JPS62209070A - Neolignane derivative - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] Industrial applications The present invention relates to novel neolignan derivatives.

Conventional techniques The compound of the present invention is a novel compound that has not been described in any literature. Conventionally, prostaglandin 12 (PGI2, prostacyclin) has been used as one of the compounds that has the strongest platelet aggregation inhibiting effect and vasodilatory effect among prostaglandins, for example in thrombosis, arteriosclerosis, ischemic disease, etc. It is expected to have a wide range of clinical uses, including as a therapeutic agent for heart diseases, asthma, gastric ulcers, and liver diseases.

Problems to be Solved by the Invention However, the above-mentioned PG I2 itself is metabolized very quickly and its physical properties are unstable, making it very difficult to apply it clinically. Therefore, it is desired to develop a compound that enhances its production.

An object of the present invention is to provide a useful compound that meets the above requirements and can be used as a PG 12 production enhancer in the pharmaceutical field.

The present inventors have conventionally discovered sour jujube leaf, which has pharmacological effects such as increasing blood flow and lowering blood pressure in addition to increasing myocardial contractile force.
I have been conducting research on Chinese herbal medicines such as Kuding tea and Gongju leaves, and in the process, I first succeeded in isolating a target compound from dried sour jujube leaves from China.
The objective compound was also successfully extracted and isolated from the Chinese holly (L lax cornuta), which led to the completion of the present invention.

Means for Solving Problem 1 The present invention provides novel compounds represented by the following general formulas (1) and (2).

General Formula (1) [In the above formula, R1 represents a hydrogen atom or a lower alkanoyl group. ] General formula (2) (In the above formula, R2 is a hydrogen atom or acetyl Δ 1-1゜ In this specification, lower alkanoyl groups include, for example, formyl, acetyl, propionyl, butyryl, pentanoyl, hexanoyl groups, etc. with a carbon number of Examples include 1 to 6 straight chain or branched chain alkanoyl groups.

The compound of the present invention has an inhibitory effect on PG I2 production, thrombolytic action, blood flow improving action, gastric acid secretion suppressing action, lllll11
It has a protective effect, a cholesterol-reducing effect, and a fertility regulating effect, 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 drug for treating liver disease,
It is useful as a blood flow improving drug and a fertility regulating drug.

The compound of the present invention can be 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 R1 is a hydrogen atom (hereinafter referred to as "Compound 1aJ") is extracted and isolated from Sanjutsu.

The above extraction and isolation can be carried out, for example, as follows. First, dry jujube leaves are extracted using ordinary polar solvents such as methanol and ethanol, and the extract is concentrated under reduced pressure to obtain a primary extract.Then, from this extract, the physicochemical properties of the target compound are utilized. The target object is collected using various methods. The target substance can be collected using conventional methods, such as a method that utilizes the difference in solubility with impurities, or a method that utilizes the difference in affinity for adsorbents such as activated carbon, amberlite, silica gel, ion exchange resin, and Sephadex. , a method that utilizes the difference in distribution ratio between two liquid phases, and a combination of these methods. As a more preferable collection method, for example, the above-mentioned primary extract is extracted using an appropriate solvent such as ethyl acetate according to the solvent volume distribution method, the extract is concentrated under reduced pressure, and the concentrated liquid is subjected to silica gel column chromatography, for example. An example is a method of elution with a suitable solvent such as methanol.

Among the compounds of the present invention, the compound represented by the general formula (1) in which R1 is a lower alkanoyl group (hereinafter referred to as [compound (11)
)J) can be obtained by a chemical synthesis method using the above-obtained compound (1a) as a starting material and utilizing a reaction as shown in Reaction Formula-1 below.

<Reaction formula-1> CH3 (1a) H1b□H (1b) [In the formula, R1b represents a lower alkanoyl group. ]Reaction formula-
The acylation reaction of compound (1a) shown in 1 can be carried out under the same conditions as for a normal acylation reaction. As the acylating agent, a wide variety of conventionally known agents can be used. Specific examples thereof include lower alkanoic acid anhydrides such as acetic anhydride, lower alkanoic acid halides such as acetyl chloride, and propionyl chloride. The amount of the acylating agent to be used is not particularly limited and can be appropriately selected from a wide range. Usually, it is preferable to use an excess amount, at least about 2 times the mole, relative to the starting material compound (1a).

The acylation reaction can be carried out in a suitable solvent, preferably in the presence of a basic compound. Examples of solvents include ketones such as acetone and methyl ethyl ketone, ethers such as ether, dioxane, and tetrahydrofuran, aromatic hydrocarbons such as benzene, toluene, and xylene, pyridine, dimethylformamide, dimethyl sulfoxide, hexamethyl phosphoric triamide, Any of the usual types such as 1,2-dimethoxyethane can be used. Examples of basic compounds include alkali metals such as sodium metal and potassium metal, hydroxides of metals such as these,
In addition to carbonates, bicarbonates, alkyl lithiums, etc., tertiary amine compounds such as pyridine, N-methylpiperidine, triethylamine, etc. can be used. The reaction is normally carried out at 0°C.
It proceeds under temperature conditions of ~80°C and is generally completed in about 1 to 24 hours.

Compound (1b) obtained in this way can be isolated and purified by conventional separation means such as solvent extraction, solvent dilution, distillation, recrystallization, silica gel column chromatography, etc.

Among the compounds of the present invention, the compound represented by the general formula (2) is derived from Chinese holly (I tex cornuta).
It is extracted and isolated from the dried leaves of.

The above extraction and isolation can be carried out, for example, as follows. That is, first, dry leaves of Chinese holly are extracted using a common polar solvent such as methanol or ethanol, and the extract is concentrated under reduced pressure to obtain a primary extract. The target substance is collected using various methods based on its properties. The target substance can be collected using a conventional method, such as a method that utilizes the difference in solubility with impurities, activated carbon, Hl)
-20, XAD-2, silica gel, ion exchange resin,
This can be carried out by a method that utilizes the difference in adsorption affinity for an adsorbent such as Sephadex, a method that utilizes the difference in the distribution ratio between two liquid phases, or a combination of these methods.

A more preferable collection method is, for example, to extract the above-mentioned first extract using an appropriate solvent such as methylene chloride according to the solvent partition method, and to subject the extract to silica gel column chromatography, for example, by extracting the above-mentioned first extract using a suitable solvent such as methylene chloride, methylene chloride, ethyl acetate, and methanol. An example is a method of elution with a suitable solvent such as a mixed solvent of.

The compounds of the present invention obtained by the various methods described above can be administered to humans and animals as they are or as active ingredients together with conventional pharmaceutical carriers. When using the compound of the present invention as a medicine, the form of a pharmaceutical preparation! g (dosage unit form fl), its W411J, its administration route, etc. can be the same as those of ordinary pharmaceutical preparations. That is, the compound of the present invention can be prepared in tablets, granules, etc. containing the effective m.
It is formulated into oral preparations such as capsules and oral solutions, and parenteral preparations such as injections, and can be administered orally or parenterally. The various forms of preparations mentioned above are prepared according to conventional methods, and the carriers used at that time may be of various commonly used carriers. For example, tablets are prepared by mixing the compound of the present invention as an active ingredient with excipients such as gelatin, starch, lactose, magnesium stearate, talc, and gum arabic. Capsules are prepared by mixing the above-mentioned active ingredients with an inert pharmaceutical filler or diluent and filling the mixture into hard gelatin capsules, soft capsules, and the like. Parenterally administered preparations such as injections are manufactured by dissolving or suspending the compound of the present invention as an active ingredient in a sterilized liquid carrier. Preferred carriers include water, physiological saline, and the like.

EXAMPLES In order to explain the present invention in more detail, production examples of the compounds of the present invention will be given below as examples.

Example 1 3-[trans-2-<3'-methoxy-4'-hydroxyphenyl)-3-hydroxymethyl-7-medoxy2,3-dihydrobenzofuranyl]-propeonic acid methyl ester [Compound (1a) ]
Production of 6K (l) of dry acid rA leaves from China was crushed and extracted three times with 60Q of methanol under reflux for 2 hours each.

(9) After collecting and filtering the resulting extracts, the solvent was distilled off under reduced pressure, and the resulting extraction residue 450Q was degreased with n-hexane, and 4:3 (v/■) of ethyl acetate and water was used. The mixed solution was distributed three times. The mixture was separated and the solvent was distilled off under reduced pressure to obtain 126 g of the residue.

20g of the extraction residue obtained in this way was treated with Sephadex 1
The residue was subjected to column chromatography using 1-1-20 (manufactured by Pharmacia) 19, and fractionated into 78 fractions by elution with methanol 3Q. The 56th to 71st fractions were collected, and the solvent was distilled off under reduced pressure to leave the remaining 17.
Collect 1 g of 0II and add it to silica gel (Wako C-
Purification was repeated using column chromatography packed with 4 g of 300 (manufactured by Wako Pure Chemical Industries, Ltd.), and fractions eluted with chloroform were collected.

The solvent was distilled off from the above fraction under reduced pressure to obtain compound 451110 of the present invention.

This was recrystallized from methylene chloride to obtain the pure target compound 4.
0 mg (q).

Properties: Colorless crystal Melting point: 190-192℃ IR (KBr):cm-': Shown in Figure 1. The main peaks are as follows.

3450.1698.1635.1610.1523.
1505.1455.1440゜1390.1340.
1280.1245.1200.1180,1150.
1115.1060.10301990.900.86
0.830' H-NMR (DMS O-ds):
δpp+++: Shown in FIG. The main peaks are as follows.

3.49 (IH, dt, J-6, 7 and 6.1Hz) 3.66 (1H, tg), 3.71 (3H, s
)3, 73 (1)1. m) 3.74 (3H,s) 3.82 (3H,s) 5.05 (1H,t, J-5,2Hz) 5.54
(IH, d, J-6,7Hz) 6.51 (1)
-1,6, J-15,9) -1z )6.76 (2H
,s) 6,92 (IH,brs) 7,27 (IH,brs) 7,28 (IH,brs) 7.60 (11-1,d, J-15,9Hz >9
．． 05 (IH,s) MS: l/Z (%): 386 (M”) (54), 368 (100), 3
56 (28), 353 (42), 137 (one) Example 2 3-[trans-2-(4'-acetoxy-3'-methoxyphenyl)-3-acetoxymethyl-7-medoxy2.3- dihydrobenzofuranyl)-propeonic acid methyl ester [Compound (1b)]
The compound (la) 5110 obtained in Production Example 1 was added to anhydrous vinegar FI.
The mixture was mixed with 0.4 mQ of t and 0.2 mQ of anhydrous pyridine, and stirred for 16 hours at the lowest temperature to carry out an acetylation reaction. After adding ice water to the reaction mixture, it was extracted with ether. The ether layer was washed successively with 2N hydrochloric acid, saturated sodium hydrogen carbonate, and saturated brine, and dried over magnesium sulfate. The ether was distilled off under reduced pressure to obtain the target compound as an oil.
I got 1g.

'H-NMR(CDCQ3):δI)pI
: Shown in Figure 3. 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 (IH,dd,J =11.2 and 7, 5H
z) 4.44 <18. dd, J=11.2 and 5,6H2
) 5.57 (1H,d, J-6,5Hz)6
．． 30 (IH, d, J-15, 8Hz)6
．． 95 (1H, dd, J-7,9 and 2.0Hz) 6.98 (1H, d, J-2,0Hz) 7
．． 03 (IH, d, J=7.9Hz)7,
02 (1I-1, bs) 7.04 (1H, bs) 7.63 (1H, d, J=15.8l-1z
) MS: m/z (%): 470 (M ÷ 3 (39), 410 (42) 3
68 (90), 233 (35), 195 (33
), 137 (48), 43 (10
0) Example 3 3β-0-(α-L-(2'-acetyl)arabinopyranosyl]-bomol W1(28→1)-β-D-glucopyranosyl ester [in general formula (2) A compound in which R2 is an acetyl group (referred to as compound <2a)] and 3β-0
-(α-L-arabinopyranosyl)-29-hydroxyoleanolic acid (28→1)-β-D-glucopyranosyl ester [compound in which R2 is a hydrogen atom in general formula (2) (compound (2b )] Manufacture of air-dried Chinese holly leaves 5k ( ) from China are crushed,
The extraction was repeated three times under reflux with 209 methanol each for 2 hours.

The extracts were collected, and the solvent was distilled off under reduced pressure. The resulting residue was dissolved in 60% methanol water. This solution was degreased with n-hexane, extracted with methylene chloride to remove impurities, and dissolved in water. The phase was extracted with ethyl acetate. 60 g of the obtained ethyl acetate extract was subjected to silica gel column chromatography (Wakogel, C-200, manufactured by Wako Pure Chemical Industries, Ltd.)
and first eluted with chloroform.

Next, elution was carried out with chloroform:methanol-9:1 (v/V), and the solvent was distilled off from the eluate under reduced pressure. 2.5 g of the obtained residue was again subjected to silica gel column chromatography in the same manner. The purified product was purified by fast wave body chromatography [Cosmosi/LzC18 (Cosmosi
lCl8), 20 x 300 mm, water:methanol-35:65 (v/v), 8 m/min, UV215
ni), 3411 of the target compound (2a)
I got 1g.

Melting point: 193-195℃ IR (KBr):cm-': It is shown in Figure 4. The main peaks are as follows.

3450.1730.1630 FABMS: ta / z: 831 (M+1) ÷ IH-NMR (pyridine-d5): δppn+: 5th
As shown in the figure. The main peaks are as follows.

0.88 (3H,s) 0.89 (3H,s) 1.06 (3H,d, J-6,5Hz) 1.07
(3H,s) 1.18 (3H,s) 1.38 (3H,s > 1.69 (3H,s) 2.09 (3H,s) 2.48 (1H,td, J-13,3 and 3.4Hz
) 2.93 (1H, s) 3.11 (IH, td, J-13, 3 and 3, 4H7
) 3.18 (IH, dd, J-11, 6 and 4, 3
FIZ) 3.78 (1H, d, J=1 1.6Hz
>4.15 (1H, dd, J-9,5 and 3.0Hz
) 4.70 (IH, d, J=7.3Hz)5
, 10 (-OH) 5.54 (IH,t, J-3,4Hz)5
．． 88 (1H, dd, J-9, 5 and 7.3) (Z
) 6.31 (IH, d, J-7, 7Hz) 6.3
5 (-OH), 6. 75 (-0)1)7,
24 (-OH), 7.40 (-OH) 7.47
(-OH)'3C-NMR (pyridine-d5>: δppm: 1
5, 5(Q), 16. 6 (Q) 16, 7 (q), 17. 4 (q)
18, 7 (t), 21. 2 (Q
)24, 1 (t), 25. 5 ((
1>26, 2 (t >, 26.4 (t
) 26, 7 (t), 27° 1 (q)
28, 0 (Q >, 29. 2 (t)
33, 6 (t), 37. 0 (s)
37, 6 (t), 38. 8 (S)
38.9 (t), 40y6 (s >
42, 1 (s), 42. 1 (d)
47, 8(d), 48. 7 (S'
) 54, 5 (d), 55. 9 (d
)62, 6 (t), 66, 9 (t
)69, 7(d), 71. 5 (d
) 72, 4 (d), 72. 8 (s
)74, 1 (d >, 74.3 (d
)78, 9(d), 79. 0 (d
') 89, 1 (d), 95. 8 (d
) 104, 4 (d), 1 28. 6
(d) 139.3 (s), 1 70.0
(s) 176.9 (S) [α) 19-20.5 f(ethanol, c-0,5>) Then, the above chloroform eluate was eluted with chloroform:methanol-8:2 (v/v). , Fraun Yon was collected, and the solvent was distilled off under reduced pressure to obtain 8 g of residue, which was subjected to silica gel column chromatography (silica gel column chromatography).
Purification with Wakogel, C-300, manufactured by Wako Pure Chemical Industries, Ltd. (chloroform:methanol-8,5:1.5), followed by column chromatography using Sephadex LH-20 (manufactured by Pharmacia, elution solvent: methanol) Purified by graphics.

The obtained eluate was further subjected to high performance liquid chromatography (
Cosmosil C18 (CC13 (Cos 018), 20
X300a+s, water:methanol-6:4 (v/v),
8 ml/min, UV254rv) to obtain 23111 g of the target compound (2b).

Properties: colorless powder Melting point: 222-223℃ IR (KBr): cr’: It is shown in FIG. The main peaks are as follows.

3440.1740 FABMS: m/z near 89 (M+1)÷IH-NMR (pyridine-d5)=δpaw: Shown in FIG. The main peaks are as follows.

0.85 (3H,s) 0.94 (3H,s) 1.09 (3H,s) 1.11 (3H,s) 1.24 (3H,s) 1.26 (3H,s) 2. 37 (1H,t, J-13,3Hz)3.3
2 (IH, dd, J-10, 7 and 4, 3H2) 3. 33 (1t() 3, 55 (2H, d, J=6.0Hz >
3.82 (IH, d, J=10.7Hz
)4, 75 <1 1-1. d,
J=6. 9 t1z) 5.47 (IH
, t , J=3.4Hz )6.15 (1H,
t, J=6. 0Hz) 6, 23 (
1H) 6.35 (IH, d, J-7, 7Hz) 6
．． 40 (IH,t, J-6,0Hz)6.
49 (11-1) 6.90 (1H, d, J-4,9Hz) 7
．． 25 (1H), 7.41 (IH) 7.45
(1H,d, J-5,4Hz)13C-NM
R (pyridine-d5): δpp+m: 15, 6
(q >, 16. 8 (Q ) 17, 5
(Q), 18. 7 (t)19, 7
(Q), 23. 5 (t)23, 8
(t), 26. 1 (Q)26, 5
(j), 28. 3 (t)28, 8
(Q), 32. 0 (t)33, 2
(t), 36. 3 (s)37, 1
(S), 38. 9 (t”)39, 5
(s), 40. 0 (s)41, 0
(d), 41. 2 (t)42, 2
(s), 47. 5 (s)48, 1
(d), 56. 0 (d)62, 4
(t >,66, 2 (t )69.1
(d), 71. 4 (d)72, 8
(t), 73. 7 (d)74, 1
(d), 74. 4 (d)78, 8
(d), 79. 0 (d)88, 8
(d), 95.7 (d) 107.0 (
d), 128.8 (d) 148, 8
(s), 1 76, 5 (s) (α)
19 = 7.3 (Ethanol, C-0,25) <Pharmacological test> Experimental method [Measurement of the amount of free l11r6-kedobrostaglandin F1α (6-kedo PGF+α) from rat aorta preparations, The Journal of Pharmacy cology, ni, 84
5 (1981), three male Wistar rats weighing 1250 to 350 g were sacrificed by exsanguination by cutting the carotid artery, the thoracotomy was performed, and 4 cm of the aorta was dissected, and cooled 10-M phosphate-buffered saline ( rll-17,4, hereinafter rP
Adipose tissue and blood were removed in a tube called BsJ.

Next, the artery was cut to a length of approximately 2 CIl, the artery was inverted, both ends were tied with sutures, and PBS was injected inside and fixed to a siliconized micropipette under constant tension.

The fixed artery preparations were 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 (02:CO2 = 95:5).

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

From the start of the test, 10 μQ of 50% ethyl alcohol was added to the test tubes for the 160-minute value and the 170-minute value, and
The test tubes for the 80-minute value and the 190-minute value contain a solution in which the specified m of the test compound is dissolved in 50% ethyl alcohol, or a suspension in which the test compound is added to 50% ethyl alcohol and then treated with ultrasound. 10 μQ of the solution was added.

After 10 minutes of reaction, immediately add 0.5N salt IS to each test tube.
! 50 μQ was added to adjust I)H to 3 to 4, and liberated PG I2 was converted to stable 6-kedo PGF+α, which was stored under water cooling until measurement.

The measurement of 6-keto PGF+α contained in each test tube solution was performed using 20 tlQ of each of the above test tube solutions separated into separate polypropylene test tubes.
sham) company %J (31-1)-6-kedo PG
It was carried out using an F+α radioimmunoassay kit.

The average value of the measured values in the test tube solutions for the 160-minute value and the 170-minute value is used as the control value, and the average value of the measured values in the test tube solutions for the 180-minute value and the 190-minute value is 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.

Table 1 Sample 5 6-Kedo PGF+
Increase rate (%) of α amount compound (μa/ml) from control value Compound of Example 1 3 25.3

[Brief explanation of drawings]

Figure 1 shows the IR of the present compound (1a) obtained in Example 1.
Figure 2 shows the spectrum diagram of the same compound (1a).
An NMR spectrum diagram is shown. Figure 3 shows the 'H of the compound (1b) of the present invention obtained in Example 2.
- Shows an NMR spectrum diagram. Figure 4 shows the IR of the present compound (2a) obtained in Example 3.
Figure 5 shows the IH-N spectrum of the same compound (2a).
An MR spectrum diagram is shown. Figure 6 shows the IR of the present compound (2b) obtained in Example 3.
Figure 7 shows the spectrum diagram of the same compound (2b).
An NMR spectrum diagram is shown. (That's all) ゛-ノ

Claims (1)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. are available ▼ [In the formula, R^1 represents a hydrogen atom or a lower alkanoyl group. ] Neolignan derivatives represented by or the general formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ [In the formula, R^2 represents a hydrogen atom or an acetyl group, and the group ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ is R^ When 2 is a hydrogen atom, ▲ there are mathematical formulas, chemical formulas, tables, etc. ▼ indicates a group, and when R^2 is an acetyl group, ▲ there are ▲ mathematical formulas, chemical formulas, tables, etc. ▼ indicates a group. ] Pomoric acid and oleanolic acid derivatives represented by these.