JPH0717852A - Preventive or therapeutic agent for ischemic-reperfusion disorder - Google Patents

Abstract

PURPOSE:To provide the preventive or therapeutic agent containing, as active ingredient, a specific saicin N derivative, exhibiting powerful activity in ischemic-reperfusion model, thus useful for cardiopathy, cerevrovascular disorders, nephropathy, hepatopathy, pulmonary diseases, digestive tract diseases, chronic arthrorheumatism, arthritis, etc. CONSTITUTION:The preventive or therapeutic agent can be obtained by formulating (A) as active ingredient, a saicin N derivative of the formula [X is carbonyl, CHORx (Rx is H, alkyl, alkenyl, aralkyl or acyl), etc.; Y and Z are each carbonyl or CH2ORy (Ry is the same as Rx); Me is methyl] (e.g. 4-benzoyloxy-5- hydroxy-2,6,6-trimethyl-2-cycloheptene-1-one) with (B) a vehicle, binder, disintegrant, lubricant, coating agent, dissolving auxiliary, emulsifier, suspending agent, stabilizer, or solvent and by subjecting the resultant formulation to pharmaceutical manufacturing into tablets, granules, capsules, infections, etc.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel preventive or therapeutic agent for ischemia-reperfusion injury. More specifically, it relates to a preventive or therapeutic agent for ischemia-reperfusion injury, which comprises a Cycin N derivative represented by the following general formula as an active ingredient.

[0002]

[Chemical 2]

[0003]

2. Description of the Related Art Ischemia-reperfusion injury is a general term for disorders that occur after resumption of blood circulation in ischemic organ tissues.
It is known to occur not only in the brain but also in many organs such as the kidney, liver, lung, pancreas and digestive tract.

It is said that this ischemia-reperfusion injury is caused by free radicals represented by active oxygen. It is known that superoxide dismutase (SOD), which has an action of removing active oxygen, is extremely effective against ischemia-reperfusion injury, but it is effective by oral administration because it is a high molecular weight protein. Can't get

[0005]

SUMMARY OF THE INVENTION It is an object of the present invention to provide a preventive or therapeutic agent for ischemia-reperfusion injury by preventing injury due to oxygen free radicals.

[0006]

[Means for Solving the Problems] The present inventors previously discovered that the Saicin N derivative has an anti-ulcer effect, and filed a patent application as Japanese Patent Application No. 4-221441.

The inventors of the present invention have made extensive studies on the pharmacological action of the Cycin N derivative.
PH, Gastroenterology, Vol. 88, No. 1162-11
(P. 67, 1985), it was found that it has an extremely strong oxygen free radical damage-preventing action, and the present invention was completed.

Representative compounds in the present invention include, for example, 4-benzoyloxy-5-hydroxy-2,6.
6-trimethyl-2-cyclohepten-1-one (Compound 1), 5-hydroxy-4- (4-nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one (Compound 2), 4- (4-aminobenzoyloxy) -5-hydroxy-2,6,6-trimethyl-2-cyclohepten-1-one (Compound 3), 5-
(4-aminobenzoyloxy) -4-methoxy-2,
6,6-Trimethyl-2-cyclohepten-1-one (Compound 4), 5- (2,4-diaminobenzoyloxy) -4-methoxy-2,6,6-trimethyl-2-cyclohepten-1-one ( Compound 5), 5- (3,4-
Diaminobenzoyloxy) -4-methoxy-2,6
6-trimethyl-2-cyclohepten-1-one (Compound 6), 4- (1-methyl-2-pyrrolylcarbonyloxy) -5-hydroxy-2,6,6-trimethyl-2
-Cyclohepten-1-one (Compound 7), 2,4-cis-1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol (Compound 8), 4- (4-aminobenzoyloxy) -1-methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene (Compound 9) and 4-
Benzoyloxy-1-diethylaminocarbonylmethoxy-2,6,6-trimethyl-2-cycloheptene-
5-ol (compound 10) can be mentioned.

The preventive or therapeutic agent for ischemia-reperfusion injury of the present invention is a heart disease, cerebrovascular disorder, renal disease, liver disease, lung disease, digestive tract disease, rheumatoid arthritis, arthritis, etc., in which oxygen free radicals are deeply involved. Can be used for.

More specifically, the ischemia-reperfusion injury prophylactic or therapeutic agent of the present invention is effective for heart disease against myocardial necrosis expansion and fatal arrhythmia often occurring immediately after coronary revascularization for myocardial infarction. is there.

Since it is known that resumption of blood flow after the onset of cerebral ischemic injury causes exacerbation of cerebral edema and cerebral injury due to microcirculatory disorder, it is also effective for cerebrovascular disorder.

Since the kidney consumes a larger amount of oxygen than other organs, it is subject to ischemia-reperfusion injury due to large oxygen stress during circulatory insufficiency, hypotension and shock, and oxygen free radicals are involved in the establishment of pathological conditions. Therefore, the preventive or therapeutic agent for ischemia-reperfusion injury of the present invention is also effective for renal injury.

In rheumatoid arthritis patients, it is said that oxygen free radicals derived from neutrophils decompose long chains of hyaluronic acid in the joint cavity to reduce the viscosity, and it is considered to be effective against rheumatoid arthritis. To be

Further, during organ transplantation, the excised organ becomes an ischemic state along with the excision, so that blood circulation disruption and reperfusion cannot be avoided. Therefore, the ischemia-reperfusion injury preventive or therapeutic agent of the present invention can improve the organ engraftment rate by being used together with an immunosuppressant at the time of reperfusion after transplantation.

[0015]

EXAMPLES The production method and toxicity value of the Saicin N derivative in the present invention are as described in Japanese Patent Application No. 4-221441.

Saicin N derivative used in the present invention is
Any dose that does not exhibit toxicity can be administered to a patient in need of treatment. Generally 1 mg per day for adults, depending on age, symptoms, etc.
It is preferable to administer 10 g in 1 to 3 divided doses.

The prophylactic or therapeutic agent for ischemia-reperfusion injury of the present invention comprises a physiologically harmless solid or liquid pharmaceutical carrier mixed with the active ingredient, Cycin N derivative, within the range that the above daily dose can be maintained. It is used as various pharmaceutical compositions described above.

This pharmaceutical composition is prepared and used in various dosage forms depending on the administration method. The formulation form is
Tablets, granules, pills, capsules, liquids, syrups,
Suspensions, emulsions or injections are mentioned. As a pharmaceutical carrier, an excipient, a binder, a disintegrant, a lubricant, which is usually used,
Coating agents, solubilizers, emulsifiers, suspending agents, stabilizers or solvents can be used.

[0019]

【The invention's effect】

[Ischemia-Reperfusion Model] Rats fasted for 24 hours were anesthetized by intraperitoneal administration of Nembutal and fixed in a dorsal position on a thermostatic pad. An airway was secured, and blood pressure was measured via a blood pressure transducer from a cannula inserted in the right carotid artery. The abdominal wall was incised to ligate the cardia of the stomach, physiological saline was injected from the pylorus to wash it, and 0.1 N hydrochloric acid was injected into the stomach at 1 ml per 100 g of body weight, and then the pylorus was ligated. After the blood pressure became stable, 2% (w / w) of body weight of blood was exsanguinated from the cannula inserted into the left carotid artery into a syringe containing heparinized physiological saline, and 20 minutes later, the exsanguinated blood was retransfused. After being left for another 20 minutes, each rat was sacrificed. The effect was expressed by the inhibition rate (%) of the decrease in the disability index of the comparative test group relative to the disability index of the control group. The area of erosion that occurred in the body of the stomach was measured, and the disorder index was calculated based on the area. About 40 mg / kg of the test substance was dissolved in dimethyl sulfoxide, and the solution was administered through the tail vein 30 minutes before the start of blood removal.

The results are shown in Table 1.

[0021]

[Table 1]

Since the Cycin N derivative showed a remarkable effect in the ischemia-reperfusion model, it is an effective preventive or therapeutic agent for ischemia-reperfusion injury.

Claims (3)

[Claims] 1. A preventive or therapeutic agent for ischemia-reperfusion injury, which comprises a Cycin N derivative represented by the following general formula as an active ingredient. [Chemical 1] 2. The Cycin N derivative is 4-benzoyloxy-5-hydroxy-2,6,6-trimethyl-
2-Cyclohepten-1-one, 5-hydroxy-4-
(4-Nitrobenzoyloxy) -2,6,6-trimethyl-2-cyclohepten-1-one, 4- (4-aminobenzoyloxy) -5-hydroxy-2,6,6-
Trimethyl-2-cyclohepten-1-one, 5- (4
-Aminobenzoyloxy) -4-methoxy-2,6
6-trimethyl-2-cyclohepten-1-one, 5-
(2,4-Diaminobenzoyloxy) -4-methoxy-2,6,6-trimethyl-2-cycloheptene-1-
On, 5- (3,4-diaminobenzoyloxy) -4
-Methoxy-2,6,6-trimethyl-2-cyclohepten-1-one, 4- (1-methyl-2-pyrrolylcarbonyloxy) -5-hydroxy-2,6,6-trimethyl-2-cycloheptene- 1-on, 2,4-cis-
1-Methoxy-2,6,6-trimethyl-8-oxabicyclo [3.2.1] octane-4-ol, 4- (4
-Aminobenzoyloxy) -1-methoxy-2,6
6-trimethyl-8-oxabicyclo [3.2.1] oct-2-ene or 4-benzoyloxy-1-diethylaminocarbonylmethoxy-2,6,6-trimethyl-2-cyclohepten-5-ol. Item 1. A preventive or therapeutic agent for ischemia-reperfusion injury according to Item 1. 3. The ischemia-reperfusion injury according to claim 1, wherein the ischemia-reperfusion injury is any one of heart disease, cerebrovascular disorder, renal disease, liver disease, lung disease, digestive tract disease, rheumatoid arthritis and arthritis. -A prophylactic or therapeutic agent for reperfusion injury.