Method of producing copolymer of sodium carboxy-methylcellulose and gossypol and use thereof in complex therapy of patients with autistic disorders and cognitive impairments

FIELD: chemistry.

SUBSTANCE: invention relates to a method of producing a copolymer of sodium carboxy-methylcellulose and gossypol of formula (I) and use thereof in complex therapy of patients with autistic disorders and cognitive impairments, where a:b:c=1:(3-6):(5-7), n=40-50; molecular weight of 120000-130000.

EFFECT: high efficiency of treating mental illnesses.

11 cl, 3 tbl

 

The invention relates to the field of organic chemistry, pharmacology and medicine and relates to a method of producing a copolymer of sodium carboxymethyl cellulose and hossipole, its application in complex therapy of patients with autism spectrum disorders and cognitive disorders, as well as to pharmaceutical compositions based on it, intended for use in complex therapy of patients with autism spectrum disorders and cognitive impairments, the combination for the treatment of patients with autism spectrum disorders and cognitive impairment and treatment for these patients.

The level of technology

The problem of finding new treatments for autism spectrum disorders accompanied by severe cognitive impairment, in recent decades, becoming more and more medical and social importance in connection with the duration of treatment, severe disability and exclusion of patients with autism spectrum disorders (Kovalev V.V. Psychiatry of childhood. - Moscow, "Medicine" - 1995, Basin V.M., Autism in childhood. - Moscow, "Medicine" - 1999, I. Maslova, Balkan SV, Studenikin V.M. et al. Cognitive neurologia//Russian journal of pediatric.- 2000.- No. 5 - P.40-41).

Autism in childhood is characterized by impaired mental development, autistic formcontacto with others, speech disorder, motor skills, stereotypical activities and behaviors that lead to social exclusion. The generally accepted concept of the etiology of autistic spectrum disorders today does not exist. The reasons can be different from the endogenous-hereditary to exogenous-organic and psychogenic. It is believed that autism in childhood has a neurobiological basis and is the result of cerebral disorders.

Known means for the treatment of autism spectrum disorders accompanied by severe cognitive impairment, which primarily include neuroleptics. Among neuroleptics for the treatment of autistic spectrum disorders with severe cognitive impairment may be used chlorpromazine, neuleptil, haloperidol, Terlingen, triftazin, Eglon, azaleptin, chlorprothixene. In addition, for the treatment of such conditions are used antidepressants (anafranil, azafen, pirazidol, amitriptyline and others), anticonvulsants (Finlepsin, trileptal, topamax). (Basin V.M. Autism in childhood. - Moscow, "Medicine" - 1999; I. Maslova, Balkan SV, Studenikin VM's and other Cognitive neurology//Russian journal of pediatric. - 2000.- No. 5, P.40-41).

It should be noted that when using very high doses the risk of unwanted side-effect is mswb, including extrapyramidal disorder, neuroleptic malignant syndrome and others With long-term treatment data of drugs, a marked adverse effects of neuroleptics and other psychotropic drugs: they can cause mental, neurological and somatovegetative disorders, which undoubtedly limits the required duration of neuroleptic therapy and its effectiveness.

Sometimes, as an additional means for the treatment of autistic spectrum disorders with severe cognitive impairment, use nootropic drugs. It is believed that nootropic drugs have a direct activating effect on learning, improve memory and mental activity, i.e. cognitive function. The nootropics that are most often used in the treatment of autistic spectrum disorders with severe cognitive impairment, should include glycine, nootropil (piracetam), entsefabol (pyritinol), acid (gammalon), Tanaka (L.M. Kuzenkova, I. Maslova, L.S. Namazova and other Nootropics in cognitive neurology of childhood//Methodological manual for doctors. - M. 2008. P.54). The destination schema nootropics selected individually. Despite the fact that, in General, nootropics are characterized by good tolerability in children with severe intellectual underdevelopment, their reception is may lead to increased motor disinhibition, irritability, emotional irritability, poor sleep. Described and other side effects of nootropics: piracetam can cause diarrhoeal disorders and exacerbation of coronary insufficiency, acid - diarrhoeal disorders, sensation of heat and fluctuations in blood pressure, pyritinol - nausea and headache, and the children's psychomotor agitation. While piracetam is contraindicated in renal failure, pyritinol - high convulsive readiness.

In addition, in recent years for the treatment of autistic spectrum disorders with severe cognitive impairment is most effectively used in the complex therapy of the above drugs. However, in this case, is often the body's resistance to treatment with neuroleptics, especially in patients with severe forms of autism that leads to the increase in average daily doses of drugs. This expected effect is not always observed, and side effects are often amplified (Ph.D GY, Neduva A.A. Treatment of mental patients: a Guide for physicians, Moscow, "Medicine"- 1988; Tihanov A.S. Pathology of mental development, Moscow, - "SCHOOL-PRESS - 2004).

In this regard, the search for new means of pathogenetic therapy, which allows to increase without the provisions and treatment of mental illness, an important clinical and social problem.

The invention

The authors of the present invention unexpectedly found that the known sodium salt of a copolymer of carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (1):

where

a:b:C=1:(3-6):(5-7),

molecular weight 120000-130000,

empirical formula:

[(C38H39NaO15)a(C6H10O5)b(C8H11NaO7)c]n,

possessing antiviral activity used for the treatment of various viral infections, can be used with success to treat patients with autism spectrum disorders and cognitive impairment.

The specified connection and method thereof are described in EN 2270708. According to a known method an aqueous solution of sodium carboxymethyl cellulose is subjected to contact with an aqueous solution of iodic acid or periodate sodium in the environment of isopropyl alcohol, followed by washing of the resulting dialdehyde of carboxymethyl cellulose with a mixture of isopropyl alcohol and water, acidified with hydrochloric acid, and the processing hossipole or gossipoksana acid, then with an aqueous solution of sodium hydroxide and separation of the target product deposition solvent.

Obtained in a known manner product contaminated the n impurities hydrochloric acid and isopropyl alcohol. In addition, working with solutions of hydrochloric acid is always associated with certain difficulties.

Therefore, the present invention was to develop an improved method of producing a copolymer of carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (1), devoid of the above disadvantages.

Thus, an object of the present invention is a method of producing a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole the above formula (I), the molecular weight 120000-130000, which includes the interaction of the aqueous solution of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 with an aqueous solution of iodic acid or periodate sodium by passing the reaction solution of carbon dioxide to achieve a solution pH of 3.0 to 4.5, followed by separation of the dialdehyde carboxymethylcellulose, processing the obtained product hossipole or gossipcasey acid, then with an aqueous solution of alkali and isolation of the target product by precipitation with an organic solvent.

To highlight dialdehyde carboxymethylcellulose reaction mixture, after establishing a pH in the range of 3.0 to 4.5, and incubated at a temperature of 5-8°C in the dark place for 15-18 hours, the resulting dialdehyde of carboxymethyl cellulose precipitated with acetone and p is washed with an organic solvent, preferably 70%aqueous acetone and 80%aqueous alcohol. Subsequent processing of the hossipole or gossipcasey acid is carried out at a temperature of 18-20°C, followed by neutralization of the reaction mixture with an aqueous solution of alkali and selection of the target product by precipitation with an organic solvent, preferably acetone.

The proposed method eliminates the need to work with isopropyl alcohol and hydrochloric acid solutions, and provides a high yield of the target product.

Another object of the present invention is the use of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole the above formula (I) in the treatment of patients with autism spectrum disorders and cognitive impairment. So, in particular, the polymer used in combination with treatment for cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof. It is most preferable to apply a specified polymer, which is obtained by the method according to the present invention.

Another object of the present invention is a pharmaceutical composition intended for use in complex therapy of patients with autism spectrum disorders and cognitive impairment, the content is Asa as an active ingredient a therapeutically effective amount of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole the above formula (I) and pharmaceutically acceptable Supplement.

The proposed pharmaceutical composition may be presented in the form of various dosage forms depending on how it is used. For oral administration the pharmaceutical composition can be used in the form of tablets, capsules or suspensions. In addition, for rectal technique to use suppositories. The number of active component in the pharmaceutical composition may vary within a wide range depending on various factors well known to experts in the field of pharmaceutics. As pharmaceutically acceptable additives can be used normally used for the above-mentioned dosage forms of the substance. For example, in tablets as filler, you can use the starch, e.g. potato starch, calcium stearate or magnesium, sugar, milk and other pharmaceutically acceptable excipients.

Currently, all the more urgent becomes the problem of the decrease in pharmaceutical preparations number allerleirauh components. In this regard, the use as pharmaceutically acceptable additives ludipress, which contains a direct compression lactose, povidone, pyrrolidone and crosspovidone, allows you to completely replace the use in pharmaceutical preparations dairy Saha is a (lactose) and to reduce the content of such allerleirauh component, as starch, as well as to reduce the content of calcium stearate or magnesium. This increases the strength of the tablets.

In this regard, in the preferred version of the proposed pharmaceutical composition may have the following composition, in wt.%:

the active component of the above formula (I)10,0-16,0
starch10,0-20,0
calcium stearate or magnesium0,6-0,8
ludipressup to 100.

Typically, the pharmaceutical composition according to the present invention, used in combination with treatment for cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof.

Thus, another object of the present invention is a combination for the treatment of patients with autism spectrum disorders and cognitive disorders, comprising a therapeutically effective amount of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole the above formula (I) or pharmaceutical compositions based on it; and therapeutically effective the number of tools for the treatment of cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof.

Accordingly, another object of the present invention is a method of treating patients with autism spectrum disorders and cognitive disorders, comprising the administration to a patient a therapeutically effective amount of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole the above formula (I) in combination with a therapeutically effective amount for the treatment of cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof.

The method can be used for the treatment of autistic spectrum disorders and cognitive impairment in children aged 6 years. The treatment regimen is chosen by the specialist based on the severity of the disease, condition and age of the patient. In particular, the treatment may be carried out according to the following scheme: reception means 3 times a day for 5 days followed by 5-day intervals. This ten-day cycle is repeated 2 more times. Total treatment duration is 30 days. The dose of the active substance is 36 mg/day. Next, the course must be repeated.

For the treatment of cognitive disorders chosen from the ranks of neuroleptics, antidepressants and against the convulsive drugs. As neuroleptics usually use chlorpromazine, neuleptil, haloperidol, Terlingen, triftazin, Eglon, azaleptin, chlorprothixene. As antidepressants can be used anafranil, azafen, pirazidola, amitriptyline as anticonvulsants are commonly used Finlepsin, trileptal, topamax.

The following are examples of the preparation of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I), as well as examples of pharmaceutical compositions and method of treatment.

Examples of obtaining 1-8

Method: In a reactor equipped with a mechanical stirrer, 100 g of sodium carboxymethyl cellulose (Na-CMC) with a degree of substitution of 0.35 to prepare a 3% aqueous solution. In the resulting solution of Na-CMC was added to 1600 ml of 1% aqueous solution of iodic acid or periodate sodium. After complete mixing passed through a solution of carbon dioxide to reach the value of pH of 3.0 to 4.5. Then the reaction mass is incubated at a temperature of 5-8°C for 15-18 hours. The reaction product precipitated and washed with 70%acetone and 80%aqueous alcohol from an excess of oxidant and products of its decomposition. In the washed product, representing a dialdehyde carboxymethylcellulose add hossipole (or gossiprocks.com acid) in an amount of 15% of the initial mass strikeback is metiltselljulozy and stirred at 18-20°C for 5 minutes. The reaction mass is neutralized with 6% aqueous sodium hydroxide solution to a pH of 9.0. The selection of the target product is carried out by precipitation with acetone. Then washed with the same solvent to remove excess hossipole or its adduct and air-dried. The yield of the target product is 88%.

Specific data on examples of the preparation of the proposed compounds 1-8 are shown in table 1.

An example of the dosage form 1. Tablets.

Tablets were obtained in the usual way, namely, by mixing the ingredients and tabletting on teletrauma car. Examples of the quantitative composition of the tablets are shown in table 2.

Table 2
Examples of quantitative composition tablets
# example123
Weight pills100 mg150 mg200 mg
ComponentsNumber, mg%Number, mg %Number, mg%
The active ingredient(*)121218122412
Potato starch101015102010
Calcium stearate0,650,650,980,651,300,65
Ludipress77,3577,35116,0277,35154,7077,35
(*) a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I)

When checking the solubility found that by dissolving the tablets in 500 ml of water at 100 rpm stirrer per minute in the solution for 45 min passes 100% of the active substance.

Treatment detail ages 6 years with autism spectrum disorders and severe cognitive impairment

Studied the efficacy and safety of application of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) in the treatment of children 6 years of age with autistic disorder and severe cognitive impairment. The children took the drug on the basis of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) (tablets containing 12 mg of the active substance, the composition of which is given in table 2) on the background of basic therapy with neuroleptics, such as neuleptil, haloperidol, chlorpromazine, Terlingen, triftazin, Eglon, azaleptin or chlorprothixene. In some cases, used antidepressants (for example, anafranil) and protivosudorozhnye drugs Finlepsin, trileptal or topamax). Antipsychotics, antidepressants and anticonvulsants used in the optimal therapeutic doses.

In the group of patients treated in addition to the basic therapy of the drug on the basis of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I), decreased resistance to therapy with neuroleptics, especially in patients with severe forms of autism. Before the introduction of drug therapy on the basis of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) in these the of patients with increasing doses of neuroleptics positive therapeutic effect was not observed, in some cases, increased complications of therapy in the form of loss of skills neatness (encopresis have, enuresis). With the introduction of the drug therapy on the basis of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) were stopped symptoms of encopresis have, enuresis, decreased catatonic disorder, improved cognitive function, it appeared. In mild or moderately severe autism was filmed behavioral stereotypes, unilateral autistic Hobbies. On a background of reception of a preparation on the basis of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) improving the mental state of patients. The use of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) in the complex therapy of children with autism spectrum disorders and severe cognitive impairment allows you to remove the body's resistance to psychotropic drugs, which leads to a therapeutic effect on the background of reduction of single and daily dosages for drugs of basic treatment, significant improvement in the cognitive functions of patients. The use of the drug on the basis of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) does not have an adverse tricatel the impact on the patient's body. The drug is well tolerated, toxic and allergic reactions are not registered. The results are presented in table 3. Thus, the present invention allows to obtain a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) in a secure way with a high yield of the target product and effectively apply the specified product in the complex therapy of patients with autism spectrum disorders and cognitive impairment.

Table no.3
The research results obtained in the baseline treatment (neuroleptics, antidepressants and protivosudorozhnye drugs) and for inclusion in therapy of study drug.
№ p/pBasic therapyThe doses used for basic treatment (per day)Pharmacotherapeutic group used medicationThe patient's condition, taking basic therapy, prior to entering therapy investigational productThe condition of the patient after therapy with the investigational drug (daily dose of 36 mg)
CHILD PSYCHOSIS*
1Aralen2 mgAdjunctModerately illEasy ill
2Taralidis2.5 mgAdjunctModerately illEasy ill
3Triftazin7.5 mgAdjunctModerately illEasy ill
Eglon50 mgAdjunct
4Terlingen1.25 mgAdjunctModerately illEasy ill
Depakine-Chrono300 mgAnticonvulsant drug
5Neuleptil4 mgAdjunctModerately illEasy ill
Triftazin15 mgAdjunct
Eglon150 mgAdjunct
Amitriptyline25 mgAntidepressant
6Neuleptil2 mgAdjunctModerately illEasy ill
Eglon50 mgAdjunct
Aralen2.5 mgNeurolep is to
Tegretol100 mgAnticonvulsant drug

p/pBasic therapyThe doses used for basic treatment (per day)Pharmacotherapeutic group used medicationThe patient's condition, taking basic therapy, prior to entering therapy investigational productThe condition of the patient after therapy with the investigational medication
ATYPICAL CHILD PSYCHOSIS*
1Chlorpromazine50 mgAdjunctModerately illEasy ill
Triftazin5 mgAdjunct
Eglon100 mgAdjunct
Finlepsin50 mgAnticonvulsant drug
2Tizertsin37.5 mgAdjunctVery seriously illIll
Aralen4 mgAdjunct
Convulex140 mgAnticonvulsant drug
3Chlorpromazine25 mgAdjunctVery seriously illIll
Triftazin5 is g Adjunct
Eglon50 mgAdjunct
Finlepsin200 mgAnticonvulsant drug
4Terlingen15 mgAdjunctVery seriously illIll
Tizertsin12.5 mgAdjunct
Convulex200 mgAnticonvulsant drug
5Aralen6 mgAdjunctModerately hard Ill
Convulex180 mgAnticonvulsant drugill

6Eglon150 mgAdjunctModerately hardModerately ill
Haloperidol0.2 mgAdjunctill
Terlingen5 mgAdjunct
Aminosyn75 mgAdjunct
Triftazin15 mgAdjunct
Isolation12.5 mgAdjunct
Depakine-Chrono150 mgAnticonvulsant drug
7Treatment prior to entering therapy investigational product:
Terlingen15 mgAdjunctIll
Triftazin10 mgAdjunct
Aminosyn50 mgAdjunct
Convulex300 mgAnticonvulsant drug
Depakine-Chrono300 mgAnticonvulsant drug
Cerebralis1 tabletNootrop
Treatment when therapy investigational product:
Triftazin10 mgAdjunctModerately hard
Aminosyn50 mgAdjunctill
Depakine-Chrono150 mgAnticonvulsant drug
* Notes: according to the classification presented in the publication Wembeley Autism in childhood" (see the link to this publication on page 2 of the description), the terms "child psychosis" and "atypical child psychosis" is equivalent to the term "infantile autism" and "atypical infantile autism"

1. A method of producing a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I):

where a:b:C=1:(3-6):(5-7),
n=40-50;
molecular weight 120000-130000, including the interaction of the aqueous solution of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 with an aqueous solution of iodic acid or periodate sodium followed by separation of the dialdehyde carboxymethylcellulose, processing the obtained product hossipole or gossipcasey acid, then with an aqueous solution of alkali and isolation of the target product by precipitation with an organic solvent, characterized in that the interaction of the aqueous solution of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 with an aqueous solution of iodic acid or periodate sodium spend when crossing the AI through the reaction solution of carbon dioxide to achieve a solution pH of 3.0 to 4.5.

2. The use of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I):

where a:b:C=1:(3-6):(5-7), n=40-50;
molecular weight 120000-130000; in the complex therapy of patients with autism spectrum disorders and cognitive impairment.

3. The use according to claim 2, where the copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) obtained by the method according to claim 1.

4. The use according to claim 2 or 3, where the copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) used in combination with treatment for cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof.

5. The pharmaceutical composition intended for use in complex therapy of patients with autism spectrum disorders and cognitive disorders, comprising as active ingredient a therapeutically effective amount of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I):

where a:b:C=1:(3-6):(5-7),
n=40-50;
molecular weight 120000-130000;
and pharmaceutically acceptable additives.

6. The pharmaceutical composition according to claim 5 of the following composition, wt.%:

the active ingredient
formulas (1)10,0-16,0
starch10,0-20,0
calcium stearate or magnesium0,6-0,8
ludipress100

7. The pharmaceutical composition according to claim 5 or 6, intended for use in conjunction with treatment for cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof.

8. Combination for the treatment of patients with autism spectrum disorders and cognitive disorders, comprising a therapeutically effective amount of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I):

where a:b:c=l:(3-6):(5-7),
n=40-50;
molecular weight 120000-130000;
or a pharmaceutical composition according to claim 5 or 6; and
a therapeutically effective amount for the treatment of cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof.

9. A method of treating patients with autism spectrum disorders and cognitive Nar is the making, includes introduction to the patient a therapeutically effective amount of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I):

where a:b:c=l:(3-6):(5-7),
n=40-50;
molecular weight 120000-130000; or a pharmaceutical composition according to claim 5 or 6 in combination with a therapeutically effective amount for the treatment of cognitive disorders selected from one or more neuroleptic, antidepressant, anticonvulsant, or combinations thereof.

10. The use of a copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I):

where
a:b:C=1:(3-6):(5-7),
t=40-50;
molecular weight 120000-130000 to obtain the pharmaceutical composition according to claim 5 or 6.

11. The use of claim 10, where the copolymer of sodium carboxymethyl cellulose with a degree of substitution of 0.35-0,80 and hossipole formula (I) obtained by the method according to claim 1.



 

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12 ex, 1 tbl, 1 dwg

FIELD: chemistry.

SUBSTANCE: absorbent material is made by treating lignin-cellulose material in the presence of a catalyst from a transition metal with oxidation. The oxidising agent is selected from a group consisting of hydrogen peroxide, hypochlorite, hypochloric acid or any combination thereof. The lignin-cellulose material is treated at pH from approximately 2 to approximately 6. The treated lignin-cellulose material has viscosity equal to or less than approximately 17 cP. The treated lignin-cellulose material is subjected to dry grinding. The dry ground lignin-cellulose treated material is used as an absorbent intermediate layer for making absorbents.

EFFECT: improved bacteria inhibition properties.

2 cl, 17 ex, 16 tbl

FIELD: oil-and-gas production.

SUBSTANCE: invention related to oil-and-gas production, can be used for boring reagent fabrication. At oxidation stage of lingosulphanate with sol of chrome hexad, at pH 1-1.5, production waste, generated at main product drying stage, additionally added into reaction zone. Production waste is lingosulphanate water solution, which includes residual amount of chrome elements at different oxidation stages.

EFFECT: injection of a waste flow into reaction zone allow to use lingosulphanate of different types and maintain the process at the stage of components active interaction, also increase boring reagent diluting factor and decrease sodium dichromate losses.

4 tbl

FIELD: chemistry.

SUBSTANCE: invention relates to a pharmaceutical composition containing primary material in form of at least one compound selected from 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde and 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde, in a combination with an acceptable carrier, for treating and/or preventing disorders or pathologies which are a result of a disorder of reuptake of the following neuromediators: dopamine, serotonin and/or noradrenaline, as well as to use of at least one compound selected from 5-[(1'R)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde and 5-[(1'S)-1'-[(1aS,3aS,4S,7R,7aR,7bS)-decahydro-7-hydroxy-1,1,3a,7-tetramethyl-1H-cyclopropa[A]naphthalen-4-yl]-3'-methylbutyl]-2,4,6-trihydroxy-1,3-benzene dicarboxaldehyde to obtain a medicinal agent.

EFFECT: improved method.

9 cl, 2 ex, 1 tbl

FIELD: medicine.

SUBSTANCE: invention refers to pharmaceutical and food industry, particularly producing compositions of biologically active substances applicable as biologically active additives. The pharmaceutical composition contains glycine enriched by crystal gamma-modification of glycin in amount 90-98 %, and an additive of non-toxic organic acids in amount 2-10 %. Gamma-modification of glycin makes up to 8-95 % of total amount of glycine. As additives of the organic acids, the non-toxic acids are specified as follows: malic, malonic, citric acid, citric acid hydrate or a mixture thereof. A method for preparing the pharmaceutical composition of glycine is implemented by the combined mechanical treatment of the ingredients in a vibrating mill for 6-60 minutes.

EFFECT: pharmaceutical composition of glycine under the invention is solid-stable.

2 cl, 6 dwg, 2 tbl, 9 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to medicine. What is described is an adhesive composition containing donepezil and a stabiliser. The stabiliser containing one or more compounds specified in a group consisting of ascorbic acid, metal salt or ester of such, isoascorbic acid or metal salt of such, ethylene-diamine-tetraacetic acid or metal salt of such, cysteine, acetylcysteine, 2-mercaptobenzimidazole, 3(2)-tert-butyl-4-hydroxyanisol, 2,6-di-tert-butyl-4-methylphenol, tetrakis[3-(3',5'-di-tert-butyl-4'-hydroxyphenyl)]propionate pentaerythrite, 3-mercapto-1,2-propanediol, tocopherol acetate, rutin, quercetin, hydroquinone, metal salt of hydroxymethansulphinic acid, metabisulphite metal salts, sulphite metal salt and thiosulphate metal salts; it is added to a layer of a pressure sensitive adhesive applied on at least one side of the substrate.

EFFECT: prepared high reliable and stable adhesive composition which inhibits formation of donepezil-related compounds in the layer of the pressure sensitive adhesive.

14 cl, 4 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to new substituted tertahydro-4H-tieno-pyrrolo[3,2- c] pyridines of general formula 1, their geometric isomers or a mixture whereof and their pharmaceutically acceptable salts. In the general formula 1 Th represents an annulated tien cycle; W represents an single bond (in this case R3 is immediately bonded to the pyrrole cycle nitrogen atom), methylene, 1,2-ethane, 1,2-ethylene, 1,2-acetylene, 1,3-propane or 1,3-allyl bridge, non-obligatorily substituted by a hydroxy group; R1 and R2 represent hydrogen, C1-C4alkyl, a halogen or -CH2OH; R3 represents hydrogen, non-obligatorily substituted phenyl, non-obligatorily substituted by azaheteroaryl; R4 represents C1- C4alkyl, CO2C2H5 or CO2C(CH3)3; R5, R6, R7 (independent of each other) represent hydrogen or C1- C4alkyl or R5 and R6 together form an ethylene bridge while R7 represents hydrogen or R5 and R7 together form an ethylene bridge while R6 represents a hydrogen atom, they representing substituted tetrahydro-4H-tieno-pyrrolo [3,2-c] pyridines pf general formula 1, their geometric isomers, a mixture of such geometric isomers, their pharmaceutically acceptable salts as per any of Items 1-5.

EFFECT: obtainment of compounds representing ligands with receptor activity with regard to alpha-oadrenoreceptors, dopamine receptors, histamine receptors and serotonin receptors which compounds may be used during prevention and treatment of central nervous system diseases and for study of peculiarities of physiologically active substances possession biological activity with regard to the said receptors.

11 cl, 3 tbl, 21 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this invention relates to new compounds with formula (I) possessing the properties of mGLuR2 antagonists, to their obtainment methods, their application for production of medicines for prevention and treatment of disorders wherein mGLuR2 plays the activation role (in particular - central nervous system disorders). In formula (I) either any of X and Y represents N while the other represents CH or each of X and Y represents N; A represents aryl representing phenyl or 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur, the heteroaryl selected from among amidazolyl, [1,2,4] oxadiazolyl, pyrrolyl, 1H-pyrazolyl, pyridinyl, [1,2,4] triazolyl, tiazolyl and pyrimidinyl, each of them substitutable by C1-6-alkyl; B represents H, cyano or represents a possibly substituted aryl selected from among phenyl or possibly substituted by 5- or 6-membered heteroaryl containing in the cycle 1-3 atoms selected from among nitrogen, oxygen or sulphur where the substitutes are selected from the group consisting of nitro, C1-6-alkyl, possibly substituted hydroxy, NRaRb where Ra and Rb independently represent H, C1-6-alkyl etc. R1 represents H, a halogen atom, C1-6-alkyl, possibly substituted hydroxy, C1-6-alcoxy, C1-6-halogenoalkyl, C3-6-cycloalkyl represents H cyano, a halogen atom, C1-6-halogenoalkyl, C1-6-alcoxy, C1-6-halogenoalcoxi-, C1-6-alkyl or C3-6-cycloalkyl R3 represents a halogen atom, H, C1-6-alcoxy, C1-6-halogenoalkyl, C1-6-alkyl, C3-6-cycloalkyl, C1-6-halogenoalcoxy R4 reprsents H or halogeno.

EFFECT: creation of new compounds of formula (I) possessing mGLuR2 antagonist properties.

104 cl, 465 ex

FIELD: chemistry.

SUBSTANCE: invention relates to new compounds of indole with formula (I) or indole pharmaceutically acceptable salts: where: ring A stands for a benzene or a tiofen ring; R1 stands for a C1-.6 alkyl that may be substituted by one or several groups selected from among -OH, - O-C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls; -O-C1-6 alkyl; a halogen; CN; 5-6-membered cyclic amine; n is equal to 0 - 4 and to 0- 2 if ring A is a benzene or a tiofen ring accordingly; R2 stands for -H, -C1-6 alkyl; R3 stands for H, -C1-6 alkyl that may be substituted by phenyl, C3-6 cycloalkyl; R4 stands for C1-6 alkyl that may be substituted by one or several groups selected from among -OH, -O- C1-6 alkyl, an amino group that may be substituted by one or two C1-6 alkyls and 5-6-membered cyclic amine; C3-6 cycloalkyl, phenyl or-OH; X1 stands for -CH2-, -O-, -S-, -CH(R°)-; X2 stands for -C(RA)(RB)-, -O-; X3 stands for -C(RC)(RD)-; m is equal to 1 - 3; R° stands for -H, or R°, together with R4, form C3-6 alkylene; RA, RB, RC and RD are identical or different and stand for -H, C1-6 alkyl where, in case m is equal to 2 or 3, each RC and R° may be identical or different provided 1- methyl-4a-phenyl-2,3,4,4a,5,9b-hexahydro-1H-indeno [1,2-b] pyridine, 4a-phenyl-2,3,4,4a,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine and 2-(1,2,3,4,5,9b-hexahydro-4aH-indeno [1,2-b] pyridine -4a-yl)-N,N-dimethylethanamine are excluded).

EFFECT: compounds possess antagonistic activity regarding NMDA receptor which enables their usage in pharmaceutical compositions for treatment of Alzheimer disease, vascular dementia, Parkinson disease, chronic depression, attention deficit hyperactivity disorder, migraines etc.

18 cl, 40 tbl, 84 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: this group of inventions relates to medicine, namely - to neurology and deals with neurogenesis stimulation and depression treatment. For the said purpose one administers 2-(2-oxopyrrolidine-1-yl)-N-(2,3-dimethyl-5,6,7,8-tetrahydrofuro (2,3-b)chinoline-4-yl) acetamide in quantities effective for generation of new nerve cells.

EFFECT: neurogenesis stimulation and depression treatment.

10 cl, 10 dwg, 12 ex

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention relates to medicine, namely - to experimental pharmacology and can be used for physical endurance stimulation. For the said purpose one administers beta-cyclodextrin conjugated with p-amino-benzoic acid.

EFFECT: invention allows extending the range of medications for physical endurance stimulation.

1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: present invention refers to organic chemistry, namely new compounds of formula , wherein A represents residues of formulae

, , , X represents O; X1-X4 represents N, CH, CR1 or C-, X9-X12 represents N, CH, CR4 or C-, X13-X16 represents N, CH, CR or C-, wherein C represents an attachment point of the group A to a residue of the structure of formula (I); R' represents H or alkyl; R represents alkoxy, or Het; R1 represents F, CI, Br, I, OH, CN, carboxy, CONR6R7, NR2COR8, NR2COOR8, alkoxy, fluorinated alkoxy, Ar, Het or OHet; or R1 represents one of the following formulas: wherein n is equal to 2 and m is equal to 3; R2 represents H, alkyl, fluorinated alkyl, cycloalkyl, Het or Het-NH-CO-; R4 represents F, Cl, Br, I, OH, alkoxy, cycloalkoxy, Het or OHet; or R4 represents one of the following formulae: , wherein n is equal to 2 and t is equal to 3; each R6 and R7 independently represents alkyl, or cycloalkyl, or R6 and R7 together represent alkylene group containing 5-6 carbon atoms which forms a cycle with N atoms; R8 represent alkyl, or cycloalkylalkyl; R9 represents alkyl; Ar represents aryl group; Het represents heterocyclic group which is completely saturated, particularly saturated or completely unsaturated containing 5 to 10 ring atoms in which at least 1 ring atom represents N, O or S atom which is unsubstituted or substituted once or several times by the substituted specified in cl. 1; and their pharmaceutically acceptable salts or solvates or N-oxides, or solvates of their pharmaceutically acceptable salts, or solvates of N-oxides of their pharmaceutically acceptable salts wherein said compound can be presented in the form of a polymorph, wherein if said compound shows chirality, it can be presented in the form of a mixture of enanthiomers or a mixture of diastereoisomers, or can be presented in the form of single enanthiomer or single diastereoisomer; and wherein at least one of the groups R, R1 or R4 represents Het or OHet, wherein the group Het is specified in each case in substituted or unsubstituted azabicyclooctyl, oxaazabicycloheptyl, diazabicycloheptyl, diazabicyclononyl, diazabicyclooctyl, pyrazolyl, dihydroimidazolyl, 1,4-diazepanyl, hezahydropyrrolopyrazinyl and octahydropyrrolopyridinyl. Also the invention refers to other compounds of formula (I), to specific compounds, to a pharmaceutical composition based on the compound of formula (I), to a method of selective activation/stimulation of α-7 nicotinic receptors, to application of the compound of formula (I) for making the drug.

EFFECT: there are produced new compounds showing effective biological properties.

53 cl, 1 tbl

FIELD: medicine, pharmaceutics.

SUBSTANCE: invention refers to azaadamantane derivatives of formula (I), to their pharmaceutically acceptable salts possessing the properties of nAChR ligands, their application, a method of treating and based pharmaceutical compositions, and also to intermediate compounds of formula (VI) and (VII) and to application of the compound of formula (V) for preparing the compound (I). In general formulas

L1 represents -O- or -NRa-; A represents -Ar1 or -Ar2-L2- Ar3; Ar1 represents 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxyalkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2, (NH2)carbonyl and oxido; Ar2 represents 5-6-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, carboxy, carboxy alkyl, cyano, halogenalkoxy, halogenalkyl, halogen, hydroxy, nitro, -NH2 and (NH2) carbonyl; Ar3 represents aryl, optionally substituted alkoxy, alkoxyhalogenalkyl, alkyl, aryl, halogenalkoxy, halogen, hydroxy and -NH2; or Ar3 5-9-member heteroaryl wherein said heteroaryl is optionally substituted by alkoxy, alkoxycarbonyl, alkyl, alkylcarbonyl, aryl, carboxy, carboxyalkyl, halogenalkyl, heterocyclyl and tritylaryl; L2 represents a bond, -O- or -C(O)NRa-; and Ra represents hydrogen.

EFFECT: preparing the pharmaceutically acceptable salts possessing the properties of nAChR ligands.

41 cl, 11 dwg, 162 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to a group of new derivatives of 4,5-dihydro-1H-pyrazole of the general formula (I):

wherein R means phenyl, thienyl or pyridyl and these indicated groups can be substituted with (C1-C3)-alkoxy-group or halogen atom; R1 means phenyl that can be substituted with (C1-C3)-alkoxy-group or pyridyl group; R2 means hydrogen atom or hydroxy-group; Aa means one group among the following groups: (i) , (ii) , (iii) , (iv) or (v) ; R4 and R5 mean independently from one another hydrogen atom or (C1-C8)-branched or unbranched alkyl; or R4 means acetamido- or dimethylamino-group or 2,2,2-trifluoroethyl, or phenyl, or pyridyl under condition that R5 means hydrogen atom; R6 means hydrogen atom at (C1-C3)-unbranched alkyl; Bb means sulfonyl or carbonyl; R3 means benzyl, phenyl or pyridyl that can be substituted with 1, 2 or 3 substitutes Y that can be similar or different and taken among the group including (C1-C3)-alkyl or (C1-C3)-alkoxy-group, halogen atom, trifluoromethyl; or R3 means naphthyl, and its racemates, mixtures of diastereomers and individual stereoisomers and as well as E-isomers, Z-isomers and mixture of E/Z-compounds of the formula (I) wherein A has values (i) or (ii), and its salt. These compounds are power antagonists of Cannbis-1 (CB1) receptor and can be used for treatment of psychiatric and neurological diseases. Except for, invention relates to a pharmaceutical composition used for treatment of some diseases mediated by CB1-receptor, to a method for preparing this composition, a method for preparing representatives of compounds of the formula (I) wherein Aa means group of the formulae (i) or (ii), intermediate compounds used for preparing compounds of the formula (I) and to a method for treatment of some diseases mediated by CB1-receptor.

EFFECT: valuable medicinal properties of compounds.

16 cl, 9 ex

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