Pharmaceutical composition for topical application for the treatment of allergic diseases of the eye and nose

 

(57) Abstract:

The invention relates to medicine, namely to the chemical-pharmaceutical industry and relates to pharmaceutical compositions for topical application for the treatment of allergic diseases of the eye and nose. The invention consists in the development of a composition which contains as an active ingredient cetirizine or its salt, and optionally includes cyclodextrine connection as excipients. The technical result consists in the development of anti-allergic composition for topical application as a therapeutic and prophylactic agent for allergic diseases in ophthalmology and otolaryngology. 11 C.p. f-crystals, 5 PL.

The invention concerns anti-allergic composition for the treatment of eyes or nose, more specifically, it relates to anti-allergic composition comprising cetirizine and suitable for treatment of allergic diseases in the field of ophthalmology and otorhinology.

Cetirizine is an anti-allergic compound of the formula

< / BR>
chemical name of which[2-[4-[(4-chlorophenyl)phenylmethyl]- 1-piperazinil]-ethoxy]acetic acid.

In allergic diseases of the eye and nose, let's take as an example, allergic eye disease, ocular symptoms are often associated symptoms relating to the entire organism, in this case, the reception antiallergic agent inside effective for treatment. However, there are cases when it is impossible to determine deviations, even if in the eyes has been a noticeable change, in particular lesions detected only in the eyes, not always accompanied by deviations relating to the entire organism. In such cases, therapy whole body prefer local therapy, because it is safe and effective. This link between the symptoms relating to the entire organism, and local symptoms remains in force and in the field of otorhinology.

Already disclosed antiallergic and antipruritic composition in the form of eye drops containing cetirizine /see, for example, JP-A 4-9339/. This composition includes anti-allergic component and antipruritic agent, which is able to exercise effective antihistamine effect when used in combination with anti-allergic agent. Cetirizine is an example of Takako so far there are no reports of the effect, achievable when using eye antiallergic compositions containing cetirizine as the sole active ingredient.

Of cetirizine, despite its easy solubility in water, there is a disadvantage of the solutions of cetirizine at low concentrations /below 1 wt./about%/ over time may be deposited insoluble substance, which reduces the stability of the aqueous solution. Apparently, this is due to the fact that cetirizine is derived from one of difenilmetana capable of the formation of molecular aggregates (see, for example, Masayukr Nakagaki (ed.), "Bussei-Batsuri (Material Science)", Nankodo, Tokyo 1986, pp. 238-239/. On the other hand, the solution of cetirizine at high concentrations, when not deposited insoluble substance, has a strong irritating properties when used for eyes and nose and may not be applied as drops to eyes or nose. For this reason, it is still not developed anti-allergic composition for practical use, containing cetirizine as the main active ingredient that can be applied as drops to eyes or nose.

In General, in most cases, it is difficult to prepare eye drops or nose with a satisfactory safety the molecular aggregates, although it depends on the medication.

It is well known that the compounds of cyclodextrin tend to take in the Central part of the molecules of the various medications with the formation of clathrate compounds of these drugs, because they are cyclic sugars. Therefore, compounds of cyclodextrin is still used to prepare solutions of various poorly soluble drugs or increase the stability of drugs. However, when compounds of cyclodextrin is mixed with certain drugs, in most cases, the drug is difficult to demonstrate effectiveness, and this problem is especially serious for outdoor products.

The authors of the present invention intensively engaged in improving containing cetirizine solutions to the eyes or nose with satisfactory security and stability, which can overcome the above described disadvantages of cetirizine and which do not have the irritating properties of the mucosa of the eyes and nose. As a result, they found that the addition of compounds of cyclodextrin water solution of cetirizine can reduce the precipitation of insoluble substances, even at low concentrations, when in normal satirizing connection with cyclodextrin can suppress the irritating effect of cetirizine on mucous membranes of the eyes or nose at high concentrations, when in normal cases detected irritation, and that such an aqueous solution may have a significant vast impact on allergic diseases of the eye and nose, in addition, they found that the addition of surfactants and/or water-soluble polymer to the aqueous solution of cetirizine, mixed with cyclodextrines connection may prevent the Association of cetirizine in aqueous solution over a long period of time. This was accomplished the present invention.

Thus, the present invention provides an anti-allergic composition acceptable to the eyes or nose, characterized in that it contains cetirizine or its salt as an active ingredient. In addition, it may contain the compound of the cyclodextrin, as well as surfactant and/or water-soluble polymer.

Antiallergic composition of the present invention almost does not irritate the eyes and nose and can be effectively used as a prophylactic and therapeutic agent for allergic diseases in the field of ophthalmology and otorhinology, such as allergic conjunctivitis /for example, conjuctive allergic rhinitis, vesen the program contains as the active ingredient cetirizine or its salt. Examples of the salt of cetirizine are salts of inorganic acids such as hydrochloride, sulfate, nitrate and phosphate, and organic acid salts such as acetate, citrate, tartrate, and maleate.

In addition, the antiallergic composition of the present invention may contain cyclodextrine compound, and a surfactant and/or water-soluble polymer.

Typical examples cyclodextrines compounds are-cyclodextrin, -cyclodextrin, -cyclodextrin, hydroxypropyl-cyclodextrin, dimethyl-cyclodextrin, maltose-cyclodextrin and-cyclodextrins. These cyclodextrine compounds can be used alone or in combination.

The number cyclodextrines connection, which should be used can vary depending on its solubility and concentration of cetirizine. However, it is desirable that the number cyclodextrines connection was 0.5 to 3.0, preferably 1.0 to 2.0 on the number of mol of cetirizine.

Surfactants used are preferably of the nonionic type. Typical examples of nonionic surfactants are Polysorbate 80, polyoxyethylenated the VA can be used singularly or in combination.

Water-soluble polymers include cellulose derivatives, vinyl polymers and polyols. Examples of the cellulose derivatives are alkylsilanes, such as methylcellulose and carboxymethylcellulose, and hydroxyethylcellulose, such as hydroxypropylcellulose and hydroxyethylcellulose. Typical examples of the vinyl compounds are polyvinylpyrrolidone and polyvinyl alcohol. Typical examples of polyols are the ranks of macrogol 200 - 6000. These water-soluble polymers can be used singularly or in combination.

The amount of surfactants or water-soluble polymer that can be used may vary depending on their type and concentration of cetirizine. However, it is desirable that the amount of surfactant was from 0.01 to 1.0, preferably from 0.05 to 0.5 by weight of cetirizine, and the amount of water-soluble polymer comprised of 0.01 to 10.0, preferably of 0.02 to 5.0 by weight of cetirizine.

Antiallergic composition of the present invention can be used in the pH interval, suitable for normal drops for eyes or nose, usually a pH of 4.0 and 9.0, preferably 5.0 to 8.0.

In addition, the antiallergic composition of the present and the data drops for eyes or nose, for example stabilizers such as n-oxybenzoates, benzylaniline and chlorbutanol; chelating agents, such as dimitrieff and sodium citrate, reagents for the preparation of isotonic solutions, such as sodium chloride, sorbitol and glycerol; buffering agents, such as phosphates, boric acid and citrates, and reagents for pH control, such as hydrochloric acid, acetic acid, and sodium hydroxide. The quantity of the ingredient that you want to apply, can be determined by experts qualified in this area, within the same interval, which is chosen for normal drops for eyes or nose.

In addition, the antiallergic composition of the present invention may contain in addition to cetirizina any therapeutic ingredients in the right quantities, does not reduce the advantages achieved by the present invention.

Antiallergic composition of the present invention can have various dosage forms, pharmaceutically acceptable in the field of ophthalmology or otorhinology, such as solutions, suspensions, emulsions, gels and ointments. It may also be prepared, for example, in powder form, which is converted to an aqueous solution using distilled water Vania may vary in accordance with the method and allergic symptoms. However, usually the concentration is in the range from about 0.01 to 4.0 wt./vol.%, preferably from about 0.05 to 2.0 wt./vol.%. For example, when used as eye drops for adults antiallergic composition of the present invention preferably take approximately 3 to 6 times a day, the dose is from one to several drops per reception. When used as a solution for nose antiallergic composition of the present invention preferably is sprayed and inhaled about 3 to 6 times a day, the dose is 1 to 2 sprays to the nasal cavity using an inhaler.

The present invention is illustrated workers and test examples, which illustrate but do not limit the invention.

Test example 1: the Study of the irritation to the eyes of rabbits.

Method.

Using male Japanese white rabbit without any deviations in the outer part of the eye /4 groups of 3 rabbits/, in the right eyes of rabbits corresponding group buried compositions C, D, E or F, prepared in the form of solutions in accordance with the formulation shown in table. 1 (PL. 1-5, see the end of the description), and in the left eye only rastonirovali macroscopic examination of the external parts of the eye and the study of fluorescent staining of the cornea before the first instillation on the first day, 30 minutes after the last instillation in each of the following days of treatment: the first, third, fifth, sixth.

Results.

In groups of rabbits that received external solution C or D after the last instillation on the first day was observed redness on conjuctive century and a nictitating membrane. These symptoms are so strong, especially in the group of rabbits receiving solution D that individual blood vessels, which must be clearly visible on normal conjuctive century, were not clearly distinguishable. In addition, it was observed dilation of blood vessels of the conjunctiva of the eyeball and swelling of the conjunctiva century. Redness, mentioned above, were still observed even after 16 hours after the last injection on the first day and up to putting on the second day. Observation on the third day of treatment also discovered redness of conjunctiva, as with observation after the last instillation on the first day, but stronger in both groups, this indicates that cetirizine has a strong irritating effect on the conjunctiva. In the study of fluorescent staining of the cornea is performed after processing the instillation was observed spots of dye on the entire surface of the horn is of the cornea. Having come to the conclusion that the eyes of rabbits will not be able to make further irritation, processing solutions C or D stopped on the third day.

In the group of rabbits treated with the solution E containing cyclodextrins connection, there was slight redness on conjuctive of the cornea and eyelids after the last instillation on the first day, while some rabbits from the group treated with the solution F were found in a small number of selections. However, no redness, no discharge from eyes, discovered on the first day, more was not observed neither in the third day or later. Even in the study of fluorescent staining of the cornea, carried out at the end of treatment, there was no change compared with the condition before treatment and all detected changes did not go beyond the norm, clearly indicating that the reduction of irritation of the eye can be achieved by adding to the composition of zetiasynthroid cyclodextrines connection. Eyes treated with solvent, do not detect the irritation caused by the solvent.

Test example 2: toxicity Study by instillation in the eye of the rabbit.

Method.

Using healthy male Japanese white is testwuide group buried ophthalmic composition F or K, prepared in the form of a solution in accordance with the formulation shown in table. 1,

Note: Qty hydrochloride sodium required to achieve a specified pH, 8 times a day one drop on admission within 28 days. In rabbits was examined General condition, feed intake, body weight and ophthalmic indicators /macroscopic observation of the external parts of the eye, the observation of the colored spots of the cornea and the fundus of the eye, intraocular pressure measurement/ within 28 days, then they did a urine analysis, blood analysis, biochemical blood analysis, dissection, measurement of the weight of the organs, histopathological study of the eyeball and electron-microscopic examination of the cornea.

Results.

As for the instillation of solutions F or K, was not detected deviations no ophthalmologic indicators or overall condition, no deviations in other studies.

Test example 3: Impact on conjunctivitis rabbits caused by histamine.

Method.

Male rabbits Wistar weighing approximately 100 g under a conjunctiva of the upper eyelid was introduced 50 ml of 0.1 wt./vol.% histamine. In both eyes of rabbits corresponding group buried every one of the introduction of the histamine. Rabbits scored one hour after the injection of histamine. Measured the mass swelling of the conjunctiva of the eyelids and used to calculate the degree of suppression of edema, using as a maximum mass of swelling of the groups that received saline. As a test of eye solutions, used a solution prepared by dissolving zetiasynthroid in solvent /2.0 wt. /about. % conc. glycerol, 0.4 wt./vol.% an aqueous solution of boric acid and sodium hydroxide /g. s/; /pH 7.0/ with obtaining the specified target concentration (hereinafter called ophthalmic solution CE/, a solution prepared by dissolving equimolar amounts of zetiasynthroid and either-or-cyclodextrin in a solvent to obtain the specified target concentration (hereinafter called ophthalmic solution CE+-CD ophthalmic solution CE+CD accordingly/ and a solution prepared by dissolving diphenhydraminebuprofen in a solvent (hereinafter called ophthalmic solution DPH/.

Results.

In the model caused by histamine conjunctivitis rats zetiasynthroid shows degree of suppression around and 88.8% at a concentration of 0.5 wt./vol.%, indicating significant antipruritic effect of zetiasynthroid in obladatelei with - or-cyclodextrin against conjunctivitis caused by histamine was determined concentration zetiasynthroid /mm/ each solution for the eyes, which showed 50% inhibition of edema /IC50/ using as a control group of rats, which were buried with saline. The values of the IC50obtained for the test solution for eyes that are listed in the table. 2.

As shown in the table. 2, the value of the IC50ophthalmic solution CE is 2,05 mm and about 0.1 wt./vol.%/; this indicates that zetiasynthroid to a certain extent has antihistaminic activity even at concentrations lower than annoying. Groups of rats treated ophthalmic solution CE or CE+CD, have essentially equal values IC50; this indicates that in this system experiment-cyclodextrin affects the efficiency of zetiasynthroid insignificant. The value of the IC50in the group of rats treated with ophthalmic solution CE+CD, was slightly higher than in the group of rats treated with ophthalmic solution CE /containing only one zetiasynthroid/. This fact suggests that the addition of cyclodextrin to the composition of zetiasynthroid causes a small decrease in the efficiency of ceritified can be saved.

Test example 4. The study of eye irritation in humans.

Method.

There is some difference between irritation of the eyes in humans and in animals by burying them in the eye solution. In addition, in the case of people's eyes need to consider certain subjective factors, such as sensation after backfilling. It is therefore necessary to conclude that the preferred eye solutions without any irritation to the eyes of the people, and in practice may not be entered any song with a strong irritant. In this regard, compositions A, B, D, E, F, G, H, J and K in the form of a solution, shown in the table. 4, measured at the feeling after applying for digging into people's eyes /I, II, III and IV/. The results are presented in table. 3.

Results.

Of ophthalmic compositions that do not contain cyclodextrin, i.e., compositions A, B and D, in the form of a solution, A solution containing 0.25 wt./vol.% zetiasynthroid, gives a small irritation, and only two of the four subjects people; this indicates that the eye irritation people zetiasynthroid significantly reduced at relatively low concentrations. In contrast, solutions B and D, concentra features, solution D is so annoying for the eye that does not find practical application.

On the other hand, the solutions E, F, G and K, containing -, - or-cyclodextrin, do not cause irritation of the eyes, although the concentration of citiesmermaid them above 1 wt./vol.%. Therefore, it is clear that adding cyclodextrins compounds to the composition of zetiasynthroid can lower irritation eye zetiasynthroid, and the resulting composition is in the form of a solution can be safely used as eye drops.

Solution H containing polyvinylpyrrolidone, and it does not irritate the eyes, but with the property that the formation of complexes with many different substances, and the solution J containing chlorbutanol, which has a local anesthetic effect and is commonly used to reduce local pain caused by the injection, give strong eye irritation; this indicates that neither polyvinylpyrrolidone or chlorbutanol are not acceptable as an additional ingredient to achieve the objective of the present invention, i.e., to inhibit irritation of the eye caused by cetirizine or its salts.

Test example 5: a Study of irritation with the expression of the human nose is more preferable, what is true for eye drops, and any song with a strong irritant effect cannot be put into practice. In this respect, the solutions C, D and F are estimated by feelings after their application when spraying in the noses of people /I, II, III/.

The results are shown in table. 4.

Results.

When the solution C was sprayed in the nose, one or three human subjects felt irritation. When applying the solution D all subjects people feel severe irritation persisting for quite a long time; this indicates that the composition containing only zetiasynthroid in the solvent, annoying and nasal mucosa.

On the other hand, the solution F containing-cyclodextrin, caused slight irritation only one of the three human subject, although the concentration of zetiasynthroid it was the same as in solution D, causing severe irritation. Moreover, the irritation of a solution F disappears after a short time. Therefore it is clear that adding cyclodextrines connection to the composition of cetirizine or its salts can inhibit irritation of the nose, and such a composition in the form of the solution can be used B2">

Were prepared with compositions A and K, are presented in table. 1, and the composition of the L-N and P-R are presented in table. 5, in the form of solutions. Each of the solutions was filtered through a membrane filter 0.45 Ám mesh, followed by sealing in a glass ampoule. These vials were kept at room temperature for 6 months, during which they were subjected to macroscopic examination to detect the insoluble substance over time.

Results.

Vials with A solution after 1 day from the beginning of storage at room temperature was observed by the precipitation of insoluble substances. In vials with solutions K and L appeared a small residue of insoluble matter in 6 months. In contrast, in vials of solutions M, N and P-R even after 6 months found no precipitate of insoluble substances.

Thus, we discovered that adding cyclodextrines connection to the composition of zetiasynthroid may reduce the Association of cetirizine, and the addition of surfactants or soluble polymer to the composition of zetiasynthroid and cyclodextrines compounds can inhibit the Association of cetirizine, creating, thus, who is tion zetiasynthroid only with surface-active agent or a water-soluble polymer is not able to prevent the precipitation of insoluble substances.

Example 1. Was prepared ophthalmic composition in the form of lyophilized powder in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 0.5 g

Boric acid 5.0 g

Sodium hydroxide - g.s

Distilled water To a volume of 100 ml

Zetiasynthroid and boric acid was dissolved in 80 ml of distilled water and brought the pH of the solution to 7.0 by addition of an aqueous sodium hydroxide solution, and then distilled water was added, bringing the total solution volume to 100 ml of the resulting solution was sterilized by filtration and was divided into portions of 2 ml, which then liofilizirovanny, thus obtaining the ophthalmic composition. Immediately before use eye composition was dissolved in 5 ml of distilled water for injection.

Example 2. was prepared ophthalmic composition in the form of a solution in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 1.0 g

-Cyclodextrin - 2.1 g

Boric acid, 2.0 grams

Sodium hydroxide - g.s

Distilled water To a volume of 100 ml

Zetiasynthroid, -cyclodextrin and boric acid was dissolved in about 80 ml distilliation water, bringing the total solution volume to 100 ml, thus obtaining the ophthalmic composition.

Example 3. Was prepared ophthalmic composition in the form of a solution in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 1.0 g

-Cyclodextrin - 2.1 g

The hypromellose - 0.1 g

Boric acid, 2.0 grams

Sodium hydroxide - g.s

Distilled water To a volume of 100 ml

About 80 ml of distilled water was heated to approximately 90oC, evenly was dispersively it hypromellose. The suspension was mixed by placing it in an ice-water bath, so that the hypromellose dissolved. After heating to room temperature the solution was to dissolve zetiasynthroid, -cyclodextrin and boric acid. the pH of the thus obtained solution was brought to 7.0 by addition of an aqueous sodium hydroxide was then added to distilled water, bringing the total solution volume to 100 ml, thus obtaining the ophthalmic composition.

Example 4. Was prepared with the composition for the nose in the form of a solution in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 2.0 grams

-Cyclades Is R> Sodium hydroxide - g.s

Distilled water To a volume of 100 ml

About 80 ml of distilled water was heated to approximately 90oC, evenly was dispersively it hypromellose. The suspension was mixed by placing it in an ice-water bath, so that the hypromellose dissolved. After heating to room temperature the solution was to dissolve zetiasynthroid, -cyclodextrin, boric acid and dimitrieff. the pH of the thus obtained solution was brought to 7.0 by addition of an aqueous sodium hydroxide solution, and then distilled water was added, bringing the total solution volume to 100 ml, thus obtaining a composition for a nose.

Example 5. Was prepared ophthalmic composition in the form of a solution in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 0.3 grams

-Cyclodextrin - 0.8 g

Polyvinyl alcohol - 0.2 g

Sodium acetate 0.1 g

Propylene glycol - 2.0 grams

Methylparaben 0.2 g

Propyl paraben 0.1 g

Sodium hydroxide - g.s

Distilled water To a volume of 100 ml

About 80 ml of distilled water was heated to approximately 90oC, evenly was dispersively it polivinil risingdragon, -cyclodextrin, sodium acetate and propylene glycol. the pH of the thus obtained solution was brought to 7.0 by addition of an aqueous sodium hydroxide solution, and then distilled water was added, bringing the total solution volume to 100 ml, thus obtaining the ophthalmic composition.

Example 6. Was prepared with the composition for the nose in the form of a solution in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 1.0 g

-Cyclodextrin - 2,47 g

The hypromellose - 0.1 g

Boric acid - 1,25 g

Dimitrieff - 0.01 g

Sodium hydroxide - g.s

Distilled water To a volume of 100 ml

About 80 ml of distilled water was heated to approximately 90oC, evenly was dispersively it hypromellose. The suspension was mixed by placing it in an ice-water bath, so that the hypromellose dissolved. After heating to room temperature the solution was to dissolve zetiasynthroid, -cyclodextrin, boric acid and dimitrieff. the pH of the thus obtained solution was brought to 7.0 by addition of an aqueous sodium hydroxide solution, and then distilled water was added, bringing the total volume of the solution to forma solution in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 0.5 g

Hydroxypropyl-cyclodextrin - 1.6 g

Polyvinylpyrrolidone - 1.0 g

Macrogol 4000 - 1.0 g

Potassium dihydrophosphate - 0.1 g

Mannitol is 5.1 grams

Benzylaniline - 0,005 grams

The potassium hydroxide - g.s

Distilled water To a volume of 100 ml

Dissolved zetiasynthroid, hydroxypropyl-cyclodextrin, polyvinylpyrrolidone, macrogol 4000, potassium dihydrophosphate, mannitol and benzylaniline about 80 ml of distilled water. the pH of the thus obtained solution was brought to 7.5 by addition of an aqueous solution of potassium hydroxide was then added to distilled water, bringing the total solution volume to 100 ml, thus obtaining a composition for a nose.

Example 8. Was prepared with the composition for the nose in the form of a solution in accordance with the following recipe:

Ingredient - Number

Zetiasynthroid - 1.0 g

-Cyclodextrin - 1.0 g

-Cyclodextrin - 1.5 grams

Sodium citrate, 0.05 g

Sodium chloride 0.9 g

The potassium hydroxide - g.s

Distilled water To a volume of 100 ml

Dissolved zetiasynthroid, hydroxypropyl-cyclodextrin, -cyclodextrin, sodium citrate and sodium chloride of prestara potassium hydroxide, then distilled water was added, bringing the total solution volume to 100 ml, thus obtaining a composition for a nose.

1. Pharmaceutical composition for topical application for the treatment of allergic diseases of the eye and nose, characterized in that it contains a compound of the formula

< / BR>
or its salt, and optionally includes cyclodextrine connection as excipients.

2. The composition according to p. 1, characterized in that said cyclodextrins compound is a compound selected from the group consisting of cyclodextrin, -cyclodextrin and cyclodextrin.

3. The composition according to p. 1, characterized in that it includes, in addition, surface-active substance.

4. Composition under item 1 or 3, characterized in that it comprises, furthermore, a water-soluble polymer.

5. The composition according to p. 3, characterized in that said surface-active agent is a surfactant nonionic type.

6. The composition according to p. 5, characterized in that said nonionic surface-active substance is a substance selected from the group consisting of Polysorbate 80 and polyoxyethylenesorbitan Casteau the tsya polymer, selected from cellulose derivatives, vinyl polymers and polyols.

8. The composition according to p. 7, characterized in that said derivative of cellulose is alkylsalicylate and hydroxyethylcellulose.

9. The composition according to p. 8, characterized in that the specified alkylsalicylate is methylcellulose and carboxymethylcellulose.

10. The composition according to p. 8, characterized in that the specified hydroxyethylcellulose is hypromellose and hydroxyethylcellulose.

11. The composition according to p. 7, characterized in that said vinyl polymer is polyvinyl alcohol and polyvinylpyrrolidone.

12. The composition according to p. 7, characterized in that said polyol is macrogol 4000.

 

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13 cl, 1 tbl, 30 ex

FIELD: organic chemistry, chemical technology, medicine, biochemistry, pharmacy.

SUBSTANCE: invention relates to new derivatives of sulfonamides of the formula (I) or their pharmaceutically acceptable salts wherein R1 means -OH or -NHOH; R2 means hydrogen atom; R3 means alkyl, alkoxyalkyl, arylalkyl, pyridylalkyl or morpholinylalkyl; A means piperidyl or tetrahydrofuranyl; n = 0; E means a covalent bond; (C1-C4)-alkylene, -C(=O)-, -C(=O)O- or -SO2-; X means hydrogen atom, alkyl, aryl, arylalkyl, alkoxyalkyl, morpholinyl or tetrahydropyranyl; each among G and G' means -C(R5)=C(R5') wherein R5 and R5' mean hydrogen atom; M means the group -CH-; z means the group -(CR7R7')a-L-R8 wherein a = 0 and each among R7 and R7' means hydrogen atom; L means a covalent bond; R8 means halogen atom or alkoxy-group. Compounds of the formula (I) are inhibitors of metalloproteases and can be used for treatment of arthritis, cancer tumors and other diseases.

EFFECT: valuable medicinal properties of compounds.

15 cl, 7 tbl, 56 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of indolylpiperidine of the formula (I): wherein A1 means (C1-C7)-alkylene, (C1-C7)-alkyleneoxy-, (C1-C7)-alkylenethio-, (C1-C7)-alkanoyl, hydroxy-(C1-C7)-alkylene; A2 means a single bond, (C1-C7)-alkylene, (C2-C5)-alkenylene; W means a single bond, phenylene, furanylene that is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkoxy- and/or alkyl groups; R1 means hydrogen atom (H), (C1-C7)-alkyl, (C2-C7)-alkenyl, (C2-C7)-alkynyl, (C2-C5)-alkoxyalkyl, (C3-C7)-alkenyloxyalkyl, (C3-C7)-alkynyloxyalkyl, (C3-C7)-alkoxyalkoxyalkyl, phenyl-(C1-C7)-alkyl wherein phenyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy- or arylalkoxy- (preferably with phenylalkoxy-) groups, or means (C3-C10)-cycloalkyl-(C1-C7)-alkyl wherein cycloalkyl is unsubstituted or substituted with one or more halogen atoms, (C1-C7)-alkyl, (C1-C7)-alkoxy-groups; R2 means hydrogen atom (H), halogen atom, (C1-C7)-alkyl, (C1-C7)-alkoxy-; R3 means carboxyl, tetrazolyl, and to their pharmaceutically acceptable salts. Compounds of the formula (I) elicit antihistaminic and anti-allergic activity that allows their using in composition used for treatment of allergic diseases including bronchial asthma, rhinitis, conjunctivitis, dermatitis and nettle rash. Also, invention describes methods for preparing compounds of the formula (I).

EFFECT: valuable medicinal properties of compounds.

15 cl, 2 sch, 3 tbl, 162 ex

FIELD: pharmaceutical chemistry.

SUBSTANCE: invention relates to treatment of patients suffering from diseases associated with pathologic activity of matrix proteases. Treatment involves administration of compounds depicted by general formula (I).

EFFECT: increased treatment efficiency.

136 cl, 448 ex

FIELD: organic chemistry, medicine.

SUBSTANCE: invention relates to new 2-aminopyridine derivatives of formula I , wherein R1 is cyano, carboxyl or carbamoyl; R2 is hydrogen, hydroxyl, C1-C6-alkoxy or phenyl; R3 and R4 are aromatic hydrocarbon such as phenyl or naphthyl, 5-14-membered 5-14-membered optionally substituted aromatic group, excepted cases, when (1) R1 is cyano, R2 is hydrogen, and R3 and R4 are simultaneously phenyl;(2) R1 is cyano, R2 is hydrogen, R3 is 4-pyridyl, and R4 is 1-pyridyl; (3) R1 is cyano, R2 is 4-methylphenyl, and R3 and R4 are simultaneously phenyl;(4) R1 is cyano, R2, R3 and R4 are simultaneously phenyl, or salts thereof. Derivatives of present invention have adenosine receptor antagonist activity and are useful in medicine for treatment of irritable bowel syndrome, constipation, and defecation stimulation.

EFFECT: 2-aminopyridine derivatives as adenosine receptor antagonists useful in medicine.

34 cl, 2 tbl, 179 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes benzamidine derivatives of the general formula (I): wherein R1 means hydrogen atom, halogen atom, (C1-C6)-alkyl or hydroxyl; R2 means hydrogen atom or halogen atom; R3 means (C1-C6)-alkyl possibly substituted with hydroxy-group, alkoxycarbonyl-(C3-C13)-alkylsulfonyl, carboxy-(C2-C7)-alkylsulfonyl; each among R4 and R5 means hydrogen atom, halogen atom, (C1-C6)-alkyl possibly substituted with halogen atom, (C1-C6)-alkoxy-group, carboxy-group, (C2-C7)-alkoxycarbonyl, carbamoyl, mono-(C2-C7)-alkylcarbamoyl, di-(C3-C13)-alkylcarbamoyl; R6 means heterocycle or similar group; each among R7 and R8 means hydrogen atom, (C1-C6)-alkyl or similar group; n = 0, 1 or 2, or their pharmacologically acceptable salts, esters or amides. Compounds elicit the excellent inhibitory activity with respect to activated factor X in blood coagulation and useful for prophylaxis or treatment of diseases associated with blood coagulation.

EFFECT: improved method for prophylaxis and treatment, valuable medicinal properties of compound.

26 cl, 2 tbl, 253 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention proposes applying N-piperidino-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methylpyrazol-3-carboxamide or its salt for manufacturing a medicinal agent used for treatment of nicotine dependence and/or symptoms of nicotine withdrawal syndrome and a method for help in ceasing using tobacco. The claimed compound is known as antagonist of central cannabinoid receptors and agent used for treatment of disorders associated with using psychoactive substances. Indicated compounds are effective with respect to complete or partial tobacco abstinence with elimination of attenuation of nicotine withdrawal syndrome and patients show reduced weight loss or its absence.

EFFECT: valuable medicinal properties of antagonist.

3 cl, 5 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to novel perfluorinated cycle-containing tertiary amines of the general formula (1): wherein n = 1; m = 2 or 3; X means or and to a mixture of perfluorinated cycle-containing tertiary amines of the general formula (1) wherein n = 1; m = 2 or 3; X means or where at n = 1 Y means CF3 and at n = 2 Y means F as a base for gas-transferring emulsions. Proposed compounds are similar by their physicochemical properties, in particular, by critical temperature dissolving in hexane. Properties of these compounds provide the improved homogeneity of fluorocarbon phase of emulsions and to enhance stability of emulsion particles stabilized with block-copolymer of ethylene oxide and propylene oxide and in the absence of toxicity for small and large animals. Also, invention relates to a method for preparing perfluorinated cycle-containing tertiary amines of the general formula (1) by electrochemical fluorination of p-piperidinoheptafluorotoluene in anhydrous hydrogen fluoride.

EFFECT: improved preparing method and valuable properties of compounds.

4 cl, w dwg, 3 tbl, 4 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of nitrogen-containing heterocyclic compounds of the general formula (I'):

wherein R represents the group:

m = 0-3; R1 represents halogen atom, cyano-group and others; X represents oxygen or sulfur atom, or the group -CH2 and others; Z1 and Z2 represents the group -CH2 and others; Q represents oxygen or sulfur atom, or the group -CH2 or -NH; R2 represents substituted phenyl; n = 0-2; R3 represents (C1-C6)-alkyl, (C1-C6)-alkoxycarbonyl group and others; R4, R5, R6 and R7 represent hydrogen atom or (C1-C6)-alkyl and others; R8 represents hydrogen atom, (C1-C6)-alkyl. Compounds of the formula (I') possess of activity modulating activity of chemokine MIP-1α receptors and can be used in medicine in treatment of inflammatory diseases and respiratory ways diseases.

EFFECT: improved preparing method, improved methods for treatment, valuable medicinal properties of compounds and composition.

20 cl, 283 ex

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