WO2018011611A1 - Salts for the production of pharmaceutical preparations - Google Patents

Salts for the production of pharmaceutical preparations Download PDF

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Publication number
WO2018011611A1
WO2018011611A1 PCT/HU2017/050028 HU2017050028W WO2018011611A1 WO 2018011611 A1 WO2018011611 A1 WO 2018011611A1 HU 2017050028 W HU2017050028 W HU 2017050028W WO 2018011611 A1 WO2018011611 A1 WO 2018011611A1
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WO
WIPO (PCT)
Prior art keywords
value
encenicline
salt
general formula
mesylate
Prior art date
Application number
PCT/HU2017/050028
Other languages
French (fr)
Inventor
László Pongó
Ádám Dezső DETRICH
Balázs VOLK
András DANCSÓ
Mária TÓTHNÉ LAURITZ
László SZLÁVIK
Katalin KÁTAINÉ FADGYAS
Zoltán VARGA
Éva SZABÓ
Péter SLÉGEL
Original Assignee
Egis Gyógyszergyár Zrt.
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Filing date
Publication date
Application filed by Egis Gyógyszergyár Zrt. filed Critical Egis Gyógyszergyár Zrt.
Publication of WO2018011611A1 publication Critical patent/WO2018011611A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D453/00—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids
    • C07D453/02—Heterocyclic compounds containing quinuclidine or iso-quinuclidine ring systems, e.g. quinine alkaloids containing not further condensed quinuclidine ring systems

Definitions

  • the object of our invention relates to the use of the general formula (I) acid addition salts of encenicline for the production of pharmaceutical preparations primarily suitable for the treatment of diseases involving cognitive disorder (schizophrenia, Alzheimer's disease).
  • the object of our invention relates to novel encenicline salts of general formula (I) suitable for being the active ingredient of pharmaceutical preparations for treating diseases involving cognitive disorder (schizophrenia, Alzheimer's disease), a method for their production, the amorphous and crystalline, as well as the hydrous and anhydrous forms and solvates of the salts according to the invention, pharmaceutical preparations containing the salts according to the invention and their therapeutic use.
  • the encenicline salts according to the invention may be produced at a high level of purity, they have great chemical stability, good water solubility and favourably low hygroscopicity, therefore they have especially favourable properties from the point of view of pharmaceutical technology.
  • the objective was to create a crystalline form of encenicline that can be reproducibly produced at industrial scales, that has a greater degree of purity, better stability and water-solubility than the encenicline base and that is less hygroscopic than the forms according to the state of the art, which, as a result of the above properties, is more suitable than the base for use in pharmaceutical preparations from the point of view of medicine formulation.
  • Figure 1 The x-ray powder diffractogram of the encenicline mesylate salt (1 :1 ) "Form I"
  • Figure 2 The water sorption isotherm of the encenicline mesylate salt (1 :1 ) "Form I” at 25 °C
  • Figure 5 The x-ray powder diffractogram of the encenicline mesylate salt (1 :1 ) monohydrate
  • Figure 7 The x-ray powder diffractogram of the hydrate of the encenicline sulphate salt (2:1 :4)
  • Figure 9 The x-ray powder diffractogram of the hydrate of the encenicline sulphate salt (2:1 :6)
  • Figure 10 The water sorption isotherm of the hydrate of the encenicline sulphate salt (2: 1 :6) at 25 °C
  • Figure 1 1 The x-ray powder diffractogram of the sesquihydrate of encenicline hydrogen bromide salt (1 :1 )
  • Figures 15-16 A comparison of the water sorption isotherms of the encenicline salt forms (25 °C)
  • X represents the acid ion of a monobasic or dibasic inorganic or organic acid
  • n 1 or 2
  • m 1 or 2
  • the value of k is 1 , 1 .5, 4 or 6,
  • X in the formula (I) encenicline salts according to the invention is preferably a bromide, sulphate, besylate or mesylate ion.
  • a further object of the invention relates to the general formula (I) salts of encenicline (I), in which
  • X represents mesylate, the value of n is 1 , the value of m is 1 , the value of k is 1 , or
  • X represents sulphate, the value of n is 2, the value of m is 2, the value of k is 4, or
  • X represents besylate, the value of n is 1 , the value of m is 1 , the value of k is 0.
  • the active substances of varying polymorphic form are significantly differentiated by the position of the x-ray powder diffraction peaks.
  • the appearance or disappearance of peaks, and changes to the peak positions indicate any solid phase transformation of the individual forms during storage.
  • the relative intensity of the peaks significantly depends on the sample preparation method used, the measurement conditions, and on the crystallite size and crystal habit.
  • X-ray tube Type Empyrean long fine focussing, high resolution tube
  • Diffusion inhibitor slit Fixed slit 1 /2 °
  • Diffusion inhibitor slit Programmable slit in fixed mode: 1 /2
  • Anode heating current 40 imA
  • Step duration 109.650 seconds
  • Carrier gas flow rate 200 imL/min
  • the object of the invention relates to the encenicline methanesulphonic acid (1 :1 ) salt, which may be produced both in anhydrous and hydrous crystalline form.
  • the anhydrous, crystalline encenicline mesylate (1 :1 ) salt according to the invention where the value of n is 1 , the value of m is 1 , the value of k is 0, may be produced in two crystalline forms.
  • the first crystalline form the Form I crystalline, anhydrous encenicline mesylate (1 :1 ) salt, where the value of n is 1 , the value of m is 1 the value of k is 0, has the following characteristic x-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 15.66; 19.53; 24.26. More specifically the form may be characterised by the following x-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 14.48; 15.66; 16.40; 17.09; 19.53; 20.00; 23.42; 24.26
  • the water sorption isotherm of the encenicline mesylate salt (1 :1 ) "Form I" recorded at 25 °C is presented in figure 2.
  • the crystalline form absorbed some 4.3% water above relative humidity (RH) of 60%.
  • the object of the invention also relates to the general formula (I) crystalline, anhydrous encenicline mesylate salt (1 :1 ) "Form II", where the value of n is 1 , the value of m is 1 , the value of k is 0, and its characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.71 ; 7.67; 9.78; 17.10.
  • the crystalline, anhydrous Form II encenicline mesylate (1 :1 ) salt may be characterised by the following x-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 5.71 ; 7.67; 9.78; 10.22; 14.52; 15.86; 17.10; 19.65; 24.77.
  • the characteristic x-ray powder diffractogram of the form can be seen in figure 3, and the 1 % or greater intensity signals are summarised in table 3.
  • the object of the invention also relates to the crystalline encenicline mesylate salt (1 :1 ) monohydrate, where the value of n is 1 , the value of m is 1 , the value of k is 1 , and its characteristic x-ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.43; 14.81 ; 17.17; 19.94; 23.46.
  • the further characterising of the crystalline encenicline mesylate salt (1 :1 ) monohydrate takes place with consideration to the following x-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.43; 14.81 ; 15.45; 17.17; 18.06; 19.94; 23.46; 24.98; 27.30.
  • the water sorption isotherm of the encenicline mesylate salt (1 :1 ) monohydrate recorded at 25 °C is presented in figure 6.
  • the substance surprisingly displays water absorption under 0.05% in the entire 0-95% RH range, therefore taking measurement uncertainty into consideration water absorption cannot be practically shown.
  • the results also show that the substance does not give up its crystalwater at 25 °C, even under extremely dry conditions.
  • the object of the invention also relates to the encenicline crystalline sulphate salts hydrated to various degrees, in which the value of n is 2, the value of m is 2 and the value of k is 4 or 6.
  • the object of the invention also relates to the crystalline encenicline sulphate salt hexahydrate (2:1 :6), where the value of n is 2, the value of m is 2, and the value of k is 6, and its characteristic x-ay powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.47; 12.73; 16.28; 17.60; 22.47. Further characterisation may be performed with the following x-ray powder diffraction peaks: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 4.47; 12.22; 12.73; 13.30; 16.28; 17.60; 18.82; 20.57; 22.47; 25.57.
  • the characteristic x-ray powder diffractogam of the form is presented in figure 9, and the 2% or greater intensity signals are summarised in table 6.
  • the object of the invention also relates to the salt of encenicline formed with hydrogen bromide (1 :1 ).
  • encenicline hydrogen bromide salt according to the invention may be produced as crystalline encenicline hydrogen bromide salt (1 :1 ) sesquihydrate, where the value of n is 1 , the value of m is 1 , and the value of k is 1 .5, and its characteristic x- ray powder diffraction peaks are the following: 2 ⁇ ( ⁇ 0.2 °2 ⁇ ): 14.32; 20.92; 23.92; 28.38.
  • Table 7 The x-ray powder diffraction data of encenicline hydrogen bromide salt (1:1) sesquihydrate (relative intensities
  • the water sorption isotherm of the encenicline hydrogen bromide salt (1 :1 ) sesquihydrate recorded at 25 °C is presented in figure 12.
  • content of the substance depends on the humidity content of the environment.
  • the salt form gives up its crystalwater under dry conditions (completely under 5% RH) at 25 °C. Above 5% RH the water content varies between 4.5 and 8.2%.
  • the object of the invention also relates to the encenicline benzenesulfonic acid (1 :1 ) salt.
  • the object of the invention also relates to the crystalline encenicline besylate salt (1 :1 ) "Form I", where the value of n is 1 , the value of m is 1 , and the value of k is 0, and its characteristic x-ray powder diffractogram peaks are the following: 2 ⁇
  • the lower hygroscopicity experienced is also preferable from the point of view of stability and preparation formulation. It is especially surprising and unforeseeable that while the anhydrous form of encenicline mesylate and encenicline sulphate hexahydrate (2:2:6) take on a significant amount of water, encenicline mesylate monohydrate and encenicline sulphate tetrahydrate (2:2:4) differing only in terms of hydration and crystal form essentially do not display any propensity to take on water.
  • the object of the invention also relates to a method for the production of the encenicline salts of general formula (I), in which formula
  • X represents the acid ion of a monobasic or dibasic inorganic or organic acid
  • the value of k is 1 , 1 .5, 4 or 6,
  • n 1 or 2
  • m 1 or 2
  • any known method according to the state of the art may be used to isolate the salt that is suitable for separating the solid phase and the liquid, such as filtering or centrifuging.
  • Inorganic acids such as hydrogen bromide or sulphuric acid and organic acids such as methanesulphonic acid or benzenesulfonic acid may be used as the acid for salt formation.
  • the organic solvent used to carry out the reaction may be preferably alcohol, 1 -4 carbon atom ether, ester or dipolar aprotic solvent, especially preferably ethyl alcohol, methyl alcohol, 2-propanol, tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile or a mixture of these.
  • the amount of acid used for salt formation is preferably 0.4 to 3.0 mol equivalents calculated for the amount of encenicline.
  • a preferable procedure used when producing the encenicline mesylate monohydrate salt (1 :1 ) is that encenicline base is stirred in acetonitrile, water or in an alcohol-type solvent or in a mixture of these, most preferably in a mixture of acetonitrile and water, then methanesulphonic acid is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried.
  • the production of the crystalline, anhydrous encenicline mesylate (1 :1 ) salt is performed by stirring encenicline mesylate monohydrate (1 :1 ) salt suspended in an alcohol-type solvent, such as ethanol at room temperature and then by isolating the precipitated crystals.
  • the crystalline, anhydrous encenicline mesylate (1 :1 ) salt obtained has Form I morphology.
  • the anhydrous Form I encenicline mesylate (1 :1 ) salt is maintained at a temperature of 120-220 °C for 10 to 180 minutes.
  • a preferable procedure used when producing the encenicline sulphate hydrate salt (2:1 :4) is that a suspension of encenicline sulphate hydrate (2:1 :6) in acetonitrile or an alcohol-type solvent, most preferably in acetonitrile is heated to 80 °C, then a solution is obtained by adding water. The solution is further stirred at 50-60 °C, then acetonitrile is added. The precipitated crystalline product is stirred at 5-10 °C, then filtered, optionally washed, then dried.
  • a preferable procedure used when producing the encenicline sulphate hydrate salt (2:1 :6) is that encenicline base is stirred in acetonitrile, water or in an alcohol-type solvent or in a mixture of these, most preferably in a mixture of acetonitrile and water, then an aqueous sulphuric acid solution is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried.
  • a preferable procedure used when producing the encenicline hydrogen bromide sesquihydrate salt (1 :1 :1 .5) is that encenicline base is stirred in acetonitrile, ethyl acetate, an alcohol-type solvent or in a mixture of these, most preferably in a mixture of acetonitrile and ethyl acetate, then 48% hydrogen bromide is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried.
  • a preferable procedure used when producing the encenicline besylate salt (1 :1 ) is that encenicline base is stirred in acetonitrile, an alcohol-type solvent or in a mixture of these, most preferably in acetonitrile, then benzenesulfonic acid is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried.
  • the invention also relates to those pharmaceutical preparations and to the production of the pharmaceutical preparations the active substance of which contains the novel encenicline salts of formula (I), as well as to therapeutic procedures during which a therapeutically effective amount of the encenicline salt of general formula (I) is administered to persons in need of treatment to prevent or treat diseases involving cognitive disorder (schizophrenia, Alzheimer's disease).
  • the object of the invention also relates to pharmaceutical preparations containing the general formula (I) salts and one or more known of in themselves carriers or excipients.
  • the pharmaceutical preparation according to the invention usually contains 0.1 to 95 mass% active substance, preferably 1 to 50 mass% active substance and most preferably 5 to 30 mass% active substance.
  • the pharmaceutical preparations according to the invention may be administered orally (such as in the form of powders, tablets, coated tablets, capsules, microcapsules, dragees, solutions, suspension or emulsions), parenterally (such as in the form of an intravenous, intramuscular, subcutaneous or intraperitoneal injection preparation or in an infusion preparation), rectally (such as in the form of a suppository), transdermal ⁇ (such as in the form of patches), as an implant or locally (such as in the form of creams, lotions or patches).
  • the solid, soft or liquid form pharmaceutical preparations of the invention may be produced using methods known of in themselves according to the state of the art.
  • the orally administered, solid pharmaceutical preparations containing the compounds of general formula (I) as active substance may contain filler or carrier materials (such as lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binding materials (such as gelatine, sorbitol, polyvinylpyrrolidone), disintegrants (such as croscarmellose, sodium carboxymethyl cellulose, crospovidone), tableting excipients (such as magnesium stearate, talc, polyethylene glycol, silica, silicon dioxide) and surfactants (such as sodium lauryl sulphate).
  • filler or carrier materials such as lactose, glucose, starch, calcium phosphate, microcrystalline cellulose
  • binding materials such as gelatine, sorbitol, polyvinylpyrrolidone
  • disintegrants such as croscarmellose, sodium carboxymethyl cellulose, crospovidone
  • tableting excipients such as magnesium stearate, talc, polyethylene glycol,
  • Orally administered liquid pharmaceutical preparations containing the compounds of general formula (I) as active substance may be, for example, solutions, suspensions or emulsions, and may contain suspending agents (such as gelatine, carboxyemthyl cellulose), emulsifying agents (such as sorbitan monooleate), solvents (such as water, oils, glycerine, propylene glycol, ethanol), pH adjustment agents (such as acetate, phosphate, citrate buffers) and stabilising agents (such as methyl 4-hydroxybenzoate).
  • suspending agents such as gelatine, carboxyemthyl cellulose
  • emulsifying agents such as sorbitan monooleate
  • solvents such as water, oils, glycerine, propylene glycol, ethanol
  • pH adjustment agents such as acetate, phosphate, citrate buffers
  • stabilising agents such as methyl 4-hydroxybenzoate
  • Parenterally administered liquid pharmaceutically preparations containing the compounds of general formula (I) as active substance may be sterile isotonic solutions, which, apart from the solvent, may contain pH adjustment agents and preservatives.
  • the soft pharmaceutical preparations containing the compounds of general formula (I) as active substance such as suppositories, contain the active substance evenly distributed in the basic material of the suppository (such as in polyethylene glycol or cocoa butter).
  • the object of the invention also relates to the use of the compounds of general formula (I) for the production of pharmaceutical preparations.
  • the pharmaceutical preparations according to the invention containing the salts of general formula (I) may be produced using the procedures of pharmaceutical production technology known in themselves.
  • the active substance is mixed with solid or liquid pharmaceutical carrier and excipient materials and then placed into galenic form.
  • the carrier materials and excipients used in pharmaceutical production and the applicable procedures are disclosed in the literature (Remington's Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990).
  • the pharmaceutical preparations according to the invention containing the compounds of general formula (I) as active substance contain the active substance packaged per dose unit.
  • the object of the invention also relates to the use of the encenicline salts of general formula (I) for the production of pharmaceutical preparations primarily serving for the treatment of diseases involving cognitive disorder (schizophrenia, Alzheimer's disease), characterised by that the encenicline salts of general formula (I) are mixed with pharmaceutically suitable excipients and carrier materials, and then placed into galenic form.
  • the object of the invention also relates to the treatment of diseases involving cognitive disorder (schizophrenia, Alzheimer's disease), characterised by that a pharmaceutically effective amount of the encenicline salts of general formula (I) is administered to the person needing such treatment.
  • diseases involving cognitive disorder schizophrenia, Alzheimer's disease
  • a pharmaceutically effective amount of the encenicline salts of general formula (I) is administered to the person needing such treatment.
  • the melting points were measured using a Kofler Boetius device, and were given without correction.
  • reaction mixture is cooled to between 0 and +5 °C, then slowly, in portions 7.5 g (0.032 mol) 7-chloro-1 -benziothiophene-2-caboxylic acid chloride is added, after this addition the reaction mixture is stirred intensively at room temperature for 4 hours.
  • the A/,A/-dimethyformamide is evaporated in a vacuum, 5% potassium carbonate is added to the remaining oily product and then extraction is performed with ethyl acetate. The ethyl acetate part is dried on magnesium sulphate, and evaporated. The remaining oily product is dissolved in methyl tert-butyl ether and the precipitated crystalline product is filtered and dried.

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  • Health & Medical Sciences (AREA)
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Abstract

The object of the invention relates to the salts of encenicline formed with inorganic and organic acids of general formula (I), as well as to the use of these for the production of pharmaceutical preparations primarily suitable for the treatment of diseases involving cognitive disorder (schizophrenia, Alzheimer's disease).

Description

SALTS FOR THE PRODUCTION OF PHARMACEUTICAL
PREPARATIONS
The object of our invention relates to the use of the general formula (I) acid addition salts of encenicline for the production of pharmaceutical preparations primarily suitable for the treatment of diseases involving cognitive disorder (schizophrenia, Alzheimer's disease).
The formula (II) 7-chloro-A/-[3(H)-quinuclidinyl]-1 -benzothiophene-2-carboxamide (international non-proprietary name: encenicline) is a novel drug candidate with the effect of a selective a-7 nicotinic acetylcholine receptor (az-nAChR) partial agonist.
The object of our invention relates to novel encenicline salts of general formula (I) suitable for being the active ingredient of pharmaceutical preparations for treating diseases involving cognitive disorder (schizophrenia, Alzheimer's disease), a method for their production, the amorphous and crystalline, as well as the hydrous and anhydrous forms and solvates of the salts according to the invention, pharmaceutical preparations containing the salts according to the invention and their therapeutic use. The encenicline salts according to the invention may be produced at a high level of purity, they have great chemical stability, good water solubility and favourably low hygroscopicity, therefore they have especially favourable properties from the point of view of pharmaceutical technology.
The production of formula (II) 7-chloro-A/-[3(fl)-quinuclidinyl]-1 -benzothiophene-2- carboxamide, hereinafter encenicline or encenicline base, is disclosed by published international patent application number WO2003055878, which also provides teaching on the production of encenicline hydrochloride. Further method for the production of the encenicline base and hydrochloride salt is disclosed in published international patent application number WO2014051055. Three polymorphous forms of encenicline hydrochloride monohydrate salt (Form I, II and X), their x-ray powder diffraction analysis, stability and solubility were published in international patent application number WO 201 1 14651 1 . During our development work the objective was to create a crystalline form of encenicline that can be reproducibly produced at industrial scales, that has a greater degree of purity, better stability and water-solubility than the encenicline base and that is less hygroscopic than the forms according to the state of the art, which, as a result of the above properties, is more suitable than the base for use in pharmaceutical preparations from the point of view of medicine formulation.
The above objective was achieved in the way according to the invention by producing salts of encenicline with inorganic and organic acids.
Description of the figures
Figure 1 : The x-ray powder diffractogram of the encenicline mesylate salt (1 :1 ) "Form I" Figure 2: The water sorption isotherm of the encenicline mesylate salt (1 :1 ) "Form I" at 25 °C
Figure 3: The x-ray powder diffractogram of the encenicline mesylate salt (1 : 1 ) "Form II" Figure 4: The water sorption isotherm of the encenicline mesylate salt (1 : 1 ) "Form II" at 25 °C
Figure 5: The x-ray powder diffractogram of the encenicline mesylate salt (1 :1 ) monohydrate
Figure 6: The water sorption isotherm of the encenicline mesylate salt (1 :1 ) monohydrate at 25 °C
Figure 7: The x-ray powder diffractogram of the hydrate of the encenicline sulphate salt (2:1 :4)
Figure 8: The water sorption isotherm of the hydrate of the encenicline sulphate salt (2:1 :4) at 25 °C
Figure 9: The x-ray powder diffractogram of the hydrate of the encenicline sulphate salt (2:1 :6)
Figure 10: The water sorption isotherm of the hydrate of the encenicline sulphate salt (2: 1 :6) at 25 °C Figure 1 1 : The x-ray powder diffractogram of the sesquihydrate of encenicline hydrogen bromide salt (1 :1 )
Figure 12: The water sorption isotherm of the sesquihydrate of encenicline hydrogen bromide salt (1 : 1 ) at 25 °C
Figure 13: The x-ray powder diffractogram of the encenicline besylate salt (1 :1 ) "Form I" Figure 14: The water sorption isotherm of the encenicline besylate salt (1 : 1 ) "Form I" at 25 °C
Figures 15-16: A comparison of the water sorption isotherms of the encenicline salt forms (25 °C)
The object of our invention relates to the compounds of general formula (I), in which general formula
X represents the acid ion of a monobasic or dibasic inorganic or organic acid,
The value of n is 1 or 2,
The value of m is 1 or 2,
The value of k is 1 , 1 .5, 4 or 6,
as well as the amorphous and crystalline forms of these salts, and their hydrates and solvates. The meaning of X in the formula (I) encenicline salts according to the invention is preferably a bromide, sulphate, besylate or mesylate ion.
A further object of the invention relates to the general formula (I) salts of encenicline (I), in which
i) X represents mesylate, the value of n is 1 , the value of m is 1 , the value of k is 1 , or
X represents sulphate, the value of n is 2, the value of m is 2, the value of k is 4, or
iii) X represents besylate, the value of n is 1 , the value of m is 1 , the value of k is 0.
It was surprising to find that the novel salts produced have significantly greater, by 2 to 4 orders of magnitude, water solubility than the Form I morphology encenicline base, and their favourable water solubility makes it possible to use preferable pharmaceutical production technology. Table 1 summarises the water solubility measured at room temperature of the encenicline base form and of the novel salts according to the present invention. The solubility of the mesylate salt monohydrate according to the present application significantly even surpasses that of the hydrochloride monohydrate Form I known from the state of the art.
Table 1 The solubility of encenicline base and various salt forms
Figure imgf000006_0001
During the development of medicines the morphology of the active substance and morphological stability have to be carefully monitored. The active substances of varying polymorphic form are significantly differentiated by the position of the x-ray powder diffraction peaks. The appearance or disappearance of peaks, and changes to the peak positions indicate any solid phase transformation of the individual forms during storage. The relative intensity of the peaks significantly depends on the sample preparation method used, the measurement conditions, and on the crystallite size and crystal habit.
In the case of all the crystalline forms presented here the x-ray powder diffraction data of the novel encenicline salt forms (and their various hydrates) according to the invention were obtained under the following measurement conditions: Device: PANalytical Empyrean x-ray powder diffractometer
Measurement alignment: Transmission
X-ray tube Type: Empyrean long fine focussing, high resolution tube
Anode: Cu
Wavelength : Ka (1 .541874 A)
Focus: line focus
Source-side optical elements
Divergence slit: Fixed slit 1 /2 °
Mirror: Focussing elliptical mirror
Soller slit: 0.04 rad
Diffusion inhibitor slit: Fixed slit 1 /2 °
Diffracted side optical elements
Diffusion inhibitor slit: Programmable slit in fixed mode: 1 /2
Soller slit: 0.04 rad
Sample table
Type: Reflection-transmission, with rotatable sample holders
Sample rotation speed : 1 rotation/second
Direct beam catcher
("beam knife"): Transmission
Detector
Type: PIXcel 3D 1 *1 area detector
Operation mode: Scanning line detector (1 D) operation mode
Active detector window
size: 3.3473°
Sample preparation: samples placed between two Mylar sheets, without pulverising Measurement conditions
Temperature: room temperature
Accelerating voltage: 45 kV
Anode heating current: 40 imA
Scanning method: continuous (Θ/Θ) scanning
Measurement range: 2.0000 - 34.9964 °2Θ Step gap: 0.0131 °2Θ
Step duration: 109.650 seconds
No of measurement cycles: 1
Measurement duration: ~20 minutes
From the point of view of pharmaceutical industry development, the water absorption tendency of a substance, its hygroscopicity has great significance, which may influence formulation, stability and the constancy of the composition of the preparation . The water absorption tendency of the encenicline salts of general formula (I) according to the invention was examined under the following measurement conditions by recording water sorption isotherms:
SMS DVS Advantage DVSA1 -STD dynamic vapour sorption
Device:
analyser
Atmosphere: nitrogen
Carrier gas flow rate: 200 imL/min
Solvent: water
Temperature: 25 °C
Regulation: Control without feedback (Open Loop")
Step size: 5% RH
Stability criterion: 0.002%/min
Stabilisation time base: 5 min
Operation mode: DMDT Minimum stabilisation time: 30 min
Maximum duration of one
360 min
step:
Data saving frequency: 1 min
Measurement range: 0% RH→ 95% RH
The object of the invention relates to the encenicline methanesulphonic acid (1 :1 ) salt, which may be produced both in anhydrous and hydrous crystalline form. The anhydrous, crystalline encenicline mesylate (1 :1 ) salt according to the invention, where the value of n is 1 , the value of m is 1 , the value of k is 0, may be produced in two crystalline forms. The first crystalline form, the Form I crystalline, anhydrous encenicline mesylate (1 :1 ) salt, where the value of n is 1 , the value of m is 1 the value of k is 0, has the following characteristic x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 15.66; 19.53; 24.26. More specifically the form may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 14.48; 15.66; 16.40; 17.09; 19.53; 20.00; 23.42; 24.26
The characteristic x-ray powder diffractogram of the form can be seen in figure 1 , and the 2% or greater intensity signals are summarised in table 2.
Table 2 The x-ray powder diffraction data of the encenicline mesylate salt (1:1) "Form I
(relative intensities≥ 2%)
Figure imgf000009_0001
Relative intensity
Peak 2Θ (°) d (A)
(%)
15 22.59 3.94 13
16 22.94 3.88 8
17 23.06 3.86 5
18 23.42 3.80 34
19 23.90 3.72 3
20 24.26 3.67 93
21 25.47 3.50 29
22 25.58 3.48 18
23 26.08 3.42 2
24 26.29 3.39 3
25 26.85 3.32 5
26 27.05 3.30 10
27 27.18 3.28 13
28 28.82 3.10 13
29 29.14 3.06 26
30 29.40 3.04 12
31 31 .02 2.88 6
32 31 .65 2.83 2
33 32.36 2.77 2
34 32.84 2.73 7
35 33.05 2.71 9
36 33.46 2.68 5
37 34.74 2.58 12
The water sorption isotherm of the encenicline mesylate salt (1 :1 ) "Form I" recorded at 25 °C is presented in figure 2. The crystalline form absorbed some 4.3% water above relative humidity (RH) of 60%. The object of the invention also relates to the general formula (I) crystalline, anhydrous encenicline mesylate salt (1 :1 ) "Form II", where the value of n is 1 , the value of m is 1 , the value of k is 0, and its characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 5.71 ; 7.67; 9.78; 17.10. More specifically, the crystalline, anhydrous Form II encenicline mesylate (1 :1 ) salt may be characterised by the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 5.71 ; 7.67; 9.78; 10.22; 14.52; 15.86; 17.10; 19.65; 24.77. The characteristic x-ray powder diffractogram of the form can be seen in figure 3, and the 1 % or greater intensity signals are summarised in table 3.
Table 3 The x-ray powder diffraction data of the encenicline mesylate salt (1:1) "Form II"
(relative intensities≥ 1%)
Figure imgf000011_0001
Relative intensity
Peak 2Θ (°) d (A)
(%)
17 18.10 4.90 2
18 18.45 4.81 2
19 19.24 4.61 3
20 19.65 4.52 63
21 20.12 4.41 62
22 20.30 4.38 5
23 21 .40 4.15 5
24 21 .68 4.10 58
25 22.25 4.00 4
26 22.63 3.93 3
27 23.17 3.84 3
28 23.44 3.80 7
29 23.83 3.73 2
30 24.05 3.70 1
31 24.35 3.66 4
32 24.77 3.59 100
33 25.41 3.51 5
34 25.98 3.43 48
35 26.17 3.41 12
36 26.83 3.32 23
37 27.35 3.26 4
38 27.79 3.21 6
39 28.66 3.1 1 26
40 29.09 3.07 9
41 29.30 3.05 3
42 29.65 3.01 5 Relative intensity
Peak 2Θ (°) d (A)
(%)
43 30.32 2.95 5
44 30.59 2.92 8
45 31 .07 2.88 3
46 31 .38 2.85 3
47 31 .82 2.81 2
48 32.26 2.78 3
49 32.81 2.73 4
50 33.51 2.67 7
51 34.05 2.63 2
The water sorption isotherm of the encenicline mesylate salt (1 : 1 ) "Form II" recorded at 25 °C is presented in figure 4. The crystalline form absorbed 4.3% to 4.5% water above relative humidity (RH) of 65%.
The object of the invention also relates to the crystalline encenicline mesylate salt (1 :1 ) monohydrate, where the value of n is 1 , the value of m is 1 , the value of k is 1 , and its characteristic x-ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 4.43; 14.81 ; 17.17; 19.94; 23.46. The further characterising of the crystalline encenicline mesylate salt (1 :1 ) monohydrate takes place with consideration to the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 4.43; 14.81 ; 15.45; 17.17; 18.06; 19.94; 23.46; 24.98; 27.30.
In the following the diffraction angle (2Θ) values are listed that provide a relative intensity signal greater than 2% under the given measurement conditions of encenicline mesylate (1 :1 ) monohydrate according to the invention: 2Θ (±0.2 °2Θ): 4.43; 13.52; 13.68; 13.82; 14.64; 14.81 ; 15.18; 15.45; 16.91 ; 17.17; 17.71 ; 18.06; 19.94; 20.92; 21 .32; 22.30; 23.46; 23.72; 23.90; 24.98; 26.76; 27.30; 27.85; 28.05; 28.23; 28.92; 29.24; 29.59; 29.86; 31 .20; 31 .62; 32.06; 32.58; 32.88; 33.69; 34.22. The characteristic x-ray powder diffractogram of the form is presented in figure 5, and the 2% or greater intensity signals are summarised in table 4. Table 4 The x-ray powder diffraction data of encenicline mesylate salt (1:1) monohydrate (relative intensities≥ 2%)
Figure imgf000014_0001
Relative intensity
Peak 2Θ (°) d (A)
(%)
25 28.23 3.16 5
26 28.92 3.08 6
27 29.24 3.05 2
28 29.59 3.02 22
29 29.86 2.99 8
30 31 .20 2.86 1 1
31 31 .62 2.83 4
32 32.06 2.79 25
33 32.58 2.75 6
34 32.88 2.72 1 1
35 33.69 2.66 4
36 34.22 2.62 10
The water sorption isotherm of the encenicline mesylate salt (1 :1 ) monohydrate recorded at 25 °C is presented in figure 6. As opposed to the mesylate salts (1 :1 ) "Form I" and "Form II", the substance surprisingly displays water absorption under 0.05% in the entire 0-95% RH range, therefore taking measurement uncertainty into consideration water absorption cannot be practically shown. The results also show that the substance does not give up its crystalwater at 25 °C, even under extremely dry conditions. The object of the invention also relates to the encenicline crystalline sulphate salts hydrated to various degrees, in which the value of n is 2, the value of m is 2 and the value of k is 4 or 6.
The crystalline encenicline sulphate salt hydrate (2:1 :4) according to the invention, where the value of n is 2, the value of m is 2 and the value of k is 4, has the following characteristic x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 13.23; 15.67; 17.77; 24.10. Further characterisation may be performed with the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 13.23; 14.56; 15.67; 17.77; 18.76; 19.87; 20.82; 24.10; 25.95; 29.36.
In the following the diffraction angle (2Θ) values are listed that provide a relative intensity signal greater than 1 % under the given measurement conditions of encenicline sulphate tetrahydrate (2:1 :4) according to the invention: 2Θ (±0.2 °2Θ): 4.43; 13.23;
13.49; 14.56; 14.78; 15.67; 16.29; 16.77; 17.77; 18.76; 19.87; 20.82; 21 .07; 21 .90;
22.38; 23.68; 24.10; 24.28; 25.33; 25.49; 25.95; 26.35; 26.52; 27.27; 27.49; 28.07;
28.54; 29.36; 29.82; 30.18; 30.54; 31 .65; 32.10; 32.78; 33.07; 33.45; 33.68; 33.92;
34.54. The characteristic x-ray powder diffractogram of the form is presented in figure 7, and the 1 % or greater intensity signals are summarised in table 5.
Table 5 The x-ray powder diffraction data of encenicline sulphate salt hydrate (2:1:4)
(relative intensities≥ 1%)
Figure imgf000016_0001
Relative intensity
Peak 2Θ (°) d (A)
(%)
16 23.68 3.75 20
17 24.10 3.69 100
18 24.28 3.66 1 1
19 25.33 3.51 6
20 25.49 3.49 6
21 25.95 3.43 44
22 26.35 3.38 12
23 26.52 3.36 10
24 27.27 3.27 16
25 27.49 3.24 17
26 28.07 3.18 9
27 28.54 3.13 13
28 29.36 3.04 56
29 29.82 2.99 17
30 30.18 2.96 32
31 30.54 2.93 8
32 31 .65 2.83 20
33 32.10 2.79 1
34 32.78 2.73 15
35 33.07 2.71 6
36 33.45 2.68 1
37 33.68 2.66 4
38 33.92 2.64 3
39 34.54 2.59 4
The water sorption isotherm of the encenicline sulphate salt hydrate (2:1 :4) recorded at 25 °C is presented in figure 8. The substance displays unforeseen low water absorption in the 0-95% RH range of under 0.01 %. On the basis of the results it may be determined that the substance surprisingly does not give up its crystalwater at 25 °C even under extremely dry conditions. The object of the invention also relates to the crystalline encenicline sulphate salt hexahydrate (2:1 :6), where the value of n is 2, the value of m is 2, and the value of k is 6, and its characteristic x-ay powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 4.47; 12.73; 16.28; 17.60; 22.47. Further characterisation may be performed with the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 4.47; 12.22; 12.73; 13.30; 16.28; 17.60; 18.82; 20.57; 22.47; 25.57. The characteristic x-ray powder diffractogam of the form is presented in figure 9, and the 2% or greater intensity signals are summarised in table 6.
Table 6 The x-ray powder diffraction data of encenicline sulphate salt hydrate (2:1:6)
(relative intensities≥ 2%)
Figure imgf000018_0001
Relative intensity
Peak 2Θ (°) d (A)
(%)
14 17.60 5.04 46
15 17.98 4.93 2
16 18.82 4.71 19
17 19.06 4.65 4
18 19.65 4.52 5
19 20.57 4.32 15
20 21 .09 4.21 4
21 21 .91 4.05 19
22 22.07 4.02 5
23 22.47 3.95 50
24 22.91 3.88 15
25 23.10 3.85 4
26 23.55 3.77 5
27 23.86 3.73 10
28 24.04 3.70 3
29 24.69 3.60 20
30 25.57 3.48 41
31 26.03 3.42 5
32 26.17 3.40 4
33 26.78 3.33 4
34 27.30 3.26 6
35 27.87 3.20 1 1
36 28.22 3.16 5
37 28.42 3.14 4
38 28.75 3.10 3
39 28.93 3.08 6 Relative intensity
Peak 2Θ (°) d (A)
(%)
40 29.1 1 3.07 8
41 29.58 3.02 15
42 30.18 2.96 2
43 30.54 2.92 5
44 30.73 2.91 4
45 30.94 2.89 2
46 31 .1 1 2.87 3
47 31 .48 2.84 9
48 31 .93 2.80 4
49 32.40 2.76 2
50 32.89 2.72 13
51 33.43 2.68 5
52 33.86 2.65 13
53 34.50 2.60 9
54 34.76 2.58 24
The water sorption isotherm of the encenicline sulphate salt hydrate (2:1 :6) recorded at 25 °C is presented in figure 10. The substance gives up its crystalwater under ~20% RH at a temperature of 25 °C. Above 20% RH the water content is nearly a constant value of between 9.0 and 10.0%
The object of the invention also relates to the salt of encenicline formed with hydrogen bromide (1 :1 ). In crystalline form encenicline hydrogen bromide salt according to the invention may be produced as crystalline encenicline hydrogen bromide salt (1 :1 ) sesquihydrate, where the value of n is 1 , the value of m is 1 , and the value of k is 1 .5, and its characteristic x- ray powder diffraction peaks are the following: 2Θ (±0.2 °2Θ): 14.32; 20.92; 23.92; 28.38. Further characterisation may be performed with the following x-ray powder diffraction peaks: 2Θ (±0.2 °2Θ): 14.32; 15.48; 16.50; 18.24; 20.92; 23.92; 24.91 ; 26.52; 28.38. The characteristic x-ray powder diffractogram of the crystalline encenicline hydrogen bromide (1 :1 ) salt sesquihydrate is shown in figure 1 1 , any the 2% or greater intensity signals are summarised in table 7.
Table 7 The x-ray powder diffraction data of encenicline hydrogen bromide salt (1:1) sesquihydrate (relative intensities
Figure imgf000021_0001
Relative intensity
Peak 2Θ (°) d (A)
(%)
20 25.33 3.51 8
21 25.73 3.46 3
22 25.87 3.44 2
23 26.52 3.36 29
24 26.73 3.33 13
25 27.14 3.28 17
26 28.05 3.18 7
27 28.38 3.14 86
28 28.65 3.1 1 22
29 28.91 3.09 23
30 29.63 3.01 5
31 30.03 2.97 2
32 30.87 2.89 10
33 31 .25 2.86 8
34 31 .83 2.81 19
35 32.46 2.76 3
36 33.45 2.68 2
37 33.87 2.64 15
38 34.57 2.59 7
The water sorption isotherm of the encenicline hydrogen bromide salt (1 :1 ) sesquihydrate recorded at 25 °C is presented in figure 12. On the basis of the results it can be seen that content of the substance depends on the humidity content of the environment. The salt form gives up its crystalwater under dry conditions (completely under 5% RH) at 25 °C. Above 5% RH the water content varies between 4.5 and 8.2%. The object of the invention also relates to the encenicline benzenesulfonic acid (1 :1 ) salt.
More specifically the object of the invention also relates to the crystalline encenicline besylate salt (1 :1 ) "Form I", where the value of n is 1 , the value of m is 1 , and the value of k is 0, and its characteristic x-ray powder diffractogram peaks are the following: 2Θ
(±0.2 °2Θ): 6.55; 7.60; 19.88; 21 .60. More specifically it may be characterised by the following x-ray powder diffractogram peaks: 2Θ (±0.2 °2Θ): 6.55; 7.60; 13.74; 16.86;
19.04; 19.88; 21 .60; 27.95. More detailed characterisation of the crystalline Form I encenicline besylate (1 :1 ) salt may be performed with the following x-ray diffraction peaks: 2Θ (±0.2 °2Θ): 6.55; 7.60; 9.49; 1 1 .99; 13.1 1 ; 13.74; 14.82; 15.23; 15.37; 15.52;
15.87; 16.86; 17.82; 18.40; 19.04; 19.88; 20.39; 20.68; 20.93; 21 .60; 21 .98; 22.68;
23.67; 24.22; 24.57; 25.01 ; 25.22; 25.67; 25.88; 26.43; 26.94; 27.36; 27.95; 28.35;
29.09; 30.01 ; 30.59; 31 .18; 31 .85; 32.08; 32.38; 32.68; 33.09; 33.76; 34.32. The characteristic x-ray powder diffractogam of the form is presented in figure 13, and the
2% or greater intensity signals are summarised in table 8.
Table 8 The x-ray powder diffraction data of encenicline besylate salt (1:1) "Form I
(relative intensities≥ 2%)
Figure imgf000023_0001
Relative intensity
Peak 2Θ (°) d (A)
(%)
12 16.86 5.26 35
13 17.82 4.98 9
14 18.40 4.82 13
15 19.04 4.66 41
16 19.88 4.47 54
17 20.39 4.36 5
18 20.68 4.30 16
19 20.93 4.25 5
20 21 .60 4.1 1 100
21 21 .98 4.04 5
22 22.68 3.92 10
23 23.67 3.76 15
24 24.22 3.67 9
25 24.57 3.62 5
26 25.01 3.56 3
27 25.22 3.53 7
28 25.67 3.47 5
29 25.88 3.44 3
30 26.43 3.37 5
31 26.94 3.31 9
32 27.36 3.26 2
33 27.95 3.19 45
34 28.35 3.15 4
35 29.09 3.07 5
36 30.01 2.98 13
37 30.59 2.92 10 Relative intensity
Peak 2Θ (°) d (A)
(%)
38 31 .18 2.87 7
39 31 .85 2.81 2
40 32.08 2.79 2
41 32.38 2.77 3
42 32.68 2.74 2
43 33.09 2.71 4
44 33.76 2.66 2
45 34.32 2.61 2
The water sorption isotherm of encenicline besylate (1 :1 ) recorded at 25 °C is presented in figure 14. The water absorption of the substance in the 0-95% RH range is surprisingly low, under 0.15%.
The sorption characteristics of the novel encenicline salt forms disclosed were compared to those of the "Form I" and "Form II" forms of the encenicline hydrogen chloride salt (1 :1 ) monohydrate disclosed in the originator's patent application number WO 201 1 14651 1 (figures 15 to 16). According to that exhibited by the measurement results among the novel encenicline form, the mesylate salt monohydrate form, the sulphate salt hydrate (2:1 :4) form and the besylate salt "Form I" have unforeseen lower hygroscopicity throughout the entire examined range than that of the encenicline hydrogen chloride crystalline form ("Form I" and "Form II" monohydrate forms) disclosed by the originator. The lower hygroscopicity experienced is also preferable from the point of view of stability and preparation formulation. It is especially surprising and unforeseeable that while the anhydrous form of encenicline mesylate and encenicline sulphate hexahydrate (2:2:6) take on a significant amount of water, encenicline mesylate monohydrate and encenicline sulphate tetrahydrate (2:2:4) differing only in terms of hydration and crystal form essentially do not display any propensity to take on water. The object of the invention also relates to a method for the production of the encenicline salts of general formula (I), in which formula
X represents the acid ion of a monobasic or dibasic inorganic or organic acid,
The value of k is 1 , 1 .5, 4 or 6,
The value of n is 1 or 2,
The value of m is 1 or 2,
In such a way that the amorphous or crystalline, anhydrous or form with crystalwater or solvate of the formula (II) encenicline base is reacted with the desired organic or inorganic acid in a suitable organic solvent, water or a mixture of these, the encenicline salt formed is isolated, then, in a desired case, washed with an organic solvent or with a mixture of an organic solvent and water and dried.
Any known method according to the state of the art may be used to isolate the salt that is suitable for separating the solid phase and the liquid, such as filtering or centrifuging.
Inorganic acids such as hydrogen bromide or sulphuric acid and organic acids such as methanesulphonic acid or benzenesulfonic acid may be used as the acid for salt formation. The organic solvent used to carry out the reaction may be preferably alcohol, 1 -4 carbon atom ether, ester or dipolar aprotic solvent, especially preferably ethyl alcohol, methyl alcohol, 2-propanol, tetrahydrofuran, diethyl ether, ethyl acetate, acetonitrile or a mixture of these. The amount of acid used for salt formation is preferably 0.4 to 3.0 mol equivalents calculated for the amount of encenicline.
A preferable procedure used when producing the encenicline mesylate monohydrate salt (1 :1 ) is that encenicline base is stirred in acetonitrile, water or in an alcohol-type solvent or in a mixture of these, most preferably in a mixture of acetonitrile and water, then methanesulphonic acid is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried. The production of the crystalline, anhydrous encenicline mesylate (1 :1 ) salt is performed by stirring encenicline mesylate monohydrate (1 :1 ) salt suspended in an alcohol-type solvent, such as ethanol at room temperature and then by isolating the precipitated crystals. The crystalline, anhydrous encenicline mesylate (1 :1 ) salt obtained has Form I morphology. In order to produce Form II, the anhydrous Form I encenicline mesylate (1 :1 ) salt is maintained at a temperature of 120-220 °C for 10 to 180 minutes.
A preferable procedure used when producing the encenicline sulphate hydrate salt (2:1 :4) is that a suspension of encenicline sulphate hydrate (2:1 :6) in acetonitrile or an alcohol-type solvent, most preferably in acetonitrile is heated to 80 °C, then a solution is obtained by adding water. The solution is further stirred at 50-60 °C, then acetonitrile is added. The precipitated crystalline product is stirred at 5-10 °C, then filtered, optionally washed, then dried.
A preferable procedure used when producing the encenicline sulphate hydrate salt (2:1 :6) is that encenicline base is stirred in acetonitrile, water or in an alcohol-type solvent or in a mixture of these, most preferably in a mixture of acetonitrile and water, then an aqueous sulphuric acid solution is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried. A preferable procedure used when producing the encenicline hydrogen bromide sesquihydrate salt (1 :1 :1 .5) is that encenicline base is stirred in acetonitrile, ethyl acetate, an alcohol-type solvent or in a mixture of these, most preferably in a mixture of acetonitrile and ethyl acetate, then 48% hydrogen bromide is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried.
A preferable procedure used when producing the encenicline besylate salt (1 :1 ) is that encenicline base is stirred in acetonitrile, an alcohol-type solvent or in a mixture of these, most preferably in acetonitrile, then benzenesulfonic acid is added to the suspension at a temperature between 0 °C and boiling point of the solvent, preferably at a temperature between room temperature and 60 °C, most preferably at room temperature. If necessary the reaction mixture obtained is cooled to 5-25 °C, the precipitated crystals are filtered, optionally washed, then dried.
The invention also relates to those pharmaceutical preparations and to the production of the pharmaceutical preparations the active substance of which contains the novel encenicline salts of formula (I), as well as to therapeutic procedures during which a therapeutically effective amount of the encenicline salt of general formula (I) is administered to persons in need of treatment to prevent or treat diseases involving cognitive disorder (schizophrenia, Alzheimer's disease).
The object of the invention also relates to pharmaceutical preparations containing the general formula (I) salts and one or more known of in themselves carriers or excipients.
The pharmaceutical preparation according to the invention usually contains 0.1 to 95 mass% active substance, preferably 1 to 50 mass% active substance and most preferably 5 to 30 mass% active substance.
The pharmaceutical preparations according to the invention may be administered orally (such as in the form of powders, tablets, coated tablets, capsules, microcapsules, dragees, solutions, suspension or emulsions), parenterally (such as in the form of an intravenous, intramuscular, subcutaneous or intraperitoneal injection preparation or in an infusion preparation), rectally (such as in the form of a suppository), transdermal^ (such as in the form of patches), as an implant or locally (such as in the form of creams, lotions or patches). The solid, soft or liquid form pharmaceutical preparations of the invention may be produced using methods known of in themselves according to the state of the art.
The orally administered, solid pharmaceutical preparations containing the compounds of general formula (I) as active substance may contain filler or carrier materials (such as lactose, glucose, starch, calcium phosphate, microcrystalline cellulose), binding materials (such as gelatine, sorbitol, polyvinylpyrrolidone), disintegrants (such as croscarmellose, sodium carboxymethyl cellulose, crospovidone), tableting excipients (such as magnesium stearate, talc, polyethylene glycol, silica, silicon dioxide) and surfactants (such as sodium lauryl sulphate).
Orally administered liquid pharmaceutical preparations containing the compounds of general formula (I) as active substance may be, for example, solutions, suspensions or emulsions, and may contain suspending agents (such as gelatine, carboxyemthyl cellulose), emulsifying agents (such as sorbitan monooleate), solvents (such as water, oils, glycerine, propylene glycol, ethanol), pH adjustment agents (such as acetate, phosphate, citrate buffers) and stabilising agents (such as methyl 4-hydroxybenzoate).
Parenterally administered liquid pharmaceutically preparations containing the compounds of general formula (I) as active substance may be sterile isotonic solutions, which, apart from the solvent, may contain pH adjustment agents and preservatives. The soft pharmaceutical preparations containing the compounds of general formula (I) as active substance, such as suppositories, contain the active substance evenly distributed in the basic material of the suppository (such as in polyethylene glycol or cocoa butter). The object of the invention also relates to the use of the compounds of general formula (I) for the production of pharmaceutical preparations.
The pharmaceutical preparations according to the invention containing the salts of general formula (I) may be produced using the procedures of pharmaceutical production technology known in themselves. The active substance is mixed with solid or liquid pharmaceutical carrier and excipient materials and then placed into galenic form. The carrier materials and excipients used in pharmaceutical production and the applicable procedures are disclosed in the literature (Remington's Pharmaceutical Sciences, Edition 18, Mack Publishing Co., Easton, USA, 1990).
The pharmaceutical preparations according to the invention containing the compounds of general formula (I) as active substance contain the active substance packaged per dose unit. The object of the invention also relates to the use of the encenicline salts of general formula (I) for the production of pharmaceutical preparations primarily serving for the treatment of diseases involving cognitive disorder (schizophrenia, Alzheimer's disease), characterised by that the encenicline salts of general formula (I) are mixed with pharmaceutically suitable excipients and carrier materials, and then placed into galenic form.
The object of the invention also relates to the treatment of diseases involving cognitive disorder (schizophrenia, Alzheimer's disease), characterised by that a pharmaceutically effective amount of the encenicline salts of general formula (I) is administered to the person needing such treatment.
The further details of the solution according to the invention are presented in the following examples without limiting the scope of protection of the invention to the mentioned examples in any way:
The melting points were measured using a Kofler Boetius device, and were given without correction.
Comparative example 1
The production of encenicline base "Form I"
[compound of general formula (II)] Using argon protective gas and a 250 ml multi-neck flask 6.5 g (0.032 mol) (R)-(+)-3- aminoquinuclidine dihydrochloride is suspended in 70 ml Ν,Ν-dimethyformamide, whilst performing water cooling 7.0 g (0.069 mol, 9.6 ml) triethylamine is added to the suspension and then the reaction mixture is stirred at room temperature for 30 minutes, then a further 3.5 g (0.035 mol, 4.8 ml) triethylamine and 0.40 g (3.3 mmol) N,N- dimethylaminopyridine are added. The reaction mixture is cooled to between 0 and +5 °C, then slowly, in portions 7.5 g (0.032 mol) 7-chloro-1 -benziothiophene-2-caboxylic acid chloride is added, after this addition the reaction mixture is stirred intensively at room temperature for 4 hours.
The A/,A/-dimethyformamide is evaporated in a vacuum, 5% potassium carbonate is added to the remaining oily product and then extraction is performed with ethyl acetate. The ethyl acetate part is dried on magnesium sulphate, and evaporated. The remaining oily product is dissolved in methyl tert-butyl ether and the precipitated crystalline product is filtered and dried.
In this way 8.9 g (86%) of the title product is obtained.
Melting point: 175 °C (DSC, onset)
Analysis calculated for the molecular formula C16H17CIN2OS (320.84):
Calculated C: 59.90% H: 5.34% CI: 11.05% N: 8.73% S: 9.99%
Measured C: 59.93% 1-1:5.31% CI: 11.03% N: 8.75% S: 9.90%
IR (cm1; KBr): 3290, 1614, 1537, 1454, 1198, 782
HNMR (DMSO, 400 MHz): 8.67 (d, J=6,8 Hz, 1H), 8.33 (s,1H), 7.97 (m, 1H), 7.60 (m, 1H), 7.50 (m, 1H), 3.96 (m, 1H), 3.13 (m, 1H), 2.89 (m, 1H), 2.68 (m, 4H), 1.88 (m, 1H), 1.82 (m, 1 H), 1.58 (m, 2H), 1.33 (m, 1 H)
CNMR (DMSO, 100 MHz): 161.32, 141.35, 140.87, 139.11, 126.86, 126.75, 125.88, 125.84, 124.45, 53.62, 47.74, 47.07, 46.57, 26.11, 25.84, 20.12
Example 1
The production of encenicline mesylate salt (1 :1) anhydrate Form I
[general formula compound (I), in which general formula X represents a mesylate anion, the value of n is 1 , the value of m is 1 , and the value of k is 0]
3.00 g (6.90 mmol) encenicline mesylate monohydrate is measured into an instrument providing intensive stirring, which then is suspended in 15 ml ethanol and then stirred for 7 days at room temperature. The crystalline product obtained is filtered and dried. In this way 2.35 g (81.8%) of the title product is obtained.
Melting point: 195-197 °C
Analysis calculated for the molecular formula C16H17CIN2OS■ CH3SO3H (416.94):
Calculated C: 48.97% H: 5.08% CI: 8.50% N: 6.72% S: 15.38%
Measured C: 48.86% H:5.14% CI: 8.41% N: 6.54% S: 15.54%
IR (cm"1; KBr): 3521, 3347, 3270, 2616, 1652, 1560, 1541, 1208, 1162, 1042
HNMR (DMSO, 400 MHz): 9.52 (b, 1H), 9.00 (bd, J=6.1 Hz, 1H), 8.35 (s, 1H), 7.99 (m, 1H), 7.62 (m, 1H), 7.52 (m, 1H), 4,34 (m, 1H), 3.72 (m, 1H), 3.37 (m), 3.25 (m), 2.38 (s, 3H), 2.22 (m, 2H), 2.14 (m, 1 H), 1.92 (m, 2H), 1.77 (m, 1 H) CNMR (DMSO, 100 MHz): 161 .62, 140,70, 140.25, 139.17, 126.99, 126.74, 126.60, 126.14, 124.56, 51 .16, 45.89, 45.39, 45.12, 24.39, 21 .60, 17.28
Example 2
The production of encenicline mesylate salt (1 :1 ) anhydrate Form II
[general formula compound (I), in which general formula X represents a mesylate anion, the value of n is 1 , the value of m is 1 , and the value of k is 0]
200 mg (0.48 mmol) of the product encenicline mesylate salt (1 :1 ) anhydrate Form I obtained in the previous example is heated in a drying pistol at 203 °C for 30 minutes. In this way 200 mg (100.0%) of the title product is obtained.
Melting point: 208-210 °C
Analysis calculated for the molecular formula C16H17CIN2OS ■ CH3SO3H (416.94):
Calculated C: 48.97% H: 5.08% CI: 8.50% N: 6.72% S: 15.38%
Measured C: 48.21 % H: 4.99% CI: 8.38% N: 6.19% S: 15.14%
IR (cm"1 ; KBr): 3521 , 3347, 3270, 2616, 1652, 1560, 1541 ,1208, 1 162, 1042
HNMR (DMSO, 400 MHz): 9.52 (b, 1 H), 9.00 (bd, J=6.1 Hz, 1 H), 8.35 (s, 1 H), 7.99 (m, 1 H), 7.62 (m, 1 H), 7.52 (m, 1 H), 4.34 (m, 1 H), 3.72 (m, 1 H), 3.37 (m), 3.25 (m), 2.38 (s, 3H), 2.22 (m, 2H), 2.14 (m, 1 H), 1 .92 (m, 2H), 1 .77 (m, 1 H)
CNMR (DMSO, 100 MHz): 161 .62, 140.70, 140.25, 139.17, 126.99, 126.74, 126.60, 126.14, 124.56, 51 .16, 45.89, 45.39, 45.12, 24.39, 21 .60, 17.28
Example 3
The production of encenicline mesylate monohydrate (1 :1 )
[general formula compound (I), in which general formula X represents a mesylate anion, the value of n is 1 , the value of m is 1 , and the value of k is 1 ]
1 .00 g (3.1 2 mmol) encenicline base is measured into an instrument providing intensive stirring, which is suspended in a mixture of 15 ml ethyl acetate and 1 ml acetonitrile. While performing iced water cooling 0.30 g (0.3 ml; 3.12 mmol) methanesulphonic acid is added to the suspension drop-by-drop. The precipitated suspension is stirred for a further one hour, then filtered and dried. In this way 1 .18 g (86.7%) of the title product is obtained.
Melting point: 127-130 °C
Analysis calculated for the molecular formula C16H17CIN2OS ■ CH3SO3H ■ H2O (434.95): Calculated C: 46.94% H: 5.33% CI: 8.15% N: 6.44% S: 14.74%
Measured C: 46.86% H: 5.24% CI: 8.18% N: 6.54% S: 14.84%
IR (cm 1 ; KBr): 3445, 3271 , 2615, 1645, 1561 , 1205, 1040
HNMR (DMSO, 400 MHz): 9.62 (b, 1 H), 9.06 (d, J=6.1 Hz, 1 H), 8.39 (s, 1 H), 7.98 (m, 1 H), 7.62 (m, 1 H), 7.52 (m, 1 H), 4.37 (m, 1 H), 3.52 (m, 1 H), 3.42 (m, 1 H), 3.28 (m, 4H), 2.44 (s, 3H), 2.23 (m, 1 H), 2.16 (m, 1 H), 1 .92 (m, 2H), 1 .77(m, 1 H)
CNMR (DMSO, 100 MHz): 161 .61 , 140.75, 140.29, 139.19, 126.98, 126.74, 126.65, 126.12, 124.57, 51 .00, 45.86, 45.39, 45.09, 39.94, 24.46, 21 .58, 17.27
Example 4
The production of encenicline sulphate hydrate (2:1 :4)
[general formula compound (I), in which general formula X represents a sulphate anion, the value of n is 2, the value of m is 2, and the value of k is 4]
2.0 g (4.77 mmol) encenicline sulphate hydrate (2:1 :6) is suspended in 20 ml acetonitrile in an instrument providing intensive stirring. The reaction mixture is heated to 72-78 °C, and 1 ml water is added to it drop-by-drop, and in this way a solution is obtained. The reaction mixture is cooled to 50-60 °C, stirred for 2 hours at 50-60 °C, then 30 ml acetonitrile is added. The precipitated crystalline product is stirred at 5-10 °C for a further 1 hour. It is then filtered, washed with acetonitrile and dried.
In this way 2.05 g (94.4%) of the title product is obtained.
Melting point: 187-191 °C Analysis calculated for the molecular formula C16H17CIN2OS ■ 1/2 H2SO4 ■ 2 H2O (405.91 ):
Calculated C: 47.34% H: 5.46% CI: 8.73% N: 6.90% S: 1 1 .85%
Measured C: 47.44% H: 5.47% CI: 8.62% N: 6.95% S: 1 1 .82% IR (cm 1 ; KBr): 3483, 3425, 3319, 2455, 1638, 1560, 1542 HNMR (DMSO, 400 MHz): 8.81 (b, 1 H), 8.32 (s, 1 H), 7.99 (m, 1 H), 7.62 (m, 1 H), 7.51 (m, 1 H), 4.13 (m, 1 H), 3.36 (b), 3.10 (m, 1 H), 2.95 (m, 4H), 2.06 (m, 1 H), 1 .97(m, 1 H), 1 .75 (m, 2H), 1 .54 (m, 1 H)
Example 5
The production of encenicline sulphate hydrate (2:1 :6)
[general formula compound (I), in which general formula X represents a sulphate anion, the value of n is 2, the value of m is 2, and the value of k is 6]
2.0 g (6.23 mmol) encenicline base is suspended in 30 ml acetonitrile in an instrument providing intensive stirring, then whilst performing cold water cooling 3.2 ml 2 M sulphuric acid is added to it drop-by-drop. The precipitated crystalline product is stirred for a further 1 hour at 5-10 °C. It is then filtered, washed with acetonitrile and dried. In this way 2.5 g (95.8%) of the title product is obtained.
Melting point: 197-199 °C
Analysis calculated for the molecular formula C16H17CIN2OS ■ 1/2 H2SO4
(423.93):
Calculated C: 45.29% H: 5.66% CI: 8.36% N: 6.60% S: 1 1 .34%
Measured C: 45.40% H: 5.44% CI: 8.46% N: 6.70% S: 1 1 .79%
IR (cm 1 ; KBr): 3479, 3400, 1635, 1559, 1543, 1453, 1202
HNMR (DMSO, 600 MHz): 9.61 (b, 1 H), 9.07 (d, J=6.1 Hz, 1 H), 8.44 (s, 1 H), 7.99 (m, 1 H), 7.63 (m, 1 H), 7.53 (m, 1 H), 4.35 (m, 1 H), 3.71 (m, 1 H), 3.42 (m, 1 H), 3.35 (m, 1 H), 3.27 (m, 3H), 2.24 (m, 1 H), 2.16 (m, 1 H), 1 .93 (m, 2H), 1 .77(m, 1 H)
CNMR (DMSO, 150 MHz): 161 .65, 140.70, 140.31 , 139.19, 127.06, 126.77, 126.74, 126.19, 124.61 , 50.96, 45.86, 45.37, 45.21 , 24.46, 21 .58, 17.35
Example 6
The production of encenicline hydrogen bromide sesquihydrate (1 :1 :1 .5)
[general formula compound (I), in which general formula X represents a bromide anion, the value of n is 1 , the value of m is 1 , and the value of k is 1 .5]
3.2 g (10.00 mmol) encenicline base is suspended in a mixture of 15 ml ethyl acetate and 5 ml acetonitrile in an instrument providing intensive stirring, then whilst cooling with cold water 1 .2 ml 48% hydrogen bromide (10.61 mmol) is added to it drop-by-drop. The precipitated crystalline product is stirred for a further 1 hour at 5-10 °C. This is then filtered, washed with acetonitrile and dried.
In this way 4.0 g (93.2%) of the title product is obtained.
Melting point: 172-175 °C
Analysis calculated for the molecular formula C16H17CIN2OS ■ HBr■ 1 .5 H2O (428.76): Calculated C: 44.82% H: 4.94% Br: 18.64% CI: 8.27% N: 6.53% S:
7.98%
Measured C: 44.89% 1-1: 4.96% Br: 19.21 % CI: 7.68% N: 6.62% S:
7.36%
IR (cm 1 ; KBr): 3486, 3399, 3307, 1635, 1559, 1544, 1452, 1202
HNMR (DMSO, 600 MHz): 9.60 (b, 1 H), 9.06 (d, J=6.1 Hz, 1 H), 8.44 (s, 1 H), 7.99 (m, 1 H), 7.63 (m, 1 H), 7.52 (m, 1 H), 4.35 (m, 1 H), 3.72 (m, 1 H), 3.2-3.5 (m), 2.24 (m, 1 H), 2.16 (m, 1 H), 1 .92 (m, 2H), 1 .77 (m, 1 H)
CNMR (DMSO, 150 MHz): 161 .65, 140.70, 140.31 , 139.19, 127.06, 126.77, 126.73, 126.19, 124.61 , 50.97, 45.87, 45.37, 45.21 , 24.46, 21 .58, 17.35
Example 7
The production of encenicline besylate salt (1 :1 )
[general formula compound (I), in which general formula X represents a besylate anion, the value of n is 1 , the value of m is 1 , and the value of k is 0]
5.0 g (15.58 mmol) encenicline base is suspended in 40 ml acetonitrile in an instrument providing intensive stirring, then whilst performing cold water cooling 2.5 ml (15.80 mmol) benzenesulfonic acid is added to it. The precipitated crystalline product is stirred for a further 1 hour at 5-10 °C. This is then filtered, washed with acetonitrile and dried. In this way 6.0 g (80.0%) of the product stated in the title is obtained.
Melting point: 222-224 °C
Analysis calculated for the molecular formula C16H17CIN2OS ■ CeHeOaS (479.01 ):
Calculated C: 53.17% H: 5.07% CI: 7.13% N: 5.64% S: 12.90%
Measured C: 53.65% H: 4.83% CI: 7.32% N: 5.86% S: 13.46% IR (cm"1; KBr): 3280, 3071, 1647, 1561, 1183, 1168, 1036, 1018, 612
HNMR (DMSO, 400 MHz): 9.42 (b, 1H), 8.92 (d, J=6.0 Hz, 1H), 8.32 (s, 1H), 7.96 (m, 1H), 7.62 (m, 3H), 7.51 (m, 1H), 7.32 (m, 3H), 4.33 (m, 1H), 3.72 (m, 1H), 3.37 (m, 1H), 3.35 (b), 3.25 (m, 4H), 2.22 (m, 1H), 2.14 (m, 1H), 1.92 (m, 2H), 1.76 (m, 1H)
CNMR (DMSO, 100 MHz): 161.64, 148.32, 140.66, 140.22, 139.17, 128.66, 127.85, 127.00, 126.74, 126.57, 126.15, 125.63, 124.55, 51.28, 45.92, 45.40, 45.13, 24.33, 21.59, 17.29

Claims

Claims:
The general formula (I) salts of encenicline, 7-chloro-A/-[3(fl)-quinuclidinyl]-1- benzothiophene-2-carboxamide, in which
X represents mesylate, the value of n is 1 , the value of m is 1 , the value of k is 1 , or X represents sulphate, the value of n is 2, the value of m is 2, the value of k is 4, or X represents besylate, the value of n is 1 , the value of m is 1 , the value of k is 0.
The encenicline mesylate salt (1:1) monohydrate of general formula (I) according to claim 1 , in which formula X represents a mesylate ion, the value of n is 1 , the value of m is 1 and the value of k is 1 , the characteristic x-ray powder diffraction peaks of which measured with a CUKQ x-ray beam are the following: 2Θ (±0.2 °2Θ): 4.43; 14.81; 17.17; 19.94; 23.46.
The salt according to claim 2, the x-ray diffractogram of which measured with a CUKQ x-ray beam contains the following reflections: 2Θ (±0.2 °2Θ): 4.43; 14.81; 15.45; 17.17; 18.06; 19.94; 23.46; 24.98; 27.30.
The salt according to claim 2, the x-ray diffractogram of which measured with a CUKQ x-ray beam contains the following reflections: 2Θ (±0.2 °2Θ): 4.43; 13.52; 13.68; 13.82; 14.64; 14.81; 15.18; 15.45; 16.91; 17.17; 17.71; 18.06; 19.94; 20.92; 21.32; 22.30; 23.46; 23.72; 23.90; 24.98; 26.76; 27.30; 27.85; 28.05; 28.23; 28.92; 29.24; 29.59; 29.86; 31.20; 31.62; 32.06; 32.58; 32.88; 33.69; 34.22.
The encenicline sulphate salt hydrate (2:1 :4) of general formula (I) according to claim 1, in which formula X represents a sulphate ion, the value of n is 2, the value of m is 2 and the value of k is 4, the characteristic x-ray powder diffraction peaks of which measured with a CUKQ x-ray beam are the following: 2Θ (±0.2 °2Θ): 13.23; 15.67; 17.77; 24.10.
The salt according to claim 5, the x-ray diffractogram of which measured with a CUKQ x-ray beam contains the following reflections 2Θ (±0.2 °2Θ): 13.23; 14.56; 15.67; 17.77; 18.76; 19.87; 20.82; 24.10; 25.95; 29.36.
7. The salt according to claim 5, the x-ray diffractogram of which measured with a CUKQ x-ray beam contains the following reflections 2Θ (±0.2 °2Θ): 4.43; 13.23; 13.49; 14.56; 14.78; 15.67; 16.29; 16.77; 17.77; 18.76; 19.87; 20.82; 21.07; 21.90; 22.38; 23.68; 24.10; 24.28; 25.33; 25.49; 25.95; 26.35; 26.52; 27.27; 27.49; 28.07; 28.54; 29.36; 29.82; 30.18; 30.54; 31.65; 32.10; 32.78; 33.07; 33.45; 33.68; 33.92; 34.54.
8. The encenicline besylate salt (1:1) of general formula (I) according to claim 1, in which formula X represents a besylate ion, the value of n is 1, the value of m is 1 and the value of k is 0, the characteristic x-ray powder diffraction peaks of which measured with a CUKQ x-ray beam are the following: 2Θ (±0.2 °2Θ): 6.55; 7.60; 19.88; 21.60.
9. The encenicline besylate salt (1 :1) according to claim 8, which may be characterised by the following x-ray powder diffraction peaks measured with a CUKQ x-ray beam 2Θ
(±0.2 °2Θ): 6.55; 7.60; 13.74; 16.86; 19.04; 19.88; 21.60; 27.95.
10. The encenicline besylate salt (1 :1) according to claim 8, which may be characterised by the following x-ray powder diffraction peaks measured with a CUKQ x-ray beam 2Θ (±0.2 °2Θ): 6.55; 7.60; 9.49; 11.99; 13.11; 13.74; 14.82; 15.23; 15.37; 15.52; 15.87; 16.86; 17.82; 18.40; 19.04; 19.88; 20.39; 20.68; 20.93; 21.60; 21.98; 22.68; 23.67; 24.22; 24.57; 25.01; 25.22; 25.67; 25.88; 26.43; 26.94; 27.36; 27.95; 28.35; 29.09; 30.01 ; 30.59; 31.18; 31.85; 32.08; 32.38; 32.68; 33.09; 33.76; 34.32. 11. Pharmaceutical preparations that contain the encenicline salt of general formula (I) according to any of claims 1 to 10, in which
X represents mesylate, the value of n is 1 , the value of m is 1 , the value of k is 1 , or X represents sulphate, the value of n is 2, the value of m is 2, the value of k is 4, or X represents besylate, the value of n is 1 , the value of m is 1 , the value of k is 0 and they contain excipients used in pharmaceutical preparations.
12. The encenicline salts of general formula (I) according to any of claims 1 to 10, in which X represents mesylate, the value of n is 1 , the value of m is 1 , the value of k is 1 , or X represents sulphate, the value of n is 2, the value of m is 2, the value of k is 4, or X represents besylate, the value of n is 1 , the value of m is 1 , the value of k is 0 for use in the treatment of diseases involving cognitive disorder, schizophrenia, Alzheimer's disease.
PCT/HU2017/050028 2016-07-14 2017-07-14 Salts for the production of pharmaceutical preparations WO2018011611A1 (en)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055878A1 (en) * 2001-12-27 2003-07-10 Bayer Healthcare Ag 2-heteroarylcarboxylic acid amides
WO2011146511A1 (en) * 2010-05-17 2011-11-24 Envivo Pharmaceuticals, Inc. A crystalline form of (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
CN105601629A (en) * 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2003055878A1 (en) * 2001-12-27 2003-07-10 Bayer Healthcare Ag 2-heteroarylcarboxylic acid amides
WO2011146511A1 (en) * 2010-05-17 2011-11-24 Envivo Pharmaceuticals, Inc. A crystalline form of (r)-7-chloro-n-(quinuclidin-3-yl)benzo[b]thiophene-2-carboxamide hydrochloride monohydrate
CN105601629A (en) * 2015-02-02 2016-05-25 苏州晶云药物科技有限公司 New crystal forms of (R)-7-chloro-N-(quinuclidinyl-3-yl)benzo[b]thienyl-2-formamide hydrochloride

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