JPH09227381A - Improving agent for motor paralysis in cerebral thorombosis - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain an improving agent for motor paralysis in cerebral thorombosis. SOLUTION: This improving agent contains a compound of the formula (R<1> is H or OH) or its acid-addition salt as an active component. The content is 0.01-20wt.%, preferably 0.1-10wt.% in the case of an injection and 0.01-20wt.% in the case of a tablet, a capsule or a liquid preparation. Motor paralysis occurs in the following process in which thrombus is formed in cerebral artery to lower a blood flow, and the corticospinal tract is directly or indirectly damaged by resultantly occurred infarction, and motor paralysis is a state in which voluntary movement of muscle has become difficult or unable. In the case of occlusion in the cerebrum, basically hemiplegia in the opposite side of a lesion occurs, and in the case of occlusion of a basilar artery, the patient is suffered from quadriplegia. The daily dose is 0.01-20mg/kg in parenteral administration and 0.02-40mg/kg in oral administration. An injection is prepared so as to enable the administration of 20-120mg a day in terms of an active component.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an agent for improving motor paralysis in cerebral thrombosis.

[0002]

2. Description of the Related Art The pathogenic mechanism of cerebral thrombosis is said to follow a series of processes including atherosclerosis, thrombus formation, blood flow reduction or interruption in cerebral arteries, cerebral ischemia, and symptom generation.
In the cerebral artery, there are two types of systems with different blood behaviors. One is a penetrating artery that branches directly from the main trunk artery at the base of the brain and feeds the deep brain, and the other is the pial artery, which is a peripheral artery of the main trunk, and the white matter artery that extends from there to the deep brain.

The latter are grouped as cortical branches, and there is a considerable difference in hemodynamics between the perforating branch and the cortical branch, which feed on the gray and subcortical white matter of the brain surface, and the resulting vascular lesions and their risk factors are also different. Is. The perforator branch is the terminal artery, and there is no room for blood flow during occlusion, whereas in the cortical branch the accessory circulation via the vascular anastomosis at the buffy coat level can be activated. Since the perfusion site is also different, there are differences in the distribution of infarct lesions and the symptoms that occur at the time of injury.

[0004] It is said that the main trunk artery of a patient with cerebral thrombosis develops a secondary blood flow path and compensates for the decrease in blood flow due to the blockage of the main trunk artery, so that the main trunk artery has relatively little thrombosis. In addition to the above-mentioned stenosis of the main trunk artery, stenosis or occlusion of the accessory circulation or small arteries is considered to be exerted, and ischemic symptoms may occur. In Japan, thrombus formation in small arteries, especially perforating branches,
Since many patients are relatively mild (mild consciousness disorder) and have paralysis of the extremities, improvement of motor paralysis in this cerebral thrombosis is of great significance.

However, the fact is that at present, most drugs effective for improving motor paralysis in cerebral thrombosis are not provided. Causes of cerebral thrombosis and a large difference in the degree of disability and clinical symptoms depending on the site where the infarct was formed, but it causes motor paralysis of the extremities, and as a result, it has a large effect on activities of daily living, This is an important problem as a sequela of this disease. Various therapeutic agents such as calcium antagonists and urokinase have been clinically used for such diseases, but the desired effects have not been recognized.

[0006]

It has been conventionally desired to provide a drug which can be expected to have a favorable effect on the improvement of motor paralysis in cerebral thrombosis.

[0007]

As a result of earnest efforts to solve the above-mentioned problems, the present inventors have found that a compound represented by the following general formula (I) or an acid addition salt thereof is particularly excellent in cerebral thrombosis. It was confirmed that it has an effect of improving motor paralysis in the disease, and confirmed to be an effective improving agent.
The present invention has been completed. That is, the present invention relates to the following general formula (I)

[0008]

Embedded image (However, R ¹ represents a hydrogen atom or a hydroxyl group in the formula) or an acid addition salt thereof is an active ingredient for improving motor paralysis in cerebral thrombosis.

What is motor paralysis as a sequela of cerebral thrombosis?
Although it develops with or as a result of cerebral thrombosis, although there are large differences in the degree of disability and clinical symptoms depending on the patient, it causes movement paralysis of the extremities and often affects daily activities. Are known.

Regarding the effect of the agent for improving motor paralysis in cerebral thrombosis according to the study group of the Ministry of Health and Welfare shown in Table 1, in order to exclude the motor paralysis associated with brain diseases other than cerebral thrombosis from the subjects to be treated by this improver. Depending on the diagnostic criteria for cerebral thrombosis,
For patients with cerebral thrombosis who have been strictly differentially diagnosed, it is necessary to confirm and judge the effect.

[0011]

[Table 1]

Patients with cerebral thrombosis caused by a disease satisfying the above-mentioned diagnostic criteria are often accompanied by motor paralysis of the extremities. Such motor paralysis is caused by a decrease in blood flow due to thrombus formation in the cerebral artery, and a direct or indirect damage to the corticospinal tract due to the resulting infarction. A state that is difficult or impossible. In the cerebrum, the hemiplegia on the opposite side of the lesion usually takes the form of a hemiplegia, which is often due to a disorder of the coronary cortex and the internal hindlimb. However, disorders of cortical branches such as the cortical motor cortex result in monoplegia on the opposite side of the lesion. In the brainstem, various pathological conditions are exhibited depending on the lesion site, but basically hemiplegia on the side opposite to the lesion. However, occlusion of the basilar artery results in quadriplegia. The following general formula (I)

[0013]

Embedded image

It is already known that the compound represented by the formula (wherein R ¹ represents a hydrogen atom or a hydroxyl group) exhibits a vasodilatory action and the like and is useful as a vasodilator or the like. For example, JP-A-61-252658, JP-A-61-227581, and JP-A-2-25
6617, JP-A-4-264030, JP-A-6-056668, JP-A-6-080569, JP-B-7-80854, British.
Journal of Pharmacology (Br.J.Ph
armacol. , 8, 1091 (1989), Journal of Pharmacology of And Experimental Therapeutics (J. Pharma).
col. Exp. Ther. , 259, 738 (199
1), European Journal of Pharmacology (Eur. J. Pharmacol). , 195
267 (1991). However, neither of these documents discloses or suggests that the compound has a particularly preferable effect for improving motor paralysis in cerebral thrombosis.

Among the compounds or acid addition salts represented by the general formula (I), the acid addition salt of the compound represented by the general formula (I) (wherein R ¹ represents a hydrogen atom) is hydrochloric acid. Fasudil is a drug already on the market and has been confirmed to have low toxicity.

The compound represented by the general formula (I) of the present invention can be prepared by a known method, for example, Chemical and Pharmaceutical Buretin (Chem. Pharm. Bu.
ll). , 40, (3) 770-773 (1992),
It can be synthesized according to the method described in JP-A-61-252658. The acid addition salt is preferably a non-toxic pharmaceutically acceptable salt, for example, hydrochloric acid, hydrobromic acid, phosphoric acid, inorganic acids such as sulfuric acid, and acetic acid, citric acid, tartaric acid, lactic acid, succinic acid, Fumaric acid,
Mention may be made of salts of organic acids such as maleic acid and methanesulfonic acid.

When the agent for improving motor paralysis in cerebral thrombosis of the present invention is prepared as a preparation in a form suitable for administration,
The compound represented by the general formula (I) or an acid addition salt thereof may be mixed with a known pharmaceutically acceptable carrier. Examples of the carrier include gelatin; sugars such as lactose and glucose; starches such as wheat, rice and corn starch; fatty acids such as stearic acid; fatty acid salts such as calcium stearate and magnesium stearate; talc;
Vegetable oils; alcohols such as stearyl alcohol and benzyl alcohol; gums; polyalkylene glycols and the like.

The liquid carrier generally includes water, physiological saline, dextrose or similar sugar solution, glycols such as ethylene glycol, propylene glycol, polyethylene glycol and polypropylene glycol. When a capsule is prepared, it is usually preferable to prepare a capsule using gelatin.

In the agent for improving motor paralysis in cerebral thrombosis of the present invention, which comprises the above carrier and the compound represented by the general formula (I) or an acid addition salt thereof, usually 0.01 to 8 is contained.
Examples include 0% by weight, preferably 0.01-60% by weight, of the active ingredient.

The method of administration includes oral administration and parenteral administration. Dosage forms suitable for oral administration include tablets, capsules, powders, granules, solutions, elixirs and the like, and dosage forms suitable for parenteral administration include liquid preparations. When parenterally administered by intramuscular injection, intravenous injection, or subcutaneous injection, salt or other solute such as glucose in order to render the compound represented by the general formula (I) and its acid addition salt isotonic Is added as a sterile solution.

When administered by injection, sterile water, lidocaine hydrochloride solution (for intramuscular injection), physiological saline, glucose, liquid for intravenous injection, electrolyte solution (for intravenous injection)
It is also preferable to dissolve them by the above method. When dissolved in this way, it is usually 0.01 to 20% by weight, preferably 0.1 to 20% by weight.
It may be prepared to contain 10% by weight of the active ingredient. In the case of a liquid preparation for oral administration, a suspension or syrup containing 0.01 to 20% by weight of the active ingredient is mentioned as a preferable example. In this case, the carrier includes aqueous excipients such as flavors, syrups, and pharmaceutical micelles.

The dose of the agent for improving motor paralysis in cerebral thrombosis of the present invention depends on the age, health condition, body weight, degree of symptoms of the recipient, type of concurrent treatment, frequency of treatment, and desired effect. Generally, it is 0.01 to 20 by parenteral administration, although it varies depending on the nature, administration route, administration schedule, etc.
mg / kg-day, 0.02-40mg / kg by oral administration
・ Days can be mentioned.

[0023]

The present invention will be described in more detail based on the following examples, but the invention is not intended to be limited by these examples. Example 1 Formulation Example (Sterile Injectable Solution) The components shown in Table 2 below were dissolved in distilled water for injection, and then distilled water for injection was added to obtain the required final weight.
1 was sealed in an ampoule and heat sterilized.

[0024]

[Table 2]

Example 2 Formulation Example (Tablets) Tablets containing the ingredients shown in Table 3 below were prepared by a conventional method.

[0026]

[Table 3]

Example 3 98 cases of patients diagnosed with cerebral thrombosis acute phase (fresh cases within 72 hours after onset, consciousness disorder before administration 3-3-)
Fasudil hydrochloride was administered at a daily dose of 20 m using any of the injections shown in Example 1)
g-120 mg (10 mg, 30 mg or 60 mg containing injection twice a day), drip infusion over 1 hour, 14
Dosing for days. The 98 cases also include cases of drug administration discontinuation.

Evaluation Items of Motor Paralysis Efficacy and Evaluation Method 1) Severity The following 6 grades of severity of motor paralysis are given before and 14 days after the administration of the therapeutic drug (or when the administration is discontinued) and 28 days after the start of administration. It was evaluated by. 4: Altitude, 3: Moderate, 2: Mild, 1: Very Mild, 0:
No symptoms? : Undecidable

2) Improvement Level On day 14 (or at the time of discontinuation of administration) of the therapeutic drug, the degree of improvement in motor paralysis was evaluated by comparing the severity on the 28th day after the administration with the severity before the administration of the therapeutic drug. That is, the degree of improvement was determined and the efficacy rate was calculated, with "improvement" as the case where the severity was improved by two levels (compared with the severity before administration). Even if the severity does not improve in two steps, the evaluation by the investigator may be prioritized and evaluated as “improved”. In addition, "-" in the column of the degree of improvement is shown including "slightly improved" in addition to "immutable" and "deteriorated".

Table 4 below shows a dose of 10 mg × 2.
The degree of motor paralysis and the degree of improvement in the case of daily administration were shown. The usage in this clinical study is 1 times twice a day.
It is administered for 4 days, and the efficacy evaluation time is before administration, on the 14th day of administration, and 28 days after the start of administration. In this condition,
The above-mentioned evaluation time was set because the effect of 14-day administration on the functional prognosis after about 1 month (28 days after the start of administration) is large.

[0031]

[Table 4]

Table 5 below shows a dose of 30 mg × 2.
The degree of motor paralysis and the degree of improvement in the case of daily administration were shown. The usage in this clinical study is 1 times twice a day.
It is administered for 4 days, and the efficacy evaluation time is before administration, on the 14th day of administration, and 28 days after the start of administration. In this condition,
The above-mentioned evaluation time was set because the effect of 14-day administration on the functional prognosis after about 1 month (28 days after the start of administration) is large.

[0033]

[Table 5]

The following Table 6 shows a dose of 60 mg × 2
The degree of motor paralysis and the degree of improvement in the case of daily administration were shown. The usage in this clinical study is 1 times twice a day.
It is administered for 4 days, and the efficacy evaluation time is before administration, on the 14th day of administration, and 28 days after the start of administration. In this condition,
The above-mentioned evaluation time was set because the effect of 14-day administration on the functional prognosis after about 1 month (28 days after the start of administration) is large.

[0035]

[Table 6]

Table 7 below shows the results of the effective rate of improving motor paralysis. The usage in this clinical study is administration twice a day for 14 days, and the efficacy evaluation time is on the 14th day of administration and 28 days after the start of administration. In this pathological condition, the above-mentioned evaluation time was set because the effect of 14-day administration on the functional prognosis after about 1 month (28 days after the start of administration) is large.

[0037]

[Table 7]

As is clear from the results in Table 7, the efficacy rate of the compound of the present invention for improving motor paralysis was compared with the placebo group on the 14th day of administration and 28 days after the initiation of administration (about 1 month after the onset). It was confirmed that it was considerably high and had an excellent effect on improvement of motor paralysis in the acute stage of cerebral thrombosis. Also, no serious side effects were observed in the administration of the compound of the present invention.

Example 4 As a result of an acute toxicity test of the compound of the present invention using rats and mice, it was confirmed to have low toxicity.
Table 8 shows the results.

[0040]

[Table 8]

[0041]

As is clear from the above experimental results, an excellent effect of improving motor paralysis in cerebral thrombosis is recognized,
It is expected to be an effective improver.

Continuation of the front page (51) Int.Cl. ⁶ Identification code Reference number within the agency FI Technical display area A61K 9/08 A61K 9/08 J 9/20 9/20 B // C07D 401/12 243 C07D 401/12 243

Claims (8)

[Claims] 1. A compound represented by the following general formula (I) An agent for improving motor paralysis in cerebral thrombosis, which comprises a compound represented by the formula (wherein R ¹ represents a hydrogen atom or a hydroxyl group) or an acid addition salt thereof as an active ingredient. 2. The improving agent for motor paralysis in cerebral thrombosis according to claim 1, wherein the improving agent is in the form of an injection. 3. The agent for improving motor paralysis in cerebral thrombosis according to claim 2, wherein the injection is a preparation for intravenous infusion. 4. The paralysis of cerebral thrombosis according to claim 2, wherein the injection is prepared so as to contain the active ingredient in an amount of 0.01 to 20% by weight, preferably 0.1 to 10% by weight. Improver. 5. A daily dose of 2 is an injection as an active ingredient.
The agent for improving motor paralysis in cerebral thrombosis according to claim 2, which is prepared so as to have a dose of 0 to 120 mg. 6. The improving agent for motor paralysis in cerebral thrombosis according to claim 1, wherein the improving agent is in the form of a preparation for oral administration. 7. The agent for improving motor paralysis in cerebral thrombosis according to claim 5, wherein the preparation for oral administration is a tablet, a capsule or a liquid. 8. The agent for improving motor paralysis in cerebral thrombosis according to claim 6, wherein the tablet, capsule or solution is prepared so as to contain 0.01 to 20% by weight of the active ingredient.