WO1999016766A1

WO1999016766A1 - Benzodioxole derivatives

Info

Publication number: WO1999016766A1
Application number: PCT/JP1998/004431
Authority: WO
Inventors: Etsuo Ohshima; Hoshisuke Nakasato; Koji Yanagawa; Haruhiko Manabe
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 1997-10-01
Filing date: 1998-10-01
Publication date: 1999-04-08
Also published as: AU9281298A

Abstract

Benzodioxole derivatives represented by general formula (I) or pharmacologically acceptable salts thereof, wherein R?1 and R2¿ are the same or different and each represents hydrogen or lower alkyl or R?1 and R2¿ in combination represent cycloalkyl; R3 represents lower alkyl; R4 represents lower alkyl, nitro, cyano, carbamoyl, formyl, lower alkoxycarbonyl, or carboxy; and X and Y are the same or different and each represents N or CR5 (wherein R5 represents hydrogen, lower alkyl, hydroxy, or halogeno).

Description

Details

Benzodioxole derivatives Technical field

The present invention has a phosphodiesterase (PDE) IV inhibitory effect, and has an inflammatory and allergic disease such as bronchial asthma, allergic rhinitis and nephritis, rheumatism, multiple sclerosis, Crohn's disease, psoriasis, and systemic lupus erythematosus. Central nervous system diseases such as immune diseases, depression, amnesia, and dementia; organ damage due to ischemia reperfusion caused by heart failure, shock, cerebrovascular disorders, etc., diabetes due to insulin resistance, wounds, AIDS, etc. The present invention relates to benzofuran derivatives useful as therapeutic agents.

Background art

Traditionally, many hormones and neurotransmitters have been linked to intracellular second messengers adenosine 3,5'-cyclic monophosphate (cAMP) or guanosine 3,5,5 monocyclic monophosphate. It is known that the effect is exhibited by increasing the concentration of (cGMP). The intracellular concentrations of cAMP and cGMP are controlled by their production and degradation, and these degradations are performed by PDEs. Therefore, inhibiting PDE will increase the concentration of these intracellular second messengers. To date, seven isozymes have been shown to exist in PDEs, and isozyme-selective PDE inhibitors exert pharmacological effects based on the physiological significance and distribution of the isozymes in vivo [Torrence, 'In a Mako!], Cal' Science (TiPS), 11, 150 (1990) and 11, 19 (1991).

It is known that increasing the intracellular cAMP of inflammatory leukocytes can suppress their activation. Activation of leukocyte cells leads to secretion of inflammatory cytokines including tumor necrosis factor (TNF), expression of cell adhesion molecules such as intercellular adhesion molecule (ICAM), and subsequent cell infiltration [Si ,, journal 'off ,, -'Medical record, Ioguchi,-(Mol. Cell. Cardiol.), 12 (Suppl. II), S61 (1989)].

It is known that increasing cAMP concentration in airway smooth muscle cells can suppress the contraction [TJ Torphy, ί,, anti-asma drug, For New Anti-Asthma Drugs), edited by Audner Asson (SR O'Donell and CGA Persson), 37 (1988). Abnormal hyperconstriction of airway smooth muscle is a major condition of bronchial asthma. In ischemia-reperfusion organ disorders such as myocardial ischemia, inflammatory leukocyte cells such as neutrophils are infiltrated in the affected area. In these inflammatory cells and tracheal smooth muscle cells, mainly type IV PDEs

(PDE IV) has been shown to be involved in cAMP degradation. Therefore, PDE IV selective inhibitors can be expected to have therapeutic and / or preventive effects on inflammatory diseases, airway obstructive diseases, and ischemic diseases.

In addition, PDE IV inhibitors suppress the secretion of inflammatory cytokines such as TNF and inulin-leukin (IL) -8 by increasing cAMP, and are further transmitted by these cytokines. Is expected to prevent the development and prolongation of the inflammatory response. For example, it has been reported that TNF reduces phosphorylation of insulin receptors in muscle and fat cells and contributes to insulin-resistant diabetes. 'Instique, J. Clin. Invest., 94, 1543 (1994)]. Similarly, TNF is involved in the development and progression of autoimmune diseases such as rheumatism, multiple sclerosis, and Crohn's disease, suggesting that PDE IV inhibitors may be effective in those diseases. [Nature Medicine, 1, 211 (1995) and Ibid, 1, 244 (1995)].

WO97 / 20833 discloses a benzofurancarboxamide derivative having a PDE IV inhibitory action.

W096 / 36624 discloses a compound having a biphenyl ring having PDE IV inhibitory activity.

However, conventional PDE IV inhibitors have the problem of inducing vomiting. [Trens, 'In' Pharmaceuticals, Cal 'Singin' (TiPS), 18, 164 (1997)]

Disclosure of the invention

PDE IV inhibitors are expected to have prophylactic or therapeutic effects on a wide range of diseases. An object of the present invention is to provide a benzodioxole derivative which has excellent anti-inflammatory activity and does not show vomiting.

The present invention provides a compound represented by the general formula (I):

(R

Wherein R ¹ and R ² are the same or different and each represents hydrogen or lower alkyl or joined together to represent cycloalkyl, R ³ represents lower alkyl, R ⁴ represents lower alkyl, nitro, Represents cyano, carbamoyl, formyl, lower alkoxycarbonyl or carboxy; X and Y are the same or different and represent N or CR ⁵ , wherein R ⁵ represents hydrogen, lower alkyl, hydroxy or halogen. Or a pharmacologically acceptable salt thereof.

Hereinafter, the compound represented by the general formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers.

The present invention also relates to a therapeutic agent for inflammatory allergic diseases comprising Compound (I) or a pharmacologically acceptable salt thereof as an active ingredient.

Further, the present invention relates to a method for treating an inflammatory allergic disease, which comprises administering an effective amount of compound (I) or a pharmacologically acceptable salt thereof. The present invention also relates to the use of compound (I) or a pharmacologically acceptable salt thereof for producing a pharmacological composition useful for treating an inflammatory allergic disease.

Pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and the like.

Pharmaceutically acceptable acid addition salts of compound (I) include inorganic acids such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, citrate and the like. Pharmacologically acceptable metal salts include alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, and zinc. Examples of the pharmacologically acceptable ammonium salts include salts of ammonium and tetramethylammonium, and examples of the pharmacologically acceptable organic amine addition salts include morpholine and pyridine. And addition salts such as azine.

In the definition in the general formula, the lower alkyl moiety of lower alkyl and lower alkoxycarbonyl represents a straight-chain or branched alkyl having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, Butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like.

Examples of the cycloalkyl include those having 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

Halogen represents each atom of fluorine, chlorine, bromine and iodine.

In the compound (I), R ¹ and R ² together represent cycloalkyl, R ⁴ represents carboxy or lower alkyl, X represents CH, and Y represents N, or R ¹ and R ² Preferred are compounds in which R ² is the same or different and represents lower alkyl, R ⁴ represents carboxy, and X and Y represent CH. C In compound (I), R ³ is alkyl having 1 to 4 carbon atoms. Some are preferred Among them, methyl is more preferable.

Next, a method for producing compound (I) will be described.

Production method: Compound (I) can be produced by the following production method.

Process 1-3

Process

(Wherein, RR \ R ³ , RX and Y each have the same meanings as above. R ⁶ represents lower alkyl, L ¹ represents chlorine, bromine or iodine, and L ² represents chlorine, bromine or iodine. Or a trifluoromethanesulfonate group.) Here, the lower alkyl represented by R ⁶ has the same meaning as the definition of the lower alkyl described above. Step 1: Production of compound (I)

Compound (I) is obtained by treating compound (II) with a base in an inert solvent at a temperature between 110 ° C and room temperature for 5 minutes to 10 hours, and then reacting 1 equivalent to an excess of halogenated compound. The metal or boron compound is allowed to react at a temperature between 100 ° C and the boiling point of the solvent used for 5 minutes to 30 hours, and then the compound (Ilia) is added in an inert solvent in excess of the catalyst amount. The reaction can be carried out in the presence of an amount of the palladium complex at a temperature between room temperature and the boiling point of the solvent used for 5 minutes to 30 hours. If necessary, a salt such as lithium chloride or silver oxide may be added in excess of the amount of the catalyst.

Bases include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (hereinafter abbreviated as LDA), potassium tert-butoxide, triethylamine, Examples include diisopropylethylamine, triptylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylbiveridine, 1,8-diazabicyclo [5.4.0] 7-indene (hereinafter abbreviated as DBU), and the like.

Examples of the metal halide include alkyltin compounds such as chlorotributyltin and chlorotrimethyltin, and zinc halides such as zinc chloride, zinc bromide, and zinc iodide. Examples of the boron compound include trimethoxy boron. Phenylboric acid, boric acid and the like.

Examples of the palladium complex include tetrakistriphenylphosphine palladium, dichlorobistriphenylphosphine palladium, dichlorobisacetonitrile palladium, diphenylphosphinophene phenyl palladium, palladium acetate and the like.

Inert solvents used in the reaction with metal halides or boron compounds include tetrahydrofuran (hereinafter abbreviated as THF), dioxane, dimethyl ether, 1,2-dimethyloxetane, diethylene glycol dimethyl ether, benzene, Examples include toluene and hexane.

Examples of the inert solvent used in the reaction in the presence of the palladium complex include THF, dioxane, dimethyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxetane, diethylene glycol dimethyl ether, and methanol. , Ethanol, butanol, isopropanol, dichloromethane, dichloromethane, benzene, toluene, dimethylacetamide (hereinafter abbreviated as DMA), dimethylformamide (hereinafter abbreviated as DMF), dimethylsulfoxide (hereinafter abbreviated as DMSO) Abbreviations) and the like.

Compound (II) can be synthesized according to the method described in Synthesis, 122 (1986). The compound (Ilia) can be synthesized according to the method described in Tetrahedron Lett., 36, 5319 (1995).

Compound (I) wherein R ⁴ is carboxy may be produced by the following steps 2 and 3.

Step 2: Preparation of compound (la)

Compound (la) can be obtained by reacting compound (II) with compound (Ilb) according to step 1. The compound (Illb) can be obtained by purchasing a commercial product or synthesizing it according to the method described in WO95 / 06640 or Falman,-(Pharmazie), 38, 591 (1983).

Step 3: Compound (lb)

Compound (lb) is prepared by converting compound (la) in the presence of a catalytic amount to a large excess of a base in an inert solvent containing water at a temperature between room temperature and the boiling point of the solvent used for 0.1 to 48 hours. It can be obtained by processing.

Bases include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, LDA, potassium tert-butoxide, triethylamine, disopropylethylamine, tributylamine, dicyclohexyl. Methylamine, N-methyl Examples include morpholine, N-methylbiperidine, DBU and the like.

Inert solvents include THF, dioxane, getyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxetane, diethylene glycol dimethyl ether, methanol, ethanol, butanol, isopropanol, dichloromethane, Black form, benzene, toluene, DMA, DMF,

DMSO is exemplified.

Compound (I) in which R ⁴ is halvamoyl is described in the following step 4,

5 may be manufactured.

Process 4, 5

Process 5

1) Oxyhalide

2) Ammonia

(I c)

(Wherein, RR ² , R ³ , R ⁶ , X and Y each have the same meaning as described above.) Step 4: Production of compound (Ic)

Compound (Ic) is prepared by converting compound (la) in a solvent-free or inert solvent from 1 equivalent to an excess amount of ammonia or ammonia dissolved in an inert solvent at a temperature between 150 ° C and the boiling point of the solvent used. It can be obtained by reacting at temperature for 5 minutes to 168 hours. Wear. If necessary, a catalytic amount to an excessive amount of ammonium chloride, sodium amide, sodium methoxide and the like may be added.

Examples of inert solvents include THF, dioxane, geethylether, ethylene glycol, triethylene glycol, 1,2-dimethoxetane, diethylene glycol dimethyl ether, methanol, ethanol, butanol, isopropanol, acetonitrile, water, Examples include acetone, DMA, DMF, and DMSO.

Step 5: Production of Compound (Ic)

Compound (Ic) can be prepared by using compound (lb) in a solvent-free or inert solvent using 1 equivalent to excess amount of inorganic halide, if necessary in the presence of an excess base from a catalytic amount, at −50 ° C. After treating for 5 minutes to 24 hours at a temperature between the boiling points of the solvent and the corresponding acid halide, 1 equivalent to an excess amount of ammonia or inert, either as is or in an inert solvent It can be obtained by reacting with ammonia dissolved in a solvent at a temperature between −50 ° C. and the boiling point of the used solvent for 5 minutes to 48 hours in the presence of a catalytic amount and an excess of a base if necessary.

Examples of the inorganic halide include thionyl chloride, phosphoryl chloride, phosphorus pentachloride, phosphorus trichloride, and phosphorus tribromide.

Examples of the base include triethylamine, diisopropylethylamine, triptylamine, pyridine and the like.

Examples of the inert solvent used for introducing the acid halide include dichloromethane, dichloroethane, chloroform, benzene, toluene, trifluoromethylbenzene, pyridine, DMA, DMF, and DMSO.

Examples of the inert solvent used in the reaction with ammonia or ammonia dissolved in an inert solvent include dichloromethane, THF, pyridine, dioxane, dimethyl ether, ethylene glycol, triethylene glycol, 1,2-dimethoxyethane, and diethylene glycol. Dimethyl ether, methanol, ethanol, Examples include butanol, isopropanol, acetonitrile, water, acetone, DMA, DMF, and DMSO.

The intermediates and target compounds in each of the above production methods are isolated and purified by separation and purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various chromatographies, etc. can do. Further, the intermediate can be subjected to the next reaction without purification.

When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, purification may be carried out as it is. When compound (I) is obtained in a free form, compound (I) may be appropriately purified. What is necessary is just to dissolve or suspend in a solvent, add an acid or a base, and isolate and purify.

Compound (I) and its pharmacologically acceptable salts may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. In addition, compound (I) may have various stereoisomers such as enantiomers and diastereoisomers, and the present invention includes these and further includes mixtures thereof.

Table 1 shows specific examples of the compound (I) obtained by the present invention.

Compound number R ¹ R ² R ³ R ⁴ XY

1-(CH ₂ ) ₄ -CH ₃ COOH CH N

2 CH ₃ CH ₃ CH ₃ COOH CH CH

3-(CH ₂ ) ₄ -CH ₃ CH ₃ CH N

4-(CH ₂ ) ₄ -CH ₃ COOH CH CCH ₃

5 CH ₃ CH ₃ CH ₃ COOH CH N

6 HH CH ₃ COOH CH N

7 HH CH ₃ COOH CH CCH ₃

8 "(CH ₂ ) ₄ -CH ₃ CONH ₂ CH N

9- (CH ₂ ) ₄ -CH ₃ CN N COH Next, the pharmacological action of the compound (I) will be specifically described with reference to test examples.

Test Example 1: Inhibition of TNF production in LPS-induced mouse sepsis model

A final concentration of 0.2 mg / ml of lipopolysaccharide (LPS, Difco) was added to 5-6 male / group BALB / c male mice (7 weeks old) (Nippon Chiral Surino, one company). The solution was dissolved in physiological saline, and administered to the tail vein at a dose of 200 veins per 20 g of body weight. The test compound was dissolved or suspended in a 0.5% methylcellulose solution to a final concentration of 1 mg / ml, and administered orally at 200 1 per 20 g body weight 90 minutes before LPS administration. Serum TNF concentration measured by enzyme-linked immunosorbent assay It was measured by the ELISA method. Specifically, 50 mg of 4 mg / ml anti-mouse TNF monoclonal antibody (Genzym) diluted with phosphate buffered saline (PBS) was added to a 96-well flat-bottom micro-Tai Yuichi plate (Nunc Imnoplate 'Maxi Sorp', Nunc). 〃 1 / well plus 4. Coated with C for 12 hours, added 200 1 / weU of phosphate buffer solution (1% BSA-PBS) containing 1% serum albumin (BSA), and allowed to stand at room temperature for 1 hour for non-specific binding After blocking, was washed with a phosphate buffer solution, and the test serum diluted 2-fold with 1% BSA-PBS was added at 100/1 / weU, and allowed to stand at room temperature for 2 hours. Recombinant mouse TNFa (Genzam) diluted with 1% BSA-PBS was used similarly as a standard substance. These plates were washed with PBS containing 0.05% polyoxyethylene sorbin monolaurate (Tween 20, Poco One).

(0.05% Tween-PBS) three times, and dilute 50% 1/1 / Pionin-labeled anti-mouse TNF polyclonal antibody (Pharmingen) diluted with 1% BSA-PBS to a concentration of 1 μg / ml. Add weU, allow to stand at room temperature for 1 hour, wash 3 times with 0.05% Tween-PBS, and add 100% horseradish peroxida-zeavidin D (Vecta) diluted 4000 times with 1% BSA-PBS. 1 / well was added and left at room temperature for 30 minutes. Finally, wash these plates three times with 0.05% Tween-PBS, add 3,3 ', 5,5'-tetramethylbenzidine at 1001 / weU, and add 10% sulfuric acid solution at 1001 / well when color develops. The reaction was stopped by measuring the absorbance at 450 nm. Serum TNF concentration was calculated from the calibration curve.

The inhibition rate of TNF production by the test compound was determined by the following equation.

(Expression)

Suppression rate (%) Two (A-B) / A

A: Control TNF α concentration, Β: TNF concentration in the presence of drug

The control TNF concentration was determined in the absence of the test compound (0.5% methylcell mouth).

-Solution alone).

Represented by the formula (Α) as a comparative compound

HCI

(A)

7-Methoxy 4- [1-oxo-1- (4-pyridyl) ethyl] spiro [2,3-dihydrobenzofuran-1,1,1-cyclopentane] 'hydrochloride (Japanese Patent Laid-Open No. 8-836624, Example 100, hereinafter referred to as compound A).

The results are shown in Table 2.

Table 2

Test Example 2 Vomiting-inducing effect using male sunkus

Male sunkus (Sunkus murinus) weighing around 60 g / group 5 to 5: Five L mice were used for the test. Matsuki et al. Sunkus is a wire-meshed cage (15cm wide x long) according to the following rules: 'Jan, off', 'Pharma,-(Jap an J. Pharmacol.), 48, 303 (1988)] (21 cm x 15 cm). The test compound was suspended in 0.5% tween 80 physiological saline and administered intraperitoneally (ip) at a volume of 101 / g. 1 hour after test compound administration The number of occurrences of vomiting was measured. The results were expressed as the number of vomiting animals / experimental animals in the test compound administration group.

Compound A was used as a comparative compound.

Table 3 shows the results.

Table 3

As shown in Tables 2 and 3, the compounds 1 to 3 of the present invention suppressed the production of TNF tx which activates inflammatory leukocyte cells. Also, the compounds of the present invention are superior to compound A in reducing vomiting, a common side effect of PDE IV inhibitors. Compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to provide it as various pharmaceutical preparations. The pharmaceutical preparations are used for animals and humans.

The pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmacologically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient. In addition, these pharmaceutical preparations are produced by mixing the active ingredient with one or more pharmacologically acceptable carriers and by any method well known in the technical field of pharmaceuticals.

The route of administration is preferably the one that is most effective in the treatment, and may be oral or non-oral, for example, oral, respiratory, rectal, subcutaneous, intramuscular, and intravenous .

Dosage forms include sprays, capsules, tablets, granules, syrups, emulsions, Suppositories, injections, ointments, tapes, etc.

Liquid preparations suitable for oral administration, for example, emulsions and syrups, include water, sugars such as sucrose, sorbitol, fructose, glycols such as polyethylene glycol, propylene glycol, sesame oil, olive oil, soybean oil. Oils such as, for example, preservatives such as p-hydroxybenzoic acid esters, and flavors such as peridotium flavor and peppermint. Capsules, tablets, powders, granules, etc. are excipients such as lactose, glucose, sucrose, mannitol, disintegrants such as starch and sodium alginate, and lubricants such as magnesium stearate and sugar. It can be produced using a binder such as polyvinyl alcohol, hydroxypropylcellulose, and gelatin, a surfactant such as a fatty acid ester, and a plasticizer such as glycerin.

Formulations suitable for parenteral administration comprise a sterile aqueous preparation containing the active compound, which is preferably isotonic with the blood of the recipient. For example, as an injection, a solution for injection is prepared using a carrier comprising a salt solution, a glucose solution, or a mixture of saline and a pudose solution. Formulations for enteral administration are prepared using carriers such as, for example, cocoa butter, hydrogenated fats or hydrogenated carboxylic acids, and are provided as suppositories. Sprays are prepared using a carrier which does not irritate the active compound itself or the oral and respiratory mucosa of the recipient and which disperses the active compound as fine particles to facilitate absorption. Specifically, lactose, glycerin and the like are exemplified. Formulations such as aerosols and dry powders are possible depending on the nature of the active compound and the carrier used.

Also, among these parenteral preparations, one or more selected from the diluents, fragrances, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for the oral preparations Further auxiliary components can also be added.

The effective amount and frequency of administration of compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the mode of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. However, the usual dosage is 0.01 mg to 1 g, preferably 0.05 to 50 mg, per adult once or several times a day when administered orally. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to 100 mg per adult is administered once to several times a day. These dosages vary depending on the various conditions described above. Hereinafter, preparation examples of the compound of the present invention are shown.

Formulation Example 1 Tablet

A tablet consisting of the following composition is prepared by a conventional method.

Compound 1 50mg

Lactose 60mg

Potato starch 50mg

Polyvinyl alcohol 2mg

Lmg magnesium stearate

Tar dye trace

Formulation Example 2 Tablet

A powder having the following composition is prepared by a conventional method.

Compound 1 50mg

Lactose 250mg

Formulation Example 3 Capsules

A capsule having the following composition is prepared by a conventional method.

Compound 1 10mg

Lactose 185mg

Croscarmellose sodium 10mg

Hydroxypropyl cellulose L 4mg

Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples. BEST MODE FOR CARRYING OUT THE INVENTION

Example 1

7- (4-carboxypyridine-1-yl) -1-4-methoxyspiro [1,3-benzodioxole-12,1,1-cyclopentane] (compound 1)

Compound a (0.28 g) obtained in Reference Example 1 was dissolved in THF (3.0 ml), a 6 N aqueous NaOH solution (1.4 ml) was added, and the mixture was stirred at room temperature for 1 hour. Water and ethyl acetate were added, and the aqueous layer was extracted. After dilute hydrochloric acid was added dropwise to make the mixture weakly acidic, the precipitated crystals were collected by filtration and washed with water to obtain Compound 1 (0.2 g, 76%) as colorless crystals.

Melting point: 187-188 ° C

! H-NMR (DMSO- ^, d ppm): 1.78-1.83 (m, 4H), 2.04-2.ll (m, 4H), 3.86 (s, 3H), 6.80 (d, J = 9Hz, 1H) , 7.25 (d, J = 9Hz, 1H), 8.09 (d, J = 8Hz, 1H), 8.23 (dd, J = 2.8Hz, 1H), 9.02 (d, J = 2Hz, 1H).

MASS (m / z): 327 (M ⁺ )

IR (KBr, cm ¹ ): 2933, 1697, 1448, 1284, 1115.

As C ₁₈ HnNO _5: elemental analysis

Measured value (%) C: 66.11, H: 5.29, N: 4.05

Calculated value (%) C: 66.05, H: 5.23, N: 4.28

Example 2

7- (4-Carboxyphenyl) 1-2,2-dimethyl-14-methoxy-11,3-benzodioxole (Compound 2)

Using compound b (0.5 g) obtained in Reference Example 2, compound 2 (0.25 g, 50%) was obtained as colorless crystals in the same manner as in Example 1.

Melting point: 237-239 ° C

! H-NMR DMSO- ^ d ppm): 1.70 (s, 6H), 3.84 (s, 3H), 6.75 (d, J = 9Hz, 1H), 7.13 (d, J = 9Hz, 1H), 7.77 ( d, J = 9Hz, 2H), 7.98 (d, J = 9Hz, 2H).

MASS (m / z): 300 (M ⁺ ) IR (KBr, cm: 2940, 1684, 1452, 1290, 1103.

Elemental analysis: as CnH ₁₆ 0 ₅ · 0.5H ₂ O

Actual value (%) C: 65.87, H: 5.32, N: 0.04

Calculated value (%) C: 66.01, H: 5.54, N: 0.00

Example 3

4-Methoxy-1 7- (4-methylviridine-1-3-yl) spiro [1,3-benzodioxol-1,2'-cyclopentane] (Compound 3)

The compound a (6.9 g) obtained in Reference Example 1, 6-methyl-3-pyridyltrifluoromethanesulfonate (2.3 g), and dichlorobistriphenylphosphinepalladium (0.33 g) were dissolved in DMF (23 ml). The mixture was stirred at ° C for 1 hour. An aqueous solution of ammonium fluoride and ethyl acetate were added to the reaction solution, and the mixture was filtered through celite, and the organic layer was extracted. After washing with saturated saline and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane = 1/3) to give compound 3 (1.1 g, 39%) as colorless crystals.

! H-NMRCCDCls, δ ppm): 1.76-1.97 (m, 4H), 2.03-2.25 (m, 4H), 2.58 (s, 3H), 3.93 (s, 3H), 6.60 (d, J = 9Hz, IH), 6.96 (d, J = 9Hz, 1H), 7.19 (d, J = 8Hz, IH), 7.85 (dd, J = 2.8Hz, IH), 8.82 (d, J = 2Hz, IH).

MASS (m / z): 297 (M ⁺ )

Example 4

7— (4-Carboxy-13-methylphenyl) -14-methoxyspiro [1,3-benzodioxo-l-un 2,1,1-cyclopentane] (Compound 4)

Using compound c (0.67 g) obtained in Reference Example 3, compound 4 (0.30 g, 49%) was obtained as colorless crystals in the same manner as in Example 1.

Melting point: 194-195 ° C

! H-NMRCCDCls, δ ppm): 1.75-1.95 (m, 4H), 2.10-2.25 (m, 4H), 3.94 (s, 3H), 6.60 (d, J = 9Hz, IH), 7.03 (d, J = 9Hz, IH), 7.59 (s, IH), 7.60 (d, J = 8Hz, oz

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(+ ι τοε: (z / ra) ssvw (HI ^<z m = r ')

006 '(HT' ^z H8'2 = f 'PP) 8S'8' (HI 'zH8 = f' Ρ) 80 "8 '(Ηΐ ^<Ζ Η6 = Γ' V) £ Z'L '(HT' zH6 = f 'P) 6 9'(HS's) 98 S '(H9' s) UI:-OSWCl) N-Hi

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K 86df / 丄: W 9991/66 ! H-NMRCDMSO- ^ d ppm): 3.89 (s, 3H), 6.13 (s, 2H), 6.84 (d, J = 9Hz, lH), 7.30 (d, J = 9Hz, lH), 8.10 ( d, J = 8Hz, lH), 8.23 (dd, J = l, 9Hz, lH), 9.03 (d, J = 1H

MASS (m / z): 273 (M ⁺ )

IR (KBr, cm ¹ ): 1645, 1321, 1286, 1084.

Elemental analysis CMHUNOS · As O.IH2O

Measured value (%) C: 60.99, H: 4.00, N: 5.10

Calculated value (%) C: 61.14, H: 4.10, N: 5.09

Example 7

7- (4-Carboxy-3-methylphenyl) -1-4-methoxy-1,3-benzodioxol (Compound 7)

Compound 7 (0.12 g, 82%) was obtained as colorless crystals in the same manner as in Example 1 using compound f (0.16 g) obtained in Reference Example 6.

Melting point: 228-229 ° C

ppm): 2.71 (s, 3H), 3.96 (s, 3H), 6.07 (s, 2H), 6.65 (d, J = 9Hz, 1H), 7.07 (d, J = 9Hz, 1H), 7.58-7.60 ( m, 2H), 8.10 (d, J = 9Hz, 1H). MASS (m / z): 286 (M ⁺ )

IR (KBr, cm ¹ ): 1693, 1300, 1290, 1084.

Example 8

7- (4-Rubamoylviridine-1-3-yl) -14-Methoxyspiro [1,3-benzodioxol-12,1, -cyclopentane] (Compound 8)

Compound 1 (100 _mg ) obtained in Example 1 was dissolved in dichloromethane (1 ml), and thionyl chloride (1 ml) was added, followed by heating under reflux for 10 minutes. After removing the solvent, a saturated ammonia ethanol solution was added, and the mixture was stirred for 2 hours. The precipitated crystals were collected by filtration and washed with ethanol to obtain Compound 8 (35 mg, 35%) as pale yellow crystals.

Melting point: 225-229 ° C iH-NMR (CDCl ₃ , (J ppm): 1.82-1.90 (m, 4H), 2.10-2.23 (m, 4H), 3.95 (s, 3H), 5.78 (brs, IH), 6.64 (d, J = 9Hz, IH), 7.04 (d, J = 9Hz, IH), 7.86 (brs, 1H), 8.12 (dd, J = 2.8Hz, IH), 8.23 (d, J = 8Hz, IH), 8.92 ( d, J = 2Hz, IH). MASS (m / z): 326 (M +)

Example 9

7- (4-Icyan-3-hydroxypyridine-12-yl) -1-4-methoxyspiro [1,3-benzodioxol-1,2,1,1-cyclopentane] (Compound 9) Obtained in Reference Example 7 Compound g (1.53 g) and cyanoacetamide (0.45 g) were dissolved in DMF (6 ml) and methanol (0.55 ml), 60% sodium hydride (0.6 g) was added, and the mixture was heated under reflux for 6 hours. After cooling, the reaction solution was poured into ice, and diluted hydrochloric acid was added dropwise to make it weakly acidic, and the precipitated crystals were collected by filtration. Recrystallization from DMF-water gave compound 9 (0.65 g, 40%) as yellow crystals.

Melting point: 245-247 ° C

! H-NMR (DMSO-i ₆ , (5 ppm): 1.77-1.82 (m, 4H), 2.02-2.19 (m, 4H), 3.87 (s, 3H), 6.78-6.81 (m, 2H), 7.32 (d, J = 9Hz, IH), 8.15 (d, J = 8Hz, 1H), 12.41 (brs, IH).

MASS (m / z): 324 (M ⁺ )

IR (KBr, cm ¹ ): 2970, 2218, 1645, 1511, 1444, 1284.

As Ci8Hi6N ₂ 0 _4: Elemental analysis

Observed value (%) C: 66.57, H: 4.98, N: 8.59

Calculated value (%) C: 66.66, H: 4.97, N: 8.64

Reference example 1

4-Methoxy Ί— (4-Methoxycarbonylpyridine-13-yl) spiro [1,3-benzodioxol-1,2,1, cyclopentane] (Compound a)

(Step A) 4-Methoxy-7-triptylsylnylspiro [1,3-benzodioxo-2,1'-cyclopentane] (Compound aa) Under an argon atmosphere, a THF solution (100 1111) of 7-bromo-1-methoxyspiro [1,3-benzodioxo-l-2, -cyclopentene] (5.5 g) was cooled to -78 ° ( A butyllithium hexane solution (1.6 M) (15 ml) was added dropwise, and the mixture was stirred at the same temperature for 1 hour, and then a drop-port triptyltin (6.3 ml) was added dropwise and stirred for 1 hour. Ether was added, and the organic layer was extracted, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain a crude target product, which was used directly in the next step without purification.

(Step B) Compound a

Using the compound aa (3.4 g) obtained in the step A, methyl 5-iodopyridine-12-carboxylate (1.2 g), and palladium diphenylphosphinophane (0.2 g), Example 3 was used. Compound a (0.78 g, 50%) was obtained as colorless crystals by a similar method.

! H-NMRCCDCls, ^ ppm): 1.86-1.89 (m, 4H), 2.17-2.19 (m, 4H), 3.95 (s, 3H), 4.03 (s, 3H), 6.63 (d, J = 9Hz, 1H ), 7.06 (d, J = 9Hz, 1H), 8.12 (dd, J = 2,8Hz, 1H), 8.18 (d, J = 8Hz, 1H), 9.09 (d, J = 2Hz, 1H).

MASS (m / z): 341 (M ⁺ )

Reference example 2

2,2-Dimethyl-1- (4-ethoxycarbonylphenyl) -1-methoxy-1,3-benzodioxol (Compound b)

(Step A) 2,2-Dimethyl-4-methoxy-17-triptyls 1,3-benzodioxol (compound b a)

7-Bromo-1,2,2-dimethyl-1-methoxy-1,3,3-benzodioxol (0.7 g) and chlorotributyltin (0.88 ml) I got something. This was used for the next step immediately without purification.

(Step B) Compound b

Using compound ba obtained in Step A, ethyl 4-benzoate (0.9 g), palladium acetate (0.037 g), and silver oxide (0.038 g), in the same manner as in Reference Example 1 Step B Conversion Compound b (0.51 g, 57%) was obtained as colorless crystals.

! H-NMRCCDCla, δ ppm): 1.40 (t, J = 7Hz, 3H), 1.70 (s, 6H), 3.84 (s, 3H), 4.39 (q, J = 7Hz, 2H), 6.75 (d, J = 9Hz, IH), 7.13 (d, J = 9Hz, IH), 7.77 (d, J = 9 Hz, 2H), 7.98 (d, J = 9Hz, 2H).

MASS (m / z): 300 (M ⁺ )

Reference example 3

7- (4-Ethoxycarbonyl-13-methylphenyl) -1-4-methoxyspiro [1,3-benzodioxo-l-2,1, -cyclopentane] (Compound c)

(Step A) (Compound c a) 7-Dihydroxyboryl-1-4-methoxyspiro [1,3-benzodioxol-12,1,1-cyclopentane

Under an argon atmosphere, a THF solution (9.9 ml) of 7-bromo-1-methoxyspiro [1,3-benzodioxol-1,1,1-cyclopentane] (0.99 g) was cooled to -78 ° C, and butyl was added. A lithium hexane solution (1.5 MK 2.7 ml) was added dropwise. After stirring at the same temperature for 10 minutes, trimethoxyborane (0.50 ml) was added dropwise, and the mixture was stirred for 30 minutes. 1N HC1 aqueous solution and ethyl acetate were added to extract an organic layer. After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain a crude target product. This was used for the next step immediately without purification.

(Step B) Compound c

A mixture of compound ca obtained in Step A, ethyl 4-bromo-2-methylbenzoate (0.96 g), palladium acetate (0.039 g), sodium carbonate (0.73 g) and DMF (8.7 ml) was heated to 110 ° C. The mixture was stirred at C for 3 hours. After cooling, water and ethyl acetate were added, and after filtration, the organic phase was extracted with ethyl acetate. After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate / hexane = 1/8) to give compound c (0.67 g, 53%) as a colorless oil.

! H-NMRCCDC ^, δ ppm): 1.40 (t, J = 7Hz, 3H), 1.75-1.97 (m, 4H), 2.05-2.25 (m, 4H), 2.66 (s, 3H), 3.93 (s, 3H), 4.37 (q, J = 7Hz, 2H), 6.59 (d, J = 9Hz, 1H), 7.00 (d, J = 9Hz, IH), 7.54 (s, 1H), 7.57 (d, J = 8Hz, IH), 7.97 (d, J = 8Hz, IH).

Reference example 4

2,2-dimethyl-1-4-methoxy-7- (4-methoxycarbonylpyridine-3-yl) -1,3-benzodioxol (compound

(Step A) 7-dihydroxyboryl-1,2-dimethyl-1-4-methoxy-1,1,

3-benzodioxol (compound da)

Using 7-bromo-12,2-dimethyl-14-methoxy-1,3-benzodioxol (1.5 g), a crude target compound was obtained in the same manner as in Reference Example 3, Step A. This was used for the next step immediately without purification.

(Step B) Compound d

Using the compound da obtained in Step A, methyl 5-pyridine-2-carboxylate (1.5 g), palladium acetate (0.063 g), sodium carbonate (1.2 g) and DMF (13 ml), Reference Example 3 Compound d (0.70 g, 38%) was obtained as colorless crystals in the same manner as in Step B.

Melting point: 114-117 ° C

ppm): 1.76 (s, 6H), 3.95 (s, 3H), 4.02 (s, 3H), 6.64 (d, J = 9Hz, IH), 7.05 (d, J = 9Hz, IH), 8.12 (dd, J = 1,7Hz, IH), 8.17 (d, J = 7Hz, IH), 9.06 (d, J = lHz, IH).

MASS (m / z): 315 (M ⁺ )

Reference example 5

4-Methoxy-7- (4-methoxycarbonylpyridine-13-yl) -11,3-benzodioxol (Compound e)

(Process A) 7-Dihydroxyboryl-1-4-methoxy-1,3-benzodioxol (compound ea)

Use 7-promo 4-methoxy-1,3-benzodioxol (1.5 g) for reference Example 3 A crude target product was obtained in the same manner as in Step A. This was used for the next step immediately without purification.

(Step B) Compound e

Using the compound ea obtained in Step A, methyl 5-iodopyridine-2-methyl carboxylate (1.5 g), palladium acetate (0.063 g), sodium carbonate (1.2 g) and DMF (13 ml), Reference Example 3 was used. Compound d (0.71 g, 44%) was obtained as colorless crystals in the same manner as in Step B.

Melting point: 152-154 ° C

! H-NMRCCDCla, δ ppm): 3.97 (s, 3H), 4.03 (s, 3H), 6.09 (s, 2H), 6.69 (d, J = 9Hz, 1H), 7.10 (d, J = 9Hz, 1H ), 8.10-8.20 (m, 2H), 9.12 (s, 1H).

MASS (m / z): 287 (M ⁺ )

Reference example 6

7- (4-ethoxycarbonyl-2-methylphenyl) -1-4-methoxy-1,3-benzodioxol (compound f)

Using the compound ea, 4-ethyl-2-ethyl benzoate (0.88 g), palladium acetate (0.043 g), sodium carbonate (0.71 g) and DMF (6.5 ml), in the same manner as in Reference Example 3, step B As a result, compound f (0.18 g, 17%) was obtained as colorless crystals.

Melting point: 118-119 ° C

! H-NMRCCDCls, δ ppm): 1.40 (t, J = 7 Hz, 3H), 2.65 (s, 3H), 3.94 (s, 3H), 4.37 (q, J = 7 Hz, 3H), 6.06 (s, 2H), 6.63 (d, J = 9Hz, 1H), 7.05 (d, J = 9Hz, 1H), 7.59-7.36 (m, 2H), 7.97 (d, J = 9Hz, 1H).

MASS (m / z): 314 (M ⁺ )

Reference Example 7

7- (3-Dimethylamino-l-oxoprovir-l-2-enyl) -l-methoxyspiro [l, 3-benzodioxol-l, l, l-cyclopentane] (Compound g) (Step A) 7- (1-Hydroxy ) Ethyl 4- (methoxyspiro) [1,3-benzodi) Oxazole-2,1, -cyclopentane] (compound ga)

7-Formyl-1-methoxyspiro [1,3-benzodioxol-1,2'-cyclopentane] (3.0 g) was dissolved in THF (30 ml), and 3 mol / 1 methyl green reagent (5. l ml) and stirred for 30 minutes. The reaction solution was poured on ice, extracted with a black hole form, washed with saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain Compound a (3.2 g, 100%) as an oil.

(Step B) 7-Acetyl-1-4-methoxyspiro [1,3-benzodioxo- 1,2,1,1-cyclopentane] (Compound gb)

Compound ga (3.2 g) obtained in Step A was dissolved in acetone (30 ml), and 2.6 mol 1 dione's reagent (5 ml) was added thereto under ice cooling, followed by stirring for 20 minutes. After the reaction solution was concentrated under reduced pressure, water and ethyl acetate were added to extract an organic layer. The organic layer was washed with brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain compound gb (2.5 g, 78%) as an oil.

(Step C) Compound g

The compound gb (2.4 g) selected in Step B was dissolved in DMF (30 ml), dimethylaldehyde dimethyl acetate (2.6 ml) was added, and the mixture was heated under reflux for 8 hours. The organic layer was extracted by adding water and getylether. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to obtain Compound g (1.8 g, 61%) as yellow crystals.

! H-NMRCDMSO- ^ d ppm): 1.78-1.83 (m, 4H), 2.05-2.10 (m, 4H), 2.83 (brs,

3H), 3.12 (brs, 3H), 3.83 (s, 3H), 5.83 (d, J = 13Hz), 6.67 (d, J = 9Hz, 1H), 7.28 (d,

J = 9Hz, 1H), 7.67 (d, J = 13 Hz, 1H).

MASS (m / z): 303 (M ⁺ )

Elemental analysis: as CnH ₂₁ N04

Found (%) C: 67.31, H: 6.98, N: 4.62

Calculated value (%) C: 67.40, H: 7.16, N: 4.49 Industrial applicability

INDUSTRIAL APPLICABILITY The present invention has a PDE IV inhibitory effect, and has asthma, allergy, rheumatism, psoriasis, myocardial infarction, depression, amnesia, multiple sclerosis, Crohn's disease, systemic lupus erythematosus, diabetes, wound, AIDS An oxygen-containing heterocyclic compound useful as a therapeutic agent can be provided.

Claims

The scope of the claims

1.-General formula (I)

Wherein R ¹ and R ² are the same or different and each represents hydrogen or lower alkyl or joined together to represent cycloalkyl, R ³ represents lower alkyl, R ⁴ represents lower alkyl, nitro, Represents cyano, carbamoyl, formyl, lower alkoxycarbonyl or carboxy, and X and Y are the same or different,

A benzodioxole derivative represented by N or CR ⁵ (wherein R ⁵ represents hydrogen, lower alkyl, hydroxy or halogen) or a pharmaceutically acceptable salt thereof.

2. In the general formula (I), R ¹ and R ² together represent cycloalkyl, R ⁴ represents carboxy or lower alkyl, X represents CH, and Y represents N. Item 4. The benzodioxol derivative or the pharmacologically acceptable salt thereof according to Item 1.

3. In the general formula (I), R ¹ and R ² are the same or different and represent lower alkyl, R ⁴ represents carboxy, X represents CH, and Y represents CH. Derivatives or pharmacologically acceptable salts thereof.

4. The benzodioxol derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to ³ , wherein, in the general formula (I), R ³ is methyl.

5. A therapeutic agent for inflammatory allergic diseases, comprising the benzodioxol derivative according to claim 1 or a pharmacologically acceptable salt thereof as an active ingredient.

6. A method for treating an inflammatory allergic disease, comprising administering an effective amount of the benzodioxole derivative according to claim 1 or a pharmacologically acceptable salt thereof.

7. A use of the benzodioxoyl derivative or the pharmaceutically acceptable salt thereof according to claim 1 for the manufacture of a pharmacological composition useful for treating an inflammatory allergic disease.