JPH09124633A - Benzofuran derivative useful as bone resorption suppressing agent and production thereof - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a new benzofuran derivative useful as a bone resorption suppressing agent and a bone metastasis suppressing agent for the prevention and treatment of bone diseases characterized by bone dysbolism such as osteoporosis. SOLUTION: The objective compound is expressed by the formula I (R<1> is formyl, a carbomyl-lower alkyl, a thiomorpholinocarbonyl-lower alkyl-S-oxide, a pyridylaminocarbonyl-lower alkyl, etc.; R<2> is a lower alkyl, a protected carboxy, etc.; R<3> is a halogen or a lower alkyl; R<4> is H, nitro, etc.; R<5> is a halogen, a lower alkyl, etc.) or its salt, e.g. 7-(2,6-dichlorobenzoylamino)-2- ethoxycarbonyl-3-methylbenzo[b]furan. The compound of the formula I can be produced by reacting a compound of the formula II, its reactive derivative at the carboxyl group or their salts with a compound of the formula III or its reactive derivative at the amino group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel benzofuran derivative useful as a bone resorption inhibitor and a salt thereof, which is useful in the field of medicine.

[0002]

2. Description of the Related Art A thionaphthene-2-carboxylic acid derivative and 3-phenyl-4H-1-benzopyran which inhibit bone resorption are disclosed in Japanese Patent Application Publication No. 48924/1985 and Japanese Patent No. 54379/1985. 4-one derivatives are disclosed. However, the compounds proposed to date do not always give sufficient effects, and there is a demand for the development of compounds showing even more excellent effects.

[0003]

DISCLOSURE OF THE INVENTION The present invention is an agent for suppressing bone resorption and an agent for suppressing bone metastasis, which is osteoporosis in human or animal (particularly postmenopausal osteoporosis): hypercalcemia; hyperparathyroidism; Bone disease; osteolysis; malignant hypercalcemia with or without bone metastasis; rheumatoid arthritis; periodontitis; osteoarthritis; bone pain; osteopenia; cancer cachexia; It is intended to provide a novel benzofuran derivative and a salt thereof which are useful for preventive and / or therapeutic treatment of bone diseases.

[0004]

The benzofuran derivative of the present invention is new and can be represented by the following general formula (I):

[0005]

Embedded image

[Wherein R ¹ is formyl, carbamoyl lower alkyl, thiomorpholinocarbonyl lower alkyl,
Thiomorpholinocarbonyl lower alkyl S-oxide,
Pyridylaminocarbonyl lower alkyl, pyrazolylaminocarbonyl lower alkyl, triazolylaminocarbonyl lower alkyl, quinolylaminocarbonyl lower alkyl which may have one or more appropriate substituents, 3
-Pyridyl lower alkylaminocarbonyl lower alkyl, 4-pyridyl lower alkylaminocarbonyl lower alkyl, pyridylethylaminocarbonyl lower alkyl, pyridyl lower alkylaminocarbonyl lower alkyl N-oxide, benzimidazolyl lower alkylaminocarbonyl lower alkyl, N-pyridyl lower Alkyl-N-acyl lower alkylaminocarbonyl lower alkyl, N-pyridyl-N-lower alkylaminocarbonyl lower alkyl, lower alkylaminocarbonyl lower alkyl, dilower alkylaminocarbonylmethyl, quinolyl, 2-hydroxyethyl, 2-hydroxy- 2-methylpropyl, cyano lower alkyl, di lower alkylamino lower alkyl, pyridyl lower alkyl, triazolyl lower alkyl, 1 or more Of pyrazolyl lower alkyl optionally having substituents, pyrimidinyl lower alkyl optionally having one or more suitable substituents, optionally having one or more suitable substituents of Dihydrophthalazinyl lower alkyl, oxadiazolyl lower alkyl optionally having one or more suitable substituents, heterocyclic lower alkenyl optionally having one or more suitable substituents,
Lower alkoxy lower alkylamino lower alkyl optionally having one or more suitable substituents, aryl lower alkylaminocarbonyl lower alkyl optionally having one or more suitable substituents, one or more Arylaminocarbonyl lower alkyl optionally having substituent (s), arylthio lower alkyl optionally having one or more suitable substituent (s), lower alkyl or imidazolyl lower alkyl, R ² is lower alkyl , Protected carboxy or cyano, R ³ is halogen or lower alkyl, R ⁴ is hydrogen, nitro or amino and R ⁵ is halogen, lower alkyl or nitro. Provided that 1) when R ¹ is methyl, R ² is protected carboxy or cyano; and 2) when R ¹ is imidazolylmethyl, R ² is protected carboxy or cyano. ] And its salts.

The object compound (I) or a salt thereof can be produced by the method represented by the following reaction formula. Method 1

[0008]

Embedded image Method 2

[0009]

Embedded image

Where R ¹ , R ² , R ³ , R ⁴ and R
⁵ is each as defined above, Z is pyridyl, pyrazolyl, triazolyl, quinolyl optionally having one or more suitable substituents, 3-pyridyl lower alkyl, 4
-Pyridyl lower alkyl, pyridyl ethyl, pyridyl lower alkyl N-oxide, benzimidazolyl lower alkyl, aryl lower alkyl optionally having one or more suitable substituents, or one or more suitable substituents Optionally aryl, R ¹ _a is pyridylaminocarbonyl lower alkyl, pyrazolylaminocarbonyl lower alkyl, triazolylaminocarbonyl lower alkyl, quinolylaminocarbonyl lower optionally having one or more suitable substituents. Alkyl, 3-pyridyl lower alkylaminocarbonyl lower alkyl, 4-pyridyl lower alkylaminocarbonyl lower alkyl, pyridylethylaminocarbonyl lower alkyl, pyridyl lower alkylaminocarbonyl lower alkyl N-oxide, benzimidazolyl low Primary alkylaminocarbonyl lower alkyl, aryl lower alkylaminocarbonyl lower alkyl optionally having one or more suitable substituents, or arylaminocarbonyl lower alkyl optionally having one or more suitable substituents And A is lower alkylene.

Suitable salts of the object compound (I) are pharmaceutically acceptable conventional non-toxic salts such as salts with inorganic bases such as alkali metal salts (eg sodium salt, potassium salt etc.). ), Alkaline earth metal salts (eg calcium salt, magnesium salt etc.), ammonium salt etc .; salts with organic bases, eg organic amine salts (eg triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt) , Dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, etc.); inorganic acid addition salt (eg, hydrochloride, hydrobromide, sulfate, phosphate, etc.); organic carboxylic acid or sulfonic acid addition salt (eg, Formate, acetate, trifluoroacetate, maleate, tartrate, fumarate, methanesulfo Acid salts, benzene sulfonates, toluene sulfonates, etc.); salts with bases or acid addition salts, such as salts with basic or acidic amino acids (eg arginine, aspartic acid, glutamic acid, etc.).

Suitable examples of the various definitions that this invention is intended to include within the scope of the above and below description of the present specification are explained in detail below. The term "lower" is used to describe a group having 1 to 6 carbon atoms unless otherwise specified. Suitable examples of "one or more" include 1 to
The number of 6 is mentioned, and among them, the number of 1 to 4 is preferable.

Suitable "lower alkyl" and "lower alkyl" moieties include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, 3-pentyl, isopentyl, tertiary. Examples thereof include linear or branched ones having 1 to 6 carbon atoms, such as primary pentyl, neopentyl, hexyl and isohexyl, and those having 1 to 5 carbon atoms are preferable.

Suitable "lower alkenyl" and "lower alkenyl" moieties include vinyl, 1- (or 2-).
Propenyl, 1- (or 2- or 3-) butenyl,
1- (or 2- or 3- or 4-) pentenyl,
1- (or 2-or 3-or 4-or 5-) hexenyl, methylvinyl, ethylvinyl, 1- (or 2-or 3-) methyl-1- (or 2-) propenyl, 1- (or 2-) Or 3-) ethyl-1- (or 2-) propenyl, 1- (or 2- or 3- or 4-) methyl-1- (or 2- or 3-) butenyl and the like can be mentioned.

Suitable "lower alkoxy" is methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t.
-Pentyloxy, hexyloxy and the like.
Suitable "aryl" and "aryl" moieties include:
Examples include phenyl, naphthyl and anthryl.

Suitable "lower alkylene" includes straight chain or branched chain such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, methylmethylene, ethylethylene and ethylpropylene. .

Suitable "halogen" and "halo" moieties include fluorine, bromine, chlorine and iodine.

Suitable "acyl" moieties include carbamoyl, aliphatic acyl groups, acyl groups containing an aromatic ring (referred to as aromatic acyl) and acyl groups containing a heterocycle (referred to as heterocyclic acyl). Suitable examples of the acyl are as follows: carbamoyl; carboxy;
Aliphatic acyl such as lower or higher alkanoyl (eg formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2
-Dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc .; cyclo-lower alkyl For example, cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl, cyclohexylcarbonyl, etc .; protected carboxy, eg protected carboxy by conventional methods [eg esterified carboxy, eg lower or higher alkoxycarbonyl (eg methoxycarbonyl, ethoxy) Carbonyl, propyloxycarbonyl, isopropyloxycarbonyl, t-butoxy Carbonyl, t-pentyloxycarbonyl, hexyl oxycarbonyl), etc.]
Etc .; lower or higher alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.); lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.); di-lower alkoxyphosphoryl (eg, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, di Butoxyphosphoryl, dipentyloxyphosphoryl, dihexyloxyphosphoryl, etc.);

Aromatic acyls such as aroyl (eg benzoyl, toluoyl, naphthoyl, etc.); Ar lower alkanoyls [eg phenyl lower alkanoyls (eg phenylacetyl, phenylpropanoyl,
Phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl lower alkanoyl (eg, naphthylacetyl, naphthylpropanoyl, naphthylbutanoyl, etc.)];
Al-lower alkenoyl [eg phenyl-lower alkenoyl (eg phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl etc.), naphthyl-lower alkenoyl (eg naphthylpropenoyl, naphthylbutenoyl etc.) Etc.]; Ar lower alkoxycarbonyl [eg phenyl lower alkoxycarbonyl (eg benzyloxycarbonyl etc.)]; Aryloxycarbonyl (eg phenoxycarbonyl, naphthyloxycarbonyl etc.); Aryloxy lower alkanoyl) (eg phenoxyacetyl, phenoxypropionyl etc. ); Arylcarbamoyl (eg, phenylcarbamoyl, etc.); Arylthiocarbamoyl (eg, phenyl Okarubamoiru etc.); aryl glyoxyloyl yl (e.g. phenyl glyoxyloyl yl, etc. naphthyl glyoxyloyl yl); arylsulfonyl (e.g. phenylsulfonyl, etc. p- tolyl sulfonyl); and.

Heterocyclic acyl, for example, heterocyclic carbonyl; heterocyclic lower alkanoyl (for example, heterocyclic acetyl, heterocyclic propanoyl, heterocyclic butanoyl, heterocyclic pentanoyl, heterocyclic hexanoyl, etc.); heterocyclic lower alkenoyl (for example, heterocyclic propenoyl, Heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.); heterocyclic glyoxyloyl; etc. Suitable "heterocycle" and "heterocycle" moieties include saturated or unsaturated monocyclic or polycyclic heterocycles containing at least one heteroatom such as oxygen, sulfur or nitrogen. To be Particularly preferred are unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic groups containing 1 to 4 nitrogen atoms, such as pyrrolyl, pyrrolinyl,
Imidazolyl, pyrazolyl, pyridyl, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (eg 4H-1,2,4-triazolyl, 1H
-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc.), tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.), etc .; saturated 3-8 member containing 1 to 4 nitrogen atoms (More preferably 5 or 6 membered) heteromonocyclic groups such as pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl); unsaturated fused heterocyclic groups containing 1 to 4 nitrogen atoms, such as indolyl, isoindolyl, indolinyl, indoridinyl. , Benzimidazolyl, quinolyl, phthalazinyl,
Dihydrophthalazinyl, isoquinolyl, indazolyl,
Benzotriazolyl, phthalimidyl, etc .; Unsaturation 3 containing 1-2 oxygen atoms and 1-3 nitrogen atoms
8-membered (more preferably 5- or 6-membered) heteromonocyclic groups such as oxazolyl, isoxazolyl, oxadiazolyl (eg 1,2,4-oxadiazolyl, 1,3,
4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.); saturated 3-8 member containing 1-2 oxygen atoms and 1-3 nitrogen atoms (more preferably 5 or 6 members)
Members) Heteromonocyclic groups such as morpholinyl, sydnonyl, etc.); Unsaturated fused heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as benzoxazolyl, benzoxazodiazolyl Etc .; unsaturated 3-8 membered (more preferably 5 or 6 membered) heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl (e.g. , 2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl), dihydrothiazinyl, etc .; 1-2 sulfur atoms and 1-3 Saturation containing nitrogen atom 3 ~
8-membered (more preferably 5- or 6-membered) heteromonocyclic group such as thiazolidinyl; unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing 1 to 2 sulfur atoms, For example, thienyl, dihydrodithynyl, dihydrodithionyl, etc .; unsaturated condensed heterocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example, benzothiazolyl, benzothiadiazolyl, etc .; 1 Unsaturated 3- to 8-membered (more preferably 5- or 6-membered) heteromonocyclic group containing an oxygen atom such as furyl, pyranyl, etc .; saturated 3- to 8-membered containing 1 to 2 oxygen atoms (more preferably Is a 5- or 6-membered) heteromonocyclic group such as oxiranyl, oxolanyl, dioxolanyl, tetrahydrofuranyl, etc .; unsaturated 3 containing one oxygen atom and 1-2 sulfur atoms. 8-membered (more preferably 5 or 6
Members) Heteromonocyclic groups such as dihydrooxathiynyl; unsaturated condensed heterocyclic groups containing 1 to 4 oxygen atoms, such as methylenedioxyphenyl, benzodioxanyl; 1 to 2 sulfur atoms An unsaturated fused heterocyclic group containing, for example, benzothienyl, benzodithynyl, etc .; an unsaturated fused heterocyclic group containing one oxygen atom and 1-2 sulfur atoms, such as benzoxathiinyl; A heterocyclic group,

The above "heterocyclic group" and "heterocyclic" moieties are hydroxy; oxo; oxide; amino; halogen (eg fluorine, bromine, chlorine and iodine); lower alkanoyl (eg formyl, acetyl, propanoyl, butanoyl). , 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl etc.); aryl (eg phenyl, naphthyl, anthryl etc.); lower alkyl (eg methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, 3-pentyl, isopentyl, tertiary pentyl, neopentyl, hexyl,
Isohexyl etc.); lower alkoxy (eg methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy, t
-Pentyloxy, hexyloxy, etc.); and may have one or more appropriate substituents such as a heterocyclic group.

Suitable conventional "protected carboxy" includes esterified carboxy and the like. And, as a preferable example of the ester, a lower alkyl ester (for example, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester,
Pentyl ester, t-pentyl ester, hexyl ester etc.); Lower alkenyl ester (eg vinyl ester, allyl ester etc.); Lower alkynyl ester (eg ethynyl ester, propynyl ester etc.); Lower alkoxy lower alkyl ester (eg methoxymethyl ester, Ethoxymethyl ester, isopropoxymethyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.); lower alkylthio lower alkyl ester (eg, methylthiomethyl ester, ethylthiomethyl ester, ethylthioethyl ester, isopropylthiomethyl ester, etc.) A mono (or di or tri) halo lower alkyl ester (eg 2-iodoethyl ester, 2,
2,2-trichloroethyl ester and the like); lower alkanoyloxy lower alkyl ester (eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl ester) Ester, 1-acetoxyethyl ester, 2-acetoxyethyl ester, 2-propionyloxyethyl ester, etc.): lower alkoxycarbonyloxy lower alkyl ester (for example, methoxycarbonyloxymethyl ester, ethoxycarbonyloxymethyl ester, propoxycarbonyloxymethyl ester, t-Butoxycarbonyloxymethyl ester, 1- (or 2-) [methoxycarbonyloxy] ethyl ester , 1- (or 2 -) [ethoxycarbonyloxy] ethyl ester, 1- (or 2
-) [Propoxycarbonyloxy] ethyl ester,
1- (or 2-) [isopropoxycarbonyloxy] ethyl ester and the like); lower alkanesulfonyl lower alkyl ester (eg, mesylmethyl ester,
2-mesylethyl ester etc.); phthalidylidene lower alkyl ester; (5-lower alkyl-2-oxo-
1,3-dioxol-4-yl) lower alkyl ester [eg (5-methyl-2-oxo-1,3-dioxol-4-yl) methyl ester, (5-ethyl-
2-oxo-1,3-dioxol-4-yl) methyl ester, (5-propyl-2-oxo-1,3-dioxol-4-yl) ethyl ester and the like]; ar lower alkyl ester, for example, one or more Optionally substituted phenyl lower alkyl ester (for example, benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, 4-
Hydroxy-3,5-di-t-butylbenzyl ester and the like); aryl ester optionally having one or more suitable substituents, such as substituted or unsubstituted phenyl ester (eg, phenyl ester, tolyl ester,
t-butylphenyl ester, xylyl ester, mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri-lower alkylsilyl ester; lower alkylthioester (eg, methylthioester, ethylthioester, etc.) There are things.

Preferred examples of "acyl" moieties include protected carboxy, with (C ₁ -C ₄ ) alkoxycarbonyl being particularly preferred and ethoxycarbonyl being especially preferred.

Preferable examples of the "lower alkyl" moiety in the expression "carbamoyl lower alkyl" include the above "lower alkyl". Preferred examples of “carbamoyl lower alkyl” include carbamoyl (C
₁ -C ₄₎ alkyl, a preferable one carbamoylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "thiomorpholinocarbonyl lower alkyl" include the above "lower alkyl". A preferable example of “thiomorpholinocarbonyl lower alkyl” is thiomorpholinocarbonyl (C ₁ -C ₄ ) alkyl, and especially preferable is thiomorpholinocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "thiomorpholinocarbonyl lower alkyl S-oxide" include the above "lower alkyl". A preferable example of “thiomorpholinocarbonyl lower alkyl S-oxide” is thiomorpholinocarbonyl (C ₁ -C ₄ ) alkyl S-oxide, and among them, preferable is thiomorpholinocarbonylmethyl S.
-Is an oxide.

Preferable examples of the "lower alkyl" moiety in the expression "pyridylaminocarbonyl lower alkyl" include the above "lower alkyl". A preferable example of “pyridylaminocarbonyl lower alkyl” is pyridylaminocarbonyl (C ₁ -C ₄ ) alkyl, and particularly preferable is pyridylaminocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "pyrazolylaminocarbonyl lower alkyl" include the above "lower alkyl". Preferred examples of “pyrazolylaminocarbonyl lower alkyl” include pyrazolylaminocarbonyl (C ₁ -C
₄ ) Alkyl, especially preferred is pyrazolylaminocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "triazolylaminocarbonyl lower alkyl" include the above "lower alkyl". "Triazolylaminocarbonyl lower alkyl"
A preferred example of is triazolylaminocarbonyl (C ₁
˜C ₄ ) Alkyl, especially preferred is triazolylaminocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "quinolylaminocarbonyl lower alkyl optionally having one or more appropriate substituents" include the above "lower alkyl". You can A preferable example of “quinolylaminocarbonyl lower alkyl” is quinolylaminocarbonyl (C ₁ -C ₄ ) alkyl, and among them, preferable is quinolylaminocarbonylmethyl.

Preferred examples of the "suitable substituent" in the expression "quinolylaminocarbonyl lower alkyl optionally having one or more suitable substituents" include halogen, and among them, preferred. Is bromine.

"Lower alkyl" in the expression "3-pyridyl lower alkylaminocarbonyl lower alkyl"
Preferable examples of the moiety include the above “lower alkyl”. Preferable examples of the "3-pyridyl-lower alkylaminocarbonyl-lower alkyl", 3-pyridyl (C ₁ ~C ₄₎ alkylaminocarbonyl (C ₁ -C
₄ ) Alkyl, especially preferred is 3-pyridylmethylaminocarbonylmethyl.

"Lower alkyl" in the expression "4-pyridyl lower alkylaminocarbonyl lower alkyl"
Preferable examples of the moiety include the above “lower alkyl”. Preferable examples of the "4-pyridyl-lower alkylaminocarbonyl-lower alkyl", 4-pyridyl (C ₁ ~C ₄₎ alkylaminocarbonyl (C ₁ -C
₄ ) Alkyl, especially preferred is 4-pyridylmethylaminocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "pyridylethylaminocarbonyl lower alkyl" include the above "lower alkyl". A preferable example of “pyridylethylaminocarbonyl lower alkyl” is pyridylethylaminocarbonyl (C ₁ -C ₄ ) alkyl, and particularly preferable is pyridylethylaminocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "pyridyl lower alkylaminocarbonyl lower alkyl N-oxide" include the above "lower alkyl". A preferable example of “pyridyl lower alkylaminocarbonyl lower alkyl N-oxide” is pyridyl (C ₁ -C ₄ ) alkylaminocarbonyl (C ₁ -C ₄ ) alkyl N-oxide, and among them, preferable is pyridylmethylamino. Carbonylmethyl N-oxide.

Preferable examples of the "lower alkyl" portion in the expression "benzimidazolyl lower alkylaminocarbonyl lower alkyl" include the above "lower alkyl". Preferred examples of “benzimidazolyl lower alkylaminocarbonyl lower alkyl” are benzimidazolyl (C ₁ -C ₄ ) alkylaminocarbonyl (C ₁ -C ₄ ) alkyl, and among these, preferred is benzimidazolylmethylaminocarbonylmethyl. Is.

Preferable examples of the "lower alkyl" moiety in the expression "N-pyridyl lower alkyl-N-acyl lower alkylaminocarbonyl lower alkyl" include the above "lower alkyl". Preferable examples of the "acyl" moiety in the expression "N-pyridyl lower alkyl-N-acyl lower alkylaminocarbonyl lower alkyl" include the aforementioned "acyl" moiety, and among them, preferred is carbamoyl or Lower alkoxycarbonyl, especially preferred is carbamoyl or ethoxycarbonyl. "N-
Preferred examples of the pyridyl lower alkyl -N- acyl-lower alkylaminocarbonyl-lower alkyl ", N- pyridyl (C ₁ ~C ₄₎ alkyl -N- carbamoyl (C ₁ ~
C ₄₎ alkylaminocarbonyl (C ₁ ~C ₄₎ alkyl or N- pyridyl (C ₁ ~C ₄₎ alkyl -N- lower alkoxycarbonyl (C ₁ ~C ₄₎ alkylaminocarbonyl (C ₁ ~C ₄₎ alkyl And especially preferred is N-pyridylmethyl-N-carbamoylmethylaminocarbonylmethyl or N-pyridylmethyl-N-ethoxycarbonylmethylaminocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "N-pyridyl-N-lower alkylaminocarbonyl lower alkyl" include the above "lower alkyl". A preferable example of “N-pyridyl-N-lower alkylaminocarbonyl lower alkyl” is N-pyridyl-N- (C ₁ -C ₄ ) alkylaminocarbonyl (C ₁ -C ₄ ) alkyl, and among them, preferable. Is N-pyridyl-N-methylaminocarbonylmethyl.

“Lower alkylaminocarbonyl lower alkyl
Preferred "lower alkyl" moieties in the expression "kill"
As examples, mention may be made of the above-mentioned "lower alkyl".
Wear. "Lower alkylaminocarbonyl lower alkyl"
A preferred example of₁~ C _Four) Alkylaminocarb
Nil (C₁~ C_Four) Alkyl, especially preferred
Is methylaminocarbonylmethyl.

Preferable examples of the "lower alkyl" moiety in the expression "di-lower alkylaminocarbonylmethyl" include the above-mentioned "lower alkyl". A preferable example of “di-lower alkylaminocarbonylmethyl” is di (C ₁ -C ₄ ) alkylaminocarbonylmethyl, and among them, dimethylaminocarbonylmethyl is preferable.

Preferred examples of "cyano lower alkyl" are:
Cyano (C ₁ -C ₄ ) alkyl, of which cyanomethyl is preferred.

Preferable examples of the "lower alkyl" moiety in the expression "pyridyl lower alkyl" include the above "lower alkyl". A preferable example of “pyridyl lower alkyl” is pyridyl (C ₁ -C ₄ ).
Alkyl, especially preferred is pyridylethyl.

Preferable examples of the "lower alkyl" moiety in the expression "triazolyl lower alkyl" include the above "lower alkyl". Preferred examples of “triazolyl lower alkyl” include triazolyl (C
₁ -C ₄₎ alkyl, in which preferable one is triazolylmethyl.

Suitable examples of the "lower alkyl" moiety in the expression "pyrazolyl lower alkyl optionally having one or more appropriate substituents" include the above "lower alkyl". A preferred example of "pyrazolyl lower alkyl" in the expression "pyrazolyl lower alkyl optionally having one or more suitable substituents" is pyrazolyl (C ₁ -C ₄ ) alkyl, and among them, preferred is It is pyrazolylmethyl. A preferred example of "suitable substituent" in the expression "pyrazolyl lower alkyl optionally having one or more suitable substituents" is hydroxy or lower alkyl, and particularly preferred is hydroxy or methyl. is there.

Suitable examples of the "lower alkyl" moiety in the expression "pyrimidinyl lower alkyl optionally having one or more appropriate substituents" include the above "lower alkyl". A preferred example of “pyrimidinyl lower alkyl” in the expression “pyrimidinyl lower alkyl optionally having one or more suitable substituents” is pyrimidinyl (C ₁ -C ₄ ) alkyl,
Of these, pyrimidinylmethyl is preferred. "1
Preferred examples of "suitable substituents" in the expression "pyrimidinyl lower alkyl optionally having one or more suitable substituents" are hydroxy, amino or lower alkyl, and among them, preferred is hydroxy, amino or It is methyl.

Preferable examples of the "lower alkyl" moiety in the expression "dihydrophthalazinyl lower alkyl optionally having one or more suitable substituents" include the above "lower alkyl". You can Preferred examples of "dihydrophthalazinyl lower alkyl" in the expression "dihydrophthalazinyl lower alkyl optionally having one or more suitable substituents" include dihydrophthalazinyl (C ₁ -C ₄ ). Alkyl, especially preferred is dihydrophthalazinylmethyl. A preferred example of "suitable substituent" in the expression "dihydrophthalazinyl lower alkyl optionally having one or more suitable substituents" is oxo.

Suitable examples of the "lower alkyl" moiety in the expression "oxadiazolyl lower alkyl optionally having one or more suitable substituents" include the above "lower alkyl". Preferred examples of "oxadiazolyl lower alkyl" in the expression "oxadiazolyl lower alkyl optionally having one or more suitable substituents" include oxadiazolyl (C ₁ -C ₄ ).
Alkyl, especially preferred is oxadiazolylmethyl. Preferred examples of "suitable substituents" in the expression "oxadiazolyl lower alkyl optionally having one or more suitable substituents" are the above-mentioned "heterocyclic groups", and among them, preferred is 1 Unsaturated 5- or 6-membered heteromonocyclic groups containing 4 to 4 nitrogen atoms, particularly preferred is pyridyl.

Preferable examples of the "heterocycle" moiety in the expression "heterocycle lower alkenyl which may have one or more appropriate substituents" include the above-mentioned "heterocycle" moiety. Of these, preferred is an unsaturated 5- or 6-membered heteromonocyclic group containing 1 to 4 nitrogen atoms, and particularly preferred is pyridyl. Suitable examples of the "lower alkenyl" moiety in the expression "heterocyclic lower alkenyl optionally having one or more appropriate substituents" include the above-mentioned "lower alkenyl". Preferred examples of “heterocycle lower alkenyl” are heterocycle (C ₂ -C ₄ ) alkenyl, of which pyridylvinyl and pyridyl-2-propenyl are particularly preferred.

"Lower alkoxy lower alkylamino lower alkyl optionally having one or more suitable substituents"
Suitable examples of the "lower alkyl" moiety in the expression include the above "lower alkyl".
Preferred examples of "lower alkoxy lower alkylamino lower alkyl" include (C ₁ -C ₄ ) alkoxy (C ₁ -C ₄ ).
C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl,
Among them, methoxyethylaminomethyl is preferable. Preferred examples of "suitable substituents" are lower alkyl, especially preferred is (C ₁ -C ₄ ) alkyl, and particularly preferred is methyl.

“Even if it has one or more suitable substituents,
Good aryl lower alkylaminocarbonyl lower alk
Preferred examples of "lower alkyl" moiety in the expression "ru"
Can include the above-mentioned "lower alkyl".
You. "Aryl lower alkylaminocarbonyl lower alkyl
A preferable example of "kill" is aryl (C₁~ C_Four) Archi
Luaminocarbonyl (C₁~ C_Four) It ’s an alkyl,
Of these, preferred is phenyl (C₁~ C_Four) Alkyria
Minocarbonyl (C ₁~ C_Four) Alkyl, especially
Preferred is benzylaminocarbonylmethyl.
“Aryl optionally having one or more suitable substituents
Lower alkylaminocarbonyl lower alkyl "
Preferred examples of "suitable substituents" in are:
Is trihalo lower alkyl, and among them, preferred is
Sulfamoyl or trihalo (C₁~ C_Four) Alkyl
And particularly preferred is sulfamoyl or tris
It is fluoromethyl.

Suitable examples of the "lower alkyl" moiety in the expression "arylaminocarbonyl lower alkyl optionally having one or more suitable substituents" include the above "lower alkyl". it can. Preferred examples of “arylaminocarbonyl lower alkyl” are arylaminocarbonyl (C ₁ -C ₄ ) alkyl, especially preferred is phenylaminocarbonyl (C ₁ -C ₄ ) alkyl, and particularly preferred is phenyl. Aminocarbonylmethyl. Preferred examples of "suitable substituents" in the expression "arylaminocarbonyl lower alkyl optionally having one or more suitable substituents" are hydroxy or carbamoyl.

Suitable examples of the "lower alkyl" moiety in the expression "arylthio lower alkyl optionally having one or more suitable substituents" include the above "lower alkyl". A preferred example of "arylthio lower alkyl" in the expression "arylthio lower alkyl optionally having one or more suitable substituents" is phenylthio (C ₁ -C ₄ ) alkyl,
Of these, phenylthiomethyl is more preferable.
"Suitable substituent" in the expression "arylthio lower alkyl optionally having one or more suitable substituents"
Is preferably acyl, and particularly preferred is carbamoyl or carboxy.

Preferable examples of the "lower alkyl" moiety in the expression "imidazolyl lower alkyl" include the above "lower alkyl". A preferable example of “imidazolyl lower alkyl” is imidazolyl (C
₁ -C ₄₎ alkyl, it is preferred imidazolylmethyl from among them.

Preferable examples of "protected carboxy" include the above-mentioned "protected carboxy". Among them, lower alkoxycarbonyl is preferable, and (C ₁ -C ₄₎ is more preferable. ) Alkoxycarbonyl, especially preferred is ethoxycarbonyl.

The method for producing the object compound (I) of the present invention will be described in detail below. Method 1 Compound (I) or a salt thereof is prepared by reacting compound (II) or a reactive derivative thereof at an amino group or a salt thereof with compound (III) or a reactive derivative at a carboxy group thereof or a salt thereof. it can. Suitable reactive derivative at the amino group of compound (II) is a Schiff base type imino compound formed by the reaction of compound (II) with a carbonyl compound such as aldehyde or ketone, or enamine which is a tautomer thereof. Type compound; silyl derivative formed by reaction of compound (II) with silyl compound such as N, O-bis (trimethylsilyl) acetamide, N-trimethylsilylacetamide; by reaction of compound (II) with phosphorus trichloride or phosgene The derivative etc. which are formed are mentioned.

Suitable reactive derivatives of compound (III) include acid halides, acid anhydrides, active esters and the like. Suitable examples are acid chlorides; acid azides; substituted phosphoric acids (eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.),
Dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, alkane sulfuric acid (eg, methanesulfonic acid, ethanesulfonic acid, etc.), sulfuric acid, alkyl carbonic acid, aliphatic carboxylic acid (eg, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid) Etc.), mixed acid anhydrides with acids such as aromatic carboxylic acids (eg benzoic acid); symmetrical acid anhydrides; active amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; active esters (eg. cyanomethyl ester, methoxymethyl ester, dimethyl imino-methyl ^{_{[(CH 3) 2 N +}} = CH-] ester, vinyl ester, propargyl ester, p- nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, Pentaku B phenyl ester, mesyl phenyl ester, phenylazophenyl ester,
Phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranylester, pyridylester, piperidylester, 8-quinolylthioester, etc.);
-Hydroxy compounds (eg, N, N-dimethylhydroxylamine, 1-hydroxy-2 (1H) -pyridone, N-hydroxysuccinimide, N-hydroxybenzotriazole, N-hydroxyphthalimide,
Ester with hydroxy-6-chloro-1H-benzotriazole and the like; and the like. These reactive derivatives can be appropriately selected from them depending on the type of compound (III) used.

This reaction is usually carried out using water, alcohol (eg methanol, ethanol, etc.), benzene, N, N.
Carried out in a solvent such as dimethylformamide, tetrahydrofuran, toluene, methylene chloride, ethylene dichloride, chloroform, dioxane, diethyl ether or any other solvent which does not adversely influence the reaction or a mixture thereof. The reaction temperature is not particularly limited, and the reaction is usually carried out under cooling or heating.

The reaction includes alkali metal (eg sodium, potassium etc.), alkali metal hydroxide (eg sodium hydroxide, potassium hydroxide etc.), alkali metal hydrogen carbonate (eg sodium hydrogen carbonate, potassium hydrogen carbonate etc.), Alkali metal carbonates (eg sodium carbonate, potassium carbonate etc.), tri-lower alkylamines (eg trimethylamine, triethylamine, diisopropylethylamine etc.), alkali metal hydrides (eg sodium hydride etc.), alkali metal lower alkoxides (eg sodium methoxide) , Sodium ethoxide), pyridine, lutidine, picoline, dimethylaminopyridine, N-lower alkylmorpholine, N, N-dilower alkylbenzylamine, N, N
It can also be carried out in the presence of an inorganic or organic base such as di-lower alkylaniline.

Method 2 The object compound (Ia) or its salt is obtained by reacting the compound (Ib) or its reactive derivative at the carboxy group or a salt thereof with the compound (IV) or a reactive derivative at its amino group or a salt thereof. Can be manufactured. Suitable reactive derivative at the carboxy group of the compound (Ib) includes acid halide, acid anhydride, active amide, active ester and the like. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid [eg, dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, etc.], dialkyl phosphorous acid, sulfurous acid, thiosulfuric acid, sulfuric acid. , Sulfonic acid [eg methanesulfonic acid etc.], aliphatic carboxylic acid [eg acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid,
Trichloroacetic acid and the like], mixed acid anhydrides with acids such as aromatic carboxylic acids [eg benzoic acid and the like]; symmetrical acid anhydrides; imidazole, 4-substituted imidazole, dimethylpyrazole, triazole, tetrazole or 1-hydroxy-1H- Active amides with benzotriazole; active esters [eg cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl [(CH ₃ ) ₂ N
⁺ = CH-] ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,
Pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester,
8-quinolyl thioester, etc.); N-hydroxy compounds (eg N, N-dimethylhydroxylamine, 1,
-Hydroxy-2 (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy-1H-benzotriazole and the like] and the like. These reactive derivatives can be appropriately selected from them according to the kind of the compound (Ib) used. Suitable salts of the compound (Ib) and its reactive derivative include those exemplified for the compound (I).

Suitable reactive derivatives at the amino group of compound (IV) include compound (IV) and aldehyde,
A Schiff base type imino compound formed by reaction with a carbonyl compound such as a ketone or an enamine type compound which is a tautomer thereof; compound (IV) and bis (trimethylsilyl) acetamide, mono (trimethylsilyl)
Examples thereof include silyl derivatives formed by reaction with silyl compounds such as acetamide and bis (trimethylsilyl) urea; derivatives formed by reaction of compound (IV) with phosphorus trichloride or phosgene. Suitable salts of the compound (IV) and its reactive derivative include those exemplified for the compound (I).

The reaction is usually carried out in a conventional solvent such as water,
Alcohols (eg methanol, ethanol, etc.),
It is carried out in acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine or any other organic solvent that does not adversely influence the reaction. These conventional solvents can also be used as a mixture with water.

In this reaction, when the compound (Ib) is used in the form of a free acid or a salt thereof, N,
N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-
Cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide; N, N'-diisopropylcarbodiimide; N
-Ethyl-N '-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1 -Alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); phosphorus trichloride; thionyl chloride; oxalyl chloride; lower alkyl haloformates [eg ethyl chloroformate, chloro Isopropyl formate, etc.]; Triphenylphosphine; 2
-Ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5- (m-sulfophenyl) isoxazolium inner salt; 1- (p-chlorobenzenesulfonyloxy) -6-chloro-1H -Benzotriazole; in the presence of a conventional condensing agent such as so-called Vilsmeier reagent prepared by the reaction of N, N-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, methanesulfonyl chloride, and the like. It is preferred to carry out the reaction at

The reaction includes alkali metal carbonate, alkali metal bicarbonate, tri-lower alkylamine, pyridine, N-
It can also be carried out in the presence of an inorganic base or an organic base such as lower alkylmorpholine and N, N-dilower alkylbenzylamine. The reaction temperature is not particularly limited, but the reaction is usually carried out under cooling or heating.

The starting compound (II) can be prepared according to the following reaction scheme. Method A

Embedded image Where R ¹ and R ² are each as defined above. The reaction of this process can be carried out by the method of Preparation Example 3 described below or a method similar thereto.

Some of the starting compounds (II) to (V) are new compounds. They are similar to the methods disclosed in the preparation examples herein below,
Alternatively, it can be prepared by any method known in the art for the preparation of compounds structurally similar to them.

The compounds obtained by the above methods 1 and 2 can be isolated and purified by a conventional method such as pulverization, recrystallization, column chromatography or reprecipitation.

Each of the object compounds (I) may include one or more stereoisomers such as optical isomers and geometric isomers based on an asymmetric carbon atom and a double bond. All such isomers and their mixtures are also included in the scope of the present invention.

The pharmaceutical composition of the present invention comprises the objective compound (I)
Alternatively, a pharmaceutically acceptable salt thereof is used as an active ingredient, which is rectal administration; pulmonary administration (nasal or buccal inhalation); intraocular administration; external application (topical application); oral administration; parenteral administration (subcutaneous, intravenous) Intramuscular and intramuscular administration); inhalation (including aerosol administration from a metered dose inhaler); administration by nebulizer or dry powder inhaler; contained as a mixture with an inorganic or organic carrier or excipient suitable for Solid, for example
It can be used in the form of pharmaceutical preparations in semisolid or liquid form.

The active ingredient is mixed with a conventional pharmaceutically acceptable non-toxic carrier, for example, and solid forms such as granules, tablets, dragees, pellets, troches, capsules and suppositories; creams. Agents; Ointments; Aerosols; Inhalation powders; Liquid forms such as injectable solutions, emulsions, suspensions; Oral ingestions; Eye drops; Other forms suitable for use. Then, if necessary, auxiliary substances such as a stabilizer, a thickener, a wetting agent, an emulsifier, a coloring agent, a flavoring agent or a buffering agent, and any other conventional additive can be added to the above-mentioned preparation.

The target compound (I) or a salt thereof also includes a solvate [eg, an inclusion compound (eg, hydrate)]. The object compound (I) or a salt thereof includes its crystalline form and amorphous form. The drug comprising the object compound (I) of the present invention is administered to humans or animals in the form of a pharmaceutical composition. The target compound (I) or a pharmaceutically acceptable salt thereof is contained in the pharmaceutical composition in a ratio sufficient to exert a desired effect on the course or condition of a disease.

The pharmaceutical composition of the present invention can be manufactured by a conventional method in this technical field. If necessary, the techniques commonly used in this technical field for improving the bioavailability of drugs can be applied to the pharmaceutical composition of the present invention.

The therapeutically effective dose of the target compound (I) is
It depends on the age and condition of each individual patient to be treated and depends on them, but in the case of intravenous administration, the daily dose is usually 0.0 per kg of human or animal body weight.
In the case of intramuscular administration, 01 to 100 mg of the target compound (I) is administered at a daily dose of 0.001 to 100 mg of the target compound (I) per 1 kg of human or animal body weight, and in the case of oral administration, The daily dose is 1 kg of human or animal body weight.
0.001 to 200 mg of the target compound (I) per day for preventing and / or treating the above-mentioned diseases
Administer to humans or animals four times.

In order to illustrate the usefulness of the target compound (I), the pharmacological test data of representative compounds of the compound (I) are shown below.

[0074]

【Example】

Test compound (1) 7- (2,6-dichlorobenzoylamino) -2
-Methyl-3- [N- (pyridin-3-yl) carbamoylmethyl] benzo [b] furan hydrochloride test (bone tissue culture): Test method Calvaria were extracted from Wistar rats and 10% fetal bovine serum and 10 ^-8 M human parathyroid hormone fragment (1
-34) The cells were cultured in the wells of a 12-well culture plate containing 2 ml of Dulbecco's modified minimum essential medium supplemented with [PTH] in the presence of the test compound. No PTH was added to the control dish. Controls and PTH controls were exposed to corresponding concentrations of carrier. After 6 days, the concentration of calcium in the medium was measured by the methylxylenol blue method, and the inhibition rate (%) of PTH-induced bone resorption was calculated according to the following formula.

(Equation 1)

Test results

[Table 1]

The following Preparations and Examples are given for the purpose of illustrating the invention in more detail.

Preparation Example 1 2-Methyl-7-nitrobenzo [b] furan (3.5
A mixture of g) and 1,3,5-trioxane (2.1 g) in concentrated hydrochloric acid (20 ml) -1,4-dioxane (10 ml) was stirred at 90 ° C. for 1 hour. The mixture was cooled to ambient temperature and water (20 ml) was added to the mixture. The precipitate was collected by filtration and washed with water to give 3-chloromethyl-2-methyl-7-nitrobenzo [b] furan (3.5 g).

Mp: 132-134 ° C. NMR (CDCl ₃ , δ): 2.60 (3H, s), 4.72 (2H, s), 7.40 (1
H, t, J = 8Hz), 7.92 (1H, d, J = 8Hz), 8.12 (1H, d, J = 8Hz)

Preparation Example 2 Potassium cyanide (1.70 g) in acetonitrile (3
0 ml) -water (7 ml) in a mixture, 3-chloromethyl-2-methyl-7-nitrobenzo [b] furan (3.0
0 g) was added. The mixture was stirred at 50 ° C. for 6 hours and water (40 ml) was added to the mixture. The resulting precipitate was collected by filtration and washed with water to give 3-cyanomethyl-2-methyl-7-nitrobenzo [b] furan (2.4 g).

Mp: 140-143 ° C. NMR (CDCl ₃ , δ): 2.60 (3H, s), 3.75 (2H, s), 7.42 (1
H, t, J = 8Hz), 7.88 (1H, d, J = 8Hz), 8.14 (1H, d, J = 8Hz)

Preparation Example 3 3-Cyanomethyl-2-methyl-7-nitrobenzo [b] furan (1.50 g) and ammonium chloride (15
Ethanol (15 ml) with 0 mg) -water (1.5 m
l) Iron (969 mg) was added to the mixture in 70 ° C.,
The reaction mixture was heated under reflux for 8 hours. The mixture was filtered through a layer of Celite and the filtrate was evaporated under reduced pressure and concentrated to give 7-amino-3-cyanomethyl-2-methylbenzo [b] furan (1.3 g) as a solid.

Mp: 82-84 ° C. NMR (CDCl ₃ , δ): 2.47 (3H, s), 3.65 (2H, s), 3.92 (2
H, br s), 6.63 (1H, d, J = 8Hz), 6.93 (1H, d, J = 8Hz), 7.0
7 (1H, t, J = 8Hz)

Preparation Example 4 N- (3-acetyl-2-hydroxyphenyl) -2,
6-Dichlorobenzamide (324 mg), ethyl bromoacetate (184 mg) and potassium carbonate (207 m
The mixture of g) in N, N-dimethylformamide (2 ml) was stirred at ambient temperature for 2 hours and the mixture was partitioned between ethyl acetate and water. The organic layer is separated and brine (brine)
Washed with, dried over sodium sulphate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography, and the obtained oil was crystallized from hexane to give [6-acetyl-2- (2,6-dichlorobenzoylamino)] phenoxyethyl acetate (235 mg). .

Mp: 103-105 ° C NMR (CDCl ₃ , δ): 1.21 (3H, t, J = 7Hz), 2.60 (3H, s),
4.10 (2H, q, J = 7Hz), 4.58 (2H, s), 7.27-7.47 (5H, m),
8.79 (1H, d, J = 8Hz), 9.97 (1H, br s)

Preparation Example 5 3-amino-2-hydroxyacetophenone (3.79)
g), 2,6-dichlorobenzoyl chloride (15.76)
g) and triethylamine (9.12 g) 1,2-
The mixture in dichloroethane (130 ml) was heated under reflux for 3 hours, allowed to cool to ambient temperature and partitioned between chloroform and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The crystalline residue was triturated with diisopropyl ether, collected, dried and then ethanol (1
(00 ml) -tetrahydrofuran (100 ml) mixture. To the solution was added 1N aqueous sodium hydroxide solution (41 ml) and the mixture was stirred at 50 ° C. for 30 minutes. After cooling to ambient temperature, the mixture was partitioned between ethyl acetate and 1N hydrochloric acid. The organic layer was separated, washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure.
The residue was purified by silica gel column chromatography, the obtained crystalline residue was triturated with diisopropyl ether, and N- (3-acetyl-2-hydroxyphenyl) -2,6-dichlorobenzamide (5.
67 g) was obtained.

Mp: 160-165 ° C NMR (CDCl ₃ , δ): 2.67 (3H, s), 7.01 (1H, t, J = 8Hz),
7.27-7.43 (3H, m), 7.15 (1H, d, J = 8Hz), 8.09 (1H, br
s), 8.80 (1H, d, J = 8Hz)

Preparation Example 6 3-Bromo-2-methyl-7-nitrobenzo [b] furan (256 mg), 8-quinolineboronic acid (432 m
g), tetrakis (triphenylphosphine) palladium (0) (23 mg) and 2M aqueous sodium carbonate solution (2.5 ml) in 1,2-dimethoxyethane (5 ml).
The medium mixture was heated under reflux for 5 hours. The resulting mixture was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and filtered. The solution was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. Elute with n-hexane / ethyl acetate (4: 1). The oil obtained was crystallized from an ethanol-water mixture to give 2-methyl-7-
Nitro-3- (8-quinolyl) benzo [b] furan (8
6 mg).

Mp: 158-159 ° C NMR (CDCl ₃ , δ): 2.58 (3H, s), 7.23-7.30 (1H, m), 7.
40 (1H, m), 7.54 (1H, d, J = 8Hz), 7.70 (1H, t, J = 8Hz), 7.
79 (1H, d, J = 8Hz), 7.96 (1H, d, J = 8Hz), 8.10 (1H, d, J = 8)
Hz), 8.29 (1H, d, J = 8Hz), 8.91 (1H, d, J = 6Hz)

Preparation Example 7 A mixture of 3-cyanomethyl-2-methyl-7-nitrobenzo [b] furan (600 mg) and 1N aqueous sodium hydroxide solution (5.6 ml) in ethanol (6 ml) was added at 60 ° C. for 1 hour. It was stirred. The resulting mixture was cooled to ambient temperature and water and ethyl acetate were added to the mixture. The separated solid was collected, washed with water to give 3-carbamoylmethyl-2-methyl-7-nitrobenzo [b] furan (26
5 mg) was obtained.

Mp: 226-228 ° C NMR (DMSO-d ₆ , δ): 2.50 (3H, s), 3.52 (2H, s), 7.04
(1H, br s), 7.45 (1H, t, J = 8Hz), 7.56 (1H, br s), 8.00
(1H, d, J = 8Hz), 8.08 (1H, d, J = 8Hz)

In the same manner as in Preparation Example 3, the following compounds (Preparation Examples 8 to 9) were obtained.

Preparation Example 8 7-Amino-3-carbamoylmethyl-2-methylbenzo [b] furan

Mp: 153-154 ° C. NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 5.12 (2H, s), 6.47
(1H, d, J = 8Hz), 6.70 (1H, d, J = 8Hz), 6.86 (1H, t, J = 8Hz),
6.91 (1H, br s), 7.40 (1H, br s)

Preparation Example 9 7-Amino-2-methyl-3- (8-quinolyl) benzo [b] furan

NMR (CDCl ₃ , δ): 2.42 (3H, s), 3.85 (2
H, br s), 6.60 (1H, d, J = 8Hz), 6.70 (1H, d, J = 8Hz), 6.98
(1H, t, J = 8Hz), 7.43 (1H, m), 7.64 (1H, t, J = 8Hz), 7.80
(1H, d, J = 8Hz), 7.88 (1H, d, J = 8Hz), 8.23 (1H, d, J = 8H)
z), 8.92 (1H, d, J = 6Hz)

Example 1 A mixture of ethyl 6-acetyl-2- (2,6-dichlorobenzoylamino) phenoxyacetate (340 mg) and potassium carbonate (229 mg) in N, N-dimethylformamide (3 ml) was added to 90%. Stir at 20 ° C for 20 hours, allow to cool to ambient temperature and partition between ethyl acetate and water. The organic layer was separated, washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the resulting oil was crystallized from hexane to give 7- (2,6-dichlorobenzoylamino) -2-ethoxycarbonyl-3-methylbenzo [b] furan (130 mg ) Got.

Mp: 200-202 ° C. NMR (CDCl ₃ , δ): 1.42 (3H, t, J = 7Hz), 2.69 (3H, s),
4.44 (2H, q, J = 7Hz), 7.30-7.48 (5H, m), 8.12 (1H, br
s), 8.61 (1H, d, J = 8Hz)

Example 2 2,6-Dichloro-3-nitrobenzoic acid (293 m
g), oxalyl chloride (0.5 ml) and a catalytic amount of N, N-dimethylformamide in dichloromethane (3 m
The mixture in 1) was stirred at ambient temperature for 2 hours. After concentration,
The residue was dissolved in 1,3-dimethyl-2-imidazolidinone (0.5 ml) and the solution was added to 7-amino-3-carbamoylmethyl-2-methylbenzo [b] furan (1
80 mg) and triethylamine (193 mg)
Added to the mixture in 3-dimethyl-2-imidazolidinone (1.5 ml). The mixture was stirred at ambient temperature for 18 hours. Water was added to the resulting mixture and the separated solid was collected.
The solid obtained was washed with ethanol to give 3-carbamoylmethyl-7- (2,6-dichloro-3-nitrobenzoylamino) -2-methylbenzo [b] furan (263 m
g) was obtained.

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 3.43 (2H, s), 6.98
(1H, br s), 7.21 (1H, t, J = 8Hz), 7.38 (1H, d, J = 8Hz),
7.50 (1H, br s), 7.88 (2H, d, J = 8Hz), 8.21 (1H, d, J = 8H
z)

The following compound was obtained in the same manner as in Example 2.

Example 3 3-Cyanomethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan

Mp: 235-238 ° C NMR (CDCl ₃ , δ): 2.48 (3H, s), 3.68 (2H, s), 7.28-7.
45 (5H, m), 7.80 (1H, s), 8.30-8.38 (1H, m)

7- (2,6-dichlorobenzoylamino) -3-hydroxymethyl-2-methylbenzo [b]
Furan (300 mg) and manganese (IV) oxide (1.8
A mixture with 7 g) in dichloromethane (15 ml) was stirred at ambient temperature for 60 hours. The resulting mixture was filtered and the filtrate was evaporated under reduced pressure to give a solid. The solid obtained was triturated with an ethanol-water mixture to give 7- (2
6-dichlorobenzoylamino) -3-formyl-2-
Methylbenzo [b] furan (233 mg) was obtained.

Mp: 237-238 ° C NMR (CDCl ₃ , δ): 2.80 (3H, s), 7.34-7.46 (4H, m), 7.
80 (1H, br s), 7.92 (1H, d, J = 8Hz), 8.34 (1H, d, J = 8Hz),
10.26 (1H, s)

Example 5 3-Cyanomethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (100 m
A mixture of g) and 1N aqueous sodium hydroxide solution (0.84 ml) in ethanol (1 ml) was heated under reflux for 18 hours. After cooling to ambient temperature, the reaction mixture was acidified with 1N hydrochloric acid to precipitate a precipitate. Collect the obtained precipitates,
Drying afforded 3-carboxymethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (115 mg).

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 3.63 (2H, s), 7.20
(1H, t, J = 8Hz), 7.30 (1H, d, J = 8Hz), 7.49 (1H, m), 7.54-
7.60 (2H, m), 7.78 (1H, d, J = 8Hz)

Example 6 3-Carboxymethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (150
To a mixture of (mg) with triethylamine (42 mg) in tetrahydrofuran (3 ml) was added pivaloyl chloride (50 mg) under ice cooling. After 30 minutes, sodium borohydride (75 mg) was added to the mixture. The mixture was stirred for 2 hours and at 50 ° C. for an additional hour. The resulting mixture was diluted with methanol and saturated aqueous ammonium chloride solution to quench the reaction and partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography to give 7- (2,6-dichlorobenzoylamino) -3- (2-hydroxyethyl) -2-methylbenzo [b] furan (61 mg), which was ethanol. Crystallized from a water mixture.

Mp: 91-95 ° C. NMR (CDCl ₃ , δ): 1.46 (1H, t, J = 7Hz), 2.42 (3H, s),
2.90 (2H, t, J = 7Hz), 3.89 (2H, q, J = 7Hz), 7.20-7.44 (5
H, m), 7.84 (1H, br s), 8.30 (1H, d, J = 8Hz)

Example 7 3-Carboxymethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (152
mg) and triethylamine (49 mg) in 1,2-dimethoxyethane (5 ml) under stirring at ambient temperature, pivaloyl chloride (54 mg) was added and the resulting mixture was stirred at ambient temperature for 1 hour. Then 2-aminopyridine (76 mg) was added to the mixture and the mixture was stirred at 60 ° C for 3
Stirred for hours. The mixture was partitioned between ethyl acetate and water, the organic layer was separated, washed with brine, dried over sodium acetate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the resulting oil was crystallized from ethyl acetate to give 7- (2,6-dichlorobenzoylamino) -2-methyl-3- [N- (pyridine-
2-yl) carbamoylmethyl] benzo [b] furan (134 mg) was obtained.

Mp: 243-246 ° C. NMR (DMSO-d ₆ , δ): 2.48 (3H, s), 3.82 (2H, s), 7.09
(1H, dd, J = 4 and 6Hz), 7.41 (1H, d, J = 8Hz), 7.45-7.6
0 (3H, m), 7.70-7.80 (2H, m), 8.03 (1H, d, J = 8Hz), 8.33
(1H, d, J = 4Hz)

Example 8 3-Carboxymethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (152
mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (115 mg) and 1-hydroxybenzotriazole (82 mg) in N, N-dimethylformamide (2 ml) at ambient temperature for 1 hour. Stir and add to this mixture 3-aminopyridine (57
mg) was added. The mixture was stirred overnight at ambient temperature and cold water was added to the mixture. The separated solid was collected, washed with water, dried and dried with 7- (2,6-dichlorobenzoylamino)-
2-Methyl-3- [N- (pyridin-3-yl) carbamoylmethyl] benzo [b] furan (175 mg) was obtained.

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.48 (3H, s), 3.27 (2H, s), 7.21
(1H, t, J = 8Hz), 7.33 (1H, dd, J = 4 and 8Hz), 7.40 (1
H, d, J = 8Hz), 7.50 (1H, dd, J = 6 and 8Hz), 7.55-7.59
(2H, m), 7.78 (1H, d, J = 8Hz), 8.03 (1H, dd, J = 2 and 8
Hz), 8.26 (1H, d, J = 4Hz), 8.75 (1H, d, J = 2Hz)

In the same manner as in Example 8, the following compounds (Examples 9-13) were obtained.

Example 9 7- (2,6-Dichlorobenzoylamino) -2-methyl-3-[[N-methyl-N- (pyridin-2-yl)] carbamoylmethyl] benzo [b] furan

Mp: 190-192 ° C NMR (DMSO-d ₆ , δ): 2.23 (3H, s), 3.32 (3H, s), 3.76
(2H, s), 7.10-7.25 (2H, m), 7.33 (1H, dd, J = 6 and 8H
z), 7.45-7.60 (4H, m), 7.77 (1H, d, J = 8Hz), 7.89 (1H,
dd, J = 6 and 8Hz), 8.52 (1H, d, J = 6Hz)

Example 10 3-[[N- (benzimidazol-2-yl) methyl] carbamoylmethyl] -7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 3.59 (2H, s), 4.49
(2H, d, J = 6Hz), 7.10-7.20 (3H, m), 7.37-7.52 (3H, m),
7.53-7.60 (3H, m), 7.77 (1H, d, J = 8Hz), 8.78 (1H, t, J =
6Hz)

Example 11 3-carbamoylmethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan

Mp:> 260 ° C. NMR (DMSO-d ₆ , δ): 2.42 (3H, s), 3.43 (2H, s), 6.97
(1H, br s), 7.20 (1H, t, J = 8Hz), 7.36 (1H, t, J = 8Hz),
7.47-7.59 (4H, m), 7.78 (12H, d, J = 8Hz)

Example 12 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- (thiomorpholinocarbonylmethyl) benzo [b] furan

Mp: 215-216 ° C. NMR (DMSO-d ₆ , δ): 2.40 (3H, m), 2.48-2.57 (4H, m),
3.69-3.82 (6H, m), 7.18 (1H, t, J = 8Hz), 7.30 (1H, d, J = 8
Hz), 7.49 (1H, m), 7.57 (2H, d, J = 8Hz), 7.77 (1H, d, J =
8Hz)

Example 13 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N-[(4-sulfamoylphenyl) methyl] carbamoylmethyl] benzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 3.56 (2H, s), 4.34
(2H, d, J = 7Hz), 7.32 (1H, t, J = 8Hz), 7.26-7.42 (5H, m),
7.48 (1H, m), 7.58 (2H, d, J = 8Hz), 7.74 (2H, d, J = 8Hz),
7.80 (1H, d, J = 8Hz), 8.64 (1H, t, J = 7Hz), 10.86 (1H, br
s)

Example 14 3-Carboxymethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (150
mg) N, N-dimethylformamide (1.5 ml)
In the solution, 1-hydroxybenzotriazole (64 m
g) and 1- (3-dimethylaminopropyl) -3-
Ethylcarbodiimide hydrochloride (91 mg) was added. The mixture was stirred at ambient temperature for 30 minutes and 4-aminomethylpyridine (51 mg) was added to the mixture. After stirring for 3 hours,
The reaction mixture was partitioned between ethyl acetate and half saturated saline.
The organic layer was washed with brine, dried over sodium sulfate and evaporated under reduced pressure. The obtained solid was dissolved in ethanol and an 8N hydrogen chloride ethanol solution was added. The resulting solid was collected by filtration and washed with ethanol to give 7- (2,6-dichlorobenzoylamino) -2-methyl-3-[[N- (pyridin-4-yl) methyl] carbamoylmethyl] benzo [b ] Furan hydrochloride (135 mg) was obtained.

Mp: 250-253 ° C. NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 2.64 (2H, s), 4.51
(2H, d, J = 6Hz), 7.21 (1H, t, J = 8Hz), 7.38 (1H, d, J = 8Hz),
7.46-7.60 (3H, m), 7.79 (3H, m), 8.80 (2H, d, J = 6Hz),
8.90 (1H, t, J = 6Hz)

The following compounds (Examples 15 to 16) were obtained in the same manner as in Example 14.

Example 15 7- (2,6-Dichlorobenzoylamino) -2-methyl-3-[[N- (pyridin-3-yl) methyl] carbamoylmethyl] benzo [b] furan hydrochloride

Mp: 238-251 ° C. NMR (DMSO-d ₆ , δ): 2.43 (3H, s), 3.60 (2H, s), 4.42
(2H, d, J = 6Hz), 7.19 (1H, t, J = 8Hz), 7.32 (1H, d, J = 8Hz),
7.47-7.60 (3H, m), 7.78 (1H, d, J = 8Hz), 7.86-7.92 (1
H, m), 8.28 (1H, d, J = 8Hz), 8.70-8.77 (2H, m), 8.83 (1
(H, t, J = 6Hz)

Example 16 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- [2- (pyridin-2-yl) ethyl]
Carbamoylmethyl] benzo [b] furan hydrochloride

Mp: 226-228 ° C NMR (DMSO-d ₆ , δ): 2.39 (3H, s), 3.12 (2H, t, J = 7Hz),
3.41 (2H, s), 3.46-4.07 (2H, m), 7.17 (1H, t, J = 8Hz),
7.24 (1H, d, J = 8Hz), 7.50 (1H, m), 7.59 (2H, d, J = 8Hz),
7.69-7.78 (3H, m), 8.20-8.30 (2H, m), 8.70 (1H, d, J =
8Hz)

Example 17 Ethanol (1.5 m) was added to sodium metal (14 mg).
1) was added and the mixture was stirred for 10 minutes. To the resulting solution was added ethyl acetate (79 mg) and 3-chloromethyl-
7- (2,6-Dichlorobenzoylamino) -2-methylbenzo [b] furan (150 mg) was added. The mixture was stirred at 50 ° C. for 2 hours, acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over sodium sulfate and evaporated under reduced pressure. The obtained solid was triturated with diethyl ether, collected by filtration, and 7- (2,6-dichlorobenzoylamino) -3- (2-ethoxycarbonyl-3).
-Oxobutyl) -2-methylbenzo [b] furan (1
27 mg) was obtained.

Mp: 174-178 ° C. NMR (CDCl ₃ , δ): 1.22 (3H, t, J = 7Hz), 2.21 (3H, s),
2.40 (3H, s), 3.07-3.25 (2H, m), 3.89 (1H, t, J = 7Hz),
4.16 (2H, q, J = 7Hz), 7.25 (1H, t, J = 8Hz), 7.80 (1H, s),
8.30 (1H, d, J = 8Hz)

Example 18 3-Chloromethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (200 m
g), pyrazole (186 mg) and triethylamine (110 mg) in 1,2-dimethoxyethane (3 m
The mixture in 1) was heated under reflux for 18 hours. The reaction mixture was diluted with dichloromethane and washed with water. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethanol to give 7- (2,6-dichlorobenzoylamino) -2-methyl-3- (pyrazole-
1-yl) methylbenzo [b] furan (95 mg) was obtained.

Mp: 221-222 ° C. NMR (DMSO-d ₆ , δ): 2.53 (3H, s), 5.43 (2H, s), 6.22
(1H, d, J = 3Hz), 7.18 (1H, t, J = 8Hz), 7.31 (1H, d, J = 8Hz),
7.42 (1H, m), 7.46-7.52 (1H, m), 7.55-7.60 (2H, m),
7.77 (1H, d, J = 8Hz), 7.86 (1H, m)

The following compound was obtained in the same manner as in Example 18.

Example 19 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- (1,2,4-triazol-1-yl) methylbenzo [b] furan hydrochloride

Mp: 231 ° C. NMR (DMSO-d ₆ , δ): 2.57 (3H, s), 5.56 (2H, s), 7.21
(1H, t, J = 8Hz), 7.39 (1H, d, J = 8Hz), 7.47-7.52 (1H, m),
7.54-7.60 (2H, m), 7.79 (1H, d, J = 8Hz), 8.02 (1H, s),
8.82 (1H, s)

Example 20 3-Chloromethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (148 m
A mixture of g), dimethylamine hydrochloride (66 mg) and triethylamine (142 mg) in 1,2-dichloroethane (3 ml) was heated under reflux for 3 hours. The mixture was allowed to cool to ambient temperature and was partitioned between dichloromethane and water. The organic layer was separated, washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel column chromatography and the resulting oil was crystallized from diisopropyl ether to give 7
-(2,6-Dichlorobenzoylamino) -3-dimethylaminomethyl-2-methylbenzo [b] furan (31
mg).

Mp: 169-171 ° C. NMR (CDCl ₃ , δ): 2.27 (6H, s), 2.43 (3H, s), 3.48 (2
H, s), 7.25 (1H, t, J = 8Hz), 7.30-7.45 (4H, m), 7.82 (1
H, br s), 8.28 (1H, d, J = 8Hz)

The following compound was obtained in the same manner as in Example 20.

Example 21 7- (2,6-dichlorobenzoylamino) -3- [N
-(2-Methoxyethyl) -N-methylamino] methyl-2-methylbenzo [b] furan

Mp: 104-106 ° C. NMR (CDCl ₃ , δ): 2.27 (3H, s), 2.42 (3H, s), 2.63 (2
H, t, J = 6Hz), 3.36 (3H, s), 3.53 (2H, t, J = 6Hz), 3.59 (2
H, s), 7.24 (1H, t, J = 8Hz), 7.30-7.45 (3H, m), 7.80 (1
H, br s), 8.28 (1H, d, J = 8Hz)

Example 22 3-Chloromethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (150 m
g), 2-mercaptobenzoic acid (69 mg) and sodium carbonate (86 mg) in N, N-dimethylformamide (2 ml) were stirred at ambient temperature for 1 hour.
The resulting mixture was diluted with water and acidified with 1N hydrochloric acid. Dichloromethane and methanol were added to the obtained organic layer, and then the insoluble material was filtered off. The filtrate was dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from an ethanol-water mixture to give 3-[(2-carboxyphenyl) thiomethyl] -7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (171m
g) was obtained.

Mp: 260-262 ° C. NMR (DMSO-d ₆ , δ): 2.46 (3H, s), 4.33 (2H, s), 7.20-
7.29 (2H, m), 7.43-7.62 (6H, m), 7.81 (1H, d, J = 8Hz),
7.89 (1H, d, J = 8Hz)

Example 23 7- (2,6-Dichlorobenzoylamino) -2-methyl-3-[[N- (pyridin-2-yl) methyl] carbamoylmethyl] benzo [b] furan (180 mg) in dichloromethane To the (5 ml) solution was added m-chloroperbenzoic acid (91 mg). The mixture was stirred at ambient temperature for 4 hours and washed with 5% aqueous sodium thiosulfate solution and saturated aqueous sodium bicarbonate solution. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The obtained solid was triturated with ethyl acetate, collected by filtration, and 7- (2,6-dichlorobenzoylamino) -2-methyl-3-[[N- (2
-Pyridyl-1-oxide) methyl] carbamoylmethyl] benzo [b] furan (145 mg) was obtained.

Mp: 232-234 ° C NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 3.62 (2H, s), 4.36
(2H, d, J = 6Hz), 7.15-7.40 (5H, m), 7.45-7.60 (3H, m),
7.80 (1H, d, J = 8Hz), 8.29 (1H, d, J = 8Hz), 8.64 (1H, t, J
= 6Hz)

The following compound was obtained in the same manner as in Example 23.

Example 24 7- (2,6-Dichlorobenzoylamino) -2-methyl-3-[(thiomorpholino-1-oxide) carbonylmethyl] benzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 2.64-2.98 (4H, m),
3.50-3.61 (1H, m), 3.73-4.02 (4H, m), 4.14-4.24 (1H,
m), 7.18 (1H, t, J = 8Hz), 7.30 (1H, d, J = 8Hz), 7.50 (1
H, m), 7.58 (2H, d, J = 8Hz), 7.78 (1H, d, J = 8Hz)

Example 25 Sodium metal (8 mg) in ethanol (1.5 ml)
Was added and the mixture was stirred for 10 minutes. In the resulting mixture,
7- (2,6-dichlorobenzoylamino) -3- (2
-Ethoxycarbonyl-3-oxobutyl) -2-methylbenzo [b] furan (150 mg) and guanidine hydrochloride (33 mg) were added. The mixture was heated under reflux overnight. The formed precipitate was collected by filtration and washed with ethanol. The obtained solid was dissolved in methanol, and a 10% hydrogen chloride methanol solution was added to the solution. The mixture was evaporated under reduced pressure to give 3- (2-amino-4-hydroxy-6-methylpyrimidin-5-yl) methyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan. The hydrochloride salt (71 mg) was obtained as a solid.

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.24 (3H, s), 2.45 (3H, s), 3.70
(2H, s), 7.17 (1H, t, J = 8Hz), 7.27 (1H, d, J = 8Hz), 7.45
-7.60 (3H, m), 7.75 (1H, d, J = 8Hz), 7.98 (1H, s)

The following compound was obtained as in Example 25.

Example 26 7- (2,6-dichlorobenzoylamino) -3- (3
-Hydroxy-5-methylpyrazol-4-yl) methyl-2-methylbenzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.00 (3H, s), 2.44 (3H, s), 3.53
(2H, s), 7.14 (1H, t, J = 8Hz), 7.32 (1H, d, J = 8Hz), 7.43
-7.59 (3H, m), 7.74 (1H, d, J = 8Hz)

Example 27 3-[(2-Carboxyphenyl) thiomethyl] -7-
Of (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (150 mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (65 mg) and 1-hydroxybenzotriazole (46 mg) N, N-dimethylformamide (2m
The mixture in 1) was stirred at ambient temperature for 30 minutes. A 28% aqueous ammonium hydroxide solution was added to this mixture under ice cooling. The mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution, the organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was crystallized from ethanol to give 3-[(2-carbamoylphenyl) thiomethyl].
-7- (2,6-Dichlorobenzoylamino) -2-methylbenzo [b] furan (104 mg) was obtained.

Mp: 215-217 ° C. NMR (DMSO-d ₆ , δ): 2.34 (3H, m), 4.28 (2H, s), 7.20-
7.26 (3H, m), 7.34-7.60 (8H, m), 7.74-7.82 (2H, m), 1
0.86 (1H, s)

Example 28 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (pyridin-2-yl) carbamoyl]
To a suspension of methylbenzo [b] furan (110 mg) in methanol was added 10% methanolic hydrogen chloride solution and the resulting solution was evaporated under reduced pressure. The residue was crystallized from ethyl acetate to give 7- (2,6-dichlorobenzoylamino) -2-methyl-3- [N- (pyridin-2-yl).
Carbamoylmethyl] benzo [b] furan hydrochloride (10
5 mg) was obtained.

Mp: 185-192 ° C. NMR (DMSO-d ₆ , δ): 2.48 (3H, s), 3.85 (2H, s), 7.15-
7.25 (2H, m), 7.43 (1H, d, J = 8Hz), 7.45-7.60 (4H, m),
7.78 (1H, d, J = 8Hz), 7.89 (1H, t, J = 8Hz), 8.00 (1H, d, J)
= 8Hz), 8.33 (1H, d, J = 4Hz)

The following compounds (Examples 29 to 31) were obtained in the same manner as in Example 28.

Example 29 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (pyridin-3-yl) carbamoylmethyl] benzo [b] furan hydrochloride

Mp: 186-190 ° C NMR (DMSO-d ₆ , δ): 3.83 (2H, s), 7.21 (1H, t, J = 8Hz),
7.43 (1H, d, J = 8Hz), 7.49 (1H, dd, J = 6 and 8Hz), 7.
57 (2H, d, J = 8Hz), 7.78 (1H, d, J = 8Hz), 7.86 (1H, dd, J = 6)
And 8Hz), 8.47 (1H, d, J = 8Hz), 8.52 (1H, d, J = 6H
z), 9.13 (1H, s)

Example 30 7- (2,6-Dichlorobenzoylamino) -2-methyl-3-[[N-methyl-N- (pyridin-2-yl)
Carbamoylmethyl] benzo [b] furan hydrochloride

Mp: 215-218 ° C. NMR (DMSO-d ₆ , δ): 2.23 (3H, s), 3.32 (3H, s), 3.77
(2H, s), 7.15 (1H, t, J = 8Hz), 7.22 (1H, d, J = 8Hz), 7.33
(1H, dd, J = 6 and 8Hz), 7.45-7.60 (4H, m), 7.77 (1
H, d, J = 8Hz), 7.90 (1H, t, J = 8Hz), 8.53 (1H, d, J = 6Hz)

Example 31 3-[[N- (benzimidazol-2-yl) methyl] carbamoylmethyl] -7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan hydrochloride

Mp: 235-237 ° C. NMR (DMSO-d ₆ , δ): 2.44 (3H, s), 3.69 (2H, s), 4.73
(2H, d, J = 6Hz), 7.16 (1H, t, J = 8Hz), 7.39 (1H, d, J = 8Hz),
7.45-7.60 (5H, m), 7.72-7.83 (3H, m), 9.10 (1H, t, J =
6Hz)

Example 32 7- (2,6-Dichlorobenzoylamino) -2-ethoxycarbonyl-3-methylbenzo [b] furan (10
0 mg) of dichloromethane (1 ml) -carbon tetrachloride (4
ml) mixture solution under stirring at 50 ° C. with N-bromosuccinimide (50 mg) and 2,2′-azobis (2,4-dimethyl-4-methoxyvaleronitrile).
(10 mg) was added and the resulting mixture was heated under reflux for 4 hours. After cooling, dilute the reaction mixture with dichloromethane,
It was washed with 5% aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution and brine. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in 1,2-dimethoxyethane (1 ml), to which imidazole (52 mg) was added. The mixture was stirred at ambient temperature for 30 minutes and then at reflux for 2 hours.
After cooling, the solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography. Elution with 2% methanol-dichloromethane gave a solid. This was treated with hot ethanol to give 7- (2,6-dichlorobenzoylamino) -2-ethoxycarbonyl-3- (imidazole-
1-ylmethyl) benzo [b] furan (44 mg) was obtained as colorless prism crystals.

Mp: 228 ° C. NMR (CDCl ₃ , δ): 1.44 (3H, t, J = 7Hz), 4.49 (2H, q, J = 7)
Hz), 5.63 (2H, s), 6.96 (1H, s), 7.01-7.10 (2H, m), 7.
29-7.45 (4H, m), 7.67 (1H, s), 8.18 (1H, br s), 8.59
(1H, d, J = 8Hz)

Example 33 7- (2,6-dichlorobenzoylamino) -3-formyl-2-methylbenzo [b] furan (200 mg),
Tributyl (3-phthalidyl) phosphonium bromide (26
A mixture of 3 mg) and triethylamine (70 mg) in dichloromethane (3 ml) was stirred at ambient temperature for 2 hours. The mixture was concentrated under reduced pressure and the residue was suspended in ethanol (6 ml). Hydrazine hydrate (0.5 ml) was added to the suspension and the mixture was heated under reflux for 3 hours. Water (6 ml) was added to the resulting mixture and the separated solids were collected to give 7- (2,6-dichlorobenzoylamino).
2-Methyl-3-[(3,4-dihydro-4-oxophthalazin-1-yl) methyl] benzo [b] furan (158 mg) was obtained.

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.48 (3H, s), 4.38 (2H, s), 7.14
(1H, t, J = 8Hz), 7.26 (1H, d, J = 8Hz), 7.48 (1H, t, J = 8Hz),
7.56 (2H, d, J = 8Hz), 7.72 (1H, d, J = 8Hz), 7.84 (1H, t,
J = 8Hz), 8.04 (1H, d, J = 8Hz), 8.26 (1H, d, J = 8Hz), 10.84
(1H, br s)

Example 34 1-Methylmagnesium bromide tetrahydrofuran solution (5.2 ml) was added to 7- (2,6-dichlorobenzoylamino) -3-methoxycarbonylmethyl-2-methylbenzo [b] while cooling with ice and stirring. ] A solution of furan (202 mg) in tetrahydrofuran (3 ml) was added dropwise. After 30 minutes, the mixture was stirred at ambient temperature for 30 minutes. The resulting mixture was diluted with saturated aqueous ammonium chloride solution under ice cooling to terminate the reaction, and partitioned between ethyl acetate and water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The solid obtained is triturated with a 2-propanol-water mixture, filtered and 7- (2,6-dichlorobenzoylamino) -3-[(2-hydroxy-2-methyl) propyl] -2-. Methylbenzo [b] furan (11
6 mg).

Mp: 190-192 ° C. NMR (CDCl ₃ , δ): 1.30 (6H, s), 1.43 (1H, s), 2.43 (3
H, s), 2.78 (2H, s), 7.22-7.43 (5H, m), 7.83 (1H, br
s), 8.29 (1H, d, J = 8Hz)

Example 35 3-Carboxymethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (200
Thionyl chloride (0.05 ml) was added dropwise to a suspension of (mg) in methanol (3 ml) under ice cooling and stirring, and the mixture was stirred at ambient temperature for 2 hours. Collect the separated solids and
-(2,6-Dichlorobenzoylamino) -3-methoxycarbonylmethyl-2-methylbenzo [b] furan (130 mg) was obtained.

Mp: 199-201 ° C. NMR (CDCl ₃ , δ): 2.42 (3H, s), 3.60 (2H, s), 3.69 (3
H, s), 7.21-7.29 (2H, m), 7.31-7.43 (3H, m), 7.80 (1H,
br s), 8.30 (1H, m)

Example 36 7- (2,6-dichlorobenzoylamino) -3- (2
-Hydroxyethyl) -2-methylbenzo [b] furan (300 mg), triethylamine (832 mg) and dimethylsulfoxide (0.9 ml) in a mixture of dichloromethane (3 ml) in a mixture of ice-cooled and stirred sulfur trioxide-
A pyridine complex (197 mg) was added, and the mixture was stirred at ambient temperature for 1 hour. Further sulfur trioxide-pyridine complex (262 mg) was added to the mixture and the mixture was stirred for 2 hours. The resulting mixture was diluted with dichloromethane, washed with water and saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate and filtered. The solution was evaporated under reduced pressure to give 7- (2
6-Dichlorobenzoylamino) -2-methyl-3-formylmethylbenzo [b] furan (332 mg) was obtained as an amorphous substance.

NMR (CDCl ₃ , δ): 2.41 (3H, s), 3.68 (2
H, s), 7.20 (1H, t, J = 8Hz), 7.23-7.43 (4H, m), 7.81-7.
93 (1H, m), 8.32 (1H, d, J = 8Hz), 9.74 (1H, s)

Example 37 (E) -7- (2,6-dichlorobenzoylamino)-
2-Methyl-3- [2- (2-pyridyl) vinyl] benzo [b] furan (100 mg) and platinum (IV) oxide
The mixture with (15 mg) was added to the mixture at atmospheric pressure at ambient temperature for 24 hours.
It was hydrotreated for an hour. The resulting mixture was filtered and evaporated under reduced pressure. The residue was purified by silica gel chromatography. Elute with n-hexane / ethyl acetate (1: 2) and crystallize the resulting oil from diethyl ether to give 7- (2,6-dichlorobenzoylamino)-
2-Methyl-3- [2- (2-pyridyl) ethyl] benzo [b] furan (37 mg) was obtained.

Mp: 193-195 ° C. NMR (CDCl ₃ , δ): 2.14 (3H, s), 3.08 (4H, t, J = 7Hz),
6.95 (1H, d, J = 8Hz), 7.11 (1H, m), 7.20-7.27 (2H, m),
7.30-7.42 (3H, m), 7.52 (1H, t, J = 8Hz), 7.80 (1H, br
s), 8.28 (1H, t, J = 8Hz), 8.57 (1H, d, J = 8Hz)

Example 38 3-Carboxymethyl-7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan (100
mg), 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (56 mg) and 1-hydroxybenzotriazole (39 mg) in N, N-dimethylformamide (1 ml) at ambient temperature.
Stirred for 0 minutes. 2-Pyridinecarboxamide oxime (40 mg) was added to the mixture and the mixture was stirred at ambient temperature for 1 hour. To the mixture was added a (1: 2) mixture of 2-propanol and water and the separated solid was collected. The obtained solid was dissolved in an acetic acid (1.5 ml) -N, N-dimethylformamide (1.5 ml) mixture, and the mixture was stirred at 100 ° C. for 2 hr. After concentration, the mixture was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The oil obtained was crystallized from ethanol to give 7- (2,6
-Dichlorobenzoylamino) -2-methyl-3-
[[3- (2-Pyridyl) -1,2,4-oxadiazol-5-yl] methyl] benzo [b] furan (76m
g) was obtained.

Mp: 228-229 ° C NMR (DMSO-d ₆ , δ): 2.50 (3H, s), 4.56 (2H, s), 7.23
(1H, t, J = 8Hz), 7.36 (1H, d, J = 8Hz), 7.50 (1H, m), 7.54-
7.61 (3H, m), 7.81 (1H, d, J = 8Hz), 7.96-8.06 (2H, m),
8.73 (1H, d, J = 6Hz)

Example 39 A mixture of 2-picolyl chloride hydrochloride (212 mg) and triphenylphosphine (372 mg) in N, N-dimethylformamide (5 ml) was stirred at 140 ° C for 20 hours. To this mixture, 7- (2,6-dichlorobenzoylamino) -3-formyl-2-methylbenzo [b] furan (300 mg) and potassium tertiary butoxide (425 mg) were added under ice cooling and stirring. 1.5 for the mixture
Stir for hours and partition between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The residue was purified by silica gel column chromatography. Elute with dichloromethane / methanol (200: 1 to 50: 1) and crystallize the resulting oil from an ethanol-water mixture to give (E) -7- (2,6-dichlorobenzoylamino) -2- Methyl-3- [2- (2-pyridyl) vinyl] benzo [b] furan (255 mg) was obtained.

Mp: 237-239 ° C. NMR (CDCl ₃ , δ): 2.60 (3H, s), 7.15 (1H, m), 7.22 (1
H, m), 7.30-7.43 (5H, m), 7.64-7.77 (3H, m), 7.88 (1
H, br s), 8.38 (1H, d, J = 8Hz), 8.61 (1H, m)

The following compound was obtained as in Example 39.

Example 40 (E) -7- (2,6-dichlorobenzoylamino)-
2-Methyl-3- [3- (2-pyridyl) -2-propenyl] benzo [b] furan

Mp: 165-167 ° C. NMR (CDCl ₃ , δ): 2.41 (3H, s), 3.58 (2H, d, J = 7Hz),
6.49 (1H, d, J = 15Hz), 6.86 (1H, dt, J = 7 and 15Hz),
7.09 (1H, t, J = 8Hz), 7.18-7.28 (3H, m), 7.30-7.42 (3
H, m), 7.59 (1H, t, J = 8Hz), 7.84 (1H, br s), 8.29 (1H,
d, J = 8Hz), 8.51 (1H, d, J = 5Hz)

The following compound was obtained in the same manner as in Example 1.

Example 41 2-Cyano-7- (2,6-dichlorobenzoylamino) -3-methylbenzo [b] furan

Mp: 298 ° C NMR (DMSO-d ₆ , δ): 2.46 (3H, s), 7.41-7.62 (4H, m),
7.65 (1H, d, J = 8Hz), 8.14 (1H, d, J = 8Hz)

The following compounds (Examples 42 to 44) were obtained in the same manner as in Example 2.

Example 42 3-carbamoylmethyl-7- (2-methyl-6-nitrobenzoylamino) -2-methylbenzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 2.47 (3H, s), 3.42
(2H, s), 6.98 (1H, br s), 7.20 (1H, t, J = 8Hz), 7.36 (1
H, d, J = 8Hz), 7.50 (1H, br s), 7.62 (1H, d, J = 8Hz), 7.72
-7.80 (2H, m), 8.08 (1H, d, J = 8Hz)

Example 43 3-carbamoylmethyl-7- (2-chloro-6-methylbenzoylamino) -2-methylbenzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.39 (3H, s), 2.42 (3H, s), 3.42
(2H, s), 6.98 (1H, br s), 7.19 (1H, t, J = 8Hz), 7.29 (1
H, m), 7.33-7.41 (3H, m), 7.51 (1H, br s), 7.62 (1H, d,
(J = 8Hz)

Example 44 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- (8-quinolyl) benzo [b] furan

Mp: 129-145 ° C. NMR (CDCl ₃ , δ): 2.43 (3H, s), 7.07 (1H, d, J = 8Hz),
7.21 (1H, t, J = 8Hz), 7.32-7.49 (4H, m), 7.66 (1H, t, J = 8)
Hz), 7.79 (1H, d, J = 8Hz), 7.88-7.98 (2H, m), 8.26 (1H,
d, J = 8Hz), 8.34 (1H, d, J = 8Hz), 8.91 (1H, m)

The following compounds (Examples 45 to 46) were obtained in the same manner as in Example 7.

Example 45 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (1H-pyrazol-3-yl) carbamoylmethyl] benzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.47 (3H, s), 3.68 (2H, s), 6.43
(1H, br s), 7.19 (1H, t, J = 8Hz), 7.40 (1H, d, J = 8Hz), 7.
48 (1H, dd, J = 6 and 8Hz), 7.52-7.60 (3H, m), 7.77
(1H, d, J = 8Hz)

Example 46 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (1H-1,2,4-triazole-3
-Yl) carbamoylmethyl] benzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 4.39 (2H, s), 7.20
(1H, t, J = 8Hz), 7.35 (1H, d, J = 8Hz), 7.45-7.60 (4H, m),
7.68 (1H, s), 7.79 (1H, d, J = 8Hz)

The following compounds (Examples 47 to 54) were obtained in the same manner as in Example 8.

Example 47 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (quinolin-8-yl) carbamoylmethyl] benzo [b] furan

Mp: 246 ° C NMR (DMSO-d ₆ , δ): 2.54 (3H, s), 4.05 (2H, s), 7.20
(1H, t, J = 8Hz), 7.44-7.70 (7H, m), 7.79 (1H, d, J = 8Hz),
8.40 (1H, d, J = 8Hz), 8.58 (1H, d, J = 7Hz), 8.88 (1H, m)

Example 48 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (2-trifluoromethylbenzyl) carbamoylmethyl] benzo [b] furan

Mp: 267 ° C. NMR (DMSO-d ₆ , δ): 2.41 (3H, s), 3.60 (2H, s), 4.56
(2H, s), 7.15-7.26 (2H, m), 7.30-7.51 (6H, m), 7.60 (1
H, d, J = 8Hz), 8.25 (1H, d, J = 7Hz)

Example 49 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- (N-methylcarbamoylmethyl) benzo [b] furan

Mp: 279-283 ° C NMR (DMSO-d ₆ , δ): 2.40 (3H, s), 2.57 (3H, d, J = 4Hz),
3.44 (2H, s), 7.18 (1H, t, J = 8Hz), 7.33 (1H, d, J = 8Hz),
7.44-7.58 (3H, m), 7.77 (1H, d, J = 8Hz), 7.93 (1H, m)

Example 50 7- (2,6-Dichlorobenzoylamino) -3-
(N, N-Dimethylcarbamoylmethyl) -2-methylbenzo [b] furan

Mp: 210-212 ° C. NMR (DMSO-d ₆ , δ): 2.38 (3H, s), 2.83 (3H, s), 3.06
(3H, s), 3.70 (2H, s), 7.17 (1H, t, J = 8Hz), 7.29 (1H, d,
J = 8Hz), 7.44-7.60 (3H, m), 7.76 (1H, d, J = 8Hz)

Example 51 7- (2,6-dichlorobenzoylamino) -3- [N
-(2-Hydroxyphenyl) carbamoylmethyl]-
2-methylbenzo [b] furan

Mp: 248 ° C. (decomposition) NMR (DMSO-d ₆ , δ): 2.46 (3H, s), 3.84 (2H, s), 6.74
(1H, t, J = 8Hz), 6.84 (1H, d, J = 8Hz), 6.94 (1H, t, J = 8Hz),
7.20 (1H, t, J = 8Hz), 7.44 (1H, d, J = 8Hz), 7.48-7.60
(3H, m), 7.78 (2H, d, J = 8Hz), 9.40 (1H, br s), 10.86 (1
H, br s)

Example 52 3- [N- (3-Bromoquinolin-8-yl) carbamoylmethyl] -7- (2,6-dichlorobenzoylamino) -2-methylbenzo [b] furan

Mp: 196 ° C. NMR (CDCl ₃ , δ): 2.55 (3H, s), 3.86 (2H, s), 7.25-7.
44 (6H, m), 7.51 (1H, t, J = 8Hz), 7.85 (1H, br s), 8.24
(1H, d, J = 2Hz), 8.33 (1H, d, J = 8Hz), 8.60 (1H, d, J = 2H)
z), 8.70 (1H, d, J = 8Hz), 9.85 (1H, br s)

Example 53 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (2-pyridylmethyl) -N- (ethoxycarbonylmethyl) carbamoylmethyl] benzo [b] furan

Mp: 121-129 ° C. NMR (CDCl ₃ , δ): 1.10-1.29 (3H, m), 2.32 (2H, s), 2.
39 (1H, s), 3.64 (0.67H, s), 3.83 (1.33H, s), 4.00-4.2
5 (4H, m), 4.74 (2H, s), 6.97 (0.67H, d, J = 8Hz), 7.13-
7.43 (5.33H, m), 7.50-7.65 (1H, m), 7.74 (0.67H, br
s), 7.80 (0.33H, br s), 8.21-8.33 (1H, m), 8.48 (0.3
3H, d, J = 5Hz), 8.55 (0.67H, d, J = 5Hz)

Example 54 3- [N- (2-carbamoylphenyl) carbamoylmethyl] -7- (2,6-dichlorobenzoylamino)
-2-Methylbenzo [b] furan

Mp: 249-252 ° C NMR (DMSO-d ₆ , δ): 2.49 (3H, s), 3.78 (2H, s), 7.08
(1H, t, J = 8Hz), 7.18 (1H, t, J = 8Hz), 7.33 (1H, d, J = 8Hz),
7.40-7.60 (4H, m), 7.68 (1H, br s), 7.77 (1H, d, J = 8H
z), 7.82 (1H, d, J = 8Hz), 8.22 (1H, br s), 8.47 (1H, d,
(J = 8Hz)

The following compounds (Examples 55 to 57) were obtained in the same manner as in Example 28.

Example 55 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (quinolin-8-yl) carbamoylmethyl] benzo [b] furan hydrochloride

Mp: 243 ° C. NMR (DMSO-d ₆ , δ): 2.55 (3H, s), 4.06 (2H, s), 7.18
(1H, t, J = 8Hz), 7.44-7.71 (7H, m), 7.79 (1H, d, J = 8Hz),
8.42 (1H, d, J = 8Hz), 8.57 (1H, d, J = 7Hz), 8.90 (1H, m)

Example 56 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (1H-1,2,4-triazole-3
-Yl) carbamoylmethyl] benzo [b] furan hydrochloride

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.45 (3H, s), 4.39 (2H, s), 7.20
(1H, t, J = 8Hz), 7.35 (1H, d, J = 8Hz), 7.49 (1H, dd, J = 6 and 8Hz), 7.52-7.60 (2H, m), 7.71 (1H, br), 7.75 (1
H, s), 7.78 (1H, d, J = 8Hz)

Example 57 7- (2,6-Dichlorobenzoylamino) -2-methyl-3- [N- (1H-pyrazol-3-yl) carbamoylmethyl] benzo [b] furan hydrochloride

Mp: 165-175 ° C. NMR (DMSO-d ₆ , δ): 2.47 (3H, s), 3.68 (2H, s), 6.43
(1H, br s), 7.19 (1H, t, J = 8Hz), 7.40 (1H, d, J = 8Hz), 7.
48 (1H, dd, J = 6 and 8Hz), 7.52-7.60 (3H, m), 7.77
(1H, d, J = 8Hz)

In the same manner as in Preparation Example 3, the following compound was obtained.

Example 58 7- (3-Amino-2,6-dichlorobenzoylamino) -3-carbamoylmethyl-2-methylbenzo [b] furan

Mp:> 250 ° C. NMR (DMSO-d ₆ , δ): 2.41 (3H, s), 3.41 (2H, s), 5.68
(2H, s), 6.84 (1H, d, J = 8Hz), 6.97 (1H, br s), 7.14-7.
21 (2H, m), 7.34 (1H, d, J = 8Hz), 7.50 (1H, br s), 7.71
(1H, d, J = 8Hz)

[0227]

The benzofuran derivative of the present invention is useful as a bone resorption inhibitor and a bone metastasis inhibitor. Therefore, according to the invention, osteoporosis in humans or animals (especially postmenopausal osteoporosis); hypercalcemia; hyperparathyroidism; Paget's bone disease; osteolysis; malignant hypercalcemia with or without bone metastasis. Rheumatoid arthritis; Periodontitis; Osteoarthritis; Bone pain; Osteopenia; Cancer cachexia; and the like, could be provided a preparation for the prevention and / or treatment of bone diseases characterized by abnormal bone metabolism.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location C07D 307/80 C07D 307/80 405/12 213 405/12 213 215 215 231 231 231 235 235 249 249 413 / 14 213 413/14 213 // (C07D 413/14 213: 16 263: 32 307: 79) (72) Inventor Teruo Oku 8-2 Midorigaoka, Tsukuba City, Ibaraki Prefecture

Claims (4)

[Claims] 1. A compound of the general formula (I) [Wherein R ¹ is formyl, carbamoyl lower alkyl,
Thiomorpholinocarbonyl lower alkyl, thiomorpholinocarbonyl lower alkyl S-oxide, pyridylaminocarbonyl lower alkyl, pyrazolylaminocarbonyl lower alkyl, triazolylaminocarbonyl lower alkyl, quino which may have one or more appropriate substituents. Rylaminocarbonyl lower alkyl, 3-pyridyl lower alkylaminocarbonyl lower alkyl, 4-pyridyl lower alkylaminocarbonyl lower alkyl, pyridylethylaminocarbonyl lower alkyl, pyridyl lower alkylaminocarbonyl lower alkyl N-oxide,
Benzimidazolyl lower alkylaminocarbonyl lower alkyl, N-pyridyl lower alkyl-N-acyl lower alkylaminocarbonyl lower alkyl, N-pyridyl-N-lower alkylaminocarbonyl lower alkyl, lower alkylaminocarbonyl lower alkyl, dilower alkylaminocarbonyl Methyl, quinolyl, 2-hydroxyethyl, 2-hydroxy-2-methylpropyl, cyano lower alkyl, di lower alkylamino lower alkyl,
Pyridyl lower alkyl, triazolyl lower alkyl, 1
One or more suitable substituents, pyrazolyl lower alkyl, one or more suitable substituents, pyrimidinyl lower alkyl, one or more suitable substituents Optionally dihydrophthalazinyl lower alkyl, oxadiazolyl lower alkyl optionally having one or more suitable substituents, heterocyclic lower alkenyl optionally having one or more suitable substituents, 1 Lower alkoxy lower alkylamino lower alkyl optionally having the above suitable substituents, aryl lower alkylaminocarbonyl lower alkyl optionally having one or more suitable substituents, one or more suitable lower substituents Arylaminocarbonyl lower alkyl which may have a substituent, arylthio lower alkyl which may have one or more appropriate substituents, lower alkyl Other is imidazolyl lower alkyl, R ² is lower alkyl, protected carboxy or cyano, R ³ is halogen or lower alkyl, R ⁴ is hydrogen, nitro or amino, R ⁵ is halogen, lower Alkyl or nitro. Provided that 1) when R ¹ is methyl, R ² is protected carboxy or cyano; and 2) when R ¹ is imidazolylmethyl, R ² is protected carboxy or cyano. ] The compound represented by these, or its salt. 2. R ¹ is carbamoyl lower alkyl, 3-
Pyridyl lower alkyl aminocarbonyl lower alkyl,
Pyridylaminocarbonyl lower alkyl, quinolylaminocarbonyl lower alkyl optionally having one or more suitable substituents, lower alkylaminocarbonyl lower alkyl, dilower alkylaminocarbonylmethyl, or one or more suitable substitutions The compound according to claim 1, which is an arylaminocarbonyl lower alkyl which may have a group, R ² is lower alkyl, R ³ is halogen, R ⁴ is hydrogen and R ⁵ is halogen. . 3. i) General formula (III): [Wherein R ³ , R ⁴ and R ⁵ are each as defined in claim 1], or a reactive derivative at the carboxy group thereof or a salt thereof is represented by the general formula (I
I) [Wherein R ¹ and R ² are each as defined in claim 1] or by reacting with a reactive derivative at its amino group or a salt thereof, or ii) the general formula (IV) [Chemical 4] [Where Z is pyridyl, pyrazolyl, triazolyl,
A quinolyl optionally having one or more suitable substituents,
3-pyridyl lower alkyl, 4-pyridyl lower alkyl, pyridyl ethyl, pyridyl lower alkyl N-oxide, benzimidazolyl lower alkyl, aryl lower alkyl optionally having one or more suitable substituents or one or more A compound which is an aryl which may have a suitable substituent], or a reactive derivative at the amino group thereof or a salt thereof, is represented by the general formula (Ib): [Wherein R ² , R ³ , R ⁴ and R ⁵ are each defined in claim 1]
And A is lower alkylene], or a reactive derivative at the carboxy group thereof or a salt thereof to give a compound of the general formula (Ia) [Wherein R ² , R ³ , R ⁴ and R ⁵ are each defined in claim 1]
R ¹ _a is pyridylaminocarbonyl lower alkyl, pyrazolylaminocarbonyl lower alkyl, triazolylaminocarbonyl lower alkyl, quinolylaminocarbonyl lower optionally having one or more suitable substituents. Alkyl, 3-pyridyl lower alkylaminocarbonyl lower alkyl, 4-pyridyl lower alkylaminocarbonyl lower alkyl, pyridylethylaminocarbonyl lower alkyl, pyridyl lower alkylaminocarbonyl lower alkyl N-oxide, benzimidazolyl lower alkylaminocarbonyl lower alkyl, 1 Aryl lower alkylaminocarbonyl lower alkyl optionally having one or more suitable substituents or arylaminocarbonyl lower alkyl optionally having one or more suitable substituents Compounds of a kill, or to produce a salt A compound according to claim 1 (I), or a manufacturing method of a benzofuran derivative, characterized in that a salt thereof. 4. A medicine comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.