Crystalline form of the sodium salt of 5-chloro-2-methoxy-n-(4 - methoxy-3 - methylenedioxyphenylacetone)ethyl) benzamide

 

The present invention relates to new crystalline forms of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone) ethyl) benzamide (benzamid I), processes for their preparation, their use and pharmaceutical preparations containing them. Benzamid I possess valuable pharmacological properties. It is suitable for the treatment of ischemic heart disease. 12 C. and 2 h.p. f-crystals.

The present invention relates to new crystalline forms of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, methods for their preparation, their use and pharmaceutical preparations containing them.

5-Chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide formula I

below in abbreviated form called "benzamid I described, for example, in U.S. patents 5574069 and 5776980 and relevant publications, for example, EP-A-612724, which are included here as a reference and the content of which is a specific part of the present disclosure. Benzamid I possess valuable pharmacological properties. It inhibits ATP-sensitive CT scan to take place, for example, in ischemic heart disease, without causing appreciable depolarization of the cell membrane-pancreatic cells and hypoglycemic action. Benzamid I and its physiologically tolerated salts are suitable as pharmaceutically active compounds for the prophylaxis and treatment of various painful conditions such as cardiac arrhythmias, such as ventricular fibrillation, ischemic heart disease or weakened contractility, or for the prevention of sudden cardiac death. Benzamid I and/or physiologically tolerated salts are preferably used for this purpose in the form of pharmaceutical compositions, which are especially designed in respect of their composition and form the introduction to achieve the desired therapeutic effect, in each case, for example, in the form of solid preparations such as tablets or capsules, or in the form of liquid preparations such as solutions for injection and infusion.

To obtain pharmaceutical drugs, it is often advantageous to use pharmaceutically active compound, which contains an acidic group or a basic group in the form of certain salts, which is included stability or in General, a more suitable set of properties. The use of certain salts, for example, may also have advantages in obtaining active compounds or pharmaceutical preparations or benefits in respect of compliance with regulatory requirements for medicines. In particular, to obtain solutions of pharmaceutically active compounds, especially solutions that the solvent contain only water or mostly water, it is often preferable to achieve adequate solubility of the use of pharmaceutically active compounds in the form of a suitable, physiologically tolerable salt.

The hydrogen atom on the nitrogen atom of the group of thiourea in benzamide I, which is associated with sulfonyloxy group, has a relatively high acidity. Benzamid I can form salts with bases, e.g. metal salts in which the hydrogen atom is replaced by ion monovalent metal or one equivalent of a polyvalent ion of metal and which can formally be represented by formula II

in which the cation M may be, for example, the cation is monovalent metal or one equivalent of a polyvalent cation of a metal, for example, ion Natr in the pharmaceutical compositions is sodium salt of the benzamide I, which can be formally represented by formula III.

Formula III, however, should not be understood in the sense that it shows in each case, for solid or dissolved sodium salts, the actual relative location of the sodium ion and an organic anion. The sodium ion may also be located in another position relative to the atoms in the anion, for example, it can be coordinated with the sulfur atom of the thiourea group. The sodium salt of the benzamide I can, for example, similarly represented by formula IV

which, however, in turn, should not be construed as meaning a single bond and a double bond, listed here are the actual bonding conditions, or it can be represented by the empirical formula C19H21ClN3NaO5S2.

Getting benzamide I carried out in accordance with the details presented in U.S. patent 5574069 and 5776980 and relevant publications, for example, EP-A-612724, deprotonation of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in an aprotic solvent, dimethylformamide, using sodium hydride is the first product, from the reaction mixture, is not described, and the sodium salt is also not characterized in more detail. Pouring the reaction mixture in chlorotoluron acid, sodium salt is transformed into a neutral sulfonylamino formula I, which are filtering. Itself sodium salt can be isolated from the reaction mixture described in the prior art, only with great difficulty. Salt clearly remains dissolved in the reaction mixture. It is impossible to besiege with the formation of filterable solids by cooling or by evaporation. When adding a non-polar solvents, such as, for example, diisopropyl ether, the reaction product precipitates as an oil, which is heavily polluted and not suitable for use in pharmaceutical compositions and may be suitable for use only after time-consuming cleaning operations. In addition, as described in the prior art method of obtaining sodium salt using sodium hydride and results in the release of gaseous hydrogen, which leads to the need for comprehensive precautionary measures in respect of equipment and safety measures for carrying out the process in a large industrial scale. The aim of the present ize method of obtaining sodium salt of the benzamide I in the form, suitable for pharmaceutical use.

Found that the sodium salt of the benzamide I can get in a solid crystalline form suitable for pharmaceutical use, the interaction of the benzamide I basic compounds of sodium, such as sodium hydroxide or sodium alcoholate. It was unexpectedly found that the solid crystalline sodium salt of the benzamide I can exist in several different crystalline modifications, i.e. polymorphic forms, which can be obtained specifically by regulating the reaction conditions and/or conditions of crystallization and which differ in their physico-chemical properties. So, these crystalline modifications differ, for example, their solubility, dissolution rate or behavior during pharmaceutical processing and allow you to get pharmaceutical drugs that have different profiles of properties, from single source connection. The present invention thus relates to a crystalline sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone-phenyl)ethyl)benzamide and, especially, individual polymorphic forms of crystalline sodium salt of 5-chloro-2-methoxy-N-(2-(4-methodology the Zico-chemical properties, mentioned below. The invention relates in particular to the crystal modification 1 (polymorphic form 1) sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram of x-ray diffraction using si K1-radiation:

strong x-ray reflection: 8,95;

medium strong x-ray reflection: 7,10, 11,35, 12,15, 15,40, 22,80, 23,00, 23,50;

crystal modification 2 (polymorphic form 2) sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram of x-ray diffraction using si K1-radiation:

strong x-ray reflection: 7,15, 11,10, 13,35, 13,80, 14,00, the 14.90, 18,95, 19,85, 21,60, 22,55, 23,90, 24,30, 25,45, 27,15, 28,25, 28,35, 28,95;

crystal modification 3 (polymorphic form 3) sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylaminomethyl-aminosulphonylphenyl)ethyl)benzamide, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram of x-ray diffraction using si K1-radiation:

strong x-ray reflection: 8,35, 11,75, 11,95, 13,70, 19,75, 20,90, 21,90, of 24.90, 26,40, 28,45;

medium strong x-ray reflection: 12,45, 15,80, 19,45, 21,40, 22,20, 23,00, to 25.15, 25,45, to 30.15.

crystalline modification 4 (polymorphic form 4) sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylaminomethyl-aminosulphonylphenyl)ethyl)benzamide, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram of x-ray diffraction using si K1-radiation:

strong x-ray reflection: 8,70, 8,95, 10,85, 12,20, 20,50, 21,30, 23,85;

medium strong x-ray reflection: 7,40, 10,45, 12,60, 15,65, 16,30, 17,75, 18,10, 19,20, 22,90, 24,60, 25,35, 25,60, 25,95. Reflection of x-rays, which have rounded the relative intensity of 50% or more of the intensity of the strongest reflection, defined here as a strong x-ray reflection and reflection of x-rays, which have rounded the relative intensity of 20% or more but less than 50%, the intensity of the strongest reflection, defined here as the medium strong x-ray reflection. Additional details related to the diagrams of x-ray diffraction, which may also serve to further characteristics of the crystal modifications 1, 2, 3 and 4, below. Chart x-ray diffraction obtained in these conditions is shown in figures 1-4 (Fig.1 is a diagram of diffraction of the crystal modification 1, Fig.2 is a graph of diffraction of the crystal modification 2, Fig.3 is a graph of diffraction of the crystal modification 3, Fig.4 is a graph of diffraction of the crystalline modification 4). In the figures, the angle of diffraction

2 Theta (

The present invention further relates to a method of obtaining sodium salt of the benzamide I, especially, the ways in which you can obtain crystalline sodium salt and, especially, crystal modifications 1, 2, 3 and 4 described above. Sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide usually get method, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide with the main connection of sodium in the presence of a solvent (or diluent) or a mixture of solvents. Regulation of the parameters of the way salt can be obtained in the desired crystalline form. Technical implementation of the reaction and product selection can be performed using standard procedures known to a person skilled in the field.

Suitable basic compounds are sodium to turn I benzamide sodium salt are, for example, sodium hydroxide and sodium alcoholate, especially sodium salt (C1-C4)-alkanols, such as sodium methoxide (sodium methylate), this is Riya, as sodium carbonate or sodium bicarbonate. Preferred basic compounds are sodium include sodium hydroxide, sodium methoxide and ethoxide sodium, especially sodium hydroxide. When turning the benzamide I in Sol may be two or more basic compounds of sodium, for example, sodium hydroxide, along with one or two of the compounds sodium methoxide and ethoxide sodium. Compounds of sodium, such as sodium hydroxide or sodium alcoholate, preferably used in equimolar amounts or in excess, based on benzamid I. In particular, it is preferable to use from about 1 to about 2 mol, very preferably from about 1 to about 1.5 mol, particularly preferably from about 1 to about 1.3 mol of sodium hydroxide and/or sodium alcoholate per mole benzamide I. Basic compounds of sodium can be used in solid form or in the form of solutions or suspensions.

The preferred solutions for the conversion of the benzamide I sodium salt are polar organic solvents such as alcohols, in particular (C1-C4)-alkanols, such as methanol, ethanol, n-propanol or isopropanol, ethers, such is La, amides, such as dimethylformamide or N-organic, and others, for example, dimethyl sulfoxide. You can also use a mixture of two or more solvents, in particular mixtures of two or more of the above solvents such as a mixture of two alcohols, such as mixtures of methanol and ethanol and mixtures of one or more alcohols with one or more ethers. In addition, can also be used as individual solvents, and a mixture of two or more solvents in the presence of water or in a mixture with water. Mixtures of two or more organic solvents or organic solvents and water may contain components in any desired proportions, and the quantitative ratio, preferably chosen such as to present a single-phase solvent mixture. Preferred solvents are methanol, ethanol, mixtures of methanol and ethanol, a mixture of methanol and water, a mixture of ethanol and water and mixtures of methanol, ethanol and water. The amount of solvent or mixture of solvents can be chosen so that the starting compound, i.e., benzamid I and the primary connection of sodium were dissolved, but the number may be selected such that one or both of the source connection ü benzamide I suddenly get a quantitatively and with high purity.

The interaction of the benzamide I with the main connection sodium can be performed in a wide temperature range. It preferably carried out at temperatures from about -10With up to approximately +100With, when working at atmospheric pressure, in particular, the use temperature of about -10C to the boiling point of the solvent or solvent mixture. It, in particular, is preferably carried out at temperatures from about -10With up to approximately +50(very preferably from approximately 0With up to approximately +35S, especially preferably approximately from +5With up to approximately +35C. Often, mainly when receiving sodium salts according to the invention to establish successive temperatures or temperature ranges, for example, by first dissolving benzamid I by heating to a higher temperature, then reduce the heat and add the primary connection sodium and later to lower the temperature even lower to highlight the sodium salt. The salt formation can similarly carry out the tenderly carried out at atmospheric pressure, that is, approximately at a pressure of 1 bar (105PA), but it can also be at a lower pressure, for example, in vacuum removal of solvent by distillation, or at higher pressures, for example, if you want the heating to temperatures above the boiling point of the solvent. It preferably carried out at a pressure from about 1 bar to about 5 bar, especially from about 1 bar to about 2.5 bar.

The transformation of the benzamide I in its sodium salt can be carried out in conventional equipment. On a large scale it is preferably carried out periodic manner in the usual mix vessels, for example, glass or glass-lined vessels or vessels made of stainless steel. First, you can enter benzamid I and then add the primary connection sodium or you can enter the main compound of sodium and then add benzamid I or both of the parent compound in the required amount, you can also enter simultaneously into the reaction vessel. Adding substances can be in the form of one or more portions or you can type continuously dosed way. The true interaction of the benzamide I with the main connection sodium is usually completely head is special in a relatively large scale, the mixture is preferably stirred under certain conditions for some time before allotment sodium salt, for example, from about 1 to about 30 hours.

Processing is preferably carried out by allocating the obtained solid crystalline sodium salt of the benzamide I by filtration or centrifugation. The sodium salt can be isolated from the solvent or mixture of solvents which provide interaction benzamide I with the main connection sodium, and at this temperature, at which conduct the interaction. Depending on the conditions under which conduct the interaction may, however, also mainly for obtaining high yield and high purity by first cooling the mixture to release sodium salt to a relatively low temperature, for example, to room temperature or approximately 0With, and/or to remove part of the solvent by distillation at atmospheric pressure or in vacuum, and/or add one or more additional solvents, such as alcohol or a simple ester, in which the sodium salt is relatively poorly soluble. Selected sodium salt can then wash and dry as usual and, if necessary, to further purify, for example, by recrystallization.

The present invention relates, the company is definitely the regulation of one or more parameters of the reaction, for example, using the choice of solvent and/or the temperature at which conduct the interaction of the benzamide I with the main compound of sodium and/or crystallization of the sodium salt, in particular receive crystal modifications 1, 2, 3 or 4 described above sodium salt. If not specified differently, the above information about the conditions of education of salt accordingly acceptable to the methods described below.

The invention thus relates to a method of obtaining crystalline modification 1 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone) ethyl)benzamide, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide with the main connection of sodium in a mixture of methanol and ethanol or a mixture of methanol, ethanol and water and treated at a temperature of from about -10With up to about 15+40C. the process is preferably carried out at temperatures from about 0With up to approximately +35S, especially preferably from about +20With up to approximately +30

The present invention relates to crystal modification 1 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which is obtained by the method of the crystalline modification described above, especially using methods and reaction conditions, e.g. temperature and quantitative relationships that are specified in the following example 3.

The invention further relates to a method for producing a crystalline modification of 2 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl) benzamide, which includes vzaimodeistvie sodium in methanol or mixtures of methanol and water and heated to a temperature of about +40With or higher, for example, to a temperature of approximately +40With up to approximately +80C. the Mixture is preferably heated in this way to a temperature of approximately +40With up to approximately +70S, particularly preferably to a temperature of from about +50With up to approximately +70C. the heating Time depends on the method chosen in the individual case and in General is from about 4 to about 30 hours, preferably from about 4 to about 20 hours. If necessary, it can be determined by analysis of the sodium salt, which is isolated from the sample taken to determine, ended is the formation of crystalline modification of 2. As illustrated above to obtain the sodium salt of the benzamide I may be preferable when conducting this method, as well as other described methods to consistently set a number of different temperatures. For example, this method of obtaining a crystalline modification of 2 benzamid I and the primary connection sodium can be mixed together at a relatively low temperature, for example PR isC, then the mixture can be heated, as indicated, and, finally, a lower temperature can be set again to highlight the sodium salt, for example, a temperature from about 0With up to approximately +10C. the Main connection sodium used for the conversion of the benzamide I in sodium salt, is preferably sodium hydroxide. If the interaction is carried out in a mixture of methanol and water, the quantitative proportions of the individual solvents contained in the solution or suspension of the first source substances contained in the solution or suspension of the second educt are variable quantities. If the interaction is carried out in a mixture of methanol and water, in General, methanol and water, is preferably used in a ratio of from about 0.001 to about 0.1 volume part of water to 1 volume parts of methanol, particularly preferably in the ratio of about 0.005 to about 0.05 volume parts of water to 1 volume parts of methanol, for example approximately from 0.002 volume parts of water to 1 volume parts of methanol to obtain a mixture of solvents which provide interaction benzamide I with the main connection nxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which is obtained by the method described above for obtaining this crystalline modification, especially with the help of methods and reaction conditions, e.g. temperature and quantitative ratios that are specified in the following example 7.

The invention further relates to a method of obtaining crystalline modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl) benzamide, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl) benzamide with the main connection of sodium in methanol, in a mixture of methanol and water, tetrahydrofuran, dimethylformamide, in N-organic or dimethylsulfoxide, or in a mixture of methanol and one or more solvents of tetrahydrofuran, dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, and the processing at temperatures from about -10With up to approximately +40C. This method is preferably carried out at a temperature from about 0With up to approximately +35S, especially preferably from about +20With up to approximately +is Riya preferably represents a sodium hydroxide or (C1-C4-sodium alkoxide, particularly preferably sodium hydroxide, sodium methoxide or ethoxide sodium, in particular sodium hydroxide. Preferred solvents are methanol and a mixture of methanol and water, in particular methanol.

If the reaction is carried out in a mixture of solvents such as methanol and water, methanol and N-methylpyrrolidone, methanol and tetrahydrofuran or methanol and dimethyl sulfoxide, the quantitative proportions of the individual solvents contained in the solution or suspension of the first source substances contained in the solution or suspension of the second educt are variable quantities. If the interaction is carried out in a mixture of methanol and water, in General, methanol and water, is preferably used in a ratio of from about 0.001 to about 0.1 volume part of water to 1 volume parts of methanol, particularly preferably about 0.005 to about 0.05 volume part 1 volume parts of methanol, for example approximately 0,02 volume parts of water to 1 volume parts of methanol, to obtain a mixture of solvents which provide interaction benzamide I with the main connection of sodium. If the interaction is carried out in a mixture of from about 0.05 to about 1 volume part of the N-methylpyrrolidone to 1 volume parts of methanol, especially preferably from about 0.1 to about 0.5 volume parts of N-methylpyrrolidone to 1 volume parts of methanol, for example, about 0.4 volumetric parts of N-methylpyrrolidone to 1 volume parts of methanol, to obtain a mixture of solvents which provide interaction benzamide I with the main connection of sodium. If the interaction is carried out in a mixture of methanol and tetrahydrofuran, methanol and tetrahydrofuran, preferably used in a ratio of from about 5 to about 40 parts by volume of tetrahydrofuran to 1 volume parts of methanol, particularly preferably from about 10 to about 30 parts by volume of tetrahydrofuran to 1 volume parts of methanol, for example about 20 parts by volume of tetrahydrofuran to 1 volume parts of methanol, to obtain a mixture of solvents which provide interaction benzamide I with the main connection sodium.

As illustrated above, to obtain the sodium salt of the benzamide I, may be preferred when carrying out this method, as well as other described methods, further adding one or more additional solvents to the mixture for separation of sodium silanol or diisopropyl ether can be added to the mixture or the mixture can in dosed quantities to enter into the solvent, such as, for example, ethanol, and the ethanol, isopropanol or isopropyl ether is a variable value. If the interaction of the benzamide I with the main connection sodium is carried out in methanol or mixtures of methanol and water, as an additional solvent, which should be added to highlight the sodium salt, it is preferable to use ethanol. When selecting the sodium salt of this type from a mixture of methanol and ethanol or methanol, water and ethanol, the ethanol is preferably used in a ratio of from about 0.5 to about 10 parts by volume of ethanol to 1 volume parts of methanol, particularly preferably in a ratio of from about 1 to about 5 parts by volume of ethanol to 1 volume parts of methanol. In this method of obtaining a crystal modification 3 the selection of the product is preferably carried out without addition of additional solvent.

The present invention relates to crystal modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which is obtained by the method of the crystalline modification described above, particularly with use of methods of the data samples below 1, 2, 4, 5, and 11.

The invention further relates to a method of obtaining crystalline modification 4 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl) benzamide, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone) ethyl)benzamide with the main connection sodium in ethanol or mixtures of ethanol and water and processing at temperatures from about -10With up to approximately +40C. This method is preferably carried out at temperatures from about 0With up to approximately +35S, especially preferably from about +20With up to approximately +30C. the Main connection sodium used for the conversion of the benzamide I in sodium salt, preferably is sodium hydroxide. If the interaction is carried out in a mixture of ethanol and water, the quantitative proportions of the individual solvents contained in the solution or suspension of the first source substances contained in the solution or suspension of the second educt are variable quantities. is the wearing of from about 0.001 to about 0.1 volume part of water to 1 volume parts of ethanol, especially preferably about 0.005 to about 0.05 volume parts of water to 1 volume parts of ethanol, for example approximately 0,02 volume parts of water to 1 volume parts of ethanol to obtain a mixture of solvents which provide interaction benzamide I with the main connection sodium.

The present invention relates to a crystalline modification 4 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which is obtained by the method described above for obtaining this crystalline modification, especially with the use of methods and reaction conditions, e.g. temperature and quantitative relationships that are specified in the following example 6.

In addition, the invention relates to the ways in which different crystalline modifications of the sodium salt of the benzamide I can be transformed into each other, for example, the conversion of one crystalline modification to another crystal modification in a solvent or mixture of solvents establishing a certain temperature, if appropriate with addition of auxiliary substances such as, for example, a dispersant or the seed crystals crystalchemistry technique to obtain sodium salt of the benzamide I benzamide I. For example, the conversion of one crystalline modification to another crystal modification can also be carried out at atmospheric pressure or can be carried out at elevated pressure in resistant high pressure reactor, for example at pressures from about 1 bar to about 5 bars or selection of product can be performed by filtration or centrifugation, if necessary, after removing part of the solvent by distillation and/or adding one or more additional solvents and/or after cooling.

The invention thus relates to a method for producing a crystalline modification of 2 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone) ethyl)benzamide, which involves the heating of the crystal modification 1 or crystalline modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide to a temperature of approximately +40With or higher, for example up to a temperature of approximately +40With up to approximately +80C, in methanol or mixtures of methanol and water. The transformation is preferably 32D/chr/176.gif">With up to approximately +70S, particularly preferably to a temperature of from about +50With up to approximately +70C. the heating Time depends on the method chosen in the individual case. In General, for complete conversion of the heating is conducted for about 4 to about 30 hours, preferably from about 4 to about 20 hours, particularly preferably from about 5 to about 10 hours. If necessary, this can be determined by analysis of the sodium salt, which is isolated from the sample taken, to establish whether there has been already fully transform into the crystalline modification of 2. If the interaction is carried out in a mixture of methanol and water, the quantitative proportions of the individual solvents are variable quantities. If the interaction is carried out in a mixture of methanol and water, water is preferably used in a ratio of from about 0.001 to about 0.1 volume part of water to 1 volume parts of methanol, particularly preferably in the ratio of about 0.005 to about 0.05 volume part 1 volume parts of methanol.

The present invention relates that wltnylfj)ethyl)benzamide, which is obtained from crystalline or crystalline modification 1 modification 3 described above, especially using the reaction conditions, such as temperature or quantitative ratios that are specified in the following examples 8 and 9.

The invention relates to a method for producing crystalline modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which involves the heating of the crystalline modification 4 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylamino-carboalumination)ethyl)benzamide to a temperature of approximately +75With or higher, for example, to a temperature of from about +75With up to approximately +100With, in ethanol or mixtures of ethanol and water. The transformation is preferably carried out in ethanol. The transformation is preferably carried out by heating to a temperature from about +75With up to approximately +95S, especially preferably, to a temperature of approximately +85With up to approximately +95With, in particular to a temperature of +85

The present invention relates to crystal modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which is obtained from the crystalline modification 4 described above, especially using the reaction conditions, such as temperature or quantitative ratios that are specified in Prikazi can also be carried out in situ, that is, the sodium salt of the benzamide I can first get to a certain crystalline modification of the benzamide I and the compound of sodium is one of the methods described above, and this crystalline modification can then be turned into another crystal modification, without selection, one of the described ways of transformation.

Benzamid I, which is required as starting material for the method described above to obtain its sodium salt by interaction with the main connection sodium, can be derived from commercially available compounds, for example, by methods described in U.S. patent 5574069 and 5776980 and relevant publications, for example EP-A-612724. In accordance with these methods, for example, 2-(4-methoxyphenyl)ethylamine first acelerou in pyridine 5-chloro-2-methoxybenzylamine to obtain 5-chloro-2-methoxy-N-(2-(4-methoxyphenyl)ethyl)benzamide, this compound is converted into 5-chloro-2-methoxy-N-(2-(4-methoxy-3-chlorosulfonylphenyl)ethyl)benzamide introduction in cold chlorosulfonic acid, sulphonylchloride converted into 5-chloro-2-methoxy-N-(2-(4-methoxy-3-aminosulphonylphenyl) ethyl) benzamide the action of ammonia in a mixture of water/acetone, sulfonamide expose the first interaction is treated by the introduction of water chlorotoluron acid. In more detail this method is described in U.S. patent 5574069 and 5776980 and relevant publications, for example, EP-A-612724, which are included here as a reference and the relevant portions of which are part of the present description. Benzamid I, which is used upon receipt of the form of sodium salt according to the invention can be used directly in the form in which it is received when it is received, or it can first be washed, for example, a solvent and/or dried, or processed in another way. Mostly, you can do without drying benzamide I, it can be used in raw form to obtain the sodium salt, especially if the solvent still contained is the same solvent in which you spend getting the sodium salt according to the invention.

Pharmacological properties of the crystalline sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide and crystal modifications 1, 2, 3 and 4 and their potential use for therapy and prevention of violations, if substances are present in the target organ or target cells in the dissolved form, do not depend on the initial form solids and, thus, correspond pharmacologists Like benzamido I and its physiologically tolerable salts, in General, its sodium salt in crystalline modifications 1, 2, 3 and 4 exactly blocks the ATP-sensitive potassium channels in the cells of the heart muscle in a deficit of ATP, for example, that takes place in the cells of the heart muscle ischemia (ATP = adenosine triphosphate). The opening of ATP-sensitive potassium channels, due to reduced levels of ATP leads to a reduction in the potential duration of action and is considered to be one of the reasons the so-called arrhythmia type of circulation of excitation, which can lead to sudden cardiac death. By using a crystalline modifications of the sodium salt of the benzamide I according to the invention it is a dangerous opening of potassium channels can be prevented. The effect of crystal modifications 1, 2, 3 and 4 can be investigated, for example, in pharmacological models that are described in the U.S. patents 5574069 and 5776980 and relevant publications, for example, EP-A-612724, which are included here as a reference and the relevant portions of which are part of the present invention.

Crystalline modifications of the sodium salt of the benzamide I according to the invention with their antifibrillatory action are, therefore, valuable as a pharmaceutical for the treatment and priest and especially, for the prevention of sudden cardiac death due to arrhythmia. Examples of arrhythmic heart disease are supraventricular arrhythmias, e.g. atrial tachycardia, atrial flutter or paroxysmal supraventricular fibrillation or ventricular arrhythmias, such as ventricular premature beats, but especially life-threatening ventricular paroxysmal tachycardia and especially dangerous ventricular fibrillation. They are particularly suitable in those cases in which arrhythmias are the result of narrowing of the coronary vessel, which, for example, occurs when there is angina or during an acute heart attack or is a chronic result of a heart attack. They are therefore, in General, are suitable for use in ischaemic heart disease and are particularly suitable for posleinfarctne patients to prevent sudden cardiac death. Other syndromes in which the arrhythmia and/or sudden cardiac death due to arrhythmia play a role are, for example, heart failure or cardiac hypertrophy in the result of chronically high blood pressure.

Chrome is the effect on the reduced contractility of the heart. In this context, the gradual associated with the disease decrease cardiac contractility may be relevant, for example, heart failure and in acute cases, such as heart damage in case of shock. In the same way, with the introduction of crystalline modifications of the sodium salt of the benzamide I according to the invention during a heart transplant heart can resume its functional throughput faster and more reliably after the surgery. The same modification is used for heart operations that require temporary stopping of cardiac activity solutions for cardioplegia. Crystalline modifications of the sodium salt of the benzamide I according to the invention can also be used to protect the organs of the donor before and during removal, for the protection of removed organs, for example, during processing or during storage in the bath in physiological fluids and during migration in the body of the recipient. The crystalline modification according to the invention can, moreover, be used for the treatment and prevention of vagusnye dysfunction.

Crystalline modifications of the sodium salt of the benzamide I according to the invention can thus be used for animals, the other pharmaceutical agent or in the form of pharmaceutical preparations (or pharmaceutical compositions). The present invention therefore also relates to the crystalline sodium salt of the benzamide I according to the invention and the crystalline modifications of the sodium salt of the benzamide I according to the invention for use as pharmaceuticals, their use for the inhibition of ATP-sensitive potassium channels and, especially, their use in therapy and prophylaxis of the abovementioned syndromes, as well as their use as medications. In addition, the present invention relates to pharmaceutical compositions which contain as active ingredient, an effective dose of the crystalline sodium salt of the benzamide I, especially the sodium salt of the benzamide I in the form of one or several crystal modifications 1, 2, 3 and 4 according to the invention and a pharmaceutically tolerable carrier, i.e. one or more fillers and/or excipients. These pharmaceutical compositions contain, for example, the sodium salt of the benzamide I in crystal modifications 1 and a pharmaceutically tolerable carrier or the sodium salt of the benzamide I in crystalline modification of 2 and a pharmaceutically tolerable carrier, or the sodium salt of the benzamide I in crystalline modification 3 and farmacisti portable media or, for example, two crystalline modification according to the invention, such as modifications 1 and 2, or modifications 1 and 3, or modifications 1 and 4, or modifications 2 and 3, or modifications 2 and 4, or modifications 3 and 4, in each case together with a pharmaceutically tolerable carrier.

The pharmaceutical preparations generally contain, for example, from about 0.2 to about 800 mg, preferably from about 1 to about 400 mg of crystalline modifications of the sodium salt of the benzamide I according to the invention and one or more pharmaceutically innocuous excipients and/or excipients (or additives or auxiliary substances) and, if necessary, one or more other active compounds. However, depending on the nature of the pharmaceutical product, the number of contained sodium salt of the benzamide I can also be higher. The pharmaceutical preparations can be obtained by a method known per se. For this purpose one or several crystalline modifications of the sodium salt of the benzamide I according to the invention is introduced into a suitable for injection dosage form together with one or more solid or liquid pharmaceutical excipients and/or excipients and, if you want to get mixed drug one the strategic action drugs can then be used as pharmaceuticals in medicine and veterinary medicine. When receiving a liquid pharmaceutical forms, especially,for example, solutions for intravenous injection, it can also favorable to carry out the stage of freeze-drying. This sodium salt of the benzamide I dissolve, and good solubility in water and high dissolution rate are particularly favorable, and after sterile filtration, the solution is dried by freezing. The obtained freeze-drying and suitably packaged product is then dissolved again before the introduction of, for example, in the water. The pharmaceutical preparations normally contain about 0.5 to about 90 wt. percent crystalline modifications of the sodium salt of the benzamide I according to the invention, but depending on the nature of the drug content can also be, for example, above. Possible other pharmaceutically active compounds are, for example, calcium antagonists, NO donors or inhibitors of ACE (the enzyme that converts angiotensin). If you, as a supplementary active compounds can also contain, for example, one or more vitamins.

Suitable nepalnet appropriate, for example, for enteral (e.g. oral) administration, parenteral (e.g. intravenous, intramuscular or subcutaneous) administration, local or dermal application or other forms of administration, for example, in the form of implants, and do not interact with the sodium salt of the benzamide I according to the invention undesirable way, for example, water, saline, vegetable oils, benzyl alcohols, polyethylene glycols, glycerol triacetate, gelatin, carbohydrates such as lactose or starch, magnesium stearate, talc, lanolin, petrolatum. For parenteral administration, e.g. by injection or infusion, preferably, use solutions, particularly preferably aqueous solutions. For oral or rectal administration, preferably, use solutions, particularly preferably, aqueous or oily solutions, suspensions, emulsions, tablets, coated tablets, capsules, syrups, juices, drops or suppositories. For local injection, preferably, ointments, creams, pastes, lotions, gels, sprays, foams, aerosols, powders or solutions, such as solutions in water or alcohols, such as ethanol, isopropanol or 1,2-propandiol or their mixtures with one another solvent or with water. For double the in addition, to contain, for example, excipients such as stabilizers, wetting agents, emulsifiers, salts, lubricants, preservatives, agents influencing the osmotic pressure, the agents to achieve a depot, buffer substances, dyes, corrigentov and/or flavors.

The dose of the crystalline modifications of the sodium salt of the benzamide I according to the invention, which is to be entered, for example, for the treatment of cardiac arrhythmias or to prevent sudden cardiac death, must be adapted to the individual conditions that will ensure the achievement of optimal actions. It, thus, depends on the nature and severity of the disease being treated, sex, age, weight and individual responsiveness of the human or animal, of which they treat, modifications, forms of introduction, from, have acute or chronic or prophylactic treatment of, or impose any other active compounds, in addition to the crystalline modifications of the sodium salt of the benzamide I according to the invention. Usually applied dose that is at least about 0.01 mg, preferably at least about 0.1 mg, in particular of at least about 1 mg, and which was carried out prevention (all the above data in mg is the amount of the crystalline modification according to the invention in mg per kg of body weight per day with the introduction of an adult, weighing approximately 75 kg). Dose can be administered as a single dose or divided into parts, for example, 2, 3 or 4 individual doses. In particular, when treating acute cases of cardiac arrhythmia, for example, in the ICU, may be the preferred parenteral administration. The preferred dose in critical situations can then be approximately 10 mg to approximately 100 mg per kg of body weight per day and can be entered, for example, in the form of intravenous continuous infusion. If appropriate, it may be necessary, depending on the individual case, to change the dose upwards or downwards.

Due to their inhibitory effect on ATP-sensitive potassium channels, the crystalline modification of the sodium salt of the benzamide I according to the invention can also be used, in addition to use as pharmaceutically active compounds in medicine and veterinary medicine, as a research tool or as an aid in study, for example, in biochemical studies, in which it is assumed effect on potassium channels of this type, and also for diagnostic purposes, for example, in vitro diagnostic cell samples in order to alsowhat as intermediate products for other pharmaceutically active compounds.

The following examples illustrate the invention.

EXAMPLE 1

5-Chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the amount of 40 kg is suspended in 80 l of methanol in enameled vessel with stirrer and the temperature is set to 27C. Then parts administered for 10 to 15 minutes a solution of 4.7 kg of sodium hydroxide in 58 l of methanol and 3.2 l of water. The mixture was stirred at 27C for 3 hours and Then added with stirring 136 l of ethanol. The mixture was then stirred for 1 h at a temperature of from 20With up to 25C. the Precipitated product is filtered and washed with ethanol. After drying receive 38,2 kg of sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone) ethyl)benzamide in the crystal modification 3.

EXAMPLE 2

The sodium hydroxide in the amount of 4.4 kg fully dissolved in 160 l of methanol at a temperature of from 20With up to 23With in vessel with stirrer. Then this solution is injected 51 kg 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone) ethyl)benzamide. The mixture was added to 625 kg of ethanol at a temperature of 20 is the temperature from 20With up to 23C for additional 3 hours, the Product is filtered and washed with ethanol. After drying receive 48 kg sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl) benzamide.

EXAMPLE 3

5-Chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the amount of 40 kg is suspended in a mixture of 80 l of methanol and 136 liters of ethanol per enameled vessel with stirrer and the temperature is set to 27C. Then dosed method administered for 10 to 15 minutes a solution of 4.7 kg of sodium hydroxide in 58 l of methanol and 3.2 l of water. The mixture was stirred at 27C for 3 h and then cooled to 23C. After filtration and washing with ethanol to 37.9 kg of sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the crystal modification 1.

EXAMPLE 4

5-Chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the amount of 11.5 g dissolved in a mixture of 50 ml of methanol and 25 ml of N-methylpyrrolidone at 70With in a glass container. The mixture is cooled to 40the first salt is precipitated by slow addition of 150 ml of diisopropyl ether, is filtered off with suction, washed with diisopropyl ether and dried in vacuum at 60C. Obtain 10.2 g of sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the crystal modification 3.

EXAMPLE 5

5-Chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in an amount of 10 g was dissolved in 360 ml of tetrahydrofuran at the boiling temperature of the glass reactor. The mixture is allowed to cool to room temperature and treated with a solution of 0.92 g of pellets of sodium hydroxide in 20 ml of methanol. The mixture was then cooled to 0C and stirred for an additional 8 hours gradual deposition of fine crystalline precipitate, which is filtered off with suction, washed with tetrahydrofuran and dried at 60With in a vacuum drying Cabinet. Obtain 9.6 g of sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the crystal modification 3.

EXAMPLE 6

The sodium hydroxide in the amount of 4.4 g mixed in 240 ml of ethanol at approximately 60To a clear solution is formed. is milfoil)ethyl)benzamide and the mixture is stirred. The mixture allow to cool for 30 minutes and stirred for another 1.5 h at 23C. It is then cooled to a temperature of from 0With up to 5C and stirred again for 40 minutes. The precipitated product is filtered, washed with 50 ml of ethanol and dried. Get 48,06 g of sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide crystalline modification 4.

EXAMPLE 7

5-Chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the amount of 40 kg is added to 80 l of methanol in a vessel with stirrer and the temperature is set between 15 andWith up to 25C. Then add a solution of 4.7 kg of sodium hydroxide in 58 l of methanol and 3.2 l of water. The mixture is stirred for 1 h at 27C, then heated to boiling and incubated for 16 h at boiling temperature. It was then cooled to 6With and allocate product by filtration. Get the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyaniline-nonsulfhydryl)ethyl)benzamide crystalline modification of 2.

EXAMPLE 8

Sodium salt of 5-Ficatio 3 in an amount of 10 g are suspended in 50 ml of methanol. The mixture is heated to boiling and stirred for 20 h at boiling temperature. It was then cooled to 5With and allocate product by filtration. Sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)Beneamata get in crystalline modification of 2.

EXAMPLE 9

Sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in the crystal modification 3 in an amount of 10 g are suspended in 200 ml of methanol resistant to high pressure reactor. The reactor is sealed and heated at 78C for 8 hours then cooled to a temperature of from 0With up to 10With and allocate product by filtration. Sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide get in crystalline modification of 2.

EXAMPLE 10

Sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide crystalline modification 4 in an amount of 10 g are suspended in 200 ml of ethanol resistant to high pressure reactor. The reactor is sealed and heated under 9 the filtering. Sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide get in crystal modification 3.

EXAMPLE 11

A mixture of methanol-wet 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide (weight in the dry state 72,5 kg) add to 145 liters of methanol with enameled vessel with stirrer and suspended at 27C. Then add a solution of 8.5 kg of pellets of sodium hydroxide in 143 l of methanol. The contents of the vessel was stirred at 27C for 3 hours the Mixture was then cooled to 10And sodium salt are filtered. The isolated product was washed with cold methanol and dried in vacuum. Get 68 kg sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone-phenyl)ethyl)benzamide in the crystal modification 3.

STUDIES of X-RAY DIFFRACTION

Chart x-ray diffraction of the crystalline modifications of the invention will be received, using crystalline powders when passing on two-round STADIP diffractometer from Stoe (Darmstadt, Germany) using radiation SiCi. Below reflect ed> or 2) in degrees (), which is the reflection of x-ray diffraction, and after him, in brackets, the relative intensity of the reflection in percent of the intensity of the strongest reflection, the intensity of which is assumed to be 100%. Relative intensities are rounded to the ratio of 5% of the intensity of the strongest reflection. These rounded relative intensity form the basis for the separation of strong and medium strong x-ray reflection above and in the claims. The angles of diffraction are rounded to the multiplicity of 0.05.

X-ray reflection crystal modification 1 (2 Theta () (relative intensity (%)))

7.10(20%), 8.95(100%), 9.40(10%), 11.35(25%), 12.15(25%), 13.00(10%). 15.40(35%), 17.95(5%), 18.85(5%), 20.00(10%), 21.40(10%), 21.90(10%), 22.80(20%), 23.00(5%), 27.70(5%), 30.80(5%), 32.25(5%).

X-ray reflection crystal modification 2

(2 Theta () (relative intensity (%)))

7.15(95%), 9.90(45%), 11.10(90%), 11.35(10%), 13.35(20%), 13.80(45%), 14.00(25%), 14.35(10%), 14.90(30%), 15.40(10%). 16.30(15%), 16.50(10%), 17.00(15%), 17.30(5%), 17.95(5%), 18.95(30%), 19.85(25%), 21.20(10%), 21.60(25%), 22.20(10%), 22.55(20%), 22.85(70%), 23.10(100%), 23.90(45%), 24.30(25%), at 25.45(20%), 26.80(65%), 27.15(25%), 27.85(5%), 28.25(25%), 28.35(25%)chr/176.gif">(10%), 31.70 s(5%). 32.30(10%), 33.80(5%).

X-ray reflection crystal modification 3

(2 Theta () (relative intensity (%)))

8.35(80%), 9.20(5%), 9.65(5%), 11.75(100%), 11.95(70%), 12.45(20%), 12.90(5%), 13.70(65%), 14.15(5%), 15.80(45%), 16.45(40%), 18.10(30%), 18.45(40%), 18.80(15%), 19.35(30%), 19.45(25%), 19.75(70%), 20.55(15%), 20.90(55%), 21.40(25%), 21.90(70%), 22.20(30%), 23.00(35%), at 23.85(10%), 24.05(10%), 24.90(90%), 25.15(40%), at 25.45(25%), 25.90(15%). 26.40(65%), 27.55(15%)chr/176.gif">(15%). 29.80(5%), 30.15(45%), 30.50(5%), 31.25(10%), 31.45(5%), 31.70 s(10%), 33.80(10%).

X-ray reflection crystalline modification 4

(2 Theta () (relative intensity (%)))

6.30(10%), 7.40(25%), 8.70(65%), 8.95(80%). 9.45(10%), 10.25(10%), 10.45(20%), 10.85(90%), 11.40(5%), 12.20(65%), 12.60(45%), 14.10(5%), 14.75(5%), 15.65(35%), 16.30(45%), 16.90(15%), 17.75(25%), 18.10(20%), 18.80(15%). 19.20(25%), 20.50(70%), 20.80(10%), 21.30(50%), at 21.85(15%), 22.25(15%), 22.90(25%), 23.35(15%), 2hr/176.gif">(20%), 25.95(30%), 26.55(15%), 27.15(10%), 27.45(15%), 27.95(10%), 28.70(20%), 29.25(5%), 29.40(5%), 30.30(5%), 30.95(5%), 32.30(10%), 33.40(5%).

RESEARCH HYGROSCOPICITY

Sorption of water vapor crystalline modification according to the invention tested at a temperature of 25With samples of substances from 12 to 16 mg analyzer using dynamic vapor sorption DVS-1 from Surface Measurement Systems. The measurements were carried out in nitrogen atmosphere, the relative humidity of which change stepwise. The mass of the sample recorded at each relative humidity after equilibrium is reached, i.e. when no more change in mass of the sample. For a number of increasing relative humidity the water content of the sample, which is determined by the weight change compared with initial masses, indicated in percent. Crystal modification 1

SOLUBILITY STUDIES

CRYSTALLINE MO IS. It dissolves within a few minutes with the initial clumping. In this way only up to 500 mg of the substance can be dissolved in 2 ml of water at a temperature of from 20With up to 25C.

CRYSTALLINE MODIFICATION of 2

The substance in quantities of 100 mg injected into 2.0 ml of water, and is formed legkoperevarivaemye suspension. Even after stirring at a temperature of from 20With up to 25C for 2 h, a clear solution is formed. By heating the suspension to a temperature between 35With up to 37Since the substance dissolves in 20 minutes. When cooled to a temperature of from 20With up to 25Since the substance is certainly dissolved.

CRYSTAL MODIFICATION 3

The substance is injected under stirring, 2.0 ml of water at room temperature portions from 50 to 100 mg. After the introduction of the first substance is present in the form of granular, easily Mixable substances, which then dissolves in a few minutes. In this way all up to 360 mg of the substance can be dissolved in 2 ml of water at a temperature of from 20With up to 25With up to 25C.

Claims

1. Crystal modification 1 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)Beneamata, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram of x-ray diffraction using radiation si Kistrong x-ray reflection: 8,95; srednezerny x-ray reflection: 7,10, 11,35, 12,15, 15,40, 22,80, 23,00, 23,50.

2. Crystalline modification of 2 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram diffraction rovsky rays: 7,15, 11,10, 22,85, 23,10, 26,80; medium strong x-ray reflection: 9,90, 13,35, 13,80, 14,00, the 14.90, 18,95, 19,85, 21,60, 22,55, 23,90, 24,30, 25,45, 27,15, 28,25, 28,35, 28,95.

3. Crystal modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram of x-ray diffraction using radiation si Kistrong x-ray reflection: 8,35, 11,75, 11,95, 13,70, 19,75, 20,90, 21,90, of 24.90, 15,80, 16,45, 18,10, of 18.45, 19,35, 19,45, 21,40, 22,20, 23,00, to 25.15, 25,45, to 30.15.

4. Crystalline modification 4 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which has an x-ray reflection at the following diffraction angles 2 Theta (in the diagram of x-ray diffraction using radiation si Kistrong x-ray reflection: 8,70, 8,95, 10,85, 12,20, 20,50, 21,30, 23,85; medium strong x-ray reflection: 7,40, 10,45, 12,60; 15,65, 16,30, 17,75, 18,10, 19,20, 22,90, increased by 28.70.

5. A method of obtaining a crystal modification 1 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide with the main connection of sodium in a mixture of methanol and ethanol or a mixture of methanol, ethanol and water and treated at a temperature of from -10 to +40C.

6. A method of obtaining a crystalline modification of 2 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide with the main connection of sodium in methanol or mixtures of methanol and water and heating the mixture to a temperature of from 40 to 80C.

7. A method of obtaining a crystal modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide with the main connection sodium methoxide, or in a mixture of methanol and one or more solvents selected from tetrahydrofuran, dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide and treated at a temperature of from -10 to +40C.

8. A method of obtaining a crystalline modification 4 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which includes the interaction of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide with the main connection sodium in ethanol or mixtures of ethanol and water and treated at a temperature of from -10 to +40C.

9. A method of obtaining a crystalline modification of 2 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which involves the heating of the crystal modification 1 or crystalline modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide to a temperature of from 40 to 80With methanol or mixtures of methanol and water.

10. A method of obtaining a crystal modification 3 sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide to a temperature of from 75 to 100With in ethanol or mixtures of ethanol and water.

11. Crystalline modification of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide, which was one of the ways in PP.5-10.

12. Crystalline modification of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide one or more of the paragraphs.1-4 and 11 for use as pharmaceuticals.

13. Pharmaceutical composition, which contains the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide in one or several crystal modifications 1, 2, 3, and 4 in one go a few paragraphs.1-4 and 11, and a pharmaceutically tolerable carrier.

14. Crystalline modification of the sodium salt of 5-chloro-2-methoxy-N-(2-(4-methoxy-3-methylenedioxyphenylacetone)ethyl)benzamide one or more paragraphs.1-4 and 11 for use for the treatment or prevention of cardiac arrhythmias, ischemic heart disease or impaired contractility of the myocardium to prevent sudden cardiac death, to improve cardiac function in heart transplant or quality

 

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