WO2004043471A1 - Medicament antipruritique - Google Patents

Medicament antipruritique Download PDF

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Publication number
WO2004043471A1
WO2004043471A1 PCT/JP2003/014446 JP0314446W WO2004043471A1 WO 2004043471 A1 WO2004043471 A1 WO 2004043471A1 JP 0314446 W JP0314446 W JP 0314446W WO 2004043471 A1 WO2004043471 A1 WO 2004043471A1
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Prior art keywords
group
optionally substituted
substituted
hydroxyl
alkyl
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PCT/JP2003/014446
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English (en)
Japanese (ja)
Inventor
Fumie Sato
Iwao Arai
Norikazu Takano
Tohru Tanami
Makoto Yagi
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Taisho Pharmaceutical Co., Ltd.
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Priority to AU2003301900A priority Critical patent/AU2003301900A1/en
Priority to JP2004551230A priority patent/JP4477504B2/ja
Publication of WO2004043471A1 publication Critical patent/WO2004043471A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A61K31/5585—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes having five-membered rings containing oxygen as the only ring hetero atom, e.g. prostacyclin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/559—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing hetero atoms other than oxygen
    • 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
    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof

Definitions

  • the present invention relates to an agent for preventing or treating pruritic symptoms (hereinafter, also referred to as an antipruritic), and particularly to an antipruritic agent which is effective in relieving pruritus caused by atopic symptoms.
  • an antipruritic an agent for preventing or treating pruritic symptoms
  • an antipruritic agent which is effective in relieving pruritus caused by atopic symptoms.
  • drugs such as topical steroids, immunosuppressants, antihistamines, and antiallergic drugs have been used for pruritic symptoms.
  • steroids and immunosuppressants has been limited due to the side effects of long-term use, and antihistamines and antiallergic agents have not been sufficiently satisfactory in terms of therapeutic effect.
  • antipruritic agents was based on the administration of itch-inducing substances such as histamine and serotonin into the skin of animals to measure the pruritic behavior.In recent years, the onset of pruritus due to pruritic symptoms such as atopic dermatitis has been observed. However, it has been reported that the reaction is not simply due to histamine etc. released from mast cells (J. Dermatological Science 25, 20-28,
  • An object of the present invention is to provide a novel drug for preventing or treating pruritic symptoms, in particular, a drug for preventing and treating atopic diseases.
  • the present inventors have studied using the evaluation method described below to achieve the above object. As a result, it was found that certain prostaglandins have few side effects and have an antipruritic effect, especially pruritus associated with atopic symptoms. And found that the present invention was effectively suppressed, and completed the present invention.
  • X represents a hydrogen atom, a methylene group, a hydroxyl group, an oxo group, an optionally substituted d- 5 alkoxy group or —S (0) nl Rs,
  • ⁇ is an ethylene group, an optionally substituted vinylene group, an ethynylene group or
  • Ri represents a hydrogen atom, a hydroxyl group or substituted with may be d- alkoxy group
  • R2 is an alkyl group optionally d-io be substituted, an optionally substituted C 2 - 10 of an alkenyl group, substituted which may be C 2 - 10 alkynyl group, one (CH 2) wQ or formula
  • R3 represents a hydrogen atom or an optionally substituted d.5 alkyl group
  • R3 forms a cycloalkyl group optionally Cs-io be connexion substitutions with R 2 and adjacent carbon atoms,
  • R represents a hydroxyl group or an optionally substituted d- 5 alkoxy group
  • R5 is a hydroxyl group, an optionally substituted dw alkoxy group, optionally substituted C 2 - 10 Arukeniruokishi group, optionally substituted C 2 - 10 Arukiniruokishi group, optionally substituted C 3 - 10 A cycloalkyloxy group, an optionally substituted aryloxy group, an optionally substituted aryl group, an optionally substituted d-10 alkyl group,
  • Each R6a and RSb is alkyl of Cno optionally substituted, optionally substituted C 2 - alkenyl group 1 (), optionally substituted C 2 - 10 alkynyl group may be substitution C 3 _ 10 represents a cycloalkyl group or 1 (CH 2 ) w ′ —Q, R 7 represents an optionally substituted C ⁇ o alkyl group or an optionally substituted aryl group,
  • R8 represents an optionally substituted d. 5 alkyl group
  • R9 is alkyl group optionally Cno be substituted, an optionally substituted C 2 - 10 of an alkenyl group, an optionally substituted C 2 - 10 alkynyl group, or,
  • a and A ' are the same or different, an ethylene group, an optionally substituted Piniren group, Echiniren group, allene group, an optionally substituted phenylene group, cycloalkylene group optionally C _ 7 be substituted
  • B and B are the same or different and each represents an oxygen atom or S ( ⁇ ) groups represented by n 2, m represents an integer of 0 to 2, n, n 1 and n 2 are the same or different 0 Represents an integer from 2 to 2, w represents an integer from 0 to 5, w 'represents an integer from 1 to 5, p, Q, r and t represent the same or different integers from 0 to 4 ( However, when E is a hydroxyl group and X is a hydrogen atom, and when both E and X are hydroxyl groups, and the compounds in the following table are excluded).
  • E and X are each different JP2003 / 014446
  • a prostaglandin derivative, or a pharmaceutically acceptable salt or hydrate thereof which is an oxo or hydroxyl group, or a methylene group or a hydroxyl group, respectively, as an active ingredient.
  • a prostaglandin derivative of the formula [1] wherein E is an oxo or methylene group and X is a hydroxyl group, a pharmaceutically acceptable salt thereof or a hydrate thereof is effective. It is intended to provide a drug for preventing or treating the above-mentioned pruritic symptoms as a component.
  • a prostaglandin derivative wherein G is —COR 5 and Y is a vinylene group or an edylene group in the formula [1], a pharmaceutically acceptable salt or a pharmaceutically acceptable salt thereof.
  • a drug for preventing or treating the above-mentioned pruritic symptoms comprising the hydrate as an active ingredient.
  • a prostaglandin derivative, a pharmaceutically acceptable salt thereof or a hydrate thereof is administered to a mammal in an amount effective for prevention or treatment of the symptoms. And a method for preventing or treating pruritic symptoms.
  • FIG. 1 shows dermatitis scores observed over time for 4 weeks after drug administration.
  • FIG. 2 shows the dermatitis score observed 4 weeks after drug administration.
  • the present invention is characterized in that a prostaglandin derivative represented by the formula [1] is used as an active ingredient.
  • the “prostaglandin derivative, pharmaceutically acceptable salt thereof” further includes all isomers (geometric isomers, optical isomers).
  • “Pharmaceutically acceptable salt” here means, for example, sodium, potassium, etc. With alkaline metals, salts with alkaline earth metals such as calcium and magnesium, ammonia, methylamine, dimethylamine, cyclopentylamine, benzylamine, piperidine, monoethanolamine, diethanolamine, monomethylmonoethanol Salts with amines, tromethamine, lysine, tetraalkylammonium, tris (hydroxymethyl) aminomethane, salts with mineral acids such as sulfuric acid, hydrochloric acid, phosphoric acid, acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, Salts with organic acids such as maleic acid, maleic sulfonic acid, and benzene sulfonic acid.
  • the terms used in the present invention are defined below
  • Halogen atom means a fluorine, chlorine, bromine or iodine atom.
  • aryl group examples include a phenyl group and a naphthyl group.
  • the substituted aryl group of the “optionally substituted aryl group” includes, for example, a hydroxyl group, a halogen atom, an alkyl group of, an alkyl group of d substituted with a halogen atom, a nitro group, a cyano group, ( :. 5 alkoxy group, d is substituted with a halogen atom 5 alkoxy, phenyl group, phenoxy group, 1 or 2 C optionally substituted amino group with an alkyl group, C 2 - 5 ⁇ Alkylcarbonyl group and
  • C 2 - 5 alkylcarbonyl group Ariru groups substituted on 1 ⁇ in selected from the group consisting of Amino group substituted by, preferably, a hydroxyl group, a halogen atom, d - s alkyl group, triflate Ruo b methyl , A nitro group, a cyano group, an alkoxy group, a phenyl group, a phenoxy group and an acetylamino group.
  • substituted aryl group examples include a phenyl group, a tolyl group, a mesityl group, a cumenyl group and a xylyl group.
  • the " ⁇ 5 alkyl group” represents a linear or branched ⁇ alkyl group having 1 to 5 carbon atoms, such as methyl, Echiru group, a propyl group, an isopropyl group, blanking butyl group, sec Examples thereof include a monobutyl group, a tert-butyl group, a pentyl group, and a tert-pentyl group.
  • the substituted C-L- 5 alkyl group of the ⁇ optionally substituted d- 5 alkyl group '' is, for example, d substituted with one or more selected from the group consisting of a hydroxyl group and an octagen atom -Means an alkyl group of 5 .
  • G is an alkyl group of which has been d-5-substituted
  • alkyl group substituted by a halogen atom d-5 is preferred.
  • R8 is a substituted d- 5 alkyl group
  • an alkyl group substituted with a hydroxyl group is preferred.
  • Examples of the d-5 alkyl group substituted with a hydroxyl group include a hydroxymethyl group,
  • Examples thereof include a 1-hydroxyethyl group, a 2-hydroxyethyl group, a 2-hydroxypropyl group, a 3-hydroxypropyl group, a 2,3-dihydroxypropyl group, and a 5-hydroxypentyl group.
  • Examples of the d-5 alkyl group substituted by a halogen atom include a dichloromethyl group, a trifluoromethyl group, a pentafluoroethyl group, and a 1,3-dibromopropyl group.
  • D. 5 alkoxy group and represents a linear or branched alkoxy group having 1 to 5 carbon atoms, such as methoxy group, ethoxy group, propoxy group, iso epoxy group, a butoxy group, sec —Butoxy group, tert-butoxy group and pentyloxy group, and methoxy group and ethoxy group are preferred.
  • the substituted ds alkoxy group of the "optionally substituted ⁇ 5 alkoxy group" is, for example, a d- 5 alkoxy group substituted by one or more selected from the group consisting of a hydroxyl group and an octagen atom Means
  • Vinyl group means a cis or trans vinylene group.
  • the substituted vinylene group in the “optionally substituted vinylene group” means a vinylene group substituted with one or more selected from the group consisting of a halogen atom and a d-5 alkyl group.
  • alkoxy group means a linear or branched alkoxy group having 1 to 10 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy. Groups, tert-butoxy group, pentoxy group, tert-pentyloxy group, 5-methylhexyloxy group, octyloxy group, decyloxy group and the like.
  • the substituted d-io alkoxy group of the "optionally substituted C ⁇ o alkoxy group” is, for example, a d-io substituted with at least one selected from the group consisting of a hydroxyl group and a halogen atom. It means an alkoxy group.
  • Alkyl group refers to a linear or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl. Group, tert-butyl group, pentyl group, tert-pentyl group, isohexyl group, heptyl group, octyl group, decyl group and the like.
  • the substituted dw alkyl group in the "optionally substituted C ⁇ o alkyl group” means, for example, a Cno alkyl group substituted with one or more selected from the group consisting of a hydroxyl group and a nodogen atom. I do.
  • the "C 2. 1 () alkenyl group” means a group having one or more double bonds at any position of the straight-chain or branched alkyl group having 2 to 10 carbon atoms Examples thereof include a vinyl group, an aryl group, a 1-propenyl group, an isopropenyl group, a 3-butenyl group, a 1,3-butenyl group, and a 7-octenyl group.
  • C 2 is substituted - "10 alkenyl group optionally substituted C 2" - 10 Aruke two Le group, for example, substituted with one or more members selected from the group consisting of hydroxyl group and ⁇ androgenic atoms means 10 alkenyl - C 2.
  • C 2. 10 alkynyl group means a group having one or more triple bonds at any position of the straight-chain or branched alkyl group having 2 to 10 carbon atoms, for example, E Examples thereof include a chel group, a 2-propenyl group, a 2-pentynyl group, and a 41-year-old cutinyl group.
  • Optionally substituted C 2 - 10 alkynyl group C 2 is substituted - with 10 Arukini Le group, for example, C substituted with one or more members selected from the group consisting of hydroxyl group and eight androgenic atoms 2 - means a 10 alkynyl group.
  • Examples of - "C 3 cycloalkyl group 10" may include a cyclopropyl group, Shikuropuchi group, cyclopentyl group, cyclohexyl group, heptyl group cycloalkyl, and cyclononyl groups.
  • Optionally substituted C 3 - 10 cycloalkyl group C 3 is substituted - 10 Sik of The alkyl group is, for example, C 5 substituted with at least one selected from the group consisting of C 5 alkyl groups which may be substituted with a halogen atom, hydroxyl group and halogen atom.
  • the ". C 2 10 Arukeniruokishi group” a linear or branched alkenyl group having a carbon number of 2 to 10 - O-has a structure composed of, for example Ariruoki sheet group And a propenyloxy group, a 1-isopropenyloxy group, a 3-butenyloxy group, a 1,3-butenyloxy group, a 7-octenyloxy group, and the like.
  • Optionally substituted C 2 - 10 Arukeniruokishi group C 2 is substituted - with 10 ⁇ Rukeniruokishi group, for example, substituted with a hydroxyl group and from selected Ru 1 or more group consisting of halogen atoms means 10 Arukeniruokishi group - C 2 was.
  • C 2 10 Arukiniruokishi group have a straight or branched configuration alkynyl groups and in which one ⁇ - was combined C2-10, such as 2-propyl Examples include a niloxy group, a 2-pentynyloxy group, and a 4-octynyloxy group.
  • Rukiniruokishi group e.g., hydroxyl and eight androgenic than selected Ru 1 or more group consisting of atoms - the "optionally substituted C 2 - 10 Arukiniruokishi group" C 2 which is substituted means 10 Arukiniruokishi group - C 2 which it is.
  • C 3 10 cycloalkyl O alkoxy group includes a cycloalkyl group c 3 10.
  • the compound has a complex form, and examples thereof include a cyclopropyloxy group, a cyclobutyloxy group, a cyclopentyloxy group, a cyclohexyloxy group, a cycloheptyloxy group, and a cyclononyloxy group.
  • C 3 is substituted - with 10 cycloalkyl O alkoxy group, for example, an alkyl group of which has been or d-5 substituted with a halogen atom , Substituted with one or more selected from the group consisting of a hydroxyl group and an octylogen atom Has been C 3 - 10 means a cycloalkyl O alkoxy group.
  • aryloxy group examples include a phenoxy group and a naphthoxy group.
  • the substituted aryloxy group of the "optionally substituted aryloxy group” is a hydroxyl group, a halogen atom, an alkyl group of ds, an alkyl group of d- 5 substituted with a halogen atom, a nitro group, a cyano group.
  • substituted aryloxy group examples include a bromophenoxy group, a chlorophenoxy group, a tolyloxy group, a cumenyloxy group, and a methoxyphenoxy group.
  • cycloalkylene C 3 _ 7 may include cyclopropylene group, cyclobutylene group, cyclopentylene group, cyclohexylene group, a etc. heptylene cyclohexylene.
  • alkyl groups may be substituted with a halogen atom, a hydroxyl group, and eight androgenic atoms means one or more substituted c 3 _ 7 of consequent opening alkylene group selected from the group consisting of.
  • Q may be substituted C 3 - as example for a cycloalkyl group 10, cyclopropylmethyl group, cyclobutyl E methyl group, consequent opening Penchirumechiru group, a cycloalkyl Examples include a hexylmethyl group, a cycloheptylmethyl group, a cyclononylbutyl group, and a 41-fluorocyclohexylmethyl group.
  • Q is an aryloxy group which may be substituted Examples thereof include a phenoxymethyl group, a phenoxypropyl group, a chlorophenoxyethyl group, a methoxyphenoxymethyl group, a trioxymethyl group and the like.
  • R2 is an (CH 2) w- Q
  • Q is C 3 - 10 cycloalkyl group or ⁇ Li
  • Ruokishi groups are preferred.
  • R6a and R6b are come as an (CH 2) w- Q, Q is C 3 - preferably a cycloalkyl group 10.
  • R8 is a d-5 alkyl group which may be substituted
  • an alkyl group substituted by a hydroxyl group is preferable.
  • prostaglandin derivative represented by the formula [1] as the active ingredient of the present invention are described below.
  • E and X are preferably respectively different oxo or hydroxyl groups, or differently different methylene groups or hydroxyl groups, and more preferably E is an oxo or methylene group and X is a hydroxyl group.
  • Y is preferably an ethylene group, an optionally substituted vinylene group, or an ethynylene group, and more preferably a vinylene group or an ethynylene group.
  • R 5 is preferably a hydroxyl group, an alkoxy group, or —NHS O2R 7 .
  • Z preferably one (CH 2) P A (CH 2) qA, (CH 2) r first and one (CH 2) p A (CH 2) q B (CH 2) a r scratch.
  • R9 is preferably an optionally substituted ( ⁇ alkyl group, more preferably a Ci-s alkyl group.
  • the prostaglandin derivative serving as the active ingredient of the present invention includes known compounds disclosed in the following publications. Patent No. 2503047, Patent No. 2571250, Patent No. 2641622, Patent No. 2677779, Patent No.
  • Typical compounds of the formula (1) according to the present invention include the following compounds.
  • Table 1 shows the prostaglandin where Z is a group represented by the formulas (CH 2 ) p A (CH 2 ) qA and (CH 2 ) r , and the formula (CH 2 ) p A (CH 2 ) q B ( The prostaglandin represented by CH 2 ) r is shown in Table 2, the prostaglandin represented by the formula (CH 2 ) P B (CH 2 ) q B '(CH 2 ) r is shown in Table 3, and the formula (CH 2) pB '(CH 2) q a' (CH 2) illustrating the prostaglandins represented by r in Table 4.
  • Table 1 shows the prostaglandin where Z is a group represented by the formulas (CH 2 ) p A (CH 2 ) qA and (CH 2 ) r , and the formula (CH 2 ) p A (CH 2 ) q B ( The prostaglandin represented by CH 2
  • Z-CH CH: cispinylene group
  • Z-C bond between Z and the adjacent 5-membered ring carbon atom
  • E-C or X-C Bond between E or X and the adjacent 5-membered carbon
  • ⁇ -G Bond between Y and the adjacent 5-membered carbon
  • R1-C bond between R1 and adjacent carbon atom
  • E-GH GH: transpinylene group
  • Z-CH CH: cis vinylene group
  • Z-G Bond between Z and adjacent 5-membered ring carbon atom
  • E-CorX-C Bond between E or X and the adjacent 5-membered carbon
  • Y-C Bond between Y and adjacent 5-membered ring carbon atom
  • Z-CH CH: cis vinylene group
  • Z-G Bond between Z and adjacent 5-membered ring carbon atom
  • E-GorX- G bond between E or X and the adjacent 5-membered carbon
  • Y-C bond between Y and an adjacent 5-membered ring carbon atom
  • R1-C Bond between R1 and adjacent carbon atom
  • Z-G Bond between Z and adjacent 5-membered ring carbon atom
  • E-G or X-G bond between E or X and the adjacent 5-membered carbon
  • Y-C Bond between Y and adjacent 5-membered ring carbon atom
  • R1-C Bond between R1 and adjacent carbon atom
  • E-CH GH: trans vinylene group
  • Gyc5 cyclopentyl group
  • Z-C Bond between Z and adjacent 5-membered carbon atom
  • E-G or X_G Bond between E or X and the adjacent 5-membered carbon
  • Y-C Bond between Y and the adjacent 5-membered ring carbon atom
  • R1- G bond between m and adjacent carbon atom
  • E-CH GH: trans vinylene group
  • Z-G Bond between Z and adjacent 5-membered ring carbon atom
  • E-G or X-G Bond between E or X and the adjacent 5-membered carbon
  • Y-G bond between Y and an adjacent 5-membered ring carbon atom
  • the antipruritic agent of the present invention is not particularly limited as long as it reduces or eliminates pruritus, and is particularly effective for pruritus due to atopy (antigen-specific immunoreaction via IgE antibody). From this point, the antipruritic agent of the present invention includes a drug for preventing or treating atopic symptoms.
  • the “pruritic condition” refers to a condition having localized or generalized itching and associated inflammation on the skin and mucous membranes. Examples include scabies, juniper measles, eczema, xeroderma (xeroderma senile, sebum deficient eczema, etc.), psoriasis, cutaneous pruritus and prurigo.
  • atopic symptom refers to a symptom having localized or generalized itching caused by atopy and inflammation related thereto on the skin and mucous membranes, that is, a pruritic symptom caused by atopy.
  • atopic symptom refers to a symptom having localized or generalized itching caused by atopy and inflammation related thereto on the skin and mucous membranes, that is, a pruritic symptom caused by atopy.
  • Examples include atopic dermatitis and atopic conjunctivitis.
  • atopic dermatitis refers to a disease in which pruritus eczema is the main lesion that repeats exacerbation and remission, and occurs in individuals with an atopic predisposition (a predisposition to produce IgE antibodies).
  • atopic dermatitis refers to a disease in which pruritus eczema is the main lesion that repeats exacerbation and remission, and occurs in individuals with an atopic predisposition (a predisposition to produce IgE antibodies).
  • the dose of the active ingredient in the antipruritic agent of the present invention can be appropriately increased or decreased according to the patient's body weight, age, sex, etc., but is usually 1 ng to 10 mg per administration, preferably 0.1 to 1.0. It can be administered once to several times a day.
  • the antipruritic agent of the present invention can also be used in combination with an antihistamine (eg, diphenhydramine, carbinoxamine, chlorpheniramine, ranitidine, a salt thereof, etc.) as an active ingredient.
  • an antihistamine eg, diphenhydramine, carbinoxamine, chlorpheniramine, ranitidine, a salt thereof, etc.
  • the antipruritic agent of the present invention can be prepared as a pharmaceutical composition using carriers, excipients, and other additives commonly used in the formulation of the active ingredient.
  • carriers and excipients for pharmaceuticals for example, water, ethanol, lactose, microcrystalline cellulose, liquid paraffin, hydrogenated oil, honey, squalane, stearyl alcohol, ethylene glycol and the like are commonly used. You can give something.
  • additives examples include disintegrants (starch, etc.), binders ⁇ hydroxypropylcellulose, low-substituted hydroxypropylsulose ⁇ , lubricants (talc, glyceryl stearate, etc.), antioxidants, preservatives ( Paraben), Cotin Agents (gelatin, hydroxypropylcellulose, etc.), coloring agents, flavoring agents, whitening agents (sodium ellagate, etc.), surfactants (such as sorbitan fatty acid esters), plasticizers, humectants (glycerin, propylene glycol) , Polyethylene dalicol, haluronic acid, etc.).
  • the antipruritic agent of the present invention is in the form of tablets, granules, powders, capsules, liquids, gels, plasters, ointments, creams, patches, aerosols, etc. (Including eye drops and nasal drops).
  • Preferred dosage forms include external preparations because they can be directly administered to the affected area, are easy to administer, and reduce the possibility of systemic side effects.
  • the "external preparation” includes a liquid preparation for external use, an aerosol, a powder for external use, an ointment, a cream, a gel, a plaster, a patch and the like.
  • drug concentration (%) means w / v%.
  • Magnets are implanted in both feet of a 20-week-old NC / Nga mouse (purchased from SLC) weighing about 30 g and developing atopic dermatitis, and the movement of the feet is sensed by detecting the magnetic force. Manufactured). Of the pulling actions, those with 1.5 seconds or more were regarded as pruritic actions, and the number of times was continuously measured. Because of the diurnal rhythm of pruritus behavior, the daily pruritus rhythm of each animal was measured 24 hours from the day before the test, and then each drug dissolved in 100% ethanol was applied to the back skin at a rate of 0.2 ml / mouse.
  • the pruritic behavior for 24 hours was measured and the number of pruritic behavior before and after drug administration was compared.
  • the pruritus suppression rate was calculated from the total number of pruritus 24 hours before and after drug application, and is shown in Table 5. The significant difference test was performed using a paired t'test for the number of pruritus before and after drug application in each animal of each drug concentration application group.
  • Itching suppression rate (%) (itch number before application / itch number after application) xlOOZ number of itching before application
  • mice After living together for 2 weeks, the purchased mice were removed and reared in separate cages at 8 per cage until the start of the test. Immediately before the start of drug application, the mice were sorted so that the Zhao flame scores of each cage became equal, and the mice were reared at 4 mice per cage.
  • Drug administration Compound 3 (0.01%) and compound 16 (solubilized in 99.5% ethanol, 99.5% ethanol) in the back skin of 20-week-old NC mice that developed skin inflammation by living with NC mice that developed skin inflammation 0.01%) was applied 200 times each once a day for 4 weeks using a micropip. The untreated group received no treatment. Each group was tested with 8 animals per group.

Abstract

L'invention concerne un médicament qui contient, en tant principe actif, un dérivé de prostaglandine de formule (1), un sel pharmaceutiquement acceptable dudit dérivé, ou un hydrate de l'un ou l'autre. Le médicament, dont les effets secondaires sont réduits, présente une action antipruritique. Il peut diminuer efficacement l'effet purigineux accompagnant en particulier le symptôme de la maladie atopique.
PCT/JP2003/014446 2002-11-13 2003-11-13 Medicament antipruritique WO2004043471A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
AU2003301900A AU2003301900A1 (en) 2002-11-13 2003-11-13 Antipruritic drug
JP2004551230A JP4477504B2 (ja) 2002-11-13 2003-11-13 鎮痒剤

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EP0069696A2 (fr) * 1981-07-03 1983-01-12 Schering Aktiengesellschaft Dérivés prostaglandines-9-fluorés, leur préparation et application comme médicament
WO1985000367A1 (fr) * 1983-07-08 1985-01-31 Schering Aktiengesellschaft Derives de 11-halogene-prostane, leur procede de fabrication et leur utilisation comme medicaments
WO1985002841A1 (fr) * 1983-12-22 1985-07-04 Schering Aktiengesellschaft Derives de 9-halogene-delta2-prostaglandine, leur procede de preparation et leur utilisation en tant que medicaments
WO1989000559A1 (fr) * 1987-07-17 1989-01-26 Schering Aktiengesellschaft Berlin Und Bergkamen Derives de 9-halogene-(z)-prostaglandine, leur procede de production et leur utilisation comme medicaments
EP0652211A1 (fr) * 1992-07-24 1995-05-10 Taisho Pharmaceutical Co. Ltd Derive de prostaglandine
EP0666256A1 (fr) * 1992-10-20 1995-08-09 Taisho Pharmaceutical Co. Ltd Derive de prostaglandine
JPH07242622A (ja) * 1994-03-07 1995-09-19 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体およびその使用
JPH07285929A (ja) * 1994-04-19 1995-10-31 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
WO1996016935A1 (fr) * 1994-11-30 1996-06-06 Taisho Pharmaceutical Co., Ltd. Derive de prostaglandines
EP0737676A1 (fr) * 1993-12-29 1996-10-16 Taisho Pharmaceutical Co. Ltd Derive de prostaglandine, son sel et utilisation de ce compose
JPH09286775A (ja) * 1996-04-24 1997-11-04 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
WO1998027971A1 (fr) * 1996-12-23 1998-07-02 Michael Albert Kamm Composition pharmaceutique destinee au traitement de l'incontinence fecale et du prurit anal
EP0860430A2 (fr) * 1997-02-04 1998-08-26 Ono Pharmaceutical Co., Ltd. Dérivés omega-cycloalkyl-prostaglandine E2
US5807892A (en) * 1994-09-30 1998-09-15 Alcon Laboratories, Inc. Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension
WO1999025358A1 (fr) * 1997-11-19 1999-05-27 Allergan Sales, Inc. Derives 2-heteroarylalcenyle de l'acide cyclopentan heptan(en)oique en tant qu'agents therapeutiques
JP2000273083A (ja) * 1999-03-19 2000-10-03 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
EP1082961A1 (fr) * 1998-05-25 2001-03-14 Taisho Pharmaceutical Co., Ltd Agent somnifere
JP2001089443A (ja) * 1999-07-19 2001-04-03 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
JP2001122786A (ja) * 1999-10-20 2001-05-08 Taisho Pharmaceut Co Ltd 睡眠誘発剤
EP1097922A1 (fr) * 1998-07-15 2001-05-09 Ono Pharmaceutical Co., Ltd. Derives de phenyl-postaglandine e 5-thia-omege-substitues, procede de production desdits derives et medicaments contenant lesdits derives en tant que principe actif
JP2001151749A (ja) * 1999-11-24 2001-06-05 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
WO2002016311A1 (fr) * 2000-08-22 2002-02-28 Ono Pharmaceutical Co., Ltd. Derives d'acide carboxylique, procede de production de ceux-ci et medicaments contenant ceux-ci comme principe actif
WO2002020462A1 (fr) * 2000-09-01 2002-03-14 Ono Pharmaceutical Co., Ltd. Derives d'acide benzoique et medicaments possedant ces derniers comme principe actif
EP1211242A1 (fr) * 1999-09-10 2002-06-05 Taisho Pharmaceutical Co., Ltd Derives de prostaglandine
EP1245562A1 (fr) * 2000-01-05 2002-10-02 Ono Pharmaceutical Co., Ltd. ALCOOLS 5-THIA-$g(v)-(PHENYLE SUBSTITUES)- PROSTAGLANDINE E, PROCESSUS DE PREPARATION DE CES ALCOOLS ET PREPARATIONS PHARMACEUTIQUES CONTENANT CES ALCOOLS COMME PRINCIPE ACTIF.
WO2003070252A1 (fr) * 2002-02-22 2003-08-28 Taisho Pharmaceutical Co., Ltd. Agents antiprurigineux
WO2004014930A1 (fr) * 2002-08-09 2004-02-19 Taisho Pharmaceutical Co., Ltd. Processus de production selective d'aryl 5-thio-$g(b)-d-aldohexopyranosides

Patent Citations (28)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0069696A2 (fr) * 1981-07-03 1983-01-12 Schering Aktiengesellschaft Dérivés prostaglandines-9-fluorés, leur préparation et application comme médicament
WO1985000367A1 (fr) * 1983-07-08 1985-01-31 Schering Aktiengesellschaft Derives de 11-halogene-prostane, leur procede de fabrication et leur utilisation comme medicaments
WO1985002841A1 (fr) * 1983-12-22 1985-07-04 Schering Aktiengesellschaft Derives de 9-halogene-delta2-prostaglandine, leur procede de preparation et leur utilisation en tant que medicaments
WO1989000559A1 (fr) * 1987-07-17 1989-01-26 Schering Aktiengesellschaft Berlin Und Bergkamen Derives de 9-halogene-(z)-prostaglandine, leur procede de production et leur utilisation comme medicaments
EP0652211A1 (fr) * 1992-07-24 1995-05-10 Taisho Pharmaceutical Co. Ltd Derive de prostaglandine
EP0666256A1 (fr) * 1992-10-20 1995-08-09 Taisho Pharmaceutical Co. Ltd Derive de prostaglandine
EP0737676A1 (fr) * 1993-12-29 1996-10-16 Taisho Pharmaceutical Co. Ltd Derive de prostaglandine, son sel et utilisation de ce compose
JPH07242622A (ja) * 1994-03-07 1995-09-19 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体およびその使用
JPH07285929A (ja) * 1994-04-19 1995-10-31 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
US5807892A (en) * 1994-09-30 1998-09-15 Alcon Laboratories, Inc. Use of certain prostaglandin analogues to treat glaucoma and ocular hypertension
WO1996016935A1 (fr) * 1994-11-30 1996-06-06 Taisho Pharmaceutical Co., Ltd. Derive de prostaglandines
JPH09286775A (ja) * 1996-04-24 1997-11-04 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
WO1998027971A1 (fr) * 1996-12-23 1998-07-02 Michael Albert Kamm Composition pharmaceutique destinee au traitement de l'incontinence fecale et du prurit anal
EP0860430A2 (fr) * 1997-02-04 1998-08-26 Ono Pharmaceutical Co., Ltd. Dérivés omega-cycloalkyl-prostaglandine E2
WO1999025358A1 (fr) * 1997-11-19 1999-05-27 Allergan Sales, Inc. Derives 2-heteroarylalcenyle de l'acide cyclopentan heptan(en)oique en tant qu'agents therapeutiques
EP1082961A1 (fr) * 1998-05-25 2001-03-14 Taisho Pharmaceutical Co., Ltd Agent somnifere
EP1083168A1 (fr) * 1998-05-25 2001-03-14 Taisho Pharmaceutical Co., Ltd Derive de prostaglandine
EP1097922A1 (fr) * 1998-07-15 2001-05-09 Ono Pharmaceutical Co., Ltd. Derives de phenyl-postaglandine e 5-thia-omege-substitues, procede de production desdits derives et medicaments contenant lesdits derives en tant que principe actif
JP2000273083A (ja) * 1999-03-19 2000-10-03 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
JP2001089443A (ja) * 1999-07-19 2001-04-03 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
EP1211242A1 (fr) * 1999-09-10 2002-06-05 Taisho Pharmaceutical Co., Ltd Derives de prostaglandine
JP2001122786A (ja) * 1999-10-20 2001-05-08 Taisho Pharmaceut Co Ltd 睡眠誘発剤
JP2001151749A (ja) * 1999-11-24 2001-06-05 Taisho Pharmaceut Co Ltd プロスタグランジン誘導体
EP1245562A1 (fr) * 2000-01-05 2002-10-02 Ono Pharmaceutical Co., Ltd. ALCOOLS 5-THIA-$g(v)-(PHENYLE SUBSTITUES)- PROSTAGLANDINE E, PROCESSUS DE PREPARATION DE CES ALCOOLS ET PREPARATIONS PHARMACEUTIQUES CONTENANT CES ALCOOLS COMME PRINCIPE ACTIF.
WO2002016311A1 (fr) * 2000-08-22 2002-02-28 Ono Pharmaceutical Co., Ltd. Derives d'acide carboxylique, procede de production de ceux-ci et medicaments contenant ceux-ci comme principe actif
WO2002020462A1 (fr) * 2000-09-01 2002-03-14 Ono Pharmaceutical Co., Ltd. Derives d'acide benzoique et medicaments possedant ces derniers comme principe actif
WO2003070252A1 (fr) * 2002-02-22 2003-08-28 Taisho Pharmaceutical Co., Ltd. Agents antiprurigineux
WO2004014930A1 (fr) * 2002-08-09 2004-02-19 Taisho Pharmaceutical Co., Ltd. Processus de production selective d'aryl 5-thio-$g(b)-d-aldohexopyranosides

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