JPH0133093B2 - - Google Patents

Description

[Detailed description of the invention]

TECHNICAL FIELD The present invention relates to naphthalene and naphthoquinone derivatives. Structure of the Invention The naphthalene and naphthoquinone derivatives of the present invention are novel compounds that have not been described in any literature, and are represented by the following general formula (1).
It is expressed as [Formula ring A is

[Formula] or

[Formula] is shown. R ₁ represents a lower alkyl group. R ² is a hydrogen atom, C ₁
~ _C20 alkyl group, phenyl lower alkyl group,
An allyl group, a C1 _{- C10} alkyl group having a benzyloxy group as a substituent, or a _C1 - _C10 alkyl group having a hydrogen group as a substituent. However, ring A
but

When represented by the formula, R ₂ must not be a hydrogen atom, a C ₁ -C ₂₀ alkyl group, or a C ₁ -C ₁₀ alkyl group having a hydroxyl group as a substituent. ] The compound of the present invention represented by the above general formula (1) is
It has anti-inflammatory, anti-complement, anti-hypertensive, heart disease treatment, anti-allergy, platelet aggregation inhibiting, anti-tumor, antibacterial, etc. anti-inflammatory, antihypertensive, and heart disease treatment agents. It is useful as an antiallergic agent, antithrombotic agent, antitumor agent, antibacterial agent, etc. In this specification, the lower alkyl group is
For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
1-6 carbon atoms such as butyl, pentyl, hexyl group, etc.
Examples include alkyl groups. Examples of C ₁ to C ₂₀ alkyl groups include methyl,
Ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
Examples include neopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undecyl, tridecyl, hexadecyl, octadecyl, and eicosyl groups. Examples of phenyl lower alkyl groups include benzyl, α-phenethyl, β-phenethyl, 1-phenylpropyl, 2-phenylpropyl, 3-phenylpropyl, 1-phenylbutyl, 2-phenylbutyl, 3-phenylbutyl, and 4-phenylbutyl. Examples include phenylbutyl, 1-phenylpentyl, 3-phenylpentyl, 5-phenylpentyl, 1-phenylhexyl, 3-phenylhexyl, 5-phenylhexyl, 1,1-dimethyl-2-phenylethyl, and the like. C ₁ - having benzyloxy group as a substituent
Examples of the C ₁₀ alkyl group include benzyloxymethyl, benzyloxyethyl, benzyloxypropyl, benzyloxybutyl, benzyloxypentyl, benzyloxyhexyl, benzyloxyheptyl, benzyloxyoctyl, benzyloxynonyl, benzyloxydecyl, 1
-benzyloxy-3,3-dimethylpropyl,
Examples include 1-benzyloxy-2,6-dimethyloctyl group. Examples of the _C1 to _C10 alkyl group having a hydroxyl group as a substituent include hydroxymethyl, hydroxyethyl, hydroxypropyl,
Hydroxybutyl, hydroxypentyl, hydroxyhexyl, hydroxyheptyl, hydroxyoctyl, hydroxynonyl, hydroxydecyl, 1-hydroxy-3,3-dimethylpropyl, 1-hydroxy-2,6-dimethyl Examples include octyl group. The compound represented by the above general formula (1) of the present invention is:
For example, it can be produced by the method shown in the following reaction scheme. [In the formula, R ₁ is the same as above. _R2 ' represents a _C1 to _C20 alkyl group, phenyl lower alkyl group, or allyl group. ] The Grignard reaction of the known compound of general formula (2) can be carried out according to a conventional method, for example, by adding a Grignard reagent to the compound of general formula (2) in a solvent such as ether or tetrahydrofuran, usually at about -20 to 60°C, preferably. The reaction may be carried out at about 0 to 25°C. The Grignard reagent is prepared by reacting about 1 mole of an alkyl halide, phenyl lower alkyl halide, or allyl halide with about 1.1 to 1.2 moles of magnesium in a conventional manner. The ratio of the compound of general formula (2) and Grignard reagent is as follows:
It is generally advisable to use the latter in an amount of 1 to 5 times the mole of the former, preferably 1 to 4 times the mole of the former. [In the formula, R ¹ is the same as above. R ₃ represents a benzyl group.
n represents an integer of 1 to 10. ] The reaction to obtain the compound of general formula (1-c) from the compound of general formula (2) is the same as the Grignard reaction in reaction scheme-1 above, except that a Grignard reagent prepared from benzyloxyalkyl halide and magnesium is used. You can do it in the same way. For the catalytic reduction of the compound of general formula (1-c), a wide range of conventionally known catalytic reduction conditions can be employed. Ethers such as ethyl acetate, N,N-dimethylformamide (DMF)
Hydrogenation may be carried out in a solvent such as at normal pressure to about 3 atm and at about 20 to 50°C. [In the formula, R ₁ and R ₂ are the same as above. ] The oxidation of the compound of general formula (1-e) is carried out using a tetravalent cerium salt [for example, ceric ammonium nitrate, (NH ₄ ) ₂ Ce(NO ₃ ) ₆ (hereinafter referred to as "CAN")],
This can be suitably carried out using dilute nitric acid-AgO or the like. When using a tetravalent cerium salt, for example, dioxane, acetonitrile, THF, dichloromethane,
In a solvent such as chloroform or ether, the general formula (1
-e) Compound is reacted with tetravalent cerium salt in an amount of about 5 times the mole, preferably about 2 to 2.5 times the mole, usually at about -20 to 60°C, preferably about 0 to 30°C. good. In addition, when using dilute nitric acid-AgO, for example, acetone, dioxane,
It can be carried out in a solvent such as THF or ether, usually at 0°C to around the boiling point of the solvent, preferably at about 0 to 60°C. AgO is usually used in an amount equivalent to about 20 times the mole of the compound of the general formula (1-e), preferably about 3 to 10 times the mole, and dilute nitric acid is used by using a 6N nitric acid aqueous solution. -Equimolar to 10 times the molar amount, preferably equimolar to 3 times the molar amount of the compound (e). Among the compounds of general formula (1-e) used as starting materials in reaction scheme-3, the compound in which R ₂ is a hydrogen atom (compound (1-g)) is a new compound, for example, the following reaction scheme - Manufactured according to 4. [In the formula, R ₁ is the same as above. ] The compound of general formula (2) is reduced to form general formula (1-g)
Conventionally known reaction conditions for reducing aldehydes to alcohols can be widely applied to the reaction to obtain the compound, such as sodium borohydride (NaBH ₄ ),
A method using lithium aluminum hydride or the like can be mentioned. In particular, the method of reacting NaBH ₄ on the compound of general formula (2) in an alcohol such as methanol, ethanol, water, THF, DMF, etc. or a mixed solvent thereof at around 0 to 30°C is easy to operate. This is preferable in this respect. In this case NaBH ₄ has the general formula
It is desirable to use the compound in an amount of about 1 to 2 times the mole of the compound (2). In the compound of the present invention represented by the above general formula (1), ring A is

Compounds with [formula] can be combined by reduction. The corresponding ring A is

It can be converted to [Formula], and ring A is

[Formula] is oxidized so that the corresponding ring A is

It can be converted into a compound having the formula: The objects obtained by each of the above reaction steps can be easily isolated and purified by conventional separation means such as solvent extraction, recrystallization, column chromatography, etc. The compounds of the present invention may have optical isomers, and such isomers are also included within the scope of the present invention. Examples Hereinafter, production examples of raw material compounds for producing the compounds of the present invention will be listed as reference examples, and then production examples of the compounds of the present invention will be listed as examples. Reference Example 2 - Production of hydroxymethyl-1,4,5,8-tetramethoxynaphthalene 4.5 g of 1,4,5,8-tetramethoxy-2-naphthalenecarbaldehyde was dissolved in 70 ml of ethanol and 35 ml of THF, and the mixture was cooled on ice. Slowly add 1g of NaBH ₄ . After stirring for 30 minutes, the solvent was distilled off, extracted with ethyl acetate, and the organic layer was washed with water, dried (MgSO ₄ ), and concentrated. Crystallization gave 4.7 g of the title compound as white crystals. Melting point 109-110℃ NMR ( _CDCl3 , δ, ppm): 6.90 (s, 1H), 6.80 (s, 2H), 4.83 (bs, 2H), 3.96 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.88 (s, 3H), 2.60 (s, 1H) Example 1 2-(1-hydroxyethyl)-1,4,5,8
-Production of tetramethoxynaphthalene (compound 1) Dissolve 3 g of 1,4,5,8-tetramethoxy-2-naphthalenecarbaldehyde in 50 ml of THF,
Add 4.25 g of methyl iodide and magnesium to this solution under water cooling.
Slowly add Grignard reagent prepared from 750 mg and 35 ml of ethyl ether. After continued stirring for 10 minutes, the reaction was transferred to saturated aqueous NH ₄ Cl and extracted with ethyl acetate. The crude product obtained by drying and concentrating the organic layer was subjected to silica gel chromatography (developing solvent: ether: n-hexane = 2:1 ~
3:1) to obtain the title compound as white crystals.
g (82%). In the same manner as above, compound 2 shown in the table below,
Compounds 3, 4, 5 and 6 were obtained. Example 2 Production of 2-(4-benzyloxy-1-hydroxybutyl)-1,4,5,8-tetramethoxynaphthalene (compound 7) 1,4,5,8-tetramethoxy-2-naphthalenecarbaldehyde 5 g was dissolved in 100 ml of THF, and a Grignard reagent prepared from 1.3 g of magnesium, 12.5 g of 3-benzyloxypropyl bromide and 125 ml of ethyl ether was slowly added to this solution under water cooling. After stirring for 10 minutes, the reaction solution was transferred to a saturated aqueous NH ₄ Cl solution and treated in the same manner as in Example 1. The resulting crude product was subjected to silica gel chromatography (developing solvent: ethyl acetate: n-
Purification with hexane (3:4) gave the title compound as an oil (6.65 g, 86%). Compounds 8 and 9 shown in the table below were obtained in the same manner as above. Example 3 2-(1,4-dihydroxybutyl)-1,4,
5,8-tetramethoxynaphthalene (compound
10) Production 76.50 g of the compound obtained above was added to 180 g of ethyl acetate.
ml and DMF50ml mixed solvent, 5% Pd-
Add 100mg of C and hydrogenate at room temperature and pressure for 24 hours. The reaction solution was filtered, concentrated, and purified by silica gel chromatography (developing solvent: chloroform: methanol = 20:1) to obtain 3.95 g (77 g) of the title compound.
%) was obtained as white crystals. In the same manner as above, compound 11 and
12 respective compounds were obtained. Example 4 6-(1,4-dihydroxybutyl)-5,8-
Dimethoxy-1,4-naphthoquinone (compound
Production of 20) Dissolve 103.58 g of the compound obtained above in 30 ml of dichloromethane, and add 16.1 g of CAN to this solution in 30 ml of water.
A solution dissolved in was added and stirred vigorously for 5 minutes at room temperature. The reaction solution was extracted with dichloromethane, the organic layer was dried, concentrated, and purified by silica gel chromatography (developing solvent: chloroform: ethyl acetate: methanol = 10:10:1) to obtain the title compound 21.
800 mg (22.8%) was obtained. In the same manner as above, compound 13 shown in the table below,
Compounds 14, 15, 16, 17, 18, 19, 21 and 22 were obtained.

【table】

[Table] Next, the results of pharmacological tests using the compounds of the present invention are shown. 5-Lipoxygenase inhibitory effect Cell conditioning and measurement of 5-lipoxygenase activity were performed using the method of GMBokoch and pwReed [j.Biol.Chem., 256, 4156 (1981)]. ] and Ochi et al. [J. Biol. Chem., 258, 5754 (1983)]. That is, guinea pigs were intraperitoneally administered with 2% casein, 14 to 16 hours later they were bled to death, and the peritoneal cavity was washed to collect infiltrated cells. 1mM _CaCl2 and 5.5mM
2.5 mL of the above cells in phosphate buffer containing glucose
The cells were suspended at a concentration of ×10 ⁷ cells/ml. After incubating this cell suspension at 30°C for 2 minutes,
Specimen at each concentration was added and incubated for an additional 2 minutes. Then 10 μM ionophore
A23187 was added followed by 10 μM ¹⁴ C-arachidonic acid. After incubation for 3 minutes, the reaction was stopped by adding 0.2M citric acid and the product was extracted with ethyl acetate. The extract was spotted on a thin layer plate, and after development, arachidonic acid, 5(S)-hydroxy-6,
8,11,14-eicosatetraenoic acid (5-
HETE) and other parts were scraped off, and ¹⁴ C was counted using a scintillator. The inhibitory activity of the sample was expressed as the inhibition rate relative to the 5-HETE production rate of the control. The results are shown below. Test compound No. 1: A is

[Formula] Compound 2 where R ₁ is a methyl group and R ₂ is a hydrogen atom: A is

[Formula] Compound 3 where R ₁ is a methyl group and R ₂ is - (CH ₂ ) ₃ -OH: A is

[Formula] Compound where R ₁ is a methyl group and R ₂ is -(CH ₂ ) ₆ - OH

【table】

Claims (1)

[Claims] 1. General formula [In the formula, ring A represents [formula] or [formula]. R ₁ represents a lower alkyl group. R ₂ is a hydrogen atom, C ₁
~ _C20 alkyl group, phenyl lower alkyl group,
An allyl group, a _C1 - _C10 alkyl group having a benzyloxy group as a substituent, or a _C1 - _C10 alkyl group having a hydroxyl group as a substituent. However, ring A
When represents [Formula], R ₂ must not be a hydrogen atom, a C ₁ -C ₂₀ alkyl group, or a C ₁ -C ₁₀ alkyl group having a hydroxyl group as a substituent. ] Naphthalene and naphthoquinone derivatives represented by these.