Therapeutic agent and diagnostic agent for cerebral diseases of caused by mitochondrial dysfunction

FIELD: medicine.

SUBSTANCE: invention refers to a therapeutic and diagnostic agent used in treatment or diagnostics of a cerebral disease caused by a mitochondrial dysfunction, or in a method for prevention within a surgical intervention and an intravascular surgery, and also to a diagnostic technique for cerebral diseases. The therapeutic agent contains an iron compound and δ-aminolevulinic acid or its salt by formula R2R1NCH2COCH2CH2COR3 (1) where each R1 and R2 independently represents hydrogen atom, and R3 represents a hydroxyl group or C1-24 alkoxy group. The diagnostic agent contains 8-aminolevulinic acid or its salt by formula specified above. The diagnostic technique for the cerebral disease caused by mitochondrial dysfunction, involves a stage of introduction of the specified diagnostic agent followed by a stage of exposure of a diagnosed brain region to light, capable to excite protoporphyrin IX, accompanied by emission of red light, and a stage of diagnostics of the involved brain by the detected emission of red light.

EFFECT: higher diagnostic efficiency.

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The technical field to which the invention relates.

The invention relates to a therapeutic agent and a diagnostic agent for a disease of the brain caused by mitochondrial dysfunction, including for example ischemic stroke.

The level of technology

The mitochondrion is an intracellular organelle that is present in almost all eukaryotic cells and is mainly contained in an amount of from several hundred to several thousand per cell. The mitochondrion has an elongated elliptical structure, surrounded by two layers - the outer layer and inner layer. As the basic functions, it produces adenosine triphosphate (ATP), which is the energy source of the cells, through the Krebs cycle and transmission electron system and oxidative phosphorylation, uniting them both, and also plays a major role in the regulation of cell death. Believe that active oxygen is released from the mitochondria, which is the reason for the decline in cell function and cell death, and it was reported that the production of active oxygen species from mitochondria is increased in aged animals.

Although the mechanism of occurrence of Alzheimer's disease is still not clear, received information that indicate that the reduced function of the mitochondria is closely associated with skipping perception nerve in Alzheimer's disease Until now, as a brain disease caused by mitochondrial dysfunction, known, in addition to Alzheimer's disease, amyotrophic lateral sclerosis (ALS); mitochondrial diseases, such as mitochondrial encephalopathy; migraine; Parkinson's disease; Alzheimer's disease; ischemic cerebral diseases, such as ischemic stroke, hypoxic encephalopathy and cerebral arteriosclerosis; manic depression; chronic fatigue syndrome; intracranial hypertension caused by hydrocephalus and traumatic brain injury; normotensive hydrocephalus; spasm of cerebral vessels after subarachnoid hemorrhage; prevention of cerebral ischemia during surgery and endovascular surgery; and the like.

Among them, cerebral infarction accounts for 70% of stroke and cerebral stroke is the third cause of death after malignant neoplasms (cancer) and heart disease according to statistics, in 2004 and accounted for 12.5% of the total number of deaths. Cerebral infarction is classified into two types, depending on the way of blocking a blood vessel. There are cerebral thrombosis, in which a blood vessel is prone to atherosclerosis and an internal cavity gradually narrows and closes, and cerebral embolism, in which is formed a blood clot in the RDA or a large blood vessel and a blood clot travels to the brain and blocks a blood vessel in the brain. Brain cells completely killed and their recovery is not possible for the few minutes during which the blood flow is completely blocked. However, because blood from the other blood vessel(s) usually remains in the same volume, even when one vessel is blocked, the blood flow completely immediately stops. Brain cells gradually die in the field, in which poor blood flow, within a few hours due to block a blood vessel. When cerebral thrombosis, symptoms slowly progress and develop within 2-3 days in some cases, but, cerebral embolism, symptoms immediately develop and usually heavier than in the case of cerebral thrombosis. Cerebral infarction additionally classified roughly into three types for some cases. Distinguish the following three types: (1) atherothrombotic cerebral infarction, in which a large blood vessel in the neck and in the head is blocked because of arteriosclerosis, (2) lacunar infarction, which blocks small blood vessel in the brain, and (3) cardiogenic embolism of the brain where the clot formed in the heart, the atrial fibrillation (one type of arrhythmia, myocardial infarction, congenital heart disease, cardiomyopathy, etc., and reaches the brain.

In medical studies of cerebral infarction, it is important for an adequate understanding never the logical symptoms and accurate diagnosis of the site of the disease. Surface neurological research can be completed within 5 minutes the doctor, however, for more accurate diagnosis and determining appropriate treatment strategies are research such as the study of CT (computed tomography), MRI (magnetic resonance imaging), Doppler ultrasound, angiography of the brain and the study of brain blood flow. All these studies are preoperative methods of diagnosis before treatment and at the moment there is no way studies are able to assess the affected area without performing surgery.

Treatment of cerebral infarction varies depending on the type of cerebral infarction, i.e. atherothrombotic cerebral infarction, lacunar infarction or cardiogenic embolism of the brain, depending on the period of time after the disease onset and severity. As a special treat, you can mark treatment aimed at reduction of brain edema, the treatment of blood clots in a blood vessel, treatment aimed at protecting nerve cells, etc. as the most effective treatment abroad is used thrombolytic therapy (tissue plasminogen activator), but thrombolytic agent should be applied within 3 hours after the onset of cerebral and is of farcta. As thrombolytic therapy, there is a detection area where a blocked blood vessel in the brain by examining the so-called cerebral angiography and liquefaction of the clot through a catheter was inserted into the plot, but you also have to perform the method in the first 3-6 hours after the onset of cerebral infarction. In addition, in the case in which thrombolytic therapy is not applicable, there is also a treatment by administering an anticoagulant or an inhibitor of blood coagulation.

However, even when these treatments, there are cases when they can be some of the effects (impairment of consciousness, impaired motor function and perception, impaired function of the higher functions of the brain, impaired attention and emotional disturbance) due to delays in execution or execution errors and, therefore, there is a real situation in which there is not a medical agent that can cure the affected area simultaneously with thrombolytic therapy.

On the other hand, with the introduction of δ-aminolevulinic acid (ALA) or its derivatives, it is known that the derived protoporphyrin IX accumulates in tumors and is effective for intraoperative diagnosis and treatment (patent document 1 and non-patent document 1). In addition, if δ-aminol velinova acid (ALA) or its derivative is applied to the head in combination with a compound of iron, the known inhibitory effect on hair growth (patent document 2). However, nothing was reported about the activity of δ-aminolevulinic acid (ALA) or its derivative on diseases of the brain.

Patent document 1: JP-A-11-501914

Patent document 2: W02005/105022

Non-patent document 1: Nou Shinkei Geka (Cranial Nerve Surgery), 29 (11): 1019-1031, 2001

Disclosure of inventions

The goals of the invention

The aim of the invention is the provision of a therapeutic agent and a diagnostic agent for a disease of the brain caused by mitochondrial dysfunction, including, for example, cerebral infarction.

Means of solving problems

Thus, the inventors have prepared a model of occlusion of the middle cerebral artery in rats, which is an experimental model of cerebral infarction, and examined the relationship between the area of cerebral infarction and activity of mitochondria. As a result, the area of cerebral infarction activity of mitochondria was reduced to zero and the inventors hypothesized that there may be a link between dysfunction of brain cells caused by cerebral ischemia such as cerebral infarction, and activity of mitochondria.

In this regard, for the use of δ-ALA in the treatment of diseases of the brain, such as cerebral infarction, need to learn is δ-ALA through hematoencephalic the second barrier (BBB) or not. Although δ-ALA passes through the BBB in brain tumors, it is not known whether passes δ-ALA through the BBB in normal condition and in the case of cerebral infarction. When the inventors studied, passes or not δ-ALA through the BBB in normal rats and in models of cerebral infarction in rats metabolite δ-ALA, protoporphyrin IX, was confirmed specific area of cerebral infarction by introducing a δ-ALA in models of cerebral infarction in rats. On the other hand, in normal rats protoporphyrin IX were not found. Thus, the passage of δ-ALA through the BBB was not observed in the normal state, and δ-ALA passed through the BBB in the case of diseases of the brain, such as cerebral infarction, and turned into protoporphyrin only on the area of cerebral infarction in the brain tissue; as a result, it was found that δ-ALA can be used to diagnose diseases of the brain, caused by mitochondrial dysfunction, such as cerebral infarction.

In addition, if δ-ALA and connect the iron to enter after occlusion of the middle cerebral artery in a model of cerebral infarction in rats, the severity index of neurological disorders (NSS), which is an indicator of the consequences of cerebral infarction, significantly increases; thus, it was found that the combined use of the compounds useful as a therapeutic agent for a disease the brain, caused by mitochondrial dysfunction, and, therefore, the invention is executed.

Specifically, the invention includes the following options.

1. Therapeutic agent for a brain disease caused by mitochondrial dysfunction, containing:

(A) δ-aminolevulinic acid represented by the formula (1), its derivative or its salt; and

(B) a compound of iron:

where R1and R2each independently represents a hydrogen atom, alkyl group, acyl group, alkoxycarbonyl group, aryl group or aracelio group; and R3represents a hydroxyl group, CNS group, Allexinno group, alkoxycarbonyl group, aryloxyalkyl group, aryloxyalkyl group or amino group.

2. Therapeutic agent for a brain disease caused by mitochondrial dysfunction, where the connection of iron is one or two or more compounds selected from ferric chloride, iron oxide, chlorophyllin-iron sodium, ferritin iron, iron citrate, iron sodium citrate, ammonium citrate, ferrous fumarate, pyrophosphate of iron (II), pyrophosphate of iron (III), saharat iron oxide, iron acetate, oksolat iron, iron succinate, sodium citrate succinate of iron, heme forms of iron, iron dextran, iron lactate, iron gluconate, dietilentriaminpentaacetic sodium iron, diethylenetriaminepentaacetate ammonium iron, ethylendiaminetetraacetic sodium iron, ethylendiaminetetraacetic ammonium iron, Triethylenetetramine iron, sodium decarboxylation iron, decarboxylation ammonium iron, kalinovy citrate of iron formate, iron, muravlenskoe iron, ammonium oxalate, potassium iron, iron sulfate, iron sulfate, ammonium sulfate, iron, iron carbonate, iron chloride and iron oxide.

3. Therapeutic agent for a brain disease caused by mitochondrial dysfunction, where a brain disease caused by mitochondrial dysfunction, is amyotrophic lateral sclerosis, mitochondrial myopathy, migraine, Parkinson's disease, hypoxic encephalopathy, cerebral arteriosclerosis, manic-depressive psychosis, chronic fatigue syndrome, intracranial hypertension, normotensive hydrocephalus, spasm of cerebral vessels after subarachnoid hemorrhage, prevention of cerebral ischemia during surgery and endovascular surgery, atherothrombotic cerebral infarction, lacunar infarction, cardiogenic embolism of the brain or Alzheimer's disease.

4. Diagnostic agent for diseases MRSA due to mitochondrial dysfunction, which contains δ-aminolevulinate is islote, represented by formula (1), its derivative or its salt:

where R1and R2each independently represents a hydrogen atom, alkyl group, acyl group, alkoxycarbonyl group, aryl group or aracelio group; and R3represents a hydroxyl group, CNS group, Allexinno group, alkoxycarbonyl group, aryloxyalkyl group, aryloxyalkyl group or amino group.

5. Diagnostic agent for diseases of the brain, caused by mitochondrial dysfunction, where a brain disease caused by mitochondrial dysfunction, is amyotrophic lateral sclerosis, mitochondrial myopathy, migraine, Parkinson's disease, hypoxic encephalopathy, cerebral arteriosclerosis, manic-depressive psychosis, chronic fatigue syndrome, intracranial hypertension, hydrocephalus at normal pressure, spasm of cerebral vessels after subarachnoid hemorrhage, prevention of cerebral ischemia during surgery and endovascular surgery, atherothrombotic cerebral infarction, lacunar infarction, cardiogenic embolism of the brain or Alzheimer's disease.

In addition, the invention includes the following options.

6. A method of treating diseases of the brain, caused mitochondri the social dysfunction, which contains the introduction:

(A) δ-aminolevulinic acid represented by the formula (1), its derivative or a salt thereof, and (C) iron compounds in effective amounts:

where R1and R2each independently represents a hydrogen atom, alkyl group, acyl group, alkoxycarbonyl group, aryl group or aracelio group; and R3represents a hydroxyl group, CNS group, Allexinno group, alkoxycarbonyl group, aryloxyalkyl group, aryloxyalkyl group or amino group.

7. Method for the diagnosis of brain disease caused by mitochondrial dysfunction, which contains the introduction of δ-aminolevulinic acid represented by the formula (1), its derivative or a salt thereof in an effective amount:

where R1and R2each independently represents a hydrogen atom, alkyl group, acyl group, alkoxycarbonyl group, aryl group or aracelio group; and R3represents a hydroxyl group, CNS group, Allexinno group, alkoxycarbonyl group, aryloxyalkyl group, aryloxyalkyl group or amino group.

8. Method for the diagnosis of brain disease caused by mitochondrial dysfunction, which contains:

introduction the definition of δ-aminolevulinic acid, represented by formula (1), its derivative or a salt thereof, and (B) compounds of iron,

taking part of the brain tissue from the analyte,

the processing part of the brain tissue coloring agent, active mitochondria, and

assessment of the activity of mitochondria in painted condition:

where R1and R2each independently represents a hydrogen atom, alkyl group, acyl group, alkoxycarbonyl group, aryl group or aracelio group; and R3represents a hydroxyl group, CNS group, Allexinno group, alkoxycarbonyl group, aryloxyalkyl group, aryloxyalkyl group or amino group.

9. Method for the diagnosis of brain disease caused by mitochondrial dysfunction, according to the above 8, wherein the coloring agent is active for mitochondria is TTC (2,3,5-triphenyltetrazolium chloride).

10. Application (A) δ-aminolevulinic acid represented by the formula (1), its derivative or a salt thereof, and (B) compounds of iron for the preparation of therapeutic agent for a brain disease caused by mitochondrial dysfunction:

where R1and R2each independently represents a hydrogen atom, alkyl group, acyl group, alkoxycarbonyl group, aryl group or aralkyl the group; and R3represents a hydroxyl group, CNS group, Allexinno group, alkoxycarbonyl group, aryloxyalkyl group, aryloxyalkyl group or amino group.

In this regard, therapeutic agent for a brain disease caused by mitochondrial dysfunction, the invention includes a composition for treating brain diseases due to mitochondrial dysfunction.

Advantages of the invention

In accordance with the diagnostic agent for diseases of the brain, caused by mitochondrial dysfunction, inventions, the affected area can be accurately determined by observation of the presence of red light emission that occurs when the excitation light, in the case of urgent care in diseases of the brain, such as cerebral infarction, e.g., during the operation. In addition, in accordance with a therapeutic agent for a brain disease caused by mitochondrial dysfunction, inventions, by introducing him after the onset of cerebral infarction, in particular using it in combination with thrombolytic therapy or similar, you can avoid consequences such as impaired consciousness, impaired motor function and perception, impaired function of the higher functions of the brain, impaired attention and emotional disturbance.

A brief description of what the blueprints

Figure 1 is a figure showing the change in the index of severity of neurological disorders (NSS index) on the model of cerebral infarction in rats.

Figure 2 is a figure showing the result of staining with TTC brain tissue in models of cerebral infarction in rats.

Figure 3 is a figure showing changes of indexes of the severity of neurological disorders in the group, which was introduced δ-ALA and the composition of iron, and in the group that was injected with saline, using a model of cerebral infarction in rats.

Figure 4 is a figure showing change of mass of a body in the group, which was introduced δ-ALA and the composition of iron, and in the group that was injected with saline, using a model of cerebral infarction in rats.

The best way of carrying out the invention

(A) δ-ALA or its derivative for use in therapeutic agent and a diagnostic agent for a brain disease of the invention represented by the above formula (1). In the formula (1), as the alkyl groups represented by R1and R2preferred is a linear or branched alkyl group having 1-24 carbon atoms, most preferred is an alkyl group having 1-18 carbon atoms, and particularly preferred is alkyl, y is the SCP, having 1-6 carbon atoms. As alkyl groups having 1-6 carbon atoms, can be mentioned methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group and the like. As the acyl group, preferred is a linear or branched alcoolica group having 1-12 carbon atoms, alkenylamine group or arolina group and alcoolica group having 1-12 carbon atoms is particularly preferred. As the acyl group, you can specify a formyl group, acetyl group, propionyl group, butyryloxy group, etc. as alkoxycarbonyl group, it is preferable alkoxycarbonyl group having 2-13 carbon atoms in total, and alkoxycarbonyl group having 2-7 carbon atoms, in particular is preferred. As alkoxycarbonyl group, can be mentioned methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group and the like. As the aryl group, the aryl group having 6-16 carbon atoms is preferred and may be mentioned, for example, phenyl group, aftilova group and the like. As Kilkenny group, preferred is a group, included aryl group, having 6-16 carbon atoms, and the above-mentioned alkyl groups having 1-6 carbon atoms, and may be, for example, benzyl group and the like.

As CNS group represented by R3preferred is a linear or branched CNS group having 1-24 carbon atoms, most preferred is a CNS group having 1-16 carbon atoms, and CNS group having 1-12 carbon atoms is particularly preferred. As CNS group, can be mentioned methoxy group, ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, sec-butoxy group, tert-butoxy group, n-pentyloxy group, isopentylamine group, neopentylene group, tert-pentyloxy group, 2-methylbutoxy group, n-hexyloxy group, isohexyl group, 3-methylpentylamino group, ethylbutyrate group, cyclohexyloxy group, octyloxy group, decyloxy group, dodecyloxy group and the like. As Allexinno group, linear or branched, alkanoyloxy group having 1-12 carbon atoms is preferred, alkanoyloxy group having 1-6 carbon atoms is particularly preferred. As acyloxy group, it can be noted acetoxy group, propionyloxy group, butyryloxy group and the like. As a researcher is as alkoxycarbonylmethyl group, alkoxycarbonylmethyl group having 2-13 carbon atoms in total is preferred, and alkoxycarbonylmethyl group having 2-7 carbon atoms, in particular is preferred. As alkoxycarbonyl group may be noted methoxycarbonylamino group, ethoxycarbonyl group, n-propoxycarbonyl group, isopropoxycarbonyl group and the like. As Allexinno group, arrochela group having 6-16 carbon atoms is preferred and can be mentioned, for example, phenoxy group, naphthyloxy group and the like. As Allexinno group, a group having the above aracelio group is preferred and can, for example, benzyloxy group and the like.

In the formula (1), as R1and R2the hydrogen atom is preferred. As R3, a hydroxyl group, CNS group or arrochela group is preferred, a hydroxyl group or CNS group having 1-12 carbon atoms is preferable, and a methoxy group or hexyloxy group in particular is preferred.

As a derivative of δ-ALA, the most preferred is the methyl ether of δ-aminolevulinic acid, ethyl ester δ-aminolevulinic acid, profileviewer δ-aminolevulinic acid, butyl ether of δ-aminolevulinic acid, pentalogy ether δ-aminolevulinic acid hexyl ester δ-aminolevulinic acid or the like, and particularly preferred is a methyl ether of δ-aminolevulinic acid or hexyl ester δ-aminolevulinic acid.

Salt of δ-ALA or its derivative is not specifically limited, but is preferred pharmaceutically suitable salt of the accession of the acid with an inorganic acid or an organic acid. As the salt of the merger with inorganic acid, it can be noted cleaners containing hydrochloride salt, hydrobromide salt, sulfate salt, nitrate salt, a phosphate salt and the like and as the salt of the merger with organic acid, it can be noted acetate salt, lactate salt, citrate salt, a salt of tartaric acid, succinate salt, maleato salt, fumaric salt, ascorbate salt and the like. In particular, the hydrochloride of δ-aminolevulinic acid or phosphate δ-aminolevulinic acid is preferred.

δ-ALA, its derivative and its salt can be obtained by any method of chemical synthesis, and methods using microorganisms and enzymes. For example, they can be obtained by methods described in JP-A-4-9360, JP-T-11-501914, JP-A-2006-182753, JP-A-2005-314361 and JP-A-2005-314360.

In therapeutic agent for the treatment of diseases grown the th brain according to the invention, (A) the above δ-ALA, its derivative or its salt and (B) a compound of iron are used in combination, but for the diagnostic agent may include a compound of iron. The composition of iron is not limited to a particular way and may, for example, include, for example, iron chloride, iron oxide, chlorophyllin-iron sodium, ferritin iron, citrate of iron, sodium, iron citrate, ammonium citrate, ferrous fumarate, pyrophosphate of iron (II), pyrophosphate of iron (III), saharat iron oxide, iron acetate, oksolat iron, iron succinate, sodium citrate succinate of iron, heme iron, iron dextran, iron lactate, iron gluconate, diethylenetriaminepentaacetate sodium iron, diethylenetriaminepentaacetate ammonium iron, ethylendiaminetetraacetic sodium iron, ethylendiaminetetraacetic ammonium iron Triethylenetetramine iron, decarboxylation sodium iron decarboxylation ammonium iron, kalinovy citrate of iron formate, iron, muravlenskoe iron, ammonium oxalate, potassium iron, iron sulfate, iron sulfate, ammonium sulfate of iron, carbonate of iron, ferric chloride and ferric oxide. In particular, it is preferable citrate, ferrous fumarate, iron pyrophosphate, saharat iron oxide or iron dextran.

Diagnostic agent for diseases of the brain may contain (a) above is annoy δ-ALA, its derivative or its salt and (B) a compound of iron, which can be used in combination. In addition, therapeutic agent for a brain disease of the invention is distinguished by the content of the component (a) and component (B). These components (a) and (b) may be included in a single composition (preparation), but can be used as two types of agents, i.e. as a composition (preparation)containing the component (A)and composition (preparation)containing the component (B).

The diagnostic agent and a therapeutic agent for a brain disease of the invention can be obtained by mixing (A) above δ-ALA, its derivative or its salt with a pharmaceutically suitable carrier, in accordance with the traditional way. As forms of agents, it can be noted compositions for oral administration, such as granules, pellets or tablets; compositions for injection, such as liquids or powders, for which application must be dissolved; formulations for subcutaneous administration such as ointments, liquids, creams and gels;

suppositories; and the like. As (V) compounds of iron, it can be noted, the compositions for oral dosage forms such as granules, fine granules, tablets or capsules; compositions for injection, such as liquids or powders, for which application must be dissolved; compositions for subcutaneous is doing, such as ointments, liquids, creams and gels; suppositories; and the like. In addition, agents can be any of the above forms containing these components (a) and (B).

Diseases of the brain, which represent targets that are sent to a diagnostic agent and a therapeutic agent for a brain disease of the invention are any diseases resulting from the dysfunction of mitochondria and may constitute, for example, amyotrophic lateral sclerosis, mitochondrial myopathy, migraine, Parkinson's disease, hypoxic encephalopathy, cerebral arteriosclerosis, manic-depressive psychosis, chronic fatigue syndrome, intracranial hypertension, normotensive hydrocephalus, spasm of cerebral vessels after subarachnoid hemorrhage, prevention of cerebral ischemia during surgery and endovascular surgery, atherothrombotic cerebral infarction, lacunar infarction, cardiogenic embolism of the brain or Alzheimer's disease. Of them atherothrombotic cerebral infarction, lacunar infarction, cardiogenic embolism of the brain or Alzheimer's disease is particularly preferred. The more it is necessary to reduce the activity of mitochondria, the more agents are suitable. Namely, it is preferable to use agents in acute is the phase of cerebral infarction.

As way of introduction of δ-ALA or salt or its derivative in the composition of the diagnostic agent and a therapeutic agent for a brain disease of the invention, it can be noted oral administration, intravenous administration, intramuscular injection, topically applying to the affected area, intraperitoneal administration, subcutaneous administration, perfectline introduction and such, while intraperitoneal injection, oral administration, local application on the affected area or intravenous administration is preferred. As way of introduction, (C) compounds of iron in the composition of the diagnostic agent and a therapeutic agent for a brain disease of the invention, it can be noted oral administration, intravenous administration, intramuscular administration, local application on the affected area, intraperitoneal administration, subcutaneous administration, perfectline introduction and such, while intraperitoneal injection, oral administration, local application on the affected area or intravenous administration is preferred.

Dosage (A) δ-ALA or salt or its derivative in the composition of the diagnostic agent and a therapeutic agent for a brain disease of the invention differs depending on the method of administration, route of administration, symptoms and body weight. In the case of oral administration, dosiro the amounts from 0.001 mg to 10 g, preferably from 0.01 to 1000 mg, and most preferably from 1 to 300 mg per kg of body weight per dose. Dosage (C) compounds of iron in the composition of the diagnostic agent and a therapeutic agent for a brain disease of the invention differs depending on the method of administration, route of administration, symptoms and body weight. In the case of oral administration, the dosage is from about 0.001 mg to 10 g, preferably from 0.01 to 1000 mg, and most preferably from 0.1 to 100 mg per kg of body weight per dose.

The period of introduction of therapeutic agent for a brain disease of the invention are not specifically limited, as manifestations of any therapeutic effect and may be suitable determined depending on the type of disease of the brain, sex, body weight, symptoms and method of administration. For example, in the case where therapeutic agent for a brain disease of the invention is applied during the acute stage of cerebral infarction, the period of introduction is not limited, but the agent is preferably introduced within 24 hours from the beginning of the attack, more preferably injected within 6 hours from the start of the attack, and most preferably is introduced for 3 hours. In addition, for a therapeutic agent for a brain disease of the invention, it is preferable to begin implementation as soon as possible from the beginning of the disease and is preferable to the introduction of the agent in the same day and continue although it depends on the state of recovery, for 2 or more days.

Therapeutic agent for a brain disease of the invention based on the findings by the present inventors that, for diseases of the brain, (A) δ-ALA, its derivative or its salt passes through the blood-brain barrier (EBB), accumulates in the mitochondria of brain cells and is converted into protoporphyrin IX on the lesion. It is known that protoporphyrin IX is excited by the exciting light, emitting red light. Therefore, the area where there is a red light by irradiation of exciting light after the introduction of the component (A) can be diagnosed as affected area of the brain. On the other hand, areas that are not subjected to brain disease, do not change color to red. If the affected area of the brain can be diagnosed during surgery, the treatment may be selectively applied to the damaged area of the brain.

Exciting light can have any wavelength, able to observe a red light, based on the excitation of protoporphyrin IX on the site of the disease, and the light having a wavelength of from 350 to 500 nm is preferred, and most preferred is a light with a wavelength of 390 to 420 nm.

The wavelength of the observed red light is 500-800 nm, preferably 600-700 nm.

Methods for the detection of red light, emitted from protoporphyrin IX instituted a stimulating light in a special way is not limited, and, for example, detection can be carried out visually. Also possible is the detection of red light using a detector.

After the introduction of a diagnostic agent for a brain disease of the invention, the time for the irradiation of the stimulating light during the operation varies depending on the method of administration and condition of the fabric, but is preferably from 0.1 to 10 hours, when the porphyrins reach maximum content, and is especially approximately from 0.5 to 5 hours.

In therapeutic agent for a brain disease of the invention, the reason why a brain disease caused by mitochondrial dysfunction, can be treated by the combined use of (A) δ-ALA, its derivative or its salt and (β) compounds of iron, is not clear, but we can assume that δ-ALA accumulates in the area of diseases of the brain and is converted into protoporphyrin IX and protoporphyrin IX forms a complex with iron on the affected area of the brain from functioning as hemoglobin and cytochrome. Thus, the activity of mitochondria is significantly enhanced and, as a result, presumably cellular damage on the affected area of the brain is restored.

So the m way when therapeutic agent for a brain disease of the invention is used in the acute stage of cerebral infarction, it is preferable to use it in combination with a medical agent that is used for the treatment of cerebral infarction in the acute phase. As a medical agent can be noted thrombolytic agents such as tissue plasminogen activator (t-PA), urokinase, and streptokinase; anticoagulants, such as heparin and warfarin; antithrombotic agents such as aspirin, ticlopidin, ozagrel sodium, and Cilostazol; blood-thinning agents such as low molecular weight dextran; antithrombine agents, such as argatroban; agents against swelling of the brain, such as glycerol and mannitol; agents that protect the brain, such as edaravone; and the like. Of them combined use with thrombolytic agent particularly suitable in connection with reperfusion of blood flow at the site of cerebral infarction and access therapeutic agent for a brain disease of the invention to the site of cerebral infarction.

In addition, in the invention it is possible to diagnose diseases of the brain, caused by mitochondrial dysfunction, by staining with a solution of TTC (2,3,5-triphenyltetrazolium chloride), which is a coloring agent that is active for mit is Hendry.

Namely, the area affected by brain disease caused by mitochondrial dysfunction, can be determined by taking the part of the brain tissue of the analyte, its staining with TTC solution, analysis of the pattern of the cut surface and to evaluate the area, which is painted red and experiencing the activity of mitochondria, and the area that whitewashing (not dyed red) and in which there is activity of mitochondria.

To take part, capable of staining, preferably prepare the cut. The slice can be obtained by the usual method.

The concentration of the solution TTC, time staining and temperature in the diagnosis of brain disease caused by mitochondrial dysfunction, may be suitable determined so that it becomes possible to normal diagnostics. For example, the concentration of TTC solution is from 0.1 to 5%, preferably from 0.5 to 3%, and particularly preferably from 1.5 to 2.5%.

Time staining (incubation) TTC solution is from 0.1 to 4 hours, preferably from 10 to 60 minutes and particularly preferably from 20 to 40 minutes.

In addition, the temperature for staining with TTC solution is from 25 to 50°C, preferably from 30 to 45°C and particularly preferably from 35 to 39°C.

The method of detecting the staining in red and white color (not dyed red) special education is not limited, and the detection may for example, be performed visually.

In accordance with a therapeutic agent for a brain disease of the invention, as an index of the severity of neurological disorders significantly increased, even when the agent is introduced after the formation of cerebral infarction, it is assumed that the neurological symptoms that will develop as consequences, such as impaired consciousness, impaired motor function and perception, impaired function of the higher functions of the brain, impaired attention and emotional disturbance can be avoided with the introduction particularly in the acute stage of cerebral infarction.

Examples

The following describes the invention more in detail with reference to examples, but the invention is not restricted by them.

Example 1

(Preparation of models of cerebral infarction in rats)

Nylon thread having a diameter of 1.5 mm, was placed in the right middle cerebral artery 7-week-old rats-females line Wister and the blood flow was stopped after 2 hours. Then, nylon thread cleaned with getting models occlusion of the middle cerebral artery (models of cerebral infarction in rats). (Confirmation model of cerebral infarction in rats)

The prepared model occlusion of middle cerebral artery in rats was evaluated in accordance with NSS (Indices of severity of neurological disorders) is before cooking, immediately after preparation (day 0) and on day 1, day 3, day 5, day 7, day 10 and day 14. As shown in figure 1, it was confirmed that the prepared model rats (6 rats) demonstrates cerebral infarction severe.

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Table 1
Indices of severity of neurological disorders (NSS)Index
The test motor activity
When the rat lifted its tail,3
1 rat bends forepaw
1 rat flexes the hindlimb
1 rat moves his head in a perpendicular direction within 30 seconds (>10 seconds)
When a rat is placed on a horizontal surface (normal=0; maximum=3),3
0 rat normal moves
1 rat may not move right
2 rat is rejected on the paralyzed side
3 rat falls on the paralyzed side2
Test sensitivity
1 stereotactic test (visual control and activity)
2 test for inborn perception (deep sensitivity, the limb is clamped against the corner of the table to irritation of the muscles of the limb)6
Test gymnastic balance beam (normal=0; maximum=6),
0 rat balances in a stable position
1 rat grabs the side of a log
2 rat caught the beam and one limb descends from logs
3 rat caught the beam and two limbs descend from logs or turn on the log (>60 seconds)
4 rat intends to balance on the beam but falls off (>40 CE is und)
5 rat is going to balance on the beam but falls off (>20 seconds)
6 rat falls: the rat has no intention of balance, nor to cling to the log (<20 seconds)
Absence of reflex and impaired motor function
1 auditory reflex (when affect auditory canal, rat shakes his head)
1 corneal reflex (when lightly touching the cornea, rat blinking an eye)
1 reflex escape from danger (motor response to short noise from tapping folders for papers)18
1 stroke, mioclauniei, muscle dystonia

The maximum index

When the rat is unable to perform the job or missing test reflex is given a single index.

13-18 index: severe impairment; 7-12 index: secondary violation; 1-6: light violation

(Fluorescent observation area damaged brain using hydrochloride δ-aminolevulinic acid)

After 6 hours, 12 hours, 24 hours and 42 hours after preparation of the model occlusion of middle cerebral artery in rats, hydrochloride δ-aminolevulinic acid was dissolved in physiological saline and intraperitoneally injected individual rats in the 100 mg/kg of body weight of the rat. 4 hours after injection, the inner part of the brain was irradiated for fluorescence excitation at a wavelength of 405 nm and watched the red light area on each model. It was confirmed that the δ-ALA is metabolized and converted into protoporphyrin IX. In addition, it was confirmed that the area of the red light was in the area of cerebral infarction. A similar experiment was performed with normal rats, but the plot of the red light was not confirmed, even when the irradiation of the internal side of the brain with fluorescence excitation at a wavelength of 405 nm. Therefore, it was shown that the diagnostic agent for a brain disease of the invention is a diagnostic agent, able to clearly distinguish diseased tissue from normal tissue during surgery. (Confirmation of activity of mitochondria)

After you confirm the model of cerebral infarction in rats, based on NSS, the rat was decapitated and immediately took out the brain. The brain was cut into equal parts, having a thickness of 2-3 mm, by means of a razor. The slice was incubated in a 2% solution of TTC (2,3,5-trifinite Rosalia hydrochloride), which is a coloring agent, active against mitochondria at 37°C for 30 minutes and immediately took a photograph of the cut surface for recording zone of infarction. It is evident from Fig. 2 it follows that the area that has the activity of mitochondria, was painted red and the area that does not have sufficient activity of mitochondria, had a white color. Thus, it was confirmed that the area where there was occlusion of the right middle cerebral artery, had a white color.

Example 2

Using the model of temporary occlusion of the right middle cerebral artery in rats, prepared in example 1 was compared in two groups, namely, 1) the group were injected intraperitoneally δ-ALA immediately after occlusion in the amount of 100 mg per kg body weight and 2 hours intravenously injected saharat iron oxide (trade name: FESIN) in an amount of 2 mg per kg of body weight (3 rats), and 2) group, which is directly after occlusion were injected intraperitoneally with saline solution and after 2 hours intravenously injected with saline (3 rats).

Before training the model, 3 hours, 1 day, 3 days, 5 days and 7 days after preparation, assessing the NSS and the measurement of body weight for each rat. As shown in figure 3, the NSS was increased from 6 to 8 indexes after 3 days and progressed thereafter in 1) group compared with 2) group. In addition, regarding the additional mass body, it was not observed significant difference between the two groups (figure 4). Based on the above results, we confirmed the effect hydrochloride δ-aminolevulinic acid and iron compounds as a therapeutic agent for a brain disease caused by mitochondrial dysfunction.

Although the invention is described in detail and provides links to specific embodiments, those skilled in this field it is obvious that various changes and modifications can be made, without departing from the nature and scope of the invention.

The present invention is based on Japanese patent application No. 2007-099508 filed April 5, 2007, and the contents are incorporated herein by reference.

Industrial applicability

In accordance with the diagnostic agent for diseases of the brain, caused by mitochondrial dysfunction, of the invention, the site of the disease can be determined by visual observation of the presence of red light by irradiation of exciting light, if necessary, with brain diseases such as cerebral infarction, e.g., during surgery. In addition, in accordance with a therapeutic agent for a brain disease caused by mitochondrial dysfunction, inventions, by introducing him after the onset of cerebral infarction, especially the items in combination with thrombolytic agent, or the like, you can avoid consequences such as impaired consciousness, impaired motor function and perception, impaired function of the higher functions of the brain, impaired attention and emotional disturbance.

1. therapeutic agent used in the treatment of brain diseases due to mitochondrial dysfunction, or in the way to prevent cerebral ischemia during surgery and endovascular surgery, comprising:
(A) δ-aminolevulinate acid of formula (1) or its salt:

where R1and R2each independently represents a hydrogen atom and R3represents a hydroxyl group or a C1-24CNS group and
(B) a compound of iron.

2. therapeutic agent according to claim 1 where the compound of iron is one, or two or more compounds selected from ferric chloride, iron oxide, chlorophyllin-iron sodium, ferritin iron, iron citrate, iron sodium citrate, ammonium citrate, ferrous fumarate, pyrophosphate of iron (III)pyrophosphate of iron (II), saharat iron oxide, iron acetate, oksolat iron, iron succinate, sodium citrate succinate of iron, heme forms of iron, iron dextran, iron lactate, iron gluconate, Diethylenetriamine-pentaacetate sodium iron, diethylenetriaminepentaacetate ammonium iron, ethylene-diaminetetraacetate sodium W is found ethylendiaminetetraacetic ammonium iron, Triethylenetetramine iron, sodium decarboxylation iron, decarboxylation ammonium iron, halinowego citrate of iron formate, iron, moravcikova iron, ammonium oxalate, potassium iron, iron sulfate, iron sulfate, ammonium sulfate of iron, carbonate of iron, ferric chloride and ferric oxide.

3. therapeutic agent according to claim 1 or 2, where a brain disease caused by mitochondrial dysfunction represents amyotrophic lateral sclerosis, mitochondrial myopathy, migraine, Parkinson's disease, hypoxic encephalopathy, cerebral arteriosclerosis, manic-depressive psychosis, chronic fatigue syndrome, intracranial hypertension, normotensive hydrocephalus, spasm of cerebral vessels after subarachnoid hemorrhage, atherothrombotic cerebral infarction, lacunar infarction, cardiogenic embolism of cerebral vessels or Alzheimer's disease.

4. Application (A) δ-aminolevulinic acid of formula (1) or a salt thereof:

where R1and R2each independently represents a hydrogen atom and R3represents a hydroxyl group or a C1-24CNS group, and
(C) compounds of iron to obtain a therapeutic agent for use according to claim 1 or 3.

5. Diagnostic agent used in the method for the diagnosis of brain disease caused by mitochondrial dysfunction, containing δ-aminolevulinate acid of formula (1), its salt:

where R1and R2each independently represents a hydrogen atom and R3represents a hydroxyl group or a C1-24CNS group and
where the method for the diagnosis of brain disease caused by mitochondrial dysfunction, includes a step of introducing a specified diagnostic agent, and after the introduction stage of the exposure detection area of the brain light that can cause the excitation of protoporphyrin IX, followed by the emission of red light, detecting the emission of red light and diagnosis of brain injury on the detected emission of red light.

6. The agent according to claim 5, where the brain disease caused by mitochondrial dysfunction is selected from amyotrophic lateral sclerosis, mitochondrial myopathy, migraine, Parkinson's disease, hypoxic encephalopathy, cerebral arteriosclerosis, manic-depressive psychosis, chronic fatigue syndrome, intracranial hypertension, normotensive hydrocephalus, spasm of cerebral vessels after subarachnoid hemorrhage, atherothrombotic cerebral infarction, lagunare the heart attack, cardiogenic embolism of cerebral vessels or Alzheimer's disease.

7. Method for the diagnosis of brain disease caused by mitochondrial dysfunction, using the diagnostic agent according to claim 5 or 6, including:
- stage introduction of the specified diagnostic agent and after the introduction
- stage exposure detection area of the brain light that can cause the excitation of protoporphyrin IX, followed by the emission of red light, detecting the emission of red light and diagnosis of brain injury on the detected emission of red light,
where a brain disease caused by mitochondrial dysfunction is selected from amyotrophic lateral sclerosis, mitochondrial myopathy, migraine, Parkinson's disease, hypoxic encephalopathy, cerebral arteriosclerosis, manic-depressive psychosis, chronic fatigue syndrome, intracranial hypertension, normotensive hydrocephalus, spasm of cerebral vessels after subarachnoid hemorrhage, atherothrombotic cerebral infarction, lacunar infarction, cardiogenic embolism of cerebral vessels or Alzheimer's disease.



 

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16 cl, 6 tbl, 6 ex, 2 dwg

FIELD: chemistry.

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11 cl, 38 ex, 3 tbl

FIELD: medicine, pharmaceutics.

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3 ex

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39 cl, 19 dwg

FIELD: medicine, pharmaceutics.

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12 cl, 13 ex, 2 dwg, 5 tbl

FIELD: medicine, pharmaceutics.

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23 cl, 32 tbl, 137 ex

FIELD: chemistry.

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9 cl, 59 ex, 1 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula

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14 cl, 18 ex, 15 tbl, 2 dwg

FIELD: medicine.

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2 ex, 3 tbl

FIELD: medicine.

SUBSTANCE: claimed are method of reducing in circulating blood of LDL-cholesterol, triglycerides, total cholesterol and their mixtures, including introduction of efficient amount of one or more phosphate derivatives of one or more electron-transfer agents, which represent monotocopheryl phosphate, dotocopheryl phosphate, monotocotrienyl phosphate, ditocotrienyl phosphate and their mixtures, their application for relief of symptoms, treatment and/or prevention of disease, selected from group which consists of chronic renal failure, primary and secondary hyperemias and dislipemia, retinopathy, enlargement of liver and spleen, xanthomas and their combinations by reduction of lipid content in circulating blood.

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5 cl, 3 dwg, 5 tbl, 2 ex

FIELD: medicine.

SUBSTANCE: claimed invention relates to medicine. Described is composition for transcutaneous absorption of denepezil or its hydrochloride. Composition for transcutaneous absorption includes 2-[(1-benzyl-4-pyperidinyl)methyl]-5,6-dimethoxyindan-1-on and/or its hydrochloride and chloride of metal in layer of adhering under pressure glue preparation, which was subjected to linking.

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10 cl, 12 ex

FIELD: chemistry.

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22 cl, 1 tbl, 3 ex, 3 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to derivatives of 5-amino-3-(2-nitroxipropyl)-1,2,4-thiadiazoles of general formula , where R1, R2 can be similar or different and independently represent hydrogen, substituted or non-substituted aryl or heteroaryl or aralkyl, alkyl, cycloalkyl, and R1 + R2 can represent heteroaryl (optionally substituted piperasin and piperidin).

EFFECT: obtained are novel compounds, which can be applied in medicine for treatment of neurodegenerative diseases.

1 cl, 3 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed group of inventions relates to medicine, namely to neurosurgery and biotechnology, and can be used for cultivation of nerve stem cells of mammal, excluding embryonic human cells, and for treatment of spasticity, rigidity, spinal cord or amniotrophic state in subject, requiring such treatment. For cultivation of said cells preliminarily incubated in culture vessel is solution, which contains poly-D-lysine in concentration from 0.1 mkg/ml to 1 mg/ml during from 5 minutes to 3 hours. After that, culture vessel is rinsed and dried. Nerve stem cells are inoculated into said culture vessel without serum. After that, solution of fibronectin and, at least, one mitogen is added into culture vessel and nerve stem cells are cultivated without serum. Then, cultivated nerve stem cells are passed until fusion. For treatment of said states nerve stem cells, cultivated be claimed method, are concentrated. Therapeutically efficient amount of said concentrated nerve stem cells is introduced into region of patient's central nervous system tissue with decreased level of GABA-producing or glycin-producing neurons.

EFFECT: group of inventions ensures efficient method of cultivating mammalian nerve stem cells, excluding embryonic human cells, which makes it possible to achieve in vitro higher degree of neuronal differentiation to the level sufficient for treatment of said states and improvement of survival in vivo of such cells, as well as efficient treatment of spasticity, rigidity or amniotrophic state in subject due to introduction into their central nervous system tissues with lower level of GABA-producing or glycin-producing neurons of cells, able to differentiate into sufficient number of GABA-producing or glycin-producing neurons in said tissue.

10 dwg, 7 ex

FIELD: chemistry.

SUBSTANCE: invention relates to a compound of formula (I), in which X denotes N or CR3, M denotes (CH2)m; m equals 0 or 1, R1 denotes H or lower alkyl which can be substituted with a group selected from a group consisting of mono- or di-lower alkylamino and -O-lower alkyl, R2 denotes H or lower alkyl, R3 denotes H or lower alkyl substituted with a group selected from a group consisting of halogen, mono- or di-lower alkylamino and cyclic amino, R41 denotes H or pyridine which can be substituted with a cyano group, R42 denotes a bridged polycyclic hydrocarbon or a bridged azacyclic hydrocarbon, each of which can be substituted, R5 denotes a group selected from a group consisting of halogen, cyano, lower alkyl-carbonyl, lower alkyl-oxycarbonyl, hydroxycarbonyl, formyl, amidinooxycarbonyl, guanidinooxycarbonyl, guanidino, carbamoyl, -C(=O)-5- or -6-member heterocycloalkyl, -C(=O)-5- or -6-member heteroaryl, lower alkyl, lower alkenyl, -O-lower alkyl, 5- or 6-member heterocycloalkyl and 5-member heteroaryl, each of which can be substituted, provided that when R5 denotes a 5-member heteroaryl, X denotes -CR3; or R41 and R15 can be bonded through a defined functional group to form divalent groups shown below: (I-A) (I-B) or (I-C), in which RA denotes H or acyl, which can be substituted, provided that the term "substituted" with respect to R4 and/or R5 denotes substitution with one or more substitutes selected from a group comprising the following substitutes: (a). halogen; (b) -OH, -O-R2, -O-phenyl, -OCO-RZ-OCONH-RZ oxo (=O); (c) -SH, -S-R2, -S-phenyl, -S-heteroaryl, -SO-R2, -SO-phenyl, -SO-heteroaryl, -SO3H, -SO2-RZ, -SO2-phenyl, - SO2-heteroaryl, sulphamoyl, which can be substituted with one or two RZ groups; (d) amino, which can be substituted with one or two RZ groups, -NHCO-RZ, -NHCO-phenyl, -NHCO2-RZ, -NHCONH2, -NHCONH-RZ, -NHSO2-R0, -NHSO2-phenyl, -NHSO2NH2, -NO2, =N-O-RZ; (e) -CHO, -CO-RZ, -CO2H, -CO2-RZ, carbamoyl, which can be substituted with one or two RZ groups, -CO-cyclic amino, -COCO-RZ, cyano; (f) RZ; (g) phenyl, which can be substituted with one or more groups selected from substitutes described above in paragraphs from (a) to (f), a 5- or 6-member heterocycloalkyl, a 5- or 6-member heteroaryl, a 5- or 6-member heterocycloaryl; or pharmaceutically acceptable salts thereof. The invention also relates to a method of producing compounds of formula II, a pharmaceutical composition based on said compounds which is a Janus kinase 3 inhibitor, a method of treating and/or preventing different immunopathological diseases, including autoimmune diseases, inflammatory diseases and allergic diseases.

EFFECT: novel compounds are obtained and described, which can be used as an active ingredient of an agent for treating or preventing diseases caused by undesirable cytokine signal transmission or diseases caused by pathological cytokine signal transmission.

14 cl, 579 ex, 72 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel pyrimidine derivatives or their pharmaceutically acceptable salts, possessing inhibiting activity with respect to glycogensintase kinase-3 (GSK3). In compound of formula I: R1 is selected from hydrogen, cyano, C1-3alogenoalkinyl, SO2NRbRc, C0-2alkyl(O)NRbRc, C1-4alkylNBbRc, SO2Ri, C(O)ORa, CH(OH)Rj and C(O)Rj; R2 and R4 are independently selected from hydrogen, halogeno, cyano, NO2, C1-4alkyl, C1-3ahalogenoalkyl, ORa, C(O)NRbRc, SO2Ri, and C(O)ORa; or R1 and R2 together with atoms, to which they are bound, are bound with formation of 5- or 6-member heterocyclic ring, which contains one S, any of the hydrogen atoms of group CH2 in said heterocyclic ring can be substituted by oxo, hydroxy, and sulphur atom in said heterocyclic ring is probably oxydised to -SO2-; R3 and R5 represent hydrogen; R6 represents tetrahydropyran; R7 is selected from hydrogen, C1-3alkyl, cyano and C1-3halogenoalkyl; R8 represents hydrogen; Ra is selected from C1-3alkyl and C1-3halogenoakryl. Other radicals are given in formula of invention.

EFFECT: compounds can be applied in manufacturing medication for prevention and/or treatment of predemential states, moderate cognitive failure and type II diabetes, Alzheimer's disease and Parkinson disease, as well as bone-associated malfunctions.

40 cl, 3 dwg, 1 tbl, 122 ex

FIELD: medicine.

SUBSTANCE: what is offered is a monoclonal antibody which binds with Aβ Globulomer containing CDRs of a heavy and light chain. There are described: composition for diagnosing Alzheimer's disease, and also a composition and an antibody-based vaccine for preventing or treating Alzheimer's disease. What is disclosed is application of the antibody for preparing a drug for the intended application stated above. There are described: versions of a diagnostic technique for Alzheimer's disease, an antibody-based diagnostic kit for Alzheimer's disease.

EFFECT: use of the invention provides new Aβ Globulomer antibodies which are detected more selectively than common antibodies.

16 cl, 10 dwg, 5 tbl, 6 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to application of neramexane or its pharmaceutically acceptable salt in a combination with a glutamate release inhibitor for treating neurodegenerative disorders, and also emotional instability and pseudobulbar affect associated with neurodegenerative disorders. The glutamate release inhibitor is selected from riluzole and its pharmaceutically acceptable salts. The neurodegenerative disorder represents a motor neuron disease.

EFFECT: therapy with the combined neramexane and riluzole provides relieved progression of the neurodegenerative disease which surpasses a relief effect induced by therapy with riluzole only.

35 cl, 4 tbl, 2 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel cyclohexylamine derivatives of formula (I), having inhibiting properties towards at least one monoamine transporter, such as serotonin transporter, dopamine transporter or norepinephrine transporter, or a combination of two or more transporters. The compounds can be used to treat and/or prevent central nervous system disorders such as pain, depression, anxiety, schizophrenia, sleep disorder etc. In formula (I) , n equals 0 or 1; s equals 1, 2 or 3, m equals a whole number from 0 to 12; Ar is

or where Y and Z are (i) both halogen; or (ii) one of Y and Z is CF3 or OCF3 and the other is hydrogen; Y1, Z1, Y2 and Z2 each independently denotes H or a halogen; each X independently denotes H, halogen, CF3, OR5, (C1-C4)alkyl, optionally substituted with halogen or OH, or NR6R7; each R1 and R2 independently denotes H or (C1-C6)alkyl; and each R3 and R4 independently denotes H or (C1-C9)alkyl optionally substituted with OH; where each R5 independently denotes H, (C1-C4)alkyl or phenyl; and each R6 and R7 independently denotes H or (C1-C4)alkyl; where at least two of R1, R2, R3, R4 and X together with atoms to which they are bonded are optionally bonded to form a 5-6-member ring, where the 5-6-member ring is selected from: a) R3 and R4 together with a nitrogen atom to which they are bonded optionally form a pyrrolidine, piperidine, piperazine or morpholine ring, which is optionally substituted with (C1-C4)alkyl; b) when R3 is H or lower alkyl, X and R4 together with atoms to which they are bonded optionally form a 1,3-oxazine ring; c) two X substitutes together with a carbon atom to which they are bonded optionally form a 1,3-dioxolane ring; and d) when R1 and R3 denote hydrogen, R2 and R4 together with atoms to which they are bonded optionally form a 5- or 6-member saturated heterocyclic ring containing one nitrogen atom.

EFFECT: high efficiency of using the compounds.

29 cl, 36 dwg, 11 tbl, 6 ex

FIELD: medicine.

SUBSTANCE: there is introduced a pharmaceutical composition containing a polyunsaturated fatty acid selected from omega-3 fatty acid or omega-6 fatty acid, uridine and choline salt.

EFFECT: intellectual improvement ensured by a synergic effect of the ingredients of the composition to increase the concentration of brain phospholipids.

19 cl, 12 ex, 9 tbl, 10 dwg

FIELD: medicine, pharmaceutics.

SUBSTANCE: claimed invention relates to novel pyrimidine derivatives or their pharmaceutically acceptable salts, possessing inhibiting activity with respect to glycogensintase kinase-3 (GSK3). In compound of formula I: R1 is selected from hydrogen, cyano, C1-3alogenoalkinyl, SO2NRbRc, C0-2alkyl(O)NRbRc, C1-4alkylNBbRc, SO2Ri, C(O)ORa, CH(OH)Rj and C(O)Rj; R2 and R4 are independently selected from hydrogen, halogeno, cyano, NO2, C1-4alkyl, C1-3ahalogenoalkyl, ORa, C(O)NRbRc, SO2Ri, and C(O)ORa; or R1 and R2 together with atoms, to which they are bound, are bound with formation of 5- or 6-member heterocyclic ring, which contains one S, any of the hydrogen atoms of group CH2 in said heterocyclic ring can be substituted by oxo, hydroxy, and sulphur atom in said heterocyclic ring is probably oxydised to -SO2-; R3 and R5 represent hydrogen; R6 represents tetrahydropyran; R7 is selected from hydrogen, C1-3alkyl, cyano and C1-3halogenoalkyl; R8 represents hydrogen; Ra is selected from C1-3alkyl and C1-3halogenoakryl. Other radicals are given in formula of invention.

EFFECT: compounds can be applied in manufacturing medication for prevention and/or treatment of predemential states, moderate cognitive failure and type II diabetes, Alzheimer's disease and Parkinson disease, as well as bone-associated malfunctions.

40 cl, 3 dwg, 1 tbl, 122 ex

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