KR20070081767A - A medicine for preventing ischemic disease in a diabetic patient - Google Patents

Abstract

A medicine for preventing ischemic disease in a diabetic patient is provided to inhibit formation of a blood clot or embolus in the diabetic patient and prevent relapse of ischemic disease in the diabetic patient after CABG(coronary artery bypass graft) or PTCA(percutaneous transluminal coronary angioplasty). The medicine for preventing ischemic disease in the diabetic patient comprises amino alkoxy nobenzyl compound represented by the formula(1), a pharmaceutically acceptable salt or ester thereof, solvates and hydrates thereof, wherein R^1 is hydrogen atom, halogen atom, C1-C5 alkoxy group, or C2-C8 dialkylamino group; R^2 is hydrogen atom, halogen atom or C1-C5 alkoxy group; R^3 is hydrogen atom, hydroxyl group, -O-(CH2)n-COOH (n is an integer from 1 to 5) or O-CO-(CH2)l-COOH ( l is an integer from 1 to 3); R^4 is -N(R^5)(R^6) or -NA; R^5 and R^6 are each independently hydrogen atom, C1-C8 alkyl group; A is C3-C5 alkylene group optionally substituted by carboxyl group and m is an integer from 0 to 5.

Description

Medication for preventing ischemic disease in diabetics {A MEDICINE FOR PREVENTING ISCHEMIC DISEASE IN A DIABETIC PATIENT}

[Patent Document 1] Japanese Patent Application Laid-Open No. 2-304022

[Patent Document 2] International Publication WO 03/26636

The present invention can exert excellent thrombosis or embolism suppression effect in diabetic patients, and is useful in medicine for the prevention of ischemic diseases caused by thrombosis or embolism formation such as cerebral infarction or acute vascular syndrome which occur frequently in diabetic patients. It is about.

Cerebral infarction mainly includes cerebral thrombosis, which is thought to originate from atherosclerosis, and cerebral embolism due to cardiac sclerosis or atrial fibrillation. Cerebral thrombosis is a transient cerebral ischemic attack that occurs in some areas due to the progression of cerebral arteriosclerosis, causing blood flow to be cut off, or ischemic circulation disorder due to significant narrowing of the vascular cavity. After repeated (TIA), large attacks often occur. Cerebral embolism occurs when blood clots formed in parts other than the brain flow into the cerebral blood circulation as electrons and occlude part of the cerebrovascular vessels. Myocardial infarction is a disease in which a large branch of the coronary artery is occluded, causing extensive necrosis in the perfusion region, and most of the coronary artery occlusion is caused by blood clots. It is also known that the tendency of thrombus and embolism to increase after a procedure of coronary artery bypass surgery (CABG) or percutaneous cervical coronary angioplasty (PTCA) performed as a treatment for acute myocardial infarction.

Patients with such ischemic attacks caused by blood clots or embolism are most often associated with basic diseases such as hypertension or diabetes mellitus, and especially in diabetic patients, it is known that such ischemic attacks occur (glycemia in Japan). The relative risk of cerebral infarction in the above is 1.60 times male and 2.97 times female, and diabetes is known to be a risk factor that increases the risk of developing cerebral infarction by two to three times: diabetes mellitus, 36, pp. 17-24, 1993; Stroke Treatment Guidelines 2004, "2. Chronic Cerebral Infarction, 2-1. Management of Risk Factors and Prevention of Relapse Diabetes"). In fact, about half of cerebral infarction patients and about one-third of myocardial infarction patients have diabetes, which is thought to be due to the easy progression of arteriosclerosis. In addition, among diabetics, it is known that small cerebral infarction such as multiple cerebral infarction or lacunar cerebral infarction tends to occur, and such small cerebral infarction proceeds gradually in a state where there is almost no subjective symptoms. Therefore, it is very important for diabetics to prevent ischemic attacks caused by blood clots or embolisms, and hence drug therapy is necessary.

Cerebral infarction and acute myocardial infarction are often caused by the coagulation of fibrinogen in the blood and the fibrin-like clot, which is caused by blood clots.Therefore, thrombolytic agents such as urokinase, a fibrin lytic enzyme activator, It is used. On the other hand, antiplatelet agents and the like are used to prevent ischemic attacks caused by blood clots or embolism. As antiplatelet agents, for example, aspirin, dipyridamole, ticlopidine, cilostazol or clopidogrel are known, but these are known to inhibit the function of platelet adhesion, aggregation, release, and the like, debate synthesis, suppression of thrombus formation, and the like. Has action.

Aspirin, a representative antiplatelet agent, is a highly stable medicament and is used for this purpose. It is widely used for this purpose. 100 mg orally is administered orally prophylactically for the purpose of suppression and inhibition of thrombus and embolism after the procedure of coronary artery bypass surgery (CABG) or percutaneous cervical coronary angioplasty (PTCA). For the effect, see the attached document of the antiplatelet drug "Bahiaspirin" (Aspirin Jang Yong-jeong, Bayer Yakuching Co., Ltd.). In addition, the use of aspirin for the prevention of ischemic heart disease in diabetic patients is recommended and encouraged by the American Diabetes Association (Diabetes Care, 27, S72, Supplement 1, January 2004).

On the other hand, amino propoxybibenzyl having a specific structure represented by safoglylate hydrochloride represented by the following formula (2) shows high selectivity to the 5HT ₂ receptor and has little effect on blood pressure, and serious side effects are also reported. It is a drug which shows high safety. As for hydrochloric acid safoglylate, it is known that it is effective for the improvement of various microcirculatory disorders based on thrombus formation and vascular contraction in diseases such as cerebral circulation disorder, ischemic heart disease, peripheral circulation disorder, etc. 2-304022), it is also known to be useful as an inhibitor of thrombus and embolism (international publication WO 03/26636). However, there is no suggestion or instruction in the international publication regarding the inhibitory action of thrombus and embolism in diabetic patients with safoacrylate hydrochloride.

An object of the present invention is to provide a medicament capable of exerting an excellent thrombus or embolism suppressing action in a diabetic patient. In addition, an object of the present invention can prevent ischemic diseases caused by thrombus or embolization such as cerebral infarction or myocardial infarction, which occur frequently in diabetic patients, and prevent thrombosis or embolism that occurs frequently in diabetic patients after CABG or PTCA. The present invention provides a medicament capable of preventing the recurrence of ischemic disease caused by.

In order to solve the above problems, the present inventors have made intensive studies, and in the process, when aspirin or safoglylate hydrochloride is administered to a non-diabetic patient to prevent cerebral infarction, recurrence of cerebral infarction is higher than that of safoglycol hydrochloride when aspirin is administered. A small number of cases were found (in 35 of 532 aspirin-treated cases, recurrence of cerebral infarction was observed, whereas in 53 of 548 cases in which safoglycerate was administered, cerebral infarction was noted). Surprisingly, however, the present inventors found that diabetic patients obtained a result opposite to that obtained in non-diabetic patients, in which the safoglylate-administered group was able to achieve a better prophylactic effect than the aspirin-administered group. The present invention has been completed based on the above findings.

That is, the present invention includes, as an active ingredient, a material selected from the group consisting of aminoalkoxybibenzyls represented by the following general formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof, Medicines for preventing ischemic disease in diabetic patients are provided.

(식 중, A는 카르복실기로 치환될 수도 있는 C₃ 내지 C₅의 알킬렌기를 나타냄)을 나타내고, m은 0 내지 5의 정수를 나타낸다. In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkoxy group of C ₁ to C ₅ , or a dialkylamino group of C ₂ to C ₆ , and R ² represents a hydrogen atom, a halogen atom or an alkoxy of C ₁ to C ₅ R ³ represents a hydrogen atom, a hydroxyl group, -O- (CH ₂ ) _n -COOH (wherein n represents an integer of 1 to 5), or O-CO- (CH ₂ ) ₁ -COOH (Wherein l represents an integer of 1 to 3), R ⁴ is -N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom or C ₁ to C ₈ represents an alkyl group) or a chemical formula

(Wherein A represents an alkylene group of C ₃ to C ₅ which may be substituted with a carboxyl group), and m represents an integer of 0 to 5.

In addition, an aminoalkoxybibenzyl compound represented by the following formula (2), a pharmaceutically acceptable salt or ester thereof, and a substance selected from the group consisting of solvates and hydrates thereof are included as active ingredients, Medicines for preventing ischemic diseases; And an aminoalkoxybibenzyl compound represented by the following formula (3), a pharmaceutically acceptable salt or ester thereof, and a substance selected from the group consisting of solvates and hydrates thereof as an active ingredient, and ischemic in diabetic patients Medicines for preventing diseases; And each of the above medicaments in the form of a hydrochloride salt.

<Formula 2>

According to a preferred embodiment of the invention, the ischemic disease is ischemic cerebrovascular disorders (preferably transient cerebral ischemic attack and cerebral infarction), or acute coronary syndrome (ACS, preferably myocardial infarction and unstable angina, etc.) The medicine; Said medicament in which ischemic disease is cerebral infarction; The medicament wherein the ischemic disease is caused by the formation of a thrombus or embolus; The medicament is provided wherein the formation of a thrombus or embolism is thrombus or embolization after the procedure of coronary artery bypass surgery (CABG) or percutaneous coronary angioplasty (PTCA).

In another aspect, the aminoalkoxy bibenzyl represented by the formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof selected from the group consisting of active ingredients, diabetes Medicines for inhibiting thrombus or embolism formation in a patient are provided by the present invention.

In another aspect, it is selected from the group consisting of aminoalkoxybibenzyls represented by Formula 1, pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof for the manufacture of the medicament by the present invention. The use of the substance; A method for preventing ischemic diseases caused by thrombus or embolism in diabetic patients, the aminoalkoxybibenzyl represented by the formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof A method comprising administering a prophylactically effective amount of a substance selected from the group consisting of to a diabetic patient; A method for inhibiting the formation of thrombi or embolism in a diabetic patient, the aminoalkoxybibenzyl represented by Formula 1, pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof. Methods are provided that include administering a prophylactically effective amount of a substance to a diabetic patient.

Best Mode for Carrying Out the Invention

The medicament of the present invention contains as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyls represented by the above formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof.

R ¹ is a hydrogen atom; Halogen atoms such as chlorine atom and fluorine atom; An alkoxy group of C ₁ to C ₅ such as a methoxy group, an ethoxy group, a butoxy group; Dimethylamino group, diethylamino group, represents a dialkylamino group of C ₂ to C ₆ such as methyl ethyl amino group. R ² is a hydrogen atom; Halogen atoms such as chlorine atom and fluorine atom; Methoxy, represents an alkoxy group of C ₁ to C _5, such as an ethoxy group, a butoxy group. R ³ is a hydrogen atom; Hydroxyl group; _{-O- (CH 2) 2 -COOH,} -O- (CH 2) 3 -O- (CH 2) n -COOH , such as -COOH (, wherein n is an integer of 1 to 5); _{-O-CO- (CH 2) 2} -COOH, -O-CO- (CH 2) 3 -O-CO- (CH 2) l -COOH ( wherein, l, such as -COOH is an integer from 1 to 3 Indicates a). R ⁴ represents an amino group or an amino group having 1 to 2 carbon atoms such as methylamino group, ethylamino group, butylamino group, hexylamino group, heptylamino group, dimethylamino group, diethylamino group, methylethylamino group, etc. The 4-6 membered polymethyleneamino group which the carboxyl group may substitute by rings, such as a trimethylene amino group, a pentamethylene amino group, and 3-carboxypentamethylene amino group, is shown.

Some of the compounds preferably used in the present invention among the compounds included in Chemical Formula 1 are shown in Table 1 below.

Among these is an amino alkoxy group, ^{_{-OCH 2 C (R 3) H-}} (CH 2) m -R 4 is compound bonded to the 2-position of the phenyl group are preferred. R ¹ is preferably a hydrogen atom, an alkoxy group of C ₁ to C ₅ , or a dialkylamino group of C ₂ to C ₆ , R ² is preferably a hydrogen atom, and R ⁴ is one or more of C ₁ to C ₈ It is preferable that it is an amino group which has an alkyl group, or the 4-6 membered polymethyleneamino group which has a trimethylene group to a pentamethylene group, and it is preferable that m is an integer of 0-2. Particularly preferred are compounds No. 15 wherein R ¹ is a methoxy group, R ² is a hydrogen atom, R ³ is a hydroxyl group, and R ⁴ is a dimethylamino group (hereinafter, the compound is also referred to herein as "M-1") and It is the 14th compound which is its succinic acid ester.

Examples of the acid that forms a pharmaceutically acceptable salt of the compound represented by Formula 1 include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, acetic acid, succinic acid, adipic acid, propionic acid, tartaric acid, maleic acid, Oxalic acid, citric acid, benzoic acid, toluenesulfonic acid, methanesulfonic acid and the like are used. As ester of the compound represented by General formula (1), organic acid ester, such as succinic acid, is mentioned, for example. In addition, solvates or hydrates of the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can also be used. Particularly preferred among these are (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl hydrogensuccinate represented by the following general formula (4). Hydrochloride (Hereinafter, this material is also referred to as "safoacrylate hydrochloride").

Aminoalkoxybibenzyls represented by the general formula (1), and pharmaceutically acceptable salts and esters thereof are known and can be easily synthesized by the method described in JP-A-58-32847 or a method similar thereto. Can be. In addition, the safoglylate hydrochloride represented by the formula (4) is commercially available from Mitsubishi Well Pharma Co., Ltd. as " Anplag ", and in the present invention, the " anflag " It is possible.

By prophylactically administering the medicine of this invention to a diabetic patient, formation of a thrombus or an embolism can be suppressed very effectively in a diabetic patient. In general, a thrombus is an ischemic state caused by clots of blood vessels that cause atherosclerosis, for example, by clogging arteries around or around it, and embolism is a blood clot of blood vessels in a remote region, for example, into the bloodstream. It is understood as an ischemic state caused by the flow of electrons in blood vessels in other regions. In particular, these terms should not be interpreted limitedly in any sense, but in the broadest sense.

The medicament of the present invention has an action of inhibiting the tendency of thrombus or embolism advancing in diabetic patients, and can effectively prevent ischemic diseases caused by the formation of thrombus or embolism in diabetic patients based on the inhibitory action. have. Ischemic diseases caused by the formation of blood clots or embolisms include ischemic cerebrovascular disorders such as cerebral infarction (including cerebral thrombosis and cerebral embolism), transient cerebral ischemic attack, or acute vascular syndrome. Asymptomatic cerebral infarction, which is not accompanied, is also included in the term ischemic disease as used herein. It is known that a high rate of recurrence of cerebral infarction or acute vascular syndrome due to thrombosis or embolism occurs in diabetic patients who have experienced a stroke of cerebral infarction or acute vascular syndrome, but the medicament of the present invention is effective in preventing the recurrence of such ischemic disease. . In addition, when diabetic patients with ischemic heart attacks such as acute coronary syndrome and ischemic cerebrovascular disorders undergo coronary artery bypass grafting (CABG) or percutaneous cervical coronary angioplasty (PTCA) to resume blood flow, high blood clots after the procedure Or embolism occurs, resulting in recurrence of acute vascular syndrome and ischemic cerebrovascular disorders. The medicine of the present invention can effectively prevent an ischemic disease caused after the procedure of CABG or PTCA in diabetic patients based on the above inhibitory action.

Although not bound to any particular theory, it is known that the medicine of the present invention already has a thrombus and embolism suppressing effect (International Publication WO 03/026636), but according to the study of the present inventors, the medicine of the present invention is a non-diabetic patient. Although ischemic diseases caused by thrombus or embolism can be prevented in humans, the prophylactic effect is mild compared to aspirin. On the other hand, when the medicament of the present invention is administered for the prevention of ischemic diseases caused by thrombus or embolism formation in diabetic patients, the medicament of the present invention can achieve a better preventive effect than aspirin. It is surprising that the medicament of the present invention can exert a particularly excellent preventive effect against ischemic diseases caused by blood clots or embolism in certain disease groups called diabetics. Although aspirin is encouraged and recommended by the American Diabetes Association for the prevention of ischemic disease (Diabetes Care, 27, S72, Supplement 1, January 2004), the medicament of the present invention is used as a medicament for the prevention of aspirin replacement for diabetics. It can be administered safely.

The medicine of the present invention can be administered to a patient who has already been given drugs such as platelet aggregation coagulants, anticoagulants, fibrin solubilizers, or the like at the same time or at a different time. It is also possible to administer the medicament of the present invention after stopping the administration of drugs such as platelet aggregation coagulants, anticoagulants or fibrin solubilizers. In addition, the medicine of the present invention can be administered to a patient who is administering a medicine for the treatment of diabetes mellitus, and can be administered concurrently or concurrently with the medicine for the treatment of diabetes.

Examples of platelet aggregation coagulants include aspirin agents (vaparin, biaspirin, etc.), ticlopidine hydrochloride (panardin, etc.), cilostazol (pritar, etc.), clopigrrel, dipyridamole (perxanthin, angenal, etc.). ), Sodium Ozagrerel (Catacrot, Key Sun, etc.), Ozagrerel Hydrochloride (Vega, Domenan), Eicosapentaate (Epadel, etc.), Veraprost Sodium (Dorner, Procyrin), Limasprost Alphadex (opalmon, prorenal), alprostadil preparations (ripple, parox, prostanin, etc.), and anticoagulants include walfarin potassium (warfarin, etc.), algatroban (novavastan, tron). Rice paddy, etc.), heparin preparations (pragmin, sodium heparin, etc.), and cellulose dissolving agents include urokinase (such as urokinase), nazapulase (such as thrombolase), and alteplase (glutopa). Etc.), Tisokinase (plus beta, etc.), Nateplaze (Millizer), Pamiteplase (Sori and ), The Monte Plata (Cleveland actors) and the like. In addition to insulin preparations, medicines for the treatment of diabetes mellitus include insulin secretion accelerators such as sulfonylurea preparations, insulin action enhancers such as biguanide preparations and insulin resistance improving agents (tyrazolidine derivatives, etc.), and glucose digestion inhibitors. It is not limited.

The method of administering the medicament of the present invention can be appropriately selected by those skilled in the art. For example, it is also possible to select a route of administration either parenterally, such as subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, or oral administration. The dosage can be appropriately determined according to the conditions of the patient's age, health condition, weight, etc., if there is a medicine to be administered at the same time, the condition such as the type or frequency of administration, or the nature of the desired effect. Generally, the daily dosage of the active ingredient is 0.5 to 50 mg, typically 1 to 30 mg per kg body weight, and may be administered once or more per day.

It is preferable that the pharmaceutical of this invention manufactures and administers the pharmaceutical composition containing the said active ingredient and the additive for 1 type (s) or 2 or more types. Pharmaceutical compositions suitable for oral administration include, for example, tablets, capsules, powders, solutions, elixirs, and the like. Pharmaceutical compositions suitable for parenteral administration include sterilized liquids such as liquids or suspending agents. In the form of pharmaceutical compositions.

The kind of the additive for preparation used in the manufacture of the pharmaceutical composition is not particularly limited, and it is possible to select an appropriate preparation for the preparation according to the form of various pharmaceutical compositions. The additive for preparation may be either solid or liquid, and for example, a solid carrier or a liquid carrier can be used. As an example of a solid carrier, a capsule of a conventional gelatin type can be used. In addition, for example, the active ingredient may be tableted together with one or two or more additives for preparation, or without using the additive for preparation, or may be prepared and packaged as a powder. Such capsules, tablets, powders may generally comprise from 5 to 95% by weight, preferably from 5 to 90% by weight of the active ingredient with respect to the total weight of the formulation and the dosage unit form is from 5 to 500 mg, preferably Contains 25 to 250 mg of active ingredient. As a liquid carrier, oil or synthetic oils of animal or plant origin, such as petroleum, peanut oil, soybean oil, mineral oil, sesame oil, are used. In general, glycols such as physiological saline solution, dextrol or similar sucrose solution, ethylene glycol, propylene glycol and polyethylene glycol are preferable as liquid carriers, and in particular, in the case of injection solution using physiological saline solution, it is usually 0.5 to 20 %, Preferably 1 to 10% by weight of the active ingredient can be prepared.

<Example>

Hereinafter, although an Example demonstrates this invention further more concretely, the scope of the present invention is not limited to the following Example. In addition, as the hydrochloride safoglylate used below, "Anflag (trademark)" marketed by Mitsubishi Well Pharma Co., Ltd. was used.

<Example 1>

Of the 1,499 patients with cerebral infarction, 747 was given 100 mg once a day of saponogric acid hydrochloride, 3 times a day (300 mg / day), and 752 patients received aspirin once 81 mg, once a day (81 mg / day). The double-blind group comparative test was performed. The duration of administration varied from case to case, but the maximum duration was 3.5 years. Among these cerebral infarction patients, there were 419 diabetic patients, 199 of whom received safoacrylate hydrochloride and the remaining patients (220) received aspirin. There were 1080 non-diabetic patients, of whom 548 were given safoglylate hydrochloride and the remaining patients (532) were given aspirin.

As a result, cerebral infarction recurrence in diabetic complications was 19 cases (9.55%) in the group treated with safoacrylate hydrochloride, whereas 23 cases (10.45%) in the group treated with aspirin showed high prophylactic effect. . The expression of systemic vascular disease (stroke, acute vascular syndrome, vascular lethality) in diabetic complications was 22 cases (11.06%) in the safoglycerate group, whereas 32 cases (14.55%) in the aspirin group. On the other hand, recurrence of cerebral infarction in non-diabetic patients was 53 cases (9.67%) in the safoglycerate group, whereas 35 cases (6.58%) in the aspirin group. Expression of systemic vascular disease in non-diabetic patients was 68 cases (12.41%) in the safoglycerate group, whereas 53 cases (9.96%) in the aspirin group.

From the above results, it was shown that safoglylate hydrochloride compared with aspirin can achieve a particularly high prevention of recurrence of cerebral infarction in diabetic complications. In addition, compared to aspirin, safoglylate hydrochloride has been shown to achieve an effect of preventing the expression of a particularly high systemic vascular disease in diabetic complications.

In addition, the proportion of hemorrhagic adverse events, which are indicative of the incidence of adverse events in the above test, was 25 cases (12.6%) in the safoglycerate group treated with diabetes and 34 cases (15.3%) in the aspirin group. In diabetic patients, 64 cases (11.6%) were treated in the saponate hydrochloride group, whereas 97 cases (18.1%) in the aspirin group were lower in the diabetic and non-diabetic patients. It has been shown to have high safety compared to aspirin.

<Example 2>

546 out of 1,108 patients with cerebral infarction received saponogline hydrochloride 100 mg once, three times a day (300 mg / day), and 562 patients received aspirin once 81 mg, once daily For the case of (81 mg / day) administration, a double-blind group comparison test was conducted to interpret the results. The duration of administration varied from case to case, but the maximum duration was 3.5 years. Among these cerebral infarction patients, there were 302 diabetic patients, 145 of them treated with saline foglate, and the remaining patients (157) received aspirin. There were 806 non-diabetic patients, of whom 401 were given safoglycol hydrochloride and the remaining patients (405) were given aspirin.

As a result, 11 cases of asymptomatic cerebral infarction in diabetic complications (7.59%, 2 cases of recurrence of cerebral infarction in Example 1) were 13 in the aspirin-administered group. As a result (8.28%), a high prophylactic effect was recognized by the safoglylate hydrochloride administered group. On the other hand, the expression of asymptomatic cerebral infarction in non-diabetic patients was 39 cases (9.73%) in the safoglycerate group, whereas 28 cases (6.9%) in the aspirin group.

From the above results, it was shown that compared to aspirin, safoglylate hydrochloride can achieve a particularly high cerebral infarction prevention effect in a group of patients with diabetes.

The medicament of the present invention can prevent ischemic diseases caused by thrombus or embolization such as cerebral infarction or acute vascular syndrome, which occurs frequently in diabetic patients, and by thromboembolism or embolism that occurs frequently in diabetic patients after CABG or PTCA. It is possible to prevent the recurrence of the ischemic disease caused.

Claims (9)

Ischemic diseases in diabetic patients, comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyls represented by the following formula (1), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof: Medications to prevent. <Formula 1>

In the formula, R ¹ represents a hydrogen atom, a halogen atom, an alkoxy group of C ₁ to C ₅ , or a dialkylamino group of C ₂ to C ₆ , and R ² represents a hydrogen atom, a halogen atom or an alkoxy of C ₁ to C ₅ R ³ represents a hydrogen atom, a hydroxyl group, -O- (CH ₂ ) _n -COOH (wherein n represents an integer of 1 to 5), or O-CO- (CH ₂ ) ₁ -COOH (Wherein l represents an integer of 1 to 3), R ⁴ is -N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ are each independently a hydrogen atom or C ₁ to C ₈ represents an alkyl group) or a chemical formula

(Wherein A represents an alkylene group of C ₃ to C ₅ which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. Isocyanate disease in diabetic patients, comprising as an active ingredient a substance selected from the group consisting of aminoalkoxybibenzyl compounds represented by the following formula (2), pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof Medications to prevent. <Formula 2>

Isocyanate disease in diabetic patients, comprising as an active ingredient an aminoalkoxybibenzyl compound represented by the following formula (3), a pharmaceutically acceptable salt or ester thereof, and a solvate and a hydrate thereof: Medications to prevent. <Formula 3>

The medicament according to any one of claims 1 to 3, which is in the form of hydrochloride. The medicament according to any one of claims 1 to 4, wherein the ischemic disease is ischemic cerebrovascular disorder or acute vascular syndrome. The pharmaceutical according to claim 5, wherein the ischemic disease is cerebral infarction. The medicament according to any one of claims 1 to 6, wherein the ischemic disease is caused by the formation of a thrombus or an embolus. The medicament according to claim 7, wherein the formation of the thrombus or the embolism is thrombus or embolization after the procedure of coronary bypass surgery or percutaneous cervical coronary angioplasty. A person having a substance selected from the group consisting of aminoalkoxybibenzyl represented by the formula (1) according to claim 1, pharmaceutically acceptable salts or esters thereof, and solvates and hydrates thereof as an active ingredient, Medicine for inhibiting thrombus or embolism formation in