WO1997044031A1 - Agent de traitement de l'eczema allergique - Google Patents

Agent de traitement de l'eczema allergique Download PDF

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Publication number
WO1997044031A1
WO1997044031A1 PCT/JP1997/001687 JP9701687W WO9744031A1 WO 1997044031 A1 WO1997044031 A1 WO 1997044031A1 JP 9701687 W JP9701687 W JP 9701687W WO 9744031 A1 WO9744031 A1 WO 9744031A1
Authority
WO
WIPO (PCT)
Prior art keywords
dermatitis
formula
compound
pharmaceutically acceptable
acceptable salt
Prior art date
Application number
PCT/JP1997/001687
Other languages
English (en)
Japanese (ja)
Inventor
Shuzo Sawada
Takashi Hironaka
Hiroichi Nagai
Original Assignee
Bayer Yakuhin, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Yakuhin, Ltd. filed Critical Bayer Yakuhin, Ltd.
Priority to AU27906/97A priority Critical patent/AU2790697A/en
Publication of WO1997044031A1 publication Critical patent/WO1997044031A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system

Definitions

  • the present invention uses the formula
  • the present invention relates to a therapeutic agent for dermatitis via delayed allergic reaction, particularly for allergic contact dermatitis or atopic dermatitis.
  • R 1 represents hydrogen, halogen or C, -C 4 -alkyl;
  • R 2 is halogen, trifluoromethyl, trifluoromethoxy or (, ⁇ (: mono- or disubstituted by 4 -alkyl) Fe that may be X represents 1 or 2, y represents 0 or 1, and cycloalkano [1,2-b] indolesulfonamide or a salt thereof inhibits platelet aggregation.
  • Tron Bokisan a 2 ⁇ shows the effect, thrombosis, thromboembolism, treatment of ischemia, or anti-asthmatic agents, and are useful as anti- ⁇ les Energy agent This is known (see Japanese Patent Publication No. 4-50301).
  • (3R) 3— (4-fluorophenylsulfonamide) -1,1,2,3,4-tetrahydro-1-9-potassium rubazolepropionic acid of the formula (I) [general name: Ramatroban ); Development number: BAY u 3405] binds to the TXA 2 receptor in bronchial smooth muscle and is a mimetics of TXA 2 U—46619 (9,11-one methanoepoxy—prostag 1 andin H 2 ) or prostaglandin Has been reported to inhibit the contraction of human and guinea pig bronchial muscles induced by carcinoma D2 [Br. J. Pharmacol., 104, 1991, pp. 585-590 and Pp.
  • TX A 2 is a substance released from etc. results mast cells or inflammatory cells are considered to be important.
  • the present inventors have been conventionally Taukaiarufa 2 competitive inhibitor, therefore, the formula for the ⁇ Les Energy dermatitis was thought to have no effect I spoon compound of (I) (ramatroban) However, surprisingly, they have found that they are also effective against allergic skin inflammation, especially skin inflammation via delayed allergic reaction, and have completed the present invention.
  • the compound of the formula (I) is a compound known per se, and can be produced, for example, by the method described in Japanese Patent Publication No. 50301/1992. Wear.
  • the compounds of the formula (I) have one asymmetric carbon atom and can be present in the form of the R-form, the S-form or a mixture thereof (racemic), in particular the R-form It is suitable.
  • the pharmaceutically acceptable salt of the compound of the formula (1) includes, for example, sodium salt, potassium salt, magnesium salt, alkali metal salt such as calcium salt, and alkaline earth metal salt.
  • Ammonium salts salts with organic amines such as ethylamine, di or triethylamine, di or triethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine, ethylenediamine and the like.
  • the compound of the formula (I) or a salt thereof is an agent for treating or preventing dermatitis via delayed (or type IV) allergic reaction, in particular, allergic contact dermatitis or atopic dermatitis.
  • Administration can be oral, parenteral, or topical, and the dosage is not particularly limited, and depends on the severity of the symptoms, age, weight, route of administration, sex, doctor's judgment, etc. It can vary over a wide range, but for adults, usually 0.1 to 10 mg Zkg gZ, preferably 0.5 to 7.SmgZkgZ, more preferably l Smg / kgZ one or more times It is convenient to administer in divided doses.
  • the compound of the formula (I) or a salt thereof may be administered depending on the administration route, for example, oral preparations such as fine granules, granules, capsules, tablets, liquids, syrups, etc .; injections, infusions Parenteral preparations such as suppositories, etc .: Can be formulated into topical (transdermal or transmucosal) preparations such as plasters, creams, cataplasms, sprays, etc. Formulation of the compound of the formula (I) or a salt thereof can be carried out by formulating the compound of the formula (I) or a salt thereof together with additives according to a conventional method.
  • Additives that can be used in the preparation of oral dosage forms include, for example, starches such as corn starch and potato starch, sugars such as lactose, sucrose, glucose, mannitol, inorganic salts such as calcium carbonate, and synthetic aluminum aluminum.
  • Paraffin, wax, oils and fats such as higher fatty acids, and excipients such as cellulosics
  • starches such as corn starch and potato starch
  • sugars such as lactose, sucrose, glucose, mannitol, dextrin, and arabic
  • Natural substances such as rubber, tragacanth, carrageenin, sodium alginate, and gelatin
  • cellulose derivatives such as methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxyquinpropylmethylcellulose, and carboxymethylcellulose sodium
  • Binders such as synthetic polymers such as lenglycol, polyvinylpyrrolidone, and polyvinyl alcohol: disintegrants such as starches, low-substituted hydroxypropylcellulose, and crystalline cellulose; magnesium stearate, talc, synthetic gay Lubricants such as aluminum phosphate;
  • Coloring agents such as various edible pigments; various natural and artificial sweeteners; acidulants such as organic acids; flavoring and flavoring agents such as heart oil; solubilizing agents such as various surfactants; benzoic acid esters, etc. And stabilizers (in the case of liquids).
  • Water is preferably used as a solvent when preparing a liquid or injection, and if necessary, a buffer adjusted to an appropriate pH can be used.
  • various amino acids, sugars, and salts can be used.
  • Etc. and solubilizing agents such as alcohols, polyethylene glycol, sodium lauryl sulfate, polysorbate, etc. Can be blended.
  • the base may be an emulsion or water-soluble base such as hydrophilic ointment, water-absorbing ointment, lanolin hydrolyzate, hydrophilic cerin, lanolin, polyethylene glycol, etc.
  • Oleaginous base such as petrolatum, vaseline, paraffin, simple ointment, white ointment, etc .; preservatives such as paraoxybenzoic acid esters; humectants such as glycerin, propylene glycol, and polyethylene glycol
  • a surfactant and the like can be blended.
  • a poultice prepared by supporting a compound of the formula (I) or a salt thereof on a film made of various materials can be suitably used.
  • Test Example 1 Inhibitory effect on experimental contact skin I »inflammation in mice
  • Ramatroban was orally administered to mice using prednisolone, sera trodust, and domitroban as control drugs, and the effect on experimental contact dermatitis was examined.
  • Ramatroban, control prednisolone, seratrodast (AA-2414) and domitroban (S-1452) were all used in a 0.5% aqueous solution of methylcellulose (MC).
  • Antigens include picryl chloride (Katayama Chemical Co., Ltd.) in ethanol and olive oil. Was used.
  • test drug was orally administered at a volume of 1 Om1Zkg.
  • the mice were fasted for at least 18 hours before the administration of the test drug.
  • thromboxane A 2 receptor antagonist is a shall be suggested to exhibit a common effect on the inhibition of skin «flame through the delayed allele formic first reaction.
  • test drug was topically applied (ear drops) twice, 1 hour before and 3 hours after the reaction.
  • Ramatroban was orally administered to mice using prednisolone and ketotiphan as control drugs, and the effect on delayed foot reaction was examined.
  • Ramatroban, prednisolone (Wako Pure Chemical Industries, Ltd.), and ketotiphan (Sigraa) are all suspended in 0.5% methylcellulose (MC) aqueous solution.
  • the antigen used was a suspension of sheep erythrocytes (abbreviated as SRBC, Denka Seiken Co., Ltd.) washed with physiological saline three times and then suspended in physiological saline. .
  • the thickness of the right and left hind legs was measured using a thickness gauge (Ozaki Seisakusho), and the difference between the right and left was defined as swelling of the legs.
  • Each dose of the test drug was orally administered at a dose of 10 ml / Zkg, 1 hour before and 16 hours after the induction of the reaction.
  • Test example 4 Inhibitory effect on mouse delayed-type foot ⁇ response
  • Ramatroban was orally administered to mice using blednisolone as a control drug, and the effect on delayed foot response was examined.
  • Ramatroban used was suspended in a 0.5% sodium carboxymethylcellulose (CMC-Na) aqueous solution.
  • CMC-Na sodium carboxymethylcellulose
  • an aqueous suspension of prednisolone (acetate) (Takeda Pharmaceutical Co., Ltd.) was used.
  • the antigen used was one obtained by washing shed red blood cells (hereinafter, abbreviated as SRBC, oriental serum) and then diluting with Hanks' solution. [experimental method]
  • mice were sensitized by subcutaneously injecting SRBC 2.5 ⁇ 10 8 cells / ml 40 ⁇ 1 into the left hind leg. After the 5th, SRBC (2.5 x 1 0 9 cells / ml 40 ⁇ 1) were injected to elicit the response. Twenty-four hours later, hind limb volume was measured with a plethysmometer (UNICOM), and the difference between the left and right hind limb volumes was defined as edema.
  • SRBC 2.5 x 1 0 9 cells / ml 40 ⁇ 1
  • Each dose of the test drug was orally administered at a dose of 10 m1 Zkg, 2 times before and 16 hours after the induction of the reaction.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pulmonology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Indole Compounds (AREA)

Abstract

Un agent de traitement de l'eczéma par une réaction allergique de type retardée comprend de l'acide 3-(4-fluorophénylsulfonamido)-1,2,3,4-tétrahydro-9-carbazolepropionique représenté par la formule (I) ou un sel pharmaceutiquement acceptable de celui-ci en tant que principe actif. Cet agent est utile pour guérir ou prévenir l'eczéma allergique tel que l'eczéma de contact allergique ou l'eczéma constitutionnel.
PCT/JP1997/001687 1996-05-21 1997-05-20 Agent de traitement de l'eczema allergique WO1997044031A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU27906/97A AU2790697A (en) 1996-05-21 1997-05-20 Agent for treating allergic dermatitis

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/148475 1996-05-21
JP14847596A JP2002241282A (ja) 1996-05-21 1996-05-21 アレルギー性皮膚炎の処置剤

Publications (1)

Publication Number Publication Date
WO1997044031A1 true WO1997044031A1 (fr) 1997-11-27

Family

ID=15453590

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1997/001687 WO1997044031A1 (fr) 1996-05-21 1997-05-20 Agent de traitement de l'eczema allergique

Country Status (3)

Country Link
JP (1) JP2002241282A (fr)
AU (1) AU2790697A (fr)
WO (1) WO1997044031A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506789B2 (en) 1998-06-03 2003-01-14 Shionogi & Co., Ltd. Methods for the treatment of itching comprising administering PGD2 receptor antagonist
WO2003097042A1 (fr) * 2002-05-16 2003-11-27 Shionogi & Co., Ltd. Antagoniste de recepteur de pdg2
WO2004006956A1 (fr) * 2002-07-12 2004-01-22 Japan Science And Technology Agency Medicaments ameliorant le pronostic de trouble cerebral et procede de criblage associe
US7534897B2 (en) 2002-05-16 2009-05-19 Shionogi & Co., Ltd. Indole arylsulfonaimide compounds exhibiting PGD 2 receptor antagonism

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003236156A1 (en) * 2003-04-24 2005-01-04 Shin-Jen Shiao Pharmaceutical compositions used for immune disease treatment and improvement

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0826990A (ja) * 1990-03-19 1996-01-30 E R Squibb & Sons Inc 潰瘍および／または炎症の予防および／または治療用組成物
WO1996017606A1 (fr) * 1994-12-07 1996-06-13 Bristol-Myers Squibb Company Utilisation de modulateurs de l'inflammation dans le traitement de lesions chroniques ou recalcitrantes de la peau
JPH08175991A (ja) * 1994-12-26 1996-07-09 Bayer Yakuhin Kk アレルギー性皮膚炎の処置剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0826990A (ja) * 1990-03-19 1996-01-30 E R Squibb & Sons Inc 潰瘍および／または炎症の予防および／または治療用組成物
WO1996017606A1 (fr) * 1994-12-07 1996-06-13 Bristol-Myers Squibb Company Utilisation de modulateurs de l'inflammation dans le traitement de lesions chroniques ou recalcitrantes de la peau
JPH08175991A (ja) * 1994-12-26 1996-07-09 Bayer Yakuhin Kk アレルギー性皮膚炎の処置剤

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
PROSTAGLANDINS, 50(2), (1995), p. 75-87. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6506789B2 (en) 1998-06-03 2003-01-14 Shionogi & Co., Ltd. Methods for the treatment of itching comprising administering PGD2 receptor antagonist
WO2003097042A1 (fr) * 2002-05-16 2003-11-27 Shionogi & Co., Ltd. Antagoniste de recepteur de pdg2
US7534897B2 (en) 2002-05-16 2009-05-19 Shionogi & Co., Ltd. Indole arylsulfonaimide compounds exhibiting PGD 2 receptor antagonism
EP2423190A1 (fr) 2002-05-16 2012-02-29 Shionogi&Co., Ltd. Composés présentant un antagonisme du récepteur PGD 2
WO2004006956A1 (fr) * 2002-07-12 2004-01-22 Japan Science And Technology Agency Medicaments ameliorant le pronostic de trouble cerebral et procede de criblage associe

Also Published As

Publication number Publication date
AU2790697A (en) 1997-12-09
JP2002241282A (ja) 2002-08-28

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