UA78544C2 - Fluorene carboxylic acid esters, use thereof as pharmaceuticals, pharmaceutical composition, intermediate - Google Patents

Abstract

The invention relates to novel fluorene carboxylic acid esters of general formula (I) wherein X- and the groups A, R, R1, R2, R3, R3', R4 and R4' have the designations cited in the claims and in the description. The invention also relates to methods for producing said novel fluorene carboxylic acid esters and to the use of the same as pharmaceuticals.

Description

Description of the invention

This invention relates to new esters of fluorenecarboxylic acids of the general formula 1 2 in! t, -

Ek h u chen

A o a v v | B "Ж 4, where X' and the residues A, РЕ, В", В2, В, в, вів can have the meanings specified in the formula of the invention and in the following description, to the method of their preparation, as well as to their use as medicinal products.

This invention offers compounds of the general formula 1 2 A -

KM Zh r-i "N

Hn o sh

IS

N-t t , then you are 6) where

A means a residue with two bonds, which is selected from the group that includes вх OR 0-0 , - and ; Z zo n,nN, nn no «t

X is a singly charged anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, sulfate, phosphate, methanesulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate, and p-toluenesulfonate, (uh)

K means hydrogen, hydroxy group, methyl, ethyl, -SEz, -СНЕ" or fluorine, M

Where is it? have the same or different values and represent -C/-Salkyl, which may optionally be substituted by -C3-Seccycloalkyl, a hydroxy group or a halogen, or

In and in? together mean -Sz-Svalkilen bridge and "; ; "have the same or different values and represent hydrogen, - -C; alkyl, e3, c, vii c b b co -c, -C. » or halogen. - c Preferred are the compounds of the general formula 1, where h» A means a residue with two bonds, which is selected from the group consisting of " mch schi 0-6 and . - And X means a singly charged anion, which is selected from the group including chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide, and K means a hydroxy group, methyl or fluorine, sl B and 82 have the same or different values and represent methyl .

ЧТ» Particularly preferred are the compounds of the general formula 1, in which means a residue with two bonds, which is selected from the group consisting of

And the choice

ЧИ вв НН:

But (F) XX means a singly charged anion selected from the group consisting of chloride, bromide and methanesulfonate,

He is mostly bromide,

K means hydroxy group, methyl or fluorine, preferably methyl or hydroxy group, 60 V and V? have the same or different values and represent methyl or ethyl, preferably methyl, and

VZ c, 3 have the same or different values and represent hydrogen, -SEz, -СНЕ" or fluorine, preferably hydrogen or fluorine.

According to the invention, compounds of the general formula 1, in which

A represents a double-bonded residue selected from the group consisting of b5

Ohm

NN

X means bromide, 9 K means a hydroxy group or methyl, preferably methyl,

In and in? have the same or different values and represent methyl or ethyl, preferably methyl, and

VZ, VU, 83rd B have the same or different values and represent hydrogen or fluorine.

The object of the invention is the corresponding compounds of formula I, which are presented under certain conditions in the form of individual /o0 bptic isomers, mixtures of individual enantiomers or racemates.

In the compounds of the general formula 1, each of the residues C in, viv, if they do not denote hydrogen, can be in the ortho-, meta- or para-position relative to the place of attachment to the "-С-К" group. If none of the residues 23, в, КУ, and В" does not represent hydrogen, then КЗ and КУ are preferably attached in the para position, and В? and 7 are preferably attached in the ortho- or meta-position, most preferably in the meta position. If one of the residues З В 75 one of the residues BZ and 7 means hydrogen, then the corresponding other residue is preferably attached in the meta- or para-position, most preferably in the para-position. If none of the residues C, c, BZ yv means hydrogen, then especially preferred according to the invention are those compounds of the general formula 1, which have residues in 3,

Ka v ive have an identical meaning.

Compounds of the general formula 1, in which the ester 720 substituent has an o-configuration with respect to the nitrogen-containing bicycle, are of particular importance according to the invention. Such compounds correspond to the general formula 1-о, и вы х -

N. p

A o o S on foot "calls Ich"

According to the invention, the following specific compounds are of particular importance: y - methobromide of tropenol ether of 9-hydroxyfluorene-9-carboxylic acid, - methobromide of tropenol ether of 9-fluorofluorene-9-carboxylic acid, co - methobromide of scopine ether of 9-hydroxyfluorene-9-carboxylic acid acids, - - 9-fluorofluorene-9-carboxylic acid scopine ether methobromide, - 9U-methylfluorene-9-carboxylic acid tropenol ether methobromide, - 9U-methylfluorene-9-carboxylic acid scopine ether methobromide. "

In the context of this description, alkyl groups mean, unless otherwise specified, branched and unbranched alkyl groups with 1-5 carbon atoms. Examples of such groups are methyl, ethyl, propyl and c or butyl. To designate similar groups, that is, methyl, ethyl, propyl, or butyl, in some cases, the corresponding abbreviated names Me, ЕІІІ, Ргор, or Вы are also used. Unless otherwise specified, the terms "propyl" and "butyl" also include all possible isomeric forms of each of these residues. So, for example, the term "propyl" includes n-propyl and isopropyl, and the term "butyl" included isobutyl, sec-butyl, tert-butyl, etc.

Alkylene groups mean, unless otherwise specified, branched and unbranched alkyl -I bridges with two bonds and 1-4 carbon atoms. Examples include methylene, ethylene, propylene or butylene. co By alkylenehalogen groups are meant, unless otherwise indicated, branched and unbranched os alkyl bridges with two bonds and with 1-4 carbon atoms, mono-, di- or tri-substituted, preferably di-substituted, with a halogen atom. Similarly, alkylene-OH groups are, unless otherwise indicated, e branched and unbranched alkyl bridges with two bonds and with 1-4 carbon atoms, one-, two- or

Chl" are trisubstituted, preferably monosubstituted, with a hydroxy group.

Alkyloxy groups mean, unless otherwise specified, branched and unbranched alkyl groups with 1-4 carbon atoms attached through an oxygen atom. An example is a methyloxy-, ethyloxy-, propyloxy- or butyloxy group. In some cases, to designate such groups, i.e., methyloxy-, ethyloxy-, propyloxy-, or butyloxy groups, the corresponding abbreviated names Meo-, EYU-, Rgoro-, or VyO are also used. If not

Unless otherwise specified, the terms "propyloxy group" and "butyloxy group" also include all possible isomeric forms of each of these residues. So, for example, the term "propyloxy group" includes n-propyloxy group and isopropyloxy group, the term "butyloxy group" includes isobutyloxy group, sec-butyloxy group, tert-butyloxy group, etc. In some cases, in this description, instead of the designation "alkyloxy group", the equivalent term "alkyloxy group" is also used. Accordingly, to denote such groups as methyloxy-, ethyloxy-, propyloxy-, or butyloxygroup, in some cases, equivalent terms methoxy-, ethoxy-, propoxy-, or butoxygroup are used.

Alkylenalkyloxy groups are, unless otherwise indicated, branched and unbranched alkyl bridges 65 With two bonds and with 1-4 carbon atoms, mono-, di- or trisubstituted, preferably monosubstituted, alkyloxy group.

By -0-CO-alkyl groups are meant, unless otherwise specified, branched and unbranched alkyl groups with 1-4 carbon atoms, which are attached through an ester group. At the same time, alkyl groups are directly attached to the carbonyl carbon atom of the ester group. The term "-0-CoO-alkylhalogen group" is interpreted in a similar way. The group -0-CO-CE»z is trifluoroacetate.

Halogen in the context of this invention is fluorine, chlorine, bromine or iodine. Unless otherwise specified, fluorine and bromine are the preferred halogens. The CO group is a carbonyl group.

The compounds proposed in the invention can be partially obtained, as described in more detail below, similarly to methods already known from the state of the art (Scheme 1). Derivatives of carboxylic acids of the formula C are known from the state of the art or they can be obtained by synthesis methods known from the state of the art. If only appropriately substituted carboxylic acids are known in the art, compounds of formula C can also be directly obtained from them by acid or base catalyzed esterification with appropriate alcohols or by halogenation with appropriate halogenating agents.

Scheme 1 v y d v / d) is t r - , a ; - x m , Kk M MN gi et ve-x z

N with no - well n

A SN A ele; And what is that eE Ge y sova ovey she shshe o

And eE 4 in Ek Gay

As follows from the above scheme 1, the starting products for obtaining compounds of the formula are the compounds of the formula 2. These compounds are known from the prior art. AND

Complex esters of the general formula 4 are obtained from compounds of the formula 2 by their interaction with derivatives of carboxylic acids of the formula 3, in which K' means, for example, chlorine or a C, -C, alkyloxy group. If K' represents a C.-C.alkyloxy group, then such an interaction can be carried out, for example, in molten sodium at an elevated temperature, preferably at a temperature in the range from approximately 50 to 1502C, most preferably from approximately 90 to 1002C, and at reduced pressure, preferably at a pressure of less than 5000mbar, most preferably less than 7B5mbar. In another variant, instead of derivatives of formula 3, in which VK is a C.-Alkyloxy group, it is also possible to use the corresponding acid chlorides (K means SI).

Compounds of formula 4 obtained in this way by their interaction with compounds of formula BK 2-X, in which B? and X can have the above values, can be translated into the necessary compounds of formula 1. This stage of synthesis can also be carried out similarly to the synthesis examples described in (MUO 92/16528| bridge, the addition of the reagent K 2-X, as is obvious to a specialist, is not required. In this case, the compounds of formula 4 have an appropriately substituted residue K" (for example -C3-Salkylenehalogen) :z" in accordance with the above-mentioned values for it, and compounds of formula 1 are obtained by intramolecular quaternization of amine.

Alternatively to the method of synthesis of compounds of formula 4 presented in Scheme 1, derivatives of formula 4, in which the nitrogen-containing bicycle is a scopine derivative, can be obtained by oxidation (epoxidation) of compounds of formula 4, in which the nitrogen-containing bicycle is a tropenyl residue. For this purpose, according to the invention, the following approach can be used. The compound of formula 4, in which A is -CH-CH-, is suspended in a polar organic solvent, preferably in a solvent selected from the group consisting of

M-methyl-2-pyrrolidone (M-MP), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and then the resulting suspension is heated to a temperature of approximately 30-902C, preferably to 40-7020. After that, an acceptable oxidant is added and stirred at a constant temperature for 2-8 hours, preferably 3 hours. As an oxidant, vanadium pentoxide mixed with Н»О» is preferably used, most preferably the complex НХО»О-urea together with vanadium pentoxide. The next processing of the reaction mixture is carried out in the usual way. Depending on its tendency to crystallization, the product can be purified by crystallization or chromatography.

In another variant, the compounds of formula 4, in which K is halogen, can also be obtained by the method that (F) is illustrated below in Scheme 2.

M Mn shi writes

A Sn A Ob - na in "so cho k V k u 4 (KovshcheOnNO ) 4 (Kaznehagalateno

In accordance with this method, compounds of formula 4, in which K is a hydroxy group, are converted using suitable halogenating agents into compounds of formula 4, in which K is halogen. The halogenation reaction carried out according to Scheme 2 is quite well known in the art.

It is obvious that in the reaction illustrated in Scheme 1, the intermediate products of the general formula 4 are important. Accordingly, another object of this invention is the intermediate compounds of the formula 4. but e in e

Е ЕЕ с 4 о where the residues A, ВЕ, В", 3 B ВТ and в can have the above values, not necessarily in the form of their acid-addition salts. Such acid-addition salts mean salts selected from group that includes hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethanesulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate Ж 1 hydro-p-toluenesulfonate, the best of which are hydrochloride, hydrobromide, hydrosulfate, hydrogen phosphate, hydrofumarate and hydromethanesulfonate.

In the compounds of the general formula 4, similarly to the compounds of the formula | each of the residues KZ, 27, VU and B", if they do not denote hydrogen, can also be attached in the ortho-, meta- or para-position relative to the site of attachment to the group "-C-B". If none of the residues VU, В", КЗ and К7 do not mean hydrogen, then ВЗ and 27 are preferably attached in the para position, and В" and ЕК? are preferably attached in the ortho- or meta-position, most preferably in the meta-position. if 27 means hydrogen, then the corresponding other residue is preferably attached in the meta- or para-position, most preferably in the para-position. If none of the residues VZ, 27, VZ | B does not mean hydrogen, then especially preferred according to the invention are compounds of the general "formula 4, in in which the residues КУ, В", ВУ and В" have an identical meaning. As starting compounds, the compounds of formula 4 are preferably used according to the invention in the form in which they have the α-configuration. In accordance with this, such compounds with o-configuration are, according to the invention, of special importance and are responsible for to the general formula 4-o, i ; -AND

NN so A s o a v Ek i" u v de 44

The next object of this invention is the use of compounds of general formula 2 to obtain compounds 5o of general formula 4. This invention also relates to the use of compounds of general formula 2 as starting materials

HF) of compounds for obtaining compounds of general formula 1. This invention also relates to the use of compounds of general formula 4 as intermediate products for obtaining compounds of general formula 1. o Below, this invention is explained using examples of synthesis. It is obvious that such examples are purely illustrative and are intended only to explain the principles underlying the invention, without limiting its scope to the specific variants of its implementation considered as examples in the following description.

Example 1: Methobromide of tropenol ether of 9-hydroxyfluorene-9-carboxylic acid b5

1.1: Methyl ether of 9-hydroxyfluorene-9-carboxylic acid Dissolve 50.4 g (0.22 mol) of 9-hydroxy-9-fluorenecarboxylic acid in 500 ml of methanol, mix with bml (0.08 Umol) of concentrated sulfuric acid and refluxed for an hour. After cooling, 100 ml of sodium bicarbonate solution (pH about 8) was added and 75% methanol was almost completely evaporated. The mixture was extracted with dichloromethane and water, the organic phase was dried and The product is purified by recrystallization from ethyl acetate.

Yield: 50.0g of white crystals (9395 from theory). 1.2: Tropenol ether of 9-hydroxyfluorene-9-carboxylic acid 4a 13.4 g (0.05 bmol) of methyl ether Za, 11.65 g (0.084 mol) of tropenol and 0.3 g of sodium in the form of a melt are heated for 4 hours. at a pressure of 75 mbar in a boiling water bath with periodic shaking. After cooling, the residual sodium is dissolved in acetonitrile, the solution is evaporated to dryness and the residue is extracted with dichloromethane/water. The organic phase is washed with water, dried over Mo5O, and the solvent is distilled off. The product is purified by recrystallization from diethyl ether.

Yield: 11.40g of white crystals (5995 from theory). Ge 1.3: Methobromide of the tropenol ether of 9-hydroxyfluorene-9-carboxylic acid about 1.75 g (0.00 bmol) of compound 4a is dissolved in 30 ml of dichloromethane and 15 ml of acetonitrile and mixed with 2.85 g (0.015 mol) of a 5095 solution of methyl bromide in acetonitrile. The reaction mixture is left for three days at room temperature, which is accompanied by crystallization of the product. The precipitated crystals are separated and recrystallized from diethyl ether for purification. AND

Yield: 1.95 g of white crystals (8895 from theory).

Idl 25090. h

Elemental analysis: iv) calculated: C (62.45) H (5.47) M (3.17) co found: C (61.53) H (5.84) M (3.22)

Example 2: Methobromide of tropenol ether of 9U-fluorofluorene-9-carboxylic acid

Me, same Meche I " du Ve Z7Z s n ;" (I Yes

Е z со 2.1: Tropenol ether of 9-fluorofluorene-9-carboxylic acid 4p «sl 1.6bml (0.009mol) of bis(2-methoxyethyl)iaminosulfotrifluoride is added to 1O0ml of dichloromethane and for 5p 2Okhv. at 15-202C, mix dropwise with a solution of 2.4 g (0.007 mol) of compound 4a in 25 ml of dichloromethane. Shk mixture for 20 hours. stir at room temperature, then cool to 02C and carefully mix with 1 mL

TH" of water with intensive stirring. After that, the pH value is set to 8 by carefully adding an aqueous solution of MansCo", the organic phase is separated, and the aqueous phase is re-extracted with dichloromethane, the combined organic phases are washed with water, dried over MozO, and evaporated to dryness. As a result, hydrochloride precipitates and is recrystallized from acetonitrile/diethyl ether. Finally, the free base is isolated again using a 1095% aqueous solution of sodium carbonate. i) Yield: 1.05 g of light yellow crystals (5395 from theory). step 2.2: Methobromide of the tropenol ether of 9U-fluorofluorene-9-carboxylic acid 1.05 g (0.00 mol) of compound 45 is dissolved in 20 ml of acetonitrile and, similarly to stage 1.3, is subjected to interaction with 001771 g (0.009 mol) of a 5095% solution of methyl bromide in acetonitrile. For purification, the product is recrystallized from acetonitrile.

Yield: 0.80 g of white crystals (6095 from theory). dl 25296.

Elemental analysis: b5 calculated: C (62.17) H (5.22) M (3.15)

found: C (62.04) H (5.23) M (3.15)

Example 3: Methobromide of 9-hydroxyfluorene-9-carboxylic acid scopine ester

Me is Me V with M

At

So-oh that's it

F c 3.1: Scopine ether of 9-hydroxyfluorene-9-carboxylic acid 4c 9.0 g (0.02 bmol) of tropenol ether 4a are suspended in 900 ml of dimethylformamide and mixed with 047 g (0.00 bmol) of vanadium oxide (M). Then, at 602C, a solution of 4.89 g (0.052 mol) of H 5O5-urea in 2 Oml of water is added dropwise and stirred for 2 hours. at 60 9C. After cooling to 20 oC, the precipitate formed is separated by vacuum filtration, the pH value of the filtrate is set to 2 with the help of 4N hydrochloric acid and mixed with a solution of Ma»boOv in water. The resulting solution was evaporated to dryness and the residue was extracted with dichloromethane/water. The pH value of the acidic aqueous phase is set to alkaline using

Ma»Co», after which it is extracted with dichloromethane, and the organic phase is dried over Ma25O and concentrated. Then, at room temperature, ml of acetyl chloride is added and the mixture is stirred for an hour. After extraction of Tn with hydrochloric acid, the pH value of the aqueous phase is set to alkaline, then it is extracted with dichloromethane, after which the organic phase is washed with water and dried over Ma95O,). Finally, the solvent is removed by distillation. Ge

The crude product is purified by recrystallization from diethyl ether. at

Yield: 2.8g of white crystals (3095 from theory). 3.2: Methobromide of the scopine ether of 9-hydroxyfluorene-9-carboxylic acid 1.3 g (0.004 mol) of compound 4c is dissolved in 20 ml of chloroform and 20 ml of acetonitrile and, similarly to stage 1.3, is reacted with 2.279 g (0.012 mol) of a 5095% solution of methyl bromide in acetonitrile. For purification, the product is recrystallized from acetonitrile. "

Yield: 1.25g of light beige crystals (6895 from theory).

Idle 243-24490. i am

Elemental analysis: c calculated: C (60.27) H (5.28) M (3.06) h- found: C (60.03) H (5.35) M (3.55)

Example 4: Methobromide of scopine ether of 9-fluorofluorene-9-carboxylic acid

Me Me - « "7 VG shi s a N . i? o i) y z sho (ee) , . - I . 4.1: Scopine ether of 9-fluorofluorene-9-carboxylic acid 4a (9) 0.885ml (0.005mol) of bis(2-methoxyethyl)uaminosulfotrifluoride is added to 25 ml of dichloromethane and similarly to stage 2.1, it is reacted with 1.42 g (0.004 mol) of compound 4c.

Yield: 1.1g of beige crystals (7595 from theory).

ЧТ» 4.2: Methobromide of scopine ether of 9-fluorofluorene-9-carboxylic acid 1.1 g (0.00 mol) of compound 44 is dissolved in 30 ml of acetonitrile and, similarly to stage 1.3, is reacted with 1.71 g (0.009 mol) of a 5096 solution of methyl bromide in acetonitrile . For purification, the product is recrystallized from isopropanol. o Yield: 0.45 g of white crystals (33905 from theory).

Idl 200-201260, ko Elemental analysis: calculated: C (60.01) H (5.04) M (3.04) found: C (59.91) H (5.18) M (3.10)

Example 5: Methobromide of tropenol ether of 9U-methylfluorene-9-carboxylic acid b5

Me, but Me - known Vg to

Ha

Method 5.1: 9-methylfluorene-9-carboxylic acid Zr a) Methyl ether of 9U-methylfluorene-9-carboxylic acid

A solution of sodium ethylate is prepared from 7.6 bg (0.3 mol) of sodium and 300 ml of ethanol, to which 69.bg (00.3 mol) of 9-fluorenecarboxylic acid is added in portions. After completion of the addition, the mixture is stirred for 2.5 hours. at 72 room temperature. After that, the mixture is evaporated to dryness, the residue is suspended in bbOml of dimethylformamide and 93.96 g (0.662 mol) of methyl iodide is added dropwise. Then the mixture is stirred for 10 minutes. at constant temperature. The cloudy solution, upon cooling, is added with stirring to 500 ml of water and 300 ml of diethyl ether and extracted, the organic phase is washed with water and a 10956 solution of sodium carbonate, dried and evaporated to dryness. The residue is purified by column chromatography using a mixture of 20 cyclohexane/ethyl acetate in the ratio of 96:4 as an eluent.

Yield: 12.61 g of white crystals (1695 from theory).

Ill. 108-10926, b) 9-methylfluorene-9-carboxylic acid Zr 12.6 g (0.053 mol) of methyl ether of 9-methylfluorene-9-carboxylic acid and 5 ml of a 2-molar aqueous solution of 25% sodium hydroxide for 24 hours. mix in 120 ml of 1,4-dioxane at room temperature. Then. (3 dioxane is distilled off, and the other mixture is mixed with water, bringing the total volume to 00 ml, and extracted with diethyl ether. The aqueous phase is acidified with 3-molar aqueous NOI, crystallized and filtered.

Yield: 11.25g of white crystals (9595 from theory). dl 168-1695S. From 30 5.2: Tropenol ether of 9-methylfluorene-9-carboxylic acid 4e "And 6.73 g (0.0 mol) of compound 30 are suspended in bOml of dichloromethane, mixed with 5.0 g of oxalyl chloride and 1 drop of dimethylformamide, and then stirred for an hour at room temperature temperature and then drive away the solvent. The remaining acid chloride is used in the next stage without further purification. ee 4.18 g (0.0 mol) of tropenol and 4.27 g (0.03 mol) of isopropylethylamine are suspended in 1000 ml of dichloroethane, at 35 З35-40еС acid chloride is added dropwise in ZOml of dichloroethane and then stirred for 24 hours. at - 402. The suspension is diluted with dichloromethane and extracted with dilute hydrochloric acid. The organic phase is then washed with water, dried over Mo50O, and the product is converted into its hydrochloride by treatment with a solution of HCIII in diethyl ether. After that, the solvent is removed. For purification, the precipitated hydrochloride is dissolved in 20% water and extracted with diethyl ether. The pH value of the aqueous phase is set alkaline using a 1095% aqueous solution of sodium carbonate and extracted with dichloromethane. Finally, the organic phase is dried over NaCl, and the solvent is distilled off. :z» Yield: 4.40g of yellow oil (4295 from theory). 5.3: Methobromide of the tropenol ether of 9U-methylfluorene-9-carboxylic acid 1.8 g (0.005 mol) of the free base 4e is subjected to a chemical transformation similar to stage 1.3. Product -1 is purified by recrystallization from acetone.

Yield: 1.80 g of white crystals (8290 from theory). (ee) il 258-25996. c Elemental analysis:

Сg» 50 is calculated: C (65.46) H (5.95) M (3.18)

T" was found: C (64.15) H (5.95) M (3.18)

Example 6: Methobromide of scopine ether of 9U-methylfluorene-9-carboxylic acid

Me. 6.1: Scopine ether of 9-methylfluorene-9-carboxylic acid 4, 2.5 g (0.007 mol) of tropenol ether 4, similarly to stage 3.1, react with 0.13 g (0.00 mol) b5 I of vanadium oxide (M) and 1.43 g (0.015 mol) of NiO»o-urea.

Yield: 1.8g of white crystals (7195 from theory). 6.2: Methobromide of the scopine ether of 9-methylfluorene-9-carboxylic acid 1.8 g (0.005 mol) of compound 4 is dissolved in 30 ml of acetonitrile and, similarly to stage 1.3, is reacted with 2.848 g (0.015 mol) of a 5095% solution of methyl bromide in acetonitrile.

Yield: 1.6g of white crystals (7095 from theory).

Ill. 21426.

Elemental analysis: 76 calculated: C (62.13) H (5.93) M (4.26) found: C (62.23) H (6.05) M (4.32)

The compounds of formula 1 proposed in the invention are, as it was established, antagonists of the MZ receptor (muscarinic receptor subtype 3). The value of Ki in the compounds proposed in the invention is relative to the affinity to

M33-receptor is less than 1OnNM. These values were determined respectively according to the methodology described below. iz Chemicals

ZN-MM5 with a specific radioactivity equal to 3071GBq/mmol (83Ky/mmol) - Ategzypat, Braunschweig. All other reagents are Zegma, Heidelberg, and Megsk, Darmstadt.

Cell membranes

In the experiments, membranes of CHO cells (from the English "spipeze patwieg omagu", Chinese hamster ovary cells), transfected with the corresponding genes of human muscarinic receptors subtypes pti-pt5 (according to the method described in Woppeg) were used as cell membranes. Cell membranes of the required subtype were thawed, manually resuspended using a glass homogenizer, and diluted with HERE5 buffer (M-2-hydroxyethylpiperazine-M'-2-ethanesulfonic acid) to a final protein concentration equal to 20-33Omg/ml.

Receptor binding studies (o)

Research on binding to the receptor was carried out using a mixture with a final volume of 1 ml, consisting of 100 μl of an unlabeled substance in various concentrations, 100 μl of a radioactive ligand (ZH-M-methylscopolamine (ZH-MM5) at a concentration of 2 nmol/l, 200 μl of drugs of cell membranes and bOOmcl of NEREZ-buffer (20mmol/l NEREZ, 1Ommol/l MoSi, 10O0mmol/l Mass, pH value 7.4, determined using Tmol/l MaonN). Nonspecific binding was determined using atropine in concentration - 10 μmol/l. The experimental mixture was incubated for 45 h at 37 2C in O9b-well titration and microplates (VesKtap company, material: polystyrene, Mo267001), conducting experiments in two parallel series. The incubation was completed by filtering through a U/paytap 0-7 filter, using the Ipoiesi harvester (type co

ZN 110). The filters were washed with Zml NEREZ-buffer, which was chilled on ice, and dried before carrying out cha measurements.

Determination of radioactivity

The radioactivity retained on the filter mats was measured simultaneously using a two-dimensional digital autoradiograph (Vepnoia, Wildbad, type 3052). "

Processing of results 8 s Ki values were calculated using equations in an implicit form, which were derived directly on the basis of the law of active masses, on the model of the reaction between 1 receptor and 2 ligands (Zuzrya software, which "" is described in ZspiykomuekKi).

The compounds of the general formula 1 proposed in the invention have wide possibilities for their use for therapeutic purposes, and accordingly have a high therapeutic potential. In particular, it should be noted - And the better possibility of using the compounds of formula 71 proposed in the invention due to their pharmaceutical effectiveness as anticholinergic agents. As an example of the use of compounds according to the invention for these purposes, it is possible to mention the therapy of asthma or COPD (chronic obstructive pulmonary disease). Compounds of general formula c may also be used for the treatment of vagus nerve-related (fluctuating) sinus bradycardia and for the treatment of heart rhythm disorders. In general, the compounds proposed in the invention are also suitable for the treatment of spasms, for example, in the gastrointestinal tract, with the achievement of an appropriate therapeutic effect.

And" The compounds proposed in the invention can also be used for the treatment of spasms in the urinary tract, as well as, for example, ailments during menstruation. Among the indications presented above as an example, special importance is attached to the use of compounds of formula I proposed in the invention! in the therapy of asthma and

COPD

The compounds of the general formula I can be used individually or in combination with other active substances of the formula 1 proposed by iF) in the invention. Under certain conditions, the compounds of the general formula 1 can also be used together with other pharmacologically active active substances. At the same time, we are primarily talking about betamimetics, antiallergic agents, platelet-activating factor (RAB) antagonists, IM type phosphodiesterase inhibitors (POE M), leukotriene antagonists, pZ8 kinase inhibitors, ESEK-kinase inhibitors, and corticosteroids, as well as various combinations of these active agents substances

As an example of betamimetics, which according to the invention can be used together with the compounds of formula 1, we can name compounds selected from the group that includes bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol , 65 Ssulfonterol, terbutaline, tolubuterol, 4-hydroxy-7-(2-42-113-(2-phenylethoxy)propyl|Isulfonyl)ethyl|aminoethyl1I-2(ZH)-benzothiazolone,

1-(2-fluoro-4-hydroxyphenyl)-2-I4-(1-benizimidazolyl)-2-methyl-2-butylamino|ethanol, 1-(3--4-methoxybenzylamino)-4-hydroxyphenylide-2-( 4-(1-benzimidazolyl)-2-methyl-2-butylamino|ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-(3-( 4-M,M-dimethylaminophenyl)-2-methyl-2-propylamino|ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-(3- (4-Methoxyphenyl)-2-methyl-2-propylamino|)ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-(3-(4 -n-butyloxyphenyl)-2-methyl-2-propylamino|)ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-14-I3-( 4-methoxyphenyl)-1,2,4-triazol-3-yl|-2-methyl-2-butylamino)ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4 -benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert-butylamino)ethanol and 70 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl) )-2-(tert-butylaminodethanol, under certain conditions in the form of their racemates, their enantiomers, their diastereomers, and also under certain conditions of their pharmacologically acceptable acid addition salts and hydrates ativ As betamimetics in combination with the compounds of formula 1 proposed in the invention, it is more preferable to use active substances selected from the group including fenoterol, formoterol, salmeterol, 1-(3--4-methoxybenzylamino)-4-hydroxyphenylide-2-(4- (1-benzimidazolyl)-2-methyl-2-butylamino|ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-(3-(4- K, Modimethylaminophenyl)-2-methyl-2-propylamino|ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-(3-(4-methoxyphenyl) )-2-methyl-2-propylamino|)ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-(3-(4-n-butyloxyphenyl) )-2-methyl-2-propylamino|)ethanol, 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-14-I3-(4-methoxyphenyl) -1,2,4-triazol-3-yl|-2-methyl-2-butyl Mino)ethanol, under certain conditions in the form of their racemates, their enantiomers, their diastereomers, and also under certain conditions of their pharmacologically acceptable acid additive salts, their solvates and/or their hydrates. Among the above betamimetics, the compounds formoterol and salmeter are particularly preferred ol, under certain conditions in the form of their racemates, their enantiomers, their diastereomers, as well as under certain conditions their pharmacologically acceptable acid addition salts and hydrates. According to the invention, the best acid addition salts of betamimetics are, for example, salts selected from the group including hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate and xinafoate. In the case of salmeterol, its preferred salts are hydrochloride, sulfate and i) xinafoate, of which xinafoate is the most preferred. In the case of formoterol, the preferred salts thereof are the hydrochloride, sulfate and fumarate, of which the hydrochloride and fumarate are most preferred. According to the invention, formoterol fumarate is particularly preferred. "g zo In the context of this invention, corticosteroids, which under certain conditions can be used in combination with compounds of the formula and, mean compounds selected from the group including flunisolide, beclomethasone, - triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide , ZUU 215864, KK 592, 5T-126 and dexamethasone. Best according to the present invention are corticosteroids selected from the group including flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, among which the most preferred are budesonide, fluticasone, mometasone and ciclesonide, primarily budesonide and fluticasone. In some cases, only the term "steroids" is used instead of the term "corticosteroids" in this description. When mentioned in this description, steroids also mean salts or derivatives that can be formed by steroids. Examples of such possible salts or derivatives include sodium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates. Under certain conditions, corticosteroids can also be presented in the form of their hydrates. z c As an example of POE IM inhibitors, which according to the invention can be used in combination with compounds of formula 1, we can name compounds selected from the group that includes enprofylline, roflumilast, ariflo, z Vau-198004, SR-325,366, VUZ343, 0 -4396 (Zsp-351591), M-11294A and AMUO-12-281. The best inhibitors of POE IM are selected from the group including enprofylline, roflumilast, ariflo and AMUO-12-281, among which AMUO-12-281 is the most preferable for use in combination with the compound of formula 1 proposed in the invention. When mentioning the above -I inhibitors of ROEIM in the context of this invention also mean their possible pharmacologically acceptable acid addition salts. According to the invention, physiologically acceptable (compatible) acid addition salts, which can be co-formed with the above-mentioned POEM inhibitors, mean pharmaceutically acceptable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid , acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. The best salts according to the invention are selected from the group consisting of acetate, hydrochloride, hydrobromide, sulfate, phosphate, and methanesulfonate.

In the context of this invention, dopamine agonists, which under certain conditions can be used in combination with compounds of formula 1, mean compounds selected from the group including bromocriptine, cabergoline, alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole , talipexol, terguride and viosan. The best according to this invention are dopamine agonists, which are suitable for use in combination with

F) compounds of formula 1 are pramipexole, talipexole and viosan, of which pramipexole is the most preferred. The above-mentioned dopamine agonists in the context of this invention also mean their possible pharmacologically acceptable acid addition salts and, under certain conditions, their hydrates. By physiologically compatible acid-addition salts that can be formed with the above-described dopamine agonists, we mean, for example, pharmaceutically acceptable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid acid, succinic

Acids, LACTIC ACID, CITRIC ACID, tartaric acid and maleic acid.

Epinastine, cetirizine, azelastine, fexofenadine, levocabastin, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipine, cexachlorpheniramine, pheniramine,

doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine, and meclozine.

The preferred antiallergic agents that according to the present invention can be used in combination with the compounds of formula 1 proposed therein are selected from the group consisting of epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, of which epinastine is particularly preferred and desloratidine. The above-mentioned antiallergic agents in the context of this invention also mean their possible pharmacologically acceptable acid additive salts.

As an example of PAP antagonists, which according to the invention can be used in combination with compounds of formula 1, we can name 70. 4-(2-chlorophenyl)-9-methyl-2-13-(4-morpholinyl)-3-propanone-1 -yl|-6H-thieno|3,2-1(11,2,4)griazolo|4,3-a||/1,4)diazepine 6-(2-chlorophenyl)-8,9-dihydro- 1-methyl-8-(4-morpholinyl)carbonyl|-4H,7H-cyclopenta-|4,5Hyeno|3,2-P(1,2,griazolo|4,3-a|(1,4diazepine.

As an example of the best ESERK kinase inhibitors, which according to the invention can be used in combination with compounds of formula 1, we can name 4-(3-chloro-4-fluorophenyl)amino1-7-I4-((K)-6- methyl-2-oxomorpholin-4-yl)butyloxy1-6-(vinylcarbonyl)amino)quinazolin, 4-(3-chloro-4-fluorophenyl)amino1-7-I4-((5)-6-methyl-2- oxomorpholin-4-yl)butyloxy1-6-((vinylcarbonyl)aminoquinazolin, 4-(3-chloro-4-fluorophenyl)amino1|-7-(2-14-((5)-(2-oxotetrahydrofuran-5- yl)carbonyl|piperazin-1-yl)ethoxy)-6-((ynylcarbonyl)amino)quinazoline, 4-(3-chloro-4-fluorophenyl)amino!1-7-(2-((5)-6 -methyl-2-oxomorpholin-4-yl)ethoxy1)-6-(vinylcarbonyl)amino)quinazoline, 4-(3-chloro-4-fluorophenyl)amino!1-6-K4-1M-(2-(ethoxycarbonyl) ethyl|-M-Ketoxycarbonyl)methyl|amino)-1-oxo-2-buten-1-yl)amino|-7-cyclopropylmethoxyquinazoline, sc 4-KK)-(1-phenylethyl)amino!-6-Ch4-( morpholin-4-yl)-1-oxo-2-buten-1-yl|1-amino)-7-cyclopropylmethoxyquinazoline and 4-(3-chloro-4-fluorophenyl)amino)|-6-3-(morpholin- 4-yl)upropyloxy|-7-methoxyquinazoline. When mentioning i) above ESEK-kinase inhibitors in the context of this invention, their possible pharmacologically acceptable acid additive salts are also meant. Physiologically, respectively pharmacologically acceptable (compatible) acid-addition salts that can be formed with similar ESEBK-kinase inhibitors, in accordance with the scope of the Invention, mean pharmaceutically acceptable salts that are selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. According to the invention, the best salts of ESEMK kinase inhibitors are salts of acetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and methanesulfonic acid. co

As an example of the best p38 kinase inhibitors, which according to the invention can be used in combination with compounds of the formula and, we can name 1-(b-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3 -(4--2-morpholin-4-ylethoxy)naphthalen-1-yl|urea, 1-(b-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl|-3-(4- (2-(1-Oxothiomorpholin-4-yl)ethoxy)naphthalen-1-yl|Urea, 1-(b-tert-butyl-2-(2-methylpyridin-5-yl)-2H-pyrazol-3-yl) -3-I4-(2-pyridin-4-ylethoxy)naphthalen-1-yl)urea, " 1-(b-tert-butyl-2-(2-methoxypyridin-5-yl)-2H-pyrazol-3- yl|-3-(4-(2-morpholin-4-ylethoxy)naphthalen-1-yl)|urea with c or 1-(b-tert-butyl-2-methyl-2H-pyrazol-3-yl|- 3-I4-(2-morpholin-4-ylethoxy)naphthalen-1-yl|urea. When mentioning the above ESEK-kinase inhibitors in the context of this invention, they also mean their possible pharmacologically acceptable acid-addition salts. Under physiologically , respectively, pharmacologically acceptable (compatible) acid addition salts that can be formed with similar inhibitors of the rZV kinase, in according to the invention are meant pharmaceutically acceptable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid acid c If the compounds of the formula i are planned to be used in combination with other active substances, then the best compounds for use in such combinations among the above-mentioned classes are steroids, and inhibitors of ROE IM or betamimetics. At the same time, special importance is attached to the use of the compounds proposed in this invention in combination with betamimetics, primarily with betamimetics of prolonged action. The combinations of compounds of the formula and with salmeterol or formoterol proposed in the invention should be considered particularly best. 5B As an example of dosage forms of compounds of formula 1 suitable for administration into the body, tablets, capsules, suppositories, solutions, etc. can be indicated. The introduction of the compounds proposed in the invention is of particular importance

F) inhalation (primarily in the treatment of asthma or COPD). The proportion of pharmaceutically active compound(s) in such dosage forms should in each case be from 0.05 to 9Omas.9o, preferably from 0.1 to 5Omas.9o, from the total weight of the drug. Suitable tablets can be made, for example, by mixing the active substance or active substances with known excipients, such as inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatin, lubricants such as magnesium stearate or talc, and/or depot agents such as carboxymethyl cellulose, cellulose acetophthalate or polyvinyl acetate. Tablets can also consist of several layers. 65 Accordingly, dragees can be made by coating the cores obtained similarly to tablets from materials that are commonly used for these purposes, such as collidon or shellac, gum arabic, talc,

titanium dioxide or sugar. To ensure a depot effect or to avoid incompatibility, the dragee core can also be made multilayered. The shell of the dragee can also consist of several layers to provide a depot effect, while the excipients mentioned above for tablets can be used.

Mixtures based on the active substances proposed in the invention, respectively combinations of active substances, may additionally include a sweetening substance, such as saccharin, cyclamate, glycerin or sugar, as well as a taste enhancer, for example, a flavoring such as vanillin or orange extract. Except

These mixtures may contain suspending excipients or thickeners such as sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or 7/o protective substances (preservatives) such as p-hydroxybenzoates.

Solutions are prepared according to known technology, for example with the addition of isotonic agents, preservatives such as p-hydroxybenzoates, or stabilizers such as salts of ethylenediaminetetraacetic acid with alkali metals, and if necessary with the use of emulsifiers and/or dispersants, while e.g. , when using water as a diluent, if necessary, you can use organic /5 Agents as hydrotropic solubilizers, respectively auxiliary solvent, and pour into injection bottles, ampoules or infusion bottles.

Capsules containing one or more active substances, respectively a combination of active substances, can be made, for example, by mixing the active substances with inert carriers, such as lactose or sorbitol, and placing the resulting mixture in gelatin capsules.

Suitable suppositories can be made, for example, by mixing the active substance or active substances with carriers intended for this purpose, such as neutral fats or polyethylene glycol, respectively, their derivatives.

Examples of excipients used in the preparation of dosage forms include water, pharmaceutically acceptable (harmless) organic solvents, such as paraffins (for example, mineral oil fractions), oils of vegetable origin (for example, peanut or sesame oil), mono- or polyfunctional ov alcohols (for example, ethanol or glycerin), carriers, such as natural rock flour (for example, kaolin, alumina, talc, chalk), synthetic rock flour (for example, highly dispersed silicic acid and and) silicates), sugar (for example, cane, milk and grape sugar), emulsifiers (eg lignin, sulfite alkali, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (eg magnesium stearate, talc, stearic acid and sodium lauryl sulfate). "g zo In the case of oral administration, in addition to the above-mentioned carriers, the corresponding tablets can, obviously, also contain such additives as, for example, sodium citrate, calcium carbonate and dicalcium phosphate, together with various fillers, such as starch, mainly potato starch, gelatin, etc. In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc can also be used in the production of tablets. In the case of aqueous suspensions, the active substances, in addition to the above-described auxiliary substances, can also be mixed with various flavor enhancers or dyes. Cha

With the best according to the invention, the use of the compounds of formula 1 for the therapy of asthma or COPD is most preferable to use dosage forms that are introduced into the body by inhalation, respectively pharmaceutical compositions. Examples of dosage forms for inhalation include inhalation powders, metered aerosols with propellant or inhalation solutions without propellant. In the context of this invention, the expression "Inhalation solutions without propellant" also means concentrates or sterile, ready-to-use solutions for inhalation. Similar dosage forms used according to this invention are discussed in more detail in the next part of the description. ;" In inhalation powders, which are used according to the invention, compounds of the formula | can be contained either individually or in a mixture with acceptable physiologically harmless excipients. If the active substances of the formula I are contained in the inhalation powders proposed in the invention in a mixture with physiologically harmless auxiliary substances, then the following physiologically harmless (compatible) auxiliary substances can be used to obtain such inhalation powders: monosaccharides (for example, glucose or arabinose), disaccharides ( e.g. lactose, sucrose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients. It is better to use mono- or disaccharides, while it is especially preferable to use lactose or glucose, primarily, but not exclusively, in the form of their hydrates. Especially preferred according to the invention is the use of lactose, most preferably lactose monohydrate, as an auxiliary substance.

The maximum average particle size of excipients used in the inhalation powders proposed in the invention is up to 250 μm, preferably from 10 to 150 μm, most preferably from 15 to 8 μm. Under certain conditions, it may be appropriate to mix them with the auxiliary substances mentioned above

F) fractions with a smaller average particle size, namely from 1 to Ωkm. Similar excipients with a smaller particle size are also selected from the group of excipients described above, which are used in inhalation powders. In addition, when preparing the inhalation powders proposed in the invention, it is suggested to mix the micronized active substance of formula 1, the average particle size of which is preferably from 0.5 to 1 µm, most preferably from 1 to 5 µm, to the mixture of auxiliary substances. Methods of obtaining the inhalation powders proposed in the invention by grinding and micronizing the components followed by their mixing are known from the state of the art. Inhalers known from the state of the art can be used to introduce the inhalation powders proposed in the invention into the body. 65 In the inhalation aerosols with propellant proposed in the invention, the active substances of the formula and can be present in a dissolved or dispersed form in the propellant. In this case, the active substances of formula 1 can be contained in separate dosage forms or in one single dosage form, and the specified components of formula 1 or both can be present in a dissolved form, or both can be present in a dispersed form, or only one of them can be present in dissolved form, and the other in dispersed form.

Propellants used to produce inhalation aerosols are known from the prior art. Propellants suitable for this purpose are selected from the group consisting of hydrocarbons such as n-propane, n-butane or isobutane and halogenated hydrocarbons such as fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above-mentioned propellants can be used individually or in the form of their mixtures. The most preferred propellants are halogenated alkane derivatives selected from the group including 70 TO134a and 10227, as well as their mixtures.

Propellant inhalation aerosols may also include other components, such as co-solvents, stabilizers, surface-active substances (surfactants), antioxidants, lubricants, as well as means for adjusting the pH value. All such components are known from the prior art.

7/5 Inhalers known from the state of the art (inhalers that deliver a measured dose of the drug) can be used to introduce the inhalation aerosols described above into the body with a propellant.

The active substances of formula 1 proposed in the invention can also be introduced into the body in the form of inhalation solutions and inhalation suspensions without propellant. Aqueous or alcoholic, preferably ethanolic, solutions can be used as such solutions. Only water or a mixture of water and ethanol can serve as a solvent. The relative content of ethanol in terms of the amount of water is not limited by any specific limits, it is preferable, however, that the maximum content of ethanol is up to 70-06.95, primarily up to 60 vol.95, most preferably up to 30 vol.95. The rest, missing up to 100o6., is water. The pH value of solutions or suspensions containing active substances of formula 1 is set to 2-7, preferably 2-5, using acids suitable for this purpose. Acids from among inorganic or organic acids can be used to adjust the pH value in order to set it to the above values. Examples of the best inorganic acids in this regard include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. As an example of the most suitable organic acids for the above purposes, we can name ascorbic i) acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, as well as others acid The best inorganic acids are hydrochloric acid and sulfuric acid. It is also possible to use acids, which, when combined with the active substances, already form an acid-additive salt. Among organic acids, ascorbic acid, fumaric acid and citric acid are the best. Under certain conditions, it is possible to use mixtures of the specified acids, primarily those acids that, along with their ability to increase acidity, also have other properties, such as flavoring substances, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid. To adjust the pH value according to the invention, it is most preferable to use hydrochloric acid. Cha

According to the invention, it is possible to abandon the addition of edetic acid (EDTC) or one of its known salts, in particular sodium edetate, as a stabilizer or complexing agent to such compositions. However, in other embodiments, the use of this compound(s) is contemplated. In one of these best options, in which the use of sodium edetate is provided, its concentration in the solution is less than 100mg per 00ml, preferably less than 50mg per 100ml, most preferably less than 20mg per 100ml. In general, the following inhalation solutions, the content of sodium edetate in which is from 0 to 10 mg per 10 Oml, are the best.

Co-solvents and/or other auxiliaries can be added to inhalation solutions that do not contain propellant;" substances As co-solvents, it is preferable to use those containing hydroxyl groups or other polar groups, for example alcohols, primarily isopropyl alcohol, glycols, primarily propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerin, polyoxyethylene alcohols and ethers of polyoxyethylene and fatty acids. Excipients and additives in this context mean any pharmacologically acceptable substance that is not an active substance, but which can be included in a composition together with the active substance(s) in a pharmacologically acceptable solvent to improve with the qualitative characteristics of such a composition. These substances should not show any or, taking into account the target 5p therapeutic effect, any more or less significant or at least no unwanted pharmacological action. Such auxiliary substances and additives include, for example, surface-active substances, such as soy lecithin, oleic acid, sorbitan ether, in particular polysorbates, polyvinylpyrrolidone, other stabilizers, complexing agents, antioxidants and/or preservatives that ensure the storage of the finished medicinal product. composition or that allow to extend its shelf life, flavors, vitamins and/or other additives known from the state of the art. Such additives also include pharmacologically harmless salts, such as, for example, sodium chloride, as isotonic agents. (F, Among the best auxiliary substances are antioxidants, such as, for example, ascorbic acid, unless it is already used to regulate the pH value, vitamin A, vitamin E, tocopherol and similar vitamins found in the human body, or provitamins 60 Preservatives can be used to protect the composition from contamination by pathogenic microorganisms. As such preservatives, substances known from the state of the art can be used, primarily cetylpyridinium chloride, benzalkonium chloride or benzoic acid, respectively benzoates, such as sodium benzoate, in concentrations known from the state of the art. The concentration of the above preservatives are preferably up to 50 mg per 100 ml of solution, most preferably from 5 to 20 mg per 100 ml of solution. 65 Preferred compositions, in addition to the solvent, which is water, and the active substance of formula 1 also contain only benzalkonium chloride and sodium edetate. In another better option, it is proposed to completely abandon application of sodium edetate yes

The prescribed dose of the compounds proposed in the invention largely depends, as is obvious, on the method of their introduction into the body and the disease to be treated. When administered by inhalation, the pronounced effect of using the compounds of the formula is manifested already when they are administered in doses that lie in the microgram range. However, the compounds of formula 1 should also be used in doses exceeding the microgram range. At the same time, the appropriate dose can, for example, be in the gram range.

The compounds proposed in the invention can be used in higher doses, first of all, when they are administered by a route other than inhalation (for example, in doses ranging from 1 to 1000 mg, but not limited to the specified limits).

Below, the invention is illustrated by examples, which present the compositions of some dosage forms and which do not limit its volume.

Examples of pharmaceutical compositions

A) Tablets

Component Content in one tablet active substance of formula 1 100mg lactose 140mg corn starch 240mg polyvinylpyrrolidone 1Bmg magnesium stearate Bmg 5OOmMg

The finely divided active substance is mixed with lactose and a part of the entire prescribed amount of pure corn starch. The resulting mixture is sieved, after which it is moistened with a solution of polyvinylpyrrolidone in water, kneaded, granulated in a wet state and dried. The obtained granulate together with the rest of the prescribed amount (o) of corn starch and magnesium stearate is sifted and mixed together. From the resulting mixture, tablets of the required shape and size are pressed.

B) Tablets "

Component Content in one tablet: active ingredient of formula 1 8mg lactose BBmg corn starch 190mg (ee)

Microcrystalline cellulose ZBmg i.e. polyvinylpyrrolidone 1Bmg sodium carboxymethyl starch 23mMg magnesium stearate 2mMg 400mg « 70 The finely divided active ingredient is mixed with a part of the entire amount of corn starch, lactose, microcrystalline cellulose and polyvinylpyrrolidone, the resulting mixture is sieved and together with the remaining amount of water processed into granules, which are dried and sieved. Next, sodium carboxymethyl starch and magnesium stearate are added, mixed and tablets of the required size are pressed from the resulting mixture. 75 B) Solution in ampoules -I (os) active substance of formula 1 Bomg sodium chloride Bomg o water at the rate of one injection 5ml iz 50

The active substance at its own pH or, if necessary, at a pH of 5.5 to 6.5 is dissolved in water and mixed with sodium chloride as an isotonic agent. The obtained solution is filtered in non-pyrogenic conditions and the filtrate is packaged in ampoules under aseptic conditions, which are then sterilized and sealed. Such ampoules can contain 5mg, 25mg and 5mg of the active substance.

D) Dosed aerosol

IF) active substance of formula 1 O,bo5mas. o name) sorbitan trioleate O.1wt.9o monofluorotrichloromethane and difluorodichloromethane in a ratio of 2:3 to 10Owt.9o 60

The suspension is poured into an ordinary aerosol can with a dosing valve. The portion of the suspension that is issued for a single click on such a valve is preferably 5 Ωcl. If necessary, the active substance can be administered in higher doses (for example, 0.02% by weight).

D) Solutions (in mg/100 ml) b5 active substance of formula 1 333, Zmg formoterol fumarate 333, Zmg Benzalkonium chloride 10, Omg

EDTK BO, Omg

NS (In) to RN 34

A solution of such a compound can be prepared using conventional technology.

E) Inhalation powder active substance of the formula 1 bmkg formoterol fumarate bmg lactose monohydrate up to 25 mg

Inhalation powder of the specified compound is obtained according to the usual technology by mixing individual components. 12 F) Inhalation powder active substance of formula 71 1Omkg lactose monohydrate to bmg

Inhalation powder of the specified compound is obtained according to the usual technology by mixing individual components.

References 1. Voppeg T.I., Mem/ ziBriurez oi tyvsagipis aseiiuIspoiipe geserioge, Tgepdz RIagtasoi. All together. 10, supplement: 11-15, 1989; spyikKomuzki K., Ragatei(eg eviitayop ip vzuvietvo oi popiipeag edtsaiop5z, Mytheg May. 68, 1994, sa sb. 129-142. (5)

Claims (1)

The formula of the invention "I 1. Compounds of the general formula 1 r "Be i myu (ee) - H « A (v) - s I: yin ' ;" do ge ti te 1) and ' in - and where so A means a residue with two bonds, which is selected from the group that includes c and B- in SHI | X means a singly charged anion, K means a hydroxy group, methyl, ethyl, -SEz, -СНЕ» or fluorine, V and B? have the same or different values and represent -C4-C5 alkyl, which 29 can optionally be substituted by -C3z-Cocycloalkyl, a hydroxy group or a halogen, or (FI B! and B2 together mean -C3-C; an alkylene bridge and 23 in, BZ 87 have the same or different values and represent hydrogen, -C4-Alkyl, -C4-C; alkyloxy group, hydroxy group, -SEz, -СНЕ», -СМ, -МО» or halogen. 2. Compounds of formula 1 according to claim 1, where A means a residue with two bonds, which is selected from the group, which includes bo x M n--60 and y chy y y no НА ' Н Н Н y Н ' Х means singly charged an anion selected from the group consisting of chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide because K represents hydroxy, methyl or fluorine, IN! 82 have the same or different values and represent methyl, ethyl or fluoroethyl, and C, c, c 187 have the same or different values and represent hydrogen, methyl, a methyloxy group, a hydroxy group, -SEz, -"СНЕ" or fluorine. C. Compounds of the general formula 1 according to claim 1 or 2, where A means a residue with two bonds, which is selected from the group consisting of НН X means a singly charged anion, which is selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide, K means hydroxy group, methyl or fluorine, preferably methyl or hydroxy group, B and B? have the same or different values and represent methyl or ethyl, preferably methyl, and BZ in, 83187 have the same or different values and represent hydrogen, -SEz, -СНЕ" or fluorine, preferably hydrogen or fluorine. 4. Compounds of the general formula 1 according to any of claims 1-3, where A means a residue with two bonds, which is selected from the group consisting of "U dk H o Hn ' Н H X means bromide, сх K means a hydroxy group or methyl, preferably methyl, B and B? have the same or different values and represent methyl or ethyl, preferably methyl, and o C, c, c 187 have the same or different values and represent hydrogen or fluorine. 5. Compounds according to any of claims 1-4, which are optionally presented in the form of their individual optical isomers, in the form of mixtures of individual enantiomers or in the form of racemates. "g zo 6. Use of the compound of the general formula 1 according to any of claims 1-5 for obtaining a medicinal product, which is intended for the treatment of asthma, chronic obstructive pulmonary disease (COPD), vagal - sinus bradycardia, heart rhythm disorders, stomach spasms -intestinal tract, spasms in the urinary tract and ailments during menstruation. 7. A pharmaceutical composition containing as an active substance one or more compounds of the general formula 1 according to SO Zb ONE WITH PP. 1-5 or their physiologically compatible salts, optionally in combination with the usual auxiliary substances and/or carriers. 8. The pharmaceutical composition according to claim 7, which is characterized by the fact that, along with one or more compounds of formula 1, it also contains at least one other active substance, which is selected from the group that includes betamimetics, antiallergic agents, platelet activation factor antagonists, phosphodiesterase inhibitors. type M, leukotriene antagonists, p3v8 kinase inhibitors, ESEK-kinase inhibitors, and corticosteroids. from p 9. Intermediate products of the general formula 4 in! . z» r - and (ee) H 1 A o t» s» E zh jah EE s 4 Geo ve ' iF) where the residues A, B, B", 3 VZ viv can have the values indicated in claims 1-4, necessarily in the form of their co-acid-additive salts. 10. Application of compounds of the general formula 2 bo b5 ra H to ono? where are the remainders of A and B! may have the values specified in claims 1-4, optionally in the form of their acid-addition salts, for obtaining compounds of formula 1 according to any of claims 1-5. 19 Official Bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2007, M 4, 15.04.2007. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. 6) « « IS) s and - - with . and? -I (ee) 1 sh» s» F) ime) 60 b5