JPH01272523A - Antiarteriosclerosis agent containing guanidinobenzoic acid derivative as active ingredient - Google Patents

Abstract

PURPOSE:To provide an antiarteriosclerosis agent having an effect strongly inhibiting the evolution of an arterial sclerosis lesion and having highly reduced toxicity, comprising a specific guanidinobenzoic acid derivative as an active ingredient. CONSTITUTION:The objective agent contains as an active ingredient P-(P- guanidinobenzoyloxy)phenylacetic acid N,N-dimethylcarbamoyl methyl ester or a non-toxic acid-added salt thereof (preferably a methane sulfonic acid salt) which has a strong trypsin or plasmin-inhibiting action and is practically used as a chronic pancreatitis remedy. The antiarteriosclerosis agent is useful not only for the treatment and prevention of arterial sclerosis-like lesion and phlebosclerosis caused by by-pass operations but also for the treatment or prevention of cerebral infarction, cerebral hemorrhage and aftereffects thereof which are caused by arterial sclerosis-like lesion. The dose of the agent is 10-200mg an adult on the oral administration and 0.1-100mg on the intravenous administration.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention relates to a novel therapeutic agent containing a guanidinobenzoic acid derivative, which is a known substance. More specifically, the present invention relates to an antiarteriosclerotic agent containing p-(p-guanidinobenzoyloxy)phenylacetic acid MN,N-di)thylcarbamoylmethyl ester or a nontoxic acid addition salt thereof as an active ingredient.

[Prior Art] p-(p-guanidinobenzoyloxy)phenylacetic acid N,N-dimethylcarbamoylmethyl ester and its nontoxic acid addition salt (hereinafter referred to as the compound of the present invention).

) is the time-opening BE 52-896 previously proposed by the applicant.
No. 40, the compound has a strong inhibitory effect on trypsin and plasmin, and is therefore effective as an anti-plasmin agent for the treatment of bleeding disorders, etc., or for the treatment of acute pancreatitis, etc. It is described that it is useful as an effective therapeutic agent for pancreatic diseases. Currently, it is used as a treatment for chronic pancreatitis under the generic name camostat mesylate.

[Purpose] As a result of intensive studies to discover new therapeutic effects of the compounds of the present invention, the present inventors have discovered that the compounds of the present invention are sufficiently useful as anti-arteriosclerotic agents, and have completed the present invention.

Until now, there has been no report that the compound of the present invention is useful for treating arteriosclerosis.

[Structure of the Invention] Therefore, the present invention provides an anti-inflammatory agent containing p-(p-guanidinobenzoyloxy)phenylacetic acid IN, N-dimethylcarbamoylmethyl ester or a non-toxic acid addition salt thereof as an active ingredient, represented by the structural formula: Regarding arteriosclerotic agents.

Non-toxic acid addition salts of the compound of formula (I) include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate or acetate; Lactate, tartrate, citrate, benzoate, metasulfonate, ethanesulfonate, pembin sulfonate, toluenesulfone M salt, ilethianate, glucuronate,
Examples include organic acid salts such as gluconate, preferably methanesulfonate.

Compounds represented by formula (I>), non-toxic acid addition salts thereof, and methods for producing them are disclosed in JP-A-51-1
38642 and 52-89640, and U.S. Pat. No. 4,021,472, and in particular, the methanesulfonate salt of the compound represented by formula (I) is described in JP-A-52-89640. and Example 13 of US Pat. No. 4,021,472.

[Effect] The compound represented by structural formula (I) and its non-toxic acid addition salt included in the present invention have the effect of strongly inhibiting the progression of arteriosclerotic lesions, and are highly toxic. Since the amount is small, it can be used as an extremely effective anti-arteriosclerotic agent.

Furthermore, considering that the compound of the present invention and its non-toxic acid addition salt had almost no effect on blood cholesterol levels, it is completely different from conventional anti-arteriosclerotic agents whose main action is to lower cholesterol. It is considered to be a new type of anti-arteriosclerotic agent with a different mechanism of action.

The effectiveness of the compound of the present invention has been confirmed for atherosclerosis of the thoracic aorta, but it can be asserted that it is useful for atherosclerosis of any vascular site thought to develop by a similar mechanism. Therefore, the anti-arteriosclerotic agent of the present invention is suitable for the treatment and prevention of arteriosclerosis-like lesions such as thoracic and abdominal aortic sclerosis, coronary artery and coronary venous sclerosis, pulmonary arteriosclerosis, and cerebral arteriosclerosis, as well as venous sclerosis caused by bypass surgery. It is also useful for the treatment and prevention of cerebral infarction, cerebral hemorrhage, and their sequelae caused by arteriosclerosis-like lesions.

In order to use the compound represented by the general formula (I>) and its non-toxic acid addition salt for the above purpose, it is usually administered systemically or locally, orally or parenterally. Although it varies depending on the symptoms, therapeutic effects, administration method, treatment time, etc., it is usually 11rl'J~ per adult.
1000 mg, preferably in the range of 10 ytg to 200 m'j, administered orally once to several times a day, or intravenously, once to several times a day in the range of 0.1 η to 1,100 III per adult. administered or once per day
It is administered intravenously continuously for a period of 24 hours to 24 hours. Of course, as mentioned above, the dosage varies depending on various conditions, so there may be cases where a smaller amount than the above dosage range is sufficient,
There are also cases where it is necessary beyond the scope.

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, glucose, hydroxypropylcellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, aluminum metasilicate. mixed with magnesium acid. The composition may be prepared in accordance with conventional methods with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as fibrin calcium gluconate, stabilizers such as lactose, glucmic acid or It may also contain solubilizing agents such as aspartic acid. 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 an absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc. - inert diluents used in boating, e.g. 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, asparagine M) 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.

[Experimental Examples and Examples] Hereinafter, the present invention will be explained in further detail using experimental examples and examples, but the present invention is not limited to these experimental examples and examples.

Experimental Example 1 Effect on arterial atherosclerosis caused by a high-cholesterol diet [Significance of the experiment 1 Cholesterol is given along with feed to artificially induce arteriosclerosis, a common method often used in arteriosclerosis research. This is an experimental model.

[Experiment method] 24 healthy male domestic rabbits (body weight >3 kg) were fed 100 g of 1% cholesterol-containing feed per day for 2 weeks, and then blood was collected. The control group was subsequently fed a diet containing 1% cholesterol for 12 weeks.The drug administration group was fed a diet containing 1% cholesterol with the compound of the present invention [p-(p-guanidinobenzoyloxy)phenyl acetate IN, N -dimethylcarbamoyl methyl ester methanesulfonate (hereinafter abbreviated as compound A)] was added at a rate of 100 mg/Kg/day and raised for 12 weeks.

During the experimental period, blood was collected every 4 weeks and serum lipids, etc. were measured. After the scheduled period, the animals were sacrificed, the aorta was removed, and the proportion of the atherosclerotic area was measured by fat staining. The results are shown in the numerical table. The area in the table represents the area obtained by tracing the aortic intima, enlarging it by copying, and then processing the image using a computer.

Table 1 (Continued) [Discussion] Compared to the control group, the lesion rate in Group 1 treated with Compound A was reduced to nearly 1/2 [there was a significant trend in the drug administration group compared to the control group ( p<0.
1) was recognized. ], the effect of Compound A on inhibiting the progression of arteriosclerosis was observed.

Furthermore, no significant difference was observed between the two groups in serum cholesterol, serum lipids such as triglycerides, and body weight measured during the same experiment.

It should be noted that the death of animal number 7 in the drug administration group due to bone fracture was completely accidental and was not caused by the administration of the drug.

Experimental Example 2 Acute toxicity test [Experimental method] (a) Oral administration An experiment was conducted using 26 male and female JCL-ICR mice. Compound A was dissolved in distilled water and administered orally. The observation period was 14 days, and the LDso value was calculated by the Litchfield-Wilcoxon method.

[1)) Intravenous administration: Experiments were conducted using six pairs of male and female JCL-ICR mice.

Compound A was dissolved in physiological saline and administered intravenously. The observation period was 14 days, and Litchfield-Wi 1 coxon
The LD5o value was calculated by the method.

The results are shown in the table below.

Table 2: Acute toxicity test [Consideration 1] As seen from Table 2 above, the toxicity of Compound A was very low both in oral and intravenous administration, and it was confirmed that it can be used safely as a pharmaceutical.

Example 1 p-(p-guanidinobenzoyloxy)phenyl vinegar 1
．． N-dimethylcarbamoyl methyl ester methanesulfonate 100g, magnesium stearate 29
and 18 g of lactose were thoroughly mixed until homogeneous and then tableted in a conventional manner to obtain 1000 tablets containing 1007'1 g of active substance in each tablet. The obtained tablets were coated with hydroxypropyl cellulose by a conventional method to obtain the intended tablets for oral administration.

Example 2 p-(p-guanidinobenzoyloxy)phenyl acetate I
Dissolve 10 g of N,N-dimethylcarbamoyl methyl ester methanesulfonate in 400 g of steamed water for injection (7!), fill 4 ampoules each with a capacity of 10, which has been sterilized using the usual method, and freeze. The mixture was dried and melt-sealed to obtain 1000 lyophilized injection preparations containing 1 orqt of active ingredient per ampoule.

Patent applicant: Ono Pharmaceutical Co., Ltd. Representative Patent Attorney Hisashi Oie

Claims (1)

[Claims] 1) p-(p-guanidinobenzoyloxy)phenylacetic acid N,N-dimethylcarbamoylmethyl ester represented by the structural formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) or its non-toxic An anti-arteriosclerotic agent containing an acid addition salt as an active ingredient.