JPH0692411B2 - Novel benzofuroquinoline derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial field of application] The present invention relates to a novel benzofuro [3,2-
c] It relates to a quinoline derivative.

More specifically, the object of the present invention is to provide a compound of the general formula (Wherein R is a hydrogen atom or a group represented by the formula R ¹ -ABO-, R ¹ is a lower alkyl group or a lower aralkyl group, A is an oxygen atom or a sulfur atom, and B is a lower group. An alkylene group or a group represented by the formula: —CH ₂ —CH (OH) —CH ₂ —) is provided for providing a benzofuro [3,2-c] quinoline derivative.

The lower alkyl group and the lower alkylene group respectively represent a linear or branched alkyl group having 1 to 6 carbon atoms and an alkylene group. Further, the lower aralkyl group refers to a linear or branched alkyl group substituted with an aromatic ring and having 7 to 10 carbon atoms.

[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 spine, 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).

So far, as a benzofuro [3,2-c] quinoline derivative like the present invention, Or the expression Compounds represented by [Bretin of the Chemical Society of Japan
(Bull.Chem.Soc.Jpn.) Volume 53, pp. 1057-1060, 1980
Year; Journal of Heterocyclic Chem. 16: 487-491,
1979; 21: 737-739, 1984].

However, these are all synthesized for the purpose of confirming synthetic interest or chemical reactivity, and regarding pharmacological activity, there is a possibility that they may have mutagenicity, carcinogenicity or anticancer activity. It is only shown and nothing about its own action.
Further, it has not been reported at all until now that the benzofuro [3,2-c] quinoline derivative of the present invention has a bone resorption inhibitory action and is useful as a therapeutic agent for osteoporosis.

[Problems to be Solved by the Invention]

Some of the inventors of the present invention have already shown that the benzofuro [3,2-c] quinoline derivative, which is an analog of the present invention, has a bone resorption inhibitory action and a bone formation promoting action, and is useful as a therapeutic agent for osteoporosis. Heading in, we have already filed a patent application (Japanese Patent Application Sho
62-128672, 62-128673, 62-132946).

The present inventors have conducted extensive studies to find a more preferable therapeutic agent for osteoporosis than the above compounds, and as a result, the benzofuro [3,2-c] quinoline derivative of the present invention has been proposed as a benzofuro [3,2-c] quinoline derivative. Similarly, the compound of the present invention has a bone resorption inhibitory action and an osteogenesis promoting action, and further has a stronger bone elongation effect as compared with the above compounds, and thus the compound of the present invention may be a more preferable therapeutic agent for osteoporosis. Heading out, the present invention was completed.

The present invention is based on these findings.

[Means for Solving the Problems]

The benzofuro [3,2-represented by the general formula (I) of the present invention
The c] quinoline derivative exhibits a bone resorption inhibitory action and a bone formation promoting action, and is useful as a therapeutic agent for osteoporosis.

The benzofuro [3,2-represented by the general formula (I) of the present invention
The c] quinoline derivative can be produced as follows. For example, the general formula A benzofuroquinoline compound represented by the formula (R ² in the formula is a hydrogen atom or a hydroxyl group) is represented by the general formula R ¹ -ABX (III) (wherein X is a halogen atom or a p-toluenesulfonyloxy group). R ¹ , A and B have the same meanings as described above), and a compound represented by the following formula is used in an inert organic solvent such as dimethylformamide: potassium carbonate, sodium hydrogen carbonate,
It can be produced by reacting in the presence of a basic substance such as sodium hydroxide.

In particular, in the general formula (I), B is represented by the formula —CH ₂ —CH (O
The compound which is a group represented by (H) -CH _2- can also be produced by the following method. That is, the compound represented by the general formula (II) is (Where X is a halogen atom in the formula) is reacted with a compound represented by the general formula in an inert organic solvent such as dimethylformamide in the presence of a basic substance such as potassium carbonate and sodium hydrogen carbonate. (Wherein R ³ is a hydrogen atom or a 2,3-epoxypropoxy group) is obtained, and then, if necessary, in the presence of a basic substance such as triethylamine or a catalyst such as alumina. And reacting with a compound represented by the general formula R ¹ -AH (VI) (wherein R ¹ and A have the same meanings as described above) without solvent or in an inert organic solvent such as methanol or dioxane. The desired product can be produced by

In this production method, the compound represented by the general formula (II) used as a raw material is a method described in the literature, for example, Bulletin of the Chemical Society of Japan (Bull.Chem.Soc.Jpn.) 53, 1057-1060. page,
1980; Journal of Heterocyclic Chem., Vol. 16, 487-491, 1979; Vol. 21, 737-739, 1984, etc., or a method similar to them. can do.

Similarly, in the present production method, the compounds represented by the general formulas (III), (IV) and (VI) used as raw materials can be obtained as commercial products.

In the benzofuroquinoline derivative represented by the general formula (I) of the present invention, the compound having a hydroxyl group has an asymmetric carbon atom substituted with the hydroxyl group and has two types of isomers. However, the steric configuration may be the R configuration, the S configuration, or a mixture of the two.

The benzofuro [3,2-represented by the general formula (I) of the present invention
The c] 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 [3,2-represented by the general formula (I) of the present invention
c] 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 [3,2-represented by the general formula (I) of the present invention
The c] quinoline derivative shows significant bone resorption inhibitory action and osteogenesis promoting action at 10 ^-5 molar concentration in in vitro experiments using chicken embryo femur, and is useful as a therapeutic agent for osteoporosis.

〔Example〕

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

Example 1 3-Methoxymethoxy-5H-benzofuro [3,2-c] quinolin-6-one (Compound 1) 30 mg of 3-hydroxy-5H-benzofuro [3,2-c] quinolin-6-one was added to dimethylformamide. , Sodium hydroxide and 0.03 ml of chloromethyl ether were added, and the mixture was stirred for 16 hours. After completion of the reaction, water was added to the reaction solution, and the precipitated crystals were collected by filtration, washed with water, and dissolved in chloroform / methanol (15/1). The organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by thin layer chromatography to give 3-methoxymethoxy-5H-benzofuro [3,2-
13 mg of c] quinolin-6-one was obtained.

Melting point: 265 to 269 ° C IR (KBr): ν _co 1660cm ^-1 NMR (CDCl ₃ ) δ: 3.55 (s, 3H), 5.31 (s, 2H), 7.00 to 7.20 (m, 2H), 7.
40 ~ 7.50 (m, 2H), 7.60 ~ 7.70 (m, 1H), 8.04 (d, 1H),
8.20-8.35 (m, 1H), 10.27 (br-s, 1H) Example 2 3- (2-isopropoxyethoxy) -5H-benzofuro [3,2
-c] quinolin-6-one (compound 2) 2-isopropoxyethanol 54mg was dissolved in pyridine,
P-Toluenesulfonic acid chloride was added under ice cooling, and the mixture was stirred for 20 minutes. The reaction solution was acidified with diluted hydrochloric acid under ice cooling and extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate to obtain 110 mg of p-toluenesulfonyl isopropyl ether. 51 mg of this ether was dissolved in 1 ml of dimethylformamide, and 3-hydroxy-5H-benzofuro [3,2-
c] Quinoline-6-one (50 mg) and potassium carbonate (37 mg) were added, and the mixture was stirred at 80 ° C for 16 hr. The reaction solution was diluted with chloroform / methanol (20/1) and purified by thin layer chromatography to give 20 mg of 3- (2-isopropoxyethoxy)-
5H-benzofuro [3,2-c] quinolin-6-one was obtained.

Melting point: 210 to 216 ° C IR (KBr): ν _co 1660cm ^-1 NMR (d ₆ -DMSO) δ: 1.23 (d, 6H), 3,65 to 3.95 (m, 3H), 4.20 to 4.35 (m, 2
H), 7.05 ~ 7.20 (m, 2H), 7.50 ~ 7.70 (m, 2H), 7.85 ~ 8.
25 (m, 3H), 11.97 (br-s, 1H) Example 3 3- (2-Hydroxy-3-isopropoxypropoxy) -5H
-Benzofuro [3,2-c] quinolin-6-one (Compound 3) 3-Hydroxy-5H-benzofuro [3,2-c] quinolin-6-one 10.0 g was dissolved in dimethylformamide to give epibromohydrin 28.0 g and 5.5 g of potassium carbonate, 55 ℃
Then, the mixture was stirred for 3 hours. After completion of the reaction, water was added and the precipitated crystals were collected by filtration. The crystals were washed with water and then dried to obtain 11.8 g of 3- (2,3-epoxypropoxy) -5H-benzofuro [3,2-c] quinolin-6-one.

15 mg of this 3- (2,3-epoxypropoxy) -5H-benzofuro [3,2-c] quinolin-6-one was suspended in isopropyl alcohol, alumina was added, and the mixture was heated under reflux at 90 ° C. for 16 hours. After removing the alumina, the solvent was distilled off, and 3- (2-hydroxy-3-isopropoxy) -5H-benzofuro [3,2-
c] Quinoline-6-one 5 mg was obtained.

Melting point: 192-198 ° C IR (KBr): ν _co 1660 cm ^-1 NMR (d ₆ -DMSO) δ: 1.22 (d, 6H), 3.25-4.30 (m, 6H), 5.28 (d, 1H), 7.
05 ~ 7.20 (m, 2H), 7.50 ~ 7.65 (m, 2H), 7.90 ~ 8.25 (m,
3H), 11.97 (br-s, 1H) Example 4 The following compound was obtained in the same manner as in Example 3 except that benzyl alcohol was used instead of isopropyl alcohol.

3- (3-benzyloxy-2-hydroxypropoxy) -5H
-Benzofuro [3,2-c] quinolin-6-one (Compound 4) Melting point: 185 to 189 ° C IR (KBr): ν _co 1670cm ^-1 NMR (d ₆ -DMSO) δ: 3.50 to 4.80 (m, 7H ), 5.38 (br, 1H), 7.05 ~ 7.20 (m,
2H), 7.35 ~ 7.70 (m, 7H), 7.90 ~ 8.25 (m, 3H), 11.97
(Br-s, 1H) Example 5 3- (3-Ethylthio-2-hydroxypropoxy) -5H-benzofuro [3,2-c] quinolin-6-one (Compound 5) 3- (2,3-epoxy Propoxy) -5H-benzofuro [3,2-
10 mg of c] quinolin-6-one was suspended in methanol, 1.0 ml of ethyl mercaptan and 0.1 ml of triethylamine were added, and the mixture was heated at 70 ° C. The reaction solution was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% citric acid solution and water to obtain 11 mg of 3- (3-ethylthio-2-hydroxypropoxy) -5H-benzofuro [3,2-c] quinolin-6-one.

Melting point: 206-209 ° C IR (KBr): ν _co 1660,1670cm ^-1 NMR (d ₆ -DMSO) δ: 1.33 (t, 3H), 2.60-2.95 (m, 4H), 4.05-4.30 (m, 3
H), 5.44 (d, 1H), 7.05 ~ 7.20 (m, 2H), 7.50 ~ 7.70 (m,
2H), 7.90-8.25 (m, 3H), 11.98 (s, 1H) Example 6 Instead of 3-hydroxy-5H-benzofuro [3,2-c] quinolin-6-one, an equimolar amount of 3, The following compounds were synthesized in the same manner as in Example 1 except that 9-dihydroxy-5H-benzofuro [3,2-c] quinolin-6-one was used and other reaction reagents were used in a 2-fold molar amount.

3,9-Bis (methoxymethoxy) -5H-benzofuro [3,2-
c] Quinoline-6-one (Compound 6) Melting point: 246 to 250 ° C IR (KBr): ν _co 1660cm ^-1 NMR (d ₆ -DMSO) δ: 3.5 (s, 6H), 5.41 (br-s, 4H ), 7.10 ~ 7.35 (m, 3H),
7.64 (d, 1H), 8.00-8.10 (m, 2H), 11.99 (br-s, 1H) Example 7 3- (2,3-epoxypropoxy) -5H-benzofuro [3,2-
c] instead of quinolin-6-one, equimolar amounts of 3,9-bis (2,3-epoxypropoxy) -5H-benzofuro [3,2-c]
The following compounds were synthesized in the same manner as in Example 5 except that quinolin-6-one was used and the other reaction reagents were used in a 2-fold molar amount.

3,9-bis (3-ethylthio-2-hydroxypropoxy)-
5H-benzofuro [3,2-c] quinolin-6-one (Compound 7) Melting point: 185 to 188 ° C IR (KBr): ν _co 1650cm ^-1 NMR (d ₆ -DMSO) δ: 1.20 to 2.95 (m, 14H), 4.05 ~ 4.30 (m, 6H), 5.35 ~ 5.
50 (m, 2H), 7.05 to 7.25 (m, 3H), 7.56 (d, 1H), 8.04
(T, 2H) Example 9 Bone resorption inhibitory action Bone resorption inhibitory action was determined by "Tissue culture applied research method", pp. 111-114 (Takeshi Yamane, edited by Hiroyoshi Endo, Soft Science Publishing, 1
985) It was measured according to the method described.

After removing the femur bone of the embryo 10 to 11 days of incubation and well removing the soft tissue attached to the bone, benzofuro of the present invention [3,2-c]
Using 1 ml of a BGJb-HW2 culture solution (hereinafter referred to as a culture solution) supplemented with a quinoline derivative, preculture is carried out at 37 ° C. for 1 day by a rotary culture method. The compound of the present invention is once dissolved in dimethyl sulfoxide to prepare a 0.01 molar solution, which is diluted 1000-fold with a culture medium to a concentration of 10 ^-5 molar. 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). Precisely aliquot a fixed amount of culture solution from the culture solution every 2, 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] [Efficacy of bone resorption inhibitory effect] Compound 4 1.01 Compound 5 1.10 Compound 6 1.05 Compound 7 1.01 Example 10 Osteogenesis promoting action The osteogenesis promoting action is described in "Tissue Culture Applied Research Method", pages 103 to 111 (Yamane, Edited by Hiroyoshi Endo, Published by Soft Science, 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. Attach one tube to each inner surface of the tube, add 2 ml of BGJb-HW2 culture solution (hereinafter referred to as culture solution) to the tube, and seal with a silicon stopper.
Incubate the cells at 7 ° C (10 times / hour). The compound of the present invention is once dissolved in dimethyl sulfoxide to prepare a 0.01 molar concentration solution, which is diluted 1000-fold with a culture medium to a concentration of 10 ⁻⁵ 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 of bone formation promoting action Compound 1 1.03 Compound 3 1.06 Compound 5 1.07 Compound 6 1.05 In addition, the potency in bone elongation action was determined by the following formula.

The results are shown below.

Compound Efficacy of bone elongation effect Compound 1 1.05 Compound 2 1.05 Compound 5 1.03 [Effect of the invention] Benzofuro [3,2-c] represented by the general formula (I) of the present invention
Quinoline derivatives have significant effects on osteogenesis promoting action and bone resorption inhibiting action such as increasing calcium content in bone or bone elongation effect at 10 ^-5 molar concentration in in vitro experiments using chicken embryo femur. Show.

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

Claims (1)

[Claims] 1. A general formula (Wherein R is a hydrogen atom or a group represented by the formula R ¹ -ABO-, R ¹ is a lower alkyl group or a lower aralkyl group, A is an oxygen atom or a sulfur atom, and B is a lower group. An alkylene group or a group represented by the formula: —CH ₂ —CH (OH) —CH ₂ —) and a benzofuro [3,2-c] quinoline derivative.