JPH0684301B2 - 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): (Wherein R is an alkoxy group, an alkenyloxy group, an aralkyloxy group, a carboxy group, a carbamoyl group or a cyano group) or a benzofuro [2,3-b] quinoline derivative or a pharmacologically acceptable thereof. The present invention provides a therapeutic agent for osteoporosis containing a salt capable of being treated.

[Prior Art] Osteoporosis refers to a pathological condition in which bone mass is reduced without affecting the chemical composition of bone, and its physiological characteristic is a decrease in proteins, calcium and phosphorus in bone.

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, the development of a more reliable formulation is strongly desired.

In recent years, a certain type of 3-
It has been reported that a phenyl-4H-1-benzopyran-4-one derivative has a bone resorption inhibitory effect and is useful as a therapeutic agent for osteoporosis (Japanese Patent Publication No. 54-13391, JP-A No. 60-489).
No. 24, No. 60-54379, No. 60-132917, No. 60-132976
issue).

Some of the benzofuro [2,3-b] quinoline derivatives of the present invention are known compounds, and were synthesized and reported by Kawase et al. [Bulletin of the Chemical Society of Japan (Bull. Chem. So
c. Jpn.) 53, 1057-1060, 1980; Journal
Of heterocyclic chemistry (J. Heterocy
clic Chem.) 16, 487-491, 1979].

However, these are all synthesized for the purpose of confirming their synthetic interest or chemical reactivity, and may have mutagenicity, carcinogenicity, or anticancer activity with regard to pharmacological activity. , But not the effect itself. Furthermore, it has not been reported at all until now that the benzofuro [2,3-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]

The 3-phenyl-4H-1-benzopyran-4-one derivative disclosed in the above-mentioned patent application has a weak bone resorption inhibitory action, and is by no means satisfactory as a therapeutic agent for osteoporosis. Therefore, the inventors of the present invention conducted extensive studies to find a compound having a stronger bone resorption inhibitory action, and found that a certain benzofuro [2,3-b] quinoline derivative or a pharmacologically acceptable salt thereof was strong. It has been 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 [2,3-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 osteogenesis promoting action, and is useful as a highly safe therapeutic agent for osteoporosis.

The benzofuro [2,3-represented by the general formula (I) of the present invention
b] The quinoline derivatives include some novel compounds, but all of them are described in the literature, for example, bulletin
Chemical Society of Japan (Bull.Chem.
Soc. Jpn.) 53: 1057-1060 (1980); Journal of Heterocyclic Chemistry (J. Hete)
rocyclic Chem.) 16, p.487-491 (1979) and the like, or a method similar thereto.

For example, benzofuro [2, represented by the above general formula (I)
3-b] quinoline derivative, wherein R is an alkoxy group, an alkenyloxy group or an aralkyloxy group. (Wherein R'is an alkyl group, an alkenyl group or an aralkyl group) is represented by the formula Manufactured by reacting a compound represented by the formula (I) with an alcohol derivative represented by the general formula R'-OH (III) (wherein R'has the same meaning as described above) in the presence of a base. You can

The benzofuro [2,3-represented by the general formula (I) of the present invention
b] The quinoline derivative in which R is a cyano group can be produced by reacting the compound represented by the above formula (II) with sodium cyanide, and the compound represented by the above general formula (I ) Benzofuro [2,3-b]
A quinoline derivative in which R is a carboxyl group or a carbamoyl group can be produced by hydrolyzing a compound in which R is a cyano group by an appropriate method.

In the production method, the above formula (II) used as a raw material
The compound represented by is a known compound, and is described in the literature, for example, Bulletin of the Chemical Society of Japan (Bull.Chem.Soc.Jpn.) 53, 1
It can be produced according to the method described on pages 057 to 1060 (1980), or a method similar thereto.

The benzofuro [2,3-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 [2,3-b] quinoline derivative represented by the general formula (I) of the present invention, R is a carboxyl group, benzofuro [2,3-b] quinoline-11-carboxylic acid is equivalent to Sodium hydroxide can be added to an alcohol solution in which the sodium hydroxide is dissolved, and the mixture is heated and then concentrated under reduced pressure to obtain a sodium salt.

The benzofuro [2,3-represented by the general formula (I) of the present invention
b) The quinoline derivative can be made into various pharmaceutical preparations according to a conventional method. That is, if necessary, an excipient, a disintegrating agent, a binder, a pharmaceutical agent such as a lubricant, and the like are mixed, and prepared according to a conventional method to prepare various preparations such as tablets,
It can be a powder, a capsule or the like.

The benzofuro [2,3-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 is injected Administered parenterally as a drug.

The benzofuro [2,3-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 an osteogenesis promoting action in an in vitro experiment using a chicken embryo femur, and is produced when a calcium-deficient diet is given. Significantly suppresses the decrease of calcium and phosphorus content in the bones. Moreover, since it has low toxicity and high safety, it is useful as an unprecedented excellent therapeutic agent for osteoporosis.

〔Example〕

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

Example 1 Kawase et al. [Bulletin of the Chemical Society of Japan (Bull.Chem.Soc.Jpn.) Volume 53]
Pp. 1057-1060 (1980)], the following compounds were synthesized. The constants of each compound were the same as those described in the literature.

11-ethoxy-benzo furo [2,3-b] quinoline (Compound 1) Melting point: 72-73 ° C. Elemental analysis: (as _{C 17 H 13 NO 2) C} % H% N% Calculated 77.55 4.98 5.32 Found 77.32 5.10 5.28 11-Methoxybenzofuro [2,3-b] quinoline (Compound 2) Melting point: 165 to 165.5 ° C Elemental analysis value: (as C ₁₆ H ₁₁ NO ₂ ) C% H% N% Calculated value 77.09 4.45 5.62 Actual measurement Value 76.83 4.51 5.49 11-Cyanobenzofuro [2,3-b] quinoline (Compound 3) Melting point: 242 to 243 ° C Elemental analysis value: (as C ₁₆ H ₈ N ₂ O) C% H% N% Calculated value 78.68 3.30 11.47 Found 78.53 3.46 11.31 11-carbamoylbenzofuro [2,3-b] quinoline (Compound 4) Melting point: 265-266 ° C Elemental analysis: (as C ₁₆ H ₁₀ N ₂ O ₂ ) C% H% N % calculated 73.27 3.84 10.68 Found 73.02 3.91 10.62 benzofuro [2,3-b] quinoline-11-carboxylic acid (compound 5) mp:> 300 ° C. elemental analysis: as (C ₁₆ H ₉ NO ₃ ) C% H% N% Calculated value 73.00 3.45 5.32 Measured value 72.86 3.52 5.29 Example 2 Using isopropyl alcohol, allyl alcohol and benzyl alcohol as alcohols, the reaction was performed according to the method of Kawase et al. The compound was synthesized.

11-Isopropyloxybenzofuro [2,3-b] quinoline (Compound 6) Melting point: 87-91 ° C NMR (CDCl ₃ ) δ: 1.51 (d, 6H), 5.03 (quint.1H), 7.38-8.33 (m , 8
H) Elemental analysis value: (as C ₁₈ H ₁₅ NO ₂ ) C% H% N% Calculated value 77.96 5.45 5.05 Actual value 77.93 5.51 5.02 11-allyloxybenzofuro [2,3-b] quinoline (Compound 7) Melting point : 99 to 101 ° C NMR (CDCl ₃ ) δ: 4.95 (t, 1H), 4.97 (t, 1H), 5.38 (dd, 1H), 5.55 (d
q, 1H), 6.19~6.31 (m , 1H), 7.39~8.34 (m, 8H) Elemental analysis: (C ₁₈ H ₁₃ as _{NO 2) C% H% N} % Calculated 78.53 4.76 5.09 Found 78.37 4.83 4.99 11-Benzyloxybenzofuro [2,3-b] quinoline (Compound 8) Melting point: 138 to 140 ° C NMR (CDCl ₃ ) δ: 5.47 (s, 2H), 7.34 to 8.28 (m, 13H) Elemental analysis value : (C as _{22 H 15 NO 2) C%} H% N% calculated 81.21 4.65 4.31 Found 81.06 4.73 4.28 example 3 bone resorption inhibiting effect bone resorption inhibitory action "tissue culture applied research methods" 111 to 114 pages ( Takashi Yamane, edited by Hiroyoshi Endo, published by Soft Science, 1
985) It was measured according to the method described.

After removing the femur bones of chicken embryos on the 10th to 11th day of incubation and thoroughly removing the soft tissues attached to the bones, benzofuro of the present invention [2,3-b]
Using 1 ml of BGJb-HW2 culture solution (hereinafter referred to as culture solution) that does not contain phenol red with quinoline derivative 37
Pre-culture is performed by a rotary culture method at 1 ° C. for 1 day. The compound of the present invention is once dissolved in dimethyl sulfoxide to prepare a 0.1 molar solution, which is then added to a culture solution at 1000
Dilute twice 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 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 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 separated ⁴⁵ Ca radioactivity in the culture broth was measured with a liquid scintillation counter to calculate the radioactivity of ⁴⁵ Ca in the whole broth. After completion of the culture, the bone tissue was left in 1N hydrochloric acid for 1 day to elute total calcium,
The radioactivity is measured and used as the final residual radioactivity in the 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.

Compound Bone resorption inhibitory effect Compound 1 1.57 Compound 2 1.11 Compound 3 1.12 Compound Bone resorption inhibitory effect Compound 4 1.07 Compound 5 1.17 Compound 6 1.43 Compound 7 1.18 Compound 8 1.14 Example 4 Bone formation promoting effect Bone The formation promoting action is described in “Tissue culture applied research method”, pp. 103-111 (edited by Yamane, and Endo Hiroyoshi, 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 this is diluted 1000-fold with a culture medium 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.

Compound Efficacy for promoting osteogenesis 11-Ethoxybenzofuro [2,3-b] quinoline 1.10 Example 5 Efficacy on calcium and phosphorus contents in rat bone fed a Ca-deficient diet Three-week-old Wistar males 20 rats, 2 per group, 10
The test compound, 11-ethoxybenzofuro [2,3-b] quinoline 300 mg / kg, was forcibly orally administered once daily in a CMC suspension to one group and divided into the other group. Was administered with a Ca-deficient diet and fed for 2 weeks, and the amount of calcium and phosphorus in the femur was measured.

The results are shown below.

Example 6 Acute toxicity 11-Ethoxybenzofuro [2,3-b] quinoline was applied to CMC, and 10 male and female 7-week-old ICR mice were used.
Oral administration of 000 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 7 Preparation of preparation (a) Tablets 11-ethoxybenzofuro [2,3-b] quinoline 100 g, lactose 95
g and 40 g corn starch, 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 11-ethoxybenzofuro [2,3-b] quinoline 100 g, lactose 59
g and 35 g of corn starch are mixed, and 6 g of talc is added to the mixture and mixed, and then 1000 hard capsules are filled.

〔The invention's effect〕

Benzofuro [2,3-b] represented by the general formula (I) of the present invention
Quinoline derivatives and their pharmacologically acceptable salts showed strong bone resorption inhibitory action and osteogenesis promoting action in in vitro experiments using chicken embryo femur, and also in rats produced when a calcium-deficient diet was given. Remarkably suppresses the decrease of calcium and phosphorus content in 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 (Wherein R is an alkoxy group, an alkenyloxy group, an aralkyloxy group, a carboxy group, a carbamoyl group or a cyano group) or a benzofuro [2,3-b] quinoline derivative or a pharmacologically acceptable thereof. A therapeutic agent for osteoporosis, which comprises the resulting salt as an active ingredient.