JPH0952899A - Leucotriene antagonist - Google Patents

Abstract

PURPOSE: To obtain the subject antagonist useful for the therapy, prophylaxis, etc., of allergosis, inflammatory affection, cardiovascular diseases, etc., by compounding a terpene derivative including new compounds isolated from an extract of a plant belonging to the family Celastraceae as an active ingredient.

CONSTITUTION: This leukotriene antagonist useful for the thereby, prophylaxis, etc., of allergosis, inflammatory affection, cardiovascular diseases, etc., contains as an active ingredient a diterpene derivative, a triterpene derivative, etc., of formula I (R₁ is a lower alkyl, H or carbonyl; R₂ and R₃ are each a lower alkyl, H or CH₂OH; R₄ is OH, H or =O; R₅ and R₆ are each a lower alkyl, H or carbonyl; R₇ is a lower alkyl; A is a group of formula II or formula III, etc.) isolated from an extract of Tripterygium wilfordii, a plant belonging to the family Celastraceae, Tripterygium regelii in the genus Tripterygium, Celastrus orbiculatus in the genus Celastrus, Euonymus alatus, Euonymus sieboldianus, etc., in the genus Euonymus, Microtropis japonica in the genus Microtropis, etc. The compounds of formulas III and IV are new compounds, respectively, among these compounds.

COPYRIGHT: (C)1997,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a leukotriene antagonist useful as a therapeutic / preventive drug for allergic diseases, inflammatory diseases, cardiovascular disorders and the like.

[0002]

[Prior Art and Problems] For the development of bronchial asthma, histamine, PAF (platelet activating factor), SRS-A (Slow Reacting Substance of An
aphylaxisis) plays an important role. In particular, leukotriene (LT) C4, D4, and E4, which are the constituents of SRS-A, have three peptides, leukotriene (pLT), compared to histamine.
Since it has a strong airway contraction action of about 100 to 1000 times, its physiological action is drawing attention.

Arachidonic acid metabolism is activated in stimulated target cells, and pLT is used as a lipoxygenase-based metabolite.
Is produced. pLT is secreted extracellularly and binds to a specific receptor on other target cells to elicit a reaction. pLT is released not only from eosinophils and mast cells but also from neutrophils and macrophages, and has a strong airway and vascular smooth muscle contractile action,
It exhibits airway mucus secretion action, vascular permeability enhancement action and the like.

[0004] Furthermore, in adult bronchial asthma, which is currently a big problem, the concentration of LTC4 and D4 in peripheral blood and the ability to produce LTC4 and D4 from neutrophils in peripheral blood due to nonspecific stimulation are higher than those of healthy subjects. It is known to be significantly higher. In addition, since these pLT enhance the action of bronchoconstrictor such as histamine, their involvement in airway hypersensitivity is also being investigated,
It is believed that pLT plays an important role in bronchial asthma.

Therefore, a drug that suppresses the production of pLT and a drug that antagonizes the action of pLT on target cells are considered to be very useful in the treatment of bronchial asthma. From this viewpoint, many leukotriene production inhibitors and anti-leukotriene drugs have been searched, and development of a drug having this activity is desired.

[0006]

Means for Solving the Problems The present inventors have sought a compound derived from a plant-derived natural product which is effective and highly safe for the treatment of the above-mentioned diseases, and has a leukotriene antagonism of many plant extracts. As a result of the investigation, it was found that the extract of the plant belonging to the family Euonymus exhibits a strong leukotriene antagonism.

[0007] Specific examples of plants of the family Euphorbiaceae include lightning Koto [Tripterygium wilfordii], plants of the genus Black vine such as black cucumber, plants of the genus Ranunculus such as daffodil, plants of the genus Euphorbia such as euonymus, Mayumi, and mocreishi such as Mokushishi. A genus plant can be mentioned.

The extraction site exhibiting leukotriene antagonism is not limited to roots, and whole plants (roots, stems, leaves, flowers, etc.) can be used.

As a result of intensive research to discover an active compound contained in this extract, a leukotriene antagonism was found in a diterpene derivative and a triterpene derivative having a completely different structure from the currently known leukotriene antagonists. completed.

That is, the present invention provides the following general formula (I) [In the formula, R1 represents a lower alkyl group, a hydrogen atom or a carbonyl group, R2 represents a lower alkyl group, a hydrogen atom or a hydroxymethyl group, R3 represents a lower alkyl group, a hydrogen atom or a hydroxymethyl group, and R4 represents Hydroxyl group, a hydrogen atom or = O, R5 is a lower alkyl group, a hydrogen atom or a carbonyl group, R6 is a lower alkyl group, a hydrogen atom or a carbonyl group, R7 is a lower alkyl group, A is Either group, (Here, R8 represents a hydroxyl group or a hydrogen atom, R9 represents a hydroxyl group, a hydrogen atom or a lower alkoxy group, R10 represents a hydroxyl group or a lower alkoxy group, R11 represents a lower alkyl group, a hydrogen atom or a carbonyl group, R12 represents = 0 or an acetonyl group, and R13 represents a lower alkyl group or a carbonyl group.). ] As an active ingredient, a leukotriene antagonist, the following formula XI A new compound represented by the following formula XII A new compound represented by the following formula XIII Is a novel compound represented by Hereinafter, the compound represented by the general formula (I) is referred to as a compound of the formula.

In the present specification, the lower alkyl group means
For example, a linear or branched alkyl group having 1 to 6 carbon atoms such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, and a hexyl group, and a carbonyl group. The group is, for example, carboxylic acid or aldehyde, and the lower alkoxy group is, for example, methoxy group, ethoxy group, propoxy group,
A linear or branched alkoxy group having 1 to 6 carbon atoms such as an isopropoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group and a hexyloxy group is shown.

To obtain the compound of the formula, there may be mentioned the above-mentioned method by extraction and isolation from the plant of the family Euonymus.

This extraction / isolation operation can be carried out by the usual extraction and isolation methods of general plant components. More specifically, the roots of Raikkouto or its related plants can be used as they are, or by a suitable method. What was pulverized with was extracted with a single or mixed solvent selected from alcohols, ethyl acetate, acetone, chloroform, petroleum ether, etc., and the residue obtained by removing the solvent from the extract was mixed with water and alcohol. -Polyacetic acid polymer such as Diaion HP-20, MCI gel CHP20P, etc. with at least one selected from the group consisting of ethyl acetate, acetone, acetone, chloroform, petroleum ether, benzene, n-hexane and the like, Sephadex Sephadex such as LH-20,
Column chromatography using silica gel, reversed-phase silica gel, polyamide, activated carbon or cellulose as a carrier
It can be obtained by fractionating while confirming the target component by thin layer chromatography.

If necessary, bilayer partitioning using water and an organic solvent immiscible with water may be employed before and after column chromatography.

Further, it may be purified by recrystallization using a suitable solvent.

The leukotriene antagonists of the present invention are tablets, powders, granules, liquids by mixing the diterpene or triterpene compound obtained as described above with a known pharmaceutical carrier as it is to prepare a pharmaceutical composition. And the like, parenteral preparations such as injections and infusions, and further suppositories and the like.

The pharmaceutical carrier can be selected according to the above-mentioned administration form and dosage form. In the case of oral preparations, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like are used. You can Further, in the preparation of the oral preparation, a binder, a disintegrating agent, a surfactant, a lubricant, a fluidity enhancer, a corrigent, a coloring agent, a fragrance and the like may be further added. Specific examples of these are as follows.

[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, calcium carboxymethyl cellulose, carboxymethyl cellulose, low-substituted hydroxypropyl cellulose.

[Surfactant] Sodium lauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 8
0.

[Lubricant] Talc, waxes, 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.

Further, oral liquid preparations may be suspensions, emulsions, syrups and elixirs, and these various dosage forms may contain flavoring agents and coloring agents.

On the other hand, in the case of parenteral agents, distilled water for injection using the compound of the formula as a diluent, physiological saline, glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil,
Prepared by dissolving or suspending in corn oil, propylene glycol, polyethylene glycol, etc., and adding bactericides, preservatives, stabilizers, isotonic agents, stabilizers, preservatives, soothing agents, etc., as needed. To be done.

The dose of this leukotriene antagonist varies depending on the route of administration, age of the patient, body weight and degree of disease, but in general, in the case of oral administration, the weight of the compound of the formula per adult per day is about 30 mg to 1 g. It may be administered in 1 to 3 divided doses. For parenteral preparations, 0.1 mg per day
~ 200mg seems appropriate.

The compound of the formula, which is the active ingredient of the present invention, has an excellent leukotriene antagonism, and, for example, compound 3 (the compound obtained in Example 3) is orally administered to rats at a dose of 1000 mg / kg. It is also highly safe as evidenced by the fact that no deaths were observed upon administration.

Next, the fact that the compound of the formula has a leukotriene antagonism will be described with reference to experimental examples.

[Experimental Example] A guinea pig was killed by exsanguination, the abdomen was opened, and the ileum was extracted. This is used as a cylindrical specimen of about 2 cm at 32 ℃ 9
It was suspended in a Magnus tube containing 5% O ₂ -5% CO ₂ gas aerated Tyrode's nutrient solution, and a load of 1 g was applied. After suspending the excised specimen,
Every 20 minutes, a 20 ml Magnus tube was filled with Tyrode nutrient solution aerated with 32 ° C. 95% O ₂ -5% CO ₂ . With histamine solution (10 ^-5 ).
After measuring and confirming constant isotonic contraction twice, and after washing for another 20 minutes, leukotriene D ₄ as control shrinkage.
An isotonic contraction (A) of 10 ⁻⁸ M was recorded. Approximately 30 minutes after washing, the test drug was added, and 10 minutes later, leukotriene D ₄ 10 ^-8 M
Was added and the isotonic contraction (B) was recorded.

The inhibition rate was calculated by the following formula, and the 50% inhibition rate (IC ₅₀ ) was determined. The results are shown in Tables 1 and 2.

Determination of activity: Inhibition rate (%) = (1-B / A) × 100

Table 1

Table 2

Next, the present invention will be described in more detail by showing specific examples of extraction, but the present invention is not limited thereto.

Example 1 Fraction B-3 obtained in Example 1 was collected by high performance liquid chromatography.
-[Column: Kusano Science CIG-Si-10 15φX300mm, Elution solvent: n-
Hexane: ethyl acetate = 7: 3]. The pi that appears in the first half
-The collected powder was collected to obtain 370 mg of white powder. This compound was determined to be Compound 1 having the following structure from the physicochemical properties shown below.

[0035]

White powder

EI-MS m / z: 316.2044 (M ⁺ ) (calc.for, C ₂₀ H
₂₈ O ₃ : 316.2039), 301,286,271,229

Specific rotation [α] ³⁰ _D +131.0 (c = 0.20, CHCl ₃ ).

UV absorption spectrum λ EtOH max nm (lo
g ε): 220 (3.96), 273 (3.24), 279 (3.24)

Infrared absorption spectrum νKBr max c
m ^-1 : 3440,2960,2872,1698

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 1.23 (3H, d, J = 6.8Hz), 1.25 (3H, d, J = 6.6Hz), 1.28 (3H, s),
1.34 (3H, s), 1.71 (1H, ddt, J = 13.1 / 12.0 / 6.0Hz), 1.98 (1H,
dddt, J = 13.1 / 6.8 / 2.2 / 1.7Hz), 2.02 (1H, ddd, J = 13.3 / 9.0 /
8.5Hz), 2.10 (1H, dd, J = 13.1 / 2.2Hz), 2.48 (1H, ddd, J = 13.3
/7.8/4.5Hz),2.57(1H,ddd,J=16.6/12.0/6.8Hz),2.62(1
H, ddd, J = 16.1 / 8.5 / 7.8Hz), 2.69 (1H, ddd, J = 16.1 / 9.0 / 4.5
Hz), 2.93 (1H, ddd, J = 16.6 / 6.0 / 1.7Hz), 2.93 (1H, s), 3.11
(1H, sep, J = 6.8Hz), 3.54 (1H, dd, J = 11.2 / 9.2Hz), 4.07 (1H,
dd, J = 11.2 / 3.2Hz), 4.78 (1H, s), 6.83 (1H, d, J = 8.2Hz), 7.0
4 (1H, d, J = 8.2Hz)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 220.0 (s), 150.1 (s), 145.6 (s), 130.5 (s), 123.7 (d), 120.7
(s), 117.7 (d), 65.7 (t), 51.1 (d), 50.8 (d), 37.3 (t), 36.9
(s), 35.0 (t), 26.9 (d), 25.4 (q), 24.8 (t), 22.7 (q), 22.5
(q), 22.1 (q), 19.1 (t)

Example 2 Silica gel column chromatography in Example 11
The fraction B (0.8 g) obtained by was further subjected to silica gel column chromatography. First, the fraction was eluted with 5% ethyl acetate-n-hexane and then with increasing content of ethyl acetate, and the fraction eluted with 15% ethyl acetate was dried.
This fraction was crystallized with methanol to obtain 50 mg of colorless needle crystals having the following physicochemical properties. From these physicochemical properties, it was determined to be compound 2 having the following structure.

[0044]

Colorless needles

Melting point: 300 ° C. or higher

EI-MS m / z: 472 (M ⁺ ), 454,248,203

Specific rotation [α] ²⁶ _D +84.1 (c = 0.18, pyridin
e)

Infrared absorption spectrum νKBr max c
m ^-1 : 3428,2940,1696

Proton nuclear magnetic resonance spectrum (δ ppm
in pyridine-d ₅ ) 0.79 (3H, s), 0.92 (3H, s), 0.96 (3H, s), 1.00 (3H, s), 1.07 (3
H, s), 1.23 (3H, s), 3.68 (1H, d, J = 11.0Hz), 3.88 (1H, d, J = 1
1.0Hz), 3.94 (1H, t, J = 2.6Hz), 5.56 (1H, t, J = 3.2Hz)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
pyridine d ₅ ): 180.2 (s), 144.9 (s), 122.6 (d), 75.7 (d), 7
1.3 (t), 48.1 (d), 46.7 (s), 46.5 (t), 43.6 (d), 42.3 (s), 42.
0 (d), 40.7 (s), 39.9 (s), 37.3 (s), 34.2 (t), 33.4 (t), 33.3
(t, q), 33.0 (t), 31.0 (s), 28.3 (t), 26.5 (t), 26.2 (q), 23.9
(t), 23.8 (q), 23.7 (t), 18.4 (t), 18.2 (q), 17.5 (q), 15.8
(q)

Example 3 Fraction B (0.8 g) obtained in Example 13 was further subjected to preparative high performance liquid chromatography- [Column: CIG (15φX300 mm, silica gel 10 μm
m, 5% acetone-n-hexane] to obtain a fraction rich in the target compound. This fraction was crystallized with methanol to obtain 35 mg of colorless needle crystals having the following physicochemical properties. A compound having the following structure based on these physicochemical properties
I decided to 3.

[0053]

Colorless needles

Melting point: 280-282 ° C (uncorrected)

EI-MS m / z: 456 (M ⁺ ), 438,304,289,259,235

Specific rotation [α] ²⁶ _D +46.9 (c = 0.525, pyridin
e)

Infrared absorption spectrum νKBr max c
m ^-1 : 3400,3036,2952,1700

Proton nuclear magnetic resonance spectrum (δ ppm
in pyridine-d ₅ ) 0.98 (3H, s), 1.00 (3H, s), 1.07 (3H, s), 1.11 (3H, s), 1.25 (3
H, s), 1.39 (3H, s), 1.42 (3H, s), 3.69 (1H, t, J = 2.8Hz), 5.75
(1H, d, J = 5.8Hz)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
pyridine-d ₅ ): 16.2 (q), 17.0 (q), 17.6 (q), 18.9 (t), 24.1
(t), 26.2 (q), 29.1 (t), 29.4 (t), 29.5 (q), 29.9 (t), 30.5
(t), 30.6 (s), 31.0 (t), 31.9 (q), 32.7 (q), 34.7 (t), 35.0
(s), 36.8 (t), 37.0 (t), 39.0 (s), 39.4 (s), 40.7 (s), 41.0
(s), 45.0 (d), 45.5 (d), 50.6 (d), 75.5 (d), 119.9 (d), 144.0
(s), 181.3 (s)

Specific Example 1 20 kg of Raikou Fujine (Tripterygium wilfordii HOOK.f.) was extracted with 100 l of methanol, and the extract was dried under reduced pressure to dryness to remove methanol.
I got Le extract. Dissolve this methanol extract in water,
It was extracted with ethyl acetate to obtain an ethyl acetate extract. Next, the ethyl acetate extract was subjected to silica gel chromatography,
First 10% ethyl acetate-n-hexane, then 50% ethyl acetate-
Elution with n-hexane gave two fractions (A, B).

Fraction B was further subjected to silica gel column chromatography, and was first eluted with 15% ethyl acetate-n-hexane, and then sequentially eluted with increasing concentration of ethyl acetate up to 50%. -1,2,3,4,5)). Fraction B-2 was further subjected to silica gel column chromatography to give 3%
Elute with acetone-benzene to obtain 5 fractions (B-21,22,23,2
4,25).

Fraction B-22 Preparative High Performance Liquid Chromatography
-[Column: CIG (15φX300 mm, silica gel 10 μm]] The crude fraction obtained by recrystallization was recrystallized from n-hexane-ethyl acetate to obtain 450 mg of a yellow needle compound. From the physicochemical properties shown in, it was determined to be compound 4 having the following structure.

[0064]

Yellow needles

Melting point: 109-110 ° C. (uncorrected)

EI-MS m / z: 330.1828 (M ⁺ ) (calc.for, C ₂₀ H
₂₆ O ₄ : 330.1828), 300,285,243,229

Specific rotation [α] ²⁸ _D +170.3 (c = 0.31, CHCl ₃ ).

Ultraviolet absorption spectrum λ EtOH max nm (lo
g ε): 258 (4.22)

Infrared absorption spectrum νKBr max c
m ^-1 : 3464,2968,2936,2876, 1682,1646,1604

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 1.100 (3H, d, J = 7.1Hz), 1.105 (3H, d, J = 6.8Hz), 1.28 (3H,
s), 1.35 (3H, s), 1.45 (1H, ddt, J = 12.9 / 11.7 / 5.2Hz), 1.83
(1H, ddd, J = 13.7 / 10.3 / 5.9Hz), 1.88 (1H, dddt, J = 12.9 / 6.6
/2.0/1.6Hz),2.01(1H,dd,J=12.9/2.0Hz),2.29(1H,ddd,J
= 20.1 / 11.7 / 6.6Hz), 2.47 (1H, ddd, J = 15.6 / 9.0 / 5.9Hz), 2.
69 (1H, ddd, J = 15.6 / 10.3 / 5.5Hz), 2.83 (1H, ddd, J = 20.1 / 5.
2 / 1.6Hz), 2.86 (1H, ddd, J = 13.7 / 9.0 / 5.5Hz), 3.00 (1H, dse
p, J = 6.8 / 1.2Hz), 3.26 (1H, brd, J = 8.5Hz), 3.46 (1H, dd, J = 1
1.5 / 10.6Hz), 4.05 (1H, dd, J = 11.5 / 2.4Hz), 6.38 (1H, d, J =
(1.2Hz)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 220.5 (s), 187.6 (s), 187.4 (s), 153.4 (s), 147.6 (s), 142.6
(s), 131.9 (d), 65.6 (t), 51.7d, 50.3 (s), 37.1 (s), 34.4
(t), 26.4 (d), 25.5 (t), 22.6 (q), 21.34 (q), 21.32 (q), 21.1
(q), 17.9 (t)

Specific Example 2 Fraction B-23 obtained in Specific Example 1 was collected by high performance liquid chromatography- [Column: Kusano Science CIG-Si-10 15φX300 mm, elution solvent;
5% -methanol-chloroform]
The crystals were recrystallized from n-hexane-ethyl acetate to obtain 30 mg of a yellow prism crystal compound. This compound was determined to be compound 5 having the following structure from the physicochemical properties shown below.

[0074]

Yellow needles

Melting point: 178-179 ° C. (uncorrected)

EI-MS m / z: 332.1978 (M ⁺ ) (calc.for, C ₂₀ H
₂₈ O ₄ : 332.1987), 314,298,269,256

Specific rotation [α] ³⁰ _D -47.7 (c = 0.23, CHCl ₃ ).

Ultraviolet absorption spectrum λ EtOH max nm (lo
g ε): 259 (4.19)

Infrared absorption spectrum νKBr max c
m ^-1 : 3372,2968,2932,2876,1644,1680,1596

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 1.09 (3H, d, J = 7.3Hz), 1.10 (3H, d, J = 6.8Hz), 1.19 (1H, dt, J
= 12.5 / 9.9Hz), 1.23 (3H, s), 1.28 (3H, s), 1.40 (1H, m), 1.82
(1H, m), 1.96 (2H, m), 2.31 (1H, ddd, J = 20.0 / 11.2 / 7.3Hz),
2.73 (1H, ddd, J = 20.0 / 5.8 / 1.0Hz), 2.81 (1H, dt, J = 13.7 / 3.
1Hz), 2.97 (1H, dsep, J = 6.8 / 1.3Hz), 3.35 (1H, d, J = 11.25H
z), 3.48 (1H, dd, J = 11.7 / 4.4Hz), 4.26 (1H, d, J = 11.25Hz),
6.33 (1H, d, J = 1.5Hz)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 187.8 (s), 187.7 (s), 153.0 (s), 149.6 (s), 142.6 (s), 131.9
(s), 80.1 (d), 64.0 (t), 51.7 (d), 43.1 (s), 37.8 (s), 34.1
(t), 28.0 (t), 26.4 (t), 26.3 (d), 22.6 (q, 2C), 21.3 (q), 20.
8 (q), 17.3 (t)

Specific Example 3 Fraction B-25 obtained in Specific Example 1 was repeatedly recrystallized with ethanol to obtain 360 mg of a colorless needle compound. This compound was determined to be compound 6 having the following structure from the physicochemical properties shown below.

[0084]

Yellow needle crystals

Melting point: 218-219 ° C. (uncorrected)

EI-MS m / z: 346 (M ⁺ ), 316,301,259,229,205

Specific rotation [α] ²⁵ _D 219 (c = 0.25, CHCl ₃ ).

UV absorption spectrum λ EtOH max nm (lo
g ε): 203 (4.67), 225 (3.94), 287 (3.53)

Infrared absorption spectrum νKBr max c
m ^-1 : 3464,2960,2872,1674,1608

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ + CD ₃ OD) 1.18 (3H, d, J = 6.9Hz), 1.19 (3H, d, J = 6.9Hz), 1.32 (3H, s),
1.38 (3H, s), 1.49 (1H, dq, J = 12.8 / 4.8Hz), 1.86 (1H, ddt, J =
12.8 / 5.9 / 1.9Hz), 1.99 (1H, dddd, J = 14.0 / 10.4 / 5.6 / 0.6H
z), 2.17 (1H, dd, J = 12.9 / 1.9Hz), 2.43 (1H, ddd, J = 15.3 / 8.9
/5.5Hz),2.56(1H,dddd,J=17.2/12.5/5.8/0.7Hz),2.72(1
H, ddd, J = 15.3 / 10.5 / 6.1Hz), 3.09 (1H, ddd, J = 17.2 / 4.8 / 1.
9Hz), 3.20 (1H, ddd, J = 14.0 / 8.9 / 6.1Hz), 3.23 (1H, sep, J =
6.9Hz), 3.68 (3H, s), 3.46 (1H, d, J = 11.5Hz), 4.16 (1H, d, J =
11.5Hz), 6.48 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ + CD ₃ OD) 19.1 (t), 20.5 (q), 22.4 (q), 23.57 (q), 23.61 (q), 26.0 (d),
26.5 (t), 34.8 (t), 35.3 (t), 37.7 (s), 50.5 (s), 53.1 (d), 6
0.7 (q), 65.7 (t), 111.0 (d), 130.1 (s), 130.6 (s), 139.3
(s), 147.7 (s), 151.7 (s), 223.4 (s)

Concrete Example 4 The peaks appearing in the latter half of preparative high performance liquid chromatography in Example 1 were collected to obtain 81 mg of white powder. This compound was determined to be compound 7 having the following structure from the physicochemical properties shown below.

[0094]

White powder

EI-MS m / z: 346.2139 (M ⁺ ) (calc.for, C ₂₀ H
₂₈ O ₃ : 346.2143), 331,316,301

Specific rotation [α] ³⁰ _D +104.1 (c = 0.22, CHCl ₃ ).

Ultraviolet absorption spectrum λ EtOH max nm (lo
g ε): 225 (3.97), 275 (3.13), 282 (3.17)

Infrared absorption spectrum νKBr max c
m ^-1 : 3448,2952,2872,1702,1612

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 1.30 (3H, d, J = 7.3Hz), 1.32 (3H, d, J = 7.1Hz), 1.33 (3H, s),
1.34 (3H, s), 1.68 (1H, ddt, J = 13.2 / 12.9 / 6.0Hz), 1.96 (1H,
ddt, J = 13.2 / 6.7 / 2.2 / 1.7Hz), 2.04 (1H, ddd, J = 13.1 / 9.0 /
8.3Hz), 2.10 (1H, dd, J = 12.9 / 2.2Hz), 2.44 (1H, ddd, J = 13.1
/8.3/4.6Hz), 2.49 (1H, ddd, J = 16.1 / 12.0 / 6.7Hz), 2.62 (1
H, dt, J = 16.0 / 8.3Hz), 2.71 (1H, ddd, J = 16.0 / 9.0 / 4.6Hz),
2.80 (1H, ddd, J = 16.1 / 6.0 / 1.7Hz), 2.93 (1H, dd, J = 9.0 / 3.2
Hz), 3.46 (1H, sep, J = 7.1Hz), 3.54 (1H, dd, J = 11.2 / 9.2Hz),
3.76 (3H, s), 4.07 (1H, dd, J = 11.2 / 2.9Hz), 4.76 (3H, s), 6.3
6 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 220.0 (s), 156.9 (s), 151.6 (s), 145.3 (s), 119.4 (s), 113.9
(s), 100.9 (d), 65.7 (t), 55.8 (q), 51.0 (s), 50.9 (d), 37.3
(t), 37.1 (s), 34.9 (t), 25.3 (q), 24.3 (d), 24.4 (t), 22.2
(q), 20.9 (q), 20.8 (q), 19.1 (t)

Example 5 Fraction B-1 obtained in Example 1 was subjected to preparative high performance liquid chromatography.
-Three fractions (B-11, 12, 1) were attached to [Column: Kusano Science CIG-Si-1015φX300mm, Elution solvent: n-Hexane: Ethyl acetate = 9: 1].
3) Fraction B-11 was repeatedly recrystallized with ethanol,
60 mg of colorless needles were obtained. This compound was determined to be compound 8 having the following structure from the physicochemical properties shown below.

[0103]

Colorless needles

Melting point: 218-219 ° C (uncorrected)

EI-MS m / z: 330,315,273,245,217

Specific rotation [α] ²⁵ _D +117.1 (c = 0.18, CHCl ₃ ).

UV absorption spectrum λ EtOH max nm (lo
g ε): 206 (4.60), 225 (3.88), 284 (3.41)

Infrared absorption spectrum νKBr max c
m ^-1 : 3356,2952,2872,1684

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 1.13 (3H, s), 1.16 (3H, s), 1.26 (3H, s), 1.36 (6H, d, J = 7.2),
1.69 (1H, dq, J = 12.7 / 5.9Hz), 1.83 (1H, m), 1.86 (1H, dd, J = 1
2.7 / 1.7Hz), 1.92 (1H, ddd, J = 13.2 / 9.2 / 8.4Hz), 2.33 (1H, d
dd, J = 11.7 / 7.2 / 3.9Hz), 2.61 (3H, m), 3.01 (1H, ddd, J = 17.1
/5.4/1.5Hz),3.43(1H,sep,J=7.3Hz),3.69(3H,s),4.87(1
H, s), 6.41 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 20.0 (t), 21.10 (q), 21.15 (q), 21.17 (q), 24.5 (q), 24.9
(t), 25.2 (d), 26.9 (q), 34.6 (t), 37.3 (s), 37.7 (t), 47.3
(s), 50.5 (d), 60.7 (q), 109.1 (d), 120.9 (s), 125.1 (s), 14
6.7 (s), 153.6 (s), 156.1 (s), 217.5 (s)

Example 6 Fraction B-12 obtained in Example 5 was repeatedly recrystallized from methanol to obtain 58 mg of colorless needle crystals. This compound 9 was determined to be a compound having the following structure from the physicochemical properties shown below.

[0113]

Colorless needles

Melting point: 216-217 ° C (uncorrected)

EI-MS m / z: 330,315,273,245,217

Specific rotation [α] ²⁶ _D +232.2 (c = 0.22, CHCl ₃ ).

Ultraviolet absorption spectrum λ EtOH max nm (lo
g ε): 206 (4.56), 225 (3.91), 287 (3.55)

Infrared absorption spectrum νKBr max c
m ^-1 : 3408,2956,2868,1692

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 1.15 (3H, s), 1.17 (3H, d, J = 6.8Hz), 1.19 (3H, s), 1.19 (3H,
d, J = 6.8), 1.57 (1H, dq, J = 12.5 / 4.6Hz), 1.81 (1H, ddt, 13.0
/6.0/2.0Hz),1.97(1H,ddd,J=15.6/10.2/6.4Hz),2.02(1
H, dd, J = 12.5 / 2.0Hz), 2.47 (1H, ddd, J = 14.6 / 8.6 / 6.0Hz),
2.58 (1H, ddd, J = 17.3 / 13.0 / 6.0Hz), 2.68 (1H, ddd, J = 15.6 /
10.2 / 6.4Hz), 3.10 (1H, ddd, J = 14.6 / 8.6 / 6.4Hz), 3.12 (1H,
ddd, J = 17.3 / 4.6 / 2.0Hz), 3.25 (1H, sep, J = 6.8Hz), 3.68 (3
H, s), 4.95 (1H, s), 6.39 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 19.96 (q), 20.04 (t), 20.5 (q), 23.76 (q), 23.81 (q), 26.1
(d), 26.5 (t), 28.4 (q), 34.4 (t), 35.5 (t), 38.1 (s), 47.2
(s), 52.0 (d), 60.7 (q), 111.8 (d), 131.2 (s), 131.4 (s), 13
9.4 (s), 149.0 (s), 150.6 (s), 219.3 (s)

Concrete Example 7 Root bark of Lightning Koto (Tripterygium wilfordii HOOK.f.) 10 kg
Was heated and refluxed twice with 40 l of ethyl acetate and filtered, and the filtrate was evaporated under reduced pressure to give ethyl acetate extract (287.55 g). Dissolve the obtained extract in 1 liter of acetone, add 500 g of Avicel (manufactured by Asahi Kasei, microcrystalline cellulose for column) and dry, then add Avicel 20
Column chromatography using 0 g, eluting with 3 l of n-hexane and then eluting with n-hexane-acetone (25%, 5 l), n
-Hexane-acetone eluate was evaporated under reduced pressure to extract 19
2.45g was obtained. Dissolve the extract in 800 ml of methanol, MCI
Column chromatography was performed using 1.5 l of gel CHP 20P (manufactured by Mitsubishi Kasei Co., Ltd.), 70% methanol-water 3 l, 80% methano
Elution was performed with 3 liters, 85% methanol 5 liters, 100% methanol 5 liters. 85
The solvent was distilled off from the% methanol eluate under reduced pressure to obtain 25.58 g of the extract, which was then crystallized with acetone to obtain 11.52 g of yellow needle crystals having the following physicochemical properties. From these physicochemical properties, it was determined to be compound 10 (demethylcellasteral) having the following structure.

[0123]

Melting point: 260 ° C (decomposition)

Specific rotation [α] ²⁵ _D -161.9 ° (c = 0.36, CHC
l ₃ )

EI-MS m / z: 480 (M ⁺ ), 465,204

Infrared absorption spectrum νKBr max c
m ^-1 : 3528,3178,2942,1705,1639

Proton nuclear magnetic resonance spectrum (δ ppm
in DMSO-d6) 0.70 (3H, s), 1.10 (3H, s), 1.19 (3H, s), 1.30 (3H, s), 1.53 (3
H, s), 6.36 (1H, s), 7.21 (1H, s), 11.0 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ -DMSO-d ₆ ) 18.7 (q), 20.5 (q), 28.7 (t), 29.6 (t), 29.8 (t), 30.5 (t), 3
0.8 (s), 31.6 (q), 32.6 (q), 33.7 (t), 34.8 (t), 36.3 (q), 36.
4 (t), 39.4 (s), 40.1 (s), 40.5 (s), 44.3 (d), 45.1 (s), 116.6
(d), 117.0 (s), 122.3 (s), 125.6 (d), 150.0 (s), 150.4 (s), 1
50.7 (s), 174.4 (s), 181.2 (s), 186.3 (s), 200.2 (d)

Specific Example 8 The 80% methanol eluate obtained by MCI gel CHP-20P column chromatography in Specific Example 7 was evaporated under reduced pressure to give an extract (4.50 g). This fraction was subjected to silica gel column chromatography and eluted with 90% chloroform-methanol to obtain fractions 1 to 5. Fraction 3 (0.62g) Preparative high performance liquid chromatography- (Column: TSK-ODS80TM, φ210 × 30
Fraction 1-3 was obtained by purification with 0 mm, elution solvent acetonitrile: methanol: water = 1: 2: 1). Fraction 2 (0.25 g) was crystallized with aqueous ethanol to give yellow needle crystals having the following physicochemical properties: 0.14
got g. From these physicochemical properties, the compound having the following structure 11 (23-nor-6-oxodemethyl-pristimerol)
I decided.

[0131]

Melting point: 355 ° C (decomposition)

Specific rotation [α] ²⁶ _D -102.4 ° (c = 0.19, pyrid
ine)

EI-MS m / z: 452 (M +), 437,271,243,217,204

Infrared absorption spectrum νKBr max c
m ^-1 : 3248,2940,2872,1720

UV absorption spectrum λ MeOH max nm (lo
g ε): 254 (4.17), 298 (3.79)

Proton nuclear magnetic resonance spectrum (δ ppm
in DMSO-d6) 0.65 (3H, s), 1.06 (3H, s), 1.12 (3H, s), 1.27 (3H, s), 1.47 (3
H, s), 0.9 to 1.8 (10H, m), 1.85 (1H, dt, J = 14.6 / 6.4Hz), 1.96
(1H, dd, J = 14.2 / 3.9Hz), 2.04 (1H, d, J = 16.1Hz), 2.24 (1H,
m), 2.34 (1H, d, J = 15.6Hz), 6.09 (1H, s), 6.90 (1H, s), 7.26
(1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
DMSO-d ₆ ) 18.0 (q), 20.3 (q), 28.3 (t), 29.1 (t), 29.3 (t), 30.0 (s), 3
0.1 (t), 31.3 (q), 32.2 (q), 33.1 (t), 34.5 (t), 36.0 (t), 36.
3 (q), 38.9 (s), 39.1 (s), 39.4 (s), 43.7 (d), 44.5 (s), 110.5
(d), 111.3 (d), 121.9 (s), 123.4 (d), 144.1 (s), 148.6 (s), 1
50.9 (s), 173.7 (s), 179.4 (s), 183.1 (s)

Specific Example 9 Fraction 3 (0.7 g) obtained by preparative high performance liquid chromatography in Specific Example 8 was crystallized with acetone to give
0.05 g of a new triterpene having the following physicochemical properties was obtained as yellow needle crystals. From these physicochemical properties, it was determined to be compound 12 having the following structure.

[0140]

Melting point: 348 ° C (decomposition)

Specific rotation [α] ²⁷ _D -98.8 ° (c = 0.32, pyridi
ne)

EI-MS m / z: 466 (M ⁺ ), 285,257,218

Infrared absorption spectrum νKBr max c
m ^-1 : 3432,2944,1702

UV absorption spectrum λ MeOH max nm (lo
g ε): 253 (4.15), 304 (3.93)

Proton nuclear magnetic resonance spectrum (δ ppm
in DMSO-d6) 0.66 (3H, s), 1.08 (3H, s), 1.12 (3H, s), 1.26 (3H, s), 1.46 (3
H, s), 0.9 to 1.9 (11H, m), 1.96 (1H, dd, J = 14.2 / 3.9Hz), 2.04
(1H, d, J = 15.6Hz), 2.19 (1H, d, J = 13.2Hz), 2.34 (1H, d, J = 1
5.1Hz), 2.47 (3H, s), 6.02 (1H, s), 6.83 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
DMSO-d ₆ ) 13.5 (q), 18.0 (q), 20.7 (q), 28.0 (t), 29.25 (t), 29.31 (t),
30.0 (2C, t, s), 31.3 (q), 32.2 (q), 33.6 (t), 34.5 (t), 36.0
(t), 37.4 (q), 38.5 (s), 39.2 (s), 39.3 (s), 43.6 (d), 44.0
(s), 108.4 (d), 121.0 (s), 124.8 (s), 125.3 (d), 141.8 (s), 1
49.1 (s), 149.3 (s), 170.2 (s), 179.3 (s), 186.0 (s)

Example 10 13.5 g of a crystal mother liquor of demethylzelastral obtained in Example 7
Was applied to Sephadex LH-20 (Pharmacia) and eluted with chloroform-ethanol (7: 3), and the ferric chloride-positive fractions that were eluted following demethylzelasterol were collected. It was concentrated under reduced pressure. This fraction (8.2 g) was crystallized with acetone to obtain 5.3 g of a colorless plate-like compound. This compound was determined to be compound 13 having the following structure by the following physicochemical properties and X-ray crystallographic analysis.

[0149]

Melting point: 194 ° C (decomposition)

Specific rotation [α] ²⁴ _D + 46.3 ° (c = 0.68 CHC
l ₃ )

EI-MS m / z: 450 (M ⁺ ), 435, 241, 214

Infrared absorption spectrum νKBr max c
m ^-1 : 3452,3308,2940,1710,1688

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ -CD ₃ OD) 0.95 (3H, s), 1.01 (3H, s), 1.01 (3H, s), 1.05 (3H, s), 1.21 (3
H, s), 2.17 (3H, s), 5.48 (1H, d, J = 4.8Hz), 6.22 (1H, d, J = 9.3
Hz), 6.39 (1H, d, J = 9.3Hz), 6.65 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ -CD ₃ OD) 11.0 (q), 19.2 (q), 19.5 (q), 22.5 (q), 23.9 (t), 29.6 (t), 3
0.7 (q), 31.4 (t), 31.7 (s), 33.1 (t), 33.1 (q), 37.1 (t), 37.
7 (t), 39.0 (s), 40.3 (s), 40.8 (s), 43.9 (s), 47.0 (d), 108.5
(s), 108.5 (d), 119.4 (d), 119.8 (s), 122.5 (d), 124.6 (s), 1
30.2 (s), 138.9 (d), 141.4 (s), 142.9 (s), 182.3 (s)

Example 11 The crystal mother liquor (8.0 g) of the compound obtained in Example 10 was subjected to silica gel column chromatography, and the contents of 5% acetone-n-hexane and then acetone were successively added to 10, 20, 30. Elution was performed by increasing the amount to%, and the resulting fractions were divided into four fractions A to D. Fraction D (1.1
g) Further preparative high performance liquid chromatography- [Column: CIG
(15φ × 300 mm, silica gel 10 μm, 25-30% acetone-n-hexane], and the three peaks that appeared (peak A, B, C) were collected. After that, 0.1 g of a new triterpene having the following physicochemical properties as colorless needles was obtained by crystallization from ether-n-hexane. I decided.

[0157]

Melting point: 182-183 ° C (uncorrected)

Specific rotation [α] ²⁶ _D -106.7 ° (c = 0.17, CHC
l ₃ )

EI-MS m / z: 508 (M ⁺ ), 451,243,201

Infrared absorption spectrum νKBr max c
m ^-1 : 3416,2940,2868,1702

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 0.63 (3H, s), 1.05 (3H, s), 1.15 (3H, s), 1.16 (3H, s), 1.42 (3
H, s), 2.07 (3H, s), 2.16 (3H, s), 0.9 to 2.2 (14H, m), 2.39 (1
H, d, J = 18.1Hz), 2.42 (1H, dd, 16.1 / 11.2Hz), 2.63 (1H, dd, J
= 16.2 / 2.4Hz), 3.84 (1H, m), 5.76 (1H, d, J = 5.9Hz), 6.73 (1
H)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 11.9 (q), 18.8 (q), 22.3 (q), 28.9 (t), 29.7 (t), 30.4 (t), 3
0.6 (s), 30.7 (t), 31.1 (q), 31.6 (q), 32.8 (q), 33.1 (d), 34.
5 (t), 35.7 (t), 36.7 (2C, t, q), 37.2 (s), 37.8 (s), 40.3 (d),
43.8 (s), 44.4 (d), 51.9 (t), 109.3 (d), 120.1 (s), 121.6
(d), 127.9 (s), 140.1 (s), 142.2 (s), 142.4 (s), 150.1 (s), 1
83.3 (s), 209.9 (s)

Specific Example 12 The solvent-eluted portion of 100% methanol obtained in Specific Example 7 was distilled off under reduced pressure to obtain 20.25 g of an extract, which was crystallized with hydrous ethanol to give the following physicochemical properties. 10.85 g of red needle crystals having From these physicochemical properties, it was determined to be compound 15 [tripterin (cerastrol)] having the following structure.

[0165]

Melting point: 198-200 ° C (uncorrected)

Specific rotation [α] ³⁰ _D -364.9 ° (c = 0.27, CHC
l ₃ )

EI-MS m / z: 450 (M ⁺ , base peak), 241,201

Infrared absorption spectrum νKBr max c
m ^-1 : 3272,2952,2942,1700,1636

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ ) 0.57 (3H, s), 1.09 (3H, s), 1.25 (3H, s), 1.28 (3H, s), 1.43 (3
H, s), 2.21 (3H, s), 6.32 (1H, d, J = 7.3Hz), 6.49 (1H, d, J = 1.2
Hz), 7.06 (1H, dd, J = 7.3 / 1.2Hz)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ ) 10.5 (q), 18.7 (q), 21.5 (q), 28.7 (t), 29.3 (t), 29.5 (t), 3
0.7 (s), 31.1 (t), 31.5 (q), 32.4 (q), 33.8 (t), 34.5 (t), 36.
4 (t), 8.3 (q), 39.3 (s), 39.9 (s), 43.1 (s), 44.3 (d), 45.3
(s), 118.3 (d), 120.4 (s), 120.6 (d), 127.6 (s), 135.4 (d), 1
47.0 (s), 165.0 (s), 172.6 (s), 178.3 (s), 182.4 (s)

Example 13 Fractions obtained by drying under reduced pressure the crystal mother liquor of the compound obtained in Example 12
(9.1 g) was subjected to silica gel column chromatography,
First 5% ethyl acetate-n-hexane, then 8% ethyl acetate-n-
Elution with hexane was performed as fractions A and B, respectively. Fraction B was crystallized with methanol to obtain 22 mg of colorless needle crystals having the following physicochemical properties. From these physicochemical properties, it was determined to be compound 16 having the following structure.

[0173]

Colorless needles

Melting point: 300 ° C. or higher

EI-MS m / z: 470 (M ⁺ ), 424,235,189,137

Specific rotation [α] ²⁵ _D -10.0 ° (c = 0.25, pyridi
ne)

Infrared absorption spectrum νKBr max c
m ^-1 : 3352,2936,1738,1710,1660,1630

Proton nuclear magnetic resonance spectrum (δ ppm
in CDCl ₃ -CD ₃ OD) 0.84 (3H, s), 0.89 (3H, s) 0.90 (3H, s), 1.040 (3H, s), 1.042
(3H, s), 1.17 (3H, s), 1.77 (3H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
CDCl ₃ -CD ₃ OD) 10.5 (q), 16.3 (q), 17.7 (q), 18.0 (t), 18.2 (q), 18.9 (q), 2
9.2 (t), 29.3 (t), 29.8 (t), 30.3 (s), 30.4 (t), 31.8 (q), 31.
9 (q), 32.6 (t), 34.4 (t), 36.2 (t), 36.7 (t), 36.8 (s), 38.5
(t), 39.3 (s), 39.3 (s), 39.6 (s), 40.3 (s), 44.4 (d), 50.2
(d), 55.8 (d), 141.7 (s), 142.7 (s), 182.1 (s), 195.5 (s)

Specific Example 14 After the peak B separated by preparative high performance liquid chromatography in Specific Example 11 was dried to dryness, the compound having the following physicochemical properties was crystallized with methanol to give colorless needles. As a crystal
0.17 g was obtained. These physicochemical properties and X of dimethyl ether crystals of this compound methylated by conventional methods
It was determined to be compound 17 having the following structure by line crystal analysis.

[0182]

Colorless needles

Melting point: 300 ° C. or higher

FAB-MS m / z: 485 (M + H) ⁺

Specific rotation [α] ²⁵ _D +496.4 (c = 0.29, pyridin
e)

Infrared absorption spectrum νKBr max c
m ^-1 : 3320,2944,1736,1706,1666,1632

Proton nuclear magnetic resonance spectrum (δ ppm
in pyridine d ₅ ) 0.77 (3H, s), 0.8 (3H, s), 1.18 (3H, s), 1.34 (3H, s) 1.47 (3H,
s), 1.90 (3H, s), 9.82 (1H, s)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
pyridine d ₅ ): 10.7 (q), 16.2 (q), 17.2 (q), 17.9 (q), 18.9
(q), 29.4 (t), 29.5 (t), 30.49 (s), 30.51 (t), 30.9 (2C, t), 3
2.1 (q), 32.3 (q), 32.7 (t), 33.3 (t), 36.6 (t), 37.1 (s), 37.
4 (t), 39.4 (s), 39.6 (s), 40.7 (s), 44.8 (d), 49.5 (d), 54.9
(s), 55.5 (d), 125.9 (s), 149.0 (s), 181.4 (s), 193.3 (s), 19
5.8 (s)

Example 15 The peak C separated by preparative high performance liquid chromatography in Example 11 was dried and crystallized with methanol to give a compound having the following physicochemical properties as colorless needles. As a crystal
0.25 g was obtained. From these physicochemical properties, it was determined to be compound 18 having the following structure.

[0192]

Colorless needles

Melting point: 300 ° C. or higher

EI-MS m / z: 488 (M ⁺ ), 413,383,125

Specific rotation [α] ²⁶ _D +4.7 (c = 0.29, pyridine)

Infrared absorption spectrum νKBr max c
m ^-1 : 3580,3276,1692

Proton nuclear magnetic resonance spectrum (δ ppm
in pyridine-d ₅ ) 0.86 (3H, s), 0.94 (3H, s), 1.14 (3H, s), 1.20 (3H, s), 1.23 (3
H, d, J = 7.1Hz), 1.43 (3H, s, 3.78,1H, d, J = 8.0Hz), 4.24 (1H,
d, J = 8.0Hz), 4.39 (1H, d, J = 3.5Hz)

¹³ C-nuclear magnetic resonance spectrum (δ ppm in
pyridine-d ₅ ): 8.4 (q), 16.92 (q), 16.94 (q), 18.1 (q), 19.7
(t), 28.8 (t), 29.6 (t), 29.8 (t), 30.5 (2C, s, t), 30.9 (t), 3
2.1 (q), 32.2 (q), 34.0 (t), 34.8 (t), 36.7 (t), 37.4 (s), 37.
5 (t), 39.3 (s), 39.6 (s), 40.7 (s), 44.8 (d), 46.9 (d) 47.5
(s), 50.5 (d), 53.3 (d), 72.1 (t), 74.2 (d), 108.1 (s), 181.3
(s)

Next, the present invention will be described with reference to formulation examples of the present invention.

[Formulation Example 1]

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).

Each tablet contains 20 mg of Compound 1, and 3 to 10 tablets for adults are to be taken in several divided doses per day.

[Formulation Example 2] Crystalline cellulose 84.5 g Magnesium stearate 0.5 g Carboxymethyl cellulose calcium 5 g Compound 2 10 g Total 100 g

According to the above formulation, a part of and was uniformly mixed, compression-molded, pulverized, and the remaining amount of and was added and mixed, and compression-molded with a tableting machine to give one tablet.
0 mg tablets were obtained.

Each tablet contains 20 mg of Compound 2, and 3 to 10 tablets for adults are to be taken in several divided doses.

[Formulation Example 3] Crystalline cellulose 79.5 g 10% Hydroxypropyl cellulose ethanol solution 50 g Carboxymethyl cellulose calcium 5 g Magnesium stearate 0.5 g Compound 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.

[0209] Each tablet contains 20 mg of compound 3, and 3 to 10 tablets for adults are to be taken in several divided doses.

[Formulation Example 4]

According to the above prescription, are uniformly mixed, compression-molded by a compression molding machine, and crushed by a crusher,
Sieve to obtain granules.

1 g of this granule contains 100 mg of compound 4, and 0.6 to 2 g for adults is to be taken in several divided doses.

[Formulation Example 5] Crystalline cellulose 86.5 g 10% Hydroxypropyl cellulose ethanol solution 35 g Compound 5 10 g Total 131.5 g

According to the above-mentioned formulation, the ingredients (1) to (4) were uniformly mixed and then blended. After granulation by an extrusion granulator, the granules were dried and sieved to obtain granules.

1 g of this granule contains 100 mg of compound 5, and 0.6 to 2 g for adults is to be taken in several divided doses per day.

[Formulation Example 6] Corn starch 89.5 g Light anhydrous silicic acid 0.5 g Compound 6 10 g Total 100 g

According to the above formulation, was mixed uniformly and 200 mg was filled in No. 2 capsule.

One capsule of this capsule contains Compound 6.
It contains 20 mg, and 3 to 10 capsules for an adult should be taken in several divided doses.

[Formulation Example 7] Distilled water for injection 89.5 g Soybean oil 5 g Soybean phospholipid 2.5 g Glycerin 2 g Compound 7 1 g Total amount 100 g

According to the above-mentioned formulation, and were dissolved in, and the solution of and was added thereto to emulsify to obtain an injection.

[Formulation Example 8] Distilled water for injection Appropriate amount Glucose 200 mg Compound 8 10 g 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. that's all

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 49/753 9049-4H C07C 49/753 C 50/38 9049-4H 50/38 (72) Invention Yasuhiro Komatsu 3586 Yoshiwara, Ami-cho, Inashiki-gun, Ibaraki Tsumura Co., Ltd. (72) Inventor Yang Norihui 407, No. 4 277, Xiangxi South Road, Xu-fui-ku, Shanghai, China (72) Inventor Qin Manchao, Xu Hui-gu, Xu-hui-ku, Shanghai, People's Republic of China 204, Room No. 23, No. 170, Room 72

Claims (4)

[Claims] 1. The following formula I [In the formula, R1 represents a lower alkyl group, a hydrogen atom or a carbonyl group, R2 represents a lower alkyl group, a hydrogen atom or a hydroxymethyl group, R3 represents a lower alkyl group, a hydrogen atom or a hydroxymethyl group, and R4 represents Hydroxyl group, a hydrogen atom or = O, R5 is a lower alkyl group, a hydrogen atom or a carbonyl group, R6 is a lower alkyl group, a hydrogen atom or a carbonyl group, R7 is a lower alkyl group, A is Either group, (Here, R8 represents a hydroxyl group or a hydrogen atom, R9 represents a hydroxyl group, a hydrogen atom or a lower alkoxy group, R10 represents a hydroxyl group or a lower alkoxy group, R11 represents a lower alkyl group, a hydrogen atom or a carbonyl group, R12 represents = 0 or an acetonyl group, and R13 represents a lower alkyl group or a carbonyl group.). ] As an active ingredient. 2. The following formula (XI) A novel compound represented by. 3. The following formula (XII) A novel compound represented by. 4. The following formula (XIII) A novel compound represented by.