JPH0586064A - Ketone compound and medicine for improving osteoporosis - Google Patents

Abstract

PURPOSE:To provide new low toxic compounds showing a bone absorption- inhibitory effect, excellent in safety and useful as a medicine for improving osteoporosis. CONSTITUTION:Compounds of formula I (Ring X is pyridine ring; Y is 0 or S; Z is single bond, alkylene, alkenylene, etc.; R<1> and R<2> are H, halogen, alkyl, alkoxy, OH, cyano, etc.; R<3> is OH, acyloxy, alkoxy, etc.; R<4> is alkyl, aralkyl, aromatic heterocycle, etc.), e.g. 2-(4-chlorobenzoyl)-3-(2-dimethylamino) ethoxythieno[2,3-b]pyridine. The compound of formula I is obtained by dehydration ring closure of a compound of formula II in the presence of a dehydrating agent such as polyphosphoric acid or phosphorus pentaoxide in a solvent such as benzene at 50-150 deg.C.

Description

Detailed Description of the Invention

[0001]

The present invention relates to a novel ketone compound having an excellent bone resorption inhibitory action and useful as a therapeutic agent for osteoporosis, a pharmaceutically acceptable salt thereof, and a ketone compound containing the novel compound and the same. It relates to the use of pharmaceutically acceptable salts.

[0002]

2. Description of the Related Art Osteoporosis is a condition in which bone mass per unit volume is abnormally decreased without changing the chemical composition (ratio of organic substance and inorganic substance) of bone substance itself. Is a syndrome that
The loss of proteins, calcium and phosphorus in bone is its physiological characteristic.

Since bone loss as a pathological condition is accompanied by a decrease in bone amount due to physiological aging, as a definition, bone loss is more prominent than that due to physiological aging. It can be said that the patient exhibited clinical symptoms such as pathological fractures and vertebral body deformities.

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

There are various causes of this osteoporosis, such as abnormal endocrinology including menopause, nutritional disorders, and vitamin D preparations which have been used as therapeutic agents for osteoporosis until now.
Targets of calcium preparations, calcitonin preparations, and bisphosphonate preparations are limited, and their effects are not certain. Further, female hormone preparations are expected to be effective, but serious side effects (genital cancer due to long-term use, etc.) are a problem. Therefore, it is strongly desired to develop a therapeutic agent for osteoporosis that is more effective and safe.

In recent years, a thionaphthen-2-carboxylic acid derivative or a 3-phenyl-4H-1-benzopyran-4-one derivative (isoflavone derivative), which has a completely different chemical structure from the above-mentioned preparation, has a bone resorption inhibitory action. Have been reported to be useful as therapeutic agents for osteoporosis [AJ
Johannesson et al., Endo-crinology
117, p. 1508, European Published Patent No. 1351
72, European Patent No. 136569, European Patent No. 146921, US Pat. No. 4,644,012].

Further, as a derivative having a bone resorption inhibitory effect, a (cycloalkylamino) methylenebis (phosphonic acid) derivative (US Pat. No. 4,970,335),
Heterocyclic bisphosphonic acid derivatives (US Pat. No. 4,905,905)
No. 03 specification), a benzofuroquinoline derivative (European Patent Publication No. 357172), and the like.

On the other hand, as a thieno or furopyridine compound, 3-hydroxyfuro [2,3-b] pyridine-
Ethyl 2-carboxylate and ethyl 3-hydroxythieno [2,3-b] pyridine-2-carboxylate are described in Journal of Heterocyclic Chemistry (J.
Heterocyclic Chem.) 23, 1465-1469, 1986, 24, 85-89, 1987.
However, these are all synthesized for the purpose of confirming their synthetic interest or chemical reactivity, and their pharmacological activity is not described at all. Moreover, Canadian Patent Publication No. 2019171 discloses 3-hydroxybenzothiophene or thienopyridine compounds for controlling in-vivo parasites. Furthermore, British Patent No. 1
No. 101946 discloses a benzothiophene compound having an analgesic and anti-inflammatory action.

The thionaphthene-2-carboxylic acid derivative or 3-phenyl-4H- reported in the above literature.
The 1-benzopyran derivative (isoflavone derivative) has a weak bone resorption inhibitory action, and is by no means satisfactory as a therapeutic drug for osteoporosis.

[0010]

Means for Solving the Problems The present inventors have synthesized various ketone compounds for the purpose of developing a better therapeutic agent for osteoporosis, and as a result of diligent search for their pharmacological effects, excellent bone resorption was found. The present invention has been completed by discovering new or known ketone compounds having an inhibitory action.
The present invention is as follows.

1. Formula (I):

[Chemical 4] [In the formula, each symbol is as described below. ] The ketone compound (I) represented by these, or its pharmaceutically acceptable salt. 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 group, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl, carbamoyl optionally substituted with alkyl, alkoxy. Carbonyl, optionally substituted phenyl, nitro, acyl, sulfamoyl optionally substituted with alkyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy, hydroxy alkyl, acyloxyalkyl, alkoxyalkyl, amino optionally substituted by alkyl alkoxy, an amino alkyl optionally substituted by alkyl, or an acyl aminoalkyl, R ¹ and R ² Alkylene which may have a substituent bonded to each other, it represents a group forming an alkylenedioxy or a benzene ring.

R ³ represents hydroxyl group, acyloxy, alkoxy, aminoalkoxy optionally substituted with alkyl, alkylsulfonylamino, aminoalkylsulfonylamino optionally substituted with alkyl, arylsulfonylamino.

R ⁴ is alkyl, aralkyl which may have a substituent, aromatic ring group which may have a substituent or heteroaromatic ring group which may have a substituent. , Halogen, alkyl, alkoxy, hydroxyl group, alkylthio, alkylsulfinyl, alkylsulfonyl,
Haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxyl, amino, carbamoyl, alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, haloalkoxy, optionally substituted aminoalkoxy with alkyl, alkyl 1 selected from optionally substituted aminoalkyl and acylaminoalkyl
To 3 substituents). Provided that R ¹ and R ² are the same or different and are hydrogen, halogen, alkyl, alkoxy, hydroxyl group, cyano, haloalkyl, carboxyl,
Carbamoyl, alkoxycarbonyl, phenyl which may have a substituent, or R ¹ and R ² are bonded to each other to form a benzene ring, R ³ is a hydroxyl group,
R ⁴ represents an acyloxy, and R ⁴ is alkyl, an aromatic ring group which may have a substituent or a heteroaromatic ring group which may have a substituent (the substituent is halogen, alkyl, alkoxy, hydroxyl group, Selected from alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, nitro, acyl, alkoxycarbonyl, carboxyl, amino optionally substituted with alkyl, carbamoyl optionally substituted with alkyl, alkylenedioxy, carboxyalkyl, carbamoylalkyl. 1 to 3 substituents are represented). 2. Formula (I "):

[0015]

[Chemical 5] [In the formula, each symbol is as described below. ] The ketone compound (I '') represented by these, or its pharmaceutically acceptable salt. 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 have the same meanings as defined above.

3. Formula (I '):

[Chemical 6] [In the formula, each symbol is as described below. ] A therapeutic agent for osteoporosis, which comprises a ketone compound (I ′) represented by the following or a pharmaceutically acceptable salt thereof as an active ingredient.

Z'represents 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 combining with R ⁴ ′. )

R ⁴ 'is hydrogen, alkyl, aralkyl which may have a substituent, aromatic ring group which may have a substituent or heteroaromatic ring group which may have a substituent (substituted). The group is halogen, alkyl, alkoxy, hydroxyl group, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxyl, amino, carbamoyl,
1 selected from alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, haloalkoxy, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, acylaminoalkyl To 3 substituents).

Rings X ', Y, R ¹ , R ² and R ³ have the same meanings as defined above. However, the ring X ′ represents a pyridine ring, and Z ′ represents a single bond, alkylene, alkenylene, alkynylene or —NR ⁵ —. (Wherein R ⁵ represents hydrogen, alkyl, acyl, or aralkyl which may have a substituent), and R ¹ and R ² are the same or different, and hydrogen, halogen, alkyl, alkoxy, hydroxyl group,
Cyano, haloalkyl, carboxyl, amino, carbamoyl, alkoxycarbonyl, phenyl which may have a substituent, or R ¹ and R ² are bonded to each other to form a benzene ring, and R ³ is R ⁴ represents a hydroxyl group or acyloxy, and R ⁴ is hydrogen, alkyl, an aralkyl which may have a substituent, an aromatic ring group which may have a substituent or a heteroaromatic ring which may have a substituent. The group (the substituent is selected from halogen, alkyl, alkoxy, hydroxyl group, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, nitro, acyl, alkoxycarbonyl, carboxy, amino, carbamoyl, alkylenedioxy, carboxyalkyl, carbamoylalkyl. 1 to 3 substituents) are excluded.

In the present specification, each symbol means the following. 1. Meaning of each symbol regarding Z and Z ′. The alkylene may be linear or branched, and its carbon number is usually 1
To 4, and specific examples thereof include methylene, ethylene, trimethylene, propylene, and tetramethylene.
The alkenylene may be linear or branched, and the carbon number thereof is usually 1 to 4, and specific examples thereof include vinylene, propenylene, butenylene and the like. Alkynylene may be linear or branched, and its carbon number is usually 1 to 4, specifically, ethynylene, propynylene,
Examples include butynylene. With respect to R ⁵ of Z ′, examples of the alkyl include the same as those for R ¹ and R ² described later. With respect to R ⁵ of Z ′, examples of the acyl include those similar to the acyls with respect to R ¹ and R ² described later. With respect to R ⁵ of Z ′, examples of the aralkyl which may have a substituent include R ⁴ and R ⁴ ′ described later.
The same as the aralkyl which may have a substituent with respect to is mentioned.

The nitrogen-containing heterocycle formed by combining with R ⁴ 'with respect to Z'is a heteroatom such as oxygen, sulfur, or an optionally substituted nitrogen atom (as a substituent, alkyl, phenylalkyl, 5 to 7-membered ring which may have (acyl etc.), and examples thereof include pyrrolidine, piperidine, morpholine, piperazine, 4-methylpiperazine and the like.

2. Meaning of each symbol for R ¹ and R ² . Halogen means fluorine, chlorine, bromine or iodine.
Alkyl may be linear or branched, and its carbon number is usually 1 to 10, preferably 1 to 8, and more preferably 1 to 6, specifically, methyl, ethyl, propyl, isopropyl, Examples include butyl, isobutyl, secondary butyl, tertiary butyl, pentyl, hexyl and octyl.

Alkoxy may be straight-chain or branched, and its carbon number is usually 1 to 10, preferably 1 to 8, more preferably 1 to 6, and specifically, methoxy and ethoxy. , Propoxy, isopropoxy, butoxy, isobutoxy, secondary butoxy, tertiary butoxy, pentyloxy, hexyloxy, octyloxy and the like.

The alkyl moiety in haloalkyl may be linear or branched, and the carbon number thereof is usually 1 to
4, preferably 1 to 3, and as the haloalkyl,
Specific examples include fluoromethyl, difluoromethyl, bromomethyl, chloromethyl, trifluoromethyl, trifluoroethyl, pentafluoropropyl and the like.

Amino in amino optionally substituted with alkyl is linear or branched and may be mono- or di-substituted with alkyl having a carbon number of preferably 1 to 4 carbon atoms, Further, the amino may be cyclic. Specific examples of such amino include amino, methylamino, dimethylamino, ethylamino, diethylamino, pyrrolidino, piperidino, morpholino and the like.

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

The alkoxy moiety in the alkoxycarbonyl may be linear or branched and has 1 to 4 carbon atoms. Specific examples of the alkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Examples include isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tertiary butoxycarbonyl and the like.

The substituents on the phenyl which may have a substituent have the same meaning as the substituents on the aromatic ring which may have a substituent or the heteroaromatic ring which may have a substituent, which will be described later with respect to R ⁴ . Those exemplified, preferably alkyl,
Examples thereof include halogen, alkoxy, hydroxyl group, aminoalkoxy optionally substituted with nitroalkyl, aminoalkyl optionally substituted with alkyl, and acylaminoalkyl. Examples of such phenyl include chlorophenyl, methylphenyl, methoxyphenyl, nitrophenyl, dimethylaminoethylphenyl, dimethylaminopropoxyphenyl, hydroxyphenyl, acetylaminoethylphenyl and the like.

The acyl may be any of aliphatic acyl, aromatic acyl and heterocyclic acyl. As the aliphatic acyl, alkanoyl is preferable, and alkanoyl having 2 to 5 carbon atoms is particularly preferable. Specific examples of the acyl include acetyl, propionyl, butyryl, pivaloyl, benzoyl, furoyl, thenoyl, nicotinoyl, isonicortyl, and the like.

In the sulfamoyl optionally substituted with alkyl, the alkyl as a substituent may be linear or branched, and may be mono-substituted di-substituted. The carbon number of the alkyl is usually 1 to 4, preferably 1 to 2. Examples of such sulfamoyl include sulfamoyl, methylsulfamoyl, ethylsulfamoyl, dimethylsulfamoyl, diethylsulfamoyl and the like.

The alkyl in alkylthio may be linear or branched, and the carbon number thereof is usually 1 to
4, preferably 1 to 2, and examples of alkylthio include methylthio, ethylthio, propylthio, isopropylthio, butylthio and the like.

Specific examples of arylthio include phenylthio, tolylthio, chlorophenylthio and the like.

The alkyl in the alkylsulfinyl may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2, and the alkylsulfinyl includes methylsulfinyl, ethylsulfinyl, butylsulfinyl and the like. Is exemplified.

Specific examples of arylsulfinyl include phenylsulfinyl, tolylsulfinyl and chlorophenylsulfinyl.

The alkyl in the alkylsulfonyl may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2, and the alkylsulfonyl includes methylsulfonyl, ethylsulfonyl, butylsulfonyl and the like. Is exemplified.

Specific examples of the arylsulfonyl include phenylsulfonyl, tolylsulfonyl, chlorophenylsulfonyl and the like.

Specific examples of aryloxy include phenoxy, tolyloxy, chlorophenoxy and nitrophenoxy.

Examples of aralkyloxy include benzyloxy, phenylethoxy, phenylbutoxy and the like.

The alkyl moiety in hydroxyalkyl may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2, and examples thereof include hydroxymethyl and hydroxyethyl.

Examples of the acyl moiety in the acyloxyalkyl include the acyl groups described above, and the alkyl moiety may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2. Yes, as the acyloxyalkyl, acetoxymethyl, acetoxyethyl, acetoxybutyl, propionyloxymethyl,
Examples thereof include pivaloyloxymethyl.

The alkoxy moiety in the alkoxyalkyl may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2, and the alkyl moiety is linear or branched. The carbon number is usually 1 to 4, preferably 1 to 2, and examples of the alkoxyalkyl include methoxymethyl, methoxyethyl, ethoxyethyl, methoxybutyl and the like.

The alkyl as the substituent in the aminoalkoxy which may be substituted with alkyl may be mono-substituted or di-substituted, and the alkyl may be linear or branched, and the number of carbon atoms thereof is Is usually 1
-4, preferably 1-2, and the alkoxy moiety may be linear or branched, and the carbon number thereof is usually 1-4, preferably 1-2. The aminoalkoxy may be cyclic aminoalkoxy. Examples of the aminoalkoxy include aminoethoxy, methylaminomethoxy, dimethylaminoethoxy, 1-pyrrolidinylmethoxy, piperidinomethoxy, and morpholinomethoxy.

Alkyl as a substituent in aminoalkyl which may be substituted with alkyl is mono-substituted,
It may be di-substituted, and the alkyl may be linear or branched, and the carbon number thereof is usually 1 to
4, preferably 1-2, and the alkyl moiety may be linear or branched, and the carbon number thereof is usually 1-4, preferably 1-2. The aminoalkyl may be cyclic aminoalkyl. Examples of the aminoalkyl include aminomethyl, methylaminomethyl, dimethylaminomethyl, ethylaminomethyl, dimethylaminopropyl, 1-pyrrolidinylmethyl, piperidinomethyl, morpholinoethyl and the like.

The acyl moiety as a substituent in the acylaminoalkyl may be linear or branched, and the carbon number thereof is usually 2 to 4, and halogen, alkyl (as a substituent on the alkanoyl or ring, Carbon 1
4, preferably 1 to 2 linear or branched alkyl), alkoxy (1 to 4 carbon atoms, preferably 1 or 2 linear or branched alkoxy), a substituent such as nitro. It is benzoyl which may be contained, and the alkyl moiety may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2. Examples of the acylaminoalkyl include acetylaminomethyl, acetylaminoethyl, propionylaminomethyl, propionylaminoethyl, benzoylaminoethyl and the like.

Substituents in the optionally formed alkylene, alkylenedioxy and benzene ring-forming groups formed by combining R ¹ and R ² with each other include R ¹ and R ² The following are included, and preferably, for example, the following are exemplified as preferable. Halogen (chlorine, bromine, fluorine, etc.) Alkyl (either linear or branched, the carbon number is usually 1 to 4, preferably 1 to 2) Alkoxy (linear or branched) Either of
Its carbon number is usually 1 to 4, preferably 1 to 2. ) Haloalkyl (the alkyl moiety may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2) Hydroxyl group Cyano nitro Alkyl optionally substituted with alkyl The portion may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2.)

The alkylene which may have a substituent is preferably one having 1 to 8 carbon atoms, for example, methylene, ethylene, trimethylene, propylene, methyltrimethylene, dimethyltrimethylene, methyltetramethylene, dimethyltetramethylene, Examples include dimethylpentamethylene.

The alkylene in alkylenedioxy which may have a substituent is preferably an alkylene having 1 to 4 carbon atoms, and examples of the alkylenedioxy include methylenedioxy, ethylenedioxy and isopropylidenedioxy. To be done.

Examples of the benzene ring-forming group which may have a substituent include chlorobenzene, methylbenzene, hydroxybenzene, methoxybenzene, trifluoromethylbenzene, cyanobenzene, nitrobenzene and dimethylaminobenzene. It

3. Meaning of each symbol relating to R ³ . Examples of acyl in acyloxy include those described for R ¹ and R ² , and examples of acyloxy include:
Examples are acetoxy, propionyloxy, benzoyloxy and the like.

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

The alkyl moiety in the alkylsulfonylamino may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2, and the alkylsulfonylamino is methylsulfonylamino,
Examples include ethylsulfonylamino and butylsulfonylamino.

The alkyl and alkyl moieties as the substituent in the aminoalkylsulfonylamino which may be substituted with alkyl may be linear or branched, and the carbon number thereof is usually 1 to 4, preferably 1 to 2, and the alkyl substitution may be mono- or di-substitution. Examples of such aminoalkylsulfonylamino include aminomethylsulfonylamino, aminoethylsulfonylamino, aminobutylsulfonylamino, methylaminoethylsulfonylamino, dimethylaminoethylsulfonylamino, dimethylaminopropylsulfonylamino and the like. The aminoalkylsulfonylamino may be cyclic aminoalkylsulfonylamino, and examples thereof include 1-pyrrolidinylmethylsulfonylamino and piperidinomethylsulfonylamino. As arylsulfonylamino,
Phenylsulfonylamino, tolylsulfonylamino,
Chlorophenylsulfonylamino and the like can be mentioned.

4. Meaning of each symbol for R ⁴ and R ^{4 ′} . Examples of alkyl include those described for 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, which will be described later with respect to R ⁴ . Examples thereof include halogen, alkyl, alkoxy, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, acylaminoalkyl and the like. Examples of such aralkyl include benzyl, phenylethyl, phenylpropyl, phenylbutyl, chlorobenzyl, methylbenzyl, methoxyphenylethyl, dimethylaminopropoxybenzyl, dimethylaminoethylbenzyl, acetylaminomethylbenzyl and the like.

The substituents on the aromatic ring which may have a substituent or the heteroaromatic ring which may have a substituent are as follows. (1) Halogen such as fluorine, chlorine and bromine; (2) C1-C4 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and tertiary butyl; (3) Methoxy, ethoxy, propoxy, Alkoxy having 1 to 4 carbon atoms such as isopropoxy, butoxy, isobutoxy, and tertiary butoxy; (4) hydroxyl group; (5) alkyl such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, and tertiary butylthio. Alkylthio having 1 to 4 carbon atoms in the moiety; (6) The number of carbon atoms in the alkyl group moiety such as methylsulfinyl, ethylsulfinyl and propylsulfinyl is usually 1
~ 4 alkylsulfinyl; (7) alkylsulfonyl such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and the like, in which the number of carbon atoms in the alkyl moiety is usually 1 to 4; (8) carbon of alkyl moiety such as trifluoromethyl, trifluoroethyl (9) cyano; (10) nitro; (11) acyl as described above, including acetyl, propionyl, butyryl, benzoyl and the like; (12) methoxycarbonyl, ethoxycarbonyl, Alkoxycarbonyl having an alkoxy having 1 to 4 carbon atoms such as propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl; (13) Carboxyl; (14) Amino, methylamino, ethylamino, 1-pyrrolidinyl, piperidino, morpholino, etc. Mono- or di-substituted with 1-4 alkyls (15) carbamoyl, methylcarbamoyl, ethylcarbamoyl and other carbamoyl which may be mono- or di-substituted by alkyl having 1 to 4 carbon atoms; (16) methylenedioxy, ethylenedioxy and the like. Alkylenedioxy having an alkylene having 1 to 4 carbon atoms; (17) Alkyl moiety such as cyanomethyl, cyanoethyl, cyanopropyl and cyanobutyl may be linear or branched, and the number of carbon atoms is usually 1 to A cyanoalkyl of 4; (18) an alkoxycarbonyl such as methoxycarbonylethyl, ethoxycarbonylethyl, etc., in which the alkyl moiety and the alkoxy moiety may each be linear or branched and whose carbon number is usually 1 to 4 Alkyl; (19) carboxymethyl, 1-carboxyethyl, 2-carboxy Carboxyalkyl having an alkyl group moiety such as cyethyl, which may be linear or branched, and has a carbon number of usually 1 to 4; (20) carbamoylmethyl, 1-carbamoylethyl, 2
A carbamoylalkyl having an alkyl having 1 to 4 carbon atoms such as carbamoylethyl; (21) the alkoxy moiety such as chloroethoxy, trifluoromethoxy, trifluoroethoxy may be linear or branched, Haloalkoxy having usually 1 to 4 carbon atoms, preferably 1 to 2; (22) Aminoalkoxy optionally substituted with alkyl such as dimethylaminomethoxy, diethylaminomethoxy, dibutylaminomethoxy, dimethylaminoethoxy, diethylaminopropoxy and the like. (23) The alkyl moiety and the alkyl as a substituent, such as aminomethyl, methylaminomethyl, dimethylaminomethyl, dimethylaminomethyl, dimethylaminoethyl, dimethylaminopropyl and the like, may be linear or branched, The carbon number is usually 1 A 4 alkyl as the substituent may be either mono- or di-substituted,
Aminoalkyl optionally substituted with alkyl; (24) acetylaminomethyl, acetylaminoethyl, propionylaminomethyl, propionylaminoethyl,
The alkyl moiety such as benzoylaminoethyl may be linear or branched, and the carbon number thereof is usually 1 to
4, preferably 1 to 2, and the acyl moiety is the same as the aforementioned acyl group, acylaminoalkyl.

One to three such substituents are substituted.
Specific examples of the aromatic ring and heteroaromatic ring which may have such a substituent include benzyl, phenylethyl, phenylpropyl, phenyl, naphthyl, indenyl, thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl,
Examples thereof include thiazolyl, oxazolyl, indolyl, pyridyl, pyrazyl, pyrimidinyl, quinolyl, isoquinolyl, thionaphthen-2 or 3-yl and the like.

The compound of the present invention is optionally made into a pharmaceutically acceptable salt. The salts include hydrochloric acid, hydrobromic acid,
Addition salts with inorganic acids such as sulfuric acid and phosphoric acid, addition salts with organic acids such as maleic acid, fumaric acid, citric acid, succinic acid, tartaric acid, methanesulfonic acid, sodium, potassium, calcium, magnesium, aluminum, etc. Examples thereof include salts with metals and salts with alkalis such as ammonium.
In addition, hydrate (hemihydrate, monohydrate, dihydrate, 3
/ 2 hydrate, etc.) are also included in the present invention.

In the case where the compound of the present invention has an asymmetric carbon, an optically active substance and a mixture thereof are also included in the scope of the present invention.

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

Method 1: Compound (I) in which R ³ is a hydroxyl group
And the production of (I ′) (1) Formula:

[Chemical 7] (Wherein each symbol has the same meaning as defined above), or a compound (II) represented by the formula

[0061]

[Chemical 8] (In the formula, each symbol has the same meaning as described above.) The compound (II ') can be produced by performing a dehydration ring-closing reaction in the presence of a dehydrating agent such as polyphosphoric acid or phosphorus pentoxide.
The reaction conditions are not particularly limited, and if necessary, the reaction is carried out at 50 to 150 ° C. for 10 minutes to 5 hours in the presence of a solvent such as benzene, toluene or xylene.

Equation (2):

[Chemical 9] (In the formula, R ⁶ represents a lower alkyl group such as methyl and ethyl, and other symbols have the same meanings as described above.), Or a compound (III) represented by the formula:

[0063]

[Chemical 10] (In the formula, R ⁶ represents a lower alkyl group such as methyl and ethyl, and the other symbols have the same meanings as described above.) The compound (III ′) represented by methanol, ethanol, propanol, isopropyl alcohol, butanol In the presence of a base (sodium methoxide, potassium tertiary butoxide, sodium hydride, triethylamine, etc.) in an alcohol solvent such as the above, the reaction can be performed at 0 to 100 ° C. for 5 minutes to 5 hours.

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

[Chemical 11] (Wherein each symbol has the same meaning as defined above), or a compound (IV) represented by the formula

[0065]

[Chemical formula 12] (Wherein each symbol has the same meaning as defined above), in the compound (IV ′) represented by the formula ( ⁴ ), aromatic ring group or heteroaromatic group in which R ⁴ or R ⁴ ′ is substituted with optionally substituted aminoalkoxy. The compound which is a ring group is produced by subjecting a compound in which R ⁴ or R ⁴ 'is an aromatic ring group or a heteroaromatic ring group substituted by haloalkoxy such as chloroalkoxy to an amination reaction known per se. ..

[0066] (4) 'in, R ⁴ or R ⁴ compound (IV) or (IV)' is an aromatic ring group or heteroaromatic ring group which is substituted by carboxyl or carboxyalkyl compound, R ⁴ or R ⁴ A compound wherein'is an aromatic ring group or a heteroaromatic ring group substituted by a group capable of leading to a carboxyl such as cyano, carbamoyl optionally substituted with alkyl, alkoxycarbonyl, cyanoalkyl, carbamoylalkyl or alkoxycarbonylalkyl. It is produced by subjecting it to a hydrolysis reaction known per se.

Method 2: Compound (I ') in which Z is NR ^5.
Manufacturing formula:

[Chemical 13] (In the formula, R ⁷ represents a hydrogen atom or a lower alkyl group such as methyl or ethyl, and other symbols have the same meanings as described above.) And a compound (V ′) represented by the formula

[0068]

[Chemical 14] (In the formula, R ⁵ and R ⁴ ′ have the same meanings as described above.) And can be produced by reacting with the compound (VI ′).

When R ⁷ is a lower alkyl group, the reaction is carried out in a suitable solvent
For example, aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, alcohols such as methanol, ethanol, propanol, isopropyl alcohol, ethylene glycol, diethylene glycol, and any mixture thereof. A solvent) or in the absence of a solvent, a base (triethylamine, sodium hydride, sodium methoxide, potassium tertiary butoxide,
(For example, potassium carbonate). The reaction temperature is not particularly limited either, and the reaction usually proceeds from room temperature to 200 ° C. in 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 dicyclohexylcarbodiimide,
Alternatively, thionyl chloride, p-toluenesulfonyl chloride, methanesulfonyl chloride, chlorocarbonic acid ester and the like are once made into active esters and then performed.

Method 3: Preparation of compounds (I) and (I ') in which R ³ is acyloxy It is prepared by subjecting compound (IV) or (IV') to an acylation reaction known per se. The acylating agent is preferably an acid halide or an acid anhydride.

Method 4: Preparation of Compounds (I) and (I ') in which R ³ is alkoxy, aminoalkoxy optionally substituted with alkyl Compound (IV) or (IV') and alkyl halide, aminoalkyl halide Inactive in the presence of deoxidizing agents (potassium carbonate, sodium hydroxide, calcium hydroxide, sodium methoxide, triethylamine, pyridine, etc.) with alkylaminoalkylhalides, dialkylaminoalkylhalides or cyclic aminoalkylhalides. Solvent (toluene, methanol, ethanol,
(Dimethylformamide, acetone, dioxane, etc.)
It is produced by reacting at a temperature of room temperature to 150 ° C.

Method 5: Preparation of Compounds (I) and (I ') wherein R ³ is alkylsulfonylamino, optionally alkyl-substituted aminoalkylsulfonylamino or arylsulfonylamino

Expression

[Chemical 15] (Wherein each symbol has the same meaning as defined above) and a compound (VII) represented by the chemical formula

[0075]

[Chemical 16] (Wherein each symbol has the same meaning as defined above) and a compound (VII ′) represented by the formula

[0076]

Embedded image R ⁸ —SO ₂ —Hal (VIII) [wherein R ⁸ is alkyl, aminoalkyl optionally substituted with alkyl (ie, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cyclic aminoalkyl) ), Aryl or haloalkyl is H
al represents halogen. ] The compound (VII
I) and deoxidizer (potassium carbonate, sodium carbonate, sodium hydrogen carbonate, dimethylamine, triethylamine,
Pyridine, quinoline, etc.) in the presence of a solvent inert to the reaction (toluene, methylene chloride, chloroform,
Dichloroethane, pyridine, dimethylformamide, etc.) at a temperature of -10 ° C to 100 ° C. Either the mono-substituted compound or the bis-substituted compound can be predominantly synthesized by appropriately selecting the amount of the sulfonyl halide agent (VIII) and the reaction conditions.

In the reaction with the compound (VIII) which is a haloalkylsulfonyl halide, a dehydrohalogenation reaction may occur to produce a haloalkenylsulfonylamino compound. These haloalkylsulfonylamino forms or haloalkenylsulfonylamino forms (for example, bis (vinylsulfonyl) amino form) are aminoalkylsulfonylaminos in which R ³ may be substituted with alkyl by subjecting to an amination reaction known per se. A compound is produced.

In addition, the compounds (I) and (I ') relating to the present invention are also produced by a known method or a method known per se. The ketone compound relating to the present invention thus obtained can be isolated and purified by a conventional method such as a recrystallization method, a chromatographic method or a distillation method, alone or in combination. If desired, the racemic compound can be resolved into an optically active substance by allowing an optically active acid (tartaric acid, diacetyltartaric acid, tartronic acid, dibenzoyltartaric acid, mandelic acid, etc.) to act. Alternatively, it can be resolved into an optically active substance by using an optically active chromatographic method. Further, a compound having a desired configuration can be stereoselectively obtained by using an optically active raw material compound.

The ketone compound relating to the present invention is optionally added with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or maleic acid, fumaric acid, citric acid, succinic acid,
It may be a pharmaceutically acceptable salt such as an addition salt with an organic acid such as tartaric acid or methanesulfonic acid, a salt with a metal such as sodium, potassium, calcium, magnesium or aluminum, or a salt with an alkali such as ammonium.

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

[Chemical 18] (In the formula, R ⁹ represents a hydrogen atom or a lower alkyl group such as methyl and ethyl, and the other symbols have the same meanings as described above.) Compounds (IX) and (IX ′) represented by potassium carbonate, In an aqueous solution of sodium carbonate, potassium hydroxide, sodium hydroxide or the like, or in tetrahydrofuran, N,
In the presence of a base such as sodium methoxide, potassium tertiary butoxide, triethylamine and sodium hydride in a solvent such as N-dimethylformamide, the compound of the formula

[0081]

[Chemical 19] (In the formula, A represents a halogen atom (synonymous with the above) or a sulfonic acid residue such as a methanesulfonyloxy group, a p-toluenesulfonyloxy group, a trifluoromethanesulfonyloxy group, and the other symbols have the same meanings as described above. .)
And a compound (X) or (X ′) represented by
It can be produced by reacting at 0 ° C. for 5 minutes to 20 hours.

Further, the compound (III) which is the starting compound
Can be produced by esterifying compound (II) using a conventional method. Further, other starting compounds can be synthesized by a method known per se.

[0083]

The compounds (I) and (I ′) of the present invention were used in vitro in mouse or rat femur or parietal bone.
In the system for measuring bone resorption activity of ro, it shows a strong inhibitory effect on bone resorption, its cytotoxicity is weak, and hypercalcemia (increased calcium concentration in serum) induced in tumor-bearing mice or rats. It has an inhibitory action and is useful as a highly safe therapeutic agent for osteoporosis.

[0084]

The effects of the compounds of the present invention on the bone resorption inhibitory action and the results are shown below. Bone resorption inhibitory action (in vitro ) The bone resorption inhibitory action in vitro using mouse femur was measured according to the following method.

The femurs of male ICR mice aged 3 to 6 weeks were aseptically excised, 10% heat-inactivated fetal bovine serum, penicillin G potassium 100 units / ml, kanamycin sulfate 60 μ.
The bone marrow cavity was washed with a halo F12 medium (hereinafter, referred to as a culture medium) containing g / ml and 0.15% sodium hydrogen carbonate, and then the soft tissue attached to the bone was thoroughly removed and used for culture.

The test compound was once dissolved in dimethyl sulfoxide to prepare a 10 mg / ml solution, which was diluted 1000 times with a culture solution to obtain a 10 μg / ml solution.

Using 1.2 ml of the culture medium containing the test compound, the femur of the ICR mouse was cultured in a 24-well plate for 6 days under the conditions of 5% carbon dioxide gas and 95% air, and after the culture was completed, the culture was performed. The supernatant was collected and the amount of calcium released in the culture supernatant was quantified by the chelate method using orthocresolphthalein.

The bone resorption inhibitory effect of the test compound was determined by the following formula using the culture of the femur without the test compound as a control.

[0089]

[Equation 1]

This experiment was carried out in 4 cases in each group. Further, in the control group, only the same amount of dimethyl sulfoxide as in the case of adding the test compound was added and the culture was performed. The results are shown in Table 1.

[0091]

[Table 1] Table 1 ───────────────────────── Test amount Bone resorption inhibitory compound (μg / ml) (% Inhibition) ───────────────────────── Example 1 1 11.4 Compound 10 44.5 Example 9 1 20.2 Compound 10 42. 0 127.6 in Production Example 1 10 32.3 ──────────────────────────

The compounds (I) and (I ′) and their pharmaceutically acceptable salts relating to the present invention may be used as they are or in a pharmaceutically acceptable carrier, excipient, disintegrant, binder, lubricant, Tablets, powders, granules, pills, capsules, syrups, injections, by mixing with fillers, diluents, solubilizers, etc., and prepared according to a conventional method.
It can be administered to patients in various formulations such as ointments and suppositories. The dose varies depending on the administration subject, administration route, symptoms, etc., but is usually 1 to 1000 m by oral administration per day for adults.
In addition, 0.1 to 100 mg is suitable for intranasal, intravenous and rectal administration, and this can be administered once or dividedly in several times.

Pharmaceutical Formulation Example A tablet containing 5 mg of the compound of the present invention can be prepared by the following formulation. Compound of Example 1 5 mg Crystalline cellulose 65 mg Corn starch 25 mg Talc 4 mg Magnesium stearate 1 mg Total amount 100 mg After thoroughly mixing the above compositions, granulating and drying, 1 using a tablet machine
Tablets are 100 mg tablets.

[0094]

The following examples are given to further illustrate the present invention, but the present invention is not limited thereto. Example 1 (1) Sodium methoxide was prepared with 30 ml of methanol and 0.7 g of metallic sodium, and 5.0 g of methyl thiosalicylate was added under ice cooling. Then α-bromo-4-
9.2 g of (3-chloropropoxy) acetophenone was gradually added, and the mixture was reacted at 0 ° C for 1 hour and further at 20 ° C for 1 hour. The precipitated crystals were collected by filtration, washed with water and then purified from methanol to obtain methyl 2- [4- (3-chloropropoxy) phenacylthio] benzoate. Melting point 103 [deg.] C.

(2) 3.2 g of methyl 2- [4- (3-chloropropoxy) phenacylthio] benzoate, 30 ml of methanol and 4.2 ml of a methanol solution of 2N-sodium methoxide were stirred at 30 ° C. for 10 minutes, It was a yellow solution. After cooling, the solution was neutralized with an aqueous acetic acid solution, and the precipitated yellow crystals were collected by filtration, washed with water, and then purified from a mixed solution of ethanol-ethyl acetate to give 2- [4- (3-chloropropoxy) benzoyl] -3-hydroxybenzothiophene. Got Melting point 8
5 to 87 ° C.

(3) 2.5 g of 2- [4- (3-chloropropoxy) benzoyl] -3-hydroxybenzothiophene, 3.3 g of 50% dimethylamine aqueous solution, N,
5 ml of N-dimethylformamide, 0.1 g of cuprous iodide
The mixture was stirred at 40 ° C. for 10 hours, the solvent was distilled off under reduced pressure, 10 ml of water was added to the residue, and the mixture was neutralized with sodium hydrogen carbonate. The liberated oily substance was extracted with chloroform, the chloroform was distilled off, and the remaining crystals were salted with maleic acid and purified from a mixed solution of ethyl acetate and ethanol.
-[4- (3-Dimethylaminopropoxy) benzoyl] -3-hydroxybenzothiophene maleate was obtained. Melting point 150-152 [deg.] C.

Example 2 In the same manner as in (3) of Example 1 except that morpholine was used instead of 50% dimethylamine, 2- [4-
(3-morpholinopropoxy) benzoyl] -3-hydroxybenzothiophene maleate was obtained. Melting point 1
48-150 ° C.

Example 3 Sodium methoxide was prepared with 60 ml of methanol and 2.1 g of metallic sodium, 5 g of methyl thiosalicylate was added thereto under ice cooling, and then 7.2 g of N-acetyl-4-chloroacetylphenethylamine was gradually added. And then stirred at 30 ° C. for 3 hours. Neutralize with aqueous acetic acid,
The precipitated crystals were collected by filtration, washed with water, and purified with ethanol to obtain 2- [4- (2-acetylaminoethyl) benzoyl] -3-hydroxybenzothiophene. Melting point 1
72-174 ° C.

Example 4 In the same manner as in Example 14 except that 2-methyl-2- (4-chloroacetyl) phenylacetamide was used in place of N-acetyl-4-chloroacetylphenethylamine, 2-methyl- 4 '-(3-Hydroxybenzothiophene-2-carbonyl) phenylacetamide was obtained. Melting point 175-176 [deg.] C.

Example 5 4.3 g of 2-methyl-4 '-(3-hydroxybenzothiophene-2-carbonyl) phenylacetamide, 4.3 g of sodium hydroxide, 43 ml of water, ethanol 20
The mixture of ml was refluxed for 3 hours. After the solvent was distilled off, water was added and the mixture was neutralized with hydrochloric acid. The candy-like substance released at this time was extracted with chloroform, the chloroform was distilled off, and the residue was purified from dichloroethane to obtain 2-methyl-4 ′-(3-hydroxybenzothiophene-2-carbonyl) phenylacetic acid. Melting point 162-164 [deg.] C.

Example 6 (1) 2-mercaptonicotinic acid (10 g) and potassium carbonate (17.8 g) were dissolved in water (100 ml), and phenacyl chloride (13.9 g) was dissolved in tetrahydrofuran (50 m).
It was dissolved in 1 and added dropwise. After stirring at 0 ° C. for 5 hours, the reaction solution was washed twice with toluene, and the aqueous layer was acidified with acetic acid. The precipitated crystals were collected by filtration and recrystallized from ethanol to give 2
11.4 g of phenacylthionicotinic acid were obtained. Melting point 1
68-173 ° C.

(2) 2-phenacylthionicotinic acid 6.
7 g was added to 67 g of polyphosphoric 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 by filtration and recrystallized from methanol to give yellow crystals of 2-benzoyl-3.
29 g of -hydroxythieno [2,3-b] pyridine were obtained. Melting point 115-116 [deg.] C.

(3) 2-benzoyl-3-hydroxythieno [2,3-b] pyridine 6 g, potassium carbonate 9.7
g, 2-dimethylaminoethyl chloride 3.7 g, and acetone 60 ml were refluxed for 24 hours and allowed to cool, then the reaction solution was filtered, the filtrate was concentrated, and the residue was purified by column chromatography in ethyl acetate. Maleate 2
-Benzoyl-3- (2-dimethylamino) ethoxythieno [2,3-b] pyridine maleate was obtained. Melting point 107-110 [deg.] C.

Example 7 2-Benzoyl-3- (3-) was prepared in the same manner as in Example 18 except that 3-dimethylaminopropyl chloride was used instead of 2-dimethylaminoethyl chloride.
Dimethylamino) propoxythieno [2,3-b] pyridine maleate was obtained. Melting point 91-93 [deg.] C.

Example 8 2-Benzoyl-3-hydroxythieno [2,3-b]
2- (4-chlorobenzoyl) -3 instead of pyridine
2- (4-chlorobenzoyl) -3- (2-dimethylamino) ethoxythieno [2,3-b] pyridine in the same manner as in Example 18 except that -hydroxythieno [2,3-b] pyridine was used. -The maleate salt was obtained. Melting point 1
13-115 ° C.

Example 9 1.4 g of 3-amino-2-benzoyl-6-isopropylfuro [2,3-b] pyridine and 10 m of chloroform
l, 0.68 g of methanesulfonyl chloride was added dropwise to a solution of 0.6 g of triethylamine under ice cooling over 40 minutes, reacted at 10 ° C. for 2 hours and at 30 ° C. for 1 hour, and water was added for liquid separation. The chloroform layer was separated, chloroform was distilled off, and the residue was extracted with toluene. After distilling off toluene, the residue was purified with ethanol to obtain 2-benzoyl-6-isopropyl-3-methanesulfonylaminofuro [2,3-b] pyridine. Melting point 166-167
° C.

Example 10 2.9 g of 3-amino-2-benzoyl-6-isopropylthieno [2,3-b] pyridine, 30 m of chloroform
To a solution of 1 and 2.2 g of triethylamine, 2.4 g of methanesulfonyl chloride was added dropwise under ice cooling over 30 minutes, reacted at 40 ° C. for 2 hours, and then water was added. After separating the chloroform layer, chloroform was distilled off, and the residue was purified by column chromatography to give 3-N, N-bis (methanesulfonyl) amino-2-benzoyl-6-isopropylthieno [2,3-b]. Pyridine was obtained. Melting point 136-138 [deg.] C.

Example 11 (1) 3-Amino-2-benzoyl-6-isopropylfuro [2,3-b] pyridine 19.4 g, chloroform 15
To a solution of 0 ml and 31.3 g of triethylamine, 25 g of 2-chloroethylsulfonyl chloride was added under ice cooling,
Reaction and treatment were carried out in the same manner as in Example 22 above, and 3-
N, N-bis (vinylsulfonyl) amino-2-benzoyl-6-isopropylfuro [2,3-b] pyridine was obtained. Melting point 133-136 [deg.] C.

(2) 2.5 g of 3-N, N-bis (vinylsulfonyl) amino-2-benzoyl-6-isopropylfuro [2,3-b] pyridine, 20 m of chloroform
A solution of 1 and 1.3 g of diethylamine was stirred at room temperature for 24 hours, the solvent was distilled off, and isopropyl ether was added for crystallization. After collection by filtration, purification from isopropyl alcohol, 2-benzoyl-3- (2-diethylamino)
Ethylsulfonylamino-6-isopropylfuro [2,2
3-b] pyridine was obtained. Melting point 146 [deg.] C.

Example 12 The procedure of Example 23 (2) was repeated except that 1-methylpiperazine was used in place of diethylamine.
Benzoyl-3- (2- (4-methyl-1-piperazinyl) ethyl) sulfonylamino-6-isopropylfuro [2,3-b] pyridine was obtained. Melting point 163 [deg.] C.

Example 13 Except that pyrrolidine is used instead of diethylamine,
In the same manner as (2) of Example 23, 2-benzoyl-3
-(2- (1-Pyrrolidinyl) ethyl) sulfonylamino-6-isopropylfuro [2,3-b] pyridine was obtained. Melting point 209 [deg.] C.

Example 14 (1) A solution of 3.9 g of 3-acetoxy-2-benzoyl-6-methylthieno [2,3-b] pyridine and 50 ml of methylene chloride was ice-cooled, and m-chloroperbenzoic acid was added thereto. After adding 3.0 g and stirring at room temperature for 5 hours, the reaction solution was washed with aqueous sodium hydrogen carbonate solution and saturated saline solution. The solvent was distilled off and the residue was purified by ethanol to give 3-acetoxy-2-benzoyl-6-methylthieno [2,3-b].
Pyridine-N-oxide was obtained. Melting point 130-133
° C.

(2) 3-acetoxy-2-benzoyl-
After reacting 2.5 g of 6-methylthieno [2,3-b] pyridine-N-oxide and 25 ml of acetic anhydride at 90 ° C. for 3 hours, the solvent was distilled off, and the residue was dissolved in chloroform and washed with water. After removing chloroform by distillation, the residue was purified from ethanol to obtain 2-acetoxy-6-acetoxymethyl-2-benzoylthieno [2,3-b] pyridine. Melting point 8
6-89 ° C.

(3) 2-acetoxy-6-acetoxymethyl-2-benzoylthieno [2,3-b] pyridine 1.0 g, potassium hydroxide 0.33 g, ethanol 10
The mixture of 10 ml of water and 10 ml of water was stirred at room temperature for 2 hours, neutralized with acetic acid, and the solvent was evaporated. The residue was extracted with chloroform, washed with water, the chloroform was distilled off, and the residue was purified from ethanol to give 2-benzoyl-3-hydroxy-6-.
Hydroxymethylthieno [2,3-b] pyridine was obtained. Melting point 118-120 [deg.] C.

Production Example 1 2-piperidinocarbonylmethylthionicotinic acid 4.9
g was dissolved in 30 ml of acetonitrile, 2.7 g of 1,8-diazabicyclo [5,4,0] undec-7-ene and 3.0 g of methyl iodide were added, and the mixture was reacted at room temperature for 24 hours. After the acetonitrile was distilled off, the residue was extracted with toluene, washed with water and aqueous sodium hydrogen carbonate, and the toluene was distilled off to obtain 4 g of a crude methyl ester compound as an oily substance. To this, 10 ml of methanol and 7 ml of 2N-sodium methoxide methanol solution were added, and the mixture was refluxed for 30 minutes.
Methanol was distilled off, water was added to dissolve it, and it was neutralized with acetic acid to precipitate crystals. After filtration, it was purified from hydrous methanol to obtain 3-hydroxy-2-piperidinocarbonylthieno [2,3-b] pyridine. Melting point 99-101 [deg.] C.

Although the present invention has been specifically described with reference to the specification including the examples, the examples can be variously changed and modified without departing from the spirit and scope of the present invention.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Kenji Chiba 3-7-25 Oyata, Iruma City, Saitama Prefecture, Tokyo Research Laboratory, Yoshitomi Pharmaceutical Co., Ltd. (72) Yusaku Amano 3-7-25 Oyada, Iruma City, Saitama Prefecture Yoshitomi Pharmaceutical Co., Ltd. Tokyo Research Center

Claims (5)

[Claims] 1. Formula (I): [In the formula, each symbol is as described below. ] The ketone compound represented by these, or its pharmaceutically acceptable salt. 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 group, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl, carbamoyl optionally substituted with alkyl, alkoxycarbonyl, substituted Optionally substituted phenyl, nitro, acyl, sulfamoyl optionally substituted with alkyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy, hydroxyalkyl, acyloxy alkyl, alkoxyalkyl, an amino alkoxy optionally substituted with alkyl, an amino alkyl optionally substituted by alkyl, or an acyl aminoalkyl, bond and R ¹ and R ² mutually Which may have a substituent Te alkylene represents a group forming an alkylenedioxy or a benzene ring. R ³ represents hydroxyl group, acyloxy, alkoxy, aminoalkoxy optionally substituted with alkyl, alkylsulfonylamino, aminoalkylsulfonylamino optionally substituted with alkyl, arylsulfonylamino. R ⁴ is alkyl, aralkyl which may have a substituent, aromatic ring group which may have a substituent or heteroaromatic ring group which may have a substituent (the substituent is halogen, Alkyl, alkoxy, hydroxyl group, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxyl, amino optionally substituted with alkyl, carbamoyl optionally substituted with alkyl, alkylenedioxy ,
Cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl, haloalkoxy, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl,
1 to 3 substituents selected from acylaminoalkyl) are shown. Provided that R ¹ and R ² are the same or different and are hydrogen, halogen, alkyl, alkoxy, hydroxyl group,
Cyano, haloalkyl, carboxyl, carbamoyl,
Alkoxycarbonyl, phenyl which may have a substituent, or R ¹ and R ² are combined to form a benzene ring, R ³ is a hydroxyl group or acyloxy, and R ⁴ is Alkyl, an aromatic ring group which may have a substituent or a heteroaromatic ring group which may have a substituent (the substituent is halogen, alkyl, alkoxy, hydroxyl group, alkylthio, alkylsulfinyl, alkylsulfonyl, 1 to 3 substituents selected from cyano, nitro, acyl, alkoxycarbonyl, carboxyl, amino optionally substituted with alkyl, carbamoyl optionally substituted with alkyl, alkylenedioxy, carboxyalkyl, carbamoylalkyl Group) is excluded. 2. The ketone compound according to claim 1, which is selected from the following compounds, or a pharmaceutically acceptable salt thereof. 2- (4-chlorobenzoyl) -3- (2-dimethylamino) ethoxythieno [2,3-b] pyridine 2-benzoyl-6-isopropyl-3-methanesulfonylaminofuro [2,3-b] pyridine 3. Formula (I ″): embedded image [In the formula, each symbol is as described below. ] The ketone compound represented by these, or its pharmaceutically acceptable salt. 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, carbamoyl optionally substituted with alkyl, alkoxycarbonyl, substituted Optionally substituted phenyl, nitro, acyl, sulfamoyl optionally substituted with alkyl, alkylthio, arylthio, alkylsulfinyl, arylsulfinyl, alkylsulfonyl, arylsulfonyl, aryloxy, aralkyloxy, hydroxyalkyl, acyloxy alkyl, alkoxyalkyl, an amino alkoxy optionally substituted with alkyl, an amino alkyl optionally substituted by alkyl, or an acyl aminoalkyl, bond and R ¹ and R ² mutually Which may have a substituent Te alkylene represents a group forming an alkylenedioxy or a benzene ring. R ^3A represents a hydroxyl group or acyloxy. R ^4A represents aminoalkyl optionally substituted with alkyl or acylaminoalkyl optionally substituted with alkyl. 4. Formula (I ′): embedded image [In the formula, each symbol is as described below. ] A therapeutic agent for osteoporosis, comprising a ketone compound represented by the following or a pharmaceutically acceptable salt thereof as an active ingredient. 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 —NR ⁵ —. (However, R ⁵ is hydrogen, alkyl, acyl, aralkyl which may have a substituent,
A group which forms a nitrogen-containing heterocycle by combining with R ⁴ 'is shown. )
R ¹ and R ² are the same or different and each is hydrogen, halogen, alkyl, alkoxy, hydroxyl group, cyano, haloalkyl, carboxyl, amino optionally substituted with alkyl,
Carbamoyl which may be substituted with alkyl, alkoxycarbonyl, phenyl which may have a substituent,
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, acylaminoalkyl, or R ¹ and R ² are bonded to each other to have a substituent Is a group which forms an alkylene, alkylenedioxy or benzene ring. R ³ represents hydroxyl group, acyloxy, alkoxy, aminoalkoxy optionally substituted with alkyl, alkylsulfonylamino, aminoalkylsulfonylamino optionally substituted with alkyl, arylsulfonylamino. R ⁴ 'is hydrogen, alkyl, aralkyl which may have a substituent, aromatic ring group which may have a substituent or heteroaromatic ring group which may have a substituent (the substituent is , Halogen, alkyl, alkoxy, hydroxyl group, alkylthio, alkylsulfinyl, alkylsulfonyl, haloalkyl, cyano, nitro, acyl, alkoxycarbonyl, carboxy, amino, carbamoyl, alkylenedioxy, cyanoalkyl, alkoxycarbonylalkyl, carboxyalkyl, carbamoylalkyl , Haloalkoxy, aminoalkoxy optionally substituted with alkyl, aminoalkyl optionally substituted with alkyl, and 1 to 3 substituents selected from acylaminoalkyl). However, the ring X ′ represents a pyridine ring, and Z ′ represents a single bond, alkylene, alkenylene, alkynylene or —NR ⁵ —. (However, R ⁵ represents hydrogen, alkyl, acyl, or aralkyl which may have a substituent.),
R ¹ and R ² are the same or different and each represent hydrogen, halogen, alkyl, alkoxy, hydroxyl group, cyano, haloalkyl, carboxyl, amino, carbamoyl, alkoxycarbonyl or phenyl which may have a substituent, or R 1
¹ and R ² represent a group which is bonded to each other to form a benzene ring, R ³ represents a hydroxyl group or acyloxy, and R ⁴ represents hydrogen, alkyl, an aralkyl which may have a substituent, or a substituent. Aromatic ring group which may have or heteroaromatic ring group which may have a substituent (substituent means halogen, alkyl, alkoxy, hydroxyl group, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, nitro, acyl 1 to 3 selected from, alkoxycarbonyl, carboxy, amino, carbamoyl, alkylenedioxy, carboxyalkyl, carbamoylalkyl.
, Which means the number of substituents). 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- (4-chlorobenzoyl) -3- (2-dimethylamino) ethoxythieno [2,3-b] pyridine 2-benzoyl-6-isopropyl-3-methanesulfonylaminofuro [2,3-b] pyridine -Hydroxy-2-piperidinocarbonylthieno [2,3-b] pyridine