JPS63295561A - 2-quinolone derivative - Google Patents

Abstract

NEW MATERIAL:The compound of formula I [R<1> is 2-10C alkyl or (OH, carboxy, carbamoyl or alkoxycarbonyl-substituted) 1-6C alkyl; R<2> is H or 1-4C alkyl]. EXAMPLE:4-Hydroxy-7-isopentyloxy-3-phenyl-2-quinolone. USE:A drug. A remedy for osteoporosis. It has low toxicity and exhibits bone- resorption suppressing action and osteogenesis-promoting action. It is administered orally at a dose of 10-1,000mg daily for adult or parenterally at a dose of 1-100mg daily for adult in the form of injection, etc. PREPARATION:A compound of formula I wherein R<2> is H can be produced by heating a compound of formula II and diethyl phenylmalonate of formula III in a solvent such as diphenyl ether or in the absence of solvent. The obtained compound can be converted to another compound of formula I wherein R<2> is 1-4C alkyl by conventional alkylation process.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel 2-quinolone derivative useful as a pharmaceutical.

More specifically, the object of the present invention is to provide the general formula (I), which has a bone resorption inhibitory effect and an osteogenesis promoting effect and is useful as a therapeutic agent for osteoporosis. A straight or branched alkyl group having 1 to 6 carbon atoms, or having one hydroxyl group, carboxy group, carbamoyl group, or alkoxycarbonyl group as a substituent; and R2 is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms.

[Conventional technology]

Osteoporosis is a pathological condition in which bone mass is decreased without any change in the chemical composition of bones, and its physiological characteristics are a decrease in protein, calcium, and phosphorus in 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.

There are a wide variety of causes of osteoporosis, including endocrine and nutritional disorders, but vitamin D preparations, calcium preparations, calcitonin preparations, phosphorus preparations, etc. that have been used as therapeutic agents for osteoporosis have been limited in scope. However, since the effectiveness of these drugs is uncertain, there is a strong desire to develop formulations that are more effective.

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-benzopyran-4-one derivatives have a bone resorption inhibitory effect and are useful as therapeutic agents for osteoporosis (Japanese Patent Publication No. 54-13391
JP-A-60-48924, JP-A No. 60-54379, JP-A No. 60-132917, JP-A No. 60-132976)
.

Until now, as 2-quinolone derivatives such as those of the present invention, compounds represented by the formula or the formula [pretinone] have been known.
The Chemical Society on Japan (Bu
ll, Chen+, Sac, Jpn,) 5
Volume 3, pages 1057-1060, 1980;
Journal on Heterocyclic Chemistry (J, HeterocyclicChem,) 21
Volume, pages 737-7'39, 1984].

However, these are all benzofuro (3,2
-c) Quinoline derivative or benzofuro [2゜3-b
] It was synthesized as an intermediate in the production of quinoline derivatives, and nothing has been described about its pharmacological action. Furthermore, it has not been reported at all that the 2-quinolone derivatives 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-4H-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 that have a stronger bone resorption inhibitory effect, and found that certain 2-quinolone derivatives or their pharmacologically acceptable salts have a stronger bone resorption inhibitory effect. However, it has been found that it has low toxicity and can be used as a therapeutic agent for osteoporosis that is 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 exhibits a strong bone resorption inhibitory effect, has low toxicity, and is highly safe and excellent for osteoporosis. It is a compound useful as a therapeutic agent.

Although the 2-quinolone derivative of the present invention represented by the general formula (1) is a new compound, all of them can be prepared by methods described in literature, such as Pretin on the Chemical Society of Japan (Bull).

Chem, Sac, Jpn,) 53 volumes,
Pages 1057-1060.

1980; Journal on Heterocyclic Chemistry (J, Heter
cyclic Chem, ) vol. 21, 737~
739, 1984, or similar methods thereof.

For example, among the 2-quinolone derivatives represented by the above general formula (I), a compound represented by the general formula H (in which R' has the same meaning as above) in which R2 is a hydrogen atom, It can be produced by heating a compound represented by the formula (R' in the formula has the same meaning as above) and diethyl phenylmalonate represented by the formula in a solvent or in the absence of a solvent.

The 2-quinolone derivative represented by the general formula (I) of the present invention in which R2 is an alkyl group is obtained by alkylating the obtained compound represented by the general formula (■') by a conventional method. It can be manufactured by

In this production method, the general formula (
ff) The compounds represented by formula (I) are all known compounds and can be produced manually as commercially available products or by methods described in literature or similar methods thereof.

The 2-quinolone permeable conductor of the present invention represented by 2N) 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
Quinolone derivatives in which R2 is a hydrogen atom or R' is an alkyl group having a carboxyl group as a substituent are added to an alcohol solution containing an equivalent amount of sodium hydroxide, heated, and then treated under reduced pressure. The sodium salt can be obtained by concentrating it to .

The 2-quinolone derivative represented by the general formula (I) of the present invention 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.

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

The 2-quinolone derivative represented by the general formula (1) of the present invention or a pharmacologically acceptable salt thereof was found to be present at a molar concentration of 10-4 to 10-5 in an in vitro experiment using chicken embryo femur. Shows significant bone resorption inhibitory effect. Moreover, 100
Even when administered orally at a dose of 0 to 3000 mg/kg, there were no deaths and no toxic symptoms were observed, so it is useful as a highly safe osteoporosis therapeutic agent.

〔Example〕

In order to further explain the present invention in detail, reference examples and examples are given below. Note that all melting points of compounds in each example are uncorrected.

Reference Example 1 3.78 g of 3-isopentyloxyaniline m-nitrophenol was dried to about 60 m/! of ethyl methyl ketone! To this was added 5.5 g of inamylpromide 40d1 anhydrous potassium carbonate, and the mixture was heated under reflux. The cold insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was dissolved in an appropriate amount of methylene chloride, washed successively with an aqueous sodium hydroxide solution and water, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was dissolved in an appropriate amount of ethanol and catalytically reduced in the presence of palladium on carbon at normal pressure. After the reaction was completed, the catalyst was filtered off, and the solvent was distilled off under reduced pressure. The residue was dissolved in an appropriate amount of diluted hydrochloric acid, washed with methylene chloride, made alkaline with sodium hydroxide, and extracted with methylene chloride. The extract was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 2.9 g (80%) of 3-isopentyloxyaniline.

NMR (CDCI, ) δ: 0.95 (d, 6H), 1.65 (q, 2
)1), 1.74-1.87 (m, LH), 3.
94 (t, 2H), 6.24-6.34 (m.

3H), 7.01-7.07 (m, IH) Reference example
2 The following aniline derivative was synthesized in the same manner as in Reference Example 1 except that the corresponding alkyl halide was used in place of inamyl bromide.

3-isopropoxyaniline NMR (d, -DMSO) δ: 1.34 (d, 68), 2.62 (Quin
t, IH), 6.95-7.0Hm, IH) 3-(1-ethoxycarbonylethoxy)aniline NM
R(CDCI,) δ: 1.25(t, 3H), 1.35(d
, 3) 1), 4.2Hq.

2H), 4.70(q, LH), 6.24
~6.32 (m, 3H).

6, 99-7.05 (m, IH) 3-(3-hydroxypropoxy)aniline NMR (CDCI, ) δ: 2.02 (quint, 2H), 3.85 (
t, 2H), 4.08(t, 2H), 6.24
~6.34 (m, 3H), 7.02~7,08 (
m, IH) 3-(1-methylhebutyloxy)aniline NMR (C
DCI, ) δ: 0.88 (t, 3B), 1.26-1.72
(m, 13H).

4, 26-4.33 (in, 01), 6.23
~6.33 (m.

3H), 7.00-7.07 (m, IH) Example
1 3-Isopentyloxyaniline 500 ■ Tophenyl diethyl malonate 598 mg Tosiphenyl ether 3 d
and heated under reflux at 270-280°C for 1.5 hours. After cooling, the reaction mixture was dissolved in a 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. 4-hydroxy-7
-Isopentyloxy-3-phenyl-2-quinolone 5
90■ (73.1%) was obtained.

Melting point = 286-288℃ IR (Kerb: ”Co 1620. 158
0 Cm-'NMR (d6-DMSO) δ: 0.95 (6,68), 1.65 (q, 2H
), 1.75-1.85 (m, IH), 4.04
(t, 2H), 6.77-6.80 (m, 2H)
.

7.25-7.37 (m, 5H), 7.84 (d,
IH), 11.24 (s.

Elemental analysis value' (as C20H21NO3) 0%
8% N% Calculated value 74.28 6.54 4.33 Actual value 74.10 6.58 4.23 Example 2 Using the aniline derivative synthesized in Reference Example 2 instead of 3-isopentyloxyaniline, etc. The following compound was synthesized in the same manner as in Example 1.

4-hydroxy-7-imbropoxy-3-phenyl-
2-quinolone melting point: >300°C IR (KBr): νco 1645 cm-
'NMR (d@-DMSO) δ: 1.43 (tun 68), 4.71-4.8
0 (m, IH).

6.87-6.9Hm, 21(), 7.37-7.
53 (m.

58), 7.96(d, IH), 11.36
(s, 1) 1) Elemental analysis value' (C+5H1JO
s) 0% 8% N% Calculated value? 3.20 5.80 4.74 Actual value 72,96 5.86 4.61
Point: 279-280°C IR (KBr): vca 1630. 160
0 c+yr'NMR (d6-DMSO) δ: 1.54 (d, 3H), 4.86 (q,
1N), 6.74-6.78 (m, 2H)
, 7.25-7.41 (m, 5H), 7.
85 (d.

IH), 11.31 (s, LH) elemental analysis value'
(as C+eH+5NOs) 6% 8%
N% Calculated value 66.46 4.65 4.31 Actual value 66.27 4.70 4.06
Point: 287-290t: (Decomposition) IR (KBr)
: vca1620. 1590 cm-'
NMR(d6-DMSO)δ: 1.9
0 (quint, 2H), 3.52 (t, 2N)
, 4.08 (t, 2H), 6.76-6.79
(m, 2H), 7.25-7.41 (m, 5H
), 7.83-7.86 (m, IH).

11.27 (s, IH) Elemental analysis value' (as C+JI+JL) 6%
8% N% Calculated value 69.44 5.50 4.50 Actual value 69.14 5.60 4.69
Point = 262~264℃ IR (KBr): vco 1630 cm-
'NMR (d, -DMSO) δ: 0.86 (t, 3ft>, 1.27-6.8
(m, 13ft).

4.45 (q, 1) 1), 6.75-6.78 (m
, 2H).

7.24-7.40 (m, 5) 1), 7.83 (d
, 1N).

11.23 (s, IH) Elemental analysis value: (as CzsHzJOs) 6%
8% N% Calculated value? 5.59 7.45 3.83 Actual value? 5.46 7.60 3.93 Example 3 323 mg of 4-hydroxy-7-isopentyloxy-3-phenyl-2-quinolone was dissolved in dry N,N-dimethylformamide 10- and 60% hydrogenated. After adding 50 mg of sodium (oil-based) and stirring for a while, 500 mg of ethyl iodide was added and stirred overnight at room temperature.

The solvent was distilled off under reduced pressure, a 5% aqueous sodium hydroxide solution was added to the residue, and the crystals were collected by filtration. After washing with water and diethyl ether, it was recrystallized from ethyl acetate-diethyl ether to obtain 63 mg (17.9%) of 4-ethoxy-7-isopentyloxy-3-phenyl-2-quinolone.

Melting point: 224-226°C IR (KBr)'L'co 1630. 16
00 cm-'N! , I R(d, −D M
S O) δ: 0.95 (d, 6H), 1.05
(t, 3N), 1.655(q.

2H), 1.76-1.83 (m, 1ft),
3.58 (q.

2H), 4.06 (t, 2ft), 6.81~6
．． 85 (m, 2H).

7.31~7.43 (m, 5H), 7.70~
7.74 (m.

1ll), 11.61 (S, 1) 1) Elemental analysis value' (as CiaLsNO,) 6% 8%
N% Calculated value 75.19 7.17 3.99 Actual value 74.94 7.13 4.13 [Effect of the invention] 2-quinolone derivatives represented by general formula (I) of the present invention and their pharmacology In vitro experiments using chicken embryo femurs show that these salts have a strong inhibitory effect on bone resorption. Moreover, there were no cases of death and no serious symptoms of toxicity were observed even after oral administration of 1000 to 3000 mg/kg.

As described above, the 2-quinolone derivative represented by the general formula (I) of the present invention is an extremely useful compound as a therapeutic agent for osteoporosis.

Claims (1)

[Claims] General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 is a linear or branched alkyl group having 2 to 10 carbon atoms, or at least one hydroxyl group. , is a linear or branched alkyl group having 1 to 6 carbon atoms and having a carboxy group, carbamoyl group or alkoxycarbonyl group as a substituent, and R^2 is a hydrogen atom or a linear or branched alkyl group having 1 to 4 carbon atoms. 2-quinolone derivatives represented by (branched alkyl group)