JPS63297324A - Remedy for osteoporosis - Google Patents

Abstract

PURPOSE:To obtain a remedy for osteoporosis, having inhibitory action on bone resorption, promoting action on bone formation and high safety, containing a benzofuro[2,3-b]quinoline derivative or a salt thereof as an active ingredient. CONSTITUTION:A benzofuro[2,3-b]quinoline derivative shown by the formula (R is H or OH) or a salt thereof is blended with a conventional drug carrier and pharmaceutically manufactured by a conventional procedure to give the aimed substance. The substance can be processed into a dosage form such as tablet, powder, capsule or injection. A dose is 10-1,000mg per adult daily in the case of oral administration and 1-100mg per adult daily in the case of parenteral administration. The compound shown by the formula is obtained by reacting m-anisidine with a phenylmalonic acid derivative, treating the reaction product with pyridine hydrochloride and dealkylating simultaneously with ring closure. 8-Hydroxy-6H-benzofuro[2,3-b]quinolin-11-one may be cited as the compound shown by the formula.

Description

Detailed Description of the Invention [Industrial Field of Application] The object of the present invention is to prepare benzofuro(2,3-b) represented by the general formula (I) (R in the formula is a hydrogen atom or a hydroxyl group). The present invention provides a therapeutic agent for osteoporosis containing a quinoline derivative or a pharmacologically acceptable salt thereof.

[Conventional technology]

Osteoporosis is a pathological condition in which the chemical composition of bones decreases, and its physiological characteristic is a decrease in protein, calcium, and phosphorus in the bones.

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

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

The causes of osteoporosis are diverse, including endocrine and nutritional disorders, but the vitamin D preparations, calcium preparations, calcitonin preparations, phosphorus preparations, etc. that have been used as therapeutic agents for osteoporosis have been limited in scope or Since the efficacy is not certain, there is a strong desire to develop a formulation with more reliable efficacy.

In recent years, a certain type of drug with a completely different chemical structure from the above-mentioned preparations has been developed.
It has been reported that -phenyl-4H-1-benzobilan-4-one derivatives have a bone resorption inhibitory effect and are useful as therapeutic agents for osteoporosis (Japanese Patent Publication No. 13391/1983).
JP-A-60-48924, JP-A No. 60-54379, JP-A No. 60-132917, JP-A No. 60-132976)
.

As the benzofuro[2,3-b)quinoline derivatives of the present invention, the formula or compounds represented by the formula have already been synthesized and reported [Pretin on the Chemical Society
On Japan (Bull, Chem, Soc.

Jpn,) Volume 53, pages 1057-1060, 1
980; Journal on Heterocyclic Chemistry
) Volume 21, pages 737-739.

1984].

However, all of these were synthesized for synthetic interest or to confirm chemical reactivity, and in terms of pharmacological activity, they may have mutagenic, carcinogenic, or anticancer effects. It is only shown that there is no explanation of its effect. Furthermore, it has never been reported that benzofuro[2,3-b)quinoline derivatives such as those of the present invention exhibit a bone resorption inhibitory effect and are useful as therapeutic agents for osteoporosis.

[Problem that the invention seeks to solve]

3-phenyl-48-1 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 intensive studies to find compounds with stronger bone resorption inhibitory effects, and found that certain benzofuro(2,3-b)quinoline derivatives or their pharmacologically acceptable salts have a stronger effect. It has been found that it has an effect of inhibiting bone resorption and also an effect of promoting bone formation, and can be an excellent therapeutic agent for osteoporosis.

The present invention is based on these findings.

[Means for solving problems]

Benzofuro (2,
3-b) Quinoline derivatives or their pharmacologically acceptable salts exhibit strong bone resorption inhibitory and bone formation promoting effects and are useful as highly safe osteoporosis therapeutic agents.

Benzofuro (2,
3-b) Some of the quinoline derivatives include new compounds, but all of them are prepared using methods described in the literature, such as pretin ion.
The Chemical Society Japan (Bul
l, Chem, Sac, Jpn,) Volume 53, 105
Pages 7-1060 (1980); Journal on Heterocyclic Chemistry (J, flet
Ero-cyclic Chem,) Volume 21, 7
37-739 (1984) or similar methods thereof.

For example, by reacting m-anisidine represented by the formula with a phenylmalonic acid derivative represented by the general formula (R' in the formula is a hydrogen atom or a lower alkoxy group),
It can be produced by preparing a compound represented by the general formula (R' in the formula has the same meaning as above), treating this with pyridine hydrochloride, and simultaneously causing dealkylation and ring closure.

In this production method, the general formula (
The compound represented by I) can be prepared by methods described in literature, for example, Journal on Heterocyclic Chemistry (J, Heterocyclic Chem.
) Volume 21, pages 737-739, (1984
It can be produced according to the method described in 2010) or a similar method.

Benzofuro [:2] represented by the general formula (1) of the present invention
．． 3-b) The quinoline derivative can be converted into a pharmacologically acceptable salt according to a conventional method. For example, the benzofuro[2゜3-b]quinoline derivative represented by the general formula (I) of the present invention is added to an alcoholic solution containing an equivalent amount of sodium hydroxide, heated, and then concentrated under reduced pressure. It can be made into a sodium salt.

Benzofuro (2,
3-b) The quinoline derivative can be made into various pharmaceutical preparations according to conventional methods. That is, by mixing with pharmaceutical additives such as excipients, disintegrants, binders, and lubricants as necessary, and preparing according to conventional methods, various preparations such as tablets, powders, capsules, etc. are prepared. be able to.

Benzofuro (2,
3-b) When using a quinoline derivative as a therapeutic agent for osteoporosis, approximately 10 to 1000 mg per day for adults is prepared into an appropriate dosage form, such as tablets, powders, capsules, etc., and administered orally, or approximately 1000 mg per day for adults is administered. 1 to 100 mg is administered parenterally in the form of an injection or the like.

Benzofuro (2,
3-b) Quinoline derivatives or their pharmacologically acceptable salts have shown strong anti-bone resorption and osteogenesis-promoting effects in in vitro experiments using chicken embryo femurs, and have low toxicity and a high level of safety. It is useful as a therapeutic agent for high osteoporosis.

〔Example〕

Examples are given below to further explain the present invention.

Note that all melting points of compounds in each example are uncorrected.

Example 1 2.7 g of m-anisidine and 5.32 g of diethyl 2-methoxyphenylmalonate were added to 20 ml of diphenyl ether.
Dissolve in water and heat at 270 to 290℃ with an air cooling tube for about 2 hours.
．． Heated for 5 hours. After cooling, 80 d of diethyl ether was added, and the precipitated crystals were collected by filtration and washed with diethyl ether to give 4-hydroxy-7-medoxy-3-(2-methoxyphenyl)-2-quinolone 5J9 g (90.7%)
I got it.

Melting point: >300℃ IR (KBr): 1620 cm-'N
MR (d6-DMSO) δ: 3.69 (s, 3H), 3.8Hs,
3H), 6.75-6.79 (m, 2N>
, 6.93-7.13 (+n, 3tl),
7.29~7.35 (m, IH), 7.76~
7.80 (m, 1tl).

9, 56 (br-s, IH), 11.18 (S
, IH) Elemental analysis value: (as C+□HISNO4) 0% N% N% Calculated value 68.68 5.09 4.71 Actual value 68.79 5.08 4.724-
A mixture of 5 g of hydroxy-7-medoxy-3-(2-methoxyphenyl)-2-quinolone and 50 g of pyridine hydrochloride was heated under reflux at 200-250°C for 2.5-3 hours. Pour the reaction mixture onto 200-300 g of hot crushed ice,
The precipitated crystals were collected by filtration and washed with water. The crude crystals were treated with alcohol to remove poorly soluble 3-hydroxy-51-benzofuro(3,2-c)quinolin-6-one by filtration, the filtrate was concentrated, and the precipitated crystals were collected by filtration. Recrystallization with aqueous alcohol yields 8-hydroxy-6H-benzofuro (2,3
-b) 1.4 g of quinolon-11-one was obtained.

Melting point: >300℃ IR (KBr): Vco 1630 cm
-'NMR (d6-DMSO) δ: 6.92-7.08 (m, 2H), 7
．． 42-7.78 (m.

3) 1), 8.12-8.25 (m, 2H),
10.47 (s.

IH), 13.25 (s, 1) 1) Elemental analysis value: (C10)19NO3〉0% 8%
N% Calculated value 71.71 3.61 5.58 Actual value 71.43 3.68 5.40 Example 2 Instead of using diethyl 2-methoxyphenylmalonate, diethyl 2.4-dimethoxyphenylmalonate or 2.5 The following compounds were synthesized in the same manner as in Reference Example 1 except that diethyl -dimethoxyphenylmalonate was used.

Melting point: >300℃ IR (KBr): vco 1625 cm
-'NMR (d6-DMSO) δ: 6.89-7.12 (m, 4H), 7
．． 89-8.25 (m.

2H), 9.81(s, IH), 10.3
6 (s, iH).

12,95 (br-s, 1)1) Elemental analysis value'
(as C+, HsNOl) 0% 8% N
% Calculated value 67.42 3.39 5.24 Actual value 67.29 3.40 5.38
Point: >300℃ IR (KBr): L'CO1630Cm-'NM
R(d6-DMSO) δ: 6.67-6.91 (m, 3H), 7.39
~8.09 (m.

31(), 9.36(s, l1l), 10.32
(s, IH).

12.99 (s, 1) 1) Elemental analysis value' (as CIS+49NO4) 0%
8% N% Calculated value 67.42 3.39 5.24 Actual value 67.69 3.48 5J6 Example 3 Bone resorption inhibitory effect Bone resorption inhibitory effect was evaluated in "Tissue Culture Applied Research Methods" 111-11
Measurement was performed according to the method described on page 4 (edited by Satoshi Yamane and Hiroyoshi Endo, published by Soft Science Publishing, 1985).

After extracting the 10-11-day-old chicken embryo femur and thoroughly removing the soft tissue attached to the bone, the benzoflo C2 of the present invention,
3-b) Using phenol red-free BGJb-HW2 culture solution (hereinafter referred to as culture solution) 1rd to which a quinoline derivative has been added, preculture is performed at 37° C. for 1 day by a rotary culture method. The compound of the present invention is first dissolved in dimethyl sulfoxide to prepare a 0.1 molar solution, which is diluted 1000 times with a culture medium to give a 10-4 molar concentration. In addition, a control group is cultured with the same volume of dimethyl sulfoxide alone added.

The next day, dissolve "CaC1" in a fresh culture solution to a concentration of 1 μCi/-, immerse the precultured chicken embryo femur in 1 ml, and culture with shaking at 37°C for 2 hours. Bone mineral is labeled with 4SCa. Immediately after culturing, the cultured bone is washed with phosphate buffered saline that has been preheated to 37°C to remove 4SCa attached to the bone.This 45Ca Culture the labeled cultured bone again in culture medium using the rotation culture method (rotating 10 times).12.24
．． 48. Every 72 hours, a certain 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. 4SCa radioactivity in the fractionated culture solution was measured using a liquid scintillation counter, and 4SCa radioactivity in the whole culture solution was measured.
Calculate the radioactivity of SCa. After culturing, the bone tissue was
The bone is left in normal 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 bone cells 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'A.

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

1% for the group of compounds of the invention compared to a value of 1% for the control group.
A large value indicates that the compound of the present invention has a bone resorption inhibitory effect. The efficacy of the bone resorption inhibitory effect of the compound of the present invention is determined by the following formula using the value of T'A.

The results are shown below.

[Compound] [Efficacy of bone resorption inhibitory action] Compound 1 1.78 Compound 2 2.59 Compound 3 1.93 Example 4 Osteogenesis promoting effect Osteogenesis promoting effect was observed in "Tissue Culture Applied Research Methods" 103-11
The measurement was performed according to the method described on page 1 (edited by Satoshi Yamane and Hiroyoshi Endo, published by Soft Science Publishing, 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 used as the compound group of the present invention and the other as the control group, and a rectangular plate for culture was used. Attach it one by one to the inner surface of the test tube, and add BGJb-HW to it.
2 culture solution (hereinafter referred to as culture solution) 21T+7! Add it, seal it with a silicone stopper, and incubate by rotating at 37℃ (10 rotations).
do. The compound of the present invention is first dissolved in dimethyl sulfoxide to prepare a 0.1 molar solution, which is diluted 1000 times with a culture medium to a 10-4 molar concentration. In addition, a control group is cultured with the same volume of dimethyl sulfoxide alone added.

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

At the end of the culture, wash the cultured bone with phosphate buffered saline,
Calcium is eluted from the bone tissue by leaving it in normal hydrochloric acid for one day, and the eluted Cal is quantified 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.

The results are shown below.

Compound Compound with osteogenesis promoting effect 21.
44 Example 5 Acute toxicity 3.8-dihydroxy-6-day-benzofuro [2,3-b
) Quinolin-11-one was suspended in CMC, and 10 male and 10 male and female 7-week-old ICR mice were used.
00.30001 g/kg was orally administered and observed for 7 days. There were no deaths and no symptoms of toxicity were observed in either group.

Example 6 Preparation of formulation (a) Tablet 3.8-dihydroxy-6H-benzofuro (2,3-b
]] Mix 100 g of quinolin-11-one, 95 g of lactose and 40 g of corn starch, and then
% hydroxypropylcellulose aqueous solution and kneaded, dried, and added 8 g of calcium carboxymethyl cellulose and 7 g of calcium stearate to the dried product.
After adding and mixing, form into 1000 tablets.

(c) Capsule 3.8-dihydroxy-6H~Benzofuro[:2.3-
b]] Quinoline-11-one 100g, lactose 59
g and 35 g of corn starch were mixed, and 6 g of talc was added to the mixture and mixed, and then filled into 1000 hard capsules.

〔Effect of the invention〕

Benzofuro (2,3-
b ] Quinoline derivatives and their pharmacologically acceptable salts were found to be 1.
It exhibits significant bone resorption inhibiting and bone formation promoting effects at 0-4 to 10-' molar concentrations, and also exhibits significant bone resorption-inhibiting and bone formation-promoting effects at 1000 to 3000 mg.
/ kg was orally administered, there were no deaths and no serious poisoning symptoms were observed.

Therefore, benzofuro (
2,3-b) Quinoline derivatives are extremely useful compounds as therapeutic agents for osteoporosis.

Claims (1)

[Claims] Benzofuro[2,3-b]quinoline derivatives represented by the general formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (R in the formula is a hydrogen atom or a hydroxyl group) or their pharmacology A therapeutic agent for osteoporosis containing a sexually acceptable salt as an active ingredient.