Benzocycloheptene compounds, methods of prevention or treatment, a pharmaceutical composition

 

(57) Abstract:

Patented N-substituted hydroxyalkyl or carboxyquinoxaline analogues 9 and/or 10-oxo-4H-benzo[4,5]cyclohepta [1,2-b]thiophene compounds or their 9-IT - and/or 10-HE-substituted analogs of formula I, where R is hydroxy WITH2-6, alkyl, carboxy, C1-6alkoxy-C1-6alkyl, which possess antihistaminic and anti-asthma properties with reduced sedative side effects. Describes their optically active isomers and pharmaceutically acceptable salts. The compound was found to have a preventive effect on the increased reactivity of smooth muscle.

< / BR>
-A-B-= -CO-CH2- (a)

-A-B-= -CH2-CO- (b)

-A-B-= -CH2-CH2(C) -

-A-B-= -SNON-CH2(d)

-A-b-= -SNON-SNON- (e)

-A-B-= -CH2-SNON- (f)

-A-b -=- - - (g)

8 C. and 12 C.p. f-crystals, 11 PL.

The invention relates to a new specified in the title of a chemical compound, which are presented below, and to methods for the treatment of painful conditions, modulating allergic, inflammatory or cholinergic activity in mammals, using the new mentioned above in Sagl the e compounds of the following formula:

< / BR>
where-a-b - a fragment having the formula

-CO-CH2- (a)

-CH2-CO- (b)

-CH2-CH2(C)

-SNON-CH2(d)

-NON-NON- (e)

-CH2-SNON- (f)

or

-CO-CO- (g)

where R is hydroxyalkyl or carboxymethyloxysuccinic fragment, and their pharmaceutically acceptable salts and optically active isomers of racemic compounds.

The compounds of this invention possess pharmacological properties, which makes these compounds useful for the prevention and treatment of allergic disease, inflammation, eye diseases of various types and various types of increased activity of smooth muscles (such as increased bronchial and uterine activity, including increased activity caused by medications).

More precisely, this invention relates to a new specified in the title chemical compounds and to methods of treatment of allergic disorders such as allergic rhinitis), pulmonary disorders (such as asthma, bronchitis, cough, and increased bronchial reactivity), skin disorders (such as, for example, urticaria, psoriasis and atopic dermatitis), gastrointestinal restructered) and other inflammatory diseases and/or allergic disorders (such as, for example, ocular conjunctivitis and ocular keratitis), without side effects such as sedative side effect, cardiac arrhythmia and eye irritation) using the new chemical compounds listed in the title.

DESCRIPTION OF THE PRIOR

This invention relates, in particular, to anti-inflammatory and antiallergic compounds that have therapeutic application in various diseases, most importantly for patients with increased airway reactivity and/or obstructive (seal) respiratory diseases, including asthma and bronchitis, skin disorders and allergic conditions including urticaria, atopic dermatitis, allergic rhinitis and retinopathy, other diseases of the small blood vessels associated with diabetes, or ocular disorders, including conjunctivitis and keratitis.

< / BR>
The connection data on chemical structure similar to ketotifen (Zaditenand not previously known to the applicants. Side sedative effect severely limited therapeutic usefulness of ketotifen, and these side effects can be reduced or eliminated is a clinical trial of ketotifen summarized in the publication Sorkin et al., Focus on Ketotifen. Ed. E. M. Sorkin. In Drugs, Sept. 1990, vol. 40, No. 3, pp. 412 - 448.

BRIEF DESCRIPTION OF THE INVENTION

This invention relates to certain specified name chemical compounds, described below, to methods of using these chemical compounds for therapeutic purposes and compositions comprising one or more pharmaceutically acceptable inert carriers and as active ingredient, a therapeutically effective amount of at least one compound, its pharmaceutically acceptable acid additive salts and its stereochemical isomeric forms, having the formula:

< / BR>
where R is selected from the group comprising hydroxy-C2-6alkyl or carboxy-C1-6alkyloxy-C1-6alkyl and

-A-b - represents the fragment having the formula

-CO-CH2- (a)

-CH2-CO- (b)

-CH2-CH2(c)

-SNON-CH2(d)

-NON-NON (e)

-CH2-SNON- (f)

or

-CO-CO- (l)

The compounds of this invention were synthesized and pharmacologically investigated. Found significant pharmacological differences between compounds of this invention and ketotifen. So ketotifen has deep side sedate the STU or not have it. It was also found that the new compounds possess antihistaminergic and anti-inflammatory properties. It is important that the new compounds have strong anti-inflammatory effect on the lungs and that they strongly inhibit the increased reactivity of the smooth bronchial muscles.

As the inflammation of the Airways of the lungs and increased reactivity of the bronchial smooth muscles are hallmarks of asthma, therefore, new connections besides the fact that are powerful antihistamines, will be useful for the clinical treatment of asthma and bronchitis without concomitant side of the sedative.

DETAILED DESCRIPTION OF THE INVENTION

BIOLOGICAL TESTING OF THE COMPOUNDS OF THIS INVENTION

As discussed above, currently it is shown that the compounds of this invention have a prior pharmacological action, useful in the treatment of various disorders such as asthma, allergies, and eye disorders. New results are described in the following biological tests.

1. Linking gistaminergicheskie receptors.

The affinity of the test compounds to histamine H1-Receptors. J. Neurochem. 1979, 32: 1653 - 1663). Briefly, membranes derived from cerebellum cows, incubated with [3N] pyrilamine and test compound at concentrations. Specific binding of the radioactive ligand to the receptor is defined as the difference between total binding and nonspecific binding determined in the presence of excess unlabeled ligand. The values of the IC50(concentration required to inhibit 50% of specific binding of [3N] pyrilamine) is determined using nonlinear regression analyses, competitive curves (table 1).

2. Binding to muscarinic receptors.

The affinity of the test compounds to muscarinic M1receptors evaluated using the experience of [3N] pirenzepine binding, modified subsequently (Luthm et al. [3H] Pirenzepine and [3H]QNB binding to brain nuscarinic cholinergic receptors. Molec. Pharmac. 1984, 26: 164-169). Briefly, the experiments are performed on veins membranes cows expressing muscarinic1-receptors. After incubation with the test compound and a suitable radioligand and flushing associated radioactivity was determined by scintillation counter, using commercial is the difference between total binding and nonspecific binding, defined in the presence of excess unlabeled ligand. The values of the IC50(concentration required to inhibit 50% of specific binding) was determined by nonlinear regression analysis of the competition curves (table 2).

3. The research side of the sedative.

Test physostigmine-induced mortality used in these experiments is a modification of the method of assessment of the sedative, described in the publication COLLIER et al., in Br. J. Pharmac., 1968, 32: 295-310. Briefly, physostigmine (1.9 mg/kg, subcutaneously) gives 100% mortality when administered to mice, which are divided into groups of 10 animals in each plastic cages (approximately 112613 cm). The mouse, which before the introduction of physostigmine injected with sedative antihistamine, are protected and survive. In this study, the test compound is administered orally 60 minutes prior to injection of physostigmine. The number of surviving mice counts after 30 minutes after administration of physostigmine. Doses in the experience of the Central nervous system comprise half of the molecular weight of the test compounds, expressed in mg/kg body weight (table 3).

4. Anti-inflammatory effect (inhibition of bronchial EasyNet 400 to 600 grams) after intraperitoneally injections of 10 ág PARADISE (factor platelet aggregation) in a 0.25% solution of serum albumin cows in physiological solution. Twenty-four hours later the animals killed using barbiturate. The trachea and exhibit kanyoro 610 ml aliquot of the buffer of the modified solution Tyrode (Tyrode''s solution (composition: NaHCO311,9, NaCl 136,9, KCl 2.7, And Na2NRA40,4, glucose of 5.6, EDTA 19,8, gelatin 0.1% wt./volume BSA with 0.5% wt./volume; pH 7.4) was injected sequentially and aspirinum with mild compression of the lungs. The total discharge of fluid usually exceeds 80%. Cell suspension concentrate using low-speed centrifugation and the resulting cell pellets re-suspended in 1 ml of Tyrode. Counting all cells are produced by diluting 10 ál of cell suspension in 90 μl of a solution Turk. The differential count of cells conduct of strokes, mixed in methanol (100%) and dyed in the dye of Leishmania. Just at least 500 cells per smear count at 1000-fold increase in order to differentiate cell types. Drugs administered for 7 days in the form of long-term subcutaneous infusion from an implanted mini-pump Also, so that exposure to PAF takes place only after the five-day period preprocessing of the test(s) connection(s).

5. The study of influences on globigerinae ileum of the Guinea pig. The fabric is pre-treated with test compounds at various concentrations before the contractile responses to bradykinin (in the absence or in the presence of atropine concentration 1 μm).

Effect of compounds on the formation of ulcers of the stomach are examined in rats. Ulceration of the stomach produce using subcutaneous injections of 30 mg/kg indomethacin.

Study groups give the test compound in the amount of 100 µg/100 g of body weight orally 30 minutes before and 5 hours after administration of indomethacin. Measure the reduction of the area of the ulcer (mm2).

CHEMICAL SYNTHESIS OF NEW COMPOUNDS. EXAMPLES

Synthesis of ketotifen, nor ketotifen and (RS)-10-OH-ketotifen described in the publication Waldvogel et al., Helv Chem. Acta, 1976, 59: 866 - 877, the contents of which are entered in the description by reference.

The new compounds of this invention are compounds of the General formula shown in Table 1, below.

The original connection for these syntheses receive in accordance with the publication Waldvogel et al.:

Connection (1) 4-(4-piperidylidene)-9,10-dihydro-4H-benzo[4,5]cyclohepta] [1,2-b]thiophene-9-he.

Connection (2) 4-(4-piperidylidene)-9,10-dihydro-4H-benzo[4,5]cyclohepta[1,2-b]thiophene-10-he.

Example 2

Join Tables 1, where R is -(CH2)nOH, a-a-b - has the formula-CH2-CO - and n=2, is produced by interaction of one gram of the compound (2) with 2-chloroethanol (3 equivalents), potassium carbonate (3 equivalents) and potassium iodide (0.4 equivalent) in 10 ml of dimethylformamide. After stirring for 4 days at room temperature the solvent is evaporated in vacuum, the residue is dissolved in chloroform (50 ml), the solution washed with water and dried with magnesium sulfate. The solvent is distilled off and the crude (technical) product purified by chromatography on silica gel, using as eluent 5% methanol in chloroform. The product is dissolved in a mixture of chloroform/diethyl ether and add a solution of hydrogen chloride in dioxane. The solvent is evaporated in vacuum, get Sample 2 (n = 2) as hydrochloride. Output: 0.87 grams. Data proton NMR consistent with the proposed structure.

Example 3

Join Tables 1, where R is -(CH2)nHE, a-b - has the formula-CH2-CH2- the presence of a basic catalyst, such as potassium carbonate, in a solvent such as N,N-dimethylformamide (DMF), under stirring with heating or without him to perform the reaction. After evaporation of the solvent the residue is mixed with water and extracted with an organic solvent, such as chloroform, methylene chloride or ethyl acetate. After evaporation of organic solvent, the product may be purified by crystallization from solvent, such as methanol or ethanol. Similar compounds, where n=3-6, can be obtained in the same way, but with halogenerte, X-(CH2)3-6Is HE, where X is chlorine or bromine. The products can be converted into the monohydrochloride salt by dissolving in a mixture of solvents, such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent yields the product as hydrochloride.

Example 4

Join Tables 1, where R is - (CH2)n-O-CH2COOH, -a-b - has the formula-CO-CH2and n=2, is obtained from the compounds of Table 1, where R is -(CH2)nHE, -a-b - has the formula-CO-CH2and n=2, processing halogenases acid, X-CH2COOH, where X = chlorine or bromine, in the presence of osnovnoj the C to the reaction. After evaporation of the solvent the residue is mixed with water, the solution is neutralized to pH 5 to 6 and the aqueous solution is extracted with an organic solvent, such as chloroform, methylene chloride or ethyl acetate. After evaporation of organic solvent, the product may be purified by crystallization from solvent, such as methanol or ethanol. Similar compounds, where n=3-6, can be obtained in the same way from the compounds of Table 1, where R is - (CH2)n-O-CH2COOH, -a-b - has the formula-CO-CH2and n=3-6. Alternative connections Table 1, where R is -(CH2)n-O-CH2-COOH, -a-b - has the formula-CO-CH2and n=2-6, can be synthesized in accordance with the General method described in Example 5, below.

Example 5

Join Tables 1, where R is -(CH2)n-O-CH2- COOH, -a-b - has the formula-CH2-CO - and n=2 is obtained in two stages. In the first stage of 1.9 grams of compound (2) is treated with (2-chloro-ethoxy)acetonitrile (2 equivalent) and potassium carbonate (2.4 equivalents) in 10 ml of dimethylformamide. After stirring for four days at room temperature the solvent is evaporated in vacuo and to the residue add 10 ml of water.

Example 6

Join Tables 1, where R is -(CH2)n-O-CH2-COOH, -a-b - has the formula-CH2-CH2and n=2, is obtained from the compounds of Table 1, where R is -(CH2)nOH, a-a-b - has the formula-CH2-CH2and n=2, processing halogenases acid, X-CH2COOH, where X = chlorine or bromine, in the presence of a basic catalyst such as potassium carbonate, in a solvent such as DMF, with stirring with heating or without it for the reaction. After evaporation of the solvent the residue is mixed with water, the solution is neutralized to pH 5 to 6 and the aqueous solution is extracted with an organic solvent, such as chlorine is by crystallization from solvent, such as methanol or ethanol. Similar compounds, where n=3-6, can be obtained in the same way from the compounds of Table 1, where R is -(CH2)nCH, -a-b - has the formula-CH2-CH2and n=3-6. Alternative connections Table 1, where R is - (CH2)n-O-CH2-COOH, -a-b - has the formula-CH2-CH2and n=2-6, can be synthesized in accordance with the General method described in Example 5.

Example 7

Join Tables 1, where R is -(CH2)nHE, -a-b - has the formula-NON-CH2and n= 2, is obtained from the compounds of Table 1, where R is -(CH2)nOH-a-b - has the formula-CO-CH2and n=2, by treatment with sodium borohydride in a solvent such as ethanol, at room temperature. After decomposition of the excess of reagent acetone solvent is evaporated and the residue is crystallized from a solvent such as methanol or ethanol, with or without the addition of diethyl ether. Similar compounds, where n=3-6, can be obtained in the same way from the compounds of Table 1, where R is -(CH2)nHE, -a-b - has the formula-CO-CH2and where n=3-6. The products can be converted into the monohydrochloride salt by dissolving in a mixture of rasteenie solvent yields the product as hydrochloride.

Example 8

Join Tables 1, where R is - (CH2)n-O-CH2-COOH, -a-b - has the formula-NON-CH2and n=2, is obtained from the compounds of Table 1, where R is -(CH2)nHE, -a-b - has the formula-CO-CH2and n=2, by treatment with sodium borohydride in a solvent such as ethanol, at room temperature. After decomposition of the excess of reagent acetone solvent is evaporated and the residue is mixed with water, the solution is neutralized with acid, such as dilute hydrochloric acid, and extracted with a solvent such as ethyl acetate. After evaporation of the organic solvent the residue is crystallized from a solvent such as methanol or ethanol, with or without the addition of diethyl ether. Similar compounds, where n=3-6, can be obtained by the same method of the compounds of Table 1, where R is -(CH2)nHE, -a-b - has the formula-CO-CH2and n=3-6.

Alternative connections Table 1, where R is - (CH2)n-O-CH2COOH, -a-b - has the formula-NON-CH2and n=2-6, can be synthesized in accordance with the General method described in Example 5.

Example 9

Join Tables 1, where R is -(CH2)nHE>H-a-b - has the formula-CH2-CO - and n=2, the processing of sodium borohydride in a solvent such as ethanol, at room temperature. After decomposition of the excess of reagent acetone solvent is evaporated and the residue is crystallized from a solvent such as methanol or ethanol, with or without the addition of diethyl ether. Similar compounds, where n=3-6, can be obtained in the same way from the compounds of Table 1, where R is -(CH2)nHE, -a-b - has the formula-CH2-CO - and n=3-6. The products can be converted into the monohydrochloride salt by dissolving in a mixture of solvents, such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent yields the product as hydrochloride.

Example 10

Join Tables 1, where R is -(CH2)n-O-CH2-COOH, -a-b - has the formula-CH2SNON and n = 2, is obtained from the compounds of Table 1, where R is - (CH2)n-O-CH2COOH, -a-b - has the formula-CH2-CO - and n=2, by treatment with sodium borohydride in a solvent such as ethanol, at room temperature. After decomposition of the excess of reagent acetone solvent is evaporated and the residue is solvent, such as ethyl acetate. After evaporation of organic solvent crystallization of the residue from a solvent, such as methanol or ethanol, with or without the addition of diethyl ether. Similar compounds, where n=3-6, can be obtained in the same way from the compounds of Table 1, where R is -(CH2)n-CH2-COOH, -a-b - has the formula-CH2-CO - and n=3-6.

Alternative connections Table 1, where R is -(CH2)n-O-CH2COOH, -a-b - has the formula-CH2-SNON and n=2-6, can be synthesized in accordance with the General method described in Example 5.

Example 11

Join Tables 1, where R is -(CH2)nOH, a-a-b - has the formula-CO-CO - and n= 2, is obtained by treatment of the parent compound (4) 2-halogenation, such as 2-bromoethanol or 2-chloroethanol, in the presence of a basic catalyst such as potassium carbonate, in a solvent such as N,N-dimethylformamide (DMF), under stirring with heating to initiate the reaction or without him. After evaporation of the solvent the residue is mixed with water and extracted with an organic solvent, such as chloroform, methylene chloride or ethyl acetate. After evaporation of organic solvent prod is, the where n=3-6, can be obtained in the same way, but with halogenerte, X-(CH2)3-6HE, where X represents chlorine or bromine.

The products can be converted into the monohydrochloride salt by dissolving in a mixture of solvents, such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvent yields the product as hydrochloride.

Example 12

Join Tables 1, where R is -(CH2)n-O-CH2COOH, -a-b - has the formula-CO-CO - and n=2, is obtained from the compounds of Table 3, where R is -(CH2)nOH, a-a-b - has the formula-CO-CO - and n=2, by processing halogenases acid, X-CH2COOH, where X= chlorine or bromine, in the presence of a basic catalyst such as potassium carbonate, in a solvent such as DMF, with stirring with heating or without it for the reaction. After evaporation of the solvent the residue is mixed with water, the solution is neutralized to pH 5 to 6 and the aqueous solution is extracted with an organic solvent, such as chloroform, methylene chloride or ethyl acetate. After evaporation of organic solvent, the product may be purified by crystallization from will dissolve the m of the compounds of table 1, where R is -(CH2)nHE, -a-b - has the formula-CO-CO - and n=3-6.

Alternative connections Table 1, where R is - (CH2)n-O-CH2-COOH, -a-b - has the formula-CO-CO -, and n=2-6, can be synthesized in accordance with the General method described in Example 5.

Example 13

Join Tables 1, where R is -(CH2)nOH, a-a-b - has the formula-NON-SNON and n=2, is obtained from the compounds of Table 1, where R is -(CH2)nHE, -a-b - has the formula-CO-CO - and n=2, by treatment with sodium borohydride in a solvent such as ethanol, at room temperature. After decomposition of the excess of reagent acetone solvent is evaporated and the residue is crystallized from a solvent such as methanol or ethanol with or without the addition of diethyl ether. Analogous compounds in which n=3-6, can be obtained in the same way from the compounds of Table 1, where R is -(CH2)nHE, -a-b - has the formula-CO-CO-.

The products can be converted into the monohydrochloride salt by dissolving in a mixture of solvents, such as chloroform/diethyl ether and adding a solution of hydrogen chloride in dioxane. Evaporation of the solvents results in p>-O-CH2-COOH, -a-b - has the formula-NON-SNON and n=2, is obtained from the compounds of Table 1, where R is - (CH2)n-O-CH2-COOH, -a-b - has the formula-CO-CO - and n=2, by treatment with sodium borohydride in a solvent such as ethanol, at room temperature. After decomposition of the excess of reagent acetone solvent is evaporated, the residue is mixed with water, the solution is neutralized with acid, such as dilute hydrochloric acid, and extracted with a solvent such as ethyl acetate. After evaporation of the organic solvent the residue is crystallized from a solvent such as methanol or ethanol, with or without dietilovogo ether. Analogous compounds in which n=3-6, can be obtained by the same method of the compounds of Table 1, where R is - (CH2)n-O-CH2-COOH, -a-b - has the formula-CO-CO-.

Alternative connections Table 1, where R is -(CH2)n-O-CH2-COOH, -a-b - has the formula-NON-SNON and n=2-6, can be synthesized in accordance with the General method described in Example 5.

This invention provides compounds described above, including the isomers, racemic compounds, and pharmaceutically acceptable Kiso invention can be obtained by separation of the racemate using traditional methods such as fractional crystallization of the diastereomeric salts with chiral acids. Other standard methods of separation known qualified the art, include, but are not limited to, crystallization and chromatography on a chiral substrate, and can also be used. Optically active isomers of the present invention can also be obtained by stereoselective synthesis.

The terms "pharmaceutically acceptable salts or its pharmaceutically acceptable salt" refers to salts derived from pharmaceutically acceptable non-toxic acids. Suitable pharmaceutically acceptable acid additive salts of the compounds of this invention include salts of acetic acid, benzosulfimide (built), benzoic, camphorsulfonic, lemon, econsultancy, fumaric, gluconic, glutamic, Hydrobromic, hydrochloric, satynowej, lactic, maleic, malic, mandelonas, methansulfonate, mucus, nitrogen, Mamonovo, attenolol, phosphoric, p-toluensulfonate, salcinovic, sulfuric, tartaric, etc., acids. Gidrofumarat is especially preferred.

This invention also provides pharmaceutical together with one or more pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially prepared for oral administration, conjunctival instillation (backfilling), sublingual administration, parenteral administration, transdermal (percutaneous) introduction, rectal administration, transbukkalno injection, local injection or for conducting inhalation, insufflating (injection) powder or aerosol.

The pharmaceutical compositions of this invention can be injected into humans and other mammals orally, sublingual, parenteral, subcutaneous, transdermal, rectal, transbukkalno, locally, the conjunctival intellasia or in the form of an aerosol for oral or nasal administration.

The term "parenteral" introduction includes intravenous, intraarterial, intramuscular, intraperitoneal, intradermal, subcutaneous, intramuscular, intraperitoneally injection and infusion. The term "transdermal" includes the use of various devices ("plaques" and so on) that can facilitate or modify the transport or absorption of drugs through the skin.

Forms for oral administration

The pharmaceutical compositions of the present invention to perorating the specialised forms, the active compound may be mixed with one or more pharmaceutically acceptable diluents or carriers (for example, sodium citrate, dicalcium phosphate), fillers (e.g. starch, lactose, sucrose, glucose, mannitol, silicic acid), binders (for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia humectants (e.g. glycerin), additives, stabilizing solution (e.g., paraffin), dezintegriruetsja means (for example, agar-agar, calcium carbonate, starch, alginic acid, silicates, sodium carbonate), absorption accelerators (for example, Quaternary ammonium compounds), wetting agents (for example, cetyl alcohol, the glycerol monostearate), absorbents (for example, kaolin, bentonite clay), lubricants (e.g. talc, calcium stearate, magnesium stearate, polyethylene glycols, nutriceuticals) and/or the buffer means.

Solid form in the form of capsules, pills, granules, pills and tablets may have a coating and/or shell (for example, intersolubility cover), known in the field of pharmaceutical preparations. The composition may also be designed to release the active(s) ingredient(s) in a certain part of the gastrointestinal tract or controlled release, slow release or dlitelnoi absorption of the active(main) ingredient(s).

Active(s) connection(s) can also be microencapsulating with one or more of the above fillers.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. The liquid dosage form may also contain commonly known diluents (e.g., water, other solvents, solubilizing components), emulsifiers (for example, ethanol, isopropyl alcohol, ethylcarbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, butyleneglycol, dimethylformamide, oils, oleic acid, glycerine, glycols, complex fatty sorbitan esters and their mixtures).

Besides inert diluents, compositions for oral administration can also include adjuvants, such as wetting, emulsifying, suspendresume sweetening or flavouring agents.

Suspensions can contain one or more suspendida agents known in the field of technology of preparation of pharmaceutical preparations.

FORMS FOR LOCAL INJECTION

(including forms for conjunctival instillation)

Compositions for the local introduction of terapevticheskii active ingredients the composition of this invention for local ocular or conjunctival injection may optionally include a variety of prescription ingredients such as antimicrobial preservatives and means regulating toychest solution. Examples of suitable antimicrobial preservatives include: benzalconi chloride, thimerosal, chlorobutanol, methylparaben, propylparaben, phenethyl alcohol, edetate disodium, sorbic acid, ONAMER M and other components known to the specialist in this field. Such preservatives, if used, will typically be used in amounts of from 0.001% to 1.0% based on the weight (wt.%). Examples of suitable tools that can be used to control toychest or osmotic pressure formulations include sodium chloride, potassium chloride, mannitol, dextrosphere and propylene glycol. Such additives, if used, will be used in the amount of from 0.1% to 10.0% based on the weight (wt.%). The compositions preferably are water and have a pH in the range from 3.5 to 8.0 and the osmotic pressure in the range from 280 to 320 mmol per liter.

Qualified it is clear that the composition can be prepared in various dosage forms suitable for local ocular administration, including solutions, suspensions, emulsions, gels and solid biodegradable ocular insert.

FORM Gltiches acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions, emulsions, and sterile powders for the conversion before use in sterile injectable solutions or dispersion. Can be used in various aqueous and nonaqueous carriers, diluents, solvents, fillers (for example, water, ethanol, glycerin, glycol), vegetable oils (e.g. olive oil), organic esters (for example, etiloleat) or mixtures thereof. Fluidity can be maintained through the application of coating materials, such as lecithin, by limiting the size of the particles, or by applying a surface-active substances.

The compositions may also contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, antibacterial agents, antifungal agents, isotonic additives and/or components, inhibiting adsorption. The increase in the duration of absorption or slowing down the absorption can be achieved through the injection of crystalline or amorphous suspensions with low solubility in water. Delayed absorption may also be obtained by dissolution or suspension of the drug in an oil carrier, or through the use of basic forms for Her biological way such as polyethyleneglycole, complex poliorcetes, polyanhydride), or by use of liposomes of different types or microemulsions for holding medicines. Formulations for injection may be subjected to sterilization in a variety of ways.

FORMS FOR RECTAL INJECTION

Compositions for rectal injection preferably represent candles.

FORMS FOR TRANSBUKKALNO INTRODUCTION

Compositions for transbukkalno introduction preferably represent toothpastes, liquid for rinsing the mouth, preparations for sublingual administration, chewing gum, etc.

FORMS FOR SUBLINGUAL INTRODUCTION

Can be used in various herbal formulation: concentrated solutions or suspensions of drugs can be applied sublingual with various drip devices; various aerosol devices may be used to spray the medication on the mucous membrane of the mouth; specially developed rapidly dissolving tablets, capsules or powders may also be used for quick delivery of a full dose.

FORMS FOR TRANSDERMAL INJECTION

Compendi etc.

ORAL OR NASAL SPRAY OR DRIP

Compositions for oral or nasal sprays or drops can be in the form of a solution, suspensions or dry powders may be formulated for nasal, transbukkalno, bronchial/pulmonary and/or gastrointestinal absorption of the drug.

THERAPEUTIC DOSE

The actual dose levels of active ingredients in the pharmaceutical compositions of this invention can vary to achieve the desired therapeutic effect. Therefore, the amount of the medicinal product varies and may depend on various factors such as the form of administration, the severity of the disease, frequency of dosing, etc. When used as medicines by patients suffering from benign disorders of the respiratory tract or bronchial disorders (such as asthma, bronchitis and so on), the oral dose of the compounds of this invention are in the range from 0.5 mg to about 200 mg, preferably from 0.5 mg to 10 mg when using from one to four times per day a patient weighing up to 60 kg, the Daily dose may be increased or decreased depending on various facto the patients suffering from allergic conjunctivitis, used oral doses of the compounds of this invention in the range of from 0.1 mg to about 100 mg, preferably from 0.2 mg to 10 mg when taken one to four times per day for patients weighing up to 60 kg For patients suffering from seasonal allergic conjunctivitis, the concentration of nor-ketotifeno solution for instillation into the conjunctival SAC is in the range from 0.01% to 2.0%, preferably from 0.02% to 1.0%. The frequency and amount of dosage will be determined clinically on the basis of various clinical factors, such as, for example, weight and severity of the disease of the patient. The application will usually include local injection of one or two drops (or the amount of solid or semi-solid dosage forms) for effects on the eye one to four times per day.

FORMULATION OF STANDARD DOSES FOR ORAL ADMINISTRATION

EXAMPLE 15. FORMULATION of TABLETS (table 4)

Active ingredient (in this example the compound of Example 5, where n=2) is mixed with lactose and cellulose until then, until it forms a homogeneous mixture. Add dye (lake) and additionally mix. Finally, in a mixture with stirring, calcium stearate is with a different content of active ingredient can be obtained by changing the ratio of the active ingredient and the excipients or the final weight of the tablets.

The invention provides methods of treatment and/or prevention of all forms of bronchial asthma, allergic bronchitis, Multisystem allergies, allergic rhinitis and allergic skin disorders in mammals, such as man, in the absence of side sedative action and other toxic effects of ketotifen. These methods include administration to a mammal in need of such treatment and/or prevention, an effective quantity of at least one compound of the invention or its pharmaceutically acceptable salt.

The invention also provides methods of joint introduction of one or more compounds of this invention with an agonist of adrenergic beta-receptor, including, but not limited to only this list, albuterol, terbutaline, fenoterol, formoterol or salmeterol, eliminating or reducing the increased bronchial reactivity, which can be induced by the specified therapy beta-agonist.

The invention also provides methods of joint introduction of the compounds of this invention with other substances or drugs that cause increased bronchial reactivity in nhibitory Cox, at elimination or reduction thus increased bronchial reactivity, which is induced by such therapy.

This invention provides methods of treatment and/or prevention of eye diseases such as allergic conjunctivitis or allergic keratitis, and inflammatory diseases such as blepharitis, conjunctivitis, episcleritis, scleritis, keratitis, anterior uveitis (anterior uveitis), posterior uveitis (posterior uveitis), endophthalmitis, optic neuritis, cranial Takayasu, sympathetic ophthalmia, in mammals such as man, while eliminating eye irritation, adverse sedative action and other toxic effects of ketotifen and steroids. These methods include administration to a mammal in need of such treatment and/or prevention, an effective quantities of the compounds of this invention or its pharmaceutically acceptable salts.

The invention also provides methods of joint introduction of the compounds of this invention with at least one drug of the following classes: ocular antihypertensive agents, adrenergic agonists or antagonists, antibacterial agents, antiviral agents, steroids, in which their medicines. In particular, this invention provides ways of introducing the compounds of this invention with eye-inflammatory drugs, such as, for example, phenylephedrine, nafazolina, tetrahydrozoline, or with antibacterial agents such as bacitracin, neomycin (neomycin and polymyxin.

The invention also provides methods of introducing the compounds of this invention in combination with surgery for minimizing inflammation or irritation and improved postoperative recovery.

The invention also provides methods of treatment or prevention of various forms of gastrointestinal diseases, such as syndromes of hypersecretion, including the syndrome of Zollinger-Ellison, gastric irritation, enteritis, gastric or duodenal ulcers, heartburn (acid indigestion) or unwanted secretion of acid in the stomach. These methods include administration to a mammal in need of such treatment and/or prevention, an effective quantities of the compounds of this invention or its pharmaceutically acceptable salts.

EQUIVALENTS

A qualified specialist will be clear or it is able estuaries of the invention, as described here. Such equivalents include the use of a single isomer and compositions containing the same isomer, in the absence of side effects, corresponding(to them) isomer(s). Such equivalents also include numerous pharmaceutically acceptable salt form, for example, sulfate, hydrobromide, hydrochloride, dihydrochloride, fumarate, methanesulfonate, hydroxynaphthoate or correspond to one or the other of their hydrated forms (see Merck Index 11thedition (1989) items 9089, 209, 3927, 4628, 8223, 5053, 5836, 8142, 2347, 7765, 1840, 9720, 7461, 1317, 4159, 963 and the links in it and Am. Rev. Resp. Dis. 1988, 137: (4; 2/2) 32). Such equivalents also include co-administration of at least one of the compounds of this invention with any other medicine that is used to suppress specified in this document diseases in mammals. Qualified specialist in the field of medicine also understood that higher or lower doses than those indicated in this description, may be preferred, and the dose can be taken more or less frequently than suggested in the description. Qualified specialist in the field of pharmacology can imagine that the compounds of this invention possess negotation, PAF-antagonistic activity, stabilizing activity against mastocytes and so on), can be useful for other indications not listed in the description. Such statements are equivalents of the specific embodiments of the invention described herein.

A qualified specialist in this field will represent that by applying a single isomer (eutomer) any racemic compounds of the present invention, Nord-ketotifen or 10-HE-norketamine you can avoid the side effects typical of other isomer. Such side effects can include, for example, cardiovascular side effects, such as, for example, cardiodepressive, side effects on the Central nervous system, such as, for example, sedative side effect. All equivalents, as implied, included in this invention.

Biological studies of the compounds according to the present invention

As mentioned above, studies were undertaken to study the pharmacological profile of new compounds. Of particular importance are studies on sedative side effects antihistamine activity and anti-inflammatory effects.

The results of the tests (sedatives; re-test)

"Example 2/HE-prop" means a compound having a structure in accordance with Example 2, where the substituent in the piperidine is hydroxypropyl. "Example 2/HE-booth" is praxibetel. "Example 2/HE-Penta" means a compound having a structure in accordance with Example 2, where the substituent in the piperidine is hydroxyphenyl. "Example 2/HE-Gex" means a compound having a structure in accordance with Example 2, where the substituent in the piperidine is hydroxyhexyl.

Connection comparison terfenadine is resedation antihistamine drug, while diphenhydramine is an antihistamine drug with sedative side effect.

Conclusions (sedatives): the results confirm the clinical effects of compounds comparison, confirming thus the objectivity of the methodology. Ketotifen has a more sedative effect than even diphenhydramine, thereby confirming the sedative side effects of this compound. With the exception of compounds, designated Example 2/HE-Penta and Example 2/HE-Gex, all new connections do not have a sedative effect.

Anti-inflammatory effects: pulmonary inflammation

Sensitized male individuals Guinea pigs Dunkin-Hartley weighing 400-600 g were administered intraperitoneally injected 10 μg PAF (factor platelet aggregation) in a 0.25% solution of serum albumin cows (BSA) in saline. Through dugout. Successively introduced aliquots modified buffer solution Tyrode (mm: Panso311,9; Na2HPO4of 0.4; KCl 2.7; The NaCl 136,9; EDTA 19,8; glucose 5,6; gelatin 0.1% weight/volume; BSA 0.5% weight/volume; pH to 7.4) and aspirated using a soft compression of the lungs. The total discharge of fluid usually exceeds 80%. Cell suspension was concentrated by using low-speed centrifugation (200 g for 10 min) and the cell sediment is re-suspended in 1 ml of modified solution Tirade. Counting all cells are produced by diluting 10 ál of cell suspension in 90 μl of a solution Turk. Differential counting of cells conduct of smears fixed in methanol (100%) and dyed in the dye of Laksmana. Just at least 500 cells per smear count at 1000-fold increase in order to differentiate cell types. Drugs administered for 6 days by subcutaneous infusion from an implanted mini-pump Also. Exposure PAF occurs after five-day treatment period subjects connections.

The results of the tests (Pulmonary inflammation): (table 6)

Findings (pulmonary inflammation):

The accumulation of inflammatory cells in the lungs and digitalisation was achieved by intraperitoneal injection of PAF Guinea pigs. The number of eosinophilic cells increased to approximately 250% of normal (BSA) level. When animals were treated with ketotifen (1 mg/kg/day subcutaneously for 6 days using osmotic mini-pump), the number of eosinophilic cells is reduced to the reference level. The introduction of the compound from Example 2 reduces the number of eosinophils even more effectively than in the case of ketotifen, whereas the compound from Example 5 in this test does not show any significant anti-inflammatory action.

Anti-inflammatory effects: Skin inflammation

The ears of male mice were treated with 20 μl of a 1.0% solution of cretonne easy oil in acetone. Groups of mice were euthanized at specified intervals after intraperitoneal administration of the compounds under study (10 mg/kg) and the ears were weighed. The weight of the ears recorded and calculated parameters are presented below in Table 7.

The results (Skin inflammation):

The average weight of the ears of control mice was 322 µg. The weight of the ears of the animals treated with vehicle (control) or test compounds shown below in table 7.

"Example 2/HE-prop" means the connection structure shown in Example 2, where the Deputy is EP 2/HE-prop" equally active as anti-inflammatory agents in trials on cutaneous inflammation. Example 5 in this test does not show any significant anti-inflammatory effects.

Antihistamine activity in vitro

The affinity of test compounds relative to H1receptors of histamine was assessed using analysis of binding of [3N] pyrilamine modified by Chang and al. (Heterogeneity of Histamine H1-Receptors. J. Neurochem. 1979, 32:1653-1663). Briefly, membranes from bovine cerebellum were incubated with [3N]pyrilamine and the test compounds at increasing concentrations. Specific binding of the radioactive ligand to the receptor was determined as the difference between total binding and nonspecific binding measured in the presence of an excess of its ligand. The value of the IC50(concentration required to inhibit 50% of specific binding of [3N]pyrilamine) were determined by nonlinear regression analysis of the competition curves.

The results (Antihistamine activity in vitro): (table 8)

"Example 2/HE-prop" means the connection structure shown in Example 2, where the Deputy of piperidine is hydroxypropyl. "Example 2/HE-buta" means the connection structure shown in Example 2, where the Deputy of piperidine is the AITA H-1 receptors. New connections is a little less active than ketotifen, and more active than diphenhydramine.

Antihistamine activity in vivo

The dorsal hair of male rats weighing 150-200 g were vestigal and dailymobile. After about twenty-four hours after depilation animals previously administered orally (2.0 ml/kg body weight) test substance, the carrier connection or comparison. Sixty (60) minutes produced two subcutaneous injections of histamine diphosphate (injection of 50 µl of 0.6 ág/ml of histamine di-Hcl). Also produced two subcutaneous injections of the carrier for a solution of histamine on nepilirovanny surface of the back. Intravenously injected dye Evans blue (20 mg/kg in 1 ml/kg) for one minute before the end time pre-treatment (= one minute before two subcutaneous injections of histamine and two subcutaneous injections media histamine). Twenty minutes were allotted for the full development of the response to the dye, after which animals were rapidly euthanized by asphyxiation WITH2. Along the back was made the cut and separated dorsal skin tissue containing intradermal dye. Parcel size blue color was measured in square millimeters, hail from the two experiments were averaged the camping histamine from about 20 mm2to about 120 mm2. The difference is called "histamine effect." In the case of animals pre-treated active investigated substances, the effect of histamine is lower than in the case of animals pre-treated media.

Inhibition was calculated in percent. The results are presented in Table 9.

"Example 2/HE-buta" means the connection structure described in Example 2, where the piperidine substituted by hydroxybutyl.

Conclusions (Antihistamine activity in vivo):

Ketotifen, Example 2 and Example 2//HE-booth was well absorbed after oral administration and in this test have shown potential antihistaminic compounds. New gidroksilirovanii compounds in this study showed the same activity and were about 50 times more active than diphenhydramine.

Antigistaminny activity derived benzocycloheptene in vivo.

Methodology. Male rats weighing 160-200 g, having the hair on the back were euthanized and subjected to depilation a commercial agent for hair removal. Four sample area on the back were marked with indelible ink, carefully avoiding the area near the spine. It is a Protocol oral (2.0 ml/kg body weight) test substance filler or control connection. Thus, the test substance was administered only once to each animal. After 60 minutes, two intradermal injections of histamine diphosphate (50 μl injection of 0.6 mg/ml of histamine diphosphate) were introduced. Two intradermal injections of filler for histamine solution were also carried out. Blue dye Evans (20 mg/kg at 1.0 ml/kg) was administered intravenously over one minute before the end of time preprocessing (= 1 minute before the two intradermal injections of histamine and two intradermal injections of a filler to histamine). Twenty minutes was allowed for full development of a response in the form of bubbles, and then animals were rapidly killed by asphyxiation with carbon dioxide. Made an incision along the back and dorsal skin, containing micro bubbles, straight. Marked blue area measured in square mm and twice the measured responses were averaged.

The treated filler of animals the area of blue spots was increased histamine from approximately 20 mm2up to approximately 120 mm2in this experimental system. The difference has been named as "the effect of histamine". In animals, the preprocessed active investigational substance, the effect of agricultural Tested compounds represented control connection diphenhydramine (Benadril) and ketotifen (Zaditen), derived benzocycloheptene according to claim 1 wherein-a-b - represents-CH3-CO - where R is hydroxyethyl (Example 2) or carboxymethoxy (Example 5) (table 10).

Conclusions:

The control connection diphenhydramine and ketotifen, new compounds of Example 2 and Example 5 were all absorbed after oral administration. Compounds of the present invention (Example 2 and Example 5) are effective antigistaminnami compounds in this experimental system, where the effect of the compounds was tested in 80 minutes after oral administration.

Compounds of the present invention, the activity is equal to the ketotifen (strongest antigistaminnogo connection among those produced and sold) and were approximately 50 times more active than diphenhydramine (table 11).

1. Benzocycloheptene compounds of General formula I

< / BR>
including their stereochemical isomeric forms and pharmaceutically acceptable salts, where R is selected from the group comprising hydroxy-C2-6alkyl and carboxy-C1-6alkyloxy-C1-6alkyl, and
-CH2- ; ()

-SNON-CH2-; (d)

-NON-NON-; (e)

-CH2-SNAN or (f)

-CO-CO-. (g)

2. Connection on p. 1-a-b - has the formula-CH2-CO-, or its pharmaceutically acceptable salt.

3. Connection on p. 1, in which R represents hydroxy-C2-6alkyl, -a-b - has the formula-CH2-CO-, or its pharmaceutically acceptable salt.

4. Connection on p. 1, in which R represents carboxy-C1-6alkyloxy-C1-6alkyl, -a-b - has the formula-CH2-CO-, or its pharmaceutically acceptable salt.

5. The method of prevention or treatment of allergic disorders which comprises administration to a mammal in need of such treatment, a therapeutically effective amount of the compounds under item 1.

6. The method according to p. 5, where the specified allergic disorder is selected from the group including allergic rhinitis, bronchitis, urticaria, atopic dermatitis and enteritis.

7. The method of prevention or treatment of eye disorders which comprises administration to a mammal in need of such treatment, a therapeutically effective amount of the compounds under item 1.

8. The method according to p. 7, in which the ocular disorder is selected from the group on tanjungenim, optic neuritis, rear evenit, retinopathy and scleritis.

9. A method of preventing or treating respiratory disorders which comprises administration to a mammal in need of such treatment, a therapeutically effective amount of the compounds under item 1.

10. The method according to p. 9, where the specified respiratory disorder selected from the group comprising chronic obstructive pulmonary disease (chronic obstructive pulmonary disease - COPD), asthma, cough and bronchitis.

11. The method of prevention or treatment of increased reactivity of smooth muscle, which includes an introduction to a mammal in need of such treatment, a therapeutically effective amount of the compounds under item 1.

12. The method of prevention or treatment of gastrointestinal disorders which comprises administration to a mammal in need of such treatment, a therapeutically effective amount of the compounds under item 1.

13. The method according to p. 12, where the specified gastrointestinal disorder selected from the group comprising a syndrome of hypersecretion syndrome Zollinger-Ellison, gastric irritation, enteritis, gastric ulcer, hyperchlorhydria and heartburn.

14. The route of administration of compounds on p. 1 to a mammal in LC, gastro-intestinal disorders, in which the connection under item 1 introduced by inhalation, by conjunctival instillation, or by nasal insufflation, or by parenteral, transdermal, transbukkalno, rectal, sublingual, nasal, local or oral administration.

15. The method according to p. 14, in which a connection on p. 1 is administered to the mammal in the recipe with a slow, prolonged release of the active substance or release of substances controlled otherwise.

16. The method according to p. 14, in which a connection on p. 1 is administered to the mammal in an amount of from about 0.2 mg to about 200 mg, preferably from 0.5 to 20 mg one to four times per day for patients weighing 60 kg

17. The method according to p. 7, in which the connection under item 1 introduced by conjunctival instillation of a solution containing from about 0.01 to 2.0% from one to four times per day.

18. Pharmaceutical composition for prevention or treatment of disorders that represent or allergic skin disease, in solid, semisolid, liquid, suspension, aerosol, or transdermal form, including t the Lee system media.

19. The method according to PP. 14-16, in which the mammal in need this, you enter a therapeutically active amount of the compounds on p. 1 together with one or more drugs from the class, including analgesics, Antibacterials, anti-inflammatories, decongestants funds vasoconstrictor tools, vasodilator, tools, suppress cough, and expectorants.

20. The method according to PP. 7 and 8, in which the mammal in need this, topically in the eye introduces a therapeutically active amount of the compounds on p. 1 together with one or more drugs from the class, including cholinergic means, means antimuskarinovoe act occurs cholinesterase inhibitors, adrenergic blocking beta-receptor means, antibacterial agents, sympathomimetics, carboxylic inhibitors of carbonic anhydrase, anti-inflammatories, decongestants tools, hemostatic means, viscosity regulators and local anesthetics.

 

Same patents:

The invention relates to orthotamine compounds of the formula I or their pharmaceutically acceptable salts, are inhibitors of prostaglandin H synthase

The invention relates to new derivatives of 4-hydroxypiperidine General formula (I), where X denotes-O-, -NH-, -CH2-, -CH= , -CO2-, -SOP(lower alkyl) -, or-CONH-, R1- R4independently from each other, is hydrogen, hydroxy, nitro-group, a lower alkylsulfonyl, 1 - or 2-imidazolyl, 1-(1,2,4-triazolyl), R5and R6independently from each other, is hydrogen, lower alkyl, hydroxy - or oxoprop, R7- R10independently from each other, is hydrogen, lower alkyl, halogen, trifluoromethyl or lower alkoxygroup, n = 0 or 1, or their pharmaceutically acceptable acid additive salts

The invention relates to 1-phenylalanine - new ligands of 5-HT4receptors of formula I, where R1- halogen; R2- H, C1-C4alkoxy; R3- C1-C4alkoxy, phenyl C1-C4alkoxy, where phenyl optionally substituted by 1-3 substituents, independently selected from C1-C4of alkyl, C1-C4alkyloxy, 3,4-methylendioxy; R2and R3together represent methylenedioxy, Ethylenedioxy; R4denotes a group of formula (a) or (b), where n = 3, 4, 5; p = 0; q = 1 or 2; R5and R6each C1-C4alkyl or together are - (CH2)4- , - (CH2)6-, - (CH2)2O(CH2)2-,

-CHR8CH2CR9R10CHR11CH2- where R8and R11each H or together are - (CH2)t- where t =1; R9- H, HE, C1-C8alkyl, C1-C4alkyloxy; R10- H, C1-C8alkyl, phenyl, - (CH2)xR12where x = 0, 1, 2, 3; R12HE, C1-C4alkyloxy, - C(O)NR13R14, - NR13C(O)OR14, -SO2NR13R14, -NR13SO2R14, -NR13SO2NR14R15, -NR13C(O)NR14R15; R13, R14, R15- independently - H, C1-C4e is phenyl optionally substituted C1-C4alkyloxy, methylendioxy, Ethylenedioxy; or R7- (CH2)z- R12where z = 2, 3

The invention relates to new tetrahydropyridine - or 4-hydroxypiperidine-alkylation formula I, where R1, R2, R3and R6denote hydrogen, halogen, C1-C6-alkyl, C1-C6-perfluoroalkyl, C1-C6-alkoxyl or two adjacent radicals can form precondensation benzene ring, And denotes the carbon atom, and the dotted line denotes an optional bond, or a denotes a carbon atom that is associated with a hydroxyl group (C-OH), and the dotted line indicates the absence of coupling, n = 2 to 6, Z1, Z2and Z3represent a nitrogen atom or a substituted carbon atom, or a physiologically favourable salts, which possess antipsychotic or anxiolytic activity

The invention relates to compounds of formula I:

< / BR>
where X denotes O, S, NH or NA;

Y represents substituted with R2aziridinyl, azetidinone, pyrolidine, piperidinyl, hexahydroazepin or pieperazinove the rest;

R1indicatesor< / BR>
R2represents CrH2r-COOR3;

R3denotes H, A or Ar;

A denotes alkyl with 1-6 C-atoms;

B denotes H, a, cycloalkyl with 3-7 C atoms, Ar-CkH2kor aydinbey the rest;

Ar denotes unsubstituted or mono - or twice substituted with A, Cl, Br, I, NO2, CN, OA, OH, NH2, NHA and/or NA2phenyl or benzyl residue;

"k" denotes 1, 2, 3 or 4;

"m" and "r" each, independently of one another, denote 0, 1, 2, 3 or 4; and

"n" represents 2, 3 or 4,

and their physiologically acceptable salts

The invention relates to new 3-intellipedia formula I, where R1, R2, R3and R4denote H, A, OH, OA, F, Cl, Br, J, CN, CF3, COOH, CONH2, CONHA, CONA2or COOA, or R1and R2and R3and R4together denote methylenedioxy, R5Is H or OH, R6- H or R5and R6together denote a bond, And represents C1- C6-alkyl, n denotes a number from 2 to 6, and their physiologically acceptable salts

The invention relates to nitrogen-containing heterocyclic compounds F.-ly (I) or their pharmaceutically acceptable salts, or isomers

< / BR>
where m is 0 or 1, n is 0,

R1is hydrogen, benzyl, (C1-C2-alkyl)-(C6-C10-aryl), heteroaryl-C1- C2-alkyl,

A represents a group

< / BR>
or

< / BR>
where R6, R7, R8, R9- C1-C6-alkyl, Z1and Z2is hydrogen, represents6-C10aryl that may be substituted for CH3or HE

The invention relates to a piperidine derivative of General formula I

< / BR>
and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to medicine, in particular to endocrinology, and for the treatment of non-insulin dependent diabetes mellitus (NIDDM)

The invention relates to medicine, specifically to pharmacology

The invention relates to new derivatives of piperidine-ketocarboxylic acids of the formula (I), where R1- COR4or SO2R4, R4means of alkenyl, substituted phenyl or pyridine, naphthyl, honokalani, chinoline, benzothiophene, dihydroxyphenyl or pyridyl, substituted with allmineral, R2- C1-C6-alkyl which can be substituted by phenyl or pyridium, R3group-OR6or other6where R6means hydrogen, C1-C6-alkyl, which may be a phenyl, pyridine or morpholinium, their tautomeric and isomeric forms, and salts

The invention relates to medicine, namely to pharmacology

The invention relates to new derivatives of biphenylamine formula (I)

< / BR>
where a IS-O-CmH2m-X1-

or denotes the formula (II)

,

where X1oxygen,

or formula (III)

< / BR>
R1- cycloalkyl with 5-7 carbon atoms, Ar1, CR4R5AG2, (CH3)2R6, R2is hydrogen, alkyl, hydroxyl, halogen, O - alkyl, R3is hydrogen, alkyl, R4- alkyl, trifluoromethyl, CH2HE, R5is hydrogen, alkyl, trifluoromethyl, or R4and R5may together form alkylene, R6- CH2OH, CONR7R8CH2R7R8provided that R1means associated through alkylene unsubstituted phenyl residue, or their acid additive salts with pharmacologically acceptable acids

The invention relates to medicine, namely, neurology, and for the treatment of Parkinson's disease

The invention relates to new derivatives of 4-hydroxypiperidine formula I

< / BR>
where X represents-O-, -NH-, -CH2-, -CH=, -SNON - or-CO-; R1-R4independently from each other denote hydrogen, a hydroxy-group, (lower) alkylsulfonyl or acetaminoph; R5-R8independently from each other denote hydrogen, a hydroxy-group, (lower)alkyl, halogen, (lower)alkoxygroup, trifluoromethyl or cryptometrics; a and b may denote a double bond, provided that when a represents a double bond, b is unable to designate a double bond; n = 0-2; m = 1-3; p = 0 or 1, and their pharmaceutically acceptable additive salts

FIELD: organic chemistry, biochemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new sulfur-containing compounds of the formula (I):

their pharmaceutically acceptable salts or solvates, or salt solvates wherein R1 represents (C1-C6)-alkyl, cycloalkyl, aryl, aliphatic or aromatic heterocyclyl substituted with one more basic group, such as amino-, amidino- and/or guanidine-group; R2 represents hydrogen atom (H), alkyl, alkylthio-, alkoxy- or cycloalkyl group; R3 represents COOR5, SO(OR5), SOR5 and others; R4 represents hydrogen atom (H) or (C1-C6)-alkyl; R6 represents hydrogen atom (H); X represents C(Z)2 or NR6CO; Y represents C(Z)2; Z represents hydrogen atom (H), (C1-C6)-alkyl, aryl or cycloalkyl. Indicated compounds inhibit activity of carboxypeptidase U and can be used for prophylaxis and treatment of diseases associated with carboxypeptidase U.

EFFECT: improved preparing method, valuable biochemical and medicinal properties of compounds.

14 cl, 36 ex

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