KR20070032071A - Agent for promoting the recovery from dysfunction after the onset of central neurological disease - Google Patents

Abstract

The present invention provides a function impairment recovery accelerator or augmentation and / or accelerator of functional recovery training effect after the onset of a novel central neurological disease. The present invention provides a functional disorder recovery promoter after central nervous system disease, and a neurotransmitter and a norepinephrine, after serotonin, which contains as an active ingredient a compound which selectively selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time. The present invention relates to an enhancer and / or an accelerator of a functional recovery training effect after the onset of central neurological disease, which contains, as an active ingredient, a compound that selectively and selectively enhances neurotransmission at the same time. The present invention is useful as providing an excellent recovery accelerator for dysfunction after the onset of central neurological disease and an enhancer and / or promoter for functional recovery training. In addition, the medicine of the present invention is useful as a safe drug without having anticholinergic action, drug dependence or circulatory action that causes side effects.

Serotonin, functional disorder after onset of central nervous system disease, stroke, brain trauma, spinal cord injury, neurodegenerative disease

Description

AGENT FOR PROMOTING THE RECOVERY FROM DYSFUNCTION AFTER THE ONSET OF CENTRAL NEUROLOGICAL DISEASE}

The present invention relates to a medicament, in particular an agent for restoring dysfunction after the onset of central neurological disease, and an enhancer and / or a promoter for the effect on the recovery of dysfunction after onset of central neuron disease.

In Japan, most patients with central nervous system diseases such as stroke, brain trauma, spinal cord injury, and neurodegenerative diseases are targeted for rehabilitation. Disorders caused by these disorders include various functional disorders such as mobility impairment of limbs, impaired gait, neurological disorders such as hemiplegia, and mental and neurological disorders such as cognitive and depressed states. Drug treatment and function recovery training are performed.

Among the patients for rehabilitation medical treatment, the proportion of stroke patients accounts for the most, and in Japan, it accounts for about 30% of the causes of lying down and the number of patients suffering from sequelae is estimated to be 1.7 million (stroke treatment guidelines 2004). (Japanese Stroke Society)). In particular, it is considered that the early function recovery training after the onset is most effective for the motor function disorder due to stroke. However, since the period is long and the training effect is not necessarily sufficient, there is a demand for a drug that can further shorten the period of functional recovery training and maximize the training effect.

(S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine hydrochloride (hereinafter referred to as compound A) has serotonin reuptake inhibitory action and 5-HT2A receptor antagonist action It was found as a compound (patent document 1). In other words, Compound A has been reported to have a neurotransmitter-enhancing action by serotonin based on serotonin reuptake inhibitory action, as well as a neurotransmitter-enhancing action by norepinephrine based on 5-HT2A receptor antagonism. It is comparable to venlafaxine, a Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) (Non-Patent Document 1, Non-Patent Document 2). That is, compound A is a compound which has a neurotransmitter-enhancing action by serotonin and norepinephrine.

It is disclosed in Patent Document 1 that Compound A is useful as a therapeutic agent for peripheral symptoms of cerebrovascular disorders such as spontaneous deterioration and congestive mood, and also has a blood viscosity improving action or an antihypoxic action and a brain function improving agent. However, there is no suggestion and specific disclosure about the recovery promoting action of the functional disorder including the motor functional disorder caused by the central nerve disease, or the enhancement and / or promotion of the functional recovery training effect.

Until now, it has been confirmed that by enhancing the neurotransmission by norepinephrine, the recovery of functional disorders after brain injury is promoted (Non-Patent Document 3, Non-Patent Document 7), in particular, the effect of D-amphetamine, a monoamine release promoter (Non-Patent Document 4, Non-Patent Document 5, and Non-Patent Document 6). On the other hand, fluoxetine, a selective serotonin reuptake inhibitor (SSRI), has also been reported to have an effect on the recovery of motor function (Non-patent Document 8).

In view of this, it is thought that a compound having a neurotransmitter-enhancing effect of norepinephrine or serotonin nerves has a recovery promoting effect of dysfunction after central nervous system disease. However, since D-amphetamine has side effects such as drug dependence, excitatory action, circulatory action, and further, the promoting action for the recovery of function of fluoxetine is not sufficient compared to D-amphetamine (Non-Patent Document 9). The drug which was excellent in the effect was calculated | required.

Patent Document 1: International Publication WO94 / 18182

[Non-Patent Document 1] Eur. J. Pharmacol. 395 (1), 31-36, 2000

Non Patent Literature 2: J. Pharmacol. Exp. Ther. 302 (3), 983-991, 2002

Non-Patent Document 3: Science 217, 855-857, 1982

Non-Patent Document 4: Stroke 29, 2381-2395, 1998

Non Patent Literature 5: Ann Neurol. 23, 94-97, 1988

Non-Patent Document 6: Stroke 26, 2254-2259, 1995

Non-Patent Document 7: Am J Phys Med Rehabi 1 72, 286-293, 1993

Non-Patent Document 8: Stroke 27, 1121-1214, 1996

Non-Patent Document 9: Am J Phys Med Rehabi 1 73, 76-83, 1994

An object of the present invention is to provide a medicament useful as an agent for promoting functional disorder recovery after the onset of central neurological disease, and an agent for enhancing and / or promoting the functional disorder recovery training effect after the onset of central neuron disease. In particular, compared to the conventionally known drugs fluoxetine, desipramine, and D-amphetamine, the present invention provides an excellent medicament in reducing the above-mentioned promoting and / or enhancing effects or side effects.

The inventors of the present invention further examined drugs that promote the recovery of functional disorders caused by central neurological diseases. As a result, compounds that selectively enhance neurotransmission by serotonin and neurotransmission by norepinephrine at the same time, in particular, Compound A, are excellent in exercise. It confirmed that it has a function recovery promoting effect, and completed this invention.

That is, the present invention, after the onset of central neurological diseases such as stroke, brain trauma, neurodegenerative diseases, spinal cord injury, etc., containing as an active ingredient a compound that selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time, respectively. Regarding an agent for enhancing and / or promoting a functional recovery training effect after central nervous system disease, comprising as an active ingredient a compound for effectively restoring a functional disorder recovery and a neurotransmission by serotonin and a neurotransmission by norepinephrine simultaneously will be.

Effect of the Invention

The present invention is useful as providing an excellent recovery promoter for dysfunction due to central neurological disease and an enhancer and / or promoter for functional recovery training. In addition, the medicine of the present invention is useful as a safe medicine without side effects or drug dependence caused by anticholinergic effects such as thirst, constipation, urination disorder, and sore eyes. In particular, compound A is a compound which is superior in the said promoting effect and / or enhancing effect or reducing side effects compared with the conventionally known medicines fluoxetine, desipramine, and D-amphetamine. In addition, Compound A has a mitochondrial protective action and affinity for sigma receptors, and therefore has a cell death inhibitory effect and a reinforcement action of neurites, which are useful as therapeutic agents of the present invention.

Best Mode for Carrying Out the Invention

Preferred embodiments of the present invention are shown in the following (1) to (8).

(1) A function impairment recovery accelerator after central nervous system disease containing a compound which selectively and selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time, respectively.

(2) Enhancement and / or accelerator for functional disability recovery training effect after the onset of central neurological disease, containing as an active ingredient a compound which selectively selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time.

(3) The agent according to (1) or (2), wherein the central nervous system disease is a stroke, brain trauma, spinal cord injury, or neurodegenerative disease.

(4) The agent according to (3), wherein the functional disorder is a motor function disorder, a sensory function disorder, or a language function disorder.

(5) duloxetine, venlafaxine, milnacipran, or (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine, or pharmaceuticals thereof A function impairment recovery accelerator after central nervous system disease development containing the salt which is accepted as an active ingredient.

(6) duloxetine, venlafaxine, milnacipran, or (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine, or a pharmaceutically acceptable salt thereof Enhancing and / or promoting agent of the functional impairment recovery training effect after the onset of central neurological disease, which is contained as an ingredient.

(7) The agent according to (5) or (6), wherein the central nervous system disease is a stroke, brain trauma, spinal cord injury, or neurodegenerative disease.

(8) The agent according to (7), wherein the functional disorder is a motor function disorder, a sensory function disorder, or a language function disorder.

(9) A function impairment recovery accelerator after central nervous system disease containing a compound having a serotonin reuptake inhibitory effect and a 5-HT2A receptor antagonism as an active ingredient.

(10) Enhancement and / or accelerator for the functional impairment recovery training effect after central neuropathy disease containing the compound which has a serotonin reuptake inhibitory effect and 5-HT2A receptor antagonism as an active ingredient.

(11) The agent according to (9) or (10), wherein the central nervous system disease is a stroke, brain trauma, spinal cord injury, or neurodegenerative disease.

(12) The agent according to (11), wherein the functional disorder is a motor function disorder, a sensory function disorder, or a language function disorder.

Further preferred embodiments of the present invention are shown below (13) to (18).

(13) Functional impairment after onset of central neurological disease, containing (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient Recovery accelerator.

(14) Functional impairment after onset of central neurological disease, containing (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient Enhancers and / or Facilitators of Restorative Training Effects.

(15) The agent according to (13) or (14), wherein the central nervous system disease is a stroke, brain trauma, spinal cord injury, or neurodegenerative disease.

(16) The agent according to (15), wherein the functional disorder is a motor function disorder, a sensory function disorder, or a language function disorder.

(17) To suppress the hyperactivity or excitability of the heart rate, containing (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient. Motor function impairment recovery promoter after stroke onset which does not accompany.

(18) To inhibit the hyperactivity or excitability of heart rate, containing (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient Enhancement and / or accelerator of motor function disorder recovery training effect after stroke onset which is not accompanied.

The present invention is further described in detail.

"Compound which selectively and selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time" is a compound which has the effect of simultaneously simultaneously strengthening these neurotransmissions by inhibiting or promoting the release of serotonin and norepinephrine. Means. That is, a compound that selectively enhances neurotransmission by serotonin (for example, fluoxetine) or a compound that selectively enhances neurotransmission by norepinephrine (for example, desipramine) is an active ingredient of the present invention. Not included in In addition, the "compound which selectively and selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time" does not include the compound which shows the enhancement effect of the neurotransmission by dopamine which is one of monoamines. That is, the conventionally known D-amphetamine promotes the release of monoamine, but cannot be said to be a compound that selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time. It is not included.

What is contained in the active ingredient of this invention is SNRI and compound A specifically, and compound A is especially preferable.

"SNRI" is a drug which selectively inhibits the reuptake of serotonin and norepinephrine, and specifically, Milnacipran (asahi Kasei), Venlafaxine (Wyeth), Duloxetine (duloxetine, Lilly), and F -98214-TA (FAES Farma) etc. are mentioned. Milnacifran, venlafaxine, and duloxetine, respectively, are known as "antidepressants", but both enhance the functional impairment recovery promoter after the onset of central neuron disease of the present invention, and enhance the functional impairment recovery training effect after the onset of the central neuron disease, and / or It is not known as an accelerator.

Motor function disorder by sensory disorder, sensory disorder, language disorder such as "function disorder after onset of central nervous system disease" that part which was injured by cause such as stroke, brain trauma, neurodegenerative disease, spinal cord injury is in charge It does not include mental disorders such as depressive symptoms or cognitive disorders such as dementia. Preferably it is motor dysfunction.

The term "stroke" is classified as hemorrhagic and non-bleeding. Examples of hemorrhagic include hemorrhagic hemorrhage, subarachnoid hemorrhage, intracranial hemorrhage due to cerebral artery malformation, and cerebral infarction as non-hemorrhagic.

The term "brain trauma" refers to a state in which the brain has been traumatically damaged due to a traffic accident or the like, and examples thereof include cerebral injury, epidural hematoma, subdural hematoma, intracranial hematoma, and diffuse axon injury.

"Spinal cord injury" refers to a condition in which the spinal cord is compressed and destroyed by fractures or dislocations of the spine and causes functional disorders.

The term "neurodegeneration disease" refers to a group of diseases in which nerve cells belonging to a specific functional system die chronically and progressively. Parkinson's disease, spinal cord cerebellar degeneration, multisystem atrophy, muscular dystrophy, and the like.

The term "motor dysfunction" means a state in which free exercise is difficult, incapable, or incapable of performing smoothly, and means exercise paralysis and ataxia. Specifically, disorders of elaborate movements, signs of Babinski, convulsive paralysis, spasticity, chronic reflexes (chronic), rigidity, movement, and unnatural movements (finger trembling) Martial arts movements, athetose, dystonia, etc.), ataxia (limb and trunk) or speech impairment, eating and swallowing disorders. Preferably it is walking function disorder and upper extremity function disorder.

"Sensory impairment" means that brain disorders are not normally recognized by superficial senses such as touch, pressure and warmth, deep senses such as positional sense and vibration angle, and complex senses such as two-point identification angle and skin cognitive sensitivity. It refers to the state that does not, depending on the degree of loss of feeling (loss), sensory deterioration (decay), hypersensitivity, paresthesia (sensation). In addition, sensory disturbance by the site | part which generate | occur | produces sensory disorders, such as half body sensory disturbance, superficial sensory disorder, and total sensory disorder, is included.

"Language dysfunction" refers to aphasia, which indicates a decline in the ability of language to hear, read, speak, and write words due to damage to the area responsible for language function, and numbness of vocal and speech organs such as lips, tongue, and vocal cords. (B) Refers to oral impairment that exhibits symptoms such as poor speech and pronunciation due to impaired exercise (ataxia). Preferably, the impaired oral impairment.

"Promoting functional disorder recovery" means recovering the functional disorder to a higher level earlier, for the purpose of shortening the hospitalization period after onset, early self-reliance of self-care, and promoting QOL (quality of life) improvement. It means to let.

Preferred uses of the invention relate to impaired motor function due to stroke, brain trauma, neurodegenerative diseases, spinal cord injury, and more preferably to impaired gait function and upper extremity function after stroke.

"Dysfunctional restorative training" is an exercise function such as muscle strength enhancement performed in the acute, recovery and maintenance phases, joint movement area training of fingers and knees, and motion training such as walking depending on the time after the central nervous system disease and the condition of the patient. Recovery training, language function recovery training, cognitive function recovery training, etc. Preferably exercise recovery function.

"Augmentation of the functional disability recovery training effect" means restoring a function to a higher level than the case where only training is performed, and reducing an obstacle.

"Promotion of functional disorder recovery training effect" means promoting functional recovery in a shorter period of time than when only training is performed.

(S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine and its pharmaceutically acceptable salts are prepared by the preparation method described in Patent Document 1, or It can be obtained easily by.

Milnacifran is the manufacturing method described in US patent US4478836, Venlafaxine is the manufacturing method described in UK patent GB2227743, Duloxetine is the manufacturing method described in US patent US5362886, F-98214-TA is described in Journal of Medicinal Chemistry (2003), 46 (25), 5512-5532], or the manufacturing method according to it, or can be easily obtained.

Compound A may form salts with acids in addition to hydrochlorides. Such salts are included in the present invention as long as they are pharmaceutically acceptable salts. Specifically, inorganic acids such as hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethane And organic acids such as sulfonic acid, p-toluenesulfonic acid, aspartic acid, or glutamic acid. Compound A also includes materials having various hydrates or solvates of the vitreous or pharmaceutically acceptable salts thereof, and crystal polymorphs.

The formulation of the present invention can be produced by a method commonly used using a pharmaceutical carrier, an excipient, and the like, which are usually used in the art. Administration is oral administration by tablets, pills, capsules, granules, powders, solutions, or the like, or injections such as intra-articular, intravenous, intramuscular, suppositories, eye drops, ointments, transdermal solutions, ointments, transdermal adhesives, transmucosal membranes. It may be in one form of parenteral administration with liquids, transmucosal adhesives, inhalants and the like.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, one or two or more active ingredients may be added to one or more inert diluents, such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone and / or meta It is mixed with magnesium aluminate silicate and the like. The composition may contain additives other than inert diluents, for example lubricants such as magnesium stearate or disintegrants such as calcium cellulose glycolate, stabilizers and dissolution aids, according to conventional methods. Tablets or pills may be coated with a film of sugar or gastric or enteric material, such as sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate, if necessary.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, and the like, and commonly used inert diluents such as purified water or ethanol. The liquid composition may contain, in addition to inert diluents, solubilizers, wetting agents, auxiliaries such as suspending agents, sweetening agents, flavoring agents, fragrances, and preservatives.

Injections for parenteral administration contain sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of the aqueous solution or suspending agent include distilled water for injection or physiological saline. Examples of the non-aqueous solution or suspending agent include vegetable oils such as propylene glycol, polyethylene glycol or olive oil, alcohols such as ethanol, and polysorbate 80 (Pharmacopoeia). Such compositions may also include isotonic agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers, or dissolution aids. These are sterilized by, for example, filtration through bacterial retention filters, blending or irradiation of fungicides. In addition, they may be used by preparing a sterile solid composition and dissolving or suspending it in sterile water or sterile injectable solvent before use.

Hard mucosa such as a nasal agent is used in the form of a solid, liquid or semi-solid, and can be prepared according to a conventionally known method. For example, well-known pH adjusters, preservatives, thickeners and excipients are appropriately added and molded into a solid, liquid or semisolid phase. Nasal agents are administered using conventional spraying devices, nasal vessels, tubes, or intranasal inserts and the like.

The medicament used in the present invention is administered to a patient with a functional disorder after onset of central neurological disease, preferably to a patient within 6 months immediately after onset, and administered during a period of functional recovery training (from 1 month up to 1 Years, preferably 3 months to 6 months). The daily dosage is usually about 0.01 to 1000 mg, preferably 0.1 to 300 mg / kg, more preferably 0.1 to 100 mg for oral administration, which is once a day during the functional recovery training period. Or, divided into 2 to 4 times. When administered intravenously, the daily dosage is suitably about 0.001 to 100 mg per body weight, divided once to several times daily. Dosage is appropriately determined in each case in consideration of symptoms, age, sex, and the like.

EMBODIMENT OF THE INVENTION Hereinafter, this invention is demonstrated in detail based on an Example.

<Example 1>

Evaluation of Gait Function in Cerebral Infarction Model Rats

Preparation of cerebral infarction model animals is described in J Cereb. Blood Flow Metab. 8, 474-485, 1988). Cerebral infarction was produced by occlusion of the left common carotid artery and the left middle cerebral artery using male hypertensive spontaneous onset rats (Hosino test animals) weighing 278 to 350 g at the time of surgery. Gait function is described in J. Neurotrauma 13, 293-307, 1996] was evaluated using the beam walking test and the foot fault test. The beam walking test measured the walking ability when walking on the leg of width 18mm and distance 122cm by scoring in 7 steps (normal = 7-impaired = 1). The foot fault test was performed for 2 minutes on a 53 cm × 36 cm, grid size 6.5 mm ² grid to measure the ratio of foot slip to the total number of steps of the distal forelimb. The test was carried out twice a week immediately after the production of cerebral infarction, 2, 3, 5 days after the production of cerebral infarction. Compound A and fluoxetine were administered from predose value measurement 2 days after cerebral infarction until the end of the evaluation. Compound A was administered 45 minutes before the gait function test and fluoxetine 60 minutes before. The same amount of distilled water was administered to the control group. D-amphetamine was administered intraperitoneally 60 minutes before the gait function test from 3 days to 2 weeks after cerebral infarction. The same amount of physiological saline was administered to the control group. Differences with predose values were calculated and statistical tests were performed by repeated measures two-batch variance analysis, and multiple comparisons were made when significant differences were identified. The results are shown in FIGS.

As shown in FIG. 1, in the beam walking test (a) and the foot fault test (b), Compound A showed a significant improvement over the control group (beam walking test; binary batch dispersion analysis; treatment effect P value = 0.0096, p value <0.001 of time effect, p value of alternating action = 0.021. Multiple comparison; * p <0.05, ** p <0.01 10 mg / kg vs. vehicle ), #p <0.05, ## p <0.01 (5 mg / kg vs. vehicle). Foot fault test; Binary batch variance analysis; P value of the therapeutic effect = 0.0019, p value of the time effect <0.001, p value of the alternating action = 0.022. Multiple comparisons; * p <0.05 (10 mg / kg vs. vehicle), #p <0.05, ## p <0.01 (5 mg / kg vs. vehicle)).

As shown in FIG. 2, D-amphetamine showed a significant improvement over the control group in the beam walking test (a) (two-way batch variance analysis; p value of the treatment effect = 0.0055, p value of the time effect <0.001 , P-value of alternating action <0.001.Multiple comparisons; *** p <0.001 (1.5 mg / kg vs. vehicle), #p <0.05, ## p <0.01 (0.75 mg / kg vs. vehicle ( However, the foot fault test (b) showed a tendency to improve compared to the control, but showed no significant effect.

As shown in FIG. 3, fluoxetine did not show a clear improvement compared to the control in the beam walking test (a) and the foot fault test (b).

Therefore, it was found by the test that Compound A has a recovery promoting effect superior to D-amphetamine and fluoxetine in the gait impairment caused by stroke.

<Example 2>

Forelimb function evaluation test (staincase test) in rats with cerebral infarction

Male hypertensive spontaneous onset rats (hoshino test animals) weighing 251 to 339 g were used. Forelimb function was performed in accordance with the method described in J Neurosci Methods 36, 219-228, 1991. Evaluation using a case). Rats that had previously restricted food were placed in staircases, and the function of eating foods installed in the recesses of each step of the stairs was acquired. The number of foods lifted and the number of foods fed by each of the left and right front legs were measured. After obtaining the intake function, cerebral infarction was prepared in the same manner as in Example 1. Compound A was orally administered at a dose of 5 mg / kg for 5 days a week from the next week to the 6th week, and D-amphetamine was administered intraperitoneally for 2 days a week from the week after the cerebral infarction to 6 weeks at a dose of 1.5 mg / kg. The same amount of distilled or physiological saline was administered to the control group. The test was done 60 minutes after drug administration. In the analysis of the efficacy, multiple comparisons were performed by the Dunnett method. The result is shown in FIG. As shown in FIG. 4, in the staircase test, as a result of comparing the forelimb dysfunction with the number of foods lifted (a) and the number of foods fed (b), the compound A-administered group was significantly higher than the control group. Improvement actions were identified (* p <0.05, ** p <0.01 vs. vehicle). The D-amphetamine-administered group showed an improvement tendency compared to the control group, but no significant action was confirmed.

Therefore, it was found by the test that Compound A has a recovery promoting effect superior to D-amphetamine against forelimb dysfunction due to stroke.

<Example 3>

Assessing Action on Momentum

As the number of walks in the foot fault test of Example 1, the influence on the momentum of D-amphetamine and Compound A was evaluated. The statistical test was performed by repeated measurement binary batch variance analysis, and when significant differences were found, multiple comparisons were performed by the Dunnett method. The results are shown in FIG.

As shown in Fig. 5, in the test, in the D-amphetamine-administered group, excitability was expressed during the administration period, and remarkable progression of walking number was confirmed (a) (two-way batch variance analysis; p-value of treatment effect <0.001, P value <0.001 of time effect, p value <0.001 of alternating action; multiple comparison; *** p <0.001 (1.5 mg / kg vs vehicle), ### p <0.001 (0.75 mg / kg vs. Vehicle, on the other hand, did not affect the number of walking in the Compound A-administered group (b).

Thus, it was found that in the drug expression dose, D-amphetamine simultaneously exhibits undesirable effects such as excitatory action, but Compound A does not.

<Example 4>

Evaluation of the action on the circulatory system

Heart rate was monitored after a cannula was placed in the total carotid artery using male hypertensive spontaneous onset rats (Hosino test animals) weighing 240-275 g. Compound A or D-amphetamine was administered orally and intraperitoneally, respectively, and measured until 4 hours after administration. Physiological saline was administered intraperitoneally to the control group, and measurement was similarly performed. Statistical test was repeated measurement one-way batch variance analysis, and when significant difference was confirmed, multiple comparison by binary batch Dunnett method was performed. The results are shown in FIG.

As shown in FIG. 6, in the D-amphetamine-administered group (a), significant improvement in heart rate was observed from 30 minutes to 1 hour after administration (p value = p <0.001 in a one-way batch variance analysis, multiple comparison; ** * p <0.001, * p <0.05 vs. basal value. On the other hand, the effect on heart rate was not confirmed in the compound A administration group (b) and the control group (c).

Accordingly, it was found that D-amphetamine simultaneously exhibits undesirable effects such as hyperactivity of the heart rate (circulatory effect) in the drug expression dose, but Compound A does not have such action.

In summary, compound A and fluoxetine first showed clear improvement effects of fluoxetine or more in the beam walking test and the foot fault test, as is clear from FIGS. 1 and 3. Therefore, Compound A is more useful than fluoxetine as an accelerator of functional disorder recovery after the onset of central neurological disease, and an enhancer and / or an accelerator of the functional disorder recovery training effect after the onset of central neurological disease.

In addition, for Compound A and D-amphetamine, Compound A has a drug equivalent to or greater than that of D-Amphetamine in the beam walking test, the foot fault test, and the staircase test, as apparent from FIGS. 1, 2, and 4. Could know. In addition, it was found from FIGS. 5 and 6 that D-amphetamine has the same medicament dose and at the same time has undesirable side effects such as excitatory action and hyperactivity of heart rate. Thus, Compound A has a safer area than D-amphetamine and enhances functional disability recovery training after the onset of central neuron disease after onset of a neuropathic disease, and does not exhibit side effects at a dose that exhibits efficacy, and / or enhances the effect on the recovery of the functional disorder after onset of the central nervous system It is an accelerator.

Figure 1 shows the walking function improvement effect of Compound A in the beam walking test (a) and foot fault test (b) (Example 1) (in the figure, score is the score of the beam walking test, day after MCAo is cerebral infarction production) Days later,% foot-faults is the ratio of foot slip to total steps in the foot fault test, vehicle (vehicle) represents solvent administration control).

Fig. 2 shows the action on the walking function of D-amphetamine in the beam walking test (a) and the foot fault test (b) (Example 1) (symbols in the drawing are the same as above).

Fig. 3 shows the action on the walking function of fluoxetine in the beam walking test (a) and the foot fault test (b) (Example 1) (symbols in the drawing are the same as above).

Figure 4 shows the action on the forelimb function of Compound A and D-amphetamine as the indicators of the number of foods lifted (a) and the number of foods fed (b) (Example 2) (in figure, Total number of pellets (D) is the number of foods lifted, Total number of pellets (E) is the number of foods eaten, Left Paw is the healthy forelimb, Right Paw is the disordered forelimb, V is the solvent-administered control group, Amp is the D-amphetamine group, Cpd.A represents Compound A administration group).

Fig. 5 shows the variation in the number of walking in the D-amphetamine (a) and Compound A (b) administration groups (Example 3) (No. of step in the figure shows the number of walking in the foot fault test, and other symbols Is the same as in FIG. 1).

Fig. 6 shows fluctuations in heart rate in the D-amphetamine administered group (a), Compound A administered group (b), and control group (c) (Example 4) (% Change in HR is the rate of change in heart rate, Time after dosing (hr) represents elapsed time after administration).

As described above, the present invention can be applied as a medicine, in particular, an impairment recovery accelerator after the onset of central neurological disease, and an enhancer and / or accelerator of the functional impairment recovery training effect after the onset of central neurological disease.

Claims (18)

A functional impairment recovery accelerator after central nervous system disease containing a compound that selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time, respectively. An enhancer and / or promoter for enhancing the functional disorder recovery training effect after the onset of central neurological disease, comprising as an active ingredient a compound which selectively selectively enhances neurotransmission by serotonin and neurotransmission by norepinephrine at the same time. The agent according to claim 1 or 2, wherein the central nerve disease is a stroke, brain trauma, spinal cord injury or neurodegenerative disease. The agent according to claim 3, wherein the functional disorder is a motor functional disorder, a sensory functional disorder, or a language functional disorder. Contains duloxetine, venlafaxine, milnacipran, or (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine, or a pharmaceutically acceptable salt thereof as an active ingredient Functional disorder recovery promoter after central nervous system disease outbreak. Contains duloxetine, venlafaxine, milnacipran, or (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine, or a pharmaceutically acceptable salt thereof as an active ingredient Enhancer and / or accelerator of functional impairment recovery training effect after central nervous system disease onset. The agent according to claim 5 or 6, wherein the central neurological disease is stroke, brain trauma, spinal cord injury or neurodegenerative disease. The formulation according to claim 7, wherein the functional disorder is a motor functional disorder, a sensory functional disorder, or a language functional disorder. A functional disorder recovery accelerator after central nervous system disease containing a compound having a serotonin reuptake inhibitory action and a 5-HT2A receptor antagonistic action as an active ingredient. An enhancer and / or accelerator for enhancing the functional disorder recovery training effect after the onset of central neurological disease, which contains as an active ingredient a compound having serotonin reuptake inhibitory action and 5-HT2A receptor antagonism. The agent according to claim 9 or 10, wherein the central neurological disease is a stroke, brain trauma, spinal cord injury or neurodegenerative disease. The formulation according to claim 11, wherein the functional disorder is a motor functional disorder, a sensory functional disorder, or a language functional disorder. (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient, promoting impairment recovery after central nervous system disease. (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient, functional disorder recovery training effect after the onset of central nervous system disease Enhancers and / or promoters. The agent according to claim 13 or 14, wherein the central neurological disease is a stroke, brain trauma, spinal cord injury or neurodegenerative disease. The formulation according to claim 15, wherein the functional disorder is a motor functional disorder, a sensory functional disorder, or a language functional disorder. (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient, not involving the hyperactivity or excitatory action of heart rate , Promoter for restoring motor dysfunction after stroke onset. (S) -2-[[(7-fluoro-4-indanyl) oxy] methyl] morpholine or a pharmaceutically acceptable salt thereof as an active ingredient, not involving the hyperactivity or excitatory action of heart rate , Enhancer and / or accelerator of motor function disorder recovery training effect after stroke onset.

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