JPH0665224A - Lignan derivative - Google Patents

Abstract

PURPOSE:To provide a new lignan derivative having bronchodilative activity, thus serviceable as a useful medicine for chronic airway-obstructive respiratory diseases. CONSTITUTION:The objective lignan derivative of the formula. This compound can be obtained by a process wherein: a cucumber tree is immersed in a lower alcohol or halogen-based solvent; the resulting extract is successively put to transfer dissolution in a low-polar organic solvent (e.g. n-hexane, petroleum ether), medium-polar organic solvent (e.g. diethyl ether, ethyl acetate), high-polar organic solvent (e.g. n-butanol, DMF), and water; the fraction for the medium- polar organic solvent is subjected to a silica gel column chromatography; of the compounds obtained from n-hexane-diethyl ether mixed solvent-eluted fractions, such a compound as to give an Rf value of 0.6 when developed on a silica get thin layer plate using an acetone/chloroform (1/9) mixed solvent is purified through silica gel chromatography or dispensing liquid chromatography.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel lignan derivative having a bronchodilator effect and a pharmaceutical composition containing the same as an active ingredient.

[0002]

2. Prior Art and Problems to be Solved by the Invention
MAGNOLIAE FLOS is a flower bud of Magnolia fargessi, and is used as an analgesic and sedative compound in Ginseng powder, but there is no report that the ingredient contained in Ginseng was used to treat respiratory diseases.

Airway remission at the time of stroke is important in the treatment of chronic respiratory diseases associated with reversible airway obstruction such as bronchial asthma, bronchitis and adult respiratory distress syndrome (Adult Respiratory Distress Syndrome). Bronchodilator is used in. The major bronchodilators currently in clinical use are β-, represented by salbutamol.
It is roughly classified into stimulants and xanthine drugs such as theophylline. In the former case, there is a drawback that the efficacy is significantly diminished along with the incurability, and in the latter case, the safety margin is narrow and there is a limitation in use.

The relationship between the lignan derivative represented by the formula (I) of the compound of the present invention and the compound described in a known document will be described below. As a compound similar to the compound of the present invention, a natural product represented by the following formula (II) in which the double bond of the 3,4-dimethoxybenzylidene group at the 4-position of the tetrahydrofuran ring is saturated is known (Phytochemistry, Volume 29, 1799-
1819, 1990-reference a).

[0005]

[Chemical 2]

A similar compound in which the 4-position of the tetrahydrofuran ring is substituted with a benzylidene group is represented by the formula (III)
The natural product represented by is known (Planta Med., Volume 40,
250-261, 1980-reference b).

[0007]

[Chemical 3]

Furthermore, 3,7-dioxabicyclo [3,3
There is a description of compounds represented by the general formula (IV) as an intermediate in a chemical production method of a 3,0] octane derivative.
(Japanese published patent publications, JP-A-63-280085, JP-A-63-287780-References c and d).

[0009]

[Chemical 4]

However, the stereochemistry of the double bond of the benzylidene moiety of the general formula (IV) described in this document is the Z-form corresponding to the geometrical isomer of the compound of the present invention, and in addition, it is supplied by this production process (IV) is a racemic compound, and only compounds having X ^1, X ² of 3,4-methylenedioxy group and m and n of 1 are described as example compounds.

Further, regarding the compounds represented by the formulas (II) to (IV), no data on the specific pharmacological action and medicinal activity has been described so far.

[0012]

Means for Solving the Problems As a result of intensive studies by the present inventor, the compound (I) of the present invention, which is different from any of the compounds disclosed in References a to d, was excellent as a bronchodilator. It is a compound and also has an inhibitory effect on platelet activating factor (PAF), which is attracting attention as an inflammatory in-vivo substance related to various inflammatory diseases (D
rugs of the Future, vol. 15, pp. 597-603, 1990) Especially, it was found that it could be an active ingredient of therapeutic agents for chronic airway obstructive respiratory diseases such as bronchial asthma, bronchitis, adult respiratory distress syndrome, etc. The present invention has been completed.

That is, the present invention relates to a lignan derivative represented by the formula (I) and a pharmaceutical composition containing the same as an active ingredient.

[0014]

[Chemical 5]

The method for isolating and extracting the compound of the present invention will be described below. The lignan derivative represented by the chemical structural formula (I) of the compound of the present invention is a lignin derivative of MAGNOLIAE FLOS (Magnolia fa
The organic solvent extract of rgessi floret can be isolated and purified by various chromatography methods known per se using an active adsorbent such as silica gel and alumina. A preferred isolation and purification method can be obtained, for example, by the following method.

An extract obtained by immersing the soy sauce in a lower alcohol (methanol, ethanol, n-propanol, etc.) or a halogen-based solvent (dichloromethane, chloroform, etc.) is used as a low polar organic solvent (n-hexane, petroleum ether, etc.) The solvent is sequentially dissolved in a medium-polar organic solvent (diethyl ether, dichloromethane, chloroform, ethyl acetate, benzene, toluene, etc.), a high-polar organic solvent (n-butanol, dimethylformamide, etc.), and water. The medium polar organic solvent transfer fraction was subjected to column chromatography using silica gel, and the fraction obtained from the n-hexane-diethyl ether mixed solvent elution fraction was a mixture of acetone-chloroform = 1: 9. The compound of the present invention can be isolated by purifying a compound showing Rf0.6 when developed on a silica gel thin layer plate by a solvent by silica gel chromatography or preparative liquid chromatography.

The chemical structure of the compound of the present invention including the absolute configurations on two asymmetric carbons and the stereochemistry of one double bond site was identified from the following spectral data.

[0018]

[Chemical 6]

<Determination of chemical structure> This compound has high resolution
In the mass spectrometry spectrum (MS), the molecular ion m / z
416 (M⁺, 25%), base peak m / z 189
From what is shown, molecular formula C _{twenty three}H₂₈O₇Is determined to be
It was Next, from the infrared absorption spectrum (IR),
Acid group (3638, 1026 cm^-1), Ether bond (1
128 cm^-1), Benzene ring (1516, 1593cm
^-1) Was suggested.

Among nuclear magnetic resonance spectra (NMR),
23 C signals were detected from ¹³ C-NMR, and ¹ H
From NMR, a signal consisting of 5 methoxy group-derived methyl protons, 1 olefin proton, 1 methylene proton adjacent to a hydroxyl group, 5 benzene ring-derived methine protons, etc. was detected. These carbon signals and all the proton signals were rationally assigned from the carbon-proton and proton-proton two-dimensional NMR analysis results, and were determined to be novel lignan derivatives (I) of tetrahydrofuran methanol type.

<Determination of Absolute Structure and Stereochemistry of Double Bond> The present compound has two (C ₄ , C ₅ ) asymmetric carbon atoms and one geometric isomer olefin (C ₁ , ₇ ). Relative placement is Nuc
rear Overhauser Effect (NO
E) From the difference spectrum, the relative configurations of the C ₄ and C ₅ positions, and the C ₁ and ₇ positions were identified as trans and E configurations, respectively.
Further, this compound has a negative specific optical rotation ([α] _D- 33.3).
° C.), and further, in ¹³ C-NMR, the chemical shift value at the C ₁ ^" -position is an equatorial-substitution type, and the absolute structure of a similar compound isolated from this plant.
(Phytochemistry, Vol. 11, 2289-2293, 1972) and the absolute structures of similar compounds isolated from other plants (Phytochemis
try, Vol. 29, pp. 1971-2094, 1990) and the like, the absolute structure at the C ₄ and C ₅ positions was determined to be 4S, 5R.

The dosage form of the lignan derivative represented by the chemical structural formula (I) of the present invention includes injections (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointments, suppositories, aerosols and the like. Parenteral administration or tablets, capsules, granules,
Oral administration by pills, syrups, solutions, emulsions, suspensions and the like can be mentioned.

The above-mentioned pharmaceutical composition containing the compound of the present invention contains about 0.1% by weight of the compound of the present invention based on the weight of the total composition.
1-99.5%, preferably about 0.5-95%.

In addition to the compounds of the present invention or compositions containing the compounds of the present invention, other pharmaceutically active compounds can be included.

The clinical dose of the compound of the present invention varies depending on the age, body weight, susceptibility of the patient, degree of symptoms, etc., but the effective dose is usually 0.003 to 1.5 g / day for an adult. It is about 0.01 to 0.6 g. However, if necessary, an amount outside the above range can be used.

The compounds of the present invention are formulated for administration by conventional pharmaceutical means. That is, tablets, capsules, granules and pills for oral administration include excipients such as sucrose, lactose, glucose, starch, mannitol; binders such as syrup, acacia, gelatin, sorbit, tragacanth, methylcellulose, Polyvinylpyrrolidone; disintegrants such as starch, carboxymethyl cellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol; lubricants such as talc, magnesium or calcium stearate, silica; lubricants such as sodium laurate, glycerol And then prepared.

Injectables, solutions, emulsions, suspensions, syrups and aerosols include active ingredient solvents such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol, polyethylene glycol; surface active agents. Agents such as sorbitan fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents such as carboxymethylcellulose sodium salt, cellulose derivatives such as methylcellulose, tragacanth, Natural gums such as gum arabic; prepared by using preservatives such as esters of paraoxybenzoic acid, benzalkonium chloride, sorbate and the like.

Suppositories include, for example, polyethylene glycol,
It is prepared using lanolin, coconut oil and the like.

[0029]

【Example】

Examples (Isolated Extraction Examples, Formulation Examples, Pharmacological Test Examples) Hereinafter, examples of the present invention (isolated extraction examples, formulation examples,
Pharmacological test examples) will be described in detail, but the present invention is not limited to these examples.

Example of Isolation and Extraction Spicy-MAGNOLIA which is commercially available as a Chinese herb raw material
1.86 kg of E FLOS is immersed in ethanol and the solvent is distilled off to obtain 370 g of an ethanol extract. This extract was added to n-hexane, diethyl ether, n-butanol,
Sequentially dissolve in various solvents of water to make 4 fractions. Of these, 189 g of the transferred portion of diethyl ether was subjected to silica gel column chromatography, and the fraction obtained by elution with n-hexane-diethyl ether = 100: 0 to 0: 100 was divided into 5 fractions. The above fractions are combined to obtain 94 g of residue.

This product is n-hexane-ethyl acetate = 2: 1.
Purification by column chromatography using the mixed solvent of as the eluent was repeated 10 times, and 450 mg of the lignan derivative of the present invention as a highly viscous oil (Rf0.6, developed on a silica gel thin layer plate with acetone-chloroform = 1: 9)
To get

MS (m / z): 416 (M ⁺ , 25%), 220 (52%), 189 (100%), 161 (38%). ¹ H-NMR (ppm, CDCl ₃ ): 6.87 ( 1H, d, 5'-H), 6.72 (1H, d,
6'-H), 6.70 (1H, s, 2'-H), 6.63 (2H, s, 2 ", 6" -H), 6.
39 (1H, dd, 7-H), 4.93 (1H, broad dd, 2-α-H), 4.86 (1
H, d, 4-H), 4.73 (1H, broad dt, 2-β-H), 3.88 (2H, b
road dq, 2 × 6-H), 2.97 (1H, m, 5-H). ¹³ C-NMR (ppm, CDCl ₃ ): 153.25 (3 ", 5" -C), 148.78 (4'-
C), 148.10 (3'-C), 139.19 (1'-C), 137.39 (4 "-C), 136.
88 (1 "-C), 129.87 (7-C), 121.59 (1-C), 120.60 (6'-C),
111.44 (2'-C), 111.20 (5'-C), 103.08 (2 ", 6" -C), 82.17
(4-C), 70.17 (2-C), 62.72 (6-C), 56.70, 55.82, 55.76
(3 × O C H ₃ ), 56.03 (2 × O C H ₃ ), 55.52 (5-C). Two-dimensional NMR: proton-proton ... Fig. 1; proton-
Carbon: Fig. 2 IR (cm ^-1 , film): 3638, 1593, 1516, 1128, 1026. (See Fig. 3) Specific rotation: [α] _D -33.3 ° (c = 2.8, CHCl ₃ ). NOE difference spectrum measurement results: FIGS.

Formulation Example Formulation Example 1 After the above ingredients were mixed by a conventional method, a sugar-coated tablet containing 50 mg of the active ingredient was prepared.

Formulation Example 2 The above ingredients were mixed by a conventional method and then filled into a gelatin capsule to give a capsule containing 50 mg of the active ingredient per capsule.

Formulation Example 3 After mixing the above components, a soft capsule was prepared by a conventional method.

Formulation Example 4 The above components were mixed by a conventional method to give a 1% ointment.

Formulation Example 5 The above composition (A) is mixed, the resulting mixed solution is charged into a container equipped with a valve, and the propellant (B) at 20 ° C. is about 2.46
A pressure of 2.81 mg / cm ² cage was applied from a valve nozzle to obtain an aerosol suspension.

Pharmacological Test Method 250-450 g of Hartley male guinea pigs were exsanguinated to death and the trachea was removed. After removing the fat and connective tissue from the trachea, cut the smooth muscle tissue into 4 to 5 parts by cutting it into a spiral shape with a width of about 2 mm.
It was divided into 2 to 3 so as to contain one. Specimen 37 ° C, 95% O ₂
It was suspended in an 8 ml organ bath containing a modified-Tyrode solution aerated with + 5% CO ₂ and a load of 1 g was applied. Muscle relaxation is an isotonic transducer (Nihon Kohden, TD-112S)
Recorded with a pen recorder (Yokogawa Kitatsu Electric, Type 3066).

The composition of the Modified-Tyrode solution is as follows (mM). NaCl 137, KCl 2.7, CaCl ₂ 1.8, MgCl ₂ 1.
0, NaHCO ₃ 20, NaH ₂ PO ₄ 0.32, Glucose 11. a) Effect on resting tension After allowing the sample to rest for 50 to 60 minutes, isoproterenol 1 μM was added to relax it. After washing and repeating this at intervals of 30 to 40 minutes until a constant relaxation response is obtained,
The test compound is added cumulatively to relax, and finally aminophyll
The maximum relaxation reaction was obtained by adding ine 1 mM. b) Effect of various airway contractors on contraction The sample was rested for 50 to 60 minutes, then contracted with 100 μM of Histamine (His), and after the reaction was fixed, it was washed and rested for 20 to 30 minutes. After adding 5 μM of Indomethacin and further incubating for 30 minutes, various airway contractors (LTD ₄ 30nM, His 10
μM, U46619 30nM, KCl 30mM) was added for contraction. After constant contraction, test compound was applied cumulatively. Finally
A maximum relaxation reaction was obtained by adding 1 mM of aminophylline.

The strength of the relaxation reaction was 5 when the contraction height before application of the test compound was 0 and the relaxation of aminophylline was 100%.
It was expressed as the concentration of drug that causes 0% relaxation (EC ₅₀ , μM). The compound was dissolved in 100% dimethylsulfoxide (DMSO) and diluted before use. Aminophylline was dissolved in distilled water and Indomethacin was dissolved in 100% ethanol. The final concentrations of DMSO and ethanol in the bath were 0.31% and 0.1% v / v or less, respectively.

Pharmacological test results Table 1 shows the bronchodilator action of the test compounds as EC ₅₀ values using aminophylline as a control compound.

[0042]

[Table 1]

[0043]

As a result of the above, it is clear that the present invention has an excellent bronchodilator effect. Therefore, the compound of the present invention can be a useful therapeutic agent for chronic airway obstructive respiratory diseases such as bronchial asthma, bronchitis and adult respiratory distress syndrome.

[Brief description of drawings]

FIG. 1 Proton-proton two-dimensional NMR

FIG. 2 Proton-carbon two-dimensional NMR

FIG. 3 Infrared absorption spectrum (IR)

FIG. 4 NOE difference spectrum

FIG. 5: NOE difference spectrum

FIG. 6 NOE difference spectrum

FIG. 7: NOE difference spectrum

FIG. 8: NOE difference spectrum

FIG. 9: NOE difference spectrum

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[Procedure amendment]

[Submission date] August 17, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Correction target item name] 0042

[Correction method] Change

[Correction content]

[0042]

[Table 1]

Claims (2)

[Claims] 1. A lignan derivative represented by the formula (I). [Chemical 1] 2. A bronchodilator containing the lignan derivative according to claim 1 as an active ingredient.