JPH01258647A - Novel drimane-type sesquiterpene carboxylic acid derivative - Google Patents

Abstract

NEW MATERIAL:The drimane-type sesquiterpene carboxylic acid derivative of formula (R<1> is H, OH or lower alkanoyloxy; R<2> is H or lower alkyl; R<3> is H or lower alkyl; R<4> is =CH2 or O; R<1> and R<2> may together form a single bond) and its salt. USE:A medicine effective in removing active oxygen seed and preventing or suppressing the formation of lipid peroxide in the body. For example, an antiulcer agent for peptic ulcer, remedy for the disorder of various tissue cells of liver, kidney, pancreas, etc., remedy for autoimmune diseases, remedy for cardiac ischemic diseases, preventive for cancer, anti-inflammatory agent and preventive for aging. PREPARATION:The compound of formula can be extracted and separated from Cryptoporus volvatus which is a fungus of family Polyporaceae.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel doliman-type sesquiterpene carboxylic acid derivatives.

DISCLOSURE OF THE INVENTION The Doliman-type sesquiterpene carboxylic acid derivative of the present invention is a novel compound not described in any literature, and is represented by the following general formula (1).
It is expressed as

[In the formula, R1 represents a hydrogen atom, a hydroxyl group, or a lower alkanoyloxy group. R2 represents a hydrogen atom or a lower alkyl group. R3 represents a hydrogen atom or a lower alkyl group. R4 represents a group=CH2 or an oxygen atom. Further, R1 and R3 may be combined to form a single bond. ] Oxygen is essential for living organisms to maintain life, such as energy production and metabolism. The oxygen becomes so-called active oxygen species such as oxygen anion radicals, peroxide ions, and hydroxyl radicals through reactions in energy production systems, enzyme reactions, ultraviolet rays, radiation, and the like. While these reactive oxygen species are useful for living organisms in terms of oxygenating enzymes and bactericidal effects on white blood cells, they also form phospholipids in biological membranes such as oleic acid, linoleic acid, lylunic acid, and arachidonic acid, which are abundant in living organisms. promotes the peroxidation of unsaturated fatty acids, forming lipid peroxides.

This lipid peroxide causes generation of alkoxy radicals and hydroxyl radicals like the above-mentioned active oxygen species, attacks biological membranes, and causes membrane damage and deactivation of various useful enzymes.
[See Metabolism, 15(10), 1978 special feature on active oxygen]
.

However, enzymes involved in the metabolic deactivation of the above-mentioned reactive oxygen species, such as SOD, catalase, and glutathione peroxidase, exist in living organisms, and various enzymes such as α-tocopherol (vitamin E) exist. There are vitamins, etc. that have antioxidant ability, and the action of these vitamins normally maintains a normal body, but for some reason, the appropriate defense mechanisms such as the enzymes, vitamins, etc. mentioned above may become defective. It is often observed that the generation of reactive oxygen species and the production and accumulation of lipid peroxides exceed the capabilities of secondary defense mechanisms. When a deficiency in such a defense mechanism occurs, serious disorders occur due to the chain reaction progression of peroxidation reactions, such as various diseases caused by platelet aggregation, inflammation, liver damage, kidney damage, gastric damage, arteriosclerosis, hemolysis, and aging. Senile dementia, retinopathy, lung damage, heart and lung damage caused by certain drugs, ischemic vascular disease, etc. occur.

Compounds that scavenge active oxygen species (radicals), which are considered to be the main cause of the various disorders mentioned above, and prevent or reduce the production and accumulation of lipid peroxides in living organisms include the above-mentioned SOD. [Superoxide and Medicine, Yoshihiko Oyanagi, 1981]
, Kyoritsu Shuppansha, pp. 137-141], butylated hydroxytoluene (BIT), butylated hydroxyanisole (BHA), α-tocopherol (vitamin E
) etc. [Makoto Mino, Hidetaka Tanaka, Pharmaceutical Journal.

19, (12), 1983, p2351-2359
and Toshihiko Suematsu, Ibid., 19(5).

1983, p. 909-914].

The active ingredient compound of the present invention has the effect of removing active oxygen species and preventing or reducing the in vivo production of lipid peroxide. Therefore, the pharmaceutical preparation for oral administration of the present invention containing the above-mentioned compound as an active ingredient can be used to treat various disorders caused by excessive generation of the above-mentioned active oxygen species, bioaccumulation of lipid peroxides, or lack of defense mechanism against the above. It is useful as a preventive and therapeutic agent for diseases. More specifically, the pharmaceutical preparation of the present invention can be used as an anti-ulcer agent for gastric, duodenal, etc.; hepatitis;
As a therapeutic agent for various tissue cell disorders such as liver diseases such as cirrhosis, kidney diseases such as nephritis, and pancreatic diseases such as pancreatitis; as a therapeutic agent for autoimmune diseases such as ulcerative colitis and malignant rheumatism, and for cardiac ischemic diseases. It is useful in the pharmaceutical field as a therapeutic agent, cancer prevention agent, anti-inflammatory agent, anti-aging agent, etc.

In this specification, the term lower alkanoyloxy group includes, for example, acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pentanoyloxy,
It means a straight or branched alkanoyloxy group having 2 to 6 carbon atoms such as tert-butylcarbonyloxy or hexanoyloxy group. Furthermore, the term "lower alkyl group" means a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl group, etc. .

The compound of the present invention represented by the above general formula (1) can be produced, for example, according to the method shown below.

That is, certain compounds of the present invention are suitable for use in the mushroom Cryptoporus fungi.
lvatus).

The above-mentioned extraction and isolation is carried out, for example, as follows. First, extract the human acutula using a common polar solvent such as ethyl acetate or ethanol. After filtering the extract, the synovial fluid is concentrated under reduced pressure to obtain a primary extract, and then the target compound is extracted from the extract. The target substance is collected using various methods that utilize its physical and chemical properties.

The target substance can be collected using conventional methods, such as a method that utilizes the difference in solubility with impurities, or a method that utilizes the difference in adsorption affinity for adsorbents such as activated carbon, Amberlite, silica gel, ion exchange resin, Sephadex, and Toyopearl. It can be carried out by a method, a method using the difference in distribution ratio between two liquid phases, a combination of these methods, etc. A more preferable collection method is, for example, subjecting the above-mentioned primary extract to silica gel column chromatography, eluting with a suitable solvent such as a mixed solvent of chloroform and ethanol, concentrating this eluate under reduced pressure, and passing the concentrated solution through a silica gel column. An example of a method is to purify by chromatography, then subject to Sephadex, elute with an appropriate solvent such as ethanol or chloroform, and then purify by silica gel column chromatography.

The compound of the present invention isolated and extracted above has the general formula (R5)20 (2) or the general formula R5
X (3) [In each of the above formulas, R5 represents a lower alkanoyl group, and X represents a halogen atom. ] By reacting a compound represented by the following, a compound of the present invention in which R1 is a lower alkanoyloxy group in the above general formula (1) can be derived.

This lower alkanoylation reaction is carried out in the presence or absence of a basic compound. Examples of the basic compounds used include alkali metals such as sodium metal and potassium metal, and hydroxides and carbonates of these alkali metals.
Examples include bicarbonate, or organic bases such as pyridine and piperidine. The reaction proceeds either without a solvent or in a solvent. Examples of the solvent include ketones such as acetone and methyl ethyl ketone, ethers such as diethyl ether and dioxane, aromatic hydrocarbons such as benzene, toluene, and xylene, water, and pyridine. The amount of the compound of general formula (2) or (3) to be used is at least equimolar to the raw material compound, but it is generally preferred to use an equimolar to large excess amount. The above reaction is 0
Although the reaction proceeds at a temperature of 200°C to 200°C, it is generally preferable to carry out the reaction at a temperature of about 0 to 150°C. The reaction time of the reaction is generally 0
．． It takes about 5 to 15 hours.

Further, by lower alkylating the compound of the present invention in which R2 and/or R3 in the above general formula (1) is a hydrogen atom, the corresponding compound of the present invention in which R2 and/or R3 is a lower alkyl group can be derived. be able to.

The lower alkylation reaction is carried out, for example, in the presence of a basic compound, by adding the above-mentioned raw material compound according to the general formula % (4) [wherein R6 represents a lower alkyl group]. X is the same as above.

] It is carried out by reacting a compound represented by the following.

As the basic compound, a wide variety of conventionally known compounds can be used, such as inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, thorium hydride, silver carbonate, etc. , alcoholades such as sodium methylate and sodium ethylate, diisopropylethylamine, triethylamine, pyridine, N,N-dimethylaniline, 1,
5-diazabicyclo[4,3,03nonene-5,1゜8
-diazabicyclo[5,4,0)undecene-7,1,
Examples include organic bases such as 4-diazabicyclo(2,2,2)octane. The reaction is carried out without a solvent or in the presence of a solvent. As a solvent, any inert solvent that does not adversely affect the reaction can be used, such as alcohols such as methanol, ethanol, impropatol, butanol, and ethylene glycol, and ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, and diglyme. , dichloromethane, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene and xylene, esters such as ethyl acetate and methyl acetate, acetonitrile, N,N-dimethylformamide , dimethyl sulfoxide, aprotic polar solvents such as hexamethyl phosphoric triamide, and the like.

The ratio of the compound of general formula (4) to the raw material compounds in the above method is not particularly limited and is appropriately selected from a wide range, but it is usually preferable to use a large excess of the latter relative to the former. The reaction temperature is also not particularly limited, but is usually room temperature to 150°C, preferably room temperature to 100°C. The reaction time is usually 0. It takes about 5 to 10 hours.

In addition, in the lower alkylation, the raw material compound and diazomethane are mixed in a solvent such as an alcohol such as methanol or ethanol, or an ether such as diethyl ether, tetrahydrofuran, or dioxane, usually at 0 to 50°C, preferably at 0°C.
This reaction can also be carried out by reacting at around room temperature for about 10 minutes to 3 hours.

Furthermore, the compound of the present invention in which R4 is =CH2 in the above general formula (1) can be induced to the corresponding compound of the present invention in which R4 is =0 by ozone oxidation.

This ozone oxidation is usually carried out in a solvent such as halogenated hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride.
This is carried out by introducing ozone at a temperature of 90 to 0°C, preferably -90 to -20°C, usually for about 10 minutes to 5 hours, and then treating with zinc-acetic acid for about 10 minutes to 5 hours.

The compounds of the present invention can be easily converted into acid addition salts by treatment with pharmaceutically acceptable acids. Examples of the acid include inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, and hydrobromic acid, oxalic acid, maleic acid, fumaric acid, malic acid,
Organic acids such as tartaric acid, citric acid and benzoic acid may be mentioned.

Further, among the compounds of the present invention, compounds having an acidic group can be easily formed into salts by reacting with a pharmaceutically acceptable basic compound. Examples of the basic compound include sodium hydroxide, potassium hydroxide, potassium carbonate, potassium hydrogen carbonate, and the like.

The target compounds obtained in each step can be easily isolated and purified by conventional separation means. Examples of the separation means include solvent extraction, dilution, recrystallization, column chromatography, and preparative thin layer chromatography.

The compound of the present invention of general formula (1) obtained by the above method can be administered to humans or animals as it is or as an active ingredient together with a conventional pharmaceutical carrier. When using the compound of the present invention as a medicine, the form of the pharmaceutical preparation (dosage unit form), its preparation, its administration route, etc. can be the same as those of ordinary pharmaceutical preparations. That is,
The compound of the present invention can be used in tablets, granules, etc. containing its effective n.
It is formulated into oral preparations such as capsules and oral solutions, and parenteral preparations such as injections, and can be administered orally or parenterally. The various forms of preparations mentioned above are prepared according to conventional methods, and the carriers used at that time may be of various commonly used carriers.

For example, tablets contain gelatin, starch,
It is formulated by mixing with excipients such as lactose, magnesium stearate, talc, and gum arabic. Capsules are prepared by mixing the active ingredient compound with an inert pharmaceutical filler or diluent and filling the mixture into hard gelatin capsules, soft capsules, and the like. Parenterally administered preparations such as injections are manufactured by dissolving or suspending the active ingredient in a sterilized liquid carrier. Preferred carriers include water, physiological saline, and the like.

The amount of the active ingredient compound to be contained in the pharmaceutical preparation of the present invention is not particularly limited and can be appropriately selected within a wide range, but is usually about 1 to 70% by weight, preferably 1 to 70% by weight based on the total composition.
The content is preferably about 30% by weight.

The method of administering the pharmaceutical preparation of the present invention is not particularly limited (it can be administered in a manner depending on various preparation forms, age, sex and other conditions of the patient, degree of disease, etc.). For example, tablets, granules, capsules, etc. In the case of oral preparations, it is administered orally.In the case of parenteral preparations such as injections, it is administered alone or with glucose,
It is administered intravenously in a mixture with a conventional replacement fluid such as amino acids, and further administered alone as needed intramuscularly, intradermally, subcutaneously, or intraperitoneally.

The dosage of the pharmaceutical preparation of the present invention is appropriately selected depending on the usage, age of the patient, gender and other conditions, degree of disease, etc., but the amount of the active ingredient compound is usually 100 mg/kg body weight per day.
The dosage is preferably about 800 mg, and it is best to administer this in divided doses from once a day to several times a day.

In addition, 1 to 200 m of the active ingredient compound in dosage unit form may be used.
It is preferable to contain about 100 g.

Hereinafter, in order to explain the present invention in more detail, production examples of the compounds of the present invention will be listed as examples, followed by pharmacological test results and formulation examples.

Example 1 Immediately after the collection, a mushroom (1.1 kg) of the mushroom (Arunocysaceae) collected in Mt. Bizan, Tokushima Prefecture was cut into pieces and extracted with ethyl acetate (3Q) overnight. After vacuum filtration,
The furnace liquid was concentrated under reduced pressure to obtain 75.96 g as an extract. Furthermore, after extracting the mushrooms with ethyl acetate (3Q) for 4 days, filtering under reduced pressure, and concentrating the filtrate under reduced pressure, 2
1.86 g was obtained, and the ethyl acetate extract was reduced to a total ff of 197.8
4g was obtained.

A portion of the ethyl acetate extract obtained above (75.60g
) with silica gel (manufactured by Merck & Co., Ltd., 70-230 mesh,
800g) Chromatography was performed on a column using chloroform/ethanol as a developing solvent while increasing the ethanol concentration. Chloroform (IQ), 4% ethanol-chloroform (IQ), 6% ethanol-chloroform (IQ), 8% ethanol-chloroform (IQ),
10% ethanol-chloroform (IR), 15% ethanol-chloroform (IQ) and 20% ethanol-
Elute with chloroform (IQ2) and from the 6% ethanol-chloroform eluate, 1 fraction = 250111
Fraction I (fraction N011-8;
7.520 g), Fraction ■ (Fraction No. 39 to 10
; 2.822 g), fraction ■ (Fraction No. 11
; 4.950 g), fraction ■ (fraction No. 12
~13; 9.310g), Fraction ■ (Fraction No.
The mixture was fractionated into six fractions: fraction No. 14-15; 7.860 g) and fraction (1) (fraction No. 16-22; 12.98 g).

Fraction I was a fraction mainly containing fatty acid esters, and fraction II was recrystallized from ethanol-diethyl ether to obtain ergosterol (2,351 g) with a mp of 166-168°C.

Fraction m (4,950 g) was purified using silica gel (Wako Gel C).
-300, 250 g) column was subjected to chromatography using chloroform:acetone:acetic acid = 1:1:0.1 as a developing solvent, and 1 fraction = 25 fractions were collected. Fraction no.

1-(driman-8-pyridenyl-11 from 23-28
-oxy)hydrogen 1,2-dimethyl 1,2.
3-propane tricarboxylate (cryptoporic acid A) (3,291 g) was obtained as a colorless oil, R1 and R2 were obtained from fractions No. 35 to 39.
is a hydrogen atom, R3 is a methyl group, and R4 is =CH2 (hereinafter referred to as "compound A") (0,
270 g) was obtained as a white powder.

Fraction IV (9,310 g) was added to Sephadex LH-20
(manufactured by Pharmacia, 500TIIQ) and eluted with chloroform:ethanol=1:1 (IQ).
1 fraction = 50 fractions, fraction No.
, 11 to 14 were collected and concentrated under reduced pressure, resulting in 7.68 g.
of oil was obtained. This oily substance was subjected to chromatography on a silica gel (Wako Gel C-300, 400 g) column using ethanol-chloroform as a developing solvent while increasing the ethanol concentration. The eluate of 12% ethanol-chloroform (fraction No. 65-91) was concentrated under reduced pressure to obtain Compound A (4°405 g) as a white powder, and 14% ethanol-chloroform (fraction No. 106-122) was obtained. R from the elution part of
2 is a hydrogen atom, R4 is =CH2, and R1 and R3 combine to form a single bond. A compound (hereinafter referred to as "Compound B") (2,105 g) of the general formula (1) was obtained as white crystals. Ta.

Fraction V (7.86 g) was added to Sephadex LH-20 (
500TIIQ (manufactured by Pharmacia), and eluted with chloroform:ethanol (1:1) to obtain 1 fraction.
When 50 fractions were collected and fractions No. 12 to 14 were collected and concentrated under reduced pressure, 5.95 g of oil was obtained. This oily substance is mixed with silica gel (Wakogel C-300,
300 g) was subjected to chromatography on a column using ethanol-chloroform as a developing solvent while increasing the ethanol concentration. The eluate of 12% ethanol-chloroform (fraction No. 76-89) was concentrated under reduced pressure to obtain compound A (0,389 g) as a white powder, and 14% ethanol-chloroform (fraction No. 76-89) was concentrated under reduced pressure.
, 93-121), compound B (3,677
g) was obtained as white crystals, and 20% ethanol-
From the elution part of chloroform (fraction No. 145-159), R1, R2 and R3 are hydrogen atoms, and R4 is =C
A compound of general formula (1) (hereinafter referred to as "compound C") (0,875 g), which is H2, was obtained as a white powder.

Fraction Vl (12,980 g) was added to Sephadex LH-
20 (manufactured by Pharmacia, IQ) and eluted with chloroform:ethanol = 1:1, 1 fraction -50
Take a portion and collect fractions No. 11 to 17.
Concentration under reduced pressure yielded an oil (9.85 g), and fraction no.

Collect 18-21 and concentrate under reduced pressure to obtain an oily substance (2.15g
)was gotten. The former oil (9.85 g) was subjected to chromatography on a silica gel (Wako Gel C-300, 500 g) column using ethanol-chloroform as a developing solvent while increasing the ethanol concentration. 20% ethanol-chloroform (fraction No. 66-93
), a compound of general formula (1) (hereinafter referred to as "compound D") (5,985 g) in which R1 is a hydroxyl group, R2 is a hydrogen atom, R3 is a methyl group, and R4 is =CH2 was obtained as a white powder. Also, from the 24% ethanol-chloroform elution part, R1 is a hydroxyl group, R2 and R3 are hydrogen atoms, and R
A compound of general formula (1) in which 4 is =CH2 (hereinafter referred to as "compound E") (2,018 g) was obtained as a white powder. The latter ζ') oil (2, I 5 g) was subjected to chromatography on a silica gel (Wako Gel C-300, 1,00 g) column using ethanol-chloroform as a developing solvent while increasing the ethanol concentration. 18
% ethanol-chloroform (fraction No. 48
~61) 1-(15-hydroxydoliman-8-pyridenyl-11-oxy)hydrogen 1,
2-Dimethyl 1.2.3-propane tricarboxylate (cryptoporic acid B) (1,772 g) was obtained as white crystals.

The physical property data of Compounds A to E obtained above are shown below.

Compound A: mp83-85°C, white powder [α) D=+61.22° (chloroform, C=0.
64) IR (KB r, cm-'): ax 3400~2400 (OH), 1740°1730
(-COOCH3), 1715°1710 (-COO
H), 1640 (''; C=CH2), 1430.1200°1160.
1120, 1035, 1010°885.745.65
5'H-NMR (400MHz, CDCQ3) δ: 0.
71 (3H, s), 0.72 (3H, s) 0.7
6 (3H,s) ,0.80 (3H,s)0,87
(3H,s), 1.94 (IH,m)2,03
(IH, m), 2. 04 (IH, m)2, 35
(iH, m) 2.64 (IH, dd, J=17.6°2.2Hz) 2.84 (2H, dd, J=17.6°10.8Hz
) 2.89 (IH, dd, J=17.6°2.9Hz) 3.48 (2H, m) 3.53 (2H, dd, J=9.5°4, 9Hz) 3.64 (IH , d, J=11.2Hz) 3.69
(3H,s), 3.76 (3H,5)3-77
(3H, s) 3.88 (IH, dd, J=9.0°9.0Hz) 3.96 (LH, dcl, J=9.5°9, 5Hz
) 4.11 (IH, d, J=11.2Hz) 4.14
(LH, d, J=5.4Hz) 4.41 (IH,
ci, J=5.4Hz)4.71 (IH,s),
4.75 (IH, s) 4.84 (IH, s)
, 4.89 (IH,s)" C-NMR, (100
, 18Hz, CDCR3) δ: 15.3 (q)
, 15.7 (q), 17.8 (q), 18.3
(t), 19.2 (t).

21.7 (q), 23.3 (t), 23.8 (
t), 31.5 (t), 32.2 (t).

33.4 (s), 33.6 (q), 35. 1
(t), 37.0 (s), 37.7 (t).

38.2 (t), 38.8 (s), 39.2 (
t), 42.0 (t), 43.4 (d).

44.2 (d), 46.7 (d), 52. 1
(q), 52°3 (q), 54.8 (d).

55, 1 (d), 55.7 (d), 67.6
(D, 68.4 (t), 71.1 (t).

76, 9 (d), 78.8 (d).

107.7 (D, 108.2 (t).

146.2 (s), 146.8 (s).

170.7 (s), 171. 1 (s).

178.2 (s), 178.7 (s) Elemental analysis value (as C4s Hs a Or 4 ・H20) CH Theoretical value (%') 63.51 8.29 Calculated value (%
) 63.39 8.26 Compound B: mp238-241°C (decomposition), colorless needle-like crystals [α)D
=+39.85° (chloroform, C=0.78) I R (KB r, cm-'): ax 3450-2500 (OH), 1740 (-COOC
H3), 1725 (-COOH).

1645 (':;C=CH2), 1460°1438
．． 1375,1200.1130゜1035.1020
,982,885°' H-NMR (400MHz,
CD CQ 3 ) δ0.70 (6H,s) , 0
．． 75 (6H, s) 1.31 (2H, dd, J=
12.5°2.4Hz) 1.95 (4H, m), 2.22 (2H, m)2
．． 73 (2H, dd, J=16.8°6.4Hz) 3.01 (2H, dd, J=16.8°7.6Hz
) 3.02 (2H, d, J-11, 2Hz) 3.35
(2H, dd, J=8.8°2.2Hz) 3.58 (2H, ddd, J-7,6°6.4,3.
4Hz) 3.79 (6H, s) 4.00 (2H, d, J=3.4Hz) 4.14
(2H, dd, J=8.8°8.8Hz) 4.50 (2H, d, J=11.2Hz) 4.84
(2H,s) ,4,97 (2H,s)' 3
C-NMR (100,18Hz, CDCQ3)
δ: 15.6 (q), 17.9 (q)
, 18.4 (t), 23.2 (t), 32.4
(t).

35.6 (t), 37.3 (t), 38.4 (
s), 39. 1 (t), 44.6 (d).

46.8 (d), 51.9 (q), 56.7 (
d), 69.3 (t), 71.3 (t).

78.6 (d), 108.7 (t).

146.4 (s), 169.3 (s).

171, 0 (s), 177.2 (s) Elemental analysis value (as C44Hs 40+ 4) CH Theoretical value (%') 64,68 7.90 Calculated value (%
) 64,39 7.87 Compound C: mp 113-115°C, white powder [α]Dmi+64.80° (Chloroform, C=1.
14) I R (KB r,!/cm-'): ax 3400~2450 (OH), 1760°1740
．． 1730 (-COOCH3).

1715 (-COOH), 1645 (C=CH2
), 1205,1120°1030.1010,880
,745 years H-NMR (400MHz, CDCQ a
) 6:0.71 (3H,s), 0.72
(3H, s) 0.76 (3H, s) , 0.81
(3H, s) 0.87 (3H, s) , 3.76
(3H, s) 3.77 (3H, s) , 4.72 (
IH, s) 4.79 (IH, s), 4.86 (I
H, s) 4.90 (IH, s) Elemental analysis value (as C4a H6s Or 4 ・H20) CH Theoretical value (%) 63.14 8.19 Calculated value (%)
62,98 8.06 Compound D: mp85-88°C, white powder [α)o = +42.57° (chloroform, C=1
．． 01) IR (KBr, ν cm-'): IIax 3450-2450 (OH), 1740 (-COOC
H3), 1715 (-COOH).

1645 (:;C=CH2), 1440°1205.
1165,1130,1035゜885.750' HNMR (400MHz, CDCQ3) δ: 0.7
1 (3H, s), 0.76 (6H, s) 0.77
(3H, s) , 1.82 (IH, m) 1.95
(2H, m) , 2.00 (IH, m) 2.37 (
2H, m) 2.64 (LH, dd, J=17.6°2.4Hz) 2.82 (2H, dd, J=17.6°9, 3Hz
) 2.97 (IH, dd, J=17.6°3,
2Hz) 3, 10 (IH, d, J=11.0Hz) 3
．． 41 (IH, d, J=11.0Hz) 3.52
(LH, dd, J=10.0°3.2Hz) 3.58 (IH, dd, J=9.5°3,
2Hz) 3.62 (IH, d, J=11.0Hz)3.
89 (IH, dd, J=9.5゜9, 5H
z) 3.96 (IH, dd, J=10.0°10,
0Hz) 4, 10 (IH, d, J=11.0Hz) 4
, 14 (2H, d, J=5.4Hz)4,
72 (IH,s), 4. 75 (LH,s
)4.85 (IH,s), 4.89 (IH,
s)” C-NMR (100, 18Hz, CDCQ
3) δ: 15.8 (q), 17.6 (
q), 18.3 (t), 18.6 (t), 23.4
(t).

23.6 (t), 31.6 (t), 32.2 (
t), 35.3 (t), 37.0 (t).

37.3 (t), 37.7 (s), 37.9 (
s), 38.3 (t), 38.7 (t).

38.6 (s), 43.5 (d), 44.3 (
d), 46.8 (d), 48.2 (d).

52.1 (q), 52.3 (q), 54.8 (
d), 55.7 (d), 67.7 (t).

68.4 (t), 71.2 (t), 72.0 (
t), 77.3 (d), 78.8 (d).

108.0 (t), 108.3 (t).

146.3 (s), 146.6 (s).

170.7 (s), 171.1 (s).

177.9 (s), 178.4 (s) Elemental analysis value (as Ca 5H6s O+ 5) CH Theoretical value (%) 63,86 8.09 Calculated value (%”
) 63,66 8.07 Compound E: mpHO ~ 114°C, white powder [α)D = +40.51° (Chloroform, C = 0
．． 98) IR (KB r, cm-'): ax 3450~2400 (OH), 2940°1755.
1740.1725 (-COOCH3), 1710 (C00H) 1645
(/C=CH2), 1440°1205.1125,
1030,1000°880.750' HNMR (400MHz, CDCQ3) δ: 0.7
1 (3H, s) , 0.75 (3H, s) 0.76
(6H, s), 1.90 (IH, m) 1.95
(2H, m), 1.99 (IH, m)2. 3
6 (2H, m) 2.64 (IH, dd, J=17.6°2, 9H
z) 2.80 (2H, dd, J=17.6°8.3Hz) 2.82 (IH, dd, J=17.6°2, 9H
z) 3.09 (IH, d, J=11.0Hz) 3.43
(IH, d, J=11.0Hz) 3.45 (2H
, m) 3.60 (2H, dd, J=9.8°3.2Hz) 3.61 (IH, d, J=11.2Hz) 3.76
(3H, s) , 3.77 (3H, s) 3.91
(IH, dd, J=9.5°9, 5Hz) 3.98 (IH, dd, J=9.8°9, 8Hz) 4.05 (LH, d, J-11,2Hz) 4.14
(IH, d, J=4.9Hz) 4.27 (
IH, d, J=4.9Hz) 4.74 (2H=
s) s 4.86 (L Hl s) 4.89
(IH, S) Elemental analysis value (as Cat H66015'H20)C
H Theoretical value (%) 61.96 8.04 Calculated value (%") 61,78 8.01 Example 2 Anhydrous potassium carbonate (2 g) and iodine were added to a solution of compound A (334 mg) in anhydrous acetone (10 mQ). Methyl chloride (2
The mixture was heated under reflux for 1 hour. The reaction solution was suction filtered, and the synovial fluid was concentrated under reduced pressure to obtain a residue (396 mg).

The residue was applied to silica gel (manufactured by Merck & Co., Ltd., 70-230 mesh, 30 g) column chromatography, eluted with 20% ethyl acetate-n-hexane, the eluate was concentrated under reduced pressure, and R
1 is a hydrogen atom, R2 and R3 are methyl groups, R4 is =CH
2 (hereinafter referred to as "compound F") (319 mg) was obtained as a colorless oil.

[α) p = +49- 53° (taloloform, C =
0.95) to IR, ν c"1): ax 2950.1760, 1745.1735 (-COOC
H3) , 1645 (,C=CH2) 1435.1
235,1200,1160゜1130.1040,8
90,750 M5: m/z 860 (M”), 641°62
6.611,247,235,219゜189.173
, 161, 137, 119°95.81, 69, 55.
41′ HNMR (400MHz, CDCQ 3) δ; 0.
72 (3H, s), 0.76 (3H, s) 0.8
0 (3H,s), 0.81 (3H,s)0.
87 (3H, s), 1.93 (IH, m)
2.01 (IH, m), 2.04 (2H, m
)2.35 (2H, m), 2.56 (IH, dd, J=17..1°5.
0Hz) 2, 57 (IH, dd, J=17.1°5
, IHz) 2.77 (IH, dd, J=17.1°10, 3
Hz) 2.79 (IH, dd, J=17.1°9, 5H
z) 3.43 (LH, m), 3.45 (LH, m
)3.53 (2H, dd, J=8.8°4,
9Hz) 3.65 (IH, d, J=11.2Hz)3.
67 (3H,s), 3.68 (3H,s)3
, 69 (3H,s), 3. 75 (3H
,s) 3, 76 (3H,s) 3.86 (IH,d, J=11.2Hz)3.
91 (2H, dd, J=8.8°8.8Hz) 4.11 (IH, d, J=4.9Hz) 4.12
(IH, d, J=4.9Hz) 4.77 (2H,
s), 4.85 (2H,s)” CNMR(1
00,18Hz, CDCQa) δ:15.3
(q), 15.7 (q), 17.5 (q), 18.
4 (t), 19.2 (t).

21.8 (q), 23.7 (t), 23.8 (t)
, 31.7 (t), 32. O(D.

33.5 (s), 33.7 (q), 35.6 (t
), 36.8 (s), 37.2 (t).

37.6 (t), 38.5 (t), 38.5 (
s), 38.7 (s), 39.2 (t).

42.0 (t), 44.4 (d), 44.6 (
d), 48.7 (d), 51.8 (q).

52.0 (q), 52. 1 (q), 52.2
(q), 55. 1 (d), 55. 5 (
d).

55.7 (d), 68.2 (t), 68.3 (
t), 73.6 (t), 78. 5(d).

78.6 (d), 108.0 (t).

108.2 (t), 146.3 (s).

146.6 (s), 170.8 (s).

171.2 (s), 172. 1 (s) Example 3 A solution of compound A (51 mg) in anhydrous diethyl ether (51 mg)
mf2) was added with a diethyl ether solution (1 decomposition) of diazomethane prepared with N-nitromethylurea and 50% potassium hydroxide under water cooling, and left for 30 minutes. Acetic acid (0.5 mf2) was added to the reaction solution to decompose excess diazomethane, and the solvent was distilled off under reduced pressure to obtain Compound F (52 mg) as a colorless oil.

Example 4 Compound B (660 mg) in diethyl ether solution (3
A diethyl ether solution of diazomethane (15 mQ) was added to the solution (15 mQ) under ice-cooling, and the mixture was allowed to stand for 30 minutes. Following treatment in the same manner as in Example 3, a compound of general formula (1) (hereinafter referred to as "compound G") in which R2 is a methyl group, R4 is =CH2, and R+ and R3 combine to form a single bond ( 6
53 mg) was obtained as a white powder.

mp175-177°C [α]p=+32.29° (Chloroform, C=0.
96) I R(KB r, !/cm-'):ax 2950.1760,1740.1730(-COOC
H3), 1645 to C=CH2) 1435.1370
．． 1240.1200°1130.1090,1040
．． 1020°985.890,750 M5: m/z 844 (M”), 391°33
5.221,203. 173. 159°146,
133. 119. 107,95°81.67.55
．． 41' HNMR (400MHz, CDCQ3) δ
:0.70 (6H, s), 0.75 (6H,
s) 1.30 (2H, dd, J=12.5°2.4Hz) 1.93 (2H, m), 1.95 (2H,
m) 2.21 (2H, m) 2, 65 (2H, dd, J=16.9゜6
, IHz) 2, 99 (2H, dd, J=16.9°8
, 3Hz) 3.09 (2H, d, J=11.2Hz)3.
55 (2H, ddd, J=8.3°6, 1,3.
”'/Hz) 3.73 (6H,s), 3.79 (6H,s
) 4, 01 (2H, d, J-3, 7Hz) 4
, 39 (2H, d, J=11.2Hz)4
．． 83 (2H,s), 4. 93 (2H,
s)'3C-NMR (100,18Hz, CDC
23) δ: 15.6 (q), 17.9
(q), 18.5 (t), 23.2 (t), 3
2.4 (t).

35, 5 (t), 37.0 (s), 37.5
(t), 38.5 (s), 39. 1 (t).

44.7 (d), 47.0 (d), 51.8 (
q), 51.9 (q), 56.5 (d).

69.4 (t), 71.2 (t), 78.7 (
d), 108.7 (t), 146. 5
(s) 169.6 (s), 171.0 (
s).

172, 1 (s) Elemental analysis value (as C4s H6s O+ a) CH Theoretical value (%') 65,38 8.11 Calculated value (%
) 65,06 8.01 Example 5 Compound D (500 mg) in diethyl ether solution (30
1rl12), add diazomethane solution (12mQ) under water cooling.
was added and left for 30 minutes. The following treatment is carried out in the same manner as in Example 3, R1 is a hydroxyl group, R2 and R3 are methyl groups, and R4
A compound of general formula (1) in which =CH2 (hereinafter referred to as "compound H") (495 mg) was obtained as a hygroscopic white powder.

mp87-89.5°C [α) D=+39.58° (Chloroform, C=0.
96) IR (KB r, !/am-'): ax 3550 (OH), 2950, 1760° 1745.
1735 (-COOCH3).

1645 (:;C=CH2), 1440°1250.
1205,1160.1130゜1040.1000,
890.750 M5: m/z 876 (M+), 262°205
．． 189,175,149,135゜109.95,8
3.47 H-NMR (400MHz, CDCQ 3
) δ: 0.75 (3H,s), 0.76
(6H, s) 0.81 (3H, s) , 2.00
(2H, m) 2.05 (2H, m) , 2.3
5 (2H, m)2.55 (LH, dd, J
=17. 1°4, 5Hz) 2.57 (IH, dd, J=17.1°4,
5Hz) 2.78 (2H, dd, J=17.1°8.
8Hz) 3.09 (IH, d, J=10.8Hz)3.
41 (IH, d, J=10.8Hz) 3.45
(2H, m) , 3.53 (2H, m) 3.6
4 (IH, d, J=11.2Hz) 3.68
(9H, s) , 3.75 (3H, s) 3.7
6 (3H, s) 3.86 (IH, d, J=11.2Hz) 3
．． 93 (2H, dd, J=9.3°9, 3Hz) 4.09 (IH, d, J=4.6Hz) 4,'
12 (IH, d, J = 4.9Hz) 4.76 (
IH, s) , 4.77 (IH, s) 4.85
(2H,s) ”C-NMR (100,18Hz, CD CQ
3) δ: 15.7 (q), 15.8 (q),
17.5 (q), 17.7 (q), 18.4 (t)
.

18.5 (t), 23.6 (t), 23°7 (t)
, 31.7 (t), 32.0 (t).

35.3 (t), 35.6 (t), 36.8 (
s), 37.2 (t), 37.3 (t).

37.9 (s), 38.5 (s), 38.6 (t)
, 38.7 (t), 44.4 (d).

44.6 (d), 48.1 (d), 48.8 (d
), 51.9 (q), 52.0 (q).

52.2 (q), 55.5 (d), 55.6 (d)
, 68.2 (t), 68.3 (t).

78.4 (d), 78. 6 (d).

108, 1 (t), 108.2 (t).

146.3 (s), 146. 5 (s).

170.8 (s), 171. 2 (s).

172, ], (s), 172. 2 (s)
Elemental analysis value (as C47R720+ 5) CH Theoretical value (%) 64.36 8.27 Calculated value (%)
64,21 8.03 Example 6 A diazomethane solution (1,51112) was added to a methanol solution (5 decomposition) of compound C (51 mg) under water cooling and left for 1 hour. The mixture was treated in the same manner as in Example 3 to obtain Compound F (52 mg) as a colorless oil.

Example 7 A diazomethane solution (2,0TIIQ) was added to a methanol solution (5-) of compound E (48 mg) under water cooling, and the mixture was allowed to stand for 1 hour. The mixture was treated in the same manner as in Example 3 to obtain Compound H (47 mg) as a white powder.

Example 8 Compound F (207 mg) in dichloromethane solution (20 m
Ozone was introduced into Q) at -78°C (dry ice-acetone) for 20 minutes. The reaction solution was mixed with zinc (5 g)-acetic acid (1
The mixture was added to a suspension of 0.0 decomposition) and stirred vigorously for 30 minutes. The reaction solution was suctioned and filtered, and the two-door solution was concentrated under reduced pressure to obtain a residue (201 m
g) was obtained. The residue was treated with silica gel (manufactured by Merck & Co., Ltd., 70
~230 meshes, 30g) subjected to column chromatography, 2
Elution with 096 ethyl acetate-chloroform and distillation of the eluate under reduced pressure yielded a compound of general formula (1) in which R1 is a hydrogen atom, R2 and R3 are methyl groups, and R4 is 10 (hereinafter referred to as "Compound I"). ) (161 mg) was obtained as a colorless oil.

[α) D=0.62” (chloroform, C=0
．． 61) IR (neat, ν cm”): ax 2950.1735 (-COO(, R3).

1710 c-o), 1435.1360°132
5.1200, 1160.1130°1040.995
,750 CD (dioxane): λ 275nmax ([θ)-6803; Δε-2,06)' H-NMR
(400MHz, CDCR3) δ: 0.74 (3H
,s) ,0.85 (6H,s)0.96 (3
H, s), 2.05 (2H, m) 2.41 (
2H, m) 2.40 (IH, dd, J=9.8°3.4H
z) 2.53 (IH, dd, J=9.8°3.4Hz) 2.58 (2H, dd, J=17.1°5, 1H
z) 2.78 (2H, dd, J=17.1°9,
3Hz) 3.42 (2H, ddd, J=9.3°5,
1,4.9Hz) 3.47 (2H, dd, J=9.8°3.4Hz) 3.57 (IH, d, J=11.0Hz) 3.68
(6H, s) , 3.69 (3H, s) 3.7
3 (3H, s), 3.75 (3H, s) 4.0
8 (IH, d, J=11.0Hz) 4, 10
(2H, dd, J=9.8°9.8Hz,) 4, 18 (LH, d, J=4.9Hz) C1
9 (IH, d, J=4.9Hz)” CNMR (
100,18Hz, CDCQ3) δ; 15.5
(q), 16.0 (q), 17.5 (Q)
, 17.9 (t), 18.8 (t).

21.6 (q), 23.3 (t), 23.6 (
D, 31.7 (t), 32.0 (t).

33.4 (s), 33.5 (Q), 37.0 (
s), 38.4 (t), 39.1 (t).

41.4 (t), 41.8 (t), 41.6 (
s), 41.9 (s), 44.2 (d).

44.3 (d), 46°6 (d), 51.8 (
q), 51.9 (q), 52.0 (q).

52, 1 (q), 63.4 (d), 63.7
(d), 65.8 (t), 65.9 (t).

79.2 (d), 79. 3 (d).

170.7 (s), 170.9 (s).

171.2 (s), 172.0 (s).

172, 1 (s), 210. 1 (s).

210, 2 (s) Example 9 Compound G (133ωg) in dichloromethane solution (201
+112), ozone was introduced for 30 minutes at -78°C.

The reaction solution was added to a suspension of zinc (5 g) and acetic acid (10 mQ), and the mixture was vigorously stirred for 2 hours. The reaction solution was suction filtered, and the filtrate solution was concentrated under reduced pressure to obtain a residue (128D). When this product is recrystallized from ethyl acetate, a compound of the general formula (1) (hereinafter referred to as "compound J") in which R2 is a methyl group, R4 is 10, and R1 and R3 combine to form a single bond is obtained ( 108m
g) was obtained as colorless prismatic crystals.

mp213.5-215°C [α) D=-40,82° (Chloroform, C=0.
83) IR(KB r, !/cm-'): aX 2850.1760, 1750.1740(-COOC
H3), 1710 (:l;C-0).

1460.1435.1260.1240°1200.
1130.985 M5: m/z 848 (M+), 833°78
9.645,628,441,425°407.221
,204,189,148°135.107,95.8
1,67.55CD (dioxane): λ 276n
mIIax ([θ)-1876; Δε-0,57)' H-N
MR (400MHz, CD CQ3)
δ; 0.68 (6H,s), 0.76 (
6H, s) 1.52 (2H, dd, J=13.
2゜4.4Hz) 2.26 (2H, m), 2.72 (2H, m
)2.63 (2H, dd, J=16.6°6,
3Hz) 2.83 (2H, dd, J=4.5゜2, 9Hz
) 3.01 (2H, dd, J=16.6°8.8
Hz) 3.58 (2H, ddd, J=8.8°6.3
, 2.9Hz) 3.59 (2H, d, J=11.2Hz)3.
82 (2H, dd, J=11.7゜2, 9H
z) 4.02 (2H, dd, J=11.7°4,
5Hz) 4,゛ 12 (2H, d, J=11.2Hz)4.
36 (2H, d, J=2.9Hz)' 3C-NM
R (100,18Hz, CDCQ3) δ: 15.8
(q), 17.6 (q), 18.2 (t)
, 23.5 (t), 33.5 (t).

35.2 (t), 38.8 (t), 42.0 (
t), 44. 1 (d), 45.6 (d).

51.8 (q), 64.2 (d), 68.2 (
t), 70.6 (t), 170.3 (s)
.

171.0 (s), 171.8 (s).

212.2 (s) Elemental analysis value (as C44Ha 40+ s) CH Theoretical value (%) 62.25 7.60 Calculated value (%)
61.96 7.41 Example 10 Compound H (355 mg) was dissolved in pyridine (5TIII2), then acetic anhydride (5 times) was added and the mixture was left at room temperature overnight. The reaction solution was poured into ice water and extracted with chloroform. The chloroform layer was washed successively with IN-hydrochloric acid, water, 5% aqueous sodium bicarbonate solution, and water, and then dried over magnesium sulfate. When the solvent is distilled off under reduced pressure, a compound of general formula (1) (hereinafter referred to as "compound K") (3
57 mg) was obtained as a colorless oil.

[α) D = +42.81° (Chloroform, C = 1
．． 93) IR-t,)/cm-') :l! 1ax 2950.1735.1745 (-Coo-)164
5 (, l; C=CH2), 1435°1375.13
60,1235,1200°1160.1125.10
35,1000°890.750' H-NMR (400MHz, CD
CQ3) δ:0.76 (6H,s),
0.81 (3H, s) 0.83 (3H, s)
, 1.99 (4H, m) 2.08 (3H, s)
, 2.35 (2H, m)2, 57 (2H,
dd, J=17.3°4, 9Hz) 2.77 (2H, dd, J=17.3°9,
3Hz) 3.43 (IH, dd, J=9.3°4, 6
Hz) 3.48 (2H, dd, J=9.3°4, 6
Hz) 3,53 (2H,m) 3.63 (IH,d, J-10,8Hz)3.
67 (LH, d, J=10.8Hz) 3.68
(6H, s) , 3.69 (3H, s) 3.7
5 (3H,s), 3.76 (3H,s)3.
88 (IH, dd, J=9. 3゜9, 3H
z) 3.92 (IH, dd, J=9.3°9, 3
Hz) 4, 11 (IH, d, J=4.9Hz) 4,
12 (IH, d, J=5.4Hz) 4.76
(IH, s) , 4.78 (IH, s) 4.85
(2H,s)” C-NMR (100,18Hz, CDCQ3)
δ: 15.6 (q), 17.3 (q), 17.4
! (q), 18.2 (t), 20.7 (
q), 123.5 (t), 31.5 (
t), 31.8 (t), 35.6 (t), 36.6
(s).

37.1 (t), 38.4 (t), 44.3
1(d), 44.5(d), 48.6(d)
.

48.8 (d), 51.6 (q), 51.7 (
q), 51.9 (q), 55.3 (d).

55.6 (d), 68. 1 (t), 72.5
(t), 73.4 (t), 78. 5(d).

108.0 (t), 146.0 (s).

146, 1 (s), 170.5 (s).

170.8 (s), 170.9 (s).

171.8 (S) Large Example 11 Compound K (357a+g) in dichloromethane solution (20
1n12), ozone was introduced at -78°C for 30 minutes.

The reaction solution was added to a suspension of zinc (5 g)-acetic acid (101rl12) and stirred vigorously for 2 hours. The reaction solution was filtered under reduced pressure, and the filtrate solution was concentrated under reduced pressure to obtain a residue (368 mg). The residue was applied to a silica gel (manufactured by Merck, 70-230 mesh, 50 g) column chromatography, and 20% ethyl acetate-
Elute with chloroform and evaporate the eluate under reduced pressure.
R1 is an acetyloxy group, R2 and R3 are methyl groups, R
A compound of general formula (1) in which 4 is =0 (hereinafter referred to as "compound L
) (267 mg) was obtained as a colorless oil.

[α]p=+5.81' (chloroform, C=2.
06) IR (NEET, cL11-1): l1aX 2950, 1760. 1740. 1735, (-
COO-), 1715 (':, c=o).

1435, 1380. 1360. 1240°12
00, 1160. 1130. 1040°1000
．． 840,750 CD (dioxane); λ 275nmax ([θ] -6196; Δε-1,88) Sodium H-
NMR (400MHz, CDC(23) δ:
0.79 (6H,s), 0.85 (3H,s
)0.87 (3H,s), 1.96 (2H,
m) 2, 11 (3H,s), 2.39 (2
H, m) 2.48 (LH, m), 2.54 (
2H, m) 2, 59 (1) (, m) 2.78 (LH, dd, J=17.3°9,
5Hz) 2.81 (IH, dd, J=17.3°7,
1Hz) 3, 42 (IH, dd, J=9.6°4,
7Hz) 3.47 (LH, dd, J=9.8°4, 9Hz
) 3.51 (2H, m) 3.56 (IH, d, J=11.0Hz) 3.
68 (3H,s), 3.69 (6H,s)3.
74 (3H,s), 3.76 (3H,s)3
．． 95 (LH, d, J=11.0Hz) 4.0
8 (2H, m) 4.19 (LH, d, J=4.9Hz) 4.21
(IH, d, J=3.7Hz)” CNMR (10
0.18Hz, CDCQ3) δ:16.0 (q)
, 17.5 (q), 17.6 (q), 17°9 (t
), 18.0 (t).

21.0 (q), 23.4 (t), 31.8 (t
), 32.0 (t), 35. 5 (t).

35, 7 (t), 36.9 (s),
37. 0 (s), 38.4 (t), 38.6
(t).

41.4 (t), 41.6 (t), 41. 7
(s), 44.2 (d), 44.4 (d).

46, 6(d), 47. 5 (d), 5
1. 9 (q), 52.1 (q), 52.2 (
q).

63.5 (d), 63.8 (d), 65.9 (
t), 72.2 (t), 72.7 (t).

79.3 (d), 79.4 (d).

170.7 (s), 170.9 (s).

171.0 (s), 171.2 (s).

172, 1 (s), 209.7 (s).

210, 1 (s) <Pharmacological Test 1> Peritoneal macrophages were collected 96 hours after intraperitoneal administration of mineral oil.

02- was measured using cytochrome C reduction method CT.

Matsumoto, Takeshige and
S, Minakami.

Biochemical and Blophysics
al Research Communications
, 88 (3), 974-979 (1979))
The following procedure was carried out according to the following. That is, macrophages were added to a final concentration of 2×10 6 to 80 μM cytochrome C solution, and the test compound or water (control group) was added, followed by incubation at 37° C. for 1 minute. 02
~As a stimulant, F M L P (Formylme
thlonylLeueylPhenylalani
ne) was added to give a final concentration of 10-7 M, and the reaction was further allowed to proceed for 1 minute. During this period, the difference in absorbance at 0D550 was measured and compared to the control group to calculate ■C5o. The results are shown in Table 1 below.

Table 1 Pharmacological Test 2 Rabbit neutrophils (PMNs) collect blood from Ficoll (Ficoll).
col I) solution (specific gravity 1.077), was obtained by centrifugation at 1500 rpm for 25 minutes, and was prepared by washing with Hank's solution (Hank's 5 solution).

02- was measured using the cytochrome C reduction method (T.

Matsumoto, Takeshige and
S, Minakami.

Biochemical and Biophysics
alRe5earchCoaunification
s, 88 (3), 974-979 (1979
)) was carried out as follows. That is, to a 50 μM cytochrome C solution, add PMN to a final concentration of 2 x 106, further add the test compound or water (control group),
Breincubate for 37 minutes. Next, 5 μg of cytochalasin B
/ynQ, concanavalin
) A was added at 100 μg/IQ and reacted for 1 minute. The absorbance difference at 0D55° during this time was measured, and the engineering C5o was calculated as a ratio to the control group. The results are shown in Table 2 below.

Table 2 Formulation Example 1 Compound A 5mg starch 132mg magnesium stearate 18 [IIg lactose
45mg total
200B A tablet having the above composition was manufactured by a conventional method.

Formulation Example 2 Compound D 200mg Glucose 250B Distilled Water for Injection
51112 After dissolving the compound and glucose in distilled water for injection 5
The mixture was injected into an ampoule of Irl12, and after purging with nitrogen, autoclaving was performed at 121° C. for 15 minutes to obtain an injection having the above composition.

[Brief explanation of the drawing]

Figure 1 is an NMR spectrum diagram of Compound A obtained in Example 1, Figure 2 is an NMR spectrum diagram of Compound B obtained in Example 1, and Figure 3 is an NMR spectrum diagram of Compound C obtained in Example 1.
MR spectrum diagram; FIG. 4 is an NMR spectrum diagram of Compound E obtained in Example 1; FIG. 5 is an NMR spectrum diagram of Compound E obtained in Example 1. (that's all)

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ [In the formula, R^1 represents a hydrogen atom, a hydroxyl group, or a lower alkanoyloxy group. R^2 represents a hydrogen atom or a lower alkyl group. R^3 represents a hydrogen atom or a lower alkyl group. R^4 represents a group=CH_2 or an oxygen atom. Also R^1
and R^3 may be combined to represent a single bond. ] Doliman-type sesquiterpene carboxylic acid derivatives and salts thereof.