JPH02243627A - Remedy for angina pectoris - Google Patents

Abstract

PURPOSE:To obtain a remedy for angina pectoris useful for treating angina pectoris, myocardial infarction, etc., having inhibitory action on cardiac function, comprising a specific alkaloid as an active ingredient. CONSTITUTION:A remedy for angina pectoris containing an alkaloid shown by formula I (R is lower alkyl) as an active ingredient. A crude drug obtained from root of Stephania tetrandra S. MOORE of the family Menispermaceae is extracted with water, an alcohol or a mixed solvent of water and an alcohol, the solvent is removed from the extracted solution, the residue is dissolved in a mixed solvent of water and an alcohol, partitioned with an organic solvent, then a liposoluble component migrating to the solvent is removed and the resulting substance is dissolved in ammonia water at pH 9. Further the solution is extracted with chloroform to give phantinolin shown by formula II, which is alkylated to give a compound shown by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an alkaloid useful for treating angina pectoris, myocardial infarction, etc.

[Prior art and problems] Powder defense is caused by Qlenispermacea
e) 5tephania teLrandra 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. In addition, some new alkaloids have already been produced by induction (Patent Application No. 47182/1982).
(Japanese Patent Application No. 136260/1983, Japanese Patent Application No. 11234/1982) and a known alkaloid having angiotensin I converting enzyme inhibitory activity (Japanese Patent Application No. 48279/1982).

On the other hand, angina pectoris has been attracting a lot of attention as an adult disease, and a number of therapeutic drugs have been developed for its treatment, but there has been a desire for the development of even more effective drugs for treating angina pectoris.

[Means for Solving the Problem] In order to develop a therapeutic agent for angina pectoris that can solve the above problems, the present inventors focused on fantinoline among the alkaloids mentioned above, and chemically modified it using it as a raw material. As a result of further research, it was found that the compound represented by the following formula I has a certain cardiac function suppressing effect as a therapeutic agent for angina pectoris, and the present invention was completed.

That is, the present invention is a therapeutic agent for angina pectoris containing an alkaloid represented by the following formula 1 (hereinafter referred to as a compound of the formula) represented by the following formula 1 (wherein R represents a lower alkyl group) as an active ingredient.

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

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, pl (9) is dissolved in ammonia water and further extracted with chloroform to obtain an ammonia water extract and a chloroform extract. The extract is extracted with at least one selected from water, methanol, chloroform, ether, hexane, benzene, and ethyl acetate, and the elution solvent is Sephadex such as Sephadex L l-120, porous polymer alumina such as Diaion HP 20, 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 using thin-layer chromatography, fantinoline represented by the following formula (■) was obtained, and this fantinoline was used as a raw material. This is dissolved in a filter solvent selected from methanol, ethanol, chloroform, ether, acetone, dichloromethane, and dissolved in potassium carbonate and isopropyl bromide, n-propyl bromide, n-butyl bromide, noadimethane, phenyltriethylammonium ethoxide, etc. It can be obtained by carrying out alkylation.

After the reaction is completed, the compound of the formula 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 with thin layer chromatography. In some cases, purification may be carried out by recrystallization using a suitable solvent such as ethanol, water, or acetone.

Next, a specific example of the production of the compound of the formula will be shown.

Specific example 1 Extract 7.76 kg of Powder Bokhi with 3012 methanol,
Methanol extract 41 is obtained by removing methanol from the extract.
I got 09. This methanol extract was dissolved in 1.512 90% methanol-water mixture, and 1.5Q n-hexane was added.
After extracting three times with
．． 5a, and the ammonia water layer and chloroform layer were concentrated under reduced pressure to obtain an ammonia water extract and a chloroform extract. Next, the chloroform extracted extract was subjected to column chromatography using alumina (aluminum oxide 90, manufactured by Merck & Co., Ltd.), and eluted with chloroform while confirming the target components by thin layer chromatography to obtain Fr, -1 (meaning fraction 1). The same applies hereinafter) and Fr-2 were obtained, and Fr,-2 was purified by silica gel column chromatography (Kieselgel 60
, Merck & Co.) and chloroform-methanol (2
0:I) and eluted with Fr, 2-1, Fr, 2-2, F
r, 2-3 and Fr, 2-4 were obtained, by removing the elution solvent from Fr, 21 and recrystallizing with acetone.
Rf value 0.34 [Thin layer plate: Kieselgel 60
Ft, 4, developing solvent; chloroform-methanol (3:
1), coloring reagent: Dragendorff reagent] was obtained as colorless needle crystals of fantinoline.

Next, phenyltriethylammonium ethquine 1.
5g of ethanol! After adding 1.39 g of silver oxide and stirring overnight, 2.2 g of fantinoline was added to the filtered filtrate and the mixture was refluxed at 120°C for 4 hours. Oxide 90 (manufactured by Merck & Co.), eluted with chloroform, distilled off the solvent, and recrystallized with a mixture of ethanol and water to obtain an Rf value of 0.37 [Thin layer plate: Kieselgel 60F*s-1 development] Solvent: chloroform-methanol (9:1), coloring reagent: Dragendorff reagent] 1.49% of colorless needle crystals were obtained. This colorless needle crystal had the following physical and chemical properties and was determined to be 7-0-ethylphantinoline.

Melting point: 109.5-111°C Specific optical rotation [α]”g: + 276.3° (c = 0
, 68 , Cl1C13) E I -M S m/z
(%): 636 (M”, 65.9), 409 (55,7).

Infrared absorption spectrum νm: xe71!2932.28
06,2796,1608°1582.1508.14
64. +444°1416.1354,1268. +2
301216.1124,838 Proton nuclear magnetic resonance spectrum (δ ppm in CDCl5): 0.80 (3H,t, J=7.08Hz).

2.33 (3H, s), 2.59 (3H, s) 3.3
7 (3H, s), 3.74 (3H, s) 3.93 (3
H,s), 5.96(1)(,s).

6.30 (IH, s).

6.3 2(t H, dd, J = 8.3.1
．． 9 51-(z).

6.5 1 (I H,s), 6.54 (I I
-1, s -1ike).

6.8 2 (I H, dd, J = 8.3.2.4
4 Hz).

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

6. 9 0 (l I-1, d-1ike).

7.1 5 (L H, dd, J=8.3, 2.4
4l-1z).

7.3 7(I I-1, dd, J=8.3, 1.9
5Hz) 3C-nuclear magnetic resonance spectrum (δ ppm in CDCl5): 14.8 (q), 22.3 (Q), 24.6 (t) 40
．． 6(t), 42.0(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).

116.0(d), 120.2(d).

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

123.1(s), 127.9(s).

128.2 (2C, s), 130.2 (d) 132.7
(d), 135.0(s).

1 35.1 (s), 136.9 (s).

144.0(s), 147.2(s).

1 4 8.6 (s), 1 4 8.8 (s
).

1 4 9.5 (s), 1 5 1.6 (s).

154.0 (s) Specific Example 2 Fantinoline 1.239 obtained in Specific Example 1 was dissolved in methanol 807d, a small amount of potassium carbonate and isopropylbromide 5IR1Q were added, and the mixture was heated under reflux for 4 hours, and then the solvent was distilled off. , extracted with chloroform, subjected the extract to alumina column chromatography, and eluted with chloroform to obtain an Rf value of 0.37 [thin layer plate: Kieselgel 60Fys].Developing solvent: chloroform-methanol (9:I), coloring reagent. : Dragendorff reagent] 125 g of the compound was obtained.

This had the following physical and chemical properties and was determined to be 7-0-isopropylphantinoline.

Specific optical rotation [αdo8: +263.2° (c = 0, 73, Cl1C13) Mass spectrum 11/z (%): 6 5 0 (M”, 4 6), 4 2 3 (44).

2+2(65), 19+(100) Proton nuclear magnetic resonance spectrum (δ ppm in CDC13) 0.75 (3H, d, J=5.86Hz).

0.90 (3H, d, J = 5.86Hz).

2.30 (3H, s), 2.56 (3H, s).

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

3.93 (3H, s), 5.87 (LH, s).

6.30 (IH, s).

6.36 (IH, dd, J=8.3, 1.95Hz)
.

6.50 (l H,s ), 6.53 (l H,s
-1ike).

6.83 (IH, dd, J=8.3.2.44ttz)
.

6.86 (2H, m).

7.16 (IH, dd, J=8.3.2.44Hz)
.

7.38 (LH, dd, J=8.3, 1.95Hz)1
30-Nuclear magnetic resonance spectrum (δ pp@in coct,): 21.3(q), 21.7(q), 22.2(t).

24.1(t), 41.0(t), 42.0(t).

42.4(q), 4 2.6(q), 4 4.3(t)
.

4 5.5 (t), 5 5.6 (q), 5 5.9 (q
).

56.2(q), 6 1.6(d), 64.6(d)7
3.9(d), 1 0 5.5(d) 1 1 1.6
(d), 1 1 3.0 (d).

1 1 5.9 (d) 1 2 0.2 (d).

1 2 1.9 (2C, d), 1 2 2.8 (d).

1 2 2.9 (s), 1 2 7.5 (s).

127.7(s), 12? , 9(s).

1 3 0.2 (d), 1 3 2.7 (d).

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

1 3 5.2 (s), 1 4 3.5 (s).

1 4 7.0 (s), 1 4 8.7 (s).

1 4 8.9 (s), 1 4 9.4 (s).

1 5 2.0 (s), 1 5 3.8 (s) Next, the usefulness of the compound of the formula as a therapeutic agent for angina pectoris will be explained using experimental examples.

Experimental Example 1 (Suppressive effect on cardiac function) The chest of male Wistar rats anesthetized with Bendoparbital C30Q7 (9, i, p,) was opened, the aorta was cut at the upper part, and the heart was removed. The heart was placed in water-cooled Krebs solution to stop beating, and the aorta was cannulated retrogradely and perfused in a Langendorff manner with a hydrostatic pressure of 75α (601x−+g).

Krebs solution kept at 37°C was used as the perfusate, and a mixed gas of 95% oxygen and 5% carbon dioxide was aerated to maintain the oxygen partial pressure (po
t) was set to about 600 Hg. Coronary perfusion is measured via an electromagnetic flowmeter probe placed just before the aortic cannula, and a balloon connected to a pressure transducer is inserted into the left ventricle through the left atrium to record left ventricular pressure (LVP). At the same time, the heart rate (HR)
) were measured. The compound of the formula was continuously injected for 1 minute at a rate of 0.2 d1 minute.

The results are shown in Tables 1 and 2.

(However, in the table, dp/dt is the stroke rate, L V P
HR represents the amount of cardiac work, and is expressed as a percentage, with the control group not injecting the compound of the formula as 100%. ) Table 1: Suppressive effect on cardiac function of the compound obtained in Specific Example 1 Table 2: Suppressive effect on cardiac function of the compound obtained in Specific Example 2> From the above results, the suppressive effect on cardiac function of the compound of the formula was confirmed. It was done.

Furthermore, when the acute toxicity of the compound of the formula was investigated using ddY male mice, no deaths were observed after oral administration of 19.

Therefore, the compound of the formula is highly safe and useful as a medicine expected to suppress cardiac function, for example, as a therapeutic agent for diseases such as angina pectoris.

Next, the dosage and formulation of compounds of formula will be described.

The compounds of the formula can be administered to animals and humans neat or with conventional pharmaceutical carriers.

The dosage form is not particularly limited and may be selected and used as required, including tablets, capsules, granules, fine granules,
Examples include oral preparations such as powders, parenteral preparations such as injections, and suppositories.

In order to exert the desired effect as an oral agent, although it varies depending on the age, weight, and severity of the disease of the patient, an adult dose of 30 to 450 mg of the compound of the present invention should be administered in divided doses several times a day. It seems appropriate to take it.

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

[Fluidity promoters: light anhydrous silicic acid, dry aluminum hydroxide gel, synthetic aluminum silicate, magnesium silicate.

The compounds of the formula can also be administered as suspensions, emulsions, tablets, and elixirs, and these various dosage forms may contain flavorings and coloring agents.

In order to exert the desired effect as a parenteral agent, it is usually necessary to administer the compound of the present invention at a static dose of 0.1 to 5019 kg per day for an adult, although this will vary depending on the age, body weight, and severity of the disease of the patient. Injection, 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, a bactericide, a preservative, and a stabilizer 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 in any way.

Example 1 ■Corn starch 44g ■Crystalline cellulose 409 ■Carboxymethylcellulose calcium 59 ■Light anhydrous silicic acid 0.59■Magnesium stearate 0.59■Compound obtained in specific example 1
109 A total of 1009 were uniformly mixed with (1) to (2) according to the above recipe, and compressed and molded using a tablet machine to obtain tablets of 200 yti each.

This tablet has specific examples! Contains 201g of the compound obtained in 1.Adults should take 5 to 15 tablets a day in several doses.

Example 2 ■Crystalline cellulose 84.59■Magnenium stearate 0.59■Carboxymethyl cellulose calcium 5g ■Compound obtained in specific example 2! 09 Total 1009 Mix ■, ■, and a part of ■ uniformly according to the above recipe, compression mold, crush, add remaining amounts of ■ and ■, mix, compress and mold using a key press. Part 2001! y tablets were obtained.

These tablets contain Compound 20II9 obtained in Example 2, and are taken by adults in 5 to 1-5 tablets per day in several doses.

Example 3 ■ Crystalline cellulose 49.59 ■ 10% hydroxypropyl cellulose ethanol solution 359 ■ Carboxymethyl cellulose calcium 59 ■ Magnesium stearate 0.5 g ■ Compound obtained in specific example 1 to9 Total 1004? According to the above recipe, ■, ■, and ■ are mixed uniformly, and the mixture is made to be neutralized by a conventional method. The extrusion granulator is used to granulate the mixture, and the mixture is dried and crushed. Compression molding yielded some 200 R9 tablets.

This tablet contains 20 mg of the compound obtained in Example 1, and is taken by adults in 5 to 15 tablets divided into several doses per day.

Example 4 ■Corn starch 34.59■Magnesium stearate 509 ■Calcium carboxymethyl cellulose 59 ■Light silicic anhydride 0.5g■Compound obtained in Example 2 Log 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 10011 obtained in specific example 2.
9, and adults should take 1 to 3 g per day in several doses.

Example 5 ■ Crystalline cellulose 559 ■ 10% hydroxypropyl cellulose ethanol solution 359 ■ Compound obtained in specific example 1 109 Total 1009 According to the above recipe, ■ to ■ were mixed uniformly and wetted. After going into an extrusion granulator and granulating, the mixture was dried and sieved to obtain granules.

1 g of this granule contains compound 10011 obtained in specific example 1.
It contains 1 to 3 g per day for adults, divided into several doses.

Example 6 ■Corn starch 89.5g■Light silicic anhydride 0.5g■Compound obtained in specific example 2
109 total l 009 Mix ■～■ uniformly according to the above recipe, and mix 200 M
9 was filled into a No. 2 capsule.

This capsule contains the compound 20119 obtained in Example 2, and is taken by adults in 5 to 15 capsules divided into several doses.

Example 7 ■For injection'f1. Seedling water suitable…■Glucose
2002V ■Compound obtained in specific example 1
Total amount of 200-9: 100 After dissolving ① and ② in distilled water for injection, they were injected into an ampoule of 5- and autoclaved at 121°C for 15 minutes to obtain an injection.

Claims (1)

[Claims] A therapeutic agent for angina pectoris containing an alkaloid represented by the following formula I ▲Mathical formula, chemical formula, table, etc.▼ I (In the formula, R represents a lower alkyl group) as an active ingredient.