Transmucosal introduction of 2,3-dimethoxy-5-methyl-6- (10-hydroxydecyl)-1,4-benzochinone

FIELD: medicine.

SUBSTANCE: what is offered is application of idebenone for preparing a drug for transmucosal introductions for treating mitochondral, neurological and neuromotor diseases, and the drug is introduced through a nasal mucosa, an oral mucosa or a colon mucosa.

EFFECT: composition for transmucosal introduction enables to avoid a considerable first-pass metabolism of idebenone, to provide introduction in a lower dose, reduced risk of side effects and higher compliance.

8 cl, 2 dwg, 7 tbl, 6 ex

 

The present invention relates to a medicine for transmucosal the introduction of 2,3-dimethoxy-5-methyl-6-(10-hydroxyacyl)-1,4-benzoquinone (idebenone).

The LEVEL of TECHNOLOGY

Idebenone is a synthetic analogue of coenzyme Q10 (CoQ10), a vital antioxidant of cell membranes, and is an essential component of the chain of electron transfer in the mitochondria, which produces adenosine triphosphate (ATP). Currently idebenone finds numerous applications in medicine. Similar to coenzyme Q10, idebenone in living organisms exposed to cycles of reduction/oxidation, while the restored idebenone is an antioxidant and a trap for radicals (A.Mordente, G..Martorana, G.Minotti, .Giardina, Chem. Res. Toxicol. 11 (1998), 54-63). It is known that idebenone protects cell membranes and mitochondria from oxidative damage due to its ability to inhibit lipid peroxidation (.Suno, .Shibota, A.Ngaoka, Arch. Gerontol. Geriatr. 8 (1989), 307-311). Idebenone also works with a chain of electron transfer, supporting the formation of ATP in conditions of ischemia. It is shown that this compound stimulates nerve growth factor. This property can be important for the treatment of Alzheimer's disease and other neurodegenerative diseases (.Yamada, A.Nitta, .Hasegawa, .Fuji, .Hiramatsu, Timerime, Y.Furukawa, .Hayashi, .Nabeshima, Behav. Brain Res. 83 (1997), 117-122). D. the TES compound is also proposed to use for the treatment of Friedreich's ataxia and other mitochondrial and neuromuscular diseases (..Hausse, Y.Aggoun, D.Bonnet, D.Sidi, A.Munnich, A.Rotig, P.Rustin, Heart 87 (2002), 346-349).

Being a lipophilic compound, idebenone well absorbed in the gastrointestinal tract after standard oral administration, which is the usual way of introducing a specified connection. Dosage forms, in particular tablets or capsules, used in clinical studies and in the quality of the delivered products. The authors of the present invention investigated the pharmacological profile idebenone and found that this compound after absorption in the intestine very rapidly metabolized during the first pass through the liver ("the effect of the first pass"). The experiments showed that during the first pass through the liver metabolizes more than 98% of idebenone. In the metabolism of idebenone in the liver oxidized side chain, reduced quinone nucleus, is the conjugation of sulphate and glucuronidase with subsequent excretion by the kidneys. High effect of the first passage leads to a rapid decrease in the concentration of the pharmacologically active free idebenone in the plasma. Due to the significant metabolism at the first passage of the oral administration of idebenone requires high doses connection to ensure the efficient level of plasma in the body. These high doses may cause undesired hair the s side effects in particular diarrhea.

Furthermore, the need of ingesting the compositions of idebenone for oral administration in practice complicates the introduction patients who have problems with swallowing, for example, patients suffering from serious diseases, in particular, myodystrophy Duchenne or ataxia, elderly or young patients.

In JP-11116470 described form of idebenone for percutaneous introduction, intended for the treatment of dementia, including senile dementia of the Alzheimer's type. Preparation for percutaneous introduction is preferably introduced in the form of a poultice, plaster or tape. However, this method is percutaneous injection has severe restrictions on the possible dose for systemic use, compliance sick mode and regimens and dosing accuracy.

The present invention allows to overcome the mentioned disadvantages of the known prototypes. Accordingly, the present invention is to provide injection mode of idebenone needy in this subject, which avoids strong metabolism at the first passage, observed after a standard oral administration, and therefore, eliminates the unwanted side effects caused by high doses of the indicated active agent. Another object of the invention is both the biscuits introduction idebenone patients having problems with swallowing.

BRIEF description of the INVENTION

This problem is solved by using idebenone in medication intended for transmucosal introduction (i.e. insertion through the mucous membrane).

BRIEF DESCRIPTION of DRAWINGS

The figure 1 shows the concentration of idebenone in plasma after administration through the mucosa of the oral cavity (4 mg/kg sublingual (s.l.)) and oral administration (40 mg/kg oral (r.o.)) idebenone. Idebenone was introduced by one and the same breed Beagle (n=3).

The figure 2 shows the concentration of total conjugated (i.e. inactive) metabolites in plasma after administration through the mucosa of the oral cavity (4 mg/kg s.l.) and oral administration (40 mg/kg r.o.) idebenone dogs.

DETAILED description of the INVENTION

The present invention relates to the use of idebenone (international nonproprietary name (International Nonproprietary Name, INN): idebenone; chemical name: 2-(10-hydroxyacyl)-5,6-dimethoxy-3-methyl-2,5-cyclohexadien-1,4-dione; registration number CAS: 58186-27-9) for obtaining a drug intended for transmucosal the introduction of a person or an animal that can be very useful to maintain or restore health. In the present application is also described compositions for transmucosal introduction, containing Lebanon as the active ingredient together with additives and fillers, which is usually used in compositions for transmucosal introduction. Additionally, describes how to obtain the corresponding compounds for transmucosal introduction.

Idebenone has the following formula:

2,3-dimethoxy-5-methyl-6-(10-hydroxyacyl)-1,4-benzoquinone, idebenone

Idebenone, member of the family of quinones, promoted on the market as a synthetic analogue of coenzyme Q10. He is also the subject of various medical research aimed at studying its effectiveness in the treatment of, for example, neuromuscular diseases, in particular of frda, or neurological diseases, in particular Alzheimer's disease. Idebenone also used for topical application in the treatment of wrinkles. Thus, idebenone can be considered to be toxicologically safe, i.e. it can be used in medicine as a pharmaceutically active agent. Toxicological safety idebenone was confirmed by a clinical study involving 536 patients who were administered up to 360 mg idebenone three times a day (t.i.d.). Compared with the control group that received placebo, did not observe any adverse effects except for a few cases of irritation of the gastrointestinal tract and a small increase in frequency orthopedic is slojneni (L.J.Thal, .Grundman, J.Berg, .Ermstrom, R.Margolin, E.Pfeiffer, M.F.Weiner, E.Zamrini, R.G.Thomas, Neurology 61 (2003), 1498-1502).

It is now known that after the standard introduction through the mouth and intestinal absorption rapid metabolism idebenone during the first pass through the liver. Major metabolites are conjugates of idebenone, in particular glucuronate and sulfates, as well as derivatives, in which the side chain of the parent compound oxidized. Metabolites of idebenone not possess significant pharmacological activity and are rapidly eliminated from the body. Because of this significant of a metabolism at the first passage, to achieve pharmacologically active concentrations in plasma by oral administration of idebenone required high doses. Such high doses cause unwanted effects, particularly diarrhea and disorders gastro-intestinal tract (GIT), which is often observed when using the drug in medical practice.

It turned out that a high concentration of free idebenone, not conjugated and not metabolizirovannom otherwise idebenone, plasma can be achieved by transmucosal introduction idebenone, in which the absorption of idebenone in the body can occur by absorption through the mucous membrane. Thus, although transmucosally introduction the coenzyme Q10 described in earlier publications (K.Fujii, .Kawabe, .Hosoe, .Hidaka, EP 1388340 A1), we were able to show that the polar compound idebenone rapidly absorbed through the mucous membranes. Application transmucosally compositions avoids significant first pass metabolism observed after a standard oral administration of idebenone.

Crawl strong metabolism idebenone the first passage allows for virtually the same high concentration of the drug in plasma at much lower injected dose. Usually consider that the lower the content of the drug is associated with reduced risk of unwanted side effects that is a therapeutic advantage and increases the compliance of the patients (i.e. commitment to this type of treatment).

In addition to preventing effect of the first pass the drug according to the invention is efficient and easy to access and, therefore, has an advantage from the point of view of practical introduction, especially to patients suffering from problems with swallowing.

In this application, the term "compounds for transmucosal introduction" or "transmucosally compounds" means compounds that have a form intended for absorption into the body through the mucous membranes. According to the invention, such compositions form the basis of medicine, sod is rasego idebenone, for transmucosal introduction.

In addition, according to the present invention, the term "mucous membrane" includes the mucous membranes of the nose, rectum and mouth. The mucous membrane of the oral cavity includes the mucous membrane of the hyoid region and the mucous membrane of the cheeks. Idebenone is preferably introduced through the mucous membrane of the mouth or nose, more preferably through the mucous membrane of the sublingual area or mucous membrane of the cheeks.

Medication for transmucosal introduction idebenone can be fabricated, for example, in the form of quick-dissolving tablets, emulsions, solutions, aerosols, gels, mucoadhesive tablets or pastes, lozenges, sublingual tablets, drops, chewable tablets, suppositories or chewing gum.

Each of these dosage forms can be obtained well-known methods using additives that are usually used for the manufacture of such compositions. Such additives used for the compositions described in this invention can contain adjuvants or excipients and the like, including solvents, buffers, flavoring agents, sweeteners, fillers, preservatives, gelling agents, carriers, diluents, surface-active agents and mucoadhesive polymers.

Preferred solvents which, you can use the medication according to the present invention are alcohols, in particular ethanol, esters of fatty acids, triglycerides, water and mixtures thereof.

Preferred preservatives are lower alkyl parahydroxybenzoate, in particular methyl and propilparagidroksibenzoat.

Examples of suitable carriers and diluents include lactose, dextrose, sucrose, sorbitol, lures, starches, gum Arabic, calcium phosphate, alginates, tragakant, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water syrup, methyl cellulose, methyl - and propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

Medication for transmucosal introduction idebenone according to the present invention can be used to treat a variety of mitochondrial and neuromuscular or neurological diseases. Examples of diseases that can be treated include, in particular but without limitation, ataxia, myodystrophy Duchenne, myodystrophy Becker, Alzheimer's disease, congenital neuropathy of the optic nerve (Leber's disease), MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis with insultopodobne episodes), Parkinson's disease and mitochondrial myopathy.

Used effective dosage of idebenone can argirova the ü, depending on, for example, diseases that are treated, and the severity of the disease that is being treated. Compared to standard oral by introducing the size of the dose for transmucosal introduction can be greatly reduced without changing the activity of idebenone. It is possible to show that the content of idebenone in plasma reaches the desired concentration at a dose reduced by ten times compared to doses in dosage forms for oral administration.

Suitable dose of idebenone entered in transmucosally the compositions are in the range from 0.01 mg/kg/day to 60 mg/kg/day. Preferably idebenone is administered in a dosage of 0.01 mg/kg/day to 20 mg/kg/day, more preferably in a dosage of 0.01 mg/kg/day to 10 mg/kg/day and more preferably in a dosage of 0.01 mg/kg/day to less than 5 mg/kg/day. The most preferred dose of the active ingredient of idebenone is from 0.1 mg/kg/day to 4 mg/kg/day. Unexpectedly, studies have shown that such low doses provide the required level of idebenone plasma, if it is introduced through the mucous membrane of the mouth. The person skilled in the art can easily install the required dosage.

In a preferred embodiment, the implementation of idebenone you can type in combination with a second therapeutic agent, the second therapeutic agent, preferred is entrusted selected from corticosteroids, such as 6A-methylprednisolone-21 sodium succinate (solumedrol®) or deflazacort (calcort®)are commonly used in the treatment of patients with myodystrophy Duchenne (DMD DMD) for the treatment of inflammation and muscle weakness. Similarly, idebenone you can type in combination with any drug used for patients suffering from myodystrophy Duchenne, for the treatment of cardiomyopathy associated with myodystrophy Duchenne, particularly with angiotensin converting enzyme inhibitors, beta-blockers and diuretics.

In another preferred embodiment, the implementation of idebenone you can type in combination with other therapeutic agents, therapeutic agents preferably are erythropoietin, vitamin E, vitamin C, mitchison (MitoQ; ..Taylor, R.Smith, WO 05019232 A1), inhibitors of cysteine protease, calpain or inhibitors of the proteasome. Preferred inhibitors of calpain described in WO 2004/078908 A1, WO 2006/021409 A1 and WO 2006/021413 A1.

Idebenone and other active agents can be used simultaneously, separately or sequentially to treat or prevent symptoms of disease. Active agents can be obtained in a single dosage form or in separate compositions, each of which contains at least one of the active agents.

The following examples illustrate the invention, one of the ako they do not limit its scope.

EXAMPLE 1

The composition in the form of microemulsions

Table 1
Ingredient[mg/ml]Function
Idebenone20The active ingredient
Miglyol 812 N144Solvent
TPGS (Tocopherol polyethylene glycol succinate)96Surfactant
Water750Solvent

Preparation: TPGS (tocopherol polyethylene glycol-400-succinate) pre-heated to approximately 60°C. Miglyol 812 N and idebenone mixed and treated with ultrasound for about 10 minutes until complete dissolution (clear orange solution). Molten TPGS was added to a solution of megliola/idebenone and mixed. The mixture was diluted and homogenized to obtain a homogeneous emulsion.

EXAMPLE 2

Tablet for sublingual introduction

Table 2
Ingredient[mg/tablet]Function
Idebenone10The active ingredient
Lactose monohydrate60Filler
Povidone K4,5Binder
Croscarmellose5Baking powder
Microcrystalline cellulose30Filler
Flavor2,5Flavoring agent
Aspartame6Sweetener
Magnesium stearate0,75The agent, providing the sliding (glidant)
Talc1,25The agent, providing the sliding

Preparation: idebenone, monohydrate lactose, flavor and aspartame mixed in the mixer with great the mi shear forces to obtain a homogeneous mixture. Povidone was dissolved in water (the solution is approximately 8-10%), was added to the dry mixture and granulated. The wet granules were dried in the fluidized bed dryer, screened and added to the previously prepared mixture of microcrystalline cellulose, magnesium stearate and talc. The mixture is compressed into tablets.

EXAMPLE 3

The composition in the form of an aerosol

Table 3
IngredientNumberFunction
Idebenone10 gThe active ingredient
Methyl parahydroxybenzoate2 gPreservative
Sodium propyl parahydroxybenzoate0.2 gPreservative
Aspartame0.6 gSweetener
Flavor0.6 gFlavoring agent
Ethanol (96%)500 mlSolvent
Distilled waterin sufficient quantitySolvent

Preparation: 10 g idebenone dissolved in 500 ml of ethanol (96%) and mixed with 400 ml of distilled water. The resulting mixture was dissolved methyl parahydroxybenzoate, sodium propyl parahydroxybenzoate and aspartame. The final volume was brought to 1000 ml by adding distilled water. The solution was filtered and filled them with suitable spray.

EXAMPLE 4

Sublingual tablet with idebenone and prednisone (17-hydroxy-17-(2-hydroxyacyl)-10,13-dimethyl-7,8,9,10,12,13,14,15,16,17-decahydro-6N-cyclopent[a]phenanthrene-3,11-dione, CAS 53-03-2)

Table 4
Ingredient[mg/tablet]Function
Idebenone10The active ingredient
Prednison2,5The active ingredient
Lactose monohydrateof 57.5Filler
Povidone K4,5Binding
Croscarmellose5Baking powder
Microcrystalline cellulose30Filler
Flavor2,5Flavoring agent
Aspartame6Sweetener
Magnesium stearate0,75The agent, providing the sliding
Talc1,25The agent, providing the sliding

Preparation: idebenone, prednisone, lactose monohydrate, flavouring and aspartame mixed in the mixer with large shear forces to obtain a homogeneous mixture. Povidone was dissolved in water (the solution is approximately 8-10%), was added to the dry mixture and granulated. The wet granules were dried in the fluidized bed dryer, screened and added to the previously prepared mixture of microcrystalline cellulose, magnesium stearate and talc. The mixture is compressed into tablets round shape.

EXAMPLE 5

Quantitative analysis of the content of idebenol is a plasma

Quantitative determination of idebenone conducted by liquid chromatography (LC)connected in-line with tandem mass spectrometry (MS/MS). Calibration samples were prepared in human plasma, and samples quality control - in the plasma of the dog.

Sample preparation

To 150 μl of plasma dog added 10 μl of a solution of ethylenediaminetetraacetic acid (edtc)obtained by dissolving 1245 mg potassium salt etc in 33 ml of 1M NH4OAc, and 300 μl of methanol. After vigorous shaking, the samples were centrifuged for 45 minutes at a relative centrifugal force (RCF) 1960 at 4°C. an Aliquot of the supernatant liquid volume of 50 µl was injected into the system LC-MS/MS. The analysis procedure was identical for all testing, calibration and control samples. The samples were stored at about 8°C for not more than 24 hours if not used immediately.

Conditions of chromatography

Idebenone separated and conducted quantitative analysis by HPLC-MS/MS: HPLC used column Synergi™ 4 μm MAX-RP (50×2 mm) (Phenomenex, Schlieren, Switzerland). The column temperature: 50°C. Mobile phase A: water + 40 mm NH4OAc; mobile phase b: Meon/H2O 100/3 (by volume) + 30 mm NH4OAc, gradient elution (table 4). Flux: 250 ál/min 400 ál/min

After the Department has conducted a quantitative analysis of idebenone by tandemly the mass spectrometry with ionization by elektrorazpredelenie and (ESI-MS/MS (API 4000, Perkin-Elmer-Europe BV, Rotkreuz, Switzerland)in the positive mode.

Table 5
The program of the gradient pump and the timing events of separation and quantitative analysis of idebenone
Time [min]Mobile phase [%]Flow [ál/min]Comments
0,0150250The initial gradient eluent of HPLC in MS
3,00-250-
3,01-400-
3,7595400The final gradient
4,5095400-
4,5150400-
5,9050 40-
5,9150250-
29.99 is50250Off pump
30,009520

In the time interval from 0.01 to 3.75 min used a linear gradient.

Quantitative analysis of conjugates of idebenone, in particular glucuronate and sulfates, held after acid hydrolysis, as described R.Artuch, .Colome, .A.Vilaseca, A.Aracil, .Pineda, J.Neurosci. Meth. 115 (2002), 63-66.

EXAMPLE 6

Data pharmacokinetics after sublingual administration idebenone

Researched content idebenone in the blood plasma of dogs (n=3) after injection of the microemulsion prepared as described in example 1. Sublingual introduction 4 mg/kg compared with orally administered 40 mg/kg, using cross-sectional diagram of the experiment. Blood samples were collected within 8 hours after injection. The concentration of idebenone in plasma were determined by HPLC-MS/MS as described in example 4, and calculated pharmacokinetic parameters.

Pharmacokinetic analysis included determination of the maximum plasma concentration (Cmax), point BP is like, in which observed maximum plasma concentration (Tmax), and area under the curve (AUC) relative to plasma concentrations in the range from 0 to 480 min (AUC0-in). Calculated relative bioavailability of idebenone after sublingual injection compared with orally administered to each dog on the normalized values of AUC (1 mg/kg). In addition, the calculated relationship AUC metabolites. Calculate the relationship Cmaxnormalized by the dose of 1 mg/kg

The results obtained are shown below in tables 6 and 7.

td align="center"> 1265 (675-2261)
Table 6
The mean values of pharmacokinetic parameters of idebenone and the United conjugated (i.e., inactive) metabolites after oral (40 mg/kg) and sublingual (4 mg/kg) administration to dogs. Numbers in parentheses indicate the minimum and maximum observed values.
DoseCmax[ng/ml]Tmax[min]AUC0-480[min*ng/ml]
4 mg/kg oromucosalidebenone105,6 (76,9-133,4)6,3 (3-8)
conjugates871 (272-1260)50 (15-120)55053
40 mg/kg oralidebenone31,9(15,21-42,04)22,7 (8-30)1079,3 (655-1692)
conjugates6206 (1824-9663)25 (15-30)446013 (272990-737465)

As shown in table 6, it is obvious that the composition of idebenone for insertion through the mucous membrane of the mouth, prepared according to example 1, provides a higher content of idebenone in plasma than traditional oral administration.

After administration of 4 mg/kg idebenone through the mucous membrane of the mouth is higher than the AUC after oral administration AUC0-in=1265 min*ng/ml, higher than the AUC after oral administration, even when idebenone have introduced more 10 times the dose (40 mg/kg, AUC0-in=1079,3 min*ng/ml).

Moreover, the maximum concentration in plasma after administration of 4 mg/kg (105,6 ng/ml) through the mucous membrane of the mouth higher and exceeds Cmaxafter oral administration, is equal to 40 mg/kg (31.9 per ng/ml).

The table is 7
Relations AUC and Cmaxfor idebenone and the United conjugated (i.e. inactive) metabolites in the introduction through the oral mucosa (4 mg/kg) and oral administration (40 mg/kg) to dogs. Relations are normalized to a dose of 1 mg/kg
Idebenone (normalized dose)The ratio of AUC11,1
The ratio of Cmax36,8
Conjugates (normalized dose)The ratio of AUC1,4
The ratio of Cmax1,4

Table 7 shows the improvement of the bioavailability of idebenone when introduced through the mucous membrane of the oral cavity compared with orally administered after normalization to a dose of 1 mg/kg normalized value AUC0-480obtained by introduction through the mucous membrane of the mouth, 11.1 times higher than the normalized value of AUC0-480obtained by oral administration of idebenone. Parallel with the increase of the normalized values of AUC0-480after insertion through the mucous membrane of the mouth in relation to oral introduction, the normalized value of Cmaxincrease of 36.8 times.

the other hand, values of Cmaxand AUC0-480for inactive conjugates of idebenone only slightly increased after the introduction through the mucous membrane of the mouth compared with oral administration (factor of 1.4).

The obtained results are further illustrated by the figures 1 and 2.

Figure 1 shows the average concentrations of idebenone in plasma after administration of 4 mg/kg via the oral mucosa compared with orally administered 40 mg/kg idebenone dogs during the first two hours after administration. Composition for administration through the oral mucosa provides a much greater value of Cmaxin an earlier Tmax.

Figure 2 shows the average concentrations of inactive conjugates of idebenone in plasma after administration of 4 mg/kg via the oral mucosa compared with orally administered 40 mg/kg idebenone dogs within 8 hours after injection.

1. The use of idebenone to get medicine for transmucosal injection for the treatment of mitochondrial, neurological and neuromuscular disorders, and medication is injected through the mucous membrane of the nose, rectum or mouth, for example, sublingual or buccal.

2. The use according to claim 1 for the treatment of Friedreich's ataxia, congenital neuropathy of the optic nerve's, mitochondrial myopathy, encephalopathy, lactic acidosis with insultation and episodes (MELAS syndrome) and mitochondrial myopathy.

3. The use according to claim 1 for the treatment of Duchenne muscular dystrophy and the condition of Becker.

4. The use according to claim 1 for the treatment of Alzheimer's disease or Parkinson's disease.

5. The use according to any one of claims 1 to 4, characterized in that idebenone is administered in a dosage of from 0.01 to 60 mg/kg/ day.

6. The use according to any one of claims 1 to 4, characterized in that idebenone is administered in a dosage of from 0.01 to 20 mg/kg/ day.

7. The use according to any one of claims 1 to 4, characterized in that the drug is in the form of suppositories, drops, chewing gum, soluble tablet or aerosol.

8. The use according to any one of claims 1 to 4, characterized in that the drug contains a second therapeutic agent.



 

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FIELD: medicine.

SUBSTANCE: method involves introduction in a patient's body cyclophosphan, a preparation of a cytostatic group which is introduced in dose 20 to 100 mg/kg of body weight and a preparation of fragmented allogenic two-chained genomic DNA with fragments having a biologically active value and composing a full genome of physiologically and genetically healthy donor (hereinafter - exogenic DNA). The exogenic DNA preparation is introduced 48 hours after each introduction of the cytostatic preparation and for the following 30 days for the scheme when the patient has taken a full course dose 6-14 g, or for the following 3-5 days after a single injection and one day before a following injection with continuing with such intermittent to a complete setting of a therapeutic or supporting dose of the cytostatic preparation.

EFFECT: use of the invention allows higher clinical effectiveness in tumours ensured by differentiated inhibition of cytotoxic and regulatory lymphocyte viability under the effect of cyclophosphan and exogenic DNA.

3 tbl, 9 dwg

FIELD: chemistry.

SUBSTANCE: invention discloses a compound of formula I

, in which radicals and groups are described in the claims. Said compounds are 5-hydroxytryptamine-6 (5-HT6) ligands and can be used to treat central nervous system disorders associated with or influenced by the 5-HT6 receptor. The invention also relates to a pharmaceutical composition and a method of treating said disorders.

EFFECT: high efficiency of using said derivatives.

19 cl, 13 tbl, 204 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine. Described is preparative form for transcutaneous introduction, which makes possible stable introduction of medication against dementia for a long period of time. Preparative form for transcutaneous introduction of medication against dementia, which is used as plaster on skin, contains, at least, one adhesive layer, intermediate membrane and layer, which is reservoir of medication, successively, from the side, which is stuck on skin, where layer, which is reservoir of medication, contains, at least, one medication against dementia, aminated polymer, polyatomic alcohol and one or several esters of carboxylic acids.

EFFECT: intermediate membrane makes possible controlled penetration of medication against dementia towards skin, adhesive layer makes it possible to stick preparative form for transcutaneous introduction on skin and is permeable for medication against dementia.

9 cl, 4 dwg, 1 tbl, 6 ex

FIELD: chemistry.

SUBSTANCE: in general formula I R1 denotes hydrogen atom, a halogen atom, hydroxy, lower alkyl, benzyloxy or -O-(CH2)-(CO)-(5-member heteroaryl with 2 heteroatoms selected from N, O), substituted with phenyl or lower alkyl; R2 denotes a hydrogen atom, a halogen atom, lower alkyl, lower alkynyl, amino, -NHC(O)Ra or -(CO)-Ra; R3 denotes a hydrogen atom, a halogen atom, cyano, lower alkyl, lower alkynyl, amino, -NHC(O)-Ra, -(CO)-Ra, 4- or 5-member heterocycloalkyl substituted with a =O group or a 5-member heteroaryl with 1-2 heteroatoms selected from N; R4 denotes a hydrogen atom or a 5-member heteroaryl with 2 heteroatoms selected from N; R5 denotes lower alkyl or C3-C7cycloalkyl; Ra denotes lower alkoxy, -(CH2)n-(6-member heteroaryl with 1 heteroatom selected from N), phenyl C3-C7-cycloalkyl or NR'R", where each of R' and R" independently denotes a hydrogen atom, lower alkyl, substituted hydroxy, lower alkynyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-member heterocycloalkyl with 1-2 heteroatoms selected from O, N) or -(CH2)n-(5- or 6-member heteroaryl with 1 heteroatom selected from N, O); n assumes values from 0 to 3. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare the medicinal agent.

EFFECT: high activity and selectivity towards GABA A receptor subunit α5.

18 cl, 72 ex

FIELD: chemistry.

SUBSTANCE: disclosed compounds have activity and selectivity towards the GABA A receptor subunit α5. In formula I , R1 denotes hydrogen, halogen, phenyl, a 6-member heterocycyl with 2 heteroatoms selected from N, O, a 5-member heteroaryl with 1-2 heteroatoms selected from S, N, cyano, lower alkyl, -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl or -(CH2)n-OH; equals 0, 1 or 2; R denotes hydrogen or lower alkyl; R2 denotes C3-C7-cycloalkyl, phenyl, 5-6-member heteroaryl with 1 heteroatom selected from N, S or a 9-10-member bicyclic heteroaryl with 1-3 heteroatoms selected from N, which are possibly substituted with one or more substitutes selected from a group comprising halogen, cyano, nitro, oxo group, lower alkyl, lower alkyl substituted with a halogen, lower alkoxy, lower alkoxy substituted with a halogen, -C(O)O-lower alkyl, lower alkylsulphonyl, -NRaRb, -C(O)-NRaRb, -C(O)-(6-member heterocyclyl with 2 heteroatoms selected from N, O), benzyloxy, 6-member heterocyclyl with 1-2 heteroatoms selected from N, S, O, possibly substituted with hydroxy, 1-2 oxo-groups, halogen or lower alkyl, or selected from a 5-6-member heteroaryl with 1-3 heteroatoms selected from N, possibly substituted with lower alkyl; Ra and Rb independently denote hydrogen, lower alkylsulphonyl, -C(O)H, -(CH2)n-N(R)2, -(CH2)n-O-lower alkyl, -(CH2)n-S-lower alkyl, -(CH2)n-S(O)2-lower alkyl, (5-member heteroaryl with 1 heteroatom selected from S)-sulphonyl, lower alkyl, -(CH2)n-(5-6-member heterocyclyl with 1 heteroatom selected from O, N), possibly substituted with lower alkyl, oxo group, or denotes -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(5-6-member heteroaryl with 1-2 heteroatoms selected from N), possibly substituted with an oxo group, -(CH2)n-OH, -(CO)-R', where R' denotes C3-C7-cycloalkyl, a 5-member heteroaryl with 1 heteroatom selected from S, or lower alkyl; R' denotes a phenyl or a 6-member heteroaryl with 1 heteroatom selected from N which are possibly substituted with a halogen or lower alkyl, optionally substituted with a halogen. The invention also relates to a medicinal agent containing one or more compounds of formula I and use of the disclosed compounds to prepare a medicinal agent.

EFFECT: high effectiveness of derivatives.

16 cl, 145 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine. Claimed invention relates to method and composition for treatment of central nervous system (CNS) disorder by intranasal application of compounds, which induce RNA interference. Composition by the invention contains molecules of short interfering nucleic acids (siPHK). Disorder is selected from dementia, Alzheimer's disease, Huntington's disease and/or Parkinson's disease, as well as congenital diseases associated with mutations in CNS genes. According to the invention method includes introduction to patient in case of necessity of efficient amount of one or more siPHK in accordance with the invention.

EFFECT: invention ensures suppression of expression of target genes, connected with changed CNS states.

20 cl, 4 ex, 8 dwg

FIELD: medicine.

SUBSTANCE: CD4+ lymphocyte or CD8+ lymphocyte expressing superficial marker CD69 are counted prior to and after mitogenetic stimulation. The related value reaching a 10-fold or maximum 30-fold limit is a sign of Alzheimer's disease (AD). A kit containing necessary components for diagnosing Alzheimer's disease (AD) is presented.

EFFECT: invention allows presenting the instant diagnostic test for Alzheimer's disease.

2 cl, 2 tbl, 1 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine and pharmacology and deals with pharmaceutical composition, possessing antihypoxic, neoroprotective and antiamnestic activity and ability to increase physical performance capacity, intended, in particular, for treatment of acute and chronic disorders of brain blood circulation, which contains as active componets semax and choline alfoscerate, taken in weight ratio from 1:50 to 1: 8000 respectively and pharmaceutically acceptable auxiliary substances.

EFFECT: invention ensures extension of arsenal of medications, possessing expressed neuroprotective activity in combination with antihypoxic and antiamnestic activity and ability to increase physical performance capacity.

7 tbl, 8 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to aryl-isoxazole-4-yl-imidazole derivatives of formula I and to their pharmaceutically acceptable acid addition salts. The compounds of the present invention exhibit GABA A α5 receptor binding site activity and selectivity. In general formula I

each of R1-R3 independently represents hydrogen atom or halogen atom; R4 represents hydrogen atom, lower alkyl, C3-C7cycloalkyl, -(CH2)n-O-lower alkyl or hydroxy substituted lowest alkyl; R5 represents -(CH2)m-phenyl or -(CH2)m-(5-6-members heteroaryl with 1-2 heteroatoms independently seected from N, O) which optionally substituted by one or more substitutes selected from a group consisting of halogen atom, cyano, nitro, lower alkyl, lower alkoxy, lower alkylsulphanyl, lower alkyl substituted by halogen atom, -C(O)-lower alkyl, -C(O)-O-lower alkyl, -NH-C(O)-O-lower alkyl or -C(O)-NH-R' where R' represents the lower alkynyl or hydroxy substituted lower alkyl, or represents -(CH2)n-C3-C7-cycloalkyl, -(CH2)n-(6-members heterocyclyl with 1-2 heteroatoms selected from N, O), -(CH2)n-(5-6-members heteroaryl with 1-2 heteroatoms selected from N, O) or -(CH2)n-phenyl optionally substituted by halogen atom; R6 represents hydrogen atom, -C(O)H, -(CH2)n-O-lower alkyl, -C(O)O-lower alkyl, lower alkyl substituted by hydroxy or halogen atom, or represents C3-C7-cycloalkyl, phenyl, or represents -(CH2)n-O-CH2-phenyl optionally substituted by halogen atom or lower alkyl, or represents -(CH2)n-O-CH2-(6-members heteroaryl with 1 heteroatom selected from N) optionally substituted by lower alkyl or lower alkyl substituted by halogen atoms, or represents -(CH2)n-NH-(CH2)o-(6-members heterocyclyl with 2 heteroatoms selected from N; n means 0, 1, 2 or 3; m means 0 or 1; o means 1, 2 or 3.

EFFECT: presented preparation of a drug containing one or more compound of formula I and application of the compounds for preparing the drug.

31 cl, 168 ex

FIELD: medicine.

SUBSTANCE: invention relates to field of medicine and pharmacology and deals with application of derivatives of aminospirits of formula

or their phosphate derivatives for manufacturing medication for treatment of various autoimmune diseases, such as disseminated sclerosis, peripheral nephritis, retrobulbar neuritis, amyotrophic lateral sclerosis and uveitis.

EFFECT: invention ensures high treatment efficiency.

7 cl, 2 dwg, 1 tbl, 1 ex

FIELD: chemistry.

SUBSTANCE: invention relates to novel compounds of the formula I

, where: m equals 0, 1 or 2, where if m=0, disappears such that an open ring or single bond forms, n equals 0, 1 or 2, wherein when n=0, disappears such that an open ring or single bond forms; m' and n' are independently equal to 0, 1 or 2; X denotes a carbon atom; Y denotes a carbon or sulphur atom; provided that m and n are not equal to 0 at the same time; denotes a single or double bond, if needed; --- absence of a bond or a single bond, if needed; R1 is selected from a group comprising CN, Hal, OAIk, OH, NRCN, C(CN)=C(OH)(OAlk), SR, NRR', (Alk)p-C(O)NRR', piperidine, wherein Alk is optionally substituted with Hal or OAlk, where p=0 or 1; R3, R4, R5 and R6 are identical or different and are independently selected from a group comprising H, OAIk, Alk, Hal, OH; R2 is selected from a group comprising H and O, and p'=0 or 1; R7 is selected from a group comprising H, O, OH, N-OH, N-aryl, N-OAlk, N-O-aryl, N-O-Alk-aryl, N-NR-CONRR', N-O-CO-Alk, or 2 R7, bonded with the same Y, together form lioksalan; wherein said Alk is optionally substituted with OAlk, -CO-(NR-Alk-CO)p'-OAlk, and p'=0 or 1; R and R', which are identical or different, are independently selected from a group comprising H, and Alk; or pharmaceutically acceptable salt or optical isomer or diastereomer thereof, except those compounds for which: R3, R4, R5, R6=H, R1=CN, denotes a single bond, and denotes -C(=N-(2,4,6-trimethylphenyl))-, -C(=N-(2,6- dimethylphenyl))-, -C(=N-(2,6-diethylphenyl))-, -C(=N(2-methylphenyl))-, -C(=N(2-ethylphenyl))-, -C(=N-(2-trifluoromethylphenyl))-, -C(=N-(2-isopropylphenyl))-, -C(=N-phenyl)-, -C(=N-(naphthyl)- or -C(=O)-, -CH2-, or R3, R5, R6=H, R4=OMe, R1=CN, denotes a single bond, and denotes -C(=O)-, or R3, R4, R5, R6=H, R1=NH2, denotes a single bond, and denotes -CH2- or -CH2-CH2-; or R3, R4, R5, R6=H, R,=NH2, denotes -CH2- or -CH2-CH2-, and denotes a single bond. The invention also relates to a cysteine protease based pharmaceutical composition based on compounds of formula I, use of the compound of formula I to prepare a drug for inhibiting cysteine protease, for treating and preventing cancer, as well as inflammatory diseases and others.

EFFECT: novel compounds which can be used in medicine are obtained and described.

38 cl, 43 ex, 2 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to (2R)-2-phenylcarbonyloxypropyl (2S)-2-amino-3-(3,4-dihydroxyphenyl)propanoate mesylate which is a levodopa prodrug and can be used to treat Parkinson's disease, schizophrenia, cognitive disorders, restless legs syndrome, periodic limp movement disorder, tardive dyskinesia, Huntington's disease, arterial hypertension and excessive diurnal drowsiness. The invention also relates to the crystalline form of the said compound, methods of producing said compound and its crystalline form, pharmaceutical compositions and treatment methods.

EFFECT: highly effective treatment.

46 cl, 6 dwg, 1 tbl, 7 ex

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