JPS63156723A - Remedy for osteoporosis - Google Patents

Abstract

PURPOSE:To obtain a remedy for osteoporosis having strong bone-resorption supressing actions and osteogenesis promoting action and high safety, by using a 2-phenyl-4H-1-benzopyran-4-one derivative as an active component. CONSTITUTION:The objective agent can be produced by mixing a compound of formula I (R<1> and R<2> are H or 1-3C alkyl) or its salt with conventional pharmaceutical additives such as vehicle, disintegrator, binder, etc., and forming the mixture in the form if a drug according to conventional method. It is administered at a does of 10-1,000mg/day for adult by oral administration in the form of tablet, powder, capsule, etc., or 1-100mg/day for adult by parenteral administration in the form of injection, etc. The compound of formula I can be produced by reacting an acetophenone derivative of formula II with benzoyl chloride, subjecting the product to Bader-Venkataraman rearrangement, heating in acetic acid in the presence of sodium acetate and, if necessary, hydrolyzing the reaction product.

Description

Detailed Description of the Invention [Industrial Field of Application] The object of the present invention is to provide compounds of the general formula (I) (wherein R1 and R2 are hydrogen atoms or carbon atoms of 1 to 3
2-phenyl-4H-, which is an alkyl group of
The present invention provides a therapeutic agent for osteoporosis containing a 1-benzopyran-4-one derivative or a pharmacologically acceptable salt thereof.

[Conventional technology]

Osteoporosis is a pathological condition in which the bone mass decreases without any change in the chemical composition of the bone, and its physiological characteristic is a decrease in protein, calcium, and phosphorus in the bone.

Osteoporosis increases with age and usually affects the spinal cord, causing back pain and shortened height. In particularly advanced cases, long bones are also affected, sometimes resulting in fractures.

It is said that most of the causes of femoral neck fractures seen in the elderly are due to senile osteoporosis.

The causes of osteoporosis are diverse, including endocrine and nutritional disorders, and therapeutic agents such as Hillion D preparations, calcium preparations, calcitonin preparations, and phosphorus preparations are used.
Since its effectiveness is uncertain, there is a strong desire to develop a formulation with more reliable efficacy.

In recent years, three types of drugs with completely different chemical structures from the above preparations have been developed.
- It has been reported that phenyl-48-1 to benzopyran-4-one derivatives (isoflavone derivatives) have a bone resorption inhibitory effect and are useful as therapeutic agents for osteoporosis (
JP 54-13391, JP 60-48924, JP 60-54379, JP 60-13291
No. 7, JP-A-60-132976>.

However, the 2-phenyl-41(-1-benzopyran-4-one derivatives or their pharmacologically acceptable salts (flavone derivatives) of the present invention exhibit bone resorption inhibitory effects and are useful as therapeutic agents for osteoporosis. This has never been reported to date.

[Problem that the invention seeks to solve]

3-phenyl-4H-1 disclosed in said patent application
-Benzopyran-4-one derivatives have a weak bone resorption inhibitory effect and are by no means satisfactory as therapeutic agents for osteoporosis. Therefore, the present inventors conducted extensive studies on the bone resorption inhibitory effect of benzopyran-4-one derivatives, and found that certain 2-phenyl-4H-1-benzopyran-4-one derivatives or their pharmacologically acceptable The resulting salt has a strong bone resorption inhibiting effect and also exhibits a bone formation promoting effect,
It has been found that it can be a better osteoporosis treatment.

The present invention is based on these findings.

[Means for solving problems]

2-phenyl-4 represented by the general formula (I) of the present invention
Day-1-benzopyran-4-one derivatives (flavone derivatives) exhibit strong bone resorption inhibitory and bone formation promoting effects, and are useful as highly safe osteoporosis therapeutic agents.

2-phenyl-4 represented by the general formula (I) of the present invention
The H-1-benzopyran-4-one derivative is a known compound and can be produced according to methods described in literature or similar methods thereof. For example, Organic Synthesis Collective Volume ■, pages 478-481 (Org, Syn, Ca11.IV.

478-481); Chim,
Ber, >43 volumes, 1966 pages; Chem, Abstr., 26 volumes, 481
6 (1932) or similar methods thereof.

That is, 2-phenyl-4H-1-benzopyran-4-one represented by the general formula (I) of the present invention is represented by the formula (R1 and R2 in the formula have the same meanings as above) An acetophenone derivative and benzoyl chloride are reacted to form a compound of formula (III) (wherein R3 and R4 are benzoyl groups or carbon atoms 1).
After obtaining a dibenzoyloxyacetophenone derivative represented by
A dibenzoylmethane derivative represented by formula (IV) (in which R3 and R4 have the same meanings as above) is obtained by heating in acetic acid in the presence of sodium acetate, and then It can be obtained by hydrolysis if necessary.

2-phenyl-4 represented by the general formula (I) of the present invention
H-1-benzopyran-4-one derivatives in which RI and R2 are alkyl groups having 1 to 3 carbon atoms are 2-phenyl-4H-1- in which at least one of R1 and R2 is a hydrogen atom; It can also be produced by reacting a benzopyran-4-one derivative with an alkyl halide having 1 to 3 carbon atoms according to a conventional method.

Furthermore, the compound represented by the general formula (I) of the present invention in which 2-phenyl-4-day-1-benzopyran-4-one i% conductors R1 and R2 are hydrogen atoms is RJ and R2.
It can also be produced by treating a 2-phenyl-4H-1-benzopyran-4-one derivative in which at least one of 2 is an alkyl group having 1 to 3 carbon atoms under acidic conditions.

In this production method, the general formula (II) used as a raw material is
The acetophenone derivative represented by ) is a known compound and can be produced by methods described in literature.

2-phenyl-4 represented by the general formula (I) of the present invention
H-1-benzopyran-4H-1-one derivative, R1
A compound in which at least one of R2 and R2 is a hydrogen atom can be converted into a pharmacologically 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 containing an equivalent amount of sodium hydroxide, heated, and then concentrated under reduced pressure. It can be made into a sodium salt.

2-phenyl-4 represented by the general formula (I) of the present invention
The di-1-benzopyran-4H-1-one derivative can be made into a pharmaceutical preparation according to a conventional method. That is, it is mixed with commonly used pharmaceutical additives such as excipients, disintegrants, binders, and lubricants, and prepared according to conventional methods to produce various preparations.
For example, it can be made into a tablet, powder, or capsule.

2-phenyl-4 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, approximately 10 to 1000 m per day for adults.
g in an appropriate dosage form, such as tablets, powders, capsules, etc., and orally administer in divided portions, or approximately 1 to 1 g per day for adults.
00 mg is administered parenterally as an injection or the like.

2-phenyl-4 represented by the general formula (I) of the present invention
In in vitro experiments using chicken embryo femurs, H-1-benzopyran-4-one derivatives have shown strong bone resorption-inhibiting and bone formation-promoting effects, and have shown that they have a strong effect on bone resorption and osteogenesis in rats fed a calcium-deficient diet. It has the effect of significantly improving the decrease in calcium and phosphorus content, and is useful as a therapeutic agent for osteoporosis.

〔Example〕

Examples are given below to further explain the present invention.

Note that the melting points of the compounds in the Examples are uncorrected.

Example 1 (a)'2,5-dibenzoyloxy-4-methoxyacetophenone 2.5-dihydroxy-4-methoxyacetophenone5. Og is dissolved in 10 mA of dry pyridine and 8.5 g of benzoyl chloride are slowly added to this solution with stirring. Heat the mixture on a boiling water bath for 10 minutes. After the reaction is completed, the reaction solution is cooled, diluted hydrochloric acid is added to make it weakly acidic, and the precipitated crystals are collected by filtration. The obtained crystals were washed with water and recrystallized from methanol-chloroform to obtain 9.3 g of 2,5-dibenzoyloxy-4-methoxyacetophone as white crystals.

Melting point: 233-234.5°C (6) 5-benzoyloxy-2-hydroxy-4
-Methoxydibenzoylmethane 20 g of 5-dibenzoyloxy-4-methoxyacetophenone and 30 g of dried N,N-dimethylformamide
Dissolve in a mixture of mA and dry pyridine. While heating this solution to 50°C, add sodium amide 4. Add Og with stirring. This mixture is reacted for 1 hour at 100° C. with stirring. After the reaction is completed, the reaction solution is cooled, poured into water in step 11, and made weakly acidic with dilute hydrochloric acid. The precipitated crystals were collected by filtration to obtain 4.0 g of methanol-chloroporin 5-benzoyloxy-2-hydroxy-4-methoxydibenzoylmethane.

Melting point; 180-182°C (C) 6-pendiyloxy-twomethoxy-2-
Phenyl-4H-1-benzopyran-4-one A mixture of 4.0 g of 5-benzoyloxy-2-hydroxy-4-methoxydibezoylmethane, 4.0 g of anhydrous sodium acetate and 25 ml of acetic acid is heated under reflux for 3 hours. After the reaction is completed, the reaction solution is poured into 100 liters of ice water, and the precipitated crystals are filtered. The obtained crystals are recrystallized from methanol-chloroform to obtain 3.6 g of 6-benzoyloxy-7-methoxy-2-phenyl-4-1-benzopyran-4-one.

Melting point: 233-235°C (d) 6-hydroxy-7-methoxy-2-phenyl-4-day-1-benzopyran-4-one 6-pendiyloxy-twomethoxy-2-phenyl-
4th day - 3.3g of 1-benzopyran-4-one was suspended in 200ml of methanol, and 5rn1. Add. The mixture is heated to reflux for 2 hours. After the reaction is completed, methanol is distilled off under reduced pressure. Water is added to the residue, carbon dioxide gas is blown into the residue, and the precipitated crystals are collected by filtration. The obtained crystals were recrystallized from ethanol-methanol to give 6-hydroxy-7-methoxy-2-phenyl-4H-1-benzopyran-4day-1-
Obtain 2.5 g of on.

Melting point: 208-210℃ Elemental analysis value (as CI88I204) 0%
H% Theoretical value 71.63 4.51 Actual value 71.90 4.39 Example 2 6.7-Simethoxy2-phenyl-4H-1-benzopyrandeone 6-hydroxy-7-methoxy-2-phenyl- 4
A mixture of 500 mg of H-1-benzopyran-4-one, 2.0 g of anhydrous potassium carbonate, 2.0 g of methyl iodide, and 30-g of dry a7ton is heated under reflux for 15 hours (2 g of methyl iodide is added twice during the process). do). Filter the reaction solution,
Wash the potassium carbonate well with acetone and add the washed acetone to the filtrate. The filtrate was concentrated under reduced pressure, and the residue was recrystallized from methanol to give 6,7-cymethoxy-2-phenyl-4H.
400 mg of -1-benzopyran-4-one are obtained.

Melting point: 192-194℃ Elemental analysis value: (as C17141404) 0%
H% Theoretical value 72.33 5.00 Actual value 72.20 4.91 Example 3 6-hydroxy-7-methoxy-2-phenyl-4
Add 800+ng of 1-benzopyran-4-one to a mixture of 8ml of hydroiodic acid and 81TLi of acetic anhydride,
Heat to reflux for 3 hours. After the reaction is completed, the reaction solution is poured into 80 m of ice water. Add saturated aqueous sodium bisulfite solution to this mixture until the red color of free iodine disappears.

The precipitated crystals were collected by filtration and recrystallized from acetic acid-water to obtain 300 mg of 6,7-dihydroxy-2-phenyl-4H-1-benzopyran-4-one monohydrate.

Melting point: 254-129℃ Elemental analysis value: (as C,5HI205) 0%
H% Theoretical value 66.17 4.44 Actual value 66.25 4.10 Example 4 Bone resorption inhibitory effect The bone resorption inhibitory effect was evaluated in "Tissue Culture Applied Research Methods" page 111
It was measured according to the method described in ~114 (Yamane Satoshi, Endo Hiroyoshi Kinshu, Soft Science Publishing, 1985).

After removing the 10-11-day-old chicken embryo femur and thoroughly removing the soft tissues attached to the bone, the 2-phenyl-4 of the present invention was removed.
Preculture is carried out using 1 mN of phenol red-free BGJb-Hll12 culture solution (hereinafter referred to as culture solution) containing an H-1-benzopyran-4-one derivative at 37° C. for 1 day by a rotary culture method. The compound of the present invention is dissolved in dimethyl sulfoxide and diluted 1000 times directly into the culture medium to give a 10-4 molar concentration.

The next day, add 1 μci/45CaC12 to fresh culture medium.
ml, pre-cultured chicken embryo femur is immersed in one fart of the solution, and cultured with shaking at 37°C for 2 hours. As a result, the bone mineral in the cultured bone is labeled with 45Ca. Immediately after culturing, the cultured bones were washed with phosphate buffered saline that had been preheated to 37°C to remove the 4S that had adhered to the bones.
Remove Ca.

This 45Ca-labeled cultured bone was again cultured in culture medium using the rotational culture method (
Preculture is performed by rotating the tube 10 times. 12.24.48
．． Every 72 hours, a precise amount of culture fluid is taken out from the culture fluid, and at the same time, the remaining culture fluid is discarded and fresh culture fluid is added. The 45Ca radioactivity in the fractionated culture solution is measured using a liquid scintillation Karakoo, and the 45Ca radioactivity in the entire culture solution is calculated. After culturing, the bone tissue is left in 1N hydrochloric acid for one day to elute all calcium, and its radioactivity is measured, which is taken as the final residual radioactivity in the cultured bone.

From the obtained measurement values, the ratio of the radioactivity remaining in the cultured bone to the total radioactivity initially incorporated into the bone tissue was calculated, and the decay curve of the residual radioactivity in the cultured bone after 24 hours was calculated. Bone mineral elution by osteocytes is linearly regressed, and from the slope of the obtained straight line, the turnover rate of calcium in bone mineral deposited on cultured bone is determined as biological half-life T%.

The compound group of the present invention and the control group were each conducted with 5 patients per group.

Compared with the T'A value of the control group, the T'A value of the compound group of the present invention
A large value of A indicates that the compound of the present invention has a bone resorption inhibitory effect, and the efficacy of the bone resorption inhibitory effect of the compound of the present invention was determined using the following formula.

The results are shown below.

Compound Effective compound with bone resorption inhibitory effect
Efficacy Example 5 of Bone Resorption Suppressing Effect Bone Formation Promoting Effect Bone formation promoting effect of “Tissue Culture Applied Research Methods” Page 103
-111 (edited by Satoshi Yamane and Hiroyoshi Endo, published by Soft Science Co., Ltd., 1985).

The femur bones of 9-day-old chicken embryos were removed, the soft tissues attached to the bones were thoroughly removed, and one of the left and right femurs of each individual was treated with 2-phenyl-4H-1-benzopyran-4- of the present invention. One derivative group and the other group were used as a control group, and each one was attached to the inner surface of a rectangular culture test tube, and BGJb-H1l
Add 2 ml of i2 medium solution (hereinafter referred to as culture solution), seal with a silicone stopper, and culture with rotation at 37°C (10 rotations). The compound of the present invention is dissolved in dimethyl sulfoxide and then directly diluted 1000 times in a nutrient solution to a concentration of 10-4 molar. Fresh culture medium is added and preculture is continued for 6 days while measuring bone length every day. At the end of the culture, the cultured bone was washed with phosphate buffered saline and left in 1N hydrochloric acid for 1 day to elute calcium from the bone tissue, and the eluted C
The amount of a is determined by the chelation method using orthocresol phthalein.

This experiment was conducted with 6 patients in each group.

The efficacy of the osteogenesis promoting effect of the compound of the present invention was determined using the following formula.

Compound Efficacy Example 6 of Bone Formation Promoting Effect Using 20 3-week-old male Rice Cous rats, 1 group 1
Divide the animals into two groups, one group being fed the A-deficient diet, and the other group being fed the Ca-deficient diet and the 6,7-dimethoxy-2-phenyl-4-day-1-benzopyran-4-one of the present invention. 300mg/
kg and raised for two weeks, and the amount of calcium and phosphorus in the femur was measured.

The results are shown below.

Example 7 Acute toxicity 6.7-Simethoxy 2-phenyl-4H-1-benzopyran-4-one was suspended in CMC and 7 week old ICR
Using 10 male and 10 female mice, 1000.2000.3
000 mg/kg was orally administered and observed for 7 days. There were no deaths and no symptoms of toxicity were observed in either group.

Example 8 Manufacture of formulation (a) Tablet 6. 100 g of 7-cymethoxy 2-phenyl-4H-1-benzopyran-4-one was mixed with 95 g of lactose and 40 g of corn starch, and then 5% hydroxypropylcellulose was added. After adding an aqueous solution and kneading, the mixture is dried, and 8 g of carboxymethyl cellulose calcium and calcium stearate are added to the dried product and mixed, and then molded into 1000 tablets.

Capsules 6. 100 g of 7-Simethoxy 2-phenyl-4H-1-benzopyran-4-4, 39 g of lactose and 35 g of corn starch were mixed, and 6 g of talc was added to the mixture and mixed. hard capsule 1000
Fill into capsules.

〔Effect of the invention〕

2-phenyl-4-day- represented by general formula (I) of the present invention
1-benzopyran-4H-1-one derivatives and their pharmacologically acceptable salts have shown to inhibit strong bone resorption and promote bone formation in in vitro experiments using chicken embryo femurs, and have also been shown to inhibit calcium deficiency. Significantly suppresses the decrease in calcium and phosphorus content in the bones of rats that occurs when fed the diet.

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 (4)

[Claims] (1) General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (R^1 and R^2 in the formula are hydrogen atoms or carbon atoms with 1
2-phenyl-4 represented by
A therapeutic agent for osteoporosis containing an H-1-benzopyran-4-one derivative or a pharmacologically acceptable salt thereof as an active ingredient. (2) 2-phenyl-4H-1-benzopyran-4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
The therapeutic agent for osteoporosis according to claim 1, which contains a -one derivative or a pharmacologically acceptable salt thereof as an active ingredient. (3) 2-phenyl-4H-1-benzopyran-4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
The therapeutic agent for osteoporosis according to claim 1, which contains an -one derivative as an active ingredient. (4) 2-phenyl-4H-1-benzopyran-4 represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼
The therapeutic agent for osteoporosis according to claim 1, which contains a -one derivative or a pharmacologically acceptable salt thereof as an active ingredient.