JP3068841B2 - Heart disease therapeutic agent containing aminoalkanesulfonic acid derivative as active ingredient - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a pharmaceutical composition containing an aminoalkanesulfonic acid derivative having an action of strengthening and protecting myocardium.

(Prior Art) Cardiomyocytes maintain homeostasis such as calcium ions through the cardiomyocyte membrane. If the cell membrane function is impaired or if excessive calcium ions are intracellularly loaded for some reason such as a drug (Ca ²⁺ -over-load), the cardiomyocytes will be damaged, resulting in a lesion called so-called cardiomyopathy. Or cause myocardial necrosis.

When the isolated myocardium is perfused for a short time with a calcium-free solution and then reperfused with a calcium-containing solution, contracture of the myocardium, loss of electrical activity, cell destruction, and outflow of intracellular enzymes are caused. This phenomenon is called calcium paradox, and it is thought that the above Ca ²⁺ -overload plays an important role in the mechanism of its occurrence. That is, Ca ²⁺ -overload has been suggested as one of the causes of myocardial damage occurring during ischemia-blood reperfusion associated with ischemic heart disease or cardiac surgery. It has been reported that calcium paradox eventually causes irreversible changes in the myocardium. For example, calcium antagonists and the like alleviate this disorder.

The present inventors have found that the aminoalkanesulfonic acid derivative of the present invention has an excellent myocardial strengthening / protective action against myocardial damage due to Ca ²⁺ -overload and the like, and completed the present invention.

(Problems to be Solved by the Invention) An object of the present invention is to provide a therapeutic agent for heart disease containing an aminoalkanesulfonic acid derivative as an active ingredient.

(Means for Solving the Present Invention) The present invention relates to a therapeutic agent for heart disease containing, as an active ingredient, an aminoalkanesulfonic acid derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. is there.

[In the formula, X represents trimethylene or hydroxytrimethylene together with hydrogen or Y, and Y represents an alkyl group (which may have a hydroxyl group, a carboxyl group, an amino group, a phenyl group or a hydroxyphenyl group), a phenyl group or X Together with trimethylene or hydroxytrimethylene. In the general formula (I), X is bonded to hydrogen or Y to form trimethylene or hydroxytrimethylene, and Y may have a hydroxyl group, a carboxyl group, an amino group, a phenyl group or a hydroxyphenyl group. Good alkyl groups, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, which may have a hydroxyl, carboxyl, amino, phenyl or hydroxyphenyl group.
Butyl, pentyl, isopentyl, neo-pentyl, t
-A linear or branched carbon number of 1 to 5 such as a pentyl group
And bond with X to represent trimethylene or hydroxytrimethylene.

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

[No. compound name]

1. 2-aminopropanesulfonic acid 2. 2-amino-3-methylbutanesulfonic acid 3. 2-amino-4-methylpentanesulfonic acid 4. 2-amino-3-methylpentanesulfonic acid 5. 2-amino- 3-hydroxypropanesulfonic acid 6. 2-amino-3-hydroxybutanesulfonic acid 7. 2-pyrrolidinylmethanesulfonic acid 8. 2- (4-hydroxypyrrolidinyl) methanesulfonic acid 9. 3-amino-4 -Sulfobutyric acid 10.4-Amino-5-sulfopentanoic acid 11.2,6-Diaminohexanesulfonic acid 12.2,5-Diaminopentanesulfonic acid 13.2-Amino-3-phenylpropanesulfonic acid 14.2- Amino-3- (4-hydroxyphenyl) propanesulfonic acid 15. 2-Amino-2-phenylethanesulfonic acid It encompasses acceptable salts, such as hydrochloric acid, sulfuric acid, nitric acid,
Hydrobromic acid, phosphoric acid, boric acid, formic acid, acetic acid, haloacetic acid,
Acids such as propionic acid, 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, and sulfanilic acid Or an alkali metal such as sodium or potassium, an alkaline earth metal such as calcium or barium, a salt with another metal such as aluminum, or a salt with ammonium or an organic amine.

Further, the compound of the present invention includes its metal complex compound, for example, a complex compound with zinc, nickel, cobalt, copper, iron and the like.

These salts and metal complex compounds can be produced from the free aminoalkanesulfonic acid derivative 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 compound of the present invention can be produced, for example, by the methods described in JP-A-2-115147 and Japanese Patent Application No. 2-192574.

(Action) Next, the pharmacological action of the compound of the present invention will be described.

(1) Cardioprotective action The fetal heart of pregnant mice on the 14th to 16th day of the ICR system was minced, and an enzyme solution of 0.06% trypsin-0.01% collagenase was added, and the mixture was reacted at 37 ° C. with shaking for 10 minutes. Was isolated. An Eagle MEM culture solution containing 10% calf serum was added thereto, followed by centrifugation, and the collected cells were redispersed in the culture solution. Cardiomyocytes have a different attachment time from fibroblast-like cells, so the redispersed cell solution is incubated at 37 ° C in 95% air-5% carbon dioxide saturated steam for 1 hour to remove fibroblasts. After preparing the cells at 2 × 10 ^{5 to} 4 × 10 ⁵ cells per ml and pre-culturing for 40 to 44 hours, the cells were used for calcium paradox experiments.

EGTA medium containing test drug after removing the medium (Ca ²⁺ -free)
Was added, and the mixture was allowed to stand at 20 to 22 ° C. for 10 minutes. Next, the cells were washed with an EGTA-free medium (Ca ²⁺ -free), and then immediately added with a 1 mM Ca ²⁺ medium containing the test drug. One minute later, the morphological changes (edema, balloon-like) of the cells were observed.

 An example of the results is shown in Table 1.

(Effect) As is clear from the results of the above pharmacological tests, the aminoalkanesulfonic acid derivative of the present invention has an excellent protective action against myocardial morphological changes caused by calcium paradox. As described above, the compound of the present invention has an excellent myocardial protective action against myocardial damage caused by Ca ²⁺ -overload and the like, ischemic heart disease such as myocardial infarction, angina pectoris, and heart failure, and ischemia during cardiac surgery. It is useful as a drug for treating and preventing myocardial damage associated with conditions.

────────────────────────────────────────────────── ─── Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C07D 207/08 C07D 207/08 207/12 207/12 (72) Inventor Kazuharu Ienaga Kinashiki Kawakitayama, Shamachi, Kato-gun, Hyogo Prefecture 442 No. 1 Research Institute of Biological Activity Science, Nippon Organ Pharmaceutical Co., Ltd. (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 31/185, 31/40 CA (STN) REGISTRY (STN)

Claims (1)

(57) [Claims] 1. A compound of the general formula (I): [In the formula, X represents trimethylene or hydroxytrimethylene together with hydrogen or Y, and Y represents an alkyl group (which may have a hydroxyl group, a carboxyl group, an amino group, a phenyl group or a hydroxyphenyl group), a phenyl group or X Together with trimethylene or hydroxytrimethylene. ] A therapeutic agent for heart disease, comprising a compound represented by the formula or a pharmaceutically acceptable salt thereof as an active ingredient.