Resolutiony crystalline 6-hydroxy-2-(4 - hydroxyphenyl)-3-[4-(2-piperidinoethyl) benzoyl]-benzo-[b]- difengidramin with antiestrogenic and antiandrogennoe activity, a pharmaceutical composition

 

(57) Abstract:

The invention relates to a new resolutional crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/benzo[b] difengidramin, which can be used as a pharmaceutically active agent, the pharmaceutical composition. 3 S. and 1 C.p. f-crystals, 9 PL.

The invention relates to a new pharmaceutical product. More specifically it relates to a new, resolutionyou crystalline form of 2-aryl-6-hydroxy-3-/4-(2-aminoethoxy) benzoyl-benzo[b]thiophene.

In U.S. patent N 4418068 revealed 6-hydroxy-2-(4-hydroxyphenyl)-3-/4- (2-piperidinoethyl)benzoyl/benzo[b] difengidramin known as raloxifenetreated, which, as shown, has a future use as a pharmaceutically active agent. Unfortunately, it turned out that this compound is extremely difficult to obtain in pure form. A particular problem associated with impurities by solvent. For example, in the production method of raloxifene described in Journal of Medicinal Chimisiy 27(8), 1057-1066 (1984), a serious disadvantage is that getting solvated compound, contaminated with chlorobenzene, which, as you know, the two the El-crafts with aluminofluoride catalyst. By these means the product contains a mixture of aluminum and various by-products-thioethers, which are difficult to remove. In addition, the product described in these literature references, differs unpleasant smell of thiol or sulfide.

In accordance with the invention found that it is possible to obtain a new, resolutionyou crystalline form of raloxifene, not containing such impurities as chlorobenzene and aluminum, due to the unknown up to the present time the synthesis method.

A new crystal form of the invention shows the diraction pattern of x-rays, are presented in table. 1.

Preferably, in the new resolutionas the form of raloxifenetreated the number of 6-hydroxy-2-(4-hydroxyphenyl) -3-/4-(2-piperidinoethyl)benzoyl/benzo[b] difengidramin present in the crystalline material was at least 95% by weight /W/W/, preferably at least 98%, more preferably at least 99%. More specifically, this preferred form practically must not contain chlorobenzene. In addition, this preferred form also preferably should not contain aluminum salts or alarmin "contains practically no chlorobenzene", in the same sense as it is used in the description refers to resolutionyou crystalline 6-hydroxy-2-/4-hydroxyphenyl/-3-/4-(2-piperidineacetic benzoyl/benzo[b] difengidramin, representing a compound containing less than 5% of chlorobenzene in the calculation of the weight (weight/weight). Preferably, the number of chlorobenzene was less than 2%, more preferably less than 1%. And it is most preferable that the number of chlorobenzene in resolutiona crystalline material was less than 0.6%.

The term "contains almost no impurities salts of aluminum or alyuminiiorganicheskikh compounds", in the sense as it is used in the description refers to resolutionyou crystalline 6-hydroxy-2 - 4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/benzo[b] difengidramin and is a crystalline compound containing less than 5% of aluminum salts or alyuminiiorganicheskikh impurities based on the weight (weight/weight). Representatives of aluminum salts include (but are not limited to, aluminum hydroxide, aluminiumoxide and their hydrated forms. Representatives alyuminiiorganicheskikh compounds include (but are not limited to, alkoxides of aluminum, complexes of aluminum (III) with compounds of the formula I or IV impurities was less than 2%, more preferably less than 1%.

The term "practically odorless" in the sense in which it is used, refers to resolutionyou crystalline 6-hydroxy-2- (4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/benzo [b]difengidramin and describes a compound that contains less than 3% impurities mercaptan or sulfide. Preferably, the amount of impurities mercaptan or sulfide was less than 2%, more preferably less than 1%. Representatives of impurities mercaptan or sulfide include (but are not limited to) C1-C6alkylthiol and methyl-C1-C6alkylsulfate.

This resolutiony crystalline material is more pure than the material received by the literature methods. This material does not contain impurities of aluminum, and contains no chlorinated aliphatic hydrocarbon solvents and aromatic solvents. This resolutiona crystalline form is particularly preferred for use in obtaining pharmaceutical compositions.

This new crystalline form of raloxifenetreated requires opening of the new method, which includes the following stud the/SUP> - C1-C4alkyl,

allermuir agent of the formula:

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where R6is chlorine, bromine or hydroxyl;

HX - NCl or HBr;

R2and R3together with the adjacent nitrogen atom form a piperidine group; in the presence , where X' is chlorine or bromine;

b) dealkylation of phenolic groups of the acylation product from stage a) by the reaction with an additional number , where X has the above meanings;

c) selection of the crystalline MES compounds of the formula:

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where R1is hydroxyl;

HX, R2and R3have the previously indicated meanings;

d) interaction of a specified crystalline MES in methanol or in a mixture of methanol and water with about one equivalent of base,

e) optional extraction solution from stage (d) aliphatic hydrocarbon solvent,

f) adding about one equivalent of hydrochloric acid to a methanol solution from stage (d) or (e) and

(g) allocation resolutionvideo crystalline substance.

In the described method, preferably, R4would methoxy, R5is methyl, R6- chlorine, HX = HCl, = BCl3, aliphatic hydrocarbon solvent would be hexanal it is used in the description, refers to the number of moles of reagent trihalide compounds of boron with respect to the number of moles of the original benzothiophene connection. So, for example, three millimole trichloride boron is subjected to interaction with one millimoles benzothiophene connection that corresponds to three molar equivalents boron trichloride.

The term "MES" means a unit that contains one or more of the molecules of such dissolved substances as the compound of formula I with a solvent molecule.

Representative solvate formed with chlorobenzene and 1,2-dichloroethane.

In the new method, which is used to produce a new crystalline form of the invention, using boron trichloride or tribromide boron as a catalyst for acylation instead of aluminofluoride, as indicated in the well-known from the literature how to get of raloxifene. With aluminofluoride difficult to work, especially on an industrial scale. In addition, acylation or dealkylation need a large number of aluminofluoride, usually six equivalents. Luminiare forms a large number of side products, which are involved in the deposition process of the product and then t, catalyzed aluminofluoride are usually reactions heterogeneous mixture. The described method is homogeneous, and by-products they are soluble boron used in the further stages of the solvents. Next, dealkylation catalyzed by aluminofluoride, requires the addition of the mercaptan or sulfide for splitting alkylacrylate, which leads to the formation of diallylsulfide, which have an unpleasant odor. These mercaptans or sulfides can be removed by recrystallization, but the result is the solvent recrystallization from odorous impurities. The new method eliminates the use of aluminum and the use of mercaptans and sulfides with an unpleasant odor. Previously known methods have received a large number of related compounds and a lot of residual aluminum salts in the final product. Examples of related substances include 6-hydroxy-2-(4-methoxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/benzo [b] thiophene, 2-(4-hydroxyphenyl)-6-methoxy-3-/4-(2-piperidinoethyl) benzoyl/benzo[b] thiophene, 6-hydroxy-3-(4-hydroxybenzoyl)-2-(4-hydroxyphenyl)benzo[b] thiophene, propyl-4-(2-piperidinoethyl)thiobenzoate, methyl-4-(2-piperidinoethyl)benzoate, 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/-7-/4-(2-piperidinoethyl)benzoyl/benzo[b] thiophene. By-products containing boron, easy to remove from the final product. In addition, the new method allows to avoid the removal of waste aluminum compounds. If the reaction of lead in 1,2-dichloroethane, the reaction is homogeneous, which allows the use of higher concentrations and to obtain a crystalline solvate, which can easily be distinguished. Compounds of formulas II and III, the original materials of the invention can be obtained using known methods of organic synthesis.

The original connection of the formula II can be easily obtained according to the scheme of synthesis, which is shown in figure 1 and illustrated in the example of a 1:

Circuit 1

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The compounds of formula II, where R4represents C1-C4alkoxy, and R5- C1-C4alkyl, can be obtained by first subjecting the interaction of 3-alkoxybenzyl with 4'-alkoxyphenyl bromide in the presence of a strong base. Suitable bases for this transformation include (but are not limited to, potassium hydroxide and sodium hydroxide. The reaction usually leads to ethanol or in a mixture of water and ethanol at a temperature of about 0 to 50oC. the Next step is the cyclization of 3-alkoxysilylated. The cyclization is usually lead, UP>oC, preferably 85 - 90oC. Benzothiophen formula II is usually purified by recrystallization. For example, if R4is methoxy, and R5- methyl, compound of formula II can be recrystallized from ethyl acetate.

Allerease agent for this method, the compound of formula III, can be obtained as shown in scheme II, where R2, R3, R6and HX have the previously mentioned meanings and R represents a C1-C4alkyl.

Scheme II

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Usually C1-C4-alkyl-4-hydroxybenzoate alkylate 1-/2 - chloroethyl/-piperidine in the presence of inorganic bases and ester group hydrolyzing to obtain the compounds of formula III, where R6represents hydroxyl. Suitable for the alkylation of bases include potassium carbonate and sodium carbonate. Suitable for such alkylation solvents are not reactive polar organic solvents, such as methyl ethyl ketone and dimethylformamide. Ester hydrolyzing using standard synthesis methods, for example the reaction of the alkylated intermediate compound with aqueous acid or base. So, for example, ethyl ester easy himatangi. In the acidification of the reaction mixture with concentrated hydrochloric acid leads to the production of the compounds of formula III, where R6represents a hydroxyl in the form of a salt is hydrochloride.

The compounds of formula III, where R6represents chlorine or bromine, can be obtained as a result of haloiding compounds of formula III, where R6represents hydroxyl. Suitable Ganoderma agents include oxalicacid, thionyl chloride, thienylboronic, trichromacy phosphorus, triphosgene and phosgene. Preferably, R6was chlorine. Suitable solvents for this reaction include methylene chloride, 1,2-dichlorobenzene, chlorobenzene and 1,2-dichloroethane. It is preferable to conduct the reaction haloiding in the same solvent and subsequent reaction of acylation. A catalytic amount of dimethylformamide, about 0.05 - 0.25 equivalents added to the reaction mixture chlorination. If the reaction of lead in 1,2-dichloroethane, the reaction is completed within 2 to 5 hours at a temperature of about 47oC. the compounds of formula III in which R6is chlorine, can be stored either in solid form or in solution, or in a mixture with methylene chloride, chlorobenzene, 1,2-dichlorobenzene or 1,2-dichloroethane. It is preferable to conduct realinvestors)benzoyl[b] tiophene can be obtained by acylation and subsequent dialkylammonium phenolic groups on two different stages or sequentially in the same reactor. Stepwise synthesis is described in the following paragraphs. Acylated intermediate derived benzothiophene, the compound of formula IV can be obtained, as shown in scheme III, where R2, R3, R4, R5, R6and HX have the previously indicated meanings.

Scheme III

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Usually benzothiophene derivative II acelerou compound of formula III, using boron trichloride or tribromide boron as a catalyst for acylation. The reaction of lead in such an organic solvent as chlorobenzene, methylene chloride, 1,2-dichloroethane, 1,2-dichlorobenzene, Brabanthal, chloroform, 1,1,2,2-tetrachlorethane, 1,2,3-trichlorpropane or torbenson. It is preferable to conduct the acylation in methylene chloride, chlorobenzene or 1,2-dichloroethane. More preferably the stage of acylation in methylene chloride. The rate of acylation of the compounds of formula II and the rate of dealkylation of phenolic esters of formulas II and IV are changed depending on the choice of solvent, reaction temperature and choice of trihalide boron. Since the compounds of formula II contain one or more of unprotected phenolic groups, they are not easy to allievate in such conditions, and the degree of dealkylation should be kept to a minimum. As trichromacy Bor n is as acylation is boron trichloride. For reactions with catalyst boron trichloride in methylene chloride acylation reaction can be conducted at room temperature, with a minimum dialkylammonium compounds of formulas II and IV. In other solvents the acylation reaction is carried out at lower temperatures, such as --10oC - +10oC, in order to minimize the degree of dealkylation reaction of starting materials and product. If R6represents chlorine, the reaction of acylation need at least 2 molar equivalents of this reagent, as triploid boron. If Alliluyeva agent use benzoic acid (R6=OH), then typically use five equivalents of trihalide boron. The compound of formula IV can be isolated in the form of a salt, hydrobromide or hydrochloride or free base.

In the stepwise method acylated intermediate compound (compound of formula (IV) dealkylase to obtain the compounds of formula I, as shown in scheme IV, where R1, R2, R3, R4, R5and HX have the previously indicated meanings.

Scheme IV

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The compound of formula 1 can be obtained by interaction or cleaners containing hydrochloride hydrobromide salts of the compounds of formula Etsa trichromacy Bor. This dealkylation reaction can be conducted in various organic solvents, such as methylene chloride. 1,2-dichloroethane, chloroform, 1,1,2,2-tetrachlorethane, 1,2,3-trichloropropane, 1,2-dichlorobenzene or torbenson. The preferred solvent is 1,2-dichloroethane. If the original connection using salt accession acid, the amount of by-product formed during dialkylamino aminoaniline group, is minimized. If the solvent used methylene chloride, and the reagent boron is boron trichloride, the reaction is usually carried out at a temperature of about 55 - 75oC, obtaining the compound of formula I without appreciable removal of aminoaniline group. In such other solvents, such as chloroform, 1,2-dichloroethane, 1,2-dichlorobenzene or torbenson, dealkylation occurs readily at room temperature. For example, if the solvent is 1,2-dichloroethane, the reaction is usually carried out at 25-35oC without appreciable removal of aminoaniline group. To complete the reaction within a reasonable time, usually using four equivalents of reagent-trihalide boron.

It is preferable to obtain the compounds of formula I in the reaction in one reactor, synthesizing them from compounds kazanie earlier values.

Scheme V

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Benzothiophen the compounds of formula II acelerou compound of formula III in the presence of boron trichloride or trichromatic boron; boron trichloride is preferred for the method "in the same reactor. The reaction can be conducted in such organic solvents as chloroform, methylene chloride, 1,2-dichloroethane, 1,2,3-dichloropropane, 1,1,2,2-tetrachlorethane, 1,2-dichlorobenzene or torbenson. The preferred solvent for this synthesis is 1,2-dichloroethane. The reaction is conducted at temperatures from about -10oC to about 10oC, preferably at 0oC. the Reaction is best conducted at concentrations benzothiophene the compounds of formula II is from about 0.2 M to about 1.0 M. the acylation Reaction is usually completed in about 2 - 8 hours

The acylated benzothiophen the compounds of formula IV into a compound of formula I without isolation. This transformation is carried out, adding more trihalide boron and heating the reaction mixture. It is preferable to add from two to five equivalents of boron trichloride to the reaction mixture, more preferably three molar equivalents. This reaction is carried out at a temperature of about 25-40oC, preferably at 35oC. Usually, the reaction is for the purpose of damping the reaction of the alcohols include methanol, ethanol and isopropanol. Preferably, the reaction mixture acylation/dealkylation to add to 95:5 mixture of ethanol and methanol (3A). 3A ethanol can be room temperature or can be heated to the boil under reflux, preferably at boiling under reflux. If the reaction is quenched thus, the compound of formula I is readily crystallized from the resulting alcohol mixture. Usually use a 1.25-3.75 ml of alcohol per millimoles source benzothiophene.

If using BCl3, crystalline product of this process in a single reactor is isolated in the form of MES cleaners containing hydrochloride salt. Such crystalline solvate get in various conditions. Usually the shape of the product obtained in this way is determined by the choice of solvent for the acylation/dealkylation, trihalide boron and treatment conditions. For example, if the solvent acylation/dealkylation is 1,2-dichloroethane, 1,2,3-trichloropropane or torbenson allocated to the crystalline MES containing 1,2-dichloroethane, 1,2,3-trichloropropane or torbenson respectively.

The most appropriate MES the compounds of formula I is MES 1,2-dichloroethane. This MES n the hat hydroxide, R2and R3together with the adjacent nitrogen atom form a piperidine group, and HX is HCl, then MES 1,2-dichloroethane can exist in two different forms. One form of the crystalline MES called crystalline form 1, it turns out, when catalyzed by boron trichloride reaction acylation/dealkylation extinguish ethanol. It is preferable to use a mixture of ethanol and methanol (95:5) upon receipt of this crystalline form. This specific crystal is characterized by the diffraction pattern of x-rays, are presented in table. 2.

The number of 6-hydroxy-2-[4-hydroxymethyl] -3-/4-[2-piperidineacetic] benzoyl/benzo[b]difengidramin in this crystalline material is about 87.1 percent according to liquid chromatography high resolution (IHVR), which are disclosed hereinafter. The amount of 1,2-dichloroethane present in the crystalline material is about to 0.55 molar equivalents according to the nuclear magnetic resonance.

Large, analytically pure single crystal form 1 MES 1,2-dichloroethane get for analysis of x-ray diffraction single crystal. Such single crystal benzo[b] difengidramin in the atmosphere, rich 1,2-dichloroethane (see example 6). Get all 8419 reflexes for less than 20 116oC, and their use for structure determination. According to x-ray diffraction clearly shows that the crystalline material is a MES 1,2-dichloroethane with respect to the number of solvent molecules to dissolved material 1: 2. theoretical range of x-ray diffraction powder, calculated on the basis of data for the diffraction pattern of single crystal, identical to that presented in table. 2, which testifies to the identity of both the solvate.

New resolutiona crystalline form of 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl) benzoyl/benzo[b] difengidramin presented in the invention, preferred for use in pharmaceutical compositions, as there is no solvent, which can have a harmful effect on the patient. This crystalline form can be obtained by recrystallization of solvated cleaners containing hydrochloride salt obtained in the process of acylation/dealkylation, and catalyzed boron trichloride. Usually solvated cleaners containing hydrochloride salt added to a solution of the hydroxide is of its and to ensure that to cleaners containing hydrochloride salt was converted into the free base. Optional add activated carbon to the solution to facilitate the removal of impurities. The resulting mixture was filtered to remove the activated carbon, if present, and any insoluble impurities. The obtained filtrate optional extracted with an aliphatic hydrocarbon solvent such as hexane or heptane, to remove the remaining part of the solvent that was used in the reaction of acylation/dealkylation. Stage extraction is necessary if the reaction of acylation/dealkylation are in aromatic solvents such as o-dichlorobenzene. The methanol solution is acidified with hydrochloric acid, for example, gaseous or aqueous hydrochloric acid, causing the crystallization of 6-hydroxy-2-(4-hydroxyphenyl)-3-/4- (2-piperidinoethyl)benzoyl/benzo[b] thiophene in the form of resolutional cleaners containing hydrochloride salt. The resulting crystalline suspension is preferably stirred at room temperature for 1-2 hours to ensure complete crystallization. Resolutionyou crystalline form are filtered, followed by drying in vacuum.

The following note is to place and dialkylamino are under positive pressure of dry nitrogen. All solvents and reagents used immediately upon receipt. Interest is usually expressed as the weight percent (weight/weight), with the exception of solvents GHUR who count in the calculation of the volume (volume/volume). Data proton nuclear magnetic resonance (1H-NMR) were obtained on a spectrometer Bruker AC-300 FTNMR with an operating frequency of 300,135 Mghz. The melting temperature is determined using differential scanning calorimeter (DSC) in THE device DCB 2920 using a closed cell at heating rate of 2oC/min Diffraction spectrum of x-rays for powders get an x-ray powder diffractometer Siemeuns D5000, using copper radiation and Si(Li) detector.

The end of the reaction is usually monitored using liquid chromatography high resolution (IHVR). The reaction obtain the acid chloride compound of formula III, where R6represents chlorine, 've been using Bond RX-C8 column (25 cm x 4.6 mm EXT.D., 5 μm particle size), elwira a mixture of 60 mm phosphate (KH2PO4) and 10 mm octanesulfonate (pH 2,0) (acetonitrile (60:40)). The compound of formula III is treated with methanol and analyzed, using as a standard for comparison of the methyl ester. The reaction is controlled by adding at and left to react. After 30 minutes add 6 ml of acetonitrile, and then dilute to 100 ml described above eluent.

After completion of the acylation reactions, dealkylation or acylation/dealkylation monitored by HPLC. Samples of the reaction mixture analyzed using column Bond RX-C8 (25 cm x 4.6 mm EXT.D., 5 μm particle size), using as eluent a gradient solvent system, are presented in table. 3.

The reaction mixture was analyzed by diluting 0.1-0.2 ml sample to a volume of 50 ml with a mixture of 60:40 A/B. Similarly, the mother liquor of precrystallization exploring, selecting samples.

Number (%) of 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/bakso[b] difengidramin in the crystalline material (purity) is determined in the following way. A sample of the crystalline solid (5 mg) is weighed into a 100 ml volumetric flask and dissolved in a mixture of 70/30 75 mm potassium phosphate buffer (pH 2.0) and acetonitrile. The aliquot of this solution (10 µl) was analyzed by liquid chromatography high resolution, using a column Bond RX-C8 (25 cm x 4.6 mm EXT.D., particle size 5 µm) and UV detector (280 nm). Using a gradient solvent system, are presented in table. 4.


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The percentage of solvent, such as methanol, ethanol or 1,2-dichloroethane, present in the crystalline material was determined by gas chromatography. Solid crystalline sample (50 mg) is weighed into a 10 ml volumetric flask and dissolved in a solution of 2-butanol (0.025 mg/ml) and dimethyl sulfoxide. A sample of this solution is analyzed by gas chromatography, using a column DB-Wax (30 m x 0.53 mm EXT.D., particle size 1 micron), at a flow rate of 10 ml/min with a flame ionization detector. The temperature of the column increases with the 35oC to 230oC for 12 minutes, the Amount of solvent is determined by comparison with the internal standard (2-butanol) using the following formula:

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where C is the ratio of the solvent in the sample,

D-average ratio standard for a specific solvent,

E - the average weight of standard,

F - weight of sample (mg),

G - sample volume (10 ml),

H - volume of standard (10 000 ml)

J - purity standard (%).

Example of getting 1. 6-methoxy-2-/4-methoxyphenyl/benzo[b]thiophene

Solution C-methoxybenzamide (100 g) and potassium hydroxide (39,1 g) in the from the cold mixture was treated with 4'-methoxybenzylamine (164 g) in several small portions. After complete addition, the mixture cool for another 10 minutes, then allow it to warm to room temperature. After three hours the mixture was concentrated in vacuo, and the residue is treated with water (200 ml). The resulting mixture was treated with ethyl acetate and the phases are separated. The organic phase is washed twice with water, sodium bicarbonate solution twice and also twice with a solution of sodium chloride. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness in vacuo to obtain 202 g -(3-methoxybenzylthio)-4-methoxyacetophenone. The crude product is crystallized from methanol and washed with hexane to obtain 158 g of substance. So melting 53oC.

930 g of polyphosphoric acid heated to 85oC and treated intermediate product obtained previously (124 g) in small portions over 30 minutes After complete addition, the resulting mixture was stirred at 90oC. after 45 min the reaction mixture is allowed to cool to room temperature. The resulting mixture was treated with crushed ice, cooling the mixture in an ice bath. The resulting mixture is treated with water (100 ml), resulting in a light pink precipitate. This precipitate are filtered, washed with water and methanol and dried spenderat in hot methanol, filtered and washed with cold methanol. The obtained solid material is recrystallized from ethyl acetate (4 l), filtered, washed with hexane and dried in vacuum to obtain 68 g specified in the title compounds. So melting 187-190,5oC.

Example of getting a 2. Ethyl-4-/2-piperidineacetic/benzoate

A mixture of ethyl-4-hydroxybenzoate (8,31 g), 1-(2-chloroethyl)piperidineacetate (10,13 g), potassium carbonate (16,5 9 g) and 60 ml of methyl ethyl ketone heated to 80oC. After one hour the mixture is cooled to 55oC and treated with an additional amount of 1-(2-chloroethyl)piperidineacetate (0,92 g). The resulting mixture was heated to 80oC. the reaction is monitored by thin layer chromatography (TCX), using plates of silica gel and a mixture of ethyl acetate(acetonitrile)triethylamine (10: 6:1 volume/volume). Add a further portion of 1-/2-chloroethyl)/piperidineacetic to the exhaustion of the original 4-hydroxybenzoate of ester. After completion of the reaction, the reaction mixture is treated with water (60 ml) and left to cool to room temperature. The aqueous layer was drained and the organic layer was concentrated in vacuo at 40oC and 40 mm RT.article The resulting oil is used in the next stage without stage is a Solution of the compound, obtained in example 2 (about 13,87 g) in 30 ml of methanol is treated with 5N. sodium hydroxide (15 ml) and heated to 40oC. After 4.5 h add 40 ml of water. The resulting mixture was cooled to 5-10oC and slowly add concentrated hydrochloric acid (18 ml). In the process of acidification crystallizes specified in the title compound. The crystalline product is collected by filtration and dried in vacuum at 40-50oC to obtain 83% of output specified in the title compounds. So melting 270-271oC.

Example 4. 4-/2-piperidineacetic/benzoyl chloride hydrochloride

A solution of the compound obtained according to the method of producing example 3 (30,01 g) and 2 ml of dimethylformamide in a 500 ml of methylene chloride is treated with oxalylamino (10.5 ml) for 30-35 minutes After stirring for about 18 h, the reaction mixture was analyzed for complete reaction with VASU. If the mixture still has the original carboxylic acid, add additional oxalicacid. After completion of the reaction, the reaction solution is evaporated to dryness in a vacuum. The residue is dissolved in 200 ml of methylene chloride and the resulting solution is evaporated to dryness. This process of dissolution/evaporation repeated to obtain the specified substance or in a 0.2 M solution in 500 ml of methylene chloride.

Example 1. 6-methoxy-2-(4-methoxyphenyl)-3-/4-(2-piperidinoethyl) benzoyl/-benzo[b]difengidramin

The mixture of compounds obtained by the method of example obtain 1 (8,46 g), and the acid chloride obtained according to the method of example for the preparation of 3 (10.0 g) in 350 ml of methylene chloride is cooled to about 20-25oC. the resulting mixture was treated with boron trichloride (2.6 ml) and everything is mechanically stirred. The reaction is monitored by HPLC, using the earlier analysis. After 85 min according to HPLC in situ output per 6-methoxy-2-(4-methoxyphenyl)-3-/4-(2-piperidinoethyl) benzoyl/benzo[b]titanovyi standard is 88%.

Example 2. 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl) benzoyl/-benzo[b] difengidramin 1,2 dichlorethane MES (Crystal form 1)

A solution of 6-methoxy-2-(4-methoxyphenyl)-3-/4-(2-piperidinoethyl)-benzoyl/benzo[b] difengidramin (2.0 g) in 20 ml of 1,2-dichloroethane is treated with boron trichloride (2.0 ml). The resulting mixture was stirred at 35oC for 18 hours the Mixture of ethanol and methanol (10 ml of 95:5, handle the resulting reaction mixture, which leads to boiling under reflux alcohol mixture. After complete addition, the resulting crystal is m ethanol (10 ml) and dried at 40oC in a vacuum to obtain 1.78 g specified in the title compounds. Diffraction pattern x-ray powder identical to the picture shown in the table. 1. The melting point of 255oC. the Degree of purity: 80.2 per cent.

1,2-dichloroethane: 7,5% (according to gas chromatography).

Example 3. 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl) benzoyl/-benzo[b]difengidramin 1,2-dichlorethane MES (Crystal form 1)

The mixture of compounds obtained as described in example getting 2, (15 g) and dimethylformamide (0.2 ml) in 250 ml of 1,2-dichloroethane is cooled to 0oC, of 8.25 ml of phosgene condense in cold funnel (fitted shirt) (-10oand add to the cold mixture for 2 minutes the resulting mixture is heated to approximately 47oC. After two and a half hours, the reaction mixture was analyzed by HPLC. To complete the reaction may need to add additional phosgene. The excess phosgene is removed by vacuum distillation at 30-32oC and a pressure of 105 to 110 mm RT.article.

After 3 to 4 hours the reaction solution is treated with a compound, obtained as described in example obtain 1 (13,52 g). The resulting solution was cooled to 0oC. boron Trichloride (12,8 ml) condense in measuring t the additional amount of boron trichloride (12,8 ml). The resulting solution was heated to 30oC. After 15 h, the reaction mixture is controlled by GHWR.

A mixture of ethanol and methanol (125 ml, 95:5, 3A) is heated to boiling under reflux and treated reaction solution obtained earlier, within 60 minutes After complete addition, the flask for reaction acylation/demethylation washed with additional ethanol (30 ml). The resulting suspension is allowed to cool to room temperature with stirring. After one hour at room temperature crystalline product is filtered off, washed it with ethanol (75 ml) and dried at 40oC in a vacuum to obtain 25,9 g specified in the title compound, a diffraction pattern x-ray powder are presented in table. 1. Melting point 261oC. the Degree of purity: 87,1%.

1,2-dichloroethane: to 0.55 molar equivalents (1H-NMR).

Example 4. 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl) benzoyl/-benzo[b] difengidramin 1,2-dichlorethane MES (Crystal form 11)

The mixture of compounds obtained as described in example obtain 1 (2,92 g), compounds obtained as described in example 4 (of 3.45 g), and 1,2-dichloroethane (52 ml) ahlusunnah cold mixture. After 8 h at 0oC, the reaction mixture was treated with an additional amount of boron trichloride (2.8 ml). The resulting solution was heated to 35oC. After 16 h the reaction is finished.

30 ml of methanol is treated with the reaction mixture obtained previously, for 20 min, resulting in boiling methanol under reflux. The resulting suspension is stirred at 25oC. After an hour, the crystalline product is filtered, washed with cold methanol (8 ml) and dried at 40oC in a vacuum to obtain 5,14 g specified in the title compounds. Because of differences in the conditions of processing of crystalline MES differs from the MES obtained in example 3. So melting 225oC. the Degree of purity: 86,8%.

1,2-dichloroethane: 6,5% (according to gas chromatography).

Example 5. 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/-benzo[b]difengidramin

The compound obtained by the method of example 3 (4.0 g), suspended in 30 ml of methanol at room temperature. The resulting mixture is treated with sodium hydroxide solution (0,313 g) in 10 ml of methanol. After complete dissolution the solution was added activated charcoal (0.4 g, Daga C-60, Aldrich Chem Co. , Inc., Milwaukee). After 30 min Cel, Aldhch Chem. Co.). The filter cake is washed with methanol (10 ml). The combined filtrates are treated (drops) 2n. hydrochloric acid (4 ml). The resulting suspension is stirred for 60 min at room temperature and filtered. The filter cake was washed with cold methanol (14 ml, 0oC) and dried in vacuum at 60oC for about 18 h to obtain 3.00 g off-white free presuposes powder. So melting 262oC. Diffraction pattern x-ray powder is the same as presented in table. 1. Degree of purity: 99.1 per cent. Related substances: 0,85%.

Example 6. 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)-benzoyl/benzo[b]difengidramin 1,2-dichlorethane MES (Crystal form 1)

A saturated solution of 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/benzo[b] difengidramin get under stirring suspension of the compound obtained by the method of example 5 in methanol at room temperature over night. The resulting mixture was filtered (filter paper Whatman No. 1). Part of the filtrate (20-25 ml) placed in an Erlenmeyer flask with a capacity of 50 ml of the flask placed in a glass vessel (8.5 x 10 cm) containing 1,2-dichloroethane (OK is lly formed from a methanol solution. These crystals are filtered and dried in vacuum. So melting 273oC. the crystal Structure was determined by automatic diffractometer Siemens R3m/V, using monochromatic radiation of copper . Crystal structure determined using direct methods TPEF software library SHEZXTZ PZUS. Refinement by full matrix least-squares variance carried out with temperature anisotropy factors for all atoms except hydrogens, which are included in calculated positions with isotropic temperature factors. Final factor was 8,02%. The results of the study of crystals, see table. 5.

X-ray analysis clearly shows that the crystalline material is 1,2-dichlorethane MES with respect to molecules of 1,2-dichloroethane to molecules of 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl)benzoyl/benzo-[b]difengidramin 1:2.

Example 7. 6-hydroxy-2-(4-hydroxyphenyl)-3-/4-(2-piperidinoethyl) benzoyl/-benzo[b]difengidramin

A solution of sodium hydroxide (0,313 g) in methanol (10 ml), diluted with another 50 ml of methanol. This solution is treated with a compound obtained by the method of example 4 (4.0 g). After 45 min at room temperatura (3 ml). The resulting filtrate is treated with 2n. hydrochloric acid (4 ml), resulting in a gain crystal suspension. After 1.5 h, this crystalline product is filtered off, washed with methanol (5 ml) and dried at 45-50oC in a vacuum to obtain 2,103 g specified in the title compounds. The diffraction pattern of x-rays is the same as presented in table. 1. So melting 261oC. the Degree of purity: 96.5 per cent.

Biological data

Osteoporosis - test method

In the examples illustrating this technique, used experimental animals with the simulated osteoporosis postmenopausal, have evaluated the effect of different treatments on the density of the femur.

From laboratories Charies River (Portage, MI) were obtained from female rats Sprague Dawley semidesyatiletnego age (their weight was 225 - 275 g). Rats were housed in a group of 3 individuals and had unlimited access to food (the amount of dietary calcium was approximately 1%) and water. Indoors maintained the temperature of 22.2 1,7oC and a relative humidity of at least 40%. Mode lighting consisted of 12 h light and 12 h darkness.

One week after arrival, rats were subjected to bilateral ovariectomy the compounds of formula I started the day of surgery after the termination of anesthesia. Oral dose was given via a stomach tube in 0.5 ml of 1% carboxymethylcellulose (CMC). Body weight was determined during surgery and then weekly doses were selected on the change of weight of the body. Ovariectomised (ovec) and neuorientierung (intact) rats treated with media or estrogen, compared in parallel with each experimental group as negative and positive control.

Rats had a dose of their tools daily for 35 days (6 rats in the experimental group), and then, on the 36th day they were killed by decapitate. 35-day period was sufficient to obtain maximum reduction of bone density, measured as described. After the slaughter of the animals was removed the uterus, cut the outside fabric and prior to determination of wet weight was removed liquid contents of the body to confirm estrogen deficiency associated with full oophorectomy. The weight of the uterus is usually decreased to approximately 75% of the original due to oophorectomy. The uterus was then placed in 10% neutral by adding buffer formalin for subsequent histological examination.

The right femur was cut out and scanned in the field of thesis the results of measurements on the densitometer represent the calculation of bone density as a function of mineral content of a bone and its width.

The effect of raloxifene on bone density.

The results of the control actions based on five separate experiments are summarized in table. 6. In General, rats oophorectomy was caused by the decrease of the density of the femur approximately 25% as compared with intact control animals treated with the carrier. Estrogen administered in active oral form of ethinyl estradiol (EE2) at a dose of 100 mg/kg, prevented the loss of bone tissue dose-dependent manner, but at the same time exerted a stimulating effect on the uterus, which was reflected in the almost same weight of the uterus, as in the intact rats. The results are presented as the mean of the measurements in 30 rats standard error of the mean.

In these experiments raloxifene administered in the form of hydrochloride, is also prevented bone loss dose-dependent manner; however, in these animals there was observed only a minimal increase in weight of the uterus compared with ovariectomized control animals. The results of five experiments with raloxifene United in the table. 7. Accordingly, each value reflects the data collected from 30 rats, and this model depicts for raloxifene typical dose-dependent method test

In the examples illustrating this technique, used experimental animals with the simulated osteoporosis postmenopausal, have evaluated the effect of different treatments on the levels of circulating lipids.

From Charles River laboratories (Portage, MI) were obtained from female rats Sprague Dawley semidesyatiletnego age (their weight was 200 - 225g). The animals were executed or bilateral oophorectomy, or the imitation of the operation in laboratories Charles River, and then a week later was taken to the place. After arrival, animals were housed in metal hanging cages in a group of 3 or 4 individuals and had unlimited access to food (the amount of dietary calcium was approximately 0.5%) and water for one week. Indoors maintained the temperature of 22.2 1,7oC and a relative humidity of at least 40%. Mode lighting consisted of 12 h light and 12 h darkness.

Dosing/sampling tissue

After a week of acclimatization period (hence, two weeks after oophorectomy) animals began daily to give the test connection. All compounds were administered orally in amounts of 1 ml/kg, unless otherwise specified. 17-estradiol was administered subcutaneously at 20% polyethylene glycol, 17-this is Oxymetazoline or 20% cyclodextrin. Animals received these doses daily for 4 days. Upon completion of this course, animals were weighed, gave them anesthetized with a mixture of ketamine and xylazine (2: 1, by vol.:about.) and taking samples of blood by puncture of the heart. Animals were then slaughtered location in the atmosphere of CO2through the middle section of the removed uterus and determined its raw weight.

Analysis for cholesterol

The blood samples were left to clotting at room temperature for 2 h, and serum was obtained by centrifugation for 10 min at 3000 revolutions per minute. Serum cholesterol was determined using analysis of cholesterol high resolution, using Boehringer Mannheim Diagnostics. Briefly cholesterol to oxidize the cholesterol-4-EN-3-one and hydrogen peroxide. The hydrogen peroxide then reacts with phenol and 4-aminophenazone in the presence of peroxidase with obtaining dye p-hennipin whose presence was recorded spectrophotometrically at 500 nm. The cholesterol concentration was then calculated from the standard curve. The analysis was fully automated using a Biomek automated installation.

Analysis of the peroxidase eosinophils (EPO) uterus

Before carrying out enzymatic analysis uterus kept at 4oC. Then sit hydrogen and 10 mm o-peniten-diamine (final concentration) in Tris-buffer for one minute at 450 nm was recorded absorption increase. The presence of eosinophils in the uterus is an indicator of estrogenic activity of compounds. The maximum rate, representing a 15-second interval, was determined in comparison with the initial, linear part of the reaction curve.

Sources of compounds

17-estradiol, 17-ethinyl estradiol and tamoxifen were purchased from Sigma Chemical, St. Louis, MO).

The experimental group

All experimental groups were composed of five or six animals.

The effect of raloxifene on serum cholesterol

The results of the control effects are presented in table. 8. In General oophorectomy in rats caused an increase in serum cholesterol as compared with intact control animals treated with the carrier. Estrogen administered in active oral form of ethinyl estradiol (EE2) at a dose of 100 mg/kg, caused a decrease in serum cholesterol dose-dependent manner, but at the same time exerted a stimulating effect on the uterus, which was reflected in the almost same weight of the uterus, as in the intact rats. The results are presented as the mean of the measurements from 5-6 rats standard error of the mean.

In these experiments, raloxifen this was observed only a minimal increase in weight of the uterus compared with ovariectomized control animals. Effects of raloxifene are presented in table. 9. Accordingly, each value reflects the data collected from 5-6 rats and on this model depicts for raloxifene typical dose-dependent curve. The results are presented as mean standard error of the mean.

Pharmaceutical compositions

Compounds according to the invention is usually administered in the form of pharmaceutical compositions, which are important and new variants of the invention, due to the presence of these compounds. You can use all known types of compositions, including tablets, chewable tablets, capsules, solutions, solutions for parenteral administration, lozenges, suppositories and suspensions. The composition is formed so that the daily dose or convenient part of the daily dose is contained in a standard dosage unit, which can be a single tablet or capsule or a convenient volume of fluid. In General, the compositions contain from about 0,000006% connections depending on the desired dose and the type of composition.

The activity of the compounds does not depend on the compositions in which they are entered, or on the concentrations of these compositions. Thus, compositions and choose so be prepared in the form of tablets, capsules and so on; it is preferable to produce solutions of water-soluble salts, such as hydrochloride.

In General, all these compositions are made according to standard techniques adopted in pharmaceutical chemistry. A discussion, which will be accompanied by typical compositions.

Capsules were made by mixing the compounds with a suitable diluent and filling capsules with a suitable amount of this mixture. The usual diluents include inert substances in the form of a powder, such as starch are so many different kinds, cellulose powder, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, flour cereals and similar edible powders.

Tablets were made by direct compression, wet granulation or dry granulation. Their formulation usually includes diluents, binding agents, lubricating agents and leavening agents, as well as the connection itself. The usual diluents include, for example, various types of starch, lactose, mannitol, kaolin, phosphate, or calcium sulfate, inorganic salts such as sodium chloride, and powdered sugar. Also suitable proizvodstva, such as starch, gelatin and sugars such as lactose, fructose, glucose, etc. is also useful natural and synthetic resins, including the Arabian gum, alginates, methylcellulose, polyvinylpyrrolidone, etc., binders can also serve as polyethylene glycol, ethylcellulose and waxes.

Lubricating agent is needed tablets to tablets and stamps are not stuck in the mold. A lubricating agent selected from such slippery solid substances as talc, magnesium stearate and calcium, stearic acid and hydrogenated vegetable oils.

Baking powder tablets are substances, swelling when wet, resulting in the tablet disintegrates and releases the active connection. They include starches, clays, cellulose, algini and gums. More specifically, it is possible to use, for example, corn and potato starches, methylcellulose, agar, bentonite, wood pulp, powdered natural sponge, cation-exchange resins, alginic acid, gum, citrus pulp and carboxymethylcellulose, and sodium lauryl sulfate.

Tablets are often coated with sugar-like taste and a sealing substance or protecting what should also be put in chewable tablets, using the composition of large quantities of palatable substances such as mannitol, with well-developed at present technologies.

If you want to enter the compound in the form of a suppository, you can use a regular basis. Cocoa butter is a common basis for suppositories, which can be modified by adding wax to a small temperature increase its melting point. Widely used miscible with water bases for suppositories, including, in particular, polyethylene glycols of various molecular weights.

The action of the compounds can delay or prolong the composition. For example, you can produce a slowly soluble pellet of the connection and put it in a pill or capsule. This technology can be improved by making several types of granules with different rates of dissolution and filling capsules with a mixture of these granules. Tablets or capsules may be coated with a film which retards the dissolution for a specified period of time. Even the parenteral preparations can be done through prolonged dissolution or suspension of the compound in oily or emulsified media, manufacture of pharmaceutical compositions are typical formulations.

Capsules mg

6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-Piperi - dimethoxy)benzoyl] benzo[B]thiophene, hydrochloride 3

Microcrystalline cellulose - 400

Pre gelatinizing starch - 95

Liquid silicone - 2

6-Methoxy-2-(4-methoxyphenyl)-3-[4-(2- piperidinyloxy)benzoyl] benzo[b] thiophene, acetate - 150

Pre gelatinizing starch - 106

Starch - 52

Liquid silicone - 1,6

6-Acetoxy-2-(4-acetoxyphenyl)-3-[4-(2-Piperi - dimethoxy)benzoyl] benzo[b]thiophene, hydrochloride 300

Pre gelatinizing starch - 200

Solutions

6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-Piperi - dimethoxy)benzoyl] benzo[b]thiophene, hydrochloride 3

Purified water is 5 cm2< / BR>
6-Hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-Piperi-dimethoxy) benzoyl] benzo[b]thiophene, hydrochloride 20 mg

Purified water is 5 cm2< / BR>
Tablets mg

6 Cyclopentane-2-(4-cyclopentadienyl)-3-[4- (2-piperidinyloxy)-benzoyl]benzo[b]thiophene - 5

Microcrystalline cellulose - 240

Starch - 45

Stearic acid - 6

Magnesium stearate - 3

Colloidal silicon dioxide is 1

6-Benzyloxy-2-(4-benzyloxyphenyl)-3-[4-(2-PI - peridynamics)benzoyl] benzo[b]thiophene, benzoate - 150

Mi is Stearic acid - 8

Magnesium stearate - 3

Colloidal silicon dioxide - 2

6 Ethoxycarbonyl-2-(4-etoxycarbonyl oksifenil)-3-[4-(2-piperidinyloxy)-benzoyl]benzo[b]thiophene - 250

Calcium phosphate - 58

Lactose - 54

Microcrystalline cellulose - 31

1. Resolutiony crystalline 6-hydroxy-2-(4 - hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] benzo[b] difengidramin, which has the following diraction pattern of x-rays obtained with copper radiator

Parameters d-lines, I/I0100

13,3864 71,31

9,3598 33,16

8,4625 2,08

7,3888 EUR 7.57

6,9907 5,80

6,6346 51,04

6,1717 29,57

5,9975 5,67

5,9135 9,87

5,6467 38,47

5,4773 10,54

5,2994 4,74

4,8680 4,03

4,7910 5,98

4,6614 57,50

4,5052 5,75

4,3701 9,03

4,2516 69,99

4,2059 57,64

4,1740 65,07

4,0819 to 12.44

3,9673 22,53

3,9318 100,00

3,8775 9,07

3,7096 33,38

3,6561 21,65

3,5576 3,36

3,5037 7,97

3,4522 18,02

3,4138 4,65

3,2738 10,23

3,1857 8,90

3,1333 6,24

3,0831 9,43

3,0025 12,13

2,9437 4,96

2,8642 7,70

2,7904 11,95

2,7246 3,05

2,6652 3,32

2,5882 7,30

2. The crystalline 6-hydroxy-2-(4-hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl] - benzo[b]difengidramin under item 1, characterized in that the number 6 least 95 wt.

3. Pharmaceutical composition having anti-estrogenic and antiandrogennoe activity, including active substance and one or more pharmaceutically acceptable carriers, diluents or excipients, characterized in that the active substance it contains resolutiony crystalline 6-hydroxy-2-(4 - hydroxyphenyl)-3-[4-(2-piperidinoethyl)benzoyl]benzo-[b] difengidramin on PP.1 and 2 in an effective amount.

4. Resolutiony crystalline 6-hydroxy-2-(4-hydroxyphenyl)- 3-[4-(piperidinoethyl)benzoyl]benzo-[b]-difengidramin on PP.1 and 2 having antiestrogenic and antiandrogennoe activity.

 

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