WO2022138700A1 - Atopic skin disease ameliorating agent, external agent for skin, and cosmetic - Google Patents

Atopic skin disease ameliorating agent, external agent for skin, and cosmetic Download PDF

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WO2022138700A1
WO2022138700A1 PCT/JP2021/047502 JP2021047502W WO2022138700A1 WO 2022138700 A1 WO2022138700 A1 WO 2022138700A1 JP 2021047502 W JP2021047502 W JP 2021047502W WO 2022138700 A1 WO2022138700 A1 WO 2022138700A1
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PCT/JP2021/047502
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俊矢 佐原
夏輝 和木田
純輝 宇田
美樹 岩井
翼 今村
浩一 仲尾次
和彦 濱田
明人 前田
安史 金田
克人 玉井
康央 堤
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ピアス株式会社
国立大学法人大阪大学
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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/40—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing nitrogen
    • A61K8/42—Amides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
    • A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin

Definitions

  • the present invention relates to an atopic skin disease improving agent, an external skin agent, and a cosmetic.
  • Atopic dermatitis is a chronic disease in which itchy eczema repeatedly worsens and improves, and it is thought that various causes affect each other in a complicated manner. Atopic dermatitis is thought to be exacerbated, for example, by the production of lipid mediators that induce allergic reactions. However, it is believed that this is not the only cause of exacerbation of atopic dermatitis.
  • an ointment containing docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA) and a tacrolimus ointment are known (Patent Document 1). ..
  • the atopic skin disease improving agent described in Patent Document 1 can suppress the production of leukotriene B4, which is one of the lipid mediators that induces an allergic reaction, and thus can improve the symptoms of atopic skin disease.
  • an object of the present invention to provide an atopic skin disease improving agent, an external skin preparation agent, and a cosmetic that can improve the atopic skin disease.
  • the atopic skin disease improving agent according to the present invention is a compound represented by the following general formula (A), a compound represented by the following general formula (B), a compound represented by the following general formula (C), and the following formula. It is characterized by containing at least one selected from the group consisting of the compound represented by (D) and the compound represented by the following formula (E).
  • D 1 to D 4 are independently H, CH 3 or NO 2
  • E 1 to E 5 are independently H, OH, NH 2 , respectively.
  • X 1 , X 2 , and X 3 are independently H, NH 2 , NO 2 , or NH-G, respectively, and the G is CH 3 , a pyridinyl group.
  • Phenyl group methylphenyl group, methoxyphenyl group, ethoxyphenyl group, monohalogenated phenyl group, or benzoic acid ester group, where A is CH, CNO 2 , or N, and Z 1 , Z 2 , And Z 3 are CH, CR or N independently, respectively, and the R is OCH 3 , Cl, Br, NO 2 , NHCOCH 3 , or when the CRs are adjacent to each other, the Rs are five.
  • a member ring or a six-membered ring may be formed, the five-membered ring is a heterocycle in which a ring is formed by a carbon atom and two nitrogen atoms, and the six-membered ring is a ring formed by a carbon atom. It is a benzene ring.)
  • L is OH or OCH 3
  • Q 1 , Q 2 and Q 3 are independently CH or CR', and the CR'is adjacent to each other.
  • R's form a six-membered ring
  • the six-membered ring is a benzene ring in which a ring is formed by a carbon atom
  • T 1 to T 5 are independently H, OH, or T 5 respectively.
  • the external skin preparation and cosmetics according to the present invention include the above-mentioned atopic skin disease improving agent.
  • the graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor of the epidermal keratinocyte The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (Filaggrin) of the epidermal keratinized cell. The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (GBA) of the epidermal keratinocyte. The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (SPLTC2) of the epidermal keratinocyte.
  • (S)-(-)-Graph showing the results of an evaluation test (in vivo test) of efficacy against atopic dermatitis when Blebbistatin O-Benzoate is used.
  • a photograph showing a tissue observation image of filaggrin protein immunostained.
  • (S)-(-)-Photograph showing the tissue observation image of the lesion part of the mouse to which Blebbistatin O-Benzoate etc. was applied.
  • a graph showing the effect of (S)-(-)-Blebbistatin O-Benzoate on blood IgE concentration.
  • an atopic skin disease improving agent an external skin agent, and a cosmetic (hereinafter, also simply referred to as a composition) according to the present invention will be described below.
  • the composition of the present embodiment has a compound represented by the following general formula (A), a compound represented by the following general formula (B), a compound represented by the following formula (C), and a compound represented by the following formula (D). It contains at least one selected from the group consisting of the compounds to be used and the compounds represented by the following formula (E). Since the composition of the present embodiment contains at least one of the above-mentioned compounds, it can improve atopic skin diseases.
  • D 1 to D 4 are independently H, CH 3 or NO 2
  • E 1 to E 5 are independently H, OH, NH 2 , respectively. Or NO 2 , where J is an OH, H, or benzoic acid ester group, and * indicates a bond which may be an enantiomer of either S or R.
  • X 1 , X 2 , and X 3 are independently H, NH 2 , NO 2 , or NH-G, respectively, and the G is CH 3 , a pyridinyl group.
  • Phenyl group methylphenyl group, methoxyphenyl group, ethoxyphenyl group, monohalogenated phenyl group, or benzoic acid ester group, where A is CH, CNO 2 , or N, and Z 1 , Z 2 , And Z 3 are CH, CR or N independently, respectively, and the R is OCH 3 , Cl, Br, NO 2 , NHCOCH 3 , or if the CRs are adjacent to each other, a five-membered ring or A six-membered ring is formed, the five-membered ring is a heterocycle in which a ring is formed by a carbon atom and two nitrogen atoms, and the six-membered ring is a benzene ring in which a ring is formed by a carbon atom.
  • L is OH or OCH 3
  • Q 1 , Q 2 and Q 3 are independently CH or CR'and the CR'is each other.
  • T 1 to T 5 are independently H, OH, or OCH 3 respectively.
  • D 1 and D 4 are both H, one of D 2 and D 3 is CH 3 or NO 2 , and the other is H.
  • all of E 1 to E 5 are H, or any one of E 2 or E 3 of E 1 to E 5 is OH, NH 2 or NO. It is preferably 2 and the others are H.
  • J is a benzoic acid ester group (see formula (A-7)), H, or OH.
  • the compound represented by the general formula (A) is preferably the S-form of the enantiomers for the bond in *.
  • the compound represented by the general formula (A) is more preferably a compound represented by any of the following formulas (A-1) to (A-18). This has the advantage that atopic skin diseases can be further improved.
  • the compound represented by the formula (A-1) is a compound called (-)-Blebbistatin.
  • the compound name is (3aS) -3a-hydroxy-6-methyl-1-phenyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one.
  • the CAS number is 856925-71-8.
  • the compound represented by the formula (A-2) is a compound called (S) -3'-hydroxy Blebbistatin.
  • the compound name is (3aS) -3a-hydroxy-1- (3-hydroxyphenyl) -6-methyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one.
  • the CAS number is 2097136-42-8.
  • the compound represented by the formula (A-3) is a compound called (S) -3'-amino Blebbistatin.
  • the compound name is (3aS) -1- (3-aminophenyl) -3a-hydroxy-6-methyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one.
  • the CAS number is 2097141-18-7.
  • the compound represented by the formula (A-4) is a compound called (S) -4'-nitro-Blebbistatin.
  • the compound name is (3aS) -3a-hydroxy-6-methyl-1- (4-nitrophenyl) -2,3-dihydropyrrolo [2,3-b] quinolin-4-one.
  • the CAS number is 1621326-32-6.
  • the compound represented by the formula (A-5) is a compound called para-amino-Blebbistatin.
  • the compound name is (3aS) -1- (4-aminophenyl) -3a-hydroxy-6-methyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one.
  • the CAS number is 2097734-03-5.
  • the compound represented by the formula (A-6) is a compound called (S) -nitro-Blebbistatin.
  • the compound name is (3aS) -3a-hydroxy-7-nitro-1-phenyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one.
  • the CAS number is 856925-75-2.
  • the compound represented by the formula (A-7) is a compound called (S)-(-)-Blebbistatin O-Benzoate.
  • the compound name is [(3aS) -6-methyl-4-oxo-1-phenyl-2,3-dihydropyrrolo [2,3-b] quinolin-3a-yl] benzoate.
  • the CAS number is 1217832-61-5.
  • the compound represented by the formula (A-8) is a compound called Deoxy Blebbistatin.
  • the compound name is 6-methyl-1-phenyl-3,3a-dihydro-2H-pyrrolo [2,3-b] quinolin-4-one.
  • the CAS number is 856925-72-9.
  • X 1 is H or NH-G.
  • NH-G is more preferably NH-CH 3 .
  • X 2 and X 3 are independently H, NO 2 or NH 2 , respectively.
  • A is CH.
  • two of Z 1 to Z 3 form a five-membered ring or a six-membered ring, or Z 1 to Z 3 are independently CH or CR. It is preferable to have.
  • At least one of X1 to X3 is NH-G, and two of Z1 to Z3 form a five-membered ring or a six-membered ring. Or, it is preferable that two of Z 1 to Z 3 are CH and one is CR.
  • the compound represented by the general formula (B) is more preferably a compound represented by any of the following formulas (B-1) to (B-18). This has the advantage that atopic skin diseases can be further improved.
  • the compound represented by the general formula (B-1) is a compound called KRIBB11.
  • the compound name is 2-N- (1H-indazol-5-yl) -6-N-methyl-3-nitropyridine-2,6-diamine.
  • the CAS number is 342639-96-7.
  • the compound represented by the formula (B-2) is a compound called Z86253669.
  • the compound name is N- (3-nitropyridin-2-yl) -1H-indazol-6-amine.
  • the compound represented by the formula (B-3) is a compound called Z86332512.
  • the compound name is N- (3-nitropyridin-2-yl) -1H-indazol-5-amine.
  • the compound represented by the formula (B-4) is a compound called STK067130.
  • the compound name is Diethyl 4,4'-[(3,5-dinitropyridine-2,6-diyl) diimino] dibenzoate.
  • the compound represented by the formula (B-5) is a compound called STK372678.
  • the compound name is (3,5-Dinitro (2-pyridyl)) naphthylamine.
  • the compound name of the compound represented by the formula (B-6) is N- ⁇ 4-[(3,5-Dinitropyridin-2-yl) amino] phenyl ⁇ acetamide.
  • the compound name of the compound represented by the formula (B-7) is 2-N, 6-N-Bis (4-methoxyphenyl) -3-nitropyridine-2,6-diamine.
  • the compound name of the compound represented by the formula (B-8) is 3-Nitro-N2, N6-diphenylpyridine-2,6-diamine.
  • the compound name of the compound represented by the formula (B-9) is 2-N, 6-N-Bis (4-chlorophenyl) -3,5-dinitropyridine-2,6-diamine.
  • the compound name of the compound represented by the formula (B-10) is 3,5-Dinitro-N- (2,4,6-trinitrophenyl) pyridin-2-amine.
  • the compound name of the compound represented by the formula (B-11) is 3,5-Dinitro-N-phenylpyridin-2-amine.
  • the compound name of the compound represented by the formula (B-12) is 3,5-Dinitro-2-N, 6-N-dipyridin-2-ylpyridine-2,6-diamine.
  • the compound name of the compound represented by the formula (B-13) is 2-N, 6-N-Bis (4-bromophenyl) -3,5-dinitropyridine-2,6-diamine.
  • the compound name of the compound represented by the formula (B-14) is 2-N, 6-N-Bis (4-bromophenyl) -3,5-dinitropyridine-2,4,6-triamine.
  • the compound name of the compound represented by the formula (B-15) is N2, N6-Bis (4-chlorophenyl) -3,5-dinitro-2,4,6-pyridinetriamine.
  • the compound name of the compound represented by the formula (B-16) is (2-Chlorophenyl) ⁇ 6-[(2-chlorophenyl) amino] -3,5-dinitro (2-pyridyl) ⁇ amine.
  • the compound name of the compound represented by the formula (B-17) is 3,5-Dinitro-2-N, 6-N-diphenylpyridine-2,4,6-triamine.
  • the compound name of the compound represented by the formula (B-18) is 2-N,6-N-Bis (4-methylphenyl) -3,5-dinitropyridine-2,4,6-triamine.
  • one of Q1 to Q3 is CH and two adjacent compounds are CR', forming a benzene ring, or Q1 to Q. It is preferable that all of 3 are CH.
  • L is preferably OH.
  • two or three of T 1 to T 5 are OH or OCH 3 and the other is H.
  • the compound represented by the general formula (C) is more preferably a compound represented by any of the following formulas (C-1) to (C-5). This has the advantage that atopic skin diseases can be further improved.
  • the compound represented by the formula (C-1) is a compound called Dyngo-4a.
  • the compound name is 3-hydroxy-N-[(Z)-(2,4,5-trihydroxyphenyl) methylideneamino] naphthalene-2-carboxamide.
  • the CAS number is 1256493-34-1.
  • the compound represented by the formula (C-2) is a compound called Dynasore.
  • the compound name is N-[(3,4-dihydroxyphenyl) methylideneamino] -3-hydroxynaphthalene-2-carboxamide.
  • the CAS number is 304448-55-3.
  • the compound name of the compound represented by the formula (C-3) is 3-Methoxy-N'-(3,4-dimethoxybenzylidene) -2-naphthohydrazide.
  • the compound name of the compound represented by the formula (C-4) is Pyrocatechol-1-carbaldehyde salicyloylhydrazone.
  • the CAS number is 92071-89-1.
  • the compound name of the compound represented by the formula (C-5) is N-[(Z)-(2,3-Dimethoxyphenyl) methylideneamino] -1-hydroxynaphthalene-2-carboxamide.
  • the compound represented by the formula (D) is a compound called GW4064.
  • the compound name is 3-[(E) -2- [2-chloro-4-[[3- (2,6-dichlorophenyl) -5-propan-2-yl-1,2-oxazol-4-yl]]. methoxy] phenyl] ethenyl] benzoic acid.
  • the CAS number is 278779-30-9.
  • the compound represented by the formula (E) is a compound called Venetoclax (ABT-199, GDC-0199).
  • the compound name is 4- [4- [[2- (4-chlorophenyl) -4,4-dimethylcyclohexen-1-yl] methyl] piperazin-1-yl] -N- [3-nitro-4- (oxan-).
  • the CAS number is 1257044-40-8.
  • the concentration of the total amount of the above-mentioned compounds may be, for example, 0.001% by mass or more and 5% by mass or less, and 0.01% by mass or more and 2.0% by mass or less. More preferred.
  • the above-mentioned content concentration has an advantage that atopic skin disease can be further improved.
  • the above composition usually contains water, and may further contain a thickener, a surfactant, a preservative, etc. in addition to the above components.
  • composition of this embodiment are not particularly limited, but are, for example, liquid.
  • the composition of the present embodiment may be in a solid state.
  • the composition of this embodiment can be produced by a general method.
  • the above composition can be produced by mixing and stirring each component to be blended.
  • a general device can be used. If necessary, the mixture may be stirred while being heated.
  • the above composition is preferably a skin external preparation (transdermal administration agent) or a cosmetic.
  • skin preparations or cosmetics are usually applied to the skin for use.
  • the above-mentioned external skin preparations or cosmetics may be applied to, for example, facial skin, neck skin, limb skin, scalp, hair, and mucous membranes in the nose, lips, ears, genital organs, anus, etc. good.
  • the above-mentioned external skin preparation or cosmetic may be used as a bath salt or as a skin patch.
  • composition of this embodiment is not necessarily bound by the classification of cosmetics, quasi-drugs, pharmaceuticals, etc. specified by laws related to pharmaceutical affairs around the world.
  • the matters disclosed herein include: (1) The compound represented by the above general formula (A), the compound represented by the above general formula (B), the compound represented by the above general formula (C), and the compound represented by the above formula (D). , And an atopic skin disease improving agent containing at least one selected from the group consisting of the compound represented by the above formula (E).
  • D 1 and D 4 are both H, one of D 2 and D 3 is CH 3 or NO 2 , and the other is H.
  • the atopic skin disease improving agent according to 1).
  • E 1 to E 5 are H, or any one of E 2 or E 3 of E 1 to E 5 is OH, NH 2 or
  • the atopic skin disease improving agent according to (1) or (2) above, which is NO 2 and the others are H.
  • the compound represented by the above general formula (A) is a compound represented by the above general formula (A-1), a compound represented by the above general formula (A-4), and the above general formula (A).
  • the atopic skin disease improving agent according to any one of (1) to (4) above.
  • X 1 is H or NH-G and X 1 is NH-G
  • NH-G is NH-CH 3
  • X 2 and X 3 are independently H, NO 2 or NH 2
  • A is CH.
  • Two of Z 1 to Z 3 form a five-membered ring or a six-membered ring, or Z 1 to Z 3 are independently CH or CR, respectively.
  • At least one of X1 to X3 is NH-G, and two of Z1 to Z3 form a five-membered or six -membered ring, or two of Z1 to Z3.
  • One of Q1 to Q3 is CH and two adjacent ones are CR'and form a benzene ring, or all of Q1 to Q3 are CH and L is OH.
  • An external skin preparation containing the same components as those contained in the atopic skin disease improving agent according to any one of (1) to (7) above.
  • a cosmetic containing the same components as those contained in the atopic skin disease improving agent according to any one of (1) to (7) above.
  • composition of the present invention is as illustrated above, but the present invention is not limited to the embodiment described above. Further, in the present invention, various forms adopted in a general composition for external use on the skin, a composition for oral administration, and the like can be adopted as long as the effects of the present invention are not impaired.
  • Test Examples 1 to 9 By dissolving each of the following components in a solvent (dimethyl sulfoxide, propylene glycol, water, etc.), the composition of each Test Example (for example, it can be used as a skin external preparation) was produced.
  • a solvent dimethyl sulfoxide, propylene glycol, water, etc.
  • SMPD1 acidic sphingomyelinase
  • HAS3 Barrier function related protein
  • RNA is purified from the cells and reversed to cDNA using the product name "ReverTra AceTM qPCR RT Master Mix” (manufactured by TOYOBO). I copied it.
  • the mRNA expression level of the barrier function-related factor was quantitatively evaluated.
  • GAPDH was used as the internal standard correction.
  • DMSO dimethyl sulfoxide
  • FIG. 1 and FIGS. 2 to 6 The graphs of the above in vitro test results are shown in FIG. 1 and FIGS. 2 to 6.
  • each of the above compounds (a-1), (b), and (e) expresses skin barrier function-related factors that are strongly associated with the improvement of atopic dermatitis. It was enhanced. Further, as can be seen from FIGS. 2 to 6, of the above (a-4), (a-5), (a-7), (a-8), (c), and (d).
  • Each compound enhanced the expression of skin barrier function-related factors that are strongly associated with the improvement of atopic dermatitis.
  • ⁇ Evaluation of efficacy for atopic skin diseases (in vivo test)> 1-1.
  • Preparation of pathological model mice NC / NgaTndCrlj 10-week-old females were used. 10 individuals were used for each group.
  • Atopic skin disease model mice were prepared by applying mite antigen ointment to each mouse twice a week for a total of 6 times. That is, a dermatitis model was prepared by applying mite antigen ointment to pathological model mice from the 0th day to the 20th day. 1-2.
  • the mite antigen ointment was not applied to the pathological model mice, but a paste containing each compound was applied daily and the transition of dermatitis was observed.
  • the paste was prepared by dissolving each compound in propylene glycol (PG) and then mixing with petrolatum so that each compound had a concentration of 0.5% by mass. A 100 mg paste was applied per day.
  • PG propylene glycol
  • a paste a mixture of propylene glycol and petrolatum in which a compound was replaced with PG was used.
  • the applied sites were the back and auricle.
  • the condition of dermatitis on a particular day was scored. 1-3. Score Criteria Each of the following items was evaluated on a 4-point scale and scored (0: asymptomatic, 1: mild, 2: moderate, 3: severe). ⁇ Redness and bleeding of the back ⁇ Crust formation and dryness of the back ⁇ Edema of the auricle ⁇ Abrasion of the auricle, tissue defect The smaller the score, the better the skin disease (dermatitis). 1-4. Observation of the condition of the lesion tissue On the final day (30th day), the skin tissue on the back was collected. The collected sample was fixed with a neutral buffered formalin solution having a concentration of 10% by mass.
  • a tissue section of the lesion was prepared by preparing a paraffin-embedded block. Hematoxylin and eosin staining (HE staining) and immunostaining with anti-Filaggrin antibody were performed, and the condition of the lesion tissue was observed using an optical microscope. The observation image is shown in FIG. It was observed that the cells of the epidermis were strongly stained with the anti-filaggrin antibody by the application of the compound ((-)-Blebbistatin) of the above (a-1). Filaggrin is known to be a protein that plays an important role in the barrier function of the skin. It is also known that the amount of filaggrin decreases in the skin with atopic dermatitis.
  • the above compound (a-1) increased the expression of filaggrin in epidermal cells in both in vitro and in vivo tests. This is considered to have improved dermatitis. It is considered that the above compound (a-1) increased the amount of filaggrin in the epidermis, which improved the barrier function and suppressed the symptoms of dermatitis.
  • FIG. 8 shows a photograph of the skin of the pathological model mouse on the final day (30th day) of the above in vivo test.
  • FIG. 10 shows a graph showing the measurement results of the epidermal thickening of the lesion.
  • the compound (a) described above improved atopic skin disease. Specifically, improvement of epidermal thickening and reduction of scabs were observed from the skin section images. In addition, it was observed from the photograph of the back that there was no improvement in edema and bleeding in the auricle and no tissue damage.
  • FIG. 11 shows a graph of the results of the above in vivo test (1-3. Total score as a result of scoring).
  • the horizontal axis in the graph represents the number of days since the paste containing each compound was started to be applied.
  • each of the above compounds (a-1) and (b) to (e) improved atopic skin disease.
  • ⁇ Evaluation of efficacy for atopic skin diseases (in vivo test)> 2-1.
  • Preparation of pathological model mice NC / Nga slc 8-week-old females were used as mice. Eight individuals were used for each group.
  • Atopy skin disease model mice were prepared by administering the mite antigen to the auricle of each mouse twice a week for a total of 5 times. That is, a dermatitis model was prepared by administering the mite antigen to the pathological model mice from the 0th day to the 14th day. After the model was created, the groups were grouped using the stratified allocation method so that the average values of the auricle thickness and the auricle skin symptom score of each group were as even as possible.
  • Hematoxylin and eosin staining were performed, and the condition of the lesion tissue was observed using a microscope. 2-5.
  • Blood was collected on the final day (35th day) of measurement of blood IgE concentration. The collected sample was allowed to stand at room temperature for 30 minutes or more, and then centrifuged to collect serum. For serum, the IgE concentration was measured using a mouse IgE measurement kit (manufactured by Yamasa Corporation).
  • a histological observation photograph (immunostaining using an anti-Filaggrin antibody) of the lesion portion in FIG. 13 is shown in FIG. 2-4.
  • a histological observation photograph (staining with hematoxylin and eosin) of the lesion in the above is shown in FIG. 2-5 above.
  • the graph of the result in FIG. 15 is shown in FIG.
  • the above-mentioned compound (a-7) also improved the atopic skin disease like the above-mentioned compound (a-1).
  • the atopic skin disease improving agent (external skin preparation, cosmetics) of the present embodiment was able to sufficiently improve the atopic skin disease.
  • the atopic skin disease improving agent of the present invention can be used, for example, as an external skin preparation or a cosmetic.
  • the external skin preparation and cosmetics of the present invention are applied to and used on the skin, for example, to prevent and reduce dry skin and to prevent and reduce inflammatory rough skin.
  • the external skin preparation of the present invention is applied directly to the stratum corneum, for example, and is suitably used for cosmetics and the like.

Abstract

Provided are an atopic skin disease ameliorating agent, an external agent for skin and a cosmetic, each containing at least one member selected from a group consisting of a plurality of compounds having a specific molecular structure.

Description

アトピー性皮膚疾患改善剤、皮膚外用剤、及び、化粧料Atopic skin disease improving agents, external skin agents, and cosmetics 関連出願の相互参照Cross-reference of related applications
　本願は、日本国特願２０２０―２１４２３４号の優先権を主張し、該出願が引用によって本願明細書の記載に組み込まれる。 This application claims the priority of Japanese Patent Application No. 2020-214234, and the application is incorporated in the description of the present application by citation.
　本発明は、アトピー性皮膚疾患改善剤、皮膚外用剤、及び、化粧料に関する。 The present invention relates to an atopic skin disease improving agent, an external skin agent, and a cosmetic.
　アトピー性皮膚疾患は、かゆみを伴う湿疹が悪化及び改善を繰り返す慢性疾患であり、様々な原因が複雑に影響し合って発症すると考えられている。アトピー性皮膚疾患は、例えば、アレルギー反応を誘発する脂質メディエーターが産生されることによって、悪化すると考えられている。しかしながら、アトピー性皮膚疾患が悪化する原因はこれだけではないと考えられている。 Atopic dermatitis is a chronic disease in which itchy eczema repeatedly worsens and improves, and it is thought that various causes affect each other in a complicated manner. Atopic dermatitis is thought to be exacerbated, for example, by the production of lipid mediators that induce allergic reactions. However, it is believed that this is not the only cause of exacerbation of atopic dermatitis.
　従来、上記のごときアトピー性皮膚疾患を改善するための様々なアトピー性皮膚疾患改善剤が知られている。 Conventionally, various atopic dermatitis improving agents for improving atopic dermatitis as described above are known.
　この種のアトピー性皮膚疾患改善剤としては、例えば、ドコサヘキサエン酸（ＤＨＡ）及び／又はエイコサペンタエン酸（ＥＰＡ）含有軟膏剤と、タクロリムス軟膏剤とを含むものが知られている（特許文献１）。 As an atopic skin disease improving agent of this kind, for example, an ointment containing docosahexaenoic acid (DHA) and / or eicosapentaenoic acid (EPA) and a tacrolimus ointment are known (Patent Document 1). ..
　特許文献１に記載のアトピー性皮膚疾患改善剤は、アレルギー反応を誘発する脂質メディエーターの１種であるロイコトリエンＢ４の産生を抑制できることから、アトピー性皮膚疾患の症状を改善できる。 The atopic skin disease improving agent described in Patent Document 1 can suppress the production of leukotriene B4, which is one of the lipid mediators that induces an allergic reaction, and thus can improve the symptoms of atopic skin disease.
日本国特開２０１７－１９７４７１号公報Japanese Patent Application Laid-Open No. 2017-197471
　しかしながら、アトピー性皮膚疾患を改善できる製剤については、未だ十分に検討されているとはいえない。 However, it cannot be said that a drug product that can improve atopic dermatitis has been sufficiently investigated.
　そこで、本発明は、アトピー性皮膚疾患を改善できるアトピー性皮膚疾患改善剤、皮膚外用剤、及び、化粧料を提供することを課題とする。 Therefore, it is an object of the present invention to provide an atopic skin disease improving agent, an external skin preparation agent, and a cosmetic that can improve the atopic skin disease.
　本発明に係るアトピー性皮膚疾患改善剤は、下記一般式（Ａ）で表される化合物、下記一般式（Ｂ）で表される化合物、下記一般式（Ｃ）で表される化合物、下記式（Ｄ）で表される化合物、及び、下記式（Ｅ）で表される化合物からなる群より選択された少なくとも１種を含むことを特徴とする。
Figure JPOXMLDOC01-appb-C000006
 （ただし、一般式（Ａ）において、Ｄ１乃至Ｄ４は、それぞれ独立してＨ、ＣＨ３、又はＮＯ２であり、Ｅ１乃至Ｅ５は、それぞれ独立してＨ、ＯＨ、ＮＨ２、又はＮＯ２であり、Ｊは、ＯＨ、Ｈ、又は安息香酸エステル基であり、＊は、Ｓ又はＲのいずれの鏡像異性体となってもよい結合を示す。）
Figure JPOXMLDOC01-appb-C000007
 （ただし、一般式（Ｂ）において、Ｘ１、Ｘ２、及びＸ３は、それぞれ独立してＨ、ＮＨ２、ＮＯ２、又は、ＮＨ－Ｇであり、前記Ｇは、ＣＨ３、ピリジニル基、フェニル基、メチルフェニル基、メトキシフェニル基、エトキシフェニル基、モノハロゲン化フェニル基、又は、安息香酸エステル基であり、Ａは、ＣＨ、ＣＮＯ２、又はＮであり、Ｚ１、Ｚ２、及びＺ３は、それぞれ独立してＣＨ、ＣＲ若しくはＮであり、前記ＲがＯＣＨ３、Ｃｌ、Ｂｒ、ＮＯ２、ＮＨＣＯＣＨ３であるか、又は、前記ＣＲが互いに隣り合う場合にＲ同士で五員環又は六員環を形成してもよく、前記五員環は、炭素原子と２つの窒素原子で環が形成された複素環であり、前記六員環は、炭素原子で環が形成されたベンゼン環である。）
Figure JPOXMLDOC01-appb-C000008
 （ただし、一般式（Ｃ）において、Ｌは、ＯＨ又はＯＣＨ３であり、Ｑ１、Ｑ２、及びＱ３は、それぞれ独立して、ＣＨ又はＣＲ’であり、前記ＣＲ’が互いに隣り合う場合にＲ’同士で六員環を形成しており、前記六員環は、炭素原子で環が形成されたベンゼン環であり、Ｔ１乃至Ｔ５は、それぞれ独立してＨ、ＯＨ、又はＯＣＨ３である。）
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000010
 The atopic skin disease improving agent according to the present invention is a compound represented by the following general formula (A), a compound represented by the following general formula (B), a compound represented by the following general formula (C), and the following formula. It is characterized by containing at least one selected from the group consisting of the compound represented by (D) and the compound represented by the following formula (E).
Figure JPOXMLDOC01-appb-C000006
 (However, in the general formula (A), D 1 to D 4 are independently H, CH 3 or NO 2 , and E 1 to E 5 are independently H, OH, NH 2 , respectively. Or NO 2 , where J is an OH, H, or benzoic acid ester group, and * indicates a bond which may be an enantiomer of either S or R.)
Figure JPOXMLDOC01-appb-C000007
 (However, in the general formula (B), X 1 , X 2 , and X 3 are independently H, NH 2 , NO 2 , or NH-G, respectively, and the G is CH 3 , a pyridinyl group. , Phenyl group, methylphenyl group, methoxyphenyl group, ethoxyphenyl group, monohalogenated phenyl group, or benzoic acid ester group, where A is CH, CNO 2 , or N, and Z 1 , Z 2 , And Z 3 are CH, CR or N independently, respectively, and the R is OCH 3 , Cl, Br, NO 2 , NHCOCH 3 , or when the CRs are adjacent to each other, the Rs are five. A member ring or a six-membered ring may be formed, the five-membered ring is a heterocycle in which a ring is formed by a carbon atom and two nitrogen atoms, and the six-membered ring is a ring formed by a carbon atom. It is a benzene ring.)
Figure JPOXMLDOC01-appb-C000008
 (However, in the general formula (C), L is OH or OCH 3 , Q 1 , Q 2 and Q 3 are independently CH or CR', and the CR'is adjacent to each other. In some cases, R's form a six-membered ring, and the six-membered ring is a benzene ring in which a ring is formed by a carbon atom, and T 1 to T 5 are independently H, OH, or T 5 respectively. OCH 3 )
Figure JPOXMLDOC01-appb-C000009
Figure JPOXMLDOC01-appb-C000010
　本発明に係る皮膚外用剤、及び、化粧料は、上記のアトピー性皮膚疾患改善剤を含む。 The external skin preparation and cosmetics according to the present invention include the above-mentioned atopic skin disease improving agent.
表皮角化細胞のバリア機能関連因子の発現に関する評価試験結果（ｉｎ　ｖｉｔｒｏ試験）を表すグラフ。The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor of the epidermal keratinocyte. 表皮角化細胞のバリア機能関連因子（Ｆｉｌａｇｇｒｉｎ）の発現に関する評価試験結果（ｉｎ　ｖｉｔｒｏ試験）を表すグラフ。The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (Filaggrin) of the epidermal keratinized cell. 表皮角化細胞のバリア機能関連因子（ＧＢＡ）の発現に関する評価試験結果（ｉｎ　ｖｉｔｒｏ試験）を表すグラフ。The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (GBA) of the epidermal keratinocyte. 表皮角化細胞のバリア機能関連因子（ＳＰＬＴＣ２）の発現に関する評価試験結果（ｉｎ　ｖｉｔｒｏ試験）を表すグラフ。The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (SPLTC2) of the epidermal keratinocyte. 表皮角化細胞のバリア機能関連因子（ＳＭＰＤ１）の発現に関する評価試験結果（ｉｎ　ｖｉｔｒｏ試験）を表すグラフ。The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (SMPD1) of the epidermal keratinocyte. 表皮角化細胞のバリア機能関連因子（ＨＡＳ３）の発現に関する評価試験結果（ｉｎ　ｖｉｔｒｏ試験）を表すグラフ。The graph which shows the evaluation test result (in vitro test) about the expression of the barrier function-related factor (HAS3) of the epidermal keratinocyte. フィラグリンタンパク質が免疫染色処理された組織観察像を表す写真。A photograph showing a tissue observation image of filaggrin protein immunostained. マウスにおける病変部の外観を表す写真。A photograph showing the appearance of a lesion in a mouse. (-)-Blebbistatinなどを適用したマウスの病変部の組織観察像を表す写真。(-)-A photograph showing a tissue observation image of a lesion in a mouse to which Blebbistatin and the like are applied. 表皮肥厚の測定結果を表すグラフ。A graph showing the measurement results of epidermal thickening. アトピー性皮膚疾患に対する有効性の評価試験結果（ｉｎ　ｖｉｖｏ試験）を表すグラフ。The graph which shows the evaluation test result (in vivo test) of the efficacy for atopic skin disease. (S)-(-)-Blebbistatin O-Benzoateを使った場合のアトピー性皮膚疾患に対する有効性の評価試験結果（ｉｎ　ｖｉｖｏ試験）を表すグラフ。(S)-(-)-Graph showing the results of an evaluation test (in vivo test) of efficacy against atopic dermatitis when Blebbistatin O-Benzoate is used. フィラグリンタンパク質が免疫染色処理された組織観察像を表す写真。A photograph showing a tissue observation image of filaggrin protein immunostained. (S)-(-)-Blebbistatin O-Benzoateなどを適用したマウスの病変部の組織観察像を表す写真。(S)-(-)-Photograph showing the tissue observation image of the lesion part of the mouse to which Blebbistatin O-Benzoate etc. was applied. 血中ＩｇＥ濃度への(S)-(-)-Blebbistatin O-Benzoateによる影響を表すグラフ。A graph showing the effect of (S)-(-)-Blebbistatin O-Benzoate on blood IgE concentration.
　本発明に係るアトピー性皮膚疾患改善剤、皮膚外用剤、及び、化粧料（以下、単に組成物ともいう）の一実施形態について以下に説明する。 An embodiment of an atopic skin disease improving agent, an external skin agent, and a cosmetic (hereinafter, also simply referred to as a composition) according to the present invention will be described below.
　本実施形態の組成物は、下記一般式（Ａ）で表される化合物、下記一般式（Ｂ）で表される化合物、下記式（Ｃ）で表される化合物、下記式（Ｄ）で表される化合物、及び、下記式（Ｅ）で表される化合物からなる群より選択された少なくとも１種を含む。
　本実施形態の組成物は、上述した化合物の少なくとも１種を含むため、アトピー性皮膚疾患を改善できる。 The composition of the present embodiment has a compound represented by the following general formula (A), a compound represented by the following general formula (B), a compound represented by the following formula (C), and a compound represented by the following formula (D). It contains at least one selected from the group consisting of the compounds to be used and the compounds represented by the following formula (E).
Since the composition of the present embodiment contains at least one of the above-mentioned compounds, it can improve atopic skin diseases.
Figure JPOXMLDOC01-appb-C000011
 （ただし、一般式（Ａ）において、Ｄ１乃至Ｄ４は、それぞれ独立してＨ、ＣＨ３、又はＮＯ２であり、Ｅ１乃至Ｅ５は、それぞれ独立してＨ、ＯＨ、ＮＨ２、又はＮＯ２であり、Ｊは、ＯＨ、Ｈ、又は安息香酸エステル基であり、＊は、Ｓ又はＲのいずれの鏡像異性体となってもよい結合を示す。）
Figure JPOXMLDOC01-appb-C000012
 （ただし、一般式（Ｂ）において、Ｘ１、Ｘ２、及びＸ３は、それぞれ独立してＨ、ＮＨ２、ＮＯ２、又は、ＮＨ－Ｇであり、前記Ｇは、ＣＨ３、ピリジニル基、フェニル基、メチルフェニル基、メトキシフェニル基、エトキシフェニル基、モノハロゲン化フェニル基、又は、安息香酸エステル基であり、Ａは、ＣＨ、ＣＮＯ２、又はＮであり、Ｚ１、Ｚ２、及びＺ３は、それぞれ独立してＣＨ、ＣＲ若しくはＮであり且つ前記ＲがＯＣＨ３、Ｃｌ、Ｂｒ、ＮＯ２、ＮＨＣＯＣＨ３であるか、又は、前記ＣＲが互いに隣り合う場合に五員環又は六員環を形成し、前記五員環が、炭素原子と２つの窒素原子で環が形成された複素環であり、前記六員環が、炭素原子で環が形成されたベンゼン環である。）
Figure JPOXMLDOC01-appb-C000013
 （ただし、一般式（Ｃ）において、Ｌは、ＯＨ又はＯＣＨ３であり、Ｑ１、Ｑ２、及びＱ３は、それぞれ独立して、ＣＨ、又は、ＣＲ’であり且つ前記ＣＲ’が互いに隣り合う場合に六員環を形成しており、前記六員環が、炭素原子で環が形成されたベンゼン環であり、Ｔ１乃至Ｔ５は、それぞれ独立してＨ、ＯＨ、又はＯＣＨ３である。）
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
Figure JPOXMLDOC01-appb-C000011
 (However, in the general formula (A), D 1 to D 4 are independently H, CH 3 or NO 2 , and E 1 to E 5 are independently H, OH, NH 2 , respectively. Or NO 2 , where J is an OH, H, or benzoic acid ester group, and * indicates a bond which may be an enantiomer of either S or R.)
Figure JPOXMLDOC01-appb-C000012
 (However, in the general formula (B), X 1 , X 2 , and X 3 are independently H, NH 2 , NO 2 , or NH-G, respectively, and the G is CH 3 , a pyridinyl group. , Phenyl group, methylphenyl group, methoxyphenyl group, ethoxyphenyl group, monohalogenated phenyl group, or benzoic acid ester group, where A is CH, CNO 2 , or N, and Z 1 , Z 2 , And Z 3 are CH, CR or N independently, respectively, and the R is OCH 3 , Cl, Br, NO 2 , NHCOCH 3 , or if the CRs are adjacent to each other, a five-membered ring or A six-membered ring is formed, the five-membered ring is a heterocycle in which a ring is formed by a carbon atom and two nitrogen atoms, and the six-membered ring is a benzene ring in which a ring is formed by a carbon atom. )
Figure JPOXMLDOC01-appb-C000013
 (However, in the general formula (C), L is OH or OCH 3 , and Q 1 , Q 2 and Q 3 are independently CH or CR'and the CR'is each other. When they are adjacent to each other, a six-membered ring is formed, and the six-membered ring is a benzene ring in which a ring is formed by a carbon atom, and T 1 to T 5 are independently H, OH, or OCH 3 respectively. Is.)
Figure JPOXMLDOC01-appb-C000014
Figure JPOXMLDOC01-appb-C000015
　一般式（Ａ）で表される化合物において、Ｄ１及びＤ４がいずれもＨであり、Ｄ２及びＤ３のうち一方がＣＨ３又はＮＯ２であり他方がＨであることが好ましい。
　一般式（Ａ）で表される化合物において、Ｅ１乃至Ｅ５のすべてがＨであるか、又は、Ｅ１乃至Ｅ５のうちＥ２又はＥ３のいずれか一方がＯＨ、ＮＨ２若しくはＮＯ２であり且つその他がＨであることが好ましい。
　一般式（Ａ）で表される化合物において、Ｊが安息香酸エステル基（式（Ａ－７）参照）、Ｈ、又は、ＯＨであることが好ましい。
　一般式（Ａ）で表される化合物は、＊における結合について鏡像異性体のうちＳ体であることが好ましい。 In the compound represented by the general formula (A), it is preferable that D 1 and D 4 are both H, one of D 2 and D 3 is CH 3 or NO 2 , and the other is H.
In the compound represented by the general formula (A), all of E 1 to E 5 are H, or any one of E 2 or E 3 of E 1 to E 5 is OH, NH 2 or NO. It is preferably 2 and the others are H.
In the compound represented by the general formula (A), it is preferable that J is a benzoic acid ester group (see formula (A-7)), H, or OH.
The compound represented by the general formula (A) is preferably the S-form of the enantiomers for the bond in *.
　一般式（Ａ）で表される化合物は、下記の式（Ａ－１）～（Ａ－１８）のいずれかで表される化合物であることがより好ましい。これにより、アトピー性皮膚疾患をより改善できるという利点がある。 The compound represented by the general formula (A) is more preferably a compound represented by any of the following formulas (A-1) to (A-18). This has the advantage that atopic skin diseases can be further improved.
　式（Ａ－１）で表される化合物は、(-)-Blebbistatinと称される化合物である。化合物名は、(3aS)-3a-hydroxy-6-methyl-1-phenyl-2,3-dihydropyrrolo[2,3-b]quinolin-4-oneである。CAS番号は、856925-71-8である。
Figure JPOXMLDOC01-appb-C000016
 The compound represented by the formula (A-1) is a compound called (-)-Blebbistatin. The compound name is (3aS) -3a-hydroxy-6-methyl-1-phenyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one. The CAS number is 856925-71-8.
Figure JPOXMLDOC01-appb-C000016
　式（Ａ－２）で表される化合物は、(S)-3'-hydroxy Blebbistatinと称される化合物である。化合物名は、(3aS)-3a-hydroxy-1-(3-hydroxyphenyl)-6-methyl-2,3-dihydropyrrolo[2,3-b]quinolin-4-oneである。CAS番号は、2097136-42-8である。
Figure JPOXMLDOC01-appb-C000017
 The compound represented by the formula (A-2) is a compound called (S) -3'-hydroxy Blebbistatin. The compound name is (3aS) -3a-hydroxy-1- (3-hydroxyphenyl) -6-methyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one. The CAS number is 2097136-42-8.
Figure JPOXMLDOC01-appb-C000017
　式（Ａ－３）で表される化合物は、(S)-3'-amino Blebbistatinと称される化合物である。化合物名は、(3aS)-1-(3-aminophenyl)-3a-hydroxy-6-methyl-2,3-dihydropyrrolo[2,3-b]quinolin-4-oneである。CAS番号は、2097141-18-7である。
Figure JPOXMLDOC01-appb-C000018
 The compound represented by the formula (A-3) is a compound called (S) -3'-amino Blebbistatin. The compound name is (3aS) -1- (3-aminophenyl) -3a-hydroxy-6-methyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one. The CAS number is 2097141-18-7.
Figure JPOXMLDOC01-appb-C000018
　式（Ａ－４）で表される化合物は、(S)-4'-nitro-Blebbistatinと称される化合物である。化合物名は、(3aS)-3a-hydroxy-6-methyl-1-(4-nitrophenyl)-2,3-dihydropyrrolo[2,3-b]quinolin-4-oneである。CAS番号は、1621326-32-6である。
Figure JPOXMLDOC01-appb-C000019
 The compound represented by the formula (A-4) is a compound called (S) -4'-nitro-Blebbistatin. The compound name is (3aS) -3a-hydroxy-6-methyl-1- (4-nitrophenyl) -2,3-dihydropyrrolo [2,3-b] quinolin-4-one. The CAS number is 1621326-32-6.
Figure JPOXMLDOC01-appb-C000019
　式（Ａ－５）で表される化合物は、para-amino-Blebbistatinと称される化合物である。化合物名は、(3aS)-1-(4-aminophenyl)-3a-hydroxy-6-methyl-2,3-dihydropyrrolo[2,3-b]quinolin-4-oneである。CAS番号は、2097734-03-5である。
Figure JPOXMLDOC01-appb-C000020
 The compound represented by the formula (A-5) is a compound called para-amino-Blebbistatin. The compound name is (3aS) -1- (4-aminophenyl) -3a-hydroxy-6-methyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one. The CAS number is 2097734-03-5.
Figure JPOXMLDOC01-appb-C000020
　式（Ａ－６）で表される化合物は、(S)-nitro-Blebbistatinと称される化合物である。化合物名は、(3aS)-3a-hydroxy-7-nitro-1-phenyl-2,3-dihydropyrrolo[2,3-b]quinolin-4-oneである。CAS番号は、856925-75-2である。
Figure JPOXMLDOC01-appb-C000021
 The compound represented by the formula (A-6) is a compound called (S) -nitro-Blebbistatin. The compound name is (3aS) -3a-hydroxy-7-nitro-1-phenyl-2,3-dihydropyrrolo [2,3-b] quinolin-4-one. The CAS number is 856925-75-2.
Figure JPOXMLDOC01-appb-C000021
　式（Ａ－７）で表される化合物は、(S)-(-)-Blebbistatin O-Benzoateと称される化合物である。化合物名は、[(3aS)-6-methyl-4-oxo-1-phenyl-2,3-dihydropyrrolo[2,3-b]quinolin-3a-yl] benzoateである。CAS番号は、1217832-61-5である。
Figure JPOXMLDOC01-appb-C000022
 The compound represented by the formula (A-7) is a compound called (S)-(-)-Blebbistatin O-Benzoate. The compound name is [(3aS) -6-methyl-4-oxo-1-phenyl-2,3-dihydropyrrolo [2,3-b] quinolin-3a-yl] benzoate. The CAS number is 1217832-61-5.
Figure JPOXMLDOC01-appb-C000022
　式（Ａ－８）で表される化合物は、Deoxy Blebbistatinと称される化合物である。化合物名は、6-methyl-1-phenyl-3,3a-dihydro-2H-pyrrolo[2,3-b]quinolin-4-oneである。CAS番号は、856925-72-9である。
Figure JPOXMLDOC01-appb-C000023
 The compound represented by the formula (A-8) is a compound called Deoxy Blebbistatin. The compound name is 6-methyl-1-phenyl-3,3a-dihydro-2H-pyrrolo [2,3-b] quinolin-4-one. The CAS number is 856925-72-9.
Figure JPOXMLDOC01-appb-C000023
　一般式（Ｂ）で表される化合物において、Ｘ１がＨ又はＮＨ－Ｇであることが好ましい。Ｘ１がＮＨ－Ｇである場合のＮＨ－Ｇは、ＮＨ－ＣＨ３であることがより好ましい。
　一般式（Ｂ）で表される化合物において、Ｘ２及びＸ３がそれぞれ独立してＨ、ＮＯ２、若しくはＮＨ２であることが好ましい。
　一般式（Ｂ）で表される化合物において、ＡがＣＨであることが好ましい。
　一般式（Ｂ）で表される化合物において、Ｚ１乃至Ｚ３のうち２つが五員環又は六員環を形成しているか、又は、Ｚ１乃至Ｚ３がそれぞれ独立してＣＨ又はＣＲであることが好ましい。
　一般式（Ｂ）で表される化合物において、Ｘ１乃至Ｘ３のうち少なくとも１つがＮＨ－Ｇであり、且つ、Ｚ１乃至Ｚ３のうち２つが五員環又は六員環を形成しているか、又は、Ｚ１乃至Ｚ３のうち２つがＣＨであり且つ１つがＣＲであることが好ましい。 In the compound represented by the general formula (B), it is preferable that X 1 is H or NH-G. When X 1 is NH-G, NH-G is more preferably NH-CH 3 .
In the compound represented by the general formula (B), it is preferable that X 2 and X 3 are independently H, NO 2 or NH 2 , respectively.
In the compound represented by the general formula (B), it is preferable that A is CH.
In the compound represented by the general formula (B), two of Z 1 to Z 3 form a five-membered ring or a six-membered ring, or Z 1 to Z 3 are independently CH or CR. It is preferable to have.
In the compound represented by the general formula (B), at least one of X1 to X3 is NH-G, and two of Z1 to Z3 form a five-membered ring or a six-membered ring. Or, it is preferable that two of Z 1 to Z 3 are CH and one is CR.
　一般式（Ｂ）で表される化合物は、下記の式（Ｂ－１）～式（Ｂ－１８）のいずれかで表される化合物であることがより好ましい。これにより、アトピー性皮膚疾患をより改善できるという利点がある。 The compound represented by the general formula (B) is more preferably a compound represented by any of the following formulas (B-1) to (B-18). This has the advantage that atopic skin diseases can be further improved.
　一般式（Ｂ－１）で表される化合物は、KRIBB11と称される化合物である。化合物名は、2-N-(1H-indazol-5-yl)-6-N-methyl-3-nitropyridine-2,6-diamineである。CAS番号は、342639-96-7である。
Figure JPOXMLDOC01-appb-C000024
 The compound represented by the general formula (B-1) is a compound called KRIBB11. The compound name is 2-N- (1H-indazol-5-yl) -6-N-methyl-3-nitropyridine-2,6-diamine. The CAS number is 342639-96-7.
Figure JPOXMLDOC01-appb-C000024
　式（Ｂ－２）で表される化合物は、Z86253669と称される化合物である。化合物名は、N-(3-nitropyridin-2-yl)-1H-indazol-6-amineである。
Figure JPOXMLDOC01-appb-C000025
 The compound represented by the formula (B-2) is a compound called Z86253669. The compound name is N- (3-nitropyridin-2-yl) -1H-indazol-6-amine.
Figure JPOXMLDOC01-appb-C000025
　式（Ｂ－３）で表される化合物は、Z86332512と称される化合物である。化合物名は、N-(3-nitropyridin-2-yl)-1H-indazol-5-amineである。
Figure JPOXMLDOC01-appb-C000026
 The compound represented by the formula (B-3) is a compound called Z86332512. The compound name is N- (3-nitropyridin-2-yl) -1H-indazol-5-amine.
Figure JPOXMLDOC01-appb-C000026
　式（Ｂ－４）で表される化合物は、STK067130と称される化合物である。化合物名は、Diethyl 4,4'-[(3,5-dinitropyridine-2,6-diyl)diimino]dibenzoateである。
Figure JPOXMLDOC01-appb-C000027
 The compound represented by the formula (B-4) is a compound called STK067130. The compound name is Diethyl 4,4'-[(3,5-dinitropyridine-2,6-diyl) diimino] dibenzoate.
Figure JPOXMLDOC01-appb-C000027
　式（Ｂ－５）で表される化合物は、STK372678と称される化合物である。化合物名は、(3,5-Dinitro(2-pyridyl))naphthylamineである。
Figure JPOXMLDOC01-appb-C000028
 The compound represented by the formula (B-5) is a compound called STK372678. The compound name is (3,5-Dinitro (2-pyridyl)) naphthylamine.
Figure JPOXMLDOC01-appb-C000028
　式（Ｂ－６）で表される化合物の化合物名は、N-{4-[(3,5-Dinitropyridin-2-yl)amino]phenyl}acetamideである。
Figure JPOXMLDOC01-appb-C000029
 The compound name of the compound represented by the formula (B-6) is N- {4-[(3,5-Dinitropyridin-2-yl) amino] phenyl} acetamide.
Figure JPOXMLDOC01-appb-C000029
　式（Ｂ－７）で表される化合物の化合物名は、2-N,6-N-Bis(4-methoxyphenyl)-3-nitropyridine-2,6-diamineである。
Figure JPOXMLDOC01-appb-C000030
 The compound name of the compound represented by the formula (B-7) is 2-N, 6-N-Bis (4-methoxyphenyl) -3-nitropyridine-2,6-diamine.
Figure JPOXMLDOC01-appb-C000030
　式（Ｂ－８）で表される化合物の化合物名は、3-Nitro-N2,N6-diphenylpyridine-2,6-diamineである。
Figure JPOXMLDOC01-appb-C000031
 The compound name of the compound represented by the formula (B-8) is 3-Nitro-N2, N6-diphenylpyridine-2,6-diamine.
Figure JPOXMLDOC01-appb-C000031
　式（Ｂ－９）で表される化合物の化合物名は、2-N,6-N-Bis(4-chlorophenyl)-3,5-dinitropyridine-2,6-diamineである。
Figure JPOXMLDOC01-appb-C000032
 The compound name of the compound represented by the formula (B-9) is 2-N, 6-N-Bis (4-chlorophenyl) -3,5-dinitropyridine-2,6-diamine.
Figure JPOXMLDOC01-appb-C000032
　式（Ｂ－１０）で表される化合物の化合物名は、3,5-Dinitro-N-(2,4,6-trinitrophenyl)pyridin-2-amineである。
Figure JPOXMLDOC01-appb-C000033
 The compound name of the compound represented by the formula (B-10) is 3,5-Dinitro-N- (2,4,6-trinitrophenyl) pyridin-2-amine.
Figure JPOXMLDOC01-appb-C000033
　式（Ｂ－１１）で表される化合物の化合物名は、3,5-Dinitro-N-phenylpyridin-2-amineである。
Figure JPOXMLDOC01-appb-C000034
 The compound name of the compound represented by the formula (B-11) is 3,5-Dinitro-N-phenylpyridin-2-amine.
Figure JPOXMLDOC01-appb-C000034
　式（Ｂ－１２）で表される化合物の化合物名は、3,5-Dinitro-2-N,6-N-dipyridin-2-ylpyridine-2,6-diamineである。
Figure JPOXMLDOC01-appb-C000035
 The compound name of the compound represented by the formula (B-12) is 3,5-Dinitro-2-N, 6-N-dipyridin-2-ylpyridine-2,6-diamine.
Figure JPOXMLDOC01-appb-C000035
　式（Ｂ－１３）で表される化合物の化合物名は、2-N,6-N-Bis(4-bromophenyl)-3,5-dinitropyridine-2,6-diamineである。
Figure JPOXMLDOC01-appb-C000036
 The compound name of the compound represented by the formula (B-13) is 2-N, 6-N-Bis (4-bromophenyl) -3,5-dinitropyridine-2,6-diamine.
Figure JPOXMLDOC01-appb-C000036
　式（Ｂ－１４）で表される化合物の化合物名は、2-N,6-N-Bis(4-bromophenyl)-3,5-dinitropyridine-2,4,6-triamineである。
Figure JPOXMLDOC01-appb-C000037
 The compound name of the compound represented by the formula (B-14) is 2-N, 6-N-Bis (4-bromophenyl) -3,5-dinitropyridine-2,4,6-triamine.
Figure JPOXMLDOC01-appb-C000037
　式（Ｂ－１５）で表される化合物の化合物名は、N2,N6-Bis(4-chlorophenyl)-3,5-dinitro-2,4,6-pyridinetriamineである。
Figure JPOXMLDOC01-appb-C000038
 The compound name of the compound represented by the formula (B-15) is N2, N6-Bis (4-chlorophenyl) -3,5-dinitro-2,4,6-pyridinetriamine.
Figure JPOXMLDOC01-appb-C000038
　式（Ｂ－１６）で表される化合物の化合物名は、(2-Chlorophenyl){6-[(2-chlorophenyl)amino]-3,5-dinitro(2-pyridyl)}amineである。
Figure JPOXMLDOC01-appb-C000039
 The compound name of the compound represented by the formula (B-16) is (2-Chlorophenyl) {6-[(2-chlorophenyl) amino] -3,5-dinitro (2-pyridyl)} amine.
Figure JPOXMLDOC01-appb-C000039
　式（Ｂ－１７）で表される化合物の化合物名は、3,5-Dinitro-2-N,6-N-diphenylpyridine-2,4,6-triamineである。
Figure JPOXMLDOC01-appb-C000040
 The compound name of the compound represented by the formula (B-17) is 3,5-Dinitro-2-N, 6-N-diphenylpyridine-2,4,6-triamine.
Figure JPOXMLDOC01-appb-C000040
　式（Ｂ－１８）で表される化合物の化合物名は、2-N,6-N-Bis(4-methylphenyl)-3,5-dinitropyridine-2,4,6-triamineである。
Figure JPOXMLDOC01-appb-C000041
 The compound name of the compound represented by the formula (B-18) is 2-N,6-N-Bis (4-methylphenyl) -3,5-dinitropyridine-2,4,6-triamine.
Figure JPOXMLDOC01-appb-C000041
　一般式（Ｃ）で表される化合物において、Ｑ１乃至Ｑ３のうち１つがＣＨであり、且つ、隣り合う２つがＣＲ’であってベンゼン環を形成しているか、又は、Ｑ１乃至Ｑ３のすべてがＣＨであることが好ましい。
　一般式（Ｃ）で表される化合物において、ＬがＯＨであることが好ましい。
　一般式（Ｃ）で表される化合物において、Ｔ１乃至Ｔ５のうち２つ若しくは３つがＯＨ又はＯＣＨ３であり且つその他がＨであることが好ましい。 In the compound represented by the general formula (C), one of Q1 to Q3 is CH and two adjacent compounds are CR', forming a benzene ring, or Q1 to Q. It is preferable that all of 3 are CH.
In the compound represented by the general formula (C), L is preferably OH.
In the compound represented by the general formula (C), it is preferable that two or three of T 1 to T 5 are OH or OCH 3 and the other is H.
　一般式（Ｃ）で表される化合物は、下記の式（Ｃ－１）～式（Ｃ－５）のいずれかで表される化合物であることがより好ましい。これにより、アトピー性皮膚疾患をより改善できるという利点がある。 The compound represented by the general formula (C) is more preferably a compound represented by any of the following formulas (C-1) to (C-5). This has the advantage that atopic skin diseases can be further improved.
　式（Ｃ－１）で表される化合物は、Dyngo-4aと称される化合物である。化合物名は、3-hydroxy-N-[(Z)-(2,4,5-trihydroxyphenyl)methylideneamino]naphthalene-2-carboxamideである。CAS番号は、1256493-34-1である。
Figure JPOXMLDOC01-appb-C000042
 The compound represented by the formula (C-1) is a compound called Dyngo-4a. The compound name is 3-hydroxy-N-[(Z)-(2,4,5-trihydroxyphenyl) methylideneamino] naphthalene-2-carboxamide. The CAS number is 1256493-34-1.
Figure JPOXMLDOC01-appb-C000042
　式（Ｃ－２）で表される化合物は、Dynasoreと称される化合物である。化合物名は、N-[(3,4-dihydroxyphenyl)methylideneamino]-3-hydroxynaphthalene-2-carboxamideである。CAS番号は、304448-55-3である。
Figure JPOXMLDOC01-appb-C000043
 The compound represented by the formula (C-2) is a compound called Dynasore. The compound name is N-[(3,4-dihydroxyphenyl) methylideneamino] -3-hydroxynaphthalene-2-carboxamide. The CAS number is 304448-55-3.
Figure JPOXMLDOC01-appb-C000043
　式（Ｃ－３）で表される化合物の化合物名は、3-Methoxy-N'-(3,4-dimethoxybenzylidene)-2-naphthohydrazideである。
Figure JPOXMLDOC01-appb-C000044
 The compound name of the compound represented by the formula (C-3) is 3-Methoxy-N'-(3,4-dimethoxybenzylidene) -2-naphthohydrazide.
Figure JPOXMLDOC01-appb-C000044
　式（Ｃ－４）で表される化合物の化合物名は、Pyrocatechol-1-carbaldehyde salicyloylhydrazoneである。CAS番号は、92071-89-1である。
Figure JPOXMLDOC01-appb-C000045
 The compound name of the compound represented by the formula (C-4) is Pyrocatechol-1-carbaldehyde salicyloylhydrazone. The CAS number is 92071-89-1.
Figure JPOXMLDOC01-appb-C000045
　式（Ｃ－５）で表される化合物の化合物名は、N-[(Z)-(2,3-Dimethoxyphenyl)methylideneamino]-1-hydroxynaphthalene-2-carboxamideである。
Figure JPOXMLDOC01-appb-C000046
 The compound name of the compound represented by the formula (C-5) is N-[(Z)-(2,3-Dimethoxyphenyl) methylideneamino] -1-hydroxynaphthalene-2-carboxamide.
Figure JPOXMLDOC01-appb-C000046
　式（Ｄ）で表される化合物は、GW 4064と称される化合物である。化合物名は、3-[(E)-2-[2-chloro-4-[[3-(2,6-dichlorophenyl)-5-propan-2-yl-1,2-oxazol-4-yl]methoxy]phenyl]ethenyl]benzoic acidである。CAS番号は、278779-30-9である。 The compound represented by the formula (D) is a compound called GW4064. The compound name is 3-[(E) -2- [2-chloro-4-[[3- (2,6-dichlorophenyl) -5-propan-2-yl-1,2-oxazol-4-yl]]. methoxy] phenyl] ethenyl] benzoic acid. The CAS number is 278779-30-9.
　式（Ｅ）で表される化合物は、Venetoclax (ABT-199, GDC-0199)と称される化合物である。化合物名は、4-[4-[[2-(4-chlorophenyl)-4,4-dimethylcyclohexen-1-yl]methyl]piperazin-1-yl]-N-[3-nitro-4-(oxan-4-ylmethylamino)phenyl]sulfonyl-2-(1H-pyrrolo[2,3-b]pyridin-5-yloxy)benzamideである。CAS番号は、1257044-40-8である。 The compound represented by the formula (E) is a compound called Venetoclax (ABT-199, GDC-0199). The compound name is 4- [4- [[2- (4-chlorophenyl) -4,4-dimethylcyclohexen-1-yl] methyl] piperazin-1-yl] -N- [3-nitro-4- (oxan-). 4-ylmethylamino) phenyl] sulfonyl-2- (1H-pyrrolo [2,3-b] pyridin-5-yloxy) benzamide. The CAS number is 1257044-40-8.
　上記の化合物としては、市販されている製品を用いることができる。上記の化合物としては、例えばTargetmol社、Cayman Chemical社、Toronto Research Chemicals社などの製品を用いることができる。 As the above compound, a commercially available product can be used. As the above compound, for example, products such as Targetmol, Cayman Chemical, and Toronto Research Chemicals can be used.
　本実施形態の組成物において、上述した化合物の総量の濃度は、例えば０．００１質量％以上５質量％以下であってもよく、０．０１質量％以上２．０質量％以下であることがより好ましい。
　上記の含有濃度であることによって、アトピー性皮膚疾患をより改善できるという利点がある。 In the composition of the present embodiment, the concentration of the total amount of the above-mentioned compounds may be, for example, 0.001% by mass or more and 5% by mass or less, and 0.01% by mass or more and 2.0% by mass or less. More preferred.
The above-mentioned content concentration has an advantage that atopic skin disease can be further improved.
　上記の組成物は、通常、水を含み、上記の成分の他に、増粘剤、界面活性剤、防腐剤などをさらに含んでもよい。 The above composition usually contains water, and may further contain a thickener, a surfactant, a preservative, etc. in addition to the above components.
　本実施形態の組成物の性状は、特に限定されないが、例えば液状である。本実施形態の組成物は、固形状であってもよい。 The properties of the composition of this embodiment are not particularly limited, but are, for example, liquid. The composition of the present embodiment may be in a solid state.
　本実施形態の組成物は、一般的な方法によって製造できる。
　例えば、配合する各成分を混合し、撹拌することによって上記組成物を製造できる。撹拌するための装置としては、一般的なものを使用できる。必要に応じて、加温しつつ撹拌してもよい。 The composition of this embodiment can be produced by a general method.
For example, the above composition can be produced by mixing and stirring each component to be blended. As a device for stirring, a general device can be used. If necessary, the mixture may be stirred while being heated.
　上記の組成物は、皮膚外用剤（経皮投与剤）又は化粧料であることが好ましい。斯かる皮膚外用剤又は化粧料は、通常、皮膚に塗布されて使用される。上記の皮膚外用剤又は化粧料は、例えば、顔の皮膚、首の皮膚、四肢の皮膚、頭皮、毛髪、また、鼻孔・唇・耳・生殖器・肛門などにおける粘膜に塗布されて使用されてもよい。また、上記の皮膚外用剤又は化粧料は、入浴剤の用途で使用されてもよく、皮膚貼付剤の用途で使用されてもよい。 The above composition is preferably a skin external preparation (transdermal administration agent) or a cosmetic. Such external skin preparations or cosmetics are usually applied to the skin for use. The above-mentioned external skin preparations or cosmetics may be applied to, for example, facial skin, neck skin, limb skin, scalp, hair, and mucous membranes in the nose, lips, ears, genital organs, anus, etc. good. In addition, the above-mentioned external skin preparation or cosmetic may be used as a bath salt or as a skin patch.
　本実施形態の組成物は、世界各国の薬事に関する法律で規定される化粧料、医薬部外品、医薬品等の分類には必ずしも拘束されない。 The composition of this embodiment is not necessarily bound by the classification of cosmetics, quasi-drugs, pharmaceuticals, etc. specified by laws related to pharmaceutical affairs around the world.
　本明細書によって開示される事項は、以下のものを含む。
（１）
　上記の一般式（Ａ）で表される化合物、上記の一般式（Ｂ）で表される化合物、上記の一般式（Ｃ）で表される化合物、上記の式（Ｄ）で表される化合物、及び、上記の式（Ｅ）で表される化合物からなる群より選択された少なくとも１種を含む、アトピー性皮膚疾患改善剤。
（２）
　上記の一般式（Ａ）で表される化合物において、Ｄ１及びＤ４がいずれもＨであり、Ｄ２及びＤ３のうち一方がＣＨ３又はＮＯ２であり他方がＨである、上記（１）に記載のアトピー性皮膚疾患改善剤。
（３）
　上記の一般式（Ａ）で表される化合物において、Ｅ１乃至Ｅ５のすべてがＨであるか、若しくはＥ１乃至Ｅ５のうちＥ２又はＥ３のいずれか一方がＯＨ、ＮＨ２若しくはＮＯ２であり且つその他がＨである、上記（１）又は（２）に記載のアトピー性皮膚疾患改善剤。
（４）
　上記の一般式（Ａ）で表される化合物において、Ｊが安息香酸エステル基、Ｈ、若しくはＯＨである、上記（１）乃至（３）のいずれかに記載のアトピー性皮膚疾患改善剤。
（５）
　上記の一般式（Ａ）で表される化合物が、上記の一般式（Ａ－１）で表される化合物、上記の一般式（Ａ－４）で表される化合物、上記の一般式（Ａ－５）で表される化合物、上記の一般式（Ａ－７）で表される化合物、及び、上記の一般式（Ａ－８）で表される化合物からなる群より選択される少なくとも１種である、上記（１）乃至（４）のいずれかに記載のアトピー性皮膚疾患改善剤。
（６）
　上記の一般式（Ｂ）で表される化合物において、
　Ｘ１がＨ又はＮＨ－Ｇであり、Ｘ１がＮＨ－Ｇである場合のＮＨ－Ｇは、ＮＨ－ＣＨ３であり、
　Ｘ２及びＸ３がそれぞれ独立してＨ、ＮＯ２、若しくはＮＨ２であり、ＡがＣＨであり、
　Ｚ１乃至Ｚ３のうち２つが五員環又は六員環を形成しているか、又は、Ｚ１乃至Ｚ３がそれぞれ独立してＣＨ又はＣＲであり、
　Ｘ１乃至Ｘ３のうち少なくとも１つがＮＨ－Ｇであり、且つ、Ｚ１乃至Ｚ３のうち２つが五員環又は六員環を形成しているか、又は、Ｚ１乃至Ｚ３のうち２つがＣＨであり且つ１つがＣＲである、上記（１）乃至（５）のいずれかに記載のアトピー性皮膚疾患改善剤。
（７）
　上記の一般式（Ｃ）で表される化合物において、
　Ｑ１乃至Ｑ３のうち１つがＣＨであり、且つ、隣り合う２つがＣＲ’であってベンゼン環を形成しているか、又は、Ｑ１乃至Ｑ３のすべてがＣＨであり、ＬがＯＨであり、
　Ｔ１乃至Ｔ５のうち２つ若しくは３つがＯＨ又はＯＣＨ３であり且つその他がＨである、上記（１）乃至（６）のいずれかに記載のアトピー性皮膚疾患改善剤。
（８）
　上記（１）乃至（７）のいずれかに記載されたアトピー性皮膚疾患改善剤の含有成分と同じ成分を含む、皮膚外用剤。
（９）
　上記（１）乃至（７）のいずれかに記載されたアトピー性皮膚疾患改善剤の含有成分と同じ成分を含む、化粧料。 The matters disclosed herein include:
(1)
The compound represented by the above general formula (A), the compound represented by the above general formula (B), the compound represented by the above general formula (C), and the compound represented by the above formula (D). , And an atopic skin disease improving agent containing at least one selected from the group consisting of the compound represented by the above formula (E).
(2)
In the compound represented by the above general formula (A), D 1 and D 4 are both H, one of D 2 and D 3 is CH 3 or NO 2 , and the other is H. The atopic skin disease improving agent according to 1).
(3)
In the compound represented by the above general formula (A), all of E 1 to E 5 are H, or any one of E 2 or E 3 of E 1 to E 5 is OH, NH 2 or The atopic skin disease improving agent according to (1) or (2) above, which is NO 2 and the others are H.
(4)
The atopic skin disease improving agent according to any one of (1) to (3) above, wherein J is a benzoic acid ester group, H, or OH in the compound represented by the above general formula (A).
(5)
The compound represented by the above general formula (A) is a compound represented by the above general formula (A-1), a compound represented by the above general formula (A-4), and the above general formula (A). At least one selected from the group consisting of the compound represented by -5), the compound represented by the above general formula (A-7), and the compound represented by the above general formula (A-8). The atopic skin disease improving agent according to any one of (1) to (4) above.
(6)
In the compound represented by the above general formula (B),
When X 1 is H or NH-G and X 1 is NH-G, NH-G is NH-CH 3 .
X 2 and X 3 are independently H, NO 2 or NH 2 , and A is CH.
Two of Z 1 to Z 3 form a five-membered ring or a six-membered ring, or Z 1 to Z 3 are independently CH or CR, respectively.
At least one of X1 to X3 is NH-G, and two of Z1 to Z3 form a five-membered or six -membered ring, or two of Z1 to Z3. The atopic skin disease improving agent according to any one of (1) to (5) above, wherein one is CH and one is CR.
(7)
In the compound represented by the above general formula (C),
One of Q1 to Q3 is CH and two adjacent ones are CR'and form a benzene ring, or all of Q1 to Q3 are CH and L is OH. can be,
The atopic skin disease improving agent according to any one of (1) to (6) above, wherein two or three of T 1 to T 5 are OH or OCH 3 and the other is H.
(8)
An external skin preparation containing the same components as those contained in the atopic skin disease improving agent according to any one of (1) to (7) above.
(9)
A cosmetic containing the same components as those contained in the atopic skin disease improving agent according to any one of (1) to (7) above.
　本発明の組成物は、上記例示の通りであるが、本発明は、上記例示の実施形態に限定されるものではない。また、本発明では、一般の皮膚外用組成物や経口投与用組成物などにおいて採用される種々の形態を、本発明の効果を損ねない範囲で採用することができる。 The composition of the present invention is as illustrated above, but the present invention is not limited to the embodiment described above. Further, in the present invention, various forms adopted in a general composition for external use on the skin, a composition for oral administration, and the like can be adopted as long as the effects of the present invention are not impaired.
　次に実施例を挙げて本発明をさらに詳しく説明するが、本発明はこれらに限定されるものではない。 Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited thereto.
（試験例１～９）
　以下に示す各成分を溶媒（ジメチルスルホキシド、プロピレングリコール、水など）に溶解させることによって、各試験例の組成物（例えば、皮膚外用剤として使用可能）を製造した。
　（ａ）上記一般式（Ａ）で表される化合物
　　（a-1）上記式（Ａ－１）で表される化合物（(-)-Blebbistatin）
　　（a-4）上記式（Ａ－４）で表される化合物（(S)-4'-nitro-Blebbistatin）
　　（a-5）上記式（Ａ－５）で表される化合物（para-amino-Blebbistatin）
　　（a-7）上記式（Ａ－７）で表される化合物（(S)-(-)-Blebbistatin O-Benzoate）
　　（a-8）上記式（Ａ－８）で表される化合物（Deoxy Blebbistatin）
　（ｂ）上記式（Ｂ－１）で表される化合物（KRIBB11）
　（ｃ）上記式（Ｃ－１）で表される化合物（Dyngo-4a）
　（ｄ）上記式（Ｄ）で表される化合物（GW-4064）
　（ｅ）上記式（Ｅ）で表される化合物（ABT-199）
　なお、濃度は、都度、１μＭ、５μＭ、１０μＭなどに設定した。 (Test Examples 1 to 9)
By dissolving each of the following components in a solvent (dimethyl sulfoxide, propylene glycol, water, etc.), the composition of each Test Example (for example, it can be used as a skin external preparation) was produced.
(A) Compound represented by the above general formula (A) (a-1) Compound represented by the above formula (A-1) ((-)-Blebbistatin)
(A-4) Compound represented by the above formula (A-4) ((S) -4'-nitro-Blebbistatin)
(A-5) Compound represented by the above formula (A-5) (para-amino-Blebbistatin)
(A-7) The compound represented by the above formula (A-7) ((S)-(-)-Blebbistatin O-Benzoate)
(A-8) Compound represented by the above formula (A-8) (Deoxy Blebbistatin)
(B) The compound represented by the above formula (B-1) (KRIBB11)
(C) Compound represented by the above formula (C-1) (Dyngo-4a)
(D) Compound represented by the above formula (D) (GW-4064)
(E) Compound represented by the above formula (E) (ABT-199)
The concentration was set to 1 μM, 5 μM, 10 μM, or the like each time.
＜表皮角化細胞のバリア機能関連因子の発現に関する評価（ｉｎ　ｖｉｔｒｏ試験）＞
　以下の表皮角化細胞のバリア機能関連因子の発現に与える影響を調べた。
（セラミド合成酵素）
　・β－グルコセレブロシダーゼ（ＧＢＡ）の遺伝子、
　・セラミド合成の律速酵素であるセリンパルミトイルトランスフェラーゼ（ＳＰＴ）のサブユニットであるＳＰＴＬＣ２遺伝子、
　・スフィンゴミエリンをセラミドに加水分解する酵素である酸性スフィンゴミエリナーゼ（ＳＭＰＤ１）の遺伝子
（ヒアルロン酸合成酵素）
　・ＨＡＳ３
（バリア機能関連タンパク質）
　・角質層の細胞を構成する主要なタンパク質フィラグリン（Ｆｉｌａｇｇｒｉｎ）の遺伝子 <Evaluation of expression of barrier function-related factors in epidermal keratinocytes (in vitro test)>
The effects of the following epidermal keratinocytes on the expression of barrier function-related factors were investigated.
(Ceramide synthase)
・ Β-Glucocerebrosidase (GBA) gene,
-The SPTLC2 gene, which is a subunit of serine lumitoyltransferase (SPT), which is the rate-determining enzyme for ceramide synthesis.
-Gene of acidic sphingomyelinase (SMPD1), which is an enzyme that hydrolyzes sphingomyelin to ceramide (hyaluronan synthase)
・ HAS3
(Barrier function related protein)
-Genes of the major protein filaggrin that constitutes the cells of the stratum corneum
＜各化合物の性能評価（ｉｎ　ｖｉｔｒｏ試験）＞
　ｉｎ　ｖｉｔｒｏ試験の詳細は、以下の通りである。
　正常ヒト表皮角化細胞（ＮＨＥＫ　クラボウ社製）を６×１０４個／１２ウェルプレートに播種し、３７℃、５％ＣＯ２の環境下において２４時間培養した。その後、培養培地を取り除き、各化合物を含む培地に交換し、続いて３７℃、５％ＣＯ２の環境下において２４時間培養した。さらに、製品名「PureLink RNA Mini kit」（ＩＮＶＩＴＲＯＧＥＮ社製）の取扱説明書に従って、細胞からｔｏｔａｌ ＲＮＡを精製し、製品名「ReverTra AceTM qPCR RT Master Mix」（ＴＯＹＯＢＯ社製）を用いてｃＤＮＡに逆転写した。このｃＤＮＡをリアルタイムＰＣＲ法によって増幅することにより、バリア機能関連因子のｍＲＮＡ発現量を定量評価した。内部標準補正としてＧＡＰＤＨを使用した。
　なお、各化合物は、ジメチルスルホキシド（ＤＭＳＯ）に溶解してストックを作製し、その後、１～１０μＭ濃度となるように培地に溶解させた。その際、細胞毒性が出ない濃度（１％以下）となるようにＤＭＳＯを希釈した。 <Performance evaluation of each compound (in vitro test)>
The details of the in vitro test are as follows.
Normal human epidermal keratinized cells (manufactured by NHEK Kurabo Industries) were seeded in 6 × 10 4 cells / 12-well plates and cultured for 24 hours in an environment of 37 ° C. and 5% CO 2 . Then, the culture medium was removed and replaced with a medium containing each compound, followed by culturing in an environment of 37 ° C. and 5% CO 2 for 24 hours. Furthermore, according to the instruction manual of the product name "PureLink RNA Mini kit" (manufactured by INVITROGEN), total RNA is purified from the cells and reversed to cDNA using the product name "ReverTra AceTM qPCR RT Master Mix" (manufactured by TOYOBO). I copied it. By amplifying this cDNA by the real-time PCR method, the mRNA expression level of the barrier function-related factor was quantitatively evaluated. GAPDH was used as the internal standard correction.
Each compound was dissolved in dimethyl sulfoxide (DMSO) to prepare a stock, and then dissolved in a medium to a concentration of 1 to 10 μM. At that time, DMSO was diluted to a concentration (1% or less) that did not cause cytotoxicity.
　上記のｉｎ　ｖｉｔｒｏ試験の結果をグラフ化したものを図１、並びに、図２～図６に示す。
　図１から把握されるように、上記の（a-1）、（ｂ）、及び、（ｅ）の各化合物によって、アトピー性皮膚疾患の改善に強く関連する、皮膚バリア機能関連因子の発現が亢進された。
　また、図２～図６から把握されるように、上記の（a-4）、（a-5）、（a-7）、（a-8）、（ｃ）、及び、（ｄ）の各化合物によって、アトピー性皮膚疾患の改善に強く関連する、皮膚バリア機能関連因子の発現が亢進された。 The graphs of the above in vitro test results are shown in FIG. 1 and FIGS. 2 to 6.
As can be seen from FIG. 1, each of the above compounds (a-1), (b), and (e) expresses skin barrier function-related factors that are strongly associated with the improvement of atopic dermatitis. It was enhanced.
Further, as can be seen from FIGS. 2 to 6, of the above (a-4), (a-5), (a-7), (a-8), (c), and (d). Each compound enhanced the expression of skin barrier function-related factors that are strongly associated with the improvement of atopic dermatitis.
＜アトピー性皮膚疾患に対する有効性の評価（ｉｎ　ｖｉｖｏ試験）＞
１－１．病態モデルマウスの作製
　マウスとしてＮＣ／ＮｇａＴｎｄＣｒｌｊ　１０週齢メスを使用した。各群につき１０個体を使用した。ダニ抗原軟膏を各マウスに、週２回、合計６回塗布することによって、アトピー性皮膚疾患モデルマウスを作製した。即ち、０日目から２０日目までダニ抗原軟膏を病態モデルマウスに塗布することによって、皮膚炎モデルを作製した。
１－２．皮膚炎スコア化
　２０日目から３０日目にかけては病態モデルマウスにダニ抗原軟膏を塗らず、各化合物を含むペーストを毎日塗布して皮膚炎の推移を観察した。
　ペーストは、プロピレングリコール（ＰＧ）に各化合物を溶解させ、その後、ワセリンと混合して、各化合物が０．５質量％濃度となるようにそれぞれ調製した。１日あたり１００ｍｇのペーストを塗布した。なお、ポジティブコントロールとしてタクロリムス軟膏（医薬品）を用い、ネガティブコントロールとして、化合物を配合せずＰＧに置き換えたペースト（プロピレングリコールとワセリンとの混合物）を用いた。
　塗布した部位は、背部及び耳介部であった。特定の日における皮膚炎の状態をスコア化した。
１－３．スコア基準
　下記の各項目を４段階で評価し、スコア化した（０：無症状、１：軽度、２：中等度、３：重度）。
　・背部の発赤、出血
　・背部の痂皮形成、乾燥
　・耳介部の浮腫
　・耳介部の擦傷、組織欠損
　スコアが小さくなるほど、皮膚疾患（皮膚炎）が改善していることを示す。
１－４．病変部組織の状態観察
　最終日（３０日目）に背部の皮膚組織を採取した。採取した試料を、１０質量％濃度の中性緩衝ホルマリン溶液で固定処理した。続いて、パラフィン包埋ブロックを作製することによって病変部の組織切片を作製した。ヘマトキシリン・エオジン染色（ＨＥ染色）、さらに抗Ｆｉｌａｇｇｒｉｎ抗体を用いた免疫染色を行い、光学顕微鏡を用いて病変部組織の状態を観察した。観察像を図７に示す。上記の（a-1）の化合物（(-)-Blebbistatin）の塗布によって、表皮の細胞が抗フィラグリン抗体によって強く染色されたことが観察された。
　フィラグリンは、皮膚のバリア機能に重要な役割を果たすタンパク質であることが知られている。また、アトピー性皮膚炎の皮膚では、フィラグリン量の低下が起こることが知られている。上記の結果では、上記の（a-1）の化合物によって、in vitro試験及びin vivo試験の両方において表皮細胞におけるフィラグリンの発現が上昇することを確認できた。これにより、皮膚炎が改善したと考えられる。上記の（a-1）の化合物によって、表皮のフィラグリン量が増え、これに伴ってバリア機能が改善し、皮膚炎の症状が抑えられたと考えられる。 <Evaluation of efficacy for atopic skin diseases (in vivo test)>
1-1. Preparation of pathological model mice NC / NgaTndCrlj 10-week-old females were used. 10 individuals were used for each group. Atopic skin disease model mice were prepared by applying mite antigen ointment to each mouse twice a week for a total of 6 times. That is, a dermatitis model was prepared by applying mite antigen ointment to pathological model mice from the 0th day to the 20th day.
1-2. Dermatitis scoring From the 20th to the 30th day, the mite antigen ointment was not applied to the pathological model mice, but a paste containing each compound was applied daily and the transition of dermatitis was observed.
The paste was prepared by dissolving each compound in propylene glycol (PG) and then mixing with petrolatum so that each compound had a concentration of 0.5% by mass. A 100 mg paste was applied per day. As a positive control, tacrolimus ointment (pharmaceutical product) was used, and as a negative control, a paste (a mixture of propylene glycol and petrolatum) in which a compound was replaced with PG was used.
The applied sites were the back and auricle. The condition of dermatitis on a particular day was scored.
1-3. Score Criteria Each of the following items was evaluated on a 4-point scale and scored (0: asymptomatic, 1: mild, 2: moderate, 3: severe).
・ Redness and bleeding of the back ・ Crust formation and dryness of the back ・ Edema of the auricle ・ Abrasion of the auricle, tissue defect The smaller the score, the better the skin disease (dermatitis).
1-4. Observation of the condition of the lesion tissue On the final day (30th day), the skin tissue on the back was collected. The collected sample was fixed with a neutral buffered formalin solution having a concentration of 10% by mass. Subsequently, a tissue section of the lesion was prepared by preparing a paraffin-embedded block. Hematoxylin and eosin staining (HE staining) and immunostaining with anti-Filaggrin antibody were performed, and the condition of the lesion tissue was observed using an optical microscope. The observation image is shown in FIG. It was observed that the cells of the epidermis were strongly stained with the anti-filaggrin antibody by the application of the compound ((-)-Blebbistatin) of the above (a-1).
Filaggrin is known to be a protein that plays an important role in the barrier function of the skin. It is also known that the amount of filaggrin decreases in the skin with atopic dermatitis. From the above results, it was confirmed that the above compound (a-1) increased the expression of filaggrin in epidermal cells in both in vitro and in vivo tests. This is considered to have improved dermatitis. It is considered that the above compound (a-1) increased the amount of filaggrin in the epidermis, which improved the barrier function and suppressed the symptoms of dermatitis.
　上記のｉｎ　ｖｉｖｏ試験の最終日（３０日目）に、病態モデルマウスの皮膚の様子を撮影した写真を図８に示す。 FIG. 8 shows a photograph of the skin of the pathological model mouse on the final day (30th day) of the above in vivo test.
　上記の１－４．における病変部の組織観察像（ヘマトキシリン・エオジン染色）の写真を図９に示す。また、病変部の表皮肥厚の測定結果を表したグラフを図１０に示す。
　上記の病変部の組織観察の結果から把握されるように、上記の（ａ）の化合物によって、アトピー性皮膚疾患が改善された。具体的には、皮膚の切片画像から、表皮の肥厚化の改善や痂皮の減少が観察された。また、背部の写真から、耳介部の浮腫や出血の改善、組織損傷のないことが観察できた。 1-4. Above. The photograph of the tissue observation image (staining with hematoxylin and eosin) of the lesion part in FIG. 9 is shown in FIG. Further, FIG. 10 shows a graph showing the measurement results of the epidermal thickening of the lesion.
As can be seen from the results of histological observation of the lesion, the compound (a) described above improved atopic skin disease. Specifically, improvement of epidermal thickening and reduction of scabs were observed from the skin section images. In addition, it was observed from the photograph of the back that there was no improvement in edema and bleeding in the auricle and no tissue damage.
　上記のｉｎ　ｖｉｖｏ試験の結果（１－３．スコア化の結果　合計スコア）をグラフ化したものを図１１に示す。グラフにおける横軸は、各化合物を含むペーストを塗布し始めてからの日数を表す。
　図１１から把握されるように、上記の（a-1）、（ｂ）～（ｅ）の各化合物によって、アトピー性皮膚疾患が改善された。 FIG. 11 shows a graph of the results of the above in vivo test (1-3. Total score as a result of scoring). The horizontal axis in the graph represents the number of days since the paste containing each compound was started to be applied.
As can be seen from FIG. 11, each of the above compounds (a-1) and (b) to (e) improved atopic skin disease.
　続いて、上記の（a-7）の化合物（(S)-(-)-Blebbistatin O-Benzoate）を使用して以下の実験を行った。上述したｉｎ　ｖｉｖｏ試験の試験方法と類似するが、一部異なるため、詳しい試験方法を以下に説明する。 Subsequently, the following experiment was performed using the above compound (a-7) ((S)-(-)-Blebbistatin O-Benzoate). The test method is similar to the above-mentioned in vivo test, but partly different, so a detailed test method will be described below.
＜アトピー性皮膚疾患に対する有効性の評価（ｉｎ　ｖｉｖｏ試験）＞
２－１．病態モデルマウスの作製
　マウスとしてＮＣ／Ｎｇａ　ｓｌｃ　８週齢メスを使用した。各群につき８個体を使用した。ダニ抗原を各マウスの耳介部に、週２回、合計５回投与することによって、アトピー性皮膚疾患モデルマウスを作製した。即ち、０日目から１４日目までダニ抗原を病態モデルマウスに投与することによって、皮膚炎モデルを作製した。モデル作製後、各群の耳介部厚及び耳介部皮膚症状スコアの平均値がなるべく均等になるように、層別割付法を用いて群分けした。
２－２．皮膚炎スコア化
　１５日目から３５日目にかけては、病態モデルマウスにダニ抗原を投与せず、各化合物を毎日塗布して皮膚炎の推移を観察した。
　（a-7）の化合物をアセトン：メタノールに溶解し、０．５質量％濃度となるように調製し、１日あたり２０μＬを塗布した。なお、ポジティブコントロールとしてタクロリムス（ ０．１質量％濃度）を用い、一方、ネガティブコントロールとして、化合物を配合しないアセトン：メタノール溶液を用いた。塗布した部位は、耳介部であった。特定の日における皮膚炎の状態をスコア化した。
２－３．スコア基準
　耳介部における下記の各項目を４段階で評価し、スコア化した（０：無症状、１：軽度、２：中等度、３：重度）。
　・発赤・紅潮
　・痂皮・表皮剥離
　・出血・血塊
　・硬化
　スコアが小さくなるほど、皮膚疾患（皮膚炎）が改善していることを示す。
２－４．病変部組織の状態観察
　最終日（３５日目）に耳介部の皮膚組織を採取した。採取した試料を、１０質量％濃度の中性緩衝ホルマリン溶液で固定処理した。続いて、パラフィン包埋ブロックを作製することによって病変部の組織切片を作製した。ヘマトキシリン・エオジン染色（ＨＥ染色）、さらに抗Ｆｉｌａｇｇｒｉｎ抗体を用いた免疫染色を行い、顕微鏡を用いて病変部組織の状態を観察した。
２－５．血中ＩｇＥ濃度の測定
　最終日（３５日目）に血液を採取した。採取した試料を３０分以上室温で静置してから遠心分離を行い、血清を採取した。血清はマウスＩｇＥ測定キット（ヤマサ醤油社製）を用いてＩｇＥ濃度を測定した。 <Evaluation of efficacy for atopic skin diseases (in vivo test)>
2-1. Preparation of pathological model mice NC / Nga slc 8-week-old females were used as mice. Eight individuals were used for each group. Atopy skin disease model mice were prepared by administering the mite antigen to the auricle of each mouse twice a week for a total of 5 times. That is, a dermatitis model was prepared by administering the mite antigen to the pathological model mice from the 0th day to the 14th day. After the model was created, the groups were grouped using the stratified allocation method so that the average values of the auricle thickness and the auricle skin symptom score of each group were as even as possible.
2-2. Dermatitis scoring From the 15th to the 35th day, the mite antigen was not administered to the pathological model mice, and each compound was applied daily to observe the transition of dermatitis.
The compound (a-7) was dissolved in acetone: methanol to prepare a concentration of 0.5% by mass, and 20 μL was applied per day. Tacrolimus (0.1% by mass) was used as a positive control, while an acetone: methanol solution containing no compound was used as a negative control. The site of application was the auricle. The condition of dermatitis on a particular day was scored.
2-3. Score Criteria Each of the following items in the auricle was evaluated on a 4-point scale and scored (0: asymptomatic, 1: mild, 2: moderate, 3: severe).
・ Redness, flushing, crust, epidermis peeling, bleeding, blood clots, hardening The smaller the score, the better the skin disease (dermatitis).
2-4. Observation of the state of the lesion tissue On the final day (35th day), the skin tissue of the auricle was collected. The collected sample was fixed with a neutral buffered formalin solution having a concentration of 10% by mass. Subsequently, a tissue section of the lesion was prepared by preparing a paraffin-embedded block. Hematoxylin and eosin staining (HE staining) and immunostaining with anti-Filaggrin antibody were performed, and the condition of the lesion tissue was observed using a microscope.
2-5. Blood was collected on the final day (35th day) of measurement of blood IgE concentration. The collected sample was allowed to stand at room temperature for 30 minutes or more, and then centrifuged to collect serum. For serum, the IgE concentration was measured using a mouse IgE measurement kit (manufactured by Yamasa Corporation).
　上記（a-7）の化合物（(S)-(-)-Blebbistatin O-Benzoate）について、上述したｉｎ　ｖｉｖｏ試験の結果（２－３．スコア化の結果　合計スコア）をグラフ化したものを図１２に示す。グラフにおける横軸は、各化合物を含む液体を塗布し始めてからの日数を表す。
　上記の２－４．における病変部の組織観察写真（抗Ｆｉｌａｇｇｒｉｎ抗体を用いた免疫染色）を図１３に示す。
　上記の２－４．における病変部の組織観察写真（ヘマトキシリン・エオジン染色）を図１４に示す。
　上記の２－５．における結果のグラフを図１５に示す。
　図１２～図１５からも把握されるように、上記の（a-7）の化合物によっても、上記の（a-1）の化合物と同様に、アトピー性皮膚疾患が改善された。 A graph showing the results of the above-mentioned in vivo test (2-3. Total score as a result of scoring) for the compound ((S)-(-)-Blebbistatin O-Benzoate) of the above (a-7). It is shown in 12. The horizontal axis in the graph represents the number of days since the start of applying the liquid containing each compound.
2-4. A histological observation photograph (immunostaining using an anti-Filaggrin antibody) of the lesion portion in FIG. 13 is shown in FIG.
2-4. A histological observation photograph (staining with hematoxylin and eosin) of the lesion in the above is shown in FIG.
2-5 above. The graph of the result in FIG. 15 is shown in FIG.
As can be seen from FIGS. 12 to 15, the above-mentioned compound (a-7) also improved the atopic skin disease like the above-mentioned compound (a-1).
　以上のように、本実施形態のアトピー性皮膚疾患改善剤（皮膚外用剤、化粧料）は、アトピー性皮膚疾患を十分に改善させることができた。 As described above, the atopic skin disease improving agent (external skin preparation, cosmetics) of the present embodiment was able to sufficiently improve the atopic skin disease.
　本発明のアトピー性皮膚疾患改善剤は、例えば、皮膚外用剤又は化粧料の用途で使用できる。本発明の皮膚外用剤、化粧料は、例えば、乾燥肌を予防軽減するため、炎症性の肌荒れを予防軽減するために、皮膚に適用されて使用される。本発明の皮膚外用剤は、例えば直接角質層に塗布され、化粧料等の用途で好適に使用される。  The atopic skin disease improving agent of the present invention can be used, for example, as an external skin preparation or a cosmetic. The external skin preparation and cosmetics of the present invention are applied to and used on the skin, for example, to prevent and reduce dry skin and to prevent and reduce inflammatory rough skin. The external skin preparation of the present invention is applied directly to the stratum corneum, for example, and is suitably used for cosmetics and the like. The

Claims (3)

  1. 　下記一般式（Ａ）で表される化合物、下記一般式（Ｂ）で表される化合物、下記一般式（Ｃ）で表される化合物、下記式（Ｄ）で表される化合物、及び、下記式（Ｅ）で表される化合物からなる群より選択された少なくとも１種を含む、アトピー性皮膚疾患改善剤。
    Figure JPOXMLDOC01-appb-C000001
     （ただし、一般式（Ａ）において、Ｄ１乃至Ｄ４は、それぞれ独立してＨ、ＣＨ３、又はＮＯ２であり、Ｅ１乃至Ｅ５は、それぞれ独立してＨ、ＯＨ、ＮＨ２、又はＮＯ２であり、Ｊは、ＯＨ、Ｈ、又は安息香酸エステル基であり、＊は、Ｓ又はＲのいずれの鏡像異性体となってもよい結合を示す。）
    Figure JPOXMLDOC01-appb-C000002
     （ただし、一般式（Ｂ）において、Ｘ１、Ｘ２、及びＸ３は、それぞれ独立してＨ、ＮＨ２、ＮＯ２、又は、ＮＨ－Ｇであり、前記Ｇは、ＣＨ３、ピリジニル基、フェニル基、メチルフェニル基、メトキシフェニル基、エトキシフェニル基、モノハロゲン化フェニル基、又は、安息香酸エステル基であり、Ａは、ＣＨ、ＣＮＯ２、又はＮであり、Ｚ１、Ｚ２、及びＺ３は、それぞれ独立してＣＨ、ＣＲ若しくはＮであり、前記ＲがＯＣＨ３、Ｃｌ、Ｂｒ、ＮＯ２、ＮＨＣＯＣＨ３であるか、又は、前記ＣＲが互いに隣り合う場合にＲ同士で五員環又は六員環を形成してもよく、前記五員環は、炭素原子と２つの窒素原子で環が形成された複素環であり、前記六員環は、炭素原子で環が形成されたベンゼン環である。）
    Figure JPOXMLDOC01-appb-C000003
     （ただし、一般式（Ｃ）において、Ｌは、ＯＨ又はＯＣＨ３であり、Ｑ１、Ｑ２、及びＱ３は、それぞれ独立して、ＣＨ又はＣＲ’であり、前記ＣＲ’が互いに隣り合う場合にＲ’同士で六員環を形成しており、前記六員環は、炭素原子で環が形成されたベンゼン環であり、Ｔ１乃至Ｔ５は、それぞれ独立してＨ、ＯＨ、又はＯＣＨ３である。）
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
         The compound represented by the following general formula (A), the compound represented by the following general formula (B), the compound represented by the following general formula (C), the compound represented by the following formula (D), and the following. An atopic skin disease improving agent containing at least one selected from the group consisting of the compounds represented by the formula (E).
    Figure JPOXMLDOC01-appb-C000001
     (However, in the general formula (A), D 1 to D 4 are independently H, CH 3 or NO 2 , and E 1 to E 5 are independently H, OH, NH 2 , respectively. Or NO 2 , where J is an OH, H, or benzoic acid ester group, and * indicates a bond which may be an enantiomer of either S or R.)
    Figure JPOXMLDOC01-appb-C000002
     (However, in the general formula (B), X 1 , X 2 , and X 3 are independently H, NH 2 , NO 2 , or NH-G, respectively, and the G is CH 3 , a pyridinyl group. , Phenyl group, methylphenyl group, methoxyphenyl group, ethoxyphenyl group, monohalogenated phenyl group, or benzoic acid ester group, where A is CH, CNO 2 , or N, and Z 1 , Z 2 , And Z 3 are CH, CR or N independently, respectively, and the R is OCH 3 , Cl, Br, NO 2 , NHCOCH 3 , or when the CRs are adjacent to each other, the Rs are five. A member ring or a six-membered ring may be formed, the five-membered ring is a heterocycle in which a ring is formed by a carbon atom and two nitrogen atoms, and the six-membered ring is a ring formed by a carbon atom. It is a benzene ring.)
    Figure JPOXMLDOC01-appb-C000003
     (However, in the general formula (C), L is OH or OCH 3 , Q 1 , Q 2 and Q 3 are independently CH or CR', and the CR'is adjacent to each other. In some cases, R's form a six-membered ring, and the six-membered ring is a benzene ring in which a ring is formed by a carbon atom, and T 1 to T 5 are independently H, OH, or T 5 respectively. OCH 3 )
    Figure JPOXMLDOC01-appb-C000004
    Figure JPOXMLDOC01-appb-C000005
  2. 　請求項１に記載されたアトピー性皮膚疾患改善剤を含む、皮膚外用剤。 An external skin preparation containing the atopic skin disease improving agent according to claim 1.
  3. 　請求項１に記載されたアトピー性皮膚疾患改善剤を含む、化粧料。
     
     
     
          A cosmetic comprising the atopic skin disease improving agent according to claim 1.
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* Cited by examiner, † Cited by third party
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JP2008500991A (en) * 2004-05-29 2008-01-17 ７ティーエム ファーマ エイ／エス CRTH2 receptor ligands for medical use
US20100075923A1 (en) * 2008-09-16 2010-03-25 Jung San Huang Method of enhancing tgf-beta signalling
CN102940631A (en) * 2012-11-02 2013-02-27 清华大学 Application of Blebbistatin in promoting stem cell survival and keeping stem cell dry
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JP2017532285A (en) * 2014-01-28 2017-11-02 バック インスティテュート フォー リサーチ オン エイジング Methods and compositions for killing senescent cells and treating aging related diseases and disorders
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2008500991A (en) * 2004-05-29 2008-01-17 ７ティーエム ファーマ エイ／エス CRTH2 receptor ligands for medical use
US20100075923A1 (en) * 2008-09-16 2010-03-25 Jung San Huang Method of enhancing tgf-beta signalling
US20170226095A1 (en) * 2009-06-12 2017-08-10 Abivax Compounds for preventing, inhibiting, or treating cancer, aids and/or premature aging
CN102940631A (en) * 2012-11-02 2013-02-27 清华大学 Application of Blebbistatin in promoting stem cell survival and keeping stem cell dry
JP2017532285A (en) * 2014-01-28 2017-11-02 バック インスティテュート フォー リサーチ オン エイジング Methods and compositions for killing senescent cells and treating aging related diseases and disorders
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