JPS6310948B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel pyrrolidine derivative having hypotensive and/or anesthetic effects, and the compound provided by the present invention is represented by the following general formula. (In the formula, R ¹ is a hydrogen atom, a lower alkyl group, or a formyl group. R ² is a hydroxymethylene group, a lower alkoxy-substituted methylene group, a lower alkylthio-substituted methylene group, a phenyl (lower) alkylthioethylthio-substituted methylene group, a lower alkoxy and/or A methyl group di-substituted with lower alkylthio or a 1,3-dithio-2-cyclopentyl group (X means an oxygen atom or a sulfur atom, respectively) Among the compounds represented by the above general formula, R ¹ is a hydrogen atom, R ² is (α-methoxy-α-methylthio)
The compound in which methyl and X are sulfur atoms was the first compound successfully isolated by the present inventors from a methanol extract of Japanese radish, and was named lavanthine. Lafuanthine is a new compound, but other compounds represented by the general formula () are also new compounds, and these are useful as antihypertensive agents and/or anesthetics and intermediates for producing them. The origin of the present invention lies in the extraction of ruffantine from radish, but it was not previously known that radish contained components that had hypotensive and anesthetic effects. However, from the methanol extract of radish, the above-mentioned rafuanthine was isolated, and from the ethanolic extract, a compound in which an ethoxy group existed in place of the methoxy group in the chemical structure of radish was isolated. The present inventors conducted various studies in an attempt to provide compounds related to these compounds, and succeeded in chemically synthesizing these related compounds, thereby completing the present invention. It came to this. In order to further explain the compound represented by the general formula (), the groups represented by R ¹ , R ² and X are explained as follows. First, as the lower alkyl group represented by R ¹ ,
Straight chain or branched saturated hydrocarbons are included, and specific examples include methyl, ethyl, propyl, isopropyl, butyl, tertiary butyl, pentyl, hexyl and the like. And more preferred is C _1-3
is an alkyl group. Next, among the groups represented by R ² , as the lower alkyl in the lower alkoxy-substituted methylene group and the lower alkylthio-substituted methylene group, the lower alkyl mentioned in the explanation of R ¹ is recited as is. Therefore, the above R ² is methoxymethylene,
Examples include ethoxymethylene, propoxymethylene, butoxymethylene, methylthiomethylene, ethylthiomethylene, propylthiomethylene, and butylthiomethylene. Further, as the (lower) alkyl in the phenyl (lower) alkylthioethylthio substituted methylene group, the same lower alkyl is recited as is. Therefore, phenyl (lower) alkylthioethylthio-substituted methylene groups can be explained more specifically as benzylthiomethylthiomethylene, 2-benzylthioethylthiomethylene, 3-
Examples include benzylthiopropylthiomethylene, 2-phenethylthioethylthiomethylene, and 3-phenethylthiopropylthiomethylene. Furthermore, the same groups are exemplified as the lower alkyl in the methyl group di-substituted with lower alkoxy and/or lower alkylthio. Therefore, "methyl groups di-substituted with lower alkoxy and/or lower alkylthio can be described more specifically as dimethoxymethyl, diethoxymethyl, α-methoxy-α-
Ethoxymethyl, dimethylthiomethyl, diethylthiomethyl, α-methylthio-α-ethylthiomethyl, α-methoxy-α-methylthiomethyl, α
-ethoxy-α-methylthiomethyl, α-methoxy-α-ethylthiomethyl, α-ethoxy-α-
Examples include ethylthiomethyl. The compound () of the present invention can be provided by the extraction method and chemical synthesis method as described above, and these methods will be explained below. (1) Extraction method This is done by extracting radish with alcohol. The radish used here is Raphanus sativus L.var.acanthi formis.
Makino), including the roots and leaves, and generally fresh materials are used. The alcohol used for extraction can be either anhydrous or water-containing.
Examples of such alcohols include methanol, ethanol, isopropanol, butanol, and the like. Next, repeat the extraction operation on the obtained extract, or concentrate the obtained extract without repeating the extraction, and then isolate lafuanthines from the extract using a known method used for the isolation of general natural products. This can be done by applying the method as is. That is, for example, properties such as solubility and solubility differences in appropriate solvents, precipitation properties and precipitation rates from solutions, adsorption affinities for various adsorbents, and distribution differences between two liquid phases are utilized. Laughanthines can be isolated using the above isolation means alone or in any combination. One example is as follows. That is, after concentrating the alcoholic radish extract as appropriate and adding water to the obtained concentrate, the active ingredients are extracted with the same volume of a suitable organic solvent such as ethyl acetate. The resulting extract is passed through an adsorbent with or without concentrating as appropriate to adsorb the active ingredients. Examples of adsorbents used here include silica gel, alumina, diatomaceous earth, cellulose powder,
Examples include florisil and activated carbon. Next, the active ingredients adsorbed on various adsorbents are eluted using various organic solvents. Examples of elution solvents include hexane-ethyl acetate, hexane-acetone, hexane-ether, chloroform-acetone, and chloroform-acetone.
Ethyl acetate, benzene-ethyl acetate, benzene-acetone, etc. are used. When the eluate thus obtained is dried, an amorphous substance is obtained. When the obtained substance is recrystallized using a suitable solvent, crystals of lafuanthines are obtained. Note that specific examples of the extraction method are shown as Examples 1 and 2. The extracted compound has the general formula (In the formula, R ³ is a lower alkyl group.) In the above general formula ('), the lower alkyl group defined as R ³ is exemplified by the same alkyl as above, but here, radish is used as alcohol. It corresponds to the type of alcohol used when extracting, for example, when methanol is used as an extraction solvent, R is a methyl group, and similarly when ethanol is used, R is an ethyl group, Hereinafter, it means an alkyl group such as isopropyl or butyl group. (2) Synthesis method Chemical synthesis is performed according to the chart below. It should be noted that the number shown in parentheses next to each process A, B, C... is the example number. Process A(3),(4) (In _the formula, ^{R 1 and} It can be obtained by N-alkylation or formylation of 2-pyrrolidone, or thiocarbonylation reaction of carbonyl at the 2-position according to Process C described below. Furthermore, all compounds appearing thereafter are new. This reaction is carried out by reacting the raw material () with formic acid ester, but it is desirable to increase the reaction activity of the raw material () by bringing the raw material () into contact with lithium diisopropylamide prior to the reaction. It can be done. Ethyl formate, propyl formate, etc. are commonly used as the formic acid ester, but the reaction proceeds in the same manner even if other esters are used. Further, when this reaction is carried out in the presence of an amine such as hexamethylphosphortriamide, the reaction progresses easily. Note that when R ¹ in the raw material ( ) is a hydrogen atom, formylation with a formic acid ester may proceed simultaneously, and such cases are also included within the scope of the present invention. The reaction is carried out under cooling in the presence of a solvent, and the solvent used is an inert solvent such as hexane or tetrahydrofuran. Process B(5) (In the formula, R ¹ and X have the same meanings as before, and R ⁴ represents a lower alkyl group.) The lower alkyl group represented by R ^{4 is}
The lower alkyl groups mentioned in the above section are directly exemplified. This process is an etherification reaction, and all etherification reactions can be used as long as they do not adversely affect other substituents, but typical examples include Williamson's method of reacting an alkyl halide, and dialkyl sulfuric acid. Examples include a method of reacting and a method of using an onium salt.
Among these, the method using dialkyl sulfuric acid uses dimethyl sulfate, diethyl sulfate, dipropyl sulfate, etc., and the method uses dimethyl sulfate, diethyl sulfate, dipropyl sulfate, etc. This suggests that the reaction is accelerated. Process C (7, 14, 15) (In the formula, R ¹ and R ² have the same meanings as before.) This process is a reaction that converts a carbonyl group into a thiocarbonyl group, using a sulfurizing agent such as pentasulfide in an inert solvent such as dioxane, tetrahydrofuran, diethyl ether, or benzene. This is done by reacting diphosphorus. Process D(6) (In the formula, R ² and X have the same meanings as before.) This process is a deformylation reaction, which usually proceeds by hydrolysis under basic conditions (eg, in the presence of potassium carbonate). There are no restrictions on the hydrolysis conditions as long as they do not adversely affect the substituent represented by R ² . The reaction is generally carried out in a solvent such as alcohol at room temperature or under heating. Process E (8, 9) (In the formula, R ¹ , R ⁴ , and X have the same meanings as before, R ⁵ represents a lower alkyl group, and Y represents an oxygen atom or a sulfur atom, respectively.) As the lower alkyl group represented by R ⁵ , R ¹
The lower alkyl groups mentioned in the above section are directly exemplified. In this process, compound () is produced by reacting compound () with a lower alcohol and an alkali metal salt of a thiol such as sodium methanethiolate or sodium ethanethiolate. This reaction is usually carried out in an alcohol such as methanol or ethanol at room temperature or under heating. In addition, at the beginning of this reaction, the general formula is mainly A compound having an α-alkoxy-α-alkylthiomethyl group represented by is obtained as a product, and as the reaction progresses, the general formula A compound having a dialkoxymethyl group represented by is mainly obtained as a product. Process F(10) (In the formula, R ¹ , R ⁴ , R ⁵ , and X have the same meanings as before.) This process is an elimination reaction step in the presence of a strong base, and the elimination reaction in Process G described below is The two differ in the way they are performed. That is, this process is carried out under anhydrous conditions in the presence of a strong base such as an alkali metal alcoholate or an alkali metal amide. The reaction solvent is selected depending on the type of strong base, but alcohols are usually used. Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under heating. Process G(11) (In the formula, R ¹ , R ⁴ , R ⁵ , and X have the same meanings as before.) This process is an elimination reaction step in the presence of a weak base, and pyridine or the like is used as the weak base. The reaction may also be carried out in the presence of water. The type of solvent is not limited, but when a liquid organic base is used, the base may also be used as a solvent, and in the case of a hydrophilic solvent, it may be used in combination with water. Although the reaction temperature is not particularly limited, it is preferable to carry out the reaction under heating. Process H(12) (In the formula, R ¹ and X have the same meanings as before, R ⁶ is 1,3-
dithio-2-cyclopentyl group) As the reaction reagent for this process, an alkanedithiol can be used in the presence of an acid catalyst. The reaction is usually carried out in an inert solvent under mild conditions ranging from room temperature to elevated temperatures. Process I (13) (In ^the formula, R ¹ , R ⁶ , and This is a cleavage reaction in which the raw material (XII) is first reacted with a phenyl (lower) alkyl halide, such as benzyl chloride or benzyl bromide, which has been reacted with a strong base (for example, sodium hydride). The reagent used then binds to the cleaved sulfur atom to produce the above compound ().
As a solvent, tetrahydrofuran, ether,
An inert solvent such as benzene is used, and the reaction temperature is not particularly limited, but it is preferable to carry out the reaction under heating. Although each process has been described above, the compounds provided herein have antihypertensive and/or anesthetic effects and can be used as medicines. Next, examples of the present invention will be shown. Example 1 Extraction of 3-(α-methoxy-α-methylthio)methyl-2-thioxopyrrolidine (natural roughanthin) 100% methanol 36 was added to 20 kg of radish root, pulverized with a mixer, and extracted overnight at room temperature. After filtering the extract, it is concentrated under reduced pressure. The residue is made up to 2.5 with water and the solution is extracted three times with the same volume of ethyl acetate. The extract was concentrated to dryness to obtain 5.5 g of residual oil. Add this to silica gel 300
The mixture was subjected to column chromatography using G, and eluted with a mixture of hexane and ethyl acetate (4:1) as a developing solvent, and the eluate was fractionated. Collect the fractions whose eluate volume is 2 to 4.5 when calculated from the beginning,
By concentrating this, 1.8 g of lafuantin is obtained. Colorless plate-like crystals are obtained by repeatedly recrystallizing this product from hexane. The physical and chemical properties of this product are as follows. Elemental analysis calculated values C43.98%, H6.81%, N8.37%, S33.51% Actual values C43.79%, H6.86%, N7.30%, S33.43% Molecular weight 191 (based on mass spectrum) Identification) Melting point 72-73℃ Specific rotation [α] ²⁵ _D = 0゜ (chloroform) Ultraviolet absorption spectrum λ ^CH3OH _nax 268mμ (ε=13500) Infrared absorption spectrum ν ^KBr _nox 3160, 3050, 2910, 2880, 2830, 1535 ,
1450, 1340, 1295, 1265, 1195, 1110, 1105,
1065, 1045, 1015, 980, 955, 930, 785, 760
cm ^-1 nuclear magnetic resonance absorption spectrum (δ (ppm),
CDCl ₃ ) 2.23 (3H, s) 2.35 (2H, q, J = 7Hz) 3.23 (1H, tofd, J = 7, 2Hz) 3.47 (3H, s) 3.60 (2H, t, J = 7Hz) 5.12 (1H , d, J=2Hz) 8.88 (1H, broad s) Solubility Soluble in methanol, acetone, ether, chloroform, sparingly soluble in hexane, insoluble in water. Color and properties of crystals Colorless plate crystals (recrystallized from hexane) Thin layer chromatography When developed with a mixed solvent of hexane and ethyl acetate (17:3) in silica gel thin layer chromatography, Rf = 0.10; : When developed with ethyl acetate (7:3), it shows Rf=0.30. When 10% sulfuric acid is sprayed on thin layer chromatography for color reaction and then heated, the color first appears green and then blue. Tests positive for Dragendorff's reagent. From the above physical and chemical properties and the results of separate research,
The structural formula of this product is estimated as follows. Example 2 Extraction of 3-(α-ethoxy-α-methylthio)methyl-2-thioxopyrrolidine Add 18 kg of ethanol to 10 kg of radish root,
After grinding with a mixer, extract at room temperature overnight.
After filtering the extract, it is concentrated to dryness. This residue is treated and purified in the same manner as in Example 1, and recrystallized from hexane to obtain colorless platelet crystals of the compound in the above-mentioned formula where R is ethyl. The physical and chemical properties of this product are as follows. Ultraviolet absorption spectrum λ ^CH3OH _nax 269mμ Infrared absorption spectrum ν ^KBr _nax 3160, 3050, 2960, 2910, 2860, 1540,
1470, 1430, 1390, 1360, 1320, 1300, 1270,
1220, 1180, 1140, 1110, 1070, 1020, 990,
960, 930, 890, 840, 790, 740, 680 cm ^-1 Thin layer chromatography In silica gel thin layer chromatography, when developed with a mixed solvent of hexane: ethyl acetate (17:3), Rf = 0.15, similarly hexane: acetic acid. When developed with ethyl (7:3), Rf=0.39 is shown. Color reaction Shows the same color reaction as rough anthin. From the above physical and chemical properties and the results of separate research,
The structural formula of this product is estimated as follows. Example 3 1-formyl-3-hydroxymethylene-2-
Production of pyrrolidone A solution (1.8 M) of n-butyllithium (11.5 g) in n-hexane (100 ml) was added to a solution of diisopropylamine (18.2 g) in hexamethylphosphoramide (80 ml), and the mixture was heated at -20°C for 1 hour. Stirred. 2- to the obtained solution of lithium diisopropylamide
A solution of pyrrolidone (5 g) in hexamethylphosphoramide (5 ml) was added, heated at -20°C for 30 minutes, and then -
Each was stirred at 10°C for 1 hour. Ethyl formate (44.5 g) was added to the reaction mixture, and the mixture was stirred at -10°C for 2 hours.
After the reaction was completed, ammonium chloride (9.6g) was added.
0.5N hydrochloric acid was added until the pH reached 3. Extracted three times with ethyl acetate (300ml), and the resulting ethyl acetate layer
Extracted with 0.1N aqueous sodium hydroxide solution. 10% hydrochloric acid was added to the aqueous layer to adjust the pH to 4, and the mixture was again extracted three times with ethyl acetate (400 ml). Add the extract to water (300ml)
and a saturated aqueous sodium chloride solution (300 ml), dried over anhydrous sodium sulfate, and then the solvent was distilled off. Treatment of the yellow residue with benzene gave crystals (1.81 g). Some of it is refined
The title compound with a mp of 123-124°C was obtained, and the remainder was used as raw material in Examples 5 and 12. IR (KBr): νmax, cm ^-1 3130, 1730, 1661, 1645, 1482, 1443, 1402,
1382, 1315, 1280, 1255, 1200, 1185, 973,
800, 740 Example 4 Production of 1-methyl-3-hydroxymethylene-2-pyrrolidone A solution of n-butyllithium (19.8 g) in hexane (168 ml) was added to a solution of dipropylamine (30.1 g) in dry tetrahydrofuran (200 ml). (1.8M)
was added and stirred at -20°C for 1 hour and 45 minutes. In the reaction solution,
A solution of N-methyl-2-pyrrolidone (20 g) in dry tetrahydrofuran (15 ml) was added, and the mixture was stirred at the same temperature for 1 hour and 50 minutes. Ethyl formate (75 g) was added to the reaction mixture, and the mixture was stirred at -78 to -50°C for 45 minutes. After the reaction was completed, ammonium chloride (32.4g) was added and 1
It was left at room temperature overnight. Next, 0.5N hydrochloric acid was added until the pH reached 3, extracted three times with ethyl acetate (300 ml), and the organic layer was extracted with 0.1N aqueous sodium hydroxide solution. The aqueous layer was adjusted to pH 4 with 10% hydrochloric acid and extracted three times with ethyl acetate (400 ml). The organic layer was washed with water (300 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off.
When the residue was recrystallized from a mixed solvent of ethyl acetate and n-hexane, the title compound (1 g) with a mp of 168-169°C was obtained.
was gotten. Example 5 Production of 1-formyl-3-methoxymethylene-2-pyrrolidone 1-formyl-3-hydroxymethylene-2-
In a solution of pyrrolidone (25 g) in acetone (500 ml),
Potassium carbonate (49g) and dimethyl sulfate (22.7g)
g) was added and stirred at room temperature for 40 minutes. The reaction mixture was filtered and the filtrate was concentrated to 1/2 volume. Next, ethyl acetate (1) and a saturated aqueous sodium bicarbonate solution (300 ml) were added, and the organic layer was separated and washed three times each with 200 ml of a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution (200 ml). This solution was dried over anhydrous sodium sulfate and the solvent was distilled off, leaving a red oily residue (21.4 g).
was obtained and developed by column chromatography on silica gel (100 g). Elute with chloroform and extract mp117-119 from the fraction containing the target substance.
The target substance was obtained as yellow crystals (3.9 g). IR (CHCl ₃ ): νmax, cm ^-1 2930, 2845, 1725, 1690, 1660, 1480, 1445,
1395, 1345, 1290, 1140, 1100, 990 NMR ( _CDCl3 ): δppm 2.68 (2H, m), 3.71 (2H, t, J = 7.6Hz),
3.91 (3H, s), 7.31 (1H, t, J = 3.0Hz),
9.11 (1H, Broad) Example 6 Production of 3-methoxymethylene-2-pyrrolidone Potassium carbonate (4 g) was added to a methanol (400 ml) solution of 1-formyl-3-methoxymethylene-2-pyrrolidone (6.27 g), 1 hour at room temperature10
Stir for 1 minute. The reaction mixture was filtered and the mother liquor was concentrated to 1/3 volume. Add ethyl acetate (1
) and a saturated aqueous sodium chloride solution (300 ml) were added for extraction. The aqueous layer was further extracted with ethyl acetate (250ml x 4). The combined ethyl acetate was washed twice with a saturated aqueous sodium chloride solution (200 ml), dried over anhydrous sodium sulfate, and the solvent was distilled off to give the title compound (3.64 g) in the form of yellow crystals, mp 111-113°C.
was gotten. IR (CHCl ₃ ): νmax, cm ^-1 3440, 3220, 2980, 2840, 1707, 1655, 1495,
1450, 1420, 1350, 1140, 1055, 980, 950,
895 UV (CH ₃ OH): λmax, mμ 241 (ε20000) NMR (CDCl ₃ ): δppm 2.71 (2H, m), 3.41 (2H, t, J = 7Hz),
3.78 (3H, s), 7.00 (1H, t, J = 2Hz) Example 7 Production of 3-methoxymethylene-2-thioxopyrrolidine 3-methoxymethylene-2-pyrrolidone (3.0
g) in dry dioxane (150 ml) with 5 sulfide 2
Phosphorus (11.5 g) was added and the mixture was stirred at room temperature overnight. Add a saturated aqueous solution of sodium bicarbonate (500
ml) and extracted three times with diethyl ether (500 ml). The organic layer was washed with water (300ml x 2), dried over anhydrous sodium sulfate, and the solvent was distilled off.
A yellow residue (1.93g) was obtained. This was developed on a column chromatograph using silica gel (40 g), and n
- Elution was carried out with a 1:1 mixed solution of hexane and ethyl acetate. Fractions containing the target substance were collected and the solvent was distilled off to obtain the title compound (1.25 g) with a mp of 148-152°C. IR (CHCl ₃ ): νmax, cm ^-1 3410, 3170, 2950, 2835, 1670, 1500, 1465,
1440, 1365, 1341, 1295, 1135, 1025, 960,
943, 895 UV: λmax, mμ 270 (ε20600) 308 (ε10500) NMR (CDCl ₃ ): δppm 2.80 (2H, m), 3.65 (2H, t, J = 8.2Hz),
3.88 (3H, s), 7.43 (1H, t, J=3.0Hz), 8.0
(1H, Broad) Example 8 Production of 3-dimethoxymethyl-2-thioxopyrrolidine Add 20% to a methanol (20 ml) solution of 3-methoxymethylene-2-thioxopyrrolidine (264 mg).
A solution of aqueous sodium methanethiolate (1.8 ml) in methanol (46 ml) was added and stirred at room temperature for 3 days. Ethyl acetate (500 ml) was added to the reaction mixture, and the mixture was washed four times with saturated aqueous sodium chloride solution (200 ml). After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off to obtain a yellow crystalline substance (224 mg). When this product is recrystallized with a mixed solvent of ethyl acetate and n-hexane (1:1), mp109-110
The title compound (92 mg) was obtained as pale yellow needles at . IR (CHCl ₃ ): νmax, cm ^-1 3400, 3180, 2950, 2840, 1517, 1470, 1448,
1348, 1295, 1120, 1082, 1063 UV (EtOH): λmax, mμ 274 (ε7600) NMR (CDCl ₃ ): δppm 3.48 (3H, s), 3.52 (3H, s), 4.88 (1H, d,
J = 2.5 Hz) Example 9 Production of 3-(α-methoxy-α-methylthio)methyl-2-thioxopyrrolidine A solution of 3-methoxymethylene-2-thioxopyrrolidine (400 mg) in methanol (20 ml) was mixed with 20 %
A solution of aqueous sodium methanethiolate (0.9ml) in methanol (30ml) was added and stirred at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate (1),
Washed with saturated aqueous sodium chloride solution (200ml x
3). After drying over anhydrous magnesium sulfate, the solvent was distilled off to obtain a yellow oily residue (430 mg). This was developed on a column chromatograph using 30 g of silica gel and eluted with a mixed solvent of n-hexane and ethyl acetate (1:1) to obtain the title compound (160 mg) in the form of yellow crystals. The structural formula of this product is as shown in [ ] above, but the 3-position carbon atom of the pyrrolidine nucleus and the first carbon atom on the side of the chain are both inhospitable carbon atoms, and the product was obtained in this example. teeth,
It was a mixture (1:1) of the natural product lafuanthine and its diastereomers. The target substance obtained above and rafuantine
A comparison of some of the NMR (CDCl ₃ , δppm) results were as follows. Natural product (roughanchin)
Synthetic product (target substance of this example) 2.23 (3H, s) ←→2.23 (3H, s) 2.30 (3H, s) * 3.47 (3H, s) ←→ 3.47 (6H, s) 5.12 (1H, d , J = 2H _z ←→ 5.05 (1H, d, J = 4Hz) * 5.12 (1H, d, J = 2Hz) * is a signal derived from diastereomer. Example 10 3-methoxymethylene-2- Production of thioxopyrrolidine Add a solution of potassium tert-butoxide in dry tertiary-butanol (potassium: 100 mg, butanol) to a solution of natural lafuanthine (methoxy form: 134 mg) obtained in the above extraction example in dry tertiary-butanol (3.5 ml). :7 ml) was added and heated under reflux for 2 hours. A small amount of water was added to the reaction mixture and extracted with ethyl acetate (200 ml). The extract was washed with saturated sodium chloride brine, and insoluble matter was filtered off. When the solvent was distilled off from the mother liquor, yellow crystals (95 mg) were obtained. When this product was recrystallized from benzene, the title compound (68 mg) was obtained.
was obtained, and as a result of identification with the compound obtained in Example 7,
The two matched perfectly. Example 11 Preparation of 3-methoxymethylene-2-thioxopyrrolidine and 3-methylthiomethylene-2-thioxopyrrolidine A solution of the same natural lafuanthine (30 mg) used in Example 10 in 50% aqueous pyridine (5 ml) was added. ,4
The mixture was heated to reflux for an hour. Diethyl ether (100 ml) was added to the reaction mixture, and the mixture was washed with 1N hydrochloric acid and then with water. After washing with anhydrous sodium sulfate, the solvent was distilled off. The obtained residue was applied to a column chromatograph using 20 g of silica gel and eluted with a mixed solvent of benzene and ethyl acetate (3:1). 3-methylthiomethylene-2-thioxopyrrolidine (8 mg) was obtained from the initial fraction. IR (CHCl ₃ ): νmax, cm ^-1 3410, 1610, 1500, 1300, 1180, 1020, 860 UV (C ₂ H ₅ OH): λmax, mμ 295, 303, 327 NMR (CDCl ₃ ): δppm 2.53 ( 3H, s), 2.75 (2H, dt, J = 2.5, 7.5
Hz), 3.70 (2H, t, J=7.0Hz), 7.53 (1H,
t, J = 2.5 Hz) 3-methoxymethylene-2-thioxopyrrolidine (7 mg) was obtained from further subsequent fractions.
This product was identified as those obtained in Examples 7 and 10, and as a result, they were completely identical. Example 12 3-(1,3-dithio-2-cyclopentyl)-
Production of 2-pyrrolidone 1-formyl-3-hydroxymethylene-2-
Add 1,
Add 2-ethanedithiol (16.4 ml) and add 3
After adding boron fluoride/diethyl ether complex (20 ml), the mixture was left at room temperature overnight. After the reaction was completed, about 200 ml of acetic acid was distilled off, and a saturated potassium carbonate aqueous solution was added to neutralize. Extract with methylene chloride (200ml),
After washing with water and drying, the solvent was distilled off, leaving a residue (13.5g).
was gotten. This product was subjected to column chromatography using 100 g of alumina and eluted with a mixed solvent of benzene and n-hexane (2:1). When the crystals obtained by distilling off the solvent are recrystallized with a mixed solvent of chloroform and n-hexane (2:1), mp143-144 is obtained.
The title compound (4.66 g) was obtained in crystalline form. Example 13 3-(2-benzylthioethylthiomethylene)-
Production of 2-pyrrolidone Sodium hydride (40%: 1.27 g) was washed several times with n-hexane under a nitrogen stream, added to dry tetrahydrofuran (130 ml), and further added with 3-(1,3-dithio-2-cyclopentyl). )-2-pyrrolidone (4 g) was added. To this reaction mixture was added benzyl chloride (2.68 g) in dry tetrahydrofuran (10 g).
ml) solution was added and heated under reflux for 5 hours. After cooling the reaction solution, chloroform (600 ml) was added and washed twice with water (200 ml). After drying the organic layer over anhydrous sodium sulfate, the solvent was distilled off. The residue (5.56 g) was chromatographed on silica gel (100 g), washed with chloroform (500 ml), and eluted with ethyl acetate to give the title compound (2.6 g) with mp 75-77°C. Example 14 3-(1,3-dithio-2-cyclopentyl)-
Production of 2-thioxopyrrolidine 3-(1,3-dithio-2-cyclopentyl)-
2-pyrrolidone (1 g) in dry dioxane (25
ml) diphosphorous pentasulfide (1.6 g) was added to the solution and stirred overnight at room temperature. The reaction solution was passed through a Celite column, and the column was washed with chloroform. Add chloroform (200 ml) to the combined flow liquid and washing liquid, and add saturated aqueous sodium bicarbonate solution (150 ml).
Washed twice with The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. Silica gel yellow residue
The mixture was developed on a 30 g column chromatograph and eluted with a mixture of benzene and ethyl acetate (3:1). The fractions containing the target substance were collected and the solvent was distilled off to obtain crystals, which were mixed with a mixture of n-hexane and ethyl acetate (1:
Recrystallization in step 3) gave the title compound (500 mg) with a mp of 150°C. Example 15 3-(2-benzylthioethylthiomethylene)-
Production of 2-thioxopyrrolidine 3-(2-benzylthioethylthiomethylene)-
2-pyrrolidone (2 g) in dry dioxane (50
ml) diphosphorous pentasulfide (3.27 g) was added to the solution, and the mixture was stirred at room temperature overnight. The reaction solution was passed through a Celite column, and the column was washed with chloroform. Add chloroform (400 ml) to the combined flow liquid and washing liquid, and add saturated aqueous sodium bicarbonate solution (300 ml).
Washed twice with The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled off. The residue (1.99 g) was chromatographed on 30 g of silica gel, washed with chloroform (200 ml), and eluted with a mixture of benzene and ethyl acetate (3:1, 200 ml). The material obtained by concentrating the latter eluate (1.40 g) was developed on a column chromatograph using 50 g of silica gel.
Elution was performed with a mixture of benzene and ethyl acetate (5:1). The solvent was distilled off from the fraction containing the target substance to obtain crystals (1.13 g). When this product is recrystallized from a mixture of cyclohexane and ethyl acetate (1:3), mp116
The title compound (315 mg) was obtained at ~117.5°C. The pharmacological effects of the compounds provided by the present invention are as follows. Using spontaneously hypertensive rats, the Rafuantine crystals extracted in Example 1 above were mixed with 5% sodium carboxymethyl cellulose at a rate of 100 mg/Kg.
It was injected intraperitoneally as a physiological saline solution containing 10% gum arabic, and blood pressure values were measured 1 hour later. When compared with the control blood pressure values before administration of lahuantine, they were 130 mmHg and 175 mmHg, respectively, indicating a decrease in blood pressure of 45 mmHg. . In addition, the minimum effective dose of anesthetic effect was determined using DD mice by observing the loss of righting reflex after intravenous injection of lafuantin.
It was 100mg/Kg. In addition, in order to compare with chemically synthesized products, the reduction in blood pressure was observed when 30 mg per rat was orally administered to the extract obtained in Example 1 (Rafanthine) and the compounds obtained in Examples 8 and 9 above. The amount and anesthesia time when 100 mg/Kg or 200 mg/Kg was intravenously injected were measured, and the results shown in Table 1 were obtained. 【table】

Claims (1)

[Claims] 1. General formula (In the formula, R ¹ is a hydrogen atom, a lower alkyl group, or a formyl group. R ² is a hydroxymethylene group, a lower alkoxy-substituted methylene group, a lower alkylthio-substituted methylene group, a phenyl (lower) alkylthioethylthio-substituted methylene group, a lower alkoxy and/or a methyl group substituted with lower alkylthio, or 1,
A pyrrolidine derivative represented by a 3-dithio-2-cyclopentyl group (X means an oxygen atom or a sulfur atom, respectively). 2. The compound according to claim 1, wherein R ¹ is a hydrogen atom. 3. The compound according to claim 1 or 2, wherein X is a sulfur atom. 4. A compound according to claim 1, 2 or 3, wherein R ² is dimethoxymethyl. 5. The compound according to claim 1, 2 or 3, wherein R ² is (α-methoxy-α-methylthiomethyl).