JPWO2005072724A1 - Preventive and / or therapeutic agent for chronic cerebral circulatory insufficiency - Google Patents

Abstract

A drug for improving cerebral circulation metabolism, comprising an aminoalkoxybibenzyl represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof, chronic brain A preventive and / or therapeutic agent for circulatory insufficiency. [Chemical 1]

Description

  The present invention relates to an agent for preventing and / or treating chronic cerebral circulatory insufficiency, and an agent for improving cerebral circulation metabolism.

  Chronic cerebral circulatory insufficiency is caused by cerebral circulatory disturbance, and subjective symptoms such as head sensation and dizziness appear swaying, but findings suggestive of vascular organic lesions may be clinically symptomatic and diagnostic. However, it is a diagnostic name given to a pathological condition that is not recognized and does not belong to the category of transient cerebral ischemic attack. It is considered that a cerebral circulation improving agent (hereinafter also referred to as “cerebral circulation metabolism improving agent”) is effective for subjective symptoms such as head sensation and dizziness (Non-patent Document 1).

  In addition, the long-term prognosis of chronic cerebral circulatory insufficiency is not clear so far, but once seizures of cerebrovascular disorders occur, the sequelae often remain, preventing chronic cerebral circulatory insufficiency. It is considered important (Non-Patent Document 1).

  The cerebral circulation metabolism improving agent is a drug that promotes recovery of brain energy metabolism. Some of them exhibit an action of increasing cerebral circulation by improving blood properties such as improvement of erythrocyte deformability, suppression of platelet aggregation, and decrease in blood viscosity. At present, as a cerebral circulation metabolism improving agent, a brain physiologically active substance such as citicoline and GABA, a cerebral circulation improving agent such as nicergoline and dihydroergotoxine mesylate, and the like are used.

  Moreover, the cerebral circulation metabolism improving agent is usually evaluated by observation of clinical symptoms or the like, but in recent years, an objective evaluation by electroencephalogram measurement has been attempted. Various studies have been made on the correlation between the electroencephalogram and the cerebral circulation metabolism improving agent. For example, when cerebral blood flow and cerebral metabolism decrease, α wave decreases and slow wave (δ wave + θ wave). (See Non-Patent Documents 2, 3 and 4).

  By the way, as a specific antagonist for serotonin (5-HT) receptor, the following general formula

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group, or a C _{2 to} C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or C _{1 to} C ₅ . Represents an alkoxy group, 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 Represents a _{1 to} C ₈ alkyl group) or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ]
Aminopropoxybibenzyls represented by the formula are known, and these aminopropoxybibenzyls are various microcirculations based on thrombus formation and vasoconstriction in diseases such as cerebral circulation disorder, ischemic heart disease and peripheral circulation disorder. It is effective in improving the obstacle (see Patent Document 1).

Non-Patent Document 5 discloses (±) -1- [O- [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethyl), which is one of the preferred compounds of the aminopropoxybibenzyls. amino) -2-propyl hydrochloride hydrogen succinate, i.e. the action of sarpogrelate hydrochloride is described to be a specific antagonism of 5-HT ₂ receptors in the platelets and vascular smooth muscle.

However, it has not been known so far that these aminopropoxybibenzyls are effective for chronic cerebral circulatory insufficiency, improve the electroencephalogram, and increase cerebral blood flow.
Japanese Patent Laid-Open No. 2-304022 Supervised by Yoshio Yazaki, etiology of cerebrovascular disorder Cerebrovascular disorder series 1, page 197, Hyundai Medical Company, 1998 Clinical EEG, Vol. 33, No. 7, p. 449 (1991) Clinical EEG, Vol. 39, No. 10, p. 653 (1997) Clinical EEG, Vol. 36, No. 10, p. 634 (1994) Therapeutic Agent Manual 2003, page 937, Medical School

  An object of the present invention is to provide a medicament having an effect of preventing and / or treating chronic cerebral circulatory insufficiency and an effect of improving cerebral circulation metabolism.

As a result of intensive studies to solve the above-mentioned problems, the present inventor found that aminopropoxybibenzyls known as 5-HT ₂ receptor antagonists have the above-described action, and completed the present invention. .

  That is, the gist of the present invention includes aminoalkoxybibenzyls represented by the following general formula (1) or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof. The present invention resides in an agent for preventing and / or treating chronic cerebral circulatory insufficiency, and an agent for improving cerebral circulation metabolism.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group, or a C _{2 to} C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or C _{1 to} C ₅ . R ³ represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, a C _{2 to} C ₅ acyloxy group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5) or O. —CO— (CH ₂ ) ₁ —COOH (wherein 1 represents an integer of 1 to 3), and R ⁴ represents —N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ each independently represents a hydrogen atom or an alkyl group C ₁ ~C _8.) or

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

  The preventive and / or therapeutic agent for chronic cerebral circulatory insufficiency and the cerebral circulation metabolism improving agent according to the present invention decrease chronic waves in the occipital region without changing mean blood pressure, and increase α waves. It has an effect of preventing or treating cerebral circulatory insufficiency, and further has an effect of improving cerebral circulation metabolism.

  In the present specification, examples of the halogen atom in the compound represented by the general formula (1) include a chlorine atom and a fluorine atom.

The alkoxy group of C ₁ -C _5, for example, a methoxy group, an ethoxy group, a propoxy group, and butoxy group, and a pentyloxy group.

Examples of the C _{2 to} C ₆ dialkylamino group include a dimethylamino group, a diethylamino group, and a methylethylamino group.

Examples of the C _{2 to} C ₅ acyloxy group include an acetoxy group, a propionyloxy group, a butyryloxy group, an isobutyryloxy group valeryl group, and an isovaleryloxy group.

The alkyl group of C ₁ -C _8, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, butyl group, isobutyl group, sec- butyl group, tert- butyl group, a pentyl group, isopentyl group, neopentyl group, A hexyl group, an isohexyl group, a heptyl group, an octyl group, etc. are mentioned.

R ¹ is preferably a hydrogen atom, a fluorine atom, a chlorine atom, a methoxy group or a dimethylamino group, or a methoxy group, and is preferably substituted at the 3-position or 4-position, particularly the 3-position.

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

R ³ is preferably a hydroxyl group, —O— (CH ₂ ) _n —COOH, or O—CO— (CH ₂ ) ₁ —COOH, n is preferably 2, and l is preferably 2.

Examples of R ⁴ include an amino group, a methylamino group, an ethylamino group, a butylamino group, a hexylamino group, a heptylamino group, a dimethylamino group, a diethylamino group and a methylethylamino group, and a trimethyleneamino group, pentamethylene. Examples thereof include an amino group and a 3-carboxypentamethyleneamino group, and a methylamino group, a dimethylamino group, a pentamethyleneamino group, or a 3-carboxypentamethyleneamino group is preferable.

  As m, an integer of 0 to 4, particularly 1, is preferable.

  In addition, it is preferable that the aminoalkoxy group is substituted at any position of 2 to 4 positions, particularly at the 4 position.

  Among the compounds represented by the general formula (1), some preferred ones are shown in Table-1.

  Among these compounds, No. 1 represented by the following formula (2). 14 compounds,

Or No. represented by the following formula (3). Fifteen compounds are preferred.

  Examples of the pharmaceutically acceptable salt include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid; acetic acid, propionic acid, succinic acid, succinic acid, adipic acid, maleic acid, tartaric acid, Examples thereof include carboxylic acids such as citric acid and benzoic acid; salts such as sulfonic acids such as toluenesulfonic acid and methanesulfonic acid.

  Particularly preferred as a compound used for the preventive and / or therapeutic agent for chronic cerebral circulatory insufficiency and the cerebral circulation metabolism improving agent according to the present invention is (±) -1- [O— represented by the following formula (4). [2- (m-methoxyphenyl) ethyl] phenoxy] -3- (dimethylamino) -2-propyl hydrogen succinate hydrochloride, ie sarpogrelate hydrochloride.

  The aminoalkoxybibenzyls represented by the general formula (1) can be produced by the method described in Japanese Patent Publication No. 63-13427 or a method analogous thereto. In addition, pharmacologically acceptable salts thereof, aminoalkoxybibenzyls, or hydrates or solvates of these salts may be produced by methods commonly used in this field. In addition, the medicine which uses sarpogrelate hydrochloride as an active ingredient is marketed as Amprag (registered trademark) by Mitsubishi Pharma Corporation, and Amprag can also be used in the present invention.

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

  The dosage of the preventive and / or therapeutic agent for chronic cerebral circulatory insufficiency and the cerebral circulation metabolism improving agent according to the present invention may be appropriately determined according to conditions such as the patient's age, health condition, and body weight. . Usually, 0.5 to 50 mg / kg body weight, preferably 1 to 30 mg / kg body weight per day is administered once or divided into several times.

  For preparations for parenteral administration or oral administration, aminoalkoxybibenzyls or a pharmaceutically acceptable salt thereof or a hydrate or solvate thereof and a conventional pharmaceutical carrier are mixed in an appropriate ratio. Thereafter, it can be prepared by a conventional method.

  The present invention will be specifically described with reference to examples. However, the present invention is not limited to the following examples as long as the gist thereof is not exceeded.

Example 1
(Method)
74 patients with peripheral circulatory insufficiency over 60 years old (40 males, 34 females) (Table 2) were divided into 2 groups. The ticlopidine group (43 patients) received ticlopidine hydrochloride 300 mg / day and the sarpogrelate group (31 patients). ) Was administered sarpogrelate hydrochloride 300 mg / day for 2 years. The ticlopidine group and sarpogrelate group were not significantly different in mean age, sex ratio, and mean blood pressure.

  After measuring average blood pressure, electroencephalograph (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 The brain wave at resting eyes was measured for 16 seconds using ATAMAPII (manufactured by Nihon Kohden Co., Ltd.). Brain waves are measured in three frequency bands of 2-8 Hz (slow wave), 8-13 Hz (α wave), and 13-30 Hz (fast wave), and a slow wave (% slow wave), α wave (% α) and The average% power of the fast wave (% fast wave) is represented by the ratio of each frequency band to the entire frequency band.

Mean blood pressure,% slow wave,% α, and% fast wave were expressed as mean ± standard deviation and compared before and after the 2-year study. Also, the entire brain region (Fp1, Fp2, F3, F4, F7, F8, C3, C4, T5, T6, O1, O2), frontal region (Fp1, Fp2, F3, F4, F7, F8, C3) In C4) and the occipital region (T5, T6, O1, O2), the difference in mean blood pressure (Δ mean blood pressure), the difference in% slow wave (Δ slow wave), and the difference in% fast wave (Δ fast wave) were compared. A t-test (Student's t-test or Welsh's t-test) and paired t-test were used and p <0.05 was considered significant.
(result)
1) Mean blood pressure Mean blood pressure changed 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 sarpogrelate group. . In addition, Δmean blood pressure was 0.4 ± 9.6 mmHg in the ticlopidine group and −1.3 ± 9.2 mmHg in the sarpogrelate group. There was no significant difference in mean blood pressure and mean blood pressure in the ticlopidine group and sarpogrelate group.
2) Electroencephalogram a) All regions The% slow wave,% α and% fast wave in the ticlopidine group increased from 46.1 ± 16.4% to 47.7 ± 16.5% and 37.0 ± 14.3%, respectively. Changed from 36.5 ± 15.9% and 16.9 ± 8.5% to 15.8 ± 7.3%, but there was no significant difference.

  The% slow wave in the sarpogrelate group tended to decrease from 47.7 ± 13.5% to 43.1 ± 13.1%. (P = 0.095). Also, the% α and% fast wave changed from 38.2 ± 12.5% to 42.2 ± 12.3% and from 14.1 ± 5.2% to 14.7 ± 5.7%. However, there was no significant difference.

Compared with the ticlopidine group, the sarpogrelate group had a significant decrease in Δ slow wave (1.5 ± 12.8% vs. −4.5 ± 14.6%, p = 0.062). On the other hand, there was no significant difference between Δα and Δspeed waves (−0.4 ± 12.4% vs. 4.0 ± 14.2%, −1.1 ± 6.1% vs. 0.5 ± 6). 0.0%).
b) Frontal For the ticlopidine group and the sarpogrelate group, there was no significant difference in% slow wave,% α and% fast wave, and Δ slow wave, Δα and Δ fast wave.
c) The occipital region In the ticlopidine group, there was no significant difference in% slow wave,% α and% fast wave, and Δ slow wave, Δα and Δ fast wave.

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

Compared to the ticlopidine group, the sarpogrelate group significantly decreased △ slow wave (0.7 ± 4.5% vs. -2.0 ± 4.8%, p = 0.013), and △ α increased significantly. (-0.5 ± 4.2% vs. 1.8 ± 4.9%, p = 0.034).
3) Relationship between △ slow wave and △ α and △ mean blood pressure a) Whole brain region In the ticlopidine group, △ mean blood pressure is in the range of -2 mmHg to 19 mmHg (conditional △ mean blood pressure -2 to 19 mmHg), △ mean A significantly negative correlation was observed between blood pressure and Δ slow wave (correlation coefficient; r = 0.70334, p value; p = 0.0369). Further, in the range of Δaverage blood pressure −6 to 19 mmHg, a significantly positive correlation was observed between Δaverage blood pressure and Δα (r = 0.39395, p = 0.0211).

  In the sarpogrelate group, a positive correlation was observed between Δmean blood pressure and Δα in the range of −25 to 18 mmHg (r = 0.357572, p = 0.0407).

In the range of the Δaverage blood pressure, the Δaverage blood pressure at which Δwaves are positive was 7.1 mmHg in the ticlopidine group. Further, in this range of Δaverage blood pressure, ΔΔ in which Δα is negative was 5.1 mmHg in the ticlopidine group and −8.2 mmHg in the sarpogrelate group.
b) Frontal In the ticlopidine group, a negative correlation was observed between Δmean blood pressure and Δα in the range of Δaverage blood pressure of −2 to 19 mmHg (r = 0.38991, p = 0. 0274). Further, in Δaverage blood pressure of 12 to 19 mmHg, a positive correlation was observed between Δaverage blood pressure and Δα (r = 0.33214, p = 0.0446).

  In the sarpogrelate group, a positive correlation was observed between Δmean blood pressure and Δα in the range of Δaverage blood pressure of −25 to 13 mmHg (r = 0.39250, p = 0.0352).

In the range of the Δaverage blood pressure, the Δaverage blood pressure in which Δwaves are positive was 5.9 mmHg in the ticlopidine group. Further, in this range of Δaverage blood pressure, ΔΔ in which Δα is negative was 12.9 mmHg in the ticlopidine group and −10.2 mmHg in the sarpogrelate group.
c) occipital region In the ticlopidine group, conditional Δmean blood pressure is in the range of 10-19 mmHg, negative correlation between Δmean blood pressure and Δslow wave (r = 0.90853, p = 0.173), Δaverage A positive correlation (r = 0.85160, p = 0.0314) was observed between blood pressure and Δα.

  In the sarpogrelate group, a negative correlation (r = 0.65924, p = 0.0381) was observed between Δaverage blood pressure and Δslow wave in the range of Δaverage blood pressure of −25 to −3 mmHg. In addition, in the range where Δaverage blood pressure is −25 to 19 mmHg, a positive correlation (y = 0.200x + 2.0436, r = 0.38773, p = 0.0356) is observed between Δaverage blood pressure and Δα. It was done.

  Within the range of the above Δaverage blood pressure, the Δaverage blood pressure at which Δwaves are positive was 14.3 mmHg in the ticlopidine group and −14.7 mmHg in the sarpogrelate group. Further, in this range of Δaverage blood pressure, ΔΔ in which Δα is negative was 12.9 mmHg in the ticlopidine group and −10.2 mmHg in the sarpogrelate group.

  By the way, both ticlopidine hydrochloride and sarpogrelate hydrochloride have an inhibitory effect on platelet aggregation and an improvement in erythrocyte deformability. It became clear that the slow wave was decreased and the α wave was increased. This indicates that not all of the drugs having antiplatelet action have an action of improving cerebral circulation metabolism, but an action peculiar to aminoalkoxybibenzyls.

  From the above test, it was revealed that aminoalkoxybibenzyls have an effect of activating cerebral circulation metabolism. Therefore, aminoalkoxybibenzyls can be used as an agent for improving cerebral circulation metabolism or a preventive and / or therapeutic agent for diseases caused by cerebral circulation metabolism disorders. Here, diseases caused by cerebral circulation metabolism disorders include coronary artery disease; peripheral circulatory disorders such as chronic arterial occlusion and obstructive arteriosclerosis; chronic cerebral circulatory insufficiency, transient ischemic attack, vertebral basilar Examples thereof include ischemic cerebrovascular disorders such as arterial circulatory disorder and cerebral thrombosis. Among these, chronic cerebral circulatory insufficiency is preferable.

Since aminoalkoxybibenzyls have an effect of activating cerebral circulation metabolism, they are useful as cerebral circulation metabolism improving agents and prophylactic and / or therapeutic agents for chronic cerebral circulatory insufficiency.

In addition, this application was filed by claiming priority from Japanese Patent Application No. 2004-25285 filed in Japan, the contents of which are included in this specification.

Claims (8)

Prevention of chronic cerebral circulatory insufficiency comprising aminoalkoxybibenzyls represented by the following general formula (1) or pharmaceutically acceptable salts thereof, or hydrates or solvates thereof; / Or therapeutic agent.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group, or a C _{2 to} C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or C _{1 to} C ₅ . R ³ represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, a C _{2 to} C ₅ acyloxy group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5) or O. —CO— (CH ₂ ) ₁ —COOH (wherein 1 represents an integer of 1 to 3), and R ⁴ represents —N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ each independently represents a hydrogen atom or an alkyl group C ₁ ~C _8.) or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ] The agent for preventing and / or treating chronic cerebral circulatory insufficiency according to claim 1, wherein the aminoalkoxybibenzyls are compounds represented by the following formula (2).

The agent for preventing and / or treating chronic cerebral circulatory insufficiency according to claim 1, wherein the aminoalkoxybibenzyl is a compound represented by the following formula (3).

The preventive and / or therapeutic agent for chronic cerebral circulatory insufficiency according to any one of claims 1 to 3, wherein the pharmaceutically acceptable salt is hydrochloride. A cerebral circulation metabolism improving agent comprising an aminoalkoxybibenzyl represented by the following general formula (1) or a pharmaceutically acceptable salt thereof, or a hydrate or solvate thereof.

[Wherein, R ¹ represents a hydrogen atom, a halogen atom, a C _{1 to} C ₅ alkoxy group, or a C _{2 to} C ₆ dialkylamino group, and R ² represents a hydrogen atom, a halogen atom, or C _{1 to} C ₅ . R ³ represents an alkoxy group, R ³ represents a hydrogen atom, a hydroxyl group, a C _{2 to} C ₅ acyloxy group, —O— (CH ₂ ) _n —COOH (wherein n represents an integer of 1 to 5) or O. —CO— (CH ₂ ) ₁ —COOH (wherein 1 represents an integer of 1 to 3), and R ⁴ represents —N (R ⁵ ) (R ⁶ ) (wherein R ⁵ and R ⁶ each independently represents a hydrogen atom or an alkyl group C ₁ ~C _8.) or

(Wherein, A represents a C _{3 to} C ₅ alkylene group which may be substituted with a carboxyl group), and m represents an integer of 0 to 5. ] The cerebral circulation metabolism improving agent according to claim 5, wherein the aminoalkoxybibenzyl is a compound represented by the following formula (2).

6. The cerebral circulation metabolism improving agent according to claim 5, wherein the aminoalkoxybibenzyl is a compound represented by the following formula (3).

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