KR20060128994A - Preventive and/or therapeutic agent for chronic cerebral circulatory failure - Google Patents

Abstract

An ameliorant for cerebral circulatory metabolism or a preventive and/or therapeutic agent for chronic cerebral circulatory failures, characterized by containing any of an aminoalkoxybibenzil compound represented by the following general formula (1), a pharmaceutically acceptable salt thereof, and a hydrate or solvate of either.

Description

Prevention and / or treatment for chronic cerebral circulatory insufficiency {PREVENTIVE AND / OR THERAPEUTIC AGENT FOR CHRONIC CEREBRAL CIRCULATORY FAILURE}

The present invention relates to agents for the prevention and / or treatment of chronic cerebral dysfunction, and for improving brain circulation metabolism.

Chronic cerebral circulatory insufficiency is caused by circulatory disturbances in the brain, and subjective symptoms such as double feeling and dizziness appear fluctuately, but findings suggesting vascular lesions are recognized in clinical symptoms and in burn diagnosis. It is also a diagnosis name given to symptoms that do not belong to the category of transient brain ischemic attack. It is thought that cerebral circulatory improvers (hereinafter sometimes referred to as "brain circulatory metabolic enhancers") are effective for subjective symptoms such as head feel and dizziness (Non-Patent Document 1).

In addition, although the long-term prognosis of chronic cerebral circulatory insufficiency is not clear at present, it is thought that it is important to prevent chronic cerebral circulatory insufficiency since it often leaves sequelae once a seizure of cerebrovascular disorder occurs. One).

Brain circulation metabolism improving agent is an agent which accelerates recovery of brain energy metabolism. The drug may also have an effect of increasing brain circulation by improving blood properties such as improving red blood cell deformability, inhibiting platelet aggregation, and decreasing blood consistency. Currently, as a brain circulation metabolism improving agent, physiologically active substances of the brain such as citcholine and GABA, and brain circulation improving agents such as nisergoline and mesyl acid dihydroertoxin are used.

In addition, the brain circulatory metabolism improving agent is usually evaluated by observation of clinical symptoms or the like, but objective evaluation by EEG measurement has recently been attempted. Various studies have been conducted on the correlation between brain waves and brain circulatory metabolism improving agents. For example, when brain blood flow and brain metabolism decrease, α waves decrease and western waves (δ wave + θ). It is evident that the wave) increases (see Non-Patent Documents 2 to 4).

By the way, as a specific antagonist to serotonin (5-HT) receptor, aminopropoxybibenzyl represented by the following general formula (1) is known, and this aminopropoxybibenzyl is a brain circulation disorder, ischemic heart disease, peripheral circulation disorder It is effective for the improvement of various microcirculation disorders resulting from thrombus formation and blood vessel contraction in such diseases (see Patent Document 1).

In the formula,

R ¹ is a hydrogen atom, a halogen atom, C ₁ To C ₅ alkoxy group, or C ₂ to C ₆ dialkylamino group,

R ² is a hydrogen atom, a halogen atom or C ₁ To alkoxy group of C ₅ ,

(여기서, A는 카르복실기로 치환될 수도 있는 C₃ 내지 C₅의 알킬렌기를 나타냄)을 나타내고, R ³ represents a hydrogen atom, a hydroxyl group, —O— (CH ₂ ) _n —COOH, where n represents an integer from 1 to 5 or O—CO— (CH ₂ ) ₁ —COOH, wherein l is Represents an integer of 1 to 3, and R ⁴ represents -N (R ⁵ ) (R ⁶ ), wherein R ⁵ and R ⁶ each independently represent a hydrogen atom or an alkyl group of C ₁ to C ₈ ; or

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

m represents the integer of 0-5.

In addition, Non-Patent Document 5 describes (±) -1- [O-2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino, which is one of preferred compounds of the above aminopropoxybibenzyl compounds. The action of the hydrochloride salt of) -2-propylhydrogensuccinate, ie Sarpogrelate hydrochloride, is described as a specific antagonistic action on the 5-HT ₂ receptor on platelets and vascular smooth muscle.

However, it is not known until now that these aminopropoxybibenzyls are effective for chronic cerebral dysfunction, improving brain waves, or increasing cerebral blood flow.

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

[Non-Patent Literature 1] Supervision of Yakio Yazaki, Adult Cerebral Vascular Disorder Series 1, page 197, Modern Medical History of Cerebral Vascular Disorders, 1998

[Non-Patent Document 2] Clinical EEG, Vol. 33, No. 7, pp. 449, 1991

[Non-Patent Document 3] Clinical EEG, Vol. 39, No. 10, page 653 (1997)

[Non-Patent Document 4] Clinical EEG, Vol. 36, No. 10, page 634 (1994)

[Non-Patent Document 5] Therapeutic Manual, 2003, page 937, Medical Vow

<Technical problem to be achieved>

An object of the present invention is to provide a medicament having a prophylactic and / or therapeutic action for chronic cerebral circulatory insufficiency and having a cerebral circulatory metabolism improving effect.

The present inventors came to a result of extensive studies, completed the present invention found that the non-aminopropoxy benzyl kind known as antagonists of 5-HT ₂ receptor has the effect in order to solve the above problems.

That is, the gist of the present invention includes aminoalkoxybibenzyl represented by the following general formula (1), or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. ) Therapeutic agent, and brain circulation metabolism improving agent.

<Formula 1>

In the formula, R ¹ is a hydrogen atom, a halogen atom, C ₁ To C ₅ alkoxy group or C ₂ to C ₆ dialkylamino group, R ² represents a hydrogen atom, a halogen atom or C ₁ To C ₅ alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, an acyloxy group of C ₂ to C ₅ , -O- (CH ₂ ) _n -COOH, where n represents an integer of 1 to 5 ) Or O-CO- (CH ₂ ) _l -COOH, where l represents an integer from 1 to 3, and R ⁴ represents -N (R ⁵ ) (R ⁶ ), wherein R ⁵ and R ⁶ Each independently represent a hydrogen atom or an alkyl group of C ₁ to C ₈ ) or

(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.

Effect of the Invention

The prophylactic and / or therapeutic agent for chronic cerebral circulatory insufficiency according to the present invention, and the cerebral circulatory metabolism improving agent, can prevent or treat chronic cerebral circulatory insufficiency by decreasing the slow wave in the larynx and increasing the α wave without changing the mean blood pressure. Effect, and further improves brain circulation metabolism.

Best Mode for Carrying Out the Invention

In this specification, as a halogen atom in the compound represented by General formula (1), a chlorine atom, a fluorine atom, etc. are mentioned, for example.

The alkoxy group of C ₁ to C _5, for example, there may be mentioned a methoxy group, an ethoxy group, a propoxy group, a butoxy group and the like pen tilok time.

A dialkylamino group of C ₂ to C _6, for example, and the like can be mentioned a dimethylamino group, diethylamino group, methyl ethyl amino group.

An acyloxy group of C ₂ to C _5, for example, and the like can be mentioned acetoxy, propionyloxy oxy group, butynyl rilok group, isobutyryl group rilok ballet group and isopropyl ballet rilok time.

Examples of the C ₁ to C ₈ alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group and neophene A methyl group, a hexyl group, an isohexyl group, a heptyl group, an octyl group, etc. are mentioned.

As R ¹ , a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or a dimethylamino group, and a methoxy group are preferable, and it is preferable that it is substituted at the 3-position or 4-position, especially 3-position.

As R ² , a hydrogen atom, a chlorine atom or a methoxy group, particularly a hydrogen atom, is preferable, and it is preferable that it is substituted at the 3-position.

As R ³ , a hydroxyl group, -O- (CH ₂ ) _n -COOH or O-CO- (CH ₂ ) ₁ -COOH is preferable, divalent as n and 2 as l are preferable.

As R ⁴ , for example, an amino group, methylamino group, ethylamino group, butylamino group, hexylamino group, heptylamino group, dimethylamino group, diethylamino group and methylethylamino group, trimethyleneamino group, pentamethyleneamino group, 3-carboxypentamethyleneamino group and the like The methylamino group, the dimethylamino group, the pentamethylene amino group, or the 3-carboxypentamethylene amino group are preferable.

As m, the integer of 0-4, especially 1 are preferable.

Moreover, it is preferable that the aminoalkoxy group is substituted by arbitrary positions, especially 4 positions of 2-4 positions.

Among the compounds represented by the formula (1), some of the preferred ones are shown in Tables 1-1 and 1-2 below.

Among these compounds, a compound of compound number 14 represented by the following formula (2) or a compound of compound number 15 represented by the following formula (3) is preferable.

Pharmaceutically acceptable salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid; Carboxylic acids such as acetic acid, propionic acid, oxalic acid, succinic acid, adipic acid, maleic acid, tartaric acid, citric acid and benzoic acid; And salts such as sulfonic acids such as toluenesulfonic acid and methanesulfonic acid.

Particularly preferred compounds for use in the prophylactic and / or therapeutic agent for chronic cerebral circulatory insufficiency according to the present invention and in the brain circulatory metabolism improving agent are (±) -1- [O- [2- (m) represented by the following general formula (4). -Methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propylhydrogen succinate hydrochloride, ie, sapogrelate hydrochloride.

The aminoalkoxy bibenzyl represented by General formula (1) can be manufactured by the method of Unexamined-Japanese-Patent No. 63-13427, or the method according to it. Moreover, the pharmacologically acceptable salt, aminoalkoxy bibenzyl, or the hydrate or solvate of the salt can be manufactured by the method conventionally used in this field. In addition, a medicament containing safogrelate hydrochloride as an active ingredient is commercially available from Mitsubishi Well Pharma Co., Ltd. as Anplag (registered trademark), and an anflag may be used in the present invention.

The agent for preventing and / or treating chronic cerebral circulatory insufficiency according to the present invention, and the brain circulation metabolism improving agent can be administered by any method. As a method of administration, for example, parenteral administration by injection such as subcutaneous injection, intravenous injection, and intramuscular injection; Oral administration by tablets, capsules, powders, solutions, elixirs, and the like.

The dosage of the prophylactic and / or therapeutic agent for chronic cerebral circulatory insufficiency and the cerebral circulatory metabolism improving agent according to the present invention can be appropriately determined according to the conditions of the patient's age, health condition, weight, and the like. Usually, 0.5 to 50 mg / kg body weight, preferably 1 to 30 mg / kg body weight, is administered once or in divided doses.

Preparations for parenteral or oral administration are prepared by conventional methods after mixing aminoalkoxybibenzyl or its pharmaceutically acceptable salts or hydrates or solvates thereof with the usual formulation carrier. can do.

Although an Example demonstrates this invention concretely, this invention is not limited to a following example, unless the summary is exceeded.

<Example 1>

(Way)

74 patients (40 males, 34 females) (Table 2) below were divided into two groups, and the ticlopidine hydrochloride (300 mg / day) 300 mg / day was added to the sarfogrelate group ( Thirty-one patients received 300 mg / day of sarfogrelate hydrochloride for 2 years. There was no significant difference in mean age, sex ratio, and mean blood pressure between the ticlopidine and sarfogrelate groups.

After measuring the average blood pressure, electroencephalogram (EEG7314 type) from 12 electrodes (Fp1, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, O1, O2) arranged according to the international 10-20 electrode system Using the ATAMAPII unit, manufactured by Nippon Kodensha Co., Ltd., the brain waves of stable closed eyes were measured for 16 seconds. EEG waves are measured in three frequency bands: 2-8 Hz (slow wave), 8-13 Hz (α wave), and 13-30 Hz (slow wave), and slow wave (% slow wave) and α wave (% The average percent intensity of α) and fast wave (% slow wave) is shown as the ratio of each frequency band to the total frequency band.

Mean blood pressure,% slow wave,% alpha and% slow wave were expressed as mean ± standard deviation and compared before and after the two-year test. In addition, the entire area of the brain (Fp1, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, O1, O2), and the frontal head (Fp1, Fp2, F3, F4, F7, F8, C3, C4) And in the back of the head (T5, T6, O1, O2), the difference of the average blood pressure (△ average blood pressure), the difference of the% slow wave (△ slow wave) and the difference of the% slow wave (△ slow wave) was compared. The t-test (student's t-test, or Wales' t-test) and the paired t-test were used, with p <0.05 being the significant difference.

(result)

1) average blood pressure

The mean blood pressure varied from 97.7 ± 8.8 mmHg to 98.2 ± 10.5 mmHg in the ticlopidine group and from 96.1 ± 10.4 mmHg to 94.9 ± 12.6 mmHg in the sarfogrelate group. The mean blood pressure was 0.4 ± 9.6 mmHg in the ticlopidine group and −1.3 ± 9.2 mmHg in the sarfogrelate group. The ticlopidine and sarfogrelate groups also showed no significant difference in mean blood pressure and Δmean blood pressure.

2) EEG

a) the whole area

The% slow wave,% alpha and% slow wave of the ticlopidine group changed from 46.1 ± 16.4% to 47.7 ± 16.5%, from 37.0 ± 14.3% to 36.5 ± 15.9%, and from 16.9 ± 8.5% to 15.8 ± 7.3%, respectively. There was no.

The% slow wave of the sarfogrelate group showed a tendency to decrease from 47.7 ± 13.5% to 43.1 ± 13.1% (p = 0.095). In addition, although% alpha and% slow wave changed from 38.2 ± 12.5% to 42.2 ± 12.3%, and from 14.1 ± 5.2% to 14.7 ± 5.7%, there was no significant difference.

Compared with the ticlopidine group, the slack was significantly lowered in the sarfogrelate group (1.5 ± 12.8% vs. −4.5 ± 14.6%, p = 0.062). On the other hand, there were no significant differences in Δα and Δsq (-0.4 ± 12.4% vs. 4.0 ± 14.2%, -1.1 ± 6.1% vs. 0.5 ± 6.0%).

b) frontal tofu

There was no significant difference in the% slow wave,% alpha and% slow wave and? Slow wave, Δ alpha and Δ slow wave with respect to the ticlopidine group and the sarfogrelate group.

c) larynx

In the ticlopidine group, there were no significant differences in the% slow wave,% alpha and% slow wave, and the? Slow wave, Δα and Δ slow wave.

In the sarfogrelate group, the% slow was significantly reduced from 14.0 ± 5.0% to 12.0 ± 4.6% (p = 0.024). In addition,% α was significantly increased from 14.6 ± 4.7% to 16.4 ± 4.4% (p = 0.049).

Compared with the ticlopidine group, Δs waves were significantly decreased (0.7 ± 4.5% vs. 12.0 ± 4.8%, p = 0.013) and Δα were significantly increased (−0.5 ± 4.2% vs. 1.8 ±) in the sprayed glorite group. 4.9%, p = 0.034).

3) Relationship between △ slow wave, Δα and △ mean blood pressure

a) the entire area of the brain

In the ticlopidine group, a significant negative correlation was observed between the mean blood pressure and the slow wave in the range of Δaverage blood pressure ranging from -2 mmHg to 19 mmHg (conditional Δaverage blood pressure -2 to 19 mmHg) (correlation coefficient r = 0.37034, p-value; p = 0.0369). In addition, in the range of Δaverage blood pressure -6 to 19 mmHg, a significant positive correlation was observed between Δaverage blood pressure and Δα (r = 0.39395, p = 0.0211).

In the sarfogrelate group, a positive correlation was observed between Δmean blood pressure and Δα in the range of −25 to 18 mmHg (r = 0.37572, p = 0.0407).

In the range of said average blood pressure, (triangle | delta) mean blood pressure with which a squid is positive was 7.1 mmHg in the ticlopidine group. In the range of the average blood pressure, the average blood pressure at which α was negative was 5.1 mmHg in the ticlopidine group and -8.2 mmHg in the sarfogrelate group.

b) frontal tofu

In the ticlopidine group, a negative correlation was observed between Δmean blood pressure and Δα in the range of Δaverage blood pressure ranging from -2 to 19 mmHg (r = 0.38991, p = 0.0274). In addition, at Δaverage blood pressure -12 to 19 mmHg, a positive correlation was observed between Δaverage blood pressure and Δα (r = 0.33214, p = 0.0446).

In the sarfogrelate group, a negative correlation was observed between Δmean blood pressure and Δα in the range of Δaverage blood pressure ranging from -25 to 13 mmHg (r = 0.39250, p = 0.0352).

In the range of said average blood pressure, (triangle | delta) mean blood pressure with which a squid was positive was 5.9 mmHg in the ticlopidine group. In the range of ΔA average blood pressure, the ΔA average blood pressure at which Δα becomes negative was 12.9 mmHg in the ticlopidine group and -10.2 mmHg in the sprayed glarite group.

c) larynx

In the ticlopidine group, in the range of conditional Δaverage blood pressure in the range of 10 to 19 mmHg, a negative correlation (Δ = 0.89053, p = 0.0173) between Δaverage blood pressure and △ slow wave, Δpositive correlation between the mean blood pressure and Δα A relationship (r = 0.85160, p = 0.0314) was observed.

In the sarfogrelate group, a negative correlation (r = 0.65924, p = 0.0381) was observed between the mean blood pressure and the slow wave in the range of -25 to -3 mmHg. In addition, in the range where the average blood pressure was -25 to 19 mmHg, a positive correlation (y = 0.200x + 2.0436, r = 0.37873, p = 0.0356) was observed between the average blood pressure and Δα.

Within the range of the above average blood pressure, the average blood pressure of which the wave was positive was 14.3 mmHg in the ticlopidine group and -14.7 mmHg in the sarfogrelate group. In the range of the average blood pressure, the average blood pressure at which α was negative was 12.9 mmHg in the ticlopidine group and -10.2 mmHg in the sarfogrelate group.

However, both ticlopidine hydrochloride and spargle hydrochloride have the effect of inhibiting platelet aggregation and improving erythrocyte deformability, while ticlopidine hydrochloride does not change the mean blood pressure and brain wave, while hydrochloric acid sparlite does not change the mean blood pressure in the posterior head. It is evident that the slow wave is reduced and the alpha wave is increased. This indicates that the effect of improving brain circulation metabolism is not unique to all drugs having antiplatelet action, but is unique to aminoalkoxybibenzyl compounds.

Through the above tests, it has been clarified that aminoalkoxybibenzyl has an effect of activating brain circulation metabolism. Therefore, aminoalkoxy bibenzyl can be used as an agent for improving brain circulation metabolism or for preventing and / or treating a disease caused by brain circulation metabolic disorder. Here, diseases due to cerebral circulatory metabolic disorders include coronary artery disease; Peripheral circulatory disorders such as chronic arterial occlusion and obstructive atherosclerosis; Ischemic cerebrovascular disorders such as chronic cerebral circulatory insufficiency, transient cerebral ischemic attack, vertebral cerebral basal artery circulatory disorder, and cerebral thrombosis, and the like.

Since aminoalkoxy bibenzyl has the effect of revitalizing brain circulation metabolism, it is useful as an agent for improving brain circulation metabolism or preventing and / or treating chronic brain circulation failure. In addition, this application is the priority application of Japanese Patent Application No. 2004-25285 for which it applied in Japan, and the content is contained in this specification all.

Claims (8)

A prophylactic and / or therapeutic agent for chronic cerebral circulatory insufficiency comprising aminoalkoxybibenzyl represented by the following formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof. <Formula 1>

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

(Wherein A represents an alkylene group of C ₃ to C ₅ which may be substituted with a carboxyl group), m represents the integer of 0-5. The preventive and / or therapeutic agent for chronic cerebral insufficiency according to claim 1, wherein the aminoalkoxybibenzyl is a compound represented by the following formula (2). <Formula 2>

The preventive and / or therapeutic agent for chronic cerebral insufficiency according to claim 1, wherein the aminoalkoxybibenzyl is a compound represented by the following formula (3). <Formula 3>

The prophylactic and / or therapeutic agent for chronic cerebral insufficiency according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is hydrochloride. Aminoalkoxybibenzyl represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, comprising: a brain circulation metabolism improving agent. <Formula 1>

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

(Wherein A represents an alkylene group of C ₃ to C ₅ which may be substituted with a carboxyl group), m represents the integer of 0-5. A brain alkoxy metabolism improving agent according to claim 5, wherein the aminoalkoxybibenzyl is a compound represented by the following formula (2). <Formula 2>

A brain alkoxy metabolism improving agent according to claim 5, wherein the aminoalkoxybibenzyl is a compound represented by the following general formula (3). <Formula 3>

8. The brain circulation metabolism improving agent according to any one of claims 5 to 7, wherein the pharmaceutically acceptable salt is a hydrochloride salt.