UA53707C2 - 4-phenylpiperidine derivatives, a process for preparation thereof (variants) and a pharmaceutical composition - Google Patents

Abstract

The invention relates to a compound, and phannaceutically 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 C1-4alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsuifonyl 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-C10alkyl group; a phenyl group optionally substituted by one or more of the following groups: a C1-C10alkyl group, a halogen group, a nitro group, hydroxy group, and/or an alkoxy group. (I).

Description

Description of the invention

This invention relates to the group of trisubstituted, 4-phenylpiperidines, the process of creating such compounds and 2 the use of such compounds for the manufacture of medicines.

The compound paroxetine, trans-4-(4'-fluorophenyl)-3-(34-methylene-dioxyphenoxymethyl)piperidine, having the formula:

IS

Pho, o c)

M

H is known and used in drugs for the treatment, in particular, of depression.

Paroxetine is used as a therapeutic agent in the form of salts of pharmaceutically acceptable acids.

The first clinical trials were conducted with acetates.

A known salt used is the hydrochloride salt of paroxetine. This salt is believed to be the active ingredient in several commercial pharmaceutical products, such as Rakhi and Zegohai. Several forms of paroxetine hydrochloride have been described: - dehydrated form in several crystalline modifications (PCT Arri. UMO 96/24595); c - hydrated form - hemihydrate (ER 223403) and in solvated forms. at

A comparison of the behavior between dehydrated and hydrated forms of paroxetine hydrochloride is described in Ipi).

Journal of Research, 42, 135 - 143 (1988).

Most of these known salts of paroxetine have unsuitable physicochemical characteristics to ensure safe and effective processing in the process of their production and creation of final forms, because they are unstable (acetate, maleate) and have undesirable hygroscopicity. at

In addition, their production by crystallization from aqueous and non-aqueous solvents is usually low-yield and difficult, because they usually contain an undefined and unpredictable amount of bound and - solvent, which is difficult to remove. with

Paroxetine hydrochloride crystalline hemihydrate solves these problems, but, as claimed in UMO 95/16448, its limited photostability causes undesirable coloration during the classical iv) wet tableting procedure.

In addition, paroxetine hydrochloride crystalline hemihydrate shows only limited solubility in water.

In general, it is assumed that in cases where the solubility in water is low, for example, Zmg/l, the rate of dissolution when applying ip mimo may be limited by the rate of absorption. The aqueous solubility of paroxetine hemihydrate at room temperature relatively slightly exceeds this threshold. The object of the present invention is to create a compound with improved characteristics. According to the first aspect, the present invention includes a compound and a pharmaceutically acceptable salt having the formula I:

H

1 and ov - g Y 2 note about Ko "I K is an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted by C..4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylene dioxy, or represents tetrahydronaphthyl, - B represents hydrogen, trifluoro (Sui.4) alkyl, alkyl or alkynyl, - X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl , hydroxy, halogen, or methylthio or aralkyl, where - B? represents: - C4-C alkyl group, 60 - phenyl group, optionally substituted by one or more of the following groups: - C4-C alkyl group, - halogen, - a nitro group, - a hydroxy group, 65 - Mmabo an oxy group.

The inventors have found that these compounds exhibit good stability and very high solubility. This is an advantage because high concentrations of the compound can be obtained in small volumes.

The K group is preferably a 3, 4 methylenedioxyphenyl group of the formula:

With and; 8)

The X group is preferably fluorine attached at position 4 to the phenyl ring.

IN? group is preferably a C1-C0 alkyl group, and most preferably a C1-C0 alkyl group, to ensure optimal solubility. 70 The compounds may have a solubility, at 20"C, of at least 1 Ωg/ml of water, preferably they have a solubility in water of at least 100, for example 500 and, most preferably, at least 100 Ωg/ml of water.

In accordance with the second aspect, the presented invention covers the process of manufacturing the above-mentioned compound, including the steps of mixing the 4-phenylpiperidine compound, a salt and/or its base having the formula: where: - K is an alkyl or alkynyl group having 1- 4 carbon atoms, or a phenyl group optionally substituted with C 4.4 alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represents tetrahydronaphthyl, c - B represents hydrogen, trifluoro (Sui.4) alkyl, alkyl or alkynyl, d) - X is hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkoxy, with sulfonic acid of the general formula Co-5Oz3H, where K2 is: - C4 - Cid alkyl group, - phenyl group, optionally substituted by one or a large number of the following groups: t - C4- Co alkyl group, av! - a halogen, - a nitro group, - - a hydroxy group, co - Mmabo an alkoxy group to create a solution, followed by separation of the formed compound from this solution.

The compounds of this invention may be prepared from the free base of 4-phenylpiperidine of formula I, preferably paroxetine, by treatment with sulfonic acid as defined above in a suitable solvent to form a solution of the target acid addition salt, after which the compound precipitates in this solution.

The reaction scheme of paroxetine free base and sulfonic acid is as follows:

E - c 2" about her about

Fe XX k no-b-ya, ----5 DE y

Go 1 (c) o Ge) (8) o MI I

N Ma - no no-iya,

Ge Sho o "m The formation of the solution can preferably occur at temperatures from approximately 0"C to the boiling point of the solvent.

If necessary, the solution can be purified by treatment with activated carbon, silica gel or other suitable materials.

Gee! Alternatively, a salt solution according to the invention can be formed by dissolving a salt of 4-phenylpiperidine having the formula HER with an organic sulfonic acid. For example, the compounds of the present invention can be prepared from paroxetine C-S carboxylate, such as acetate, by adding an appropriate organic sulfonic acid to a solution of said carboxylate according to the following scheme: b5

IS

Oh, and HER oh no note -- oh oh

M. G.

Nn Ma.

H notes, 6;

In accordance with a third aspect, the present invention encompasses a compound obtainable by this 72 process.

According to the fourth aspect, the present invention relates to the use of the above-mentioned compound for use as a medicament and, according to the fifth aspect, the invention relates to a medicament containing such a compound and its use for the treatment of depression, obsessive-compulsive disorder, panic disorder, bulimia, anorexia , pain, obesity, dementia, migraine, social phobia, depression caused by premenstrual tension.

According to the sixth aspect, the present invention relates to the use of the compound of this invention as a reagent in further synthesis. More specifically, the compounds of the present invention can be used as a starting reagent for the further creation of acid-addition salts, for example, for the further preparation of acid-addition salts of paroxetine, by interaction with the appropriate reagent, i.e. with 29 the appropriate acid. For example, the formation of paroxetine maleate according to the presented invention takes place according to the following reaction scheme:

IS

E m

Zo o (8; y y; 4 | on o -z- (ze)

Go) 6) ON);

Go! oh my

M Her o ." nono-i-v, M

But oh but them - with but and? 0) and the formation of paroxetine acetate occurs according to the following reaction scheme: 1

E o E -i («c) o 16) " m Ж NOde --k » o (9) o o)

She

M b no-ya-y M

F) N Y M. o nods ho) o vo This is an advantageous way, because, using essentially pure salts of sulfonic acid according to the present invention as a starting reagent, obtaining the next salt, as indicated above, leads in the future to the formation of a salt that has a high degree of purity. The inventors have shown that such salts have a remarkably high purity.

Similarly, the compounds of this invention can interact with a base, such as an inorganic and/or an organic base to form (release) the free bases of the corresponding compounds.

This is illustrated by the example of paroxetine, when the reaction occurs according to the following scheme:

And E

U masn o - : ---zh»» U z snuvo, ma o o Ge! (o; 70 (i

Ts no-y-ya, M n (in;

The free bases released from the compounds of the present invention seem to have a higher degree of purity 79 than if they were formed using known methods, which is especially important in the case of their use for the production of medicinal products.

Accordingly, the novel compounds in the first aspect of the present invention may also form hydrates and/or solvates upon interaction with appropriate reagents, i.e. with water and/or solvent. Examples of such further salts, hydrates and solvates, for example paroxetine salts, hydrates and solvates, are: hydrochloride oxalate dihydrate hydrobromide succinate trihydrate hydroiodide tartrate hexahydrate acetate citrate methanolate se propionate embonate ztanolate he) maleate hemihydrate fumarate hydrate

The inventors have shown that such salts have a relatively high degree of purity. uh-

Examples of bases that can be used in the preparation of free bases are: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, trimethylamine, pyridine, etc. -

Since the compounds of the present invention exhibit high solubility, they can be dosed, for example, by injection, in high concentrations in small volumes of solution, such a method of dosing is particularly advantageous in the treatment of certain patients, such as those with manic-depressive syndrome M, etc., that is, patients who cannot or do not want to swallow medications.

The compounds of the present invention can be presented in various types of pharmaceutical compositions for the treatment of humans and animals. Pharmaceutical compositions according to the present invention contain the compound of this invention alone or together with a pharmaceutically acceptable carrier or solvent. Compositions for oral use (tablets, capsules) are preferred, but compositions for parenteral or local use are also within the scope of the present invention. The high degree of solubility in water of the compounds of the present invention allows for a high dissolution rate of solid dosage forms based on the compounds of the present invention during the release of the drug, as well as good bioavailability after oral administration of the drug.

Tablets containing the compound of the present invention can be produced both by a tableting procedure in which water is present (for example, wet granulation) and by using 1 tableting methods where water is absent (direct compression, dry granulation) and can be coated shell by any of these acceptable coating methods.

The present invention will be further explained using the following examples and results. -i EXPERIMENT o 50 The seed crystal of paroxetine methanesulfonate was prepared in the following way: 2.7 g (8.2 mmol) of paroxetine was dissolved in 15 ml of hot ethanol. that 1.0 g (10.4 mmol) of methanesulfonic acid was added to 15 ml of ethanol and the mixture was cooled to room temperature. After the mixture reached room temperature, it was moved to a freezer at -20"C overnight. No crystalline compound was obtained.

The mixture was evaporated to a dry residue to give an oil. o After a 1-month stay at room temperature, a solid wax-like substance was obtained.

Part of this substance was collected, and the remainder was dissolved in 10 ml of EtOAc. Waxy crystals were added, and the mixture was placed in a freezer at -20°C overnight. A white crystalline product was precipitated. After filtration and drying in a vacuum oven, 2.5 g (5.9 mmol) of paroxetine methanesulfonate was obtained. Yield 72905.

This seed crystal was then used in the following examples 1 and 3.

Examples

Example 1

Paroxetine methanesulfonate from paroxetine 65 To a solution of 43.5 g (132 mmol) of paroxetine prepared using the procedure described in the patent

USA 4007196,

12.77 (1582 mmol) of methanesulfonic acid was added to 150 ml of boiling ethyl acetate. The mixture was left at room temperature for 2 hours. Then the mixture was placed overnight at -207C with the seed crystal. The resulting solid was filtered and washed

B5Oml ether. The resulting white solid was dried overnight in a vacuum oven. 47.1 g (111 mmol) of product was obtained.

Output 99,595.

The obtained analytical characteristics of the obtained compound are shown in Table 1. The purity of the obtained compound was 9896 (NRI C). 70 Example 2

Paroxetine benzenesulfonate from paroxetine

3.8 g (11.5 mmol) of paroxetine was dissolved in 1 b0 ml of hot ethyl acetate. Then 1.82 (11.5 mmol) of anhydrous benzenesulfonic acid was added. The mixture was left at room temperature for 2 7/5 hours. The mixture was evaporated to a dry residue and dissolved in dichloromethane, after which it was evaporated again to a dry residue, obtaining an oil. This oil solidified under vacuum evaporation (0.mm Na) to give 5.0g (1.3mmol) of an off-white solid. To this solid was added bml of acetone and the suspension was stirred for 5 minutes, during which time a white suspension was obtained. The solid was filtered off and dried under vacuum. 4.8 g (9.9 mmol) of product was obtained.

Exit 85905.

Analytical characteristics of the obtained compound are shown in Table 1. The purity of the obtained compound was 99.4960 (NRIO).

Example From school

Paroxetine p-toluenesulfonate from paroxetine 5.0 g (15 mmol) of paroxetine was dissolved in 25 ml of hot ethyl acetate. i) 2.9 g (15 mmol) of p-toluenesulfonic acid was added. The mixture was left at room temperature for 2 hours and then placed in a seed crystal freezer for 14 hours. The solid was filtered off and washed once with 10 ml of n-hexane. The resulting solid was dried overnight in a vacuum oven. 4.8g (1Omol) of a white solid was obtained. at

Exit 67905. h-

Analytical characteristics of the obtained compound are shown in Table 1. The purity of the obtained compound was 99.4960 (NRG OS). me)

Example 4

Paroxetine p-chlorobenzene sulfonate from paroxetine 1.1 g (3.0 mmol) of paroxetine was dissolved in

Zml of hot ethyl acetate. 0.7 bg (3.3 mmol) of 9090% p-chlorobenzenesulfonic acid was added. The mixture was left at room temperature for 1 hour and then washed with 3 ml of water. The organic layer was dried over NaCl, filtered and evaporated to a dry residue to give 1.5 g (2.9 mmol) of a white solid.

Exit 8895.

Analytical characteristics of the obtained compound are shown in Table 1. The purity of the obtained compound was 99.4960 s (NRIO).

Example 5 o Paroxetine maleate from paroxetine methanesulfonate - And 1.0 g (2 4 mmol) of paroxetine methanesulfonate was dissolved in bml of hot water. About 0.32 g (2.8 mmol) of maleic acid was added to this solution. The mixture was kept at 47C overnight, after which solid "M" with yellow oil precipitated to the bottom of the flask. The solid/oil mixture was filtered and washed 3 times with 10 ml of ether and dried in a vacuum oven.

O,vg (2,Omol) of whitish crystals was obtained.

Exit 85905.

F) The purity of the obtained compound was 99.595 (NRI C). ka Example 6

Paroxetine acetate from paroxetine methanesulfonate in 1.0 g (24 mmol) of paroxetine methanesulfonate was dissolved in bml of hot iso-propanol. 0.2 g (3.2 mmol) of acetic acid was added to this solution. The mixture was placed overnight at 4"C, after which a solid precipitated. The solid was filtered and washed three times with 10 ml of ether and dried in a vacuum oven.

0.5 g (1.3 mmol) of white crystals were obtained. 65 Exit 54965.

The purity of the obtained compound was 99.595 (NRI C).

Example 7

Paroxetine free base from paroxetine methanesulfonate 10.0g (24.0mmol) of paroxetine methanesulfonate was dissolved in 15Oml of hot water and 200ml of ethyl acetate. To this solution was added 12.4 g (Zimmol) of an aqueous solution of TOwag. 95 MaonN and the suspension was stirred for 15 minutes. The layers were separated and the aqueous layer was extracted once using

B5Oml of ethyl acetate. The combined organic layers were washed once with 70 ml of water and dried over NaCl. Ma»ZO,) was filtered and washed once with 50 ml of ethyl acetate. Ethyl acetate was evaporated to give 7.5 g (22.8 mmol) of an oily product.

Exit 9595.

The purity of the obtained compound was 99.595 (NRI C).

Table 1

Characteristics of salts of paroxetine with some organic sulfonic acids H-5OzH

H-CH" - (paroxetine methanesulfonate): m.p.: 1427-1446

DSC curve (closed cup, 10/min.); beginning 145.87, 79.0 Jug. high school

IR spectra (KVh, cm'): 531, 546, 777, 838, 931, 962, 1038, 1100, 1169, 1208, 1469, 1500, at 1515, 1615, 2577, 2869, 2900, 3023. cha 1H-NMR (h./million): 1.99 (sh d, Nesk; 1H); 2.27 (ddd, Nvak; 1H); 2.48-2.85 (m, Ne, 1NU; 2.82-2.92 o (m, Nu, SNU, 4H); 2.95-3.20 (m, Noak, Neak; 2H); 3.47 (dd, N., 1H); 3.58-3.74 (m, Naovkv; Neekv; IN, - so zv ZN); 5.88 (s, H", 2 H); 6.10 (dd, He, 1H); 6.33 (d, He", 1H); 6 ... , 1H). 130-NMR (ppm): 30.0 (s, Sv); 39.3 (s, Sv); 39.5 (s, Ca); 41.7 (s, 5SU; 44.6 (s, Sv); 46.8 (c, "shi c C"); 87.4 (c, St); 97.8 (c, So"); 101.2 (c, C"); 105.4 (c, Se); 107.8 (c, Se); 115.8 (d . d, Xia); v-Sen - (paroxetine benzenesulfonate): 1 xu m.p.: 557-607С iv. 50 IR spectra (KVh, cm' in: 530, 564, 614, 689, 728, 764, 828, 929. (w d, Neek; 1H); 2.10-2.28 (m, Nezk, 1H)U; 2.38-2.52 (m, Nz, 1H); 2.82 o (ddd, Na, 1H); 3.02-3.18 (m, Novak; Nvak 2H); 3.37 (dd , Well, 1H); 3.48 (d, H,, 1H); 3.80-3.82 (m, ko Novo Neekv 2H); 5.87 (c, No, 2 H); 6.06 (dd, No. 1H); 6.29 (d, Ne", 1H); 6.60 (d. No, 1H); 6.90 bo (dd, Na; Ne, 2H); 7.04 (dd, H», Ne, 2H)U; 7.40 (d, AS, ZNU; 7.94 (d, REPLACEMENT, 2); 8.81 (w d, b5

Table 1

Mnke 1H); 9.04 (sh d, Mak 18). 13C-NMR (ppm): 29.9 (s, Sv); 39.2 (c, Sz); 41.5 (c, Sa); 44.8 (c, St); 47.0 (c, Sg); 67.3 (c, y So); 97.9 (s, Se; 101.2 (s, Se); 105.5 (s, Se); 107.8 (s, St); 115.7 (d, St, St); 125.9 (s, St); 128.6 (s, Se); 128.8 (s, Se, Sg); 130.6 (s, Sep); 137.1 (s, Sg); 141.9 (s, St); 144.1 (s, Se); 148.2 (s, Su; 153.7 (s, Si") 161.8 (c, Xia);

A-l-SNUSeNa - (paroxetine p-toluenesulfonate): m.p.: 14841507С

DSC curve (closed bowl, 10/min); beginning 151.67, 71.6 J/h.

IR spectra (KVh, cm"): 529, 557, 671, 771, 800, 814, 921, 936, 1000, 1029, 1100, 1157, 1186, ch 71 4229,1471, 1507, 1600, 2557, 2829, 3029 1H-NMR (ppm): 1.89 (w d, Nvek» 1H); 2-10-2.50 (m, Nyak; CH», 5H); 2.82 (ddd, Na, 1H); 1.89 ( Sh d, Neskv; 1H); 2.10-2.50 (m, Naak Nz, SN», 5H); 2.82 (ddd, Ne, 1H); 2.97-3.18 (m, Naaks, Nevks" and. 2H); 3.36 (d , H", 2H); 8.06 (dd, No", 1H); 6.29 (d, Ne", 1H); 6.60 (d, Ne", TN); 6.90 (dd, Ne", H", im 2H3; 7.04 (dd, NU, 1H); 3.48 (dd, NU, 1); 3.52-3.77 (m, Nova; Nvekv A); 5.87 (s, H", 2H); 6.06 at 7 (dd, Ne, 1; 6.28 (d, Ne", 14; 8.59 (d, Ne, 1NU; 6.90 (dd, Ne, Me, 28); 7.05 (dd, H", Ne, 2); her 7.24 (d, SNaAg, 2H); 8.91 (w d, MNek, 1H); 9.17 (w d, MNako, 1H). « s 70 13C-NMR (ppm): 21.3 (s , Se); 29.9 (s, C"); 39.2 (s, Sz); 41.5 (s, Sa); 44.7 (s, Sv); 46.9 (s, 8 khz" Sg); 67.3 (s, St); 97.8 (c, C"); 101.1 (c, St); 105.5 (c, Ce); 107.8 (c, Ce); 115.6 (d, C", Ce); 15 125.8 (c, C); 129.0 (c . Se»); 153.8 161.8 (c, Xia»); 161.8 (d, Xia). - and Ve-l-SiSeNa - (paroxetine p-chlorobenzenesulfonate):

FO | hplotvuvos

IR spectra (KVh, cm): 486, 557, 643, 736, 821, 1000, 1029, 1086, 1114, 1186, 1229, 1471, 1486, 1514, 1600, 1657, 2857, 3029. o 1H-NMR ( h./million): 1.91 (sh d, Neyu; 1H); 2.15 (Sunday, Sunday, 1H); 2.37-2.52 (m, Na, 1H); 2.81 (ddd, and Na, 1H); 2.93-3.21 (m, Noako Nejo; NU; 3.37 (dd, Nu, 1H); 3.49 (d, NU, 1H); 3.61-3.81 (ddd, Nu, b5

Table

Characterization of paroxetine salts with some organic sulfonic acids H-ZOzH 1NU; 2.93-3.21 (m, Nayako Nvak" 28) 33.37 (dd, H, 1H); 3.49 (d, NU, 1H);. 3.61-3.81 (m, Noekv;

Nav, 2H); 5.88 (c, H", 2NU; 6.05 (dd, Ne, 1H); 6.27 (d, H",, 1H); 6.59 (d, Ne", 1NU; 6.91 (dd,

Well, No, 2NU; 7.03 (dd, No», No, 2H); 7.39 (d, SIL, 2H); 7.86 (d, CJSC, 2H); 8.78 (w d, MNek; 1H); 9.02 (w d, MNako; TN). then 13C-NMR (ppm): 30.0 (s, C5); 39.3 (c, Sz); 41.5 (c, Sa); 44.9 (c, St); 47.1 (c, C"); 67.3 (c,

WITH; 97.9 (c, C"); 101.2 (c, C"); 105.5 (c, Se"); 107.9 (s, Se"; 115.8 (d, St, Se); 127.6 (s, St); 128.8 (s, Se, Se); 132.0 (s, Sa); 137.0 (s, Se); 137.2 (s, Seu; 141.8 (s, St); 142.0 (s, Sv); 148.2 (s, Se); 153.6 (s, St"); 161.8 (d, Xia).

The compounds of the invention are crystalline substances with defined melting points, DSC curves and

IR spectra. It cannot be excluded that in different conditions of their formation and under specific conditions, they could also exist in crystalline or polymorphic modifications that may differ from those described here. The compounds of the invention are also generally very stable and non-hygroscopic.

It should be understood that, in the present invention, the acid addition salts with organic M zo bulphonic acids are essentially free of bound organic solvent. Preferably, the amount of bound organic solvent should be less than 2.095 (w/w) on an anhydrous basis. at

They may, however, contain water of crystallization and also unbound water, that is, water that is not water M of crystallization.

The following tables 2 and 3 show the results of the study of hygroscopicity and stability (compared to known salts of paroxetine). yu « 4 Z p 111 pdrochloridi/ 31111111 kovi z y her i slo voy vos

What is the meaning of birth?

C 1 metvnoulronat| pluolulphonate because Ethanol! 207 36 BO

Sv r 1 r111khvoo) viyu vo o vyu111111331111100zv te 111131111111vooi o rvav hoov

Examples of analytical data for the study of paroxetine salts and free bases obtained in examples 5 - 7 are given in table b.

Table b

Characterization of paroxetine salts/free bases

Paroxetine maleate: 201 nm 128-1307s 1H-NMR (part.laln.): 1.65 (m, Neek; Neva 2H); 2.00-2.50 (m, No, 1H); 2.55-3.15 (m, Nodko Nvak» Na, s ovo ZN); 3.15-3.75 (m, Noeks, Negv, Nu, 2ZN); 5.67 (c, H», 2H); 5.97 (c, Na, 1H); 6,12 (dd, Ne", 1H); at 6.42 (d, No, 1H); 6.67 (d, Ne", 1H); 8.95-7.35 (m, No, No, No, No, 4H). cha zo Paroxetine acetate: "c) mp: 123-135 76 ich- 1H-NMR (ppm): 1.70-2.00 (m, Neva; Neak, 2H); 1.97 (c, Na, ZN); 2.05-2.50 (m, Na, 1H); 2.50 a.m

IS c) 3.00 (m, Na, Naako; Do you KNOW); 3.05-3.75 (m, Neoekv» Nveka, NU, ZN); 65.05 (c, H", 2H); 6.28 (dd, Ne", 1H); 6.58 (d, No, 1NU; 6.65 (d, No", 1H); 7.10-7.50 (m, No, Nu, No, No, 4H). "70 paroxetine: 8 s with" 3H-NMR (h ./yumln.)y: 1.60-2.00 (m, Nvekv; Neako2H); 2.00-2.35 (m, Na, 1H); 2.40-2.95 (m, Na, Nak, 15 Neva ZN); 3.15-3.70 (m, Novkv; Nevekv, NU, 23H); 5.67 (s, NU, 2H); 6.11 (dd, Ne", 1H); 6.43 (d, Ne", 1 s 1H)); 6.62 (d, No, 1H); 6.80-7.35 (m, H», No, No, No, 4H). ш- It should be understood that the invention is not limited to the above description, but is rather defined

Oz 070 with the following formula.

Sources of information "M Rezusporpaptasiodu, 57, 151 - 153 (1978); Iria. 68, 229 - 233 (1980), Eigoreap doigpa | oi Ripagtasiodu, 47, 351 - 358 (1978); in OBR 4007196, a description of the manufacture of paroxetine maleate is given.

Claims (1)

FORMULA OF THE INVENTION. 1. Compound and pharmaceutically acceptable salts of formula I: HF) X heme) Ok bo uyuo-Y I b de: 65 - K is an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group, optionally substituted with C 4.alkyl, alkylthio, alkoxy, halogen . , alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or aralkyl, - B? represents: - C4- Cd alkyl group, - phenyl group, optionally substituted by one or more of the following groups: - C4- C alkyl group, - halogen group, - nitro group, - hydroxy group, - Mma or alkoxy group. 2. The compound, according to point 1, where K is C, 4 methylenedioxyphenyl group of the formula: ФО, at C. A compound according to claim 1 or 2, wherein the X group is preferably a fluoro group attached at the 4-position to the phenyl ring. 4. The compound according to clauses 1-3, where vo is a C - Su alkyl group. 5. The compound according to clauses 1-4, where vo is a C - C alkyl group. 6. A compound according to any of the preceding clauses, having a solubility at 207C of at least 1Omg/ml of water. 7. The compound according to point b, having a solubility in water of at least 100, preferably 500 and most preferably 100 Ωg/ml. with 8. The method of obtaining a compound according to any of the previous clauses, which includes the steps of mixing d) the compound, its salt and/or base having the formula I: ; K is an alkyl or alkynyl group having 1-4 carbon atoms, or a phenyl group optionally substituted with C 4-alkyl, alkylthio, alkoxy, halogen, nitro, acylamino, methylsulfonyl or methylenedioxy, or represented by tetrahydronaphthyl, " - B' represents hydrogen, trifluoro(C3 4)alkyl, alkyl or alkynyl, - - X represents hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, with methylthio or aralkoxy, with sulfonic acid of the general formula Co-5OZN, Iz" where B2 represents: - C4- Cd alkyl group, - phenyl group, optionally substituted by one or more of the following groups: сл 15 - C4- Co with an alkyl group, - a halogen, (95) - a nitro group, - - a hydroxy group, - Mma or an alkoxy group, (ав) 50 to form a solution, after which the solid formed can be separated from this solution. -h 9. The compound, according to any of items 1 - 7, obtained by the method according to item 8. 10. A compound according to any of items 1 - 7 and 9, for use as a medicament. 11. A medicament comprising a compound according to any of items 1 to 7, 9 and 10 and pharmaceutically acceptable carriers/solvents. 59 12. Use of the compound according to any of items 1 - 7, 9 and 10 for the manufacture of medicaments. GF) 13. Use of a compound according to any of items 1 - 7 for the manufacture of a medicament for the treatment of 7 depression, obsessive-compulsive disorder, panic disorder, bulimia, anorexia, pain, obesity, senile dementia, social phobia, premenstrual-induced depression voltage in 14. Use of the compound according to any items 1-7, 9, and 110 as a reagent in further synthesis. 15. The method of making ions of salts or solvates, including the stages of mixing the compound according to any of the clauses! - 7, 9 and 10 with a reagent selected from the group consisting mainly of: hydrofluoric acid, citric acid, hydrobromic acid, embonic/pamic acid, hydroiodic acid, sulfuric acid, acetic acid, water, propionic acid, methanol, maleic acid, ethanol, fumaric acid, oxalic acid, succinic acid tartaric acid 70 16. Salt obtained by the method according to point 15. 17. The salt according to item 16, having a purity of at least 100%, preferably at least 95% and more preferably at least 98%. 18. Paroxetine maleate having a purity of at least 98965. 19. Paroxetine acetate having a purity of at least 98905. 75 20. A method for obtaining a free base, including the step of mixing the compound according to any of items 1 - 7, 9, 10 with an organic and/or inorganic base. 21 The method according to item 20, where the base is selected from the group consisting mainly of: sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, trimethylamine, pyridine. 22. The free base obtained by the method according to item 20 or 21 having a purity of at least 95 95 and more preferably at least 98905. 23. The free base of paroxetine, according to item 22, having a purity of at least 98905. The formula of the invention with points 6) 1. The compound and pharmaceutically acceptable salts having the formula 1: х и- Зо о ча о ка (зе) ИВ) Mono -5-и юю 1 и а де: « K - 34-methylenedioxyphenyl group, B! - hydrogen, trifluoro(C.d)alkyl, alkyl or alkynyl, - with X - hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or a aralkoxy, and » в2 : С1- C3o alkyl group, phenyl group, optionally substituted by one or more of the following groups: o - C4-C1o alkyl group, c - halogen, - nitro group, - - hydroxy group, o 50 - Mmabo alkoxy group. 2. The compound according to point 1, where the K group is a 34"-methylenedioxyphenyl group of the formula: - (ЧИ and С, о and Б! are hydrogen. C. A compound according to item 1 or 2, wherein the X group is preferably a fluoro group attached at position 4 to the phenyl ring. 4. Compound according to any of items 1-3, where B? group is a C1-C1 alkyl group. 60 5. Compound according to any of items 1-4, where B? group is a C-C alkyl group. 6. A compound according to any of the preceding claims, having a solubility at 202C of at least 10 mg per ml of water. 7. The compound according to point b, having a solubility in water of at least 100, preferably 500 and most preferably 1000 mg/ml. bo 8. A compound according to any of the preceding clauses, selected from the group consisting mainly of: - paroxetine methanesulfonate (formula 1), where X is fluorine in the l-position, K is 3'Y-methylenedioxyphenyl, B is hydrogen and B2 is methyl; - paroxetine benzenesulfonate (formula 1), where X is fluorine in the l-position, K is 3'4-methylenedioxyphenyl, B is hydrogen and B2 is phenyl; - paroxetine l-toluenesulfonate (formula 1), where X is fluorine in the l-position, K is 3'4-methylenedioxyphenyl, v' is hydrogen and 2 is methyl,phenyl; - paroxetine l-chlorobenzenesulfonate (formula 1), where X is fluorine in the l-position, B is 3'4-methylenedioxyphenyl, B! - hydrogen and B? - chlorophenyl; 9. The method of obtaining a compound according to any of the previous clauses, which consists in mixing a compound, its salt and/or a base having the formula II: х Ок М И и Кк where: - К - 34-methylenedioxyphenyl group , - B". hydrogen, trifluoro(C dalalkyl, alkyl or alkynyl, c - X - hydrogen, alkyl having 1-4 carbon atoms, alkoxy, trifluoroalkyl, hydroxy, halogen, methylthio or o-aralkoxy, with sulfonic acid of the general formula Co-ZOzZN, where в2-: - C41-C4ou alkyl group, - - phenyl group, optionally substituted by one or more of the following groups: o - C41-C14ou alkyl group, - halogen, - - nitro group, c - hydroxy group, Zo - Mmabo with an alkoxy group, o with the formation of a solution from which the solid substance formed can be isolated. 10. The method of obtaining a compound according to any of clauses 1-8 in the form of a solvate, which consists in mixing the compound according to any of clauses 1-8 with a reagent selected from the group consisting of, mainly " PROCEDURE, 3: water o) with methanol "" ethanol. " 11. The compound according to any of items 1-8 or its solvate obtained by the method according to item 9 or 10. 12. A compound according to any of items 1-8 and 11 for use as a medicament. 13. Medicine, which includes a compound according to any of items 1-8, 11, 12 and pharmaceutically acceptable carriers and/or solvents. 2) 14. The method of obtaining a salt, which consists in mixing the compound according to any of items 1-8 with a reagent selected from the group consisting mainly of: - hydrochloric acid, hydrobromic acid, hydroiodic acid , acetic acid, propionic acid, maleic acid, fumaric acid, oxalic acid, succinic acid, tartaric acid, citric acid, embonic/pamic acid, sulfuric acid. "m 15. Salt obtained according to the method according to item 16. 16. The salt according to item 17, having a purity of at least 90% by weight, preferably at least 95% by weight, and more preferably at least 98% by weight. 59 17. Paroxetine maleate having a purity of at least 98965. GF) 18. Paroxetine acetate having a purity of at least 98905. 19. The method of obtaining free bases, which includes mixing the compound according to any of items 1-8, 11 with an organic and/or inorganic base. 20. The method according to item 21, where the base is selected from the group consisting of: sodium hydroxide, 60 potassium hydroxide, calcium hydroxide, ammonium hydroxide, sodium carbonate, methylamine, dimethylamine, trimethylamine, pyridine. 21. The free base obtained by the method according to item 21 or 22 having a purity of at least 95 95 and more preferably at least 9895. 22. The paroxetine free base according to claim 23 having a purity of at least 98905. b5 Official bulletin "Industrial Property". Book 1 "Inventions, useful models, topographies of integrated microcircuits", 2003, M 2, 15.02.2003. State Department of Intellectual Property of the Ministry of Education and Science of Ukraine. s o cha o cha so IS c) shi s z 1 (95) - And at 50 what F) name) 60 b5