WO1998022452A1 - Benzofuran derivatives - Google Patents

Abstract

Benzofuran derivatives represented by general formula (I) and pharmacologically acceptable salts thereof wherein R1 is hydrogen or substituted or unsubstituted lower alkyl; R?2, R3 and R4¿ are each independently hydrogen or the like; R5a is hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl or the like, and R5b is substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl or the like, or alternatively R?5a and R5b¿ may be united to form a substituted or unsubstituted nitrogenous heterocyclic group; and R?6a and R6b¿ are each independently hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted heteroarylalkyl or substituted or unsubstituted aralkyl, or alternatively R?6a and R6b¿ may be united to form a substituted or unsubstituted nitrogenous heterocyclic group.

Description

 Specification

 Derivative

Technical field

 The present invention has a phosphodiesterase (PDE) IV inhibitory effect and raises intracellular cAMP concentration to increase allergic diseases such as bronchial asthma, allergic rhinitis and nephritis, rheumatism, multiple sclerosis Autoimmune diseases such as Crohn's disease, psoriasis, systemic lupus erythematosus, central nervous system diseases such as depression, amnesia, and dementia; organs associated with ischemia reperfusion caused by heart failure, shock, cerebrovascular disorders The present invention relates to a benzofuran derivative or a pharmacologically acceptable salt thereof, which is useful as a therapeutic agent for disorders, insulin-resistant diabetes, wounds, and AIDS.

Background technology

 Traditionally, many hormones and neurotransmitters have been linked to intracellular second messengers, adenosine 3,5'-cyclic monophosphate (cAMP) or guanosine 3,5,5-cyclic monophosphate ( It is known that the effect is exerted 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 result in increased levels 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 isozyme in the body [TiPS, 11, 150 (1990) or 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 secretion of inflammatory cytotoxicity, including tumor necrosis factor (TNF), expression of cell adhesion molecules such as intercellular adhesion molecule (ICAM), and subsequent cell infiltration [J. Mol. Cell. Cardiol., 12 (Suppl. II), S61 (1989)].

Increased cAMP concentration in tracheal smooth muscle cells can suppress their contraction It is well known [TJ Torphy in Directions for New Anti-Asthma Drugs, eds SR O'Donell and CGA Persson, 37, Birkhauser-Verlag (1988)]. Contraction of the tracheal smooth muscle is the main condition of bronchial asthma. In ischemia-reperfusion organ damage such as myocardial ischemia, infiltration of inflammatory white blood cells such as neutrophils is found in the affected area. In these inflammatory cells and tracheal smooth muscle cells, it has been shown 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 or preventive effect on inflammatory diseases, airway obstructive diseases or ischemic diseases.

 In addition, PDE IV inhibitors suppress the secretion of inflammatory site forces such as TNFa and interleukin (IL) -8 by increasing cAMP, and It is expected that the prolonged progress of the transmitted inflammatory response can be prevented. 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. Clin. Invest., 94, 1543-1549 ( 1994)]. Similarly, TNFa 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; 244-248 (1995)].

 In addition, compounds having a benzofuran structure and having PDE IV inhibitory activity have been reported [Bioorganic Med. Chem. Lett., 14, 1855-1860 (1994), EP 06854 74, EP 0685475, EP 0685479, EP 073 1099, WO 96/03399, WO 96/36626, WO 96/36625 and WO 97/20833

 Conventionally, benzofuran derivatives are industrially useful, and patents have been disclosed as intermediates for production raw materials, light-emitting elements, pesticides, anthelmintics, pharmaceuticals, and the like.

 EP 0307 172 and US 4910193 disclose benzofuran derivatives having serotonin (5HT) 3 receptor antagonism.

Chim. Therap., 87-97 (1966) (Chemical Abstract, 64, 17518b, 1966) Discloses a 7-methoxybenzofuran-12-force lipoxamide derivative having several substituents at the 4-position.

Disclosure of the invention

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

(In the formula, R ¹ represents hydrogen or substituted or unsubstituted lower alkyl, and R ² , R ³ and R ⁴ are the same or different and are hydrogen, halogen, lower alkyl, cycloalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted aralkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkyl group, substituted or unsubstituted alkyl group alkyl group, lower alkoxy group Represents carbonyl or cyano, and R ^5a is hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Represents unsubstituted aralkyl or substituted or unsubstituted heteroarylalkyl. And R ^5b is a substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, or substituted or unsubstituted R ^5a and R ^5b together represent a substituted or unsubstituted heterocyclic group formed containing N, and R ^6a and R ^6b are the same or different. , Hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted aralkyl, or a substituent formed by N containing R ^6a and R ^6b Or a non-substituted heterocyclic group.) Or a pharmacologically acceptable salt thereof. Hereinafter, the compound represented by the formula (I) is referred to as a compound (I). Compounds of other formula numbers The same applies to.

 In the definition of each group of the formula (I), the lower alkyl moiety of lower alkyl and lower alkoxy, lower alkanoyloxy, lower alkanol, lower alkoxycarbonyl and heteroarylalkyl is preferably a straight-chain or branched carbon atom having 1 to 4 carbon atoms. 8 including, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl and the like. Cycloalkyl and the cycloalkyl portion of cycloalkylcarbonyl include those having 3 to 10 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, and the like. Polycycloalkyl includes those having 4 to 12 carbon atoms, such as bicyclo [3.2.1] octyl, bicyclo [4.3.2] indesyl, adamantyl, noradamantyl and the like. Aryl includes phenyl, naphthyl and the like, and aralkyl includes C7-C15, for example, benzyl, phenethyl, phenylpropyl, benzhydryl, naphthylmethyl and the like. The heteroaryl moiety of the aromatic heterocyclic group and heteroarylalkyl includes pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, triazolyl, triazolyl, triazolyl Includes chenyl, furyl, thiazolyl, oxazolyl, indolyl, indazolyl, benzimidazolyl, benzotriazolyl, prenyl and the like. Heterocyclic groups formed containing N include pyrrolidinyl, piperidino, piperazinyl, morpholino, thiomorpholino, homopiperidino, homopiperazinyl, tetrahydropyridinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and the like. Halogen means atoms of fluorine, chlorine, bromine and iodine.

 Examples of the substituent in the substituted lower alkyl include the same or different substituents having 1 to 2 substituents, for example, cycloalkyl, and cycloalkyl has the same meaning as described above.

Substituted aryl, substituted aralkyl and substituted aromatic heterocyclic groups, substituted heteroaryl The substituents in the alkyl or substituted lower alkanoyl or substituted cycloalkylcarbonyl may be the same or different and have 1 to 3 substituents, for example, aryl, lower alkyl, hydroxy, lower alkoxy, lower alkanol, lower alkoxylity. Carboxy, carbamoyl, trifluoromethyl, amino, mono- or di-lower alkyl-substituted amino, cyano, nitro, halogen and the like. Here, lower alkyl, lower alkoxy, lower alkanol, lower alkoxycarbonyl or the lower alkyl portion of mono- or di-lower alkyl-substituted amino, aryl and halogen have the same meanings as above.

 Examples of the substituent in the substituted heterocyclic group formed containing N include the same or different and having 1 to 3 substituents such as lower alkyl, cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aralkyl, Lower alkoxy, lower alkyl, lower alkoxycarbonyl, lower alkoxy, lower bamoyl, aromatic heterocyclic groups and the like are included. Here, the lower alkyl portion of lower alkyl, lower alkoxy, lower alkanol or lower alkoxycarbonyl, cycloalkyl, aryl, aralkyl and aromatic heterocyclic group have the same meanings as described above. Further, the substituents of the substituted aryl and the substituted aralkyl have the same meanings as described above.

 Substituents in the substituted lower alkoxy include the same or different and have 1 to 3 substituents, for example, halogen, and halogen has the same meaning as described above.

The pharmaceutically acceptable salts of compound (I) include pharmaceutically acceptable acid addition salts, metal salts, ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of acid addition salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, formate, acetate, benzoate, maleate, fumarate, and succinate. And organic acid salts such as tartrate, citrate, oxalate, metasulfonate and P-toluenesulfonate. Examples of the metal salt include an alkali metal salt such as a lithium salt, a sodium salt, and a potassium salt; an alkaline earth metal salt such as a magnesium salt and a calcium salt; an aluminum salt; a zinc salt; and the like. Ammo Salts such as dimethyl and tetramethylammonium; organic amine addition salts such as morpholine and piperidine; amino acid addition salts such as glycine, phenylalanine, glutamic acid, lysine and aspartic acid; Addition salts.

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

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

Process 1

(Wherein, R ¹ , RR ³ , R ⁴ , R ^5a and R ^5b each have the same meaning as described above)

 The starting compound (II) can be obtained according to a known method [J. Med. Chem., 30, 62-67 (1987)].

Compound (IV) can be obtained by a dehydration condensation reaction between starting compound (II) and amine (III). Many methods are known for this dehydration condensation reaction (see the fourth edition of Experimental Chemistry, Maruzen 1990, Vol. 22, p. 138), and can be applied. For example, compound (II) can be prepared in an inert solvent or in the absence of a solvent using 1 equivalent to a large excess of thionyl chloride, oxalyl chloride or phosphorus pentachloride, if necessary, in the presence of a catalytic amount to an excess of base. After treatment at a temperature between O and the boiling point of the solvent used for 5 minutes to 10 hours to lead to the corresponding acid chloride, 1 equivalent to a large excess of compound (III) is required in an inert solvent. Then, in the presence of 1 equivalent to an excess of a base, the reaction can be carried out at a temperature between 150 ° C. and the boiling point of the solvent used for 5 minutes to 10 hours. In addition, when ethyl chloroformate or the like is used instead of thionyl chloride or the like, a mixed acid anhydride can be obtained instead of acid chloride. The corresponding mixed anhydride of the compound (II) can be treated with the amine (III) in the same manner as the acid chloride to obtain the compound (IV). Bases include sodium hydroxide, potassium hydroxide, sodium methoxide, Potassium ethoxide, sodium hydride, potassium hydride, butyllithium, lithium diisopropylamide (LDA), potassium tert-butoxide, triethylamine, diisopropylethylamine, tributylamine, dicyclohexylmethylamine, N-methylmorpholine , N-methylpiperidine, diazabicycloundecene (DBU), diazabicyclononene (DBN) and the like. Inert solvents include tetrahydrofuran (THF), dioxane, getyl ether, ethylene glycol, triethylene glycol, glyme, diglyme, methanol, ethanol, butanol, isopropanol, dichloromethane, chloroform, benzene, benzene, toluene, and dimethyl. Examples include formamide (DMF) and dimethyl sulfoxide (DMSO).

Process 2

(Wherein, RR ² , R ³ , R ⁴ , R ^5a and R ^5b each have the same meaning as described above). Compound (V) can be produced by formylating compound (IV). Many methods are known for formylation of aromatic compounds (see the 4th edition Experimental Chemistry, Maruzen 1990, Vol. 21, p. 106), and are applicable. For example, compound (IV) can be prepared in an inert solvent, more preferably in a halogenated solvent such as dichloromethane, with one equivalent to a large excess of dichloromethyl methyl ether and one equivalent to an excess of an acid, more preferably The desired compound (V) can be obtained by reacting in the presence of titanium tetrachloride at a temperature between 1501 and the boiling point of the solvent used for 5 minutes to 48 hours.

 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.

Inert solvents include THF, dioxane, getyl ether, ethylenedali Examples include coal, triethylene glycol, glyme, diglyme, dichloromethane, chloroform, benzene, and toluene.

Process 3

(Wherein, RRR 3, RR ^5a , R ^5b , R ^6a and R ^6b each have the same meaning as described above)

 The desired compound (I) can be produced by reductive amination of compound (V). Several methods are known for the reductive amination of aromatic aldehydes (see the 4th edition of Experimental Chemistry, Maruzen 1990, Vol. 20, p. 300), and are applicable. For example, compound (V) is mixed with 1 equivalent to a large excess of amine (VI) in an inert solvent, and if necessary, an appropriate acid or salt is added, and 1 equivalent to an excess of a reducing agent, more preferably a hydrogenated tria. The desired compound (I) can be obtained by reacting at a temperature between 15 and the boiling point of the used solvent for 5 minutes to 48 hours in the presence of cetoxyboron. As the reducing agent, sodium borohydride, sodium cyanoborohydride and the like can also be used.

 Examples of the acid include acetic acid, methanesulfonic acid, hydrochloric acid, sulfuric acid, and trifluoroacetic acid.

 Examples of the salt include ammonium acetate, ammonium chloride, ammonium sulfide and the like.

 Examples of the inert solvent include THF, dioxane, getyl ether, dichloromethane, chloroform, benzene, toluene, methanol, ethanol, isopropanol and the like.

The structures of typical examples of the compound (I) are shown in Table 1 '. In the table, Me, Et, Pr, i Pr, Bu and Bn represent methyl, ethyl, propyl, isopropyl, butyl and benzyl, respectively.

Table 1 (2)

Compound number MP ^5a Fi ^5b NR ^6a R ^6b

Table 1 (3)

Compound number NR ^5a R ^5b NR ^6a R ^6b

\

Table 1 (4)

Compound number N ^{5 5b} NR ^6a R ^6b

Table 1 (5)

Compound number _NR 6a _R 6b

NR ^5a R ^5b

 One hundred one

 ] Ό 0, / ≤ d: ^ a £ 〇

 To H

 89

 H eight

90- ^N

 91

 92

 93-N

 95-96

 97

99 _ ^N 3

 -N p

100 Table 1 (6)

Compound number NR ^5a R ^5b NR ^6a R ^6b

 H

 101? ? ? ? ? ? ? -N Ichigo e

 H

 102 -N

 -Λ ソ-Λν /-/ oοoop .., bΡ0 o,--o-NEt

 r

109 -N one N v 110 — N-H

 111 -NMe

 H

 112 -NEt

 H

 113 -NPr

 H

 114-N-iPr

 H

 115 -NBu

 H c 116

 H

 117

 H

 118 -NBn

 / 119 -N

120 91

 ^ Assault 3

(z) Halla τ

Hi 0 / 6di7JL d: Table 1 (8)

Compound number NR ^5a R ^5b NR ^6a R ^6b

Έ M

et

Table 1 (9) NR ^ba R ^5b

, NR ^6a R ^6b Compound number NR ^5a R ^5b NR ^6a R ^6b

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 predicted amino acid sequence is the sequence (HSPD4A5) reported by Bolger, G. et al. [Mol. Cell. Biol. 13, 6558-6571 (1993)] with 223 amino acids deleted at the N-terminal. This recombinant protein was expressed and purified using an E. coli expression plasmid. PDE activity was measured by the following two-step process according to the method of Kincaid, R., L. and Manganiello, V., C. [Method. Enzymol. 159, 457-470 (1988)]. The substrate is [ ³ H] cAMP

Using a final concentration of 1 μιηοΙ / L, the reaction was performed using N, N-bis (2-hydroxyethyl) -2-aminoaminosulfonic acid (50 mmol / L, pH 7.2)> MgCl ₂ (1 mmol / L). ) And Soybean trypsin inhibitor (0.1 mg / mL) in a standard mixture. The reaction was started by addition of the enzyme and incubated at 30 for 10-30 minutes. The reaction was stopped by 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 in a scintillation counter. The drug is dissolved in DMSO

(Concentration 1.7%).

 In this test, the compound showed an enzyme inhibitory activity of 50% or more at 10 μιηοΙ / L.

 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. The 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, powders, granules, syrups, emulsions, suppositories, injections, ointments, tapes and the like.

 Liquid preparations suitable for oral administration, for example, emulsions and syrups, include water, sugars such as sucrose, sorbit, fructose, glycols such as polyethylene glycol, 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. Capsules, tablets, powders, granules and the like include excipients such as lactose, glucose, sucrose and mannitol; disintegrants such as starch and sodium alginate; lubricants such as magnesium stearate and talc; It can be produced using a binder such as polyvinyl alcohol, hydroxypropylcellulose and gelatin, a surfactant such as fatty acid ester, and a plasticizer such as daricerin.

 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, in the case of 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 glucose solution. Formulations for enteral administration are prepared using carriers such as cocoa butter, hydrogenated fats or hydrogenated carboxylic acids and 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 for these parenteral preparations, select from the glycols, oils, flavors, preservatives, excipients, disintegrants, lubricants, binders, surfactants, plasticizers, etc. exemplified for the oral preparation. One or more auxiliary ingredients can also be added.

The effective amount and the number of administration of the compound (I) or a pharmaceutically acceptable salt thereof are as follows: Depending on the dosage form, the age and weight of the patient, the nature or severity of the condition to be treated, usually 0.01 mg to lg, preferably 1 to 50 Omg per day for an adult It is administered once or several times. In the case of parenteral administration such as intravenous administration, 0.001 to 100 mg per adult, preferably 0.01 to Omg is administered once or several times a day. However, these dosages vary depending on the various conditions described above.

 Hereinafter, examples and reference examples of the present invention will be described.

BEST MODE FOR CARRYING OUT THE INVENTION

Example 1: N-cyclohexyl-7-methoxy-4-morpholinomethylbenzofuran-2-carboxamide (Compound 1)

 The starting compound, 7-methoxybenzofuran-2-carboxylic acid (5.0 g) was dissolved in dichloromethane (75 ml), oxalyl chloride (3.4 ml) was added, and the mixture was stirred at room temperature for 3 hours. After the residue obtained by concentration under reduced pressure was dried, the residue was dissolved in dichloromethane (75 ml), and triethylamine (5.44 ml) and cyclohexylamine (3.57 ml) were added, followed by stirring at room temperature for 1 hour. After adding silica gel (3 g) and stirring for 3 hours, the mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound a (6.51 g, 92%) as a white solid.

_{NMR (CDC1 3, δ, ppm} ); 1.17-1.44 (m, 6H), 1.69-1.81 (m, 4H), 2.01-2.05 (m, 1H), 4.0 2 (s, 3H), 6.59 (m, 1H ), 6.90 (dd, J = 1.5, 8Hz, 1H), 7.20 (t, J = 8Hz, IH), 7.25 (dd, J = l, 8Hz, IH), 7.45 (s, IH).

MASS (m / z); 273 (M +)

 Compound la (200 mg) was dissolved in dichloromethane (5 ml), dichloromethyl methyl ether (132 U 1) and titanium tetrachloride (241 H 1) were added, and the mixture was stirred at room temperature for 5 hours. After adding sodium sulfate hydrate, the mixture was filtered through a short column and the filtrate was concentrated to give N-cyclohexyl-4-formyl-7-methoxybenzofuran-1-carboxamide (compound lb) (219 mg) as a white solid As obtained.

_{NMR (CDC1 3, δ, ppm} ); 1.22-1.46 (m, 6H), 1.65-1.81 (m, 4H), 2.02-2.07 (m, 1H), 4.1 2 (s, 3H), 6.54 (m, 1H ), 7.01 (d, J = 8Hz, 1H), 7.74 (d, J = 8Hz, IH), 8.15 (s, IH), 10.07 (s, 1H).

 MASS (m / z); 301 (M +)

 Dissolve the obtained compound lb (HOmg) in dichloromethane (15 ml), add morpholine (64 ^ 1), acetic acid (10/1), and triacetoxyboron hydride (232 mg), and stir at room temperature for 24 hours. did. After adding a 1N aqueous sodium hydroxide solution (2 ml), the organic layer was washed with a 1N aqueous sodium hydroxide solution and saturated saline, dried over sodium sulfate, and concentrated under reduced pressure to give Compound 1 (85 mg, 63%) as a white solid. As obtained.

_{NMR (CDC1 3, (5,} ppm); 1.23-1.46 (m, 6H), 1.65-1.81 (m, 4H), 2.02-2.09 (m, 1H), 2.4 l-2.44 (m, 4H), 3.65 ( s, 2H), 3.66-3.72 (m, 4H), 4.01 (s, 3H), 6.55 (m, 1H), 6.81 (d, J = 8 Hz, 1H), 7.09 (d, J = 8Hz, 1H) , 7.69 (s, 1H).

MASS (m / z); 372 (M ⁺ )

Example 2: N-cyclohexyl-1 7-methoxy-1-methylaminomethylbenzofuran 1-2-carboxamide (Compound 2)

 In the same manner as in Example 1, compound 2 was obtained as colorless crystals using compound 1b and methylamine monohydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.14

Example 3 4-Ethylaminomethyl-N-cyclohexyl-7-methoxybenzofuran-1-carboxamide (Compound 3)

 Compound 3 was obtained as colorless crystals in the same manner as in Example 1 using Compound 1b and ethylamine monohydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.20

Example 4: N-cyclohexyl-1 7-methoxy-4-propylaminomethylbenzofuran 1-2-carboxamide (compound 4)

 In the same manner as in Example 1, Compound 4 was obtained as colorless crystals using Compound 1b and n-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.26

Example 5: N-cyclohexyl-7-methoxy-4- (2-propylaminomethyl Tyl) benzofuran-2-carboxamide (compound 5)

 Compound 5 was obtained as colorless crystals in the same manner as in Example 1 using Compound 1b and 2-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.26

Example 6: 4-butylaminomethyl-N-cyclohexyl-7-methoxybenzofuran-2-carboxamide (compound 6)

 In the same manner as in Example 1, Compound 6 was obtained as colorless crystals using Compound 1b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.34

Example 7: N-cyclohexyl-4-cyclobutylaminomethyl-7-methoxybenzofuran-2-carboxamide (compound 7)

 In the same manner as in Example 1, compound 7 was obtained as colorless crystals using compound 1b and cyclobutylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.17

Example 8: N-cyclohexyl-4-cyclopentylaminomethyl-7-methoxybenzofuran-1-carboxamide (compound 8)

 In the same manner as in Example 1, compound 8 was obtained as colorless crystals using compound 1b and cyclopentylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.34

Example 9: N-cyclohexyl_4-cyclohexylaminomethyl-7-methoxybenzofuran-12-force lipoxamide (compound 9)

 In the same manner as in Example 1, compound 9 was obtained as colorless crystals using compound 1b and cyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.45

Example 10: N-cyclohexyl-4-cyclooctylaminomethyl-7-methoxybenzofuran_2-carboxamide (compound 10)

In the same manner as in Example 1, compound 1b and cyclooctylamine were used. Thus, Compound 10 was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.29

Example 11 1: N-cyclohexyl-7-methoxy-4- (2,3-dimethylcyclohexylaminomethyl) benzofuran-2-kelpoxamide (Compound 11) In the same manner as in Example 1, Compound 11 was obtained as colorless crystals using compound lb and 2,3-dimethylcyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.31

Example 12: 4_benzylaminomethyl-N-cyclohexyl-7-methoxybenzofuran-2-carboxamide (Compound 12)

 In the same manner as in Example 1, Compound 12 was obtained as colorless crystals using Compound 1b and benzylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.63

Example 13: N-cyclohexyl-7-methoxy-4-piperidinomethylbenzofuran-2-force lipoxamide (Compound 13)

 In the same manner as in Example 1, compound 13 was obtained as colorless crystals using compound 1b and piperidine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.57

Example 14: N-cyclohexyl-7-methoxy-4-1- (1-pyrrolidinylmethyl) benzofuran-1-carboxamide (Compound 14)

 In the same manner as in Example 1, compound 14 was obtained as colorless crystals using compound 1b and pyrrolidine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.23

Example 15: N-cyclohexyl-7-methoxy-1- (4-methylbiperazinylmethyl) benzofuran-2-potassium lipoxamide (Compound 15)

 In the same manner as in Example 1, compound 15 was obtained as colorless crystals using compound 1b and 1-methylbiperazine.

Rf (CHCl ₃ : MeOH = 9: l); 0.23 Example 16: N-cyclohexyl-7-methoxy-41- (2-phenylethylaminomethyl) benzofuran-2-force lipoxamide (Compound 16)

 In the same manner as in Example 1, compound 16 was obtained as colorless crystals using compound 1b and 2-phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.51

Example 17: N-cyclohexyl-17-methoxy-14- [1-1 (S) -phenylethylaminomethyl] benzofuran-2-caproloxamide (Compound 17) The compound was prepared in the same manner as in Example 1. Compound 17 was obtained as colorless crystals using lb and 1- (S) -phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.57

Example 18: N-cyclohexyl 7-methoxy-41- (3-phenylpropylaminomethyl) benzofuran-2-carboxamide (compound 18)

 By a method similar to that in Example 1, compound 18 was obtained as colorless crystals using compound 1b and 3-phenylpropylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.54

Example 19: N-cyclohexyl-7-methoxy-4- [2- (2-pyridyl) ethylaminomethyl] benzofuran-2-carboxamide (Compound 19) In the same manner as in Example 1, compound lb was obtained. Compound 19 was obtained as colorless crystals using and 2- (2-pyridyl) amine.

Rf (CHCl ₃ : MeOH = 9: l); 0.29

Example 20: N-cyclohexyl-7-methoxy-4- (2-morpholinoethylaminomethyl) benzofuran-2-caproloxamide (Compound 20)

 In the same manner as in Example 1, compound 20 was obtained as colorless crystals using compound 1b and 2-morpholinoethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.34

Example 21: 4-Cyclobutylaminomethyl-7-methoxy-N- (3-phenylpropyl) benzofuran-1-carboxamide (Compound 21) In the same manner as in Example 1, 7-methoxybenzofuran-2-carboxylic acid was used as a starting compound and reacted with 3-phenylpropylamine to react with 7-methoxy-N- (3-phenylpropyl) benzofuran-2 —Caproloxamide (Compound 21a) and further formylation to give 7-methoxy-4-formyl-1-N— (3-phenylpropyl) benzofuran-1-carboxamide (Compound 2 lb), and then react with cyclobutylamine Compound 21 was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.25

Example 22: 4-Cyclooctylaminomethyl-7-methoxy-1-N- (3-phenylpropyl) benzofuran-2-carboxamide (Compound 22)

 By a method similar to that in Example 21, compound (compound 22) was obtained as colorless crystals using compound 21b and cyclooctylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 23: 4- (2,3-dimethylcyclohexylaminomethyl) -7-methoxy-N- (3-phenylpropyl) benzofuran-2-carboxamide (Compound 23)

 By a method similar to that in Example 21, compound 23 was obtained as colorless crystals using compound 21b and 2,3-dimethylcyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 24: 7-Methoxy-4-I- (4-methylpiperazinylmethyl) -N- (3-phenylpropyl) benzofuran-l-carboxamide (Compound 24) In the same manner as in Example 21, Compound 24 was obtained as colorless crystals using compound 21b and 1-methylbiperazine.

Rf (CHCl ₃ : MeOH = 9: l); 0.50

Example 25: 7-Methoxy-N- (3-phenylpropyl) -4-1 (1-pyrrolidinylmethyl) benzofuran-1-carboxamide (Compound 25)

Compound 25 was obtained as colorless crystals using compound 21b and pyrrolidine in the same manner as in Example 21. Rf (CHCl ₃ : MeOH = 9: l); 0.19

Example 26: 7-methoxy-4- (2-phenylethylaminomethyl) -N- (3-phenylpropyl) benzofuran-2-carboxamide (Compound 26) Compound 2 was prepared in the same manner as in Example 21. Compound 26 was obtained as colorless crystals using 1b and 2-phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.56

Example 27: 7-methoxy-4_ [1- (S) -phenylethylaminomethyl] -1-N- (3-phenylpropyl) benzofuran-2-carboxamide (Compound 27)

 By a method similar to that in Example 21, compound 27 was obtained as colorless crystals using compound 2lb and 1- (S) -phenethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.61

Example 28: 7-methoxy-N- (3-phenylpropyl) -4- (3-phenylpropylaminomethyl) benzofuran-1-carboxamide (Compound 28) Compound 21 was prepared in the same manner as in Example 21. Compound 28 was obtained as colorless crystals using b and 3-phenylpropylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.53

Example 29: N- (3-phenylpropyl) _7-methoxy-4_ [2- (2-pyridyl) ethylaminomethyl] benzofuran-2-carboxamide (Compound 29)

 By a method similar to that in Example 21, compound 29 was obtained as colorless crystals using compound 21b and 2- (2-pyridyl) ethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.42

Example 30: 7-Methoxy-N- (3-phenylpropyl) -1- (2-morpholinoethylaminomethyl) benzofuran-2-carboxamide (Compound 30) A compound was prepared in the same manner as in Example 21. Compound 30 was obtained as colorless crystals using 21b and 2-morpholinoethylamine. Rf (CHCl ₃ : MeOH = 9: l); 0.39

Example 31: 7-Methoxy-4-monomethylaminomethyl-N-phenylpentazofuran 2-carpoxamide (Compound 31)

 In the same manner as in Example 1, 7-methoxybenzofuran-l-monorubic acid was used as a starting compound, and reacted with aniline to react with N-phenyl-17-methoxybenzofuran-2-carboxamide (compound 3la) and formyl The compound was converted to N-phenyl-14-formyl-17-methoxybenzofuran-12-carboxamide (Compound 31b) and reacted with methylamine'1 hydrochloride to give Compound 31 as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.18

Example 32: 4-Ethylaminomethyl-7-methoxy-N-phenylbenzofuran-2-carpoxamide (Compound 32)

 In the same manner as in Example 31, compound 32 was obtained as colorless crystals using compound 31b and ethylamine monohydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.21

Example 33: 7-Methoxy-N-phenyl-4-propylaminomethylbenzofuran-2-carboxamide (Compound 33)

 By a method similar to that in Example 31, compound 33 was obtained as colorless crystals using compound 31b and n-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.29

Example 34: 7-Methoxy-N-phenyl-1- (2-propylaminomethyl) benzofuran-1-carboxamide (Compound 34)

 By a method similar to that in Example 31, compound 31b was obtained as colorless crystals using compound 31b and 2-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.26

Example 35: 4-Monobutylaminomethyl-7-methoxy-N-phenylbenzofuran-2-carboxamide (Compound 35) By a method similar to that of Example 31, compound 35 was obtained as colorless crystals using compound 31b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.44

Example 36: 4-cyclobutylaminomethyl-7-methoxy-N-phenylbenzofuran-l2-carboxamide (compound 36)

 By a method similar to that of Example 31, compound 36 was obtained as colorless crystals using compound 31b and cyclobutylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 37: 4-cyclopentylaminomethyl-7-methoxy-N-phenylbenzofuran-1-carboxamide (Compound 37)

 By a method similar to that of Example 31, compound 37 was obtained as colorless crystals using compound 31b and cyclopentylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.44

Example 38: 4-cyclohexylaminomethyl-7-methoxy-N-phenylbenzofuran-1-carboxamide (compound 38)

 By a method similar to that of Example 31, compound 38 was obtained as colorless crystals using compound 31b and cyclohexylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.50

Example 39: 4-cyclooctylaminomethyl-17-methoxy-N-phenylbenzofuran-2-carboxamide (Compound 39)

 By a method similar to that of Example 31, compound 39 was obtained as colorless crystals using compound 31b and cyclooctylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 40: 7-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) 1-N-phenylbenzofuran-2-carboxamide (Compound 40) Compound 3 lb was prepared in the same manner as in Example 31. Compound 40 was obtained as colorless crystals using 2,3-dimethylcycloamine. τε

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wo v-6 = uom: ^£ DH3) JH Rf (CHCl ₃ : MeOH = 9: l); 0.14

Example 45: 7-Methoxy-4- (4-methylbiperazinylmethyl) -1-N-phenylbenzofuran-2-carboxamide (Compound 45)

 By a method similar to that in Example 31, compound 45 was obtained as colorless crystals using compound 31b and 1-methylbiperazine.

Rf (CHCl ₃ : MeOH = 9: l); 0.61

Example 46: 7-Methoxy N-phenyl-4- (2-phenylethylaminomethyl) benzofuran-2-carboxamide (Compound 46)

 By a method similar to that in Example 31, compound 46 was obtained as colorless crystals using compound 31b and 2-phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.57

Example 47: 7-Methoxy-N-phenyl 4- [1- (S) -phenylethylaminomethyl] benzofuran-2-carboxamide (Compound 47)

 By a method similar to that in Example 31, compound 47 was obtained as colorless crystals using compound 3 lb and 1- (S) -phenethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.69

Example 48: 7-Methoxy-N-phenyl-4_ (3-phenylpropylaminomethyl) benzofuran-2-force lipoxamide (Compound 48)

 'Compound 48 was obtained as colorless crystals using compound 31b and 3-phenylpropylamine in the same manner as in Example 31.

Rf (CHCl ₃ : MeOH = 9: l); 0.63

Example 49: 7-Methoxy-N-phenyl 4 _ [2- (2-pyridyl) ethylaminomethyl] benzofuran-2-carboxamide (Compound 49)

 By a method similar to that of Example 31, compound 49 was obtained as colorless crystals using compound 3 lb and 2_ (2-pyridyl) ethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.35

Example 50: 7-Methoxy-N-phenyl-4_ (2-morpholinoethylamine Nomethyl) benzofuran-2-propanolamide (compound 50)

 By a method similar to that of Example 31, compound 50 was obtained as colorless crystals using compound 31b and 2-morpholinoethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.44

Example 51 1: N-benzyl-1 7-methoxy-4 monomethylaminomethyl benzofuran 1-2-caproloxamide (compound 51)

 In the same manner as in Example 1, 7-methoxybenzofuran-12-carboxylic acid was used as a starting compound, reacted with benzylamine to react with N-benzyl-7-methoxybenzofuran-2-carboxamide (compound 5la) and further formylation. To give N-benzyl-41-formyl-7-methoxybenzofuran-12-hydroxylpoxamide (compound 51b), and then react with methylamine monohydrochloride to give compound 51 as colorless crystals. Was.

Rf (CHCl ₃ : MeOH = 9: l); 0.15

Example 52: 4-Ethylaminomethyl-N-benzyl-7-methoxybenzofuran-1-carboxamide (Compound 52)

 By a method similar to that in Example 51, compound 52 was obtained as colorless crystals using compound 5 lb and ethylamine * 1 hydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.26

Example 53: N-benzyl-7-methoxy-4-propylaminomethylbenzofuran-2-carboxamide (compound 53)

 By a method similar to that in Example 51, compound 53 was obtained as colorless crystals using compound 51b and n-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.37

Example 54: N-benzyl-7-methoxy-4- (2-propylaminomethyl) benzofuran-2-carboxamide (compound 54)

By a method similar to that of Example 51, compound 54 was obtained as colorless crystals using compound 51b and 2-propylamine. Rf (CHCl ₃ : MeOH = 9: l); 0.35

Example 55: N-benzyl-4-butylaminomethyl-7-methoxybenzofuran-2-caproloxamide (compound 55)

 By a method similar to that in Example 51, compound 55 was obtained as colorless crystals using compound 51b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.50

Example 56: N-benzyl-4-cyclobutylaminomethyl-7-methoxybenzofuran-2-carpoxamide (compound 56)

 By a method similar to that in Example 51, compound 56 was obtained as colorless crystals using compound 51b and cyclobutylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.21

Example 57: N-benzyl-4-cyclopentylaminomethyl_7-methoxybenzofuran-2-carboxamide (compound 57)

 By a method similar to that in Example 51, compound 57 was obtained as colorless crystals using compound 51b and cyclopentylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.50

Example 58: N-benzyl-4-cyclohexylaminomethyl-7-methoxybenzofuran-12-force lipoxamide (compound 58)

 By a method similar to that in Example 51, compound 58 was obtained as colorless crystals using compound 51b and cyclohexylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.56

Example 59: N-benzyl-4-cyclooctylaminomethyl-1 7-methoxybenzofuran-2-carboxamide (Compound 59)

 By a method similar to that in Example 51, compound 59 was obtained as colorless crystals using compound 51b and cyclooctylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.31

Example 60: N-benzyl-4- (2,3-dimethylcyclohexylaminomethyl (Tyl)-1-methoxybenzofuran-2-force lipoxamide (Compound 60) In the same manner as in Example 51, Compound 5 was obtained as colorless crystals using Compound 5 lb and 2,3-dimethylcyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 61: N-benzyl-4-benzylaminomethyl-7-methoxybenzofuran-12-caprolupoxamide (Compound 61)

 By a method similar to that in Example 51, compound 61 was obtained as colorless crystals using compound 51b and benzylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.59

Example 62: N-benzyl-7-methoxy-4-piperidinomethylbenzofuran 2-carboxamide (Compound 62)

 By a method similar to that in Example 51, compound 62 was obtained as colorless crystals using compound 51b and piperidine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.56

Example 63: N-benzyl-7-methoxy-14-morpholinomethylbenzofuran-2-force lipoxamide (Compound 63)

 By a method similar to that in Example 51, compound 63 was obtained as colorless crystals using compound 51b and morpholino.

_{Rf (CHCl 3: MeOH = 9} : l); 0.79

Example 64: N-benzyl-7-methoxy-4- (1-pyrrolidinylmethyl) benzofuran-2-carboxamide (Compound 64)

 In the same manner as in Example 51, compound 64 was obtained as colorless crystals using compound 51b and pyrrolidine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.17

Example 65: N-benzyl-7-methoxy-41- (4-methylbiperazinylaminomethyl) benzofuran-2-force lipoxamide (Compound 65)

Compound 51b and 1-methylbiperazine were obtained in the same manner as in Example 51. Compound 65 was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.21

Example 66: N-benzyl-7-methoxy-4- (2-phenylethylaminomethyl) benzofuran-1-carboxamide (Compound 66)

 By a method similar to that in Example 51, compound 66 was obtained as colorless crystals using compound 51b and 2-phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.54

Example 67: N-benzyl 4- [1- (S) -phenylethylaminomethyl] _7-methoxybenzofuran-12-caproloxamide (Compound 67)

 By a method similar to that in Example 51, compound 67 was obtained as colorless crystals using compound 5 lb and 1- (S) -phenethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.66

Example 68: N-benzyl-7-methoxy-4 _ (3-phenylpropylaminomethyl) benzofuran-2-force lipoxamide (Compound 68)

 By a method similar to that in Example 51, compound 68 was obtained as colorless crystals using compound 51b and 3-phenylpropylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.46

Example 69: N-benzyl-7-methoxy-4-1- [2- (2-pyridyl) ethylaminomethyl] benzofuran_2-carboxamide (Compound 69)

 By a method similar to that in Example 51, compound 69 was obtained as colorless crystals using compound 5 lb and 2- (2-pyridyl) ethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.37

Example 70: N-benzyl-7-methoxy-4- (2-morpholinoethylaminomethyl) benzofuran-2-potassium lipoxamide dihydrochloride (Compound 70)

 By a method similar to that in Example 51, compound 70 was obtained as colorless crystals using compound 51b and 2-morpholinoethylamine.

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5 ') ½ 寸 寸 Γ''(HI' ΖΗ0 "8 = Γ 'Ρ) Γ XUZ' ΖΗ0ΖΗ9 = Γ 'Ρ) 8% UZ ^ (\) ZV' (Η £ 's) 0 0 / m 6dfALOd: Z / 86 O. Example 74: N-cyclobutyl-7-methoxy-1- (2-propylaminomethyl) benzofuran-1-carboxamide (compound 74)

 By a method similar to that of Example 71, compound 74 was obtained as colorless crystals using compound 71b and 2-propylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.28.

Example 75: 4-Monobutylaminomethyl-N-cyclobutyl-7-methoxybenzofuran-2-carboxamide (Compound 75)

 By a method similar to that in Example 71, compound 75 was obtained as colorless crystals using compound 71b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 76: N-cyclobutyl-4-cyclopentylaminomethyl-7-methoxybenzofuran-12-carboxamide (compound 76)

 By a method similar to that of Example 71, compound 76 was obtained as colorless crystals using compound 71b and cyclopentylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.36

Example 77: N-Cyclobutyl-4-cyclohexylaminomethyl-7-methoxybenzofuran-2-carboxamide (Compound 77)

 By a method similar to that of Example 71, compound 77 was obtained as colorless crystals using compound 71b and cyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.42

Example 78: 4-Benzylaminomethyl-N-cyclobutyl-7-methoxybenzofuran-2_carboxamide (Compound 78)

 By a method similar to that of Example 71, Compound 78 was obtained as colorless crystals using Compound 71b and benzylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.53

Example 79: N-cyclobutyl-7-methoxy-4-

Furan-2-carboxamide (compound 79) Compound 79 was obtained as colorless crystals using compound 71b and piperidine in the same manner as in Example 71.

Rf (CHCl ₃ : MeOH = 9: l); 0.56

Example 80: N-cyclobutyl-7-methoxy-4-morpholinomethylbenzofuran-2-force lipoxamide (compound 80)

 By a method similar to that in Example 71, compound 80 was obtained as colorless crystals using compound 71b and morpholine.

Rf (CHCl ₃ : MeOH = 9: l); 0.75

Example 81: N-cyclopentyl-7-methoxy-4-methylaminomethylbenzofuran-12-carboxamide (compound 81)

 In the same manner as in Example 1, 7-methoxybenzofuran-2-carboxylic acid was used as a starting compound, reacted with cyclopentylamine to react with N-cyclopentyl-7-methoxybenzofuran-2-carboxamide (compound 8 la), and Formylation gave N-cyclopentyl-4-formyl-17-methoxybenzofuran-12-force ruboxamide (compound 8 lb), which was reacted with methylamine monohydrochloride to give compound 81 as colorless crystals. .

Rf (CHCl ₃ : MeOH = 9: l); 0.17

Example 82: N-cyclopentyl-4-ethylaminomethyl-7-methoxybenzofuran-2-carboxamide (compound 82)

 By a method similar to that of Example 81, compound 82 was obtained as colorless crystals using compound 81 and ethylamine * 1 hydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.21

Example 83: N-cyclopentyl-7-methoxy-4-propylaminomethylbenzofuran-12-carboxamide (compound 83)

 In the same manner as in Example 81, compound 83 was obtained as colorless crystals using compound 81b and n-propylamine.

Rf (CHC: MeOH = 9: l); 0.39 Example 84: N-Cyclopentyl-7-methoxy-41- (2-propylaminomethyl) benzofuran-2-carboxamide (Compound 84)

 By a method similar to that of Example 81, compound 84 was obtained as colorless crystals using compound 81b and 2-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 85: 4-butylaminomethyl-N-cyclopentyl-7-methoxybenzofuran-2-carboxamide (compound 85)

 By a method similar to that of Example 81, compound 85 was obtained as colorless crystals using compound 81b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 86: N-cyclopentyl-4-cyclopentylaminomethyl-7-methoxybenzofuran-2-carboxamide (compound 86)

 By a method similar to that in Example 81, compound 86 was obtained as colorless crystals using compound 81b and cyclopentylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.39

Example 87: 7-Methoxy-14-cyclohexylaminomethyl-N-cyclopentylbenzofuran-1-carboxamide (Compound 87)

 By a method similar to that of Example 81, compound 87 was obtained as colorless crystals using compound 81b and cyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.42

Example 88: 4-benzylaminomethyl-N-cyclopentyl-7-methoxybenzofuran-1-carboxamide (Compound 88)

 By a method similar to that in Example 81, compound 88 was obtained as colorless crystals using compound 81b and benzylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.56

Example 89: N-cyclopentyl-7-methoxy-14-piperidinomethylbenzofuran-12-force lipoxamide (Compound 89) By a method similar to that in Example 81, compound 89 was obtained as colorless crystals using compound 81b and piperidine.

Rf (CHCl ₃ : MeOH = 9: l); 0.56

Example 90: N-cyclopentyl-7-methoxy-4-morpholinomethylbenzofuran-2-carboxamide (compound 90)

 By a method similar to that of Example 81, compound 90 was obtained as colorless crystals using compound 81b and morpholine.

Rf (CHCl ₃ : MeOH = 9: l); 0.77

Example 91: 7-methoxy-4-methylaminomethyl-2-pyrrolidinylcarbonylbenzofuran (compound 91)

In the same manner as in Example 1, 7-methoxybenzofuran-12-carboxylic acid was used as a starting compound, reacted with pyrrolidine to react with 7-methoxy-2-pyrrolidinylcarbonylbenzofuran (compound 9la), and further formylated to form After obtaining formyl-7-methoxy-2-pyrrolidinylcarbonylbenzofuran (compound 9 lb), it was reacted with methylamine'1 hydrochloride to obtain compound 91 as colorless crystals. Rf (CHCl ₃ : MeOH = 9: l); 0.11

Example 92: 4-ethylaminomethyl-7-methoxy-2-pyrrolidinylcarbonylbenzofuran (compound 92)

 By a method similar to that of Example 91, Compound 92 was obtained as colorless crystals using Compound 91b and ethylamine monohydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.19

Example 93: 7-Methoxy-4-monopropylaminomethyl-2-pyrrolidinylcarboxylbenzofuran (compound 93)

 In the same manner as in Example 91, compound 93 was obtained as colorless crystals using compound 91b and n-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 9 4: 7-Methoxy-1- (2-propylaminomethyl) -2-pyrrolid Dinylcarbonylbenzofuran (Compound 94)

 By a method similar to that of Example 91, compound 94 was obtained as colorless crystals using compound 91b and 2-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 95: 4-butylaminomethyl-7-methoxy-1-pyrrolidinylcarbonylbenzofuran (compound 95)

 By a method similar to that in Example 91, compound 95 was obtained as colorless crystals using compound 91b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.34

Example 96: 4-Cyclopentylaminomethyl-7-methoxy-2-pyrrolidylcarbanolpenzafuran (compound 96)

 By a method similar to that in Example 91, compound 96 was obtained as colorless crystals using compound 91b and cyclopentylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 97: 4-cyclohexylaminomethyl-7-methoxy-2-pyrrolidinylcarponyl benzofuran (compound 97)

 By a method similar to that of Example 91, compound 97 was obtained as colorless crystals using compound 91b and cyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.34

Example 98: 4-Benzylaminomethyl-7-methoxy-2-pyrrolidinylcarbodilpenzafuran (Compound 98)

 By a method similar to that in Example 91, compound 98 was obtained as colorless crystals using compound 91b and benzylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.61

Example 99: 7-Methoxy-4-piperidinomethyl-2-pyrrolidinylcarbodilpenzafuran (Compound 99)

In the same manner as in Example 91, the compound was synthesized using compound 91b and piperidine. Compound 99 was obtained as colorless crystals.

_{Rf (CHCl 3: MeOH = 9} : l); 0.55

Example 100: 7-Methoxy-2-pyrrolidinylcarbonyl 4-morpholino methylbenzofuran (Compound 100)

 In the same manner as in Example 91, compound 100 was obtained as colorless crystals using compound 91b and morpholine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.58

Example 101: 7-Methoxy-4-methylaminomethyl-2-piperidinocarbonylbenzofuran (Compound 101)

In the same manner as in Example 1, 7-methoxybenzofuran-2-carboxylic acid was used as a starting compound, and reacted with pyrrolidine to react with 7-methoxy-2-piperidinocarbodilpenzafuran (compound 10 la). After obtaining formyl 17-methoxy-2-piperidinocarbodilpenzafuran (compound 10 lb), it was reacted with methylamine monohydrochloride to give compound 101 as colorless crystals. _{Rf (CHC1 3: MeOH = 9} : l); 0.14

Example 102: 4-Ethylaminomethyl-7-methoxy-2-piperidinocarbonylbenzofuran (Compound 102)

 By a method similar to that in Example 101, compound 102 was obtained as colorless crystals using compound 101b and ethylamine monohydrochloride.

_{Rf (CHCl 3: MeOH = 9} : l); 0.17

Example 103: 7-Methoxy-14-propylaminomethyl-2-piperidinocarpanolpyrzofuran (Compound 103)

 By a method similar to that of Example 101, compound 103 was obtained as colorless crystals using compound 101b and n-propylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.17

Example 104: 7-Methoxy-1- (2-propylaminomethyl) -2-piridinocarbonylcarbonylbenzofuran (Compound 104) By a method similar to that of Example 101, compound 104 was obtained as colorless crystals using compound 101b and 2-propylamine.

Rf (CHCl ₃ : eOH = 9: l); 0.22

Example 105: 4-Monobutylaminomethyl-7-methoxy-2-piperidinocarbonylbenzofuran (Compound 105)

 By a method similar to that of Example 101, compound 105 was obtained as colorless crystals using compound 101b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.22

Example 106: 4-cyclopentylaminomethyl-1-piperidinocarbonyl-7-methoxybenzofuran (compound 106)

 In the same manner as in Example 101, compound 106 was obtained as colorless crystals using compound 101b and cyclopentylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 107: 4-cyclohexylaminomethyl-17-methoxy-12-piperidinocarbodilpenzafuran (compound 107)

 By a method similar to that of Example 101, compound 107 was obtained as colorless crystals using compound 101b and cyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 108: 4 -Benzylaminomethyl-7-methoxy-2-piperidinocalpanol benzofuran (Compound 108)

 By a method similar to that of Example 101, compound 108 was obtained as colorless crystals using compound 101b and benzylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.50

Example 109: 7-methoxy-2-piperidinocarbonyl-4-piperidinomethyl benzofuran (compound 109)

By a method similar to that in Example 101, compound 109 was obtained as colorless crystals using compound 101b and piperidine. _{Rf (CHCl 3: MeOH = 9} : l); 0.47

Example 1 10: 7-Methoxy-2-piperidinocarbonyl 4-morpholinomethyl benzofuran (Compound 110)

 By a method similar to that in Example 101, compound 110 was obtained as colorless crystals using compound 101b and morpholine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.67

Example 1 1 1: 7-methoxy-4-methylaminomethyl-2-morpholinocarbonylbenzofuran (compound 1 11)

In the same manner as in Example 1, 7-methoxybenzofuran-12-carboxylic acid was used as a starting compound, reacted with morpholine to react with 7-methoxy-2-morpholinocarbonylbenzofuran (compound 11a) and further formylated. After obtaining 4-formyl-7-methoxy-2-morpholinocarborylbenzobenzofuran (compound 11 lb), it was reacted with methylamine 'monohydrochloride to obtain compound 111 as colorless crystals. _{Rf (CHCl 3: MeOH = 9} : l); 0.17

Example 112: 4-Ethylaminomethyl-7-methoxy-2-morpholinocarbonylbenzofuran (Compound 112)

 By a method similar to that in Example 111, Compound 112 was obtained as colorless crystals using Compound 111 and ethylamine * 1 hydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.20

Example 1 13: 7-Methoxy-4-propylaminomethyl-2-morpholino force Luponyl benzofuran (Compound 113)

 By a method similar to that of Example 111, Compound 113 was obtained as colorless crystals using Compound 111b and n-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.25

Example 1 14: 7-methoxy-41- (2-propyl) aminomethyl-2-mol holinocarborpenzafuran (compound 114)

Compound 11 1b and 2-propylamine were prepared in the same manner as in Example 11 9

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6ΖΌ ί (ΐ ^: 6 = Η09Μ: ^£ DH3) J¾ [¾ ¾ ¾ つ ^ ¾¾¾ II ひ 0/6 dTAi: O As a result, compound 118 was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.50

Example 1 19: 7-Methoxy-1-4-piberidinomethyl-2-morpholino-potanol Rilpenzofuran (Compound 119)

 By a method similar to that of Example 111, Compound 119 was obtained as colorless crystals using Compound 111b and piperidine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.46

Example 120: 7-Methoxy-2-morpholinocarbonyl 4-morpholinomethyl benzofuran (Compound 120)

 Compound 120 was obtained as colorless crystals using compound 111b and morpholine in the same manner as in Example 11-11.

Rf (CHCl ₃ : MeOH = 9: l); 0.69

Example 121: 4-Methylaminomethyl-7-methoxy-N- (2-phenylethyl) benzofuran-1-carboxamide (Compound 121)

 According to the same method as in Example 1, 7-methoxybenzofuran-2-carboxylic acid was used as a starting compound and reacted with 2-phenethylamine to react with 7-methoxy-N- (2-phenylethyl) benzofuran-1-carboxamide (compound 12 la ) And formylation to give 4-formyl-7-methoxy-N- (2-phenylethyl) benzofuran-2-carpoxamide (compound 12 lb), which is reacted with methylamine-1 hydrochloride to give compound 121 Was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.14

Example 122: 4-Ethylaminomethyl-7-methoxy-N- (2-phenylethyl) benzofuran-2-carboxamide (Compound 122)

 In the same manner as in Example 121, compound 122 was obtained as colorless crystals using compound 121b and ethylamine monohydrochloride.

Rf (CHCl ₃ : MeOH = 9: l); 0.21

Example 123: 7-Methoxy-N- (2-phenylethyl) 1-41-propyla Minomethylbenzofuran-2-force lpoxamide (Compound 123) In the same manner as in Example 121, Compound 123 was obtained as colorless crystals using Compound 121b and n-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.29

Example 124: 7-Methoxy-N- (2-phenylethyl) 1-141 (2-propylaminomethyl) benzofuran-1-carboxamide (Compound 124) Compounds 12 1b and 2 were prepared in the same manner as in Example 121. Compound 124 was obtained as colorless crystals using propylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.34

Example 125: 4-butylaminomethyl-7-methoxy-N- (2-phenylethyl) benzofuran-2-carboxamide (Compound 125)

 By a method similar to that of Example 121, Compound 125 was obtained as colorless crystals using Compound 121b and n-butylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.37

Example 126: 4-Cyclobutylaminomethyl-7-methoxy-N- (2-phenylethyl) benzofuran-1-2-propoxamide (Compound 126)

 In the same manner as in Example 121, compound 126 was obtained as colorless crystals using compound 121b and cyclobutylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.26

Example 127: 4-cyclopentylaminomethyl-N- (2-phenylethyl) —7-methoxybenzofuran-2-carboxamide (Compound 127) In the same manner as in Example 121, compound 121b and cyclopentylamido were prepared. Compound 127 was obtained as colorless crystals using the compound.

_{Rf (CHCl 3: MeOH = 9} : l); 0.37

Example 128: 4-Cyclohexylaminomethyl-7-methoxy-1-N- (2-phenylethyl) benzofuran-2-carboxamide (Compound 128)

Compound 121b and cyclohexylamido were prepared in the same manner as in Example 121. Compound 128 was obtained as colorless crystals using the compound.

Rf (CHCl ₃ : MeOH = 9: l); 0.63

Example 129: 4-Cyclooctylaminomethyl-7-methoxy-1-N- (2-phenylethyl) benzofuran-2-carboxamide (Compound 129)

 By a method similar to that of Example 121, compound 129 was obtained as colorless crystals using compound 121b and cyclooctylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.26

Example 130: 7-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) -N- (2-phenylethyl) benzofuran-2-carboxamide

 In the same manner as in Example 121, compound 130 was obtained as colorless crystals using compound 121b and 2,3-dimethylcyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.38

Example 131: 4-Benzylaminomethyl-7-methoxy-N- (2-phenylethyl) benzofuran-1-carpoxamide (Compound 131)

 By a method similar to that of Example 121, compound 131 was obtained as colorless crystals using compound 121b and benzylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.64

Example 132: N- (2-phenylethyl) -7-methoxy-4-piperidinomethylbenzofuran-2-carboxamide (Compound 132)

 In the same manner as in Example 121, compound 132 was obtained as colorless crystals using compound 121b and piperidine.

Rf (CHCl ₃ : MeOH = 9: l); 0.60

Example 133: 7-methoxy-N- (2-phenylethyl) -4-morpholinomethylbenzofuran-2-carboxamide (Compound 133)

By a method similar to that of Example 121, Compound 133 was obtained as colorless crystals using Compound 121b and morpholine. ος

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£ 8Ό ί (χ: 6 = Η09Ν: ^£ DHD) JH ZlZtO /, 6df / X3J Zi Zme O Compound 137 was obtained as colorless crystals using thiamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.54

Example 138: 7-Methoxy-N- (2-phenylethyl) -4-1 (3-phenylpropylaminomethyl) benzofuran-2-caproloxamide (Compound 138)

 By a method similar to that of Example 121, compound 138 was obtained as colorless crystals using compound 121b and 3-phenylpropylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.46

Example 139: 7-Methoxy-N- (2-phenylethyl) 1-4- [2- (2-pyridyl) ethylaminomethyl] benzofuran-2-carpoxamide (Compound

139)

 Compound 139 was obtained as colorless crystals using compound 12 lb and 2 _ (2-pyridyl) ethylamine in the same manner as in Example 121.

_{Rf (CHC1 3: MeOH = 9} : l); 0.29

Example 140: 7-Methoxy-N- (2-phenylethyl) -14- (2-morpholinoethylaminomethyl) benzofuran-1-carpoxamide (Compound 140)

 In the same manner as in Example 121, Compound 140 was obtained as colorless crystals using Compound 121b and 2-morpholinoethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.29

Example 141: 4-Methylaminomethyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-2-caproloxamide (Compound 141)

 In the same manner as in Example 1, 7-methoxybenzofuran-2-carboxylic acid was used as a starting compound to react with 11- (S) -phenethylamine to react with 7-methoxy-N- [1- (S) -phenylethyl] benzofuran. I 2- 2-Lupoxamide (compound

141 a) and further formylated to form 4-formyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-2-carboxamide (Compound 141 After b) was obtained, it was reacted with methylamine'1 hydrochloride to give Compound 141 as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.11

Example 142: 4-Ethylaminomethyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-2-caproloxamide (Compound 142)

 By a method similar to that of Example 141, compound 142 was obtained as colorless crystals using compound 141b and ethylethylamine hydrochloride.

_{Rf (CHCl 3: MeOH = 9} : l); 0.17

Example 143: 7-Methoxy-N- [1- (S) -phenylethyl] —4-heppyraminomethylpentazofuran-21-Lupoxamide (Compound 143) Compound 141b was prepared in the same manner as in Example 141. Compound 143 was obtained as colorless crystals using and n-propylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.34

Example 144: 7-Methoxy-N- [1- (S) -phenylethyl] —4- (2-propylaminomethyl) benzofuran-2-carboxamide (Compound 144)

 By a method similar to that of Example 141, compound 144 was obtained as colorless crystals using compound 141b and 2-propylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.31

Example 145: 4-butylaminomethyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-2-carboxamide (Compound 145)

 By a method similar to that of Example 141, compound 145 was obtained as colorless crystals using compound 141b and n-butylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.31

Example 146: 4-cyclobutylaminomethyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-2-carpoxamide (Compound 146) Compound 141b and cyclobutyla were prepared in the same manner as in Example 141. Min Was used to obtain Compound 146 as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.23

Example 147: 4-Cyclopentylaminomethyl_7-methoxy-N— [1- (S) -phenylethyl] benzofuran-1-carboxamide (Compound 147) Compound 141b and cyclopentylamine were obtained in the same manner as in Example 141. Compound 147 was obtained as colorless crystals by using.

_{Rf (CHCl 3: MeOH = 9} : l); 0.43

Example 148: 4-Cyclohexylaminomethyl-N- [1- (S) -phenyl-2-ethyl] _7-methoxybenzofuran-2-carboxamide (Compound 148) Compound 141 was prepared in the same manner as in Example 141. Compound 148 was obtained as colorless crystals using b and cyclohexylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.43

Example 149: 4-Cyclooctylaminomethyl-7-methoxy-N-tl-CS) -phenylethyl] benzofuran-2-caproloxamide (Compound 149) In the same manner as in Example 141, compound 141b and cyclohexane Compound 149 was obtained as colorless crystals using octylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.26

Example 150: 7-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) —N— [1- (S) -phenylethyl] benzofuran—2-caproloxamide (Compound 150)

 In the same manner as in Example 141, compound 150 was obtained as colorless crystals using compound 141b and 2,3-dimethylcyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.38

Example 15 5 1: 4-benzylaminomethyl-7-methoxy-N- [1- (S) -phenylethyl] benzofuran-12-caproloxamide (Compound 151) Compound 141b was prepared in the same manner as in Example 141. Compound 151 was obtained as colorless crystals using benzylamine. _{Rf (CHCl 3: MeOH = 9} : l); 0.54

Example 152: N- [1- (S) -phenylethyl] -7-methoxy-4-piperidinomethylbenzofuran-2-carboxamide (Compound 152)

 By a method similar to that in Example 141, compound 152 was obtained as colorless crystals using compound 141b and piperidine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.57

Example 153: 7-Methoxy-N- [1- (S) -phenylethyl] 1-4-morpholinomethylbenzofuran-12-carboxamide (Compound 153)

 In the same manner as in Example 141, compound 153 was obtained as colorless crystals using compound 141b and morpholine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.68

Example 154: 7-Methoxy-N_ [1- (S) -phenylethyl] -4- (1-pyrrolidinylmethyl) benzofuran-1-carboxamide (Compound 154)

 By a method similar to that of Example 141, compound 154 was obtained as colorless crystals using compound 141b and pyrrolidine.

Rf (CHCl ₃ : MeOH = 9: l); 0.15

Example 1 55: N- [1-(S) -phenylethyl] —4- (4-methylpyrazinylmethyl) —7-methoxybenzofuran-1-carboxamide (Compound 155)

 By a method similar to that of Example 141, compound 155 was obtained as colorless crystals using compound 141b and 1-methylbiperazine.

Rf (CHCl ₃ : MeOH = 9: l); 0.23

Example 1 56: 7-Methoxy-N_ [1- (S) -phenylethyl] -1-4_

(2-phenylethylaminomethyl) benzofuran-2-carboxamide (Compound 156)

In the same manner as in Example 141, compound 141b and 2-phenethylamine Compound 156 was obtained as colorless crystals by heating.

_{Rf (CHCl 3: MeOH = 9} : l); 0.42

Example 1 57: 7-Methoxy-N- [1- (S) -phenylethyl] -4-1

 [1- (S) -phenylethylaminomethyl] benzofuran-1-carboxamide (Compound 157)

 By a method similar to that in Example 141, compound 157 was obtained as colorless crystals using compound 14 lb and 1_ (S) -phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.47

Example 158: 7-methoxy-N— [1- (S) —phenylethyl] —4—

(3-Phenylpropylaminomethyl) benzofuran-1-carboxamide (158)

 By a method similar to that in Example 141, compound 158 was obtained as colorless crystals using compound 141b and 3-phenylpropylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.42

Example 159: N- [1- (S) -phenylenyl] -7-methoxy-41

 [2- (2-Pyridyl) ethylaminomethyl] benzofuran-2-pyrupoxamide (Compound 159)

 By a method similar to that of Example 141, compound 159 was obtained as colorless crystals using compound 14 lb and 2- (2-pyridyl) ethylamine.

Rf (CHCI3: MeOH = 9: l); 0.33

Example 160: N- [1- (S) -phenylethyl] _7-methoxy-4-

(2-morpholinoethylaminomethyl) benzofuran-2-carboxamide (compound 160)

 By a method similar to that of Example 141, compound 160 was obtained as colorless crystals using compound 141b and 2-morpholinoethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 161: N- (4-cyclophenyl) -4-cyclobutylaminomethyl 1-71-Methoxybenzofuran-2-carboxamide (Compound 161) In the same manner as in Example 1, using 7-methoxybenzofuran-12-carboxylic acid as a starting compound, reacting with 4-chloroaniline to give N- (4-chlorophenyl) 17-methoxybenzofuran-12-carpoxamide (compound 16 la), and further formylated to give N- (4-chlorophenyl) —4-formyl—7-methoxybenzofuran—2-caproloxamide ( After the compound 161b) was obtained, it was reacted with cyclobutylamine to give compound 161 as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 162: N- (4-chlorophenyl) -4-cyclooctylaminomethyl 7-methoxybenzofuran-2-carboxamide (Compound 162)

 By a method similar to that in Example 161, compound 162 was obtained as colorless crystals using compound 161b and cyclooctylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 163: N- (4-chlorophenyl) -7-methoxy-4- (2,3-dimethylcyclohexylaminomethyl) benzofuran-1-carboxamide (Compound 163)

 By a method similar to that of Example 161, compound 163 was obtained as colorless crystals using compound 16 lb and 2,3-dimethylcyclohexylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.31

Example 164: N- (4-chlorophenyl) -4- (4-methylbiperazinylmethyl) -1-7-methoxybenzofuran-2-carboxamide (Compound 164) Compound 164 was obtained as colorless crystals using 16 1b and 1-methylbiperazinamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.50

Example 165: N- (4-chlorophenyl) -17-methoxy-4- (1-pyrrolidinylmethyl) benzofuran-1-carboxamide (Compound 165)

In the same manner as in Example 161, using compound 16 1b and pyrrolidine Compound 165 was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.19

Example 166: N- (4-chlorophenyl) -7-methoxy-41- (2-phenylethylmethyl) benzofuran-2-carboxamide (Compound 166) Compound 16 1 was prepared in the same manner as in Example 161. Compound 166 was obtained as colorless crystals using b and 2-phenethylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.42

Example 167: N— (4-chlorophenyl) 1-7-methoxy-1 41 [1—

(S) -Phenylethylaminomethyl] benzofuran-1- 2-propoxamide (compound 167)

 By a method similar to that of Example 161, compound 167 was obtained as colorless crystals using compound 16 lb and 1- (S) -phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.56

Example 168: N- (4-cyclophenyl) -17-methoxy-14- (3-phenylpropylaminomethyl) benzofuran-1-carboxamide (compound 168)

 By a method similar to that of Example 161, compound 168 was obtained as colorless crystals using compound 161b and 3-phenylpropylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.56

Example 169: N— (4-chlorophenyl) —4 -— [2- (2-pyridyl) ethylaminomethyl] -17-methoxybenzofuran-1-carboxamide (Compound 169)

 By a method similar to that of Example 161, compound 169 was obtained as colorless crystals using compound 16 lb and 2- (2-pyridyl) ethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.28

Example 170: N- (4-chlorophenyl) -1-7-methoxy-4- (2-morpholinoethylaminomethylbenzofuran-2-force lipoxamide (compound 170) By a method similar to that of Example 161, compound 170 was obtained as colorless crystals using compound 161b and 2-morpholinoyl.

Rf (CHCl ₃ : MeOH = 9: l); 0.25

Example 171: N- (4-t_butylphenyl) -4-cyclobutylaminomethyl-7-methoxybenzofuran-2-carboxamide (Compound 111)

 In the same manner as in Example 1, 7-methoxybenzofuran-12-carboxylic acid was used as a starting compound and reacted with 4-t-butylaniline to react with N- (4-t-butylphenyl) -7-methoxybenzofuran-2. —Carboxamide (compound 17 la) and further formylation to give N_ (4-t-butylphenyl) —4-formyl—7-methoxybenzofuran-12-carboxamide (compound 17 lb), and then react with cyclobutylamine Compound 171 was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.25

Example 172: N- (4-tert-butylphenyl) -4-cyclooctylaminomethyl-7-methoxybenzofuran-1-carboxamide (Compound 172) By the same method as in Example 171, compound 171b and Compound 172 was obtained as colorless crystals using cyclooctylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Example 1 73: N- (4-t-butylphenyl) -17-methoxy-41- (2,3-dimethylcyclohexylaminomethyl) benzofuran-2-force lipoxamide (Compound 173)

 By a method similar to that of Example 171, compound 173 was obtained as colorless crystals using compound 171b and 2,3-dimethylcyclohexylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.36

Example 1 74: N- (4-t-butylphenyl) -7-methoxy-4- (4-methylbiperazinylmethyl) benzofuran-1-carboxamide (Compound 174)

Compound 17 1b and 1-methylbiperazi were prepared in the same manner as in Example 17. Compound 174 was obtained as colorless crystals using the compound.

_{Rf (CHCl 3: MeOH = 9} : l); 0.51

Example 175: N- (4-t-butylphenyl) -17-methoxy-41- (11-pyrrolidinylmethyl) benzofuran-12-carboxamide (Compound 175) A compound was prepared in the same manner as in Example 17-1. Compound 175 was obtained as colorless crystals using 17 1b and pyrrolidine.

Rf (CHCl ₃ : MeOH = 9: l); 0.23

Example 176: N- (4-t-butylphenyl) -7-methoxy-41- (2-phenylethylaminomethyl) benzofuran-1-carboxamide (compound 176)

 Compound 176 was obtained as colorless crystals using compound 171b and 2-phenethylamine in the same manner as in Example 171.

Rf (CHCl ₃ : MeOH = 9: l); 0.50

Example 177: N- (4-t-butylphenyl) -1 7-methoxy-4- [1- (S) -phenylethylaminomethyl) benzofuran-12-carpoxamide (compound 177)

 Compound 177 was obtained as colorless crystals using compound 17 lb and 1- (S) -phenethylamine in the same manner as in Example 171.

_{Rf (CHCl 3: MeOH = 9} : l); 0.64

Example 1 78: N- (4-t-butylphenyl) -17-methoxy-14- (3-phenylpropylaminomethyl) benzofuran-12-caproloxamide (compound 178)

 Compound 178 was obtained as colorless crystals by using the compound 171b and 3-phenylpropylamine in the same manner as in Example 1771.

Rf (CHCl ₃ : MeOH = 9: l); 0.61

Example 179: N- (4-t-butylphenyl) 1 7-methoxy-4- [2- (2-pyridyl) ethylaminomethyl] benzofuran 1-2-caproloxaxamide Compound 179)

 Compound 179 was obtained as colorless crystals using compound 17 lb and 2- (2-pyridyl) eduramine in the same manner as in Example 171.

Rf (CHCl ₃ : MeOH = 9: l); 0.39

Example 180: N- (4-t-butylphenyl) -7-methoxy-4- (2-morpholinoaminomethyl) benzofuran-1-carpoxamide (Compound 180) By a method similar to that in Example 171, compound 171b and Compound 180 was obtained as colorless crystals using 2-morpholinoethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.39

Example 181: 4-cyclobutylaminomethyl-7-methoxy-1-N- (4-methoxyphenyl) benzofuran-1-carboxamide (compound 181)

 In the same manner as in Example 1, 7-methoxybenzofuran-2-carboxylic acid was used as a starting compound and reacted with P-anisidine to react with 7-methoxy-1-N- (4-methoxyphenyl) -1-benzofuran-2- Carboxamide (compound 18 la) and further formylation to give 4-formyl-N- (4-methoxyphenyl) -17-methoxybenzofuran-2-carboxamide (compound 18 lb) were reacted with cyclobutylamine. Compound 181 was obtained as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.23

Example 182: 4-cyclooctylaminomethyl-7-methoxy-N- (4-methoxyphenyl) benzofuran-2-carpoxamide (Compound 182) In the same manner as in Example 181, compound 18 1b and cycloalkyl Compound 182 was obtained as colorless crystals using octylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.31

Example 183: 7-Methoxy-N- (4-methoxyphenyl) -14- (2,3-dimethylcyclohexylaminomethyl) benzofuran-1-carboxamide (Compound 183)

In the same manner as in Example 181, compound 18 1b and 2,3-dimethyl Compound 183 was obtained as colorless crystals using chlorohexylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.34

Example 184: 7-methoxy-N- (4-methoxyphenyl) 1-4- (4-methylpiperazinylmethyl) benzofuran-2-force lipoxamide (Compound 184) A compound was prepared in the same manner as in Example 181. Compound 184 was obtained as colorless crystals using 18 1b and 1-methylbiperazine.

Rf (CHCl ₃ : MeOH = 9: l); 0.21

Example 185: 7-Methoxy-N- (4-methoxyphenyl) -14- (1-pyrrolidinylmethyl) benzofuran-2-carboxamide (Compound 185)

 Compound 185 was obtained as colorless crystals using compound 181b and pyrrolidine in the same manner as in Example 181.

Rf (CHCl ₃ : MeOH = 9: l); 0.14

Example 186: 7-methoxy-1-N- (4-methoxyphenyl) -14- (2-phenylethylaminomethyl) benzofuran-2-carboxamide (compound 186)

 By a method similar to that in Example 181, compound 186 was obtained as colorless crystals using compound 181b and 2-phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.54

Example 187: 7-methoxy-N- (4-methoxyphenyl) -4-1

(S) -phenylethylaminomethyl] benzofuran-2-carboxamide (compound 187)

 Compound 187 was obtained as colorless crystals using compound 18 lb and 1- (S) -phenethylamine in the same manner as in Example 181.

Rf (CHCl ₃ : MeOH = 9: l); 0.63

Example 188: 7-Methoxy-N- (4-methoxyphenyl) -4- (3-phenylpropylaminomethyl) benzofuran-1-2-propanolamide (Compound 188) By a method similar to that of Example 181, compound 1888 was obtained as colorless crystals using compound 181b and 3-phenylpropylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.41

Example 18 9: 7-methoxy-N- (4-methoxyphenyl) —4— [2-

(2-Pyridyl) ethylaminomethyl] benzofuran-1-carboxamide (compound 1889)

 By a method similar to that of Example 181, compound 1889 was obtained as colorless crystals using compound 18lb and 2_ (2-pyridyl) ethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.24

Example 190: 7-Methoxy-N- (4-methoxyphenyl) _4-1 (2-morpholinoethylaminoethyl) benzofuran-1-carboxamide (Compound 190)

 By a method similar to that of Example 181, compound 190 was obtained as colorless crystals using compound 181b and 2-morpholinoethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.24

Example 19 9 1: 4-cyclobutylaminomethyl-7-methoxy-N- (2-methoxyphenyl) benzofuran-12-carpoxamide (compound 1991)

 In the same manner as in Example 1, 7-methoxybenzofuran-12-carboxylic acid was used as a starting compound and reacted with o-anisidine to react with 7-methoxy-N- (2-methoxyphenyl) -benzofuran-12_. Carboxamide (compound 19 la) and further formylation to give 4-formyl-N- (2-methoxyphenyl) -17-methoxybenzofuran-2_caprolupoxamide (compound 191b) followed by cyclobutylamine To give compound 191 as colorless crystals.

Rf (CHCl ₃ : MeOH = 9: l); 0.24

Example 192: 4-Cyclooctylaminomethyl_7-methoxy-N- (2-methoxyphenyl) benzofuran-2-carpoxamide (Compound 192) Compound 19 in the same manner as in Example 19 1b and cyclooctylami Compound 192 was obtained as colorless crystals using the compound.

_{Rf (CHC1 3: MeOH = 9} : l); 0.24

Example 193: 7-Methoxy-N- (2-methoxyphenyl) -4- (2,3-dimethylcyclohexylaminomethyl) benzofuran-1-carboxamide (Compound 193)

 By a method similar to that in Example 191, compound 193 was obtained as colorless crystals using compound 19 lb and 2,3-dimethylcyclohexylamine.

_{Rf (CHC1 3: MeOH = 9} : l); 0.31

Example 194: 7-methoxy-N- (2-methoxyphenyl) -4-1 (4-methylpiperazinylmethyl) benzofuran-2-carboxamide (Compound 194) A compound was prepared in the same manner as in Example 191. Compound 194 was obtained as colorless crystals using 191b and 1-methylbiperazine.

Rf (CHCl ₃ : MeOH = 9: l); 0.19

Example 195: 7-Methoxy-1-N- (2-methoxyphenyl) -4- (1-pyrrolidinylmethyl) benzofuran-12-caproloxamide (Compound 195) Compound 191 was obtained in the same manner as in Example 191. Compound 195 was obtained as colorless crystals using b and pyrrolidine.

Rf (CHCl ₃ : MeOH = 9: l); 0.12

Example 196: 7-Methoxy-1-N- (2-methoxyphenyl) -1-41- (2-phenylethylaminomethyl) benzofuran-2-carpoxamide (Compound 196)

 By a method similar to that in Example 191, compound 196 was obtained as colorless crystals using compound 191b and 2-phenethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.50

Example 197: 7-Methoxy-N- (2-methoxyphenyl) 1-4_ [1-1

(S) -Phenylethylaminomethyl] benzofuran-2-carboxamide (Compound 197) By a method similar to that of Example 191, compound 197 was obtained as colorless crystals using compound 19 lb and 1- (S) -phenethylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.58

Example 1 98: 7-Methoxy-1-N- (2-methoxyphenyl) -14- (3-phenylpropylaminomethyl) benzofuran-1-carboxamide (Compound 198)

 By a method similar to that in Example 191, compound 198 was obtained as colorless crystals using compound 191b and 3_phenylpropylamine.

_{Rf (CHCl 3: MeOH = 9} : l); 0.55

Example 199: 7-Methoxy-N- (2-methoxyphenyl) -4-1 [2-

(2-Pyridyl) ethylaminomethyl] benzofuran-2-carboxamide (Compound 199)

 Compound 199 was obtained as colorless crystals in the same manner as in Example 191 using compound 191b and 2- (2-pyridyl) ethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.29

Example 200: 7-Methoxy-N- (2-methoxyphenyl) benzofuran-4- (2-morpholinoethylaminoethyl) -2-carboxamide (Compound 200)

 In the same manner as in Example 191, compound 200 was obtained as colorless crystals using compound 191b and 2-morpholinoethylamine.

Rf (CHCl ₃ : MeOH = 9: l); 0.33

Industrial applicability

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

Claims

The scope of the claims

 1. Formula (I)

(In the formula, R ¹ represents hydrogen or substituted or unsubstituted lower alkyl, and R ² , R ³ and R ⁴ are the same or different and are hydrogen, halogen, lower alkyl, cycloalkyl, substituted or unsubstituted Aryl, substituted or unsubstituted aralkyl, hydroxy, substituted or unsubstituted lower alkoxy, lower alkanoyloxy, substituted or unsubstituted lower alkanol, substituted or unsubstituted cycloalkyl propyl, lower alkoxycarbonyl Or R ^5a is hydrogen, substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted Represents a substituted aralkyl or a substituted or unsubstituted heteroarylalkyl. And R ^5b is a substituted or unsubstituted lower alkyl, cycloalkyl, polycycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted aromatic heterocyclic group, substituted or unsubstituted aralkyl, or substituted or unsubstituted Or R ^5a and R ^5b together represent a substituted or unsubstituted heterocyclic group formed containing N, and R ^6a and R ^6b are the same or different, and Represents hydrogen, substituted or unsubstituted lower alkyl, substituted or unsubstituted heteroarylalkyl, or substituted or unsubstituted aralkyl, or R ^fia and R ^6b are linked together to form a substituted or unsubstituted N A benzofuran derivative represented by the formula: or a pharmacologically acceptable salt thereof.