UA73804C2 - Anticholinergic agents being used as medicaments, a method for the preparation thereof and a pharmaceutical composition - Google Patents

Abstract

The invention relates to novel anticholinergic agents of general formula (1), wherein A, X- and radicals R1, R2, R3, R4, R5, R6 and R7 can have the meanings as cited in the claims and in the description. The invention also relates to the use of these agents as medicaments.

Description

Description of the invention

This invention relates to new anticholinergic agents of the general formula I vai x: shk

And about ro "b in which A, X and residues B", 2, KZ, K7, B", 5 Her Kk" can have the meanings indicated in the formula of the invention and in the further description, the method of their preparation, as well as their use as medicinal products .

The use of anticholinergic agents is expedient from a therapeutic point of view in many diseases. At the same time, it should be especially noted, for example, the therapy of asthma or COPD (chronic obstructive pulmonary disease). For the treatment of similar diseases, UUO 92/16528 proposed anticholinergic agents, the molecular basis of which is formed by the scopine, tropenol or tropine skeleton.

The task underlying the invention claimed in MUO 92/16528 was to propose compounds that have anticholinergic activity, characterized by an effect that persists over a long period of time. To solve this problem, UUO 92/16528 of the past proposed, among others, benzyl ethers of scopine, tropenol, or tropine.

For drug therapy of chronic diseases, it is often desirable to have at one's disposal drugs that have a long-lasting effect. Due to this, as a rule, it is possible for a long period of time to ensure the maintenance of the concentration of the active substance in the body necessary to achieve the therapeutic effect without the need for excessively frequent repeated administration of the medicinal product. On the other hand, the administration of the active substance with less frequency greatly contributes to the patient's well-being. At the same time, it is most desirable to have at one's disposal a medicine that would allow you to achieve the desired therapeutic effect when it is administered once a day (that is, a medicine designed for a single dose per day). The advantage associated with the use of the medicinal product only once a day is the convenience of such a treatment regimen for the patient due to relatively quick habituation to the regular intake of the medication at a certain period of the day.

There are special requirements for the active substance intended for introduction into the body so that it can be used as a medicine, which is designed for one-time use per day. On the one hand, the necessary action should occur relatively quickly after the introduction of the medicinal product, the effectiveness of which, in the ideal case, should be maintained at a constant level as much as possible during the next rather long period of time. On the other hand, the duration of action of the medicinal product should not significantly exceed one day. In an ideal case, the active substance should have such a profile of action that it is possible to purposefully manage the process of obtaining a once-a-day medicinal product containing the active substance in therapeutically optimal doses. -at

It was established that the benzyl ethers of scopine, tropenol, or tropine described in UMO 92/16528 do not meet such high requirements. These compounds, because their effect is maintained for an exceptionally long period of time, significantly exceeding the above-mentioned period of time, which is approximately one day, are not suitable for their therapeutic use as medicaments calculated for one dose per day.

Based on the above, the basis of this invention was the task of offering new -1 395 anticholinergic agents, which, thanks to their profile of action, would allow to obtain on their basis medicinal preparations designed for single administration per day. Another object of the invention was to provide (95) compounds with relatively rapid onset of action. The task of the invention was also to offer compounds, the effectiveness of which would be maintained after the rapid onset of their action, preferably at a constant level during the following rather long period of time. Another object of the invention was to (av) 50 offer compounds whose duration of action when used in therapeutically optimal doses is not

And" would significantly exceed a period of time equal to approximately one day. In addition, the task of the invention was also to offer compounds with such an action profile that would allow for effective regulation of their therapeutic effect (that is, their therapeutic effect should be fully manifested without the side effect of accumulating the compound in the patient's body).

During the creation of the invention, it was unexpectedly established that the above-mentioned problems can be solved by means of (F) with the help of compounds of the general formula 1, in which the residue B" does not mean a hydroxy group. According to this, the present invention offers compounds of the general formula 1.

A 9; (o) in t G- I. 65 in which

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

X stands for singly charged anion,

In and in? mean C-C 1-6 alkyl, which may optionally be substituted by a hydroxy group or a halogen,

With, 7, in i 2? have identical or different meanings and are hydrogen, C .-Sulalkyl, C4-C, alkyloxy group, hydroxy group, CEz, CM, MO" or halogen,

B means hydrogen, C1-C1alkyl, C1-C1alkyloxy group, C1-C1alkylene halogen, halogen-C-C1alkyloxy group,

C.-Salkylene-OH, CEz, - C.-C.alkylene-C.i-C.alkyloxy group, -O-SOS.-Slalkyl, -O-SOS.-C.alkylhalogen, 70 -O-SOSE" or halogen, while in the case that A is a residue Mch then n, n,

B and 2 mean methyl,

Z, 87, B and 25 mean hydrogen, and

B cannot stand for hydrogen.

Preferred compounds of general formula 1, in which A is a double-bonded residue selected from the group consisting of

X represents a singly charged anion selected from the group consisting of chloride, bromide, methyl sulfate, 4-toluenesulfonate and methanesulfonate, preferably bromide,

IN! c: have identical or different values and represent a residue selected from the group that includes methyl, ethyl, n-propyl and isopropyl, while such residue may optionally be substituted by a hydroxy group or with 29 fluorine, preferably unsubstituted methyl, Ge)

C, 27, c and 29 have the same or different meanings and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CM, CEz or MO" and "/ means hydrogen, methyl, ethyl, methyloxy group, ethyloxy group, -СНо-Е, -СНО-СНо-Е, -0-СНо-Е, "-0-сСнН.-СНО-Р, -СНо.ОН, -СНоАСНООН, СЕз, -"СНу--ОМе . at

More preferred compounds of the general formula 1, in which A means a residue with two bonds, selected from the co group, which includes co 0, . s, u-

X represents a singly charged anion selected from the group consisting of chloride, bromide and methanesulfonate, preferably bromide,

V'ev: have identical or different values and represent a residue selected from the group that includes methyl and ethyl, while such a residue may optionally be substituted by a hydroxy group or fluorine, preferably "70 unsubstituted methyl, in c 3, 27, c and 29 have the same or different meanings and are hydrogen, methyl, ethyl, methyloxy, cethyloxy, hydroxy, fluorine, chlorine or bromine and "B" means hydrogen, methyl, ethyl, methyloxy, ethyloxy, CE3, or fluorine .

According to the invention, the compounds of the general formula 1 are also preferred, in which A means a residue with two bonds, selected from the group which includes and95) X: means bromide,

Go! In it, 22 have identical or different values and represent a residue selected from the group that includes methyl and o 50 ethyl, preferably methyl, | | that 23, c", KZ and KU have identical or different values and are hydrogen, methyl, methyloxy group, chlorine "z" or fluorine and

"BE" means hydrogen, methyl or fluorine.

Particularly preferred according to the invention are compounds of the general formula 1, in which A represents a residue with two bonds selected from the group consisting of

GF) with i same ;

Nya non

Io) X means bromide,

In its 82 have identical or different values and represent methyl or ethyl, preferably methyl, 60 C, 87, in and 25 have identical or different values and represent hydrogen or fluorine, preferably hydrogen, and

B" means hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl.

The object of the invention is the corresponding compounds of formula X, presented under certain conditions in the form of individual optical isomers, mixtures of individual enantiomers or racemates.

In the compounds of the general formula 1, each of the residues 23, b, b b, if they do not represent hydrogen, may be in the ortho-, meta- or para-position relative to the place of attachment to the "-C-B" group. If none from the residues KU, B", 5 and 25 does not mean hydrogen, then BZ and B? are preferably attached in the para-position, and VK" and B are preferably attached in the ortho- or meta-position, most preferably in the meta-position. If one of the residues BZ and 27 and one of the residues E. and 29 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 introduced BZ residues represents hydrogen, then particularly preferred according to the invention are compounds of the general formula 1, in which the residues

With, 7, in? and 25 have identical meaning.

Particularly preferred according to the invention are compounds of the general formula 1, in which the ester substituent in the bicyclic nitrogen atom has an α-configuration. Such compounds correspond to the general formula 1-9, c. K x u- /n

And oh /0 5 th

In Chapter

According to the invention, the following compounds are of particular importance: - 2,2-diphenylpropionic acid tropenol ether methobromide, - 2,2-diphenylpropionic acid scopine ether methobromide, - 2-fluoro-2,2-diphenylacetic acid scopine ether methobromide, - tropenol ether methobromide 2-fluoro-2,2-diphenylacetic acid.

In the context of this description, alkyl groups mean, unless otherwise specified, branched and unbranched alkyl groups with 1-4 carbon atoms. Examples include methyl, ethyl, propyl or butyl. For the designation of similar groups, i.e. methyl, ethyl, propyl, or butyl, in some cases, corresponding abbreviated names Me, ЕЙ, Ргор, or Вы are also used. Unless otherwise specified, the terms "propyl" and (o)butyl" also include all possible isomeric forms of each such residue. So, for example, the concept of "propyl" includes n-propyl and isopropyl, and the concept of "butyl" includes isobutyl, sec-butyl, tert-butyl, etc.

Alkylene groups mean, unless otherwise specified, branched and unbranched alkyl - 20 bridges with two bonds and with 1-4 carbon atoms. Methylene, ethylene, propylene or butylene can be mentioned as an example. (av)

Alkylenhalogen groups are, unless otherwise indicated, branched and unbranched alkyl compounds with two bonds and 1-4 carbon atoms, mono-, di- or tri-substituted, preferably mono-substituted, halogen. In a similar way, alkylene-OH groups are, unless otherwise indicated, branched and (ze) unbranched alkyl bridges with two bonds and 1-4 carbon atoms, mono-, di- or tri-substituted, M is mostly mono-substituted, hydroxy group .

Alkyloxy groups mean, unless otherwise specified, branched and unbranched alkyl groups with 1-4 carbon atoms attached through an oxygen atom. As an example, a methyloxy-, ethyloxy-, propyloxy- or butyloxy group can be mentioned. In some cases, corresponding abbreviations Meo-, E-, Phoro-, or Vy- are also used to designate such groups, i.e. methyloxy-, ethyloxy-, propyloxy-, or butyloxy groups. Unless otherwise specified, the terms "propyloxy group" and "butyloxy group" also include all possible c isomeric forms of each such residue. 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. In accordance with this, for -1 that designates such groups as methyloxy-, ethyloxy-, propyloxy-, or butyloxygroup, in some cases equivalent concepts of methoxy-, ethoxy-, propoxy-, or butoxy group are used for them. (95) Alkylenalkyloxy groups are, unless otherwise indicated, branched and unbranched alkyl bridges with two bonds and 1-4 carbon atoms, mono-, di- or tri-substituted, preferably mono-substituted, 5-alkyloxy groups. (ав) By -0-CO-alkyl groups are meant, unless otherwise indicated, branched and unbranched alkyl

T" groups with 1-4 carbon atoms attached through an ester group. At the same time, alkyl groups are directly attached to the carbonyl carbon of the ester group. The concept of "-0-CO-alkylhalogen group" is interpreted in a similar way. The -0-CO-SEz group is trifluoroacetate. 5 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. (F) The compounds of the invention can be prepared in part as described in more detail below,

It is similar to methods already known from the state of the art (scheme 1). Carboxylic acid derivatives of formula C are known in the art or can be obtained by synthetic methods known in the art. If only appropriately substituted carboxylic acids are known from the prior art, then 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. b5

Scheme 1 « t v! And au eat and in how x

Re ro S uU n n n

And he A o. ro A o. to 70 2 « 1

Complex esters of general formula 4 are obtained starting from compounds of formula 2 by their interaction with carboxylic acid derivatives of formula C, 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 approximately 50-1502C, most preferably at approximately 90-1009C, and at 75 reduced pressure, preferably at pressure less than 500 mbar, most preferably less than 75 mbar. In another variant, instead of the derivatives of formula 3, in which K is a C.-C.alkyloxy group, it is also possible to use the corresponding acid chlorides (K means CI).

Compounds of formula 4 obtained in this way by interaction with compounds of formula B 2-X, in which B? and X can have the values indicated above, can be translated into the necessary compounds of formula 1. This stage of synthesis can also be carried out similarly to the examples of synthesis considered in УЧО 92/16528.

As an alternative 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 represents -CH-CH-, is suspended in a polar organic solvent, preferably in a solvent selected from the group that includes o

M-methyl-2-pyrrolidone (M-MP), dimethylacetamide and dimethylformamide, preferably dimethylformamide, and then the obtained suspension is heated to a temperature of the order of 30-902C, preferably 40-702C. After that, an acceptable oxidant is added and stirred at a constant temperature for 2-8 hours, preferably 3 hours. As an oxidant, it is preferable to use vanadium pentoxide in a mixture with HO", most preferably the complex H»aOo-urea in combination with vanadium pentoxide. The next processing of the reaction mixture is carried out in the usual way. at

Depending on its tendency to crystallize, the product can be purified by crystallization or chromatography.

In another variant, compounds of formula 4, in which B is halogen, can also be prepared by the method illustrated below in Scheme 2.

Scheme 2 in y -

M M rt rya

A (e; (c) A o. (9)

According to this method, benzyl ethers of formula 5 are converted with the use of acceptable "halogenating agents" into compounds of formula 4, in which KB" means halogen. The halogenation reaction carried out according to scheme 2 is quite well known in the art.

Benzyl ethers of formula 5 are obtained according to known or similar methods known from the state of the art (see, for example, UUO 92/16528).

It is obvious that intermediate products of general formula 4 are important in the reaction illustrated in scheme 1. Accordingly, another object of this invention is intermediate compounds of formula 4 (ee)' in o 50 M

And chn

T" A o. 20 g, t Sh

Kk in 4

GF) in which

A means a double-bonded residue selected from the group consisting of about 2Honone 60 B" means S.-Sulfylalkyl, which may optionally be substituted by a hydroxy group or a halogen, 23, 7, 5 and 29 have identical or different values and represent, hydrogen, C 1-C alkyl, C-C alkyloxy group, hydroxy group, CEz, CM, MO" or halogen and

B means hydrogen, C.i.-C.alkyl, C.-C.alkyloxy group, C.i.-C.alkylene halogen, halogen-C--C.alkyloxy group, 65 C.-C.-alkylene-OH, | C3, -C4-Salkylene-Ci-C;.alkyloxy group, -0-COS.-Sulalkyl, -0-COS.-C.alkylhalogen, -0-COC3 or halogen, while in the case that A is a residue with K , to n, n,

B" means methyl, 23, 27, B and 25 mean hydrogen, and

B cannot stand for n-propyl.

Preference is given to those compounds of the general formula 4, in which A means a residue with two bonds, selected from the group that includes 09 x y x 6-6. 0-0 and ; n, n, nn non

B" represents a residue selected from the group that includes methyl, ethyl, n-propyl and isopropyl, while such a residue may optionally be substituted by a hydroxy group or fluorine, it is preferably an unsubstituted methyl, и и и Br. и

BZ, 7, BZ and K9 have identical or different values and are hydrogen, methyl, ethyl, methyloxy group, ethyloxy group, hydroxy group, fluorine, chlorine, bromine, CM, CEz or MO" and

B means hydrogen, methyl, ethyl, methyloxy group, ethyloxy group, -СНо-Е, -СНо-СНо-Е, -О-СН»-Е, -0-сСнН.-СНО-Р, -СНо.ОН, -СНоАСНООН, СЕз, -"СН".ОМе, -СН.СНО-ОМе, -СНО-ОБ -СНо-СНо-ОБи -0-СоМе, -0-СОБЕИ, -ОО-СОСЕЗ, -0-СОСЕЗ, fluorine, chlorine or bromine.

More preferred are those compounds of the general formula 4, in which A is a residue with two bonds selected from the group consisting of ча ччч 272 non and Ge

B is a residue selected from the group that includes methyl and ethyl, while such a residue may optionally be substituted by a hydroxy group or fluorine, it is preferably an unsubstituted methyl, 23, 87, and 29 have identical or different values and represent itself, hydrogen, methyl, ethyl, methyloxy group, ethyloxy group, hydroxy group, fluorine, chlorine or bromine and

B represents hydrogen, methyl, ethyl, methyloxy, ethyloxy, C3, or fluorine. "

According to the invention, compounds of the general formula 4, in which o

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

M We (ee) 6-60, and ,

NN, nn no'n so

B" is a residue selected from the group that includes methyl and ethyl, preferably methyl, 23, 27, Bo and U have identical or different values and are, hydrogen, methyl, methyloxy, chlorine - or fluorine and

"BE" means hydrogen, methyl or fluorine.

The most preferred according to the invention are compounds of the general formula 4, in which A means a residue with "two bonds, selected from the group that includes -o x b-c and -, c B nich: c" B" represents methyl or ethyl, preferably methyl,

C, c, c and 5 have identical or different values and are hydrogen or fluorine, preferably hydrogen, and

B represents hydrogen, methyl or fluorine, preferably methyl or fluorine, most preferably methyl. -i In intermediate compounds of formula 4, similarly to compounds of general formula 1, each of the residues KZ, B", c K5 p, if they do not mean hydrogen, can also be in the ortho-, meta- or para-position relative to the site of attachment to the group "-C-OH". If none of the residues B C, 27, 25 and 25 is hydrogen, then B C and 5 are preferably attached in the para position, and KE" and 29 are preferably attached in the ortho or meta position, most (av) mostly in the meta-position. If one of the residues B and B" and one of the residues 2? and KZ? means hydrogen, then

HT" the corresponding other residue is preferably attached in the meta- or para-position, most preferably in the para-position. If none of the residues Ж, 87, 5 and К5 is hydrogen, then intermediate compounds of general formula 4 in which the residues КУ, Б", 2? and 2? have identical values are especially preferred according to the invention.

Below, the present invention is explained by synthesis examples. It is obvious that such examples have an exclusively illustrative nature and serve only to explain the principles underlying the invention, not iF) limiting its scope to the specific variants of its implementation considered in the following description as examples. Example 1: Methobromide of 2,2-diphenylpropionic acid scopine ether

Me, I, Me in;

M, 7 "ku o. 2 o

Me. 1.1: Chloroanhydride of 2,2-diphenylpropionic acid. and

52.08 g (0.33 mol) of oxalyl chloride is slowly added dropwise to a suspension of 25.0 g (0.11 mol) of 2,2-diphenylpropionic acid, 1000 ml of dichloromethane and 4 drops of dimethylformamide at 202C. Next, the mixture is stirred for an hour at 202C and for 0.5 hours at 502C. After that, the solvent is distilled off and the resulting residue is used at the next stage without further purification. 1.2: Scopine ester of 2,2-diphenylpropionic acid 4a

The residue obtained at stage 1.1 is dissolved in 100 ml of dichloromethane and at 409C is mixed dropwise with a solution of 51.45 g (0.33 mol) of scopine in 200 ml of dichloromethane. The resulting suspension is stirred for 24 hours at 409C, after which the precipitate formed is separated by vacuum filtration and the filtrate is subjected to acid extraction first with water and then with aqueous hydrochloric acid. The pH value of the combined aqueous phases is set to alkaline with the help of an aqueous solution of sodium carbonate, extracted with dichloromethane, the organic phase is dried over Ma»5O), evaporated to dryness and the hydrochloride is precipitated from the residue. The product is purified by recrystallization from acetonitrile.

Yield: 20.85g (47905 from theory).

TLC: K value: 0.24 (solvent system: tert-butanol/"formic acid/water in the ratio 75 75:15:10).

Ill 203-20496. 1.3: Methobromide of scopine ether of 2,2-diphenylpropionic acid 11.98g (0.033 mol) of compound 4a are combined at 202С with 210ml of acetonitrile, 7Oml of dichloromethane and 20.16g (0.1 mol) of 46.9296-bromomethane in acetonitrile and leave to stand for three days. After that, the solution is evaporated to dryness and the residue is recrystallized from isopropanol.

Yield: 11.34g (7595 from theory).

Ill 208-20926.

SodNovMozHVg (458.4).

Elemental analysis: calculated: C (62.89) H (6.16) M (3.06) s found: C (62.85) H (6.12) M (3.07) o

Example 2: 2-Fluoro-2,2-diphenylacetic acid scopine methobromide

Mmeuk/e ve os de n "I 0.0 o

E s o o i 2.1: Benzyl acid scopine ether base (ze)

Preparation of scopine ether of benzylic acid is known from the state of the art and is described in UUO 92/16528. m 2.2: Scopine ether of 2-fluoro-2.2-diphenylacetic acid 4r 2.66 g (0.02 mol) of dimethylaminosulfur trifluoride is cooled in 10 ml of dichloromethane to 029 and a solution of 5.48 g (0.015 mol) of scopine ether of benzylic acid 5a in 100 ml is added dropwise dichloromethane. Further, it is stirred for 30 minutes at 02C and for 30 minutes at 2020. After that, the solution is mixed with "0 Water, added Manso" (to pH 7-8) and the organic phase is separated. The aqueous phase is extracted with dichloromethane, the combined organic phases are washed with water, dried over NaCl, and evaporated to dryness. The hydrochloride is precipitated from the residue and recrystallized from acetonitrile. with Yield: 6.90g (8595 from theory). il 227-23096. 2.3: Methobromide of scopine ether of 2-fluoro-2,2-diphenylacetic acid -I 2.88 g (0.0078 mol) of the free base of scopine ether of benzylic acid is subjected to a chemical transformation similar to stage 1.3. The product is purified by recrystallization from isopropanol. and Output: 2.62g (7390 from theory).

Go! TLC: KE value: 0.31 (the solvent system is similar to stage 1.2). ill 130-13426. o Example 3: Methobromide of tropenol ether of 2,2-diphenylpropionic acid

Their" Me, t /me in " more about ko 3.1: Methyl ether of 2.2-diphenylpropionic acid Zr

To a suspension of 50.8 g (0.225 mol) of 2,2-diphenylpropionic acid and 200 ml of acetonitrile at 209, 60 drops of 37.60 g (0.247 mol) of DBU are added. 70.10 g (0.494 mol) of methyl iodide is then added dropwise to the resulting solution within 30 minutes. After that, stir overnight at 20 °C. Finally, the solvent is evaporated, the residue is extracted with diethyl ether/water, the organic phase is washed with water, dried over NaCl, dried and evaporated to dryness.

Yield: 48.29 g of viscous residue 3B (8995 from theory). bo 3.2: Tropenol ether of 2,2-diphenylpropionic acid 4c 4.80g (0.02 mol) methyl ether of 2,2-diphenylpropionic acid Zb, 2.78g (0.02 mol) tropenol and 0.046g of sodium are heated in the form of a melt for 4 hours at pressure of 75 mbar in a boiling water bath with moderate shaking. After cooling, the sodium residues are 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 Mo95O, and evaporated to dryness. From the residue, compound 4c is precipitated in the form of hydrochloride, which is recrystallized from acetone.

Output: 5.13Zg (6790 from theory).

TLC: KE value: 0.28 (solvent system: tert-butanol/"formic acid/water in the ratio 75:15:10). ill 134-13596. 70 3.3: Methobromide of tropenol ether of 2,2-diphenylpropionic acid 2.20g ( 0.006 mol) of compound 4c is subjected to a chemical transformation similar to example 1, stage 1.3.

The formed crystals are separated by vacuum filtration, washed with dichloromethane, dried and finally recrystallized from methanol/diethyl ether.

Output: 1.84g (66905 from theory).

TLC: KE value: 0.11 (solvent system similar to stage 1.2). dl 222-22396.

SodNovMO»ХВг (442 4).

Elemental analysis: calculated: C (65.16) H (6.38) M(3.17) found: C (65.45) H (6.29) M(3.16)

Example 4: Methobromide of tropenol ether of 2-fluoro-2.2-bis(3.4-difluorophenyl)optic acid me, "me in " o. lo in ХО о и "АХ, (8) 4.12: Ethyl ether of 3.3.4.4'-tetrafluorobenzyl acid Zs Reagent Grinyar is obtained from 2.24 g (0.092 mol) of magnesium shavings, a few small pieces of iodine and 17.80 g (0.092 mol) of 1-bromo-3,4-difluorobenzene in 100 ml of THF at 502 C. After the addition of the halide is completed, the mixture is stirred again within an hour. The Grignard reagent obtained in this way is added dropwise to 18.81 g (0.088 mol) of ethyl ether at 10-15 "С

of 3,4-difluorophenylglyoxylic acid in VOml THF and the resulting mixture is stirred for 2 hours at 520. After that, the white suspension for processing is poured onto a mixture of ice and sulfuric acid, extracted with ethyl acetate, and the organic phase is washed with water, dried over NaOH, and evaporated to dryness. The crude product is purified by column chromatography (solvent: toluene).

Yield: 10.80 g of oil (3895 from theory). in 4.2: Tropenol ether of 3.3.4.4-tetrafluorobenzyl acid 5p 4.27 g (0.013 mol) of ethyl ether of 3,3'4,4"-tetrafluorobenzyl acid Cc, 1.81 g (0.013 mol) of tropenol and 0.03 g of sodium are heated in the form melt for 4 hours at a pressure of 75 mbar in a boiling water bath with moderate shaking. After cooling, the sodium residues are 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 Moss, and evaporated to dryness. The resulting residue mixed with diethyl ether/petroleum ether (in a 1:9 ratio), separated by vacuum filtration and washed.

Yield: 2.50g (46905 from theory).

TLC: K value: 0.29 (solvent system: tert-butanol/"formic acid/water in the ratio 7B15:10). -I dl 147-14896. (95) 4.3: 2-fluoro-2,2-bis tropenol ether (3.4-difluorophenyl)acetic acid 4a 2.66 g (0.012 mol) of bis(2-methoxyethyl)aminosulfur trifluoride are added to 1 Oml of dichloromethane and for 20 minutes

So at 15-202С; mix dropwise with a solution of 0.01 mol of compound 56 in boml of dichloromethane. After that, for 20-20 hours, stir at room temperature, cool to 02C, and with intensive stirring carefully

T" is mixed with ZVOml of water. Then the pH value is set to 8, carefully adding an aqueous solution of Manso with, the organic phase is separated, the aqueous phase is re-extracted with dichloromethane, the combined organic phases are washed with water, dried over MazO, and evaporated to dryness. Finally, the hydrochloride is precipitated and recrystallized from acetonitrile/diethyl ether. Yield: 2.60g of white crystals (5790 from theory).

Ill. 23396. (F) 4.4: Methobromide of tropenol ether of 2-fluoro-2,2-bis(3,4-difluorophenyl)acetic acid, 2.20 g (0.0052 mol) of 4a is subjected to a chemical transformation similar to example 1, stage 1.3. The formed crystals are separated by vacuum filtration, washed with dichloromethane, dried and finally recrystallized from methanol/diethyl ether.

Yield: 1.95g (7290 from theory).

TLC: KeE value: 0.17 (solvent system: n-butanol/water/formic acid (conc.)/acetone/dichloromethane in the ratio 36:15:15:15:5).

Ill 24726. 65 SozNai EBMO»xHVg (518.3).

Elemental analysis: calculated: C (53.30) H (4.08) M (2.70)

found: C (53.22) H (4.19) M (2.69)

Example 5: Ethyl bromide of 2,2-diphenylpropionic acid scopine ether

Matt is silent Sun and Shchi. 40 1.81 g (0.005 mol) of compound 4a are combined at 202C with 35 ml of acetonitrile and 1.64 g (0.015 mol) of ethyl bromide and left to stand for 3 days. After that, the solution is evaporated to dryness and the residue is recrystallized from ethanol.

Yield: 1.38g (58905 from theory).

Ipl: 208-20926. 12 TLC: KE value: 0.33 (solvent system similar to stage 1.2).

Idl: 210-21126.

СоБНзоМО»зхХВг (472.42);

Elemental analysis: calculated: C (63.56) H (6.40) M (2.96) found: C (63.49) H (6.24) M (2.88)

Example 6: 2-Fluoro-2,2-bis(3,4-difluorophenyl)acetic acid scopine methobromide

Me ie Ve" o. ro s p, is (o)

MOX, 6.1: Scopine ether of 3,34,4"-tetrafluorobenzyl acid 5c 3.61 g (0.011 mol) ethyl ether of 3,3'4,4"-tetrafluorobenzyl acid Cs, 1.71 g (0.011 mol) of scopine and "Ezo 0.0 g of sodium is heated in the form of a melt for 4 hours at a pressure of 75 mbar in a boiling water bath with moderate shaking. After cooling, the sodium residues are 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 evaporated to dryness. The obtained residue is mixed with diethyl ether/petroleum ether (in a ratio of 1:9), separated by vacuum filtration and washed. and

Yield: 1.75g (36905 from theory). uh-

Ill: 178-17996, 6.2: Scopine ether of 2-fluoro-2,2-bis(3,4-difluorophenyl)acetic acid de

O.bml (0.0033 mol) of bis(2-methoxyethyl)aminosulfur trifluoride is reacted with 1.2 g (0.0028 mol) of compound 5c similarly to example 4, stage 4.3. "

Yield: 1.15 g of colorless oil 01 (9595 from theory). шщ с 6.3: Methobromide of scopine ether of 2-fluoro-2,2-bis(3,4-difluorophenyl)acetic acid and 1.15 g (0.0026 mol) of compound 4e and 1.5 g (0.0079 mol) of 50956 methyl bromide solution is subjected to a chemical "" transformation similar to example 1, stage 1.3. The formed crystals are separated by vacuum filtration, washed with dichloromethane, dried and finally recrystallized from acetone.

Output: 0.88g (63905 from theory). -I TLC: KeE value: 0.27 (solvent system: n-butanol/water/formic acid (conc.)/acetone/dichloromethane in the ratio 36:15:15:15:5). o dl: 21296. (Fe) SozNai EBMOzHVg (535.33). o 50 Example 7: Methobromide of tropenol ether of 2-fluoro-2,2-bis(4-fluorophenyl)optic acid meh kume V iz» food n 0. -0 in

FO,

F, 7.1: Methyl ether of 4.4-difluorobenzyl acid According to 7.1.1:4 4-difluorobenzyl acid

A solution of 24.62 g (0.1 mol) of 4,4"-difluorobenzyl in 250 ml of dioxane is added dropwise to a solution of 49.99 g (1.25 mol) of MaOH tablets in 30 ml of water at a temperature of approximately 1002C and stirred for 2 hours. After most of this dioxane is distilled off and the remaining aqueous solution is extracted with dichloromethane. When this aqueous solution is acidified with sulfuric acid, a precipitate forms, which is separated by vacuum filtration, washed and dried. The filtrate is extracted with dichloromethane, the organic phase is dried over Ma»2O4 and evaporated to dryness. 65 Yield: 25.01g (9595 from theory).

Ill: 133-136260.

7.1.2: Methyl ether of 4,4-difluorobenzyl acid

To a solution of sodium ethanolate freshly prepared from 2.17 g (0.095 mol) of sodium and 200 ml of ethanol at 20 °C, add 25.0 g (0.095 mol) of 4,4-difluorobenzyl acid and stir for 3 hours. After that, the solution is evaporated to dryness, the residue is dissolved in DMF, at 2022 it is mixed dropwise with 22.57 g (0.16 mol) of methyl iodide and stirred for 24 hours. Processing and purification are carried out similarly to the compound Zb.

Yield: 21.06g (8095 from theory). 7.2: Tropenol ether of 4,4"-difluorobenzyl acid 5a 11.13 g (0.04 mol) methyl ether of 4,4'--difluorobenzyl acid За and 5.57 g (0.04 mol) of tropenol 70 are reacted with 0.09 g sodium similarly to example C, stage 3.2 The product is recrystallized from acetonitrile.

Yield: 10.43g (6295 from theory).

Idl: 233-23590. 7.3: Tropenol ester of 2-fluoro-2,2-bis(4-fluorophenyl)acetic acid 4 and 2.94 g (0.013 mol) of bis(2-methoxyethyl)aminosulfur trifluoride similarly to example 4, stage 4.3, are subjected to interaction with 3.85 g (0 .01 mol) of compound 5a in 100 ml of dichloromethane. The product is recrystallized as its hydrochloride from acetonitrile.

Output: 2.93g (69905 from theory). 7.4: Methobromide of tropenol ether of 2-fluoro-2,2-bis(4-fluorophenyl)acetic acid 2.bg (0.0067 mol) of compound 41 and 1.9g (0.0079 mol) of 50956 solution of methyl bromide are subjected to chemical transformation similarly to example 1, stage 1.3. The formed crystals are separated by vacuum filtration, washed with dichloromethane, dried and finally recrystallized from methanol/diethyl ether.

Yield: 2.82g of white crystals (87905 from theory).

TLC: KEeE value: 0.55 (solvent system: according to example 1, stage 1.2). Ge

Idl: 230-231 20. Fr

С23Но2зЕзМО»хХВг (482.34).

Elemental analysis: calculated: C (57.27) H (4.81) M(2.90) found: C (57.15) H (4.84) M(2.96)

Example 8: Methobromide of 2-fluoro-2.2-bis(4-fluorophenyl)acetic acid scopine ester "I

Me, kim Ve o ne (ee) o no dah y

Е с С Е - 8.1: Scopinic ether of 4,4"-difluorobenzyl acid and 4.22 g (0.01 mol) of tropenol ether of 4,4-difluorobenzyl acid 5a are suspended in VOml of DMF. Then, at an internal temperature of the order of 402C, solution 2 is added, 57 g (0.0273 mol) of NoO»o-urea in 20 ml of water, as well as

0.2 g (0.0011 mol) of vanadium oxide (M) and stirred for 4.5 hours at 60 2С. After cooling to 20 C - 70 C, the formed precipitate is separated by vacuum filtration, the pH value of the filtrate is set to 3 with the help of 4. s of hydrochloric acid and mixed with Ma»ZoOv dissolved in water. The resulting green 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 with the help of Ma»CO»z, after which it is extracted with dichloromethane, the organic phase is dried over Ma 550, and concentrated. After that, at a temperature of about 15923, 0.5 ml of acetyl chloride is added and stirred for - 15 1.5 hours. After extraction of O0, Tn. with hydrochloric acid, the pH value of the aqueous phase is set to alkaline, extracted with dichloromethane, the organic phase is dried over Ma»5O, and evaporated to dryness. The hydrochloride is precipitated from the residue and (95) is then recrystallized from methanol/diethyl ether. so Yield: 3.61 g of white crystals (78905 from theory).

Idl: 243-24426. ("c") 20 8.2: Scopine ester of 2-fluoro-2.2-bis(4-fluorophenyl)acetic acid 449

T» 1.48 g (0.0067 mol) of bis(2-methoxyethyl)aminosulfur trifluoride is reacted similarly to example 4, stage 4.3, with 2.0 g (0.005 mol) of compound B in 10 ml of dichloromethane. The product is recrystallized as its hydrochloride from ethanol.

Yield: 2.07g (94965 from theory).

Idl: 238-23920. (Ф) 8.3: Methobromide of 2-fluoro-2.2-bis(4-fluorophenyl)acetic acid scopine ether with 1.6 g (0.004 mol) of compound 44 and 1.14 g (0.0079 mol) of 5096 methyl bromide solution are subjected to chemical transformation similarly to example 1, stage 1.3. The formed crystals are separated by vacuum filtration, washed with dichloromethane, dried and finally recrystallized from acetonitrile.

Yield: 1.65 g of white crystals (6195 from theory).

TLC: KEeE value: 0.25 (solvent system: according to example 1, stage 1.2).

Idl: 213-21426.

Со3НозЕзМОзхХВг (498.34). 65 Elemental analysis: calculated: C (55.43) H (4.65) M(2.81) found: C (54.46) H (4.67) M(2.80)

Example 9: Methobromide of 2-fluoro-2,2-diphenylacetic acid tropenol ester

Me, "Me B" 2 emo 9.1: Tropenol ether of benzylic acid 5

Tropenol ether of benzylic acid, as well as the method of its preparation, are known from UUO 92/16528. 9.2: Tropenol ether of 2-fluoro-2,2-diphenylacetic acid Ap 15.866 ml (0.086 mol) of bis(2-methoxyethyl)aminosulfur trifluoride are reacted similarly to example 4, stage 4.3, with 25 g (0.072 mol) of compound 5 in 48 x 0 ml chloroform. The product is recrystallized as its hydrochloride from acetone.

Yield: 18.6g of white crystals (6790 from theory). 19 poison: 181-1825C. 9.3: Methobromide of tropenol ether of 2-fluoro-2,2-diphenylacetic acid 11.12 g (0.032 mol) of compound 4P and 18.23 g (0.096 mol) of a 50956 solution of methyl bromide are subjected to a chemical transformation similar to example 1, stage 1.3. The formed crystals are recrystallized from acetonitrile. 20 Yield: 11.91g of white crystals (8395 from theory).

TLC: KE value: 0.4 (solvent system: according to example 4, stage 4.4). pl: 238-239960.

C2z3NoBEMO»xVg (446.36).

Elemental analysis: calculated: С (61.89) Н (5.65) М(3.14) сх 25 found: С (62.04) Н (5.62) М(З3.17)

Example 10: Methobromide of tropenol ester of 2-fluoro-2,2-(3-chlorophenyl)acetic acid o

10.1: Methyl ether of 3.3-dichlorobenzyl acid Ze so 10.1.1:3,3'-dichlorobenzyl so

100 ml of ethanol is loaded into the reaction vessel at room temperature and 50.0 g (0.356 mol) of 35 chlorobenzaldehyde and 4.54 g (0.018 mol) of 3-ethyl-5-(2-hydroxyethyl)-4-methylthiazolium bromide are added. After that, 10.7 g (0.11 mol) of triethylamine is added dropwise. Then it is boiled under reflux and evaporated to dryness. The residue is dissolved in ethyl acetate and extracted with water, sodium pyrosulfite in water, and a solution of Ma»CO»z. After drying over Mo5O; evaporate to dryness. The obtained product is recrystallized from isopropanol and petroleum ether. From t0 Yield: 13.2 g of white crystals (1395 from theory). s dl: 69-705С. 13.0 g of acyloin obtained in this way is dissolved in 460 ml of acetonitrile at room temperature, 0.0867 g of vanadium oxytrichloride is added and oxygen is introduced. After 1.5 hours, the solution is evaporated to dryness, extracted with ethyl acetate and water, as well as with a solution of Ma»CO3, dried over Mo5O, and evaporated to dryness. The resulting -1 395 residue is isolated by mixing with petroleum ether/ethyl acetate (95:5 ratio).

Yield: 12.59g of yellow crystals (97905 from theory). (95) Idl: 116-117290, so 10.1.2:3,3'-dichlorobenzylic acid

51.45 g (1.286 50 y y y (a) moles) of sodium hydroxide in 100000 ml of water are loaded into the reaction vessel with intensive stirring in a boiling water bath, after which a solution of 28.5 g (0.102 mol) is added dropwise.

1" of 3,3-dichlorobenzyl in 700 ml of dioxane and then stirred for 1 hour. After cooling, dioxane is evaporated, the residue is diluted with water and extracted with diethyl ether. The pH value of the organic phase is set to acidic, after which it is extracted with dichloromethane, dried over Mo5O), and evaporated to dryness.

Output: 32.7g (7195 from theory). 10.1.3: Methyl ether of 3,3'-dichlorobenzyl acid

GF) A solution of sodium ethanolate is prepared from 100 ml of ethanol and 1.97 g (0.0855 mol) of sodium, to which 26.6 mg (0.0855 mol) of 3,3'-dichlorobenzyl acid in 500 ml of ethanol is then added dropwise. After that, stir for 4 hours at room temperature. After distilling off the solvent, the residue is dissolved in 150 ml of DMF, 24.27 g (0.171 mol) of methyl iodide is added dropwise and then stirred for the next 24 hours. Then, under cooling with ice, 30 ml of water and 200 ml of diethyl ether are added dropwise, the phases are separated, the aqueous phase is extracted with diethyl ether, after which the organic phases are washed with BiagbOz solution and shaken with water until the reaction is neutral. After drying over Ma»5O, evaporate to dryness. Yield: 22.91 g of yellow oil (8290 from theory).

Yu.2.: Tropenol ether of 3,3-dichlorobenzyl acid, 22.9 g (0.074 mol) of 3,3-dichlorobenzyl acid methyl ether, 15.37 g (0.11 mol) of tropenol and 0.17 g of sodium are heated in in the form of a melt for 4 hours at a pressure of 75 mbar in a boiling water bath with moderate shaking. After cooling, the sodium residues are 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 MAO5O, and evaporated to dryness. The product is recrystallized as its hydrochloride from acetonitrile.

Yield: 16.83g of white crystals (5095 from theory).

Ill: 184-185260. 10.3: Tropenol ether of 2-fluoro-2,2-bis(3-chlorophenyl)acetic acid 4Y 1.48 g (0.0067 mol) of bis(2-methoxyethyl)aminosulfur trifluoride is added to 100 ml of dichloromethane and mixed dropwise for 20 min at 15-202С7 with a solution of 2.09 g of compound 5d in bbml of dichloromethane. Then, for 20 hours, 70 is stirred at room temperature, cooled to 09C and, with intensive stirring, carefully mixed with 8Oml of water. After that, the pH value is set to 8, carefully adding an aqueous solution

Manso»z, the organic phase is separated, the aqueous phase is re-extracted with dichloromethane, the combined organic phases are washed with water, dried over Mo53O, and evaporated to dryness. Finally, the hydrochloride is precipitated and then recrystallized from acetonitrile/diethyl ether.

Yield: 1.20g of white crystals (5395 from theory).

Ill: 136-13726. 10.4: Methobromide of tropenol ether of 2-fluoro-2,2-bis(3-chlorophenyl)acetic acid 1.0 g (0.002 mol) of compound 4p is subjected to a chemical transformation similar to example 1, stage 1.3.

The formed crystals are separated by vacuum filtration, washed with dichloromethane, dried and finally recrystallized from methanol/diethyl ether.

Yield: 0.82 g of white crystals (8095 from theory).

TLC: KeE value: 0.14 (solvent system: n-butanol/water/formic acid (conc.)/acetone/dichloromethane in the ratio 36:15:15:15:5).

Ill: 180-18126. Gee!

SozNozSi2EMO»xHVg (515.25). at

Compounds of the general formula 1 have, as it was established, wide possibilities for use with a therapeutic purpose, accordingly, they have a high therapeutic potential. In particular, it should be noted the superior possibility of using the compounds of formula 1 proposed in the invention, due to their pharmaceutical action as anticholinergic agents. As an example of the use of the compounds according to the invention for these purposes, it is possible to name "therapy of asthma or COPD (chronic obstructive pulmonary disease). The compounds of general formula 1 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 d) spasms, for example, in the gastrointestinal tract with the achievement of an appropriate therapeutic effect. with

The compounds proposed in the invention can also be used for the treatment of spasms in the urinary tract, as well as, for example, painful sensations during menstruation. Among the indications and examples presented above, special importance is attached to the use of the compounds of formula 1 proposed in the invention in the treatment of asthma and COPD.

The compounds of the general formula 1 can be used individually or in combination with other active substances of the formula 1 proposed in the invention. Under certain conditions, the compounds of the general formula 1 can also be used in combination with other pharmacologically active active substances. At the same time, we are primarily talking about betamimetics, antiallergic agents, platelet-activating factor h antagonists (PARH), leukotriene antagonists and corticosteroids, as well as various combinations of such active substances. -» As an example of betamimetics, 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 bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol , - salmeterol, sulfonterol, terbutaline, tolubuterol, o 4-hydroxy-7-(2-42-113-(2-phenylethoxy)propyl|Isulfonyl)ethyl|aminoethyl1I-2(ZH)-benzothiazolone, 1-(2-fluoro -4-hydroxyphenyl)-2-I4-(1-benzimidazolyl)-2-methyl-2-butylamino|ethanol, so 1-(3--4-methoxybenzylamino)-4-hydroxyphenyl|-2-I(4-( 1-benzimidazolyl)-2-methyl-2-butylamino|ethanol, about 50 1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-ylI-2-I3-(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-benzoxase in-8-yl|-2-14-I3-(4-methoxyphenyl)-1,2,4-triazol-3-yl|-2-methyl-2-butyl mino)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

Gee! 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert-butylamino)ethanol, under certain conditions in the form of their racemates, their enantiomers, their diastereomers, as well as under certain conditions their pharmacologically acceptable de acid- additive salts and hydrates. As betamimetics, it is more preferable to use active substances selected from the group that includes fenoterol, 60 formoterol, salmeterol, 1-(3--4-methoxybenzylamino)-4-hydroxyphenyl|-2-I( 4-(1-benzimidazolyl)-2-methyl-2-butylamino|ethanol, 1-(2nH-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl1-2-(3-(4 -H.H-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, 65 /1-(2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl|-2-14-(3 -(4-methoxyphenyl)-1,2,4-triazol-3-yl|-2-methyl-2-butylamino)ethanol, 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. 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, preferred acid addition salts of betamimetics are salts selected from the group consisting of hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, and xinafoate. In the case of salmeterol, its preferred salts are hydrochloride, sulfate, and xinafoate, of which sulfates and xinafoates are the most preferred. According to the invention, salmeterolx1/2H5504 and salmeterol xinafoate are particularly preferred. In the case of formoterol, its preferred salts are the hydrochloride, sulfate, and fumarate, of which the hydrochloride and fumarate are the most preferred. According to the invention, formoterol fumarate is particularly preferred.

In the context of the present invention, corticosteroids, which under certain conditions can be used in combination with compounds of formula 1, mean compounds selected from the group that includes flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, ZUU 215864, CC 592, 5T-126 and /5 dexamethasone. Preferred corticosteroids according to the present invention are selected from the group that includes flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide and dexamethasone, among which budesonide, fluticasone, mometasone and ciclesonide are most preferred, 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 are also meant to include salts or derivatives that can be formed from 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.

In the context of the present invention, dopamine agonists, which under certain conditions can be used in combination with compounds of formula 1, are meant compounds selected from the group that includes bromocriptine, cabergoline, sch ov alpha-dihydroergocriptine, lisuride, pergolide, pramipexole, roxindole, ropinirole, talipexole, terguride and viosan. Preferred according to the present invention dopamine agonists suitable for use in combination (8) with compounds of formula 1 are pramipexole, talipexole and viosan, of which pramipexole is most preferred. The above-mentioned dopamine agonists in the context of this invention also mean their possible pharmacologically acceptable acid-additive salts and, under certain conditions, their hydrates. Physiologically compatible acid-addition salts, which can be formed from the above-described dopamine agonists, mean, for example, pharmaceutically acceptable salts selected from the salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid acid, fumaric acid, succinic Fu acid, lactic acid, citric acid, tartaric acid and maleic acid.

As an example of antiallergic agents, which according to the invention can be used in combination with me)

Among the compounds of formula 1, epinastine, cetirizine, azelastine, fexofenadine, levocabastine, iloratadine, mizolastine, ketotifen, emedastine, dimetindene, clemastine, bamipine, cexchlorpheniramine, pheniramine, doxylamine, chlorphenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine can be named. and meclozine.

Preferred antiallergic agents, which according to the present invention can be used in combination with the compounds of formula 1 proposed therein, are selected from the group that includes epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, ebastine, desloratidine and mizolastine, of which especially preferred with c epinastine and desloratidine. The above-mentioned antiallergic agents in the context of this invention also mean their possible pharmacologically acceptable acid additive salts. c As an example of PAP antagonists, which according to the invention can be used in combination with compounds of formula 1, we can name 4-(2-chlorophenyl)-9-methyl-2-I3-(4-morpholinyl)-3-propanone-1- yl|-6H-thieno|3,2-1(11,2,4)griazolo|4,3-a||/1,4)diazepi -i H, 6-(2-chlorophenyl)-8,9- dihydro-1-methyl-8-(4-morpholinyl)carbonyl|-4H,7H-cyclopenta-|4,5Hyeno|3,2-P(1,2,griazo o lo|4,3-a)11,41 diazepine

Go! If compounds of the formula | it is intended to be used in combination with other active substances, then the most preferred compounds for use in such combinations among their classes indicated above are steroids or betamimetics. At the same time, special importance is attached to the use of the compounds proposed in the invention in combination with betamimetics, primarily with betamimetics of prolonged action. Combinations of the compounds of formula 1 proposed in the invention with salmeterol or formoterol should be particularly preferred, and the combination with formoterol is the most preferred. 5B As an example of compounds of formulas and dosage forms suitable for administration, tablets, capsules, suppositories, solutions, etc. can be named. Of particular importance is the introduction of the compounds proposed in the invention by inhalation

F) (primarily in the treatment of asthma or COPD). The share of pharmaceutically active compound(s) in such dosage forms should in each case be from 0.05 to UOmas. 95, preferably from 0.1 to 5Omas. 95, 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 acetate phthalate or polyvinyl acetate. Tablets can also consist of several layers. 65 Accordingly, dragees can be made by coating cores obtained similarly to tablets from materials commonly used for these purposes, such as collidon or shellac, gum arabic, talc, titanium dioxide, or sugar. To ensure the effect or to avoid incompatibility, the dragee core can also be made multilayered. In the same way, the shell of the dragee can also consist of several layers to provide a depot effect, while the excipients specified above for tablets can be used.

Mixtures based on the active substances proposed in the invention, respectively combinations of active substances, can additionally include a sweetener, such as saccharin, cyclamate, glycerin or sugar, as well as a taste enhancer, for example, a flavoring such as vanillin or orange extract. In addition, the mixtures may contain suspending aids or thickeners such as 7/0 sodium carboxymethyl cellulose, wetting agents such as condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.

The solutions are prepared according to known technology, for example with the addition of isotonic agents, preservatives such as i-hydroxybenzoates, or stabilizers such as alkali metal salts of ethylenediaminetetraacetic acid, and if necessary with the use of emulsifiers and/or dispersants, with this, for example , when using water as a diluent, if necessary, organic solvents can be used as hydrotropic solubilizers, respectively, an auxiliary solvent, and are poured into injection bottles, ampoules or infusion bottles.

Capsules that contain 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 including the resulting mixture in gelatin capsules.

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

As an example of excipients used in the preparation of dosage forms, we can mention water, pharmaceutically acceptable, (harmless) organic solvents, such as paraffins (for example, fractions of mineral oil), vegetable oils (for example, peanut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerin), carriers such as natural rock flour (e.g. kaolin, and) alumina, talc, chalk), synthetic rock flour (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane, milk and grape sugar), emulsifiers (such as lignin, sulfite shell, methylcellulose, starch, and polyvinylpyrrolidone) and lubricants (such as magnesium stearate, talc, stearic acid, and sodium lauryl sulfate).

Administration is carried out according to the usual method, while in the treatment of asthma or COPD, inhalation administration is preferred. co

In the case of oral administration, the corresponding tablets may, of course, in addition to the above-mentioned carriers also contain additives such as, for example, sodium citrate, calcium carbonate and dicalcium phosphate, together with various me)

Zzb5 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 auxiliary substances described above, can also be mixed with various flavor enhancers or dyes.

The prescribed dose of the compounds proposed in the invention depends significantly, as is obvious, on the route of administration and the disease to be treated. During inhalation, the pronounced effect of the use of compounds of formula 1 with c is revealed already when they are administered in doses in the microgram range. However, the compounds of formula 1 should also be used in doses that exceed 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 Ωg, but not limited to the indicated limits). -I Below, the invention is illustrated by examples, which present the compositions of some dosage forms and which do not limit its scope. o Examples of pharmaceutical compositions o A) Tablets o sh with o 111 voomo ime)

The finely divided active substance is mixed with lactose and a part of the entire prescribed amount of 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 resulting granulate together with another amount of corn starch and magnesium stearate is sieved and mixed together. From the resulting mixture, tablets of the desired shape and size are pressed.

B) Tablets for the Component Content based on one tablet tallow y y y y what n. y

The finely divided active substance 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 another amount of corn starch and water, processed into a granulate, which is 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.

C) Solution in ampoules and water for one injection! Bml

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 resulting 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 of monofluorotrichloromethane and difluorodichloromethane in a ratio of 2:3) to 1O0Omas.9o av)

The suspension is poured into a regular aerosol can equipped 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 wt. 9b). and -

D) Solutions (mmetosml! formoterol fumarate / 333, Zmg " o Edtk -; c Ne (In) to pH ZA ;" " The solution of such a compound can be prepared according to the usual technology.

E) Powder for inhalation - formoterol fumarate (ee)

Powder for inhalation of the specified composition is obtained by conventional technology by mixing individual components. "with"

G) Powder for inhalation of SH rya

GF) The powder for inhalation of the specified composition is obtained according to the usual technology by mixing individual components. name)

Claims (11)

60 Formula of the invention 1. Compounds of the general formula 1 b5 1 1 in: - SAME - H A o o 5 4 E E 7 in E E 3 in which A is a residue with two bonds selected from the group consisting of Ni xx H on X means a singly charged anion, B! its 82 have identical or different values and represent a residue selected from the group that includes methyl, ethyl, n-propyl and isopropyl, while such residue may optionally be substituted by a hydroxy group or a fluorine group, o 23, 27, Vo and B have the same or different meanings and represent hydrogen, methyl, ethyl, methyloxy, ethyloxy, hydroxy, fluorine, chlorine, bromine, CM, CEz or MO", and B means methyl, ethyl, methyloxy, ethyloxy, -CHO-E . СНо-ОМе, -СНО-ОБ, -"СНо-СНо-ОБЕ, -О-СОМе, -О-СОКИ, -О-СОСГ", "And fluorine, chlorine or bromine, (ав) not necessarily in the form of separate optical isomers, mixtures of individual enantiomers or racemates. 2. Compounds of the general formula 1 according to claim 1, in which d) X is preferably selected from the group that includes chloride, bromide, methyl sulfate, 4-toluenesulfonate and methanesulfonate. Zo 3. Compounds of the general formula 1 according to claim 1 or claim 2, in which y-A means a residue with two bonds selected from the group that includes sts and M "z НН Н en - X" means a single-charged anion selected from the group , which includes chloride, bromide and methanesulfonate. C, 7, o and 9 have the same or different meanings and represent hydrogen, methyl, ethyl, methyloxy, - and ethyloxy, hydroxy, fluorine, chlorine or bromine, and "B" means methyl, ethyl, methyloxy, ethyloxy, CEz or fluorine, optionally in the form of individual optical isomers, mixtures of individual enantiomers or racemates. 4. Compounds of the general formula 1 according to any of claims 1 - 3, in which o 20 A means a residue with two bonds, selected from the group that includes Y" x Y Ni H on X 7" means bromide, F) In it, 22 have identical or different values and represent a residue selected from the group consisting of methyl and ka ethyl, 23, 7, 5 and 29 have identical or different values and represent hydrogen, methyl, methyloxy, chlorine or fluorine, and B" means methyl or fluorine, optionally in the form of individual optical isomers, mixtures of individual enantiomers, or racemates. 5. Compounds of general formula 1 according to any one of claims 1-4, in which A is a residue with two bonds selected from the group consisting of b5 I o H and X means bromide, B her 82 have identical or different values and represent methyl or ethyl, BZ, VU, BZ and EX have identical or different values and represent hydrogen or fluorine, and 70 B" means methyl or fluorine , not necessarily in the form of individual optical isomers, mixtures of individual enantiomers or racemates. 6. Use of the compound of general formula 1 according to any of claims 1-5 as a medicinal product. 7. Use of a compound of the general formula 1 according to any of claims 1-5 for the preparation of a medicinal product intended for the treatment of asthma, chronic obstructive pulmonary disease (COPD), vagal /5 sinus bradycardia, heart rhythm disorders, spasms in the gastrointestinal tract , spasms in the urinary tract and painful sensations during menstruation. 8. Use of the compound of general formula 1 according to claim 7 for the preparation of a medicinal product intended for the treatment of asthma or COPD. 9. A pharmaceutical composition that contains as an active substance one or more compounds of the general formula 1 or according to any of claims 1-5 or their physiologically acceptable salts, optionally in combination with usual excipients and/or carriers. 10. The pharmaceutical composition according to claim 8, which is characterized in that it, together with one or more compounds of formula 1, also contains at least one other active substance selected from the group that includes betamimetics, antiallergic agents, antagonists of platelet activation factor, leukotriene antagonists and steroids , . 11. The method of obtaining the compound of the general formula 1 (o) 1 1 in: - ЖЕ - « Н | "c) (ee) A o o (ze) 5 4 i - Е Е 7 в Е З Е е " in which A, Kh residues B", K2, KZ, 7, B", 29th K" can have the specified in claims 1-5, a value that differs - in that at the first stage the compound of the general formula З Е "З и? db 5 4 КК Е -и 7 в Е (95) Е З bo in which the residues КЗ, В", VK, b Her / can have the values indicated in claims 1-5, and B means chlorine or av | 20 C.-C alkyloxy group, are subjected to interaction with the compound of the formula 2 1 2 из» Kk YIM g H 9) A On in which A and 2! can have the values indicated in claims 1-5, with the preparation of the compound of formula 4 60 b5 1 4 Х IR H A o o 5 4 E E 7 c and c E in which A and the residues KK", KZ, 7, B", K5 and B" can have the values specified in claims 1-5, and then this compound by interaction with the compound of the formula in which B2 and X can have the values specified in claims 1-5, are subjected to quaternization to the compound of formula 1. Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2005, M 9, 15.09.2005. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. with o " o s so i - shi s ;" -And (95) (ee) at 50 s» F) name) 60 b5