WO1992003427A1 - Ketone compound and remedy for osteoporosis - Google Patents

Abstract

The use of a compound of general formula (I') or a salt thereof in treating osteoporosis and a novel compound included in the above compound, wherein the ring X' represents benzene or pyridine; Y represents oxygen or sulfur; Z' represents a single bond, alkylene, alkenylene, alkynylene or NR5, wherein R5 represents hydrogen, alkyl, acyl, optionally substituted aralkyl or a group which forms a nitrogenous heterocyclic ring together with R?4'; R1 and R2¿ represent each hydrogen, halogen, alkyl, alkoxy, hydroxy, cyano, haloalkyl, carboxyl, optionally alkyl-substituted amino, optionally alkyl-substituted carbamoyl, alkoxycarbonyl, optionally substituted phenyl, nitro, acyl, optionally alkyl-substituted sulfamoyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, optionallly alkyl-substituted aminoalkyl or acylaminoalkyl, or alternatively R?1 and R2¿ may be combined together to represent optionally substituted alkylene, alkylenedioxy or a benzene ring; R3 represents hydroxy, acyloxy, alkoxy, optionally alkyl-substituted aminoalkoxy, alkylsulfonylamino, optionally alkyl-substituted aminoalkylsulfonylamino or arylsulfonylamino; and R4' represents hydrogen, alkyl, optionally substituted aralkyl, an optionally substituted aromatic group or an optionally substituted heteroaromatic group.

Description

 Specification

 Ketone compounds and therapeutic agents for osteoporosis

 `` Technical field J

 INDUSTRIAL APPLICABILITY The present invention has an excellent bone resorption inhibiting action, and is useful as a therapeutic agent for osteoporosis, a novel ketone compound and a pharmaceutically acceptable salt thereof, and a ketone compound including the novel compound and a pharmaceutically acceptable salt thereof. Related to the use of salt.

 `` Background technology J

 Osteoporosis is a syndrome that refers to a condition in which the amount of bone per unit volume is abnormally reduced without changing the chemical composition of the bone itself (the ratio between organic and inorganic substances). Calcium and phosphorus reduction are its physiological characteristics.

 Because bone loss as a pathological condition is accompanied by a decrease in bone mass due to physiological aging, the definition of bone loss is more pronounced than that due to physiological aging. It can be said that the patient had clinical symptoms such as a mechanical fracture and vertebral deformity.

 Osteoporosis increases with age and usually affects the spinal cord, causing lower back and back pain and shorter height. Especially in advanced cases, the long bones are also affected, and sometimes fractures may occur. It is said that most of the causes of femoral fractures in the elderly are due to senile osteoporosis.

The causes of osteoporosis are diverse, including endocrine abnormalities, including menopause, and nutritional disorders.However, vitamin D, calcium, calcitonin, and bisphosphonate, which have been used as treatments for osteoporosis, are targeted Or its effect But it is not certain. Although female hormone preparations can be expected to be effective, serious side effects (eg, genitals caused by long-term use) are problematic.

 Therefore, there is a strong demand for the development of a more effective and safe osteoporosis therapeutic agent.

 In recent years, thonaphthene-121-ruvonic acid derivatives or 3-phenyl-2-H-benzo-pyran-141-one derivatives (isoflavone derivatives), which have a completely different chemical structure from the above preparations, have been used for the production of bone resorption inhibitors. And has been reported to be useful as a therapeutic agent for osteoporosis [AJ Johannesson et al., Endocrinology, Vol. 117, page 1508, European Patent Publication No. 1351 No. 72, U.S. Patent Publication No. 1 366 569, U.S. Patent Publication No. 1,469,211, U.S. Patent No. 4,644,012 ].

 Further, as derivatives having a bone resorption inhibiting action, a (cycloalkylamino) methylenebis (phosphonic acid) derivative (US Pat. No. 4,970,335), a heterocyclic bisphosphonic acid derivative (US Pat. No. 0503) and benzofuroquinoline derivatives (Japanese Patent Publication No. 3571172).

On the other hand, thieno or furopyridine compounds include 3-hydroxyl xyph [2,3-b] pyridin-l-2-ethyl ethyl ribonate and 3-hydroxythieno [2,3-b] pyridine-12-cal J. Heterocyclic Chem. 23, 1465-1469, 1986 Year, Vol. 24, pp. 85-89, reported in 1987. However, these are all synthesized for the purpose of confirming their interest in synthesis or chemical reactivity, and do not describe any pharmacological activity. Further, Canadian Published Patent Application No. 2009-171 discloses a 3-hydroxybenzthiophene or chenoviridine compound for controlling in vivo parasites. In addition, British Patent No. 1119496 discloses a benzothiophene compound having an analgesic and anti-inflammatory effect and the like.

 The activity of suppressing the bone resorption of the thionaphthene 1-2-carburonic acid derivative or the 3-phenyl-4H-1 benzovirane derivative (isoflavone derivative) reported in the above-mentioned literature is weak, and is never satisfactory as a therapeutic agent for osteoporosis. is not.

 "Disclosure of Invention J

 The present inventors have synthesized various ketone compounds for the purpose of developing a better therapeutic agent for osteoporosis, and have conducted intensive studies on their pharmacological actions. The inventors have found ketone compounds and have completed the present invention. The present invention is as follows.

 1. Formula (I)

 [In the formula, each symbol is as described below. ]

The ketone compound (I) represented by or a pharmaceutically acceptable ili 0 Ring X represents a pyridine ring.

 Y represents an oxygen atom or a sulfur atom.

 Z represents a single bond, alkylene, alkenylene, or alkynylene.

R ¹ and R ² may be the same or different, and may be hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl, rubamoyl optionally substituted with alkyl, alkoxycarbonyl, Optionally substituted phenyl, nitro, acetyl, sulfamoyl optionally substituted with alkyl, alkylthio, aryloxy, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy Represents hydroxyalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl which may be substituted with alkyl, aminoalkyl which may be substituted with alkyl, or acylaminoalkyl. R ¹ and R ² alkylene which may have a bond to a substituent from each other, even alkylenedioxy O carboxymethyl properly represents a group forming a benzene present.

R ³ represents a hydroxyl group, an acyloxy, an alkody, an aminoalkoxy optionally substituted with an alkyl, an alkylsulfonylamino, an aminoaminosulfonylamino optionally substituted with an alkyl, or an arylsulfonylamino.

R is alkyl, aralkyl which may have a substituent, aromatic ring which may have a substituent or heteroaromatic group which may have a substituent (the substituent is halogen, Alkyl, Arco W

 Five

 Xy, hydroxyl, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxyl, amino, alkamoyl, alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoyl Alkenyl, haloalkoxy, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, and 1-3 amino substituents).

 2. Equation (I '')

X '(Γ')

 Purchase Ci V

 [In the formula, each symbol is as described below. )

 Or a pharmaceutically acceptable salt thereof (I '') represented by

 Cyclic X ′ represents a benzene ring or a pyridine ring.

R ^3A represents a hydroxyl group or acyloxy.

R ^4A represents aminoalkyl optionally substituted with alkyl or acylaminoalkyl optionally substituted with alkyl.

 Other symbols are as defined above.

3. Equation (I ')

[In the formula, each symbol is as described below. ]

A therapeutic agent for osteoporosis comprising, as an active ingredient, a ketone compound (1 ') represented by the formula: or a pharmaceutically acceptable salt thereof.

Z ′ represents a single bond, alkylene, alkenylene, alkynylene or 1 NR ⁵ —. (However, R ⁵ represents hydrogen, alkyl, acyl, aralkyl which may have a substituent, or a group which forms a nitrogen-containing heterocycle by bonding with R * ′.)

R ⁴ ′ is hydrogen, alkyl, an optionally substituted arylalkyl, an optionally substituted aromatic ring group or an optionally substituted heteroaromatic ring group (substituent and Are halogen, alkyl, alkoxy, hydroxyl, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, cyano, nitro, acsyl. Alkoxycarbonyl, carboxyl, carboxyl, amino, alkylamino. (1 to 3 substituents selected from aminoalkoxy, aminoalkyl optionally substituted with alkyl, haloalkoxy, aminoalkoxy which may be substituted with alkyl, aminoalkyl optionally substituted with alkyl) Is shown.

Rings X ′, Y, R ¹ , R ² , and R ³ have the same meaning as defined above. 4. Use of the compound (1 ') or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for treating osteoporosis.

 5. A method for treating osteoporosis using an effective amount of compound (1 ') or a pharmaceutically acceptable salt thereof for treating osteoporosis.

 In this specification, each symbol means the following.

 1. The meaning of each symbol for Z and Z '.

 The alkylene may be linear or branched, and usually has 1 to 4 carbon atoms, and specific examples include methylene, ethylene, trimethylene, propylene, and tetramethylene.

 Alkenylene may be linear or branched, and usually has 1 to 4 carbon atoms, and specific examples thereof include vinylene, bronylene, butenylene and the like.

 Alkynylene may be linear or branched, and usually has 1 to 4 carbon atoms. Specific examples thereof include ethynylene, brovinylene, and petinylene.

As for R ^s of Z ′, examples of the alkyl include those similar to the alkyl for R ¹ and R ² described below.

Regarding R ⁵ of Ζ ′, examples of the acyl include the same as those described below for R ¹ and R ² .

Examples of the aralkyl which may have a substituent with respect to R ⁶ of Ζ ′ include the same as the aralkyl which may have a substituent with respect to R ⁴ and below.

Examples of the nitrogen-containing heterocyclic ring formed by bonding Z ′ to R ⁴ ′ include oxygen, sulfur, or a nitrogen atom which may be substituted as a hetero atom (substituents such as alkyl, phenylalkyl, and a And a 5- to 7-membered ring which may have pyrrolidine, piperidine, morpholine, virazine, 4-methylbiperazine and the like.

2. The meaning of each symbol relating to R ¹ and R ^2.

 C D-gen means fluorine, chlorine, bromine, and iodine.

 Alkyl may be either straight or branched, and usually has 1 to 10, preferably 1 to 8, and more preferably 1 to 6, carbon atoms. Specifically, methyl, ethyl, propyl, isopropyl Butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl, octyl and the like.

 Alkoxy may be linear or branched, and usually has 1 to 10, preferably 1 to 8, and more preferably 1 to 6, carbon atoms. Specifically, methoxy, ethoxy , Propoxy, isopropoxy, butoxy, isobutoxy, second-butoxy, third-butoxy, pentyloxy, hexyloxy, octyloxy and the like.

 The alkyl moiety in the haloalkyl may be either linear or branched, and usually has 1 to 4, preferably 1 to 3 carbon atoms.Specific examples of haloalkyl include fluoromethyl, difluoromethyl, Bromomethyl, chloromethyl, trifluoromethyl, trifluorethyl, and pentafluorov mouth building are exemplified.

Amino in amino which may be substituted with alkyl may be mono- or di-substituted with alkyl having 1 to 4 carbon atoms, preferably in a linear or branched form, In addition, No. may be annular. Specific examples of such amino include amino, methylamino, dimethylamino, ethylamino, ethylamino, pyrrolidino, biperidino, morpholino, and the like.

 Alkyl as a substituent in the sorbamoyl which may be substituted with alkyl has usually 1 to 5, preferably 1 to 3 carbon atoms. The amino may be cyclic. Specific examples of such rubamoyl include rubamoyl, methylcarbamoyl, dimethylcarbamoyl, and morpholino rubamoyl.

 The alkoxy moiety in the alkoxycarbonyl may be linear or branched, and has 1 to 4 carbon atoms. Examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, and propoxycarbonyl. , Isopropoxycarbonyl, butoxycarbonyl, isobutoxydicarbonyl, third-butoxycarbonyl and the like.

The substituent in the phenyl which may have a substituent is the same as the substituent in the aromatic ring which may have a substituent or the heteroaromatic ring which may have an S group described below for R ^4. Examples are preferably alkyl, halogen, alkoxide, hydroxyl group, aminoalkoxy optionally substituted with nitroalkyl, aminoalkyl optionally substituted with alkyl, and acylaminoalkyl. Examples of such phenyl include chlorophenyl, methylphenyl, methoxyphenyl, nitrophenyl, dimethylaminoethylphenyl, dimethylaminobromoboxyl Phenyl, hydroxyphenyl, acetylaminoethylphenyl and the like.

 The acyl may be any of an aliphatic acyl, an aromatic acyl, and a heterocyclic acyl. The aliphatic acyl is preferably an Al-oil, and particularly preferably an Al-oil having 2 to 5 carbon atoms. Specific examples of acetyl include acetyl, bropionyl, butyryl, bivaloyl, benzoyl, floyl, tenyl, nicotinyl, and isonicotinyl.

 The alkyl as a substituent in the sulfamoyl optionally substituted with argyl may be either linear or branched, and may be mono-substituted or di-substituted. The alkyl has usually 1 to 4, preferably 1 to 2, carbon atoms. Examples of such sulfamoyl include sulfamoyl, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, and getylsulfamoyl.

 Alkyl in alkylthio may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms.As alkylthio, methylthio, ethylthio, propylthio, isobrovirthio, Butylthio and the like.

 Specific examples of arylthio include phenylthio, tolylthio, and chlorofluorothio.

Alkyl in alkylsulfinyl may be linear or branched, and usually has 1 to 4, preferably 1 to 2, carbon atoms.Examples of alkylsulfinyl include methylsulfinyl, ethylsulfiel, butylsulfinyl and the like. Is exemplified You.

 Specific examples of arylsulfinyl include phenylsulfinyl, tolylsulfenyl, and chlorophenylsulfinyl.

 Alkyl in alkylsulfonyl may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms.Examples of alkylsulfonyl include methylsulfonyl, ethylsulfonyl, and butylsulfoyl. Is exemplified.

 Specific examples of arylsulfonyl include phenylsulfonyl, trisulfonyl, and chlorophenylsulfonyl.

 Specific examples of aryloxy include phenyloxy, trioxy, chlorooxy, nitrooxy, and the like. Examples of aralkyloxy include benzyloxy, phenylethoxy, and fuyunylbutoxy.

 The alkyl moiety in the hydroxyalkyl may be linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, and includes hydroxymethyl, hydroxyxetyl and the like.

Examples of the acyl moiety in the acyloxyalkyl include the acyl as described above, and the alkyl moiety may be either linear or technical, and usually has 1 to 4, preferably 1 to 2 carbon atoms. Examples of the acyloxyalkyl include acetoxmethyl, acetoxityl, acetooxybutyl, bropionoxyloxymethyl, and bivaloyloxymethyl. The alkoxy moiety in the alkoxyalkyl may be either linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. The carbon number is usually 1 to 4, preferably 1 to 2, and the alkoxyalkyl is exemplified by methoxymethyl, methoxyl, ethoxyl, methoxybutyl and the like.

 Alkyl as a substituent in the aminoalkoxy which may be substituted with alkyl may be either mono-substituted or di-substituted, and the alkyl may be any of straight-chain or branched-chain, and its carbon number is Usually, it is 1-4, preferably 1-2, and the alkoxy moiety may be either linear or branched, and its carbon number is usually 1-4, preferably 1-2. Further, the amino alkoxy may be a cyclic amino alkoxy. Examples of the aminoalkoxy include aminoethoxy, methylaminomethoxy, dimethylaminoethoxy, 1-pyrrolidinylmethoxy, biperidinomethoxy, morpholinomethoxy and the like.

Alkyl as a substituent in aminoamino which may be substituted with alkyl may be either mono-substituted or di-substituted, and the alkyl may be either linear or branched, and the number of carbon atoms is usually The alkyl moiety may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms. In addition, the aminoalkyl may be a cyclic aminoalkyl. Examples of the aminoalkyl include aminomethyl, methylaminomethyl, and dimethylaminomethyl. Examples thereof include methyl, ethylaminomethyl, dimethylaminobutyrol, 1-pyrrolidinylmethyl, piberidinomethyl, and morpholinoethyl.

 The acyl moiety as a substituent in the acylaminoalkyl may be linear or branched, and usually has 2 to 4 carbon atoms. As the alkanoyl or cyclic substituent, halogen, alkyl (1 to 4 carbon atoms) may be used. , Preferably a straight-chain or branched alkyl having 1 to 2 carbon atoms, an alkoxy group (a straight-chain or branched alkody having 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms), and a nitro group. And the alkyl moiety may be either linear or branched, and usually has 1-4 carbon atoms, preferably 1-2 carbon atoms. Examples of the acetylaminoalkyl include acetylaminomethyl, acetylaminoethyl, brovonylaminomethyl, propionylaminoethyl, benzoylaminoethyl and the like.

Examples of the substituent in the alkylene, alkylenedioxy and benzene ring which may be substituted, which are formed by bonding R ¹ and R ² to each other, include R ′ and R ² . The following are included, and preferably, for example, the following are exemplified as preferred.

 ①Halogen (chlorine, bromine, fluorine, etc.)

 (2) Alkyl (It may be straight-chain or divided, and its carbon number is usually 1 to 4, preferably 1 to 2.)

(3) Alkoxy (It may be either straight-chain or branched, and its carbon number is usually 1-4, preferably 1-2.) (4) Haloalkyl (The alkyl moiety may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms.)

 ⑤ hydroxyl group

 ⑥ Siano

 Penit mouth

 ぃ Amino may be substituted by alkyl (the alkyl moiety may be either linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms.)

 The alkylene which may have a substituent preferably has 1 to 4 carbon atoms, and examples thereof include methyltrimethylene, dimethyltrimethylene, methyltetramethylene, dimethyltetramethylene, and dimethylpentamethylene.

 Alkylene in alkylenedioxy which may have a substituent has 1 to 4 carbon atoms, and alkylenedioxy includes methylenedioxy, ethylenedioxy, isopropylidenedioxy and the like.

 Examples of the group which forms a benzene ring which may have a substituent include benzene, methylbenzene, hydroxybenzene, methoxybenzene, trifluoromethylbenzene, cyanobenzene, nitrobenzene, dimethylaminobenzene and the like. Is exemplified.

3. The meaning of each symbol related R ^3.

Examples of the acyl in the acyloxy include those described for R ¹ and R ^2. Examples include cetoxy, bropionyloxy, benzoyloxy and the like.

Examples of alkoxy include those as described for R ¹ and R ² .

Examples of aminoalkoxy which may be substituted with alkyl include those described for R ¹ and R ² .

 The alkyl moiety in the alkylsulfonylamino may be either linear or branched, and usually has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms. Sulfonylamino, ethylsulfonylamino, butylsulfonylamino and the like can be mentioned.

 The alkyl and the alkyl moiety as the substituents in the aminoalkylsulfonylamino which may be substituted with alkyl may be either straight-chain or branched, respectively, and usually have 1 to 4 carbon atoms. Preferably, it is 1-2, and the alkyl substitution may be either mono or di substitution. Examples of the aminoalkylsulfonylamino include aminomethylsulfonylamino, aminoethylsulfonylamino, aminobutylsulfonylamino, methylaminoethylsulfonylamino, dimethylaminoethylsulfonylamino, dimethyl Pyrsulfonylamino amino and the like. The aminoalkylsulfonylamino may be a cyclic aminoalkylsulfonylamino, such as pyrrolidinomethylsulfonylamino, piperidinomethylsulfonylamino, and the like.

Phenylsulfonylamino as phenylsulfonylamino Mino, tolylsulfonylamino, black phenylsulfonylamino, and the like.

4., The meaning of the symbols relating to R ⁴ '.

Examples of the alkyl include those described with respect to R ¹ and R ² .

The substituent in the aralkyl which may have a substituent is the same as the substituent in the aromatic ring which may have a substituent or the heteroaromatic ring which may have a substituent for R ⁴ described below. And preferably include halogen, alkyl, alkoxy, aminoalkoxy optionally substituted with alkyl, aminoamino optionally substituted with alkyl, acylaminoalkyl, and the like. Examples of such aralkyl include benzyl, phenylethyl, phenylpropyl, phenylbutyl, chlorobenzyl, methylbenzyl, methoxyphenylethyl, dimethylaminobromoboxylbenzyl, dimethylaminoethylbenzyl, acetylaminomethylmethylbenzyl and the like. Is done.

 The substituent on the aromatic ring which may have a substituent or the heteroaromatic ring which may have a substituent is as follows.

 ①Halogen such as fluorine, chlorine and bromine;

 (2) C 1-4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, etc .;

③ Alkoxy with 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and tert-butoxy;

④ hydroxyl group; Alkylthio having usually 1 to 4 carbon atoms in the alkyl moiety, such as methylthio, ethylthio, brovirthio, isopropylthio, butylthio, isobutylthio, and tert-butylthio;

 Alkyl sulfiel whose alkyl group moiety such as methylsulfiel, ethylsulfinyl and propylsulfinyl usually has 1 to 4 carbon atoms;

 ア ル キ ル alkylsulfonyl wherein the alkyl moiety such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like is usually 1 to 4;

 Haloalkyl in which the alkyl portion of the alkyl moiety such as trifluoromethyl, trifluorethyl and the like usually has 1 to 4 carbon atoms;

 ⑨ Siano;

 ⑩nit mouth;

 An acyl as described above, including diacetyl, propionyl, butyryl, benzoyl and the like;

 ア ル コ キ シ alkoxycarbonyl having 1 to 4 carbon atoms, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl; ⑬carboxyl;

 Amino which may be mono- or di-substituted by alkyl having 1 to 4 carbon atoms, such as diamino, methylamino, ethylamino, pyrrolidino, pyridino, morpholino;

力 Capacyl which may be mono- or di-substituted by alkyl having 1 to 4 carbon atoms, such as carbamoyl, methylcarbamoyl and ethylcarbamoyl; ア ル キ レ ン alkylene dioxy having alkylene having 1 to 4 carbon atoms, such as methylene dioxy and ethylene dioxy;

 An alkyl moiety such as cyanomethyl, cyanoethyl, cyanobutyl pill, cyanobutyl, etc., which may be straight or branched, and whose carbon number is usually 1 to 4;

Alkyl and alkoxy moieties such as methoxycarbonylethyl and ethoxycarbonylethyl may be either linear or branched, each having 1 to 4 carbon atoms, alkoxycarbonylalkyl;

 ⑩ The alkyl group portion such as carboxymethyl, 1-carboxyethyl, 2-carboxyethyl and the like may be linear or branched, and a carboxylalkyl having an alkyl group usually having 1 to 4 carbon atoms;

 力 carbamoylmethyl, 1-carbamoylethyl, 2-carbamoylethyl or the like having 1 to 4 carbon atoms;

 @Haloalkoxy wherein the alkoxy moiety such as chloroethoxy, trifluoromethoxy, trifluorethoxy, etc. may be either linear or branched, and usually has 1 to 4, preferably 1 to 2 carbon atoms;

 @Amino alcohol optionally substituted with alkyl such as dimethylamino methoxy, getyl amino methoxy, dibutyl amino methoxy, dimethyl amino ethoxy, dimethyl amino bromoboxy;

®Aminomethyl, methylaminomethyl, dimethylaminomethyl Alkyl, dimethylaminoethyl, ethylaminomethyl, dimethylaminophenol and the like as the alkyl moiety and the substituent may be either straight-chain or branched, and usually have 1 to 4 carbon atoms. The alkyl as a substituent may be either mono- or di-substituted, aminoalkyl optionally substituted with alkyl;

 The alkyl moiety of the alkyl moiety such as @acetylaminomethyl, acetylaminoethyl, propionylaminomethyl, brovonylaminoethyl, benzoylaminoethyl, etc., may be either straight-chain or branched, and usually has 1-4 carbon atoms, preferably 1-4 carbon atoms. 2, wherein the acyl moiety is the same as the above-mentioned acyl group, acylamino alkyl.

 Such substituents are substituted with 1-3.

 Specific examples of the aromatic ring and the heteroaromatic ring which may have a substituent include benzyl, phenylethyl, phenylpropyl, phenyl, naphthyl, indenyl, chenyl, frill, phenyl, imidazolyl, virazolyl, and thiazolyl. Examples thereof include oxazolyl, indolyl, pyridyl, virazyl, pyrimidinyl, quinolyl, isoquinolyl, and thionaphthene 1-2 or 3-yl.

The compound of the present invention is converted into a pharmaceutically acceptable salt if necessary. The salts include addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and addition with organic acids such as maleic acid, fumaric acid, cunic acid, succinic acid, tartaric acid, and methanesulfonic acid. Salt or sodium, calcium, calcium, magnesium, ammonium And other salts. Hydrates (1/2 dihydrate, monohydrate, dihydrate, 3Z dihydrate, etc.) are also included in the present invention. When the compound of the present invention has an asymmetric carbon, optically active substances and mixtures thereof are also included in the scope of the present invention.

 In the present invention, the production methods of the compounds (I) and (1 ′) are as follows. In the following description, the compound (1 ′) is used as a concept including the compound (I ″).

Method 1: Preparation of compounds (I) and (I ′) in which R ³ is a hydroxyl group (1) Formula

 (In the formula, each symbol is as defined above.)

A compound (H) represented by

 (In the formula, each symbol is as defined above.)

Can be produced by subjecting the compound (1 ') represented by the following formula to a dehydration ring-closing reaction in the presence of a dehydrating agent such as polyborinic acid or phosphorus pentoxide. According to The reaction is carried out at 50 to 150 for 10 minutes to 5 hours in the presence of a solvent such as benzene, toluene, or xylene.

 Equation (2)

(Wherein, the R ^e methyl, shows a low pole alkyl group such Echiru, and other symbols are as defined above.)

 A compound (M) represented by

 (In the formula, R ′ represents a lower alkyl group such as methyl and ethyl, and other symbols are as defined above.)

 The compound (Μ ') is represented by the following formula: In an alcohol solvent such as methanol, ethanol, bromonol, isobromo alcohol, or butanol, a base (sodium methoxide, potassium tertiary butoxy-'node, sodium hydride) , Triethylamine, etc.) at 0 to 100 for 5 minutes to 5 hours.

(3) Formulas produced by Method 1- (1) or 1-1 (2) )

(In the formula, each symbol is as defined above.)

A compound represented by the formula (ir):

 (In the formula, each symbol is as defined above.)

In the compound (W ′) represented by the formula (I), a compound in which R ⁴ or R <′ is an aromatic or heteroaromatic ring group substituted by an optionally substituted aminoalkoxy is represented by R <or R ⁴ 'Is produced by subjecting a compound in which' is an aromatic or heteroaromatic group substituted by haloalkoxy such as cycloalkoxy to an amination reaction known per se.

(4) In the compound (: ΠΟ or (ΪΓ), in which R ⁴ or R * ′ is an aromatic or heteroaromatic group substituted by carboxyl or carboxyalkyl, R * or R <′ is cyano Alkoxycarbonyl, alkoxycarbonyl, cyanoalkyl, alkenylcarbonyl or alkenylcarbonyl, etc. It is produced by subjecting a compound which is an aromatic ring group or a heteroaromatic ring group substituted by a susceptible group to a hydrolysis reaction known per se.

The method 2: Z is NR ⁵ compounds of (I ') produced

 Expression

(In the formula, R ⁷ represents a hydrogen atom or a lower alkyl group such as methyl or ethyl, and other symbols are as defined above.)

(V ') and the compound represented by

(Wherein, R ⁵ and R ⁴ ′ are as defined above.)

 Can be produced by reacting with the compound (II) represented by

When R ⁷ is a lower alkyl group, the reaction is carried out in a suitable solvent (any solvent may be used as long as it does not interfere with the reaction; for example, aromatic hydrocarbons such as benzene, toluene, xylene, dichloromethane, dichloroethane, and chloroform). Halogenated hydrocarbons such as methanol, ethanol, propanol, alcohols such as isobromovir alcohol, ethylene glycol and diethylene glycol, and any mixed solvents thereof) in or in the absence of a solvent (Triethylamine, sodium hydride, sodium methoxide, potassium butoxide, potassium carbonate ) In the presence or absence. The reaction temperature is not particularly limited, and the reaction usually proceeds from room temperature to 200 for 5 minutes to 10 hours.

When R ⁷ is a hydrogen atom, the reaction is carried out in the presence of a dehydrating agent such as dicyclohexyl carpamide, or thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, chlorocarbonate, etc. Is performed after the active ester is once formed.

Method 3: Preparation of compounds (I) and (I ′) in which R ³ is acyloxy

 It is produced by subjecting compound (W) or (IV ') to a known acylation reaction. As the acylating agent, an acid halide and an acid anhydride are preferable.

Method 4: Production of compounds (I) and (I ') in which R ³ is alkoxydi or an aminoalkoxy optionally substituted with alkyl. Compound (1Y) or (Ι) and alkyl halide, aminoalkyl halide, alkylamino Alkyl halide, dialkylaminoalkyl halide or cyclic aminoalkyl halide is used as a deoxidizing agent (potassium carbonate, sodium hydroxide, calcium hydroxide, sodium methoxide, triethylamine, pyridine, etc.) It is produced by reacting in a solvent inert to the reaction (toluene, methanol, ethanol, dimethylformamide, acetone, dioxane, etc.) at a temperature between room temperature and 150 ° C.

Method 5: R ³ is substituted with alkylsulfonylamino or alkyl For the preparation of compounds (I) and ( ^If ) which are aminoalkylsulfonylamino or arylsulfonylamino which may be

 (In the formula, each symbol is as defined above.)

 Compound (W) represented by or a formula

， (W)

,

 (In the formula, each symbol is as defined above.)

 (Vr) represented by the formula and the formula

_{^{R 8 - S 0 2 - H}} a £ (Έ) wherein, R ⁸ is alkyl, alkyl optionally substituted § Mi Noarukiru (i.e., amino Noarukiru, alkylamino Noah alkyl, Jiarukiruami Noarukiru, cyclic § Mi Noarukiru ), Aryl or haloalkyl, and H a represents halogen. In the presence of a deoxidizing agent (such as potassium carbonate, sodium carbonate, sodium bicarbonate, dimethylamine, triethylamine, pyridine, quinoline, etc.) In an inert solvent (toluene, methylene chloride, chloroform, dichloroethane, pyridine, dimethylformamide, etc.)

The amount of _c- sulfonyl halide produced by reacting at a temperature of 100 ° C. from 100 ° C. and the reaction conditions are appropriately selected. By this, either the mono-substituted product or the bis-substituted product can be predominantly synthesized.

In the reaction with the compound (II) which is a haloalkylsulfonyl halide, a dehydrohalogenation reaction occurs, and a haloalkenylsulfonylamino compound may be formed. These haloalkylsulfonyl Niruamino body or halo alkenylsulfonyl § Mino body (for the Ebabisu (vinylsulfonyl) amino compound) is Yoi even if R ³ is substituted with alkyl by subjecting the known per se § Mi Roh reaction A compound that is an aminoalkylsulfonylamino is produced.

 In addition, the compounds (I) and (I) of the present invention can be produced by a known method or a method known per se.

The ketone compound according to the present invention obtained in this manner can be purified individually by a common method such as a recrystallization method, a chromatographic method, and distillation alone or in combination. If desired, the racemic compound can be split into optically active substances by the action of, for example, an optically active acid (tartaric acid, diacetyltartaric acid, tartronic acid, dibenzoyltartaric acid, mandelic acid, etc.). Alternatively, it can be separated into optically active substances by using an optically active chromatographic method. In addition, a compound having a desired configuration can be stereoselectively obtained by using an optically active raw material compound. If necessary, the ketone compound according to the present invention may be an addition salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or an organic salt such as maleic acid, fumaric acid, cunic acid, succinic acid, tartaric acid, methanesulfonic acid or the like. Addition salts with acids and sodium, potassium, calcium, Pharmaceutically acceptable salts such as magnesium salts, ammonium salts and the like can be used.

 The compound (I) used as a raw material in the present invention has the general formula

(In the formula, Ra represents ^a hydrogen atom or a lower alkyl group such as methyl or ethyl, and other symbols are as defined above.)

Compounds (K) and (Κ ') represented by the following formulas are dissolved in an aqueous solution such as potassium carbonate, sodium carbonate, hydroxylated sodium hydroxide or sodium hydroxide, or in a solvent such as tetrahydrofuran, フ ラ ン, Ν-dimethylformamide, In the presence of a base such as sodium methoxide, potassium 3-butoxide, triethylamine, sodium hydride, etc.

(In the formula, ハ ロ ゲ ン represents a halogen atom (as defined above) or a sulfonic acid residue such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluorosulfone methanesulfonyloxy group, and the other symbols are as above. Is synonymous with.)

By reacting the compound (X) or (X ′) represented by the following formula with 0 to 100 for 5 minutes to 20 hours. In addition, compound (H), which is a raw material compound, passes through compound (I). It can be produced by esterification using a conventional method. Further, other starting compounds can be synthesized by a method known per se.

 The compounds (I) and (I ') of the present invention show a strong inhibitory action on bone resorption in an in vitro bone resorption measuring system using femurs or parietal bones of mice or rats, and have low cytotoxicity. In addition, it has the effect of suppressing hypercalcemia (increased serum calcium concentration) induced by tumor-bearing mice or tumor-bearing rats, and is useful as a highly safe therapeutic agent for osteoporosis.

 Next, the method of measuring the bone resorption inhibiting action of the compound according to the present invention and the results will be described.

Inhibition of bone resorption (in vitro)

 The in vitro bone resorption inhibitory action using mouse femurs was measured according to the following method.

 The femur of a 3-6 week old male ICR mouse was aseptically removed and

100% heat-inactivated fetal calf serum, penicillin G potassium 100 units

After washing the medullary cavity with Halo F12 medium (hereinafter referred to as culture solution) containing Zml, 60 mg / ml kanamycin sulfate and 0.15% sodium bicarbonate, the soft bone adhering to the bone The tissue was removed and used for culture.

 The test compound was once dissolved in dimethyl sulfoxide to prepare a solution of 100 ingZml, which was diluted 100-fold with a culture solution to obtain a solution of 10 gZml.

Using 1.2 ml of the culture medium containing the test compound, ICR mouse femurs were placed in a 24-hole plate for 6 days with 5% carbon dioxide and 95% air. Culture was performed under the following conditions. After completion of the culture, the culture supernatant was collected, and the amount of calcium released in the culture supernatant was quantified by a chelate method using orthocresol phthalein.

 The bone resorption inhibiting effect of the test compound was determined by the following formula using the femoral culture in the absence of the test compound as a control.

 Test compound Test compound

 Unadded place was added

 Free Ca case

 Quantity Ca quantity

Bone resorption inhibitor-lOO

 (96) Test compound

 Unadded amount

 Free Ca

 Quantity

 This experiment was performed with four cases in each group. In the control group, only the same amount of dimethyl sulfoxide was added as in the case where the test compound was added, and the cells were cultured.

The results are shown in Table 1.

Table 1 Test amount Bone resorption inhibitory compound (g / ml) (% Inhibition) 1 19.1 compound of Example 1 10 4 7.2 Compound 1 20.1 of Example 2 1 compound 10 4 1.4 Example 3 1 2 6.4

Compound 104 45.6 Example 1 1 of 12.6

Compound 10 4 5.6 Example 20 1 1 1.1.4

Compound 1 0 44.5 Example 2 1 1 20.2

Compound 1 0 4 2.0 Compound 3 6 1 2 6.8

1 0 5 4. 7 Compound 3 8 1 3 6.6

 1 0 58.2 Compound 4 3 1 18.2

 1 0 4 3.3 Compound 4 8 1 1 5.9

 1 0 4 0.8 Compound 5 4 1 2 1.3

 1 0 4 3.0 Manufacturing Example 7 17.8

 Compound 1 0 3 4.3 Preparation Example 8 1 2 0.6

 Compound 1 0 25.1 Preparation example 1 0 1 2 7.6

Compound 103.2.3 Compounds (I) and ( ^If ) and pharmaceutically acceptable salts thereof according to the present invention can be used as they are or as pharmaceutically acceptable carriers, excipients, and disintegrants. Tablets, by mixing with binders, lubricants, bulking agents, diluents, solubilizing agents, etc., and dispensing according to the usual methods. Preparations, powders, granules, pills, capsules, syrups, injections, ointments, suppositories and the like can be administered to patients. The dosage varies depending on the subject of administration, administration route, symptoms, etc., but is usually 1 to 100 mg / day for oral administration and 0.1 to 100 mg / day for nasal, intravenous and rectal administration per adult. It is appropriate and can be administered in one or several doses.

Formulation example

 A tablet containing 5 ng of the compound of the present invention can be prepared according to the following formulation.

 Compound of Example 1 5 mg Microcrystalline cellulose 65 mg Corn starch 25 mg Talc 4 mg Magnesium stearate nng Total amount 100 mg The above composition was thoroughly mixed, granulated, dried and compressed with a tableting machine. Lock 1

0 o mg tablets.

 Reference Examples and Examples will be given below for further details of the present invention, but the present invention is not limited to these Reference Examples and Examples.

Reference example 1

2 — Dissolve 10 g of mercaptonicotinic acid and 17.8 g of lithium carbonate in 10 ml of water and at 0 dissolve 13.9 g of phenacyl chloride in 5 ml of tetrahydrofuran. , Dripped. 0. After stirring with C for 5 hours, the reaction solution was washed twice with toluene, and the aqueous layer was acidified with acid. I made it. After collecting the precipitated crystals, the crystals were recrystallized from ethanol to obtain 11.4 g of 2-phenacylthionicotinic acid as yellow crystals. With a melting point of 1668-173.

 Reference example 2

 1-1.4 g of 2-phenacylthionicotinic acid was dissolved in 60 ral of pyridine, and at 0, 9.5 g of p-toluenesulfonyl chloride was added, followed by stirring for 2 hours. 1.6 g of methanol was dissolved in 5 ml of pyridine, and added dropwise at 0 at 1 hour. After stirring at 0 for 2 hours, 20 O ml of water was added to the reaction solution. The precipitated crystals were recrystallized with ethanol to obtain 4.7 g of methyl 2-phenacylthionicotinate as white crystals. Mp 91-92.

 Reference example 3

 2.0 g of 2-hydroxymethyl 6-isopropylnicotinate was dissolved in 4 Om of N, N-dimethylformamide, and at 0, 1.4 g of potassium tertiary butoxide was added. After stirring at room temperature for 1 hour, phenacyl chloride was added and stirred for 2 hours. 100 ml of water was added to the reaction solution, and extracted three times with 50 ml of toluene. The toluene layer was washed with brine, dried and concentrated. The obtained crystals were recrystallized from isobutyl bil ether to obtain 1.2 g of white crystals as methyl 6-isopropyl-221-phenacyloxynicotinate. With a melting point of 93-94.

Example 1

6.7 g of monophenacylonicotinic acid was added to 67 g of polyborinic acid, and the mixture was stirred at 100 ° C. for 30 minutes. The reaction solution was poured into water, and the precipitated crystals were collected. The crystals were recrystallized from methanol to give yellow crystals. There was obtained 2.9 g of benzoyl-3-hydroxythieno [2,3-b] pyridine. With a melting point of 1 15 to 1 16.

Example 2

 3-Hydroxy-2- (4-hydroxybenzyl) in the same manner as in Example 1 except that 2- (4-1hydroxyphenacylthio) nicotinic acid is used instead of 2-phenacylthionicotinic acid. Ceso (2,3-b) pyridine was obtained, mp 290 V (decomposition).

Example 3

 2-Benzoyl 3-hydroxy 6-isoprovircheno C 2 in the same manner as in Example 1 except that 6-isobutyryl nicotinic acid is used instead of 2-phenacyl nicotinic acid. , 3-b] pyridine was obtained. Mp 69-71.

Example 4

 2-Methyl-4'-l- (3-hydridyl) in the same manner as in Example 1 except that 2- (4- (1-l-lumbamoylethyl) phenacyl) -thionicotinic acid was used instead of 2-phenacylnicotinic acid. Xythieno [2,3-b) pyridine-l-carbonyl) phenylacetamide was obtained. Mp 180-182.

Example 5

In the same manner as in Example 1 except that 2- (2,4-difluorophenacylthio) nicotinic acid is used instead of 2-phenacylthionicotinic acid, 2- (2,4-difluorobenzoyl) -1-one is used. 3-Hydroxythieno [2,3-b] pyridine was obtained. Melting point 194 to 196 * C.

 Example 6

 Instead of using 2-funacylthionicotinic acid, 2- (4-1- (3-hydroxy) was used in the same manner as in Example 1 except that 2- (4- (1-ylrubamoylethyl) phenacylthio) nicotinic acid was used. Cithieno (2,3-b] pyridin-1-2-carbonyl) phenyl) propionic acid was obtained, mp 164-16.5.

 Example 7

 3. Og of methyl 6-methyl-2-phenacylthionicotinate was dissolved in 3 Oml of methanol, 6.0 ml of a 2N sodium methoxide methanol solution was added, and the mixture was stirred at room temperature for 1 hour. 30 ml of water was added to the reaction solution to make it acidic with acetic acid. After precipitating the precipitated crystals, the crystals were recrystallized with ethanol to obtain 1.9 g of yellow crystals of 2-benzoyl-3-hydroxy-6-methylthieno [2,3-b] pyridine. Mp 103-105.

Example 8

 As in Example 7, except that methyl 2- (3,5-di-tert-butyl-4-hydroxyphenacylthio) nicotinate is used instead of using methyl 6-methyl-2-phenacylthionicotinate 2- (3,5-Ditert-butyl-4-hydroxybenzoyl) -1-3-hydroxythieno [2,3-b] pyridine was obtained. Melting point 2 1 2 to 2 1 'Co

Example 9

6-Methyl-2-methyl phenacylthionicotinate Instead of using 2- (4-Isopropoxyv nacilcio) nicotine Except for using methyl acid salt, 3-hydroxy-2- (4-isopropoxydibenzoyl) thieno [2,3-b] pyridine was obtained in the same manner as in Example 7. Melting point 96-98 'C o

Example 10

 2-Benzyl-1-hydroxy 6- in the same manner as in Example 7 except that methyl 6-isobromo-1-2-phenacyloxynicotinate is used instead of using methyl 6-methyl-2-phenacylthionicotinate. Isopropylfuro (2,3-b) pyridine was obtained, mp 83-85.

Example 1 1

 2-Benzoyl 3-hydroxythieno [2,3-b] 0.9 g of pyridine and 0.3 g of pyridine are dissolved in 50 ml of methylene chloride, and 0.3 g of acetyl chloride is cooled under ice-cooling. The mixture was added dropwise and stirred for 3 hours under ice cooling. After completion of the reaction, the reaction solution was washed with water and dried, and the solvent was distilled off. The remaining crystals were purified by ethanol to give 3-acetoxy-2-benzoylthieno [2,3-b] pyridine. Melting point 1 2 4 to 1 2 5 'C o

Example 1 2

(1) Sodium methoxide was prepared with methanol 30 rol and sodium gold sodium 0.7 g, and 5.0 g of methyl thiosalicylate was added under ice cooling. Then, 9.2 g of α-bromo-41- (3-chlorobromobox) acetophenone was gradually added, and the mixture was reacted at 0 for 1 hour and further at 20 at 1 hour. The precipitated crystals were collected, washed with water and purified from methanol to obtain methyl 2- [4- (3-chlorobromobox) phenacylthio] benzoate. With a melting point of 103. (2) 2- (4- (3-chlorobromoboxy) phenacylthio;) 3.2 g of methyl benzoate, 30 ml of methanol, and 4.2 ml of a methanol solution of 2N-sodium methoxide at 30 were stirred at 30 for 10 minutes. A yellow solution was obtained. Under cooling, the solution was neutralized with an aqueous acetic acid solution. The precipitated yellow crystals were collected, washed with water, and purified from a mixed solution of ethanol and ethyl acetate to give 2-C4- (3-chlorobromoboxyl) benzoyl] -13-hydroxy. Benzothiophene was obtained. Mp 85-87 'C.

 (3) 2-([1- (3-chlorobromoboxy) benzoyl] 2.5 g of 1-3-hydroxybenzothiophene, 3.3 g of 50% aqueous dimethylamine solution, N, N-dimethylformamide 5nil, iodide- 0.1 g of the mixture was stirred at 40 for 10 hours, the solvent was distilled off under reduced pressure, and the residue was added with 10 ml of water and neutralized with sodium hydrogen carbonate. The released oil was extracted with chloroform and the chloroform was distilled off. The remaining crystals were converted into salts using maleic acid, and purified from a mixed solution of ethyl sulphate and ethanol. 3-dimethylaminobromoboxyl) -1-3-hydroxybenzothiophene maleate was obtained. Mp 150-152.

Example 13

 2-C4- (3-morpholino-broboxy) benzoyl] -13-hydroxybenzothiol was obtained in the same manner as in Example 12 (3) except that 50% dimethylamine was replaced with morpholine. The phen 'maleate was obtained. M.p. 148-150.

Example 14

Prepare sodium methoxide with 60 ml of methanol and sodium sodium 2.lg and add methyl thiosalicylate under water cooling. 5 g was added, followed by N- Asechiru 4 was gradually added an chloroacetyl off energy Chiruami emissions 7. 2 g, was stirred for 3 h at 3 0 ^e C. Neutralized with an aqueous acetic acid solution, the precipitated crystals are collected, washed with water, and purified from ethanol to give 2- [4- (2-acetamidoethyl) benzoyl] -13-hydroxybenzothiophene. I got With a melting point of 17 2 to 17 4.

Example 15

 2-Methyl-2- (4-chloroacetyl) phenylacetamide was used in place of N-acetyl-phenylphenethylamine in the same manner as in Example 14 above, except that 2-methyl-2- (4-chloroacetyl) phenylacetamide was used. 4'-I- (3-hydroxybenzenethiophene-2-carbonyl) phenylacetamide was obtained. Mp 175-176. Example 16

 2-Methyl-4 '-(3-hydroxybenzothiophene-2 mono-rubonyl) phenylacetamide 4.3 g, sodium hydroxide 4.3 g, water 43 ml, ethanol 20 ml of the mixture was refluxed for 3 hours. After evaporating the solvent, water was added and neutralized with hydrochloric acid. At this time, the released syrup was extracted with chloroform and the chloroform was distilled off. The residue was purified from dichloroethane, and 2-methyl-4 '-(3-hydroxybenzothiophene-2-carbonyl was purified. ) Phenylacetic acid was obtained. With a melting point of 16 2 to 16 4.

Example 17

Example 2 was repeated in the same manner as in Example 14 except that 3,5-di-tert-butyl-4-hydroxyhydroxypromide bromide was used instead of N-acetyl-4-chloroacetylphenethylamine. — (3, 5-di-tert-butyl-4-hydroxybenzoyl) 1-3-hydroxybenzothiophene was obtained. Melting point 13 8-13 9 'Co Example 18

 2-Benzoyl 3-hydroxythieno [2,3—b] Pyridin 6 g, potassium carbonate 9.7 g, 2-dimethylaminoethyl chloride 3.7 g, acetone 80 ml mixed solution for 24 hours After the mixture was refluxed and allowed to cool, the reaction solution was passed, and the resulting solution was concentrated. The residue was purified by column chromatography to give a maleate salt in ethyl acetate, and it was converted to 2-benzoyl 3- (2-dimethylamido). G) Ethoxythieno [2,3-b] pyridin maleate was obtained. Mp 107-110.

 Example 19

 2-Benzoyl 3- (3-dimethylamino) propoxythieno [2, 3—] in the same manner as in Example 18 above, except that 3-dimethylamino knob and Birk's mouth were used instead of 2-dimethylaminoethyl chloride. b] Pyridin 'maleate was obtained. Mp 91-93.

Example 20

 2—Benzoyl 3-Hydroxythieno [2,3—b] Implemented in place of pyridine, but with 2— (4-cyclobenzoyl) -13-Hydroxyshithieno [2,3—b] Pyridine In the same manner as in Example 18, 2— (4-chlorobenzoyl) -13- (2-dimethylamino) ethoxythieno [2,3-b] pyridine.maleate was obtained. Melting point 11-13: at I15.

Example 2 1 3-Amino 2-benzoyl 6-Isobrovirfur [2,3-b] Pyrididine 1.4 g, chloroform 10 ml, triethylamine 0.6 g, and methane under ice-cooling 0.68 g of sulfoyurc-mouth ride was added dropwise over 40 minutes, and the mixture was reacted at 10 for 2 hours and at 30 for 1 hour, and then water was added for liquid separation. After separation, the chloroform was distilled off, and the residue was extracted with toluene. After the toluene was distilled off, the residue was purified with ethanol to obtain 2-benzoyl-6-isopropyl-13-methanesulfonylaminoff [2,3-b] pyridine. Mp 166-16-17. Example 22

 3-Amino 2-Benzoyl 6-Isoprovircheno [2,3—b] Pyridine 2.9 g, 30 ml of porcine form, 3.2 g of triethylamine, methane under ice-cooling 2.4 g of sulfonyl chloride was added dropwise over 30 minutes, and the mixture was reacted at 40 for 2 hours, and then water was added. After separating the chromate form layer, the chromate form is distilled off, and the residue is purified by column chromatography. 3 — N, N—bis (methanesulfonyl) amino-2-benzoyl 6—isopropylcheno [2 , 3-b] pyridine, mp 136-138.

Example 23

(1) 3-Amino 2-Benzoyl 6-Isopropirfuro [2,3-b] Pyridine 19.4 g, Clo-form 150 ml, Triethylamine 31.3 g Under ice-cooling, 25 g of 2-chloroethylsulfonyl chloride was added, reacted and treated in the same manner as in Example 22 above, and treated with 3-N, N-bis (vinylsulfonyl chloride). L) Amino 2-benzoyl 6-isopropylfuro [2,3-b] pyridine was obtained. Melting point 13 3 to 13 6 · (.

 (2) 3-N, N-bis (vinylsulfonyl) amino 2-benzobenzene 6-isopropylfur [2,3—b] pyridine 2.5 g, black-mouthed form 20 ml, getylamine 1 .3 g of the solution was stirred at room temperature for 24 hours. After the solvent was distilled off, isopropyl ether was added for crystallization. After purification, the product was purified from isopropyl alcohol to give 2-benzoyl 3- (2-ethylethylamino) ethylsulfonylamino 6-isopropylfuro (2,3-b) pyridine with a melting point of 144.

 Example 2 4

 Except for using 1-methylbiperazine in place of getylamine, the same procedure as in (2) of Example 23 was carried out in the same manner as in 2-benzylol 3- (2- (4-methyl-1-piperazinyl) ethyl) sulfonyl. Luminor 6-isopropylfuro [2,3-b] pyridin was obtained. With a melting point of 16 3.

Example 2 5

 In the same manner as in Example 23 (2) except that pyrrolidine is used instead of getylamine, 2-benzoyl 3- (2- (1-pyrrolidinyl) ethyl) sulfonylamino 6-isopropylfuro [2] , 3—b]. Melting point 2 0 9 'Co

Example 26

(1) 3-Acetoxy 2-benzoyl 6-methylthieno [2, 3 — b] pyridine 3.9 g, methylene chloride 5 O ml solution was cooled on ice, and m-chloro Add 3.0 g of benzoic acid, After stirring at room temperature for 5 hours, the reaction solution was washed with aqueous sodium hydrogen carbonate and saturated saline. The solvent was distilled off and the residue was purified from ethanol to give 3-acetoxy-2-benzoyl-6-methylthieno.

(2,3-b) pyridine-N-oxide was obtained, mp 130-

In 1 3 3

 (2) 3-Acetoxy 2-benzoyl-6-methylthieno (2,3-b) pyridine-N-oxide (2.5 g) and acetic anhydride (25 ml) were reacted at 90 for 3 hours. The solvent was distilled off, the residue was dissolved in chloroform and washed with water, chloroform was distilled off, and the residue was purified from ethanol and purified with 2-acetoxoxy 16-acetoxymethyl 2-benzoylthieno [2,3-b]. Pyridine was obtained with a melting point of 86-89.

 (3) 2-acetoxy 6-acetoxymethyl-2-benzoylthieno [2,3-b] pyridine 1.0 g, potassium hydroxide 0.33 g, ethanol 1 O ml, water 1 O The mixture was stirred at room temperature for 2 hours, neutralized with acetic acid, and the solvent was distilled off. The residue was extracted with chloroform and washed with water, and the chloroform was distilled off. The residue was purified from ethanol, and then 2-benzoyl 3-hydroxy 6-hydroxymethylthieno [2,3-b] Pyridine was obtained. Melting point 1 18-: at I 20.

 Hereinafter, the following compound can be synthesized in the same manner.

 (27) 2-Benzoyl 3-Hydroxythieno [3, 2-c] pyridine

(28) 2-Benzoyl 3,5-dihydroxythieno (2,3—b) pyridine (29) 2-benzoyl 3,6-dihydroxythieno [2,3-b] pyridine

 (30) 2-Benzoyl 5-Chloro 3-Hydroquinine thieno [2, 3-b] pyridine

 (31) 2-Benzoyl 3-Hydroxy 5-Methoxy chen [2, 3-b] pyridine

 (32) 2—Benzoyl 3—Hydroxy 6—Methoxymethoxy [2,3—b] Pyridine

 (33) 2-Benzoyl 3-Hydroxy 6-PhenylCeno [2,3-b] Pyridine

 (34) 2-Benzoyl 5-Cyan 3-Hydroxythieno (2, 3-b) Viridin

 (35) 2-Benzoyl 3-Hydroxythieno [2, 3-b] Viridin-1-5-Rubonic acid

 (36) 2-Benzoyl 3-hydroxy 4, 6-dimethyl thieno [2,3-b] pyridine, mp 1 39

 (37) 2-Benzoyl 3-Hydroxythieno [2,3-b] pyridin-5-Methyl rubonate

 (38) 2-Venzoyl 3-Hydroxythieno [2,3-b] quinoline, melting point 193-19.4

 (39) 3-hydroxy 2- (3-phenylpropionyl) thieno [2,3-b) pyridine

 (40) 2-cinnamoyl 3-hydroxythieno [2,3-b] pyridine

(41) 3-Hydroxy 2- (3-Fenylbro-pioloyl) Thieno [2, 3 — b] pyridine

 (42) 2-Acetyl-3-Hydroxythieno [2,3-b] pyridine

 (43) 2-(4 benzoyl)-3-hydroxyhydroxy (2, 3-b) pyridine, mp 172-174

 (44) 3-Hydroxy-2- (4-methylthiobenzyl) thieno [2,3-b] pyridine

 (45) 3-Hydroxy-2- (4-methylsulfinylbenzyl) thieno [2,3-b] viridine

 (46) 3-Hydroxy 2- (4-methylsulfonylbenzoyl) thieno [2,3-b] pyridine

 (47) 3-Hydroxy 2-((412-trobenzyl) ceno [2,3-b] pyridine · hemihydrate, mp 210-209 • C

 (48) 3-Hydroxy 2- (2-naphthyl) thieno (2,3-b) pyridine, mp 147-148.

 (49) 3-Hydroxy-2- (3-thenoyl) thieno [2,3-b] pyridine, melting point 182-184

 (50) 3-Hydroxy-1- (2-furoyl) thieno [2,3-b] pyridine, melting point 161-16-12

 (51) 3-Hydroxy 2-nicotinoylthieno [2,3-b] pyridine

 (52) 3-Hydroxy-2- (2-thiazolylcarbonyl) thieno (2,3-b) viridine

(53) 2— (4-Cyanbenzoyl) 1—3-Hydroxyche (2,3-b) pyridine, melting point 205-207

 (54) 3-Hydroxy-2- (4-methylbenzoyl) ceno [2,3-b] pyridine, mp 155-157.

 (55) 2- (4-bromobenzoyl) -13-hydroxyoxy [2,3-b] pyridine, mp 165-167.

 (56) 2- (3-benzobenzene) 1-3-Hydroxycheno [2,3-b] pyridine, melting point 118-121

 (57) 2— (4-fluorobenzoyl) 1-3-Hydroxythieno [2,3-b] pyridine, melting point 149-15-11

 (58) 2— (2-chlorobenzoyl) -1-3-hydroxyphenol [2,3—b] pyridine, melting point 155-15-158

 (59) 3-acetoxy 2- (4-fluorobenzoyl) thieno [2,3-b] pyridine, mp 106-107

 (60) 3 -acetoxy 2- (4-methylbenzoyl) ceno [2,3-b] pyridine, mp 105-106.

 (61) 3-acetoxy 2-benzoyl 6-methylthieno [2,3-b] pyridine, mp 95-97.

 (62) 3-Acetoxy 2-benzoyl 6-bromomethyl thieno [2,3-b] pyridine, melting point 1336 to 1339 Production Example 1

N-phenyl-2-hydroxythieno [2] in the same manner as in Example 7 except that methyl 2- (phenylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate. , 3-b] Pyridine-12-carboxamide was obtained. Mp 23-239. Production Example 2

 N- (2,4) was prepared in the same manner as in Example 7 except that methyl 2- (2,4-difluorophenylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate. —Difluorophenyl) -13-hydroxythieno [2,3-b] pyridine-12-carboxamide was obtained. With a melting point of 25 1 to 25 4.

Production Example 3

 In the same manner as in Example 7, except that methyl 6-methyl-2-phenacylthionicotinate was replaced with methyl 2-((2,4-difluoroph: dicarbamoylmethylthio) -6-isopropylnicotinate) (2,4-Difluorophenyl) -13-hydroxy-6-isoprovircheno [2,3-b] pyridin-12-carboxamide was obtained. With a melting point of 2 2 4 to 2 2 9.

Production Example 4

 In the same manner as in Example 7 except that methyl 6-methyl-2-phenylphosphonicotinate instead of using methyl 2- (2,4-difluorophenylcarbamoylmethylthio) -1-6-methylnicotinate was used. (2,4-Difluorophenyl) -13-hydroxy-6-methylthieno [2,3-b] pyridine-12-carboxamide was obtained. Mp 274-278.

Production Example 5

Same as Example 7 except that methyl 2- (2,6-dimethylphenylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate Thus, N- (2,6-dimethylphenyl) -13-hydroxythieno [2,3-b] pyridin-12-carboxamide was obtained. With a melting point of 210-212.

 Production Example 6

N- (3-chlorophenyl) 1-3 in the same manner as in Example 7 except that methyl 2- (3-chlorophenylcarbamoylmethylthio) nicotinate is used instead of using methyl 6-methyl-2-phenacylthionicotinate. - heat Dorokishichieno. [2, 3 - b] pyridine-one 2-Karubokisami de mp 2 4 9 (decomposition) _q production example 7

 N— (3-—) was prepared in the same manner as in Example 7 except that methyl 2- (3-trifluoromethylphenylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate. Trifluoromethylphenyl) -3-Hydroxyxythieno (2,3-b) pyridine-12-caproloxamide was obtained with a melting point of 223-224 (decomposition).

Production Example 8

 N-Hexyl-3-hydroxythieno [2,3] in the same manner as in Example 7 except that methyl 2- (hexylcarbamoylmethylthio) nicotinate was used instead of using methyl 6-methyl-2-phenacylthionicotinate. — B] Pyridine-12-carboxamide was obtained. With a melting point of 1 16 to 1 18.

Production Example 9

Dissolve 4.2 g of 3-hydroxythieno [2,3-b] pyridin-methyl 2-carbonate in 20 ml of ethylene glycol and add benzene. 4.4 g of ziramine was added, and the mixture was stirred at 130 with stirring for 2 hours. An aqueous sodium hydroxide solution was added to the reaction solution, which was washed with toluene. The aqueous layer was acidified with acetic acid, and the precipitated crystals were collected. The crystals were recrystallized from methanol, and yellow crystals of N-benzyl 3-hydroxythieno (2,3-b) pyridin-12-carboxamide 1.2 g With a melting point of 16 4 to 16 5.

Production Example 10

 Dissolve 4.9 g of 2-piperidinocarboylmethylthionicotinic acid in 30 ml of acetonitrile, and add 1,8-diazabicyclo [5,4,0] pentade 7-ene 2 «7 g, methyl iodide 3 Og was added and reacted at room temperature for 24 hours. After the acetonitrile was distilled off, the mixture was extracted with toluene, washed with water and aqueous sodium hydrogen carbonate, and toluene was distilled off to obtain 4 g of a crude methyl ester as an oil. To this, 10 ml of methanol and 7 ml of a 2N-sodium methoxide methanol solution were added, and the mixture was refluxed for 30 minutes. Methanol was distilled off, water was added for dissolution, and the mixture was neutralized with acetic acid to precipitate crystals. After collection, purification was carried out from aqueous methanol to obtain 3-hydroxy-12-biperidinocarbonylthieno [2,3-b] pyridine. Mp 99-101.

 Although the present invention has been described in detail with reference to the description including the embodiments, the embodiments can be variously changed and modified without departing from the spirit and scope of the present invention.

Claims

 92/03427  4 9 Claims Equation (I)

 [In the formula, each symbol is as described below. ]  Or a pharmaceutically acceptable salt thereof. Ring X represents a pyridine ring.  Y represents an oxygen atom or a sulfur atom.  z represents a single bond, alkylene, alkenylene, or alkynylene. R ¹ and R ² are the same or different and are hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, haloalkyl, carboxyl, amino which may be substituted with alkyl, rubamoyl which may be substituted with alkyl, alkoxy Carbonyl, optionally substituted phenyl, nitro, acyl, sulfamoyl optionally substituted with alkyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy , Hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aminoalkyl optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, and acylaminoalkyl , R 'and R ² and are bonded to each other alkylene which may have a substituent group, is also alkylene O carboxymethyl properly represents a group forming a benzene ring. R ³ represents a hydroxyl group, acyloxy, alkyne, aminoalkoxy optionally substituted with alkyl, alkylsulfonylamino, aminoalkylsulfonylamino optionally substituted with alkyl, or arylsulfonylamino.  R * is an alkyl, an aralkyl which may have a substituent, an aromatic ring which may have a substituent or a heteroaromatic group which may have a substituent (substituent means halogen , Alkyl, alkoxy, hydroxyl, alkylthio, alkylsulfiel, alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxyl, alkyl or substituted with amino or alkyl Rubamoyl, alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, haloalkoxydi, aminoalkyl optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, acyloxy Selected from aminoalkyl 1 to 3 substituents).  2. The ketone compound according to claim 1, selected from the following compounds, or a pharmaceutically acceptable salt thereof.  • 2-Benzoyl 3-Hydroxythieno [2, 3-b] pyridine  • 3—Hydroxy-2— (4-Hydroxybenzoyl) ceno [2,3-b) pyridine • 2—Benzoyl 3—Hydroxy 6—Isopropylpyreno [2, 3—b] pyridine • 3-Acetoxy 2-Benzoylthieno [2,3-b] pyridine  • 2— (4-methylbenzene) 1-3-dimethylamino ethoxythieno [2,3—b] pyridine  • 2—Benzoyl 6—Isobrovir-1 ′ 3-Methanesulfonylaminofuro [2,3-b] pyridine  • 2—Benzoyl 3—Hydroxy 4, 6—Dimethyl Cheno [2, 3—b] Pyridine  • 2—Benzoru 3—Hydroquinthieno [2, 3—b] quinoline  • 2— (4 benzoyl) 1-3—Hydroxythieno [2, 3—b] pyridine  • 3-Hydroxy 2- (2-naphthyl) thieno [2,31-b] pyridine  • 3—Hydroxy 2— (4-Methylbenzoyl) thieno (2,3—b) pyridine  3. Expression (") (I, ')

 [In the formula, each symbol is as described below. ] Or a pharmaceutically acceptable salt thereof.  Ring X ′ represents a benzene ring or a pyridine ring.  Y represents an oxygen atom or a sulfur atom. R ¹ and R ² are the same or different and are hydrogen, halogen, alkyl, Alkoxy, hydroxyl group, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl, rubamoyl optionally substituted with alkyl, alkoxycarbonyl, phenyl, nitro, acyl, alkyl optionally having substituent (s) Optionally substituted by sulfamoyl, alkylthio, arylthio, alkylsulfiel, arylsulfiel, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, alkyl in an optionally substituted Yoi § Mi Noaru Kokishi, alkyl optionally substituted with amino Noarukiru, or shows a § Shiruami Noarukiru, even R ¹ and R ² have bonded to substituents mutually Good a Killen, alkylene O carboxymethyl be properly represents a group forming a benzene ring. R ^{3 A} represents a hydroxyl group or acyloxy. R ^{4 A} represents aminoalkyl which may be substituted with alkyl or acylaminoalkyl which may be substituted with alkyl.  4 Formula (I ')

[In the formula, each symbol is as described below. ] A therapeutic agent for osteoporosis comprising, as an active ingredient, a ketone compound represented by or a pharmaceutically acceptable salt thereof. Ring X ′ represents a benzene ring or a pyridine ring.  Y represents an oxygen atom or a sulfur atom. Ζ ′ represents a single bond, alkylene, alkenylene, alkynylene or 1 NR ⁵ —. (However, R ⁵ represents hydrogen, alkyl, acyl, aralkyl which may have a substituent, or a group which forms a nitrogen-containing heterocyclic ring by bonding with R.) R ¹ and R ² are the same or different and are hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, haloalkyl, carboxyl, amino which may be substituted with alkyl, rubamoyl which may be substituted with alkyl, alkoxy Carbonyl, optionally substituted phenyl, nitro, acyl, sulfamoyl optionally substituted with alkyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy , Hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, and acylaminoalkyl , Which may have R ¹ and R ²锆合to substituents together alkylene, also alkylene O carboxymethyl properly represents a group forming a benzene ring. R ³ represents a hydroxyl group, an alkoxy, an alkoxy, an aminoalkoxy optionally substituted with an alkyl, an alkylsulfonylamino, an aminoalkylsulfonylamino which may be substituted with an alkyl, or an arylsulfonylamino. R * 'is hydrogen, alkyl, or an optionally substituted Or an aromatic ring group which may have a substituent or a heteroaromatic group which may have a substituent (substituent means halogen, alkyl, alkoxy, hydroxyl, alkylthio, alkylsulfiel, alkylsulfonyl , Haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxy, amino, carbamoyl, alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, haloalkoxy, alkyl Good aminoalkoxy, aminoalkyl optionally substituted with alkyl, and 1 to 3 substituents selected from acylaminoalkyl).  5. The therapeutic agent for osteoporosis according to claim 4, wherein the ketone compound or a pharmaceutically acceptable salt thereof is selected from the following compounds.  • 2-Benzoyl 3-Hydroxythieno [2, 3-b] pyridine  • 3—Hydroxy 2— (4-Hydroxybenzoyl) ceno [2, 3—b] pyridine  ■ 2-benzoyl 3-hydroxy 6-isopropyl [2,3-b] pyridine  • 3-Acetoxy 2-Benzoylthieno [2,3-b) pyridine  • 2 — (4 benzoyl) 1-3-dimethylamino xythithieno [2, 3 — b] pyridine • 2—Benzoyl 6-Isopropyl-13-Methanesulfonylaminonofuro [2,3—b] pyridine ■ 2—Benzoyl 3—Hydroxy 4, 6-dimethyl ceno [2, 3—b] pyridine  • 2-Benzoyl 3-Hydroxythieno [2, 3-b] quinoline  '2— (4 benzoyl) 1-3—Hydroxythieno [2, 3—b] pyridine  • 3-Hydroxy 2- (2-naphthyl) thieno [2,31-b] pyridine  -3—Hydroxy-2- (4-methylbenzoyl) thieno [2,3-b] pyridine  • N— (3-trifluoromethylphenyl) -1-3-hydroxythithieno [2,3-b] pyridine-12-carboxamide  • N—Hexyl-3—Hydroxythieno [2,3-b] pyridin-1-2-carboxamide  • 3-Hydroxy 2-biveridinocarbonylthieno [2,3–b] pyridine  6. Formula (I ') for the manufacture of a medicament for the treatment of osteoporosis X '(I')  Y, C0-Z '-R' [In the formula, each symbol is as described below. ] Use of a ketone compound represented by or a pharmaceutically acceptable salt thereof. Ring X ′ represents a benzene ring or a pyridine ring. Y represents an oxygen atom or a sulfur atom. Z ′ represents a single bond, alkylene, alkenylene, alkynylene or 1 NR ⁵ —. (However, R ^s represents hydrogen, alkyl, acyl, aralkyl which may have a substituent, or a group which forms a nitrogen-containing heterocycle by bonding with R ⁴ ′.) R ¹ and R ² are the same or different and are hydrogen, halogen, alkyl, alkoxide, hydroxyl group, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl, alkyl optionally substituted with alkyl, rubamoyl, alkoxycarbonyl, Optionally substituted phenyl, nitro, acyl, sulfuamoyl optionally substituted with alkyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy, phenyl A hydroxyalkyl, an alkoxyalkyl, an alkoxyalkyl, an aminoalkyl which may be substituted with alkyl, an aminoalkyl which may be substituted with alkyl, or an acylaminoalkyl; R ¹ and R ² represent an alkylene, alkylenedioxy or a benzene ring which may be substituted with each other to form a substituent. R ³ represents a hydroxyl group, an acyloxy, an alkoxy, an aminoalkoxy optionally substituted with an alkyl, an alkylsulfonylamino, an aminoaminosulfonylamino optionally substituted with an alkyl, or an arylsulfonylamino. R ⁴ ′ is hydrogen, alkyl, an optionally substituted aralkyl, an optionally substituted aromatic ring group or a substituted A heteroaromatic group which may be substituted (substituents include halogen, alkyl, alkoxy, hydroxyl, alkylthio, alkylsulfiel, alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxy, amino, dylambamoyl, Selected from alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, rubamoylalkyl, haloalkoxy, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, and acylaminoalkyl 1 to 3 substituents).  7. The use according to claim 6, wherein the ketone compound or a pharmaceutically acceptable salt thereof is selected from the following compounds.  • 2—Benzoru 3—Hydroxythieno [2, 3—b] pyridine  -3—Hydroxy 2 — (4-Hydroxybenzoyl) ceno [2,3—b] pyridine  • 2—Benzoyl 3—Hydroxy 6—Isobrovireno [2, 3—b] Pyridine  '3-acetoxy 2-benzoylthieno [2, 3-b] pyridine  • 2 — (4 benzoyl) 1 3 — Dimethylamino ethoxythithieno [2, 3 — b] pyridine  • 2-Benzoyl 6-Isopropyl-13-Methanesulfonylaminonofuro [2,3—b] pyridine • 2—Benzoru 3—Hydroxy 4, 6—Dimethylche No [2,3-b] pyridine  • 2—Benzoru 3—Hydroxythieno [2,3—b] quinoline  ■ 2- (4-benzobenzene) 1-3-hydroxythieno [2,3-b] pyridine  • 3—Hydroxy 2— (2-Naphthyl) thieno [2,3-) pyridine  • 3-Hydroxy 2- (4-methylbenzoyl) thieno [2,3-b] pyridine  • N— (3-trifluoromethylphenyl) -1-3-hydroxythithieno [2,3-b] pyridine-1-carboxamide  • N-Hexylul 3-Hydroxythieno [2,3-b) pyridin-1-2-carboxamide  • 3-Hydroxy 2-piperidino liponylthieno [2,3-b] pyridine  8. Formula for effective amount for treating osteoporosis (Γ)

 [In the formula, each symbol is as described below. ] A method for treating osteoporosis using a ketone compound represented by the formula: or a pharmaceutically acceptable salt thereof.  Ring X ′ represents a benzene ring or a pyridine ring.  Y represents an oxygen atom or a sulfur atom. Z * is a single bond, alkylene, alkenylene, alkynylene Or NR 5 —. (However, R ⁵ represents hydrogen, alkyl, acyl, aralkyl which may have a substituent, or a group which forms a nitrogen-containing heterocycle by bonding with R ⁴ ′.) R ¹ and R ² may be the same or different and may be hydrogen, halogen, alkyl, alkoxy, hydroxyl, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl, alkyl substituted with alkyl, alkamoyl, alkoxy Carbonyl, phenyl optionally substituted, nitro, acyl, sulfamoyl optionally substituted with alkyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyl Represents rookiji, hydroxyalkyl, acyloxyalkyl, alkoxyalkyl, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, and acylaminoalkyl , R 'and R ² and are bonded to each other alkylene which may have a substituent group, is also alkylene O carboxymethyl properly represents a group forming a benzene ring. R ³ is a hydroxyl group, an alkoxy, an alkoxy, an aminoalkoxy optionally substituted with an alkyl, an alkylsulfonylamino, an aminoalkylsulfonylamino, optionally substituted with an alkyl, or an arylsulfonylamino. Show. R ⁴ ′ is hydrogen, alkyl, an optionally substituted arylalkyl, an optionally substituted aromatic ring group or an optionally substituted heteroaromatic ring group (substituent and Is halogen, alkyl, alkoxy, hydroxyl, alkylthio, alkylsulfinyl, Alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxy, amino, carbamoyl, alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, haloalkoxy, alkyl Good aminoalkoxy, 1 to 3 substituents selected from aminoalkyl which may be substituted with alkyl, and acylaminoalkyl).  9. The method for treating osteoporosis according to claim 8, wherein the ketone compound or a pharmaceutically acceptable salt thereof is selected from the following compounds.  • 2—Benzoru 3—Hydroxythieno [2,3—b] pyridine  • 3-Hydroxy 2— (4-Hydroxybenzoyl) Cheno [2, 3—b] pyridine  • 2—Benzoyl 3—Hydroxy 6—Isoprovircheno [2, 3—b] pyridine  • 3-Acetoxy 2-Benzoylthieno [2,3-b] pyridine  • 2 — (4 benzoyl) 1-3-dimethylamino xythithieno [2, 3 — b] pyridine  • 2-Benzoyl 6-Isoprovir-1-3-Methanesulfonylaminofuro [2,3-b] pyridine  • 2—Benzoyl.3—Hydroxy 4, 6-dimethyl ceno [2,3-b) pyridine • 2—Benzoru 3—Hydroxythieno [2, 3—b] Norin  • 2-(4 benzoyl) 1-3-hydroxythieno (2, 3-b) pyridine  '3-Hydroxy 2-(2-naphthyl) thieno [2,3-1b] pyridine  • 3-Hydroxy 2- (4-methylbenzoyl) thieno [2,3-b) pyridine  • N— (3-trifluoromethylphenyl) -1-3-hydroxythithieno [2,3-b] pyridin-1-2-potoxolemide  • N-Hexylyl 3-Hydroxythieno [2,3-b] pyridin-1-2-hydroxylpoxamide  • 3-Hydroxy 2-biperidinocarbonylthieno [2,3—b] pyridine