution containing 50% ethylene glycol (p
H7.4), and after ultrasonic treatment 10,000 × G
The mixture was centrifuged at 10 ° C. for 10 minutes and further at 105,000 × G for 60 minutes, and the supernatant was used as a 5-lipoxygenase enzyme preparation.

10 μM arachidonic acid as a substrate, an enzyme preparation prepared as described above, and an acetone solution of the compound obtained in the specific examples or examples were placed in a test tube at a final concentration of 10 μM, and the mixture was placed at 10 ° C. at 10 ° C. Let react for minutes. As an internal standard, 10 μl of 0.25 mM butyl-3,5-dinitrobenzoate was added, and the mixture was extracted with 1.8 ml of hexane. The amount of 5-HETE in this was measured by high performance liquid chromatography [column, TSK-gel ODS-80T.
M (TOYO SODA); mobile phase, tetrahydrofuran: acetonitrile: 1% acetic acid (5: 5: 9); flow rate,
1 ml / min; detection, ultraviolet ray (235 nm)].

From this result, the inhibition rate was calculated by the following equation to obtain the inhibition rate (%). C: 5-HETE peak area when the compound obtained in the Example or the specific example is not included (corrected by the internal standard) S: 5-HETE peak area when the compound obtained in the Example or the specific example is added (Corrected by internal standard)

The inhibition rates of the compounds obtained in the examples are shown in Table 1.

Table 1

As is clear from Table 1, the compound of the present invention was confirmed to have an excellent 5-lipoxygenase inhibitory action.

Next, the dose and formulation of the compound of the present invention will be explained.

The compound of the present invention can be administered to animals and humans as it is or together with a conventional pharmaceutical carrier. The dosage form is not particularly limited and may be appropriately selected and used as needed, and examples thereof include oral preparations such as tablets, capsules, granules, fine granules and powders, parenteral preparations such as injections and suppositories. Be done.

In order to exert a desired effect as an oral preparation, it varies depending on the age, body weight and degree of disease of a patient, but it is usually 10 mg to 1 g as a weight of the compound of the present invention in an adult.
It is considered appropriate to take this in several divided doses a day.

In the present invention, oral preparations such as tablets, capsules, granules and the like are produced by a conventional method using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, corn starch, inorganic salts and the like.

In this type of preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity promoter, a corrigent, a coloring agent, a fragrance, etc. may be used in addition to the above-mentioned excipients. You can
Specific examples of each are as shown below.

[Binder] Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methyl cellulose, sodium carboxymethyl cellulose, hydroxypropyl cellulose, crystalline cellulose, ethyl cellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, carboxymethyl cellulose calcium, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

[Lubricant] Talc, wax, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the present invention can also be administered as suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents. ..

In order to exert the desired effect as a parenteral agent, it depends on the age, body weight and degree of disease of the patient.
0.1 mg / day as the weight of the compound of the present invention in an adult
Intravenous infusion up to 100 mg, intravenous infusion, subcutaneous injection, and intramuscular injection may be suitable.

This parenteral preparation is manufactured by a conventional method, and is generally used as a diluent in distilled water for injection, physiological saline, glucose aqueous solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol. Etc. can be used. Further, if necessary, a bactericidal agent, a preservative, and a stabilizer may be added. Further, from the viewpoint of stability, this parenteral preparation can be frozen after filling in a vial or the like, water is removed by a usual freeze-drying technique, and a liquid preparation can be re-prepared from the freeze-dried product immediately before use. Further, if necessary, a tonicity agent, a stabilizer, a preservative, a soothing agent and the like may be added appropriately.

Other parenteral agents include external preparations, coating agents such as ointments, and suppositories for rectal administration.
It is manufactured according to a conventional method.

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

Example 1 100 kg of finely divided spicy meat was divided into 10 kg aliquots, and 96 l of methanol was used for heating and reflux extraction twice for 2 hours each.
The obtained extracts were combined and the solvent was distilled off under reduced pressure to obtain 6.2 kg of a dried extract.

The dried extract was suspended in 30 liters of water and partitioned and extracted 5 times with 10 liters of hexane.

The aqueous layer was partitioned and extracted 5 times with 10 l of n-butanol to obtain an n-butanol extract, and the solvent was distilled off under reduced pressure to obtain 2.2 kg of a dry extract.

The dried extract was suspended in 3 liters of water and subjected to a column chromatography on a porous polymer gel (Diaion HP-20, manufactured by Mitsubishi Kasei Co.) to obtain 70 liters of water and 40 liters of water.
100% methanol, 80 l of methanol, and 70 l of acetone were sequentially eluted.

In the 40% methanol eluate, the solvent was distilled off under reduced pressure to obtain 130.2 g of dried extract. The extract was subjected to column chromatography (10 cmφ × 60 cm) using silica gel (Kieselgel 60, 70 to 230 mesh, manufactured by Merck), and the fraction eluted with a mixed solvent of chloroform-methanol (98: 2) was subjected to medium pressure. The fraction was subjected to silica gel column chromatography (CIG column, 25 cmφ × 40 cm, manufactured by Kusano Science Co., Ltd.), and the fraction eluted with chloroform was concentrated under reduced pressure.

1.22 g of the obtained residue was subjected to high performance liquid chromatography [column; YMCpack (I-15, 15).
ODS) S-343, mobile phase; water: methanol (3:
1), flow rate; 5 ml / min, detection; UV254 nm]
Attached to.

The fraction eluted at a retention time of 56 to 64 minutes was concentrated under reduced pressure to obtain 523.0 mg of a colorless oily substance.

The physicochemical properties of this colorless oily substance are as shown below. From these data, 5-hydroxy-4,7,7-trimethyl-8-oxabicyclo [3.
2.1] Hept-3-en-2-one [5-hydro
xy-4,7,7-trimethyl-8-oxab
icyclo [3.2.1] hept-3-en-2
-One] was determined.

Although this compound has optical isomers, it goes without saying that each isomer is included in the present invention.

Infrared absorption spectrum (IR, ν max
cm ⁻¹ , CCl ₄ ): 3380, 1710 UV absorption spectrum [λ max nm (log
ε), MeOH]: 233 (3.85) mass spectrum (GC-EI-MS) m / z (%): 1
82 (M ⁺ , 50), 111 (100) High-resolution mass spectrum C ₁₀ H ₁₄ O ₃ (M ⁺ ): Calculated value: 182.0943 Measured value: 182.0948 Proton nuclear magnetic resonance spectrum (δ ppm in C)
_{DCl 3): 0.98 (3H,} s), 1.37 (3H,
s), 1.79 (1H, d, J = 12.7 Hz), 1.
96 (1H, d, J = 12.7Hz), 2.04 (3
H, d, J = 1.5 Hz), 4.05 (1H, d, J =
1.5 Hz), 5.81 (1H, quint, J = 1.
5 Hz) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CD
Cl ₃ ): 17.8 (q), 24.8 (q), 31.6
(Q), 39.4 (s), 49.7 (t), 90.8
(D), 104.8 (s), 124.2 (d), 16
7.1 (s), 197.0 (s)

Example 2 100 mg of the compound obtained in Example 1 was mixed with 1 ml of dry pyridine.
And dissolved in 0.5 ml of acetic anhydride, 100 mg of N, N-dimethylaminopyridine was added, and the mixture was stirred at room temperature for 2 hours.
Partition extraction was performed with 1.

The chloroform layer was dried over sodium sulfate, and the residue obtained by distilling off the solvent under reduced pressure was recrystallized with a mixed solvent of n-hexane-ethyl acetate to give a colorless plate-like substance. 106 mg was obtained.

The physicochemical properties of this colorless plate-like substance are as shown below. From these data, 5-acetoxy-4,7,7-trimethyl-8-oxabicyclo [3.
2.1] Hept-3-en-2-one [5-aceto
xy-4,7,7-trimethyl-8-oxab
icyclo [3.2.1] hept-3-en-2
-One] was determined.

Melting point: 71 to 72 ° C. Infrared absorption spectrum (IR, ν max cm ^-1 , K
Br): 2968, 1756, 1684, 1620, 1
268, 1226, 1192, 1144, 1116, 1
050 UV absorption spectrum [λ max nm (log
[epsilon]), MeOH]: 234 (4.06) mass spectrum (EI-MS) m / z (%): 224
(M ⁺ , 7), 182 (30), 111 (100) High resolution mass spectrum C ₁₂ H ₁₇ O 4 (M + H) ⁺ : Calculated value: 225.1127 Measured value: 225.1127 Proton nuclear magnetic resonance spectrum (δ ppm in C
_{DCl 3): 1.01 (3H,} s), 1.39 (3H,
s), 1.95 (1H, d, J = 12.5 Hz), 1.
95 (3H, d, J = 1.5Hz), 2.13 (1H,
d, J = 12.5 Hz), 2.16 (3H, s), 4.
14 (1H, d, J = 1.5 Hz), 5.84 (1H,
qint, J = 1.5 Hz) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CD
_{Cl 3): 17.5 (q)} , 21.3 (q), 24.7
(Q), 31.4 (q), 38.2 (s), 48.0
(T), 91.8 (d), 106.1 (s), 124.
5 (d), 164.5 (s), 168.4 (s), 19
4.9 (s)

Example 3 50 mg of the compound obtained in Example 1 was dissolved in 3 ml of dry pyridine to prepare para-bromobenzoyl chloride and N, N.
-Adding 100 mg each of dimethylaminopyridine,
After stirring at room temperature for 3 hours, the reaction solution was left in ice water and partitioned and extracted with 100 ml of chloroform.

The chloroform layer was dried over sodium sulfate,
The residue obtained by distilling off the solvent under reduced pressure,
The residue obtained by subjecting to medium pressure silica gel column chromatography (CIG column, 25 cmφ × 40 cm, manufactured by Kusano Science Co., Ltd.) and eluting with a mixed solvent of benzene-ethyl acetate (35: 1) was added to n-hexane- Recrystallization from a mixed solvent of ethyl acetate gave 24 mg of a colorless plate-like substance.

The physicochemical properties of this colorless plate-like substance are as shown below, and from these data, 5-parabromobenzoyloxy-4,7,7-trimethyl-8-oxabicyclo [3.2.1]. ] Hept-3-en-2-one [5-p-bromobenzyloxy-4,7,
7-trimethyl-8-oxabicyclo
It was determined to be [3.2.1] hept-3-en-2-one].

Melting point: 122 to 123 ° C. Infrared absorption spectrum (IR, ν max cm ^-1 , K
Br): 2960, 1736, 1688, 1624, 1
590, 1454, 1280, 1258, 1142, 1
010,752 UV absorption spectrum [λ max nm (log
ε), MeOH]: 248 (4.27) Mass spectrum (EI-MS) m / z (%): 366
[C ₁₇ H ₁₇ O ₄ ⁸¹ Br (M ⁺ ), 9], 364 [C ₁₇ H ₁₇
O ₄ ⁷⁹ Br (M ⁺ ), 9], 157 (100), 155
(100) High-resolution mass spectrum C ₁₇ H ₁₈ O ₄ ⁸¹ Br (M + H) ⁺ : Calculated value: 367.0369 Measured value: 367.0369 C ₁₇ H ₁₈ O ₄ ⁷⁹ Br (M + H) ⁺ : Calculated value: 365. Found: 365.0382 Proton Nuclear Magnetic Resonance spectrum (δ ppm in C
_{DCl 3): 1.06 (3H,} s), 1.44 (3H,
s), 1.99 (3H, d, J = 1.5Hz), 2.0
9 (1H, d, J = 12.5Hz), 2.32 (1H,
d, J = 12.5 Hz), 4.20 (1H, d, J =
1.5 Hz), 5.90 (1H, quint, J = 1.
5 Hz), 7.63 (2H, dd, J = 8.6, 2.3)
Hz), 7.93 (2H, dd, J = 8.6, 2.3H
z) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CD
Cl ₃ ): 17.6 (q), 24.8 (q), 31.5
(Q), 38.4 (s), 48.0 (t), 91.8.
(D), 106.8 (s), 124.7 (d), 12
8.1 (s), 129.2 (s), 131.5 (d),
132.0 (d), 163.4 (s), 164.3
(S), 194.8 (s)

Example 4 The residue eluted with the mixed solvent of benzene-ethyl acetate (35: 1) in the medium pressure silica gel column chromatography shown in Example 3 was recrystallized with the mixed solvent of n-hexane-ethyl acetate. By doing so, colorless plate-like substance 20 m
g was obtained.

The physicochemical properties of this colorless plate-like substance are as shown below. From these data, 5-parabromobenzoyloxy-2,6,6-trimethylcyclohept-2-ene-1,4 was obtained. -Dione [5-p-bromob
enzyloxy-2,6,6-trimethyl
cyclohept-2-en-1,4-dione]
Was decided.

Melting point: 124 to 125 ° C. Infrared absorption spectrum (IR, ν max cm ^-1 , K
Br): 2972, 1754, 1728, 1686, 1
616, 1592, 1442, 1372, 1272, 1
116, 1104, 1012, 850, 756 UV absorption spectrum [λ max nm (log
ε), MeOH]: 247 (4.07) mass spectrum (EI-MS) m / z (%): 366
[C ₁₇ H ₁₇ O ₄ ⁸¹ Br (M ⁺ ), 3], 364 [C ₁₇ H ₁₇
O ₄ ⁷⁹ Br (M ⁺ ), 3], 185 (100), 183
(100) High-resolution mass spectrum C ₁₇ H ₁₈ O ₄ ⁸¹ Br (M + H) ⁺ : Calculated value: 367.0369 Measured value: 367.0372 C ₁₇ H ₁₈ O ₄ ⁷⁹ Br (M + H) ⁺ : Calculated value: 365. Found: 365.0392 Proton Nuclear Magnetic Resonance spectrum (δ ppm in C
_{DCl 3): 1.24 (3H,} s), 1.25 (3H,
s), 2.01 (3H, d, J = 1.5Hz), 2.7
0 (2H, s), 5.10 (1H, s), 6.45 (1
H, q, J = 1.5 Hz), 7.61 (2H, dd, J
= 8.6, 2.2 Hz), 7.86 (2H, dd, J =
8.6, 2.2 Hz) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CD
Cl ₃ ): 19.3 (q), 23.9 (q), 27.2
(Q), 33.7 (s), 55.5 (t), 85.5.
(D), 128.1 (s), 128.9 (s), 13
1.3 (d) × 2,132.0 (d) × 2,132.5
(D), 150.8 (s), 165.0 (s), 19
5.1 (s), 200.0 (s)

Example 5 Chloroform-methanol (98:
The fraction eluted with the mixed solvent of 2) was subjected to medium pressure silica gel column chromatography (CIG column, 25c).
mφ × 40 cm, manufactured by Kusano Science Co., Ltd.), and the fraction eluted with chloroform was concentrated under reduced pressure.

0.65 g of the obtained residue was again subjected to medium pressure silica gel column chromatography (CIG column, 2
5 cmφ × 40 cm, manufactured by Kusano Science Co., Ltd.), and the fraction eluted with a mixed solvent of n-hexane-ethyl acetate (1: 1) was concentrated under reduced pressure to obtain 280 mg of white powder.

The physicochemical properties of this white powder are as follows: From these data, 3-hydroxy-4,
5- (methylenedioxy) benzyl alcohol [3-h
ydroxy-4,5- (methylenediox
y) -benzylcohol.

Infrared absorption spectrum (IR, ν max
cm ^-1 , KBr): 3400, 3052, 1644,
1512, 1450, 1236, 1064, 1032
846, 802 UV absorption spectrum [λ max nm (log
ε), MeOH]: 274 (2.91), 242 (3.
53) Mass spectrum (EI-MS) m / z (%): 168
(M ⁺ , 100), 151 (57) High-resolution mass spectrum C ₈ H ₈ O ₄ (M) ⁺ : Calculated value: 168.0423 Measured value: 168.0424 Proton nuclear magnetic resonance spectrum (δ ppm in C)
D ₃ OD): 4.43 (2H, s), 5.87 (2H,
s), 6.40 (1H, d, J = 1.2 Hz), 6.4
3 (1H, d, J = 1.2 Hz) ¹³ C-nuclear magnetic resonance spectrum (δ ppm in CD
₃ OD): 65.3 (t), 100.8 (d), 10
2.2 (t), 111.0 (d), 134.8 (s),
137.3 (s), 141.9 (s), 150.4
(S)

Example 6 Corn starch 44 g Crystalline cellulose 40 g Carboxymethyl cellulose calcium 5 g Light anhydrous silicic acid 0.5 g Magnesium stearate 0.5 g Compound obtained in Example 1 10 g Total 100 g

According to the above formulation, the ingredients (1) to (2) were uniformly mixed and compression-molded with a tableting machine to give tablets (200 mg each). 20 mg of the compound obtained in Example 1 is contained in each tablet.
It is contained in 3 to 10 tablets for adults and divided into several doses per day.

Example 7 Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound obtained in Example 2 10 g Total 100 g

According to the above formulation, a part of and was uniformly mixed, compression-molded, crushed, and the remaining amount of and was added and mixed, and compression-molded by a tableting machine to give one tablet.
A 00 mg tablet was obtained.

This tablet contains 20 mg of the compound obtained in Example 2, and 3 to 10 tablets for an adult are to be taken in several divided doses.

Example 8 Crystalline cellulose 79.5 g 10% Hydroxypropyl cellulose ethanol solution 50 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound obtained in Example 3 10 g Total 145 g

According to the above formulation, and were uniformly mixed, the mixture was kneaded by a conventional method, granulated by an extrusion granulator, dried and crushed, and then mixed, and compressed by a tableting machine. It was molded to obtain a tablet of 200 mg each.

Each tablet contains 20 mg of the compound obtained in Example 3, and 3 to 10 tablets for adults are to be taken in several divided doses per day.

Example 9 Corn starch 84 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Light silicic acid 0.5 g Compound obtained in Example 4 10 g Total 100 g

According to the above recipe, the components (1) to (4) are uniformly mixed, compression-molded by a compression molding machine, and then crushed by a crusher,
Sieve to obtain granules.

1 g of this granule contains 100 mg of the compound obtained in Example 4, and 0.6 to 2 g per day for an adult
Take in several divided doses.

Example 10 Crystalline cellulose 86.5 g 10% hydroxypropylcellulose ethanol solution 35 g Compound obtained in Example 5 10 g Total 131.5 g

According to the above recipe, the ingredients (1) to (4) were mixed uniformly and kneaded. After granulating with an extrusion granulator, it was dried and sieved to obtain granules.

1 g of this granule contains 100 mg of the compound obtained in Example 5, and 0.6 to 2 g per day for an adult
Take in several divided doses.

Example 11 Corn starch 89.5 g Light anhydrous silicic acid 0.5 g Compound obtained in Example 1 10 g Total 100 g

According to the above-mentioned formulation, 1 to 3 were mixed uniformly, and 200 mg was filled in a No. 2 capsule.

One capsule of this capsule contains Example 1
20mg of the compound obtained in 1.
Take 10 capsules in several doses.

Example 12 Distilled water for injection Appropriate amount Glucose 200 mg Compound obtained in Example 2 10 mg Total amount 15 ml

After dissolving and in distilled water for injection, the mixture was poured into a 5 ml ampoule, and autoclaved at 121 ° C. for 15 minutes to obtain an injection.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display area C07D 493/08 B 7329-4C // A61K 35/78 C 7180-4C

Claims (4)

[Claims] 1. The following formula I (In the formula, R ₁ represents a hydroxyl group, a para-bromobenzoyloxyl group or an acetoxyl group.) A novel monoterpene. 2. The following formula II A novel monoterpene derivative represented by. 3. The following formula III A new C ₆ -C ₁ compound represented by: 4. The following formula I, (In the formula, R ₁ represents a hydroxyl group, a para-bromobenzoyloxyl group or an acetoxyl group.) The following formula II Or the following formula III A 5-lipoxygenase inhibitor comprising a compound represented by