JPH0278681A - Novel alkaloid and hypotensor containing said alkaloid as active ingredient - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R represents lower alkyl; X represents N-CH3 or N-CH(CH3)2; Y represents formula II or N- CH(CH3)2]. EXAMPLE:(1beta)-7-Ethoxy-6,6',12-trimethoxy-2'-isopropyl-2-methylberba mane. USE:A hypotensor. PREPARATION:Stephania tetrandra S.Moore is extracted with water, alcohols, etc., and the solvent is removed from the resultant extract to from a residue, which is then dissolved in a mixed solvent of water with the alcohols and distributed with an organic solvent such as n-hexane. After removing a fat-soluble component transferred to the organic solvent, it is dissolved in water, aqueous ammonia and further extracted with chloroform, etc., to afford an extract. Then the organic solvent extract is subjected to column chromatography by using water, methanol, etc., as an eluting solvent to afford a composed expressed by formula III (A represents H or CH3), which is then dissolved in a solvent such as methanol and converted to an N-oxide using an oxidizing agent such as aqueous hydrogen peroxide.

Description

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

[Conventional techniques and issues] Powder protection is based on the family Menispermaceae.
e) 5Lephania tetrandra S,
It is a crude drug based on the root of MOORH, 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. In addition, some new alkaloids have already been produced by induction (Patent Application No. 47 of 1988).
No. 182, Patent Application No. 136260 of 1986, Showa 6
2 years patent application No. 11234) and angiotensin! Known alkaloids with converting enzyme inhibitory action (1932)
1 year patent application No. 48279).

On the other hand, drugs currently used to treat hypertension generally have a rapid onset of effect, but their effect duration is short, so they must be taken several times a day, which places a burden on patients. It has the problem of being large, and there has been a desire to develop a drug that can improve this problem.

[Means for Solving the Problems] In order to develop an antihypertensive agent that has a slow onset of action and a sustained antihypertensive effect, the present inventors used fantinoline or tetrandrine as a raw material among the alkaloids contained in Powdered Bottle. As a result of chemical modification and intensive research, we succeeded in deriving a new alkaloid having a hypotensive effect that meets the above objectives, leading to the completion of the present invention.
・That is, the present invention relates to formula I (wherein, R represents a lower alkyl group, and X represents N-C
H, or N-CH(CH,), and Y is N-C
The present invention is an antihypertensive agent containing a novel alkaloid represented by (representing H3 or N -CH(CHa)-) and the alkaloid (hereinafter referred to as the compound of the present invention) as an active ingredient.

For example, the following methods can be used to obtain the compound of the present invention.

After extracting Powder Bok 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, an organic solvent such as n-hexane or petroleum ether is extracted. After partitioning with a solvent and removing fat-soluble components that migrate to the organic solvent, it is dissolved in water or aqueous ammonia (preferably pH 9 to 1O), further extracted with an organic solvent such as chloroform, methylene chloride, or ether, and dissolved in water. Or obtain an ammonia water extract and an organic solvent extract. Next, the organic solvent extracted extract is mixed with Sephadex such as Sephadex LH20, porous polymer such as Diaion HP20, alumina or 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, fantinoline (A=H) or tetrantolidine (A= C1-13) and performing at least one of the operations shown below using these as raw materials.

(1) N-oxidation using an oxidizing agent such as hydrogen peroxide or m-chloroperbenzoic acid dissolved in a solvent selected from methanol, ethanol, acetone, and dichloromethane.

(2) Potassium carbonate and isopropyl bromide, n-propyl bromide, n-butyl bromide, diazomethane, dissolved in a solvent selected from methanol, ethanol, chloroform, ether, acetone, dichloromethane,
Alkylation using phenyltriethylammonium ethoxide etc.

However, when alkylating the 2-position and/or 2-position methyl group to an isopropyl group, first dissolve it in anhydrous tetrahydrofuran or 1,2-dimethoxyethane,
It was treated with methyl chloroformate to form a carbamate, then treated with 10% potassium hydroxide-ethylene glycol,
It is demethylated to give a carboxylic acid, and further decarboxylated under acidic conditions to give a nor form, which is then alkylated by the method described above.

After the reaction is completed, the compound of the present invention can be obtained by subjecting it to column chromatography using a carrier such as alumina or silica gel, and fractionating while confirming the target component using thin layer chromatography. In some cases, it may be purified by recrystallization using a suitable solvent such as methanol, ethanol, water, or acetone.

The order in which the above operations are carried out can be arbitrarily combined depending on the target substance.

Specific examples of the production of tetrandrine and fantinoline are as follows.

Specific example 1 Tetrandrine> Powder protection 7.76 to 9 to 3 (extracted with methanol of N2,
Methanol extract 41 is obtained by removing methanol from the extract.
I got 09. This methanol extract was dissolved in 1.51ml of a 90% methanol-water mixture, extracted three times with 1.5 parts of n-hexane to remove fat-soluble components, and then the 90% methanol-water mixture was concentrated under reduced pressure. Add 1.5Q of aqueous ammonia of 1-19 to the residue obtained, dissolve it, and add 1.5Q of aqueous ammonia of 1-19, and add 1
．． 512 five times, and the ammonia aqueous layer and chloroform layer were each concentrated under reduced pressure to obtain an ammonia aqueous extract,
A chloroform extract was obtained. The chloroform extract was then 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-14. :1 under reduced pressure
By condensation and recrystallization using methanol, Rf
Colorless needle-like crystals with a value of 0.54 [thin layer plate: Kieselgel 60F, developing solvent: chloroform-methanol (3:1), coloring reagent: Dragendorff reagent] were obtained.

The physicochemical properties of this compound were consistent with the properties of tetrandrine described in the literature [Masao Tomita, Mutsuo Kozuka, Morinori Kiki, Yakushu, 87(3) 316 (1967)].

Specific Example 2 Fantinoline> The Fr-2 obtained in Specific Example 1 was mixed with silica gel (Kieselgel 6
Pr2
- I5Fr2-2, Fr2-3 and Fr2-4 were obtained, the elution solvent was removed from Fr2-1, and recrystallization was performed with acetone to obtain I? f value 0.34 [thin plate:
Colorless needle crystals of Kieselgel 60Fts+, developing solvent: chloroform-methanol (3:1), coloring reagent: Dragendorff reagent] were obtained. A specific example is the monomethyl ether obtained by methylating this compound with diazomethane! The physicochemical properties were consistent with those of tetrandrine shown in .

Next, the fact that the compound of the present invention has a hypotensive effect and is useful as an antihypertensive agent will be explained with reference to experimental examples.

Experimental Example 1 Male rats with spontaneous stroke-onset hypertension (6 rats per group)
The subjects were fasted from 16:00 on the day before the start of the experiment.

On the day of the experiment, the rat was placed in a holder heated to 37℃! 5
After ~20 minutes, the tail-cuff
According to the Act, a non-invasive blood pressure and heart rate measuring device (PS-200
The systolic blood pressure in the caudal artery was measured indirectly using a 3D model (RIKEN Developed by RIKEN).

Examples below! The compound obtained in steps 3 to 3 was dissolved in distilled water and administered orally, and blood pressure was measured over time. In addition, only distilled water 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.

Next, an acute toxicity test of the compound of the present invention was conducted using ddY male mice, and there was no death after oral administration of 19/kg and intraperitoneal administration of 100119/kg.

As described above, the compounds of the present invention have extremely low toxicity and are highly safe.

Next, the dosage and formulation of the compound of the present invention will be explained.

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, and may include oral dosage forms such as tablets, capsules, granules, fine granules, and powders, and parenteral dosage forms such as injections and suppositories. It will be done.

In order to exert the desired effect as an oral agent, it is usually necessary for an adult to administer 30 to 450 my of the compound of the present invention divided into several times a day, although this will vary depending on the age, weight, and severity of the disease of the patient. It seems appropriate to take .

In the present invention, oral preparations such as tablets, capsules, and granules are manufactured according to conventional methods using, for example, starch, lactose, sucrose, mannitol, carboxymethyl cellulose, cornstarch, inorganic salts, and the like.

In addition to the excipients mentioned above, binders, disintegrants, surfactants, lubricants, fluidity promoters, flavoring agents, coloring agents, fragrances, and the like can be used in this type of preparation as appropriate. Specific examples of each are shown below.

[Binder co-starch, dextrin, gum arabic powder, gelatin,
Hydroxypropyl starch, methylcellulose, sodium carboxymethylcellulose, hydroxypropylcellulose, crystalline cellulose, ethylcellulose, polyvinylpyrrolidone, macrogol.

[Disintegrant] Starch, hydroxypropyl starch, sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, carboxymethyl cellulose, low substituted hydroxypropyl cellulose.

[Surfactant Sodium colauryl sulfate, soybean lecithin, sucrose fatty acid ester, polysorbate 80° [Lubricant] Talc, waxes, hydrogenated vegetable oil, sucrose fatty acid ester, magnesium stearate, calcium stearate, aluminum stearate, polyethylene glycol.

[Fluidity promoter] Light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the invention can also be administered as suspensions, emulsions, syrups, elixirs,
These various dosage forms may contain flavoring agents and coloring agents.

In order to exert the desired effect as a parenteral agent, although it varies depending on the patient's age, weight, and degree of disease, the compound of the present invention is usually administered intravenously in an amount of 0.1 to 5,019 kg per day for adults. , intravenous drip, subcutaneous injection, and intramuscular injection are considered appropriate.

This parenteral preparation is manufactured according to a conventional method, and generally uses distilled water for injection, physiological saline, aqueous glucose solution, vegetable oil for injection, sesame oil, peanut oil, soybean oil, corn oil, propylene glycol, polyethylene glycol, etc. as a diluent. be able to. Furthermore, bactericides, preservatives, and stabilizing agents may be added as necessary. In addition, from the viewpoint of stability, this parenteral preparation may be filled into a vial or the like, then frozen, water removed by ordinary freeze-drying techniques, and a liquid preparation prepared from the freeze-dried product immediately before use. Furthermore, isotonizing agents, stabilizers, preservatives, soothing agents, etc. may be added as appropriate.

Other parenteral preparations include liquid preparations for external use, liniments such as ointments, suppositories for rectal administration, and the like, which are manufactured according to conventional methods.

The present invention will be explained in more detail below with reference to Examples, but the present invention is not limited thereto.

Example 1 Fantinoline 59 obtained in Example 2 was mixed with ethanol 200
After adding phenyltriethylammonium ethoxide and heating under reflux for 5 hours, the solvent was distilled off under reduced pressure, and column chromatography was performed using alumina as a carrier, eluting with chloroform, and 7-0-ethyl Fantinoline 59 was obtained. Dissolve this in acetone 1607, add 30% hydrogen peroxide solution 207, stir at 50°C for 3 hours, cool, add manganese dioxide to decompose excess hydrogen peroxide, filter, and reduce the pressure of the filtrate. The lower solvent was distilled off.

The residue was subjected to column chromatography using silica gel as a carrier, eluted with chloroform-methanol (20:l), and the solvent was removed under reduced pressure to obtain 850 ff9 of the target substance in powder form. The physicochemical properties of this substance are as shown below, and from these data, 7-0-ethylphantinoline-2'-N-a-oxide (7-0
-ethylfangchinoline-2゛-N-
The structure was determined to be α-oxide).

Specific optical rotation [α] 8′: +215.6° (c = 0
, 76, ClICl5) Mass spectrum m/z
(%): 652 (M”) Proton nuclear magnetic resonance spectrum (δ ppfi in CDC1,): 0.84 (3
H,t, J = 7.08 Hz).

2.32 (3H, s).

3.40 (3H, s).

3.52 (3H, s).

3.72 (3H, s), 3.93 (3H, s).

4゜4 8 (IH, dd, J=1 1.5, 5.1Hz
).

5.9 9 (I H, s), 6.29 (L H, s)
.

6.29 (IH, dd, J=8.3, 2.2Hz).

6.5 0 (l H, s-1ike).

6.5 8 (l H, s).

6.8 5 (I H, d, J = 8.06 Hz).

6.8 7 (11-1, dd, J = 8, 3, 2.44
Hz).

6.9 0 (IH, d-1ike).

7.1 9(l H, dd, J = 8.3, 2.4
4Hz).

7.37 (IH, dd, J=8.3, 2.2Hz) +3
0-Nuclear magnetic resonance spectrum (δppm in CDCl!+): 14.7(q), 22.1(t), 24.7(t).

41.0(t), 41.8(t), 42.3(q).

44.1(t), 55.8(2C,q).

56.2 (Q), 55.7 (L), 58.5 (q).

61.6(d), 68.6(t), 77.3(d).

106.1Cd), 111.8(cJ).

1 1 2.2 (d), l 6, 2 (d).

1.20.5(d), 1.22.5(d).

1 22.6 (d), 1 22.8 (s).

1 23.0 (d), 1 24.3 (s).

1 24.5 (s), 1 28.0 (s).

+ 3 0.3 (d), 1 3 1.3 (s).

1 32.7 (d), 1 35.2 (s).

1 36.7 (s), 1 44.4 (s).

I 4 7.0 (s), 1 48.4 (s).

1 4 9.2 (s), 1 49.6 (s).

1 5 1.7 (s), 1 54.8 (s) Example 2 Example! 7-0-Ethylphanthinoline 59 obtained in 59 was dissolved in 200% of anhydrous tetrahydrofuran, 6d of methyl chloroformate was added, and the mixture was stirred at room temperature for 4 hours. Ammonia was added thereto, and the solvent was distilled off under reduced pressure. The product was subjected to column chromatography using silica gel as a carrier and eluted with chloroform-methanol (150:l) to obtain 1.359 of the 2°-N-carbamate of 7-0-ethylphantinoline. Add this to 10% potassium hydroxide-ethylene glycol 2
〇－Medium! Stir at 80°C for 1 hour, cool, make acidic by adding hydrochloric acid, leave for 5 minutes, make alkaline by adding ammonia, extract with chloroform, 7-〇-ethyl-2゛-
750 m9 of N-norphantinoline was obtained. this,
The solution was dissolved in ethanol 20-, and a small amount of potassium carbonate and isopropylbromide 4Id were added thereto. After heating and refluxing for 6 hours, the solvent was distilled off under reduced pressure, the residue was extracted with chloroform, and subjected to column chromatography using alumina as a carrier. The mixture was eluted with chloroform, and the solvent was removed under reduced pressure to obtain 730 yti of the target substance in powder form.

The physicochemical properties of this substance are as shown below, and from these data, (lβ)-7-nitoxy6゜6', +
2-trimethoxy-2'-isopropyl-2-methylberbamane [(Iβ17-ethoxy-6,6',
l 2-1rimethoxy-2°-4sopro
py12-methylberbaman].

Specific optical rotation [α]”o: +237.1” (c = 0, 64, CHCla) Mass spectrum m/z (%); 664 (M”) Proton nuclear magnetic resonance spectrum (δ ppm in CDC1*): 0 .78 (3H, t, J=7.08Hz).

1.13 (3H, d, J=6.35Hz).

1.25 (3H, d, J=6.35Hz).

2.32 (3H, s), 3.38 (3H, s).

3.74 (3H, s), 3.92 (3H, s).

6.05 (IH,s).

6.20 (I H, dd, J = 8.3.2.2
[-1z).

6.30 (IH9s).

6.53 (IH, 5-1ike), 6.56 (IH,
s).

6.78 (I H, dd, J=8.3, 2.441-1
z).

6.86 (2H, m).

7.13 (I H, dd, J = 8.3, 2.44 H
z).

7.33 (IH, dd, J=8.3, 2.2I-1z)
130-Nuclear magnetic resonance spectrum (δ ppm+ in CDC13): 14.7
(q), 18.9(q), 20.4(q).

2 2.1(t), 2 7.3(t), 4 1.7(t
).

42.3(q), 44.3(t), 44.4(t).

4 5.4 (t), 5 2.8 (d), 5 5.7 (q
).

5 5.9 (q), 5 6.1 (q), 6 0.3
(d).

6 1. 7(d), 6 8.1(t), I 0 5
．． 8(d).

1 1 1. 7(d), I　　　　　2.4(d).

1 1 5.9 (d), I 9.7 (d).

1 2 1.7 (2C, d), 1 22.7 (s).

1 2 2.9 (d), 1 2 8.1 (s).

1 2 8.8 (s), 1 2 9.7 (, d).

1 3 1.0 (s), 1 3 2.2 (d).

1 3 4.8 (s), 1 3 5.1 (s).

136.8(s), 144.1(s).

1 4 7.1 (s), 1 4 8.5 (2C, s).

1 4 9.3 (s), 1 5 1.5 (s).

153.7(s) Example 3 Specific example! The tetrandrine 69 obtained above was dissolved in 200 g of anhydrous tetrahydrofuran, methyl chloroformate was added thereto, and the mixture was stirred at room temperature for 24 hours, then ammonia was added, the solvent was distilled off under reduced pressure, and the residue was extracted with chloroform. This was subjected to column chromatography using silica gel as a carrier, and eluted with chloroporm-methanol (200:l).
I got 29. To this was added 10% potassium hydroxide, ethylene, and glycol lO-, the mixture was stirred at 180°C for 2 hours, cooled, made acidic by adding hydrochloric acid, left for 5 minutes, made alkaline by adding ammonia, and extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using phosphoric acid gel as a carrier and eluted with chloroform-methanol (40:1) to obtain 1.979 of 2,2°-dinoltetrandrine. Add this to ethanol 10011
After adding a small amount of potassium carbonate and 10 l of isopropyl bromide to the solution and heating under reflux for 24 hours, the solvent was distilled off under reduced pressure, extracted with chloroform, and concentrated under reduced pressure. Dissolve 1.2 g of this residue in anhydrous methylene chloride 100111, add aluminum chloride 49, stir at room temperature for 2 hours, add a small amount of water, methanol, and ammonia while cooling, extract with chloroform, and evaporate the solvent under reduced pressure. I left. The residue was subjected to column chromatography using phosphor gel as a carrier, eluted with chloroform-methanol (30:1), and 6,6°, 12-trimethoxy-2,2′-
isoprobil berbaman-7-ol at 620 rp;
I got ti. This was dissolved in ethanol 2 (ld), 9 parts of potassium carbonate and isopropyl bromide were added, and the mixture was heated under reflux for 6 hours, the solvent was distilled off under reduced pressure, and the residue was subjected to column chromatography using alumina as a carrier. The target substance 615!9 was obtained by elution with chloroform and removal of the solvent under reduced pressure.The physicochemical properties of this substance are as shown below, and from these data, (lβ)-7
-Itsuproboxy 6.6°, 12-trimethoquino-2
, 2′-isoprobilberbaman [(lβ)-7-1s
opropoxy-6,6°, l 2-trimet
hoxy-2, 2'-isopropylberba
man].

Specific optical rotation [α]”o: +232.8° (c = 0.72, CHCl3) Mass spectrum m/z (%) A 06 (M’).

Proton nuclear magnetic resonance spectrum (δ ppm in CDC13): 0.73 (9H, d, J=6.1!-1z).

0.90 (3H, d, J = 6.1 Hz).

1.13 (3H, d, J=6.35Hz).

1.2 5 (3H, d, J=6.3 5l-1z)
.

3.34 (3H, s), 3.72 (3H, s).

3.94 (3H, s), 5.97 (IH, s).

6.20 (I H, dd, J = 8.3, 1.96 l-
1z).

6.24(l Hls), 6.50(I 1(,5-1
ike).

6.57 (IH,s).

6.74 (lH, dd, J=8.3, 2.44Hz).

6.83 (2H, m).

7.16 (I H, dd, J = 8.3.2.44 H
z).

7.35 (I H, dd, J = 8.3.1.961
-Iz)13C-Nuclear magnetic resonance spectrum (δppHin CDC13): 19.1(q), 20.7(Q), 21.2(Q).

2 1.2 6(q), 2 1.3 4(q), 2 1
．． 7(q).

2 5.3 (t), 2 7.6 (t), 4 1.1 (t
).

42.0(t), 4 4.5(t), 4 e, 5(t
).

5 2.2(d), 5 2.4(d), 5 2.4(d
).

5 5.5 (d), 5 5.6 (q), 5 5.7 (q
).

5 6.1(q), 6 0.4(d), 7 4.0(d
).

1 0 5.6 (d), 1 1 1.0 (d).

1 1 2.2 (d), I 1 5.5 (d).

1 1 9.5 (d), 1 2 1.5 (d).

1 2 1.8 (d),! 23.3 (, d).

124.8(s),! 29.1(s).

Indigo 2 9.7 (s), 1 2 9.9 (d).

1 3 0.9 (s), 1 3 2.4 (d).

1 34.8 (s), 1 34.9 (s).

1 3 5.6 (s), 1 4 3.4 (s
).

1 4 6.8 (s), I 4 B, 1 (s).

1 4 8.3 (s), 1 4 9.2 (s).

1 5 1.7 (s), 1 5 3.6 (s).

1 0 6.0 (d), 1 1 1.7 (d).

1 1 2.9 (d), 1 1 6.2 (d).

120.2(d), 121.9(2C,d).

1.2.2.8(d), 1.23.1(s).

1 2 7.9 (s), 1 28.0 (s).

1 2 8.2 (sc! 3 0.1 (d).

l　　　　　2.6(d), 1　3　5.0(s).

1 35.2 (s), 1 37.1 (s).

1 44.0 (s), 1 4 7.0 (s)
.

1 4 8.5 (s), 1 4 8.6 (s).

1 4 9.4 (s), 1 5 1.5 (s).

153.8 (s) Example 4 ■Corn starch 449 ■Crystalline cellulose 409 ■Carboxymethylcellulose calcium 5g ■Light anhydrous silicic acid 0.590 Magnesium stearate 0.59■ Compound obtained in Example 1
10g total 1009 According to the above recipe, ① to ② were mixed uniformly and compressed using a tablet machine to obtain a portion of 200 yr9 tablets.

This tablet contains 20 compounds, and adults should take 3 to 15 tablets a day in several doses.

Example 5 ■ Crystalline cellulose 84.59 ■ Magnesium stearate 0.59 ■ Calcium carboxymethyl cellulose 59 ■ - Compound obtained in Example 2 10 g Total 1009 According to the above recipe, ■, ■, and a part of ■ were uniformly mixed. After compression molding, the mixture was pulverized, the remaining amounts of (1) and (2) were added and mixed, and the mixture was compressed and molded using a tablet machine to obtain 200 to 200 tablets.

This tablet contains 20 compounds, which can be used for adults for 3 to 3 days a day! Take 5 tablets in several doses.

Example 6 ■ Crystalline cellulose 49.59 ■ 10% hydroxypropyl cellulose ethanol solution 359 ■ Carboxymethyl cellulose calcium 59 ■ Magnesium stearate 0.59 ■ Compound obtained in Example 3 10 g Total 100 g ■, ■ and ■ according to the above recipe After uniformly mixing, neutering by a conventional method, granulating with an extrusion granulator, drying and crushing, mix ■ and ■, compression mold with a tablet machine, and make a portion of 200 xti. tablets were obtained.

These tablets contain compound 20jI9, and are taken by adults in 3 to 15 tablets a day in several doses.

Example 7 ■Corn starch 34.59 ■Magnesium stearate 509 ■Calcium carboxymethyl cellulose 59 ■Light silicic anhydride 0.59 ■Compound obtained in Example 1 109 Total 1009 Mix ■-■ uniformly according to the above recipe, After compression molding using a compression molding machine, the mixture was crushed using a crusher and sieved to obtain granules.

This granule 19 contains compound 100319, and is taken by adults in 0.5 to 39 doses per day in several doses.

Example 8 ■ Crystalline cellulose 559 ■ 1O% hydroxypropyl cellulose ethanol solution 359 ■ Compound obtained in Example 2 Log total 1009 According to the above recipe, ■ to ■ were uniformly mixed and suspended. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

This granule 19 contains 100 yty of the compound, and is taken by adults in doses of 0.5 to 3 g in several doses per day.

Example 9 ■Corn starch 89.59■Light silicic anhydride 0.5g '■Compound obtained in Example 3 109 Total 1009 Mix ■~■ uniformly according to the above recipe, and prepare 200 R
9 was filled into a No. 2 capsule.

This capsule! The capsules contain Compound 20 Shoulder 9, and adults should take 3 to 15 capsules several times a day.

Example 10 ■ Soybean oil 59 ■ Distilled water for injection 89.59 ■ Soybean phospholipid
2.5g ■ Glycerin 2g example! 19 compounds obtained in total 1009 According to the above recipe, dissolve ■ in ■ and ■, and add ■ to this.
The solutions of (1) and (2) were added and emulsified to obtain an injection.

Claims (2)

[Claims] (1) The following formula I (wherein, R represents a lower alkyl group, and X represents N-C
Indicates H_3 or N-CH(CH_3)_2, Y is ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ or N-CH (CH
_3) A new alkaloid represented by _2). (2) The following formula I ▲There are mathematical formulas, chemical formulas, tables, etc.▼ I (However, in the formula, R represents a lower alkyl group, and X represents N-C
Indicates H_3 or N-CH(CH_3)_2, Y is ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼ or N-CH (CH
_3) An antihypertensive agent containing an alkaloid represented by _2) as an active ingredient.