EA045559B1 - ACID ADDITION SALTS OF SELECTIVE HISTAMINE H3 RECEPTOR ANTAGONIST AND METHOD FOR THEIR PREPARATION - Google Patents

Description

Field of technology

The present invention relates to physically and chemically stable salts of a selective antagonist of histamine H3 receptors - the compound 1-[4-(4-{3-[(2K)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone formula 1

Formula 1 and/or their polymorphs, and/or their hydrates/solvates, the method of their preparation, pharmaceutical compositions containing these compounds, and their use in the treatment and/or prevention of conditions requiring modulation of histamine H3 receptors ( for example, Alzheimer's disease, obesity, schizophrenia, myocardial ischemia, migraine, autism spectrum disorder).

Prior Art

Histamine H3 receptor antagonists have been widely studied to obtain drugs that would provide treatment for various diseases such as Alzheimer's disease, obesity, schizophrenia, myocardial ischemia, migraine, nasal congestion, etc. (Leurs et al., Nat. Rev. Drug. Disc. 2005, 4(2): 107-120; Berlin et al., J. Med. Chem. 2011, 54(1):26-53). Many compounds have shown promising results in preclinical studies and have entered the clinical phase of research in diseases such as excessive daytime sleepiness (EDS) associated with Parkinson's disease, obstructive sleep apnea, epilepsy, schizophrenia, dementia and attention deficit hyperactivity disorder (Kuhne et al., Exp. Opin. Inv. Drugs 2011, 20(12): 1629-1648). It has been suggested that histamine H3 receptor antagonists/inverse agonists may also be useful for the pharmacotherapeutic treatment of sleep disorders (Barbier and Bradbury, CNS Neurol. Disord. Drug Targets 2007, 6(1):31-43), but so far Only one histamine H3 receptor antagonist, pitolisant (brand name Wakix), has received marketing authorization for the treatment of narcolepsy with or without cataplexy in adults (KollbSielecka et al., Sleep Med. 2017, 33:125-129).

Publication 2014/136075 describes the synthesis of chemically modifiable, selective and drug-like H3 receptor antagonists and inverse agonists. The publication discloses the preparation and determination of the properties of these compounds, which are phenoxypiperidine derivatives, which bind to H3 receptors with high affinity and high selectivity and are drug-like.

Among the compounds disclosed in publication 2014/136075, the hydrochloride salt of 1 -[4-(4-{3-[(2К)-2-methylpyrrolidin-1 -yl]propoxy}phenoxy)piperidin-1 -yl] attracts attention. ethanone of formula (1). When preparing the compound by the method described in Example 11, the starting material was 4-(4-{3-[(2K)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidine dihydrochloride salt. After liberation of the base, the reaction mixture was treated with acetyl chloride in dichloromethane and after aqueous extraction of the reaction mixture, a dried solution of the resulting base of formula (1) in dichloromethane was evaporated. Excess hydrochloric acid in ethyl acetate was added to a solution of the crude product in dichloromethane. The precipitate was filtered from ethyl acetate and washed with diethyl ether to obtain the crystalline product, 1-[4-(4-{3-[(2H)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone hydrochloride salt.

The general requirement for active ingredients when developing a pharmaceutical composition is that the active ingredient must have appropriate physical, physicochemical and chemical parameters. Examples of such parameters include solubility, in particular solubility in water. Other important properties to consider in industrial production are ease of handling and good release, which are especially important to ensure an economical production process. Another important aspect is that the solid form of the active ingredient must have suitable physical and chemical stability, for example, it must not be hygroscopic and must not degrade significantly. In addition, different polymorphic forms of these salts may have different solid phase characteristics and different physical and chemical stability.

From the perspective of drug development, the ability of a substance to bind water, that is, the degree of its hygroscopicity (ability to absorb water), is of utmost importance, since environmental humidity, along with temperature, has a significant effect. The degree of hygroscopicity of active ingredients affects handling, storage, stability, use in compositions and many other properties of the substance. There are several approaches and methods to characterize the hygroscopic properties of active ingredients and determine the degree of their hygroscopicity, which are discussed in detail in the publication of Newman et al. (Newman et al., J. Pharm.

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Sci. 2007, 97(3): 1047-1059). In a typical case, the literature uses such categories as non-hygroscopic substance, weakly hygroscopic, moderately hygroscopic, highly hygroscopic and deliquescent (dispersing due to the absorption of moisture) substance, while in the pharmacopoeia (European Pharmacopeia 9.0, 5.11 Character Section in Monographs) such categories are used , as a weakly hygroscopic, hygroscopic, highly hygroscopic and deliquescent substance, depending on the increase in mass at a certain temperature and relative humidity under test conditions over a certain time. Static and dynamic measurement methods are available to investigate hygroscopic tendencies. Among dynamic measurements, Dynamic Vapor Sorption (DMS) analysis is a technique commonly used in the pharmaceutical industry that typically measures the change in mass of a substance (sorption and desorption curves) as a function of relative humidity under isothermal conditions. , from which conclusions can be drawn on the nature, mechanism and phase transitions of the sorption process.

When studying the hygroscopicity of active substances, it is especially important to determine whether the substance is prone to deliquescence, that is, where is the point at which a solid material becomes dissolved when interacting with environmental humidity (Mauer et al., Pharm. Dev. Techn. 2010, 15(6):582-594). Deliquescence of a substance occurs when the relative humidity (RH) reaches or exceeds the critical relative humidity (CRH) and a film corresponding to a saturated solution of the substance forms on the surface of the solid. With a further increase in humidity, the substance continuously absorbs moisture, which leads to a rapid increase in mass due to complete dissolution of the material and dilution of the resulting solution. Even a small surface deliquescence of a substance can have a significant effect on the chemical stability of a compound, since in the case of compounds with acidic or basic properties, a microenvironment may typically arise that will lead to the decomposition of compounds sensitive to acids or alkalis. Deliquescence and the pronounced ability of crystalline drugs to absorb moisture are typically due to their good solubility.

Determination of the critical relative humidity is possible gravimetrically, for example by means of DVS, wherein the relative humidity is changed in appropriately selected steps and a sufficiently long time is used to begin to establish quasi-equilibrium. After reaching the critical relative humidity, the sorption curve exhibits a greater or lesser change in slope, which is usually followed by a monotonic increase and a significant increase in mass, the magnitude of which and the shape of the sorption curve are not related to the formation of the hydrate form.

The essence of the invention

The main form of the salts of the present invention, 1-[4-(4-{3-[(2K)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone of formula 1, cannot be isolated in crystalline form, only in the form oils

The object of the present invention was to obtain a solid form (salt and/or polymorph) of 1-[4-(4{3-[(2K)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone, which would have the appropriate properties in respect of the above aspects, would exhibit sufficient physical and chemical stability, would be slightly hygroscopic but not deliquescent, thereby making it easier to isolate and handle, and would have excellent solubility.

In the process of obtaining the crystalline form of the hydrochloride acid addition salts of 1-[4-(4-{3-[(2K)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone base, it was discovered that two crystalline polymorphs (form A and form B) having monohydrochloride stoichiometry can be obtained. Moreover, in addition to the monohydrochloride, a crystalline dihydrochloride salt of the compound can also be obtained.

It was unexpectedly discovered that, in contrast to the monohydrochloride and dihydrochloride salts of 1-[4-(4-{3-[(2K)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone, new The dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts have outstanding properties, being less hygroscopic, easier to separate, their physical and chemical stability are more favorable, and they have excellent solubility. All these beneficial properties of the new dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts of 1-[4(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone make they are suitable for the development of pharmaceutical compositions for the treatment of diseases aimed at selective modulation of H3 receptors.

The present invention relates to dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts of 1-[4-(4-{3-[(2K)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone, and/ or to their polymorphs, and/or to their hydrates/solvates, to the method of their preparation, to pharmaceutical compositions containing these compounds, and to their use in the treatment and/or prevention of conditions requiring modulation of histamine H3 receptors (for example, Alzheimer's disease , obesity, schizophrenia, myocardial ischemia, migraine, autism spectrum disorder).

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Brief description of graphic materials

Fig. 1 - X-ray powder diffraction (XRPD; from English: X-ray powder diffraction) picture of form A of the monohydrochloride salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy )piperidin-1-yl]ethanone (example 6).

Fig. 2 - graph of the dynamic vapor sorption (DVS) isotherm of form A of the monohydrochloride salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone ( example 6).

Fig. 3 - X-ray powder diffraction (XRPD) pattern of Form B of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monohydrochloride salt (example 7).

Fig. 4 - infrared (IR; from English: infrared) spectrum of form B of the monohydrochloride salt 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl] ethanone (example 7).

Fig. 5 - Raman spectrum of form B of the monohydrochloride salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone (example 7).

Fig. 6 - graph of the dynamic vapor sorption (DVS) isotherm of form B of the monohydrochloride salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone ( example 7).

Fig. 7 - X-ray powder diffraction (XRPD) pattern of 1-[4(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrochloride salt (Example 2).

Fig. 8 - thermogravimetric (TG; from English: thermogravimetric) curve of the dihydrochloride salt of 1[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone ( example 2).

Fig. 9 - thermogram of the dihydrochloride salt 1-[4-(4-{3-[(2R)-2-methylpyrrolidin1-yl]propoxy}phenoxy)piperidine-1 obtained by differential scanning calorimetry (DSC); -yl]ethanone (example 2).

Fig. 10 - infrared (IR) spectrum of the dihydrochloride salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 2).

Fig. 11 - Raman spectrum of the dihydrochloride salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone (example 2).

Fig. 12 is a graph of the dynamic vapor sorption (DVS) isotherm of the dihydrochloride salt of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 2) .

Fig. 13(a) and 14(b) - graphs of dynamic sorption of vapors of the studied salts (relative change in mass in % as a function of relative humidity in %) at 25°C: (a) deliquescent salts, (b) non-dequescent salts.

Fig. 15 - X-ray powder diffraction (XRPD) pattern of Form A of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt (example 17).

Fig. 16 - infrared (IR) spectrum of form A of the monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone (example 17).

Fig. 17. Raman spectrum of Form A of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt (Example 17).

Fig. 18 - X-ray powder diffraction (XRPD) pattern of Form B of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt (example 18).

Fig. 19 - infrared (IR) spectrum of form B of the monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone (example 18).

Fig. 20 - Raman spectrum of Form B of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt (Example 18).

Fig. 21 is a graph of the dynamic vapor sorption (DVS) isotherm of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt (Example 17) .

Fig. 22 - X-ray powder diffraction (XRPD) pattern of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate salt (Example 20).

Fig. 23 - infrared (IR) spectrum of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate salt (example 20).

Fig. 24 - Raman spectrum of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate salt (example 20).

Fig. 25 is a graph of the dynamic vapor sorption (DVS) isotherm of 1-[4-(4-{3-[(2R)2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate salt (Example 20) .

Fig. 26 - X-ray powder diffraction (XRPD) pattern of 1-[4(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrobromide salt (Example 9).

Fig. 27 - infrared (IR) spectrum of the dihydrobromide salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 9).

Fig. 28 - Raman spectrum of the dihydrobromide salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone (example 9).

Fig. 29 is a graph of the dynamic vapor sorption (DVS) isotherm of the dihydrobromide salt of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone (Example 9) .

Fig. 30 - X-ray powder diffraction (XRPD) pattern of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone sulfate salt (Example 10).

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Fig. 31 - infrared (IR) spectrum of sulfate salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 10).

Fig. 32 - Raman spectrum of the sulfate salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 10).

Fig. 33 is a graph of the dynamic vapor sorption (DVS) isotherm of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy}phenoxy)piperidin-1-yl]ethanone sulfate salt (Example 10).

Fig. 34 - X-ray powder diffraction (XRPD) pattern of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone oxalate salt (Example 13).

Fig. 35 - infrared (IR) spectrum of the oxalate salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 13).

Fig. 36 - Raman spectrum of the oxalate salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 13).

Fig. 37 is a graph of the dynamic vapor sorption (DVS) isotherm of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1 -yl]propoxy}phenoxy)piperidin-1-yl]ethanone oxalate salt (Example 13).

Information confirming the possibility of implementing the invention

The basic form of the salts of the present invention, 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone of formula (1), cannot be isolated in crystalline form , only in the form of oil. The base according to the procedure described in example 11 of WO 2014/136075 can be obtained by evaporation of a solution of the resulting product in dichloromethane or, after isolation of the hydrochloride salt, in a manner known to those skilled in the art, that is, by releasing the base.

Hydrochloride acid addition salts of the base 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone (example 1) were obtained in crystalline form (examples with 2 to 8). It was found that two crystalline polymorphs (Form A and Form B) of the salt, characterized by monohydrochloride stoichiometry (Examples 4 to 8), X-ray powder diffraction (XRPD) patterns, infrared (IR) spectra, Raman spectra, and dynamic sorption isotherm plots could be obtained vapors (DVS) of which are shown in figures 1 to 6. Both monohydrochloride polymorphs (form A and form B) are highly hygroscopic and subject to deliquescence. Based on DVS analysis at 25°C, it is shown that Form A at relative humidity above 40%, and Form B even at relative humidity above 30%, exhibit a significant continuous increase in mass during the sorption process, which is caused by deliquescence of the substance.

In further experiments, it was found that, in addition to monohydrochloride, crystalline dihydrochloride salt (di-HCl) (Example 2 and Example 3), X-ray powder diffraction (XRPD) pattern, thermogravimetric (TG) curve, thermogram obtained by differential scanning Calorimetry (DSC), infrared (IR) and Raman spectra and dynamic vapor sorption (DVS) isotherm plot of which are shown in Figures 7 to 12. Compound 1-[4-(4-{3-[(2R)-2-methylpyrrolidine -1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone contains one strongly basic site (pyrrolidine nitrogen) that is capable of forming a stoichiometric salt with an equimolar hydrochloride, so the formation of dihydrochloride stoichiometry was not expected based on the acid-base nature of the compound. According to the results of TG and DSC analysis, the second molar amount of hydrochloride is less strongly bound to the crystal lattice and behaves as a volatile component. The compound has low thermal stability, according to the results of TG analysis, the release of volatile HCl can be observed already at room temperature, but it becomes intense at temperatures ranging from 70 to 80°C (Fig. 8). According to the results of DSC and microscopic analysis, in parallel with this process, the sample, starting from about 100°C, melts during decomposition (Fig. 9).

Another disadvantage of the dihydrochloride form is that it is highly hygroscopic; According to the results of DVS analysis (dynamic vapor sorption) at 25°C, a significant monotonic increase in mass is observed on the sorption curve at relative humidity above 60%, which demonstrates deliquescence of the substance (Fig. 12).

The hygroscopic nature of the mono- and dihydrochloride salts of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone poses many challenges in pharmaceutical drug development. handling, storage, stability and possibility of using these substances in formulations. It has been experimentally established that hydrochloride salts are subject to deliquescence even under isolation conditions, so their isolation by filtration and handling are problematic. The tendency of substances to decompose is also clearly related to their hygroscopic nature, since deacetylation of compounds can occur under the influence of acid in the presence of moisture.

Therefore, it was necessary to obtain salts of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone, which are less hygroscopic and easier to handle , and which are physically and chemically more stable than mono- and dihydrochloride salts.

In our experiments, dihydrobromide salt (example 9), sulfate salt (examples 10 to 12),

- 4 045559 oxalate salt (example 13 and example 14), monocitrate salt (examples 15 to 18) and dicitrate salt (examples 19 to 22) 1-[4-(4-{3-[(2R)-2- methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone have been obtained in crystalline form and are preferred over the mono- and dihydrochloride salts because they are less hygroscopic (Table 1) and therefore easier to isolate and they are easier to handle and their stability is much more favorable (Table 2).

Powder X-ray diffraction, infrared and Raman spectrometry results suitable for describing the properties of polymorphs of crystalline salts of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone , are given in tables 3 to 5.

Accordingly, the present invention relates to pharmaceutically acceptable, less hygroscopic acid addition salts of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone , which can be prepared using organic or inorganic acids, and/or their polymorphs, and/or their hydrates/solvates. Examples of acid addition salts that can be prepared using organic or inorganic acids include those derived from hydrobromic acid, sulfuric acid, oxalic acid or citric acid.

Preferably, the present invention relates to the dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl] ethanone, and/or their polymorphs, and/or their hydrates/solvates.

The present invention also relates to the preparation of pharmaceutically acceptable, less hygroscopic acid addition salts of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone , which can be prepared using organic or inorganic acids, preferably to obtain its dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts, and/or their polymorphs, and/or their hydrates/solvates.

The present invention also relates to the dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone for use in the treatment and/or prevention of conditions requiring modulation of histamine H3 receptors.

The present invention relates to the use of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone salts in the production of a pharmaceutical composition.

The present invention also relates to a pharmaceutical composition containing a therapeutically effective amount of dihydrobromide, sulfate, oxalate, monocitrate and dicitrate salts of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy) piperidin-1-yl]ethanone together with pharmaceutically acceptable excipients.

The present invention also relates to the use of the pharmaceutical composition from the previous paragraph in the treatment and/or prevention of conditions requiring modulation of histamine H3 receptors, preferably in the treatment and/or prevention of autism spectrum disorder.

For example, the preparation of salts from a base can be accomplished as follows: the base 1-[4(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone is dissolved in a suitable solvent or a mixture of solvents, after which an acid or its salt formed with a base weaker than 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidine1 is added -yl]ethanone, or their solution to the mixture. In addition, the base 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone can be prepared from its salt, and after releasing the base and after appropriate separation and/or solvent exchange produces the desired salt by adding an acid without isolating the base. If necessary, the reaction mixture is concentrated, the precipitated product is separated by filtration at room temperature or after cooling, then, if necessary, dried at an appropriate temperature. If necessary, the resulting salt is crystallized from its solution by adding a suitable antisolvent at room temperature or after reflux and the precipitated product is isolated by filtration, then, if necessary, dried at an appropriate temperature.

The salts of the present invention can be easily isolated and can be obtained with a high degree of purity according to the method of the present invention, which makes them particularly valuable for pharmaceutical use. With regard to the implementation of the present invention, the monocitrate and dicitrate salts are particularly preferred for the preparation of the pharmaceutical composition, since in this case the product of the highest quality and most stable is obtained with excellent yields. Monocitrate and dicitrate salts are slightly hygroscopic, do not exhibit deliquescence, and their physical and chemical stability and solubility are excellent.

Both citrate salts have a higher melting point than the dihydrochloride salt. In the case of monocitrate, an increase in the melting point of about 15°C can be observed, while in the case of dicitrate - by about 30°C, which indicates higher stability and is more

- 5 045559 more preferable for the preparation of a pharmaceutical composition. The monocitrate salt is stable under normal laboratory conditions in its monohydrate form (monocitrate Form A), but when the temperature is increased from room temperature to a temperature ranging from about 70°C to about 90°C, it loses loosely bound structural water and converts to anhydrate (anhydrous) form (form B monocitrate). The dried sample also absorbs a stoichiometric amount of water relatively quickly when interacting with environmental moisture. The dicitrate salt is stable in the anhydrate form, does not convert to the hydrate form and has a fairly high melting point, which is favorable from a development point of view.

A comparison of dynamic vapor sorption curves measured at 25°C for the studied 1-[4(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone salts is shown in fig. 13(a) and FIG. 14(b), which show relative mass change (percentage change in mass relative to mass at 0% relative humidity) as a function of relative humidity (RH%).

According to the sorption curve of the monohydrochloride salt Form A (Fig. 2), it binds approximately 3% water to 40% RH, and then liquefies at higher humidity (95% RH - relative weight change: 97%).

According to the sorption curve of the monohydrochloride salt form B (Fig. 6), it binds only 0.3% water to 30% RH, presumably through surface adsorption, and then liquefies at higher humidity (95% RH - relative weight change: 61% ).

According to the sorption curve of the dihydrochloride salt (Fig. 12), it binds approximately 0.7% of water in terms of dry weight up to 60% RH, and then dilutes at higher humidity (at 70% RH the relative increase in weight is already 17%, at 90% RH relative weight increase is 63%). In the case of the DVS measurement of dihydrochloride salt, in contrast to the general description of the method, measurements were not carried out in the measurement cycle at 5 and 95% relative humidity, but this difference does not have a significant impact on the determination of the onset of deliquescence (see below).

According to the sorption curve of dihydrobromide salt (Fig. 29), it absorbs approximately 6% moisture up to 70% RH and then liquefies at higher humidity (95% RH - relative weight change: 90%).

According to the sorption curve of sulfate salt (Fig. 33), it binds approximately 5% water to 80% RH and then liquefies at higher humidity (95% RH - relative weight change: 53%).

According to the oxalate salt sorption curve (Fig. 37), a relative increase in weight equal to about 4.7% of dry weight is observed in the RH range from 10 to 50%, which appears to remain constant up to about 70% RH. This change in mass is associated with the formation of a hydrate form having a stoichiometry close to that of the monohydrate. Further water uptake begins at relative humidity greater than 80% RH, but the oxalate salt did not exhibit deliquescence even at relative humidity greater than 90% RH under test conditions. In a desorption cycle ranging from 20% RH to 70% RH, it stabilized at a relative mass increase ranging from 7.1 to 7.3%, indicating the formation of a stoichiometry corresponding to the dihydrate form. Thus, the oxalate salt is stabilized in the form of a hydrate, which has a different composition depending on the humidity.

According to the DVS curves of the monocitrate salt (Fig. 21), the monohydrate (form A) and anhydrate (form B) states of the sample can be easily distinguished. At an RH greater than 30%, the salt absorbs 2.6 to 4.3% of water from the dry weight of the substance, which is close to the theoretical calculated value for monocitrate monohydrate (3.2%). The monohydrate form has been shown to be so stable that during desorption, monohydrate form A is converted to anhydrate form B only at relative humidity below 10% RH.

The monohydrate salt does not exhibit deliquescence even at relative humidity above 90% RH.

According to the sorption curve of dicitrate salt (Fig. 25), it binds 3.2% water up to 80% RH, 6.8 up to 90% RH, does not exhibit deliquescence at relative humidity above 90% RH, and its mass decreases reversibly during the phase desorption.

The commonly observed hygroscopic nature of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone salts is, among other things, due to their good solubility. In model gastric fluid (SGF (from English: simulated gastric fluid) without pepsin, pH = 1.3), the dihydrochloride salt has a solubility exceeding 59 mM, the solubility of the monocitrate salt exceeds 44 mM, and the solubility of the dicitrate salt is equal to 469 mM.

The deliquescence tendency of each salt is characterized by its critical relative humidity (CRH) value (Table 1), which was determined from sorption curves obtained at the measurement parameters indicated below by DVS analysis under isothermal conditions at 25 °C as specified below.

The derivative of the sorption curve was obtained from the sorption curve in the range from 10% RH to 90% RH by determining the differences in the relative mass changes with a change of 10% RH:

At = m2 - m1,

- 6 045559 where ml and m2 are the quasi-equilibrium relative mass changes (% mass change relative to mass at a relative humidity of 0%) at a given percentage of relative humidity RH1 and RH2 according to the sorption curves, and

ARH = RH2-RH1 = 10.

If for a given sorption step Δm/ΔRH > 0.5, then RH1 is taken as the critical relative humidity (CRH) value indicating the end point of the physical stability of the substance. The value determined in this way corresponds well to the beginning of a significant monotonic increase in mass, observed visually on the sorption curve. At relative humidity values exceeding the critical relative humidity, the process of deliquescence of the substance occurs, which determines the increase in mass observed on the sorption curve.

Table 1

Values of critical relative humidity (CRH) and Am/ARH obtained based on DVS analysis at 25°C and characterizing the deliquescence of the studied salts

Salt mohoHCI Form Form B A diNS1 diNVg sulfate oxalate mono citrate dicitrate CRH thirty% 40% 60% 70% 80% Indelicious RH! Am/ARH 0% 0.0 0.0 0.0 0.0 0.4 0.0 0.0 0.0 10% ο,ο ο,ο 0.0 0.0 0.0 o,1 0.0 0.0 20% 0.0 0.0 0.0 0.0 0.0 0.1 0.2 0.0 thirty% 0.6 0.3 0.0 0.0 0.0 0.2 0.1 0.0 40% 0.7 1.1 0.0 0.1 0.0 0.1 0.0 0.0 50% 0.4 0.5 0.0 0.1 0.0 0.0 0.0 0.0 60% 0.6 0.6 1.7 0.3 0.0 0.0 0.0 0.0 70% 0.9 1.1 2.4 3.1 0.1 0.0 0.0 0.0 80% 1.5 2.6 2.1 3.3 1.6 0.1 0.0 0.1

It can be noted that, compared to monohydrochloride salts, di-HBr and sulfate salts begin to exhibit deliquescence at significantly higher critical relative humidity values, indicating a reduced tendency towards hygroscopicity associated with their greater physical stability. Surprisingly, it was found that the oxalate, monocitrate and dicitrate salts did not deliquify under the conditions of the DVS analysis and turned out to be the physically most stable salts.

Increased stability with respect to environmental humidity is preferred for long-term physical and chemical stability of the active ingredient. The relationship between the reduced hygroscopic nature and the associated increased chemical stability is shown for the most preferred citrate salts compared to the dihydrochloride salt.

In table Figure 2 shows the results of a high performance liquid chromatography (HPLC) purity test after a 10-day test of the dihydrochloride, monocitrate, and dicitrate salts for solid stability under stress. From the results, it is clear that the dichloride salt is slightly decomposed by heat, but is significantly decomposed by the combined action of heat and humidity. In contrast, the monocitrate and dicitrate salts are stable under these conditions and are therefore much more preferred.

table 2

HPLC Purity Test Results of Dihydrochloride, Monocitrate and Dicitrate Salts after 10 Day Stress Solid Stability Test

Conditions Storage conditions Original sample 40°C, 75%RH 50°C, 75%RH 50°C 75°С Open vessel Open vessel Closed vessel Closed vessel Salt form All contaminants (area in %) Di hydrochloride 0.85% 59.56% 51.32% 0.98% 1.50% Monocitrate 0.19% 0.19% 0.19% 0.20% 0.19% Dicitrate 0.23% 0.24% 0.25% 0.23% 0.24%

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Table 3

Characteristics of powder X-ray diffraction of crystalline salts of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone and their polymorphs

Dihydrochloride

Peak position [°2 theta] d-distance [A] Rel. INT. [%] 2.8 31.5 20 14.2 6.3 6 15.2 5.8 98 15.8 5.6 67 16.8 5.3 57 17.0 5.2 36 17.7 5.0 9 18.8 4.7 12 19.7 4.5 7 20.3 4.4 15 22.0 4.0 37 25.6 3.5 100 26.1 3.4 15 28.7 3.1 19 30.7 2.9 9 31.2 2.9 eleven Monohydrochloride Form A Peak position d-distance Rel. int. [°2 theta] [A] [%] 6.0 14.7 15 12.1 7.3 13 14.4 6.2 9 15.0 5.9 9 15.3 5.8 44 16.1 5.5 100 16.7 5.3 31 17.6 5.0 8 18.1 4.9 10 18.6 4.8 39 19.2 4.6 39 20.8 4.3 52 21.2 4.2 16 21.5 4.1 13 22.5 4.0 29 22.6 3.9 24 23.0 3.9 eleven 24.0 3.7 26 25.5 3.5 12 25.7 3.5 15 27.0 3.3 24 27.7 3.2 19 30.2 3.0 8 30.9 2.9 7

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Monohydrochloride Form B

Peak position [°2 theta] d-distance [A] Rel. INT. [%] 15.3 5.8 91 15.6 5.7 50 16.0 5.5 100 16.3 5.5 47 16.8 5.3 42 17.3 5.1 20 17.9 5.0 21 18.1 4.9 25 20.0 4.4 20 21.3 4.2 49 22.1 4.0 8 23.3 3.8 8 24.5 3.6 10 25.9 3.4 71 27.0 z, z 12 27.7 3.2 13 28.1 3.2 7 28.5 3.1 eleven 30.0 3.0 6 30.6 2.9 9 Dicitrate Peak position d-distance Rel. INT. [°2 theta] [A] [%] 10.1 8.7 40 12.0 7.4 100 12.8 6.9 39 14.1 6.3 28 15.9 5.6 24 16.8 5.3 12 17.1 5.2 32 17.9 5.0 eleven 18.2 4.9 17 19.0 4.7 58 19.3 4.6 45 19.6 4.5 52 20.2 4.4 13 20.5 4.3 66 21.1 4.2 21 22.1 4.0 8 22.8 3.9 41 23.5 3.8 16 24.1 3.7 eleven 25.9 3.4 9 26.2 3.4 13 27.0 3.3 15 27.4 3.3 eleven 28.8 3.1 8 30.4 2.9 8

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Monocitrate Form A Peak position [°2 theta] d-distance [A] Rel. INT. [%] 3.4 26.2 14 9.4 9.4 35 10.2 8.7 6 11.1 8.0 54 11.8 7.5 12 12.1 7.3 23 13.5 6.6 59 15.9 5.6 20 16.2 5.5 13 16.6 5.3 25 18.0 4.9 47 18.8 4.7 32 19.5 4.5 100 19.8 4.5 82 20.3 4.4 34 21.5 4.1 58 22.3 4.0 8 24.3 3.7 22 24.6 3.6 22 25.8 3.5 18 26.5 3.4 8 26.6 3.3 10 27.9 3.2 12 30.3 3.0 15 32.3 2.8 eleven 33.4 2.7 8

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Monocitrate Form B Peak position [°2 theta] d-distance [A] Rel. INT. [%] 3.4 25.5 18 9.5 9.3 27 10.4 8.5 7 11.3 7.8 38 11.9 7.5 14 12.2 7.2 eleven 13.4 6.6 12 13.7 6.4 28 14.0 6.3 28 15.5 5.7 13 15.8 5.6 17 16.4 5.4 20 17.8 5.0 32 18.1 4.9 13 19.1 4.7 100 19.5 4.6 27 19.9 4.5 35 20.4 4.3 48 21.0 4.2 7 21.9 4.1 10 22.3 4.0 38 22.7 3.9 12 24.4 3.6 20 25.1 3.6 17 26.0 3.4 17 28.3 3.2 10 31.2 2.9 8 32.4 2.8 5

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Dihydrobromide

Peak position [°2 theta] d-distance [A] Rel. INT. [%] 2.8 31.6 18 5.6 15.7 17 8.4 10.5 8 11.3 7.8 24 14.1 6.3 7 14.9 6.0 23 15.4 5.8 17 16.4 5.4 33 16.7 5.3 63 17.0 5.2 100 17.7 5.0 17 19.5 4.5 9 20.2 4.4 22 21.6 4.1 7 22.0 4.0 33 23.7 3.8 eleven 24.7 3.6 88 26.0 3.4 35 27.2 3.3 7 28.5 3.1 38 29.0 3.1 10 29.9 3.0 21 30.4 2.9 7 31.0 2.9 eleven 32.1 2.8 7 Oxalate Peak position d-distance Rel. INT. [°2 theta] [A] [%] 4.1 21.4 8 8.5 10.4 44 9.3 9.5 eleven 14.6 6.1 13 14.8 6.0 23 15.4 5.8 thirty 16.5 5.4 24 16.6 5.3 22 17.4 5.1 thirty 18.7 4.7 13 20.8 4.3 100 21.6 4.1 12 22.3 4.0 29 22.5 3.9 50 23.6 3.8 23 26.7 3.3 14 27.4 z, z 14 29.0 3.1 37 37.0 2.4 8

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Sulfate Peak position d-distance Rel. INT. [°2 theta] [A] [%] 7.8 11.4 5 11.4 7.7 8 11.7 7.6 10 12.6 7.0 6 13.4 6.6 3 14.2 6.2 2 14.7 6.0 6 15.6 5.7 19 16.1 5.5 3 16.5 5.4 18 17.1 5.2 9 17.7 5.0 9 18.0 4.9 37 18.5 4.8 77 19.6 4.5 40 19.9 4.5 55 21.0 4.2 5 21.6 4.1 3 22.5 4.0 eleven 22.9 3.9 100 23.9 3.7 9 24.4 3.6 4 25.2 3.5 12 25.5 3.5 8 27.5 3.2 13 28.3 3.2 12 28.7 3.1 4 30.4 2.9 3 32.8 2.7 3

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Table 4

Characteristic peaks measured in the IR spectra of crystalline salts of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone and their polymorphs [cm ^-1 ]

Peaks Dicitrate Monocitrate Form A Monocitrate Form B Oxalate Sulfate diNS! HCI Form B diNVg 1 3523 3466 2962 3431 3389 3364 3429 3419 2 3038 3011 2872 2938 2955 3044 2953 3043 3 2951 2962 1732 2881 2615 2959 2695 2958 4 2521 2859 1637 2513 2513 2931 1621 2930 5 1966 1731 1595 1987 1590 2903 1507 2901 6 1727 1618 1508 1706 1507 2874 1456 2843 7 1687 1594 1477 1693 1487 2604 1392 2614 8 1587 1507 1452 1624 1453 2519 1366 2520 9 1507 1479 1398 1507 1374 2184 1271 1840 10 1489 1454 1367 1470 1360 1773 1218 1685 eleven 1475 1394 1316 1455 1269 1682 1131 1616 12 1426 1318 1288 1367 1220 1616 1118 1508 13 1394 1285 1271 1220 1112 1508 1038 1469 14 1358 1270 1217 1134 1044 1468 998 1441 15 1315 1217 1172 1044 1010 1441 970 1413 16 1276 1175 1131 1008 975 1422 829 1337 17 1216 1133 1068 976 924 1337 781 1284 18 1130 1043 1043 948 855 1285 748 1232 19 1116 1004 1000 832 816 1232 595 1133 20 1062 974 975 805 777 1162 527 1117 21 22 23 24 25 26 27 1030 1000 962 948 933 872 825 937 908 847 806 771 746 665 951 908 818 746 664 601 521 752 722 648 593 478 722 646 624 591 516 448 436 1118 1092 1075 1053 1030 1006 975 1091 1074 1053 1033 1005 938 949 28 805 601 489 939 938 29 782 535 434 918 817 thirty 736 488: 897 755 31 695 434: 818 718 32 661 754 670 33 606 722 584 34 588 671 571 35 497 576 516 36 477 //////y 516 495 37 443 U////// 496 όν/Ζ

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Table 5

Characteristic peaks measured in the Raman spectra of crystalline salts of 1-[4-(4-{3-[(2R)2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone and their polymorphs [cm ^-1 ]

Peaks Dicitrate Monocitrate Form A Monocitrate Form B Oxalate Sulfate diNS! HCI Form B diNVg 1 3070 3065 3086 3077 3076 3073 3074 3072 2 3011 3012 3011 3033 3059 3048 3051 3045 3 2971 2979 2982 2984 2992 3023 2981 3022 4 2933 2961 2961 2935 2935 2958 2932 2983 5 1719 2931 2930 2883 2907 2935 2875 2958 6 1611 2905 2881 2757 2893 2878 2767 2935 7 1585 2888 2853 1733 1613 2766 1615 2902 8 1489 2849 1718 1707 1584 1662 1583 2876 9 1457 1715 1628 1611 1487 1614 1469 1687 10 1394 1618 1615 1477 1453 1583 1442 1613 11 1274 1603 1586 1443 1378 1468 1362 1583 12 1256 1585 1476 1364 1360 1442 1311 1469 13 1191 1480 1454 1305 1304 1325 1257 1442 14 1158 1457 1365 1268 1257 1312 1164 1265 15 1132 1438 1307 1246 1172 1266 1133 1198 16 1053 1370 1251 1203 1152 1198 1095 1164 17 1031 1304 1169 1178 1133 1163 1041 1034 18 1000 1283 1134 1157 1106 1093 1005 910 19,936 1252 1043 1137 1053 1068 910 852 20 910 1242 999 1108 1011 1034 886 843 21,854 1169 930 1068 961 911 853 719 22,782 1134 857 1044 926 853 837 671 23 720 1053 718 1009 854 809 724 638 24 660 1039 665 981 821 722 668 519 25 640 1006 647 958 792 706 638 378 26,607 950 602 928 723 672 518 319 27,516 935 513 858 706 638 464 261 28 460 859 380 842 644 517 413 29 371 840 308 807 625 496 378 30 314 804 745 581 466 31,257 722 725 519 418 32 666666^ ³⁴ 6ύ//6^/ ³⁵ i β 665 642 619 515 470 389 309 708 648 621 514 489 456 428 482 469 420 381 379 299 39 7/¼¼ 265 382 ⁴⁰ 66666 ⁴¹ /6666 42 66666, 329 298 222

For analytical studies in the solid phase, the following experimental conditions were used.

Measurement parameters via

IR spectroscopy with p] Fourier transform Device Thermo-Nicolet 6700 Phase KVg plates Spectral resolution 4 cm' ¹ Detector DTGS Beam splitter HT-KVg Mirror speed 0.6329 Number of scans 100

Fourier Transform Raman Spectroscopy Measurement Parameters

Device Thermo-Nicolet NXR9650 measurement range From 3500 cm' ¹ to 200 cm' ¹ Spectral resolution 4 cm' ¹ Detector Ge Beam splitter _CaF2 Mirror speed 0.1581 Number of scans 256 Laser operating mode 500 mW

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Powder X-ray Diffraction Measurement Parameters

Device PANanalytical X'Pert PRO MPD Radiation CuKa Accelerating voltage 40 kV Anode current 40 mA Goniometer PW3050/60 Scan speed 0.0305 °/s Increment 0.0131 ⁰ Sample holder PW1818/25 & 40 (transmission, sample between sheets of foil) Device for rotating the sample holder PW3064/60 (reflective transmission device Sample holder rotation speed 1 revolution/s Detector PIXcel (PW3018/00) Measurement uncertainty 20 ±0.2°

Thermogravimetric (TG) Measurement Parameters

Device TA Instruments TGA Q5000 or Discovery TGA 5500 Heating rate 10 °C/min Sample weight From about 5 mg to about 10 mg Atmosphere 60 ml/min N ₂

Differential Scanning Calorimetry (DSC) Measurement Parameters

Device TA Instruments DSC Q1000 or Discovery DSC 2500 Heating rate 10 °C/min Sample weight From about 1 mg to about 2 mg Container type Open AI container Atmosphere 50 ml/min N ₂

Dynamic Vapor Sorption (DVS) Measurement Parameters

Device SMS DVS Advantage 1 dm/dt criterion 0.002%/min Time limit max./min. 360 min/10 min Temperature 25 °C Cycle 0-5-10-20-30-40-50-60-70-80-90-95-90-80-70-60-50-40- 30-20-10-5-0% RH Volumetric gas velocity 150 ml/min N ₂ Solvent Water

Pharmaceutical compositions.

The salts of the present invention can be administered by any pharmaceutically acceptable route, for example, orally, parenterally, buccally, sublingually, nasally, rectally or transdermally in accordance with the composition of the pharmaceutical composition. The therapeutically effective dose ranges from 0.01 mg/day to 40 mg/day.

The following example formulations illustrate the pharmaceutical compositions of the present invention. However, the present invention is not limited to these compositions.

A) Solid dosage form for oral administration. Tablet__________

Active ingredient(s) 0.005%-90% Filler 1%-99.9% Binder 0%-20% Disintegrant 0%-20% Lubricant 0%-10% Other specific excipient(s) 0%-50%

B) Dosage form for parenteral administration. Intravenous injection

Active ingredient(s) 0.001%-50% Solvent 10%-99.9% Co-solvent 0%-99.9% Osmotic agent 0%-50% Buffer How much do you need

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C) Another dosage form. Suppository

Active ingredient(s) 0.0003%-50% Suppository base 1%-99.9% Surfactants 0%-20% Lubricant 0%-20% Preservative How much do you need

Description of embodiments of the invention

The present invention is further illustrated by the following reference and working examples, which do not limit the scope of the present invention.

Reference examples.

Example 1. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone.

g 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin1-yl]ethanone hydrochloride salt prepared according to Example 11 of WO 2014/136075 was dissolved in 480 ml of dichloromethane at a temperature ranging from 0 to 5°C, and then added 168 ml of 1 M NaOH aqueous solution. After stirring for 10 minutes, the aqueous and organic phases were separated and the organic phase was washed twice with 120 ml of deionized water, dried over 25 g of sodium sulfate and filtered. The solution was concentrated under vacuum to an oil. Residue after evaporation: 32.8 g oil.

Example 2. 1 -[4-(4-{3-[(2R)-2-Methylpyrrolidin-1 -yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrochloride salt.

2.0 g (5.55 mmol) 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone was dissolved in 20 ml of acetone at room temperature. The mixture was cooled to a temperature ranging from 0 to 5°C, and 0.8 ml of hydrochloric acid solution with a concentration greater than or equal to 37% was added dropwise. After stirring for 30 minutes at a temperature ranging from 0 to 5°C, the crystals were isolated by filtration, covered with 1.5 ml of cold acetone and dried at room temperature. White crystalline material. Yield: 1.7 g.

Example 3. 1 -[4-(4-{3-[(2R)-2-Methylpyrrolidin-1 -yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrochloride salt.

0.548 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone was dissolved in 1.1 ml of isopropanol at room temperature. 0.391 g of a solution of hydrochloric acid in isopropanol with a concentration of 30% was added dropwise to the base solution at room temperature. The precipitated suspension was isolated by filtration and then dried for 2 hours under vacuum under nitrogen at 40°C. Yield: 0.42 g.

Example 4. 1 -[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monohydrochloride salt of form A.

11.831 mg of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrochloride salt was weighed into a platinum container and heat treated in a TA apparatus Instruments TGA Q50 until 1 mol HCl is removed according to the following program.

1. Heating to 90°C at a heating rate of 10°C/min.

2. Hold at 90°C for 103.7 minutes.

3. Heating to 95°C at a heating rate of 10°C/min.

4. Hold at 95°C for 12.9 minutes.

5. Heating to 100°C at a heating rate of 10°C/min.

6. Hold at 100°C for 180 minutes.

Example 5. 1 -[4-(4-{3-[(2R)-2-Methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone monohydrochloride salt of form A.

0.4 ml of an aqueous solution of sodium bicarbonate (97.5 mg NaHCO ₃ /1 ml H ₂ O) was added to 0.2 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidine-dihydrochloride salt 1 -yl] propoxy} phenoxy) piperidin-1 -yl] ethanone. When an equimolar amount of base is used, 1 mol of HCl is released during vigorous foaming of the solution. 1 ml of 1,4-dioxane was added to the solution and after evaporation an oil was obtained. 20 mg to 30 mg of oil was mixed with 0.5 ml of methyl ethyl ketone, filtered and precipitated with 0.5 ml of diisopropyl ether to obtain an oil. As a seed, the monohydrochloride salt of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone, obtained by heat treatment in Example 4, was introduced into the oil After crystallization, the product was isolated by filtration and dried at room temperature. Yield: 27 mg.

Example 6. 1 -[4-(4-{3-[(2R)-2-Methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1-yl]ethanone monohydrochloride salt of form A.

0.1 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrochloride salt was dissolved in 0.2 ml of deionized water and added 0.2 ml of an aqueous solution of sodium bicarbonate (97.5 mg NaHCO ₃ /1 ml H ₂ O). The resulting solution was concentrated at 50°C and 70 mbar, then dissolved in 5 ml of methyl ethyl ketone, filtered and washed with 1 ml of methyl ethyl ketone.

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11.5 ml of diisopropyl ether was added to the solution and the product from Example 4 was used as a seed, precipitation of an oily substance was observed. The solution was concentrated to dryness, the residue was dissolved in 1 ml of dimethylformamide, 15 ml of methyl tert-butyl ether was added and the product from Example 5 was used as a seed. The next day, the precipitated crystalline product was isolated by filtration. Yield: 25 mg.

Example 7. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monohydrochloride salt of form B.

2.0 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base was dissolved in 20 ml of acetone at room temperature. The mixture was cooled to a temperature ranging from 0 to 5°C, and 0.4 ml of hydrochloric acid solution with a concentration greater than or equal to 37% was added dropwise. After stirring for 30 minutes at a temperature ranging from 0 to 5°C, the mixture was concentrated to constant weight in a water bath at 40°C under vacuum. Then 30 ml of toluene were evaporated twice. White crystalline material. Yield: 1.5 g.

Example 8. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monohydrochloride salt of form B.

0.548 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base was dissolved in 0.55 ml of methyl tert-butyl ether at room temperature. Slowly, dropwise, 0.18 g of a 30% solution of hydrochloric acid in isopropanol was added dropwise to the base solution at room temperature. The initially two-phase mixture became miscible with stirring and then developed into a thick suspension of crystals. The precipitated suspension was isolated by filtration and dried for 2 hours under vacuum in a nitrogen atmosphere at 40°C. Yield: 0.33 g.

Working examples.

Example 9. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrobromide salt.

0.53 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base was dissolved in 5 ml of ethyl acetate at room temperature, after adding the solution acetic acid saturated with 0.8 ml of hydrobromic acid, a salt was formed. After isolation by filtration, it was washed twice with 1 ml of acetic acid, saturated hydrobromic acid. The mass of the dried product was 0.65 g.

Example 10. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]nropoxy}phenoxy)piperidin-1-yl]ethanone sulfate salt.

0.1 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base oil was dissolved in 9 ml of acetone at room temperature and then slowly , 0.125 ml of a 20.4% H ₂ SO ₄ solution was added dropwise. The resulting solution initially became opalescent, then a crystalline suspension was obtained, which was stirred at room temperature for 2 hours. The product was isolated by filtration and washed twice with 0.5 ml of acetone. It was dried under vacuum at 40°C for 2 hours under a nitrogen atmosphere. Yield: 0.08 g.

Example 11. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]nropoxy}phenoxy)piperidin-1-yl]ethanone sulfate salt.

0.99 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base oil was dissolved in 20 ml of acetone, then 1.3 ml of 18.4% H2SO4 solution. The product from example 10 (with the addition of 0.05 ml of water) was added to the mixture as a seed. The product was precipitated with 20 ml of acetone, stirred for half an hour, isolated by filtration, washed and dried at 40°C under nitrogen. Yield: 0.814 g. Melting point of product (based on DSC peak): 79.5°C.

Example 12. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]nropoxy}phenoxy)piperidin-1-yl]ethanone sulfate salt.

1.008 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base oil was mixed with 0.935 ml of 3M H ₂ SO ₄ solution and stirred in for 15 minutes. 20 ml of acetone was added and the product from Example 11 was used as a seed, after which it was stirred at room temperature overnight. The product was isolated by filtration and dried at 40°C under nitrogen to constant weight. Yield: 0.895 g. Melting point of product (based on DSC peak): 79.3°C.

Example 13. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]nropoxy}phenoxy)piperidin-1-yl]ethanone oxalate salt.

0.1 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base oil was dissolved in 0.1 ml of acetone at room temperature and added a solution of 0.055 g of oxalic acid in 0.5 ml of acetone. The product was precipitated with 0.3 ml of ethyl acetate. The product was isolated by filtration and then dried under nitrogen to constant weight. Yield: 128 mg. Product melting point (based on DSC peak): 54.2°C.

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Example 14. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone oxalate salt.

0.5 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base oil was dissolved in 0.5 ml of acetone and then the solution was added 0.275 g of oxalic acid in 1.5 ml of acetone and 0.05 ml of water. The precipitated material was isolated by filtration and then stirred in a mixture of 0.05 ml of water and 2.75 ml of acetone in the presence of 0.1755 g of oxalic acid. The resulting product was isolated by filtration and dried. Yield: 392 mg.

Example 15. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt of form A.

To 0.13 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin1-yl]ethanone base oil was added 0.081 g of citric acid monohydrate at room temperature and stirring. Add 0.5 ml of acetone and stir overnight. The next day, after adding another 1 ml of acetone, the mixture was stirred for an additional 30 minutes, then filtered and washed with 0.5 ml of acetone. The resulting sample was dried under vacuum in a nitrogen atmosphere at 25°C. Yield: 0.163 g.

Example 16. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt of form A.

To 0.513 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin1-yl]ethanone base oil was added a solution of 0.315 g of citric acid monohydrate in 5 ml of acetone at room temperature and stirring. The product from Example 15 was added to the solution as a seed. After stirring for two hours, another 2 ml of acetone was added and stirred over the weekend. The mixture was filtered and washed with 5 ml of acetone. The resulting crystalline material was dried under vacuum under a nitrogen atmosphere at 25°C. Yield: 0.63 g. Karl Fischer water content: 3.1%.

Example 17. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt of form A.

1.020 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base oil was weighed into a 100 ml reactor and stirred with 15 ml of acetone at room temperature. To this solution at room temperature was added 15 ml of citric acid monohydrate solution (0.872 g of citric acid monohydrate dissolved in 20 ml of acetone). Meanwhile, a suspension of the monocitrate salt obtained in Example 16 (0.0767 g, suspended in 0.5 ml of acetone) was added to the solution as a seed. The resulting suspension was stirred at room temperature for 1 hour, then the precipitated salt was isolated by filtration and washed with 10 ml of acetone. The resulting crystalline material was dried at 25°C under a nitrogen atmosphere. Yield: 1.385 g. Product melting point (DSC start): 114.3°C. Karl Fischer water content: 3.5%.

Example 18. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone monocitrate salt of form B.

The monocitrate salt of Form B from Example 17 was dried at a temperature ranging from 70 to 90° C. under a nitrogen atmosphere to constant weight.

Example 19. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate salt.

0.5 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone base oil was dissolved in 1 ml of acetone, then a solution of 0.962 g was added citric acid monohydrate in 4 ml of acetone. After stirring for 1 hour 15 minutes at reflux temperature, the mixture was cooled to room temperature, then filtered and washed with 10 ml of acetone. The resulting sample was dried overnight at 25°C under vacuum under a nitrogen atmosphere. Yield: 0.832 mg.

Example 20. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate salt.

1.928 g of citric acid monohydrate was added to a 100 ml reactor and dissolved in 15 ml of acetone at room temperature. To this solution was added a suspension in acetone (0.1039 g/0.5 ml) of the dicitrate salt obtained in Example 19. To this solution was added a solution of 15 ml of the base in acetone (1.695 g of the base oil 1-[4-(4-{ 3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin1-yl]ethanone, dissolved in 17.5 ml of acetone). The solution was stirred at room temperature for 1 hour, then the product was isolated by filtration and washed with 10 ml of acetone. The resulting sample was dried for 1 day at 25°C in a nitrogen atmosphere. Yield: 2.81 g. Product melting point (DSC start): 133.1°C. Karl Fischer water content: 0.4%.

Example 21. 1-[4-(4-{3-[(2R)-2-Methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate salt.

17.6 kg of dichloromethane were placed in the reactor, inerted with nitrogen and the temperature was set to 0 to 5°C. Added 1.1 kg of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrochloride and then added a mixture of 5.7 kg of purified water and 0.19 kg NaOH, while the temperature was maintained in the range from 0 to 5°C. After a reaction time ranging from 15 to 20 minutes, the organic phase was transferred to another reactor, which

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Claims (34)

was also inerted with nitrogen. 2200 ml of dichloromethane was added to the organic phase and after stirring for a period of time ranging from 30 to 40 minutes, the organic phase was again separated. The next step was repeated twice: 3300 ml of purified water was added to the organic phase and after stirring for a period of time ranging from 30 to 40 minutes, the organic phase was again separated. To the separated organic phase was added a solution of 0.66 kg NaCl in 2.6 L of purified water and after stirring for a period of time ranging from 30 to 40 minutes, the organic phase was again separated. The organic phase was concentrated under vacuum at a pressure of 0.5 bar, at a temperature not exceeding 35°C, to the maximum stirring volume (3 l to 4 l). The procedure was repeated three times, adding 8.8 kg of acetone and concentrating the liberated base under vacuum at a pressure of 0.7 bar and at a temperature not exceeding 45°C to the maximum stirring volume (3 L to 4 L). 1.1 kg of citric acid monohydrate was dissolved in 7.0 kg of acetone, maintaining the solution temperature in the range of 20 to 25°C. 5.0 g of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dicitrate seed crystals were added to the resulting citric acid solution. To the resulting solution was added a solution of concentrated base 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone in acetone for a period of time ranging from from 110 to 130 min, while the temperature was maintained in the range from 20 to 25°C. After addition, the mixture was heated to a temperature ranging from 55 to 60°C and stirred at this temperature for a period of time ranging from 10 to 12 minutes, after which it was cooled to a temperature ranging from 20 to 25° C, and stood for an additional 10 hours. At the end of the mixing period, the material was separated by centrifugation and dried. Yield: 1.398 kg. Product melting point (DSC start): 132.7°C. Example 22. 1 -[4-(4-{3-[(2R)-2-methylpyrrolidin-1 -yl]propoxy} phenoxy)piperidin-1 -yl]ethanone dicitrate salt. 70 g of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone dihydrochloride salt were weighed and dissolved in 840 ml of dichloromethane at a temperature in the range from 0 to 5°C, after which a solution of 11.9 g of NaOH in 350 ml of deionized water was added. After stirring for 15 minutes, the mixture was separated and the aqueous phase was transferred to 140 ml of dichloromethane. The combined organic phase was extracted twice with 210 ml of deionized water and then with 210 ml of brine. The solution was concentrated to an oil under vacuum (at a temperature not exceeding 35°C). The mixture was diluted three times with 700 ml of acetone and evaporated. The residue after evaporation was brought to 560 ml with acetone. A solution of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1yl]propoxy}phenoxy)piperidin-1-yl]ethanone in acetone was added to a solution of 64 g of citric acid anhydrate in 560 ml of acetone and 6 ml of water (at a temperature of 20 to 25°C) for two hours, maintaining the temperature in the range of 20 to 25°C. After stirring for 15 minutes at reflux, the suspension was cooled to room temperature and after further stirring for 2 hours, the precipitate was isolated by filtration, washed twice with 60 ml of acetone and dried at 50°C under vacuum. Yield: 101.6 g. Product melting point (DSC start): 132.6°C. CLAIM 1. Salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-ul]nronoxy}phenoxy)piperidin-1-yl]ethanone, characterized in that, based on the results of dynamic vapor sorption analysis (DVS) at 25°C it: a) demonstrates deliquescence only at relative humidity above 70%, that is, the critical relative humidity (CRH) value determined in the range from 10% relative humidity (RH) to 90% relative humidity (RH) according to the sorption curve, indicating the onset of deliquescence, equal to at least 70%; or b) does not demonstrate deliquescence, that is, it differs in the value of 0.5 > Am/ARH in the range from 10 to 90% RH along the sorption curve, and Ash=w2-w1, the difference between the quasi-equilibrium relative changes in mass m2 and w1, corresponding to the relative humidity values RH2 and RH1, and ARH=RH2-RH1=10, wherein the salt is selected from the group consisting of dihydrobromide salt, salts formed with sulfuric acid, oxalic acid and citric acid. 2. Salt according to claim 1, characterized in that the salt is a monocitrate salt. 3. Salt according to claim 2, characterized in that it is a monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form A, having characteristic reflections in its powder x-ray diffraction pattern, measured at the wavelength CuKa, presented in the range of scattering angles equal to 9.4; 11.1; 13.5; 18.0; 19.5; 19.8; 21.5 ± 0.2° 2θ. 4. Salt according to claim 2, characterized in that it is a monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form A, has - 20 045559 cabbage absorption bands in its infrared spectra, presented in ranges of values equal to 3466; 3011; 2962; 1731; 1618; 1594; 1507; 1217; 1043; 665 ± 4 cm ^-1 . 5. Salt according to claim 2, characterized in that it is a monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form A, having absorption bands in its Raman spectra presented in ranges of values equal to 3065; 2961; 2931; 1715; 1618; 1480; 1242; 1134; 859; 840; 722 ± 4 cm ^-1 . 6. Salt according to claim 2, characterized in that it is a monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form B, having characteristic reflections in its powder X-ray diffraction pattern, measured at wavelength CuKa, presented in the range of scattering angles equal to 9.5; 11.3; 13.4; 13.7; 14.0; 17.8; 19.1; 20.4; 22.3 ± 0.2° 2θ. 7. Salt according to claim 2, characterized in that it is a monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form B, having absorption bands in its infrared spectra presented in ranges of values equal to 2962; 2872; 1732; 1637; 1595; 1508; 1217; 1068; 1043; 818 ± 4 cm- ¹ . 8. Salt according to claim 2, characterized in that it is a monocitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form B, having absorption bands in its Raman spectra presented in ranges of values equal to 3086; 2930; 2881; 1718; 1628; 1476; 1251; 857; 718 ± 4 cm- ¹ . 9. Salt according to claim 1, characterized in that the salt is a dicitrate salt. 10. Salt according to claim 9, characterized in that it is a dicitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in a crystalline form having characteristic reflections in its powder X-ray diffraction pattern, measured at the wavelength CuKa, presented in the range of scattering angles equal to 10.2; 12.0; 12.8; 14.1; 19.0; 19.3; 20.5; 22.8 ± 0.2° 2θ. 11. Salt according to claim 9, characterized in that it is a dicitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form having absorption bands in its infrared spectra presented in ranges of values equal to 3523; 3038; 2521; 1727; 1687; 1587; 1507; 1216; 782; 661 ± 4 cm- ¹ . 12. Salt according to claim 9, characterized in that it is a dicitrate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form having absorption bands in its Raman spectra presented in ranges of values equal to 3070; 2971; 2933; 1611; 1489; 936; 854; 782; 720; 660 ± 4 cm- ¹ . 13. Salt according to claim 1, characterized in that the salt is a dihydrobromide salt. 14. Salt according to claim 13, characterized in that it is a dihydrobromide salt of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form, having characteristic reflections in its powder X-ray diffraction pattern, measured at the wavelength CuKa, presented in the range of scattering angles equal to 5.6; 11.3; 16.4; 16.7; 17.0; 24.7; 28.5 ± 0.2° 2θ. 15. Salt according to claim 13, characterized in that it is a dihydrobromide salt of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form, having absorption bands in its infrared spectra presented in ranges of values equal to 3419; 2930; 2614; 1685; 1616; 1508; 1232; 817 ± 4 cm- ¹ . 16. Salt according to claim 13, characterized in that it is a dihydrobromide salt of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form, having absorption bands in its Raman spectra presented in ranges of values equal to 3072; 3022; 3045; 2935; 1613; 1265; 1164; 852 ±4 cm- ¹ . 17. Salt according to claim 1, characterized in that the salt is a sulfate salt. 18. The salt according to claim 17, characterized in that it is a sulfate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in a crystalline form having characteristic reflections in its powder X-ray diffraction pattern, measured at the wavelength CuKa, presented in the range of scattering angles equal to 7.8; 11.7; 15.6; 18.0; 18.5; 19.6; 19.9; 22.9 ± 0.2° 2θ. 19. The salt according to claim 17, characterized in that it is a sulfate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form having absorption bands in its infrared spectra presented in ranges of values equal to 3389; 2955; 2615; 2513; 1590; 1507; 1220; 1044; 855; 591 ± 4 cm- ¹ . 20. The salt according to claim 17, characterized in that it is a sulfate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form having absorption bands in its Raman spectra presented in ranges of values equal to 3076; 3059; 2935; 1613; 1584; 1453; 1257; 1053; 854; 723 ± 4 cm- ¹ . - 21 045559 21. Salt according to claim 1, characterized in that the salt is an oxalate salt. 22. The salt according to claim 21, characterized in that it is an oxalate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in a crystalline form having characteristic reflections in its powder X-ray diffraction pattern, measured at wavelength CuKa, presented in the range of scattering angles equal to 8.5; 14.8; 15.4; 16.5; 17.4; 20.8; 22.5 ± 0.2° 2θ. 23. The salt according to claim 21, characterized in that it is an oxalate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form having absorption bands in its infrared spectra presented in ranges of values equal to 3431; 2513; 1987; 1706; 1693; 1507; 1220; 832; 722 ± 4 cm ^-1 . 24. The salt according to claim 21, characterized in that it is an oxalate salt of 1-[4-(4-{3-[(2R)-2methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone in crystalline form having absorption bands in its Raman spectra presented in ranges of values equal to 3077; 2935; 2883; 1611; 1477; 1443; 858; 842; 725 ± 4 cm ^-1 . 25. A method for producing a salt according to any one of claims 1 to 24, characterized in that the base is 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidine-1- yl]ethanone is dissolved in a suitable solvent or mixture of solvents, after which an acid or its salt formed with a base weaker than 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl) is added ]propoxy}phenoxy)piperidin-1yl]ethanone, or a solution thereof to a mixture; then either increase the concentration of the reaction mixture or do not increase it; the product that precipitates at room temperature or after cooling is isolated by filtration. 26. A method for producing a salt according to any one of claims 1 to 24, characterized in that the base is 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidine-1- yl]ethanone is dissolved in a suitable solvent or mixture of solvents, after which an acid or its salt formed with a base weaker than 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl) is added ]propoxy}phenoxy)piperidin-1yl]ethanone, or a solution thereof to a mixture; the salt is then crystallized using a suitable antisolvent added to the resulting solution at room temperature or after cooling, and the precipitated product is isolated by filtration. 27. The method according to claim 25, characterized in that the salt is a monocitrate or dicitrate salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidine-1 -yl]ethanone according to claims 2-12, and: (i) dissolution of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin1-yl]ethanone base is carried out in acetone and (ii) crystallization of the citrate salt is carried out by adding a solution of citric acid in acetone to a solution of the base in acetone. 28. The method according to claim 25, characterized in that the salt is a monocitrate or dicitrate salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidine-1 -yl]ethanone according to claims 2-12, and: (i) dissolution of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin1-yl]ethanone base is carried out in acetone and (ii) crystallization of the citrate salt is carried out by adding a solution of the base in acetone to a solution of citric acid in acetone. 29. The method according to claim 25, characterized in that the salt is a dicitrate salt of 1-[4-(4-{3[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl] ethanon according to claims 9-12, and: (i) starting with the dihydrochloride salt of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone, release the base and evaporate the solution after replacement solvent for acetone; and (ii) crystallization of the dicitrate salt is accomplished by adding a solution of the base in acetone to a solution of citric acid in acetone. 30. Use of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone salt according to any one of claims 1 to 31 for treatment and/or prevention of conditions requiring modulation of histamine H3 receptors. 31. Use of 1-[4-(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1yl]ethanone salt according to any one of claims 1 to 24 for the production of a pharmaceutical composition. 32. Pharmaceutical composition containing a therapeutically effective amount of 1-[4(4-{3-[(2R)-2-methylpyrrolidin-1-yl]propoxy}phenoxy)piperidin-1-yl]ethanone salt according to any one of claims 1 -24 together with one or more pharmaceutically acceptable excipients. 33. Use of a pharmaceutical composition according to claim 32 for the treatment and/or prevention of conditions requiring modulation of histamine H3 receptors. 34. Use of a pharmaceutical composition according to claim 32 for the treatment and/or prevention of autism spectrum disorder. -