JPH10147585A - Oxygen-containing heterocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a novel compound that has phosphodiesterase IV inhibitory action and is useful as a therapeutic agent for bronchial asthma, inflammatory allergic diseases, autoimmune diseases, central nervous system diseases, organophathy, diabetes, AIDS and the like. SOLUTION: This compound is represented by formula I [R<1> and R<2> are each a (substituted) lower alkyl, a cycloalkyl; R<3> is H, a (substituted) aryl, a halogen; A is -C(R<7> )(R<8> ) (R<7> and R<8> are each H, a lower alkyl); B is O, NR<9> (R<9> is H, a lower alkyl); R<4> is OH, a lower alkoxy, R<5> is an aryl, an aromatic heterocyclic group; R<6> is H, a lower alkyl], typically 5-(3,5-dichloro-4- pyridylaminocarbonyl)-8-methoxy-2,2-dimethylbenzopyrane. The compound of formula I is prepared by dehydration condensation reaction between a compound of formula II and a compound of the formula: R<5> R<6> NH.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention has a phosphodiesterase (PDE) IV inhibitory activity, and has an inflammatory allergic disease such as bronchial asthma, allergic rhinitis and nephritis, rheumatism, multiple sclerosis, Crohn's disease, psoriasis, and whole body. Autoimmune diseases such as systemic lupus erythematosus, depression, amnesia, diseases of the central nervous system such as dementia, heart failure, shock, organ damage due to ischemia reperfusion caused by cerebrovascular disorders, diabetes due to insulin resistance, The present invention relates to an oxygen-containing heterocyclic compound useful as a therapeutic agent for wounds, AIDS, and the like.

[0002]

2. Description of the Related Art Conventionally, many hormones and neurotransmitters are adenosine 3 ', 5'-cyclic monophosphate (cAMP) or guanosine 3', 5'-cyclic monophosphate, which are second messengers in cells. 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 PDEs results in increased levels of these intracellular second messengers. It has been clarified that seven types of isozymes exist in PDE so far, and an isozyme-selective PDE inhibitor exerts a pharmacological effect based on the physiological significance and distribution of the isozyme in a living body. [TiPS, 11 , 150 (1990) and Ti
PS, 12 , 19 (1991)].

It is known that increasing the intracellular cAMP of inflammatory leukocytes can suppress their activation. Activation of leukocytes leads to secretion of inflammatory cytokines, including tumor necrosis factor (TNF), expression of cell adhesion molecules such as intercellular adhesion molecules (ICAMs), and subsequent cell infiltration [J. Mol. Cell . Cardiol., 12 (Suppl. I
I), S61 (1989)].

[0004] It is known that increasing cAMP concentration in tracheal smooth muscle cells can suppress the contraction (TJ
Torphy in Directions for New Anti-Asthma Drugs, ed
s SR O'Donell and CGA Persson, 1988, 37, Bi
rkhauser-Verlag). Contraction of the tracheal smooth muscle is a major condition of bronchial asthma. In ischemia-reperfusion organ damage such as myocardial ischemia, infiltration of inflammatory white blood cells such as neutrophils is observed in the lesion. In these inflammatory cells and tracheal smooth muscle cells, it has been revealed that type IV PDE (PDE IV) is mainly involved in cAMP degradation. Therefore, a PDE IV selective inhibitor can be expected to have a therapeutic and / or preventive effect on inflammatory diseases, airway obstructive diseases, and ischemic diseases.

[0005] In addition, since PDE IV inhibitors suppress the secretion of inflammatory cytokines such as TNFα and interleukin (IL) -8 by increasing cAMP, the inflammatory response transmitted by these cytokines is further suppressed. Is expected to be able to prevent prolonged progress. For example, TNF α
Has been reported to reduce the mechanism of insulin receptor phosphorylation in muscle and fat cells and contribute to insulin resistant diabetes [J. Clin. Invest., 94 , 1543-
1549 (1994)]. Similarly, TNFα is involved in the development 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, 211-214
(1995) and 244-248].

It has been reported that a drug that increases cAMP promotes wound healing [68th Annual Meeting of the Japanese Pharmacological Association (Nagoya), title P3-116, 1995]. WO96-0
0218, WO96-00215, WO95-35285, WO95-35284, WO95-352
83, WO95-35281, WO95-28926, WO95-27692, WO95-2438
1, WO95-22520, WO95-20578, WO95-17399, WO95-17392,
WO95-14681, WO95-14680, WO95-14667, WO95-09837, W
O95-09836, WO95-09627, WO95-09624, WO95-09623, WO9
5-08534, WO95-04046, WO95-04045, WO95-03794, WO95-
01338, WO95-00516, WO95-00139, US5461056, EP068547
9, EP0685475, EP0685474, EP0671389, WO93-25517, WO9
4-25437, EP0623607, WO94-20446, WO94-20455, WO94-1
4800, WO94-14742, WO94-12461, WO94-10118, WO94-024
65, WO93-19751, WO93-19750, WO93-19749, WO93-1974
8, WO93-19747, WO93-18024, WO93-15048, WO93-07141,
In JP-A-5-117239, WO92-19594 and EP0497564,
PDE IV selective inhibitors having a catechol structure have been disclosed.

Further, it has a benzofuran structure and has a PDE
Compounds with IV inhibitory activity have been reported [Bioorgan
ic Med.Chem. Lett., 14, 1855-1860 (1994), EP06854
79 and WO 96-03399]. BACKGROUND ART Conventionally, benzofuran derivatives are industrially useful, and patents have been disclosed as production raw material intermediates, light-emitting elements, pesticides, anthelmintics, pharmaceuticals, and the like.

[0008] J. Med. Chem., 31, 84-91 (1988), JP-A-61-50977, JP-A-61-126061, JP-A-61-143371 and JP-A-62-230760 disclose carboxyl groups. A benzofuran derivative, a benzopyran derivative and a benzodioxole derivative having a group or a tetrazolyl group are disclosed, and it is described that these have a leukotriene antagonism, a phospholipase inhibitory action, a 5α reductase inhibitory action, an aldose reductase inhibitory action, and the like. .

[0009] WO92-01681 and WO92-12144 include acyl
A benzofuran derivative and a benzopyran derivative having a CoA acetyltransferase (ACAT) inhibitory action are disclosed. WO93-01169 discloses a benzofuran derivative having a tachykinin antagonistic action.

[0010] EP0307172 and US4910193 disclose benzofuran derivatives having serotonin (5HT) ₃ receptor antagonism.

[0011]

[Problems to be Solved by the Invention] New and useful PDE IV
Inhibitors are expected and expected to have a preventive or therapeutic effect on a wide range of diseases. The purpose of the present invention is to
An object of the present invention is to provide a novel oxygen-containing heterocyclic compound which has an IV-selective inhibitory effect and increases bronchodilator and anti-inflammatory effects by increasing intracellular cAMP concentration.

[0012]

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

[0013]

Embedded image

Where R¹And R^TwoAre the same or different
Is a substituted or unsubstituted lower alkyl, cycloalkyl
Alkyl, polycycloalkyl, lower alkenyl or
Represents chloroalkenyl;^ThreeIs hydrogen, substituted or
Represents an unsubstituted aryl or halogen;^FourThe
Doxy or substituted or unsubstituted lower alkoxy
A represents -C (R⁷) (R⁸)-(Where R⁷You
And R⁸Are the same or different and are hydrogen, substituted or
Unsubstituted lower alkyl, cycloalkyl, or polycyclic
B) represents O, N
R⁹中 where R⁹Is hydrogen, lower alkyl, cycloal
Kill, polycycloalkyl, lower alkenyl, cycloa
Alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted
Is an unsubstituted aromatic heterocyclic group, aralkyl or-(CH
_Two)_n-E¹-CO-G¹[Where E¹Is a bond,
Or NH¹Is hydrogen, substituted or unsubstituted
Lower alkyl, cycloalkyl, polycycloalkyl
, Substituted or unsubstituted aryl, substituted or unsubstituted
A substituted aromatic heterocyclic group, aralkyl, OR^Ten(Where R^Ten
Is hydrogen, lower alkyl, cycloalkyl, polycyclo
Alkyl, substituted or unsubstituted aryl, substituted or
Represents an unsubstituted aromatic heterocyclic group or aralkyl)
Or NR¹¹R¹²(Where R¹¹And R¹²Are the same or
Are different from hydrogen, lower alkyl, cycloalkyl,
Licycloalkyl, substituted or unsubstituted aryl, substituted
Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted
Represents a substituted aralkyl or heteroarylalkyl
Or R¹¹And R¹²Are formed together with N
Represents a substituted or unsubstituted heterocyclic group);
Represents an integer of 0 to 4];⁹And R^TwoBut one
｝, -C (R¹³) (R¹⁴)-
[Wherein, R¹³Is hydrogen, substituted or unsubstituted lower alkyl
Kill, cycloalkyl, polycycloalkyl, lower alkyl
Kenyl, cycloalkenyl, substituted or unsubstituted ants
, Substituted or unsubstituted aromatic heterocyclic group, aralkyl
Le, cyano or-(CH_Two)_m-E^Two-CO-G
^Two(Where E^Two, G ^TwoAnd m are each the aforementioned E¹,
G¹And n have the same meanings)¹⁴Is
Substituted or unsubstituted lower alkyl, cycloalkyl,
Licycloalkyl, lower alkenyl, cycloalkenyl
, Substituted or unsubstituted aryl, substituted or unsubstituted
A substituted aromatic heterocyclic group, aralkyl, cyano or-(C
H_Two)_p-E^Three-CO-G^Three(Where E^Three, G^Threeand
p is the E¹, G¹And the same meaning as n
] Or -C (R^Fifteen) (R¹⁶) -C
(R¹⁷) (R¹⁸)-(Where R^FifteenAnd R¹⁶Are the same
Or differently, hydrogen, substituted or unsubstituted lower alkyl
, Cycloalkyl, aralkyl, substituted or unsubstituted
Represents an aryl, substituted or unsubstituted aromatic heterocyclic group
Waska, R^FifteenAnd R¹⁶Together represent O, and R¹⁷You
And R¹⁸Are the same or different and are hydrogen, substituted or
Unsubstituted lower alkyl, cycloalkyl, aralkyl,
Substituted or unsubstituted aryl, substituted or unsubstituted
Represents an aromatic heterocyclic group;¹⁸And R¹⁶Together
Represents a single bond or R¹⁸And R¹⁶Are each two adjacent
Together with two carbon atoms represents a saturated carbocycle)
I, R^FiveIs a substituted or unsubstituted aryl,
Or an unsubstituted aromatic heterocyclic group, cycloalkyl,
Gin-N-oxide, cyano or lower alkoxycar
Stands for bonyl, R⁶Is hydrogen, lower alkyl, cyclo
Alkyl, aralkyl, substituted or unsubstituted aryl
Or a substituted or unsubstituted aromatic heterocyclic group.
Or an oxygen-containing heterocyclic compound represented by the formula
For the salt to be carried.

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

[0016]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of each group of the formula (I), the lower alkyl moiety of lower alkyl and lower alkoxy, lower alkoxycarbonyl and heteroarylalkyl is a straight-chain or branched C1-C8 group. For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, etc., and cycloalkyl has 3 to 10 carbon atoms, for example, cyclopropyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like, polycycloalkyl has 4 to 12 carbon atoms,
For example, bicyclo [3.2.1] octyl, bicyclo [4.3.2] undecyl, adamantyl, noradamantyl and the like are included. Lower alkenyl is straight or branched having 2 carbon atoms.
To 8, for example, vinyl, 1-propenyl, allyl, methacryl, 1-butenyl, crotyl, pentenyl, isoprenyl, hexenyl, heptenyl, octenyl and the like;
Cycloalkenyl includes those having 4 to 10 carbon atoms such as cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclononenyl, cyclodecenyl and the like. Aryl is phenyl,
The aralkyl includes naphthyl and the like, and the aralkyl includes benzyl, phenethyl, benzhydryl, naphthylmethyl and the like having 7 to 15 carbon atoms. The heteroaryl portion of the aromatic heterocyclic group and the heteroarylalkyl includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl,
Isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, thienyl,
Furyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl,
Prinyl and the like. Heterocyclic groups formed containing N include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, etc.
A saturated carbocycle together with two carbon atoms has 3 to 3 carbon atoms.
Ten, including, for example, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclononane, cyclodecane, and the like.
Halogen means each atom of fluorine, chlorine, bromine and iodine.

The substituent in the substituted lower alkyl includes the same or different and has 1 or 2 substituents, for example, cycloalkyl, and cycloalkyl has the same meaning as described above. Substituents in the substituted aryl, substituted aromatic heterocyclic group and substituted aralkyl may be the same or different and have 1 to 3 substituents, for example, lower alkyl, hydroxy, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carboxy, carbamoyl, tricarboxy. Fluoromethyl, amino, cyano, nitro, halogen and the like are included. The lower alkyl portion of the lower alkanoyl has the same meaning as the lower alkyl, and the lower alkyl, the lower alkoxy, the lower alkoxycarbonyl and the halogen have the same meanings as described above.

The substituents in the substituted heterocyclic group formed containing N may be the same or different and have 1 to 3 substituents.
For example, lower alkyl, cycloalkyl, aryl,
Aralkyl and the like are included. Lower alkyl, cycloalkyl, aryl and aralkyl each have the same meaning as described above. Examples of the substituent in the substituted lower alkoxy include the same or different substituents having 1 to 3 substituents, for example, halogen, and halogen has the same meaning as described above.

The pharmacologically acceptable salts of compound (I) include pharmacologically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts and the like. The pharmacologically acceptable acid addition salts of compound (I) include inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate, citrate and the like. Organic acid salts, and pharmacologically acceptable metal salts include alkali metal salts such as sodium salts and potassium salts;
Magnesium salts, alkaline earth metal salts such as calcium salts, aluminum salts, zinc salts and the like, and pharmacologically acceptable ammonium salts include ammonium,
Salts such as tetramethylammonium and the like, and pharmacologically acceptable organic amine addition salts include addition salts such as morpholine and piperidine.

Next, a method for producing the compound (I) will be described. Production method: Compound (I) can be produced according to the following reaction steps.

[0021]

Embedded image

Wherein A, B, R ¹ , R ² , R ³ ,
R ⁴ , R ⁵ and R ⁶ each have the same meaning as described above. The starting compound (II) can be prepared by a known method [J. Org. Chem., 52,
4072 (1987), Org.Prep.Proced.Int., 21, 763 (19
89), Synthesis, 1978, 886, Arzneim.-Forsch., 21, 2
04 (1971), WO93-18024 and WO94-12461], and can be obtained according to the methods described in Reference Examples or according to them.

The desired compound (I) is obtained by a dehydration condensation reaction between the starting compound (II) and the compound (III).
For this purpose, the fourth edition of Experimental Chemistry Course (edited by The Chemical Society of Japan, 19
Numerous methods are known and applicable, as described in Vol. 22, pp. 137-172. For example, first, compound (II) is prepared by adding 1 equivalent to a large excess of thionyl chloride, phosphorus pentachloride, oxalyl chloride or the like in an inert solvent in the presence of a catalytic amount to 20 equivalents of a base, if necessary, at 0 ° C. 0.1 to a temperature between the boiling points of the solvents used.
After treatment for 48 hours, the corresponding acid chloride is obtained. Next, the obtained acid chloride and 0.5 to 50 equivalents of the compound (III) are optionally added in an inert solvent in the presence of 0.5 equivalents to a large excess of a base at 0 ° C to the boiling point of the solvent used. By reacting at a temperature between 0.1 and 48 hours,
The desired compound (I) can be obtained.

As the base, sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (LDA), potassium t
Examples include tert-butoxide, triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylpiperidine, diazabicycloundecene (DBU), diazabicyclononene (DBN), and the like.

As the inert solvent, tetrahydrofuran (THF), dioxane, dichloromethane, chloroform,
Examples include benzene, toluene, dimethylformamide (DMF), and dimethylsulfoxide (DMSO). The target compound in the above production method is a separation and purification method commonly used in organic synthetic chemistry, for example, filtration, extraction, washing, drying, concentration,
It can be isolated and purified by recrystallization, various types of chromatography and the like.

Some of the compounds (I) may exist as stereoisomers such as geometric isomers and optical isomers. However, the present invention relates to all possible isomers including these, and their isomers. And mixtures. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt, it may be purified as it is, and when compound (I) is obtained in a free form, compound (I) may be dissolved in an appropriate solvent. It may be dissolved or suspended, and then isolated and purified by adding an acid or a base. The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention.

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

[0028]

[Table 1]

Next, the pharmacological action of the representative compound (I) will be specifically described with reference to experimental examples.

EXPERIMENTAL EXAMPLE 1 Canine Bronchial PDE IV Enzyme Inhibition Test cAMP-specific phosphodiesterase (PDE IV) was obtained from Torphy
[Molecular Pharmacol., 37 , 206-214 (1990)]
Was isolated and purified from canine bronchial smooth muscle. PDE activity was measured by the method of Kincaid and Manganiello et al. [Method i
n Enzymology (JDCorbin and RAJonson, Eds.), 19
9, 457-470 (1988)]. [ ³ H] cAMP (final concentration 1 μM) was used as the substrate.
The reaction is performed with N, N-bis (2-hydroxyethyl) -2-
Aminoethanesulfonic acid (50 mM, pH = 7.2), MgCl ₂ (1 m
M) and a standard mixture containing soybean trypsin inhibitor (0.1 mg / ml). The reaction was started by addition of the enzyme and incubated at 30 ° C. for 10-30 minutes.
The reaction was stopped with hydrochloric acid, and the generated 5′-AMP was completely decomposed by 5′-nucleotidase. DEAE-Sephadex
Chromatography was performed using A-25, and the eluted [ ³ H] adenosine was counted using a scintillation counter.
The drug was dissolved in DMSO (concentration 1.7%) and added.

In this test, compound 2 showed a 92% enzyme inhibitory action at 1.0 mM.

Experimental Example 2 Effect on Anaphylactic Airway Contraction Response 1 ml of anti-ovalbumin rabbit serum was injected intraperitoneally into guinea pigs.
Was administered and passive sensitization was performed, and the anaphylactic airway constriction response, which appeared by intravenous administration of the antigen ovalbumin 16-24 hours later, was measured using a modified Kotzet-Andresler method. At the end of the measurement, the tracheal cannula was completely occluded, and this contraction was taken as the maximum contraction, and the height of the contraction was shown as a percentage over time. The area under the shrinkage curve (AUC), which is an index of the strength of the reaction, was calculated using an image analyzer (MCID system, Imaging Research). The drug was orally administered one hour before the antigen administration, and the inhibition rate was determined.
In this test, Compound 2 showed a 69% inhibitory effect at 10 mg / kg oral administration.

The 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.
These pharmaceutical preparations are used for animals and humans. The pharmaceutical preparation according to the present invention can contain Compound (I) or a pharmaceutically 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 prepared 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 administration route is preferably the one which is most effective in the treatment, and is orally or, for example, oral,
Parenteral, such as in the respiratory tract, rectally, subcutaneously, intramuscularly and intravenously. Dosage forms include sprays,
Capsules, tablets, granules, powders, syrups, emulsions,
Suppositories, injections, ointments, tapes, etc.

Liquid preparations suitable for oral administration, such as, for example, emulsions and syrups include water, sucrose, sorbitol,
Sugars such as fructose, glycols such as polyethylene glycol and propylene glycol, sesame oil, olive oil,
It can be produced using oils such as soybean oil, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. Also,
Capsules, tablets, powders and granules include excipients such as lactose, glucose, sucrose, mannitol, starch, disintegrants such as sodium alginate, magnesium stearate,
It can be produced using a lubricant such as talc, 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 sterile aqueous preparations containing the active compounds which are preferably isotonic with the blood of the recipient. For example, in the case of an injection, a solution for injection is prepared using a carrier composed of a salt solution, a glucose solution or a mixture of saline and a glucose solution. Formulations for enteral administration are prepared using carriers such as cocoa butter, hydrogenated fats or hydrogenated carboxylic acids and are provided as suppositories. Sprays are prepared using the active compound itself or a carrier which does not irritate 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. Depending on the nature of the active compound and the carrier used,
Formulations such as aerosols and dry powders are possible.

Also, in these parenteral preparations, glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers and the like exemplified for the oral preparations One or more auxiliary components selected from the following may also be added. The effective amount of compound (I) or a pharmacologically acceptable salt thereof and the number of administrations vary depending on the form of administration, the age and weight of the patient, and the nature or severity of the condition to be treated. The dose is 0.01 mg to 1 g, preferably 0.05 to 50 mg per adult, divided once or several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg per adult, preferably 0.1 to 100 mg.
01 to 10 mg is administered once or several times a day. However, these dosages vary depending on the various conditions described above. Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples.

[0038]

【Example】

Example 1 5- (3,5-dichloro-4-pyridylaminocarbonyl) -8-methoxy-2,2-dimethylbenzopyran (Compound 1) Compound a (0.43 g) obtained in Reference Example 1, thionyl chloride (2.0 ml) and dichloromethane (5.0 ml) in 40
Heated to reflux for minutes. After cooling, the solvent was distilled off, and the residue was dissolved in dry toluene. The solvent was distilled off under reduced pressure to remove the remaining thionyl chloride, thereby obtaining a crude acid chloride. 4-amino-3,5-dichloropyridine (0.36 g)
Dissolve in THF (4ml) and add sodium hydride (0.18g) under ice-cooling
Was added and the mixture was stirred at room temperature for 15 minutes, and cooled again with ice. A solution of the crude acid chloride obtained above in THF (4 ml) was added dropwise under ice cooling, and the mixture was further stirred under ice cooling for 1 hour. Dilute hydrochloric acid was added, and the precipitated crystals were collected by filtration and washed with water and hexane. The obtained crystals were recrystallized from ethanol / water to give Compound 1 (0.23 g, 33%) as colorless crystals. Mp _{174~178 ℃ NMR (CDCl 3, δ} , ppm) 1.51 (s, 6H), 3.92 (s, 3H), 5.77 (d, J
= 10Hz, 1H), 6.82 (d, J = 9Hz, 1H), 6.95 (d, J = 10Hz, 1H), 7.
29 (d, J = 9Hz, 1H), 7.41-7.52 (brs, 1H), 8.58 (s, 2H). MASS (m / e) 378 (M ⁺ ). IR (KBr, cm ^-1 ) 1660,1480 , 1280 Found as elemental analysis _{C 18 H 16 Cl 2 N 2} O 3 (%) C:. 57.12, H: 4.37, N: 7.23 calculated (%) C: 57.01, H : 4.25, N: 7.39

Example 2 5- (3,5-Dichloro-4-pyridylaminocarbonyl) -8-methoxy-2,2-dimethyl-3,4-dihydrobenzopyran (Compound 2) Compound b obtained in Reference Example 2 Example 1 using (1.1 g)
Compound 2 (0.94 g, 56%) was obtained as colorless crystals in the same manner as in the above. Mp _{155~156 ℃ NMR (CDCl 3, δ} , ppm) 1.42 (s, 6H), 1.82 (t, J = 7Hz, 2H), 3.
05 (t, J = 7Hz, 2H), 3.91 (s, 3H), 6.79 (d, J = 8Hz, 1H), 7.28
(d, J = 8Hz, 1H), 7.38-7.59 (brs, 1H), 8.56 (s, 2H) .MASS
(m / e) 380 (M ⁺ ). IR (KBr, cm ^-1 ) 1680, 1480, 1280. Elemental analysis: C ₁₈ H ₁₈ Cl ₂ N ₂ O ₃ Found: (%) C: 56.71, H: 4.84 , N: 7.22 Calculated value (%) C: 56.71, H: 4.76, N: 7.35

Example 3 7- (3,5-Dichloro-4-pyridylaminocarbonyl) -4-methoxy-2,2-dimethyl-1,3-benzodioxole (Compound 3) Compound obtained in Reference Example 3 Example 1 using c (0.50 g)
Compound 3 (0.63 g, 77%) was obtained as colorless crystals in the same manner as described above. Mp _{162~163 ℃ NMR (CDCl 3, δ} , ppm) 1.84 (s, 6H), 3.97 (s, 3H), 6.68 (d, J
= 9Hz, 1H), 7.64 (d, J = 9Hz, 1H), 8.56 (s, 2H), 8.72 (brs, 1
H). MASS (m / e) 368 (M ⁺ ). IR (KBr, cm ^-1 ) 1704,1490,1446,1276. Elemental analysis C ₁₆ H ₁₄ Cl ₂ N ₂ O ₄ Actual value (%) C : 52.01, H: 3.82, N: 7.48 Calculated value (%) C: 52.05, H: 3.82, N: 7.59

Example 4 4-methoxy-2,2-dimethyl-7- (4-pyridylaminocarbonyl) -1,3-benzodioxole (compound 4) Compound c (0.30 g) obtained in Reference Example 3 and Using 4-aminopyridine (0.19 mg), compound 4 (0.32 g, 77%) was obtained as colorless crystals in the same manner as in Example 1. 180-181 ° C NMR (CDCl ₃ , δ, ppm) 1.85 (s, 6H), 3.97 (s, 3H), 6.67 (d, J
= 9Hz, 1H), 7.64-7.57 (m, 3H), 8.54-8.52 (m, 2H), 8.80 (b
rs, 1H). MASS (m / e) 300 (M ⁺ ) .IR (KBr, cm ^-1 ) 1592,1446,1280,1112.

Reference Example 1 8-methoxy-2,2-dimethylbenzopyran-5-carboxylic acid (compound a) (Step A) 3- (1,1-dimethyl-2-propyne-1)
-Yloxy) -4-methoxybenzoic acid methyl ester (compound aa) 3-hydroxy-4-methoxybenzoic acid methyl ester (5.4 g), 3-chloro-3-methyl-1-butyne (10 m
l), a mixture of cesium carbonate (19 g) and DMF (54 ml) was stirred at 80 ° C. for 1 hour. Further, 3-chloro-3-methyl-1-butyne (5 ml) was added, and the mixture was stirred at 90 ° C. for 3 hours. After cooling, water was added and extracted with ether. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and saturated saline, dried over sodium sulfate, and evaporated. The residue was chromatographed on silica gel (hexane / ethyl acetate =
7a), compound aa (2.3 g, 31 g) was obtained.
%) As a brown oil. NMR (CDCl ₃ , δ, ppm) 1.68 (s, 6H), 2.54 (s, 1H), 3.87 (s, 3
H), 3.88 (s, 3H), 6.90 (d, J = 8Hz, 1H), 7.79 (dd, J = 1,8Hz,
1H), 8.09 (d, J = 1Hz, 1H).

(Step B) 8-methoxy-2,2-dimethylbenzopyran-5-carboxylic acid methyl ester (compound ab) The compound aa (2.30 g) obtained in the step A was dissolved in diethylaniline (14 ml). And stirred at 160 ° C. for 5 hours. After cooling, a diluted hydrochloric acid aqueous solution was added, and the mixture was extracted with ether. The organic layer was washed with brine, dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (hexane / ethyl acetate = 7/1) to give compound ab (2.1 g, 92%) as a pale yellow oil. NMR (CDCl ₃ , δ, ppm) 1.48 (s, 6H), 3.86 (s, 3H), 3.90 (s, 3
H), 5.78 (d, J = 9HzH), 6.78 (d, J = 8Hz, 1H), 7.33 (d, J = 9H
z, 1H), 7.56 (d, J = 8Hz, 1H).

(Step C) Compound a Compound ab (0.38 g) obtained in Step B was mixed with ethanol (2m
l), 2N aqueous sodium hydroxide solution (2 ml) was added, and the mixture was refluxed for 2 hours. A hydrochloric acid aqueous solution was added dropwise at 0 ° C., and the precipitated crystals were collected by filtration to obtain Compound a (0.34 g, 96.
1%) as colorless crystals. Mp _{159~166 ℃ NMR (CDCl 3, δ} , ppm) 1.50 (s, 6H), 3.92 (s, 3H), 5.80 (d, J
= 9Hz, 1H), 6.80 (d, J = 9Hz, 1H), 7.41 (d, J = 9Hz, 1H), 7.69
(d, J = 9Hz, 1H). MASS (m / e) 234 (M ⁺ ).

Reference Example 2 8-methoxy-2,2-dimethyl-3,4-dihydrobenzopyran-5-carboxylic acid (compound b) (Step A) 8-methoxy-2,2-dimethyl-3,4-
Dihydrobenzopyran-5-carboxylic acid methyl ester (compound ba) Compound ab (1.8 g) obtained in Reference Example 1 Step B was dissolved in ethanol (20 ml), 10% palladium on carbon (0.36 g) was added, and the mixture was cooled to room temperature. The hydrogenation reaction was performed at normal pressure for 3 hours. After removing the catalyst, the filtrate was concentrated to give compound ba (1.3 g,
73%) as colorless crystals. Mp _{67 ~70 ℃ NMR (CDCl 3,} δ, ppm) 1.40 (s, 6H), 1.70-1.87 (m, 2H), 3.0
3-3.20 (m, 2H), 3.85 (s, 3H), 3.90 (s, 3H), 6.73 (d, J = 8H
z, 1H), 7.57 (d, J = 8Hz, 1H). MASS (m / e) 250 (M ⁺ ).

(Step B) Compound b Using compound ba (1.3 g) obtained in Step A, Reference Example 1
Compound b (1.3 g, 96%) was obtained as colorless crystals in the same manner as in Step C. NMR (CDCl ₃ , δ, ppm) 1.40 (s, 6H), 1.75-1.90 (m, 2H), 3.1
1-3.26 (m, 2H), 3.91 (s, 3H), 6.78 (d, J = 9Hz, 1H), 7.73
(d, J = 9Hz, 1H). MASS (m / e) 236 (M ⁺ ).

Reference Example 3 7-methoxy-2,2-dimethyl-1,3-benzodioxole-4-carboxylic acid (compound c) (Step A) 4-methoxy-2,2-dimethyl-1,3 −
Benzodioxole (compound ca) 3-Methoxycatechol (25 g) was dissolved in benzene, dimethoxyacetal (35 ml) and a catalytic amount of tosylic acid were added, and the mixture was heated under reflux for 6 hours. After cooling, an aqueous sodium hydroxide solution was added to make the mixture basic, and the mixture was extracted with ether. The organic layer was washed with saturated saline, dried over magnesium sulfate,
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 99/1) to give compound ca (19.4 g, 60.5%) as a white solid. NMR (CDCl ₃ , δ, ppm) 1.68 (s, 6H), 3.86 (s, 3H), 6.42-6.4
9 (m, 2H), 6.69-6.75 (m, 1H). MASS (m / e) 180 (M ⁺ ).

(Step B) 7-methoxy-2,2-dimethyl-1,3-benzodioxole-4-carbaldehyde (compound cb) The compound ca (20 g) obtained in the step A was treated with DMF (140 ml). And, under ice-cooling, add dropwise phosphorus oxychloride (41.4 ml),
The mixture was heated and stirred at 0 ° C. for 10 hours. The reaction solution was poured into ice water and extracted with ether. The organic layer was washed with brine, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate = 24/1) to give compound cb.
(4.05 g, 17.7%) as a white solid. NMR (CDCl ₃ , δ, ppm) 1.68 (s, 6H), 3.87 (s, 3H), 6.50 (d, J
= 9Hz, 1H), 7.18 (d, J = 9Hz, 1H), 9.88 (s, 1H). MASS (m / e) 208 (M ⁺ ).

(Step C) Compound c Compound cb (3.8 g) obtained in Step B was dissolved in an 80% aqueous acetic acid solution (60 ml), and sulfamic acid (2.5 g) was added.
Stirred for 0 minutes. Then, an 80% aqueous solution of sodium chlorite (1.82 g, 9.1 ml) was added dropwise under ice cooling, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the precipitated solid was collected by filtration to obtain Compound c (1.91 g, 46.9%) as a white solid. NMR (CDCl ₃ , δ, ppm) 1.78 (s, 6H), 3.94 (s, 3H), 6.56 (d, J
= 9Hz, 1H), 7.48 (d, J = 9Hz, 1H). MASS (m / e) 224 (M ⁺ ).

Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method. Compound 1 50mg Lactose 60mg Potato starch 50mg Polyvinyl alcohol 2mg Magnesium stearate 1mg Tar dye Trace amount

Formulation Example 2 Powder A powder having the following composition is prepared by a conventional method. Compound 1 50mg Lactose 250mg

Formulation Example 3 Nasal Inhalation Formulation A nasal inhalation formulation having the following composition is prepared by a conventional method. Compound 1 1mg Lactose 20mg

Formulation Example 4 Ophthalmic Formulation An ophthalmic formulation having the following composition is prepared by a conventional method. Compound 1 10mg Sodium chloride 20mg Methyl paraben 0.1mg Propyl paraben 0.1mg Water for injection qs (1.0ml total)

Formulation Example 5 Transdermal absorption preparation A transdermal absorption preparation having the following composition is prepared by a conventional method. Compound 1 10g Salami beeswax 80g Stearyl alcohol 30g Cholesterol 30g White petrolatum Suitable amount (total 1000g)

Formulation Example 6 Suppositories A suppository having the following composition is prepared by a conventional method. Compound 1 10mg Witebsol W-15 1.79g

Formulation Example 7 Injection An injection having the following composition is prepared by an ordinary method. Compound 1 10mg water for injection appropriate amount (total amount 1.0ml)

Formulation Example 8 Syrup A syrup having the following composition is prepared by a conventional method. Compound 1 10mg Sucrose 300mg Methylparaben 0.5mg Sodium benzoate 0.5mg Lemon flavor appropriate amount Colorant appropriate amount Purified water appropriate amount (total amount 1.0ml)

Formulation Example 9 Nasal Spray A nasal spray having the following composition is prepared by a conventional method. Compound 1 10mg Sodium chloride 8mg Benzalkonium chloride 0.1mg Carbopol 10mg Purified water qs (total volume 1.0ml)

Formulation Example 10 Tablet A tablet having the following composition is prepared by a conventional method. Compound 1 10mg Lactose 140mg Corn starch 45mg Croscarmellose sodium 10mg Hydroxypropylcellulose L 4mg Magnesium stearate 1mg

Formulation Example 11 Capsules A capsule having the following composition is prepared by a conventional method. Compound 1 10mg Lactose 185mg Croscarmellose sodium 10mg Hydroxypropylcellulose L 4mg Magnesium stearate 1mg

Formulation Example 12 Dry Syrup A dry syrup having the following composition is prepared by a conventional method. Compound 1 10mg White sugar 0.7g D-mannitol 0.28g Pullulan 20mg

Formulation Example 13 Granules Granules having the following composition are prepared by a conventional method. Compound 1 10mg Lactose 0.8g Corn starch 0.17g Hydroxypropylcellulose L 30mg

[0063]

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

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/44 ABA A61K 31/44 ABA ABF ABF ABG ABG ABM ABM ABN ABN ABS ABS ACD ACD ADA AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD AD A AGZ AGZ C07D 307/86 C07D 307/86 317/48 317/48 (72) Inventor Haruhiko Shinbe 343-32 Shimotsukari, Nagaizumi-cho, Sunto-gun, Shizuoka Prefecture (72) Inventor Soichiro Sato 10-2 Fujimidai, Mishima-shi, Shizuoka Prefecture

Claims (1)

[Claims] 1. A compound of the general formula (I)中 where R¹And R^TwoAre the same or different and are substituted
Or unsubstituted lower alkyl, cycloalkyl, poly
Cycloalkyl, lower alkenyl or cycloalkenyl
And R^ThreeIs hydrogen, substituted or unsubstituted ant
R or halogen^FourIs hydroxy or
Represents a substituted or unsubstituted lower alkoxy;
Is -C (R⁷) (R⁸)-(Where R⁷And R
⁸Are the same or different and are hydrogen, substituted or unsubstituted
Lower alkyl, cycloalkyl or polycycloal
Represents a kill) or O, B represents O, NR
⁹中 where R⁹Is hydrogen, lower alkyl, cycloalkyl
, Polycycloalkyl, lower alkenyl, cycloal
Kenyl, substituted or unsubstituted aryl, substituted or
Unsubstituted aromatic heterocyclic group, aralkyl or-(C
H_Two)_n-E¹-CO-G¹[Where E¹Is a bond, O
Or NH, G¹Is hydrogen, substituted or unsubstituted
Substituted lower alkyl, cycloalkyl, polycycloalkyl
, Substituted or unsubstituted aryl, substituted or unsubstituted
A substituted aromatic heterocyclic group, aralkyl, OR^Ten(Where R^Ten
Is hydrogen, lower alkyl, cycloalkyl, polycyclo
Alkyl, substituted or unsubstituted aryl, substituted or
Represents an unsubstituted aromatic heterocyclic group or aralkyl)
Or NR¹¹R¹²(Where R¹¹And R¹²Are the same or
Are different from hydrogen, lower alkyl, cycloalkyl,
Licycloalkyl, substituted or unsubstituted aryl, substituted
Substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted
Represents a substituted aralkyl or heteroarylalkyl
Or R¹¹And R¹²Are formed together with N
Represents a substituted or unsubstituted heterocyclic group);
Represents an integer of 0 to 4];⁹And R^TwoBut one
｝, -C (R¹³) (R¹⁴)-
[Wherein, R¹³Is hydrogen, substituted or unsubstituted lower alkyl
Kill, cycloalkyl, polycycloalkyl, lower alkyl
Kenyl, cycloalkenyl, substituted or unsubstituted ants
, Substituted or unsubstituted aromatic heterocyclic group, aralkyl
Le, cyano or-(CH_Two)_m-E^Two-CO-G
^Two(Where E^Two, G ^TwoAnd m are each the aforementioned E¹,
G¹And n have the same meanings)¹⁴Is
Substituted or unsubstituted lower alkyl, cycloalkyl,
Licycloalkyl, lower alkenyl, cycloalkenyl
, Substituted or unsubstituted aryl, substituted or unsubstituted
A substituted aromatic heterocyclic group, aralkyl, cyano or-(C
H_Two)_p-E^Three-CO-G^Three(Where E^Three, G^Threeand
p is the E¹, G¹And the same meaning as n
] Or -C (R^Fifteen) (R¹⁶) -C
(R¹⁷) (R¹⁸)-(Where R^FifteenAnd R¹⁶Are the same
Or differently, hydrogen, substituted or unsubstituted lower alkyl
, Cycloalkyl, aralkyl, substituted or unsubstituted
Represents an aryl, substituted or unsubstituted aromatic heterocyclic group
Waska, R^FifteenAnd R¹⁶Together represent O, and R¹⁷You
And R¹⁸Are the same or different and are hydrogen, substituted or
Unsubstituted lower alkyl, cycloalkyl, aralkyl,
Substituted or unsubstituted aryl, substituted or unsubstituted
Represents an aromatic heterocyclic group;¹⁸And R¹⁶Together
Represents a single bond or R¹⁸And R¹⁶Are each two adjacent
Together with two carbon atoms represents a saturated carbocycle)
I, R^FiveIs a substituted or unsubstituted aryl,
Or an unsubstituted aromatic heterocyclic group, cycloalkyl,
Gin-N-oxide, cyano or lower alkoxycar
Stands for bonyl, R⁶Is hydrogen, lower alkyl, cyclo
Alkyl, aralkyl, substituted or unsubstituted aryl
Or a substituted or unsubstituted aromatic heterocyclic group.
Or an oxygen-containing heterocyclic compound represented by the formula
Salt to be carried.