JPH10273464A - Substituted catechol derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having effects of a urine protein suppression and improvements in serum test results (cholesterol, etc.) and useful as a treating agent of nephritis. SOLUTION: This substituted catechol derivative is a compound of formula I [R1 is H or COR9 ; R2 , R3 are each H, a lower alkyl or a (substituted) arylalkyl; X is O, S; R4 to R8 are each H, OH, a lower alkyl, etc.; R9 is a (substituted) lower alkyl or an aryl; (m) is 0-2; (n) is 0-3], e.g. 4,4'-(oxydiethylene) bis (1,2-benzenediol). The compound of the formula I wherein X is O, is obtained by reacting an alcohol compound of formula II (R10 is a protecting group of OH) with a sulfonic acid ester of formula III (Ts is p-toluenesulfonyl) in the presence of a base to obtain a corresponding ether compound, and then removing a protecting group such as benzyl and methoxymethyl as the R10 .

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a substituted catechol derivative useful as a therapeutic agent for nephritis, a pharmacologically acceptable salt thereof, and a medicament containing the same.

[0002]

2. Description of the Related Art Many crude drugs have been used in clinical practice for a long time. However, since all of them are extracts from nature, the production process is complicated and the yield is poor. Because of limited production, there was a problem in terms of economics when developing as a pharmaceutical.

In recent years, with the development of instrumental analysis and compound separation means, active ingredients in crude drugs have been separated and identified.
Based on this result, chemical synthesis of active ingredients of crude drugs has been attempted. Also, based on the above findings, new compounds having the same skeleton as the active ingredient of crude drugs have been developed. The present inventors have repeated studies from the process of elucidating the mechanism of action of acteoside, a ground yellow component searched for as a therapeutic agent for nephritis, and as a result, a derivative represented by the following formula (1) has a better pharmacological action. And completed the present invention.

That is, the present invention provides the following equation (1)

[0005]

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Wherein R ₁ is a hydrogen atom or —COR ₉
Wherein R ₂ and R ₃ are the same or different and represent a hydrogen atom, a lower alkyl group or an optionally substituted arylalkyl group, X represents an oxygen atom or a sulfur atom, and R _{4 to} R ₈ are Hydrogen atom, hydroxyl group, lower alkyl group,
Represents an arylalkoxy group, an optionally substituted lower alkoxy group or —OCOR ₉ , and R ₉ represents an optionally substituted lower alkyl group or an aryl group. Further, m represents 0 to 2, and n represents 0 to 3. ) Or a pharmaceutically acceptable salt thereof (hereinafter, the substituted catechol derivative or a pharmaceutically acceptable salt thereof described above is collectively referred to as “the compound (1) of the present invention”). ) And a therapeutic agent for nephritis comprising the compound (1) of the present invention as an active ingredient.

In the compound (1) of the present invention, the lower alkyl group represented by R _{2 to} R ₉ includes a linear or branched alkyl group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, an n- Propyl group, isopropyl group, n-butyl group,
It means an isobutyl group, 1-methylpropyl group, tert-butyl group, n-pentyl group, isoamyl group, 1-ethylpropyl group, n-hexyl group and the like.

The arylalkyl groups represented by R ₂ and R ₃ include a benzyl group and a phenethyl group.
For example, it may be substituted with a hydroxyl group or the like.

The lower alkoxy group represented by R _{4 to} R ₈ is
It means all lower alkoxy groups derived from the above lower alkyl groups, for example, methoxy group, ethoxy group,
Examples include a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, a 1-ethylpropoxy group, and a hexyloxy group. Further, these alkoxy groups may be substituted with another alkoxy group or the like. Examples of the arylalkoxy group represented by R _{4 to} R ₈ include a benzyloxy group and a phenethyloxy group.

The aryl group represented by R ₉ includes, for example, a phenyl group and the like, and may be substituted with a suitable substituent such as an acyloxy group. Examples of the substituent of the lower alkyl group represented by R ₉ include an amino group and a carboxyl group. Incidentally, the amino group may be substituted with a lower alkoxy-carbonyl group.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION The method for producing the compound (1) of the present invention will be described in detail. The compound (1) of the present invention can be produced by various methods. As a typical method, the methods shown in the following reaction formulas (1) to (3) can be exemplified.

(1) When X in the formula (1) is an oxygen atom (wherein R _{1 to} R ₈ , m and n have the same meanings as above), the following general formula (2)

[0013]

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(Wherein R ₁₀ represents a hydroxyl-protecting group which can be easily removed; R ₂ , R ₃ and m have the above-mentioned meanings).

[0015]

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(Wherein Ts represents a p-toluenesulfonyl group, and n and R _{4 to} R ₈ have the same meaning as described above), and the corresponding ether is reacted with a sulfonate ester in the presence of a base. Body (4)

[0017]

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(Wherein R _{2 to} R ₈ , m, n and R ₁₀ have the above-mentioned meanings), and then R ₁₀ which is a protecting group for a hydroxyl group is removed to obtain one of the target substances: Equation (5)

[0019]

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(Wherein, R _{2 to} R ₈ , m and n have the same meanings as described above).

In the reaction, a solvent which does not participate in the reaction, which is appropriately selected from dimethylformamide, benzene, toluene, tetrahydrofuran, dioxane, acetonitrile and the like, can be used as the solvent. As a catalyst, a tetrabutylammonium salt or the like can be used.

As the bases, for example, inorganic bases such as sodium hydride, sodium hydroxide and potassium hydroxide, and tertiary amines such as 2,6-lutidine and 2,4,6-collidine are used. Is done. The reaction temperature is not particularly limited, but is preferably from room temperature to about 150 ° C. After completion of the reaction, the ether compound (4) is isolated by a conventional method.

As the hydroxyl-protecting group, a benzyl group, a methoxymethyl group, a methoxyethoxymethyl group and the like are used. The removal of these protecting groups depends on the type of the protecting groups, but preferably catalytic reduction or acid hydrolysis using palladium-carbon as a catalyst is employed.

The representative method for producing the compound (5) has been described above. The hydroxyl group of the compound (5) is further converted by acylation or the like to obtain another target substance represented by the following formula (6).

[0025]

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Wherein R _{2 to} R ₉ , m and n have the meanings given above.

(2) In the formula (1), X is a sulfur atom,
R ₂ = R ₃ = R ₄ = R ₅ = R ₈ = H, R ₆ = R ₇ = OR ₁ , and n = 1 to 3 (wherein R ₁ and m have the above-mentioned meaning) In this case, it can also be manufactured by the following method.

[0028]

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That is, the reaction is carried out according to the general formula (7)
Represents a halogen atom, and R ₁ and m have the same meanings as described above), and is reacted with sodium sulfide by a conventional method to give a thioether compound (8) (8) R ₁ and m have the meaning described above).

In this reaction, examples of the solvent include a mixture of a solvent such as methanol, ethanol or dimethylformamide and water. The reaction temperature is not particularly limited, but is preferably from room temperature to 60 ° C. After completion of the reaction, the target substance is isolated by a conventional method.

(3) In equation (1), n = 0 (where
R _{1 to} R ₈ , X and m have the above-mentioned meanings).

[0032]

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(Wherein X and R _{4 to} R ₈ have the same meanings as above)
The following general formula (10)

[0034]

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(Wherein R _{1 to} R ₃ , m and Ts have the above-mentioned meanings) and a sulfonic acid ester represented by the following formula: (11)

[0036]

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(Wherein R _{1 to} R ₈ , m and X have the same meanings as described above).

In this reaction, dimethylformamide, acetone, tetrahydrofuran and the like can be used as a solvent, and inorganic bases such as potassium hydroxide and potassium carbonate, and tertiary amines such as pyridine and diisopropylethylamine can be used as bases. Can be used. The reaction temperature is not particularly limited, but is preferably from room temperature to 50 to 60.
C. is sufficient, and after completion of the reaction, the target substance is isolated by a conventional method.

The compound (1) of the present invention has an effect of suppressing urine protein and improving serum test values (cholesterol and the like), and is useful as a therapeutic agent for nephritis. In addition, when an acute toxicity test was conducted by oral administration using a mouse (BALB / C♂) for the compound of Example 16 which is a typical compound of the present invention, no death occurred even after administration of 976 mg / kg. It was not observed, and the LD ₅₀ was estimated to be 976 mg / kg or more, which proved to be low toxic.

In order to prepare the compound (1) of the present invention, it is combined with a known pharmaceutical carrier, and is used as an oral preparation such as tablets, capsules, granules, fine granules, powders, liquids, injections, Parenteral preparations such as drops and suppositories are included.

The pharmaceutical carrier can be selected according to the administration form and dosage form. In the case of an oral preparation, for example, starch, lactose, sucrose, mannitol, carboxymethylcellulose, corn starch, inorganic salts and the like are used. You. In addition, in preparing an oral preparation, a binder, a disintegrant,
Surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents,
Flavors and the like can be blended. Specific examples thereof include the following.

(Binder) Starch, dextrin, gum arabic powder, gelatin, hydroxypropyl starch,
Methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

(Disintegrant) Starch, hydroxypropyl starch, sodium carboxymethylcellulose, calcium carboxymethylcellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose.

(Surfactant) Sodium lauryl sulfate,
Soy lecithin, sucrose fatty acid ester, polysorbate 80.

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

(Fluidity promoter) Light anhydrous silicic acid, dried aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The composition can also be administered as an oral liquid suspension, emulsion, syrup, or elixir. These various dosage forms may contain flavoring agents and coloring agents. good.

Further, parenteral preparations are prepared by using the active ingredient of the present invention as a diluent in distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil,
It is prepared by dissolving or suspending in soybean oil, corn oil, propylene glycol, polyethylene glycol or the like, and adding a bactericide, a preservative, a stabilizer, an isotonic agent, a soothing agent and the like, if necessary.

Other parenteral preparations include liquid preparations for external use, ointments and other suppositories, suppositories for rectal administration, and the like.
It is manufactured according to the usual method.

When the compound (1) of the present invention is used as a therapeutic agent for nephritis, its dosage varies depending on the administration route, the degree of the disease, the age of the recipient and the like. The dose of about 300 mg may be administered in 1 to 3 divided doses.

[0051]

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

Example 1 <Synthesis of 4,4 ′-(oxydiethylene) bis (1,2-benzenediol)>

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3,4-bis (benzyloxy) phenethyl alcohol (2.59 g, 7.75 mmol), 3,4-bis (benzyloxy) phenethyl = p-toluenesulfonate (3.78 g, 7.75 m)
mol) and 2,4,6-collidine (2.05 ml, 15.5 mmol) were stirred at 110 ° C. for 3 days. After cooling, 2N hydrochloric acid was added, and the mixture was extracted with ethyl acetate. After drying over anhydrous magnesium sulfate, the solvent was distilled off, and the residue was subjected to silica gel column chromatography.
The desired 3,3 ', 4,4'-tetrakis (benzyloxy) -1,1'-(oxydiethylene) dibenzene was separated and purified by (hexane: ethyl acetate = 5: 1) to give pale yellow crystals. 1.81 g (36%) was obtained.

Next, this product (1.80 g, 2.77 mmol) was dissolved in ethyl acetate, and 10% palladium / carbon (50% wet, 0.18 g) /
Added to the ethanol suspension. Replace the inside of the system with hydrogen gas,
Stirred overnight. The palladium / carbon was filtered off, 1 drop of 2N hydrochloric acid was added, the solvent was distilled off, and the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 3: 2) to obtain the following physical properties. 755 mg of the title compound (94
%). * Properties: Melting point 92-99 ° C * MS (m / e): 290 (M ⁺ ), 137 (bp) * ¹ H-NMR (CD ₃ OD, TMS) δ: 2.68 (4H, t, J = 7.1Hz) ), 3.
57 (4H, t, J = 7.1Hz), 6.48-6.68 (6H, m)

The following compounds were obtained in the same manner as in Example 1.

(Example 2)

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* Properties: oily * MS (m / e): 274 (M ⁺ ), 121 (bp) * ¹ H-NMR (CD ₃ OD, TMS) δ: 2.67 (2H, t, J = 7.1 Hz) , 2.
71 (2H, t, J = 7.1Hz), 3.557 (2H, t, J = 7.1Hz), 3.561
(2H, t, J = 7.1Hz), 6.48-6.53 (1H, m), 6.67-6.73 (5H,
m), 6.95-7.02 (2H, m)

(Embodiment 3)

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* Properties: oily * MS (m / e): 470 (M ⁺ ), 91 (bp) * ¹ H-NMR (CD ₃ OD, TMS) δ: 2.65 (2H, t, J = 7.1 Hz) , 2.
72 (2H, t, J = 7.1Hz), 3.54 (2H, t, J = 7.1Hz), 3.56 (2
H, t, J = 7.1Hz), 5.056 (2H, s), 5.063 (2H, s), 6.46-
6.91 (6H, m), 7.23-7.44 (10H, m)

(Example 4)

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* Properties: oil * ¹ H-NMR (CD ₃ OD) δ: 2.68 (2H, t, J = 7.1 Hz), 2.74 (2
H, t, J = 7.1Hz), 3.59 (4H, t, J = 7.1Hz), 3.79 (3H,
s), 6.48-6.78 (6H, m)

(Embodiment 5)

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* Property: oil * MS (m / e): 318 (M ⁺ ), 151 (bp) * ¹ H-NMR (CDCl ₃ , TMS) δ: 2.73 (2H, t, J = 7.1 Hz), 2.81
(2H, t, J = 7.1Hz), 3.62 (2H, t, J = 7.1Hz), 3.65 (2H,
t, J = 7.1Hz), 3.79 (3H, s), 3.81 (3H, s), 6.59-6.79
(8H, m)

(Embodiment 6)

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* Properties: oil * MS (m / e): 318 (M ⁺ ), 43 (bp) * ¹ H-NMR (CD ₃ OD, TMS) δ: 1.22 (6H, s), 2.64 (2H,
t, J = 7.1Hz), 3.37 (2H, s), 3.49 (2H, t, J = 7.1Hz),
6.46-6.83 (6H, m)

(Embodiment 7)

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* Properties: solid * MS (m / e): 412 (M ⁺ ), 137 (bp) * ¹ H-NMR (CD ₃ OD, TMS) δ: 2.63-2.70 (5H, m), 3.49- 3.
56 (4H, m), 6.28-6.68 (9H, m)

(Embodiment 8)

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* Properties: oily * MS (m / e): 380 (M ⁺ ), 137 (bp) * ¹ H-NMR (CD ₃ OD, TMS) δ: 2.63-2.75 (3H, m), 2.90-
3.05 (2H, m), 3.47-3.55 (4H, m), 6.42-6.71 (6H, m),
6.91-7.16 (5H, m)

Example 9 <Synthesis of 3- [3-[(3,4-dihydroxyphenethyl) oxy] propyl] -1,2-benzenediol>

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60% sodium hydride (270 mg, 6.75 mmol)
And 3,4-bis (benzyloxy) phenethyl alcohol
(1.34 g, 4.01 mmol) and dimethylformamide (2 ml) were added, and the mixture was stirred at room temperature for 20 minutes, and then 3- [2,3-bis [(2-methoxyethoxy) methoxy] phenyl] propyl = p-toluenesulfonate ( A solution of 2.00 g (4.01 mmol) in dimethylformamide (8 ml) was added, and the mixture was stirred at room temperature for 23 hours. Ice water was added to the reaction solution, extracted with ethyl acetate, washed with brine,
After drying over magnesium sulfate, the solvent was distilled off. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 1- [3-[[3,4-bis (benzyloxy) phenethyl] oxy] propyl] -2,3-bis [ 2.19 g (82%) of (2-methoxyethoxy) methoxy] benzene were obtained as an oil.

Methanol (1 ml) was added to 5% palladium on carbon (200 mg) catalyst, followed by 1- [3-[[3,4-bis (benzyloxy) phenethyl] oxy] propyl] -2,3-bis [( 2-
Methoxyethoxy) methoxy] benzene (2.17g, 3.29mmo
l) A mixed solution of ethyl acetate-methanol (4 ml) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 62 hours. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure.

Methanol and concentrated hydrochloric acid were added to the residue,
For 1 hour and at room temperature for 30 minutes. The solvent of the reaction mixture was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 3) to give 824 mg (82%) of the title compound having the following physical properties. * Properties: oily * MS (m / e): 304 (M ⁺ ) * ¹ H-NMR (acetone-d ₆ ) δ: 1.77-1.91 (2H, m), 2.62-
2.75 (4H, m), 3.43 (2H, t, J = 6.5Hz), 3.55 (2H, t, J
= 7.1Hz), 6.56-6.76 (6H, m), 7.60 (4H, br).

The following compounds were synthesized in the same manner as in Example 9.

(Embodiment 10)

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* Properties: oil * ¹ H-NMR (CDCl ₃ ) δ: 1.64-1.84 (2H, m), 2.40-2.50
(2H, m), 2.72-2.82 (2H, m), 3.31-3.41 (2H, m), 3.50
-3.60 (2H, m), 5.12 (2H, s), 5.13 (2H, s), 6.42-6.5
5 (2H, m), 6.70-6.79 (2H, m), 6.86-6.91 (2H, m),
7.30-7.45 (10H, m).

(Embodiment 11)

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* Properties: oily * MS (m / e): 304 (M ⁺ ). * ¹ H-NMR (acetone-d ₆ ) δ: 1.85-1.70 (2H, m), 2.56 (2
H, t, J = 7.6Hz), 2.71 (2H, t, J = 7.1Hz), 3.41 (2H, t,
J = 6.4Hz), 3.54 (2H, t, J = 7.1Hz), 6.26 (1H, dd, J =
8.1Hz, 2.4Hz), 6.37 (1H, d, J = 2.4Hz), 6.57 (1H, d
d, J = 8.1Hz, 2.2Hz), 6.72 (1H, d, J = 8.1Hz), 6.75 (1
H, d, J = 2.2Hz), 6.83 (1H, d, J = 8.1Hz), 7.70 (4H, b
r).

(Embodiment 12)

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* Properties: oily * MS (m / e): 378 (M ⁺ ). * ¹ H-NMR (CDCl ₃ ) δ: 1.77-1.85 (2H, m), 2.52 (2H,
t, J = 7.6Hz), 2.83 (2H, t, J = 7.1Hz), 3.41 (2H, t, J =
6.3Hz), 3.60 (2H, t, J = 7.1Hz), 5.04 (2H, s), 5.36
(1H, brs), 5.54 (1H, brs), 6.52-6.56 (2H, m), 6.73
(1H, d, J = 8.5Hz), 6.91 (2H, d, J = 8.8Hz), 7.14 (2
(H, d, J = 8.8Hz), 7.30-7.41 (5H, m).

(Embodiment 13)

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* Properties: oil * MS (m / e): 288 (M ⁺ ). * ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.75 (2H, m), 2.35-2.44
(2H, m), 2.68 (2H, t, J = 7.1Hz), 3.29-3.36 (2H, m),
3.47 (2H, t, J = 7.1Hz), 6.37 (1H, dd, J = 8.0Hz, 2.0
Hz), 6.54 (1H, d, J = 2.0Hz), 6.60 (1H, d, J = 8.0Hz),
6.66 (2H, d, J = 8.5Hz), 7.01 (2H, d, J = 8.5Hz).

(Embodiment 14)

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* Properties: melting point 118-119 ° C. (CHCl ₃ ). * MS (m / e): 302 (M ⁺ ). * ¹ H-NMR (CD ₃ OD) δ: 1.90-2.04 (2H, m) , 2.12 (3H,
s), 2.14 (3H, s), 2.16 (3H, s), 2.65 (2H, t, J = 7.5H
z), 3.82 (2H, t, J = 6.2Hz), 6.46 (1H, s), 6.51 (1H,
(dd, J = 8.1Hz, 2.1Hz), 6.64 (1H, d, J = 2.1Hz), 6.66
(1H, d, J = 8.1Hz).

(Example 15)

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* Properties: oily * MS (m / e): 304 (M ⁺ ). * ¹ H-NMR (acetone-d ₆ ) δ: 1.76-1.90 (2H, m), 2.60
(2H, t, J = 7.3Hz), 2.71 (2H, t, J = 7.3Hz), 3.43 (2H, t, J = 7.3Hz)
t, J = 7.3Hz), 3.55 (2H, t, J = 7.3Hz), 6.47-6.76 (6H,
m)

(Embodiment 16)

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* Properties: oil * ¹ H-NMR (CD ₃ OD) δ: 1.77 (2H, m), 2.48 (2H, t, J =
7.7Hz), 2.70 (2H, t, J = 7.0Hz), 3.40 (2H, t, J = 6.4H
z), 3.55 (2H, t, J = 7.0Hz), 6.40-6.70 (6H, m)

(Embodiment 17)

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* Properties: oil * ¹ H-NMR (CD ₃ OD) δ: 1.80 (4H, m), 2.53 (4H, m), 3.
39 (4H, t, J = 6.4Hz), 6.45-6.70 (6H, m)

(Embodiment 18)

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* Properties: oil * ¹ H-NMR (CDCl ₃ ) δ: 1.42 (18H, s), 1.80-1.95 (2H,
m), 2.58 (2H, m), 2.78 (2H, t, J = 7.1Hz), 3.51 (2H,
t, J = 6.5Hz), 3.63 (2H, t, J = 7.1Hz), 5.04 (1H, s),
5.75 (1H, br), 5.90 (1H, br), 6.60-6.75 (3H, m),
6.96 (2H, s)

Example 19 <Synthesis of 4,4 ′-(thiodiethylene) bis (1,2-benzenediol)>

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Sodium sulfide 9 hydrate (41.63 g, 166.5 mmo
l) to a mixed solution of 500 ml of methanol and 60 ml of water under ice-cooling and stirring.
Chloro-3 ', 4'-dihydroxyacetophenone (62.10g, 3
33 mmol) and stirred at room temperature for 4 days. The precipitated crystals were collected by filtration and washed with methanol and water to obtain 40.60 g (73%) of 1,1'-bis (3,4-dihydroxyphenyl) -2,2'-thiodietanone as off-white crystals. * MS (m / e): 334 (M ⁺ ). * ¹ H-NMR (DMSO-d ₆ ) δ: 3.95 (4H, s), 6.81 (2H, br)
d, J = 8.5Hz), 7.35-7.39 (4H, m).

1,1'-bis (3,4-dihydroxyphenyl)
To a suspension of -2,2'-thiodiethanone (469 mg, 1.40 mmol) in trifluoroacetic acid (10 ml, 130 mmol) was added a solution of triethylsilane (2.8 ml, 17.6 mmol) in dichloromethane (24 ml) with stirring at room temperature, and the reaction was carried out for 90 hours. I let it. Ethyl acetate was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Silica gel column chromatography of the residue
After purification with (hexane: ethyl acetate = 1: 1), recrystallized from ethyl acetate-hexane, the title compound having the following physical properties 172 mg
(40%). * Properties: Melting point 105-108 ° C * MS (m / e): 306 (M ⁺ ) * ¹ H-NMR (Acetone-d ₆ ) δ: 2.7-3.1 (8H, m), 6.5-6.8
(6H, m), 7.7 (4H, br).

The following compounds were synthesized in the same manner as in Example 19.

(Example 20)

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* Properties: melting point 135-141 ° C * MS (m / e): 278 (M ⁺ ) * ¹ H-NMR (Acetone-d ₆ ) δ: 3.52 (4H, s), 6.6-6.9 (6
H, m), 7.8 (4H, br).

Example 21 <4- [3-[(4-hydroxyphenyl) thio] propyl]
Synthesis of -1,2-benzenediol>

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3- [3,4-bis [(2-methoxyethoxy) methoxy] phenyl] propyl p-toluenesulfonate and 4-hydroxythiophenol were dissolved in dimethylformamide (4 ml), and potassium carbonate (0.27 g, 1.98) was dissolved. mmol) and reacted at room temperature for 21 hours. Ethyl acetate was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: ethyl acetate = 1: 1) to give 4-[[3-
[3,4-Bis [(2-methoxyethoxy) methoxy] phenyl] propyl] thio] phenol (0.89 g, 100%) was obtained.

To a solution of this thioether compound (0.86 g, 1.90 mmol) in methanol (6 ml) was added 1 drop of concentrated hydrochloric acid while stirring at room temperature.
The reaction was performed for 4 days. Ethyl acetate was added to the reaction solution, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (355 mg, 68%) having the following physical properties. * Properties: melting point 136-138 ° C * MS (m / e): 276 (M ⁺ ) * ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.75 (2H, m), 2.43-2.51
(2H, m), 2.74 (2H, t, J = 7.1Hz), 6.38 (1H, dd, J = 7.
9Hz, 2.0Hz), 6.53 (1H, d, J = 2.0Hz), 6.60 (1H, d, J =
7.9Hz), 6.72 (2H, d, J = 8.6Hz), 7.20 (2H, d, J = 8.6H
z), 8.69 (2H, br), 9.50 (1H, br).

Example 22 <Synthesis of Oxybis (ethylene-1,3,4-benzenetriyl) = tetraacetate>

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4,4 '-(oxydiethylene) bis (1,2-benzenediol) was dissolved in pyridine (5 ml), and acetic anhydride (1.02 g, 4.5 eq.) Was added under ice cooling. After stirring at room temperature for 15 hours, the mixture was poured into ice-cooled 2N hydrochloric acid. The aqueous solution was extracted with ethyl acetate, and the organic layer was collected, washed once with 2N hydrochloric acid, twice with saturated brine, and dried over anhydrous magnesium sulfate. After evaporating the solvent, the residue was separated and purified by silica gel column chromatography (hexane: ethyl acetate = 2: 1) to give 454 mg (45%) of the title compound having the following physical properties.
I got * Properties: oil * MS (m / e): 458 (M ⁺ ), 137 (bp) * ¹ H-NMR (CDCl ₃ , TMS) δ: 2.28 (12H, s), 2.85 (4H,
t, J = 6.8Hz), 3.63 (4H, t, J = 6.8Hz), 7.03-7.26 (6H,
m)

In the same manner as in Example 22, the following compounds were synthesized.

(Example 23)

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* Properties: oil * ¹ H-NMR (CDCl ₃ ) δ: 1.85-2.00 (2H, m), 2.27 (3H,
s), 2.28 (3H, s), 2.29 (3H, s), 2.68-2.77 (2H, m),
2.92 (2H, t, J = 7.0Hz), 3.48 (2H, t, J = 6.2Hz), 3.65
(2H, t, J = 7.0Hz), 6.97-7.43 (13H, m), 7.50-7.68 (3
H, m), 8.03-8.10 (2H, m), 8.19-8.25 (1H, m).

Example 24 <Synthesis of 4- [3-[[4-[(2-methoxyethoxy) methoxy] phenethyl] oxy] propyl] -1,2-benzenediol

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Ethyl acetate (20 ml) was added to 10% palladium on carbon (1.83 g) catalyst, followed by 1,2-
Bis (benzyloxy) -4- [3-[[4-[(2-methoxyethoxy) methoxy] phenethyl] oxy] propyl]
A solution of benzene (18.3 g, 32.9 mmol) in ethyl acetate (80 ml) was added, and the mixture was stirred at room temperature under a hydrogen atmosphere for 60 hours. The reaction mixture was filtered through celite, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound having the following physical properties 11.
4 g (91%) were obtained. * Properties: oily * MS (m / e): 376 (M ⁺ ). * ¹ H-NMR (CDCl ₃ ) δ: 1.72-1.92 (2H, m), 2.50 (2H,
t, J = 7.4Hz), 2.82 (2H, t, J = 6.9Hz), 3.37 (3H, s), 3.
40 (2H, t, J = 6.4Hz), 3.54-3.60 (2H, m), 3.60 (2H,
t, J = 6.9Hz), 3.80-3.86 (2H, m), 5.23 (2H, s), 6.00
(1H, brs), 6.14 (1H, brs), 6.48 (1H, dd, J = 7.8Hz,
2.0Hz), 6.53 (1H, d, J = 2.0Hz), 6.72 (1H, d, J = 7.8H
z), 6.97 (2H, d, J = 8.7Hz), 7.13 (2H, d, J = 8.7Hz).

Example 25 <4- [3-[[4-[(2-methoxyethoxy) methoxy] phenethyl] oxy] propyl] -o-phenylene = bis [2
-[(Tert-butoxycarbonyl) amino] acetate
Synthesis of

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Dichloromethane (15 ml) was added to Boc-glycine (12.6 g, 72.0 mmol), and a dichloromethane solution (30 ml) of N, N'-dicyclohexylcarbodiimide (14.8 g, 71.8 mmol) was added thereto under ice-cooling. Stirred at 0 ° C. for 30 minutes. Then, 4-
[3-[[4-[(2-methoxyethoxy) methoxy] phenethyl] oxy] propyl] -1,2-benzenediol (11.4
g, 30.3 mmol) in dichloromethane (45 ml) was added dropwise at 0 ° C., and the mixture was stirred at room temperature for 18 hours. Ethyl acetate was added to the reaction mixture, insolubles were filtered off, the filtrate was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue and left at room temperature for 2 days. The insolubles were filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give the title compound (15.4 g, 7
3%). * Properties: Oil * ¹ H-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 1.70-2.00 (2H,
m), 2.60-2.70 (2H, m), 2.78-2.86 (2H, m), 3.37 (3H,
s), 3.36-3.44 (2H, m), 3.52-3.62 (4H, m), 3.79-3.8
4 (2H, m), 4.10-4.14 (4H, m), 5.24 (2H, s), 5.40-
5.60 (2H, br), 6.90-7.20 (7H, m).

Example 26 <Synthesis of 4- [3-[(4-hydroxyphenethyl) oxy] propyl] -o-phenylene = bis (2-aminoacetate) dihydrochloride>

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4- [3-[[4-[(2-methoxyethoxy) methoxy] phenethyl] oxy] propyl] -o-phenylene = bis [2-[(tert-butoxycarbonyl) amino] acetate] (6.03 g) , 9.13 mmol) was dissolved in ether (50 mml), and hydrogen chloride gas was blown into the solution under ice cooling.
Stirred at room temperature for 3 hours. The precipitated crystals were collected by filtration and dried to give 4.21 g (97%) of the title compound having the following physical properties. * Properties: melting point 160-166 ° C * ¹ H-NMR (CD ₃ OD) δ: 1.72-1.92 (2H, m), 2.63-2.79
(4H, m), 3.42 (2H, t, J = 6.0Hz), 3.57 (2H, t, J = 6.8H
z), 4.26 (2H, s), 4.27 (2H, s), 6.71 (2H, d, J = 8.6H
z), 7.05 (2H, d, J = 8.6Hz), 7.06-7.14 (2H, m), 7.23
(1H, d, J = 7.8Hz)

The following compounds were synthesized in the same manner as in Examples 24, 25 and 26.

(Example 27)

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* Properties: oil * ¹ H-NMR (CDCl ₃ ) δ: 1.46 (18H, s), 1.72-1.96 (2H,
m), 2.56-2.72 (2H, m), 2.72-2.88 (2H, m), 3.32-3.48
(2H, m), 3.58 (2H, t, J = 7.1), 4.08-4.17 (4H, m),
5.04 (2H, s), 5.32-5.52 (2H, br), 6.91 (2H, d, J =
8.8Hz), 6.92-7.12 (3H, m), 7.15 (2H, d, J = 8.8Hz),
7.28-7.48 (5H, m).

(Example 28)

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* Properties: amorphous * ¹ H-NMR (DMSO-d ₆ ) δ: 1.60-1.80 (2H, m), 2.35-2.4
4 (2H, m), 2.76-2.88 (2H, m), 3.30-3.40 (2H, m), 3.
53-3.61 (2H, m), 4.07 (2H, brs), 6.34-6.39 (1H, m),
6.54-6.69 (2H, m), 7.09 (2H, d, J = 8.5Hz), 7.33 (2
(H, d, J = 8.5Hz), 8.48-8.64 (2H, br).

(Example 29)

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* Properties: oil * ¹ H-NMR (CDCl ₃ ) δ: 1.46 (36H, s), 1.70-2.00 (2H,
m), 2.60-2.70 (2H, m), 2.80-2.90 (2H, m), 3.36-3.43
(2H, m), 3.56-3.64 (2H, m), 4.10-4.14 (8H, m), 5.4
4-5.64 (4H, br), 6.93-7.11 (6H, m).

(Example 30)

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* Properties: amorphous * ¹ H-NMR (DMSO-d ₆ ) δ: 1.70-1.90 (2H, m), 2.56-2.72
(2H, m), 2.80-2.96 (2H, m), 3.28-3.70 (4H, m), 4.2
3 (8H, brs), 7.14-7.29 (6H, m).

(Example 31)

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* Properties: oil * ¹ H-NMR (CDCl ₃ ) δ: 1.46 (27H, s), 1.77-1.92 (2H,
m), 2.59-2.67 (2H, m), 2.83-2.91 (2H, m), 3.37-3.44
(2H, m), 3.57-3.64 (2H, m), 4.10-4.18 (6H, m), 5.0
0-5.60 (3H, br), 6.80-7.25 (7H, m).

(Example 32)

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* Properties: amorphous * ¹ H-NMR (CDCl ₃ ) δ: 1.79-1.93 (2H, m), 2.64-2.73
(2H, m), 2.89 (2H, t, J = 6.7Hz), 3.45 (2H, t, J = 6.1H
z), 3.60-3.70 (2H, m), 4.13 (2H, s), 4.26 (2H, s),
4.27 (2H, s), 7.00-7.35 (7H, m).

[0126]

[Experimental Example] BALB / c mice (5 weeks old, purchased from Charles River Japan) were quarantined and acclimated for about 1 week before the experiment. In the experiment, the animals were divided into several groups so that the average body weight and the standard deviation were almost the same. Mouse anti-GBM nephritis
After immunization with 1 mg of globulin, it was induced on day 5 by intravenous injection of anti-mouse GBM rabbit serum. Each drug was administered by oral gavage with an oral sonde almost simultaneously with intravenous injection of anti-GBM serum. On days 5 and 10 after intravenous injection, urine was collected in a plastic urine collection cage and urine protein was measured (Otsuka Tonein TP
2). On the 11th day, blood was collected by carotid artery transection, and Toshiba TBA-380
Serum cholesterol, serum creatinine, and BUN were measured by an automatic analyzer.

The results are as shown in the following table.

[0128]

[Table 1]

+ Indicates suppression tendency (1 point), ++ indicates risk ratio 0.05
Below, significant improvement (2 points) is shown, and +++ indicates significant improvement (3 points) at a risk rate of 0.01 or less. Valid score is 5 days and 1
The score on day 0 is multiplied by 3 (urine protein is the most important index), and the score for total cholesterol, BUN, and creatinine is added.

[0130]

The compound (1) of the present invention is a novel compound and, as shown in the above-mentioned test examples, has a urinary protein inhibitory effect and an effect of improving serum test values (cholesterol). Therefore, the compound (1) of the present invention can be used, for example, as a therapeutic drug for renal disorders and the like.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/235 A61K 31/235 31/27 31/27 35/78 35/78 C C07C 43/23 C07C 43/23 D 69 / 035 69/035 69/773 69/773 69/86 69/86 271/22 271/22 323/16 323/16 323/20 323/20 (72) Inventor Tatsuhiro Obata 3586 Yoshihara, Ami-cho, Inashiki-gun, Ibaraki Prefecture Tsumura Co., Ltd. (72) Inventor Wang Wei No. 18, Dongzhongmen North Xinchang, Beijing, China People's Republic of China China Institute of Chinese Medicine Research Institute (72) Inside the Chinese Anther Research Institute (72) Inventor Yang Hua 18th China East Medical Center Research Institute of Chinese Medicine

Claims (2)

[Claims] 1. The following formula (1): (In the formula, R ₁ represents a hydrogen atom or -COR _9, R ₂
And R ₃ are the same or different and represent a hydrogen atom, a lower alkyl group or an arylalkyl group which may be substituted, X represents an oxygen atom or a sulfur atom, and R _{4 to} R ₈
Represents a hydrogen atom, a hydroxyl group, a lower alkyl group, an arylalkoxy group, an optionally substituted lower alkoxy group or —OCOR ₉ , and R ₉ represents an optionally substituted lower alkyl group or an aryl group. Also, m is 0
2, n represents 0 to 3. Or a pharmacologically acceptable salt thereof. 2. A therapeutic agent for nephritis comprising the substituted catechol derivative represented by the formula (1) according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.