JPH0729921B2 - Osteoporosis treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] 2-phenyl-4H-1-benzopyran represented by the formula (R ¹ , R ² and R ³ may be the same or different and each is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms). The present invention provides a therapeutic agent for osteoporosis containing a 4--4-one derivative or a pharmacologically acceptable salt thereof.

[Conventional technology]

Osteoporosis refers to a pathological condition in which bone mass is reduced without changing the chemical composition of bone, and its physiological characteristic is a decrease in bone protein, calcium and phosphorus.

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

There are various causes of this osteoporosis such as endocrine and nutritional disorders, and vitamin D preparations, calcium preparations, calcitonin preparations, phosphorus preparations, etc. are used as therapeutic agents, but their effects are not certain, so more effective There is a strong demand for the development of various formulations.

In recent years, a certain 3
It has been reported that a -phenyl-4H-1-benzopyran-4-one derivative (isoflavone derivative) has a bone resorption inhibiting effect and is useful as a therapeutic agent for osteoporosis (Japanese Patent Publication No. 54-13391). Sho-60-48924, JP-A-60-
54379, JP-A-60-132917, JP-A-60-132976
issue).

However, the 2-phenyl-4H-1-benzopyran-4-one derivative (flavone derivative) of the present invention or a pharmacologically acceptable salt thereof exhibits a bone resorption inhibitory action,
It has never been reported to be useful as a therapeutic agent for osteoporosis.

[Problems to be solved by the invention]

3-phenyl-4H-1-disclosed in said patent application
Benzopyran-4-one derivative (isoflavone derivative)
Has a weak effect on suppressing bone resorption, and is never satisfactory as a therapeutic agent for osteoporosis. Therefore, the present inventors diligently studied the bone resorption inhibitory effect of benzopyran-4-one derivatives, and found that certain 2-phenyl-4H-1-benzopyran-4-one derivatives (flavone derivatives) or their drugs It has been found that a physically acceptable salt has a strong bone resorption inhibitory action and also an osteogenesis promoting action, and can be a more excellent therapeutic agent for osteoporosis.

The present invention is based on these findings.

[Means for solving problems]

2-phenyl-4H represented by the general formula (I) of the present invention
The -1-benzopyran-4-one derivative (flavone derivative) or a pharmacologically acceptable salt thereof exhibits a strong bone resorption inhibitory action and a bone formation promoting action, and is useful as a highly safe therapeutic agent for osteoporosis.

2-phenyl-4H represented by the general formula (I) of the present invention
The -1-benzopyran-4-one derivative is a known compound, and can be produced according to the method described in the literature or a method similar thereto. For example, Organic Synthesis Collective Volume IV, pages 478-481 (Org.Sy
n.Coll.Vol.IV, 478-481); Proceedings of the Indian Academy of Sciences (Proc.Indian Acad.Sci.) 23A, 134 pages, (1946
Year) or the like or a similar method.

That is, 2-phenyl-represented by the general formula (I)
The 4H-1-benzopyran-4-one derivative has the general formula (Wherein R ¹ , R ² and R ³ have the same meanings as described above), the acetophenone derivative is reacted with benzoyl chloride to give a compound of the general formula (R ⁴ , R ⁵ and R ⁶ in the formula are benzoyl groups or 1 carbon atoms
A benzoyloxyacetophenone derivative represented by the formula (3) is an alkyl group of 3 to 3), and is then subjected to Baker Venkataraman rearrangeme
nt) (Wherein R ⁴ , R ⁵ and R ⁶ have the same meanings as described above) to obtain a dibenzoylmethane derivative, which is then dehydrated and ring-closed in the presence of sodium acetate in acetic acid and hydrolyzed if necessary. It can be manufactured.

2-phenyl-4H represented by the general formula (I) of the present invention
-1-benzopyran-4-one derivative with R ¹ , R ² and R ³
A compound in which a part or all of is a hydrogen atom is a compound in which a part or all of R ¹ , R ² and R ³ is a lower alkyl group is an acid such as acetic acid or acetic anhydride in hydroiodic acid or hydrogen bromide. It can also be produced by dealkylation in the presence of an acid.

In the 2-phenyl-4H-1-benzopyran-4-one derivative represented by the general formula (I) of the present invention, all of R ¹ , R ² and R ³ are alkyl groups having 1 to 3 carbon atoms. Certain compounds include 2-phenyl-4H-1-benzopyran-4 of the present invention wherein at least one of R ¹ , R ² and R ³ is a hydrogen atom.
It can also be produced by reacting a -one derivative with an alkyl halide.

In this production method, the acetophenone derivative represented by the general formula (II) used as a raw material is a known compound, and the method described in the literature, for example, Journal of the
Chemical Society 1941 , 662 pages (JCS 1941 , 66
2) It can be manufactured according to the method described or a method similar thereto.

2-phenyl-4H represented by the general formula (I) of the present invention
-1-benzopyran-4-one derivative, wherein R ¹ , R ² and
The compound in which at least one of R ³ is a hydrogen atom can be converted into a pharmaceutically acceptable salt according to a conventional method.
For example, the 2-phenyl-4H-1-benzopyran-4-one derivative represented by the general formula (I) of the present invention is added to an alcohol solution in which an equivalent amount of sodium hydroxide is dissolved,
After heating, it can be converted to a sodium salt by concentrating under reduced pressure.

2-phenyl-4H represented by the general formula (I) of the present invention
The -1-benzopyran-4-one derivative can be made into a pharmaceutical preparation according to a conventional method. That is, excipients, disintegrators, binders, lubricants and other commonly used pharmaceutical additives are mixed and prepared according to a conventional method to prepare various preparations such as tablets, powders and capsules.

2-phenyl-4H represented by the general formula (I) of the present invention
When the -1-benzopyran-4-one derivative is used as a therapeutic agent for osteoporosis, about 10 to 1000 mg per day for an adult is made into an appropriate dosage form, such as tablets, powders, capsules, etc., and orally administered, or about 1 day per adult. 1 to 100 mg is parenterally administered as an injection or the like.

2-phenyl-4H represented by the general formula (I) of the present invention
The -1-benzopyran-4-one derivative or a pharmacologically acceptable salt thereof exhibits a strong bone resorption inhibitory action and an osteogenesis promoting action in an in vitro experiment using a chicken embryo femur, and a calcium-deficient diet It has an effect of remarkably suppressing the decrease in the calcium and phosphorus contents in the bones of the rat that occurs when given, and is useful as a highly safe therapeutic agent for osteoporosis.

〔Example〕

The following examples are given to further illustrate the present invention.
The melting points of the compounds in the examples are uncorrected.

Example 1 2-Phenyl-6,7,8-trimethoxy-4H-1-benzopyran-4-one (a) 2-benzoyloxy-3,4,5-trimethoxyacetophenone 2-hydroxy-3,4, 3.2 g of 5-trimethoxyacetophenone is dissolved in 15 ml of dry pyridine, 2.6 ml of benzoyl chloride is added dropwise to this solution with stirring at room temperature, and the mixture is stirred for about 10 minutes and then heated for about 20 minutes. After cooling the reaction solution, a small amount of ice water is added to the reaction solution, and diluted hydrochloric acid is added to make it weakly acidic. The precipitated crystals are collected by filtration, washed with dilute hydrochloric acid and then with water, and then dissolved in chloroform. The chloroform solution is concentrated under reduced pressure. The residue is dissolved in 10 ml of methanol, and after cooling, the precipitated crystals are collected by filtration to obtain 4.0 g of crude 2-benzoyloxy-3,4,5-trimethoxyacetophenone.

Melting point: 117-124 ° C. (b) 2-Hydroxy-3,4,5-trimethoxydibenzoylmethane Crude 2-benzoyloxy-3,4,5 obtained in (a) above.
4.0 g of trimethoxyacetophenone are dissolved in 50 ml of dry N, N-dimethylformamide, to which 0.8 g of 55% sodium hydride (oily) is added in small portions under cooling. After stirring at room temperature for 3 hours, the reaction solution is poured into 200 ml of ice water and diluted hydrochloric acid is added to make it weakly acidic. The precipitated oil is extracted with diethyl ether. The ether solution is extracted with 10% aqueous sodium hydroxide solution, and the aqueous layer is acidified with dilute hydrochloric acid under cooling. This acidic solution was extracted with ether, the ether layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 3.5 g of oily 2-hydroxy-3,4,5-trimethoxydibenzoylmethane.

(C) 2-phenyl-6,7,8-trimethoxy-4H-1
-Benzopyran-4-one oily 2-hydroxy-3,4, obtained in (b) above
A mixture of 3.5 g of 5-trimethoxydibenzoylmethane, 15 g of sodium acetate and 60 ml of acetic acid is heated under reflux for 4 hours. After cooling the reaction solution, it is poured into 600 ml of ice water and the precipitated crystals are collected by filtration. The crystals are recrystallized from an aqueous ethanol solution to obtain 1.5 g of 2-phenyl-6,7,8-trimethoxy-4H-1-benzopyran-4-one.

Melting point: 145.5 to 148 ° C. Elemental analysis: (C ₁₈ as _{H 16 O 5) C% H} % Calculated 69.22 5.16 Found 69.36 5.06 EXAMPLE 2 7,8-dimethoxy-6-hydro-2-phenyl - 4H-1-benzopyran-4-one (a) 2,5-dibenzoyloxy-3,4-dimethoxyacetophenone 2,5-dihydroxy-3,4-dimethoxyacetophenone (5 g) was dissolved in dry pyridine (10 ml). Add 5.8 ml of benzoyl chloride to the solution and warm on a water bath for about 10 minutes. After cooling the reaction solution, acidify the reaction solution with dilute hydrochloric acid. The precipitated crystals were collected by filtration, dissolved in methanol, treated with decolorizing carbon,
Recrystallization is performed twice with methanol to obtain 7.2 g of 2,5-dibenzoyloxy-3,4-dimethoxyacetophenone.

Melting point: 141-144 ° C (b) 5-benzoyloxy-3,4-dimethoxy-2
-Hydroxydibenzoylmethane 2,5-dibenzoyloxy-3,4-dimethoxyacetophenone (6 g) is dissolved in dry pyridine (60 ml), sodium amide (1.4 g) is added to the solution, and the mixture is reacted at room temperature for 2 hours. After completion of the reaction, the reaction solution is poured into ice water and acidified with diluted hydrochloric acid. Precipitated pale yellow crystals are collected by filtration, and the crystals are recrystallized from an aqueous solution of methanol to obtain 5-dibenzoyloxy-3,4-dimethoxy-2-hydroxydibenzoylmethane (3.8 g).

Melting point: 159 to 161 ° C (c) 6-benzoyloxy-7,8-dimethoxy-2
-Phenyl-4H-1-benzopyran-4-one 5-benzoyloxy-3,4-dimethoxy-2-hydroxydibenzoylmethane 3.6 g, sodium acetate 36
A mixture of g and 20 ml of acetic acid is heated under reflux for 3 hours. After cooling the reaction solution, it is poured into ice water and the precipitated crystals are collected by filtration. The crystals were recrystallized from methanol to give 6-benzoyloxy-7,8-dimethoxy-2-phenyl-4H-1-benzopyran-4-.
Get 2g on.

(D) 7,8-Dimethoxy-6-hydroxy-2-
Phenyl-4H-1-benzopyran-4-one 6-benzoyloxy-7,8-dimethoxy-2-phenyl-4H-1-benzopyran-4-one 2 g methanol 30
Add 0 ml to this solution and add potassium hydroxide to this solution.
Add 2 ml of an aqueous solution containing g and reflux for about 30 minutes. After completion of the reaction, methanol is distilled off and the residue is dissolved in water. Carbon dioxide gas is blown into this solution and the precipitated crystals are collected by filtration. The crystals are dissolved in chloroform, the chloroform solution is washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is recrystallized from methanol to obtain 0.4 g of 7,8-dimethoxy-6-hydroxy-2-phenyl-4H-1-benzopyran-4-one.

Melting point: one hundred sixty-seven to one hundred sixty-eight ° C. Elemental analysis: (C ₁₇ H ₁₄ as O ₅₎ C% H% Calculated 68.45 4.73 Found 68.39 4.58 Example 3 2-phenyl-6,7,8-tri Hydroxyfluoran -4H -1-
A mixture of 0.8 g of benzopyran-4-one 7,8-dimethoxy-6-hydroxy-2-phenyl-4H-1-benzopyran-4-one, 8 ml of 57% hydroiodic acid and 8 ml of acetic acid is refluxed for 2 hours. After cooling the reaction solution, it is poured into an aqueous sodium hydrogen sulfite solution and extracted with chloroform. The chloroform layer is washed with an aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue is recrystallized from methanol to obtain 0.5 g of 2-phenyl-6,7,8-trihydroxy-4H-1-benzopyran-4-one.

Melting point: 280 ° C (decomposition) Elemental analysis value: (as C ₁₅ H ₁₀ O ₅ ) C% H% Calculated value 62.50 4.20 Measured value 62.65 4.15 Example 4 6,7-Dimethoxy-8-hydroxy-2- Phenyl-4H-1-benzopyran-4-one (a) 2,3-dibenzoyloxy-4,5-dimethoxyacetophenone 2,3-dihydroxy-4,5-dimethoxyacetophenone 1 g was dissolved in dry pyridine 2 ml. Add 1.6 g of benzoyl chloride to this solution and warm on a water bath for 10 minutes. The reaction solution
Pour into 40 ml of water and extract with chloroform. The chloroform layer is washed with water, treated with decolorizing carbon, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. A small amount of methanol is added to the residue for crystallization. The crystals are collected by filtration, 50%
It is washed with an aqueous solution of methanol and dried to obtain 1.8 g of crude 2,3-dibenzoyloxy-4,5-dimethoxyacetophenone.

Melting point: 121-130 ° C (b) 3-benzoyloxy-4,5-dimethoxy-2
-Hydroxydibenzoylmethane 2,3-dibenzoyloxy-4,5-dimethoxyacetophenone (6 g) is dissolved in dry pyridine (60 ml), sodium amide (1.4 g) is added, and the mixture is stirred at room temperature for 75 minutes. 80 reaction mixture
Pour into 0 ml water and acidify with dilute hydrochloric acid. The acidic solution is extracted with chloroform, treated with decolorizing carbon and dried over anhydrous magnesium sulfate. The chloroform solution was concentrated under reduced pressure, the residue was heated and dissolved in methanol, left overnight, and the precipitated crystals were collected by filtration to obtain 2.3 g of 3-benzoyloxy-4,5-dimethoxy-2-hydroxydibenzoylmethane. .

Melting point: 164 to 172 ° C (c) 8-benzoyloxy-6,7-dimethoxy-2
-Phenyl-4H-1-benzopyran-4-one 3-benzoyloxy-4,5-dimethoxy-2-hydroxydibenzoylmethane 1.8 g, sodium acetate 1.8 g
A mixture of and 30 ml of acetic acid is heated to reflux for 3 hours. The reaction solution is poured into 200 ml of water and extracted with chloroform. The chloroform layer is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Ethanol was added to the residue for crystallization, and the precipitated crystals were collected by filtration, and 8-benzoyloxy-6,7-dimethoxy-2-phenyl-4H-1-benzopyran-4-one was collected.
Get 1.5g.

Melting point: 190-194 ° C (d) 6,7-dimethoxy-8-hydroxy-2-
Phenyl-4H-1-benzopyran-4-one 8-benzoyloxy-6,7-dimethoxy-2-phenyl-4H-1-benzopyran-4-one 3.15 g was dissolved in 400 ml of methanol and added to this suspension. Add 10 ml of 30% potassium hydroxide solution and heat on a water bath for 5 minutes until a solution is obtained. After the reaction was completed, the reaction mixture was concentrated under reduced pressure, and the residue was mixed with 200 ml of water.
Dissolve in. Carbon dioxide gas is blown into this solution for neutralization,
The precipitated crystals were collected by filtration and recrystallized from methanol,
-Dimethoxy-8-hydroxy-2-phenyl-4H
1.95 g of -1-benzopyran-4-one are obtained.

Melting point: two hundred twenty-six to two hundred twenty-seven ° C. Elemental analysis: (C ₁₇ H ₁₄ as O ₅₎ C% H% Calculated 68.45 4.73 Found 68.26 4.63 EXAMPLE 5 6,8-hydro-7-methoxy-2-phenyl -4H-1-benzopyran-4-one 6,7-dimethoxy-8-hydroxy-2-phenyl-4H-1-benzopyran-4-one 0.2 g was dissolved in acetic acid 15 ml, and 47% bromide was added to this solution. Add 40 ml of hydrogen acid and heat to reflux for 20 minutes. The reaction solution is poured into 200 ml of water, concentrated under reduced pressure and the precipitated crystals are collected by filtration. The crystals are recrystallized from acetone to obtain 0.1 g of 6,8-dihydroxy-7-methoxy-2-phenyl-4H-1-benzopyran-4-one.

Melting point: 280 to 290 ° C Elemental analysis value: (as C ₁₆ H ₁₂ O ₅ ) C% H% Calculated value 67.60 4.26 Measured value 67.28 4.14 Example 6 Bone resorption inhibitory effect Page 111 ~ 1
14 (Osamu Yamane, Hiroyoshi Endo, Soft Science Publishing, 1
985) It was measured according to the method described.

After femurs of chicken embryos on day 10 to 11 of incubation were extracted and the soft tissues attached to the bones were removed well, 2-phenyl-4H-1 of the present invention was obtained.
Pre-culture is carried out by a rotary culture method at 37 ° C. for 1 day using 1 ml of a BGJb-HW2 culture solution (hereinafter referred to as a culture solution) containing no phenol red to which a benzopyran-4-one derivative is added. The compound of the present invention is once dissolved in dimethyl sulfoxide to prepare a 0.1 molar solution, which is diluted 1000-fold with a culture medium to a concentration of 10 ^-4 molar. Also,
The control group is cultured by adding only the same volume of dimethyl sulfoxide.

The next day, ⁴⁵ CaCl ₂ is dissolved in a fresh culture medium at a concentration of 1 μCi / ml, the pre-cultured chicken embryo femur is immersed in 1 ml thereof, and shake-cultured at 37 ° C. for 2 hours. This resulted in ⁴⁵ bone minerals in the cultured bone.
Labeled with Ca. Immediately after completion of the culture, the cultured bone is washed with phosphate buffered saline preheated to 37 ° C to remove ⁴⁵ Ca attached to the bone. The ⁴⁵ Ca-labeled cultured bone is cultured again in the culture medium by the rotary culture method (10 revolutions / hour). Accurately collect a fixed amount of the culture solution from the culture solution every 12, 24, 48, and 72 hours, discard the remaining culture solution, and add a new culture solution. The separated ⁴⁵ Ca radioactivity in the culture broth was measured with a liquid scintillation count coater, to calculate the radioactivity of ⁴⁵ Ca in the whole broth. After culturing, 1 bone tissue
It is allowed to stand in normal hydrochloric acid for 1 day to elute total calcium, and its radioactivity is measured to obtain the final residual radioactivity in cultured bone.

From the obtained measured values, the ratio of the radioactivity remaining in the cultured bone to the total radioactivity that was initially taken into the bone tissue was calculated, and the radioactivity residual decay curve in the cultured bone after 24 hours was used to calculate the ratio. The bone salt elution by bone cells is linearly regressed, and the turnover rate of calcium in the bone mineral deposited on the cultured bone is determined as the biological half-life T1 / 2 from the obtained linear gradient.

The compound group of the present invention and the control group each consisted of 5 cases.

T1 / 2 of the compound group of the present invention compared to the value of T1 / 2 of the control group
A large value of indicates that the compound of the present invention has a bone resorption inhibitory effect. The efficacy of the compound of the present invention for inhibiting bone resorption is determined by the following formula using the value of T1 / 2.

The results are shown below.

Compounds Efficacy of inhibiting bone resorption 2-Phenyl-6,7,8-trihydrooxy-4H-1-benzopyran-4-one 1.45 7,8-Dimethoxy-6-hydrooxy-2-phenyl-4H- 1-Benzopyran-4-one 1.95 2-Phenyl-6,7,8-trimethoxy-4H-1-benzopyran-4-one 1.70 Example 7 Osteogenesis promoting action Bone formation promoting action was performed by the "Tissue culture applied research method". Pages 103-1
11 (Osamu Yamane, Hiroyoshi Endo, Soft Science Publishing, 1
985) It was measured according to the method described.

The femur of a chicken embryo on the 9th day of incubation was excised, and the soft tissue attached to the bone was well removed, and one of the left and right femurs of one individual was treated with the 2-phenyl-4H-1-benzopyran-4-one derivative of the present invention. Using the group and the other as the control group, attach each one to the inner surface of the flat culture tube for culture, add 2 ml of BGJb-HW2 culture solution (hereinafter referred to as culture solution) to it, and seal with a silicon stopper, 37 ° C.
Spin culture (10 rpm) for 10 minutes. The compound of the present invention was once dissolved in dimethyl sulfoxide to prepare a 0.1 molar solution, which was adjusted to 10 ^-4 molar by culture.
Dilute 1000 times. In the control group, the same volume of dimethyl sulfoxide alone is added and the culture is performed.

Bone culture is continued for 6 days while measuring the bone length every day and replacing with fresh culture medium.

At the end of culturing, the cultured bone was washed with phosphate buffered saline, 1
Calcium is eluted from the bone tissue by allowing it to stand in normal hydrochloric acid for 1 day, and the amount of eluted Ca is determined by the chelate method using orthocresolphthalein.

This experiment was carried out in 6 cases in each group.

The potency of the osteogenesis promoting action of the compound of the present invention was determined by the following formula.

The results are shown below.

Compound Efficacy of promoting bone formation 7,8-dimethoxy-6-hydrooxy-2-phenyl-4H-1-benzopyran-4-one 1,26 Example 8 In rat bone fed a Ca-deficient diet Efficacy for calcium and phosphorus amount 20 Wistar male rats aged 3 weeks 2 in groups of 10
The present invention is divided into groups, one group of which is 7,8-dimethoxy-6-hydroxy-2-phenyl-4H-1-benzopyran-4.
-On 300 mg / kg of CMC suspension was orally administered once daily once daily, and the other one group was administered with the same amount of CMC only and fed with Ca-deficient diet for 2 weeks. Then, the amount of calcium and phosphorus in the femur was measured.

The results are shown below.

Example 9 Acute toxicity 7,8-dimethoxy-6-hydroxy-2-phenyl-4H-1-benzopyran-4-one was applied to CMC, and 10 mice each of 7 week-old ICR mice were used. , 200
Oral administration was performed at 0 and 3000 mg / kg, and observation was performed for 7 days. There were no deaths in any group and no toxic symptoms were observed.

Example 10 Preparation of formulation (a) Tablets 7,8-dimethoxy-6-hydroxy-2-phenyl-4H-1-benzopyran-4-one 100 g, lactose 95 g and corn starch 40 g are mixed and then 5% An aqueous solution of hydroxypropyl cellulose is added and kneaded, followed by drying. To the dried product, 8 g of carboxymethyl cellulose calcium and 7 g of calcium stearate are added and mixed, and then molded into 1000 tablets.

(B) Capsule 7,8-dimethoxy-6-hydroxy-2-phenyl-4H-1-benzopyran-4-one 100 g, lactose 59 g and corn starch 35 g are mixed, and further talc 6 g is added to the mixture and mixed. After that, fill 1000 hard capsules.

〔The invention's effect〕

2-phenyl-4H-1 represented by the general formula (I) of the present invention
-Benzopyran-4-one derivatives and their pharmacologically acceptable salts show a strong bone resorption inhibitory action and osteogenesis promoting action in in vitro experiments using chicken embryo femur,
Further, it markedly suppresses the decrease in the calcium and phosphorus contents in the bones of the rat, which occurs when the calcium-deficient diet is fed.

Therefore, the 2-phenyl-4H-1-benzopyran-4-one derivative represented by the general formula (I) of the present invention is useful as a therapeutic agent for osteoporosis.

Claims (6)

[Claims] 1. A general formula 2-phenyl-4H-1-benzopyran represented by the formula (R ¹ , R ² and R ³ may be the same or different and each is a hydrogen atom or an alkyl group having 1 to 3 carbon atoms). A therapeutic agent for osteoporosis, which contains a -4-one derivative or a pharmacologically acceptable salt thereof as an active ingredient. 2. A formula 2-phenyl-4H-1-benzopyran-4-
The therapeutic agent for osteoporosis according to claim 1, which comprises an on derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 3. A formula 2-phenyl-4H-1-benzopyran-4-
The therapeutic agent for osteoporosis according to claim 1, which comprises an on derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 4. A formula 2-phenyl-4H-1-benzopyran-4-
The therapeutic agent for osteoporosis according to claim 1, which comprises an on derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 5. A formula 2-phenyl-4H-1-benzopyran-4-
The therapeutic agent for osteoporosis according to claim 1, which comprises an on derivative or a pharmaceutically acceptable salt thereof as an active ingredient. 6. A formula 2-phenyl-4H-1-benzopyran-4-
The therapeutic agent for osteoporosis according to claim 1, which contains an on derivative as an active ingredient.