Anhydrate paroxetine hydrochloride, solvate paroxetine hydrochloride and methods for their production

 

(57) Abstract:

The present invention relates to anhydrate paroxetine hydrochloride essentially free of bound propan-2-ol in the form of several new forms (a, b, C and D), the manner of receiving them and to new intermediate compounds used to obtain anhydrate, namely, solvate paroxetine hydrochloride, other than MES propan-2-ol and the method of its production. Anhydrate paroxetine hydrochloride essentially free from propan-2-ol in the form of a, b, C, D is used to treat a number of diseases, namely alcoholism, anxiety, depression, and other 9 C. and 4 h.p. f-crystals, 11 ill.

The present invention relates to new compounds, methods for their preparation and their use for the treatment of diseases.

The application EP-B-223403 (Beecham group PLC) describes hemihydrate paroxetine hydrochloride and its use for the treatment of certain diseases. Example 8 description this application relates to the production of anhydrate paroxetine hydrochloride in the form of plates with a melting point 118oC and having a spectrum band at 890, 1200, 1490, 3400 and 3640 cm-1a crystallization from aqueous solvent. This material is hereinafter referred to as form z By the IDA, in the document there is no specific reference to any alternative method or mod method to obtain anhydrate.

Anhydrate paroxetine hydrochloride is also disclosed in International Journal of Pharmaceutics 42, (1988) 135 - 143, article published by Elsevier. It says that anhydrate obtained by crystallization paroxetine hydrochloride of anhydrous propan-2-ol. Subsequent repetition of this process gave propan-2-ol MES paroxetine hydrochloride. That is to say that in the product there are bound propan-2-ol. Associated propan-2-ol cannot be removed using conventional methods of drying, such as drying in a vacuum oven.

Anhydrate paroxetine hydrochloride essentially free of bound propan-2-ol, was not described in the literature, was not disclosed any way which would result in just such a product. In the present invention found a method of producing anhydrate paroxetine hydrochloride essentially free of bound propan-2-ol. Moreover, surprisingly, we identified four new forms of anhydrate paroxetine hydrochloride, and the means of obtaining. These forms are referred to herein as A, B, C and D, respectively. Characterizing data for forms A, B, C and D with the camping anhydrate paroxetine hydrochloride, essentially free of bound propan-2-ol.

The invention also provides anhydrate paroxetine hydrochloride essentially free of bound organic solvent.

The present invention also offers anhydrate paroxetine hydrochloride essentially free from propan-2-ol, provided that he is not in the form z

The expression "essentially free of bound organic solvent" means that the compound contains fewer propane-2-ol, than the amount which remains solvated, i.e., bound within the crystal lattice of the product under traditional conditions of drying in a vacuum oven.

The present invention also relates to a solvate of paroxetine hydrochloride, other than MES propan-2-ol as starting materials for the production of anhydrate paroxetine hydrochloride essentially free of bound organic solvent. Examples of the solvate include solvate alcohols (other than propane-2-ol) such as propan-1-ol and ethanol; a solvate of organic acids such as acetic acid; a solvate of organic bases, such as pyridine; a solvate of nitrides, such as acetonitrile; evagorou, such as chloroform and solvate hydrocarbons, such as toluene.

It is desirable that anhydrate paroxetine essentially free of bound propan-2-ol, was obtained in almost pure form. Anhydrate paroxetine hydrochloride free of bound propan-2-ol is obtained in a purity of more than 50%, preferably more than 60: still more preferably 70%, and more than 80% and even 90%. It is most preferable to obtain the above-mentioned anhydrate in virtually pure form, i.e., anhedral paroxetine hydrochloride essentially free of bound propan-2-ol, with a net of more than 95%.

It should be clear that proposed by the present invention anhydrate paroxetine hydrochloride essentially free from propan-2-ol, may contain unbound water, i.e. water, which does not include water of crystallization.

Usually the amount of bound organic solvent based on the weight/weight. will be less than 2.0%, preferably less than 1.8%, preferably less than 1.5%, more preferably less than 1.0%, less than 0.5% and preferably less than 0.1%.

In the present invention, all percentages are weight/weight unless otherwise specified.

Preferred vornicescu solvent, include:

i) anhedral paroxetine hydrochloride in the form of A; (as defined below);

ii) anhedral paroxetine hydrochloride in the form B; (as defined below);

iii) anhedral paroxetine hydrochloride in the form C; (as defined below);

iv) anhedral paroxetine hydrochloride in the form D; (as defined below).

Form anhydrate paroxetine hydrochloride, also as a form obtained according to the method described in EP-B-0223403 and International Journal of Pharmaceutics 42, (1988), 135 - 143, you can distinguish between crystalline form, analysis of the solvent or by methods such as infrared spectroscopy, melting point determination, x-ray diffraction, NMR, DSC, microscopy and other analytical techniques with which distinguish one form from another.

For example, form A, essentially free of solvent, is distinguished from other forms by using the following analytical data. The form has A melting point of about 123 - 125oC, if received with a clean, similar to the product described in example 1, which can be determined by usual methods, such as GHUR and bands in the IR spectrum (Fig.1), about 513, 538, 571, 592, 613, 665, 722, 761, 783, 806, 818, 839, 888, 906, 924, 947, 966, 982, 1006, 1034, 1068, 1091, 1134, 1194, 1221, 1248, 1286, 1340, 1387, 1493, 1513, 1562, 1604, 3402, 3631 cm-1oC open ditch and a maximum of about 121oC in a closed cell. Form A has an x-ray diffraction pattern similar to those shown in Fig. 4, for example, characteristic peaks are at 6.6, 8.0, 11.2, 13.1 degrees 2 theta, and an NMR spectrum in the solid state is similar to the spectrum shown in Fig. 7 with the characteristic peaks at 154.3, 149.3, 141.6, 138.5 frequent./million

Form B is essentially free of solvent, can be distinguished from other forms by the following analytical data, i.e., it has a melting point of about 138oC, when you get it with purity, similar to the product described in example 7, and which can be defined by traditional methods, such as GHUR and bands in the IR spectrum (Fig. 2) at about 538, 574, 614, 675, 722, 762, 782, 815, 833, 884, 925, 938, 970, 986, 1006, 1039, 1069, 1094, 1114, 1142, 1182, 1230, 1274, 1304, 1488, 1510, 1574, 1604, 1631 cm-1.

DSC of ectotherm measured at heating rate of 10oC per minute, shows a maximum at about 137oC as in closed and open cells. Form B has an x-ray diffraction pattern similar to those shown in Fig. 5, for example, characteristic peaks are at 5.7, 11.3, 12.4, 14.3 degrees 2 theta, and the range of NMR in the solid state is almost the same as the spectrum presented on the RM by the following analytical data, i.e. it has a melting point of about 164oC, when you get it with purity, similar to the product described in example 8, which can be defined by traditional methods, such as GHUR and bands in the IR spectrum (Fig. 3) at about 540, 574, 615, 674, 720, 760, 779, 802, 829, 840, 886, 935, 965, 984, 1007, 1034, 1092, 1109, 1139, 1183, 1218, 1240, 1264, 1280, 1507, 1540, 1558, 1598, 1652 cm-1.

DSC of ectotherm measured at heating rate of 10oC per minute, shows a maximum at about 161oC in closed and open cells.

Form C has an x-ray diffraction pattern is also similar to the one shown in Fig. 6, for example, characteristic peaks are at 10.1, 12.1, 13.1, 14.3 degrees 2 theta, and an NMR spectrum in the solid state is almost the same as the spectrum shown in Fig. 7 typical on 154.0, 148.5, 143.4, 140.4 part/million

Form D can be distinguished from other forms such analytical data: it exists in a semi-crystalline solid with a melting point of about 125oC, when obtained with a purity similar to the product described in example 14, which can be determined by traditional methods, such as GHUR.

Form D is also characterized by the fact that its physical characteristics are basically the same, the th MES toluene has a significant bands in the IR spectrum at about 1631, 1603, 1555, 1513, 1503, 1489, 1340, 1275, 1240, 1121, 1185, 1168, 1140, 1113, 1101, 1076, 1037, 1007, 986, 968, 935, 924, 885, 841, 818, 783, 760, 742, 720, 698, 672, 612, 572, 537 and 465 cm-1and characterized by x-ray diffraction peaks at 7.2, 9.3, 12.7 and 14.3 degrees 2 theta.

The person skilled in the art, using traditional techniques and based on the data presented above, which are given in the examples, and any other traditional methods, can easily determine what specific form represents a particular sample anhydride paroxetine hydrochloride.

Preferably forms A and B exist in the form of needle-shaped crystals, and form C is a needle crystals or prisms.

The present invention also provides a method of obtaining anhydrate paroxetine hydrochloride essentially free from propan-2-ol, which comprises crystallization of paroxetine hydrochloride or:

i) an organic solvent or mixture of organic solvents, which form the MES with paroxetine hydrochloride and which are not removed by traditional methods of drying;

ii) an organic solvent or mixture of organic solvents that form or not form a MES with paroxetine hydrochloride, but which removed the traditional schaltungen displacing agent, in case ii) removing the solvent.

The present invention also provides a method of obtaining solvate paroxetine hydrochloride, other than MES propan-2-ol, which comprises crystallization of paroxetine hydrochloride in an organic solvent or mixture of solvents, which form the MES with paroxetine hydrochloride and which are not removed by traditional methods of drying.

The present invention also provides a method of producing anhydrate paroxetine hydrochloride essentially free of bound organic solvent, which includes the displacement of solvated solvent or solvents from the MES paroxetine hydrochloride using the displacing agent.

In one of the preferred variants of the invention, the crystallization of anhydrite paroxetine hydrochloride is achieved by contacting the solution of the free base of paroxetine in the organic solvent or solvents with dry gaseous hydrogen chloride.

The water contained in the paroxetine hydrochloride, can be removed before crystallization azeotropic distillation. Therefore, suitable solvents include those which form an azeotrope with water, is water.

Thus, in another aspect of the invention, anhedral paroxetine hydrochloride crystallized by dissolution of hemihydrate paroxetine hydrochloride in an appropriate solvent essentially free of water, which forms an azeotrope with water. The solvent is removed by distillation and fresh solvent is essentially free of water, is added until, until all the water is removed.

Hemihydrate paroxetine hydrochloride or free base can be obtained by methods described in EP-B-0223403.

Organic solvents should be essentially free from water so that during crystallization, the presence of an insufficient number were not given the possibility to form the hydrochloride hemihydrate. Organic solvents which are essentially free of water can be obtained in the usual way. For example, they can be dried using conventional techniques, such as drying over molecular sieves, or they can be purchased.

Factors that affect the form of the product, include some choice of organic solvent or solvents, depending on what type of product desired.

How Atalanta method i) an organic solvent or solvents, which form MES with crystalline paroxetine hydrochloride and which are not removed by traditional methods of drying may be determined by the usual method of experimentation. Examples of such organic solvents include, but are not limited to: alcohols, especially such as propan-2-ol, standard and propan-1-ol; organic acids such as acetic acid; organic bases such as pyridine; NITRILES, such as acetonitrile; ketones, such as acetone; ethers such as tetrahydrofuran and chlorine substituted hydrocarbons, such as chloroform.

MES paroxetine hydrochloride obtained by the alternative method (i) is easily detected, and dried by conventional methods, such as drying in a vacuum for removal of part or all of the free or unbound solvent. Was unexpected that the degree of drying is controlled so that only removes free solvent. The associated solvent then displacing agent such as water or supercritical carbon dioxide. You can use other displacing agents that are selected experimentally.

As the displacing agent is preferable to use a gaseous or liquid water. It is important that Sol is arranged solvent, but not to cause conversion into hydrochloride hemihydrate.

The amount of water, its shape, i.e., liquid or gaseous, and the time during which the MES paroxetine hydrochloride in contact with water, different for different solvate. It mainly depends on the solubility of MES.

The specific ratio of MES paroxetine hydrochloride and water indicated in the examples below (example 1, 4 - 6, 9 - 11, 13 and 15). Still think MES pyridine is more soluble in water than, for example, MES propan-2-ol. Thus, the conventional ion effects of the application of dilute hydrochloric acid can help prevent the dissolution of the MES and the subsequent conversion into the hydrochloride hemihydrate.

After contact with water to displace the associated solvent the product is dried, for example, in vacuum at elevated temperature. Also acceptable drying over a desiccant, such as patikis phosphorus.

When using nadkriticheskikh carbon dioxide can be controlled flow rate, temperature and pressure of carbon dioxide for optimal removal of the solvent from the MES paroxetine hydrochloride. Typically, the elevated temperature, for example, between 50-80oC. More preferably between 55-75oC.

To receive the form, it is preferable to use A variant of the method (i), preferably the crystallization of the original MES form anhydrate paroxetine hydrochloride to facilitate the addition of seed source MES form anhydrate paroxetine hydrochloride.

In another case, the seed forms anhydrate paroxetine hydrochloride can be used to facilitate crystallization source of solvate form A of anhydrate paroxetine hydrochloride.

For the variant of method (ii) an organic solvent or mixture of organic solvents that form or not form a MES with paroxetine hydrochloride, but which removed the traditional drying in a vacuum furnace can be determined by ordinary experimentation.

An example of a solvent which forms associated MES with paroxetine hydrochloride, but which removes the traditional drying in a vacuum furnace is toluene.

Toluene is preferably used to obtain the form d

The initial crystallization of the solvate form D anhydrate paroxetine of hydrochloride can be facilitated by adding a seed source is rexetin hydrochloride can be used to facilitate crystallization of the original solvate form D anhydrate paroxetine hydrochloride.

Examples of solvents that do not form a linked MES with paroxetine hydrochloride, but which removed the traditional drying in a vacuum furnace, are butane-1-ol and ethyl acetate.

Butane-1-ol is preferably used to obtain form B and butane-1-ol or ethyl acetate to obtain the form C

If the desired form B, it can be obtained according to the methods of example 7 or similar.

In order to facilitate the crystallization of form B, it is preferable to use seed crystals of form B.

If you need a C shape, it can be obtained according to the methods of examples 8 and 12, or similar methods.

It should be said that the use of seed form C can be used to facilitate crystallization of the form C

Seed crystals of form A, B, C, and D can be obtained according to the methods described herein, or upon request in Corporate Intellectual Property, SmitKline Beecham plc at New Frontiers Science Park, Third Avenue, Harlow, Essex, CM19 5AW, United Kingdom. Form A is BRL 29060F; form B - BRL 29060G; form C - BRL 29060H; form D - BRL 29060H. Samples of seed crystals of form A, B, C and D can also be obtained from NCIMB, 23 St. Machor Drive, Aberdeen, AB2 1RY, Scotland, United Kingdom.

Anhydrate paroxetine hydrochloride essentially free from propan-2-ol and forms A, B, C and D (all iusa diseases: alcoholism, anxiety, depression, obsessive compulsive disorders, panic States, chronic pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia, premenstrual syndrome (PMS), depression, adolescents, trichotillomania, dysthymia, substance abuse.

These disorders are here referred to as "diseases".

The present invention further provides a method of treatment and/or prevention of one or more of the diseases, the use of effective and/or prophylactically effective amounts of the products of the invention to a subject in need of it.

The present invention further provides a pharmaceutical composition for use in treatment and/or prophylaxis of diseases, which consists of the products of the invention in a mixture with a pharmaceutically acceptable carrier.

In addition, the invention provides the use of the products of the invention for the treatment and/or prevention of diseases.

The present invention also provides the use of a product for the production of medicaments for treatment and/or prevention of diseases.

Preferred diseases include depression, obsessive compulsive disorders (Asaraty for dissolving and injecting also included in the scope of the invention.

The composition is generally formulated in unit doses containing from 1 to 200 mg of active ingredient in the calculation of the free base, as a rule from 5 to 100 mg, for example, 10-50 mg, for example, 10, 12.5, 15, 20, 25, 30 or 40 mg for reception by the person. More preferably, the unit dose contains 20 mg of the active ingredient in the calculation of the free base. This song take from 1 to 6 times a day, for example, 2, 3 or 4 times a day, so the total number of input active ingredient is 5-400 mg of active ingredient, based on the free base. It is preferable to take a dose 1 time per day.

A preferred form of unit doses include tablets or capsules.

The compositions of this invention can be molded by traditional methods of mixing, such as mixing, filling and pressing.

Suitable carrier materials for use in the invention include a diluent, a binder agent, loosening agent, a coloring agent, a perfume and/or a preservative. These agents can be used in a traditional way, for example, as are used for the preparation of antidepressants.

Specific examples of pharmaceutical compositions include the examples described is.

The following examples illustrate the present invention:

Example 1. Crystalline anhydrate paroxetine hydrochloride essentially free of bound propan-2-ol (form A)

i) MES propan-2-ol paroxetine hydrochloride

Hemihydrate paroxetine hydrochloride (150 g) was mixed with propane-2-I (1000 ml) and toluene (300 ml) in a flask with a round bottom and is heated to boiling. The solvent was removed by distillation, the total volume was maintained by addition of fresh propane-2-ol, up until the boiling point reached approximately 82oC, which indicates that all the water is removed.

The mixture was allowed to cool to approximately the 50oC when she caprisonne crystallized. The contents of the flask quickly froze to a thick paste, which was diluted propane-2-I (approximately 500 ml) and vigorously stirred. The resulting suspension was allowed to cool to approximately 30oC and it was filtered under vacuum, to avoid absorption of atmospheric moisture. Wet solvent the residue was dried in high vacuum over pjatiokisi phosphorus.

The yield of solvated paroxetine hydrochloride was 151 g, the content of propane-2-ol is 13.0% (determined by NMR).

Aklomide (form A)

MES paroxetine hydrochloride in propan-2-OLE (110 g, the content of propane-2-ol is 13.0%) were mixed in a beaker with water (275 ml) for 20 minutes. The mixture was filtered under vacuum and the wet solid was dried in vacuum over pathlogist phosphorus to constant weight.

The output forms A anhydride paroxetine hydrochloride is 91.0,

The water content of 0.13% (KF), the content of propane-2-ol of 0.05% (determined by NMR).

Melting point: 123-125oC.

DSC of ectotherm measured at heating rate of 10oC / minute, showed a maximum at about 126oC using an open cell and a maximum of about 121oC in a sealed cuvette.

IR spectrum (Nujol mull) showed characteristic bands at 665, 3631 and 3402 cm-1(see Fig.1).

Elemental analysis: calculated for anhydrate paroxetine hydrochloride: C, 62.38, H 5.79, N 3.83%

Found: C, 62.10, H 5.89, N 3.67%

The sample was also investigated by x-ray powder diffraction (see Fig. 4) and the solid state C13 NMR (see Fig. 7).

Example 2. MES propan-2-ol paroxetine hydrochloride

Free base paroxetine dissolved (42.09 g) in propan-2-OLE (sort Fisons SLR, 210 ml). Through a cooled flask containing solution (containing approximately 4.6 g of hydrogen chloride) was rapidly added to a solution of paroxetine and the mixture is rapidly stirred. After approximately 1 minute began crystallization and the mixture is quickly froze into a paste, which was not mixed and left for 1 hour. The product was collected by filtration, washed with propan-2-I (50 ml) and dried in vacuum at ambient temperature to constant weight in a desiccator containing phosphorus oxide. The sample was analyzed by NMR spectroscopy and as it turned out, contained approximately 6% propan-2-ol by weight. The portion of the sample was placed in a vacuum oven set at 50oC and further dried to a constant weight, which took another 4 days. NMR spectroscopy showed that the sample contained approximately 2 wt.% propane-2-ol.

Example 34. MES propan-2-ol paroxetine hydrochloride

Free base of paroxetine (52.37 g) was dissolved in dry propan-2-OLE (250 ml) and rapidly with stirring was added a solution of gaseous hydrogen chloride in dry propan-2-OLE (50 g of a solution containing approximately 5.8 g of hydrogen chloride). After 30 seconds began crystallization, and the mixture was mixed for another 30 minutes at ambient temperature to complete crystallization. The product was separated by vacuum filtration, was washed with 25 ml of dry propan-2-ol and dried in a desiccator, which was on NMR and was found to contained 10.3% propan-2-ol. The remaining material was dried for 3 days to a constant weight in a vacuum with fresh oxide of phosphorus in a desiccator. NMR analysis showed that the product contained 5.7% weight/weight of propane-2-ol.

Example 4. Crystalline anhydrate paroxetine hydrochloride essentially free of bound pyridine (form A)

i) Receiving MES paroxetine hydrochloride in pyridine.

Paroxetine hydrochloride containing approximately 2% propan-2-ol (20.0 g) was dissolved in hot pyridine (200 ml) and part of the solvent was removed by distillation. The flask was backed up and was left to cool, after which the pale red solution spontaneously crystallized. Thick suspension is mixed well, filtered, avoiding excessive contact with atmospheric moisture and the solid was washed on the filter with pyridine (25 ml). The product was dried in high vacuum over pjatiokisi phosphorus.

The output was 22.0 g

Microscopic examination showed that the product has the form of needle-shaped crystals and NMR analysis showed the presence of 15.2 wt.% pyridine (theoretically for MES 1:1-17,77%). The IR spectrum of MES pyridine (Nujol mull) differed from the spectrum of hemihydrate and which has a characteristic x-ray powder diffraction pattern.

ii) Obtaining anhydrate paroxetine hydrochloride (form A)

MES pyridine paroxetine hydrochloride (5.00 g) was added to 5 molar hydrochloric acid (25 ml) in a beaker and stirred for 5 minutes. The mixture was filtered, well drained on a filter and washed with water (15 ml). The crystals were dried in high vacuum over phosphorus pentoxide.

The output was 4.00,

IR spectrum (Nujol mull) corresponds to anhydrate paroxetine hydrochloride forms a and NMR analysis were not detected pyridine.

Example 5. Anhydrate paroxetine hydrochloride essentially free of combined acetic acid (form A)

i) Receiving MES acetic acid paroxetine hydrochloride

Paroxetine hydrochloride containing approximately 2% propan-2-ol (30.0 g) was dissolved in hot glacial acetic acid (120 ml) and part of the solvent was removed by distillation. The flask was backed up and was left to cool overnight. In the clear light yellow solution was made of the seed crystals of the company anhydrate paroxetine hydrochloride was subjected to ultrasonic treatment and stirred at room temperature for several hours. The mixture was left to stand for 24 Ihad was 17.29,

The NMR analysis showed the presence of 13.5 wt.% acetic acid (theoretically for MES 1: 14.10 1%). The IR spectrum of MES acetic acid (Nujol mull) differed from the spectrum hemihydrate paroxetine hydrochloride, and anhydrate forms A and, in particular, showed a strong band at 1705 cm-1pointing to a linked acetic acid, and no significant bands in the region of 3000 cm-1. Chart x-ray diffraction of the crystal lattice of the powder is also characteristic.

ii) Obtaining anhydrate paroxetine hydrochloride (form A)

MES paroxetine hydrochloride in acetic acid (1.00 g) was treated with 5 molar hydrochloric acid (5 ml) and stirred for 5 minutes. The mixture was filtered, well drained, and the crystals were dried in high vacuum in a desiccator containing phosphoric anhydride.

Yield 0.80 g

IR spectrum (Nujol mull) confirmed that the product is anhedral paroxetine hydrochloride form A. NMR Analysis showed the presence of about 0.4% acetic acid. Microscopic examination showed that the material has the form of fragmented needle-shaped crystals.

Example 6. Anhydrate paroxetine hydrochloride essentially of chloride

Form anhydrate paroxetine hydrochloride obtained by the method of example 1 (10.8 g) was dissolved in warm anhydrous acetonitrile (40 ml) in a conical flask, was backed up and was cooled in the refrigerator for 1 hour, the time during which separated some crystals. The mixture was subjected to ultrasonic treatment, came back and was left overnight. The contents froze to a thick paste. The next morning, the pasta was broken by vigorous shaking and ultrasound and the mixture was filtered. The product was dried in high vacuum in a desiccator containing phosphoric anhydride.

Output 9.30 g, the content of acetonitrile, 2.5% (by NMR),

ii) Obtaining anhydrate paroxetine hydrochloride (form A)

MES acetonitrile paroxetine hydrochloride (4.23 g) was mixed in water (20.6 g) for 10 minutes. The solid was collected by vacuum filtration, was washed on the filter with water (10 ml) and dried in a vacuum oven containing phosphoric anhydride, 50oC.

Yield 3.75 g

The IR spectrum showed that the product is a form of anhydrate paroxetine hydrochloride.

The content of acetonitrile about 0.5% (by NMR).

Example 7. Anhydrate paroxetine hydrochloride.picture and was added to a solution of gaseous florodora (1,25 d) butane-1-Ola (15 ml). Transparent pale red-brown solution was backed up and stored in the fridge all night. A small amount of crystalline material is formed on the bottom of the flask, and ultrasound was used for crystallization of the remaining part. The mixture was again kept in the refrigerator overnight, then was left to warm to room temperature and filtered. The product was dried in high vacuum in a desiccator containing phosphoric anhydride.

Microscopic examination polarizing microscope showed that the sample has the shape of crystals in the form of steam. Melting point: 137-138oC.

An NMR spectrum (CDCl3corresponded to the spectrum of a standard sample of paroxetine hydrochloride.

Elemental analysis was consistent with anhydrous paroxetine hydrochloride.

Calculated for C19H21NClFO3, %: C, 62.38, H 5.79, C 19.69, N 3.83

Found, %: C, 62.08, H 5.75, Cl 9.62, N 3.81.

X-ray powder diffraction pattern confirmed that the sample was crystalline (see Fig. 5). The diffraction pattern was different from the pattern hemihydrate, and forms anhydrate.

IR spectrum (Nujol mull) also differed from the spectrum of the hemihydrate, and forms anhydrate about 137oC in closed and open cells.

The sample was investigated by C13 NMR in the solid state (see Fig. 8).

Example 8. Anhydrate paroxetine hydrochloride (form C)

Hemihydrate paroxetine hydrochloride (300 g) and toluene (1200 ml) was heated under reflux and water was removed using the apparatus of Dean-stark. When the water had not intended, most of the toluene was removed by distillation and replaced by anhydrous butane-1-I. Distillation was continued until the temperature of the mixture did not reach 117oC, indicating that all of the toluene is removed. The mixture was diluted to about 1200 ml of butane-1-ol and was left to cool. At about 42oC was added seed crystals of form B anhydrate paroxetine hydrochloride (needle shape). Although he started the crystallization, it was clear that the product formed in the form of well-formed prisms, indicating that the product crystallizes in a form different from the form of crystals added seed.

The mixture was left to stand overnight, then filtered. The crystals were washed on the filter butane-1-I, then dried in vacuum at 50oC over phosphorus pentoxide.

Output 250 g

Temperature pin hydrochloride and showed the presence of traces of butane-1-ol (approximately 0.1% by weight). IR spectrum (Nujol mull) was different from the spectrum of form A or B (see Fig. 3).

The water content of 0.06% (KF)

Elemental analysis was consistent with anhydrous paroxetine hydrochloride:

calculated for C19H21NClFO, %: C, 62.38, H 5.79, N 3.83, Cl, 9.69

found, %: C, 62.23, H 5.67, N 3.83, Cl 9.74

DSC of ectotherm measured at heating rate of 10oC / minute showed a maximum at about 161oC both in open and in closed cuvettes.

X-ray powder diffraction pattern confirmed that the sample is crystalline (see Fig. 6). The diffraction pattern was different from the diffraction pattern of form A of anhydrate and form B anhydrate.

The sample was also studied by C13 NMR in the solid state (see Fig. 9).

Example 9. Anhydrate paroxetine hydrochloride essentially free from the associated acetone (form A)

i) MES acetone paroxetine hydrochloride

Free base paroxetine (10.51 g) was dissolved in acetone (40 ml, dried 4A molecular sieves), and with stirring was added a solution of gaseous hydrogen chloride (1.31 g) in dry acetone (10 ml). Crystallization occurred spontaneously within 1 minute, and the mixture quickly became difficult to stir. After acture environment during the night.

Product weight: 11,24, the acetone (a certain NMR) 4% weight/weight. The IR spectrum showed a characteristic band at 667 cm-1.

Approximately half of the product was placed in a vacuum oven set at 50oC when further dried to a constant weight. The NMR analysis of the obtained product showed the presence of 1.2% weight/weight of acetone.

ii) Anhedral paroxetine hydrochloride (form A)

Sample MES acetone (5.18 g) was mixed for 10 minutes in water (20 ml), filtered and dried at 50oC in a vacuum oven containing phosphoric anhydride.

Product weight: 4.63, NMR Analysis showed the presence of 0.6% weight/weight. of acetone. The infrared spectrum was consistent with the spectrum forms anhydrate paroxetine hydrochloride and showed a characteristic band at 665 cm-1.

Example 10. Anhydrate paroxetine hydrochloride essentially free from the associated ethanol (form A)

i) MES paroxetine hydrochloride - ethanol.

Free base paroxetine (11.25 g) was dissolved in absolute ethanol (41 ml) and with stirring was added a solution of gaseous hydrogen chloride (1.9 g) dissolved in absolute ethanol (20 ml). Signs of crystallization after 10 minutes was not observed, so that p is signs of crystallization, and the solution was evaporated under reduced pressure to approximately half volume and re-made the seed this time was slow crystallization and the mixture was left for another hour. The resulting crystalline mass was dried at ambient temperature in a vacuum desiccator containing phosphoric anhydride.

Product weight: 11.87 per year ethanol Content (defined YAR) 4% weight/weight. The IR spectrum showed a characteristic band at 667 cm-1.

A small sample was placed in a vacuum oven set at 50oC, and then were dried. NMR analysis of the obtained product showed the presence of 0.7% weight/weight of ethanol. The infrared spectrum was consistent with the spectrum forms anhydrate paroxetine hydrochloride and showed a characteristic band at 665 cm-1.

ii) Anhedral paroxetine hydrochloride (form A)

Sample MES ethanol (5.3 g) were mixed for 10 minutes in water (20 ml), filtered and dried overnight at a temperature environment in a desiccator containing phosphoric anhydride.

Product weight: 4,56 g (NMR analysis showed the presence of less than 0.4% weight/weight of ethanol. The infrared spectrum was consistent with the spectrum forms anhydrate paroxetine hydrochloride and showed the characteristic band Hloroform (form A)

i) MES paroxetine hydrochloride - chloroform.

Free base paroxetine (8.54 g) was dissolved in chloroform (30 ml) and with stirring was added a solution of gaseous hydrogen chloride (1.05 g) dissolved in chloroform (10 ml). After 5 minutes there was no sign of crystallization and a clear solution was patruleasa form anhydrate paroxetine hydrochloride. After 15 minutes still there were no signs of crystallization and after the solution was barotiwala hydrogen chloride until then, until the orange color disappeared. After 1 hour showed signs of a very slow crystallization from the visible to the eye of a needle crystals. The mixture was left for crystallization in a stoppered flask for another hour, then filtered and dried at ambient temperature in a vacuum desiccator containing phosphoric anhydride.

Product weight: 5.65, Content chloroform (defined NMR) 12.5% weight/weight. The IR spectrum showed a characteristic band at 667 cm-1.

A small sample was placed in a vacuum oven set at 50oC and dried. NMR analysis of the obtained product showed the presence of 3.4% weight/weight of chloroform.

ii) Anhedral paroxetine hydrochloride (form A)

About what was isusually overnight in a vacuum oven at 50oC. product Weight: 1.09 g, NMR analysis showed the presence of approximately 0.8% weight/weight of chloroform. The infrared spectrum was consistent with the spectrum forms onggirat paroxetine hydrochloride and showed a characteristic band at 665 cm-1.

Example 12. Anhydrate paroxetine hydrochloride (form C)

Free base paroxetine (8.5 g) was dissolved in ethyl acetate (40 ml) and barotiwala gas of hydrogen chloride until then, until the weight of the flask content is not increased by 1.1, after 15 minutes of evidence of crystallization was not observed and a clear solution was patruleasa form anhydrate paroxetine hydrochloride. After stirring for a further 1 hour you could see the signs of a very slow crystallization. The mixture was left with stirring overnight for crystallization in a stoppered flask, then filtered and dried at ambient temperature in a vacuum desiccator containing phosphoric anhydride.

Product weight: 7.56, the Content of ethyl acetate (specific NMR) 0.4% weight/weight. The IR spectrum was different from the spectra and hemihydrate paroxetine hydrochloride and anhydrate form A, and is compatible with the IR spectrum obtained in example 8.

Example 13. Anhydrate paroxetine hydrochloride essentially is.

Free base paroxetine (10.6 g) was dissolved in propan-1-Ola (30 ml) and the solution was passed gaseous hydrogen chloride (1.25 g). The warm solution was patruleasa form B anhydrate paroxetine hydrochloride and subjected to sonication, and then the light red solution quickly crystallized. The thick suspension was diluted propane-1-I (25 ml), filtered, avoiding excessive contact with atmospheric moisture, and the product was dried in a vacuum oven over phosphoric anhydride.

Yield 10.3 g

The NMR analysis showed the presence of approximately 7 wt.% propane-1-ol. IR spectrum (Nujol mull) showed that the product is not of the form B, and solvated form with a significant band at 667 cm-1. MES propan-1-ol gave a different picture of the x-ray diffraction of the crystal lattice of the powder.

ii) Obtaining anhydrate paroxetine hydrochloride (form A)

MES paroxetine hydrochloride in propane-1-Ola (5.24 g) was mixed in water (25 ml) for 10 minutes. The mixture was filtered and the product was rinsed with water (10 ml). The crystals were dried in high vacuum over phosphorus pentoxide at 50oC.

The output of 4.35 g

IR spectrum (Nujol mull) confirmed that PR">

Example 14. Anhydrate paroxetine hydrochloride (form D).

i) Receiving MES paroxetine hydrochloride - toluene.

Hemihydrate paroxetine hydrochloride (100 g) were mixed while heating under reflux in toluene (1000 ml) and water was removed using the apparatus of Dean-stark. The solution was allowed to cool, strassle form of A paroxetine hydrochloride and was subjected to sonication. Crystallization was not observed, but after stirring for 40 minutes at room temperature the contents of the flask immediately froze into a thick paste. The product was collected by filtration and dried in vacuum over phosphorus pentoxide.

The product analysis by NMR showed the presence of about 10% weight/weight of toluene. MES toluene gave a distinct IR spectrum with a characteristic band at 672 cm-1.

The above method was repeated using a dose of MES toluene and the product was dried in vacuum over phosphorus pentoxide. The output of the MES of toluene was 106.7,

The product analysis by NMR showed the presence of about 10% weight/weight. of toluene. The product gave the characteristic x-ray powder diffraction pattern.

ii) Desalvatore of MES toluene

MES toluene (20.0 g) Naga is toluene.

Water content: 0.08% (KF).

Melting point: about 125oC.

Example 15. Anhydrate paroxetine hydrochloride essentially free from the associated tetrahydrofuran (form A)

i) MES paroxetine hydrochloride - tetrahydrofuran.

Free base of paroxetine (10.26 g) was dissolved in dry tetrahydrofuran (35 ml), and with rapid stirring, was added a solution of gaseous hydrogen chloride (1.3 g) dissolved in dry tetrahydrofuran (15 ml). After a short period, during which the solution remained transparent, began a rapid crystallization so that within a few minutes, the mixture could no longer be stirred. After a half hour, the product was collected by filtration and were dried at ambient temperature in a vacuum desiccator containing phosphoric anhydride.

Product weight: 12.31, the Content of tetrahydrofuran (determined by NMR) 11.4% weight/weight. The IR spectrum showed a band characteristic of MES at 667 cm-1.

A small sample was placed in a vacuum oven set at 50oC, and dried over the weekend. The NMR analysis of the obtained product showed the presence of 1.3% weight/weight. tetrahydrofuran (THF).

ii) Anhedral p is g), mixed for 10 minutes in water (20 ml), filtered and dried in a vacuum oven at 50oC. product Weight 3.79 g, NMR analysis showed the presence of about 0.02% weight/weight. tetrahydrofuran (THF). The infrared spectrum was consistent with the spectrum forms anhydrate paroxetine hydrochloride and showed a characteristic band at 665 cm-1.

Example 16. Anhydrate paroxetine hydrochloride essentially free of bound propan-2-ol (form A)

MES paroxetine hydrochloride in propan-2-OLE (70 mg, containing 11.6% propan-2-ol) (example 2 or 3) was treated with a stream of carbon dioxide (3 ml) min, 55oC and 175 kg/cm2. After 30 minutes the contents of propan-2-ol was reduced to 5.2% and after 120 minutes it was reduced even up to 0.4%. Then the temperature was raised to 75oC, and after 30 minutes the contents of propan-2-ol was 0.13%. After another 60 minutes at 75oC content of propane-2-ol was 0.07%.

In another experiment, 70 mg of MES propan-2-ol was extracted with carbon dioxide (3 ml)/min, 75oC and 175 kg/cm2. After 150 minutes, the content of propane-2-ol was 0.19%. This experiment was repeated on a larger sample of MES (350 mg) in the same conditions and the content of propane-2-ol amounted to 0.16% by anticensura seed crystals

Form C anhydrate paroxetine hydrochloride (7.0 g) was heated to boiling in anhydrous 2-butanone (40 ml) and the solution was allowed to cool to approximately 40oC. was Added seed crystals of form C and stirred mixture was allowed to cool to room temperature. The product was collected by filtration, were washed anhydrous 2-butanone (20 ml) and dried in an oven at 100oC.

The weight of the dried product 5.95,

Melting point: 162-163oC.

IR spectrum (Nujol mull) corresponded to the form C anhydrate paroxetine hydrochloride.

Example 18. Crystallization paroxetine hydrochloride from toluene using seed crystals

Form C anhydrate paroxetine hydrochloride (20 g) was dissolved in boiling toluene (200 ml) and the contents were divided into 4 conical flasks, each was added to approximately 50 ml. Each flask was again heated to boiling, with a pair of toluene was evaporated to remove the seed. Flask 1 was immediately backed up by a round glass tube and cooled. Other flasks were closed with foil and a little cool down before adding the seed crystals as follows.

In flask 3 was added to the crystals MES paroxetine of hydrochl is ochloride as seed.

In flask 4 was added to the crystals of form C anhydrate paroxetine hydrochloride as a seed.

Added the seed remained undissolved. The flask was backed up in a round glass tubes, the contents were mixed gently for a few seconds and cooled. Crystallization in flask 2 was pretty quick, and in flasks 3 and 4 more slowly. When this bulb 1 remained completely transparent and all 4 of the flask was left at room temperature overnight. The next morning in flask 1 was only a few crystals, while flasks 2, 3 and 4 showed a significant crystallization.

The contents of flask 1 was gently stirred for several hours, during which the main part of the paroxetine hydrochloride crystallized.

The product from each flask was collected by filtration and dried at 50oC in vacuum.

The bulb 1 (without seed)

Product weight: 4.25 grams

Appearance: short needles/hooks.

IR-spectrum: conforms to the shape C anhydrate paroxetine hydrochloride.

Melting point: 161-162oC.

The flask 2 (seed crystals MES toluene)

Product weight: 3.80 g

Appearance: long, thin needle.

Melting point: first, the product melts at about 70oC, followed by curing and subsequent melting at 161-162oC.

The flask 3 (with seed crystals of form B anhydrate)

Product weight: 4.20 g

Appearance: needle.

IR-spectrum: conforms to the shape B anhydrate paroxetine hydrochloride.

The solvent content: 0.8% weight/weight in NMR.

Melting point: 138-140oC.

The flask 4 (with seed crystals of form C anhydrate).

Product weight: 4.93 g

Appearance: needle.

IR-spectrum: conforms to the shape C anhydrate paroxetine hydrochloride.

The solvent content: 0.8% weight/weight. toluene in NMR.

Melting point: 161-162oC.

Example 19. Crystalline anhydrate paroxetine hydrochloride essentially free of bound propan-2-ol (form A)

Dried in a vacuum oven MES paroxetine hydrochloride in propan-2-Ola, containing 2.6% propan-2-ol (1 g) were placed in a glass tube. The tube was immersed in a water bath at 50oC and through the sample was passed nitrogen, saturated with water vapor at a temperature of 40oC. after 10 hours had taken a small obcu, up to 80oC, and the temperature at which the gas was passed through the sample was increased to 70oC. After 10 hours the contents of the tube were taken for analysis again and analyzed by NMR, which showed that the level of propane-2-ol fell to 1.0%.

Example 20. Anhydrate paroxetine hydrochloride essentially free from the associated acetone (form A)

i) Receiving MES paroxetine hydrochloride acetone.

The suspension is of the form C (prism) anhydrate paroxetine hydrochloride (5.0 g) in acetone (75 ml) was heated to boiling with obtaining the mass of a thin needle-shaped crystals. The flask was backed up and vestibules overnight at room temperature. The solvent was removed at low temperature using a rotary evaporator and was replaced with hexane (100 ml). The solvent was again removed at low temperature with obtaining MES acetone in the form of a crystalline residue. The NMR analysis showed the presence of acetone (12.2% by weight), and the infrared spectrum (Nujol mull) showed characteristic bands at 667 and 1714 cm-1.

ii) Obtaining anhydrate paroxetine hydrochloride (form A) from MES acetone.

Form C paroxetine hydrochloride (5.3 g) was transformed into MES acetone by the method similar to that described what was collected by filtration, carefully drained from the filter and drained in a vacuum oven at 50oC. Yield 4.60, the Content of acetone (NMR) 0.1 wt.%. IR spectrum (Nujol mull) corresponded to the spectrum of the standard sample form anhydrate paroxetine hydrochloride.

Example 21. Anhydrate paroxetine hydrochloride (form D)

i) Receiving MES paroxetine hydrochloride toluene.

Preparing an anhydrous solution of paroxetine hydrochloride in toluene boiling under reflux a mixture of hemihydrate paroxetine hydrochloride in toluene in the apparatus dick-stark, until the water has ceased to meet. The solution was allowed to cool and strawley the MES paroxetine hydrochloride in toluene. The product was collected by filtration, rinsed with toluene and dried in a vacuum oven at 50oC. NMR Analysis showed the presence of 18 wt.% of toluene. The IR spectrum collected at the 22oC using a spectrometer Perkin-Elmer 1720X FT-IR, connected to the microscope Spectra-Tech IR-Plan shown in Fig. 10A and 10B.

ii) the form D anhydrate paroxetine hydrochloride

A small sample of MES paroxetine hydrochloride in toluene (toluene 18% weight/weight. ) was heated at 80oC and the resulting form D anhydrate paroxetine hydrochloride was studied IR micro the initial IR spectrum is shown in Fig. 11A and 11B.

1. Anhydrate paroxetine hydrochloride essentially free of solvent, in particular from propan-2-ol in the form of a, which differs in that it has a melting point okolo - 125oC with a solvent content less than 2 wt.% and has significant bands in the IR spectrum at about 513, 538, 571, 592, 613, 665, 722, 761, 783, 806, 818, 839, 888, 906, 924, 947, 966, 982, 1006, 1034, 1068, 1091, 1134, 1194, 1221, 1248, 1286, 1340, 1387, 1493, 1513, 1562, 1604, 3402, 3631 cm-1and DSC of ectotherm measured at heating rate of 10oC per minute, has a maximum at about 126oC using the open cell and the maximum at about 121oC using a closed cell, has an x-ray diffraction pattern having characteristic peaks at 6.6, 8.0, 11.2, 13.1 degrees 2 theta, and the NMR spectrum of the solid state, having characteristic peaks at 154.3 149.3, 141.6, 138.5 frequent./million

2. Anhydrate paroxetine hydrochloride essentially free of solvent, in particular from propan-2-ol in the form, which is characterized in that it has a melting point of about 138oC, and has a significant bands in the IR spectrum at about 538, 574, 614, 675, 722, 762, 782, 815, 833, 884, 925, 938, 970, 986, 1006, 1039, 1069, 1094, 1114, 1142, 1182, 1230, 1274, 1304, 1488, 1510, 1574, 1604, 1631 cm-1, The DSC ectothermy measured at heating rate of 10oC is tagammu, having characteristic peaks at 5.7, 11.3, 12.4, 14.3, the C 2 test and an NMR spectrum of a solid state having characteristic peaks at 154.6, 148.3, 150.1, 141.7, 142.7, 139.0 part/million

3. Anhydrate paroxetine hydrochloride essentially free from organic solvent, in particular from propan-2-ol in the form, which differs in that it has a melting point of about 164oC if the solvent content less than 2 wt.% and has significant bands in the IR spectrum at about 540, 574, 615, 674, 720, 760, 779, 802, 829, 840, 886, 935, 965, 984, 1007, 1034, 1092, 1109, 1139, 1183, 1216, 1240, 1263, 1280, 1507, 1540, 1558, 1598, 1652 cm-1, DSC of ectotherm measured at heating rate of 10oC per minute, shows a maximum of about 161oC in both open and closed cells, it also has the x-ray diffraction pattern including characteristic peaks at 10.1, 12.1, 13.1, 14.3 degrees 2 theta, and an NMR spectrum of a solid state, including characteristic peaks at 154.0, 148.5, 143.4, 140.4 part/million

4. Anhydrate paroxetine hydrochloride essentially free from organic solvent, in particular from propan-2-ol in the form D, which differs in that it exists in the form of a semi-crystalline solid with a melting point of about 125oC content will dissolve the desiccant, the original MES toluene has a significant bands in the IR spectrum at about 1631, 1603, 1555, 1513, 1503, 1489, 1340, 1275, 1240, 1221, 1185, 1168, 1140, 1113, 1101, 1076, 1037, 1007, 986, 968, 935, 924, 885, 841, 818, 783, 760, 742, 720, 698, 672, 612, 572, 537 and 465 cm-1and characterized by x-ray diffraction peaks at 7.2, 9.3, 12.7 and 14.3 degrees 2 theta.

5. Anhydrate paroxetine hydrochloride under item 1 in the form of needle crystals.

6. Anhydrate paroxetine hydrochloride under item 2 in the form of needle crystals.

7. Anhydrate paroxetine hydrochloride under item 3 in the form of needle-shaped crystals or prisms.

8. Connection on p. 1, which is selected from the group consisting of crystalline anhydrate paroxetine hydrochloride essentially free of bound pyridine (form a) anhydrate paroxetine hydrochloride essentially free of combined acetic acid (form A), anhydrate paroxetine hydrochloride essentially free from the bound acetonitrile (form A), anhydrate paroxetine hydrochloride essentially free from the associated acetone (form A), anhydrate paroxetine hydrochloride essentially free from the associated ethanol (form A), anhydrate paroxetine hydrochloride, essentially free from the associated chloroform (form A), angika the hydrochloride, essentially free from the associated tetrahydrofuran (form A).

9. The solvate paroxetine hydrochloride, other than MES propan-2-ol, characterized in that the MES is chosen from the group consisting of a solvate of alcohols other than propane-2-ol, organic acids, organic bases, NITRILES, ketones, esters, chlorinated hydrocarbons and hydrocarbons.

10. MES paroxetine hydrochloride p. 9, selected from the group consisting of a solvate propan-1-ol, ethanol, acetic acid, pyridine, acetonitrile, acetone, tetrahydrofuran, chloroform and toluene.

11. The method of obtaining anhydrate paroxetine hydrochloride essentially free from propan-2-ol in the form A, B, C and D, which includes the crystallization of paroxetine hydrochloride either (i) an organic solvent or mixture of organic solvents, which form the MES with paroxetine hydrochloride and which cannot be removed by vacuum drying, and subsequent displacement of solvated solution or solvent using a displacing agent, or (ii) an organic solvent or mixture of organic solvents that form or not form a MES with paroxetine hydrochloride is drochloride, other than MES propan-2-ol, as described in paragraph 9, which includes the crystallization of paroxetine hydrochloride in an appropriate organic solvent or mixture of solvents, which form the MES with paroxetine hydrochloride and which can be removed by vacuum drying.

13. The method of obtaining anhydrate paroxetine hydrochloride essentially free of bound organic solvent in the form A, B, C and D, which includes the displacement of solvated solvent or solvents from the MES paroxetine hydrochloride using the displacing agent.

Priority points:

06.02.95 and 17.02.95 - p. 9;

15.05.95 - PP.1 - 7, 9, 11, 12 and 13P

 

Same patents:

The invention relates to methods for taxan with side chain and their intermediates and to new compounds of the formula III obtained by these methods

The invention relates to vasoconstrictor /(benzodioxan, benzofuran and benzopyran)-alkylamino/-alkyl-substituted guanidine formula I, their pharmaceutically acceptable salts, or their stereochemical isomers, where X = O, CH2or a direct bond; R1= H, C1-C4alkyl, R2= H, C1-C6alkyl, C3-C6alkenyl, C3-C6quinil, R3= H, C1-C4alkyl; or R2and R1taken together, may form a bivalent radical of the formula/CH2/m-, where m = 4 or 5; or R1and R2taken together may form a bivalent radical of formula-CH=CH -, or the formula/CH2/n-, where n = 2, 3 or 4; or R3may indicate a relationship when R1and R2taken together form a bivalent radical of formula-CH=CH-CH= -, -CH= CH-N= or-CH=N-CH=; where one or two hydrogen atom substituted by a halogen atom, a C1-C6alkoxygroup, C1-C6the alkyl, CN, NH, mono - or di(C1-C6alkyl) amino group, aminocarbonyl, C1-C6alkylaminocarbonyl, R4-H or C1-C6-alkyl; Alk1denotes a divalent C1-C3-ascandilwy radical, A denotes dwuhvalentny a radical of the formula /, lk2represents C2-C15-alcander or C5-C7-cycloalkenyl, and each "R" represents 0, 1, 2, R7and R8each independently is H, a halogen atom, a C1-C6by alkyl, hydroxyl, C1-C6allyloxycarbonyl, C1-C6alkoxygroup, cyano, amino, C1-C6the alkyl, carboxyla, nitro or amino group, aminocarbonyl, C1-C6alkylcarboxylic or mono - or di-(C1-C6)alkylamino, provided that excluded /2-/ (2,3-dihydro-1,4-benzodioxin-2-yl)-methyl/-amino/-ethyl-guanidine

The invention relates to pyrazole derivative of the General formula I, where g2, g3and g6hydrogen; g4- chlorine atom or bromine, WITH1-C3-alkyl, trifluoromethyl, or phenyl; g5is hydrogen or chlorine atom; w2, w3, w5and w6is hydrogen or chlorine atom; w4is hydrogen, a chlorine atom, a C1-C3-alkyl, C1-C3-alkoxy or nitro; X is a direct bond or the group -(CH2)nN(R3)-, where R3is hydrogen or C1-C3-alkyl; n is 0 or 1; R4is hydrogen or C1-C3-alkyl and, when X is a direct bond, R is a group-NR1R2where R1is hydrogen, C1-C6-alkyl or cyclohexyl, and R2- C1-C6-alkyl, non-aromatic carbocyclic radical WITH3-C15possibly substituted by a hydroxyl group, one or more1-C5-alkilani,1-C5alkoxygroup or halogen; amino group WITH1-C4-alkyl in which the amino may dazamide1-C3-alkyl, cyclohexyl1-C3-alkyl; phenyl, unsubstituted or substituted with halogen, or WITH1-C5-alkyl; phenyl WITH1-C3-alkyl, diphenyl1-C3-Olinala, hinokitiol and oxybutylene, unsubstituted or substituted C1-C3-alkyl or benzyl; 1-adamantaneacetic; C1-C3-alkyl, substituted aromatic heterocycle selected from pyrrolyl, pyridyl or indolyl, unsubstituted or substituted C1-C5-alkyl, or R1and R2form together with the nitrogen atom to which they relate, pyrrolidinyl, piperidyl or morpholinyl; or the group R5that represents phenyl WITH1-C3-alkyl, unsubstituted or substituted C1-C5-alkyl; cyclohexyl1-C3-alkyl, or 2-norbornylene; when X represents a group -(CH2)nN(R3)-, R represents a group R2Athat represents a non-aromatic carbocyclic radical WITH3-C15; phenyl substituted by halogen; phenyl WITH1-C3-alkyl, possibly substituted with halogen; indolyl, possibly substituted C1-C5alkoxygroup; anthracene, or group with other2bin which R2b- cyclohexyl, substituted, phenyl, unsubstituted or substituted by one or two halogen atoms, WITH1-C5-alkyl or C1-C5alkoxygroup or their acid additive salts

The invention relates to new derivatives of hinoklidilkarbinola General formula where n is an integer 1, 2, 3, R1-halogen or trihalomethyl, R2is hydrogen, R3-furanyl, tetrahydrofuranyl, DIOXOLANYL, pyranyl, tetrahydropyranyl, optionally substituted by 1, 2 or 3 substituents selected from the group comprising oxoprop and C1-C3-alkyl

The invention relates to new derivatives of N-(3-hydroxy-4-piperidinyl) (dihydro-2H-benzopyran or dihydrobenzoic) carboxamide, having valuable pharmaceutical properties, namely activity to stimulate gastrointestinal peristalsis

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention describes compound of the formula (I):

as a free form or salt wherein Ar means group of the formula (II):

wherein R1 means hydrogen atom or hydroxy-group; R2 and R3 each means independently of one another hydrogen atom or (C1-C4)-alkyl; R4, R5, R6 and R7 each means independently of one another hydrogen atom, (C1-C4)-alkoxy-group, (C1-C4)-alkyl or (C1-C4)-alkyl substituted with (C1-C4)-alkoxy-group; or R5 and R6 in common with carbon atoms to which they are joined mean 6-membered cycloaliphatic ring or 6-membered heterocyclic ring comprising two oxygen atoms; R8 means -NHR13 wherein R13 means hydrogen atom, (C1-C4)-alkyl or -COR14 wherein R14 means hydrogen atom; or R13 means -SO2R17 wherein R17 means (C1-C4)-alkyl; R9 means hydrogen atom; or R8 means -NHR18 wherein -NHR18 and R9 in common with carbon atoms to which they are joined mean 6-membered heterocycle; R10 means -OH; X means (C1-C4)-alkyl; Y means carbon atom; n = 1 or 2; p = 1; q = 1; r = 0 or 1. Also, invention describes pharmaceutical composition based on compound of the formula (I), a method for preparing compound of the formula (I) and intermediate compound that is used in the method for preparing. Compounds elicit the positive stimulating effect of β2-adrenoceptor.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

13 cl, 3 tbl, 35 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to derivatives of benzodiazepine. Invention describes a derivative of benzodiazepine of the formula (I): wherein dotted lines show the possible presence of a double bond; R1, R2, R3, R4 and R5 are given in the invention claim; n represents 0, 1, 2, 3 or 4; X represents sulfur atom (S) or -NT wherein T is give in the invention claim; A represents hydrogen atom, (C6-C18)-aryl group substituted optionally with one or more substitutes Su (as given in the invention claim) or (C1-C12)-alkyl; or in alternative variant R4 and R5 form in common the group -CR6=CR7 wherein CR6 is bound with X and wherein R6 and R7 are given in the invention claim, and their pharmaceutically acceptable salts with acids or bases. It is implied that compounds corresponding to one of points (a)-(e) enumerated in the invention claim are excluded from the invention text. Also, invention describes methods for preparing compounds of the formula (I) and a pharmaceutical composition eliciting the hypolipidemic activity. Invention provides preparing new compounds eliciting the useful biological properties.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

20 cl, 6 tbl, 192 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of borrelidin of the general formula (I)

wherein R represents the group of the general formulae -COOR1, -CONR2R3, -CONR4CONR2R5 or -CH2OR6 wherein R1 represents (C2-C6)-alkyl group, (C1-C6)-alkyl group substituted with hydroxyl group or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprise oxygen atom in addition to nitrogen atom) or 5-6-membered nitrogen-containing aromatic heterocyclic group or (C3-C6)-cycloalkyl group; R2 and R3 are similar or different and represent independently hydrogen atom or (C1-C6)-alkyl group that can be substituted optionally with hydroxyl, (C2-C5)-alkoxycarbonyl or 5-8-membered saturated nitrogen-containing heterocyclic group (it can comprises oxygen atom in addition to nitrogen atom) or 5-6-membered aromatic homocyclic group or aromatic heterocyclic group comprising oxygen and/or nitrogen atom, 5-6-membered cycloalkyl or heteroaryl group; R4 and R5 are similar or different and represent independently hydrogen atom or (C3-C6)-cycloalkyl group; R6 represents hydrogen atom; also, invention relates to tautomers, solvates of these compounds, their mixtures and acid-additive salts. Also, invention relates to pharmaceutical compositions comprising compounds of the general formula (I) as an active component. Angiogenesis inhibitors of the present invention inhibit formation of new vessels in tissues of live organisms and can be used for prophylaxis and inhibition of the angiogenesis process arising in the tumor proliferation, and for prophylaxis of formation of tumor metastasis. Invention provides preparing new derivatives of borrelidin eliciting the value physiological effect.

EFFECT: valuable medicinal properties of compounds.

8 cl, 15 ex

FIELD: organic chemistry, pharmaceutical compositions.

SUBSTANCE: invention relates to substituted 3-oxo-1,2,3,4-tetrahydroxinoxalines of general formula 1 , wherein R1 represents substituted sulfanyl or substituted sulfonyl group, containing as substituent optionally substituted C1-C4-alkyl, optionally substituted C3-C8-cycloalkyl, aryl-(C1-C4)alkyl optionally substituted in aril or alkyl group, heterocyclyl-(C1-C4)alkyl optionally substituted in heterocycle or alkyl group; R2 and R3 independently represent hydrogen, halogen, CN, NO2, optionally substituted hydroxyl, optionally substituted amino group, optionally substituted carboxylic group, optionally substituted carbamoyl group, optionally substituted arylcarbonyl group or optionally substituted heterocyclylcarbonyl group; R4 and R5 independently represent hydrogen or inert substituent. Claimed compounds are high effective kaspase-3 inhibitors and are useful in production of pharmaceutical compositions for treatment of diseases associated with excess apoptosis activation, as well as for experimental investigations of apoptosis in vivo and in vitro. Also disclosed are pharmaceutical composition in form of tablets, capsules or injections in pharmaceutically acceptable package, as well as method for production thereof and therapy method.

EFFECT: pharmaceutical composition for apoptosis treatment and investigation.

6 cl, 3 dwg, 8 ex, 1 tbl

FIELD: bioactive compounds.

SUBSTANCE: invention relates to new 3-phenyl-1,2,4-benzotriazines and their derivatives of general formula 1

wherein R1 and R2 are independently fluorine or C1-C4-alkoxy, optionally substituted with halogen or tetrahydrofuryl. Compounds of present invention are useful in treatment and prophylaxis of diseases, induced by pathogenic for human and animals viruses including pathogenic for human orthopoxviruses, as well as postvaccinal sequelae.

EFFECT: compounds with improved antiviral activity.

1 cl, 12 ex, 7 tbl

FIELD: organic chemistry, pharmacology.

SUBSTANCE: invention relates to new flavone, xanthone and coumarone derivatives of formula I

[R and R1 each are independently lower C1-C6-alkyl or together with nitrogen atom attached thereto form 4-8-membered heterocycle, optionally containing one or more heteroatoms, selected from group comprising N or O, wherein said heterocycle is optionally substituted with benzyl; Z has formula (A) , wherein R3 and R4 each are independently hydrogen, optionally substituted aromatic group containing in cyclic structure from 5 to 10 carbon atoms, wherein substituents are the same or different and represent lower C1-C4-alkyl, OR10 (OR10 is hydrogen, saturated or unsaturated lower C1-C6-alkyl or formula ) or linear or branched C1-C6-hydrocarbon; or R2 and R3 together with carbon atom attached thereto form 5-6-membered carbocycle; and R4 represents hydrogen or attaching site of group –OCH2-C≡CCH2NRR1; or formula (B) , wherein R5 is hydrogen, linear or branched lower C1-C6-hydrocarbon, with the proviso, that when Z represents R and R1 both are not methyl or R and R1 together with nitrogen atom attached thereto cannot form groups , or ]. Also disclosed are drug component with proliferative activity for prophylaxis or treatment of neoplasm and pharmaceutical composition with proliferative activity based on the same. Derivatives of present invention have antyproliferative properties and are useful as modulators of drug resistance in cancer chemotherapy; as well as in pharmaceuticals for prophylaxis or treatment of neoplasm, climacteric disorders or osteoporosis.

EFFECT: new compounds with value bioactive effect.

31 cl, 2 tbl, 32 ex

FIELD: pharmaceutical industry, medicine.

SUBSTANCE: invention relates to 5-membered N-heterocyclic compounds and salts thereof having hypoglycemic and hypolipidemic activity of general formula I , wherein R1 is optionally substituted C1-C8-alkyl, optionally substituted C6-C14-aryl or optionally substituted 5-7-membered heterocyclic group, containing in ring 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; or condensed heterocyclic group obtained by condensation of 5-7-membered monoheterocyclic group with 6-membered ring containing 1-2 nitrogen atoms, benzene ring, or 5-membered ring containing one sulfur atom; { is direct bond or -NR6-, wherein R6 is hydrogen atom or C1-C6-alkyl; m = 0-3, integer; Y is oxygen, -SO-, -SO2- or -NHCO-; A ring is benzene ring, condensed C9-C14-aromatic hydrocarbon ring or 5-6-membered aromatic heterocyclic ring containing 1-3 heteroatoms selected from oxygen and nitrogen, each is optionally substituted with 1-3 substituents selected from C7-C10-aralkyloxy; hydroxyl and C1-C4-alkoxy; n = 1-8, integer; B ring is nitrogen-containing 5-membered heterocycle optionally substituted with C1-C4-alkyl; X1 is bond, oxygen or -O-SO2-; R2 is hydrogen atom, C1-C8-alkyl, C7-C13-aralkyl or C6-C14-aryl or 5-6-membered heterocyclic group containing in ring 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, optionally substituted with 1-3 substituents; W is bond, C1-C20-alkylene or C1-C20-alkenylene; R3 is -OR8 (R8 is hydrogen or C1-C4-alkyl) or -NR9R10 (R9 and R10 are independently hydrogen or C1-C4-alkyl). Compounds of present invention are useful in treatment of diabetes mellitus, hyperlipidemia, reduced glucose tolerance, and controlling of retinoid-associated receptor.

EFFECT: new medicines for treatment of diabetes mellitus, hyperlipidemia, etc.

26 cl, 518 ex, 3 tbl

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of tetrahydroisoquinoline of the formula [I] wherein R1 represents hydrogen atom or lower alkyl; R2 represents alkyl having optionally a substitute taken among alkoxycarbonyl and carboxy-group, cycloalkyl, cycloalkylalkyl, aryl having optionally a substitute taken among lower alkyl, arylalkyl having optionally a substitute taken among lower alkyl, lower alkoxy-group, halogen atom and acyl, alkenyl, alkynyl, or monocyclic heterocyclylalkyl wherein indicated heterocycle comprises 5- or 6-membered ring comprising nitrogen atom and having optionally a substitute taken among lower alkyl; R3 represents hydrogen atom or lower alkoxy-group; A represents a direct bond or >N-R5 wherein R5 represents lower alkyl; B represents lower alkylene; Y represents aryl or monocyclic or condensed heterocyclyl comprising at least one heteroatom taken among oxygen atom and nitrogen atom and having optionally a substitute taken among lower alkyl, carboxy-group, aryl, alkenyl, cycloalkyl and thienyl, or to its pharmaceutically acceptable salt. Also, invention relates to pharmaceutical composition eliciting hypoglycaemic and hypolipidemic effect based on these derivatives. Invention provides preparing new compounds and pharmaceutical agents based on thereof, namely, hypoglycaemic agent, hypolipidemic agent, an agent enhancing resistance to insulin, therapeutic agent used for treatment of diabetes mellitus, therapeutic agent against diabetic complication, agent enhancing the tolerance to glucose, agent against atherosclerosis, agent against obesity, an anti-inflammatory agent, agent for prophylaxis and treatment of PPAR-mediated diseases and agent used for prophylaxis and treatment of X-syndrome.

EFFECT: valuable medicinal properties of compounds and composition.

13 cl, 7 tbl, 75 ex

FIELD: organic chemistry, medicine, pharmacy.

SUBSTANCE: invention relates to new derivatives of cyanoaryl (or cyanoheteroaryl)-carbonylpiperazinyl-pyrimidines of the general formula and their physiologically acceptable salts that elicit the broad spectrum of biological activity exceeding activity of structurally related known compounds. In the general formula (I) R1 represents radical OR3 wherein R3 represents saturated hydrocarbon radical with linear or branched chain and comprising from 1 to 4 carbon atoms; R2 represents phenyl radical substituted with cyano-radical (-C≡N) or radical representing 5- or 6-membered heteroaromatic ring wherein heteroatom is taken among oxygen (O), nitrogen (N) or sulfur (S) atom and substituted with cyano-radical (-C≡N). Also, invention relates to methods for preparing compounds of the general formula (I) that involve incorporation of group of the formula:

into piperazinyl-pyrimidine compound or by the condensation reaction of corresponding pyrimidine with piperazine comprising group of the formula:

. Also, invention relates to pharmaceutical composition and applying these compounds. Compounds can be used for preparing medicinal agents useful in human therapy and/or for therapeutic applying in veterinary science as agents eliciting ant-convulsive and soporific effect or for the general anesthesia.

EFFECT: valuable medicinal properties of compounds and pharmaceutical composition.

13 cl, 7 sch, 8 tbl, 41 ex

FIELD: organic chemistry, chemical technology, medicine.

SUBSTANCE: invention relates to a method for preparing derivatives of indole of the general formula (I):

wherein R1 represents hydroxy-group; R2 represents hydrogen atom, (C1-C6)-alkyl, (C1-C6)-alkoxy-group, (C2-C6)-alkoxyalkyl or 4-methoxybenzyl; R3 represents hydrogen atom or (C1-C6)-alkyl; each among R4 and R represents independently hydrogen atom, (C1-C6)-alkyl or (C1-C6)-alkoxy-group; D represents an ordinary bond, (C1-C6)-alkylene, (C2-C6)-alkenylene or (C1-C6)-oxyalkylene; in the group-G-R6 wherein G represents an ordinary bond, (C1-C6)-alkylene; R represents saturated or unsaturated carbocyclic ring (C3-C15) or 4-15-membered heterocyclic ring comprising 1-5 atoms of nitrogen, sulfur and/or oxygen wherein this ring can be substituted. Also, invention describes a method for preparing derivatives of indole and DP-receptor antagonist comprising derivative of the formula (I) as an active component. As far as compounds of the formula (I) bind with DP-receptors and they are antagonists of DP-receptors then they can be useful for prophylaxis and/or treatment of diseases, for example, allergic diseases.

EFFECT: improved preparing method, valuable medicinal properties of compounds.

11 cl, 7 tbl, 353 ex

Up!