JPH10265385A - Autokinesis aberration improver - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine capable of improving autokinesis aberration by including a piperazine derivative. SOLUTION: This medicine contains, at the active ingredient, a compound shown by the formula (R1 and R2 are each H or a halogen; (n) is 0 to 3; and R3 and R4 are each H or a substitutable phenyl) or its salt, e.g. 1-[4,4-bis(4- fluorophenyl)butyl]-4-(2-hydroxy-3-phenylaminopropyl)piperazine. This medicine is made into a preparation so as to contain the compound shown by the formula or its salt at 1 to 70 wt.%, preferably 10 to 50 wt.%. The medicine is dosed once to several times a day, at a daily dosage of 10 to 2000 mg for an adult. It can be used for prevention or treatment of various diseases, e.g. catalepsy, hyperkinetic syndrome, narcolepsy, agraphia, akathisia, akinesia, apraxia, bradykinesia and catatonia.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an agent for ameliorating voluntary movement abnormalities useful for prevention and treatment of catalepsy, hyperactivity disorder and narcolepsy.

[0002]

2. Description of the Related Art Diseases associated with abnormal voluntary movements, such as catalepsy, hyperactivity disorder, and narcolepsy, are often accompanied by seizures that make sudden voluntary movements impossible. It is known that social life itself is often restricted. Therefore, there is a need for a drug that suppresses such seizures, and various efforts have been made for this development. As a result, methylphenidate has been developed, but it has the disadvantage of insufficient central toxicities and effects, and a drug for improving abnormalities of voluntary movement has been awaited.

On the other hand, compounds represented by the following general formula (I) and / or physiologically acceptable salts thereof have calcium antagonism, dopamine reuptake inhibitory action, serotonin reuptake inhibitory action, antioxidant action, It is known to have an effect on narcotic receptors, but it is not known at all to have an effect of improving abnormalities in voluntary movement.

[0004]

DISCLOSURE OF THE INVENTION The present invention has been made under such circumstances, and an object of the present invention is to provide a medicine for improving abnormalities in voluntary movement.

[0005]

Means for Solving the Problems In view of such circumstances, the present inventors have sought a substance that improves abnormalities in voluntary movement, and as a result of extensive studies on screening and the like, have found that the compound represented by the general formula (I) And / or found that these physiologically acceptable salts have an excellent ameliorating effect on abnormal voluntary movements, and have completed the invention. Hereinafter, the embodiment of the present invention will be described in detail mainly.

[0006]

Embedded image General formula (I) (wherein, R1 and R2 each independently represent a hydrogen atom or a halogen atom, n represents an integer of 0 to 3, R3,
R4 each independently represents a hydrogen atom or a phenyl group which may have a substituent. )

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION

(1) The agent for improving the state of abnormal voluntary movement of the present invention The agent for improving the state of abnormal voluntary movement of the present invention is represented by the above general formula (I)
And / or a physiologically acceptable salt thereof. Examples of the compound represented by the general formula (I) include 1- [4,4-bis (4-fluorophenyl) butyl] -4- (2-hydroxy-3-phenylaminopropyl) piperazine (Compound 1), 1- [4,4
-Bis (4-fluorophenyl) methyl] -4- (2-hydroxy-3-phenylaminopropyl) piperazine (compound 2), 1- [4,4-bis (4-fluorophenyl) propyl] -4- (2 -Hydroxy-3-phenylaminopropyl) piperazine (compound 3), 1-
[4,4-bis (4-fluorophenyl) butyl] -4
-[3- (4-chlorophenylamino) -2-hydroxypropyl] piperazine (compound 4), 1- [4,4-
Bis (4-fluorophenyl) butyl] -4- [3-
(4-Fluorophenylamino) -2-hydroxypropyl] piperazine (compound 5), 1- [4,4-bis (4-fluorophenyl) butyl] -4- [3- (3,
4-dichlorophenylamino) -2-hydroxypropyl] piperazine (compound 6), 1- [4,4-bis (4
-Fluorophenyl) butyl] -4- [2-hydroxy-3- (4-methoxyphenylamino) propyl] piperazine (compound 7), 1- [4,4-bis (4-fluorophenyl) butyl] -4- [ 2-hydroxy-3-
(3,4,5-trimethoxyphenylamino) propyl] piperazine (compound 8) and the like. Among these compounds represented by the general formula (I), preferred is compound 1. Further, in these compounds, the carbon bonded to the hydroxyl group is an asymmetric carbon, and there are optical isomers. However, as an agent for improving the voluntary abnormal movement state of the present invention, an optically active substance can also be used. However, they can also be used in racemic form. It is preferable to use the inner (-) form of the optically active substance.

The compound represented by the above general formula (I) can be used as a free form, or can be used as a salt with an acid or the like. When used, it is preferable to use it as a salt from the viewpoint of improving solubility in water and stability during storage. Preferred salts are not particularly limited as long as they are physiologically acceptable. For example, mineral salts such as hydrochloride, sulfate, nitrate, and phosphate, maleate, fumarate, and citric acid Organic salts such as salts and oxalates can be exemplified. Of these, preferred are the hydrochloride,
It is a maleate or a fumarate, and the hydrochloride is particularly preferred from the viewpoints of workability, stability and economy.

The compound represented by the general formula (I) and / or
Alternatively, these physiologically acceptable salts can be produced from a known compound by a known method. That is, for example, diphenylpiperazine (1) and glycidyl tosylate are reacted to form a diphenylpiperazine hydroisotosylate (2), which may be condensed with an aromatic amine in the presence of an alkali. In order to form a salt, it may be dissolved in ether or alcohol, and the corresponding acid may be added to precipitate a crystal. General formula (I) thus obtained
And / or their physiologically acceptable salts can be purified by ordinary methods such as column chromatography and recrystallization.

[0010]

Embedded image

[0011]

Embedded image Compound 1

[0012]

Embedded image Compound 2

[0013]

Embedded image Compound 3

[0014]

Embedded image Compound 4

[0015]

Embedded image Compound 5

[0016]

Embedded image Compound 6

[0017]

Embedded image Compound 7

[0018]

Embedded image Compound 8

(2) The preventive / therapeutic agent for a disease associated with abnormal voluntary movement according to the present invention
It is characterized by containing as an active ingredient the ameliorating agent for voluntary movement abnormalities, that is, the compound represented by the general formula (I) and / or a physiologically acceptable salt thereof. The prophylactic / therapeutic agents referred to in the present invention mean a medicine for preventing the onset of disease, a medicine for preventing the worsening of the disease, a medicine for improving the symptoms of the disease, and a medicine for treating the disease itself. The agent for preventing or treating diseases associated with abnormal voluntary movement according to the present invention comprises the above-mentioned agent for improving voluntary movement abnormalities, that is, the compound represented by the general formula (I) and / or a physiologically acceptable salt thereof. One or more selected ones can be contained. The preferred content of these compounds is 1 to 70% by weight, more preferably 5 to 60% by weight, and still more preferably 10 to 50% by weight. The preventive / therapeutic agent for diseases associated with abnormal voluntary movements of the present invention is usually formulated as a medicament in addition to the compound represented by the general formula (I) which is an essential component and / or a physiologically acceptable salt thereof. Optional components used for the above can be contained. Such optional components include, for example, excipients, binders, coatings, lubricants,
Sugar coating, disintegrant, bulking agent, flavoring agent, emulsification / solubilization /
Dispersants, stabilizers, pH adjusters, isotonic agents and the like can be exemplified.
As the administration route, if it is an administration route usually used in medicine, it can be used without particular limitation, for example, vein, artery, portal vein, intramuscular, subcutaneous, intradermal,
Intra-peritoneal injection or instillation, oral administration using tablets, granules, powders, capsules, etc., rectal administration using suppositories, transdermal administration using an external preparation for skin or a patch and the like. The preferred dose of the preventive / therapeutic agent for a disease associated with abnormal voluntary movement of the present invention is a symptom, physical strength of a patient, sex, weight,
Depending on height, etc., roughly, per adult per day,
It is appropriate to administer 10 to 2000 g once or several times. These medicaments can be manufactured according to a generally known method. The thus obtained preventive / therapeutic agent for a disease associated with abnormal voluntary movement can improve the abnormality of voluntary movement and prevent / treat such a disease.
Examples of such diseases include catalepsy, hyperactivity disorder, narcolepsy, ataxia, akathisia, akinesia, inability to act, apraxia, bradykinesia, catathony, dysgrafia, displacia and the like.

[0020]

EXAMPLES The present invention will be described in detail below with reference to Examples, but it goes without saying that the present invention is not limited to these Examples.

<Example 1> Action to improve voluntary movement abnormalities [0021] The compound (1) -trihydrochloride of the (-1) compound, which is a model for voluntary movement abnormalities, is an agent for improving voluntary movement abnormalities according to the present invention by a forced swimming test. The effect of improving voluntary movement abnormalities was examined. That is, a ddY male mouse (weight: 25 to 35 g) was placed in a water tank (water temperature: 21 to 23 ° C.) having a diameter of 14.5 cm, a height of 19 cm, and a depth of 6 cm, and a forced swimming test was performed for 15 minutes. The average immobility time for one minute was measured. (First trial) The next day, 20m
Samples of various doses at a dose of 1 / kg were orally administered, and the same test was performed one hour later. (Second trial) The results are shown in FIG.
It is shown in FIG. From this figure, it can be seen that the trihydrochloride salt of the (-) form of Compound 1 reduces the immobility time at both 10 mg / kg and 15 mg / kg. That is, it turns out that it is excellent in the action of improving the voluntary movement abnormality.

<Example 2> Catalepsy inhibitory action The male (3) hydrochloride of compound 1 was orally administered to male SD rats that had been fasted for 18 to 24 hours, and 30 minutes later, a dose of 2 mg / kg of haloperidol was administered. Was administered intraperitoneally. One hour after the administration, catalepsy judgment was made, and observation was made every hour for up to 5 hours. Catalepsy rating is 1 height
The duration of the immobile posture in which both forelimbs of the rat were hung on an iron rod having a thickness of 2 cm and a thickness of 2 mm was measured, and evaluated by the following scores. In order to increase the reliability of the data, observation was performed two trials at a time, and the one with a longer fixed posture was adopted. The results are shown in FIG. From this, it can be seen that the (−)-form trihydrochloride of compound 1, which is an agent for improving abnormal voluntary movements of the present invention, suppresses haloperidol-induced catalepsy in a dose-dependent manner.

According to the present invention, it is possible to provide a medicine for improving abnormalities of voluntary movement.

[Brief description of the drawings]

FIG. 1 shows the trihydrochloride of the (−) form of Compound 1 (10 mg /
FIG. 7 is a diagram showing the results of a forced swim test of (kg).

FIG. 2 shows the trihydrochloride of the (−) form of compound 1 (15 mg /
FIG. 7 is a diagram showing the results of a forced swim test of (kg).

FIG. 3 is a graph showing the suppression of catalepsy of trihydrochloride in the (−) form of compound 1.

Claims (3)

[Claims] 1. An agent for improving abnormal voluntary movements, comprising a compound represented by the general formula (I) and / or a physiologically acceptable salt thereof. Embedded image General formula (I) (wherein, R1 and R2 each independently represent a hydrogen atom or a halogen atom, n represents an integer of 0 to 3, R3,
R4 each independently represents a hydrogen atom or a phenyl group which may have a substituent. ) 2. A preventive / therapeutic agent for a disease associated with abnormal voluntary movement, comprising the compound according to claim 1 and / or a physiologically acceptable salt thereof as an active ingredient. 3. The preventive / therapeutic agent according to claim 2, wherein the disease associated with abnormal voluntary movement is catalepsy, hyperactivity disorder, or narcolepsy.