JPH0696556B2 - 2-quinolone derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel 2-quinolone derivative useful as a medicine and a pharmacologically acceptable salt thereof.

More specifically, the object of the present invention is to provide a compound of the general formula (I) which has a bone resorption inhibitory action and an osteogenesis promoting action and is useful as a therapeutic agent for osteoporosis. (In the formula, R ¹ is a linear or branched alkyl group having 2 to 10 carbon atoms, or ^{1 to 1} carbon atoms having at least one hydroxyl group, carboxy group, carbamoyl group or alkoxycarbonyl group as a substituent. 6 is a straight-chain or branched alkyl group, and R ² is a hydrogen atom or a straight-chain or branched alkyl group having 1 to 4 carbon atoms. To provide a pharmacologically acceptable salt thereof.

[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, the 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 / 1988).
60-48924, 60-54379, 60-132917, 60-1329
No. 76).

So far, as 2-quinolone derivatives like the present invention, Or the expression The compound represented by
The Chemical Society of Japan (Bul
L.Chem.Soc.Jpn.) 53, 1057-1060, 1980; Journal of Heterocyclic Chem. 21: 737-739, 1984
Year〕.

However, all of these are benzofuro [3,2-
c] a quinoline derivative or a benzofuro [2,3-b] quinoline derivative, which was synthesized as a production intermediate.
Nothing is mentioned about its own pharmacological actions.
Furthermore, it has not been reported at all that the 2-quinolone derivative as in 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]

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, the present inventors have conducted extensive studies to find a compound having a stronger bone resorption inhibitory action, and as a result, a certain 2-quinolone derivative or a pharmacologically acceptable salt thereof has a strong bone resorption inhibitory action. However, it has been found that it has a low toxicity and can be a therapeutic agent for osteoporosis superior to conventional therapeutic agents.

The present invention is based on these findings.

[Means for solving problems]

The 2-quinolone derivative represented by the general formula (I) of the present invention or a pharmacologically acceptable salt thereof has a strong bone resorption inhibitory action, low toxicity, and high safety as an excellent osteoporosis therapeutic agent. It is a useful compound.

The 2-quinolone derivative represented by the above general formula (I) of the present invention is a novel compound, but all are described in the literature, for example, Bulletin of the Chemical Society of Japan (Bull.Chem.Soc.Jpn.). Volume 53, 1057-1
060, 1980; Journal of Heterocyclic Chem., Vol. 21, 737.
~ 739 pages, 1984, etc., or similar methods.

For example, in the 2-quinolone derivative represented by the general formula (I), R ² is a hydrogen atom. (Wherein R ¹ has the same meaning as described above) is represented by the general formula (Wherein R ¹ has the same meaning as described above), It can be produced by heating diethyl phenylmalonate represented by in a solvent or without a solvent.

The 2-quinolone derivative represented by the general formula (I) of the present invention in which R ² is an alkyl group is obtained by alkylating the obtained compound represented by the general formula (I ′) by a conventional method. It can be manufactured.

In the present production method, the compounds represented by the general formula (II) and the formula (III) used as raw materials are all known compounds, and are commercially available, or produced according to the method described in the literature or a method similar thereto. can do.

The 2-quinolone derivative represented by the general formula (I) of the present invention can be converted into a pharmacologically acceptable salt according to a conventional method. For example, 2- represented by the general formula (I) of the present invention
A quinolone derivative in which R ² is a hydrogen atom or R ¹
A compound in which is an alkyl group having a hydroxyl group or a carboxyl group as a substituent can be converted to a sodium salt by adding it to an alcohol solution in which an equivalent amount of sodium hydroxide is dissolved, warming the solution, and concentrating under reduced pressure. it can.

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

When the 2-quinolone derivative represented by the above general formula (I) of the present invention is used as a therapeutic agent for osteoporosis, it is about 1
10 to 1000 mg in a suitable dosage form, such as tablets, powders, capsules, etc., and is orally administered, or about 1 per adult per day
~ 100mg is parenterally administered as an injection.

The 2-quinolone derivative represented by the above general formula (I) of the present invention or a pharmacologically acceptable salt thereof is used in an in vitro experiment using a chicken embryo femur at a concentration of 10 ^-5 to 10 ^-4 molar. It shows a significant bone resorption inhibitory effect. Moreover, 1000 to 3000 mg / k
Since there are no deaths and no symptoms of poisoning even after oral administration of g, it is useful as a highly safe therapeutic agent for osteoporosis.

〔Example〕

Reference examples and examples are given below to further describe the present invention. The melting points of the compounds in each example are uncorrected.

Reference Example 1 3.78 g of 3-isopentyloxyaniline m-nitrophenol was dissolved in about 60 ml of dry ethyl methyl ketone, and 40 ml of isoamyl bromide was added thereto.
5.5 g of anhydrous potassium carbonate was added, and the mixture was heated under reflux overnight. After cooling, the insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was dissolved in an appropriate amount of methylene chloride, washed successively with aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in an appropriate amount of ethanol and subjected to catalytic reduction under atmospheric pressure in the presence of palladium carbon. After completion of the reaction, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in an appropriate amount of dilute hydrochloric acid, washed with methylene chloride, made alkaline with sodium hydroxide, and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure to obtain 2.9 g (80%) of 3-isopentyloxyaniline.

NMR (CDCl ₃ ) δ: 0.95 (d, 6H), 1.65 (q, 2H), 1.74 to 1.87 (m, 1H), 3.
94 (t, 2H), 6.24 to 6.34 (m, 3H), 7.01 to 7.07 (m, 1H) Reference Example 2 Instead of isoamyl bromide, a corresponding alkyl halide was used, and the same procedure as in Reference Example 1 was followed. Was synthesized.

3-isopropoxyaniline NMR (d ₆ -DMSO) δ: 1.34 (d, 6H), 2.62 (quint, 1H), 6.95 to 7.01 (m, 1
H) 3- (1-ethoxycarbonylethoxy) aniline NMR (CDCl ₃ ) δ: 1.25 (t, 3H), 1.35 (d, 3H), 4.21 (q, 2H), 4.70 (q,
1H), 6.24 to 6.32 (m, 3H), 6.99 to 7.05 (m, 1H) 3- (3-hydroxypropoxy) aniline NMR (CDCl ₃ ) δ: 2.02 (quint, 2H), 3.85 (t, 2H), 4.08 (t, 2H), 6.24
~6.34 (m, 3H), 7.02~7.08 (m, 1H) 3- (1- methyl-heptyloxy) aniline _{NMR (CDCl 3) δ: 0.88} (t, 3H), 1.26~1.72 (m, 13H), 4.26 ~ 4.33 (m,
1H), 6.23 to 6.33 (m, 3H), 7.00 to 7.07 (m, 1H) Example 1 4-hydroxy-7-isopentyloxy-3-phenyl-2-quinolone 3-isopentyloxyaniline 500 mg and phenylmalon 598 mg of diethyl acid was dissolved in 3 ml of diphenyl ether, and the mixture was heated under reflux at 270 to 280 ° C for 1.5 hours. After cooling, the reaction mixture was dissolved in 10% aqueous sodium hydroxide solution, neutral and basic substances were removed with diethyl ether, acidified with hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol-water. To give 590 mg (73.1%) of 4-hydroxy-7-isopentyloxy-3-phenyl-2-quinolone.

Melting point: 286 to 288 ° C IR (KBr): ν _CO 1620,1580cm ^-1 NMR (d ₆ -DMSO) δ: 0.95 (d, 6H), 1.65 (q, 2H), 1.75 to 1.85 (m, 1H), Four.
04 (t, 2H), 6.77 ~ 6.80 (m, 2H), 7.25 ~ 7.37 (m, 5H),
7.84 (d, 1H), 11.24 (s, 1H) Elemental analysis: (C ₂₀ as _{H 21 NO 3) C% H} % N% Calculated 74.28 6.54 4.33 Found 74.10 6.58 4.23 Example 2 3-isopentyloxy The following compounds were synthesized in the same manner as in Example 1 except that the aniline derivative synthesized in Reference Example 2 was used instead of aniline.

4-hydroxy-7-isopropoxy-3-phenyl-
2-quinolone Melting point:> 300 ° C. IR (KBr): ν _CO 1645 cm ⁻¹ NMR (d ₆ -DMSO) δ: 1.43 (d, 6H), 4.71 to 4.80 (m, 1H), 6.87 to 6.91 (m, 2
H), 7.37 to 7.53 (m, 5H), 7.96 (d, 1H), 11.36 (s, 1H) Elemental analysis value: (as C ₁₈ H ₁₇ NO ₃ ) C% H% N% Calculated value 73.20 5.80 4.74 Measured Value 72.96 5.86 4.61 7- (1-carboxyethoxy) -4-hydroxy-3
-Phenyl-2-quinolone Melting point: 279 to 280 ° C IR (KBr): ν _CO 1630,1600 cm ^-1 NMR (d ₆ -DMSO) δ: 1.54 (d, 3H), 4.86 (q, 1H), 6.74 to 6.78 (M, 2H), 7.
25〜7.41 (m, 5H), 7.85 (d, 1H), 11.31 (s, 1H) Elemental analysis value: (as C ₁₈ H ₁₅ NO ₅ ) C% H% N% Calculated value 66.46 4.65 4.31 Measured value 66.27 4.70 4.06 4-hydroxy-7- (3-hydroxypropoxy)-
3-Phenyl-2-quinolone Melting point: 287-290 ° C (decomposition) IR (KBr): ν _CO 1620,1590cm ^-1 NMR (d ₆ -DMSO) δ: 1.90 (quint, 2H), 3.52 (t, 2H) , 4.08 (t, 2H), 6.76
~ 6.79 (m, 2H), 7.25 ~ 7.41 (m, 5H), 7.83 ~ 7.86 (m, 1
H), 11.27 (s, 1H ) Elemental analysis: (C ₁₈ as _{H 17 NO 4) C% H} % N% Calculated 69.44 5.50 4.50 Found 69.14 5.60 4.69 4-hydroxy-7- (1-methyl-heptyloxy ) −
3-Phenyl-2-quinolone Melting point: 262-264 ° C IR (KBr): ν _CO 1630cm ^-1 NMR (d ₆ -DMSO) δ: 0.86 (t, 3H), 1.27-1.68 (m, 13H), 4.45 ( q, 1H),
6.75 ~ 6.78 (m, 2H), 7.24 ~ 7.40 (m, 5H), 7.83 (d, 1
H), 11.23 (s, 1H) Elemental analysis value: (as C ₂₃ H ₂₇ NO ₃ ) C% H% N% Calculated value 75.59 7.45 3.83 Measured value 75.46 7.60 3.93 Example 3 4-Ethoxy-7-isopentyloxy -3-phenyl-2-quinolone 4-hydroxy-7-isopentyloxy-3-phenyl-2-quinolone 323 mg was dissolved in dry N, N-dimethylformamide 10 ml, and 60% sodium hydride (oil-based)
After adding 50 mg and stirring for a while, 500 mg of ethyl iodide was added, and the mixture was stirred at room temperature overnight. The solvent was distilled off under reduced pressure, 5% aqueous sodium hydroxide solution was added to the residue, and crystals were collected by filtration. After washing with water and diethyl ether, it was recrystallized from ethyl acetate-diethyl ether to give 4-ethoxy-7-
63 mg of isopentyloxy-3-phenyl-2-quinolone
(17.9%) was obtained.

Melting point: 224 to 226 ° C IR (KBr): ν _CO 1630, 1600 cm ^-1 NMR (d ₆ -DMSO) δ: 0.95 (d, 6H), 1.05 (t, 3H), 1.655 (q, 2H), 1.76 ~
1.83 (m, 1H), 3.58 (q, 2H), 4.06 (t, 2H), 6.81 to 6.85
(M, 2H), 7.31 to 7.43 (m, 5H), 7.70 to 7.74 (m, 1H), 11.
61 (s, 1H) Elemental analysis value: (as C ₂₂ H ₂₅ NO ₃ ) C% H% N% Calculated value 75.19 7.17 3.99 Measured value 74.94 7.13 4.13 [Effect of the invention] Shown by the general formula (I) of the present invention. The 2-quinolone derivative and the pharmacologically acceptable salts thereof described above show a strong bone resorption inhibitory effect in an in vitro experiment using chicken embryo femur. In addition, there are no deaths even after oral administration of 1000 to 3000 mg / kg, and no serious poisoning symptoms are observed.

Thus, the 2-quinolone 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 (In the formula, R ¹ is a linear or branched alkyl group having 2 to 10 carbon atoms, or ^{1 to 1} carbon atoms having at least one hydroxyl group, carboxy group, carbamoyl group or alkoxycarbonyl group as a substituent. 6 is a linear or branched alkyl group, and R ² is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. A physically acceptable salt.