JP2828474B2 - Active oxygen production inhibitor - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION (Industrial field of application) The present invention relates to pharmaceuticals, especially 1- (3-methyl-3-phenylbutyl)-represented by
The present invention relates to an active oxygen production inhibitor and a methylguanidine production inhibitor containing 4-[(2RS, 4R) -2- (3-pyridyl) thiazolidine-4-ylcarbonyl] piperazine or a salt thereof as an active ingredient.

(Prior Art) For living organisms, oxygen is indispensable for maintaining life such as energy production and metabolism. Oxygen is converted into a so-called active oxygen species such as an oxygen anion radical, a peroxide ion, or a hydroxyl radical by a reaction in an energy producing system, an enzymatic reaction, or a reaction by ultraviolet light or radiation. Reactive oxygen species are useful for expressing oxygen-adding enzymes, bactericidal action of leukocytes, etc.
Oleic acid, linoleic acid,
Promotes peroxidation of linolenic acid, arachidonic acid, etc., and forms lipid peroxide. This lipid peroxide, like active oxygen species, generates alkoxy radicals and hydroxyl radicals, aggresses biological membranes (cell membranes) to cause membrane damage, and inactivates various useful enzymes [ Metabolism, Vol. 15, No. 10, 19
Special feature active oxygen in 1989].

Enzymes such as superoxide dismutase (SOD), catalase, glutathione peroxidase and α
-Vitamins having antioxidant activity such as tocopherol (vitamin E) are biological substances involved in metabolic inactivation of active enzyme species, but for some reason, the appropriate defense mechanism by these substances is deficient. Occurrence of reactive oxygen species or the production and accumulation of lipid peroxides that exceed the capacity of these defense mechanisms is often observed. When the defense mechanism is deficient, peroxidation proceeds in a chain reaction, causing various serious biological disorders. Representative of these disorders are various diseases caused by platelet aggregation, inflammation, lung disorders, arteriosclerosis, hemolysis, aging or senile dementia, retinopathy, lung disorders, heart and lung disorders caused by certain drugs, ischemic vascular diseases. And the like.

(Problems to be Solved by the Invention and Means for Solving the Problems) Compound (I) or a salt thereof, which is an active ingredient of the medicament of the present invention, has an action of suppressing the production of active oxygen, It is useful for various diseases. In addition, since it has an activity of inhibiting the production of active oxygen, it is clear that compound (I) further has an activity of inhibiting the production of methylguanidine.

As a pharmaceutical effect of compound (I), a platelet activating factor (PAF) antagonism is conventionally known (European Patent Application Publication No. 279681), but the above effect cannot be predicted from the PAF antagonism.

Here, specific examples of the salt of compound (I) include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, hydroiodic acid, acetic acid, oxalic acid, succinic acid, citric acid and the like. Acid, maleic acid, malic acid, fumaric acid, tartaric acid, picric acid,
Acid addition salts with organic acids such as metal sulfonic acid and ethane sulfonic acid; salts with acidic amino acids such as glutamic acid and aspartic acid; and quaternary compounds by bonding with alkyl halides such as methyl chloride, methyl bromide and methyl iodide. Secondary ammonium salts and the like.

The methods for producing compound (I) and salts thereof are described in European Patent Application Publication No. 279681 and Japanese Patent Application No. 63-37224.

(Effect of the Invention) The active ingredient of the medicament of the present invention suppresses the production of active oxygen in a living body, and thus is useful as an agent for preventing and treating various diseases caused by the production of active oxygen. Reactive oxygen mainly degrades and destroys cells (membranes) by converting lipids into lipid peroxides, and inhibits vital activities in cells. The above-mentioned diseases are caused by inhibition of the vital activity of cells. The medicament of the present invention is useful for treating or preventing these diseases.

In addition, active oxygen is said to be involved in the growth of cancer cells due to the promotion of the carcinogenesis process and the free radicalization of carcinogens at the initiation. Is considered to be suppressed. Since compound (I) has an active oxygen production inhibitory action, it can suppress the generation and proliferation of cancer.

Further, compound (I) has an action of suppressing the production of active oxygen, thereby suppressing the production of the uremic substance methylguanidine.
It has the effect of delaying the time of blood dialysis, improving renal function decline, preserving renal reserve, and suppressing uremic outbreaks.

Compound (I) or a salt thereof is administered orally or parenterally. The dosage varies depending on age, body weight, symptoms and administration method, but it is usually 10 mg to 2000 mg orally per adult per day.
mg, preferably in the range of 100 mg to 1000 mg, in one to several divided doses. For parenteral administration, 1 mg to 100 mg / day
It is intravenously administered once or several times in the range of 0 mg.

As preparations for oral administration, solid preparations such as tablets, powders and granules and liquid preparations such as emulsions, solutions, suspensions, syrups and elixirs can be used. These preparations for oral administration can be prepared by a usual formulation technique. That is, in the case of a solid preparation, excipients such as corn starch, mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc. , Other disintegrants, stabilizers, solubilizers and the like are appropriately compounded. In the case of a liquid preparation, for example, a mixture of a diluent such as purified water or ethanol and an auxiliary agent such as a wetting agent or a suspending agent, a sweetening agent, a flavoring agent, a fragrance, or a preservative is used.

Next, as an injection for parenteral administration, a sterile aqueous or non-aqueous dissolving agent, suspension, or emulsion is used. These are prepared using a non-aqueous solution such as distilled water for injection or propylene glycol. Preparations for parenteral administration can also be in the form of dissolution at the time of administration, such as lyophilized preparations.

(Experimental Examples and Examples) Next, the present invention will be further described with reference to experimental examples and examples.

Experimental Example 1 (Suppression of production of active oxygen) Significance of the experimental system Creatinine is thought to be oxidized by the participation of active oxygen and eventually decomposed into methylguanidine. By measuring the amount of methylguanidine produced, it can be used as an indicator of the amount of active oxygen production [Kidney International, 32 (22), 229 (198
7), and kidney and dialysis Vol 24 No.2, 77 (1988)].

Experimental Method An isolated hepatocyte suspension was obtained by the Berry-Fried method using Wistar rats weighing 300 to 350 G [see J. Cell Boil., 43 , 506 (1969)]. .

Isolated hepatocytes obtained by the above method (1 × 10 ⁷ to 2 × 10
⁷ ) were suspended in 6 ml of Krebs-Henseleit bicarbonate buffer and cultured with shaking in the presence of a mixed gas of oxygen (95%)-carbon dioxide (5%) for 6 hours. However, Krebs-Henseleit bicarbonate buffer contains bovine serum albumin (final concentration 3%), 10m
Sodium M lactate and creatinine at a final concentration of 200 mg / dl were added, and the effect of the compound of the present invention on the conversion rate of creatinine to methylguanidine in hepatocytes was examined by adding this compound to this buffer at different concentrations. At this time, the present inventors examined the case where puromycin aminonucleoside (known as a substance which induces nephrosis in rats) and the case where the puromycin aminonucleoside, which the present inventors found to promote the production of active oxygen, were present. Was.

After the cultivation, the reaction was terminated by adding trichloroacetic acid (100% wt / v; 0.6 ml), and the amount of methylguanidine produced in 0.25 ml of the supernatant obtained by centrifugation at 0 ° C and 1700 g for 15 minutes was measured by HP.
It was measured by LC and used as an index of active oxygen production. The result is shown in FIG. FIG. 1 shows that the compound of the present invention significantly suppressed the purification of methylguanidine and the production of active oxygen both in the presence and absence of puromycin aminonucleoside as compared with the case where no compound was added. Recognize.

Experimental Example 2 (Acute toxicity) 1) Oral administration: A group of 30 ICR male mice weighing 25 to 38 g
0.5% of compound (I) fumarate
The methylcellulose suspension was orally administered in five steps from 0 to 1000 mg / kg. The results showed that LD ₅₀ was 450 mg / kg.

2) Intravenous administration: Three ICR male mice weighing 25 to 38 g were used in each group, and 0.5 mg of fumarate of compound (I) was used.
% Methylcellulose suspension was intravenously administered in four steps from 0 to 200 mg / kg. LD ₅₀ was 120 mg / kg.

Example 1 (Tablets) Compound (I) fumarate 20 mg Lactose 57 mg Corn starch 38 mg Hydroxypropyl cellulose 4 mg Magnesium stearate 1 mg Total amount 120 mg Compound (I) fumarate 20 g, lactose 57 g and corn starch 38 g are uniformly mixed. Next, 40 g of a 10% hydroxypropylcellulose solution is added and wet granulation is performed. After sieving,
dry. Magnesium stearate is added to the obtained granules.
Add 1 g and mix. The tablets are tableted with a 7m / m5.6R mortar and punch.

Example 2 (Capsule) Fumarate of Compound (I) 15 mg Crystalline cellulose 40 mg Crystallized lactose 144 mg Magnesium stearate 1 mg Total 200 mg Compound (I) fumarate 15 g, crystalline cellulose 40 g,
144 g of crystalline lactose and 1 g of magnesium stearate are uniformly mixed and filled into a No. 3 capsule with a capsule filling machine to obtain a capsule.

Example 3 (Freeze-dried preparation) In a vial 1 mg of fumarate of compound (I) 1 mg 50 mg of D-mannitol Total amount 51 mg Take 800 ml of water, add 1 g of fumarate of compound (I) and 50 G of D-mannitol sequentially and dissolve. , Water and add to 1 After aseptically filtering this solution, place it in a vial.
Fill 1 ml each, freeze-dry, and use as a ready-to-use injection.

[Brief description of the drawings]

FIG. 1 shows the inhibitory effect of fumarate of compound (I) on methylguanidine production in hepatocytes.

──────────────────────────────────────────────────続 き Continued on front page (58) Field surveyed (Int.Cl. ⁶ , DB name) C07D 401/00-421/14

Claims (2)

(57) [Claims] (1) Expression 1- (3-methyl-3-phenylbutyl)-represented by
An active oxygen production inhibitor containing 4-[(2RS, 4R) -2- (3-pyridyl) thiazolidine-4-ylcarbonyl] piperazine or a salt thereof as an active ingredient. (2) 1- (3-methyl-3-phenylbutyl)-represented by
A methylguanidine production inhibitor containing 4-[(2RS, 4R) -2- (3-pyridyl) thiazolidine-4-ylcarbonyl] piperazine or a salt thereof as an active ingredient.