JPH05271067A - Fibrosis-suppressing agent - Google Patents

Abstract

PURPOSE:To obtain a fibrosis-suppressing agent effective in suppressing the fibrosis of organs and useful for the treatment of fibrosis by using a gallic acid ester as an active component. CONSTITUTION:The objective agent contains a gallic acid ester of formula (R is 1-20C alkyl, 2-20C alkenyl, aryl, cycloalkyl, aralkyl, etc.) as an active component. The compound can be produced by a conventional process comprising the reaction of a gallic acid halide with an alcohol. The content of the active component in the agent is 0.1-500 mg per unit dose and the component is administered at a daily rate of 5-300 mg by oral administration or 0.1-50mg/kg by parenteral administration for adult. A gallic acid ester is effective in suppressing the formation of collagen fiber of a fiber-forming mutant cell (M- strain cell) originated from a rat liver cell at a low concentration. (+)- Catechin-3'-O-gallate and (+)-catechin-4'-O-gallate, etc., obtained from a wild grape are also preferable examples of the gallic acid ester.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an agent for suppressing fibrosis of organs.

[0002]

BACKGROUND OF THE INVENTION Excessive deposition of collagen fibers in fibrosis such as pulmonary fibrosis, arteriosclerosis, and liver cirrhosis is due to an increase in collagen synthesis of fibroblasts. Collagen synthesis inhibitors are considered to be useful for the prevention and treatment of these diseases.

Japanese Patent Publication No. 60-7974 discloses a prophylactic and therapeutic agent for liver cirrhosis, which is mainly composed of an alcoholic extract of Nogrape fruit. It is known that the alcoholic extract of Nogrape fruit has a collagen fiber formation inhibitory action (Prog. Med., 6, 1035-1040 (1986)).

Further, Japanese Patent Laid-Open No. 2-48533 discloses that
A therapeutic agent for liver diseases consisting of extracts of Nogrape root has been proposed,
Resveratrol and its related substances have been isolated as liver damage suppressing substances. These compounds show an inhibitory effect on rat liver damage caused by carbon tetrachloride.

Furthermore, 3,4-dihydroxybenzoic acid and the like are known to inhibit collagen synthase proline hydroxylase in vitro (K. Majama).
a, et al. J. Biol. Chem., 261 , 7819 (1986)). However, these are effective only in high concentration on cultured cells, and their usefulness as pharmaceuticals has not been recognized.

[0006]

Therefore, an object of the present invention is to provide a fibrosis-inhibiting agent effective for treating fibrosis.

[0007]

As a result of intensive studies to achieve the above object, the present inventors have found that gallic acid ester has a large fibrosis-inhibiting effect, and completed the present invention.

That is, the present invention provides a fibrosis inhibitor containing an effective amount of gallic acid ester.

The gallic acid ester is preferably a gallic acid ester represented by the following general formula (1).

[0010]

[Chemical 4] (In the formula, R is an alkyl group having 1 to 20 carbon atoms and 2 to 2 carbon atoms.
20 alkenyl groups, aryl groups, cycloalkyl groups,
Aralkyl group, group represented by the following formula (2) or (3)

[0011]

[Chemical 5]

[0012]

[Chemical 6] Examples of the alkyl group include, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-
Butyl, t-butyl, pentyl, isopentyl (isoamyl), neopentyl, t-pentyl, hexyl, isohexyl, heptyl, octyl, 2-ethylhexyl,
Nonyl, decyl, undecyl, dodecyl, tridecyl,
Examples thereof include linear or branched alkyl groups such as tetradecyl, hexadecyl (cetyl), octadecyl (stearyl), and icosyl. Among these alkyl groups, gallic acid esters having an alkyl group having 1 to 20 carbon atoms, and particularly an alkyl group having 7 to 18 carbon atoms, have a high activity of suppressing cell fibrogenesis.

Examples of the alkenyl group include vinyl,
Allyl, 1-propenyl, isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-
Butenyl, 2-ethyl-1-butenyl, 3-methyl-2
-Butenyl, 1,3-butadienyl, 1-pentenyl,
2-pentenyl, 3-pentenyl, 4-pentenyl, 4
-Methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-octenyl, 2-octenyl, 3-octenyl, 4-octenyl, 5-octenyl, 6-octenyl. , 7-octenyl, 7-decenyl, 7-decenyl, 8
-Decenyl, 9-decenyl, 1-undecenyl, 2-undecenyl, 3-undecenyl, 4-undecenyl, 5
Examples include -undecenyl, 6-undecenyl, 7-undecenyl, 8-undecenyl, 9-undecenyl, 10-undecenyl, oleyl, and linoleyl group.

Aryl groups include, for example, phenyl and naphthyl groups, and cycloalkyl groups include, for example:
Included are cyclohexyl, cyclooctyl groups and the like.

The aralkyl group includes, for example, benzyl, phenethyl and benzhydryl groups.

The aryl group, the cycloalkyl group and the aryl group of the aralkyl group are, for example, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-hydroxyhexyl, 2,4-dihydroxyphenyl and 2,4. -Dihydroxycyclohexyl, 2,
It may have about 1 to 3 hydroxyl groups such as 4,6-trihydroxyphenyl and 2,4,6-trihydroxycyclohexyl groups.

Among the above gallic acid esters, the ester having an alkyl group having 7 to 18 carbon atoms and the ester having a group represented by the formula (2) or (3) are particularly preferable.

The gallic acid ester having these groups R can be produced by a conventional method, for example, an acid halide method of a gallic acid halide and a corresponding alcohol; an esterification method of a gallic acid and a corresponding alcohol. [R
ecl., Trans., Chim., Pays-Bas., 70 , 277 (1959)].

More specifically, in the acid halide method, gallic acid halides such as gallic acid chloride and gallic acid bromide can be used. The reaction between the halide of gallic acid and the alcohol can be carried out in an organic solvent inert to the reaction, and the reaction is carried out at -10 ° C to the reflux temperature of the solvent,
It can be preferably carried out at about 0 to 75 ° C.

The esterification reaction between gallic acid and alcohol can be carried out in the presence of an acid catalyst while removing water produced in an organic solvent. Examples of the acid catalyst include inorganic acids such as hydrochloric acid, sulfuric acid and phosphoric acid; organic acids such as p-toluenesulfonic acid. Examples of the organic solvent include aliphatic hydrocarbons such as hexane and octane; alicyclic hydrocarbons such as cyclohexane and cyclooctane; aromatic hydrocarbons such as benzene, toluene and xylene; and mixed solvents thereof. The reaction is
It can be carried out at 50 ° C to the reflux temperature of the solvent.

A gallic acid aryl ester is described, for example, in US Pat. No. 4,394,389 and US Pat.
It can be produced by the method described in No. 448730 or the like or a method similar thereto.

The gallic acid ester represented by the above general formula (1) can be isolated and purified by subjecting the reaction product to a conventional separation and purification means such as recrystallization, solvent extraction, distillation and column chromatography. ..

The gallic acid ester having the groups represented by the above formulas (2) and (3) is a nouvelle [amperopsis
Prebi Pedul Kurata (Maxim) Touratobu (Ampelo
psisbrevipedunculata (Maxim) Trautv.)] and acacia (Acacia gerrardii). In the present invention, (+)-catechin-3′-O-gallate and (+)-catechin-4′-O-gallate obtained from Nogrape, or the tea component (−)
-Epicatechin-3-O-gallate and (-)-epigallocatechin-3-O-gallate (J. Chem. Soc., 2249
(1948)] and the like are also preferred examples.

The gallic acid ester having a group represented by the above formulas (2) and (3) is, in a preferred embodiment, subjected to the extraction step with alcohol of stems, leaves and fruits of Nogrape, and the obtained alcohol extract is obtained. It can be obtained by separation and purification. The grapes may be used as a dry powder if necessary. As alcohol, for example,
Methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol and the like can be mentioned. If necessary, ethers such as dioxane and tetrahydrofuran; ketones such as acetone may be used in combination.

For the extraction operation, a mixed solvent of water and alcohol, especially an aqueous solution of methanol and ethanol, is often used. In the mixed solvent, the alcohol concentration is, for example,
It is about 10 to 100% by weight, preferably about 25 to 100% by weight.

The extraction with alcohol can be carried out at 0 ° C. to the reflux temperature of the solvent, preferably at room temperature to 100 ° C. The extraction with alcohol may be performed multiple times.

The alcohol extract obtained is usually concentrated and then (a) partitioned between water and alcohol, or (b).
Subject to a partitioning step with methanol and a suitable immiscible organic solvent.

As the alcohol in the above (a),
An alcohol that is not miscible with water, such as butanol,
Examples include isobutanol, t-butanol, cyclohexanol and the like. Preferred alcohols include butanol.

Examples of the immiscible organic solvent in the above (b) include aliphatic hydrocarbons such as hexane and octane; alicyclic hydrocarbons such as cyclohexane, benzene, and the like.
Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as dichloromethane, dichloroethane and carbon tetrachloride; ketones such as methyl ethyl ketone; esters such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, etc. Can be mentioned. Preferred immiscible organic solvents include esters such as ethyl acetate.

The organic layer obtained by the partitioning operation is concentrated, if necessary, and subjected to chromatography (column chromatography, high performance liquid chromatography, thin layer chromatography, gel chromatography, etc.), ion exchange resin, recrystallization, solvent extraction and the like. The compound can be isolated by subjecting it to a separation and purification means that is a combination thereof.

In a preferred isolation procedure for isolating a compound having a group represented by the above formula (2) or (3),
The extract obtained through the partitioning step (b), particularly the extract obtained by concentrating the organic layer of the ester, is a high porous polymer such as Diaion HP-20, Sephadex LH-20 or MCI gel CHP. Fractionated by gel filtration such as -20P. Above all, it is preferable to subject them to gel chromatography using them as a carrier. Furthermore, it is preferable to combine with a carrier using other gel as a carrier for gel chromatography.

More specifically, in the case of isolating (+)-catechin and the like through the partitioning step (a), the dried powder of Nou grape stems, leaves and fruits is mixed in an amount of about 3 to 10 times 40. %
(V / W) Cold soak in an ethanol aqueous solution for a whole day and night, and the same operation is repeated a plurality of times, and the cold soak solution is also concentrated to obtain an ethanol extract.

The extract is suspended in water and ethanol is added to concentrate the soluble part. Then, the residue is partitioned with butanol and water, the butanol layer is separated, the aqueous layer is further subjected to an extraction operation with butanol, and the butanol layers are combined and concentrated to obtain a butanol extract. The butanol extract is subjected to column chromatography using, for example, Sephadex LH-20 or the like to fractionate into 5 fractions.

The third fraction was subjected to chromatography on silica gel, and the crystals obtained by eluting with an eluent, for example, chloroform-methanol, were recrystallized from water.
Gallic acid ethyl ester is obtained.

When the crystals obtained from the fifth fraction were recrystallized from hydrous acetic acid, the following formula (4)

[0036]

[Chemical 7] The (+)-catechin represented by is obtained.

A compound having a group represented by the above formulas (2) and (3) can be isolated from a methanol extract obtained by the same extraction operation as described above using methanol instead of ethanol.

That is, the methanol extract is distributed between hexane and methanol, the methanol layer is separated and concentrated, and the obtained extract is distributed between ethyl acetate and water. The ethyl acetate layer is separated, the aqueous layer is further subjected to extraction operation with ethyl acetate, and the ethyl acetate layers are combined and concentrated to obtain an ethyl acetate extract. The ethyl acetate extract is subjected to chromatography using a high porous polymer (for example, Diaion HP-20, etc.) and eluted with water-containing methanol to fractionate into 3 fractions. The target product can be obtained by subjecting each fraction to various chromatographys, including chromatography using a cation exchange resin as a carrier.

For example, methyl gallate is obtained from the first fraction, and (+)-catechin is obtained from the second fraction. Furthermore, the third fraction is, for example, MCI gel CHP-
When subjected to column chromatography using 20P or Sephadex LH-20 or the like, a light brown powder is obtained.

This slightly brown powder forms an equilibrium mixture of the two components which cannot be isolated in aqueous solution. The light brown powder is methylated with ditylsulfuric acid in acetone in the presence of a base such as potassium carbonate and the product is separated and purified by silica gel chromatography to give two components.

The spectral data and physicochemical constants of these components are hexa-O-methyl-(+)-catechin-
3'-O-gallate and hexa-O-methyl-(+)
-Catechin-4'-corresponds to O-gallate. Therefore, the structures of the components are (+)-catechin-3'-O-gallate and (+)-represented by the following formulas (5) and (6).
It is determined to be catechin-4'-O-gallate.

[0042]

[Chemical 8]

[0043]

[Chemical 9] Isolation of gallic acid esters having groups of formulas (2) and (3) from acacia is described in E. Malan and DH Pie.
naar, Phytochemistry, 26 , 2049 (1987). That is, acacia bark powder is extracted with hexane and then with acetone, and the acetone extract is subjected to silica gel column chromatography. The gallic acid ester is isolated and purified by eluting with an acetone-benzene mixed solvent and subjecting it to thin layer chromatography.

The gallic acid ester has a characteristic that it exerts a high inhibitory effect on the collagen fiber formation of cells at a low concentration. For example, gallic acid ester is 0.3-
A low concentration of 100 μM suppresses collagen fiber formation in rat hepatocyte-derived fibrogenic mutant cells (M cell lines).

The gallic acid ester is a naturally-occurring compound or a compound derived therefrom and has low toxicity and high safety. For example, when gallic acid propyl ester is orally administered to rats, the LD50 value is Is 3.
It is 8 g / kg.

Although gallic acid esters have hitherto been used as antioxidants, they are not known to have a collagen fiber formation inhibitory action.

The fibrogenesis inhibitor of the present invention has the formula (1) above.
The compound represented by is included as an active ingredient. The content of the compound represented by the formula (1) is not particularly limited, but is usually
It is about 0.1 to 500 mg per dosage unit. The compound represented by formula (1) can be administered orally and parenterally. The dose can be appropriately determined depending on the kind of compound, administration route, age, degree of symptoms, etc., but usually, it is about 5 to 300 mg per day for an adult and about 0.1 to 50 mg / kg for parenteral administration. is there. The frequency of administration is not particularly limited, and the administration can be performed once or separately.

Dosage forms include tablets, granules, powders,
Solid agents such as pills and capsules; liquid agents such as suspensions, emulsions, injections and infusions.

For the preparation of solid preparations, conventional ingredients, for example, sugars such as starch, lactose, sucrose, mannitol and corn starch, excipients such as crystalline cellulose, carboxymethyl cellulose and silicic acid; polyvinyl alcohol, polyvinyl pyrrolidone, Polyvinyl ether, ethyl cellulose, gum arabic, tragacanth, gelatin,
Hydroxypropyl cellulose, calcium citrate,
Binders such as dextrin and pectin; lubricants such as magnesium stearate, talc and polyethylene glycol; disintegrating agents such as carboxymethyl cellulose calcium, disintegrating aids, stabilizers and coloring agents can be used.

The above-mentioned dosage forms can be manufactured by a conventional method. Usually, the fibrosis-suppressing agent of the present invention is obtained by mixing an effective amount of the compound of formula (1) with the above-mentioned conventional additive components, if desired.

[0051]

INDUSTRIAL APPLICABILITY Gallic acid ester suppresses collagen fiber formation in rat hepatocyte-derived fibrogenic mutant cell line (M cell line) at low concentration. Therefore, a fibrosis inhibitor containing gallic acid ester is useful for treating fibrosis.

[0052]

EXAMPLES The present invention will be described in more detail based on the following examples.

Example 1 [Ampelopsis brevipedu] [Ampelopsis brevipedu]
nculata Trautv. var. The same operation was repeated twice more, and the extracts were combined and concentrated to obtain 40% ethanol extract.

The ethanol extract was suspended in water, ethanol was added to remove the insoluble portion, and the mixture was partitioned with butanol and water. The butanol layer was separated, concentrated under reduced pressure, subjected to chromatography using Sephadex LH-20, and eluted with butanol to fractionate into 5 fractions.

The third fraction was chromatographed on silica gel with chloroform-methanol (20:
The crystals obtained by elution in 1) were recrystallized from water to give colorless needle crystals of gallic acid ethyl ester.

Mp: 152-154 ° C. UV absorption spectrum, infrared absorption spectrum, ¹ H-
The nuclear magnetic resonance spectrum and ¹³ C-nuclear magnetic resonance spectrum were in agreement with the preparation. Also, Rf value of thin layer chromatography and tR value of high performance liquid chromatography are
It was in direct agreement with the standard.

The crystals obtained from the fifth fraction were recrystallized from hydrous acetic acid to obtain slightly yellow needle-like (+)-catechin.

Mp: 175 to 177 ° C. [α] _D : + 14.2 ° (C = 0.26, ethanol) UV absorption spectrum, infrared absorption spectrum, ¹ H-
The nuclear magnetic resonance spectrum and ¹³ C-nuclear magnetic resonance spectrum are in perfect agreement with the standard, and the R
The f value and tR value of high performance liquid chromatography were also in agreement with the standard in a direct comparison.

Example 2 (+)-catechin-3'-O-gallate and (+)-
Extraction and isolation of catechin-4'-O-gallate In the same manner as in Example 1, 10 kg of Nogrape dust was extracted with methanol to obtain a methanol extract. The methanol extract was partitioned between hexane and methanol, the methanol layer was separated and concentrated, the obtained residue was partitioned between ethyl acetate and water, and the ethyl acetate layer was separated. The aqueous layer was extracted twice more with ethyl acetate, and the ethyl acetate extracts were combined to obtain a concentrated ethyl acetate extract.

Ethyl acetate extract was added to Diaion HP-
It was subjected to chromatography using 20 and fractionated into 3 fractions. Gallic acid methyl ester was obtained from the first fraction. In addition, (+)-catechin was obtained from the second fraction.

The third fraction was further added to Sephadex LH-
Chromatography with 20 gave (+)-catechin-3'-O-gallate and (+)-as pale brown powders.
Catechin-4'-O-gallate was obtained.

Ultraviolet absorption spectrum λ max (nm): 2
08,282 infrared absorption spectrum ν max (cm ^-1 ): 3400,1
710, 1610 ¹ H-nuclear magnetic resonance spectrum (deuterated methanol) δ: 7.
24 (2H, s), 7.23 (2H, s), 7.2-
6.9 (6H, m), 5.95 (2H, t, J = 2.4)
5.Hz), 5.90 (1H, d, J = 2.4Hz), 5.
87 (1H, d, J = 2, 4Hz), 4.67 (1H,
d, J = 7.4 Hz), 4.59 (1H, d, J = 8.
2 Hz) 3.99 (2H, m), 2,53 (2H, m) ¹³ C-nuclear magnetic resonance spectrum (deuterated methanol) δ: 16
7.2, 167.1, 157.8, 157.7, 15
7.6, 157.5, 156.8, 156.7, 15
0.2, 146.5, 140.4, 140.3, 14
0.1, 140.0, 139.5, 132.2, 12
7.1, 124.0, 123.1, 120.7, 12
0.6, 119.7, 117.7, 116.6, 11
0.9, 101.0, 100.8, 96.5, 95.
6, 82.5, 82.4, 69.0, 28.9, 28.
3 (+)-catechin-3'-O-gallate and (+)-
Methylation of catechin-4'-O-gallate To a mixture of (+)-catechin-3'-O-gallate and (+)-catechin-4'-O-gallate 200 mg, potassium carbonate 1.0 g and acetone 10 ml, below freezing,
1 ml of ditylsulfate was added, and the mixture was heated under reflux for 12 hours. After removing the insoluble matter and concentrating the filtrate, the residue was chromatographed on silica gel, the first fraction was precipitated with isopropyl ether and hexa-O-methyl-(+)-catechin-3'-O-. 79 mg of gallate was obtained.

[Α] _D : -6.8 ° (C = 1.0, chloroform) UV absorption spectrum λ max nm (log ε): 274
(4.12), 209 (4.89) Infrared absorption spectrum ν max (cm ⁻¹ ): 3450,1
735, 1620, 1590 ¹ H-nuclear magnetic resonance spectrum (deuterated chloroform) δ:
7.46 (2H, s, 2 ", 6" -H), 7.33 (1
H, dd, J = 8.4, 1.8 Hz, 6'-H), 7.
26 (1H, d, J = 1.8Hz, 2'-H), 7.0
4 (1H, d, J = 8.4 Hz, 5'-H), 6.13
(1H, d, J = 2.4 Hz, 8-H), 6.10 (1
H, d, J = 2.4 Hz, 6-H), 4.71 (1H,
d, J = 8.0 Hz, 2-H), 4.04 (1H, m,
3-H), 3.94 (3H, s, 4 "-OMe), 3.
93 (6H, s, 3 ", 5" -OMe), 3.84 (3
H, s, OMe), 3.80 (3H, s, OMe),
3.75 (3H, s, OMe), 3.04 (1H, d
d, J = 16.4, 5.6 Hz, 4-H), 2.60
(1H, dd, J = 16.4,8.8Hz, 4-H) The second fraction was precipitated from isopropyl ether to give 81 mg of hexa-O-methyl-(+)-catechin-4'-O-gallate. Obtained.

[Α] _D : -19.0 ° (C = 1.0, chloroform) UV absorption spectrum λ max nm (log ε): 275
(4.16), 209 (4.91) Infrared absorption spectrum ν max (cm ⁻¹ ): 3450,1
735, 1620, 1590 ¹ H-nuclear magnetic resonance spectrum (deuterated chloroform) δ:
7.47 (2H, s, 2 ", 6" -H), 7.19 (1
H, d, J = 8.4 Hz, 5'-H), 7.10 (1
H, b, 2'-H), 7.08 (1H, dd, J = 8.
4, 1.8 Hz, 6'-H), 6.17 (1H, d, J
= 2.4 Hz, 8-H), 6.13 (1H, d, J =
2.4 Hz, 6-H), 4.76 (1 H, d, J = 8.
0 Hz, 2-H), 4.04 (1H, m, 3-H),
3.95 (9H, s, 3 ", 4", 5 "-OMe),
3.84 (3H, s, OMe), 3.82 (3H, s,
OMe), 3.78 (3H, s, OMe), 3.06
(1H, dd, J = 16.4, 5.8Hz, 4-H),
2.62 (1H, dd, J = 16.4, 10.2Hz,
4-H) Examples 3 to 16 and Comparative Example A rat hepatocyte-derived M strain cell containing Williams' E solution (50% 1 U / ml) containing 10% fetal calf serum.
Penicillin, 50 [mu] g / ml streptomycin) with on the glass slide chamber, 5% CO ₂ -9
The cells were cultured in a carbon dioxide incubator maintained at 37 ° C under a gas phase of 5% air.

The following gallic acid esters were added from the time when cells formed a monolayer, and after culturing for 10 days, the degree of fibrosis was observed under a phase-contrast microscope, and the effectiveness of fibrosis-suppressing action was confirmed. The minimum concentration (MEC) obtained was evaluated. The test was performed using 3 chambers in each group, and the average value is shown. The results are shown in the table.

Comparative Examples: Gallic Acid Example 3: Gallic Acid Methyl Ester Example 4: Gallic Acid Ethyl Ester Example 5: Gallic Acid Propyl Ester Example 6: Gallic Acid Butyl Ester Example 7: Gallic Acid Isoamyl Ester Example 8: gallic acid heptyl ester Example 9: gallic acid octyl ester Example 10: gallic acid nonyl ester Example 11: gallic acid decyl ester Example 12: gallic acid dodecyl ester Example 13: gallic acid tetradecyl ester Example 14 : Cetyl gallate Example 15: Stearyl gallate Example 16: (+)-catechin-3'-O-gallate and (+)-catechin-4'-O-gallate.

[0067]

[Table 1] As is clear from the above results, the gallic acid ester, which is the active ingredient of the present invention, suppresses the collagen fiber formation of M cell lines derived from rat hepatocytes at a low concentration.

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Claims (2)

[Claims] 1. A fibrosis inhibitor comprising an effective amount of gallic acid ester. 2. A gallic acid ester is represented by the formula (1): (In the formula, R is an alkyl group having 1 to 20 carbon atoms and 2 to 2 carbon atoms.
20 alkenyl groups, aryl groups, cycloalkyl groups,
A group represented by the following formula (2) or (3): [Chemical 3] The fibrosis-suppressing agent according to claim 1, which is represented by