JPS63179878A - Novel alkaloid - Google Patents

Abstract

NEW MATERIAL:An alkaloid expressed by formula I. USE:A medicine and antihypertensive agent having hypotensive action of long duration. PREPARATION:FUNBOI (dried radix of Stephania tetrandra S. Moore) which is a crude drug originated from a root of the Stephania tetrandra S. Moore belonging to the family Menispermaceae is extracted with water, alcohols or a mixed solvent of water with alcohols. The solvent is then removed to give a residue, which is subsequently dissolved in the above-mentioned mixed solvent and distributed with an organic solvent to remove fat-soluble components. The resultant substance is dissolved in aqueous ammonia at pH 9 and then extracted with chloroform to provide an aqueous ammonia extract and chloroform extract essences. The chloroform extract essence is subsequently subjected to column chromatography several times using alumina, etc., as a carrier to give fangchinoline expressed by formula II, which is then ethylated with an ethylating agent, e.g. phenyltriethylammonium, etc., in a solvent. After the reaction, the solvent is distilled away and the residue is subjected to column chromatography using alumina, etc., as a carrier to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION "Field of Industrial Application" The present invention relates to a novel alkaloid that has a hypotensive effect and is useful for treating hypertension and the like.

[Prior Art and Problems] Powder protection is a method of powder control that is carried out by Menispermacea
e) 5tephania tetrandra S,
It is a crude drug based on MOORE roots, and pharmacological research in China has proven that it has analgesic, anti-inflammatory, anti-allergic, and antihypertensive effects. It is known that the root of Porphyra contains about 1.2% of alkaloids such as tetrandrine, fantinoline, menisin, menisidine, and sifuranoline, and the present inventors investigated these alkaloid components. There are already some new alkaloids (Japanese Patent Application No. 61-47812, Patent Application No. 611362).
No. 60) and known alkaloids having angiotensin I converting enzyme inhibitory action (Patent Application No. 61-48279)
I am getting .

On the other hand, the drugs currently used to treat hypertension have problems such as rapid onset of effect and short duration of effect, and the development of drugs to improve these problems. was desired.

[Means for solving the problem] In order to develop an antihypertensive agent with a sustained antihypertensive effect, the present inventors focused on fantinoline, one of the alkaloids mentioned above, and chemically modified it using it as a raw material. As a result of intensive research, we succeeded in deriving the novel alkaloid of the present invention.

That is, the present invention is a novel alkaloid represented by formula (I) (hereinafter referred to as the compound of the present invention).

For example, the following method can be used to obtain the novel alkaloid of the present invention.

After extracting the Powdered Bottle with water, alcohol, or a mixed solvent of water and alcohol, and dissolving the residue obtained by removing the solvent from the extract in a mixed solvent of water and alcohol, it is extracted with n-hexane, petroleum ether, etc. After partitioning with an organic solvent and removing fat-soluble components transferred to the organic solvent, it is dissolved in p)+9 ammonia water and further extracted with chloroform to obtain an ammonia water extract and a chloroform extract. Next, the loloform extracted extract was mixed with Sephadex LT (Sephadex LT 20, porous polymer Diaion HP20, alumina, etc.) using at least one selected from water, methanol, chloroform, ether, hexane, benzene, and ethyl acetate as an elution solvent. Alternatively, fantinoline represented by the following formula (I[) (II) is obtained by subjecting it to column chromatography several times using silica gel or the like as a carrier, and fractionating while confirming the target component by thin layer chromatography. This fantinoline is dissolved in a solvent selected from ethanol, methanol, chloroform, and ether, and motylated using an ethylating agent such as diazoethane or phenyltriethylammonium.
The compound of the present invention can be obtained by distilling off the reaction minor solvent, subjecting it to column chromatography using alumina or silica gel as a carrier, and fractionating while confirming the target component with thin layer chromatography. . In some cases, it may be purified by recrystallization using a suitable solvent such as ethanol, water, or acetone.

A specific example of the production of the compound of the present invention is as follows.

Specific example Powder Defense 7.76 to 9 is extracted with 3012 methanol,
Methanol extract 41 is obtained by removing methanol from the extract.
Obtained 0g. This methanol extract was dissolved in 1.5 ff of a 90% methanol-water mixture, and 1.51 ff of n-hexane was added.
2 to remove fat-soluble components, and then 90% methanol-water was concentrated under reduced pressure.
Add and dissolve 1.5 g of ammonia water, extract 5 times with 1.5 ρ of chloroform, and concentrate the ammonia water layer and chloroform layer under reduced pressure to obtain an ammonia water extract,
A chloroform extract was obtained. Next, the chloroform extract was subjected to alumina (aluminum oxide 90 manufactured by Merck & Co.) column chromatography and eluted with chloroform to obtain Fr-1 (fraction) and Fr-2, and Fr-2 was purified using silica gel. (Kieselgel 6o manufactured by Merck & Co.) column chromatography and eluted with chloroform-methanol (20:1) to obtain Fr2-1, Fr2-2, Fr2-3 and Fr2-4, and the elution solvent from Fr2-1 By removing and recrystallizing with acetone, a colorless needle with an Rf value of 0.34' [thin layer plate; Kieselgel 60F254, developing solvent: chloroform-methanol (3:1), coloring reagent: Dragendorff reagent] was obtained. Crystalline fantinoline was obtained.

Next, phenyltriethylammonium iosito 150
Dissolve m g in ethanol + 011 fl, silver oxide 1
Fantinoline 22011? was added to the filtrate, which was stirred overnight and then filtered. Add I 20 'C1
After refluxing for 4 hours, the solvent was distilled off under reduced pressure and subjected to alumina (aluminum oxide 90, manufactured by Merck & Co.) column chromatography and eluted with chloroform to obtain an Rf value of 0.37 [thin layer plate: Kieselgel 60' P2
64, developing solvent: chloroform-methanol (9:l)
, coloring reagent: Dragendorff reagent] Compound 225
I got N. This was recrystallized using a mixture of ethanol and water, and 1491 colorless needle crystals with the following physical and chemical properties were obtained.
I got R9.

Melting point: 109.5-111'C [α cocrystalline 3: +276.3° (c=0.6
8, CHCl5) E I -MS m/z (
%): 636 (M”, 65.9).

409(55,7), 205(I00) infrared absorption spectrum ν::H,l: 2932.2836, 2796.1608.1582,
+508.1464,1444゜1416.1354
．． 126B, 1230°12+6.1124,838 Proton nuclear magnetic resonance spectrum (δppm in CDC1G): 0.80(3) (, t, J=7.08).

2.33 (3H, s), 2.59 (3H, s).

3.3 7 (3H, s), 3.74 (3H, s).

3.93 (3H, s), 5.96 (IH, s).

6.30 (I H, s).

6.32 (IH, dd, J=8.3.1.95).

6.51 (I H,s), 6.54 (IH, 5-1ik
e).

6.82 (IH, dd, J=8.3, 2.44).

6.8 5 (I H, d, J = 8.3).

6, 90 (IH, d-1ike).

7.1 5 (IH, dd, J = 8.3, 2.44).

7.37 (IH, dd, J=8.3, 1.95) 13G
Nuclear magnetic resonance spectrum (δppm in CDC13): 14.8 (q), 22.3 (t), 24.6 (t).

40.6(t), 4.2.0(t), 42.5(q).

42.7(q), 44.4(t), 45.7(t).

55.9 (2c, q), 56.3 (q), 61.6 (d
).

64.5(d), 68.2(t), 106.0(d).

111.9(d), 113.0(d).

116.3(d), 120.2(d).

121.9 (2c, d), 122.9 (d).

123.1(s), 127.9(s).

1 28.2 (2c, s), 1 30.2 (d).

1 3 2.7 (d), 1 3 5.0 (s).

1 35.1 (s), 1 36.9 (s).

1 44.0 (s), I 47.2 (s).

1 48.6 (s), 1 48.8 (s).

149.5 (s), 151.6 (s).

154.0(s) The compound of the present invention has a hypotensive effect and is useful as a pharmaceutical agent as an antihypertensive agent. This will be explained using an experimental example.

Experimental example: Stroke-prone spontaneously hypertensive male rats (group I, 6 rats)
Six days before the start of the experiment, the animals were anesthetized by intraperitoneal administration of 50 rq/kg of bendoparbital sodium, and a cannula filled with 200 U/d of heparin sodium was inserted into the abdominal aorta from the femoral artery.

The other end of the cannula with a stopper was passed subcutaneously and fixed to the back of the neck. Rats were housed in private cages and fasted from the day before the experiment.

On the day of the experiment, connect the arterial cannula with a pressure transducer (CP
-01, Century Technology) and blood pressure recording device (P^-011, 5tar Med
ical; Recti-Horiz-8K.

The mean blood pressure was measured without anesthesia and without restraint using 5an-ei).

The compounds of the present invention obtained in the specific examples were dissolved in distilled water and administered orally, and blood pressure was measured over time. Distilled water alone was administered orally, and blood pressure was measured in the same manner as a control group. The results are shown in Table 1.

Table 1 Effect of the compound of the present invention on blood pressure in rats with spontaneous stroke-onset hypertension The above results confirmed that the compound of the present invention has a long-lasting antihypertensive effect.

In addition, the compound of the present invention obtained in the specific example was administered to rats (group I, 10
The safety of the compound of the present invention was confirmed as no deaths were observed even after oral administration to 197 to 9 mice.

The compound of the present invention can also be used as a salt commonly used as a pharmaceutical such as hydrochloric acid, sulfuric acid, succinic acid, etc. in order to achieve a pharmaceutical effect.

The compounds of the present invention can be administered to animals and humans either neat or with conventional pharmaceutical carriers. The dosage form is not particularly limited and may be selected and used as necessary, including oral preparations such as tablets, capsules, and granules, injection preparations,
Examples include parenteral agents such as halved. Oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods. Tablets are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc.; capsules are prepared by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic, etc.; It is manufactured by mixing it with an active pharmaceutical filler or diluent and filling it into hard gelatin capsules, soft gelatin capsules, etc. Syrups and elixirs are prepared by mixing the compound of the invention with a sweetening agent such as sucrose, preservatives such as methyl and propylparabens, coloring agents, flavoring agents, flavoring agents, and adjuvants.

Parenteral preparations are manufactured according to conventional methods, and distilled water for injection, physiological saline, aqueous dextrose solution, propylene glycol, etc. can generally be used as diluents. Furthermore, a bactericide, a preservative, and a stabilizer may be added as necessary.

In addition, from the viewpoint of stability, this parenteral preparation is frozen after being filled into capsules, etc., and the water is removed using normal freeze-drying technology.
Solutions can also be reconstituted from the lyophilizate immediately before use.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, and halved preparations for intrarectal administration, and are manufactured according to conventional methods.

Claims (1)

[Claims] Formula (I) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) A new alkaloid represented by