WO1999037640A1

WO1999037640A1 - Oxygenic heterocyclic compounds

Info

Publication number: WO1999037640A1
Application number: PCT/JP1999/000269
Authority: WO
Inventors: Etsuo Ohshima; Tohru Matsuzaki; Kyoichiro Iida; Haruhiko Manabe; Michio Ichimura; Rie Koike; Yoshisuke Nakasato
Original assignee: Kyowa Hakko Kogyo Co., Ltd.
Priority date: 1998-01-26
Filing date: 1999-01-25
Publication date: 1999-07-29
Also published as: AU1983599A

Abstract

Benzofuran derivatives represented by the formula (I) or pharmacologically acceptable salts thereof wherein R1 represents CH¿2, NR?3, N(CH¿2)pOR?4, O, or S; m and n each is an integer of 1 to 4; X represents NH or CH2; and Y represents CR2aR2b when X is NH, and represents NH3 when X is CH¿2?.

Description

Specification

Oxygen-containing heterocyclic compound technology

The present invention has a phosphodiesterase (PDE) IV inhibitory effect, and has an inflammatory allergic disease such as bronchial asthma, allergic rhinitis, nephritis, rheumatism, multiple sclerosis, Clone disease, psoriasis, systemic lupus erythematosus, etc. Diseases of the central nervous system such as autoimmune diseases, depression, amnesia, and dementia; organ damage due to ischemia reperfusion caused by heart failure, shock, cerebrovascular disease, etc., diabetes due to insulin resistance, wounds, AIDS And other oxygen-containing heterocyclic compounds useful as therapeutic agents. Background technology

Traditionally, many hormones and neurotransmitters have been found to contain intracellular second messengers, adenosine 3 ', 5'-cyclic monophosphate (cAMP) or guanosine 3', 5'-cyclic monophosphate (cGMP) It is known that the action is expressed by increasing the amount. 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. To date, seven isozymes have been identified in PDEs, and isozyme-selective PDE inhibitors exert pharmacological effects based on the physiological significance and distribution of the isozymes in vivo. Expected to do

[TiPS, 11, 150 (1990), TiPS, 12, 19 (1991)].

It is known that increasing the intracellular cAMP of inflammatory leukocytes can suppress their activation. Activation of leukocyte cells leads to the secretion of inflammatory cytokines, including tumor necrosis factor (TNF), the expression of cell adhesion molecules such as intercellular adhesion molecules (ICAM), and subsequent cell infiltration [J. Mol Cell. Cardiol., 12 (Suppl. II), S61 (1989)] ₀

Increasing cAMP levels in airway smooth muscle cells can suppress their contraction Known [TJ Torphy in Directions for New Anti-Asthma Drugs, eds. SR O'Donell and CGA Persson, 37 (1988) Birkhauser-Verlag]. Airway smooth muscle contraction is the primary 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 clarified that mainly type IV PDE (PDE IV) is involved in cAMP degradation. Therefore, a PDE IV selective inhibitor can be expected to have a therapeutic and / or Z- or prophylactic effect on inflammatory diseases, airway obstructive diseases, and ischemic diseases.

In addition, PDE IV inhibitors suppress the secretion of inflammatory cytodynamics such as TNFa and inter-kin (IL) -8 by increasing cAMP, and are further transmitted by these cytodynamics. Is expected to be able to prevent the prolonged progress of the inflammatory response. For example, it has been reported that TNFa reduces the phosphorylation mechanism of insulin receptors in muscle and fat cells and contributes to insulin-resistant diabetes

[J. CUn. 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 these diseases [Nature Medicine, 1, 211-214 (1995) and 1244-248 (1995)].

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

W096 / 36624 discloses a benzofuran derivative having a PDE IV inhibitory action.

W096 / 36625 discloses a PDE IV inhibitor having a biphenyl ring. Disclosure of the invention

New and useful 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 have a PDE IV-selective inhibitory effect, to exhibit an excellent anti-inflammatory effect by increasing cAMP concentration in cells, and to induce vomiting. To provide an oxygen-containing heterocyclic compound not shown.

The present invention provides a compound of the formula (I)

{Wherein Ri is CH ₂ , NR3 (where R ³ represents hydrogen or lower alkyl),

N (CH ₂ ) _P OR ⁴ (wherein, R ⁴ represents hydrogen or lower alkyl, p represents an integer of 1 to 4), 0 or S, and m and n are each an integer of 1 to 4 the stands, X represents NH or CH _2, Y is X represents when NH CR ^² aR ² b (wherein, R ² a and R ² b is hydrogen or lower alkyl the same or different), When X is CH ₂ NR ³

Wherein R ³ represents hydrogen or lower alkyl; or a pharmacologically acceptable salt thereof.

From another aspect, the present invention is, among benzofuran derivatives represented by the above formula (I), X represents NH, Y is in CR ^² aR ² b (wherein, R ² a and is as defined above The present invention relates to a benzofuran derivative or a pharmacologically acceptable salt thereof. In the benzofuran derivative represented by the above formula (I), X represents C, and Y represents NR ³ (wherein

R3 has the same meaning as defined above) or a pharmacologically acceptable salt thereof.

From still another viewpoint, the present invention relates to a medicament containing the above-mentioned benzofuran derivative or a pharmacologically acceptable salt thereof as an active ingredient. Examples of the drug include a phosphodiesterase (PDE) IV inhibitor, a therapeutic agent for inflammatory allergic disease, or a therapeutic agent for bronchial asthma.

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

In the definition of each group of formula (I), lower alkyl is straight-chain or branched having 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, Includes tert-butyl, pentyl, hexyl, heptyl, octyl and the like.

The pharmacologically acceptable salts of compound (I) include inorganic salts such as hydrochloride, sulfate, nitrate and phosphate, acetate, maleate, fumarate and citrate. Organic acid salts are mentioned.

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

Production method 1: Among compound (I), compound (la) in which X is CH ₂ and Y is NR ₃ can be produced by the following production method.

Process 1— 1

Compound (ΙΠ) can be obtained by formylating known raw material compound (Π) [Bull. Soc. Chim. Fr., 2355 (1973)]. Many methods are known for the formylation of aromatics [Experimental Chemistry Lecture, 4th edition, Vol. 21, p. 106 (1990) Maruzen], and applicable. For example, compound (II) can be prepared in an inert solvent, more preferably in a halogenated solvent such as dichloromethane, in an amount of 1 equivalent to a large excess of dichloromethylmethyl ether, and 1 equivalent to an excess of an acid, more preferably Is the target compound by reacting in the presence of titanium tetrachloride at a temperature between -50 and the boiling point of the solvent used for 5 minutes to 48 hours

(III) can be obtained.

Examples of the acid include methanesulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, boron trifluoride, aluminum chloride, stannic chloride, titanium tetrachloride, zinc chloride, ferric chloride and the like.

Examples of the inert solvent include tetrahydrofuran (THF), dioxane, getyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.

Process 1-2

Compound (V) can be obtained by a condensation reaction of compound (III) obtained in step 1-1 with compound (IV). Compound (IV) derived from 3,5-dichrolic pyridine (see Reference Example 1, Step 2) was converted to a base in an inert solvent at a temperature between -100 and the boiling point of the solvent used for 5 minutes to 10 hours. After that, the compound (V) can be obtained by reacting the starting compound (III) with -100 at a temperature between the boiling points of the solvents used for 5 minutes to 30 hours. Examples of the base include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (LDA), potassium tert-butoxide, triethylamine, and diisopropyl ether. Examples thereof include min, triptylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylbiperidine, diazabicycloundecene (DBU), diazabicyclononene (DBN) and the like.

Inert solvents include THF, dioxane, getyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, dimethyl. Examples include formamide (DMF) and dimethyl sulfoxide (DMSO).

Process 1-3

Compound (VI) is obtained by converting compound (V) obtained in step 1-2 in an inert solvent containing water. It can be obtained by treating with an oxidizing agent at a temperature between 0 and the boiling point of the solvent used for 5 minutes to 72 hours.

Examples of the oxidizing agent include manganese dioxide, potassium permanganate, pyridinium chromate (PCC), and pyridinium dichromate (PDC).

Examples of the inert solvent include THF, dioxane, dimethyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, acetone, methyl vinyl ketone, dichloromethane, chloroform, benzene, toluene, DMF, DMSO, and the like. You.

Process 1-4

)

Compound (VII) is obtained by alkaline hydrolysis of compound (VI) obtained in step 1-3. It can be obtained by reacting compound (VI) with an aqueous alkali solution in an inert solvent at a temperature between 0 "C and the boiling point of the solvent used for 5 minutes to 10 hours.

Examples of the alkaline aqueous solution include aqueous solutions of sodium hydroxide and potassium hydroxide, and examples of the inert solvent include dioxane, methanol, and THF. Process 1-5

(Wherein, Ri, R ³ , m and n are as defined above)

Compound (la) is obtained by condensing compound (VII) obtained in step 1-4 with amine (IX). The reaction can be carried out in an inert solvent at a temperature between -80 and 50 for 5 minutes to 30 hours in the presence of the agent. If necessary, N-hydroxysuccinimide, 1-hydroxybenzotriazole, 3-hydroxy-14-oxo-1,3,4-dihydro-1,2,3-benzotriazine and the like may be added.

Examples of the condensing agent include dicyclohexyl carbodiimide, diisopropyl carbodiimide, N-ethyl-Ν '-(3-dimethylaminopropyl) carbodiimide and its hydrochloride, benzotriazo-l-luyl 1-yllute tris (dimethylamino) phosphonidium hexafluorin Chloride salts, diphenylphosphoryl azide and the like. Examples of the inert solvent include THF, dioxane, dimethyl ether, dichloromethane, chloroform, dichloroethane, DMF, DMSO, water and the like.

Production method 2: Compound (la) can also be produced by the following production method. Process 2-1

(Wherein R ¹ , R ² , m and n are as defined above)

Compound (X) can be obtained by a dehydration condensation reaction between compound (VIII) and amine (IX) obtained by a known method [J. Med. Chem., 62-67 (1987)]. Many methods are known for this dehydration-condensation reaction [see Experimental Chemistry Course, 4th Edition, Maruzen, Vol. 22, p. 137 (1992)], and can be applied. For example, compound (VIII) can be prepared in an inert solvent using 1 equivalent to a large excess of thionyl chloride, if necessary, in the presence of a catalytic amount to an excess of base, at a temperature between room temperature and the boiling point of the solvent used for 30 minutes. After treatment for up to 10 hours, the corresponding acid chloride is converted to the corresponding acid chloride, and then used in an inert solvent in the presence of 1 equivalent to an excess of amine (IX) and 1 equivalent to an excess of a base at -75. The reaction can be carried out at a temperature between the boiling points of the solvents used for 5 minutes to 10 hours. In addition, if ethyl ethyl chloroformate or the like is used instead of thionyl chloride, a mixed acid anhydride can be obtained instead of acid chloride. The corresponding mixed acid anhydride of the compound (VIII) can also be reacted with the amine (IX) in the same manner as the acid chloride to give the compound (X). Examples of the base used in the reaction of thionyl chloride include pyridine, triethylamine, diisopropylamine, triptylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylbiperidine, DBU, DBN and the like.

Bases used for the reaction of amines include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, lithium hydride, butyllithium, LDA, potassium tert-butoxide, triethylamine, and diisonium. Examples include propylethylamine, triptylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methylpiperidine, pyridine, DBU, DBN and the like.

As the inert solvent, the same solvent is used in the above two steps. THF, dioxane, getyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform Examples include mouth form, benzene, toluene, DMF, and DMSO. Process 2-2

(Wherein, Ri, R ³ , m and η are as defined above)

Compound (XI) can be obtained according to the method of step 1 using compound (X) obtained in step 2-1.

Step 2-3

(Wherein, Ri, R3, _m and _n are as defined above)

Compound (XII) can be obtained by oxidation of compound (XI) obtained in step 2-2. It is known that the oxidation of aldehydes with halogens or hypohalous acids and their salts can be oxidized to the corresponding esters in the presence of alcohol. [Refer to Maruzen, 4th Edition, Experimental Chemistry, Vol. 23, p. 485 (1991)]. For example, by reacting compound (XI) with an iodine alcohol solution in an inert solvent containing methanol at -50 t: a temperature between the boiling points of the solvents used for 5 minutes to 48 hours, Compound (XII) can be obtained.

Examples of the halogen include bromine, chlorine, and iodine. Examples of the inert solvent include THF, dioxane, getyl ether, ethylene glycol, triethylene daryl, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene. Is exemplified.

Process 2—4

(Wherein, Ri, R3, m and n are as defined above)

Compound (la) can be obtained by a condensation reaction between compound (XII) obtained in step 2-3 and compound (IV) according to the method of step 1-2.

Production method 3: Among compound (I), compound (lb) in which X is NH and Y is CR ² aR ² b can be produced by the following production method.

Process 3-1

(Wherein, R ^² a, R ² b and _m are as defined above)

Compound (XIV) is a known compound obtained by a known method (W093 / 6624) (XIII) is treated with 1 equivalent to a large excess of a base in an inert solvent at a temperature between -100 and the boiling point of the solvent used for 5 minutes to 10 hours, and then 1 equivalent to a large excess of the compound (XV ) And −100 at a temperature between the boiling points of the solvents used for 5 minutes to 30 hours.

Examples of the base include sodium hydroxide, potassium hydroxide, sodium methoxide, potassium ethoxide, sodium hydride, potassium hydride, butyllithium, LDA, potassium tert-butoxide, triethylamine, diisopropylethylamine, and tributylamine. , Dicyclohexylmethylamine, N-methylmorpholine, N-methylpiperidine, DBU, DBN and the like.

Inert solvents include THF, dioxane, getyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, toluene, DMF, DMSO and the like are exemplified.

Process 3-2

(Wherein, R ¹ , R 2a, R 2b, _m and _n are as defined above)

Compound (lb) is prepared by converting compound (XIV) with 1 equivalent to a large excess of, for example, alkyl or arylsulfonyl chloride in an inert solvent in the presence of 1 equivalent to a large excess of base at -20t: to 0. The reaction is carried out for 5 minutes to 5 hours at a temperature between 1 minute and a large excess of the compound (XVI) at a temperature between 0 and the boiling point of the solvent used for 5 minutes to 48 hours. Obtainable.

Bases include sodium hydride, potassium hydride, butyllithium, LDA, potassium tert-butoxide, triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorpholine, N-methyl Tilpiperidine, pyridine, DBU, DBN and the like are exemplified.

Examples of the alkyl or arylsulfonyl chloride include methyl sulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and the like.

Examples of the inert solvent include THF, dioxane, getyl ether, glyme, diglyme, dichloromethane, chloroform, benzene, toluene, DMF, DMSO and the like.

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

When it is desired to obtain a salt of compound (I), compound (I) may be dissolved or suspended in an appropriate solvent, and then isolated and purified by adding an acid.

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

Table 1

Compound number R ¹ m η XY

1 0 2 2 CH ₂ NH

2 CH ₂ 2 2 CH ₂ NH

3 N-CH ₃ 3 2 CH ₂ NH

4 O 2 2 H CH ₂

5 N-CH, 2 2 NH CH ₂ Next, the pharmacological action of the representative compound (I) will be specifically described with reference to test examples. Test Example 1: Recombinant human PDE IVA enzyme inhibition test

Human phosphodiesterase cDNA (HSPDE4A) was isolated from testis. The amino acid sequence is the sequence reported by Bolger, G. et al. [Mol. Cell. Biol, 13, 6558-6571 (1993)].

A recombinant protein in which the N-terminal side of (HSPD4A5) had 223 amino acids deleted was expressed and purified using an E. coli expression plasmid. The PDE activity was measured by the following two-step process according to the method of Kincaid, RL and Manganiello, VC [Method. Enzymol., 159, 457-470 (1988)]. The substrate ^[3 H] cAMP (final concentration lMmol / L) with the reaction, N, N-bis (2-hydroxy E chill) one 2-amino ethanesulfonate phosphate (50 mmol / tooth pH 7.2), The test was performed in a standard mixture containing MgCl ₂ (l mmol / L) and soybean trypsin inhibitor (O.lmg / ml). The reaction was started by the addition of the enzyme and incubated at 30 for 10-30 minutes. The reaction was stopped with hydrochloric acid, and the generated 5'-AMP was completely decomposed by 5'-nucleotidase. Chromatography was performed using DEAE-Sephadex A-25, and the eluted [ ³ H] adenosine was counted using a scintillation counter. The drug was dissolved in DMSO (1.7% concentration) and added.

In this test, Compounds 1 to 5 showed an enzyme inhibitory activity of 50% or more at ΙΟμιηοΙ / L.

Test Example 2: Inhibition of TNF α production in LPS-induced mouse sepsis model

5 to 6 male BALB / c mice (7 weeks old) (Nippon Charls River Co., Ltd.) were treated with lipopolysaccharide (LPS, Difco) at a final concentration of 0.2 mg / ml in saline. After dissolving in water, the solution was administered to the tail vein at a dose of 200 μl 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 μl per 20 g body weight 90 minutes before LPS administration. TNFα concentration in serum was measured by enzyme-linked immunosorbent assay (ELISA). That is, a 4 mg / ml anti-mouse TNF monoclonal antibody (Pharmingen) diluted with a phosphate buffer solution (PBS) (Pharmingen) was used in a 96-well flat-bottom microtiter plate (Nunc Imnoplate 'MaxiSorp', Nunc). 5 (l / well), coat with 4 for 12 hours, phosphate buffer solution containing 1% serum albumin (BSA) (1% BSA-PBS) was added to 200μ1Λνθ11, left undisturbed at room temperature for 1 hour to block non-specific binding, washed with phosphate buffer solution, and diluted with 1% BSA-PBS twice to test serum To

ΙΟΟμΙ / well was added and left at room temperature for 2 hours. As a standard substance, a recombinant mouse TNFa (Genzam) diluted with 1% BSA-PBS was used in the same manner. Place these plates in 0.05% polyoxyethylene sorbitan monolaure.

—Pionin-labeled anti-mouse TNFα polyclonal antibody (Tween 20, Pico One) washed three times with PBS containing 0.05% Tween-PBS and diluted with 1% BSA-PBS to a concentration of lmg / ml ( Pharmingen) and 5 (^ 1 / _W ell was added and after standing for 1 hour at room temperature

Washed three times with 0.05% Tween-PBS, added horseradish peroxidida-zeavidin D (Vecta) (4000-fold diluted with 1% BSA-PBS) at ΙΟΟμΙΟΟ / well, and allowed to stand at room temperature for 30 minutes. Finally, wash these plates three times with 0.05% Tween-PBS,

3,3 ′, 5,5′-Tetramethylbenzidine was added at ΙΟΟμΙ / well, and when the color developed, the reaction was stopped by adding 10% sulfuric acid solution at ΙΟΟμΙ / well, and the absorbance at 450 nm was measured. The serum TNFa concentration was calculated from the calibration curve.

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

, _/ , Control TNF a concentration-TNF a concentration inhibition rate in the presence of drug (%) =

TNF concentration in control mouth The TNFα concentration in the control is the value in the absence of the test compound (0.5% methylcell mouth mouth solution alone).

The results are shown in Table 2.

Table 2 Compound No. Dose (mg / kg) Inhibition rate (%)

1 10 75

4 10 65

5 10 65 Test Example 3: Emetic effect in Suntus

Male sunkus (Sunkus murinus) weighing around 60 g per group 5 to 15 animals were used for the test. According to the method of Matsuki et al. [Japan J. Pharmacol., 48, 303 (1988)], Sunks was manufactured by wire mesh. Were kept in a cage (15 cm wide x 21 cm long x 15 cm high). The test compound was suspended in 0.5% tween 80 physiological saline and administered intraperitoneally (ip) in a volume of ΙΟμ ^. One hour after the administration of the test compound, observation was performed, and the number of occurrences of vomiting was measured. The results are shown in Table 3 in terms of the number of animals that developed vomiting / the number of animals in the test compound administration group.

Table 3

Compound No.Dose (mg / kg) Number of animals with emesis Number of animals

1 10 0/5

4 10 0/5

5 10 3/5 Test Example 4: Inhibition of eosinophil and neutrophil infiltration in BN rats

Active sensitization and antigen exposure were performed by partially modifying the method of Howell et al. [Pulmonary Pharmacology, 8, 83-89 (1995)].

Male Brown-Norway rats, 6 weeks old (Charles River Japan), were subcutaneously administered with 1 mg of ovalbumin (hereinafter OA) and 200 mg of aluminum hydroxide, followed by intraperitoneal administration of pertussis-killed bacteria. After 14 days, the rats were placed in a plastic chamber (30 × 50 × 30 cm), and a 1% (w / v) OA solution was inhaled for 10 minutes to perform antigen induction. An ultrasonic nebulizer (NE-U12, OMRON) was used for inhalation.

Drug is suspended in 0.5% methylcellulose and orally administered 1 hour before antigen induction

(p.o.) A group to which 0.5% methylcellulose was administered and OA was inhaled was set as an OA group, and a group to which saline was inhaled instead of OA was set as a saline group.

Bronchoalveolar lavage (BAL) was performed 24 hours after antigen challenge. Brown-Norway rats are anesthetized with pentobarbi (100 mg / kg ip), and at 37, 4 ml of physiological saline is injected into a disposable syringe (5 ml thermosyringe, Terumo) via a tracheal forceps. Collected after 15 seconds. This operation was repeated twice to obtain bronchoalveolar lavage fluid (BALF). The BALF is centrifuged at 950 rpm for 10 minutes at 4 for 4 minutes, and the precipitated cells are suspended in 1 ml of physiological saline. Then, the total leukocytes are counted using an automatic hemocytometer (Celltac MEK-6158, Nihon Kohden). The number was measured. Cells were smeared using Cytospin S (Shandon, Pittsburgh) and stained with Giemsa. 500 cells under light microscope 偭 was observed, and the ratio was calculated from the number of eosinophils (Eos), neutrophils (Neu), lymphocytes (Lym), macrophages (Mac) and other cells (Oth). Further, this was multiplied by the total leukocyte count to calculate each cell count.

In this test, Compound 1 in the Examples showed 100% inhibitory activity against eosinophils and 92% inhibitory activity against neutrophils at a dose of 30 mg / kg.

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 may contain the compound (I) or a pharmaceutically acceptable salt thereof alone or as a mixture with any other active ingredient for treatment as an active ingredient. it can. 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.

It is desirable to use the most effective route for treatment, and it can be oral or parenteral, for example, oral, respiratory, rectal, subcutaneous, intramuscular and intravenous. .

Dosage forms include sprays, capsules, tablets, granules, syrups, emulsions, suppositories, injections, ointments, tapes and the like.

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

Formulations suitable for parenteral administration include active compounds that are preferably isotonic with the blood of the recipient. And a sterile aqueous agent containing 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 a carrier such as cocoa butter, hydrogenated fat or hydrogenated sulfonic acid, and provided as suppositories. Sprays are prepared using a carrier or the like which does not irritate the active compound itself or the mucosa of the mouth and respiratory tract of the recipient and 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 can be made depending on the nature of the active compound and the carrier used.

Among these parenteral preparations, one selected from the diluents, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. exemplified for the oral preparations Alternatively, more auxiliary components can be added.

The effective amount and frequency of administration of Compound (I) or a pharmaceutically acceptable salt thereof will vary depending on the form of administration, the age and weight of the patient, the nature or severity of the condition to be treated, etc. The dosage is oral, O.Olmg ~: Lg, preferably 0.05 ~ 50mg per adult, administered once or several times a day. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg, preferably 0.01 to: LOmg per adult is administered once to 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. BEST MODE FOR CARRYING OUT THE INVENTION

Example 1 N- (2-morpholinoethyl) -4- (2- (3,5-dichloropyridine-4-yl) -11-oxo) ethyl-7-methoxybenzofuran-12-force lipoxamide (Compound 1) )

Ν, Ν-Diisopropylamine (0.70 ml) was dissolved in anhydrous THF (15 ml), n-butyllithium (1.63 M hexane solution, 2.8 ml) was added dropwise with -78, and the mixture was stirred at 0 for 5 minutes. The mixture was cooled again to -78, and 3,5-diclopic picoline (0.56 g, see Reference Example 1, Step 2) was added, followed by stirring at 0 for 20 minutes. Compound obtained in Reference Example 2 (Xlla)

(0.40 g) in THF (5 ml) was added dropwise, and the mixture was stirred at 0 as it was for 30 minutes. Saturation so / 66fcvl> s I / OAV

^^ 长? 7 eight

89ΐ-

9

IsΗ) (οH2ε ((s ォ ΐ s. MASS (m / z): 489 (M ⁺ ).

IR (KBr, cm-i): 1201, 1301, 1575, 1660, 1677.

Elemental analysis C ₂ 4H ₂₅ Cl ₂ N ₃ O ₄ '0.3H ₂ O

Actual IH (%): C: 58.07, H: 5.18, N: 8.40

Calculated value (%): C: 58.14, H: 5.20, N: 8.48.

Example 3 N- [3- (4-Methyl-1-piperazinyl) propyl] —4- [2- (3,5-dichloropyridine-4-yl) -11-oxo] ethyl-7-methoxybenzofuran One-two-potassium lipoxamide dihydrochloride (compound 3)

Compound 3 (0.18 _g , 39%) was obtained as colorless crystals in the same manner as in Example 2 using compound (VII) (0.30 g) obtained in Reference Example 1.

Melting point: 199-200

NMR (DMSO-d ₆ , δ, ppm): 1.63 (m, 2H), 2.17 (s, 3H), 2.84-3.30 (m, 12H), 3.77 (s, 3H), 4.53 (s, 2H), 6.94 (d, J = 8.5Hz, 1H), 7.68 (s, 1H), 8.03 (d, J = 8.5Hz, 1H).

MASS (m / z): 518 (M ⁺ ).

IR (KBr, cm- ¹ ): 1207, 1307, 1407, 1573, 1618, 1658.

As Elemental Analysis _{_{_{_{C 25 H 30 Cl 2 N 4}}}} O 4 · 2H 2 0

Observed value (%): C: 47.85, H: 5.46, N: 8.67

Calculated value (%): C: 47.79, Η: 5.43, Ν: 8.Ό2.

Example 4: Ν- (3,5-dichrolic pyridine-14-yl) -2- (4-morpholinopyryl) -17-methoxybenzofuran-14-carboxamide (compound 4)

The first step: Ν— (3,5-dichrolic pyridine-4-yl) —2— [4- (methylsulfonyloxy) ptyryl] -1-7-methoxybenzofuran-14-force lipoxamide (compound Β)

The compound (XIVa) (1.34 g) obtained in Reference Example 3 was dissolved in anhydrous pyridine (10 ml), methanesulfonyl chloride (0.30 ml) was added dropwise at 0, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain crude crystals of Compound B (1.59 _g , quantitative). 66fcv3d OS OAV

HHHfp (size 08) Hls) Dimension 2 (size LS) 08 size = Z says s.

H H8HHf 008808 HSS9ΌΐH Z "S .. *. MASS (m / z): 504 (M ⁺ ).

IR (KBr, cm-i): 1285, 1484, 1664, 1681.

As Elemental Analysis _{_{_{_{C 24 H 26 C1 2 N40 4}}}} · 0.3H 2 O

(%): C: 56.51, N-.5.22, Ν 0.69

Calculated value (%): C: 56.43, H: 5.24, N: 10.96.

Reference Example 1: 4- [2- (3,5-dichloropyridine-4-yl) -11-oxo] ethyl-7-methoxybenzofuran-12-carboxylic acid [Compound (VII)]

Stage 1: 4-Formyl-7-methoxybenzofuran-2-ethyl carboxylate [Compound (III)]

7-Methoxybenzofuran-2-carboxylic acid ethyl ester [Compound (II), 10 g] is dissolved in anhydrous dichloromethane (200 ml), and under ice-cooling, dichloromethyl methyl ether (8.2 ml) and titanium tetrachloride (10 ml) are added dropwise. And stirred for 30 minutes. After returning to room temperature and stirring for 1.5 hours, 1M HC1 aqueous solution was added dropwise to decompose the remaining titanium tetrachloride and extracted with chloroform. The extract was washed with 1M aqueous NaOH solution and saturated saline, dried over sodium sulfate, and evaporated. The residue was suspended in ether and collected by filtration to give compound (III) (8.9 g, 79%) as colorless crystals.

_{NMR (CDC1 3, δ, ppm} ): 1.43 (t, J = 7Hz, 3H), 4.12 (s, 3H), 4.46 (q, J = 7Hz, 2H), 7.01 (d, J = 8Hz, 1H), 7.75 (d, J = 8Hz, 1H), 8.22 (s, 1H), 10.0 (s, 1H).

MASS (m / z): 248 (M ⁺ ).

Second stage: 4- [2- (3,5-Dichrolic pyridine-14-yl) -1-hydroxy] ethyl-7-methoxybenzofuran-2-carboxylic acid ethyl ester [Compound (V)]

Ν, Ν-Diisopropylamine (65.6ml) was dissolved in anhydrous THF (150ml), n-butyllithium (1.54M hexane solution, 300ml) was added dropwise at -78 under argon gas atmosphere, and the mixture was stirred for 5 minutes did. 3,5-Dichloropyridine (63g) in anhydrous THF

(600 ml) solution was added dropwise and stirred for 1 hour, then methyl iodide (29.2 ml) was added dropwise and stirred for 1.5 hours. The reaction was stopped by adding water, extracted with ethyl acetate, washed with saturated saline, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 10: 1), and the resulting residue was purified by hexane. And collected by filtration to give 3,5-dichloropicoline (62.8 g, 91%) as colorless crystals.

Dissolve N, N-diisopropylamine (8.5 ml) in anhydrous THF (150 ml), add n-butyllithium (1.65 M hexane solution, 32 ml) dropwise at -78 under argon gas atmosphere, and stir for 5 minutes did. After stirring at room temperature for 3 minutes, the mixture was cooled again to -78, 3,5-dichloropicoline (7.2 g) was added, and the mixture was stirred for 30 minutes. This was added dropwise over 1 hour to a solution of compound (III) (I0g) in anhydrous THF (500 ml) under an atmosphere of -78 and argon. After stirring at -78 for 2.5 hours, the temperature was returned to room temperature, water was added to terminate the reaction, and the mixture was diluted with ethyl acetate. After washing with saturated saline and drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was suspended in isopropanol and collected by filtration.

(V) (I4.3 g 87%) was obtained as colorless crystals.

_{NMR (CDC1 3, δ, ppm} ): 1.43 (t, J = 7Hz, 3H), 3.32 (dd, J = 13Hz, 5Hz, 1H), 3.60 (dd, J = 13Hz, 8.5Hz, 1H), 4.01 ( s, 3H), 4.45 (q, J = 7Hz, 2H), 5.34 (m, 1H), 6.83 (d, J = 8Hz, 1H), 7.11 (d, J = 8Hz, 1H), 7.80 (s, 1H ), 8.41 (s, 2H).

MASS (m / z): 409 (M ⁺ ).

Step 3: 4- [2- (3,5-Dichrolic pyridine-4-yl) -11-year-old oxo] ethyl-7-methoxybenzofuran-2-carboxylate ethyl compound [Compound (VI)] compound (V ) (I0g) was dissolved in acetone (200ml), and a Dione's reagent (2.76M solution, 9.7ml) was added dropwise under ice cooling, and the mixture was stirred for 20 minutes as it was. Isopropanol was added, and the mixture was stirred at room temperature for 30 minutes to stop the reaction, and the solvent was distilled off under reduced pressure. The mixture was extracted with chloroform, washed with brine and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was suspended in isopropanol and collected by filtration to obtain compound (VI) (8.34 g, 84%) as colorless crystals.

_{NMR (CDC1 3, δ, ppm} ): 1.39 (t, J = 7Hz, 3H), 4.13 (s, 3H), 4.42 (q, J = 7Hz, 2H), 4.73 (s, 2H), 6.99 (d, J = 8Hz, 1H), 8.04 (d, J = 8Hz, 1H), 8.21 (s, 1H), 8.54 (s, 2H). MASS (m / z): 407 (M ⁺ ).

Step 4: Compound (VII)

Compound (VI) (6.0 g) is dissolved in methanol (60 ml), and the mixture is cooled on ice with a 5 M NaOH aqueous solution. (15 ml), and the mixture was returned to room temperature and stirred for 1 hour. The reaction solution was acidified by dropwise addition of 1M HC1 under ice cooling, and the precipitated crystals were collected by filtration and washed with water to obtain Compound (VII) (5.4 _g , 96%).

NMR (DMSO-d ₆ , δ, ppm): 4.09 (s, 3H), 4.86 (s, 2H), 7.29 (d, J = 8.5 Hz, 1H), 8.38 (d, J = 8.5 Hz, 1H), 8.68 (s, 2H).

MASS (m / z): 379 (M ⁺ ).

Reference Example 2: 2- (2-morpholinoethyl) rubamoyl-7-methoxybenzofuran-4-carboxylic acid methyl ester [Compound (Xlla)]

Stage 1: N- (2-morpholinoethyl) -7-methoxybenzofuran-2-carpoxamide [Compound (Xa)]

A 7-methoxybenzofuran-1-carboxylic acid [compound (VIII), 10 g] obtained by a known method [J. Med. Chem., 30, 62-67 (1987)] was added to anhydrous dichloromethane.

(150 ml), oxalyl chloride (6.8 ml) was added, and the mixture was stirred at room temperature for 22 hours. The residue obtained by evaporating the solvent under reduced pressure was dried in vacuo, dissolved in anhydrous dichloromethane (40 ml), and triethylamine (1.9 ml) and 2-morpholinoethylamine (0.91 ml) were added, followed by stirring at room temperature for 6 hours. The reaction was quenched by adding a 1M KOH aqueous solution, extracted with dichloromethane, washed with saturated saline, dried over potassium carbonate, and the solvent was distilled off under reduced pressure. The residue was suspended in ethyl ether and collected by filtration to obtain compound (Xa) (1.0 g, 71%) as colorless crystals.

_{NMR (CDC1 3, δ, ppm} ): 2.5-2.6 (m, 4H), 2.6-2.7 (m, 2H), 3.55-3.65 (m, 2H), 3.7- 3.8 (m, 4H), 4.03 (s, 3H), 6.92 (dd, J = 7Hz, 2Hz, 1H), 7.20 (br.s, 1H), 7.22 (dd, J = 7Hz, 7Hz, 1H), 7.25 (dd, J = 7Hz, 2Hz, 1H) , 7.46 (s, 1H).

Second step: 4-Formyl-N- (2-morpholinoethyl) _7-methoxybenzofuran-2-force lipoxamide [Compound (XIa)]

Compound (Xa) (0.90 g) was dissolved in anhydrous dichloromethane (50 ml), dichloromethyl methyl ether (0.40 ml) and titanium tetrachloride (0.97 ml) were added, and the mixture was stirred at room temperature for 12 hours. The mixture was poured into ice water containing an aqueous solution of potassium hydroxide, extracted with black hole form, and washed with saturated saline. After drying over potassium carbonate, the solvent was distilled off under reduced pressure, and the residue was removed. The residue was suspended in ethyl ether and collected by filtration to obtain Compound (XIa) (0.55 mg, 58%) as colorless crystals.

_{NMR (CDC1 3, δ, ppm} ): 2.5-2.6 (m, 4H), 2.6-2.7 (m, 2H), 3.55-3.65 (m, 2H), 3.7- 3.8 (m, 4H), 4.12 (s, 3H), 7.01 (d, J = 8Hz, IH), 7.20 (br.s, 1H), 7.74 (d, J = 8Hz, IH), 8.15 (s, IH), 10.07 (s, IH).

Stage 3: Compound (Xlla)

Compound (XIa) (0.35 g) was dissolved in dichloromethane (10 ml) -methanol (10 ml), potassium hydroxide (0.35 g) and iodine (0.4 _g ) were added, and the mixture was stirred for 5 hours. After diluting with dichloromethane, washing with saturated saline and drying with potassium carbonate, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (chloroform: methanol = 50: 1) to give compound (Xlla) (0.46 g, 85%) as a colorless oil. _{NMR (CDC1 3, δ, ppm} ): 2.5-2.6 (m, 4H), 2.6-2.7 (m, 2H), 3.55-3.65 (m, 2H), 3.7- 3.8 (m, 4H), 3.96 (s, 3H), 4.05 (s, 3H), 6.89 (d, J = 8Hz, 1H), 7.35 (br.s, IH), 7.94 (s, IH), 7.97 (d, J = 8Hz, IH).

MASS (m / z): 362 (M ⁺ ).

Reference Example 3: N- (3,5-Dichroic pyridine-4-yl) —2- (4-hydroxy) butylyl 7-methoxybenzofuran—4-carboxamide [Compound (XlVa)] N— (3,5-Dichloropyridine-4-yl) -7-methoxybenzofuran-4-carboxamide [Compound (XIII), lO.Og] THF solution (500 ml) was cooled to -78, and then Ν, Ν, Ν′Ν′-Tetramethylethylenediamine (13.43 ml) and n-butyllithium (1.57M hexane solution, 56.67 ml) were added dropwise, and the mixture was stirred at the same temperature for 1.5 hours. Thereto, carboxylactone (11.4 ml) was added dropwise, and the mixture was stirred at the same temperature for 2 hours. The temperature was raised to 0, an aqueous solution of ammonium salt was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane: ethyl acetate = 1: 2) to give compound (XlVa) (6.34 g, 51%) as colorless crystals.

Melting point: 210.0-211.0

NMR (DMSO-d ₆ , δ, ppm): 1.78 (tt, J = 7.0 Hz, 7.0 Hz, 2H), 3.03 (t, J = 7.0 Hz, 2H), 3.45 (dt, J = 5.0Hz, 7.0Hz, 2H), 4.08 (s, 3H), 4.57 (t, J = 5.0Hz, 1H), 7.32 (d, J = 8.0Hz,

1H), 8.09 (s, 1H), 8.10 (d, J = 8.0Hz, 1H), 8.79 (s, 2H), 10.68 (br.s, 1H).

MASS (m / z): 422 (M ⁺ ).

IR (KBr, cm- ¹ ): 1282, 1486, 1687.

Elemental analysis: as _{_{_{_{Ci 9 H 16 Cl 2 N 2}}}} 0 5

Observed value (%): C: 53.91, H: 3.83, N: 6.54

Calculated value (%): C: 53.91, H: 3.81, N: 6.61. Industrial applicability

The present invention has a phosphodiesterase (PDE) IV inhibitory effect, and has an inflammatory allergic disease such as bronchial asthma, allergic rhinitis, nephritis, rheumatism, multiple sclerosis, Crohn's disease, psoriasis, and systemic lupus erythematosus. CNS diseases such as autoimmune diseases, depression, amnesia, dementia, etc., organ diseases associated with ischemic reperfusion caused by heart failure, shock, cerebrovascular disorders, etc., diabetes due to insulin resistance, wounds, It provides a benzofuran derivative that is useful as a remedy for AIDS and the like and does not cause vomiting as a side effect.

Claims

The scope of the claims

Equation α)

{Wherein Ri is CH ₂ , NR ³ (where R ³ represents hydrogen or lower alkyl), N (CH ₂ ) _P OR ⁴ (where R ⁴ represents hydrogen or lower alkyl, p is 1 to display the to 4 integer), 0 or S, m and n represent integers of 1 to 4, X represents NH or CH _2, Y when X is NH is CR ^2a R ^2b (wherein Wherein R ^2a and R ^2b are the same or different and represent hydrogen or lower alkyl), and when X is CH ₂ , NR ³

(Wherein, R ³ represents hydrogen or lower alkyl).} Or a pharmacologically acceptable salt thereof.

2. The benzofuran derivative according to claim 1, wherein X represents NH, and Y represents CR ² aR ² b (wherein R ² ^ and R ² b have the same meanings as described above), or a pharmaceutically acceptable salt thereof. ¾ acceptable.

3. The benzofuran derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein X represents CH ₂ and Y represents NR ³ (wherein R ³ has the same meaning as described above).

4. A medicament comprising the benzofuran derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

5. A phosphodiesterase (PDE) IV inhibitor comprising the benzofuran derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.

6. A therapeutic agent for an inflammatory allergic disease, comprising the benzofuran derivative according to any one of claims 1 to 3 or a pharmacologically acceptable salt thereof as an active ingredient.

7. A therapeutic agent for bronchial asthma, comprising the benzofuran derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof as an active ingredient.