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.

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Citations (2)

• 1993
  • 1993-12-24 AU AU57159/94A patent/AU5715994A/en not_active Abandoned
  • 1993-12-24 WO PCT/JP1993/001871 patent/WO1994014444A1/ja not_active Ceased
  • 1993-12-29 TW TW82111135A patent/TW235241B/zh active

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