WO2017073060A1 - Collagen production inhibitor - Google Patents

Collagen production inhibitor Download PDF

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WO2017073060A1
WO2017073060A1 PCT/JP2016/004714 JP2016004714W WO2017073060A1 WO 2017073060 A1 WO2017073060 A1 WO 2017073060A1 JP 2016004714 W JP2016004714 W JP 2016004714W WO 2017073060 A1 WO2017073060 A1 WO 2017073060A1
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formula
group
represented
integer
collagen production
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PCT/JP2016/004714
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French (fr)
Japanese (ja)
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智徳 石井
節也 相場
阿部　高明
川口　鎮司
智昭 樋口
謙一郎 林
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国立大学法人東北大学
学校法人加計学園
学校法人東京女子医科大学
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Priority to JP2017547621A priority Critical patent/JP6872195B2/en
Publication of WO2017073060A1 publication Critical patent/WO2017073060A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin

Definitions

  • the present invention relates to a preparation for suppressing collagen production and an agent for preventing or treating skin fibrosis.
  • Skin fibrosis is a skin reaction that has been damaged due to trauma, burn, etc., but the skin has been damaged for some reason, resulting in excessive skin repair and excessive accumulation of collagen fibers (collagen) in the skin. It is. Fibrotic skin is accompanied by significant dysfunction and causes skin fibrosis diseases such as scleroderma, atopic dermatitis, psoriasis and keloid.
  • Patent Documents 1 and 2 certain pyridine derivatives (Patent Documents 1 and 2) and certain benzene derivatives (Patent Document 3) are known.
  • An object of the present invention is to provide a collagen production inhibitor containing a low-molecular compound having an action of effectively inhibiting (preventing) collagen production as an active ingredient, and skin fibrosis capable of effectively preventing or treating skin fibrosis diseases. It is to provide a preventive or therapeutic agent for a disease.
  • Patent Document 4 the compound in Patent Document 4 (4- (2,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid; referred to as Compound # 5 in Patent Document 4)
  • the compound (5- (3,5-dimethoxybenzyloxy) -3-indoleacetic acid; expressed as Compound # 35 in Patent Document 4) was examined and studied.
  • the inventors have found that specific indole derivatives reduce collagen production in skin fibrosis cells and are useful for the prevention or treatment of skin fibrosis diseases, and have completed the present invention.
  • R 1 and R 2 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or an organic group represented by OR X.
  • a collagen production inhibitor comprising one or more selected from the compounds represented by the formula (I) and salts thereof (hereinafter sometimes referred to as “the present compounds”).
  • a prophylactic or therapeutic agent for dermal fibrosis comprising one or more selected from the compounds represented by the formula (I) and salts thereof.
  • collagen production is increased by administering a collagen production inhibitor containing one or more selected from the present compounds to patients who need to inhibit collagen production.
  • a collagen production inhibitor containing one or more selected from the present compounds for use as a method for treating diseases such as skin function decline, skin damage, skin inflammation caused by increased collagen production or inflammation in the skin
  • one or two or more uses selected from the present compounds for producing the collagen production inhibitor can be mentioned.
  • a prophylactic or therapeutic agent for skin fibrosis disease comprising one or more selected from the present compounds, a patient in need of prevention or treatment of skin fibrosis disease 1 or 2 or more selected from the present compounds for use as a preventive or therapeutic agent for skin fibrosis, or as a prophylactic or therapeutic agent for skin fibrosis,
  • a prophylactic or therapeutic agent for skin fibrosis disease comprising one or more selected from the present compounds, a patient in need of prevention or treatment of skin fibrosis disease 1 or 2 or more selected from the present compounds for use as a preventive or therapeutic agent for skin fibrosis, or as a prophylactic or therapeutic agent for skin fibrosis
  • One or two or more types of use selected from the present compounds for producing a prophylactic or therapeutic agent for chemical diseases can be mentioned.
  • excessive accumulation of collagen in the skin caused by suppression or prevention of collagen fiber (collagen) production in the skin, degradation of the function of the skin due to some cause, damage, etc.
  • skin fibrosis disease skin fibrosis disease
  • skin fibrosis disease such as scleroderma (systemic) Scleroderma, localized scleroderma), atopic dermatitis, psoriasis, keloids
  • scleroderma systemic
  • Scleroderma localized scleroderma
  • atopic dermatitis psoriasis
  • keloids atopic dermatitis
  • psoriasis keloids
  • the scleroderma-derived dermal fibroblasts were cultured in the absence (“-TGF ⁇ 1” in the figure) or in the presence (“+ TGF ⁇ 1” in the figure) of TGF- ⁇ 1 and the compound of the formula (1-1) (hereinafter referred to as “-TGF ⁇ 1” in the figure)
  • -TGF ⁇ 1 the compound of the formula (1-1)
  • the present compound # 1 is a diagram showing the results of analyzing the amount of collagen produced in the presence.
  • the amount of collagen production on the vertical axis is expressed as a relative ratio when the result of culturing in the absence of TGF- ⁇ 1 and in the presence of Compound # 1 (“-DMF of TGF ⁇ 1” in the figure) is 1.
  • the scleroderma-derived dermal fibroblasts were cultured in the absence (“-TGF ⁇ 1” in the figure) or in the presence (“+ TGF ⁇ 1” in the figure) of TGF- ⁇ 1 and the compound of formula (2-1) (hereinafter referred to as “-TGF ⁇ 1” in the figure)
  • the present compound # 2 For convenience, it is sometimes referred to as “the present compound # 2”.
  • FIG. The amount of collagen production on the vertical axis is shown as a relative ratio when the result of culturing in the presence of Compound # 2 (“-TGF ⁇ 1 DMSO” in the figure) in the absence of TGF- ⁇ 1 is 1.
  • the left and right bar graphs in each sample show the results of cell culture for 48 hours and 72 hours, respectively.
  • FIG. 3A, B, and C show the results after 1 hour, 6 hours, and 24 hours, respectively, after the onset of atopic dermatitis.
  • the vertical axis indicates the thickness (ear ⁇ thickness) of the inflamed site (auricle), and the horizontal axis indicates each compound (10 ⁇ M, 100 ⁇ M, and 1000 ⁇ M of the present compound # 1, 10 ⁇ M, 100 ⁇ M, and 1000 ⁇ M) used for local administration.
  • the vertical axis indicates the thickness (ear thickness) of the psoriasis onset site (auricle), and the horizontal axis indicates each compound (10 ⁇ M, 100 ⁇ M, and 1000 ⁇ M of the present compound # 1, 10 ⁇ M, 100 ⁇ M, and 1000 ⁇ M of the present compound # 2) is shown.
  • the collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention are not particularly limited as long as they contain one or more selected from the present compounds. Detailed description of the compounds contained in the present compounds will be given below.
  • R 1 and R 2 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an organic oxy represented by OR X Represents a group.
  • m1 represents an integer of 0 to 5
  • m2 represents an integer of 0 to 5.
  • R 3 and R 4 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an organic oxy represented by OR X Represents a group.
  • m3 represents an integer of 0 to 5
  • m4 represents an integer of 0 to 4.
  • Examples of the halogen atom in the formula (1) and the formula (2) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • the C1-C6 alkyl group in the formulas (1) and (2) means a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent. Is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group Etc.
  • the C2-C6 alkenyl group in the formulas (1) and (2) means a linear or branched alkenyl group having 2 to 6 carbon atoms which may have a substituent. Includes a vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1,3-butenyl group, 1-pentenyl group, 1-hexenyl group, and the like. Can do.
  • the C2 to C6 alkynyl group in the formulas (1) and (2) means a linear or branched alkynyl group having 2 to 6 carbon atoms which may have a substituent.
  • R X represents a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group.
  • the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group in R X are the same as the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group. Definition.
  • Examples of the substituent which may have a substituent include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and a group having 2 to 6 carbon atoms. Examples thereof include alkynyl groups and C6-C10 aryl groups.
  • the halogen atom, the alkyl group having 1 to 6 carbon atoms, the alkenyl group having 2 to 6 carbon atoms, and the alkynyl group having 2 to 6 carbon atoms are the halogen atoms in formula (1) and formula (2), The same as the alkyl group, the alkenyl group having 2 to 6 carbon atoms, and the alkynyl group having 2 to 6 carbon atoms.
  • Examples of the C6 to C10 aryl group include a phenyl group and a naphthyl group.
  • a compound represented by the following formula (1 ′) or a salt thereof is preferable.
  • R ⁇ 1 >, m1 is the same definition as R ⁇ 1 >, m1 in Formula (1). Further, among R 1 , a halogen atom is preferable, m1 is preferably 1 to 3, and 2 is more preferable. In addition, the substitution position of R 1 may be any of the ortho position, the meta position, and the para position with respect to the adjacent carbonyl group, but the ortho position and the para position are preferred.
  • R ⁇ 3 >, m3 is the same definition as R ⁇ 3 >, m3 in Formula (2).
  • an organic oxy group represented by OR X is preferable, and a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group are more preferable.
  • M3 is preferably 1 to 3, and more preferably 2.
  • the substitution position of R 3 may be any of the ortho, meta, and para positions with respect to the adjacent carbonyl group, but the meta position is preferred.
  • the compound of the formula (1-1) (4- (2,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid (the present compound #) 1)).
  • the compound of the formula (2-1) (5- (3,5-dimethoxybenzyloxy) -3-indoleacetic acid (present compound # 2)) is preferable.
  • the salts in the compounds include metal salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc., N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N— Examples include organic salts generated from methyl glucamine, lysine, procaine and the like.
  • the compound represented by Formula (1) can be obtained by Michael reaction of the carboxylic acid compound represented by Formula (3) and the indole derivative represented by Formula (4) as shown below.
  • R 1, R 2, m1, m2 in the formula (3) and (4) is the same definition as R 1, R 2, m1, m2 in the equation (1).
  • the carboxylic acid compound represented by the above formula (3) can be synthesized by a Friedel-Crafts reaction between the benzene derivative (5) and maleic anhydride as shown below.
  • Such Friedel-Crafts reaction is carried out by using Lewis acid, phosphoric acid, polyphosphoric acid or the like as a catalyst, and aluminum chloride is preferably used as the catalyst.
  • R 1 and m1 in the above formula (5) and formula (3) have the same definitions as R 1 and m1 in formula (1).
  • a commercially available product can be used as the indole derivative represented by the above formula (4).
  • Examples of commercially available indole derivatives include 4-fluoroindole, 4-chloroindole, 4-bromoindole, 6-fluoroindole, 6-chloroindole, 6-bromoindole, and 5-methylindole.
  • the indole derivative represented by the above formula (4) can also be obtained by an organic synthesis method using a known organic chemical reaction.
  • R 2 is a halogen atom
  • an indole represented by the above formula (4) is obtained by allowing a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, and N-iodosuccinimide to act on a commercially available indole.
  • a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, and N-iodosuccinimide
  • R 2 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or an organic oxy group represented by OR X
  • a commercially available indole is halogenated as described above.
  • an indole derivative represented by the above formula (4) can be obtained by reaction with an organolithium reagent such as alkyl lithium, Suzuki-Miyaura coupling reaction, or the like.
  • the compound represented by the formula (2) can be synthesized using a 5-hydroxy-3-indoleacetic acid derivative represented by the formula (6) as a starting material. Specifically, 5-hydroxy-3-indoleacetic acid represented by the formula (6) is reacted in an alcohol such as methanol, ethanol, propanol, isopropanol, or the like under an acidic condition to represent the formula (7). To the ester form. Next, the compound represented by the formula (9) can be synthesized by reacting the ester compound with the halogen compound represented by the formula (8) in the presence of a base.
  • an alcohol such as methanol, ethanol, propanol, isopropanol, or the like
  • Examples of the base include sodium hydride and alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate. Then, the compound represented by Formula (2) is synthesize
  • R Y represents a C1-C3 alkyl group such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
  • X represents halogen atoms, such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • R 3 , R 4 , m3, and m4 in the above formula (6), formula (7), formula (8), and formula (9) have the same definitions as R 3 , R 4 , m3, and m4 in formula (2). is there.
  • the 5-hydroxy-3-indoleacetic acid derivative represented by the above formula (6) may be commercially available 5-hydroxy-3-indoleacetic acid or the like, but is obtained by an organic synthesis method using a known organic chemical reaction. You can also.
  • R 4 is a halogen atom
  • a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide or the like is allowed to act on commercially available 5-hydroxy-3-indoleacetic acid.
  • a 5-hydroxy-3-indoleacetic acid derivative represented by 6) can be obtained.
  • R 4 is a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic oxy group represented by OR X , as described above, a commercially available 5-hydroxy-3 -Obtaining a 5-hydroxy-3-indoleacetic acid derivative represented by the above formula (6) by halogenating indoleacetic acid and then reacting with an organolithium reagent such as alkyllithium, Suzuki-Miyaura coupling reaction, etc. Can do.
  • organolithium reagent such as alkyllithium, Suzuki-Miyaura coupling reaction, etc.
  • halogen compounds represented by the above formula (8) are commercially available benzyl bromide, 4-methylbenzyl bromide, 2-methylbenzyl bromide, 3-methylbenzyl bromide, 3-chlorobenzyl bromide, 2-chlorobenzyl bromide, 2, 6-Dichlorobenzyl bromide, 3-fluorobenzyl bromide, 4-fluorobenzyl bromide, 3,5-dimethoxybenzyl bromide and the like may be used, but they can also be obtained by an organic synthesis method using a known organic chemical reaction.
  • R 3 is a halogen atom
  • it is represented by the above formula (8) by allowing a commercially available benzyl bromide to act on a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide.
  • a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide.
  • a halogen compound can be obtained.
  • R 3 is a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic oxy group represented by OR X
  • the above-mentioned commercially available halide may be used, or After halogenating commercially available benzyl bromide as described above, the halogen compound represented by the above formula (8) can be obtained by reaction with an organolithium reagent such as alkyl lithium, Suzuki-Miyaura coupling reaction or the like.
  • All the above organic reactions can be carried out in a solvent, but the solvent is appropriately selected depending on the reaction temperature, reactants and the like. Moreover, the reaction temperature of the said organic reaction is suitably selected according to conditions, such as the boiling point of the solvent to be used. When using a solvent in the organic reaction, after concentrating the obtained reaction solution as necessary, the residue may be used as it is in the next reaction. After appropriate post-treatment, the formula (1) It may be used as a represented compound. Specific methods of the post-treatment include known purification such as extraction treatment and / or crystallization, recrystallization, chromatography and the like.
  • the present compounds have an action of suppressing or preventing the production of collagen fibers (collagen) in skin-derived cells and excessive accumulation of collagen (skin fibrosis) in skin-derived cells. Therefore, the collagen production inhibitor of the present invention containing the present compounds as an active ingredient and the prophylactic or therapeutic agent for skin fibrosis of the present invention are caused by skin fibrosis, skin fibrosis, or skin fibrosis. It is possible to suppress the progression of skin function decline or disorder (skin fibrosis disease) associated with. Therefore, the collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention can be advantageously applied to collagen accumulation inhibitors in skin and skin fibrosis inhibitors.
  • the dermal fibrosis include scleroderma (systemic scleroderma, localized scleroderma), atopic dermatitis, psoriasis, keloid, and the like. Atopic dermatitis, psoriasis Or scleroderma is preferred.
  • a dosage form such as powder, granule, tablet, capsule, syrup, suspension, etc.
  • a dosage form such as a solution, an emulsion, or a suspension can be injected or sprayed, and can be directly administered to fibrotic skin.
  • the dosage of the collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention is appropriately determined according to age, weight, sex, symptom, dosage form, drug sensitivity, and the like.
  • the dosage range of 1 ⁇ g to 200 mg / day preferably in the dosage range of 2 ⁇ g to 2000 ⁇ g / day, more preferably in the dosage range of 3 to 200 ⁇ g / day, still more preferably 4 to 20 ⁇ g / day.
  • the dose is administered once or multiple times per day (for example, 2 to 4 times) within the day dose range, but the dose may be adjusted according to the state of symptom improvement.
  • the collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention are pharmaceutically acceptable ordinary carriers, binders, stabilizers, excipients, diluents as necessary. , PH buffer, disintegrant, isotonic agent, additive, coating agent, solubilizer, lubricant, lubricant, solubilizer, lubricant, flavor, sweetener, solvent, gelling agent, nutrient What added the compounding ingredients, such as these, can be illustrated.
  • ingredients include water, saline, animal fats and oils, vegetable oils, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, polyalkylene glycol, Polyvinyl alcohol and glycerin can be exemplified.
  • RPMI1640 culture medium (Manufactured by GIBCO) in RPMI1640 (GIBCO) culture medium (hereinafter referred to as “RPMI1640 culture medium”) and cultured under 5% CO 2 /20% O 2 and 37 ° C. conditions.
  • the present compounds # 1 and # 2 were synthesized according to the synthesis method of compound # 5 (present compound # 1) and # 35 (present compound # 2) described in Patent Document 4, respectively.
  • Compound 1 or # 2 When adding Compound 1 or # 2, recombinant human TGF- ⁇ 1 (Transforming Growth Factor- ⁇ 1) (Roche) is added to the RPMI 1640 culture solution at 10 ng / mL to promote collagen production. (See “+ TGF ⁇ 1” in FIGS. 1 and 2).
  • Ear swelling was measured 1 hour, 6 hours, and 24 hours after the onset of atopic dermatitis (see FIG. 3).
  • a positive control an experiment in which an ethanol solution containing 0.1% tacrolimus (FK506), which is an application agent for atopic dermatitis, was applied to atopic dermatitis model mice was performed ("FK506" in the figure).
  • FK506 an ethanol solution containing 0.1% tacrolimus
  • Ear swelling was measured 12 and 14 days after the onset of psoriasis (see FIG. 4).
  • As a negative control an experiment (“control” in the figure) in which physiological saline was applied to a psoriasis model mouse was performed.
  • the present invention since collagen production in the skin and excessive accumulation of collagen in the skin can be suppressed, skin function deterioration or damage caused by skin fibrosis or accompanying skin fibrosis (skin fibrosis disease) Specifically, it contributes to the development of a preventive or therapeutic agent for scleroderma, atopic dermatitis, psoriasis and keloid.

Abstract

The present invention addresses the problem of providing a collagen production inhibitor, which comprises as an active ingredient a low-molecular compound having an effect of effectively inhibiting (preventing) collagen production, and a prophylactic or therapeutic agent for skin fibrotic diseases which is capable of effectively preventing or treating skin fibrotic diseases. A preparation comprising one or more members selected from compounds represented by formulae (1) and (2) and salts thereof is used as a collagen production inhibitor or a prophylactic or therapeutic agent for skin fibrotic diseases.

Description

コラーゲン産生抑制剤Collagen production inhibitor
　本発明は、コラーゲン産生を抑制するための製剤や、皮膚線維化疾患の予防又は治療剤に関する。 The present invention relates to a preparation for suppressing collagen production and an agent for preventing or treating skin fibrosis.
　皮膚線維化は、外傷、熱傷等により障害を受けた皮膚の修復反応が、何らかの理由により正常性を失った結果、過剰な皮膚修復が起こり、膠原線維（コラーゲン）が皮膚に過剰に蓄積したものである。線維化した皮膚は、著しい機能障害を伴い、強皮症、アトピー性皮膚炎、乾癬、ケロイド等の皮膚線維化疾患の原因となる。 Skin fibrosis is a skin reaction that has been damaged due to trauma, burn, etc., but the skin has been damaged for some reason, resulting in excessive skin repair and excessive accumulation of collagen fibers (collagen) in the skin. It is. Fibrotic skin is accompanied by significant dysfunction and causes skin fibrosis diseases such as scleroderma, atopic dermatitis, psoriasis and keloid.
　このため、皮膚線維化疾患の治療には、コラーゲンの過剰な産生・蓄積を抑制し、皮膚線維化を抑制することが重要である。コラーゲン産生を抑制する効果を有する化合物として、例えば、ある種のピリジン誘導体（特許文献１、２）や、ある種のベンゼン誘導体（特許文献３）が知られている。 Therefore, in the treatment of skin fibrosis diseases, it is important to suppress excessive production and accumulation of collagen to suppress skin fibrosis. As compounds having an effect of suppressing collagen production, for example, certain pyridine derivatives (Patent Documents 1 and 2) and certain benzene derivatives (Patent Document 3) are known.
　一方、４－（２，４－ジフルオロフェニル）－２－（１Ｈ－インドール－３－イル）－４－オキソ－ブタン酸や５－（３，５－ジメトキシベンジルオキシ）－３－インドール酢酸は、ミトコンドリアの治療効果を有することや（特許文献４）、４－（２，４－ジフルオロフェニル）－２－（１Ｈ－インドール－３－イル）－４－オキソ－ブタン酸は、ミトコンドリア病（Ｌｅｉｇｈ脳症）患者由来の線維芽細胞の酸化ストレスによる細胞死を抑制する効果を有することが報告されている（非特許文献１）。しかしながら、これらインドール誘導体が、コラーゲン産生を抑制する効果を有し、皮膚線維化疾患の治療に有用であるかどうかは不明であった。 On the other hand, 4- (2,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid and 5- (3,5-dimethoxybenzyloxy) -3-indoleacetic acid are It has a mitochondrial therapeutic effect (Patent Document 4) and 4- (2,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid is a mitochondrial disease (Leigh encephalopathy). ) It has been reported that it has an effect of suppressing cell death due to oxidative stress of patient-derived fibroblasts (Non-patent Document 1). However, it has been unclear whether these indole derivatives have an effect of suppressing collagen production and are useful for treatment of skin fibrosis diseases.
特表２００２－５０７６０１号公報Japanese translation of PCT publication No. 2002-507601 特開２００１－８９４５０号公報JP 2001-89450 A 特開２００１－８９４１２号公報JP 2001-89412 A 国際公開第２０１４／０８０６４０号パンフレットInternational Publication No. 2014/080640 Pamphlet
　本発明の課題は、コラーゲン産生を効果的に抑制（予防）する作用を有する低分子化合物を有効成分として含有するコラーゲン産生抑制剤や、皮膚線維化疾患を効果的に予防又は治療できる皮膚線維化疾患の予防又は治療剤を提供することにある。 An object of the present invention is to provide a collagen production inhibitor containing a low-molecular compound having an action of effectively inhibiting (preventing) collagen production as an active ingredient, and skin fibrosis capable of effectively preventing or treating skin fibrosis diseases. It is to provide a preventive or therapeutic agent for a disease.
　本発明者らは、上記課題を解決すべく鋭意研究を続けている。その過程において、特許文献４における化合物（４－（２，４－ジフルオロフェニル）－２－（１Ｈ－インドール－３－イル）－４－オキソ－ブタン酸；特許文献４において化合物＃５と表記）や、化合物（５－（３，５－ジメトキシベンジルオキシ）－３－インドール酢酸；特許文献４において化合物＃３５と表記）に着目し、検討した。その結果、特定のインドール誘導体は、皮膚線維化細胞におけるコラーゲン産生を低下させ、皮膚線維化疾患の予防又は治療に有用であることを見いだし、本発明を完成するに至った。 The inventors of the present invention are continuing intensive studies to solve the above problems. In the process, the compound in Patent Document 4 (4- (2,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid; referred to as Compound # 5 in Patent Document 4) The compound (5- (3,5-dimethoxybenzyloxy) -3-indoleacetic acid; expressed as Compound # 35 in Patent Document 4) was examined and studied. As a result, the inventors have found that specific indole derivatives reduce collagen production in skin fibrosis cells and are useful for the prevention or treatment of skin fibrosis diseases, and have completed the present invention.
　すなわち、本発明は以下のとおりである。
［１］式（１）；
Figure JPOXMLDOC01-appb-C000001
 （式中、Ｒ１、Ｒ２は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ１は０～５の整数を表し、ｍ２は０～５の整数を表す。）、及び
　式（２）；
Figure JPOXMLDOC01-appb-C000002
 （式中、Ｒ３、Ｒ４は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ３は０～５の整数を表し、ｍ４は０～４の整数を表す。）
で表される化合物、並びにそれらの塩（以下、「本件化合物類」ということがある）から選択される１種又は２種以上を含有することを特徴とするコラーゲン産生抑制剤。
［２］式（１）で表される化合物が、以下の式（１’）であることを特徴とする上記［１］に記載のコラーゲン産生抑制剤。
Figure JPOXMLDOC01-appb-C000003
 （式中、Ｒ１は、同一でも異なっていてもよく、ハロゲン原子を表す。ｍ１は１～３の整数を表す。）
［３］式（２）で表される化合物が、以下の式（２’）であることを特徴とする上記［１］に記載のコラーゲン産生抑制剤。
Figure JPOXMLDOC01-appb-C000004
 （式中、Ｒ３は、同一でも異なっていてもよく、ＯＲＸで表される有機オキシ基を表す。ｍ３は１～３の整数を表す。）
［４］式（１）で表される化合物が、以下の式（１－１）であることを特徴とする上記［１］に記載のコラーゲン産生抑制剤。
Figure JPOXMLDOC01-appb-C000005
 ［５］式（２）で表される化合物が、以下の式（２－１）であることを特徴とする上記［１］に記載のコラーゲン産生抑制剤。
Figure JPOXMLDOC01-appb-C000006
 ［６］式（１）；
Figure JPOXMLDOC01-appb-C000007
 （式中、Ｒ１、Ｒ２は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ１は０～５の整数を表し、ｍ２は０～５の整数を表す。）、及び
　式（２）；
Figure JPOXMLDOC01-appb-C000008
 （式中、Ｒ３、Ｒ４は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ３は０～５の整数を表し、ｍ４は０～４の整数を表す。）
で表される化合物、並びにそれらの塩から選択される１種又は２種以上を含有することを特徴とする皮膚線維化疾患の予防又は治療剤。
［７］式（１）で表される化合物が、以下の式（１’）であることを特徴とする上記［６］に記載の予防又は治療剤。
Figure JPOXMLDOC01-appb-C000009
 （式中、Ｒ１は、同一でも異なっていてもよく、ハロゲン原子を表す。ｍ１は１～３の整数を表す。）
［８］式（２）で表される化合物が、以下の式（２’）であることを特徴とする上記［６］に記載の予防又は治療剤。
Figure JPOXMLDOC01-appb-C000010
 （式中、Ｒ３は、同一でも異なっていてもよく、ＯＲＸで表される有機オキシ基を表す。ｍ３は１～３の整数を表す。）
［９］式（１）で表される化合物が、以下の式（１－１）であることを特徴とする上記［６］に記載の予防又は治療剤。
Figure JPOXMLDOC01-appb-C000011
 ［１０］式（２）で表される化合物が、以下の式（２－１）であることを特徴とする上記［６］に記載の予防又は治療剤。
Figure JPOXMLDOC01-appb-C000012
 ［１１］皮膚線維化疾患が、アトピー性皮膚炎、乾癬、又は強皮症であることを特徴とする上記［６］～［１０］のいずれかに記載の予防又は治療剤。 That is, the present invention is as follows.
[1] Formula (1);
Figure JPOXMLDOC01-appb-C000001
 (In the formula, R 1 and R 2 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or an organic group represented by OR X. Represents an oxy group, m1 represents an integer of 0 to 5, m2 represents an integer of 0 to 5), and formula (2);
Figure JPOXMLDOC01-appb-C000002
 Wherein R 3 and R 4 may be the same or different, and are a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic group represented by OR X Represents an oxy group, m3 represents an integer of 0 to 5, and m4 represents an integer of 0 to 4.)
A collagen production inhibitor comprising one or more selected from the compounds represented by the formula (I) and salts thereof (hereinafter sometimes referred to as “the present compounds”).
[2] The collagen production inhibitor as described in [1] above, wherein the compound represented by the formula (1) is the following formula (1 ′).
Figure JPOXMLDOC01-appb-C000003
 (In the formula, R 1 may be the same or different and each represents a halogen atom. M1 represents an integer of 1 to 3.)
[3] The collagen production inhibitor as described in [1] above, wherein the compound represented by the formula (2) is the following formula (2 ′).
Figure JPOXMLDOC01-appb-C000004
 (Wherein R 3 may be the same or different and represents an organic oxy group represented by OR X. m3 represents an integer of 1 to 3)
[4] The collagen production inhibitor as described in [1] above, wherein the compound represented by the formula (1) is the following formula (1-1).
Figure JPOXMLDOC01-appb-C000005
 [5] The collagen production inhibitor as described in [1] above, wherein the compound represented by the formula (2) is the following formula (2-1):
Figure JPOXMLDOC01-appb-C000006
 [6] Formula (1);
Figure JPOXMLDOC01-appb-C000007
 (In the formula, R 1 and R 2 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or an organic group represented by OR X. Represents an oxy group, m1 represents an integer of 0 to 5, m2 represents an integer of 0 to 5), and formula (2);
Figure JPOXMLDOC01-appb-C000008
 Wherein R 3 and R 4 may be the same or different, and are a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic group represented by OR X Represents an oxy group, m3 represents an integer of 0 to 5, and m4 represents an integer of 0 to 4.)
A prophylactic or therapeutic agent for dermal fibrosis, comprising one or more selected from the compounds represented by the formula (I) and salts thereof.
[7] The prophylactic or therapeutic agent according to the above [6], wherein the compound represented by the formula (1) is the following formula (1 ′).
Figure JPOXMLDOC01-appb-C000009
 (In the formula, R 1 may be the same or different and each represents a halogen atom. M1 represents an integer of 1 to 3.)
[8] The prophylactic or therapeutic agent according to the above [6], wherein the compound represented by the formula (2) is the following formula (2 ′).
Figure JPOXMLDOC01-appb-C000010
 (Wherein R 3 may be the same or different and represents an organic oxy group represented by OR X. m3 represents an integer of 1 to 3)
[9] The prophylactic or therapeutic agent according to the above [6], wherein the compound represented by the formula (1) is the following formula (1-1).
Figure JPOXMLDOC01-appb-C000011
 [10] The prophylactic or therapeutic agent according to the above [6], wherein the compound represented by the formula (2) is the following formula (2-1).
Figure JPOXMLDOC01-appb-C000012
 [11] The prophylactic or therapeutic agent according to any one of [6] to [10] above, wherein the skin fibrosis disease is atopic dermatitis, psoriasis, or scleroderma.
　また本発明の実施の他の形態として、本件化合物類から選択される１種又は２種以上を含むコラーゲン産生抑制剤を、コラーゲン産生の抑制を必要とする患者に投与することにより、コラーゲン産生増加に起因する、或いはコラーゲン産生増加に伴う皮膚機能低下、皮膚障害、皮膚における炎症などの疾患を治療する方法や、コラーゲン産生抑制剤として使用するための本件化合物類から選択される１種又は２種以上や、上記コラーゲン産生抑制剤を製造するための本件化合物類から選択される１種又は２種以上の使用を挙げることができる。 Further, as another embodiment of the present invention, collagen production is increased by administering a collagen production inhibitor containing one or more selected from the present compounds to patients who need to inhibit collagen production. 1 type or 2 types selected from the present compounds for use as a method for treating diseases such as skin function decline, skin damage, skin inflammation caused by increased collagen production or inflammation in the skin As mentioned above, one or two or more uses selected from the present compounds for producing the collagen production inhibitor can be mentioned.
　また本発明の実施の他の形態として、本件化合物類から選択される１種又は２種以上を含む皮膚線維化疾患の予防又は治療剤を、皮膚線維化疾患の予防又は治療を必要とする患者に投与することにより、皮膚線維化疾患を予防又は治療する方法や、皮膚線維化疾患の予防又は治療剤として使用するための本件化合物類から選択される１種又は２種以上や、上記皮膚線維化疾患の予防又は治療剤を製造するための本件化合物類から選択される１種又は２種以上の使用を挙げることができる。 Further, as another embodiment of the present invention, a prophylactic or therapeutic agent for skin fibrosis disease comprising one or more selected from the present compounds, a patient in need of prevention or treatment of skin fibrosis disease 1 or 2 or more selected from the present compounds for use as a preventive or therapeutic agent for skin fibrosis, or as a prophylactic or therapeutic agent for skin fibrosis, One or two or more types of use selected from the present compounds for producing a prophylactic or therapeutic agent for chemical diseases can be mentioned.
　本発明によると、皮膚における膠原線維（コラーゲン）産生を抑制又は予防したり、皮膚が何らかの原因によってその機能が低下したり、障害を受けたこと等が原因で生じる、皮膚におけるコラーゲンの過剰な蓄積を抑制又は予防できるため、皮膚線維化を予防又は抑制したり、皮膚線維化に起因する、或いは皮膚線維化に伴う皮膚機能低下又は障害（皮膚線維化疾患）、例えば、強皮症（全身性強皮症、限局性強皮症）、アトピー性皮膚炎、乾癬、ケロイドを予防又は治療することができる。 According to the present invention, excessive accumulation of collagen in the skin caused by suppression or prevention of collagen fiber (collagen) production in the skin, degradation of the function of the skin due to some cause, damage, etc. Can prevent or suppress skin fibrosis, or decrease or impair skin function due to skin fibrosis or accompanying skin fibrosis (skin fibrosis disease) such as scleroderma (systemic) Scleroderma, localized scleroderma), atopic dermatitis, psoriasis, keloids can be prevented or treated.
強皮症由来皮膚線維芽細胞を、ＴＧＦ－β１の非存在下（図中の「－ＴＧＦβ１」）又は存在下（図中の「＋ＴＧＦβ１」）でかつ、式（１－１）の化合物（以下、便宜上「本件化合物＃１」ということがある）存在下で培養し、コラーゲン産生量を解析した結果を示す図である。縦軸のコラーゲン産生量は、ＴＧＦ－β１非存在下でかつ本件化合物＃１存在下で培養した結果（図中の「－ＴＧＦβ１のＤＭＳＯ」）の結果を１としたときの相対比で示す。The scleroderma-derived dermal fibroblasts were cultured in the absence (“-TGFβ1” in the figure) or in the presence (“+ TGFβ1” in the figure) of TGF-β1 and the compound of the formula (1-1) (hereinafter referred to as “-TGFβ1” in the figure) For convenience, it is sometimes referred to as “the present compound # 1”) and is a diagram showing the results of analyzing the amount of collagen produced in the presence. The amount of collagen production on the vertical axis is expressed as a relative ratio when the result of culturing in the absence of TGF-β1 and in the presence of Compound # 1 (“-DMF of TGFβ1” in the figure) is 1. 強皮症由来皮膚線維芽細胞を、ＴＧＦ－β１の非存在下（図中の「－ＴＧＦβ１」）又は存在下（図中の「＋ＴＧＦβ１」）でかつ、式（２－１）の化合物（以下、便宜上「本件化合物＃２」ということがある）存在下で培養し、コラーゲン産生量を解析した結果を示す図である。縦軸のコラーゲン産生量は、ＴＧＦ－β１非存在下でかつ本件化合物＃２存在下で培養した結果（図中の「－ＴＧＦβ１のＤＭＳＯ」）を１としたときの相対比で示す。各々のサンプルにおける左側及び右側の棒グラフは、それぞれ４８時間及び７２時間細胞培養を行った結果を示す。The scleroderma-derived dermal fibroblasts were cultured in the absence (“-TGFβ1” in the figure) or in the presence (“+ TGFβ1” in the figure) of TGF-β1 and the compound of formula (2-1) (hereinafter referred to as “-TGFβ1” in the figure) For convenience, it is sometimes referred to as “the present compound # 2”). FIG. The amount of collagen production on the vertical axis is shown as a relative ratio when the result of culturing in the presence of Compound # 2 (“-TGFβ1 DMSO” in the figure) in the absence of TGF-β1 is 1. The left and right bar graphs in each sample show the results of cell culture for 48 hours and 72 hours, respectively. アトピー性皮膚炎モデルマウスの炎症部位（耳介）に、本件化合物＃１又は＃２を塗布し、耳介膨張を計測した結果を示す図である。図３Ａ、Ｂ、及びＣは、それぞれアトピー性皮膚炎の惹起後１時間、６時間、及び２４時間後の結果を示す。縦軸は、炎症部位（耳介）の厚み（ear thickness）を示し、横軸は、局所投与に用いた各化合物（１０μＭ、１００μＭ、及び１０００μＭの本件化合物＃１や、１０μＭ、１００μＭ、及び１０００μＭの本件化合物＃２や、０．１％のＦＫ５０６）を示す。また、図中の「＃」、「＃＃」、及び「＃＃＃」は、「control」と比較したときに統計学的な有意差（それぞれ、ｐ＜０．０５、ｐ＜０．０１、ｐ＜０．００１［Dunnett multiple t-test］）があることを示し、「＊＊＊」は、「control」と比較したときに統計学的な有意差（ｐ＜０．００１［Aspin-Welch’s t-test又はStudent’s t-test)］）があることを示す。It is a figure which shows the result of having applied this compound # 1 or # 2 to the inflammation site | part (auricle) of the atopic dermatitis model mouse, and measuring auricle expansion | swelling. 3A, B, and C show the results after 1 hour, 6 hours, and 24 hours, respectively, after the onset of atopic dermatitis. The vertical axis indicates the thickness (ear 炎症 thickness) of the inflamed site (auricle), and the horizontal axis indicates each compound (10 μM, 100 μM, and 1000 μM of the present compound # 1, 10 μM, 100 μM, and 1000 μM) used for local administration. The present compound # 2 and 0.1% FK506). In addition, “#”, “##”, and “##” in the figure are statistically significant differences (p <0.05, p <0.01, respectively) when compared with “control”. , P <0.001 [Dunnett multiple t-test]), and “***” indicates a statistically significant difference (p <0.001 [Aspin− Welch's-t-test or Student's-t-test)]). 乾癬モデルマウスの乾癬発症部位（耳介）に、本件化合物＃１又は＃２を塗布し、耳介膨張を計測した結果を示す図である。縦軸は、乾癬発症部位（耳介）の厚み（ear thickness）を示し、横軸は、局所投与に用いた各化合物（１０μＭ、１００μＭ、及び１０００μＭの本件化合物＃１や、１０μＭ、１００μＭ、及び１０００μＭの本件化合物＃２）を示す。It is a figure which shows the result of having applied this compound # 1 or # 2 to the psoriasis onset site (auricle) of a psoriasis model mouse, and measuring auricular swelling. The vertical axis indicates the thickness (ear thickness) of the psoriasis onset site (auricle), and the horizontal axis indicates each compound (10 μM, 100 μM, and 1000 μM of the present compound # 1, 10 μM, 100 μM, and 1000 μM of the present compound # 2) is shown.
　本発明のコラーゲン産生抑制剤や本発明の皮膚線維化疾患の予防又は治療剤としては、本件化合物類から選択される１種又は２種以上を含有するものであれば特に制限されるものではなく、本件化合物類に含まれる化合物の詳細な説明は以下に示す。 The collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention are not particularly limited as long as they contain one or more selected from the present compounds. Detailed description of the compounds contained in the present compounds will be given below.
（化合物）
　本件化合物類に含まれる化合物は、以下の式（１）又は式（２）で表される化合物である。 (Compound)
The compound contained in the present compounds is a compound represented by the following formula (1) or formula (2).
Figure JPOXMLDOC01-appb-C000013
Figure JPOXMLDOC01-appb-C000013
　式中、Ｒ１、Ｒ２は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ１は０～５の整数を表し、ｍ２は０～５の整数を表す。 In the formula, R 1 and R 2 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an organic oxy represented by OR X Represents a group. m1 represents an integer of 0 to 5, and m2 represents an integer of 0 to 5.
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000014
　式中、Ｒ３、Ｒ４は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ３は０～５の整数を表し、ｍ４は０～４の整数を表す。 In the formula, R 3 and R 4 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, an organic oxy represented by OR X Represents a group. m3 represents an integer of 0 to 5, and m4 represents an integer of 0 to 4.
　式（１）及び式（２）におけるハロゲン原子としては、フッ素原子、塩素原子、臭素原子、ヨウ素原子等を挙げることができる。 Examples of the halogen atom in the formula (1) and the formula (2) include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
　式（１）及び式（２）におけるＣ１～Ｃ６のアルキル基とは、置換基を有していてもよい炭素数１～６の直鎖状または分岐状のアルキル基を意味し、具体的には、メチル基、エチル基、ｎ－プロピル基、イソプロピル基、ｎ－ブチル基、イソブチル基、ｓｅｃ－ブチル基、ｔｅｒｔ－ブチル基、ｎ－ペンチル基、イソペンチル基、ネオペンチル基、ｎ－へキシル基等を挙げることができる。 The C1-C6 alkyl group in the formulas (1) and (2) means a linear or branched alkyl group having 1 to 6 carbon atoms which may have a substituent. Is a methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group Etc.
　式（１）及び式（２）におけるＣ２～Ｃ６のアルケニル基とは、置換基を有していてもよい炭素数２～６の直鎖状または分岐状のアルケニル基を意味し、具体的には、ビニル基、１－プロペニル基、２－プロペニル基、１－ブテニル基、２－ブテニル基、３－ブテニル基、１，３－ブテニル基、１－ペンテニル基、１－ヘキセニル基等を挙げることができる。 The C2-C6 alkenyl group in the formulas (1) and (2) means a linear or branched alkenyl group having 2 to 6 carbon atoms which may have a substituent. Includes a vinyl group, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1,3-butenyl group, 1-pentenyl group, 1-hexenyl group, and the like. Can do.
　式（１）及び式（２）におけるＣ２～Ｃ６のアルキニル基とは、置換基を有していてもよい炭素数２～６の直鎖状または分岐状のアルキニル基を意味し、具体的には、エチニル基、１－プロピニル基、１－ブチニル基、１－ペンチニル基、１－ヘキシニル基等を挙げることができる。 The C2 to C6 alkynyl group in the formulas (1) and (2) means a linear or branched alkynyl group having 2 to 6 carbon atoms which may have a substituent. Can include ethynyl, 1-propynyl, 1-butynyl, 1-pentynyl, 1-hexynyl and the like.
　式（１）及び式（２）のＯＲＸで表される有機オキシ基における、ＲＸは、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基を表す。また、ＲＸにおけるＣ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基は、前記Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基と同じ定義である。 In the organic oxy group represented by OR X in the formulas (1) and (2), R X represents a C1-C6 alkyl group, a C2-C6 alkenyl group, or a C2-C6 alkynyl group. In addition, the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group in R X are the same as the C1-C6 alkyl group, the C2-C6 alkenyl group, and the C2-C6 alkynyl group. Definition.
　上記「置換基を有していてもよい」の置換基としては、ハロゲン原子、水酸基、カルボキシル基、炭素数１～６のアルキル基、炭素数２～６のアルケニル基、炭素数２～６のアルキニル基、Ｃ６～Ｃ１０のアリール基を挙げることができる。上記ハロゲン原子、炭素数１～６のアルキル基、炭素数２～６のアルケニル基、炭素数２～６のアルキニル基は、式（１）及び式（２）におけるハロゲン原子、炭素数１～６のアルキル基、炭素数２～６のアルケニル基、炭素数２～６のアルキニル基と同じである。また、上記Ｃ６～Ｃ１０のアリール基としては、フェニル基、ナフチル基を挙げることができる。 Examples of the substituent which may have a substituent include a halogen atom, a hydroxyl group, a carboxyl group, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 2 to 6 carbon atoms, and a group having 2 to 6 carbon atoms. Examples thereof include alkynyl groups and C6-C10 aryl groups. The halogen atom, the alkyl group having 1 to 6 carbon atoms, the alkenyl group having 2 to 6 carbon atoms, and the alkynyl group having 2 to 6 carbon atoms are the halogen atoms in formula (1) and formula (2), The same as the alkyl group, the alkenyl group having 2 to 6 carbon atoms, and the alkynyl group having 2 to 6 carbon atoms. Examples of the C6 to C10 aryl group include a phenyl group and a naphthyl group.
　本件化合物類における式（１）で表される化合物の中でも、好ましくは、以下の式（１’）で表される化合物又はその塩である。 Among the compounds represented by the formula (1) in the present compounds, a compound represented by the following formula (1 ′) or a salt thereof is preferable.
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000015
　上記式（１’）中、Ｒ１、ｍ１は、式（１）におけるＲ１、ｍ１と同じ定義である。また、Ｒ１の中でも、ハロゲン原子が好ましく、ｍ１は１～３が好ましく、２がより好ましい。そしてまた、Ｒ１の置換位置としては、隣接するカルボニル基に対し、オルト位、メタ位、パラ位のいずれでもよいが、オルト位、パラ位が好ましい。 In said formula (1 '), R < 1 >, m1 is the same definition as R < 1 >, m1 in Formula (1). Further, among R 1 , a halogen atom is preferable, m1 is preferably 1 to 3, and 2 is more preferable. In addition, the substitution position of R 1 may be any of the ortho position, the meta position, and the para position with respect to the adjacent carbonyl group, but the ortho position and the para position are preferred.
　本件化合物類における式（２）で表される化合物の中でも、好ましくは、以下の式（２’）で表される化合物又はその塩である。
Figure JPOXMLDOC01-appb-C000016
 Among the compounds represented by the formula (2) in the present compounds, a compound represented by the following formula (2 ′) or a salt thereof is preferable.
Figure JPOXMLDOC01-appb-C000016
　上記式（２’）中、Ｒ３、ｍ３は、式（２）におけるＲ３、ｍ３と同じ定義である。また、Ｒ３の中でも、ＯＲＸで表される有機オキシ基が好ましく、メトキシ基、エトキシ基、ｎ－プロポキシ基、イソプロポキシ基がより好ましい。上記ｍ３は１～３が好ましく、２がより好ましい。そしてまた、Ｒ３の置換位置としては、隣接するカルボニル基に対し、オルト位、メタ位、パラ位のいずれでもよいが、メタ位が好ましい。 In said formula (2 '), R < 3 >, m3 is the same definition as R < 3 >, m3 in Formula (2). Among R 3 , an organic oxy group represented by OR X is preferable, and a methoxy group, an ethoxy group, an n-propoxy group, and an isopropoxy group are more preferable. M3 is preferably 1 to 3, and more preferably 2. The substitution position of R 3 may be any of the ortho, meta, and para positions with respect to the adjacent carbonyl group, but the meta position is preferred.
　式（１）で表される化合物は、具体的には、以下に示す化合物を例示することができる。 Specific examples of the compound represented by the formula (1) include the compounds shown below.
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000017
Figure JPOXMLDOC01-appb-C000018
Figure JPOXMLDOC01-appb-C000018
　上記化合物の中でも、好ましくは、式（１－１）の化合物（４－（２，４－ジフルオロフェニル）－２－（１Ｈ－インドール－３－イル）－４－オキソ－ブタン酸（本件化合物＃１））である。 Among the above compounds, the compound of the formula (1-1) (4- (2,4-difluorophenyl) -2- (1H-indol-3-yl) -4-oxo-butanoic acid (the present compound #) 1)).
　式（２）で表される化合物は、具体的には、以下に示す化合物を例示することができる。 Specific examples of the compound represented by the formula (2) include the following compounds.
Figure JPOXMLDOC01-appb-C000019
Figure JPOXMLDOC01-appb-C000019
　上記化合物の中でも、好ましくは、式（２－１）の化合物（５－（３，５－ジメトキシベンジルオキシ）－３－インドール酢酸（本件化合物＃２））である。 Among the above compounds, the compound of the formula (2-1) (5- (3,5-dimethoxybenzyloxy) -3-indoleacetic acid (present compound # 2)) is preferable.
　本件化合物類における塩には、アルミニウム、カルシウム、リチウム、マグネシウム、カリウム、ナトリウム、亜鉛等から生成された金属塩や、Ｎ，Ｎ’－ジベンジルエチレンジアミン、クロロプロカイン、コリン、ジエタノールアミン、エチレンジアミン、Ｎ－メチルグルカミン、リジン、プロカイン等から生成された有機塩などが含まれる。 The salts in the compounds include metal salts formed from aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, etc., N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N— Examples include organic salts generated from methyl glucamine, lysine, procaine and the like.
（化合物の合成）
　式（１）及び式（２）で表される化合物は、公知の有機化学反応を用いる有機合成手法によって得ることができる。 (Synthesis of compounds)
The compounds represented by the formulas (1) and (2) can be obtained by an organic synthesis method using a known organic chemical reaction.
［式（１）で表される化合物の合成］
　式（１）で表される化合物は、以下に示すように式（３）で表されるカルボン酸化合物と式（４）で表されるインドール誘導体とをマイケル反応させることにより得ることができる。 [Synthesis of Compound Represented by Formula (1)]
The compound represented by Formula (1) can be obtained by Michael reaction of the carboxylic acid compound represented by Formula (3) and the indole derivative represented by Formula (4) as shown below.
Figure JPOXMLDOC01-appb-C000020
Figure JPOXMLDOC01-appb-C000020
　上記式（３）及び式（４）におけるＲ１、Ｒ２、ｍ１、ｍ２は、式（１）におけるＲ１、Ｒ２、ｍ１、ｍ２と同じ定義である。 R 1, R 2, m1, m2 in the formula (3) and (4) is the same definition as R 1, R 2, m1, m2 in the equation (1).
　上記式（３）で表されるカルボン酸化合物は、以下に示すようにベンゼン誘導体（５）と無水マレイン酸とのフリーデル－クラフツ反応により合成することができる。かかるフリーデル－クラフツ反応は、ルイス酸、リン酸、ポリリン酸等を触媒として作用させることで行い、触媒として好適には塩化アルミニウムが好適に用いられる。 The carboxylic acid compound represented by the above formula (3) can be synthesized by a Friedel-Crafts reaction between the benzene derivative (5) and maleic anhydride as shown below. Such Friedel-Crafts reaction is carried out by using Lewis acid, phosphoric acid, polyphosphoric acid or the like as a catalyst, and aluminum chloride is preferably used as the catalyst.
Figure JPOXMLDOC01-appb-C000021
Figure JPOXMLDOC01-appb-C000021
　上記式（５）及び式（３）におけるＲ１、ｍ１は、式（１）におけるＲ１、ｍ１と同じ定義である。 R 1 and m1 in the above formula (5) and formula (3) have the same definitions as R 1 and m1 in formula (1).
　上記式（４）で表されるインドール誘導体は、市販品を用いることができる。市販のインドール誘導体としては、４－フルオロインドール、４－クロロインドール、４－ブロモインドール、６－フルオロインドール、６－クロロインドール、６－ブロモインドール、５－メチルインドール等を挙げることができる。 A commercially available product can be used as the indole derivative represented by the above formula (4). Examples of commercially available indole derivatives include 4-fluoroindole, 4-chloroindole, 4-bromoindole, 6-fluoroindole, 6-chloroindole, 6-bromoindole, and 5-methylindole.
　また、上記式（４）で表されるインドール誘導体は、公知の有機化学反応を用いる有機合成手法によって得ることもできる。例えば、Ｒ２がハロゲン原子である場合、市販のインドールに、Ｎ－ブロモスクシンイミド、Ｎ－クロロスクシンイミド、Ｎ－ヨードスクシンイミド等のハロゲン化剤を作用させることにより上記式（４）で表されるインドール誘導体を得ることができる。また、Ｒ２がＣ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基である場合、上述のように市販のインドールをハロゲン化した後、アルキルリチウム等の有機リチウム試薬との反応、鈴木－宮浦カップリング反応等によって、上記式（４）で表されるインドール誘導体を得ることができる。 The indole derivative represented by the above formula (4) can also be obtained by an organic synthesis method using a known organic chemical reaction. For example, when R 2 is a halogen atom, an indole represented by the above formula (4) is obtained by allowing a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, and N-iodosuccinimide to act on a commercially available indole. Derivatives can be obtained. When R 2 is a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or an organic oxy group represented by OR X , a commercially available indole is halogenated as described above. Thereafter, an indole derivative represented by the above formula (4) can be obtained by reaction with an organolithium reagent such as alkyl lithium, Suzuki-Miyaura coupling reaction, or the like.
［式（２）で表される化合物の合成］
　式（２）で表される化合物は、式（６）で表される５－ヒドロキシ－３－インドール酢酸誘導体を出発原料として、合成することができる。具体的には、式（６）で表される５－ヒドロキシ－３－インドール酢酸を、メタノールやエタノール、プロパノール、イソプロパノール等のアルコール中、酸性条件下で反応させることにより、式（７）で表されるエステル体へと誘導する。
　次に、上記エステル体と式（８）で表されるハロゲン化合物とを塩基の存在下反応させることで、式（９）で表される化合物を合成できる。上記の塩基としては、水素化ナトリウムや、炭酸リチウム、炭酸ナトリウム、炭酸カリウム、炭酸セシウムといったアルカリ金属の炭酸塩が挙げられる。
　続いて、式（９）で表される化合物のエステル部分を加水分解することにより、式（２）で表される化合物が合成される。 [Synthesis of Compound Represented by Formula (2)]
The compound represented by the formula (2) can be synthesized using a 5-hydroxy-3-indoleacetic acid derivative represented by the formula (6) as a starting material. Specifically, 5-hydroxy-3-indoleacetic acid represented by the formula (6) is reacted in an alcohol such as methanol, ethanol, propanol, isopropanol, or the like under an acidic condition to represent the formula (7). To the ester form.
Next, the compound represented by the formula (9) can be synthesized by reacting the ester compound with the halogen compound represented by the formula (8) in the presence of a base. Examples of the base include sodium hydride and alkali metal carbonates such as lithium carbonate, sodium carbonate, potassium carbonate, and cesium carbonate.
Then, the compound represented by Formula (2) is synthesize | combined by hydrolyzing the ester part of the compound represented by Formula (9).
Figure JPOXMLDOC01-appb-C000022
Figure JPOXMLDOC01-appb-C000022
　上記式（７）、（９）中、ＲＹは、メチル基、エチル基、ｎ－プロピル基、イソプロピル基等のＣ１～Ｃ３アルキル基を表す。
　上記式（８）中、Ｘは、フッ素原子、塩素原子、臭素原子、ヨウ素原子等のハロゲン原子を表す。
　上記式（６）、式（７）、式（８）、式（９）におけるＲ３、Ｒ４、ｍ３、ｍ４は、式（２）におけるＲ３、Ｒ４、ｍ３、ｍ４と同じ定義である。 In the above formulas (7) and (9), R Y represents a C1-C3 alkyl group such as a methyl group, an ethyl group, an n-propyl group, or an isopropyl group.
In said formula (8), X represents halogen atoms, such as a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
R 3 , R 4 , m3, and m4 in the above formula (6), formula (7), formula (8), and formula (9) have the same definitions as R 3 , R 4 , m3, and m4 in formula (2). is there.
　上記式（６）で表される５－ヒドロキシ－３－インドール酢酸誘導体は、市販の５－ヒドロキシ－３－インドール酢酸等を用いてもよいが、公知の有機化学反応を用いる有機合成手法によって得ることもできる。例えば、Ｒ４がハロゲン原子である場合、市販の５－ヒドロキシ－３－インドール酢酸に、Ｎ－ブロモスクシンイミド、Ｎ－クロロスクシンイミド、Ｎ－ヨードスクシンイミド等のハロゲン化剤を作用させることにより上記式（６）で表される５－ヒドロキシ－３－インドール酢酸誘導体を得ることができる。また、Ｒ４がＣ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基である場合、上述のように市販の５－ヒドロキシ－３－インドール酢酸をハロゲン化した後、アルキルリチウム等の有機リチウム試薬との反応、鈴木－宮浦カップリング反応等によって、上記式（６）で表される５－ヒドロキシ－３－インドール酢酸誘導体を得ることができる。 The 5-hydroxy-3-indoleacetic acid derivative represented by the above formula (6) may be commercially available 5-hydroxy-3-indoleacetic acid or the like, but is obtained by an organic synthesis method using a known organic chemical reaction. You can also. For example, when R 4 is a halogen atom, a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide or the like is allowed to act on commercially available 5-hydroxy-3-indoleacetic acid. A 5-hydroxy-3-indoleacetic acid derivative represented by 6) can be obtained. When R 4 is a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic oxy group represented by OR X , as described above, a commercially available 5-hydroxy-3 -Obtaining a 5-hydroxy-3-indoleacetic acid derivative represented by the above formula (6) by halogenating indoleacetic acid and then reacting with an organolithium reagent such as alkyllithium, Suzuki-Miyaura coupling reaction, etc. Can do.
　上記式（８）で表されるハロゲン化合物は、市販のベンジルブロミド、４－メチルベンジルブロミド、２－メチルベンジルブロミド、３－メチルベンジルブロミド、３－クロロベンジルブロミド、２－クロロベンジルブロミド、２，６－ジクロロベンジルブロミド、３－フルオロベンジルブロミド、４－フルオロベンジルブロミド、３，５－ジメトキシ臭化ベンジル等を用いてもよいが、公知の有機化学反応を用いる有機合成手法によって得ることもできる。例えば、Ｒ３がハロゲン原子である場合、市販のベンジルブロミドに、Ｎ－ブロモスクシンイミド、Ｎ－クロロスクシンイミド、Ｎ－ヨードスクシンイミド等のハロゲン化剤を作用させることにより上記式（８）で表されるハロゲン化合物を得ることができる。また、Ｒ３がＣ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基である場合、上記の市販のハロゲン化物を用いるか、上述のように市販のベンジルブロミドをハロゲン化した後、アルキルリチウム等の有機リチウム試薬との反応、鈴木－宮浦カップリング反応等によって、上記式（８）で表されるハロゲン化合物を得ることができる。 The halogen compounds represented by the above formula (8) are commercially available benzyl bromide, 4-methylbenzyl bromide, 2-methylbenzyl bromide, 3-methylbenzyl bromide, 3-chlorobenzyl bromide, 2-chlorobenzyl bromide, 2, 6-Dichlorobenzyl bromide, 3-fluorobenzyl bromide, 4-fluorobenzyl bromide, 3,5-dimethoxybenzyl bromide and the like may be used, but they can also be obtained by an organic synthesis method using a known organic chemical reaction. For example, when R 3 is a halogen atom, it is represented by the above formula (8) by allowing a commercially available benzyl bromide to act on a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimide. A halogen compound can be obtained. When R 3 is a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic oxy group represented by OR X , the above-mentioned commercially available halide may be used, or After halogenating commercially available benzyl bromide as described above, the halogen compound represented by the above formula (8) can be obtained by reaction with an organolithium reagent such as alkyl lithium, Suzuki-Miyaura coupling reaction or the like.
　上記のすべての有機反応は、それぞれ溶媒中で行うことができるが、溶媒は反応温度や反応物等によって適宜選択される。また、上記有機反応の反応温度は、用いる溶媒の沸点等の条件によって適宜選択される。上記有機反応で溶媒を用いる場合、得られた反応溶液を必要に応じて濃縮した後、残渣をそのまま次の反応に使用してもよく、適宜な後処理を行った後に、式（１）で表される化合物として用いてもよい。後処理の具体的な方法としては、抽出処理及び／又は晶出、再結晶、クロマトグラフィー等の公知の精製を挙げることができる。 All the above organic reactions can be carried out in a solvent, but the solvent is appropriately selected depending on the reaction temperature, reactants and the like. Moreover, the reaction temperature of the said organic reaction is suitably selected according to conditions, such as the boiling point of the solvent to be used. When using a solvent in the organic reaction, after concentrating the obtained reaction solution as necessary, the residue may be used as it is in the next reaction. After appropriate post-treatment, the formula (1) It may be used as a represented compound. Specific methods of the post-treatment include known purification such as extraction treatment and / or crystallization, recrystallization, chromatography and the like.
　本件化合物類は、皮膚由来の細胞における膠原線維（コラーゲン）の産生や、皮膚由来の細胞におけるコラーゲンの過剰な蓄積（皮膚線維化）を抑制又は予防する作用を有する。このため、本件化合物類を有効成分として含有する本発明のコラーゲン産生抑制剤や本発明の皮膚線維化疾患の予防又は治療剤は、皮膚線維化や、皮膚線維化に起因する、或いは皮膚線維化に伴う皮膚機能低下又は障害（皮膚線維化疾患）の進行を抑制することができる。したがって、本発明のコラーゲン産生抑制剤や本発明の皮膚線維化疾患の予防又は治療剤は、皮膚におけるコラーゲン蓄積抑制剤や、皮膚線維化抑制剤に有利に適用することができる。 The present compounds have an action of suppressing or preventing the production of collagen fibers (collagen) in skin-derived cells and excessive accumulation of collagen (skin fibrosis) in skin-derived cells. Therefore, the collagen production inhibitor of the present invention containing the present compounds as an active ingredient and the prophylactic or therapeutic agent for skin fibrosis of the present invention are caused by skin fibrosis, skin fibrosis, or skin fibrosis. It is possible to suppress the progression of skin function decline or disorder (skin fibrosis disease) associated with. Therefore, the collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention can be advantageously applied to collagen accumulation inhibitors in skin and skin fibrosis inhibitors.
　上記皮膚線維化疾患としては、具体的に、強皮症（全身性強皮症、限局性強皮症）、アトピー性皮膚炎、乾癬、ケロイド等を挙げることができ、アトピー性皮膚炎、乾癬、又は強皮症が好ましい。 Specific examples of the dermal fibrosis include scleroderma (systemic scleroderma, localized scleroderma), atopic dermatitis, psoriasis, keloid, and the like. Atopic dermatitis, psoriasis Or scleroderma is preferred.
　本発明のコラーゲン産生抑制剤や本発明の皮膚線維化疾患の予防又は治療剤の投与形態としては、粉末、顆粒、錠剤、カプセル剤、シロップ剤、懸濁液等の剤型で投与する経口投与や、溶液、乳剤、懸濁液等の剤型を注射、又はスプレー剤の型で、線維化した皮膚への直接投与を挙げることができる。 As the administration form of the collagen production inhibitor of the present invention or the preventive or therapeutic agent for skin fibrosis of the present invention, oral administration administered in a dosage form such as powder, granule, tablet, capsule, syrup, suspension, etc. In addition, a dosage form such as a solution, an emulsion, or a suspension can be injected or sprayed, and can be directly administered to fibrotic skin.
　本発明のコラーゲン産生抑制剤や本発明の皮膚線維化疾患の予防又は治療剤の投与量は、年齢、体重、性別、症状、投与形態、薬剤への感受性等に応じて適宜決定される。通常、１μｇ～２００ｍｇ／ｄａｙの投与量の範囲で、好ましくは２μｇ～２０００μｇ／ｄａｙの投与量の範囲で、より好ましくは３～２００μｇ／ｄａｙの投与量の範囲で、さらに好ましくは４～２０μｇ／ｄａｙの投与量の範囲で、一日あたり単回又は複数回（例えば、２～４回）に分けて投与されるが、症状の改善の状況に応じて投与量を調節してよい。 The dosage of the collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention is appropriately determined according to age, weight, sex, symptom, dosage form, drug sensitivity, and the like. Usually, in the dosage range of 1 μg to 200 mg / day, preferably in the dosage range of 2 μg to 2000 μg / day, more preferably in the dosage range of 3 to 200 μg / day, still more preferably 4 to 20 μg / day. The dose is administered once or multiple times per day (for example, 2 to 4 times) within the day dose range, but the dose may be adjusted according to the state of symptom improvement.
　本発明のコラーゲン産生抑制剤や本発明の皮膚線維化疾患の予防又は治療剤は、必要に応じて、薬学的に許容される通常の担体、結合剤、安定化剤、賦形剤、希釈剤、ｐＨ緩衝剤、崩壊剤、等張剤、添加剤、被覆剤、可溶化剤、潤滑剤、滑走剤、溶解補助剤、滑沢剤、風味剤、甘味剤、溶剤、ゲル化剤、栄養剤等の配合成分がさらに添加されたものを例示することができる。かかる配合成分としては、具体的に、水、生理食塩水、動物性脂肪及び油、植物油、乳糖、デンプン、ゼラチン、結晶性セルロース、ガム、タルク、ステアリン酸マグネシウム、ヒドロキシプロピルセルロース、ポリアルキレングリコール、ポリビニルアルコール、グリセリンを例示することができる。 The collagen production inhibitor of the present invention and the prophylactic or therapeutic agent for skin fibrosis of the present invention are pharmaceutically acceptable ordinary carriers, binders, stabilizers, excipients, diluents as necessary. , PH buffer, disintegrant, isotonic agent, additive, coating agent, solubilizer, lubricant, lubricant, solubilizer, lubricant, flavor, sweetener, solvent, gelling agent, nutrient What added the compounding ingredients, such as these, can be illustrated. Specific examples of such ingredients include water, saline, animal fats and oils, vegetable oils, lactose, starch, gelatin, crystalline cellulose, gum, talc, magnesium stearate, hydroxypropyl cellulose, polyalkylene glycol, Polyvinyl alcohol and glycerin can be exemplified.
　以下、実施例により本発明をより具体的に説明するが、本発明の技術的範囲はこれらの例示に限定されるものではない。 Hereinafter, the present invention will be described more specifically by way of examples. However, the technical scope of the present invention is not limited to these examples.
１．本件化合物類がコラーゲン産生抑制作用を有することの確認
　本件化合物類がコラーゲン産生抑制作用を有することを確認するために、強皮症由来皮膚線維芽細胞を用い、コラーゲン産生量を指標とした解析を行った。なお、強皮症由来皮膚線維芽細胞（東京女子医大の川口教授より分与）は、１００Ｕ／ｍＬペニシリン（GIBCO社製）、１００μｇ／ｍＬストレプトマイシン（GIBCO社製）、１０％ウシ胎児血清（ＦＢＳ）（GIBCO社製）を含むＲＰＭＩ１６４０（GIBCO社製）培養液（以下、「ＲＰＭＩ１６４０培養液」という）中で５％ＣＯ２／２０％Ｏ２、３７℃条件下で培養・維持した。
また、本件化合物＃１及び＃２は、それぞれ特許文献４に記載の化合物＃５（本件化合物＃１）及び＃３５（本件化合物＃２）の合成方法にしたがって合成した。 1. Confirmation that the compounds have an inhibitory action on collagen production To confirm that the compounds have an inhibitory action on collagen production, analysis using scleroderma-derived skin fibroblasts and the amount of collagen production as an index was conducted. went. Scleroderma-derived dermal fibroblasts (distributed by Prof. Kawaguchi, Tokyo Women's Medical University) were 100 U / mL penicillin (GIBCO), 100 μg / mL streptomycin (GIBCO), 10% fetal bovine serum (FBS). ) (Manufactured by GIBCO) in RPMI1640 (GIBCO) culture medium (hereinafter referred to as “RPMI1640 culture medium”) and cultured under 5% CO 2 /20% O 2 and 37 ° C. conditions.
The present compounds # 1 and # 2 were synthesized according to the synthesis method of compound # 5 (present compound # 1) and # 35 (present compound # 2) described in Patent Document 4, respectively.
１－１　方法
　１２穴細胞培養プレートに１ウエルあたり３×１０６個の強皮症由来皮膚線維芽細胞を撒いた後２４時間培養し、本件化合物＃１又は＃２を１、１０、又は１００μＭとなるようにＲＰＭＩ１６４０培養液に添加した（図１及び２の「－ＴＧＦβ１」参照）。本件化合物１又は＃２の添加の際、リコンビナントヒトＴＧＦ－β１（Transforming Growth Factor-β1）（Roche社製）を、１０ｎｇ／ｍＬとなるようにＲＰＭＩ１６４０培養液に添加し、コラーゲン産生量を促進させた条件下での実験も行った（図１及び２の「＋ＴＧＦβ１」参照）。４８時間及び７２時間培養後、培養液中に産生されたコラーゲン産生量を、ヒトI型コラーゲンＥＬＩＳＡ定量キット（ACEL社製）を用いて測定した。また、コントロールとして化合物及びＴＧＦ－β１非存在下で培養した細胞（図１及び２中の「－ＴＧＦβ１のＤＭＳＯ」）や、化合物非存在下でかつＴＧＦ－β１存在下で培養した細胞（図１及び２中の「＋ＴＧＦβ１のＤＭＳＯ」）を用いた。なお、図１の「－ＴＧＦβ１」は、ＴＧＦ－β１非存在下の細胞培養を４８時間行った結果を示し、「＋ＴＧＦβ１」は、ＴＧＦ－β１存在下の細胞培養を７２時間行ったときの結果を示す。 1-1 Method 3 × 10 6 scleroderma-derived dermal fibroblasts per well are seeded in a 12-well cell culture plate for 24 hours, and then Compound # 1 or # 2 is 1, 10, or 100 μM. (See “-TGFβ1” in FIGS. 1 and 2). When adding Compound 1 or # 2, recombinant human TGF-β1 (Transforming Growth Factor-β1) (Roche) is added to the RPMI 1640 culture solution at 10 ng / mL to promote collagen production. (See “+ TGFβ1” in FIGS. 1 and 2). After culturing for 48 hours and 72 hours, the amount of collagen produced in the culture solution was measured using a human type I collagen ELISA quantification kit (manufactured by ACEL). In addition, as a control, cells cultured in the absence of the compound and TGF-β1 (“DMF of −TGFβ1” in FIGS. 1 and 2) and cells cultured in the absence of the compound and in the presence of TGF-β1 (FIG. 1). And “+ DMF1 DMSO” in 2). In FIG. 1, “-TGFβ1” indicates the result of cell culture in the absence of TGF-β1 for 48 hours, and “+ TGFβ1” indicates the result of cell culture in the presence of TGF-β1 for 72 hours. Indicates.
１－２　結果
　強皮症由来皮膚線維芽細胞を、ＴＧＦ－β１の非存在下及び存在下のいずれの条件下で培養したときも、本件化合物＃１又は＃２を加えることによりその濃度依存的にコラーゲン産生を抑制することが明らかとなった（図１及び２参照）。この結果は、本件化合物類（本件化合物＃１及び＃２）は、ＴＧＦ－β１の有無にかかわらず、皮膚におけるコラーゲン産生や、皮膚におけるコラーゲンの過剰な蓄積を抑制する効果を有することを示すとともに、皮膚線維化の予防又は抑制や、強皮症等の皮膚線維化疾患の予防又は治療に有用であることを示している。 1-2 Results When scleroderma-derived dermal fibroblasts are cultured in the absence or presence of TGF-β1, the concentration depends on the addition of Compound # 1 or # 2 It was revealed that collagen production was suppressed (see FIGS. 1 and 2). This result shows that the present compounds (the present compounds # 1 and # 2) have an effect of suppressing collagen production in the skin and excessive accumulation of collagen in the skin regardless of the presence or absence of TGF-β1. It is useful for the prevention or suppression of skin fibrosis and the prevention or treatment of skin fibrosis diseases such as scleroderma.
２．本件化合物類がアトピー性皮膚炎の治療効果を有することの確認
　本件化合物類はコラーゲン産生抑制作用を有することが確認されたので、コラーゲン産生増加が原因として生じる皮膚線維化疾患の治療効果の有無について、アトピー性皮膚炎モデルマウスを用いて解析を行った。 2. Confirmation that the compounds have a therapeutic effect on atopic dermatitis Since the compounds have been confirmed to have a collagen production-inhibiting action, whether or not they have a therapeutic effect on skin fibrosis caused by increased collagen production The analysis was performed using atopic dermatitis model mice.
２－１　方法
　雌ＢＡＬＢ／Ｃマウスの両耳介表裏に、それぞれ０．１５％ジニトロクロロベンゼン（ＤＮＣＢ）溶液を２５μＬずつ（計１００μＬ）塗布し、かかる塗布処理を隔日にさらに４回（計５回）行うことにより、ＤＮＣＢ感作アトピー性皮膚炎モデルマウスを調製した。２週間後に、かかるモデルマウスに再度ＤＮＣＢを塗布し、アトピー性皮膚炎を惹起させた。かかる惹起当日の１時間前と、惹起２～１０日前のそれぞれの日に、本件化合物＃１又は＃２溶液を、マウスの両耳介表裏に、それぞれ２５μＬずつ（計１００μＬ［計１０、１００、又は１０００μＭ］）塗布した。アトピー性皮膚炎の惹起から１時間、６時間、及び２４時間後に、耳介膨張を計測した（図３参照）。なお、陽性コントロールとして、アトピー性皮膚炎モデルマウスに、アトピー性皮膚炎に対する塗布剤である０．１％タクロリムス（ＦＫ５０６）含有エタノール溶液を塗布した実験を行い（図中の「ＦＫ５０６」）、また、陰性コントロールとして、正常マウスに生理食塩水を塗布した場合の実験（図中の「vehicle」）と、アトピー性皮膚炎モデルマウスに、生理食塩水を塗布した場合の実験（図中の「control」）を行った。 2-1 Method Apply 25 μL each of 0.15% dinitrochlorobenzene (DNCB) solution (100 μL in total) on both front and back of female BALB / C mice, and perform this application treatment four times every other day (5 times in total). ) To prepare a DNCB-sensitized atopic dermatitis model mouse. Two weeks later, DNCB was applied again to the model mice to induce atopic dermatitis. One day before the induction day and 2 to 10 days before the induction, 25 μL each of the present compound # 1 or # 2 solution was placed on the front and back of both ears of the mouse (total 100 μL [total 10, 100, Or 1000 μM]). Ear swelling was measured 1 hour, 6 hours, and 24 hours after the onset of atopic dermatitis (see FIG. 3). As a positive control, an experiment in which an ethanol solution containing 0.1% tacrolimus (FK506), which is an application agent for atopic dermatitis, was applied to atopic dermatitis model mice was performed ("FK506" in the figure). As a negative control, an experiment in which normal saline was applied to normal mice ("vehicle" in the figure) and an experiment in which physiological saline was applied to atopic dermatitis model mice ("control in the figure") )).
２－２　結果
　アトピー性皮膚炎の惹起から少なくとも６～２４時間後において、本件化合物＃１又は＃２を投与すると、耳介膨張の有意な抑制効果が認められた。この結果は、本件化合物類（本件化合物＃１及び＃２）は、アトピー性皮膚炎の予防又は治療に有用であることを示している。 2-2 Results When this compound # 1 or # 2 was administered at least 6 to 24 hours after the onset of atopic dermatitis, a significant inhibitory effect on ear swelling was observed. This result shows that the present compounds (the present compounds # 1 and # 2) are useful for the prevention or treatment of atopic dermatitis.
３．本件化合物類が乾癬の治療効果を有することの確認
　本件化合物類が、アトピー性皮膚炎の予防又は治療効果を有することが確認されたので、アトピー性皮膚炎以外の皮膚線維化疾患である乾癬の治療効果の有無について、乾癬モデルマウスを用いて解析を行った。 3. Confirmation that the compounds have a therapeutic effect on psoriasis Since the compounds have been confirmed to have a preventive or therapeutic effect on atopic dermatitis, psoriasis, a skin fibrosis disease other than atopic dermatitis, has been confirmed. The presence or absence of therapeutic effect was analyzed using a psoriasis model mouse.
３－１　方法
　雌ＢＡＬＢ／Ｃマウスの両耳介表裏に、それぞれベセルナクリーム５％（イミキモド１２．５ｍｇ／クリーム２５０ｍｇ；持田製薬社製）を塗布し、かかる塗布処理を隔日にさらに４回（計５回）行うことにより、イミキモド感作乾癬モデルマウスを調製した。２週間後に、かかるモデルマウスに再度ベセルナクリーム５％を塗布し、乾癬を惹起させた。かかる惹起当日の１時間前と、惹起２～１０日前のそれぞれの日に、本件化合物＃１又は＃２溶液を、マウスの両耳介表裏に、それぞれ２５μＬずつ（計１００μＬ［計１０、１００、又は１０００μＭ］）塗布した。乾癬の惹起から１２及び１４日後に、耳介膨張を計測した（図４参照）。なお、陰性コントロールとして、乾癬モデルマウスに、生理食塩水を塗布した場合の実験（図中の「control」）を行った。 3-1 Method Beselna cream 5% (imiquimod 12.5 mg / cream 250 mg; manufactured by Mochida Pharmaceutical) was applied to the front and back of both auricles of female BALB / C mice. 5 times), imiquimod-sensitized psoriasis model mice were prepared. Two weeks later, 5% Beserna cream was applied to the model mice again to induce psoriasis. One day before the induction day and 2 to 10 days before the induction, 25 μL each of the present compound # 1 or # 2 solution was placed on the front and back of both ears of the mouse (total 100 μL [total 10, 100, Or 1000 μM]). Ear swelling was measured 12 and 14 days after the onset of psoriasis (see FIG. 4). As a negative control, an experiment (“control” in the figure) in which physiological saline was applied to a psoriasis model mouse was performed.
３－２　結果
　乾癬の惹起から少なくとも１２～１４日後において、本件化合物＃１又は＃２を投与すると、耳介膨張の有意な抑制効果が認められ、乾癬の症状が抑制されることが確認された。この結果は、本件化合物類（本件化合物＃１及び＃２）は、乾癬の予防又は治療に有用であることを示している。 3-2 Results At least 12-14 days after the onset of psoriasis, administration of Compound # 1 or # 2 confirmed a significant inhibitory effect on ear swelling and confirmed psoriasis symptoms. . This result shows that the present compounds (the present compounds # 1 and # 2) are useful for the prevention or treatment of psoriasis.
　本発明によると、皮膚におけるコラーゲン産生や、皮膚におけるコラーゲンの過剰な蓄積を抑制することができるため、皮膚線維化に起因する、或いは皮膚線維化に伴う皮膚機能低下や障害（皮膚線維化疾患）、具体的には、強皮症、アトピー性皮膚炎、乾癬、ケロイドの予防又は治療薬の開発に資するものである。 According to the present invention, since collagen production in the skin and excessive accumulation of collagen in the skin can be suppressed, skin function deterioration or damage caused by skin fibrosis or accompanying skin fibrosis (skin fibrosis disease) Specifically, it contributes to the development of a preventive or therapeutic agent for scleroderma, atopic dermatitis, psoriasis and keloid.

Claims (11)

  1. 　式（１）；
    Figure JPOXMLDOC01-appb-C000023
     （式中、Ｒ１、Ｒ２は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ１は０～５の整数を表し、ｍ２は０～５の整数を表す。）、及び
    　式（２）；
    Figure JPOXMLDOC01-appb-C000024
     （式中、Ｒ３、Ｒ４は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ３は０～５の整数を表し、ｍ４は０～４の整数を表す。）
    で表される化合物、並びにそれらの塩から選択される１種又は２種以上を含有することを特徴とするコラーゲン産生抑制剤。     Formula (1);
    Figure JPOXMLDOC01-appb-C000023
     (In the formula, R 1 and R 2 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or an organic group represented by OR X. Represents an oxy group, m1 represents an integer of 0 to 5, m2 represents an integer of 0 to 5), and formula (2);
    Figure JPOXMLDOC01-appb-C000024
     Wherein R 3 and R 4 may be the same or different, and are a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic group represented by OR X Represents an oxy group, m3 represents an integer of 0 to 5, and m4 represents an integer of 0 to 4.)
    A collagen production inhibitor comprising one or more selected from the compounds represented by the formula:
  2. 　式（１）で表される化合物が、以下の式（１’）であることを特徴とする請求項１に記載のコラーゲン産生抑制剤。
    Figure JPOXMLDOC01-appb-C000025
     （式中、Ｒ１は、同一でも異なっていてもよく、ハロゲン原子を表す。ｍ１は１～３の整数を表す。）     The compound represented by Formula (1) is the following Formula (1 '), The collagen production inhibitor of Claim 1 characterized by the above-mentioned.
    Figure JPOXMLDOC01-appb-C000025
     (In the formula, R 1 may be the same or different and each represents a halogen atom. M1 represents an integer of 1 to 3.)
  3. 　式（２）で表される化合物が、以下の式（２’）であることを特徴とする請求項１に記載のコラーゲン産生抑制剤。
    Figure JPOXMLDOC01-appb-C000026
     （式中、Ｒ３は、同一でも異なっていてもよく、ＯＲＸで表される有機オキシ基を表す。ｍ３は１～３の整数を表す。）     The compound represented by formula (2) is the following formula (2 '), wherein the collagen production inhibitor according to claim 1 is characterized.
    Figure JPOXMLDOC01-appb-C000026
     (Wherein R 3 may be the same or different and represents an organic oxy group represented by OR X. m3 represents an integer of 1 to 3)
  4. 　式（１）で表される化合物が、以下の式（１－１）であることを特徴とする請求項１に記載のコラーゲン産生抑制剤。
    Figure JPOXMLDOC01-appb-C000027
         The collagen production inhibitor according to claim 1, wherein the compound represented by the formula (1) is represented by the following formula (1-1).
    Figure JPOXMLDOC01-appb-C000027
  5. 　式（２）で表される化合物が、以下の式（２－１）であることを特徴とする請求項１に記載のコラーゲン産生抑制剤。
    Figure JPOXMLDOC01-appb-C000028
         The collagen production inhibitor according to claim 1, wherein the compound represented by the formula (2) is the following formula (2-1).
    Figure JPOXMLDOC01-appb-C000028
  6. 　式（１）；
    Figure JPOXMLDOC01-appb-C000029
     （式中、Ｒ１、Ｒ２は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ１は０～５の整数を表し、ｍ２は０～５の整数を表す。）、及び
    　式（２）；
    Figure JPOXMLDOC01-appb-C000030
     （式中、Ｒ３、Ｒ４は、同一でも異なっていてもよく、ハロゲン原子、Ｃ１～Ｃ６のアルキル基、Ｃ２～Ｃ６のアルケニル基、Ｃ２～Ｃ６のアルキニル基、ＯＲＸで表される有機オキシ基を表す。ｍ３は０～５の整数を表し、ｍ４は０～４の整数を表す。）
    で表される化合物、並びにそれらの塩から選択される１種又は２種以上を含有することを特徴とする皮膚線維化疾患の予防又は治療剤。     Formula (1);
    Figure JPOXMLDOC01-appb-C000029
     (In the formula, R 1 and R 2 may be the same or different, and are a halogen atom, a C1-C6 alkyl group, a C2-C6 alkenyl group, a C2-C6 alkynyl group, or an organic group represented by OR X. Represents an oxy group, m1 represents an integer of 0 to 5, m2 represents an integer of 0 to 5), and formula (2);
    Figure JPOXMLDOC01-appb-C000030
     Wherein R 3 and R 4 may be the same or different, and are a halogen atom, a C1 to C6 alkyl group, a C2 to C6 alkenyl group, a C2 to C6 alkynyl group, or an organic group represented by OR X Represents an oxy group, m3 represents an integer of 0 to 5, and m4 represents an integer of 0 to 4.)
    A prophylactic or therapeutic agent for dermal fibrosis, comprising one or more selected from the compounds represented by the formula (I) and salts thereof.
  7. 　式（１）で表される化合物が、以下の式（１’）であることを特徴とする請求項６に記載の予防又は治療剤。
    Figure JPOXMLDOC01-appb-C000031
     （式中、Ｒ１は、同一でも異なっていてもよく、ハロゲン原子を表す。ｍ１は１～３の整数を表す。）     The compound represented by Formula (1) is the following Formula (1 '), The preventive or therapeutic agent of Claim 6 characterized by the above-mentioned.
    Figure JPOXMLDOC01-appb-C000031
     (In the formula, R 1 may be the same or different and each represents a halogen atom. M1 represents an integer of 1 to 3.)
  8. 　式（２）で表される化合物が、以下の式（２’）であることを特徴とする請求項６に記載の予防又は治療剤。
    Figure JPOXMLDOC01-appb-C000032
     （式中、Ｒ３は、同一でも異なっていてもよく、ＯＲＸで表される有機オキシ基を表す。ｍ３は１～３の整数を表す。）     The prophylactic or therapeutic agent according to claim 6, wherein the compound represented by the formula (2) is the following formula (2 ').
    Figure JPOXMLDOC01-appb-C000032
     (Wherein R 3 may be the same or different and represents an organic oxy group represented by OR X. m3 represents an integer of 1 to 3)
  9. 　式（１）で表される化合物が、以下の式（１－１）であることを特徴とする請求項６に記載の予防又は治療剤。
    Figure JPOXMLDOC01-appb-C000033
         The prophylactic or therapeutic agent according to claim 6, wherein the compound represented by the formula (1) is the following formula (1-1).
    Figure JPOXMLDOC01-appb-C000033
  10. 　式（２）で表される化合物が、以下の式（２－１）であることを特徴とする請求項６に記載の予防又は治療剤。
    Figure JPOXMLDOC01-appb-C000034
         The preventive or therapeutic agent according to claim 6, wherein the compound represented by the formula (2) is the following formula (2-1).
    Figure JPOXMLDOC01-appb-C000034
  11. 　皮膚線維化疾患が、アトピー性皮膚炎、乾癬、又は強皮症であることを特徴とする請求項６～１０のいずれかに記載の予防又は治療剤。 The preventive or therapeutic agent according to any one of claims 6 to 10, wherein the skin fibrosis disease is atopic dermatitis, psoriasis, or scleroderma.
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