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WO2004089368A1 - Agent therapeutique ou prophylactique conte la dermatite - Google Patents

Agent therapeutique ou prophylactique conte la dermatite Download PDF

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Publication number
WO2004089368A1
WO2004089368A1 PCT/JP2004/005021 JP2004005021W WO2004089368A1 WO 2004089368 A1 WO2004089368 A1 WO 2004089368A1 JP 2004005021 W JP2004005021 W JP 2004005021W WO 2004089368 A1 WO2004089368 A1 WO 2004089368A1
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WIPO (PCT)
Prior art keywords
optionally substituted
lower alkyl
dermatitis
active ingredient
hydrogen atom
Prior art date
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PCT/JP2004/005021
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English (en)
Japanese (ja)
Inventor
Yozo Hori
Kenji Kuwabara
Mitsuo Takeuchi
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Shionogi and Co Ltd
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Shionogi and Co Ltd
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Publication of WO2004089368A1 publication Critical patent/WO2004089368A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • 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.
  • a therapeutic or prophylactic agent for dermatitis comprising a c-PLA 2 (cytoplasmic PLA 2 > inhibitor) having a pyrrolidine skeleton as an active ingredient.
  • allergic dermatitis including psoriasis and contact dermatitis
  • a therapeutic or prophylactic agent for atopic dermatitis atopic dermatitis.
  • Phospholipase A 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.
  • PLA 2 Phospholipase A 2
  • 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.
  • 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.
  • 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.
  • Non-Patent Document 3 KaoruSeno et al., Journal of Medicinal Chemistry 2000, Vol. 43, No. 6, p. 1042- 1044
  • 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)
  • 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.
  • 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;
  • 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.
  • 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:
  • 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.
  • 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 ⁇ ⁇ , — OCH 2 —, — CH 2 0 CH 2 —, — CH 2 —N (R 2 °) — CH 2 — (where R ' 2 Q is a hydrogen atom, lower al
  • 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.
  • R 1 Z, R 18 , X 3 , Y 2 , ⁇ , and wavy line ( ⁇ ) are as defined in 7)
  • an optically active form thereof a prodrug thereof, or a compound thereof.
  • the therapeutic or prophylactic agent according to 7 which comprises a pharmaceutically acceptable salt or a solvate thereof as an active ingredient.
  • ⁇ 2 is the formula Or (CH 2 ) p
  • 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
  • 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.
  • 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:
  • 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 is optionally substituted aryl
  • the therapeutic or prophylactic agent according to any one of 1) to 1).
  • 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.
  • R- and S-isomers 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.
  • 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.
  • 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.
  • 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.
  • prodrugs examples 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
  • 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)).
  • 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.
  • 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.
  • 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.
  • 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. '
  • allergic dermatitis means a skin reaction (inflammation) among biological reactions caused by allergen stimulation.
  • 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.
  • 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.
  • plaque lesions 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 is chronic for infants of 2 months or more, and for others of 6 months or more.
  • lower alkyl refers to a linear or branched C i -C 1 ⁇ alkyl. Includes With preference given to C i to C 6 alkyl linear or branched.
  • R i, R 2 , R 3 , R i 7 , R 18 , R 19 , and R 2 are preferred.
  • methyl is preferred.
  • R 16 methyl, ethyl, isopropyl, isobutyl and isopentyl are preferred.
  • isopropyl, isobutyl and isopentyl are mentioned.
  • 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)
  • alkyl e.g., cyclopropyl, cycloheptyl cyclopentyl, cyclobutyl, cyclohexane cyclohexyl, cyclohexylene, Shikurookuchiru
  • lower alkyl is meant.
  • cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl can be mentioned.
  • cycloalkyl includes C 3 -C 7 cycloalkyl.
  • cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl can be mentioned.
  • cyclopentyl and cyclohexyl are preferred.
  • 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.
  • vinyl, aryl, propenyl, crotonyl, isopentenyl, various butenyl isomers and the like can be mentioned.
  • C2-C6 alkenyl is mentioned.
  • a C2-C4 alkenyl is mentioned.
  • cycloalkenyl includes C 3 -C 7 cycloalkenyl having one unsaturated bond in the ring.
  • cyclopropenyl cyclopentene And cyclohexenyl.
  • cyclohexenyl is used.
  • 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.
  • aryl includes a monocyclic or condensed cyclic aromatic hydrocarbon group, or a group in which two or more monocyclic aromatic hydrocarbons are continuously present.
  • aryl includes a monocyclic or condensed cyclic aromatic hydrocarbon group, or a group in which two or more monocyclic aromatic hydrocarbons are continuously present.
  • phenyl 1-naphthyl, 2-naphthyl, biphenyl, indenyl, 2-P-terphenyl, 2-m-terphenyl, 2-o-terphenyl, anthryl, phenyl Ril and the like.
  • phenyl 1-naphthyl, 2-naphthyl, anthryl, phenanthryl, 2-biphenyl, 3-biphenyl, 4-biphenyl, 2-p-terphenyl, 2-m- Terfeniryl and 2-o-terpanilyl.
  • 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.
  • 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.
  • aralkyl refers to the above “lower alkyl” and the above “aryl” Include those substituted.
  • benzyl, phenyl, 3-phenyl n-propyl, benzhydryl, naphthylmethyl, 2-naphthylethyl and the like can be mentioned.
  • benzyl, benzhydryl, phenethyl and naphthylmethyl are mentioned.
  • benzyl and benzhydryl are preferable.
  • alkylene refers to a divalent group derived from C i C g alkyl. Examples include methylene, ethylene, trimethylene, tetramethylene, and pentamethylene.
  • alkenylene means a divalent group derived from C 2 to C 4 alkenyl.
  • vinylene, propenylene, and butenylene are mentioned.
  • arylene means a divalent group derived from the above “aryl”.
  • phenylene, naphthylene and the like can be mentioned.
  • 1,2-phenylene, 1,3-phenylene, 1,4-phenylene and the like can be mentioned.
  • heteroarylene means a divalent group derived from the following “heteroaryl”.
  • Tiofenzil, Franjyl and the like can be mentioned. More specifically, 2,5—chofenzir and 2,5—furanjyl are exemplified.
  • heterodiyl means a divalent group derived from the above “non-aromatic heterocycle”.
  • pyrrolidinezil, piperidinezil, and piperazinezil can be mentioned. More specifically, 1,4-piperidinediyl and the like can be mentioned.
  • hydroxy lower alkyl means the above “lower alkyl” substituted by hydroxy.
  • hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl and the like can be mentioned.
  • 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.
  • Preferable examples include pyridyl, phenyl, furyl, benzo [b] chenyl, benzo [b] furanyl and indolinole.
  • 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.
  • 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
  • Dazolylmethyl for example, 1-indazolylmethyl
  • benzotriazolylmethyl for example, 1-benzotriazolylmethyl
  • benzoquinolylmethyl for example, 2-benzoquinolylmethyl
  • benzoymidazolylmethyl for example, 2-benzoisomidazolylmethyl
  • pyridylmethyl for example
  • 2 Pyridinium Jirumechiru 3-pyridylmethyl, and 4 one-pyridylmethyl
  • 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-d
  • 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. '
  • “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.
  • halogen eg, fluorine, chlorine, bromine, iodine
  • lower alkyl eg, methyl, ethyl, n-propyl, isopropyl
  • Lower alkyloxy eg, methyloxy, ethyloxy
  • trihaloalkyl eg, trifluoro
  • 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.
  • 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.
  • 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
  • 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, methyl
  • 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.
  • 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.
  • heteroaryl when the hetero atom is a nitrogen atom, the nitrogen atom may be substituted with an optionally substituted lower alkyl or acyl.
  • 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.
  • 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 "”.
  • 2,5-thiofenzil is used.
  • optionally substituted arylcarbonyl means carbonyl which may be substituted by the above “optionally substituted aryl”.
  • optionally substituted lower alkyl include lower alkyloxy, lower alkyloxycarbonyl, carboxy, monoalkyl Substituted amino, dialkyl-substituted amino and the like can be mentioned.
  • acyl includes an alkylcarbonyl in which the alkyl moiety is the “lower alkyl” or the arylcarbonyl in which the aryl moiety is the “aryl”.
  • the aryl moiety of "arylcarbonyl” may be substituted with lower alkyl, halogen, and the like.
  • acetyl, propionyl, penzyl, toluoyl and the like can be mentioned.
  • 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.
  • methylamino, ethylamino, n-propylamino, dimethylamino, acetylamino, ethylmethylamino, benzylamino, acetylamino, benzoylamino and the like can be mentioned.
  • halogen means fluorine, chlorine, bromine, or iodine.
  • 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.
  • 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.
  • 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.
  • 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.
  • the carrier is a solid, liquid, or mixture of a solid and a liquid.
  • 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.
  • a suitable excipients such as sodium acid, lactose, calcium phosphate and the like.
  • the carrier is a finely divided solid, which is in a mixture with the finely divided active component.
  • 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.
  • 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.
  • 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.
  • a surfactant for example, sorbitan fatty acid ester, glycerin fatty acid ester, propylene glycol monostearate, etc.
  • Solvents eg, N-methyl-12-pyridone, benzyl alcohol, propylene carbonate, water, etc.
  • solvents eg, N-methyl-12-pyridone, benzyl alcohol, propylene carbonate, water, etc.
  • 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.
  • antioxidants for example, carboxylic acids such as ascorbic acid and citric acid; phenols such as tocoprol and dibutylhydroxytoluene
  • preservatives for example, parabens
  • the ointment may be prepared by a method well known to those skilled in the art.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • TPA 12-0-tetradecanoylphorbol-13-acetate
  • 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.
  • an ear-punched biopsy was taken, weighed and used as an indicator of edema.
  • MPO myeloperoxidase
  • eicosanoid levels which are indicators of neutrophil infiltration.
  • mice 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.
  • TNCB Trinitrochlorobenzene
  • 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.
  • PEG polyethyleneglycol
  • 0.1% protocol ointment registered trademark: Fujisawa Pharmaceutical Co., Ltd.
  • 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.).
  • Ftdmariii registered trademark: Shionogi & Co., Ltd.
  • Ftdmariii registered trademark: Shionogi & Co., Ltd.
  • 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).
  • each inflammation site is photographed with a Polaroid camera, and the area is measured using computer software WinROOF (registered trademark: Mitani Corporation).
  • WinROOF registered trademark: Mitani Corporation
  • 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).
  • 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.
  • 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. '
  • mice 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 ⁇ L) 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.
  • TNCB Trinitrochlorobenzene
  • M-17 and AA-14 significantly suppressed TNCB-induced skin inflammation. It also showed a tendency to suppress PGE 2 levels.
  • mice 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.
  • 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.).
  • 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' ⁇ -test. When P ⁇ 0.05, it was determined that there was a significant difference.
  • Treatment Treatment amount and inflamed area of inflammation Example and days Intensity (cm 2 ) Number
  • active ingredient means a compound of formula (I) ′, a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a solvate thereof.
  • Hard gelatin capsules are manufactured using the following ingredients:
  • Tablets are prepared using the following ingredients: dose
  • Propellant 22 (chlorodifluoromethane) 74.0 0
  • Tablets containing 60 mg of the active ingredient are prepared as follows:
  • 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.
  • Capsules containing 8 O mg of the active ingredient are prepared as follows:
  • 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. ⁇
  • Suppositories containing 2 25 mg of active ingredient are prepared as follows:
  • a suspension containing 50 mg of the active ingredient is prepared as follows:
  • 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.
  • An intravenous formulation is prepared as follows:
  • the lyophilized formulation (1 vial) is prepared as follows:
  • 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
  • the refreezing step is performed at 140 ° C for 3 hours.
  • the first drying step was performed at 0 ° C and 10 Pa for 60 hours
  • the second drying step was performed at 60 ° C and 4 Pa at 5:00 Do it for a while.
  • a freeze-dried preparation can be obtained.
  • a nasal preparation containing the following ingredients is prepared.
  • a skin preparation containing the following components is produced.
  • 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.
  • 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.
  • 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.

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Abstract

L'invention concerne un agent thérapeutique ou prophylactique contre la dermatite allergique comprenant le psoriasis et la dermatite de contact et contre la dermatite atopique, qui contient comme principe actif un composé représenté par la formule générale (I), dans laquelle R1 représente éventuellement aralkyle substitué, etc. ; Z représente S-, etc. ; X1 représente (CH2)s-N(R18)-CO- (R18 représentant hydrogène, etc. et s un entier situé entre 0 et 3), etc. ; A, B et E représentent chacun indépendamment oxygène ou soufre ; D représente hydrogène, etc. ; Y1 représente (CH2)mCO- (m étant un entier situé entre 0 et *), etc. ; et Y2 représente éventuellement aryle substitué, etc.
PCT/JP2004/005021 2003-04-08 2004-04-07 Agent therapeutique ou prophylactique conte la dermatite Ceased WO2004089368A1 (fr)

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JP2003-104543 2003-04-08

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033797A1 (fr) * 1997-01-31 1998-08-06 Shionogi & Co., Ltd. Derives de pyrrolidine ayant une activite inhibant la phospholipase a2

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998033797A1 (fr) * 1997-01-31 1998-08-06 Shionogi & Co., Ltd. Derives de pyrrolidine ayant une activite inhibant la phospholipase a2

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
BURKE J.R.: "Targeting phospholipase A2 for the treatment of inflammatory skin deseases", CURRENT OPINION IN INVESTIGATIONAL DRUGS, vol. 2, no. 11, 2001, pages 1549 - 1552, XP002979908 *

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