JPH0780868B2 - Coumarin derivative - Google Patents

Description

TECHNICAL FIELD The present invention relates to a novel coumarin derivative.

2. Description of the Related Art The coumarin derivative of the present invention is a novel compound not described in the literature.

Problems to be Solved by the Invention An object of the present invention is to provide a compound useful as a medicine as described below.

Means for Solving Problems According to the present invention, a compound represented by the following general formula (1) is provided.

[In the formula, R ¹ is a hydrogen atom and R ² is Or Or R ¹ is Or And R ² represents a hydrogen atom. ) The compound of the present invention represented by the above general formula (1) has an action to relieve convulsions (convulsive inhibitory action), and therefore epilepsy, tremor paralysis, convulsive paralysis, Thomsen's disease and the like caused by striated muscle spasm It is useful as a remedy for breathing, gastric cramps, and angina due to smooth muscle spasms.

The compound of the present invention can be produced according to the types of R ¹ and R ^{2 in} the general formula (1), for example, by the methods shown in the following reaction process formulas -1 to -4.

<Reaction process formula-1> According to Reaction Scheme-1, the compound (1a) of the present invention can be produced from the known 4-geranyloxycoumarin (2).

The above method is carried out by reacting the compound (2) with a peroxide in a suitable inert solvent. Here, the inert solvent is not particularly limited, and various known solvents that do not adversely affect the reaction can be widely used. Specific examples thereof include ethers such as diethyl ether, dioxane and tetrahydrofuran, and halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. As the peroxide, any of various known ones can be used, and particularly preferable ones are, for example, m-chloroperbenzoic acid, perchlorobenzoic acid, onoperoxyphthalic acid, performic acid and peracetic acid. Can be exemplified. The reaction is generally about -20 to
About 40 ℃, preferably about 15 ~ 25 ℃ temperature conditions,
It takes about 1 to 24 hours, preferably about 15 hours. The amount of the above-mentioned peroxide to be used is not particularly limited, but is usually in the range of about equimolar amount, preferably about 1 to 1.2 times the molar amount with respect to the compound (2) as a raw material. Is good.

<Reaction process formula-2> According to Reaction Scheme-2, the compound of the present invention (1b) can be produced from the compound of the present invention (1a).

The above method is carried out by hydrolyzing the compound (1a) in the presence of a suitable acid in a suitable inert solvent. As the inert solvent, various kinds of solvents similar to those shown in the above reaction process formula-1 can be used, and dioxane, tetrahydrofuran and the like are particularly preferable. As the acid, any of various known acids can be used. As typical examples thereof, for example, perchloric acid, diluted hydrochloric acid, diluted sulfuric acid, p-
Examples thereof include toluene sulfonic acid. The above-mentioned oxidation reaction is generally carried out under a temperature condition of about -20 to 40 ° C, preferably about 15 to 25 ° C, for about 0.5 to 2 hours, preferably about 1 hour. The amount of the acid used is usually selected from the range of at least about 0.1 times the molar amount of the compound (1a), preferably about 0.5 to 2 times the molar amount.

<Reaction process formula-3> According to the reaction process formula-3, the compound of the present invention (1c) is obtained from the known 7-geranyloxycoumarin (aurpten) (3).
Can be manufactured.

The above method is carried out by reacting compound (3) with a suitable oxidizing agent in a suitable inert solvent. Here, as an inert solvent, any of various ordinary solvents that do not adversely affect the above reaction can be used. Specific examples thereof include alcohols such as methanol, ethanol and butanol, ketones such as acetone, methyl ethyl ketone and diisobutyl ketone, and aromatic hydrocarbons such as benzene, toluene and xylene. As the oxidizing agent, various known ones can be used, and selenium dioxide is particularly preferable. The above-mentioned oxidation reaction is generally carried out under a temperature condition of about 20-100 ° C, preferably about 60-80 ° C for about 1-20 hours, preferably about 7 hours.
It takes ~ 10 hours. The amount of oxidant used is
It is usually selected from the range of at least an equimolar amount, preferably about 2-3 times the molar amount of the compound (3).

According to the reaction shown in the above reaction process formula-3, auraptenal [compound (4) used as a raw material in the method shown in the following reaction process formula-4] is produced together with the objective compound (1c) of the present invention. However, each compound can be easily separated from the reaction system.

<Reaction process formula-4> According to the above reaction process formula-4, auraptenal (4)
Thus, the compound (1d) of the present invention can be produced.

The above method is carried out by reacting compound (4) with a suitable reducing agent in a suitable inert solvent. Here, as an inert solvent, any of various ordinary solvents that do not adversely affect the above reaction can be used. Specific examples thereof include alcohols such as methanol, ethanol and butanol, and a mixed solvent of the above solvent and water. As the reducing agent, various known agents such as tetracarbonyl ferrate derived from iron pentacarbonyl can be used. The reduction reaction is generally performed at a temperature of about -20 to 40 ° C, preferably about 15 to 25 ° C for about 5 to 24 hours, preferably about 15 to 20 ° C.
It takes about time. The amount of the reducing agent used is usually selected from the range of at least an equimolar amount, preferably about 4 times the molar amount of the compound (4).

The compound of the present invention obtained in each of the above steps can be easily isolated and purified from the reaction system by a usual separation means. Examples of the separating and purifying means include solvent extraction method, solvent dilution method, column chromatography, preparative thin layer chromatography and the like.

The compound of the present invention thus obtained can be administered to humans and animals as it is or in the form of a pharmaceutical preparation containing the compound as an active ingredient together with a conventional pharmaceutical carrier. The form of the pharmaceutical preparation containing the compound of the present invention, its preparation, its administration route and the like can be the same as those of ordinary pharmaceutical preparations.

That is, the compound of the present invention is formulated orally or non-orally in the form of tablets, granules, capsules, oral preparations such as oral solutions and parenteral preparations such as injections containing the effective amount thereof. It can be administered orally. The above-mentioned various forms of preparations
The carrier prepared by a conventional method and used at that time may be any of various commonly used carriers. For example, a tablet is prepared by mixing the compound of the present invention as an active ingredient with an excipient such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, and shaping. Capsules are prepared by mixing the above-mentioned active ingredient with an inert formulation filler or diluent and filling it into hard gelatin capsules, soft capsules or the like. Parenteral administration agents such as injections are produced by dissolving or suspending the compound of the present invention as an active ingredient in a sterilized liquid carrier. Examples of preferred carriers used here include water and physiological saline.

The amount of the compound of the present invention to be contained in the pharmaceutical preparation prepared as described above is not particularly limited and is appropriately selected from a wide range, but it is usually about 1 to 70% by weight in the pharmaceutical composition, preferably The amount is preferably about 1 to 30% by weight.

The pharmaceutical preparation thus obtained is administered by various administration routes depending on the form of the preparation, the age, sex and other conditions of the patient to whom the preparation is applied, the degree of disease and the like. For example, oral agents such as tablets, granules and capsules are orally administered. Parenteral agents such as injections are intravenously administered alone or in admixture with usual replenishers such as glucose and amino acids, or if necessary, intramuscularly, sarcasmally, subcutaneously or intraperitoneally. .

The dose of the above-mentioned pharmaceutical preparation is appropriately selected according to the form of the pharmaceutical preparation, usage, patient's age, sex and other conditions, degree of disease, etc., but the active ingredient usually contained in the preparation (the present The amount of the invention compound) is about 0.1 to 20 mg per 1 kg of body weight per day.
The amount should be a moderate amount, and it is generally administered once to several times a day. The amount of the active ingredient compound in the dosage unit form is appropriately selected from the range of about 1 to 200 mg.

Examples Hereinafter, in order to explain the present invention in more detail, production examples of the compound of the present invention will be given as Examples, and then pharmacological test examples will be given.

Example 1 400 mg of 4-geranyloxycoumarin is dissolved in 20 ml of ether, and 463 mg of an ether solution of m-chloroperbenzoic acid is added to the solution, and the mixture is stirred overnight at room temperature, which is washed with an aqueous sodium hydrogen carbonate solution and warm water. The extract was dried over anhydrous magnesium sulfate and concentrated. Obtained oily substance 464.7 m
g was subjected to silica gel column chromatography and eluted with benzene / acetone (95 / 15V / V). The eluate was concentrated and again subjected to silica gel column chromatography,
Elution with benzene / acetone (95/5). The solvent was distilled off under reduced pressure to obtain 370 mg of 4-geranyloxycoumarin epoxide.

Properties: Oily substance ¹ H-NMR (CDCl ₃ ) δ: 1.29 (6H, s), 1.80 (3H, s), 2.29 (4, m), 2.72 (1H,
t, J = 6.0Hz), 4.70 (2H, d, J = 6.6Hz), 5.59 (1H, t, J
= 6.6Hz), 5.69 (1H, S), 7.28-7.91 (4H, m) UVλ _max (EtOH) nm (log ε): 264 (3.7), 275 (3.7), 301 (3.6), 315 (sh) Example 2 80 mg of 4-geranyloxycoumarin epoxide was dissolved in 3 ml of dioxane, 1 ml of 3% perchloric acid was added thereto, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added to the reaction mixture, extracted with methylene chloride, washed with brine, dried and concentrated. The obtained oily substance 101 mg was purified by Sephadex LH-20 (manufactured by Pharmacia) using methanol as a developing solvent to obtain 4-geranyloxycoumarin diol 92 mg.

Properties: viscous oily substance ¹ H-NMR (CDCl ₃ ) δ: 1.20 (6H, s), 1.80 (3H, s), 2.24 (4, m), 3.34 (1H,
dd, J = 9.0,3.6Hz), 4.72 (2H, d, J = 7.2Hz) 5.54 (1H,
t, J = 7.2Hz), 5.69 (1H, s), 7.28-7.91 (4H, m) UVλ _max (EtOH) nm (log ε): 262 (3.7), 273 (3.7), 300 (3.6), 315 (Sh) Example 3 In 2.0 g of 7-geranyloxycoumarin, 1.5 g of selenium dioxide and 80 ml of ethanol, the mixture was heated under reflux for 10 hours. After evaporating the solvent under reduced pressure, the residue was extracted with methylene chloride and concentrated.

The obtained oily matter was subjected to silica gel column chromatography, and was first eluted with a mixed solvent of benzene / acetone (98/2) to obtain 303 mg of auraptenal.

Next, elute with a mixed solvent of benzene / acetone (95/5) to obtain auraptenol [7- (8-hydroxy-3,7
-Dimethyl-2,6-octadienyloxy) coumarin] 2
84 mg was obtained.

The physical properties of each compound obtained above were as follows.

[Auraptenal] Melting point: 52-55 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.73 (3H, s), 1.78 (3H, s), 2.35 (4H, m), 4.60 (2
H, d, J = 7.2Hz), 5.50 (1H, t, J = 7.2Hz), 6.24 (1H, d,
J = 9.6Hz), 6.43 (1, t, J = 7.2Hz), 6.81 (2H, m), 7.
35 (1H, d, J = 10.8Hz), 7.63 (1H, d, J = 9.6Hz), 9.35
(1H, s) [Auraptenol] Melting point: 43-45 ° C ¹ H-NMR (CDCl ₃ ) δ: 1.66 (3H, s), 1.76 (3H, s), 2.15 (4H, s), 3.99 ( 2H,
s), 4.61 (2H, d, J = 7.2Hz), 5.38 (1H, t, J = 7.2H)
z), 5.48 (1H, t, J = 7.2Hz), 6.25 (1H, d, J = 9.6H)
z), 6.84 (2H, m), 7.36 (1H, d, J = 10.8Hz), 7.65 (1
H, d, J = 9.6 Hz) Example 4 Iron pentacarbonyl [Fe (CO) ₅ ] 500 mg and NaOH 51 mg were dissolved in 10 ml of a mixed solvent of methanol: water = 95: 5 (V / V), and a nitrogen stream was generated. Stir underneath for 5 minutes at room temperature.

Auraptenal (200 mg) was added to the obtained dark brown solution, and the mixture was reacted at room temperature for 19 hours. Then, an ether solution of iodine was gently added to decompose excess reducing agent, and the mixture was partitioned between water and ether. The organic layer was washed with an aqueous Na ₂ S ₂ O ₃ solution, dried and concentrated to obtain 201 mg of an oily substance.

This oily substance was subjected to silica gel column chromatography (developing solvent; benzene: acetone = 95: 5) operation repeatedly to obtain dihydroauraptenal [7- (3,7-dimethyl-7-formyl-2-heptenyloxy) coumarin].
Got 109 mg.

Properties: colorless oil ▲ [α] ²⁵ _D ▼ ＝ 8.33 ° (C = 0.30, methanol) ¹ H-NMR (CDCl ₃ ) δ: 1.10 (3H, d, J = 6.6Hz), 1.51 (4H, m) , 1.74 (3H,
s), 2.09 (2H, m), 2.41 (1H, m), 4.61 (2H, d, J = 6.0
Hz), 5.48 (1H, t, J = 6.0Hz), 6.24 (1H, d, J = 9.6H)
z), 6.84 (2H, m), 7.36 (1H, d, J = 10.8Hz), 7.63
(1H, d, J = 9.6Hz), 9.62 (1H, d, J = 2.0Hz) UVλ _max (EtOH) nm (lof ε): 242 (sh), 252 (sh), 322 (3.8) <Pharmacological test Example> Effect on antispasmodic activity in guinea pig small intestine A part (3 cm in length) of the small intestine of male guinea pig is exfoliated,
It was fixed in a Magnus tube containing Tyrode's solution having the following composition.

[Tyrode's composition] Sodium chloride 8.0g Magnesium chloride 0.2g Potassium chloride 0.1g Sodium dihydrogen phosphate 0.05g Sodium hydrogencarbonate 1.0g Glucose 1.0g Amount of water as 1 The solution is bubbled through air and brought to 37 ° C. Maintained. Each of the compounds of the present invention was dissolved in dimethyl sulfoxide as a test compound, and a predetermined amount thereof was added to the Tyrode solution (final concentration 5 × 10 ⁻⁵ mol / l), and then barium chloride was added to a final concentration of 3 × It was added at 10 ⁴ mol / l.

The vertical muscle spasm of the small intestine piece was observed with a recorder using a force displacement transducer (Nihon Kohden Isonic Transducer Balancing Box JD-1125, manufactured by Nihon Kohden). As a control, muscle spasm in the case where the test compound was not added was also tested in the same manner and recorded and observed. For each muscle spasm, the strength (amplitude) at the time when the muscle showed a constant contractile movement and reached a steady state was measured.

Based on the control twitch contraction value,
The reduction rate of spasm due to each test compound was calculated and used as the inhibition rate (%).

After the above test using each test compound, the muscle was washed with Tyrode's solution, barium chloride was added again, and the contraction state of the muscle was examined. .

The results of the above-mentioned tests using the compounds of the present invention obtained in each of the above-mentioned Examples as test compounds are shown in Table 1 below.

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ is a hydrogen atom and R ² is Or R ¹ is Or And R ² represents a hydrogen atom. ) A coumarin derivative represented by.