JPS60224622A - Cardiotonic agent - Google Patents

Abstract

PURPOSE:A cardiotonic agent, containing evodiamine present in a fruit of Evodia rutaecarpa Benth. of the family Rutaceae as an active constituent, having excellent contraction enhancing action on cardiac muscle, and useful as a remedy for various cardiac insufficiencies. CONSTITUTION:A cardiotonic agent containing evodiamine of the formula. The evodiamine of the formula can be prepared by separation and purification from a fruit of Evodia rutacecarpa Benth. of the family Rutaceae, and is found to have cardiotonic action with improved dosage dependence and to be usable as the cardiotonic agent. The amount for treatment is 0.1-1mg/kg/day for parenteral administration and 1-10mg/kg/day for oral administration. The agent is used in the form of a tablet, capsule or solution, etc. for the oral administration and a sterilized solution, e.g. liquid or suspension, for the parenteral administration.

Description

[Detailed description of the invention] 111!1(7)Yu''Ll The present invention relates to cardiotonic agents.

More specifically, the present invention relates to a cardiotonic agent having an excellent cardiotonic effect in a dose-dependent manner.

Structure of the Invention The present inventors are exploring physiologically active substances contained in various plants and studying their medicinal efficacy. Evodiamine, which is present in the fruit of Goshuyu (Wulai@), a plant belonging to the Rutaceae family, has an outstanding contraction-enhancing effect on the heart muscle.
The present invention was achieved by confirming that scales can be used as a cardiotonic agent.

The gist of the present invention resides in a cardiotonic agent containing evodiamine represented by the following formula (1) as an active ingredient.

In detail, the present invention will be described in detail. Ivodiamins, which is an active ingredient of the present invention, is used in the MerOk Index (The MerOk Index), for example.
).

io edition, page 561, 31;! 7 (1953), has the structure of the formula (1) shown above, is soluble in acetonate, slightly soluble in alcohol, ether, chloroform, etc., and slightly soluble in water, benzene, etc., and has a yellow color. It is a plate-shaped substance (recrystallized from alcohol).

Evodiamine is prepared, for example, by separating and purifying the fruit of Goshuyu (Wulaai). In other words, after crushing the dried Goshuyu fruit and defatting it, the soluble content is removed using a solvent such as acetone. Evodiamine is isolated by extraction and repeated column chromatographic purification of the extract. Evodiamine can also be chemically synthesized.

When evodiamine is used as a cardiotonic agent, it is administered alone or in combination with a pharmaceutically acceptable carrier. Its composition is determined by the route of administration, administration schedule, etc.

The dosage is determined by the patient's age, health condition, weight, severity of symptoms, type of concurrent treatment, if any, frequency of treatment, nature of desired effect, etc.The therapeutic dose is generally administered parenterally. So 0. /~l-・With this oral administration/~/ 014/Kg・
It is day.

When evodiamine is administered orally, it is used in the form of tablets, capsules, powders, granules, solutions, elixirs, etc., and when administered parenterally, it is used in sterile liquid forms such as liquids or suspensions. When used in the forms described above, solid or liquid non-toxic pharmaceutical carriers can be included in the composition. In any case, it is desirable to use an appropriate solubilizer in combination to make the composition as easily soluble or dispersible as possible.

As an example of a solid carrier, conventional gelatin-type capsules are used. The active ingredient may also be tabletted, granulated, or packaged as a powder with or without adjuvants. Excipients used in combination include water: gelatin:
Sugars such as lactose and glucose; Starches such as corn, wheat, rice, and arrowroot starch; Fatty acids such as nistearic acid; Fatty acid salts such as calcium nistearate and magnesium stearate; Talc (vegetable oil varnish); Tearyl alcohol; Examples include alcohols such as alcohols, gums, polyalkylene glycols, and the like.

These capsules, tablets, granules and powders are commonly available! -1
00% by weight of active ingredient, preferably 25-100% by weight.

As the liquid carrier, water or oil of animal or vegetable origin, such as petroleum, soybean oil, peanut oil, sesame oil, mineral oil, or synthetic oil, is used. Generally, physiological saline, dextrose or similar saccharide solutions, and glycols such as propylene glycol, polyethylene glycol, and the like are preferred liquid carriers.

When administered parenterally by intramuscular, intravenous, or subcutaneous injection, evodiamine is used as a sterile solution with the addition of other solutes, such as saline or glucose, to make the solution isotonic.

Suitable vehicles for injection include sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, dextrose, intravenous fluids, electrolyte solutions (for intravenous injection), and the like. In the case of these injection solutions, the active ingredient should normally be contained in an amount of O,S-O by weight, preferably /~IO by weight.

In the case of liquid preparations for oral administration, suspensions or syrups containing from 10 to 10 parts by weight of the active ingredient are preferred.

In this case, aqueous excipients such as fragrances, syrups, and pharmaceutical micelles are used as carriers.

Effects of the Invention Evodiamine according to the present invention has cardiotonic action and is therefore useful as a therapeutic agent for various types of heart failure.

EXAMPLES The present invention will be explained in more detail with reference to Examples below, but the present invention is not limited in any way by the Examples unless the gist thereof is exceeded.

Example / (1) Preparation of evodiamine Grind dried goshuyu fruit and add 31 ml of powder.
- After degreasing by extracting twice with hexane at room temperature, the residue is extracted three times with 3 tons of acetone at room temperature, the extracts are combined, and the acetone is distilled off. Acetone extraction residue 609
is dissolved in a mixture of methanol and acetone (/:/), 901/l of celite is added thereto and mixed well, and the methanol-acetone is distilled off to dryness. The dried product was placed on a silica gel column packed with a mixed solution of Coop's silica gel and 7 tons of benzene (A:/), and the column was eluted with the same solution. A mixture of evodiamine and lutaecarpine precipitated by concentrating the eluate / 4! After 60 g of Celite was added and mixed well, the acetone was distilled off to dryness. The above dried product was placed on a silica gel column packed with a silica gel of psθ9 packed with a mixture of benzene-acetone (/?:/), and both eluted fractions eluted with the same solution were concentrated, and the crude evodiamine precipitated was Obtain crystal cot. Recrystallization from ethanol gave evodiamine i, rtt as pale yellow plate crystals.The physical properties of the obtained evodiamine were as follows.

Melting point: ,277-27g°C Optical rotation: [63g+3° (in acetone) Molecular formula “IIHH'sO Molecular weight: ,30.3..3!; Infrared absorption (IR) spectrum: (in KBr)/b, 3
0. /600. /310i1 Ultraviolet absorption (UV) spectrum: (OI (, ON) 27.2 (log t 1
．． 0゜2KO (41,02), 29ba 3.90), J
3! ;(3,30)nrn(2n inotropic effect on isolated guinea pig atrium) (j, tθ~yzott
), the heart was rapidly removed, and the left atrium and right atrium Krebs Ringer were separated from the heart and suspended in a 20 ml Magnue tube containing Krebθ-R1nger solution.

The nutrient solution was kept at 1-430°C and 95% 0. -5% CO
, was ventilated. A resting tension of /l was applied to the atrium and incubated for 1 hour before drug administration. When examining the effect on the left atrium, electrical stimulation (2Hz, jmse
c, Changes in the strength of contraction caused by 5 V) and changes in the strength of automatic contraction caused by the action on the right atrium were recorded on a polygraph via a transducer. As a result, as shown in Fig. 1, evodiamine dose-dependently enhanced the contractile force of the left atrium of guinea pigs at concentrations of IO4~/If'M, whereas control force was increased at concentrations of /F'M. The contraction force was increased to approximately 1.1 times that of
For the guinea pig right atrium, epodiamine is /θ4~J
At the concentration of
Increased by 7 times.

[Brief explanation of drawings]

FIG. 1 is a diagram showing the cardiotonic effect of the cardiotonic agent of the present invention on isolated guinea pig atrium. In FIG. 1, the vertical axis shows the increase in contraction rate of the guinea pig atrium due to evodiamine, and the horizontal axis shows the molar concentration (g) of evodiamine. Applicant: Mitsubishi Chemical Industries, Ltd. Agent: Chief Patent Attorney in each state - 7 others Figure 1

Claims (1)

[Claims] (1) The following formula (1) A cardiotonic agent whose active ingredient is evodiamine expressed by