WO2004089368A1

WO2004089368A1 - Therapeutic or preventive agent for dermatitis

Info

Publication number: WO2004089368A1
Application number: PCT/JP2004/005021
Authority: WO
Inventors: Yozo Hori; Kenji Kuwabara; Mitsuo Takeuchi
Original assignee: Shionogi & Co. Ltd.
Priority date: 2003-04-08
Filing date: 2004-04-07
Publication date: 2004-10-21
Also published as: TW200503698A

Abstract

A therapeutic or preventive agent for allergic dermatitis including psoriasis and contact dermatitis and for atopic dermatitis, which contains as an active ingredient a compound represented by the general formula (I): wherein R1 is optionally substituted aralkyl, etc.; Z is -S-, etc.; X1 is -(CH2)s-N(R18)-CO- (wherein R18 is hydrogen, etc. and s is an integer of 0 to 3), etc.; A, B, and E each independently is oxygen or sulfur; D is hydrogen, etc.; Y1 is -(CH2)mCO- (wherein m is an integer of 0 to 3), etc.; and Y2 is optionally substituted aryl, etc.

Description

Description Agent for treating or preventing dermatitis

The present invention relates to a therapeutic or prophylactic agent for dermatitis comprising a c-PLA ₂ (cytoplasmic PLA ₂ > inhibitor) having a pyrrolidine skeleton as an active ingredient. In particular, allergic dermatitis including psoriasis and contact dermatitis And a therapeutic or prophylactic agent for atopic dermatitis.

Phospholipase A ₂ (PLA ₂ ) is a generic name for enzymes that hydrolyze the ester bond at the 2-position of phospholipids, and is involved in the generation and metabolism of phospholipids in biological membranes, as well as lipid mediators such as prostanoids. It functions as an initiation enzyme for arachidonic acid cascade leading to production. Currently, the presence of a variety of PLA ₂ in a mammal Ri Contact been clarified, the station patency, molecular weight, based on the substrate specificity, etc., secretory _{_{PLA 2 (s PLA 2),}} C a 2 + - independent type _{_{P LA 2 (i P LA 2}} ), it has been classified into families one such cytosolic _{_{P LA 2 (c PLA 2)}} . .

c The PLA2 inhibitor BMS-2299724 reduced prostaglandin E2 and leukotriene B4 levels in a model of chronic auricular skin inflammation induced by phorbol ester (TPA) in mice. Non-patent document 1 reports that not only lowering but also suppressing edema and neutrophil infiltration. Further, also BMS one 1 8 1 1 6 2 a PLA ₂ inhibitor reduce the level of prostaglandin E2 and leuco preparative Lin B4 in the model are reported in Non-Patent Document 2.

On the other hand, p-lysine derivative compounds having c PLA ₂ inhibitory activity and having a thiazolidinedione in the side chain at position 2 are described in Patent Documents 1, 2, and 3, and Non-Patent Documents 3, 4, and 5. ing. Although c PLA ₂ inhibitor in Patent Document 3 is Rukoto to have a antiarrhythmic action have been described, c PLA ₂ inhibitor dermatitis with pyro lysine skeletons in any of the literature, in particular psoriasis, contact It is not described that it is effective for treating or preventing allergic dermatitis including atopic dermatitis, and atopic dermatitis.

[Patent Document 1]

International Publication No. 97/0 5 13 5 Pamphlet

[Patent Document 2]

International Publication No. 98/33 797 7 Pamphlet

[Patent Document 3]

International Publication No. 0 1/3 0 3 8 7 Pamphlet

[Non-Patent Document 1]

Paul L. Stanley et al., The Journal of Pharmacology and Experimental Therapeutics 2001, Vol. 298, No. 1, p. 376, The Journal of Pharmacology and Experimental Therapeutics. -385

[Non-Patent Document 2]

Paul L. Stanley et al., The Journal of Pharmacology and Experimental Therapeutics 1994, Vol. 71, No. 2, p. .852-859

[Non-Patent Document 3] KaoruSeno et al., Journal of Medicinal Chemistry 2000, Vol. 43, No. 6, p. 1042- 1044

[Non-Patent Document 4]

Michael H. Gelb et al., Biochimica et Biophysica Acta, 2001, Vol. 1513, p. 160-166.

[Non-Patent Document 5]

Kaoru Seno et al., Bioorganic & Medicinal Chemistry Letters, 2001, Vol. 11, p. 587-590.

Therapeutic or prophylactic agent for dermatitis containing c PLA ₂ inhibitors with pyro lysine backbone as an active ingredient, in particular psoriasis, allergic dermatitis, including contact dermatitis, and the therapeutic or prophylactic agent for Atopi dermatitis provide. The present invention provides: 1) a general formula (I)

(In the formula, R ¹ is a hydrogen atom, lower alkyl, optionally substituted aryl, aryl fused with a non-aromatic hydrocarbon ring or a non-aromatic heterocyclic ring, and may be substituted. Aralkyl, optionally substituted arylcarbonyl, or optionally substituted heteroaryl; Z is —S—, one SO—, —0—, one OCH ₂ —, one CO NH—, — C 0 NH CH ₂ —, — N (R ¹⁶ ) one (where R ¹⁶ is a hydrogen atom, Lower alkyl, C ₃ -C ₈ cycloalkyl lower alkyl, or aralkyl), or single bond;

X ¹ is — (CH ₂ ) s -N (R ¹⁸ ) 1 CO— (where R ¹⁸ is a hydrogen atom or lower alkyl, s is an integer of 0 to 3), and 1 CH ₂ N (R ¹⁹ ) CO CH = CH- (where R ¹⁹ is a hydrogen atom or lower alkyl);

A, B, and E each independently represent an oxygen or sulfur atom;

D is a hydrogen atom or a hydroxy lower alkyl;

Y ¹ is one (CH ₂ ) m CO—,-(CH 2) mC ONH—, one (CH ₂ ) m CSNH-,-(CH 2) m S 0 ₂ -,-(CH 2) m COO-, _{- (CH 2) n NHC 0-} , - (CH 2) nNH S 0 2 -, or a single bond, m is an integer of 0 to 3, n represents 1-3 integer;

Y ² is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted lower alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted Aryl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroarylalkyl or optionally substituted amino;

A wavy line (~) indicates that D has a cis or trans relationship to E), its optically active form, its prodrug, or its pharmaceutically acceptable salt, Or a therapeutic or prophylactic agent for a disease selected from psoriasis, allergic dermatitis, and atopic dermatitis, which comprises a solvate thereof as an active ingredient.

The details are related to the following 2) to 14).

2) General formula (II):

(Wherein, R ¹ Z, R ¹⁸ , Y ² , B, and wavy line (~) have the same meaning as in 1)), an optically active form thereof, a prodrug thereof, or a pharmaceutical thereof. 1) The therapeutic or prophylactic agent according to 1), which comprises a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

3) General formula (I I I):

(Wherein RZ, R ¹⁹ , Υ ² , Β, and wavy line have the same meaning as in 1)), an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a salt thereof. The leprosy or prophylactic agent according to 1), comprising a solvate of the above as an active ingredient. 4) Psoriasis, allergy containing a compound selected from the following compound group, its optically active substance, its prodrug, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient: For the treatment or prevention of diseases selected from atopic dermatitis and atopic dermatitis.

5) Use of the compound according to any one of 1) to 4) for producing a medicament for treating a disease selected from psoriasis, allergic dermatitis, and atopic dermatitis.

6) administering to a mammal including a human a therapeutically effective amount of the compound according to any one of 1) to 4), the psoriasis, allergic dermatitis, and atopic dermatitis of the mammal; A method for treating a disease selected from the group consisting of:

7) General formula (la):

(In the formula, R ¹ is a hydrogen atom, lower alkyl, optionally substituted aryl, aryl fused with a non-aromatic hydrocarbon ring or a non-aromatic heterocyclic ring, and may be substituted. Aralkyl, optionally substituted arylcarbonyl, or optionally substituted heteroaryl; Z is one S—, one SO—, one 0—, one OCH ₂ —, — C ONH—, one C ONH CH ₂ —, — N (R ¹⁶ ) — (where R ¹⁶ is a hydrogen atom, lower alkyl, C ₃ -C 8 cycloalkyl lower alkyl, or aralkyl), or a single bond;

X ¹ is — (CH ₂ ) q-C 0-(where QL is an integer of 0 to 3),-(CH ₂ ) r-C 0-N (R ¹⁷ )-(where R ¹⁷ Is a hydrogen atom or lower alkyl, r is 0-3 _{Integer), - CH 2 NH S 0} 2 -, - (CH 2) s- N (R 1 8) - CO- ( wherein, R ^{1 8} is hydrogen atom or lower alkyl, s is an integer of 0 to 3) , One CH ₂ NH COCH ₂₀ —, — CH ₂ N (R ¹⁹ ) COCH = CH— (where R ¹⁹ is a hydrogen atom or lower alkyl), — CH ₂ NH CS—, — CH ₂ 〇一, — OCH ₂ —, — CH ₂ 0 CH ₂ —, — CH ₂ —N (R ² °) — CH ₂ — (where R ' ^{2 Q} is a hydrogen atom, lower alkyl, or acyl), Alkylene, alkenyl.lene, or single bond; ·

X ² is an optionally substituted arylene, an optionally substituted heteroarylene, a heterocyclic diyl, one c≡c one, or a single bond;

X ³ is alkylene, alkenylene, or a single bond;

A, B, and E each independently represent an oxygen or sulfur atom;

D is a hydrogen atom or a hydroxy lower alkyl;

Y Rimmer (CH ₂₎ m CO -, one (CH 2) mC ONH -, - (CH 2) m CSNH-, one _{(CH 2) m S 0 2} -, - (CH 2) m C 00- one _{(CH 2) n NHC 0-,} - (CH 2) nNH S 0 2 -, or a single bond, m is an integer of from 0 to 3, n represents an integer from 1 to 3;

Y ² is a hydrogen atom, an optionally substituted lower alkyl, an optionally substituted lower alkenyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted Allyl, optionally substituted aralkyl, optionally substituted heteroaryl, optionally substituted heteroalkyl, or optionally substituted amino;

Dashed line (--) indicates the presence or absence of a bond;

A wavy line (~) indicates that D has a cis or trans relationship to E), an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof. Or a solvate thereof as an active ingredient, for treating or preventing a disease selected from psoriasis, allergic dermatitis, and atopic dermatitis. 8) General formula (IIa):

(Wherein ¹ , Z, X ¹ , X ² , X ³ , Y ² , B, and wavy line (~) are as defined in 7)), an optically active form thereof, a prodrug thereof, or Contains a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

9) General formula (I l i a):

(Wherein, R ¹ Z, R ¹⁸ , X ³ , Y ² , Β, and wavy line (~) are as defined in 7)), an optically active form thereof, a prodrug thereof, or a compound thereof. 7. The therapeutic or prophylactic agent according to 7), which comprises a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.

10) General formula (IVa):

(Wherein, R ¹ Z, R ¹⁹ , X ³ , Y ² , Β, and wavy line have the same meanings as in 7)), an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable compound thereof. 7) The therapeutic or prophylactic agent according to 7), which comprises a salt or a solvate thereof as an active ingredient.

1) Υ ² is the formula

Or (CH ₂ ) p

(Wherein R ² and R ³ are both hydrogen atoms, or an aryl which may be substituted on one side, a heteroaryl which may be substituted, or a cycloalkyl which may be substituted, The other is a hydrogen atom or a lower alkyl; R ⁴ , R ′ ⁵ , G ring, J ring and L ring are each independently optionally substituted aryl, optionally substituted heteroaryl, substituted A dashed line (--) represents the presence or absence of a bond; p represents an integer of 0 to 2); a compound represented by the following formula: The therapeutic or prophylactic agent according to any one of 7) to 10), which comprises a body, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient.

(If p is 0, it means a single bond)

1 2) Z is —S— or 1 N (R ¹⁶ ) 1 (where R ¹⁶ is the same as 7), X ³ is a single bond, R ¹ is an optionally substituted aralkyl, Y ² is the formula:

(Wherein R ⁵ is optionally substituted aryl), an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. The therapeutic or prophylactic agent according to any one of 1) to 1).

13) The therapeutic or prophylactic agent according to 12), wherein R ⁵ is 2,4-difluorophenyl.

14) The therapeutic or prophylactic agent according to any one of 1) to 13), wherein the disease is psoriasis.

15) The therapeutic or prophylactic agent according to any one of 1) to 13), wherein the disease is allergic dermatitis.

1 6) The therapeutic or prophylactic agent according to 1 5), wherein the allergic dermatitis is contact dermatitis. 17) The therapeutic or prophylactic agent according to any one of 1) to 13), wherein the disease is atopic dermatitis. ,

18) Use of the compound according to any one of 7) to 13) for producing a medicament for treating a disease selected from psoriasis, allergic dermatitis, and atopic dermatitis.

1 9) administering psoriatic, allergic monodermatitis, and psoriasis in mammals, comprising administering a therapeutically effective amount of the compound according to any one of 7) to 13) to mammals including humans. A method for treating a disease selected from atopic dermatitis.

20) Crystals of the compound according to any one of 1) to 13), an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof. An agent for treating or preventing a disease selected from psoriasis, allergic dermatitis, and atopic dermatitis, which is produced from the obtained crystals. The compound contained in the therapeutic or prophylactic agent of the present invention is not limited to a specific isomer, but includes all possible isomers and racemates. Specifically, when the compound has one or more chiral centers, it may be present as an optically active substance. Similarly, if the compound contains alkenyl or alkenylene, the possibility of the cis and trans isomers exists. Mixtures of the R- and S-isomers, mixtures of the R- and S-isomers, including mixtures and racemic mixtures of the isomers, are included within the scope of the invention. Asymmetric carbon atoms can also be present in substituents, such as alkyl groups. All such isomers, as well as their mixtures, are included in the present invention. If a particular stereoisomer is desired, the starting material with a pre-resolved asymmetric center can be prepared by methods known to those skilled in the art of subjecting to a stereospecific reaction, or And then dividing the mixture by a known method. Prodrugs, compounds of the present invention having chemically or metabolically degradable groups A derivative that is a pharmaceutically active compound of the present invention upon solvolysis or in vivo under physiological conditions. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. When the compound of the present invention has a hydroxyl group, an ester derivative produced by reacting a basic acidic compound with a suitable alcohol, or a basic amine and a suitable amine are reacted. An example is a prodrug such as an amide derivative produced by the reaction. Particularly preferred esters as prodrugs include methyl ester, ethyl ester, n-propyl ester, isopropyl ester, n-butyl ester, isobutyl ester, "tert-butyl ester, morpholinoethyl ester, N, N-ethyl ester Glycol amide esters, etc. When the compound of the present invention has a hydroxyl group, for example, an acyloxy derivative produced by reacting a compound having a hydroxyl group with a suitable acyl halide or a suitable acid anhydride. Examples of preferred prodrugs include, but are not limited to, one OCOC ₂ H ₅ , -0 C 0 (t-Bu), — OCOC ₁₅ H ₃₁ , one OCO (m— COON a - P h), ten _{_{CO CH 2 CH 2 CO ON a}} , - OCOCH (NH 2) CH 3, - OCOCH 2 N (CH a) 2 and the like When the compound of the present invention has an amino group, a prodrug such as an amide derivative produced by reacting the compound having an amino group with an appropriate acid halide or an appropriate mixed acid anhydride is used. Particularly preferred amides as the prodrug include 1 NHCO (CH 2) ₂₀ CH ₃ , 1 NHCO CH. (NH ₂ ) CH _3, etc. The compound of the present invention In the case of a compound having an acidic or basic functional group, the compound has higher water solubility than the original compound and can form various physiologically suitable salts. The acceptable salts include salts of alkali metals (lithium, sodium, calcium, etc.) and salts of alkaline earth metals (calcium, magnesium). And salts such as, but not limited to, aluminum. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by contacting the acid with an ion exchange resin. Relatively non-toxic addition salts of inorganic and organic bases of the compounds of the present invention, for example, amine cations, ammoniums and quaternary ammoniums derived from nitrogen salts which have sufficient basicity to form salts with the compounds are Included in the definition of pharmaceutically acceptable salts (eg, S. M. Berge et al., "Pharmaceutical Salts," J. Phar. Sci., 66, 1-19 ( 1 9 7 7)). Further, the basic group of the compound of the present invention is reacted with an appropriate organic or inorganic acid to react with acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bisulfate, borate, promide, potassium sulfate, potassium carbonate. , Chloride, crablanate, citrate, edetate, edisileto, estrate, esylate, fluoride, fumarate, gluceptate, darconate, gururemate, glycorial sanilate, hexyl resorcinate , Hydroxynaphthoate, iodide, isotionate, lactate, lactobionate, laurate, maleate, maleate, mandelate, mesylate, methylpromide, methylnitrate, methylsulfate, methyl sulfate , Nabsylate, nitrate, oleate, oxalate, palmitate, pantosenate, phosphate, polygalactone, salicylate, stearate, subacetate, succinate, succinate, evening salt, tartrate, tosylate, tochilate Forms salts such as fluoracetate, trifluormethanesulfonate, and norerate. Preferably, salts with hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, acetic acid, citric acid, maleic acid, fumaric acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like, that is, chloride, bromide, phosphate , Sulfate, acetate, citrate, maleate, fumarate, benzenesulfonate, tosylate.

The term "pharmaceutically acceptable" means compatible with the other ingredients in the formulation and not harmful to the recipient. In the present specification, “solvate” includes, for example, solvates with organic solvents, hydrates, and the like. When forming a hydrate, it may be coordinated with any number of water molecules. As used herein, "psoriasis" is a disease characterized by localized 'isolated' fusogenic, reddish, patchy papules with silvery scales. Lesions are particularly prevalent on the elbows, knees, scalp, and trunk, and microscopically show characteristic parakeratosis and prolonged epidermal processes. '

In the present specification, “allergic dermatitis” means a skin reaction (inflammation) among biological reactions caused by allergen stimulation. In particular, the skin reaction that occurs when a person who is hypersensitive to an allergen directly contacts the allergen is called contact dermatitis and is included in allergic dermatitis.

In the present specification, “atopic dermatitis” is a disease in which pruritus eczema is the main lesion, which repeatedly worsens and remits. Most patients have 1) a family history or history (either bronchial asthma, allergic rhinitis, conjunctivitis, or atopic dermatitis, or multiple diseases), or 2) a predisposition to produce IgE antibodies , With the indicated atopic predisposition. One of the criteria for diagnosis is pruritus. The second most characteristic eruption is eczema lesions.Acute lesions include erythema, invasive erythema, papules, serous papules, scales, and crusts. Includes plaque lesions, prurigo, scales, scabs. The characteristics of the distribution are left-right contralateral, and the most common sites are the forehead, eye circumference, mouth, lips, auricles, neck, limb joints, and trunk. Can be Age-related features that can be used as a reference are that in infancy, the head and face begin with the body and often fall to the trunk and limbs, and in infancy, cervical and limb flexion lesions are included, and puberty In adulthood, rashes tend to be strong on the upper body (face, neck, chest, back). The chronic and repetitive course (often a mixture of old and new eruptions) is chronic for infants of 2 months or more, and for others of 6 months or more. A diagnosis of atopic dermatitis will be made for those who meet these criteria, regardless of the severity of the symptoms. In the present specification, “lower alkyl” refers to a linear or branched C i -C 1 _α alkyl. Includes With preference given to C i to C ₆ alkyl linear or branched. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, n- Nonyl, n-decyl, (2,6-dimethylheptane) -14-yl and the like. ·

R i, R ² , R ³ , R ^{i 7} , R ¹⁸ , R ¹⁹ , and R ² . As the "lower alkyl" in the above, methyl, ethyl, n-propyl, isopropyl and (2,6-dimethylheptane) 141 are preferred. Particularly, methyl is preferred.

As the “lower alkyl” for R ¹⁶ , methyl, ethyl, isopropyl, isobutyl and isopentyl are preferred. Preferably, isopropyl, isobutyl and isopentyl are mentioned.

The "C ₃ ~ C 8 cycloalkyl lower alkyl" for R ^{1 6,} substituted with C ₃ ~ C 8 consequent opening alkyl (e.g., cyclopropyl, cycloheptyl cyclopentyl, cyclobutyl, cyclohexane cyclohexyl, cyclohexylene, Shikurookuchiru) The above "lower alkyl" is meant. For example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl can be mentioned.

In the present specification, “cycloalkyl” includes C ₃ -C ₇ cycloalkyl. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl can be mentioned. Preference is given to cyclopentyl, cyclohexyl and cycloheptyl. Particularly, cyclopentyl and cyclohexyl are preferred. As used herein, the term "lower alkenyl" refers to a straight-chain or branched-chain monovalent hydrocarbon having 2 to 8 carbon atoms and having one or more double bonds. Include groups. For example, vinyl, aryl, propenyl, crotonyl, isopentenyl, various butenyl isomers and the like can be mentioned. Preferably, C2-C6 alkenyl is mentioned. More preferably, a C2-C4 alkenyl is mentioned.

In this specification, “cycloalkenyl” includes C ₃ -C ₇ cycloalkenyl having one unsaturated bond in the ring. For example, cyclopropenyl, cyclopentene And cyclohexenyl. Preferably, cyclohexenyl is used. The term “non-aromatic heterocycle” as used herein means a non-aromatic 5- to 7-membered ring containing one or more oxygen atoms, sulfur atoms or nitrogen atoms in the ring, It includes a ring condensed by at least one. For example, pyrrolidine, piperidine, piperazine, oxyhydroquinoline, tetrahydrofuran, tetrahydropyran and the like can be mentioned. In the present specification, the term “aryl” includes a monocyclic or condensed cyclic aromatic hydrocarbon group, or a group in which two or more monocyclic aromatic hydrocarbons are continuously present. For example, phenyl, 1-naphthyl, 2-naphthyl, biphenyl, indenyl, 2-P-terphenyl, 2-m-terphenyl, 2-o-terphenyl, anthryl, phenyl Ril and the like. Preferably, phenyl, 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-p-terphenyl, 2-m- Terfeniryl and 2-o-terpanilyl.

In the present specification, the term "aryl fused with a non-aromatic hydrocarbon ring" includes phenyl, 1-naphthyl, and 2-naphthyl fused with the "cycloalkyl". Examples include indanil, 1, '2,3,4-tetrahedral naphthyl, acenaphthyl and the like. Preference is given to indanil, 1,2,3,4-tetrahydronaphthyl.

In the present specification, the term "aryl which is condensed with a non-aromatic heterocycle" includes phenyl, 1-naphthyl, and 2-naphthyl condensed with the "non-aromatic heterocycle". Examples include indolyl, isoindryl, 2,3,6,7-tetrahydro 1H, 5H-pyrido [3,2,1-ij] quinolyl, isochromanil, chromanil and the like. . Preference is given to 2,3,6,7-tetrahydro 1H, 5H-pyrido [3,2,11-ij] quinolyl.

In the present specification, “aralkyl” refers to the above “lower alkyl” and the above “aryl” Include those substituted. For example, benzyl, phenyl, 3-phenyl n-propyl, benzhydryl, naphthylmethyl, 2-naphthylethyl and the like can be mentioned. Preferably, benzyl, benzhydryl, phenethyl and naphthylmethyl are mentioned. Particularly, benzyl and benzhydryl are preferable. As used herein, the term “alkylene” refers to a divalent group derived from C i C g alkyl. Examples include methylene, ethylene, trimethylene, tetramethylene, and pentamethylene.

In the present specification, “alkenylene” means a divalent group derived from C ₂ to C ₄ alkenyl. For example, vinylene, propenylene, and butenylene are mentioned. In the present specification, “arylene” means a divalent group derived from the above “aryl”. For example, phenylene, naphthylene and the like can be mentioned. More specifically, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene and the like can be mentioned. In the present specification, “heteroarylene” means a divalent group derived from the following “heteroaryl”. For example, Tiofenzil, Franjyl and the like can be mentioned. More specifically, 2,5—chofenzir and 2,5—furanjyl are exemplified.

In the present specification, “heterodiyl” means a divalent group derived from the above “non-aromatic heterocycle”. For example, pyrrolidinezil, piperidinezil, and piperazinezil can be mentioned. More specifically, 1,4-piperidinediyl and the like can be mentioned.

In this specification, “hydroxy lower alkyl” means the above “lower alkyl” substituted by hydroxy. For example, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and the like can be mentioned.

As used herein, the term "heteroaryl" refers to a 5- to 6-membered monocyclic heteroaromatic containing one or more N, 0, or S atoms in the ring or a ring obtained by condensing the ring with a phenyl. Means ring. For example, pyrrole, pyrrolyl, pyridyl, chenyl, furyl, ben Zofril, benzobenzene, indolyl and the like. Preferable examples include pyridyl, phenyl, furyl, benzo [b] chenyl, benzo [b] furanyl and indolinole.

In the present specification, the term "heteroarylalkyl" refers to a compound obtained by substituting one or more of the above "heteroaryl" at any position of the above "lower alkyl", and these are substituted at all possible positions. Can. For example, thia. Zolylmethyl (eg, '4-thiazolylmethyl), thiazolylethyl (eg, 5-thiazolyl-2-ethyl), benzothiazolylmethyl (eg, (benzothiazol-2-yl) methyl), Indolylmethyl (for example, (indole-3-yl) methyl), imidazolylmethyl (for example, 4-imidazolylmethyl), benzothiazolylmethyl (for example, 2-benzothiazolylmethyl), and Dazolylmethyl (for example, 1-indazolylmethyl), benzotriazolylmethyl (for example, 1-benzotriazolylmethyl), benzoquinolylmethyl (for example, 2-benzoquinolylmethyl), benzoymidazolylmethyl (for example, 2-benzoisomidazolylmethyl), pyridylmethyl (for example) For example, 2 Pyridinium Jirumechiru, 3-pyridylmethyl, and 4 one-pyridylmethyl) or the like. In the present specification, the “optionally substituted aryl” in R ¹ includes phenyl C ₂ -C ₄ alkenyl (eg, phenyletenyl), lower alkyl (eg, methyl, ethyl, isopropyl, isobutyl, t-butyl), cycloalkyl (eg, cyclopentenyl, cyclohexenyl), halogen (eg, fluorine, chlorine, bromine, iodine), lower alkyloxy (eg, methyloxy, ethyloxy), trihalo lower alkyl (eg, , Trifluoromethyl, trichloromethyl), nitro, phenyl, naphthyl (for example, 11-naphthyl, 2-naphthyl), phenanthril (for example, 9-phenanthryl), benzo-1,3-dioxolanyl (for example, 41- Benzo 1,3-dioxolanyl, 5-benzo-1, 3-dioxolanil), heteroaryl (eg, 3-pyridyl, 3-phenyl, 2-benzoyl) Phenyl), aralkyl (eg, benzyl, phenethyl), aryloxy (eg, phenyloxy), hydroxy, amino, mono- or disubstituted amino (eg, dimethylamino, getylamino, phenylamino, N-methyl-N-phenylamino, N-methyl-N-benzylamino), piperazinyl (eg, 4-methylbiperazinyl) which may be substituted with the above-mentioned "lower alkyl" or the like, which may be substituted at one or more positions. Ariel ". '' For example, phenyl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 1-naphthyl, 2-naphthyl, 2-p-terphenyl, 2-m-terphenyl, 2-o-terphenyl, 2-isopropylphenyl , 2-t-butylphenyl, 2-isobutylphenyl, 2-cyclopentylphenyl, 2-bromophenyl, 3-bromophenyl, 2-odophenyl, 2- (4-benzo-1,1,3-dioxolanyl) phenyl 2, 2- (5-benzo-1,3-dioxolanyl) phenyl, 2-phenyloxyphenyl, 2-penzylphenyl, 2- (3-pyridyl) phenyl, 3-dimethylaminophenyl, 3-ethylethyl Minophenyl, 3-phenylaminophenyl, 3- (N-methyl-N-phenylamino) phenyl, 2- (1-naphthyl) phenyl, 2- (2-naphthy ) Phenyl, 3-(] L-naphthyl) phenyl, 3-(2 naphthyl) phenyl, 4-(ethenylphenyl) phenyl, 2-bromo-6-isopropylpropyl, 2-isopropyl-6-phenyl-1) Phenyl, 2-isopropyl-1-6- (1-naphthyl) phenyl, 2-bromo-1-6-nitrophenyl,

2-Methyloxy-6- (1-naphthyl) phenyl, 2,2-methyl-1-biphenyl, 2,1-isopropyl-12-biphenyl, 2'-methyloxy-2-biphenyl, 3, methyl-2-biphenyl, 3, -Trifluoromethyl-1-biphenyl, 3,1-nitro-2-biphenyl, 3, -methyloxy-2-biphenyl,

3'-Ethyloxy 2-biphenyl, 3-hydroxy-1-biphenyl, 3-methyloxy 2-biphenyl, 6-phenyl 2-naphthyl, 1-bromo

6-senyl-2-naphthyl, 1,6-diphenyl-12-naphthyl, 4-phenyl-1-naphthyl, 2- (4-methylpiperazinyl) phenyl and the like. In the present specification, “optionally substituted aryl” in R ² , R ³ , R ⁴ , R ⁵ , G ring, J 璟, and L ring means a halogen (eg, fluorine, chlorine, bromine) , Iodine), lower alkyl (eg, methyl, ethyl, n-propyl, isopropyl), lower alkyloxy (eg, methyloxy, ethyloxy), trihaloalkyl (eg, trifluoromethyl), alkyloxycarbonyl (eg, methyloxy) The above-mentioned “aryl” which may be substituted at one or two or more places by carbonyl, carbonyl, acetyl (eg, acetyl), amino, mono- or di-substituted amino (eg, acetylamino, methylamino), etc. Include. '

In the present specification, “optionally substituted aryl” in Y ² means halogen (eg, fluorine, chlorine, bromine, iodine), lower alkyl (eg, methyl, ethyl, n-propyl, isopropyl) ), Lower alkyloxy (eg, methyloxy, ethyloxy), trihaloalkyl (eg, trifluoromethyl), alkyloxycarbonyl (eg, methyloxycarbonyl), acyl (eg, acetyl), amino, mono or mono. disubstituted amino (e.g., Ashiruamino, main. Chi Ruamino) is the which may be substituted 1 or 2 or more positions with such "§ Li Ichiru", Contact and one COR ⁵ (wherein R ⁵ is as defined above ) Includes the above-mentioned “aryl”. Further, it may be condensed with a non-aromatic hydrocarbon ring condensed with aryl or a non-aromatic hydrocarbon ring condensed with heteroaryl.

Herein. The term "optionally substituted Ararukiru" in R ^1, the "lower alkyl" is, the "" optionally substituted Ariru in R ¹ '"and / or below The term “{optionally substituted heteroaryl in R ¹ ” ”means one or more substituted ones. For example, benzyl, phenethyl, 2-biphenylmethyl, 3-biphenylmethyl, 4-biphenylmethyl, 1-naphthylmethyl, 2-naphthylmethyl, 2-p-terphenylmethyl, 2-m-terphenylmethyl, 2-o-terph Enylmethyl, diphenylmethyl, 2-isobutylpyrphenylmethyl, 2-t-butylphenylmethyl, 2-isobutylphenylmethyl, 2-cyclopentylphenylmethyl, 2-bromophenylmethyl, 3 1-bromophenylmethyl, 2-odoodophenylmethyl, 2- (4-benzo-1,3-dioxolanyl) phenylmethyl, 2- (5-benzo-1,3-dioxolanyl) phenylmethyl, 2-phenyl Cyphenylmethyl, 2-benzylphenylmethyl, 2-phenylethylmethyl, 2- (3-phenyl) phenylmethyl, 2- (2-benzophenyl) phenylmethyl, 2- (3-pyridyl) phenylmethyl, 3-dimethylaminophenylmethyl, 3-ethylethylamino Phenylmethyl, 3-phenylaminophenyl, 3- (N-methyl-1-N-phenylamino) phenylmethyl, 2- (1-naphthyl) phenylmethyl, 2- (2-naphthyl) phenylmethyl, 3- (1 1-naphthyl) phenylmethyl, 3- (2-naphthyl) phenylmethyl, 2- (9-phenyl Enanthryl) phenylmethyl, 4- (ethenylphenyl) phenylmethyl, 2-promo — 6-isopropylphenylmethyl, 2-isopropyl, 6-phenyl-1-phenylmethyl, 2-isopropyl-1 6— (1 -Naphthyl) phenylmethyl, 2-promo 6-2-trophenylmethyl, 2-methyloxy-1 6- (1-naphthyl) phenylmethyl, 2,1-methyl-12-biphenylmethyl, 2,1-isopropyl-12-biphenylmethyl , 2,1-Methyloxy-2-biphenylmethyl, 3'-Methyl-2-biphenylmethyl, 4, -Fluoro D-2

—Biphenylmethyl, 3′—Trifluoromethyl-2—Biphenylmethyl ， 3,12-nitro-12—Biphenylmethyl, 3,1-methyloxy-2-biphenylmethyl,

3,1-Ethyloxy-2-biphenylmethyl, 3,1-hydroxy-12-biphenylmethyl, 3-methyloxy-12-biphenylmethyl, 6-phenyl-2-naphthylmethyl, 1-bromo-6-phenyl-2- Naphthylmethyl, 1,6-diphenyl 2-naphthylmethyl, 4-phenyl-2-naphthylmethyl, 1-phenyl

— 2 — naphthylmethyl, 1-phenylphenylmethyl, 2—phenylphenylmethyl, 2,6-diphenylphenylmethyl, 1,1-di (4-methyloxyphenyl) phenylmethyl, 1,1-di (3— Fluorene phenyl) phenylmethyl,

1,1-diphenyl (3,5-diphenyl) methyl, 1,1-diphenyl (3,5-dimethylphenyl) methyl, 1,1-di (3-methylphenyl) methyl Phenylmethyl, tosyl, 1,1-diphenyl (4-methyloxyphenyl) methyl, 1,1-diphenyl (4-methylphenyl) methyl, 1,1,1—tri (4-fluorophenyl) methyl, 1,1 Diphenyl (2-methylphenyl) methyl, 1,1-diphenyl (3-methylphenyl) methyl, 1,1,1-tri (4-cyclophenyl) methyl, 1,1-diphenyl (3-isopropylphenyl) methyl ) Methyl, 1,1-diphenyl (2-phenyl) methyl, 1,1-diphenyl (2-fluorophenyl) methyl, 1,1-diphenyl (3-sulfophenyl) methyl, 1,1-diphenyl (4-fluorophenyl) methyl, and the like. In the present specification, the `` heteroaryl which may be substituted '' in R ¹ is the above-mentioned `` optionally substituted aryl '' in the above-mentioned `` II ¹ ''"Heteroaryl" is included.

In the present specification, the “optionally substituted heteroaryl” in Y ² includes a nodogen (eg, fluorine, chlorine, bromine, iodine), a lower alkyl (eg, methyl, ethyl, n-propyl, isopropyl), Lower alkyloxy (eg, methyloxy, ethyloxy), trihaloalkyl (eg, trifluoromethyl), alkyloxycarbonyl (eg, methyloxycarbonyl), acyl (eg, acetyl), amino, mono or di The above-mentioned "heteroaryl" which may be substituted at one or two or more places with a substituted amino (eg, acylamino, methylamino); and one COR ⁵ (wherein R ⁵ has the same meaning as described above). The term "heteroaryl" is also included. Further, it may be condensed with a non-aromatic hydrocarbon ring condensed with aryl or a non-aromatic hydrocarbon ring condensed with heteroaryl. In the present specification, the “optionally substituted heteroaryl” in R ² , R ³ , R ⁴ , the RG ring, the J ring, and the L ring means that the carbon atom on the ring is halogen (eg, fluorine) , Chlorine, bromine, iodine), lower alkyl (for example, methyl, ethyl), lower alkyloxy (for example, methyloxy, ethyloxy), alkyloxy group, and the like. Teroaryl ". However, when the hetero atom is a nitrogen atom, the nitrogen atom may be substituted with an optionally substituted lower alkyl or acyl. In the present specification, “arylene” in “arylene which may be substituted” has the same meaning as the above “arylene”, and the substituent is the same as the above “R ² , R ³ , R ⁴ , R ⁵ , G ring: The same as the substituents for the “optionally substituted aryl” in the ring and L ring. Examples thereof include 1,4-phenylene and 2-hydroxy-1,4-phenylene. Preferably, 1,4-phenylene is used.

In the present specification, substituents of "Teroari Ren to which may be substituted", the ^{^{^{"R 2, R 3, R 4}}} , R 5, G ring, and" substituted in J ring, and L ring And the same as the substituents indicated by "". For example, 2,5—Chofenzil, 2,5—Franzyl, 2,5—Pyridylzyl. Preferably, 2,5-thiofenzil is used.

In the present specification, “optionally substituted arylcarbonyl” means carbonyl which may be substituted by the above “optionally substituted aryl”.

In the present specification, "optionally substituted lower alkyl", "optionally substituted cycloalkyl", "optionally substituted lower alkenyl", "optionally substituted cycloalkenyl" , “Optionally substituted heteroarylalkyl”, and “optionally substituted aralkyl” for Y ² , include lower alkyloxy, lower alkyloxycarbonyl, carboxy, monoalkyl Substituted amino, dialkyl-substituted amino and the like can be mentioned.

In the present specification, the term “acyl” includes an alkylcarbonyl in which the alkyl moiety is the “lower alkyl” or the arylcarbonyl in which the aryl moiety is the “aryl”. Furthermore, the aryl moiety of "arylcarbonyl" may be substituted with lower alkyl, halogen, and the like. For example, acetyl, propionyl, penzyl, toluoyl and the like can be mentioned. In the present specification, the “optionally substituted amino” includes aminos which may be substituted at one or two positions with the above “lower alkyl”, the above “aralkyl”, the above “asil” and the like. For example, methylamino, ethylamino, n-propylamino, dimethylamino, acetylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino and the like can be mentioned.

In the present specification, “halogen” means fluorine, chlorine, bromine, or iodine. In the present specification, “lower alkyloxy” includes lower alkyloxy wherein the alkyl moiety is the above “lower alkyl”. For example, methyloxy, ethyloxy, n-propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, t-butyloxy and the like. Preferably, methyloxy, ethyloxy, n-propyloxy are mentioned.

In the present specification, the “optionally substituted lower alkyloxy” means the above-mentioned “lower alkyloxy j” which may have a substituent in the “optionally substituted lower alkyl”. —Methyloxycarbonylmethyloxy, methyloxycarbonyl, ethyloxycarbonylmethyloxy, ethyloxycarbonylethyloxy, dimethylaminomethyloxy, dimethylaminoethyloxy Etc. Best mode for carrying out the invention

The therapeutic or prophylactic agent for dermatitis of the present invention, in particular, the therapeutic or prophylactic agent for allergic unilateral dermatitis including psoriasis and contact dermatitis, and atopic dermatitis includes oral, aerosol, rectum and dermal. It can be administered by various routes, including intravenous, intramuscular, and intranasal. In particular, skin is preferred. The formulations of the present invention are prepared by combining (eg, mixing) a therapeutically effective amount of the compound with a pharmaceutically acceptable carrier or diluent. The formulations of the present invention are prepared by known procedures using well-known, readily available ingredients.

In preparing the compositions of the present invention, the active ingredient is mixed with or diluted with a carrier. Or placed in a carrier in the form of a capsule, sash, paper, or other container. When the carrier acts as a diluent, the carrier is a solid, semi-solid, or liquid material that acts as a vehicle, which is a tablet, pill, powder, buccal, elixir, suspension, emulsion, solution Preparations, syrups, elixirs, aerosols (solids in liquid media), ointments, gels, creams, lotions and patches, eg up to 10% Active compounds. The compound having a therapeutic or preventive effect on the dermatitis of the present invention, in particular, a compound having a therapeutic or preventive effect on psoriasis, allergic dermatitis including contact dermatitis, and atopic dermatitis is administered prior to administration. Formulation is preferred.

Any suitable carrier known to those skilled in the art can be used for this formulation. In such formulations, the carrier is a solid, liquid, or mixture of a solid and a liquid. For example, for intravenous injection, the compound of the present invention is dissolved in a 4% dextrosoda 0.5% aqueous sodium citrate solution to a concentration of 2 mg / ml. Solid formulations include powders, tablets and capsules. A solid carrier is one or more substances that also serve as ingredients for flavoring, lubricants, dissolving agents, suspending agents, binders, tablet disintegrants, and capsules. Tablets for oral administration include calcium carbonate, charcoal along with disintegrants such as corn starch and alginic acid, and / or binders such as gelatin and acacia, and lubricants such as magnesium stearate, stearate, and talc. Contains suitable excipients such as sodium acid, lactose, calcium phosphate and the like. In powders, the carrier is a finely divided solid, which is in a mixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. Powders and tablets contain from about 1 to about 99% by weight of the active ingredient, a novel compound of the present invention. Suitable solid carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting wax, cocoa Butter.

Sterile liquid preparations include suspensions, emulsions, syrups, and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent, or a mixture of both. The active ingredient often can be dissolved in a suitable organic solvent, for example, aqueous propylene glycol. Other compositions can also be prepared by dispersing the active ingredient in aqueous starch, sodium carboxymethyl cellulose solution, or in a suitable oil.o Ointments are known to those skilled in the art. A base may be added. For example, petrolatum (eg, white / serine / yellow / serine), paraffin (eg, liquid paraffin), plastibase, lanolin, animal and vegetable oils, natural wax, wax (eg, wax) An oil base may be added. Further, a surfactant (for example, sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol monostearate, etc.) well known to those skilled in the art may be added. Solvents (eg, N-methyl-12-pyridone, benzyl alcohol, propylene carbonate, water, etc.) can also be added. Further, the ointment may contain not only the above-mentioned additives but also various other pharmacologically acceptable additives as long as the object of the present invention is not impaired. For example, antioxidants (for example, carboxylic acids such as ascorbic acid and citric acid; phenols such as tocoprol and dibutylhydroxytoluene), and preservatives (for example, parabens) are added. No problem. In order to produce the ointment of the present invention, the ointment may be prepared by a method well known to those skilled in the art. For example, in the case of manufacturing by a melting method, the oleaginous base and the surfactant are heated and melted, mixed, and half-cooled, and then the pharmaceuticals other than the base are added to a small amount of a solvent or the above-dissolved base solution. A softening agent may be prepared by dissolving, adding the remaining base material, stirring until the whole quality is uniform, and kneading.

For creams, for example, a base is first manufactured under heating and stirring, and Is added with heating and stirring, and the resulting emulsion is cooled to room temperature to produce the emulsion. The lotion is prepared, for example, by adding the base or a solution containing the base to a mixed base of an oily base or a heated and melted oily base and an aqueous base under heating and stirring, and then adding the aqueous base. Add and produce the resulting liquid by cooling to room temperature.

To formulate into a poultice, it is advisable to mix the powder of the main drug and the essential oil component to make a mud. Similarly to the above, various external preparations can be produced according to methods well known to those skilled in the art.

Dosage will also vary depending on disease state, route of administration, age or weight of patient, and will ultimately be at the discretion of a physician, but if administered orally to adults, is usually between 1 and 100 rag / kg / kg. For parenteral administration, usually 0.1 to 10 mg / kg / day, preferably 1 to 5 mg / kg / day, preferably 10 to 50 mg / kg / day. It may be administered once or divided into several doses. In the case of transdermal administration, an ointment containing 0.01% to 15% may be appropriately applied to the affected area once to several times a day. The following methods can be used to confirm whether the agent is effective for treating or preventing dermatitis, especially for treating or preventing allergic dermatitis including psoriasis, contact dermatitis, and atopic dermatitis. ) To c). The TPA-induced dermatitis model is a general dermatitis model, especially a model of proliferative dermatitis such as psoriasis or atopic dermatitis, and the TNGB-induced dermatitis model is allergic dermatitis or atopic dermatitis as a model, DS-Nh mouse spontaneous dermatitis model as a model of § preparative peak one dermatitis, c PLA ₂ inhibitors can be confirmed to be useful as a therapeutic or prophylactic agent for each disease.

a) TPA-induced dermatitis model

For the experiment, a 7-week-old female CD-I mouse is used. Apply 0.01% 12-0-tetradecanoylphorbol-13-acetate (TPA) acetone solution on the front and back of both ears in 10 ZL on days 0, 2, 4, 7, and 9. c PLA ₂ inhibitor is applied as an acetone solution of 10 ZZL: on the front and back of both ears twice daily on days 7-9 and once on day 10. Six hours after the last application of the drug, an ear-punched biopsy was taken, weighed and used as an indicator of edema. Immediately after flash freezing, use for the measurement of myeloperoxidase (MPO) activity and eicosanoid levels, which are indicators of neutrophil infiltration.

b) TNCB-induced dermatitis model

Seven-week-old female BALB / c mice are used for the experiment. 10 L of a 0.5% solution of Trinitrochlorobenzene (TNCB) in acetone was applied to the front and back of both ears on days 0, 7, 9, 11, 14, 16, 18 and 21. c PLA ₂ inhibitors (except Saturday and Sunday) Aseto emissions 9-18 days to ten on both sides of both ears as a solution twice daily, Day 21 is applied once. After measuring the thickness of the pinna 6 hours after the final application of TNCB, an ear punch biopsy is taken, and its weight is measured as an indicator of edema.Immediately frozen immediately and myelopoxidase (MPO) activity And for measuring eicosanoid levels.

c) Spontaneous dermatitis model of λ9-Λ¾ mouse

Use 6- to 10-month-old DS-N female mice with spontaneous onset of severe dermatitis. c PLA ₂ inhibitor is prepared as an ointment based on 0.5% polyethyleneglycol (PEG). 0.1% protocol ointment (registered trademark: Fujisawa Pharmaceutical Co., Ltd.) is used as a control drug. During the efficacy evaluation tests in Experiments 1 and 2, mice are kept in a conventional environment with liquid feed mixed with Otsuka MV injection (Otsuka Pharmaceutical Co., Ltd.) and AMINOTRIPA 2 (registered trademark: Otsuka Pharmaceutical Co., Ltd.). Also, 200 mg / kg / day of Ftdmariii (registered trademark: Shionogi & Co., Ltd.) is intraperitoneally administered for 5 days to remove yellow staphylococci at the site of inflammation, and then application of the test substance is started. About 50 mg of each ointment should be applied to the site of inflammation on the face (neck or shoulder if necessary) twice a day on weekdays and once a day on holidays for 22 or 29 days. The intensity of inflammation is determined according to the following criteria (flammability: 0: no change, 1: slightly reddish, dry, 2: red and moist, 3: reddish). At the same time, each inflammation site is photographed with a Polaroid camera, and the area is measured using computer software WinROOF (registered trademark: Mitani Corporation). In addition, after the final determination of inflammation intensity or the next day, inflamed tissue is collected approximately 4 hours after additional application of the softener. Tissue frozen quickly for analysis of Eikosanoi de _{_{(PGD 2, PGE 2, LTB}} 4). The pi-lysine derivative, which is an active ingredient of the therapeutic or prophylactic agent for dermatitis of the present invention, has extremely excellent properties when used as a pharmaceutical (for example, toxic effects such as chromosomal abnormalities and hepatotoxicity). Surface, absorption, excretion, pharmacokinetics, metabolic stability, etc.) These pyrrolidine derivatives can be synthesized in large quantities. Further, the two parts of the pyrrolidine derivative itself or a pharmaceutically acceptable salt thereof can be crystallized and purified, and can be industrially synthesized. Therefore, the agent for treating or preventing dermatitis according to the present invention is suitable as a pharmaceutical. Patent Document 1 discloses a therapeutic or preventive agent for dermatitis of the present invention, in particular, a pyrrolidine derivative used as a therapeutic or preventive agent for allergic dermatitis including psoriasis, contact dermatitis, and atopic dermatitis. , 2, and 3 can be synthesized in the same manner. For example, the following compounds shown in Tables 1 to 43 can be synthesized, and these compounds are useful for treating psoriasis, allergic dermatitis including contact dermatitis, and atopic dermatitis Or it is useful as a prophylactic agent. '

The following abbreviations are used in the table.

M e: Methyl

Et: Etil.

iBu: isobutyl

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ΐ 3 Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto.

Example 1 Induced dermatitis model

For the experiment, a 7-week-old female CD-I mouse was used. A 10% 0.01% solution of 12-0-tetradecanoylpliorbol-13-acetate (TPA) was applied to the front and back of both ears on days 0, 2, 4, 7 and 9. c PLA ₂ inhibitors AA-14 HC1 salt and BB-1 were applied in 10 L each as an acetone solution on the front and back of both ears twice daily on days 7-9 and once on day 10. . Six hours after the last application of the drug, an ear punch biopsy was taken, weighed and used as an indicator of edema, and immediately frozen and used for measurement of myelin peroxidase (MPO) activity and eicosanoid levels. Each data is shown as the average soil standard error. Statistical examination was performed by the Welch's t-test, and when P <0.05, it was determined that there was a significant difference.

Table 44

Ear edema MPO activity LTB ₄ PGE ₂

(mg) (U / tissue) (ng / tissue) (ng / tissue) N No treatment 28.5 ± 0.8 0.005 ± 0.002 0.19 ± 0.03 1.82 ± 0.21 7 Medium 60.3 ± 0.3 0.594 ± 0.113 0.51 ± 009 3.77 ± 0.27 7

AA-14 0.1 57.1 ± 2.4 0.530 ± 0.110 0.18 ± 0.03 * 2.12 ± 0.50 7

HC1 salt 0.3, 50.3 + 1.6 ** 0.410 ± 0.090 0.25 ± 0.06 * 1.53 ± 0.19 ** 7

1.0 49.8 ± 1.6 ** 0.190 ± 0.043 * 0.27 ± 0.03 * 1.46 ± 0.12 ** 6

BB-1 0.1 57.7 ± 2.6 0.496 ± 0.047 0.52 ± 0.10 2.58 ± 0.46 7

0.3 48.3 ± 1.8 ** 0.191 ± 0.031 ** 0.13 ± 0.01 ** 1.68 ± 0.28 ** 7

1.0 43.6 ± 1.6 ** 0.112 ± 0.016 * * 0.20 ± 0.03 * 1.62 ± 0.62 * 7

BMS- 0.3 57.8 ± 2.9 0.832 ± 0.137 0.21 ± 0.02 * 2.02 ± 0.30 ** 7

229 724 1.0 59.1 ± 3.5 0.391 ± 0.044 0.22 ± 0.03 ** 1.27 ± 0.26 ** 7

*; P <0.05, **; P <0.01 vs. medium

As shown in Table 44, both AA-14HC1 salt and BB-1 significantly suppress TPA-induced skin inflammation. Moreover, comparing the inhibitory effect of BMS-229724 with the inhibitory effect of the above two compounds, the effect is remarkable. In addition, eicosanoid levels are significantly reduced. I won. Example 2 TNCB-induced dermatitis model

Seven-week-old female BALB / c mice were used for the experiment. On the 0, 7, 9, 11, 14, 16, 18 and 21 days, 0.5% Trinitrochlorobenzene (TNCB) acetone solution (10 βL) was applied to the front and back of both ears. c PLA ₂ inhibitor § Se tons solution and to 10 〃 L 9 ~ 18 days on the front and back of both ears one by twice daily (excluding weekends), day 21 was applied once. After measuring the thickness of the pinna 6 hours after the final application of TNCB, an ear punch biopsy was taken and its weight was measured to serve as an indicator of edema. ) Used to measure activity and eicosanoid levels. Each data is shown by the average soil standard error. Statistical examination was performed by Welch's t-test method in Tables 45 and 46, it was judged that there was a significant difference when P <0.05, and in Table 47 by Dunnett's test, P <0.05 It was determined that there was a significant difference. Table 4 5

*; P <0.05, **; P <0.01 vs. medium

Table 4 6

*; P <0.05, * *; P <0.01 vs. medium Table 4 7

As shown in Table 45, M-17 and AA-14 significantly suppressed TNCB-induced skin inflammation. It also showed a tendency to suppress PGE ₂ levels.

As shown in Table 46, AA-14 and BB-1 dose-dependently and significantly suppressed TNCB-induced skin inflammation. LTB ₄ levels were also dose-dependently and significantly suppressed.

As shown in Table 47, AA-14 dose-dependently and significantly suppressed TNCB-induced skin inflammation. In addition, the inhibitory effect is remarkable when compared with the same dose of BMS-229724. Example 3 ^ -N¾ mouse spontaneous dermatitis model

A DS-Nh female mouse with spontaneous onset of severe dermatitis, 6 to 10 months old, was used. c PLA ₂ inhibitors M-17 and AA-14 were prepared as ointments based on 0.5% polyethyleneglycol PEG). 0.1% protopic ointment (registered trademark: Fujisawa Pharmaceutical Co., Ltd.) was used as a control drug. During the efficacy evaluation tests in Experiments 1 and 2, the mice were kept in a conventional environment on a liquid feed mixed with Otsuka MV injection (Otsuka Pharmaceutical Co., Ltd.) and AMINOTRIPA 2 (registered trademark: Otsuka Pharmaceutical Co., Ltd.). Also, to remove Staphylococcus aureus at the site of inflammation; Funarm (registered trademark: Shionogi & Co., Ltd.) 200 mg / _kg / day was intraperitoneally administered for 5 days, and then application of the test substance was started. About 50 mg of each ointment was applied to the site of inflammation on the face (neck or shoulder if necessary) twice a day on weekdays and once a day on holidays for 22 or 29 days. The inflammation intensity was determined according to the following criteria (inflammation level 0: no change, 1: slightly reddish and dry, 2: red and moist, 3: reddish). At the same time, each inflammation site was photographed with a Polaroid camera, and the area was measured using computer software WinROOF (registered trademark: Mitani Corporation). Further, after the final judgment of the inflammation intensity or the next day, about 4 hours after the additional application of the ointment, the inflamed tissue was collected. Tissues were frozen quickly for the analysis of Eikosano I de _{_{(PGD 2, PGE 2, LTB}} 4). The data are shown as mean soil S.E. Statistical analysis was performed using WUcoxon's signed rank test or Paired t-test or Welch'ί-test. When P <0.05, it was determined that there was a significant difference.

Table 4 8

Treatment Treatment amount and inflamed area of inflammation Example and days Intensity (cm ² ) Number

(Grade)

Experiment 1

Medium 50 mg X 25 Treatment 4.6 ± 0.5 0.83 ± 0.10 8 times 22 刖

After 4.9 ± 0.4 0.75 ± 0.01

0.5% 50 mg 25 treatment 4.4 ± 0.3 0.87 ± 0.11 8 AA-14 times / 22 days

Treatment 3.9 ± 0.2 0.58 + 0.06

*

Two

Medium 50 mg 3o Treatment 4.8 ± 0.4 0, 68 ± 0.09 8 times / 22

Treatment 4.8 ± 0.3 0.64 + 0.08

0.5% 50 mg 3o Treatment 4.8 ± 0.4 0.62 ± 0.09 8 M-17 times / 22 days I'J

Treatment 4.2 ± 0.3 0.37 ± 0.05

*

0.2% 50 mg X 3D treatment 4.7 ± 0.5 0.69 ± 0.08 8 AA-14 times / 22 days 刖

After 3.9 ± 0.5 0.45 ± 0.07 *

0.5% 50 mg 3D treatment 4.9 ± 0.4 0.62 ± 0.07 8 AA-14 times / 22 days 刖

Treatment 4.4 ± 0.3 After 0.50 ± 0.04

Three

Medium 50 mg X 48 Treatment 4.8 ± 0.2 0.82 ± 0.06 8 times 29 days

Treatment 5.1 ± 0.2 0.95 ± 0.07

0.5% 50 mg X 48 treatment 5.0 ± 0.3 0.62 ± 0.03 8 M-17 times 29 days,

Treatment 3.6 + 0.4 0.54 ± 0.07

*

After

0.5% 50 mg 48 treatment 4.9 ± 0.3 0.63 + 0.06 8 AA-14 times Z29 days 刖

Treatment 3.8 + 0.3 0.61 ± 0.07

*

rear *; P 0.05 0.05, * *; P 0.01 0.01 vs. before treatment (Wilcoxon's signed rank test or Paired t -te st) #; P 0.05 0.05 vs. medium (Welch 'ί-te st),

In Experiment 1, the ointment was applied once a day until the 15th day, and then twice a day until the 22nd day.

In Experiment 3, animals were kept on solid feed without treatment with Fulmariii (registered trademark: Shionogi & Co., Ltd.).

As shown in Table 48, the 0.5% M-17 and 0.5% AA-14 ointments significantly reduced the intensity of inflammation as well as the area of inflammation. These compounds also significantly reduced eicosanoid levels in inflamed tissues. The inhibitory effect of 0.5% M-17 ointment and 0.5% AA-1 ointment was almost the same as that of 0.1% protopic ointment (registered trademark: Fujisawa Pharmaceutical Co., Ltd.). Formulation example

Formulation Examples 1 to 13 shown below are merely examples, and are not intended to limit the scope of the invention in any way. The term “active ingredient” means a compound of formula (I) ′, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Formulation Example 1

Hard gelatin capsules are manufactured using the following ingredients:

Dose

(m capsule)

Active ingredient 2 5 0

Starch (dry) 2 0 0

Magnesium stearate 1 0

4 6 0 mg in total

Formulation Example 2

Tablets are prepared using the following ingredients: dose

(mg tablet)

Active ingredient 2 5 0

Cellulose (microcrystal) 4 0 0

Silicon dioxide (Hyu 10 '

Stearate 5

Total 6 6 5 mg

Mix the ingredients and compress into tablets weighing 665 mg each

Formulation Example 3

Produce an aerosol solution containing the following components: Active ingredient 0.2 5

Ethanol 2 5.75

Propellant 22 (chlorodifluoromethane) 74.0 0

Total 1 0 0. 0 0

The active ingredient and the ethanol are mixed, and this mixture is added to a portion of the propellerant 22, cooled to 130 ° C, and transferred to a filling device. Then supply the required amount to a stainless steel container and dilute with the remaining propeller. Attach the bubble unit to the container. Formulation Example 4 ■

Tablets containing 60 mg of the active ingredient are prepared as follows:

Active ingredient 60 mg

4 5 mg

Microcrystalline cellulose 35 mg

Polyvinyl pyrrolidone (10% solution in water) 4 mg

Sodium carboxymethyl starch 4.5 mg

Magnesium stearate 0.5 mg

talc Total 150 mg Active ingredient, starch, and cellulose are screened through No. 45 mesh lj. S. and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the obtained powder, and the mixture is passed through a No. 14 mesh U.S. sieve. The granules thus obtained are dried at 50 ° C and passed through a No. 18 mesh U.S. sieve. Sodium pre-filtered through a No. 60 mesh U.S. sieve: sodium: peroxymethyl starch, magnesium stearate, and talc are added to the granules, mixed, and compressed using a tablet press. Tablets weighing 150 mg each are obtained.

Formulation Example 5

Capsules containing 8 O mg of the active ingredient are prepared as follows:

Active ingredient 80 mg

Starch 5 9 mg

Microcrystalline cellulose 5 9 mg

Magnesium stearate 2 mg

Total 200 mg

The active ingredient, starch, cellulose, and magnesium stearate are mixed and passed through a No. 45 Mesh U.S. sieve into 200 mg hard gelatin capsules. ·

Formulation Example 6

Suppositories containing 2 25 mg of active ingredient are prepared as follows:

Active ingredient 2 25 mg

Saturated fatty acid glyceride 200 _mg

Total 2 2 2 5 mg

The active ingredient is passed through a No. 60 mesh S. sieve and suspended in the saturated fatty acid glyceride previously heated and melted to the minimum necessary. The mixture is then cooled in a 2 g mold. Formulation Example 7

A suspension containing 50 mg of the active ingredient is prepared as follows:

Active ingredient 50 mg

Sodium carboxymethyl cellulose 50 mg

Syrup 1 2 5 ml

Benzoic acid solution

Perfume q.v.

Dye q.v.

Add purified water for a total of 5 ml

The active ingredient is sifted through a No. 45 mesh S S. sieve and mixed with sodium carboxymethylcellulose and syrup to a smooth paste. Add the benzoic acid solution, flavor and dye diluted with some of the water and stir. Then add enough water to make up the required volume.

Formulation Example 8

An intravenous formulation is prepared as follows:

Active ingredient 100 mg

Water for injection 1 0 0 0 ml

Solutions of the above components are usually administered intravenously to a patient at a rate of 1 ml per minute. Formulation Example 9 '

The lyophilized formulation (1 vial) is prepared as follows:

Active ingredient 1 2 7 mg

Sodium sodium citrate dihydrate '36 mg

Mannitol 1 800 mg

The above components are dissolved in water to give an injection having an active ingredient concentration of 10 mg / g. The first freezing step is performed at 140 ° C for 3 hours, the heat treatment step is performed at 10 ° C for 10 Bf, and the refreezing step is performed at 140 ° C for 3 hours. Then, the first drying step was performed at 0 ° C and 10 Pa for 60 hours, and the second drying step was performed at 60 ° C and 4 Pa at 5:00 Do it for a while. Thus, a freeze-dried preparation can be obtained.

Example 10

A nasal preparation containing the following ingredients is prepared.

Active ingredient 2mg

Carboxy vinyl polymer 1 5mg

L-arginine .10mg '

Sodium chloride 0.6mg

84.2mg purified water

lOOmg

After melting the active ingredient in carboxyvinyl polymer, L-arginine and sodium chloride were added. The pH was adjusted, and the viscosity was adjusted by adding purified water to obtain a drug solution.

Formulation Example 1 1

A skin preparation containing the following components is produced.

Active ingredient 10mg Isopropyl myristate 990mg

lOOOmg

After dispersing the active ingredient in D-pill isoprist myristate, it was mixed with an acrylic adhesive (for example, dikasol) and attached to a support for application to obtain a dermal preparation. Formulation Example 1 2

An ointment containing the following ingredients is produced.

Active ingredient 10mg Liquid paraffin 75mg White petrolatum 915mg

lOOOmg

The active ingredient and liquid paraffin were dispersed and kneaded with white cellulose to obtain an ointment. Formulation Example 1 3

An external cream containing the following components is produced.

Active ingredient 0.05 g

Glycerin monostearate 7.2

Sorbine monostearate 3.2 g

SENO NOR-7.3 S

White Celine 3.5 s

Liquid paraffin 9.0 g

Propyl paraben 0.05 g

Polyoxyethylene hydrogenated castor oil 60 4.0 g

Propylene glycol 6.5 g

Methylno "? Laven 0.05 g

F appropriate amount

100 g

A mixture of glyceryl monostearate, sorbitan monostearate, cetanol, white petrolatum, liquid paraffin, propylparaben, and polyoxyethylene hardened castor oil 60 was heated and dissolved at about 7 CTC, and the active ingredient was dissolved in the mixture. Was added and the mixture was stirred and dispersed. To this mixture, an aqueous phase component in which propylene glycol and methylparaben were dissolved in purified water (about 59.15 _g ) at about 70 ° C. was added, and purified water was further added to adjust the total amount to 100 g. Thereafter, the emulsion obtained by sufficiently stirring is cooled to room temperature while stirring to obtain a cream preparation.

Industrial applicability

c Discovered that PLA ₂ inhibitors can be used as therapeutic or preventive agents for dermatitis, especially for allergic dermatitis including psoriasis, contact dermatitis, and atopic dermatitis Was.

Claims

Claims General formula (I)

(In the formula, R ¹ is a hydrogen atom, lower alkyl, optionally substituted aryl, aryl fused with a non-aromatic hydrocarbon ring or a non-aromatic heterocycle, optionally substituted Aralkyl, optionally substituted arylcarbonyl, or optionally substituted heteroaryl; Z is one S—, one SO—, one 0—, one O CH ₂ —, one CO NH—, — C 〇NH CH ₂ —, N (R ¹⁶ ) 1 (where R ¹⁶ is a hydrogen atom, lower alkyl, C ₃ -C ₈ cycloalkyl lower alkyl, or aralkyl), or a single bond;

X ¹ is — (CH ₂ ) s-N (R ¹⁸ ) -CO— (where R ¹⁸ is a hydrogen atom or lower alkyl, s is an integer of 0 to 3),, and one CH ₂ N (R ^{1 9) C 0 CH = CH -} ( wherein, R ^{1 9} is hydrogen atom or lower alkyl);

A, B, and E each independently represent an oxygen atom or a sulfur atom;

D is a hydrogen atom or a hydroxy lower alkyl;

Y or — (CH ₂ ) m CO—,-(CH 2) m CO NH—,-(CH ₂ ) m CSNH-, one (CH 2) m S 0 _2- , one (CH 2) m COO—, -(CH ₂ ) n NHC 0—, — (CH a) nNH S〇 ₂ — or a single bond, m is an integer of 0 to 3, n is an integer of 1 to 3;

Y ² is a hydrogen atom, a lower alkyl which may be substituted, a lower alkenyl which may be substituted, a cycloalkyl which may be substituted, a cycloalkylenyl which may be substituted, an aryl which may be substituted An optionally substituted aralkyl, an optionally substituted heteroaryl, an optionally substituted heteroaryl Arylalkyl or optionally substituted amino;

A wavy line (~) indicates that D has a cis or trans relationship to E ^ :), an optically active form thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, Or a therapeutic or preventive agent for a disease selected from psoriasis, allergic monodermatitis, and atopic dermatitis, which comprises a solvate thereof as an active ingredient.

2. General formula (II):

(Wherein, I ¹ , Z, R ¹⁸ , Υ ² , Β, and wavy line (~) are as defined in claim 1), an optically active form thereof, a prodrug thereof, or 2. The therapeutic or prophylactic agent according to claim 1, comprising a pharmaceutically acceptable salt thereof or a solvate thereof as an active ingredient.

3. General formula (I I I):

^{^{(Wherein, R. 1 Z, R 1 9}} , Y 2, Β, and the wavy line as defined claim 1, wherein) a compound represented by, an optically active form thereof, a prodrug thereof, may be properly pharmaceutically 2. The therapeutic or prophylactic agent according to claim 1, which contains an acceptable salt or a solvate thereof as an active ingredient.

4. ₍ A compound selected from the following compounds, its optically active substance, its prodrug, or a pharmaceutically acceptable salt thereof, or a solvate thereof is used as an active ingredient. An agent for treating or preventing a disease selected from psoriasis, allergic dermatitis, and atopic dermatitis.

5. Use of the compound according to any one of claims 1 to 4 for the manufacture of a medicament for treating a disease selected from psoriasis, allergic dermatitis, and atopic dermatitis. .

6. administering to a mammal, including a human, a therapeutically effective amount of the compound according to any one of claims 1 to 4, to the mammal, including humans, psoriasis, allergic dermatitis, and A method for treating a disease selected from atopic dermatitis.