JPH0725673B2 - ATP enhancing composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention has the general formula (I): [In the formula, R and R'represent a lower alkyl group which may be the same or different, n represents an integer of 0 or 1 or 2, and A represents -CH _2- , (In the formula, M represents a hydrogen atom or a salt-forming residue.),
_{-CH = CH -, - CH 2} -CH 2 -, Represents ] An adenosine triphosphate (abbreviated herein as ATP) -enhancing composition containing a dithia derivative represented by

The compound represented by the general formula (I) (hereinafter referred to as the present compound) is a compound known as a therapeutic agent for liver diseases. As a result of extensive studies on the pharmacological action of these compounds, the present invention has been confirmed. The present inventors have found that this compound has an important pharmacological action which cannot be predicted from the conventional knowledge, and completed the present invention.

That is, this compound is to be administered to a living body, which raises the concentration of ATP, which is one of the high-energy phosphate compounds in the living body, and increases the tissue energy of each organ such as the liver and heart (energy charge increasing action). I got the knowledge to do.

Generally, production and consumption of energy are essential for each organ of the living body to exhibit its unique function. Among them, ATP is the most important substance as an energy source for living tissues. AT
The energy generated by the decomposition of P is specifically used for active transport, muscle contraction, and the like.

It is well known that dysfunction is detected in organs that require high energy such as the heart using ATP concentration or Energy Charge as an index. 1), 2), 3) [1] Thomas C Vary et al, Circulation Research V
ol.45, No.2: 218p ~ (1979) 2) Michael J Rovetto, Texas Report Biology and M
edicine.Vol.39: 397p ~ (1979) 3) Kazue Ozawa, Metabolism Vol, 15 No.11: 71p ~ (1978)].

For example, when this compound was administered to a living body, this compound had a hypotensive effect in the heart and circulatory system, and also in a model of ischemic heart disease, this compound showed a clear anti-corrosive effect.

On the other hand, when ATP is administered to humans as a pharmaceutical preparation, it has been observed in a wide range of organs and tissues such as kidney, heart and nervous system. 4) [4] Nakamoto Norimasa Pharmaceutical Research Vol.16 No.3: 567p ~ (1
985)] Therefore, this compound can be administered by administering it to a living body.
Since it has the effect of increasing the concentration of ATP in the living body and increasing the tissue energy, the cardiovascular disorder, such as cerebrovascular disorder, sequelae of head trauma, which has a medicinal effect by the administration of the ATP preparation in the above-mentioned document 4), is narrowed. Heart disease, coronary atherosclerosis, heart failure, muscular dystrophy, acute poliomyelitis, cerebral palsy (relaxed), tinnitus, deafness, eye fatigue, chronic gastritis,
It is expected to have a medicinal effect on acute and chronic gastritis, cardiomyopathy, myocarditis, etc.

The compounds represented by formula (I) used in the present invention and their toxicity are as follows.

When the compound represented by the general formula (I) is used as an ATP-enhancing composition, it may be used in a form convenient for obtaining the intended drug effect. This compound is ATP as it is
It can be a potentiating composition and a therapeutic agent for the various diseases mentioned above.

The compounds may also be formulated in admixture with pharmaceutically acceptable diluents and / or other pharmacological agents according to dosing conventions.

Further, the pharmaceutical agent of the present invention may be provided in a dosage unit form containing the present compound alone or as a mixture with a pharmaceutically acceptable diluent and / or other pharmacologically active substance.

The medicament of the present invention can be applied orally or parenterally. Therefore, the medicament of the present invention can take any form for oral or parenteral administration.

The pharmaceutical agent of the present invention can also be provided in a unit dosage form. In this case, an effective amount of the active ingredient compound is contained. Further, the effective dose needs to be within a certain range depending on various conditions.

The medicine of the present invention includes, for example, powders, granules, tablets, dragees, pills, capsules, suppositories, suspensions, solutions, emulsions, ampoules,
It may be provided in various forms such as an injection solution. In addition, the medicament of the present invention is provided in a sterile state or an isotonic solution, if necessary.

The preparation of the medicament of the present invention includes an embodiment in which the compound is contained in the form of a mixture with a pharmaceutically acceptable diluent.
Here, the diluent means a material other than the present compound, and may be a solid, a semi-solid, a liquid, or an ingestible capsule, and various ones can be mentioned. For example, excipients, fillers, binders, wetting agents, disintegrating agents, surfactants, lubricants, dispersants, buffers, flavoring agents, flavoring agents, dyes, perfumes, preservatives, solubilizing agents. , Solvent, etc.

They are also used as a mixture of one or more. Such pharmaceutically acceptable diluents may be used in admixture with other pharmacological agents and are within the scope of this invention.

The medicament of the present invention may be produced by any known method. For example, the active ingredient is mixed with a diluent to give granules and the composition is then shaped into tablets. Parenteral preparations should be sterile. It should also be isotonic with blood if necessary.

In the present invention, the present compound is generally contained in the composition as an active ingredient in an amount of 0.01 to 100% (by weight). When the preparation is in the form of a dosage unit, the individual preparation parts forming the preparation may have different forms or the same form.

The compounds are applied to humans and animals by the usual methods in the field and are administered orally or parenterally. Oral administration includes sublingual administration. Parenteral administration includes administration by injection (including subcutaneous, intramuscular, intravenous injection, and drip).

Dosage of the pharmaceutical of the present invention, whether the subject is an animal or human, sensitivity difference, age, sex, body weight, administration method, timing of administration, interval, medical condition, physical condition, property of pharmaceutical preparation, preparation It varies depending on various causes such as the type and the type of active ingredient.

Therefore, in some cases, a dose smaller than the minimum dose described below may be sufficient, and in other cases, it may be necessary to administer more than the upper limit dose of the following dose. In the case of large dose administration, it is preferable to administer in several divided doses per day.

In order to obtain effective results in animals, when orally administered as an active ingredient, 0.1 to 500 m / day per 1 kg body weight
g, preferably 1-100 mg, 0.01-250 m for parenteral administration
A range of g, preferably 0.1 to 25 mg, is advantageous.

The dose required to obtain effective results in humans is
Considering the difference in sensitivity and safety from the effective dose in animals, when orally administered as the active ingredient, per 1 mg of body weight,
An advantageous range is 0.1 to 250 mg, preferably 0.5 to 50 mg per day, and 0.01 to 100 g, preferably 0.1 to 25 mg for parenteral administration.

Examples are shown below, where all parts are parts by weight.

The kinds and proportions of the blended components can be changed variously.

Example 1 Compound No. 12 10 parts Heavy magnesium oxide 10 parts Lactose 80 parts are uniformly mixed to give a powder in the form of powder or granules.

Example 2 Compound No. 14 10 parts Synthetic aluminum silicate 10 parts Calcium hydrogen phosphate 5 parts Lactose 75 parts is used and made into a powder according to Example 1.

Example 3 Compound No. 9 50 parts Starch 10 parts Lactose 15 parts Crystalline cellulose 20 parts Polyvinyl alcohol 5 parts Water 30 parts After uniformly kneading, crushing and granulating, drying and sieving to obtain granules.

Example 4 99 parts of the granules obtained in Example 3 are mixed with 1 part of calcium stearate and compression-molded to give tablets having a diameter of 10 mm.

Example 5 Compound No. 4 95 parts Polyvinyl alcohol 5 parts Using 30 parts of water, a granule is prepared in the same manner as in Example 3. To 90 parts of this granule, 10 parts of crystalline cellulose is added and compression-molded to give tablets with a diameter of 8 mm. Further, a sugar-coated tablet is prepared by using an appropriate amount of syrup, gelatin, a mixed suspension of precipitated calcium carbonate and a pigment in the tablet.

Example 6 Compound No. 11 0.5 part Nonionic surfactant 2.5 parts Physiological saline 97 parts is mixed by heating and sterilized to obtain an injection.

Example 7 The powder of Example 1 is filled into a commercially available capsule container and encapsulated.

A test example is shown below.

Test Example 1 1) Test method Compound No. 4 was orally administered to healthy Wistar rats (♂) at a rate of 250 mg / kg, and 12 hours after that, the rats were sacrificed.
The liver was immediately frozen by an aluminum clamp cooled in liquid nitrogen, and the adenine nucleotide content in the liver [ATP (abbreviation of adenosine triphosphate), ADP
(Abbreviation of adenosine diphosphate), and ATP (adenosine-
5'-Phosphoric acid)] was measured by high performance liquid chromatography.

The results are shown by the content of ATP, which is a typical high-energy phosphate compound, and Adenylate Energy Charge (hereinafter referred to as AEC), which represents the energy state necessary for maintaining normal functions of the living body.

AEC is Atkinson's formula: Sought by.

2) Results 3) Discussion Compound No. 4 showed a significantly higher value than that of the control group by administering it in both items of hepatic ATP content and AEC.

An ATP-elevating effect equivalent to that obtained in Test Example 1 was also observed in the galactosamine-injured liver and the partially excised liver by the administration of this compound.

Test Example 2 1) Test Method SHR / SR rats (♀) were fed a high-fat, high-cholesterol diet (hereinafter referred to as HFC) and 1% saline for 3 weeks, and 250 mg / kg of compound No. 4 in the latter 1 week. Was orally administered every day at a ratio of. Meanwhile, blood pressure was measured at 2 weeks and 3 weeks before the start of the test. Heart adenine nucleotide content is 3
The examination was performed only in the week, and the measurement was performed in the same manner as in Test Example 1. The results of the 3rd week are shown below.

2) Results 3) Treatment of the devised HFC and saline increases blood pressure,
When compound No. 4 was administered in the latter half week, the present compound group showed a low blood pressure value not only in the HFC + NaCl treated group but also in the control group. The heart, ATP content, and AEC decreased by treatment with HFC and saline showed the same values as those of the control group by administration of compound Na.4.

Test Example 3 1) Test method A rat isolated heart perfusion sample was prepared according to the method of Langendorff. Compound Na.4 and compound Na.20 were dissolved in ethanol and diluted with perfusate (37 ° C., O ₂ , saturated Krebs Henseleit solution) to 10 ⁻⁵ M, and treated for 5 minutes 20 minutes after preperfusion. 1 after treating compound Na.4 or compound Na.20
Perfusion was stopped for 20 minutes, followed by reperfusion for 10 minutes. The cardiac adenine nucleotide content was measured in the same manner as in Test Example 1 after reperfusion for 10 minutes.

The results are shown below.

2) Results 3) Discussion The ATP content and AEC in the group treated with the present compound for 5 minutes before the perfusion was stopped were higher than those in the control group.

Claims (3)

[Claims] 1. General formula (I): [Wherein, R and R'represent a lower alkyl group which may be the same or different, n represents an integer of 0 or 1 or 2, and A represents (In the formula, M represents a hydrogen atom or a salt-forming residue),
_{CH = CH -, - CH 2} -CH 2 -, Represents ] It is characterized by containing a dithia derivative represented by
ATP enhancing composition. 2. The ATP-enhancing composition according to claim 1, which is an agent for circulatory organs. 3. The ATP-enhancing composition according to claim 2, which is a hypotensive agent.