MXPA99011355A - 4-phenylpiperidine compounds - Google Patents

Abstract

The invention relates to a compound, and pharmaceutically acceptable salts, having formula (I), wherein:R represents an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C1-4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl;R1 represents hydrogen, trifluoro (C1-4) alkyl, alkyl or alkynyl;X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy;R2 represents:a C1-C10 alkyl group;a phenyl group optionally substituted by one or more of the following groups:a C1-C10 alkyl group, a halogen group, a nitro group, hydroxy group, and/or an alkoxy group.

Description

COMPOUNDS OF 4-PHENYLPIPERIDINE Description of the invention; The present invention relates to a group of 4-phenylpiperidines tri-sus ti tuted, to a process for the preparation of such compounds, to a medicament comprising such compounds, and to the use of such compounds for the manufacture of a medicament. The compound paroxetine, trans-4- (4'-fuorophenyl) -2- (3 ', 4'-methylenedioxy phenoxymethyl) -piperidine has the following formula: It is known and has been used in medicines for the treatment, among other diseases, of depression. Paroxetine has been used as a therapeutic agent, in the form of a salt with pharmaceutically acceptable acids. The first clinical tests were conducted with the acetate salt. REF 32056 A useful, known paroxetine salt is the hydrochloride. This salt is considered as the active substance in several commercialized pharmaceutical products, for example Paxil or Seroxat. A number of forms of d-e-paroxetine hydrochloride have been described: the anhydrous form in various crystalline modifications (PCT Application WO) 96/24595); - the hydrated form - a heminidrate (European Patent EP 223403) and in solvated forms. The comparison of the behavior between the anhydrous and hydrated form of paroxetine hydrochloride is described in the Intl. Journal of Pharmaceutics, 42: 135-143 (1988). European Patent EP 223403 discloses paroxetine hydrochloride or ihydrate and pharmaceutical compositions based thereon. Most of these known paroxetine salts have unsuitable physical-chemical characteristics to ensure safe and efficient handling during the production of the same and the formulation in final forms, since these are unstable (acetate, maleate) and possess undesirable hygroscopicity. Furthermore, their formation by crystallization from aqueous or non-aqueous solvents is generally of low yield and problematic, since these usually contain an undefined and predictable amount of bound solvent, which is difficult to remove. Crystalline paroxetine hydrochloride hemihydrate faces these problems, but as set forth in WO 95 / 1TT448, its limited photostability causes undesirable coloration during the classic tabletting process on a wet basis. In addition, crystalline paroxetine hemihydrate hydrochloride shows only limited solubility in water. It has been generally suggested that where the aqueous solubility is low, for example, less than 3 mg / ml, the rate of dissolution in the intravenous administration could be limiting of the speed in the absorption process. The aqueous solubility of the paroxetine hedihydrate at room temperature exceeds this threshold by a relatively small margin.

An object of the present invention is to provide a compound with improved characteristics. According to a first aspect, the present invention comprises a compound, and pharmaceutically acceptable salts, having the formula I: - R represents an alkyl or alkynyl group having 1 to 4 carbon atoms, or a phenyl group optionally substituted with an alkyl of 1 to 4 carbon atoms, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents te rahydronaphthyl, - R 1 represents hydrogen, trifluoroalkyl of 1 to 4 carbon atoms, alkyl or alkynyl, X represents hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy, trifluoroalkyl, hydroxyl, halogen, methylthio or aralkoxy, - R represents: - an alkyl group of 1 to 10 carbon atoms, a phenyl group optionally substituted with one or more of the following groups: - an alkyl group of 1 to 10 carbon atoms, - a halogen group, - a nitro group, a hydroxyl group, - and / or an alkoxy group. The inventors have found that these compounds show good stability and very high solubility. This has the advantage that high concentrations of the compound are obtainable in small volumes. The group R is preferably the 3,4-methylenedioxyphenyl group of the formula: X3Q The group X is preferably a fluorine group coupled at the 4-position on the phenyl ring.

The group R2 preferably represents an alkyl group of 1 to 4 carbon atoms, and more preferably represents an alkyl group of 1 to 2 carbon atoms, in order to provide optimum solubility. The compounds can have a solubility at about 20 ° C of at least about 10 mg / ml of water, preferably have a solubility in water of at least 100, for example 500 and more preferably at least 1000 mg / ml of water. According to a second aspect of the present invention, there is provided a process for the preparation of a compound as described above, comprising the steps of mixing together a 4-phenylpiperidine compound, a salt and / or a base thereof which has the formula II: wherein: R represents an alkyl or alkynyl group having 1 to 4 carbon atoms, or a phenyl group optionally substituted with alkyl of 1 to 4 carbon atoms, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl. Ri represents hydrogen, trifluoroalkyl of 1 to 4 carbon atoms, alkyl or alkynyl, -X represents hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy, trifluoroalkyl, hydroxyl, halogen, methylthio or aralkoxy, with an acid sulphonic of the general formula R2-S03H, wherein R2 represents: an alkyl group of 1 to 10 carbon atoms, a phenyl group optionally substituted with one or more of the following groups: an alkyl group of 1 to 10 carbon atoms, - a halogen group, a nitro group, a hydroxyl group, and / or an alkoxy group, to form a solution, followed by the separation of the compound formed from this solution.

The compounds of the invention can be prepared from the free base of the 4-phenylpiperidine having the formula II, this being preferably paroxetine, by treatment with a sulfonic acid as defined above in a suitable solvent, to form a solution of the desired salt by addition of acid, after which it is precipitated from the solution. The equation for the free base of paroxetine and sulfonic acids is as follows: The formation of a solution may preferably proceed at temperatures of about 0 ° C to the boiling point of the solvent. Optionally, the solution can be purified by the treatment of activated mineral carbon, silica gel, diatomite or other suitable materials.

Alternatively, the solution of a salt of the invention can be formed by dissolving a salt of the 4-phenylpiperidine having the formula II with an organic sulfonic acid. For example, the compounds of the invention can be prepared from a paroxetine carboxylate of 1 to 5 carbon atoms, such as acetate, by addition of the corresponding organic sulfonic acid to the carboxylate solution, as follows: According to a third aspect of the present invention, a compound obtainable by this process is provided. According to a fourth aspect of the present invention, the above compound is provided for use as a medicament and, according to a fifth aspect, a medicament comprising this compound, and the use thereof for the treatment of depressions, disorders obsessive-compulsive, panic disorders, bulimia, anorexia, pain, obesity, senile dementia, migraine, anorexia, social phobia, depressions that arise from premenstrual tension. According to a sixth aspect of the present invention, the use of a compound of the invention as a reagent in subsequent syntheses is provided. More specifically, the compounds of the present invention can be used as an initial reagent for the formation of additional acid addition salts, for example for the addition of paroxetine acid addition salts, by reaction with a suitable reagent, by example with a corresponding acid. For example, the formation of paroxetine maleate according to the present invention proceeds by the following equation: and the formation of paroxetine acetate proceeds as follows: This is an advantageous route, since by using the substantially pure sulfonic acid salts, according to the present invention, as an initial reagent, the preparation of a salt as described above, results in this additional salt having a high purity The inventors have shown that such salts have a surprisingly high purity. Similarly, the compounds of the present invention may react with a base, such as an inorganic base and / or an organic base, to form (release) free bases of the corresponding compounds. As exemplified in paroxetine, the reaction proceeds according to the equation: The free bases released from the compounds of the present invention have surprisingly higher purity than if prepared by known methods, which is especially important in the case of their use for the production of pharmaceutical products. Accordingly, the novel compounds of the first aspect of the invention can also form hydrates and / or solvates by contact with a corresponding reaction partner, for example with water and / or with a solvent. Examples of such additional salts, hydrates and solvates, for example those of paroxetine, are the following: hydrochloride oxalate dihydrate brom idrate succinate trihydrate iodhydrate tartrate hexahydrate acetate citrate methanolate propionate embonate ethanolate maleate hemihydrate fumarate hydrate The inventors have shown that such salts have a surprisingly high purity. Examples of bases that can be used in the preparation of the free bases are: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, pyridine and the like. Since the compounds according to the present invention show high solubility, they can be dosed, for example, injected, in a high concentration, low volume solution, this dosing method is particularly advantageous with certain patients, such as manic depressants and similar, for example, patients who are unable or unwilling to take the medicine. The compounds of the present invention can be formulated in various types of pharmaceutical compositions for the treatment of humans and animals. The pharmaceutical compositions according to the present invention comprise a compound of the invention alone or together with a pharmaceutically acceptable carrier or diluent. Preferred formulations are those for the oral formulation (tablets, capsules) but are also within the scope of the invention, formulations for parenteral or topical administration. The high water solubility of the compounds of the invention makes it possible to obtain high dissolution rates in the solid dosage forms based on the compounds of the invention, during in vitro release as well as good bioavailability after peroral application. in vi vo. Tablets containing the compounds of the present invention can be prepared by a tabletting process in which water is present (eg, aqueous granulation) as well as by processing tablets in which water is absent (direct compression). , granulation on dry basis) and can be coated by any suitable coating means. The present invention will now be elucidated further by means of the following examples and results.

EXPERIMENTAL A seeding crystal of paroxetine methanesulfonate was made, as follows: 2. 7 g (8.2 mmol) of paroxetine was dissolved in 15 ml of hot methanol. 1.0 g (10.4 mmol) of methanesulfonic acid in 15 ml of methanol were added and the mixture was cooled to room temperature. When the mixture had reached room temperature, the mixture was placed in the freezer at -20 ° C overnight. No crystalline line compound was obtained. The mixture was evaporated to dryness leaving an oil. After 1 month at room temperature a waxy solid was obtained. Part of this solid separated and the rest dissolved in ml of ethyl acetate. The waxy crystals were added and the mixture was placed in the freezer at -20 ° C overnight. A white crystalline product precipitated. After filtration and drying in a vacuum oven, 2.5 g (5.9 mmol) of paroxetine methanesulfonate was obtained. Yield 72% This seed crystal was subsequently used in the following examples 1 and 3.

EXAMPLES Example 1 Paroxetine methansulfonate from paroxetine To a solution of 43.5 g (132 mmol) of paroxetine, prepared by the procedure described in US Pat. No. 4007196, were added 12. 7 g (132 mmol) of methanesulfonic acid to 150 ml of boiling ethyl acetate. The mixture was left at room temperature for 2 hours. Subsequently the mixture was placed overnight at -20 ° C, with a seed crystal. The solid obtained was filtered and washed with 50 ml of ether. The white solid obtained was dried overnight in a vacuum oven. 47.1 g (111 mmol) of the product Yield 99.5% The analytical characterization of the obtained compound is shown in Table 1. The purity of the obtained compound was 98% (High Performance Liquid Chromatography (HPLC)).

Example 2 Paroxetine bencensulfonate from paroxetine 3.8 g (11.5 mmol) of paroxetine were dissolved in 10 ml of hot ethyl acetate. 1.82 g (11.5 mmol) of anhydrous benzenesulfonic acid were added. The mixture was left at room temperature for 2 hours. The mixture was evaporated to dryness and dissolved in dichloromethane, and evaporated again to dryness leaving an oil. This oil was solidified by evaporation at high vacuum (0.1 mmHg) leaving 5.0 g (1.3 mmol) of an off-white solid. To this solid was added 5 ml of acetone and the suspension was stirred for 5 minutes, during which time a white suspension was obtained. The solid was filtered and dried in vacuo. 4.8 g (9.9 mmol) of the product were obtained. Performance 85%. The analytical characterization of the obtained compound is shown in Table 1. The purity of the obtained compound was 99.4% (HPLC).

Example 3 Paroxetine P-toluenesulfonate from paroxetine .0 g (15 mmol) of paroxetine were dissolved in 25 ml of hot ethyl acetate. 2.9 g (15 mmol) of p-toluenesulfonic acid was added. The mixture was left at room temperature for 2 hours, and subsequently placed in the freezer, with a seed crystal, for 14 hours. The solid was filtered and washed once with 10 ml of n-hexane. The white solid obtained was dried overnight in a vacuum oven. 4.8 g (10 mmol) of a white solid were obtained. Yield 67% The analytical characterization of the obtained compound is shown in Table 1. The purity of the obtained compound was 99.4% (HPLC).

Example 4 paroxetine p-chlorobenzenesulfonate from paroxetine 1.1 g (-2-r? -mmol) of paroxetine was dissolved in 3 ml of hot ethyl acetate. 0.76 g (3.3 mmol) of 90% p-chlorobenzenesulfonic acid was added. The mixture was left at room temperature for 1 hour, and washed with 5 ml of water. The organic layer was dried with sodium sulfate, filtered and evaporated to dryness leaving 1.5 g (2.9 mmol) of an off-white solid. Yield 88% The analytical characterization of the compound obtained is shown in Table 1. The purity of the compound obtained was 99.4% (HPLC).

Example 5 Paroxetine maleate from paroxetine methanesulfonate A solution of 1.0 g (2.4 mmol) of paroxetine methanesulfonate in 5 ml of hot water was prepared. To this solution was added 0.32 g (2.8 mmol) of maleic acid. The mixture was placed in an oven at 4 ° C overnight, after which a solid with a yellow oil was precipitated on the bottom of the flask. The solid / oil was filtered and washed 3 times with 10 ml of ether and dried in a vacuum oven. 0.8 g (2.0 mmol) of whitish crystals were obtained. Yield 85% The purity of the compound obtained was 99.5% (HPLC).

Example 6 Paroxetine acetate from paroxetine methanesulfonate A solution of 1.0 g (2.4 mmol) of paroxetine methanesulfonate in 5 ml of hot iso-propanol was prepared. To this solution was added 0.2 g (3.2 mmol) of acetic acid. The mixture was placed at 4 ° C overnight, after which a solid precipitated. The solid was filtered and washed 3 times with 10 ml of ether and dried in a vacuum oven. 0.5 g (1.3 mmol) of whitish crystals were obtained. Yield 54% The purity of the compound obtained was 99.5% (HPLC).

Example 7 Paroxetine-free base from paroxetine methanesulfonate .0 g (24.0 mmol) of paroxetine methanesulfonate were placed in 150 ml of water and 200 ml of ethyl acetate. To this solution was added 12.4 g (31 mmol) of a 10% by weight aqueous solution of sodium hydroxide, and the suspension was stirred for 15 minutes. The layers were separated and the aqueous layer was extracted once with 50 ml of ethyl acetate. The combined organic layers were washed once with 100 ml of water and dried over sodium sulfate. The sodium sulfate was filtered and washed once with 50 ml of ethyl acetate. The ethyl acetate was evaporated, leaving 7.5 g (22.8 mmol) of an oily product. Yield 95% The purity of the compound obtained was 99.5% (HPLC). A number of the obtained compounds were analyzed, the results being as shown in the following tables 1-5: Table 1 Characterization of paroxetine salts with certain organic sulphonic acids R-SO 3 H R = CH 3 - (paroxetine methanesulfonate): p.f. : 142 ° -144 ° C. DSC curve (closed bread, 10 ° C / min.): Start 145. 8 ° C, 79.0 J / g. IR spectrum (KBr, in cm "1); 531, 546, 777, 838, 931, 962, 1038, 1100, 1169, 1208, 1469, 1500, 1515, 1615, 2577, 2869, 2900, 3023. aH NMR (ppm): 1.99 (broad d, H5eq, 1H); 2.77 (ddd, -tl5ax, 1H); 2.48-2.65 (m, H3, 1H); 2 82-2. 92 (m, H4, CH 3, 4H); 2.95- • 3.20 (m, H2aX / H6a 2H); 3.47 (dd, H7, 1H); 3.58-3 • 74 (mA H2eq, Hseq, H7, 3H); 5.88 (s, H7 ', 2H); 6.10 (dd, H6 », 1H); 6.33 (d, H2", 1H); 6. 61 (d, H5-, 1H); 7.09 (dd, H5-, 2H); 7.22 (dd, H2-, ü6r, 2H); 8.85 (broad d, NHeq, 1H); 9.11 (broad d, NHax, 1H). 13 C NMR (ppm); 30.0 (s, C5); 39.3 (s, C3), 39.5 (s, C4); 41.7 (s, SC); 44.6 (s, C6); 46.8 (s, C2); 67.4 (s, C7); 97.8 (s, c2 »); 101.2 (s, c7 »); 105.4 (s, C6-); 107.8 (s, C5 «); 115.8 (d, C3-, C5-), 128.4 (s, C6 < , C2 «); 137.1 (s, C4 «); 142.0 (s, C? <); 148.2 (s, C3 »); 153.7 (s, Ci-); 161.9 (d, C4X, R = CH3- (paroxetine benzenesulfonate): mp: 55 ° -60 ° C IR spectrum (KBr, in cm "1): 530, 564, 614, 689, 728, 764, 828, 929, 993, 1007, 1029, 1121, 1179, 1229, 1443, 1471, 1486, 1514, 1600, 1628, 2557, 2842, 3029. aH NMR (ppm): 1.90 (broad d, H5eq, 1H); 2.10-2.28 (m, H5ax, 1H); 2.38-2.52 (m, H3, 1H); 2.82 (ddd, H4, 1 HOUR); 3.02-3.18 (m, H2aX / H6ax, 2H); 3.37 (dd, H7, 1 HOUR); 3.48 (d, H7, 1H); 3.60-3.82 (m, H2eq, Histeq, 2H); . 87 ^ (s, H7 », 2H); 6.06 (dd, H6-, 1H); 6.29 (d, H2 », 1 HOUR); 6.60 (d, H5", 1H), 6.90 (dd, H3., H5 ', 2H); 7. 04 (dd, H2., 2H); 7.40 (d, ArH, 3H); 7.94 (d, SAH, 2H); 8.81 (broad d, NHeq, 1H); 9.04 (broad d, NHax, 1H). 13 C NMR (ppm); 29.9 (s, C5); 39.2 (s, C3); 41.5 (s, 13 C NMR (ppm), 21.3 (s, Ce), 29.9 (e, C5), 39.2 (s, C3); 41.5 (s, C4); 44.7 (-S, S6); 46. 9 (s, c2); 67.3 (s, C7); 97.8 (s, c2 »); 101.1 (s, c7-> 105. 5 (s, C6-), 107.8 (s, C5 ..); 115.6 (d, C3 ', 5r); 1-25 .. 8 (s, Cb), 129.0 (s, C6 <, C2, 129.1 (S, Ce), 137. 2 (s, c4 «), 140.8 (s, Cd), 1 1 ^ 5 (s, ca), 141.9 (s, Ci.); 148. 2 (s, C3 ..); 153.8 (s, 'Ci-); 161.8 (d.C4-). R = p-ClC6H4 (paroxetine p-chlorobenzenesulfonate): p.p. : 75 ° -80 ° C. IR spectrum (KBr, in cm "1); 486, 557, 643, 736, 821, 1000, 1029, 1086, 1114 1186, 1229, 1471, 1486, 1514, 1600, 1657, 2857, 3029. 1 H NMR (ppm): 1.9] (broad d, "5eq / 1 H); 2.15 (ddd, Hsax? 1 HOUR); 2.37-2. 52 (m / H3, 1H); 2.81 (ddd 1 H4, 1 HOUR); 2.93-3.21 (m, H2ax, H6a? / 2H); 3.37 (dd / H7, 1 HOUR); 3.49 (d, H7, 1H); 3 .61-3. 81 (m, H2eq, l6eq / 2H); . 88 (s, H7 .., 2H); 6.05 (dd, H s -, 1 H; 6.27 (d, H2 «, 1 HOUR); 6.59 (d, H5-, 1H); 6.91 • (dd, H3 <, H5 ', 2H); 7. 03 (dd, H2., H6., 2H); 7.39 (d, ClArH, 2H); 7.86 (d, SArH, 2H); 8. 78 (d amplify), NHeq, 1H); 9. 02 (d ampl io, NHax, 1H) 13 C NMR (ppm); 30. 0 (s, C5); 39.3 (s, c3); 41. 5 (s, c4); 44.9 (s, C6); 47.1 (s, C2; 67. 3 (s, C7); 97.9 (s, C2 ..); 101.2 (S, C7 «); 105. 5 (s, Ce-); 107. 9 (s, c 5"), 115.8 (d, C3 • C5 '), 127. 6 (s, Cb), 128. 8 (s, C6-, C2') / 132.0 (s, Cd); 137.0 (s, Cc); 137.2 (s, c4.); 141.8 (s, C?; 142.0 (s, cH); 148.2 (s, C3 «), 153. 6 (s, Ci-), 161.8 (s, C4 »).

The compounds of the invention are crystalline, with well defined melting points, DSC curves and IR spectrum. It can not be excluded that, under different conditions of their formation and under specific conditions, these could also exist in other crystalline or polymorphic modifications which may differ from those described herein. The compounds of the invention are also generally very stable and non-hygroscopic. It should be understood that the present invention comprises the salts by addition of acid with organic sulfonic acids, which are substantially free of the bound organic solvent. Preferably, the amount of bound organic solvent must be less than 2.0% (w / w) as calculated in the anhydrous base. However, these may contain water of crystallization and also unbound water, that is, water that is different from water of crystallization.

In the following tables 2 and 3, the examples of the results of the hygroscopicity tests and stability tests (in comparison with the known salts of paroxetine) are presented.

Table 2 Hygroscopicity of certain paroxetine salts (40 ° C, 75% relative humidity) water content (in%) at t = 0 t - = 4 weeks metansulfonate 0.35 + 0.04 p-toluenesulfonate 0.70 < 0.02 hydrochloride + 2.5 Table 3 Solubility of paroxetine salts in water (in mg / ml) 20 ° C 50 ° C me tansulfonate > 1000/10 1300 min. p-toluenesulfonate > 1000 > 1000 hydrochloride hemihydrate 4.9 12.6 anhydrous chlorhydrate 8.2 24.2 Table 4 Stability of paroxetine salts using HPLC (total amount of rad ation in%). degradation 20 ° C 80 ° C unobserved methanesulfonate < 0.2%, 3 months p-toluenesulfonate not observed < 0.2%, 3 months maleate 0.2%, 12 months- > 50%, 5 days Table 5 Solubility of paroxet ina salts in nonaqueous solvents (in mg / ml) methanesulfonate n-toluenesulfonate Ethanol 20 ° C 36 50 78 ° C 250 > 500 2-propanol 20 ° C 7 14 82 ° C 330 > 500 Acetone 20 ° C 5 16 56 ° C 37 125 Ethyl acetate 20 ° C 2 22 77 ° C 25 > 500 n-hexane 20 ° C < 0.05 < 0.05 69 ° C 0.05 < 0.05 I Examples of analytical data of the paroxetine salts and the free base prepared in Examples 5 to 7 are given in Table 6.

Table 6 Characterization of salts / base 1 of P aroxetine maleate of paroxetrinar p.f. : 128 ° -130 ° C. NMR tE (ppm): 1.65-2.00 (m, H; > e < q, "5ax 2H); 2.00-2.50 (m, H3, 1H); 2.55- 3.15 (m, H2ax, Hßax? H4 , 3H); 3. 15 -3.75 (m, H2eq, ri eq, H7, 3H); 5.67 (s, H7-, 2H); . 97 (s, Ha, 1H); 6.12 (dd, He-, 1H); 6. 42 (d, H2-, 1 HOUR); 6.67 (d, H5-, 1H); 6.95 -7. 35 (d, H2 ', H3', H5 '/ acet ato of paroxet ina: mp: 123 ° -125 ° C. XH NMR (ppm): 1.70- -2.00 (m, 3"i5eq r H5ax, 2H; 1.97 (s, Ha, 3H); 2.05-2.50 (m, H3, 1H); 2.50- -3. 00 (m, H4, H2a, Hßax, 3H); 3. 05-3. 75 (m, H2eq, Hess H7, 3H); 6. 05 (s, H7-, 2H); 6.28 (dd, H6-, 1H); 6. 58 (d, H2-, 1 HOUR); 6.65 (d, H5- 1 H); 7.10 -7. 50 (m, H2 'H3 », H5', paroxetine: 2 H NMR (ppm): 1.60-2.00 (m, H5 ax, ri5ec '2H); 2.00-2.35 (m, H3, 1H); 2.40- 2.95 (m, H4, H5 ax, H6ax, 3H); 3. 15-3.70 (m, H2eq, H6eq, H7 2H); 5.67 (s, H7-, 2H); 6. 11 (dd, H6-, 1H); 6.43 (d, H2-, 1H); 6.62 (d, H5", 1 HOUR); 6.80-7.35 (m, H2., H3-, H5-, H6., 4H).

It will be clear that the invention is not limited to the above description, but rather is determined by the following claims.

Reference Psychopharmacology, 57, 151-153 (1978); ibid. 68, 229-233 (1980), European Journal of Pharmacology, 47, 351-358 (1978); in USP 4007196, the preparation of paroxetine maleate is reported.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (24)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1. A compound, and pharmaceutically acceptable salts, having the formula I: characterized in that: R represents a 3'4'-methylenedioxyphenyl group, R1 represents hydrogen, trifluoroalkyl of 1 to 4 carbon atoms, alkyl or alkynyl, X represents hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy, trifluoroalkyl, hydroxyl, halogen, methylthio or aralkoxy, - R represents: an alkyl group * of 1 to 10 carbon atoms, a phenyl group optionally substituted with one or more of the following groups: an alkyl group of 1 to 10 carbon atoms , - a halogen group, - a nitro group, a hydroxyl group, - and / or an alkoxy group.

2. The compound according to claim 1, characterized in that the R group is the 3,4-methylenedioxyphenyl group of the formula: > and R1 represents hydrogen.

3. The compound according to claim 1 or 2, characterized in that the group X is preferably a fluorine group attached at the 4-position on the phenyl ring.

4. The compound according to claims 1 to 3, characterized in that the group R2 represents an alkyl group of 1 to 4 carbon atoms.

5. The compound according to claims 1 to 4, characterized in that the group R2 is an alkyl group of 1 to 2 carbon atoms.

6. The compound according to any of the previous claims, characterized in that it has a solubility at about 20 ° C of at least about 10 mg per ml of water.

The compound according to claim 6, characterized in that it has a water solubility of at least 100, preferably at least 500 and more preferably at least 1000 mg per ml.

8. The compound according to any of the preceding claims, characterized in that it is selected from the group consisting essentially of: paroxetine methanesulfonate (formula I) wherein X is fluorine at the P position, R is 3,4'-methylene- dioxyphenyl, R1 is hydrogen and R2 is methyl; paroxetine benzenesulfonate (formula I) wherein X is fluorine at the P position, R is 3 '4' -methylene-dioxyphenyl, R1 is hydrogen and R2 is phenyl; paroxetine p-toluenesulfonate (formula I) wherein X is fluorine at the P position, R is 3,4'-methylene dioxyphenyl, R1 is hydrogen and R2 is methylphenyl; - paroxetine p-chlorobenzenesulfonate (formula I) wherein X is fluorine at the P position, R is 3 '4' -methylene-dioxyphenyl, R1 is hydrogen and R2 is chlorophenyl.

9. The process for the preparation of a compound according to any of the previous claims, characterized in that it comprises the steps of mixing together a compound, a salt and / or a base thereof, having the formula I I: wherein R represents a 3'4'-methylene dioxyphenyl group, R1 represents hydrogen, trifluoroalkyl of 1 to 4 carbon atoms, alkyl or alkynyl, X represents hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy , trifluoroalkyl, hydroxyl, halogen, methylthio or aralkoxy, with a sulfonic acid of the general formula R2-S03H, wherein R2 represents: an alkyl group of 1 to 10 carbon atoms, - a phenyl group optionally substituted with one or more of the following groups: an alkyl group of 1 to 10 carbon atoms, a halogen group, - a nitro group, a hydroxyl group, and / or an alkoxy group, to form a solution, after which the solid formed can be separated .

The process for the provision of a compound according to any of claims 1 to 8, in the form of a solvate, characterized in that it comprises the steps of mixing together a compound according to any of claims 1 to 8. with a reagent selected from the group consisting essentially of: oxalic acid, succinic acid, tartaric acid.

11. The compound according to any of claims 1 to 8, or a solvate thereof, characterized in that it is obtainable by a process according to claims 9 or 10.

The compound according to any of claims 1 to 8, and 11, for use as a medicament.

13. A medicament, characterized in that it comprises a compound according to any of claims 1 to 8, 11, 12 and the pharmaceutically acceptable carriers and / or diluents.

14. The use of a compound according to any of claims 1 to 8, 11, 12 for the preparation of a medicament.

15. The use of a compound according to any of claims 1 to 8 and 11, for the manufacture of a medicament for the treatment of depressions, obsessive-compulsive disorders, panic disorders, bulimia, anorexia, pain, obesity, senile dementia , migraine, anorexia, social phobia, depressions that arise from premenstrual tension.

16. A process for the provision of a saline ion, characterized in that it comprises the steps of mixing together a compound according to any of claims 1 to 8 with a reagent selected from the group consisting essentially of: hydrochloric acid oxalic acid hydrobromic acid succinic acid hydriodic acid tartaric acid acetic acid citric acid propionic acid embonic acid / pamoic acid maleic acid sulfuric acid fumaric acid.

17. The salts obtainable by the process according to claim 16.

18. The salt according to claim 17, characterized in that it has a purity of at least 90% by weight, preferably at least 95% and more preferably at least 98%.

19. Paroxetine maleate, characterized in that it has a purity of at least 98%.

20. Paroxetine acetate, characterized in that it has a purity of at least 98%.

21. The process for the provision of a free base, characterized in that it comprises the step of mixing together a compound according to any of claims 1 to 8, 11 with an organic and / or inorganic base.

22. The process according to claim 21, characterized in that the base is selected from the group consisting essentially of: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, triethylamine, pyridine.

23. A free base obtainable by the process according to claim 21 or 22, characterized in the free base because it has a purity of at least 95% and more preferably of at least 98%.

24. The paroxetine free base according to claim 23, characterized in that it has a purity of at least 98%.