WO2006082834A1 - ケラチノサイト増殖に起因する疾患の予防・治療剤 - Google Patents
ケラチノサイト増殖に起因する疾患の予防・治療剤 Download PDFInfo
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- WO2006082834A1 WO2006082834A1 PCT/JP2006/301636 JP2006301636W WO2006082834A1 WO 2006082834 A1 WO2006082834 A1 WO 2006082834A1 JP 2006301636 W JP2006301636 W JP 2006301636W WO 2006082834 A1 WO2006082834 A1 WO 2006082834A1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- 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
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- 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
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
Definitions
- the present invention relates to a prophylactic 'therapeutic agent and prophylactic' therapeutic method for diseases caused by keratinocyte proliferation, such as psoriasis.
- Psoriasis is a skin disease that is included in the field of inflammatory keratosis, and a reddish rash (erythema) is attached to scales like dandruff that are silver-white and forcefully peeled off. It is a non-infectious disease that is manifested by excessive keratinocyte growth, accumulation of inflammatory cells, and excessive angiogenesis in the stratum corneum. Psoriasis is clinically classified into psoriasis vulgaris, erythrodermic psoriasis, psoriatic arthritis, psoriasis psoriatic, and pustular psoriasis. The cause of the onset remains unknown.
- Changes in the metabolism of keratinocytes are considered to be the most important in the induction of disease. It is also considered as a disease affected by multiple factors such as genetic factors and environmental factors. The underlying treatment of this disease is lacking, so the aim of treatment is to extend the period of relief of symptoms.
- Non-Patent Documents 1 to 3 Therapeutic agents currently used in clinical settings include steroids, etretinate, vitamins such as retinoids and Bonalpha, and immunosuppressants such as methotrexate and cyclosporine, but the effect is insufficient.
- steroids are known to have effects, but have side effects such as skin atrophy and capillary vasodilation.
- retinoid vitamin A
- active vitamin D3 has side effects such as hypercalcemia and local stimulation sensitivity S (Non-patent Documents 1 and 3).
- Cyclosporine has side effects such as transient increase in blood pressure and renal dysfunction (Non-patent Document 5).
- Non-patent Document 6 Non-patent Document 6
- psoriasis treatment in terms of efficacy, safety and economy Development of agents is desired.
- Patent Literature l WO 03Z002536
- Patent Document 2 WO 03Z002554 pamphlet
- Patent Document 3 WO 03Z020703
- Non-Patent Document 1 Expert Opin. Investig. Drugs (2000) 9, 79-93
- Non-Patent Document 2 Expert Opin. Investig. Drugs (2003) 12, 1111-1121
- Non-Patent Document 3 Lancet (2003) 361, 1197-1204
- Non-Patent Document 4 Dermatol. Clin. (2004) 22, 467-476
- Non-Patent Document 5 Br. J. Dermatol. (2004) 150, 1-10
- Non-Patent Document 6 Expert Opin. Pharmacother. (2003) 4, 1525-1533
- Non-Patent Document 7 Expert Opin. Pharmacother. (2003) 4, 1887
- An object of the present invention is to provide a more useful preventive 'therapeutic agent and prophylactic' treatment method for diseases caused by keratinocyte proliferation represented by psoriasis.
- Patent Documents 1 to 3 the inventors synthesized various active compounds in the course of research on cell adhesion induction inhibitors, and applied for patents (Patent Documents 1 to 3). Surprisingly, the inventors have found that a compound represented by the following general formula (1), which is a part of these compounds, has an inhibitory effect on keratinocyte proliferation, and completed the present invention.
- the present invention relates to the general formula (1)
- [0008] represents a group selected from:
- X represents CH or N
- Z represents CH or N
- R 1 represents a C to C linear or branched alkoxy group
- R 2 and R 3 each independently represent a C to C linear or branched alkyl group
- R 4 is a C to C linear or branched alkyl group
- [0010] indicates a group selected from
- R 5 each independently represents a C to C linear or branched alkoxy group or C to C
- 1 6 represents a linear or branched alkylthio group of I ′
- n an integer of 1 to 3
- n represents an integer of 1 or 2
- o represents an integer of 1 or 2.
- the present invention also provides a method for preventing or treating a disease caused by keratinocyte proliferation, comprising administering an effective amount of the compound represented by the general formula (1), a salt thereof, or a solvate thereof. Is to provide.
- the present invention provides use of a compound represented by the above general formula (1), a salt thereof, or a solvate thereof for the manufacture of a prophylactic / therapeutic agent for diseases caused by keratinocyte proliferation To do.
- FIG. 1 is a diagram showing the inhibitory effect of the compound of the present invention on hairless mouse TPA-stimulated skin thickening.
- FIG. 2 is a diagram comparing the inhibitory effect on proliferation of human cultured epidermal keratinocytes and the VCAM 1 expression inhibitory effect of the compound of the present invention.
- examples of the C to C linear or branched alkoxy group represented by R 1 include
- methoxy group ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec butoxy group, t-butoxy group, pentyloxy group and hexyloxy group can be mentioned.
- a methoxy group is preferable.
- Examples of the C 2 -C linear or branched alkyl group represented by R 2 and R 3 include a methyl group
- Examples include til group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, t-butyl group, pentyl group and hexyl group. Of these, methyl and isopropyl groups are preferred.
- the C 4 to C linear or branched alkyl group of R 4 includes the same substituents as described above.
- Examples of the C to C linear or branched alkoxy group for R 5 include the same substituents as described above.
- Examples of the C to C linear or branched alkylthio group of R 5 include, for example, a methylthio group
- a methylthio group is preferred.
- m represents an integer of 1 to 3, and 3 is particularly preferable.
- n an integer of 1 or 2, and 1 is particularly preferable.
- o represents an integer of 1 or 2.
- (R 1 ) — is particularly preferable when a methoxy group is substituted at the 3, 4 and 5 positions on the benzene ring.
- (A1) is particularly preferred.
- X is preferably CH
- Y is preferably CH
- n is preferably 1. in this case,
- the ring containing X and Y is a piperidine ring.
- R 4 is particularly preferably a methyl group, a methylthiophenyl group, a methoxyphenyl group or a dimethoxyphenyl group! /.
- a selected compound, a salt thereof or a solvate thereof is preferred. Further, compounds 1 to 4 are particularly preferable.
- the acid addition salt of the compound is not particularly limited as long as it is a pharmaceutically acceptable salt.
- hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate Acid addition salts of mineral acids such as nitrates; benzoates, methanesulfonates, ethanesulfonates, benzenesulfonates, p-toluenesulfonates, oxalates, maleates, fumarate, tartaric acid
- acid addition salts of organic acids such as salts, citrates and acetates.
- the compound (1) is also included in the present invention as a solvate capable of existing in the form of a solvate represented by a hydrate.
- the compound (1) is described in WO 03/002532 pamphlet, WO 03/002536 pamphlet, WO 03/002540 non-fret, WO 03/002554 non-fret, WO 0 3/020703 pamphlet. It can be produced by this method or a similar method.
- the compound (1) strongly inhibits the growth of keratinocytes, and thus is useful as a prophylactic / therapeutic agent for diseases caused by keratinocyte proliferation, such as psoriasis.
- psoriasis include psoriasis vulgaris, erythrodermic psoriasis, psoriatic arthritis, psoriasis vulgaris, psoriasis vulgaris and the like.
- the present inventor evaluated the correlation between the keratinocyte proliferation inhibitory action and the cell adhesion molecule induction inhibitory action (VCAM-1 expression inhibitory activity), there was no correlation between them. Therefore, the keratinocyte proliferation inhibitory action of the compound of the present invention is considered to be unrelated to the cell adhesion molecule induction inhibitory action.
- the prophylactic / therapeutic agent of the present invention comprises the compound (1), a salt thereof, or a solvate thereof as an active ingredient, and is prepared in the form of a general pharmaceutical preparation.
- Such preparations are prepared using commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, 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, solutions, suspensions, emulsions, granules, capsules, suppositories, injections ( Liquids, suspensions, etc.), sprays such as inhalants, external aerosols, and liquid preparations, lotions, liniments, ointments, creams, poultices, and other external preparations. It is preferable to use an agent.
- a carrier conventionally known in this field can be widely used.
- lactose sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystals
- Excipients such as cellulose and carboxylic acid, water, ethanol, propanol, simple syrup, dextrose solution, starch solution, gelatin solution, carboxymethylcellulose, ceramic, methylcellulose, potassium phosphate, binder such as polybulurpyrrolidone, dry starch , Sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose, white sugar, stearin, strength Disintegration inhibitors such as butter, hydrogenated oil, quaternary ammonium base, absorption promoters such as sodium lauryl sulfate, hume
- excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc and the like
- examples thereof include binders such as gum arabic powder, tragacanth powder, gelatin and ethanol, and disintegrants such as laminaran and agar.
- conventionally known carriers can be widely used, and examples thereof include polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic dalycerides.
- the preparation of an injection it is preferably prepared in the form of solutions, emulsions and suspensions, usually sterilized and isotonic with blood.
- any of those conventionally used in this field as diluents can be used, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol. And polyoxylated isostearyl alcohol and polyoxyethylene sorbitan fatty acid esters.
- a sufficient amount of sodium chloride, glucose or glycerin is contained to prepare an isotonic solution.
- Ordinary solubilizing agents, buffering agents, soothing agents, etc., and if necessary, coloring agents, preservatives, fragrances, flavoring agents, sweetening agents, and other pharmaceuticals may be included in the therapeutic agent. Good.
- dispersants and propellants known in this field can be used.
- the dispersant include lecithins such as soybean lecithin and egg yolk lecithin, oleic acid, Examples thereof include fatty acids such as linoleic acid and linolenic acid, and sorbitans such as sorbitan trioleate and sorbitan monooleate.
- the propellant include ordinary nonflammable liquid gases such as Freon 11, Freon 12, and Freon 114.
- Liquid paraffin mineral oil, white petrolatum, yellow straw serine, petrolatum jelly, paraffin (node paraffin, paraffin wax), microcrystalline wax, hydrocarbons such as polyethylene, squalane, squalene; dimethylpolysiloxane, polydimethylsilsiloxane, etc.
- Silicones higher alcohols such as myristyl alcohol, lauryl alcohol, cetenoleanolecanol, stearyl alcohol, cetostearyl alcohol, oleyl alcohol, vanitol, citronellol, eugenol; lanolin, liquid lanolin, lanolin wax, isopropyl lanolin, Steryls or sterol esters such as acetylated lanolin, lanolin alcohol, cholesterol; lauric acid, myristic acid, palmitic acid, stearin Higher fatty acids such as oleic acid; carnauba wax, beeswax, beeswax, polyethylene glycolenoester, ethyleneglycololeester, glycerin monoester, sorbitol ester, sorbitan ester, isopropyl myristite, isopropyl palmitate, isopropyl adipate, etc.
- higher alcohols such as myristyl
- Esters such as almond oil, corn oil, cottonseed oil, olive oil, soybean oil, peanut oil, coconut oil, fractionated coconut oil, sesame oil and other vegetable oils. These bases may be used alone or in combination of two or more.
- conventional additives such as metal sarcophagus, animal or plant extracts, vitamins, hormones, amino acids and other medicinal agents, surfactants, pigments, dyes, pigments, fragrances,
- An ultraviolet absorber, a humectant, a thickener, an antioxidant, a preservative, an absorption accelerator, a sequestering agent, a pH adjuster and the like can be appropriately blended as necessary.
- the amount of the compound (1), a salt thereof or a solvent thereof to be contained in the preventive / therapeutic agent of the present invention is not particularly limited and is selected within a wide range.
- a propellant or the like it is usually 0.01 to 70% by mass, preferably 1 to 50% by mass in the whole composition.
- the administration method of the prophylactic / therapeutic agent of the present invention is not particularly limited, and is administered by a method according to the patient's age, sex and other conditions, the degree of disease, and the like.
- tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered.
- injections it can be used alone or as a normal replacement fluid such as glucose or amino acids.
- a suppository it is administered intrarectally.
- Sprays are administered by spraying into the oral cavity or nasal cavity.
- Pharmaceutically acceptable carriers in the medicament of the present invention include excipients, diluents, extenders, disintegrants, stabilizers, preservatives, buffers, emulsifiers, fragrances, colorants, sweeteners, Examples include thickeners, flavoring agents, flavoring agents, solubilizing agents, and other additives.
- a pharmaceutical composition in the form of an external preparation such as an external aerosol, a liquid coating agent, a lotion, a liniment, an ointment, a cream or a cataplasm can be prepared, but is preferably used as an external preparation.
- the compound of the present invention is used as an oral preparation, it is appropriately selected depending on the patient's weight, age, sex, symptoms, etc. In general, for adults, 1 to 3000 mg, preferably 2 to 300mg should be administered. In addition, dosing once a day or divided into two or more times.
- the amount throughout the affected area can be applied by application to the affected area 1 to several times a day.
- Example 1 Effect of the compound of the present invention on proliferation of normal human keratinocytes (newborn foreskin-derived epidermal keratinocytes)
- Normal human keratinocytes purchased from Kurabo Industries Co., Ltd. were seeded in 48 well plates (Coster) at 4 ⁇ 10 4 cells ZwellZ500 L and cultured at 37 ° C. in the presence of 5% CO.
- the present invention
- Compound or active vitamin D3 (calcitriol; manufactured by Wako Pure Chemical Industries, Ltd.) has a final concentration.
- Carrot was added to a concentration of 01-10M and cultured for 22 hours. After adding H 3 -thymidine (Amersham) and culturing for 2 hours, the cells were washed and collected, and the radioactivity incorporated into the cells was measured with a liquid scintillation counter (Packard). The results are shown in Table 1. Radioactivity incorporated during drug addition (control) is 100% Expressed as a percentage of activity.
- the IC value which is the concentration of the drug when the radioactivity uptake is suppressed to 50% relative to Control, is 1
- any of 50 to 8 was lower than calcitriol.
- compound 4 and calcitriol each have an IC value of 0.247.
- IX M compound 4 was about 8 times more potent than calcitriol.
- Abnormal hyperproliferation of epidermal cells is the most characteristic of psoriasis, and strong suppression of epidermal cell proliferation is useful in the treatment of psoriasis.
- Example 2 Hairless Mice of Compound of the Present Invention Inhibitory Effect on Acupuncture-stimulated Skin Thickening
- Ares mice were used to stimulate 12- tetra-tetradecanol phorbol 13 acetate (hereinafter referred to as acupuncture) ( Sato et al. Dermatology (1996) 192, 233 238).
- TPA lOnmol dissolved in acetone was applied to the back of 7- to 8-week-old female SKH1-hrBR- Hairless mice (Nippon Chiruzu River Co., Ltd.), and then the drug dissolved in acetone or Bon Alpha High (Teijin) (Pharmace) was applied in an amount of 50 ⁇ L. After 24 hours, the skin thickness of the back was measured with a dial thickness gauge (Peacock G-1A, Ozaki MFG Co. Ltd.), and the difference from the skin thickness measured before TPA application was determined. The results are shown in Fig. 1. The application of active vitamin D3 preparation (Bon Alpha High) suppressed skin thickness thickening. In addition, application of Compound 4 suppressed skin thickening.
- HBSSZBSA Hank's balanced salt solution
- ICN immunoglobulin C
- Fig. 2 shows a comparison of the inhibitory effect on the proliferation of cultured human epidermal cells and the inhibitory action on VCAM-1 expression. There was no strong correlation between the inhibitory effect on the proliferation of cultured human epidermal cells and the inhibitory action on VCAM-1 expression.
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Abstract
本発明は、一般式(1)
(式中、Aは次式(A1)及び(A2)から選ばれる基を示し;
XはCH又はNを示し;
YはCH2又はC=Oを示し;
ZはCH又はNを示し;
R1はアルコキシ基を示し;
R2及びR3はアルキル基を示し;
R4はアルキル基及び次式
(2)から選ばれる基を示し;
R5はアルコキシ又はアルキルチオ基を示し;
mは1~3の整数を示し、
nは1又は2の整数を示し、
oは1又は2の整数を示す。〕
で表される化合物、その塩又はそれらの溶媒和物を有効成分とするケラチノサイト増殖に起因する疾患の予防・治療剤。
Description
明 細 書
ケラチノサイト増殖に起因する疾患の予防'治療剤
技術分野
[0001] 本発明は、ケラチノサイト増殖に起因する疾患、例えば乾癬の予防'治療剤及び予 防'治療方法に関する。
背景技術
[0002] 乾癬は炎症性角化症という分野に含まれる皮膚病で、赤く盛り上がった発疹 (紅斑 )に、銀白色の力さ力さしたフケのような鱗屑が付着し、それがはがれ落ちてしまう非 伝染性の疾患であり、角質ケラチノサイトが過度に成長し、炎症細胞が蓄積し、角質 層内の過度の血管新生により現れる。乾癬は臨床的に、尋常性乾癬、乾癬性紅皮症 、関節症性乾癬、滴状乾癬、膿疱性乾癬に分類される。発症の原因は未だに不明で ある力 ケラチノサイトの代謝の変化が病気の誘発において一番重要なものと考えら れている。また、遺伝的要因や環境要因などの複数の因子が影響する疾患として考 えられている。この病気は、根本的治療法がなぐ従って、症状の緩和された期間を 長くすることが治療の目的となっている。
[0003] 現在臨床の場で使用されている治療剤としては、ステロイド剤、エトレチナート、レチ ノイドやボンアルファなどのビタミン剤、メトトレキセートゃシクロスポリンなどの免疫抑 制剤などがあるが、効果が不十分であったり、副作用の問題があり、十分満足できる ものは無い(非特許文献 1〜3)。例えばステロイド剤は、効果を示す一方で、皮膚萎 縮、毛細血管拡張などの副作用を有することが知られている。また、レチノイド (ビタミ ン A)には催奇形性、粘膜皮膚毒性、関節痛や筋痛、肝障害などの副作用がある (非 特許文献 4)。また、活性型ビタミン D3剤は副作用として高 Ca血症や局所の刺激感 力 Sある (非特許文献 1、 3)。また、シクロスポリンは一過性の血圧上昇ゃ腎機能障害 などの副作用がある (非特許文献 5)。
最近、 T細胞の活性ィ匕を抑制する抗体、融合蛋白質、リコンビナントのインターロイ キン等の生物製剤が乾癬治療剤として開発されているが、経済性も重要な問題であ る(非特許文献 6、 7)。従って、効果、安全性、経済性において、より有用な乾癬治療
剤の開発が望まれている。
特許文献 l :WO 03Z002536号パンフレツ卜
特許文献 2 :WO 03Z002554号パンフレット
特許文献 3 :WO 03Z020703号パンフレツ卜
非特許文献 1 : Expert Opin. Investig. Drugs (2000) 9, 79-93
非特許文献 2 : Expert Opin. Investig. Drugs (2003) 12, 1111-1121
非特許文献 3 : Lancet (2003) 361, 1197-1204
非特許文献 4: Dermatol. Clin. (2004) 22, 467-476
非特許文献 5 : Br. J. Dermatol.(2004)150, 1-10
非特許文献 6 : Expert Opin. Pharmacother. (2003) 4, 1525-1533
非特許文献 7 : Expert Opin. Pharmacother. (2003) 4, 1887
発明の開示
発明が解決しょうとする課題
[0004] 本発明の目的は、乾癬に代表されるケラチノサイト増殖に起因する疾患のより有用 な予防'治療剤及び予防'治療方法を提供することにある。
課題を解決するための手段
[0005] 以前に本発明者らは、細胞接着誘導阻害剤の研究の過程で種々の活性化合物を 合成し、特許出願した (特許文献 1〜3)。驚くべきことに、これらの化合物の一部であ る、後記一般式(1)で表される化合物がケラチノサイト増殖抑制作用を有することを 見出し、本発明を完成した。
[0006] すなわち、本発明は一般式(1)
[0007] [化 1]
(A2)
[0008] から選ばれる基を示し;
Xは CH又は Nを示し;
Yは CH又は C = 0を示し;
2
Zは CH又は Nを示し;
R1は C〜Cの直鎖又は分岐鎖のアルコキシ基を示し;
1 6
R2及び R3はそれぞれ独立して C〜Cの直鎖又は分岐鎖のアルキル基を示し;
1 6
R4は C〜Cの直鎖もしくは分岐鎖のアルキル基及び次式
1 6
[0009] [化 2]
[0010] カゝら選ばれる基を示し;
R5はそれぞれ独立して、 C〜Cの直鎖もしくは分岐鎖のアルコキシ基又は C〜C
1 6 I ' の直鎖もしくは分岐鎖のアルキルチオ基を示し;
mは 1〜3の整数を示し、
nは 1又は 2の整数を示し、
oは 1又は 2の整数を示す。 )
で表される化合物、その塩又はそれらの溶媒和物を有効成分とするケラチノサイト増 殖に起因する疾患の予防 ·治療剤を提供するものである。
[0011] また、本発明は、上記一般式(1)で表される化合物、その塩又はそれらの溶媒和物 を有効量投与することを特徴とするケラチノサイト増殖に起因する疾患の予防'治療 方法を提供するものである。
[0012] さらに、本発明は、ケラチノサイト増殖に起因する疾患の予防 *治療剤を製造するた めの上記一般式(1)で表される化合物、その塩又はそれらの溶媒和物の使用を提供 するものである。
発明の効果
[0013] 本発明により、ケラチノサイト増殖に起因する疾患、例えば乾癬の予防'治療剤及 び予防'治療方法を提供することができる。
図面の簡単な説明
[0014] [図 1]本発明化合物のへアレスマウス TPA刺激皮膚肥厚に対する抑制効果を示した 図である。
[図 2]本発明化合物のヒトの培養表皮角化細胞の増殖に対する抑制効果と VCAM 1発現抑制作用を比較した図である。
発明を実施するための最良の形態
[0015] 一般式(1)において、 R1の C〜Cの直鎖又は分岐鎖のアルコキシ基としては、例
1 6
えば、メトキシ基、エトキシ基、 n—プロポキシ基、イソプロポキシ基、 n—ブトキシ基、ィ ソブトキシ基、 sec ブトキシ基、 t ブトキシ基、ペンチルォキシ基、へキシルォキシ 基が挙げられる。このうち、メトキシ基が好ましい。
[0016] R2、 R3の C〜Cの直鎖又は分岐鎖のアルキル基としては、例えば、メチル基、ェ
1 6
チル基、 n プロピル基、イソプロピル基、 n ブチル基、イソブチル基、 sec ブチル 基、 t—ブチル基、ペンチル基、へキシル基が挙げられる。このうち、メチル基、イソプ 口ピル基が好ましい。
[0017] R4の C〜Cの直鎖又は分岐鎖のアルキル基としては、前記と同様の置換基が挙
1 6
げられる。このうち、メチル基が好ましい。
R5の C〜Cの直鎖又は分岐鎖のアルコキシ基としては、前記と同様の置換基が挙
1 6
げられる。このうち、メトキシ基が好ましい。
R5の C〜Cの直鎖又は分岐鎖のアルキルチオ基としては、例えば、メチルチオ基
1 6
、ェチルチオ基、 n—プロピルチオ基、イソプロピルチオ基、 n—ブチルチオ基、イソブ チルチオ基、 sec—ブチルチオ基、 tーブチルチオ基、ペンチルチオ基、へキシルチ ォ基が挙げられる。このうち、メチルチオ基が好ましい。
[0018] mは 1〜3の整数を示し、 3が特に好ましい。
nは 1又は 2の整数を示し、 1が特に好ましい。
oは 1又は 2の整数を示す。
[0019] 一般式(1)中、(R1) —は、ベンゼン環上の 3、 4及び 5位にメトキシ基が置換する 場合が特に好ましい。また、式 (A1)及び (A2)のうち、(A1)が特に好ましい。また一 般式(1)において、 Xは CH、 Yは CHが好ましぐさらに nは 1が好ましい。この場合、
2
X及び Yを含む環はピペリジン環である。
[0020] 一般式(1)中、次の式(la)
[0021] [化 3]
[0022] (式中、 R4は前記と同じ)
で表される化合物がより好ましい。ここで R4としては、メチル基、メチルチオフエ-ル基 、メトキシフエ二ル基又はジメトキシフエ-ル基が特に好まし!/、。
[0023] 前記一般式(1)の内、特に次式
[0024] [化 4]
化合物 7 化合物 8
[0025] 力 選ばれる化合物、その塩又はそれらの溶媒和物が好ましい。さらに化合物 1〜4 が特に好ましい。
[0026] 前記化合物の酸付加塩としては、薬学上許容される塩であれば特に制限はないが 、例えば塩酸塩、臭化水素酸塩、ヨウ化水素酸塩、硫酸塩、リン酸塩、硝酸塩のよう な鉱酸の酸付加塩;安息香酸塩、メタンスルホン酸塩、エタンスルホン酸塩、ベンゼ ンスルホン酸塩、 p—トルエンスルホン酸塩、シユウ酸塩、マレイン酸塩、フマル酸塩、 酒石酸塩、クェン酸塩、酢酸塩のような有機酸の酸付加塩を挙げることができる。 また、前記化合物(1)は、水和物に代表される溶媒和物の形態で存在しえる力 当 該溶媒和物も本発明に包含される。
[0027] 前記化合物(1)は WO 03/002532号パンフレット、 WO 03/002536号パンフ レツ卜、 WO 03/002540号ノ ンフレット、 WO 03/002554号ノ ンフレット、 WO 0 3/020703号パンフレットに記載の方法、あるいは類似の方法により製造することが できる。
[0028] 前記化合物(1)は、後記実施例に示すように、ケラチノサイトの増殖を強く抑制する ことから、ケラチノサイトの増殖に起因する疾患、例えば乾癬の予防'治療薬として有 用である。乾癬としては、尋常性乾癬、乾癬性紅皮症、関節症性乾癬、滴状乾癬、濃 疱性乾癬等が挙げられる。
また、本発明者がケラチノサイト増殖抑制作用につ 、て細胞接着分子誘導抑制作 用 (VCAM— 1発現抑制活性)との相関性を評価したところ、これらの間に相関性は なかった。従って、本発明化合物のケラチノサイト増殖抑制作用は細胞接着分子誘 導阻害作用とは無関係と考えられる。
[0029] 本発明の予防'治療剤は、前記化合物 (1)、その塩、又はそれらの溶媒和物を有効 成分とするものであり、一般的な医薬製剤の形態に調製される。そのような製剤は通 常使用される充填剤、増量剤、結合剤、付湿剤、崩壊剤、表面活性剤、滑沢剤など の希釈剤あるいは賦形剤を用いて調製される。この医薬製剤としては各種の形態が 治療目的に応じて選択でき、その代表的なものとして錠剤、丸剤、散剤、液剤、懸濁 剤、乳剤、顆粒剤、カプセル剤、坐剤、注射剤 (液剤、懸濁剤等)など、また吸入剤、 外用エアゾル剤など噴霧剤、さらに、液状塗布剤、ローション剤、リニメント剤、軟膏 剤、クリーム剤、パップ剤等の外用剤などが挙げられ、外用剤とすることが好ましい。
[0030] 錠剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使 用でき、例えば乳糖、白糖、塩ィ匕ナトリウム、ブドウ糖、尿素、デンプン、炭酸カルシゥ ム、カオリン、結晶セルロース、ケィ酸などの賦形剤、水、エタノール、プロパノール、 単シロップ、ブドウ糖液、デンプン液、ゼラチン溶液、カルボキシメチルセルロース、 セラミック、メチルセルロース、リン酸カリウム、ポリビュルピロリドンなどの結合剤、乾 燥デンプン、アルギン酸ナトリウム、カンテン末、ラミナラン末、炭酸水素ナトリウム、炭 酸カルシウム、ポリオキシエチレンソルビタン脂肪酸エステル類、ラウリル硫酸ナトリウ ム、ステアリン酸モノグリセリド、デンプン、乳糖などの崩壊剤、 白糖、ステアリン、力力
ォバター、水素添加油などの崩壊抑制剤、第四級アンモ-ゥム塩基、ラウリル硫酸ナ トリウムなどの吸収促進剤、グリセリン、デンプンなどの保湿剤、デンプン、乳糖、カオ リン、ベントナイト、コロイド状ケィ酸などの吸着剤、精製タルク、ステアリン酸塩、ホウ 酸末、ポリエチレングリコールなどの滑沢剤などが例示できる。さらに錠剤は必要に 応じ通常の剤皮を施した錠剤、例えば糖衣錠、ゼラチン被包錠、腸溶被錠、フィルム コーティング剤あるいは二重錠、多層錠とすることができる。
[0031] 丸剤の形態に成形するに際しては、担体としてこの分野で従来公知のものを広く使 用でき、例えば、ブドウ糖、乳糖、デンプン、カカオ脂、硬化植物油、カオリン、タルク などの賦形剤、アラビアゴム末、トラガント末、ゼラチン、エタノールなどの結合剤、ラミ ナラン、カンテンなどの崩壊剤などが例示できる。坐剤の形態に成形するに際しては 、担体として従来公知のものを広く使用でき、例えばポリエチレングリコール、カカオ 脂、高級アルコール、高級アルコールのエステル類、ゼラチン、半合成ダリセライドな どを挙げることができる。
[0032] 注射剤として調製される場合には、液剤、乳剤及び懸濁剤の形態に調製され、通 常滅菌処理されるとともに血液と等張にするのが好ましい。これら液剤、乳剤及び懸 濁剤の形態に成形するのに際しては、希釈剤としてこの分野において慣用されてい るものをすベて使用でき、例えば水、エチルアルコール、プロピレングリコール、エト キシ化イソステアリルアルコール、ポリオキシ化イソステアリルアルコール、ポリオキシ エチレンソルビタン脂肪酸エステル類などを挙げることができる。なお、血液と等張に するために、等張性の溶液を調製するに充分な量の食塩、ブドウ糖あるいはグリセリ ンを含有させる。また通常の溶解補助剤、緩衝剤、無痛化剤などを、さらに必要に応 じて着色剤、保存剤、香料、風味剤、甘味剤などや他の医薬品を該治療剤中に含有 せしめてもよい。
[0033] 噴霧剤の形態にする際には、分散剤及び噴射剤としてこの分野で公知のものを広 く使用でき、分散剤としては例えば大豆レシチン、卵黄レシチン等のレシチン類、ォ レイン酸、リノール酸、リノレン酸等の脂肪酸、ソルビタントリオレート、ソルビタンモノ ォレート等のソルビタン類等が例示できる。また噴射剤として例えばフレオン 11、フレ オン 12、フレオン 114等の通常の不燃性液ィ匕ガス等が例示できる。
[0034] 軟膏剤として用いる場合は、親油性基剤を用いて調製され、用いられる親油性基 剤としては以下のものが挙げられる。液体パラフィン、鉱油、白色ワセリン、黄色ヮセリ ン、ワセリンゼリー、パラフィン (ノヽードパラフィン、パラフィンワックス)、微結晶性ヮック ス、ポリエチレン、スクヮラン、スクワレン等の炭化水素類;ジメチルポリシロキサン、ポ リジメシルシロキサン等のシリコン類;ミリスチルアルコール、ラウリルアルコール、セチ ノレアノレコーノレ、ステアリルアルコール、セトステアリルアルコール、ォレイルアルコー ル、ァネトール、シトロネロール、オイゲノール等の高級アルコール類;ラノリン、液状 ラノリン、ラノリンワックス、イソプロピルラノリン、ァセチル化ラノリン、ラノリンアルコール 、コレステロール等のステロール類もしくはステロールエステル類;ラウリン酸、ミリスチ ン酸、パルミチン酸、ステアリン酸、ォレイン酸等の高級脂肪酸類;カルナウパロウ、ミ ッロウ、餘ロウ、ポリエチレングリコーノレエステル、エチレングリコーノレエステル、グリセ リンモノエステル、ソルビトールエステル、ソルビタンエステル、イソプロピルミリスティト 、イソプロピルパルミティト、イソプロピルアジベイト等のエステル類;アーモンド油、ト ゥモロコシ油、綿実油、ォリーブ油、大豆油、ピーナッツ油、ヤシ油、分画ヤシ油、ゴ マ油等の植物油などが挙げられる。これらの基剤は単独で使用してもよいし、 2種以 上混合して使用してもよい。本発明の乾癬治療剤には、慣用の添加剤、例えば金属 石鹼、動物又は植物抽出物、ビタミン剤、ホルモン剤、アミノ酸等の薬効剤、界面活 性剤、色素、染料、顔料、香料、紫外線吸収剤、保湿剤、増粘剤、酸化防止剤、保 存剤、吸収促進剤、金属イオン封鎖剤、 pH調整剤等を必要に応じて適宜配合する ことができる。
[0035] 本発明の予防 ·治療剤中に含有されるべき化合物 (1)、その塩あるいはそれらの溶 媒和物の量は特に限定されず広範囲に選択されるが、経口剤、注射剤、噴霧剤など では通常、全組成物中 0.01〜70質量%、好ましくは 1〜50質量%であり、外用剤と して用いる場合は、通常、全組成物中 0.001〜10質量%、好ましくは 0.1〜5質量% 程度である。本発明の予防'治療剤の投与方法には特に制限はなぐ各種製剤形態 、患者の年令、性別その他の条件、疾患の程度などに応じた方法で投与される。例 えば錠剤、丸剤、液剤、懸濁剤、乳剤、顆粒剤及びカプセル剤の場合には経口投与 される。また注射剤の場合には単独であるいはブドウ糖、アミノ酸などの通常の補液
と混合して静脈内投与され、さらには必要に応じて単独で筋肉内、皮内、皮下もしく は腹腔内投与される。坐剤の場合には直腸内投与される。また、噴霧剤は口腔内又 は鼻腔内に噴霧して投与される。
[0036] 本発明の医薬における製薬上許容される担体としては、賦形剤、希釈剤、増量剤、 崩壊剤、安定剤、保存剤、緩衝剤、乳化剤、芳香剤、着色剤、甘味剤、粘稠剤、矯 味剤、矯臭剤、溶解補助剤あるいはその他の添加剤等が挙げられる。そのような担 体の一つ以上を用いることにより、錠剤、丸剤、散剤、顆粒剤、注射剤、液剤、カプセ ル剤、トローチ剤、エリキシル剤、懸濁剤、乳剤、シロップ剤、吸入剤、外用エアゾル 剤、液状塗布剤、ローション剤、リニメント剤、軟膏剤、クリーム剤、パップ剤等の外用 剤等の形態の医薬組成物を調製することができるが、外用剤とすることが好ましい。
[0037] 本発明化合物を経口剤として用いる場合は、患者の体重、年齢、性別、症状等によ つて適宜選択されるが、通常成人の場合は、 1日当たり、 l〜3000mg、好ましくは 2 〜300mg投与するのが良い。さらに、投与は、 1日 1回、あるいは 2回以上に分けて 投与してちょい。
[0038] 本発明化合物を外用剤として用いる場合は、患部全体にいきわたる量を 1日 1〜複 数回、該患部への塗布等により適用することができる。
実施例
[0039] 以下、実施例を挙げて本発明を詳細に説明するが、本発明はこれらに限定される ものではない。
[0040] 実施例 1 正常ヒトケラチノサイト (新生児包皮由来表皮角化細胞)の増殖に及ぼす 本発明化合物の影響
正常ヒトケラチノサイト( (株)クラボウより購入)を 48wellプレート(Coster社製)に 4 X 104cellsZwellZ500 Lで播種し、 5%CO存在下、 37°Cでー晚培養した。本発明
2
化合物又は活性型ビタミン D3 (カルシトリオール;和光純薬社製)を終濃度が。. 01 〜 10 Mとなるように添カロし、 22時間培養した。 H3— thymidine (Amersham社製)を 添加し 2時間培養後、細胞を洗浄後回収して、液体シンチレーシヨンカウンター (パッ カード社製)で細胞に取り込まれた放射活性を測定した。その結果を表 1に示した。 薬剤無添カ卩時 (Control)の放射活性を 100%とし、薬剤添加時に取り込まれた放射
活性の割合で示した。 Controlに対し放射活性の取り込みを 50%に抑えた時の薬剤 の濃度である IC 値は、化合物 1
50 〜8のいずれにおいてもカルシトリオールより低値 であった。例えば化合物 4及びカルシトリオールでそれぞれ IC 値は 0. 247
50 、 1. 9
IX Mであり、化合物 4はカルシトリオールの約 8倍の効力を示した。乾癬では表皮細 胞の異常な増殖亢進が最も特徴的であり、表皮細胞の増殖を強く抑制することは乾 癬の治療において有用である。
[0041] [表 1]
[0042] 実施例 2 本発明化合物のへアレスマウス ΤΡΑ刺激皮膚肥厚に対する抑制効果 乾癬の動物モデルとして 12— Ο—テトラデカノィルホルボール 13 アセテート( 以下 ΤΡΑという)刺激へアレスマウスを用いた(Satoら Dermatology (1996) 192, 233 238)。すなわち、 7— 8週齢の雌の SKH1— hrBR— Hairlessマウス(日本チヤ一 ルズリバ一株式会社)の背部にアセトンに溶解した TPA lOnmolを塗布後、ァセト ンに溶解した薬剤又はボンアルファハイ (帝人ファーマ)を 50 μ L塗布した。 24時間 後、背部の皮膚厚をダイヤルシックネスゲージ(Peacock G—1A, Ozaki MFG C o. Ltd. )で測定し、 TPA塗布前に測定した皮膚厚との差を求めた。その結果を図 1 に示した。活性型ビタミン D3製剤(ボンアルファハイ)の塗布により皮膚厚の肥厚が 抑制された。また、化合物 4の塗布により皮膚厚の肥厚が抑制された。
[0043] 実施例 3 VCAM— 1発現抑制活性
ヒト臍帯静脈血管内皮細胞 (HUVEC) (三光純薬)を EGM— 2培地 (三光純薬)に 5 X 104細胞 ZmLの濃度に懸濁し、 96穴マイクロプレート(コーユング)一穴当たり 1 X 104細胞ずっ播いた。 5%CO存在下、 37°Cで 4日間培養後、培地 100 μ Lを除
去し、被験物質及び TNF a (終濃度 10ngZmL、 Peprotech)を 25 μ Lずつ加えた。 37°Cで 4.5時間インキュベーション後、培地を除去し、 0.5%ゥシ血清アルブミン、 0. 02%アジィ匕ナトリウムを含むハンクス平衡塩溶液 (HBSSZBSA) 100 Lで各穴を 一回洗浄した。次 、でブロッキング溶液(1 %ャギ全血清 (ICN) /HBSS/BSA)を 30 μ L添カ卩し、氷上 30分 放置した。 100 μ Lの HBSS/BSAで一回洗净後、 1 μ gZmLの抗ヒト VCAM— 1抗体(Genzyme— Techne)を各穴 30 μ Lずつ加え、氷上 1 時間インキュベーションした。 HBSSZBSA (200 μ L)で 3回洗浄後、 HBSSZBS Aで 2000倍希釈したペルォキシダーゼ標識ャギ抗マウス IgG抗体(Pierce)を 30 μ L Ζ穴ずつ添加し、 1時間反応させた。先述のように HBSSZBSAで 5回洗浄後、 ΤΜ B基質(Moss)を 100 LZ穴加え、 15〜30分間、 25°Cで酵素反応させた後、 lmo 1ZL硫酸を 25 Lずつ添加して反応を停止させた。 96穴プレート対応分光光度計 Multiscan MS— UV (Labsystems)を用いて 620nmをレファレンス波長に 492nmの 吸光度を測定した。薬物未添加 TNF α刺激時の吸光度を 100%として阻害率を求 めた。なお、各群 3重測定を行なった。その結果を表 2に示す。
[表 2]
ヒトの培養表皮細胞の増殖に対する抑制効果と VCAM— 1発現抑制作用を比較し た結果を図 2に示す。ヒトの培養表皮細胞の増殖に対する抑制効果と VCAM— 1発 現抑制作用との間の相関はな力つた。
Claims
(A2)
から選ばれる基を示し;
Xは CH又は Nを示し;
Yは CH又は C = 0を示し;
2
Zは CH又は Nを示し;
R1は C〜Cの直鎖又は分岐鎖のアルコキシ基を示し;
1 6
R2及び R3はそれぞれ独立して C〜Cの直鎖又は分岐鎖のアルキル基を示し;
1 6
R4は C〜Cの直鎖又は分岐鎖のアルキル基及び次式
1 6
[化 2]
R5はそれぞれ独立して、 C〜Cの直鎖もしくは分岐鎖のアルコキシ基又は C〜C
1 6
の直鎖もしくは分岐鎖のアルキルチオ基を示し;
mは 1〜3の整数を示し、
nは 1又は 2の整数を示し、
oは 1又は 2の整数を示す。 )
で表される化合物、その塩又はそれらの溶媒和物を有効成分とするケラチノサイト増 殖に起因する疾患の予防,治療剤。
有効成分が、式 (la)
[化 3]
(式中、 R4は前記と同じ)
で表される化合物、その塩又はそれらの溶媒和物である請求項 1記載の予防,治療 剤。
有効成分が、次式
[化 4]
有効成分が、次式
[化 5]
[5] 疾患が乾癬である請求項 1〜4のいずれか 1項記載の予防'治療剤。
[6] 乾癬が、尋常性乾癬、乾癬性紅皮症、関節症性乾癬、滴状乾癬又は濃疱性乾癬 である請求項 5記載の予防 ·治療剤。
[7] 一般式 (1)
[化 6]
(A2) から選ばれる基を示し;
Xは CH又は Nを示し;
Yは CH又は C = 0を示し;
2
Zは CH又は Nを示し;
R1は C〜Cの直鎖又は分岐鎖のアルコキシ基を示し;
1 6
R2及び R3はそれぞれ独立して C〜Cの直鎖又は分岐鎖のアルキル基を示し;
1 6
R4は C〜Cの直鎖又は分岐鎖のアルキル基及び次式
1 6
R5はそれぞれ独立して、 C〜Cの直鎖もしくは分岐鎖のアルコキシ基又は C
1 6
の直鎖もしくは分岐鎖のアルキルチオ基を示し;
mは 1〜3の整数を示し、
nは 1又は 2の整数を示し、
oは 1又は 2の整数を示す。 )
で表される化合物、その塩又はそれらの溶媒和物を有効量投与することを特 ί るケラチノサイト増殖に起因する疾患の予防 ·治療方法。 式(la)
[化 8]
(式中、 R4は前記と同じ)
で表される化合物、その塩又はそれらの溶媒和物を有効量投与するものである請求 項 7記載の予防'治療方法。
[9] 次式
[化 9]
[10] 次式
[化 10]
[11] 疾患が乾癬である請求項 7〜10のいずれか 1項記載の予防'治療方法。
[12] 乾癬が、尋常性乾癬、乾癬性紅皮症、関節症性乾癬、滴状乾癬又は濃疱性乾癬 である請求項 11項記載の予防'治療方法。
[13] ケラチノサイト増殖に起因する疾患の予防 ·治療剤を製造するための一般式(1)
[化 11]
(A2) から選ばれる基を示し;
Xは CH又は Nを示し;
Yは CH又は C = 0を示し;
2
Zは CH又は Nを示し;
R1は C〜Cの直鎖又は分岐鎖のアルコキシ基を示し;
1 6
R2及び R3はそれぞれ独立して C〜Cの直鎖又は分岐鎖のアルキル基を示し;
1 6
R4は C〜Cの直鎖又は分岐鎖のアルキル基及び次式
1 6
R5はそれぞれ独立して、 C〜Cの直鎖もしくは分岐鎖のアルコキシ基又は C
1 6
の直鎖もしくは分岐鎖のアルキルチオ基を示し;
mは 1〜3の整数を示し、
nは 1又は 2の整数を示し、
oは 1又は 2の整数を示す。 )
で表される化合物、その塩又はそれらの溶媒和物の使用。
一般式(1)で表される化合物、その塩又はそれらの溶媒和物が式(la)
[化 13]
(式中、 R4は前記と同じ)
で表される化合物、その塩又はそれらの溶媒和物である請求項 13記載の使用。 一般式(1)で表される化合物、その塩又はそれらの溶媒和物が次式
[化 14]
[化 15]
乾癬が、尋常性乾癬、乾癬性紅皮症、関節症性乾癬、滴状乾癬又は濃疱性乾癬 である請求項 17記載の使用。
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP06712779A EP1844778A4 (en) | 2005-02-02 | 2006-02-01 | AGENT FOR THE PREVENTION / THERAPY OF A DISEASE CAUSED BY THE DEVELOPMENT OF KERATINOCYTES |
JP2007501584A JPWO2006082834A1 (ja) | 2005-02-02 | 2006-02-01 | ケラチノサイト増殖に起因する疾患の予防・治療剤 |
US11/815,376 US20090042901A1 (en) | 2005-02-02 | 2006-02-01 | Agent for prevention/therapy of disease caused by keratinocyte growth |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2005-026178 | 2005-02-02 | ||
JP2005026178 | 2005-02-02 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2006082834A1 true WO2006082834A1 (ja) | 2006-08-10 |
Family
ID=36777218
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/JP2006/301636 WO2006082834A1 (ja) | 2005-02-02 | 2006-02-01 | ケラチノサイト増殖に起因する疾患の予防・治療剤 |
Country Status (4)
Country | Link |
---|---|
US (1) | US20090042901A1 (ja) |
EP (1) | EP1844778A4 (ja) |
JP (1) | JPWO2006082834A1 (ja) |
WO (1) | WO2006082834A1 (ja) |
Citations (9)
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JP2001178258A (ja) * | 2000-11-24 | 2001-07-03 | Iseki & Co Ltd | 脱穀機の排藁搬送装置 |
WO2003002554A1 (fr) * | 2001-06-29 | 2003-01-09 | Kowa Co., Ltd. | Composes de piperazine |
WO2003002536A1 (fr) * | 2001-06-29 | 2003-01-09 | Kowa Co., Ltd. | Compose diamine cyclique asymetrique |
WO2003020703A1 (fr) * | 2001-08-30 | 2003-03-13 | Kowa Co., Ltd. | Compose d'amine cyclique |
WO2003076400A1 (en) * | 2002-03-13 | 2003-09-18 | Janssen Pharmaceutica N.V. | New inhibitors of histone deacetylase |
WO2003086397A1 (en) * | 2002-04-12 | 2003-10-23 | Kowa Co., Ltd. | Medicine for treating cancer |
JP2003535087A (ja) * | 2000-05-31 | 2003-11-25 | 田辺製薬株式会社 | αLβ2介在細胞接着阻害剤 |
WO2004052859A1 (ja) * | 2002-12-06 | 2004-06-24 | Kowa Co., Ltd. | エリスロポエチン産生促進剤 |
WO2005034953A1 (ja) * | 2003-10-10 | 2005-04-21 | Kowa Co., Ltd. | 血管新生抑制薬 |
Family Cites Families (5)
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IL99368A (en) * | 1991-09-02 | 1996-01-19 | Teva Pharma | Preparations for the treatment of psoriasis and atopic dermatitis, which contain the result of xanthine |
TW314467B (ja) * | 1993-03-31 | 1997-09-01 | Hoechst Ag | |
WO2000021935A1 (fr) * | 1998-10-09 | 2000-04-20 | Nihon Nohyaku Co., Ltd. | Derives de la pyridazinone |
US6395753B1 (en) * | 2001-08-30 | 2002-05-28 | Kowa Co., Ltd. | Cyclic amine compounds and pharmaceutical composition containing the same |
CA2479906C (en) * | 2002-04-03 | 2011-02-08 | Topotarget Uk Limited | Carbamic acid compounds comprising a piperazine linkage as hdac inhibitors |
-
2006
- 2006-02-01 JP JP2007501584A patent/JPWO2006082834A1/ja active Pending
- 2006-02-01 EP EP06712779A patent/EP1844778A4/en not_active Withdrawn
- 2006-02-01 WO PCT/JP2006/301636 patent/WO2006082834A1/ja active Application Filing
- 2006-02-01 US US11/815,376 patent/US20090042901A1/en not_active Abandoned
Patent Citations (9)
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JP2003535087A (ja) * | 2000-05-31 | 2003-11-25 | 田辺製薬株式会社 | αLβ2介在細胞接着阻害剤 |
JP2001178258A (ja) * | 2000-11-24 | 2001-07-03 | Iseki & Co Ltd | 脱穀機の排藁搬送装置 |
WO2003002554A1 (fr) * | 2001-06-29 | 2003-01-09 | Kowa Co., Ltd. | Composes de piperazine |
WO2003002536A1 (fr) * | 2001-06-29 | 2003-01-09 | Kowa Co., Ltd. | Compose diamine cyclique asymetrique |
WO2003020703A1 (fr) * | 2001-08-30 | 2003-03-13 | Kowa Co., Ltd. | Compose d'amine cyclique |
WO2003076400A1 (en) * | 2002-03-13 | 2003-09-18 | Janssen Pharmaceutica N.V. | New inhibitors of histone deacetylase |
WO2003086397A1 (en) * | 2002-04-12 | 2003-10-23 | Kowa Co., Ltd. | Medicine for treating cancer |
WO2004052859A1 (ja) * | 2002-12-06 | 2004-06-24 | Kowa Co., Ltd. | エリスロポエチン産生促進剤 |
WO2005034953A1 (ja) * | 2003-10-10 | 2005-04-21 | Kowa Co., Ltd. | 血管新生抑制薬 |
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See also references of EP1844778A4 * |
Also Published As
Publication number | Publication date |
---|---|
US20090042901A1 (en) | 2009-02-12 |
EP1844778A1 (en) | 2007-10-17 |
JPWO2006082834A1 (ja) | 2008-06-26 |
EP1844778A4 (en) | 2010-11-03 |
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