Title of Invention	METHOD FOR PREPARATION OF AN OPTICALLY ACTIVE DIMETHOXYNAPTHALENE COMPOUND
Abstract	Dermatitis remedies for external use, containing as the active ingredient compounds represented by the general formula [I] or pharmacologically acceptable salts thereof: [I] wherein R1 and R2 are each lower alkoxy; =X- is the group represented by the following formula: or the group represented by formula: =N-; A is a saturated or unsaturated nitrogen-containing heterobicyclic group having one to four substituents selected from among hydroxyl, oxo, lower alkoxy, di(lower alkyl)aminophenyl, piperidino(lower alkoxy), morpholino(lower alkoxy), cyclo(lower alkyl)amino(lower alkyl)amino, pyridyl, and morpholino; and symbol represents a single or double bond.

Title of Invention

METHOD FOR PREPARATION OF AN OPTICALLY ACTIVE DIMETHOXYNAPTHALENE COMPOUND

Abstract

Dermatitis remedies for external use, containing as the active ingredient compounds represented by the general formula [I] or pharmacologically acceptable salts thereof: [I] wherein R1 and R2 are each lower alkoxy; =X- is the group represented by the following formula: or the group represented by formula: =N-; A is a saturated or unsaturated nitrogen-containing heterobicyclic group having one to four substituents selected from among hydroxyl, oxo, lower alkoxy, di(lower alkyl)aminophenyl, piperidino(lower alkoxy), morpholino(lower alkoxy), cyclo(lower alkyl)amino(lower alkyl)amino, pyridyl, and morpholino; and symbol represents a single or double bond.

Full Text	1 SPECIFICATION DERMATITIS TREATING AGENT TECHNICAL FIELD [0001] The present invention relates to a novel topical agent useful for treatment of dermatitis such as atopic dermatitis and the like. BACKGROUND ART [0002] Dermatitis is an inflammatory disease at the skin against various kinds of endogenetic and exogenetic invasion, and the disease includes atopic dermatitis, contact dermatitis, seborrheic dermatitis, nummular eczema, autosensitization eczema and the like. These dermatitises accompany itching in many cases. Also, of these, atopic dermatitis is a refractory chronic inflammatory disease which repeats remission and exacerbation, and involvement of a late phase reaction that accompanies invasion of eosinophils or lymphocyte and production of various kinds of cytokines at a site of inflammation has been suggested for pathogeny and chronicity of the disease (Non-Patent Literatures 1 and 2). For the treatment of atopic dermatitis, a treatment by a medicament depending on the symptom has been employed in combination with removal of factors of causing diseases or exacerbation and skin care, and a topical steroid agent has mainly been used against inflammation. Also, tacrolimus which is a kind of an immunosuppressive agent has recently been used for the treatment of atopic dermatitis. However, these existing medicaments are not necessarily satisfied in the points of safety and side effects. Thus, it has been desired to develop a therapeutic agent for dermatitis not only having 2 effectiveness but also high safety. It has been known that Compound [I] which is an active ingredient of the present invention has selective phosphodiesterase IV (PDE IV) inhibitory activity, and useful as an agent for prophylaxis and treatment of asthma and the like. (Patent Literatures 1 and 2). However, it has not been reported that said Compound [I] is useful as an agent for treatment of dermatitis such as atopic dermatitis and the like. [0003] Patent Literature 1: EP 748,805 B (p. 2) Patent Literature 2: EP 848,000 B (p. 2) Non-Patent Literature 1: Iwamoto et al., J. Leukoc. Biol., Vol.52, pp.572-578 (1992) Non-Patent Literature 2: Frigas et al., J. Allergy Clin. Immunol., Vol. 77, pp.527-537 (1986) DISCLOSURE OF THE INVENTION PROBLEMS TO BE SOLVED BY THE INVENTION [0004] The present invention is to provide a novel topical agent useful for treatment of dermatitis such as atopic dermatitis and the like. MEANS TO SOLVE THE PROBLEMS [0005] The present invention relates to a topical dermatitis treating agent which comprises, as an active ingredient, a compound represented by the following formula [I]: 3 wherein R1 and R2 each represent a lower alkoxy group, =X- represents a group represented by the formula: or a group represented by the formula: =N-, Ring A represents a saturated or unsaturated bicyclic nitrogen-containing heterocyclic group having 1 to 4 substituents selected from oxo group, hydroxyl group, a lower alkoxy group, a di-lower alkylaminophenyl group, a pyperidino-lower alkoxy group, a morpholino- lower alkoxy group, a cyclo-lower alkylamino-lower alkylamino group, pyridyl group and morpholino group, and rrrr represents a single bond or a double bond, or a pharmaceutically acceptable salt thereof. [0006] The present invention also relates to a use of the compound represented by the above-mentioned formula [I] or a pharmaceutically acceptable salt thereof for the manufacture of a preparation to be used for a topical treatment of dermatitis. The present invention further relates to a method for treating dermatitis which comprises applying a preparation comprising the compound represented by the above-mentioned formula [I] or a pharmaceutically acceptable salt thereof as an active ingredient to affected part. EFFECTS OF THE INVENTION [0007] The topical dermatitis treating agent of the present invention showed an excellent ear swelling inhibitory effect in a dermatitis model (mouse), so that it is useful for the treatment of dermatitis such as atopic dermatitis and the like. Also, it has a little side effect on a skin (photosensitivity, cytotoxicity and the like), so that it has a characteristic that safety is high as a topical dermatitis treating agent. 4 BEST MODE TO CARRY OUT THE INVENTION [0008] In Compound [I] which is an active ingredient of the present invention, as the saturated or unsaturated bicyclic nitrogen-containing heterocyclic group represented by Ring A, there may be mentioned, for example, quinolyl group, dihydroquinolyl group, tetrahydroquinolyl group, isoquinolyl group, dihydroisoquinolyl group, tetrahydro- isoquinolyl group, phthalazinyl group, dihydrophthalazinyl group or the like. Of these, tetrahydroquinolyl group or dihydroisoquinolyl group is preferred. Specific examples of the substituents on these heterocyclic group may be mentioned 1 to 4 groups selected from oxo group, hydroxyl group, a lower alkoxy group (methoxy group and the like), a di-lower alkylaminophenyl group (dimethylaminophenyl group and the like), a piperidino-lower alkoxy group (piperidino- ethoxy group and the like), a morpholino-lower alkoxy group (morpholinoethoxy group and the like), a cyclo-lower alkylamino-lower alkylamino group (cyclohexylaminopropyl- amino group and the like), pyridyl group and morpholino group. As the lower alkoxy group of R1 and R2, there may be mentioned, for example, methoxy group, ethoxy group or the like, and of these, methoxy group is preferred. Among Compounds [I] which are active ingredients of the present invention, specific examples of the preferred compounds may be mentioned a compound wherein R1 and R2 are methoxy groups, and =X- is a group represented by the formula: As the other preferred Compound [I], there may be mentioned a compound wherein R1 and R2 are methoxy groups, and =X- is a group represented by the formula: =N-. [0009] Among Compounds [I] which are active ingredients of 5 the present invention, more preferred compounds may be mentioned a compound wherein Ring A is a group represented by the formula: [0010] Among the above-mentioned active ingredients according to the present invention, particularly preferred compounds may be mentioned a compound selected from 1-[2-(1,2-dihydro-3-morpholino-2-oxoquinolin-l-yl)pyridin- 4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene; 1-[2-[1,2-dihydro-5-(2-piperidinoethoxy)-1-oxoisoquinolin- 2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene; 1-[2-[1,2-dihydro-5-(2-morpholinoethoxy)-1-oxoisoquinolin- 2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene; 1-[2-[l,2-dihydro-3-oxoisoquinolin-2-yl]pyridin-4-yl]-2,3- bis(hydroxymethyl)-6,7-dimethoxynaphthalene; 1-[2-(4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl)pyridin-4- yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene; 1-[2-[(4S)-4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl]- 6 pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene; 1-[2-[(4R)-4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl]- pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene; 1-[2-[1,2-dihydro-4-[3-(cyclohexylamino)propylamino]-2- oxoquinolin-1-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7- dimethoxynaphthalene; 1-[2-[4-(dimethylaminophenyl)phthalazin-l(2H)-one-2-yl]- pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene,- 1-[2-[6,7-dimethoxy-4-(3-pyridyl)phthalazin-l(2H)-one-2- yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene; and (3S)-1- [2- [4-(dimethylaminophenyl)phthalazin-1(2H)-one-2- yl]pyridin-4-yl]-3,4-dihydro-3-hydroxymethyl-6,7-dimethoxy- isoquinoline; or a pharmaceutically acceptable salt thereof. [0011] In Compound [I] which is an active ingredient of the present invention, when it has an asymmetric carbon on the dihydroisoquinoline skeleton or the cyclic group A, there are a plural number of stereoisomers (diastereomeric isomer, optical isomer) based on the asymmetric carbon(s), and both of either one of stereoisomers and a mixture thereof are contained in the active ingredient(s) of the present invention. Moreover, in Compound [I] which is an active ingredient of the present invention, solvated products such as a hydrate and the like are contained. As a pharmaceutically acceptable salt of the above- mentioned Compound [I], there may be mentioned, for example, an inorganic salt such as hydrochloride, sulfate and hydrobromide, an organic acid salt such as acetate, fumarate, oxalate, methanesulfonate, maleate and p-toluene- sulfonate. 7 [0012] The topical dermatitis treating agent of the present invention is useful for treatment of atopic dermatitis, contact dermatitis, seborrheic dermatitis, psoriasis, eczema (nummular eczema, autosensitization eczema and the like) and the like. Also, in Compound [I] which is an active ingredient of the present invention, a compound which does not substantially show toxicity such as local irritation, skin photosensitivity and the like, at least in the range of an effective dose for topical dermatitis treatment. A topical dermatitis treating agent comprising such a compound of the present invention is useful in the point of safety. [0013] The above-mentioned Compound [I] or a pharmaceuti- cally acceptable salt thereof can be obtained by a known method (for example, a method disclosed in EP Patent No. 748,805 or EP Patent No. 848,000: see the following reaction scheme). In the above-mentioned reaction scheme, Ra represents a protective group for carboxyl group, =XX- represents a group represented by the formula: =N- or represented by the formula: (Rb represents a protective group for carboxyl group) Y represents a halogen atom, and the other symbols 8 have the same meanings as defined above. As the protective group for the carboxyl group, there may be mentioned, for example, a lower alkyl group and the like. Among Compound [I] which is an active ingredient of the present invention, a compound wherein Ring A is a group represented by the following formula: can be prepared, for example, by condensing an optically active tetrahydroquinoline compound represented by the following formula: wherein OZ represents a protected hydroxyl group, and Compound [II], reducing said reaction product by sodium borohydride and the like, and then, removing the protective group (for example, tert-butyldimethylsilyl group and the like) for the hydroxyl group from the product. The above-mentioned optically active tetrahydro- quinoline compound [III-a] or [Ill-b] can be prepared, for example, by subjecting a 4-oxotetrahydroquinoline compound represented by the formula [V]: wherein R represents a protective group for amino group, to asymmetric reduction in the presence of a CBS catalyst such as (R)- or (S)-2-methyl-CBS-oxazaborolidine and a 9 hydrogenated boron compound, then, introducing a protective group such as a tert-butyldimethylsilyl group and the like, into the hydroxyl group at the 4-position of the product, and removing the protective group (R) for the amino group. As the protective group for the amino group, there may be mentioned, for example, benzyloxycarbonyl group and the like. [0014] In the topical dermatitis treating agent of the present invention, in addition to Compound [I] or a pharma- ceutically acceptable salt thereof which is an active ingredient, an additive for a pharmaceutical preparation such as an absorption enhancer, a pH adjusting agent, a preservative, a flavoring agent, a dispersing agent, a humectant, a stabilizer, a suspending agent, a surfactant and the like, may be formulated alone or in combination of two or more in admixture, if desired. As the absorption enhancer, there may be mentioned, for example, a monohydric alcohol having 2 0 or less carbon atoms (ethyl alcohol, isopropyl alcohol, stearyl alcohol and the like), pyrrolidone derivatives (2-pyrrolidone, 1- methyl-2-pyrrolidone and the like), ureas (urea, thiourea and the like), cyclodextrins (a-cyclodextrin and the like), menthol, l-dodecylazacycloheptan-2-one, calcium thioglycol- ate, limonene and the like. A content of the absorption enhancer may vary depending on the dosage form, ingredients of the base and the like, and in general, it is desirably 0.1% by weight or more, preferably 0.3% by weight or more for the purpose of effectively producing a absorption- enhancing action, and desirably 10% by weight or less, preferably 5% by weight or less for the purpose of inhibiting side effect. Specific examples of the pH adjusting agent may be mentioned, for example, an inorganic acid such as hydro- chloric acid, sulfuric acid, phosphoric acid and the like, an organic acid such as acetic acid, succinic acid, fumaric 10 acid, malic acid and the like, a metal salt of these acids and the like. An amount of the pH adjusting agent to be formulated may vary depending on the dosage form or ingredients of the base, and in general, it is preferably so formulated that a pH of the preparation becomes 4 to 8. Specific examples of the preservative may be men- tioned, for example, p-hydroxybenzoic acid, methylparaben, chlorobutanol, benzyl alcohol, methyl p-hydroxybenzoate and the like. Specific examples of the flavoring agent may be mentioned, for example, menthol, rose oil, eucalyptus oil, d-camphor and the like, and specific examples of the dispersing agent may be mentioned, for example, sodium metaphosphate, potassium polyphosphate, silicic acid anhydride and the like. Specific examples of the humectant may be mentioned, for example, propylene glycol, glycerin, sorbitol, sodium lactate, sodium hyaluronate and the like, and specific examples of the stabilizer may be mentioned, for example, sodium hydrogen sulfite, tocopherol, ethylenediamine tetraacetic acid (EDTA), citric acid and the like. Specific examples of the suspending agent may be mentioned, for example, tragacanth powder, Gum Arabic powder, bentonite, sodium carboxymethyl cellulose and the like, and specific examples of the surfactant may be mentioned, for example, polyoxyethylene hardened caster oil, sorbitan fatty acid ester such as sorbitan sesqui- oleate and the like, polyoxyl stearate and the like. [0015] A dermatitis treating agent of the present invention can be used as a topical agent for the purpose of directly administering it to a dermatitis area, and a dosage form thereof may be mentioned, for example, an ointment, a cream, a lotion, a liniment, a cataplasm, a plaster, a patch, a plaster, a liquid and the like. When the above-mentioned dosage form is an ointment 11 or a cream, an oleaginous base, a water-soluble base, an emulsion base or a suspension base can be used as a base. As the oleaginous base, there may be mentioned, for example, a hydrocarbon (a hydrocarbon having 12 to 32 carbon atoms, liquid paraffin, white vaseline, squalene, squalane, plastibase and the like), a higher alcohol (an aliphatic monohydric alcohol having 12 to 3 0 carbon atoms such as lauryl alcohol, cetyl alcohol, stearyl alcohol, oleyl alcohol and the like), a higher fatty acid (a saturated or unsaturated fatty acid having 6 to 32 carbon atoms such as palmitic acid and stearic acid), a higher fatty acid ester (a fatty acid ester such as mirystyl palmitate and stearyl stearate; an ester of a fatty acid having 10 to 32 carbon atoms such as lanolin and carnauba wax, and an aliphatic monohycric alcohol having 14 to 32 carbon atoms; an ester of a saturated or unsaturated fatty acid having 10 to 22 carbon atoms and glycerin, such as glyceryl monolaurate, and its hydrogenated product, and the like), vegetable oil, animal oil and the like. As the water-soluble base, there may be mentioned, for example, a glycol (ethylene glycol, propylene glycol, polyethylene glycol and the like), and the like. As the emulsion base, there may be mentioned, for example, an oil-in-water type base, a water-in-oil type base and the like. As the oil-in-water type base, there may be mentioned a base prepared by emulsifying or dispersing a component such as the above-mentioned lanolin, propylene glycol, stearyl alcohol, vaseline, silicone oil, liquid paraffin, glyceryl monostearate, polyethylene glycol and the like, in an aqueous phase in the presence or in the absence of a surfactant, and the like. As the water-in-oil type base, there may be mentioned a base prepared by adding water to a component such as vaseline, a higher aliphatic alcohol, liquid paraffin and the like, in the presence of a nonionic surfactant, and emulsifying or dispersing the mixture, and the like. Also, as the suspension base, there 12 may be mentioned an aqueous base prepared by adding a suspending agent such as starch, glycerin, a high viscosity carboxymethyl cellulose, carboxyvinyl polymer and the like to water to make a gel, and the like. A dermatitis treatment agent of the present invention can be prepared by a conventionally employed preparation method of a topical preparation. For example, an ointment or a cream can be prepared by mixing and kneading, emulsifying or suspending raw materials of a base depending on the respective dosage form to prepare the base, adding an active ingredient(s) and various kinds of additives, and mixing it in a mixer such as a screw mixer and the like. [0016] The lotion can be used in any form such as a suspension type, emulsion type and solution. As a base for the suspension type lotion, there may be mentioned a mixture of a suspending agent including gums such as gum arabic, gum tragacanth and the like, celluloses such as methyl cellulose, hydroxyethyl cellulose and the like, clays such as bentonite and the like with water, and the like. As a base for the emulsion type lotion, there may be mentioned a base in which water and an oily substance including an aliphatic acid such as stearic acid, oleic acid and the like, a higher alcohol such as stearyl alcohol, cetyl alcohol and the like, are emulsified, and the like. As a base for the solution type lotion, there may be mentioned water and an alcohol such as ethanol, glycerin, propylene glycol and the like. The lotion can be prepared, for example, by adding various base components to purified water, mixing and stirring the same, then, adding an active ingredient(s) and an additive(s) to the mixture, and subjecting to filtration, if necessary. As a base for the liniment, there may be mentioned, for example, vegetable oils such as olive oil and the like, alcohols such as ethanol, isopropanol and the like, or a mixture of the above with water, and the like. The 13 liniment can be prepared, for example, by dissolving an active ingredient in the base, and adding an additive(s) for a preparation to the mixture if desired and mixing the same. As a base for a cataplasm, there may be mentioned, for example, water-soluble polymer such as polyacrylic acid, polyvinyl alcohol and polyvinyl pyrrolidone and the like. The cataplasm can be prepared, for example, by mixing an active ingredient, the base and an optionally desired additive(s) for a preparation, heating the same and then cooling. As a base for the plaster, patch or plaster, there may be used, for example, a support such as non-woven fabric and the like, an elastomer such as natural rubber, isoprene rubber and the like, a filler such as zinc flower, titanium oxide and the like, a tackifier such as a terpene resin and the like, a peeling agent such as vinyl acetate and the like, a softening agent such as liquid paraffin and the like, an anti-aging agent such as dibutylhydroxytoluene (BHT) and the like, in an optional combination thereof. The plaster, patch, plaster and the like can be prepared by the conventional manner such as a solution method, a thermocompression method and the like. As the solvent for the preparation of the liquid, there may be mentioned, for example, water, ethanol, isopropyl alcohol, benzyl alcohol, polyethylene glycol (PEG400 and the like), propylene glycol, propylene carbonate or a mixture thereof, and the like. Also, said liquid may be used by impregnating with gause, a wound dressing and the like. [0017] An amount of the active ingredient to be formulated into the above-mentioned preparation may vary depending on a form of the preparation, and, for example, in the case of an ointment or a cream, it is preferably 0.0025 to 5% by weight, particularly 0.005 to 0.5% by weight, and in the 14 case of a liquid, it is preferably 0.1 to 200 mg/mL, particularly 0.2 to 2 0 mg/mL. An administration dose of the dermatitis treating agent of the present invention may be determined depending on a kind or symptom of dermatitis and the like, and a suitable amount of the above-mentioned preparation may be applied to a diseased area once to several times per day. In the present specification, the term lower alkyl or lower alkoxy means an alkyl or alkoxy having 1 to 6 carbon atoms, preferably an alkyl or alkoxy having 1 to 4 carbon atoms, and cyclo-lower alkyl means a cycloalkyl having 3 to 8 carbon atoms, preferably a cycloalkyl having 3 to 6 carbon atoms. EXAMPLES [0018] In the following, the present invention is specific- ally explained by referring to Experiments and the like, but the present invention is not limited by these Experi- ments and the like. Experiment (1) Effects of test compounds in contact dermatitis model (method) BALB/c male mice (BALB/c AnNCrlCrlj, 5-weeks old, acclimating term: one week, body weight: 2 0 to 3 0 g, one group: 4 to 6 mice, available from CHARLES RIVER LABORATORIES JAPAN, INC.) were sensitized by epicutaneous application of 100 uL 0.5% (w/v) oxazolone solution (Solvent: acetone) on the shaved abdomen (Day 0). At the 7th day (Day 7) after sensitization, mice were challenged on both sides of right ears by topical application of 20 uL (10 uL for each side) 0.5% (w/v) oxazolone solution containing 1% (w/v) of respective test compounds (Solvent: acetone or an equal amount mixture of acetone/ethanol). Ear thickness was measured before and 24 hours after challenge by using a thickness gauge. In the control group, sensitized animals were challenged with 20 uL 0.5% 15 (w/v) oxazolone solution containing no test compound (Solvent: acetone) on right ears. (Test compound) Test compounds used in this Experiment are shown in the following Tables 1 to 3. [0022] (Results) Effects of the respective test compounds were expressed as ear swelling inhibitory rate (%) given by the following formula. The results are as shown in the following Table 4. Ear swelling inhibitory rate (%)=[l-(mean ear swelling of group treated with test compound/mean ear swelling of control group)]xl0 0 Note) Ear swelling = Ear thickness 24 hours after challenge at Day 7 - Ear thickness before challenge at Day 7 [0023] (2) Effects of test compounds on dermatitis models induced by repeated topical application of hapten (method) At Day 7, BALB/c male mice (BALB/c AnNCrlCrlj, 5- weeks old, acclimating term: one week, body weight: 20 to 3 0 g, one group: 4 to 6 mice, available from CHARLES RIVER LABORATORIES JAPAN, INC.) were sensitized on both sides of 19 right ears by a topical application of 2 0uL (10 uL for each side) 0.5% (w/v) oxazolone solution (Solvent: acetone)(Day -7) . At the respective points of the 7th day (Day 0) , 9th day (Day 2), 11th day (Day 4), 14th day (Day 7) and 16th day (Day 9) after sensitization, mice were challenged on the both sides of right ears by topical application of 2 0uL (10 uL for each side) 0.5% (w/v) oxazolone solution containing 1% (w/v) of the respective test compounds (Solvent: acetone or an equal amount mixture of acetone/ethanol). Ear thickness was measured before challenge of the test compound solution or suspension by using a thickness gauge. At the final day (Day 9), ear thickness was measured also 24 hours after challenge. In control group, sensitized animals were challenged with 20 uL 0.5% (w/v) oxazolone solution containing no test compound (Solvent: acetone) on right ears. Test compound: Compounds described in the above-mentioned Tables 1 to 3 were used. Results: Effects of the respective test compounds were expressed as ear swelling inhibitory rate (%) given by following formula. The results are as shown in Table 4. Ear swelling inhibitory rate (%)=[1-(mean ear swelling of group treated with test compound/mean ear swelling of control group)]xl00 Note) Ear swelling = (Thickness of ear 24 hours after final challenge at Day 9) - (Thickness of ear before sensitization at Day -7) [0024] [0025] Preparation example 1 (1) 200 mL of a toluene solution containing 20.00 g of 1- (2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxy- naphthalene was sonicated under reduced pressure, then, 975 mg of palladium acetate, 1009 mg of tri-tert-butyl- phosphonium tetrafluoroborate, 13.72 g of (4S)-4-(tert- butyldimethylsilyloxy) -1, 2 , 3 , 4-tetrahydroquinoline and 6.2 6 g of sodium tert-butoxide were added to the mixture under room temperature, and after replacing the atmosphere with 21 nitrogen, the mixture was stirred at 100°C for 4 hours. After cooling the mixture by allowing to stand, 10 0 mL of a saturated aqueous ammonium chloride solution, 100 mL of water and 100 mL of ethyl acetate were added to the reaction mixture, and said mixture was filtered with Celite. Celite was washed with 100 mL of ethyl acetate, and the organic layer was separated. Said organic layer was washed with 100 g of 20% saline solution, dried over anhydrous magnesium sulfate and then concentrated. The resulting residue was purified by column chromatography on silica gel (n-hexane:ethyl acetate=5:l to 4:1) to obtain 22.31 g (Yield: 80%) of 1-[2-[(4S)-4-(tert-butyldimethyl- silyloxy)-1,2,3,4-tetrahydroquinolin-l-yl]-4-pyridyl]-2,3- bis(methoxycarbonyl)-6,7-dimethoxynaphthalene. MS (APCI) m/z: 643 [M+H]+ [α]D28=-62° (methanol, c=l) [0026] (2) To 212 mL of a tetrahydrofuran solution containing 21.21 g of the compound obtained in the above-mentioned (1) was added 8.74 g of sodium borohydride at room temperature, and then, 16.9 mL of methanol was added dropwise to the mixture at 60°C over 2 hours. To said reaction mixture was further added 8.74 g of sodium borohydride at the same temperature, and 16.9 mL of methanol was added dropwise to the mixture over 2 hours. After cooling the mixture by allowing to stand, 212 g of 20% saline solution was added to the reaction mixture, and the mixture was extracted with 212 mL of ethyl acetate. The aqueous layer was extracted with 212 mL of ethyl acetate, the organic layers were combined and washed with 212 g of 20% saline solution, dried over 10.6 g of anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (Solvent; n-hexane/ethyl acetate=l/l to 2/1) to obtain 17.86 g (Yield: 92%) of 1-[2-[(4S)-4-(tert-butyldimethyl- silyloxy)-1,2,3,4-tetrahydroquinolin-l-yl]-4-pyridyl]-2,3- 22 bis(hydroxymethyl)-6,7-dimethoxynaphthalene. MS (APCI) tn/z: 587 [M+H]+ [α]D28=-77° (methanol, c=1) [0027] (3) To 17.00 g of the compound obtained by the above- mentioned (2) were added 8.3 mL of acetic acid and 289 mL of 1M tetrabutyl ammonium fluoride-tetrahydrofuran solution in a water-bath, and the mixture was stirred at room tem- perature for 4 hours. To the reaction mixture was further added 145 mL of 1M tetrabutyl ammonium fluoride-tetrahydro- furan solution at room temperature, and the mixture was stirred at the same temperature for 2 hours. To the reaction mixture were added 6% aqueous sodium hydrogen carbonate solution and 25% saline solution, and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and the filtrate was concen- trated under reduced pressure. The resulting residue was purified by column chromatography on silica gel (Solvent; chloroform/methanol=99/l to 96/4) to obtain 10.4 g (Yield: 72%) of 1-[2-[ (4S)-4-hydroxy-l,2,3,4-tetrahydroquinolin-l- yl]-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene as a crude product. To 3 0.6 mL of an ethanol solution containing 10.2 g of said compound was added 10.6 mL of water at 40°C. After precipitation of crystals, 306 mL of water was added to the mixture to cool the same. Precipitated crystals were collected by filtration, washed with 2 0.6 mL of water, and dried at room temperature under reduced pressure to obtain 8.66 g (Yield: 85%, Optical purity: 99.9% ee) of 1-[2-[(4S)-4-hydroxy-l,2,3,4-tetra- hydroquinolin-1-yl]-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7- dimethoxynaphthalene as crystals. MS (APCI) m/z: 493 [M+H]+ [α]D22=-92.2° (methanol, c = l) [0028] Preparation example 2 Corresponding starting compounds were treated in the 23 same manner as in Preparation example 1 to give l-[2-[(4R)- 4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl]-4-pyridyl]-2,3- bis(hydroxymethyl)-6,7-dimethoxynaphthalene. [0029] Reference example (1) In 20 mL of tetrahydrofuran was dissolved 5.04 g of 2,3-dihydro-4-quinolone at 25°C, then, to the solution were added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water and 4.73 g of potassium carbonate under ice-cooling, and said mixture was stirred at 25°C for 24 hours. Ethyl acetate was added to the reaction mixture, and the organic layer was separated, dried over anhydrous magnesium sul- fate, and then, filtered. The filtrate was concentrated, and the residue was dissolved in 35 mL of isopropyl alcohol under heating. Said solution was gradually cooled, and the precipitated crystals were collected by filtration under ice-cooling. The resulting crystals were washed with 25 mL of cold isopropyl alcohol, and dried at 50°C for 16 hours to obtain 8.98 g (Yield: 93%) of l-benzyloxycarbonyl-2,3- dihydro-4 -quinolone. MS (APCI) m/z: 282 [M+H]+ IR (ATR) v=1708, 1683cm"1 [0030] (2) To a mixture comprising 1.0 mL of a (R)-2-methyl-CBS- oxazaborolidine solution and 5 mL of tetrahydrofuran was added dropwise 1.4 mL of 1.0M borane•tetrahydrofuran complex at 25°C, and the mixture was stirred at the same temperature for 15 minutes. To said reaction mixture was added dropwise 7 mL of a tetrahydrofuran solution contain- ing 281 mg of the compound obtained in the above-mentioned (1) over 5 minutes. After adding 1 mL of methanol dropwise to the reaction mixture, the mixture was concentrated under reduced pressure, and 10 mL of dichloromethane and 10 mL (pH 4.0) of a phthalate buffer were added to the residue. The aqueous layer was removed from said mixture, and then, water was added to the same. The organic layer was 24 collected by separation, dried over anhydrous magnesium sulfate, and then, filtered. The filtrate was concentrat- ed, and the resulting residue was purified by column chromatography on silica gel (Solvent; hexane/ethyl acetate=2:l) to obtain 283 mg (Yield: quantitative, Optical purity: 97% ee) of (4S)-l-benzyloxycarbonyl-4-hydroxy- 1,2,3,4-tetrahydroquinoline. MS (APCI) m/z: 301 [M+H]+ IR (ATR) v=3417, 1686cm"1 [0031] (3) To 424 mL of a dimethylformamide solution containing 28.33 g of the compound obtained in the above-mentioned (2) were added 40.85 g of imidazole and 45.22 g of tert-butyl- dimethylsilyl chloride at room temperature, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was concentrated, and then, 280 mL of ethyl acetate and 14 0 mL of water were added to the residue to wash the same. The organic layer was washed with 140 mL of 10% aqueous citric acid solution, 140 mL of 3% aqueous sodium hydrogen carbonate solution and 57 mL of 2 0% saline solution, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under reduced pressure to obtain 39.28 g (Yield: 98.8%) of (4S)-1-benzyl oxycarbonyl-4-tert-butyldimethylsilyloxy-l,2,3,4-tetra- hydroquinoline . [0032] (4) To 3 93 mL of an ethanol solution containing 3 9.28 g of the compound obtained in the above-mentioned (3) was added 1.96 g of palladium carbon under nitrogen atmosphere, and the mixture was stirred under hydrogen atmosphere for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated. The resulting residue was purified by column chromatography on silica gel (Solvent; n- hexane/ethyl acetate=30/l to 20/1) to obtain 14.82 g (Yield: 56.9%, Optical purity: 98.8% ee) of (4S)-4-tert- butyldimethylsilyloxy-1,2,3,4-tetrahydroquinoline. 25 [α]D28=-128.6° (methanol, c = 1.10) UTILIZABILITY IN INDUSTRY [0033] The topical dermatitis treating agent of the present invention shows excellent ear swelling inhibitory effect in dermatitis model so that it is useful for treatment of dermatitis such as atopic dermatitis, contact dermatitis and the like. 26 CLAIMS 1. A topical dermatitis treating agent which comprises a pyridine compound represented by the following formula [I]: wherein R1 and R2 each represent a lower alkoxy group, =X- represents a group represented by the formula: or a group represented by the formula: =N-, Ring A represents a saturated or unsaturated bicyclic nitrogen-containing heterocyclic group having 1 to 4 substituents selected from hydroxyl group, oxo group, a lower alkoxy group, a di-lower alkylaminophenyl group, a pyperidino-lower alkoxy group, a morpholino- lower alkoxy group, a cyclo-lower alkylamino-lower alkylamino group, pyridyl group and morpholino group, and represents a single bond or a double bond, or a pharmaceutically acceptable salt thereof as an active ingredient. 2. The topical dermatitis treating agent according to Claim 1, wherein the saturated or unsaturated bicyclic nitrogen-containing heterocyclic group is quinolyl group, dihydroquinolyl group, tetrahydroquinolyl group, iso- quinolyl group, dihydroisoquinolyl group, tetrahydroiso- quinolyl group, phthalazinyl group or dihydrophthalazinyl group. 3. The topical dermatitis treating agent according to 27 Claim 1, wherein R1 and R2 are methoxy groups, and =X- is a group represented by the formula: 4. The topical dermatitis treating agent according to Claim 1, wherein R1 and R2 are methoxy groups, and =X- is a group represented by the formula: =N-. 5. The topical dermatitis treating agent according to Claim 1, wherein Ring A is a group represented by the formula: 6. A topical dermatitis treating agent which comprises a compound selected from 1-[2-(1,2-dihydro-3-morpholino-2-oxoquinolin-l-yl)pyridin- 4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene; 1-[2-[1,2-dihydro-5-(2-piperidinoethoxy)-1-oxoisoquinolin- 2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene; 28 1-[2-[l,2-dihydro-5-(2-morpholinoethoxy)-1-oxoisoquinolin- 2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy- naphthalene; 1-[2-[l,2-dihydro-3-oxoisoquinolin-2-yl]pyridin-4-yl]-2,3- bis (hydroxymethyl) -6, 7-ditnethoxynaphthalene; 1-[2-(4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl)pyridin-4- yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene; 1-[2-[(4S)-4-hydroxy-1,2,3,4-tetrahydroquinolin-l-yl]- pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphtha- lene; 1-[2-[(4R)-4-hydroxy-1,2,3,4-tetrahydroquinolin-l-yl]- pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphtha- lene; 1-[2-[1,2-dihydro-4-[3-(cyclohexylamino)propylamino]-2- oxoquinolin-1-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7- dimethoxynaphthalene ,- 1-[2-[4-(dimethylaminophenyl)phthalazin-l(2H)-one-2-yl]- pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphtha- lene; 1-[2-[6,7-dimethoxy-4-(3-pyridyl)phthalazin-l(2H)-one-2- yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7- dimethoxynaphthalene; and (3S)-1-[2-[4-(dimethylaminophenyl)phthalazin-1(2H)-one-2- yl]pyridin-4-yl]-3,4-dihydro-3-hydroxymethyl-6,7-dimethoxy- isoquinoline or a pharmaceutically acceptable salt thereof as an active ingredient. 7. The topical dermatitis treating agent according to Claim 1, wherein the agent is a treating agent for atopic dermatitis, contact dermatitis, seborrheic dermatitis, psoriasis or eczema. 8. Use of the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof according to Claim 1 for the manufacture of a preparation to be used for a 29 topical dermatitis treating agent. 9. A method of treating dermatitis which comprises applying a preparation comprising the compound represented by the formula [I] or a pharmaceutically acceptable salt thereof according to Claim 1 as an active ingredient to an affected part. 10. A method for preparing a compound represented by the following formula [I]: wherein R1 and R2 each represent a lower alkoxy group, =X- represents a group represented by the formula: Ring A represents a group represented by the following formula: which comprises the following steps of (1) to (6): (1) subjecting a 4-oxotetrahydxoquinoline compound represented by the formula [V]: 30 wherein R represents a protective group for amino group, to asymmetric reduction in the presence of a CBS catalyst and a hydrogenated boron compound, (2)introducing a protective group (Z) into the hydroxyl group at the 4-position of the product obtained in the step (1), (3)rexnoving the protective group (R) for the amino group from the product obtained in the step (2). (4)condensing an optically active tetrahydroquinoline compound obtained in the step (3) represented by the following formulaJ wherein 02 represents a protected hydroxyl group, and a compound represented by the following formula [II]: wherein Ra represents a protective group for carboxyl group, =Xi- represents a group represented by the formula: (Rb represents a protective group for carboxyl group), r represents a halogen atom, and the other symbols have the same meanings as defined above, (5)reducing the product obtained in the step (4), and (6) removing the protective group (Z) for the hydroxyl group from the product obtained in the step (5). 11. The method according to claim 10, wherein the CBS catalyst is (R)- or (S)-2-methyl-CBS-oxazaborolidine. Dermatitis remedies for external use, containing as the active ingredient compounds represented by the general formula [I] or pharmacologically acceptable salts thereof: [I] wherein R1 and R2 are each lower alkoxy; =X- is the group represented by the following formula: or the group represented by formula: =N-; A is a saturated or unsaturated nitrogen-containing heterobicyclic group having one to four substituents selected from among hydroxyl, oxo, lower alkoxy, di(lower alkyl)aminophenyl, piperidino(lower alkoxy), morpholino(lower alkoxy), cyclo(lower alkyl)amino(lower alkyl)amino, pyridyl, and morpholino; and symbol represents a single or double bond.

Full Text

1
SPECIFICATION
DERMATITIS TREATING AGENT
TECHNICAL FIELD
[0001]
The present invention relates to a novel topical
agent useful for treatment of dermatitis such as atopic
dermatitis and the like.
BACKGROUND ART
[0002]
Dermatitis is an inflammatory disease at the skin
against various kinds of endogenetic and exogenetic
invasion, and the disease includes atopic dermatitis,
contact dermatitis, seborrheic dermatitis, nummular eczema,
autosensitization eczema and the like. These dermatitises
accompany itching in many cases. Also, of these, atopic
dermatitis is a refractory chronic inflammatory disease
which repeats remission and exacerbation, and involvement
of a late phase reaction that accompanies invasion of
eosinophils or lymphocyte and production of various kinds
of cytokines at a site of inflammation has been suggested
for pathogeny and chronicity of the disease (Non-Patent
Literatures 1 and 2).
For the treatment of atopic dermatitis, a treatment
by a medicament depending on the symptom has been employed
in combination with removal of factors of causing diseases
or exacerbation and skin care, and a topical steroid agent
has mainly been used against inflammation. Also,
tacrolimus which is a kind of an immunosuppressive agent
has recently been used for the treatment of atopic
dermatitis. However, these existing medicaments are not
necessarily satisfied in the points of safety and side
effects. Thus, it has been desired to develop a
therapeutic agent for dermatitis not only having

2
effectiveness but also high safety.
It has been known that Compound [I] which is an
active ingredient of the present invention has selective
phosphodiesterase IV (PDE IV) inhibitory activity, and
useful as an agent for prophylaxis and treatment of asthma
and the like. (Patent Literatures 1 and 2). However, it
has not been reported that said Compound [I] is useful as
an agent for treatment of dermatitis such as atopic
dermatitis and the like.
[0003]
Patent Literature 1: EP 748,805 B (p. 2)
Patent Literature 2: EP 848,000 B (p. 2)
Non-Patent Literature 1: Iwamoto et al., J. Leukoc. Biol.,
Vol.52, pp.572-578 (1992)
Non-Patent Literature 2: Frigas et al., J. Allergy Clin.
Immunol., Vol. 77, pp.527-537 (1986)
DISCLOSURE OF THE INVENTION
PROBLEMS TO BE SOLVED BY THE INVENTION
[0004]
The present invention is to provide a novel topical
agent useful for treatment of dermatitis such as atopic
dermatitis and the like.
MEANS TO SOLVE THE PROBLEMS
[0005]
The present invention relates to a topical dermatitis
treating agent which comprises, as an active ingredient, a
compound represented by the following formula [I]:

3
wherein R1 and R2 each represent a lower alkoxy group,
=X- represents a group represented by the formula:

or a group represented by the formula: =N-, Ring A
represents a saturated or unsaturated bicyclic
nitrogen-containing heterocyclic group having 1 to 4
substituents selected from oxo group, hydroxyl group,
a lower alkoxy group, a di-lower alkylaminophenyl
group, a pyperidino-lower alkoxy group, a morpholino-
lower alkoxy group, a cyclo-lower alkylamino-lower
alkylamino group, pyridyl group and morpholino group,
and rrrr represents a single bond or a double bond,
or a pharmaceutically acceptable salt thereof.
[0006]
The present invention also relates to a use of the
compound represented by the above-mentioned formula [I] or
a pharmaceutically acceptable salt thereof for the
manufacture of a preparation to be used for a topical
treatment of dermatitis.
The present invention further relates to a method for
treating dermatitis which comprises applying a preparation
comprising the compound represented by the above-mentioned
formula [I] or a pharmaceutically acceptable salt thereof
as an active ingredient to affected part.
EFFECTS OF THE INVENTION
[0007]
The topical dermatitis treating agent of the present
invention showed an excellent ear swelling inhibitory
effect in a dermatitis model (mouse), so that it is useful
for the treatment of dermatitis such as atopic dermatitis
and the like. Also, it has a little side effect on a skin
(photosensitivity, cytotoxicity and the like), so that it
has a characteristic that safety is high as a topical
dermatitis treating agent.

4
BEST MODE TO CARRY OUT THE INVENTION
[0008]
In Compound [I] which is an active ingredient of the
present invention, as the saturated or unsaturated bicyclic
nitrogen-containing heterocyclic group represented by Ring
A, there may be mentioned, for example, quinolyl group,
dihydroquinolyl group, tetrahydroquinolyl group,
isoquinolyl group, dihydroisoquinolyl group, tetrahydro-
isoquinolyl group, phthalazinyl group, dihydrophthalazinyl
group or the like. Of these, tetrahydroquinolyl group or
dihydroisoquinolyl group is preferred. Specific examples
of the substituents on these heterocyclic group may be
mentioned 1 to 4 groups selected from oxo group, hydroxyl
group, a lower alkoxy group (methoxy group and the like), a
di-lower alkylaminophenyl group (dimethylaminophenyl group
and the like), a piperidino-lower alkoxy group (piperidino-
ethoxy group and the like), a morpholino-lower alkoxy group
(morpholinoethoxy group and the like), a cyclo-lower
alkylamino-lower alkylamino group (cyclohexylaminopropyl-
amino group and the like), pyridyl group and morpholino
group.
As the lower alkoxy group of R1 and R2, there may be
mentioned, for example, methoxy group, ethoxy group or the
like, and of these, methoxy group is preferred.
Among Compounds [I] which are active ingredients of
the present invention, specific examples of the preferred
compounds may be mentioned a compound wherein R1 and R2 are
methoxy groups, and =X- is a group represented by the
formula:

As the other preferred Compound [I], there may be
mentioned a compound wherein R1 and R2 are methoxy groups,
and =X- is a group represented by the formula: =N-.
[0009]
Among Compounds [I] which are active ingredients of

5
the present invention, more preferred compounds may be
mentioned a compound wherein Ring A is a group represented
by the formula:

[0010]
Among the above-mentioned active ingredients
according to the present invention, particularly preferred
compounds may be mentioned a compound selected from
1-[2-(1,2-dihydro-3-morpholino-2-oxoquinolin-l-yl)pyridin-
4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene;
1-[2-[1,2-dihydro-5-(2-piperidinoethoxy)-1-oxoisoquinolin-
2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene;
1-[2-[1,2-dihydro-5-(2-morpholinoethoxy)-1-oxoisoquinolin-
2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene;
1-[2-[l,2-dihydro-3-oxoisoquinolin-2-yl]pyridin-4-yl]-2,3-
bis(hydroxymethyl)-6,7-dimethoxynaphthalene;
1-[2-(4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl)pyridin-4-
yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene;
1-[2-[(4S)-4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl]-

6
pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene;
1-[2-[(4R)-4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl]-
pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene;
1-[2-[1,2-dihydro-4-[3-(cyclohexylamino)propylamino]-2-
oxoquinolin-1-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-
dimethoxynaphthalene;
1-[2-[4-(dimethylaminophenyl)phthalazin-l(2H)-one-2-yl]-
pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene,-
1-[2-[6,7-dimethoxy-4-(3-pyridyl)phthalazin-l(2H)-one-2-
yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene; and
(3S)-1- [2- [4-(dimethylaminophenyl)phthalazin-1(2H)-one-2-
yl]pyridin-4-yl]-3,4-dihydro-3-hydroxymethyl-6,7-dimethoxy-
isoquinoline;
or a pharmaceutically acceptable salt thereof.
[0011]
In Compound [I] which is an active ingredient of the
present invention, when it has an asymmetric carbon on the
dihydroisoquinoline skeleton or the cyclic group A, there
are a plural number of stereoisomers (diastereomeric
isomer, optical isomer) based on the asymmetric carbon(s),
and both of either one of stereoisomers and a mixture
thereof are contained in the active ingredient(s) of the
present invention.
Moreover, in Compound [I] which is an active
ingredient of the present invention, solvated products such
as a hydrate and the like are contained.
As a pharmaceutically acceptable salt of the above-
mentioned Compound [I], there may be mentioned, for
example, an inorganic salt such as hydrochloride, sulfate
and hydrobromide, an organic acid salt such as acetate,
fumarate, oxalate, methanesulfonate, maleate and p-toluene-
sulfonate.

7
[0012]
The topical dermatitis treating agent of the present
invention is useful for treatment of atopic dermatitis,
contact dermatitis, seborrheic dermatitis, psoriasis,
eczema (nummular eczema, autosensitization eczema and the
like) and the like.
Also, in Compound [I] which is an active ingredient
of the present invention, a compound which does not
substantially show toxicity such as local irritation, skin
photosensitivity and the like, at least in the range of an
effective dose for topical dermatitis treatment. A topical
dermatitis treating agent comprising such a compound of the
present invention is useful in the point of safety.
[0013]
The above-mentioned Compound [I] or a pharmaceuti-
cally acceptable salt thereof can be obtained by a known
method (for example, a method disclosed in EP Patent No.
748,805 or EP Patent No. 848,000: see the following
reaction scheme).

In the above-mentioned reaction scheme, Ra represents
a protective group for carboxyl group, =XX- represents
a group represented by the formula: =N- or represented
by the formula:

(Rb represents a protective group for carboxyl group)
Y represents a halogen atom, and the other symbols

8
have the same meanings as defined above.
As the protective group for the carboxyl group, there
may be mentioned, for example, a lower alkyl group and the
like.
Among Compound [I] which is an active ingredient of
the present invention, a compound wherein Ring A is a group
represented by the following formula:

can be prepared, for example, by condensing an optically
active tetrahydroquinoline compound represented by the
following formula:

wherein OZ represents a protected hydroxyl group,
and Compound [II], reducing said reaction product by sodium
borohydride and the like, and then, removing the protective
group (for example, tert-butyldimethylsilyl group and the
like) for the hydroxyl group from the product.
The above-mentioned optically active tetrahydro-
quinoline compound [III-a] or [Ill-b] can be prepared, for
example, by subjecting a 4-oxotetrahydroquinoline compound
represented by the formula [V]:

wherein R represents a protective group for amino
group,
to asymmetric reduction in the presence of a CBS catalyst
such as (R)- or (S)-2-methyl-CBS-oxazaborolidine and a

9
hydrogenated boron compound, then, introducing a protective
group such as a tert-butyldimethylsilyl group and the like,
into the hydroxyl group at the 4-position of the product,
and removing the protective group (R) for the amino group.
As the protective group for the amino group, there may be
mentioned, for example, benzyloxycarbonyl group and the
like.
[0014]
In the topical dermatitis treating agent of the
present invention, in addition to Compound [I] or a pharma-
ceutically acceptable salt thereof which is an active
ingredient, an additive for a pharmaceutical preparation
such as an absorption enhancer, a pH adjusting agent, a
preservative, a flavoring agent, a dispersing agent, a
humectant, a stabilizer, a suspending agent, a surfactant
and the like, may be formulated alone or in combination of
two or more in admixture, if desired.
As the absorption enhancer, there may be mentioned,
for example, a monohydric alcohol having 2 0 or less carbon
atoms (ethyl alcohol, isopropyl alcohol, stearyl alcohol
and the like), pyrrolidone derivatives (2-pyrrolidone, 1-
methyl-2-pyrrolidone and the like), ureas (urea, thiourea
and the like), cyclodextrins (a-cyclodextrin and the like),
menthol, l-dodecylazacycloheptan-2-one, calcium thioglycol-
ate, limonene and the like. A content of the absorption
enhancer may vary depending on the dosage form, ingredients
of the base and the like, and in general, it is desirably
0.1% by weight or more, preferably 0.3% by weight or more
for the purpose of effectively producing a absorption-
enhancing action, and desirably 10% by weight or less,
preferably 5% by weight or less for the purpose of
inhibiting side effect.
Specific examples of the pH adjusting agent may be
mentioned, for example, an inorganic acid such as hydro-
chloric acid, sulfuric acid, phosphoric acid and the like,
an organic acid such as acetic acid, succinic acid, fumaric

10
acid, malic acid and the like, a metal salt of these acids
and the like. An amount of the pH adjusting agent to be
formulated may vary depending on the dosage form or
ingredients of the base, and in general, it is preferably
so formulated that a pH of the preparation becomes 4 to 8.
Specific examples of the preservative may be men-
tioned, for example, p-hydroxybenzoic acid, methylparaben,
chlorobutanol, benzyl alcohol, methyl p-hydroxybenzoate and
the like.
Specific examples of the flavoring agent may be
mentioned, for example, menthol, rose oil, eucalyptus oil,
d-camphor and the like, and specific examples of the
dispersing agent may be mentioned, for example, sodium
metaphosphate, potassium polyphosphate, silicic acid
anhydride and the like.
Specific examples of the humectant may be mentioned,
for example, propylene glycol, glycerin, sorbitol, sodium
lactate, sodium hyaluronate and the like, and specific
examples of the stabilizer may be mentioned, for example,
sodium hydrogen sulfite, tocopherol, ethylenediamine
tetraacetic acid (EDTA), citric acid and the like.
Specific examples of the suspending agent may be
mentioned, for example, tragacanth powder, Gum Arabic
powder, bentonite, sodium carboxymethyl cellulose and the
like, and specific examples of the surfactant may be
mentioned, for example, polyoxyethylene hardened caster
oil, sorbitan fatty acid ester such as sorbitan sesqui-
oleate and the like, polyoxyl stearate and the like.
[0015]
A dermatitis treating agent of the present invention
can be used as a topical agent for the purpose of directly
administering it to a dermatitis area, and a dosage form
thereof may be mentioned, for example, an ointment, a
cream, a lotion, a liniment, a cataplasm, a plaster, a
patch, a plaster, a liquid and the like.
When the above-mentioned dosage form is an ointment

11
or a cream, an oleaginous base, a water-soluble base, an
emulsion base or a suspension base can be used as a base.
As the oleaginous base, there may be mentioned, for
example, a hydrocarbon (a hydrocarbon having 12 to 32
carbon atoms, liquid paraffin, white vaseline, squalene,
squalane, plastibase and the like), a higher alcohol (an
aliphatic monohydric alcohol having 12 to 3 0 carbon atoms
such as lauryl alcohol, cetyl alcohol, stearyl alcohol,
oleyl alcohol and the like), a higher fatty acid (a
saturated or unsaturated fatty acid having 6 to 32 carbon
atoms such as palmitic acid and stearic acid), a higher
fatty acid ester (a fatty acid ester such as mirystyl
palmitate and stearyl stearate; an ester of a fatty acid
having 10 to 32 carbon atoms such as lanolin and carnauba
wax, and an aliphatic monohycric alcohol having 14 to 32
carbon atoms; an ester of a saturated or unsaturated fatty
acid having 10 to 22 carbon atoms and glycerin, such as
glyceryl monolaurate, and its hydrogenated product, and the
like), vegetable oil, animal oil and the like.
As the water-soluble base, there may be mentioned,
for example, a glycol (ethylene glycol, propylene glycol,
polyethylene glycol and the like), and the like.
As the emulsion base, there may be mentioned, for
example, an oil-in-water type base, a water-in-oil type
base and the like. As the oil-in-water type base, there
may be mentioned a base prepared by emulsifying or
dispersing a component such as the above-mentioned lanolin,
propylene glycol, stearyl alcohol, vaseline, silicone oil,
liquid paraffin, glyceryl monostearate, polyethylene glycol
and the like, in an aqueous phase in the presence or in the
absence of a surfactant, and the like. As the water-in-oil
type base, there may be mentioned a base prepared by adding
water to a component such as vaseline, a higher aliphatic
alcohol, liquid paraffin and the like, in the presence of a
nonionic surfactant, and emulsifying or dispersing the
mixture, and the like. Also, as the suspension base, there

12
may be mentioned an aqueous base prepared by adding a
suspending agent such as starch, glycerin, a high viscosity
carboxymethyl cellulose, carboxyvinyl polymer and the like
to water to make a gel, and the like.
A dermatitis treatment agent of the present invention
can be prepared by a conventionally employed preparation
method of a topical preparation. For example, an ointment
or a cream can be prepared by mixing and kneading,
emulsifying or suspending raw materials of a base depending
on the respective dosage form to prepare the base, adding
an active ingredient(s) and various kinds of additives, and
mixing it in a mixer such as a screw mixer and the like.
[0016]
The lotion can be used in any form such as a
suspension type, emulsion type and solution. As a base for
the suspension type lotion, there may be mentioned a
mixture of a suspending agent including gums such as gum
arabic, gum tragacanth and the like, celluloses such as
methyl cellulose, hydroxyethyl cellulose and the like,
clays such as bentonite and the like with water, and the
like. As a base for the emulsion type lotion, there may be
mentioned a base in which water and an oily substance
including an aliphatic acid such as stearic acid, oleic
acid and the like, a higher alcohol such as stearyl
alcohol, cetyl alcohol and the like, are emulsified, and
the like. As a base for the solution type lotion, there
may be mentioned water and an alcohol such as ethanol,
glycerin, propylene glycol and the like. The lotion can be
prepared, for example, by adding various base components to
purified water, mixing and stirring the same, then, adding
an active ingredient(s) and an additive(s) to the mixture,
and subjecting to filtration, if necessary.
As a base for the liniment, there may be mentioned,
for example, vegetable oils such as olive oil and the like,
alcohols such as ethanol, isopropanol and the like, or a
mixture of the above with water, and the like. The

13
liniment can be prepared, for example, by dissolving an
active ingredient in the base, and adding an additive(s)
for a preparation to the mixture if desired and mixing the
same.
As a base for a cataplasm, there may be mentioned,
for example, water-soluble polymer such as polyacrylic
acid, polyvinyl alcohol and polyvinyl pyrrolidone and the
like. The cataplasm can be prepared, for example, by
mixing an active ingredient, the base and an optionally
desired additive(s) for a preparation, heating the same and
then cooling.
As a base for the plaster, patch or plaster, there
may be used, for example, a support such as non-woven
fabric and the like, an elastomer such as natural rubber,
isoprene rubber and the like, a filler such as zinc flower,
titanium oxide and the like, a tackifier such as a terpene
resin and the like, a peeling agent such as vinyl acetate
and the like, a softening agent such as liquid paraffin and
the like, an anti-aging agent such as dibutylhydroxytoluene
(BHT) and the like, in an optional combination thereof.
The plaster, patch, plaster and the like can be prepared by
the conventional manner such as a solution method, a
thermocompression method and the like.
As the solvent for the preparation of the liquid,
there may be mentioned, for example, water, ethanol,
isopropyl alcohol, benzyl alcohol, polyethylene glycol
(PEG400 and the like), propylene glycol, propylene
carbonate or a mixture thereof, and the like. Also, said
liquid may be used by impregnating with gause, a wound
dressing and the like.
[0017]
An amount of the active ingredient to be formulated
into the above-mentioned preparation may vary depending on
a form of the preparation, and, for example, in the case of
an ointment or a cream, it is preferably 0.0025 to 5% by
weight, particularly 0.005 to 0.5% by weight, and in the

14
case of a liquid, it is preferably 0.1 to 200 mg/mL,
particularly 0.2 to 2 0 mg/mL. An administration dose of
the dermatitis treating agent of the present invention may
be determined depending on a kind or symptom of dermatitis
and the like, and a suitable amount of the above-mentioned
preparation may be applied to a diseased area once to
several times per day.
In the present specification, the term lower alkyl or
lower alkoxy means an alkyl or alkoxy having 1 to 6 carbon
atoms, preferably an alkyl or alkoxy having 1 to 4 carbon
atoms, and cyclo-lower alkyl means a cycloalkyl having 3 to
8 carbon atoms, preferably a cycloalkyl having 3 to 6
carbon atoms.
EXAMPLES
[0018]
In the following, the present invention is specific-
ally explained by referring to Experiments and the like,
but the present invention is not limited by these Experi-
ments and the like.
Experiment
(1) Effects of test compounds in contact dermatitis model
(method)
BALB/c male mice (BALB/c AnNCrlCrlj, 5-weeks old,
acclimating term: one week, body weight: 2 0 to 3 0 g, one
group: 4 to 6 mice, available from CHARLES RIVER
LABORATORIES JAPAN, INC.) were sensitized by epicutaneous
application of 100 uL 0.5% (w/v) oxazolone solution
(Solvent: acetone) on the shaved abdomen (Day 0). At the
7th day (Day 7) after sensitization, mice were challenged
on both sides of right ears by topical application of 20 uL
(10 uL for each side) 0.5% (w/v) oxazolone solution
containing 1% (w/v) of respective test compounds (Solvent:
acetone or an equal amount mixture of acetone/ethanol).
Ear thickness was measured before and 24 hours after
challenge by using a thickness gauge. In the control
group, sensitized animals were challenged with 20 uL 0.5%

15
(w/v) oxazolone solution containing no test compound
(Solvent: acetone) on right ears.
(Test compound)
Test compounds used in this Experiment are shown in
the following Tables 1 to 3.

[0022]
(Results)
Effects of the respective test compounds were
expressed as ear swelling inhibitory rate (%) given by the
following formula. The results are as shown in the
following Table 4.
Ear swelling inhibitory rate (%)=[l-(mean ear swelling of
group treated with test compound/mean ear swelling of
control group)]xl0 0
Note) Ear swelling = Ear thickness 24 hours after challenge
at Day 7 - Ear thickness before challenge at Day 7
[0023]
(2) Effects of test compounds on dermatitis models induced
by repeated topical application of hapten
(method)
At Day 7, BALB/c male mice (BALB/c AnNCrlCrlj, 5-
weeks old, acclimating term: one week, body weight: 20 to
3 0 g, one group: 4 to 6 mice, available from CHARLES RIVER
LABORATORIES JAPAN, INC.) were sensitized on both sides of

19
right ears by a topical application of 2 0uL (10 uL for each
side) 0.5% (w/v) oxazolone solution (Solvent: acetone)(Day
-7) . At the respective points of the 7th day (Day 0) , 9th
day (Day 2), 11th day (Day 4), 14th day (Day 7) and 16th
day (Day 9) after sensitization, mice were challenged on
the both sides of right ears by topical application of 2 0uL
(10 uL for each side) 0.5% (w/v) oxazolone solution
containing 1% (w/v) of the respective test compounds
(Solvent: acetone or an equal amount mixture of
acetone/ethanol). Ear thickness was measured before
challenge of the test compound solution or suspension by
using a thickness gauge. At the final day (Day 9), ear
thickness was measured also 24 hours after challenge. In
control group, sensitized animals were challenged with 20
uL 0.5% (w/v) oxazolone solution containing no test
compound (Solvent: acetone) on right ears.
Test compound:
Compounds described in the above-mentioned Tables 1
to 3 were used.
Results:
Effects of the respective test compounds were
expressed as ear swelling inhibitory rate (%) given by
following formula. The results are as shown in Table 4.
Ear swelling inhibitory rate (%)=[1-(mean ear swelling of
group treated with test compound/mean ear swelling of
control group)]xl00
Note) Ear swelling = (Thickness of ear 24 hours after
final challenge at Day 9) - (Thickness of ear before
sensitization at Day -7)
[0024]

[0025]
Preparation example 1
(1) 200 mL of a toluene solution containing 20.00 g of 1-
(2-bromo-4-pyridyl)-2,3-bis(methoxycarbonyl)-6,7-dimethoxy-
naphthalene was sonicated under reduced pressure, then, 975
mg of palladium acetate, 1009 mg of tri-tert-butyl-
phosphonium tetrafluoroborate, 13.72 g of (4S)-4-(tert-
butyldimethylsilyloxy) -1, 2 , 3 , 4-tetrahydroquinoline and 6.2 6
g of sodium tert-butoxide were added to the mixture under
room temperature, and after replacing the atmosphere with

21
nitrogen, the mixture was stirred at 100°C for 4 hours.
After cooling the mixture by allowing to stand, 10 0 mL of a
saturated aqueous ammonium chloride solution, 100 mL of
water and 100 mL of ethyl acetate were added to the
reaction mixture, and said mixture was filtered with
Celite. Celite was washed with 100 mL of ethyl acetate,
and the organic layer was separated. Said organic layer
was washed with 100 g of 20% saline solution, dried over
anhydrous magnesium sulfate and then concentrated. The
resulting residue was purified by column chromatography on
silica gel (n-hexane:ethyl acetate=5:l to 4:1) to obtain
22.31 g (Yield: 80%) of 1-[2-[(4S)-4-(tert-butyldimethyl-
silyloxy)-1,2,3,4-tetrahydroquinolin-l-yl]-4-pyridyl]-2,3-
bis(methoxycarbonyl)-6,7-dimethoxynaphthalene.
MS (APCI) m/z: 643 [M+H]+
[α]D28=-62° (methanol, c=l)
[0026]
(2) To 212 mL of a tetrahydrofuran solution containing
21.21 g of the compound obtained in the above-mentioned (1)
was added 8.74 g of sodium borohydride at room temperature,
and then, 16.9 mL of methanol was added dropwise to the
mixture at 60°C over 2 hours. To said reaction mixture was
further added 8.74 g of sodium borohydride at the same
temperature, and 16.9 mL of methanol was added dropwise to
the mixture over 2 hours. After cooling the mixture by
allowing to stand, 212 g of 20% saline solution was added
to the reaction mixture, and the mixture was extracted with
212 mL of ethyl acetate. The aqueous layer was extracted
with 212 mL of ethyl acetate, the organic layers were
combined and washed with 212 g of 20% saline solution,
dried over 10.6 g of anhydrous magnesium sulfate, and
concentrated under reduced pressure. The resulting residue
was purified by column chromatography on silica gel
(Solvent; n-hexane/ethyl acetate=l/l to 2/1) to obtain
17.86 g (Yield: 92%) of 1-[2-[(4S)-4-(tert-butyldimethyl-
silyloxy)-1,2,3,4-tetrahydroquinolin-l-yl]-4-pyridyl]-2,3-

22
bis(hydroxymethyl)-6,7-dimethoxynaphthalene.
MS (APCI) tn/z: 587 [M+H]+
[α]D28=-77° (methanol, c=1)
[0027]
(3) To 17.00 g of the compound obtained by the above-
mentioned (2) were added 8.3 mL of acetic acid and 289 mL
of 1M tetrabutyl ammonium fluoride-tetrahydrofuran solution
in a water-bath, and the mixture was stirred at room tem-
perature for 4 hours. To the reaction mixture was further
added 145 mL of 1M tetrabutyl ammonium fluoride-tetrahydro-
furan solution at room temperature, and the mixture was
stirred at the same temperature for 2 hours. To the
reaction mixture were added 6% aqueous sodium hydrogen
carbonate solution and 25% saline solution, and extracted
with ethyl acetate. The extract was dried over anhydrous
magnesium sulfate, filtered and the filtrate was concen-
trated under reduced pressure. The resulting residue was
purified by column chromatography on silica gel (Solvent;
chloroform/methanol=99/l to 96/4) to obtain 10.4 g (Yield:
72%) of 1-[2-[ (4S)-4-hydroxy-l,2,3,4-tetrahydroquinolin-l-
yl]-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene as a crude product. To 3 0.6 mL of an ethanol
solution containing 10.2 g of said compound was added 10.6
mL of water at 40°C. After precipitation of crystals, 306
mL of water was added to the mixture to cool the same.
Precipitated crystals were collected by filtration, washed
with 2 0.6 mL of water, and dried at room temperature under
reduced pressure to obtain 8.66 g (Yield: 85%, Optical
purity: 99.9% ee) of 1-[2-[(4S)-4-hydroxy-l,2,3,4-tetra-
hydroquinolin-1-yl]-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-
dimethoxynaphthalene as crystals.
MS (APCI) m/z: 493 [M+H]+
[α]D22=-92.2° (methanol, c = l)
[0028]
Preparation example 2
Corresponding starting compounds were treated in the

23
same manner as in Preparation example 1 to give l-[2-[(4R)-
4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl]-4-pyridyl]-2,3-
bis(hydroxymethyl)-6,7-dimethoxynaphthalene.
[0029]
Reference example
(1) In 20 mL of tetrahydrofuran was dissolved 5.04 g of
2,3-dihydro-4-quinolone at 25°C, then, to the solution were
added 5.6 mL of benzyloxycarbonyl chloride, 15 mL of water
and 4.73 g of potassium carbonate under ice-cooling, and
said mixture was stirred at 25°C for 24 hours. Ethyl
acetate was added to the reaction mixture, and the organic
layer was separated, dried over anhydrous magnesium sul-
fate, and then, filtered. The filtrate was concentrated,
and the residue was dissolved in 35 mL of isopropyl alcohol
under heating. Said solution was gradually cooled, and the
precipitated crystals were collected by filtration under
ice-cooling. The resulting crystals were washed with 25 mL
of cold isopropyl alcohol, and dried at 50°C for 16 hours
to obtain 8.98 g (Yield: 93%) of l-benzyloxycarbonyl-2,3-
dihydro-4 -quinolone.
MS (APCI) m/z: 282 [M+H]+
IR (ATR) v=1708, 1683cm"1
[0030]
(2) To a mixture comprising 1.0 mL of a (R)-2-methyl-CBS-
oxazaborolidine solution and 5 mL of tetrahydrofuran was
added dropwise 1.4 mL of 1.0M borane•tetrahydrofuran
complex at 25°C, and the mixture was stirred at the same
temperature for 15 minutes. To said reaction mixture was
added dropwise 7 mL of a tetrahydrofuran solution contain-
ing 281 mg of the compound obtained in the above-mentioned
(1) over 5 minutes. After adding 1 mL of methanol dropwise
to the reaction mixture, the mixture was concentrated under
reduced pressure, and 10 mL of dichloromethane and 10 mL
(pH 4.0) of a phthalate buffer were added to the residue.
The aqueous layer was removed from said mixture, and then,
water was added to the same. The organic layer was

24
collected by separation, dried over anhydrous magnesium
sulfate, and then, filtered. The filtrate was concentrat-
ed, and the resulting residue was purified by column
chromatography on silica gel (Solvent; hexane/ethyl
acetate=2:l) to obtain 283 mg (Yield: quantitative, Optical
purity: 97% ee) of (4S)-l-benzyloxycarbonyl-4-hydroxy-
1,2,3,4-tetrahydroquinoline.
MS (APCI) m/z: 301 [M+H]+
IR (ATR) v=3417, 1686cm"1
[0031]
(3) To 424 mL of a dimethylformamide solution containing
28.33 g of the compound obtained in the above-mentioned (2)
were added 40.85 g of imidazole and 45.22 g of tert-butyl-
dimethylsilyl chloride at room temperature, and the mixture
was stirred at the same temperature for 1 hour. The
reaction mixture was concentrated, and then, 280 mL of
ethyl acetate and 14 0 mL of water were added to the residue
to wash the same. The organic layer was washed with 140 mL
of 10% aqueous citric acid solution, 140 mL of 3% aqueous
sodium hydrogen carbonate solution and 57 mL of 2 0% saline
solution, dried over anhydrous magnesium sulfate, and
filtered. The filtrate was concentrated under reduced
pressure to obtain 39.28 g (Yield: 98.8%) of (4S)-1-benzyl
oxycarbonyl-4-tert-butyldimethylsilyloxy-l,2,3,4-tetra-
hydroquinoline .
[0032]
(4) To 3 93 mL of an ethanol solution containing 3 9.28 g of
the compound obtained in the above-mentioned (3) was added
1.96 g of palladium carbon under nitrogen atmosphere, and
the mixture was stirred under hydrogen atmosphere for 4
hours. The reaction mixture was filtered, and the filtrate
was concentrated. The resulting residue was purified by
column chromatography on silica gel (Solvent; n-
hexane/ethyl acetate=30/l to 20/1) to obtain 14.82 g
(Yield: 56.9%, Optical purity: 98.8% ee) of (4S)-4-tert-
butyldimethylsilyloxy-1,2,3,4-tetrahydroquinoline.

25
[α]D28=-128.6° (methanol, c = 1.10)
UTILIZABILITY IN INDUSTRY
[0033]
The topical dermatitis treating agent of the present
invention shows excellent ear swelling inhibitory effect in
dermatitis model so that it is useful for treatment of
dermatitis such as atopic dermatitis, contact dermatitis
and the like.

26
CLAIMS
1. A topical dermatitis treating agent which comprises a
pyridine compound represented by the following formula [I]:

wherein R1 and R2 each represent a lower alkoxy group,
=X- represents a group represented by the formula:

or a group represented by the formula: =N-, Ring A
represents a saturated or unsaturated bicyclic
nitrogen-containing heterocyclic group having 1 to 4
substituents selected from hydroxyl group, oxo group,
a lower alkoxy group, a di-lower alkylaminophenyl
group, a pyperidino-lower alkoxy group, a morpholino-
lower alkoxy group, a cyclo-lower alkylamino-lower
alkylamino group, pyridyl group and morpholino group,
and represents a single bond or a double bond,
or a pharmaceutically acceptable salt thereof as an active
ingredient.
2. The topical dermatitis treating agent according to
Claim 1, wherein the saturated or unsaturated bicyclic
nitrogen-containing heterocyclic group is quinolyl group,
dihydroquinolyl group, tetrahydroquinolyl group, iso-
quinolyl group, dihydroisoquinolyl group, tetrahydroiso-
quinolyl group, phthalazinyl group or dihydrophthalazinyl
group.
3. The topical dermatitis treating agent according to

27
Claim 1, wherein R1 and R2 are methoxy groups, and =X- is a
group represented by the formula:

4. The topical dermatitis treating agent according to
Claim 1, wherein R1 and R2 are methoxy groups, and =X- is a
group represented by the formula: =N-.
5. The topical dermatitis treating agent according to
Claim 1, wherein Ring A is a group represented by the
formula:

6. A topical dermatitis treating agent which comprises a
compound selected from
1-[2-(1,2-dihydro-3-morpholino-2-oxoquinolin-l-yl)pyridin-
4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene;
1-[2-[1,2-dihydro-5-(2-piperidinoethoxy)-1-oxoisoquinolin-
2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene;

28
1-[2-[l,2-dihydro-5-(2-morpholinoethoxy)-1-oxoisoquinolin-
2-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxy-
naphthalene;
1-[2-[l,2-dihydro-3-oxoisoquinolin-2-yl]pyridin-4-yl]-2,3-
bis (hydroxymethyl) -6, 7-ditnethoxynaphthalene;
1-[2-(4-hydroxy-l,2,3,4-tetrahydroquinolin-l-yl)pyridin-4-
yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene;
1-[2-[(4S)-4-hydroxy-1,2,3,4-tetrahydroquinolin-l-yl]-
pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphtha-
lene;
1-[2-[(4R)-4-hydroxy-1,2,3,4-tetrahydroquinolin-l-yl]-
pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphtha-
lene;
1-[2-[1,2-dihydro-4-[3-(cyclohexylamino)propylamino]-2-
oxoquinolin-1-yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-
dimethoxynaphthalene ,-
1-[2-[4-(dimethylaminophenyl)phthalazin-l(2H)-one-2-yl]-
pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphtha-
lene;
1-[2-[6,7-dimethoxy-4-(3-pyridyl)phthalazin-l(2H)-one-2-
yl]pyridin-4-yl]-2,3-bis(hydroxymethyl)-6,7-
dimethoxynaphthalene; and
(3S)-1-[2-[4-(dimethylaminophenyl)phthalazin-1(2H)-one-2-
yl]pyridin-4-yl]-3,4-dihydro-3-hydroxymethyl-6,7-dimethoxy-
isoquinoline
or a pharmaceutically acceptable salt thereof as an active
ingredient.
7. The topical dermatitis treating agent according to
Claim 1, wherein the agent is a treating agent for atopic
dermatitis, contact dermatitis, seborrheic dermatitis,
psoriasis or eczema.
8. Use of the compound represented by the formula [I] or a
pharmaceutically acceptable salt thereof according to Claim
1 for the manufacture of a preparation to be used for a

29
topical dermatitis treating agent.
9. A method of treating dermatitis which comprises
applying a preparation comprising the compound represented
by the formula [I] or a pharmaceutically acceptable salt
thereof according to Claim 1 as an active ingredient to an
affected part.
10. A method for preparing a compound represented by the
following formula [I]:

wherein R1 and R2 each represent a lower alkoxy group,
=X- represents a group represented by the formula:

Ring A represents a group represented by the following
formula:

which comprises the following steps of (1) to (6):
(1) subjecting a 4-oxotetrahydxoquinoline compound represented
by the formula [V]:

30
wherein R represents a protective group for amino group,
to asymmetric reduction in the presence of a CBS catalyst and
a hydrogenated boron compound,
(2)introducing a protective group (Z) into the hydroxyl group
at the 4-position of the product obtained in the step (1),
(3)rexnoving the protective group (R) for the amino group from
the product obtained in the step (2).
(4)condensing an optically active tetrahydroquinoline
compound obtained in the step (3) represented by the following
formulaJ
wherein 02 represents a protected hydroxyl group,
and a compound represented by the following formula [II]:

wherein Ra represents a protective group for carboxyl
group, =Xi- represents a group represented by the formula:

(Rb represents a protective group for carboxyl group), r
represents a halogen atom, and the other symbols have the
same meanings as defined above,
(5)reducing the product obtained in the step (4), and
(6) removing the protective group (Z) for the hydroxyl group from
the product obtained in the step (5).
11. The method according to claim 10, wherein the CBS catalyst
is (R)- or (S)-2-methyl-CBS-oxazaborolidine.

Dermatitis remedies for
external use, containing as the active
ingredient compounds represented by the
general formula [I] or pharmacologically
acceptable salts thereof: [I] wherein R1
and R2 are each lower alkoxy; =X- is
the group represented by the following
formula: or the group represented by
formula: =N-; A is a saturated or unsaturated
nitrogen-containing heterobicyclic group
having one to four substituents selected from
among hydroxyl, oxo, lower alkoxy, di(lower
alkyl)aminophenyl, piperidino(lower alkoxy),
morpholino(lower alkoxy), cyclo(lower
alkyl)amino(lower alkyl)amino, pyridyl, and
morpholino; and symbol represents a single
or double bond.

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=oeQGIBeaQY+i6Cm8/uuZdw==&loc=wDBSZCsAt7zoiVrqcFJsRw==

« Previous Patent

Next Patent »

Patent Number

269258

Indian Patent Application Number

1601/KOLNP/2008

PG Journal Number

42/2015

Publication Date

16-Oct-2015

Grant Date

13-Oct-2015

Date of Filing

22-Apr-2008

Name of Patentee

MITSUBISHI TANABE PHARMA CORPORATION

Applicant Address

2-10, DOSHO-MACHI 3 CHOME, CHUO-KU, OSAKA-SHI, OSAKA

Inventors:

#	Inventor's Name	Inventor's Address
1	NAOTSUKA ATSUKO	C/O MITSUBISHI TANABE PHARMA CORPORATION, 2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505
2	KIKUCHI MATSUO	C/O MITSUBISHI TANABE PHARMA CORPORATION, 2-10, DOSHO-MACHI 3-CHOME, CHUO-KU, OSAKA-SHI, OSAKA 541-8505

PCT International Classification Number

A61K 31/4709

PCT International Application Number

PCT/JP2006/319932

PCT International Filing date

2006-10-05

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	2005-292040	2005-10-05	Japan