JPH06263688A - Phenanthrene derivative - Google Patents

Abstract

PURPOSE:To provide a new compound useful for treating and preventing chronic inflammatory diseases such as chronic articular rheumatism as an interleukin- inhibiting agent. CONSTITUTION:A compound of formula I (R<1>, R<4> are lower alkyl; R<2> is formyl; R<3> is hydroxy; or R<2> and R<3> form an oxo; R<5> is H, hydroxy lower alkyl, etc.; R<6> is H, or R<6> and R<5> form a double bond; R<7> is H, lower alkyl; but when R us lover alkyl, R us not hydroxymethyl), for example, 5,8-dimethoxy-1,4a- dimethyl-7-(1-methylethyl)-4,4a,9,10-tetrahydro-2(3H)-phenanthrenone. The compound is obtained e.g. by oxidizing a compound of formula II (R<2>' is R<2>, carboxyl, etc.; R<5>' is R<5>, formyl, etc.; R<7a> is lower alkyl; R<8a> is lower alkoxy; R<12> is H, OH) with an oxidizing agent such as chromic anhydride in an inert solvent such as DMF. The compound of formula II is a new substance and is extracted and isolated from e.g. Tripterygium wilfordii.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel phenanthrene derivative, more specifically interleukin-1 (IL-
The present invention relates to a novel derivative having the inhibitory activity of 1) and useful as an IL-1 inhibitor.

[0002]

2. Description of the Related Art The phenanthrene derivative of the present invention is a novel compound which has not been published in the literature.

At the 2nd International Lymphokine Workshop, the Lymphocyte Activator
ting Factor; LAF), mitogenic protein (Mitog
enicProtein), Helper peak-1
, T-cell replacing factor III
(TRF-III), T-cell replacing factor M φ (TRFM)], B
B-cell Activati
ng factor), B lymphocyte differentiation factor (B-cell differentiat
It has been determined that all physiologically active substances that have been reported under the names such as ion factor) are unified under the name of interleukin 1 (IL-1) [Cellular Immunol. , 48,
433-436 (1979)]. This determination is based on the reason that the above-mentioned physiologically active substances are indistinguishable as substances and merely represent physiological activities by grasping them from different angles.

IL-1 is known as an important biological substance that induces and transmits a systemic biological reaction to, for example, infection and inflammation, and has a strong antitumor activity itself [Hirai Y. et al., "Gann Monograph on Ca
ncer Research ", Japan Scientific Societies Press,
Tokyo (1988)], but at the same time, fever, increase in white blood cell count, activation of lymphocytes, induction of acute phase protein biosynthesis in the liver, etc.
It has been found to induce a reaction found in the body during inflammation [Dinarello CA: Interleukin-1; Rev. Infect.
Dis., 6, 51-95 (1984), Kluger, MJ, Oppenheim, JJ &
Powanda, M, C. The Physiologic, Metabolic and Immuno
logic Actions of interleukin-1, Alan R. Liss, Inc, New
York (1985)].

The biological effects of IL-1 are diverse,
It is considered to be an important biological substance for maintaining homeostasis in the living body.
When an abnormality occurs in the L-1 production regulation function, IL-1 production is enhanced, and excessive production occurs, it is considered to cause various diseases. For example, in rheumatoid arthritis, it is reported that there is a strong correlation between the degree of inflammation of the synovial membrane, the degree of bone destruction, and the expression level of the HLA-DR antigen in the synovial tissue. [Miyasaki, N., Sato.K., Got
o, M.Sasano, M., Natsuyama, M., Inoue, K.and Nishioka,
K., Augmented interleukin-1 production and HLA-DR e
xpression in thesynovium of rheumatoid arthritis p
atient Arthritis Rheum, 31 ,, (4), 480-486 (1988)]. Therefore, if excessive IL-1 release from cells is inhibited, IL
It is thought that various physiological actions of -1 can be blocked.

[0006] Currently, glucocorticoid hormone is used as a therapeutic agent for chronic inflammatory diseases, and it is known that a part of its action is suppression of IL-1 production.
[Lew, W., Oppenheim, JJ & Matsushima, k., Analysis of
the suppression of IL- 1α and IL- 1β production i
n human peripheral blood mononuclear adherent cell
s by a glucocorticoid hormone, J. Immunol., 140 (6), 1
895-1902 (1988)], but the glucocorticoid has a disadvantage of causing various serious side effects due to its various physiological actions. Therefore, in the present field, there is no side effect as seen in glucocorticoids, and a new substance that is highly safe in terms of other toxicity and side effects and has high selectivity is desired especially in the therapeutic field of chronic inflammatory diseases. It is in.

[0007]

DISCLOSURE OF THE INVENTION An object of the present invention is to provide a new substance useful as an IL-1 inhibitor which meets the above-mentioned demands of the art.

Further, the present invention aims at providing an intermediate for producing the above-mentioned useful substance.

[0009]

According to the present invention, there is provided a phenanthrene derivative represented by the following general formula (1).

[0010]

[Chemical 4]

[Wherein R ¹ is a lower alkyl group, R ² is a formyl group, R ³ is a hydroxy group, or R ^{2 is}
And R ³ represent an oxo group, and R ³ may bond to R ⁵ described later to form a double bond. R ⁴ is a lower alkyl group, R ⁵ is a hydrogen atom, a hydroxy lower alkyl group or R ³ or R ³ or R ⁶ described later to form a double bond, and R ⁶ is a hydrogen atom or R ⁵ to each other. To form a double bond, and R ⁷ represents a hydrogen atom or a lower alkyl group, respectively. However, when R ⁷ is a lower alkyl group, R ^7
5 is not a hydroxymethyl group. Further, according to the present invention, there is provided a phenanthrene derivative represented by the following general formula (2), which is useful as an intermediate for producing the compound of the general formula (1).

[0012]

[Chemical 5]

[In the formula, R ¹ , R ⁴ and R ⁷ are the same as defined above. R ^2a is a formyl group, a tri-lower alkylsilyloxy group, a trifluoromethylsulfonyloxy group or a group

[0014]

[Chemical 6]

(In the formula, R ¹⁰ represents a lower alkyl group.)
R ^3a represents a hydroxy group, or R ^2a and R ^{3a represent an} oxo group or a group R ¹⁰ O—CH═ (in the formula, R ¹⁰ is the same as the above), and R ^3a represents R described later. ^5a may be bonded to each other to form a double bond. R ^5a is bonded to a hydrogen atom, a hydroxy lower alkyl group or R ^3a or R ^6a described below to form a double bond, and R ^6a is bonded to a hydrogen atom or R ^5a to form a double bond, R ⁸ represents a hydrogen atom or a lower alkoxy group, and R ⁹ represents a lower alkyl group. However, when R ⁷ is a lower alkyl group, R ^5a is not a hydroxymethyl group, and when R ⁷ and R ⁸ are simultaneously hydrogen atoms, R ^{5a and} R ^6a are bonded to each other to form a double bond. I will not do it. Specific examples of the groups of the general formulas (1) and (2) include the following groups. That is, examples of the lower alkyl group include linear or branched lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl groups.

Examples of the hydroxy lower alkyl group include hydroxymethyl, 1-hydroxyethyl, 1-hydroxypropyl, 1-hydroxybutyl, 1-hydroxypentyl and 1-hydroxyhexyl groups.

Examples of the tri-lower alkylsilyloxy group include trimethylsilyloxy, triethylsilyloxy, tripropylsilyloxy, tributylsilyloxy, tritert-butylsilyloxy, tripentylsilyloxy, trihexylsilyloxy groups and the like. .

Examples of the lower alkoxy group include linear or branched lower alkyl groups such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentyloxy and hexyloxy groups.

The phenanthrene derivative of the present invention can be produced by various methods. A specific example is shown in the following reaction process formula.

[Reaction Process Formula-1]

[0021]

[Chemical 7]

[Wherein R ¹ , R ³ , R ⁴ , R ⁶ and R ⁹
Is the same as above. R ^{2 ′} is the same as R ² or is a hydrogen atom, a carboxyl group, a lower alkoxycarbonyl group,
A hydroxyl group or a lower alkanoyloxy group is shown. R ^{5 '}
Is the same as R ⁵ or represents a formyl group, a carboxyl group or a lower alkanoyloxymethyl group.
R ^7a is a lower alkyl group, R ^8a is a lower alkoxy group,
R ¹² represents a hydrogen atom or a hydroxyl group. In the above, examples of the lower alkanoyl group such as the lower alkanoyloxy group and the lower alkanoyloxymethyl group include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, hexanoyl groups and the like.
The linear or branched alkanoyl group of 6 can be exemplified.

Compound (2a) shown in the above reaction process formula-1
The oxidation reaction of is carried out in an inert solvent such as acetonitrile, dichloromethane, N, N-dimethylformamide (DMF) or the like, with the addition of ceric ammonium nitrate [(NH
₄ ) ₂ Ce (NO ₃ ) ₆ ] (hereinafter abbreviated as CAN), chromic anhydride or the like can be used. The amount of the above-mentioned oxidizing agent to be used may be about 1 to 3 times the molar amount of the compound (2a), and the reaction is generally completed at a temperature of about 0 to 50 ° C. for about 10 minutes to 3 hours. Thus, the target compound (1a) is obtained.

[Reaction Process Formula-2]

[0025]

[Chemical 8]

[In the formula, R ¹ , R ⁴ and R ⁹ are the same as defined above. R ^5b represents a hydroxy lower alkyl group. The dealkylation reaction of the compound (2b) shown in the above-mentioned reaction process formula-2 is carried out by reacting the compound (2b) in an inert solvent such as tetrahydrofuran (THF), acetonitrile and dichloromethane.
It is carried out by treating b) with a dealkylating agent such as boron tribromide, anhydrous ammonium chloride, hydrobromic acid and the like. The amount of the dealkylating agent used is the compound (2
The amount is usually 1 to 3 times the molar amount of b), and the reaction is generally carried out at a temperature of about -78 ° C to 50 ° C for about 30 minutes to 5 hours.

Next, the target compound (1b) can be obtained by oxidizing the compound (3) obtained above. The oxidation reaction is carried out in an inert solvent such as ethanol or dichloromethane by using, for example, potassium dinitrosulfonate, potassium nitrosodisulfonate, chromic acid or the like as an oxidizing agent, usually about 1 to 3 times the molar amount of the compound (3). It is carried out for about 5 to 20 hours under a temperature condition of about 0 to 50 ° C., using an additive such as dipotassium hydrogen phosphate if necessary.

The compounds (2a) and (2b) used as starting materials in the above reaction process formulas-1 and 2
Are novel compounds, and some of them are clozzle (Tripterygium wilfordii Hookfil var.
egelii Makino) or by isolation or by subsequent suitable chemical treatment. Further, the respective compounds [compound (2c) to compound (2f)] belonging to the above compound (2a) and compound (2b) can be produced according to the methods shown in the respective reaction process formulas below.

[Reaction process formula-3]

[0030]

[Chemical 9]

[0031]

[Chemical 10]

[In the formula, R ¹ , R ⁴ , R ^7a , R ^8a , R ⁹ and R ¹⁰ are the same as defined above. Ph represents a phenyl group. R ¹¹ represents a lower alkyl group, X represents a halogen atom, and the broken line represents the presence of one double bond. ] The above compound (4)
In the halogenation reaction of, a halogenating agent such as N-bromosuccinimide (NBS) or bromine is used in an inert solvent such as DMF or chloroform in an amount of about 1 to 1.5 times the molar amount of the compound (4). 1 to 20 at a temperature condition of about 0 to 50 ° C.
It will take about time.

The obtained compound (5) is converted to the compound (6) by alkylating it. The alkylation reaction is carried out without solvent or in a suitable inert solvent such as diethyl ether or acetone in the presence of a deoxidizing agent such as an aqueous solution of potassium hydroxide or potassium carbonate, if necessary, with dimethyl sulfate, diazomethane or iodination. The reaction is carried out using an alkylating agent such as methyl, and the reaction is carried out at a temperature of about 0 to 30 ° C for 30 minutes to
It will be completed in about 2 hours.

Subsequently, the conversion reaction of the compound (6) into the compound (7) is carried out in an inert solvent such as DMF and methanol.
It is carried out by using a lower metal alkoxide such as sodium methoxide or sodium ethoxide in the presence of copper (I) iodide. The reaction conditions are about 50 to 10
A temperature of 0 ° C. for about 30 minutes to 5 hours is adopted.

Next, the reduction reaction of the compound (7) is carried out by treating it with an alkali metal, preferably sodium metal, in a solvent such as methanol, ethanol or liquid ammonia at a temperature of about 30 to 80 ° C. for 10 minutes to 1 hour. It is carried out by.

The compound (8) thus obtained is converted to the compound (9) by hydrolysis with an acid such as oxalic acid or hydrochloric acid in an inert solvent such as methanol or ethanol. The reaction is completed in 5 to 24 hours at a temperature of about 50 to 80 ° C.

Subsequently, the compound (9) is treated with an alkyl halide such as methyl iodide or ethyl iodide in the presence of an amine such as pyrrolidine or piperidine in an inert solvent such as benzene, dioxane or toluene. , Is converted to the alkylated compound (10). More preferably, first, the compound (9) is reacted with the above amine in the above inert solvent at a temperature of 20 to 50 ° C. for 3 to 6 hours, and then the above alkyl halide is added to the reaction mixture to about 50 to 80 ° C.
The reaction is carried out at the temperature of 10 to 50 hours.

The compound (10) can be converted to the target compound (2c) by performing a cyclization reaction with the vinyl ketone derivative (11). The cyclization reaction is carried out in an inert solvent such as methanol, ethanol or THF in the presence of a base such as an aqueous solution of potassium hydroxide or an aqueous solution of sodium hydroxide in an amount of 1 to 1.3 times the molar amount of the compound (10). It is carried out using the vinyl ketone derivative (11). The reaction is
It takes 5 to 15 hours under the temperature condition of about -30 to 30 ° C.

Further, the compound (2c) is the same as the compound (1
By reacting 2), the compound (2d) is converted. The reaction is carried out in the presence of an alkyllithium such as n-butyllithium and an amine such as diisopropylamine and diethylamine in an inert solvent such as THF and the compound (2
1 to 1.5 times the molar amount of compound (12) with respect to c), and 1 to 3 at a temperature condition of about -78 to -60 ° C.
Complete in time.

The compound (2d) obtained above is DM
The compound (2e) is converted by reduction with a hydride compound such as potassium hydride or sodium hydride in an inert solvent such as F, THF, or diethyl ether. The reduction reaction is carried out under the temperature condition of about -30 to 10 ° C.
It takes 0 minutes to 2 hours.

Then, the compound (2e) is hydrolyzed to obtain the compound (2f). The hydrolysis reaction is carried out using an acid such as oxalic acid aqueous solution and hydrochloric acid in an inert solvent such as methanol and ethanol. In addition, it is necessary to carry out the reaction in an inert gas atmosphere such as argon or nitrogen using the solvent and acid all degassed, and the reaction is carried out at a temperature condition of 50 ° C. to the boiling point of the solvent for 1 to 6 hours. Is completed.

The compound (2f) thus obtained can be obtained by subjecting the compound (2f) to a conventional oxidation reaction.
The aldehyde (CHO) group of f) is replaced with a carboxyl group (C
OOH), which results in R ^{2 '.}
A corresponding compound (2a) in which is a carboxyl group can be obtained.

[Reaction Process Formula-4]

[0044]

[Chemical 11]

[In the formula, R ¹ , R ⁴ and R ^7a are the same as defined above. R ^8b is the same as R ^8a or represents a lower alkanoyloxy group. R ^9b is the same as R ⁹ or represents a hydrogen atom or a lower alkanoyl group. R ^2b represents a tri-lower alkylsilyloxy group. According to the method shown in the above-mentioned reaction scheme-4, from the compound (2c), the compound (2
f), compound (2g), compound (2h) and compound (2
i) can be obtained.

That is, first, the compound (2c) is reduced to obtain the compound (2g). The reduction reaction is carried out by catalytic reduction with 1 mol of hydrogen in an inert solvent or by using an alkali metal such as metallic sodium or metallic lithium in liquid ammonia (Birch reduction).

Next, the conversion reaction to the compound (2h) is carried out by silylating the Birch reduction product of the compound (2c) in the state of the metal enolate obtained by removing ammonia without isolation. It can be carried out by carrying out a chemical reaction. The silylation reaction is carried out in an inert solvent such as THF or diethyl ale using a silylating agent such as trialkylsilyl chloride in the presence of a deoxidizing agent such as triethylamine or pyridine at a temperature of about -10 to 10 ° C. It takes about 10 minutes to 1 hour.

The resulting compound (2h) is treated in an inert solvent such as THF or ether in the presence of alkyllithium such as methyllithium or butyllithium at a temperature of -10 ° C to 30 ° C for 30 minutes to 1 hour. After that, N-phenyltrifluoromethanesulfonimide (PhNTf ₂ ) and about -78
By treating at a temperature of -10 ° C for 5 to 15 hours,
Converted to compound (2i).

Further, the compound (2i) can be synthesized by Stille et al.
t al.) method [J.Am.Chem.Soc., 108 (3) , 452 (1986)] The presence of on the basis of lithium chloride and tetrakis (triphenylphosphine) palladium _{[Pd (Ph 3 P) 4} ] Then, the compound (2f) can be converted by reacting with carbon monoxide and tin hydride such as tin butyl trihydride. The reaction temperature and time are about 30 to 60 ° C. and 15 to
About 60 hours is adopted for each.

[Reaction Process Formula-5]

[0051]

[Chemical 12]

[In the formula, R ¹ , R ⁴ , R ^7a , R ^8a , R ⁹ and R ¹⁰ are the same as defined above. ] The oxidation reaction of the compound (2e) shown in the above reaction scheme-5 is performed by the method of Schmidt et al.
m., 71 , 176 (1959)]. That is, DMF
In a water-containing inert solvent such as water, in the presence of oxygen (air), the compound (2e) is added to the complex of palladium (II) chloride and copper (II) chloride at a temperature of about 50 to 100 ° C. for 10 to 2
The compound (2j) can be obtained by acting for about 4 hours.

[Reaction Process Formula-6]

[0054]

[Chemical 13]

[Wherein R ¹ , R ^2b , R ⁴ , R ^5b and R ⁹
Is the same as above. The compound (2b) of the present invention can be obtained from the known compound (13) by the method shown in reaction scheme-6.

That is, the compound (13) is first reduced and then silylated to obtain the compound (14). The reduction reaction and the silylation reaction are carried out by the compound (2c) in reaction process formula-4.
The reduction reaction and the silylation reaction of can be performed in the same manner.

Then, the compound (15) is treated with an aldehyde such as formaldehyde gas in the presence of a desilylating agent such as tetrabutylammonium fluoride (TBAF) in an inert solvent such as THF and ether. Thus, the target compound (2b) can be obtained. The reaction is completed in about 10 minutes to 1 hour at a temperature of about −78 to 30 ° C.

The phenanthrene derivative of the present invention obtained by the method shown in each of the above reaction schemes can be isolated and purified by a conventional separation means. Examples of the means include adsorption chromatography, recrystallization, solvent distillation, precipitation, solvent extraction and the like.

The compounds of the present invention also include stereoisomers,
Optical isomers are naturally included.

[0060]

The phenanthrene derivative of the present invention represented by the general formula (1) has IL-1 inhibitory activity,
It is useful as an L-1 inhibitor for the treatment and prevention of chronic inflammatory diseases such as rheumatoid arthritis. Further, the phenanthrene derivative of the present invention represented by the general formula (2) is useful as a synthetic intermediate for the compound of the general formula (1).

[0061]

EXAMPLES In order to explain the present invention in more detail, production examples of the compounds of the present invention will be given below as Examples.

[0062]

Example 1 Preparation of 5,8-dimethoxy-1,4a-dimethyl-7- (1-methylethyl) -4,4a, 9,10-tetrahydro-2 (3H) -phenanthrenone 2-isopropyl- 5 g of 6-methoxy-1-naphthol
Was dissolved in 100 ml of DMF, and a solution of 4.03 g of N-bromosuccinimide in DMF (50 ml) was added under ice cooling.
The mixture was stirred under ice cooling for 3 hours. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform = 10: 5).
It was purified by 0: 1) to obtain 6.1 g of 4-bromo-2-isopropyl-6-methoxy-1-naphthol. Melting point: 81.5-83.5 ° C.

¹ H-NMR (δ: ppm) [CDC
l ₃ ]: 8.06 (1H, d, J = 8.8), 7.58 (1H, s), 7.41 (1H, d, J = 2.4), 7.16
(1H, dd, J = 8.8,2.4), 5.18 (1H, brs), 3.96 (3H, s), 3.20 (1H,
sept, J = 6.8), 1.33 (3H, d, J = 6.8).

Then, to 1.7 ml of water in which 956 mg of potassium hydroxide was dissolved, 1 g of the compound obtained above was added under ice cooling, 1.1 ml of dimethylsulfate was added, and the mixture was stirred for 45 minutes under ice cooling. After the reaction was completed, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform = 5: 100:
Purified in 2), 4-bromo-2-isopropyl-
1 g of 1,6-dimethoxynaphthalene was obtained. Melting point: 10
8 to 110 ° C.

¹ H-NMR (δ: ppm) [CDC
l ₃ ]: 7.99 (1H, d, J = 9.0), 7.65 (1H, s), 7.43 (1H, d, J = 2.3), 7.18
(1H, dd, J = 9.0,2.3), 3.95 (3H, s), 3.89 (3H, s), 3.50 (1H, se
pt, J = 7.3), 1.28 (6H, d, J = 7.3).

Then, 3 ml of methanol and 1.7 ml of DMF were added to 631 mg of sodium methoxide, and 559 mg of copper (I) iodide was added, and the mixture was heated to 90 ° C. There, 901 mg of DMF (1.
17 ml) solution was added dropwise and heated under reflux for 2 hours. After cooling, the insoluble solid matter was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform = 5: 100:
Purification in 2) yielded 700 mg of 2-isopropyl-1,4,6-trimethoxynaphthalene. Melting point: 80-
81.5 ° C.

¹ H-NMR (δ: ppm) [CDC
l ₃ ]: 7.93 (1H, d, J = 9.3), 7.48 (1H, d, J = 2.5), 7.16 (1H, dd, J = 9.
3,2.5), 6.67 (1H, s), 3.99 (3H, s), 3.92 (3H, s), 3.85 (3H,
s), 3.57 (1H, sept, J = 7.3), 1.29 (3H, d, J = 7.3).

16 g of the compound obtained above was dissolved in 100 ml of ethanol, and sodium metal 1 was added at 50-60 ° C.
0.3 g was added over 45 minutes. The mixture was refluxed for 30 minutes, 17 ml of ethanol was added to react excess metal sodium, and the mixture was allowed to cool. Water was added, the mixture was extracted with diethyl ether, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was dissolved in 170 ml of methanol, an aqueous solution (30 ml) of 7.3 g of oxalic acid was added, and the mixture was refluxed for 21 hours. After allowing to cool, water was added, the mixture was extracted with diethyl ether, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated.
The obtained crude product was purified by silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform = 20: 140: 3) to give 5,8-dimethoxy-6-isopropyl-3,4-. Dihydro-2
14.5 g (oil) of (1H) -naphthalenone was obtained.

¹ H-NMR (δ: ppm) [CDC
l ₃ ]: 6.64 (1H, s), 3.81 (3H, s), 3.70 (3H, s), 3.48 (2H, s), 3.36 (1
H, sept, J = 7.3), 3.11 (2H, dd, J = 7.3,6.8), 2.55 (2H, dd, J =
7.3, 6.8), 1.25 (6H, d, J = 7.3).

15.3 g of the compound obtained above was dissolved in 91 ml of benzene to prepare 1 of Molecular Sieves 3A.
2.6 g and 5.1 g of pyrrolidine were added and stirred at room temperature for 4.5 hours. The mixture is concentrated under reduced pressure and dioxane 100 is added.
ml and 90 g of methyl iodide were added and the mixture was refluxed for 45 hours.
Next, 45 ml of 5% hydrochloric acid was added and the mixture was refluxed for 3 hours. After allowing to cool, water was added, the mixture was extracted with diethyl ether, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product is purified by silica gel column chromatography (eluent ... diethyl ether: n-hexane: chloroform = 20: 140: 3),
5,8-dimethoxy-6-isopropyl-1-methyl-
3,4-Dihydro-2 (1H) -naphthalenone 11.5
g was obtained.

¹ H-NMR (δ: ppm) [CDC
l ₃ ]: 6.65 (1H, s), 3.81 (3H, s), 3.75 (1H, q, J = 7.3), 3.69 (3H, s),
3.36 (1H, sept, J = 6.8), 3.28 (1H, ddd, J = 16.0,6.3,3.7), 2.
91 (1H, ddd, J = 16.0,12.3,4.9), 2.73 (1H, ddd, J = 16.4,4.9,
3.7), 2.40 (1H, ddd, J = 16.4,12.3,6.3), 1.35 (3H, d, J = 7.
3), 1.27 (3H, d, J = 6.8), 1.23 (3H, d, J = 6.8).

An aqueous solution of 1.51 g of potassium hydroxide (4 m
1) was cooled to 0 ° C., 45 ml of methanol was added, and 6.3 g of the compound obtained above was added to methanol (9 ml).
The solution was added. The mixture was cooled to −20 ° C., 2 g of ethyl vinyl ketone was added, and the mixture was stirred at −20 ° C. for 1 hour and then at room temperature for 15 hours. After completion of the reaction, dilute hydrochloric acid was added to make the mixture acidic, water was further added, and the mixture was extracted with chloroform. The chloroform layer was washed with saturated brine, dried over magnesium sulfate and concentrated, and the resulting crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n
-Hexane: chloroform = 25: 125: 3) to obtain 4.7 g of the target compound.

Structure and physical properties of the obtained compound (melting point and
¹ H-NMR) is shown in Table 1.

[0074]

Example 2 2-hydroxy-5,8-dimethoxy-
1,4a-Dimethyl-7- (1-methylethyl) -2-
Preparation of (1-methoxy-1-diphenylphosphine oxidemethyl) -2,3,4,4a, 9,10-hexahydrophenanthrene THF in which 0.65 ml of diisopropylamine was dissolved
(13.5 ml) was cooled to −78 ° C., and 6.1 ml of a THF solution (1.6M) of n-butyllithium was added, and 25
Stir for minutes. THF in which 1.15 g of methoxymethyldiphenylphosphine oxide was dissolved at −78 ° C.
13.5 ml was added and it stirred at -78 degreeC for 25 minutes. 750 mg of the compound obtained in Example 1 in THF
(6 ml) solution was added, and the mixture was stirred at -78 ° C for 2.5 hr. After completion of the reaction, add 19 ml of 10% aqueous citric acid solution to -1
The mixture was added at 0 ° C and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: chloroform: ethyl acetate = 10:
Purification in 1) yielded 1.3 g of the target compound.

The structure and physical properties of the obtained compound are also shown in Table 1.

[0076]

Example 3 2- (2-Methoxyvinylidenyl) -5,
Preparation of 8-dimethoxy-1,4a-dimethyl-7- (1-methylethyl) -2,3,4,4a, 9,10-hexahydrophenanthrene DMF 19.6 in which 930 mg of potassium hydride was suspended.
ml was cooled to -10 ° C, a solution of the compound obtained in Example 2 (1.53 g) in DMF (19.6 ml) was added, and the mixture was added to 0 ° C.
It was stirred for 1 hour. To the reaction mixture was added 10% aqueous citric acid solution (40 ml), the mixture was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform = 5: 50: 1) to obtain 923 mg of the target compound.

The structure and physical properties of the obtained compound are also shown in Table 1.

[0078]

Examples 4 and 5 5,8-dimethoxy-1,4a-dimethyl-7- (1-methylethyl) -3,4,4a,
Production of 9,10,10a-hexahydro-2-phenanthrene aldehyde (trans form and cis form) 2.1 g of the compound obtained in Example 3 was dissolved in 45 ml of degassed methanol, and 690 mg of degassed oxalic acid was dissolved. An aqueous solution (7 ml) was added, and the mixture was refluxed for 4.5 hours in an argon atmosphere. After allowing to cool, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n
-Hexane: chloroform = 20: 300: 3) to obtain 350 mg of the target compound whose ring junction is trans from the latter fraction and 1.45 g of the target compound whose ring junction is cis from the previous fraction. It was

The structure and physical properties (melting point and ¹ H-NMR) of each compound thus obtained are also shown in Table 1.

[0080]

Example 6 5,8-Dimethoxy-1,4a-dimethyl-7- (1-methylethyl) -3,4,4a, 9,1
Preparation of 0,10a-hexahydro-2 (1H) -phenanthrenone 28.5 metallic lithium in 15.6 ml liquid ammonia.
mg was added at -78 ° C and stirred for 5 minutes. There, a THF solution containing the compound (500 mg) obtained in Example 1 (15.
6 ml) was slowly added dropwise. After stirring at -78 ° C for 1.5 hours, ammonia was distilled off, water was added, and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform = 5: 5).
Purification at 0: 1) gave 270 mg of the desired compound.

The structure and physical properties of the obtained compound are shown in Table 1.

[0082]

Example 7 2-Hydroxy-5,8-dimethoxy-
1,4a-dimethyl-7- (1-methylethyl) -2,
Production of 3,4,4a, 9,10-hexahydro-2-phenanthrene aldehyde 211 mg of palladium (II) chloride and copper (II) chloride
1.3 g was added into 9.9 ml of 10: 1 DMF-water,
Stirred at room temperature for 1 hour. To this, a solution of 750 mg of the compound obtained in Example 3 in DMF (13.5 ml) was added,
The mixture was stirred at 70 ° C for 21 hours. After the reaction was completed, the solid matter was filtered off, water was added to the filtrate, and the mixture was extracted with ethyl acetate.

The organic layer was washed with saturated saline, dried over magnesium sulfate and concentrated. The obtained crude product is
Silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform = 5: 50:
Purification in 1) yielded 300 mg of the target compound.

The structure and physical properties of the obtained compound are also shown in Table 1.

From the previous fraction by chromatography,
As a by-product, 5,8-dimethoxy-1,4a-dimethyl-7- (1-methylethyl) -3,4,4a, 9-tetrahydro-2-phenanthrene aldehyde 150 mg
Got Melting point: 107 ° C or higher (decomposition).

¹ H-NMR (δ: ppm) [CDC
l ₃ ]: 10.31 (1H, s), 6.67 (1H, s), 6.39 (1H, dd, J = 5.1,3.1), 3.84
(3H, s), 3.71 (3H, s), 3.68 (1H, dd, J = 14.4,5.1), 3.50 (1H, d
d, J = 14.4,3.1), 3.32 (1H, sept, J = 6.8), 3.05-3.11 (1H, m),
2.47-2.55 (1H, m), 2.35 (3H, s), 2.28-2.36 (1H, m), 1.41-1.
51 (1H, m), 1.31 (3H, s), 1.26 (3H, d, J = 6.8), 1.23 (3H, d, J =
6.8).

[0087]

Example 8 1,4a-Dimethyl-1-hydroxymethyl-8-methoxy-3,4,4a, 9,10,10a-
Preparation of Hexahydro-2 (1H) -phenanthrenone 0.82 g of metallic lithium was added to 30 ml of liquid ammonia at -78 ° C, and the mixture was stirred for 15 minutes. There, 1, 4a
-Dimethyl-8-methoxy-4,4a, 9,10-tetrahydro-2 (3H) -phenanthrenone (5 g) and THF (35 ml) containing 3.7 ml of t-butanol were added, and the mixture was stirred at -78 ° C for 30 minutes. did. After completion of the reaction, 9 ml of isoprene was added to react with excess reagent, and ammonia was distilled off under a nitrogen stream.

Then, 50 ml of THF was added to the residue to dissolve it, and under cooling with ice, THF (40 ml) containing 12.8 g of trimethylsilyl chloride and 11.8 g of triethylamine was added, and the mixture was stirred for 30 minutes under cooling with ice. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with diethyl ether, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 1).
9) and purified to give 1,4a-dimethyl-8-methoxy-2-trimethylsilyloxy-3,4,4a, 9,1.
5.95 g of 0,10a-hexahydrophenanthrene was obtained. Melting point: 79 ° C.

¹ H-NMR (δ: ppm) [CDC
l ₃ ]: 6.51-7.10 (3H, m), 3.76 (3H, s), 1.66-2.87 (9H, m), 1.57 (3
H, brs), 0.97 (3H, s), 0.10 (9H, s).

In a THF (80 ml) in which 4.9 g of the compound obtained above was dissolved, formaldehyde gas was bubbled together with nitrogen gas into the reaction vessel at −78 ° C., while a solution of tetrabutylammonium fluoride in THF (1 ．
2M ml (0M) was added. The mixture was stirred at room temperature for 10 minutes, poured into ice water, and extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane: = 1: 4) to obtain 3.6 g of the target compound.

The structure and physical properties of the obtained compound are also shown in Table 1.

[0092]

Example 9 Preparation of 1,4a-dimethyl-5,8-dimethoxy-7- (1-methylethyl) -2-trimethylsilyloxy-3,4,4a, 9,10,10a-hexahydrophenanthrene 127 mg of metallic lithium was added to 30 ml of liquid ammonia at −78 ° C., and the mixture was stirred for 15 minutes. Example 1 there
THF (7 ml) in which 1 g of the compound obtained in 4 and 450 mg of t-butanol were dissolved was added, and the mixture was stirred at -78 ° C for 30 minutes. After completion of the reaction, 1.37 ml of isoprene was added to react with excess reagent, and ammonia was distilled off under a nitrogen stream.

Next, 8 ml of THF was added to the residue to dissolve it, and under cooling with ice, THF (7 ml) containing 1.95 g of trimethylsilyl chloride and 2.47 g of triethylamine dissolved therein was added, and the mixture was stirred for 30 minutes under cooling with ice. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture, the mixture was extracted with diethyl ether, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n-hexane =).
Purification at 1:20) gave 930 mg of the desired compound.

The structure and physical properties of the obtained compound are also shown in Table 1.

[0095]

Example 10 1,4a-Dimethyl-5,8-dimethoxy-7- (1-methylethyl) -2-trifluoromethylsulfonyloxy-3,4,4a, 9,10,10a
-Preparation of hexahydrophenanthrene 500 mg of the compound obtained in Example 9 are dissolved in 7 ml of THF, 1.07 ml of 1.4M methyllithium diethyl ether solution is added at 0 ° C, and the mixture is allowed to stand at 0 ° C for 15 minutes and then at room temperature. And stirred for 30 minutes. The reaction solution was cooled to −78 ° C., and N-phenyltrifluoromethanesulfonimide 4
THF (7 ml) in which 75 mg was dissolved was added, and the temperature was 0 to 5 ° C.
The mixture was stirred at 9.5 hours. Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent ... diethyl ether: n-hexane: = 1: 50) to obtain 310 mg of the target compound.

The structure and physical properties of the obtained compound are also shown in Table 1.

On the other hand, 402 mg of tetrakis (triphenylphosphine) palladium and 30 mg of lithium chloride were suspended in 8 ml of THF, 160 mg of the compound of Example 10 was added, and the mixture was stirred at room temperature for 15 minutes under an argon stream. Next, the reaction solution was heated to 50 ° C. and stirred for 2 hours while blowing carbon dioxide, and then 5 ml of THF in which 118 mg of tributyltin hydride was dissolved was added dropwise at 50 ° C. over 3.5 hours and stirred at 50 ° C. for 21 hours. did.
Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n
-Hexane: chloroform = 20: 300: 3) to obtain 45 mg of the same compound as the compound of Example 4.

[0098]

[Table 1]

[0099]

[Table 2]

[0100]

[Table 3]

[0101]

[Table 4]

[0102]

[Table 5]

[0103]

[Table 6]

[0104]

Example 11 1,4a-Dimethyl-7- (1-methylethyl) -5,8-dioxo-3,4,4a, 5,8,
Production of 9,10,10a-octahydro-2-phenanthrene aldehyde (cis form) 310 mg of the compound of Example 5 was added to 10 ml of acetonitrile.
5 ml of an aqueous solution of CAN 1.24 g was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was diluted with water and extracted with chloroform. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n-hexane: chloroform =
Purified at 10: 50: 1), 150 mg of the target compound
Got

The structure and physical properties of the obtained compound are also shown in Table 2.

[0106]

Examples 12 to 14 In the same manner as in Example 11, the compounds of Examples 12 to 14 were obtained. The structure and physical properties of the obtained compound are also shown in Table 2.

[0107]

Example 15 8-Hydroxymethyl-4b, 8-dimethyl-5,6,8,8a, 9,10-hexahydro-
Production of 1,4,7 (4bH) -phenanthrenetrione 150 mg of the compound of Example 8 was dissolved in 4 ml of dichloromethane, and under ice cooling, a solution of boron tribromide in n-hexane (1.
1.2 ml of 0M) was added. After stirring for 1.5 hours at 0 ° C,
Saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. 34 mg of the obtained crude crystals were added to 10 ml of ethanol.
Aqueous solution (6.8 ml) of potassium dinitrosulfonate (83 mg) and dipotassium hydrogenphosphate (34 mg) was added, and the mixture was stirred at room temperature for 13 hours. The reaction solution was diluted with water, extracted with chloroform, the organic layer was washed with saturated brine, dried over magnesium sulfate and concentrated. The obtained crude product was purified by silica gel column chromatography (eluent: ethyl acetate: n-hexane = 1: 9) to obtain 1 mg of the target compound.

Table 2 shows the structure and physical properties of the obtained compound.

[0109]

[Table 7]

[0110]

[Table 8]

[0111]

[Table 9]

[0112]

[Pharmacological test] The results of the pharmacological test of the compound of the present invention are shown below.

[Interleukin-1 (IL-1) Release Inhibition Test from Human Peripheral Blood Adherent Cells] Peripheral blood of healthy humans was collected and mononuclear cells were obtained using Ficoll-Pak (Pharmacia LKB Biotechnology Inc.). Collected and RPMI-16 containing 100 units / ml penicillin and 0.1 μg / ml streptomycin
A cell amount of 5 × 10 ⁶ cells / ml was suspended in 40 medium (Nissui Pharmaceutical Co., Ltd.). 100 μl of this cell suspension was put into a 96-well culture plate, and the carbon dioxide incubator (5
% CO ₂ /95% air atmosphere), after culturing for 1 hour at 37 ° C., the supernatant was aspirated and R containing 10% fetal calf serum was added.
100 μl of PMI-1640 medium was added to each plate to give an adherent cell plate. After adding the test compound to this, 100 μl of lipopolysaccharide (LPS) further adjusted to 3 μg / ml
1 was added. Then, it was cultured in a carbon dioxide gas incubator at 37 ° C. for 24 hours in the same manner as above, and the culture supernatant was collected by centrifugation.

IL-1α and IL-1β released from cells upon stimulation with LPS were measured by enzyme immunoassay (EI).
A) method was used. That is, a mouse monoclonal antibody against IL-1α or IL-1β is immobilized on a 96-well plate for EIA, and then blocking treatment is performed.
Samples are added to this plate and washed after the reaction, and then IL-1
A rabbit polyclonal antibody against α or IL-1β is added and further reacted. After washing the plate, horseradish peroxidase (P
OD)] Labeled anti-rabbit globulin is added and after reaction, unbound POD labeled anti-rabbit globulin is washed away. A substrate solution (orthophenylenediamine and hydrogen peroxide) is added and reacted, and then the absorbance at 492 nm is measured. IL-
1 Release inhibition rate (%) was calculated by the following formula.

IL-1 release inhibition rate (%) = 100 × (1
-T ₄₉₂ ÷ C ₄₉₂ ) where T ₄₉₂ is the absorbance at 492 nm when the culture supernatant containing the test compound was used as a sample, and C ₄₉₂ was the absorbance at 492 nm when the culture supernatant containing the solvent was used as the sample. Show.

According to the above test, the IL when the compound of the present invention (1 × 10 ⁻⁵ g / ml) obtained in the above-mentioned Example was used.
-1α and IL-1β release inhibition rate was calculated as the third
Shown in the table.

[0117]

[Table 10]

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] September 7, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0097

[Correction method] Change

[Correction content]

On the other hand, 402 mg of tetrakis (triphenylphosphine) palladium and 30 mg of lithium chloride were suspended in 8 ml of THF, 160 mg of the compound of Example 10 was added, and the mixture was stirred at room temperature for 15 minutes under an argon stream. Next, the reaction solution is heated to 50 ° C. and stirred for 2 hours while blowing carbon monoxide , then 5 ml of THF in which 118 mg of tributyltin hydride is dissolved is added dropwise at 50 ° C. over 3.5 hours, and then at 50 ° C. for 21 hours. It was stirred.
Water was added to the reaction mixture and the mixture was extracted with diethyl ether. The organic layer was washed with saturated brine, dried over magnesium sulfate and crimped. The obtained crude product was subjected to silica gel column chromatography (eluent: diethyl ether: n
-Hexane: chloroform = 20: 300: 3) to obtain 45 mg of the same compound as the compound of Example 4.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07F 7/18 A 8018-4H 9/53 9155-4H // A61K 31/12 ABE 9283-4C AED 9283-4C (72) Inventor Yukihisa Ono 41-18 Kawakubo, Taimahama, Kitajima-cho, Itano-gun, Tokushima Prefecture (72) Inventor Yoshihiro Taniguchi 5-2, Kanaoka, Kawauchi-cho, Tokushima-shi, Tokushima La Foret Kawauchi 407 (72) Invention Employee Asahi Takahiro 146-11 Motomura, Tokumi, Aizumi-cho, Itano-gun, Tokushima Prefecture Aiichi Heights 506

Claims (2)

[Claims] 1. A general formula: [Wherein R ¹ represents a lower alkyl group, R ² represents a formyl group, R ³ represents a hydroxy group, or R ² and R ³ represent an oxo group, and R ³ represents R ⁵ which will be described later. They may combine with each other to form a double bond. R ⁴ is a lower alkyl group, R ⁵ is a hydrogen atom, a hydroxy lower alkyl group or R ³ or R ³ or R ⁶ described later to form a double bond, and R ⁶ is a hydrogen atom or R ⁵ to each other. To form a double bond, and R ⁷ represents a hydrogen atom or a lower alkyl group, respectively. However, when R ⁷ is a lower alkyl group, R ⁵ is not a hydroxymethyl group. ] The phenanthrene derivative represented by these. 2. A general formula: [In the formula, R ¹ , R ⁴ and R ⁷ are the same as defined above. R ^2a is a formyl group, a tri-lower alkylsilyloxy group, a trifluoromethylsulfonyloxy group or a group (Wherein R ¹⁰ represents a lower alkyl group), R ^3a represents a hydroxy group, or R ^2a and R ^{3a represent an} oxo group or a group R ¹⁰ O—CH═ (wherein R ¹⁰ is as described above). The same.)
R ^3a may combine with R ^5a described later to form a double bond. R ^5a is bonded to a hydrogen atom, a hydroxy lower alkyl group or R ^3a or R ^6a described below to form a double bond, and R ^6a is bonded to a hydrogen atom or R ^5a to form a double bond, R ⁸ represents a hydrogen atom or a lower alkoxy group, and R ⁹ represents a lower alkyl group. However, R ⁷
Is a lower alkyl group, R ^5a is not a hydroxymethyl group, and when R ⁷ and R ⁸ are hydrogen atoms at the same time, R ^5a does not bond with R ^6a to form a double bond. . ] The phenanthrene derivative represented by these.