JPH02215718A - Drug containing 4-(1-imidazolylmethyl)cinnamic acid as active ingredient - Google Patents

Abstract

PURPOSE:To obtain an active oxygen production suppressing agent containing 4-(1-imidazolylmethyl)cinnamic acids as an active ingredient, having action capable of suppressing production of active oxygen in vivo and production of methylguanidine and useful for suppression of occurrence of cancer and delay of progress of renal insufficiency, etc. CONSTITUTION:The aimed drug contains a compound expressed by the formula and nontoxic salt thereof, acid addition salt thereof and hydrate thereof. When the drug is used for prevention and treatment for various diseases originated in production of active oxygen, the drug is normally systemically or locally administered in oral or parenteral method. The drug is normally administered orally in a dose of 10-200mg/adult day or intravenously in a dose of 1-1000mg/ adult day, through the dose is different from age, weight, symptoms, treating effects administration method.

Description

DETAILED DESCRIPTION OF THE INVENTION 1 Tojo Example Sararitan 1 The present invention provides a known compound, 4-(1
- Concerning the use of imidazolylmethyl)cinnamic acid as a novel therapeutic agent.

More specifically, the present invention relates to a drug containing 4-(1-imidazolylmethyl)cinnamic acid represented by the formula as an active ingredient.

■Active oxygen (free radicals) have long been thought to have little involvement in reactions in living organisms, but 19
Since HcCord and Fr1dOriCh discovered the existence of superoxide dismutase (SOD) in 1969, it has become clear that radicals are involved in many biological reactions, especially pathological reactions.

Active oxygen usually refers to superoxide, hydroxy radical, singlet oxygen, and triplet oxygen, but in a broader sense, it also includes free radicals such as hydrogen peroxide, alkoxy radicals, and peroxy radicals, and organic peroxides. . Among these, hydroxyl radicals are said to have the strongest oxidizing effect.

Although the mechanism by which these active oxygen species occur is not well understood,
It is said to be caused by environmental factors such as air pollutants and drugs, as well as stress and ischemia.

When lipids, proteins, and nucleic acids in living organisms are exposed to active oxygen, lipids mainly cause cell membranes to denature, proteins to enzymes and receptors to denature, and nucleic acids to cause lesions such as cancer. It is believed that.

Particularly in the case of lipids, the generated lipid peroxide itself is poisonous, and as it oxidizes adjacent lipids one after another, cell membranes are destroyed.

What acts enzymatically as a radical scavenger to remove these active oxygen (free radicals) (SO
D, catalase, glutathione peroxidase, etc.) and those that act non-enzymatically, such as ascorbic acid, ubinoquinone,
Albumin, etc.) are known.

The compounds represented by the general formula (I), non-toxic salts, acid addition salts and hydrates thereof disclosed in the present invention are disclosed in Japanese Patent Application Laid-open No. 55-313 and No. 57, filed earlier by the present application. -131
769 @Disclosed in the specification. Among these, the compound has an inhibitory effect on thromboxane A2 biosynthesis, and has therefore been shown to be useful as a therapeutic agent for various diseases caused by thromboxane A2, such as inflammation, hypertension, thrombosis, heart disease, and asthma. has been done.

As a result of intensive studies to find a compound that has the effect of suppressing the production of active oxygen, the present inventors found that the compound of formula (I)
The present invention was completed based on the discovery that imidazolylmethylcinnamic acid represented by the following formula achieves the object.

In general, it is clear that the production of methylguanidine is suppressed by suppressing the production of active oxygen.

These medicinal effects have been disclosed in the previous application by the present applicant (Japanese Patent Laid-Open No. 1983-1999).
313 and 57-131769).

Structure of the Invention The present invention relates to 4-(1-imidazolylmethyl)cinnamic acid represented by the formula;
The present invention relates to drugs containing non-toxic salts, acid addition salts or hydrates thereof as active ingredients, more specifically, (1) active oxygen production inhibitors, and (2) methylguanidine production inhibitors.

The compound represented by general formula (I) is converted into the corresponding salt by a known method. Preferably, the salt is non-toxic and water-soluble. Suitable salts include alkali metal (potassium, sodium, etc.) salts, alkaline earth metal (calcium, magnesium, etc.) salts, ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, triethylamine, methylamine, etc.). Examples include salts of dimethylamine, cyclopetylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, jetanolamine, tris(hydroxymethyl)amine, lysine, arginine, N-methyl-〇-glucamine, etc.).

Preferred is the sodium salt.

In addition, non-toxic acid addition salts of the compound represented by formula (I) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate, or acetate and lactate. , citrate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, glucuronate, gluconate. Preferably it is a hydrochloride.

In general, salts include stable hydrates of the above salts and acid addition salts (
(hydrochloride-hydrate, etc.) are also included.

The method for producing the compound of the present invention represented by formula (1), its non-toxic salt, non-toxic acid addition salt, and hydrate is described in detail in JP-A-55-313 and JP-A-57-131769. has been done.

As is clear from the experiments described later, the compound of the present invention strongly suppresses the production of active oxygen in vivo, and is therefore useful for the prevention and treatment of various diseases caused by the production of active oxygen. It is.

Active oxygen (free radicals) mainly affect living tissues by converting lipids into peroxidized lipids, thereby damaging cells (Il).
It degenerates and destroys cells and inhibits the life activities taking place in cells.

Therefore, various diseases occur due to cell degeneration and cell necrosis. Examples include arteriosclerosis, ischemic heart disease, cerebrovascular disorder, stroke, gastric mucosal disorder, intestinal mucosal disorder, liver disorder (drug-induced liver disorder, etc.), diabetes, renal disorder (renal failure, etc.).

The compound of the present invention represented by formula (I) has an active oxygen production inhibiting effect and is therefore useful for treating and preventing the above-mentioned diseases.

In addition, active oxygen is said to be involved in the proliferation of cancer cells by promoting the carcinogenic process and in the conversion of carcinogens into free radicals during initiation, and by suppressing the production of active oxygen, cancer It is thought that the occurrence and proliferation of can be suppressed.

The compound represented by formula (I) has an action of inhibiting active oxygen production, and therefore can inhibit the occurrence and proliferation of cancer.

In general, as a result of suppressing the production of active oxygen, the compound of the present invention has the effect of suppressing the production of methylguanidine, a powerful uremic substance, and has the effect of delaying or suppressing the progression of renal failure and delaying the time for blood dialysis. , has the effect of improving renal function decline, preserving renal reserve, and suppressing urinary toxicity.

The compound represented by formula (I), its non-toxic salt, acid addition salt or hydrate thereof is usually administered systemically or locally, orally or parenterally, for the above purposes. The dosage varies depending on age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 1011 fI to 2000 Irtg per day, preferably 100/day per adult.
ffff to 1000111 g, administered orally once to several times a day, or intravenously, in the range of 1 ml to ICtOOmg per adult per day, once to several times a day. Administered for 1 to 2 hours per day
It is administered continuously intravenously over a period of 4 hours.

Of course, as mentioned above, the time between administrations varies depending on various conditions, and therefore an amount smaller than the above-mentioned dosage range may be sufficient in some cases.

Solid compositions for oral administration according to the present invention include tablets, powders, granules, and the like. In such solid compositions, one or more active substances are present in at least one inert diluent, such as lactose, mannitol, -dextrose, bitroxyprobyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, Mixed with magnesium aluminate metasilicate. The composition is prepared in accordance with conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as fibrillar calcium glycolate, stabilizers such as lactose, glutamic acid or asparagine. It may also contain solubilizing agents such as acids. Tablets or pills may be coated with a film of gastric or enteric substances such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc., or may be coated with two or more layers, if necessary.

Capsules may also be made of absorbable substances such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, liqueurs, etc., and commonly used inert diluents, such as purified Contains water and ethanol. In addition to inert diluents, this composition may contain adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents,
It may contain aromatics and preservatives.

Other compositions for oral administration include sprays containing one or more active substances and formulated in a manner known per se.

Injections for parenteral administration according to the present invention include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of aqueous solutions and suspensions include distilled water for injection and physiological saline. Examples of non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and polysorbate 80.

Such compositions may further contain preservatives, wetting agents, emulsifying agents,
Adjuvants such as dispersants, stabilizers (eg, lactose), solubility aids (eg, glutamic acid, aspartic acid) may also be included. These can be sterilized, for example, by filtration through bacteria-retaining filters, by incorporation with disinfectants or by irradiation. They can also be prepared as sterile solid compositions and dissolved in sterile water or sterile injectable solvents before use.

EXAMPLES The present invention will be explained in more detail below using experimental examples and examples, but the present invention is not limited to these experimental examples and examples.

Effect of suppressing production of active oxygen in free hepatocytes of Jangyu Yan Yurat: Significance of the experimental system Creatinine is thought to be oxidized by the involvement of active oxygen and ultimately decomposed into methylguanidine. By measuring the production amount of the final product methylguanidine, it is used as an indicator of the production amount of active oxygen [KidneV International,
32 (22), 229 (1987), and Kidney and Dialysis Vol 24 No. 2.77 (1988)].

! Using Wistar rats weighing 300 to 350 g, an isolated hepatocyte suspension was obtained using the method of 8erry-Frfecl [J, Cell Bo
ii, 43°506 (1969)].

Isolated hepatocytes obtained by the above method (1 x 107 - 2 x 10
7 pieces) to 6d rebs-HerlSe I e i
were suspended in bicarbonate buffer and cultured with shaking for 6 hours in the presence of a mixed gas of oxygen (95%) and carbon dioxide (5%). However, Krebs-11enseleit bicarbonate buffer contains live serum alpsin (final concentration 3%), 10mM
Sodium lactate and final concentration 200/l1g/d, Il
of creatinine was added to this buffer, and the compound of the present invention was added to this buffer at varying concentrations to examine the effect on the conversion rate of creatinine to methylguanidine in hepatocytes. At this time, the buffer contained buromycin aminotacleoside (a substance known to induce nephrosis in rats), which the present inventors found had the effect of promoting the production of active oxygen.
We investigated the cases with and without the presence of .

After culturing, tritaloloacetic acid ('100% Wt/V: 016
m> was added to terminate the reaction, and 15
The amount of methylguanidine produced in 0.25 d of supernatant obtained by centrifugation for 1 minute was measured by HPLC and used as an index of active oxygen production. The results are shown in FIG.

From Figure 1, the compound of the present invention significantly inhibited the purification of methylguanidine and the production of active oxygen in both the presence and absence of puromycin aminoscreoside, compared to when it was not added. I know that there is.

Acute toxicity (LD5Q) test: Experimental method a) Oral administration 2 6 withdrawn SD male and female rats 1 group 10
They were used as animals. The compound of the present invention was dissolved in distilled water and administered orally. The observation period was 14 days.

b) Intravenous administration 2 6 withdrawn SD male and female rats, group 1
It was used as 0 animals. The compound of the present invention was dissolved in physiological saline and administered intravenously, and the observation period was 14 days.

The results are shown in Table 1.

Discussion As shown in Table 1, the toxicity of the compounds of the present invention was extremely low both when administered orally and intravenously, and it was confirmed that they were sufficiently safe to be used as pharmaceuticals.

The following ingredients are mixed in a conventional manner and then compressed to produce 1000 tablets each containing 2001 ftg of active ingredient.
Got the lock.

-4.-(1-imidazolylmethyl)cinnamate hydrochloride-
Hydrate...100g-lactose
... 48 bi- Carboxymethylcellulose calcium... 10g - Microcrystalline cellulose... 40cJ
- Calcium stearate... 29 ml of active ingredient 2 Mix the following ingredients in a conventional manner, fill 5 d each into ampoules, sterilize and freeze-dry in a conventional manner, - 20 d of active ingredient in each ampoule. 100 ampoules were obtained.

-4-(1-imidazolylmethyl)cinnamate sodium salt...2g- Citric acid anhydride...200■- Distilled water
...500fd1

[Brief explanation of the drawing]

FIG. 1 is a graph showing the inhibitory effect of the compounds of the present invention on methylguanidine production in hepatocytes.

Claims (1)

[Claims] 1) 4-(1-imidazolylmethyl)cinnamic acid represented by the formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I);
An active oxygen production inhibitor containing a non-toxic salt, an acid addition salt, or a hydrate thereof as an active ingredient. 2) 4-(1-imidazolylmethyl)cinnamic acid represented by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I),
A methylguanidine production inhibitor containing a non-toxic salt, an acid addition salt or a hydrate thereof as an active ingredient.