JPH0615535B2 - Neolignan derivative - Google Patents

Description

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

2. Description of the Related Art The compound of the present invention is a novel compound not described in the literature. However, conventionally, prostaglandin I ₂ (PGI ₂ , prostacyclin) is one of the compounds having the strongest platelet aggregation inhibitory action and vasodilatory action among prostaglandins, for example, thrombosis, arteriosclerosis, Widespread clinical use is expected as a therapeutic drug for ischemic heart disease and the like, as an asthma therapeutic drug, a gastric ulcer therapeutic drug, and a liver disease drug.

Problems to be Solved by the Invention However, the metabolism of PGI ₂ itself is very fast,
Further, its physical properties are unstable, and it is considerably difficult to apply it clinically. Therefore, it has been desired to develop a compound that enhances the production of PGI ₂ instead of the PGI ₂ .

An object of the present invention is to provide a useful compound which meets the above-mentioned needs and can be used in the pharmaceutical field as a PGI ₂ production enhancer.

The present inventors have conventionally used acid-juice leaves having a pharmacological action such as a coronary blood flow increasing action and a hypotensive action in addition to a myocardial contractile force increasing action,
We have been studying Chinese herbs such as Kitchingcha and Gongfu leaf.In the process, we succeeded in isolating one target compound from dried acid-jujuba leaves from China, and using it,
The target compound, which is this derivative, was successfully synthesized, and the present invention was completed here.

Means for Solving the Problems The present invention provides a novel neolignan derivative represented by the following general formula (1).

General formula (1) [In the above formula, R ¹ represents a hydrogen atom or a lower alkanoyl group. In the present specification, examples of the lower alkanoyl group include linear or branched alkanoyl groups having 1 to 6 carbon atoms such as formyl, acetyl, propionyl, butyryl, pentanoyl and hexanoyl groups.

The compound of the present invention is a PGI ₂ production enhancer action, thrombolytic action, blood flow improving action, gastric acid secretion inhibitory action, cytoprotective action,
It has a decholesterolizing action and a fertility regulating action, and is a preventive and therapeutic drug for thrombosis and arteriosclerosis, a therapeutic drug for ischemic heart disease, an anti-asthma drug, an anti-ulcer drug, a therapeutic drug for liver disease, a blood flow improving drug, and It is useful as a fertility regulator.

The compound of the present invention is produced, for example, by the method shown below.

That is, among the compounds of the present invention, the compound represented by the general formula (1) in which R ¹ is a hydrogen atom (hereinafter, referred to as “compound 1a”) is extracted and isolated from sour leaves.

The above extraction and isolation can be carried out, for example, as follows. First, dried acid palm leaves are extracted with a normal polar solvent such as methanol and ethanol, the extract is concentrated under reduced pressure to obtain a primary extract, and then the physicochemical properties of the target compound are used from the extract. The target product is collected by the various methods described above. Collection of the target substance is a conventional method, for example, a method utilizing a difference in solubility with impurities, a method utilizing a difference in adsorption affinity for an adsorbent such as activated carbon, amberlite, silica gel, an ion exchange resin, and Sephadex, It can be carried out by a method of utilizing the difference in distribution ratio between the two liquid phases, a combination of various methods, and the like. As a more preferable collection method, for example, the above-mentioned primary extract is extracted with a suitable solvent such as ethyl acetate according to the method of partitioning between solvents, the extract is concentrated under reduced pressure, and the concentrate is subjected to silica gel column chromatography. An example is a method of eluting with a suitable solvent such as methanol.

Among the compounds of the present invention, a compound represented by the general formula (1) in which R ¹ is a lower alkanoyl group (hereinafter referred to as “compound (1
b) ”) is a compound (1a) obtained by the above.
Can be obtained by a chemical synthesis method using the reaction shown in the following reaction formula 1 as a starting material.

<Reaction formula-1> [In the formula, R ¹ b represents a lower alkanoyl group. The acylation reaction of the compound (1a) represented by reaction formula-1 can be carried out under the same conditions as in a usual acylation reaction. As the acylating agent, various conventionally known ones can be widely used. Specific examples thereof include lower alkanoic acid anhydrides such as acetic anhydride and lower alkanoic acid halides such as acetyl chloride and propionyl chloride. The amount of the acylating agent used is not particularly limited and can be appropriately selected from a wide range. Usually an excess amount with respect to the raw material compound (1a),
It is preferable that the amount is at least about twice the molar amount.

The acylation reaction can be carried out in a suitable solvent, preferably in the presence of a basic compound. As the solvent, for example, acetone, ketones such as methyl ethyl ketone, ethers, dioxane, ethers such as tetrahydrofuran, benzene, toluene, aromatic hydrocarbons such as xylene, pyridine, dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide, Any of various ordinary ones such as 1,2-dimethoxyethane can be used. Examples of the basic compound include, for example, metal hydroxides, carbonates, bicarbonates and the like of alkali metals such as metal sodium and metal potassium and the like, alkyl lithium and the like,
Tertiary amine compounds such as pyridine, N-methylpiperidine and triethylamine can be used. The reaction usually proceeds under a temperature condition of about 0 ° C to 80 ° C, and generally about 1 to 24 ° C.
Complete in time.

The compound (1b) thus obtained is obtained by a conventional separation means,
For example, it can be isolated and purified by a solvent extraction method, a solvent dilution method, a distillation method, a recrystallization method, a silica gel column chromatography and the like.

The compound of the present invention obtained by the above various methods can be administered to humans or animals as it is or as an active ingredient together with a conventional pharmaceutical carrier. When the compound of the present invention is used as a medicine, the form of the pharmaceutical preparation (dosage unit form), its adjustment, 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 in the form of tablets, granules, capsules, oral preparations such as oral solutions and parenteral preparations such as injections containing the effective amount thereof, and orally or parenterally. Can be administered. The above-mentioned preparations in various forms may be prepared according to a conventional method, and the carrier used at that time may be any of the commonly used carriers. For example, tablets are prepared by using the compound of the present invention as an active ingredient, gelatin,
It is shaped by mixing with excipients such as starch, lactose, magnesium stearate, talc, and gum arabic. 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 preferable carriers include water and physiological saline.

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.

Example 1 3- [trans-2- (3'-methoxy-4'-hydroxyphenyl) -3-hydroxymethyl-7-methoxy-2,3-dihydrobenzofuranyl] -propionic acid methyl ester [Compound (1a )] Manufacture 6 kg of dried sour leaves from China, crush them for 2 hours,
Extraction was repeated 3 times under reflux with 60 methanol each.

The obtained extracts were collected, and the solvent was distilled off under reduced pressure. 450 g of the obtained extraction residue was defatted with n-hexane, and then the mixture was mixed with ethyl acetate-water 4: 3 (v / v) mixed solution to give 3 It was distributed twice. The organic layer was separated and the solvent was distilled off under reduced pressure to obtain 126 g of a residue.

20 g of the extraction residue thus obtained is used as Sephadex L
It was subjected to column chromatography using H-20 (manufactured by Pharmacia), eluted with methanol 3 and fractionated into 78 fractions. The 56th to 71st fractions were collected and the solvent was distilled off under reduced pressure to obtain 170 mg of residue.
The column was further purified by column chromatography packed with 4 g of silica gel (Wako C-300, manufactured by Wako Pure Chemical Industries, Ltd.), and the fraction eluted with chloroform was collected.

The solvent was distilled off under reduced pressure from the above fractions to obtain 45 mg of the compound of the present invention.

This was recrystallized from methylene chloride to give pure target compound 4
0 mg was obtained.

Property: colorless crystal Melting point: 190-192 ° C. IR (KBr): cm ⁻¹ : As shown in FIG. The main peaks are as follows.

3450, 1698, 1635, 1610, 1523,
1505, 1455, 1440, 1390, 1340,
1280, 1245, 1200, 1180, 1150,
1115, 1060, 1030, 990, 900, 86
_{^{0,830 1 H-NMR (DMSO-}} d 6): δppm: shown in Figure 2. The main peaks are as follows.

3.49 (1H, dt, J = 6.7 and 6.1 Hz) 3.66 (1H, m) 3.71 (3H, s) 3.73 (1H, m) 3.74 (3H, s) ) 3.82 (3H, s) 5.05 (1H, t, J = 5.2Hz) 5.54 (1H, d, J = 6.7Hz) 6.51 (1H, d, J = 15.9Hz) ) 6.76 (2H, s) 6.92 (1H, brs) 7.27 (1H, brs) 7.28 (1H, brs) 7.60 (1H, d, J = 15.9Hz) 9.05 (1H, s) MS: m / z (%): 386 [M ⁺ ] (54), 368 (100), 356
(28), 353 (42), 137 (19) Example 2 3- [trans-2- (4'-acetoxy-3'-methoxyphenyl) -3-acetoxymethyl-7-methoxy-2,3-dihydro. Preparation of benzofuranyl] -propionic acid methyl ester [compound (1b)] 5 mg of the compound (1a) obtained in Example 1 was added to 0.4 ml of acetic anhydride.
ml and anhydrous pyridine 0.2 ml, and the mixture was stirred at room temperature for 16 hours to carry out an acetylation reaction. Ice water was added to the reaction mixture, and the mixture was extracted with ether. 2N ether layer
The extract was washed successively with hydrochloric acid, saturated sodium hydrogen carbonate and saturated brine, and dried over magnesium sulfate. The ether was distilled off under reduced pressure to obtain 6 mg of the desired compound as an oily substance. ¹ H-NMR (CDCl ₃ ): δppm: shown in FIG. The main peaks are as follows.

2.06 (3H, s) 2.30 (3H, s) 3.80 (3H, s) 3.81 (3H, s) 3.93 (3H, s) 4.33 (1H, dd, J = 11.2 and 7.5 Hz) 4.44 (1H, dd, J = 11.2 and 5.6 Hz) 5.57 (1H, d, J = 6.5 Hz) 6.30 (1H, d, J =) 15.8Hz) 6.95 (1H, dd, J = 7.9 and 2.0Hz) 6.98 (1H, d, J = 2.0Hz) 7.03 (1H, d, J = 7.9Hz) 7.02 (1H, bs) 7.04 (1H, bs) 7.63 (1H, d, J = 15.8Hz) MS: m / z (%): 470 [M ⁺ ] (39), 410 ( 42), 368 (9
0), 233 (35), 195 (33), 137 (4
8), 43 (100) <Pharmacological test> Experimental method [Measurement of free 6-keto-prostaglandin F _1α (6-keto-PGF _1α ) amount from rat aortic preparation, the
Journal of Pharmacology, 31 , 845
(1981)] Male Wistar rats weighing 250 to 350 g were sacrificed by bleeding by carotid artery cutting, then thoracotomy was performed to peel off about 4 cm of the aorta, and chilled 10 mM phosphate buffered saline (pH 7. 4, hereinafter referred to as "PBS") to remove adipose tissue and blood.

Then, it was cut to a length of about 2 cm, the artery was inverted, the both ends were squeezed with sutures, and PBS was injected inside and fixed to a siliconized micropipette under a constant tension.

The fixed arterial preparation was incubated in a polypropylene test tube containing 1 ml of PBS at 37 ° C. for 10 minutes while passing a mixed gas of oxygen and carbon dioxide (O ₂ : CO ₂ = 95: 5).

The arterial preparations fixed at 10 minute intervals were sequentially transferred to the next test tube, and this operation was repeated until 190 minutes after the start of incubation.

From the start of the test, 10 μ of 50% ethyl alcohol was added to the test tubes for the 160-minute value and the 170-minute value, and 1
In the test tubes for the 80-minute value and the 190-minute value, a solution prepared by dissolving a predetermined amount of the test compound in 50% ethyl alcohol or the test compound was added to 50% ethyl alcohol and sonicated and suspended. 10 μl of the solution was added.

After reacting for 10 minutes, immediately add 0.5N hydrochloric acid 5 in each test tube.
0 μ was added to adjust pH to 3-4, and free PGI
₂ was converted into stable 6-keto-PGF _1α and stored under ice-cooling until the measurement.

The 6-keto PGF _1α contained in each test tube solution was measured by measuring Amersham (Amers) for each 20 μm of each test tube solution dispensed into another polypropylene test tube.
HAM) [ ³ H] -6-keto-PGF _1α radioimmunoassay kit.

The average value of the measured values in the test tube liquid for the 160-minute value and the 170-minute value was used as a control value, and the average value of the measured values of the test tube liquid for the 180-minute value and 190-minute value was used as the test compound value. The increase rate (%) of the test compound value from the control value is determined. The results are shown in Table 1 below.

[Brief description of drawings]

FIG. 1 shows the IR of the compound (1a) of the present invention obtained in Example 1.
Fig. 2 shows the ¹ H-N spectrum of the compound (1a).
An MR spectrum diagram is shown. FIG. 3 shows ¹ H of the compound (1b) of the present invention obtained in Example 2.
-Shows a NMR spectrum.

Continuation of front page (51) Int.Cl. ⁵ Identification number Reference number within the agency FI Technical indication location A61K 31/34 ADN AEL (72) Inventor Wu Xiahua Beijing, China Huai Tong Da Chiaor No. 12 (72) ) Inventor Chiao Chi Yunjie No.12, Jiayangmen Huai Tong Da Chiaor, Beijing, China

Claims (1)

[Claims] 1. A general formula [In the formula, R ¹ represents a hydrogen atom or a lower alkanoyl group. ] A neolignan derivative represented by: