WO2006116953A1

WO2006116953A1 - A method for the preparation of tegaserod and slected salts thereof

Info

Publication number: WO2006116953A1
Application number: PCT/CZ2006/000029
Authority: WO
Inventors: Josef Hajicek; Tomas Pilarcik
Original assignee: Zentiva, A.S.
Priority date: 2005-05-02
Filing date: 2006-05-02
Publication date: 2006-11-09

Abstract

A method of preparing tegaserod of formula (I) and pharmaceutically acceptable salts derived therefrom.

Description

A METHOD FOR THE PREPARATION OF TEGASEROD AND SELECTED SALTS THEREOF

Technical Field

The invention concerns a new method of preparation of 2-[(5-methoxy-lH-indol-3- yl)methylene]-N-pentyl-hydrazinecarboximideamide of formula I

H

known under the name tegaserod, new salts thereof and method for obtaining said salts. Tegaserod is an indole derivative of aminoguanidine from the group of carbazimideamides, and is used for the treatment of gastrointestinal tract (GIT) disorders, such as chronic idiopathic constipation or IBS (irritable bowel syndrome), and particularly for the symptomatic treatment of irritable bowel syndrome with occurrence of constipation (IBS-C), which is encountered solely in female population. It acts, in the human organism, as a selective agonist of 5-HT₄ serotonine receptors (it does not bind to 5-HT₃ and dopamine receptors). Tegaserod activates the 5-HT₄ receptors in GIT, thus stimulating the peristaltic reflex, interstitial secretion, and inhibiting the visceral sensitiveness. Tegaserod maleate is known as ZELNORM of Novartis.

Background Art

Preparation of tegaserod I and its intermediates has been described in several patents

(EP 0 505 322, SK 279 214, WO 2005/014544, WO 2004/085393, EP 1 321 142) and publications (J Med. Chem. 1995, 38, 2331-2338; Drugs of the Future 1999, 24, 38-44), where its synthesis is usually mentioned as a part of the structural and activity study of a number of similar compounds. The only published methods of preparation of tegaserod that are relevant to this invention are those that use condensation of salts of N-pentyl-iV'- aminoguanidine (hydroiodide IV or hydrobromide VIII) with a general 3-formyl-5- alkoxyindole in an acid environment (WO 2005/014544, J Med. Chem. 1995, 38, 2331-2338).

H H

^H ₂ ^N'Nγ^N-

NH - HX

VIII X = Br

IV X = I

According to J Med. Chem. 1995, 38, 2331-2338, the hydroiodide of _V-pentyl-_V - aminoguanidine IV is prepared from thiosemicarbazide II, which, by reacting with methyl iodide, yields S-methyl isothiosemicarbazide hydroiodide III. The latter then reacts with pentylamine, yielding the hydroiodide of iV-pentyl-iV'-aminoguanidine IV (Scheme 1).

Scheme 1

C₅H₁₁NH₂ZMeOH

NH ^• HI reflux, 4 h

II III IV

Product IV is a crude orange oil, which smells of the poisonous methyl mercaptan, which is released during the reaction of substance III with pentylamine. The crude IV can also contain the unreacted starting thiosemicarbazide II, which belongs to extremely dangerous poisons. IV does not go, according to the authors⁷, through any process of purification, and is used, in its crude form, for the condensation reaction with 3-formyl-5-alkoxyindole (specifically, 5- benzyloxyindole-3-carbaldehyde V) in an acid environment (HCl, pH = 3-4), affording the hydrochloride of the 5-benzyloxy analogue of tegaserod VI, in 69% yield (Scheme 2).

Scheme 2

IV VI J. Med. Chem. 1995, 38, 2331-2338 gives the melting point 155 °C of the product obtained when this method of preparation is applied to preparation of the tegaserod base.

The only specific published method of preparation of tegaserod according to WO 2005/014544 also starts with thiosemicarbazide II (Scheme 3). In this case, S-alkyl isothiosemicarbazide VII is prepared by reaction of II with dodecyl bromide, which has the advantage, as compared to methyl iodide, of not being poisonous, and the reaction of thus formed S-dodecyl isothiosemicarbazide hydrobromide VII with pentylamine does not form the poisonous and bad-smelling methyl mercaptan, but dodecyl mercaptan.

Scheme 3

A:

II VII

B:

VII VIII C:

VIII IX X

Gaseous hydrogen chloride is then, under reduced pressure, added to thus prepared N-pentyl- N'-aminoguanidine hydrobromide VIII (pH is kept within the range of 1 to 4), and 5- methoxyindole-3-carbaldehyde IX is added in several doses, thus forming crude tegaserod hydrobromide. WO 2005/014544 gives the melting point 124 ⁰C of the product obtained when this method of preparation is applied to preparation of the tegaserod base.

The above described methods suffer from the considerable drawback of the demanding conditions for condensation of 5-alkoxy-3-formylindoles with salts of N-pentyl-JV'- amiiioguanidine. As far as the first method is concerned, condensation proceeds in an environment of concentrated hydrochloric acid, and pH has to be kept within a narrow range (pH = 3 to 4). In the second synthesis, condensation proceeds by addition of gaseous HCl under reduced pressure, pH being constantly kept within the range of 1 to 4.

US patent 5,510,353 and its European counterpart EP 0 505 322 are the first to describe the group of aminoguanidine derivatives, including tegaserod, and their pharmaceutically acceptable salts which act as agonists of the 5-HT₄ receptors. Examples of pharmaceutically acceptable salts of tegaserod (as well as of other carbazimideamides) formally listed there include: hydrochloride, hydrobromide, hydrofiuoride, sulphate, bisulphate, phosphate, hydrogen phosphate, acetate, benzylate, citrate, fumarate, gluconate, lactate, maleate, malonate, mesylate, succinate, and tartrate, the hydrogen maleate being regarded as the preferable form of a salt of tegaserod for medical use.

US patent 5,510,353 describes preparation of the free tegaserod base from indole-3- carbaldehyde by reaction with aminoguanidine in a protic solvent in the presence of an organic or mineral acid (e.g. in methanol in the presence of hydrochloric acid). However, US patent 5,510,353 does not describe any method of crystallization of the base, or a method of preparing the crystalline tegaserod maleate. The tegaserod base and tegaserod maleate are only characterized by their melting points therein: 124 °C and 190 ⁰C, respectively. Characterization of the tegaserod maleate using ¹H and ¹³C NMR analyses was published later (Jing, T. et al. Guangdong Weiliang Yuansu Kexue, 2002, 9/2, 51). Literature (Buchheit, K. H. et al., J. Med. Chem., 1995, 38, 2331) describes a general method of preparation of carbazimideamides by condensation of aminoguanidines with substituted indole-3-carbaldehydes in methanol in an acid environment (pH = 3 - 4, HCl). The product obtained after distilling off the solvent can be converted into the hydrochloride by adding an ethereal solution of hydrogen chloride and subsequent recrystallization from the methanol/diethyl ether system.

The tegaserod base, which was prepared using this method, is characterized only by its melting point: 155 °C. According to patent application WO 05/058819, it is the polymorphous form F of the tegaserod base, characterized by a DSC curve with one endothermic peak at about 154 °C, and typical signals in an X-ray spectrum: 10.2, 11.3, 18.3, 19.2, 22.7, 24.4 degrees 2-theta. The second and, so far, the last known, polymorphous form of the tegaserod base - form H - is characterized by a DSC curve with two endothermic peaks, at 134 °C and 156 ⁰C, and typical signals in the X-ray spectrum: 8.8, 15.1, 17.6, 21.8, 23.9 degrees 2-theta. The double peak in the DSC spectrum implies thermal conversion of polymorph H into polymorph F. Another form of the tegaserod base which is known is the amorphous form, characterized by a DSC curve with a wide endotherm around 100 ⁰C and two endothermic peaks at 132 °C and 156 ⁰C.

It was published that tegaserod hydrogen maleate can exist in more than one crystalline (polymorphous) form, or in the form of solvates. In Chinese patent CN 142565 IA, X-ray diffraction patterns of two crystalline forms of tegaserod maleate - polymorphous forms B2 and C, and also the hydrate form S (the names of the polymorphous forms according to patent application WO 05/058819) - were presented for the first time. In patent application WO 04/085393, four new crystalline forms of tegaserod maleate, called polymorphous forms I — rv, are characterized. However, this fact is refuted in patent application WO 05/014544, which calls polymorphous form I form A, defines polymorphous form B, and three forms of solvates with isopropanol, acetone, and ethanol. Some of the crystalline forms of tegaserod maleate that were regarded as polymorphous forms in patent application WO 04/085393 are defined as solvates in patent application WO 05/014544. Moreover, mixtures of polymorphs A and B were identified. Patent application WO 05/058819 describes new polymorphous forms of tegaserod maleate, B, Bl, B2, B3, C, D, E, tegaserod hemimaleate, two polymorphous forms of the tegaserod base, F and H, and an amorphous form of the tegaserod base. Moreover, data concerning the crystalline structure of another pharmaceutically acceptable salt, namely tegaserod acetate - polymorphous form J - are there published for the first time. It is necessary to say here that ZELNORM of Novartis contains polymorphous form A of tegaserod hydrogen maleate.

Accordingly, only two salts of tegaserod, namely tegaserod hydrogen maleate in several crystalline forms, and tegaserod acetate, have been prepared so far. m both cases, the salts were prepared exclusively from the crystalline form of the free tegaserod base prepared according to EP 505 322 Bl. Various polymorphous forms of tegaserod maleate were obtained by precipitation in various types of solvents, or by recrystallizations of individual polymorphous forms under various conditions (see WO2005/058819). In one case, tegaserod acetate was allegedly obtained from tegaserod maleate by stirring in a mixture ethyl acetate/water 1:1 in the presence of sodium hydroxide.

The above drawbacks of the known methods are eliminated by the new method of preparation of tegaserod which is the subject matter of the present invention. The present invention further includes new salts of tegaserod and methods for preparation thereof.

Disclosure of Invention

The invention concerns a new method of preparation of tegaserod of formula I, which is used for preparation of pharmaceutically useful salts, particularly of tegaserod hydrogen maleate.

The method is based on preparation of an intermediate which has not been described so far - the thiosemicarbazone of 5-methoxyindole-3-carbaldehyde of formula XI

XI

The intermediate XI is formed by reaction of 5-methoxyindole-3-carbaldehyde IX with thiosemicarbazide II (Scheme 4A). This reaction is not demanding about the reaction conditions, proceeds in a wide range of solvents, such as C₁-C₄ alcohols, C₂-C₃ carboxylic acids, esters Of C₁-C₃ carboxylic acids with C₁-C₃ alcohols, ethers, ketones, acetonitrile, their mixtures and mixtures with water in any ratio, and at a wide temperature range, particularly from room temperature to the boiling point of the reaction mixture. Use a C₁ to C₄ alcohol, particularly ethanol, at the boil of the reaction mixture has proved to be especially preferable for this reaction. When ethanol was used as the solvent at the boil of the reaction mixture, a practically quantitative yield of intermediate XI was obtained. Other preferable solvents include methanol, isopropanol, n-propanol, and butanol. The reaction preferably proceeds in a mixture of methanol, acetic acid, and water. A preferable embodiment includes carrying out the reaction of substances IX and II at the boil. Product I is then prepared from intermediate XI by a two-step reaction (Scheme 4B).

In the first step, thiosemicarbazone XI reacts with an alkyl halide RX (wherein R is a C₁ to C₁₂ alkyl, and X is F, Cl, Br, or I), forming the hydrohalide of the S-alkyl isothiosemicarbazone of 5-methoxyindole-3-carboxaldehyde XII. The reaction is preferably carried out in a solvent selected from the group comprising C₁-C₄ alcohols, C₂-C₃ carboxylic acids, esters of C₁-C₃ carboxylic acids with C₁-C₃ alcohols, ethers, ketones, acetonitrile, and their mixtures in any ratio. Preferable solvents include ethanol, methanol, isopropanol, n-propanol and butanol. Preferably, the reaction of the compound of formula XI with the compound of formula RX is carried out within the temperature range of 40 to 100 °C.

Intermediate XII can be isolated or, preferably, enters directly (without isolation from the reaction mixture) into the reaction with pentylamine, forming the crude product I in an almost quantitative yield with respect to XI.

The reaction of the compound of formula XII with pentylamine C₅H₁₁NH₂ is preferably carried out in a solvent selected from the group comprising C₁-C₄ alcohols, C₂-C₃ carboxylic acids, esters of C₁-C₃ carboxylic acids with C₁-C₃ alcohols, ethers, ketones, acetonitrile, and their mixtures in any ratio. Preferable solvents include ethanol, methanol, isopropanol, n-propanol and butanol. Preferably, the reaction of the compound of formula XII with pentylamine C₅H₁₁NH₂ is carried out at the boil. The compound of formula XII is reacted with pentylamine C₅H₁₁NH₂ preferably for 24 to 72 hours, most preferably for 48 hours. Preferably, pentylamine is charged into the reaction mixture in a molar ratio of 1.1 to 5 with respect to the substance of formula XII.

Scheme 4

A:

IX II XI

B: ,,one-pot, two-step procedure"

XI XII

XII I (crude)

C:

I (crude)

Then, purification of crude product I follows, wherein, first, extraction into a suitable organic solvent, preferably in the presence of an aqueous solution of an alkali metal hydroxide (e.g. 15% NaOH), is carried out. The solvent can be selected from the group of C₂ to C₄ alkyl acetates (e.g. ethyl acetate), halogenated organic solvents (e.g. methylene chloride, chloroform), aliphatic ethers (e.g. diethyl ether), etc. The organic phase is then concentrated and mixed with another portion of the solvent, preferably from the group of C₂ to C₄ alkyl acetates (e.g. isopropyl acetate). The precipitated solid is then filtered, washed, and dried.

The tegaserod base I was identified by means of ¹H and ¹³C NMR spectroscopy (Table 2), and, in addition, with DEPT 135, COSY 90, and HSQC. The purity of the crystalline base I obtained was verified by the analytical HPLC method. It has turned out that, when using the method according to the invention, it is possible to prepare the tegaserod base I with purity higher than 99.9 % (see the chromatogram - Fig. 1).

The method of preparation of the tegaserod base according to the invention has a big advantage of an extraordinary simplicity, which makes it a method especially suitable for industrial production. It has turned out that not only the second part of the synthesis, starting with intermediate XI, but the whole preparation can be carried out without isolation of any intermediates (reactions 4A and 4B can be combined), without the final product being negatively influenced by this significant simplification of preparation. The method is not demanding about the reaction conditions - it avoids introduction of gaseous HCl into the reaction mixture, or use of the concentrated acid to keep pH within a narrow range. A single solvent can be used for the whole synthesis, e.g. ethanol, which, moreover, need not be anhydrous. It is not necessary to carry out any operations outside the range of O to 100 °C. Other advantages include the high yield and high purity of the resulting product (see the chromatogram, Fig. 1), the tegaserod base I, from which it is possible to prepare any desired pure salt, e.g. tegaserod hydrogen maleate in various crystalline forms, and other pharmaceutically acceptable salts, without the necessity of subsequent purification, which usually results in reduction of the yield. Preparation of these pharmaceutically acceptable salts of tegaserod from the tegaserod base resides in a classic neutralization reaction with an appropriate acid from the group of hydrogen halides, such as hydrochloric or hydrobromic acid, or inorganic oxygen-containing acids, such as sulphuric and phosphoric acids, or organic acids, such as acetic, oxalic, maleic, fumaric, citric, tartaric, mandelic, and camphorsulfonic acids. A melting point value in the range of temperatures of 131-133 °C was determined for the crystalline tegaserod base prepared according to the invention even in classical determination using a melting point apparatus, which is a value different from the prior published results. The method according to WO 2005/014544 resulted in tegaserod having the melting point of 124 °C, and according to J Med. Chem. 1995, 38, 2331-2338 the melting point of the tegaserod base was as high as 155 °C. It can be judged from the comparison of the melting points that either an impure product was obtained in the prior methods of preparation (WO 2005/014544, J Med. Chem. 1995, 38, 2331-2338), or a new crystalline form of tegaserod was prepared using the method according to the invention. By means of the differential scanning calorimetry (DSC) method, a phase change peak was determined at 132.5 °C (onset at 130.2 °C), at the heating rate of 10 °C/min (Fig. 2). It is apparent that the melting point of the tegaserod base obtained using the method according to the invention is substantially different from those of the products of earlier-known syntheses. Structural characteristics of this crystalline form, called form I here, were, in addition to DSC, determined by X-ray powder diffraction (XRPD) (Fig. 3, Table 3) and by solid-state nuclear magnetic resonance (CP/¹³C MAS NMR) (Fig. 4, Table 4).

Characteristic reflections from the XRPD spectrum, 2Θ, with the highest relative intensity (I_rei given in parentheses) are: 15.10 (85), 16.92 (70), 21.82 (100), 22.83 (55), and 23.97 (47). A complete list of the measured 2Θ, d, and I_rei values is shown in Table 3. The characteristic chemical shifts from the CP/¹³C MAS NMR spectrum correlate with those in the carbon NMR spectrum measured in a dimethyl sulfoxide solution. The characteristic signals are, e.g., the peak at 157.29 ppm, corresponding to the C₉ quaternary carbon of the aminoguanidine system, the peak of the C₈ carbon at 145.66 ppm in the -CH=N- imine system of the molecule, or the signal at 54.39 ppm corresponding to the methoxy substituent in position 5 of the indole ring. The pentyl substituent is characterized by signals at 13.35 (C₁₄ methyl) and in the interval of 22.24 to 42.24 ppm, where signals of the four methylene groups C_1O-C₁₃ are situated. A complete list of chemical shifts of the crystalline tegaserod base prepared according to the invention, including the assignment of individual signals, is shown in Table 4

The present invention further includes new pharmaceutically acceptable salts of tegaserod from the group of fumarate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulphate, and hydrogen sulphate, of which tegaserod fumarate, tegaserod hydrogen bromide, and tegaserod oxalate are especially suitable for preparation of a pharmaceutical, and a method for the preparation thereof, which provides for obtaining a pure salt of tegaserod without the need to isolate the tegaserod base. The method of preparation according to the invention comprises suspending a crude salt of tegaserod of formula XIII in an organic solvent from the group Of C₁-C₄ alkyl esters of acetic acid, alkalizing the mixture with an aqueous solution of ammonia or an alkali metal hydroxide, separating the aqueous phase and washing the organic phase with water, adding the appropriate mineral or organic acid from the group of maleic, fumaric, DL-tartaric, citric, methanesulfonic, lactic, succinic, oxalic, hydrochloric, salicylic, glutaric, adipic, hydrobromic, and sulphuric acids, in the solid state or in the form of a solution in a solvent from the group of C₁-C₄ alcohols or water, to the organic phase, and isolating the respective crystalline salt of tegaserod. Tegaserod hydrogen maleate has turned to be a salt which is able to form numerous crystalline forms. These crystalline forms, comprising solvates, polymorphs, and mixtures of polymorphs, often, owing to the effect of temperature, change into one another. Thermal instability of the crystalline forms of tegaserod hydrogen maleate can manifest itself negatively during the technological processing of the salt, for example during drying, or it can influence the stability of the substance. Therefore, a well-defined and reproducible salt of tegaserod, which would be formed by a single, thermally stable crystalline form, has been sought. In searching for new stable crystalline forms a new method for the preparation of salts has also been developed:

The method of preparing salts issues from the above described method for the preparation of the tegaserod base, which is technologically very advantageous for its simplicity, and, at the sane time, yields a product of high purity. The method for the preparation of the tegaserod base consists in condensation of 5-methoxy-substituted indole-3-carbaldehyde of formula IX with thiosemicarbazide of formula II in the environment of a protic solvent from the group of Ci-C₄ alcohols or water, preferably methanol, most preferably ethanol, at elevated temperature within the range of 40 ⁰C to 100 °C, preferably at 60 °C, most preferably at a temperature near the boiling point of the solvent, for 6 to 24 hours, most preferably 20 hours. To a solution of the crude product of the condensation, the thiosemicarbazone of formula XI, an alkyl halide from the group of alkyl fluorides, alkyl chlorides, alkyl bromides, or alkyl iodides is added at elevated temperature according to the invention, wherein the alkyl can be a C₁-C₂₀ hydrocarbon radical. During the reaction at elevated temperature for 6 to 24 hours, most preferably 8 hours, an S-alkylated intermediate of formula XII is formed, which is, as a solution, mixed, at increased temperature, with pentylamine. By reacting at increased temperature for 12 to 72 hours, preferably 24 hours, most preferably 48 hours, followed by distilling off the solvent and crystallization, a crude salt - tegaserod hydrohalide, depending on the used alkyl halide, is obtained in a high yield (Scheme 5). The latter can be processed into a pure crystalline form of the free tegaserod base, or into a wide variety of pharmaceutically acceptable salts of tegaserod (Scheme 6). Big advantages of this production process include: a) it proceeds in one reaction vessel, b) it uses one solvent for all three steps of the reaction, c) it is not necessary to isolate the intermediates.

The whole production process of tegaserod is thus extremely simplified and highly effective. The release of the tegaserod base from the crude salt of tegaserod is carried out by mixing the crude salt (alkyl halide) of tegaserod with a solvent from the group Of C₁-C₄ alkyl esters of acetic acid, such as butyl acetate, preferably ethyl acetate, and alkalizing the mixture, under cooling, with an aqueous solution of ammonia, sodium or potassium hydroxide, preferably of sodium hydroxide, with a concentration of 5 to 30%, most preferably 15 to 20%. In this way, a solution of pure tegaserod base in an organic solvent is obtained, which is separated from the aqueous solution of the alkali, and further processed either to yield a pharmaceutically acceptable salt of tegaserod (see below), or the solvent is distilled off, and the evaporation residue is mixed with a solvent from the group of C₁-C₄ alkyl esters of acetic acid, such as butyl acetate, preferably ethyl acetate, most preferably isopropyl acetate, yielding a crystalline form of the tegaserod base which is characterized by an endotherm in the DSC spectrum containing one peak with a maximum at 132.4 °C, by signals in the carbon solid-state NMR spectrum at 157.29, 152.58, 145.66, 133.50, 130.04, 125.70, 112.95, 109.01, 106.78, 54.38, 42.24, 31.22, 28.40, 22.24, 13.34 ppm, and by typical signals in the X-ray spectrum (2Θ/I_rel) 15.1 (85), 16.9 (70), 21.8 (100), 22.8 (56). By comparing the DSC and XRPD spectra of thus prepared tegaserod base with the results published in patent application WO 05/058819, we have come to the conclusion that, although the X-ray data correspond to a considerable extent with the data concerning polymorphous form H, the data from DSC analysis unambiguously show that polymorphous form H, prepared according to patent application WO 05/058819, is thermally unstable and changes into form F with a melting point of 155 ⁰C. The tegaserod base we prepared is stable, and does not convert, under the influence of temperature, into form F. Therefore, we can say that the method for the preparation of the tegaserod base we have developed offers a pure, thermally stable polymorph with a melting point of 132 ⁰C. Scheme 5: A method for the preparation of tegaserod

(IX) (II) (XI)

(XI) (XII)

(XII) tegaserod "crude salt" (XIII)

Scheme 6: Processing of crude tegaserod hydrohalide

CRYSTALLIZATIOI POLYMORPH G OF

% TEGASEROD BASE

CRUDE BASE SOLUTION TEGASEROD SOLVENT OF TEGASEROD BASE

SALTS

ACID OF TEGASEROD

We have now surprisingly found out that it is possible to prepare salts of tegaserod directly from a crude solution of the tegaserod base (Scheme 6) by adding a solution of the appropriate acid in a protic solvent from the group Of C₁-C₄ alcohols or water, or the acid in the solid state, without any negative influence of this technological simplification on the quality of the salt of tegaserod obtained. In doing so, it is not necessary to dry the solution of the tegaserod base in the organic solvent after the alkaline liberation with an aqueous solution of a base. Moreover, partial crystallization of the tegaserod base occurs during drying, which is then difficult to separate from the desiccant used. Possible smaller amounts of water present in the solution of the tegaserod base (typically below 10 wt. %) cause no problem in terms of crystallization. It is possible to add the acid to the organic phase containing 0.1 to 15, preferably 0.5 to 10, and especially 3 to 8 wt. % of water. It is advisable to carry out the preparation of salts of tegaserod at increased temperature, most preferably within the range of 45 to 65 °C.

In order to find a thermally stable and easily reproducible salt of tegaserod constituted by a single crystalline form, the following salts have been prepared using the method according to the invention: tegaserod maleate, tegaserod fumarate, tegaserod tartrate, tegaserod citrate, tegaserod mesylate, tegaserod lactate, tegaserod succinate, tegaserod oxalate, tegaserod hydrochloride, tegaserod salicylate, tegaserod glutarate, tegaserod adipate, tegaserod hydrobromide, tegaserod sulphate, and tegaserod hydrogen sulphate. Except for tegaserod maleate, none of the aforementioned salts of tegaserod has been described so far.

The crystalline forms of tegaserod maleate and of the aforementioned new salts of tegaserod have been characterized by the methods of X-ray powder diffraction (XRPD), differential scanning calorimetry (DSC), and solid-state nuclear magnetic resonance (¹³C CP MAS NMR). For identification of the products, the methods of high performance liquid chromatography (HPLC), and a combination of gas chromatography and mass detection (GC- MS) have further been used. The following Table lists the new salts of tegaserod, including their melting points and values from the DSC.

Table 1: Salts of tegaserod prepared, their melting points, and values from DSC

determined on a Boetius block

Tegaserod maleate is characterized by an X-ray spectrum with typical signals at 5.16 (100), 18.22(44), 22.93(30), 26.06(30) ± 0.2 degrees 2θ(Irel.), and a DSC curve with an endotherm containing one peak at 189 °C. Its preparation includes: a) adding maleic acid to the solution of the tegaserod base prepared according to Example 6, wherein the acid is dissolved in a solvent from the group of C₁-C₄ alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate. Tegaserod fumarate is characterized by an X-ray spectrum with typical signals at 10.72(100), 11.71(93), 21.14(82), 25.66(91) ± 0.2 degrees 2θ(I_rel.), and a DSC curve with an endotherm containing one peak at 240 °C. Its preparation includes: a) adding fumaric acid to the solution of the tegaserod base prepared according to Example 6, wherein the acid is dissolved in a solvent from the group of C₁-C₄ alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate.

Tegaserod tartrate is characterized by an X-ray spectrum with typical signals at 7.53(100), 14.26(19), 18.88(60), 24.69(28) ± 0.2 degrees 2θ(I_rei.), and a DSC curve with an endotherm containing two peaks, at 103 °C and 163 °C. Its preparation includes: a) adding tartaric acid to the solution of the tegaserod base prepared according to Example 6, wherein the acid is dissolved in a solvent from the group of C₁-C₄ alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate.

Tegaserod citrate is characterized by an X-ray spectrum with typical signals at 4.36(37), 4.64(100), 9.30(55), 18.58(19) ± 0.2 degrees 2θ(I_rel.), and a DSC curve with an endotherm containing one peak at 82 ⁰C. Its preparation includes: a) adding citric acid to the solution of the tegaserod base prepared according to Example 6, wherein the acid is dissolved in a solvent from the group Of C₁-C₄ alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate.

Tegaserod lactate is characterized by an X-ray spectrum with typical signals at 5.07(100),

13.69(21), 20.58(22), 23.67(27) ± 0.2 degrees 2θ(I_rei.), and a DSC curve with an endotherm containing one wide peak at 143 °C. Its preparation includes: a) adding lactic acid to the solution of the tegaserod base prepared according to Example 6, wherein the acid is dissolved in a solvent from the group of C₁-C₄ alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate. Tegaserod mesylate is characterized by an X-ray spectrum with typical signals at 8.42(25), 14.76(100), 18.81(22), 19.99(18) ± 0.2 degrees 2θ(I_re].), and a DSC curve with an endotherm containing three peaks, at 151, 170, and 173 °C. Its preparation includes: a) adding methanesulfonic acid to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

Tegaserod succinate is characterized by an X-ray spectrum with typical signals at 4.98(100), 5.08(38), 9.95(5), 19.94(5) ± 0.2 degrees 2θ(I_rel.), and a DSC curve with an endotherm containing three peaks, at 131, 160, and 181 °C. Its preparation includes: a) adding succinic acid to the solution of the tegaserod base prepared according to Example 6, wherein the acid is dissolved in a solvent from the group Of C₁-C₄ alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate.

Tegaserod oxalate is characterized by an X-ray spectrum with typical signals at 5.60(74), 5.67(100), 5.77(67), 20.43(26) ± 0.2 degrees 2θ(I_rei.), and a DSC curve with an endotherm containing one peak at 176 °C. Its preparation includes: a) adding oxalic acid to the solution of the tegaserod base prepared according to Example 6, wherein the acid is dissolved in a solvent from the group of C₁-C₄ alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate.

Tegaserod hydrochloride is characterized by an X-ray spectrum with typical signals at 5.22(63), 6.10(100), 24.6(45), 27.35(13) ± 0.2 degrees 2θ(I_rel), and a DSC curve with an endotherm containing one peak at 231 °C. Its preparation includes: a) adding an ethereal solution of hydrogen chloride to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

Tegaserod hydrobromide is characterized by an X-ray spectrum with typical signals at 5.30(100), 10.51(3), 21.01(13), 31.69(2) ± 0.2 degrees 2θ(I_rel.), and a DSC curve with an endotherm containing one peak at 223 ⁰C. Its preparation includes: a) adding hydrobromic acid to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

Tegaserod glutarate is characterized by an X-ray spectrum with typical signals at 4.05(40),

5.02(100), 5.13(22), 19.72(40) ± 0.2 degrees 2θ(I_rel), and a DSC curve with an endotherm containing one peak at 77 ⁰C. Its preparation includes: a) adding glutaric acid to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

Tegaserod adipate is characterized by an X-ray spectrum with typical signals at 8.24(19), 14.16(60), 19.02(45), 24.50(100) ± 0.2 degrees 2θ(I_rei.), and a DSC curve with an endotherm containing three peaks, at 105, 192, and 218 ⁰C. Its preparation includes: a) adding adipic acid to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

Tegaserod sulphate is characterized by an X-ray spectrum with typical signals at 4.79(49), 16.29(28), 20.72(31), 25.44(100) ± 0.2 degrees 2θ(I_rei.), and a DSC curve with an endotherm containing three peaks, at 90, 122, and 167 °C. Its preparation includes: a) adding sulphuric acid to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

Tegaserod hydrogen sulphate is characterized by an X-ray spectrum with typical signals at 5.30(100), 18.46(6), 22.95(6), 25.78(9) ± 0.2 degrees 2θ(I_rei.), and a DSC curve with an endotherm containing one peak at 164 ⁰C. Its preparation includes: a) adding sulphuric acid to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

Tegaserod salicylate is characterized by an X-ray spectrum with typical signals at 5.20(100), 5.32(90), 9.90(55), 25.63(96) ± 0.2 degrees 2θ(I_rel.), and a DSC curve with an endotherm containing four peaks, at 85, 97, 152, and 174 °C. Its preparation includes: a) adding salicylic acid to the solution of the tegaserod base prepared according to Example 6, b) obtaining the crystalline form as the precipitate.

All the salts prepared were characterized by high substance purity above 90 %, mostly over 99 %. hi all cases we have succeeded in preparing crystalline substances, none of the salts prepared was amorphous (according to the data obtained from XRPD and CP MAS IMMR). While some of the salts were susceptible to thermally induced polymorphous conversions, which could be observed by differential scanning calorimetry, or mixtures of crystalline forms or hydrates were isolated, other salts formed a pure crystalline polymorphous form characterized by an endotherm with a single temperature maximum. These salts with a pure polymorphous structure include: tegaserod fumarate, tegaserod oxalate, tegaserod hydrogen sulphate, tegaserod hydrobromide, and tegaserod hydrochloride.

We have further made solubility tests of these five salts to compare their dissolution properties with commercial tegaserod hydrogen maleate. Solubility of tegaserod hydrogen maleate, polymorphous form A, which is used in the pharmaceutical product ZELNORM, is not quantified anywhere in the literature, or even in patent documents. We have subjected the obtained standard of the polymorphous form of tegaserod hydrogen maleate to solubility testing and we have found out that the substance dissolves in a 0.1 M solution of hydrochloric acid at elevated temperature. The solubility is 1.33 mg/ml at 50 °C. When the temperature is reduced to 40 ⁰C, solubility of polymorphous form A of tegaserod hydrogen maleate is about 1 mg/ml of 0.1 M HCl. We have compared solubilities of selected salts with this standard value. We have prepared suspensions of the selected salts in a 0.1 M solution of HCl, with a concentration of 1 g/1, and heated them slowly, under stirring, to 40 ⁰C. We have found out that solubilities of all the selected salts are practically the same as that of tegaserod hydrogen maleate, polymorphous form A (within the range of 40.0 - 41.2 °C). None of the salts have shown any remarkably different properties either in terms of worse or better solubility at the given concentration and temperature. Further, using X-ray powder diffraction, thermal stability of the crystalline structures of these five forms has been studied. The salts were exposed to the temperature of 40 ⁰C at the relative humidity of 75 % in a stability chamber for 14 days. Excellent results have been achieved in the cases of the salts fumarate, hydrogen bromide, and oxalate, for which no changes of the crystalline structures have occurred in the course of heating. It follows from the aforementioned data that we have succeeded in finding three pharmaceutically acceptable salts which have significant advantages over commonly used tegaserod maleate. Tegaserod fumarate, tegaserod hydrobromide, and tegaserod oxalate, which are thermally stable crystalline forms, have particularly suitable properties for use in the pharmaceutical industry. Moreover, they have solubilities comparable with that of tegaserod maleate, and they can be obtained from a solution of the base in high purity and yield.

Brief Description of Drawings

Figure 1: a record from the HPLC analysis of the tegaserod base I prepared according to

Examples 1, 2, and 4A. Figure 2: a record from the DSC analysis of the tegaserod base I prepared according to

Examples 1, 2, and 4 A.

Figure 3: an XRPD pattern of the crystalline tegaserod base I prepared according to Examples 1, 2, and 4A.

Figure 4: a record from the CP/ ¹³C solid-state MAS NMR analysis of the crystalline tegaserod base I prepared according to Examples 1, 2, and 4 A. Figure 5: HPLC chromatogram of the crude salt of tegaserod obtained by the method according to Example 5. Figure 6: HPLC chromatogram of the tegaserod base liberated from the crude salt according to Example 6. Figure 7: HPLC chromatogram of tegaserod maleate obtained from a solution of the base according to Example 7.

Figure 8: HPLC chromatogram of tegaserod fumarate obtained from a solution of the base according to Example 8.

Figure 9: HPLC chromatogram of tegaserod tartrate obtained from a solution of the base according to Example 9. Figure 10: HPLC chromatogram of tegaserod citrate obtained from a solution of the base according to Example 10. Figure 11: HPLC chromatogram of tegaserod lactate obtained from a solution of the base according to Example 11.

Figure 12: HPLC chromatogram of tegaserod mesylate obtained from a solution of the base according to Example 12. Figure 13: HPLC chromatogram of tegaserod succinate obtained from a solution of the base according to Example 13. Figure 14: HPLC chromatogram of tegaserod oxalate obtained from a solution of the base according to Example 14. Figure 15: HPLC chromatogram of tegaserod hydrochloride obtained from a solution of the base according to Example 15. Figure 16: HPLC chromatogram of tegaserod hydrobromide obtained from a solution of the base according to Example 16.

Figure 17: HPLC chromatogram of tegaserod glutarate obtained from a solution of the base according to Example 17.

Figure 18: HPLC chromatogram of tegaserod adipate obtained from a solution of the base according to Example 18. Figure 19: HPLC chromatogram of tegaserod sulphate obtained from a solution of the base according to Example 19. Figure 20: HPLC chromatogram of tegaserod hydrogen sulphate obtained from a solution of the base according to Example 20. Figure 21: HPLC chromatogram of tegaserod salicylate obtained from a solution of the base according to Example 21.

Figure 22: DSC curve of the crude salt of tegaserod obtained by the method according to Example 5.

Figure 23: DSC curve of the tegaserod base liberated from the crude salt according to

Example 6. Figure 24: DSC curve of tegaserod maleate obtained from a solution of the base according to

Example 7. Figure 25: DSC curve of tegaserod fumarate obtained from a solution of the base according to

Example 8. Figure 26: DSC curve of tegaserod tartrate obtained from a solution of the base according to

Example 9.

Figure 27: DSC curve of tegaserod citrate obtained from a solution of the base according to Example 10.

Figure 28: DSC curve of tegaserod lactate obtained from a solution of the base according to

Example 11. Figure 29: DSC curve of tegaserod mesylate obtained from a solution of the base according to

Example 12. Figure 30: DSC curve of tegaserod succinate obtained from a solution of the base according to

Example 13. Figure 31: DSC curve of tegaserod oxalate obtained from a solution of the base according to

Example 14. Figure 32: DSC curve of tegaserod hydrochloride obtained from a solution of the base according to Example 15.

Figure 33: DSC curve of tegaserod hydrobromide obtained from a solution of the base according to Example 16.

Figure 34: DSC curve of tegaserod glutarate obtained from a solution of the base according to

Example 17. Figure 35: DSC curve of tegaserod adipate obtained from a solution of the base according to

Example 18. Figure 36: DSC curve of tegaserod sulphate obtained from a solution of the base according to

Example 19. Figure 37: DSC curve of tegaserod hydrogen sulphate obtained from a solution of the base according to Example 20.

Figure 38: DSC curve of tegaserod salicylate obtained from a solution of the base according to Example 21.

Figure 39: XRPD pattern of the crude salt of tegaserod obtained by the method according to

Example 5. Figure 40: XRPD pattern of the tegaserod base liberated from the crude salt according to

Example 6. Figure 41: XRPD pattern of tegaserod maleate obtained from a solution of the base according to Example 7. Figure 42: XRPD pattern of tegaserod fumarate obtained from a solution of the base according to Example 8.

Figure 43: XRPD pattern of tegaserod tartrate obtained from a solution of the base according to Example 9.

Figure 44: XRPD pattern of tegaserod citrate obtained from a solution of the base according to

Example 10. Figure 45: XRPD pattern of tegaserod lactate obtained from a solution of the base according to Example 11. Figure 46: XRPD pattern of tegaserod mesylate obtained from a solution of the base according to Example 12. Figure 47: XRPD pattern of tegaserod succinate obtained from a solution of the base according to Example 13. Figure 48: XRPD pattern of tegaserod oxalate obtained from a solution of the base according to Example 14.

Figure 49: XRPD pattern of tegaserod hydrochloride obtained from a solution of the base according to Example 15.

Figure 50: XRPD pattern of tegaserod hydrobromide obtained from a solution of the base according to Example 16. Figure 51: XRPD pattern of tegaserod glutarate obtained from a solution of the base according to Example 17. Figure 52: XRPD pattern of tegaserod adipate obtained from a solution of the base according to Example 18. Figure 53: XRPD pattern of tegaserod sulphate obtained from a solution of the base according to Example 19.

Figure 54: XRPD pattern of tegaserod hydrogen sulphate obtained from a solution of the base according to Example 20.

Figure 55: XRPD pattern of tegaserod salicylate obtained from a solution of the base according to Example 21. Figure 56: CP ¹³C MAS NMR spectrum of the crude salt of tegaserod obtained by the method according to Example 5. Figure 57: CP ¹³C MAS NMR spectrum of the tegaserod base liberated from the crude salt according to Example 6. Figure 58: CP ¹³C MAS NMR spectrum of tegaserod maleate obtained from a solution of the base according to Example 7.

Figure 59: CP ¹³C MAS NMR spectrum of tegaserod fumarate obtained from a solution of the base according to Example 8.

Figure 60: CP ¹³C MAS NMR spectrum of tegaserod tartrate obtained from a solution of the base according to Example 9. Figure 61: CP ¹³C MAS NMR spectrum of tegaserod citrate obtained from a solution of the base according to Example 10. Figure 62: CP ¹³C MAS NMR spectrum of tegaserod lactate obtained from a solution of the base according to Example 11. Figure 63: CP ¹³C MAS NMR spectrum of tegaserod mesylate obtained from a solution of the base according to Example 12. Figure 64: CP ¹³C MAS NMR spectrum of tegaserod succinate obtained from a solution of the base according to Example 13.

Figure 65: CP ¹³C MAS NMR spectrum of tegaserod oxalate obtained from a solution of the base according to Example 14.

Figure 66: CP ¹³C MAS NMR spectrum of tegaserod hydrochloride obtained from a solution of the base according to Example 15. Figure 67: CP ¹³C MAS NMR spectrum of tegaserod hydrobromide obtained from a solution of the base according to Example 16. Figure 68: CP ¹³C MAS NMR spectrum of tegaserod glutarate obtained from a solution of the base according to Example 17. Figure 69: CP ¹³C MAS NMR spectrum of tegaserod adipate obtained from a solution of the base according to Example 18.

Figure 70: CP ¹³C MAS NMR spectrum of tegaserod sulphate obtained from a solution of the base according to Example 19.

Figure 71: CP ¹³C MAS NMR spectrum of tegaserod hydrogen sulphate obtained from a solution of the base according to Example 20. Figure 72: CP ¹³C MAS NMR spectrum of tegaserod salicylate obtained from a solution of the base according to Example 21.

Examples

The invention is further illustrated in the following examples. Example 1: Preparation of 5-methoxyindole-3-carbaldehyde thiosemicarbazone XI

IX II XI

A: 647 mg of 5-methoxyindole-3-carboxaldehyde (3.7 mmol) IX was dissolved in 10 ml of hot methanol, and a solution of thiosemicarbazide (357 mg, 3.9 mmol) II in 5 ml of hot 30% acetic acid was added to the solution. The reaction mixture was then refluxed for 3 hours while the reaction was monitored by TLC. After the starting indole has reacted out, the reaction mixture was cooled to room temperature, and distilled water was added, under stirring, until the reaction mixture became turbid. The precipitated crystals were sucked off. The yield of the preparation of XI was 70 %.

B: 1.773 g of 5-methoxyindole-3-carboxaldehyde (10.12 mmol) IX and 930 mg of thiosemicarbazide (10.2 mmol, 1.01 eq.) II were dissolved in 50 ml of ethanol and refluxed for 5 hours while the reaction was monitored by TLC. After the starting indole has reacted out, ethanol was distilled off partially and the mixture was allowed to crystallize overnight under gradual cooling. Crystals have precipitated, which were sucked off and dried. The yield of this preparation of XI was 95 %. The melting point of substance XI is 202-203 °C.

Example 2: Preparation of crude tegaserod (hydroiodide) I from 5-methoxyindole-3- carbaldehyde thiosemicarbazone XI

XI I (crude)

2.28 g of thiosemicarbazone XI (9.2 mmol) was weighed into a 100-ml furnished with a stirrer, and 60 ml of ethanol was added thereto. The suspension was heated to 60 °C, and 1.1 equivalents of methyl iodide (0.6 ml) were added at this temperature. The temperature was then raised, and the reaction mixture was refluxed for 6 hours (XII is formed). Then, 1.5 equivalents of pentylamine (1.5 ml) were added, and the reaction mixture was refluxed for 48 hours. The reaction was monitored by TLC. After the starting compound has reacted out, ethanol and the excess of amine were distilled off in a vacuum evaporator. The crude evaporation residue was cooled in an ice bath, triturated with ethyl acetate, and filtered. 95 % (based on XI) of the crude product with a melting point of 183-184 °C was obtained.

Example 3: Preparation of tegaserod I - preparation method without isolation of intermediates XI and XII

IX I (crude)

1.0 equivalent of 5-methoxyindole-3-carbaldehyde IX and 1.1 equivalents of thiosemicarbazide II were dissolved in ethanol (5 ml/1 mmol), and the reaction mixture was then refluxed for 5 hours (until the starting substance has reacted out, according to TLC or GC). The reaction mixture was then concentrated to half its volume and cooled down. Crystals of thiosemicarbazone XI precipitate, which are allowed to settle on the bottom, and partial decantation of ethanol is carried out. The reaction mixture was then re-heated to 40 to 60 °C, and 1.1 equivalents of methyl iodide were added at this temperature. The temperature was raised to the boiling point, and the reaction mixture was refluxed for 6 hours, giving the hydroiodide of 5-methoxyindole S-methyl-isothiosemicarbazone XII (until the starting substance has reacted out, according to TLC or GC). Then, pentylamine (1.5 eq.) is added, and the reaction mixture is heated to 90 to 95 °C for at least 24 hours, better for 48 hours (until the starting substance has reacted out, according to TLC or GC). When no starting substance is present in the reaction mixture any more, ethanol and the excess of amine are distilled off in a vacuum evaporator. The crude evaporation residue was triturated with cooled ethyl acetate, and filtered. 94 % of a crude product with the melting point of 181-187 °C was obtained. Example 4: Preparation of tegaserod base I from the crude product of Examples 2 and 3

A: 1.75 g of the crude product prepared according to Example 2 was suspended in 50 ml of ethyl acetate. 15% aqueous solution of sodium hydroxide was added gradually to the suspension. The suspension dissolved under stirring and cooling in an ice bath. The organic phase was separated, and the liquor was extracted two times with ethyl acetate. The extracts were combined, dried with sulphate, filtered, and concentrated. The concentration residue was mixed with isopropyl acetate and allowed to crystallize overnight. After filtration and drying, 1.23 g of base I (99 %) with a melting point of 131 °C was obtained.

B: 0.86 g of the crude product prepared according to Example 3 was processed according to the method described in Example 4A with the yield of tegaserod base I being 0.53 g (88 %).

Example 5: Preparation of a crude salt of tegaserod XIII 175.1 g (l mol) of 5-methoxyindole-3-carbaldehyde IX and HO g (1.2 mol) of thiosemicarbazide II were weighed into a 20-litre reactor. The substances were suspended in 6 litres of ethanol and heated to 100 ⁰C (temperature of the bath) under reflux for 20 hours, leading to the formation of thiosemicarbazone XI. 310 ml of dodecyl bromide (1.3 mol) was then added, over 5 minutes, to the boiling solution, and the solution was further heated at 100 ⁰C (temperature of the bath) for 8 hours, leading to the formation of intermediate XII, wherein R = dodecyl, X = Br. 175 ml of pentylamine (1.5 mol) was then, at a constant boil, added, over 10 minutes, to the solution, and it was heated at 100 ⁰C (temperature of the bath) under reflux for 48 hours. Ethanol was then distilled off, under reduced pressure (membrane pump), from the reaction mixture at 35 °C. The suspension obtained was cooled with ice to 5 °C, and 1000 ml of ethyl acetate and 1000 ml of hexane were, under stirring, added dropwise over 30 minutes. The suspension was then filtered through a sintered glass filter (Sl). The filter cake was washed with 500 ml of hexane and dried at 50 °C. 310 g of the crude product - salt (hydrobromide) of tegaserod with a melting point of 219-221 °C - was obtained. HPLC, DSC, CP ¹³C MAS NMR, and XRPD analyses are in Figures 5, 22, 39, and 56. Example 6: Liberation of the tegaserod base from the crude salt prepared according to Example 5.

21.0O g of the product prepared according to Example 5 was suspended in 200 ml of ethyl acetate. A 15% aqueous solution of sodium hydroxide was, under stirring and cooling in an ice bath, added gradually into the suspension until the suspension dissolved. The organic phase was then separated, and the liquor was extracted with ethyl acetate (2 x 50 ml). The organic extracts were combined, washed with water (2 x 100 ml), and a 30 ml portion (1/10 of the total volume) was collected, which was dried with magnesium sulphate, filtered, and concentrated in a vacuum evaporator. The concentration residue was mixed with isopropyl acetate (15 ml) and left in a refrigerator overnight. The crystals formed were sucked off, and, after drying, 1.51 g of the product (90 %) with a melting point of 131-132 °C was obtained. The product was analyzed by HPLC, DSC, CP ¹³C MAS NMR, and XRPD, and defined as the tegaserod base, polymorphous form G (analyses in Figs. 6, 23, 40, 57). The remaining ethyl-acetate solution of the base was used for preparation of salts according to Examples 7 to 20.

Example 7: Preparation of tegaserod maleate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (26 ml contains about 0.7 ml of water and 1.23 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, a solution of maleic acid (495 mg) in 15 ml of water was added in one portion, and the reaction mixture was stirred at 70 ⁰C for 2 hours. The flask was then taken out of the bath, and the reaction mixture cooled naturally and crystallized in a refrigerator overnight. The crystals formed were sucked off and dried. 1.42 g of the product (83 %) with a melting point of 188-190 ⁰C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod hydrogen maleate, polymorphous form A (Figs. 7, 24, 41, 58).

Example 8: Preparation of tegaserod fumarate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, a solution of fumaric acid (495 mg) in 15 ml of boiling water was added in one portion, and the reaction mixture was stirred at 50 ⁰C for 2 hours. The flask was then taken out of the bath, and the reaction mixture cooled naturally and crystallized at room temperature overnight. The crystals formed were sucked off and dried. 0.99 g of the product (71 %) with a melting point of 235-239 °C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod hydrogen fumarate (Figs. 8, 25, 42, 59).

Example 9: Preparation of tegaserod tartrate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, a solution of tartaric acid (523 mg) in 1 ml of boiling water was added in one portion, and the reaction mixture was stirred at 50 °C for 1 hour. The flask was then taken out of the bath, and the reaction mixture cooled naturally and crystallized at room temperature overnight. The crystals formed were filtered by suction and dried. 1.34 g of the product (90 %) with a melting point of 159-162 ⁰C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod tartrate (Figs. 9, 26, 43, 60).

Example 10: Preparation of tegaserod citrate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 ⁰C. At this temperature, a solution of citric acid monohydrate (733 mg) in 2 ml of boiling water was added in one portion, and the reaction mixture was stirred at 50 °C for 30 minutes. The flask was then taken out of the bath, and the reaction mixture cooled naturally and crystallized at room temperature overnight. The crystals formed were sucked off and dried. 1.27 g of the product (78 %) with a melting point of 97-100 °C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod citrate (Figs. 10, 27, 44, 61).

Example 11: Preparation of tegaserod lactate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, 0.365 ml of 75% lactic acid was added dropwise, and the reaction mixture was stirred at 50 ⁰C for 1 hour. The flask was then taken out of the bath, and ethyl acetate was distilled out of the reaction mixture in a vacuum evaporator. 5 ml of diethyl ether and 15 ml of hexane were added to the evaporation residue. The crystals formed were sucked off and dried. 1.30 g of the product (100 %) was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod lactate (Figs. 11, 28, 45, 62).

Example 12: Preparation of tegaserod mesylate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, 0.237 ml of methanesulfonic acid was added dropwise, and the reaction mixture was stirred at 50 ⁰C for 10 minutes. The flask was then taken out of the bath, and ethyl acetate was distilled out of the reaction mixture in a vacuum evaporator. The crude evaporation residue was triturated with diethyl ether. The crystals formed were sucked off and dried. 1.24 g of the product (94 %) was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod mesylate (Figs. 12, 29, 46, 63).

Example 13: Preparation of tegaserod succinate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, a solution of 430 mg of succinic acid in 2 ml of water was added in one portion, and the reaction mixture was stirred at 50 ⁰C for 10 minutes. The flask was then taken out of the bath, and the reaction mixture crystallized under cooling in a refrigerator overnight. The crystals formed were sucked off and dried. 0.91 g of the product (65 %) with a melting point of 128-150 ⁰C was obtained, which was, using HPLC, DSC, CP 13C MAS NMR, and XRPD, defined as tegaserod succinate (Figs. 13, 30, 47, 64).

Example 14: Preparation of tegaserod oxalate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 ⁰C. At this temperature, a solution of 460 mg of oxalic acid dihydrate in 2 ml of hot water was added in one portion, and the reaction mixture was stirred at 50 °C for 30 minutes. The flask was then taken out of the bath, and the reaction mixture crystallized under cooling in a refrigerator overnight. The crystals formed were sucked off and dried. 1.06 g of the product (82 %) with a melting point of 177-179 °C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod oxalate (Figs. 14, 31, 48, 65).

Example 15: Preparation of tegaserod hydrochloride from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was stirred in a 100-ml flask at 20 °C. At this temperature, 5 ml of ethereal hydrogen chloride was added dropwise until pH = 1. The flask was then taken out of the bath, and the reaction mixture was concentrated to half its volume. The crystals formed were, after having been cooled in ice, sucked off and dried. 0.99 g of the product (88 %) with a melting point of 228-230 °C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod hydrochloride (Figs. 15, 32, 49, 66).

Example 16: Preparation of tegaserod hydrobromide from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was stirred in a 100-ml flask at 2O ⁰C. At this temperature, 0.4 ml of 48% hydrobromic acid was added dropwise, and the reaction mixture was stirred at 20 °C for 1 hour. The crystals formed were sucked off and dried. 1.27 g of the product (100 %) with a melting point of 222-225 °C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod hydrobromide (Figs. 16, 33, 50, 67).

Example 17: Preparation of tegaserod glutarate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, 482 mg of solid glutaric acid was added in one portion. The reaction mixture was stirred at 50 °C for 10 minutes. The flask was then taken out of the bath, and the reaction mixture crystallized under cooling in a refrigerator overnight. The crystals formed were sucked off and dried. 1.30 g of the product (90 %) with a melting point of 75-79 °C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod glutarate (Figs. 17, 34, 51, 68).

Example 18: Preparation of tegaserod adipate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, 534 mg of solid adipic acid was added in one portion. The reaction mixture was stirred at 50 °C for 10 minutes. The flask was then taken out of the bath, and the reaction mixture crystallized under cooling in a refrigerator overnight. The crystals formed were sucked off and dried. 1.40 g of the product (94 %) with a melting point of 182-186 ⁰C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod adipate (Figs. 18, 35, 52, 69).

Example 19: Preparation of tegaserod sulphate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was stirred in a 100-ml flask at 20 °C. At this temperature, 0.093 ml of 96% sulphuric acid was added dropwise. The reaction mixture was stirred for 1 hour. The crystals formed were sucked off and dried. 1.01 g of the product (86 %) was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod sulphate (Figs. 19, 36, 53, 70).

Example 20: Preparation of tegaserod hydrogen sulphate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about 0.5 ml of water and 1.0 g of the base) was stirred in a 100-ml flask at 20 ⁰C. At this temperature, 0.185 ml of 96% sulphuric acid was added dropwise. The reaction mixture was stirred for 10 minutes. The crystals formed were sucked off and dried. 1.12 g of the product (84 %) with a melting point of 160-162 °C was obtained, which was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod hydrogen sulphate (Figs. 20, 37, 54, 71). Example 21: Preparation of tegaserod salicylate from the solution of tegaserod base prepared according to Example 6.

The solution of tegaserod base prepared according to Example 6 (20 ml contains about

0.5 ml of water and 1.0 g of the base) was heated in a 100-ml flask to 50 °C. At this temperature, 504 mg of solid salicylic acid was added in one portion. The reaction mixture was stirred at 50 ⁰C for 10 minutes. The flask was then taken out of the bath, 20 ml was added, and the reaction mixture crystallized under cooling in a refrigerator overnight. The crystals formed were sucked off and dried. 1.24 g of the product (85 %) with a melting point of 152—

156 ⁰C was obtained. The product was, using HPLC, DSC, CP ¹³C MAS NMR, and XRPD, defined as tegaserod salicylate (Figs. 21, 38, 55, 72).

List of analytical methods used:

HPLC - High Pressure Liquid Chromatography HPLC analysis of the tegaserod base I prepared according to Examples 1, 2, and 4A is shown in Figure 1.

HPLC analyses of the tegaserod base and salts of tegaserod prepared according to Examples 5 to 21 were carried out using Waters ALIANCE W 2690/5. The Symmetry C8 column (250 x 4.6 mm, 5 μm) was used for the measurements. The chromatograms are shown in Figures 5 to 21.

NMR - Nuclear Magnetic Resonance

Liquid-state NMR analysis was carried out using Bruker 250 DPX spectrometer.

DMSOd₆ was used as the solvent, and the following analyses were carried out: ¹H, ¹³C, DEPT, COSY 90, and HSQC. Chemical shifts and the assignment of individual signals of hydrogens and carbons of the molecule of the tegaserod base prepared according to the invention are listed in Table 1.

CP/ ¹³C solid-state MAS NMR of the crystalline tegaserod base I prepared according to

Examples 1, 2, and 4A is shown in Fig. 4. ¹³C solid-state NMR analyses of crystalline forms of the salts of tegaserod and tegaserod base prepared according to Examples 5 to 21 are shown in

Figs. 56 to 72. The measurement was carried out using Bruker AVANCE 500 MHz spectrometer, in a 4-mm cell at a spinning frequency of 13 kHz. Chemical shifts in CP/ ¹³C

MAS NMR spectrum with the assignment to individual carbons are listed in Tables 4, 5 and 6. X-Ray Powder Diffraction (XRPD)

An XRPD pattern of the crystalline tegaserod base I prepared according to Examples 1,

2, and 4A is shown in Figure 3. XRPD patterns of crystalline forms of the pharmaceutically acceptable salts and tegaserod base prepared according to Examples 5 to 21 are shown in

Figures 39 to 55. The values of characteristic diffraction angles are listed in Tables 3 and 7 to

23. The diffraction pattern was measured using the XTERT PRO MPD diffractometer under the following experimental conditions: CuKa (λ=1.5402A ) radiation, graphite monochromator, excitation voltage: 45 kV, anode current: 40 mA, measurement range: 4 - 40° 2Θ, step size: 0.008° 2Θ, time per step: 50 s, flat sample: surface thickness: 2.5 mm; irradiated area: 10 mm.

DSC - Differential Scanning Calorimetry

A DSC curve of the tegaserod base I prepared according to Examples 1, 2, and 4A is shown in Figure 2. The results of DSC analyses of the pharmaceutically acceptable salts and tegaserod base prepared according to Examples 5 to 21 are shown in Figures 22 to 38. The heating rate was 10 °C/min (within the range of 50 to 300 °C). The values obtained by the measurements are listed in Table 1.

Table 2: Results of H, 13 C NMR analysis of the tegaserod base I prepared according to Examples 1, 2, and 4A.

Position δ(c) 6(H) Mult. /(H,H)

2 128.24 7.59 S -

3 113.56 _

4 103.72 7.67 d 2.5 (4.6)

5 154.10 -

6 112.01 6.83 d 8.8 (6.7), 2.5 (6.4)

7 112.23 7.33 d 8.8 (7.6)

8 142.58 8.32 S

9 157.64 -

10 40.35 3.17 bt 6.8 2H

11 29.33 1.52 pent. 6.8 2H

12 28.88 1.32 m - 2H

13 22.11 1.31 m - 2H

14 14.10 0.93 t 6.8 3H

15 55.32 3.83 S - 3H

16 125.29 _

17 132.13

Table 3: The values of characteristic diffraction angles 2Θ, interplanar distances d, and relative intensities from the XRPD pattern (Fig. 3) of the crystalline tegaserod base I prepared according to Examples 1, 2, and 4A.

Table 4: Chemical shifts in the CP/ ¹³C MAS NMR spectrum of the tegaserod base I prepared according to Examples 1, 2, and 4A.

Table 5: Values of chemical shifts in CP ¹³C MAS NMR spectra (± 0.2 ppm), characteristic of the substances prepared according to Examples 5 to 12.

Table 6: Values of chemical shifts in CP ¹³C MAS NMR spectra (± 0,2 ppm), characteristic of the substances prepared according to Examples 13 to 21.

Table 7: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of the crude salt of tegaserod obtained by the method according to Example 5.

Table 8: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of the tegaserod base liberated from the crude salt of tegaserod by the method according to Example 6.

Table 9: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod maleate obtained from a solution of the base according to Example 7.

Table 10: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod fumarate obtained from a solution of the base according to Example 8.

Table 11: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod tartrate obtained from a solution of the base according to Example 9.

Table 12: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod citrate obtained from a solution of the base according to Example 10.

Table 13: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod lactate obtained from a solution of the base according to Example 11.

Table 14: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod mesylate obtained from a solution of the base according to Example 12.

Table 15: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod succinate obtained from a solution of the base according to Example 12.

Table 16: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod oxalate obtained from a solution of the base according to Example 14.

Table 17: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod hydrochloride obtained from a solution of the base according to Example 15.

Table 18: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod hydrobromide obtained from a solution of the base according to Example 16.

Table 19: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod glutarate obtained from a solution of the base according to Example 17.

Table 20: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod adipate obtained from a solution of the base according to Example 18.

Table 21 : X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod sulphate obtained from a solution of the base according to Example 19.

Table 22: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod hydrogen sulphate obtained from a solution of the base according to Example 20.

Table 23: X-ray characteristic peaks (values of diffraction angles 2Θ, interplanar spacings d, and relative intensities Irel) of tegaserod salicylate obtained from a solution of the base according to Example 21.

Claims

1. A method for the preparation of tegaserod of formula I

and of pharmaceutically acceptable salts derived therefrom, which method comprises

a) preparing an intermediate, 5-methoxyindole-3-carboxaldehyde thiosemicarbazone of formula XI, by reaction of 5-methoxyindole-3-carboxaldehyde of formula IX with thiosemicarbazide of formula II

II IX XI

b) converting the intermediate of formula XI by a two-step reaction into the crude product I, wherein, in the first step, the compound of formula XI is reacted with an alkyl halide of formula RX, wherein R is a C₁ to C₁₂ alkyl, and X is F, Cl, Br, or I, thus forming a hydrohalide of 5-methoxyindole-3-carboxaldehyde S-alkyl isothiosemicarbazone of formula XII

XII

which is subsequently reacted with pentylamine to give the crude product of formula I; c) purifying the crude product of formula I by means of extraction into an organic solvent from the group of C₂ to C₄ alkyl acetates, halogenated organic solvents, or aliphatic ethers in the presence of an aqueous solution of an alkali metal hydroxide, and optionally by recrystallization from a solvent from the group of C₂ to C₄ alkyl acetates.

2. The method according to claim 1, characterized in that the reaction of the substance of formula IX with the substance of formula II is carried out in a solvent selected from the group comprising C₁-C₄ alcohols, C₂-C₃ carboxylic acids, esters of C₁-C₃ carboxylic acids with C₁-C₃ alcohols, ethers, ketones, acetonitrile, their mixtures and mixtures with water in any ratio.

3. The method according to claim 2, characterized in that the solvent used is a mixture of methanol, acetic acid, and water.

4. The method according to claim 2, characterized in that the solvent used is ethanol.

5. The method according to claim 2, characterized in that the solvent used is methanol.

6. The method according to claim 2, characterized in that the solvent used is isopropanol.

7. The method according to claim 2, characterized in that the solvent used is n-propanol.

8. The method according to claim 2, characterized in that the solvent used is butanol.

9. The method according to claim 1, characterized in that the reaction of the substance of formula IX with the substance of formula II is carried out at the boil.

10. The method according to claim 1, characterized in that the reaction of the compound of formula XI with the compound of formula RX is carried out in a solvent selected from the group comprising C₁-C₄ alcohols, C₂-C₃ carboxylic acids, esters of C₁-C₃ carboxylic acids with C₁-C₃ alcohols, ethers, ketones, acetonitrile, and their mixtures in any ratio.

11. The method according to claim 10, characterized in that the solvent used is ethanol.

12. The method according to claim 10, characterized in that the solvent used is methanol.

13. The method according to claim 10, characterized in that the solvent used is isopropanol.

14. The method according to claim 10, characterized in that the solvent used is n-propanol.

15. The method according to claim 10, characterized in that the solvent used is butanol.

16. The method according to claim 1, characterized in that the reaction of the compound of formula XI with the compound of formula RX is carried out within the temperature range of 40 to 100 ⁰C.

17. The method according to claim 1, characterized in that the reaction of the compound of formula XII with pentylamine C₅H₁₁NH₂ is carried out in a solvent selected from the group comprising C₁-C₄ alcohols, C₂-C₃ carboxylic acids, esters of C₁-C₃ carboxylic acids with Ci-C₃ alcohols, ethers, ketones, acetonitrile, and their mixtures in any ratio.

18. The method according to claim 17, characterized in that the solvent used is ethanol.

19. The method according to claim 17, characterized in that the solvent used is methanol.

20. The method according to claim 17, characterized in that the solvent used is isopropanol.

21. The method according to claim 17, characterized in that the solvent used is n-propanol.

22. The method according to claim 17, characterized in that the solvent used is butanol.

23. The method according to claim 1, characterized in that the reaction of the compound of formula XII with pentylamine C₅Hi₁NH₂ is carried out at the boil.

24. The method according to claim 1, characterized in that the compound of formula XII is reacted with pentylamine CsH₁₁NH₂ for 24 to 72 hours.

25. The method according to claim 24, characterized in that the compound of formula XII is reacted with pentylamine CsH₁₁NH₂ for 48 hours.

26. The method according to claim 1, characterized in that pentylamine is charged into the reaction mixture in a molar ratio of 1.1 to 5 with respect to the substance of formula XII.

27. The method according to claim 1, characterized in that the conversion of the intermediate of formula XI into the product of formula I is carried out without isolation of the compound of formula XII.

28. The method according to claim 1, characterized in that the intermediates of formulae XI and XII are not isolated.

29. The method according to claim 1, characterized in that the crude product of formula I is extracted into ethyl acetate.

30. The method according to claim 1, characterized in that the crude product of formula I is extracted into chloroform.

31. The method according to claim 1, characterized in that the crude product of formula I is extracted into methylene chloride.

32. The method according to claim 1, characterized in that the crude product of formula I is extracted into diethyl ether.

33. The method according to claim 1, characterized in that the crude product of formula I is extracted into tert-butyl methyl ether.

34. The method according to claim 1, characterized in that the extraction of the crude product of formula I is carried out in the presence of sodium hydroxide or potassium hydroxide.

35. The method according to claim 1, characterized in that in the end of the purification process the product of formula I is obtained by recrystallization from isopropyl acetate.

36. A crystalline product of the tegaserod base, characterised by the following 2Θ values of characteristic diffraction angles in an X-ray diffraction pattern: 15.10, 16.92, 21.82, 22.83, 23.97.

37. A crystalline product of the tegaserod base, characterised by the following 2Θ values of characteristic diffraction angles in an X-ray diffraction pattern: 7.37, 8.83, 9.10, 10.96, 11.87, 15.10, 15.87, 16.92, 17.64, 18.16, 19.35, 19.59, 20.43, 20.68, 21.39, 21.82, 22.83, 23.97, 24.47, 25.47, 26.44, 26.71, 29.91, 32.20, 34.92.

38. A crystalline product of the tegaserod base, characterised by the signals at 157.293, 152.584, 145.661, 133.500, 130.041, 125.703, 112.953, 109.007, 106.783, 54.389, 42.240, 31.022, 28.740, 22.244, 13.346 ppm in a CP/13C MAS NMR spectrum.

39. A crystalline product of the tegaserod base, having a phase change peak at 132.5 °C and an onset at 130.2 ⁰C in a thermograph obtained by differential scanning calorimetry DSC at a heating rate of 10 °C/min.

40. A method for the preparation of a highly pure, pharmaceutically acceptable salt of tegaserod by reaction of tegaserod base of formula I with an appropriate acid from the - group of hydrogen halides, such as hydrochloric and hydrobromic acid, or from the group of inorganic oxygen-containing acids, such as sulphuric or phosphoric acids, or from the group of organic acids, such as acetic, oxalic, maleic, fumaric, citric, tartaric, mandelic, or camphorsulfonic acids, characterized in that the tegaserod base according to claims 36 to 39 is used for the reaction.

41. The compound of formula XI

XI

42. The compound of formula XI, having a melting point of 202-203 °C.

43. A method for the preparation of pharmaceutically acceptable salts of tegaserod from the group of tegaserod maleate, fumarate, tartrate, citrate, mesylate, lactate, succinate, oxalate, hydrochloride, salicylate, glutarate, adipate, hydrobromide, sulphate, and hydrogen sulphate, characterized in a) suspending a crude salt of tegaserod of formula XIII

wherein X is F, Cl, Br, or I, obtained in step (b) of claim 1, in an organic solvent from the group OfC₁-C₄ alkyl esters of acetic acid, b) alkalizing the mixture by gradual addition of an aqueous solution of ammonia or an alkali metal hydroxide until the suspension dissolves, c) separating the water phase and washing the organic phase with water, d) adding the appropriate mineral or organic acid from the group of maleic, fumaric, DL- tartaric, citric, methanesulfonic, lactic, succinic, oxalic, hydrochloric, salicylic, glutaric, adipic, hydrobromic, and sulphuric acids to the organic phase in the corresponding ratio, the acid being in the solid state or in the form of a solution in a solvent from the group of Cj-C₄ alcohols or water, e) isolating the crystalline salt of tegaserod.

44. The method according to claim 43, characterized in that the alkalization by adding an aqueous solution of ammonia or an alkali metal hydroxide in step (b) is carried out under cooling of the mixture.

45. The method according to claims 43 to 44, characterized in that the alkalization is carried out with an aqueous solution of ammonia or an alkali metal hydroxide with a concentration of 5 to 30 wt. %.

46. The method according to claim 45, characterized in that the alkalization is carried out with an aqueous solution of ammonia or an alkali metal hydroxide with a concentration of 15 to 20 wt. %.

47. A method according to claims 43 to 46, characterized in that the alkalization is carried out with an aqueous solution of sodium hydroxide.

48. The method according to claim 43, characterized in that ethyl acetate is used as the C₁- C₄ alkyl ester of acetic acid in step (a).

49. The method according to claim 43, characterized in that isopropyl acetate is used as the C₁-C₄ alkyl ester of acetic acid in step (a).

50. The method according to claim 43, characterized in that the appropriate mineral or organic acid in step (d) is added to the organic phase containing 0.1 to 15 wt. % of water.

51. The method according to claim 43, characterized in that the appropriate mineral or organic acid in step (d) is added to the organic phase containing 0.5 to 10 wt. % of water.

52. The method according to claim 43, characterized in that the appropriate mineral or organic acid in step (d) is added to the organic phase containing 3 to 8 wt. % of water.

53. The crystalline salt of tegaserod fumarate.

54. The crystalline salt of tegaserod fumarate, characterized, by an X-ray spectrum with typical signals at 10.72(100), 11.71(93), 21.14(82), 25.66(91) ± 0.2 degrees 2θ(I_rel.), and by a DSC curve with an endotherm containing one peak with a maximum at 240 ⁰C.

55. The crystalline salt of tegaserod hydrobromide.

56. The crystalline salt of tegaserod hydrobromide, characterized by an X-ray spectrum with typical signals at 5.30(100), 10.51(3), 21.01(13), 31.69(2) ± 0.2 degrees 2θ(I_re].), and by a DSC curve with an endotherm containing one peak with a maximum at 223 ⁰C.

57. The crystalline salt of tegaserod oxalate.

58. The crystalline salt of tegaserod oxalate characterized by an X-ray spectrum with typical signals at 5.60(74), 5.67(100), 5.77(67), 20.43(26) ± 0.2 degrees 2θ(I_rei.), and by a DSC curve with an endotherm containing one peak with a maximum at 176 ⁰C.