A method of obtaining a 1-substituted 3-hydroxymethyl-4-(4 - forfinal)piperidine, the method of obtaining (-)trans-4-(4 - forfinal)-3-{[3,4-methylendioxy)phenoxy]methyl}piperidine

 

This invention relates to a method for producing 1-substituted 3-hydroxymethyl-4-(4-forfinal)piperidine of the formula I by restoring the connection specified in the claims of the formula (II) hydride metals in the environment of a diluent, preferably a simple ester, in the presence of preferably inorganic halide salts and the method of production of (-)TRANS-4-(4-forfinal)-3-{ [3,4-methylendioxy)phenoxy] methyl} piperidine (paroxetine). The described method has a small amount of by-products. 2 C. and 8 C.p. f-crystals, 2 PL.

The invention relates to a method for producing (-)-TRANS-1-benzyl-3-hydroxymethyl-4-(4-forfinal)piperidine, which represent valuable intermediate connection for receiving paroxetine (paroxetine=(-)-TRANS-4-(4-forfinal)-3-{ [3,4-(methylendioxy)phenoxy] methyl}piperidine) and to a method for paroxetine.

From U.S. patent 4,007,196 known compounds with antidepressant effects. One of the compounds described in this patent, known as "paroxetine" and has a structure according to the formula As:It was found that this link is narodnoi application published under WO 96/36636 (which is included in this description by reference), describes one of these ways. Stage C according to the main claim of this application describes the recovery of the compounds of formulaobtaining the compounds of formula Within which X is halogen, preferably fluorine, and R1means alkyl with 2 to 5 carbon atoms, phenylalkyl with 1 to 5 carbon atoms in the alkyl part or substituted phenylalkyl with 1 to 5 carbon atoms in the alkyl part. The restoration carried out using a metal hydride, according to p. 4 formulae preferably represents LiAIH4or NaAIH4. The only example given in this application, refers to the compound of the formula In which X is fluorine and R1- ethyl, and which was restored with the use of a mixture of sodium hydride and lithium aluminum hydride.

It was found that when carrying out the reaction under the conditions described in the application WO 96/36636, when X is fluorine and R1- benzyl, there is an unacceptable degree of detonirovanie. Separation of this mixture to the desired product at this stage is difficult and leads to tonirovany similar paroxetine from paroxetine. The result requires a long process of separation, which lead to loss of material and increasing the value of the process.

The objective of the invention is to develop a method of producing 1-substituted 3-hydroxymethyl-4-(4-forfinal)piperidine, with fewer side products.

The problem is solved in the method of obtaining the compounds of formula (I)in which R1means aminosidine group, by restoring the compounds of formula (II)

in which R1has the above value, the metal hydride in the environment diluent due to the fact that the process is conducted in the presence of an inorganic salt selected from the group comprising salt of lithium, sodium, magnesium, calcium, zinc, lanthanum, or iron or their mixture, and is used as a compound of the formula (II), which aminosidine group selected from the group comprising a) allyl, b) benzhydryl,) methoxymethyl, g) benzoyloxymethyl, d) tetrahydropyranyl, e) unsubstituted or substituted benzyl, W) di(p-methoxyphenyl)methyl, C) triphenylmethyl, and) (p-methoxyphenyl)diphenylmethyl, K) diphenyl-4-pyridylmethyl, l) 2,4,6-trimethylbenzenesulfonyl, m) toluensulfonyl, n) bansilalpet, o) alkyl with 1 to 6 ATO is on ammonium, and as a metal hydride is a compound selected from the group including sodium hydride, potassium, magnesium or calcium, sodium borohydride, potassium or lithium, alumoweld lithium or sodium hydride aluminum, bis-(2-methoxyethoxy)alumoweld sodium, mono(C1-4-alkoxy)alumoweld lithium di(C1-4-alkoxy)alumoweld lithium diethylaluminum sodium or a mixture thereof.

It is advisable aminosidine group is inert in relation to the recovery of the metal hydride. Preferably aminosidine group is a benzyl, unsubstituted or substituted on the phenyl ring by one or more of the following groups: alkyl with 1 to 4 carbon atoms, alkoxygroup with 1 to 4 carbon atoms, halogen, the nitro-group. More preferably R1means benzyl.

Preferably, the metal hydride is alumoweld lithium or sodium, and most preferably of alumoweld lithium.

The metal hydride is usually used in an amount of from 0.5 to 5 molar equivalents, calculated on the amount of the compounds of formula (II). Preferably the amount of metal hydride is from 0.75 to 1.25 molar equivalents, and more preferably from 0.90 to 1.10 is molar equivalents.

Preferably neoli their mixture. Even more preferably the inorganic salt is selected from the group including lithium chloride, sodium, calcium, zinc, iron (II), iron (III), lanthanum or magnesium, magnesium fluoride, magnesium bromide or magnesium iodide or mixtures thereof. Most preferably the inorganic salt is a chloride, bromide or magnesium iodide. Especially preferred salt is magnesium chloride.

The details of the mechanism of the proposed method were studied. The specialists of this field will agree that active recovery agent can be formed in the reaction initially used metal hydride with an inorganic salt. For example, in the case of lithium aluminum hydride and magnesium chloride, the active compound may be at least one compound from the group comprising magnesium hydride, alumoweld chlorine-magnesium, alumoweld magnesium or alumoweld lithium magnesium or a complex of magnesium chloride and lithium aluminum hydride. The proposed method includes all the possibilities.

Usually inorganic salt is used in an amount of from 0.25 to 5 molar equivalents, calculated on the amount of the compounds of formula (II). Preferably the amount of inorganic salt is from 0.5 to 1.5 molar equivalents, and idcast, inert in terms of the metal hydride, preferably which is also a solvent for the compounds of formula (II). Preferably the diluent is a simple ether or hydrocarbon, or a mixture. More preferably the diluent is selected from the group comprising tetrahydrofuran, toluene, dioxane, diethyl ether, simple diisopropyl ether, a simple t-butyl methyl ether, dimethyl ether of diethyleneglycol, etilenglikolevye dimethyl ether and mixtures thereof. The most preferred diluent is tetrahydrofuran.

Typically, the diluent is used in an amount of from 1 to 100 weight. including in terms of the amount of the compounds of formula (II). Preferably the amount of solvent is from 2 to 50 weight.h. in terms of the amount of the compounds of formula (II), and even more preferably from 3 to 10 weight.h.

It is advisable proposed method is carried out at a temperature from -70oC to the boiling point of the used solvent. Preferred is a temperature in the range of 0oWith up to 150oC, more preferred in the range of 0oWith up to 100oS, and most preferred in the range of 50oWith up to 70oC.

The number formed by deformirovannogo high-performance liquid chromatography under the conditions below in the examples. Preferably the number formed by deformirovannogo codeninja is from 0.001 to 0.5%, more preferably from 0.001 to 0.2%.

The advantage of the proposed method is that it can be used to obtain the predecessor of paroxetine in pure form. Paroxetine can be obtained in pure form from compounds of formula (I) through (a) conversion of the hydroxy-group in tsepliaeva group, for example halo - or tailorshop, b) interaction with sesamol (= 3,4-methylenedioxyphenol) or its salt, (C) removal of the protective group R1and if necessary, g) salt, such as hydrochloride in anhydrous form or hemihydrate.

Therefore a further object of this invention is a method for paroxetine or its salts by restoring the compounds of formula (II)

in which R1means aminosidine group, a metal hydride in an environment of diluent and transfer of the hydroxyl group of the resulting compound of formula (I)

in which R1have the above significance, in the group that you want with subsequent interaction with 3,4-methylenedioxyphenol or its salt, the removal and the recovery of the compounds of formula (II) with a metal hydride is carried out in the presence of inorganic salts, selected from the group comprising a salt of lithium, sodium, magnesium, calcium, zinc, lanthanum, or iron or their mixture, and is used as a compound of the formula (II), which aminosidine group selected from the group comprising a) allyl, b) benzhydryl,) methoxymethyl, g) benzoyloxymethyl, d) tetrahydropyranyl, e) unsubstituted or substituted benzyl, W) di(p-methoxyphenyl)methyl, C) triphenylmethyl, and) (p-methoxyphenyl)diphenylmethyl, K) diphenyl-4-pyridylmethyl, l) 2,4,6-trimethylbenzenesulfonyl, m) toluensulfonyl, n) bansilalpet, o) alkyl with 1 to 6 carbon atoms, p) triptorelin with 1 to 4 carbon atoms, R) quinil and (C) p-methoxybenzyl or unsubstituted or substituted ammonium, and as a metal hydride is a compound selected from the group including sodium hydride, potassium, magnesium or calcium, sodium borohydride, potassium or lithium, alumoweld lithium or sodium hydride aluminum, bis-(2-methoxyethoxy)alumoweld sodium, mono(C1-4-alkoxy)alumoweld lithium di(C1-4-alkoxy)alumoweld lithium diethylaluminum sodium or a mixture thereof.

Preferable as the inorganic salt used halide salt. More preferable as the inorganic salt is used, the chloride, bromide or iodide magnesium.

Predpochtitelnei examples. The products obtained according to the examples, characterized by using one of the following methods: gas liquid chromatography, high performance liquid chromatography, elemental analysis, nuclear magnetic resonance, infrared spectroscopy.

Calcium sodium codeinone is a (-)-TRANS-1-benzyl-3-hydroxymethyl-4-phenylpiperidine.

EXAMPLES
Example 1. (-)-TRANS-1-benzyl-3-hydroxymethyl-4-(4-forfinal)piperidine
2.0 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran in a nitrogen atmosphere with caution to add to 0,19 g in General, anhydrous (1.5 % in water) of magnesium chloride. The resulting mixture was stirred and heated to a temperature of 50oWith, and then for about 2 minutes drops add a solution of 0.60 g of (+)-1-benzyl-3-hydroxymethyl-4-(4-forfinal)-1,2,3,6-tetrahydropyridine (receipt see application WO 96/36636) in 1.7 ml of tetrahydrofuran. The reaction mixture is stirred and refluxed in a period of 4.2 hours. Then cooled to room temperature and stirred in an ice/water bath while adding the first 0.1 ml of water, and then 0.1 ml of 5 M sodium hydroxide solution and 0.1 ml of water. The suspension was diluted by adding 5 ml of tetrahydrofuran, and the mixture washing solutions are evaporated under reduced pressure, resulting in a gain of 0.49 g of yellow oil, which are examined by gas-liquid chromatography, chiral high-performance liquid chromatography and1H-NMR.

Conditions of gas-liquid chromatography:
Column: DB1 1.5 mm, 15 m x 0.53 mm
The flow of gaseous media (In): 4.5 ml/min, initial temperature:
40oC for 1 minute. Temperature rise: 5oWith a minute to 300oC for 7 minutes.

Conditions of high performance liquid chromatography:
Column: length 15 cm, inner diameter 4.6 mm, filled with particles of silica gel the surface of which is modified chemically bound octylsilane groups; particle size: 5 μm, the temperature in the column: 35oWith the wavelength: 214 nm.

Mobile phase: about 15. % of acetonitrile, with 0.1% vol. from orthophosphoric acid and 0.1 wt.% in terms of volume butanesulfonate sodium in water.

According to the internal normalization of the obtained product has a purity of 98.7 per cent and contains 0.3% deformirovannogo connection according to a study using high-performance liquid chromatography.

Example 2. (-)-TRANS-1-benzyl-3-hydroxymethyl-4-(4-forfinal)piperidine
of 16.7 ml of 1 M solution of lithium aluminum hydride in tetrahedrons stirred and heated to a temperature of 50oWith, after which within about 5 minutes drops add a solution of 5.0 g of (+)-1-benzyl-3-hydroxymethyl-4-(4-forfinal)-1,2,3,6-tetrahydropyridine to 14.2 ml of tetrahydrofuran. The reaction mixture is stirred and refluxed for 6 hours. Then cooled to room temperature and stirred in an ice/water bath while adding the first 0.8 ml of water, and then 0.8 ml of 5 M sodium hydroxide solution and 0.8 ml of water. The suspension was diluted by adding 5 ml of tetrahydrofuran, and the mixture is filtered. The residue is washed three times, each time using 10 ml of tetrahydrofuran, and the combined filtrate and washing solutions are evaporated under reduced pressure, resulting in a gain of 3.3 g of yellow oil, which are examined by gas-liquid chromatography, chiral high-performance liquid chromatography and1H-NMR under the above conditions. The resulting product has a purity 97,0% and according to the internal normalization contains 0.2% deformirovannogo compounds according to high performance liquid chromatography.

Examples 3-8
Examples 3-8 carried out analogously to example 1 under the conditions shown in table 1. Table 1 uses the following abbreviations:
M EQ. (Grafia, WPGH - performance liquid chromatography, % (-F) - % deformirovannogo codeninja, THF is tetrahydrofuran.

Specified in these columns values refer to percent according to the internal normalization.

Example 9. (-)-TRANS-1-benzyl-3-hydroxymethyl-4-(4-forfinal)piperidine
2.0 ml of 1 M solution of aluminum hydride, sodium in tetrahydrofuran in a nitrogen atmosphere with caution to add to 0,19 g in General, anhydrous (1.5 % in water) of magnesium chloride. The resulting mixture was stirred and heated to a temperature of 50oWith, and then for about 2 minutes drops add a solution of 0.60 g of (+)-1-benzyl-3-hydroxymethyl-4-(4-forfinal)-1,2,3,6-tetrahydropyridine in 1.7 ml of tetrahydrofuran. The reaction mixture is stirred and refluxed for 4 hours. Then cooled to room temperature and stirred in an ice/water bath while adding the first 0.1 ml of water, and then 0.1 ml of 5 M sodium hydroxide solution and 0.1 ml of water. The suspension was diluted by adding 5 ml of tetrahydrofuran, and the mixture is filtered. The residue is washed three times, each time using 5 ml of tetrahydrofuran, and the combined filtrate and washing solutions are evaporated under reduced pressure, resulting in a gain of 0.49 g of yellow oil, the cat is the philosophy and1H-NMR under the above conditions. According to gas-liquid chromatography to get the product there is the original connection in the amount of 13.2 %. According to high performance liquid chromatography the number deformirovannogo connection is less than 0.1%.

Example 10. (-)-TRANS-1-benzyl-3-hydroxymethyl-4-(4-forfinal)piperidine
2.0 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran, and 0.69 ml of toluene in a nitrogen atmosphere while carefully add to 0,53 g in General, anhydrous (1.5% in water) of magnesium chloride. The resulting mixture was stirred and heated to a temperature of 50oWith, after which within about 5 minutes, add drops of the solution 2,60 g (+)-1-benzyl-3-hydroxymethyl-4-(4-forfinal)-1,2,3,6-tetrahydropyridine (obtained by the method according to the application WO 96/36636) in 3.6 ml of tetrahydrofuran and 0.4 ml of toluene. The reaction mixture is stirred and refluxed for 3.5 hours. Then cooled to room temperature and stirred in an ice/water bath while adding to 4.1 ml of 5 M sodium hydroxide solution. The suspension was diluted by adding 10 ml of tetrahydrofuran, and the mixture is filtered. The residue is washed with 10 ml of tetrahydrofuran, and the combined oil, which are examined by gas-liquid chromatography, chiral high-performance liquid chromatography and1H-NMR. The obtained target product contains calcium sodium compound in the amount of 0.24 %.

Example 11. (-)-TRANS-1-benzyl-3-hydroxymethyl-4-(4-forfinal)piperidine
3,76 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran in a nitrogen atmosphere with caution to add to 0.55 g in total of anhydrous magnesium bromide. The resulting mixture was stirred and heated to a temperature of 50oWith, after which within about 5 minutes drops add a solution of 1.12 g of (+)-1-benzyl-3-hydroxymethyl-4-(4-forfinal)-1,2,3,6-tetrahydropyridine in 2.2 ml of tetrahydrofuran. The reaction mixture is stirred and refluxed in a period of 4.2 hours. Then cooled to room temperature and stirred in an ice/water bath while adding 2 ml of 0.5 M sodium hydroxide solution and 0.1 ml of water. The suspension was diluted by adding 7 ml of tetrahydrofuran, and the mixture is filtered. The residue is washed with 7 ml of tetrahydrofuran, and the combined filtrates and promine solutions are evaporated under reduced pressure, resulting in a gain of 0.99 g of a yellow oil, which are examined by gas-liquid chromatog contains 0.18% deformirovannogo connection.

Example 12. (-)-TRANS-1-benzyl-3-hydroxymethyl-4-(4-forfinal)piperidine
7,24 ml of 1 M solution of lithium aluminum hydride in tetrahydrofuran in a nitrogen atmosphere while stirring gently add to 0,698 g in total of anhydrous magnesium chloride in 32 ml of tetrahydrofuran, not allowing the temperature to rise to 20oC. the resulting mixture was stirred and heated to a temperature of 50oWith, then within about 30 minutes drops add a solution of 2.15 g of (+)-1-benzyl-3-hydroxymethyl-4-(4-forfinal)-1,2,3,6-tetrahydropyridine (obtained by the method according to the application WO 96/36636) 3.92 ml of tetrahydrofuran and 2,32 ml of toluene. The reaction mixture is stirred and refluxed for 4 hours. Then cooled in an ice/water bath to a temperature of 0 to 5oWith, while adding 2,48 ml of 5 wt.%-aqueous solution of sodium hydroxide. The suspension is filtered, the residue is washed with 8 ml of tetrahydrofuran, and the combined filtrate and washing solutions are evaporated under reduced pressure, resulting receives a yellow oil, which are examined by gas-liquid chromatography, chiral high-performance liquid chromatography and1H-NMR. The obtained target product contains 0,24% deformirovannogo caedym molar equivalent of the metal salt, specified in table 2.

Example 15
Exercise example 12 with the difference that instead of tetrahydrofuran as a solvent used toluene and the mixture when the mixture is heated at a temperature of 110oC for 2 hours. The result is a product with a purity of 93.7% of (according to gas-liquid chromatography), according to high performance liquid chromatography containing 1,07% deformirovannogo connection.

Other 1-substituted 3-hydroxymethyl-4-(4-forfinal)piperidine General formula (I), where R1means aminosidine group selected from the group comprising allyl, benzhydryl, methoxymethyl, benzoyloxymethyl, tetrahydropyranyl, unsubstituted or substituted benzyl, di(p-methoxyphenyl)methyl, triphenylmethyl, (p-methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl, 2,4,6-trimethylbenzenesulfonyl, toluensulfonyl, bansilalpet, alkyl with 1 to 6 carbon atoms, triptorelin with 1 to 4 carbon atoms, quinil and p-methoxybenzyl or unsubstituted or substituted ammonium get a similar way, and is used as a compound of the formula (II), where R1has the above value, the metal hydride selected from the group including sodium hydride, potassium, magnesium or calcium, dried sodium, mono(C1-4-alkoxy)alumoweld lithium di(C1-4-alkoxy)alumoweld lithium diethylaluminum sodium or a mixture thereof and an inorganic salt selected from the group comprising salt of lithium, sodium, magnesium, calcium, zinc, lanthanum or iron or a mixture thereof.

(-)TRANS-4-(4-forfinal)-3-{ [3,4-methylendioxy)phenoxy]methyl} piperidine or its salt get similar to the above method, when using the compounds of formula (II), where R1means aminosidine group selected from the group comprising allyl, benzhydryl, methoxymethyl, benzoyloxymethyl, tetrahydropyranyl, unsubstituted or substituted benzyl, di(p-methoxide-nil)methyl, triphenylmethyl, (p-methoxyphenyl)diphenylmethyl, diphenyl-4-pyridylmethyl, 2,4,6-trimethylbenzenesulfonyl, toluensulfonyl, bansilalpet, alkyl with 1 to 6 carbon atoms, triptorelin with 1 to 4 carbon atoms, quinil and p-methoxybenzyl or unsubstituted or substituted ammonium, a metal hydride selected from the group including sodium hydride, potassium magnesium or calcium, sodium borohydride, potassium or lithium, alumoweld lithium or sodium hydride aluminum, bis-(2-methoxyethoxy)alumoweld sodium, mono(C1-4-alkoxy)alumoweld lithium di(C1-4-alkoxy)alumoweld lithium, IER magnesium, calcium, zinc, lanthanum or iron or a mixture thereof.

Comparative examples
In comparative examples carried out without inorganic salts, the number formed by deformirovannogo compounds is in the range from 2 to 4% and it was found that the removal of this deformirovannogo connection is very difficult.


Claims

1. A method of obtaining a 1-substituted 3-hydroxymethyl-4-(4-forfinal)piperidine derivatives of formula (I)

in which R1means aminosidine group,
by restoring the compounds of formula (II)

in which R1has the above value,
the metal hydride in the environment of a diluent, wherein the process is conducted in the presence of an inorganic salt selected from the group comprising salt of lithium, sodium, magnesium, calcium, zinc, lanthanum, or iron or their mixture, and is used as a compound of the formula (II), which aminosidine group selected from the group comprising a) allyl, b) benzhydryl,) methoxymethyl, g) benzoyloxymethyl, d) tetrahydropyranyl, e) unsubstituted or substituted benzyl, W) di(p-methoxyphenyl)methyl, C) triphenylmethyl, and) (p-methoxyphenyl)diphenylmethyl, K)volumes of carbon p) triptorelin with 1-4 carbon atoms, R) quinil and (C) p-methoxybenzyl or unsubstituted or substituted ammonium, and as a metal hydride is a compound selected from the group including sodium hydride, potassium, magnesium or calcium, sodium borohydride, potassium or lithium, alumoweld lithium or sodium hydride aluminum, bis-(2-methoxyethoxy)alumoweld sodium, mono(C1-4-alkoxy)alumoweld lithium di(C1-4-alkoxy)alumoweld lithium diethylaluminum sodium or a mixture thereof.

2. The method according to p. 1, characterized in that the compound of formula (I) in which R1means benzyl.

3. The method according to p. 1 or 2, characterized in that the metal hydride used alumalite lithium or sodium.

4. The method according to any of paragraphs. 1-3, characterized in that the inorganic salt used halide salt.

5. The method according to p. 4, characterized in that the inorganic salt is used, the chloride, bromide or iodide magnesium.

6. The method according to any of the preceding paragraphs, characterized in that as a diluent use a simple ether, a hydrocarbon or a mixture thereof.

7. The method of obtaining (-)TRANS-4-(4-forfinal)-3-{ [3,4-methylendioxy)phenoxy] methyl} piperidine derivatives of the formula
1means aminosidine group,
the metal hydride in the environment of a diluent and transfer of the hydroxyl group of the resulting compound of formula (I)

in which R1has the above value,
in the group that you want with subsequent interaction with 3,4-methylenedioxyphenol or its salt, removing aminosidine group R1and the selection of the target product in free form or in salt form, characterized in that the recovery of the compounds of formula (II) with a metal hydride is carried out in the presence of inorganic salt selected from the group comprising salt of lithium, sodium, magnesium, calcium, zinc, lanthanum, or iron or their mixture, and is used as a compound of the formula (II), which aminosidine group selected from the group comprising a) allyl, b) benzhydryl,) methoxymethyl, g) benzoyloxymethyl, d) tetrahydropyranyl, e) unsubstituted or substituted benzyl, W) di(p-methoxyphenyl)methyl, C) triphenylmethyl, and) (p-methoxyphenyl)diphenylmethyl, K) diphenyl-4-pyridylmethyl, l) 2,4,6-trimethylbenzenesulfonyl, m) toluensulfonyl, n) bansilalpet, o) alkyl with 1 to 6 carbon atoms, p) triptorelin with 1 to 4 carbon atoms, R) quinil and (C) p-methoxybenzyl or unsubstituted or substituted ammonium, and to whom, OrderID sodium, potassium or lithium, alumoweld lithium or sodium hydride aluminum, bis-(2-methoxyethoxy)alumoweld sodium, mono(C1-4-alkoxy)alumoweld lithium di(C1-4-alkoxy)alumoweld lithium, diethylaluminum sodium or a mixture thereof.

8. The method according to p. 7, characterized in that the inorganic salt used halide salt.

9. The method according to p. 8, characterized in that the inorganic salt is used, the chloride, bromide or iodide magnesium.

10. The method according to any of paragraphs. 7-9, characterized in that as a diluent use a simple ether, a hydrocarbon or a mixture thereof.

 

Same patents:

The invention relates to the field of organic chemistry and relates to compounds of formula (I) and their pharmaceutically acceptable salts and difficult ether derivatives

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where Ar represents a phenyl group which may be optionally substituted from 1 to 3 substituents selected from the group consisting of halogen atoms and triptorelin groups having antifungal activity

The invention relates to sulfonamidnuyu to the compound of formula I, where R1- alkyl, alkenyl, quinil; a represents optionally substituted heterocyclic group, excluding benzimidazolyl, indolyl, 4,7-dehydrobenzperidol and 2,3-dihydrobenzofuranyl; X - alkylene, oxa, oxa(lower) alkylene; R2- optional substituted aryl, substituted biphenyl, its salts and pharmaceutical compositions comprising this compound

The invention relates to the derivatives of hintline formula I, where m is an integer from 1 to 2; R1represents hydrogen, nitro or1-3alkoxy; R2represents hydrogen or nitro; R3represents hydroxy, halogen, C1-3alkyl, C1-3alkoxy, C1-3alkanoyloxy or cyano; X1represents-O-, -S-, -SO - or-SO2-; R4is one of 13 groups described in paragraph 1 of the claims

The invention relates to an improved process for the preparation of dihydrochloride 1-[[[5-(4-chlorophenyl)-2-furanyl] methylene] amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione used as antifibrillatory and antiarrhythmic agent, the General formula

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incorporating the following stages: a) interaction 1- [[[5-(4-chlorophenyl)-2-furanyl] methylene]amino]-2,4-imidazolidinedione formula

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with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichlorobutane, 1,4-dibromobutane and their mixtures, in the presence of a weak base selected from the group comprising potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione 4-methylpiperazine education 1-[[[5-(4-chlorophenyl)-2-furanyl] the methylene]amino]-3-[4-(4-methyl-1-piperazinil)butyl] -2,4-imidazolidinedione

The invention relates to an improved process for the preparation of 1,3-disubstituted 4-oxocyclohexa ureas used as antifibrillatory and antiarrhythmic agents, the General formula

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where R1, R2and R3independently selected from the group consisting of H, Cl, F, Br, NH2, NO2, COOH, CH3SO2NH, SO3H, HE, alkoxy, alkyl, alkoxycarbonyl, hydroxyalkyl, carboxyethyl, acyloxy; R4selected from the group consisting of substituted or unsubstituted alkyl, alkenyl, quinil, alkylaryl and heteroalkyl; and a represents a substituted or unsubstituted, saturated or unsaturated, unbranched or branched alkyl or alkenylamine, containing 1-7 carbon atoms; or a represents a substituted or unsubstituted, saturated or unsaturated heterocycle having 5, 6 or 7 members containing at least one nitrogen, and R4attached to the nitrogen; incorporating the following stages: a) the interaction of 1-substituted 4-oxocyclohexa urea having the formula

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with reagent with carbon chain selected from 1-bromo-4-chlorobutane, 1,4-dichloro is tons of potash, sodium carbonate, potassium bicarbonate, sodium bicarbonate, and a polar aprotic solvent to form a 3-N-alkylated 2,4-imidazolidinedione; and (b) interaction of the specified crude 3-N-alkylated 2,4-imidazolidinedione with amine with the formation of 1,3-disubstituted 4-oxocyclohexa urea

The invention relates to new derivatives of pyrimidinediamine General formula I and fungicides for agriculture or horticulture on the basis of their

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The invention relates to a new crystalline (-)-3R,4R-TRANS-7-methoxy-2,2-dimethyl-3-phenyl-4-{ 4-[2-(pyrrolidin-1-yl)ethoxy] phenyl} chromane hydrofolate, method thereof, pharmaceutical compositions on the basis and method of reducing or preventing the rarefaction of bone, including the introduction to the patient an effective amount of the specified new connection

The invention relates to a derivative of biphenylamine General formula (1), where R1represents a hydrogen atom; L represents a direct bond or C1-4-alkylenes group; R2represents a carboxyl group;1-8-alkoxycarbonyl group; karbamoilnuyu group, and a nitrogen atom that is part of carbamoyl group, may be substituted mono - or di-C1-8is an alkyl group or may be a nitrogen atom in the amino acid; C1-8-alkylcarboxylic group; R3represents a hydrogen atom; X represents any of the groups-O-, -NH-CO-NH-, -N(R4)-, -CO-N(R5)-, -N(R5)-CO-, in which R4represents a hydrogen atom, a C1-10is an alkyl group, a C1-10-alkylcarboxylic group1-10-alkylsulfonyl group, R5represents a hydrogen atom, a C1-10is an alkyl group, Y represents a C4-8-cycloalkyl the group in which the methylene group in the C4-8-cycloalkyl may be substituted WITH1-8is an alkyl group WITH1-8-CNS group, carbamoyl group1-8-alkoxycarbonyl group, a carboxyl group, or the following 5-8-membered ring of formula I-1

The invention relates to new derivatives of 1,2,3,4-tetrahydronaphthalene formula (I) as (R)-enantiomers, (S)-enantiomers or racemates, in the form of free base or pharmaceutically acceptable salt or solvate, where X is N or CH; Y is NR2-CH2, NR2-CO or CO-NR2; R2represents N or C1-C6-alkyl; R1represents N or C1-C6-alkyl; R3represents phenyl which may be mono - or Disaese4; R4represents H, halogen, CN, CF3WITH1-C6-alkoxy, optionally substituted heterocyclic ring containing one or two heteroatoms selected from N, O, or COR8; R8represents a heterocyclic ring containing one or two heteroatoms selected from N, O; R9is1-C6-alkyl, ОСНF2HE, halogen, C1-C6-alkoxy, C1-C6-alkoxy - C1-C6-alkyl

The invention relates to a piperidine derivative of General formula I

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and their pharmaceutically acceptable salts, where R1is hydrogen, C1-C6-alkyl, C2-C6alkenyl, C3-C8-cycloalkyl, C6-C10aryl that may be substituted for CH3, halogen, OR5where R5- C1-C6-alkyl, C1-C2-alkyl-heteroaryl containing as heteroatoms of S, N or O; And a is phenyl, substituted carbonyl or amino group; - C6-C10-aryl or C5-C10-heteroaryl containing as heteroatoms of S, N or O

The invention relates to new niftystories compounds of formula I, where R1and R2- H, -OH, -O(C1-C4alkyl), -OCOC6H5, -OCO(C1-C6alkyl), -OSO2(C4-C6alkyl); R3- 1-piperidinyl, 1-pyrrolidinyl, methyl-1-pyrrolidinyl, dimethyl-1-pyrrolidinyl, 4-morpholino, dimethylamino, diethylamino, 1 hexamethyleneimino; intermediate compounds, which are suitable for easing symptoms of postmenopausal syndrome, including osteoporosis, hyperlipemia and estrogenzawisimy cancer, and inhibition of uterine fibroids, endometriosis and proliferation of aortic smooth muscle cells

The invention relates to new aryl-substituted derivatives of piperidine, which has antagonistic activity to the receptor NK3person, to a method for their production and to their use in pharmaceutical compositions

The invention relates to an improved process for the preparation of 4-(4'-forfinal)-3-hydroxyethylpiperazine f-ly I, where R3represents hydrogen; C1-C6-alkyl or C1-C6-alkylaryl, the recovery of the corresponding piperidine 2,6-dione f-crystals II, where R3have the above values, R4- C1-C6-alkyl, in the presence of a reducing agent - DIBORANE in an inert solvent, such as tetrahydrofuran or dimethoxyethane

FIELD: organic chemistry, pharmaceuticals.

SUBSTANCE: invention relates to new crystalline forms of 4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydoxybuthyl1-dymethylbenzeneacetic acid (), more particularly, to new form of A-phexophenadine having the next powder X-ray pattern (d, E): 23.11; 11.50; 8.29; 7.03; 6.67; 6.16; 6.02; 5.75; 5.43; 5.33; 5.07; 4.69; 4.63; 4.44; 4.20; 4.15; 4.07; 3.55;4.44; as well as to crystalline form of X-phexophenadine hydrochloride, having the next powder X-ray pattern (d, E): 16.05; 12.98; 8.29; 8.06; 6.25; 5.97; 5.54; 5.41; 4.89; 4.70; 4.55;4.37; 4.32; 4.15; 4.03; 3.80; 3.67; 3.57; 3.42; and to methods for production thereof. New crystalline phexophenadine forms of high purity (content of one isomer is higher than 99.5 %) are manufactured with essentially quantitative yield and are useful as antihistamine and antiallergic agents.

EFFECT: new phexophenadine forms useful as antihistamine and antiallergic agents.

18 cl, 10 dwg, 2 tbl, 5 ex

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