WO1994014444A1 - Psoriasis remedy - Google Patents

Psoriasis remedy Download PDF

Info

Publication number
WO1994014444A1
WO1994014444A1 PCT/JP1993/001871 JP9301871W WO9414444A1 WO 1994014444 A1 WO1994014444 A1 WO 1994014444A1 JP 9301871 W JP9301871 W JP 9301871W WO 9414444 A1 WO9414444 A1 WO 9414444A1
Authority
WO
WIPO (PCT)
Prior art keywords
psoriasis
salt
composition
acid
derivative
Prior art date
Application number
PCT/JP1993/001871
Other languages
English (en)
French (fr)
Japanese (ja)
Inventor
Ichirou Kurokawa
Toshiki Kitazawa
Yoshio Kawamura
Original Assignee
Otsuka Pharmaceutical Co., 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 Otsuka Pharmaceutical Co., Ltd. filed Critical Otsuka Pharmaceutical Co., Ltd.
Priority to AU57159/94A priority Critical patent/AU5715994A/en
Publication of WO1994014444A1 publication Critical patent/WO1994014444A1/ja

Links

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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • the present invention relates to a therapeutic agent for psoriasis, and more specifically, a compound of the general formula (1)
  • ⁇ represents a lower alkylene group
  • R represents a cycloalkyl group.
  • the bond between the 3- and 4-positions of the carbostyryl skeleton is a single bond or a double bond.
  • the present invention relates to a composition for treating psoriasis, comprising an auxiliary agent, and a method for treating psoriasis using the composition.
  • the carbostyryl derivative represented by the above general formula (1) and a method for producing the same are described in JP-B-63-200235. It is also known that they are used for r as a platelet aggregation inhibitor.
  • Psoriasis is thought to be affected by a variety of factors such as the environment, in addition to transmission factors. Therefore, steroid drugs, non-steroid anti-inflammatory drugs, A variety of drugs such as vitamins have been tried and some effects have been observed, or the effects are still inadequate or satisfied with the question of collaborative work ffl. There is no current situation. For example, steroid II is used topically or orally, but there are problems with long-term use in terms of side effects, and oral administration of vitamin A acid is teratogenic in pregnant women. Due to this problem, side effects such as pathological fractures occur in children. It has also been reported that papaverine, which is known as a phosphodiesterase inhibitor, also has psoriasis treatment effects (J. Invest.
  • Dermatol. 64; 124-127) , 197 2 has both effects and side effects and has not been put to practical use at present.
  • a variety of other drugs known as phosphodiesterase inhibitors have been reported in addition to papaverine.However, their effects on phosphodiesterase inhibition and psoriasis are not always confirmed. It is not considered to have the same mechanism of action, and none has yet been put to practical use because of its inadequate efficacy as a treatment for psoriasis. Therefore, there is a demand for the development of even better psoriasis treatment agents.
  • the present inventors have conducted various studies and found that the above-mentioned general formula
  • the carbostyryl derivative represented by (1), above all, 6- [4 (1—cyclohexinole-1,2,3,4—tetrazoru 5—Ilkub Tokishi] 1-3,4-Dihydrohydrostyryl or a salt thereof shows an excellent inhibitory action on psoriasis and is found to be useful as a therapeutic agent for psoriasis That is, the present invention provides a compound of the present invention, which is a compound represented by the above general formula (1), particularly, 6- [4— (1-cyclohexyl).
  • FIG. 1 is a graph showing the effect of the compound of the present invention on pinna edema, particularly on the pinna thickness.
  • FIG. 2 is a graph showing the effect of the compound of the present invention on pinna edema, particularly on the pinna epidermis thickness.
  • FIG. 3 is a graph showing the effect of the compound of the present invention on epidermal cell proliferation.
  • a carbostyril derivative represented by the formula (wherein A and R are as defined above) as a psoriasis therapeutic agent
  • a composition for treating psoriasis comprising the derivative as an active ingredient
  • the lower alkylene group of ⁇ in the formula methylene ethylene, trimethylene, tetramethylene, pentamethylene Alkylene groups having 1 to 6 carbon atoms, such as dimethylene, hexamethylene, and 2—methyltrimethylene; and tetramethylene is particularly preferred.
  • the cyclic alkyl group for R in the formula includes cyclopropyl, cyclopentyl, cyclopentino, cyclohexyl, Cycloalkyl groups having 3 to 8 carbon atoms, such as cycloheptyl and cyclooctyl, are exposed, and cyclohexyl is particularly preferred.
  • A is tetramethylene and R is cycloalkylalkyl.
  • 6 [4— (1—1 mouth opening——1,2 , 3,4-Tetrasol-1-5-yl) butoxy] —3,4—Dihydrocarbostyrinole or a salt thereof is particularly preferably used.
  • the therapeutic agent for psoriasis of the present invention is prepared by preparing a carbostyril derivative represented by the general formula (1) or a salt thereof in the form of a general pharmaceutical preparation. Such formulations are prepared with commonly used diluents or excipients, such as fillers, extenders, binders, humectants, disintegrants, surfactants, lubricants and the like.
  • this pharmaceutical preparation can be selected according to the purpose of treatment, and typical examples are tablets, pills, powders, liquids, suspensions, emulsions, and granules. Preparations, capsules, suppositories, injections (solutions, suspensions, etc.), sprays such as inhalants, external aerosols, and liquid coatings and lotions. And external preparations such as linen preparations, ointments, creams, pulp and the like.
  • those widely known in the field can be widely used as carriers, such as lactose, sucrose, sodium chloride, glucose, urea, and the like.
  • Starch, calcium carbonate, kaolin, crystalline cellulose, forms such as gay acid, water, ethanol, propanol, single syrup, Dextrose solution, starch solution, gelatin solution, carboxyl methylcellulose, ceramics, methinoresoranolose, phosphoric acid lithium, polish Binders such as vinyl pyrrolidone, dried starch, sodium alginate, cadmium powder, lamina lan powder, sodium bicarbonate , Calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium raurylsulfate Disintegrators such as um, stearic acid monoglyceride, starch, lactose, sucrose, stearin, cocoa butter, water Disintegration inhibitors such as oils with added oils, quaternary ammonium bases, absorption promoters such as sodium peryl
  • those conventionally known in this field can be widely used as a carrier, such as glucose, lactose, starch, and cocoa butter.
  • Excipients such as hardened vegetable oils, kaolin, silver, etc., binders such as arabia rubber powder, tragacanth powder, gelatin, ethanol, lamina And disintegrants such as cadmium.
  • suppositories a wide variety of conventionally known products can be used, for example, polyethylene glycol, cocoa butter, high-grade ⁇ . Examples include alcohol, high alcohol alcohol esters, gelatin, and semi-synthetic glyceride.
  • a solution, emulsion or suspension When prepared as an injection, it is preferably prepared in the form of a solution, emulsion or suspension, usually sterilized and made isotonic with blood.
  • any of the diluents commonly used in this field can be used, such as water, Ethyl alcohol, propylene glycol / ETOKIN ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • Examples include fatty acid esters.
  • a sufficient amount of salt, glucose or glycerin should be contained to prepare an isotonic solution.
  • a propellant a wide variety of dispersants and propellants known in the art can be used, and examples of the dispersant include soy lecithin. , Lecithins such as egg yolk lecithin, fatty acids such as oleic acid, linoleic acid, linolenic acid, sorbitan trioleate, sozolebitan monono Solving evenings such as foliage can be exemplified.
  • the propellant include ordinary non-combustible liquefied gas such as Freon 11, Freon 12 and Freon 114.
  • a softener In the form of a softener, it may be mixed with a known lipophilic base.
  • lipophilic base used in such an ointment examples include the following lipophilic bases.
  • -Ruester higher fatty acids such as rauric acid, myristic acid, lumitic acid, stearic acid, oleic acid, etc .
  • Row, Millo, Perrow Polyethylene glycol ester, ethylene glycol ester, Glycerin monoester Sonorbitol ester, Solvitan ester, Isopropyl mirristate, Isopropyl palpalmitit, Isopropyl zipper Esters such as it; Armone oil, corn oil, cottonseed oil, olive oil, soybean oil, peanut oil, pear oil, fractionated oil Vegetable oils such as oil and sesame oil are available.
  • one of these substrates may be used alone, or two or more thereof may be used in combination.
  • composition of the present invention may contain conventional additives such as metal stones.
  • Carbostyril to be contained in the therapeutic agent for psoriasis of the present invention The amount of the derivative (I) or its salt is not particularly limited and may be selected in a wide range, but is usually 0.01 to 70% by weight, preferably 1 to 5% by weight in the total composition. 0% by weight.
  • the administration method of the therapeutic agent for psoriasis of the present invention is not particularly limited, and is administered by a method according to various preparation forms, age of the patient, gender and other conditions, degree of disease, and the like.
  • tablets, pills, solutions, suspensions, emulsions, granules and capsules are orally administered.
  • they are administered intravenously either alone or as a mixture with normal replacement fluids such as glucose and amino acid, and if necessary intramuscularly or intradermally alone. It is administered subcutaneously or intraperitoneally.
  • Suppositories are administered rectally.
  • the spray is administered by spraying into the oral cavity or the nasal cavity.
  • the dosage of the therapeutic agent for psoriasis of the present invention is appropriately selected depending on the usage, age of the patient, gender and other conditions, and the degree of the disease. Usually, however, the carbostyryl derivative (I) or its derivative is used.
  • the amount of salt is preferably 0.6 to 5 Omg per 1 kg of body weight, and the dosage unit form should contain 100 to 100 mg of the active ingredient. Good.
  • the amount of the carbostyryl derivative (I) of the present invention or a salt thereof is not particularly limited, but is usually about 0.001 to 10% by weight. It is about 0.1 to 2% by weight.
  • the therapeutic agent for psoriasis of the present invention When used in a topical form, it is applied once or more times a day in an amount sufficient to spread over the entire affected area. It can be applied by spraying or applying to the affected area.
  • composition of the present invention has a remarkable effect when taken orally or intravenously, particularly when taken orally.
  • Active compounds of the present invention citric acid, ratatoose, dicanole phosphate, punorelonic F-68 and sodium lauryl sulphate Mix.
  • the above mixture is screened with a No. 600 screen, containing polyvinyl alcohol, carboxes 150,000 and 600,000. Wet granulation with a alcoholic solution. If necessary, add alcohol to make the paste into a paste-like mass. Add cone start and continue mixing until uniform particles are formed. Pass through a N.10 screen and dry in a tray at 100 ° C open for 12 to 14 hours. The dried particles are screened with N 0.16 screen, dried sodium lauryl sulfate and dried magnesium stearate are added and mixed, and then a tableting machine is used. Compress to desired shape.
  • Treat the above core with a crocodile spray the talc to prevent moisture absorption.
  • An undercoat layer is applied around the core. Apply enough varnish coating for internal use.
  • an undercoat layer and a flat luster S are applied. Color coating is performed until the desired color is obtained. After drying, the coated tablet ⁇ is polished to obtain a tablet with uniform gloss.
  • the ointment used for external use is manufactured according to the following formula. 6 — [4 — (1-Cyclohexyl
  • TPA Tetradecanol-Holvo-Norre 13 — Acetate
  • Derma— tology, vol. 1, pp. 51-58, Karger. Base 1.1985) TAP (acetonate solution) 4 on the pinna of a 7-week-old ICR mouse. ⁇ g Z ear was applied, and 30 minutes after that, 0.2 mg / ear of silose evening zone (aceton solution) was applied.
  • Betamethasone antagonist (steroid) was used as a positive control. From 4 hours to 24 hours after the administration of TPA, the thickness of the pinna was measured over time using a dialness gauge. Four days after the application of TPA, the pinna was removed, fixed with formalin, a histopathological specimen was prepared (HE staining), and the thickness of the epidermis was measured on the specimen.
  • Fig. 1 shows the effect of silos-sol on the pinna thickness
  • Fig. 2 shows the effect on the epidermal thickness.
  • Fig. 1 shows the average value of the six repetitions, but the standard error of each repetition is also shown according to the average value.
  • Fig. 2 the average value of 6 repetitions is shown, but the standard error is also shown.
  • Betamethazolone bellflower acid significantly (p ⁇ 0.05) suppressed edema at all times.
  • silosol sol increased epidermal thickening by about 45 % Suppressed.
  • microscopic examination showed that neutrophil infiltration into the dermis was significantly suppressed in the silose evening group-administered group compared to the control group.
  • silosyl sol was added to adjust the concentration to 1 to 10 M.
  • 2 X 1 0 _ 7 M Lee emission scan Li down, 0 5 ⁇ g Roh m 1 arsenide mud co over switch zone down, 1 0 -. 4 M ethanolate Rua Mi was added.
  • BHE hypothalamus extract
  • the patient was a 72-year-old man who complained of pruritic eruption of the whole body.She had seen exfoliative eruption on the whole body several decades ago and had been using topical steroids. In addition, erythema with exfoliation was clearly defined on the lower leg. Three months after the patient received 100 mg / day of Silos evening Zole preparation After that, the rash almost disappeared.
  • the patient was a 53-year-old woman who complained of pruritic eruption of the head.She had a scalp rash on her scalp about 5 years ago, and had been using steroids for external use. As a result, erythema efflorescence was found on the scalp. When the patient was given Silox Evenzol for 100 mg Z days, the rash regressed two months later.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
PCT/JP1993/001871 1992-12-24 1993-12-24 Psoriasis remedy WO1994014444A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU57159/94A AU5715994A (en) 1992-12-24 1993-12-24 Psoriasis remedy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4/343986 1992-12-24
JP34398692 1992-12-24

Publications (1)

Publication Number Publication Date
WO1994014444A1 true WO1994014444A1 (en) 1994-07-07

Family

ID=18365769

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1993/001871 WO1994014444A1 (en) 1992-12-24 1993-12-24 Psoriasis remedy

Country Status (3)

Country Link
AU (1) AU5715994A (enrdf_load_stackoverflow)
TW (1) TW235241B (enrdf_load_stackoverflow)
WO (1) WO1994014444A1 (enrdf_load_stackoverflow)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011026A1 (en) * 1993-10-21 1995-04-27 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative for inhibiting production of interleukin-8
WO1996021448A1 (en) * 1995-01-10 1996-07-18 Otsuka Pharmaceutical Co., Ltd. Resin particle, medical material and pharmaceutical preparation containing said resin particle
WO1996041878A1 (en) * 1995-06-13 1996-12-27 The Australian National University Nucleic acid molecule and its uses in determining pathogenicity of staphylococcus
WO2004075897A1 (en) * 2003-02-25 2004-09-10 Otsuka Pharmaceutical Co., Ltd. Pten inhibitor or maxi-k channels opener

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5645414A (en) * 1979-09-19 1981-04-25 Otsuka Pharmaceut Co Ltd Phosphodiesterase inhibitor
JPS5649378A (en) * 1979-08-25 1981-05-02 Otsuka Pharmaceut Co Ltd Tetrazolylalkoxycarbostyril derivative

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5649378A (en) * 1979-08-25 1981-05-02 Otsuka Pharmaceut Co Ltd Tetrazolylalkoxycarbostyril derivative
JPS5645414A (en) * 1979-09-19 1981-04-25 Otsuka Pharmaceut Co Ltd Phosphodiesterase inhibitor

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995011026A1 (en) * 1993-10-21 1995-04-27 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative for inhibiting production of interleukin-8
US5637597A (en) * 1993-10-21 1997-06-10 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives for inhibiting production of interleukin-8
WO1996021448A1 (en) * 1995-01-10 1996-07-18 Otsuka Pharmaceutical Co., Ltd. Resin particle, medical material and pharmaceutical preparation containing said resin particle
WO1996041878A1 (en) * 1995-06-13 1996-12-27 The Australian National University Nucleic acid molecule and its uses in determining pathogenicity of staphylococcus
WO2004075897A1 (en) * 2003-02-25 2004-09-10 Otsuka Pharmaceutical Co., Ltd. Pten inhibitor or maxi-k channels opener
AU2004216340B2 (en) * 2003-02-25 2008-07-31 Otsuka Pharmaceutical Co., Ltd. PTEN inhibitor or Maxi-K channels opener
AU2004216340B9 (en) * 2003-02-25 2008-09-18 Otsuka Pharmaceutical Co., Ltd. PTEN inhibitor or Maxi-K channels opener
US8329731B2 (en) 2003-02-25 2012-12-11 Otsuka Pharmaceutical Co., Ltd. PTEN inhibitor or Maxi-K channels opener
US8653104B2 (en) 2003-02-25 2014-02-18 Otsuka Pharmaceutical Co., Ltd. PTEN inhibitor or Maxi-K channels opener
CN101829116B (zh) * 2003-02-25 2015-11-25 大塚制药株式会社 Pten抑制剂或maxi-k通道开放剂

Also Published As

Publication number Publication date
AU5715994A (en) 1994-07-19
TW235241B (enrdf_load_stackoverflow) 1994-12-01

Similar Documents

Publication Publication Date Title
CN102123707A (zh) 用于经皮介入心导管插入术的达比加群
JPH11508233A (ja) 癌治療薬の製造のための１，２，４−トリアゾール誘導体の使用
CN103833713B (zh) 硝克柳胺化合物晶iii型、其制法和其药物组合物与用途
EP0277352B1 (de) Synergistische Kombination von Azelastin und Theophyllin oder Azelastin und Beta-Mimetika
JP3098544B2 (ja) サイトカイン活性増強剤およびサイトカインの働きが低下した疾病の治療剤
WO1994014444A1 (en) Psoriasis remedy
JPH1067656A (ja) 細胞接着抑制剤
WO1986005395A1 (en) Composition for treating skin disease
WO2015051763A1 (zh) 一种含埃克替尼的皮肤外用药物组合物及其应用
DE69419954T2 (de) Arzneimittel zur Behandlung von Hauterkrankungen
EP0471388B1 (de) Mittel zur Behandlung der Herzinsuffizienz
JP2003531113A (ja) 皮脂腺障害のためのコレステロールエステルとワックスエステルの合成の二重阻害剤
AU705751B2 (en) An agent for inhibiting carcinogenesis
KR100192534B1 (ko) 소마토스타틴 분비증가제와 분비저하 억제제
JP3583158B2 (ja) 化粧料
JP5438239B1 (ja) シコニン誘導体を有するペリオスチンの発現抑制剤
CN104271140B (zh) I型和ii型糖尿病的治疗
JPH06239745A (ja) 乾癬治療剤
JPH0374329A (ja) 胃炎治療剤
JPS6293230A (ja) 組合せ製剤
JPH05503510A (ja) 光学的に純粋な（ｓ）―アテノロールを含む組成物と方法
JPH03287537A (ja) 抗動脈硬化症剤
JP3401476B2 (ja) 化粧料
JP2702284B2 (ja) ソマトスタチン増加用またはソマトスタチン低下抑制用薬剤
JPS6013713A (ja) 抗腫瘍作用剤

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA