JPH02138272A - 1,2,5-benzothiazepin derivative and its production and its use - Google Patents

Abstract

NEW MATERIAL:1,2,5-Benzothiazepin derivative of formula I [R<1>, R<2> are identical or different and represent H, halogen, alkyl, hydroxyl, acyl, or the adjacent R<1> and R<2> connect to each other to form a ring given by the formulas: -(CH2)m- (m is 3 to 5), -0-. (CH2)n-O-(n is 1 to 3)] R<3> is H, alkyl, aralkyl; R<4> is H, hydrocarbon residue; R<5> is H, hydrocarbon residue, heterocyclic group, or R<4> and R<5> bond to each other to form a ring of the formula: -(CH2)k-, (k is 3 to 5)] and its salt. EXAMPLE:3-Nethyl-2,3,4,5-tetrahydro 1,2,5-benzothiazepin-4-one. USE:It is used as a preventive against mammalian osteoporosis. It shows excellent action to suppress the bone resorption. PREPARATION:A compound of formula II Is subjected to condensation ring closure to give the compound of formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention has bone resorption inhibitory activity! , 2,5-benzothiadiazepine derivatives, their production methods and uses.

Osteoporosis is a pathological condition or disease in which the amount of bone has decreased beyond a certain level, causing some symptoms or danger. The main symptoms are vertebral kyphosis, fractures of the abdominal spine, vertebral bodies, femoral neck, lower end of the radius, ribs, upper end of the humerus, etc.

The causes are diverse, including endocrine and nutritional disorders.

Traditionally, therapeutic drugs include estrogen agents, calcitonin,
Vitamin D and calcium preparations have been administered.

Problems to be Solved by the Invention However, when administering the above-mentioned therapeutic agents, sufficient effects are not obtained because the recipients are limited or the effects are uncertain.

Means for Solving the Problems The present inventors conducted intensive research with the aim of developing a more general drug that directly acts on bones to suppress bone resorption. As a result, the following general formulas (r) and ( I [1 represented by [),
The present invention was completed by discovering that 2,5-benzothiadiazepine derivatives act directly on bones and exhibit excellent bone resorption inhibitory effects.

That is, the present invention provides (1) general formula (I) [wherein R' and R'' are the same or different and represent hydrogen, halogen, optionally substituted alkyl, optionally substituted hydroxyl, or acyl; or adjacent R1 and R1 are connected to each other to form the formula -(CH,)- [wherein m is 3 to 5
[indicates an integer of] Azen Rui or the expression -'0-(C)! , )-0- [where n is 1 to
represents an integer of 3], Rs represents hydrogen, alkyl or aralkyl, R4 represents hydrogen or an optionally substituted hydrocarbon residue, R@
represents hydrogen or an optionally substituted hydrocarbon residue or heterocyclic group, or R4 and R11
are connected to each other to form the formula -(CHff1), -[wherein k
represents an integer of 3 to 5] or a salt thereof; (2) a compound represented by the general formula (II) [wherein R1, R', R', R and RI' have the same meanings as above. ] A method for producing compound (1) or a salt thereof, characterized by subjecting a compound represented by the formula (1) to a condensation ring-closing reaction, (3) an osteoporosis preventive and therapeutic agent containing compound (1) or a salt thereof, and (4) ) General formula [wherein R1 and R are the same or different and represent hydrogen, halogen, optionally substituted alkyl, optionally substituted hydroxyl or acyl, or adjacent RI and R1 are connected to each other and the formula -(CH,)-[in the formula, Peng represents an integer of 3 to 5] or the formula -0-(CHl)-0-[in the formula, n represents an integer of 1 to 3] ] indicates the formation of a ring represented by R
3 represents hydrogen, alkyl or aralkyl, 4 represents hydrogen or an optionally substituted hydrocarbon residue, R8 represents hydrogen or an optionally substituted hydrocarbon residue or heterocyclic group, or R4 and R are connected to each other to form the formula (cut)h [wherein, 翫 is 3 to 5]
[indicates an integer] may form a ring.

e represents 1 or 2. ] The present invention relates to an osteoporosis preventive and therapeutic agent containing the compound represented by or a salt thereof.

In formulas (1), (n) and (III), examples of the halogen represented by RI or R include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferred.

The alkyl in the optionally substituted alkyl represented by RI or R1 preferably has 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, 5ec-butyl, tert-butyl, pentyl, Examples include inpentyl, neopentyl, and hexyl.

Examples of the optionally substituted hydroxyl group represented by R1 or R1 include a hydroxyl group and a suitable substituent on the hydroxyl group, such as alkoxy, aralkyloxy, acyloxy, etc. It will be done. The alkoxy is preferably an alkoxy having 1 to 6 carbon atoms (e.g., methoxy, ethoxy, propoxy, 'isopropoxy, butoxy, imbutoxy, 5ec-butoxy, jerk-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, etc.). . As the aral bovine fluoroxy, for example, 7-enyl-C1
-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.). As the acyloxy,
Alkanoyloxy having 2 to 4 carbon atoms (e.g., acetyloxy, propionyloxy, n-butyryloxy, 1so
-butyryloxy, etc.).

The acyl represented by R1 or R1 includes formyl or a bond between an alkyl having 1 to 6 carbon atoms and a carbonyl group as described above for R and R (e.g., acetyl, propionyl, butyryl, isobutyryl, valeryl,
Invaleryl, pivaloyl, etc.).

When R1 and R are adjacent to each other, R1 and R1
are connected, (CHI)- or -O-(CHs)
A ring represented by -〇- may be formed, and such a ring includes a 5- to 7-membered ring formed with a carbon atom of a benzene ring. In these rings, l is 3 or 405-6
A membered ring and a 5- to 6-membered ring in which n is 1 or 2 are preferred.

As the alkyl represented by R3, the above-mentioned R1 and R3
Those having 1 to 6 carbon atoms as described above are preferable. As the aralkyl represented by R3, phenyl-C'l-4 alkyl such as benzyl and phenethyl is preferred.

Examples of the hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R4 include alkyl and aralkyl. The alkyl may be linear, branched, or cyclic with 1 to 1 carbon atoms, and examples thereof include:
In addition to C1- and alkyl mentioned for R- and R8, examples include heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.

Examples of the aralkyl include those similar to the aralkyl represented by R3.

The hydrocarbon residue in the optionally substituted hydrocarbon residue represented by R6 is alkyl.

Examples include aralkyl, alkenyl, and aromatic groups, and examples of the alkyl and aralkyl include those described for R4.

The alkenyl preferably has 2 to 6 carbon atoms,
Examples include allyl, vinyl, crotyl,
2-penten-1-yl, 3-penten-1-yl, 2
-hexen-1-yl, 3-hexen-1-yl, 2-
Cyclohexenyl, 2-cyclopentenyl, 2-methyl-2-propen-1-yl, 3-methyl-2-butene-
1-yl and the like.

Examples of the aromatic group include 08□6 aryl such as phenyl, naphthyl, anthryl and phenanthryl.

Examples of the optionally substituted heterocycle represented by R6 include a 5- to 7-membered heterocycle containing one sulfur atom, nitrogen atom, or oxygen atom, and a 5- to 7-membered heterocycle containing 2 to 4 nitrogen atoms. 6-membered heterocycles, 5- to 6-membered heterocycles containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom; It may be fused with a benzene ring or a 5-membered ring containing one sulfur atom.

Specific examples of the above-mentioned heterocycles include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, inthiazolyl, oxacylyl, inoxacylyl, pyrido[2,3- d] pyrimidyl, benzopyranyl, 1,8-naphthyridyl, l,5-naphthyridyl, 1
．． 6-naphthyridyl, 17-naphthyridyl, quinolyl,
Cheno[2,3-b]pyrimidyltetrazolyl, thiadiazolyl, bosadiazolyl, triazinyl, triazolyl; thienyl, pyrrolyl, pyrrolinyl, furyl, pyrrolidinyl, benzothienyl, indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, Examples include morpholino.

R4 and R5 are mutually connected, -(CHt), -(k
represents an integer of 3 to 5), and such a ring includes a 5- to 7-membered ring formed together with the carbon atom and nitrogen atom of the thiadiazepine ring. Among these rings, a 5- to 6-membered ring in which k is 3 or 4 is preferred.

Examples of the substituent in the optionally substituted alkyl represented by R1 or R1 include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, and carbon number 1.
-6 alkoxy (eg, methoxy, ethoxy, propoxy, inpropoxy, butoxy, pentyloxy, hexyloxy, etc.), and the number of substituents is preferably 1 to 3.

Specific examples of alkyl substituted for R1 and R' include trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, l-hydroxyethyl, 2-hydroxyethyl, methoxyethyl, ethoxyethyl, l -methoxyethyl, 2-methoxyethyl, 2,2-dimethoxyethyl,
Examples include 2,2-jethoxyethyl.

Examples of the substituents in the optionally substituted alkyl shown as the optionally substituted hydrocarbon residue represented by R4 include halogen (e.g., fluorine, chlorine, bromine, iodine, etc.), hydroxyl group, carbon number 1 ~6 alkoxy,
Amino which may be substituted with alkyl having 1 to 6 carbon atoms or acyl having 1 to 10 carbon atoms (e.g. dimethylamino,
diethylamino, dipropylamino, acetylamino,
propionylamino, benzoylamino, etc.), carbon number 1
Carbamoyl optionally substituted with ~6 alkyl (
(e.g., dimethylcarbamoyl, ethoxycarbamoyl, dipropylcarbamoyl, etc.), alkoxycarbonyl having 1 to 6 carbon atoms (e.g., methoxycarbonyl, °ethoxycarbonyl, propoxycarbonyl, etc.), dialkoxyphosphoryl (e.g., jetoxyphosphoryl, dimethoxyphosphoryl, etc.) ), the above-mentioned heterocycles, and the like. Regarding R4, specific examples of substituted alkyl include trifluoromethyl J trifluoroethyl, difluoromethyl, trichloromethyl, 2-hydroxyethyl, 2
-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 2,2-jethoxyethyl, 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, impropoxycarbonylethyl, tert-butoxycarbonylpropyl, jetoxyphosphorylethyl, dimethoxyphosphorylpropyl, etc. can be given.

Regarding R4, specific examples of substituted aralkyl include 4-chlorobenzyl, 3-(2-fluorophenyl)propyl, 3-methoxybenzyl, 3.4-dimethoxyphenethyl, 4-ethylbenzyl, 4-( 3-
Examples include 1-trifluorophenyl)butyl, 4-acetylaminobenzyl, 4-dimethylaminophenethyl, 4-jethoxyphosphorylbenzyl, 4-jethoxyphosphorylmethylbenzyl, and the like.

Substituents for the optionally substituted alkyl exemplified as the optionally substituted hydrocarbon residue represented by R11 include, for example, halogen (e.g., fluorine, chlorine,
bromine, iodine, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms, or acyl having 1 to 10 carbon atoms (e.g., dimethylamino, diethylamino, dipropylamino) , acetylamino, propionylamino, benzoylamino, etc.), carbamoyl optionally substituted with alkyl having 1 to 6 carbon atoms, dimethylcarbamoyl, ethoxycarbamoyl, dipropylcarbamoyl, etc.), alkyl dicarbonyl having 1 to 6 carbon atoms (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), dialkoxyphosphoryl (eg, jetoxyphosphoryl, diisopropoxyphosphoryl, etc.), and the above-mentioned heterocycles.

Regarding RS, specific examples of substituted alkyl include:
For example, trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl, 2-hydroxyethyl, 2-methoxyethyl, 2-ethoxyethyl, 2.
2-dimethoxyethyl, 2.2-jethoxyethyl, 2
-pyridylmethyl, 3-pyridylmethyl, 4-biridylmethyl, 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-dimethylcarbamonylpentyl, ethoxycarbonylmethyl, impropoxycarbonylethyl, tart↑butoxycarbonylpropyl, 3-jethoxyphosphorylpropyl,
Examples include 2-dimethoxyphosphorylethyl.

Examples of substituents in the optionally substituted aralkyl, aromatic group, and heterocycle exemplified as the optionally substituted hydrocarbon residue represented by R11 include halogen (
Examples, fluorine, chlorine, bromine, iodine, etc.), alkoxy having 1 to 6 carbon atoms, alkyl having 1 to 6 carbon atoms, halogenated C1
-, alkyl (L trifluoromethyl, difluoromethyl, 2.2.2-trifluoroethyl, 2,2.2
4-lichloroethyl, etc.), amino optionally substituted with alkyl having 1 to 6 carbon atoms or acyl having 1 to 10 carbon atoms (e.g., methylamine, dimethylamino, diethylamino, dibutylamino, propionylamino, acetylamino, benzoylamino) 7 etc.), dialkoxyphosphoryl (
e.g., dimethoxyphosphoryl, jetoxyphosphoryl, etc.)
, dialkoxyphosphorylmethyl, 2-dialkoxyphosphorylethyl, aromatic groups similar to those mentioned above (however, they may be substituted with halogen), and the like.

Regarding R', specific examples of substituted aralkyl include 4-chlorobenzyl, 3-(2-fluorophenyl)propyl, 3-methoxybenzyl, 3.4-dimethoxyphenethyl, 4-ethylbenzyl, 4- (3-
(trifluorophenyl)butyl, 4-acetylaminobenzyl, 4-dimethylaminophenethyl, 4-jethoxyphosphorylbenzyl, 4-dimethoxyphosphorylmethylbenzyl, and the like.

Regarding R6, specific examples of substituted aromatic groups include:
For example, 4-chlorophenyl, 2,4-difluorophenyl, 6-medoxy-2-naphthyl, 3,4-jethoxyphenyl, 3,4-dimethylphenyl, 3-trifluorophenyl, 4-cyclohexylphenyl, 4-acetyl Aminophenyl, 2-benzoylaminophenyl,
Examples include 4-jethoxyphosphorylphenyl, 4-jethoxyphosphorylmethylphenyl, 4-(2-diisopropoxyethyl)phenyl, and the like.

Regarding R11, specific examples of substituted heterocycles include:
For example, 5-chloro-2-pyridyl, 3-methoxy-2
-pyridyl, 5-methyl-2-benzothiazolyl, 5-
Methyl-4-phenyl-2-thiazolyl, 3-phenyl-5-ynoxasilyl, 4-(4-chlorophenyl)
-5-Methyl-2=oxasilyl, 4-butyl-1-piperazinyl, 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-
Examples include furanyl, 4-methyl-2-morpholinyl, and the like.

More specifically, compounds (1), (II) and (I
Regarding the substituent R'-R' in II), R1 and R'' are chlorine, fluorine, hydrogen + Cl-3 alkyl, and hydroxyl group.

C3-, alkoxy, phenyl-〇t-t alkyloxy or CI-4 acyl, R is hydrogen, C,-, alkyl or phenylC+-t alkyl, R4 is hydrogen.

Cl+ll alkyl or phenyl C7-4 alkyl,
R'+;! Water i, C, -. Alkyl or phenyl C1
-4-alcohol is particularly preferred.

The above compound (1) can be produced, for example, as follows. That is, it can be obtained by heating method A compound (II) in a suitable solvent or without a solvent. Such solvents include, for example, methanol, ethanol, propatool, 2
- Alcohols such as propatool, butanol, 2-methoxyethanol, ethers such as dioxane, tetrahydrofuran, dimethoxyethane, aromatic hydrocarbons such as benzene, toluene, xylene, ethyl acetate,
Acetonitrile, pyridine, N,N-dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, l,l.

Examples include 2.2-tetrachloroethane or a mixed solvent thereof. In this reaction, an appropriate base such as potassium carbonate, triethylamine, N-methylmorpholine, 4-(N,N-dimethylamino)pyridine, N,
It can also be carried out in the presence of N-dimethylaniline or the like.

The amount of base used is 0.1-10 per mole of compound (■)
A molar level is preferable. The reaction temperature is approximately ℃ in both cases.
The temperature is about 200°C, preferably about 0°C to about 150°C, and the reaction time is usually 0.5 to 100 hours, preferably about 2 to 30 hours.

In the present invention, a compound (I') of the following formula obtained in Method A using a compound (II-1) in which R3 of compound (II) is hydrogen [wherein R', R'', R' and R' have the same meanings as above] and the formula % formula % () [wherein R3' represents alkyl or aralkyl,
represents a leaving group]. The alkyl and aralkyl represented by R3/ are the same as those represented by R3 above. Examples of the leaving group represented by ), C1-C4 alkylphosulfonyloxy group (e.g. methanesulfonyloxy group) or diphenylphosphoryloxy group, dibenzylphosphoryloxy group, dimethylphosphoryl which is a residue of organic phosphoric acid Examples include oxy groups. This reaction is carried out in an organic solvent in the presence of a base. The solvent varies depending on the type of base used, but examples include alcohols such as methanol and ethanol,
Tetrahydrofuran, dioxane, dimethoxyethane,
Ethers such as diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, etc. can be used as appropriate. Examples of bases that can be used include potassium carbonate, sodium carbonate, sodium methoxide, sodium ethoxide, potassium Lert, -butoxide, sodium hydride, potassium hydride, and sodium amide. In this reaction, compound (1') and a base are first reacted in a solvent to form an anion, and then compound (I') is reacted with a base to form an anion.
Preferably, V) is reacted. The reaction temperature is usually about -1
The reaction time is generally 0.5 to 10 hours, preferably about 1 to 5 hours.

The 1,2,5-benzothiadiazepine derivative (1) thus obtained is isolated by known separation and purification methods such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution, chromatography, etc. Can be purified.

Compound (Ill) can be produced by subjecting compound (1) obtained by Method A and Method B to an oxidation reaction.

Method C (III) [In the formula, R', R'', R', R', R' and Q have the same meanings as above.] This oxidation reaction is carried out using an oxidizing agent such as ffi-chloroperoxide. Benzoic acid, hydrogen peroxide, peres
ters), sodium metaperiodate, etc. This oxidation is performed using an organic solvent that is inert under the reaction conditions.
For example, halogenated hydrocarbons (eg, methylene chloride, chloroform, dichloroethane, etc.), hydrocarbons (eg, benzene, toluene, etc.), alcohols (methanol, ethanol, propatool, etc.) are advantageously used. The amount of oxidizing agent used is for compounds with Q of 1 (Ill-■)
For the production of compound (1), it is used in an equimolar amount or in slightly excess amount, and for the production of compound (III-2) where a is 2, it is used in an amount of 2 to 3 moles relative to compound (I). When the oxidizing agent is used in an amount of 1 to 2 equivalents based on compound (1), (III
-1) and (I[l-2) can be obtained as a mixture. This reaction is carried out at room temperature or below, preferably at about -50°C.
It is usually carried out at a temperature of 0.degree. C. to -20.degree. C. for 0.5 to 10 hours. Compound (1) thus obtained can be isolated and purified by known separation and purification means such as concentration, vacuum concentration, solvent extraction, crystallization, recrystallization, dissolution, and chromatography.

The starting compound (If) of the present invention can be produced, for example, by the following method.

Method D [wherein, R', R'l R'l and R
S has the same meaning as above, Y and Z represent a leaving group]
In the above formula (Vl), the leaving groups represented by Y and Z include the same ones as X described above.

In the actual process, (V) is first acylated to form (■), then reacted with amines (■) to form (IX), and then oxidized to produce (n). The reaction between (V) and (Vl) is carried out in an appropriate solvent. Examples of the solvent include aromatic hydrogenated hydrogen such as benzene, toluene, and xylene, dioxane,
Ethers such as tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propatool, ethyl acetate, acetonitrile, pyridine, N
, N-dimethylformamide, dimethyl sulfoxide,
Chloroform, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane or water,
and mixed solvents thereof.

The reaction between (V) and (Vl) can be carried out using an appropriate alkali metal salt such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, or sodium bicarbonate, or an amine such as pyridine, triethylamine, N,N-dimethylaniline, etc. It can also be carried out in the presence of a base. This reaction is usually −
20°C-150°C, preferably about -10°C to 60°C
It will be held in

The reaction between (■) and amines (■) is carried out in an appropriate solvent. 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 furopanol, ethyl acetate, acetonitrile, pyridine, and N,N-dimethylformamide. , dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloroethane, 1,1°2,2-tetra, chloroethane, water, and mixed solvents thereof. Amines (■) are compounds (■
) is preferably used in excess (about 2 to 6 equivalents). This reaction is usually carried out at -20'C to 150C, preferably at about -10C to 100C.

Furthermore, (IX) is oxidized to produce compound (n).

This oxidation reaction is carried out according to a conventional method using an oxidizing agent such as chloroperbenzoic acid, hydrogen peroxide, perester.
s), sodium metaperiodate, etc.

This oxidation can be carried out using organic solvents that are inert under the reaction conditions, such as halogenated hydrocarbons ((L methylene chloride, chloroform, dichloroethane, etc.) or hydrocarbons (e.g.
benzene, toluene, etc.), alcohols (methanol,
(ethanol, propatool, etc.). The oxidizing agent is used in an equimolar amount or in slightly excess amount relative to compound (IX). This reaction is carried out at room temperature or lower, preferably at a temperature of about -50°C to 20°C, usually at a temperature of 0°5 to 20°C.
It will take 10 hours. Compound (II) thus obtained can also be used in the condensation ring closure reaction to form a thiadiazepine derivative (+) without being isolated and purified.

Compound (■) can also be obtained by the following method.

Method E (V) (■) [In the formula, R', R'', R3, R' and Z have the same meanings as above] The condensation reaction of (V) and (X) of this method can be carried out by ordinary peptide synthesis means. The method for synthesizing the peptide may be carried out in the same manner as in M.

Peptide Synthesis, by M. A. Bodansky and M. A. Ondetti.
esis), Interscience, New York, 1
966; P. M. Finn and Ilorm
The Pro-tei by Ann
ns), Volume 2, 11. Nenrath, R.L.
l1111m collection, Akademitsu Press Inc. 9,
New York, ■976; Methods described in Nobuo Izumiya et al., "Basics and Experiments of Peptide Synthesis", Maruzen Co., Ltd., 1985, such as acid anhydride method, mixed acid anhydride method, DC
C method, activated Nister method, method using Woodward reagent K, carbonyldiimidazole method, redox method, DC
Examples include the C/HONB method.

This condensation reaction can be carried out in a solvent. Examples of the solvent include anhydrous or hydrous dimethylformamide, dimethyl sulfoxide, pyridine, chloroform, dichloromethane, tetrahydrofuran, acetonitrile, or a suitable mixture thereof. The reaction temperature is usually about -20°C to about 50°C, preferably -10°C to 30°C.
It is.

The reaction time is 1-100 hours, preferably 2-40 hours.

Amino compound (IX) can also be obtained by the following method.

Method F (V) (XI) [In the formula, R', R', R", R' and R'g have the same meanings as above, and A is the protection of the amine 7 group in a normal peptide synthesis reaction. In this method, (V) is reacted with a protected amino acid salt conductor (Kari) to form an amide derivative (X[), which is then subjected to a deprotection reaction to synthesize IX).

Examples of the protecting group represented by A include benzyloxycarbonyl, tert-butoxycarbonyl, tert-amyloxycarbonyl, inbornyloxycarbonyl,
Examples include chloro- or nitro-substituted benzyloxycarbonyl, para-methoxybenzyloxycarbonyl, trityl, diphenylphosphinothioyl, 2,3,6-drimethylbenzenesulfonyl, and the like.

The condensation reaction of (V) and (XI) is carried out under the same conditions as the peptide synthesis method described above.

Examples of the method for removing the protecting group from the amine 7 group of compound (Xll) include acid treatment with anhydrous hydrogen fluoride, methanesulfonic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, or a mixture thereof. , In addition, reduction with sodium in liquid ammonia, etc. can also be mentioned. The deprotecting group reaction by the above acid treatment is generally carried out with
It is carried out at an appropriate temperature of 0°C to 50°C for 0.5 to 10 hours.

Compounds (f) and (III) of the present invention have 2 basic functionalities in their molecules! (amino group, pyridyl group, oxacylyl group, thiazolyl group, pyrimidyl group, etc.), compounds (1) and (I[[) can be converted into pharmacologically acceptable salts by commonly used means. good. Examples of the salt include hydrochloride, bromate, iodate, phosphate, nitrate, sulfate, acetate, citrate, and the like.

Next, the method and results for measuring the bone resorption inhibitory effect of compounds (1) and (III) will be shown.

[Bone resorption inhibitory effect] Bone resorption effect can be measured by Royce's method [Sitonal of
Clinical Investigation (J.

Cl1n, Invest,) Volume 44, Page 103-l1
6, 1965]. That is, one Sprague-Dawley rat on day 19 of gestation was given 4S.
Ca (calcium isotope, CaC1m solution) at 50
μCi was injected subcutaneously, the abdomen was opened the next day, the fetal rat was removed aseptically, and the left and right forearm bones of the fetal rat were examined under a dissecting microscope.
The radial bones and ulna) were separated from the trunk, and connective tissue and cartilage were removed as much as possible to prepare bone culture samples.

Cut each piece of bone into 0.6 meter BGJ, medium (Fitt
on-Jackson modification,
[G I B C0 Laboratories (USA)
) contains bovine serum albumin r2txg/d).
After culturing at °C for 24 hours, the culture was continued for another 2 days in the above medium to which the compound was added at a concentration of 10 μg/d.
The radioactivity of a was measured, and the ratio (%) of Ca released from the bone into the medium was determined according to the following formula.

Ratio (%) of 46Ca released from bone into medium =
"Ca count in medium" Ca count in X100 medium 46 Ca count in bone bones Bones obtained from fetuses from the same litter were similarly cultured for 2 days without adding any compound and were used as a control group. The standard deviation above the mean value of the values obtained from five bones in each group was determined, and the ratio (%) of this value to the value of the control group was determined and shown in Table 1.

Compound bone resorption inhibitory effect O 64,5 84,4 75,3 71,1 62,5 66,5 66,9 63,7 62,4 66,3 45,0 48,5 66,9 73,7 69, 4 66,8 66,3 76,0 83,0 Compound Bone resorption inhibitory effect 70.4 77.8 89.0 61.0 Regarding the toxicity of compounds (1) and (III), see Example 20, for example. and 30 of the compound obtained in 38
No deaths were observed even when administered orally to mice at a rate of 0 mg/kg.

As mentioned above, compounds (1) and (
III) has an excellent bone resorption inhibitory effect and low toxicity.

Therefore, compounds (1) and (III) of the present invention can be used in mammalian animals (e.g., mice, rats, rabbits, dogs, cats,
It can be used for the prevention or treatment of osteoporosis in cattle, pigs, humans, etc.).

When administering this compound to humans, the administration method may be either oral or parenteral. Compositions for oral administration include solid or liquid dosage forms, in particular tablets (including dragees and film-coated tablets), emulsions,
Granules, powders, capsules (including soft capsules)
, syrups, emulsions, p771i agents, etc. Such compositions are prepared by methods known per se and contain carriers or excipients commonly used in the pharmaceutical field;
It is something that you have. For example, carriers and excipients for tablets include lactose, starch, sucrose, and magnesium stearate.

Compositions for parenteral administration include, for example, injections,
Examples include suppositories, and injections include dosage forms such as subcutaneous injections, subcutaneous injections, and intramuscular injections. Such an injection can be prepared by a method known per se, that is, compounds (1) and (III).
It is prepared by suspending or emulsifying the compound in a sterile aqueous or oily liquid commonly used for injections. Examples of aqueous solutions for injection include physiological saline and isotonic solutions, which may be used in combination with appropriate suspending agents such as sodium carboxymethyl cellulose, nonionic surfactants, etc., if necessary. Examples of the oily liquid include sesame oil, soybean oil, etc., and benzyl benzoate, benzyl alcohol, etc. may be used in combination as the solubilizing agent. The prepared injection solution is usually filled into suitable ampoules.

When the present compounds (1) and (III) or a salt thereof is used as a preventive treatment for osteoporosis, the daily dose for an adult is 1-500s+g for oral administration, preferably 10 to 150 mg, and parenteral administration. For administration: 0°1~loo
ag, preferably 0.1 to 20 mg.

Next, the present invention will be explained in more detail with reference to reference examples and examples. Note that all melting points were measured by the hot plate method and are uncorrected.

Reference Example 1 2-chloropropionyl chloride (2.8 g) was added to a mixture of 2-allylthioaniline (3.3 g), triethylamine (2.2 g) and dichloromethane (30d) under water cooling.
) in dichloromethane (5d) was added dropwise.

After stirring at room temperature for 2.5 hours, the reaction solution was washed with water and dried.
A (MgSO,) L, ta. The solvent was distilled off and the residue was subjected to column chromatography (70 g of silica gel).

Elute with ethyl acetate and beef sanitation (10.v/v) N-
(2-allylthiophenyl)-2-chloropropionamide was obtained as an oil (4.2 g, yield: 82%).

NMR (δppm in CD C12s): 1.8
3 (311, d, J=711z).

3.34 (211, d, J=7.5Hz), 4.56
(l11.q, J=711z), 4°75-5.05
(211, m), 5.55-6.05 (III, m
), 7.06 (III.

double t, J=7.5 and 2Hz),
7.35 (III, double L.

J=7.5 and 211z), 7.52(III
, double d, J=7.5and 211z),
8.40 (lIl, double d, J=1.5
and 2).

9.73 (IIl, broads).

IR(neat): 332G, 1690. 1
580. 1525.1440°1350cm-' C,,H,,CQN Teno calculated value as OS: C,56,35: ti, 5.52. N
, 5.4g.

Analysis value: C, 56,53; H, 5,52; N,
5.53° Reference Examples 2 to 12 Compounds shown in Table 2 were obtained in the same manner as in Reference Example 1.

Reference Example 13 N-(2-allylthiophenyl)chloroacetamide (
1.2 g), cyclohexanemethylamine (l.

7g) and methanol (20〆) at room temperature.
I stirred the time. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO,), and then the solvent was distilled off. The residual oil was purified by column chromatography (60 g of silica gel). From the part eluted with vinegar M ethyl-hexane (1:3.v/v), N-(2-allylthiophenyl)-2-(cyclohexylamino)acetamide was extracted as an oil (1.4 g, 88.0%). obtained as.

NMR (δppm in CD CQs>: 0.75
-2.0 (1211, m).

2.54 (211, d, J=611z), 3.35 (
211,d, J=611z), 3.41(211,s
), 4.8-5.1 (211, m), 5.
55-6.05 (ill, m).

6.99 (ill, double t, J=8 and
211z), 7.31 (lit.

double t, J=8 and 1.511z),
7.46(lIl, double d.

J=8 and 211z), 8.45(lIl, d
double d, J=8 andl, 511z),
10.37 (III, broad s).

C,,H,,N,Calculated value as OS: C,6? . 88; H, 8, 23; N, 8
．． 80° analysis value: C, 67, 90, H, 8, 13;
N, 8.81° Reference Example 14 2-chlorobutanoic acid (1.1 g) in dichloromethane (2
0d) Add N,N'-carponyldiimitazole (1
, 6g) and stirred for 20 minutes, a solution of 2-allylthioaniline (1.7g) in dichloromethane (lOd'') was added and stirred at room temperature for 22 hours.The reaction solution was diluted with IN hydrochloric acid,
Sequentially washed with saturated sodium bicarbonate and water and dried (MgS
O,) I did. The solvent was distilled off and the residue was subjected to silica gel column chromatography (100 g of Si0°). N from the part eluted with ethyl acetate-hexane (1:10)
-(2-allylthiophenyl)-2-chloroptyramide (1.5 g, 55% yield) was obtained as a colorless oil.

NMR (δppm in CD C123): 1.1
1 (311,t, J=7).

1.9-2.4 (211, m), 3.35 (211,
d, J=7), 4.46 (III.

double d, J=5.5 and 7),
4.7-5.1 (21, m).

5.5-6.1 (III, m), 7.04 (III,
double t, J=8 andl, 5), 8.3
9(ill, double d, J=8 and 1.
5), 9.70 (IH, br, s).

Reference Example 15 Similarly to Reference Example 14, N-(2-allylthiophenyl)- was prepared from 2-bromocaproic acid and 2-allylthioaniline.
2-Bromohexamite was obtained as an oil. Yield 50
%.

NMR (δppm in CDCI2s): 0.92
(311,t, J=5.5).

1, 1-1.7 (4H, m), 2.0-2.3 (21
1, a), 3.35 (211, d.

J=7.5), 4.44 (III, double d
, J=7.5 and 6).

4.75-5.1 (211, m), 5.5-6.1 (
lIl, m), 7.05 (III.

double t, J=8 and 1.5), 7.
33 (III, double t, J=7.5 and
2), 7.51 (lit, double d, J=
7.5 andl, 5), 8.38(ill, dou
ble d, J-8 and 2), 9.50 (lit
, broads).

C+sHtoB rN Calculated value as OS: C, 52,63; H, 5,89: N,
4.09゜Analysis value: C, 52.8g, H, s, gg
; N, 4.17° Reference Example 16 2-allylthioaniline and 2-bromovaleryl bromide were treated in the same manner as in Reference Example 1 to obtain N-(2-allylthiophenyl)-2-7'romopentamide. was obtained as an oil. Yield 88%.

NMR (δppm in CD C123): o,
97 (3H, t, J=8).

1, 4-1.8 (211, a), 2.0-2.4 (2
11, s), 3.33 (211, t.

J=7), 4.44 (IH, t, J==7),
4.7-5.1 (2H, a).

5.3-6.1 (IH, m), 7.05 (lIl, d
double t, J=8 andl, s), 7.35
(LH, double L, J=8 and 1.5)
, 8.37(lIl, double d, J=8 a
nd 1. s), 9.45 (111, br, s).

Calculated values as C14HIIB rN OS: C, 51, 22, H, 5, 53: N, 4
．． 27° analysis value: C, 51,15; H, 5,53:
N, 4.23° Reference Example 17 2-Allylthioaniline and 2-bromoisovaleryl chloride were treated in the same manner as in Reference Example 1 to form N-(2-allylthiophenyl)-2-bromoisopentamite into an oily state. I got it as a thing. Yield 79%.

NMR (δppya in CD CQ3): 1.0
5 (311, d, J=7).

1.09 (311, d, J=7), 2.2-2.6
(ill, Peng), a, :(2(211, d.

J=7), 4.39 (lIl, d, J=5), 4.
7-5.0 (211, yes.

s, 5-6.1 (III, m), 7.02 (IH
, double d, J= 8 and2), 7
．． 31 (III, double d, J=8 and
1.5), 7.48 (111, double di
=8 and 2)+8.36(l11.doub
led.

J=8 and 1.5), 9.55 (11, br
, s).

Calculated values as C+aHtsBrNO3: C,51,22: H,5,53; N,
4.27° Analysis value: C, st, to; H, 5,55
; N, 4.24° Reference Example 18 2-allylthioaniline and 2-bromooctanoyl chloride were treated in the same manner as in Reference Example 1 to produce N-(2-allylthiophenyl)-2-promooctanamide in an oily state. I got it as a thing. Yield 73%.

NMR (δppm in CD C12s):
O,,87 (311,t, J=6).

1.1-1.7 (811,s), 1.8-2.4 (2
11, s), 3.36 (211, d.

j=7), 4.3-4.6 (111, m), 4.
7-5.1 (211, s+), 5.5-6.1 (1
11, s), 7.05 (III, double
t, J-7and 1.5), 7.33(IH, d
doublet, J=8 and 1.5),
7.50 (Ill.

double d, J=7.5 and 1. s),
8.38(fil, double t.

J=8 and 1), 9.44 (0,5H,br,
g), 9.69 (0,511, br, 11).

Reference Example 19 N-(2-allylthiophenyl)chloroacetamide (
1.2g), cyclohexanemethylamine (1°7g)
and methanol (20d) was stirred at room temperature for 18 hours. The reaction solution was poured into water and extracted with ethyl acetate.

The ethyl acetate layer was washed with water, dried (MgSO4), and then the solvent was distilled off. The residual oil was subjected to column chromatography (60 g of silica gel).

N-(2-allylthiophenyl)-2(cyclohexylamino)acetamide was extracted as an oil (1.4 g,
Yield: 88.0%).

NMR (δppa+ in CDCQs>: 0.75
-2.0 (1211, m).

2.54 (211, d, J-611z), 3.35 (
211, d, J=611z), 3.41 (21+,
s), 4.8-5.1 (211, s+), 5.55
-6.05 (IIl, m).

6.99 (III, double t, J=8 and
211z), 7.31(ill.

double t, J=8 and 1.511z),
7.46 (III, double d.

J=8 and 211z), 8.45(1!I,d
double d, J=8 and l.

511z), 10.37 (III, broad s)
.

CIIIH□N, calculated value as OS: C, 67, 88: H, 8, 23; N, 8
．． 80° analysis value: C, 67, 90: H, 8, 13;
N, 8.81° Reference Examples 20-49 Compounds shown in Table 3 were obtained in the same manner as in Reference Example 13.

(Leaving space below) Reference Example 5O To a solution of N-(2-allylthiophenyl)-2-chlorobutyramide (1.7 g) in methanol (30 dl) were added benzylamine (2.0 g) and potassium iodide (1.7 g).
g) was added and heated under reflux for 7 days. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO), the solvent was distilled off, and the residue was subjected to silica gel column chromatography (SiO = 60 g). N-(2-allylthiophenyl)-2-benzylaminobutyramide (1.2 g, yield 155%) was obtained as an oil from the fraction eluted with ethyl acetate-hexane (1:1 O).

NMR (δppm+ in CD Cff5): 1.
00 (311, t, J=6).

1.5-2.1 (31Lo+), 3.15-3.4 (
311, m), 3.7(1(ill, d.

J=13), 3.96 (III, d, J=13),
4.7-5.0 (211, a).

5, 5-6.0 (IIl, m), 7.01 (IIl
, double t, J=7.5and 2),
7.2-7.6 (711, m), 8.51 (III,
double d.

J=8 and 2), 10.5(III, br, s
).

C,,1-I,,N,OS,Teno calculation value: C,
? 0.55: H, 7,10; N, 8.23° Analysis value: C, 70,59; H, 7,06; N, 8.
13° Reference Examples 51 to 54 In the same manner as Reference Example 50, the compounds shown in Table 4 were obtained as oils.

Table 4 NIIR' 51 (C113) ICI+-113, 5 days 0.95
(311, d, J=7), 1.01 (311, d, J=
7.5), 2.0-2゜4 (lit, m), 3.1
2 (III, d, J=4.5), 3.31 (2+1
．． d, J=7).

3, 65 (III, d, J= 15), 3.96
(ill, d, j = 15), 4.7-5.0
(2H, m), 5.5-6.0 (III, m).

7,00(III, double t, J=gan
d 1.5), 7.2-7.6 (711°111)+
g, 51 (lII+ double d*J='
1.5 and 1.5), 10.49 (III,
br, s).

to be continued 2, 0 (411, m), 3.30 (IIl, t.

J=6), 3.32 (211, d, J=7).

3,71 (Ill, d, J= 13.5), 3゜96 (III, d, J= 13.5), 4.75
-5.0 (211,s), 5.5-6.0 (III,
m), 7.00 (III, doublet, J=
8 and 1.5), 7.2-7, 6 (711,
s), 8.49 (111° double d+ J=
8 and 1.5) 54 CI+3 (C11ri 5-
38 5.5 days 0, 85 (3H, t, J=5), 1
．． 1-2, 0 (1011, m), 3.2-3.4 (3
11, m), 3.72 (III, d, J=3), 3.
97 (11, d, J = 13), 4.7-5.1 (
2+11), 5.5-6.0 (111, m), 7.
0(lit, doublet, J=1.5 and
2), 7.2-7, 6 (711, m), 8.50
(ill.

double d, J=8 and 2)+2,0(
611, m), 3.2-3.4 (311°s), 3.
71 (111, d, J=13), 4°7-5.1 (21
1, m), 5.5-6.0 (III, 1ll), 7
．． 0(III, doublet, J-7,5and
1.5), 7.2-7.6 (711, m), 8.4
9 (III.

double d, J=8 and 1.5) Continued Reference Example 55 D, L-N-tert, To a dichloromethane (30d) solution of butoxycarbonylalanine (3.3g), triethylamine (1.8g) and ethyl chloroformate (1.
8g) in this order and stirred at room temperature for 30 minutes.
- allylthioalanine (2.8 g) in dichloromethane (
5d) Added solution. The mixture was stirred at room temperature for 2 hours, then washed with water and dried (MgSO4). The solvent was evaporated and the residue was dissolved in dichloromethane (lOd) and treated with tanthiol (0,25JE12) and trifluoroacetic acid (20ml).
2) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated, a saturated aqueous sodium bicarbonate solution was added, and the mixture was extracted with chloroform. After washing the chloroform layer with water and drying (MgSO*),
The solvent was distilled off and the residue was subjected to column chromatography (silica gel, 100 g). Elute with chloroform-methanol (ioll, v/v) to obtain an oil of N-(2-allylthiophenyl)-2-aminopropionamide (
1.73 g (yield 42%) was obtained.

NMR (699m in CDCl25): 1.45
(311, d, J=7.5).

1.63 (211, broad s), 3.37 (
211, d, J= ), 3.67 (III.

9,'' = 7.5), 4.8-5.02 (211, m
), 5.6-6.06 (l11.at), 7.0
0(lIl, double L, J='1.5 and
1.5), 7-32 (III, double L,
J=8 and 1.5), 7.48(llLdo
ub, le d.

J=7.5 and 1.5), 8.47(fH,d
double d, J=8 andl, 5), 10.
47 (111, broads).

Calculated value as C0H*jNmS, C,60,99: H,6,82: N,
11.85° Analysis value: C, at, oa: H, 6,8
2; N, 11.58° Reference Example 56 In the same manner as in Reference Example 55, an oily product of N-(2-allylthiophenyl)-2-amino-3-phenylpropionamide was obtained. Yield 75%.

NMR (δppm in CDCI2a): 1.54
(2H, broads).

2, 84 (IIl, double d, J= 14
and 9), 3.2-3.5(:(II.

m), 3.79 (III, double d, J=9
and 4.5), 4.75-5, 05 (2H,a
), 5.53-6.0 (III, a), 7.01
(Ill.

double L, J=8 and 2), 7.15
-7.55 (711, a), 8°51 (111, do
uble d, j=8 and 1.5), 10.1
5 (Ill.

broads).

Reference Example 57 N-(2-allylthio-5-chlorophenyl)-2-piperidinamide was obtained in the same manner as in Reference Example 55. 5p7
1-72°C (isopropyl ether hexane).

C,,H,,N,Calculated value as OS:C,57,96;H,6,16;N,9
．． 01° Analysis value: C, 5g, 23: H, 6,23;
N, 9.03° Reference Example 58 A solution of N-(2-allylthiophenyl)methylaminoacetamide (1.16 g) in chloroform (15111) was cooled with water and chloroperbenzoic acid (80%, 1.1 g) was added. A chloroform (Ioj!I2) solution was added dropwise. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution and water, and then dried (
MgSO□). The solvent was distilled off, and the residue was subjected to silica gel column chromatography (Sins, 50 g). From the portion eluted with chloroform-methanol (30:1), an oily substance of N-(2-allylsulfinylphenyl)methylaminoacetamide ( 0.18g, yield 15%)
I got it.

NMR (δppm in CDCI2s): 2.50
(311, s), 3.39 (2If, s), 3.7
1 (211, d, J=7.5), 5.1-6.0 (3
11, m), 7゜0-7.7 (4H, a), 8.4
7 (III, d, J-8).

IR(neat): 16gG, 1575.150
0.1435.1295°103103O' Reference Example 59 In the same manner as Reference Example 58, N-(2-allylsulfinylphenyl)aminoacetamide was obtained as an oil. Yield 89%.

NMR (δppta in CDCffa): 2.0
3(2!(,br,s), 3゜19(211,s)
, 3.74 (211, d, J=7), 5.1
5.9 (311, a).

7.0-7.6 (311, s), 8.44 (In,
d, J=8), 10.9 (III.

br, s).

I R(neat) 2 3250. 16g5.
1580. 1510. 1435°1290, 10
3103O' Reference Example 60 N-(2-allylsulfinylphenyl)benzylaminoacetamide was obtained as an oil in the same manner as in Reference Example 58. Yield 68%.

NMR (δpp+min CDC123)+2.2
(11(,br,s), 3.45(2!1.s),
3.71(211,d, J=7), :(,86(21
1,s), 5.0-5.9(311,o,), 7.
0-7.6(811,s), 8.43(lIl,d,
J=8).

I R (neat): 169G, 158G, 15
10.1435.1295°1025es-breath Example I N-(2-allylthiophenyl)-2-aminopropionamide (1,73 g), cone, HCQ (0,
A water-cooled solution of chloroperbenzoic acid (80%, 1.58 g) in methanol (10d) was added dropwise to the mixture of 7d) and methanol (15d). After stirring at room temperature for 1 hour, the mixture was poured into a saturated aqueous sodium bicarbonate solution (100d) and extracted with chloroform. The chloroform layer was washed with water, dried (MgSOn), the solvent was distilled off, and the residue was oMr (20d
) and stirred at 60°C to 70°C for 3 hours. The reaction solution was poured into ethyl acetate (150x12), washed with water and dried (
MgS04). The solvent was distilled off, and the residue was purified by column chromatography (70 g of silica gel). 3 from the part eluted with chloroform-methanol (40:1)
-Methyl-2,3゜4.5-tetrahydro-1,2,5
- Crystals of benzothiadiazepin-4-one (552 mg
, 38.9%) obtained. It was recrystallized from chloroform-isopropyl ether. Colorless prism product, mp16
6167°C9 C,H,. N, calculated value as OS: C, 55, 65; H, 5, 19; N,
14.42° Analysis value: C, 55, 50: H, 5, 2
6, N, +4.43° Examples 2 to 35 The compounds shown in Table 5 were obtained in the same manner as in Example 1.

Example 36 N-(2-allylsulfinylphenyl)methylaminoacetamide (0.18 g) in chloroform (5112
) The solution was heated under reflux for 3 hours. The solvent was distilled off and the residue was subjected to silica gel column chromatography.
ins 25 g), ethyl acetate-hexane (1:l)
2-methyl-2,3,4゜5-tetrahydro-1,2,5-benzothiadiazepine-4-
(29 mg, 21% yield) was obtained.

Recrystallized from ethyl acetate-hexane. Colorless prism product, 5p145-146℃.

C.H. N, 31 calculation value as OS: C, 55, 65; H, 5, 19: N,
14.42° Analysis value: C, 55, 57; H, 5,
21; N, 14.37゜Example 37 A solution of N-(2-allylsulfinylphenyl)amide/acetamide (3.2 g) in DMF (253!+2) was
Stir at 0°C for 5 hours. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4
), the solvent was distilled off, and the residue was subjected to silica gel column chromatography (Side 100 g).

Elute with ethyl acetate-hexane (2:1), 2.3°4
．． 5-tetrahydro-1,2,5-benzothiadiazepin-4-one (303 mg, yield I3%) was obtained. Recrystallized from ethyl acetate-hexane. colorless needle crystals, ap
178-179°C.

Calculated values as C, H, N, O3: C, 53,31; H, 4,47; N,
15.54° Analysis value: C, 53,34; H, 4,3
4: N, 15.41° Example 38 2-benzyl-2,3° 4.5 in the same manner as Example 37
-tetrahydro-1,2,5-benzothiadiazepin-4-one was obtained. Recrystallization from ethyl acetate yielded 46%. Calculated value as colorless prism product, mp159-160°C1 CrsHl-N to S: C, 66,64; H, 5,22; N,
10.36° Analysis value: C, 66,43; H, 5,2
1,N, 10゜32゜Example 39 N-(2-allylthiophenyl)phenylaminoacetamide (4.44 g) in methanol (5
onc, HCi2 (1,5d) and then water-cooled with chloroperbenzoic acid M (80%, 3.2g>(1)
) solution was added dropwise. The reaction solution was poured into saturated sodium hydrogen carbonate (200ml) and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO,)
The solvent was then distilled off. The residue was dissolved in DMF (25111), N,N-dimethylaminopyridine (0.36 g) was added, and the mixture was stirred at 60°C for 5 hours. Water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (ljgsQJ), the solvent was distilled off, and the solvent residue was subjected to silica gel column chromatography (Sins 80g). 2-phenyl-2,3,4,
5-tetrahydro-1,2,5-benzothiadiazepin-4-one (62 gg, yield 1.6%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless prism product, m
p184-187°C1C,, H, tN, calculated value as OS: C, as, ao; H, 4,72; N,
10.93° Analysis value: C, 65, 71: H, 4, 6
7; N, 11.23° Example 40 2-benzyl-2,3,4,5-tetrahydro-1,2
To a solution of ,5-benzothiadiazepine (500++g) in dimethylformamide (5d) was added oily sodium hydride (60%, 81mg) under water cooling, and after stirring for 20 minutes, methyl iodide (0.28g) was added and the mixture was heated to room temperature. I stirred for another 3 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO,), the solvent was distilled off, and the residue was subjected to column chromatography (silica gel, 20 g).

Elute with chloroform 2-benzyl-5-methyl 2.3
, 4,5-tetrahydro-1,2,5-benzothiadiazepine crystals (329a+g, 62.5%) were obtained. It was recrystallized from beef starch in acetic acid solution.

Colorless needles, leaves 140-141℃.

C, , H, , N , Teno calculation value with OS: C, 67,58; H, 5,67; N,
9.85, analysis value: C, 67, 57, H, s, aa;
N, 9.64° Example 41 5-benzyl-2-propyl-
2,3,4,5-tetrahydro-1,2,5-benzothiadiazepin-4-one was obtained. Yield 62.0%, recrystallized from beef starch to isopropyl ether, mp103
104°C Example 42 2-benzyl-2,3,4,5-tetrahydro-1,2
, 5-Benzothiadiazepin-4-one (1°0g) in chloroform (20d) was mixed with metachloroperbenzoic acid (
A solution of 80% (1.6 g) in chloroform (20d) was added dropwise while cooling with water. After stirring at room temperature for 5 hours, it was washed with a saturated aqueous sodium hydrogen carbonate solution and water in that order, and dried (MgSO
,) did. The solvent was distilled off, the residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (1
:2-benzyl-2,3,4,
5-tetrahydro-1,2,5-benzothiadiazepin-4-one-1,1-dioxide (0,826 g,
74%). Recrystallized from ethyl acetate-hexane.

Colorless needle-like crystals, 5p142 143°C0ClsH14N
Calculated values as to 3S: C, 59, 59; H, 4, 67; N,
9.27° Analysis value: C,! if1. ag;)I,
4.67: N, 9.22° Examples 43-48 The compounds shown in Table 6 were obtained in the same manner as in Example 42.

Example 49 2-benzyl-2,3,4,5-tetrahydro-1,2
,5-benzothiadiazepine-4-one (0°4g)
A solution of metachloroperbenzoic acid (80%, 0.32 g) in chloroform (5 d) was added dropwise to the chloroform (15d) solution under water cooling. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution and then with water, and dried (MgSO, ). The solvent was distilled off, and the residue was subjected to silica gel column chromatography, and 2-benzyl-2,3,4,5-tetrahydro-1,2,5 was extracted from the portion eluted with ethyl acetate-hexane (1:2). -Benzothiadiazepine-4-one-
1-oxide (0.37 g, 86%) was obtained. Recrystallized from ethyl acetate-hexane.

Colorless needles, mp 167-168°C.

Calculated values as C,,H,,N,O,S: C,62,92; H,4,93; N,
9.7g.

Analysis value: C, 62,91, H, 4,93, N, 9.
68° Examples 50 to 54 The compounds shown in Table 7 were obtained in the same manner as in Example 49.

Formulation Example 1 Composition in one tablet (1) Compound (compound obtained in Example 20) 50B (
2) Cornstarch 30B
(3) Lactose 113.
4mg (4) Hydroxypropyl cellulose 6
B (5) Water (0
゜03 d) (6) Magnesium stearate
0.6m total 200 B Among the above compositions, (1), (2), (3) and (
4), add water and knead, then heat to 40°C.
.

The mixture was vacuum dried for 16 hours, crushed in a mortar, and passed through a 16-mesh sieve to form granules. Add (6) to this granule and mix.
2 per tablet with rotary 2 tablet press (Kikusui Seisakusho 12)
00+g tablets were produced.

Formulation Example 2 (1) Compound (compound obtained in Example 22) 50 mg
(2) Cornstarch 30
mg(3) lactose 11
3.4118(4) Hydroxycellulose
6111g (5) water
(Q, 03 xft> (6) Magnesium stearate 0.6 mg (7) Cellulose acetate phthalate 10 mg (8) Acetone
(0,2d>total
210 mg Among the above compositions, (1), (2)
, (3), (4), (5) and (6) in the same manner as in Formulation Example 1 to produce tablets. Enteric-coated tablets containing 210 mg per tablet were prepared by adding the acetone solution of (7) to the tablets using Filmco L (manufactured by Freund).

Formulation Example 3 Composition in capsule (1) Compound C (compound obtained in Example 38) 30
B (2) Cornstarch 40
°g (3) Lactose 74
B(4) Hydroxypropyl cellulose 6
mg(5) water 0,0
2〆Total 150 mg Among the above compositions, (1), (2), (3) and (4) were mixed, water was added thereto, kneaded, and then heated to 40°C.
The mixture was vacuum dried for 16 hours, ground in a mortar, and passed through a 16-mesh sieve to form granules. The granules were filled into gelatin No. 3 capsules using a capsule filling machine (manufactured by Xanaci, Italy) to produce capsules.

Formulation Example 4 (1) Compound (compound obtained in Example 16) 5 mg (
2) Sodium salicylate 50 mg
(3) Sodium chloride 180 m
g(4) Sodium metabisulfite 20
mg(5) Methyl-paraben 36
mg(6) Propifure Paraben 4
sg(7) Distilled water for injection (
2d) Total 295 mg Among the above compositions, (2), (3), (4), (5) and (6) are dissolved in about half of the above amount of distilled water at 80°C with stirring. The resulting solution is cooled to 40°C, and the compound of the present invention is dissolved in the solution. The solution is then adjusted to the final volume by adding distilled water for injection and sterilized by sterile filtration using a suitable filter paper.
Prepared injections.

Since the compound (1) of the present invention has an excellent bone resorption inhibitory effect, it is useful for preventing and treating skeletal dislocation in mammals.

Claims (4)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent hydrogen, halogen, optionally substituted alkyl, or optionally substituted hydroxyl group. Alternatively, it represents acyl, or adjacent R^1 and R^2 are connected to each other to form the formula -(CH_
2) Forming a ring represented by the formula _m- [in the formula, m represents an integer of 3 to 5] or the formula -O-(CH_2)_n-O- [in the formula, n represents an integer of 1 to 3] R
^3 is hydrogen, alkyl or aralkyl, R^4 is hydrogen or an optionally substituted hydrocarbon residue, R^
5 represents hydrogen, an optionally substituted hydrocarbon residue or a heterocyclic group, or R^4 and R
^5 may be linked to each other to form a ring represented by the formula -(CH_2)_k- [wherein k represents an integer of 3 to 5]] or a salt thereof. (2) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent hydrogen, halogen, optionally substituted alkyl, or optionally substituted hydroxyl group. Alternatively, it represents acyl, or adjacent R^1 and R^2 are connected to each other to form the formula -(CH_
2) Forming a ring represented by the formula _m- [in the formula, m represents an integer of 3 to 5] or the formula -O-(CH_2)_n-O- [in the formula, n represents an integer of 1 to 3] R
^3 is hydrogen, alkyl or aralkyl, R^4 is hydrogen or an optionally substituted hydrocarbon residue, R^
5 represents hydrogen, an optionally substituted hydrocarbon residue or a heterocyclic group, or R^4 and R
^5 may be linked to each other to form a ring represented by the formula -(CH_2)_k- [wherein k represents an integer of 3 to 5]] is subjected to a condensation ring-closing reaction. General formulas characterized by the addition of formulas ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^1, R^2, R^3, R^4 and R^5
has the same meaning as above. ] A method for producing a compound represented by or a salt thereof. (3) A prophylactic and therapeutic agent for osteoporosis comprising the compound of claim 1 or a salt thereof. (4) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 and R^2 are the same or different and represent hydrogen, halogen, optionally substituted alkyl, or optionally substituted hydroxyl group. Alternatively, it represents acyl, or adjacent R^1 and R^2 are connected to each other to form the formula -(CH_
2) Forming a ring represented by the formula _m- [in the formula, m represents an integer of 3 to 5] or the formula -O-(CH_2)_n-O- [in the formula, n represents an integer of 1 to 3] R
^3 is hydrogen, alkyl or aralkyl, R^4 is hydrogen or an optionally substituted hydrocarbon residue, R^
5 represents hydrogen, an optionally substituted hydrocarbon residue or a heterocyclic group, or R^4 and R
^5 may be connected to each other to form a ring represented by the formula -(CH_2)_k- [wherein k represents an integer of 3 to 5]. l represents 1 or 2. ] A preventive and therapeutic agent for osteoporosis comprising a compound represented by or a salt thereof.