JPH0477423A - Therapeutic agent for heart disease - Google Patents

Abstract

PURPOSE:To provide the subject preventive and therapeutic agent containing a taurine dipeptide or its salt as the active component and having an affect on heart diseases such as ischemic heart disease, myocardial disorders in ischemic state, e.g. during a cardiac operation, heart failure or angina. CONSTITUTION:A medicine for heart diseases containing one or more compounds selected from e.g. glycyltaurine or alanyltaurine of the formula (R is amino acid residue) and pharmaceutically permissible salts (e.g. acid adduct salts or metallic salts) thereof as the active components. Complex compounds between Zn, Ni, Co, Cu, Fe, etc., are included in the compounds of the formula and, in case of existence of optically active isomers, all the isomers are also included. Compounds of the formula have an effect on protecting myocardium and an enhancing action on the same. The compounds also reduce the lowering in amplitude of myocardial pulsation in a low Ca state and normalize functions of myocardium.

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial Field of Application) The present invention relates to a heart disease therapeutic agent containing as an active ingredient taurine dipeptide, which has excellent myocardial strengthening and protecting effects.

(Prior Art) Cardiomyocytes maintain homeostasis of calcium ions and the like through the cardiomyocyte membrane. When there is a disorder in this cell membrane function or when excessive calcium ions are loaded into the cell due to some cause such as drugs (Ca”-overload)
, myocardial cells are damaged, resulting in lesions called cardiomyopathy or causing myocardial necrosis.

If the isolated myocardium is perfused briefly with a calcium-free solution and then reperfused with a calcium-containing solution, myocardial contracture occurs.

This causes loss of electrical activity, cell destruction, and leakage of intracellular enzymes. This phenomenon is called the calcium paradox, and the mechanism of its occurrence is explained in the above Ca'overl.
oad is believed to play an important role.

In other words, Ca''-overload has been suggested as one of the causes of myocardial damage caused by ischemia-blood reperfusion. Ca''-overload ultimately causes irreversible changes in the myocardium due to the calcium paradox, but It has been reported that this disorder is alleviated.

The present inventors have demonstrated that the taurine dipeptide of the present invention
We have completed the present invention by discovering that it has an excellent myocardial strengthening and protecting effect against myocardial damage caused by ERLOAD, etc., and decreased cardiac performance in low calcium conditions.

(Problems to be Solved by the Invention) An object of the present invention is to provide a therapeutic agent for heart disease containing taurine dipeptide or a pharmaceutically acceptable salt thereof as an active ingredient.

(Means for Solving the Present Invention) The present invention is a therapeutic agent for heart disease containing at least one compound represented by the following general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient.

RNHCHI CHz 5O3H (I) In the above general formula (1), R represents an amino acid residue, preferably glycine, alanine, valine, leucine, isoleucine, serine, threonine, methionine, proline, hydroxyproline, aspartic acid, β -Aspartic acid, glutamic acid, T-glutamic acid, phenylalanine, tyrosine, etc.

Particularly preferred compounds among the compounds of the present invention are as follows.

[Floor Combined elderly]

1, glycyl taurine 2.7 ranyl taurine 3, baryl taurine 4, leucyl taurine 5, inleucyl taurine 6, seryl taurine 7, threonyl taurine 8, methionyl taurine 9, prolyl taurine 10, hydroxyprolyl taurine 11.7 Subarthyl taurine 12, β-aspartyl taurine 13, glutamyl taurine 14, γ-glutamyl tauric acid 15, phenylalanyl taurine 16, tyrosyl taurine The taurine dipeptide of the present invention includes pharmaceutically acceptable salts thereof For example, hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, phosphoric acid, boric acid, formic acid, acetic acid, haloacetic acid, propionic acid,
Acids such as glycolic acid, citric acid, tartaric acid, succinic acid, gluconic acid, lactic acid, malonic acid, fumaric acid, anthranilic acid, benzoic acid, cinnamic acid, P-toluenesulfonic acid, naphthalenesulfonic acid, sulfanyl 8, etc. Examples include addition salts, salts with alkali metals such as sodium and potassium, alkaline earth metals such as calcium and barium, other metals such as aluminum, and salts with ammonium and organic amines.

Furthermore, the compound of the present invention includes its metal complex compounds, such as complex compounds with zinc, dichelium, cobalt, copper, iron, and the like.

These salts and metal complex compounds can be produced from the free taurine dipeptide of the present invention by known methods, or can be converted into each other.

When optical isomers exist in the compound of the present invention,
The present invention includes both of them.

The compounds of the present invention are known substances, such as 'Chen.

Pharm, Bull, 36(1), To-77
(1988) J and 'Che+e'.

Pharm, Bull, 36(8), 2796-
2801 (198B) J and the like.

(effect) Next, the pharmacological effects of the compounds of the present invention will be described.

(1) Cardioprotective effect The fetal heart of a 14- to 16-day lipstick-pregnant mouse using the ICR system was cut into small pieces, an enzyme solution of 0.06% trypsin and 0.01% collagenase was added, and the mixture was shaken at 37°C for 10 minutes. The cells were separated while reacting. Eagle's MEM culture solution containing 10% calf serum was added to this and centrifuged, and then the collected cells were redispersed in the culture solution. Since cardiomyocytes have a different adhesion time than fibroblast-like cells, the redispersed cell solution was heated at 37°C.
After incubating for 1 hour in 95% air-5% carbon dioxide saturated water vapor conditions to remove fibroblasts, the number of fibroblasts was adjusted to 2X10' to 4XIG' per IMl and 40 to 4
After 4 hours of pre-incubation, the cells were used for calcium paradox experiments. 'Remove the medium and replace with EGTA medium (Ca''-f) containing the test drug.
After adding 1 IW of 100% of the mixture, the mixture was left at 20 to 22°C for 10 minutes. The cells were then grown in EGTA-free medium (Ca”
After washing with "-free", 1 mM 2° medium containing the test drug was immediately added, and changes in cell morphology (water type, balloon-like) were observed after 1 minute. An example of the results is shown in Table 1. Shown below.

Table 1 Percentage of cells with changed morphology (%) Control 10mM compound 1 10mM compound 2 10mM compound 3 10mM compound 4 10mM compound 5 10mM compound 6 10mM compound 8 10mM compound 9 10mM compound 1 10mM compound 1 10mM compound 1 10mM compound 1 20mM Compound 1 10mM Compound 1 47.4 ± 3.5 33.2 ± 0.8 40.5 ± 5,3 37.4 ± 0.7 40.3 ± 1.9 40.7 ± 2.8 43.4 ± 2.3 27.9 ± 2.7 35.6 ± 4.2 28.2 ± 2.7 40.3 ± 4.9 3B, 2 ± 3.0 32.6 ± 3.0 36.7 ± 1.7 34.3 ± 4.2 (2) Myocardial strengthening effect The medium for myocardial cells was a low calcium medium (0.5mMCa”
), the cell pulsation amplitude decreases. A test drug was coexisted in this low-calcium medium, and its effect on the amplitude reduction of myocardial cells was investigated.

An example of the results is shown in FIG.

(Effect) As is clear from the test results in Table 1, the taurine dipeptide of the present invention has an excellent protective effect against morphological changes in myocardium caused by calcium paradox.

Furthermore, as shown in FIG. 1, the compound of the present invention significantly reduces the decrease in myocardial pulsation amplitude in a low-calcium medium.

Thus, the compound of the present invention has a Ca”-overload
It has an excellent myocardial protective effect against myocardial damage caused by the like, and also has a myocardial strengthening effect that reduces the decrease in myocardial pulsation amplitude in a low calcium state and normalizes myocardial function. Therefore, the taurine dipeptide of the present invention is useful as a therapeutic or preventive drug for various heart diseases such as ischemic heart diseases such as myocardial infarction, myocardial damage caused by ischemic conditions during cardiac surgery, heart failure, and angina pectoris.

[Brief explanation of drawings]

FIG. 1 shows the results of measuring changes in the pulsation amplitude of cardiomyocytes in a low calcium medium (0.5mMCa''°).

Claims (1)

[Claims] (1) General formula (I): R-NH-CH_2-CH_2-SO_3H (I) [
In the formula, R represents an amino acid residue. ] A therapeutic agent for heart disease containing at least one of the compounds represented by the following or a pharmaceutically acceptable salt thereof as an active ingredient.