JP3165866B2 - Sulfur-containing heterocyclic compounds - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sulfur-containing heterocyclic compound having a bone resorption inhibiting action or a salt thereof, and an agent for preventing or treating osteoporosis containing the compound as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION Osteoporosis is a pathological condition or disease in which the loss of bone has increased to some extent, thereby causing some symptoms or danger. The main symptoms are kyphosis of the spine, lumbar spine and fractures of the vertebral body, femoral neck, lower radius, ribs, upper humerus and the like. The causes are diverse, including endocrine and nutritional disorders. Conventionally, estrogen agents, calcitonin, vitamin D, calcium agents, and the like have been administered as therapeutic agents.

[0003]

However, when the above-mentioned therapeutic agents are administered, the target of administration is limited or the effect is uncertain, so that a sufficient effect has not been obtained.

[0004]

Means for Solving the Problems The present inventors have conducted intensive studies for the purpose of developing a more general drug which acts directly on bone and suppresses bone resorption, and as a result, the following general formula (I) It has been found that the compound represented by the formula (1) directly acts on bone and exhibits an excellent bone resorption inhibiting action, and thus completed the present invention.

That is, the present invention relates to (1) a compound represented by the general formula (I)

Embedded image [Wherein, ring A represents an optionally substituted benzene ring;
Represents a hydrogen atom or a hydrocarbon group which may be substituted,
B represents a carboxyl group which may be amidated, a portion containing a broken line represents a carbon-carbon single bond or a double bond, k represents 0 or 1, and n represents 0, 1, or 2]. Sulfur-containing heterocyclic compound or a salt thereof, (2) General formula

Embedded image Wherein B 'is a carboxyl group which may be esterified, and other symbols have the same meanings as described above, or a salt thereof is subjected to a reduction reaction. General formula characterized by being subjected to a reaction and / or an oxidation reaction

Embedded image Wherein each symbol is as defined above, or a method for producing a salt thereof, (3) a general formula

Embedded image [Wherein, Z is a leaving group, R ¹ and R ² are each a hydrogen atom,
A hydrocarbon group which may be substituted or a 5- to 7-membered heterocyclic group which may be substituted, and other symbols are as defined above] or a salt thereof is subjected to an elimination reaction. General formula characterized by the following:

Embedded image Wherein each symbol is as defined above, or a method for producing a salt thereof, (4) a sulfur-containing heterocyclic compound (I)
Or a preventive or therapeutic agent for osteoporosis characterized by containing a salt thereof.

In the above general formula, examples of the substituent in the substituted benzene ring represented by ring A include a halogen atom, a nitro group, an optionally substituted alkyl group, an optionally substituted hydroxyl group, Optionally substituted thiol group, optionally substituted amino group, acyl group, mono- or di-alkoxyphosphoryl group, phosphono group,
An optionally substituted aryl group, an optionally substituted aralkyl group or an optionally substituted aromatic heterocyclic group is used, and these substituents are the same or different, and 1 to 4, preferably 1 Alternatively, two or more benzene rings may be substituted.

Here, as the halogen atom, for example, fluorine, chlorine, bromine, iodine and the like are used. The alkyl group in the alkyl group which may be substituted is preferably a linear or branched alkyl group having 1 to 10 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. For example, butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, nonyl or decyl, and a cyclic alkyl group having 3 to 7 carbon atoms such as cyclopropyl, cyclobutyl, cyclohexyl or cycloheptyl are used. Atoms (e.g.,
Fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, 1 to 1 carbon atoms
6 alkoxy groups (eg, methoxy, ethoxy, propoxy, butoxy, hexyloxy, etc.), mono- or di-
It may be substituted with 1 to 3 (alkoxy having 1 to 6 carbon atoms) phosphoryl, phosphono, or the like.

Specific examples of the substituted alkyl group include:
For example, trifluoromethyl, 2,2,2-trifluoroethyl, trichloromethyl, hydroxymethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-diethoxyphosphorylethyl, phosphonomethyl and the like can be mentioned.

As the substituted hydroxyl group, aryloxy and the like in addition to alkoxy, alkenyloxy, aralkyloxy, acyloxy and the like having an appropriate substituent for the hydroxyl group, particularly those having a hydroxyl group are used. . The alkoxy has 1 to 1 carbon atoms.
10 linear or branched alkoxy groups (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, heptyloxy, nonyloxy, etc.) And a cyclic alkoxy group having 4 to 6 carbon atoms (eg, cyclobutoxy, cyclopentoxy or cyclohexyloxy, etc.)
Is used, and the alkenyloxy group is preferably an alkenyloxy group having 2 to 10 carbon atoms, for example, allyl (a
llyl) oxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, and the like. The aralkyloxy group preferably has 6 carbon atoms.
To an aralkyloxy group, more preferably an aryl having 6 to 14 carbon atoms-an alkyloxy group having 1 to 4 carbon atoms
(Eg, benzyloxy, phenethyloxy, etc.), and the acyloxy group is preferably an alkanoyloxy group, for example, an alkanoyloxy group having 2 to 10 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, isobutyioxy) Ryloxy, hexanoyloxy, etc.) are used. As the aryloxy group, an aryloxy group having preferably 6 to 14 carbon atoms (eg, phenoxy,
Biphenyloxy and the like are used, and these are further substituted with, for example, 1 to 3 halogen atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, mono- or di- (alkoxy having 1 to 6 carbon atoms) phosphoryl, and the like. It may be. Specific examples of the substituted hydroxyl group include, for example, trifluoromethoxy, 2,2,2-trifluoroethoxy, difluoromethoxy, 2-methoxyethoxy, 4-chlorobenzyloxy, 2- (3,4-dimethoxyphenyl) ethoxy And the like.

The substituted thiol group includes, for example, alkylthio, aralkylthio, acylthio, and the like, which have an appropriate substituent on the thiol group, particularly those having a thiol group. The alkylthio group is preferably a linear or branched alkylthio group having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isobutylthio, Pentylthio, neopentylthio, hexylthio, heptylthio, nonylthio, etc.)
A cyclic alkylthio group having 7 carbon atoms (eg, cyclobutylthio, cyclopentylthio, cyclohexylthio, cyclopentylthio, etc.) is used, and the aralkylthio is preferably an aralkylthio group having 7 to 19 carbon atoms, more preferably 6 carbon atoms. To 14 aryl-C1 to C4 alkylthio groups such as benzylthio and phenethylthio, and the acylthio group is preferably an alkanoylthio group such as an alkanoylthio group having 2 to 10 carbon atoms (eg, acetylthio, Propionylthio, n-butyrylthio, iso-butyrylthio, hexanoylthio, etc.)
Which are further substituted with 1 to 3 halogen atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, mono- or di- (alkoxy having 1 to 6 carbon atoms), and the like. Is also good. Specific examples of the substituted thiol group include, for example, trifluoromethylthio, difluoromethylthio, 2,2,2-trifluoroethylthio, 2-methoxyethylthio, 4-chlorobenzylthio, 3,4-dichlorobenzylthio, 4-fluorobenzylthio, 2- (3,4-dimethoxyphenyl) ethylthio and the like.

Examples of the acyl group include an organic carboxylic acid acyl group and a sulfonate acyl group having a hydrocarbon group having 1 to 6 carbon atoms (eg, methyl, ethyl, n-propyl, iso-propyl, hexyl, phenyl, etc.). Examples of the organic carboxylic acid acyl group include formyl and the aforementioned alkyl-carbonyl group having 1 to 10 carbon atoms (eg, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl,
Octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, etc.), alkenyl-carbonyl group having 2 to 10 carbon atoms (eg, crotonyl, 2-cyclohexenecarbonyl, etc.) or aryl-carbonyl having 6 to 14 carbon atoms Group (eg, benzoyl etc.), aralkyl-carbonyl group having 7 to 19 carbon atoms (eg, phenylacetyl etc.), 5 or 6
Membered heteroaromatic carbonyl group (eg, nicotinoyl, 4-
A 5- or 6-membered aromatic heterocyclic acetyl group (eg, 3-pyridylacetyl, 4-thiazolylacetyl, etc.) and has a hydrocarbon group having 1 to 6 carbon atoms. As the acyl group, methanesulfonyl, ethanesulfonyl and the like are used, and these are further substituted with 1 to 3 substituents such as the above-mentioned halogen atom, hydroxyl group, alkoxy group having 1 to 6 carbon atoms, amino group and the like. Is also good. Specific examples of the substituted acyl group include, for example, trifluoroacetyl, 3-cyclohexyloxypropionyl, 4-chlorobenzoyl, 6-chloronicotinoyl, 2-methyl-4-phenyl-5-thiazolylacetyl and the like. Can be

The substituent in the substituted amino group includes the aforementioned alkyl group having 1 to 10 carbon atoms and 2 to 2 carbon atoms.
10 alkenyl groups (e.g., allyl, vinyl, 2-penten-1-yl, 3-penten-1-yl, 2-hexen-1-yl, 3-hexen-1-yl, 2-cyclohexenyl, 2- Cyclopentenyl, 2-methyl-2-
A propen-1-yl, 3-methyl-2-buten-1-yl and the like, an aryl group having 6 to 14 carbon atoms (for example, phenyl,
Naphthyl, anthryl, etc.), one or two of the above-mentioned aralkyl groups having 7 to 19 carbon atoms or the above-described acyl groups are the same or different, and these substituents are the above-mentioned halogen atom, alkoxy having 1 to 3 carbon atoms. Group, mono- or di- (alkoxy having 1 to 6 carbon atoms) phosphoryl, phosphono group and the like. Specific examples of the substituted amino group include, for example, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino,
Diallylamino, cyclohexylamino, phenylamino, N-methyl-N-phenylamino, acetylamino, propionylamino, benzoylamino or methanesulfonylamino.

The mono- or di-alkoxyphosphoryl group preferably has a lower alkoxy group. For example, dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, dibutoxyphosphoryl, ethylenedioxy Phosphoryl and the like are used.

As the aryl group in the optionally substituted aryl group, an aryl group having 6 to 14 carbon atoms, for example, phenyl, naphthyl, anthryl and the like are preferably used. Base,
It may be substituted with one to three halogen atoms, a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, or the like. Specific examples of the substituted aryl group include, for example, 4-chlorophenyl,
3,4-dimethoxyphenyl, 4-cyclohexylphenyl, 5,6,7,8-tetrahydro-2-naphthyl and the like can be mentioned.

The aralkyl group in the optionally substituted aralkyl group is preferably an aralkyl group having 7 to 19 carbon atoms, for example, benzyl, naphthylethyl, trityl and the like. Alkyl group of 1 to 6, halogen atom, hydroxyl group, carbon number 1
1 to 3 alkoxy groups or the like may be substituted. Specific examples of the substituted aralkyl group include, for example, 4-chlorobenzyl, 3,4-dimethoxybenzyl,
2- (4-isopropylphenyl) ethyl, 2- (5,6,
7,8-tetrahydro-2-naphthyl) ethyl and the like.

The aromatic heterocyclic group in the optionally substituted aromatic heterocyclic group is preferably a 5- to 6-membered aromatic heterocyclic group having 1 to 4 nitrogen, oxygen or / and sulfur atoms. For example, furyl, thienyl, imidazolyl, triazolyl, isoxazolyl, pyridyl, pyrimidyl, pyrazinyl, thiazolyl, oxazolyl, thiadiazolyl and the like are used.
6 alkyl groups, halogen atoms, hydroxyl groups, 1 to 6 carbon atoms
May be substituted with 1 to 3 alkoxy or the like.

When two alkyl groups are substituted adjacent to each other on a benzene ring, they are linked together to form a group of the formula-(CH ₂ ) _m-
Wherein m represents an integer of 3 to 5; an alkylene group (for example, trimethylene, tetramethylene, pentamethylene) may be formed, and when two alkoxy groups are substituted adjacent to each other, An alkylenedioxy group represented by the formula —O— (CH ₂ ) _p —O—, wherein p represents an integer of 1 to 3 (for example, methylenedioxy, ethylenedioxy,
Trimethylenedioxy) may be formed. In such a case, a 5- to 7-membered ring is formed together with the carbon atom of the benzene ring.

Examples of the hydrocarbon group in the optionally substituted hydrocarbon group represented by R include an alkyl group (preferably an alkyl group having 1 to 10 carbon atoms) and an alkenyl group (preferably having a carbon number of 1 to 10). An alkenyl group having 2 to 10 carbon atoms, an aryl group (preferably an aryl group having 6 to 14 carbon atoms), an aralkyl group (preferably an aralkyl having 7 to 19 carbon atoms) and the like are used. Examples of the substituent on the hydrocarbon group include the aforementioned 5- to 6-membered aromatic heterocyclic group, a halogen atom,
A dialkoxyphosphoryl group, a phosphono group and the like are used.

R is preferably, for example, methyl, ethyl,
Propyl, isopropyl, butyl, isobutyl, sec.-
It is an unsubstituted alkyl group having 1 to 6 carbon atoms such as butyl, tert.-butyl, pentyl, neopentyl and hexyl.

The amidated carboxyl group represented by B is preferably a compound of the formula —CON (R ¹ ) (R ² ) wherein R ¹ and R ² are a hydrogen atom, an optionally substituted hydrocarbon And a 5- or 7-membered heterocyclic group which may be substituted, respectively.] Examples of the hydrocarbon group in the optionally substituted hydrocarbon group represented by R ¹ and R ² include an alkyl group, preferably the above-mentioned alkyl group having 1 to 10 carbon atoms and alkenyl group, preferably 2 to 10 carbon atoms. An alkenyl group, an aryl group, preferably an aryl group having 6 to 14 carbon atoms and an aralkyl group, preferably an aralkyl group having 7 to 19 carbon atoms.
(Eg, fluorine, chlorine, bromine, iodine, etc.), a hydroxyl group, an alkoxy group having 1 to 6 carbon atoms, and an amino group which may be substituted with an alkyl group having 1 to 6 carbon atoms (eg, dimethylamino, diethylamino, Propylamino), an amino group substituted with an acyl group (eg, an alkanoyl group having 1 to 10 carbon atoms) (eg, acetylamino, propionylamino, benzoylamino), or an alkyl group having 1 to 6 carbon atoms A carbamoyl group (eg, dimethylcarbamoyl, ethoxycarbamoyl, etc.), an alkoxycarbonyl group having 1 to 6 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, etc.), a mono- or di-alkoxyphosphoryl group (eg, dimethoxy Phosphoryl, diethoxyphosphoryl, ethylenedioxyphosphoryl, etc.), phosphono group, aromatic heterocyclic group, etc. It may be conversion.

The 5- to 7-membered heterocyclic group, which may be substituted and is represented by R ¹ and R ² , is
For example, a 5- to 7-membered heterocyclic group containing one sulfur, nitrogen or oxygen atom, a 5- to 6-membered heterocyclic group containing 2 to 4 nitrogen atoms
A 5- to 6-membered heterocyclic group containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom is used, and these heterocyclic groups are 6-membered containing 2 or less nitrogen atoms. It may be condensed with a ring, a benzene ring or a 5-membered ring containing one sulfur atom.

Specific examples of the above heterocyclic ring include, for example, 2
-Pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl,
Pyrido [2,3-d] pyrimidyl, benzopyranyl, 1,8
-Naphthyridyl, 1,5-naphthyridyl, 1,6-naphthyridyl, 1,7-naphthyridyl, quinolyl, thieno [2,
3-b] pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl, triazinyl, triazolyl, thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, morpholino, and the like.

R ¹ and R ² may be linked to each other by a carbon chain which may contain an oxygen atom, a sulfur atom or a nitrogen atom to form a 5- to 7-membered ring. formula
It represents a 5- to 7-membered ring formed together with the nitrogen atom of the acid amide of (I). These rings include, for example, morpholine,
Piperidine, thiomorpholine, homopiperidine, piperidine, pyrrolidine, thiazolidine, azepine and the like.

Specific examples of the substituted alkyl group represented by R ¹ or R ² include, for example, trifluoromethyl,
Trifluoroethyl, difluoromethyl, trichloromethyl, 2-hydroxyethyl, 2-methoxyethyl, 2
-Ethoxyethyl, 2,2-dimethoxyethyl, 2,2-
Diethoxyethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl, 2- (2-thienyl) ethyl, 3- (3-furyl) propyl, 2-morpholinoethyl, 3-pyrrolylbutyl, 2-piperidinoethyl, 2-
(N, N-dimethylamino) ethyl, 2- (N-methyl-N
-Ethylamino) ethyl, 2- (N, N-diisopropylamino) ethyl, 5- (N, N-dimethylamino) pentyl, N, N-dimethylcarbamoylethyl, N, N-dimethylcarbamoylpentyl, ethoxycarbonylmethyl, Isopropoxycarbonylethyl, tert-butoxycarbonylpropyl, 2-diethoxyphosphorylethyl, 3-dipropoxyphosphorylpropyl, 4-dibutoxyphosphorylbutyl, ethylenedioxyphosphorylmethyl, 2-phosphonoethyl, 3-phosphonopropyl, etc.
Specific examples of the substituted aralkyl group include, for example, 4-
Chlorobenzyl, 3- (2-fluorophenyl) propyl, 3-methoxybenzyl, 3,4-dimethoxyphenethyl, 4-ethylbenzyl, 4- (3-trifluorophenyl) butyl, 4-acetylaminobenzyl, 4-dimethyl Specific examples of substituted aryl groups such as aminophenethyl, 4-diethoxyphosphorylbenzyl, and 2- (4-dipropoxyphosphorylmethylphenyl) ethyl include, for example, 4-chlorophenyl, 4-cyclohexylphenyl, 5,6,7 , 8-tetrahydro-2-naphthyl,
3-trifluoromethylphenyl, 4-hydroxyphenyl, 3,4,5-trimethoxyphenyl, 6-methoxy-2-naphthyl, 4- (4-chlorobenzyloxy) phenyl, 3,4-methylenedioxyphenyl, 4- (2,
2,2-trifluoroethoxy) phenyl, 4-propionylphenyl, 4-cyclohexanecarbonylphenyl, 4-dimethylaminophenyl, 4-benzoylaminophenyl, 4-diethoxycarbamoylphenyl, 4
-Tert-butoxycarbonylphenyl, 4-diethoxyphosphorylphenyl, 4-diethoxyphosphorylmethylphenyl, 4- (2-diethoxyphosphorylethyl) phenyl, 2-diethoxyphosphorylmethylphenyl,
3-diethoxyphosphorylmethylphenyl, 4-dipropoxyphosphorylphenyl, 4- (2-phosphonoethyl)
Specific examples of the substituted 5- to 7-membered heterocyclic group such as phenyl, 4-phosphonomethylphenyl, and 4-phosphonophenyl include, for example, 5-chloro-2-pyridyl, 3-methoxy-2-pyridyl, -Methyl-2-benzothiazolyl,
5-methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-isoxazolyl, 4- (4-chlorophenyl) -5-methyl-2-oxazolyl, 3-phenyl-
1,2,4-thiadiazol-5-yl, 5-methyl-
1,3,4-thiadiazol-2-yl, 5-acetylamino-2-pyrimidyl, 3-methyl-2-thienyl,
4,5-dimethyl-2-furanyl, 4-methyl-2-morpholinyl and the like. Among the above, ring A is preferably a benzene ring which may be substituted with a halogen atom, an alkyl group or an alkoxy group.

The substituent B is preferably of the formula --CON (R ¹ ) (R
² ) wherein R ¹ and R ^{2 each} represent a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted 5- to 7-membered heterocyclic group.

The substituent R is preferably a hydrogen atom, having 1 carbon atom.
To 6 alkyl groups or phenyl groups. Preferred compounds include N- (4-diethoxyphosphorylphenyl) -6,7-dimethyl-3,4-dihydro-1H-2-
Benzothiopyran-1-carboxamide, N- (4-diethoxyphosphorylphenyl) -7,8-dimethyl-1,
2-dihydro-3-benzothiepin-2-carboxamide, N- (4-diethoxyphosphorylphenyl) -7,8
-Dimethyl-1,2,4,5-tetrahydro-3-benzothiepin-2-carboxamide, N- (4-chlorophenyl) -4-methyl-7,8-methylenedioxy-1,2
-Dihydro-3-benzothiepin-2-carboxamide, N- (4-diethoxyphosphorylmethylphenyl)-
3,4-dihydro-1H-2-benzothiopyran-1-
And carboxamide 2,2-dioxide. Compound (I) or a salt thereof can be produced by a method known per se. For example, it can be manufactured according to the following method. As the salts of the compounds described below, those similar to the compounds (I) are used.

(1) Method A General formula (I-1)

Embedded image Wherein each symbol is as defined above, or a salt thereof is represented by the general formula (III)

Embedded image [In the formula, B 'represents a carboxyl group which may be esterified, and other symbols have the same meanings as described above. ] Or a salt thereof is subjected to a reduction reaction. As the esterified carboxyl group represented by B ', those similar to those defined in B are used.
B 'is preferably an alkyl ester, especially a C1-6
An ester with an alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, pentyl, neopentyl, hexyl, or an aralkyl ester, particularly an ester with an aralkyl group having 7 to 19 carbon atoms; For example, esters with benzyl, phenethyl, 3-phenylpropyl and the like.

The present reduction reaction is carried out in the same manner as ordinary Wolff-Kishner reduction. The synthesis means may be in accordance with any known method, for example, R. Todd
Written by Organic Reactions
s), vol. 4, p. 378 [John Willie and Sons
Inc., New York (John Wiley & Sons, Inc. New
York) 1948]; New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (I) (Maruzen 1977). For example, it can be carried out by the following method. This reaction is generally performed using compound (III)
Is heated in diethylene glycol with hydrazine hydrate and sodium (potassium hydroxide). The amount of hydrazine hydrate used is preferably about 2 to 10 mol per 1 mol of compound (III), and the amount of sodium (potassium) hydroxide used is preferably about 2 to 10 mol per 1 mol of compound (III). The reaction temperature is about 80 ° C to about 230 ° C, preferably about 100 ° C to about 200 ° C, and the reaction time is usually 0.5 to 100 hours, preferably about 1 to 30 hours.

(2) Method B General formula (I-2)

Embedded image [Wherein each symbol has the same meaning as described above] or a salt thereof can be produced by subjecting compound (I-1) or a salt thereof to an amidation reaction. This reaction is carried out by reacting compound (I-1) or a salt thereof with an amine compound.

The amine compound is preferably of the general formula (II)

Embedded image [The symbols in the formula are as defined above] are used. The reaction of compound (I-1) or a salt thereof with an amine compound is generally carried out in the same manner as in a well-known condensation reaction in peptide synthesis. This reaction is carried out in a manner known per se, for example by M. Bodansky and MA Ondetti, Peptide Synthesis, Interscience New York 1966; FM Finn and
K. Hofmann, The Proteins, vol. 2, edited by H. Nenrath, RL Hill, Academic Press, Inc. New York, 1976; Nobuo Izumiya et al. Azide method, chloride method, acid anhydride method, etc.
Mixed acid anhydride method, DCC method, active ester method, method using Woodward reagent K, carbonyldiimidazole method,
It can be carried out according to a redox method, a DCC / HONB method, and a method using diethyl cyanophosphate. For example, this reaction can be carried out by the following method. The amine compound (II) is used in an amount of 1 to 1 mol of the compound (I-1) or a salt thereof.
About 10 to about 10 mol may be used. This reaction is performed in a solvent that does not adversely influence the reaction. As such a solvent, for example, dimethylformamide, dimethylsulfoxide, pyridine, chloroform, dichloromethane, ethyl acetate, ethyl ether, tetrahydrofuran, acetonitrile or a mixture of these at an appropriate ratio is used. These solvents can be used either in an anhydrous state or in a water-containing state. The reaction temperature is usually about -20 ° C to 50 ° C.
° C, preferably about -10 ° C to 30 ° C. The reaction time is about 1 to 100 hours, preferably about 2 to 40 hours.

(3) Method C General Formula (I-3)

Embedded image Wherein each symbol is as defined above, or a salt thereof is represented by compound (IV)

Embedded image [Wherein, Z is a leaving group, and other symbols are as defined above]
Alternatively, they can be produced from their salts. Examples of the leaving group represented by Z include, for example, halogen, preferably chlorine, bromine or iodine, or a hydroxyl group activated by esterification, such as a residue of an organic sulfonic acid.
(E.g., p-toluenesulfonyloxy group), having 1 to 4 carbon atoms
And a diphenylphosphoryloxy group, a dibenzylphosphoryloxy group, and a dimethylphosphoryloxy group, which are the residues of organic phosphoric acid. The reaction is N,
It is advantageously carried out by heating in N-dimethylformamide (DMF) in the presence of lithium bromide and lithium carbonate. The amount of lithium bromide used is about 1 to 3 mol per 1 mol of compound (IV), and the amount of lithium carbonate used is
V) The amount is preferably about 2 to 10 mol per 1 mol. The reaction temperature ranges from about 40 ° C to about 200 ° C, preferably from about 70 ° C to about 1 ° C.
60 ° C., and the reaction time is usually 0.5 to 100 hours,
Preferably, it is about 1 to 30 hours.

(4) Method D General formula (I-5)

Embedded image Wherein n ′ is 1 or 2, and the other symbols are as defined above, or a salt thereof is a compound (I-4)

Embedded image [Wherein each symbol has the same meaning as described above] or a salt thereof, which is subjected to an oxidation reaction. This oxidation reaction is carried out by oxidizing with an oxidizing agent according to a conventional method. As such an oxidizing agent, a mild oxidizing agent which does not substantially act on the skeleton of the sulfur-containing heterocyclic compound, preferably, m-chloroperbenzoic acid, hydrogen peroxide, perester (p
eresters) and sodium metaperiodate. This reaction is performed in an organic solvent that does not adversely influence the reaction. Examples of the solvent include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), hydrocarbons (eg, benzene, toluene, etc.), alcohols (methanol, ethanol, propanol, etc.), or a mixture thereof. A solvent or the like is used. When the oxidizing agent is used in an equimolar amount or less than the equimolar amount with respect to the compound (I-4), the compound of formula (I-5) in which n 'is 1 is preferentially formed. The compound of the formula (I-5) wherein n 'is 2 is a compound of the formula (1-5)
The compound of formula (I-5) wherein n 'is 1 is further oxidized to form. This reaction proceeds at room temperature (10 ° C to 30 ° C) or lower. Preferably, the temperature is from about -50C to 20C.
The reaction time is about 30 minutes to 10 hours.

(5) Method E In this method, a compound containing a phosphono group or a salt thereof is produced using a compound containing a mono- or di-alkoxyphosphoryl group among the compounds prepared by the methods A to D. This reaction is carried out using an inorganic acid such as hydrochloric acid or hydrobromic acid or a trialkylsilicon halide in a solvent that does not adversely influence the reaction. When using inorganic acids such as hydrochloric acid or hydrobromic acid, the solvent may be alcohols such as methanol, ethanol, 2-methoxyethanol, ethylene glycol, propanol and butanol;
Water or a mixed solvent thereof is used. The amount of the acid used is usually a large excess, and the reaction temperature is 0 ° C to 150 ° C,
Preferably, the reaction time is 30 ° C to 100 ° C, and the reaction time is 1 to 50 hours. When using alkyl silicon halides such as chlorotrimethylsilicon, bromotrimethylsilicon and trimethylsilicon iodide, the solvent may be carbon tetrachloride, chloroform, dichloromethane, 1,2-dichloroethane,
Carbon halides such as 1,1,2,2-tetrachloroethane, acetonitrile, a mixed solvent thereof and the like are used. The amount of alkyl silicon halides used is mono-
Alternatively, the amount is 1 to 10 equivalents, preferably 2 to 5 equivalents, based on the compound containing a di-alkoxyphosphoryl group. The reaction temperature is -30 ° C to 100 ° C, preferably -10 ° C to 50 ° C,
The reaction time is 30 minutes to 100 hours. The sulfur-containing heterocyclic compound (I) thus obtained is a known separation and purification means,
For example, it can be isolated and purified by concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like. In the production of the following starting compounds, they can be isolated and purified in the same manner as described above. Raw material compound of the present invention (II
Although I) and (IV) can be produced by a method known per se, for example, they can be produced by the following method.

(1) F method general formula (III-1)

Embedded image [Wherein B ″ represents an esterified carboxyl group,
The other symbols are as defined above] or a salt thereof is represented by the general formula (V)

Embedded image [Wherein, Y represents a hydroxy group or a halogen atom, and other symbols have the same meanings as described above] or a salt thereof, which is produced by subjecting the compound to a ring closure reaction. As the esterified carboxyl group represented by B ″, those similar to those defined in B are used. B '' is preferably an alkyl ester, particularly an ester with an alkyl group having 1 to 6 carbon atoms, such as an ester with methyl, ethyl, propyl, isopropyl, butyl, tert.-butyl, pentyl, neopentyl, hexyl, etc., or aralkyl. Esters, particularly esters with an aralkyl group having 7 to 19 carbon atoms, such as esters with benzyl, phenethyl, 3-phenylpropyl and the like.

The present ring closure reaction is carried out in the same manner as in a usual Friedel-Crafts reaction. The synthesis means may be in accordance with any known method, for example, R. Adams
Written by Organic Reactions
s), Vol. 2, p. 114 [John Willie and Sons
Inc., New York (John Wiley & Sons, Inc. New Y
ork) 1962]; New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds (II) (Maruzen 1977).

For example, it can be carried out by the following method. This reaction is generally performed in a solvent that does not adversely influence the reaction, or without a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, diethyl ether, and tetrahydrofuran. And the like, nitrobenzene, nitromethane, carbon disulfide, a mixed solvent thereof and the like. This reaction is performed in the presence of a Lewis acid. As the Lewis acid, for example, hydrogen fluoride, sulfuric acid, phosphoric acid, phosphoric anhydride, aluminum chloride, tin tetrachloride, zinc chloride and the like are used. The amount of Lewis acid used is compound (V) or its salt 1
It is preferably about 2 to 10 mol per mol. The reaction temperature is in each case from about -20C to about 200C, preferably from about 0C to about 100C. The reaction time is usually about 30 minutes to
It is 100 hours, preferably about 1 to 30 hours.

(2) G method General formula (III-2)

Embedded image [The symbols in the formula are as defined above] or a salt thereof can be produced by subjecting compound (III-1) or a salt thereof to a hydrolysis reaction. This hydrolysis reaction is carried out in a water-containing solvent or water according to a conventional method. As the aqueous solvent, for example, an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran or dioxane, a mixed solvent of N, N-dimethylformamide, dimethylsulfoxide, acetone, and water are used. This reaction is performed in the presence of a base or an acid. As the base, for example, potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide and the like are used. As the acid, for example, hydrochloric acid, sulfuric acid, acetic acid, hydrobromic acid and the like are used. The acid or base is a compound (III-
1) excess (base: 1.2 to 6 equivalents, acid: 2 to 50)
(Equivalent). This reaction is usually carried out at about -20.
C. to 150.degree. C., preferably about -10.degree.

(3) Method H The compound represented by the general formula (IV) or a salt thereof is a compound (III)
-2) or a salt thereof is subjected to a reduction reaction after an amidation reaction, followed by a halogenation reaction or a sulfonylation reaction or the like. The amidation reaction is performed in the same manner as in Method B, and the compound (VI)

Embedded image Wherein each symbol in the formula is as defined above. Subsequently, the compound represented by the general formula (VI) or a salt thereof is subjected to a reduction reaction to obtain a compound (VII).

Embedded image Wherein each symbol in the formula is as defined above. This reaction is a reduction reaction known per se, for example, a new experimental chemistry course 15
Oxidation and reduction [II] (Maruzen 1977). For example, this reaction is carried out by treating compound (VI) or a salt thereof with a reducing agent. Examples of the reducing agent include alkali metal borohydrides, for example, metal hydride complex compounds such as sodium borohydride and lithium borohydride, metals such as organotin compounds (such as triphenyltin hydride), nickel compounds, and zinc compounds. A catalytic reducing agent using a metal salt, a transition metal catalyst such as palladium, platinum, rhodium and hydrogen and reduction by a hydrogen transfer reaction are used. This reaction is performed in an organic solvent that does not adversely influence the reaction. Examples of the solvent include halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.) or hydrocarbons (eg, benzene, toluene, etc.), alcohols (methanol, ethanol, propanol,
Ethers such as isopropanol), diethyl ether, dioxane, tetrahydrofuran and the like, amides such as N, N-dimethylformamide, and a mixed solvent thereof are appropriately selected and used depending on the type of the reducing agent. The reaction temperature is preferably from 0 ° C to 130 ° C, particularly preferably from 10 ° C to 100 ° C. The reaction time is about 30 minutes to 24 hours.

Compound (VII) is subjected to a halogenation reaction or a sulfonylation reaction to produce compound (IV). As the halogenating agent, thionyl chloride, phosphorus tribromide and the like are preferable. In this case, a compound (IV) in which Z is chlorine or bromine or a salt thereof is produced. This halogenation reaction is performed in an inert solvent (eg, benzene, toluene, xylene, chloroform, dichloromethane, or the like) or using an excess of a halogenating agent as a solvent. The reaction temperature is about 10-80 ° C. The amount of the halogenating agent used is the compound (V
It is about 1 to 20 mol based on II) or a salt thereof. Mesyl chloride, tosyl chloride,
Benzenesulfonyl chloride is preferably used.
(IV) represented by mesyloxy, tosyloxy and benzenesulfonyloxy, respectively, or a salt thereof. The sulfonylation reaction is carried out in an inert solvent (e.g., benzene,
Toluene, xylene, ethyl ether, ethyl acetate, tetrahydrofuran, chloroform, dichloromethane, etc.). The reaction is preferably performed in the presence of a base (eg, triethylamine, N-methylmorpholine, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, etc.). The reaction temperature is about 0 to 130
° C, preferably 10 to 100 ° C. Reaction time is about 1
0 minutes to 5 hours. The amounts of the sulfonylating agent and the base to be used are about 1 to 1.2 mol, respectively, per 1 mol of compound (VII) or a salt thereof. Compound (V) can be synthesized by the following method.

Embedded image In the above formula, Z represents a leaving group, Y 'represents a halogen atom, and other symbols have the same meanings as described above.

First Step Reaction This reaction is a step of producing compound (V-1) or a salt thereof by reacting compound (VIII) or a salt thereof with compound (IX) or a salt thereof in the presence of a base. The reaction of compound (VIII) or a salt thereof with compound (IX) or a salt thereof is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol, esters such as ethyl acetate, and nitriles such as acetonitrile. , Pyridines such as pyridine and lutidine, amides such as N, N-dimethylformamide, sulfoxides such as dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane,
Halogenated hydrocarbons such as 1,1,2,2-tetrachloroethane, ketones such as acetone and 2-butanone, and mixed solvents thereof are used. This reaction involves sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate,
The reaction is carried out in the presence of an inorganic base such as sodium bicarbonate and an organic base such as tertiary amines such as pyridine, triethylamine and N, N-dimethylaniline. The amount of the base to be used is preferably about 1 to 5 mol with respect to compound (VIII) or a salt thereof. This reaction is carried out usually at -20 ° C to 150 ° C, preferably at about -10 ° C to 100 ° C. Starting compound (VII
I) or a salt thereof can be used, for example, in Chemical and Pharmaceutical Bretane (Chem. Pharm. Bull.) 30
Volume 3580, 1982; Chemical and Pharmaceutical Bretane (Chem. Pharm. Bull.) 3
The compound can be synthesized according to the method described in Vol. 0, p. 3601 (1982).

Second Step Reaction This reaction is a step of subjecting compound (V-1) or a salt thereof to a halogenation reaction to produce compound (V-2) or a salt thereof. This method is performed according to a method known per se. For example, New Laboratory Chemistry 14, Synthesis and Reaction of Organic Compounds [II] (Maruzen 1
977). For example, this reaction is carried out by reacting compound (V-1) or a salt thereof with a halogenating agent such as a chlorinating agent (eg, phosphorus pentachloride, thionyl chloride, oxalyl chloride, etc.). The reaction is carried out in a solvent that does not adversely influence the reaction or in the absence of a solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; nitriles such as acetonitrile;
Amides such as dimethylformamide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-
Halogenated hydrocarbons such as tetrachloroethane and a mixed solvent thereof are used. This reaction is carried out under heating (20 ° C
To 120 ° C). Reaction time is from 1 hour to 20
It is about an hour. The compound (V-1) can also be synthesized by the following method.

Embedded image In the above formula, R 'represents a lower alkyl group, and other symbols have the same meanings as described above.

Reaction of the First Step This reaction is a step of producing a compound (XI) by reacting a compound (VIII) with a compound (X) or a salt thereof in the presence of a base.
The leaving group represented by Z is as described above, and the lower alkyl group represented by R 'is methyl, ethyl, propyl, isopropyl, butyl, isobutyl and the like.
Are given. The reaction between compound (VIII) and compound (X) or a salt thereof is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene; ethers such as dioxane, tetrahydrofuran and dimethoxyethane; esters such as ethyl acetate; amides such as N, N-dimethylformamide; and dimethyl sulfoxide. Sulfoxides such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, and the like; ketones such as acetone and 2-butanone; and a mixed solvent thereof. This reaction is carried out using an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium hydrogen carbonate, pyridine, triethylamine, N,
The reaction is performed in the presence of an organic base such as a tertiary amine such as N-dimethylaniline. The amount of the base used is the same as that of the compound (V
About 1 to 5 mol is preferable to III). This reaction is generally carried out at -20 ° C to 150 ° C, preferably at about -10 ° C to 100 ° C.
Done in The reaction time is usually 30 minutes to 10 hours.

Second Step Reaction This reaction is a step of subjecting compound (XI) to a hydrolysis reaction in the presence of a base to produce compound (XII). This reaction is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include alcohols such as methanol, ethanol, propanol, isopropanol, and 2-methoxyethanol;
These alcohols, tetrahydrofuran, acetone,
A mixed solvent of N, N-dimethylformamide or dimethylsulfoxide and water can be used. This reaction is carried out in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide or potassium carbonate, ammonia or a secondary amine such as dimethylamine, diethylamine, morpholine or piperidine. The amount of the base to be used is preferably about 1 to 10 mol with respect to compound (XI). This reaction is usually carried out at −2
It is carried out at 0 ° C to 150 ° C, preferably at about -10 ° C to 80 ° C.

Third Step Reaction This reaction is a step of reacting compound (XII) or a salt thereof with compound (XIII) or a salt thereof in the presence of a base to produce compound (V-1) or a salt thereof. The reaction of compound (XII) or a salt thereof with compound (XIII) or a salt thereof is performed in a solvent that does not adversely influence the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol, esters such as ethyl acetate, and nitriles such as acetonitrile. , Pyridines such as pyridine and lutidine, amides such as N, N-dimethylformamide, sulfoxides such as dimethylsulfoxide, halogens such as chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane and the like. Hydrocarbons, ketones such as acetone and 2-butanone, and mixed solvents thereof are used. This reaction is carried out in the presence of an inorganic base such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, or an organic base such as tertiary amines such as pyridine, triethylamine, N, N-dimethylaniline. Done. The amount of the base to be used is preferably about 1 to 5 mol with respect to compound (XII) or a salt thereof. This reaction is usually performed at -20 ° C to 150 ° C,
It is preferably carried out at about -10C to 100C.

As the salt of the compound (I) of the present invention, a pharmacologically acceptable salt is preferably used. As pharmacologically acceptable salts, salts with inorganic bases, salts with organic bases, salts with organic acids, salts with basic or acidic amino acids and the like are used. Salts that can form these salts include:
Inorganic bases include alkali metals (eg, sodium, potassium, etc.) and alkaline earth metals (calcium, magnesium, etc.). Organic bases include, for example, trimethylamine, triethylamine, pyridine, picoline, N, N-
Dibenzylethylenediamine, diethanolamine, etc., as inorganic acids, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, sulfuric acid, etc., and as organic acids, formic acid,
Acetic acid, trifluoroacetic acid, oxalic acid, tartaric acid, fumaric acid, maleic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, and the like. Formic acid, glutamic acid and the like are used.
Among these salts, the salt with a base is a salt formed when a carboxyl group represented by B of compound (I) or a carboxyl group, a sulfo group, or another acidic group is present in ring A, substituents B and R. The salt with an acid means a salt that can be formed when a basic group such as an amino group is present in ring A, substituents B and R of compound (I).

The toxicity of compound (I) or a salt thereof is extremely low. The compound (I) or salt of the present invention has an excellent inhibitory action on bone resorption. In other words, it has the effect of suppressing the effect of bone dissolving into the body, being absorbed and becoming smaller. Further, the compound (I) of the present invention or a salt thereof has an osteogenesis promoting effect. Therefore, the compound (I) of the present invention or a salt thereof is
It is used as a medicine for humans and livestock, and is used safely for the prevention or treatment of various diseases caused by bone resorption, such as osteoporosis. Compound (I) or a salt thereof may be orally or parenterally (eg, injected intravenously or intramuscularly).
Can be administered.

As the preparation for oral administration, solid or liquid dosage forms, specifically, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, granules, powders, capsules
(Including soft capsule), syrup, elixir,
Emulsions, suspensions and the like are used. This preparation for oral administration can be produced by mixing with a carrier or excipient usually used in the field of preparation and following a method known per se. Such carriers and excipients include, for example, syrup, gum arabic, gelatin, sorbitol, tragacanth,
Binders such as polyvinylpyrrolidone, lactose, saccharides,
Fillers such as corn starch, calcium phosphate, glycine and the like, hardeners such as magnesium stearate, talc, polyethylene glycol and silica, disintegrators such as potato starch, wetting agents such as sodium lauryl sulfate and the like are used. Examples of preparations for parenteral administration include injections (eg, subcutaneous injections, intradermal injections, intramuscular injections, etc.), suppositories and the like.

Such injections can be produced by a method known per se, for example, by suspending or emulsifying Compound (I) or a salt thereof in a sterile aqueous or oily liquid usually used for injections. Aqueous liquids for injections include physiological saline, isotonic solutions and the like.
For example, it may be used in combination with sodium carboxymethylcellulose, a nonionic surfactant and the like. Sesame oil, soybean oil and the like are used as the oily liquid, and benzyl benzoate, benzyl alcohol and the like may be used in combination as a solubilizing agent.
The prepared injection is usually filled in a suitable ampoule.
Active ingredients with other bone resorption inhibiting effects in these preparations
(Eg, Osten (trade name)) can be mixed to prepare a preparation exhibiting a stronger bone resorption inhibiting action.

Compound (I) or a salt thereof can be used as an agent for preventing and treating diseases based on bone resorption, for example, osteoporosis. The daily dose of the compound (I) or a salt thereof varies depending on the condition and weight of the patient, the method of administration, and the like. In the case of oral administration, the active ingredient (compound (I) or a salt thereof) per adult (50 kg body weight) ) As 10 to 10
00 mg, preferably 15 to 600 mg, administered in 1 to 3 divided doses per day.

[0050]

The compound (I) of the present invention or a salt thereof has a strong inhibitory action on bone resorption, an action for improving bone metabolism and an action for promoting bone formation, and various diseases based on the bone resorption action in humans and animals. , For example, for the prevention and treatment of osteoporosis. The compound (I) of the present invention or a salt thereof has low toxicity and can be used extremely safely. Hereinafter, Test Examples, Reference Examples, and Examples are shown to further explain the present invention. However, these are merely examples and do not limit the present invention in any way.

Test Example 1 Test for Bone Resorption Inhibition Bone resorption was measured by the method of Royce [Journal of
Clinical Investigation (J. Clin. Inves
t.) 44 , 103-116 (1965)]. That is, ⁴⁵ Ca (an isotope of calcium, used as a CaCl ₂ solution) of 50 μCi was used for one Sprague-Dawley rat on the 19th day of pregnancy.
(Microcury) injected subcutaneously. The following day, the abdomen was opened, the fetal rat was aseptically removed, and the right and left forearms (radius, ulna) of the fetal rat were separated from the trunk under a dissecting microscope. Furthermore, bone culture samples were obtained by removing connective tissue and cartilage as much as possible. Fit bone-0.6g BGJ _b medium, Fitton-Jackson Modification (Fitton-Jack
son modification) [Product name, GIBCO Laboratories (USA)] Bovine serum albumin, 2mg /
) at 37 ° C for 24 hours, and then the compound was added to the above culture solution containing 10 µg / ml for 2 hours.
After continuing the days of culture, the radioactivity of ⁴⁵ Ca ⁴⁵ radioactivity and in bone Ca in the culture medium was measured to determine the ratio of ⁴⁵ Ca which was released from the bone into the culture broth (%) according to the following formula .

Embedded image A = Ratio of ⁴⁵ Ca released from bone into the culture solution (%) B = Count of ⁴⁵ Ca in the culture solution C = Count of ⁴⁵ Ca in the bone Bone obtained from a fetus of the same litter was not added with the test compound In the same manner, those cultured for 2 days were used as a control group. The average of the values obtained from 5 bones in each group was determined, the ratio of this value to the value of the control group was determined, and Table 1 was expressed as (%) with respect to the control value.
It was shown to.

[Table 1] The symbols in the following Reference Examples and Examples have the following meanings. s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, m:
Multiplet, broad: broad, J : coupling constant THF: tetrahydrofuran DMF: N, N-dimethylformamide

REFERENCE EXAMPLE 1 Dichloromethane (500 m) of aluminum chloride (48.0 g) was used.
l) Ethyl oxalyl chloride (48.0) was added to the suspension under ice-cooling.
g) and then phenylcyclohexane (48.0 g) was added dropwise. After stirring for 30 minutes under ice cooling, the reaction solution was poured into ice water to separate an organic layer. The aqueous layer is extracted with chloroform
The organic layers were combined, washed with water, dried (MgSO ₄ ), and distilled under reduced pressure. There was obtained ethyl 4-cyclohexylphenylglyoxylate (68.0 g, yield 87%). bp.163-165 ° C./0.3 mmHg NMR (δ ppm, CDCl ₃ ): 1.40 (3H, t, J = 7 Hz), 1.4-2.1
(8H, m), 2.60 (1H, m), 4.43 (2H, q, J = 7Hz), 7.34 (2H, d, J =
9Hz), 7.96 (2H, d, J = 7Hz).

Reference Examples 2 to 5 In the same manner as in Reference Example 1, the compounds shown in Table 2 were obtained.

[Table 2]

Reference Example 6 Sodium borohydride (2.0 g) in ethanol (100 m
l) The solution was added dropwise to a solution of 5,6,7,8-tetrahydro-2-naphthylglyoxylic acid ethyl ester (34.5 g) in ethanol (200 ml) under ice cooling. After dropping, acetic acid (6 ml)
Was added, and the reaction mixture was poured into water and extracted with chloroform. The chloroform layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. 2-Hydroxy-2- (5,6,7,8-tetrahydro-2-naphthyl) acetic acid ethyl ester (34.5 g, yield 99%) )). NMR (δ ppm, CDCl ₃ ): 1.22 (3H, t, J = 7 Hz), 1.8 (4H,
m), 2.7 (4H, m), 3.32 (1H, d, J = 6Hz), 4.0-4.4 (2H, m), 7.
1 (3H, m).

Reference Examples 7 to 11 In the same manner as in Reference Example 6, the compounds shown in Table 3 were obtained.

[Table 3]

Reference Example 12 Thionyl chloride (100 ml) was added to ethyl 2-hydroxy-2- (4-cyclohexylphenyl) acetate (52 g), and the mixture was heated under reflux for 1 hour, concentrated under reduced pressure, poured into water and added with ether. Extracted. The ether layer is washed with water and dried (MgSO 4
₄ ) Then, the residue was subjected to distillation under reduced pressure to give 2-chloro-2- (4-cyclohexylphenyl) acetic acid ethyl ester (50 g, yield 89).
%). bp. 160-162 ° C / 0.5mmHg NMR (δppm, CDCl ₃ ): 1.24 (3H, t, J = 7Hz), 1.2-2.0
(10H, m), 2.5 (1H, m), 4.21 (2H, q, J = 7Hz), 5.3 (1H, s),
7.18 (2H, d, J = 9 Hz), 7.40 (2H, d, J = 9 Hz).

Reference Examples 13 to 16 In the same manner as in Reference Example 12, the compounds shown in Table 4 were obtained.

[Table 4]

Reference Example 17 Et ₃ N (46.5 g) was added to thioglycolic acid (20.8 g),
Chloro-2- (4-hexylphenyl) acetic acid ethyl ester (58
g) and DMF (250 ml) were added dropwise under ice cooling. After the dropwise addition, the mixture was further stirred for 1 hour under ice cooling, and the reaction mixture was poured into water and extracted with ether. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer is washed with water,
After drying (MgSO ₄ ) and concentration, ethoxycarbonyl (4-hexylphenyl) methylthioacetic acid was added to the crude oil (63.5).
g, yield 92%). NMR (δ ppm, CDCl ₃ ): 0.83 (3H, t, J = 7 Hz), 1.26 (3H,
t, J = 7Hz), 1.1-1.8 (8H, m), 2.59 (2H, t, J = 7Hz), 3.11 (1
H, d, J = 15Hz), 3.30 (1H, d, J = 15Hz), 4.1-4.4 (2H, m), 4.8
4 (1H, s), 7.26 (2H, d, J = 9Hz), 7.35 (2H, d, J = 9Hz).

Reference Examples 18 to 22 In the same manner as in Reference Example 17, the compounds shown in Table 5 were obtained.

[Table 5]

Reference Example 23 Potassium thioacetate (CH ₃ COSK, 8.31 g) was added in small portions to a solution of ethyl 2-chloro-2- (3,4-dimethylphenyl) acetate (15 g) in DMF (80 ml). The mixture was stirred at room temperature for 2 hours, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off to give ethyl 2-acetylthio-2- (3,4-dimethylphenyl) acetate (16.5 g, 94%) as an oil. NMR (δ ppm, CDCl ₃ ): 1.22 (3H, t, J = 7 Hz), 2.21 (6H,
s), 2.30 (3H, s), 4.0-4.35 (2H, m), 5.2 (1H, s), 7.05-7.
2 (3H, m).

REFERENCE EXAMPLE 24 Morpholine (21.6 g) was added dropwise to a solution of ethyl 2-acetylthio-2- (3,4-dimethylphenyl) acetate (16.5 g) in ethanol (80 ml) at room temperature. After further stirring at room temperature for 2 hours, the reaction mixture was poured into water and 2N HCl was added.
And extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and the residue was subjected to silica gel column chromatography. Elution with chloroform-hexane (1: 3, v / v) gave 2-thio-2-
Ethyl (3,4-dimethylphenyl) acetate (8.8 g, 63
%) As an oil. NMR (δ ppm, in CDCl ₃ ): 1.23 (3H, t, J = 7 Hz), 2.23
(6H, broad s), 2.53 (1H, d, J = 7.5Hz), 4.17 (2H, q, J = 7H
z), 4.60 (1H, d, J = 7.5HZ), 7.0-7.3 (3H, m).

Reference Example 25 Ethyl 2-thio-2- (3,4-dimethylphenyl) acetate
(4.5 g), 2-bromobutyric acid (3.3 g), potassium carbonate (5.5
A mixture of g) and DMF (30 ml) was stirred at room temperature for 1 hour, then poured into water and extracted with ether. The aqueous layer is acidified with concentrated hydrochloric acid and extracted with ether.The ether layer is washed with water and dried.
(MgSO ₄ ). The solvent was distilled off and 2- [ethoxycarbonyl (3,4-dimethylphenyl) methylthio] butyric acid (5.5
g, 89%) as an oil. NMR (δ ppm, CDCl ₃ ): 0.9-1.1 (3H, m), 1.1-1.3 (3H,
m), 1.6-2.0 (2H, m), 2.25 (6H, s), 2.97 (1H × 1/2, t, J = 7H
z), 3.38 (1H × 1/2, t, J = 7Hz), 4.1-4.3 (2H, m), 4.78 (1H
× 1/2, s), 4.80 (1H × 1/2, s), 7.0-7.3 (3H, m)

Reference Example 26 In the same manner as in Reference Example 25, 2- [ethoxycarbonyl (3,
4-Dimethylphenyl) methylthio] acetic acid was obtained. Yield 90
%. NMR (δ ppm in CDCl ₃ ): 1.23 (3H, t, J = 7Hz), 2.25
(6H, s), 3.05 (1H, d, J = 16Hz), 3.29 (1H, d, J = 16Hz), 4.18
(2H, q, J = 17Hz), 5.13 (1H, s), 7.0-7.3 (3H, m), 9.98 (1H,
brs)

Reference Example 27 Methoxycarbonyl (4-chlorophenyl) methylthioacetic acid (71 g) was dissolved in THF (400 ml), and oxalyl chloride (39 g) was added dropwise, followed by DMF (5 drops). The mixture was left overnight at room temperature and concentrated, and the residue was dissolved in dichloromethane (100 ml). Add this solution to aluminum chloride
(69 g) was added dropwise to a suspension of dichloromethane (400 ml) under ice cooling. After the dropwise addition, the reaction mixture was further stirred at room temperature for 3 hours and then poured into ice water to separate an organic layer. The aqueous layer was extracted with chloroform, and the combined organic layers were washed with water and dried (MgS
O ₄ ). The solvent was distilled off, and the residue was subjected to silica gel chromatography. From the portion eluted with ether-hexane (1: 1 (v / v)), 6-chloro-3,4-dihydro-1H-2
Crystals of methyl-benzothiopyran-4-one-1-carboxylate (27 g, yield 40%) were obtained. Recrystallization from ethyl acetate-hexane gave colorless plate crystals. mp. 118-119 ° C Elemental analysis: as C ₁₁ H ₉ O ₃ SCl Calculated: C, 51.47; H, 3.53 Analytical: C, 51.40; H, 3.58 6-chloro- Methyl 3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (21.5 g) was suspended in methanol (100 ml) and 2N-KOH (70 ml) was added.
After stirring at room temperature for 1 hour, the reaction solution was poured into water, acidified, and extracted with ethyl acetate. The ethyl acetate layer is washed with water,
After drying (MgSO ₄ ), the solvent was distilled off and 6-chloro-3,4-
Dihydro-1H-2-benzothiopyran-4-one-1
-Carboxylic acid (18.8 g, 93% yield) was obtained. Recrystallization from ethyl acetate gave colorless prism crystals. mp. 220-221 ° C Elemental analysis: as C ₁₀ H ₇ O ₃ SCl Calculated: C, 49.49; H, 2.91 Analytical: C, 49.51; H, 2.91

Reference Example 28 Ethoxycarbonyl (4-hexylphenyl) methylthioacetic acid (63 g) was dissolved in ether (500 ml), and thionyl chloride (33 g) was added dropwise, followed by pyridine (5 drops). The mixture was heated under reflux for 30 minutes and concentrated, and the residue was dissolved in dichloromethane (50 ml). This solution was added dropwise to a suspension of aluminum chloride (50 g) in dichloromethane (350 ml) under ice cooling. After the dropwise addition, the reaction mixture was further stirred under ice cooling for 3 hours, and then poured into ice water to separate an organic layer. The aqueous layer is extracted with chloroform, and the combined organic layers are washed with water and dried.
(MgSO ₄ ). The solvent was distilled off, and the residue was subjected to silica gel chromatography. From the portion eluted with ether-hexane (1: 2 (v / v)), 6-hexyl-3,4-dihydro-
Ethyl 1H-2-benzothiopyran-4-one-1-carboxylate was obtained as an oil (42 g, 70% yield). NMR (δ ppm, CDCl ₃ ): 0.83 (3H, t, J = 7 Hz), 1.2-1.7
(8H, m), 1.30 (3H, t, J = 7Hz), 2.64 (2H, t, J = 7Hz), 3.27 (1
H, dd, J = 16 and 1Hz), 4.24 (2H, q, J = 7Hz), 4.27 (1H, dd, J =
16 and 1Hz), 4.41 (1H, s), 7.1-7.4 (2H, m), 7.94 (1H, d, J = 2
Ethyl 6-hexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (41 g) was suspended in methanol (150 ml) and 2N-KOH (150 ml) was added.
After l) was added and the mixture was stirred at room temperature for 1 hour, the reaction solution was poured into water, acidified, and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off to give 6-hexyl-3,4-dihydro-1H-2-benzothiopyran-4.
-One-l-carboxylic acid (27.5 g, yield 74%) was obtained. Recrystallization from ether-hexane gave colorless plate crystals. mp. 66-67 ° C Elemental analysis: C ₁₆ H ₂₀ O ₃ S Calculated: C, 65.72; H, 6.89 Analytical: C, 65.73; H, 6.90

Reference Example 29 In the same manner as in Reference Example 28, 6-cyclohexyl-3,4
-Dihydro-1H-2-benzothiopyran-4-one-
Ethyl 1-carboxylate was obtained. Yield 69%. Recrystallization from hexane gave colorless prism crystals. mp. 51-52 ° C Elemental analysis: as C ₁₈ H ₂₂ O ₃ S Calculated: C, 67.89; H, 6.96 Analytical: C, 68.08; H, 7.01 6-cyclohexyl- Ethyl 3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylate (5
2 g) was suspended in methanol (200 ml) and 2N-KOH
(100 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water, acidified, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off. 6-Cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (33 g, yield 7)
3%). Recrystallization from ethyl acetate-hexane gave colorless plate crystals. mp. 171-172 ° C Elemental analysis: C ₁₆ H ₁₈ O ₃ S Calculated: C, 66.18; H, 6.25 Analytical: C, 66.16; H, 6.28

Reference Example 30 In the same manner as in Reference Example 28, 6,7-ethylenedioxy-
3,4-dihydro-1H-2-benzothiopyran-4-
Ethyl on-l-carboxylate was obtained as an oil. NMR (δ ppm, CDCl ₃ ): 1.31 (3H, t, J = 7 Hz), 3.21 (1H,
(dd, J = 16 and 1Hz), 4.15-4.35 (6H, m), 6.72 (1H, s), 7.66
(1H, s). 6,7-ethylenedioxy-3,4-dihydro-1H-2
-Ethyl benzothiopyran-4-one-1-carboxylate
(55 g) was suspended in ethanol (200 ml), and 2N-NaO was added.
After adding H (200 ml) and stirring at room temperature for 1 hour, the reaction solution was poured into water, acidified, and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off.
7-ethylenedioxy-3,4-dihydro-1H-2-
Benzothiopyran-4-one-1-carboxylic acid (32.5
g, 65% yield). Recrystallization from ethyl acetate gave colorless prism crystals. 207-208 ° C Elemental analysis: C ₁₂ H ₁₀ O ₅ S Calculated: C, 54.13; H, 3.79 Analytical: C, 54.37; H, 3.82

Reference Example 31 In the same manner as in Reference Example 28, 3,4-dihydro-1H-2-
Methyl benzothiopyran-4-one-1-carboxylate was obtained as an oil. 73% yield NMR (δ ppm, CDCl ₃ ): 3.25 (1H, d, J = 24 Hz), 3.77 (3
H, s), 4.26 (1H, d, J = 24Hz), 4.47 (1H, s), 7.0-7.5 (5H,
m), 7.9-8.1 (1H, m) .3,4-dihydro-1H-2-benzothiopyran-4-
Methyl on-1-carboxylate (32 g) was added to methanol (15
0N), 2N-KOH (150 ml) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into water and acidified.
Extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (Mg
After SO ₄ ), the solvent was distilled off and 3,4-dihydro-1H-2-
Benzothiopyran-4-one-1-carboxylic acid (22 g,
73%). Recrystallization from ethyl acetate-hexane gave colorless prisms. mp. 124 ° -125 ° C. Elemental analysis: C ₁₀ H ₈ O ₃ S Calculated: C, 57.68; H, 3.87 Analytical: C, 57.88; H, 3.90

Reference Examples 32-37 In the same manner as in Reference Example 28, the compounds shown in Table 6 were obtained.

[Table 6]

Reference Example 38 6-Cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-4-one-1-carboxylic acid (500 mg)
Was dissolved in DMF (10 ml), and diethyl cyanophosphate (8
5%, 365mg) and stir for 30 minutes under ice-cooling.
3-Aminopyridine (160 mg) was added followed by triethylamine (202 mg). The reaction mixture was further stirred for 1 hour under ice cooling, poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO ₄ ), and the solvent was distilled off to give 6-cyclohexyl-N- (3-pyridyl) -3,4.
-Dihydro-1H-2-benzothiopyran-4-one-
1-carboxamide (490 mg, yield 79%) was obtained. Recrystallization from ethyl acetate-hexane gave colorless plate crystals. mp. 194-195 ° C Elemental analysis: C ₂₁ H ₂₂ N ₂ O ₂ S Calculated: C, 68.82; H, 6.05; N, 7.64 Analytical: C, 68.59; H , 5.90; N, 7.63

Reference Examples 39 to 43 The compounds of Table 7 were obtained in the same manner as in Reference Example 38.

[Table 7]

Reference Example 44 Sodium borohydride (102 mg) was added to 6-cyclohexyl-N- (3,4-methylenedioxyphenyl) -3,4-
Dihydro-1H-2-benzothiopyran-4-one-1
-Added to a solution of carboxamide (1.1 g) in ethanol (20 ml) and stirred at room temperature for 2 hours. After adding acetic acid (1 ml),
Poured into water and extracted with ethyl acetate. The ethyl acetate layer is water,
After washing with saturated NaHCO ₃ water and water in that order and drying (MgSO ₄ ), the solvent was distilled off to give 6-cyclohexyl-N- (3,4-methylenedioxyphenyl) -c -4-hydroxy-3,4-.
Dihydro-1H-2-benzothiopyran- r -1-carboxamide (0.97 g, 88% yield) was obtained. Recrystallization from ethyl acetate gave colorless prism crystals. mp. 208-209 ° C Elemental analysis: C ₂₃ H ₂₅ NO ₄ S Calculated: C, 67.13; H, 6.12; N, 3.40 Analysis: C, 66.91; H, 6 .19; N, 3.15

Reference Example 45 N- (4-Chlorophenyl) -6,7-dimethyl-3,4-
Dihydro-4-oxo-1H-2-benzothiopyran-
1-carboxamide (3.46 g) in ethanol (70 ml)
And sodium borohydride (0.378 g) was added thereto, followed by stirring at room temperature for 2 hours. After adding acetic acid (4 ml)
The reaction mixture was poured into water (200ml) and extracted with ethyl acetate. The precipitated crystals were collected by filtration and recrystallized from ethanol-chloroform to give cis-N- (4-chlorophenyl) -6,7-dimethyl-3,4-dihydro-4-hydroxy-1H-2.
-Benzothiopyran-1-carboxamide (2.7 g, 7
8%). Colorless prism crystals, mp. Calculated for C ₁₈ H ₁₈ NO ₂ SCl: C, 62.15; H, 5.22; N, 4.03 Analytical value: C, 62.02; H, 5.18; N, 4.06

Reference Example 46 cis-N- (4-chlorophenyl) -6,7-dimethyl-
3,4-dihydro-4-hydroxy-1H-2-benzothiopyran-1-carboxamide (3.1 g) benzedene (80
ml), phosphorus tribromide (1.2 g) was added, and the mixture was added at 70 ° C for 1 hour.
After stirring for a while, pour the reaction mixture into water (200 ml),
Extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (Mg
(SO ₄ ) and then the solvent was distilled off.trans-4-bromo-N- (4-
(Chlorophenyl) -6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-1-carboxamide
(3.1 g, 84%). Recrystallized from ethyl acetate-hexane, colorless needles, mp. Calculated for C ₁₈ H ₁₇ NOSBrCl: C, 52.63; H, 4.17; N, 3.41 Analytical value: C, 52.95; H, 4.03; N, 3.52

Reference Example 47 In the same manner as in Reference Example 17, 2-carboxymethylthio-
Methyl 3-phenylpropionate was obtained. NMR (δ ppm in CDCl ₃ ): 3.00 (1H, double d, J = 14 a
nd 7Hz), 3.23 (1H, double d, J = 14 and 9Hz), 3.35 (1H,
d, J = 16Hz), 3.50 (1H, d, J = 16Hz), 3.68 (3H, s), 3.74 (1H,
double d, J = 9 and 7Hz), 7.1-7.45 (5H, m).

Reference Example 48 In the same manner as in Reference Example 17, 2-carboxymethylthio-
Methyl 3- (3,4-methylenedioxyphenyl) propionate was obtained. NMR (δ ppm in CDCl ₃ ): 2.92 (1H, double d, J = 14 a
nd 7Hz), 3.13 (1H, double d, J = 14 and 7Hz), 3.35 (1H,
d, J = 16Hz), 3.50 (1H, d, J = 16Hz), 3.6-3.8 (1H, m), 3.70 (3H
H, s), 5.93 (2H, s), 6.6-6.8 (3H, m).

Reference Example 49 In the same manner as in Reference Example 17, 2-carboxymethylthio-
Methyl 3- (3,4-ethylenedioxyphenyl) propionate was obtained. NMR (δ ppm in CDCl ₃ ): 2.89 (1H, double d, J = 14 a
nd 7Hz), 3.12 (1H, double d, J = 14 and 7Hz), 3.34 (1H,
d, J = 16Hz), 3.49 (1H, d, J = 16Hz), 3.6-3.8 (1H, m), 3.70 (3
H, s), 4.23 (4H, s), 6.6-6.8 (3H, m).

Reference Example 50 In the same manner as in Reference Example 17, methyl 2- (1-carboxyethylthio) -3- (3,4-methylenedioxyphenyl) propionate was obtained.

Reference Example 51 In the same manner as in Reference Example 28, methyl 1,2,4,5-tetrahydro-5-oxo-3-benzothiepin-2-carboxylate was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 3.23 (1H, double d, J = 14 a
nd 5Hz), 3.41 (1H, d, J = 18Hz), 3.4-3.82 (2H, m), 3.82
(H, s), 4.20 (1H, d, J = 18Hz), 7.2-7.6 (3H, m), 7.91 (1H, d
ouble d, J = 9 and 2Hz). Then, 1,2,4,5-tetrahydro-5-oxo-3
-Methyl-benzothiepine-2-carboxylate Reference Example 28
Is hydrolyzed in the same manner as described above, and 1,2,4,5-tetrahydro-5
-Oxo-3-benzothiepine-2-carboxylic acid was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. 215-216 ° C.

Reference Example 52 Methyl 2-carboxymethylthio-3- (3,4-methylenedioxyphenyl) propionate (29.0 g) was added to THF.
(200 ml) and oxalyl chloride (14.8 g).
Followed by DMF (3 drops). The mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (250ml). To this solution, tin tetrachloride (SnCl ₄ ) (55.6 g) was added dropwise under ice cooling.
The reaction mixture was further stirred for 1 hour under ice cooling, and then 2N
HCl (100 ml) was added dropwise. The dichloromethane layer was separated, washed with water and dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure.
7,8-methylenedioxy-5-oxo-1,2,4,5-
Methyl tetrahydro-3-benzothiepine-2-carboxylate (17.0 g, 63%) was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. 165-166 ° C. Then, 7,8-methylenedioxy-5-oxo-1,2,2,
Methyl 4,5-tetrahydro-3-benzothiepin-2-carboxylate was hydrolyzed in the same manner as in Reference Example 28 to give 7,8
-Methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepin-2-carboxylic acid was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. 234-235 ° C.

Reference Example 53 Methyl 2- (1-carboxyethyl) thio-3- (3,4-methylenedioxyphenyl) propionate (27.8 g) was dissolved in THF (200 ml), and oxalyl chloride (13.
6 g) and then DMF (3 drops). The mixture was stirred at room temperature for 1.5 hours and then concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (250ml). To this solution, tin tetrachloride (SnCl ₄ ) (51.0 g) was added dropwise under ice cooling. The reaction mixture was further stirred for 1 hour under ice cooling,
2N HCl (100 ml) was added dropwise. The dichloromethane layer was separated, washed with water and dried (MgSO ₄ ), and the solvent was distilled off under reduced pressure. The remaining oil was dissolved in methanol (250 ml) and a solution of sodium methoxide in methanol (28%,
10 ml) and stirred at room temperature for 1.5 hours. The reaction mixture was poured into 2N HCl (250 ml), and the precipitated crystals were collected by filtration.
Trans 7,8-methylenedioxy-4-methyl-5
There was obtained methyl-oxo-1,2,4,5-tetrahydro-3-benzothiepin-2-carboxylate (19.0 g, 73%). Recrystallized from ethyl acetate. Colorless prism crystals.
171-172 ° C. Then, transformer 7,8-
Methylenedioxy-4-methyl-5-oxo-1,2,
Methyl 4,5-tetrahydro-3-benzothiepin-2-carboxylate was hydrolyzed in the same manner as in Reference Example 28 to give trans 7,8-methylenedioxy-4-methyl-5-oxo-1,2,4,5. -Tetrahydro-3-benzothiepin-2-carboxylic acid was obtained. Recrystallized from ethyl acetate.
Colorless prism crystals. 219-220 ° C.

Reference Example 54 In the same manner as in Reference Example 52, 7,8-ethylenedioxy-
Methyl 5-oxo-1,2,4,5-tetrahydro-3-benzothiepin-2-carboxylate was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 181-182
° C. Then, 7,8-ethylenedioxy-5-oxo-
1,2,4,5-tetrahydro-3-benzothiepin-2
-Hydrolyzing methyl carboxylate in the same manner as in Reference Example 28,
7,8-ethylenedioxy-5-oxo-1,2,4,5-
Tetrahydro-3-benzothiepin-2-carboxylic acid was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. 208-209 ° C.

Reference Example 55 7,8-Methylenedioxy-5-oxo-1,2,4,5-
Tetrahydro-3-benzothiepin-2-carboxylic acid
(3.2 g) was dissolved in THF (50 ml), oxalyl chloride (1.83 g) was added dropwise, followed by DMF (one drop).
The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residual oil was dissolved in THF (25ml). This solution was treated with 4-chloroaniline (1.68 g), triethylamine
(1.34 g) and THF (80 ml) were added dropwise at room temperature. The reaction mixture was further stirred at room temperature for 30 minutes, poured into water and extracted with ethyl acetate. Ethyl acetate layer 1
After washing with NHCl and water, it was dried (MgSO ₄ ). The solvent was distilled off and N- (4-chlorophenyl) -7,8-methylenedioxy-5-oxo-1,2,4,5-tetrahydro-3-benzothiepin-2-carboxamide (4.29)
g, 95%). Recrystallized from ethyl acetate. Colorless prism crystals. 247-248 [deg.] C.

Reference Example 56 In the same manner as in Reference Example 55, trans N- (4-chlorophenyl) -4-methyl-7,8-methylenedioxy-5
-Oxo-1,2,4,5-tetrahydro-3-benzothiepine-2-carboxamide was obtained. Recrystallized from ethyl acetate. Colorless needles. 255-256 ° C.

Reference Example 57 In the same manner as in Reference Example 55, N- (4-chlorophenyl)-
5-oxo-1,2,4,5-tetrahydro-3-benzothiepin-2-carboxamide was obtained. Recrystallized from dichloromethane-methanol. Colorless needles. Melting point 20
4-205 ° C.

Reference Example 58 In the same manner as in Reference Example 55, N- (4-chlorophenyl)
-7,8-ethylenedioxy-5-oxo-1,2,4,5
-Tetrahydro-3-benzothiepine-2-carboxamide was obtained. It was recrystallized from chloroform-methanol. Colorless needles. Melting point 279-280 [deg.] C.

Reference Example 59 In the same manner as in Reference Example 44, N- (4-chlorophenyl)-
5-hydroxy-7,8-ethylenedioxy-1,2,4,
5-Tetrahydro-3-benzothiepine-2-carboxamide was obtained. Recrystallized from acetone. Colorless needles.
258-259 ° C.

Reference Example 60 In the same manner as in Reference Example 44, N- (4-chlorophenyl)-
5-hydroxy-7,8-methylenedioxy-1,2,4,
5-Tetrahydro-3-benzothiepine-2-carboxamide was obtained. It was recrystallized from chloroform-methanol. Colorless needles. Melting point 228-229 [deg.] C.

Reference Example 61 In the same manner as in Reference Example 44, N- (4-chlorophenyl)-
4-Hydroxy-3,4-dihydro-1H-2-benzothiopyran-1-carboxamide was obtained. Recrystallized from ethanol. Colorless prism crystals. Melting point 170-171
° C.

Reference Example 62 In the same manner as in Reference Example 44, N- (4-chlorophenyl)-
5-Hydroxy- t -4-methyl-7,8-methylenedioxy-1,2,4,5-tetrahydro-3-benzothiepin- r- 2-carboxamide was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 214
-215 [deg.] C.

Reference Example 63 In the same manner as in Reference Example 46, 5-bromo-N- (4-chlorophenyl) -t -4-methyl-7,8-methylenedioxy-1,2,4,5-tetrahydro- 3-benzothiepine- r- 2-carboxamide was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 207-2
08 ° C.

Reference Example 64 In the same manner as in Reference Example 46, 5-bromo-N- (4-chlorophenyl) -1,2,4,5-tetrahydro-3-benzothiepine-2-carboxamide was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 164
-165 ° C.

Reference Example 65 In the same manner as in Reference Example 46, 5-bromo-N- (4-chlorophenyl) -7,8-methylenedioxy-1,2,4,5
-Tetrahydro-3-benzothiepine-2-carboxamide was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. 223-224 [deg.] C.

[0094] In the same manner as in Reference Example 66 Reference Example 46, 5-bromo -N- (4- chlorophenyl) -7,8-d Chirenjiokishi -1,2,4,5
-Tetrahydro-3-benzothiepine-2-carboxamide was obtained. Recrystallized from ethyl acetate. Colorless needles.
212-213 ° C.

Reference Example 67 In the same manner as in Reference Example 46, 4-bromo-N- (4-chlorophenyl) -3,4-dihydro-1H-2-benzothiopyran-1-carboxamide was obtained. Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 175-17
6 ° C.

Example 1 6-Cyclopentyl-3,4-dihydro-4-oxo-
1H-2-benzothiopyran-1-carboxylic acid (2.8
g), KOH (2.2 g), hydrazine monohydrate (85%,
A mixture of 1.5 ml) and diethylene glycol (30 ml) was stirred at 200 ° C. for 5 hours. The reaction mixture was washed with water (20
0 ml) and extracted with ethyl acetate. The aqueous layer was acidified with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off. Crystals of 6-cyclopentyl-3,4-dihydro-1H-2-benzothiopyran-1-carboxylic acid (1.3 g, 50%) I got Recrystallized from ethyl acetate-hexane, colorless prisms, mp
146-147 ° C. Calculated for C ₁₅ H ₁₈ O ₂ S: C, 68.67; H, 6.91 Analytical value: C, 68.60; H, 7.10

Examples 2 to 6 In the same manner as in Example 1, the compounds shown in Table 8 were obtained.

[Table 8]

Example 7 N, N of 6-cyclopentyl-3,4-dihydro-1H-2-benzothiopyran-1-carboxylic acid (0.262 g)
Dimethylformamide (DMF) (5 ml) solution under ice-cooling,
Diethyl cyanophosphate (DEPC) (90%, 0.217 g)
After stirring for 30 minutes, add 4-chloroaniline (0.1
53 g) and triethylamine (0.121 g) were added in this order. The reaction mixture was stirred for 1 hour under ice cooling,
Poured into water and extracted with ethyl acetate. The ethyl acetate layer is water,
The mixture was washed with 2N HCl and water in that order and dried (MgSO ₄ ). The solvent was distilled off to obtain N- (4-chlorophenyl) -6-cyclohexyl-3,4-dihydro-1H-2-benzothiopyran-1-carboxamide (0.285 g, 77%).
Recrystallized from ethyl acetate-hexane. Colorless needles, mp
147-148 ° C. Calculated for C ₂₁ H ₂₂ NOSCl: C, 67.82; H, 5.96; N, 3.77 Analytical value: C, 67.66; H, 5.96; N, 3.74.

Examples 8 to 23 In the same manner as in Example 7, the compounds shown in Tables 9 to 11 were obtained.

[Table 9]

[Table 10]

[Table 11]

Example 24 3,4-Dihydro-1H-2-benzothiopyran-1-
Carboxylic acid (2.0 g) in tetrahydrofuran (THF) (3
Oxalyl chloride (1.5 g) and N, N-dimethylformamide (DMF) (1 drop) were added to the solution, stirred at room temperature for 3 hours, and concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (20 ml) and the solution was treated with 2-amino-4.
Phenylthiazole (2.0 g), potassium carbonate (3.0 g)
g) and dichloromethane (30 ml).
After the reaction mixture was stirred at room temperature for 1 hour, it was poured into water and the organic layer was separated. The organic layer was washed with water, 2N HCl and water in that order, and dried (MgSO ₄ ). The solvent is distilled off and 3,4-dihydro-N- (4-phenyl-2-thiazolyl) -1H-2
-Benzothiopyran-1-carboxamide (0.72 g,
21%). Recrystallized from ethanol. Colorless prisms, mp 185-186 ° C. Calculated for C ₁₉ H ₁₆ N ₂ OS ₂ : C, 64.74; H, 4.58; N, 7.95 Analytical value: C, 64.66; H, 4.76; N, 7.74

Example 25 4-bromo-N- (4-chlorophenyl) -6,7-dimethyl-3,4-dihydro-1H-2-benzothiopyran-1-carboxamide (2.8 g), lithium bromide (0 g) .7
A mixture of 38 g), lithium carbonate (1.3 g) and N, N-dimethylformamide (DMF) (40 ml) was stirred at 120 DEG C. for 3 hours, then poured into water (200 ml) -acetic acid (4 ml) and ethyl acetate. Extracted. Ethyl acetate layer is washed with water and dried
(MgSO ₄ ), and the solvent was distilled off to give N- (4-chlorophenyl).
-6,7-dimethyl-1H-2-benzothiopyran-1
-Carboxamide (2.0 g, 91%) was obtained. Recrystallized from ethyl acetate. Colorless columnar crystals, mp 193-194 ° C. C ₁₈ H ₁₆ calculated for NOSCl: C, 65.54; H, 4.89; N, 4.77 Analytical values: C, 65.62; H, 4.86 ; N, 4.25

Example 26 cis-6-cyclohexyl-N- (3,4-methylenedioxyphenyl) -3,4-dihydro-4-hydroxy-1
H-2-benzothiopyran-1-carboxamide (0.6
1 g) suspended in benzene (10 ml) and phosphorus tribromide (0.54).
After stirring for 1 hour at room temperature and then under reflux for 15 minutes, the reaction mixture was poured into water (200 ml) and extracted with ethyl acetate. The ethyl acetate layer is washed with water and dried (MgSO ₄ )
Afterwards the solvent was distilled off. The residual oil was dissolved in N, N-dimethylformamide (DMF) (10 ml) and lithium bromide (0.1 mL) was added.
166 g) and lithium carbonate (0.296 g).
After stirring at 0 ° C. for 2 hours, water (100 ml) -acetic acid (2 ml)
And extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and N- (3,4-methylenedioxyphenyl) -6-cyclohexyl-1H-
2-benzothiopyran-1-carboxamide (0.48
g, 83%). Recrystallized from ethyl acetate. Colorless needles, mp 183-184 ° C. Calculated for _{C 23 H 23 NO 3 S:} C, 70.20; H, 5.89; N, 3.56 Analytical values: C, 69.86; H, 5.92 ; N, 3.37

Example 27 6-Cyclohexyl-N- (4-diethoxyphosphorylmethylphenyl) -3,4-dihydro-4-oxo-1H
-2-benzothiopyran-1-carboxamide (2.1
g) was suspended in ethanol (40 ml), sodium borohydride (0.227 g) was added, and the mixture was stirred at room temperature for 2 hours. After adding acetic acid (4 ml), the reaction mixture was washed with water (200 ml).
And extracted with ethyl acetate. The ethyl acetate layer is washed with water,
After drying (MgSO ₄ ), the solvent was distilled off. The residual oil was suspended in benzene (40 ml), phosphorus tribromide (0.542 g) was added, and the mixture was stirred at 70 ° C. for 1 hour.
00 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), after which the solvent was distilled off. The residual oil was dissolved in N, N-dimethylformamide (DMF) (20 ml), lithium bromide (0.522 g), lithium carbonate (0.5 ml).
828g) and stir at 120 ° C for 2 hours.
The mixture was poured into water (100 ml) -acetic acid (2 ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ), the solvent was distilled off, and 6-cyclohexyl-N- (4-diethoxyphosphorylmethylphenyl) -1H-2-benzothiopyran-1-carboxamide (0.28 g, 14 %). Recrystallized from ethyl acetate-hexane. Colorless needles, mp 1
29-130 ° C. Calculated for C ₂₇ H ₃₄ NO ₄ PS: C, 64.91; H, 6.86; N, 2.80 Analytical value: C, 64.55; H, 6.83; N, 2.55

Example 28 In the same manner as in Example 27, N- (4-diethoxyphosphorylmethylphenyl) -6,7-dimethyl-1H-2-benzothiopyran-1-carboxamide was obtained. Yield 26
%. Recrystallized from ethyl acetate-hexane. Colorless prisms, mp 146-147 ° C. Calculated for C ₂₃ H ₂₈ NO ₄ PS: C, 62.01; H, 6.33; N, 3.14 Analytical value: C, 61.79; H, 6.38; N, 2.87

Examples 29 to 30 The compounds of Table 12 were obtained in the same manner as in Example 27.

[Table 12]

Example 31 N- (4-Diethoxyphosphorylphenylmethylphenyl) -6,7-dimethyl-3,4-dihydro-1H-2-
Benzothiopyran-1-carboxamide (3.0 g), trimethylbromosilicon (3.1 g) and acetonitrile
(40 ml) was stirred at room temperature for 6 hours, poured into water, and the precipitated crystals were collected by filtration and recrystallized from ethyl acetate-methanol to give N- (4-phosphonomethylphenyl) -6,7-dimethyl-. 3,4-Dihydro- 1H-2-benzothiopyran-1-carboxamide (2.3 g, 88%) was obtained. Colorless needles, mp 239-240 ° C. Calculated for C ₁₉ H ₂₂ NO ₄ PS: C, 58.30; H, 5.67; N, 3.58 Analytical value: C, 57.99; H, 5.88; N, 3.45

Example 32 N- (4-Diethoxyphosphorylmethylphenyl) -3,
To a solution of 4-dihydro-1H-2-benzothiopyran-1-carboxamide (0.42 g) in chloroform (10 ml) was added a solution of metachloroperbenzoic acid (85%, 0.487 g) in chloroform (10 ml) under ice cooling. . The reaction mixture was allowed to stand at room temperature overnight, washed with a saturated aqueous solution of sodium hydrogen carbonate and water, dried (MgSO ₄ ), and the solvent was distilled off.
Diethoxyphosphorylmethylphenyl) -3,4-dihydro-1H-2-benzothiopyran-1-carboxamide 2,2-dioxide (0.425 g, 94%) was obtained. Recrystallized from ethanol-chloroform. Colorless needles,
mp 249-250 ° C. Calculated for C ₂₁ H ₂₆ NO ₆ PS: C, 55.87; H, 5.80; N, 3.10 Analytical value: C, 55.80; H, 5.86; N, 3.04

Example 33 N- (4-Diethoxyphosphorylmethylphenyl) -3,
To a solution of 4-dihydro-1H-2-benzothiopyran-1-carboxamide (0.42 g) in chloroform (10 ml) was added a solution of metachloroperbenzoic acid (85%, 0.203 g) in chloroform (10 ml) under ice cooling. . The reaction mixture was further stirred for 1 hour under ice-cooling, washed with a saturated aqueous solution of sodium hydrogen carbonate and water in that order, dried (MgSO ₄ ), and the solvent was distilled off to give N- (4-diethoxyphosphorylmethylphenyl)-.
3,4-dihydro-1H-2-benzothiopyran-1-
Carboxamide 2-oxide (1,2-trans form and 1,1
A mixture of the 2-cis form, about 2: 1) (0.400 g, 92%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless columnar crystals, mp 150-151 ° C. Calculated for C ₂₁ H ₂₆ NO ₅ PS: C, 57.92; H, 6.02; N, 3.22 Analytical value: C, 57.68; H, 5.98; N, 3.11

Example 34 In the same manner as in Example 25, N- (4-chlorophenyl)-
1H-2-benzothiopyran-1-carboxamide was obtained. Recrystallized from ethyl acetate. Colorless platelets. Melting point 1
75-176 ° C.

Example 35 In the same manner as in Example 25, N- (4-chlorophenyl)-
4-Methyl-7,8-methylenedioxy-1,2-dihydro-3-benzothiepin-2-carboxamide was obtained.
Recrystallized from dichloromethane-isopropyl ether. Colorless prism crystals. 206-207 ° C.

Example 36 In the same manner as in Example 25, N- (4-chlorophenyl)-
7,8-Ethylenedioxy-1,2-dihydro-3-benzothiepin-2-carboxamide was obtained. Ethyl acetate
Recrystallized from hexane. Colorless prism crystals. Melting point 21
2-213 ° C.

Example 37 In the same manner as in Example 25, N- (4-chlorophenyl)-
7,8-Methylenedioxy-1,2-dihydro-3-benzothiepin-2-carboxamide was obtained. Recrystallized from ethyl acetate. Colorless prism crystals. 230-231
° C.

Example 38 In the same manner as in Example 32, N- (4-diethoxyphosphorylmethylphenyl) -3,4-dihydro-1H-2-benzothiopyran-1-carboxamide 2,2-dioxide was obtained. Recrystallized from ethanol-chloroform. Colorless prism crystals. 249-250 ° C.

Example 39 In the same manner as in Example 27, N- (4-chlorophenyl)-
1,2-Dihydro-3-benzothiepine-2-carboxamide 3,3-dioxide was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 197-
198 ° C.

Example 40 In the same manner as in Example 27, N- (4-chlorophenyl)-
1H-2-benzothiopyran-1-carboxamide
2,2-dioxide was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism crystals. Melting point 232-233
° C.

Formulation Example 1 Of the above composition, (1), (2), (3) and (4) were mixed, water was added thereto and kneaded, then dried at 40 ° C. for 16 hours under vacuum, crushed in a mortar, Granules were passed through a 16 mesh sieve. Add (6) to the granules and mix.
(Manufactured by Kikusui Seisakusho) to produce tablets of 200 mg per tablet.

Formulation Example 2 Tablets were produced in the same manner as in Preparation Example 1, using (1), (2), (3), (4), (5) and (6) among the above compositions. This tablet
The acetone solution of (7) was film-coated with a Harcoater (manufactured by Freund) to produce enteric-coated tablets of 210 mg per tablet.

Formulation Example 3 Of the above composition, (1), (2), (3) and (4) were mixed, water was added thereto and kneaded, followed by vacuum drying at 40 ° C. for 16 hours and grinding in a mortar, 16 mesh To obtain granules.
The granules were filled into gelatin No. 3 capsules using a capsule filling machine (manufactured by Xanasea, Italy) to produce capsules.

Formulation Example 4 Of the above composition, (2), (3), (4), (5) and (6) are dissolved in about half of the above distilled water at 80 ° C. with stirring. The obtained solution is cooled to 40 ° C., and the compound of the present invention is dissolved in the solution. Next, distilled water for injection is added to the solution to adjust the final volume, and the solution is sterilized by sterile filtration using an appropriate filter paper to prepare an injection.

Continuation of the front page (51) Int.Cl. ⁷ Identification code FI C07D 337/08 C07D 337/08 495/04 111 495/04 111 116 116 C07F 9/6553 C07F 9/6553 (56) References Heterocycl. Chem. , (1985), 22 (6), p. 1527-9 Arch. Pharm. (Weinh em, Ger.), (1974), 307 (3), p. 218-21 Chemical Abstracts, vol. Columns 61 and 8265, column h, column 8266, column c (58) Fields investigated (Int. Cl. ⁷ , DB name) C07D 335/06 A61K 31/38 A61K 31/381 A61K 31/67 A61P 19/10 C07D 337 / 08 C07D 495/04 111 C07D 495/04 116 C07F 9/6553 CA (STN) REGISTRY (STN)

Claims (4)

(57) [Claims] 1. A compound of the general formula [Wherein ring A represents an optionally substituted benzene ring, R
Represents a hydrogen atom or a hydrocarbon group which may be substituted,
B represents a carboxyl group which may be amidated, a portion containing a broken line represents a carbon-carbon single bond or a double bond, k represents 0 or 1, and n represents 0, 1, or 2]. Sulfur-containing heterocyclic compound (however, Or its salts). 2. A compound of the general formula Wherein B ′ is a carboxyl group which may be esterified, and other symbols have the same meanings as described above, or a salt thereof, and if desired,
General formula characterized by subjecting to amidation reaction and / or oxidation reaction [Wherein each symbol is as defined above] (provided that: Or a method for producing the salt thereof. 3. A compound of the general formula Wherein Z is a leaving group, R ¹ and R ² are each a hydrogen atom,
A hydrocarbon group which may be substituted or a 5- to 7-membered heterocyclic group which may be substituted, and other symbols are as defined above] or a salt thereof. A general formula characterized by the following: [Wherein each symbol is as defined above] or a salt thereof. 4. An agent for preventing or treating osteoporosis, comprising the compound of claim 1 or a salt thereof.