UA80124C2 - Medicaments containing betamimetic drugs and a novel anticholinesterase drug - Google Patents

Abstract

The invention relates to novel medicament compositions based on long-acting beta2 agonists and salts of a novel anticholinesterase drug (I), to methods for the production of these compositions and their use in treating respiratory tract diseases. 1 (I)

Description

Description of the invention

The present invention relates to new medicinal compositions based on long-acting beta-agonists and 2 salts of a new anticholinergic agent, to the method of their preparation, as well as their use in the treatment of respiratory tract diseases.

The present invention offers new medicinal compositions based on long-acting beta-agonists and salts of the new anticholinergic agent 1, a method of their preparation, as well as their use in the treatment of respiratory tract diseases. 70 Salts of formula 1 1 are used as an anticholinergic agent according to this invention

Me, I Me - I x

N o. (8) 1, in which 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, EM benzoate and p-toluenesulfonate. "-

It is preferable to use salts of the formula 1, in which X" is a singly charged anion selected from the group that includes chloride, bromide, 4-toluenesulfonate and methanesulfonate, preferably bromide.

It is more preferable to use salts of the formula 1, in which X" is a single-charged anion selected from the (se) group, which includes chloride, bromide and methanesulfonate, preferably bromide.

Particularly preferred according to the invention is the salt of formula 1, in which X" represents bromide.

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 |in UUO 92/16528| other anticholinergic agents were proposed, the basic molecules of which are formed by the scopine, tropenol, or tropine skeleton. m It is the basis of the declared |in UUHO 92/16528| The object of the invention was to provide compounds that have anticholinergic activity with an effect that persists for a long time. To solve this problem, among others, benzylates of scopine, tropenol, or tropine were proposed.

For drug therapy of chronic diseases, it is often desirable to have at one's disposal medicinal (ee) products 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 for achieving a therapeutic effect, without the need for excessively frequent repeated administration of the medicinal product. Otherwise, the introduction of the active substance into the body with less frequency greatly contributes to the patient's well-being. 7 50 At the same time, it is most desirable to have at one's disposal a medicine that would allow to achieve the necessary therapeutic effect when it is administered once a day to the body (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 for the possibility of its use as a medicine, or calculated for a single use per day. On the one hand, the necessary effect should occur relatively quickly after the introduction of the medicinal product into the body, the effectiveness of which should, in an ideal case, be maintained at a constant level as much as possible during the subsequent rather long period of time. On the other hand, the duration of action of the medicinal product should not significantly exceed 60 one day. In an ideal case, the active substance should have such a profile of action that allows you to purposefully manage the process of obtaining a medicinal product designed for single administration per day, which contains the active substance in therapeutically optimal doses.

It was established that (described in MO 92/165281 benzylates of scopine, tropenol, or tropine do not meet such increased requirements. These compounds, because their action persists for an exceptionally long period of time, which significantly exceeds the above-mentioned period of time, which is approximately one per day, not suitable for their therapeutic use as once-a-day medicaments.In contrast, the salts of formula 1 meet similar requirements.

According to the invention, it was established that when using an anticholinergic agent of formula 1 in combination with one or more betamimetics 2, a positive therapeutic effect and primarily a synergistic effect in the treatment of inflammatory or obstructive diseases of the respiratory tract is unexpectedly manifested. The presence of a similar synergistic effect allows the medicinal compositions proposed in the invention to be used in a lower dosage than would be necessary in the opposite case with traditional monotherapy, which in order to achieve a similar effect involves the use of each of the compounds separately. In addition, the use of medicinal compositions proposed in the invention allows, in what is another positive aspect of it, /0 to reduce unwanted side effects, which under certain conditions can accompany, for example, the use of betamimetics. As an example of such side effects in this regard, the stimulating effect on the heart, which is caused in some cases by betamimetics, primarily tachycardia, rapid heartbeat, complications resembling angina pectoris, as well as arrhythmia, should be noted.

The above-mentioned positive effects can be manifested when both active 7/5 substances are simultaneously administered into the body as part of one drug, and when they are sequentially administered into the body as part of separate drugs.

According to the invention, the simultaneous introduction into the body of both active substances in the composition of one preparation, of which they are components, is preferable.

By its compound, which is mentioned in some cases in the description of this invention, it is meant a pharmacologically active cation, which is contained in salts 1 of the following formula i.

Me, I Me and i o - (o) « and S

R s! -

F F o 1 1". co

In the combinations of medicinal substances indicated above, the active substances can either be jointly included in one single dosage form, or can be separately included in two separate dosage forms. Preferred "

According to the invention, medicinal products in which active substances 1 and 2 are present in one single dosage form. z c As betamimetics 2, which have a long-lasting effect, according to the invention, it is preferable to use salts of salmeterol or formoterol. Betamimetics of formula 2, which are mentioned in this description, are meant as well as their enantiomers or their mixtures. Accordingly, compounds 2, which are mentioned in this description as preferred, for use in the intended purposes of the invention, which are salts of salmeterol and formoterol, mean specific enantiomeric salts of K-salmeterol, Z-salmeterol, K,K-formoterol,

Go! K,K-formoterol, K,5Z-formoterol, 5,K-formoterol, as well as their mixtures, while special importance is attached to the enantiomeric salts of K-salmeterol and K,K-formoterol. According to the invention, compounds 2 can be represented further in the form of their hydrates or solvates. - As betamimetics 2, which have a long-lasting effect, salts of compounds of the formula 2a and H 2a can also be used

T» H 4 z yu 60 I and o for! b5

In which

IN! and B? have identical or different meanings and mean hydrogen or C.-C. alkyl,

BZ and c" have identical or different meanings and mean hydrogen C /-C.alkyl, -O-C.-Slalkyl or -C.-C alkylene-O-C.4-Slalkyl or

ВЗ and В" jointly mean one of such groups that form a bridge, such as -C4-C.alkylene- or -O-C.4-Cu-alkylene-O-.

In the combinations proposed in the invention, it is preferable to use salts of compounds of formula 2a, in which

IN! and 22 have the same or different meanings and represent hydrogen, methyl or ethyl,

BZ and B" have identical or different meanings and mean hydrogen, methyl, ethyl, propyl, butyl, methoxygrune, ethoxygrune, methoxymethyl or methoxyethyl, or BZ and B together mean one of such groups that form a bridge, such as propyl, butylene, - O-ethylene-O- or -O-propylene-O-,

It is more preferable to use in the combinations proposed in the invention salts of compounds of formula 2a, in which

IN! and B? have identical or different meanings and mean hydrogen or ethyl, preferably hydrogen,

BZ and c"! have identical or different meanings and represent hydrogen, methyl, ethyl, propyl, butyl or methoxymethyl or

BZ and B together mean one of such groups that form a bridge, such as butylene or -O-ethylene-O-.

It is most preferable to use in the combinations proposed in the invention salts of the following compounds of formula 2a, in which a) B! and B? mean hydrogen, and ЕЗ and БЕ" mean ethyl, or b) B" and B? mean hydrogen, and BZ and B" mean methyl, or c) B! and B? mean ethyl, and KZ and B" mean hydrogen, or d) B and B? mean hydrogen, and KZ and ВЕ" mean together butylene, or 12р2 35 ра: с d) К' and К- mean hydrogen, and К" and К" mean jointly -О-ethylene-О-, or f) В! и B? means hydrogen, and KZ and B" mean tert-butyl, or (8) is) B! and 22 mean hydrogen, and KZ and B" mean isopropyl, or) B" and B? mean hydrogen, and 2? and B" mean methoxymethyl.

Compounds of formula 2a are known from UMO 00/75114. AND

Among the compounds considered above, special importance according to the invention is given to the use in the medicinal compositions proposed in the invention of the structure specified in paragraph a), where ВЕ! and B? mean hydrogen, and B? and KVK? mean ethyl. The acid-addition salts of this compound in the following description are also designated as compounds -- 2aa, while the same compound, when it is presented as a free base, is designated below as compound o 2aa, which corresponds to the following formula d) d" 2aa nn " fi F - s z» dov) | (in 15 ethyl (ee)

F o head

Pniv - ko 20 Salts of compounds of formula 2a can be used in the medicinal compositions proposed in the invention in

GT" in the form of their racemates, enantiomers or their mixtures. It is possible to separate racemates into separate enantiomers by methods known from the state of the art (for example, chromatography on chiral phases and other methods). When using salts of compounds of formula 2a in the form of their enantiomers, it is most preferable to use enantiomers with the K-configuration with the C-OH group.

In the context of this description, alkyl groups mean, unless otherwise specified, branched and

HF) unbranched alkyl groups with 1-4 carbon atoms. An example of such groups is methyl, ethyl, propyl 7 or butyl. To designate similar groups, that is, methyl, ethyl, propyl, or butyl, in some cases, their corresponding abbreviated names Me, Eyi, Pgor, or Vy are also used. Unless otherwise specified, the terms "propyl" and "butyl" also include all possible isomeric forms of each such residue. So, for example, n-propyl and isopropyl are included in the 60 concept of "propyl", and isobutyl, sec-butyl and tert-butyl are included in the concept of "butyl", etc.

Alkylene groups mean, unless otherwise specified, branched and unbranched alkyl bridges with two bonds and 1-4 carbon atoms. Methylene, ethylene, propyl or butylene can be mentioned as an example. because Alkyloxy groups (which are also denoted as -0-C -C.alkyl groups) mean, unless otherwise specified, branched and unbranched alkyl groups with 1-4 carbon atoms attached through an oxygen atom. As an example, methyloxy-, ethyloxy-, propyloxy- or butyloxygrune can be mentioned. In some cases, to designate such groups, i.e., methyloxy-, ethyloxy-, propyloxy-, or butyloxygroups, their corresponding abbreviated names MeO-, EYU-, PgorO-, or ViO- are also used. Unless otherwise specified, the terms "propyloxy group" and "butyloxy group" also include all possible isomeric forms of each such residue. So, for example, the concept of "propyloxy group" includes n-propyloxy group and isopropyloxy group, the concept of "butyloxy group" includes isobutyloxy group, sec-butyloxy group and tert-butyloxy group, etc. In some cases, in this description, instead of the designation "alkyloxy group", the equivalent 7/0 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 butoxy group are used.

Alkylenalkyloxy groups are, unless otherwise specified, branched and unbranched alkyl bridges with two bonds and 1-4 carbon atoms, mono-, di- or trisubstituted, preferably monosubstituted, /5 alkyloxy group.

In the context of this invention, compounds 2 mean physiologically compatible acid-addition salts.

Physiologically compatible acid-addition salts of betamimetics 2 according to the invention 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, mMlactic acid, citric acid acid, tartaric acid, 1-hydroxy-2-naphthapinecarboxylic acid, 4-phenylcinnamic acid, 5-(2,4-difluorophenyl)salicylic acid or maleic acid. In some cases, mixtures of the above acids can also be used to obtain salts 2. Preferred salts of betamimetics 2 according to the invention are selected from the group that includes hydrochloride, hydrobromide, sulfate, phosphate, fumarate, methanesulfonate, 4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate, maleate and xinafoate. The most preferred salts of compound 2 in the case of salmeterol are selected from the group that includes hydrochloride, sulfate, 4-phenylcinnamate, 5-(2,4-difluorophenyl)salicylate and xinafoate, among which special importance is attached to i) 4-phenylcinnamate, 5- (2,4-difluorophenyl) salicylate and primarily xinafoate. The most preferred salts of compound 2 in the case of formoterol are selected from the group consisting of hydrochloride, sulfate and fumarate, among which the hydrochloride and fumarate are particularly preferred. The most important value according to the invention is formoterol fumarate. The most preferred salts of compound 2 in the case of compound 2aa are selected from the group consisting of hydrochloride and maleate, among which maleate is particularly preferred. with

When in the context of this invention we are talking about betamimetics, which are not presented in the form of a salt, then in this case such compounds can be distinguished from others by the designation 2 used for them. For example, under the preferred in the context of this invention betamimetics 2, which represented not in the form of a salt, is meant formoterol or salmeterol in the form of a free base or a compound of formula 2a, while by the most preferred in the context of the present invention compounds 2 is meant, for example, salmeterol xinafoate, formoterol fumarate or an acid addition salt 2a compounds of formula 2a..

Betamimetics 2 in the context of this invention are sometimes also called sympathomimetics or beta-agonists (r.-agonists). All such names are considered equivalent in the context of this invention. "

Another object of this invention is the above-mentioned medicinal products, the composition of which, along with active substances 1 and 2, taken in therapeutically effective amounts, also includes a pharmaceutically acceptable carrier. The next object of this invention is the above-mentioned medicinal products, which, apart from active substances 1 and 2, taken in therapeutically effective amounts, do not contain any pharmaceutically acceptable carrier.

The present invention also relates to the use of salts 1, taken in a therapeutically effective amount, for the preparation of a medicinal product, which also contains betamimetics 2, which have a long-lasting effect, intended for the treatment of inflammatory or obstructive diseases of the respiratory tract. The present invention mainly relates to the above-mentioned use of both active substances for the preparation of a medicinal product intended for the treatment of asthma or COPD. - According to this invention, compounds 1 and 2 can be introduced into the body simultaneously or sequentially, while

According to the invention, it is preferable to simultaneously introduce compounds 1 and 2 into the body.

And" in therapeutically effective amounts, for the treatment of inflammatory or obstructive diseases of the respiratory tract, primarily asthma or COPD.

The ratio in which both active substances 1 and 2 can be used in the proposed invention

Combinations, is a variable. Active substances 1 and 2 under certain conditions can be presented in the form of their solvates or hydrates. Depending on the selected salts 1, respectively 2 used according to the present invention and F), the mass ratio between both of these components changes due to the differences in the molecular weights of the various co salts. Therefore, in the following mass ratios, cation 1 is taken as a basis, and also presented in the form of free bases 2" preferred according to the invention are betamimetics, which are salmeterol, formoterol, and 60 is also the compound gas! (corresponds to the compound of formula 2a, in which B and B ? means hydrogen, and C and B" mean ethyl).

The mass ratio between cation 1 and betamimetic 2" in the combinations of medicinal substances proposed in the invention can, in the case of formoterol, be from 1:10 to 3001, preferably from 1:5 to 20071, more preferably from 1:3 to 150:1, most preferably from 1:2 to 100:1.

Preferred combinations of active substances 1 and 2 proposed in the invention may contain cation 1", and formoterol 65 2, for example, in the following mass ratios (but not limited to them): 1:5, 1:4, 1:35, 1:22 , 171, 2:11, 31, 41, 51, 6:11, 7:11, 8:11, 91, 1011, 111, 12:11, 131, 14:11, 15:1, 16:1, 17 :1, 18:11, 19:11, 201,

21:11, 22:11, 23:11, 241, 25:11, 26:11, 27:1, 28:11, 29:11, 30:1, 31:1, 32:1, 331, З3А: 1, 35:1, 36:11, 37:1, 381, 39:1, 40:11, 41:11, 42:1, 43:1, 441, 45:11, 461, 471, 48:1, 49:1, 50:1, 51:11, 52:1, 53:11, 541, 551, 561, 57:1, 58:11, 59:1, 60:1, 61:1, 62:1, 63:1, 641, 65:1, 661, 67:1, 68:1, 69:1, 70:11, 71:11, 72:11, 731, 741, 75:1, 76:1, 77: 1, 78:11, 79:11, 80:1, 81:1, 82:1, 831, 841, 85:1, 86:1, 87:1, 88:11, 89:11, 90:11, 91:11, 9271, 93:1, 94:1, 95:1, 96:1, 97:1, 98:1, 99:1, 100:1.

Usually, when using the medicinal products proposed in the invention, which contain combinations of active substances 1 and 2, pharmacologically active cation 1" and formoterol 2" are jointly injected into the body in a dosage that is calculated for one dose from 5 to 500 Ωkg, preferably from 10 to 200 Ωkg, more preferably from 15 7/0 to 100 Ωkg, preferably from 20 to 80 Ωkg, according to the invention preferably from 30 to bOO Ωkg, most preferably from 40 to 5О0 Ωkg.

The combinations of active substances 1 and 2 proposed in the invention contain cation 1" and formoterol 2", for example, in such amounts that correspond to the total dosage, which is equal to the calculation for one dose of 1Omkg, 1Bmkg, 20mkg, 25mkg, ZOmkg, ЗBmkg, 4Omkg, 4Bmkg, BOmkg, B5bmkg, bOmkg, bbmkg, 7Omkg, 7bmkg, 8Omkg, 85mKkgH,

OMKG, UBBBMKG, 10 Marcg, 1O5MKG, 11ok, 115mkg, 115mkg, 12mkg, 125mkg, 125 mcg, 1 ZOMKG, 1Z5 mcg, 14mkg, 145 mcgm, 15mcg, 155mkg, 15mkg, 15MKG, 15mkg, 155mkg. 215мкг, 22Омкг, 225Ммкг, 23Омкг, 23Бмкг, 24Омкг, 245мкг, 25О0мкг, 25Б5мМкг, 2бОмкг, 265мкг, 27Омкг, 275мкг, 280мкг, 285мКкГг, 29О0мкг, 29Б5мкг, ЗООмкг, ЗОБбБмкг, Зі'Омкг, Зібмкг, З2Омкг, З25мкг, ЗЗОмкг, ЗЗБбБмкг, З4Омкг, 3З45мкг, З5БОмКкгГ,

ЗББмкг, ЗбОмкг, Зббмкг, З7Омкг, З7Ббмкг, З8Омкг, З8Бмкг, З9Омкг, ЗО9Бмкг, 40Омкг, 405мкг, 41Омкг, 415мкГг, 42Омкг, 425мкг, 4ЗОмкг, 4ЗБмкг, 44Омкг, 445мкг, 45Омкг, 455мкг, 4бОмкг, 46б5Бмкг, 47Омкг, 475мкг, 48 OhmKgHg,

A48B5mcg, 49Omkg, 49B5mkg, B50Omkg, 5O5Bmkg, 51Omkg, 515mkg, 52Omkg, 525mkg, 5ZOmkg, 5ZBmkg, 54Omkg, 545mKkgH,

B5BOmkg, B5BBbmkg, 5bOmkg, 5bBbBmkg, 57Omkg, 575mMkg, 58Omkg, 585bmMkg, 59Omkg, 59BbBmkg, bOOmkg or a similar amount. Doses in which the combination of active substances proposed in the invention can be administered to the body on a single dose basis are not limited by the specific quantitative values indicated above, which reflect possible amounts only as an example. It is obvious that the combination of active substances proposed in the invention can be introduced into the body in other doses that differ from the above quantitative values in one way or the other (8) by an amount in the range of approximately -2.5 μg, primarily in the range of tenths. In such dosing intervals, the mass ratio between active substances 1 and 2" corresponds to the above values. "And

The combinations of active substances 1 and 2 proposed in the invention can contain cation 17 and formoterol 2, for example, in such quantities (but not limited to them) to ensure the introduction of 8.Mkg 1 and 2.5mcg of component 2 into the body at one time. . 19.bmcg of component 2", 8.3mcg of component 1, and 24.4mcg of component 2", 16.5mcg of component 1" and 2.5mcg of component 2, about 16b.50mcg of component T and 4.9mcg of component 2, 16.5mcg of component 1, and 9.8 μg of component 2", 16.5 μg of He) of component 1" and 14.7 μg of component 2, 16.5 μg of component 1' and 19.bmkg of component 2", 16.5 μg of component 1 and 24.4 μg of component 2", 33, Ohmkg of component 1 and 2, B5μg of component 2", З3Z, Ohmkg of component 1 and 4.9μg of component 2", 33.О0μg of component 1 and 9.8μg of component 2", 33.О0μg of component 1 and 14 7 μg of component 2,

3, Ohmkg of component 17 and 19, bmkg of component 27, 33, Ohmkg of component 1, and 24.4μg of component 2", 49.5μg of "Component 1 and 2.5μg of component 2", 49.5μg of component 1" and 4.9μg component 2, 49.5 micrograms of component 1 and //sh-) with 9, micrograms of component 2", 49.5 micrograms of component 17 and 14.7 micrograms of component 27, 49.5 micrograms of component 71 and 19, micrograms and component 2" 49.5 micrograms of component 1" and 24.4 μg of component 2", 82.6 μg of component 1" and 2.5 μg of I component 2, and? 82.bmkg of component 1 and 4.9μg of component 2, 82.bmkg of component 1 and 9.8μg of component 2", 82.bmkg of component 1" and 14.7μg of component 2", 82.6μg of component 1' and 19.bmkg of component 2", 82.6 µg of component 1 and 244 µg of component 2, 165.1 µg of component T and 2.5 µg of component 2", 165.1 µg of component 1 and 4.9 µg of component 2", 165.1 µg of component 1' and 9.v µg component 2", 165.1mcg of component 1 and 14.7mcg of component 2", 165.1mcg of component 1" and 19.bmcg of component 2", 165.1mcg of component 1" and 24.4mcg of component 2", 206.4mcg of component 1' and 2.5 μg of component 2", 206.4 μg of component 1' and 4.9 μg of component 2", 206.4 μg of component 1 and - 9.8 μg of component 2, 206.4 μg of component 1 and 14.7 μg of component 2", 206.44mcg of component 1 and 19.bmcg of Component 2", 206.4mcg of component T and 24.4mcg of component 2", 412.8mcg of component 1" and 2.5mcg of component 27, about 412.8mcg of component 1 and 4.9mcg of component 2, 412.8 μg of component 1 and 9.8 μg of component 2", 412.8 μg

Ta» of component 1 and 14.7 mcg of component 2", 412.8 mcg of component 1' and 19.bmcg of component 2", 412.vmcg of component 1' and 24 4mcg of component 2.

If the preferred combination of active substances 1 and 2 according to the invention is a combination in which salt 1 is bromide and component 2 is formoterol fumarate, then the above are indicated as an example of the number of active substances 1" and 2", which are introduced into the body in one reception, correspond to the following quantities of active substances 1 and iF) 2 based on one dose: 1 Ωkg of component 1 and 2.9 mcg of component 2, 1 Ωkg of component 1 and 5.7 mcg of component 2, 1 Ωkg of component 1 and 11.5 mcg of component 2, 1 µg of component 1 and 17.2 µg of component 2, 1 µg of component 1 and 22.9 µg of component 2, 1 µg of component 1 and 28.5 µg of component 2, 20 µg of component 1 and 2.9 µg of Kcomponent 2, 20 µg of component 1 and 5.7 µg of component 2 , 20mcg of component 1 and 11.5mcg of component 2, 20mcg of component 1 and 17.2mcg of component 2, 20mcg of component 1 and 22.9mcg of component 2, 20mcg of component 1 and 28.5mcg of component 2, 40mcg of component 1 and 2.9mcg of component 2 ,40 μg of component 71 and 5.7 μg of component 2, 40 μg of component 1 and 11.5 μg of component 2.4O0mcg of component 1 and 17.2mcg of component 2, 40mcg of component 1 and 22.9mcg of component 2, 40mcg of component 1 and 28.5mcg of component 2, bOmkg of component 1 and 2.9mcg of component 2, bOmkg 65 of component 1 and 5.7mcg component 2, boOmkg of component 1 and 11.5μg of component 2, boOmkg of component 1 and 17.2μg of component 2, boOmkg of component 1 and 22.9μg of component 2, bOmkg of component 1 and 28.5μg of component 2, 10Omkg of component 1 and 2.9μg component 2, 100mcg of component 1 and 5.7mcg of component 2, 100mcg of component 1 and 11.5mcg of component 2, 100mcg of component 1 and 17.2mcg of component 2, 10O0mcg of component 1 and 22.9mcg of component 2, 10Omkg of component 1 and 28.5mcg component 2, 200mcg of component 1 and 2.9mcg of component 2, 200mcg of component 1 and 5.7mcg of Component 2, 200mcg of component 1 and 11.5mcg of component 2, 200mcg of component 1 and 17.2mcg of component 2, 200mcg of component 1 and 22.9mcg component 2, 200mcg of component 1 and 28.5mcg of component 2, 250mcg of component I and 2.9mcg of component 2, 250mcg of component 1 and 5.7mcg of component and 2, 250 μg of component 1 and 11.5 μg of component 2, 250 μg of component 1 and 17.2 μg of component 2, 250 μg of component 1 and 22.9 μg of component 2, 250 μg of component 1 and 28.5 μg of component 2, 500 μg of component 1 and 2.9 μg component 2, 500μg of component 1 and 5.7μg of component 2, 70 BOOμg of component 1 and 11.5μg of component 2, 50μg of component 1 and 17.2μg of component 2, 500μg of component 1 and 22.9μg of component 2, 50μg of component 1 and 28 .5 μg of component 2.

If the combination of active substances 1 and 2 is preferred according to the invention, the combination is used in which component 2 is formoterol fumarate dihydrate, and salt 1 is bromide, then the above are indicated as an example of the number of active substances 1 and 2", which are introduced into the body in one reception, correspond to the following amounts of active substances /5 to her 2 based on one dose: 1Omkg of component 1 and Zmkg of component 2, 1Omkg of component 1 and bmkg of component 2, TOmkg of component 1 and 12mkg of component 2, 1Omkg of component 1 and 18mkg of component 2, 1Omkg of component 1 and 24mcg of component 2, 1Omkg of component 1 and ZOmkg of component 2, 20mcg of component 3mkg of component 2, 20mcg of component 1 and bmkg of component 2, 20mcg of component 1 and 12mcg of component 2, 20mcg of component 1 and 18mcg of component 2, 20mcg of component 1 and 24μg of component 2, 2o0μg of component 1 and ZOmkg of Component 2, 40μg of component 1 and Zmkg of component 2, 4O0μg of component 1 and bmkg of component 2, 40Omkg of component 1 and 12μg of component 2, 4O0μg of component 1 and 18μg of component 2, 4O0mcg of component 1 and 24mcg of component 2, 40O0mcg of component 1 and ZOmkg of component 2, bOmkg of component 1 and Zmkg of component 2, bOmkg of component 1 and bmkg of component 2, bOmkg of component 1 and 12mcg of component 2, bOmkg of component 1 and 18mcg of component 2 , bomkg of component 1 and 24mcg of component 2, bOomkg of component 1 and ZOmkg of component 2, 100mcg of sb of Component 1 and Zmkg of component 2, 10O0mcg of component 1 and bmkg of component 2, 10Omkg of component 1 and 12mcg of component 2, 100mcg of component 1 and 18mcg of component 2 . 2, 20 µg of component 1 and 24 µg of component 2, 200 µg of component 1 and ZO µg of component 2, 250 µg of component 1 and Z µg «g

From Component 2, 250mcg of component 1 and bmkg of component 2, 250mcg of component 1 and 12mcg of component 2, 250mcg of component 1 and 18mcg of component 2, 250mcg of component 1 and 24mcg of component 2, 250mcg of component 1 and ZOmkg of component 2, 50Omkg of component 1 and Zmkg of component 2, 50 µg of component 1 and bmkg of component 2, 500 µg of component 1 and 12 µg of component 2, 500 µg of component 1 and 18 µg of component 2, 500 µg of component 1 and 24 µg of component 2, 50 µg of component 1 and ZO µg of component 2.

In the same case, for example, the salmeterol mass ratio between cation 1 and betamimetic 2 in the combinations of medicinal substances proposed in the invention can be from 1:30 to 400:1, preferably from 1:25 to 200:1, more preferably from 1:20 to 100:1, most preferably from 1:15 to 50:1.

Preferred combinations of active substances 1 and 2 proposed in the invention may contain cation 1' and salmeterol 2, for example, in the following mass ratios (but not limited to them): 1:15, 1:14, 1:13, 1:12, " 1:11, 1:10, 1:9, 1:68, 1:17, 16,15, 14,13, 12,11, 21, 31, 41, 571, 61, 771, 81, 9:71, 101, 111, -9 s 12:11, 18:11, 141, 15:11, 161, 17:11, 18:1, 191, 20:11, 21:11, 22:11, 23:11, 24 :11, 25:11, 26:1,27:1, 28:1,2971,

And 30:1, 31:1, 32:1, 33:1, 34:1, 35:1. and?" Usually, when using the medicinal products proposed in the invention, which contain combinations of active substances 1 and 2, the pharmacologically active cation 1' and salmeterol 2' are jointly injected into the body in a dosage that is based on a single dose from 5 to 500 Ωkg, preferably from 10 to 200 Ohmkg, more preferably from 15

Go! up to 100 Ωkg, preferably from 20 to 800 Ωkg, according to the invention preferably from 30 to 75 Ωkg, most preferably from 40 to 700 Ωkg. o The combinations of active substances 1 and 2 proposed in the invention contain cation 1 and salmeterol 2", for example, in - such quantities that correspond to the total dosage, which is equal to the calculation for one dose of 15 mcg, 20 mcg, 25 mcg, ZOmkg, ЗBmkg, 4Omkg, 4Bmkg , Bomkg, 5bmkg, Bomkg, BBMKG, 7omcg, 7bmkg, 8omcg, 85bmkG, UMKG, where OBMKG, T1OOMKG, 1B5MKG, 115Mkg, 120mkg, 120mkg, 1CMKG, 1ZMKG, 1ZMKG, 1ZMKG, 1ZMKG, 1ZMKG, 1ZMKG, 1ZMKG, 1ZMKG, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 120mcg, 125mcg, 120mcg, 125mcg, 125mcg, 125mcg. 1бБбБмкг, 17Омкг, 175мкг, 18Омкг, 18Б5мкг, 19Омкг, 19Бмкг, 200мкг, 205мкг, 21Омкг, 215мкг, 22Омкг, 225Ммкг, 23Омкг, 23Бмкг, 24Омкг, 245мкг, 25О0мкг, 25Б5мМкг, 2бОмкг, 265мкг, 27Омкг, 275мкг, 280мкг, 285мКкГг, -

ЗББмкг, ЗбОмкг, Зббмкг, З7Омкг, З7Ббмкг, З8Омкг, З8Бмкг, З9Омкг, ЗО9Бмкг, 40Омкг, 405мкг, 41Омкг, 415мкГг, 42Омкг, 425мкг, 4ЗОмкг, 4ЗБмкг, 44Омкг, 445мкг, 45Омкг, 455мкг, 4бОмкг, 46б5Бмкг, 47Омкг, 475мкг, 48ОмКкГг, (Ф) А48Б5мкг, 49Омкг, 49Б5мкг, Б50Омкг, 5О5Бмкг, 51Омкг, 515мкг, 52Омкг, 525мкг, 5ЗОмкг, 5ЗБмкг, 54Омкг, 545мКкгГ, ка 5БОмкг, 55Б5мМкг, 5бОмкг, 5бБбБмкг, 57Омкг, 575мкг, 58Омкг, 585мМкг, 59Омкг, 595мкг, бООмкг, бОБбБмкг, 6б1Омкг, б1Бмкг, 620Омкг, 6б25мкг, бЗОмкг, бЗБмкг, б4Омкг, 6б4Бмкг, бБбБОмкг, ббБомкг, ббОмкг, ббомкг, б7Омкг, 675мкГг, во бвОмкг, б85мкг, б9Омкг, 695мкг, 70Омкг або аналогічній кількості. Doses in which the combination of active substances proposed in the invention can be administered to the body for one dose are not limited by the specific quantitative values indicated above, which only represent possible amounts as an example. It is obvious that the combination of active substances proposed in the invention can be introduced into the body in other doses, which differ from the above quantitative values in one way or another by a value in the interval 65 of approximately -2.5 μg, primarily in the interval of tenths. In such dosing intervals, the mass ratio between active substances 1" and 2 corresponds to the values indicated above.

The combinations of active substances 1 and 2 proposed in the invention can contain cation 7 and salmeterol 2, for example, in such amounts (but not limited to them) to ensure the introduction into the body of 8.3 mcg of component 17 and 12.5 mcg of component 2 at one time. . " and 200μg of component 2", 16.5μg of component 1' and 12.5μg of component 2", 16.5μg of component 1" and 2Bmkg of component 2, 16.5μg of component 1 and BOmkg of component 2", 16.5mMkg of component 1" and 7BbBmkg of component 2", 16.5mcg of component 1" and 100mcg of component 2", 16.5mcg of component 1 and 200mcg of component 2", 33.O0mcg of component 1' and 12.5mcg of component 2", 33.O0mcg of component 1" and 25mcg of component 70 2", 3, Ωkg of component 17 and BbBOmkg of component 2, 33, Ωkg of component 17 and 7UBbmkg of component 2", 33, Ωkg of component 1" and 100μkg of component 2", 33, О0μkg of mponenta 1" and 200mcg of component 2", 49.5mcg of component 1 and 12.5mcg of component 2", 49.5mcg of component 1" and 25mcg of component 2", 49.5mcg of component 1" and 5Omkg of component 2", 49.Bmkg of component 17 and 7bmkg of component 27, 49.B5mkg of component 1 and 10Omkg of component 2", 49.5mkg of component 1" and 200mkg of component 2", 82.b6mkg of component 1" and 12.5mkg of component 2", 82.6mkg of component 1" and 25μg of component 2", 82.6μg of component 1" and 5μg of component 2", 82.6μg of component 1" and 75μg of component 2", 82.b6μg of component 1" and 1О0μg of component 2", 82.b6μg of component 1" and 20О0μg of component 2", 165.1 mcg of component 1" and 12.5 mcg of component 2", 165.1 mcg of component 1" and 25 mcg of component 2", 165.1 mcg of component 1 and

Bomkg of component 2", 165.1mcg of component 1" and 75mcg of component 2", 165.1mcg of component 1" and 100mcg of component 2", 165.1mcg of component 1" and 200O0mcg of component 2", 206.4mcg of component 1" and 12, 5μg of component 2", 206.4μg of Component 1 and 25μg of component 2", 206.4μg of component 1" and 5Ωmkg of component 2", 206.4μg of component 1" and 75μg of component 2", 206b.4μg of component 1 and 7OOmkg of component 2" . 1 and 7bmkg of component 2", 412.8mMkg of component 1! and 100mkg of component 2", 412.vmkg of component 1! and 200 μg of component 2".

If the preferred combination of active substances 1 and 2 according to the invention is a combination in which salt 1 is bromide, and component 2 is salmeterol xinafoate, then the amounts of i) active substances 1" and 2" that are introduced into the body according to one dose, correspond to the following quantities of active substances I and 2 per dose: 1Omkg of component 1 and 18.2μg of component 2, 1Omkg of component 1, and 36.Omkg of component 2, 1Omkg of component 1 and 72.bmkg of component 2, 1O0μg of component 1 and 108.9 µg of component 2, 1 µg "g

From Component 1 and 145.2 µg of Component 2, 1 µg of Component 1 and 290.4 µg of Component 2, 20 µg of Component 1 and 18.2 µg of Component 2, 20 µg of Component 1 and 36.3 µg of Component 2, 20 µg of Component 1 and 72.6 µg of Component 2, with 20 mcg of component 1 and 108.9 mcg of component 2, 20 mcg of component 1 and 145.2 mcg of component 2, 20 mcg of component y and "- 290.4 mcg of component 2, 40 mcg of component 18.2 mcg of component 2, 40 mcg of component 1 and 36.3 mcg of component 2, d4Omkg of component 1 and 72.bmkg of component 2, 40mkg of component 1 and 108.9mkg of component 2, 40mkg of component 1 and o 145.2mkg of component 2, 40mkg of component 1 and 290.4mkg of component 2, bOmkg of component 1 and 18.2mkg of component 2, so bomkg of component 1 and 36, Zmkg of component 2, bOmkg of component 1 and 72, bOmkg of component 2, bOmkg of component 1 and 108.9μg of component 2, bomKg of component 1 and 145.2μg of component 2, bOmkg of component 1 and 290, 4 mcg of component 2, 100 mcg of component 1 and 18.2 mcg of component 2, 100 mcg of component 1 and 36.3 mcg of component 2, 100 mcg of component 1 and 72.6 mcg of component 2, 10O0mcg of component 1 and 108.9mcg of component 2, 10O0mcg of component 1 and 145.2mcg "Component 2, 10O0mcg of component 1 and 290.4mcg of component 2, 200mcg of component 1 and 18.2mcg of component 2, pt") with 200mcg of component 1 and 36.Zmkg of component 2, 200mcg of component 1 and 72.6mcg of component 2, 200mcg of component 1 and 108.9mcg of component 2, 200mcg of component 1 and 145.2mcg of component 2, 200mcg of component 1 and 290.4mcg of component 2, 250mcg of component 1 and 18.2 μg of component 2, 250 μg of component 1 and 36.0 μg of component 2, 25 μg of component 1 and 72.6 μg of component 2, 250 μg of component 1 and 108.9 μg of component 2, 250 μg of component 1 and 145.2 μg of component 2, 250 μg of component 1 and 290.4 µg of component 2, 50 µg of component 1 and 18.2 µg of component

Go! 2, BO0Omkg of component 1 and 36.33µg of component 2, 50Omkg of component 1 and 72.6µg of component 2, 50O0µg of component 1 and 108.9µg of component 2, 50Omkg of component 1 and 145.2µg of component 2, 50O0µg of component 1 and 290.4µg of component 2. - The amounts of active substances that are introduced into the body at one time in the medicinal compositions proposed in the invention are calculated in a similar way, in which instead of salmeterol xinafoate, which is also preferable for use according to the invention, the salt of salmeterol with 4-phenylcinnamic acid is used acid (4-phenylcinnamate) and salmeterol salt with 5-(2,4-difluorophenyl)salicylic acid (5-2,4-difluorophenyl)salicylate).

The mass ratio between cation 1 and betamimetic 2aa in the combinations of medicinal substances proposed in the invention can, for example, be from 1:30 to 400:1, preferably from 1:25 to 200:1, more preferably from 1:20 to 100:1, most preferably from 1:15 to 50:1.

F) Preferred combinations of active substances 71 and 2 proposed in the invention may contain a cation and a compound ka 2aa, for example, in the following mass ratios (but not limited to them): 1:15, 1:14, 1:13, 1:12 , 1:11, 1:10, 1:9, 1:88, 1:17, 16, 1:5, 14, 13, 1:22, 1:11, 2:11, 3:11, A1, 5 :11, 6:11, 7:11, 8:1, 9:1, 1071, 60 11:11, 12:11, 1311, 14:11, 15:11, 1611, 17:11, 18:11, 19:21, 20:11, 21:71, 221, 231, 241, 251, 26:1,27:1,28:1,29:1, 30:1, 31:11, 32:1, 33: 1, ZA:1, 35.1.

Usually, when using the medicinal products proposed in the invention, which contain combinations of active substances 1 and 2, cation 1 and compound 2aa are jointly injected into the body in a dosage that is calculated for one dose from 5 to 500 Ωkg, preferably from 10 to 200 Ωkg, more preferably from 15 to 100 Ohmkg, preferably 65 from 20 to 80 Ohmkg, according to the invention preferably from 30 to 75O0umkg, most preferably from 40 to 7OOomkg.

The combinations of active substances 1 and 2 proposed in the invention contain cation 1 and compound 2aa, for example, in such amounts that correspond to the total dosage, which is equal to the calculation for one dose of 15μg, 20μg, 25μg, ZOmkg, ЗBmkg, 4Omkg, 4Bmkg, BOmkg, 5bmkg, bOmkg, bbmkg, 7Omkg, 7Bmkg, 8Omkg, 85Bmkg, UOmkg,

OBMKG, T1OOMKG, 1B5MKG, 11mkg, 115mkg, 120mkg, 120mkg, 12bmkg, 1 ZOMKG, 1ZMKG, 2155MKG, 145mcg, 155mcg, 155mcg, 1bmkg, 1bmkg, 1bmkg, 1bmkg, 1bmkg, 1bmkg, 1bmkg. 22Омкг, 225Ммкг, 23Омкг, 23Бмкг, 24Омкг, 245мкг, 25О0мкг, 25Б5мМкг, 2бОмкг, 265мкг, 27Омкг, 275мкг, 280мкг, 285мКкГг, 29О0мкг, 29Б5мкг, ЗООмкг, ЗОБбБмкг, Зі'Омкг, Зібмкг, З2Омкг, З25мкг, ЗЗОмкг, ЗЗБбБмкг, Z4Omkg, 3Z45mkg, Z5BOmKkgH,

ЗББмкг, ЗбОмкг, Зббмкг, З7Омкг, З7Ббмкг, З8Омкг, З8Бмкг, З9Омкг, ЗО9Бмкг, 40Омкг, 405мкг, 41Омкг, 415мкГг, 42Омкг, 425мкг, 4ЗОмкг, 4ЗБмкг, 44Омкг, 445мкг, 45Омкг, 455мкг, 4бОмкг, 46б5Бмкг, 47Омкг, 475мкг, 48ОмКкГг, 70 А48Б5мкг, 49Омкг, 49Б5мкг, Б50Омкг, 5О5Бмкг, 51Омкг, 515мкг, 52Омкг, 525мкг, 5ЗОмкг, 5ЗБмкг, 54Омкг, 545мКкгГ, 5БОмкг, 55Б5мМкг, 5бОмкг, 5бБбБмкг, 57Омкг, 575мкг, 58Омкг, 585мМкг, 59Омкг, 595мкг, бООмкг . Doses in which the combination of active substances proposed in the invention can be administered to the body for one dose are not limited by the above 7/5 Specific quantitative values, which only represent possible amounts as an example. It is obvious that the combination of active substances proposed in the invention can be introduced into the body in other doses, which differ from the above quantitative values in one way or another by an amount in the range of approximately -2.5 μg, primarily in the range of tenths. In such dosing intervals, the mass ratio between the active substances 1" and 2aa corresponds to the values indicated above.

The combinations of active substances 1 and 2 proposed in the invention can contain cation 1 and compound 2aa, for example, in such quantities (but not limited to them) to ensure the introduction into the body of 8.3 mcg of component 1" and 12.5 mcg of component 2aa at one time . 1 and 200 mcg of component 2aa, 16b, 5 mcg of component 1 and 12.5 mcg with

Component 2aa, 16.5mcg of component 1" and 25mcg of component 2aa, 16.5mcg of component 1 and 5µg of component 2aa, 16.5mcg of component 1" and 75mcg of component 2aa, 16.5mcg of component 1" and 100 μg of component 2aa", 16 .5μg of component 1" and 200μg of component 2aa, 33.Omkg of component 1" and 12.5μg of component 2aa, 33.O0μg of component 1 and 25μg of component 2aa, 33.Omkg of component 1" and BOmkg of component 2aa, 33.Omkg of component 1 and 75 mcg of component 2aa, 33.Omkg of component 1" and 100mcg of component 2aa, 33.Omkg of component 1" and 200mcg of component "I 2aa, 49.5mcg of component 1 and 12.5mcg of component 2aa, 49.5mcg of component 1" and 25mcg of component 2aa, 49.5 μg of component 1" and BOmkg of component 2aa". 49.5 mcg of component 1" and 75 mcg of component 2aa, 49.5 mcg of component 1 and 10O0 mcg of component 2aa, 49.5 mcg of component 1" and 200 mcg of component 2aa, 82.bmcg of component 1 and 12.5mmcKg of component 2aa, 82.bmcg of component 2aa 1" and 25μg of component 2aa, 82,b6μg of component 1" and BbBOmkg of component 2aa, 82,bmkg of component 1" and 75μg of component 2aa. 82,bmkg of component 1" and 100μg of component 2aa, 82,bmkg of Component 1" and 200μg of component 2aa, 165.1mcg of component 1' and 12.5mcg of component 2aa, 165.1mcg of component 1 and 25mcg of component 2aa, 165.1mcg of component 1" and BOmkg of component 2aa, 165.1mcg of component 1" and 75mcg of component 2aa", 165, 1mcg of component 1" and 100mcg of component 2aa, 165.1mcg of component 1" and 200mcg of component 2aa, 206.4mcg of component 1" and 12.5mcg of component 2aa, 206.4mcg of component 1 and 25mcg of component 2aa, "206.4mcg of component 1" and BbBOmkg of component 2aa, 206.4mcg of component 1" and 75bmcg of component 2aa, 206.4mcg of Kcomponent 1" and 100mcg of component 2aa, 206.4mcg of component 1" and 200mcg of comp nenta 2aa", 412.8mcg of component - c 1 and 12.5mcg of component 2aa", 412.8mcg of component 1" and 25mcg of component 2aa", 412.vmcg of component 1" and BOmkg of component 2aa, 412.8mcg of component 1 and 75mcg of component 2aa, 412.mkg of component 1" and 100mcg of component "» 2aa, 412.8mcg of component 1" and 200mcg of component 2aa.

If the combination of active substances 1 and 2 is used as the preferred combination according to the invention,

If salt 1 is the bromide, and salt 2aa is the maleate of the compound 2aa, then the amounts of active substances (os) 1 and 2aag given above as an example, which are introduced into the body in one dose, correspond to the following amounts of active substances 1 and 2aa based on one dose : 1 omkg of component 16.2 mcg of component 2aa, 1 omkg of component 1 and 32.4 mcg of component 2aa, 1 omkg of component 1 and 64.8 mcg of component 2aa, 100 mcg of component 1 and 97.2 mcg of component 2aa, - 1 omkg of component 1 and 129.bmcg of component 2aa, 1Okg of component 1 and 259.2mcg of component 2aa, 20mcg of component 16.2mcg of component 2aa, 20mcg of component 1 and 32.4mcg of component 2aa, 20mcg of component 1 and about 64.8mcg of component 2aa, 2Omcg of component 1 and 97.2mcg of component 2aa, 20mcg of component 1 and 129.bmkg "g" of component 2aa, 20mcg of component 1 and 259.2mcg of component 2aa, 40mcg of component 1 and 16.2mcg of component 2aa, dOmkg of component 1 and 32.4mcg of component 2aa, 400mcg of component 1 and 64 ,vmcg of component 2aa, 40mcg of component 1 and 97.2mcg of component 2aa, 4O0mcg of component a 1 and 129.bmkg of component 2aa, 40μg of component 1 and 259.2μg of Component 2aa, bOmkg of component 1 and 16.2μg of component 2aa, bOmkg of component 1 and 32.4μg of component 2aa, bOmkg of component 1 and 64.8μg of component 2aa, bOmkg of component 1 and 97.2 µg of component 2aa, bomkg of component 1

F, and 129.bmkg of component 2aa, bOmkg of component 1 and 259.2μg of component 2aa, 10O0μg of component 16.2μg of component 2aa, 100μg of component 1 and 32.4μg of component 2aa, 100μg of component 1 and 64.8μg of component 2aa, 10Ωm component 71 and 97.2 mcg of component 2aa, 10O0mcg of component 1 and 129.bmcg of component 2aa, 100mcg of component 1 and 259.2mcg of component 2aa, 200mcg of component 16.2mcg of component 2aa, 200mcg of component 1 and 32.4mcg of component 2aa, 200mcg component 1 and 64.8μg of component 2aa, 200μg of component 1 and 97.2μg of component 2aa, 200μg of component 1 and 129.b6μg of component 2aa, 200μg of component 1 and 259.2μg of component 2aa, 250μg of component 1 and 16.2μg of component 2aa, 250μg component 1 and 32.4 mcg of component 2aa, 250mmcg of component 1 and 64.8mcg of component 2aa, 250mcg of component 1 and 97.2mcg of component 2aa, 250mcg of component 1 and 65 129.6mcg of component 2aa, 25O0mcg of component 1 and 259.2mcg of component 2aa, 500 µg of component 1 and 16.2 µg of component 2aa, 50 µg of component 1 and 32.4 µg component 2aa, 500mcg of component 1 and 64.8mcg of component 2aa,

BOOmkg of component 1 and 97.2mcg of component 2aa, BOOmkg of component I and 129.bmcg of component 2aa, 50Omkg of component 1 and 259.2mcg of component 2aa.

The combinations of active substances 1 and 2 proposed in the invention are preferably introduced into the body by inhalation.

For this purpose, components 1 and 2 should be presented in dosage forms suitable for inhalation. Such inhaled dosage forms include powders for inhalation, metered aerosols with propellant or solutions for inhalation without propellant. According to the invention, powders for inhalation, which contain a combination of active substances 1 and 2, can consist only of the indicated active substances or of a mixture of the indicated active substances with physiologically compatible excipients. In the context of this invention, the expression "7/0 solutions for inhalation without propellant" also means concentrates or sterile, ready-to-use solutions for inhalation. According to the invention, both active substances 1 and 2, used in combination with each other, can be contained either together in one dosage form, or separately in two separate dosage forms. Such dosage forms used according to the present invention are considered in more detail in the following part of the description.

A) Powders for inhalation, which contain the combinations of active substances 1 and 2 proposed in the invention

In the powders for inhalation proposed in the invention, active substances 1 and 2 can be contained either individually or in a mixture with acceptable physiologically harmless auxiliary substances.

If the active substances 1 and 2 are contained in the powders for inhalation 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 powders: monosaccharides (for example, glucose or arabinose), disaccharides (for example, lactose , sucrose, maltose), oligo- and polysaccharides (for example, dextran), polyalcohols (for example, sorbitol, mannitol, xylitol), salts (for example, sodium chloride, calcium carbonate) or mixtures of these excipients. It is preferable 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.

The maximum average particle size of auxiliary substances used in the powders for inhalation 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 admix with the auxiliary substances indicated above i) fractions with a smaller average particle size, which is 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 powders for inhalation. In addition, when preparing the powders for inhalation proposed in the invention, it is suggested to add micronized active substances 1 and 2 to the mixture of auxiliary substances, the average particle size of which is preferably from 0.5 to 1 µm, most preferably from 1 to bµm. The methods of obtaining the powders proposed in the invention for inhalation by grinding and micronizing the components followed by their mixing are known from the state of the art. The powders for inhalation proposed in the invention can be obtained and used either in the form of a single mixture of powders, which simultaneously contains both active substances 1 and 2, or in the form of separate powders for inhalation, each of which contains only one of the active substances 1 and 2, respectively. co

Inhalers known from the state of the art can be used to introduce the inhalation powders proposed in the invention into the body. For the introduction of powders for inhalation proposed in the invention, which, together with the active substances 1 and 2, also contain a physiologically harmless (compatible) auxiliary substance, it is possible to use, for example, inhalers in which a single dose from the dispensing capacity is issued with the help of a dosing chamber, "described, in particular, in patent 05 45706301, or with the help of other devices (described, in particular, in OE 3625685 ntsh) with A). For the introduction into the body of the powders for inhalation proposed in the invention, which contain active substances 1 and 2, not necessarily in combination with a physiologically harmless (compatible) auxiliary substance, it is possible to use, for example, the inhaler known by the name TigropaIekyae, respectively inhalers (described , for example, in ER 237507 A)Y. However, the inhalation powders proposed in the invention, which, together with active substances 1 and 2, also contain a physiologically harmless (compatible) auxiliary substance, preferably

Go! pack into capsules (to obtain the so-called inhalers), which are used in inhalers (described, for example, in UUO 94/289581I. o To use the medicinal compositions proposed in the invention in inhalers, it is most preferable to use the inhaler shown in Fig. 1. Such an inhaler (pocket inhaler) intended for inhalation of powdered medicinal products from capsules, is characterized by the presence of a body 1 with two windows 2, and a lamellar partition 3, in which air inlets are provided and which is equipped with a grid 5, which is kept in the assembled state by the corresponding fastening element 4, connected to the lamellar partition of the chamber 6 for the inhalation composition, on the side of which there is a push button 9, equipped with two polished needles 7 and made movable against the force of the spring 8, as well as the presence of a mouthpiece 12, which is made in the Folding with the possibility rotation around the axis 10, which connects it to the body 1, the lamellar partition C and the cap 11, and through holes 13 for the passage of air, which serve to adjust the aerodynamic (F, resistance. If the powders for inhalation proposed in the invention, taking into account the above-mentioned preferred method of their use, are supposed to be packaged in capsules (to obtain inhalers), then it is advisable to fill each capsule with powder for inhalation in the amount of 1 to ZOmg. The content of the indicated amounts of active substances, which are used together or separately, corresponds according to the invention to the above-mentioned for components 1, respectively 1" and 2", respectively 2 dosage based on one dose.

B) Inhalation aerosols with propellant, which contain the combinations of active substances 1 and 2 proposed in the invention

In the inhalation aerosols with propellant proposed in the invention, active substances 1 and 2 can be present in a dissolved or dispersed form in the propellant. At the same time, active substances 1 and 2 can be contained in separate dosage forms or in one single dosage form, and the specified components 1 and 2 can either 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.

The propellants used to produce the inhalation aerosols proposed in the invention are known from the state of the art. Propellants suitable for this purpose are selected from the group that includes hydrocarbons such as "-propane, n-butane or isobutane, and halogenated hydrocarbons such as preferably chlorinated and fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The above propellants can be used individually or in the form of their mixtures. The most preferred propellants are halogenated derivatives of alkanes selected from the group that includes 1011, T012, TO134a (1,1,1,2-tetrafluoroethane) and T0227 70 (1,1, 1,2,3,3,3-heptafluoropropane), as well as their mixtures, among which propellants T134a, 15227 and their mixtures are preferred.

Other components such as co-solvents, stabilizers, surface-active substances (surfactants), antioxidants, lubricants, as well as means for adjusting the pH value can also be included in the composition of inhalation aerosols with propellant proposed in the invention. All such components are known from the prior art.

Inhalation aerosols with propellant proposed in the invention can contain up to 5 wt.95 of the active substance 1 and/or 2. So, for example, the aerosols proposed in the invention can contain the active substance 1 and/or 2 in an amount from 0.002 to B5 wt.9o, from 0, 01 to Zmas.9o, from 0.015 to 2mas.95, from 0.1 to 2mas.9o, from 0.5 to 2mas.o or from 0.5 to 1mas.95.

If the active substances 1 and/or 2 are presented in a dispersed form, then the average size of their particles is preferably up to 1 µm, more preferably from 0.1 to 5 µm, most preferably from 1 to 5 µm.

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

Accordingly, another object of this invention is a drug in the form of the above-described propellant aerosols in combination with one or more inhalers suitable for the administration of such aerosols. Another object of this invention are inhalers, which differ in that they contain compositions for obtaining the above-described propellant aerosols proposed in the invention. The present invention also relates to replaceable canisters (cartridges), which are equipped with a suitable valve and can be used in a suitable i) inhaler and which contain one of the compositions described above for obtaining the inhalation aerosols with propellant proposed in the invention. Such interchangeable canisters and methods of filling them with compositions for obtaining the propellant inhalation aerosols proposed in the invention are known from the state of the art. "g zo B) Solutions or suspensions for inhalation without propellant, which contain the combinations of active substances 1 and 2 s proposed in the invention

Solutions and suspensions for inhalation without propellant proposed in the invention contain as solvents, "- for example, water or alcohols, preferably ethanol, and in some cases ethanol mixed with water. When using mixtures of water and ethanol as solvents, the relative content of ethanol in terms of the amount of water is not limited by any specific limits, preferably, however, so that the maximum content of ethanol is up to 70 vol.90, so primarily up to bOob.95 o. The rest, which is not enough to 10006.95, is accounted for by water. The pH value of solutions or suspensions containing components 1 and 2 separately or together is set to 2-7, preferably 2-5, using acids suitable for this purpose. Acids from the list of inorganic or organic acids can be used to adjust the pH to the above values. Examples of the most preferred inorganic acids in this regard include hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. As an example of organic acids most suitable for use for the specified purposes, we can name ascorbic acid, citric acid, malic acid;" acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, and other acids. The preferred inorganic acids are hydrochloric

Acid and sulfuric acid. It is also possible to use acids, which with one of the active substances already form an acid additive salt. Among organic acids, ascorbic acid, fumaric acid and citric acid are predominant. Under certain conditions, it is permissible to use mixtures of the specified acids, primarily in the case of those acids that, along with their properties that increase acidity, have other properties, for example, as flavoring substances, antioxidants or complexing agents, such as, for example, citric acid or ascorbic acid acid.

To adjust the pH value according to the invention, it is most preferable to use hydrochloric acid. 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 the drug proposed in it. However, in other embodiments, the use of this compound(s) is contemplated. In one of these preferred options, in which the use of sodium edetate is provided, its concentration in the double solution is less than 100 mg per 100 ml, preferably less than 50 mg per 100 ml, most preferably less than 20 mg per 100 ml. In principle, such solutions for inhalation are preferred, the content of sodium edetate in which is from 0 to 1Omg (F, per 100 ml. ka. Co-solvents and/or other auxiliary substances can be added to the solutions for inhalation without propellant proposed in the invention. As such co-solvents, it is preferable to use the following , which contain hydroxyl groups or other polar groups, such as alcohols, primarily isopropyl alcohol, glycols, primarily propylene glycol, polyethylene glycol, polypropylene glycol, glycol ether, glycerin, polyoxyethylene alcohols and polyoxyethylene and fatty acid esters. Excipients and additives in this context are means any physiologically compatible substance which is not an active substance but which can be included in a preparation together with the active substance(s) in a physiologically acceptable solvent to improve the quality 65 characteristics of such a preparation. These substances shall not show no or, taking into account the target therapeutic effect, no scales no significant or at least no adverse pharmacological effects. Such excipients 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, which ensure the preservation of the finished medicinal product or which extend its shelf life, flavors, vitamins and/or other additives known from the state of the art. Such additives also include physiologically harmless salts, such as, for example, sodium chloride, as agents that provide isotonicity.

Preferred excipients include antioxidants such as ascorbic acid, unless it is already used for pH regulation, vitamin A, vitamin E, 7/0 tocopherol and similar vitamins found in the human body, or provitamins.

Preservatives can be used to protect the drug 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-mentioned preservatives preferably ranges from 5 to 50 mg per 100 ml of solution, most preferably from 5 to 20 mg per 100 ml of solution.

Preferred preparations, in addition to the solvent, which is water, and combinations of active substances 1 and 2 also contain only benzalkonium chloride and sodium edetate. In another preferred option, it is proposed to completely abandon the use of sodium edetate.

For introducing into the body the solutions for inhalation without propellant proposed in the invention, such inhalers are most suitable, which allow spraying a small amount of a liquid drug in a therapeutically necessary dosage in the form of an aerosol, which is administered by inhalation for therapeutic purposes, within a few seconds. According to the present invention, such inhalers are preferable, which, in the optimal case, even when they are activated once (in one stroke of the piston), allow to dispense a sprayed in the form of an aerosol with an average droplet size of less than 20 μm, preferably less than 1 μm, a solution of the active substance or active substances in a portion less sch 10O0mcl, preferably less than 5Omcl, most preferably from 20 to ZOmcl, so that the inhaled aerosol dose, that is, which directly enters the respiratory tract, already corresponds to the therapeutically effective i) amount of the active substance or active substances.

A similar device, intended for inhalation administration of a liquid medicinal product, which sprays in metered amounts in the form of an aerosol without the aid of a propellant, is considered in detail (for example, in the application "Ezo UMO 91/14468), as well as in the application UUO 97/12687) ( in particular, presented in Fig. 65 of this application). The nebulizers or inhalers (devices) described in the specified applications are also known by the name Kezritai?, with

It is such an inhaler (Kezritai U) that is most expedient to use for obtaining the inhaled aerosols proposed in the invention, which contain a combination of active substances 1 and 2. The patient can always have a similar device with him, which, thanks to its close to cylindrical shape and hand-picked dimensions , which are from less than 9 to 15 cm in length and from 2 to 4 cm in width, are comfortable to hold in the hand and do not take up (er) much space. Such an inhaler allows, due to the creation of high pressure, to spray through small nozzles a strictly defined volume of the drug with the formation of inhaled aerosols.

In the preferred version, such an inhaler consists mainly of an upper body part, a pump body, a spray head with a nozzle, a locking and clamping mechanism, a body part for placing a spring, a spring and a dispensing capacity, and is characterized by the presence - c - of a pump body, which (body) fixed in the upper housing part and at one end of which there is a spray head with a nozzle, respectively a system of nozzles, " - a hollow piston with a valve element, - a driven flange in which a hollow piston is fixed and which is located in the upper housing part, (ee) - a locking and clamping mechanism located in the upper body part, o - a body part with a spring placed in it, which (body part) is mounted on the upper body part in a swivel support with the possibility of rotation relative to this upper body part, and - - the lower body part , mounted in the axial direction on the body part for placing the spring. t 50 The above-mentioned hollow piston with a valve element corresponds to the device described in the application UUO 97/12687. This hollow piston partially protrudes into the cylinder of the pump body and can move in this cylinder in the axial direction. In this regard, first of all, reference should be made to Fig. 1-4 of the specified application, in particular in Fig. 3, and to the corresponding sections of the description of this application. At the moment of release or descent of the spring, a hollow piston with a valve element creates on the side of its high pressure applied to the liquid, that is, to the dosed solution of the active substance or active substances substances, the pressure is from 5 to bOMPa (approximately from 50 to bb0bbar), preferably from 10 to b0MPa (from approximately 100 to bObbar). At the same time, the volume of one portion

IF) of the medicinal product released in one stroke of the piston is preferably from 10 to 50 μl, more preferably from 10 to 20 μl, most preferably 15 μl.

The valve element is preferably located at the end of the hollow piston, which is turned 60 to the spray head.

The nozzle in the spray head is mostly micro-structured, that is, it is made by micro-engineering methods. Microstructured spray heads (described, for example, in MO application 94/07607|, which is hereby incorporated in its entirety into this description by reference, referring primarily to Fig. 1 of the drawings attached to this application and to the description of this Fig. 1. 65 The spray head consists, for example, of two plates of glass and/or silicon firmly connected to each other, of which at least one plate has one or more microstructured channels that connect the inlet side of the nozzle to its outlet side. the nozzle has at least one round or non-round hole with a depth of 2 to 1 µm and a width of 5 to 15 µm, while the preferred values of the depth of such a hole are from 4.5 to b.5 µm, and the length is from 7 to µm. When using several, preferably two spray holes, they can pass in the spray head parallel to each other and thereby form parallel jets, or they can converge at an angle to each other in the direction you the forward side of the nozzle. In a spray head with at least two spray holes on the outlet side, the angle formed between the jets formed by them and inclined to each other can be from 20 to 1602, preferably from 60 to 1502, primarily from 80 to 1002. Spray holes 7/0 are preferably located at a distance from 10 to 200 µm to each other, more preferably at a distance from 10 to 100 µm, especially preferably from 30 to 7 µm. The most preferred distance between the spray holes is 5Ωm. Accordingly, the jets formed by such spray holes cross directly near them.

As already mentioned above, the liquid medicinal composition is pumped to the spray head under a pressure that 7/5 reaches 600 bar at the entrance to it, preferably from 200 to ZbObar, and then it is sprayed through the spray holes in the form of an inhaled aerosol. The droplet size of such an aerosol is preferably up to 20 µm, preferably from 3 to 1 µm.

The locking and clamping mechanism contains a spring, preferably a cylindrical helical compression spring, as an accumulator of mechanical energy. A similar spring affects the driven flange, which is an element that pushes out in a jerky manner, the movement of which is determined by the position of the stopper. The movement of the driven flange is precisely limited by the upper and lower stops. Compression (raising) of the spring is preferably provided by a transmission mechanism in the form of a force converter, for example, a helical gear that provides translational movement of the links, under the action of external torque, which is created when the upper body part is rotated relative to the body part, which is located in the lower body part, for placement of the spring. In this case, the upper body part and the driven flange contain a single or multi-way wedge mechanism. and)

The stopper together with its locking surfaces surrounds the driven flange with a ring. Such a stopper is, for example, an elastically deformed ring made of plastic or metal in the radial direction. This ring is located in a plane perpendicular to the longitudinal axis of the inhaler. After squeezing or cocking "I

From the spring, the locking surfaces of the stopper move to the side and are in the way of the driven flange, thereby preventing the spring from being unzipped. The stopper is unlocked using the trigger button. Such a trigger button is connected or linked to a stopper. To lower the locking and clamping mechanism, it is necessary "- to press the trigger button, moving it parallel to the plane of the location of the ring indicated above, preferably inside the atomizer, which is accompanied by the deformation of such a deformed ring in o

Зз5 the plane of its location. The design features of such a locking and clamping mechanism are described in more detail in the MO application 97/20590).

The lower housing part is mounted in the axial direction on the housing part for placing the spring and closes the fastening elements, respectively the support elements, the spindle drive and the output container with liquid.

When the inhaler is activated, the upper housing part is turned relative to the lower housing part, "along with which the housing part is simultaneously turned to accommodate the spring. At the same time, the 8s spring is compressed and retracted by means of a screw gear, and the locking mechanism is automatically fixed in the locked position. Preferably, the angle of rotation of the upper housing part relative to the lower housing part "" should be an integer times less than 3602, for example equal to 1802. Simultaneously with the compression of the spring, the driven part (driven flange) moves in the upper housing part by a given distance, and the hollow piston is moved back inside the cylinder in the pump housing, as a result of which a certain portion of liquid is sucked into the high-pressure cavity (ee) located in front of the nozzle from the output tank.

In the inhaler, if necessary, you can successively insert and use several variable dispensing containers (replaceable canisters) that contain atomized liquid. At the same time, the dispensing capacity is filled with the water-based aerosol composition proposed in the invention.

To spray the drug, you need to press the trigger a little. At the same time, the locking mechanism unlocks the driven part (driven flange), clearing its path. At the same time, the compressed spring, "from" unzipping, moves the piston into the cylinder of the pump housing. As a result, the liquid comes out of the inhaler nozzle in a sprayed form.

In more detail, other design features of such a device are described in applications MUO 97/12683 and MO З7/20590)|, which are therefore fully included in this description as a reference.

Details and elements of the inhaler (aerosol sprayer) are made of the appropriate material taking into account their functional purpose. So, in particular, the body of the inhaler, as well as its other parts, if we can assume from the point of view of the function they perform, are mostly made of plastic, for example, by injection molding.

In general, 60 physiologically harmless materials will be used to manufacture devices intended for medical purposes.

Figures 2a and 26b attached to this description, which are identical to Figures 6b and 6b |UMO application 97/12687|, show an inhaler (Bevrit(U)), which is mainly used for inhalation of the water-based aerosol compositions proposed in the invention.

In Fig. 2a, the inhaler is shown in a longitudinal section with a compressed (bent) spring, and in Fig. 2b 65, the inhaler is shown in a longitudinal section with a compressed spring.

The upper housing part (51) houses the pump housing (52), at the end of which (housing) there is a spray head holder (53) with a nozzle. In the holder there is a spray head (54) and a filter (55).

Fixed in the driven flange (56) of the locking and clamping mechanism, the hollow piston (57) partially protrudes into the cylinder of the pump housing. At one end of this hollow piston is a valve element (58). The hollow piston is sealed with a seal (59). The driven flange has a stop (60), which limits the movement of this driven flange inside the upper body part when the spring is compressed. The driven flange also has a stop (61), which limits the movement of this driven flange when the spring is compressed. After compressing and clamping the spring, the stopper (62) moves into the gap between the stop (61) and the support (63) in the upper body part. The trigger button (64) is connected to the stopper. The upper body part ends with a mouthpiece (65) and 7/o Closed with a removable protective cap (66), which is put on it.

The housing part (67) together with the compression spring (68) placed in it is fixed on the upper housing part with the help of latches-clips (69) and is mounted in a rotary support with the possibility of rotation relative to this upper housing part. The lower body part (70) is mounted on the body part for placing the spring. Inside the body part for placing the spring there is a variable output capacity 72). Dispensing /5 The capacity is closed by a plug (73), through which a hollow piston protruding into the dispensing capacity passes, immersed at one end in a liquid (in a solution of an active substance or active substances).

The spindle (74) of the mechanical counter is built into the side outer wall of the housing part for placing the spring. At the end of this spindle, which is turned to the upper housing part, there is a drive gear (75). A slider (76) is installed on the spindle.

The inhaler described above can be used to spray the aerosol compositions proposed in the invention in the form of an agrosol suitable for inhalation.

When using the above-described device (Rezritai?) for spraying the drug proposed in the invention, the portion of the composition that is released at least at 9795, preferably at least at 9895, of all cycles of inhaler actuation (strokes of the piston), must correspond to some given amount of medicinal Ha of the drug at a permissible deviations from this amount, which is equal to a maximum of 2595, preferably 2095. At the same time, such a given portion of the drug, which is issued in one stroke of the piston, is preferably from 5 to ZOmg, most preferably from 5 to 20mg.

For spraying the drug proposed in the invention, however, it is possible to use not only the inhaler described above, but also inhalers of other types, for example jet inhalers, or other stationary inhalers. "AND

Accordingly, another object of this invention is medicinal products in the form of the above-described solutions or suspensions for inhalation without propellant in combination with a device suitable for their introduction into the body, preferably in combination with an inhaler of Tina Kezrit (U. Regarding this in the preferred variant in this invention (-- solutions or suspensions for inhalation without propellant are proposed, which differ in that their composition includes the combination of active substances 1 and 2 proposed in the invention and that such solutions are intended for their spraying using the known as Kezritai? The present invention also relates to the inhalation devices described above, preferably the Kezritai U device, which differ in that they contain the solutions or suspensions for inhalation described above proposed in the invention without propellant.

Preferred according to the invention are solutions for inhalation, which contain active substances 1 and 2 in a single dosage form. Such a single dosage form also means dosage forms in which both components 1 and 2 are contained in two-chamber replaceable canisters (described, for example, in the UMO application o) c 00/23037|)|. This application is incorporated herein by reference in its entirety. Solutions or suspensions proposed in the invention for inhalation without propellant, in addition to those considered above, provided for use in combination with the Kevritai mud device. Solutions or suspensions can also be presented in the form of concentrates or sterile, ready-to-use solutions, respectively suspensions for inhalation. From similar concentrates by adding to them, for example, solutions of table salt, which

They provide isotonicity, ready-to-use preparations can be obtained. For the introduction of such sterile, av! ready-to-use drugs can be powered by stationary or mobile nebulizers that create inhaled aerosols using ultrasound or compressed air based on the Venturi principle or another principle. ka 20 Accordingly, another object of this invention is medicinal products in the form of the above-described solutions or suspensions for inhalation without propellant, which are presented in the form of concentrates or sterile, ready-made

T" for the use of drugs, in combination with a device suitable for introducing such solutions or suspensions into the body, which differ in that such a device is a stationary or mobile nebulizer working from an energy source, which creates inhaled aerosols using ultrasound or compressed air on the basis of 25 venturi principle or other principle.

GF) The examples presented below, which are exclusively illustrative in nature, serve for a more detailed explanation of the principles underlying this invention, and do not limit its scope to the specific variants of its implementation described below.

In the following description, the preparation of compounds 60 1 and 2 used according to this invention will be considered first, if they are not yet known from the state of the art. 1) Preparation of compounds of formula 1 1.a: Chlorohydride of 2,2-diphenylpropionic acid

52.08 g (0.3 mol) of oxalyl chloride is slowly added dropwise to a suspension of 25.0 g (0.1 mol) of 2,2-diphenylpropionic acid, 100 00 ml of dichloromethane and 4 drops of dimethylformamide at 2092C. Next, the mixture is stirred for 71 h at 2029 and for 0.5 h at 502. After that, the solvent is distilled off and the resulting residue is used in the next stage without additional purification. 1.6: Scopine ester of 2,2-diphenylpropionic acid

The residue obtained at stage 1.4 is dissolved in 100 ml of dichloromethane and at 402C is mixed dropwise with a solution of 51.45 g (0.333 mol) of scopine in 200 ml of dichloromethane. The resulting suspension is stirred for 24 hours. at 409С, after which the formed precipitate 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 using an aqueous solution of sodium carbonate, after which it is extracted with dichloromethane, and then the organic phase is dried over Ma»5O), evaporated to dryness and 70% hydrochloride is precipitated from the residue. The product is purified by recrystallization from acetonitrile.

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

Idl: 203-20420. 1. in: Methobromide of scopine ether of 2,2-diphenylpropionic acid 11.98 g (0.03 mol) of the product obtained at stage 1.6 is combined at 202 with 210 ml of acetonitrile, 7 0 ml of dichloromethane and 20.16 g (0.0 mol) of 46.9295- of bromomethane in acetonitrile and allowed to stand for 3 days.

After that, the solution is evaporated to dryness and the residue is recrystallized from isopropanol.

Yield: 11.34g (7595 from theory).

ID: 208-209260,

SodNovMO".-Vg (458,4).

Elemental analysis: calculated: C(62.89) H(b,16) M(3.06) found: C(62.85) H(b,12) M(3.07) s

Analogously to stage 1 in, it is also possible to obtain salts of formula 1, in which X" is another singly charged anion different from (5) bromide. 2) Preparation of compounds of formula 2 2.1: 4-phenylcinnamate salt of salmeterol 25 i « c no - - " | "in)

He so -yu shi s F . and 8 (ee) 1.35 g (bmmol) of 4-phenylcinnamic acid are dissolved in 75 ml of ethyl acetic acid under reflux. A warm solution of 2.5 g (bmmol) of salmeterol in 25 ml of ethyl acetic acid is added to this solution. Then the solution is allowed to cool and stirred for 16 hours at room temperature. After that, the suspension is filtered, the precipitate is washed with acetic acid ethyl ether and 750 tert-butyl methyl ether and dried in a vacuum at 25-302C. In this way, 3.47 g of the title compound are obtained as a colorless solid. i" Ipl: 1092S. 2,2: 5-(2,4-difluorophenyl)salicylate salt of salmeterol 2c

F) name) 60 b5 i nn

There is one

30 g of salmeterol when heated under reflux is dissolved in 300 ml of ethyl acetic acid 20 acid. 18.3 g of 5-(2,4-difluorophenyl)salicylic acid (diflunisal) is added to this solution. Then the solution is allowed to cool to room temperature. After that, the suspension is filtered, the precipitate is washed with ethyl acetic acid and dried in a vacuum at 359. In this way, 46 g of the salt specified in the title is obtained as a colorless solid.

ID: 10420. Ge

The following examples of compositions of drugs or dosage forms, which can be obtained analogously to methods known from the state of the art, serve for a more detailed explanation of this invention, the scope of which, however, is not limited to the compositions specifically considered in these examples.

Examples of drug compositions or dosage forms

A) Powders for inhalation "I 1) Components Quantity in mcg per capsule c 1-bromide 200 h formoterol fumarate dihydrate lactose 12 av 24788

Total 25000 (ee) 2) Components Quantity in mcg per capsule « 1-bromide 100 salmeterol xinafoate 50 lactose 12350 ne) s Total 12500 . and? 3) Components Amount in mcg per capsule 1-bromide 200 (Fe) xinafoate salmeterol 50 lactose 12250 ("in Total 12500 - lower 4) Components Amount in mcg per capsule 1-bromide 200" formoterol fumarate dihydrate lactose 24 24716

Total 25000 7 5) Components Quantity in mcg per capsule 1-bromide 100 compound 25 50 60 lactose 12350

Total 12500 b) Components Quantity in mcg per capsule b5

1-bromide 200 compound 2c 50 lactose 12250

Total 12500 7) Components Quantity in mcg per capsule 1-bromide 100 maleate salt of compound 2aa' lactose 65 70 12335

Total 12500 8) Components Quantity in mcg per capsule 1-bromide 200 maleate salt of compound 2aa' lactose 65 12235

A total of 12,500

B) Inhalation aerosols with propellant 1) Suspension for obtaining an aerosol:

Components Quantity by weight 9o 1-bromide 0.020 Salmeterol hexinafoate 0.066 soy lecithin 02 (o)

ТО11/7012 in a ratio of 2:3 to 100 2) Suspension for obtaining an aerosol: "І о о с

Components Amount in mass.9o 1-bromide 0.039 che xinafoate of salmeterol 0.033 ethanol, absolute 0.5 av) isopropyl myristate 01 to227 to 100 (ee)

Claims (26)

The formula of the invention «| And what? Y shi c 1. Medicinal preparation, which differs in that it contains one or more salts of the formula 1 1 - her z" Me zh Me ("c) - mu a --khy ime) zh o, y - y I in which 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 , in combination with one or more betamimetics (2), optionally in the form of their enantiomers, mixtures of enantiomers or in the form of racemates, optionally in the form of solvates or hydrates, and optionally together with a pharmaceutically acceptable excipient. 2. Medicinal preparation according to claim 1, which differs in that the active substances 1 and 2 are contained either together in one single dosage form, or in two separate dosage forms. C. Medicinal product according to claim 1 or 2, which differs in that betamimetics 2 are salmeterol salts, formoterol salts, or acid-addition salts of compounds of the formula 2а which B, its 82 have identical or different values and mean hydrogen or C.-C. alkyl, BZ and B! have identical or different meanings and mean hydrogen, C 4-Salylalkyl, -O-C.-C,alkyl or -O 4-C,alkylene-O-C.4-Sulalkyl, or B3 and B" together mean one of the following groups , which form a bridge, such as -C.4-C.alkylene- or -O-C.-Sualkylene-O-. 4. Medicinal preparation according to item C, which differs in that compounds 2 are present in the form of salts of hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid, 1-hydroxy-2-naphthalenecarboxylic acid, 4-phenylcinnamic acid, 5-(2,4-difluorophenyl)salicylic acid or maleic acid. with 5. Medicinal product according to item 3 or 4, which differs in that compounds 2 are salmeterol xinafoate, (U 4-phenylcinnamate of salmeterol or 5-(2,4-difluorophenyl)salicylate of salmeterol. 6. Medicinal preparation according to item 3 or 4, which differs in that compounds 2 are salts of compounds of formula 2a;, in which B its 82 have identical or different values and mean hydrogen, methyl or ethyl, " BZ its 27 have identical or different meanings and mean hydrogen, methyl, ethyl, propyl, butyl, methoxy group, ethoxy group, methoxymethyl or methoxyethyl, or with VZ Her 87 together mean one of such groups that form a bridge, such as propyl, butylene, -O-ethylene-O- or "- -O-propylene-O-, 7. Medicinal preparation according to claim 3, 4 or 6, which differs in that compounds 2 are salts of compounds of formula 2a, in which B" have identical or different values and mean hydrogen or ethyl, with B3 and Cl? have identical or different meanings and mean hydrogen, methyl, ethyl, propyl, butyl or methoxymethyl, or VZ Her VU together mean one of such groups that form a bridge, such as butylene or -O-ethylene-O-. " 8. Medicinal preparation according to claim 3, 4, 6 or 7, which differs in that compounds 2 are salts of compounds of formula 2a, in which t c a) ВЕ! and 2 mean hydrogen, and KZ and E7 mean ethyl, or » b) B and B? represent hydrogen, and EZ and B" represent methyl, or c) B! and B? represent ethyl, and BZ and B" represent hydrogen, or 15 g) B! and B? mean hydrogen, and BZ and B? together mean butylene, or e) БЕ" and 22 mean hydrogen, and KZ and E7 together mean -O-ethylene-O-, or e) KE! and 22 mean hydrogen, and KZ and E7 mean tert-butyl, or o 1:;p2 Z: ri I I is) K' and K- mean hydrogen, and K" and K" mean isopropyl, or - g) B and 82 mean hydrogen, and KZ and B" mean methoxymethyl. of 20 9. Medicinal preparation according to any of claims 3-5, which differs in that the mass ratio between the cation 1" of the compound 1 c" F) ko bo b5 Me - Me t I v yu O. lo Me, so | that of salmeterol 2" is about 1:30 to 400:1, preferably 1:25 to 200:1. 10. Medicinal preparation according to item 3 or 4, which is characterized by the fact that compounds 2 are formoterol hydrochloride, formoterol sulfate or formoterol fumarate. 11. Medicinal preparation according to claim 10, which differs in that the mass ratio between the cation 1! compounds 1 Me - Me t Ya M s schi her 6) « O. what sch Me, - Shen yad (av) | | d) and formoterol 2" is from about 1:10 to 300:1, preferably from 1:5 to 2001. 12. Medicinal preparation according to any of claims 1-11, which differs in that it is presented in the form of a dosage form suitable for inhalation. with 13. Medicinal preparation according to claim 12, which is characterized by the fact that the dosage form is selected from the group consisting of powders for inhalation, metered aerosols with propellant and solutions for inhalation without propellant. 14. Medicinal preparation according to claim 13, which is characterized by the fact that it is a powder for inhalation, which 15 contains compounds 1 and 2 in a mixture with acceptable physiologically harmless excipients selected from the group consisting of monosaccharides, disaccharides, oligo- and polysaccharides, polyhydric alcohols, salts and mixtures of such auxiliary substances. (av) 15. Medicinal preparation according to claim 14, which is characterized by the fact that the maximum average particle size of the excipient is up to 250 μm, preferably from 10 to 150 μm. 16. Medicinal product according to claim 13, which differs in that it is a powder for inhalation, which contains as its components only active substances 1 and 2. GT" 17. Medicinal preparation according to claim 13, which is characterized by the fact that it is an inhalation aerosol with a propellant that contains active substances 1 and 2 in a dissolved or dispersed form. 18. Medicinal product according to claim 17, which differs in that it contains hydrocarbons such as n-propane, n-butane or isobutane or halogenated hydrocarbons such as chlorinated and/or fluorinated derivatives of methane, ethane, propane, butane as a propellant , cyclopropane or cyclobutane. GF) 19. Medicinal preparation according to claim 18, which differs in that the propellant is T11, T512, To134a, 15227 or 7 of their mixtures, preferably To134a, 1227 or their mixture. 20. Medicinal preparation according to any of claims 17-19, which differs in that the content of active substance 1 and/or 2 in it can reach 5 wt.95. 21. Medicinal preparation according to claim 13, which is characterized by the fact that it is a solution for inhalation without a propellant, which contains water, ethanol or a mixture of water and ethanol as a solvent. 22. Medicinal preparation according to claim 21, which is characterized by the fact that it does not necessarily contain other co-solvents and/or excipients. in 23. Medicinal preparation according to claim 22, which differs in that it contains as co-solvents components that contain 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 polyoxyethylene and fatty acid esters. 24. Medicinal preparation according to claim 22 or 23, which is characterized by the fact that it contains surfactants, stabilizers, complexing agents, antioxidants and/or preservatives, flavors, pharmacologically acceptable salts and/or vitamins as excipients. 25. Medicinal preparation according to claim 24, which differs in that it contains editic acid or a salt of editic acid, preferably sodium edetate, as a complexing agent. 26. Use of the drug according to any one of claims 1-25 for obtaining a medication intended for 7/0 treatment of inflammatory or obstructive diseases of the respiratory tract, primarily asthma or chronic obstructive pulmonary disease. c) 6) "c" - "c) d) - and? (ee) («c) - name) c» name) 60 b5