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WO2006116953A1 - Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé - Google Patents

Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé Download PDF

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Publication number
WO2006116953A1
WO2006116953A1 PCT/CZ2006/000029 CZ2006000029W WO2006116953A1 WO 2006116953 A1 WO2006116953 A1 WO 2006116953A1 CZ 2006000029 W CZ2006000029 W CZ 2006000029W WO 2006116953 A1 WO2006116953 A1 WO 2006116953A1
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tegaserod
formula
base
solution
solvent used
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Josef Hajicek
Tomas Pilarcik
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Zentiva KS
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Zentiva KS
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Priority claimed from CZ20050278A external-priority patent/CZ298399B6/cs
Priority claimed from SK5106-2005A external-priority patent/SK287320B6/sk
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Publication of WO2006116953A1 publication Critical patent/WO2006116953A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/14—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system

Definitions

  • the invention concerns a new method of preparation of 2-[(5-methoxy-lH-indol-3- yl)methylene]-N-pentyl-hydrazinecarboximideamide of formula I
  • 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.
  • GIT gastrointestinal tract
  • IBS irritable bowel syndrome
  • IBS-C constipation
  • It acts, in the human organism, as a selective agonist of 5-HT 4 serotonine receptors (it does not bind to 5-HT 3 and dopamine receptors).
  • Tegaserod activates the 5-HT 4 receptors in GIT, thus stimulating the peristaltic reflex, interstitial secretion, and inhibiting the visceral sensitiveness.
  • Tegaserod maleate is known as ZELNORM of Novartis.
  • 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).
  • 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.
  • 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.
  • 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-HT 4 receptors.
  • 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).
  • 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 0 C, respectively. Characterization of the tegaserod maleate using 1 H and 13 C NMR analyses was published later (Jing, T. et al.
  • 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 0 C, 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 0 C and two endothermic peaks at 132 °C and 156 0 C.
  • tegaserod hydrogen maleate can exist in more than one crystalline (polymorphous) form, or in the form of solvates.
  • 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.
  • patent application WO 04/085393 four new crystalline forms of tegaserod maleate, called polymorphous forms I — rv, are characterized.
  • 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.
  • 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.
  • 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.
  • 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
  • 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 C 1 -C 4 alcohols, C 2 -C 3 carboxylic acids, esters Of C 1 -C 3 carboxylic acids with C 1 -C 3 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.
  • solvents such as C 1 -C 4 alcohols, C 2 -C 3 carboxylic acids, esters Of C 1 -C 3 carboxylic acids with C 1 -C 3 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
  • thiosemicarbazone XI reacts with an alkyl halide RX (wherein R is a C 1 to C 12 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 C 1 -C 4 alcohols, C 2 -C 3 carboxylic acids, esters of C 1 -C 3 carboxylic acids with C 1 -C 3 alcohols, ethers, ketones, acetonitrile, and their mixtures in any ratio.
  • Preferable solvents include ethanol, methanol, isopropanol, n-propanol and butanol.
  • 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 C 5 H 11 NH 2 is preferably carried out in a solvent selected from the group comprising C 1 -C 4 alcohols, C 2 -C 3 carboxylic acids, esters of C 1 -C 3 carboxylic acids with C 1 -C 3 alcohols, ethers, ketones, acetonitrile, and their mixtures in any ratio.
  • a solvent selected from the group comprising C 1 -C 4 alcohols, C 2 -C 3 carboxylic acids, esters of C 1 -C 3 carboxylic acids with C 1 -C 3 alcohols, ethers, ketones, acetonitrile, and their mixtures in any ratio.
  • Preferable solvents include ethanol, methanol, isopropanol, n-propanol and butanol.
  • the reaction of the compound of formula XII with pentylamine C 5 H 11 NH 2 is carried out at the boil.
  • the compound of formula XII is reacted with pentylamine C 5 H 11 NH 2 preferably for 24 to 72 hours, most preferably for 48 hours.
  • pentylamine is charged into the reaction mixture in a molar ratio of 1.1 to 5 with respect to the substance of formula XII.
  • 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 C 2 to C 4 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 C 2 to C 4 alkyl acetates (e.g. isopropyl acetate).
  • the precipitated solid is then filtered, washed, and dried.
  • the tegaserod base I was identified by means of 1 H and 13 C 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.
  • 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.
  • Characteristic reflections from the XRPD spectrum, 2 ⁇ , with the highest relative intensity (I re i 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 2 ⁇ , d, and I re i values is shown in Table 3.
  • the characteristic chemical shifts from the CP/ 13 C MAS NMR spectrum correlate with those in the carbon NMR spectrum measured in a dimethyl sulfoxide solution.
  • the pentyl substituent is characterized by signals at 13.35 (C 14 methyl) and in the interval of 22.24 to 42.24 ppm, where signals of the four methylene groups C 1O -C 13 are situated.
  • Table 4 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 C 1 -C 4 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 C 1 -C 4 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-C 4 alcohols or water, preferably methanol, most preferably ethanol, at elevated temperature within the range of 40 0 C 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.
  • 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 C 1 -C 20 hydrocarbon radical.
  • an S-alkylated intermediate of formula XII is formed, which is, as a solution, mixed, at increased temperature, with pentylamine.
  • 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 C 1 -C 4 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%.
  • a solvent from the group Of C 1 -C 4 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
  • 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 C 1 -C 4 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
  • 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.
  • 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 ( 13 C CP MAS NMR).
  • XRPD X-ray powder diffraction
  • DSC differential scanning calorimetry
  • 13 C CP MAS NMR solid-state nuclear magnetic resonance
  • HPLC high performance liquid chromatography
  • GC- MS gas chromatography and mass detection
  • 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 2 ⁇ (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 C 1 -C 4 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 2 ⁇ (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 C 1 -C 4 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 2 ⁇ (I re i.), 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 C 1 -C 4 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 2 ⁇ (I rel .), and a DSC curve with an endotherm containing one peak at 82 0 C.
  • 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 C 1 -C 4 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),
  • 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 C 1 -C 4 alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water, b) obtaining the crystalline form as the precipitate.
  • a solvent from the group of C 1 -C 4 alcohols, such as methanol, ethanol, n-propanol, isopropanol or butanol, or in water
  • 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 2 ⁇ (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 2 ⁇ (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 C 1 -C 4 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 2 ⁇ (I re i.), 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 C 1 -C 4 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 2 ⁇ (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 2 ⁇ (I rel .), and a DSC curve with an endotherm containing one peak at 223 0 C. 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),
  • 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 2 ⁇ (I re i.), and a DSC curve with an endotherm containing three peaks, at 105, 192, and 218 0 C. 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 2 ⁇ (I re i.), 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 2 ⁇ (I re i.), and a DSC curve with an endotherm containing one peak at 164 0 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 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 2 ⁇ (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.
  • salts with a pure polymorphous structure include: tegaserod fumarate, tegaserod oxalate, tegaserod hydrogen sulphate, tegaserod hydrobromide, and tegaserod hydrochloride.
  • 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.
  • the solubility is 1.33 mg/ml at 50 °C.
  • solubility of polymorphous form A of tegaserod hydrogen maleate is about 1 mg/ml of 0.1 M HCl.
  • solubility of selected salts is about 1 mg/ml of 0.1 M HCl.
  • solubilities of selected salts with this standard value.
  • 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.
  • Figure 1 a record from the HPLC analysis of the tegaserod base I prepared according to
  • 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/ 13 C 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.
  • Example 8 DSC curve of tegaserod tartrate obtained from a solution of the base according to
  • 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 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
  • 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 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 13 C MAS NMR spectrum of the crude salt of tegaserod obtained by the method according to Example 5.
  • Figure 57 CP 13 C MAS NMR spectrum of the tegaserod base liberated from the crude salt according to Example 6.
  • Figure 58 CP 13 C MAS NMR spectrum of tegaserod maleate obtained from a solution of the base according to Example 7.
  • Figure 59 CP 13 C MAS NMR spectrum of tegaserod fumarate obtained from a solution of the base according to Example 8.
  • Figure 60 CP 13 C MAS NMR spectrum of tegaserod tartrate obtained from a solution of the base according to Example 9.
  • Figure 61 CP 13 C MAS NMR spectrum of tegaserod citrate obtained from a solution of the base according to Example 10.
  • Figure 62 CP 13 C MAS NMR spectrum of tegaserod lactate obtained from a solution of the base according to Example 11.
  • Figure 63 CP 13 C MAS NMR spectrum of tegaserod mesylate obtained from a solution of the base according to Example 12.
  • Figure 64 CP 13 C MAS NMR spectrum of tegaserod succinate obtained from a solution of the base according to Example 13.
  • Figure 65 CP 13 C MAS NMR spectrum of tegaserod oxalate obtained from a solution of the base according to Example 14.
  • Figure 66 CP 13 C MAS NMR spectrum of tegaserod hydrochloride obtained from a solution of the base according to Example 15.
  • Figure 67 CP 13 C MAS NMR spectrum of tegaserod hydrobromide obtained from a solution of the base according to Example 16.
  • Figure 68 CP 13 C MAS NMR spectrum of tegaserod glutarate obtained from a solution of the base according to Example 17.
  • Figure 69 CP 13 C MAS NMR spectrum of tegaserod adipate obtained from a solution of the base according to Example 18.
  • Figure 70 CP 13 C MAS NMR spectrum of tegaserod sulphate obtained from a solution of the base according to Example 19.
  • Figure 71 CP 13 C MAS NMR spectrum of tegaserod hydrogen sulphate obtained from a solution of the base according to Example 20.
  • Figure 72 CP 13 C MAS NMR spectrum of tegaserod salicylate obtained from a solution of the base according to Example 21.
  • Example 1 Preparation of 5-methoxyindole-3-carbaldehyde thiosemicarbazone XI
  • Example 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 0 C (temperature of the bath) under reflux for 20 hours, leading to the formation of thiosemicarbazone XI.
  • 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 13 C 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.
  • 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 0 C 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.
  • Example 8 Preparation of tegaserod fumarate from the solution of tegaserod base prepared according to Example 6.
  • 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 0 C 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.
  • Example 9 Preparation of tegaserod tartrate from the solution of tegaserod base prepared according to Example 6.
  • 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.
  • Example 10 Preparation of tegaserod citrate from the solution of tegaserod base prepared according to Example 6.
  • 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 0 C. 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.
  • Example 11 Preparation of tegaserod lactate from the solution of tegaserod base prepared according to Example 6.
  • 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 0 C 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 13 C 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.
  • 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 0 C 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 13 C 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.
  • 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 0 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.
  • Example 14 Preparation of tegaserod oxalate from the solution of tegaserod base prepared according to Example 6.
  • 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 0 C. 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.
  • Example 15 Preparation of tegaserod hydrochloride from the solution of tegaserod base prepared according to Example 6.
  • Example 16 Preparation of tegaserod hydrobromide from the solution of tegaserod base prepared according to Example 6.
  • 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 0 C. 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 13 C 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.
  • 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.
  • Example 18 Preparation of tegaserod adipate from the solution of tegaserod base prepared according to Example 6.
  • 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.
  • Example 19 Preparation of tegaserod sulphate from the solution of tegaserod base prepared according to Example 6.
  • 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 13 C 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.
  • 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.
  • Liquid-state NMR analysis was carried out using Bruker 250 DPX spectrometer.
  • 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/ 13 C
  • 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.
  • Table 3 The values of characteristic diffraction angles 2 ⁇ , 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/ 13 C MAS NMR spectrum of the tegaserod base I prepared according to Examples 1, 2, and 4A.
  • Table 5 Values of chemical shifts in CP 13 C 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 13 C 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , 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 2 ⁇ , interplanar spacings d, and relative intensities Irel) of tegaserod salicylate obtained from a solution of the base according to Example 21.

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Abstract

L'invention porte sur un procédé de préparation de tégasérod de formule (I) et de sels pharmacocompatibles dérivés de ce composé.
PCT/CZ2006/000029 2005-05-02 2006-05-02 Procede de preparation de tegaserod et de sels sélectionnés dérivés de ce composé Ceased WO2006116953A1 (fr)

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CZ20050278A CZ298399B6 (cs) 2005-05-02 2005-05-02 Zpusob prípravy 2-[(5-methoxy-1 H-indol-3-yl) methylen]-N-pentylkarbazimidamidu (tegaserodu)
CZPV2005-278 2005-05-02
SKPP5106-2005 2005-12-21
SK5106-2005A SK287320B6 (sk) 2005-12-21 2005-12-21 Spôsob prípravy farmaceuticky akceptovateľných solí 2-[(5-metoxy- 1H-indol-3-yl)metylén]-N-pentylkarbazimidamidu (tegaserodu)

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Cited By (22)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008055994A1 (fr) * 2006-11-09 2008-05-15 Generics [Uk] Limited Nouveau procédé
WO2007119109A3 (fr) * 2005-10-06 2008-06-12 Medichem Sa Compositions et procédés utiles pour la préparation de maléate de tégaserod
EP1939176A1 (fr) * 2006-12-22 2008-07-02 Novartis AG Sels de Tegaserod
WO2008149138A1 (fr) * 2007-06-04 2008-12-11 Generics [Uk] Limited Maléate de tégasérod et formes polymorphiques
WO2008149136A1 (fr) * 2007-06-04 2008-12-11 Generics [Uk] Limited Bésylate de tégasérod et formes polymorphes
WO2009053733A2 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines
WO2009053750A2 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines et amorphes
WO2009053754A2 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines
WO2009053732A1 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouveau sel
WO2009063247A1 (fr) * 2007-11-15 2009-05-22 Generics [Uk] Limited Nouvelles formes cristallines
WO2008149154A3 (fr) * 2007-06-05 2009-07-23 Generics Uk Ltd Nouveaux sels et nouvelles formes polymorphiques
WO2009092994A1 (fr) * 2008-01-23 2009-07-30 Generics [Uk] Limited Nouveau sel de tégasérod
WO2008149139A3 (fr) * 2007-06-04 2009-07-30 Generics Uk Ltd Nouvelles formes polymorphes
WO2009063248A3 (fr) * 2007-11-15 2009-07-30 Generics Uk Ltd Nouvelles formes cristallines
WO2008149140A3 (fr) * 2007-06-04 2009-07-30 Generics Uk Ltd Nouvelles formes polymorphes
WO2009092993A1 (fr) * 2008-01-23 2009-07-30 Generics [Uk] Limited Nouveau sel de tégasérod
WO2009141572A1 (fr) * 2008-05-21 2009-11-26 Generics [Uk] Limited Nouveau polymorphe
WO2009141573A1 (fr) * 2008-05-21 2009-11-26 Generics [Uk] Limited Nouveau polymorphe d'adipate de tegaserod
WO2009141571A1 (fr) * 2008-05-21 2009-11-26 Generics [Uk] Limited Nouveau polymorphe d'hydrochlorure de tegaserod
WO2010015794A1 (fr) * 2008-08-07 2010-02-11 Generics [Uk] Limited Nouvelles formes polymorphes
EP2390547A2 (fr) 2010-05-26 2011-11-30 Grupo Navec Servicios Industriales, SL Procédé de réparation et/ou de prévention de fuites dans des récipients ou des canalisations sous pression et renforcement composite structurel utilisé
WO2008149137A3 (fr) * 2007-06-04 2013-07-04 Generics [Uk] Limited Benzoate de tégasérod et formes polymorphes

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Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007119109A3 (fr) * 2005-10-06 2008-06-12 Medichem Sa Compositions et procédés utiles pour la préparation de maléate de tégaserod
WO2008055994A1 (fr) * 2006-11-09 2008-05-15 Generics [Uk] Limited Nouveau procédé
EP1939176A1 (fr) * 2006-12-22 2008-07-02 Novartis AG Sels de Tegaserod
WO2008077871A1 (fr) * 2006-12-22 2008-07-03 Novartis Ag Sels de tégasérod
WO2008149138A1 (fr) * 2007-06-04 2008-12-11 Generics [Uk] Limited Maléate de tégasérod et formes polymorphiques
WO2008149136A1 (fr) * 2007-06-04 2008-12-11 Generics [Uk] Limited Bésylate de tégasérod et formes polymorphes
WO2008149137A3 (fr) * 2007-06-04 2013-07-04 Generics [Uk] Limited Benzoate de tégasérod et formes polymorphes
WO2008149140A3 (fr) * 2007-06-04 2009-07-30 Generics Uk Ltd Nouvelles formes polymorphes
WO2008149139A3 (fr) * 2007-06-04 2009-07-30 Generics Uk Ltd Nouvelles formes polymorphes
WO2008149154A3 (fr) * 2007-06-05 2009-07-23 Generics Uk Ltd Nouveaux sels et nouvelles formes polymorphiques
WO2009053754A3 (fr) * 2007-10-24 2009-09-03 Generics [Uk] Limited Nouvelles formes cristallines
WO2009053750A3 (fr) * 2007-10-24 2009-08-06 Generics Uk Ltd Nouvelles formes cristallines et amorphes
WO2009053733A2 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines
WO2009053732A1 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouveau sel
WO2009053733A3 (fr) * 2007-10-24 2009-09-03 Generics [Uk] Limited Nouvelles formes cristallines
WO2009053754A2 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines
WO2009053750A2 (fr) 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines et amorphes
WO2009063248A3 (fr) * 2007-11-15 2009-07-30 Generics Uk Ltd Nouvelles formes cristallines
WO2009063247A1 (fr) * 2007-11-15 2009-05-22 Generics [Uk] Limited Nouvelles formes cristallines
WO2009092993A1 (fr) * 2008-01-23 2009-07-30 Generics [Uk] Limited Nouveau sel de tégasérod
WO2009092994A1 (fr) * 2008-01-23 2009-07-30 Generics [Uk] Limited Nouveau sel de tégasérod
WO2009141572A1 (fr) * 2008-05-21 2009-11-26 Generics [Uk] Limited Nouveau polymorphe
WO2009141573A1 (fr) * 2008-05-21 2009-11-26 Generics [Uk] Limited Nouveau polymorphe d'adipate de tegaserod
WO2009141571A1 (fr) * 2008-05-21 2009-11-26 Generics [Uk] Limited Nouveau polymorphe d'hydrochlorure de tegaserod
WO2010015794A1 (fr) * 2008-08-07 2010-02-11 Generics [Uk] Limited Nouvelles formes polymorphes
EP2390547A2 (fr) 2010-05-26 2011-11-30 Grupo Navec Servicios Industriales, SL Procédé de réparation et/ou de prévention de fuites dans des récipients ou des canalisations sous pression et renforcement composite structurel utilisé

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