JP2554497B2 - Pharmaceutical composition containing epoxysuccinic acid derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a pharmaceutical composition containing an epoxysuccinic acid ester, more specifically, the following general formula (I): (Wherein R represents a hydrogen atom, an alkyl group, an aralkyl group or an aryl group, and n represents an integer of 0 to 3), and the anthraquinone derivative containing the non-toxic salt thereof as an active ingredient. The present invention relates to a pharmaceutical composition having a therapeutic and preventive action against myocardial damage caused by a cyclin antibiotic.

Cardiomyopathy is not a disease caused by hypertension, congenital abnormalities, abnormalities of valvular, coronary arteries, or myocardium, but is a disease that temporarily affects the myocardium.

Cardiomyopathy is divided into idiopathic cardiomyopathy, which is a myocardial disease of unknown cause, and secondary myocardial disease (special myocardial disease) whose cause or association is clear, depending on its origin. Examples of various diseases that cause this secondary myocardial disease include various myocarditis, cardiac amyloidosis, myocardial sarcoidosis, hypersensitivity reaction due to drugs and poisoning. As a cardiomyopathy caused by a drug, a myocardial lesion caused by an anthracycline antibiotic is known.

1967, Streptom by F.Arcamone et al.
Doxorubicin HCl (adriamycin), an anthracycline antibiotic isolated from the culture fluid of yces peucetius var. caesius, inhibits cancer cell division by inhibiting the process of nucleic acid synthesis in cancer cells, and Has an antitumor effect. Moreover, its anti-cancer spectrum is wide and effective against acute and chronic leukemia, malignant lymphoma (rhinosarcoma, lymphosarcoma, etc.), lung cancer, breast cancer, fire extinguisher cancer (gastric cancer, liver cancer, colon cancer, etc.), bladder tumor, etc. Therefore, it is currently widely used as an anticancer agent.

By the way, it is known that the above-mentioned adriamycin causes myelosuppression such as leukopenia and anemia, digestive disorders such as anorexia and vomiting, hair loss, and myocardial disorders as side effects.

In particular, it is known that the incidence of myocardial damage rapidly increases when the total dose is 500 to 550 mg / m ² (body surface area) or more. (Kubo Akiyoshi; Cancer Chemotherapy, 1985, 69-72)
Page) Myocardial damage of adriamycin is a non-inflammatory disorder, and the mechanism of its development includes nuclear DNA synthesis damage, intracellular Ca accumulation due to increased Ca permeability of myocardial cell membrane, and vasoactive substances such as catecholamines. It is thought that there is a release effect of ATP and impaired ATP production at the level of mitochondrial CoQ ₁₀ related enzyme system.
Antagonists, beta blockers, CoQ _10, etc. are used.

The present inventors have conducted intensive studies in view of the above circumstances, and as a result, the compound represented by the general formula (I) known as a CANP (calcium-dependent neutral protease) inhibitor is an anthracycline-based compound. The present invention has been completed by discovering that it has a therapeutic and preventive effect on myocardial damage caused by antibiotics.

That is, an object of the present invention is to provide a pharmaceutical composition containing an epoxysuccinic acid derivative pair represented by the above general formula (I) or a non-toxic salt thereof as an active ingredient, which has a therapeutic and prophylactic action against myocardial damage due to anthracycline antibiotics. Providing a composition.

It is known by the present inventors that the compound represented by the general formula (I) has already been effective in an experimental model of myocardial infarction by coronary artery ligation and is useful as a preventive and therapeutic agent for myocardial infarction. . (JP-A-57-169478, JP-A-5
8-126879). However, myocardial infarction resulting from myocardial ischemia described in the above patent is completely different from cardiomyopathy, particularly myocardial damage due to anthracycline antibiotics, in its generation mechanism and pathological condition.

When R in the general formula (I) is an alkyl group, examples thereof include C _{1 to} C ₅ lower alkyl such as methyl group, ethyl group, propyl group, isobutyl group, n-butyl group, sec-butyl group. Examples of the aralkyl group include a benzyl group, a phenethyl group, a benzhydryl group, and the like.
Moreover, a phenyl group etc. are mentioned as an aryl group.

The oxirane of the general formula (I) is preferably in the trans form, that is, (2S, 3S) or (2R, 3R) coordination.

As the non-toxic salt, sodium, potassium, calcium, magnesium, trialkylamine, dibenzylamine, N-lower alkylpiperidine,
Non-toxic salts such as α-phenethylamine, 1- (1-naphthyl) ethylamine and N-benzyl-β-phenethylamine, or non-toxic with hydrochloric acid, hydrobromic acid, formic acid, sulfuric acid, fumaric acid, maleic acid, tartaric acid, etc. Examples include salt.

The compound represented by the general formula (I) can be obtained, for example, by the following method.

(In the formula, R and n have the same meanings as described above.) Specific examples of the compound represented by the general formula (I) include
The following can be mentioned.

(2R, 3R) -3-[(s) -1- {4- (4-methoxyphenylmethyl) piperazin-1-ylcarbonyl}-
3-Methylbutylcarbamoyl] oxirane-2-carboxylic acid, (2R, 3R) -3-[(s) -1- {4- (3,4-dimethoxyphenylmethyl) piperazin-1-ylcarbonyl}
-3-Methylbutylcarbamoyl] oxirane-2-carboxylic acid, (2R, 3R) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2R, 3R) -3-[(s) -3-methyl-1- {4-
(3,4,5-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2R, 3R) -3-[(s) -1- (4-benzylpiperazin-1-ylcarbonyl) -3-methylbutylcarbamoyl] oxirane- 2-carboxylic acid, (2S, 3S) -3-[(s) -1- {4- (4-methoxyphenylmethyl) piperazin-1-ylcarbonyl}-
3-Methylbutylcarbamoyl] oxirane-2-carboxylic acid, (2S, 3S) -3-[(s) -1- {4- (3,4-dimethoxyphenylmethyl) piperazin-1-ylcarbonyl}
-3-Methylbutylcarbamoyl] oxirane-2-carboxylic acid, (2S, 3S) -3-[(s) -3-methyl-1- {4-
(2,3,4-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2S, 3S) -3-[(s) -3-methyl-1- {4-
(3,4,5-Trimethoxyphenylmethyl) piperazine-
1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid, (2S, 3S) -3-[(s) -1- (4-benzylpiperazin-1-ylcarbonyl) -3-methylbutylcarbamoyl] oxirane- 2-carboxylic acid.

Esters or non-toxic salts of these compounds are also the active ingredients of the present invention.

As anthracycline antibiotics, in addition to the above-mentioned adriamycin, daunomycin, aclacinomycin A (Aclacinomycin A) and the like are known.

Next, the epoxysuccinic acid derivative represented by the general formula (I) or a non-toxic salt thereof, which is the active ingredient of the present invention,
It is adriamycin in rats and the active ingredient of the present invention (2R, 3R) -3-that shows the therapeutic and preventive effect on myocardial damage by anthracycline antibiotics.
[(S) -3-Methyl-1- {4- (2,3,4-trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid ethyl 1/2 sulfate (hereinafter , Abbreviated as active ingredient A) 16
It became clear by the daily and single-dose administration experiments.

That is, the survival rate in the group administered with adriamycin alone was
66.7%, compared to 80 in the combination group with active ingredient A
%, And 70.6% in the CoQ ₁₀ combination group used as a control. In addition, the incidence of myocardial necrosis in surviving cases (the number of visual fields with respect to the total number of visual fields) was
Compared to 31.4%, the active ingredient A combination group was 22.1%, which revealed that active ingredient A suppresses or prevents myocardial lesions caused by adriamycin.

Further, the compound represented by the general formula (I), which is the active ingredient of the present invention, is already known to be a highly safe substance to the living body by an acute toxicity test in mice. (JP-A-58-126879) The dose of the compound of the general formula (I) and its non-toxic salt in the present invention varies depending on the kind of the compound and the degree of symptom of the patient, but usually about 10 mg to 1 g per day. It may be administered to patients.

When the compound represented by the general formula (I) or a salt thereof is used as a pharmaceutical composition having a therapeutic and prophylactic action against myocardial damage caused by anthracycline antibiotics, it is usually used in the form of a pharmaceutical composition together with a pharmaceutical carrier. To be done. It can also be used as a compounding agent with other drugs.

As the carrier, diluents or excipients such as a bulking agent, a binder, a disintegrating agent, a lubricant and the like which are usually used for preparing a drug depending on the usage form are used.

The dosage form may be any of injections, powders, capsules, granules, tablets and the like.

When used in the form of tablets, as a carrier, for example, lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, crystalline cellulose, excipients such as silicic acid, water, ethanol, propanol, glucose solution, starch solution, gelatin. Solution, carboxymethyl cellulose,
Binders such as methylcellulose and potassium phosphate, dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, stearic acid monoglyceride, starch, disintegrating agents such as lactose, stearate, boric acid powder, solid polyethylene glycol, etc. Lubricants and the like widely used in this field can be used. Furthermore, if necessary, sugar-coated tablets, gelatin-coated tablets, film-coated tablets and the like can be used.

When prepared as an injection, examples of the diluent include water, ethyl alcohol, propylene glycol, polyoxyethylene sorbit, sorbitan ester and the like. At this time, salt, glucose or glycerin may be contained in an amount sufficient to prepare an isotonic solution, and a usual solubilizing agent, buffer, soothing agent, preservative, etc. are required. You may make it contain according to it.

As described above, a pharmaceutical composition containing the epoxysuccinic acid derivative represented by the general formula (I) or a non-toxic salt thereof has an excellent action for treating and preventing myocardial damage caused by anthracycline antibiotics. And is a useful pharmaceutical composition.

 Next, the present invention will be specifically described with reference to examples.

Example Experimental method Rats were divided into 3 groups, and 2 mg / kg (iv) of adriamycin was administered to the first group 4 times every 4 days for a total of 8 mg / kg and sacrificed on the 16th day. For death cases, survival rate is 16
Calculation was performed on the day, and myocardium was observed morphologically for the surviving cases. Adriamycin was administered to the second group in the same manner as in the first group, and they were the active ingredients of the present invention (2R, 3).
R) -3-[(s) -3-methyl-1- {4- (2,3,4-
Trimethoxyphenylmethyl) piperazin-1-ylcarbonyl} butylcarbamoyl] oxirane-2-carboxylic acid ethyl 1/2 sulfate (active ingredient A) 100 mg / k daily
g (ip) was administered. Adriamycin was administered to Group 3 in the same manner as Group 1, and the combined daily doses were CoQ ₁₀ 10 mg / kg.
(Ip) was administered.

The observation of the myocardium was carried out by observing the excised heart or the cross section of the heart in 20% on the 16th day. The observation method is the left ventricular myocardium
Scanning was performed at 200 times, and the number of visual fields with myocardial lesions was expressed as a percentage of the total number of visual fields. Regarding the myocardial lesion, the part where the lesion was present was regarded as a finding.

 The results are shown in Table 1.

Claims (1)

(57) [Claims] 1. A general formula (In the formula, R represents a hydrogen atom, an alkyl group, an aralkyl group, or an aryl group, and n represents an integer of 0 to 3) or an epoxysuccinic acid derivative or a nontoxic salt thereof is contained as an active ingredient. , A pharmaceutical composition having a therapeutic and prophylactic action against myocardial damage caused by anthracycline antibiotics.