JP4352918B2 - PDE4 inhibitor - Google Patents

Description

  The present invention relates to PDE4 inhibition comprising 6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline compound or a pharmaceutically acceptable salt thereof as an active ingredient. It relates to the agent.

  Intracellular second messengers cAMP and cGMP are degraded and inactivated by phosphodiesterase (PDE). When PDE is inhibited, the concentration of intracellular cAMP and cGMP increases. PDE is classified into several isozymes. Substrate (cAMP, cGMP) specificity, biodistribution, etc. are different for each isozyme. Among the PDE isozymes, type 4 PDE (PDE4) specifically degrades cAMP. It has been known.

  In addition, by inhibiting PDE4 activity, release of inflammatory mediators can be inhibited (see, for example, Non-Patent Document 1), and PDE4 inhibitors are cytokines released by mononuclear phagocytes in response to immune stimulation. It is known that the production of certain TNF-α is suppressed and useful for the treatment of various inflammatory diseases involving TNF-α (see, for example, Patent Documents 1 to 6).

  Theophylline, which is a typical PDE inhibitor, has been used for the treatment of asthma from the past, but its non-specific PDE inhibitory action has cardiotonic and central effects in addition to bronchial smooth muscle relaxing action, Therefore, always be aware of side effects. For this reason, among various PDE isozymes, development of a novel drug having a specific inhibitory action on PDE4, which is particularly abundant in bronchial smooth muscle and inflammatory cells, has been demanded. Such a drug is considered to be an excellent prophylactic / therapeutic agent for asthma (or a prophylactic / therapeutic agent for inflammatory diseases).

  On the other hand, regarding 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline, the compound exhibits a central inhibitory action and a blood pressure lowering action. (For example, refer nonpatent literature 2). However, no mention is made in this report as to whether or not the compound has PDE4 inhibitory activity, and no mention is made of any pharmacologically acceptable salt of the compound.

JP 2000-503678 A (pages 9-25) JP 2000-502724 A (pages 15-23) JP 2000-510105 A (pages 5-9) JP 2000-514804 (pages 32 to 33) JP 2000-502350 A (pages 6-15) JP 2000-501741 (pages 12 to 21) Journal of Molecular and Cellular Cardiology, Volume 12 (Suppl. II), S61, 1989 Indian Journal of Chemistry, Vol. 13, pp. 230-237, 1975

  The present invention relates to PDE4 inhibition comprising a 6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline compound or a pharmacologically acceptable salt thereof as an active ingredient. An agent is provided.

  The present invention relates to general formula [I]:

(In the formula, R ¹ and R ² are the same or different and represent a hydroxyl group or a lower alkoxy group.)
Or a pharmacologically acceptable salt thereof as a PDE4 inhibitor.

  Compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has an excellent inhibitory action on PDE4, and is useful for the prevention and treatment of various diseases involving PDE4. is there.

  In addition, since the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof selectively inhibits PDE4, there are few side effects.

  Furthermore, the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has a feature of low toxicity and high safety as a medicine.

Among the compounds [I] which are the active ingredients of the present invention, preferred compounds include those in which R ¹ and R ² in formula [I] are the same or different and are lower alkoxy groups, and more preferred compounds are R ^1. And a compound in which R ² is a methoxy group or an ethoxy group. Of these, 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline is particularly preferred.

  Compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has an excellent inhibitory action on PDE4, and is useful for the prevention and treatment of various diseases involving PDE4. is there. Such diseases include various inflammatory diseases and allergic diseases. More specifically, for example, asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, atopic dermatitis, urticaria, allergic disease Rhinitis, allergic conjunctivitis, spring catarrh, eosinophilia, psoriasis, rheumatoid arthritis, septic shock, ulcerative colitis, Crohn's disease, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome, Examples include osteoarthritis.

  The compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof is useful as a bronchoconstriction inhibitor because it has an excellent inhibitory effect on bronchoconstriction.

  The present applicant has found that a compound having a PDE4 inhibitory action is useful for promoting fracture healing and repairing treatment of cartilage diseases (for example, osteoarthritis) (Japanese Patent Application No. 2001-154064). And Japanese Patent Application No. 2001-154048). Based on this finding, compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof is useful for promoting fracture healing and repairing treatment for cartilage diseases (for example, osteoarthritis).

  In addition, since the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof selectively inhibits PDE4, there are few side effects. Furthermore, the compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof has a feature of low toxicity and high safety as a medicine. For example, 100 mg / kg of 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline was administered to mice (BDF1 strain, male, 3 cases ) Was subcutaneously administered once and the course was observed for 1 day, but no deaths were observed.

  Compound [I], which is an active ingredient of the present invention, can be used for pharmaceutical use either in a free form or in the form of a pharmacologically acceptable salt thereof. Examples of pharmaceutically acceptable salts include inorganic acid salts such as hydrochloride, sulfate, phosphate or hydrobromide, acetate, fumarate, oxalate, citrate, methanesulfone, and the like. And organic acid salts such as acid salts, benzenesulfonate, tosylate and maleate. Of these, hydrochloride is particularly preferred.

  Compound [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, includes any of its internal salts and adducts, solvates or hydrates thereof.

  Compound [I], which is an active ingredient of the present invention, has a plurality of stereoisomers (diastereoisomers, optical isomers) based on asymmetric atoms. Any one of the stereoisomers or a mixture thereof is included.

  Compound [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, can be administered orally or parenterally, and can also be used for tablets, granules, capsules, powders, injections. It can be used as a conventional pharmaceutical preparation such as an inhalant.

  The dose of compound [I], which is an active ingredient of the present invention, or a pharmacologically acceptable salt thereof varies depending on the administration method, patient age, body weight, and condition. About 0.01 to 10 mg / kg per day, especially about 0.03 to 3 mg / kg, usually about 0.1 to 30 mg / kg per day for oral preparations, especially about 0.3 to 10 mg / kg It is preferable that

<Production Method of 6-Phenyl-1,3,4,6,11,11a-Hexahydro-2H-pyrazino [1,2-b] isoquinoline Compound>
Compound [I], which is an active ingredient of the present invention, can be produced by the following methods, but is not limited thereto.

(Wherein R ³ represents a lower alkyl group, and other symbols have the same meaning as described above)
The reaction for producing compound [IV] from compound [II] can be carried out using a conventional esterification reaction (for example, in the presence of ethanol / acetyl chloride, ethanol / thionyl chloride, ethanol / hydrogen chloride, etc.). .

  The reaction for producing compound [VI] from compound [IV] and compound [V] is carried out by using a conventional condensing agent (for example, dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide / hydrochloride / 1- In the presence of hydroxybenzotriazole monohydrate and the like.

  The reaction for producing the compound [VII] from the compound [VI] is carried out by, for example, condensing using phosphorus oxychloride, phosphorus pentachloride, etc., and then using a conventional reducing agent (for example, platinum oxide / hydrogen, palladium (carbon) / hydrogen). Etc.).

  The reaction for producing compound [IX] from compound [VII] and compound [VIII] can be carried out in the presence of a conventional condensing agent (for example, carbonyldiimidazole and the like). Compound [IX] is prepared by treating compound [VIII] with an activator (eg, isobutyl chlorocarbonate, ethyl chlorocarbonate) and a base (eg, triethylamine, N-methylmorpholine, etc.) to form a mixed acid anhydride. After the conversion, the mixed acid anhydride can be reacted with compound [VII].

  The reaction for producing compound [X] by intramolecular ring closure of compound [IX] can be carried out by heating compound [IX] after treatment with acid (eg, trifluoroacetic acid, hydrochloric acid, etc.).

  The reaction for producing compound [I] by reducing compound [X] is carried out in the presence of a suitable reducing agent (for example, borane / dimethyl sulfide complex, lithium aluminum hydride, bis (2-methoxyethoxy) aluminum hydride, etc.). Can be implemented.

Compound [I], which is an active ingredient of the present invention, converts the substituent on R ¹ , R ² and / or ring A of the compound obtained as described above into another desired substituent. Can also be manufactured. What is necessary is just to select suitably the conversion method of such a substituent according to the kind of target substituent. For example, the compound [I] in which R ¹ and / or R ² in the general formula [I] is lower alkoxy includes a corresponding compound [I] in which R ¹ and / or R ² is a hydroxyl group and a lower alkylating agent (for example, It can also be produced by reacting dimethyl sulfate, methyl halide, etc.) in the presence of a base (for example, sodium hydroxide, sodium hydride, potassium carbonate, sodium methoxide, etc.). The amount of the lower alkylating agent used can be 1 equivalent to 8 equivalents, preferably 1.2 equivalents to 2.2 equivalents, relative to compound [I]. This reaction suitably proceeds at 0 ° C to 50 ° C, particularly 10 ° C to 40 ° C.

  Compound [I] obtained by the above-described production method can be converted into a pharmacologically acceptable salt according to a method known to those skilled in the art.

  In the production of the above compound [I], each intermediate compound is not limited to those shown in the above sentence or in the chemical reaction formula, as long as it does not adversely influence the reaction, their salts or their reactive derivatives It can be used as appropriate. Examples of the salt include metal salts such as sodium, potassium, lithium, calcium and magnesium, salts with organic bases such as pyridine, triethylamine and diisopropylethylamine, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid and the like. Salts with inorganic acids, acetic acid, oxalic acid, citric acid, benzenesulfonic acid, benzoic acid, malonic acid, citric acid, formic acid, fumaric acid, maleic acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid, etc. Examples include salts with organic acids.

  In addition, when the compound [I], which is the active ingredient of the present invention, and the raw material compound are produced, when the raw material compound or each intermediate has a functional group, in addition to the above, each functional group is converted into a functional group by a conventional synthetic chemistry method. Appropriate protecting groups may be introduced, and those protecting groups may be removed as appropriate when they are no longer needed.

  Each of the above reactions can be carried out in a suitable solvent or without a solvent as necessary. The solvent is not particularly limited as long as it does not adversely affect the reaction. For example, dioxane, ethylene glycol dimethyl ether, dimethylacetamide, dimethylformamide, hexamethylphosphoric triamide (HMPA), hexamethylphosphorous triamide ( HMPT), benzene, tetrahydrofuran, toluene, xylene, ethyl acetate, lower alcohol, methylene chloride, chloroform, carbon tetrachloride, 1,3-dimethyl-2-imidazolidinone, acetic acid, diethyl ether, diisopropyl ether, dimethoxyethane, dimethyl Sulfoxide, acetone, methyl ethyl ketone, acetonitrile, water or a mixed solvent thereof can be appropriately selected and used.

  In the present invention, examples of the lower alkoxy group include linear or branched ones having 1 to 6 carbon atoms, particularly those having 1 to 4 carbon atoms.

Experimental example

Experimental Example 1 [PDE4 inhibitory action]
(Preparation of PDE4 partially purified preparation)
The supernatant obtained by centrifuging a lung homogenate excised from a Hartley male guinea pig was fractionated by anion exchange column chromatography. ~ 4. Fractions satisfying the above conditions were mixed to prepare a partially purified preparation of phosphodiesterase 4.
1. Selectively hydrolyze cAMP.
2. The cAMP hydrolysis activity is not affected by cGMP.
3. Not inhibited by CI-930, a PDE3 selective inhibitor.
4). Strong inhibition by Rolipram, a PDE4 selective inhibitor.
(Measurement of PDE4 activity)
The method of Thompson et al. (Advanced in Cyclic Nucleotide Research, Vol. 10, Raven Press, New York, 69-92, 1979) was partially modified. That is, 100 μl of PDE4 partially purified preparation diluted with 50 mM Tris-HCl, pH 8.0 to hydrolyze about 10% of the total substrate was added to a glass test tube. 200 μl of a buffer solution for reaction (50 mM Tris-HCl, pH 8.0, 12.5 mM MgCl ₂ , 10 mM 2-mercaptoethanol) was added, and then a sample compound dissolved in dimethyl sulfoxide (a compound described later) (100-fold concentration) 5 μl) was added. After pre-incubation at 30 ° C. for 5 minutes, 200 μl of 2.5 μM [3H] cAMP (3.7 kBq / 200 μl) was added to initiate the reaction (final concentration 50 mM Tris-HCl, pH 8.0, 5 mM MgCl ₂ , 4 mM). 2-mercaptoethanol, 1 μM cAMP). After the reaction at 30 ° C. for 30 minutes, the test tube was transferred into a boiling water bath to stop the reaction. After 90 seconds, the test tube was transferred into an ice water bath, and the temperature of the reaction solution was lowered. After pre-incubation at 30 ° C. for 5 minutes, 100 μl of 1 mg / ml snake venom aqueous solution was added and reacted at 30 ° C. for 30 minutes. After stopping the reaction by adding 500 μl of methanol, 1 ml of the reaction solution was applied to a column to which 200 μl of Dowex resin (trade name: Dowex 1 × 8, manufactured by Sigma) was previously added. Subsequently, the Dowex resin was washed by adding 1 ml of methanol. The reaction solution was passed through the column and the washing solution, and its radioactivity was measured. Calculate the inhibition rate of each sample with respect to the control by adding the buffer solution without adding the enzyme sample as blank and adding the enzyme sample but adding only dimethyl sulfoxide instead of the sample solution as the control. did. The calculation of the IC ₅₀ value of each specimen was performed by obtaining the inhibition rate at three or more concentrations and performing regression using a 4-parameter logistic equation method.
(Sample)
(Specimen compound A): 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline.
(Specimen compound B): 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride.
(Specimen Compound C): (6S, 11aS) -8,9-dimethoxy-6-phenyl-dimethoxy-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline Dihydrochloride.
(result)
The PDE4 inhibitory activity (IC ₅₀ ) of the sample compounds was 0.004 μM.

Experimental Example 2 (Inhibition of antigen-induced bronchoconstriction)
(procedure)
Hartley male guinea pigs (n = 2) were passively sensitized by intravenous administration of rabbit anti-ovalbumin antiserum (0.25 mL / kg, iv). The next day, anesthetized with α-chloralose (120 mg / kg, iv), and after immobilization with tracheal cannula, immobilized with gallamine trithiodide (5 mg / kg, iv) under artificial respiration. The sample compound (8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride) (1 mg / kg) It was administered intravenously 2 minutes before administration of antigen (ovalbumin; 30 μg / kg, iv). The action of the sample compound on the trachea (bronchial constriction inhibitory action) is determined by the Konzett-Roessler method [Naunin-Schmeideberg's Archivology (Naunin-Schmiedebergs Alheaf Huer Experimente Pathology und Pharmacology). fur Experimentelle Pathology unpharmacology), 195, 71, 1940]. In addition, the group (n = 2) to which only the antigen was administered was used as a control.
(result)
The bronchoconstriction inhibitory action (inhibition rate against bronchoconstriction by antigen administration) of the sample compound was 84%.

Production example

Production Example 1
(1) 98.6 g of 2-amino-3- (3,4-dihydroxyphenyl) propanoic acid is dissolved in 900 ml of formic acid, 300 ml of acetic anhydride is added thereto, and the mixture is stirred at room temperature for 3 hours. The reaction solution is concentrated under reduced pressure, distilled water is added to the residue, and the mixture is concentrated again under reduced pressure. The residue is dissolved in 150 ml of distilled water, and 150 ml of 10M aqueous sodium hydroxide and 95 ml of dimethyl sulfate are added under ice cooling. Furthermore, 285 ml of dimethylsulfuric acid is added in 3 portions every 30 minutes, during which time 290 ml of 10M aqueous sodium hydroxide solution is added dropwise, keeping the reaction temperature below 40 ° C. and the pH between 5-9. After stirring overnight at room temperature, 50 ml of 10M aqueous sodium hydroxide solution is added and stirred at room temperature for 30 minutes. The pH is adjusted to 2 with sulfuric acid, ethyl acetate is added, and the organic layer is dried over magnesium sulfate and concentrated under reduced pressure. The residue is suspended in 1300 ml of ethanol, 280 ml of acetyl chloride is added dropwise under ice cooling, and the mixture is stirred at room temperature for 3 days. After evaporating the solvent under reduced pressure, methylene chloride was added, and the organic layer was washed with an aqueous potassium carbonate solution, dried over magnesium sulfate, concentrated under reduced pressure, and ethyl 2-amino-3- (3,4-dimethoxyphenyl) propanoate. 111 g are obtained as an oil. MS (m / z): 253 (M ^<+> ).
(2) 111 g of the compound obtained in the above (1) and 73.6 ml of triethylamine are dissolved in 300 ml of methylene chloride, and 51.1 ml of benzoyl chloride is added dropwise under ice cooling. Saturated aqueous sodium hydrogen carbonate solution is added, and the organic layer is washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration with diethyl ether to obtain 144 g of ethyl 3- (3,4-dimethoxyphenyl) -2- (phenylcarbonylamino) propanoate. Melting point: 82-83 ° C. MS (m / z): 357 (M ^<+> ).
(3) 71.5 g of the compound obtained in (2) above is dissolved in 200 ml of phosphorus oxychloride and heated to reflux overnight. After distilling off phosphorus oxychloride, the residue is diluted with methylene chloride. Wash with aqueous potassium carbonate, dry over magnesium sulfate, and concentrate under reduced pressure. Dissolve the residue in ethanol, add 20 ml of concentrated hydrochloric acid, and concentrate under reduced pressure. The residue is dissolved in 200 ml of methanol, 1 g of platinum dioxide is added, and the mixture is stirred at room temperature under hydrogen pressure (3 atm) for 4 hours. The insoluble material is removed by filtration and concentrated under reduced pressure. The residue is dissolved in chloroform, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The precipitated crystals are collected by filtration to obtain 54.4 g of ethyl 6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylate. Melting point: 215-217 ° C (decomposition). MS (m / z): 341 (M ^<+> ).
(4) 21.6 g of 2-[(tert-butoxy) carbonylamino] acetic acid was dissolved in 75 ml of tetrahydrofuran, 18.7 ml of triethylamine and 17.4 ml of isobutyl chloroformate were added dropwise at -20 ° C, and the mixture was stirred at -10 ° C for 5 minutes. Stir. A suspension of 38.2 g of the compound obtained in (3) above in 110 ml of tetrahydrofuran is added dropwise thereto and stirred overnight at room temperature. The reaction mixture is concentrated under reduced pressure and extracted with chloroform. The extract is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. After crystallizing with diethyl ether, the mixture was collected by filtration to give 2- {2-[(tert-butoxy) carbonylamino] acetyl} -6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline- 31.7 g of ethyl 3-carboxylate are obtained. Melting point: 166-167 ° C. MS (m / z): 498 (M ^<+> ).
(5) Under ice cooling, 60 ml of trifluoroacetic acid is added to 31.7 g of the compound obtained in the above (4), and the mixture is stirred for 1 hour. The reaction mixture is concentrated under reduced pressure, dissolved in chloroform, and neutralized with triethylamine. The extract is washed with a saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue is dissolved in 350 ml of toluene and heated to reflux for 3 hours. After the solvent was distilled off, the precipitate was collected by filtration with diethyl ether, and 8,9-dimethoxy-6-phenyl-2,3,11,11a-tetrahydro-6H-pyrazino [1,2-b] isoquinoline-1 , 4-dione (20.6 g) is obtained. Melting point: 265-267 [deg.] C. MS (m / z): 352 (M ^<+> ).
(6) Under a nitrogen atmosphere, 22.7 ml of borane-dimethylsulfide complex is ice-cooled, and 20 g of the compound obtained in (5) above is dissolved in 500 ml of tetrahydrofuran. After heating at reflux overnight, 50 ml of 6M hydrochloric acid is added and the solvent is distilled off. The residue is diluted with chloroform, washed with aqueous sodium hydroxide solution, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue is purified by silica gel column chromatography using chloroform: methanol (9: 1) as an elution solvent, and the obtained crystals are dissolved in a mixed solvent of chloroform-methanol. 4M hydrochloric acid / ethyl acetate solution is added thereto, and then the solvent is distilled off. The precipitate was filtered with ethanol, and 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride 7 .6 g is obtained. Melting point: 220-224 ° C. (decomposition). MS (m / z): 324 (M ^<+> ).

Production Example 2
By using (2S) -2-amino-3- (3,4-dihydroxyphenyl) propanoic acid (L-DOPA) and subsequently performing the same operation as in Production Example 1, (6S, 11aS) -8,9 -Dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride is obtained. Melting point: 225-229 ° C. (decomposition). MS (m / z): 324 (M ^<+> ).

Claims (10)

Formula [I]:

(In the formula, ^{R 1} and ^{R 2} represent the same or different low-grade alkoxy group.)
Or a pharmacologically acceptable salt thereof as a PDE4 inhibitor. PDE4 comprising 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline or a pharmaceutically acceptable salt thereof as an active ingredient Inhibitor. The PDE4 inhibitor according to claim 1 or 2, which is a pharmacologically acceptable salt. The PDE4 inhibitor according to claim 3 , wherein the pharmacologically acceptable salt is hydrochloride. A PDE4 inhibitor comprising 8,9-dimethoxy-6-phenyl-1,3,4,6,11,11a-hexahydro-2H-pyrazino [1,2-b] isoquinoline dihydrochloride as an active ingredient. The PDE4 inhibitor according to any one of claims 1 to 5, which is a prophylactic / therapeutic agent for inflammatory diseases or allergic diseases. Asthma, Chronic obstructive pulmonary disease (COPD), Chronic bronchitis, Atopic dermatitis, Urticaria, Allergic rhinitis, Allergic conjunctivitis, Spring catarrh, Eosinophilia, Psoriasis, Rheumatoid arthritis, Septic shock The PDE4 inhibitor according to any one of claims 1 to 5, which is a preventive or therapeutic agent for ulcerative colitis, Crohn's disease, reperfusion injury, chronic glomerulonephritis, endotoxin shock, adult respiratory distress syndrome or osteoarthritis. The PDE4 inhibitor according to any one of claims 1 to 5, which is a bronchoconstriction inhibitor. The PDE4 inhibitor according to any one of claims 1 to 5, which is a fracture healing promoter or a cartilage disease therapeutic agent. The PDE4 inhibitor according to claim 9 , wherein the cartilage disease is osteoarthritis.