JPH01238529A - Osteoporosis preventing and treating agent - Google Patents

Abstract

PURPOSE:To provide the subject preventing and treating agent directly acting to bones to exhibit an excellent bone absorption-inhibiting action, by containing a specific 1,2,4-benzothiadiazine derivative. CONSTITUTION:The agent contains a compound of the formula [R<1> and R<2> are H, halogen, (substituted) alkyl, (substituted) OH or acyl or the adjacent R<1> and R<2> are combined to form -(CH2)m)- (m is 3-5) or -O-(CH2)n-O- (n is 1-3); R<3> is H, alkyl or aralkyl; R<4> is H or alkyl, aralkyl, aromatic group or carbon ring group which may be substituted], e.g., 8-chloro-2methyl-1,2,4- benzothiadiazine-3(4H)-one, as an active ingredient. The compound is administered in a dose of 10mg-1g, preferably 10-100mg, per day for an adult orally or 0.1-100mg, preferably 0.1-10mg, parenterally.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to a preventive and therapeutic agent for osteoporosis containing a 1,2,4-benzothiadiazine derivative.

BACKGROUND OF THE INVENTION Osteoporosis is a pathological condition or disease in which the quantitative loss of bone exceeds a certain level, causing some symptoms or dangers. The main symptoms are vertebral kyphosis, fractures of the lumbar spine, vertebral body, 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 are being 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 to Solve the Problems The present inventors conducted extensive 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 formula ([) 1, 2.4 expressed as
- It was discovered that benzothiadiazine derivatives act directly on bones and exhibit excellent bone resorption inhibitory effects, and the present invention was completed.

That is, the present invention General formula (1) %formula% [In the formula, R1 and R2 are the same or different and are hydrogen.

It represents a halogen atom, an optionally substituted lower alkyl, an optionally substituted hydroxyl group, or a lower acyl, or when adjacent R1 and R1 are connected to each other and the formula +
CHffi)-[in the formula, m represents an integer of 3 to 5] or formula -〇-GCH, Io-E, in the formula, n represents an integer of 1 to 3]. R3 represents hydrogen, lower alkyl or aralkyl, and R4 represents hydrogen or an optionally substituted alkyl, aralkyl, alkenyl, aromatic or heterocyclic group. ]
The present invention relates to a preventive and therapeutic agent for osteoporosis containing the compound represented by or a salt thereof.

In the formula (1), examples of halogen represented by R1 or 'R1 include fluorine, chlorine, bromine and iodine, with chlorine being particularly preferred.

The lower alkyl in the optionally substituted lower alkyl represented by R1 or Rt preferably has 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, and isobutyl.

Examples include 5ec-butyl, tert-butyl, pentyl, inpentyl, neopentyl, hexyl, and the like.

Examples of the optionally substituted hydroxyl group represented by R1 or R2 include a hydroxyl group and a suitable substituent on the hydroxyl group, such as alkoxy, aralkyloxy, acyloxy, etc. . The alkoxy has 1 to 6 carbon atoms.
lower alkoxy (e.g., methoxy, ethoxy, propoxy, impropoxy, butoxy, imbutoxy, 5e
e-butoxy.

tert-butoxy, pentoxy, isopentoxy, neopentoxy, hexyloxy, etc.) are preferred.

As the aralkyloxy, for example, phenyl-C1
-, alkyloxy (eg, benzyloxy, phenethyloxy, etc.). As the acyloxy,
Alkanoyloxy having 2 to 4 carbon atoms (e.g. acetyloxy, propionyloxy, n-butyryloxy, 1
so-butyryloxy, etc.) are preferred.

The lower acyl represented by R' or R' is formyl or a group having 1 to 6 carbon atoms as described above for R' or R''.
A combination of an alkyl group and a carbonyl group (e.g., acetyl, propionyl, butyryl, imbuf'),
ttleryl, invaleryl, pivaloyl, etc.).

When R1 and R1 are adjacent to each other, R1 and Rt
are connected to -(CHt')- or -0-GCH-
It may form a ring represented by 0- (such rings include 5- to 7-membered rings formed with carbon atoms of a benzene ring. In these rings, m is 3 or 4, and 5- to 6-membered rings ring, and a 5- to 6-membered ring in which n is 1 or 2 are preferred.

The lower alkyl represented by R3 preferably has 1 to 6 carbon atoms as described above for R1 and R1.

As the aralkyl represented by R3, phenyl-CI-4 alkyl such as benzyl and phenethyl is preferred.

The alkyl in the optionally substituted alkyl represented by R4 may be linear, 9-branched, or cyclic having 1 to 10 carbon atoms, and examples thereof include C0-8 alkyl described for R1 and Rt. Additionally, examples include heptyl, octyl, nonyl, decyl, cyclopropyl, cyclobutyl, cyclobentyl, cyclohexyl, and the like.

Examples of the aralkyl in the optionally substituted aralkyl represented by R4 include those similar to the aralkyl represented by R3.

Examples of the aromatic group in the optionally substituted aromatic group represented by R' include phenyl.

C11 such as naphthyl, anthryl and phenanthryl
-14 aryl is mentioned.

The heterocycle in the optionally substituted heterocycle represented by R4 is, for example, one sulfur atom.

A 5- to 7-membered chlorine ring containing a nitrogen atom or an oxygen atom.

5-6 membered heterocycle containing 2 to 4 nitrogen atoms, 5 containing 1 to 2 nitrogen atoms and 1 sulfur or oxygen atom
to 6-membered chlorinated rings; these heterocycles may be fused with a 6-membered ring containing up to 2 nitrogen atoms, a benzene ring or a 5-membered ring containing one sulfur atom.

Specific examples of the above heterocycle include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, thiazolyl, inthiazolyl, oxasilyl, inxazolyl, pyrido[2,3-d] Pyrimidyl, benzopyranyl, 1,8-naphthyridyl, 1,5-naphthyridyl, 1,
6-naphthyridyl, ■, 7-naphthyridyl, 2,7-naphthyridyl, 2,6-naphthyridyl, quinolyl, cheno[2,3-b]pyridyl, tetrazolyl, thiadiazolyl, oxadiazolyl.

Triazinyl, triazolyl, thienyl, pyrrolyl.

pyrrolinyl, furyl, pyrrolidinyl, benzothienyl,
Examples include indolyl, imidazolidinyl, piperidyl, piperidino, piperazinyl, morpholinyl, morpholino, and the like.

The alkenyl in the optionally substituted alkenyl represented by R4 preferably has 2 to 6 carbon atoms,
Examples are allyl, vinyl.

Crotyl, 2-penten-1-yl, 3-penten-1
-yl, 2-hexen-1-yl, 3-hexene-1-yl
yl, 2-cyclohecymonyl. 2-cyclopentenyl,
2-methyl-2-propen-1-yl, 3-methyl-2
-buten-1-yl and the like.

Examples of the substituent in the optionally substituted alkyl represented by R1 or R'' 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 lower alkyl substituted for R+ and R' include, for example, trifluoromethyl.

Trifluoroethyl, difluoromethyl, trichloromethyl, hydroxymethyl, ■-hydroxyethyl, 2-
hydroxyethyl, methoxymethyl, ethoxymethyl,
(1)-Methoxyethyl, 2-methoxyethyl, 2-ethoxymethyl, 2,2-dimethoxyethyl, 2,2-jethoxyethyl and the like.

Examples of the substituent on the optionally substituted alkyl represented by R4 include halogen (e.g., fluorine, chlorine, bromine, trivalent, etc.), hydroxyl group, alkoxy having 1 to 6 carbon atoms, and alkoxy having 1 to 6 carbon atoms. Amino optionally substituted with alkyl or acyl having 1 to 10 carbon atoms (e.g., dimethylamino, diethylamino, dipropylamino, acetylamino, propionylamino, benzoylamino, etc.), substituted with alkyl having 1 to 6 carbon atoms carbamoyl (e.g., dimethylcarbamoyl, diethylcarbamoyl, dipropylcarbamoyl, etc.), alkoxycarbonyl having 1 to 6 carbon atoms (e.g., methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, etc.), the above-mentioned heterocycles, etc. It will be done. Specific examples of alkyl substituted for R4 include trifluoromethyl, trifluoroethyl, difluoromethyl, trichloromethyl,
2-Hydroxyethyl.

2-methoxyethyl, 2-ethoxymethyl, 2,2-simethoxyethyl, 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-diisopropylamine)ethyl, 5-(N,N-dimethylamine)pentyl, N,N-diethylcarbamoylmethyl, N,N-
Dimethylcarbamoylethyl, N,N-dimethylcarbamoylpentyl, ethoxycarbonylmethyl, impropoxycarbonylethyl.

Examples include tert-butoxycarbonylprobyl.

Examples of the substituent on the optionally substituted aralkyl, aromatic group, and heterocycle represented by R4 include halogen (eg, fluorine, chlorine, bromine, iodine, etc.).

Alkoxy having 1-6 carbon atoms, alkyl having 1-6 carbon atoms,
Cl-8 alkyl halide (e.g., trifluoromethyl, difluoromethyl, 2,2,2-)lifluoroethyl, 2,2,2-trichloroethyl, etc.), carbon number 1-6
Amino optionally substituted with alkyl or acyl having 1 to 10 carbon atoms (e.g., methylamino, dimethylamino, diethylamino, dibutylamino, acetylamino,
propionylamino, 'benzoylamino, etc.), C,
Phosphoryl or phosphoryl-C+-s alkyl optionally substituted with alkoxy (e.g., jetoxyphosphoryl, jetoxyphosphorylmethyl, etc.), aromatic groups similar to those described above (however, they may be substituted with halogen). Examples include.

Regarding R4, specific examples of substituted aralkyl include 4-chlorobenzyl, 3-(2-fluorophenyl)propyl, 3-methoxybenzyl, 3.4-dimethoxyphenethyl, 4-ethylbenzyl, 3.4- dimethylphenethyl, 3-trifluoromethylbenzyl,
4-(3-trifluorophenyl)butyl, 4-acetylaminobenzyl.

Examples include 2-propionylaminophenethyl.

Specific examples of substituted aromatic groups for R" 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 and 4-jethoxyphosphorylmethylphenyl.

Specific examples of substituted heterocycles for R4 include 5-chloro-2-pyridyl, 3-methoxy-2-
Pyridyl, 5-methyl-2-benzothiazolyl, 5-methyl-4-phenyl-2-thiazolyl, 3-phenyl-
5-Inoxacylyl.

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-furanyl, 4-methyl-2-morpholinyl, and the like.

Examples of the substituent for the optionally substituted alkenyl represented by R4 include the same substituents as for the optionally substituted alkyl represented by R4.

For R4, substituted alkenyl group (11 is 2,2-difluorovinyl, 4-ethoxycrotyl,
1-cyclohexenylmethyl, 3-cyclohexyl-2
-Buten-1-yl, 4-(2-pyridyl)-2-buten-1-yl, 4-(N,N-diethylamino)crotyl, 3-(5-methyl-2-phenyl-4-oxacylyl)- Examples include 2-propen-1-yl, 4-(N,N-dimethylcarbamoyl)crotyl, and the like.

In the above compound (I), when R4 is methyl, ethyl or benzyl, the compound in which at least one of R', R- and R3 is substituted is a new compound.

The above compound (1) can be produced, for example, as follows.

That is, method A can be obtained by heating the compound represented by the general formula R3 [wherein R', R", R" and R4 have the same meanings as above] in a suitable solvent or without a solvent. . Examples of such solvents include methanol, ethanol, propatool, and 2-propateol.

Alcohols such as butanol and 2-methoxyethanol, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, aromatic hydrocarbons such as benzene, toluene and xylene, and ethyl acetate.

Acetonitrile, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, chloroform.

Dichloromethane, l, 2-dichloroethane, l, 1゜2
．． Examples include 2-tetrachloroethane or a mixed solvent thereof. This reaction can also be carried out in the presence of an appropriate base such as potassium carbonate, triethylamine, N-methylmorpholine, N,N-dimethylaminopyridine, N,N-dimethylaniline, pyridine, and the like. The amount of base used is 0.1 to 1 mole of compound (n).
It is preferably about 10 mol. The reaction temperature is in each case about 10°C to about 200°C, preferably about 0°C to about 150°C.
°C, and the reaction time is usually about 0.5 to 100 hours.
Preferably it is about 2 to 20 hours.

In Danko's method, a compound obtained by using a compound (II-1) in which R4 of compound (II) is hydrogen in method A (
b) R' [wherein R1, R4 and R3 have the same meanings as above; X represents a leaving group] A compound represented by [[] can be obtained by reacting the compound represented by Examples of the leaving group represented by Certain arylsulfonyloxy groups (e.g. p
-toluenesulfonyloxy group, benzenesulfonyloxy group), alkylsulfonyloxy group having 1 to 4 carbon atoms (e.g. methanesulfonyloxy group), diphenylphosphoryloxy group which is a residue of organic phosphoric acid, cybenzylphos Examples thereof include a fluoryloxy group, a dialkylphosphoryloxy group having 1 to 4 carbon atoms (eg, a dimethylphosphoryloxy group), and the like. This reaction is carried out in an organic solvent in the presence of a base.

The solvent may vary depending on the type of base used, but for example alcohols such as methanol and ethanol, ethers such as tetrahydrofuran, dioxane, dimethoxyethane and diethyl ether, N,N-dimethylformamide, dimethyl sulfoxide, etc. can be used as appropriate. can. Examples of the base include potassium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium methoxide, sodium ethoxide, potassium t-butoxide,
Sodium hydride, potassium hydride, sodium amide, etc. are used. In this reaction, it is preferable to first react compound (■') with a base in a solvent to form an anion, and then react with compound (I[[). The reaction temperature is usually about -10°C to about 100°C, preferably about O'
C to about 40° C., and the reaction time is usually about 0.5 to 10 hours, preferably about 1 to 5 hours.

In this method, in method A, compound (II-2) in which R3 is hydrogen in compound (n) is used, or in method B, compound (1') in which R3 is hydrogen in compound (do) is used.
-1) A compound of the following formula (do') [wherein R', R' and R4 have the same meanings as above and a compound represented by 1 and the formula % formula % () 1 in the formula, R" represents lower alkyl or aralkyl,
X has the same meaning as above. ] Compound (I
V). R3
The lower alkyl and aralkyl represented by / are the above-mentioned R3
Examples include those similar to those shown in . This reaction can be carried out under exactly the same conditions as the reaction of compound (1') and compound ([II) in Method B.

The 1,2,4-benzothiadiazine 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.

The starting compound (II) of the present invention can be produced, for example, by the method shown in Method D below.

(White space below) に (■) (■) (IX) ↑ R3R3 (■) [In the formula, R1-R4 and X have the same meanings as above] In this magazine, (V) is first expressed as allyl. (■
), and then reacted with isocyanates (■) to obtain ureido derivative (IX), which was reacted with (X) and then oxidized to produce ([1)]. The reaction between (V) and (Vl) 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 propatool, ethyl acetate, acetonitrile, pyridine, N, N- Dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-
Examples include dichloromethane, 1,1,2,2-tetrachloroethane, water, and mixed solvents thereof.

Examples of the base include alkali metal salts such as sodium hydroxide, potassium hydroxide, potassium carbonate, and sodium carbonate, and amines such as pyridine, triethylamine, and N,N-dimethylaniline.

This reaction is usually carried out at about -10 to 150°C, preferably about 0 to 150°C.
Performed at 50°C.

The reaction between (■) and incyanates (■) 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, methanol,
Alcohols such as ethanol and furopanol, ethyl acetate, acetonitrile, pyridine, N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1,2-dichloromethane, 1,1,2.
2=tetrachloroethane; Examples include acetic acid, water, or a mixed solvent thereof. This reaction is usually about -10°C to 15°C.
0°C1 preferably about 0.5 at about 20'C to 100°C
The reaction is carried out for ~20 hours.

The obtained (IX) is then reacted with compound (X) to produce (XI). This reaction step can be carried out in exactly the same manner as the reaction of compound (do) and compound (III) in Method B.

Furthermore, (XI) is oxidized to produce compound (II).

This oxidation reaction is carried out according to a conventional method using an oxidizing agent such as m-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 (e.g. methylene chloride, chloroform, dichloroethane, etc.) or hydrocarbons (e.g.
benzene, toluene, etc.), alcohols (methanol,
(ethanol, propatool, etc.). If hydrogen peroxide is used as the oxidizing agent, the oxidation can also be carried out in acetic acid, aqueous acetic acid. It is preferable to use the oxidizing agent in a slightly excessive amount. This reaction is carried out at room temperature or lower, preferably at a temperature of about -50°C-to'C, usually for about 0.5 to 10 hours.

The ureido derivative (IX) can also be obtained by the following method.

(Left space below) Method E (XII) (XII [) In the actual procedure, first, a benzoic acid derivative (:ll) is converted into an isocyanate (XIII) by a normal Curtius rearrangement reaction.

This reaction may be carried out according to any known method, for example, New Experimental Chemistry Course, Volume 14, "Synthesis and Reaction of Organic Compounds [1]
] J (1978) or a similar method. For example, (XII) is converted into an acid chloride using oxalyl chloride or thionyl chloride, and then converted into an acid azide by reaction with sodium azide. Incyanates (Xn
l) is obtained. Then (XIII) was converted into amines (XI
V) to produce a ureido derivative (IX).

This reaction step consists of compound (■) and compound (■) in method D.
(It can be carried out in the same manner.)

Test results showing the pharmacological effects of compound (1) are shown below.

[Bone resorption inhibitory effect] Bone resorption effect is measured by Royce's method [Journal of
Clinical Investigation (J, Cl1n
, Invest, )44. 103-116 (196
5)]. That is, Sprag on the 19th day of pregnancy.
One ue-Dawley rat was subcutaneously injected with 50 μCi of Ca (calcium isotope, CaCL solution), the abdomen was opened the next day, the fetal rat was removed aseptically, and the left and right forearm bones ( The radius (1 ulna) was separated from the trunk, and connective tissue and cartilage were removed as much as possible to prepare a bone culture sample.
b medium (Fitton-Jackson mod
ification + [GIBCO Laborato
ries (USA)] containing bovine serum albumin, 2 mg/d) at 37°C for 24 hours, and then the compound obtained in the example described below was added to the above medium to give IO μg/d. After continuing the culture for two more days,
The radioactivity of "ca" in the medium and the radioactivity of 4SCa in the bone were measured, and the ratio (%) of 4SCa released from the bone into the medium was determined according to the following formula.

Counting of 45Ca in bones A control group consisted of bones obtained from fetuses from the same litter and similarly cultured for 2 days without the addition of the compound. The average principal standard deviation 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 the results are shown in Table 1.

1st Table 2 75.6 5 80.7 11 B8.5 14 70.7 21 54.9 22 71.4 23 55.7 27 59.4 31 63J 33 63.3 34 61.0 35 65.2 41 50.3 45 85.9 46 74.0 47 68.1 48 75.6 49 70.5 50 64.6 51 75.4 52 75.2 53 87.7 54 77.0 55 g3.3 Regarding the toxicity of (1), for example, Example No. 3. No, 4. No, 11 or No,
Even when the compound synthesized in step 12 was orally administered to mice at a rate of 300 mg/kg/body weight, no deaths were observed.

As described above, the compound (1) of the present invention has an excellent bone resorption inhibitory effect and low toxicity.

Therefore, the compound (1) of the present invention is suitable for mammals (e.g.
mice, rats, rabbits, dogs, cats, cows, pigs, humans, etc.)
It can be used for the prevention and treatment of osteoporosis.

In order to use the compound (1) of the present invention as a prophylactic or therapeutic agent for osteoporosis in mammals, for example, compound (1) may be mixed with a pharmacologically acceptable carrier, such as an excipient (e.g., lactose, starch, sucrose, etc.), disintegrants (e.g., starch, carboxymethyl cellulose calcium, etc.).

Mix appropriately with lubricants (e.g., magnesium stearate, talc, etc.), binders (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, macrogol, etc.), and form into dosage forms such as capsules, granules, and powders. It can be administered orally.

In addition, when administering parenterally, compound (1) may be added with additives commonly used in liquid preparations, such as buffers for pH adjustment (
phosphate buffers, borate buffers, citrate buffers, tartrate buffers, acetate buffers, etc.), tonicity agents (sorbitol, glycerin, polyethylene glycol, phlopylene gellicol, glucose, sodium chloride, etc.), preservatives Fungicide(
roseoxybenzoic acid esters, benzyl alcohol,
parachlormetaxinol, chlorcresol, phenethyl alcohol, sorbic acid or its salts, thimerosal, chlorobutanol, parabens, etc.), chelating agents (
(sodium edetate, sodium citrate, condensed sodium phosphate, etc.), thickening agents (carboxymethylcellulose, sodium, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, polyvinyl alcohol, sodium polyacrylate), etc., in the commonly used amounts. It may be prepared as an injection by blending the compound (1) with, for example, a triglyceride of a medium-chain or higher fatty acid, polyethylene glycol, etc. in a commonly used amount, followed by molding.

When administered orally, the dosage is usually about 10 mg to 1 g per adult per day, preferably about 10 mg.
~100 mg for adults 1 when administered parenterally.
Usually about 0.1 mg to 100 mg per person per day, preferably about 0.1 mg to 10 mg.

EXAMPLES 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-aminothiophenol (200g), 6NNa
Allylbromide (194 g) was added dropwise to a mixture of OH (267 m2) and MeOH (200 m) over 1 hour while cooling with water. After further stirring for 1.5 hours, water was added and the mixture was extracted with ether. After washing the ether layer with water and drying (MgSO,), the solvent was distilled off, and the residue was distilled under reduced pressure to yield 2-allylthioaniline (256.8 g).

97.1%). bp 108-114℃/4m
mHg, NMR (δ Ppm in CD CIs)
: 3.34 (2H, d.

J = 7), 4.33 (2H, br s), 4.8
-5.1 (2H, m), 5.6-6, 1 (18°a+
), 6.5-6.8 (211, m), 7.09 (i
ll, double t, j = 7.5and
2), 7.33 (LH, double d,
J=7.5 and 2) Reference Examples 2 to 9 Compounds shown in Table 2 were obtained in the same manner.

(Left below) Reference Example 10 2-allylthio-5-trifluoromethylaniline (1
,7g), phenyl isocyanate (1.1g).

The mixture of toluene (7d) was stirred for 2 hours. The solvent was distilled off under reduced pressure, and the remaining crystals were collected by filtration.

Recrystallization from isopropyl ether gave N-(2-allylthio-5-trifluoromethylphenyl)-N'-phenylurea as colorless crystals.

Yield 2.1 g (81.0%). mp135 136°C
Calculated value as 0 elemental analysis value C, 7H,, F, N, O5:
C, 57,95; H, 4,29; N, 7.95 Actual value: C, 58,07; H, 4,39; N, 7.88
Reference Examples 11-29 The compounds shown in Table 3 were obtained in the same manner as in Reference Example 10.

(Margin below) Reference Example 30 A solution of potassium cyanate (3.0 g) in water (10 d) was added dropwise to a solution of 2-allylthio-6-nitylaniline (6.0 g) in acetic acid (20, d) at 60°C. After stirring at the same temperature for 30 minutes, water was added and the precipitated crystals were collected by filtration. Ethyl acetate was recrystallized from beef starch to give N-(2-allylthio-
6-Nitylphenyl)urea was obtained as colorless crystals. Yield: 1 ton 5.8 g (79.0%).

Melting point: 163-164°C.

Elemental analysis value C,,H,,N,calculated value as OS:C,
6G, 99; H, 6,82; N, 11.85 Actual value: C, 61,07; H, 6,83; N, 11.91
Reference Examples 31-37 The compounds shown in Table 4 were obtained in the same manner as in Reference Example 30.

(Margin below) Reference Example 38 N-(2-allylthiophenyl)urea (3.12g)
Oily sodium hydride (0,
6 g) was added thereto, and the mixture was stirred for 15 minutes under water cooling and then for 15 minutes at room temperature. Cooled with water again and diluted with methyl iodide (0,9331
! 12) was added and stirred for 1.5 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 purified by column chromatography [silica gel (100 g), eluted with ethyl acetate]. N-(2-allylthiophenyl)-N-methylurea was obtained as an oil. Yield 2.8
4g (85,3%). NMR (δppm in CD
Cl5): 3.17 (3■, s), 3.56 (2
H, d, J = 6.5Hz), 4.38 (2H,
br s), 5.03-5.40 (a+.

28), 5.66-6, 20(a+, LH), 7
．． 17-7, 47 (a, 4■) I R (neat):
3476.3320.3200.1660 am'
Elemental analysis value C, , H, , N, calculated value as OS: C, 5
9,43; H, 6,35; N, 12.60 Actual value:
C, 59,22; H, 6,42; N, 12.45 Reference Example 39 N-(2-allylthiophenyl)-N-benzylurea was obtained in the same manner as in Reference Example 38. Yield 69.4%. Recrystallized from ethyl acetate-hexane.

Colorless plate crystals. mp, 111-112°C.

Elemental analysis value C,,H,,N,calculated value as OS:C,
68,43; H, 6,08; N, 9.39 Actual value:
C, 68,73; H, 6,13; N, 9.45 Reference Example 4O ) A solution of m-chloroperbenzoic acid (80% content, 0.39 g) in chloroform (63!) under water cooling.
12) The solution was added dropwise. The reaction solution was washed with a saturated aqueous sodium bicarbonate solution and water in that order, and then dried. The solvent was distilled off and the residue was subjected to column chromatography [silica gel (30 g)].
2-(allylsulfinyl-5-trifluoromethylphenyl)
Colorless needle crystals of -N'-tert-butylurea were obtained. Yield: 0.59g (94.0%). mp, 1
13 114℃.

Calculated values for elemental analysis values C, H, F, N, O, S: C, 51,7t; H, 5,50; N, 8.04
Actual value: C, 51,75; H, 5,55; N, 1.
98 Reference Examples 41-68 The compounds shown in Table 5 were obtained in the same manner as in Reference Example 40.

(Left below) Reference Example 75 2-allylthiobenzoic acid (9.2g) in THF (50d
To the solution, oxalyl chloride (7.2 g) was added, followed by DMF (1 drop), and the mixture was stirred at room temperature for 2 hours. The solvent was distilled off, the residue was dissolved in acetone (15d), and sodium azide (4.6g) was dissolved in water (15d).
It was added dropwise to the solution at 13-15°C. After stirring for 1 hour, the mixture was extracted with benzene (20dX3).

The benzene extract layer was washed with water, dried (MgSO,), and then heated at 65°C.
I stirred it for an hour. The solvent was distilled off, and the residue was distilled under reduced pressure to obtain 2-allylthiophenyl isocyanate as a colorless oil (7.2 g, 80%).

bp98°C/0, 7 mmHg NMR (δppm in CDC13) + 3.
88 (2H, d, J=7.5fiz), 4.85~5
．． 15 (2H, m), 5.6-6.1 (IH, m),
6.9-7.5 (4H, m) IR (neat): 2270.2220.158
0.1500.920.755 (cIll-') Reference Example 76 2-allylthiophenyl isocyanate (0.96g)
and diethyl p-aminobenzylphosphonate (1,
2g) was dissolved in toluene (5m) and heated under reflux for 30 minutes. The reaction mixture was cooled with water, hexane was added, and the precipitated crystals were collected by filtration. Recrystallized from ethyl acetate to give diethyl 4-
[3-(2-allylthiophenyl)ureido]benzylphosphonate (2°Og, 91%) was obtained as colorless prismatic crystals.

mpH7118°C Elemental analysis value C,,H! , N, O, PS as:
C, 5g, 05; H, 6,26, N, 6.45 Actual value: C, 57,94, H, 6,23; N, 6.61 Reference Example 77 Diethyl 4- [3-(2-allylthiophenyl)ureido]phenylphosphonate was obtained. Yield 83%. mp133-134°C (ethyl acetate-hexane) Elemental analysis value C2°H,, N, O, PS Calculated value:
C, 57,13, H, 5,99; N, 6.66 Actual value: C, 57,25; H, 5,96; N, 6.52
Example I Method A: N-(2-allylsulfinyl-3-chlorophenyl)-N'-methylurea (1,93 g), 4-
A mixture of dimethylaminopyridine (0.86 g) and chloroform (20d) was heated under reflux for 13.5 hours. The reaction mixture was concentrated and the residue was subjected to column chromatography [
Carrier: 100 g of silica gel, ethyl acetate-hexane (
1:2) elution] and purified with 8-chloro-2-methyl-1
, 2,4-benzothiadiazin-3(4H)-one crystals were obtained. Recrystallized from ethyl acetate-hexane. Colorless needle crystals. mp, 165-166°C0 yield 1.03g (yield 67°8%).

Calculated value as elemental analysis value C, H, CIN, O8: C, 4
4,76; H, 3,29; N, 13.05 Actual value:
C, 44,75; H, 3,21, N, 13.19 Example 2 Method B 6-trifluoromethyl-1,2,4-benzothiadiazin-3(4H)-one (1,17 g) N.

Oily sodium hydride (60%, 0.2 g) was added to the N-dimethylformamide (DMFX6t12) solution under water cooling, and the mixture was stirred for tlo minutes. Then, 2-bromoethylbenzene (0.92 g) was added, and the mixture was stirred at room temperature for 5.5 hours, and the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO), and the solvent was distilled off. The residue was purified by silica gel column chromatography [elution with ethyl acetate-hexane (1:2) and 2-phenethyl-6-trifluoromethyl-1,2,4-benzothiadiazine-3(4H) -:t I got a crystal.

Recrystallized from isopropyl ether-hexane. Colorless plate crystals. mp.

152-153℃. Yield 838 mg (49.6%).

Elemental analysis value C,, H, 3F3N, OS and shite calculation value: C
, 56,80; H, 3,87; N, 8.28 Actual value: C, 56,72; H, 3,87, N, 8.26 Examples 3 to 41 Same as Examples 1 and 2 The compounds shown in Table 6 were obtained.

Example 58 Composition in one tablet (1) Compound A (compound obtained in Example 1) 50 mg
(2) Cornstarch 30
mg(3) lactose
113.4mg (4) Hydroxypropylcellulose
6 mg (5) water
(0,03a11) Among the above compositions, (1
), (2), (3) and (4) were mixed, water was added thereto for kneading, the mixture was vacuum dried at 40°C for 216 hours, ground in a mortar, and passed through a 16-mesh sieve to form granules. (6) was added to the granules and mixed, and tablets of 200 mg each were manufactured using a rotary tablet press (manufactured by Kikusui Seisakusho).

Example 59 (1) Compound B (compound obtained in Example 23) 5
0 B (2) Cornstarch
30 mg (3) lactose
113.4mg (4) Hydroxycellulose
6 mg (5) water
(0,03d) (6) Magnesium stearate 0.6 mg (7) Cellulose acetate phthalate to sag (8
) acetone (o, 2d
) Total 210 sag Among the above compositions, (1), (2), (3), (4),
Tablets were produced in the same manner as in Example 42 using (5) and (6). These tablets were film-coated with the a7tone solution (7) using a bar coater (manufactured by Freund) to produce enteric-coated tablets containing 210 mg per tablet.

Example 60 Composition in capsule (1) Compound C (compound obtained in Example 20) 3
0 mg (2) cornstarch
40 Ilg(3) Lactose
74-g (4) Hydroxypropylcellulose 6 mg (5) Water
(0,02m) total 150 mg Among the above compositions, (1), (2), (3) and (4)
After mixing, adding water and kneading, 40℃, 1
The mixture was vacuum dried for 6 hours, crushed 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.

Example 61 (1) Compound D (compound obtained in Example 11) 5 mg
(2) Sodium salicylate 50
mg(3) sodium chloride
180 mg (4) Sodium Metabisulfite
20 mg (5) Methyl-paraben
36 mg (6) Propyl-paraben 4 mg (7) Distilled water for injection
(2, OJ!12) Total 295
B Of the above compositions, (2), (3), (4), (5) and (6) are dissolved in about half the amount of distilled water above at 80° C. with stirring. The resulting solution is cooled to 40° C. and compound (D) is dissolved in the solution. The solution was then adjusted to the final volume by adding water for injection and filtered through a sterile filter.
An injection was prepared by sterile filtration using Delapore (manufactured by Millipore Filters).

Effects of the Invention The compound (1) of the present invention has an excellent bone resorption inhibitory effect and is therefore useful as an agent for preventing and treating osteoporosis in mammals.

Claims (1)

[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, a halogen atom, an optionally substituted lower alkyl,
Indicates an optionally substituted hydroxyl group or lower acyl, or adjacent R^1 and R^2 are connected to each other to form the formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, m is 3
[indicates an integer from 1 to 3] or the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. In lower alkyl or aralkyl, R^4 represents hydrogen or an optionally substituted alkyl, aralkyl, alkenyl, aromatic or heterocyclic group. ] A preventive and therapeutic agent for osteoporosis comprising a compound represented by or a salt thereof.