JPH02142723A - Rental disorder-improving agent - Google Patents

Abstract

PURPOSE:To provide a renal damage-improving agent having a nephrosis- suppressing action, useful for treating renal diseases and having reduced adverse reactions by containing at least one of lignan compounds as an active ingredient. CONSTITUTION:At least one selected from guaiaretic acid and meso- dihydroguaiaretic acid contained in the resin of Guaicum officinale L., etc., arctin and arctigenin contained in Arctium lappa L., etc., and asarinin contained in Asiasari Radix, etc., is added and prepared into the objective agent by a conventional method. The agent can be prepared into the shape of an oral administration agent such as tablets, capsules, granules, grains or powders or a parenteral administration agent such as injections or suppositories. The agent is administered at a total dose of 50mg-2g per day several times per day in the case of the oral administration and is also injected at a dose of 0.1mg-1g per day in the case of the parenteral administration.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention is for nephrotic syndrome, acute progressive nephritis,
The present invention relates to a renal impairment improving agent that is effective in treating renal diseases such as chronic glomerulonephritis and nephrotic syndrome.

[Prior art and issues] Currently, drugs that are effective as therapeutic agents for renal diseases represented by acute progressive nephritis, chronic glomerulonephritis, and nephrotic syndrome include corticosteroids, immunosuppressants, platelet aggregation inhibitors, and anti-inflammatory drugs. Although they are coagulant fibrinolytics, their therapeutic effects cannot be said to be definitive. Therefore, it has been desired to develop a renal disorder improving agent that is effective in treating renal diseases and has fewer side effects.

[Means for Solving the Problems] In order to solve the above problems, the present inventors have been conducting research on various crude drugs, and have so far found that dibenzocyclooctadiene-type lignan compounds have excellent renal damage-improving effects. has been discovered and disclosed (Patent Publication No. 1 in 1986)
No. 19422).

This time, as a result of further intensive research, we found that guaiaretic and mesodihydroguaaretic andd contained in guaiac fat, arctiin and arctigenin that are eaten in foods such as beef stew, and also edible in spicy and other foods. The present inventors have discovered that azarinine, which is combined with azarinine, has an excellent ability to improve renal damage, and have completed the present invention.

Specifically, the present invention is a renal disorder improving agent containing as an active ingredient at least one compound selected from guaiaretic acid, mesodihydroguaiaretic acid, arctiin, arctigenin, and azarinin.

Hereinafter, the above-mentioned lignan compounds are collectively referred to as "J" active ingredient compounds.

For example, the following methods can be used to obtain the active ingredient compound.

■How to obtain guaiaretic acid, mesodihydroguaiaretic acid Guaicum officinale
I) by subjecting it to column chromatography one or more times using silica gel or the like as a carrier, and in some cases by crystallizing it using a solvent commonly used for crystallization such as methanol or water. Obtainable.

Examples of the solvent used in chromatography include a single solvent or a mixed solvent of more than one selected from n-hexane, cyclohexane, benzene, ether, tetrahydrofuran, chloroform, methylene chloride, ethyl acetate, acetone, ethanol, and methanol.

■How to obtain arctiin, arctigenin, or azarinine: Add the fruit of ArcLium 1appa L or Asiasari Radix to one or more mixed solvents selected from water, methanol, ethanol, acetone, and ethyl acetate. Extract using.

At this time, heating or reflux extraction may be performed depending on the case.

This extract is subjected to partition extraction using an organic solvent such as ether, n-hexane, or n-butanol, and the extract is subjected to column chromatography once as it is or after drying using silica gel, porous polymer gel, etc. as a carrier. Alternatively, the sample may be subjected to several times, and further subjected to high performance liquid chromatography if necessary. At this time, the elution solvents were water, methanol, ethanol, acetone, tetrahydrofuran, ethyl acetate, acetonyl-lyl, chloroform 1, benzene,
Solvents such as ether and n-hexane may be used alone or in combination.

By recrystallizing and powdering both components obtained in this way, if necessary, it can be further dissolved in a solvent such as ethanol,
It can be obtained by reacting with mineral acids such as sulfuric acid and hydrochloric acid.

Next, a specific example of the production of the active ingredient compound will be shown.

Specific example 1 (guaiaretic annots) Guaiac oil (manufactured by Kokusan Kagaku Co., Ltd.) 2759 was mixed with silica gel (manufactured by Merck & Co., Ltd., Kieselgel 60.70-230 mesh, the same hereinafter) 1
It was subjected to column chromatography using n-
Elution was performed using a hexane:acetone mixed solvent with increasing acetone ratio in sequence. The fractions eluted with n-hexane:acetone (4.1) were combined and concentrated under reduced pressure to obtain a residue of 30.39. 303 g of this residue was again subjected to column chromatography using 540 g of silica gel, and the fractions eluted with n-hexane:acetone (III) were combined and concentrated under reduced pressure to obtain a residue of 238 g.
g was crystallized from a mixed solvent of methanol and water to obtain 5.89 g of colorless plate crystals.

The physical and chemical properties of this colorless plate crystal are as follows, and are described in the literature [Y, Ikeya, Il, Taguchi, 1. Yo
shioka and H, Kobayashi, Che
m, Pharm, Bull, 27.1583-158
8 (1979)] described in guaiaretic and (g
uaialetic acid), i.e. (I Z,
35) The physical and chemical properties of -1,4bis-(4-hydroquine-3-methquinophenyl)-23-dimethyl-1-butene were consistent.

Properties: Colorless plate-like crystal Melting point 99.5-100.58C Specific rotation [α] 23 -77.7° (c = 1,00, CHCl3) Infrared absorption spectrum ν +n Intoxication cM-'3440 16+0
15]0 Ultraviolet absorption spectrum λ madH7111W (l
ogε): 206 (4,64), 260 (4,17) mass spectrum (E I -M S ) m/z (%):
3 2 B (M', 8.2), + 9 1 (59)
+ 5 9 (l OO), I 3 7 (19) High resolution mass spectrum C7°H, 04 (M') Calculated value: 328. +675 Actual value: 328.1671 Elemental analysis C2°H,,O,: Calculated value: C,73,13, H,7,37 Actual value: C,7
2,96, H, 7,28 proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 1.08 (3H, d, J = 6.7 Hz) 1.82 (
3H,d, J = 1.3 Hz).

2.51 (2H, m).

2.75 (IH, dd, J=13.6.5Hz).

3.84 (3H, s), 3.86 (3H, s).

5.47 (I H, br, s), 5.54 (I H
, br, s) 6.11 (I H, br, s), 6.3
8 (3H, m).

6.71 (IH, dd, J=8, 1.7Hz).

6.82 (IH, d, J = 8 Hz).

6.85 (IH9d, J=8Hz) 13c-nuclear magnetic resonance spectrum (δ pPm in CDCl5) 15.0(q), 19.0(q), 41.7(t).

4.5.6(d), 55.9(q)X2111.6(d
), 111.7(d).

114.0(d) x2, 121.8(d).

122.0(d), 124.6(d) 131.0(s), 133.1(s) 141.0(s), 143.7(s) 143.9 (s), 146.1 (s).

146.2(s) Specific Example 2 (Mesodihydroguaiaretic acid) Fractions eluted with n-hexane:acetone C7:3) in the second silica gel column 11 chromatography in Specific Example 1 were combined and concentrated under reduced pressure. 1.8 g of the resulting residue was crystallized from a mixed solvent of methanol and water to obtain 637.59 colorless spines.

The physical and chemical properties of this colorless needle crystal are as follows, and are described in the literature [Y, 1keya, 11. Taguchi,
1. Yoshioka and H, Kobayashi
, Chem, Pharm, Bull, , 27. +583
1588 (1979)].
retic acid), that is, (2R, 3S 11
．． 4-bis-(4-hydroquine 3-methoxyphenyl)
This was consistent with the physical and chemical properties of -2,3-dimethylbutane.

Properties: Colorless needle crystals Melting point: 8 B, 5-89.5°C Specific rotation = [α] 380° (c = 0, 91, CHCl3) Infrared absorption spectrum ν 2! zα visit: 3420, +610 151
0 Ultraviolet absorption spectrum λ ■A2Hy+m(logε
): 222(4,13), 2g2(3,80) Mass spectrum (E l -M S ) m/z (%) 330 (
M', 22), + 37 (100) elemental analysis C2,
H,60,: Calculated value/C,72,70, H97,93 actual value: C,7
2,61・87.92 Proton nuclear magnetic resonance spectrum (δ ppm in CDC13) 0.84 (614, d, J=6.7Hz) 1. 7 5
(2H, m).

2.27 (2H, dd, J = 13.9 Hz).

2.73 (2H, dd, J = 13.5 Hz)
3.85 (6H, s), 5.46 (2H, br, s) 6
．． 61 (2H,d, J = 2 Hz).

6.65 (214, dd, J = 8.2 Hz)6
．． 82 (2H, d, J = 81 (z) 3C-nuclear magnetic resonance spectrum (δ ppm in CDCl5) 16.3 (q) x 2, 39.0 (t) x 2 ° 39.2 (
d)X2.55.9(q)X2111.5(d)X2,
114.1 (d) x 212 +, 8 (d) x 2.133
．． 8(s)X2143.7(S)X2.146.4(s
) x 2 Specific Example 3 (Arctiin) Grind 2 kg of dried Ushiseko fruit and add 7 kg of methanol.
Reflux extraction was carried out at ρ for 7 hours. The extraction residue was further extracted twice in the same manner. The three extracts were combined and dried under reduced pressure to obtain a methanol extract of 426.79. The methanol extract was dissolved in 2.6ff of water, extracted three times with 25g of ether, and further extracted three times with 2ρ of n-butanol.

The n-butanol extract was concentrated under reduced pressure to obtain 252.0y of n-butanol extract. This n-butanol mixture was subjected to column chromatography using 1 kg of Norikakel (Merck Kieselkar 60230 Menono J, manufactured by Merck & Co., Ltd.), and eluted with a mixed solvent of chloroporum and methanol, increasing the proportion of methanol in sequence. did. The fractions eluted with chloroporum-methanol (9:1) were combined and concentrated under reduced pressure to give a dry extract of 132.2
I got a 9. 416g of this dry extract is Io, 4ril'
4 times, preparative high performance liquid column C7 chromatography [column, Waters prep pak-500/c +e
(diameter 3.80, length 30.), mobile phase acetonitrile-water (3N), flow rate: 150d/old n]. Combine fractions eluted at retention times 7 to 95 minutes,
The residue 3059 obtained by concentration under reduced pressure was crystallized from a mixed solvent of ethyl acetate and water to obtain colorless shime crystals 12C2.

The physical and chemical properties of this colorless cylindrical crystal are described in the literature [M, Chiba
f 11, Tsukamoto, S, hisada a
nd S, NishN15hibeSyoyaku
arctin, described in Zasshi, 33.150 (+979)], that is, (2R,3S)
-2-(4-βD-glucobylanoneroxy3-methoxybennol)3-(3,4-methoxybennol)-γ
-It was consistent with the physical and chemical properties of butyrolactone.

Properties: Colorless needle crystals Melting point: 116-117°C Specific rotation: [α] -480° (c = 2, OO, ClIC13) Mass spectrum (F D -M S ) m/z: 573 (M' +K
), 557(M”4-Na)534 [Cy7H340
11(M')]3C-Nuclear magnetic resonance vector (δ ppm in CDCl5) 35.4(t), 38.8(t), 42.5(d) 47
．． 5(d), 56.2(qX2), 56.8(q)62
．． 5(t), 71.3(d), 72.8(t) 74.9
(d), 77.8(d), 78.0(d) 102.9(
d), l 13.7(d)+14 9(d) +(d) 7(s) 8(s) 4(s) 9(d) 0(d) 2(s) 1(s) 6(s ) 181.2(s) Specific example 4 (arctigenin) 7.0 g of arctiin obtained in specific example 3 was dissolved in 60 g of ethanol.
7, added 20% sulfuric acid, and refluxed at 78°C for 2 hours. After cooling, the reaction mixture was diluted with 100 d of water, and the reaction mixture was extracted three times with 100 d of ether. The ether extract was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to column chromatography (diameter 2 mm, length 22 m) using silica gel (Kieselgel 60.230-400 Metsushiko manufactured by Merck & Co.).

Elution was performed with n-hexane-ethyl acetate (+:l) 5007d. The fractions eluted with n-hexane-ethyl acetate (1:I) were combined and concentrated under reduced pressure. 35 g of the resulting residue was crystallized from a mixed solvent of n-hexane and acetone to obtain 2.0 g of colorless prism crystals. Obtained.

The physical and chemical properties of this colorless prism crystal are described in the literature [S, Tan
don and R, P, Rastogi, Phyto
Chemistry, 151789 (1976)] physicochemical properties of arctigenin.

Properties: Colorless prism melting point: 99-100°C Specific rotation: [α]'3 -37.6° (c = 0.905, CHCl5) Infrared absorption spectrum ν A Iα 3525, +763.1605.1512 Mass spectrum ( E I - M S ) m/z (%) 372 (M”
, 40), l 77 (13) + 5 2 (29), +
5 1 (71)+37(+00) High-resolution mass spectrum Cp+H+40 eCalculated value・372.1573 Actual value+372. l592 Proton nuclear magnetic resonance spectrum (δ ppm in CDC13) 2.57 (41-1, br s ), 2.93 (2
H, m).

3.84 (61-1, s), 3.87 (3H, s).

3.90-4.38 (2H, m) 5.75 (LH,brs).

6.49-6.92 (6H, m) 13cm nuclear magnetic resonance spectrum (δ ppm in CDC13) 35.2(t), :38.5(t), 42.2(d).

47.4(d), 56.3(qx3), 72.5(t)
.

112.9(d), 113.4(d) 113.7(d), I t 6. o(d) 121.8(
d), 122.9 (d) 130.6 (s), I 32.5 (s) 1 4 6.1
(s), 1 4 8.6 (s) 1 4 8.8 (s),
1 5 0.1 (s) 180.9 (s) Specific example 5 (Azarinin) Grind 5 kg of chili pepper, extract under reflux with methanol 36ρ for 2 hours, concentrate the extract under reduced pressure, and obtain methanol extract 658
．． I got 59. Suspend the methanol extract in 3Q water,
- After extraction with 5g of hexane 3 times, extract with n-butanol 5Q 3 times.
Extracted twice. The n-butanol extract extract was concentrated under reduced pressure to obtain 121.59 g of n-butanol extract. The n-butanol extract was subjected to column chromatography using Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation) 5ff, and 1 g of water,
40% methanol 15g, methanol 8a1 acetone 6
0. It was eluted sequentially. The residue 32.59 obtained by concentrating the acetone eluate under reduced pressure was crystallized from acetone to obtain colorless button-shaped crystals 6.519. The physical and chemical properties of this colorless needle crystal are described in the literature [T., Kaku, N., Kutani and
J, Takahashi.

Yakugaku Zassbi, 56,361 (19
36)] described in 1-asarinin (1-asarinin
), i.e. (IR,2R,5R6S)-2,6-di(
The physical and chemical properties of 3,4-methylenezoxyphenyl)3,7-thioxabicyclo[3,3,0]octene were consistent.

Properties Colorless needle crystals Melting point + I l 9.0-120.5°C Specific rotation ratio variation [α
]", 9 -108.3° (c = 0, I l
, CHCl5) mass spectrum (E I -M S )
m/z354 (M”), 323), +49 ultraviolet absorption spectrum λ EIOII nm (,ogε)2
05.4 (4,64), 241.2 (3,91) 288
．． 4(3,92) Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 2.86 (I H, m), 3.30 (2H, m)3
．． 83 (IH, dd, J = 9.6l-1z) 3.84
(I H, dd, J = + 2.2l-1z)4.1
0(IH, dd, J=9.IHz) 4.39(IH, d
, J=7Hz) 4.83 (IH, d, J=6Hz) 5.95 (2H, s), 5.96 (2H, s) 6.78
(IH, d, J = 8T (z) 6.82 (I H, d, J = 8 Hz) 6.8
3 (I H9d, J = 8 Hz) 6.86 (2H, br s) "c-nuclear magnetic resonance spectrum (δ ppm in CDCl5): 50.2 (d), 54.7 (d), 69.7 ( t).

70.9(t), 82.0(d), 87.7(d).

101.0 (tx2), 106.5 (d) 108.1 (
dX2), 118.7(d).

119.5(d), 132.3(s).

1 3 5.2 (s), 1 4 6.6 (s) 1 4
7.2 (s), 1 4 7.7 (s).

148.0 (s) Next, the fact that the active ingredient compound has a nephrosis-inhibiting effect and is effective in treating renal diseases will be explained using experimental examples.

Experimental Example I Using 5-week-old Wistar male rats, 10 m of Bureau Mine Amino Nucleond (manufactured by Sigma) was used once a day.
By intraperitoneal administration for 9.6 days on September 9th,
caused ze. The active ingredient compound was suspended in 1% Tween 80 (manufactured by Tokyo Kasei Co., Ltd.) and administered intraperitoneally four times every other day from the second white of the eyes after the final administration of Bureaumine Amino Nucleond.
1p) or orally (p, o,), and the total amount of protein in the urine was measured orally.

A group to which only 1% Tween 80 (Idj/&g) containing no active ingredient compound was administered was used as a control group.

The results are shown in Tables 1 and 2.

Table 1 shows the nephrosis-suppressing effect of Guaiaretic Ando; Table 2 shows the nephrosis-suppressing effect of arctiin, arctiin, and azarinin; Excretion volume decreased. From this, it was confirmed that the active ingredient compound had an improving effect on nephrosis, and its usefulness as a therapeutic agent for renal diseases was confirmed.

Furthermore, no side effects were observed due to administration of the active ingredient compound.

Next, the acute toxicity of the active ingredient compounds was investigated using ddy male mice, and although the active ingredient compounds were observed for up to 72 hours after intraperitoneal administration of 0.5'11 kg, no deaths occurred.

As mentioned above, the active ingredient compounds have low toxicity and are highly safe.

Next, the dosage and formulation of the active ingredient compound will be explained.

The active ingredient compounds can be administered to animals and humans as such or together with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and suppositories. It will be done.

In order to exert the desired effect as an oral agent, although it varies depending on the age, weight, and severity of the disease of the patient, it is usual for an adult to administer 50 to 2 g of the compound of the present invention in divided doses several times a day. It seems appropriate to take it.

Oral agents include, for example, starch, lactose, sucrose, mannitol,
It is manufactured using conventional methods using carboxymethyl cellulose, corn starch, inorganic salts, etc.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[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, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, Polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The active ingredient compound can also be administered as a suspension, emulsion, syrup, or elixir.
These various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, although it varies depending on the age, weight, and severity of the disease of the patient, it is usually necessary to administer the compound of the present invention at a dosage of 0.1 Q to 1 g per day for adults. Injection, intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for intrarectal administration, and the like, which are manufactured according to conventional methods.

Example 1 ■Corn starch 449 ■Crystalline cellulose 409 ■Carpoquinedylcellulose calcium 59 ■Light silicic anhydride 0.59■Magnesium stearate 0.5g■Compound obtained in specific example 1
IO Total: 1009 According to the above recipe, ■ to ■ were mixed uniformly and compression molded using a key press to obtain one tablet of 2001!9.

This tablet-tablet contains the compound 20R9 obtained in Example 1, and an adult should take 10 to 25 tablets in several doses per day.

Example 2 Example 3 ■Crystalline cellulose 84.59 ■Magnenium stearate 059 ■Carboquine methylcellulose calcium 5g ■Compound obtained in Example 2 10g Total 100g Mix ■, ■, and part of ■ uniformly according to the above recipe After compressing and molding, the mixture was pulverized, and the remaining amounts of (1) and (2) were added and mixed, and the mixture was compressed and molded using a tablet machine to obtain a portion of 20 OR9 tablets.

This tablet contains 1 g of the compound 20I obtained in Example 2, and an adult should take 10 to 25 tablets in several doses per day.

■ Crystalline cellulose 34.59 ■ 10% hydroquinepropylcellulose in ethanol @ 5og ■ Carboquinomethylcellulose calcium 59 ■ Magnesium stearate 0.59 ■ Compound obtained in Example 3 1009 Total according to the above recipe ■, ■ and ■ After uniformly mixing the ingredients, neutering them using a conventional method, granulating them using an extrusion granulator, drying and crushing them, and then mixing ■ and ■ and compressing them using a tablet machine to make a portion of 200 R9. tablets were obtained.

This tablet contains 20 tablets of the compound obtained in Example 3, and is taken by adults in 10 to 25 tablets a day in several doses.

Example 4 ■Corn starch 849■Magnenoum stearate 059 ■Carboxine methylcellulose calcium 5g ■Light anhydrous silicic acid 0.5g ■Compound obtained in Example 4 109 Total 100ir Mix ■～■ uniformly according to the above recipe and compress. After compression molding with a molding machine, it was crushed with a crusher and sieved to obtain granules.

This granule 19 contains 100 x the compound obtained in specific example 4.
9, and adults should take 2 to 5 g per day in several doses.

Example 5 ■ Crystalline cellulose 559 ■ 1O% hydroxypropyl cellulose ethanol solution 359 ■ Compound obtained in specific example 5 109 Total 1009 According to the above recipe, ■ to ■ were uniformly mixed and suspended. After granulation using an extrusion granulator, the mixture was dried and sieved to obtain granules.

This granule 19 contains compound 10011 obtained in specific example 5.
Adults should take 2 to 59 doses in several doses per day.

Example 6 ■Corn starch 89.59■Light silicic anhydride 0.59■Compound obtained in specific example 1
109 Total 1009 Mix ■～■ uniformly according to the above recipe, 200 R
9 was filled into a No. 2 capsule.

This capsule contains the compound 20R9 obtained in Example 1, and an adult should take 10 to 25 capsules a day in several doses.

Example 7 ■ Soybean oil 59 ■ Distilled water for injection 8959 ■ Soybean phospholipid 2.5g ■ Glycerin
2g ■ Compound obtained in Example 2 1900g Dissolve ■ in ■ and ■ according to the above recipe, and add ■ to this.
The solutions of (1) and (2) were added and emulsified to obtain an injection.

Claims (1)

[Claims] A renal disorder improving agent containing as an active ingredient at least one compound selected from guaiaretic acid, mesodihydroguaiaretic acid, arctiin, arctigenin, and azarinin.