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WO2017073060A1 - Inhibiteur de production de collagène - Google Patents

Inhibiteur de production de collagène Download PDF

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Publication number
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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Prior art keywords
formula
group
represented
integer
collagen production
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Ceased
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PCT/JP2016/004714
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English (en)
Japanese (ja)
Inventor
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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Tohoku University NUC
Kake Educational Institution
Tokyo Womens Medical University
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Tohoku University NUC
Kake Educational Institution
Tokyo Womens Medical University
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Priority to JP2017547621A priority Critical patent/JP6872195B2/ja
Publication of WO2017073060A1 publication Critical patent/WO2017073060A1/fr
Anticipated expiration legal-status Critical
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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.

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Abstract

La présente invention aborde le problème de fourniture d'un inhibiteur de production de collagène, qui comprend, en tant que substance active, un composé de faible poids moléculaire ayant un effet d'inhibition (prévention) efficace de la production de collagène, et un agent prophylactique ou thérapeutique pour des maladies fibrotiques cutanées qui est capable de prévenir ou traiter efficacement des maladies fibrotiques cutanées. Une préparation comprenant un ou plusieurs membres choisis parmi des composés représentés par les formules (1) et (2) et des sels de ceux-ci est utilisée en tant qu'inhibiteur de production de collagène ou agent prophylactique ou thérapeutique pour des maladies fibrotiques cutanées.
PCT/JP2016/004714 2015-10-29 2016-10-27 Inhibiteur de production de collagène Ceased WO2017073060A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
WO2019112031A1 (fr) * 2017-12-08 2019-06-13 サイエンスファーム株式会社 Agent thérapeutique de la sclérodermie systémique
WO2019235455A1 (fr) * 2018-06-05 2019-12-12 国立大学法人東北大学 Séquence activatrice de la fonction de fécondation du sperme

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