JPH0720867B2 - Osteoporosis treatment - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The object of the present invention is to provide a compound represented by the general formula (I): The present invention provides a therapeutic agent for osteoporosis containing a benzofuro [3,2-b] quinoline derivative represented by the formula (wherein R is a lower alkyl group or a carboxy group) or a pharmacologically acceptable salt thereof. is there.

[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 a variety of causes of this osteoporosis such as endocrine and nutritional disorders, but the targets of vitamin D preparations, calcium preparations, calcitonin preparations, phosphorus preparations, etc., which have been used as therapeutic agents for osteoporosis so far, are limited. Since the effect is not certain, development of a more reliable formulation is strongly desired.

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

The benzofuro [3,2-b] quinoline derivative of the present invention is a known compound, and has already been synthesized and reported by several methods [Chem. Berichte (Chem.
r.) 98, 419 ~, 1965; Archives of
Pharmacology (Arch. Pharm.) Volume 300, 829 pages ~,
1967; Journal of Indian Chemicals
Society (J. Indian Chem. Soc.) Vol. 13, 700-, 1936].

However, these are all synthesized for the purpose of confirmation of synthetic interest or scientific reactivity, and their pharmacological actions are not described. Furthermore, it has not been reported at all until now that the benzofuro [3,2-b] quinoline derivative of the present invention exhibits a bone resorption inhibitory action and is useful as a therapeutic agent for osteoporosis.

[Problems to be solved by the invention]

3-phenyl-4H-1-disclosed in said patent application
The benzopyran-4-one derivative has a weak bone resorption inhibitory action, and is by no means satisfactory as a therapeutic agent for osteoporosis. Therefore, as a result of intensive investigations by the present inventors to find out a compound having a stronger bone resorption inhibitory action, a certain benzofuro [3,2-b] quinoline derivative or a pharmacologically acceptable salt thereof is strong. It was found that it has a bone resorption inhibitory action and also exhibits a bone formation promoting action, and can be a more excellent therapeutic agent for osteoporosis.

The present invention is based on these findings.

[Means for solving problems]

The benzofuro [3,2] represented by the general formula (I) of the present invention
-B] The quinoline derivative or a pharmacologically acceptable salt thereof exhibits a strong bone resorption inhibitory action and an osteogenesis promoting action,
It is useful as a highly safe therapeutic agent for osteoporosis.

The benzofuro [3,2] represented by the general formula (I) of the present invention
-B] The quinoline derivatives are all described in the literature, for example, Hemische Berichide (Chem. Ber.) Volume 98, 419-, 1965; Archives of Pharmacology (Arch. Pharm.) Volume 300, 829-, 1967; Journal of Indian Chemical Society (J. Indian Chem. Soc.) Vol. 13, p. 700-, 1936, etc., or similar methods.

For example, benzofuro [3, represented by the general formula (I)
2-b] quinoline derivative, wherein R is a lower alkyl group, the general formula The compound represented by the formula (R 'in the formula is a lower alkyl group) has the general formula (Wherein R ′ has the same meaning as described above), It can be produced by heating the compound represented by and in a solvent or without a solvent.

The benzofuro [3,2] represented by the general formula (I) of the present invention
-B] The quinoline derivative in which R is a carboxy group can be produced by reacting isatin with the compound represented by the above formula (III).

In the present production method, the compounds represented by the general formulas (II) and (III) and isatin used as raw materials are all known compounds, and are commercially available, or the methods described in the literature or similar methods thereof. Can be manufactured according to.

The benzofuro [3,2] represented by the general formula (I) of the present invention
The -b] quinoline derivative can be converted into a pharmacologically acceptable salt according to a conventional method. For example, in the benzofuro [3,2-b] quinoline derivative represented by the general formula (I) of the present invention, 6-carboxybenzofuro [3,2-b] quinoline in which R is a carboxyl group is equivalent to this. After adding to the alcohol solution in which sodium hydroxide is dissolved and heating,
The sodium salt can be obtained by concentrating under reduced pressure.

The benzofuro [3,2] represented by the general formula (I) of the present invention
The b-quinoline derivative can be made into various pharmaceutical preparations according to a conventional method. That is, if necessary, an excipient,
Various formulations such as tablets, powders, capsules and the like can be prepared by mixing with a pharmaceutical additive such as a destructive agent, a binder, a lubricant and the like and preparing them according to a conventional method.

The benzofuro [3,2] represented by the general formula (I) of the present invention
-B] When the quinoline 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 and the like, and orally administered, or about 1 to 100 mg per day for an adult. It is parenterally administered as an injection.

The benzofuro [3,2] represented by the general formula (I) of the present invention
-B] The quinoline derivative or a pharmacologically acceptable salt thereof shows a strong bone resorption inhibitory action and a bone formation promoting action in an in vitro experiment using a chicken embryo femur, and is produced when a calcium-deficient diet is given. It has an action of remarkably suppressing the decrease of calcium and phosphorus contents in rat bones, and is useful as a highly safe therapeutic agent for osteoporosis.

〔Example〕

 The following examples are given to further illustrate the present invention.

Example 1 Bone Resorption Inhibitory Action The bone resorption inhibitory action is described in “Tissue culture applied research method”, pages 111 to 114 (edited by Yamane, Hiroshi Endo, Soft Science Publishing, 1
985) It was measured according to the method described.

After removing the femur bones of chicken embryos at 10 to 11 days of incubation and well removing the soft tissues attached to the bones, the benzofuro [3,2-
b] 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 quinoline derivative is added. In addition,
The compound of the present invention was once dissolved in dimethylsulfoxide to prepare a 0.1 molar solution, which was then added to a culture solution at 100
Dilute 0-fold to make 10 ^-4 molar concentration. In addition, the control group is cultured by adding only the same volume of dimethyl sulfoxide.

The next day, ⁴⁵ CaCI ₂ is dissolved in a fresh culture medium at a concentration of 1 μCi / ml, and the precultured chicken embryo femur is immersed in 1 ml of the culture medium and shake-cultured at 37 ° C. for 2 hours. This resulted in ⁴⁵ bone minerals in the cultured bone.
Labeled with Ca. Immediately after the 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 radioactivity of ⁴⁵ Ca in the collected culture broth is measured with a liquid scintillation counter, and the radioactivity of ⁴⁵ Ca in the whole culture is calculated. 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, calculate the ratio of the radioactivity remaining in the cultured bone to the total radioactivity that was initially taken into the bone tissue, and calculate the radioactivity residual decay curve in the cultured bone after 24 hours. The elution of bone mineral by osteoclasts 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.

Example 2 Bone formation promoting action Bone formation promoting action is described in "Tissue culture applied research method", pages 103 to 111 (edited by Yamane, Hiroshi Endo, Soft Science Publishing, 1
985) It was measured according to the method described.

A chicken embryo femur on day 9 of incubation was excised, the soft tissue attached to the bone was removed well, and one of the left and right femurs of one individual was used as a compound group of the present invention and the other as a control group, and a flat angle test for culture was performed. One tube is attached to each inner surface of the tube, 2 ml of BGJb-HW2 culture solution (hereinafter referred to as culture solution) is added to the tube, the tube is sealed with a silicon stopper, and rotation culture (10 rotations / hour) is performed at 37 ° C. The compound of the present invention was once dissolved in dimethyl sulfoxide to give 0.1
A solution having a molar concentration is prepared, and these are diluted 1000-fold with a culture solution to a concentration of 10 ^-4 molar. In addition, the control group is cultured by adding only the same volume of dimethyl sulfoxide.

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.

Example 3 Effect on Calcium and Phosphorus Levels in Bone of Rats Fed a Ca-Deficient Diet Twenty male Wistar rats aged 3 weeks were grouped into two groups of 10 rats each.
The test compound, 6-carboxybenzofuro [3,2-b] quinoline, 300 mg / kg, was divided into groups, and 1 day a day with CMC suspension.
Orally administered once daily forcibly, and the other group was given the same dose.
CMC alone was administered and fed with a Ca-deficient diet, and the rats were bred for 2 weeks to measure the amount of calcium and phosphorus in the femur.

The results are shown below.

Example 4 Acute toxicity 6-Carboxybenzofuro [3,2-b] quinoline was applied to CMC, and 10 male and female 7-week-old ICR mice were used.
Oral administration of 0, 2000 and 3000 mg / kg was carried out and observation was carried out for 7 days. There were no deaths in any group and no toxic symptoms were observed.

Example 5 Preparation of preparation (a) Tablet 6-carboxybenzofuro [3,2-b] quinoline 100 g,
Lactose (95 g) and corn starch (40 g) are mixed, and then 5% hydroxypropyl cellulose aqueous solution is added and kneaded, followed by drying, and 8 g of carboxymethyl cellulose calcium and 7 g of calcium stearate are added to the dried product and mixed to form 1000 tablets. .

(B) Capsule 6-carboxybenzofuro [3,2-b] quinoline 100 g,
Lactose (59 g) and corn starch (35 g) are mixed, talc (6 g) is added to the mixture, and the mixture is filled into 1000 hard capsules.

〔The invention's effect〕

The benzofuro [3,2-represented by the general formula (I) of the present invention
b] Quinoline derivatives and their pharmacologically acceptable salts show strong bone resorption inhibitory action and osteogenesis promoting action in in vitro experiments using chicken embryo femur, and also occur when a calcium-deficient diet is given. Remarkably suppresses the decrease of calcium and phosphorus content in rat bone.

Therefore, the benzofuro [2,3-b] quinoline derivative represented by the general formula (I) of the present invention is useful as a therapeutic agent for osteoporosis.

Claims (1)

[Claims] 1. A general formula A therapeutic agent for osteoporosis, comprising a benzofuro [3,2-b] quinoline derivative represented by the formula (wherein R is a lower alkyl group or a carboxy group) or a pharmacologically acceptable salt thereof as an active ingredient.